Conditions: Ulcerative Colitis
Keywords: Ulcerative colitis Etrasimod APD334 UC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 234
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether oral etrasimod is a safe and effective treatment for moderately active ulcerative colitis in adult participants.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: Etrasimod 2 mg tablet by mouth, once daily up to 52 weeks of treatment intervention 2: Etrasimod matching placebo tablet by mouth, once daily up to 52 weeks of treatment

Protocol document:
Prot_000.pdf: 
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 
Are na P har mace uticals, I nc.  
C o nfi de ntial  
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 . 
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 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  
 
 
 
 
 
 
 
 
 
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)


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

SAP_001.pdf: 
Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C5041011 (APD334-210)
A Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Assess the 
Efficacy and Safety of Etrasimod in Subjects with Moderately Active Ulcerative Colitis
Statistical Analysis Plan (SAP)
Version: 3.0
Date:
23 July 2024
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................8
2.1. Modifications to the Analysis Plan Described in the Protocol..................................8
2.2. Study Objectives, Endpoints, and Estimands..........................................................10
2.2.1. Study Objectives.........................................................................................10
2.2.2. Study Endpoints..........................................................................................10
2.2.3. Primary Estimand (Estimand 1)..................................................................11
2.2.4. Secondary Estimand (Estimand 2)..............................................................12
2.3. Study Design ...........................................................................................................13
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................15
3.1. Primary Endpoint ....................................................................................................15
3.1.1. Derivation of subscores for RB, SF and MMS...........................................15
3.1.2. Definition of Clinical Remission................................................................16
3.1.3. Derivation of Clinical Remission ...............................................................16
3.2. Secondary Endpoint(s) ............................................................................................16
3.2.1. Efficacy Endpoint(s)...................................................................................16
3.2.2. Safety Endpoint(s) ......................................................................................18
3.2.2.1. Adverse Event ...........................................................................18
3.2.2.2. Laboratory Data.........................................................................20
3.2.3. PK Endpoints..............................................................................................20
3.3. Other Safety Endpoint(s).........................................................................................20
3.3.1. 12-lead ECGs..............................................................................................20
3.3.2. Cardiac Holter Endpoints ...........................................................................21
3.3.2.1. Binary Endpoints.......................................................................21
3.3.2.2. Continuous Endpoints ...............................................................22
3.3.3. Vital signs...................................................................................................22
3.3.4. Pulmonary Function Tests..........................................................................22
3.3.5. Ophthalmoscopy and Optical Coherence Tomography (OCT)..................23
3.4. Other Endpoints.......................................................................................................23
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
3.4.1. Exploratory Efficacy Endpoints .................................................................23
3.4.2. HRQoL Endpoints ......................................................................................25
3.4.3. Efficacy-Related Biomarkers Endpoints ....................................................26
3.5. Baseline Variables...................................................................................................26
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................29
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................29
5.1. Hypotheses and Decision Rules ..............................................................................29
5.2. General Methods .....................................................................................................30
5.2.1. Analyses for Binary Efficacy Endpoints ....................................................30
5.2.2. Analyses for Continuous Non-Cardiac Endpoints......................................31
5.2.3. Analyses for Cardiac Endpoints .................................................................31
5.3. Methods to Manage Missing Data ..........................................................................31
5.3.1. Binary Efficacy Endpoints..........................................................................31
5.3.1.1. Primary Missing Data Handling Method ..................................32
5.3.1.2. Sensitivity Missing Data Handling Methods ............................32
5.3.2. Continuous Non-Cardiac Endpoints...........................................................35
5.3.3. Cardiac Endpoints.......................................................................................35
5.4. Supplementary Analyses for Primary and Key Secondary Efficacy Endpoints .....35
6. ANALYSES AND SUMMARIES ......................................................................................36
6.1. Summaries and Analyses for Efficacy, HRQoL  and Efficacy-Related 
Biomarker Endpoints.................................................................................................36
6.2. Summaries and Analyses for PK Endpoints ...........................................................38
6.3. Safety Summaries and Analyses .............................................................................38
6.3.1. Adverse Events...........................................................................................39
6.3.1.1. All TEAEs.................................................................................39
6.3.1.2. TEAEs Leading to Discontinuation of Study Treatment 
and TEAEs Leading to Interruption of Study Treatment ..................39
6.3.1.3. Serious and Non-Serious TEAEs ..............................................39
6.3.1.4. TEAEs of Special Interest.........................................................39
6.3.1.5. Overall Summary of Adverse Events........................................40
6.3.2. Other Safety Summaries and Analyses Endpoint(s)...................................41
6.3.2.1. Laboratory Data.........................................................................41
6.3.2.2. ECG Evaluations.......................................................................43
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
6.3.2.3. Cardiac Holter Monitoring........................................................44
6.3.2.4. Vital Sign...................................................................................45
6.3.2.5. Pulmonary function tests...........................................................46
6.3.2.6. Ophthalmoscopy and Optical coherence tomography ..............47
6.3.2.7. Tuberculosis Questionnaire.......................................................47
6.4. Subset Analyses.......................................................................................................47
6.5. Baseline and Other Summaries and Analyses.........................................................48
6.5.1. Baseline Summaries....................................................................................48
6.5.2. Study Conduct and Participant Disposition................................................48
6.5.3. Study Treatment Exposure .........................................................................49
6.5.3.1. Duration of Study Treatment Exposure ....................................49
6.5.3.2. Dose interruption and Overdose................................................49
6.5.3.3. Study Treatment Compliance....................................................49
6.5.4. Concomitant Medications and Nondrug Treatments..................................50
7. INTERIM ANALYSES.......................................................................................................50
8. REFERENCES ....................................................................................................................51
9. APPENDIX..........................................................................................................................53
9.1. Data Derivation Details...........................................................................................53
9.1.1. Demographics and Baseline Characteristics Related variables..................53
9.1.2. Reference Start Date and Study Day ..........................................................53
9.1.3. Retests, Unscheduled Visits, and Early Termination Data.........................53
9.1.4. Definition and Use of Visit Windows in Reporting ...................................53
9.1.5. Partial Date Convention..............................................................................55
9.1.6. Protocol Deviation Categories....................................................................58
9.1.7. Hourly Timepoint Determination in Cardiac Analysis...............................59
9.2. Endpoint Derivations...............................................................................................59
9.2.1. WPAI-UC Scoring Rules............................................................................59
9.2.2. IBDQ Scoring Rules...................................................................................60
9.2.3. SF-36 Scoring Rules...................................................................................60
9.3. Classification of Rescue Therapy............................................................................61
9.4. Programming Conventions for Outputs ..................................................................67
9.5. Abbreviations ..........................................................................................................69
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
LIST OF TABLES
Table 1. Summary of Changes...................................................................................................6
Table 2. Summary of Modification............................................................................................8
Table 3. Disease Specific Inclusion Criteria............................................................................13
Table 4. Randomization Stratification.....................................................................................13
Table 5. Summary of Analysis Sets.........................................................................................29
Table 6. Planned Analyses for Primary and Key Secondary Efficacy Endpoints ...................36
Table 7. Planned Analyses for Other Secondary Efficacy, Exploratory Efficacy, 
HRQoL and Efficacy-Related Biomarker Endpoints ...............................37
Table 8. Markedly Abnormal Criteria for Vital Signs.............................................................45
Table 9. Analysis Visit Windows for Efficacy and Safety Analyses ......................................54
Table 10. Algorithm for Treatment Emergence of Adverse Events ........................................55
Table 11. Algorithm for Prior and Concomitant medications .................................................56
Table 12. Algorithm for Starting Date of Hospitalization and Start/Stop Dates of 
Concomitant Medication ..........................................................................57
Table 13. Treatment Group Display ........................................................................................68
Table 14. Visit and Study Period Display................................................................................69
Table 15. List of Abbreviations ...............................................................................................69
LIST OF FIGURES
Figure 1. Study Design ............................................................................................................14
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 6
1. VERSION HISTORY
Table 1. Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1.0/
17 April 2024
2.0
N/A
N/A
2.0/
25 April 2024
2.0
Align the 
definition of 
clinical 
remission for the 
mildly to 
moderately 
active UC
population with 
the FDA Draft 
Guidance
Revise the 
criteria of 
potentially 
important PFT 
measurements.
Make the 
definition of 
analysis visit 
windows clearer  
Section 3.1.2 Second bullet was changed as:

Definition per FDA Draft Guidance: 
clinical remission is defined as SF 
subscore = 0 or = 1 and no greater than 
baseline, RB subscore = 0, and ES ≤ 1 
(excluding friability), based on the 2022 
FDA Draft Guidance; Ulcerative Colitis:  
Developing Drugs for Treatment
Section 6.3.2.5 Potentially important PFT 
measurements criteria were changed from “>30%” 
to “≥30%” as:

Percent decrease from Baseline ≥30% in 
FEV1, ie, percent change from Baseline ≤-
30%

Percent decrease from Baseline ≥30% in 
FVC, ie, percent change from Baseline ≤-
30%
Appendix 9.1.4 Table 9 and footnotes were revised.
3.0/
Xx July 2024
2.0
Per FDA 
feedback of 
03July2024 for 
the SAP
Sections 2.2.3, 2.2.4, 5.3.1.1, discontinuation of the 
study treatment for any reason will be treated as 
intercurrent event.
Section 3.1 clarified that per FDA Draft Guidance, 
the SF and RB subscores will be calculated by 
averaging the most recent 3 consecutive days daily 
subscores (if not available, by averaging the most 
recent 4 nonconsecutive days daily subscores) 
within the 7 days prior to the day of bowel 
preparation, excluding the day of bowel preparation
(for visit without endoscopy, prior to the date of 
visit).
Sections 3.1 and 3.2 clarified that

RB/SF subscore derivation algorithm per 
protocol is the primary algorithm.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 7
Table 1. Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
MedDRA 
version and 
WHO Drug 
dictionary update
Week 20 is not a 
scheduled visit
Ukraine war
Additional 
subgroup 
analyses
Week 20 is not a 
scheduled visit

Clinical remission definition per FDA 
Draft Guidance will be used for the 
primary analysis.

Clinical remission based on clinical 
remission definition per FDA Draft 
Guidance using derivation of subscores 
for RB and SF per protocol will be used 
for the primary analysis.
Section 5.1, the sequential testing order was 
changed. Complete symptomatic remission at Week 
52 and complete symptomatic remission at Week 12 
were moved to the end of the sequence. The order 
of key secondary endpoints in Section 2.2.2, Section 
3.2.1, and Table 6 was changed as well to consistent 
with Section 5.1.
Section 5.3.1.2, random seeds were added for 
multiple imputations.
Section 6.3.1.5, severe TEAE was added to the 
comparative analysis list. Difference for EAIR 
between etrasimod and placebo with 95% CI was 
added as well.
Section 6.4 added subgroup analysis for Sex (Male, 
Female), Race (White, Black or African American, 
Asian, Other), Ethnicity  (Hispanic or Latino vs Not 
Hispanic or Latino).
Section 3.2.2.1, MedDRA version was updated as 
v27.0. Section 6.5.4, WHO Drug dictionary was 
updated as GlobalB3 March 2024.
Section 3.4.1, week 20 was removed from the list of 
visits for symptomatic remission and symptomatic 
response.
Sections 5.3.1 and 5.3.1.2.4, Ukraine war impact 
was added to hybrid imputation.
Section 6.4 added subgroup analysis for prior Oral 
5-ASA Failure Only (yes, no), Naïve to biologic or 
JAK inhibitor therapy who failed corticosteroid
and/or thiopurines (yes, no).
Appendix 9.1.4 Table 9, Week 20 was removed, 
windows for week 16 and week 24 were adjusted.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
Table 1. Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Partial date 
convention was 
mixed for TEAE 
and prior and 
concomitant 
medication
Appendix 9.1.5 Table 10 was separated to 2 tables: 
Table 10 is for TEAE, Table 11 is for prior and 
concomitant medication.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C5041011 (APD334-210). This SAP is 
based on the Clinical Study Protocol Amendment 2.0, dated 4 August 2022. 
The following analyses will be specified in separate analysis plans.

A population PK analysis using plasma concentrations over time will be described in 
a separate PK analysis plan.
2.1. Modifications to the Analysis Plan Described in the Protocol
Table 2. Summary of Modification
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Modification 
1.0/
17 April
2024
Amendment 2.0, 
dated 4 August 
2022
(1) The new definition of
clinical remission is per  
FDA Draft Guidance, 
Ulcerative Colitis: 
Developing drugs for 
treatment (Section 8
References).
(2) FDA’s recommendation 
for C5041011 (APD334-
210) Protocol Amendment 
2.0 (“FDA Letter IND 
125154 Advice-Information 
Request IND”, received on 
12/02/2022).
(1) Add new definition of clinical 
remission per FDA Draft Guidance, 
Ulcerative Colitis: Developing drugs for 
treatment (Section 8 References).
(2) Add the alternative derivation method 
of rectal bleeding (RB) and stool 
frequency (SF) subscores per FDA Draft 
Guidance, Ulcerative Colitis: Developing 
drugs for treatment.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)
CCI


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9
Table 2. Summary of Modification
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Modification 
(3) The change from 
baseline in RB/SF subscore 
is included in USPI 
Velsipity-etrasimod-tablets.
(4) To evaluate Cardiac 
Holter monitoring related 
assessments based on Holter 
recording, such as the 
treatment-emergent AV 
conduction changes, 
treatment-emergent 
bradycardia, recovery of 
nadir Mean hourly heart rate 
and short-term cardiac 
treatment-emergent adverse 
events.
(5) To be consistent with the 
language of definition for 
mucosal healing used in Full 
Prescribing Information of 
VELSIPITY™ (etrasimod), 
after VELSIPITY™ 
(etrasimod) was approved 
by FDA on October 12, 
2023.
(6) 2022 FDA Draft 
Guidance; Ulcerative 
Colitis:  Developing Drugs 
for Treatment.
(7) Efficacy analyses will be 
based on the estimand
framework.
(8) Per FDA comments.
(9) Add additional 
exploratory endpoints.
(3) Add analyses for modified Mayo score
(MMS) and change from Baseline by 
visit, RB, SF, and composite RB/SF 
subscores and change from Baseline by 
visit.
(4) Add Cardiac Holter endpoints (Section 
3.3.2) and corresponding planned analyses 
for the Cardiac Holter endpoints (
“Cardiac Holter Monitoring” part of 
Section 6.3.2).
(5) Add the definition for mucosal 
healing, and rename it as Histologic-
Endoscopic Mucosal Improvement (listed 
as key secondary efficacy endpoint at 
Week 52 and other secondary efficacy 
endpoint at Week 12) in Section 2.2.2, per 
Full Prescribing Information of  
VELSIPITY™ (etrasimod) (Section 8
References).
(6) The primary efficacy analysis 
population is defined to be consistent with 
the FDA Draft Guidance for mildly to 
moderately active UC. 
(7) Per protocol analysis set is irrelevant 
and is removed.
(8) Endoscopic improvement at Week 12
and complete symptomatic remission at 
Week 12 and Week 52 are considered as
key secondary endpoints and are included 
in type I error controlled family.
Symptomatic remission at Week 52 is 
now considered as a secondary endpoint.
(9) Clinically meaningful improvement in 
bowel urgency at Week 12 and Week 52;
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 10
Table 2. Summary of Modification
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Modification 
(10) Add two secondary 
endpoints.
bowel urgency remission at Week 12 and 
Week 52; complete bowel urgency 
remission at Week 12 and Week 52 are 
added as exploratory endpoints.
(10) 12-week corticosteroid-free clinical 
remission at Week 52 among participants 
receiving corticosteroids at baseline; 4-
week corticosteroid-free clinical remission 
at Week 52.
2.2. Study Objectives, Endpoints, and Estimands
2.2.1. Study Objectives

Primary objective: to assess the efficacy of etrasimod on clinical remission in 
participants with mildly to moderately active UC after 52 weeks of treatment. 

Secondary objective: to assess the efficacy of etrasimod on endoscopic improvement, 
histologic response, clinical response, and symptomatic remission, at timepoints up to 
52 weeks of treatment.

Safety objective: to assess the long-term safety of etrasimod after daily doses of 2 mg 
for up to 52 weeks.

Other objectives: to evaluate etrasimod pharmacokinetics (PK) and the effect of 
etrasimod on health-related participant-reported outcomes and biomarkers.
2.2.2. Study Endpoints
This section lists the study endpoints. Their definitions are given in section 3.
The primary efficacy endpoint is: 

Clinical remission at Week 52. 
The key secondary efficacy endpoints are:

Endoscopic improvement at Week 52. 

12-week Corticosteroid-free clinical remission at Week 52.

Clinical remission at Week 12

Endoscopic improvement at Week 12.

Sustained clinical remission (clinical remission at both Weeks 12 and 52).
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 11

Histologic-Endoscopic Mucosal Improvement at Week 52.

Complete symptomatic remission at Week 52.

Complete symptomatic remission at Week 12.  
The other secondary efficacy endpoints and exploratory efficacy endpoints to be assessed in 
this study are listed in Section 3.2.1 and Section 3.4.1, respectively.
The safety endpoints are:

Incidence and severity of adverse events 

Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, coagulation, and 
urinalysis) 

Incidence of clinically significant vital sign abnormalities and changes from baseline 
The Cardiac Holter endpoints to be assessed in this study are described in Section 3.3.2. The 
Pharmacokinetic (PK) endpoints to be assessed in this study are described in Section 3.2.3.
The Health-related Quality of Life (HRQoL) endpoints to be assessed in this study are 
described in Section 3.4.2. The efficacy-related biomarker endpoints to be assessed in this 
study are described in Section 3.4.3.
2.2.3. Primary Estimand (Estimand 1)
The primary estimand of this study is a composite estimand, which estimates the effect of 
randomized treatment accounting for treatment adherence and response. 

Treatment: Etrasimod 2 mg vs Placebo

Population: Participants with mildly to moderately active UC as defined in 2022   
FDA Draft Guidance; Ulcerative Colitis:  Developing Drugs for Treatment (Section 8
References)

Variable: primary efficacy endpoint of clinical remission at week 52 and all binary 
efficacy endpoints as described in Sections 3.1, 3.2.1 and 3.4.1

Intercurrent events: the following intercurrent events are defined: 
1) Discontinue the study treatment during the double blind treatment period for any 
reasons
2) Initiate a rescue medication for UC (Section 9.3)
3) Have an increase in dose over baseline levels in their existing UC medication
following the rules in Section 9.3
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 12
4) Have a rescue non-drug treatment (eg, colectomy, ileostomy, or sigmoidectomy) 
during the study (Section 9.3)
Participants having any of the intercurrent events as defined in 1) - 4) above will be 
considered as nonresponders, that is, have a known outcome of nonresponse at 
applicable timepoints. Missing measurements due to other reasons will be treated as 
missing. The method of dealing with missing data is presented in Section 5.3

Population-level summary: Proportion of participants who are responders in each 
treatment group and differences in proportions of responders between Etrasimod 2
mg group and placebo group. 
2.2.4. Secondary Estimand (Estimand 2)
The secondary estimand of this study is a hypothetical estimand, which estimates the effect 
of randomized treatment as if all participants maintain their randomized treatment.  

Treatment: Etrasimod 2 mg vs Placebo

Population: Participants with mildly to moderately active Ulcerative Colitis (UC) as
described in 2022 FDA Draft Guidance; Ulcerative Colitis:  Developing Drugs for 
Treatment.

Variable: change from baseline in MMS and other continuous variables for 
exploratory efficacy endpoints, HRQoL endpoints and efficacy-related biomarker 
endpoints as described in Sections 3.4.1, 3.4.2 and 3.4.3, respectively.

Intercurrent events: The following intercurrent events are defined: 
1) Discontinue the study treatment during the double blind treatment period for any 
reasons
2)
Initiate a rescue medication for UC (Section 9.3)
3) Have an increase in dose over baseline levels in their existing UC medication
following the rules in Section 9.3.
4) Have a rescue non-drug treatment (eg, colectomy, ileostomy, or sigmoidectomy) 
during the study (Section 9.3)
For participants having any of the intercurrent events as defined in 1) - 4) above, their 
data collected up to the intercurrent events will be used for analysis.  

Population-level summary: Least-squares mean (LSM) (Section 5.2.2) in each 
treatment group and differences in LSMs between Etrasimod 2 mg group and placebo 
group (Section 5.2.2).
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 13
2.3. Study Design
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of etrasimod 2 mg in participants with mildly to moderately active UC. 
The study consists of a 28-Day Screening Period, a 52 week treat-through design consisting 
of a 12-Week Treatment Period and a 40-Week Treatment Period, and a 4-Week Follow-Up 
Period (with 2 visits) (Figure 1. Study Design). 
The target participant population will include: 
1. Participants who have had an inadequate response to, loss of response to, or 
intolerance to conventional therapy and are naïve to biologic or Janus kinase (JAK) 
inhibitor therapy.
2. Participants who have had an inadequate response to, loss of response to, or 
intolerance to a biologic or JAK inhibitor (participants in this category may have 
received prior conventional therapy).
Participant eligibility will be determined during a Screening Period of 4 weeks (28 days). 
Entry criteria will be based on confirmation of mildly to moderately active UC. In order to 
align with the definition of mildly to moderately active UC based on the 2022 FDA Draft
Guidance; Ulcerative Colitis: Developing Drugs for Treatment, the disease-specific inclusion 
criteria in Protocol C5041011 (APD334-210) amendment 2.0 is updated as follows (Table 3): 
Table 3. Disease Specific Inclusion Criteria
Protocol Version 
Disease Specific Inclusion Criteria 
Prior to amendment 2.0
Inclusion criteria 5: MMS of 4 to 6 and an ES ≥ 1.
Amendment 2.0
Inclusion criteria 5:  MMS of 4 to 6 and an ES ≥ 2 and RB score ≥ 1. 
Eligible participants will be randomized (2:1 ratio) to receive either etrasimod (2 mg, once 
daily) or matching placebo (once daily) in a double-blind fashion for up to 52 weeks (12-
Week Treatment Period + 40-Week Treatment Period). Due to the disease specific inclusion 
criteria update as described in Table 3 above, randomization stratification in Protocol 
C5041011 (APD334-210) amendment 2.0 is updated as follows (Table 4).
Table 4. Randomization Stratification
Protocol Version 
Randomization Stratification
Prior to amendment 2.0
(a) naïve to biologic or JAK inhibitor therapy at study entry (yes or no) (b) 
baseline corticosteroid use (yes or no) and (c) baseline ES>1 (yes or no)
Amendment 2.0
(a) naïve to biologic or JAK inhibitor therapy at study entry (yes or no) and 
(b) baseline corticosteroid use (yes or no)
End of 12-Week Double-Blind Treatment Period 
At the end of the 12-Week Treatment Period, participants will undergo the Week 12 efficacy 
and safety assessments and procedures. Participants whose UC condition in the opinion of 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 14
the Investigator is stable or improving compared with baseline (Week 0/Day 1) will continue 
with their double-blind treatment and move into the 40-Week Treatment Period. 
End of 40-Week Double-Blind Treatment Period (Week 52) 
At the end of the 40-Week Treatment Period (ie, Week 52) and following completion of all 
study procedures, participants will have the option to enter into the Open-Label Extension 
(OLE) study (Study APD334-303) provided they meet all eligibility criteria. 
Participants who do not participate in the OLE study will have 2-Week and 4-Week Follow-
Up visits after their last treatment administration. 
Open-Label Extension Study [Study C5041012 (APD334-303)] 
Participants whose UC condition in the opinion of the Investigator has not improved or has 
worsened, compared with baseline (Week 0/Day 1), may be eligible to enroll in the OLE 
study. Participants must complete Week 12 to be considered for the OLE study. 
Disease worsening will continue to be monitored by Investigators through the 40-Week 
Treatment Period (ie, from Weeks 13 to 52). Participants who either experience disease 
worsening in the 40-Week Treatment Period or complete all study procedures at Week 52 
will have the option to enroll into the OLE study if they meet all eligibility criteria. 
Figure 1. Study Design
Based on a 2-group Fisher’s exact test, a two-sided significance level of 0.05, and a 2:1 
randomization ratio, approximately 183 subjects (122 etrasimod, 61 placebo) are required to 
achieve at least 80% power to detect a difference of 20% in the primary endpoint of clinical 
remission (based on MMS) at Week 52 between the etrasimod treatment group (34%) and the 
placebo treatment group (14%). Alternatively, based on the same assumptions, using normal 
approximation to the binomial distribution, a two-sided test would achieve at least 90% 
power. The assumptions are based on the final analysis results in the Phase 3 Studies 
APD334-301 and APD334-302. Sample size is calculated using the EAST® software. 
Based on the updated inclusion criteria in Protocol C5041011 (APD334-210) amendment 
2.0, approximately 45 participants among the already randomized participants (assuming 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 15
approximately 2:1 ratio of etrasimod:placebo) did not meet the amended Inclusion Criterion 
5, which includes ES score ≥ 2 and RB score ≥ 1. As a result, these participants will be 
excluded from the Primary Analysis Set (Section 4). Therefore, approximately 225 total 
participants (150 etrasimod, 75 placebo) were required to be enrolled into study C5041011 
(APD334-210) under Protocol amendment 2.0.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
3.1.1. Derivation of subscores for RB, SF and MMS

Derivation 1 for RB and SF subscores (per protocol): 

For RB and SF used to qualify for randomization. SF and RB subscores will be
derived from the participant eDiary entries using the scores from the 3 most 
recent consecutive days within the 7 days prior to the day of bowel preparation, 
(excluding the day of bowel preparation), averaged and rounded to the nearest 
integer. Participants who do not have 3-consecutive days of eDiary data within 
that 7-day period and who do not have a minimum of 7 days of eDiary data prior 
to bowel preparation are not eligible for randomization. 

For RB and SF in treatment period. SF and RF subscores will be derived using the 
scores from the 3 most recent consecutive days within the 7 days prior to the day 
of bowel preparation (excluding the day of bowel preparation), averaged and 
rounded to the nearest integer. If 3 consecutive days are not available, then the 
average of the 2 most recent consecutive days within the 7 days will be used. On 
visits without endoscopy, the SF and RB are derived using the scores from the 3 
most recent consecutive days within the 7 days prior to the date of visit, averaged 
and rounded to the nearest integer. If 3 consecutive days are not available, then 
the average of the 2 most recent consecutive days within the 7 days will be used.
The above RB and SF subscore derivation algorithm per protocol will be the primary 
algorithm used for the primary analysis.

Derivation 2 for RB and SF subscores (per 2022 FDA Draft Guidance; Ulcerative 
Colitis: Developing Drugs for Treatment)

The SF and RB subscores will be calculated from the participant eDiary entries
using the daily scores from the most recent 3 consecutive days or if not available, 
from the most recent 4 non-consecutive days within the 7 days prior to the day of 
bowel preparation, excluding the day of bowel preparation (for visit without 
endoscopy, prior to the date of visit), averaged and then rounded to the nearest 
integer. A minimum of 3 consecutive days of completed diary entries or 4 
nonconsecutive days within 7-day period are necessary. Otherwise, the subscore 
for the visit will be missing.
The MMS includes the ES, RB, and SF components of the Mayo Clinic Score (MCS; and 
related composite scores). The total score range of the MMS is from 0 to 9, with each 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 16
component ranging from 0 to 3 (0 = normal, 1 = mild, 2 = moderate, 3 = severe). The MMS 
will be derived based on each of derivations for RB and SF above, respectively as follows:

MMS Derivation 1 (per protocol), based on derivation 1 for RB and SF 

MMS Derivation 2 (per 2022 FDA Draft Guidance; Ulcerative Colitis:  Developing 
Drugs for Treatment), based on derivation 2 for RB and SF 
3.1.2. Definition of Clinical Remission

Definition per protocol: clinical remission is defined as SF subscore = 0 (or = 1 with a 
≥ 1-point decrease from Baseline), RB subscore = 0, and endoscopic score (ES) ≤ 1 
(excluding friability)

Definition per FDA Draft Guidance: clinical remission is defined as SF subscore = 0 
or = 1 and no greater than baseline, RB subscore = 0, and ES ≤ 1 (excluding 
friability), based on the 2022 FDA Draft Guidance; Ulcerative Colitis:  Developing 
Drugs for Treatment. 
The definition of clinical remission per FDA Draft Guidance will be used for the primary 
analysis.
3.1.3. Derivation of Clinical Remission 
The primary efficacy endpoint is clinical remission at Week 52. Based on above different 
derivation algorithms for RB/SF subscores, and different definitions for clinical remission,
the clinical remission will be derived based on the following 3 approaches, respectively: 

Clinical remission 1, based on clinical remission definition per protocol and RB and 
SF derivation per protocol (Derivation 1, Section 3.1.1)

Clinical remission 2, based on clinical remission definition per FDA Draft Guidance
and RB and SF derivation per protocol (Derivation 1, Section 3.1.1)

Clinical remission 3, based on clinical remission definition per FDA Draft Guidance  
and RB and SF derivation per FDA Draft Guidance (Derivation 2, Section 3.1.1)
Clinical remission 2 will be used for the primary analysis. 
3.2. Secondary Endpoint(s)
3.2.1. Efficacy Endpoint(s)
The study includes the following key secondary efficacy endpoints:

Endoscopic improvement at Week 52. Endoscopic improvement is defined as ES ≤ 1 
(excluding friability).

12-week corticosteroid-free clinical remission at Week 52: clinical remission at Week 
52 and corticosteroid-free for ≥12 weeks immediately prior to Week 52. The 3 
clinical remissions defined in Section 3.1.3 will be applied, respectively.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 17

Clinical remission at Week 12. The 3 clinical remissions described in Section 3.1.3
above will be applied.

Endoscopic improvement at Week 12.

Sustained clinical remission (clinical remission at both Weeks 12 and 52). The 3 
clinical remission definitions defined in Section 3.1.2 will be applied, respectively.

Histologic-Endoscopic Mucosal Improvement at Week 52. Histologic-Endoscopic 
Mucosal Improvement is defined as ES ≤ 1 (excluding friability) with Geboes Index 
score < 2.0.

Complete symptomatic remission at Week 52. Complete symptomatic remission is 
defined as RB subscore = 0 and SF subscore = 0. Its derivation will be based on the 
following 2 approaches, respectively.

Complete symptomatic remission 1, based on RB and SF derivation 
per protocol (Derivation 1, Section 3.1.1)

Complete symptomatic remission 2, based on RB and SF derivation 
per FDA Draft Guidance (Derivation 2, Section 3.1.1)

Complete symptomatic remission at Week 12. Two complete symptomatic remission
definitions described above will be applied, respectively.
The study also includes the following other secondary efficacy endpoints.

12-week corticosteroid-free clinical remission at Week 52 among participants 
receiving corticosteroids at baseline: clinical remission at Week 52 and 
corticosteroid-free for ≥12 weeks immediately prior to Week 52. The 3 clinical 
remissions defined in Section 3.1.3 will be applied, respectively.

4-week corticosteroid-free clinical remission at Week 52: clinical remission at Week 
52 and corticosteroid-free for ≥4 weeks immediately prior to Week 52. The 3 clinical 
remissions defined in Section 3.1.3 will be applied, respectively.

4-week corticosteroid-free clinical remission at Week 52 among participants 
receiving corticosteroids at baseline: clinical remission at Week 52 and 
corticosteroid-free for ≥4 weeks immediately prior to Week 52. The 3 clinical 
remissions defined in Section 3.1.3 will be applied, respectively.

Clinical response at Week 12. Clinical response is defined as a ≥2-point and ≥ 30% 
decrease from baseline in MMS, and a ≥1-point decrease from baseline in RB 
subscore or an absolute RB subscore ≤1. Its derivation will be based on each of 2
derivations of RB and MMS in Section 3.1.1, respectively as follows:

Clinical response 1, based on RB and MMS derivation per protocol (Derivation 1, 
Section 3.1.1)
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 18

Clinical response 2, based on RB and MMS derivation per FDA Draft Guidance 
(Derivation 2, Section 3.1.1)

Clinical response at Week 52. Two clinical responses described above will be 
applied.

Histologic-Endoscopic Mucosal Improvement at Week 12.

Symptomatic remission at Week 52. Symptomatic remission is defined as SF 
subscore = 0 (or = 1 with a ≥ 1-point decrease from baseline) and RB subscore = 0.
Its derivation will be based on the following 2 approaches, respectively. 

Symptomatic remission 1, based on RB and SF per protocol (Derivation 1, 
Section 3.1.1)

Symptomatic remission 2, based on RB and SF derivation per FDA Draft 
Guidance (Derivation 2, Section 3.1.1)

Symptomatic remission at Week 12. Two symptomatic remissions described above 
for symptomatic remission at Week 52 will be applied, respectively.

Reduction from baseline in both ES and RB or in both ES and SF at Week 12.
Derivations 1 and 2 for RB and SF described in Section 3.1.1 will be applied, 
respectively.

Histologic response based on the Geboes Grading System at Week 12. Histologic 
response based on the Geboes Grading System is defined as Geboes Index score ≤
3.1.

Histologic response based on Robarts Histopathology Index (RHI) at Week 12. 
Histologic response based on RHI is defined as decrease in RHI of  ≥7 points from 
baseline. 
3.2.2. Safety Endpoint(s)
3.2.2.1. Adverse Event
AEs will be coded using MedDRA (v27.0). The version used to code AEs will be displayed 
in the analyses. Treatment-emergent adverse events (TEAEs) are defined as AEs that started 
or worsened in severity on or after the first dose of study treatment.
Refer to Section 9.1.5 for handling of partial dates for AEs for the purpose of assigning
treatment-emergent flags. In the case where it is not possible to define an AE as treatment-
emergent or not, the AE will be classified as treatment-emergent.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 19
Severity of TEAEs
Severity is classified as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-
threatening, Grade 5: Death related to AE, using the Common Terminology Criteria for
Adverse Events, v5.0 (CTCAE v5.0).
Relationship of TEAEs to Study Treatment
Relationship is classified as “not related”, “unlikely related”, “probably related”, or “related” 
by the Investigator.
TEAEs Leading to Discontinuation of Study Treatment
TEAEs leading to discontinuation of study treatment will be identified by action taken being
recorded as “Drug withdrawal” on the Adverse Events electronic case report form (eCRF).
Serious and Non-Serious TEAEs
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events
eCRF.
TEAEs Leading to Death
TEAEs leading to Death are those events which are recorded with an outcome as “Fatal” on 
the Adverse Events eCRF.  
TEAEs of Special Interest
Categories of Targeted Medical Events (TMEs) and a list of preferred terms associated with
these TME categories were developed based on the mechanism of action of etrasimod, prior
experience with other agents acting via a similar mechanism, and disease-specific clinical
judgment. The proposed candidate terms will be reviewed along with other supportive data 
(eg, vital signs, lab) to identify which events reflect AESI.
Categories and subcategories of TEAEs of special interest are the following:

Cardiovascular Events

Bradycardia

AV conduction delay

Hypertension

Macular Edema

Pulmonary Disorders

Airflow obstruction (forced expiratory volume in 1 second [FEV1], forced vital
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 20

capacity [FVC])

Decrease gas exchange (diffusing capacity of the lungs for carbon monoxide

[DLCO]

Infections

Severe infections

Opportunistic infections (Narrow)

Herpes simplex and herpes zoster

Liver Injury

Liver transaminases elevation

Bilirubin elevation

Posterior Reversible Encephalopathy Syndrome (PRES)

Malignancies
3.2.2.2. Laboratory Data
Detailed descriptions of the laboratory data and other tests that are collected per protocol can 
be found in Table 5 (“Clinical Laboratory Tests”) of Protocol C5041011 (APD334-210) 
amendment 2.0.
3.2.3. PK Endpoints
Plasma concentrations of etrasimod will be assessed from samples collected pre-dose and 4 
hours post-dose (after 12-lead ECG) on Week 0/Day 1, and pre-dose (trough) at Weeks 2, 4, 
8, 12, 16, 24, 32, 48, 52, and ET (only required if ET visit ≤ 30 hours since last treatment 
administration), and at the 2-Week and 4-Week Follow-Up visits (for participants not 
enrolled into any extension study). A PK sample should also be drawn, if possible, at the 
time of any SAE or adverse event leading to study treatment discontinuation. 
Plasma samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, or to assess other actions of etrasimod with plasma 
constituents. 
3.3. Other Safety Endpoint(s)
3.3.1. 12-lead ECGs
ECGs are recorded on a 12-lead ECG machine and read locally and centrally. The following 
ECG parameters are reported for this study:

HR (bpm)
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 21

PR interval (ms)

RR interval (ms)

QRS interval (ms)

QT interval (ms)

QTcF interval (ms)

AV conduction abnormalities

First-degree AV Block 

First-degree AV Block with PR>230ms 

Second-degree AV Block Type 1 

Second-degree AV Block Type 2 

Third-degree AV Block or Higher
3.3.2. Cardiac Holter Endpoints
3.3.2.1. Binary Endpoints

Incidence of mean hourly heart rate based on Holter recording (hHR) recovery. 
o
Note: hHR was generated by the cardiac central laboratory for each 60-
minute interval based on date/time of first dose and Holter recording 
date/time, with hour 1 starting at the time of dosing. See Section 9.1.7 for 
additional detail on how partial hourly interval is handled by the cardiac 
central laboratory and how hourly timepoint will be programmatically 
derived. For the analysis purpose, if hHR was associated with a time 
interval of <10 minutes, then its value will be set to missing for the 
summary. Per cardiac central laboratory, if the Holter recording was 
started < 60 seconds prior to dosing, then no pre-dose record is derived for 
the participant. In such case, all the Holter recording will contribute to 
post-dose calculation only. 

Incidence of low heart rate over the entire Holter monitoring period and at each 
post-dose hourly timepoint defined by:

hHR <40

hHR <50

hHR <50 bpm plus > 10 bpm decrease from baseline 

Incidence of first nadir hHR reached at each post-dose hourly timepoint
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 22

Incidence of additional abnormal findings flagged by cardiac central laboratory 

Mobitz I 2nd Degree AV Block 

Mobitz II 2nd Degree AV Block 

2:1 AV Block 

High Grade AV Block 

Complete Heart Block 

Varying Conduction Ratio AV Block

Evidence of new onset of transient bundle branch block (BBB) or
Intraventricular conduction delay

Other specified (any abnormality detected other than the list above must be 
specified under “Other” and alert notified at discretion of reading 
Cardiologist)
3.3.2.2. Continuous Endpoints

hHR and change from baseline by post-dose hourly timepoint

Time to first nadir hHR (based on Holter hourly data)
3.3.3. Vital signs
The following vital signs measurements are reported for this study:

Systolic blood pressure (SBP) (mm Hg)

Diastolic blood pressure (DBP) (mm Hg)

Heart rate (bpm)

Respiratory rate (resp/min)

Temperature (°C), where Temperature (°C) = (5/9) (Temperature (°F) – 32)
3.3.4. Pulmonary Function Tests
The following pulmonary function tests (PFT) measurements (actual and % predicted) will 
be reported for this study:

FEV1

FVC

Total Lung Capacity (TLC)
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 23

FEV1/FVC ratio

Forced Expiratory Flow (FEF) 25-75

DLCO (if available)
3.3.5. Ophthalmoscopy and Optical Coherence Tomography (OCT)
Ophthalmoscopy and OCT assessment will be performed according to the Schedule of 
Assessments (Table 6 in Protocol C5041011 (APD334-210) amendment 2.0 Appendix 1). 
The endpoint is the categorical result in ophthalmoscopy with OCT parameters by visit (the 
categories are listed on the eCRF).  
3.4. Other Endpoints
3.4.1. Exploratory Efficacy Endpoints

Symptomatic remission at each study visit (Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, and 
52). Two symptomatic remission derivations described in Section 3.2.1 will be 
applied, respectively.

Symptomatic response at each study visit (Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, and 
52). Symptomatic response is defined as ≥ 30% decrease from baseline in composite 
RB and SF subscores. Its derivation will be based on the following 2 approaches, 
respectively.

Symptomatic response 1, based on RB and SF derivation per protocol 
(Derivation 1, Section 3.1.1)

Symptomatic response 2, based on RB and SF derivation per FDA 
Draft Guidance (Derivation 2, Section 3.1.1)

Clinical remission at Week 52 among participants achieving clinical response at 
Week 12. Three derivations for clinical remissions described in Section 3.1.3 will be
applied, respectively.

Reduction from baseline in both ES and RB or in both ES and SF at Week 52.
Derivation 1 and 2 for RB and FS in Section 3.1.1 will be applied, respectively.

Clinical response based on total Mayo score (TMS) at Week 52. The TMS includes 
all four components (ES, RB, SF and PGA) of the MCS. The total score range of the 
TMS is from 0 to 12 with each component ranging from 0 to 3 (0 = normal, 1 = mild, 
2 = moderate, 3 = severe) and higher scores indicating more severe disease. Clinical 
response based on TMS is defined as a ≥ 3-point and ≥ 30% decrease from baseline in 
TMS, and a ≥ 1-point decrease from baseline in RB subscore or an absolute RB 
subscore ≤ 1. The TMS will be derived based on each of derivations for RB and SF 
(as defined in Section 3.1.1), respectively.

TMS clinical response 1, based on RB and SF derivation per protocol 
(Derivation 1, Section 3.1.1)

TMS clinical response 2, based on RB and SF derivation per FDA 
Draft Guidance (Derivation 2, Section 3.1.1)
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 24

Histologic response based on Geboes Grading System at Week 52. 

Histologic remission based on the Geboes Grading System at Week 12. Histologic 
remission based on the Geboes Grading System is define as Geboes Score (GS) ≤ 2.0

Histologic remission based on the Geboes Grading System at Week 52

Histologic response based on the RHI at Week 52. 

Histologic remission based on the RHI at Week 12. Histologic remission based on 
RHI is defined as a RHI score ≤ 3 with lamina propria neutrophils subscore = 0 and 
neutrophils in epithelium subscore = 0 

Histologic remission based on the RHI at Week 52 

Clinical remission based on the Ulcerative Colitis 100 (UC-100) index at Week 12. 
UC-100 index is based on SF subscore, ES, and RHI score. These 3 components are 
incorporated into a calculable final index. The formula for the composite UC-100 
score is: (1 + 16 × SF subscore [0 to 3] + 6 × ES [0 to 3] + 1 × RHI score [0 to 33]).
Clinical remission based on the UC-100 index is defined as UC-100 index ≤ 25. Its 
derivation will be based on the following 2 approaches, respectively.

UC-100 clinical remission 1, based on RB and SF derivation per 
protocol (Derivation 1, Section 3.1.1)

UC-100 clinical remission 2, based on RB and SF derivation per FDA 
Draft Guidance (Derivation 2, Section 3.1.1)

Clinical remission based on the UC-100 index at Week 52. Two UC-100 clinical 
remissions described above will be applied, respectively.

Clinical remission based on the TMS at Week 12. Clinical remission based on TMS is 
defined as a TMS  ≤ 2 with all subscores ≤1. Its derivation will be based on the 
following 2 approaches, respectively.

TMS clinical remission 1, based on RB and SF derivation per protocol 
(Derivation 1, Section 3.1.1)

TMS clinical remission 2, based on RB and SF derivation per FDA 
Draft Guidance (Derivation 2, Section 3.1.1)

Clinical remission based on the TMS at Week 52. Two TMS clinical remissions
described above will be applied, respectively.

MMS and Change from Baseline by visit. Derivations 1 and 2 for MMS in Section 
3.1.1 will be applied, respectively.

RB, SF, and composite RB/SF subscores and change from Baseline by visit.
Derivations 1 and 2 for RB and SF in Section 3.1.1 will be applied.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 25

Clinically meaningful improvement in bowel urgency at Week 12 and Week 52: 
Decrease from baseline in Urgency NRS ≥ 3 points.

Bowel urgency remission at Week 12 and Week 52: Urgency NRS ≤ 1 point.

Complete bowel urgency remission at Week 12 and Week 52: Urgency NRS = 0 
point.
3.4.2. HRQoL Endpoints 

Scores and change from baseline at Weeks 12, 32 (UC-PRO only), and 52 in the 
following:

Two Ulcerative Colitis Patient-Reported Outcomes (UC-PRO) modules. UC-
PRO scoring is derived by calculating the average using at least 4 out of 7 
daily scores, using the visit date to determine the days to be used. UC-PRO is 
available on the participants eDiary 14 days prior to and 14 days after the 
projected visit date. Participant should complete UC-PRO when it becomes 
available on the device for the visit, continuing until the visit occurs.
−
UC-PRO Signs and Symptoms (UC-PRO/SS). It is a 9-item 
questionnaire containing 2 domains: Bowel movement signs and 
symptoms (6 items) and functional symptoms (3 items). An 
average score is calculated for each domain; a higher score 
indicates worse symptoms. 
−
UC-PRO Systemic Symptoms. The Systemic Symptoms measure 
includes 5 items, scored as a single scale, to address the presence 
and severity of systemic symptoms including pain, feeling tired, 
lack of appetite, feeling weak, and thirst.

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). It is a 
13-item fatigue instrument utilized to assess fatigue/ tiredness and its impact 
on daily activities and functioning in a number of chronic diseases. The 
instrument includes items such as tiredness, weakness, listlessness, lack of 
energy, and the impact of these feelings on daily functioning (eg, sleeping, 
and social activities).

Work Productivity and Activity Impairment Questionnaire – Ulcerative 
Colitis (WPAI-UC). It consists of 6 questions asking about the effect of UC 
on the participant’s ability to work and perform regular activities. The percent 
work time missed due to problem (absenteeism), percent impairment while 
working due to problem (presenteeism), percent overall work impairment due 
to problem, and percent activity impairment due to problem are derived on 
the eCRF directly. Details about derivation can be found in Section 9.2.1.

Urgency numeric rating scale (NRS). It is a single item that measures the 
severity for the urgency (sudden or immediate need) to have a bowel 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 26
movement in the past 24 hours using an 11-point NRS ranging from 0 (no 
urgency) to 10 (worst possible urgency).

Inflammatory Bowel Disease Questionnaire total score (IBDQ). It is a 32-
item self-administered questionnaire which has 4 dimensions: bowel 
symptoms (10 items), systemic symptoms (5 items), emotional health (12 
items), and social function (5 items). Responses are graded on a 7-point 
Likert scale where 7 denotes “not a problem at all” and 1 denotes “a very 
severe problem”. Scores range from 32 to 224, a higher score indicates better 
quality of life. Details about scoring rules for IBDQ total score and 4 domain 
subscores can be found in Section 9.2.2.

Medical Outcomes Study 36-Item Short Form Health Survey, version 2 
physical and mental component and domain scores (SF-36). The 36-Item 
Short Form Health Survey (SF-36) is a 36-item, participant-reported survey 
of participant health. The SF-36 consists of 36 questions measuring 8 health 
domains: Physical functioning, bodily pain, role limitations due to physical 
problems, role limitations due to emotional problems, general health 
perceptions, mental health, social function, and vitality. The participant’s
responses are solicited using Likert scales that vary in length, with 3 to 6 
response options per item. The SF-36 will be scored using 2 overall summary 
scores: Physical component summary and mental component summary 
scores. A higher score indicates better health status. Details about scoring 
rules and derivations of domain scores can be found in Section 9.2.3

Patient Global Impression of Change (PGIC). It is the PRO counterpart to the 
Clinical Global Impressions (CGI) scale, which was published in 1976 by the 
National Institute of Mental Health (US). It consists of one item taken from 
the CGI and adapted to the patient.

UC-related hospitalizations.

UC-related surgeries, including colectomy.
3.4.3. Efficacy-Related Biomarkers Endpoints

Change from baseline in level of fecal calprotectin at Weeks 2, 4, 8, 12, 24, and 52.

Change from baseline in level of high-sensitivity C-reactive protein (hs-CRP) at 
Weeks 2, 4, 8, 12, 16, 24, 32, 48, and 52.

Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, 
12, 16, 24, 32, 48, and 52.
3.5. Baseline Variables
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to the first dose (including unscheduled assessments). If measurements include time 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 27
(except for health-related quality of life instruments), the date/time will be used to define 
Baseline. Otherwise, only dates will be compared. For health-related quality of life 
instruments, only the date will be used to derive Baseline. In the case where the last 
nonmissing measurement and the date of first dose coincide and time is not collected, if the 
measurement was planned in the protocol to be done prior to the date of first dose, that 
measurement will be considered in defining Baseline.
Regarding cardiac analyses, for the analysis of hHR endpoints in Section 3.3.2, the last pre-
dose hHR as derived by the cardiac central laboratory from Holter recording will be used as 
the baseline measurement (which may be based on recording from a partial hourly interval; 
see derivation of hourly timepoint in Section 9.1.7), except in the analysis of time to nadir 
hHR by baseline ECG HR, where baseline mean heart rate from pre-dose 12-lead ECG will 
be used.
The following demographic data and Baseline characteristics will be summarized:  

Age on consent (years)

Sex

Race

Ethnicity

Woman of childbearing potential (Yes or No)

Height (cm)

Weight (kg)

Body mass index (BMI) (kg/m2)

Alcohol consumption (Yes or No)

Caffeine consumption (Yes or No)

Tobacco use (Yes or No)

Region (North America, Western Europe, Easter Europe, Other)
The following Baseline characteristics related to UC will be summarized:

Baseline MMS

Baseline RB subscore

Baseline SF subscore

Baseline ES
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 28

Baseline Physician’s Global Assessment (PGA)

Baseline TMS

Duration of UC (years)

Any acute exacerbations within past 12 months (Yes, No, Ongoing), including the 
number of acute exacerbations among those with any acute exacerbation = Yes  

Colonoscopy within past 12 months (Yes or No)

Surgery for UC (Yes or No), including the number of surgeries

Hospitalizations for UC (Yes or No), including the number of hospitalizations

Naïve to biologic or JAK inhibitor therapy (Yes or No) – Reported (used for
stratification at randomization)

Naïve to biologic or JAK inhibitor therapy (Yes or No) – Actual (medications
reported on the eCRF)

Baseline corticosteroid use (Yes or No) – Reported (used for stratification at
randomization)

Baseline corticosteroid use (Yes or No) – Actual (medications reported on the eCRF)

Naïve to biologic or JAK inhibitor therapy – Difference between the Reported and the
Actual

Baseline corticosteroid use (Yes or No) – Difference between the Reported and the
Actual

Prior failure of oral 5-ASA only (Yes or No)

Prior failure of anti-TNF α (Yes or No)

Prior failure of anti-TNF α or vedolizumab (Yes or No)
Additional baseline characteristics related to UC can be added, if deemed needed.
Prior treatment
Prior treatment for UC will be summarized, including category of treatment, reason for
discontinuation, and estimated duration (weeks) of corticosteroid use over the last 12 months.
Medical history
Medical history will be collected on the medical history eCRF and coded using Medical
Dictionary for Regulatory Activities (MedDRA, v26.1). The version used to code medical
history will be displayed in the outputs. 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 29
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis set prior to unblinding the database and classifications will be 
documented per standard operating procedures. The description of each analysis set is 
provided in Table 5 below.
Table 5. Summary of Analysis Sets
Analysis Set
Description
Screened Set
The Screened Set will consist of all participants who sign informed 
consent to participate in the study.
Randomized Set
The Randomized Set will consist of all participants who are 
randomized to study treatment.
Full Analysis Set (FAS)
The FAS will consist of all randomized participants, who receive at 
least 1 dose of study treatment. Under this approach, participants will 
be summarized by the treatment group to which they were randomized, 
regardless of the treatment actually received during the study.
Primary Analysis Set (PAS):
The Primary Analysis Set will consist of participants in FAS with 
baseline MMS 4-6, baseline ES ≥2 and baseline RB score ≥ 1. This 
analysis set will be the primary analysis set for analyses of all efficacy 
endpoints.
Modified Primary Analysis Set 
(mPAS)
The mPAS will consist of all participants in PAS, who receive at least 
1 dose of study treatment and have a baseline and at least 1 post-
randomization measurement. Under this approach, participants will be 
summarized by treatment to which they were randomized, regardless 
of the treatment received during the study. Note that the mPAS can 
vary with endpoints since some participants may have the needed data 
for inclusion in the mPAS for some endpoints but others may not.
Safety Set
The Safety Set will include all randomized participants who receive at 
least 1 dose of study treatment. For this set, participants will be 
analyzed according to the treatment received, regardless of 
randomization. The Safety Set will be used for all safety analyses
Modified Safety Set
The Modified Safety Set will include all participants who receive at 
least 1 dose of study treatment and have Holter recording data on Day 
1. Unless stated otherwise,  the analyses of Cardiac Holter endpoints 
(Section 3.3.2) will be performed for the Modified Safety Set.  For this 
set, participants will be analyzed according to the treatment received, 
regardless of randomization.
Pharmacokinetic Set
The Pharmacokinetic Set will include all participants in the Safety Set 
with at least 1 quantifiable postdose etrasimod concentration which is 
not impacted by protocol violations or events with potential to affect 
the etrasimod concentration.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There are multiple null hypotheses for the comparison of etrasimod 2 mg versus placebo for 
the following primary endpoint and key secondary efficacy endpoints. The family-wise type-
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 30
I error rate will be controlled at the level of 0.05 using the fixed sequential testing approach 
in the order specified below.
(1) Clinical remission at Week 52 (Primary efficacy endpoint)
(2) Endoscopic improvement at Week 52
(3) 12-week corticosteroid-free clinical remission at Week 52 
(4) Clinical remission at Week 12
(5) Endoscopic improvement at Week 12
(6) Sustained clinical remission (clinical remission at both Week 12 and Week 52)
(7) Histologic-Endoscopic Mucosal Improvement at Week 52
(8) Complete symptomatic remission at Week 52  
(9) Complete symptomatic remission at Week 12  
Hypotheses for all other efficacy endpoints not described above are to be tested at 
the nominal 5% (2-sided) significance level, without adjusting for multiple comparisons.
5.2. General Methods
In general, for descriptive analyses, number and percent will be presented for binary 
variables.  Number, mean, standard deviation, median, minimum, maximum, first and third 
quartiles will be presented for continuous variables.
The general considerations for data derivation details can be found in Section 9.1 Data 
Derivation Details of Section 9. Appendix, such as derivations for some demographics and 
baseline characteristics related variables (Section 9.1.1), reference start date and study day 
(Section 9.1.2), retests, unscheduled visits, and early termination data (Section 9.1.3), 
definition and use of visit windows in reporting (Section 9.1.4), etc.
5.2.1. Analyses for Binary Efficacy Endpoints
The primary analysis of all binary efficacy endpoints will be performed based on the Mantel–
Haenszel (MH) weighted method, stratified by (a) naïve to biologic or JAK inhibitor therapy 
at study entry (yes or no) and (b) baseline corticosteroid use (yes or no). Results will be 
presented as the number of participants with response, proportion of participants with 
response, estimated common risk difference and associated two-sided 95% confidence 
intervals (CIs), and p-values from the MH weighted method.
For (a) and (b) mentioned above that are used in MH weighted method, the reported strata 
(which are based on randomization system) will be used for the statistical analyses. Analyses 
may be repeated using actual strata (which are based on medications reported in eCRF) if the 
strata data recorded in the randomization system and the actual strata data recorded in the 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 31
CRF are inconsistent for more than 10% of the randomized participants. i.e., if there are more 
than 10% of randomized participants whose reported strata are not the same as actual strata.
The methods for handling with missing data are described in Section 5.3 below.
5.2.2. Analyses for Continuous Non-Cardiac Endpoints
All continuous exploratory efficacy endpoints, HRQoL endpoints and efficacy-related 
biomarker endpoints measured longitudinally will be summarized by visit using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum), and 
presented in a listing. They will also be analyzed using a linear mixed-effect model, with 
factors for naïve to biologic or JAK inhibitor therapy at study entry (yes or no), baseline
corticosteroid use (yes or no), treatment, visit, treatment by visit interaction and baseline 
value. Reported strata will be used in the model. Unstructured covariance will be used. If 
there is a convergence issue in fitting the unstructured covariance, other covariance 
structures, such as a compound symmetry covariance structure will be considered as 
appropriate. LSM for each treatment group, standard errors (SEs), LSMs in treatment 
difference and associated 95% CIs, and p-values by visit will be reported.  
Analyses above based on linear mixed-effect model may be repeated using actual strata if 
mis-classification occurs in more than 10% of randomized participants. i.e., if there are more 
than 10% of randomized participants whose reported strata are not the same as actual strata.
5.2.3. Analyses for Cardiac Endpoints
For binary cardiac endpoints, data will be summarized using descriptive statistics, including 
number of participants (n), percentage, and 2-sided 95% Clopper-Pearson CI. No missing 
data will be imputed.
For continuous cardiac endpoints, data will be summarized using descriptive statistics, 
including number of participants (n), mean, median, SD, 2-sided 95% CI, first quartile (Q1), 
third quartile (Q3), minimum, and maximum by timepoint. No missing data will be 
imputed.
For count cardiac endpoints, data will be summarized using the same descriptive statistics as 
for continuous endpoints. No missing data will be imputed.
5.3. Methods to Manage Missing Data
5.3.1. Binary Efficacy Endpoints
Participants with a missing binary efficacy outcome will be included in the analyses using the
following method:

Primary method: participants with missing data will be treated as nonresponders. 

Other methods for sensitivity analyses: 
1) Multiple imputation under missing at random (MAR) assumption.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 32
2) Tipping point analysis.
3) multiple imputation with Copy Reference (CR) under missing not at random 
(MNAR) assumption.
4) Hybrid imputation with multiple imputation to handle missing endoscopy data 
due to the COVID-19 pandemic impact and Ukraine war impact, 
nonresponder imputation (NRI) for missing data not due to the COVID-19 
pandemic impact and Ukraine war impact.
More details are provided in Sections 5.3.1.1 and 5.3.1.2 below.
5.3.1.1. Primary Missing Data Handling Method
For binary efficacy endpoints, participants having any of intercurrent events 1) discontinue
the study treatment during the double blind treatment period for any reasons, or 2) initiate a 
rescue medication for UC, or 3) have an increase in dose over Baseline levels in their 
existing UC medication, or 4) have a rescue non-drug treatment (eg, colectomy, ileostomy, or 
sigmoidectomy) during the study will be considered as nonresponders, that is, have a known 
outcome of nonresponse at any applicable timepoints.
For primary analysis, all participants with missing data for other reasons will be treated as 
nonresponders. That is, all missing data will be treated as nonresponse regardless of reasons.
5.3.1.2. Sensitivity Missing Data Handling Methods
Other methods of handling missing data will be applied for primary and key secondary 
efficacy endpoints, which are all binary, assuming different missing mechanisms: multiple 
imputation under MAR assumption, tipping point analysis, and copy to reference under 
MNAR assumption. The analyses based on these methods will all be performed for PAS
only.
5.3.1.2.1. Multiple Imputation Under MAR Assumption
Missing data (eg, component scores of MMS at the planned assessment timepoints) will be 
imputed under the MAR assumption. Binary endpoints will subsequently be computed from 
observed and imputed data and analyzed using the same method as in the primary endpoint 
analysis for each imputed dataset. Then the results will be combined using multiple 
imputation methodology (Rubin, 1987 Section 8 References). 
The following steps will be implemented:
Step 1
Regardless of the arbitrary missing data pattern (ie, non-monotone or monotone), a fully
conditional specification (FCS) method with predictive mean matching for continuous 
variables will be used to impute the missing data at all timepoints. The FCS method allows 
for separate conditional distributions for each imputed variable. The predictive mean 
matching approach creates a regression model using parameters sampled from the posterior 
distribution and then a predicted value for each missing value is computed. The missing 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 33
value is replaced by randomly selecting an observation from a set of ‘k’ values that are the 
closest predicted values to the missing predicted value. Missing data imputation will be 
performed using the SAS PROC MI procedure (SAS Software v9.4. SAS Institute Inc, 
Section 8 References). The number of imputations will be 40. A separate imputation model 
will be used for each treatment group. The RB subscore, SF subscore, ES, PGA, stratification 
variables, a binary variable indicating if a participant is a prior UC treatment failure of oral 5-
ASA only (ie, participant had an inadequate response, loss of response, or intolerance to 
previous treatment with oral 5-ASA and did not have an inadequate response, loss of 
response, or intolerance to any other previous UC medication), Geboes index score, and 
biomarker measurements (absolute lymphocyte count [ALC], fecal calprotectin [FCP], hs-
CRP, log-transformed) at each planned visit will be included in the imputation models. The 
random seed 8238946 will be used.
Step 2
For each of the imputed datasets at Week 12 and Week 52, participants will be classified as
responder or nonresponder. For each dataset, the proportion of responders will be calculated. 
For endpoints requiring MMS, MMS will be recomputed by summing the scores of ES, SF, 
and RB.
Step 3
The MH weighted method, stratified by naïve to biologic or JAK inhibitor therapy at study 
entry (Yes or No) and baseline corticosteroid use (Yes or No) will be run for each of the 40
imputed  datasets to obtain 40 estimators of interest at Week 12 and Week 52.
Step 4
Use Rubin’s rule and SAS PROC MIANALYZE (Rubin, 1987; SAS Software v9.4. SAS 
Institute Inc Section 8 References) to produce an overall pooled estimate (mean of 40
estimates) with its associated SE, CI and p-value.
5.3.1.2.2. Tipping Point Analysis
The response status (yes/no) of a participant with missing data is multiply imputed by
randomly drawing from a Bernoulli distribution with changing underlying probability
independently for each treatment arm. The detailed steps are described below.

Step 1: Assume a response proportion p for all participants with missing data in the
placebo group and a response proportion p for all participants with missing data in
the etrasimod group.

Step 2: Impute the missing response for each participant from the Bernoulli
distribution with response probability p for placebo group and response probability 
pfor etrasimod group, independently. Combine with the participants with 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 34
nonmissing response to have a complete dataset. The random seed 8238946 will be 
used.

Step 3: Repeat Step 2 and generate N (eg, N=40) complete datasets.

Step 4: For each complete dataset, obtain the estimated common risk difference and 
its standard error using the weighted MH weighted method, stratified by (a) naïve to
biologic or JAK inhibitor therapy at study entry (yes or no) and (b) baseline
corticosteroid use (yes or no).

Step 5: Combine and obtain the final estimated common risk difference, its 95% 2-
sided confidence intervals and test p-values based on the Rubin’s rule and SAS
PROC MIANALYZE 

Step 6: For each combination of (p , p) over a plausible region (say, p from to 0.3, 
and p from 0.0 to 0.5), repeat Step 1 through Step 5 to produce a significance tipping 
point map to help the determination of the tipping point boundary.
5.3.1.2.3. Copy Reference (CR) Multiple Imputation Under MNAR Assumption
Missing data will also be explored assuming an MNAR approach. MNAR assumes the 
missing values depend on unobserved outcomes even after accounting for the observed data. 
Therefore, participants cannot be modelled based on participants with observed data, and 
more assumptions are needed. Copy Reference approach (Carpenter et al, 2013) will be used. 
It is a type of missing data handling approach, assuming MNAR, where each missing value 
of MMS subscores for participants in the treatment group will be imputed using observed 
MMS subscores in the placebo group, and missing values of MMS subscores for participants 
in the placebo group will be imputed under the MAR approach. Once the missing MMS 
subscores are imputed, all binary efficacy endpoints (based on MMS) will be derived based 
on observed and imputed MMS subscores and analyzed using the same method described in
Section 5.2.1 for each imputed dataset. Then the results will be combined using multiple
imputation methodology based on the Rubin’s rule. The random seed 8238946 will be used.
Step 1
Step 1 (a)
Intermittent missing data (before discontinuation from study) at each scheduled visit will be
imputed, separately for each treatment group, under the MAR assumption using a 
multivariate normal imputation model and the Markov Chain Monte Carlo (MCMC) method 
with multiple chains. The number of imputations will be 40. The resulting data will have a 
monotone missing data pattern. The imputed data will be used together with the observed 
data to impute post discontinuation missing values.
Step 1 (b)
Only after Step 1a is completed, the remaining monotone missing data after discontinuation 
will be imputed using the FCS predictive mean matching method based on data from the 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 35
placebo group only. The RB, SF, ES, and PGA subscores, stratification variables, a binary 
variable indicating if a participant is a treatment failure, and biomarker measurements (ALC, 
FCP, hs-CRP, log-transformed) at each planned visit will be included in the imputation 
model.
Step 2
Same as Step 2 described in Section 5.3.1.2.1 above.
Step 3
Same as Step 3 described in Section 5.3.1.2.1 above.
Step 4
Same as Step 4 described in Section 5.3.1.2.1 above.
5.3.1.2.4. Hybrid Imputation For Missing Data Due to COVID-19 Pandemic and 
Ukraine war
The COVID-19 pandemic and Ukraine war introduces unexpected and unknown impact on 
the clinical study due to unforeseen intercurrent events. As a sensitivity analysis for primary 
and key secondary efficacy endpoints, missing endoscopy data will be handled using a hybrid 
approach combining nonresponder Imputation (NRI) and multiple imputation, where 
participants with missing endoscopy data due to COVID-19 pandemic and Ukraine war will 
be imputed using multiple imputation method under a MAR assumption, as described in 
Section 5.3.1.2.1. The random seed 8238946 will be used. Missing data for any other reason 
will be considered a nonresponse.  
5.3.2. Continuous Non-Cardiac Endpoints
For all non-cardiac continuous (i.e., exploratory efficacy endpoints, HRQoL endpoints and 
efficacy-related biomarker endpoints) endpoints measured longitudinally, missing values 
post baseline will not be imputed explicitly.  For such endpoints, assuming that the missing 
data mechanism is missing at random (MAR), the data will be analyzed based on a linear 
mixed-effect model for these continuous endpoints (Section 5.2.2)
5.3.3. Cardiac Endpoints
For all cardiac endpoints, missing values will not be imputed explicitly.  
5.4. Supplementary Analyses for Primary and Key Secondary Efficacy Endpoints
For primary endpoint analysis, the primary model as described in Section 5.2.1 will be 
repeated using the mPAS (with data as observed) as a supplementary analysis.
For key secondary efficacy endpoint analyses, the primary model as described in Section 
5.2.1 will be repeated using the mPAS (with data as observed) as supplementary analyses.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 36
6. ANALYSES AND SUMMARIES
6.1. Summaries and Analyses for Efficacy, HRQoL and Efficacy-Related Biomarker 
Endpoints
The detailed summaries of analyzing the efficacy, HRQoL and efficacy-related biomarker 
endpoints listed in Sections 3.1, 3.2.1, 3.4.1, 3.4.2 and 3.4.3 are provided in Table 6 and 
Table 7 below. All outputs will be based on the PAS, unless otherwise specified.  
Table 6. Planned Analyses for Primary and Key Secondary Efficacy Endpoints
Endpoint
Main Analysis
Main Missing 
Data Handling
Sensitivity 
Missing Data 
Handling
Supplementary
Analyses
Primary endpoint
Clinical remission 
at Week 52
MH weighted 
method (Section 
5.2.1) based on 
PAS
NRI
MI assuming 
MAR, Tipping 
point analysis, CR 
MI assuming 
MNAR, hybrid 
imputation
mPAS (observed 
data)
Key secondary 
efficacy endpoint
Endoscopic 
improvement at 
Week 52
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
12-week 
corticosteroid-free 
clinical remission at 
Week 52
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Clinical remission 
at Week 12
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Endoscopic 
improvement at 
Week 12
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Sustained clinical 
remission (clinical 
remission at both 
Week 12 and Week 
52)
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Histologic-
Endoscopic 
Mucosal 
Improvement at 
Week 52
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 37
Table 6. Planned Analyses for Primary and Key Secondary Efficacy Endpoints
Endpoint
Main Analysis
Main Missing 
Data Handling
Sensitivity 
Missing Data 
Handling
Supplementary
Analyses
Complete 
symptomatic 
remission at Week 
52
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Complete 
symptomatic 
remission at Week 
12
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Same as primary 
endpoint
Table 7. Planned Analyses for Other Secondary Efficacy, Exploratory Efficacy, 
HRQoL and Efficacy-Related Biomarker Endpoints
Endpoint
Main Analysis
Main Missing 
Data Handling
Sensitivity 
Missing Data 
Handling
Supplementary
Analyses
Other secondary 
efficacy endpoints 
(Section 3.2.1)
Same as primary 
endpoint
Same as primary 
endpoint
N/A
N/A
Exploratory 
efficacy endpoints: 
binary endpoints
(Section 3.4.1)
Same as primary 
endpoint
Same as primary 
endpoint
N/A
N/A
Exploratory 
efficacy endpoints: 
continuous 
endpoints (Section 
3.4.1)
linear mixed-effect 
model based on
PAS (Section 
5.2.2)
Data will not be 
imputed explicitly, 
assuming MAR 
(Section 5.3.2)
N/A
N/A
HRQoL endpoints
(Section 3.4.2)
Same as 
continuous 
exploratory 
efficacy endpoint
Same as 
continuous 
exploratory 
efficacy endpoint
N/A
N/A
Efficacy-related 
biomarker 
endpoints (Section
3.4.3)
Same as 
continuous 
exploratory 
efficacy endpoint
except that the 
analysis for 
lymphocyte counts 
will be based on 
Safety Set, not 
PAS
Same as 
continuous 
exploratory 
efficacy endpoint
N/A
N/A
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 38
For continuous endpoint, line plots over time for LS mean and SE by treatment will be 
provided if deemed appropriate.
6.2. Summaries and Analyses for PK Endpoints
Unless otherwise specified, PK summaries will use the Pharmacokinetic Set. 
Plasma concentrations of Etrasimod will be assessed from PK samples collected prior to 
dosing and 4 hours (± 15 minutes) postdose (after 12-lead ECG) on Week 0/Day 1.
Additionally, PK samples will be collected prior to dosing (trough) at Weeks 2, 4, 8, 12, 16, 
20, 24, 32, 40, 48, and 52, and for PK samples collected at the 2-Week and 4-Week Follow-
Up visits for participants not enrolled into any extension study.
Concentrations below the limit of quantitation (BLQ) will be assigned a numerical value of 
zero for the calculation of descriptive statistics. For geometric mean and geometric % 
coefficient of variation [CV], the zero values will be excluded.
Individual participant etrasimod plasma concentrations (and etrasimod metabolite
concentrations, if applicable) will be presented in the data listings, including participant ID, 
treatment received, nominal timepoint, actual blood collection date/time, concentration, and 
time since last dose and also summarized using descriptive statistics (n, mean, SD, % CV,
geometric mean, geometric % CV, median, minimum, and maximum) by nominal timepoint.
All participants are expected to achieve steady-state plasma concentration by Week 2. For 
each participant, the average steady-state trough (predose) plasma concentration based on 
Week 2 to Week 52 trough concentrations (C	
,,W2-W52) per participant will also be 
calculated and presented in a data listing and summarized using descriptive statistics.
Mean (± SD) etrasimod concentration versus nominal time (Weeks 0 to 52) will be plotted on
a linear scale. 
The pharmacokineticist will determine the strategy for dealing with data affected by protocol 
deviations or events which may impact the quality of PK concentration data on a case-by-
case basis with input from the study physician and clinical pharmacologist, as needed. 
Examples for protocol deviations or events include, but may not be limited to, vomiting on 
the day prior to trough sample collection, sample processing errors that lead to inaccurate 
bioanalytical results, and/or inaccurate dosing prior to PK sampling.  
The plasma concentrations over time will be used in a population PK analysis, which will be
described in a separate analysis plan.
6.3. Safety Summaries and Analyses
All outputs for safety outcomes will be based on the Safety Set. 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 39
6.3.1. Adverse Events
6.3.1.1. All TEAEs
All TEAEs will be summarized by SOC and PT. This summary table and all other TEAE
summaries by SOC and PT will be presented by descending frequency in the etrasimod 
group.
All AEs, regardless of treatment-emergent status, will be included in an AE listing. 
Additionally, a listing of other AE details as collected on the CRF will be presented.
Exposure-adjusted incidence rate (EAIR) of TEAEs will be summarized by SOC and PT.
Exposure is defined as the sum of either time (year) from first dose to the onset of first such
event for those who experienced this AE, or time (year) from first dose to last participation 
for those who did not experience this AE. The EAIR is calculated as the number of 
participants with the AE divided by the total exposure in participant-years.
Severity
All TEAEs will be summarized by SOC, PT, and maximum severity, with SOC and PT
presented by descending frequency. If a participant reports a TEAE more than once within a
SOC/PT, the AE with the worst-case severity will be used in this summary.
Relationship to Study Treatment
All related TEAEs will be summarized by SOC, PT, and maximum severity, with SOC and 
PT presented by descending frequency. If a participant reports a TEAE more than once 
within a SOC/PT, the AE with the worst-case severity will be used in this summary. A 
“related TEAE” for the purpose of this summary is defined as a TEAE with relationship to 
study treatment of “probably related” or “related”.
6.3.1.2. TEAEs Leading to Discontinuation of Study Treatment and TEAEs Leading to 
Interruption of Study Treatment
All TEAEs leading to discontinuation of study treatment will be summarized by SOC and 
PT. TEAEs leading to interruption of study treatment will be summarized by SOC and PT as 
well.
6.3.1.3. Serious and Non-Serious TEAEs
All serious TEAEs will be summarized by SOC and PT. If the seriousness is missing, the AE
will be considered as “Serious” for summary tabulation purpose only. All nonserious TEAEs 
will be summarized by SOC and PT.
6.3.1.4. TEAEs of Special Interest
TEAEs of special interest will be summarized by category, subcategory, and PT by
descending frequency by treatment group. 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 40
For each category, subcategory, and PT, model-based analysis will be performed to compare
treatment effect between etrasimod and placebo. An extended Cox regression model will be 
used to handle recurring AEs (Cao 2011, Section 8 References). The stratification variables, 
naïve to biologic or JAK inhibitor therapy status at study entry (Yes or No) and Baseline 
corticosteroid use (Yes or No), will be included in the model. A participant with K events 
contributes (K+1) observations to the input data set; here K might be 0. The k-th observation 
of the participant identifies the time interval from the start date of the (k-1)-th event, or time 
0 (if k = 1), to the start date of the kth event, k = 1, …, K. The (K+1)-th observation
represents the time interval from the K-th event to the date of censorship, ie, the date of last 
dose or date of last study visit up to Week 52, whichever is later. Hazard ratios (Etrasimod 
group vs placebo group), 95% CIs, and 2-sided p-values for treatment effect comparison will 
be presented.
6.3.1.5. Overall Summary of Adverse Events
In addition to the summaries above, an overview of TEAEs will be summarized by number 
and frequency of participants and by number of AEs:

Any TEAE

Any related TEAE*

Any serious TEAEs

Any related serious TEAEs*

TEAEs leading to death

Liver-related TEAEs leading to death

TEAEs leading to study treatment discontinuation

Related TEAEs leading to study treatment discontinuation*

Liver-related TEAEs leading to study treatment discontinuation

TEAEs leading to study treatment interruption

Related TEAEs leading to study treatment interruption*

TEAEs by maximum severity

Related TEAEs by maximum severity*

TEAEs by relationship to study treatment
* “Related TEAEs” refers to TEAEs related or probably related to study treatment or are 
missing relationship.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 41
Comparative analyses will be performed for the following:

TEAEs leading to Deaths

Severe TEAEs (CTCAE grade ≥3)

Serious TEAEs

TEAEs leading to study treatment discontinuation.

TEAEs of special interest

Treatment-emergent Serious infections

Treatment-emergent Opportunistic infections (Narrow)

Treatment-emergent Malignancies
Risk differences between etrasimod and placebo along with 95% CIs using the Wilson’s 
score method will be presented. Differences between “Exposure-Adjusted Incidence
Rates” (EAIR) comparing treatment to placebo along with 95% CIs based on large-sample 
approximation assuming Poisson standard errors for the estimated incidence rates as 
described in Liu et al. will be presented as well.
6.3.2. Other Safety Summaries and Analyses Endpoint(s)
6.3.2.1. Laboratory Data
In general, no local laboratory assessments will be used in any summaries except for lipid 
panel and thyroid panel tests. No local laboratory assessments will be used to derive
maximum /minimum/worst value unless specified otherwise. Local laboratory assessments 
will be listed.
For the sites and/or countries where central laboratory assessments are not available (due to 
reason such as war in Ukraine) and local laboratory assessments are collected, the local 
laboratory assessments could be considered for laboratory related analyses, if deemed 
appropriate.
Safety Laboratory Evaluations
Hematology, serum chemistry, coagulation, and urinalysis will be analyzed and reported by 
central laboratory and sometimes by local laboratory. Results out of reference range are 
flagged by the performing laboratory (eg, low, high). A full list of laboratory assessments to 
be included in the outputs is included in Table 5 (“Clinical Laboratory Tests”) of Clinical 
Study Protocol C5041011 (APD334-210) amendment 2.0.
In general, presentations will use SI units. Quantitative laboratory measurements reported as
“< X” or “> X”, where X may be the lower limit of quantitation (LLQ) or the upper limit of
quantitation (ULQ), respectively, will be converted to X for the purpose of quantitative
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 42
summaries, but will be presented as recorded, ie, as “< X” or “> X” in the listings. For 
urinalysis, only pH and specific gravity are considered as quantitative tests. If local and 
central laboratory assessments are available from the same day, central laboratory 
assessments will be used in the summary as per Section 9.1.4.
The following summaries will be provided for laboratory data:

Value and change from Baseline by visit (e.g., hematology, serum chemistry, and 
coagulation)

Incidence of markedly abnormal lymphocytes and neutrophils at anytime post-
baseline, End of Treatment, any Follow up.
o
Markedly Abnormal lymphocytes and neutrophil is defined as Lymphocytes < 
0.2 × 109/L, 0.5 × 109/L, or Neutrophils < 0.5 × 109/L, 1 × 109/L.

Shift from end of treatment to each follow-up visit in incidence of lymphocytes for 
participants with abnormal low value at end of treatment. 

Evaluation of drug-induced serious hepatotoxicity (eDISH) plots for the following
laboratory assessments (using values after the first administration of study treatment):

Maximum aspartate aminotransferase (AST) versus same-day total bilirubin

Maximum alanine aminotransferase (ALT) versus same-day total bilirubin
The eDISH plots above will be repeated with adjustment for elevated Baseline.

Incidence of hepatic enzyme elevations by visit and overall post baseline

> 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 ×, 20 × upper limit of normal (ULN) elevation in ALT

> 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 ×, 20 × ULN elevation in AST

> 3 ×, 5 ×, 10 ×, 20 × ULN elevation in either ALT or AST

> 1 ×, 1.5 ×, 2 ×, 3 × ULN elevation in total bilirubin

> 1 ×, 1.5 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in ALP

> 1 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in GGT

> 3 × ULN elevation in either ALT or AST and > 1.5 × ULN elevation in total

bilirubin

> 3 × ULN elevation in either ALT or AST and > 2 × ULN elevation in total

bilirubin
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 43

> 3 × ULN elevation in either ALT or AST and > 1.5 × ULN elevation in ALP

> 3 × ULN elevation in either ALT or AST in temporal association with
treatment-emergent nausea, vomiting, anorexia, abdominal pain, or fatigue
identified by PT, where temporal association is defined as ±14 days of onset date
from the time of elevation.
If both central and local assessments of total bilirubin are available on the same day, the 
central result will take precedence over the local result in the eDISH plot. If the maximum 
AST, ALT, GGT, or ALP assessment occurs at 2 different dates, the assessment with the 
higher accompanying Bilirubin value will be used. Two versions of the eDISH plots will be 
presented, with one showing values as multiples of ULN, and the other one showing values 
as multiples of ULN, or participant’s baseline, whichever is higher.
Participant’s laboratory assessments at all timepoints will be listed in chronological order. 
Values outside of the laboratory reference range will be flagged. Values obtained from local 
laboratory will be flagged. A listing of lymphocytes and neutrophils over time in participants 
who ever had lymphocytes < 0.5 × 109/L or neutrophils < 1 × 109/L will also be provided.
Pregnancy Tests
Pregnancy tests are performed throughout the study (Serum β-hCG test at Screening; urine 
pregnancy test at all other visits) in female participants of childbearing potential. All 
pregnancy test results (positive or negative) will be listed in chronological order. Number of 
female participants with positive urine/serum pregnancy test will be summarized.
Other Screening Laboratory Assessments
Other screening laboratory assessments conducted per Table 5 (“Clinical Laboratory Tests”) 
of Protocol C5041011(APD334-210) amendment 2.0 will be listed. 
6.3.2.2. ECG Evaluations
The ECG parameters reported for this study per Protocol C5041011 (APD334-210) 
amendment 2.0 will be summarized by visits.
ECG Markedly Abnormal Criteria
Markedly abnormal quantitative ECG measurements will be identified in accordance with the
following predefined markedly abnormal criteria:

Absolute values in QT and QTcF:
−
≥450 ms (male) or ≥470 ms (female) in QTcF
−
> 500 ms in QT

Change from Baseline in QT and QTcF:
−
> 30 ms increase from Baseline
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 44
−
> 60 ms increase from Baseline
ECG Evaluations
The following summaries will be provided for ECG data:

Value and change from Baseline by visit (for quantitative measurements).

Incidence of markedly abnormal values (defined in “ECG Markedly Abnormal 
Criteria” above) and AV blocks by visit.
Listings of ECG results, including first dose cardiac monitoring, and discharge criteria for 
first dose cardiac monitoring will be provided.
A listing of all ECG assessments over time in participants meeting markedly abnormal 
criteria will also be provided. In this listing, 

For each participant, only ECG parameters ever meeting markedly abnormal criteria 
will be included. 

For each participant, if there is at least one assessment meeting markedly abnormal 
criteria for a given ECG parameter, then all assessments collected of this ECG 
parameters over time will be included. 
6.3.2.3. Cardiac Holter Monitoring
hHR
Value and change from baseline in hHR will be descriptively summarized by hourly 
timepoint. 
Time to first nadir hHR post-dose will be descriptively summarized as a continuous outcome 
measure in the Modified Safety Set. The number and percentage of participants who reached 
their first nadir hHR at each nominal hourly timepoint (eg, hour 1, hour 2, etc.) will also be 
descriptively summarized.
Cardiac Abnormal Findings
Incidence of participants with abnormal findings flagged by cardiac central laboratory will 
be descriptively summarized.
Incidence of participants with low heart rate as defined in Section 3.3.2.1 will be 
descriptively summarized.
Data Listings
Holter recording data on Day 1 will be listed.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 45
6.3.2.4. Vital Sign
The vital sign parameters reported for this study per Protocol C5041011 (APD334-210) 
amendment 2.0 will be summarized by visits. Table 8 below lists the markedly abnormal 
criteria for vital signs.
Table 8. Markedly Abnormal Criteria for Vital Signs
Vital Sign Parameter
Unit
Low
High
SBP 
mm Hg
≤ 90 mm 
 > 150 mm Hg
DBP 
mm Hg
≤ 50 mm
 > 90 mm Hg
Heart rate
bpm 
< 40 bpm 
< 50 bpm
< 50 bpm and decrease from 
predose (Baseline) of > 10 
bpm at 4 hours on Day 1 or 
Day 2 or remonitoring visit
  > 100 bpm
bpm: beats per minute; DBP:  diastolic blood pressure; SBP: systolic blood pressure
The following summaries will be provided for vital signs data:

Value and change from Baseline by visit.

Value and change from predose on Day 1 (as reported on the eCRF) by timepoint.

For heart rate only, value and change from predose to minimum postdose heart
rate on Day 1 will be included in the same table.

Incidence of markedly abnormal values (defined in Table 8 above).

Listing of participants meeting markedly abnormal criteria.

Incidence of minimum heart rate on Day 1 by postdose timepoint (1, 2, 3, 4, and > 4 
hours postdose, and Day 1 overall) and heart rate interval (≥65, 60 to 64, 55 to 59, 50 
to 54, 45 to 49, 40 to 44, < 40 bpm).

If minimum heart rate is attained at multiple postdose timepoints, only the earliest 
timepoint will be counted in this incidence summary.

Time to minimum heart rate on Day 1 by planned hourly timepoint (if minimum heart 
rate is attained at multiple postdose timepoints, only the earliest timepoint will be 
counted).

Actual time elapsed from first dose to minimum heart rate on Day 1 will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and 
maximum) in the same table.
For participants with extended monitoring or remonitoring, a listing of systolic blood 
pressure, diastolic blood pressure, heart rate values, and change from predose in all 
parameters on Day 1, Day 2, and any remonitoring visit will be provided.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 46
Vital signs derivation for temperature: temperature (°C) = (5/9) (temperature (°F) – 32).
6.3.2.5. Pulmonary function tests
PFT Markedly Abnormal and Potentially Important Criteria
Markedly abnormal quantitative PFT measurements will be identified in accordance with the
following predefined markedly abnormal criteria:

% Predicted FEV1 < 50%

% Predicted FVC < 50%

% Predicted FEV1/FVC ratio < 50%
Potentially important PFT measurements will also be identified using the criteria below:

Percent decrease from Baseline > 20% in FEV1, ie, percent change from Baseline < -
20%

Percent decrease from Baseline > 20% in FVC, ie, percent change from Baseline < -
20%

Percent decrease from Baseline >20% in DLCO (if available), ie, percent change 
from Baseline < -20%

Percent decrease from Baseline ≥30% in FEV1, ie, percent change from Baseline ≤-
30%

Percent decrease from Baseline ≥30% in FVC, ie, percent change from Baseline ≤-
30%

Percent decrease from Baseline ≥30% in DLCO (if available), ie, percent change 
from Baseline ≤-30% 
The PFT parameters reported for this study per Protocol C5041011 (APD334-210) 
amendment 2.0 will be summarized by visits.
The following summaries will be provided for PFT data descriptively:

Value and change from Baseline by visit.

Incidence of markedly abnormal and/or potentially important PFT values by visit per 
“PFT Markedly Abnormal and Potentially Important Criteria” above.
All PFT data will be listed. Abnormal PFTs, markedly abnormal and/or potentially important 
PFT values will be flagged in the listing.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 47
6.3.2.6. Ophthalmoscopy and Optical coherence tomography
The following summaries will be provided for ophthalmoscopy and optical coherence
tomography (OCT) data:

Values and change from Baseline in central foveal thickness and intraocular pressure 
by visit.

Incidence of markedly abnormal change in central foveal thickness (CFT) ( > 40 μm 
increase from Baseline in CFT in either eye) by Visit.

Categorical result in ophthalmoscopy with OCT parameters by visit (the categories 
are listed on the eCRF).
A listing of all ophthalmoscopy and OCT assessments will be provided. A listing of 
participants who ever reported an abnormality in OCT will also be provided. Additionally, a 
listing of retinal photograph and eye pressure assessments will be provided for participants 
who experienced an AE related to eye disorders.
6.3.2.7. Tuberculosis Questionnaire
Tuberculosis Questionnaire at screening and post screening will be listed. 
6.4. Subset Analyses
The following major subgroup analyses for the primary and key secondary efficacy endpoints 
will be performed based on PAS, in order to explore whether the treatment effects are 
consistent across different subgroups.

Age (years): 

> or ≤ median value (based on PAS)

≥ or < 65 years 

Sex (Male, Female)

Race (White or Non-White)

Race (White, Black or African American, Asian, Other, where Other captures the 
remaining races)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Region (North America, Western Europe, Eastern Europe, Other)

Baseline oral corticosteroid usage (yes or no) *

Naïve to biologic or JAK inhibitor therapy at study entry (yes or no) *

Baseline fecal calprotectin > or ≤ median value (based on PAS)

Baseline CRP > or ≤ median value (based on FAS)

Prior Oral 5-ASA Failure Only (yes or no)
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 48

Naïve to biologic or JAK inhibitor therapy who failed corticosteroid and/or 
thiopurines (yes or no)
*actual stratum (based on medications reported on the eCRF)
The main subgroup analyses for primary and key secondary efficacy endpoints will be based 
on the same MH weighted method as mentioned in Section 5.2.1 except that

For subgroup baseline oral corticosteroid usage (yes or no), the reported stratum of 
baseline oral corticosteroid usage (yes or no) will not be used in MH weighted 
method.

For subgroup naïve to biologic or JAK inhibitor therapy at study entry (yes or no), the 
reported stratum of naïve to biologic or JAK inhibitor therapy at study entry (yes or 
no) will not be used in MH weighted method.
Additional subgroups may be assessed, if deemed necessary. If any subgroup includes < 5% 
of all participants, no inferential statistics will be generated.
Graphical display (eg, forest plots) of the treatment differences between treatment groups 
will be presented for each of the primary and key secondary efficacy endpoints.  The 
treatment differences between treatment groups, along with 95% CIs, that are obtained from 
MH weighted method mentioned above will be displayed.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographics and medical history including variables defined in Section 3.5  will be
summarized by treatment group.
6.5.2. Study Conduct and Participant Disposition
Among the randomized participants, the number and percent of participants who 
completed/discontinued study treatment, reasons off treatment, the number and percent of 
participants who completed/discontinued the study, and reasons off study will be 
summarized. This summary will also be provided by region and country. The number and 
percent of participants in each analysis set will be summarized for all randomized 
participants. An additional summary of the number of participants screened, the number of 
screen-failed participants, and reason for screen failure will be presented for all screened 
participants. If there are participants whose blind was broken during the study, a listing of 
these participants will be provided. The number of participants whose visit was impacted by 
the COVID-19 pandemic will also be summarized.
According to ICH E3 and ICH E3(R1), important protocol deviations are a subset of protocol
deviations that might significantly affect the completeness, accuracy, and/or reliability of the
study data or that might significantly affect a participant's rights, safety, or well-being (ICH 
1996, ICH 1998). All-important protocol deviations will be identified before study 
unblinding. The identified important protocol deviations will be summarized by protocol 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 49
deviation categories (Section 9.1.6). All protocol deviations will be listed, including whether 
a protocol deviation that occurred during by the COVID-19 pandemic was impacted by the
COVID-19 pandemic (Yes or No) or the war between Russia and Ukraine (Yes or No).
6.5.3. Study Treatment Exposure
6.5.3.1. Duration of Study Treatment Exposure
The date of first and last study treatment administration will be taken from the Day 1 Onsite
Dosing Administration eCRF and the End of Study eCRF, respectively. Interruptions,
compliance, and dose changes are not taken into account for duration of exposure. Exposure 
to study treatment in weeks will be summarized for the Safety Set.
Duration of exposure (weeks) = (date of last study treatment administration – date of first 
study treatment administration + 1) / 7. For participants with missing Date of Last Dose on 
the End of Study eCRF, their date of last study treatment administration will be imputed by 
the last date of all dosing administration start/stop dates recorded.
6.5.3.2. Dose interruption and Overdose
For dose interruptions, the frequency and percentage will be provided for the following:

participants who had at least 1 dose interruption

participants who had at least 1 dose interruption of > 7 days

participants who had at least 1 dose interruption of > 14 days
For overdose, the frequency and percentage will be provided for the following:

participants who had 1 overdose

participants who had > 1 overdose will be summarized.
6.5.3.3. Study Treatment Compliance
For study treatment compliance, the total number of tablets expected, total number of tablets 
taken, total number of tablets missed, overall compliance with study treatment, and 
frequency and percentage of participants with overall compliance of < 80% or > 120% will 
be summarized for the Safety Set for the entire study.
Compliance to study treatment is based on the Drug Accountability eCRF and will be 
calculated as the total number of tablets taken (total dispensed – total returned) divided by 
the number of tablets expected during the Treatment Period, expressed as a percentage, refer 
to calculations below.
The total number of tablets expected is defined as the number of tablets that a participant is 
expected to have taken between their first and last study treatment administration and is 
numerically identical to the participant’s overall study treatment exposure, since the 
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 50
medication is to be taken once daily. On any site visit day, the medication is to be held and 
taken at the site, after all predose assessments have been completed.  

Overall compliance to study treatment will be calculated as follows; total number of 
tablets returned subtracted from total number of tablets dispensed, divided by the 
duration of treatment, multiplied by 100.
For all bottles not returned, it will be assumed that all dispensed tablets were taken. For each
participant, if a high percentage (> 25%) of bottles were not returned by a participant, 
additional analyses may be done where bottles not returned are excluded from the overall 
compliance calculation for the participant. In such analysis, the date of last dose or the date 
of last bottle return, whichever is earlier, will be used as the “date of last dose” in the 
calculation above.
Both scheduled and unscheduled study treatment dispensations will be used in the 
compliance calculation. Overall compliance calculations will be performed for the entire 
study and will be used in determining inclusion/exclusion of participants in the respective Per 
Protocol Set.  
6.5.4. Concomitant Medications and Nondrug Treatments
Medications will be captured on the Concomitant Medications eCRF and coded using the 
WHO Drug dictionary (GlobalB3_March 2024). Refer to Section 9.1.5 for handling of partial 
dates for medications. In the case where it is not possible to define a medication as prior or 
concomitant, the medication will be classified by the worst case (ie, concomitant)

‘Prior’ medications are medications which started and stopped prior to the first dose 
of study treatment.

‘Concomitant’ medications are medications which started prior to, on or after the first
dose of study treatment AND ended on or after the date of first dose of study 
treatment or were ongoing at the end of the study.
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC)
Level 2 and Preferred Drug name for the Safety Set. Concomitant medications used for UC 
will be flagged as such on the Concomitant Medications eCRF and summarized by ATC 
Level 2 and Preferred Drug name for the Safety Set.
7. INTERIM ANALYSES
There are no interim analyses planned for this study.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 51
8. REFERENCES
Cao D, He X. Statistical analysis of adverse events in randomized clinical trials using SAS.
PharmaSUG Conference Proceedings; 2011.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol
deviation: A framework for relevant, accessible assumptions, and inference via multiple
imputation. J Biopharm Stat. 2013;23(6):1352-71.
FDA. Statistical considerations for clinical trials during the COVID-19 public health 
emergency. U.S. Department of Health and Human Services, Food and Drug Administration. 
Guidance for Industry Web site. https://www.fda.gov/media/139145/download. Published 
2020. 
FDA. (2022). Ulcerative colitis: Developing drugs for treatment. US Department of
Health and Human Services, Food and Drug Administration, Silver Spring, MD.
Guidance for Industry, https://www.fda.gov/media/158016/download. 
FDA. (2022). Multiple endpoints in clinical trials. U.S. Department of Health and Human
Services, Food and Drug Administration. Guidance for Industry.
https://www.fda.gov/media/162416/download   
FDA. (2020). Conduct of clinical trials of medical products during the COVID-19 public
health emergency. U.S. Department of Health and Human Services, Food and Drug
Administration. Guidance for Industry, https://www.fda.gov/media/136238/download.
FDA (to Pfizer). (2022) FDA Letter IND 125154 Advice-Information Request IND
ICH. (1996). Structure and content of clinical study reports, E3. International Conference
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use. Guideline for Industry, https://www.fda.gov/media/71271/download.
ICH. (1998) Statistical principles for clinical trials, E9. International Council for
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use. Guidance for Industry, 
https://database.ich.org/sites/default/files/E9_Guideline.pdf. Accessed: 05 July 2023.
Liu GF, Wang J, Liu K, et al. Confidence intervals for an exposure adjusted incidence
rate difference with applications to clinical trials. Stat Med. 2006;25(8):1275-86.
Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: John Wiley and
Sons; 1987. 296 p.
Pfizer (to FDA). (2023) Response to FDA-Clinical IR received 02 December 2022, Study 
C5041011/APD334-210 (GLADIATOR) Pfizer (to FDA). (2023) Etrasimod UC_Type C 
Meeting_FDA_GLADIATOR_Proposed Analysis Plan_August 2023
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 52
Pfizer (2023). Full Prescribing Information of VELSIPITY™ (etrasimod), 
https://www.velsipity.com
SAS Software v9.4. SAS Institute Inc., Cary, NC, USA.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 53
9. APPENDIX
9.1. Data Derivation Details
9.1.1. Demographics and Baseline Characteristics Related variables 

Duration of UC (year) = (Informed consent date – Date of diagnosis + 1) / 365.25

Weight (kg) = Weight (lb) × 0.4536

Height (cm) = Height (in) × 2.54

Height (m) = Height (in) × 0.0254 = Height (cm) × 0.01

BMI (kg/m2) = Weight (kg) / Height (m)2
9.1.2. Reference Start Date and Study Day
Study Day will be calculated from the reference start date and will be used to show start/stop 
day of assessments and events. Reference start date is defined as the date of first dose (Day 
1) and will appear in every listing where an assessment date or event date appears.

If the date of the event is on or after the reference start date, then:
Study Day = (date of event – reference start date) + 1

If the date of the event is prior to the reference start date, then:
Study Day = (date of event – reference start date)
In the situation where the event date is partial or missing, Study Day and any corresponding
durations will appear missing in the listings.
9.1.3. Retests, Unscheduled Visits, and Early Termination Data
For by-visit analyses and summaries, efficacy, safety, HRQoL, and biomarker data 
(including scheduled, retests, unscheduled, and early termination) will be assigned to visits 
after the application of the windowing conventions described in Section 9.1.4  below. All 
measurements will be considered in summaries of abnormalities or worst-case values post-
Baseline. The visit windowing will be applied before missing data are imputed. Listings will 
include scheduled, unscheduled, retest, and early termination data.
9.1.4. Definition and Use of Visit Windows in Reporting
All scheduled study visits are defined relative to Study Day 1, the date of first dose. 
Scheduled visit windows are defined in Clinical Study Protocol APD334-210 Amendment 
2.0 Appendix 1: SCHEDULE OF ASSESSMENTS. A windowing convention will be used to 
determine the analysis visit value for a given measurement and will be applicable for all by-
visit summaries and analyses for efficacy and safety data. Refer to Table 9 below for specific 
visit windows.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 54
Table 9. Analysis Visit Windows for Efficacy and Safety Analyses
For all efficacy (except endoscopy/MMS/histology), efficacy-related biomarkers, safety labs and vital 
signs
Scheduled Study Visit (Protocol 
Scheduled Day)
Analysis Visit Window (Study Day)
Baseline 
≤1
Week 0 (Day 1)
1
Week 0 (Day 2)
2
Week 2 (Day 15 ± 3)
2 to 22, or 3 to 22 
Week 4 (Day 29 ± 3)
23 to 43
Week 8 (Day 57 ± 3)
44 to 71
Week 12 (Day 85 ± 7)
72 to 99
Week 16 (Day 113 ± 7)
100 to 141
Week 24 (Day 169 ± 7)
142 to 197
Week 32 (Day 225 ± 7)
198 to 253
Week 40 (Day 281 ± 7)
254 to 309
Week 48 (Day 337 ± 7)
310 to 351
Week 52 (Day 365 ± 14)
> 351
For endoscopy/MMS/histology/all composite endpoints that include an endoscopy component and/or
RB/SF component, Physician’s Global Assessment, health-related quality of life, ECGs, OCT, and PFT
Scheduled Study Visit (Protocol 
Scheduled Day)
Analysis Visit Window (Study Day)
Baseline 
≤ 1
Week 0 (Day 1)
1
Week 0 (Day 2)
2
Week 12 (Day 85 ± 7)$
66 to 113 (66 to 141 for assessments impacted by COVID-19 
pandemic, or impacted by the war in Ukraine) .
Week 32 (Day 225 ± 7) [PFT only]
198 to 253 (198 to 281 for assessments impacted by COVID-19 
pandemic, or impacted by the war in Ukraine) .
Week 52 (Day 365 ± 14) $
337 to 393 (337 to 421 for assessments impacted by COVID-19 
pandemic, or impacted by the war in Ukraine) .
a. Applicable only for participants who require extended monitoring on Day 2 for vital signs and ECGs.
b Applicable to all Week 12 and Week 52 efficacy endpoints based on any component of Mayo clinic score, such as 
clinical remission and symptomatic remission.
c Assessments impacted by the COVID 19 pandemic are reported in the Date of Visit eCRF. COVID-19, coronavirus 
disease 2019; ECG, electrocardiogram; eCRF, electronic case report form; MMS, modified Mayo Score; OCT, optical 
coherence tomography; PFT, pulmonary function test; RB, rectal bleeding; SF, stool frequency. Assessments impacted 
by the war in Ukraine are reported in the protocol deviation document.
For cardiac remonitoring upon treatment reinitiation after Day 2, as manifested by more than 
1 timed measurement in vital signs or electrocardiogram (ECG) parameters on the same 
collection date of an unscheduled visit, measurements will be mapped to analysis visit of 
Cardiac Remonitoring 1, Cardiac Remonitoring 2, etc. in the respective analysis dataset. For 
analysis, each timed measurement will be programmatically assigned to the nearest hourly 
timepoint (eg, Predose, 1-hour Postdose) based on their relationship to the dosing time on the 
same day. If the dosing date/time on the same day is missing, the timepoint will remain 
missing. Once mapped, these timed measurements from cardiac remonitoring visits will not 
be considered for any other analysis visit.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 55
Windowing will be applied prior to any missing data calculations. The last nonmissing
measurement taken prior to Day 1 (including unscheduled assessments) will be labeled as
“Baseline”. In the case where the last nonmissing measurement and the date of first
dose coincide and time is not collected, if the measurement was planned in the protocol to be
done prior to the date of first dose, that measurement will be labeled as “Baseline”, not 
“Week 0”. Unless stated otherwise, data from all visits including scheduled, unscheduled, 
and ET visits will be eligible for allocation to an analysis visit. The 2-Week and 4-Week 
Follow-Up visits will not be included in the visit windows and will be summarized separately 
without any window applied.
If two or more measurements for an endpoint fall in a same analysis visit window, the 
measurement with the date closest to the protocol scheduled visit day will be used in the 
analysis. If 2 measurements in the same analysis visit window are equidistant from the 
protocol scheduled visit day, the earlier one will be used in the analysis. If multiple 
measurements are available on the same day, then the average of the measurements will be 
used in the analysis, except for laboratory and ECG data where the assessment at the earliest 
time of the same day will be used. If both central and local assessments of the same ECG or 
lab test are available on the same day, the central result will take precedence over the local 
result.
For the overlapping visit windows at Week 12 and Week 8/16, a hierarchical algorithm will 
be applied as follows: always map to the Week 12 study visit if the study day falls within the 
visit window of the Week 12 study visit, then assess the other records for the Week 8 or 
Week 16 study visit. The same algorithm will be used for Week 48 and Week 52, with Week 
52 taking priority.
9.1.5. Partial Date Convention
Imputed dates will NOT be presented in the listings.
Table 10. Algorithm for Treatment Emergence of Adverse Events
Start Date  
    Stop Date  
  Action
Known 
Known, Partial, 
or Missing

If AE start date < study treatment first dose 
date, then not TEAE

If AE start date ≥ study treatment first dose 
date, then TEAE
Partial, but known components 
show that it cannot be on or after 
date of first dose of study
treatment
Known, Partial, 
or Missing
Not TEAE
Partial, could be on or after date 
of first dose of study treatment
Known

If AE stop date < study treatment first dose 
date, then not TEAE
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 56
Table 10. Algorithm for Treatment Emergence of Adverse Events
Start Date  
    Stop Date  
  Action

If AE stop date ≥ study treatment first dose 
date, then TEAE
Partial
Impute AE stop date as latest possible date (ie, last 
day of month if day unknown or 31st December if 
day and month are unknown), then:

If AE stop date < study treatment first dose 
date, then not TEAE

If AE stop date ≥ study treatment first dose 
date, then TEAE
Missing
Assumed TEAE
Table 11. Algorithm for Prior and Concomitant medications
Start Date  
    Stop Date  
  Action
Known
Known

If medication stop date < study treatment 
first dose date, assign as prior

If medication stop date ≥ study treatment 
first dose date, assign as concomitant
Partial
Impute stop date as latest possible date (ie, last day 
of month if day
unknown or 31st December if day and month are 
unknown), then:

If medication stop date < study treatment 
first dose date, assign as prior

If medication stop date ≥ study treatment 
first dose date, assign as concomitant
Missing
If medication stop date is missing could never be 
assumed a prior
medication, assign as concomitant
Partial
Known
Impute start date as earliest possible date (ie, first 
day of month if day unknown or 1st January if day 
and month are unknown), then:

If medication stop date < study treatment 
first dose date, assign as prior

If medication stop date ≥ study treatment 
first dose date, assign as concomitant
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 57
Table 11. Algorithm for Prior and Concomitant medications
Start Date  
    Stop Date  
  Action
Partial
Impute start date as earliest possible date (ie, first 
day of month if day unknown or 1st January if day 
and month are unknown) and impute stop date as 
latest possible date (ie, last day of month if day 
unknown or 31st December if day and month are 
unknown), then:

If medication stop date < study treatment 
first dose date, assign as prior.

If medication stop date ≥ study treatment 
first dose date, assign as concomitant
Missing
Impute start date as earliest possible date (ie, first 
day of month if day unknown or 1st January if day 
and month are unknown), then:
If medication stop date is missing could never be 
assumed a prior medication, assign as concomitant
Missing
Known

If medication stop date < study treatment 
first dose date, assign as prior

Else assign as concomitant
Partial
Impute stop date as latest possible date (ie, last day 
of month if day unknown or 31st December if day 
and month are unknown), then:

If medication stop date < study treatment 
first dose date, assign as prior

If medication stop date ≥ study treatment 
first dose date, assign as concomitant
Missing
Assign as concomitant
Table 12. Algorithm for Starting Date of Hospitalization and Start/Stop Dates of 
Concomitant Medication
Start Date  
    Stop Date  
  Action
Partial
Partial 
Impute start date as earliest possible date (ie, first 
day of month if day unknown or 1st January if day 
and month are unknown). Impute stop date to latest 
possible date (ie, last day of month if day unknown 
or 31st December if day and month are unknown).
No partial stop date imputation for hospitalization
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 58
Table 12. Algorithm for Starting Date of Hospitalization and Start/Stop Dates of 
Concomitant Medication
Start Date  
    Stop Date  
  Action
Missing
Missing
Impute start date as informed consent date. Impute 
stop date as last visit date when the concomitant 
medication timepoint is not ongoing. No missing 
stop date imputation for hospitalization.
9.1.6. Protocol Deviation Categories
Protocol deviation categories include but are not limited to the following:

Informed consent and Process

Inclusion criteria

Exclusion Criteria

Concomitant Medication

PK/PD

Laboratory Assessment

Study Procedures

Patient Reported Outcome

Safety

Efficacy

IP Administration

Visit Schedule

IP Conditions

Participant IP Compliance

Participant Discontinuation

Randomization

Administrative
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 59

Other
9.1.7. Hourly Timepoint Determination in Cardiac Analysis
Based on dosing date/time, the cardiac central laboratory divided the collection period into 
60-minute intervals (eg, from dosing time to dosing time + 60 minutes, from dosing time + 
60 minutes to dosing time + 120 minutes, etc.). In some cases, recording from a partial 
hourly interval was used to derive hourly data if the Holter recording end time didn’t 
coincide with a multiple of 60 minutes from dosing. For Holter recording data before dosing, 
per study design, each participant is expected to have one pre-dose Holter record with a 
duration of about 15 minutes. However, there may exist multiple pre-dose Holter records 
derived by the cardiac central laboratory for the same participant, based on every 60-minute 
increment backwards from dosing time until the overall Holter start time is reached. 
Similarly, pre-dose (eg, hour 0) data may be based on recording from a partial hourly 
interval, depending on Holter recording start/stop time relative to dosing. 
The hourly timepoint will be programmatically calculated as the Holter hourly data stop time 
minus dosing time, converted to hours and rounded to the nearest whole number. If there are 
more than 1 hourly timepoint from this derivation, the latter one will be assigned to the next 
whole hourly timepoint. This applies to both pre-dose and post-dose timepoints.
9.2. Endpoint Derivations
9.2.1. WPAI-UC Scoring Rules
The Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis (WPAI-
UC) questionnaire was developed to measure the effect of general health and symptom 
severity on work productivity and regular activities. The questionnaire includes the following 
questions.
Questions:
1 = Are you currently employed?
2 = During the past seven days, how many hours did you miss from work due to your 
problems associated
with UC?
3 = During the past seven days, how many hours did you miss from work because of any 
other reasons?
4 = During the past seven days, how many hours did you actually work?
5 = During the past seven days, how much did your UC affect your productivity while you 
were working?
6 = During the past seven days, how much did your UC affect your ability to do your regular 
daily activities, other than work at a job?
Derivation:
1) Calculate work time missed score as: Q2/(Q2 + Q4)
2) Calculate impairment while working score as: Q5/10
3) Calculate overall work impairment score as: Q2/(Q2 + Q4) + [(1 - Q2/(Q2 + Q4)) x 
(Q5/10)]
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 60
4) Calculate activity impairment score as: Q6/10
Multiply each score by 100 in order to express as percentages.
9.2.2. IBDQ Scoring Rules
The Inflammatory Bowel Disease Questionnaire (IBDQ) is a 32-item self-administered 
questionnaire which has 4 dimensions: Bowel symptoms (10 items), systemic symptoms (5 
items), emotional health (12 items), and social function (5 items). Responses are graded on a 
7-point Likert scale where 7 denotes “not a problem at all” and 1 denotes “a very severe
problem”. Scores range from 32 to 224, a higher score indicates better quality of life.
The 4 dimensions are defined as:

Bowel symptoms: Questions 1, 5, 9, 13, 17, 20, 22, 24, 26, 29

Systemic symptoms: Questions 2, 6, 10, 14, 18

Emotional health: Questions 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32

Social function: Questions 4, 8, 12, 16, 28
A IBDQ total score can also be calculated as the sum of all 32 items.
9.2.3. SF-36 Scoring Rules
The Medical Outcomes Study 36 Item Short Form Health Survey (SF-36) is a 36-item self-
administered questionnaire which has 8 scales: Physical functioning (10 items), role 
limitations due to physical health (4 items), role limitations due to emotional problems (3 
items), vitality (4 items), mental health (5 items), social functioning (2 items), bodily pain (2 
items), and general health (5 items). Each item response is scored from 0 to 100 and items in 
the same scale are averaged together to create 8 subscores. Scores range from 0 to 100. A 
higher score indicates a more favorable health state.
The 8 dimensions are defined as:

Physical functioning: Questions 3 to 12

Role limitations due to physical health: Questions 13 to 16

Role limitations due to emotional problems: Questions 17 to 19

Vitality: Questions 23, 27, 29, 31

Mental health: Questions 24 to 26, 28, 30

Social functioning: Questions 20, 32
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 61

Bodily Pain: Questions, 21, 22

General health: Questions 1, 33 to 36
9.3. Classification of Rescue Therapy
This appendix outlines the algorithm for the Pfizer clinical team/medical reviewers to 
classify rescue therapies for ulcerative colitis (UC) in a blinded manner. This will help 
establish intercurrent events for the efficacy estimands. All rescue therapies identified by the 
medical reviewers per the algorithm below will be imported in programming. This process 
will be repeated until database lock and the list of all rescue therapies identified will be 
finalized before study unblinding.
Only medications and medical procedures reported on the electronic case report forms 
(eCRFs) can be assessed whether they are rescue therapy for UC. If the exposure happens in 
the follow-up period (beginning on or after the date of last study treatment administration), 
then it would not be considered as a rescue therapy. Impact of rescue therapy use in the 
analysis is timing-dependent, eg, if a participant starts a rescue therapy between their Week 
12 and Week 52 endpoint assessments, then it may have potential impact on Week 52 
endpoint analysis but will have no impact on Week 12 endpoints. The rules outlined below 
apply to both new use and increase in dose from Baseline.
Biologics with immunomodulatory properties

Rule:

Any exposure after first dose

List of medications:

AntiTNFα antibodies:
−
ADALIMUMAB
−
CERTOLIZUMAB
−
CERTOLIZUMAB PEGOL
−
GOLIMUMAB
−
INFLIXIMAB

Other Biologics:
−
USTEKINUMAB
−
VEDOLIZUMAB
−
MIRIKIZUMAB
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 62
Nonbiologics with immunomodulatory properties

Immunosuppressants

Rules to consider for Week 12 efficacy endpoints:
−
After first dose and up to and including Week 8: any increase from baseline 
for more than 5 days
−
After Week 8: Any dose above baseline

Rules to consider for Week 52 efficacy endpoints:
−
After Week 12 and up to and including Week 40: any increase from baseline 
for more than 5 days
−
After Week 40: Any dose above baseline

List of medications:
−
Thiopurines
o
MERCAPTOPURINE
o
AZATHIOPRINE
−
TIOGUANINE
−
METHOTREXATE
−
METHOTREXATE SODIUM

5-ASA COMPOUNDS

Rules to consider for Week 12 efficacy endpoints:
−
After first dose and up to and including Week 8: any increase from baseline 
for more than 5 days
−
After Week 8: Any dose above baseline

Rules to consider for Week 52 efficacy endpoints:
−
After Week 12 and up to and including Week 40: any increase from baseline 
for more than 5 days
−
After Week 40: Any dose above baseline
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 63

List of medications:
−
MESALAZINE
−
MESALAMINE
−
BALSALAZIDE
−
BALSALAZIDE DISODIUM DIHYDRATE
−
BALSALAZIDE SODIUM
−
OLSALAZINE SODIUM
−
SULFASALAZINE
−
BECLOMETASONE W/MESALAZINE

Routes:
−
ORAL
−
RECTAL
Other small molecule immunomodulatory active agents

Rules to consider for Week 12 efficacy endpoints:
−
After first dose and up to and including Week 8: any increase from baseline 
(including new use) for more than 5 days
−
After Week 8: Any dose above baseline

Rules to consider for Week 52 efficacy endpoints:
−
After Week 12 and up to and including Week 40: any increase from baseline 
(including new use) for more than 5 days
−
After Week 40: Any dose above baseline

List of medications:
−
CICLOSPORIN
−
TACROLIMUS
−
TOFACITINIB
−
TOFACITINIB CITRATE
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 64
−
UPADACITINIB

Systemic glucocorticoids

Systemic glucocorticoids given via oral or rectal routes of administration
−
Rules to consider for Week 12 efficacy endpoints:
o
After first dose and up to and including Week 8: any increase from
baseline for more than 7 days
o
After Week 8: Any dose above baseline
−
Rules to consider for Week 52 efficacy endpoints:
o
After Week 12 and up to and including Week 40: any increase from 
baseline for more than 7 days
o
After Week 40: Any dose above baseline

List of medications:
o
BETAMETHASONE
o
BETAMETHASONE DIPROPIONATE
o
BETAMETHASONE SODIUM PHOSPHATE
o
DEXAMETHASONE
o
DEXAMETHASONE SODIUM PHOSPHATE
o
DEXAMETHASONE VALERATE
o
METHYLPREDNISOLONE
o
METHYLPREDNISOLONE SODIUM SUCCINATE
o
PREDNISOLONE
o
PREDNISOLONE SODIUM PHOSPHATE
o
PREDNISOLONE METASULFOBENZOATE SODIUM
o
PREDNISONE
o
TRIAMCINOLONE
o
HYDROCORTISONE
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 65
o
HYDROCORTISONE ACETATE
o
HYDROCORTISONE BUTYRATE
o
HYDROCORTISONE SODIUM SUCCINATE
−
Routes:
o
ORAL
o
RECTAL

Systemic given via parenteral routes of administration

Rule for Week 12 endpoint:
−
Any exposure after first dose up to Week 12

Rules for Week 52 endpoint:
−
After Week 12 and up to and including Week 40: more than one dose
−
Any exposure after Week 40

List of medications:
−
BETAMETHASONE
−
BETAMETHASONE DIPROPIONATE
−
BETAMETHASONE SODIUM PHOSPHATE
−
DEXAMETHASONE
−
DEXAMETHASONE SODIUM PHOSPHATE
−
DEXAMETHASONE VALERATE
−
METHYLPREDNISOLONE
−
METHYLPREDNISOLONE SODIUM SUCCINATE
−
PREDNISOLONE
−
PREDNISOLONE SODIUM PHOSPHATE
−
PREDNISOLONE METASULFOBENZOATE SODIUM
−
PREDNISONE
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 66
−
TRIAMCINOLONE
−
HYDROCORTISONE
−
HYDROCORTISONE ACETATE
−
HYDROCORTISONE BUTYRATE
−
HYDROCORTISONE SODIUM SUCCINATE

Routes:
−
INTRAVENOUS
−
INTRAMUSCULAR

Topical Glucocorticoids

Rules for Week 12 endpoints:
−
After first dose and up to and including Week 8: any exposure above baseline 
(or new use) for more than 5 days
−
After Week 8: Any dose above baseline

Rules for Week 52 endpoints:
−
After Week 12 and up to and including Week 40: any increase from baseline 
for more than 5 days
−
After Week 40 any increase above baseline

List of medications:
−
BUDESONIDE

Routes:
−
ORAL
−
RECTAL

Beclomethasone

Rules for Week 12 endpoints:
−
After first dose and up to and including Week 8: Any increase above baseline 
for more than 5 days
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 67
−
After Week 8: Any dose above baseline

Rules for Week 52 endpoints:
−
After Week 12 and up to and including Week 40: Any increase from baseline 
for more than 5 days
−
After Week 40 any increase above baseline

List of medications:
−
BECLOMETASONE
Medical procedures

Leukocyte apheresis, other apheresis, and plasma exchange

Rule:
−
Any exposure after first dose

List of medical procedures
−
APHERESIS
−
LEUKAPHERESIS
−
COLECTOMY (partial or total)
−
SIGMOIDECTOMY
−
COLOSTOMY
−
ILEOSTOMY
9.4. Programming Conventions for Outputs
OUTPUT CONVENTIONS
Outputs will be presented as shown in the Output shells.
DECIMALS, PERCENTAGES, AND P-VALUES

If the original data has N decimal places, then the summary statistics should have the
following decimal places:

Minimum and maximum: N

Mean (and LS Means), median: N + 1

SD or SE: N + 2
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 68

Percentages will be reported to one decimal place. Where counts are zero,
percentages will not appear in the output.

P-values will be reported to three decimal places, except values < 1.000 but > 0.999
will be presented as ‘> 0.999’ (eg, 0.9998 is presented as > 0.999).

Values < 0.001 will be presented as ‘< 0.001’ (eg, 0.0009 is presented as < 0.001).
Rounding will be applied after the < 0.001 and > 0.999 rule
CONVENTIONS RELATED TO PHARMACOKINETIC DATA
All etrasimod concentrations will be reported and analyzed with the same precision as the 
source data provided by the bioanalytical laboratory regardless of how many significant 
figures or decimals the data carry. The derived PK data (etrasimod concentration) will be 
rounded to carry 3 significant digits and considered the source data for the calculation of 
descriptive statistics and the statistical analysis source data.
For the reporting of descriptive statistics, the mean, geometric mean, median, SD, % CV, and 
% geometric CV will be presented with 4 significant digits. The minimum and maximum 
will be presented with 3 significant digits.
DATES AND TIMES
Depending on data available, dates and times will take the form DDMMMYYYY or 
DDMMMYYYY:hh:mm.
SPELLING FORMAT
English US.
PRESENTATION OF TREATMENT GROUPS
For outputs, treatment groups will be represented as follows and in that order:
Table 13. Treatment Group Display
Treatment Group 
For Tables, Figure, and Listings
Etrasimod  
Etrasimod  
Placebo  
Placebo  
Screen Failure  
Screen Failure  
Not Treated3
Not Treated
a. To be used for participants in safety listings who are randomized but do not receive study treatment.
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 69
PRESENTATION OF VISITS AND STUDY PERIOD
For outputs, visits and study periods will be represented as follows and in that order
Table 14. Visit and Study Period Display
Visit Name  
  Study Period
Screening
Screening
Baseline, Day 1, Week 2, Week 4, Week 8, Week 12, Week 
16, Week 20, Week 24, Week 32, Week 40, Week 48, and 
Week 52
Treatment
End of Study/Early Termination Dependent on
Dependent on Analysis Visit assigned, 
described in
Section 9.1.4
2-Week Follow-Up, 4-Week Follow-Up 
Follow-Up
LISTINGS
All listings will be ordered by the following, unless otherwise specified:

Randomized treatment group (or treatment received if it is a safety output), first by
Etrasimod, then Placebo, then Screen Failure and then No Treatment (only in safety
listings if there are any randomized participants who did not receive study treatment)

Participant number (which is expected to incorporate study site/center)

Date (where applicable)
9.5. Abbreviations
Table 15. List of Abbreviations
Abbreviation
Term
5-ASA
5-aminosalicylic acid
AE
adverse event
AESI 
adverse events of special interest
ALC 
absolute lymphocyte count
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST 
aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical
AV 
atrioventricular
β-hCG 
beta-human chorionic gonadotropin
BLQ 
below the limit of quantitation
BMI 
body mass index
Bpm
bpm beats per minute
CI 
confidence interval
CM 
concomitant medication
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 70
Table 15. List of Abbreviations
Abbreviation
Term
CMH 
Cochran-Mantel-Haenszel
COVID-19 
coronavirus disease 2019
CR 
copy reference
CRP 
C-reactive protein
CS 
clinically significant
CSR 
clinical study report
CTCAE 
Common Terminology Criteria for Adverse Events
Ctrough,ss 
average steady-state trough plasma concentration
CV 
coefficient of variation
DBP 
diastolic blood pressure
DLCO 
diffusing capacity of the lungs for carbon monoxide
EAIR 
exposure-adjusted incidence rate
ECG 
Electrocardiogram
eCRF  
electronic case report form
eDISH  
evaluation of drug-induced serious hepatotoxicity
EIM  
extraintestinal manifestation
ES  
endoscopic score
FAS  
Full Analysis Set
FCP  
fecal calprotectin
FCS  
fully conditional specification
FDA  
Food and Drug Administration
FEF  
forced expiratory flow
FEV1  
forced expiratory volume in 1 second
FVC  
forced vital capacity
GGT  
gamma-glutamyl transferase
HR heart rate
heart rate
HRQoL  
health-related quality of life
hs-CRP  
high-sensitivity C-reactive protein
IBDQ  
Inflammatory Bowel Disease Questionnaire
ICF  
informed consent form
JAK  
Janus kinase
LLQ  
lower limit of quantitation
LOESS  
locally estimated scatterplot smoothing
LS  
least squares
MAR  
missing at random
MCMC  
Markov Chain Monte Carlo
MedDRA 
Medical Dictionary for Regulatory Activities
mFAS 
modified Full Analysis Set
MMS 
modified Mayo score
MNAR 
missing not at random
NCS 
not clinically significant
NHI 
Nancy Histological Index
NRI 
nonresponder imputation
NRS 
numeric rating scale
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)


Protocol C5041011 (APD334-210) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 71
Table 15. List of Abbreviations
Abbreviation
Term
OCT 
optical coherence tomography
OLE 
open-label extension
PFT 
pulmonary function test
PAS
Primary Analysis Set
PGA 
Physician’s Global Assessment
PK
pharmacokinetics
PRES 
posterior reversible encephalopathy syndrome
PT 
preferred term
RB 
rectal bleeding
RHI 
Robarts Histopathology Index
RNA 
ribonucleic acid
SAE 
serious adverse event
SAP 
statistical analysis plan
SBP 
systolic blood pressure
SD 
standard deviation
SDTM 
Study Data Tabulation Model
SE 
standard error
SF 
stool frequency
SF-36 
Study 36-Item Short Form Health Survey
SI  
International System of Units
SOC  
system organ class
ss 
steady state
TB 
tuberculosis
TEAE  
treatment-emergent adverse event
TLC  
total lung capacity
TME  
targeted medical event
TMS 
total Mayo score
TNFα 
tumor necrosis factor alpha
UC  
ulcerative colitis
ULN  
upper limit of normal
ULQ  
upper limit of quantitation
USPI
United States Prescribing Information
WHO  
World Health Organization
WPAI-UC 
Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis
090177e1a14198db\Approved\Approved On: 25-Jul-2024 01:30 (GMT)