A Randomized, Double Blind, Placebo Controlled, 52 Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects With Moderately Active Ulcerative Colitis
Phase: PHASE2
Conditions: Ulcerative Colitis
Sponsor: Pfizer

C LI NI C A L S T U D Y P R O T O C O L   
Pr ot oc ol n u m ber:  
A P D 3 3 4 -2 1 0  
 
 
Pr ot oc ol title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, 5 2 -Wee k St u d y t o 
Assess t he Efficac y a n d Safet y of Etrasi m o d i n S u bjects wit h 
M o deratel y Acti ve Ulcerati ve C olitis  
Brief title:  
G L A DI A T O R U C: Etrasi m o d Vers us Place b o f or t he Treat me nt of 
M o deratel y Acti ve Ulcerati ve C olitis  
 
 
St u d y dr u g:  
Etrasi m o d ( A P D 3 3 4)  
I n dic ati o n: 
Ulcerati ve c olitis  
P h ase:  
2  
I N D n u m ber: 
1 2 5 1 5 4  
E u dr a C T n u m ber:  
2 0 2 0 -0 0 3 5 0 7 -3 4  
 
 
S p o ns or n a me:  
Are na P har mace uticals, I nc.  
6 1 5 4 Na nc y Ri d ge Dri ve  
Sa n Die g o, C A 9 2 1 2 1 , U S A 
S p o ns or’s Res p o nsi ble 
Me dic al Officer:  
Pa ul Strec k, M D, M B A  
Se ni or Vice Presi de nt, Cli nical De vel o p me nt a n d C hief Me dical Officer  
 
 
Cli nic al le a d:  
 M D  
Tel:
E -mail:
S A E re p orti n g:  
I Q VI A P har mac o vi gila nce  
P h o ne:  1 -8 6 6 -5 9 9 -1 3 4 1  
Fa x:  
1 -8 6 6 -5 9 9 -1 3 4 2  
E -mail:  Are na Safet y @i q via.c o m  
Versi o n:  
A me n d me nt 2 . 0, 0 4 A u g ust 2 0 2 2  
S p o ns or a p pr o v al:  
T his pr ot oc ol was a p pr o ve d b y t he S p o ns or’s Res p o nsi ble Me dical 
Officer or del e gate. T he electr o nic si g nat ure ma nifest is a p pe n de d.  
 
 
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of Are na P har mace uticals, I nc. U na ut h orize d 
distri b uti o n, c o p yi n g, or discl os ure is strictl y pr o hi bite d u nless re q uire d b y a p plica ble la w. Pers o ns 
recei vi n g t his i nf or mati o n m ust be n otifie d t hat it is c o nfi de ntial a n d ma y n ot be f urt her distri b ute d, 
c o pie d, or discl ose d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
P P D
P P D
P P D
P P D

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2  of 1 0 7  
P R O T O C O L HI S T O R Y   
D oc u me nt  
A m e n d me nt T y pe  
D ate  
A me n d me nt 2. 0  
Gl o bal  
0 4 A u g ust 2 0 2 2  
A me n d me nt 1. 1  
Re gi o n -S pecific  
1 7  J u ne 2 0 2 1 
A me n d me nt 1. 0  
Gl o bal  
0 2  J u ne 2 0 2 1  
A me n d me nt 0. 3  
Re gi o n -S pecific  
2 4  N o ve m ber 2 0 2 0  
A me n d me nt 0. 2  
Re gi o n -S pecific  
3 0  Oct o ber  2 0 2 0  
A me n d me nt 0. 1  
Re gi o n -S pecific  
0 2  Se pte m ber  2 0 2 0  
Ori gi nal Pr ot oc ol  
N ot a p plica ble  
2 0  J ul y 2 0 2 0  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3  of 1 0 7  
P R O T O C O L S Y N O P SI S   
S p o ns or: Are na P har mace uticals, I nc.  
N a me of i n vesti g ati o n al st u d y dr u g: Etrasi m o d ( A P D 3 3 4)  
Pr ot oc ol n u m ber: A P D 3 3 4 -2 1 0  
Pr ot oc ol title: A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, 5 2 -Wee k St u d y t o Assess 
t he Efficac y a n d Safet y of Etrasi m o d i n S u bjects wit h M o deratel y Acti ve Ulcerati ve C olitis  
P h ase: 2  
Re gi o ns: N ort h A merica, E ur o pe , Asia  P acific, Mi d dle East , a n d Africa  
O bjecti ves:  
Pri mar y : 
T he pri mar y o bjecti ve is t o assess t he efficac y of etrasi m o d o n cli nical re missi o n i n s u bjects 
wit h m o deratel y acti ve ulcerati ve c olitis ( U C) after 5 2  wee ks of treat me nt.  
Sec o n dar y : 
T he sec o n dar y o bjecti ve is t o assess t he efficac y of etrasi m o d o n e n d osc o p ic i m pr o ve me nt, 
hist ol o gic res p o nse, cli nical res p o nse, a n d s y m pt o matic re missi o n,  at ti me p oi nts u p t o 5 2  wee ks 
of treat me nt.  
Safet y : 
T he safet y o bjecti ve is t o assess t he l o n g -ter m safet y of etrasi m o d after dail y d oses of 2 m g f or 
u p t o 5 2  wee ks.  
Ot her : 
O t her o bjecti ves i ncl u de e val uati o n of etrasi m o d p har mac o ki netics ( P K) a n d t he effect of 
etrasi m o d o n healt h -relate d s u bject-re p orte d o utc o mes a n d bi o mar kers. 
St u d y desi g n:  
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d  st u d y t o e val uate t he 
efficac y a n d safet y of etrasi m o d 2  m g i n s u bjects wit h m o deratel y acti ve U C. T he st u d y 
c o nsists of a 2 8 -Da y Scree ni n g Peri o d , a 5 2 wee k treat -t hr o u g h desi g n c o nsisti n g of  a 1 2-Wee k 
Treat me nt Peri o d  an d  a 4 0 -Wee k Treat me nt Peri o d, a n d a 4 -Wee k F oll o w -U p Peri o d  ( wit h 
2  visits)  (Fi g ure  1 ). 
T he tar get s u bject p o p ulati o n will i ncl u de:  
1.  S u bjects w h o ha ve ha d a n i na de q uate res p o nse t o, l oss of res p o nse t o, or i nt olera nce t o 
c o n ve nti o nal t hera p y a n d are naï ve t o bi ol o gic or Ja n us ki nase (J A K) i n hi bit or t hera p y  
2.  S u bjects w h o ha ve ha d a n i na de q uate res p o nse t o, l oss of res p o nse t o, or i nt olera nce t o a 
bi ol o gic or J A K i n hi bit or ( su bjects i n t his cate g or y ma y ha ve recei ve d pri or c o n ve nti o nal 
t hera p y) 
S u bject eli gi bilit y will be deter mi ne d d uri n g a Scree ni n g Peri o d of 4  wee ks ( 2 8  da ys). E ntr y 
criteria will be base d o n c o nfir mati o n of m o deratel y ac ti ve U C, defi ne d b y a m o difie d Ma y o 
sc ore ( M M S) of 4 t o 6 i ncl u di n g a n e n d osc o pic sc ore ( E S)  ≥ 2 a n d rectal blee di n g 
( R B) sc ore ≥ 1 . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4  of 1 0 7  
Eli gi ble s u bjects will be ra n d o mize d ( 2: 1  rati o) t o recei ve eit her etrasi m o d ( 2 m g o nce dail y) or 
matc hi n g place b o ( o nce da il y) i n a d o u ble-bli n d fas hi o n f or u p t o 5 2  wee ks  ( 1 2 Wee k 
Treat me nt Peri o d + 4 0 Wee k Treat me nt Peri o d) . Ra n d o mizati o n will be stratifie d b y (a)  naï ve 
t o bi ol o gic or J A K i n hi bit or t hera p y at st u d y e ntr y ( yes or  n o)  a n d ( b) baseli ne c ortic oster oi d 
use ( yes  or  n o).  
E n d of 1 2 -Wee k D o u ble -Bli n d Tre at me nt Peri o d  
At t he e n d of t he 1 2 -Wee k  Treat me nt Peri o d, s u bjects will u n der g o t he Wee k  1 2 efficac y a n d 
safet y assess me nts a n d pr oce d ures. S u bjects w h ose U C c o n diti o n i n t he o pi ni o n of t he 
I n vesti gat or is sta ble or i m pr o vi n g c o m pare d wit h baseli ne ( Wee k 0/ Da y  1) will c o nti n ue  wit h 
t heir d o u ble-bli n d treat me nt a n d m o ve i nt o t he 4 0 -Wee k  Treat me nt Peri o d.   
E n d of 4 0 -Wee k D o u ble -Bli n d Tre at me nt Peri o d ( Wee k  5 2)  
At t he e n d of t he 4 0 -Wee k Treat me nt Peri o d (ie, Wee k  5 2) a n d f oll o wi n g c o m pleti o n of all 
st u d y pr oce d ures, s u bjects will ha ve t he o pti o n t o e nter i nt o t he  O pe n -La bel E xte nsi o n (O L E ) 
st u d y ( St u d y A P D 3 3 4 -3 0 3) pr o vi de d t he y meet all eli gi bilit y criteria.  
S u bjects w h o d o n ot partici pate i n t he O L E st u d y will ha ve 2 -Wee k a n d 4 -Wee k F oll o w -U p 
visits after t heir last treat me nt a d mi nistrati o n.  
O pe n -L a bel E xte nsi o n St u d y ( St u d y A P D 3 3 4 -3 0 3)  
S u bjects w h ose U C  c o n diti o n i n t he o pi ni o n of t he I n vesti gat or has n ot i m pr o ve d or has 
w orse ne d, c o m pare d wit h baseli ne ( Wee k 0/ Da y  1),  ma y be eli gi ble t o e nr oll i n t he O L E  st u d y.  
S u bjects m ust c o m plete Wee k 1 2 t o be c o nsi dere d f or t he O L E st u d y.   
Disease w orse ni n g will c o nti n ue t o be m o nit ore d b y I n vesti gat ors t hr o u g h t he 4 0 -Wee k 
Treat me nt Peri o d (ie, fr o m Wee ks  1 3  t o 5 2). S u bjects w h o eit her e x perie nce disease w orse ni n g 
i n t he 4 0-Wee k Treat me nt Peri o d or c o m plete all st u d y pr oce d ures at Wee k  5 2 will ha ve t he 
o pti o n t o e nr oll i nt o t he O L E st u d y if t he y meet all eli gi bilit y criteria.  
S u bjects ma y be eli gi ble t o e nr oll i n t he O L E  st u d y pr o vi de d t heir E S is ≥ 2 a n d t he y meet 1 of 
t he f oll o wi n g e ntr y criteria: 
•  R B s u bsc ore ≥ 2 at 2  ti me p oi nts at least 7 da ys a n d n o m ore t ha n 1 4  da ys a part  
•  R B  +  st o ol fre q ue nc y ( S F) s u bsc ores ≥ 4 at 2  ti me p oi nts at least 7 da ys a n d n o m ore 
t ha n 1 4 da ys a part  
•  R B s u bsc ore ≥ 2 or R B + S F s u bsc ores ≥ 4 (i n a n y or der) at 2  ti me p oi nts at least 7 da ys 
a n d n o m ore t ha n 1 4  da ys a part  
F or s u bjects disc o nti n ui n g pri or t o Wee k  5 2, a n e n d osc o pic e val uati o n is re q uire d t o c o nfir m 
eli gi bilit y f or t he O L E  st u d y. A n e n d osc o p y s h o ul d be perf or me d u p o n t he a p peara nce of U C 
s y m pt o m w orse ni n g b ut n o m ore t ha n 1 4 da ys after t he sec o n d ti me p oi nt f or s y m pt o m criteria 
a b o ve. A pr oct osi g m oi d osc o p y d oes n ot nee d t o be re peate d if perf or me d wit hi n t he last 
4  wee ks.  
N u m ber of s u bjects ( pl a n ne d):  
A p pr o xi matel y 2 2 5  s u bjects are pla n ne d t o be e nr olle d i nt o t his st u d y.  
Eli gi bilit y criteri a:  
I ncl usi o n criteria: 
S u bjects m ust meet A L L of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i nt o t he 
st u d y: 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5  of 1 0 7  
1.  Me n or w o me n 1 8  t o 8 0  years of a ge, i ncl usi ve, at t he ti me of c o nse nt (asse nt i n c o u ntries 
w here re q uire d per l ocal la w a n d re g ulati o n).  
2.  A bilit y t o pr o vi de writte n i nf or me d c o nse nt  /asse nt a n d t o be c o m plia nt wit h t he sc he d ule 
of pr ot oc ol assess me nts. P arent or le gal g uar dia n m ust pr o vi de c o nse nt f or a s u bject w h o 
has asse nte d t o partici pate i n t he st u d y as re q uire d per l ocal re g ulati o ns.  
Dise ase -s pecific i ncl usi o n criteri a: 
3.  Dia g n ose d wit h U C ≥ 3  m o nt hs pri or t o scree ni n g. T he dia g n osis of U C m ust be c o nfir me d 
b y e n d osc o pic a n d hist ol o gic e vi de nce. T he e n d osc o p y a n d hist ol o g y re p ort s h o ul d be 
prese nt i n t he s o urce d oc u me nts; h o we ver, if n ot a vaila ble, t he scree ni n g e n d osc o p y a n d 
hist ol o g y ma y ser ve as s uc h.  
4.  Acti ve U C c o nfir me d b y e n d osc o p y wit h ≥ 1 0  c m recta l i n v ol ve me nt. S u bjects wit h 
pr octitis o nl y at baseli ne m ust meet ot her eli gi bilit y criteria, i ncl u di n g t he M M S a n d 
e n d osc o pic criteria.  
5.  M o deratel y acti ve U C  defi ne d as a n M M S of 4  t o 6 a n d a n E S  ≥ 2 a n d R B sc ore ≥ 1 . 
6.  Recei ve d a s ur veilla nce c ol o n osc o p y ( p erf or me d acc or di n g t o l ocal sta n dar d) wit hi n 
1 2  m o nt hs bef ore baseli ne t o r ule o ut d ys plasia i n s u bjects wit h pa nc olitis >  8  years 
d urati o n or s u bjects wit h left -si de d c olitis > 1 2  years d urati o n. S u bjects wit h o ut a 
s ur veilla nce c ol o n osc o p y wit hi n t he pri or 1 2 m o nt hs will ha ve a c ol o n osc o p y at scree ni n g 
(ie, i n place of scree ni n g pr oct osi g m oi d osc o p y). A n y a de n o mat o us p ol y ps m ust be 
re m o ve d acc or di n g t o r o uti ne practice pri or t o t heir first d ose of st u d y treat me nt. 
Pri or tre at me nt : 
7.  De m o nstrate d a n i na de q uate res p o nse t o, 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 t hera pies as defi ne d bel o w: 
C o n ve nti o n al t her a p y  
a. Oral 5 -a mi n osalic ylic aci d ( 5 -A S A) c o m p o u n ds  
b.  C ortic oster oi ds  
c. T hi o p uri nes  
Bi ol o gic t her a p y or J A K i n hi bit or t her a p y 
a. A nti -t u m or necr osis fact or al p ha ( T N F α) a nti b o dies (e g, i nfli xi ma b, a dali m u ma b, 
g oli m u ma b, or bi osi milars)  
b.  A nti -i nte gri n a nti b o dies (e g, ve d oliz u ma b) 
c. A nti -i nterle u ki n 1 2/ 2 3 a nti b o dies (e g, uste ki n u ma b) 
d.  J A K i n hi bit ors (e g, t ofaciti ni b) 
N ote: T he me d icati o n use d t o q ualif y t he s u bject f or e ntr y i nt o t his cate g or y m ust be 
a p pr o ve d f or t he treat me nt of U C i n t he c o u ntr y of use a n d t he s u bject m ust ha ve 
recei ve d a n a de q uate c o urse of t hera p y base d o n l ocal g ui deli nes f or t hat t hera p y. 
C o nc o mit a nt tre at me nts : 
8.  S u bjects are per mitte d t o be recei vi n g a t hera pe utic d ose of t he f oll o wi n g dr u gs:  
•  Oral 5 -A S A c o m p o u n ds pr o vi de d t he d ose has bee n sta ble f or ≥ 2  wee ks 
i m me diatel y pri or t o ra n d o mizati o n. 
•  Oral c ortic oster oi d t hera p y ( pre d nis o ne at a sta ble d ose ≤ 2 0  m g/ da y, b u des o ni de at 
a sta ble d ose ≤ 9  m g/ da y, or e q ui vale nt ster oi d) pr o vi de d t he d ose has bee n sta ble 
f or t he 4 wee ks i m me diatel y pri or t o t he scree ni n g e n d osc o p y assess me nt. ( N ote: 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6  of 1 0 7  
S u bjects o n e xisti n g oral c ortic oster oi d t hera p y will be ta pere d d uri n g t he 4 0 -Wee k 
Treat me nt Peri o d.)  
•  I m m u n os u p pressi ve a ge nts s uc h as oral azat hi o pri ne or 6-merca pt o p uri ne m ust be 
disc o nti n ue d ≥ 2  wee ks pri or t o ra n d o mizati o n.  
•  Pr o bi otics (e g, C ult urelle ® , S acc h ar o myces b o ul ar dii ) pr o vi de d t he d ose has bee n 
sta ble f or t he 2 wee ks i m me diatel y pri or t o ra n d o mizati o n.  
If oral 5-A S A or c ortic oster oi ds ha ve bee n rece ntl y disc o nti n ue d, t he y m ust ha ve bee n 
st o p pe d f or at least 2 wee ks pri or t o t he e n d osc o p y use d f or t he baseli ne M M S. 
Ot her ge ner al i ncl usi o n criteri a : 
9.  A de q uate he mat ol o gical f u ncti o n defi ne d b y w hite bl o o d cell c o u nt ≥ 3. 5  ×  1 0 9/ L wit h 
a bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5  ×  1 0 9/ L, l y m p h oc yte c o u nt ≥ 0. 8  ×  1 0 9/ L, platelet 
c o u nt ≥ 1 0 0  ×  1 0 9/ L, a n d he m o glo bi n ≥ 8  g/ d L.  
1 0.  A de q uate he patic f u ncti o n defi ne d b y a t otal bilir u bi n le vel ≤ 1. 5  × t he u p per li mit of 
n or mal ( U L N) ra n ge a n d as partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase 
( A L T) le vels ≤ 2. 0  ×  U L N. S u bjects wit h a n is olate d t otal bilir u bi n a n d n or mal A S T a n d 
A L T dia g n ose d wit h Gil bert’s s y n dr o me ma y partici pate.  
1 1.  A de q uate re nal f u ncti o n defi ne d b y a n esti mate d gl o mer ular filtrati o n rate 
≥ 3 0  m L/ mi n/ 1. 7 3  m 2 b y t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
e q uati o n at scree ni n g.  
1 2.  Fe males  m ust meet eit her a or b of t he f oll o wi n g criteria a n d males m ust meet criteri o n c t o 
q ualif y f or t he st u d y:  
a. A fe male w h o is n ot  of c hil d beari n g p ote ntial m ust meet 1 of t he f oll o wi n g:  
− P ost me n o pa usal, defi ne d as n o me nses f or 1 2  m o nt hs wit h o ut a n alter nati ve 
me dical ca use  
− Per ma ne nt sterilizati o n pr oce d ure, s uc h as h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect o m y 
b.  N o n pre g na nt fe male of c hil d beari n g p ote ntial m ust a gree t o usi n g a hi g hl y effecti ve 
c o ntrace pti o n met h o d d uri n g treat me nt a n d f or 3 0 da ys f oll o wi n g treat me nt t hat ca n 
ac hie ve a fail ure rate of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y. 
T he f oll o wi n g are c o nsi dere d hi g hl y effecti ve birt h c o ntr ol met h o ds:  
− C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g)  h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n, w hic h ma y be oral, i ntra va gi nal, or 
tra ns der mal 
− Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n, w hic h ma y be oral, i njecte d, or i m pla nte d  
− I ntra uteri ne de vice (I U D) 
− I ntra uteri ne h or m o ne-releasi n g s yste m 
− Bilateral t u bal occl usi o n  
− Vasect o mize d part ner, pr o vi de d t hat part ner is t he s ole se x ual part ner of t he 
fe male of c hil d beari n g p ote ntial trial s u bject a n d t hat t he vasect o mize d part ner 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7  of 1 0 7  
has recei ve d me dical assess me nt of t he s ur gical s uccess  
− Se x ual a bsti ne nce (c o m plete se x ual a bsti ne nce defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse f or t he e ntire peri o d of ris k ass ociate d wit h st u d y 
treat me nts). T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n 
t o t he d urati o n of t he cli nical st u d y a n d t he preferre d a n d us ual lifest yle of t he 
s u bject. Peri o dic a bsti ne nce (cale n dar, s y m pt ot her mal, p ost-o v ulati o n met h o ds) 
is n ot acce pta ble 
c. A male s u bject wit h a pre g na nt or n o n pre g na nt fe male of c hil d beari n g p ote ntial 
part ner m ust a gree t o usi n g c o n d o ms d uri n g treat me nt a n d f or 3 0  da ys f oll o wi n g 
treat me nt. 
E xcl usi o n criteria : 
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 will n ot be eli gi ble f or e nr oll me nt 
i nt o t he st u d y: 
Excl usi o ns rel ate d t o ge ne r al he alt h: 
1.  Se vere e xte nsi ve c olitis as e vi de nce d b y:  
•  P h ysicia n j u d ge me nt t hat t he s u bject is li kel y t o re q uire h os pitalizati o n f or me dical 
care or s ur gical i nter ve nti o n of a n y ki n d f or U C (e g, c olect o m y) wit hi n 1 2  wee ks 
f oll o wi n g ra n d o mizati o n 
•  C urre nt e vi de nce of f ul mi na nt c olitis, t o xic me gac ol o n or rece nt hist or y ( wit hi n last 
6  m o nt hs) of t o xic me gac ol o n, or b o wel perf orati o n  
•  Pre vi o us t otal or partial c olect o m y  
2.  Dia g n osis of Cr o h n’s disease or i n deter mi nate c olitis or t he prese nce or hist or y of a fist ula 
c o nsiste nt wit h Cr o h n’s disease.  
3.  Dia g n osis of micr osc o pic c olitis, isc he mic c olitis, or i nfecti o us c olitis.  
4.  H os pitalizati o n f or e xacer bati o n of U C re q uiri n g i ntra ve n o us (I V) ster oi ds wit hi n 1 2  wee ks 
of scree ni n g (a si n gle d ose of I V ster oi ds gi ve n is acce pta ble).  
5.  P ositi ve assa y or st o ol c ult ure f or pat h o ge ns ( o va a n d parasite e xa mi nati o n, bacteria) or 
p ositi ve test f or Cl ostri di oi des difficile (f or merl y k n o w n as Cl ostri di u m difficile ) t o xi n at 
scree ni n g. ( N ote: If C.  diffici le is p ositi ve, t he s u bject ma y be treate d a n d reteste d 
≥ 4  wee ks after c o m pleti n g treat me nt.)  
6.  Pre g na nc y, lactati o n, or a p ositi ve ser u m beta -h u ma n c h ori o nic g o na d otr o pi n ( β -h C G) 
meas ure d d uri n g scree ni n g.  
7.  Cli nicall y rele va nt ne ur ol o gical, e n d ocri ne, meta b olic (i ncl u di n g, b ut n ot li mite d t o, 
h y p o - a n d h y per kale mia), ps yc hiatric, c o g niti ve i m pair me nt, alc o h ol/ dr u g 
a b use/ de pe n de nce, or ot her maj or s yste mic disease ma ki n g i m ple me ntati o n of t he pr ot oc ol 
or i nter pretati o n of t he st u d y diffic ult or w o ul d p ut t he s u bject at ris k. 
8.  Ha ve a n y of t he f oll o wi n g c o n diti o ns or recei vi n g treat me nts t hat ma y affect 
car di o vasc ular f u ncti o n:  
•  M y ocar dial i nfarcti o n, u nsta ble a n gi na, str o ke/tra nsie nt isc he mic attac k, 
dec o m pe nsate d heart fail ure re q uiri n g h os pitalizati o n or Class  III/I V heart fail ure 
≤ 6  m o nt hs pri or t o or d uri n g t he Scree ni n g Peri o d  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8  of 1 0 7  
•  Hist or y or prese nce of sec o n d -de gree or t hir d -de gree atri o ve ntric ular bl oc k, sic k 
si n us s y n dr o me, or peri o ds of as yst ole f or > 3  sec o n ds wit h o ut a f u ncti o nal 
pace ma ker  
•  Hist or y or prese nce of rec urre nt s y m pt o matic bra d ycar dia or rec urre nt car di o ge nic 
s y nc o pe 
•  Scree ni n g or Wee k  0/ Da y  1 prera n d o mizati o n vital si g ns (ta ke n i n t he sitti n g 
p ositi o n) wit h a heart rate <  5 0  beats per mi n ute ( b p m) O R s yst olic bl o o d press ure 
( B P) < 9 0  m m  H g O R dia st olic B P < 5 5  m m  H g. Vital si g ns ma y be re peate d u p t o 
3  ti mes d uri n g a visit t o c o nfir m a b n or mal rea di n gs 
•  Scree ni n g or Wee k  0/ Da y  1 prera n d o mizati o n electr ocar di o gra m ( E C G) wit h P R 
i nter val > 2 0 0  ms or Fri dericia’s c orrecte d Q T i nter val ( Q Tc F) ≥ 4 5 0  ms i n me n or 
≥ 4 7 0  ms i n w o me n  
•  Start, st o p, c ha n ge, or pla n ne d c ha n ge i n d osa ge of a n y a nti -arr h yt h mic dr u gs 
( Class I t o I V) ≤ 1  wee k bef ore scree ni n g or wit hi n  1  wee k bef ore or after 
ra n d o mizati o n 
9.  F orce d e x pirat or y v ol u me i n 1  sec o n d ( F E V1) or f orce d vital ca pacit y ( F V C) <  7 0 % of 
pre dicte d val ues a n d F E V 1/ F V C rati o < 0. 7 0 at scree ni n g.  
1 0.  U nc o ntr olle d dia betes as deter mi ne d b y he m o gl o bi n A 1c ( H b A 1c) >  9 % at scree ni n g, or 
s u bjects wit h dia betes wit h si g nifica nt c o m or bi d c o n diti o ns s uc h as reti n o pat h y. 
1 1.  Hist or y of mac ular e de ma or reti n o pat h y.  
1 2.  Hist or y of acti ve t u berc ul osis ( T B), hist or y of u ntreate d or i na de q uatel y treate d late nt T B 
i nfecti o n, acti ve or late nt T B i nfecti o n at scree ni n g. T he f oll o wi n g are E X C E P TI O N S t o 
t his e xcl usi o n criteri o n: 
•  S u bjects wit h late nt T B, w h o ha ve bee n r ule d o ut f or acti ve T B, ha ve c o m plete d a n 
a p pr o priate c o urse of T B pr o p h yla xis treat me nt per nati o nal/l ocal me dical g ui deli nes 
or W orl d Healt h Or ga nizati o n g ui deli nes, ha ve a c hest ra di o gra p h wit h o ut c ha n ges 
s u g gestive of acti ve T B i nfecti o n, a n d ha ve n ot ha d rece nt cl ose c o ntact wit h a 
pers o n wit h acti ve T B are eli gi ble t o e nr oll i n t he st u d y. It 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 T B treat me nt a n d pr o vi de 
a p pr o priate d oc u me nt ati o n of treat me nt c o m plia nce.  
•  S u bjects dia g n ose d wit h late nt T B at scree ni n g, r ule d o ut f or acti ve T B a n d recei ve d 
at least 4 wee ks of a n a p pr o priate T B pr o p h yla xis re gi me n ma y be rescree ne d f or 
e nr oll me nt. S u bjects will c o m plete t heir pr o p h ylactic re gi me n d uri n g t he trial.  
1 3.  A cli nicall y si g nifica nt acti ve i nfecti o n (e g, seri o us a n d/ or at y pical) ≤ 2 8  da ys pri or t o 
ra n d o mizati o n, re q uire d I V me dicati o n ≤ 1 4  da ys pri or t o ra n d o mizati o n, or t hat ma y 
w orse n (i n t he o pi ni o n of t he I n vesti gat or) if t he s u bject is  treate d wit h a dr u g ha vi n g 
i m m u n os u p pressa nt effects (ie, etrasi m o d). F u n gal i nfecti o n of nail be ds is all o we d. 
1 4.  Ha ve h u ma n i m m u n o deficie nc y vir us ( HI V)/ac q uire d i m m u ne deficie nc y s y n dr o me  
( AI D S) or test p ositi ve f or HI V a nti b o dies at scree ni n g.  
1 5.  Ha ve ac ute  or c hr o nic he patitis  B i nfecti o n or test p ositi ve f or he patitis  B vir us ( H B V) at 
scree ni n g ( detecta ble H B V D N A, or p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g], or 
ne gati ve f or H Bs A g a n d p ositi ve f or a nti -he patitis  B c ore a nti b o d y i n c o nj u ncti o n wit h 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9  of 1 0 7  
detecta ble H B V D N A).  
1 6.  Ha ve c urre nt he patitis  C i nfecti o n or test p ositi ve f or he patitis  C vir us ( H C V) at scree ni n g 
as defi ne d b y p ositi ve f or he patitis  C a nti b o d y a n d detecta ble H C V R N A.  
1 7.  Hist or y of a n o p p ort u nistic i nfecti o n (e g, P ne u m ocystis  jir ovecii, cr ypt oc occal me ni n gitis, 
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y) or hist or y of disse mi nate d her pes si m ple x or 
disse mi nate d her pes z oster.  
1 8.  Hist or y of or c urre ntl y acti ve pri mar y or sec o n dar y i m m u n o deficie nc y.  
1 9.  Hist or y of ca ncer wit hi n t he last 5  years, i ncl u di n g s oli d t u m ors a n d he mat ol o gical 
mali g na ncies (e xce pt basal cell a n d i n  sit u s q ua m o us cell carci n o mas of t he s ki n t hat ha ve 
bee n e xcise d a n d res ol ve d)  or c ol o nic m uc osal d ys plasia.  
2 0.  Hist or y of l y m p h o pr oliferati ve dis or der, l y m p h o ma, le u ke mia, m yel o pr oliferati ve dis or der, 
or m ulti ple m yel o ma.  
Excl usi o ns rel ate d t o me dic ati o ns : 
2 1.  H y perse nsiti vit y t o etrasi m o d or a n y of t he e xci pie nts or place b o c o m p o u n ds.  
2 2.  Pri or treat me nt wit h s p hi n g osi ne 1-p h os p hate rece pt or m o d ulat ors. 
2 3.  Treat me nt wit h a bi ol o gic a g e nt ≤ 8  wee ks or a s mall m olec ule a ge nt ≤ 5 eli mi nati o n 
half -li ves a n d detecta ble dr u g le vel pri or t o ra n d o mizati o n. 
2 4.  Treat me nt wit h a n i n vesti gati o nal t hera p y ≤ 3  m o nt hs pri or t o ra n d o mizati o n.  
2 5.  Treat me nt wit h ≥ 3 bi ol o gic a ge nts or ≥ 2 bi ol o gics pl us a J A K  i n hi bit or a p pr o ve d f or 
treat me nt of U C. 
2 6.  Treat me nt wit h t o pical rectal 5 -A S A, s h ort -c hai n fatt y aci d e ne mas, or ster oi ds ≤ 2  wee ks 
pri or t o a n d d uri n g scree ni n g.  
2 7.  Treat me nt wit h t o pical rectal tra diti o nal me dici ne (e g, C hi nese me dici ne), her b e ne mas, or 
s u pp osit ories ≤ 2  wee ks pri or t o ra n d o mizati o n  
2 8.  Treat me nt wit h met h otre xate ≤ 8  wee ks of scree ni n g or c ycl os p ori ne, tacr oli m us, 
sir oli m us, or m yc o p he n olate m ofetil ( M M F) ≤ 1 6  wee ks pri or t o a n d d uri n g scree ni n g.  
2 9.  Recei pt of a li ve vacci ne ≤ 4  wee ks pri or t o ra n d o mizati o n. 
3 0.  Pre vi o us treat me nt wit h nataliz u ma b.  
3 1.  Pre vi o us treat me nt wit h l y m p h oc yte-de pleti n g  t hera pies (e g, ale mt uz u ma b, a nti-C D 4 , 
cla dri bi ne, rit u xi ma b, ocreliz u ma b, c ycl o p h os p ha mi de, mit o xa ntr o ne, t otal b o d y 
irra diati o n, b o ne marr o w tra ns pla ntati o n, dacliz u ma b). 
3 2.  Pre vi o us treat me nt wit h D -pe nicilla mi ne , t hali d o mi de, di met h yl f u marate, or p yri mi di ne 
s y nt hesis i n hi bit ors. 
3 3.  Treat me nt wit h I V i m m u n ogl o b uli n or plas ma p heresis ≤ 3  m o nt hs pri or t o ra n d o mizati o n.  
3 4.  Use of m o derate or str o n g i n hi b it ors or in d ucers t hat i n hi bit or i n d uce at least 2 of t he 
f oll o wi n g: c yt oc hr o me P 4 5 0 ( C Y P) 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 (e g, fl uc o naz ole, 
rifa m pi n, e nzal uta mi de) wit hi n 4 wee ks pri or t o ra n d o mizati o n. 
Test pr o d uct, f or m ul ati o n, m o de of a d mi nistr ati o n, a n d d ose:  
Etrasi m o d, 2  m g ta blets, b y m o ut h, o nce dail y  
St u d y d ur ati o n:  
T he o verall d urati o n of t his st u d y is e x pecte d t o be a p pr o xi matel y 3. 5  years.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0  of 1 0 7  
Refere nce t her a p y, descri pti o n, m o de of a d mi nistr ati o n:  
Place b o ta blets, b y m o ut h, o nce dail y.  
Effic ac y assess me nts:  
T he Ma y o Cli nic sc ore ( M C S ) a n d its c o m p o ne nt s u bsc ores will be use d t o assess efficac y. 
T he T ot al M a y o Sc ore  (T M S ) is t he s u m of t he f o ur c o m p o ne nt sc ores ( E S, R B, S F a n d P G A) 
of t he M C S. T he sc ore ra n ge of t he T M S is fr o m 0 t o 1 2 wit h eac h c o m p o ne nt sc ore ra n gi n g 
fr o m 0 t o 3 ( 0 =  n or mal, 1 = mil d, 2 = m o derate, 3 = se vere) a n d hi g her sc ores i n dicati n g m ore 
se vere disease. 
T he M o difie d M a y o Sc ore  (M M S ) is t he s u m of t he E S, R B, a n d S F c o m p o ne nt sc ores of t he 
M C S. T he ra n ge of t he M M S is fr o m 0 t o 9, wit h eac h c o m p o ne nt sc ore ra n gi n g fr o m 0 t o 3 
( 0 =  n or mal, 1 = mil d, 2 = m o derate, 3 = se vere). Cli nical re missi o n a n d res p o nse, u nless 
ot her wise n ote d, will be base d o n M M S.  
T he U lcer ati ve C olitis 1 0 0 ( U C -1 0 0 ) i n de x is base d o n t he Ma y o Cli nic S F  s u bsc ore, t he Ma y o 
Cli nic E S , a n d t he R o barts Hist o pat h ol o g y I n de x ( R HI) sc ore. T hese 3 c o m p o ne nts are 
i nc or p orate d i nt o a calc ula ble fi nal i n de x. T he f or m ula f or t he c o m p osite U C-1 0 0 sc ore is: 
( 1 +  1 6  ×  Ma y o Cli nic S F s u bsc ore [ 0  t o 3] + 6  ×  Ma y o Cli nic E S [ 0 t o 3]  +  1  ×  R HI sc ore 
[ 0 t o 3 3]).  
Defi niti o ns : 
•  Cli nical re missi o n: S F  s u bsc ore =  0 ( or =  1 wit h a ≥ 1 -p oi nt decrease fr o m baseli ne), 
R B  s u bsc ore =  0, a n d E S  ≤ 1 (e xcl u di n g fria bilit y)  
•  Cli nical re missi o n base d o n T M S: T M S ≤ 2 wit h all s u bsc ores ≤ 1  
•  E n d osc o pic i m pr o ve me nt: E S  ≤ 1 (e xcl u di n g fria bilit y)  
•  Hist ol o gic res p o nse: Decrease i n R HI of ≥ 7  p oi nts fr o m baseli ne  
•  M uc osal heali n g: E n d osc o pic i m pr o ve me nt a n d hist ol o gic re missi o n  base d o n t he 
Ge b oes Gra di n g S yste m  
•  Cli nical res p o nse: A ≥ 2 -p oi nt a n d ≥ 3 0 % decrease fr o m baseli ne i n M M S, 
a n d a ≥ 1 -p oi nt decrease fr o m baseli ne i n R B s u bsc ore or a n a bs ol ute 
R B  s u bsc ore ≤ 1  
•  Cli nical res p o nse base d o n T M S: A ≥ 3 -p oi nt a n d ≥ 3 0 % decrease fr o m baseli ne i n 
T M S, a n d a ≥ 1 -p oi nt decreas e fr o m baseli ne i n R B s u bsc ore or a n a bs ol ute R B 
s u bsc ore ≤ 1  
•  Hist ol o gic re missi o n base d o n R HI: A R HI sc ore ≤ 3 wit h la mi na pr o pria 
ne utr o p hils s u bsc ore  =  0 a n d ne utr o p hils i n e pit heli u m s u bsc ore  =  0  
•  Hist ol o gic re missi o n base d o n t he Ge b oes Gra di n g S yste m: A Ge b oes Sc ore 
( G S) ≤ 2  
•  S y m pt o matic re missi o n: S F s u bsc ore =  0 ( or =  1 wit h a ≥ 1 -p oi nt decrease fr o m 
baseli ne) a n d R B s u bsc ore  =  0  
•  Cli nical re missi o n base d o n t he U C -1 0 0 i n de x: U C -1 0 0 i n de x ≤ 2 5  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 1  of 1 0 7  
Pri mar y efficac y e n d p oi nts : 
•  T he pr o p orti o n of s u bjec ts ac hie vi n g cli nical re missi o n at Wee k 5 2  
Ke y sec o n dar y efficac y e n d p oi nts : 
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g e n d osc o pic i m pr o ve me nt at Wee k 5 2 
•  T he p r o p orti o n of s u bjects ac hie vi n g s y m pt o matic re missi o n at Wee k 5 2  
•  T he pr o p orti o n of s u bjects ac hie vi n g  m uc osal heali n g at Wee k  5 2  
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at b ot h Wee ks  1 2 a n d 5 2  
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at Wee k  5 2 a n d w h o ha d n ot 
bee n recei vi n g c ortic oster oi ds f or ≥ 1 2  wee ks i m me diatel y pri or t o Wee k  5 2  
P h ar m ac o ki netic assess me nts:  
Plas ma c o nce ntrati o ns of etrasi m o d  will be assesse d fr o m sa m ples c ollecte d pre -d ose  a n d 
4  h o urs p ost -d ose  (after 1 2-lea d E C G) o n Wee k  0/ Da y  1, a n d pre -d ose  (tr o u g h) at Wee ks  2, 4, 
8, 1 2, 1 6, 2 4, 3 2, 4 8, 5 2 , a n d Earl y Ter mi nati o n  ( E T) (o nl y re q uire d if E T visit  ≤ 3 0  h o urs si nce 
last treat me nt a d mi nistrati o n), a n d at t he 2-Wee k a n d 4 -Wee k F oll o w -U p visits. A P K sa m ple 
s h o ul d als o be dra w n, if p ossi ble, at t he ti me of a n y seri o us a d verse e ve nt ( S A E) or a d verse 
e ve nt lea di n g t o st u d y treat me nt disc o nti n uati o n.  
Plas ma sa m ples ma y als o be use d f or pr ofili n g of dr u g bi n di n g pr otei ns, bi oa nal ytical met h o d 
vali dati o n p ur p oses, sta bilit y asse ss me nts, or t o assess ot her acti o ns of etrasi m o d wit h plas ma 
c o nstit ue nts. 
Ot her assess me nts:  
Bi o mar ker e n d p oi nts : 
•  C ha n ge fr o m baseli ne i n le vel of fecal cal pr otecti n at Wee ks  2, 4, 8, 1 2, 2 4, a n d 5 2  
•  C ha n ge fr o m baseli ne i n le vel of hi g h -se nsiti vit y C-reacti ve pr otei n at Wee ks  2, 4, 8, 1 2, 1 6, 
2 4, 3 2, 4 8, a n d 5 2  
•  C ha n ge a n d perce nta ge c ha n ge fr o m baseli ne i n l y m p h oc yte c o u nts at Wee ks  2, 4, 8, 1 2, 1 6, 
2 4, 3 2, 4 8, a n d 5 2  
Healt h -relate d q ualit y of life e n d p oi nts: 
•  Sc ores a n d c ha n ge fr o m baseli ne at Wee ks  1 2, 3 2 ( U C -P R O o nl y), a n d 5 2 i n t he f oll o wi n g:  
− T w o Ulcerati ve C olitis Patie nt -Re p orte d O utc o mes ( U C -P R O) m o d ules:  
− U C -P R O Si g ns a n d S y m pt o ms ( U C -P R O/ S S) a n d  
− U C -P R O S yste mic S y m pt o ms  
− F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y -Fati g ue ( F A CI T -F)  
− W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire –  Ulcerati ve C olitis 
( W P AI-U C)  
− Ur ge nc y n u meric rati n g scale ( N R S)  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 2  of 1 0 7  
− I nfla m mat or y B o wel Disease Q uesti o n naire t otal sc ore (I B D Q) 
− Me dical O utc o mes St u d y 3 6 -Ite m S h ort F or m Healt h S ur ve y, versi o n 2 p h ysical a n d  
me ntal c o m p o ne nt a n d d o mai n sc ores ( S F -3 6)  
− Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C)  
•  T he pr o p orti o n of s u bjects wit h U C -relate d h os pitalizati o ns 
•  T he pr o p orti o n of s u bjects re q uiri n g U C -relate d s ur geries, i ncl u di n g c olect o m y 
S afet y assess me nts:  
Safet y will be assesse d usi n g m o nit ori n g of a d verse e ve nts, cli nical la b orat or y fi n di n gs, 1 2 -lea d 
E C Gs , H olter rec or di n g, p h ysical e xa mi nati o ns, vital si g ns, p ul m o nar y f u ncti o n tests, 
o p ht hal m osc o p y, a n d  o ptical c o here nce t o m o gra p h y ( O C T) . 
Saf et y e n d p oi nts : 
•  I nci de nce a n d se verit y of a d verse e ve nts 
•  I nci de nce a n d se verit y of la b orat or y a b n or malities, a n d c ha n ge fr o m baseli ne i n la b orat or y 
val ues (t o i ncl u de he mat ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d uri nal ysis)  
•  I nci de nce of cli nicall y si g nifica nt vital si g n a b n or malities a n d c ha n ges fr o m baseli ne  
St atistic al met h o ds:  
Deter mi nati o n of sa m ple size 
Base d o n a 2 -gr o u p Fis her’s e xact test, a t w o -si de d si g nifica nce le vel of 0. 0 5, a n d a 2: 1 
ra n d o mizati o n rati o, a p pr o xi matel y 1 8 3 s u bjects ( 1 2 2 etrasi m o d, 6 1 place b o) are re q uire d t o 
ac hie ve at least 8 0 % p o wer t o detect a differe nce of 2 0 % i n t he pri mar y e n d p oi nt of cli nical 
re missi o n ( base d o n M M S) at Wee k 5 2 bet wee n the etrasi m o d treat me nt gr o u p ( 3 4 %) a n d t he 
place b o treat me nt gr o u p  ( 1 4 %). Alter nati vel y,  base d o n t he sa me ass u m pti o ns , usi n g n or mal 
a p pr o xi mati o n t o t he bi n o mial distri b uti o n , a t w o-si de d test w o ul d ac hie ve at least 9 0 % p o wer . 
T he ass u m pti o n s are base d o n t he fi nal a nal ysis i n t he P hase 3 St u dies A P D 3 3 4 -3 0 1 a n d 
A P D 3 3 4 -3 0 2. Sa m ple size is calc ulate d usi n g t he E A S T® s oft ware. 
At t he ti me of t his a me n d me nt, a p pr o xi matel y 4 5 s u bjects a m o n g t he alrea d y ra n d o mize d 
s u bjects (ass u mi n g a p pr o xi matel y 2: 1 rati o of etrasi m o d: place b o) d o n ot meet t he a me n de d 
i ncl usi o n criteri o n 5  i n St u d y A P D 3 3 4-2 1 0 pr ot oc ol a me n d me nt 2. 0 w hic h i ncl u des  E S ≥ 2 a n d 
R B sc ore ≥ 1. As a res ult, t hese s u bjects will be e xcl u de d fr o m t he Pri mar y A nal ysis Set (refer 
t o Secti o n  1 0. 3 ) b ut t hese s u bjects will be i ncl u de d i n ot her a nal ysis sets as dee me d a p pr o priate. 
T heref ore, a p pr o xi matel y 2 2 5 t otal s u bjects ( 1 5 0 etrasi m o d, 7 5 place b o) are re q uire d t o be 
e nr olle d i nt o st u d y.  
Efficac y a nal ysis  
T he pri mar y a nal ysis of t he bi nar y efficac y e n d p oi nts will be carrie d o ut usi n g t he 
C oc hra n -Ma ntel -Hae nszel ( C M H) met h o d, stratifie d b y (a) n aï ve t o bi ol o gic or J A K i n hi bit or 
t hera p y at st u d y e ntr y ( yes or  n o)  a n d ( b) baseli ne c ortic oster oi d use ( yes or  n o) . T he pri mar y 
a nal ysis will be base d o n Pri mar y A nal ysis Set (refer t o Secti o n 1 0. 3). Res ults will be e x presse d 
as t he n u m ber of s u bjects i n re missi o n, re missi o n perce nta ges, differe nce i n re missi o n 
perce nta ges, o d ds rati o, a n d ass ociate d 9 5 %  c o nfi de nce i nter vals ( CIs) a n d p -val ues.  
 
M ulti ple c o m paris o n pr oce d ure  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 3  of 1 0 7  
 
T here are m ulti ple n ull h y p ot heses f or t he c o m paris o n of etrasi m o d a n d place b o i n t he pri mar y  
a n d sec o n dar y efficac y e n d p oi nts. T he fa mil y -wise t y pe -I err or rate will be c o ntr olle d at t he 
le vel of 0. 0 5. T he pri mar y efficac y e n d p oi nt will be teste d at a si g nifica nce le vel of 0. 0 5. O nl y 
if t he pri mar y n ull h y p ot hesis is rejecte d, ca n si g nifica nce clai ms pr ocee d f or t he ke y sec o n dar y 
e n d p oi nts. T he fa mil y of h y p ot heses a n d t he m ulti ple c o m paris o n pr oce d ure use d t o c o ntr ol t he 
fa mil y-wise t y pe -I err or rate will be clearl y s pecifie d i n t he Statistical A nal ysis Pla n ( S A P ) a n d 
ma y i ncl u de s o me of ot her sec o n dar y ef ficac y e n d p oi nts. 
P har mac o ki netic a nal ysis  
A descri pti ve s u m mar y of o bser ve d plas ma c o nce ntrati o n will be dis pla ye d b y ti me a n d b y 
treat me nt gr o u p. 
Safet y a nal ysis  
All safet y data will be liste d a n d s u m marize d b y treat me nt gr o u p. All treat me nt -e mer ge nt 
a d verse e ve nts will be c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities a n d ta b ulate d b y S yste m Or ga n Class a n d Preferre d Ter m. I nci de nce of a d verse 
e ve nts, S A Es, a n d a d verse e ve nts lea di n g t o disc o nti n uati o n will be s u m mariz e d a n d prese nte d 
i n desce n di n g or der of fre q ue nc y. Ass ociate d la b orat or y para meters s uc h as he patic e nz y mes, 
re nal f u ncti o n, a n d he mat ol o g y val ues will be gr o u pe d a n d prese nte d t o get her. I n di vi d ual 
s u bject val ues will be liste d a n d val ues o utsi de of t he sta n dar d refere nce ra n ge will be fla g ge d. 
S hift ta bles a n d a nal yses of c ha n ges fr o m baseli ne will be pr o d uce d.  
F ull details of all efficac y, P K, a n d safet y a nal yses will be pr o vi de d i n t he S A P.  
I nteri m a nal ysis 
N ot a p plica ble . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 4  of 1 0 7  
T A B L E  O F C O N T E N T S  
C LI NI C A L S T U D Y P R O T O C O L  ..................................................................................................1  
P R O T O C O L HI S T O R Y  ..................................................................................................................2  
P R O T O C O L S Y N O P SI S .................................................................................................................3  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ................................................2 0  
1.  
I N T R O D U C TI O N ......................................................................................................2 4  
1. 1.  
Ulcerat i ve C olitis ........................................................................................................2 4  
1. 2.  
Etrasi m o d  ....................................................................................................................2 4  
1. 3.  
Be nefit/ R is k Assess me nt ............................................................................................2 5  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................2 6  
2. 1.  
Pri mar y O bjecti ve  .......................................................................................................2 6  
2. 2.  
S ec o n dar y O bjecti ve  ...................................................................................................2 6  
2. 3.  
Safet y O bjecti ve  ..........................................................................................................2 6  
2. 4.  
Ot her O bjecti ves  .........................................................................................................2 6  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................2 6  
3. 1.  
S u m mar y of St u d y Desi g n  ..........................................................................................2 6  
3. 1. 1.  
E n d of 1 2 -Wee k D o u ble -Bli n d Treat me nt Peri o d  ......................................................2 7  
3. 1. 2.  
E n d of 4 0 -Wee k D o u ble -Bli n d Treat me nt Peri o d  ......................................................2 8  
3. 2.  
Rati o nale f or St u d y Desi g n  .........................................................................................2 8  
3. 3.  
St u d y D urati o n  ............................................................................................................2 9  
3. 4.  
I n de pe n de nt Data M o nit ori n g C o m mittee ..................................................................2 9  
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ................................................................3 0  
4. 1.  
I ncl usi o n Criteria ........................................................................................................3 0  
4. 2.  
E xcl usi o n Criteria  .......................................................................................................3 3  
5.  
R E M O V A L O F S U BJ E C T S F R O M S T U D Y T R E A T M E N T O R 
A S S E S S M E N T  ...........................................................................................................3 6  
5. 1.  
Disc o nti n uati o n fr o m St u d y Treat me nt  ......................................................................3 6  
5. 1. 1.  
Disc o nti n uati o n fr o m D o u ble -Bli n d Treat me nt f or Disease W orse ni n g  ....................3 7  
5. 2.  
Disc o nti n uati o n fr o m t he St u d y  ..................................................................................3 8  
5. 3.  
S u bjects L ost t o F oll o w -U p Pri or t o Last Sc he d ule d Visit  .........................................3 8  
5. 4.  
Pre mat ure Ter mi nati o n of t he St u d y  ...........................................................................3 9  
6.  
S T U D Y T R E A T M E N T S  ............................................................................................3 9  
6. 1.  
Treat me nts A d mi nistere d  ............................................................................................3 9  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 5  of 1 0 7  
6. 2.  
I n vesti gati o nal St u d y Treat me nt .................................................................................4 0  
6. 3.  
D osa ge a n d A d mi nistrati o n  ........................................................................................4 0  
6. 3. 1.  
I nstr ucti o ns f or Misse d D ose(s) ..................................................................................4 0  
6. 3. 2.  
D ose I nterr u pti o ns  ......................................................................................................4 0  
6. 4.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt  ..............................................................4 1  
6. 5.  
Bli n di n g  ......................................................................................................................4 1  
6. 6.  
Treat me nt C o m plia nce  ................................................................................................4 1  
6. 7.  
C o nc o mita nt T hera p y  .................................................................................................4 2  
6. 7. 1.  
Re q uire d C o nc o mita nt T hera p y  ..................................................................................4 2  
6. 7. 2.  
All o we d C o nc o mita nt T hera p y  ...................................................................................4 2  
6. 7. 2. 1.  
Per mitte d Me dicati o ns f or t he Treat me nt of Ulcerati ve C olitis  .................................4 2  
6. 7. 2. 2.  
C ortic oster oi d Ta per  ...................................................................................................4 2  
6. 7. 2. 3.  
Vacci nes  ......................................................................................................................4 3  
6. 7. 3.  
Pr o hi bite d C o nc o mita nt T hera p y  ................................................................................4 3  
7.  
S U BJ E C T R E S T RI C TI O N S  ......................................................................................4 4  
8.  
S T U D Y T R E A T M E N T M A T E RI A L S A N D M A N A G E M E N T  ..............................4 5  
8. 1.  
Pac ka gi n g a n d La beli n g  ..............................................................................................4 5  
8. 2.  
St u d y Treat me nt St ora ge a n d Ha n dli n g  ......................................................................4 5  
8. 3.  
St u d y Treat me nt Pre parati o n  ......................................................................................4 5  
8. 4.  
St u d y Treat me nt Acc o u nta bilit y  .................................................................................4 5  
8. 5.  
St u d y Treat me nt Rete nti o n a n d Dis p osal  ...................................................................4 5  
9.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ......................................................4 6  
9. 1.  
Ge neral I nstr ucti o ns  ....................................................................................................4 6  
9. 2.  
S u bject I nf or mati o n  ....................................................................................................4 6  
9. 2. 1.  
I nf or me d C o nse nt .......................................................................................................4 6  
9. 3.  
Scree ni n g a n d Eli gi bilit y  ............................................................................................4 6  
9. 3. 1.  
T u berc ul osis Scree ni n g a n d C hest X -Ra y  ..................................................................4 7  
9. 3. 2.  
Rescree ni n g  .................................................................................................................4 7  
9. 3. 3.  
De m o gra p h y a n d Ot her S u bject C haracteristics  .........................................................4 7  
9. 3. 4.  
S ocial Hist or y  .............................................................................................................4 7  
9. 3. 5.  
Pri or a n d O n g oi n g T hera pies  ......................................................................................4 7  
9. 3. 6.  
Ulcerati ve C olitis Hist or y/ Me dical Hist or y  ................................................................4 8  
9. 3. 7.  
Vital Si g ns  ..................................................................................................................4 8  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 6  of 1 0 7  
9. 3. 8.  
P ul m o nar y F u ncti o n Test  ............................................................................................4 8  
9. 3. 9.  
O p ht hal m osc o p y  a n d O ptical C o here nce T o m o gra p h y  ..............................................4 8  
9. 3. 1 0.  
Cli nical La b orat or y Assess me nts  ...............................................................................4 8  
9. 3. 1 1.  
Pr oct osi g m oi d osc o p y/ C ol o n osc o p y a n d M o difie d Ma y o Sc ore Deri vati o n  ..............4 8  
9. 4.  
Ra n d o mizati o n/ Treat me nt Peri o d  ...............................................................................4 9  
9. 4. 1.  
Wee k  0/ Da y  1: Prera n d o mizati o n  ...............................................................................4 9  
9. 4. 2.  
Treat me nt Peri o d  ........................................................................................................4 9  
9. 4. 2. 1.  
G ui da nce f or Car diac M o nit ori n g F oll o wi n g Treat me nt I nitiati o n or 
Re -I nitiati o n ................................................................................................................5 0  
9. 4. 3.  
E nr oll me nt i n O pe n -La bel E xte nsi o n St u d y A P D 3 3 4 -3 0 3  ........................................5 3  
9. 5.  
F oll o w -U p Peri o d  .......................................................................................................5 3  
9. 6.  
Virt ual/ H y bri d Visits  ..................................................................................................5 3  
9. 7.  
P har mac o ki netics  ........................................................................................................5 4  
9. 8.  
Efficac y Assess me nts  .................................................................................................5 5  
9. 8. 1.  
Ma y o Cli nic Sc ore  ......................................................................................................5 5  
9. 8. 2.  
R o barts Hist o pat h ol o g y I n de x  ....................................................................................5 6  
9. 8. 2. 1.  
E n d osc o p y  ...................................................................................................................5 6  
9. 8. 2. 2.  
E n d osc o pic Bi o psies  ...................................................................................................5 6  
9. 8. 3.  
E xtrai ntesti nal Ma nifestati o ns  ....................................................................................5 7  
9. 8. 4.  
A d diti o nal Healt h -Relate d S u bject -Re p orte d O utc o mes  ............................................5 7  
9. 8. 5.  
Efficac y -Relate d Bi o mar kers  ......................................................................................5 8  
.5 9  
9. 9.  
Safet y  ..........................................................................................................................6 0  
9. 9. 1.  
P h ysical E xa mi nati o n  .................................................................................................6 0  
9. 9. 2.  
Vital Si g ns  ..................................................................................................................6 0  
9. 9. 3.  
1 2 -Lea d Electr ocar di o gra m  ........................................................................................6 0  
9. 9. 4.  
H olter Rec or di n g  ........................................................................................................6 1  
9. 9. 5.  
P ul m o nar y F u ncti o n Test  ............................................................................................6 1  
9. 9. 6.  
O p ht hal m osc o p y a n d O ptical C o here nce T o m o gra p h y  ..............................................6 2  
9. 9. 7.  
T u berc ul osis Scree ni n g a n d C hest X -Ra y  ..................................................................6 3  
9. 9. 8.  
Cli nical La b orat or y Tests  ...........................................................................................6 3  
9. 9. 8. 1.  
Scree ni n g  ....................................................................................................................6 6  
9. 9. 8. 2.  
Cli nical C he mistr y, He mat ol o g y, C oa g ulati o n, a n d Uri nal ysis  .................................6 7  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 7  of 1 0 7  
9. 9. 9.  
A d verse E ve nts  ...........................................................................................................6 7  
9. 9. 9. 1.  
Defi niti o ns  ..................................................................................................................6 7  
9. 9. 9. 2.  
Eliciti n g a n d Rec or di n g A d verse E ve nts  ....................................................................7 0  
9. 9. 9. 3.  
Re p orti n g A d verse E ve nts  ..........................................................................................7 1  
9. 9. 1 0.  
Pre g na nc y a n d Lactati o n  .............................................................................................7 2  
9. 9. 1 0. 1.  
Pre g na nc y  ...................................................................................................................7 2  
9. 9. 1 0. 2.  
E x p os ure D uri n g Breastfee di n g  ..................................................................................7 2  
9. 9. 1 1.  
E n vir o n me ntal E x p os ure  ............................................................................................7 2  
9. 9. 1 1. 1.  
D uri n g Pre g na nc y  .......................................................................................................7 2  
9. 9. 1 1. 2.  
D uri n g Breastfee di n g  ..................................................................................................7 3  
9. 9. 1 1. 3.  
Occ u pati o nal  ...............................................................................................................7 3  
9. 9. 1 2 . 
Lac k of Efficac y  .........................................................................................................7 3  
9. 9. 1 3.  
Me dicati o n Err ors  .......................................................................................................7 3  
9. 1 0.  
Pr oce d ures f or O ver d ose  .............................................................................................7 3  
1 0.  
P L A N N E D S T A TI S TI C A L M E T H O D S  ...................................................................7 4  
1 0. 1.  
Ge neral C o nsi derati o ns  ...............................................................................................7 4  
1 0. 2.  
Deter mi nati o n of Sa m ple Size  ....................................................................................7 4  
1 0. 3.  
A nal ysis Sets  ...............................................................................................................7 4  
1 0. 4.  
Missi n g Data  ...............................................................................................................7 5  
1 0. 5.  
Efficac y E n d p oi nt Defi niti o ns  ....................................................................................7 6  
1 0. 5. 1.  
Calc ulati o n of Ma y o Sc ore a n d C o m p o ne nt Sc ores  ...................................................7 7  
1 0. 6.  
Pri mar y E n d p oi nts  ......................................................................................................7 7  
1 0. 7 . 
Sec o n dar y E n d p oi nts  ..................................................................................................7 7  
1 0. 7. 1.  
Ke y Sec o n dar y Efficac y E n d p oi nts  ............................................................................7 7  
1 0. 7. 2.  
Ot her Sec o n dar y Efficac y E n d p oi nts  ..........................................................................7 8  
1 0. 8.  
E x pl orat or y E n d p oi nts  ................................................................................................7 8  
1 0. 8. 1.  
E x pl orat or y Efficac y E n d p oi nts  .................................................................................7 8  
1 0. 9.  
P har mac o ki netic Assess me nts  ....................................................................................7 9  
1 0. 1 0.  
Ot her Assess me nts  ......................................................................................................7 9  
1 0. 1 0. 1.  
Bi o mar ker E n d p oi nts  ..................................................................................................7 9  
1 0. 1 0. 2.  
Healt h -Relate d Q ualit y of Life  ...................................................................................8 0  
1 0. 1 0. 3.  
S u b gr o u p A nal yses  .....................................................................................................8 0  
1 0. 1 1.  
Safet y Assess me nts  .....................................................................................................8 0  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 8  of 1 0 7  
1 0 . 1 1. 1. 
Safet y E n d p oi nts  .........................................................................................................8 1  
1 0. 1 2.  
Testi n g Strate g y  ..........................................................................................................8 1  
1 0. 1 2. 1.  
Efficac y A nal ysis  ........................................................................................................8 1  
1 0. 1 2. 2.  
Safet y A nal ysis  ...........................................................................................................8 1  
1 0. 1 3.  
I nteri m A nal ysis ..........................................................................................................8 1  
1 1.  
E T HI C A L C O N SI D E R A TI O N S  ................................................................................8 2  
1 1. 1.  
Et hical C o n d uct of t he St u d y  ......................................................................................8 2  
1 1. 2.  
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 A p pr o val ..................8 2  
1 1. 3.  
I nf or me d C o nse nt .......................................................................................................8 2  
1 1. 4.  
C o nfi de ntialit y  ............................................................................................................8 3  
1 1. 5.  
Pr ot oc ol C o m plia nce  ..................................................................................................8 3  
1 2.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................8 3  
1 2. 1.  
Trai ni n g of St u d y Site Pers o n nel  ................................................................................8 4  
1 2. 2.  
M o nit ori n g  ..................................................................................................................8 4  
1 2. 3.  
A u dit  ...........................................................................................................................8 4  
1 3.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ......................................................8 4  
1 3. 1.  
Data Ma na ge me nt  .......................................................................................................8 4  
1 3. 1. 1 . 
Case Re p ort F or ms  .....................................................................................................8 4  
1 3. 1. 2.  
S o urce D oc u me nts  ......................................................................................................8 5  
1 3. 2 . 
St u d y D oc u me ntati o n a n d Rec or ds Rete nti o n  ............................................................8 5  
1 3. 3.  
Cli nical St u d y Re p ort  .................................................................................................8 6  
1 3. 4.  
Discl os ure of St u d y Res ults  ........................................................................................8 6  
1 4.  
R E S P O N SI BI LI TI E S  .................................................................................................8 6  
1 4. 1.  
I nvesti gat or Res p o nsi bilities  .......................................................................................8 6  
1 4. 2.  
S p o ns or’s Me dicall y Q ualifie d I n di vi d ual  ..................................................................8 6  
1 4. 3.  
S p o ns or Res p o nsi bilities  .............................................................................................8 7  
1 4. 4.  
Re p orti n g of Safet y Iss ues a n d Seri o us Breac hes of t he Pr ot oc ol or I C H G C P  .........8 7  
1 5.  
R E F E R E N C E S  ...........................................................................................................8 8  
1 6.  
A P P E N DI C E S  ............................................................................................................9 0  
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 9  of 1 0 7  
LI S T O F A P P E N DI C E S  
A P P E N DI X 1:  S C H E D U L E O F A S S E S S M E N T S  ....................................................................9 0  
A P P E N DI X 2:  T U B E R C U L O SI S S C R E E NI N G  .......................................................................9 5  
A P P E N DI X 3:  M A Y O C LI NI C S C O R E –  S A M P L E  ..............................................................1 0 1  
A P P E N DI X 4:  HI S T O L O GI C A L S C O RI N G I N DI C E S  .........................................................1 0 2  
A P P E N DI X 5:  G UI D A N C E F O R T H E A S S E S S M E N T O F P O T E N TI A L 
P R O G R E S SI V E M U L TI F O C A L L E U K O E N C E P H A L O P A T H Y  .........................1 0 3  
A P P E N DI X 6:  LI V E R S A F E T Y: S U G G E S T E D A C TI O N S A N D F O L L O W -U P 
A S S E S S M E N T S  .......................................................................................................1 0 4  
A P P E N DI X 7:  I N V E S TI G A T O R SI G N A T U R E .....................................................................1 0 6  
A P P E N DI X 8:  S P O N S O R SI G N A T U R E  ................................................................................1 0 7  
LI S T O F T A B L E S  
Ta ble  1:  
St u d y Treat me nt  ..........................................................................................................3 9  
Ta ble 2:  
Pr oce d ures t o be Perf or me d D uri n g t he M o nit ori n g Peri o d  .......................................5 1  
Ta ble 3:  
Disc har ge Criteria After Car diac M o nit ori n g  .............................................................5 1  
Ta ble  4:  
Disc o nti n uati o n of St u d y Treat me nt Relate d t o P ost -D ose Car diac 
M o nit ori n g  ..................................................................................................................5 2  
Ta ble  5:  
Cli nical La b orat or y Tests  ...........................................................................................6 5  
Ta ble  6:  
Sc he d ule of Assess me nts  ............................................................................................9 0  
LI S T O F FI G U R E S  
Fi g ur e 1:  
St u d y Desi g n  ...............................................................................................................2 8  
Fi g ure  2:  
Pr o gressi ve M ultif ocal Le u k oe nce p hal o pat h y Case E val uati o n Al g orit h m  .............1 0 3  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
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Pa ge 2 0  of 1 0 7  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S   
A b bre vi ati o n  
Defi niti o n  
A D L  
acti vities of dail y li vi n g  
A D R  
a d verse dr u g reacti o n  
AI D S  
ac q uire d i m m u ne deficie nc y s y n dr o me  
A L C  
a bs ol ute l y m p h oc yte c o u 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 nt  
A P D 3 3 4  
etrasi m o d  
5 -A S A  
5 -a mi n osalic ylic aci d  
A S T  
as partate a mi n otra nsferase  
A V  
atri o ve ntric ular  
A Z A  
azat hi o pri ne  
β -h C G  
beta -h u ma n c h ori o nic g o na d otr o pi n  
B P  
bl o o d press ure  
b p m  
beats per mi n ute  
C B C  
c o m plete bl o o d c o u nt  
C D  
Cr o h n’s disease  
C F R  
C o de of Fe deral Re g ulati o ns  
C GI  
Cli nical Gl o bal I m pressi o ns 
c G M P  
c urre nt G o o d Ma n ufact uri n g Practices  
CI  
c o nfi de nce i nter val  
C M H  
C oc hra n -Ma ntel -Hae nszel  
C M P  
Cli nical M o nit ori n g Pla n  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C R O  
c o ntract researc h or ga nizati o n  
C R P  
C -reacti ve pr otei n 
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  
DI LI  
dr u g i n d uce d li ver i nj ur y  
D L C O  
diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de  
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  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 1  of 1 0 7  
A b bre vi ati o n  
Defi niti o n  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E D B  
e x p os ure d uri n g breastfee di n g  
e Diar y  
electr o nic diar y  
E D P  
e x p os ure d uri n g pre g na nc y  
EI Ms  
e xtrai ntesti nal ma nifestati o ns  
E S  
e n d osc o pic sc ore  
E T  
earl y ter mi nati o n  
F A CI T -F  
F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y -Fati g ue  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F E V 1 
f orce d e x pirat or y v ol u me i n 1 sec o n d  
F V C  
f orce d vital ca pacit y 
G C P  
G o o d Cli nical Practice  
H b A 1c  
he m o gl o bi n A 1c  
H Bs A g  
he patitis  B s urface a nti ge n  
H B V  
he patitis  B vir us  
H C V  
he patitis  C vir us  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
heart rate  
H R Q o L  
healt h -relate d q ualit y of life 
hs -C R P  
hi g h -se nsiti vit y C-reacti ve pr otei n 
I B 
I n vesti gat or’s 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 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 nisati 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 
I G R A 
i nterfer o n-ga m ma release assa y  
I OI B D 
I nter nati o nal Or ga nizati o n f or t he St u d y of I nfla m mat or y B o wel Diseases  
I N D 
I n vesti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 2  of 1 0 7  
A b bre vi ati o n  
Defi niti o n  
I U D 
i ntra uteri ne de vice 
I V 
i ntra 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 
6 -M P  
6 -merca pt o p uri ne  
M A R  
missi n g at ra n d o m  
M D R  
m ulti -dr u g resista nt  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m F A S  
m o difie d F ull A nal ysis Set  
M M F  
m yc o p he n olate m ofetil  
M M S  
m o difie d Ma y o S c ore 
M QI  
me dicall y q ualifie d i n di vi d ual  
N F  
Nati o nal F or m ular y  
N R S  
n u meric rati n g scale  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g 
O C T  
o ptical c o here nce t o m o gra p h y  
O L E  
O pe n -La bel E xte nsi o n  
P F T  
p ul m o nar y f u ncti o n test  
P G A  
P h ysicia n’s Gl o bal Assess me nt  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P h. E ur.  
E ur o pea n P har mac o p oeia  
P K  
p har mac o ki netics  
P M L  
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
P P D  
p urifie d pr otei n deri vati ve  
Q Tc F  
Fri dericia’s c orrecte d Q T i nter val  
R B  
rectal blee di n g 
R HI  
R o barts Hist o pat h ol o g y I n de x  
R N A  
ri b o n ucleic aci d 
S 1 P  
s p hi n g osi ne 1-p h os p hate  
S 1 P 1 
s p hi n g osi ne 1-p h os p hate rece pt or 1  
S A E  
seri o us a d verse e ve nt 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 3  of 1 0 7  
A b bre vi ati o n  
Defi niti o n  
S A P  
Statistical A n al ysis Pla n  
S A R S -C o V -2  
se vere ac ute r es pirat or y s y n dr o me c or o na vir us 2  
S F  
st o ol fre q ue nc y 
S F -3 6  
Me dical O utc o mes St u d y 3 6 -Ite m S h ort F or m Healt h S ur ve y 
S O P  
sta n dar d o perati n g pr oce d ure 
T B  
t u berc ul osis 
T M F  
Trial Master File  
T M S  
T otal Ma y o Cli nic sc ore  
T N F  
t u m or necr osis fact or 
T N F α  
t u m or necr osis fact or al p ha 
T S T  
t u berc uli n s ki n test 
U C  
ulcerati ve c olitis  
U C -1 0 0  
ulcerati ve c olitis 1 0 0  
U C -P R O  
Ulcerati ve C olitis Patie nt -Re p orte d O utc o mes  
U C -P R O/ S S  
Ulcerati ve C olitis Patie nt -Re p orte d O utc o mes Si g ns a n d S y m pt o ms  
U L N  
u p per li mit of n or mal 
U S  
U nite d States  
U S P  
U nite d States P har mac o peia  
W B C  
w hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
W P AI -U C  
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire –  Ulcerati ve C olitis  
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 4  of 1 0 7  
1.  
I N T R O D U C TI O N  
1. 1.  
Ulcer ati ve C olitis   
I nfla m mat or y b o wel disease (I B D) descri bes c o n diti o ns wit h c hr o nic or rec urri n g i m m u ne 
res p o nse a n d i nfla m mati o n of t he gastr oi ntesti nal tract. T here are 2 maj or t y pes of I B D: Cr o h n’s 
disease ( C D) a n d ulcerati ve c olitis ( U C). T hese are c hr o nic rec urre nt, re mitte nt, or pr o gressi ve 
i nfla m mat or y c o n diti o ns t hat ma y affect t he e ntire gastr oi ntesti nal tract ( C D) or t he c ol o nic 
m uc osa ( U C), a n d are ass ociate d wit h a n i ncrease d ris k f or c ol o n ca ncer (Kaser 2 0 1 0 ). 
Ulcerati ve c olitis is c haracterize d b y diff use m uc osal i nfla m mati o n li mite d t o t he c ol o n a n d 
i n v ol ves t he rect u m i n a p pr o xi matel y 9 5 % of cases a n d i nfla m mati o n ma y e xte n d pr o xi mall y i n 
a s y m metrical, circ u mfere ntial, a n d u ni nterr u pte d patter n t o i n v ol ve pa rts or all of t he lar ge 
i ntesti ne (K or n bl ut h 2 0 1 0 ). S y m pt o ms f or U C ca n var y, de pe n di n g o n t he l ocati o n a n d se verit y 
of i nf la m mati o n, b ut s o me of t he m ost c o m m o n are diarr hea, a b d o mi nal cra m ps, a n d rectal 
blee di n g  ( R B). T he hall mar k cli nical s y m pt o m is bl o o d y diarr hea ofte n wit h pr o mi ne nt 
s y m pt o ms of rectal ur ge nc y a n d te nes m us (K or n bl ut h 2 0 1 0 ). U C is a pr o gressi ve disease w hic h, 
if n ot o pti mall y treate d, ca n lea d t o seri o us c o m plicati o ns i ncl u di n g hi g h rates of c olect o m y a n d 
m or bi dit y (Hi n dr yc k x 2 0 1 8 ). 
Ulcerati ve  c olitis se verit y is ge nerall y cate g orize d o n a s pectr u m as mil d -m o derate a n d 
m o derate -se vere disease acti vit y. Patie nts wit h mil d-m o derate disease w h o ha ve m ore fre q ue nt 
b o wel m o ve me nts, m ore pr o mi ne nt rectal blee di n g, or greater o verall i nfla m mat or y b ur d e n ma y 
be c haracterize d as ha vi n g m o derate disease (K o 2 0 1 9 ). 
Treat me nt f or s u bjects wit h U C is ge nerall y f or s y m pt o matic care (relief of s y m pt o ms) a n d 
e n d osc o pic i m pr o ve me nt a n d i ncl u des 5  maj or classes of me dicati o ns: 5 -a mi n osalic ylic aci d 
( 5-A S A), a nti bi otics, c ortic oster oi ds, i m m u n o m o d ulat ors, bi ol o gic t hera pies (e g, t u m or necr osis 
fact or [ T N F] i n hi bit ors a n d a nti-i nte gri ns) a n d m ost rece ntl y Ja n us ki nase (J A K) i n hi bit or 
t hera p y. T hese treat me nts ma y be prescri be d i n a “ste p-u p” a p pr oac h, wit h escalati o n of t he 
me dical re gi me n u ntil a res p o nse is ac hie ve d, or a “ste p -d o w n” ma n ner, wit h i nitiati o n of 
treat me nt wit h bi ol o gics a n d i m m u n o m o d ulat ors (R o we 2 0 2 0 ). 
T here re mai ns a n u n met me dical nee d f or m ore t olera ble, orall y a d mi nistere d t hera pies f or t he 
treat me nt of U C, partic ularl y, as ma n y patie nts treate d wit h bi ol o gic t hera pies e x perie nce 
si g nifica nt pri mar y n o nres p o nse or i na de q uate res p o nse a n d i m m u n o ge nicit y. M ore o ver, t he 
bi ol o gic t hera pies a n d t he ne wer oral a d va nce d t hera pies are als o ass ociate d wit h si g nifica nt 
a d verse e ve nts (Oli vera 2 0 1 7 , U n gar 2 0 1 6 ). 
1. 2.  
Etr asi m o d   
Etrasi m o d ( A P D 3 3 4) is a n orall y a d mi nistere d, selecti ve, s y nt hetic s p hi n g osi ne 1 -p h os p hate 
( S 1 P) rece pt or 1, 4, 5 m o d ulat or t hat is bei n g de vel o pe d t o treat i m m u ne -me diate d i nfla m mat or y 
dis or ders, i ncl u di n g U C.  
T he S 1 P 1 (s p hi n g osi ne 1-p h os p hate rece pt or 1) is a cell s urface e x presse d pr otei n t hat has bee n 
s h o w n t o re g ulate l y m p h oc yte mi grati o n o ut of l y m p h oi d tiss ues (Bri n k ma n n 2 0 1 0 ). S y nt hetic 
s mall m olec ule S 1 P 1 a g o nists ha ve bee n o bser ve d t o act as f u ncti o nal a nta g o nists b y i n d uci n g 
s ustai ne d rece pt or i nter nalizati o n, t h us i n hi biti n g l y m p h oc yte mi grati o n o ut of l y m p h oi d tiss ues 
a n d l o weri n g t he a m o u nt of peri p heral bl o o d l y m p h oc ytes a vaila ble t o be recr uite d t o  sites of 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 5  of 1 0 7  
i nfla m mati o n. M o d ulati o n of t he S 1 P/ S 1 P rece pt or a xis is t h o u g ht t o be a p ote ntial t hera pe utic 
a p pr oac h t o t he ma na ge me nt of i m m u ne -me diate d i nfla m mat or y dis or ders (Nielse n 2 0 1 7 ); as 
s uc h, etrasi m o d is e x pecte d t o p ote ntiall y pr o vi de t hera pe utic be nefit t o patie nts wit h U C. A 
P hase  2 st u d y wit h etrasi m o d i n s u bjects wit h m o deratel y t o se verel y acti ve U C de m o nstrate d 
c o nsiste nt a n d cli nicall y mea ni n gf ul i m pr o ve me nts i n e n d p oi nt mea s ures reflecti n g car di nal 
s y m pt o ms of U C a n d o bjecti ve fi n di n gs of e n d osc o pic i m pr o ve me nt (Sa n d b or n 2 0 2 0 ). I n t w o 
rece ntl y c o m plete d P hase 3 st u dies ( A P D 3 3 4‑ 3 0 1 a n d A P D 3 3 4‑ 3 0 2), treat me nt wit h 
etrasi m o d  2  m g res ulte d i n sta tisticall y si g nifica nt a n d cli nicall y mea ni n gf ul i m pr o ve me nts base d 
o n cli nical, e n d osc o pic, s y m pt o matic, a n d e n d o -hist ol o gic e n d p oi nts i n a d ults wit h m o deratel y t o 
se verel y acti ve U C. N o ne w safet y fi n di n gs were o bser ve d wit h etrasi m o d 2 m g treat me nt f or  u p 
t o 5 2 wee ks (Sa n d b or n 2 0 2 2 ). A n  O pe n -La bel E xt e nsi o n ( O L E) st u d y ( St u d y A P D 3 3 4 -3 0 3) t o 
e val uate t he l o n g-ter m efficac y a n d safet y of etrasi m o d i n s u bjects wit h m o deratel y t o se verel y 
acti ve U C is c urre ntl y o n g oi n g. Refer t o t he c urre nt e diti o n of t he I nvesti gat or’s Br oc h ure (I B) 
f or a c o m plete s u m mar y of t he cli nical a n d n o ncli nical data rele va nt t o t he i n vesti gati o nal 
pr o d uct a n d its st u d y i n h u ma n s u bjects.  
1. 3.  
Be nefit/ Ris k Assess me nt   
C o nsi deri n g t he si g nifica nt u n met nee d f or safe a n d effecti ve, orall y a d mi nistere d treat me nts f or 
U C, etrasi m o d ma y p ote ntiall y pr o vi de t hera pe utic be nefit via S 1 P rece pt or m o d ulati o n.  
A d verse e ve nts t hat ha ve bee n re p orte d wit h S 1 P rece pt or m o d ulat ors i ncl u de bra d ycar dia at t he 
first d ose or atri o ve ntric ular ( A V) bl oc k, mac ular e de ma, h y perte nsi o n, hea dac he, c o u g h, 
d ys p nea, bac k pai n, i nfl ue nza, a n d diarr hea.  
Safet y a n d t olera bilit y of etrasi m o d has bee n e val uate d i n P hase  1 st u dies wit h heal t h y a d ult 
s u bjects at si n gle d oses u p t o 5 m g a n d re peate d d oses u p t o 4  m g o nce dail y. Re peate d d oses of 
2  m g ha ve bee n e val uate d i n P hase  2 st u dies of s u bjects wit h m o deratel y t o se verel y acti ve U C 
(refer t o t he c urre nt e diti o n of t he I B). Etrasi m o d was f o u n d t o be safe a n d well t olerate d i n t hese 
st u dies, wit h n o cli nicall y si g nifica nt safet y c o ncer ns wit h res pect t o vital si g ns, 
electr ocar di o gra ms ( E C Gs), p ul m o nar y f u ncti o n tests ( P F Ts), o p ht hal m osc o p y, or cli nical 
la b orat or y tests. Etrasi m o d pr o d uce d a d ose -de pe n de nt s ustai ne d decrease i n t otal l y m p h oc yte 
c o u nt, w hic h is e x pecte d gi ve n etrasi m o d’s mec ha nis m of acti o n. L y m p h oc yte c o u nts were  
wit hi n n or mal li mits b y 7  da ys after t he last d ose.  
Detaile d i nf or mati o n re gar di n g t he k n o w n a n d e x pecte d be nefits  a n d ris ks a n d reas o na bl y 
e x pecte d a d verse e ve nts of etrasi m o d ca n be f o u n d i n t he I B , w hic h ser ves as a si n gle refere nce 
safet y d oc u me nt f or t his st u d y. 
Base d o n t he mec ha nis m of acti o n of etrasi m o d a n d pri or e x perie nce wit h ot her a ge nts acti n g via 
a si milar mec ha nis m, m o nit ori n g f or s pecific safet y para meters are pla n ne d f or t his st u d y, w hic h 
i ncl u de a usc ultati o n of t he l u n gs as part of t he p h ysical e xa m, P F Ts; e xcl usi o n of s u bjects wit h 
mac ular e de ma or reti n o pat h y, wit h assess me nt of o ptical c o here nce t o m o gra p h y ( O C T) 
occ urri n g t hr o u g h o ut t he st u d y; a n d e xcl usi o n of s u bjects wit h certai n car diac ris ks, wit h 
assess me nt of vital si g ns i n t he peri o d f oll o wi n g d osi n g.  
•  A usc ultati o n of l u n gs will be c o n d ucte d as part of t he p h ysical e xa mi nati o n  
•  Pr os pecti ve s u b jects wit h a hist or y of mac ular e de ma or reti n o pat h y will be e xcl u de d 
fr o m t he st u d y. All ra n d o mize d s u bjects will be assesse d b y O C T at st u d y e ntr y, 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 6  of 1 0 7  
peri o dicall y t hr o u g h o ut t he treat me nt peri o d, a n d as cli nicall y i n dicate d a n y ti me 
d uri n g t he st u d y  
•  S u bjec ts wit h certai n car diac ris ks will als o be e xcl u de d fr o m t he st u d y. Ra n d o mize d 
s u bjects will be m o nit ore d f or a peri o d f oll o wi n g d osi n g, a n d vital si g ns will be 
assesse d f or deter mi nati o n of t he s u bject’s healt h bef ore disc har ge. S u bjects re q uiri n g 
f oll o w-u p m o nit ori n g will be e val uate d i n t he cli nic u ntil car diac varia nces ret ur n t o 
acce pta ble le vels  
Base d o n t he n o ncli nical a n d cli nical data t hat has bee n ge nerate d fr o m etrasi m o d st u dies a n d t he 
preca uti o ns o utli ne d a b o ve, t he be nefit/ris k assess me nt j ust ifies t he assess me nt of etrasi m o d i n 
s u bjects wit h m o deratel y acti ve U C i n t he c urre nt P hase 2 st u d y.  
T he c urre nt st u d y is a P hase  2 m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y 
t o e val uate t he efficac y a n d safet y of etrasi m o d i n s u bjects wit h m o deratel y acti ve U C. S u bjects 
w h o c o m plete t he t otal 5 2 -wee k treat me nt or s u bjects wit h w orse ni n g disease after t he Wee k  1 2 
visit assess me nts ( Secti o n  5. 1. 1 ) ma y ha ve t he o p p ort u nit y t o e nr oll i nt o a n O pe n-La bel 
E xte nsi o n ( O L E) st u d y t hat will pr o vi de a d diti o nal i nf or mati o n o n t he l o n g -ter m efficac y a n d 
safet y of etrasi m o d. 
2.  
S T U D Y O B J E C TI V E S   
2. 1.  
Pri m ar y O bjecti ve   
T he pri mar y o bjecti ve is t o assess t he efficac y of etrasi m o d o n cli nical re missi o n i n s u bjects wit h 
m o deratel y acti ve U C after 5 2  wee ks of treat me nt.  
2. 2.  
Sec o n d ar y O bjecti ve   
T he sec o n dar y o bjecti ve is t o assess t he efficac y of etrasi m o d o n e n d osc o pic i m pr o ve me nt, 
hist ol o gic res p o nse, cli nical res p o nse, a n d s y m pt o matic re missi o n,  at ti me p oi nts u p t o 5 2 wee ks 
of treat me nt.  
2. 3.  
S afet y O bjecti ve   
T he safet y o bjecti ve is t o assess t he l o n g -ter m safet y of etrasi m o d after dail y d oses of 2 m g f or 
u p t o 5 2  wee ks.  
2. 4.  
Ot her O bjecti ves   
Ot her o bjecti ves i nc l u de e val uati o n of etrasi m o d p har mac o ki netics ( P K) a n d t he effect of 
etrasi m o d o n healt h -relate d s u bject-re p orte d o utc o mes a n d bi o mar kers. 
3.  
I N V E S TI G A TI O N A L P L A N  
3. 1.  
S u m m ar y of St u d y D esi g n   
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o e val uate t he efficac y 
a n d safet y of etrasi m o d 2  m g i n s u bjects wit h m o deratel y acti ve U C. T he s t u d y c o nsists of a 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 7  of 1 0 7  
2 8 -Da y Scree ni n g Peri o d, a 5 2-W ee k treat-t hr o u g h desi g n c o nsisti n g of  a 1 2-Wee k Treat me nt 
Peri o d  a n d a 4 0-Wee k Treat me nt Peri o d, a n d a 4 -Wee k F oll o w -U p Peri o d  ( wit h 2 visits) 
(Fi g ure  1 ). 
N ote: Pri or t o t he c o m pleti o n of St u dies A P D 3 3 4 -3 0 1 a n d A P D 3 3 4 -3 0 2, s u bject recr uit me nt f or 
St u d y A P D 3 3 4 -2 1 0 was o nl y c o nsi dere d fr o m t he p o p ulati o n t hat di d n ot meet t he disease 
acti vit y eli gi bilit y criteria f or t h ose P hase 3 st u dies.  
T he tar get s u bject p o p ulati o n will i ncl u de:  
1.  S u bjects w h o ha ve ha d a n i na de q uate res p o nse t o, l oss of res p o nse t o, or i nt olera nce t o 
c o n ve nti o nal t hera p y a n d are naï ve t o bi ol o gic or J A K i n hi bit or t hera p y  
2.  S u bjects w h o ha ve ha d a n i na de q uate res p o nse t o, l oss of res p o nse t o, or i nt olera nce t o a 
bi ol o g ic or J A K i n hi bit or (s u bjects i n t his cate g or y ma y ha ve recei ve d pri or c o n ve nti o nal 
t hera p y) 
S u bject eli gi bilit y will be deter mi ne d d uri n g a Scree ni n g Peri o d of 4  wee ks ( 2 8  da ys). E ntr y 
criteria will be base d o n c o nfir mati o n of m o deratel y acti ve U C, defi ne d b y a m o difie d Ma y o 
sc ore ( M M S) of 4 t o 6 i ncl u di n g a n e n d osc o pic sc ore ( E S)  ≥ 2  a n d rectal blee di n g 
( R B) sc ore ≥ 1 . 
Eli gi ble s u bjects will be ra n d o mize d ( 2: 1  rati o) t o recei ve eit her etrasi m o d ( 2 m g o nce dail y) or 
matc hi n g place b o ( o nce dail y) i n a d o u ble -bli n d fas hi o n f or u p t o 5 2  wee ks  ( 1 2-Wee k Treat me nt 
Peri o d + 4 0 -Wee k Treat me nt Peri o d) . Ra n d o mizati o n will be stratifie d b y (a) naï ve t o bi ol o gic or 
J A K i n hi bit or t hera p y at st u d y e ntr y ( yes  or  n o)  a n d ( b) baseli ne c ortic oster oi d use ( yes  or  n o).  
3. 1. 1.  
E n d of 1 2 -Wee k D o u ble -Bli n d Tre at me nt Peri o d   
At t he e n d of t he 1 2 -Wee k Treat me nt Peri o d, s u bjects will u n der g o t he Wee k  1 2 efficac y a n d 
safet y assess me nts a n d pr oce d ures. S u bjects w h ose U C c o n diti o n i n t he o pi ni o n of t he 
I n vesti gat or is sta ble or i m pr o vi n g c o m pare d wit h baseli ne ( Wee k 0/ Da y  1) will c o nti n ue wit h 
t heir d o u ble-bli n d treat me nt a n d m o ve i nt o t he 4 0 -Wee k Treat me nt Peri o d.  
S u bjects w h ose U C c o n diti o n i n t he o pi ni o n of t he  I n vesti gat or has n ot i m pr o ve d or has 
w orse ne d, c o m pare d wit h baseli ne ( Wee k  0/ Da y  1) , ma y be eli gi ble t o e nr oll i n t he O L E  stu d y . 
S u bjects m ust c o m plete Wee k 1 2 t o be c o nsi dere d  f or t he O L E st u d y ( St u d y A P D 3 3 4-3 0 3) . 
Disease w orse ni n g will c o nti n ue t o be m o nit ore d b y I n vesti gat ors t hr o u g h t he 4 0 -Wee k 
Treat me nt Peri o d (ie, fr o m Wee ks  1 3  t o 5 2). S u bjects w h o , i n t he o pi ni o n of t he I n vesti gat or, 
e x perie nce disease w orse ni n g i n t he 4 0 -Wee k Treat me nt Peri o d or s u bjects w h o c o m plete all 
st u d y pr oce d ures at Wee k  5 2 will ha ve t he o pti o n t o e nr oll i nt o t he O L E st u d y if t he y meet all 
eli gi bilit y criteria.  
S u bjects ma y be eli gi ble t o e nr oll i n t he O L E pr o vi de d t heir E S is ≥ 2 a n d t he y meet 1 of t he 
f oll o wi n g e ntr y criteria: 
•  R B s u bsc ore  ≥ 2 at 2  ti me p oi nts at least 7 da ys a n d n o m ore t ha n 1 4  da ys a part  
•  R B  +  st o ol fre q ue nc y ( S F) s u bsc ores ≥ 4 at 2  ti me p oi nts at least 7 da ys a n d n o m ore 
t ha n 1 4 da ys a part  
•  R B s u bsc ore ≥ 2 or R B + S F s u bsc ores  ≥ 4 (i n a n y or der) at 2  ti me p oi nts at least 
7  da ys a n d n o m ore t ha n 1 4  da ys a part 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 8  of 1 0 7  
F or s u bjects disc o nti n ui n g pri or t o Wee k  5 2, a n e n d osc o pic e val uati o n is re q uire d t o c o nfir m 
eli gi bilit y f or t he O L E. A n e n d osc o p y s h o ul d be perf or me d u p o n t he a p peara nce of U C s y m pt o m 
w orse ni n g b ut n o m ore t ha n 1 4  da ys after t he sec o n d ti me p oi nt f or  s y m pt o m criteria a b o ve. 
A  pr oct osi g m oi d osc o p y d oes n ot nee d t o be re peate d if perf or me d wit hi n t he last 4  wee ks.  
S u bjects w h o d o n ot partici pate i n t he O L E st u d y will ha ve 2 -Wee k a n d 4 -Wee k F oll o w -U p 
visits after t heir last treat me nt a d mi nistrati o n ( Ta ble  6 ). 
3. 1. 2.  
E n d of 4 0 -Wee k D o u ble -Bli n d Tre at me nt Peri o d   
At t he e n d of t he 4 0 -Wee k Treat me nt Peri o d (ie, Wee k  5 2) a n d f oll o wi n g c o m pleti o n of all st u d y 
pr oce d ures, s u bjects will ha ve t he o pti o n t o e nter i nt o t he O L E st u d y ( St u d y  A P D 3 3 4 -3 0 3) 
pr o vi de d t he y meet all eli gi bilit y criteria.  
S u bjects w h o d o n ot partici pate i n t he O L E st u d y wi ll ha ve 2-Wee k a n d 4 -Wee k F oll o w -U p 
visits after t heir last o n -treat me nt visit/Earl y Ter mi nati o n  (E T ) visit ( A p pe n di x  1 , Ta ble  6 ). 
Fi g ure  1 : 
St u d y Desi g n   
 
J A K, Ja n us ki nase; U C, ulcerati ve c olitis 
3. 2.  
R ati o n ale f or St u d y Desi g n   
T his st u d y is desi g ne d t o e val uate t he efficac y a n d safet y of etrasi m o d i n s u bjects wit h 
m o deratel y acti ve U C. T he p r ot oc ol was  a me n de d t o versi o n 2 . 0 t o better  ali g n wit h t he 
A pril  2 0 2 2  F D A draft g ui da nce o n t he de vel o p me nt of dr u gs t o treat ulcerati ve c olitis w hic h 
s u g gests t he p o p ulati o n of mil dl y t o m o deratel y acti ve U C i ncl u de s u bjects wit h a sc ore of at 
least 4 o n t he M M S, i ncl u di n g a n e n d osc o p y s u bsc ore of at least 2 a n d an  R B  s u bsc ore of at 
least 1  (F D A 2 0 2 2 ). T his st u d y will e nr oll s u bjects wit h an  M M S of 4 t o 6 a n d E S ≥ 2  a n d R B 
sc ore ≥ 1.  T he a bilit y t o assess etrasi m o d i n t his p o p ulati o n will hel p f urt her t he u n dersta n di n g of 
t he a p pr o priate ma na ge me nt of U C acr oss a br oa der s pectr u m of disease acti vit y.  
S u bjects ma y c o nti n ue e xisti n g n o n bi ol o gic t hera p y f or U C (e g, 5 -A S A, c ortic oster oi ds) per t he 
c o nc o mita nt me dicati o n a n d sta ble d ose criteria. As pree xisti n g bac k gr o u n d t hera p y is all o we d, a 
place b o c o m parat or is j ustifie d.  
T he d urati o n of st u d y treat me nt is u p t o 5 2  wee ks, w hic h i ncl u des 1 2 -Wee k a n d 4 0 -Wee k 
Treat me nt Peri o ds. T he 4 0 -Wee k Treat me nt Peri o d is e x pecte d t o pr o vi de a de q uate ti me f or 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 2 9  of 1 0 7  
se parati o n of efficac y effects bet wee n etrasi m o d a n d place b o. T he 2-Wee k a n d 4 -Wee k 
F oll o w -U p visits will pr o vi de off -treat me nt safet y i nf or mati o n. 
T he etrasi m o d d ose of 2  m g o nce dail y is base d o n fi n di n gs of pre vi o us P hase  1 a n d P hase  2 
st u dies, a n d i n partic ular data fr o m t he P hase 2 A P D 3 3 4 -0 0 3 place b o -c o ntr olle d st u d y. I n t he 
A P D 3 3 4 -0 0 3 st u d y, s u bjects recei ve d etrasi m o d 1  m g, etrasi m o d 2  m g, or place b o (Sa n d b or n 
2 0 2 0 ). S u bjects i n t he etrasi m o d 2 m g gr o u p e x perie nce d a statisticall y si g nifica nt i m pr o ve me nt 
i n t he pri mar y e n d p oi nt, t he mea n differe nce fro m place b o at Wee k  1 2 i n t he m o difie d  Ma y o 
Sc ore (least s q uares mea n [sta n dar d err or] differe nce: −0. 9 9 [ 0. 4 2]; p  =  0. 0 0 9 1) c o m pare d wit h  
place b o. T he etrasi m o d 2  m g gr o u p als o e x perie nce d si g nifica nt i m pr o ve me nt i n all sec o n dar y 
e n d p oi nts c o m pare d wit h t h e place b o gr o u p at Wee k  1 2 i ncl u di n g, i m pr o ve me nt i n t he t otal 
Ma y o Sc ore (esti mate d least s q uares mea n [sta n dar d err or] differe nce fr o m place b o: −1. 2 7 
[ 0. 5 5]; p =  0. 0 1 0 0), a n d hi g her perce nta ge of s u bjects wit h e n d osc o pic i m pr o ve me nt ( 4 1. 8 %, 
differe nce fr o m place b o: 2 4. 4 %, p  =  0. 0 0 3).  
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) i n t he 1  m g, 2  m g, a n d place b o gr o u ps were 
re p orte d f or 5 9. 6 %, 5 6. 0 %, a n d 5 0. 0 % of s u bjects, res pecti vel y; treat me nt-relate d T E A Es were 
re p orte d f or 7. 7 %, 1 0. 0 %, a n d 5. 6 % of s u bjects, res pecti vel y; seri o us a d verse e ve nts ( S A Es) 
were re p orte d f or 5. 8 %, 0 %, a n d 1 1. 1 % of s u bjects, res pecti vel y; a n d T E A Es lea di n g t o 
disc o nti n uati o n of st u d y treat me nt were re p orte d f or 5. 8 %, 8. 0 %, a n d 0 % of s u bjects, 
res pecti vel y. N o s u bjects die d d uri n g t he st u d y. O verall, t he 2  m g d ose de m o nstrate d a fa v ora ble 
safet y pr ofile a n d was c h ose n as t he d ose f or t he c urre nt P hase 2 pr o gra m.  
T he pri mar y e n d p oi nt of cli nical re missi o n at Wee k  5 2 , as assesse d usi n g t he m o difie d  Ma y o 
S c ore ( M M S), is a sta n dar d, wi del y use d i n de x. I n t his st u d y, clinical re missi o n  a n d res p o nse  
e n d p oi nts , u nless ot her wise n ote d, will be base d o n M M S. Ot her e n d p oi nts f or t he st u d y are 
wi del y use d a n d c o nsi dere d relia ble meas ures of efficac y a n d safet y.  
As detaile d i n Secti o n  1 0. 2 , t he st u d y is p o were d t o t he pri mar y e n d p oi nt f or de m o nstrati n g a 
statisticall y si g nifica nt differe nce i n cli nical re missi o n bet ween etrasi m o d t hera p y a n d place b o at 
Wee k  5 2 . T he 2: 1 ra n d o mizati o n sc he me will ma xi mize t he n u m ber of s u bjects recei vi n g a 
p ote ntiall y be neficial t hera p y.  
S u bjects meeti n g pre defi ne d eli gi bilit y criteria fr o m t he e n d of t he 1 2 -Wee k Treat me nt Peri o d 
a n d d uri n g t he 4 0 -Wee k Treat me nt Peri o d will be eli gi ble t o e nter t he A P D 3 3 4 -3 0 3 O L E st u d y 
( Secti o n 5. 1. 1 ). 
3. 3.  
St u d y D ur ati o n   
T he st u d y c o nsists of a 2 8 -Da y Scree ni n g Peri o d, a 1 2 -Wee k Treat me nt Peri o d, a 4 0 -Wee k 
Treat me nt Peri o d, a n d a 4 -Wee k F oll o w -U p Peri o d  ( wit h 2 visits). T he st u d y d urati o n is 
e x pecte d t o be a p pr o xi matel y 3. 5  years.  
T he E n d of St u d y is t he date w he n t he last s u bject c o m pletes his/ her last st u d y visit.  
3. 4.  
I n de pe n de nt D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C ) will be utilize d t o m o nit or t he safet y of 
s u bjects a n d t o e n ha nce t he i nte grit y a n d cre di bilit y of t he st u d y. T he r oles a n d res p o nsi bilities of 
t he D M C are descri be d i n detail i n t he D M C C harter. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 0  of 1 0 7  
T he D M C will a bi de b y t he pri nci ples set f ort h i n t he F D A G ui da nce f or I n d ustr y, Cli nic al Tri al 
S p o ns ors, Est a blis h me nt a n d O per ati o n of Cli nic al Tri al D at a M o nit ori n g C o m mittees  (F D A 
2 0 0 6 ). As part of its r ole, t he D M C will c o n d uct re vie ws of acc u m ulati n g safet y a n d efficac y 
data at s pecifie d i nter vals d u ri n g t he c o n d uct of t he trial, acc or di n g t o t he g ui deli nes detaile d i n 
t he D M C C harter. D M C rec o m me n dati o ns t o t he st u d y tea m will be c o m m u nicate d i n a bli n de d 
fas hi o n (ie, treat me nt assi g n me nt f or i n di vi d ual s u bjects will n ot be s hare d). T o e ns ure t he 
scie ntific i nte grit y of t he st u d y, me m bers of t he D M C will n ot be directl y i n v ol ve d i n t he 
o n g oi n g ma na ge me nt of t he st u d y.  
I n a d diti o n t o me m bers of t he D M C, a n i n de pe n de nt statisticia n res p o nsi ble f or i nteracti n g wit h 
t he D M C will ha ve access t o u n bli n de d st u d y data. T his statisticia n will n ot be directl y i n v ol ve d 
i n t he c o n d uct of t he st u d y. 
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N   
N ote: Pri or t o t he c o m pleti o n of St u dies A P D 3 3 4 -3 0 1 a n d A P D 3 3 4 -3 0 2, eli gi bilit y assess me nts 
perf or me d d uri n g t he Scree ni n g Peri o d f or t hese st u dies , if c o m plete d wit hi n 2 8 da ys pri or t o t he 
ra n d o mizati o n i n St u d y A P D 3 3 4-2 1 0 , were use d t o assess eli gi bilit y i n t his st u d y . 
4. 1.  
I ncl usi o n Criteri a  
S u bjects m ust meet A L L of t he f oll o wi n g i ncl usi o n criteria t o be  eli gi ble f or e nr oll me nt i nt o t he 
st u d y: 
1.  Me n or w o me n 1 8  t o 8 0  years of a ge, i ncl usi ve, at t he ti me of c o nse nt (asse nt i n c o u ntries 
w here re q uire d per l ocal la w a n d re g ulati o n).  
2.  A bilit y t o pr o vi de writte n i nf or me d c o nse nt/asse nt  a n d t o be c o m plia nt wit h t he sc he d ule 
of pr ot oc ol assess me nts. P are nt or le gal g uar dia n m ust pr o vi de c o nse nt f or a s u bject w h o 
has asse nte d t o partici pate i n t he st u d y as re q uire d per l ocal re g ulati o ns.  
Dise ase -s pecific i ncl usi o n criteri a: 
3.  Dia g n ose d wit h U C ≥ 3  m o nt hs pri or t o scree ni n g. T he dia g n osis of U C m ust be 
c o nfir me d b y e n d osc o pic a n d hist ol o gic e vi de nce. T he e n d osc o p y a n d hist ol o g y re p ort 
s h o ul d be prese nt i n t he s o urce d oc u me nts; h o we ver, if n ot a vaila ble, t he scree ni n g 
e n d osc o p y a n d hist ol o g y ma y ser ve as s uc h. 
4.  Acti ve U C c o nfir me d b y e n d osc o p y wit h ≥ 1 0  c m rectal i n v ol ve me nt. S u bjects wit h 
pr octitis o nl y at baseli ne m ust meet ot her eli gi bilit y criteria, i ncl u di n g t he M M S a n d 
e n d osc o pic criteria.  
5.  M o deratel y acti ve U C defi ne d as a n M M S of 4  t o 6 a n d a n E S  ≥ 2  a n d R B sc ore ≥ 1 . 
6.  Recei ve d a s ur veilla nce c ol o n osc o p y ( perf or me d acc or di n g t o l ocal sta n dar d) wit hi n 
1 2  m o nt hs bef ore baseli ne t o r ule o ut d ys plasia i n s u bjects wit h pa nc olitis >  8  years 
d urati o n or s u bjects wit h left -si de d c olitis > 1 2  years d urati o n. S u bjects wit h o ut a 
s ur veilla nce c ol o n osc o p y wit hi n t he pri or 1 2 m o nt hs will ha ve a c ol o n osc o p y at 
scree ni n g (ie, i n place of scree ni n g pr oct osi g m oi d osc o p y). A n y a de n o mat o us p ol y ps m ust 
be re m o ve d acc or di n g t o r o uti ne practice pri or t o t heir first d ose of st u d y treat me nt.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 1  of 1 0 7  
Pri or tre at me nt : 
7.  De m o nstrate d a n i na de q uate res p o nse t o, 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 t hera pies as defi ne d bel o w:  
C o n ve nti o n al t her a p y  
a. Oral 5 -A S A c o m p o u n ds  
b.  C ortic oster oi ds  
c. T hi o p uri nes  
Bi ol o gic t her a p y or J A K i n hi bit or t her a p y 
a. A nti -t u m or necr osis fact or al p ha ( T N F α) a nti b o dies (e g, i nfli xi ma b, a dali m u ma b, 
g oli m u ma b, or bi osi milars)  
b.  A nti -i nte gri n a nti b o dies (e g, ve d oliz u ma b) 
c. A n ti-i nterle u ki n 1 2/ 2 3 a nti b o dies (e g, uste ki n u ma b) 
d.  J A K i n hi bit ors (e g, t ofaciti ni b) 
N ote: T he me dicati o n use d t o q ualif y t he s u bject f or e ntr y i nt o t his cate g or y m ust be 
a p pr o ve d f or t he treat me nt of U C i n t he c o u ntr y of use a n d t he s u bject m ust ha ve 
recei ve d a n a de q uate c o urse of t hera p y base d o n l ocal g ui deli nes f or t hat t hera p y. 
I na de q uate res p o nse, l oss of res p o nse, a n d i nt olera nce are defi ne d as: 
•  I na de q uate res p o nse: Si g ns a n d s y m pt o ms of persiste ntl y acti ve disease des pite a 
hist or y of c o m pleti n g a d osi n g re gi me n.  F or c ortic o ster oi ds, t his will i ncl u de dail y 
d ose of at least  0. 7 5 m g/ k g or ≥ 4 0 m g of pre d nis o ne  ( or c ortic oster oi d e q ui vale nt) 
gi ve n orall y f or 2 wee ks , or i ntra ve n o usl y f or 3 da ys or base d o n l ocal g ui deli nes.  
•  L oss of res p o nse: Rec urre nce of s y m pt o ms of acti ve disease d uri n g treat me nt 
f oll o wi ng pri or cli nical be nefit ( disc o nti n uati o n des pite cli nical be nefit d oes n ot 
q ualif y as ha vi n g faile d or bei n g i nt olera nt t o U C bi ol o gic t hera p y).  
•  I nt olera nce: I ncl u di n g, b ut n ot li mite d t o i nf usi o n- or i njecti o n -relate d reacti o n, 
de m yeli nati o n, c o n gesti ve heart fail ure, i nfecti o n, or a n y ot her relate d a d verse e ve nt 
t hat le d t o a re d ucti o n i n d ose or disc o nti n uati o n of t he me dicati o n. 
N ote: T o be c o nsi dere d i na de q uate res p o nse, l oss of res p o nse, a n d i nt olera nce after 
treat me nt wit h a bi ol o gic or t ofaciti ni b, t he s u bject m ust ha ve recei ve d a d osi n g re gi me n 
c o nsiste nt wit h t he l ocal pr o d uct la beli n g a n d/ or i nstit uti o nal sta n dar d of care.  
C o nc o mit a nt tre at me nts : 
8.  S u bjects are per mitte d t o be recei vi n g a t hera pe utic d ose of t he f oll o wi n g dr u gs:  
•  Oral 5 -A S A c o m p o u n d s pr o vi de d t he d ose has bee n sta ble f or ≥ 2  wee ks i m me diatel y 
pri or t o ra n d o mizati o n.  
•  Oral c ortic oster oi d t hera p y ( pre d nis o ne at a sta ble d ose ≤ 2 0  m g/ da y, b u des o ni de at a 
sta ble d ose ≤ 9  m g/ da y, or e q ui vale nt ster oi d) pr o vi de d t he d ose has bee n sta ble f or  
t he 4 wee ks i m me diatel y pri or t o t he scree ni n g e n d osc o p y assess me nt. ( N ote: 
S u bjects o n e xisti n g oral c ortic oster oi d t hera p y will be ta pere d d uri n g t he 4 0 -Wee k 
Treat me nt Peri o d.)  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 2  of 1 0 7  
•  I m m u n os u p pressi ve a ge nts s uc h as oral azat hi o pri ne ( A Z A) or 6-merca pt o p uri ne 
( 6-M P) m ust be disc o nti n ue d ≥ 2  wee ks pri or t o ra n d o mizati o n.  
•  Pr o bi otics (e g, C ult urelle ® , S acc h ar o myces b o ul ar dii ) pr o vi de d t he d ose has bee n 
sta ble f or t he 2 wee ks i m me diatel y pri or t o ra n d o mizati o n.  
If oral 5-A S A or c ortic oster oi ds ha ve b ee n rece ntl y disc o nti n ue d, t he y m ust ha ve bee n 
st o p pe d f or at least 2 wee ks pri or t o t he e n d osc o p y use d f or t he baseli ne M M S.  
Ot her ge ner al i ncl usi o n criteri a : 
9.  A de q uate he mat ol o gical f u ncti o n defi ne d b y w hite bl o o d cell c o u nt ≥ 3. 5  ×  1 0 9/ L wit h 
a bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5  ×  1 0 9/ L, l y m p h oc yte c o u nt ≥ 0. 8  ×  1 0 9/ L, platelet 
c o u nt ≥ 1 0 0  ×  1 0 9/ L, a n d he m o gl o bi n ≥ 8  g/ d L.  
1 0.  A de q uate he patic f u ncti o n defi ne d b y a t otal bilir u bi n le vel ≤ 1. 5  × t he u p per li mit of 
n or mal ( U L N) ra n ge a n d as partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase 
( A L T) le vels ≤ 2. 0  ×  U L N. S u bjects wit h a n is olate d t otal bilir u bi n a n d n or mal A S T a n d 
A L T dia g n ose d wit h Gil bert’s s y n dr o me ma y partici pate.  
1 1.  A de q uate re nal f u ncti o n defi ne d b y a n esti mate d gl o mer ular fil trati o n rate 
≥ 3 0  m L/ mi n/ 1. 7 3  m 2 b y t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
e q uati o n at scree ni n g.  
1 2.  Fe males m ust meet eit her a or b of t he f oll o wi n g criteria a n d males m ust meet criteri o n c 
t o q ualif y f or t he st u d y: 
a. A fe male w h o is n ot  of c hil d beari n g p ote ntial m ust meet 1 of t he f oll o wi n g:  
− P ost me n o pa usal, defi ne d as n o me nses f or 1 2  m o nt hs wit h o ut a n alter nati ve 
me dical ca use  
− Per ma ne nt sterilizati o n pr oce d ure, s uc h as h ysterect o m y, bilateral sal pi n gect o m y, 
or bilateral o o p h orect o m y  
b.  A n o n pre g na nt fe male of c hil d beari n g p ote ntial m ust a gree t o usi n g a hi g hl y effecti ve 
c o ntrace pti o n met h o d d uri n g treat me nt a n d f or 3 0  da ys f oll o wi n g treat me nt t hat ca n 
ac hie ve a fail ure rate of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y. 
T he f oll o wi n g are c o nsi dere d hi g hl y effecti ve birt h c o ntr ol met h o ds:  
− C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n, w hic h ma y be oral, i ntra va gi nal, or 
tra ns der mal 
− Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n, 
w hic h ma y be oral, i njecte d, or i m pla nte d  
− I ntra uteri ne de vice (I U D) 
− I ntra uteri ne h or m o ne-releasi n g s yste m 
− Bilateral t u bal occl usi o n  
− Vasect o mize d part ner, pr o vi de d t hat part ner is t he s ole se x ual part ner of t he 
fe male of c hil d beari n g p ote ntial trial s u bject a n d t hat t he vasect o mize d part ner 
has recei ve d me dical assess me nt of t he s ur gical s uccess  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 3  of 1 0 7  
− Se x ual a bsti ne nce (c o m plete se x ual a bsti ne nce defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse f or t he e ntire peri o d of ris k ass ociate d wit h st u d y 
treat me nts). T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n 
t o t he d urati o n of t he cli nical st u d y a n d t he preferre d a n d us ual lifest yle of t he 
s u bject. Peri o dic a bsti ne nce (cale n dar, s y m pt ot her mal, p ost-o v ulati o n met h o ds) is 
n ot acce pta ble.  
c. A male s u bject wit h a pre g na nt or n o n pre g na nt fe male of c hil d beari n g p ote ntial 
part ner m ust a gree t o usi n g c o n d o ms d uri n g treat me nt a n d f or 3 0  da ys f oll o wi n g 
treat me nt. 
4. 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 will n ot be eli gi ble f or e nr oll me nt i nt o 
t he st u d y: 
Excl usi o ns rel ate d t o ge ner al he alt h : 
1.  Se vere e xte nsi ve c olitis as e vi de nce d b y:  
•  P h ysicia n j u d ge me nt t hat t he s u bject is li kel y t o re q uire h os pitalizati o n f or me dical 
care or s ur gical i nter ve nti o n of a n y ki n d f or U C (e g, c olect o m y) wit hi n 1 2  wee ks 
f oll o wi n g ra n d o mizati o n 
•  C urre nt e vi de nce of f ul mi na nt c olitis, t o xic me gac ol o n or rece nt hist or y ( w it hi n last 
6  m o nt hs) of t o xic me gac ol o n, or b o wel perf orati o n  
•  Pre vi o us t otal or partial c olect o m y  
2.  Dia g n osis of C D or i n deter mi nate c olitis or t he prese nce or hist or y of a fist ula c o nsiste nt 
wit h C D.  
3.  Dia g n osis of micr osc o pic c olitis, isc he mic c olitis, or i n fecti o us c olitis. 
4.  H os pitalizati o n f or e xacer bati o n of U C re q uiri n g i ntra ve n o us (I V) ster oi ds wit hi n 
1 2  wee ks of scree ni n g (a si n gle d ose of I V ster oi ds gi ve n is acce pta ble).  
5.  P ositi ve assa y or st o ol c ult ure f or pat h o ge ns ( o va a n d parasite e xa mi nati o n, bacte ria) or 
p ositi ve test f or Cl ostri di oi des difficile (f or merl y k n o w n as Cl ostri di u m difficile ) t o xi n at 
scree ni n g. ( N ote: If C.  difficile  is p ositi ve, t he s u bject ma y be treate d a n d reteste d 
≥ 4  wee ks after c o m pleti n g treat me nt.)  
6.  Pre g na nc y, lactati o n, or a p ositi ve ser u m β -h C G meas ure d d uri n g scree ni n g.  
7.  Cli nicall y rele va nt ne ur ol o gical, e n d ocri ne, meta b olic (i ncl u di n g, b ut n ot li mite d t o, 
h y p o - a n d h y per kale mia), ps yc hiatric, c o g niti ve i m pair me nt, alc o h ol/ dr u g 
a b use/ de pe n de nce, or ot her maj or s yste mic disease ma ki n g i m ple me ntati o n of t he 
pr ot oc ol or i nter pretati o n of t he st u d y diffic ult or w o ul d p ut t he s u bject at ris k.  
8.  Ha ve a n y of t he f oll o wi n g c o n diti o ns or recei vi n g treat me nts t hat ma y affect 
car di o vasc ular f u ncti o n:  
•  M y ocar dial i nfarcti o n, u nsta ble a n gi na, str o ke/tra nsie nt isc he mic attac k, 
dec o m pe nsate d heart fail ure re q uiri n g h os pitalizati o n or Class  III/I V heart fail ure 
≤ 6  m o nt hs pri or t o or d uri n g t he Scree ni n g Peri o d 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 4  of 1 0 7  
•  Hist or y or prese nce of  sec o n d-de gree or t hir d -de gree atri o ve ntric ular bl oc k, sic k si n us 
s y n dr o me, or peri o ds of as yst ole f or > 3  sec o n ds wit h o ut a f u ncti o nal pace ma ker 
•  Hist or y or prese nce of  rec urre nt s y m pt o matic bra d ycar dia or rec urre nt car di o ge nic 
s y nc o pe 
•  Scree ni n g or Wee k  0/ Da y  1 prera n d o mizati o n vital si g ns (ta ke n i n t he sitti n g 
p ositi o n) wit h a heart rate ( H R) <  5 0  beats per mi n ute ( b p m) O R s yst olic bl o o d 
press ure ( B P) <  9 0  m m  H g O R dias t olic B P < 5 5  m m  H g. Vital si g ns ma y be 
re peate d u p t o 3 ti mes d uri n g a visit t o c o nfir m a b n or mal rea di n gs 
•  Scree ni n g or Wee k  0/ Da y  1 prera n d o mizati o n electr ocar di o gra m ( E C G) wit h P R 
i nter val > 2 0 0  ms or Fri dericia’s c orrecte d Q T i nter val ( Q Tc F) ≥ 4 5 0  ms i n  me n or 
≥ 4 7 0  ms i n w o me n  
•  Start, st o p, c ha n ge or pla n ne d c ha n ge i n d osa ge of a n y a nti -arr h yt h mic dr u gs 
( Class I t o I V) ≤ 1 wee k bef ore scree ni n g or wit hi n  1  wee k bef ore or after 
ra n d o mizati o n 
9.  F orce d e x pirat or y v ol u me i n 1  sec o n d ( F E V1) or f orce d vital ca pacit y ( F V C) <  7 0 % of 
pre dicte d val ues a n d F E V 1/ F V C rati o < 0. 7 0 at scree ni n g.  
1 0.  U nc o ntr olle d dia betes as deter mi ne d b y he m o gl o bi n A 1c ( H b A 1c) >  9 % at scree ni n g, or 
s u bjects wit h dia betes wit h si g nifica nt c o m or bi d c o n diti o ns s uc h as reti n o pat h y. 
1 1.  Hist or y of mac ular e de ma or reti n o pat h y.  
1 2.  Hist or y of acti ve t u berc ul osis ( T B), hist or y of u ntreate d or i na de q uatel y treate d late nt T B 
i nfecti o n, acti ve or late nt T B i nfecti o n at scree ni n g (refer t o A p pe n di x 2  f or details o n T B 
scree ni n g re q uire me nts a n d i nter pretati o n of test res ults). T he f oll o wi n g are 
E X C E P TI O N S t o t his e xcl usi o n criteri o n : 
•  S u bjects wit h late nt T B, w h o ha ve bee n r ule d o ut f or acti ve T B, ha ve c o m ple te d a n 
a p pr o priate c o urse of T B pr o p h yla xis treat me nt per nati o nal/l ocal me dical g ui deli nes 
or W H O g ui deli nes, ha ve a c hest ra di o gra p h wit h o ut c ha n ges s u g gesti ve of acti ve T B 
i nfecti o n, a n d ha ve n ot ha d rece nt cl ose c o ntact wit h a pers o n wit h acti ve T B are 
eli gi ble t o e nr oll i n t he st u d y. It 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 T B treat me nt a n d pr o vi de a p pr o priate d oc u me ntati o n of 
treat me nt c o m plia nce. 
•  S u bjects dia g n ose d wit h late nt T B at scree ni n g, r ule d o ut f or acti ve T B a n d recei ve d 
at least 4 wee ks of a n a p pr o priate T B pr o p h yla xis re gi me n ma y be rescree ne d f or 
e nr oll me nt. S u bjects will c o m plete t heir pr o p h ylactic re gi me n d uri n g t he trial.  
1 3.  A cli nicall y si g nifica nt acti ve i nfecti o n (e g, seri o us a n d/ or at y pical) ≤ 2 8  da ys pri or t o 
ra n d o mizati o n, re q uire d I V me dicati o n ≤ 1 4  da ys pri or t o ra n d o mizati o n, or t hat ma y 
w orse n (i n t he o pi ni o n of t he I n vesti gat or) if t he s u bject is treate d wit h a dr u g ha vi n g 
i m m u n os u p pressa nt effects (ie, etrasi m o d). F u n gal i nfecti o n of nail be ds is all o we d.  
1 4.  Ha ve h u ma n i m m u n o deficie nc y vir us ( HI V)/ac q uire d i m m u ne deficie nc y s y n dr o me 
( AI D S) or test p ositi ve f or HI V a nti b o dies at scree ni n g.  
1 5.  Ha ve ac ute or c hr o nic he patitis  B i nfecti o n or test p ositi ve f or he patitis  B vir us ( H B V) at 
scree ni n g ( detecta ble H B V D N A, or p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g], or 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 5  of 1 0 7  
ne gati ve f or H Bs A g a n d p ositi ve f or a nti -he patitis  B c ore a nti b o d y i n c o nj u ncti o n wit h 
detecta ble H B V D N A).  
1 6.  Ha ve c urre nt he patitis  C i nfecti o n or test p ositi ve f or he patitis  C vi r us ( H C V) at scree ni n g 
as defi ne d b y p ositi ve f or he patitis  C a nti b o d y a n d detecta ble H C V R N A.  
1 7.  Hist or y of a n o p p ort u nistic i nfecti o n (e g, P ne u m ocystis  jir ovecii, cr y pt oc occal 
me ni n gitis, pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y) or hist or y of disse mi nate d 
her pes si m ple x or disse mi nate d her pes z oster.  
1 8.  Hist or y of or c urre ntl y acti ve pri mar y or sec o n dar y i m m u n o deficie nc y.  
1 9.  Hist or y of ca ncer wit hi n t he last 5  years, i ncl u di n g s oli d t u m ors a n d he mat ol o gical 
mali g na ncies (e xce pt basal cell a n d i n  sit u s q ua m o us cell carci n o mas of t he s ki n t hat ha ve 
bee n e xcise d a n d res ol ve d) or c ol o nic m uc osal d ys plasia.  
2 0.  Hist or y of l y m p h o pr oliferati ve dis or der, l y m p h o ma, le u ke mia, m yel o pr oliferati ve 
dis or der, or m ulti ple m yel o ma.  
Excl usi o ns rel ate d t o me dic ati o ns : 
2 1.  H y perse nsiti vit y  t o etrasi m o d or a n y of t he e xci pie nts or place b o c o m p o u n ds. 
2 2.  Pri or treat me nt wit h S 1 P rece pt or m o d ulat ors.  
2 3.  Treat me nt wit h a bi ol o gic a ge nt ≤ 8  wee ks or a s mall m olec ule a ge nt ≤ 5  eli mi nati o n 
half -li ves a n d detecta ble dr u g le vel pri or t o ra n d o mizati o n. 
2 4.  Trea t me nt wit h a n i n vesti gati o nal t hera p y ≤ 3  m o nt hs pri or t o ra n d o mizati o n.  
2 5.  Treat me nt wit h ≥ 3  bi ol o gic a ge nts or ≥ 2  bi ol o gics pl us a J A K i n hi bit or a p pr o ve d f or 
treat me nt of U C. 
2 6.  Treat me nt wit h t o pical rectal 5 -A S A, s h ort -c hai n fatt y aci d e ne mas, or ster oi ds ≤ 2  wee ks 
pri or t o a n d d uri n g scree ni n g.  
2 7.  Treat me nt wit h t o pical rectal tra diti o nal me dici ne (e g, C hi nese me dici ne), her b e ne mas, 
or s u p p osit ories ≤ 2 wee ks pri or t o ra n d o mizati o n . 
2 8.  Treat me nt wit h met h otre xate ≤ 8  wee ks p ri or t o a n d d uri n g scree ni n g or c ycl os p ori ne, 
tacr oli m us, sir oli m us, or m yc o p he n olate m ofetil ( M M F) ≤ 1 6  wee ks pri or t o a n d d uri n g 
scree ni n g. 
2 9.  Recei pt of a li ve vacci ne ≤ 4  wee ks pri or t o ra n d o mizati o n.  
3 0.  Pre vi o us treat me nt wit h nataliz u ma b.  
3 1.  Pre vi o us treat me n t wit h l y m p h oc yte-de pleti n g t hera pies (e g, ale mt uz u ma b, a nti -C D 4, 
cla dri bi ne, rit u xi ma b, ocreliz u ma b, c ycl o p h os p ha mi de, mit o xa ntr o ne, t otal b o d y 
irra diati o n, b o ne marr o w tra ns pla ntati o n, dacliz u ma b). 
3 2.  Pre vi o us treat me nt wit h D -pe nicilla mi ne, t hali d o mi de, di met h yl f u marate, or p yri mi di ne 
s y nt hesis i n hi bit ors. 
3 3.  Treat me nt wit h I V i m m u n ogl o b uli n or plas ma p heresis ≤ 3  m o nt hs pri or t o 
ra n d o mizati o n. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 6  of 1 0 7  
3 4.  Use of m o derate or str o n g i n hi bit ors or i n d ucers  t hat i n hi bit or i n d uce at least 2 of t he 
f oll o wi n g: cyt oc hr o me P 4 5 0 ( C Y P) 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 (e g, fl uc o naz ole, 
rifa m pi n, e nzal uta mi de) wit hi n 4 wee ks pri or t o ra n d o mizati o n. 
5.  
R E M O V A L O F S U B J E C T S F R O M S T U D Y T R E A T M E N T O R 
A S S E S S M E N T   
5. 1.  
Disc o nti n u ati o n fr o m St u d y Tre at me nt   
A s u bject’s d o u ble -bli n d treat me nt ma y be disc o nti n ue d f or a n y of t he f oll o wi n g reas o ns:  
•  W orse ni n g of disease (N ote: If a s u bject disc o nti n ues d o u ble -bli n d treat me nt at a n y 
ti me starti n g wit h t he Wee k 1 2 assess me nt, t he s u bject ma y be eli gi ble t o e nter t he 
A P D 3 3 4 -3 0 3 O L E st u d y [ Secti o n  5. 1. 1 ]) 
•  A d verse e ve nt t hat i n t he j u d ge me nt of t he I n vesti gat or a n d/ or Me dical M o nit or t he 
s u bject s h o ul d n ot c o nti n ue st u d y treat me nt 
•  S u bject n o nc o m plia nce  wit h t he pr ot oc ol or st u d y treat me nt t hat is c o nsi dere d 
si g nifica nt b y t he Me dical M o nit or 
•  I n vestigat or decisi o n  
•  Wit h dra wal b y s u bject or pare nt/ g uar dia n (if a p plica ble)  
•  Lac k of efficac y  
•  L ost t o f oll o w -u p  
•  St u d y ter mi nati o n b y S p o ns or  
•  Ot her, n o n -a d verse e ve nt  
A s u bject’s d o u ble -bli n d treat me nt m ust be disc o nti n ue d f or a n y of t he f oll o wi n g reas o ns: 
•  Decli ne i n P F T val ues ( F E V 1 a n d/ or F V C) bel o w 5 0 % of t he pre dicte d val ues  
•  C o nfir me d dia g n osis of cli nicall y si g nifica nt mac ular e de ma  
•  C o nfir me d dia g n osis of acti ve T B  
•  S u bjects w h o ha ve a car di o vasc ular treat me nt -relate d s y m pt o matic e ve nt (e g, c hest 
pai n, dizzi ness, pal pitati o ns, li g ht hea de d ness, s h ort ness of breat h, or s y nc o pe) 
ass ociate d wit h re d ucti o n of t he heart  rate or ass ociate d wit h cli nicall y rele va nt E C G 
c ha n ges at a n y ti me d uri n g t he 4 -h o ur m o nit ori n g pe ri o d o n Da y 1 or Da y  2 (as 
a p plica ble) ( Secti o n  9. 4. 2. 1 ) 
•  S u bjects w h o ha ve n ot met t he disc har ge criteria o n Da y  1 after ≥ 4  h o urs of e xte n de d 
m o nit ori n g , or Da y 2 b y 4  h o urs p ost -d ose  (Ta ble 3 ). 
•  Pre g na nc y ( Secti o n  9. 9. 1 0 ) 
•  S us pecte d dr u g i n d uce d li ver i nj ur y as defi ne d b y t he 2 0 0 9 F D A G ui da nce f or 
I n d ustr y (F D A 2 0 0 9 ) 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 7  of 1 0 7  
− A L T or A S T >  8  ×  U L N  
− A L T or  A S T >  5  ×  U L N f or >  2  wee ks  
− A L T or A S T >  3  ×  U L N a n d (t otal bilir u bi n >  2  ×  U L N or i nter nati o nal 
n or malize d rati o >  1. 5)  
− A L T or A S T >  3  ×  U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e o si n o p hilia ( > 5 %)  
Beca use tra nsie nt fl uct uati o ns of A L T or A S T are c o m m o n, a n d pr o gressi o n t o se vere 
dr u g -i n d uce d li ver i nj ur y or ac ute li ver fail ure is u nc o m m o n, a ut o matic disc o nti n uati o n of st u d y 
treat me nt u p o n fi n di n g a greater t ha n 3 ×  U L N ele vati o n of  A L T or A S T ma y be u n necessar y.  If 
a dr u g -i n d uce d li ver i nj ur y is i de ntifie d, refer t o A p pe n di x 6  f or g ui da nce. 
S u bjects w h o disc o nti n ue treat me nt pre mat urel y, re gar dless of t he reas o n, s h o ul d be i nstr ucte d t o 
ret ur n f or a n E T visit wit hi n 7 da ys of t he last a d mi nistrati o n of st u d y treat me nt ( A p pe n di x  1 , 
Ta ble  6 ) a n d bef ore i nitiati o n of a n y ne w treat me nts t o c o m plete all of t he E T assess me nts. If a 
s u bject disc o nti n ues d ue t o pre g na nc y, t he y are n ot re q uire d t o c o m plete t he e n d osc o p y. If t he 
E T visit is wit hi n 4  wee ks of t he last si g m oi d osc o p y a n d bi o ps y, t hese pr oce d ures d o n ot nee d t o 
be re peate d.  
If t he E T visit is ≥ 2  wee ks of t he last a d mi nistrati o n of st u d y treat me nt, t he 2 -Wee k F oll o w -U p 
visit is n ot re q uire d; h o we ver, t he 4 -Wee k F oll o w -U p visit s h o ul d be sc he d ule d a n d c o m plete d. 
If t he E T visit  is ≥ 4  wee ks of t he last a d mi nistrati o n of st u d y treat me nt, t he 4 -Wee k F oll o w -U p 
visit is n ot re q uire d  u nless t he a bs ol ute l y m p h oc yte c o u nt ( A L C) is n ot wit hi n n or mal li mits . 
If treat me nt disc o nti n uati o n is c o nsi dere d a n a d verse e ve nt, refe r t o Secti o n  9. 9. 9. 3  f or A E/ S A E 
re p orti n g g ui da nce. 
5. 1. 1.  
Disc o nti n u ati o n fr o m D o u ble -Bli n d Tre at me nt f or Dise ase W orse ni n g   
Starti n g wit h t h e Wee k 1 2 assess me nt, s u bjects w h ose U C c o n diti o n i n t he o pi ni o n of t he 
I n vesti gat or has n ot i m pr o ve d or has w orse ne d, c o m pare d wit h baseli ne ( Wee k 0/ Da y  1) , ma y be 
eli gi ble t o e nr oll i n t he O L E st u d y ( St u d y  A P D 3 3 4 -3 0 3) pr o vi de d t heir E S is ≥ 2 a n d t he y meet 
o ne of t he f oll o wi n g e ntr y criteria:  
•  R B s u bsc ore ≥ 2 at 2  ti me p oi nts at least 7 da ys a n d n o m ore t ha n 1 4  da ys a part  
•  R B  +  S F s u bsc ores ≥ 4 at 2  ti me p oi nts at least 7 da ys a n d n o m ore t ha n 1 4  da ys a part  
•  R B s u bsc ore ≥ 2 or R B  +  S F s u bsc ores ≥ 4 (i n a n y or d er) at 2  ti me p oi nts at least 
7  da ys a n d n o m ore t ha n 1 4  da ys a part  
F or s u bjects disc o nti n ui n g pri or t o Wee k  5 2, a n e n d osc o pic e val uati o n is re q uire d t o c o nfir m 
eli gi bilit y f or t he O L E. A n e n d osc o p y s h o ul d be perf or me d u p o n t he a p peara nce of U C 
s y m pt o ms b ut n o m ore t ha n 1 4  da ys after t he sec o n d ti me p oi nt f or s y m pt o m criteria a b o ve. A 
pr oct osi g m oi d osc o p y d oes n ot nee d t o be re peate d if perf or me d wit hi n t he last 4  wee ks.  
T he Da y  1 visit of t he O L E st u d y m ust occ ur wit hi n 1 4  da ys of t he last o n treat me nt visit of t his 
st u d y. I n t he e ve nt t here is a ga p bet wee n t he last o n treat me nt visit a n d W 0/ D 1 of t he O L E, t he 
s u bject s h o ul d c o nti n ue t heir d o u ble-bli n d st u d y treat me nt fr o m St u d y  A P D 3 3 4 -2 1 0 u ntil t he da y 
bef ore  t he W 0/ D 1 visit. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 8  of 1 0 7  
5. 2.  
Disc o nti n u ati o n fr o m t he St u d y   
S u bjects ma y be disc o nti n ue d fr o m t he st u d y at a n y ti me f or a n y of t he f oll o wi n g reas o ns:  
•  Wit h dra wal b y s u bject or pare nt/ g uar dia n  
•  De viati o n/ n o nc o m plia nce wit h t he st u d y pr ot oc ol t hat i n t he j u d ge me nt of t he 
I n vesti gat or a n d/ or Me dical M o nit or t he s u bject s h o ul d n ot c o nti n ue st u d y treat me nt 
•  St u d y ter mi nati o n b y S p o ns or  
•  L ost t o f oll o w -u p  
•  Deat h  
•  Ot her  
A s u bject ma y wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n wit h o ut prej u dice t o t heir 
f ut ure me dical care b y t he p h ysicia n or at t he i nstit uti o n. If a s u bject wit h dra ws c o nse nt, n o 
f urt her e val uati o n s h o ul d be perf or me d, a n d n o a d diti o nal data s h o ul d be c ollecte d. T he S p o ns or 
ma y retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h wit h dra wal of c o nse nt. T he 
I n vesti gat or s h o ul d ma ke a reas o na ble atte m pt t o d oc u me nt t he s pecific reas o n w h y c o nse nt was 
wit h dra w n.  
I n t he e ve nt t hat a s u bject fails t o atte n d a n y f oll o w -u p visits, all reas o na ble eff orts will be ma de 
t o c o ntact t he s u bject t o e ns ure t hat he/s he is i n satisfact or y healt h. 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.  
5. 3.  
S u bjects L ost t o F oll o w -U p Pri or t o L ast Sc he d ule d Visit   
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o atte n d a sc he d ule d 
visit a n d is u na ble t o be c o ntacte d b y t he st u d y site.  
T he f oll o w i n g acti o ns m ust be ta ke n if a s u bject fails t o atte n d a re q uire d o nsite, offsite, virt ual, 
or h y bri d visit  ( Secti o n 9. 6 ): 
•  T he site m ust atte m pt t o c o n tact t he s u bject a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he s u bject wis hes t o a n d or s h o ul d c o nti n ue i n 
t he st u d y. 
•  Bef ore a s u bje ct is dee me d l ost t o f oll o w -u p, t he I n vesti gat or or desi g nee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he s u bject ( w here p ossi ble, 3  tele p h o ne calls a n d 
if necessar y, a certifie d letter t o t he s u bject’s last k n o w maili n g a d dress or l ocal 
e q ui vale nt me t h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he s u bject’s 
file. 
S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n fr o m 
t he st u d y. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 3 9  of 1 0 7  
5. 4.  
Pre m at ure Ter mi n ati o n of t he St u d y   
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y at a n y ti me. Reas o ns f or ter mi nati n g t he st u d y 
ma y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  T he i nci de nce or se verit y of a d verse e ve nts i n t his or ot her st u dies  i n dicates a 
p ote ntial healt h hazar d t o s u bjects  
•  S u bject e nr oll me nt is u nsatisfact or y  
•  U p o n re q uest of healt h a ut h orities  
T he S p o ns or will n otif y I n vesti gat ors if t he st u d y is place d o n h ol d or if t he S p o ns or deci des t o 
disc o nti n ue t he st u d y or de vel o p me nt pr o gra m. Healt h a ut h orities a n d I n de pe n de nt Et hics 
C o m mittees/I nstit uti o nal Re vie w B oar d (I E Cs/I R Bs) will be i nf or me d a b o ut t he ter mi nati o n of 
t he st u d y i n acc or da nce wit h a p plica ble re g ulati o ns. 
T he S p o ns or has t he ri g ht t o re place a st u d y site at a n y ti m e. Reas o ns f or re placi n g a st u d y site 
ma y i ncl u de, b ut are n ot li mite d t o:  
•  E xcessi vel y sl o w recr uit me nt  
•  P o or pr ot oc ol a d here nce  
•  I nacc urate or i nc o m plete data rec or di n g 
•  N o n -c o m plia nce wit h t he I C H g ui deli ne f or G C P.  
6.  
S T U D Y T R E A T M E N T S   
6. 1.  
Tre at me nts A d mi nistere d   
S u bjects will be ra n d o ml y assi g ne d t o 1 of 2 treat me nt gr o u ps (etrasi m o d or  place b o) i n a 
2: 1  rati o. St u d y treat me nt is o utli ne d i n Ta ble  1 . 
T a ble  1 : 
St u d y Tre at me nt   
St u d y treat me nt na me:  
Etrasi m o d  
Place b o  
D osa ge f or m ulati o n:  
2  m g ta blet  
Matc hi n g ta blet  
U nit d ose stre n gt h/ d osa ge le vel:  
1  ta blet o nce dail y 
1  ta blet o nce dail y 
R o ute of a d mi nistrati o n: 
B y m o ut h  
B y m o ut h  
Pac ka gi n g a n d la beli n g:  
St u d y treat me nt will be pr o vi de d i n 
4 0  cc, i n d ucti o n -seale d, hi g h-de nsit y 
p ol yet h yle ne b ottles wit h 
c hil d-resista nt scre w ca ps. Eac h 
b ottle will be la bele d as re q uire d per 
c o u ntr y re q uire me nt. T hes e b ottles 
s h o ul d be st ore d at 1 5 t o 2 5° C 
( 5 9 t o 7 7° F).  
St u d y treat me nt will be pr o vi de d i n 
4 0  cc, i n d ucti o n -seale d, hi g h-de nsit y 
p ol yet h yle ne b ottles wit h 
c hil d-resista nt scre w ca ps. Eac h 
b ottle will be la bele d as re q uire d per 
c o u ntr y re q uire me nt. T hese b o ttles 
s h o ul d be st ore d at 1 5 t o 2 5° C 
( 5 9 t o 7 7° F).  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 0  of 1 0 7  
6. 2.  
I n vesti g ati o n al St u d y Tre at me nt  
T he acti ve p har mace utical i n gre die nt i n etrasi m o d ta blets is A P D 3 3 4 L -ar gi ni ne (t he ar gi ni ne s alt 
of ( R )-2 -( 7-( 4-c ycl o pe nt yl -3 -(trifl u or o met h yl) be nz yl o x y)-1, 2, 3, 4 -tetra h y dr oc ycl o pe nta[b ]i n d ol-
3 -yl)acetic aci d), w hic h is a n off -w hite t o li g ht -br o w n s oli d wit h a n a q ue o us s ol u bilit y of 
a p pr o xi matel y 1. 3 8  m g/ m L at p H  =  8. 9 a n d 3 0° C. A P D 3 3 4 L -ar gi ni ne i s ma n ufact ure d, 
pac ka ge d, teste d, a n d release d i n c o m plia nce wit h c G M P.  
T he dr u g pr o d uct is a bl ue, r o u n d, bic o n ve x, plai n, i m me diate -release, fil m-c oate d ta blet. 
Etrasi m o d ta blets are s u p plie d i n t he d osa ge stre n gt h ( base d o n etrasi m o d free -aci d c o nte nt) 
of  2  m g.  
T he place b o ta blet f or m ulati o n is c o m p ose d of e xci pie nts ( micr ocr ystalli ne cell ul ose N F, 
P h.  E ur.; ma n nit ol U S P, P h.  E ur.; s o di u m starc h gl yc olate N F, P h.  E ur.; ma g nesi u m stearate N F, 
P h.  E ur.; a n d O pa dr y ®  II Bl ue  8 5 F 9 0 9 5 1). Place b o ta blets are i d e ntical i n a p peara nce t o t he 
acti ve-dr u g ta blets as descri be d a b o ve.  
6. 3.  
D os a ge a n d A d mi nistr ati o n   
O ne ta blet is t o be ta ke n eac h da y ( wit h water, eit her wit h or wit h o ut f o o d). Ta blets s h o ul d be 
ta ke n at a p pr o xi matel y t he sa me ti me eac h da y, prefera bl y i n t he m or ni n g. O n st u d y visit da ys, 
s u bjects s h o ul d wait a n d ta ke t heir d ose after bl o o d dra ws f or P K a n d after all pre-d ose  
assess me nts a n d pr oce d ures ha ve bee n c o m plete d. T he ti me of P K sa m ple c ollecti o n a n d last 
d osi n g pri or t o t he P K sa m ple s h o ul d 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).  
6. 3. 1.  
I nstr ucti o ns f or Misse d D ose(s)  
S u bjects s h o ul d be i nstr ucte d t hat if t he y f or get t o ta ke a d ose, t he y ca n ta ke t he d ose wit hi n 
8  h o urs of t he n or mal d osi n g ti me; ot her wise, t he y s h o ul d ta ke t heir ne xt d ose at t he re g ular ti me 
o n t he f oll o wi n g da y. If t he s u bject v o mits t he ta blet, he/s he s h o ul d be i nst r ucte d n ot t o ta ke 
a n ot her ta blet o n t he sa me da y, b ut t o ta ke t he ne xt d ose at t he re g ular ti me o n t he f oll o wi n g da y. 
Misse d d oses s h o ul d be rec or de d i n t he s u bject’s electr o nic diar y (e Diar y), as i n dicate d i n t he 
Sc he d ule of Assess me nts, Ta ble  6 . S u bjects s h o ul d be i nstr ucte d t o c o ntact t he I n vesti gat or if 
t he y miss m ore t ha n 2 c o nsec uti ve d oses.  
S u bjects w h o d o n ot ta ke t he st u d y treat me nt f or ≥ 2  c o nsec uti ve da ys wit hi n t he first w ee k of 
treat me nt or f or ≥ 7  c o nsec uti ve da ys after t he first wee k of treat me nt m ust c o ntact t he 
I n vesti gat or t o disc uss treat me nt re-i nitiati o n. T he s u bject m ust ta ke t he ne xt d ose of st u d y 
treat me nt at t he st u d y site, a n d t he i n-cli nic car diac m o nit ori n g as o utli ne d i n Secti o n  9. 4. 2. 1  
s h o ul d be perf or me d. 
6. 3. 2.  
D ose I nterr u pti o ns   
If t he I n vesti gat or dee ms it necessar y t o wit h h ol d st u d y treat me nt, te m p orar y wit h h ol di n g is 
per mitte d f or u p t o 6  da ys wit h o ut o btai ni n g pri or a p pr o val fr o m t he Me dical M o nit or. If st u d y 
treat me nt i nterr u pti o n ≥ 7  da ys is re q uire d f or a me dical reas o n, t he I n vesti gat or m ust c o ntact t he 
Me dical M o nit or.  
T he first -d ose m o nit ori n g as o utli ne d i n Secti o n  9. 4. 2. 1  s h o ul d be perf or me d a n y ti me a s u bject 
misses st u d y treat me nt as f oll o ws:  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 1  of 1 0 7  
•  ≥ 2  c o nsec uti ve da ys wit hi n t he first wee k of treat me nt, or  
•  ≥ 7  c o nsec uti ve da ys after t he first wee k of treat me nt  
6. 4.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt   
S u bjects will be ce ntrall y assi g ne d t o ra n d o mize d st u d y treat me nt usi n g a n I nteracti ve We b 
Res p o nse S yste m (I W R S). Bef ore t he st u d y is i nitiate d, t he l o g i n i nf or mati o n a n d directi o ns f or 
t he I W R S will be pr o vi de d t o eac h st u d y site. 
S u bjects will be r a n d o mize d t o st u d y treat me nt via stratifie d ra n d o mizati o n. Ra n d o mizati o n will 
be stratifie d b y (a)  naï ve t o bi ol o gic or J A K i n hi bit or  t hera p y at st u d y e ntr y ( yes  or  n o)  a n d 
( b) baseli ne c ortic oster oi d use ( yes  or  n o).  
Eac h s u bject will be dis pe nse d bli n de d  st u d y treat me nt at st u d y visits (A p pe n di x  1 , Ta ble  6 ). 
6. 5.  
Bli n di n g   
T his is a d o u ble -bli n d st u d y wit h li mite d access t o t he ra n d o mizati o n c o de. T he st u d y treat me nt 
a n d place b o ta blets a n d b ottles are i de ntical i n p h ysical a p peara nce. T he treat me nt eac h s u bject 
recei ves will n ot be discl ose d t o t he I n vesti gat or, st u d y site staff, s u bject, S p o ns or pers o n nel 
i n v ol ve d wit h t he c o n d uct of t he st u d y ( wit h t he e xce pti o n of t he cli nical s u p pl y staff a n d 
desi g nate d safet y staff), or st u d y ve n d ors. T he I W R S will h ol d treat me nt c o des a n d b ottle 
n u m bers f or st u d y treat me nt.  
Treat me nt assi g n me nts 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. I n case of a n e mer ge nc y, t he I n vesti gat or has t he s ole 
res p o nsi bilit y f or deter mi ni n g if u n bli n di n g of a s u bject’s treat me nt assi g n me nt is warra nte d t o 
pr o vi de a p pr o priate me dical care. S u bject safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g 
s uc h a deter mi nati o n. T he I W R S is pr o gra m me d wit h bli n d-brea ki n g i nstr ucti o ns t o g ui de t he 
I n vesti gat or o n h o w t o o btai n treat me nt assi g n me nt i n t he e ve nt of a n e mer ge nc y u n bli n di n g. 
T he I n vesti gat or is re q ueste d t o c o ntact t he Me 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. If a s u bject’s treat me nt assi g n me nt is u n bli n de d, t he S p o ns or m ust be n otifie d wit hi n 
2 4  h o urs after brea ki n g t he bli n d. T he date a n d reas o n t he bli n d was br o ke n m ust be rec or de d i n 
t he s o urce d oc u me ntati o n a n d e C R F, as a p plica ble. 
F or S us pecte d, U ne x pecte d, Seri o us A d verse Reacti o ns, t he S p o ns or’s P har mac o vi gila nce 
desi g nee res p o nsi ble f or ma na gi n g S A Es, will access t he I W R S t o o btai n t he s u bject’s treat me nt 
assi g n me nt f or t he p ur p ose of re g ulat or y re p orti n g.  
If a s u bject’s treat me nt assi g n me nt is u n bli n de d pri or t o Wee k 1 2 f or a n y reas o n, t he y will be 
disc o nti n ue d fr o m t he st u d y. S u bjects w h o are u n bli n de d o n or after Wee k  1 2 ma y be eli gi ble t o 
e nr oll i nt o t he O L E st u d y ( Secti o n  5. 1. 1 ). 
6. 6.  
Tre at me nt C o m pli a nce   
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat s u bjects are c orrectl y i nstr ucte d o n h o w t o 
ta ke t heir st u d y treat me nt a n d t hat eac h s u bject is c o m plia nt wit h t heir assi g ne d re gi me n. T he 
st u d y treat me nt s h o ul d be dis pe nse d b y t he I n vesti gat or, or b y a q ualifie d i n di vi d ual u n der t he 
I n vesti gat or’s s u per visi o n. A n u p-t o-date treat me nt i n ve nt or y/ dis pe nsi n g rec or d m ust be 
mai ntai ne d as descri be d i n Secti o n  8. 4 . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 2  of 1 0 7  
S u bject c o m plia nce will be base d o n ta blet c o u nt. O verall treat me nt c o m plia nce will be 
calc ulate d at t he e n d of st u d y treat me nt a n d ta blet c o u nts < 8 0 % or > 1 2 0 % of t he e x pecte d val ue 
at t he e n d of treat me nt s h o ul d be d oc u me nte d as a pr ot oc ol de viati o n. If t here is a discre pa nc y 
bet wee n t he ta blet c o u nt a n d t he s u bject’s c o m plia nce per t he e Diar y bet wee n visits, it s h o ul d be 
disc usse d wit h t he s u bject t o i m pr o ve c o m plia nce a n d n ote d i n t he s o urce d oc u me nts.  
6. 7.  
C o nc o mit a nt T her a p y   
All o ver -t he-c o u nter a n d prescri be d c o nc o mita nt me dicati o ns, vacci nes, bl o o d pr o d ucts, 
pr oce d u res, vita mi ns, a n d h olistic pr o d ucts a d mi nistere d d uri n g t he Scree ni n g Peri o d a n d d uri n g 
t he st u d y t hr o u g h t he safet y re p orti n g peri o d m ust be rec or de d i n t he e C R F, as a p pr o priate. 
Re g ular c o ntrace pti o n c o nfir mati o n s h o ul d ta ke place at eac h sc he d ule d visit a n d will be 
ca pt ure d i n s o urce d oc u me nts . I n a d diti o n, s u bjects m ust be i nstr ucte d t o call t he st u d y site 
i m me diatel y if t he a gree d co ntrace pti o n met h o d is disc o nti n ue d , c ha n ge d, or if pre g na nc y is 
s us pecte d. 
6. 7. 1.  
Re q uire d C o nc o mit a nt T her a p y   
N ot a p plica ble . 
6. 7. 2.  
All o we d C o nc o mit a nt T her a p y   
C o nc o mita nt me dicati o n f or me dical c o n diti o ns ot her t ha n U C are per mitte d as cli nicall y 
i n dicate d s u bject t o s pecific pr ot oc ol re q uire me nts o utli ne d i n Secti o n 4. 1  a n d Secti o n  4. 2 . 
6. 7. 2. 1.  
Per mitte d Me dic ati o ns f or t he Tre at me nt of Ulcer ati ve C olitis   
Oral 5 -A S A, A Z A, 6 -M P, oral c ortic oster oi ds, or me dici nal pr o bi otics are all o we d at t he ti me of 
scree ni n g a n d as per t he i ncl usi o n criteria ( Secti o n 4. 1 ); h o we ver, t hese pr o d ucts s h o ul d n ot be 
starte d d uri n g scree ni n g or d uri n g t he treat me nt peri o d i n s u bjects w h o are n ot alrea d y recei vi n g 
t he m. I m m u n os u p pressi ve a ge nts s uc h as oral A Z A or 6-M P m ust be disc o nti n ue d ≥ 2  wee ks 
pr i or t o ra n d o mizati o n. 
S u bjects recei vi n g 5 -A S A or me dici nal pr o bi otics s h o ul d mai ntai n a sta ble d ose t hr o u g h o ut t he 
st u d y. 
Oral c ortic oster oi d t hera p y ( pre d nis o ne at a sta ble d ose ≤ 2 0  m g/ da y, b u des o ni de at a sta ble d ose 
≤ 9  m g/ da y, or e q ui vale nt ster oi d) is all o we d t o be c o nti n ue d d uri n g t he 1 2-Wee k Treat me nt 
Peri o d pr o vi de d t he d ose has bee n sta ble f or t he 4  wee ks i m me diatel y pri or t o t he scree ni n g 
e n d osc o p y assess me nt; h o we ver, s u bjects will be ta pere d off c ortic oster oi ds d uri n g t he 4 0 -Wee k 
Treat me nt Per i o d ( Secti o n 6. 7. 2. 2 ). 
6. 7. 2. 2.  
C ortic oster oi d T a per   
D uri n g t he 1 2 -Wee k Treat me nt Peri o d, s u bjects are t o mai ntai n t heir sta ble baseli ne 
c orticoster oi d d ose.  
F oll o wi n g t he Wee k  1 2 assess me nt, c ortic oster oi ds s h o ul d be ta pere d f or s u bjects e nteri n g t he 
4 0 -Wee k Treat me nt Peri o d. T he rec o m me n de d ta peri n g sc he d ule f or oral c ortic oster oi ds ( ot her 
t ha n b u des o ni de e xte n de d-release ta blets [ b u des o ni de M MX]) is as f oll o ws:  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 3  of 1 0 7  
a. D ose >  1 0  m g/ da y pre d nis o ne or e q ui vale nt: Ta per dail y d ose b y 5  m g/ wee k u ntil 
recei vi n g 1 0 m g/ da y, a n d t he n c o nti n ue ta peri n g at 2. 5  m g/ wee k u ntil 0  m g/ da y  
b.  D ose ≤ 1 0  m g/ da y pre d nis o ne or e q ui vale nt: Ta per dail y d ose b y 2. 5  m g/ wee k u ntil  
0  m g/ da y  
T he rec o m me n de d ta peri n g sc he d ule f or s u bjects recei vi n g oral b u des o ni de M M X 9  m g/ da y is t o 
re d uce ta blets t o 9 m g e ver y ot her da y f or 2  wee ks, f oll o we d b y 9  m g e ver y t hir d da y f or 
2  wee ks, a n d t he n disc o nti n ue.  
F or s u bjects w h o ca n n ot t olerate t he c ortic oster oi d ta per wit h o ut rec urre nce of cli nical s y m pt o ms 
of eit her U C or ster oi d wit h dra wal, t he c ortic oster oi d d ose ma y be i ncrease d ( u p t o t he d ose at 
st u d y e ntr y if re q uire d), b ut ta peri n g s h o ul d be gi n a gai n wit hi n 2 wee ks.  
6. 7. 2. 3.  
V acci nes   
Vacci nati o ns are per mitte d as cli nicall y i n dicate d e xce pt f or li ve vacci nes (refer t o  
Secti o n  6. 7. 3 ). At t his ti me, t here are n o data o n t he effect of etrasi m o d o n vacci nati o n i ncl u di n g 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  (S A R S -C o V -2 ) (c or o na vir us disease 2 0 1 9 
[C O VI D -1 9 ]) vacci nes. T he I nter nati o nal Or ga nizati o n f or t he St u d y of I nfla m mat or y B o wel 
Diseases (I OI B D) has p u blis he d rec o m me n dati o ns t hat patie nts wit h I B D s h o ul d be vacci nate d 
a gai nst S A R S -C o V -2; t hat S A R S -C o V -2 vacci nes, i ncl u di n g messe n ger R N A, 
re plicati o n-i nc o m pete nt vect or, i nacti vate d a n d rec o m bi na nt vacci nes are safe t o a d mi nister t o 
patie nts wit h I B D; a n d t h us s h o ul d n ot be deferre d beca use a patie nt wit h I B D is recei vi n g 
i m m u ne-m o dif yi n g t hera pies  (Sie gel 2 0 2 1 ). 
If a s u bject recei ves a vacci nati o n, t he vacci nati o n date a n d t y pe (e g, S A R S -C o V -2) will be 
ca pt ure d as descri be d i n Secti o n  9. 3. 5  i n t he C o nc o mita nt Me dicati o n e C R F. T he vacci ne bra n d, 
ma n ufact urer, a n d l ot n u m ber s h o ul d be ca pt ure d i n t he C o nc o mita nt Me dicati o n e C R F as 
a vaila ble. 
6. 7. 3.  
Pr o hi bite d C o nc o mit a nt T her a p y   
T he f oll o wi n g c o nc o mita nt me dicati o ns are pr o hi bite d d uri n g t he st u d y:  
N ote:  S u bjects w h o e nter t he 4 -Wee k F oll o w -U p Peri o d will n o l o n ger nee d t o a bstai n fr o m t he 
me dicati o ns t hat were pr o hi bite d d uri n g t he treat me nt peri o ds, u nless n ote d ot her wise (e g, li ve 
atte n uate d vacci nes f or 4 wee ks after t he last d ose of st u d y dr u g).  O nce a s u bject has 
disc o nti n ue d t heir st u d y me dicati o n a n d ha d t heir Wee k 5 2 / E T  visit , a s u bject ma y ha ve t heir 
w orse ni n g Ulcerati ve C olitis / Ulcerati ve C olitis flare treate d acc or di n g t o t he l ocal sta n dar d of 
care. T he In vesti gat or ma y i nitiate a resc ue treat me nt d uri n g t he F oll o w -U p peri o d . 
•  Treat me nts f or U C ot her t ha n t h ose liste d i n Secti o n  6. 7. 2. 1  (eit her a p pr o ve d or 
i n vesti gati o nal) 
•  All li ve vacci nes, d uri n g st u d y treat me nt a n d wit hi n 4  wee ks after t he last 
a d mi nistrati o n of st u d y trea t me nt 
•  M o derate/str o n g i n hi bit ors or i n d ucers  t hat i n hi bit or i n d uce at least 2 of t he 
f oll o wi n g e nz y mes: C Y P 2 C 8 , C Y P 2 C 9, a n d C Y P 3 A 4  (e g, fl uc o naz ole, rifa m pi n, 
e nzal uta mi de)  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 4  of 1 0 7  
•  Start, st o p, or c ha n ge i n d osa ge of a n y a nti -arr h yt h mic dr u gs ( Class  I t o I V) wit hi n 
1  wee k bef ore or after treat me nt re -i nitiati o n f oll o wi n g dr u g i nterr u pti o n as s pecifie d 
i n Secti o n 6. 3. 2  
•  C hr o nic n o nster oi dal a nti -i nfla m mat or y dr u gs ( N S AI D) use ( N ote: Occasi o nal use of 
N S AI Ds a n d aceta mi n o p he n [e g, hea dac he, art hritis, m yal gias, or me nstr ual cra m ps] 
a n d as piri n u p t o 3 2 5  m g per da y is per mitte d)  
•  Mar kete d bi ol o gic t hera pies  
•  I m m u n os u p pressi ve a ge nts (e g, A Z A, 6-M P, t o faciti ni b) 
•  A n y per rect u m t hera p y i ncl u di n g e ne mas (e g, 5 -A S A, c ortic oster oi d), ot her t ha n t hat 
re q uire d f or e n d osc o p y pre parati o n 
•  C ycl os p ori ne, tacr oli m us, sir oli m us, met h otre xate, or M M F  
•  C h olest yra mi ne or ot her dr u gs i nterferi n g wit h e nter o he patic circ ulati o n, u nless t he 
treat me nt has bee n sta ble f or > 6  m o nt hs pri or t o scree ni n g  
•  A n y i n vesti gati o nal dr u g ot her t ha n t he st u d y treat me nt  
•  Treat me nt wit h D -pe nicilla mi ne, t hali d o mi de, di met h yl f u marate, or p yri mi di ne 
s y nt hesis i n hi bit ors 
•  Tre at me nt wit h l y m p h oc yte -traffic ki n g i n hi bit ors (e g, nataliz u ma b, fi n g oli m o d, 
si p o ni m o d, oza ni m o d) 
•  I m m u n os u p pressi ve a ge nts t hat de plete l y m p h oc ytes (e g, ale mt uz u ma b, a nti-C D 4, 
cla dri bi ne, rit u xi ma b, ocreliz u ma b, c ycl o p h os p ha mi de, mit o xa ntr o ne, dacliz u ma b)  
T he f oll o wi n g c o nc o mita nt pr oce d ures are pr o hi bite d d uri n g t he st u d y:  
•  Maj or electi ve s ur ger y  
•  I m m u n oa ds or pti o n c ol u m ns 
•  I V i m m u n o gl o b uli n or plas ma p heresis 
•  Bl o o d d o nati o ns d uri n g t he st u d y a n d f or 1 4  da ys after t he last a d mi nistrati o n of st u d y 
treat me nt 
•  S per m  or o oc yte d o nati o ns d uri n g t he st u d y a n d f or 3 0  da ys after t he last 
a d mi nistrati o n of st u d y treat me nt  
7.  
S U B J E C T R E S T RI C TI O N S   
Pr o hi bite d c o nc o mita nt t hera p y is descri be d i n Secti o n  6. 7. 3 . A d diti o nall y, s u bjects are restricte d 
fr o m t he f oll o wi n g: 
•  P o p p y see ds: C o ns u m pti o n of p o p p y see ds wit hi n 4 8  h o urs pri or t o dr u g scree ni n g 
ma y ca use a p ositi ve dr u g scree n. S u bjects w h o re p ort t hat t he y ha ve c o ns u me d 
p o p p y see ds wit hi n 4 8  h o urs of t he Scree ni n g Visit s h o ul d n ot be scree ne d. T he y ma y 
ret ur n 4 8 h o urs after t he last p o p p y see d c o ns u m pti o n f or scree ni n g. P o p p y see ds 
s h o ul d n ot be eate n bet wee n scree ni n g a n d Wee k  0/ Da y  1.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 5  of 1 0 7  
•  St . J o h n’s W ort : S u bjects s h o ul d be i nstr ucte d t o a bstai n fr o m c o ns u mi n g her bal 
re me dies c o ntai ni n g St. J o h n’s W ort  d uri n g t he st u d y as t hese ma y i nterfere wit h t he 
meta b olis m of etrasi m o d.  
8.  
S T U D Y T R E A T M E N T M A T E RI A L S A N D M A N A G E M E N T   
8. 1.  
P ac k a gi n g a n d L a beli n g   
St u d y treat me nt will be pr o vi de d i n 4 0  cc, i n d ucti o n -seale d, hi g h-de nsit y p ol yet h yle ne b ottles 
wit h c hil d -resista nt scre w ca ps. Eac h b ottle will be la bele d as re q uire d per c o u ntr y re q uire me nt. 
8. 2.  
St u d y Tre at me nt St or a ge a n d H a n dli n g   
B ottles s h o ul d be st ore d 1 5  t o 2 5° C ( 5 9  t o 7 7° F). I n t he case w here a s u bject atte n ds a virt ual 
visit (refer t o Secti o n  9. 6 ) a n d re q uires a d diti o nal st u d y treat me nt t o c o nti n ue o n t he st u d y, st u d y 
treat me nt ma y be dis pe nse d a n d deli vere d b y a n a p pr o ve d c o urier, w here per mitte d b y l ocal la w 
a n d re g ulati o n. Alter nati vel y, a f ut ure s u p pl y of st u d y me dicati o ns ma y be dis pe nse d t o t he 
s u bject at a n o nsite visit t o c o ver st u d y me dicati o ns t o be dis pe nse d at t he ne xt pla n ne d virt ual 
visit. A d va nce d pla n ni n g a n d c o m m u nicati o n will be nee de d t o dis pe nse f ut ure s u p pl y of st u d y 
me dicati o ns at a n earlier o nsite visit. S hi p pi n g g ui deli nes a n d i nstr ucti o n s will be pr o vi de d 
se paratel y. 
8. 3.  
St u d y Tre at me nt Pre p ar ati o n   
N ot a p plica ble.  
8. 4.  
St u d y Tre at me nt Acc o u nt a bilit y   
At eac h visit, pre vi o usl y dis pe nse d st u d y treat me nt ta blets will be c ollecte d b y t he I n vesti gat or or 
q ualifie d i n di vi d ual a n d c o m plia nce assesse d.  S u bjects will rec or d ta blet self -a d mi nistrati o n 
dail y i n a n e Diar y t hat will be re vie we d at eac h treat me nt visit b y st u d y site staff.  
T he I n vesti gat or m ust mai nt ai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss, or ot her 
dis p ositi o n of t he st u d y treat me nt. T o e ns ure a de q uate rec or ds, all st u d y treat me nt s u p plies will 
be acc o u nte d f or a n d will be m o nit ore d b y c o u nti n g of u n use d ta blets fr o m i n di vi d ual b ottles 
ret ur ne d b y t he s u bject at eac h visit ( A p pe n di x 1, Ta ble  6 ). 
8. 5.  
St u d y Tre at me nt Rete nti o n a n d Dis p os al   
All st u d y treat me nt will be rec o ncile d b y t he cli nical m o nit or a n d t he n ret ur ne d t o t he de p ot or 
destr o ye d acc or di n g t o a p plica ble c o u ntr y re g ulati o ns. St u d y  sites wit h  a p har mac y  perf or mi n g  
st u d y treat me nt acc o u nta bilit y  a n d destr ucti o n  bef ore  t he cli nical m o nit or  ca n c o n d uct  
rec o nciliati o n acti vities  is o nl y  per mitte d  wit h  p ri or a p pr o val  fr o m t he S p o ns or . Pri or t o a n y 
acti o n bei n g ta ke n wit h st u d y treat me nt, t he I n vesti gat or will c o ntact t he S p o ns or ( or c o ntract 
researc h or ga nizati o n [ C R O]) f or a p pr o val of s uc h acti o n. O n-site destr ucti o n f oll o wi n g all l ocal 
re g ulati o ns a n d in acc or da nce wit h a p plica ble site sta n dar d o perati n g pr oce d ures ( S O Ps) is 
per mitte d. Fi nal rec o nciliati o n will be perf or me d at st u d y c o m pleti o n.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 6  of 1 0 7  
9.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S   
9. 1.  
Ge ner al I nstr ucti o ns   
•  St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ule of Assess me nts 
(A p pe n di x  1 , Ta ble  6 ). Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d.  
•  Res ults of all pr ot oc ol -re q uire d pr oce d ures will be rec or de d i n t he e C R F w he ne ver 
a p plica ble. 
•  I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he Me dical M o nit or 
i m me diatel y u p o n occ urre nce or a ware ness t o deter mi ne if t he s u bject s h o ul d 
c o nti n ue or disc o nti n ue st u d y treat me nt.  
•  A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule 
of Assess me nts ( A p pe n di x 1,  Ta ble  6 ), is esse ntial a n d re q uire d f or st u d y c o n d uct. 
•  St u d y visits s h o ul d be sc he d ule d i n t he m or ni n g, w he ne ver p ossi ble.  
•  All la b orat or y assess me nts re q uire d b y t he pr o t oc ol will be perf or me d b y a ce ntral 
la b orat or y u nless ot her wise state d. 
•  F or o nsite a n d offsite st u d y visits (refer t o Secti o n  9. 6  a n d Ta ble  6 ), s u bjects s h o ul d 
ta ke t heir st u d y treat me nt after bl o o d dra ws f or P K a n d after all pre-d ose  assess me nts 
a n d pr oce d ures ha ve bee n c o m plete d.  
T he I n vesti gat or will mai ntai n a scree ni n g l o g a n d e nr oll me nt l o g t o rec or d details of all s u bjects 
scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as a p plica ble . 
9. 2.  
S u bject I nf or m ati o n   
9. 2. 1.  
I nf or me d C o nse nt  
T he I n vesti gat or, or a pers o n desi g nate d b y t he I n vesti gat or,  will o btai n writte n i nf or me d c o nse nt 
fr o m eac h s u bject or t he s u bject’s le gall y acce pta ble re prese ntati ve, pare nt(s), or le gal g uar dia n 
a n d t he s u bject’s asse nt w he n a p plica ble, bef ore a n y st u d y -s pecific acti vit y is perf or me d 
( Secti o n 1 1. 3  f or a d diti o nal details). 
9. 3.  
Scree ni n g a n d Eli gi bilit y   
S u bject eli gi bilit y will be assess e d base d o n pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria. All 
scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m p ote ntial s u bjects meet all 
eli gi bilit y criteria.  
Scree ni n g pr oce d ures m ust be c o m plete d wit hi n 2 8  da ys pri or t o recei vi n g t he first d ose of st u d y 
treat me nt (A p pe n di x  1 , Ta ble  6 ). T he Scree ni n g Peri o d ma y be e xte n de d f or s u bjects w h o 
re q uire a d diti o nal dia g n ostic testi n g/c o ns ults t o deter mi ne stat us of eit her late nt T B or C.  difficile  
i nfecti o n. If t he s u bject is plan ne d t o be ra n d o mize d >  2 8  da ys fr o m t he si g ni n g of t he i nf or me d 
c o nse nt f or m (I C F), t he Me dical M o nit or s h o ul d be c o ns ulte d t o see if re peate d testi n g is nee de d. 
T he 2 8 -Da y Scree ni n g Peri o d ma y als o be e xte n de d o n a case -b y -case basis t o acc o m m o date 
reas ona ble dela ys i n s pecific scree ni n g assess me nts (e g, P F Ts, O C T) d ue t o testi n g a vaila bilit y. 
T he Me dical M o nit or m ust be c o ns ulte d pri or t o e xte nsi o n i n eac h case.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 7  of 1 0 7  
S u bjects ma y ha ve a n a b n or mal la b orat or y assess me nt re peate d 1  ti me o nl y. If a d diti o nal retests 
are c o nsi dere d, t he a bilit y t o re peat t he la b orat or y assess me nt s h o ul d be disc usse d wit h t he 
Me dical M o nit or a n d t he o utc o me of t he c o n versati o n s h o ul d be d oc u me nte d.  
9. 3. 1.  
T u berc ul osis Scree ni n g a n d C hest X -R a y   
All s u bjects will c o m plete T B scree ni n g t o deter mi ne eli gi bilit y (refer t o A p pe n di x 2 ). If a n 
I n vesti gat or feels t he test f or late nt T B is a b n or mal, a retest t o c o nfir m late nt T B stat us s h o ul d be 
disc usse d a n d a p pr o ve d b y t he Me dical M o nit or.  
9. 3. 2.  
Rescree ni n g   
S u bjects w h o fail t o meet t he eli gi bilit y criteria ca n be rescree ne d per I n vesti gat or discreti o n. 
A d diti o nal scree ni n g atte m pts be y o n d t he first s h o ul d be a p pr o ve d b y t he Me dical M o nit or pri or 
t o rescree ni n g. Eac h s u bject m ust be rec o nse nte d pri or t o eac h scree ni n g atte m pt.  
S u bjects wit h a Scree ni n g Visit or Wee k  0/ Da y  1 prera n d o mizati o n 1 2 -lea d E C G s h o wi n g a 
sec o n d- or t hir d -de gree A V bl oc k, peri o ds of as yst ole >  3  sec o n ds, P R i nter val > 2 0 0  ms, or 
Q Tc F ≥ 4 5 0  ms ( me n) or Q Tc F ≥ 4 7 0  ms ( w o me n) are n ot  eli gi ble f or rescree ni n g.  
If a s u bject re q uires pr o p h ylactic t hera p y f or late nt T B, t he y ma y be rescree ne d as o utli ne d i n 
Secti o n  4. 2 . 
If a s u bject is p ositi ve f or C.  difficile  at scree ni n g, t he s u bject ma y be treate d a n d 
rescree ne d ≥ 4  wee ks after c o m pleti n g treat me nt.  
9. 3. 3.  
De m o gr a p h y a n d Ot her S u bject C h ar acteristics   
De m o gra p hics i ncl u di n g year of birt h, se x at birt h, His pa nic et h nicit y, a n d race as descri be d b y 
t he s u bject will be c ollecte d at scree ni n g. 
9. 3. 4.  
S oci al Hist or y   
At scree ni n g, a s ocial hist or y i ncl u di n g t he a m o u nt a n d d urati o n of t o bacc o, alc o h ol, a n d caffei ne 
usa ge will be c ollecte d.  
A sta n dar d uri ne dr u g scree n will be perf or me d. S u bjects w h o test p ositi ve will be as sesse d f or 
eli gi bilit y i n st u d y partici pati o n b y t he I n vesti gat or.  
9. 3. 5.  
Pri or a n d O n g oi n g T her a pies   
Pri or t hera pies relate d t o t he treat me nt of U C will be c ollecte d d uri n g scree ni n g. I n a d diti o n, 
d oc u me ntati o n s h o ul d als o i ncl u de t he pri or treat me nt res p o nse as o ne of t he f oll o wi n g: 
Ina de q uate res p o nse t o, l oss of res p o nse t o, or i nt olera nce t o ( Secti o n  4. 1 , I ncl usi o n Criteri o n 7 , 
f or details). 
All me dicati o ns ta ke n a n d pr oce d ures carrie d o ut wit hi n 3 0  da ys pri or t o t he first  st u d y treat me nt 
a d mi nistrati o n a n d all o n g oi n g me dicati o ns will be rec or de d at scree ni n g. U p dates f or ne w 
me dicati o ns pri or t o d osi n g at t he Da y  1 visit s h o ul d be ma de as nee de d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 8  of 1 0 7  
9. 3. 6.  
Ulcer ati ve C olitis Hist or y/ Me dic al Hist or y   
I n or der t o deter mi ne t he s u bject’s eli gi bilit y t o t he st u d y, a c o m plete me dical hist or y of eac h 
s u bject will be c ollecte d a n d d oc u me nte d d uri n g scree ni n g. T he hist or y s h o ul d i n cl u de rece nt 
bl o o d d o nati o ns ( ≤ 3 0  da ys pri or t o t he Scree ni n g Peri o d), ill nesses, a n d partici pati o n i n ot her 
i n vesti gati o nal dr u g st u dies. 
I n a d diti o n, a detaile d hist or y of t he s u bject’s U C, i ncl u di n g date of dia g n osis, disease se verit y, 
h os pitalizati o ns , a n d e xtrai ntesti nal ma nifestati o ns ( EI Ms), will be c ollecte d. 
9. 3. 7.  
Vit al Si g ns   
At scree ni n g, vital si g ns (resti n g heart rate , s yst olic a n d diast olic B P, b o d y te m perat ure, a n d 
res pirat or y rate) will be meas ure d w hile sitti n g.  
9. 3. 8.  
P ul m o n ar y F u ncti o n Test   
P ul m o nar y f u ncti o n tests i ncl u di n g F E V 1 a n d F V C meas ure me nts will be perf or me d. I n a d diti o n, 
diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de  ( D L C O) meas ure me nts will be perf or me d 
w here l ocall y a vaila ble (sites w here D L C O is n ot a vaila ble s h o ul d c o ns ult t he S p o ns or or 
S p o ns or’s dele gate).  
9. 3. 9.  
O p ht h al m osc o p y  a n d O ptic al C o here nce T o m o gr a p h y   
O p ht hal m osc o p y  a n d O C T will be perf or me d. A ge neral o p ht hal m ol o gist ca n d o t he 
e xa mi nati o n; alt h o u g h, a reti nal s pecialist w o ul d be preferre d w here ver p ossi ble . Ot her 
healt hcare pr ofessi o ns t hat are q ual ifie d base d o n l ocal or c o u ntr y s pecific re g ulati o ns ma y 
perf or m  t hese e xa mi nati o ns  wit h a p pr o val fr o m t he S p o ns or . S u bjects wit h a hist or y of mac ular 
e de ma or reti n o pat h y are n ot eli gi ble f or t he st u d y ( Secti o n  4. 2 ). 
9. 3. 1 0.  
Cli nic al L a b or at or y Assess me nts   
Scree ni n g sa m ples f or c o m plete bl o o d c o u nt ( C B C) wit h differe ntial, platelet c o u nt, l y m p h oc yte 
c o u nts,
 ser u m 
c he mistr y, vir ol o g y, t h yr oi d pa nel, c oa g ulati o n, uri nal ysis, hi g h -se nsiti vit y C-reacti ve pr otei n 
( hs-C R P), T B scree n, a n d st o ol sa m ple s h o ul d be o btai ne d a n d res ults m ust be a vaila ble a n d 
re vie we d pri or t o ra n d o mizati o n. I n t he case of ne w cli nical la b orat or y a b n or malities detecte d 
pri or t o ra n d o mizati o n, t he eli gi bilit y of t he s u bject s h o ul d be rec o nsi dere d wit h t he g ui da nce o f 
t he Me dical M o nit or. 
9. 3. 1 1.  
Pr oct osi g m oi d osc o p y/ C ol o n osc o p y a n d M o difie d M a y o Sc ore Deri v ati o n   
•  Pr oct osi g m oi d osc o p y/c ol o n osc o p y m ust be perf or me d pri or t o ra n d o mizati o n of 
treat me nt t o all o w ce ntral rea der re vie w ( ma y ta ke a p pr o xi matel y 5 t o 1 2 da ys) a n d 
c o nfir mati o n of eli gi bilit y. Prefera bl y, pr oct osi g m oi d osc o p y/c ol o n osc o p y s h o ul d be 
perf or me d after ot her criteria f or i ncl usi o n (e g, la b orat or y criteria) ha ve bee n met.  
•  Dete r mi n ati o n of M M S sc ore t o q u alif y f or r a n d o miz ati o n:  
− T he M M S will be e val uate d at Da y  1. T he s u bsc ores f or S F a n d R B are deri ve d 
fr o m t he s u bject e Diar y e ntries usi n g t he sc ores fr o m t he 3 m ost rece nt 
c o nsec uti ve da ys wit hi n t he 7  da ys pri or t o t he da y of b o wel pre parati o n 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 4 9  of 1 0 7  
(e xcl u di n g t he da y of b o wel pre parati o n), a vera ge d a n d r o u n de d t o t he nearest 
i nte ger. T he sc ori n g will be calc ulate d electr o nicall y. S u bjects w h o d o n ot ha ve 
3 -c o nsec uti ve da ys  of e Diar y data wit hi n t hat 7 -da y peri o d a n d w h o d o n ot ha ve a 
mi ni m u m of 7  da ys of e Diar y data pri or t o b o wel pre parati o n are n ot eli gi ble f or 
ra n d o mizati o n. T he M M S m ust be 4 t o 6, i ncl u di n g a n E S  ≥ 2  a n d R B sc ore ≥ 1  
f or t he s u bject t o be eli gi ble f or ra n d o mizati o n. 
− F or t he n or mal S F, it is esse ntial f or t he s u bj ect t o be as ke d t o i de ntif y h o w ma n y 
st o ols he or s he has i n a 2 4-h o ur peri o d w he n i n re missi o n fr o m U C. S u bjects 
s h o ul d be i nstr ucte d t hat a st o ol is defi ne d as a tri p t o t he t oilet w he n t he s u bject 
has eit her a b o wel m o ve me nt, or passes bl o o d al o ne, bl o o d a n d m uc us, or m uc us 
o nl y. If t he s u bject d oes n ot re p ort t hat he or s he has ac hie ve d re missi o n, t he n t he 
s u bject s h o ul d be as ke d t o i de ntif y t he n u m ber of st o ols he or s he ha d bef ore 
i nitial o nset of si g ns a n d s y m pt o ms of U C. 
9. 4.  
R a n d o miz ati o n/ Tre at me nt Peri o d   
9. 4. 1.  
Wee k  0/ D a y  1: Prer a n d o miz ati o n   
At t he Wee k  0/ Da y  1 visit ( A p pe n di x  1 , Ta ble  6 ), pri or t o ra n d o mizati o n, a 1 2 -lea d E C G i n t he 
s u pi ne p ositi o n a n d resti n g vital si g ns i n t he sitti n g p ositi o n (heart rate , s yst olic a n d diast olic B P, 
b o d y te m perat ure, a n d res pirat or y rate) will be c ollecte d. Caffei ne a n d/ or nic oti ne are n ot 
per mitte d wit hi n 3 0  mi n utes pri or t o B P meas ure me nts.  
S u bjects wit h t he f oll o wi n g m ust n ot be ra n d o mize d a n d s h o ul d be c o nsi dere d scree n fail ures:  
•  Sitti n g v ital si g n assess me nt: Heart  rate <  5 0  b p m O R s yst olic B P <  9 0  m m  H g O R 
diast olic B P <  5 5  m m  H g  
•  1 2 -lea d E C G s h o wi n g a sec o n d-de gree or t hir d -de gree A V bl oc k, peri o ds of as yst ole 
>  3  sec o n ds, P R i nter val > 2 0 0  ms, or Q Tc F ≥ 4 5 0  ms ( me n) or Q Tc F  ≥ 4 7 0  ms 
( w o me n) 
All pre -d ose  1 2 -lea d E C Gs s h o ul d be o btai ne d pri or t o bl o o d sa m ple c ollecti o n. 
S u bjects w h o c o nti n ue t o meet all eli gi bilit y criteria will be ra n d o mize d as o utli ne d i n 
Secti o n  6. 4 . 
9. 4. 2.  
Tre at me nt Peri o d   
After ra n d o mizati o n, t he 1 2 -Wee k Treat me nt Peri o d of t he st u d y will be gi n 
(A p pe n di x  1 , Ta ble  6 ). A st u d y visit wi n d o w of ±  3  da ys is per mitte d at eac h visit be gi n ni n g wit h 
Wee k  2/ Da y  1 5 ( P F T a n d O C T assess me nts ha ve a wi n d o w of ±  7  da ys).  After t he Wee k  1 2 
visit, a st u d y visit wi n d o w of ±  7  da ys is per mitte d. St u d y visits s h o ul d be sc he d ule d f or t he 
m or ni n g.  
T he s u bsc ores f or S F a n d R B are deri ve d fr o m t he s u bject e Diar y e ntries. O n visits w he n M M S 
is calc ulate d, t hese s u bsc ores are deri ved usi n g t he sc ores fr o m t he 3  m ost rece nt c o nsec uti ve 
da ys wit hi n t he 7  da ys pri or t o t he da y of b o wel pre parati o n (e xcl u di n g t he da y of b o wel 
pre parati o n), a vera ge d a n d r o u n de d t o t he nearest i nte ger. If 3  c o nsec uti ve da ys are n ot a vaila ble, 
t he n t he a vera ge of t he 2 m ost rece nt c o nsec uti ve da ys wit hi n t he 7  da ys will be use d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 0  of 1 0 7  
O n visits wit h o ut e n d osc o p y, t he S F a n d R B s u bsc ores are deri ve d usi n g t he sc ores fr o m t he 
3  m ost rece nt c o nsec uti ve da ys wit hi n t he 7  da ys pri or t o t he date of visit, a vera ge d a n d r o u n de d 
t o t he nearest i nte ger. If 3 c o nsec uti ve da ys are n ot a vaila ble, t he n t he a vera ge of t he 2 m ost 
rece nt c o nsec uti ve da ys wit hi n t he 7  da ys will be use d.  
It is rec o m me n de d t hat pr oce d ures are perf or me d i n a c o nsiste nt or der a n d at a p pr o xi matel y t he 
same ti me of da y f or eac h visit. Bel o w is t he rec o m me n de d se q ue nce of e ve nts:  
•  Q uesti o n naire a d mi nistrati o n  
•  A d verse e ve nt re vie w  
•  Vital si g ns  
•  1 2 -lea d E C G (as i n dicate d i n t he Sc he d ule of Assess me nts, A p pe n di x  1 , Ta ble  6 ) 
•  P h ysical e xa mi nati o n  
•  EI Ms (as i n dicate d i n t he Sc he d ule of Assess me nts,  A p pe n di x  1 , Ta ble  6 ) 
•  P F T (as i n dicate d i n t he Sc he d ule of Assess me nts,  A p pe n di x  1 , Ta ble  6 ) 
•  O C T (as i n dica te d i n t he Sc he d ule of Assess me nts, A p pe n di x  1 , Ta ble  6 ) 
•  Bl o o d sa m ple c ollecti o n f or la b orat or y tests a n d pre -d ose  P K sa m pli n g  
9. 4. 2. 1.  
G ui d a nce f or C ar di ac M o nit ori n g F oll o wi n g Tre at me nt I niti ati o n or 
Re -I niti ati o n  
Prera n d o mizati o n (ie, pre -d ose / baseli ne) f ull vital si g ns (resti n g heart  rate, s yst olic a n d diast olic 
B P, b o d y te m perat ure, a n d res pirat or y rate) a n d a  1 2 -lea d E C G (ta ke n wit h t he s u bject i n t he 
s u pi ne p ositi o n) will be assesse d a n d use d as t he baseli ne meas ure me nt. T he l o west pre -d ose 
heart  rate meas ure me nt u si n g vital si g ns will be use d f or c o m paris o n t o t he  p ost -d ose 
meas ure me nt. After c o nfir mi n g e nr oll me nt eli gi bilit y, a H olter m o nit or will be place d o n 
s u bjects pri or t o treat me nt a d mi nistrati o n. S u bjects s h o ul d recei ve t he first d ose of st u d y 
treat me nt bef ore 1 2: 0 0 P M  ( n o o n). First D ose Car diac M o nit ori n g will be gi n u p o n treat me nt 
a d mi nistrati o n.  
H olter Rec or di n g  
H olter rec or di n g will be c o n d ucte d i n a d diti o n t o F irst D ose C ar diac M o nit ori n g if/ w he n 
a vaila ble a n d w here all o we d b y re g ulat or y a ut h orities a n d l ocal et hics c o m mittees.  
At t he Wee k  0/ Da y  1 visit (Ta ble  6 ), o nce eli gi bilit y is c o nfir me d, a H olter m o nit or will be 
place d o n t he s u bject at t he st u d y site a n d c o nti n u o us H olter rec or di n g s h o ul d be gi n 
a p pr o xi matel y 1 5  mi n utes bef ore first a d mi nistrati o n of st u d y treat me nt. If t he s u bject meets t he 
disc har ge criteria after car diac m o nit ori n g i n <  8  h o urs f oll o wi n g t he first a d mi nistrati o n of st u d y 
treat me nt, t he s u bject will be disc har ge d fr o m t he st u d y site wit h t he H olter m o nit or i n place a n d 
c o nti n ue t o wear t he H olter m o nit or u ntil H o ur  8  (±  1 5  mi n utes) p ost -treat me nt a d mi nistrati o n. 
S u bjects will be i nstr ucte d o n h o w t o re m o ve t he H olter m o nit or at H o ur  8  ( ± 1 5  mi n utes) a n d t o 
ret ur n t he de vice f or a nal ysis at t he ne xt i n-pers o n st u d y visit. If t he s u bject re q uires e xte n de d 
i n-cli nic car diac m o nit ori n g ≥ 8  h o urs, t he H olter will be re m o ve d o nsite at H o ur  8  
( ± 1 5  mi n utes) , pri or t o disc har ge.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 1  of 1 0 7  
A d diti o nal details a b o ut t he H olter rec or di n g pr oce d ure  will be pr o vi de d i n t he H olter Ma n ual 
a n d s u bject i nstr ucti o ns.  
First D ose C ar di ac M o nit ori n g  
I n-cli nic car diac m o nit ori n g, of at least 4  h o urs, will occ ur o n Da y  1 a n d will i ncl u de t he 
f oll o wi n g (Ta ble 2 ): 
•  After t he first a d mi nistrati o n of st u d y treat me nt o n Da y  1, s u bjects m ust re mai n u n der 
o bser vati o n i n t he cli nic f or at least 4  h o urs.  
•  At H o urs  1, 2, a n d 3 ( ±  1 5  mi n utes) p ost -d ose , t he heart  rate a n d syst olic a n d diast olic 
B P will be assesse d wit h t he s u bject i n t he sitti n g p ositi o n, wit h t he ti me rec or de d. If 
t he s u bject has a heart  rate <  5 0  b p m or if car di o vasc ular s y m pt o ms de vel o p, t he n t he 
s u bject s h o ul d re mai n cl osel y m o nit ore d, i ncl u di n g 1 2-lea d E C Gs as cli nicall y 
i n dicate d, u ntil t he H o ur 4 disc har ge assess me nt.  
•  At t he H o ur  4 ( ±  1 5  mi n utes) disc har ge assess me nt, heart  rate a n d s yst olic a n d 
diast olic B P will be assesse d wit h t he s u bject i n t he sitti n g p ositi o n a n d a 1 2 -lea d 
E C G ( wit h t he s u bject i n t he s u pi ne p ositi o n) will be perf or me d. S u bjects ma y be 
disc har ge d fr o m t he cli nic after t he 4 -h o ur assess me nt if t he y meet t he criteria 
descri be d i n Ta ble 3 . S u bjects n ot meeti n g t he disc har ge criteria will re q uire e xte n de d 
m o nit ori n g as descri be d bel o w.  
•  S u bjects e x perie nci n g a cli nicall y rele va nt treat me nt -relate d s y m pt o matic e ve nt (e g, 
c hest pai n, dizzi ness, pal pitati o ns, or s y nc o pe) ass ociat e d wit h re d ucti o n of t he heart  
rate or cli nicall y rele va nt 1 2 -lea d E C G c ha n ges at a n y ti me d uri n g t he 4-h o ur 
m o nit ori n g peri o d m ust be disc o nti n ue d fr o m treat me nt ( Ta ble  4 ). 
T a ble 2 : 
Pr oce d ures t o be Perf or me d D uri n g t he M o nit ori n g Peri o d  
Pr oce d ure  
Pre -d ose  
H o urs  1, 2, 3 P ost -d ose a        
H o ur  4 P ost -d ose a 
Bl o o d press ure a n d heart rate b         
x  
x  
x  
1 2 -lea d E C G 
x  
 
x  
Assess disc har ge criteria  
 
 
x  
a Meas ure me nts ma y be ta ke n ±  1 5  mi n utes of t he sc he d ule d ti me.   
b Heart rate is base d o n vital si g ns.  
E C G, electr ocar di o gra m  
T a ble 3 : 
Disc h ar ge Criteri a After C ar di ac M o nit ori n g  
S u bjects will be rele ase d fr o m t he cli nic al site after d osi n g o n D a y  1 ( b ut n o s o o ner t h a n 4  h o urs p ost -d ose) 
w he n t he y f ulfill t he f oll o wi n g disc h ar ge criteri a: 
•  
Heart rate ≥ 5 0  b p m or n o m ore t ha n 1 0  b p m l o wer t ha n t he pre -d ose  ( baseli ne) val ue 
•  
N o e vi de nce of sec o n d -de gree  A V bl oc k or hi g her  
•  
N o car diac s y m pt o ms (e g, c hest pai n, dizzi ness, pal pitati o ns, li g ht hea de d n ess, s h ort ness of breat h, 
or s y nc o pe)  
N ote:  S u bjects s h o ul d ha ve writte n i nstr ucti o ns o n w he n t o ret ur n t o t he cli nic a n d a 2 4 -h o ur c o ntact p h o ne n u m ber t o call i n t he 
e ve nt of a n y ne w or w orse ne d car di o vasc ular s y m pt o ms.  
A V, atri o ve ntric ular ; b p m, beats per mi n ute  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 2  of 1 0 7  
E xte n de d C ar di ac M o nit ori n g  
S u bjects w h o d o n ot meet disc har ge criteria at 4  h o urs p ost -d ose  will re q uire e xte n de d car diac 
m o nit ori n g:  
•  Vital si g ns will be assesse d h o url y a n d 1 2 -lea d E C G ma y be perf or me d, as cli nicall y 
i n dicate d, u ntil t he s u bject meets t he disc har ge criteria (Ta ble 3 ). 
•  T he Me dical M o nit or s h o ul d be c o ntacte d if t he s u bject d oes n ot meet t he disc har ge 
criteria after ≥ 4  h o urs of e xte n de d car diac m o nit ori n g (ie, a p pr o xi matel y 8  h o urs 
after d osi n g).  
•  A n y s u bject w h o re q uires e xte n de d m o nit ori n g o n Da y  1 m ust ret ur n o n Da y  2 f or t he 
sec o n d d ose a n d will be re-m o nit ore d as o n Da y  1 , i ncl u di n g 8-h o ur H olter rec or di n g 
(refer t o Se cti o n 9. 9. 4 ). S u bjects will be disc o nti n ue d fr o m st u d y treat me nt if t he y d o 
n ot meet t he disc har ge criteria at 4  h o urs after t he sec o n d d ose  o n Da y  2 . F or t he 
safet y of t he s u bject, e xte n de d car diac m o nit ori n g s h o ul d be c o nti n ue d u ntil t he 
s u bject meets t he disc har ge criteria (Ta ble 3 ). 
•  S u bjects e x perie nci n g a s y m pt o matic e ve nt (e g, c hest pai n, dizzi ness, pal pitati o ns, 
li g ht hea de d ness, s h ort ness of breat h, or s y nc o pe) at a n y ti me d uri n g t he 4-h o ur 
m o nit ori n g peri o d  o n Da y 1  t hat is n ot ass ociate d wit h eit her a re d ucti o n i n heart rate 
or c li nicall y rele va nt c ha n ge i n 1 2-lea d E C G, ma y be disc har ge d pr o vi de d t he y meet 
t he disc har ge criteria (Ta ble 3 ), a n d as dee me d a p pr o priate b y t he I n vestigat or; 
h o we ver,  t hese s u bjects m ust ret ur n o n Da y 2 f or t he sec o n d d ose a n d will be 
re-m o nit ore d as o n Da y  1. T hese s u bjects m ust be disc o nti n ue d fr o m treat me nt if t he y 
d o n ot meet t he disc har ge criteria at 4  h o urs after t he sec o n d d ose o n Da y  2 a n d 
e xte n de d car diac m o nit ori n g s h o ul d be c o nti n ue d u ntil t he s u bject meets t he 
disc har ge criteria  
(Ta ble 3 ). 
St u d y Tre at me nt Disc o nti n u ati o n Rel ate d t o P ost -D ose  C ar di ac M o nit ori n g  
A c o m plete list of reas o ns f or st u d y treat me nt disc o nti n uati o n is pr o vi de d i n Secti o n  5. 1 . 
Reas o ns f or st u d y treat me nt disc o nti n uati o n s pecific t o p ost -d ose  car diac m o nit ori n g are 
pr o vi de d i n  Ta ble  4 . T he Me dical M o nit or s h o ul d be c o ntacte d bef ore disc o nti n ui n g a s u bject.  
T a ble  4 : 
Disc o nti n u ati o n of St u d y Tre at me nt Rel ate d t o P ost -D ose  C ar di ac 
M o nit ori n g   
Re as o ns f or St u d y Tre at me nt Disc o nti n u ati o n Rel ate d t o P ost -d ose C ar di ac M o nit ori n g a        
•  
S u bjects w h o ha ve a car di o vasc ular treat me nt-relate d s y m pt o matic e ve nt (e g, c hest pai n, dizzi ness, 
pal pitati o ns, li g ht hea de d ness, s h ort ness of breat h, or s y nc o pe) ass ociate d wit h re d ucti o n of t he heart 
rate or ass ociate d wit h cli nicall y rele va nt 1 2-lea d E C G c ha n ges at a n y ti me d uri n g t he 4 -h o ur  
m o nit ori n g p eri o d o n Da y  1 or Da y  2 (as a p plica ble).  
•  
S u bjects w h o ha ve n ot met t he disc har ge criteria o n Da y  1 after ≥ 4  h o urs of e xte n de d m o nit ori n g, 
or Da y  2 b y 4  h o urs p ost -d ose . 
a All treat me nt disc o nti n uati o ns s h o ul d be disc usse d wit h t he Me dical M o nit or. 
E C G, electr ocar di o gra m  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 3  of 1 0 7  
C ar di ac M o nit ori n g U p o n Tre at me nt Re -I niti ati o n F oll o wi n g D ose I nterr u pti o n 
S u bjects s h o ul d u n der g o t he sa me F irst D ose C ar diac M o nit ori n g pr oce d ures as t he ori gi nal 
treat me nt i nitiati o n w he n st u d y treat me nt d osi n g is re-i nitiate d after i nterr u pti o n f or: 
•  ≥ 2  c o nsec uti ve da ys wit hi n t he first wee k of treat me nt  
•  ≥ 7  c o nsec uti ve da ys after t he first wee k of treat me nt  
H olter rec or di n g will n ot be re peate d f or treat me nt re-i nitiati o n. 
9. 4. 3.  
E nr oll me nt i n O pe n -L a bel E xte nsi o n St u d y A P D 3 3 4 -3 0 3   
At t he Wee k  1 2 assess me nt a deter mi nati o n will be ma de re gar di n g c o nti n uati o n i nt o t he 
4 0 -Wee k Treat m e nt Peri o d or eli gi bilit y f or e ntr y i nt o t he O L E ( Secti o n  5. 1. 1 ). 
S u bjects w h o disc o nti n ue treat me nt pre mat urel y s h o ul d ha ve a n E T  visit as i n dicate d  i n t he 
Sc he d ule of Assess me nts ( A p pe n di x  1 , Ta ble  6 ). If t he E T  visit is wit hi n 4  wee ks of t he last 
pr oct osi g m oi d osc o p y a n d bi o ps y, t hese pr oce d ures d o n ot nee d t o be re peate d.  
T he Da y  1 visit of t he O L E st u d y m ust occ ur wit hi n 1 4  da ys of t he last o n treat me nt visit of t his 
st u d y. I n t he e ve nt t here is a ga p bet wee n t he last o n treat me nt visit a n d W 0/ D 1 of t he O L E, t he 
s u bject s h o ul d c o nti n ue t heir d o u ble-bli n d st u d y me dicati o n fr o m St u d y  A P D 3 3 4 -2 1 0 u ntil t he 
da y bef ore t he W 0/ D 1 visit. A d diti o nal d o u ble -bli n d st u d y me dicati o n ma y be dis pe nse d, if 
re q uire d. 
9. 5.  
F oll o w -U p Peri o d   
F or s u bjects n ot partici pati n g i n t he O L E st u d y, f oll o w -u p visits will be perf or me d at 2  a n d 
4  w ee ks after t he last a d mi nistrati o n  of st u d y treat me nt as i n dicate d i n t he Sc he d ule of 
Assess me nts ( A p pe n di x  1 , Ta ble  6 ). 
If t he E T or St u d y C o m pleti o n visit is ≥ 2  wee ks after t he last a d mi nistrati o n of st u d y treat me nt, 
t he 2-Wee k F oll o w -U p visit is n ot re q uire d; h o we ver, t he 4 -Wee k F oll o w -U p visit s h o ul d be 
sc he d ule d a n d c o m plete d. If t he E T or St u d y C o m pleti o n visit is ≥ 4  wee ks after t he la st 
a d mi nistrati o n of st u d y treat me nt, t he 4 -Wee k F oll o w -U p visit is n ot re q uire d.  
If t he a bs ol ute peri p heral l y m p h oc yte c o u nt is n ot wit hi n n or mal li mits at t he 4-Wee k F oll o w -U p 
visit, s u bjects s h o ul d ret ur n f or C B C wit h differe ntial acc or di n g t o l ocal sta n dar d of care 
(ca pt ure d as s u bse q ue nt F oll o w-U p visit or u nsc he d ule d visit).  
All a d verse e ve nts s h o ul d be rec or de d f or 3 0  da ys after last a d mi nistrati o n of st u d y treat me nt 
( Secti o n 9. 9. 9. 2. 2 ). 
9. 6.  
Virt u al/ H y bri d Visits   
St u d y visits after Da y  1 ma y be c o n d ucte d via o nsite (i n -pers o n), virt ual (e g, tele p h o ne, vi de o 
c o nfere nce), h o me healt h visit b y st u d y staff or desi g nee, or a c o m bi nati o n of af ore me nti o ne d 
visit t y pes de pe n di n g o n t he nat ure of t he st u d y assess me nt, tec h n ol o gical ca pa bilit y, a n d 
acce pta bilit y wit h i nstit uti o nal practices a n d i n ali g n me nt wit h l ocal la w a n d re g ulat or y 
re q uire me nts. A h y bri d visit ma y c o nsist of virt ual, i n-h o me assess me nts a n d/ or o nsite 
assess me nts t hat ma y be perf or me d o n differe nt da ys wit hi n t he st u d y visit wi n d o w.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 4  of 1 0 7  
Certai n assess me nts a n d/ or pr oce d ures will n ot  be perf or me d i n t he h o me setti n g (e g, 
e n d osc o pies, O C T, P F T, car diac m o nit ori n g  f oll o wi n g treat me nt i nitiati o n or re-i nitiati o n, a n d 
1 2 -lea d E C G). 
Pre g na nc y testi n g a n d ce ntral la b orat or y assess me nts (e g, bl o o d, st o ol, a n d uri ne sa m ples) ca n be 
perf or me d b y eit her o nsite visit or offsite vi sit. 
Assess me nts or pr oce d ures t hat ma y be c o n d ucte d virt uall y, if all o we d b y l ocal la w a n d 
re g ulati o n, i ncl u de f or e xa m ple: M e dical a n d me dicati o n hist or y t o assess eli gi bilit y criteria, 
re vie w of de m o gra p hic i nf or mati o n, s ocial hist or y, A E q uer y, re vie w of c o nc o mita nt 
me dicati o ns, e Diar y trai ni n g, a n d c o m plia nce re vie w/ m o nit ori n g i ncl u di n g st u d y dr u g 
a d mi nistrati o n.  
D uri n g a virt ual assess me nt, a s u bject ma y re p ort a n A E  t hat re q uires a f oll o w-u p 
s y m pt o m-f oc use d p h ysical e xa m or dia g n ostic test, as deter mi ne d b y t he I n vesti gat or. I n t his 
sce nari o, t he I n vesti gat or ma y ha ve t he s u bject ret ur n t o t he st u d y site f or a n u nsc he d ule d st u d y 
visit t o perf or m t he assess me nt.  
F or st u d y dr u g acc o u nta bilit y, t he me dicati o n b ottle a n d re mai ni n g ta blets ma y be vis uall y 
i ns pecte d a n d c o u nte d o n vi de o c o nfere nci n g. S u bjects m ust ret ur n t he dis pe nse d b ottle wit h t he 
re mai ni n g ta blets al o n g wit h a n y e m pt y b ottles t o t he st u d y site at t he ne xt o nsite visit. Refer t o 
Secti o n  8  f or st u d y treat me nt ma na ge me nt. 
Re gar dless of h o w a st u d y visit a n d its ass ociate d pr oce d ures are c o n d ucte d, all st u d y pr oce d ures 
s h o ul d be perf or me d b y a p pr o priatel y q ualifie d st u d y site staff or q ualifie d i n di vi d ual as 
dele gate d b y t he Pri nci pal I n vesti gat or.  
St u d y visits are desi g nate d acc or di n gl y i n t he Sc he d ule of Assess me nts ( A p pe n di x  1 , Ta ble  6 ). 
9. 7.  
P h ar m ac o ki netics   
Bl o o d sa m ples f or a nal ysis of etrasi m o d  will be c ollecte d at t he f oll o wi n g ti me p oi nts fr o m all 
s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g (et rasi m o d or place b o): 
•  Pre -d ose  a n d at 4  h o urs ( ±  1 5  mi n utes) p ost -d ose  (after 1 2-lea d E C G) o n 
Wee k  0/ Da y  1  
•  Pre -d ose  (tr o u g h) at Wee ks  2, 4, 8, 1 2, 1 6, 2 4, 3 2, 4 8, 5 2 , a n d E T  ( o nl y re q uire d if E T 
visit  ≤ 3 0  h o urs si nce last treat me nt a d mi nistrati o n ) 
•  At 2 -Wee k a n d 4 -Wee k F oll o w -U p  visits  
•  If p ossi ble, at t he ti me of a n y S A E or a d verse e ve nt lea di n g t o st u d y treat me nt 
disc o nti n uati o n  
S u bjects s h o ul d be i nstr ucte d t o d oc u me nt t he ti me of t heir last a d mi nistrati o n of st u d y treat me nt 
pri or t o t he st u d y visit a n d t he ti me m ust be rec or de d i n t he e C R F. T he ti me of a d mi nistrati o n of 
st u d y treat me nt d uri n g t he st u d y visit m ust als o be rec or ded i n t he s o urce al o n g wit h t he ti me of 
eac h P K sa m ple.  
Bl o o d sa m ples will be pr ocesse d f or c ollecti o n of plas ma fracti o ns f or deter mi nati o n of t he 
c o nce ntrati o ns of etrasi m o d.  F or t he place b o gr o u p, a selecte d n u m ber of sa m ples will be 
a nal yze d. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 5  of 1 0 7  
Plas ma P K sa m ples ma y als o be use d f or pr ofili n g of dr u g-bi n di n g pr otei ns, bi oa nal ytical 
met h o d vali dati o n p ur p oses, sta bilit y assess me nts, or t o assess ot her acti o ns of etrasi m o d wit h 
plas ma c o nstit ue nts.  
N o uri ne sa m ples will be c ollecte d f or P K a nal ysis.  
Sa m ple c ollecti o n, pre parati o n, a n d s hi p pi n g will be detaile d i n a La b orat or y Ma n ual.  
9. 8.  
Effic ac y Assess me nts   
T he Ma y o Cli nic Sc ore ( M C S ), a n d its c o m p o ne nt s u bsc ores will be use d t o assess efficac y. T he 
efficac y  e n d p oi nt  defi niti o ns f or  M M S  a n d T M S are  o utli ne d i n Secti o n  1 0. 5 . 
9. 8. 1.  
M a y o Cli nic Sc ore   
T his st u d y utilizes t he M C S , a c o m p osite of 4 assess me nts eac h rate d fr o m 0 t o 3: S F, R B, E S, 
a n d P h ysicia n’s Gl o bal Assess me nt ( P G A). T he M M S is a deri vati ve of t he M C S  a n d base d o n a 
c o m p osite of 3  assess me nts o nl y: S F, R B, a n d E S.  
B ot h T M S a n d M M S re q uire dail y s u bject -re p orte d R B a n d S F sc ores; t heref ore, t he i m p orta nce 
of dail y rec or di n g of R B a n d S F b y s u bjects i n t heir dail y e Diar y s h o ul d be stresse d b y t he 
I n vesti gat ors ( A p pe n di x 1, Ta ble  6 ). 
E n d osc o p y will be use d t o vis ualize t he m uc osa t o e na ble calc ulati o n of t he E S.  
E n d osc o pic sc ore ( E S): T he E S re p orts t he w orst a p peara nce of t he m uc osa o n fle xi ble 
si g m oi d osc o p y or c ol o n osc o p y, o n a 4-p oi nt scale ( A p pe n di x 3 ). Co nsiste nt wit h re g ulat or y 
a d vice, t his st u d y e xcl u des fria bilit y fr o m t he defi niti o n of a n E S of 1. T he E S will be 
deter mi ne d b y a bli n de d ce ntral rea der.  
Rect al blee di n g ( R B): T he R B s u bsc ore is a s u bject -re p orte d meas ure. T his ite m re p orts t he 
m ost se ver e a m o u nt of bl o o d passe d per rect u m i n a 2 4 -h o ur peri o d, o n a 4 -p oi nt scale 
(A p pe n di x 3 ). T he s u bject will rec or d t his i n t heir dail y e Diar y. T he meth o d f or calc ulati n g t he 
R B s u bsc ore is descri be d i n Secti o n  9. 4. 2 . 
St o ol fre q ue nc y ( S F):  T he S F s u bsc ore is a s u bject -re p orte d meas ure. T his ite m re p orts t he 
n u m ber of st o ols i n a 2 4 -h o ur peri o d, relati ve t o t he n or mal n u m ber of st o ols f or t hat s u bject i n 
t he sa me peri o d, o n a 4-p oi nt scale ( A p pe n di x 3 ). A st o ol is defi ne d as a tri p t o t he t oilet w he n 
t he s u bject has eit her a b o wel m o ve me nt, passa ge of bl o o d al o ne, passa ge of bl o o d a n d m uc us, 
or passa ge of m uc us o nl y. T he t otal n u m ber of st o ols passe d i n a 2 4 -h o ur peri o d will be rec or de d 
b y t he s u bject i n t heir dail y e Diar y. T he refere nce “ n or mal” S F f or t hat s u bject will be rec or de d 
electr o nicall y at t he Scree ni n g Visit a n d is t he n u m ber of st o ols i n a 2 4 -h o ur peri o d w he n t he 
s u bject is i n re missi o n. If t he s u bject has ne ver ac hie ve d re missi o n, t he re p orte d S F bef ore i nitial 
o nset of si g ns a n d s y m pt o ms of U C will be use d as t he refere nce S F. T he met h o d f or calc ulati n g 
t he S F s u bsc ore is descri be d i n Secti o n 9. 4. 2 . 
P h ysici a n’s Gl o b al Assess me nt ( P G A): T he P G A is a p h ysicia n -re p orte d meas ure t hat is a 
c o m p o ne nt of t he M C S  a n d is use d i n t he calc ulati o n of T M S. T he P G A s u m marizes t he 
I n vesti gat or’s assess me nt of t he s u bject’s U C disease acti vit y o n a 4 -p oi nt scale ( A p pe n di x 3 ). 
T he P G A ac k n o wle d ges t he 3 ot her M C S criteria , t he s u bject’s dail y rec ollecti o n of a b d o mi nal 
disc o mf ort a n d  ge neral se nse of well -bei n g, a n d ot her o bser vati o ns, s uc h as p h ysical fi n di n gs 
a n d t he s u bject’s perf or ma nce stat us. T he I n vesti gat or will rec or d t he P G A i n s o urce 
d oc u me ntati o n a n d t he e C R F at t he s pecifie d st u d y visits ( A p pe n di x  1 , Ta ble  6 ). 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 6  of 1 0 7  
9. 8. 2.  
R o b arts Hist o p at h ol o g y I n de x   
R o barts Hist o pat h ol o g y I n de x ( R HI) is a n e val uati ve i n de x, deri ve d fr o m t he Ge b oes sc ore, t hat 
is desi g ne d t o be re pr o d uci ble a n d res p o nsi ve t o cli nicall y mea ni n gf ul c ha n ge i n disease acti vit y 
o ver ti me  (A p pe n di x 4 ). 
U C -1 0 0 I n de x:  T he U C -1 0 0 i n de x is base d o n t h e Ma y o Cli nic S F  s u bsc ore, t he Ma y o Cli nic  
E S , a n d t he R HI sc ore. T hese 3 c o m p o ne nts are i nc or p orate d i nt o a calc ula ble fi nal i n de x. T he 
f or m ula f or t he c o m p osite U C-1 0 0 sc ore is: ( 1  +  1 6  ×  Ma y o Cli nic S F s u bsc ore [ 0  t o 3] + 
6  ×  Ma y o Cli nic  E S [ 0  t o 3] + 1  ×  R HI sc ore [ 0  t o 3 3]).  
9. 8. 2. 1.  
E n d osc o p y   
A fle xi ble pr oct osi g m oi d osc o p y, perf or me d wit h a vi de o e n d osc o pe f oll o wi n g clea nsi n g 
pre parati o n ( oral or rectal cat hartic), will be perf or me d d uri n g scree ni n g ( pri or t o 
Da y  1/r a n d o mizati o n), at Wee k  1 2, a n d at Wee k  5 2/ E T visit. A d diti o nal pr oct osi g m oi d osc o pies 
ma y be perf or me d t o c o nfir m disease w orse ni n g a n d are re q uire d f or q ualificati o n i nt o t he O L E 
( Secti o n 5. 1. 1 ). 
T o e ns ure q ualit y data a n d sta n dar dizati o n, t he sa me e n d osc o pist s h o ul d be use d t hr o u g h o ut t he 
st u d y w here ver p ossi ble. E n d osc o p y i ma ges will be o btai ne d d uri n g eac h e n d osc o p y a n d will be 
se nt f or ce ntral rea di n g a n d deter mi nati o n of t he Ma y o Cli nic E S . A detaile d i ma ge re vie w 
c harter fr o m t he ce ntral rea di n g la b orat or y will o utli ne t he e n d osc o pic pr oce d ures, vi de o 
rec or di n gs, a n d e q ui p me nt. F or eac h s u bject, a vi de o rec or di n g of t he e ntire e n d osc o pic 
pr oce d ure  will be perf or me d usi n g a n acce pta ble st ora ge me di u m. T he e n d osc o pic rec or di n gs 
will be rea d ce ntrall y i n a bli n de d ma n ner f or m uc osal lesi o ns a n d e n d osc o pic se verit y b y a 
q ualifie d gastr oe nter ol o gist acc or di n g t o t he i ma ge re vie w c harter. T he E S will be e val uate d b y 
t he I n vesti gat or a n d t he ce ntral rea der. T he ce ntral rea d will be use d f or deter mi nati o n of efficac y 
e n d p oi nts; h o we ver, treat me nt decisi o ns will be ma de b y t he treati n g I n vesti gat or.  
Re peate d fle xi ble pr oct osi g m oi d osc o p y ma y be per mitte d b y t he S p o ns or w he n t he ce ntral rea der 
i n dicates t hat t he vi de o e n d osc o pe data were ac q uire d i nc orrectl y or di d n ot meet t he mi ni mal 
re q uire d q ualit y sta n dar ds. 
N ote:  F or s u bjects wit h pa nc olitis >  8  years d urati o n or s u bjects wit h left -si de d c olitis > 1 2  years 
wit h o ut a s ur veilla nce c ol o n osc o p y wit hi n 1 2  m o nt hs pri or t o baseli ne ( Secti o n  4. 1 , I ncl usi o n 
Criteri o n  6 ), a c ol o n osc o p y a n d bi o psies ta ke n i n acc or da nce wit h l ocal sta n dar d of care at 
scree ni n g t o r ule o ut d ys plasia (ie, i n place of scree ni n g pr oct osi g m oi d osc o p y) is re q uire d. A ny 
a de n o mat o us p ol y ps m ust be re m o ve d pri or t o t heir first a d mi nistrati o n of st u d y treat me nt.  
9. 8. 2. 2.  
E n d osc o pic Bi o psies   
Per i ncl usi o n criteria ( Secti o n  4. 1 ), a hist o pat h ol o g y re p ort s u p p orti n g t he dia g n osis of U C m ust 
be a vaila ble i n t he s o urce d oc u me nts pri or t o ra n d o mizati o n. P ost -ra n d o mizati o n detecte d p ol y ps 
or s us pici o us fi n di n gs d uri n g e n d osc o p y will be ma na ge d as per l ocal sta n dar d of care. If a 
hist o pat h ol o g y re p ort is n ot a vaila ble, t he scree ni n g e n d osc o p y ma y ser ve as s uc h wit h hist ol o g y 
e val uate d at t he l ocal hist ol o g y la b orat or y.  
Bi o psies will be o btai ne d  at eac h e n d osc o p y t o s u p p ort assess me nt of t he hist o pat h ol o g y 
e n d p oi nts a n d, w here per mitte d,
 U p t o 4 bi o ps y 
pairs (ie, t otal 8) will be c ollecte d fr o m t he m ost affecte d area 1 5  t o 2 5  c m fr o m t he a nal ver ge. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 7  of 1 0 7  
F or s u bjects wit h pr octitis o nl y at baseli ne, bi o psies s h o ul d be ta ke n 8  t o 1 0  c m fr o m t he a nal 
ver ge.  
T he ori gi nal l ocati o n (c ol o nic se g me nt) of bi o ps y s peci me ns ac q uire d at scree ni n g m ust be 
clearl y i n dicate d. Detaile d i nstr ucti o ns f or e n d osc o pic bi o psies  (e g, n u m ber of bi o psies, a nat o mic 
site, n or mal or i nfla me d m uc osa) will be pr o vi de d. 
Bi o ps y sa m ples will be pr ocesse d b y a ce ntral la b orat or y a n d hist o pat h ol o gic sc ori n g usi n g t he 
Ge b oes, R o barts, a n d Na nc y hist o pat h ol o g y ( A p pe n di x 4 ) i n dices will be perf or me d b y a bli n de d 
ce ntral hist o pat h ol o g y rea der (Ge b oes 2 0 0 0 , Marc hal -Bresse n ot 2 0 1 7 , M osli 2 0 1 7 ). 
Bi o ps y s peci me n tra nsfer, pr ocessi n g, sli de pre parati o n a n d di gitizati o n of sli des f or 
hist o pat h ol o gic sc ori n g pr oce d ures will be detaile d i n a hist o pat h ol o g y ma n ual. Hist o pat h ol o g y 
res ults will n ot be ma de a vaila ble t o st u d y sites. 
 
. 
9. 8. 3.  
E xtr ai ntesti n al M a nifest ati o ns   
D uri n g t he s pecifie d f ull p h ysical e xa mi nati o ns ( A p pe n di x  1 , Ta ble  6 ) s pecific s yste ms (s uc h as 
e yes, li ver, s ki n, a n d j oi nts) will be e xa mi ne d f or EI Ms f or U C.  
9. 8. 4.  
A d diti o n al He alt h -Rel ate d S u bje ct-Re p orte d O utc o mes   
S u bject -re p orte d q ualit y of life i nstr u me nts will be c o m plete d electr o nicall y a n d c hec ke d f or 
c o m plete ness at t he st u d y site as i n dicate d i n t he Sc he d ule of Assess me nts (A p pe n di x  1 , Ta ble  6 ) 
a n d will be use d i n s u p p ort of t he efficac y o utc o mes.  
I nfl a m m at or y B o wel Dise ase Q uesti o n n aire (I B D Q): T he I B D Q is a vali date d 3 2 -ite m 
q uesti o n naire use d t o assess healt h -relate d q ualit y of life ( H R Q o L) i n s u bjects wit h I B D ( U C a n d 
C D). Res p o nse t o eac h of t he q uesti o ns is gra de d fr o m 1  t o 7 wit h o verall sc ore ra n gi n g fr o m 
3 2  ( ver y p o or H R Q o L) t o 2 2 4 ( perfect H R Q o L). 
Ulcer ati ve C olitis P atie nt -Re p orte d O utc o mes: T he U C -P R O is use d t o gat her d ata o n t he 
gastr oi ntesti nal si g ns a n d s y m pt o ms of U C directl y fr o m t he s u bject.  T he U C -P R O  is c o m prise d 
of 2 m o d ules U C -P R O/ S S a n d S yste mic S y m pt o ms . 
U C -P R O sc ori n g is deri ve d b y calc ulati n g t he a vera ge usi n g at least 4 o ut of 7 dail y sc ores, usi n g 
t he visit date t o deter mi ne t he da ys t o be use d. U C-P R O is a vaila ble o n t he s u bjects e Diar y 
1 4  da ys pri or t o a n d 1 4 da ys after t he pr ojecte d visit date. S u bject s h o ul d c o m plete U C -P R O 
w he n it bec o mes a vaila ble o n t he de vice f or t he visit, c o nti n ui n g u ntil t he vis it occ urs. 
•  Si g ns a n d S y m pt o ms ( U C -P R O/ S S): T he U C -P R O/ S S is a 9 -ite m q uesti o n naire 
c o ntai ni n g 2 d o mai ns: B o wel m o ve me nt si g ns a n d s y m pt o ms ( 6  ite ms) a n d f u ncti o nal 
s y m pt o ms ( 3 ite ms). A n a vera ge sc ore is calc ulate d f or eac h d o mai n; a hi g her sc ore 
i n dicates w orse s y m pt o ms.  
•  S yste mic S y m pt o ms : T he S yste mic S y m pt o ms meas ure i ncl u des 5 ite ms, sc ore d as a 
si n gle scale, t o a d dress t he prese nce a n d se verit y of s yste mic s y m pt o ms i ncl u di n g 
pai n, feeli n g tire d, lac k of a p petite, feeli n g wea k, a n d t hirst.  
F u ncti o n al As sess me nt of C hr o nic Ill ness T her a p y-F ati g ue  (F A CI T -F): T he F A CI T -F is a  
1 3 -ite m fati g ue i nstr u me nt utilize d t o assess fati g ue/ tire d ness a n d its i m pact o n dail y acti vities 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 8  of 1 0 7  
a n d f u ncti o ni n g i n a n u m ber of c hr o nic diseases. T he i nstr u me nt i ncl u des ite ms s uc h as tire d ness, 
wea k ness, listless ness, lac k of e ner g y, a n d t he i m pact of t hese feeli n gs o n dail y f u ncti o ni n g (e g, 
slee pi n g, a n d s ocial acti vities). 
Me dic al O utc o mes St u d y 3 6 -Ite m S h ort F or m He alt h S ur ve y Versi o n 2 P h ysic al a n d 
Me nt al C o m p o ne nt a n d D o m ai n Sc ores ( S F -3 6):  T he S F -3 6 is a 3 6 -ite m, s u bject-re p orte d 
s ur ve y of s u bject healt h. T he S F-3 6 c o nsists of 3 6  q uesti o ns meas uri n g 8  healt h d o mai ns: 
p h ysical f u ncti o ni n g, b o dil y pai n, r ole li mitati o ns d ue t o p h ysical pr o ble ms, r ole li mitati o ns d ue 
t o em oti o nal pr o ble ms, ge neral healt h perce pti o ns, me ntal healt h, s ocial f u ncti o n, a n d vitalit y. 
T he s u bject’s res p o nses are s olicite d usi n g Li kert scales t hat var y i n le n gt h, wit h 3  t o 6  res p o nse 
o pti o ns per ite m. T he S F -3 6 will be sc ore d usi n g 2  o verall s u m m ar y sc ores: P h ysical c o m p o ne nt 
s u m mar y a n d me ntal c o m p o ne nt s u m mar y sc ores. 
W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q uesti o n n aire –  Ulcer ati ve C olitis 
( W P AI-U C):  T he W P AI -U C c o nsists of 6  q uesti o ns as ki n g a b o ut t he effect of U C o n t he 
s u bject’s a bilit y to w or k a n d perf or m re g ular acti vities.  
Ur ge nc y N u meric R ati n g Sc ale ( N R S):  T he ur ge nc y N R S is a si n gle ite m t hat meas ures t he 
se verit y f or t he ur ge nc y (s u d de n or i m me diate nee d) t o ha ve a b o wel m o ve me nt i n t he past 
2 4  h o urs usi n g a n 1 1 -p oi nt N R S ra n gi n g fr o m 0 ( n o ur ge nc y) t o 1 0 ( w orst p ossi ble ur ge nc y).  
T he P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C):  T he P GI C is t he P R O c o u nter part t o t he 
Cli nical Gl o bal I m pressi o ns ( C GI) scale, w hic h was p u blis he d i n 1 9 7 6 b y t he Nati o nal I nstit ute 
of Me ntal Healt h ( U S). I t c o nsists of o ne ite m ta ke n fr o m t he C GI a n d a da pte d t o t he patie nt. 
9. 8. 5.  
Effic ac y -Rel ate d Bi o m ar kers   
Sa m ples f or bi o mar ker assess me nts will be c ollecte d acc or di n g t o t he Sc he d ule of  Assess me nts 
(A p pe n di x  1 , Ta ble  6 ). Bl o o d, tiss ue, a n d st o ol sa m ples will be a nal yze d b y t he ce ntral or 
s pecialt y la b orat or y. Details f or c ollecti o n, pr ocessi n g, a n d st ora ge will be pr o vi de d i n t he 
La b orat or y Ma n ual. Resi d ual sa m ples will be st ore d a n d ma y be use d f or a d diti o nal a nal yses if 
t he s u bject has gra nte d c o nse nt w here all o we d b y t he re g ulat or y a ut h orities a n d l ocal et hics 
c o m mittees. 
C -re acti ve pr otei n ( C R P):  C R P is a n ac ute p hase pr otei n e x presse d b y he pat oc ytes i n res p o nse 
t o i nfla m mat or y c yt o ki nes a n d will be assesse d usi n g a hs-C R P assa y. I n vesti gat ors will be 
bli n de d t o t he hs -C R P res ults d uri n g t he treat me nt a n d f oll o w -u p peri o ds . 
Fec al c al pr otecti n:  Fecal cal pr otecti n is a c o m ple x c o nsisti n g of calci u m -bi n di n g pr otei ns. It is 
e x presse d b y acti vate d ne utr o p hils (a n d t o a lesser e xte nt b y macr o p ha ges a n d m o n oc ytes) a n d 
fecal le vels c orrelate wit h t he n u m ber of ne utr o p hils i n t he g ut. It is use d as a bi o mar ker of 
i ntesti nal i nfla m mati o n. I n vesti gat ors will be bli n de d t o t he fecal cal pr otecti n res ults d uri n g t he 
treat me nt a n d f oll o w-u p peri o ds.  
L y m p h oc yte c o u nts: Etrasi m o d is belie ve d t o m o d ulate l y m p h oc yte traffic ki n g res ulti n g i n a 
re d ucti o n i n peri p heral l y m p h oc yte c o u nt a n d l y m p h oc yte a vaila bilit y f or recr uit me nt t o sites of 
i nfla m mati o n. D uri n g t he treat me nt peri o d, t he I n vesti gat or will be bli n de d t o t he w hite bl o o d 
cell ( W B C) a n d differe ntial c o u nts d uri n g t he treat me nt a n d f oll o w -u p peri o ds. D uri n g t he 
treat me nt peri o d, W B C differe ntial res ults will be assesse d b y a n u n bli n de d Me dical M o nit or 
( n ot pr o vi di n g direct me dical o versi g ht of st u d y c o n d uct). If eit her of t he f oll o wi n g occ ur, t he 
u n bli n de d Me dical M o nit or will n otif y t he  I n vesti gat or wit h a d diti o nal i nstr ucti o ns. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 5 9  of 1 0 7  
•  A N C <  1 0 0 0  cells/ μ L 
•  A L C <  2 0 0  cells/ μ L 
If t he A N C is c o nfir me d bel o w t he 1 0 0 0 cells/ µ L li mit, t he I n vesti gat or will be re q ueste d t o 
cl osel y m o nit or f or seri o us i nfecti o n a n d i nstit ute a p pr o priate f oll o w -u p at his or her discreti o n.  
If t he A L C is c o nfir me d bel o w t he 2 0 0 cells/ µ L li mit, st u d y treat me nt m ust be i nterr u pte d a n d 
s h o ul d n ot be re-i nitiate d if t he A L C re mai ns bel o w t his t hres h ol d. I n t his sit uati o n, t he 
u n bli n de d Me dical M o nit or will n otif y t he I n vest i gat or a n d pr o vi de i nstr ucti o ns o n a d diti o nal 
acti o ns t hat t he I n vesti gat or ma y nee d t o ta ke. W he n t here is at least o ne meas ure me nt of A L C 
<  2 0 0  cells/ µ L, bli n de d val ues ma y be release d t o treati n g p h ysicia ns a n d I n vesti gat ors as 
dee me d me dicall y necessar y t o m o nit or i nfecti o n a n d/ or ai d i n dia g n ostic w or k -u p as cli nicall y 
i n dicate d, a n d/ or as a t o ol t o assess t he effecti ve ness of t hera pe utic i nter ve nti o ns f or a n i nfecti o n. 
I n vesti gat ors will re peat C B C wit h differe ntials wee kl y u ntil A L C > 5 0 0  cells/ µ L. 
R e-i nitiati o n of t he st u d y treat me nt ca n o nl y be c o nsi dere d w he n A L C > 5 0 0  cells/ µ L. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 0  of 1 0 7  
9. 9.  
S afet y   
T he I n vesti gat or or site staff will be res p o nsi ble f or detecti n g, d oc u me nti n g, a n d re p orti n g e ve nts 
t hat meet t he defi niti o n of a n a d verse e ve nt or S A E ( Secti o n 9. 9. 9. 1 ). A d verse e ve nts will be 
c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A).  
9. 9. 1.  
P h ysic al E x a mi n ati o n   
F ull a n d s y m pt o m -directe d p h ysical e xa mi nati o ns will be perf or me d acc or di n g t o t he Sc he d ule 
of Assess me nts (A p pe n di x  1 , Ta ble  6 ). 
F ull p h ysical e xa mi nati o n i ncl u des t he f oll o wi n g assess me nts:  
•  Ge neral i ns pecti o n  
•  Wei g ht/ hei g ht ( hei g ht at scree ni n g o nl y)  
•  S ki n  
•  Hea d/ears/e yes/ n ose/t hr oat e xa mi nati o n  
•  Nec k  
•  Car diac e xa mi nati o n  
•  A usc ultati o n of l u n gs  
•  A b d o mi nal e xa mi nati o n (li ver, s plee n, a n d l o wer a b d o me n) 
•  Ne ur ol o gical assess me nt  
•  M usc ul os keletal assess me nt t o i ncl u de l o wer e xtre mit y e de ma e val uati o n  
S y m pt o m -directe d (f oc use d) p h ysical e xa mi nati o ns s h o ul d assess cli nicall y si g nifica nt c ha n ges 
fr o m f ull p h ysical e xa mi nati o ns or a n y ne w si g ns or s y m pt o ms.  
9. 9. 2.  
Vit al Si g ns   
Resti n g vital si g ns meas ure me nts will be perf or me d acc or di n g t o t he Sc he d ule of Assess me nts 
(A p pe n di x  1 , Ta ble  6 ) wit h t he s u bject i n t he sitti n g p ositi o n. Vital si g ns will be meas ure d pri or 
t o a n y bl o o d dra ws t hat occ ur at t he sa me st u d y visit. 
Bl o o d pres s ure ma y be meas ure d ma n uall y or b y a ut o mate d de vice. Pr o per tec h ni q ue s h o ul d be 
utilize d d uri n g t he meas ure me nt of B P t o i ncl u de t he f oll o wi n g:  
•  T he s u bject’s ar m s h o ul d be bare a n d s u p p orte d at heart le vel.  
•  A n a p pr o priatel y size d c uff (c uff bla d der e ncirc li n g at least 8 0 % of t he ar m) s h o ul d 
be utilize d. S u bject’s le gs s h o ul d n ot be cr osse d d uri n g t he e val uati o n.  
9. 9. 3.  
1 2 -Le a d Electr oc ar di o gr a m   
All 1 2 -lea d E C Gs will be perf or me d acc or din g t o Secti o n  9. 4. 2. 1  a n d t he Sc he d ule of 
Assess me nts (A p pe n di x  1 , Ta ble  6 ), a n d if cli nicall y i n dicate d at a n y ti me d uri n g t he treat me nt 
peri o d per I n vesti gat or discreti o n. All E C Gs will be rec or de d fr o m a 1 2-lea d E C G mac hi ne wit h 
t he s u bject i n t he s u pi ne p ositi o n. E ver y atte m pt s h o ul d be ma de t o e ns ure t he s u bject 1 2-lea d 
E C G rea di n gs are o btai ne d usi n g t he sa me mac hi ne t hr o u g h o ut t he st u d y.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 1  of 1 0 7  
I nter vals t o be pr o vi de d o n t he c o nfir me d rea d f or eac h safet y 1 2-lea d E C G are: R R, P R, Q R S, 
Q T, a n d Q Tc F. If a n E C G s h o ws a ne w o nset Q Tc i nter val >  5 0 0  ms d uri n g t he treat me nt peri o d, 
a re peate d E C G is warra nte d. If t his a b n or mal fi n di n g is c o nfir me d, st u d y treat me nt m ust be 
i nterr u pte d. Effecti ve dia g n ostic a n d t hera pe utic strate gies s h o ul d be e m pl o ye d. 
Re versi ble ca uses of pr ol o n ge d Q Tc i nter val (e g, electr ol yt e a b n or malities or h y p o ma g nese mia), 
s h o ul d be c orrecte d as cli nicall y i n dicate d. W he n e val uati n g a s u bject wit h ne w o nset Q Tc 
i nter val a b o ve 5 0 0 ms, referral t o a car di ol o gist e x perie nce d i n treati n g car diac c o n d ucti o n 
dis or ders s h o ul d be c o nsi dere d. Re -i nitiati o n of st u d y treat me nt ca n o nl y be c o nsi dere d after all 
of t he f oll o wi n g ha ve occ urre d:  
•  T he Q Tc F i nter val is <  4 5 0  ms ( me n) or <  4 7 0  ms ( w o me n)  
•  I n di vi d ual ris k-be nefit is fa v ora ble (as deter mi ne d b y t he I n vesti gat or, i n a gree me nt 
wit h t he car di ol o gist ), A N D  
•  After disc ussi o n wit h t he Me dical M o nit or.  
T he I n vesti gat or will be res p o nsi ble f or re vie w a n d i nter pretati o n of 1 2 -lea d E C Gs o nsite a n d 
deter mi ni n g if t he 1 2 -lea d E C G is n or mal, a b n or mal cli nicall y i nsi g nifica nt, or a b n or mal 
cli nicall y si g nifica nt.  Fi n di n gs will be d oc u me nte d i n t he e C R F.  
All 1 2 -lea d E C Gs perf or me d s h o ul d be a vaila ble f or c ollecti o n u p o n re q uest. 
9. 9. 4.  
H olter Rec or di n g   
C o nti n u o us H olter rec or di n g will be perf or me d w he n a vaila ble a n d w here all o we d b y re g ulat or y 
a ut h orities a n d l ocal et hics c o m mittees o n Wee k  0/ Da y  1 t hr o u g h 8 h o urs p ost-treat ment 
a d mi nistrati o n of Da y 1 as s pecifie d i n Secti o n  9. 4. 2. 1  a n d Ta ble  6 . T he H olter m o nit or will be 
w or n d uri n g t he First D ose Car diac M o nit ori n g. H olter data will be ca pt ure d o n t he de vice a n d 
se nt t o t he H olter la b orat or y. T he H olter la b orat or y will be res p o nsi ble f or ce ntral rea di n g, 
a nal ysis, a n d i nt er pretati o n. H olter rec or di n g re p orts will be a vaila ble t o t he I n vesti gat or 
f oll o wi n g a nal ysis b y t he H olter la b orat or y. 
A d diti o nal i nf or mati o n is pr o vi de d t o t he site i n t he H olter s u p p ort ma n ual. A c harter fr o m t he 
ce ntral H olter la b orat or y will o utli ne t he rec or di n g para meters, a nal ysis pr oce d ures, a n d 
e q ui p me nt. 
H olter rec or di n g will pri nci pall y be use d f or deter mi nati o n of heart rate a n d p ote ntial 
arr h yt h mias (e g, pa uses, A V bl oc k). T he ce ntral H olter la b orat or y ma y deter mi ne a d diti o nal 
para meters or p erf or m a d diti o nal a nal yses fr o m di gitize d H olter m o nit or rec or di n gs i ncl u di n g 
b ut n ot li mite d t o t h ose i n dicate d b y t he i nitial a nal yses or safet y e ve nts.  
9. 9. 5.  
P ul m o n ar y F u ncti o n Test   
P F Ts will be perf or me d acc or di n g t o t he Sc he d ule of Assess me nts (A p pe n di x  1 , Ta ble  6 ) a n d 
i ncl u des F E V1 a n d F V C meas ure me nts. All s u bjects will ha ve P F Ts perf or me d at Scree ni n g, 
Wee k  1 2, a n d Wee k  5 2, or at t he E T visit. P F Ts occ urri n g at t he E T visit t hat are wit hi n 4 wee ks 
o f t he last assess me nt will o nl y be re q uire d if cli nicall y i n dicate d. T he 2-Wee k F oll o w -U p visit 
assess me nt is o nl y re q uire d if cli nicall y i n dicate d.  
S u bjects wit h a hist or y of mil d p ul m o nar y disease (e g, ast h ma, c hr o nic o bstr ucti ve p ul m o nar y 
disease) will ha ve a d diti o nal P F Ts perf or me d at Wee k  3 2. S u bjects re p orti n g res pirat or y a d verse 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 2  of 1 0 7  
e ve nts s uc h as d ys p nea d uri n g t he treat me nt peri o d ma y ret ur n at a n  u nsc he d ule d visit f or 
assess me nt per I n vesti gat or discreti o n; a d diti o nal P F Ts ma y be perf or me d as cli nicall y i n dicate d.  
W he n a vaila ble, D L C O meas ure me nts will als o be perf or me d. W he n D L C O is n ot a vaila ble, 
sites s h o ul d c o ns ult t he S p o ns or or S p o ns or’s dele gate. T hese tests will be perf or me d at a 
q ualifie d p ul m o nar y f u ncti o n la b orat or y or res pirat or y de part me nt.  Refer t o t he A merica n 
T h oracic S ociet y/ E ur o pea n Res pirat or y S ociet y g ui deli nes f or sta n dar dizati o n of s pir o metr y a n d 
si n gle breat h deter mi nati o n of car b o n m o n o xi de u pta ke i n t he l u n g (MacI nt yre 2 0 0 5 , Miller 
2 0 0 5a , Miller 2 0 0 5 b ). 
T he safet y of trial s u bjects a n d site staff is para m o u nt, s o it is at t he I n vesti gat or’s discreti o n 
w het her P F T ca n be safel y a d mi nistere d t o trial s u bjects d uri n g t he treat me nt peri o d. T he 
I n vesti gat or s h o ul d e val uate o n a case-b y -case basis h o w best t o pr ocee d base d o n t he s u bject’s  
me dical hist or y, t he I n vesti gat or’s cli nical j u d ge me nt, a n d i n c o ns ultati o n wit h t he Me dical 
M o nit or. All reas o na ble eff orts s h o ul d be ma de t o e ns ure safet y a n d a d here nce t o t he pr ot oc ol. 
W he n a vaila ble, s pir o metr y ma y be c o n d ucte d at t he cli nical site i n stea d of at t he p ul m o nar y 
la b orat or y. If t he decisi o n is ma de t hat it is n ot a p pr o priate t o c o n d uct P F Ts d ue t o t he safet y 
c o ncer ns (e g, S A R S -C o V -2  [ C O VI D-1 9] tra ns missi o n), t he n t his decisi o n a n d rati o nale s h o ul d 
be a p pr o priatel y ca pt ure d i n t he s u bject’s  s o urce d oc u me ntati o n. W he n a vaila ble a n d safe ( d ue t o 
lifti n g of l ocal restricti o ns, re-o pe ni n g of l ocal P F T la bs, or i m pr o ve d safet y c o n diti o ns) t he tests 
s h o ul d be c o n d ucte d as s o o n as p ossi ble a n d as cl ose t o t he ti me p oi nts as o utli ne d i n t he 
pr ot oc ol.  
9. 9. 6.  
O p ht h al m osc o p y a n d O ptic al C o here nce T o m o gr a p h y   
A c o m plete o p ht hal m osc o p y a n d O C T assess me nt will be perf or me d acc or di n g t o t he Sc he d ule 
of Assess me nts (A p pe n di x  1 , Ta ble  6 ). O C T occ urri n g at t he E T visit t hat are wit hi n 4 wee ks of 
t he last assess me nt will o nl y be re q uire d if cli nicall y i n dicate d. T he 2-Wee k F oll o w -U p visit 
assess me nt is o nl y re q uire d if cli nicall y i n dicate d. A sta n dar d vis ual ac uit y c hart s h o ul d be use d 
f or t he vis ual ac uit y assess me nt. T he O C T mac hi ne use d s h o ul d prefera bl y n ot be c ha n ge d 
d uri n g t he st u d y t o all o w f or c o m paris o n of ce ntral f o veal t hic k ness meas ure me nts wit hi n eac h 
s u bject acr oss ti me p oi nts. 
Scree ni n g Visit : 
At t he scree ni n g o p ht hal m ol o g y visit, t he e ye e xa mi nati o n will i ncl u de:  
•  O p ht hal m ol o gic hist or y  
•  Best c orrecte d vis ual ac uit y meas ure me nt ( usi n g S nelle n c hart i nter nati o nall y [if 
a vaila ble])  
•  O p ht hal m osc o p y ( ma y i ncl u de c o ntact le ns bi o micr osc o p y t o e xa mi ne t he mac ula a n d 
o ptic disc). A dilate d f u n d us e xa m s h o ul d be perf or me d i n all s u bjects at t he 
Scree ni n g Visit a n d as nee de d at s u bse q ue nt visits i n s u bjects wit h si g nifica nt 
a b n or malities i de ntifie d o n t he scree ni n g e xa m.  
•  Meas ure me nt of ce ntral f o veal t hic k ness b y O C T (rec or de d i n micr o meters; re q uire d 
f or all s u bjects re gar dless of t he res ults of vis ual ac uit y or o p ht hal m osc o p y) 
•  Slit la m p e xa mi nati o n s h o ul d be perf or me d t o esta bli s h u veitis disease stat us ( yes/ n o). 
U veitis s h o ul d be c haracterize d a n d gra de d usi n g t he Sta n dar dizati o n of U veitis 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 3  of 1 0 7  
N o me nclat ure criteria. S u bjects wit h acti ve u veitis wit h o ut mac ular e de ma at 
Scree ni n g are eli gi ble t o e nr oll i n t he st u d y  
•  If t here is a s uspici o n of mac ular e de ma b y o p ht hal m osc o p y a n d i ncrease d ce ntral 
f o veal t hic k ness b y O C T, t he n a d diti o nal testi n g s h o ul d be c o nsi dere d at t he 
discreti o n of t he o p ht hal m ol o gist (f or e xa m ple, fl u orescei n a n gi o gra m ma y be 
perf or me d). S u bjects wit h dia g n ose d ma c ular e de ma at Scree ni n g s h o ul d be dee me d a 
scree ni n g fail ure a n d s h o ul d n ot be ra n d o mize d. 
•  O pti o nal pr oce d ures i n case of cli nicall y si g nifica nt a b n or malities o n o p ht hal mic 
e xa m ma y i ncl u de b ut are n ot li mite d t o:  
− Reti nal p h ot o gra p hs  
− I ntra oc ular press ure 
Sc he d ule d p ost -scree ni n g visits: 
At t he sc he d ule d o p ht hal m ol o g y visit, t he e ye e xa mi nati o n will i ncl u de:  
•  Best c orrecte d vis ual ac uit y meas ure me nt  
•  O p ht hal m osc o p y ( ma y i ncl u de c o ntact le ns bi o micr osc o p y t o e xa mi ne t he mac ula a n d 
o ptic disc)  
•  Meas ure me nt of ce ntral f o veal t hic k ness b y O C T  
•  F or s u bjects wit h u veitis fi n di n gs o n o p ht hal mic e xa m, a d diti o nal testi n g s h o ul d be 
c o nsi dere d (f or e xa m ple, fl u orescei n a n gi o gra m)  
S u bjects e x perie nci n g u ne x pecte d o p ht hal mic s y m pt o ms wit h o ut a k n o w n s us pecte d eti ol o g y or 
e x perie nci n g a rele va nt o p ht hal mic A E ma y nee d t o ha ve re peate d o p ht hal m osc o p y a n d O C T 
testi n g perf or me d. 
9. 9. 7.  
T u berc ul osis Scree ni n g a n d C hest X -R a y   
All s u bjects will c o m plete T B scree n i n g t o deter mi ne eli gi bilit y. A T B scree ni n g q uesti o n naire 
will be c o m plete d d uri n g t he Scree ni n g Peri o d b y t he Pri nci pal I n vesti gat or or dele gate d site 
staff f or eac h s u bject a n d a p plica ble i nf or mati o n will be e ntere d i nt o t he e C R F. F or s u bjects 
resi di n g i n c o u ntries wit h a hi g h b ur de n of T B or m ulti-dr u g resista nt ( M D R) T B as i de ntifie d b y 
W orl d Healt h Or ga nizati o n ( W H O), t he T B scree ni n g q uesti o n naire will be c o m plete d at e ver y 
st u d y visit (A p pe n di x 2 ). F or s u bjects w h o are recei vi n g T B pr o p h yla xis treat me nt, t he T B 
q uesti o n naire will be c o m plete d at e ver y st u d y visit ( u ntil T B pr o p h yla xis treat me nt c o urse is 
c o m plete d). 
9. 9. 8.  
Cli nic al L a b or at or y Tests   
Refer t o Ta ble  5  f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t he Sc he d ule of 
Assess me nts ( A p pe n di x  1 , Ta ble  6 ) f or ti mi n g a n d fre q ue nc y f or eac h test. Details re gar di n g 
cli nical la b orat or y sa m ple c ollecti o n, pre parati o n, a n d s hi p me nt are pr o vi de d i n t he La b orat or y 
Ma n ual b y t he ce ntral la b orat or y.  
Cli nical safet y la b orat or y tests s h o ul d be c o m plete d pre -d ose . T he I n vesti gat or m ust re vie w t he 
la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y cli nicall y rele va nt c ha n ges occ urri n g 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 4  of 1 0 7  
d uri n g t he st u d y i n t he a d verse e ve nt secti o n of t he e C R F. Res ults of t he t otal W B C a n d A L C 
will be re vie we d a n d m o nit ore d as d escri be d i n Secti o n  9. 8. 5 . T he la b orat or y re p orts m ust be 
file d wit h t he s o urce d oc u me nts. Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose 
t hat are n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he I n vesti gat or t o be m ore 
se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n. 
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g partici pati o n 
i n t he st u d y or wit hi n 3 0  da ys after t he last a d mi nistrati o n of st u d y treat me nt s h o ul d be re peate d 
u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y 
t he I n vesti gat or or Me dical M o nit or. 
•  If s uc h val ues d o n ot retur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d 
reas o na ble b y t he I n vesti gat or, t he eti ol o g y s h o ul d be i de ntifie d, a n d t he S p o ns or 
s h o ul d be n otifie d. 
•  All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n t he Sc he d ule of 
Assess me nts ( A p pe n di x  1 , Ta ble  6 ), m ust be c o n d ucte d i n acc or da nce wit h t he 
La b orat or y Ma n ual.  
•  If la b orat or y val ues fr o m n o n-pr ot oc ol -s pecifie d la b orat or y assess me nts perf or me d at 
t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n s u bject ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or (e g, a d verse e ve nt, S A E, or d ose 
m o dificati o n), t he n t he res ults m ust be rec or de d i n t he e C R F.  
F or g ui da nce o n m o ni t ori n g s u bjects wit h n ota ble l y m p h o pe nia, refer t o Secti o n 9. 8. 5 . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 5  of 1 0 7  
T a ble  5 : 
Cli nic al L a b or at or y Tests   
S C R E E NI N G  O N L Y  
Vir ol o g y  
HI V, H Bs A g, H C V ( RI B A)  
St o ol S a m ple  
Bacterial c ult ure, o va a n d parasites, C. difficile  
Dr u gs of A b use  
A m p heta mi ne, bar bit urates, be nz o diaze pi nes, c ocai ne, met ha d o ne, 
met ha m p heta mi ne, met h yle ne di o x y met ha m p heta mi ne, o piate, o x yc o d o ne, 
p he nc ycli di ne  
Ot hers  
He m o gl o bi n A 1 C, Q ua nti F E R O N  
 
P R E G N A N C Y T E S TI N G  
Ser u m pre g na nc y test β -h C G - Scree ni n g  
Uri ne β -h C G ( o nl y f or w o me n of c hil d beari n g p ote ntial)  
C LI NI C A L C H E MI S T R Y, H E M A T O L O G Y, A N D C O A G U L A TI O N  
He m at ol o g y  
Ser u m C he mistr y  
He mat ocrit  
He m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n  
Mea n c or p usc ular v ol u me  
Platelet c o u nt  
Re d bl o o d cell c o u nt  
W hite bl o o d cell c o u nt wit h 
differe ntial a  
C o a g ul ati o n  
Pr ot hr o m bi n ti me  
Acti vate d partial t hr o m b o plasti n 
ti me 
I nter nati o nal n or malize d rati o 
Al b u mi n  
Al ka li ne p h os p hatase 
Ala ni ne a mi n otra nsferase  
As partate a mi n otra nsferase  
Bicar b o nate  
Bl o o d urea nitr o ge n  
C -reacti ve pr otei n 
Calci u m  
C hl ori de  
Creati ni ne  
Creati ne ki nase  
Direct bilir u bi n  
Gl uc ose  
Ga m ma -gl uta m yl tra nsferase  
Lactate de h y dr o ge nase  
P h os p h or us  
P otassi u m  
S o di u m  
T h yr oi d -sti m ulati n g h or m o ne 
T h yr o xi ne free  
T otal bilir u bi n  
Trii o d ot h yr o ni ne free  
T otal c h olester ol  
T otal pr otei n  
Tri gl yceri des  
Uric aci d  
U RI N A L Y SI S  
A p peara nce  
Bilir u bi n  
C ol or  
Gl uc ose  
Ket o nes  
Micr osc o pic e xa mi nati o n of 
se di me nt 
Nitrite  
Occ ult bl o o d  
p H  
Pr otei n  
S pecific gra vit y  
Ur o bili n o ge n  
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 6  of 1 0 7  
T a ble  5 : 
Cli nic al L a b or at or y Tests ( C o nti n ue d)  
BI O M A R K E R S  
L y m p h oc ytes a,b  
hs -C R P b 
Fecal cal pr otecti n b 
S T O O L S A M P L E c  
O va a n d parasites, C. difficile  
a T otal W B C, ne utr o p hil, l y m p h oc yte, a n d  
will be a vaila ble f or re vie w pri or t o ra n d o mizati o n. After ra n d o mizati o n, t he 
t otal W B C, ne utr o p hil, l y m p h oc yte, a n d 
cell c o u nts will be re vie we d b y a n u n bli n de d Me dical M o nit or w h o will 
pr o vi de i nstr ucti o ns  t o t he site i n vesti gat or i n t he e ve nt of si g nifica nt l y m p h o pe nia. Refer t o Secti o n  9 . 8. 5 f or a d diti o nal details. 
b I n vesti gat ors will re mai n bli n de d t o t he res ults after ra n d o mizati o n. 
c St o ol sa m ple f or bacterial c ult ure, o va, a n d parasite e val uati o n, a n d C. difficile  assa y at a n y p oi nt i n t he st u d 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.  
β -h C G, beta -h u ma n c h ori o nic g o na d otr o pi n; H Bs A g, he patitis  B s urface a nti ge n; H C V, he patitis  C vir us; HI V, h u ma n 
i m m u n o deficie nc y vir us; hs -C R P, hi g h -se nsiti vit y C-reacti ve pr otei n; RI B A, rec o m bi na nt i m m u n o bl ot assa y; 
; W B C, w hite bl o o d cells 
9. 9. 8. 1.  
Scree ni n g  
9. 9. 8. 1. 1.  Dr u gs of A b use  
A sta n dar d uri ne dr u g scree n will be perf or me d ( Ta ble  5 ). S u bjects w h o test p ositi ve will be 
assesse d f or eli gi bilit y f or st u d y partici pati o n b y t he I n vesti gat or.  
9. 9. 8. 1. 2.  Pre g n a nc y Testi n g  
A ser u m pre g na nc y test f or β -h C G will be perf or me d  o n w o me n of c hil d beari n g p ote ntial t o 
deter mi ne eli gi bilit y. P ost -scree ni n g uri ne pre g na nc y tests ( β-h C G) s h o ul d be perf or me d as 
i n dicate d i n t he Sc he d ule of Assess me nts (A p pe n di x  1 , Ta ble  6 ). A m o nt hl y h o me pre g na nc y test 
i n n o n-visit m o nt hs s h o ul d be perf or me d a n d a n y p ositi ve res ult i m me diatel y re p orte d t o t he 
st u d y site. If t he uri ne pre g na nc y test is perf or me d at s u bject’s h o me i nstea d of o nsite, pre g na nc y 
test res ult s h o ul d be d oc u me nte d i n t heir e Diar y. Uri ne pre g na nc y test kits will be s u p plie d t o 
s u bjects as nee de d. 
If at a n y p oi nt t here is a case of a p ositi ve uri ne β-h C G test, t he s u bject will ha ve st u d y treat me nt 
i nterr u pte d a n d a ser u m sa m ple s u b mitte d t o t he ce ntral la b orat or y f or β-h C G testi n g. If t he 
ser u m test c o nfir ms p ositi ve, t he s u bject will be wit h dra w n fr o m t he st u d y treat me nt a n d all t he 
necessar y f oll o w -u p assess me nts will be c o n d ucte d as per Secti o n  9. 9. 1 0 . If t he ser u m test is 
ne gati ve, t he s u bject ma y res u me st u d y treat me nt.  
Ne gati ve pre g na nc y test res ults m ust be d oc u me nte d f or all w o me n of c hil d beari n g p ote ntial 
pri or t o d osi n g at a p plica ble st u d y visits. W o me n w h o are s ur gicall y sterile or w h o are 
p ost me n o pa usal are n ot c o nsi dere d t o be of c hil d beari n g p ote ntial. P ost me n o pa usal is defi ne d as 
1 2  c o nsec uti ve m o nt hs wit h n o me nses wit h o ut a n alter nati ve me dical ca us e. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 7  of 1 0 7  
9. 9. 8. 1. 3.  Vir ol o g y   
Scree ni n g HI V a nti b o d y, he patitis  B (ie, H Bs A g), a n d H C V (rec o m bi na nt i m m u n o bl ot assa y, if 
p ositi ve H C V R N A s h o ul d be use d t o c o nfir m i nfecti o n).  
9. 9. 8. 2.  
Cli nic al C he mistr y, He m at ol o g y, C o a g ul ati o n, a n d Uri n al ysis   
Cli nical c he mistr y, he mat ol o g y, c oa g ulati o n, a n d uri nal ysis para meters t hat will be assesse d 
d uri n g t he st u d y are i de ntifie d i n  Ta ble  5 . 
S u bjects will be i n a seate d or s u pi ne p ositi o n d uri n g bl o o d c ollecti o n. All la b orat or y sa m ples 
s h o ul d be c ollecte d pri or t o t he a d mi nistrati on of st u d y treat me nt at a p plica ble visits (refer t o 
Secti o n  9. 7  f or ti mi n g of bl o o d dra ws f or P K). 
9. 9. 9.  
A d verse E ve nts   
9. 9. 9. 1.  
Defi niti o ns   
9. 9. 9. 1. 1.  A d verse E ve nt   
A n a d verse e ve nt is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o nal 
s u bject a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n, 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 relate d t o t he me dici nal pr o d uct.  
A d verse e ve nts  ca n be a n y of t he f oll o wi n g:  
•  U nfa v ora ble c ha n ges i n ge neral c o n diti o n  
•  S u bjecti ve or o bjecti ve si g ns/s y m pt o ms  
•  C o nc o mita nt disease or acci de nts  
•  Cli nicall y rele va nt a d verse c ha n ges i n la b orat or y para meters o ver t he c o urse of t he 
st u d y 
•  Pree xisti n g c o n diti o ns t hat w orse n i n se verit y, i ncrease i n fre q ue nc y, or ha ve ne w 
si g ns/s y m pt o ms 
9. 9. 9. 1. 2.  Seri o us A d verse E ve nt   
A n a d verse e ve nt s h o ul d be classifie d as a n S A E if it meets o ne of t he f oll o wi n g cr iteria: 
Fatal:  
A d verse e ve nt res ulte d i n deat h.  
Life -t hreate ni n g: 
T he a d verse e ve nt place d t he s u bject at i m me diate ris k of deat h. T his 
classificati o n d oes n ot a p pl y t o a n a d verse e ve nt t hat h y p ot heticall y 
mi g ht ca use deat h if it were m ore se vere.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 8  of 1 0 7  
H os pitalizati o n:  
T he a d verse e ve nt re q uire d or pr ol o n ge d a n e xisti n g i n patie nt 
h os pitalizati o n. H os pitalizati o ns f or electi ve me dical or s ur gical 
pr oce d ures or treat me nts pla n ne d bef ore t he si g ni n g of i nf or me d 
c o nse nt i n t he st u d y or r o uti ne c hec k -u ps are n ot S A Es b y t his 
defi niti o n.  
Disa bli n g/ 
i nca pacitati n g: 
T he a d verse e ve nt res ulte d i n a persiste nt or si g nifica nt i nca pacit y or 
s u bsta ntial disr u pti o n of t he s u bject’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
C o n ge nital a n o mal y 
or birt h defect:  
A n a d ver se o utc o me i n a c hil d or fet us of a s u bject e x p ose d t o t he 
m olec ule or st u d y treat me nt re gi me n bef ore c o nce pti o n or d uri n g 
pre g na nc y.  
Me dicall y si g nifica nt:  T he a d verse e ve nt di d n ot meet a n y of t he a b o ve criteria b ut c o ul d 
ha ve je o par dize d t he s u bject a n d mi g ht ha ve re q uire d me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve or 
i n v ol ves s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n 
i nfecti o us a ge nt. 
9. 9. 9. 1. 3.  A d verse Dr u g Re acti o n   
A n a d verse dr u g reacti o n ( A D R) i n t he pre -a p pr o val cli nical e x perie nce wit h a ne w me dici nal 
pr o d uct or its ne w usa ges, partic ularl y as t he t hera pe utic d ose(s) ma y n ot be esta blis he d, is a n y 
n o xi o us a n d u ni nte n de d res p o nse t o a me dici nal pr o d uct relate d t o a n y d ose. T he p hrase 
“res p o nses t o a me dici nal pr o d uct” mea ns t hat a ca usal relati o ns hi p bet wee n a me dici nal pr o d uct 
a n d a n a d verse e ve nt is at least a reas o na ble p ossi bilit y (ie, t he relati o ns hi p ca n n ot be r ule d o ut).  
9. 9. 9. 1. 4.  A d verse E ve nts of S peci al I nterest   
Base d o n t he mec ha nis m of acti o n of etrasi m o d a n d pri or e x perie nce wit h ot her a ge nts acti n g via 
a si milar mec ha nis m, p ote ntial a d verse e ve nts of s pecial i nterest ma y be i de ntifie d. I n a d diti o n t o 
a p pr o priate re p orti n g of t hese e ve nts as a n a d verse e ve nt or S A E, s u p ple me ntar y detaile d 
i nf or mati o n ma y be c ollecte d. 
If t here are a n y si g ns of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L)-relate d s y m pt o ms, 
the I n vesti gat or s h o ul d wit h h ol d st u d y treat me nt a n d perf or m a p pr o priate dia g n ostic e val uati o n 
per l ocal sta n dar d of care at t he first si g ns s u g gesti ve of P M L. T y pical s y m pt o ms ass ociate d wit h 
P M L are di verse, pr o gress o ver da ys t o wee ks, a n d ma y i ncl u de pr o gressi ve wea k ness o n o ne 
si de of t he b o d y or cl u msi ness of li m bs, dist ur ba nce of visi o n, a n d c ha n ges i n t hi n ki n g, me m or y, 
a n d orie ntati o n lea di n g t o c o nf usi o n a n d pers o nalit y c ha n ges. T he I n vesti gat or m ust n otif y t he 
Me dical M o nit or of s uc h a n e ve nt.  
G ui da nce f or t he Assess me nt of P ote ntial Pr o gressi ve M ultif ocal Le u k oe nce p hal o pat h y is 
pr o vi de d i n A p pe n di x 5 . 
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Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 6 9  of 1 0 7  
9. 9. 9. 1. 5.  Se verit y   
T he se verit y of eac h a d verse e ve nt will be assesse d at t he o nset b y a n urse/ or p h ysicia n. W he n 
rec or di n g t he o utc o me of t he a d verse e ve nt t he ma xi m u m se verit y of t he a d verse e ve nt 
e x perie nce d will als o be rec o r de d. T he se verit y of eac h a d verse e ve nt will be gra de d acc or di n g 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 5. 0:  
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; mi ni mal, 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 acti vities of dail y li vi n g ( A D L).  
Gra de 3:  
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 (e 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).  
Gra de 4:  
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. 
Gra de 5:  
Deat h relate d t o a d verse e ve nt.  
9. 9. 9. 1. 6.  Rel ati o ns hi p   
T he I n vesti gat or ( or desi g nee) will ma ke a deter mi nati o n of t he relati o ns hi p of t he A E t o t he 
st u d y dr u g usi n g a 4-cate g or y s yste m acc or di n g t o t he f oll o wi n g g ui deli nes:  
N ot Relate d:  
T he A E is defi nitel y ca use d b y t he s u bject’s cli nical state or t he st u d y 
pr oce d ure/c o n diti o ns.  
U nli kel y Relate d:  
T he te m p oral ass ociati o n bet wee n t he A E a n d t he dr u g is s uc h t hat t he 
dr u g is n ot li kel y t o ha ve a n y reas o na ble ass ociati o n wit h t he A E.  
Pr o ba bl y Relate d:  
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of 
t he dr u g a n d ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n 
c haracteristics of t he s u bject’s cli nical st ate, e n vir o n me ntal, or t o xic 
fact ors, or ot her m o des of t hera p y a d mi nistere d t o t he s u bject. 
Relate d:  
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of 
t he dr u g, a bates u p o n disc o nti n uati o n of t he dr u g, f oll o ws a k n o w n or 
h y p ot hesize d c a use-effect relati o ns hi p, a n d (if a p pr o priate) rea p pears 
w he n t he dr u g is rei ntr o d uce d.  
T he I n vesti gat or will use cli nical j u d ge me nt t o deter mi ne t he relati o ns hi p. Alter nati ve ca uses, 
s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k factors, as well as t he 
te m p oral relati o ns hi p of t he e ve nt t o t he st u d y treat me nt a d mi nistrati o n s h o ul d be c o nsi dere d a n d 
i n vesti gate d. T he I n vesti gat or s h o ul d c o ns ult t he I B a n d t he Pr o d uct I nf or mati o n of mar kete d 
pr o d ucts wit hi n t he dr u g class, w he n a p plica b le. F or eac h a d verse e ve nt/ S A E, t he I n vesti gat or 
m ust d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d t he a d verse e ve nt/ S A E a n d has 
pr o vi de d a n assess me nt of ca usalit y. T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d a n d 
t he I n vesti gat or has mini mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or; h o we ver, 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 0  of 1 0 7  
it is ver y i m p orta nt t hat t he I n vesti gat or al wa ys ma ke a n i nitial assess me nt of ca usalit y f or e ver y 
e ve nt bef ore t he i nitial tra ns missi o n of t he S A E t o t he S p o ns or. T he I n vesti gat o r ma y c ha n ge 
his/ her o pi ni o n of ca usalit y base d o n s u bse q ue nt recei pt of i nf or mati o n a n d se n d a n S A E 
f oll o w-u p re p ort wit h t he u p date d ca usalit y assess me nt. T he ca usalit y assess me nt is o ne of t he 
criteria use d w he n deter mi ni n g re g ulat or y re p orti n g re q uire m e nts. 
9. 9. 9. 2.  
Eliciti n g a n d Rec or di n g A d verse E ve nts   
9. 9. 9. 2. 1.  Eliciti n g A d verse E ve nts   
S u bjects will be i nstr ucte d t hat  t he y ma y re p ort a d verse e ve nts at a n y ti me. A n o pe n-e n de d or 
n o n directe d met h o d of q uesti o ni n g s h o ul d be use d at eac h st u d y visit t o elicit t he re p orti n g of 
a d verse e ve nts.  
9. 9. 9. 2. 2.  Rec or di n g A d verse E ve nts   
T he a d verse e ve nt re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he s u bject is i nitiall y 
i ncl u de d i n t he st u d y ( date of first si g nat ure of i nf or me d c o nse nt) a n d c o nti n ues u p t o 3 0 da ys 
after t he last a d mi nistrati o n of st u d y treat me nt. If a n a d verse e ve nt is n ot res ol ve d or sta bilize d 
b y t his ti me, t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or will deci de w het her t o c o nti n ue t o 
m o nit or t he a d verse e ve nt or cl ose o ut t he e ve nt i n t he data base if n o f urt her f oll o w -u p is 
necessar y.  
I n vesti gat ors are not o bli gate d t o acti vel y see k i nf or mati o n o n A Es or S A Es after t he s u bject has 
c o ncl u de d st u d y partici pati o n. A n y S A E s us pecte d t o be relate d t o t he st u d y treat me nt m ust be 
re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he last a d mi nistrati o n of 
st u d y treat me nt. 
I n vesti gat ors a n d st u d y pers o n nel will rec or d all a d verse e ve nts a n d S A Es w het her recei ve d 
t hr o u g h a n u ns olicite d re p ort b y a s u bject, elicite d d uri n g s u bject q uesti o ni n g, disc o vere d d uri n g 
p h ysical e xa mi nati o n, la b orat or y test i n g, a n d/ or ot her mea ns b y rec or di n g t he m o n t he e C R F 
a n d/ or S A E F or m, as a p pr o priate. T he f oll o wi n g i nf or mati o n s h o ul d be rec or de d o n t he a d verse 
e ve nt e C R F: 
•  Descri pti o n i ncl u di n g o nset a n d res ol uti o n dates  
•  W het her it met S A E criteria  
•  Se verit y  
•  Relati o ns hi p t o st u d y treat me nt or ot her ca usalit y  
•  O utc o me  
F or S A Es, e ve nts occ urri n g sec o n dar y t o t he pri mar y e ve nt s h o ul d be  ca pt ure d a n d re p orte d via 
t he esta blis he d safet y re p orti n g mec ha nis m. 
T he f oll o wi n g s h o ul d be c o nsi dere d w he n rec or di n g S A Es:  
•  Deat h is a n o u tc o me of a n e ve nt. T he e ve nt t hat res ulte d i n t he deat h s h o ul d be 
rec or de d a n d re p orte d o n t he e C R F. 
•  F or h os pitalizati o ns, s ur gical, or dia g n ostic pr oce d ures, t he ill ness lea di n g t o t he 
s ur gical or dia g n ostic pr oce d ure s h o ul d be rec or de d as t he S A E, n ot t he pr oce d ure 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 1  of 1 0 7  
itself. T he pr oce d ure s h o ul d be ca pt ure d i n t he narrati ve as part of t he acti o n ta ke n i n 
res p o nse t o t he ill ness. 
9. 9. 9. 2. 3.  Di a g n osis Vers us Si g ns or S y m pt o ms   
I n ge neral, t he use of a u nif yi n g dia g n osis is preferre d t o t he listi n g o ut of i n di vi d ual s y m pt o ms. 
Gr o u pi n g of s y m pt o ms i nt o a dia g n osis s h o ul d o nl y be d o ne if eac h c o m p o ne nt si g n a n d/ or 
s y m pt o m is a me dicall y c o nfir me d c o m p o ne nt of a dia g n osis as e vi de nce d b y sta n dar d me di cal 
te xt b o o ks. If a n y as pect of a si g n or s y m pt o m d oes n ot fit i nt o a classic patter n of t he dia g n osis, 
re p ort t he i n di vi d ual s y m pt o m as a se parate a d verse e ve nt. 
9. 9. 9. 3.  
Re p orti n g A d verse E ve nts   
All S A Es are s u bject t o re p orti n g re q uire me nts.  
9. 9. 9. 3. 1.  Seri o us A d verse E ve nts   
A n y a d verse e ve nt c o nsi dere d seri o us b y t he I n vesti gat or or S u b -I n vesti gat or or t hat meets 
seri o us criteria s h o ul d be re p orte d t o t he desi g nate d safet y c o ntact wit hi n 2 4  h o urs of bec o mi n g 
a w are of t he e ve nt . E nter t he S A E i nf or mati o n i nt o e C R F a n d se n d all a vaila ble perti ne nt 
i nf or mati o n t o t he desi g nate d S p o ns or C o ntact via esta blis he d re p orti n g  mec ha nis m .  
I Q VI A P har mac o vi gila nce 
P h o ne: + 1 -8 6 6 -5 9 9 -1 3 4 1  
Fa x: + 1 -8 6 6 -5 9 9 -1 3 4 2  
E -m ail ( preferre d met h o d): Are n a S afet y @i q vi a.c o m  
If a d diti o nal i nf or mati o n is re q uire d or bec o mes a vaila ble f or a pre vi o usl y re p orte d S A E, e ntr y 
of t he ne w i nf or mati o n i nt o e C R F a n d f or war di n g of all a vaila ble perti ne nt i nf or mati o n t o t he 
desi g nate d S p o ns or C o ntact via esta blis he d re p orti n g mec ha nis m s h oul d be c o m plete d wit hi n 
2 4  h o urs of a w are ness.  
Electi ve h os pitalizati o n a n d/ or s ur ger y f or clearl y pree xisti n g c o n diti o ns (e g, a s ur ger y t hat has 
bee n sc he d ule d pri or t o t he s u bject’s e ntr y i nt o t he st u d y) will n ot be re p orte d as a n S A E.  
A n y S A E t hat is o n g oi n g w he n t he s u bject c o m pletes t he st u d y or disc o nti n ues t he st u d y will be 
f oll o we d b y t he I n vesti gat or u ntil t he e ve nt res ol ve d, sta bilize d or ret ur ne d t o baseli ne stat us. 
9. 9. 9. 3. 2.  Seri o us, U ne x pecte d A d verse Dr u g Re acti o ns   
All A D Rs t hat are b ot h seri o us a n d u ne x pecte d are s u bject t o e x pe dite d re p orti n g t o re g ulat or y 
a ge ncies. A n u ne x pecte d A D R is o ne f or w hic h t he nat ure or se verit y is n ot c o nsiste nt wit h 
i nf or mati o n i n t he rele va nt s o urce d oc u me nts. 
Si nce etrasi m o d is a n i n vesti gati o nal me dici nal pr o d uct t hat has n ot yet bee n a p pr o ve d f or 
mar keti n g i n a n y c o u ntr y, t he c urre nt e diti o n of t he I B i n effect d uri n g t he st u d y will ser ve as t he 
Refere nce Safet y I nf or mati o n f or deter mi ni n g w het h er a n A E is e x pecte d or u ne x pecte d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 2  of 1 0 7  
9. 9. 1 0.  
Pre g n a nc y  a n d L act ati o n  
9. 9. 1 0. 1.  Pre g n a nc y   
If at a n y p oi nt a ser u m β-h C G pre g na nc y test is p ositi ve, t he s u bject will be wit h dra w n fr o m t he 
st u d y treat me nt. 
Details of all pre g na ncies i n fe male s u bjects a n d fe male part ners of male s u bjects will be 
c ollecte d after t he start of st u d y treat me nt a n d u ntil 3 0  da ys after t he last  d ose.  
Pre g na nc y ( d uri n g mater nal or pater nal e x p os ure t o st u d y treat me nt) d oes n ot meet t he defi niti o n 
of a n a d verse e ve nt; h o we ver, t o f ulfill re g ulat or y re q uire me nts, a n y pre g na nc y a n d/ or pre g na nc y 
o utc o me s h o ul d be re p orte d via t he esta blis he d re p orti n g mec ha nis m (e g, pre g na nc y re p orti n g 
f or m) t o t he desi g nate d S p o ns or C o ntact wit hi n 2 4  h o urs of a w are ness  t o c ollect data o n t he 
pre g na nc y a n d o n t he o utc o me f or b ot h t he m ot her a n d t he fet us.  
A b n or mal pre g na nc y o utc o mes (e g, s p o nta ne o us a b orti o n, fetal de at h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y) are c o nsi dere d S A Es a n d s h o ul d be re p orte d as s uc h (f oll o wi n g 
t he S A E re p orti n g pr ocess) e ve n if o utsi de t he S A E re p orti n g peri o d. 
9. 9. 1 0. 2.  E x p os ure D uri n g Bre astfee di n g   
A n e x p os ure d uri n g breastfee di n g ( E D B) occ urs if:  
•  A fe male s u bject is f o u n d t o be breastfee di n g w hile recei vi n g or after disc o nti n ui n g 
st u d y treat me nt.  
E x p os ure d uri n g breastfee di n g d oes n ot meet t he defi niti o n of  a n a d verse e ve nt; h o we ver, t o 
f ulfill re g ulat or y re q uire me nts, s h o ul d be re p orte d via t he esta blis he d re p orti n g mec ha nis m t o t he 
desi g nate d S p o ns or C o ntact wit hi n 2 4  h o urs of a w are ness  t o c ollect data o n t he e x p os ure a n d 
o n t he o utc o me f or b ot h t he m ot her  a n d t he c hil d . 
9. 9. 1 1.  
E n vir o n me nt al E x p os ure   
E n vir o n me ntal e x p os ure occ urs w he n a pers o n n ot e nr olle d i n t he st u d y as a s u bject recei ves 
u n pla n ne d direct c o ntact wit h or e x p os ure t o t h e st u d y treat me nt. S uc h e x p os ure ma y or ma y n ot 
lea d t o t he occ urre nce of a n A E or S A E. Pers o ns at ris k f or e n vir o n me ntal e x p os ure i ncl u de 
healt hcare pr o vi ders, fa mil y me m bers, a n d ot hers w h o ma y be e x p ose d. A n e n vir o n me ntal 
e x p os ure ma y i ncl u de  e x p os ure d uri n g pre g na nc y  (E D P ), E D B, a n d occ u pati o nal e x p os ure. 
E xa m ples of e n vir o n me ntal e x p os ure ma y i ncl u de oral i n gesti o n of, i n halati o n of, or s ki n c o ntact 
wit h a ta blet t hat is br o ke n/cr us he d.  
A n y s uc h e x p os ures t o t he st u d y treat me nt are re p orta ble t o t he desi g nate d S p o ns or C o ntact via 
esta blis he d re p orti n g mec ha nis m wit hi n 2 4 h o urs of I n vesti gat or a ware ness,  irres pecti ve of 
w het her a n A E has occ urre d . 
9. 9. 1 1. 1.  D uri n g Pre g n a nc y   
A n e n vir o n me ntal  e x p os ure d uri n g pre g na nc y  (E D P ) occ urs if:    
•  A fe male n o n partici pa nt is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g bee n 
e x p ose d t o st u d y treat me nt beca use of e n vir o n me ntal e x p os ure.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 3  of 1 0 7  
•  A male n o n partici pa nt w h o has bee n e x p ose d t o t he st u d y treat me nt t he n i nse mi nates 
his fe male part ner pri or t o  or ar o u n d t he ti me of e x p os ure .  
9. 9. 1 1. 2.  D uri n g Bre astfee di n g   
A n e n vir o n me ntal e x p os ure d uri n g breastfee di n g ( E D B ) occ urs if:    
•  A fe male n o n partici pa nt is f o u n d t o be breastfee di n g w hi le bei n g e x p ose d or ha vi n g bee n 
e x p ose d t o st u d y treat me nt. 
9. 9. 1 1. 3.  Occ u p ati o n al   
T he In vesti gat or m ust re p ort a n y i nsta nce of occ u pati o nal e x p os ure a n d all a vaila ble perti ne nt 
i nf or mati o n t o t he desi g nate d S p o ns or C o ntact via esta blis he d re p orti n g mec ha nis m wit hi n 
2 4  h o urs of t he In vesti gat or’s a ware ness, re gar dless of w het her t here is a n a ss ociate d A E. Si nce 
t he i nf or mati o n a b o ut t he occ u pati o nal e x p os ure d oes n ot pertai n t o a s u bject e nr olle d i n t he 
st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y of t he c o m plete d S A E 
re p orti n g f or m m ust be mai ntai ne d i n t he In vesti gat or si te file. 
9. 9. 1 2.  
L ac k of Effic ac y   
T he In vesti gat or m ust re p ort si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
efficac y . Refer t o Secti o n 5. 1  f or circ u msta nces w hic h ma y lea d t o disc o nti n uati o n fr o m st u d y 
treat me nt. Lac k of efficac y or fail ure of e x pecte d p har mac ol o gical acti o n is re p orta ble t o t he 
desi g nate d S p o ns or C o ntact o nl y if ass ociate d wit h a n S A E .   
9. 9. 1 3.  
Me dic ati o n Err ors   
Me dicati o n err ors ma y res ult fr o m treat me nt a d mi nistrati o n b y t he wr o n g s u bject. 
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y a n A E, as deter mi ne d b y t he i n vesti gat or, 
t he me dicati o n err or a n d p ote ntiall y ass ociate d A E/ S A E are rec or de d i n t he e C R F . S A Es m ust be 
re p orte d t o t he desi g nate d S p o ns or C o ntact via esta blis he d re p orti n g mec ha nis m wit hi n 2 4 h o urs  
o f a ware ness. 
9. 1 0.  
Pr oce d ures f or O ver d ose  
T he c urre nt e diti o n of t he I B s h o ul d be refere nce d f or o ver d ose pr oce d ures.  
T here is n o esta blis he d o ver d ose t hres h ol d f or t his cli nical st u d y, n or is t here a n y rec o m me n de d 
s pecific treat me nt f or a n o ver d ose b ut t o pr o vi de s u p p orti ve care if cli nicall y i n dicate d.  
I n t he e ve nt of a s us pecte d o ver d ose, t he I n vesti gat or a n d/ or treati n g p h ysicia n s h o ul d: 
1.  Cl osel y m o nit or t he s u bject f or a n y A E/ S A E a n d la b orat or y a b n or malities a n d f oll o w t he 
A E re p orti n g pr ocess, i ncl u di n g c o ntacti n g t he Me dical M o nit or  
2.  O btai n a plas ma sa m ple f or P K a nal ysis wit hi n 7  da ys fr o m t he date of t he last d ose of 
st u d y treat me nt, if p ossi ble, a n d if re q ueste d b y t he Me dical Mo nit or  
3.  D oc u me nt t he t otal q ua ntit y of t he e xcess d ose, ta ki n g i nt o c o nsi derati o n t he d urati o n of 
t he o ver d ose i n t he e C R F a n d t he ti me fra me 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 4  of 1 0 7  
S u bjects w h o o ver d ose will be c o u nsele d o n c orrect d osi n g a n d a d mi nistrati o n of st u d y 
treat me nt. Decisi o ns re gar di ng st u d y disc o nti n uati o n, d ose i nterr u pti o ns, or d ose m o dificati o ns 
will be ma de b y t he I n vesti gat or i n c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical 
e val uati o n of t he s u bject.  
1 0.  
P L A N N E D S T A TI S TI C A L M E T H O D S   
1 0. 1.  
Ge ner al C o nsi der ati o ns   
All i n di vi d ual s u bject data f or all ra n d o mize d s u bjects will be prese nte d i n data listi n gs. All 
efficac y a n d safet y e n d p oi nts will be s u m marize d b y treat me nt gr o u p.  F ull details of t he 
statistical c o nsi derati o ns a n d pla n ne d a nal yses will be descri be d i n t he st u d y Statistical A nal ysis 
Pla n  ( S A P). 
1 0. 2.  
Deter mi n ati o n of S a m ple  Size   
Base d o n a 2 -gr o u p Fis her’ s e xact test, a tw o -si de d si g nifica nce le vel of 0. 0 5, a n d a 2: 1 
ra n d o mizati o n rati o, a p pr o xi matel y 1 8 3 s u bjects ( 1 2 2 etrasi m o d, 6 1 place b o) are req uire d t o 
ac hie ve at least 8 0 % p o wer t o detect a differe nce of 2 0 % i n t he pri mar y e n d p oi nt of cli nical 
re missi o n ( base d o n M M S) at Wee k 5 2 bet wee n t he etrasi m o d treat me nt gr o u p ( 3 4 %) a n d t he 
place b o treat me nt gr o u p ( 1 4 %). Alter nati vel y, base d o n t he sa me a ss u m pti o ns, usi n g n or mal 
a p pr o xi mati o n t o t he bi n o mial distri b uti o n, a t w o -si de d test w o ul d ac hie ve at least 9 0 % p o wer. 
T he ass u m pti o ns are base d o n t he fi nal a nal ysis res ults i n t he P hase 3 St u dies A P D 3 3 4 -3 0 1 a n d 
A P D 3 3 4 -3 0 2. Sa m ple size is calc ulate d usi n g t he E A S T ®  s oft ware. 
At t he ti me of t his a me n d me nt, a p pr o xi matel y 4 5  s u bjects a m o n g t he alrea d y ra n d o mize d 
s u bjects (ass u mi n g a p pr o xi matel y 2: 1 rati o of etrasi m o d: place b o) d o n ot meet t he a me n de d 
Incl usi o n C riteri o n 5  i n St u d y A P D 3 3 4 -2 1 0 pr ot oc ol a me n d me nt 2. 0 , w hic h i ncl u des E S sc ore 
≥ 2 a n d R B sc ore ≥ 1 . As a res ult, t hese s u bjects will be e xcl u de d fr o m t he Pri mar y A nal ysis Set 
(refer t o secti o n 1 0. 3) b ut t hese s u bjects will be i ncl u de d i n ot her a nal ysis sets as dee me d 
a p pr o priate. T heref ore, a p pr o xi matel y 2 2 5 t otal s u bjects ( 1 5 0 etrasi m o d, 7 5 place b o) are 
re q uire d t o be e nr olle d i nt o st u d y. 
1 0. 3.  
A n al ysis Sets   
All a nal ysis sets will be defi ne d i n t he S A P pri or t o data base l oc k. T he f oll o wi n g a nal ysis sets 
ma y be use d i n t he statistical a nal ysis:  
F ull A n al ysis Set ( F A S): T he F A S will c o nsist of all ra n d o mize d s u bjects, w h o recei ve at l east 
1  d ose of st u d y treat me nt. U n der t his a p pr oac h, s u bjects will be a nal yze d i n t he treat me nt gr o u p 
t o w hic h t he y were ra n d o mize d, re gar dless of t he treat me nt recei ve d d uri n g t he st u d y. 
P ri m ar y  A n al ysis  Set : T he Pri mar y A nal ysis Set will c o nsist of  s u bjects i n F A S wit h b aseli ne 
E S  ≥ 2 a n d R B sc ore ≥ 1 . T he pri mar y a nal yses of efficac y e n d p oi nts will be base d o n t his 
pri mar y a nal ysis set. 
Per Pr ot oc ol Set: T he Per Pr ot oc ol Set will c o nsist of all s u bjects i n t he F A S w h o a d here t o t he 
pr ot oc ol. T his se t will be use d i n se nsiti vit y a nal yses o n t he pri mar y res ults. S pecific reas o ns f or 
warra nti n g e xcl usi o n fr o m t his set will be d oc u me nte d pri or t o data base l oc k. T he S A P, w hic h 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 5  of 1 0 7  
will be fi nalize d pri or t o data base l oc k, will be t he fi nal d oc u me ntati o n f or t he Per Pr ot oc ol 
defi niti o n.  
M o difie d F ull A n al ysis Set ( m F A S): T he m F A S will c o nsist of all ra n d o mize d s u bjects, w h o 
recei ve at least 1 d ose of st u d y treat me nt a n d ha ve a baseli ne a n d at least 1 p ost -ra n d o mizati o n 
meas ure me nt. U n der t his a p pr oac h, s u bjects  will be c o u nte d i n t he treat me nt gr o u p t o w hic h t he y 
were ra n d o mize d, re gar dless of t he treat me nt recei ve d d uri n g t he st u d y. N ote t hat t he m F A S ca n 
var y wit h e n d p oi nts si nce s o me s u bjects ma y ha ve t he nee de d data f or i ncl usi o n i n t he m F A S f or 
s o me e n d p oi nts b ut ot hers ma y n ot. 
S afet y Set: T he Safet y Set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of 
st u d y treat me nt. F or t his set, s u bjects will be a nal yze d acc or di n g t o t he treat me nt recei ve d, 
re gar dless of ra n d o mizati o n. T he Safet y Set will be use d f or all safet y a nal yses.  
1 0. 4.  
Missi n g D at a   
S u bjects wit h w orse ni n g of disease bef ore Wee k  1 2 a n d s u bjects w h o meet t he criteria f or 
w orse ni n g disease after Wee k  1 2, as de fi ne d i n Secti o n 5. 1. 1 , will be c o nsi dere d as ha vi n g a 
treat me nt n o nres p o nse o utc o me i n t he a nal ysis of all bi nar y efficac y e n d p oi nts, i ncl u di n g t he 
pri mar y e n d p oi nt. I n a d diti o n, s u bjects w h o i nitiate a n a ge nt n ot all o we d i n c o m bi nati o n wit h t he 
st u d y treat me nt t hat ca n affect t he efficac y of t he st u d y treat me nt, s uc h as a n i m m u n os u p pressa nt 
or c ortic oster oi d, or w h o ha ve a n i ncrease i n d ose o ver baseli ne le vels f or treat me nt of w orse ni n g 
disease s y m pt o ms will be c o nsi dere d n o nres p o n ders f or bi nar y res p o n der -t y pe e n d p oi nts 
t hereafter or be ha n dle d b y per pr ot oc ol a nal ysis.  
S u bjects disc usse d a b o ve will be c o nsi dere d as ha vi n g a k n o w n o utc o me at t he a nal ysis 
ti me p oi nt (ie, a treat me nt fail ure o utc o me) a n d n ot as ha vi n g missi n g data. S u bjects w h o 
disc o nti n ue t he d o u ble -bli n d treat me nt peri o d f or reas o ns ot her t ha n w orse ni n g disease or 
a d verse e ve nt relate d t o U C will be c o nsi dere d as ha vi n g missi n g data a n d will be ha n dle d i n t he 
pri mar y a n d se nsiti vit y a nal yses as f oll o ws.  
A f ull descri pti o n of t he ha n dli n g of missi n g data will be pr o vi de d i n t he S A P.  
Pri m ar y Met h o d of H a n dli n g Missi n g D at a  
I n t he pri mar y a nal ysis of t he pri mar y e n d p oi nt a n d mai n a nal yses of all bi nar y res p o n der-t y pe 
e n d p oi nts, all s u bjects wit h missi n g data, re gar dless of reas o n f or missi n g ness, will be c o nsi dere d 
as n o n -res p o n ders. 
I n t he mai n a nal ysis of c o nti n u o us or sc ore e n d p oi nts, s uc h as c ha n ges fr o m baseli ne i n M M S 
s u bsc ores, bi o mar ker meas ures, ur ge nc y N R S, a n d healt h-relate d q ualit y of life meas ures, t hese 
c o nti n u o us e n d p oi nts will be a nal yze d wit h a mi xe d -effect m o del wit h re peate d meas ures. 
Detaile d met h o ds will be pr o vi de d i n t he S A P.  
Se nsiti vit y A n al yses f or Missi n g D at a  
Se nsiti vit y a nal yses will be perf or me d u n der se veral alter nati ve ass u m pti o ns re gar di n g missi n g 
data, ie, data missi n g i nter mitte ntl y, after disc o nti n uati o n fr o m t he d o u ble -bli n d st u d y f or reas o ns 
ot her t ha n w orse ni n g diseases, or after i nitiati o n of e xcl u de d me dicati o ns.  
•  A n ass u m pti o n of data missi n g at ra n d o m ( M A R) wit hi n eac h treat me nt gr o u p will be 
i n vesti gate d. Missi n g data, e g, c o m p o ne nt sc ores of M M S at t he pla n ne d assess me nt 
ti me p oi nts, will be i m p ute d usi n g m ulti ple i m p utati o n met h o d ol o g y (R u bi n 1 9 8 7 ) 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 6  of 1 0 7  
u n der t he M A R ass u m pti o n. Bi nar y res p o n der -t y pe e n d p oi nts will s u bse q ue ntl y be 
c o m p ute d fr o m o bser ve d a n d i m p ute d data a n d a nal yze d usi n g t he sa me met h o d as i n 
t he pri mar y a nal ysis. 
•  A ti p pi n g p oi nt a nal ysis will be perf or me d f or t he pri mar y a n d ke y sec o n dar y 
e n d p oi nts b y c o nsi deri n g all p ossi ble c o m bi nati o ns of t he n u m ber of res p o n ders a n d 
n o nres p o n ders a m o n g s u bjects wit h missi n g data i n eac h treat me nt gr o u p. T he res ults 
of a nal ysis f or all p ossi ble c o m bi nati o ns will be s u m marize d gra p hicall y, de picti n g a 
b o u n dar y bet wee n c o m bi nati o ns t hat res ult i n a statisticall y si g nifica nt treat me nt 
effect vers us n ot statisticall y si g nifica nt. Cli nical pla usi bilit y of t he c o m bi nati o ns o n 
t he b o u n dar y will be disc usse d i n t he cli nical st u d y re p ort t o e val uate r o b ust ness of 
st u d y c o ncl usi o ns t o missi n g data. 
•  A mec ha nis m of missi n g ness n ot at ra n d o m will be i n vesti gate d f or s u bjects wit h 
missi n g data. T hese s u bjects, re gar dless of t he ra n d o mize d treat me nt gr o u p, will be 
ass u me d t o ha ve a si milar distri b uti o n of o utc o mes after disc o nti n uati o n as s u bjects 
wit h a vaila ble data i n t he place b o gr o u p. T his is a ki n t o m o deli n g t he missi n g 
o utc o mes as if t he s u bjects c o nti n ue d o n t heir bac k gr o u n d t hera p y o nl y a n d 
acc o u nti n g f or t he st u d y effect o bser ve d i n s u bjects o n place b o. T his will be 
i m ple me nte d usi n g a m ulti ple i m p utati o n a p pr oac h of C o p y Refere nce t o i m p ute 
missi n g val ues, e g, c o m p o ne nt sc ores of M M S at t he pla n ne d assess me nt ti me p oi nts.  
C o m plete descri pti o ns of t he se nsiti vit y a nal yses a n d detaile d m ulti ple i m p utati o n met h o d a n d 
pr oce d ures will be pr o vi de d i n t he S A P pri or t o data base l oc k.  
1 0. 5.  
Effic ac y E n d p oi nt Defi niti o ns   
S u m mar y sc ores calc ulate d fr o m t he c o m p o ne nts of t he M C S  will be u se d f or deter mi nati o n of 
t he efficac y e n d p oi nts (refer t o Secti o n  9. 8. 1 ). T hese i ncl u de:  
T he T ot al M a y o Sc ore  (T M S ) is t he s u m of t he f o ur c o m p o ne nt sc ores ( E S, R B, S F a n d P G A) 
of t he  M C S. T he sc ore ra n ge of t he T M S is fr o m 0 t o 1 2 wit h eac h c o m p o ne nt sc ore ra n gin g 
fr o m 0 t o 3 ( 0  =  n or mal, 1 = mil d, 2 = m o derate, 3 = se vere) a n d hi g her sc ores i n dicati n g m ore  
se vere disease. 
T he M o difie d M a y o Sc ore  (M M S ) is t he s u m of t he E S, R B, a n d S F c o m p o ne nt  sc ores  of t he 
M C S.  T he ra n ge of t he M M S is fr o m 0 t o 9, wit h eac h c o m p o ne nt sc ore ra n gi n g fr o m 0 t o 3 
( 0 =  n or mal, 1 = mil d, 2 = m o derate, 3 = se vere).  Cli nical re missi o n  a n d res p o nse, u nless 
ot her wise n ote d, will be base d o n M M S.  
T he f oll o wi n g defi niti o ns will be use d t o assess efficac y o utc o mes : 
•  C li nical re missi o n: S F s u bsc ore =  0 ( or =  1 wit h a ≥ 1 -p oi nt decrease fr o m baseli ne), 
R B  s u bsc ore =  0, a n d E S  ≤ 1 (e xcl u di n g fria bilit y)  
•  Cli nical re missi o n base d o n T M S: T M S ≤ 2 wit h all s u bsc ores ≤ 1  
•  E n d osc o pic i m pr o ve me nt: E S  ≤ 1 (e xcl u di n g fria bilit y)  
•  Cli nical r e missi o n base d o n t he U C -1 0 0 i n de x: U C -1 0 0 i n de x ≤ 2 5  
•  S y m pt o matic re missi o n: S F s u bsc ore =  0 ( or =  1 wit h a ≥ 1 -p oi nt decrease fr o m 
baseli ne) a n d R B s u bsc ore  =  0  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 7  of 1 0 7  
•  C li nical res p o nse: A ≥ 2 -p oi nt a n d ≥ 3 0 % decrease fr o m baseli ne i n M M S, a n d 
a ≥ 1 -p oi nt decrea se fr o m baseli ne i n R B s u bsc ore or a n a bs ol ute R B s u bsc ore ≤ 1  
•  Cli nical res p o nse base d o n T M S: A ≥ 3 -p oi nt a n d ≥ 3 0 % decrease fr o m baseli ne i n 
T M S, a n d a ≥ 1 -p oi nt decrease fr o m baseli ne i n R B s u bsc ore or a n a bs ol ute R B 
s u bsc ore ≤ 1  
•  Hist ol o gic re missi o n  ba se d o n R HI : A R HI sc ore ≤ 3 wit h la mi na pr o pria ne utr o p hils 
s u bsc ore =  0 a n d ne utr o p hils i n e pit heli u m s u bsc ore  =  0  
•  Hist ol o gic re missi o n base d o n t he Ge b oes Gra d i n g S yste m : A Ge b oes Sc ore ( G S) ≤ 2  
•  Hist ol o gic res p o nse: Decrease i n R HI of ≥ 7  p oi nts fr o m bas eli ne 
•  M uc osal heali n g: E n d osc o pic i m pr o ve me nt a n d hist ol o gic re missi o n base d o n t he 
Ge b oes Gra di n g S yste m  
1 0. 5. 1.  
C alc ul ati o n of M a y o Sc ore a n d C o m p o ne nt Sc ores   
I n ge neral, t he e Diar y data ( S F a n d R B sc ores) wit hi n 7  da ys pri or t o t he tar get a nal ysis 
ti me p oi nt (e g, Wee ks 1 2 a n d 5 2) , al o n g wit h t he E S, will be use d t o c o m p ute t he M M S a n d  
T M S . C o m plete details of t he Ma y o s y m pt o m s u bsc ore c o m p utati o n met h o d are pr o vi de d 
Secti o n  9. 8. 1  a n d Secti o n  9. 4. 2 . 
1 0. 6.  
Pri m ar y E n d p oi nts   
T he pri mar y efficac y e n d p oi nt will e val uate etrasi m o d vers us place b o i n : 
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at Wee k  5 2  
Cli nical re missi o n is base d o n t he M M S (as defi ne d i n Secti o n  1 0. 5 ). 
1 0. 7.  
Sec o n d ar y E n d p oi nts   
Cli nical re missi o n a n d res p o nse, u nless ot her wise n ote d, will be base d o n M M S.  
1 0. 7. 1.  
Ke y Sec o n d ar y Effic ac y E n d p oi nts   
T he ke y sec o n dar y efficac 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 cli nical re missi o n at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g e n d osc o pic i m pr o ve me nt at Wee k 5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g s y m pt o matic re missi o n at Wee k 5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g m uc osal heali n g at Wee k  5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at b ot h Wee ks 1 2 a n d 5 2  
•  T he pr o p orti o n of s u bjects  ac hie vi n g  cli nical re missi o n at Wee k  5 2 a n d w h o ha d n ot 
bee n recei vi n g c ortic oster oi ds f or ≥ 1 2  wee ks i m me diatel y pri or t o Wee k  5 2  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 8  of 1 0 7  
1 0. 7. 2.  
Ot her  Sec o n d ar y Effic ac y E n d p oi nts   
T he ot her sec o n dar y efficac y e n d p oi nts are: 
•  T he pr o p orti o n of s u bjects w h o ha d n ot recei ve d c ortic oster oi ds f or ≥ 4 wee ks a n d 
ac hie ve d cli nical re missi o n at Wee k 5 2 a m o n g s u bjects recei vi n g c ortic oster oi ds at 
baseli ne  
•  T he p r o p orti o n of s u bjects ac hie vi n g  cli nical res p o nse at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  a cli nical res p o nse at Wee k 5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g e n d osc o pic i m pr o ve me nt at Wee k 1 2  
•  T he pr o p orti o n of s u bjects ac hie vi n g  m uc osal heali n g at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g s y m pt o matic re missi o n at Wee k 1 2 
•  T he p r o p orti o n of s u bjects wit h a cli nical res p o nse at Wee k 1 2 
•  T he p r o p orti o n of s u bjects wit h re d ucti o n fr o m baseli ne i n b ot h E S a n d R B O R  i n 
b ot h E S a n d S F at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic res p o nse  base d o n t he Ge b oes 
Gra di n g S yste m  at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic res p o nse base d o n R HI at Wee k 1 2  
1 0. 8.  
E x pl or at or y E n d p oi nts   
Cli nical re missi o n a n d res p o nse, u nless ot her wise n ote d, will be base d o n M M S.  
1 0. 8. 1.  
E x pl or at or y Effic ac y E n d p oi nts   
E x pl orat or y efficac 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 s y m pt o matic re missi o n at  eac h st u d y v isit 
(Wee ks 2, 4, 8,  1 2,  1 6, 2 0, 2 4, 3 2, 4 0, 4 8 , a n d 5 2) 
•  T he pr o p orti o n of s u bjects ac hie vi n g s y m pt o matic res p o nse at eac h st u d y visit 
( Wee ks 2, 4, 8, 1 2, 1 6, 2 0, 2 4, 3 2, 4 0, 4 8, a n d 5 2) 
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at Wee k 5 2 a m o n g s u bjects 
ac hie vi n g cli nical res p o nse at Wee k 1 2  
•  T he p r o p orti o n of s u bjects wit h re d ucti o n fr o m baseli ne i n b ot h E S a n d R B O R  i n 
b ot h E S a n d S F at Wee k  5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  c o m plete s y m pt o matic re missi o n at Wee k  1 2 
( R B s u bsc ore =  0 a n d S F  =  0)  
•  T he p r o p orti o n of s u bjects ac hie vi n g  c o m plete s y m pt o matic re missi o n at Wee k  5 2 
( R B s u bsc ore =  0 a n d S F  =  0)  
•  T he p r o p orti o n of s u bjects ac hie vi n g  e n d osc o pic i m pr o ve me nt at Wee k  5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  a cli nical res p o nse base d o n T M S  at Wee k  5 2  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 7 9  of 1 0 7  
•  T h e p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic res p o nse  base d o n Ge b oes Gra di n g 
S yste m  at Wee k 5 2 
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic re missi o n base d o n t he Ge b oes 
Gra di n g S yste m at Wee k 1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic re missi o n base d o n t he Ge b oes 
Gra di n g S yste m at Wee k 5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic res p o nse base d o n t he R HI at 
Wee k  5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic re missi o n base d o n t he R HI at 
Wee k  1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  hist ol o gic re missi o n base d o n t he R HI at 
Wee k  5 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g cli nical re miss i o n base d o n t he U C-1 0 0 i n de x at 
Wee k  1 2  
•  T he p r o p orti o n of s u bjects ac hie vi n g  cli nical re missi o n base d o n t he U C -1 0 0 i n de x at 
Wee k  5 2  
•  T he pr o p orti o n of s u bjects ac hie vi n g cli nical re missi o n at b ot h Wee ks  1 2 a n d 5 2  
•  Cli nical re missi o n base d o n t he T M S at Wee k 1 2  
•  Cli nical re missi o n base d o n t he T M S at W ee k 5 2  
1 0. 9.  
P h ar m ac o ki netic Assess me nts   
•  Plas ma c o nce ntrati o ns of etrasi m o d  will be assesse d fr o m sa m ples c ollecte d pre -d ose  
a n d 4 h o urs p ost -d ose  (after 1 2 -lea d E C G) o n Wee k  0/ Da y  1, a n d pre -d ose  (tr o u g h) at 
Wee ks  2, 4, 8, 1 2, 1 6, 2 4, 3 2, 4 8, 5 2 , a n d E T (o nl y re q uire d if E T visit  ≤ 3 0  h o urs 
si nce last treat me nt a d mi nistrati o n), a n d at t he 2-Wee k a n d 4 -Wee k F oll o w -U p  visits. 
A P K sa m ple s h o ul d als o be dra w n, if p ossi ble, at t he ti me of a n y S A E or a d verse 
e ve nt lea di n g t o st u d y treat me nt disc o nti n uati o n.  
•  Plas ma sa m ples ma y als o be use d f or pr ofili n g of dr u g bi n di n g pr otei ns, bi oa nal ytical 
met h o d vali dati o n p ur p oses, st a bilit y assess me nts, or t o assess ot her acti o ns of 
etrasi m o d wit h plas ma c o nstit ue nts.  
A descri pti ve s u m mar y of o bser ve d plas ma c o nce ntrati o n will be dis pla ye d b y ti me a n d b y 
treat me nt gr o u p. 
F ull details of P K a nal ysis will be pr o vi de d i n t he S A P.  
1 0. 1 0.  
Ot her A ssess me nts  
1 0. 1 0. 1.  
Bi o m ar ker E n d p oi nts   
•  C ha n ge fr o m baseli ne i n le vel of fecal cal pr otecti n at Wee ks  2, 4, 8,  1 2, 2 4, a n d 5 2  
•  C ha n ge fr o m baseli ne i n le vel of hs -C R P  at Wee ks  2, 4, 8, 1 2, 1 6, 2 4, 3 2, 4 8, a n d 5 2  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 0  of 1 0 7  
•  C ha n ge a n d perce nta ge c ha n ge fr o m baseli ne i n l y m p h oc yte c o u nts at Wee ks  2, 4, 8, 
1 2, 1 6, 2 4, 3 2, 4 8, a n d 5 2  
1 0. 1 0. 2.  
He alt h -Rel ate d Q u alit y of Life   
•  Sc ores a n d c ha n ge fr o m baseli ne at Wee ks  1 2, 3 2 ( U C -P R O  o nl y), a n d 5 2 i n t he 
f oll o wi n g: 
− T w o U C -P R O m o d ules:  
− U C -P R O/ S S a n d  
− U C -P R O S yste mic S y m pt o ms  
− F A CI T -F  
− W P AI -U C  
− Ur ge nc y N R S  
− I B D Q 
− S F -3 6  
− P GI C  
•  T h e pr o p orti o n  of s u bjects wit h U C -relate d h os pitalizati o ns  
•  T he pr o p orti o n  of s u bjects re q uiri n g U C -relate d s ur geries, i ncl u di n g c olect o m y 
1 0. 1 0. 3.  
S u b gr o u p A n al yses   
T he f oll o wi n g maj or s u b gr o u p a nal yses f or t he pri mar y a n d ke y sec o n dar y efficac y e n d p oi nts 
will be perf or me d i n or der t o e x pl ore w het her t he treat me nt effects are c o nsiste nt acr oss differe nt 
s u b gr o u ps. T he S A P will pr o vi de a c o m plete list a n d defi niti o n of t he s u b gr o u ps a n d a nal ysis 
met h o ds.  
•  Se x ( male, fe male)  
•  A ge: > or ≤ me dia n a ge, ≥ or <  6 5  years  
•  Race  
•  Baseli ne oral c ortic oster oi d usa ge ( yes or n o)  
•  Naï ve t o bi ol o gic or J A K i n hi bit or  t hera p y at st u d y e ntr y ( yes  or  n o)  
•  Baseli ne fecal cal pr otecti n > or ≤ me dia n val ue  
•  Baseli ne C R P > or ≤ me dia n val ue  
1 0. 1 1.  
S afet y Assess me nts   
Safet y will be assesse d usi n g m o nit or i n g of a d verse e ve nts, cli nical la b orat or y fi n di n gs, 1 2-lea d 
E C Gs, p h ysical e xa mi nati o ns, vital si g ns, p ul m o nar y f u ncti o n tests, o p ht hal m osc o p y, a n d o ptical 
c o here nce t o m o gra p h y.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 1  of 1 0 7  
1 0. 1 1. 1.  
S afet y E n d p oi nts   
•  I nci de nce a n d se verit y of a d verse e ve nts 
•  I nci de nce a n d se verit y of la b orat or y a b n or malities, a n d c ha n ge fr o m baseli ne i n 
la b orat or y val ues (t o i ncl u de he mat ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d 
uri nal ysis)  
•  I nci de nce of cli nicall y si g nifica nt vital si g n a b n or malities a n d c ha n ges fr o m baseli ne 
1 0. 1 2.  
Testi n g Str ate g y   
F ull details of all efficac y  a n d safet y a nal yses will be d oc u me nt pri or t o data base l oc k  i n t he 
S A P.  
1 0. 1 2. 1.  
Ef fic ac y A n al ysis  
T he pri mar y a nal ysis of t he bi nar y  efficac y e n d p oi nts will be carrie d o ut usi n g t he 
C oc hra n -Ma ntel -Hae nszel ( C M H) met h o d, stratifie d b y (a) naï ve t o bi ol o gic or J A K i n hi bit or 
t hera p y at st u d y e ntr y ( yes or n o) a n d ( b) baseli ne c ortic oster oi d use ( yes or n o). T he pri mar y 
a nal ysis will be base d o n Pri mar y A nal ysis Set (refer t o  Secti o n  1 0. 3 ). Res ults will be e x presse d 
as t he n u m ber of s u bjects i n re missi o n, re missi o n perce nta ges, differe nce i n re missi o n 
perce nta ges, o d ds rati o, a n d ass ociate d 9 5 % c o nfi de nce i nter vals ( CIs) a n d p -val ues.  
T here are m ul ti ple n ull h y p ot heses f or t he c o m paris o n of etrasi m o d a n d place b o i n t he pri mar y 
a n d sec o n dar y efficac y e n d p oi nts. T he fa mil y -wise t y pe -I err or rate will be c o ntr olle d at t he le vel 
of 0. 0 5. T he pri mar y efficac y e n d p oi nt will be teste d at a si g nifica nce le v el of 0. 0 5. O nl y if t he 
pri mar y n ull h y p ot hesis is rejecte d, ca n si g nifica nce clai ms pr ocee d f or t he ke y sec o n dar y 
efficac y e n d p oi nts. T he fa mil y of h y p ot heses a n d t he m ulti ple c o m paris o n pr oce d ure use d t o 
c o ntr ol t he fa mil y -wise t y pe -I err or rate will be clearl y s pecifie d i n t he S A P  a n d ma y i ncl u de 
s o me of ot her sec o n dar y efficac y e n d p oi nts.  
1 0. 1 2. 2.  
S afet y A n al ysis   
All safet y data will be liste d a n d s u m marize d b y treat me nt gr o u p. All tr eat me nt-e mer ge nt 
a d verse e ve nts will be c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities a n d ta b ulate d b y S yste m Or ga n Class a n d Preferre d Ter m. I nci de nce of a d verse 
e ve nts, S A Es, a n d a d verse e ve nts lea di n g t o disc o nti n uat i o n will be s u m marize d a n d prese nte d i n 
desce n di n g or der of fre q ue nc y. Ass ociate d la b orat or y para meters s uc h as he patic e nz y mes, re nal 
f u ncti o n, a n d he mat ol o g y val ues will be gr o u pe d a n d prese nte d t o get her. I n di vi d ual s u bject 
val ues will be liste d a n d val u es o utsi de of t he sta n dar d refere nce ra n ge will be fla g ge d. S hift 
ta bles a n d a nal yses of c ha n ges fr o m baseli ne will be pr o d uce d. 
1 0. 1 3.  
I nteri m A n al ysis  
N ot a p plica ble . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 2  of 1 0 7  
1 1.  
E T HI C A L C O N SI D E R A TI O N S   
1 1. 1.  
Et hic al C o n d uct of t he St u d y   
T his st u d y will be c o n d ucte d i n acc or da nce wit h t he et hi cal pri nci ples t hat ha ve t heir ori gi n i n 
t he Declarati o n of Helsi n ki a n d t hat are c o nsiste nt wit h G C P, I C H g ui deli nes, a n d a p plica ble 
re g ulat or y re q uire me nts. 
1 1. 2.  
I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee 
A p pr o v al   
Bef ore i nitiati n g a st u d y, t he I n vesti gat or m ust ha ve writte n a n d date d a p pr o val fr o m t he 
I R B/I E C f or t he st u d y pr ot oc ol, writte n I C F, s u bject recr uit me nt materials a n d pr oce d ures 
(e g, a d vertise me nts or we bs ites), a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o s u bjects. 
A p pr o val fr o m t he c o m mittee m ust be d oc u me nte d i n a letter t o t he I n vesti gat or s pecif yi n g t he 
pr ot oc ol n u m ber, pr ot oc ol versi o n, d oc u me nts re vie we d, a n d t he date o n w hic h t he c o m mittee 
me t a n d gra nte d t he a p pr o val. 
All d oc u me nts s u bject t o re vie w d uri n g t he st u d y, i ncl u di n g a n y m o dificati o ns ma de t o t he 
pr ot oc ol after recei pt of I R B/I E C a p pr o val, m ust als o be s u b mitte d t o t he c o m mittee f or a p pr o val 
pri or t o i m ple me ntati o n. T he I n vesti gat or  m ust als o pr o vi de peri o dic re p orts as re q uire d a n d 
pr o m ptl y re p ort i m p orta nt safet y i nf or mati o n (ie, S A Es, ne w i nf or mati o n t hat ma y a d versel y 
affect t he safet y of s u bjects or t he c o n d uct of t he st u d y, de viati o ns fr o m or c ha n ges i n t he 
pr ot oc ol t o eli mi nat e i m me diate har m t o s u bjects) a n d pr ot oc ol vi olati o ns, as a p pr o priate, t o t he 
I R B/I E C. 
As part of t he I n vesti gat or’s writte n a p plicati o n t o t he I R B/I E C, t he I n vesti gat or s h o ul d pr o vi de 
t he c o m mittee wit h a c urre nt c o p y of t he etrasi m o d I B. If t he I B is u p date d d uri n g t he st u d y, t he 
I n vesti gat or s h o ul d s u p pl y a n u p date d c o p y t o t he c o m mittee. 
1 1. 3.  
I nf or me d C o nse nt  
T he I n vesti gat or will f ull y i nf or m t he s u bject of all perti ne nt as pects o f t he st u d y, i ncl u di n g t he 
a p pr o val of t he st u d y b y t he I R B/I E C. Bef ore i nf or me d c o nse nt ma y be o btai ne d, t he 
I n vesti gat or s h o ul d pr o vi de t he s u bject a m ple ti me a n d o p p ort u nit y t o i n q uire a b o ut details of t he 
st u d y a n d t o deci de w het her t o partici pate. 
Pri or t o a s u bject’s partici pati o n i n t he st u d y, t he I R B/I E C -a p pr o ve d I C F m ust be si g ne d a n d 
pers o nall y date d b y t he s u bject a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt 
disc ussi o n. If a s u bject is u na ble t o rea d, a n i m partial wit ness will be prese nt d uri n g t he e ntire 
i nf or me d c o nse nt disc ussi o n. 
T he writte n I C F a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o s u bjects s h o ul d be re vise d 
w he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he s u bject’s 
c o nse nt. A n y re vise d wr itte n I C F or st u d y materials t o be a vaila ble a n d/ or s u p plie d t o s u bjects 
s h o ul d recei ve t he I R B/I E C’s a p pr o val i n a d va nce of use. T he s u bject will be i nf or me d i n a 
ti mel y ma n ner if ne w i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he s u bject’s 
wil li n g ness t o c o nti n ue partici pati o n i n t he st u d y. T he c o m m u nicati o n of t his i nf or mati o n s h o ul d 
be d oc u me nte d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 3  of 1 0 7  
D uri n g a s u bject’s partici pati o n i n t he st u d y, t he s u bject will recei ve a n u p date d versi o n of t he 
I R B/I E C-a p pr o ve d si g ne d a n d date d c o nse nt d oc u me n t, as a p plica ble, a n d a n y u p dates t o t he 
I R B/I E C-a p pr o ve d writte n i nf or mati o n pr o vi de d t o s u bjects.  
1 1. 4.  
C o nfi de nti alit y   
All i nf or mati o n ge nerate d i n t his st u d y is c o nsi dere d hi g hl y c o nfi de ntial a n d m ust n ot be 
discl ose d t o a n y pers o n or e ntit y n ot directl y i n v ol ve d wit h t he st u d y u nless pri or writte n c o nse nt 
is pr o vi de d fr o m t he S p o ns or. 
Pri or t o st u d y partici pati o n, t he I n vesti gat or s hall i nf or m t he s u bject t hat t he m o nit or(s), 
a u dit or(s), I R B/I E C, a n d t he re g ulat or y a ut h orities will be gra nte d direct access t o t he s u bject’s 
ori gi nal me dical rec or ds f or verificati o n of cli nical st u d y pr oce d ures a n d/ or data, a n d t hat, b y 
si g ni n g a writte n I C F, t he s u bject is a ut h orizi n g s uc h access. 
I n a d diti o n, pri or t o st u d y partici pati o n, t he s u bject m ust be i nf or me d t hat t he rec or ds i de ntif yi n g 
t he s u bject will n ot be ma de p u blicl y a vaila ble; if t he res ults of t he st u d y are p u blis he d, t he 
s u bject’s i de ntit y will re mai n c o nfi de ntial. 
1 1. 5.  
Pr ot oc ol C o m pli a nce   
T he I n vesti gat or/i nstit uti o n will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y 
t he S p o ns or a n d re g ulat or y a ut h orities (if a p plica ble) a n d t hat was a p pr o ve d b y t he I R B/I E C. T he 
I n vesti gat or/i nstit uti o n a n d t he S p o ns or s h o ul d si g n t he pr ot oc ol, or if a p plica ble a n alter nati ve 
c o ntract, t o c o nfir m a gree me nt.  
T he I n vesti gat or s h o ul d n ot i m ple me nt a n y de viati o n fr o m, or c ha n ges t o, t he pr ot oc ol wit h o ut 
a gree me nt b y t he S p o ns or a n d pri or re vie w a n d d oc u me nte d a p pr o val fr o m t he I R B/I E C of a n 
a me n d me nt, e xce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o s u bjects or w he n t he 
c ha n ge i n v ol ves o nl y l o gistical or a d mi nistrati ve as pects of t he st u d y (e g, c ha n ge i n m o nit or, 
c ha n ge of tele p h o ne n u m ber).  
W he n a n i m p orta nt de viati o n fr o m t he pr ot oc ol is dee me d necessar y f or a n i n di vi d ual s u bject, 
t he I n vesti gat or m ust c o ntact t he Me dical M o nit or f or t he st u d y. S uc h c o ntact m ust be ma de as 
s o o n as p ossi ble t o per mit a re vie w b y t he S p o ns or t o deter mi ne t he i m pact of t he de viati o n o n 
t he s u bject’s partici pati o n a n d/ or t he assess me nt of safet y or efficac y i n t he st u d y. A n y 
si g nifica nt pr ot oc ol de viati o ns affecti n g s u bject eli gi bilit y a n d/ or safet y m ust be re p orte d b y 
I n vestigat or or site dele gate t o t he I R B/I E C a n d re g ulat or y a ut h orities, as a p plica ble, pri or t o 
i m ple me ntati o n. 
T he I n vesti gat or s h o ul d d oc u me nt a n d e x plai n a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol.  
1 2.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E   
Q ualit y ass ura nce a n d q ualit y c o ntr ol s yste ms s hall be i m ple me nte d a n d mai ntai ne d wit h writte n 
S O Ps t o e ns ure t hat t he st u d y is c o n d ucte d, a n d data are ge nerate d, d oc u me nte d (rec or de d), a n d 
re p orte d i n co m plia nce wit h t he st u d y pr ot oc ol, G C P, a n d t he a p plica ble re g ulat or y 
re q uire me nt(s). Q ualit y c o ntr ol s hall be a p plie d t o eac h sta ge of data ha n dli n g t o e ns ure t hat all 
data are relia ble a n d ha ve bee n pr ocesse d c orrectl y.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 4  of 1 0 7  
A n a gree me nt m ust be sec ure d fr o m all i n v ol ve d parties t o e ns ure direct access t o all st u d y -
relate d sites, s o urce d oc u me nts, a n d re p orts f or t he p ur p ose of m o nit ori n g a n d a u diti n g b y t he 
S p o ns or a n d/ or desi g nee a n d i ns pecti o n b y re g ulat or y a ut h orities.  
1 2. 1.  
Tr a i ni n g of St u d y Site Pers o n nel  
Pri or t o st u d y acti vities bei n g i nitiate d at t he st u d y site, t he S p o ns or or desi g nee will trai n st u d y 
site pers o n nel o n t he pr ot oc ol a n d a p plica ble pr oce d ures. Trai ni n g m ust be d oc u me nte d.  
N ote: If ne w st u d y site pers o n nel are assi g ne d t o t he st u d y after t he i nitial trai ni n g, st u d y sites 
s h o ul d c o ntact t he st u d y m o nit or t o c o or di nate trai ni n g. Q ualifie d st u d y pers o n nel ma y c o n d uct 
trai ni n g, as a p pr o priate. Trai ni n g of ne w st u d y pers o n nel m ust als o be d oc u me nte d. 
1 2. 2.  
M o nit ori n g   
St u d y site m o nit ori n g is c o n d ucte d t o e ns ure t he st u d y is pr o gressi n g as e x pecte d, t he ri g hts a n d 
well -b ei n g of h u ma n s u bjects are pr otecte d, t he re p orte d st u d y data are acc urate, c o m plete, a n d 
verifia ble, a n d t he c o n d uct of t he st u d y is i n c o m plia nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol, 
wit h G C P a n d wit h a p plica ble re g ulat or y re q uire me nts a n d l ocal la ws. P r ot oc ol de viati o ns 
i de ntifie d will be d oc u me nte d. 
Details of st u d y site m o nit ori n g are d oc u me nte d i n t he st u d y Cli nical M o nit ori n g Pla n ( C M P) or 
si milar d oc u me nt. T he C M P descri bes i n detail w h o will c o n d uct t he m o nit ori n g, at w hat 
fre q ue nc y m o nit ori n g will be d o ne, at w hat le vel of detail m o nit ori n g will be perf or me d (e g, 
tar gete d a n d/ or ris k base d), a n d t he distri b uti o n of m o nit ori n g re p orts. M o nit ori n g ma y i ncl u de a 
st u d y site selecti o n visit, w hic h ma y be c o n d ucte d i n-pers o n or via c o m m u ni cati o n me dia (e g, 
telec o nfere nce, o nli ne meeti n g) or ma y be wai ve d i n acc or da nce wit h p olic y a n d pr oce d ures 
bei n g f oll o we d f or t he st u d y, if a p pr o priate. M o nit ori n g will i ncl u de a st u d y site i nitiati o n visit, 
i nteri m m o nit ori n g visit(s), a n d a st u d y site cl ose o ut visit. A n i nteri m m o nit ori n g visit ma y be 
c o m bi ne d wit h a cl ose o ut visit, if a p plica ble.  
1 2. 3.  
A u dit   
A n a u dit of o ne or m ore partici pati n g st u d y sites ma y be perf or me d i n de pe n d e ntl y of, a n d 
se paratel y fr o m, r o uti ne m o nit ori n g t o e val uate cli nical st u d y c o n d uct a n d c o m plia nce wit h t he 
pr ot oc ol, S O Ps, G C P, a n d t he a p plica ble re g ulat or y re q uire me nts.  
1 3.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G   
1 3. 1.  
D at a M a n a ge me nt   
1 3. 1. 1.  
C ase Re p ort F or ms   
A n e C R F m ust be c o m plete d f or eac h s u bject scree ne d/e nr olle d i n t his st u d y. T hese f or ms will 
be use d t o tra ns mit i nf or mati o n c ollecte d d uri n g t he st u d y t o t he S p o ns or a n d re g ulat or y 
a ut h orities, as a p plica ble.  
T he d oc u me ntati o n relate d t o t he vali dati o n of t he e C R Fs will be mai ntai ne d i n t he Trial Master 
File ( T M F). T he T M F will be mai ntai ne d b y t he C R O a n d t he S p o ns or.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 5  of 1 0 7  
T he I n vesti gat or will d oc u me nt s u bject data i n his/ her o w n s u bject files. T hese s u bject files will 
ser ve as s o urce data f or t he st u d y. All e C R F data re q uire d b y t his pr ot oc ol will be rec or de d b y 
st u d y site pers o n nel. All data e ntere d i nt o t he e C R F will be s u p p orte d b y s o urce d oc u me ntati o n.  
T he I n vesti gat or or a n a ut h orize d me m ber of t he I n vesti gat or’s staff will ma ke a n y necessar y 
c orrecti o ns t o t he e C R F. All c ha n ge d i nf or mati o n , i ncl u di n g t he date a n d pers o n perf or mi n g t he 
c orrecti o ns, will be a vaila ble via t he a u dit trail, w hic h will be part of t he electr o nic data ca pt ure 
s yste m. F or a n y c orrecti o n, a reas o n f or t he alterati o n will be pr o vi de d. T he e C R Fs will be 
re vie we d peri o dicall y f or c o m plete ness a n d acce pta bilit y b y S p o ns or pers o n nel ( or t heir 
re prese ntati ves). T he S p o ns or ( or t heir re prese ntati ves) will als o be all o we d access t o all s o urce 
d oc u me nts perti ne nt t o t he st u d y i n or der t o verif y e C R F e ntries. T he I n vesti gat or w ill re vie w t he 
e C R Fs f or c o m plete ness a n d acc urac y a n d pr o vi de his or her electr o nic si g nat ure a n d date t o t he 
e C R Fs as e vi de nce t here of.  
1 3. 1. 2.  
S o urce D oc u me nts   
Per re g ulat or y re q uire m e nts, t he I n vesti gat or or desi g nee will mai ntai n acc urate a n d u p -t o-date 
st u d y d oc u me ntati o n, i ncl u di n g s o urce d oc u me ntati o n f or eac h s u bject. S o urce d oc u me nts are 
defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds. T hese ma y i ncl u de, b ut are n ot li mite d t o,  
h os pital rec or ds, cli nical a n d office c harts, e n d osc o p y re p orts, la b orat or y data/i nf or mati o n, 
s u bjects’ e Diaries or e val uati o n c hec klists, p har mac y dis pe nsi n g a n d ot her rec or ds, rec or de d data 
fr o m a ut o mate d i nstr u me nts, E C Gs, X-ra ys, ultras o u n ds, ri g ht heart cat heterizati o n re p orts, 
ec h ocar di o gra ms. Data c ollecte d d uri n g t his st u d y m ust be rec or de d o n t he a p pr o priate s o urce 
d oc u me nts.  
T he I n vesti gat or(s)/i nstit uti o n(s) will per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, 
a n d re g ulat or y i ns pecti o n( s) a n d will pr o vi de direct access t o t he s o urce data. 
1 3. 2.  
St u d y D oc u me nt ati o n a n d Rec or ds Rete nti o n   
T he I n vesti gat or a n d st u d y staff ha ve t he res p o nsi bilit y of mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m c o ntai ni n g all st u d y -relate d d oc u me ntati o n. T hese files m ust be 
a vaila ble f or i ns pecti o n b y t he S p o ns or, re prese ntati ves of t he S p o ns or, t he I R B/I E C, a n d 
re g ulat or y a ut h orities (ie, F D A or i nter nati o nal re g ulat or y a ut h orities) at a n y ti me, a n d s h o ul d 
c o nsist of t he f oll o wi n g ele me nts:  
•  S u bject files: C o ntai ni n g t he c o m plete d e C R Fs (if a p plica ble), s u p p orti n g s o urce 
d oc u me ntati o n i ncl u di n g me dical rec or ds, la b orat or y data, a n d si g ne d I C Fs  
•  Re g ulat or y files: C o ntai ni n g t he pr ot oc ol wit h all a me n d me nts a n d I n vesti gat or 
si g nat ure pa ges, c o pies of all ot her re g ulat or y d oc u me ntati o n, all c orres p o n de nce 
bet wee n t he st u d y site a n d t he I R B/I E C a n d S p o ns or, a n d dr u g acc o u nta bilit y files, 
i ncl u di n g a c o m plete acc o u nt of t he recei pt a n d dis p ositi o n of t he st u d y treat me nt.  
Rec or ds are t o be a vaila ble f or 2  years after t he last mar keti n g a p plicati o n a p pr o val, or if t he 
a p plicati o n is n ot a p pr o ve d or ne ver s u b mitte d, 2  years after t he a p pr o priate re g ulat or y 
a ut h orities ha ve bee n n otifie d of  t he disc o nti n uati o n of cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d uct. T he S p o ns or will pr o vi de writte n n otificati o n w he n it is a p pr o priate f or 
t he I n vesti gat or t o discar d t he st u d y-s pecific d oc u me nts refere nce d a b o ve. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 6  of 1 0 7  
D uri n g t he rec or d rete nti o n per i o d, t he I n vesti gat or or desi g nee m ust i nf or m t he S p o ns or or 
desi g nee (e g, C R O), of t he f oll o wi n g:  
•  L ocati o n of st u d y d oc u me ntati o n  
•  If t he c ust o d y of d oc u me ntati o n will be tra nsferre d or m o ve d t o a n ot her l ocati o n 
•  If t he I n vesti gat or is u na ble t o retai n d oc u me ntati o n f or t he s pecifie d peri o d 
1 3. 3.  
Cli nic al St u d y Re p ort   
W het her t he st u d y is c o m plete d or pre mat urel y ter mi nate d, a cli nical st u d y re p ort will be 
pre pare d a n d pr o vi de d t o t he re g ulat or y a ge ncies acc or di n g t o a p plica ble re g ulat or y 
re q uire me nt(s). 
1 3. 4.  
Discl os ure of St u d y Res ults   
T he S p o ns or will p ost t he res ults of t he st u d y i n a p u blicl y accessi bl e data base i n acc or da nce 
wit h t he a p plica ble la ws a n d re g ulati o ns.  
1 4.  
R E S P O N SI BI LI TI E S   
1 4. 1.  
I n vesti g at or Res p o nsi bilities  
T he I n vesti gat or m ust c o m pl y wit h t his pr ot oc ol a n d t he c o n d uct of all st u d y pr oce d ures. T he 
I n vesti gat or will discl ose t o t he S p o ns or s ufficie nt, acc urate, fi na ncial i nf or mati on t o all o w t he 
S p o ns or t o s u b mit acc urate discl os ure state me nts t o t he F D A per 2 1 C o de of Fe deral Re g ulati o ns 
( C F R) Part 5 4 ( Fi na ncial Discl os ure b y Cli nical I n vesti gat ors) or t o ot her re g ulat or y a ut h orities 
t hat ha ve si milar re q uire me nts. T he I n vesti gat or is res p o nsi ble f or c o m plia nce wit h a p plica ble 
secti o ns of I C H G C P re q uire me nts. T he I n vesti gat or ma y als o be res p o nsi ble f or c o m plia nce 
wit h 2 1 C F R Part 3 1 2, S u b part D, ( Res p o nsi bilities of I n vesti gat ors), a n d ot her I C H G C P 
g ui deli nes a n d/ or re q uire me nts,  fe deral, a n d l ocal la ws, a p plica ble t o c o n d ucti n g dr u g st u dies. 
T he I n vesti gat or is res p o nsi ble f or e ns uri n g a n i n vesti gati o n is c o n d ucte d acc or di n g t o t he si g ne d 
I n vesti gat or state me nt, t he i n vesti gati o nal pla n, a n d a p plica ble re g ulati o ns; f or pr otecti n g t he 
ri g hts, safet y, a n d welfare of s u bjects u n der t he I n vesti gat or’s care; a n d f or t he c o ntr ol of dr u gs 
u n der i n vesti gati o n. A n I n vesti gat or s hall, i n acc or da nce wit h t he pr o visi o ns of I C H G C P 
g ui deli nes a n d/ or 2 1 C F R Part 5 0, o btai n t he i nf or me d c o nse nt of eac h h u ma n s u bject t o w h o m 
t he dr u g is a d mi nistere d. 
1 4. 2.  
S p o ns or’s Me dic all y Q u alifie d I n di vi d u al   
T he c o ntact i nf or mati o n f or t he S p o ns or ’s me dicall y q ualifie d i n di vi d ual (M QI) f o r t he st u d y is 
d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he s u p p orti n g st u d y d oc u me ntati o n. 
T o facilitate access t o t heir i n vesti gat or a n d t he S p o ns or ’s M QI f or st u d y-relate d me dical 
q uesti o ns or pr o ble ms fr o m n o n -st u d y healt hcare pr ofessi o nals, s u bjects are pr o vi de d wit h a n 
i nf or mati o n car d at t he ti me of i nf or me d c o nse nt. T he i nf or mati o n car d will c o ntai n, (a) pr ot oc ol 
a n d st u d y treat me nt i de ntifiers, ( b) s u bject’s stu d y i de ntificati o n n u m ber, (c) site e mer ge nc y 
p h o ne n u m ber acti ve 2 4 h o urs/ da y, 7 da ys per wee k, a n d ( d) S p o ns or’s desi g nate d p h o ne 
n u m ber.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 7  of 1 0 7  
T his c o ntact i nf or mati o n is i nte n de d t o a u g me nt, n ot re place, t he esta blis he d c o m m u nicati o n 
pat h wa ys bet wee n t he s u b ject a n d t heir In vesti gat or a n d site staff, a n d bet wee n t he In vesti gat or 
a n d s p o ns or st u d y tea m. T he i nf or mati o n car d is o nl y t o be use d b y healt hcare pr ofessi o nals n ot 
i n v ol ve d i n t he researc h st u d y, as a mea ns of reac hi n g t he In vesti gat or or site staff r elate d t o t he 
care of a s u bject. T he n u m ber o n t he i nf or mati o n car d is t o be use d w he n t he In vesti gat or a n d 
site staff are u na vaila ble. T he S p o ns or desi g nate d n u m ber is n ot f or use b y t he s u bject directl y; if 
a s u bject calls t hat n u m ber directl y, t he y will  be directe d bac k t o t he i n vesti gat or site . 
1 4. 3.  
S p o ns or Res p o nsi bilities   
T he S p o ns or is res p o nsi ble f or c o m plia nce wit h a p plica ble secti o ns of I C H E 6( R 2) a n d 2 1 C F R 
Part 3 1 2, S u b part  D ( Res p o nsi bilities of S p o ns ors). T he S p o ns or is res p o nsi ble f or selecti n g 
q ualifie d I n vesti gat ors, pr o vi di n g t he m wit h t he i nf or mati o n t he y nee d t o c o n d uct a n 
i n vesti gati o n pr o perl y, a n d e ns uri n g pr o per m o nit ori n g of t he i n vesti gati o n(s). S p o ns ors are als o 
res p o nsi ble f or e ns uri n g t he i n vesti gati o n(s) is c o n d ucte d i n acc or da nce wit h t he ge neral 
i n vesti gati o nal pla n a n d pr ot oc ols c o ntai ne d i n t he I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n 
( or e q ui vale nt), mai ntai ni n g a n effecti ve I N D ( or e q ui vale nt) wit h res pect t o t he i n vesti gati o ns, 
a n d e ns uri n g t he F D A (a n d/ or ot her re g ulat or y a ut h orities as a p plica ble), a n d all partici pati n g 
I n vesti gat ors are pr o m ptl y i nf or me d of si g nifica nt ne w a d verse effects or ris ks wit h res pect t o t he 
dr u g.  
1 4. 4.  
Re p orti n g of S afet y Iss u es a n d Seri o us Bre ac hes of t he Pr ot oc ol or 
I C H G C P  
I n t he e ve nt of a n y pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
re g ulat or y a ut h orit y i n a n y area of t he w orl d, or if t he I n vesti gat or is a ware of a n y ne w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he st u d y treat ment , 
t he S p o ns or s h o ul d be i nf or me d i m me diatel y.  
I n a d diti o n, t he In vesti gat or will i nf or m t he S p o ns or i m me diatel y of a n y ur ge nt safet y meas ures 
ta ke n b y t he In vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y i m me diate hazar d, a n d of a n y 
seri o us breac hes of t his pr ot oc ol or of t he I C H G C P g ui deli nes. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 8  of 1 0 7  
1 5.  
R E F E R E N C E S   
Bri n k ma n n V, Billic h A, Ba u mr u ker T, et al. Fi n g oli m o d ( F T Y 7 2 0): Disc o ver y a n d de vel o p me nt 
of a n oral dr u g t o treat m ulti ple scler osis. N at Rev Dr u g Disc ov. 2 0 1 0; 9( 1 1): 8 8 3 -8 9 7.  
F D A. Esta blis h me nt a n d o perati o n of cli nical trial data m o nit ori n g c o m mittees. U. S. De part me nt 
of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or Cli nical Trial 
S p o ns ors We b site. 
htt ps:// w w w.f da. g o v/ d o w nl oa ds/re g ul at or yi nf or mati o n/ g ui da nces/ uc m 1 2 7 0 7 3. p df . P u blis he d 
2 0 0 6. Accesse d Marc h 4, 2 0 1 9.  
F D A. Dr u g -i n d uce d li ver i nj ur y: Pre mar keti n g cli nical e val uati o n. U. S. De part me nt of Healt h 
a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y We b site. 
htt ps:// w w w.f da. g o v/ d o w nl oa ds/ g ui da nces/ U C M 1 7 4 0 9 0. p df . P u blis he d 2 0 0 9. Accesse d A pril 
2 5, 2 0 1 9.  
F D A. Ulcerati ve c olitis: De vel o pi n g dr u gs f or treat me nts. U S De part me nt of Healt h a n d H u ma n 
Ser vices, F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y ( draft ) We b site. 
htt ps:// w w w.f da. g o v/ me dia/ 1 5 8 0 1 6/ d o w nl oa d . P u blis he d 2 0 2 2. U p date d A pril 2 0 2 2. Accesse d 
J ul y 2 5. 
Ge b oes K, Ri d dell R, Ost A, Je nsfelt B, Perss o n T, L of ber g R. A re pr o d uci ble gra di n g scale f or 
hist ol o gical assess me nt of i nfla m mati o n i n ulcerati v e c olitis. G ut. 2 0 0 0; 4 7( 3): 4 0 4 -4 0 9.  
Hi n dr yc k x P, N o va k G. Ca n we m o ve directl y fr o m 5 -A S A t o a bi ol o gic a ge nt i n ulcerati ve 
c olitis? Best Pr act Res Cli n G astr oe nter ol. 2 0 1 8; 3 2 -3 3: 9 -1 5.  
Kaser A, Zeissi g S, Bl u m ber g R S. I nfla m mat or y b o wel disease. A n n u Rev  I m m u n ol. 
2 0 1 0; 2 8: 5 7 3 -6 2 1.  
K o C W, Si n g h S, Fe uerstei n J D, et al. A G A cli nical practice g ui deli nes o n t he ma na ge me nt of 
mil d -t o-m o derate ulcerati ve c olitis. G astr oe nter ol o gy. 2 0 1 9; 1 5 6( 3): 7 4 8 -7 6 4.  
K or n bl ut h A, Sac har D B, Practice Para meters C o m mittee of t h e A merica n C olle ge of 
Gastr oe nter ol o g y. 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. A m J G astr oe nter ol. 2 0 1 0; 1 0 5( 3): 5 0 1 -5 2 3.  
MacI nt yre N, Cra p o R O, Vie gi G, et al. Sta n dar disati o n of t he si n gle -breat h deter mi nati o n of 
car b o n m o n o xi de u pta ke i n t he l u n g. E ur Res pir J. 2 0 0 5; 2 6( 4): 7 2 0 -7 3 5.  
Marc hal -Bresse n ot A, Saller o n J, B o ula g n o n -R o m bi C, et al. De vel o p me nt a n d vali dati o n of t he 
Na nc y hist ol o gical i n de x f or U C. G ut. 2 0 1 7; 6 6( 1): 4 3 -4 9.  
Miller M R, Cra p o R, Ha n ki ns o n J, et al. Ge neral c o nsi derati o ns f or l u n g f u ncti o n testi n g. E ur 
Res pir J. 2 0 0 5a; 2 6( 1): 1 5 3 -1 6 1.  
Miller M R, Ha n ki ns o n J, Br usasc o V, et al. Sta n dar disati o n of s pir o metr y. E ur Res pir J. 
2 0 0 5 b; 2 6( 2): 3 1 9 -3 3 8.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 9  of 1 0 7  
M osli M H, Fea ga n B G, Z o u G, et al. De vel o p me nt a n d vali dati o n of a hist ol o gical i n de x f or U C. 
G ut. 2 0 1 7; 6 6( 1): 5 0 -5 8.  
Nielse n O H, Li Y, J o ha nss o n -Li n d b o m B, C os k u n M. S p hi n g osi ne -1 -p h os p hate si g nali n g i n 
i nfla m mat or y b o wel disease. Tre n ds M ol Me d. 2 0 1 7; 2 3( 4): 3 6 2 -3 7 4.  
Oli vera P, Da nese S, Pe yri n -Bir o ulet L. Ne xt ge nerati o n of s mall m olec ules i n i nfla m mat or y 
b o wel disease. G ut. 2 0 1 7; 6 6( 2): 1 9 9 -2 0 9.  
R o we W A, Lic hte nstei n G R. I nfla m mat or y b o wel disease. Me dsca pe. 
htt ps://e me dici ne. me dsca pe.c o m/article/ 1 7 9 0 3 7 -o ver vie w . P u blis he d 2 0 2 0. Accesse d J ul y 1 3, 
2 0 2 0.  
R u bi n D B. M ulti ple i m p ut ati o n f or n o nres p o nse i n s urveys.  Ne w Y or k, N Y: J o h n Wile y a n d 
S o ns; 1 9 8 7. O n file at Are na.  
Sa n d b or n WJ, Pe yri n -Bir o ulet L, Z ha n g J, et al. Efficac y a n d safet y of etrasi m o d i n a P hase 2 
ra n d o mize d trial of patie nts wit h ulcerati ve c olitis. G astr oe nter ol o gy. 2 0 2 0; 1 5 8: 5 5 0 -5 6 1.  
Sa n d b or n WJ, Ver meire S, Pe yri n -Bir o ulet L, et al. Etrasi m o d 2  m g o nce dail y as treat me nt f or 
m o deratel y t o se verel y acti ve ulcerati ve c olitis: Res ults fr o m t he p hase 3 E L E V A T E U C 5 2 a n d 
E L E V A T E U C 1 2 trials. Sc h olar O ne A bstracts; Ma y 2 4, 2 0 2 2; Virt ual.  
Sie gel C A, Mel me d G Y, Mc G o ver n D P B, et al. S A R S -C o V -2 vacci nati o n f or patie nts wit h 
i nfla m mat or y b o wel diseases: Rec o m me n dati o ns fr o m a n i nter nati o nal c o nse ns us meeti n g. G ut. 
2 0 2 1; 7 0( 4): 6 3 5 -6 4 0.  
U n gar B, K o p yl o v U. A d va nces i n t he de vel o p me nt of ne w bi ol o gics i n i nfla m mat or y b o wel 
disea se. A n n G astr oe nter ol. 2 0 1 6; 2 9( 3): 2 4 3 -2 4 8. O n file at Are na.  
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 0  of 1 0 7  
1 6.  
A P P E N DI C E S   
A P P E N DI X 1 : 
S C H E D U L E O F A S S E S S M E N T S   
T a ble  6 : 
Sc he d ule of Assess me nts   
E v al u ati o n  
Scree ni n g   
1 2 -Wee k Tre at me nt Peri o d a 
4 0 -Wee k Tre at me nt Peri o d a 
 
 
−2 8  t o −1  
W 0/  
D 1  
W 2/  
D 1 5  
±  3  
W 4/  
D 2 9  
±  3  
W 8/  
D 5 7  
±  3  
W 1 2/  
D 8 5  
±  3 b  
W 1 6/  
D 1 1 3  
±  7  
W 2 4/  
D 1 6 9  
±  7  
W 3 2/  
D 2 2 5  
±  7  
W 4 0/  
D 2 8 1  
±  7  
( virt ual) 
W 4 8/  
D 3 3 7  
±  7  
W 5 2/ D
3 6 5/  
E T  
±  7 b  
2 W  
F/ U  
±  3 c 
4 W  
F/ U  
±  3 c 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical a n d s ocial hist or y d  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Ulcerati ve c olitis hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C hest X -ra ye  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
T u berc ul osis testf  
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
T u berc ul osis q uesti o n naire f 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vir ol o g y scree n ( HI V, H B V, 
H C V) g  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
e Diar y i nstr ucti o nh  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
e Diar y re vie w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
P G A i  
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
M M S/ T M S
j 
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
St o ol fre q ue nc y a n d rectal 
blee di n g s u bsc ores k       
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 1  of 1 0 7  
E v al u ati o n  
Scree ni n g   
1 2 -Wee k Tre at me nt Peri o d a 
4 0 -Wee k Tre at me nt Peri o d a 
 
 
−2 8  t o −1  
W 0/  
D 1  
W 2/  
D 1 5  
±  3  
W 4/  
D 2 9  
±  3  
W 8/  
D 5 7  
±  3  
W 1 2/  
D 8 5  
±  3 b  
W 1 6/  
D 1 1 3  
±  7  
W 2 4/  
D 1 6 9  
±  7  
W 3 2/  
D 2 2 5  
±  7  
W 4 0/  
D 2 8 1  
±  7  
( virt ual) 
W 4 8/  
D 3 3 7  
±  7  
W 5 2/ D
3 6 5/  
E T  
±  7 b  
2 W  
F/ U  
±  3 c 
4 W  
F/ U  
±  3 c 
I B D Q, U C-P R O l, S F -3 6, 
W P AI -U C, F A CI T -F, ur ge nc y 
N R S, a n d P GI C  
 
X  
 
 
 
X  
 
 
X m  
 
 
X  
 
 
A d verse e ve nt assess me nt  
 
Vital si g nsn  
X n 
X n ,o      
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
1 2 -lea d E C G p  
X q 
X p , q      
 
 
 
X  
 
 
 
 
 
X  
 
 
H olter m o nit or r  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa mi nati o n s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
E xtrai ntesti nal ma nifestati o ns t  
X  
 
 
 
 
X  
 
 
 
 
 
X  
X  
X  
P ul m o nar y f u ncti o n testu  
X v 
 
 
 
 
X  
 
 
X  
 
 
X  
X  
 
O p ht hal m osc o p y wit h O C T w   
X  
 
 
 
 
X  
 
 
 
 
 
X  
X  
 
Uri ne dr u g scree nx  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y testy  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
C B C wit h differe ntial a n d 
platelets z  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
La b orat or y tests i ncl u di n g 
hs -C R P aa  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
 
St o ol sa m ple/fecal 
cal pr otecti n b b  
X  
 
X  
X  
X  
X  
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
E n d osc o p y a n d bi o ps y 
( hist ol o gic i n dices)cc      
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 2  of 1 0 7  
E v al u ati o n  
Scree ni n g   
1 2 -Wee k Tre at me nt Peri o d a 
4 0 -Wee k Tre at me nt Peri o d a 
 
 
−2 8  t o −1  
W 0/  
D 1  
W 2/  
D 1 5  
±  3  
W 4/  
D 2 9  
±  3  
W 8/  
D 5 7  
±  3  
W 1 2/  
D 8 5  
±  3 b  
W 1 6/  
D 1 1 3  
±  7  
W 2 4/  
D 1 6 9  
±  7  
W 3 2/  
D 2 2 5  
±  7  
W 4 0/  
D 2 8 1  
±  7  
( virt ual) 
W 4 8/  
D 3 3 7  
±  7  
W 5 2/ D
3 6 5/  
E T  
±  7 b  
2 W  
F/ U  
±  3 c 
4 W  
F/ U  
±  3 c 
P K assess me nts d d  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
Bi o mar kers bl o o d sa m ple w  
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
C o nc o mita nt me dicati o ns a n d 
pr oce d ures ee      
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dr u g 
dis pe nsati o n/acc o u nta bilit y ff  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
 
 
St u d y treat me nt 
a d mi nistrati o n g g 
 
X –  O nce dail y  
X –  O nce dail y  
 
 
a All visits be y o n d W 0/ D 1 ma y be virt ual or h y bri d visits ( Secti o n  9. 6 ). 
b F or s u bjects w h o c o m plete Wee k  1 2, t he Wee k  1 2 visit will be use d t o be gi n assessi n g eli gi bilit y f or t he A P D 3 3 4 -3 0 3 O L E st u d y. S u bjects disc o nti n ui n g treat me nt pri or t o 
Wee k  5 2/ Da y  3 6 5 s h o ul d ha ve a n E T visit wit hi n 7  da ys of t he last st u d y treat me nt a d mi nistrati o n a n d bef ore i nitiati o n of a n y ne w treat me nts. F or s u bjects wit h w orse ni n g 
disease or w h o c o m plete Wee k  5 2 a n d wis h t o e nter t he A P D 3 3 4 -3 0 3 O L E st u d y, t he Wee k  5 2/ E T visit will be use d t o assess eli gi bilit y f or t he O L E st u d y.  
c F or s u bjects n ot partici pati n g i n t he A P D 3 3 4 -3 0 3 O L E st u d y, a f oll o w -u p visit will be perf or me d at 2 a n d 4  wee ks after t he last a d mi nistrati o n of s t u d y treat me nt. If t he E T or 
St u d y C o m pleti o n visit is ≥ 2  wee ks after t he last a d mi nistrati o n of st u d y treat me nt, t he 2 -Wee k F oll o w -U p visit is n ot re q uire d; h o we ver, t he 4 -Wee k F oll o w -U p visit s h o ul d be 
sc he d ule d a n d c o m plete d. If t he E T or St u d y C o m pleti o n visit is ≥ 4  wee ks after t he last a d mi nistrati o n of st u d y treat me nt, t he 4 -Wee k F oll o w -U p visit is n ot re q uire d. If t he 
a bs ol ute peri p heral l y m p h oc yte c o u nt is n ot wit hi n n or mal li mits at t he 4 -Wee k F oll o w -U p visit, s u bjects s h o ul d ret ur n f or C B C wit h differe ntial acc or di n g t o l ocal sta n dar d of 
care (ca pt ure d as s u bse q ue nt F oll o w -U p visit or u nsc he d ule d visit).  
d Me dical hist or y, i ncl u di n g pri or a n d o n g oi n g me dicati o n use, will be c ollecte d d uri n g scree ni n g a n d s h o ul d be u p date d f or a n y  ne w c o n diti o ns o r me dicati o ns as nee de d pri or t o 
d osi n g at t he D 1 visit ( Secti o n  9. 3. 6 ). 
e A c hest X -ra y ta ke n wit hi n t he pre vi o us 6 m o nt hs fr o m t he Scree ni n g Visit ma y als o be use d.  
f All s u bjects will c o m plete T B scree ni n g t o deter mi ne eli gi bilit y (refer t o A p pe n di x 2 ). T he Q ua nti F E R O N T B G ol d a n d t u berc uli n s ki n test s h o ul d n ot be perf or me d i n s u bjects 
pre vi o usl y dia g n ose d wit h T B i nfecti o n. T he T B q uesti o n naire will be c o m plete d f or all s u bjects d uri n g t he Scree ni n g Peri o d  a n d at e ver y st u d y visit f or s u bjects resi di n g i n 
c o u ntries wit h a hi g h T B b ur de n or M D R T B as i de ntifie d b y t he W H O. F or s u bjects w h o are recei vi n g T B pr o p h yla xis treat me nt, t he T B q uesti o n naire will be c o m plete d at 
e ver y st u d y visit ( u ntil T B pr o p h yla xis treat me nt c o urse is c o m plete d). T he T B test  is n ot re q uire d at t he E T visit. 
g S u bjects will be teste d f or HI V a nti b o dies as well as H B V a n d H C V i nfecti o n at scree ni n g ( Secti o n  9. 9. 8. 1. 3 ). 
h S u bjects will be gi n e Diar y e ntries t he first da y of scree ni n g after e Diar y trai ni n g is c o m plete d. T he e Diar y s h o ul d be c o m plete d dail y  t o ca pt ure data, i ncl u di n g dail y S F a n d R B 
(t he 2 s u bject-re p orte d o utc o me meas ures c o ntri b uti n g t o t he calc ulati o n of the M M S  a n d T M S), a n d st u d y treat me nt a d mi nistrati o n. T he s u bject e Diar y will be re vie we d b y 
st u d y site staff at eac h treat me nt visit. 
i T he P G A will  be prese nt  i n s o urce d oc u me ntati o n a n d t he e C R F at s pecifie d st u d y visits.  
j T he T M S a n d M M S will be calc ulate d electr o nicall y at t he Wee k 0/ Da y  1 , Wee k  1 2 , Wee k  5 2 , a n d E T visits. T he s u bsc ores f or S F a n d R B are deri ve d fr o m t he s u bject e Diar y 
e ntries usi n g t he sc ores fr o m t he 3  m ost rece nt c o nsec uti ve da ys  wit hi n t he 7  da ys pri or t o t he da y of b o wel pre parati o n (e xcl u di n g t he da y of b o wel pre parati o n), a vera ge d a n d 
r o u n de d t o t he nearest i nte ger ( Secti o n 9. 3. 1 1 ). 
k S F a n d R B s u bject -re p orted o utc o mes will be rec or de d dail y usi n g electr o nic s u bject e Diaries . T he R B a n d S F s u bsc ores will be calc ulate d as i n dicate d i n Secti o n 9. 3. 1 1 . 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 3  of 1 0 7  
l U C -P R O is a vaila ble o n t he s u bjects e Diar y d uri n g t he Scree ni n g peri o d, 1 4 da ys pri or t o a n d 1 4 da ys after t he pr ojecte d visit d ate d uri n g t he Treat me nt Peri o d e xce pt f or E T visit 
w hic h is 7 da ys  pri or a n d 7 da ys after. S u bject s h o ul d c o m plete U C -P R O w he n it bec o mes a vaila ble o n t he de vice f or t he visit, c o nti n ui n g u ntil t he visit occ urs. 
m  F or U C -P R O o nl y . 
n Safet y vital si g ns (resti n g heart rate a n d s yst olic a n d diast olic B P, b o d y te m perat ure, a n d res pirat or y rate) ta ke n wit h s u bj ects i n t he sitti n g p osit i o n will be perf or me d at 
Scree ni n g a n d pri or t o ra n d o mizati o n o n Wee k  0/ Da y  1 ( baseli ne). If t he s u bject’s heart rate is <  5 0  b p m, or s yst olic B P  <  9 0  m m  H g, or diast olic B P  <  5 5  m m  H g, or has 
s y m pt o ms of l o w heart  rate or l o w B P, t he s u bject m ust n ot be r a n d o mize d a n d s h o ul d be c o nsi dere d a scree n fail ure.  
o O n Da y  1, vital si g n assess me nts will be c o n d ucte d as descri be d i n Secti o n  9. 9. 2 . 
p Safet y 1 2 -lea d E C Gs wit h t he s u bject i n t he s u pi ne p ositi o n will be o btai ne d pri or t o bl o o d sa m ple c ollecti o n at Scree ni n g a n d pri or t o ra n d o mizati o n o n Wee k 0/ Da y  1 
( baseli ne). S u bjects wit h a 1 2-lea d E C G s h o wi n g a sec o n d or t hir d-de gree A V bl oc k, peri o ds of as yst o le > 3  sec o n ds, P R i nter val > 2 0 0  ms, Q Tc F  ≥ 4 5 0  ms ( me n) or 
Q Tc F  ≥ 4 7 0  ms ( w o me n) m ust n ot be ra n d o mize d a n d s h o ul d be c o nsi dere d a scree n fail ure.  
q After d osi n g o n Da y  1, a 1 2 -lea d E C G wit h t he s u bject i n t he s u pi ne p ositi o n will be perf or me d 4 h o urs ( ±  1 5  mi n utes) p ost -d ose  as descri be d i n Secti o n  9. 4. 1 . Details re gar di n g 
a d diti o nal E C Gs are pr o vi de d i n Secti o n  9. 4. 2. 1 . 
r H olter rec or di n g will be c o n d ucte d if/ w he n a vaila ble. T he H olter m o nit or will be place d a p pr o xi matel y 1 5 mi n utes pri or t o t he first treat me nt a d mi nistrati o n a n d re m o ve d 
8  h o urs ( ±  1 5 mi n utes) p ost -treat me nt a d mi nistrati o n. H olter rec or di n g will be re peate d o n Da y 2 f or s u bjects re q uiri n g e x te n de d car diac m o nit ori n g as descri be d i n 
Secti o n  9. 4. 2. 1 . A d diti o nal i nf or mati o n is pr o vi de d t o t he st u d y sites i n t he H olter s u p p ort ma n ual. A c harter fr o m t he ce ntral H olter la b orat or y will o utli ne t he rec or di n g 
para meters, a nal ysis pr oce d ures, a n d e q ui p me nt.  
s C o m plete p h ysical e xa mi nati o n) s h o ul d be perf or me d at scree ni n g  a n d t he Wee k  1 2/ Wee k  5 2/ E T visits  (as descri be d i n Secti o n  9. 9. 1 ). All ot her visits s h o ul d ha ve a f oc use d 
(c o m plai nts, si g ns, a n d s y m pt o ms)  p h ysical e xa mi nati o n . 
t D uri n g t he s pecifie d f ull p h ysical e xa mi nati o ns, s pecific s yste ms (e yes, li ver, s ki n, a n d j oi nts) will be e xa mi ne d f or EI Ms. 
u A P F T will i ncl u de F E V 1 a n d F V C meas ure me nts. W he n a vaila ble, D L C O meas ure me nts will als o be perf or me d. W he n D L C O is n ot a vaila ble, sites s h o ul d c o ns ult t he S p o ns or 
or S p o ns or’s dele gate).  T he 2 -Wee k F oll o w -U p visit assess me nt is o nl y re q uire d if cli nicall y i n dicate d. Details re gar di n g a d diti o nal P F Ts are pr o vi de d i n Secti o n  9. 9. 5 . T he 
Wee k  3 2 assess me nt is o nl y re q uire d f or s u bjects wit h a hist or y of mil d p ul m o nar y disease (e g, ast h ma, c hr o nic o bstr ucti ve p ul m o na r y disease). 
v P F Ts  s h o ul d be perf or me d ± 7  da ys of t he st u d y treat me nt peri o d a n d p ost -treat me nt peri o d (ie, 2 -Wee k F oll o w -U p visit), t he Scree ni n g P F T s h o ul d be d o ne wit hi n t he 2 8 -D a y 
Scree ni n g Peri o d . T he 2 -Wee k F oll o w -U p visit assess me nt is o nl y re q uire d if cli nicall y i n dicate d. Details re gar di n g a d diti o nal P F Ts are pr o vi de d i n Secti o n  9. 9. 5 . 
w  T he Scree ni n g O C T s h o ul d be perf or me d wit hi n t he 2 8 -D a y Scree ni n g Peri o d . S u bse q ue nt o p ht hal m osc o p y wit h O C T  s h o ul d be perf or me d ± 7  da ys i n t he st u d y treat me nt 
peri o d a n d p ost -treat me nt peri o d (ie, 2 -Wee k F oll o w -U p visit). O C T occ urri n g at t he E T visit t hat are wit hi n 4  wee ks of t he last assess me nt will o nl y be re q uire d if cli nicall y 
i n dicate d. T he 2-Wee k F oll o w -U p visit assess me nt is o nl y re q uire d if cli nicall y i n dicate d.  Details re gar di n g o p ht hal m osc o p y a n d O C T assess me nts are pr o vi de d i n Secti o n  9. 9. 6 . 
x Uri ne dr u g scree n acc or di n g t o Secti o n  9. 9. 8. 1. 1 . 
y O nl y f or w o me n of c hil d beari n g p ote ntial. Ser u m β -h C G test re q uire d at S cree ni n g; uri ne pre g na nc y test at all ot her visits.  A m o nt hl y h o me pre g na nc y test i n n o n -visit m o nt hs 
s h o ul d be perf or me d a n d res ult s h o ul d be d oc u me nte d i n t heir e Diar y ( Secti o n  9. 9. 8. 1. 2 ). If at a n y p oi nt t here is a p ositi ve uri ne β -h C G test, t he s u bject will ha ve st u d y treat me nt 
i nterr u pte d a n d a ser u m sa m ple s u b mitte d t o t he ce ntral la b orat or y f or β-h C G testi n g ( Secti o n  9. 9. 1 0 ). 
z Sa m ples s h o ul d be c ollecte d o n t he i n dicate d da ys pri or t o t he dail y d osi n g as a p plica ble. 
 
 
aa Cli nical la b orat or y tests will i ncl u de ser u m c he mistr y, he mat ol o g y (i ncl u di n g c oa g ulati o n), uri nal ysis, a n d hs -C R P. Scree ni n g sa m ples s h o ul d be o btai ne d, a n d res ults m ust be 
a vaila ble a n d re vie we d pri or t o t he first d ose of st u d y treat me nt. O n ot her st u d y visits, sa m ples s h o ul d be o btai ne d pri or t o  t he dail y d osi n g. 
b b St o ol sa m ple is f or fecal cal pr otecti n (all  i n dicate d visits) a n d bacterial c ult ure, o va a n d parasite e val uati o n, a n d C.  difficile  assa y at scree ni n g a n d at a n y p oi nt i n t he st u d 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.  St o ol sa m ple f or  
 c ollecti o n is n ot re q uire d at E T visit.  
cc E n d osc o p y vi de os are t o be rea d b y a bli n de d ce ntral rea der. E n d osc o p y ( pr oct osi g m oi d osc o p y/c ol o n osc o p y) m ust be perf or me d pr i or t o ra n d o mizati o n of treat me nt t o all o w 
ce ntral rea der re vie w ( ma y ta ke a p pr o xi matel y 5 t o 1 2  da ys) a n d c o nfir m eli gi bilit y ( Secti o n  9. 3. 1 1 ). If t he E T visit is wit hi n 4 wee ks of t he last e n d osc o p y a n d bi o ps y, t hese 
pr oce d ures d o n ot nee d t o be re peate d. Hist ol o gic i n dices ( R o barts, Ge b oes, Na nc y I n de x) t o be rea d b y bli n de d ce ntral hist o pat h ol o g y rea der.  
d d  P har mac o ki netic bl o o d sa m ples are t o be c ollecte d pre -d ose, 4  h o urs ( ±  1 5  mi n utes) p ost -d ose o n Wee k  0/ Da y  1 ( P K sa m ple t o be c ollecte d after 1 2 -lea d E C G), a n d pre-d ose  
(f or tr o u g h le vel) o n all ot her i n dicate d da ys. A P K sa m ple s h o ul d be ta ke n, if p ossi ble, at t he ti me of a n y S A E or a d verse e ve nt lea di n g t o st u d y treat me nt disc o nti n uati o n. I n 
a d diti o n, f or s u bjects n ot e nr olli n g i nt o t he A P D 3 3 4 -3 0 3 st u d y, a bl o o d sa m ple f or P K s h o ul d be dra w n at t he 2 -Wee k a n d 4 -Wee k F oll o w -U p visits. F or all P K bl o o d dra ws, t he 
ti me of t he last treat me nt a d mi nistrati o n s h o ul d be d oc u me nte d. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 4  of 1 0 7  
ee All c o nc o mita nt me dicati o ns a n d pr oce d ures s h o ul d be c ollecte d fr o m Scree ni n g t hr o u g h t he safet y re p orti n g peri o d ( Secti o n  6. 7 ). C o ntrace pti o n c o nfir mat i o n s h o ul d ta ke place 
at eac h sc he d ule d visit a n d will be d oc u me nte d i n s o urce data. O nl y re q uire d f or E T if E T visit ≤ 3 0 h o urs si nce last treat me nt d ose . 
ff S t u d y treat me nt s h o ul d be dis pe nse d at Wee k 1 2 if t he s u bject c o nti n ues treat me nt i n t he 4 0 -Wee k Treat me nt Peri o d. F or s u bjects w h o c o nse nt a n d are eli gi ble f or t he 
A P D 3 3 4 -3 0 3 O L E st u d y pri or t o Wee k  5 2, d o u ble -bli n de d st u d y treat me nt ma y be dis pe nse d i n t he e ve nt t here is a ga p bet wee n t he last o n treat me nt visit of t he A P D 3 3 4 -2 1 0 
st u d y a n d W 0/ D1 of t he O L E. St u d y treat me nt ma y be dis pe nse d at Wee k  5 2 if t he s u bject q ualifies f or a n d has o pte d t o partici pate i n t he A P D 3 3 4 -3 0 3 O L E st u d y  b ut w h o d o 
n ot e nter t he O L E st u d y o n t he sa me da y as t heir Wee k  5 2 visit.  
g g O n da ys wit h sc he d ule d st u d y visit s, s u bjects s h o ul d n ot  ta ke t heir d ose of st u d y treat me nt u ntil t he y ha ve c o m plete d pre-d ose  st u d y pr oce d ures. T he d ose will be ta ke n after 
bl o o d dra ws f or P K a n d after all pre-d ose  assess me nts a n d pr oce d ures ha ve bee n c o m plete d.  
A V, atri o ve ntric ular; β -h C G, beta -h u ma n c h ori o nic g o na d otr o pi n; B P, bl o o d press ure; C B C, c o m plete bl o o d c o u nt; D, da y; D L C O, diff usi n g ca pacit y of t he l u n gs f o r car b o n 
m o n o xi de; E C G, electr ocar di o gra m; e Diar y, electr o nic diar y; EI M, e xtrai ntesti nal ma nifestati o n; E T, earl y ter mi nat i o n; F A CI T-F, F u ncti o nal Assess me nt of C hr o nic Ill ness 
T hera p y -Fati g ue; F E V 1, f orce d e x pirat or y v ol u me i n 1 sec o n d; F/ U, F oll o w-U p; F V C, f orce d vital ca pacit y; he patitis B s urface a nti ge n; H B V, he patitis B vir us; H C V, he patitis C 
vir us; HI V, h u ma n i m m u n o de ficie nc y vir us; H R, heart rate; hs-C R P, hi g h -se nsiti vit y C-reacti ve pr otei n; I B D Q, I nfla m mat or y B o wel Disease Q uesti o n naire; M D R, m ulti-dr u g 
resista nt; M M S, m o difie d Ma y o sc ore; O C T, o ptical c o here nce t o m o gra p h y; O L E, O pe n-La bel E xte nsi o n; P F T, p ul m o nar y f u ncti o n test; P G A, P h ysicia n’s Gl o bal Assess me nt; 
P GI C, Patie nt Gl o bal I m pressi o n of C ha n ge; P K, p har mac o ki netics; Q Tc F, Fri dericia’s c orrecte d Q T i nter val; R B, rectal blee di n g; S A E , seri o us a d verse e ve nt S F, st o ol fre q ue nc y; 
S F -3 6, Me dical O utc o mes St u d y 3 6 -Ite m S h ort F or m Healt h S ur ve y; T B, t u berc ul osis;
 Ter m, ter mi nati o n; 
U C, ulcerati ve c olitis; U C -P R O, Ulcerati ve C olitis Patie nt -Re p orte d O utc o mes; U C -P R O / S S, Ulcerati ve C olitis Patie nt -Re p orte d O utc o mes  Si g ns a n d S y m pt o ms ; W, wee k; 
W H O, W orl d Healt h Or ga nizati o n; W P AI -U C, W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire –  Ulcerati ve C olitis  
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C CI

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2. 1  
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 5  of 1 0 7  
A P P E N DI X 2 : 
T U B E R C U L O SI S S C R E E NI N G   
All s u bjects m ust u n der g o scree ni n g f or a hist or y of t u berc ul osis ( T B) i nfecti o n a n d testi n g f or 
late nt/acti ve T B i nfecti o n. T heir me dical hist or y re vie w must i ncl u de s pecific q uesti o ns a b o ut a 
hist or y of T B or k n o w n occ u pati o nal or ot her pers o nal e x p os ure t o i n di vi d uals wit h acti ve T B. 
S u bjects s h o ul d be as ke d a b o ut past testi n g f or T B, i ncl u di n g c hest ra di o gra p h res ults a n d res ults 
of i nterfer o n -ga m ma rele ase assa y (i nterfer o n -ga m ma release assa y [I G R A], e g, 
Q ua nti F E R O N -T B G ol d I n -T u be, T -S P O T T B) or res p o nse t o t u berc uli n s ki n test ( T S T) a n d 
hist or y of Bacill us Cal mette -G uéri n vacci nati o n.  
a. S u bjects wit h o ut a hist or y of late nt or acti ve T B w h o ha ve a ne gati ve I G R A or T S T 
res ult at scree ni n g are eli gi ble t o e nr oll i n t he st u d y. 
b.  A T B q uesti o n naire will be c o m plete d f or all s u bjects (refer t o q uesti o n naire bel o w) 
d uri n g t he Scree ni n g Peri o d . 
c. F or s u bjects resi di n g i n c o u ntries wit h a hi g h b ur de n of T B or m ulti -d r u g resista nt 
( M D R) T B as i de ntifie d b y W H O, t he T B scree ni n g q uesti o n naire will be c o m plete d 
at e ver y st u d y visit ( per pr ot oc ol Sc he d ule of Assess me nts). F or s u bjects w h o are 
recei vi n g T B pr o p h yla xis treat me nt t he T B q uesti o n naire will be c o m plete d at e ver y 
st u d y visit ( u ntil T B pr o p h yla xis treat me nt c o urse is c o m plete d). T his q uesti o n naire 
will m o nit or f or a n y e mer ge nt s y m pt o ms of acti ve T B a n d c o m plia nce wit h a n y T B 
pr o p h yla xis treat me nt.  
•  F or a c o m plete list of T B hi g h b ur de n a n d M D R T B hi g h b ur de n c o u nt ries 
d uri n g t he peri o d 2 0 2 1  t o 2 0 25 , visit: 
o  htt ps:// w w w.st o pt b. or g/sec uri n g -q ualit y -t b-care-all/ hi g h-b ur de n -
c o u ntries -t u berc ul osis 
o  htt ps://c d n. w h o.i nt/ me dia/ d ocs/ defa ult -s o urce/ h q-
t u berc ul osis/ w h o _ gl o bal h bclistst b _ 2 0 2 1-
2 0 2 5 _ bac k gr o u n d d oc u me nt. p df?sf vrs n =f 6 b 8 5 4c 2 _ 9  
o  htt ps:// w w w. w h o.i nt/ p u blicati o ns/i/ite m/ 9 7 8 9 2 4 0 0 3 7 0 2 1  
d.  T he I G R A or T S T is N O T re q uire d at scree ni n g ( or a n n uall y) f or s u bje cts wit h a 
hist or y of acti ve/late nt T B i nfecti o n.  
− S u bjects wit h past or c urre nt hist or y of acti ve T B, re gar dless of treat me nt hist or y, 
are e xcl u de d fr o m e nr oll me nt.  
− S u bjects wit h a hist or y of late nt T B i nfecti o n dia g n ose d pri or t o scree ni n g m ust 
ha ve d oc u m e ntati o n of treat me nt wit h at least 4 wee ks of a n acce pta ble T B 
pr o p h yla xis treat me nt re gi me n t o q ualif y f or e nr oll me nt. It 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 T B treat me nt a n d pr o vi de 
a p pr o priate d oc u me ntati o n ( Dir ect O bser vati o n T hera p y re p ort w here a vaila ble).  
e. Acce pta ble T B pr o p h yla xis treat me nt re gi me ns 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. If n o l ocal c o u ntr y g ui deli nes f or t he treat me nt of late nt T B 
e xist, W orl d Healt h Or ga nizati o n ( W H O) g ui deli nes m ust be f oll o we d.  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2. 1  
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 6  of 1 0 7  
f. S u bjects wit h a ne wl y i de ntifie d p ositi ve I G R A ( o ne retest is all o we d wit h a p pr o val 
fr o m t he Me dical M o nit or per Secti o n 9. 3. 1 ) or T S T res ult at Scree ni n g m ust be 
c o nsi dere d a Scree n Fail ure, h o we ver t he y are eli gi ble f or rescree ni n g o nce t he y 
u n der g o a n e val uati o n t o r ule o ut acti ve T B (c hest X -ra y t o r ule o ut p ul m o nar y T B) 
a n d i nitiate a n acce pta ble T B pr o p h yla xis treat me nt re gi me n f or late nt T B at least 
4  wee ks pri or t o rescree ni n g ( wit h a pla n t o c o m plete t he T B treat me nt c o urse d uri n g 
st u d y partici pati o n) bef ore t he y ca n be c o nsi dere d f or e nroll me nt. F or s u bjects 
dia g n ose d wit h late nt T B i nfecti o n a n d resi de i n c o u ntries wit h hi g h b ur de n of T B or 
M D R T B: A c hest c o m p ute d t o m o gra p h y sca n s h o ul d be perf or me d t o r ule o ut 
c urre nt/ past p ul m o nar y T B i n t he e ve nt t he c hest X -ra y is e q ui v ocal. 
g.  A n asse ss me nt of a de q uac y of t he T B pr o p h yla xis treat me nt re gi me n a n d d urati o n of 
treat me nt m ust be perf or me d b y a n i nfecti o us disease c o ns ulta nt or p h ysicia n T B 
e x pert. 
h.  I G R A a n d T S T i nter pretati o n 
− S u bjects will be c o nsi dere d t o ha ve a ne gati ve dia g n ostic test f o r T B if at least 
o ne of t he f oll o wi n g circ u msta nces a p plies:  
− Ne gati ve Q ua nti F E R O N -T B G ol d test.  
− C o m bi nati o n of a ne gati ve Q ua nti F E R O N -T B G ol d test a n d ne gati ve 
p urifie d pr otei n deri vati ve ( P P D) T S T (i n c o u ntries w here I G R A is n ot 
c o nsi dere d a vali date d tes t). 
− A c o m bi nati o n of 2 i n deter mi na nt Q ua nti F E R O N -T B G ol d tests a n d a ne gati ve 
P P D T S T (i n c o u ntries w here I G R A is n ot c o nsi dere d a vali date d test). A n 
i n deter mi na nt I G R A test res ult s h o ul d be re peate d. I n t he e ve nt t hat t he sec o n d 
I G R A test res ult is als o i n deter mi nate, t he s u bject ma y be e nr olle d wit h o ut 
treat me nt f or late nt T B if his/ her c hest ra di o gra p h s h o ws n o a b n or malit y 
s u g gesti ve of T B (acti ve or ol d, i nacti ve T B) a n d t he s u bject has n o a d diti o nal 
ris k fact ors f or T B as deter mi ne d b y a p h ysicia n T B e x pert p h ysicia n.  
− If t he I G R A is n ot c o nsi dere d a vali date d test or is n ot re gistere d f or use i n t he 
s u bject’s c o u ntr y, a ne gati ve T S T res ult is re q uire d t o r ule o ut late nt T B i nfecti o n. 
− A p ositi ve T S T reacti o n is ≥ 1 0  m m of i n d urati o n, or ≥ 5  m m of i n d ura ti o n f or 
s u bjects recei vi n g e q ui vale nt of pre d nis o ne > 1 5  m g/ da y f or a n y me dical 
c o n diti o ns a n d s u bjects resi di n g i n c o u ntries i de ntifie d b y W H O as a hi g h T B 
b ur de n c o u ntr y or hi g h M D R T B b ur de n c o u ntr y.  
i. Res o urces  
− F or t he W H O g ui deli nes f or t he treat me nt o f late nt T B visit: 
htt ps://a p ps. w h o.i nt/iris/ bitstrea m/ ha n dle/ 1 0 6 6 5/ 4 4 1 6 5/ 9 7 8 9 2 4 1 5 4 7 8 3 3 _e n g. p df;j
sessi o ni d = 1 1 5 F 8 0 7 C 3 0 0 8 D 6 8 8 F 7 5 1 1 8 A F 1 6 E A 5 3 F 0?se q ue nce = 1 
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2. 1  
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 7  of 1 0 7  
T u berc ul osis Scree ni n g Q uesti o n n aire  
Etrasi m o d Pr o gra m  
T u berc ul osis Scree ni n g Q uesti o n naire  
Create d b y Are na P har mace uticals, I nc.  
Versi o n 1. 0, 1 7Ja n 2 0 2 0  
 
Site #:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
S u bject #: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
S o urce D oc u me nt W or ks heet  
I nstr ucti o ns: 
1.  T his s o urce d oc u me nt w or ks heet s h o ul d be c o m plete d b y t he PI or dele g a te d site 
st aff. 
2.  T his s o urce d oc u me nt w or ks heet s h o ul d N O T  be gi ve n t o t he s u bject f or 
c o m pleti o n. 
3.  Ple ase c o m plete f or A L L  s u bjects d uri n g t he Scree ni n g visit. 
4.  Ple ase c o m plete at e ver y st u d y visits f or s u bjects w h o are recei vi n g T B pr o p h yl a xis 
tre at me nt ( u ntil t he T B pr o p h yl a xis tre at me nt c o urse is c o m plete d) a n d at 
desi g n ate d p ost -b aseli ne st u d y visits ( per pr ot oc ol sc he d ule of assess me nts) f or 
s u bjects w h o reside i n c o u ntries wit h a hi g h b ur de n of T B or m ulti -dr u g resist a nt 
( M D R) T B as i de ntifie d b y W H O. T he c urre nt W H O T B hi g h b ur de n c o u ntr y 
( H B C) a n d M D R T B H B C lists c a n be f o u n d at t he f oll o wi n g U R Ls:  
a.  htt ps://c d n. w h o.i nt/ me di a/ d ocs/ def a ult -s o urce/ h q-
t u berc ulosis/ w h o _ gl o b al h bclistst b _ 2 0 2 1 -
2 0 2 5 _ b ac k gr o u n d d oc u me nt. p df ?sf vrs n =f 6 b 8 5 4c 2 _ 9 ,  
b.  htt ps:// w w w. w h o.i nt/ p u blic ati o ns/i/ite m/ 9 7 8 9 2 4 0 0 3 7 0 2 1 ,  
c. a n d htt ps:// w w w.st o pt b. or g/sec uri n g -q u alit y -t b-c are-all/ hi g h -
b ur de n -c o u ntries-t u berc ul osis. 
5.  E nter all a p plic a ble i nf or m ati o n o n t he c orres p o n di n g e C R F.  
Was t he T u berc ul osis Scree ni n g q uesti o n naire c o m plete d?  
Ye s  N o  
 
If yes, please e nter c o m pleti o n date 
( D D/ M M/ Y Y Y Y): 
 
 
 
If n o, s pecif y reas o n: 
 
 
Date of c o m pleti o n of T B Scree ni n g Q uesti o n naire, if 
a p plica ble: 
 
 
 
St u d y Visit N u m ber:  
 
 
 
Secti o n 1: Q uesti o ns t o as k t he su bject  
 
* Ti me fra me: i n t he past year or si nce y o ur last st u d y visit.  
 
1.   H a ve y o u e x perie nce d a n y of t he f oll o wi n g s y m pt o ms? * 
 
 
a.  
A pr o d ucti ve c o u g h (c o u g hi n g u p p hle g m) f or m ore t ha n 3 wee ks 
Ye s  N o  
 
b.  
He m o pt ysis (c o u g hi n g u p bl o o d)  
Ye s  N o  
 
c. 
U ne x plai ne d wei g ht l oss  
Ye s  N o  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2. 1  
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 8  of 1 0 7  
 
d.  
Fe ver, c hills, or ni g ht s weats f or n o k n o w n reas o n  
Ye s  N o  
 
e. 
Persiste nt s h ort ness of breat h ( diffic ult y breat hi n g)  
Ye s  N o  
 
f. 
U ne x plai ne d  fati g ue 
Ye s  N o  
 
g.  
C hest pai n   
Ye s  N o  
2.   Ha ve y o u ha d c o ntact wit h a n y o ne wit h acti ve t u berc ul osis disease? *  
Ye s  N o  
3.   Ha ve y o u bee n dia g n ose d wit h late nt T B i nfecti o n?  
Ye s  N o  
 
a.  
If yes, list me dicati o n(s) use d t o treat late nt T B i nfecti o n a n d treat me nt dates ( please 
e ns ure liste d o n C o nc o mita nt Me dicati o n S o urce L o g a n d e C R F, as a p plica ble).  
 
Me dicati o n # 1  
 
 
 
Start date of Me dicati o n # 1:   
 
 
 
 
E x pecte d st o p date of Me dicati o n # 1:    
 
 
 
Ha ve y o u misse d ta ki n g a n y d oses of Me dicati o n # 1?  
Ye s  N o  
 
 
Dates of Misse d D oses:   
 
 
 
 
# of Misse d D oses:   
 
 
 
 
 
 
 
 
Me dicati o n # 2  
 
 
 
 
 
Start date of Me dicati o n # 2 :  
 
 
 
 
E x pecte d st o p date of Me dicati o n # 1:    
 
 
 
Ha ve y o u misse d ta ki n g a n y d oses of Me dicati o n # 1?  
Yes  
N o  
 
 
Dates of Misse d D oses:   
 
 
 
 
# of Misse d D oses:   
 
 
 
 
 
 
 
 
Me dicati o n # 3  
 
 
 
 
 
Start date of Me dicati o n # 3 :  
 
 
 
 
E x pecte d st o p date of Me dicati o n # 1:    
 
 
 
Ha ve y o u misse d ta ki n g a n y d oses of Me dicati o n # 1?  
Yes  
N o  
 
 
Dates of Misse d D oses:   
 
 
 
 
# of Misse d D oses:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2. 1  
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 9 9  of 1 0 7  
 
 
 
 
 
 
Me dicati o n # 4  
 
 
 
 
 
Start date of Me dicati o n # 4 :  
 
 
 
 
E x pecte d st o p date of Me dicati o n # 1:    
 
 
 
Ha ve y o u misse d ta ki n g a n y d oses of Me dicati o n # 1?  
Yes  N o  
 
 
Dates of Misse d D oses:   
 
 
 
 
# of Misse d D oses:   
 
 
 
 
 
 
 
 
 
 
 
 
Please pr o vi de details t o a n y q uesti o n a ns were d “ Yes.”  
 
 
 
 
 
 
 
 
 
 
 
C o m plete d b y (si g n at ure)  
 
D ate  
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 0  of 1 0 7  
Secti o n 2: T o be c o m plete d b y t he i n vesti g at or  
I. 
T he partici pa nt is o n c o nc o mita nt me dicati o n(s) wit h i m m u n os u p pressi ve effects: Yes / N o  
If yes, s pecif y me dicati o n(s) ( na me, d osa ge):  
Me dicati o n # 1:  
 
Me dicati o n # 2:  
 
Me dicati o n # 3:  
 
Me dicati o n # 4:  
 
 
II. 
T B Q ua nti F E R O N or T u berc uli n S ki n Test res ult:  
  
Date:  
  
C hest x -ra y/c o m p uter t o m o gra p h y ( C T) sca n d o ne t o r ule o ut 
p ul m o nar y T B?  
Yes  
N o  
 
If yes, date of c hest x-ra y or C T sca n:  
 
A n y e vi de nce of acti ve p ul m o nar y T B disease o n c hest x -ra y 
or C T sca n? 
Yes  
N o  
Ot her assess me nt c o m plete d?  
Yes  
N o  
 
If yes, s pecif y assess me nt:  
 
 
 
If yes, date of ot her assess me nt:  
 
 
 
A n y e vi de nce of acti ve T B disease o n assess me nt?  
Yes  
N o  
III. 
U p o n re vie w of t he res p o nses a n d disc ussi o n wit h t he partici pa nt, I rec o m me n d t he 
f oll o wi n g: 
 
Perf or m scree ni n g test f or late nt T B  i nfecti o n  
 
Perf or m a d diti o nal assess me nts t o r ule o ut acti ve T B  disease  
 
Refer t o p h ysicia n T B e x pert f or e val uati o n a n d  treat me nt 
 
F oll o w u p at t he ne xt T B -desi g nate d st u d y visit a n d re peat T B scree ni n g  
q uesti o n naire  
 
 
 
I n vesti g at or (si g n at ure) 
 
D ate  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 1  of 1 0 7  
A P P E N DI X 3 : 
M A Y O C LI NI C S C O R E –  S A M P L E   
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 2  of 1 0 7  
A P P E N DI X 4 : 
HI S T O L O GI C A L S C O RI N G I N DI C E S   
Ge b oes Gr a di n g S yste m  
T he Ge b oes Gra di n g S yste m is a ste p wise gra di n g s yste m use d f or t he e val uati o n of micr osc o pic 
i nfla m mati o n a n d hist o pat h ol o gic disease acti vit y i n ulcerati ve c olitis ( U C). T he micr osc o pic 
a p peara nce of t he m uc osa is cate g orize d i nt o 6 gra des. A decrease of  t he Ge b oes Sc ore gra di n g 
s yste m t o Gra de zer o ( 0) or o ne ( 1) i n dicates m uc osal heali n g (Ge b oes 2 0 0 0 ). 
N a nc y Hist ol o gic al I n de x  
T he Na nc y Hist ol o gical I n de x is a vali da te d i n de x f or assessi n g hist ol o gical disease acti vit y i n 
U C. It is c o m p ose d of 3 hist ol o gical ite ms defi ni n g 5 gra des of disease acti vit y: A bse nce of 
si g nifica nt hist ol o gical disease ( Gra de 0), c hr o nic i nfla m mat or y i nfiltrate wit h n o ac ute 
i nfla m mat or y i nfiltrate ( Gra de 1), mil dl y acti ve disease ( Gra de 2), m o deratel y acti ve disease 
( Gra de 3), a n d se verel y acti ve disease ( Gra de 4). T he prese nce of ulcerati o n o n t he bi o ps y 
s peci me n c orres p o n ds t o se verel y acti ve disease ( Gra de 4). If t here is n o ulcerati o n, a c ute 
i nfla m mat or y cells i nfiltrate ( prese nce of ne utr o p hils) is assesse d. M o derate or se vere ac ute 
i nfla m mat or y cells i nfiltrate c orres p o n ds t o m o deratel y acti ve disease ( Gra de 3), w hile mil d 
ac ute i nfla m mat or y cells i nfiltrate c orres p o n d t o mil dl y acti ve disease ( Gra de 2). If t here is n o 
ac ute i nfla m mat or y cells i nfiltrate, assess me nt of c hr o nic i nfla m mat or y i nfiltrate (l y m p h oc ytes 
a n d plas mac ytes) is ma de. A bi o ps y s peci me n s h o wi n g m o derate or mar ke d c hr o nic 
i nfla m mat or y i nfiltrate c orres p o n ds t o m o derate or mar ke d c hr o nic ac ute i nfla m mat or y i nfiltrate 
( Gra de 1). A bi o ps y s peci me n s h o wi n g mil d or n o c hr o nic i nfla m mat or y i nfiltrate c orres p o n ds t o 
a bse nce of si g nifica nt hist ol o gical disease ( Gra de 0) (Marc hal -Bresse n ot 2 0 1 7 ). 
R o b arts Hist o p at h ol o g y I n de x  
T he R o barts Hist o pat h ol o g y I n de x ( R HI) is a n e val uati ve i n de x, deri ve d fr o m t he Ge b oes sc ore, 
t hat is desi g ne d t o be re pr o d uci ble a n d res p o nsi ve t o cli nicall y mea ni n gf ul c ha n ge i n disease 
acti vit y o ver ti me. T he t otal R HI sc ore ra n ges fr o m 0 ( n o disease ac ti vit y) t o 3 3 (se vere disease 
acti vit y) a n d is calc ulate d as f oll o ws: R HI  =  1  ×  c hr o nic i nfla m mat or y i nfiltrate + 2  ×  la mi na 
pr o pria ne utr o p hils + 3  ×  ne utr o p hils i n e pit heli u m + 5  ×  er osi o n or ulcerati o n (M osli 2 0 1 7 ). 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 3  of 1 0 7  
A P P E N DI X 5 : 
G UI D A N C E F O R T H E A S S E S S M E N T O F P O T E N TI A L 
P R O G R E S SI V E M U L TI F O C A L 
L E U K O E N C E P H A L O P A T H Y   
If a s u bject e x hi bits si g ns a n d s y m pt o ms s us pici o us f or pr o gressi ve multif ocal 
le u k oe nce p hal o pat h y ( P M L), t he I n vesti gat or m ust i nterr u pt st u d y treat me nt a n d perf or m a 
tar gete d ne ur ol o gic e xa mi nati o n t o assess f or si g ns of P M L, w hic h are di verse, pr o gress o ver 
da ys t o wee ks, a n d ma y i ncl u de pr o gressi ve wea k ness o n o ne si de of t he b o d y or cl u msi ness of 
li m bs or diffic ult y wit h wal ki n g or writi n g or fi ne m ot or s kills, dist ur ba nce of visi o n, c ha n ges i n 
t hi n ki n g, me m or y a n d orie ntati o n lea di n g t o c o nf usi o n a n d (e x pressi ve a p hasia), a n d/ or a g n osia 
(rece pti ve a p hasia). C o ns ultati on wit h a l ocal ne ur ol o gist ma y be warra nte d, as prese nte d i n t he 
P M L case e val uati o n al g orit h m i n Fi g ure  2 . 
T he Me dical M o nit or s h o ul d be i nf or me d of a n y s us pecte d cases of P M L a n d, if nee de d, will 
facilitate I n vesti gat or/l ocal ne ur ol o gist c o ns ultati o n wit h P M L me dical e x perts o n t he 
i n de pe n de nt a dj u dicati o n c o m mittee. 
Fi g ure  2 : 
Pr o gressi ve M ultif oc al Le u k oe nce p h al o p at h y C ase E v al u ati o n Al g orit h m  
 
N ote: I P d osi n g ma y res u me, a n d n o f urt her e val uati o n is nee de d if t he I n vesti gat or assess me nt re veals n o o bjecti ve  si g ns of 
P M L, t he l ocal ne ur ol o gist c o nfir ms t hat t he s u bject d oes n ot ha ve P M L, or t he I A C’s re vie w of t he e vi de nce c o ncl u des t hat 
P M L is r ule d o ut.  
C E, c o ntrast -e n ha nce d; C S F, cere bral s pi nal fl ui d; I A C, i n de pe n de nt a dj u dicati o n c o m mittee; I P, i n vesti ga ti o nal pr o d uct; J C V, 
J o h n C u n ni n g ha m Vir us; M RI, ma g netic res o na nce i ma gi n g; P C R, p ol y merase c hai n reacti o n; P M L, pr o gressi ve m ultif ocal 
le u k oe nce p hal o pat h y; r/ o, r ule o ut 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 4  of 1 0 7  
A P P E N DI X 6 : 
LI V E R S A F E T Y: S U G G E S T E D A C TI O N S A N D 
F O L L O W -U P A S S E S S M E N T S   
P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y  
H u ma ns e x p ose d t o a dr u g w h o s h o w n o si g n of li ver i nj ur y (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y b ut a da pt are 
ter me d “a da pt ors.” I n s o me s u bjects, tra nsa mi nase ele vati o ns are a har bi n ger of a m ore seri o us 
p ote ntial o utc o me. T hese s u bjects fail t o a da pt a n d t heref ore are “s usce pti ble” t o pr o gressi ve a n d 
seri o us li ver i nj ur y, c o m m o nl y referre d t o as a dr u g i n d uce d li ver i nj ur y ( DI LI). S u bjects w h o 
e x perie nce a tra nsa mi nase ele vati o n  a b o ve 3 × u p per li mit of n or mal (U L N ) s h o ul d be m o nit ore d 
m ore fre q ue ntl y t o deter mi ne if t he y are “a da pt ors” or are “s usce pti ble.”  
I n t he maj orit y of DI LI cases, ele vati o ns i n as partate a mi n otra nsferase (A S T ) a n d/ or ala ni ne 
a mi n otra nsferase (A L T ) prece de  t otal bili r u bi n ele vati o ns ( >  2 × U L N) b y se veral da ys or wee ks. 
T he i ncrease i n t otal bili r u bi n t y picall y occ urs w hile A S T/ A L T is/are still ele vate d 
a b o ve  3  ×  U L N (ie, A S T/ A L T a n d t otal bili r u bi n val ues will be ele vate d wit hi n t he sa me 
la b orat or y sa m ple). I n rare i nsta nces, b y t he ti me t otal bili r u bi n ele vati o ns are detecte d, 
A S T/ A L T val ues mi g ht ha ve decrease d. T his occ urre nce is still re gar de d as a p ote ntial DI LI. 
T heref ore, a b n or mal ele vati o ns i n eit her A S T  or  A L T i n a d diti o n t o t otal bili r u bi n t hat meet t he 
criteria o utli ne d bel o w are c o nsi dere d p ote ntial DI LI (assesse d per H y’s La w  criteria) cases  a n d 
s h o ul d al wa ys be c o nsi dere d i m p orta nt me dical e ve nts, e ve n bef ore all ot her p ossi ble ca uses of 
li ver i nj ur y ha ve bee n e xcl u de d. 
T he t hres h ol d of la b orat or y a b n or malities f or a p ote ntial DI LI case de pe n ds o n t he s u bject’s 
i n di vi d ual baseli ne val ues a n d u n derl yi n g c o n diti o ns. S u bjects  w h o prese nt wit h t he f oll o wi n g 
la b orat or y a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI ( H y’s La w ) cases t o 
defi niti vel y deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:  
•  S u bjects  wit h A S T/ A L T a n d t otal bili r u bi n baseli ne val ues wit hi n t he n or mal ra n ge 
w h o s u bse q ue ntl y prese nt wit h A S T  or  A L T val ues ≥ 3 × U L N a n d a t otal bili r u bi n 
val ue ≥ 2  ×  U L N wit h n o  e vi de nce of he m ol ysis a n d a n al kali ne p h os p hatase 
val ue  <  2  ×  U L N or n ot a vaila ble.  
•  F or s u bjects wit h baseli ne A S T or  A L T or  t otal bili r u bi n val ues a b o ve t he U L N, t he 
f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, 
de pe n d i n g o n w hic h val ues are a b o ve t he U L N at baseli ne: 
− Pree xisti n g A S T or A L T baseli ne val ues a b o ve t he n or mal ra n ge:  A S T or A L T 
val ues ≥ 2  ti mes t he baseli ne val ues a n d ≥ 3 ×  U L N; or ≥ 8  ×  U L N ( w hic he ver is 
s maller). 
− Pree xisti n g val ues of t otal bili r u bi n a b o ve t he n or mal ra n ge: t otal bili r u bi n le vel 
i ncrease d fr o m baseli ne val ue b y a n a m o u nt of ≥ 1 × U L N or if t he  val ue 
reac hes ≥ 3  ×  U L N ( w hic he ver is s maller).  
Rises i n A S T/ A L T a n d t otal bili r u bi n se parate d b y m ore t ha n a fe w wee ks s h o ul d be assesse d 
i n di vi d uall y base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as t o w het her it 
re prese nts a p ote ntial H y’s La w  case s h o ul d be re vie we d wit h t he S p o ns or .  
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 5  of 1 0 7  
T he s u bjects s h o ul d ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8  h o urs fr o m a ware ness of t he a b n or mal res ults. T his e val uati o n s h o ul d 
i ncl u de la b orat or y tests, detaile d hist or y, a n d p h ysical assess me nt.  
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A L T a n d t otal bili r u bi n f or s us pecte d H y’s 
La w  cases, a d diti o nal la b orat or y tests s h o ul d i ncl u de al b u mi n, creati ne ki nase  (C K ), direct a n d 
i n direct bilir u bi n, ga m ma -gl uta m yl tra nsferase  (G G T ), pr ot hr o m bi n ti me/ i nter nati o nal 
n or malize d rati o ( P T/I N R ), t otal bile aci ds, a n d al kali ne p h os p hatase. C o nsi derati o n s h o ul d als o 
be gi ve n t o dra wi n g a se parate t u be of cl otte d bl o o d a n d a n a ntic oa g ulate d t u be of bl o o d f or 
f urt her testi n g, as nee de d, f or f urt her c o nte m p ora ne o us a nal yses at t he ti me of t he rec og nize d 
i nitial a b n or malities t o deter mi ne eti ol o g y. A detaile d hist or y, i ncl u di n g rele va nt i nf or mati o n, 
s uc h as re vie w of et ha n ol, aceta mi n o p he n/ paraceta m ol (eit her b y itself or as a c of or m ulate d 
pr o d uct i n prescri pti o n or o ver -t he-c o u nter me dicati o ns), re creati o nal dr u g, or s u p ple me nt 
( her bal) use a n d c o ns u m pti o n, fa mil y hist or y, se x ual hist or y, tra vel hist or y, hist or y of c o ntact 
wit h a ja u n dice d pers o n, s ur ger y, bl o o d tra nsf usi o n, hist or y of li ver or aller gic disease, a n d 
p ote ntial occ u pati o nal e x p os ure t o c he micals, s h o ul d be c ollecte d. F urt her testi n g f or ac ute 
he patitis  A, B, C, D, a n d E i nfecti o n, li ver i ma gi n g (e g, biliar y tract), a n d c ollecti o n of ser u m 
sa m ples f or aceta mi n o p he n/ paraceta m ol dr u g a n d/ or pr otei n a d d uct le vels ma y be warra nte d.  
All cas es de m o nstrate d o n re peat testi n g as meeti n g t he la b orat or y criteria of A S T/ A L T a n d t otal 
bili r u bi n ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y’s La w ) cases if n o 
ot her reas o n f or t he li ver f u ncti o n test (L F T ) a b n or malities has yet bee n  f o u n d. S uc h p ote ntial 
DI LI ( H y’s La w ) cases are t o be re p orte d as seri o us a d verse e ve nts (S A Es ), irres pecti ve of 
a vaila bilit y of all t he res ults of t he i n vesti gati o ns perf or me d t o deter mi ne eti ol o g y of t he L F T 
a b n or malities.   
A p ote ntial DI LI ( H y’s La w ) case bec o mes a c o nfir me d case o nl y after all res ults of reas o na ble 
i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y. 
0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)

Cli nical St u d y Pr ot oc ol  
A P D 3 3 4 -2 1 0  
P hase  2, 5 2 -Wee k St u d y i n M o derate U C ( G L A DI A T O R U C)  
A me n d me nt 2 . 0 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 1 0 6  of 1 0 7  
A P P E N DI X 7 : 
I N V E S TI G A T O R SI G N A T U R E  
 
St u d y title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, 5 2 -Wee k St u d y t o Assess t he 
Efficac y a n d Safet y of Etrasi m o d i n S u bjects wit h M o deratel y Acti ve Ulcerati ve 
C olitis  
St u d y n u m ber:  A P D 3 3 4 -2 1 0  
 
 
I ha ve rea d t he pr ot oc ol descri be d a b o ve. I a gree t o c o m pl y wit h all a p plica ble re g ulati o ns a n d t o 
c o n d uct t he st u d y as descri be d i n t he pr ot oc ol.  
 
 
 
 
 
 
 
I n vesti g at or Si g n at ure 
 
D ate  
 
 
 
 
 
 
I n vesti g at or N a me a n d C re de nti als - Pri nte d  
 
 
 
 
 
 
 
 
I nstit uti o n N a me - Pri nte d  
 
 
 
 
 
 
 
 
 
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0 9 0 1 7 7 e 1 a 2 0 0 2 9 9 4\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 4 0 3: 1 1 ( G M T)
P P D
P P D
P P D
P P D