A Multicentre, Randomised, Double-blind (Sponsor Unblinded), Placebo-controlled Study With Open Label Extension to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2982772 in Subjects With Active Ulcerative Colitis
Phase: PHASE2
Conditions: Colitis, Ulcerative
Sponsor: GlaxoSmithKline

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
2 0 2 1 5 2
1
TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A m ultice ntre, ra n d o mise d, d o u ble- bli n d (s p o ns or -u n bli n de d), 
place b o -c o ntr olle d st u d y wit h o pe n la bel e xte nsi o n t o i n vesti gate 
t he safety a n d t olera bilit y, p har mac o ki netics, 
p har mac o d y n a mics, a n d efficac y of G S K 2 9 8 2 7 7 2 i n s u bjects 
wit h acti ve ulcerati ve c olitis.
C o m p o u n d N u m ber:
G S K 2 9 8 2 7 7 2
De vel o p me nt P h ase:
II
Effecti ve D ate:
2 0 -A P R - 2 0 1 7
Pr ot oc ol A me n d me nt N u m ber:  0 1
A ut h or (s):
 
Re visi o n C hr o n ol o g y
G l a x oS mit h K li ne
D oc u me nt N u m ber
D ate
Versi o n
2 0 1 5 N 2 5 1 7 5 8 _ 0 0
2 0 1 6 -M A Y - 2 3
Ori gi nal
2 0 1 5 N 2 5 1 7 5 8 _ 0 1
2 0 1 7 -A P R - 2 0
A me n d me nt N o. 1
C ha n ge i n d osi n g re gi me n fr o m 6 0 m g BI D t o 6 0 m g TI D , u p dates t o I ncl usi o n criteria 3 
a n d 6 a n d E xcl usi o n criteria 3, 9, 2 1 a n d 2 2, all o wa nce f or rescree ni n g , a n d a d diti o n of 
s uici dalit y st o p pi n g criteria pl us s o me mi n or pr ot oc ol clarificati o ns a n d a d mi nistrati ve 
c ha n ges.
C o p y ri g ht 2 0 1 7 t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All ri g hts reser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.
 
P P D
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

 
P P D
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
P P D

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3
M E DI C A L M O NI T O R/ S P O N S O R I N F O R M A T I O N P AG E
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n: 
R ol e
N a m e
D ay Ti m e P h o n e N u m b er a n d 
e m ail a d dr ess
Aft er -
h o urs 
P h o n e/ C el
l/
P a g er 
N u m b er
F ax 
N u m b e
r
Sit e A d dr ess
Pri m ary 
M e dic al 
M o nit or 
 
T el e p h o n e : 
E m ail: 
M o bil e:  
 
 
N A
G S K 
St ockl ey 
P ark W est, 
1- 3 
Ir o n bri d g e 
R o a d, 
Ux bri d g e ,
Mi d dl es ex, 
U B 1 1 1 B T, 
U K
S ec o n d ary 
M e dic al 
M o nit or
 
M o bil e:  
E m ail:  
M o bil e: 
 N A
1 2 5 0 S. 
C oll e g evill e 
R o a d, 
C oll e g evill e, 
P A  1 9 4 2 6 
U S A
S A E 
c o nt act  
i nf or m ati o n 
M e dic al 
M o nit or as 
a b ov e
S p o ns or Le g al Re gistere d A d dress: 
Gla x o S mit h Kli ne Researc h & De vel o p me nt Li mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y be t he l ocal Gla x o S mit h Kli ne Affiliate 
C o m pa n y  ( or desi g nee). If a p plica ble, t he details of t he alter nati ve S p o ns or a n d c o ntact 
pers o n i n t he territ or y  will be pr o vi de d t o t he rele va nt re g ulat or y a ut h orit y as part of t he 
cli nical trial a p plicati o n.   
Re g ulat or y  A ge nc y Ide ntif y i n g N u m ber(s): I N D 1 2 9, 7 6 6; E u dra C T 2 0 1 6-0 0 1 8 3 3 - 2 9
 
P P D
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
P P D
P P D
P P D
P P
D
P P D
P P D
P P D

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4
I N V E S TI G AT O R P R O T O C O L A G R E E M E N T P A G E
F or pr ot oc ol n u m ber 2 0 2 1 5 2
I c o nfir m a gree me nt t o 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, as a me n de d b y 
t his pr ot oc ol a me n d me nt.
I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y  c o n d uct. I a gree t o pers o nall y 
c o n d uct or s u per vise t he descri be d st u d y.
I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m pl o y ees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or me d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure t hat site 
staff recei ves t he a p pr o priate i nf or mati o n t hr o u g h o ut t he st u d y. 
I n vesti gat or Na me:
I n vesti gat or A d dress:
I n vesti gat or P h o ne N u m ber:
I n vesti gat or Si g nat ure
Date
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5
T A B L E O F C O N T E N T S
P A G E
1.
P R O T O C O L S Y N O P SI S F O R S T U D Y 2 0 2 1 5 2 ........................................................8
2.
I N T R O D U C TI O N....................................................................................................1 3
2. 1.
St u d y R ati o n al e ..........................................................................................1 3
2. 2.
Bri ef B a c k gr o u n d ........................................................................................1 4
3.
O B J E C TI V E( S) A N D E N D P OI N T( S) ......................................................................1 5
4.
S T U D Y D E SI G N ....................................................................................................1 7
4. 1.
O v er all D e si g n ............................................................................................1 7
4. 2.
Tr e at m e nt Ar m s a n d D ur ati o n .....................................................................1 8
4. 2. 1.
S cr e e ni n g ....................................................................................1 8
4. 2. 2.
Tr e at m e nt P eri o d .........................................................................1 8
4. 2. 3.
F oll o w -u p P eri o d ..........................................................................1 9
4. 3.
T y p e a n d N u m b er of S u bj e ct s .....................................................................1 9
4. 4.
D e si g n J u stifi c ati o n .....................................................................................1 9
4. 5.
D o s e J u stifi c ati o n ........................................................................................2 0
4. 6.
B e n efit: Ri s k A s s e s s m e nt ............................................................................2 1
4. 6. 1.
Ri s k A s s e s s m e nt .........................................................................2 2
4. 6. 2.
B e n efit A s s e s s m e nt .....................................................................2 7
4. 6. 3.
O v er all B e n efit: Ri s k C o n cl u si o n ...................................................2 7
5.
S E L E C TI O N O F S T U D Y P O P U L A TI O N A N D WI T H D R A W A L C RI T E RI A .............2 7
5. 1.
I n cl u si o n Crit eri a.........................................................................................2 7
5. 2.
E x cl u si o n Crit eri a ........................................................................................3 0
5. 3.
S cr e e ni n g/ B a s eli n e/ R u n -i n F ail ur e s............................................................3 2
5. 4.
Wi t h dr a w al/ St o p pi n g Crit eri a.......................................................................3 3
5. 4. 1.
I n di vi d u al S af et y St o p pi n g Crit eri a...............................................3 4
5. 4. 2.  
Gr o u p S af et y St o p pi n g Crit eri a ....................................................3 4
5. 4. 3.
Li v er C h e mi str y St o p pi n g Crit eri a ................................................3 4
5. 4. 3. 1.
St u d y Tr e at m e nt R e st art or R e c h all e n g e ....................3 5
5. 4. 4.
Q T c St o p pi n g Crit eri a ..................................................................3 5
5. 4. 5.
H a e m at ol o gi c St o p pi n g Crit eri a ...................................................3 6
5. 5.
S u bj e ct a n d St u d y C o m pl eti o n ....................................................................3 6
6.
S T U D Y T R E A T M E N T ............................................................................................3 6
6. 1.
I n v e sti g ati o n al Pr o d u ct a n d Ot h er St u d y Tr e at m e nt....................................3 6
6. 2.
Tr e at m e nt A s si g n m e nt ................................................................................3 7
6. 3.
Pl a n n e d D o s e A dj u st m e nt s .........................................................................3 7
6. 4.
Bli n di n g .......................................................................................................3 8
6. 5.
P a c k a gi n g a n d L a b eli n g ..............................................................................3 8
6. 6.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y ..............................................3 9
6. 7.
C o m pli a n c e wit h St u d y Tr e at m e nt A d mi ni st r ati o n .......................................3 9
6. 8.
Tr e at m e nt of St u d y Tr e at m e nt O v er d o s e ....................................................3 9
6. 9.
Tr e at m e nt aft er t h e E n d of t h e St u d y ..........................................................4 0
6. 1 0.
Lif e st yl e a n d/ or Di et ar y R e stri cti o n s ............................................................4 0
6. 1 0. 1.
A cti vit y .........................................................................................4 0
6. 1 1.
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ....................................4 0
6. 1 1. 1.
P er mitt e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ..........................4 0
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6
6. 1 1. 2.
Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s .........................4 1
7.
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 2
7. 1.
Ti m e a n d E v e nt s T a bl e ...............................................................................4 4
7. 2.
S cr e e ni n g a n d Criti c al B a s eli n e A s s e s s m e nt s ............................................4 8
7. 3. 
S af et y .........................................................................................................4 8
7. 3. 1.
A d v er s e E v e nt s ( A E) a n d S eri o u s A d v er s e E v e nt s ( S A E s) ..........4 8
7. 3. 1. 1.
Ti m e p eri o d a n d Fr e q u e n c y f or c oll e cti n g A E 
a n d S A E i nf or m ati o n ...................................................4 8
7. 3. 1. 2.
M et h o d of D et e cti n g A E s a n d S A E s ...........................4 9
7. 3. 1. 3.
F oll o w -u p of A E s a n d S A E s ........................................4 9
7. 3. 1. 4.
C ar di o v a s c ul ar a n d D e at h E v e nt s ..............................4 9
7. 3. 1. 5.
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s ............5 0
7. 3. 2.
Pr e g n a n c y ...................................................................................5 0
7. 3. 3.
P h y si c al E x a m s ...........................................................................5 0
7. 3. 4.
Vit al Si g n s ....................................................................................5 1
7. 3. 5.
El e ctr o c ar di o gr a m ( E C G) .............................................................5 1
7. 3. 6.
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s ......................................5 1
7. 3. 7.
S ui ci d al Ri s k M o nit ori n g ...............................................................5 3
7. 4.
Effi c a c y .......................................................................................................5 3
7. 4. 1.
P ati e nt R e p ort e d O ut c o m e s .........................................................5 3
7. 4. 1. 1.
I nfl a m m at or y B o w el Di s e a s e Q u e sti o n n air e 
(I B D Q)........................................................................5 3
7. 4. 2.
Cli ni c al Di s e a s e A s s e s s m e nt s .....................................................5 4
7. 4. 2. 1.
M a y o S c or e ................................................................5 4
7. 4. 2. 2.
Ul c er ati v e C oliti s E n d o s c o pi c I n d e x of S e v erit y 
( U C EI S)......................................................................5 5
7. 4. 3.  
Hi st ol o gi c al Di s e a s e A s s e s s m e nt s ...............................................5 6
7. 4. 3. 1.
G e b o e s I n d e x .............................................................5 6
7. 4. 3. 2.
M o difi e d Ril e y S c or e ( M R S)
.......................................5 7
7. 5.
P h ar m a c o ki n eti c s .......................................................................................5 8
7. 5. 1.
Bl o o d S a m pl e C oll e cti o n ..............................................................5 8
7. 5. 2.
S a m pl e A n al y si s ..........................................................................5 8
7. 5. 3.
C ol o n Ti s s u e Bi o p s y f or P h ar m a c o ki n eti c A s s a y .........................5 8
7. 5. 4.
S a m pl e A n al y si s ..........................................................................5 9
7. 6.
Bi o m ar k er( s)/ P h ar m a c o d y n a mi c Bi o m ar k er s ..............................................5 9
7. 6. 1.
C R e a cti v e Pr ot ei n ( C R P) ............................................................5 9
7. 6. 2.
F a e c al C al pr ot e cti n ( F C P) ...........................................................5 9
7. 6. 3.
Ti s s u e Bi o p s y ..............................................................................5 9
7. 6. 4.
N o v el P h ar m a c o d y n a mi c Bi o m ar k er s ..........................................6 0
7. 6. 4. 1.
RI P 1 T ar g et E n g a g e m e nt i n Bl o o d .............................6 0
7. 6. 4. 2.
RI P 1 T ar g et E n g a g e m e nt i n Bi o p s y Ti s s u e .................6 0
7. 6. 4. 3.
P at h w a y Bi o m ar k er s i n Bi o p s y Ti s s u e ........................6 0
7. 6. 5.
E x pl or at or y N o v el Bi o m ar k er s ......................................................6 0
7. 7.
G e n eti c s .....................................................................................................6 1
8.
D A T A M A N A G E M E N T ...........................................................................................6 1
9.
S T A TI S TI C A L C O N SI D E R A TI O N S A N D D A T A A N A L Y S E S .................................6 1
9. 1.
S a m pl e Si z e C o n si d er ati o n s .......................................................................6 1
9. 1. 1.
S a m pl e Si z e A s s u m pti o n s ...........................................................6 1
9. 1. 2.
S a m pl e Si z e S e n siti vit y ................................................................6 3
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7
9. 1. 3.
S a m pl e Si z e R e -e sti m ati o n or A dj u st m e nt ...................................6 3
9. 2.
D at a A n al y si s C o n si d er ati o n s .....................................................................6 3
9. 2. 1.
A n al y si s P o p ul ati o n s ....................................................................6 3
9. 2. 2.
I nt eri m A n al y si s ...........................................................................6 4
9. 3.
K e y El e m e nt s of A n al y si s Pl a n ...................................................................6 4
9. 3. 1.
Pri m ar y A n al y s e s .........................................................................6 4
9. 3. 2.
S e c o n d ar y A n al y s e s ....................................................................6 5
9. 3. 3.
Ot h er A n al y s e s ............................................................................6 5
9. 3. 3. 1.
E x pl or at or y A n al y s e s ..................................................6 5
1 0.
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S ........................................................6 6
1 0. 1.
P o sti n g of I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al R e gi st er s ............6 6
1 0. 2.
R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d 
C o n s e nt Pr o c e s s ........................................................................................6 6
1 0. 3.
Q u alit y C o ntr ol ( St u d y M o nit ori n g) ..............................................................6 6
1 0. 4.
Q u alit y A s s ur a n c e .......................................................................................6 7
1 0. 5.
St u d y a n d Sit e Cl o s ur e ...............................................................................6 7
1 0. 6.
R e c or d s R et e nti o n ......................................................................................6 8
1 0. 7.
Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s, P o sti n g of I nf or m ati o n 
o n P u bli c all y A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d P u bli c ati o n .................6 8
1 1.
R E F E R E N C E S .......................................................................................................7 0
1 2.
A P P E N DI C E S ........................................................................................................7 3
1 2. 1.
A p p e n di x 1 – A b br e vi ati o n s a n d Tr a d e m ar k s ...............................................7 3
1 2. 2.
A p p e n di x 2: Li v er S af et y R e q uir e d A cti o n s a n d F oll o w u p 
A s s e s s m e nt s ..............................................................................................7 7
1 2. 3.
A p p e n di x 3: Pr e d ni s ol o n e a n d 5 -A S A E q ui v al e nt D o s e T a bl e s ...................7 9
1 2. 4.
A p p e n di x 4 - G e n eti c R e s e ar c h ...................................................................8 0
1 2. 5.
A p p e n di x 5: D efi niti o n of a n d Pr o c e d ur e s f or R e c or di n g, E v al u ati n g, 
F oll o w -U p a n d R e p orti n g of A d v er s e E v e nt s ...............................................8 4
1 2. 5. 1.
D efi niti o n of A d v er s e E v e nt s ........................................................8 4
1 2. 5. 2.
D efi niti o n of S eri o u s A d v er s e E v e nt s ...........................................8 5
1 2. 5. 3.
D efi niti o n of C ar di o v a s c ul ar E v e nt s .............................................8 7
1 2. 5. 4.
R e c or di n g of A E s a n d S A E s ........................................................8 7
1 2. 5. 5.
E v al u ati n g A E s a n d S A E s ............................................................8 8
1 2. 5. 6.
R e p orti n g of S A E s t o G S K ...........................................................8 9
1 2. 6.
A p p e n di x 6: M o difi e d Li st of Hi g hl y Eff e cti v e M et h o d s f or A v oi di n g 
Pr e g n a n c y i n F R P a n d C oll e cti o n of Pr e g n a n c y I nf or m ati o n .......................9 0
1 2. 6. 1.
M o difi e d Li st of Hi g hl y Eff e cti v e M et h o d s f or A v oi di n g 
Pr e g n a n c y i n F e m al e s of R e pr o d u cti v e P ot e nti al ( F R P) ..............9 0
1 2. 6. 2.  
C oll e cti o n of Pr e g n a n c y I nf or m ati o n ............................................9 1
1 2. 7.
A p p e n di x 7:  Pr ot o c ol A m e n d m e nt C h a n g e s ...............................................9 3
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8
1.
P R O T O C O L S Y N O P SI S F O R S T U D Y 2 0 2 1 5 2
R ati o n al e
T his st u d y  is t he first e x perie nce wit h G S K 2 9 8 2 7 7 2, a rece pt or-i nteracti n g pr otei n- 1 
( RIP 1) ki nase i n hi bit or, i n s u bjects wit h acti ve ulcerati ve c olitis ( U C).
T he pri mar y o bjecti ve of t his st u d y has n ot c ha n ge d wit h a me n d me nt 0 1 ; h o we ver t he 
d osi n g re gi me n d oes c ha n ge t o G S K 2 9 8 2 7 7 2 ( 6 0 m g t hree ti mes dail y f or b ot h Parts A 
a n d B).
T he pri mar y  o bjecti ve will be t o i n vesti gate t he safet y a n d t olera bilit y of re peat oral d oses 
of G S K 2 9 8 2 7 7 2 6 0 m g or place b o t hree ti mes dail y  f or 4 2 da ys ( Part A) f oll o we d b y 
o pe n la bel wit h G S K 2 9 8 7 7 2 6 0 m g t hree ti mes dail y  f or 4 2 da ys ( Part B). I n a d diti o n t o 
p har mac o ki netics ( P K), a n u m ber of e x peri me ntal a n d cli nical e n d p oi nts will be 
e m pl o ye d t o o btai n i nf or mati o n o n t he p har mac o d y na mics ( P D), a n d preli mi nar y  efficac y 
i n s u bjects wit h acti ve U C. Alt h o u g h n o f or mal h y p ot hesis will be teste d, t hese e n d p oi nts 
will e na ble a br oa der u n dersta n di n g of t he mec ha nis m of acti o n a n d p ote ntial f or cli nical 
efficac y of G S K 2 9 8 2 7 7 2 i n U C, b y ma ki n g f ull use of t he i nf or mati o n o btai ne d fr o m 
eac h s u bject e nr olle d.
O bj e cti v e( s)/ E n d p oi nt( s)
O bj e cti v e s
E n d p oi nt s
Pri m ar y

T o i nv esti g at e t h e s af ety a n d t ol er a bility 
of 6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

A dv ers e ev e nts.

Cli nic al l a b or at ory v al u es (cli nic al 
c h e mistry, h a e m at ol o gy a n d uri n alysis).

Vit al si g n m e as ur e m e nts ( bl o o d pr ess ur e, 
h e art r at e, r es pir at ory r at e, a n d b o dy 
t e m p er at ur e).

1 2 -L e a d E C G m o nit ori n g.
S e c o n d ar y

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g m uc os al 
h e ali n g aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
a n a bs ol ut e M ay o e n d osc o py s u bsc or e 
of 0 or 1 at D ays 4 3 ( W e ek 6) a n d 8 5 
( W e ek 1 2).

C h a n g e fr o m b as eli n e i n m uc os al 
a p p e ar a nc e d et er mi n e d by Ulc er ativ e 
C olitis E n d osc o pic I n d ex of S ev erity 
( U C EI S).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
bi o m ark ers of dis e as e activity i n s u bj ects 
wit h activ e ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n m ark ers w hic h 
m ay i ncl u d e, b ut ar e n ot li mit e d t o, m e a n 
C R P a n d f a ec al c al pr ot ecti n ( F C P).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 

C h a n g e fr o m b as eli n e i n hist ol o gic 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9
O bj e cti v e s
E n d p oi nt s
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
hist ol o gic dis e as e activity i n s u bj ects 
wit h activ e ulc er ativ e c olitis.
s ev erity, i ncl u di n g b ut n ot li mit e d t o 
M o difi e d Ril ey Sc or e a n d G e b o es I n d ex.

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 i n 
ac hi evi n g cli nic al r es p o ns e a n d 
r e missi o n aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r es p o ns e d efi n e d as r e d ucti o n by 
≥3 p oi nts or ≥3 0 % i m pr ov e m e nt fr o m 
b as eli n e c o m pl et e M ay o sc or e, al o n g 
wit h a d ecr e as e i n t h e r ect al bl e e di n g 
sc or e of ≥1 p oi nt, at D ays 4 3 ( W e ek 6) 
a n d 8 5 ( W e ek 1 2).

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r e missi o n d efi n e d as a c o m pl et e 
M ay o sc or e of 2 p oi nts or l o w er, wit h n o 
i n divi d u al s u bsc or e exc e e di n g 1 p oi nt, at 
D ays 4 3 ( W e ek 6) a n d 8 5 ( W e ek 1 2).

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g sy m pt o m atic 
cli nic al r e missi o n aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n p arti a l M ay o 
sc or e.

T o i nv esti g at e t h e pl as m a c o nc e ntr ati o ns 
of G S K 2 9 8 2 7 7 2 f oll o wi n g 6 0 m g t hr e e 
ti m es d aily i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

Pr e- d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 at D ay 4 3 ( W e ek 6). 

P ost -d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 o n D ays 1 a n d 4 3 ( W e ek 
6) at 1, 2, 4 a n d 6 h o urs.

Tr o u g h c o nc e ntr ati o ns o n D ay 8 5 ( W e ek 
1 2).
E x pl or at or y

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 2 2 o n 
ex pr essi o n of i nfl a m m at ory bi o m ark ers i n 
m uc os al tiss u e bi o psi es i n s u bj ects wit h 
activ e ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n i nfl a m m at ory 
m ark ers w hic h m ay i ncl u d e, b ut ar e n ot 
li mit e d t o I L- 1, I L- 6, I L-8, M M P 3, T N F α, 
I F Nγ.

T o i nv esti g at e p at h w ay a n d t ar g et 
e n g a g e m e nt f oll o wi n g 6 0 m g t hr e e ti m es 
d aily d os es of G S K 2 9 8 2 7 7 2 i n bl o o d a n d 
c ol o n bi o psy tiss u e.

P h ar m ac ol o gy bi o m ark er e n d p oi nts m ay 
i ncl u d e, b ut ar e n ot li mit e d t o t h e 
f oll o wi n g, pr e-d os e at D ays 1, 4 3 ( W e ek 
6) a n d tr o u g h o n D ay 8 5 ( W e ek 1 2), as 
a p plic a bl e a n d if ev al u a bl e s a m pl es a n d 
d at a p er mit:
o
T ar g et E n g a g e m e nt Ass ay RI P 1 
( T E A R 1) i n bl o o d a n d c ol o n 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0
O bj e cti v e s
E n d p oi nt s
tiss u e.
o
P h os p h oryl at e d or t ot al RI P 1, 
M L K L, RI P 3, cl e av e d a n d t ot al 
c as p as e 3 a n d c as p as e 8 
si g n at ur es i n c ol o n tiss u e.

T o i nv esti g at e t h e c o nc e ntr ati o n of 
G S K 2 9 8 2 7 7 2 a n d p ossi bl e dr u g -r el at e d 
m at eri al, as w ell as s p ecific distri b uti o n 
wit hi n tiss u e if f e asi bl e, i n t h e c ol o n 
tiss u e aft er 6 0 m g t hr e e ti m es d aily 
d os es of G S K 2 9 8 2 7 7 2.

Pr e- d os e G S K 2 9 8 2 7 7 2 a n d p ossi bl e 
dr u g -r el at e d m at eri al c o nc e ntr ati o ns, as 
w ell as s p ecific distri b uti o n wit hi n tiss u e 
if f e asi bl e, i n c ol o n bi o psi es at D ays 4 3 
( W e ek 6) a n d 8 5 ( W e ek 1 2), as 
ev al u a bl e s a m pl es a n d d at a p er mit.

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
q u ality of lif e i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n I nfl a m m at ory 
B o w el Dis e as e Q u esti o n n air e (I B D Q).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
g e n e ex pr essi o n i n t h e bl o o d s u bj ects 
wit h activ e ulc er ativ e c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol at e d fr o m bl o o dD ays 1 a n d 4 3 
( W e ek 6) a n d tr o u g h o n D ay 8 5 ( W e ek 
1 2).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
g e n e ex pr essi o n i n c ol o n tiss u e bi o psi es 
i n s u bj ects wit h activ e ulc er ativ e c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol ate d fr o m c ol o n tiss u e bi o psi es at 
Scr e e ni n g, a n d D ays 4 3 ( W e ek 6) a n d 
tr o u g h o n D ay 8 5 ( W e ek 1 2).
O v er all D e si g n
T his is a m ultice ntre, ra n d o mize d, d o u ble -bli n d (s p o ns or -u n bli n de d), place b o -c o ntr olle d 
( Part A) st u dy wit h a n o pe n la bel e xte nsi o n ( Part B) t o i n vesti gate t he safet y  a n d 
t olera bilit y, P K, P D, a n d preli mi nar y efficac y of G S K 2 9 8 2 7 7 2 i n s u bjects wit h acti ve 
U C.  T he st u d y  desi g n sc he matic is de picte d i n Fi g ure 1 bel o w.
Fi g ur e 1
St u d y  O v er vi e w
A me n d me nt 0 1:
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 1
Pri or t o a me n d me nt 0 1:
K e y a s s e s s m e nt s:
S af et y a s s e s s m e nt s, P K s a m pl e s, M a y o s c or e, M o difi e d 
Ril e y S c or e, G e b o e s I n d e x,  I B D Q, P D s a m pl e s
Tr e at m e nt A r m s a n d D ur ati o n
Eac h s u bject will partici pate i n t he st u d y  f or a p pr o xi matel y 2 0 wee ks.  T his i ncl u des a 
scree ni n g peri o d u p t o 3 0 da ys, a n 8 4 da y ( 1 2 wee k) treat me nt peri o d, a n d a 2 8 da y 
f oll o w-u p peri o d after t he last d ose.
Wit hi n 3 0 da y s of t he scree ni n g visit ( defi ne d as da y of c o nse nt si g ni n g), s u bjects w h o 
are eli gi ble will e nter t he 2 -part treat me nt peri o d ( Part A a n d Part B) a n d start treat me nt 
( or d osi n g) o n Da y 1.  
T he F oll o w -u p Peri o d is 2 8 da y s ( 4 wee ks) l o n g.  
Part A:  A p pr o xi matel y  3 6 s u bjects w h o ha ve c o m plete d scree ni n g assess me nts a n d are 
eli gi ble will be ra n d o mize d i n a 2: 1 rati o (acti ve t o place b o) t o o ne of t he f oll o wi n g st u d y  
treat me nts f or 4 2 da ys:
G S K 2 9 8 2 7 7 2 6 0 m g t hree ti mes dail y  ( TI D) 
Place b o t hree ti mes dail y ( T I D) 
Part B:  Is a 6 wee k o pe n la bel e xte nsi o n w here all s u bjects w h o ha ve c o m plete d Part A 
will recei ve 6 0 m g G S K 2 9 8 2 7 7 2 t hree ti mes dail y ( TI D) f or 4 2 da ys.
Pri or t o a me n d me nt 0 1 bei n g effe cti ve i n eac h c o u ntr y, s u bjects ha ve bee n ra n d o mise d i n 
a 2: 1 rati o (acti ve t o place b o) t o o ne of t he f oll o wi n g treat me nts f or Part A:
G S K 2 9 8 2 7 7 2 6 0 m g t w o ti mes dail y ( BI D) x 4 2 da ys
Place b o t w o ti mes dail y ( BI D) x 4 2 da ys
Part B:  A 6 wee k o pe n la bel e xt e nsi o n w here all s u bjects w h o ha ve c o m plete d Part A 
recei ve d 6 0 m g G S K 2 9 8 2 7 7 2 t w o ti mes dail y ( BI D) f or 4 2 da ys.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 2
T y p e a n d N u m b er of S u bj e ct s
A s ufficie nt n u m ber of s u bjects will be scree ne d s o t hat a p pr o xi matel y  3 0 -3 6 s u bjects 
wit h acti ve U C will be ra n d o m ise d i nt o t he st u d y o n a TI D re gi me n. Pri or t o pr ot oc ol 
a me n d me nt 0 1 bei n g a p pr o ve d i n eac h c o u ntr y , n o m ore t ha n 1 8 s u bjects will be 
ra n d o mise d i nt o t he st u d y o n a BI D re gi me n. S h o ul d t he dr o p o ut rate i n Part A [ Da y 1 
t hr o u g h 4 3 ( Wee k 6)] be hi g her t ha n a ntici pate d, or t he sa m ple size re vie w warra nts a n 
i ncrease i n ra n d o mise d s u bjects, a d diti o nal or re place me nt s u bjects ma y be ra n d o mise d 
( u p t o an o verall t otal ma xi m u m of 6 0 ) i nt o t he st u d y at t he discreti o n of t he S p o ns or.  
S u bjects w h o disc o nti n ue parti ci pati o n d uri n g t he o pe n la bel p hase i n Part B [( Da y  4 3 
( Wee k 6) t hr o u g h Da y 8 5 ( Wee k 1 2)] will n ot be re place d.
A n al y si s
T he safet y a n d t olera bilit y of G S K 2 9 8 2 7 7 2 f oll o wi n g 6 a n d 1 2 wee ks of treat me nt will 
be base d o n s u m maries of a d verse e ve nts, cli nical la b orat or y val ues, vital si g n 
meas ure me nts a n d 1 2 -lea d E C G m o nit ori n g.
T w o i nteri m a nal ys es are pla n ne d.  T he first I nteri m A nal y sis will be c o n d ucte d o n t he 
rec o m me n dati o n of t he Data Re vie w C o m mittee t o assess f utilit y base d o n 6 wee ks of 
treat me nt, or w he n a n a p pr o priate n u m ber ha ve c o m plete d 6 wee ks of treat me nt, 
w hic he ver is earliest.  T he p ur p ose of t he I nteri m A nal y sis w o ul d be t o assess w het her t o 
st o p t he st u d y f or f utilit y a n d, if a p pr o priate, t o perf or m a sa m ple size re-esti mati o n.  T his 
i nteri m a nal ysis ma y als o facilitate decisi o n ma ki n g re gar di n g t he s u bse q ue nt cli nical 
de vel o p me nt of G S K 2 9 8 2 7 7 2 f or U C.
I nteri m A nalys is # 2 will occ ur w he n a n a p pr o priate n u m ber ha ve c o m plete d 1 2 wee ks of 
treat me nt.  T he p ur p ose of t he I nteri m A nalys is will be to assess w het her t o st o p t he 
st u d y f or f utilit y.  T his i nteri m a nalys is ma y als o facilitate decisi o n ma ki n g re gar di n g t he 
s u bse q ue nt cli nical de vel o p me nt of G S K 2 9 8 2 7 7 2 f or U C. 
O n g oi n g re vie ws of a vaila ble efficac y , p har mac o d yna mic a n d mec ha nistic e n d p oi nt s will 
be c o n d ucte d d uri n g t he st u d y  b y a Data Re vie w C o m mittee ( D R C), c o nsisti n g of a 
li mite d n u m ber of Gla x o S mit h Kli ne ( G S K) i n di vi d uals, s o me of w h o are als o me m bers 
of t he G S K st u d y  tea m w h o are n ot i n v ol ve d wit h t he da y-t o-d a y  r u n ni n g of t he st u d y.  
T he pri mar y  p ur p ose of t hese re vie ws is t o m o nit or m uc osal heali n g rates a n d a n y 
a vaila ble tar get e n ga ge me nt a n d i nfla m mat or y  bi o mar ker data f or i nter nal decisi o n 
ma ki n g.
A data re vie w c harter will o utli ne i n detail t he acti vities of t he i nf or mal re vie ws a n d t he 
i nteri m a nal yses, f utilit y criteria, a n d h o w t he i nte grity of t he st u d y will be mai ntai ne d.
Safet y  data c ollecte d i n Part A a n d Part B of t he st u d y will be c o m bi ne d a n d s u m marise d 
acc or di n g t o treat me nt recei ve d f or t he first si x wee ks of treat me nt a n d o verall.  Efficac y, 
P D a n d bi o mar ker data will be s u m marise d f or Part A, a n d s u p p orti n g s u m maries a n d 
a nal ys es, as a p pr o priate, will be s u m marise d f or Part A a n d Part B c o m bi ne d acc or di n g t o 
treat me nt recei ve d.  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 3
C o m paris o ns bet wee n treat me nt gr o u ps i n Part A o n a n y  c ha n ges o bser ve d will be 
c o n d ucte d f or t he sec o n dar y  e n d p oi nts if dee me d a p pr o priate, e. g. c ha n ges i n t he mea n 
tar get e n ga ge me nt a n d c ha n ges i n i nfla m mat or y mar kers will be statisticall y  a nalyz e d 
usi n g a Mi xe d -effect M o del Re peat Meas ure me nt s (M M R M) c o m pari n g G S K 2 9 8 2 7 7 2 
wit h place b o at eac h ti me p oi nt. T he pr o p orti o n of s u bjects ac hie vi n g Ma y o E n d osc o p y  
Re missi o n ( Sc ores of 0 or 1), will be statisticall y  a nal yse d usi n g a Ge neralise Esti mati n g 
E q uati o ns ( G E E) m o del c o m pari n g G S K 2 9 8 2 7 7 2 wit h pl ace b o at eac h ti me p oi nt if 
a p pr o priate. Si milar a nal y ses will be c o n d ucte d f or ot her sec o n dar y e n d p oi nts if dee me d 
a p pr o priate.
T he relati o ns hi p bet wee n eac h of t he mec ha nistic e n d p oi nts a n d als o wit h t he cli nical 
e n d p oi nts ma y als o be gra p hically prese nt e d a n d a nal yse d usi n g a n a p pr o priate statistical 
m o del i de ntif y i n g a ny tre n ds. T he m o del will deter mi ne w het her t he mec ha nistic effect 
si g nifica ntly e x plai ns or pre dicts t he effect o n t he ot her mec ha nistic or cli nical e n d p oi nts 
(e. g., Ma yo E n d osc o p y S c ores). T his ma y be c o n d ucte d t hr o u g h c o m pari n g statistical 
m o dels i nc or p orati n g differe nt e x pla nat or y  ter ms (i.e., mec ha nistic e n d p oi nts) wit h t he 
‘ n ull’ m o del ( n o mec ha nistic e n d p oi nts); or if dee me d a p pr o priate, m ulti variate statistical 
met h o ds ma y  als o be ap plie d t o deter mi ne t he relati o ns hi p bet wee n t he ke y  e n d p oi nts. 
T he c o nsiste nc y  i n t he c ha n ges o ver ti me bet wee n t he e n d p oi nts will als o be assesse d. 
I n a d diti o n, base d o n t he data t hat we o bser ve i n t he st u d y, pr o ba bilities of s uccess will 
be deter mi ne d, w here t he defi niti o n of s uccess will be de pe n de nt o n t he e n d p oi nt. F or 
e xa m ple, w hat is t he pr o ba bilit y  t hat we w o ul d o bser ve a certai n pr o p orti o n of Ma yo 
E n d osc o pic Re missi o n ( 0 or 1) (i.e., c o m parat or y  rate), base d o n t he data t hat we ha ve 
o bser ve d i n t he st u d y. F urt her details re gar di n g t he statistical a nal ys is will be o utli ne d i n 
t he Re p orti n g a n d A nalysis Pla n ( R A P).
2.
I N T R O D U C TI O N
2. 1.
St u d y R ati o n al e
T his st u d y  is t he first e x perie nce wit h G S K 2 9 8 2 7 7 2, a rece pt or-i nteracti n g pr otei n- 1 
( RIP 1) ki nase i n hi bit o r, i n s u bjects wit h acti ve ulcerati ve c olitis ( U C) w h o are c urre ntly 
bei n g treate d wit h sta n dar d of care t hera p y.  All s u bjects will be all o we d t o c o nti n ue 
sta n dar d of care t hera py d uri n g t he st u d y, pr o vi de d t hat t he me dicati o n t y pe a n d d ose is 
sta ble t hr ou g h o ut t he st u d y .
T he pri mar y  o bjecti ve of t his st u d y has n ot c ha n ge d wit h a me n d me nt 0 1; h o we ver t he 
d osi n g re gi me n d oes c ha n ge t o G S K 2 9 8 2 7 7 2 ( 6 0 m g t hree ti mes dail y  f or b ot h Parts A 
a n d B).
T he pri mar y  o bjecti ve will be t o i n vesti gate t he safet y a n d t olera bilit y of re peat oral d oses 
of G S K 2 9 8 2 7 7 2 ( 6 0 m g t hree ti mes dail y f or 4 3 a n d 8 4 da ys). I n a d diti o n, a n u m ber of 
e x peri me ntal a n d cli nical e n d p oi nts will be e m pl o y e d t o o btai n i nf or mati o n o n t he 
p har mac o ki netics ( P K), p har mac o d y n a mics ( P D) a n d preli mi nar y efficac y  i n s u bjects 
wit h acti ve U C.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 4
2. 2.
Bri ef B a c k gr o u n d
RI P 1 is a me m ber of t he rece pt or -i nteracti n g Seri ne/ T hre o ni ne ki nase fa mil y c o ntai ni n g 
a n a mi n o-ter mi nal ki nase d o mai n, a n i nter me diate d o mai n a n d a car b o xy- ter mi nal deat h 
d o mai n.  RI P 1 is a ke y  si g nalli n g n o de w hic h pla ys a n esse ntial r ole i n i nfla m mati o n a n d 
cell deat h i n res p o nse t o si g nals i ncl u di n g T N F fa mil y  c yt o ki nes, li ga n ds f or 
T L R 3/ T L R 4, se ns ors of viral i nfecti o n, a n d i nterfer o ns [Ofe n gei m , 2 0 1 3].  T hr o u g h ti g ht 
re g ulati o n b y u bi q uityl ati o n, de u bi q uit ylati o n a n d i nteracti o n wit h its rece pt ors, RIP 1 has 
d ual r oles as a ki nase a n d a scaff ol di n g pr otei n, a n d ser ves as  a n u pstrea m c hec k p oi nt f or 
b ot h c ell deat h a n d s ur vi val [ Ofe n gei m , 2 0 1 3]. Detaile d u n dersta n di n g of RI P 1 ki nase 
f u ncti o n has n ot bee n f ull y el uci date d, b ut it is k n o w n t hat RIP 1 e xerts it si g nalli n g 
f u ncti o ns t hr o u g h b ot h its catalyt ic ki nase acti vit y a n d b y acti n g as a scaff ol di n g pr otei n 
f or si g nalli n g c o m ple xes.  Rece nt w or k has de m o nstrate d t hat RIP 1 catal yt ic ki nase 
acti vit y ca n re g ulate T N F-me diate d necr o pt osis [ Ofe n gei m , 2 0 1 3] a n d n o nca n o nical 
a p o pt osis [ Wa n g , 2 0 0 8, D o n deli n ger , 2 0 1 3]. I n a d diti o n, t he pr o d ucti o n of certai n 
i nfla m mat or y c yt o ki nes ca n be re g ulate d b y RIP 1 ki nase acti vit y  [In vesti gat or’s Br oc h ure 
(I B) [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].  In c o ntrast, RI P 1’s 
scaff ol di n g f u ncti o n acts t o facilitate ot her i m m u ne pr ocesses i ncl u di n g T N F me diate d 
classical a p o pt osis a n d N F- k B -si g nalli n g [Ofe n gei m , 2 0 1 3, H u m p hries , 2 0 1 5].  Wit h t his, 
a n i n hi bit or of RIP 1 ki nase acti vit y  wit h G S K 2 9 8 2 7 7 2 ma y fill a u ni q ue nic he i n t he 
treat me nt of i nfla m mat or y c o n diti o ns t hr o u g h m ulti ple mec ha nis ms, i ncl u di n g i n hi biti o n 
of i nfla m mati o n-i n d uce d cell deat h ( necr o pt osis a n d a p o pt osis) a n d i n hi biti o n of t he 
pr o d ucti o n of certai n pr o -i nfla m mat or y c yt o ki nes.  
Ulcerati ve c olitis ( U C) is a f or m of i nfla m mat or y  b o wel disease (I B D) c haracterize d b y 
c hr o nic rela psi n g a n d re mitti n g i nfla m mati o n of t he c ol o n.  Hist ol o gicall y , t here is 
e vi de nce f or b ot h necr osis a n d a p o pt osis i n bi o psies fr o m U C s u bjects [D o ur mas h ki n , 
1 9 8 3; Vitali , 2 0 1 1], [Sei deli n , 2 0 1 3; Re geli n g , 2 0 1 6; Sei deli n , 2 0 1 5; Si p os , 2 0 0 5].  
I nteresti n gl y, i n hi biti o n of RIP K 1 bl oc ks s p o nta ne o us c y t o ki ne release i n bi o psies fr o m 
U C patie nts i n e x vi v o c ult ure m o dels [ Gla x o S mit h Kli ne D oc u me nt N u m ber
2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].  In a d diti o n t o h u ma n tra nslati o nal data i n I B D, b ol us a d mi nistrati o n 
of T N F t o mice res ults i n a se vere i nt esti nal i nfla m mati o n t hat is e ntirel y  RIP K 1 -
de pe n de nt [ D u prez , 2 0 1 1; Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ], a n d 
m uri ne m o dels t hat ge neticall y s ke w T N F si g nali n g d o w n t he RI P K 1 pat h wa y  i n t he g ut 
res ults i n s p o nta ne o us ileal a n d c ol o nic i nfla m mati o n [G ü nt her , 2 0 1 1; Welz , 2 0 1 1].  
O verall, t hese data b uil d a c o m pelli n g case f or t he r ole of RI P K 1 i n I B D pat h o ge nesis.
W hile t he pat h o bi ol o g y  of U C is c o m ple x, t he i ntr o d ucti o n of a nti-T N F bi ol o gics has 
i m pr o ve d t he treat ment la n dsca pe f or U C patie nts wit h m o derate t o se vere disease. 
A d diti o nal e mer gi n g t hera pies i ncl u de bi ol o gics w hic h i nterfere wit h g ut -s pecific 
l ym p h oc y te traffic ki n g.  H o we ver, all bi ol o gics ma y ha ve li mitati o ns wit h re gar d t o l o n g-
ter m efficac y, de vel o p me nt of a nti - dr u g a nti b o dies, a n d si de effect pr ofiles.  T here 
re mai ns a hi g h u n met nee d f or n o vel treat me nts w hic h will n ot o nl y re d uce si g ns a n d 
s ym pt o ms, b ut will mai ntai n m uc osal heali n g a n d ac hie ve l o n g ter m re missi o n.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 5
3.
O B J E C TI V E( S) A N D E N D P OI N T( S)
O bj e cti v e s
E n d p oi nt s
Pri m ar y

T o i nv esti g at e t h e s af ety a n d t ol er a bility 
of 6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n s u bj ects wit h m o d er at e 
t o s ev er e ulc er ativ e c olitis.

A dv ers e ev e nts.

Cli nic al l a b or at ory v al u es (cli nic al 
c h e mistry, h a e m at ol o gy a n d uri n alysis).

Vit al si g n m e as ur e m e nts ( bl o o d pr ess ur e, 
h e art r at e, r es pir at ory r at e, a n d b o dy 
t e m p er at ur e).

1 2 -L e a d E C G m o nit ori n g.
S e c o n d ar y

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g m uc os al 
h e ali n g aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
a n a bs ol ut e M ay o e n d osc o py s u bsc or e 
of 0 or 1 at D ays 4 3 ( W e ek 6) a n d 8 5 
( W e ek 1 2).

C h a n g e fr o m b as eli n e i n m uc os al 
a p p e ar a nc e d et er mi n e d by Ulc er ativ e 
C olitis E n d osc o pic I n d ex of S ev erity 
( U C EI S).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
bi o m ark ers of dis e as e activity i n s u bj ects 
wit h activ e ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n m ark ers w hic h 
m ay i ncl u d e, b ut ar e n ot li mit e d t o, m e a n 
C R P a n d f a ec al c al pr ot ecti n ( F C P).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
hist ol o gic dis e as e activity i n s u bj ects 
wit h activ e ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n h ist ol o gic 
s ev erity, i ncl u di n g b ut n ot li mit e d t o 
M o difi e d Ril ey Sc or e a n d G e b o es I n d ex.

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 i n 
ac hi evi n g cli nic al r es p o ns e a n d 
r e missi o n aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects with activ e 
ulc er ativ e c olitis.

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r es p o ns e d efi n e d as r e d ucti o n by 
≥3 p oi nts or ≥3 0 % i m pr ov e m e nt fr o m 
b as eli n e c o m pl et e M ay o sc or e, al o n g 
wit h a d ecr e as e i n t h e r ect al bl e e di n g 
sc or e of ≥1 p oi nt, at D ays 4 3 ( W e ek 6) 
a n d 8 5 ( W e ek 1 2).

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r e missi o n d efi n e d as a c o m pl et e 
M ay o sc or e of 2 p oi nts or l o w er, wit h n o 
i n divi d u al s u bsc or e exc e e di n g 1 p oi nt, at 
D ays 4 3 ( W e ek 6) a n d 8 5 ( W e ek 1 2).

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t hr e e ti m es d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g sy m pt o m atic 
cli nic al r e missi o n aft er 6 a n d 1 2 w e eks of 

C h a n g e fr o m b as eli n e i n p arti al M ay o 
sc or e.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 6
O bj e cti v e s
E n d p oi nt s
tr e at m e nt i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

T o i nv esti g at e t h e p l as m a c o nc e ntr ati o ns 
of G S K 2 9 8 2 7 7 2 f oll o wi n g 6 0 m g t hr e e 
ti m es d aily i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

Pr e- d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 at D ay 4 3 ( W e ek 6). 

P ost -d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 o n D ays 1 a n d 4 3 ( W e ek 
6) at 1, 2, 4 a n d 6 h o urs.

Tr o u g h c o nc e ntr ati o ns o n D ay 8 5 ( W e ek 
1 2).
E x pl or at or y 

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 2 2 o n 
ex pr essi o n of i nfl a m m at ory bi o m ark ers i n 
m uc os al tiss u e bi o psi es i n s u bj ects wit h 
activ e ulc er ativ e c ol itis.

C h a n g e fr o m b as eli n e i n i nfl a m m at ory 
m ark ers w hic h m ay i ncl u d e, b ut ar e n ot 
li mit e d t o I L- 1, I L- 6, I L-8, M M P 3, T N F α, 
I F Nγ.

T o i nv esti g at e p at h w ay a n d t ar g et 
e n g a g e m e nt f oll o wi n g 6 0 m g t hr e e ti m es 
d aily d os es of G S K 2 9 8 2 7 7 2 i n bl o o d a n d 
c ol o n bi o psy tiss u e.

P h ar m ac ol o gy bi o m ark er e n d p oi nts m ay 
i ncl u d e, b ut ar e n ot li mit e d t o t h e 
f oll o wi n g, pr e-d os e at D ays 1, 4 3 ( W e ek 
6) a n d tr o u g h o n D ay 8 5 ( W e ek 1 2), as 
a p plic a bl e a n d if ev al u a bl e s a m pl es a n d 
d at a p er mit:
o
T ar g et E n g a g e m e nt Ass ay Ri P 1 
( T E A R 1) i n bl o od a n d c ol o n 
tiss u e.
o
P h os p h oryl at e d or t ot al RI P 1, 
M L K L, RI P 3, cl e av e d a n d t ot al 
c as p as e 3 a n d 8 si g n at ur es i n 
c ol o n tiss u e.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 7
O bj e cti v e s
E n d p oi nt s

T o i nv esti g at e t h e c o nc e ntr ati o n of 
G S K 2 9 8 2 7 7 2 a n d p ossi bl e dr u g -r el at e d 
m at eri al, as w ell as s p ecific distri b uti o n 
wit hi n tiss u e i f f e asi bl e, i n t h e c ol o n 
tiss u e aft er 6 0 m g t hr e e ti m es d aily 
d os es of G S K 2 9 8 2 7 7 2.

Pr e- d os e G S K 2 9 8 2 7 7 2 a n d p ossi bl e 
dr u g -r el at e d m at eri al c o nc e ntr ati o ns, as 
w ell as s p ecific distri b uti o n wit hi n tiss u e 
if f e asi bl e, i n c ol o n bi o psi es at D ays 4 3 
( W e ek 6) a n d 8 5 ( W e ek 1 2), as 
ev al u a bl e s a m pl es a n d d at a p er mit.

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
q u ality of lif e i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n I nfl a m m at ory 
B o w el Dis e as e Q u esti o n n air e (I B D Q).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
g e n e ex pr essi o n i n t h e bl o o d s u bj ects 
wit h activ e ulc er ativ e c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol at e d fr o m bl o o d D ays 1 a n d 4 3 
( W e ek 6) a n d tr o u g h o n D ay 8 5 ( W e ek
1 2).

T o i nv esti g at e t h e eff ect of 6 0 m g t hr e e 
ti m es d aily d os es of G S K 2 9 8 2 7 7 2 o n 
g e n e ex pr essi o n i n c ol o n tiss u e bi o psi es 
i n s u bj ects wit h activ e ulc er ativ e c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol at e d fr o m c ol o n tiss u e bi o psi es at 
Scr e e ni n g, a n d D a ys 4 3 ( W e ek 6) a n d 
tr o u g h o n D ay 8 5 ( W e ek 1 2).
4.
S T U D Y D E SI G N
4. 1.
O v er all D e si g n
T his is a m ultice ntre, ra n d o mize d, d o u ble -bli n d (s p o ns or -u n bli n de d), place b o -c o ntr olle d 
st u d y wit h a n o pe n la bel e xte nsi o n t o i n vesti gate t he safet y a n d t olera bilit y, P K, P D, a n d 
preli mi nar y  efficac y of G S K 2 9 8 2 7 7 2 i n s u bjects wit h acti ve U C.  T he st u d y desi g n 
sc he matic is de picte d i n Fi g ure 2 bel o w.
Fi g ur e 2
St u d y  O v er vi e w
A me n d me nt 0 1:
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 8
Pri or t o a me n d me nt 0 1:
K e y a s s e s s m e nt s:
S af et y a s s e s s m e nt s, P K s a m pl e s, M a y o s c or e, M o difi e d 
Ril e y S c or e, G e b o e s I n d e x,  I B D Q, P D s a m pl e s
4. 2.
Tr e at m e nt A r m s a n d D ur ati o n
It is a ntici pate d t hat t he t otal d urati o n of partici pati o n i n t he st u d y will be a p pr o xi matel y 
2 0 wee ks fr o m scree ni n g t o t he last st u d y  visit.
4. 2. 1.
S cr e e ni n g
Wit hi n 3 0 da y s of t he scree ni n g visit (defi ne d as da y  of c o nse nt si g ni n g), s u bjects will 
e nter t he 2- part treat me nt peri o d ( Part A a n d Part B) a n d start treat me nt ( or d osi n g) o n 
D a y  1.
4. 2. 2.
Tr e at m e nt P eri o d
S u bjects will be ra n d o ml y assi g ne d t o eit her G S K 2 9 8 2 7 7 2 6 0 m g or place b o orall y  t hree 
ti mes dail y  (a p pr o xi matel y 8 h o urs a part) f or 4 2 da y s ( 6 wee ks) i n a 2: 1 rati o i n Part A.  
All s u bjects will m o ve t o o pe n la bel i n Part B t o recei ve G S K 2 9 8 2 7 7 2 6 0 m g t hree ti mes 
dail y  (a p pr o xi matel y 8 h o urs a part) f or a n a d diti o nal 4 2 da y s ( 6 wee ks).  Treat me nt 
d urati o n is a t otal of 8 4 da y s ( 1 2 wee ks) i ncl usi ve of Parts A a n d B.  S u bjects t hat were 
ra n d o mise d pri or t o pr ot oc ol a me n d me nt 0 1 bei n g a p pr o ve d i n eac h c o u ntr y were 
ra n d o ml y assi g ne d t o eit her G S K 2 9 8 2 7 7 2 6 0 m g or place b o orally t w o ti mes dail y 
(a p pr o xi matel y 1 2 h o urs a part) f or 4 2 da ys f oll o we d b y G S K 2 9 8 2 7 7 2 6 0 m g BI D f or 4 2 
da y s.
F urt her g ui da nce a n d i nf or mati o n f or st u d y treat me nt a n d d osi n g are pr o vi de d i n t he 
St u d y  Refere nce Ma n ual ( S R M).  
D uri n g t he 8 4 da y  ( 1 2 wee k) treat me nt peri o d, s u bjects will atte n d t he cli nical site f or 
visits o n Da y s 1, 1 5, 2 9, 4 3, 5 7, 7 1 a n d 8 5.  At s pecific visits, s u bjects m ust n ot ta ke 
st u d y treat me nt pri or t o t heir sc he d ule d visit (see Secti o n 7. 1 ).  O n Da ys 8, 2 2, 3 6, 5 0, 6 4 
a n d 7 8 eac h s u bject will be c o ntacte d b y tele p h o ne a n d as ke d a b o ut t heir ge neral healt h , 
st u d y me dicati o n c o m plia nce a n d diar y car d c o m pleti o n. S u bjects will be gi ve n a diar y 
car d at eac h of t he visits w hic h will t he y will be i nstr ucte d t o rec or d t heir dail y st u d y 
me dicati o n a n d c o nc o mita nt me dicati o n a d mi nistrati o n a n d a n y a d verse e ve nts.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 9
4. 2. 3.
F oll o w - u p P eri o d
After t he o pe n la bel ( Part B) Treat me nt Peri o d, t he s u bject will e nter t he F oll o w - u p 
Per i o d w hic h lasts f or 2 8 da ys p ost t he last a d mi nistrati o n of st u d y me dicati o n, i n or der 
c o m plete f oll o w-u p assess me nts per t he Ti me a n d E ve nts Ta ble (see Secti o n 7. 1 ).
4. 3.
T y p e a n d N u m b er of S u bj e ct s
A s ufficie nt n u m ber of s u bjects will be scree ne d s o t hat a p pr o xi matel y  3 0 - 3 6 s u bjects 
wit h acti ve U C will be ra n d o mise d i nt o t he st u d y o n a TI D re gi me n. Pri or t o pr ot oc ol 
a me n d me nt 0 1 bei n g a p pr o ve d i n eac h c o u ntr y, n o m ore t ha n 1 8 s u bjects will be 
ra n d o mise d i nt o t he st u d y o n a BI D re gi me n. S h o ul d t he dr o p o ut rate i n Part A [ Da y 1 
t hr o u g h 4 3 ( Wee k 6)] be hi g her t ha n a ntici pate d, or t he sa m ple size re vie w warra nt a n 
i ncrease i n s u bject n u m bers, a d diti o nal or re place me nt s u bjects ma y be ra n d o mise d ( u p t o 
an o verall t otal ma xi m u m of 6 0 ) i nt o t he st u d y at t he discreti o n of t he S p o ns or.  S u bjects 
w h o disc o nti n ue partici pati o n d uri n g t he o pe n la bel p hase i n Part B [( Da y  4 3 ( Wee k 6) 
t hr o u g h Da y 8 5 ( Wee k 1 2)] will n ot be re place d.
4. 4.
D e si g n J u stifi c ati o n
As t his is t he first trial of G S K 2 9 8 2 7 7 2 i n s u bjects wit h U C, t he pri mar y  e n d p oi nt is t he 
safety a n d t olera bilit y of G S K 2 9 8 2 7 7 2.  I n a d diti o n, t his st u d y  will i ncl u de assess me nts 
of tar get e n ga ge me nt a n d d o w nstrea m P D ef fects of G S K 2 9 8 2 7 7 2, al o n g wit h 
preli mi nar y  efficac y i n ac hie vi n g m uc osal heali n g, t o u n dersta n d w het her G S K 2 9 8 2 7 7 2 
is i n hi biti n g t he pat h wa y of i nterest i n t his disease.
Beca use m uc osal heali n g has bee n i ncreasi n gl y rec o g nize d as a ke y  e n d p oi nt i n U C 
ra n do mise d c o ntr olle d trials ( R C Ts), si g m oi d osc o p y  will be perf or me d at baseli ne 
(scree ni n g) a n d at t he Da y 4 3 ( Wee k 6) a n d Da y 8 5 ( Wee k 1 2) ti me p oi nts.   T he mi d-
p oi nt Da y  4 3 ( Wee k 6) e n d osc o pic assess me nt was c h ose n base d o n e vi de nce t hat 
i m pr o ve me nt i n m uc osal i nfla m mati o n ma y be ac hie va ble as early as 4 wee ks after 
i nitiati o n of a nti-T N F t hera p y [ Fratila , 2 0 1 0] a n d 6 wee ks wit h a nti-i nte gri n t hera p y 
[Fea ga n , 2 0 1 3]. T his s u g gests e n d osc o pic e vi de nce of disease i m pr o ve ment ma y  be m ore 
se nsiti ve i n meas uri n g t hera pe utic efficac y t ha n tra diti o nal disease acti vit y i n de x sc ores 
i n sh orter d urati o n trials. T he 8 5 da y  ( 1 2 wee k) d urati o n of treat me nt is base d o n re vie w 
of pre vi o us pr o of of mec ha nis m a n d pr o of of c o nce pt st u dies i n U C [ Rei ni sc h, 2 0 1 1; 
Sa n d b or n , 2 0 1 2; Sa n d b or n , 2 0 1 4] a n d is li mite d b y  t he s u p p orti n g 1 3 wee k t o xic ol o g y 
st u dies.  
It is e x pecte d t hat a n effecti ve t hera py s h o ul d ca use tre n ds i n gr o u p le vel c ha n ges i n t he 
mec ha nistic para meters b y b ot h t he Da y  4 3 ( Wee k 6) a n d Da y 8 5 ( Wee k 1 2) ti me p oi nts.   
T he plac e b o gr o u p was dee me d necessar y as pri mar y o bjecti ve is safety, a n d i deall y t his 
w o ul d be re vie we d i n a place b o c o ntr olle d bli n de d trial.  H o we ver, t he size of t he place b o 
gr o u p has bee n ke pt t o a mi ni m u m a n d is li mite d t o Part A [ Da y  1 t hr o u g h 4 3 ( Wee k 6)]. 
Part B [ Da y  4 3 ( Wee k 6) t hr o u g h Da y 8 5( Wee k 1 2)] was desi g ne d as a n o pe n la bel 
e xte nsi o n st u d y t o ai d recr uit me nt a n d rete nti o n as well as t o o btai n a d diti o nal safety, P K 
a n d bi o mar ker data i n t his st u d y . All s u bjects will be all o we d t o c o nti n ue sta n dar d of care 
t hera py d uri n g t he st u d y ( wit h t he e xce pti o n of bi ol o gics), pr o vi de d t hat t he me dicati o n 
a n d d ose is sta ble t hr o u g h o ut t he st u d y .
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 0
4. 5.
D o s e J u stifi c ati o n
T he i nitial selecti o n of t he 6 0 m g BI D d ose bei n g teste d i n t his st u d y is base d o n t he 
safety, P K, a n d P D data fr o m t he First Ti me i n H u ma n ( F Ti H) st u d y , 2 0 0 9 7 5.  
G S K 2 9 8 2 7 7 2 a d mi nistere d at 6 0 m g BI D f or 1 4 da ys was well t olerate d a n d n o safet y 
c o ncer ns were i de ntifie d. A BI D d osi n g re gi me n was i nitiall y selecte d o ver a Q D d osi n g 
re gi me n d ue t o t he s h ort half-life of G S K 2 9 8 2 7 7 2 i n h u ma ns ( ~ 2 h).  Base d o n 
preli mi nar y  P K/ P D m o delli n g fr o m t he si n gle d ose asce n di n g part of st u d y 2 0 0 9 7 5, a 6 0 
m g BI D d ose was pre dicte d t o ha ve o n a vera ge 9 5 % RI P 1 tar get e n ga ge me nt a n d 
a p pr o xi matel y 9 0 % of s u bjects will ha ve >9 0 % tar get e n ga ge me nt at C mi n usi n g a n o vel 
i n-h o use e x -vi v o P D/tar get e n ga ge me nt assa y  base d s olel y o n t he T N F pat h wa y w hic h is 
belie ve d t o be a ke y  c o m p o ne nt of t he RIP 1 pat h wa y .   
H o we ver, base d o n fi nal P K/ P D m o delli n g fr o m t he f ull re peat d ose part o f t he St u d y 
2 0 0 9 7 5 ( u p t o 1 2 0 m g BI D), a 6 0 m g BI D d ose is n o w pre dicte d t o ha ve o n a vera ge 9 9 % 
RI P 1 tar get e n ga ge me nt i n bl o o d a n d a p pr o xi matel y  9 0 % of s u bjects will ha ve > 8 5 % 
tar get e n ga ge me nt at Cmi n . T his is l o wer t ha n o ur tar get of ac hie vi n g > 9 0 % tar g et 
e n ga ge me nt i n at least 9 0 % of s u bjects at C mi n .  T heref ore, a 6 0 m g T I D c o h ort is n o w 
bei n g pr o p ose d.  
T he C mi n val ues at 6 0 m g TI D are pre dicte d t o be a p pr o xi matel y 3. 5 f ol d hi g her t ha n f or 
6 0 m g BI D.  Usi n g t he fi nal P K/ P D, a 6 0 m g TI D d ose is pre dic te d t o ha ve o n a vera ge 
9 9 % RI P 1 tar get e n ga ge me nt i n bl o o d a n d a p pr o xi matel y  9 0 % of s u bjects will ha ve > 
9 6 % tar get e n ga ge me nt at C mi n .  N o data is c urre ntl y a vaila ble a b o ut t he distri b uti o n of 
G S K 2 8 9 2 7 7 2 i nt o gastr oi ntesti nal ( GI) tiss ue.  
I n a d diti o n, beca use of t he s h ort half-life, a m o difie d release f or m ulati o n is n o w bei n g 
de vel o pe d wit h t he ai m t o pr o vi de a o nce dail y d osi n g re gi me n.  B y i ncreasi n g t he 
fre q ue nc y of d osi n g t o t hree ti mes daily ( TI D) wit h t he c urre nt i m me diate release 
f or m ulati o n, t his will m ore cl osel y matc h t he P K, safet y a n d efficac y pr ofile of a 
preferre d o nce dail y  m o difie d release f or m ulati o n.
T he safet y of i ncreasi n g t he d ose fre q ue nc y t o 6 0 m g TI D is j ustifie d base d o n 
n o ncli nical safet y fi n di n gs t o date wit h G S K 2 9 8 2 7 7 2. It is a ntici pate d t hat a h u ma n d ose 
of 6 0 m g T I D ( 1 8 0 m g/ da y) will pr o d uce A U C( 0-2 4) a n d C ma x val ues of a p pr o xi matel y  
9. 9 u g. h/ m L a n d 0. 8 u g/ m L, res pecti vely, w hic h are a p pr o xi matel y 1/ 5 t h a n d 1/ 1 5 t h of t he 
ge n der -a vera ge d A U C ( 4 8. 4 u g. h/ m L) a n d C ma x ( 1 2. 3 u g/ m L) ac hie ve d i n t he 1 3 wee k 
m o n ke y  st u d y at t he n o a d verse effect le vel ( N O A E L) d ose of 3 0 m g/ k g/ da y. Please see 
G S K 2 9 8 2 7 7 2 I B [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].
As of 0 3 A pr 2 0 1 7, a t otal of a p pr o xi matel y  9 3 s u bjects acr oss 4 cli nical st u dies ha ve 
bee n ra n d o mise d t o recei ve G S K 2 9 8 2 7 7 2. I n St u d y 2 0 0 9 7 5, G S K 2 9 8 2 7 7 2 a d mi nistere d 
u p t o 1 2 0 m g BI D f or 1 4 da y s a n d was well t olerate d a n d n o safet y c o ncer ns were 
i de ntifie d. A t otal of 9 s u bjects ha d recei ve d 1 2 0 m g BI D i n t hat st u d y.  Please see 
G S K 2 9 8 2 7 7 2 I B [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ]. I n t he 
o n g oi n g P hase 2a st u dies i n Ps oriasis [( Ps O); St u d y 2 0 3 1 6 7] a n d R he u mat oi d Art hritis 
[( R A); St u d y 2 0 3 1 6 8], a t otal of 2 6 s u bjects ha ve bee n ra n d o mise d t o G S K 2 9 8 2 7 7 2 6 0 
m g BI D.
N o s u bjects ha ve bee n ra n d o mise d y et t o t his st u d y ( St u d y 2 0 2 1 5 2).  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 1
G S K 2 9 8 2 7 7 2 was well t olerate d a n d n o dr u g -relate d S A Es ha ve bee n re p orte d.  I n St u d y  
2 0 3 1 6 7, t here was a deat h of a 1 9 year ol d male s u bject d ue t o a n acci de ntal o ver d ose 
wit h 3, 4 -met h y le ne di o x y-met ha m p heta mi ne ( M D M A) t hat was n ot c o nsi dere d dr u g 
relate d by t he Pri nci pal I n vesti gat or ( PI).  
4. 6.
B e n efit: Ri s k A s s e s s m e nt
S u m maries of fi n di n gs fr o m b ot h cli nical a n d n o n-cli nical st u dies c o n d ucte d wit h 
G S K 2 9 8 2 7 7 2 ca n be f o u n d i n t he In vesti gat or’s Br oc h ure [ Gla x o S mit h Kli ne D oc u me nt 
N u m ber
2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].   T he f oll o wi n g secti o n o utli nes t he ris k assess me nt a n d 
miti gati o n strate g y  f or t his pr ot oc ol:  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 2
4. 6. 1.
Ri s k A s s e s s m e nt
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
I n v e sti g ati o n al Pr o d u ct (I P) G S K 2 9 8 2 7 7 2
C e ntr al N erv o us Syst e m ( C N S) eff ects
N o n -cli ni c al d at a : 
I n t h e 4-w e ek G L P t oxic ol o gy st u dy, C N S fi n di n gs w er e 
o bs erv e d i n 4/ 1 2 m o nk eys w hic h w er e a d mi nist er e d 1 0 0 or 
3 0 0 m g/k g/ d ay.  C N S fi n di n gs i ncl u d e d u nc o or di n ati o n, 
irr e g ul ar g ait, tr e m bli n g, h u nc h e d a p p e ar a nc e, a n d 
d ecr e as e d activity. T h e cli nic al r el ev a nc e of t h es e fi n di n gs 
i n h u m a ns is n ot k no w n.  T h e N O A E L f or t his st u dy w as 
d et er mi n e d at 1 0 m g/k g/ d ay.
I n t h e 1 3-w e ek G L P t oxic ol o gy st u dy, t h er e w er e n o C N S 
fi n di n gs o bs erv e d i n m o nk eys a d mi nist er e d 1 0, 3 0 or 1 0 0 
m g/k g/ d ay.  T h e N O A E L f or t his st u dy w as d et er mi n e d at 
3 0 m g/k g/ d ay.  
Cli ni c al d a t a:
A First Ti m e i n H u m a n ( F Ti H) st u dy wit h si n gl e asc e n di n g 
a n d m ulti pl e asc e n di n g d os es h as b e e n p erf or m e d i n 6 7 
h e alt hy m al e v ol u nt e ers t o d at e.  S e e I B f or G S K 2 9 8 2 7 7 2 
[ Gl ax o S mit h Kli n e D oc u m e nt N u m b er 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].  
N o dr u g -ass oci at e d C N S a dv ers e ev e nts w er e i d e ntifi e d 
a n d n o S eri o us A dv ers e Eff ects ( S A Es) w er e r e p ort e d.
S u bj e ct S el cti o n :

S u bj ects wit h k n o w n hist ory of si g nific a nt pr o gr essiv e 
n e ur ol o gic dis o r d ers i ncl u di n g b ut n ot li mit e d t o 
pr o gr essiv e m ulti pl e scl er osis ( M S), A my otr o p hic 
l at er al scl er osis ( A L S), Alz h ei m er’s a n d d e m e nti a will 
b e excl u d e d.

I n divi d u als wit h p ot e nti ally i ncr e as e d s usc e pti bility f or 
n e ur ol o gic eff ects will b e excl u d e d b as e d o n m e dic al 
hist ory at scr e e ni n g.
S u bj e ct M o nit ori n g :

S u bj ects will b e m o nit or e d f or st a n d ar d C N S -r el at e d 
a dv ers e ev e nts.
I m m u n os u p pr essi o n
T h e p ossi bility of i m m u n os u p pr essi o n, i ncl u di n g a n 
i ncr e as e i n t h e fr e q u e ncy a n d/ or s ev erity of i nf ecti o n, m ay 
r es ult fr o m t h e i nt e n d e d p h ar m ac ol o gic eff ect of 
G S K 2 9 8 2 7 7 2.  T his m ay b e e n h a nc e d i n s u bj ects t aki n g 
ot h er i m m u n o m o d ul ati n g dr u gs or c ortic ost er oi ds.
S u bj e ct S el e cti o n :

S u bj ects wit h r ec urr e nt, c hr o nic or activ e i nf ecti o ns 
will b e excl u d e d fr o m t h e st u dy.

S u bj ect s will b e scr e e n e d f or T B, HI V, H e p atitis B a n d 
C, a n d excl u d e d fr o m t h e st u dy if p ositiv e.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 3
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
Cli ni c al d at a :
I n t h e F Ti H st u dy, n o S A Es w er e r e p ort e d.  O n e s u bj ect 
ex p eri e nc e d a n A E h er p es z ost er a p pr oxi m at ely 4 2 d ays 
aft er r ec eivi n g his l ast d os e wit h G S K 2 9 8 2 7 7 2.  T h e 
bli n d e d I nv esti g at or d et er mi n e d t his t o b e p ot e nti ally dr u g -
r el at e d.
S u bj e ct M o nit ori n g :

S u bj ects will b e m o nit or e d f or si g ns of i nf ecti o n.

S e e I n divi d u al St o p pi n g Crit eri a f or aty pic al or 
o p p ort u nistic i nf ecti o ns ( S ecti o n 5. 4. 1 ).
V acci n ati o ns
T h er e is a t h e or etic al risk t h at G S K 2 9 8 2 7 7 2 c o ul d 
d ecr e as e a n i n divi d u al’s i m m u n e r es p o ns e t o v acci n es or 
all o w sy m pt o ms t o d ev el o p f oll o wi n g v acci n ati o n wit h a liv e 
v acci n e w h e n a d mi nist er e d w hil e o n t h er a py.
S u bj e ct S el e cti o n :

Att e n u at e d or liv e v acci n es s h o ul d n ot b e 
a d mi nist er e d t o s u bj ects fr o m 3 0 d ays pri or t o t h e first 
d os e of G S K 2 9 8 2 7 7 2, d uri n g t h e st u dy a n d f or 5 h alf -
liv es pl us 3 0 d ays (t ot al 3 2 d ays) aft er G S K 2 9 8 2 7 7 2 
is disc o nti n u e d.

If i n dic at e d, n o n-liv e v acci n es ( e. g. i n activ at e d 
i nfl u e nz a v acci n es) m ay b e a d mi nist er e d w hil e 
r ec eivi n g G S K 2 9 8 2 7 7 2 b as e d o n a tr e ati n g p hysici a n 
ass ess m e nt of t h e b e n efit:risk ( e. g., ri sk of t h e or etic al 
d ecr e as e d r es p o nsiv e n ess). 

I nv esti g at ors ar e ex p ect e d t o f oll o w l oc al a n d/ or 
n ati o n al g ui d eli n es wit h r es p ect t o v acci n ati o ns, 
i ncl u di n g a g ai nst i nfl u e nz a a n d p n e u m oc occ us, i n 
s u bj ects wit h U C.
R es pir at ory
N o n -cli ni c al d at a :
I n t h e si n gl e-d os e S af ety C ar di ov asc ul ar a n d R es pir at ory 
St u dy i n m o nk eys, a d ecr e as e i n mi n ut e v ol u m e ( M V) a n d 
r es pir at ory r at e w as o bs erv e d at all d os es ( 1 0, 1 0 0, a n d 
3 0 0 m g/k g).  T h es e fi n di n gs w er e n ot e d t o b e r ev ersi bl e 
a n d mil d i n s ev erity.
I n a 1 4-d ay r e p e at d os e S af ety R es pir at ory St u dy i n 
m o nk eys, n o r es pir at ory eff ects o n t ot al p ul m o n ary 
v e ntil ati o n ( mi n ut e v ol u m e) or r es pir at ory r at e w er e 
S u bj e ct M o nit ori n g :

S u bj ects s h o ul d b e m o nit or e d f or st a n d ar d 
r es pir at ory-r el at e d a dv ers e ev e nts.

Vit al si g ns will b e m o nit or e d d uri n g st u dy visits.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 4
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
o bs erv e d at d os es of 1 or 1 0 m g/k g/ d ay. S e e I B f or 
G S K 2 9 8 2 7 7 2 [ Gl ax o S mit h Kli n e D oc u m e nt N u m b er
2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].
Cli ni c al d at a :
I n t h e F Ti H st u dy, r e p e at d os es of G S K 2 9 8 2 7 7 2 u p t o 6 0 
m g BI D w er e a d mi nist er e d x 1 4 d ays i n 3 6 h e alt hy m al e 
v ol u nt e ers. Ext e nsiv e r es pir at ory m o nit ori n g wit h e n d -ti d al 
C O 2 ( E T C O 2), oxy g e n s at ur ati o n ( S p O 2) a n d n oct ur n al 
r es pir at ory r at e m o nit ori n g w as p erf or m e d.   N o S A Es 
occ urr e d, a n d n o dr u g -ass oci at e d r es pir at ory -r el at e d 
a dv ers e ev e nts w er e i d e ntifi e d.
S uici d ality
G S K 2 9 8 2 7 7 2 is c o nsi d er e d t o b e a C N S -activ e dr u g b as e d 
u p o n pr e -cli nic al st u di es.
Cli ni c al d at a :
I n t h e F Ti H st u dy, t h er e h av e b e e n s o m e r e p orts of 
l et h ar gy, a b n or m al dr e a ms, a n d d e pr ess e d m o o d.  N o 
ev e nts of s uici d al i d e ati o n or b e h avi o ur or c h a n g es i n 
b e h avi o ur w er e r e p ort e d.    
S u bj e ct S el e cti o n :

S u bj ects wit h a c urr e nt hist ory of s uici d al i d e ati o n a n d 
b e h avi o ur ( SI B) as m e as ur e d usi n g t h e C o l u m bi a 
S uici d e S ev erity R ati n g Sc al e ( C -S S R S) or a hist ory 
of att e m pt e d s uici d e will b e excl u d e d fr o m t h e st u dy.
S u bj e ct M o nit ori n g:

S u bj ects s h o ul d b e m o nit or e d a p pr o pri at ely a n d 
o bs erv e d cl os ely f or s uici d al i d e ati o n a n d b e h avi o ur 
or a ny ot h er u n us u al c h a n g es i n b e h avi o ur.

B as eli n e a n d tr e at m e nt e m er g e nt ass ess m e nt of 
s uici d ality will b e c o n d uct e d by tr ai n e d sit e p ers o n n el 
usi n g t h e ( C ol u m bi a S uici d e S ev erity R ati n g Sc al e) C -
S S R S i n all s u bj ects.  S e e S ecti o n 7. 3. 7 .
R e pr o d uctiv e t oxicity
N o n -cli ni c al d at a :
I n a n e arly r at e m bry of et al d ev el o p m e nt st u dy, t h er e w as 
n o m at er n al or d ev el o p m e nt al t oxicity at d os es 2 0 0 
m g/k g/ d ay.
I n a n e arly r a b bit e m bry of et al d ev el o p m e nt st u dy, 
G S K 2 9 8 2 7 7 2 w as a d mi nist er e d at d os es of 0, 1 0, 1 0 0, 3 0 0 
or 6 0 0 m g/k g/ d ay o n g est ati o n d ay 7 t o 1 9.  N o 
S u bj e ct S el e cti o n :

M al e a n d f e m al e s u bj ects of c hil d b e ari n g p ot e nti al will 
b e i ncl u d e d i n t his st u dy o nly if t h ey a gr e e t o us e 
hi g hly eff ectiv e m et h o ds of c o ntr ac e pti o n a n d av oi d 
c o nc e pti o n f or d efi n e d p eri o ds of ti m e b ef or e first 
a d mi nistr ati o n of st u dy dr u g u ntil 3 0 d ays (f e m al es) 
a n d 9 0 d ays ( m al es) aft er t h e l a st a d mi nistr ati o n of 
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 5
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
d ev el o p m e nt al t oxicity w as evi d e nt at d os es u p t o 3 0 0 
m g/k g/ d ay.
st u dy dr u g (A p p e n dix 6 ). 

F e m al es of c hil d b e ari n g p ot e nti al will u n d er g o s er u m 
pr e g n a ncy t est at scr e e ni n g a n d t h e n uri n e pr e g n a ncy 
t esti n g at r e g ul ar i nt erv als d uri n g t h e st u dy. 

Pr e g n a nt a n d l act ati n g f e m al es ar e n ot eli gi bl e f or 
i ncl usi o n i n t h e st u dy.
Wit h dr a w al crit eri a :

If a f e m al e s u bj ect s h o ul d b ec o m e pr e g n a nt d uri n g 
t h e st u dy, st u dy m e dic ati o n s h o ul d b e disc o nti n u e d.  
T h e s u bj ect will b e f oll o w e d t o d et er mi n e t h e o utc o m e 
of t h e pr e g n a ncy.  A ny pr e g n a ncy c o m plic ati o n or 
el ectiv e t er mi n ati o n of a pr e g n a ncy will b e r e p ort e d as
a n A E or S A E.
Dr u g I nt er acti o n
N o n -cli ni c al d at a :
I n vitr o st u di es wit h G S K 2 9 8 2 7 7 2 ass essi n g p ot e nti al dr u g-
dr u g i nt er acti o ns wit h Cyt oc hr o m e P 4 5 0 3 A 4 ( C Y P 3 A 4) 
s u bstr at es a n d P-glyc o pr ot ei n ( P g p) i n hi bit ors w er e 
c o m pl et e d.  T o d at e, f or m al dr u g i nt er acti o n st u di es i n 
h u m a ns h av e n ot b e e n p erf or m e d wit h G S K 2 9 8 2 7 7 2. 
T h er e is a l o w risk t h at G S K 2 9 8 2 7 7 2 c o ul d b e a n i n d uc er 
of C Y P 3 A 4 a n d t h er ef or e m ay l o w er circ ul ati n g l ev els of 
c o nc o mit a nt m e dic ati o ns t h at ar e m et a b olis e d by C Y P 3 A 4 
w h e n c o a d mi nist er e d wit h G S K 2 9 8 2 7 7 2.
G S K 2 9 8 2 7 7 2 is a P g p s u bstr at e a n d t h e r ef or e c o 
a d mi nistr ati o n wit h c o nc o mit a nt m e dic ati o ns t h at ar e P g p 
i n hi bit ors c o ul d i ncr e as e circ ul ati n g l ev els of G S K 2 9 8 2 7 7 2.
S e e S ecti o n 4. 3. 6 of G S K 2 9 8 2 7 7 2 I B [ Gl ax o S mit h Kli n e 
D oc u m e nt N u m b er 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].
S u bj e ct S el e cti o n s :

S u bj ects w h o ar e t aki n g c o nc o mit a nt m e dic ati o ns 
k n o w n t o i n hi bit P g p or ar e C Y P 3 A 4 n arr o w 
t h er a p e utic i n d ex ( N TI) s u bstr at es will b e excl u d e d 
fr o m t h e st u dy.  S e e S ecti o n 6. 1 1. 2 f or a 
c o m pr e h e nsiv e list of m e dic ati o ns.
S u bj e ct M o nit ori n g:

S u bj ects’ c o nc o mit a nt m e dic ati o n us a g e will b e 
r evi e w e d pri or t o i ncl usi o n a n d m onit or e d t hr o u g h o ut 
t h e st u dy.

S u bj ects s h o ul d b e m o nit or e d t hr o u g h o ut t h e st u dy 
f or p ot e nti al eff ects of i nt er acti o n b et w e e n 
G S K 2 9 8 2 7 7 2 a n d ot h er c o nc o mit a nt m e dic ati o ns.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 6
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
St u d y Pr o c e d ur e s
Si g m oi d osc o py wit h bi o psy
P ot e nti al risks of t h e pr oc e d ur e i ncl u d e disc o mf ort, 
p erf or ati o n or bl e e di n g.
S u bj e ct M a n a g e m e nt :

Si g m oi d osc o py, r at h er t h a n c ol o n osc o py will b e us e d 
w hic h is t h o u g ht t o r e d uc e t h e risk of e n d osc o py 
r el at e d c o m plic ati o ns by u p t o 5 0 %.

Si g m oi d osc o py will b e p erf or m e d by ex p eri e nc e d a n d 
tr ai n e d st aff o nly.  

S u bj ects will b e i nstr uct e d a b o ut a m o u nt of ex p ect e d 
bl e e di n g p ost -pr oc e d ur e a n d will b e i nstr uct e d t o 
c o nt act t h e cli nic al sit e s h o ul d t h er e b e a ny a dv ers e 
cli nic al ev e nts aft er t h e pr oc e d ur e. 
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 7
4. 6. 2.
B e n efit A s s e s s m e nt
T here are a d diti o nal treat me nt o pti o ns a vaila ble f or s u bjects w h o ha ve a n i na de q uate 
res p o nse t o c urre nt t hera pies f or U C.  It is p ossi ble t hat treat me nt wit h G S K 2 9 8 2 7 7 2 ma y 
be effecti ve i n t he treat me nt of U C, as t he F Ti H st u d y  de m o nstrate d t hat t he dr u g 
e n ga ge d wit h t he tar get a n d pr o d uce d ex viv o P D effects i n s u p pressi o n of RI P 1 -
de pe n de nt c y t o ki nes  MI P 1a n d MI P 1[ Gla x o S mit h Kli ne D oc u me nt N u m ber
2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].  T here will be li mite d direct be nefit t o t he s u bject t hr o u g h t heir 
c o ntri b uti o n t o t he pr ocess of de vel o pi n g ne w t hera pies i n a n a rea of u n met nee d.  
4. 6. 3.
O v er all B e n efit: Ri s k C o n cl u si o n
Ta ki n g i nt o acc o u nt t he meas ures ta ke n t o mi ni mize ris k t o s u bjects par tici pati n g i n t his 
st u d y, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h G S K 2 9 8 2 7 7 2 are acce pta ble base d 
o n li mite d direct be nefits t hat ma y be aff or de d t o patie nts wit h acti ve U C b y  c o ntri b uti n g 
t o t he u n dersta n di n g of t he disease a n d t he de vel o p me nt of ne w t hera pies f or patie nts 
wit h U C i n t he f ut ure.  
5.
S E L E C TI O N O F S T U D Y P O P U L A TI O N A N D 
WI T H D R A W A L C RI T E RI A
S pecific i nf or mati o n re gar di n g war ni n gs, preca uti o ns, c o ntrai n dicati o ns, a d verse e ve nts, 
a n d ot her perti ne nt i nf or mati o n o n t he G S K i n vesti gati o nal pr o d uct or ot her st u d y  
treat me nt t hat ma y i m pact s u bject eli gi bilit y is pr o vi de d i n t he I B [ Gla x o S mit h Kli ne 
D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 ].
I n a d diti o n, In vesti ga t ors are e x pecte d t o f oll o w l ocal a n d/ or nati o nal g ui deli nes wit h 
res pect t o vacci nati o ns, i ncl u di n g vacci nati o ns f or i nfl ue nza a n d p ne u m oc occ us, i n 
s u bjects wit h U C.
De viati o ns fr o m i ncl usi o n a n d e xcl usi o n criteria are n ot all o we d beca use t he y ca n 
p ote nti all y je o par dize t he scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y or 
s u bject safety. T heref ore, a d here nce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial.
5. 1.
I n cl u si o n Crit eri a
A s u bject will be eli gi ble f or i ncl usi o n i n t his st u d y o nl y if all of t he f oll o wi n g criteria 
a p pl y:
A G E
1.
Bet wee n 1 8 a n d 7 5 ye ars of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.
T Y P E O F S U BJ E C T A N D DI A G N O SI S I N C L U DI N G DI S E A S E S E V E RI T Y
2.
S u bjects t hat d o n ot ha ve a n y  me dical c o n diti o ns, ot her t ha n acti ve U C, t hat i n t he 
o pi ni o n of t he I n vesti gat or p ut t he s u bject at u nacce pta ble ris k or i nterfere wit h st u d y  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 8
assess me nts or i nte grit y of t he data.  T hese me dical c o n diti o ns s h o ul d be sta ble at t he 
ti me of scree ni n g a n d are e x pecte d t o re mai n sta ble f or t he d urati o n of t he st u d y. 
3.
S u bject has ha d a c o nfir me d dia g n osis of acti ve U C, as d oc u me nte d b y c o m plete 
dia g n ostic c ol o n osc o p y t o t he ter mi nal ile u m ( TI) wit h bi o ps y  perf or me d 3 m o nt hs
pri or t o scree ni n g. If dia g n ostic c ol o n osc o py was n ot perf or me d t o t he TI , it m ust be 
d oc u me nte d b y  t he PI t hat t he s u bject has diff use i nfla m mati o n fr o m t he rect u m
e xte n di n g pr o xi mall y t o t he c ol o n i n a c o nti n u o us a n d u nif or m wa y .
4.
A C o m plete Ma y o Sc ore of ≥3  p oi nts a n d e n d osc o p y  s u b sc ore of 2 t o 3 at scree ni n g, 
des pite c o nc urre nt treat me nt wit h at le ast 1 of t he f oll o wi n g ( oral c ortic oster oi ds or 
a n y oral 5-a mi n osalic ylates ( 5-A S A) or p uri ne a nal o g ues or all as defi ne d bel o w):
a.
Oral 5 -A S A at a sta ble d ose (e q ui vale nt t o ≥ 2. 4 g/ da y  of Asac ol) f or at least 4 
wee ks pri or t o first d ose.  M ust re mai n o n a sta ble d ose u ntil e n d of treat me nt.
b.
P uri ne a nal o g ues (azat hi o pri ne, merca pt o p uri ne, t hi o p uri nes) or met h otre xate 
f or at least 1 2 wee ks pri or t o first d ose. M ust re mai n o n a sta ble d ose u ntil e n d 
of treat me nt.
c.
Sta ble l o w d ose oral c ortic oster oi d ( u p t o 2 0 m g pre d nis ol o ne or e q ui vale nt) 
f or 2 wee ks pri or t o si g m oi d osc o p y. M ust re mai n o n a sta ble d ose u ntil e n d of 
treat me nt.
5.
If o n rectal 5-A S A or c ortic oster oi ds, m ust re mai n o n a sta ble d ose f or at least 4 
wee ks pri or t o first d ose. M ust re mai n o n sta ble d ose u ntil t he e n d of treat me nt.
6.
S u bject is nai ve t o a n y  bi ol o gical t hera pies f or U C.
O R
S u bject ma y  ha ve ha d pre vi o us e x p os ure t o a si n gle a nti-T N F bi ol o gic a ge nt w hic h 
was disc o nti n ue d f or reas o ns ot her t ha n pri mar y  n o n-res p o nse m ore t ha n 8 wee ks ( or 
5 half li ves w hic he ver is l o n ger) pri or t o first d ose.  
O R
S u bject ma y  ha ve ha d pre vi o us e x p os ure t o a si n gle bi ol o gic a ge nt (e. g., 
v e d oliz u ma b) i n t he c o nte xt of a pre vi o us cli nical trial.  T he bi ol o gic a ge nt m ust ha ve 
bee n disc o nti n ue d m ore t ha n 8 wee ks ( or 5 half li ves w hic he ver is l o n ger) pri or t o 
first d ose.  
N ote:  E x p os ure t o a si n gle bi ol o gic a ge nt is n ot re q uire d i n a d diti o n t o I ncl usi o n 
# 4 a n d # 5 a b o ve.
W EI G H T
7.
A b o d y  mass i n de x ( B MI) wit hi n ra n ge of 1 8. 5 – 3 5 k g/ m 2 (i ncl usi ve) at scree ni n g.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
2 9
S E X
8.
Male a n d fe male s u bjects:
M ales:
Male s u bjects wit h fe male part ners of c hil d beari n g p ote ntial m ust c o m pl y  wit h t he 
f oll o wi n g c o ntrace pti o n re q uire me nts i n A p pe n di x 6 .
Fe m ales : 
A fe male s u bject is eli gi ble t o partici pate if s he is n ot pre g na nt (as c o nfir me d b y  a 
ne gati ve ser u m h u ma n c h ori o nic g o na d otr o p hi n ( h C G) t est), n ot lactati n g, a n d at least 
o ne of t he f oll o wi n g c o n diti o ns a p plies:
a.
N o n -re pr o d ucti ve p ote ntial defi ne d as:
Pre -me n o pa usal fe males wit h o ne of t he f oll o wi n g:

D oc u me nte d t u bal li gati o n

D oc u me nte d h ys ter osc o pic t u bal occl usi o n pr oce d ure wit h f oll o w- u p
c o nfir mati o n of bilateral t u bal occl usi o n 

H y sterect o m y

D oc u me nte d Bilateral O o p h orect o m y

P ost me n o pa usal defi ne d as 1 2 m o nt hs of s p o nta ne o us a me n orr hea i n 
q uesti o na ble cases a bl o o d sa m ple wit h si m ulta ne o us f ollicle sti m ulati n g 
h or m o ne ( F S H) a n d estra di ol le vels c o nsiste nt wit h me n o pa use (refer t o 
la b orat or y refere nce ra n ges f or c o nfir mat or y le vels).  Fe males o n h or m o ne 
re place me nt t hera py ( H R T) a n d w h ose me n o pa usal stat us is i n d o u bt will be 
re q uire d t o use o ne of t he hi g hl y effecti ve c o ntrace pti o n met h o ds ( See 
A p pe n di x 6 ) if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u dy.  Ot her wise, 
t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost-me n o pa usal stat us 
pri or t o st u d y  e nr ol me nt.
b.
Re pr o d ucti ve p ote ntial a n d a grees t o f oll o w o ne of t he o pti o ns liste d i n t he M o difie d 
List of Hi g hl y Effecti ve Met h o ds f or A v oi di n g Pre g na nc y i n Fe males of 
Re pr o d ucti ve P ote ntial ( F R P) (see A p pe n di x 6 ) fr o m 3 0 da ys pri or t o t he first d ose 
of st u d y  me dicati o n a n d u ntil at least 2 da ys after t he last d ose of st u d y me dicati o n 
a n d c o m pleti o n of t he f oll o w -u p visit.
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat s u bjects u n dersta n d h o w t o pr o perly use 
t hese met h o ds of c o ntrace pti o n.
I NF O R M E D C O N S E N T
9.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n Secti o n 1 0. 2 w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he c o nse nt f or m 
a n d i n t his pr ot oc ol.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 0
5. 2.
E x cl u si o n Crit eri a
A s u bject will n ot be eli gi ble f or i ncl usi o n i n t his st u d y  if a ny of t he f oll o wi n g criteria 
a p pl y:
C O N C U R R E N T C O N DI TI O N S/ M E DI C A L  HI S T O R Y (I N C L U D E S LI V E R 
F U N C TI O N A N D Q Tc I N T E R V A L) 
1.
S u bject wit h dia g n osis of i n deter mi nate c olitis, Cr o h n’s Disease, i nfecti o us c olitis, or
isc he mic c olitis.
2.
S u bject wit h f ul mi na nt U C, or U C li mite d t o t he rect u m ( disease e xte nt < 1 5 c m fr o m
t he a nal ver ge).   
3.
S u bject wit h pre vi o us s mall b o wel or c ol o nic s ur ger y ( wit h e xce pti o n of
a p pe n dect o m y), hist ol o gical e vi de nce of c ol o nic d y s plasia or b o wel strict ure.
4.
S u bject wit h c ol ost o m y, fist ulae or k n o w n s ym pt o matic ste n osis of t he i ntesti ne.
5.
S u bject wit h t o xic me gac ol o n.
6.
S u bject wit h p ositi ve Cl ostri di u m difficile t o xi n test or acti ve/ pre vi o us c ol o nic C M V
i nfecti o n.
7.
S u bject wit h c urre nt hist or y of s uici dal i deati o n be ha vi o ur ( SI B) as meas ures usi n g
t he C ol u m bia S uici de Se verit y Rati n g Scale ( C-S S R S) or hist or y of atte m pte d
s uici de.
8.
A n acti ve i nfecti o n, or a hist or y of i nfecti o ns as f oll o ws:

H os pitalisati o n f or treat me nt of i nfecti o n wit hi n 6 0 da ys bef ore first d ose 
( Da y 1).

C urre ntl y  o n a n y s u p pressi ve t hera py f or a c hr o nic i nfecti o n (s uc h as 
p ne u m oc y stis, c yt o me gal o vir us, her pes si m ple x vir us, her pes z oster a n d 
at ypical m y c o bacteria).

Use of pare nteral (I V or i ntra m usc ular) a nti bi otics (a nti bacterials, a nti virals, 
a ntif u n gals, or a nti parasitic a ge nts) f or a n i nfecti o n wit hi n 6 0 da y s bef ore first 
d ose.

A hist or y  of o p p ort u nistic i nfecti o ns wit hi n 1 year of scree ni n g (e. g. 
p ne u m oc y stis jir o vecii, C M V p ne m o nitis, as per gill osis).  T his d oes n ot 
i ncl u de i nfecti o ns t hat ma y occ ur i n i m m u n oc o m pete nt i n di vi d uals, s uc h as 
f u n gal nail i nfecti o ns or va gi nal ca n di diasis, u nless it is of a n u n us ual se verit y 
or rec urre nt nat ure.

Rec urre nt or c hr o nic i nfecti o n or ot her acti ve i nfecti o n t hat, i n t he o pi ni o n of 
t he In vesti gat or mi g ht ca use t his st u d y  t o be detri me ntal t o t he patie nt.

Hist or y  of T B, irres pecti ve of treat me nt stat us.

A p ositi ve dia g n ostic T B test at scree ni n g defi ne d as a p ositi ve 
Q ua nti F E R O N -T B G ol d test or T -s p ot test.  In cases w here t he Q ua nti F E R O N 
or T -s p ot test is i n deter mi nate, t he s u bject ma y ha ve t he test re peate d o nce, 
b ut t he y  will n ot be eli gi ble f or t he st u dy u nless t he sec o n d test is ne gati ve. I n 
cases w here t he Q ua nti F E R O N or T -s p ot test is p ositi ve, b ut a f oll o w-u p c hest 
x- ra y, l ocall y rea d by a ra di ol o gist, s h o ws n o e vi de nce of c urre nt or pre vi o us 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 1
p ul m o nar y  t u berc ul osis, t he s u bject ma y be eli gi ble f or t he st u d y at t he 
discreti o n of t he I n vesti gat or a n d G S K Me dical M o nit or.
9.
Q Tc > 4 5 0 msec or Q Tc > 4 8 0 msec f or s u bjects wit h b u n dle bra nc h bl oc k at 
scree ni n g.
T he Q Tc is t he Q T i nter val c orrecte d f or heart rate acc or di n g t o eit her Bazett’s 
f or m ula ( Q Tc B), Fri dericia’s f or m ula ( Q Tc F), or a n ot her met h o d, mac hi ne or ma n ual 
o ver rea d.
T he s pecific f or m ula t hat will be use d t o deter mi ne eli gi bilit y  a n d disc o nti n uati o n f or 
a n i n di vi d ual s u bject s h o ul d be deter mi ne d pri or t o i nitiati o n of t he st u d y . I n ot her 
w or ds, se veral differe nt f or m ulae ca n n ot be use d t o calc ulate t he Q Tc f or a n 
i n di vi d ual s u bject a n d t he n t he l o west Q Tc val ue use d t o i ncl u de or disc o nti n ue t he 
s u bject fr o m t he trial. F or p ur p oses of data a nal ysis, Q Tc B, Q Tc F, a n ot her Q T 
c orrecti o n f or m ula, or a c o m p osite of a vaila ble val ues of Q Tc will be use d as 
s pecifie d i n t he Re p orti n g a n d A nalys is Pla n ( R A P).
1 0. A L T > 2 x U L N a n d bilir u bi n > 1. 5 x U L N (is olate d bilir u bi n > 1. 5 x U L N is acce pta ble if 
bilir u bi n is fracti o nate d a n d direct bilir u bi n < 3 5 %) at scree ni n g.
1 1. C urre nt acti ve or c hr o nic hist or y  of li ver or biliar y disease ( wit h t he e xce pti o n of 
Gil bert’s s y n dr o me or as y m pt o matic gallst o nes).
1 2. C urre nt or hist or y  of re nal disease or esti mate d gl o mer ular filtrati o n rate ( G F R) by 
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 ( C K D-E PI) 
calc ulati o n < 6 0 m L/ mi n/ 1. 7 3 m 2 at scree ni n g.
1 3. Here ditar y  or ac q uire d i m m u n o deficie nc y dis or der, i ncl u di n g i m m u n o gl o b uli n 
deficie nc y  u nless s u bject has a d oc u me nte d histor y  of selecti ve I g A deficie nc y.  
1 4. A maj or or ga n tra ns pla nt (e. g., heart, l u n g, ki d ne y, li ver) or he mat o p oietic ste m 
cell/ marr o w tra ns pla nt.
1 5. A n y  pla n ne d s ur gical pr oce d ure d uri n g t he st u d y.  
1 6. A hist or y  of mali g na nt ne o plas m wit hi n t he last 5 years, e xce pt f or a de q uatel y treate d 
n o n - metastatic ca ncers of t he s ki n ( basal or s q ua m o us cell) or carci n o ma i n sit u of t he 
uteri ne cer vi x t hat has bee n f ull y treate d a n d s h o ws n o e vi de nce of rec urre nce.
C O N C O MI T A N T M E DI C A TI O N S
1 7. T he s u bject has recei ve d treat me nt wit h t he t hera pies liste d i n Secti o n 6. 1 1. 2 , or 
c ha n ges t o t h ose treat me nts, wit hi n t he prescri be d ti mefra me.  If i n d o u bt, or t he 
t hera py is n ot liste d please c o ns ult wit h t he G S K me dical m o nit or.

Ot her me dicati o ns (i ncl u di n g vita mi ns, her bal a n d dietar y  s u p ple me nts) will 
be c o nsi dere d o n a case -b y -case basis, a n d will be all o we d if i n t he o pi ni o n of 
t he I nvesti gat or t he me dicati o n will n ot i nterfere wit h t he st u d y  pr oce d ures or 
c o m pr o mise s u bject safet y.
R E L E V A N T H A BI T S
1 8. Hist or y  of alc o h ol or dr u g a b use t hat w o ul d i nterfere wit h t he a bility t o c o m pl y  wit h 
t he st u d y.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 2
C O N T R AI N DI C A TI O N S 
1 9. Hist or y  of se nsiti vit y t o a n y of t he st u dy treat me nts, or c o m p o ne nts t here of or a 
hist or y  of dr u g or ot her aller g y t hat, i n t he o pi ni o n of t he I n vesti gat or or Me dical 
M o nit or, c o ntrai n dicates t heir partici pati o n.
2 0. Recei ve d a li ve or atte n uate d vacci ne wit hi n 3 0 da ys o f ra n d o mizati o n O R pla n t o 
recei ve a vacci nati o n d uri n g t he st u dy u ntil 5 half -li ves ( or 2 da ys) pl us 3 0 da ys after 
recei vi n g G S K 2 9 8 2 7 7 2.
2 1. T he s u bject has partici pate d i n a cli nical trial a n d has recei ve d a n i n vesti gati o nal 
pr o d uct wit hi n 3 0 da y s or 5 half-li ves, w hic he ver is l o n ger bef ore t he first d ose of 
st u d y me dicati o n, or pla ns t o ta ke part i n a n ot her cli nical trial ( n ot i ncl usi ve of a ny 
U C re gistr y  st u d y w here n o st u d y me dicati o n is bei n g a d mi nistere d) at t he sa me ti me 
as partici pati n g i n t his cli nica l trial.
DI A G N O S TI C A S S E S S M E N T S A N D O T H E R C RI T E RI A
2 2. Hae m o gl o bi n < 1 0 g/ d L ; hae mat ocrit < 3 0 %, w hite bl o o d cell c o u nt ≤3, 0 0 0/ m m 3 ( ≤3. 0 
x 1 0 9/ L); platelet c o u nt ≤ 1 0 0, 0 0 0/ µ L  ( ≤1 0 0 x 1 09/ L); a bs ol ute ne utr o p hil c o u nt ≤1. 5 
x 1 0 9/ L.
2 3. Prese nce of he patitis B s urface a nti ge n ( H Bs A g), p ositi ve he patitis C a nti b o d y test 
res ult at scree ni n g or wit hi n 3 m o nt hs pri or t o first d ose of st u d y treat me nt. As 
p ote ntial f or a n d ma g nit u de of i m m u n os u p pressi o n wit h t his c o m p o u n d is u n k n o w n, 
s u bjects wit h prese nce of he patitis B c ore a nti b o d y ( H Bc A b) s h o ul d be e xcl u de d.
2 4. A p ositi ve ser ol o g y  f or h u ma n i m m u n o deficie nc y vir us ( HI V) 1 or 2 at scree ni n g.
2 5. W here partici pati o n i n t he st u d y w o ul d res ult i n d o nati o n of bl o o d or bl o o d pr o d ucts 
i n e xcess of 5 0 0 m L wit hi n 3 m o nt hs.
2 6. E x p os ure t o m ore t ha n 4 i n vesti gati o nal me dici nal pr o d ucts wit hi n 1 2 m o nt hs pri or t o 
t he first d ose.
5. 3.
S cr e e ni n g/ B a s eli n e/ R u n -i n F ail ur e s
Scree n fail ures are defi ne d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical trial b ut 
are ne ver s u bse q ue ntl y ra n d o mize d. I n or der t o e ns ure tra ns pare nt re p orti n g of scree n 
fail ure s u bjects, meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) 
p u blis hi n g re q uire me nts, a n d res p o n d t o q ueries fr o m Re g ulat or y  a ut h orities, a mi ni mal 
set of scree n fail ure i nf or mati o n is re q uire d i ncl u di n g De m o gra p hy, Scree n Fail ure 
details, Eli gi bilit y  Criteria, a n d Seri o us A d verse E ve nts ( S A Es).  See Secti o n 7. 3. 1. 5 .
S u bjects w h o d o n ot q ualif y  t o partici pate i n t he st u d y d ue t o a scree ni n g la b orat or y val ue 
or E C G a b n or malit y ca n re peat t he test o nce wit hi n t he ori gi nal scree ni n g wi n d o w, if t he 
I n vesti gat or belie ves t here is a reas o na ble p ossi bilit y t hat t he s u bject w o ul d be eli gible if 
re-teste d.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 3
S u bjects ca n be re -scree ne d o nl y o n a p pr o val of t he G S K Me dical M o nit or a n d o nl y 
o nce.  Re -scree ni n g is all o we d w he n a s u bject faile d i ncl usi o n/e xcl usi o n criteria or s o me 
ot her scree ni n g c o n diti o n i nitiall y ( prefera bly bef ore perf or mi n g s i g m oi d osc o p y), b ut t he 
I n vesti gat or belie ves t here is a reas o na ble pr o ba bilit y t hat t he s u bject w o ul d be eli gi ble if 
re-scree ne d.
5. 4.
Wit h dr a w al/ St o p pi n g Crit eri a
S u bjects ma y  be wit h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:

A s u bject ma y  wit h dra w fr o m st u d y  treat me nt at a n y ti me at his/ her o w n re q uest, 
or ma y  be wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safet y, 
be ha vi o ural or a d mi nistrati ve reas o ns.  If a s u bject wit h dra ws fr o m t he st u d y, 
he/s he ma y  re q uest destr ucti on of a n y sa m ples ta ke n, a n d t he I n vesti gat or m ust 
d oc u me nt t his i n t he site st u d y  rec or ds.  T he reas o n f or wit h dra wal s h o ul d be 
d oc u me nte d i n t he C R F.

T he S p o ns or’s re q uest, f or reas o ns s uc h as si g nifica nt pr ot oc ol de viati o ns or 
s u bject safety c o ncer n (a n d after disc ussi o n wit h t he I n vesti gat or).

If a s u bject is wit h dra w n fr o m st u d y treat me nt, t his s u bject is als o c o nsi dere d t o 
be wit h dra w n fr o m t he st u d y .

St u d y  is ter mi nate d b y t he S p o ns or.
If a s u bject is wit h dra w n, t he S p o ns or ma y deci de t o re place t hat s u bject a n d t his will be 
d o ne t hr o u g h t he I nteracti ve Res p o nse Tec h n ol o g y S ys te m (I R T S).
If a s u bject c h o oses t o wit h dra w fr o m t he st u dy after d osi n g t he n t he I n vesti gat or m ust 
ma ke e ver y  eff ort t o c o m plete t he f oll o w- u p assess me nts detaile d i n t he Time a n d E ve nts 
Ta ble ( Secti o n 7. 1 ).
T he f oll o wi n g acti o ns m ust be ta ke n i n relati o n t o a s u bject w h o fails t o atte n d t he cli nic 
f or a re q uire d st u dy visit:

T he site m ust atte m pt t o c o ntact t he s u bject a n d re- sc he d ule t he misse d visit as 
s o o n as p ossi ble. 

T he site m ust 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. 

I n cases w here t he s u bject 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 h e s u bject’s last 
k n o w n maili n g a d dress or l ocal e q ui vale nt met 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 me dical rec or d. 

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, o nl y t he n will he/s he be c o nsi dere d 
t o ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of “ L ost t o F oll o w-u p”. 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 4
5. 4. 1.
I n di vi d u al S af et y St o p pi n g Crit eri a
St u d y  me dicati o n will be disc o nti n ue d i n t he e ve nt of a n y of t he f oll o wi n g:

If a s u bject e x perie nces a seri o us or se vere cli nicall y si g nifica nt A E t hat i n t he 
cli nical j u d ge me nt of t he I n vesti gat or, after c o ns ultati o n wit h t he me dical m o nit or, 
is p ossi bl y, pr o ba bly or defi nitel y relate d t o i n vesti gati o nal pr o d uct.

T he s u bject bec o mes pre g na nt.

T he s u bject i nitiates treat me nt wit h a n y  pr o hi bite d me dicati o n f or t he treatme nt of 
U C as liste d i n Secti o n 6. 1 1. 2 .

T he s u bject de vel o ps a seri o us o p p ort u nistic or at y pical i nfecti o n.

If a ny of t he li ver c he mistr y st o p pi n g c riteria ( Secti o n 5. 4. 3 ), Q Tc st o p pi n g 
criteria ( Secti o n 5. 4. 4 ), or Hae mat ol o gic st o p pi n g criteria ( Secti o n 5. 4. 5 ) are met.

T he s u bject e x perie nces a n y  si g ns of s uici dal i deati o n or be ha vi o ur ( Secti o n 
7. 3. 7 ).
5. 4. 2.
Gr o u p S af et y  St o p pi n g Crit eri a
I n a d diti o n t o t he criteria s pecifie d a b o ve, A Es, S A Es, la b orat or y a b n or malities, E C G 
a b n or mal ities a n d c ha n ges i n vital si g ns occ urri n g acr oss all ra n d o mise d s u bject will be 
re g ularly re vie we d b y t he S p o ns or Safet y Re vie w Tea m ( S R T) i n or der t o e ns ure 
a p pr o priate s u bject safet y.  A n y c ha n ges t o t he st u d y d ue t o safety reas o ns will be 
pr o m ptl y  c o m mu nicate d t o t he a p pr o priate Re g ulat or y  A ut h orities.
5. 4. 3.
Li v er C h e mi str y St o p pi n g Crit eri a
Li ver c he mistr y st o p pi n g a n d i ncre ase d m o nit ori n g criteri a ha ve bee n desi g ne d t o 
ass ure s u bject safet y a n d e val uate li ver e ve nt eti ol o g y (i n ali g n me nt wit h t he F D A 
pre mar keti n g cli nical li ver safet y  g ui da nce). 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ U C M 1 7 4 0 9 0. p df
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 5
Fi g ur e 3
P h a s e II Li v er C h e mi str y  St o p pi n g Crit eri a – Li v er St o p pi n g E v e nt s 
Al g orit h m
  Li ver Safet y Re q uire d Acti o ns a n d F oll o w u p Assess me nts Secti o n ca n be f o u n d i n 
A p pe n di x 2 . 
5. 4. 3. 1.
St u d y  Tr e at m e nt R e st art or R e c h all e n g e
St u d y  treat me nt restart or rec halle n ge after li ver c he mistr y  st o p pi n g criteria are met b y 
a n y s u bject partici pati n g i n t his st u d y is n ot all o we d.
5. 4. 4.
Q T c St o p pi n g Crit eri a
A s u bject w h o meets eit her of t he b ullete d criteria bel o w will be wit h dra w n fr o m t he 
st u d y:

Qtc  > 5 0 0 msec or U nc orrecte d Q T > 6 0 0 msec

C ha n ge fr o m baseli ne of Q Tc > 6 0 msec
F or patie nts wit h u n derl yi n g b u n dle bra nc h bl oc k, f oll o w t he disc o nti n uati o n criteria 
liste d bel o w:
B aseli ne Q Tc wit h B u n dle Br a nc h 
Bl oc k
Disc o nti n u ati o n Q Tc wit h B u n dle 
Br a nc h Bl oc k
< 4 5 0 msec
> 5 0 0 msec
4 5 0 – 4 8 0 msec
5 3 0 msec
C o nti n u e  St u d y Tr e at m e nt 
Di s c o nti n u e  St u d y Tr e at m e nt 
Pl u s
Bi lir ubi n ≥2 x
U L N ( > 35 % 
dir e ct ) 
or  pl us
I NR > 1. 5,  if 
m e a s ur e d *
P o s si bl e
H y ’ s La w
A L T ≥3 x U L N
A L T ≥5 x U L N
A L T ≥3 x U L N
Pl u s
S y m pt o m s  of 
li ver  inj ur y
or  
h y p er s e n s iti vit y
A L T ≥3 x U L N
b ut  abl e t o 
m o ni t or 
w e e k l y for  
4 w e e k s
N o
Y e s
Y e s
Y e s
Y e s
N o
N o
N o
N o
Y e s
A L T ≥3 x U L N
p er si st  for
4 w e e k s or  
st o p pi n g  
cr it eri a 
m et
Y e s
N o
*I NR v al u e n o t a p pli c a bl e t o s ubj e ct s o n  ant i c o a g ul a nts
Y e s

If s u bj e ct  to b e m o nit or e d w e e kl y m u st  ref er  t o Li v e r S af et y R e q ui r ed  Act i on s a n d  Fol l ow  up 
A s s e s s m e n t s  se ct i on  i n  t he  Ap p e n di x

M u st r ef er t o Li v er Saf et y R e q ui r ed A ct i on s  an d F ol l ow  up A s s e s s m e nt s  se ct i on i n th e A p p e n di x

R e p or t a s a n S A E if po s si bl e H y ’ s La w c a s e:  A L T ≥3 x U L N a n d  Bilir u b i n≥2 x U L N  (> 3 5 % di r ect )  or  
I NR > 1. 5,  if m e a s ur e d*
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 6

T he s a me Q T c orrecti o n f or m ula m ust be use d f or e ac h i n divi d u al s u bject t o 
deter mi ne eli gi bilit y  f or a n d disc o nti n uati o n fr o m t he st u d y.  T his f or m ula ma y 
n ot be c ha n ge d or s u bstit ute d o nce t he s u bject has bee n e nr olle d.
F or e xa m ple, if a s u bject is eli gi ble f or t he pr ot oc ol base d o n Q Tc B , t he n Q Tc B m ust be 
use d f or disc o nti n uati o n of t his i n di vi d ual s u bject as well.

O nce t he Q T c orrecti o n f or m ula has bee n c h ose n f or a s u bject’s eli gi bilit y , t he s a me 
f or m ul a m ust c o nti n ue t o be use d f or t hat s u bject f or all Q Tc d at a bei n g c ollecte d f or 
d at a a n alysis .  Safet y E C Gs a n d ot her n o n-pr ot oc ol s pecifie d E C Gs are a n 
e xce pti o n.  

T he decisi o n t o wit h dra w a s u bject will be base d o n a n a vera ge Q Tc val ue of 
tri plicate E C Gs.  If a n E C G de m o nstrates a pr ol o n ge d Q Tc, o btai n 2 m ore E C Gs 
o ver a brief peri o d ( 5 -1 0 mi n utes), a n d t he n use t he a vera ge d Q Tc val ues of t he 3 
E C Gs t o deter mi ne w het her t he s u bject s h o ul d be disc o nti n ue d fr o m t he st u d y .
5. 4. 5.
H a e m at ol o gi c St o p pi n g Crit eri a
St u d y  treat me nt will be st o p pe d f or a s u bject if a n y of t he f oll o wi n g hae mat ol o gical 
st o p pi n g criteria is met:

Hae m o gl o bi n < 9 g/ d L or a n a bs ol ute decrease of  ≥ 3 g/ d L fr o m baseli ne ( pre -d ose 
D a y  1)

Platelets < 5 0 × 1 0 9/ L
5. 5.
S u bj e ct a n d St u d y  C o m pl eti o n
A c o m plete d s u bject is o ne w h o has c o m plete d all p hases of t he st u d y i ncl u di n g t he 
f oll o w-u p visit.
T he e n d of t he st u d y is defi ne d as t he last s u bject’s last visit.
6.
S T U D Y T R E A T M E N T
6. 1.
I n v e sti g ati o n al Pr o d u ct a n d Ot h er St u d y Tr e at m e nt
T he ter m ‘st u d y treat me nt’ is use d t hr o u g h o ut t he pr ot oc ol t o descri be a n y c o m bi nati o n 
of pr o d ucts recei ve d b y t he s u bject as per t he pr ot oc ol desi g n. St u d y  treat me nt ma y 
t heref ore refer t o t he i n di vi d ual st u d y treat me nts or t he c o m bi nati o n of t h ose st u d y 
treat me nts.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 7
St u d y Tr e at m e nt
Pr o d u ct n a m e:
G S K 2 9 8 2 7 7 2
Pl ac e b o
D o s a g e f or m:
T a bl et
T a bl et
U nit d o s e 
str e n gt h( s)/ D o s a g e 
l e v el( s):
3 0 m g
N A
R o ut e of A d mi ni str ati o n
F or or al us e o nly
F or or al us e o nly
D o si n g i n str u cti o n s 
( wit h a m e n d m e nt 0 1):
T ak e T W O t a bl ets t hr e e 
ti m es a d ay as dir ect e d by 
y o ur p hysici a n
T ak e T W O t a bl ets t hr e e 
ti m es a d ay as dir ect e d by 
y o ur p hysici a n
D o si n g i n str u cti o n s
( pri or t o a m e n d m e nt 0 1):
T ak e T W O t a bl ets i n t h e 
M O R NI N G a n d T W O 
t a bl ets i n t h e E V E NI N G as 
dir ect e d
T ak e T W O t a bl ets i n t h e 
M O R NI N G a n d T W O 
t a bl ets i n t h e E V E NI N G as 
dir ect e d
P h y si c al d e s cri pti o n:
W hit e t o al m ost w hit e, 
r o u n d, fil m c o at e d t a bl et
W hit e t o al m ost w hit e, 
r o u n d, fil m c o at e d t a bl et
S o ur c e of pr o c ur e m e nt
St u dy m e dic ati o n is 
s u p pli e d by 
Gl ax o S mit h Kli n e
Pl ac e b o is s u p pli e d by 
Gl ax o S mit h Kli n e
6. 2.
Tr e at m e nt A s si g n m e nt
At Scree ni n g a u ni q ue S u bject N u m ber will be assi g ne d t o a n y s u bject w h o has si g ne d a 
c o nse nt f or m.  T he u ni q ue S u bject N u m ber will be use d t o i de ntif y  i n di vi d ual s u bjects 
d uri n g t he c o urse of t he st u d y .  A ny s u bject t hat is re -scree ne d o utsi de of t he all o we d 
scree ni n g wi n d o w at t he a p pr o val of t he G S K Me dical M o nit or, m ust be assig ne d a ne w 
u ni q ue S u bject N u m ber.
S u bjects w h o meet scree ni n g eli gi bilit y  criteria will be ra n d o mise d t o a treat me nt gr o u p 
t hr o u g h a n I nteracti ve Res p o nse Tec h n ol o g y Sys te m (IR T S).  T he I R T S will c o nfir m t he 
s u bject’s C R F n u m ber ( S u bject N u m ber) a n d pr o vi de t he ra n d o misati o n n u m ber, w here:

A ra n d o misati o n n u m ber will be assi g ne d fr o m a ra n d o misati o n sc he d ule 
ge nerate d b y Cli nical Statistics, pri or t o t he start of t he st u d y, usi n g vali date d 
i nter nal s oft ware.  O nce assi g ne d, t his n u m ber m ust n ot be reassi g ned t o a n y  ot her 
s u bject i n t he st u d y.
T heref ore, t he ra n d o misati o n is ce ntrall y  c o ntr olle d b y t he I R T S.
I n Part A, s u bjects will be ra n d o mise d t o recei ve eit her G S K 2 9 8 2 7 7 2 or place b o i n a 2: 1 
rati o f or 4 2 da ys.  I n Part B, all s u bjects w h o ha ve c o m plete d Part A will t he n recei ve 
G S K 2 9 8 2 7 7 2 i n o pe n la bel f or 4 2 da y s.
6. 3.
Pl a n n e d D o s e A dj u st m e nt s
N o d ose a dj ust me nts are all o we d.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 8
6. 4.
Bli n di n g
T his will be d o u ble bli n d (s p o ns or u n bli n de d) st u d y a n d t he f oll o wi n g will a p pl y : 

S p o ns or u n bli n de d refers o nl y  t o t he Data Re vie w C o m mittee, c o nsisti n g of t he 
G S K Pr oject P h y sicia n Lea d ( P P L), st u d y statisticia n, st u d y p har mac o ki neticist, 
Patter n Rec o g niti o n Rece pt or ( P R R) Disc o ver y  Perf or ma nce U nit ( D P U) Hea d, 
Earl y De vel o p me nt Lea der ( E D L), a n d Safet y Re vie w Tea m ( S R T) Lea der, or 
t heir desi g nees o n a n o n g oi n g basis.  A p hys icia n e xter nal t o t he G S K 2 9 8 2 7 7 2 
pr oject tea m ma y  als o be i n v ol ve d i n t he data re vie w.  A data re vie w c harter will 
i de ntif y t he s pecific G S K i n di vi d uals i n v ol ve d; o utli ne i n detail t he acti vities of 
t his re vie w, a n d h o w t he i nte grity of t he st u d y will be mai ntai ne d. T he rest of t he 
c ore G S K st u d y tea m will re mai n bli n de d.

T he I n vesti gat or or treati n g p h ys icia n ma y u n bli n d a s u bject’s treat me nt 
assi g n me nt o nl y i n t he c ase of a n e mer ge nc y O R i n t he e ve nt of a seri o us 
me dical c o n diti o n w he n k n o wle d ge of t he st u d y treat me nt is esse ntial f or t he 
a p pr o priate cli nical ma na ge me nt or welfare of t he s u bject as j u d ge d b y t he 
I n vesti gat or.  I n vesti gat ors ha ve direct access t o t he s u bject’s i n di vi d ual st u d y 
treat me nt.

It is preferre d ( b ut n ot re q uire d) t hat t he I n vesti gat or first c o ntacts t he Me dical 
M o nit or or a p pr o priate G S K st u d y  pers o n nel t o disc uss o pti o ns bef ore u n bli n di n g 
t he s u bject’s treat me nt assi g n me nt. 

If G S K pers o n nel are n ot c o ntacte d bef ore t he u n bli n di n g, t he I n vesti gat or m ust 
n otif y  G S K as s o o n as p ossi ble after u n bli n di n g, b ut wit h o ut re veali n g t he 
treat me nt assi g n me nt of t he u n bli n de d s u bject t o his/ her st u d y staff or G S K, 
u nless t hat i nf or mati o n is i m p orta nt f or t he safet y  of s u bjects c urre ntl y i n t he 
st u d y. 

T he date a n d reas o n f or t he u n bli n di n g m ust be f ull y  d oc u me nte d i n t he C R F. 

A s u bject will be wit h dra w n if t he s u bject’s treat me nt c o de is u n bli n de d b y t he 
I n vesti gat or or treati n g p h ysicia n.  T he pri mar y reas o n f or disc o nti n uati o n (t he 
e ve nt or c o n diti o n w hic h le d t o t he u n bli n di n g) will be rec or de d i n t he C R F.

G S K’s Gl o bal Cli nical Safet y a n d P har mac o vi gila nce ( G C S P) staff ma y u n bli n d 
t he treat me nt assi g n me nt f or a ny s u bject wit h a n S A E. If t he S A E re q uires t hat a n 
e x pe dite d re g ulat or y re p ort be se nt t o o ne or m ore re g ulat or y  a ge ncies, a c o p y of 
t he re p ort, i de ntif yi n g t he s u bject’s treat me nt assi g n me nt, ma y be se nt t o 
I n vesti gat ors i n acc or da nce wit h l ocal re g ulati o ns a n d/ or G S K p olic y.
6. 5.
P a c k a gi n g a n d L a b eli n g
T he c o nte nts of t he la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y 
re q uire me nts.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
3 9
6. 6.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
N o s pecial pre parati o n of st u d y  treat me nt is re q uire d.

O nl y  s u bjects e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nly 
a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y treat me nt.  All st u d y 
treat me nts m ust be st ore d i n a sec ure e n vir o n me ntall y c o ntr olle d a n d m o nit ore d 
( ma n ual or a ut o mate d) area i n acc or da nce wit h t he la belle d st ora ge c o n diti o ns 
wit h access li mite d t o t he a ut h orize d site staff . 

T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here 
a p plica ble) is res p o nsi ble f or st u d y treat me nt acc o u nta bilit y, rec o nciliati o n, a n d 
rec or d mai nte na nce (i.e. recei pt, rec o nciliati o n a n d fi nal dis p ositi o n rec or ds).  

F urt her g u i da nce a n d i nf or mati o n f or fi nal dis p ositi o n of u n use d st u d y treat me nt 
are pr o vi de d i n t he S R M. 

U n der n or mal c o n diti o ns of ha n dli n g a n d a d mi nistrati o n, st u d y  treat me nt is n ot 
e x pecte d t o p ose si g nifica nt safet y ris ks t o site staff .  

A Material Safet y  Data S heet ( M S D S)/e q ui vale nt d oc u me nt descri bi n g 
occ u pati o nal hazar ds a n d rec o m me n de d ha n dli n g preca uti o ns eit her will be 
pr o vi de d t o t he I n vesti gat or, w here t his is re q uire d b y  l ocal la ws, or is a vaila ble 
u p o n re q uest fr o m G S K.
6. 7.
C o m pli a n c e wit h St u d y  Tr e at m e nt Ad mi ni str ati o n
W he n s u bjects are d ose d at t he site, t he y  will recei ve st u d y treat me nt directl y fr o m t he 
I n vesti gat or or desi g nee, u n der me dical s u per visi o n.  T he date a n d ti me of eac h d ose 
a d mi nistere d i n t he cli nic will be rec or de d i n t he s o urce d oc u me n ts.  T he d ose of st u d y 
treat me nt a n d st u d y s u bject i de ntificati o n will be c o nfir me d at t he ti me of d osi n g by a 
me m ber of t he st u d y site staff.  
W he n s u bjects self- a d mi nister st u d y treat me nt(s) at h o me, c o m plia nce wit h G S K 2 9 8 2 7 7 2 
a n d place b o will be assess e d a n d d oc u me nte d t hr o u g h t he re vie w of t he s u bject’s diar y  
car d a n d q uer yi n g t he s u bject d uri n g t he site visits.  A rec or d of t he n u m ber of 
G S K 2 9 8 2 7 7 2 or place b o ta blets dis pe nse d t o a n d ta ke n b y eac h s u bject m ust be 
mai ntai ne d a n d rec o ncile d wit h st u d y  treat me nt a n d c o m plia nce rec or ds.  Treat me nt start 
a n d st o p dates, i ncl u di n g dates f or treat me nt dela ys a n d/ or d ose re d ucti o ns will als o be 
rec or de d i n t he st u d y diar y car ds a n d t he C R F.
6. 8.
Tr e at m e nt of St u d y  Tr e at m e nt O v er d o s e
F or t his st u d y , a n y d ose of G S K 29 8 2 7 7 2 > 1 8 0 m g  daily will be c o nsi dere d a n o ver d ose.  
G S K d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.  T he I n vesti gat or will use 
cli nical j u d ge me nt t o treat a n y o ver d ose as a n d w he n t he y are ma de a ware of t his.
I n t he e ve nt of a n o ver d ose t he In vesti gat or or treati n g p h y sicia n s h o ul d:
1.
C o ntact t he Me dical M o nit or i m me diatel y .
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 0
2.
Cl osel y  m o nit or t he s u bject f or a d verse e ve nts ( A Es)/seri o us a d verse e ve nts ( S A Es) 
f or at least 4 8 h o urs f oll o wi n g t he last d ose of G S K 2 9 8 2 7 7 2.
3.
O btai n a plas ma sa m ple f or p har mac o ki netic ( P K) a nal ys is if re q ueste d b y t he 
Me dical M o nit or ( deter mi ne d o n a case -b y -case basis).
4.
D oc u me nt all details of t he o ver d ose i n t he C R F.
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he I n vesti gat or 
i n c o ns ultati on 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.
6. 9.
Tr e at m e nt aft er t h e E n d of t h e St u d y
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat c o nsi derati o n has bee n gi ve n t o t he p ost -
st u d y care of t he s u bject’s me dical c o n diti o n, w het her or n ot G S K is pr o vi di n g s pecific 
p ost -st u d y treat me nt.
S u bjects will n ot recei ve a n y a d diti o nal treat me nt fr o m G S K after c o m pleti o n of t he 
st u d y beca use t he 1 2 wee k d urati o n of treat me nt is li mite d b y t he s u p p orti n g 1 3 wee k 
t o xic ol o g y st u dies.
6. 1 0.
Lif e st yl e a n d/ or Di et ar y  R e stri cti o n s

S u bjects m ust a d here t o t he c o ntrace pti ve re q uire me nts liste d i n A p pe n di x 6 .
6. 1 0. 1.
A c ti vit y

S u bjects will a bstai n fr o m stre n u o us e xerci se m ore t ha n t heir n or mal r o uti ne f or 
4 8 h o urs pri or t o eac h bl o o d c ollecti o n f or cli nical la b orat or y  tests.  

S u bject will a bstai n fr o m stre n u o us e xercise f or 2 4 h o urs after si g m oi d bi o ps y  
pr oce d ures.
6. 1 1.
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
6. 1 1. 1.
P er mitt e d M e di c ati o n s a n d N o n- Dr u g T h er a pi e s
Me dicati o ns f or t he treat me nt of U C ma y  be ta ke n, wit h s pecific re q uire me nts liste d i n 
Ta ble 1 , a n d as l o n g as the y  are n ot pr o hi bite d ( Secti o n 6. 1 1. 2 ).  All c o nc o mita nt 
me dicati o ns ta ke n d uri n g t he st u d y  will be rec or de d i n t he s o urce d oc u me nt a n d C R F.  
T he mi ni m u m re q uire me nt is t hat dr u g na me a n d dates of a d mi nistrati o n are rec or de d.
T a bl e 1
S p e cifi c R e q uir e m e nt s f or P er mitt e d M e di c ati o n s D uri n g t h e St u d y
Dr u g
R e q uir e m e nt
5 -A S A ( ≥ 2. 4 g/ d ay)
St a bl e d os e r e gi m e n f or at l e ast 4 w e eks pri or 
t o first d os e ( D ay 1) a n d t hr o u g h o ut t h e st u dy.  
P uri n e a n al o g u es ( az at hri o pri n e, 
m erc a pt o p uri n e, t hi o p uri n es)
St a bl e d os e r e gi m e n f or at l e ast 1 2 w e eks pri or 
t o first d os e ( D ay 1) a n d t hr o u g h o ut t h e st u dy. 
M et h otr ex at e ( M T X)
St a bl e d os e r e gi m e n f or at l e ast 1 2 w e eks fr o m 
first d os e ( D ay 1) a n d t hr o u g h o ut t h e st u dy.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 1
Dr u g
R e q uir e m e nt
Or al c ortic ost er oi ds ( u p t o 2 0 m g pr e d nis ol o n e 
or e q uiv al e nt).  S e e A p p e n dix 3 f or e q uiv al e nt 
d os es.
St a bl e d os e r e gi m e n f or at l e ast 2 w e eks pri or 
t o si g m oi d osc o py a n d t hr o u g h o ut t h e st u dy.
T o pic al (r ect al) c ortic ost er oi ds or 5 -A S A
St a bl e d os e r e gi m e n f or at l e ast 4 w e eks pri or 
t o first d os e ( D ay 1) a n d t hr o u g h o ut t h e st u dy.
6. 1 1. 2.
Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
Ta ble 2 lists pr o hi bite d me dicati o ns f or defi ne d peri o ds of ti me bef ore a n d d uri n g t he 
st u d y u ntil after t he f oll o w u p visit.
S u bjects w h o start pr o hi bite d me dicati o ns or t hera pies as a treat me nt f or U C or ot her 
reas o ns d uri n g t he st u dy will be wit h dra w n fr o m st u d y  treat me nt f or safety reas o ns.  If i n 
a n y d o u bt, I n vesti gat ors are a d vise d t o disc uss me dicati o ns wit h t he G S K me dical 
m o nit or.
T a bl e 2
Pr o hi bit e d M e di c ati o n s
T h er a p y
Ti m e p eri o d
A c h a n g e i n d os e of 5 -A S A
4 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2)
A c h a n g e i n d os e of p uri n e a n al o g u e
1 2 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2)
A c h a n g e i n d os e of M T X
1 2 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2).
Gr e at er t h a n 2 0 m g/d ay or al pr e d nis ol o n e ( or 
e q u iv al e nt c ortic ost er oi d) or a c h a n g e i n d os e 
of c ortic ost er oi d.
2 w e eks pri or t o si g m oi d osc o py u ntil aft er t h e 
f oll o w u p visit ( D ay 1 1 2).
A c h a n g e i n d os e or fr e q u e ncy of t o pic al 
(r ect al) c ortic ost er oi ds or t o pic al (r ect al) 5-A S A.
4 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2).
Ex p os ur e t o m or e t h a n o n e a nti -T N F bi ol o gic 
t h er a py i ncl u di n g b ut n ot li mit e d t o a nti-T N F 
bi ol o gics, i nflixi m a b, a d ali m u m a b, a n d 
g oli m u m a b.
E x c e pti o n :  Ex p os ur e t o a si n gl e a nti-T N F -
bi ol o gic f or w hi c h t h e s u bj ect t h e s u bj ect 
disc o nti n u e d f or a r e as o n ot h er t h a n pri m ary 
n o n -r es p o ns e.
C a n n ot h av e b e e n ex p os e d t o m or e t h a n 1 
a nti -T N F bi ol o gic or b e o n bi ol o gic t h er a py at 
a ny ti m e d uri n g t h e st u dy.
I n t h e c as e of a si n gl e a nti-T N F bi ol o gic f or 
w hic h t h e s u bj ect disc o nti n u e d f or a r e as o n 
ot h er t h a n pri m ary n o n -r es p o ns e, t h e s u bj ect 
m ust n ot b e o n f or 8 w e eks or 5 h alf liv es 
( w hic h ev er is l o n g er) pri or t o first d os e u ntil 
aft er t h e f oll o w u p visit ( D ay 1 1 2).  
Ex p os ur e t o a si n gl e b i ol o gic t h er a py f or t h e 
tr e at m e nt of U C ( ot h er t h a n a nti-T N F as 
d et ail e d a b ov e), i ncl u di n g b ut n ot li mit e d t o 
C a n n ot h av e b e e n o n at a ny ti m e , exc e pt f or 
v e d oliz u m a b i n a cli nic al tri al s etti n g w h er e it 
m u st h av e b e e n disc o nti n u e d f or 8 w e eks or 5 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 2
T h er a p y
Ti m e p eri o d
v e d oliz u m a b. 
E x c e pti o n :  v e d oliz u m a b pr evi o usly 
a d mi nist er e d i n a cli nic al tri al s etti n g .
h alf liv es (w hic h ev er is l o n g er ) pri or t o first 
d os e.
P -glyc o pr ot ei n ( P g p) i n hi bit ors i ncl u di n g b ut n ot 
li mit e d t o a mi o d ar o n e, azit hr o myci n, c a pt o pril, 
c arv e dil ol, cl arit hr o myci n, c o niv a pt a n, 
cycl os p ori n e, dilti az e m, dr o n e d ar o n e, 
eryt hr o myci n, f el o di pi n e, itr ac o n az ol e, 
k et oc o n az ol e, l o pi n avir, rit o n avir, q u erc eti n, 
q ui ni di n e, r a n ol azi n e, tic a gr el or, v er a p a mil 
[F D A , 2 0 1 2].
4 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2).
N arr o w t h er a p e utic i n d ex ( N TI) C Y P 3 A 4 
s u bstr at es i ncl u di n g b ut n ot li mit e d t o alf e nt a nil, 
ast e miz ol e, cis a pri d e, cycl os p ori n e, 
di hy dr o er g ot a mi n e, er g ot a mi n e, f e nt a nyl, 
pi m ozi d e, q ui ni di n e, sir oli m us, t acr oli m us, 
t erf e n a di n e [F D A , 2 0 1 2].
4 w e eks pri or t o t h e first d os e ( D ay 1) u ntil 
aft er t h e f oll o w u p vis it ( D ay 1 1 2).
Liv e v acci n ati o n
Liv er or att e n u at e d v acci n ati o ns ar e n ot 
p er mitt e d wit hi n 3 0 d ays of r a n d o miz ati o n or 
pl a n t o r ec eiv e a v acci n ati o n d uri n g t h e st u dy 
u ntil f oll o w -u p visit.  If i n dic at e d, n o n-liv e 
v acci n es ( e. g. i n activ at e d i nfl u e nz a v acci n e s) 
m ay b e a d mi nist er e d w hilst r ec eivi n g 
G S K 2 9 8 2 7 7 2 b as e d o n a n ass ess m e nt of t h e 
b e n efit:risk ( e. g. risk of d ecr e as e d 
r es p o nsiv e n ess).  I nv esti g at ors ar e ex p ect e d 
t o f oll o w l oc al a n d/ or n ati o n al g ui d eli n es wit h 
r es p ect t o v acci n ati o ns, i ncl u di n g a g ai nst 
i nfl u e nz a, i n s u bj ects wit h U C.
7.
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
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d wit h t he e xce pti o n of i m me diate safet y  
c o ncer ns. T heref ore, 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 Ti me a nd E ve nts Ta ble, are esse ntial a n d re q uire d f or st u d y  c o n d uct.
S u p ple me ntar y  st u d y c o n d uct i nf or mati o n n ot ma n date d t o be prese nt i n t his pr ot oc ol is 
pr o vi de d i n t he St u d y  Refere nce Ma n ual ( S R M) a n d la b orat or y ma n ual.  T he S R M a n d 
la b orat or y ma n ual will pr ovi de t he site pers o n nel wit h a d mi nistrati ve a n d detaile d 
tec h nical i nf or mati o n t hat d oes n ot i m pact s u bject safety.
T his secti o n lists t he pr oce d ures a n d para meters of eac h pla n ne d st u d y assess me nt.  T he 
e xact ti mi n g of eac h assess me nt is liste d i n t he Ti m e a n d E ve nts Ta ble Secti o n 7. 1 . 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 3

At st u d y  visits, t he Patie nt Re p orte d O utc o mes ( P R Os) s h o ul d be c o m plete d 
pri or t o a n y ot her st u d y assess me nts.

T he ti mi n g a n d n u m ber of pla n ne d st u d y  assess me nts, i ncl u di n g safety, 
p har mac o ki netic, p har mac o d y na mic/ bi o mar ker or ot her assess me nts ma y  be 
altere d d uri n g t he c o urse of t he st u d y  base d o n ne wl y a vaila ble data (e. g., t o 
o btai n data cl oser t o t he ti me of pe a k plas ma c o nce ntrati o ns) t o e ns ure 
a p pr o priate m o nit ori n g. 

T he c ha n ge i n ti mi n g or a d diti o n of ti me p oi nts f or a n y  pla n ne d st u dy 
assess me nts m ust be d oc u me nte d i n a N ote t o File w hic h is a p pr o ve d b y t he 
rele va nt G S K st u d y tea m me m ber a n d t he n arc hi ve d i n t he st u d y s p o ns or a n d 
site st u d y files, b ut t his will n ot c o nstit ute a pr ot oc ol a me n d me nt. 

N o m ore t ha n 5 0 0 m L of bl o o d will be c ollecte d o ver t he d urati o n of t he st u d y , 
i ncl u di n g a ny e xtra assess me nts t hat ma y be re q uire d.

T he I nstit uti o nal Re vie w B oar d /In de pe n de nt Et hics C o m mittee (I R B/I E C) will 
be i nf or me d of a n y safet y iss ues t hat re q uire alterati o n of t he safet y m o nit ori n g 
sc he me or a me n d me nt of t he Inf or me d C o nse nt F or m. 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 4
7. 1.
Ti m e a n d E v e nt s T a bl e
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
Sit e Visit
X
X
X
X
X
X
X
X
X
X
X
P h o n e c all
X
X
X
X
X
X
G e n er al/ S af et y A s s e s s m e nt s a n d Pr o c e d ur e s
I nf or m e d C o ns e nt
X
S u bj ect D e m o gr a p hy
X
F ull m e dic al hist ory 1
X
I ncl usi o n/ Excl usi o n Crit eri a
X
F ull p hysic al ex a m 2
X
X 
X
X
Bri ef p hysic al ex a m
X 4
X
X
X 4
X
X
Vit al si g ns ( B P, H R, R R, t e m p er at ur e)
X
X 4
X
X
X 4
X
X
X 
X
X
1 2 -l e a d E C G3
X
X 4
X
X
X 4
X
X
X 
X
X
C o nc o mit a nt m e dic ati o n r evi e w & A E 
r e p orti n g/ S A Es5
X ------------------------------------------------------------------------------------------------------------------------------------------X
P R O s/ Q u e sti o n n air e s/ Di s e a s e A s s e s s m e nt s a n d Pr o c e d ur e s
C ol u m bi a S uici d e S ev erity R ati n g 
Sc al e ( C -S S R S)
X
X 4
X 4
X 
X
I B D Q6
X 4
X 4
X 
X
U C EI S, M o difi e d Ril ey, G e b o es
X -------X 7
X 4
X
X
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 5
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
M ay o Sc or e (i ncl u di n g si g m oi d osc o py 
a n d bi o psy)
X -----X 7
X 4, 8
X 
X 9
P arti al M ay o Sc or e
X -----X 7
X
X
X 4
X 
X
St u d y Tr e at m e nt
R a n d o mis ati o n
X
St u dy m e dic ati o n ( t hr e e ti m es d aily) 10
X ----------------------------------------------------------X X -------------------------------------------------------X 11
Dis p e nsi n g of st u dy m e dic ati o n
X
X
X
Dis p e nsi n g of di ary c ar ds
X
X
X
X
X
X
C oll ecti o n of di ary c ar ds
X
X
X
X
X
X
L a b or at or y ( S af et y) A s s e s s m e nt s a n d Pr o c e d ur e s
T B, HI V, H e p B, H e p C A b, C. Difficil e 
t oxi n 
X
F S H & estr a di ol  (if a p plic a bl e)
X
S er u m pr e g n a ncy t est ( W C B P o nly)
X
Uri n e pr e g n a ncy t est ( W C B P o nly) 12
X 4
X
X
X 4
X
X
X 
X
X
H a e m at ol o gy, c h e mistry, uri n alysis 
X
X 4
X
X 13
X 4
X 13
X 13
X 
X
X
F a ec al c al pr ot ecti n 14
X 
X
X
X
X
X
X
X 
X
Bl o o d s a m pl e f or ex pl or at ory 
bi o m ark ers a n d T E 15
X 4
X 4
X 
X
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 6
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
P K bl o o d s a m pl es G S K 2 9 8 2 7 7 2 16
X
X 4
X 
X
Bi o psi es f or P K, i nfl a m m at ory 
bi o m ark ers, m R N A, T E & p at h w ay 
m ark er a n alysis
X -------X 7
X 4
X 
X 8
P h ar m ac o g e n etic s a m pl e ( P Gx) 17
X
F o ot n ot es:
1.
F ull m e dic al hist ory (i ncl u d es p ast a n d c urr e nt c o n diti o ns, m e dic ati o n hist ory, s u bst a nc e us a g e, a n d f a mily hist ory of pr e m at ur e C V dis e as e).
2.
F ull p hysic al ex a m (i ncl u d es h ei g ht/ w ei g ht at scr e e ni n g, h ei g ht n ot m e as ur e d at l at er ti m e p oi nts).
3.
Tri plic at e E C G t o b e p erf or m e d at scr e e ni n g o nly.
4.
Pr e -d os e.  
5.
A ny S A Es ass ess e d as r el at e d t o st u dy p artici p ati o n ( e. g., pr ot oc ol -m a n d at e d pr oc e d ur es, i nv asiv e t ests, or c h a n g e i n existi n g t h er a py) or r el at e d t o a G S K p r o d uct will b e 
r ec or d e d fr o m t h e ti m e a s u bj ect c o ns e nts t o p artici p at e i n t h e st u dy u p t o a n d i ncl u di n g a ny f oll o w-u p.  A Es will b e c oll ect e d fr o m t h e st art of St u dy Tr e at m e nt u ntil t h e f oll o w -u p 
c o nt act.
6.
P R O ass ess m e nts s h o ul d b e c o n d uct e d b ef or e a ny t es ts, pr oc e d ur es or ass ess m e nts t o av oi d i nfl u e nci n g t h e s u bj ects’ p erc e pti o n.
7.
Si g m oi d osc o py m ay b e p erf or m e d at a ny ti m e d uri n g t h e scr e e ni n g wi n d o w as a n a d diti o n al visit (if r e q uir e d) u p t o D ay -7 i n or d er f or c e ntr al r e a di n g c o nfir m ati o n of M ay o Sc or e 
f or i ncl usi o n.  If a s h ort er wi n d o w is r e q uir e d ( e. g., wit hi n D ay -3 t o D ay -7), t his will b e p er mitt e d as l o n g as it h as b e e n c o nfir m e d wit h t h e s p o ns or a n d c e ntr al r e a d er t h at r es ults 
of t h e M ay o e n d osc o py sc or e will b e av ail a bl e b ef or e e n d of t h e scr e e ni ng wi n d o w.  Hist ol o gic al dis e as e ( e. g., U C EI S, M R S a n d G e b o es I n d ex) al o n g wit h M ay o sc or e 
ass ess m e nts will als o b e c o m pl et e d.
8.
Si g m oi d osc o py m ay b e p erf or m e d o n a s e p ar at e d ay wit hi n t h e D ay 4 3 visit wi n d o w all o w a nc e ( 3 d ays).  A s e p ar at e visit t o p erf or m si g m oi d osc o py is o nly all o w e d t o 
acc o m m o d at e sc h e d uli n g.  T his s e p ar at e visit s h o ul d b e d o n e b ef or e t h e f ull D ay 4 3 visit w h er e P K, cli nic al l a b or at ory t ests a n d all ot h er r e q uir e d D ay 4 3 pr oc e d ur es ar e 
p erf or m e d.  S u bj ects m ust n ot t ak e t h eir st u dy m e dic a ti o n at h o m e i n t h e m or ni n g b ef or e t h e si g m oi d osc o py pr oc e d ur e a n d als o t h e m or ni n g b ef or e t h e f ull D ay 4 3 visit, if b ei n g 
d o n e o n a s e p ar at e d ay. Dis p e nsi n g of st u dy m e dic ati o n m ust b e d o n e at t h e 2 n d visit (if s e p ar at e visits ar e p erf or m e d).
9.
Bi o psy o nly r e q uir e d at E arly Wit h dr a w al visit if aft er at l e ast 1 4 d ays of tr e at m e nt a n d pri or t o D ay 4 3 or if aft er D ay 5 7 a n d pri or t o D ay 8 5.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 7
1 0.
S u bj ects m ust t ak e st u dy m e dic ati o n t hr e e ti m es a d ay a p pr oxi m at ely 8 h o urs a p art. Ex act ti m e of d osi n g t o b e r ec or d e d i n di ary c ar ds. O n D ay 4 3 a n d 8 5, s u bj ects m ust n ot t ak e 
t h eir st u dy m e dic ati o n at h o m e i n t h e m or ni n g. S u bj ects will c o m pl et e s p ecifi e d pr e-d os e ass ess m e nts a n d t h e n will b e a d mi nist er e d t h eir m or ni n g d os e of m e dic ati o n at sit e o n 
D ay 4 3.  O n D ay 8 5, s u bj ec ts ar e n o l o n g er r ec eivi n g st u dy m e dic ati o n.
1 1.
I n P art A, s u bj ects will b e r a n d o mis e d 2: 1 t o G S K 2 9 8 7 2 2 6 0 m g or pl ac e b o t hr e e ti m es d aily f or 4 2 d ays.  At t h e D ay 4 3 visit, all s u bj ects w h o h av e c o m pl et e d P art A, will m ov e i n 
t o P art B o p e n l a b el tr e at m e nt wit h G S K 2 9 8 2 7 7 2 6 0 m g t hr e e ti m es d aily f or 4 2 d ays.
1 2.
If uri n e pr e g n a ncy t est is p ositiv e, a c o nfir m at ory s er u m pr e g n a ncy t est m ust b e p erf or m e d.
1 3.
Uri n alysis n ot r e q uir e d o n D ays 2 9, 5 7 a n d 7 1.
1 4.
S u bj ects c a n pr ovi d e a f a ec al s a m pl e at a ny ti m e d uri n g t h e scr e e ni n g wi n d o w a n d u p t o 4 8 h o urs pri or t o a ny visit w h er e F C P is b ei n g c oll ect e d.  Pl e as e s e e l a b or at ory m a n u al 
f or f ull d et ails o n s a m pl e h a n dli n g a n d pr oc e d ur e.
1 5.
Bl o o d s a m pl es f or ex pl or at ory bi o m ark ers a n d T ar g et e n g a g e m e nt.  S e e l a b or at ory m a n u al f or f ull d et ails o n s a m pl e c oll ecti o n, h a n dli n g a n d s hi p m e nt.
1 6.
P K bl o o d s a m pl es f or G S K 2 9 8 2 7 7 2 will b e t ak e n pr e -d os e o n D ay 4 3. P ost -d os e s eri al P K s a m pl es will b e t ak e n o n D ays 1 a n d D ay 4 3 at t h e f oll o wi n g ti m e p oi nts: 1, 2, 4, a n d 6 
h o urs a n d tr o u g h o n D ay 8 5 o r E arly Wit h dr a w al.
1 7.
A P Gx bl o o d s a m pl e is c oll ect e d at t h e b as eli n e visit ( D ay 1), aft er t h e s u bj ect h as b e e n r a n d o miz e d a n d pr ovi d e d i nf or m e d c o ns e nt f or g e n etic r es e arc h.  If t h e s a m pl e is n ot 
c oll ect e d at t h e b as eli n e visit, it c a n b e c oll ect e d at a ny t i m e d uri n g t h e st u dy aft er r a n d o miz ati o n.
1 8.
Visit wi n d o ws d uri n g t h e tr e at m e nt p eri o d ar e r el ativ e t o D ay 1.
1 9.
If a s u bj ect wit h dr a ws fr o m t h e st u dy, ev ery eff ort will b e m a d e f or t h e s u bj ect t o c o m pl et e a n E arly Wit h dr a w al visit pri or t o t h e F oll o w U p visit.
2 0.
F oll o w -u p visit s h o ul d b e c o m pl et e d 2 8 d ays ( 3 d ays) aft er t h e l ast d os e of st u dy m e dic ati o n.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 8
7. 2.
S cr e e ni n g a n d Criti c al B a s eli n e A s s e s s m e nt s
After writte n i nf or me d c o nse nt, scree ni n g assess me nts will be p erf or me d as o utli ne d i n 
t he Ti me a n d E ve nts Ta ble ( Secti o n 7. 1 ).
T he f oll o wi n g de m o g ra p hic para meters will be ca pt ure d: year of birt h, se x, race a n d 
et h nicit y.
Me dical/ me dicati o n/fa mil y  hist or y, E C G a n d la b orat or y tests will be assesse d as relate d 
t o t he i ncl usi o n/e xcl usi o n criteria liste d i n Secti o n 5 .  
Car di o vasc ular me dical hist or y /ris k fact ors a n d s m o ki n g hist or y (as detaile d i n t he C R F) 
will be assesse d at scree ni n g.
Patie nt Re p orte d O utc o mes q uesti o n naires m ust be c o m plete d b y  s u bjects bef ore a n y 
ot her assess me nt at a cli nic visit.
7. 3.
S af et y
Pla n ne d ti me p oi nts f or all safet y  assess me nts are liste d i n t he Ti me a n d E ve nts Ta ble 
( Secti o n 7. 1 ).  A d diti o nal ti me p oi nts f or safet y tests (s uc h as vital si g ns, p h ysical e xa ms 
a n d la b orat or y safety tests) ma y be a d de d d uri n g t he c o urse of t he st u d y base d o n ne wl y 
a vaila ble data t o e ns ure a p pr o priate safet y m o nit ori n g.
T he I n vesti ga t or will be res p o nsi ble f or deter mi ni n g t he cli nical si g nifica nce of a ny 
res ults t hat fall o utsi de of t he la b orat or y n or mal ra n ges.
I n li ne wit h r o uti ne p har mac o vi gila nce, a n i nter nal G S K Safety Re vie w Tea m ( S R T), 
w hic h will i ncl u de 2 0 2 1 5 2 st u d y  tea m me m bers, will re vie w bli n de d safet y data, 
i ncl u di n g cli nical la b orat or y para meters a n d a d verse e ve nts, at a p pr o priate i nter vals 
d uri n g t he peri o d of st u d y  c o n d uct.
7. 3. 1.
A d v er s e E v e nt s ( A E) a n d S eri o u s A d v er s e E v e nt s ( S A E s)
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 5 .
T he I n vesti gat or a n d t heir desi g nees are 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 E or S A E.
7. 3. 1. 1.
Ti m e p eri o d a n d Fr e q u e n c y  f or c oll e cti n g AE a n d S A E i nf or m ati o n

A n y  S A Es assesse d as relate d t o st u d y partici pati o n (e. g., pr ot oc ol-ma n date d 
pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g t hera p y) or relate d t o a G S K 
pr o d uct will be rec or de d fr o m t he ti me a s u bject c o nse nts t o partici pate i n t he 
st u d y u p t o a n d i ncl u di n g a n y f oll o w-u p c o ntact. 

A Es will be c ollecte d fr o m t he start of St u d y  Treat me nt u ntil t he f oll o w- u p 
c o ntact (see Secti o n 7. 3. 1. 3 ), at t he ti me p oi nts s pecifie d i n t he Ti me a n d E ve nts 
Ta ble ( Secti o n 7. 1 ).
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
4 9

Me dical occ urre nces
t hat be gi n pri or t o t he start of st u d y treat me nt b ut after 
o btai ni n g i nf or me d c o nse nt ma y  be rec or de d o n t he Me dical Hist or y/ C urre nt 
Me dical C o n diti o ns secti o n of t he C R F.

All S A Es will be rec or de d a n d re p orte d t o G S K wit hi n 2 4 h o urs, as i n dicate d i n 
A p pe n di x 5 . 

I n vesti gat ors are n ot o bli gate d t o acti vely see k A Es or S A Es i n f or mer st u d y 
s u bjects. H o we ver, if t he I n vesti gat or lear ns of a ny S A E, i ncl u di n g a de at h, at a n y 
ti me after a s u bject has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he 
e ve nt reas o na bl y relate d t o t he st u d y  treat me nt or st u d y partici pati o n, t he 
I n vesti gat or m ust pr o m ptl y n otif y G S K.
N O T E : T he met h o d of rec or di n g, e val uati n g a n d assessi n g ca usalit y of A Es a n d S A Es 
pl us pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts t o G S K are pr o vi de d i n 
A p pe n di x 5 .
7. 3. 1. 2.
M et h o d of D et e cti n g A E s a n d S A E s
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d 
a n d n o n -lea di n g ver bal q uesti o ni n g of t he s u bject is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nce.  A p pr o priate q uesti o ns i ncl u de:

“ H o w are y o u feeli n g?” 

“ Ha ve y o u ha d a n y ( ot her) me dical pr o ble ms si nce yo ur last visit/c o ntact?”

“ Ha ve y o u ta ke n a n y ne w me dici nes, ot her t ha n t h ose pr o vi de d i n t his st u d y , si nce 
y o ur last visit/c o ntact?” 
7. 3. 1. 3.
F oll o w- u p of A E s a n d S A E s
After t he i nitial A E/ S A E re p ort, t he I n vesti gat or i s re q uire d t o pr oacti vely f oll o w eac h 
s u bject at s u bse q ue nt visits/c o ntacts.  All S A Es, a n d n o n-seri o us A Es of s pecial i nterest 
(as defi ne d i n Secti o n 4. 6. 1 ) will be f oll o we d u ntil res ol uti o n, u ntil t he c o n diti o n 
sta bilizes, u ntil t he e ve nt is ot her wise e x plai ne d, or u ntil t he s u bject is l ost t o f oll o w- u p 
(as defi ne d i n Secti o n 5. 4 ). F urt her i nf or mati o n o n f oll o w-u p pr oce d ures is gi ve n i n 
A p pe n di x 5 .
7. 3. 1. 4.
C ar di o v a s c ul ar a n d D e at h E v e nt s
F or a n y car di o vascular e ve nts detaile d i n A p pe n di x 5 a n d all deat hs, w het her or n ot t he y 
are c o nsi dere d S A Es, s pecific Car di o vasc ular ( C V) a n d Deat h sec ti o ns of t he C R F will 
be re q uire d t o be c o m plete d.  T hese secti o ns i ncl u de q uesti o ns re gar di n g car di o vasc ular 
(i ncl u di n g s u d de n car diac deat h) a n d n o n-car dio vasc ular deat h.
T he C V C R Fs are prese nte d as q ueries i n res p o nse t o re p orti n g of certai n C V Me d D R A 
ter ms.  T he C V i nf or mati o n s h o ul d be rec or de d i n t he s pecific car di o vasc ular secti o n of 
t he C R F wit hi n o ne wee k of recei pt of a C V E ve nt data q uer y pr o m pti ng its c o m pleti o n.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 0
T he Deat h C R F is pr o vi de d i m me diatel y after t he occ urre nce or o utc o me of deat h is 
re p orte d.  I nitial a n d f oll o w- u p re p orts re gar di n g deat h m ust be c o m plete d wit hi n o ne 
wee k of w he n t he deat h is re p orte d.
7. 3. 1. 5.
R e g ul at or y  R e p orti n g R e q uir e m e nt s f or S AE s
Pr o m pt n otificati o n b y  t he I n vesti gat or t o G S K of S A Es relate d t o st u d y treat me nt (e ve n 
f or n o n- i nter ve nti o nal p ost-mar keti n g st u dies) is esse ntial s o t hat le gal o bli gati o ns a n d 
et hical res p o nsi bilities t o war ds t he safet y of s u bjects a n d t he safe t y of a pr o d uct u n der 
cli nical i n vesti gati o n are met. 
G S K has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h ority a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a pr o d uct u n der cli nical i n vesti gati o n.  G S K will 
c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts relati n g t o safety re p orti n g t o t he 
re g ulat or y a ut h ority, I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee 
(I E C) a n d I n vesti gat ors.
I n vesti gat or safet y re p orts are pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns acc or di n g t o l ocal re g ulat or y re q uire me nts a n d G S K p olic y a n d are f or war de d 
t o In vesti gat ors as necessar y .
A n I n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E(s) or ot her 
s pecific safety i nf or mati o n (e. g., s u m mar y or listi n g of S A Es) fr o m G S K will file it wit h 
t he I B a n d will n otif y t he IR B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
7. 3. 2.
Pr e g n a n c y

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 d os i n g a n d f or 3 0 u p t o 9 0 da ys (as a p plica ble) 
after t he last d ose.

If a pre g na nc y is re p orte d wit hi n 3 0 da ys ( 9 0 da ys i n part ners) after t he last d ose 
t he n t he I n vesti gat or s h o ul d i nf or m G S K wit hi n 2 wee ks of lear ni n g of t he 
pre g na nc y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 6 .
7. 3. 3.
P h y si c al E x a m s

A c o m plete p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nt of t he 
hea d, e y es, ears, n ose, t hr oat, s ki n, t h yr oi d, j oi nt, l ym p h n o des, car di o vasc ular, 
res pirat or y, gastr oi ntesti nal a n d ne ur ol o gical s yste ms. Hei g ht a n d wei g ht will als o 
be meas ure d a n d rec or de d at t he first p h y sical e xa mi nati o n. 

A brief p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m assess me nts of t he l u n gs, 
car di o vasc ular s ys te m, a n d a b d o me n (li ver a n d s plee n).

I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
seri o us ill nesses.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 1
7. 3. 4.
Vit al Si g n s

Vital si g ns will be meas ure d i n a s u pi ne or se mi- s u pi ne p ositi o n after 
a p pr o xi matel y 5 mi n utes rest a n d will i ncl u de te m perat ure, s yst olic a n d diast olic 
bl o o d press ure, p ulse rate a n d res pirat or y  rate. 
7. 3. 5.
El e ctr o c ar di o gr a m ( E C G)

Tri plicate 1 2 -lea d E C Gs will be o btai ne d at scree ni n g a n d si n gle 1 2-lea d E C Gs 
o btai ne d at e ver y  ti me p oi nt d uri n g t he st u dy usi n g a n E C G mac hi ne t hat 
a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc ( F or 
B) i nter vals.  A ma n ual o ve r rea d is als o all o we d.  Refer t o Secti o n 5. 4. 4 f or Q Tc 
wit h dra wal criteria a n d a d diti o nal Q Tc rea di n gs t hat ma y  be necessar y.

T he Q Tc s h o ul d be ba se d o n a vera ge d Q Tc val ues of tri plicate electr ocar di o gra ms 
o btai ne d o ver a brief (e. g., 5 -1 0 mi n utes) rec or di n g peri o d.  

E C G t o be meas ure d i n a se mi -s u pi ne or s u pi ne p ositi o n after a p pr o xi matel y 5 
mi n utes rest.
7. 3. 6.
Cli ni c al S af et y  L a b or at or y As s e s s m e nt s
All pr ot oc ol re q uire d la b orat or y  assess me nts, as defi ne d i n Ta ble 3 , 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, a n d Pr ot oc ol Ti me a n d E ve nts Sc he d ule.
La b orat or y  re q uisiti o n f or ms m ust be c o m plete d a n d sa m ples m ust be clearl y la belle d 
wit h t he s u bject n u m ber, pr ot oc ol n u m ber, site/ce ntre n u m ber, a n d visit date.
Details f or 
t he pre parati o n a n d s hi p me nt of sa m ples will be pr o vi de d by t he l a b orat or y a n d are 
detaile d la b orat or y  ma n ual. Refere nce ra n ges f or all safety para meters will be pr o vi de d t o 
t he site b y t he la b orat or y res p o nsi ble f or t he assess me nts.
If a d diti o nal n o n-pr ot oc ol s pecifie d la b orat or y  assess me nts are perf or me d at t he 
i nstituti o n’s l ocal la b orat or y a n d res ult i n 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., S A E or A E or d ose 
m o dificati o n) t he res ults m ust be rec or de d i n t he C R F.
Refer t o t he la b orat or y  ma n ual f or a p pr o priate pr ocessi n g a n d ha n dli n g of sa m ples t o 
a v oi d d u plicate a n d/ or a d diti o nal bl o o d dra ws.
All st u d y -re q uire d la b orat or y assess me nts will be perf or me d by a ce ntral la b orat or y, a part 
fr o m:

Hae mat ol o g y , platelets a n d c oa g ulati o n sa m ple if t he y are re q uire d to be ta ke n 
cl oser t o t he bi o psies (as per l ocal practices) t ha n s pecifie d i n Secti o n 5. 4. 5 .
N O T E :  L ocal la b orat or y res ults are o nly re q uire d i n t he e ve nt t hat t he ce ntral la b orat or y  
res ults are n ot a vaila ble i n ti me f or eit her a treat me nt a n d/ or res p o nse e val uati o n t o be 
perf or me d.  If a l ocal sa m ple is re q uire d, it is i m p orta nt t hat t he sa m ple f or ce ntral 
a nal ys is be o btai ne d at t he sa me ti me.  A d diti o nall y, if t he l ocal la b orat or y res ults are 
use d t o ma ke eit her a treat me nt or res p o nse e val uati o n, t he res ults m ust be e ntere d i nt o 
t he C R F.
Hae mat ol o g y , cli nical c he mistr y, uri nalys is a n d a d diti o nal para meters t o be teste d are 
liste d i n Ta ble 3 . 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 2
T a bl e 3
Pr ot o c ol R e q uir e d S af et y  L a b or at or y As s e s s m e nt s
L a b or at or y 
Assess me nts
P ar a meters
Hae mat ol o g y  
1, 2
Pl at el et C o u nt
R B C I n dic es:
W B C c o u nt wit h Diff er e nti al :
R B C C o u nt
M C V
N e utr o p hils
H e m o gl o bi n
M C H
Ly m p h ocyt es
H e m at ocrit
M o n ocyt es
E osi n o p hils
B as o p hils
Cli nical 
C he mistr y  3
B U N
P ot assi u m
A S T ( S G O T)
T ot al a n d dir ect 
bilir u bi n
Cr e ati ni n e
S o di u m
A L T ( S G P T)
T ot al Pr ot ei n
Gl uc os e 4 
C alci u m
Alk ali n e p h os p h atis e
Al b u mi n
C R P
Tri glyc eri d es 4
T ot al C h ol est er ol 4
H D L c h ol est er ol 4
L D L 
c h ol est er ol 4
R o uti ne 
Uri nal y sis

S pecific gra vit y

p H, gl uc ose, pr otei n, bl o o d a n d ket o nes b y di pstic k

Micr osc o pic e xa mi nati o n (if bl o o d or pr otei n is a b n or mal)
Ot her 
Scree ni n g a n d 
R o uti ne Tests

HI V 1 & 2

He patitis B ( H Bs A g)

He patitis B c ore a nti b o d y  ( H Bc A b)

He patitis C ( He p C a nti b o d y )

Q ua nti Fer o n G ol d Test

T- s p ot (if Q ua nti Fer o n is i n deter mi na nt)

F S H a n d estra di ol (as nee de d i n w o me n of n o n -c hil d beari n g 
p ote ntial o nl y )

Uri ne h C G Pre g na nc y  test (as nee de d f or w o me n of c hil d beari n g 
p ote ntial) 5

Ser u m h C G (as nee de d f or w o me n of c hil d beari n g p ote ntial) t o be 
d o ne at scree ni n g a n d if uri ne test p ositi ve at ot her ti me p oi nts i n t he 
st u d y.

Esti mate d gl o mer ular filtrate rate (e G F R) will be calc ulate d usi n g 
t he C K D-E PI f or m ula.

C. Difficile t o xi n.
F o ot n ot e s :
1.
T h e s u bj ect’s C B C r es ults fr o m t h e pr evi o us sc h e d ul e d visit m ay b e c h eck e d pri or t o t h e si g m oi d osc o py acc or di n g 
t o l oc al pr actices a n d m ay b e r e p e at e d at t h e discr eti o n of t h e I nv esti g at or.
2.
D et ails of H a e m at ol o gic St o p pi n g Crit eri a ar e giv e n i n S ecti o n 5. 4. 5 .
3.
D et ails of Liv er C h e mistry St o p pi n g Crit eri a a n d R e q uir e d Acti o ns a n d F oll o w -U p Ass ess m e nts aft er liv er st o p pi n g 
or m o nit ori n g ev e nt ar e giv e n i n S ecti o n 5. 4. 3   a n d A p p e n dix 2 .
4.
N o f asti n g r e q uir e d.  A ny a b n or m al r es ult f or gl uc os e or li pi ds  ( n o n-f ast e d) m ay b e r e p e at e d at t h e discr eti o n of 
t h e I nv esti g at or.
5.
L oc al uri n e t esti n g will b e st a n d ar d f or t h e pr ot oc ol u nl ess s er u m t esti n g is r e q uir e d by l oc al r e g ul ati o n or et hics 
c o m mitt e e.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 3
All la b orat or y  tests wit h val ues t hat are c o nsi dere d cli nicall y si g nifica ntly a b n or mal 
d uri n g partici pati o n i n t he st u d y  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.  If s uc h val ues d o n ot ret ur n t o n or mal wit hi n a peri o d 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 n otifie d.
7. 3. 7.
S ui ci d al Ri s k M o nit ori n g
G S K 2 9 8 2 7 7 2 is c o nsi d ere d t o be a C N S -acti ve dr u g. T here has bee n s o me c o ncer n t hat 
s o me C N S-acti ve dr u gs ma y be ass ociate d wit h a n i ncrease d ris k of s uici dal t hi n ki n g or 
be ha vi o ur w he n gi ve n t o s o me patie nts wit h U C.  Alt h o u g h t his dr u g has n ot bee n s h o w n 
t o be ass ociate d with a n i ncrease d ris k of s uici dal t hi n ki n g or be ha vi o ur w he n gi ve n t o 
healt h y  v ol u nteers, G S K c o nsi ders it i m p orta nt t o m o nit or f or s uc h e ve nts bef ore or 
d uri n g cli nical st u dies wit h c o m p o u n ds s uc h as t his.   
S u bjects bei n g treate d wit h G S K 2 9 8 2 7 2 2 s h o ul d be m o nit ore d a p pr o priatel y  f or s uici dal 
i deati o n a n d be ha vi o ur or a ny ot her u n us ual c ha n ges i n be ha vi o ur. St u d y  me dicati o n 
m ust be i m me diatel y  disc o nti n ue d i n all s u bjects w h o e x perie nce si g ns of s uici dal 
i deati o n or be ha vi o ur.
Fa milies a n d care gi vers of s u bjects bei n g treate d wit h G S K 2 9 8 2 7 7 2 s h o ul d be alerte d 
a b o ut t he nee d t o m o nit or s u bjects f or t he e mer ge nce of u n us ual c ha n ges i n be ha vi o ur, as 
well as t he e mer ge nce of s uici dal i deati o n a n d be ha vi o ur a n d t o re p ort s uc h s y m pt o ms 
i m me diatel y t o t he st u d y In vesti gat or.
At Scree ni n g a n d baseli ne ( pre -d ose Da y  1), t he ‘ Baseli ne/ Scree ni n g C S S R S’ will be 
c o m plete d.  At Da ys 4 3 ( Wee k 6) a n d 8 5 ( Wee k 1 2), t he ‘ Si nce Last Visit C S S R S’ will 
be c o m plete d.  G S K Versi o n 4. 1 of b ot h rati n g scales will be use d.
S u bjects w h o a ns wer ‘ yes’ t o a n y  s uici dal be ha vi o ur or ‘ yes’ t o s uici dal i deati o n 
Q uesti o ns 4 or 5 will be referre d t o t heir G P or a p pr o priate ps yc hiatric care.  T he me dical 
m o nit or will be n otifie d.  If a p pr o priate, a n A E or S A E s h o ul d be re p orte d (see 
Secti o n 7. 3. 1 A E a n d S A E).  I n a d diti o n, t he I n vesti gat or s h o ul d c o m plete a P ossi ble 
S uici dalit y  Relate d A d verse E ve nt ( P S R A E) f or m t o c ollect detaile d i nf or mati o n o n t he 
circ u msta nces of t he re p orte d A Es w hic h, i n t he I n vesti gat or’s o pi ni o n, are p ossi bl y  
s uici dalit y-relate d.  T hese ma y i ncl u de, b ut are n ot li mite d t o, a n e ve nt i n v ol vi n g s uici dal 
i deati o n, a pre parat or y act t o war d i m mi ne nt s uici dal be ha vi o ur, a s uici de atte m pt, or a 
c o m plete d s uici de.
7. 4.
Effi c a c y
7. 4. 1.
P ati e nt R e p ort e d O ut c o m e s
Patie nt Re p orte d O utc o mes q uesti o n naires s h o ul d be c o m plete d b y  s u bjects bef ore a n y 
ot her assess me nt at a cli nic visit.
7. 4. 1. 1.
I nfl a m m at or y B o wel Di s e a s e Q u e sti o n n air e (I B D Q)
T he I B D Q is a 3 2-ite m I nfla m mat or y B o wel Disease-s pecific healt h y relate d q ualit y of 
life i nstr u me nt e val uati n g ge neral acti vities of dail y li vi n g, i ntesti nal f u ncti o n, s ocial 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 4
perf or ma nce, pers o nal i nteracti o ns, a n d e m oti o nal stat us.  T he I B D Q q uesti o n naire will 
be c o m plete d b y eac h s u bject as detaile d i n Secti o n 7. 1 .  Ite ms res p o nses are s u m me d- u p 
f or a t otal sc ore a n d als o a vera ge d a m o n g f o ur di me nsi o ns: b o wel f u ncti o n ( 1 0 ite ms), 
s yste mic sy m pt o ms ( 5 ite ms), s ocial f u ncti o n ( 5 ite ms), a n d e m oti o nal stat us ( 1 2 ite ms).
7. 4. 2.
Cli ni c al Di s e a s e A s s e s s m e nt s
Brief details are gi ve n bel o w a n d detaile d pr oce d ural i nstr ucti o ns are gi ve n i n t he S R M.
7. 4. 2. 1.
M a y o S c or e
T he Ma y o Sc ore is a 1 2-p oi nt sc ori n g s ys te m (Ta ble 4 ) use d t o assess U C disease acti vit y 
base d o n 
 a n d  
.  
A partial Ma y o Sc ore is a sc ori n g s ys te m w here disease acti vit y is e val uate d base d o n 
 a n d 
, wit h o ut e n d osc o pic 
c o m p o ne nts. 
T otal a n d Partial Ma y o Sc ores will be c ollecte d a n d sc ore d ce ntrall y at all ti me p oi nts 
i n dicate d i n Secti o n 7. 1 .
T a bl e 4
M a y o S c or e
Si g n/ S y m pt o m
S c or e
 
C CI
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or 
i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 5
7. 4. 2. 2.
Ul c er ati v e C oliti s E n d o s c o pi c I n d e x of S e v erit y  ( U C EI S)
U C EI S will be use d as a n a d diti o nal t o ol t o assess disease acti vit y base d o n e n d osc o pic 
 a n d  
 (Ta ble 5 ).  It has bee n s h o w n t o 
acc uratel y pre dict o verall assess me nt of e n d osc o pic se verit y of U C [ Tra vis , 2 0 1 2].  T he 
U C EI S is a sc ori n g s ys te m U C EIS will be c ollecte d a n d sc ore d ce ntrall y at  all ti me p oi nts 
i n dicate d i n Secti o n 7. 1 .
T a bl e 5
U C EI S
D e s cri pt or ( s c or e m o st 
s e v er e l e si o n s)
Li k ert s c al e a n c h or p oi nt s
D efi nititi o n
 
C CI
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 6
D e s cri pt or ( s c or e m o st 
s e v er e l e si o n s)
Li k ert s c al e a n c h or p oi nt s
D efi nititi o n
7. 4. 3.
Hi st ol o gi c al Di s e a s e A s s e s s m e nt s
Bi o ps y  sa m ples ta ke n d uri n g si g m oi d osc o py will be sc ore d ce ntrall y usi n g b ot h t he 
Ge b oes I n de x [ Ge b oes , 2 0 0 0] a n d M o difie d Rile y Sc ore [Rile y , 1 9 9 1] w hic h are 
hist ol o gical sc ori n g i n dices f or e val uati o n of disease acti vit y  i n U C.  
Hist ol o g y  will be assesse d at t he ti me p oi nts i n dicate d i n Secti o n 7. 1 .
7. 4. 3. 1.
G e b o e s I n d e x
T he Ge b oes I n de x is s h o w n i n Ta ble 6 .  U p o n sc ori n g of all c o m p o ne nts of t he i n de x, t he 
hi g hest gra de wit h a s u b gra de a b o ve 0 will be rec or de d as a hist ol o gical sc ore. 
T a bl e 6
G e b o e s I n d e x
Gr a d e
S u b gr a d e
0
Str u ct ur al ( ar c hit e ct ur al 
c h a n g e)
0. 0
N o a b n or m ality
0. 1
Mil d a b n or m ality
0. 2
Mil d or m o d er at e diff us e or m ultif oc al a b n or m aliti es
0. 3
S ev er e diff us e or m ultif oc al a b n or m aliti es
1
C hr o ni c i nfl a m m at or y 
i nfiltr at e
1. 0
N o i ncr e as e
1. 1
Mil d b ut u n e q uiv oc al i ncr e as e
1. 2
M o d er at e i ncr e as e
1. 3
M ark e d i ncr e as e
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 7
Gr a d e
S u b gr a d e
2
L a mi n a pr o pri a e o si n o p hil s 
a n d n e utr o p hil s (t o b e 
gr a d e d s e p ar at el y)
2. 0
N o i ncr e as e
2. 1
Mil d b ut u n e q uiv oc al i ncr e as e
2. 2
M o d er at e i ncr e as e
2. 3
M ark e d i ncr e as e
3
N e utr o p hil s i n e pit h eli u m
3. 0
N o n e
3. 1
< 5 % cry pts i nv olv e d
3. 2
< 5 0 % cry pts i nv olv e d
3. 3
> 5 0 % cry pts i nv olv e d
4
Cr y pt d e str u cti o n
4. 0
N o n e
4. 1
Pr o b a bl e – l oc al exc ess of n e utr o p hils i n p art of cry pt
4. 2
Pr o b a bl e – m ark e d att e n u ati o n
4. 3
U n e q uiv oc al cry pt d estr ucti o n
5
Er o si o n or ul c er ati o n
5. 0
N o er osi o n, ulc er ati o n, or gr a n ul ati o n tiss u e
5. 1
R ec ov eri n g e pit h eli u m pl us a dj ac e nt i nfl a m m ati o n
5. 2
Pr o b a bl e er osi o n – f oc ally stri p p e d
5. 3
U n e q uiv oc al er osi o n
5. 4
Ulc er or gr a n ul ati o n tiss u e
7. 4. 3. 2.
M o difi e d Ril e y  S c or e ( M R S)
T he M o difie d Rile y  Sc ore ( M R S) s h o w n i n Ta ble 7 .  T his is a 4 p oi nt scale ( n o ne, mil d, 
m o derate a n d se vere) w hic h sc ores hist ol o gic acti vit y base d o n l ocalizati o n a n d 
q ua ntificati o n of ne utr o p hils i n t he m uc osa.  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 8
T a bl e 7
M o difi e d Ril e y  S c or e
A cti vit y
Hi st ol o gi c al C h ar a ct eri sti c s
N o n e
0
N e utr o p hils i n e pit h eli u m = n o n e
Mil d
1
N e utr o p hils i n e pit h eli u m = < 2 5 % cry pts i nv olv e d 
2
N e utr o p hils i n e pit h eli u m = 2 5 % t o 7 5 % cry pts i nv olv e d
3
N e urtr o p hils i n e pit h eli u m = > 7 5 % cry pts i nv olv e d
M o d er at e
4
L a mi n a pr o pri a n e utr o p hils = Mil d b ut u n e q uiv oc al i ncr e as e
5
L a mi n a pr o pri a n e utr o p hils = M o d er at e i ncr e as e
6
L a mi n a pr o pri a n e utr o p hils = M ark e d i ncr e as e
S e v er e
7
Er osi o n or ulc er ati o n = Pr es e nt
7. 5.
P h ar m a c o ki n eti c s
7. 5. 1.
Bl o o d S a m pl e C oll e cti o n
Bl o o d sa m ples f or P K a nal y sis of G S K 2 9 8 2 7 7 2 will be c ollecte d at t he ti me p oi nts 
i n dicate d i n Secti o n 7. 1 Ti me a n d E ve nts Ta ble.  T he act ual date a n d ti me of eac h bl o o d 
sa m ple c ollecti o n will be rec or de d.  T he ti mi n g of P K sa m ples ma y be altere d a n d/ or P K 
sa m ples ma y be o btai ne d at a d diti o nal ti me p oi nts t o e ns ure t h or o u g h P K m o nit ori n g.  
Details of bl o o d sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g pr oce d ures are 
pr o vi de d i n t he la b orat or y ma n ual.
7. 5. 2.
S a m pl e A n al y si s
Plas ma a nal y sis will be perf or me d at a bi oa nal ytical site (t o be detaile d i n t he S R M) 
u n der t he c o ntr ol of Platf or m Tec h n ol o g y  a n d Scie nce I n vitr o/I n vi v o Tra nslati o n ( P T S 
I VI V T), Gla x o S mit h Kli ne a n d T hir d Party Res o urce. C o nce ntrati o ns of G S K 2 9 8 2 7 7 2 
will be deter mi ne d i n plas ma sa m ples usi n g t he c urre ntl y a p pr o ve d bi oa nal ytical
met h o d ol o g y .
Ra w data will be arc hi ve d at t he bi oa nalyt ical site ( detaile d i n t he S R M). 
O nce t he plas ma has bee n a nal yz e d f or G S K 2 9 8 2 7 7 2 a n y re mai ni n g plas ma ma y be 
a nal yz e d f or ot her c o m p o u n d -relate d material a n d t he res ults ma y be re p orte d u n der a 
se parate P T S- I VI V T, Gla x o S mit h Kli ne pr ot oc ol.
7. 5. 3.
C ol o n Ti s s u e Bi o p s y  f or P h ar m a c o ki n eti c As s a y
See Secti o n 7. 6. 3 f or m ore details o n bi o psies.  C ol o nic tiss ue bi o psies will be ta ke n at 
Scree ni n g ( o n or pri or t o Da y  -7), Da y s 4 3 ( Wee k 6) a n d 8 5 ( Wee k 1 2) t o meas ure t he 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
5 9
c o nce ntrati o n of G S K 2 9 8 2 7 7 2 a n d p ossi ble dr u g -relate d material, as well as s pecific 
distri b uti o n wit hi n tiss ue if feasi ble as sa m ple a vaila bi lit y all o ws.
7. 5. 4.
S a m pl e A n al y si s
C ol o n tiss ue bi o ps y  sa m ple a nalys is will be perf or me d u n der t he c o ntr ol of P T S IVI V T, 
Gla x o S mit h Kli ne.  I nf or mati o n o n pr ocessi n g t he tiss ue bi o psies f or t he c ol o nic 
p har mac o ki netic assa y  will be pr o vi de d i n t he la b orat or y ma n ual.  T he res ults ma y be 
re p orte d u n der a se parate P T S-I VI VT, Gla x o S mit h Kli ne pr ot oc ol.
7. 6.
Bi o m ar k er( s)/ P h ar m a c o d y n a mi c Bi o m ar k er s
7. 6. 1.
C R e a cti v e Pr ot ei n ( C R P)
A bl o o d sa m ple will be ta ke n as part of t he c he mistr y  la b orat or y sa m ple t o meas ure C R P 
at t he ti me p oi nts i n dicate d i n Secti o n 7. 1 .  Inf or mati o n o n sa m ple pr ocessi n g will be 
pr o vi de d i n t he la b orat or y ma n ual.
7. 6. 2.
F a e c al C al pr ot e cti n ( F C P)
A faecal sa m ple will be ta ke n t o meas ure faecal cal pr otecti n at  t he ti me p oi nts i n dicate d 
i n Secti o n 7. 1 .  Inf or mati o n o n sa m ple pr ocessi n g will be pr o vi de d i n t he la b orat or y  
ma n ual.
7. 6. 3.
Ti s s u e Bi o p s y
A t otal of 6 u p t o 1 2 ( ma xi m u m) ra n d o m bi o psies will be ta ke n t hr o u g h o ut t he i nfla me d 
si g m oi d d uri n g t he si g m oi d osc o p y at t he scree ni n g visit ( o n or pri or t o Da y -7), at pre -
d ose o n Da y  4 3 ( Wee k 6) a n d o n Da y 8 5 ( Wee k 1 2).  Tiss ue sa m ples will be di vi de d 
acc or di n gl y f or hist ol o gical assess me nt (e. g., Ge b oes I n de x a n d M R S), P K, tar get a n d 
pat h wa y  e n ga ge me nt, a n d ge ne e x pressi o n a nalys es as feasi bilit y dictates.  A variety of 
tec h ni q ues i ncl u di n g q-P C R, m R N A pr ofili n g a n d i m m u n o hist oc he mistr y  (IH C) ma y  be 
use d.  Details of bi o ps y s a m ple c ollecti o n pr ocessi n g, st ora ge a n d s hi p pi n g pr oce d ures 
are pr o vi de d i n t he la b orat or y ma n ual).  
m R N A ma y  be is olate d fr o m tiss ue bi o psies, as feasi bilit y dictates, t o deter mi ne t he 
effect of place b o a n d G S K 2 9 8 2 7 7 2 o n mar kers of i nfla m mati o n a n d tiss ue heali n g (e. g., 
ma y  i ncl u de a n d n ot be li mite d t o I L-1, I L -6, I L -8, M M P 3, T N F α, I F Nγ a n d ot her 
c he m o ki nes a n d c yt o ki nes).  Bi o psy tiss ue c ollecte d f or R N A tra nscri pti o nal a nal ysis 
ma y be utilise d t o deter mi ne t he effect of G S K 2 9 8 2 7 7 2 o n c yt o ki ne a n d rece pt or 
e x pressi o n, i n a d diti o n t o ot her mar kers of i nfla m mati o n a n d tiss ue heali n g, as feasi bilit y  
all o ws.  F or e xa m ple, t his ma y i ncl u de b ut is n ot li mite d t o, meas ure me nt of ac ute p hase 
pr otei ns, ot her c he m o ki nes a n d c y t o ki nes.  E xa m ples of tec h n ol o gies t hat ma y be use d 
f or t hese a nalys es i ncl u de, b ut are n ot li mite d t o, q ua ntitati ve P C R, micr oarra y , a n d R N A 
se q ue nci n g.
Als o see S R M f or f ull details of t he di visi o n of bi o ps y  tiss ues f or s pecific a nalys es.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 0
7. 6. 4.
N o v el P h ar m a c o d y n a mi c Bi o m ar k er s
7. 6. 4. 1.
RI P 1 T ar g et E n g a g e m e nt i n Bl o o d
Bl o o d sa m ples f or RI P 1 tar get e n ga ge me nt will be c ollecte d at t he ti me p oi nts i n dicate d 
i n Secti o n 7. 1 t o meas ure le vels of free a n d dr u g-b o u n d RI P 1 pr otei n.
7. 6. 4. 2.
RI P 1 T ar g et E n g a g e m e nt i n Bi o p s y Ti s s u e
C ol o n tiss ue bi o ps y  sa m ples will be c ollecte d at t he ti me p oi nts i n dicte d i n Secti on 7. 1 t o 
meas ure le vels of free a n d dr u g- b o u n d RI P 1 pr otei n if sa m ple q ua ntit y  a n d data all o w.
7. 6. 4. 3.
P at h w a y  Bi o m ar k er s i n Bi o p s y Ti s s u e
C ol o n tiss ue bi o ps y  sa m ples will be c ollecte d at t he ti me p oi nts i n dicate d i n Secti o n 7. 1
t o meas ure t otal or p h os p h or ylate d RIP 1, RI P 3, M L K L a n d clea ve d or t otal cas pase 3 a n d 
cas pase 8 if sa m ple q ua ntit y  a n d data all o w.
7. 6. 5.
E x pl or at or y  N o v el Bi o m ar k er s
Wit h t he s u bject’s c o nse nt, tiss ue a n d bl o o d sa m ple(s) will be c ollecte d d uri n g t his st u d y 
a n d ma y be use d f or t he p ur p oses of meas uri n g n o vel bi o mar kers t o i de ntif y fact ors t hat 
ma y  i nfl ue nce disease/c o n diti o n f or st u d y  treat me nt, a n d/ or me dically relate d c o n diti o ns, 
as well as t he bi ol o gical a n d cli nical res p o nses t o G S K 2 9 8 2 7 7 2.  If rele va nt, t his 
a p pr oac h will be e xte n de d t o i ncl u de t he i de ntificati o n of bi o mar kers ass ociate d wit h 
a d verse e ve nts.
Sa m ples will be c ollecte d at t he ti me p oi nts i n dicate d i n Secti o n 7. 1 . T he ti mi n g of t he 
c ollecti o ns ma y be a dj uste d o n t he basis of e mer gi n g P K or P D data fr o m t his st u d y  or 
ot her ne w i nf or mati o n i n or der t o e ns ure o pti mal e val uati o n of t he P D e n d p oi nts.
N o vel ca n di date bi o mar kers a n d s u bse q ue ntl y  disc o vere d bi o mar kers of t he bi ol o gical 
res p o nse ass ociate d wit h U C or me dically relate d c o n diti o ns a n d/ or t he acti o n of 
G S K 2 9 8 2 7 7 2 ma y  be i de ntifie d b y a p plicati o n of:

Ge ne e x pressi o n a nal y sis ma y be c o n d ucte d o n t he bl o o d a n d/ or c ol o n tiss ue bi o psies 
usi n g micr oarra y , R N A-se q ue nci n g, a n d/ or alter nati ve e q ui vale nt tec h n ol o gies, 
w hic h facilitates t he si m ulta ne o us meas ure me nt (a n d c o nfir mati o n) of t he relati ve 
a b u n da nces of t h o usa n ds of R N A s pe cies res ulti n g i n a tra nscri pt o me pr ofile f or eac h 
bl o o d a n d/ or c ol o n tiss ue sa m ple.

S ol u ble i nfla m mat or y  me diat ors i n t he bl o o d ma y be assa ye d f or c yt o ki ne a n d 
i nfla m mat or y me diat ors i ncl u di n g, b ut n ot li mite d t o, pr o-i nfla m mat or y a n d a nti-
i nfla m mat or y c yt o ki nes, c he m o ki nes, a n d ac ute p hase pr otei ns. 
T hese a nal y ses ma y be re p orte d u n der se parate pr ot oc ol f oll o wi n g t he c o m pleti o n of t he 
st u d y.  All sa m ples will be retai ne d f or a ma xi m u m of u p t o 1 5 years after t he last s u bject 
c o m pletes t he trial.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 1
7. 7.
G e n eti c s
I n c o nse nti n g s u bjects, a bl o o d sa m ple f or p har mac o ge netics ( P G x) researc h will be 
dra w n o n Da y  1 ( or a n y ti me p oi nt p ost ra n d o misati o n a n d pri or t o st u d y c o m pleti o n) t o 
better c haracterize ge netic varia bilit y  t hat ma y affect efficac y or safety e n d p oi nt s. 
I nf or mati o n re gar di n g ge netic researc h is i ncl u de d i n A p pe n di x 4 .
8.
D A T A  MA N A G E M E N T

F or t his st u d y , s u bject data will be e ntere d i nt o G S K defi ne d C R Fs, tra ns mitte d 
electr o nicall y t o G S K or desi g nee a n d c o m bi ne d wit h data pr o vi de d fr o m ot her 
s o urces i n a vali date d data s yste m.  

Ma na ge me nt of cli nical data will be perf or me d i n acc or da nce w it h a p plica ble 
G S K sta n dar ds a n d data clea ni n g pr oce d ures t o e ns ure t he i nte grit y of t he data, 
e. g., re m o vi n g err ors a n d i nc o nsiste ncies i n t he data.

A d verse e ve nts a n d c o nc o mita nt me dicati o ns ter ms will be c o de d usi n g Me d D R A 
(Me dical Dicti o nar y  f or Re g ulat or y Acti vities) a n d a n i nter nal vali date d 
me dicati o n dicti o nar y , G S K Dr u g.  

C R Fs (i ncl u di n g q ueries a n d a u dit trails) will be retai ne d b y G S K, a n d c o pies will 
be se nt t o t he I n vesti gat or t o mai ntai n as t he I n vesti gat or c o p y.  S u bject i nitials 
a n d date of birt h will n ot be c ollecte d or tra ns mitte d t o G S K acc or di n g t o G S K 
p olic y .
9.
S T A TI S TI C A L C O N SI D E R A T I O N S A N D D AT A  
A N A L Y S E S
T he pri mar y  o bjecti ve of t he st u d y is t o i n vesti gate t he safety a n d t olera bilit y of 
G S K 2 9 8 2 7 7 2 f oll o wi n g 1 2 wee ks of treat me nt. N o f or ma l statistical h yp ot heses will be 
c o n d ucte d t o assess t his o bjecti ve. 
If a p pr o priate, c o m paris o ns bet wee n t he G S K 2 9 8 2 7 7 2 a n d t he place b o ar m t hr o u g h wee k 
6 will be ma de t o i n vesti gate t he sec o n dar y  p har mac o d yna mic, mec ha nistic a n d efficac y  
o bjecti ves. 
Tre n ds o ver ti me will be i n vesti gate d f or b ot h treat me nt ar ms al o n g wit h ass ociati o ns 
bet wee n eac h of t he para meters. 
9. 1.
S a m pl e Si z e C o n si d er ati o n s
9. 1. 1.
S a m pl e Si z e A s s u m pti o n s
T he st u d y  is n ot p o were d t o detect pre-defi ne d differe nces. A p pr o xi matel y  3 0- 3 6 s u bjects 
will be ra n d o mise d i nt o t he st u d y  t o eit her G S K 2 9 8 2 7 7 2 or place b o i n a 2: 1 rati o. Pri or t o 
pr ot oc ol a me n d me nt 0 1 bei n g a p pr o ve d i n eac h c o u ntr y , s u bjects will be ra n d o mise d i nt o 
t he st u d y t o eit her G S K 2 9 8 2 7 7 2 6 0 m g BI D or place b o i n a 2: 1 rati o. O verall u p t o 4 8 
s u bjects will be ra n d o mise d i nt o t he st u d y t o eit her a BI D or TI D re gi me n i n a 2: 1 rati o of 
G S K 2 9 8 2 7 7 2 or place b o res pecti vel y. Ta ble 8 s u m marises t he t otal pla n ne d sa m ple sizes 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 2
f or BI D a n d TI D re gi me ns. S h o ul d t he dr o p o ut rate i n Part A [ Da y  1 t hr o u g h 4 3 ( Wee k 
6)] be hi g her t ha n a ntici pate d, a d diti o nal or re place me nt s u bjects ma y  be ra n d o mise d ( u p 
t o an o verall t otal ma xi m u m of 6 0 ) i nt o t he st u dy at t he discreti o n of t he S p o ns or.  
S u bjects w h o disc o nti n ue partici pati o n d uri n g t he o pe n la bel p hase i n Part B [( Da y  4 3 
( Wee k 6) t hr o u g h Da y 8 5 ( Wee k 1 2)] will n ot be re place d.
T a bl e 8
S u m m ar y  of T ot al S a m pl e Si z e b y D o si n g R e gi m e n
N u m b er R a n d o mi s e d t o 
G S K 2 9 8 2 7 7 2 6 0 m g BI D or 
Pl a c e b o BI D
N u m b er R a n d o mi s e d t o 
G S K 2 9 8 2 7 7 2 6 0 m g TI D or 
Pl a c e b o 6 0 m g
R e vi s e d 
M a x 
T ot al 
S a m pl e 
Siz e
T ot al + 
A d diti o n al/ 
R e pl a c e m e nt 
S u bj e ct s
0 - 6
3 0 - 36
3 6
4 8
7 - 1 2
3 0 - 36
4 2
5 4
1 2 - 18
3 0 - 36
4 8
6 0
T he pri mar y  o bjecti ve of t he st u d y is safet y a n d t olera bilit y, w here t here will be u p t o 2 4 
s u bjects ra n d o mise d t o G S K 2 9 8 2 7 7 2 6 0 m g TI D, a n d u p t o 1 2 s u bjects ra n d o mise d t o 
G S K 2 9 8 2 7 7 2 6 0 m g BI D i n Part A. Usi n g a Ba yesia n a p pr oac h t o deter mi ne t he 
c o nfi de nce i nter val ar o u n d a n o bser ve d safet y e ve nt, we w o ul d ass u me a flat Beta ( 1, 1) 
pri or, a n d if we were t o o bser ve o ne safet y e ve nt i n 2 4 t he n t he p osteri or distri b uti o n 
w o ul d be Beta ( 2, 2 4), as o utli ne d bel o w i n Fi g ure 4 . 
Fi g ur e 4
O n e E v e nt i n 2 4 S u bj e ct s:  B et a ( 2, 2 4) Di stri b uti o n
T h us, we ca n be 9 5 % certai n t hat t he tr ue pr o ba bilit y  of t he safety e ve nt lies bet wee n 
0. 0 1 a n d 0. 1 8. 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 3
9. 1. 2.
S a m pl e Si z e S e n siti vit y
A sa m ple size se nsiti vit y  a nalys is has bee n c o n d ucte d o n t he pri mar y e n d p oi nt t o 
i n vesti gate t he differe nt safety e ve nt rates. If t he n u m ber of s u bjects w h o c o m plete t he 1 2 
wee ks is l o wer t ha n 2 4 i n t he G S K 2 9 8 2 7 7 2 6 0 m g TI D gr o u p, t he n t he tr ue i nci de nce 
rates of t he safet y e ve nts t hat c o ul d n ot be r ule d o ut (as o utli ne d i n Secti o n 9. 1. 1 ) w o ul d 
c ha n ge.  T hese c ha n ges are o utli ne d i n Ta ble 9 .
T a bl e 9
S a m pl e Si z e S e n siti vit y
G S K 2 9 8 2 7 7 2 s u bj e ct s 
c o m pl eti n g t h e st u d y
N u m b er of a p arti c ul ar s af et y 
e v e nt o b s er v e d wit h 
G S K 2 9 8 2 7 7 2
U p p er li mit of e x a ct 9 5 % CI 
i n di c ati n g t h at a tr u e 
i n ci d e n c e r at e of x % c o ul d 
n ot b e r ul e d o ut
2 4
0
1 3. 7 %
2 4
1
2 0. 4 %
2 4
2
2 6. 0 %
2 0
0
1 6. 1 %
2 0
1
2 3. 8 %
2 0
2
3 0. 4 %
1 6
0
1 9. 5 %
1 6
1
2 8. 7 %
1 6
2
3 6. 4 %
9. 1. 3.
S a m pl e Si z e R e -e sti m ati o n or A dj u st m e nt
A f or mal sa m ple size re -esti mati o n will be c o n d ucte d at t he pla n ne d I nteri m A nal y ses 
wit h t he p ur p ose of t he assessi n g t he pr o ba bilit y of ac hie vi n g a cli nicall y mea ni n gf ul 
i ncrease i n pre-deter mi ne d cli nical e n d p oi nts o ver place b o at t he e n d of t he st u d y . T he 
sa m ple size ma y nee d t o be re-esti mate d if hi g her varia bilit y  or differi n g place b o mea ns 
are o bser ve d o n t hese e n d p oi nts.  A rec o m me n de d i ncrease i n sa m ple size a b o ve 6 0
ra n d o mise d s u bjects w o ul d re q uire a pr ot oc ol a me n d me nt.
9. 2.
D at a A n al y si s C o n si d er ati o n s
9. 2. 1.
A n al y si s P o p ul ati o n s
All S u bjects P o p ul ati o n: T he ‘ All S u bjects P o p ulati o n’ is defi ne d as s u bjects w h o were 
scree ne d f or t he st u d y.  T his p o p ulati o n is use d f or t he s u m mar y of selecte d 
acc o u nta bilit y data.
S afet y P o p ul ati o n: T he ‘ Safet y P o p ulati o n’ is defi ne d as s u bjects w h o recei ve at least 
o ne d ose of st u d y me dicati o n. T his p o p ulati o n is use d f or t he s u m mar y of all data 
i ncl u di n g de m o gra p hy, safet y, efficac y  a n d e x pl orat or y data b ut e xcl u di n g P K data.
P h ar m ac o ki netic P o p ul ati o n: T he ‘ P K P o p ulati o n' is defi ne d as s u bjects i n t he ‘ Safet y’ 
p o p ulati o n w h o recei ve d a n acti ve d ose a n d f or w h o m a G S K 2 9 8 2 7 7 2 p har mac o ki netic 
sa m ple was o btai ne d a n d a nalys e d.   T his p o p ulati o n is use d f or t he s u m mar y of P K data 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 4
o nl y .  A ny P K P D a nal yses will be c o n d ucte d o n t he S afet y p o p ulati o n s uc h t hat s u bjects 
recei vi n g place b o ca n be i ncl u de d.
9. 2. 2.
I nt eri m An al y si s
T w o i nteri m a nal ys es will be c o n d ucte d d uri n g t he st u d y .  A d diti o nall y t w o re vie w tea ms 
will m o nit or data o n a n o n g oi n g basis f or r o uti ne p har mac o vi gila nce a n d decisi o n ma ki n g 
re gar di n g t he s u bse q ue nt cli nical de vel o p me nt of G S K 2 9 8 2 7 7 2 f or U C.
I n li ne wit h r o uti ne p har mac o vi gila nce, a n i nter nal G S K Safety Re vie w Tea m ( S R T) 
w hic h will i ncl u de me m bers of t he G S K 2 9 8 2 7 7 2 pr oject tea m, will re vie w bli n de d safet y 
data, i ncl u di n g cli nical la b orat or y para meters a n d a d verse e ve nts, at a p pr o priate i nter vals 
d uri n g t he peri o d of st u d y  c o n d uct.
O nce a n a p pr o priate n u m ber of s u bjects ha ve c o m plete d Da y  4 3 ( Wee k 6), m uc osal 
heali n g will be re vie we d i n a n u n bli n de d ma n ner b y  t he Data Re vie w C o m mittee, 
c o nsisti n g of t he G S K Pr oject P h y sicia n Lea d ( P P L), t he st u d y statisticia n, t he st u d y 
p har mac o ki neticist, t he P R R D P U Hea d, E D L a n d S R T L ea der or desi g nees o n a n 
o n g oi n g basis.  A p h ys icia n e xter nal t o t he G S K 2 9 8 2 7 7 2 pr oject tea m ma y als o be 
i n v ol ve d i n t he data re vie w. A d diti o nal i nfla m mat or y bi o mar kers, cli nical a n d 
mec ha nistic e n d p oi nts (e. g. tar get e n ga ge me nt) ma y be re vie we d if a vaila ble. N o ot her 
me m ber of t he G S K c ore st u d y tea m will be u n bli n de d t o t his data. T he pri mar y  p ur p ose 
of t hese re vie ws will be t o m o nit or m uc osal heali n g rates.  O n re vie w of m uc osal heali n g 
data, t he re vie w gr o u p ma y  rec o m me n d a n i nteri m a nal ysis of ke y cli nical a n d 
mec ha nistic data is first c o n d ucte d pri or t o a n y decisi o n t o ter mi nate t he st u d y f or f u tilit y.  
A data re vie w c harter will i de ntif y  t he s pecific G S K i n di vi d uals i n v ol ve d; o utli ne i n 
detail t he acti vities of t his re vie w a n d h o w t he i nte grit y  of t he st u d y will be mai ntai ne d.
T he ti mi n g of I nteri m A nal y sis # 1 will eit her be o n t he rec o m me n dati on of t he Data 
Re vie w C o m mittee t o assess f utilit y  base d o n 6 wee ks of treat me nt, or w he n a n 
a p pr o priate n u m ber ha ve c o m plete d 6 wee ks of treat me nt, w hic he ver is earliest.  T he 
p ur p ose of t he I nteri m A nal y sis w o ul d be t o assess w het her t o st o p t he st u d y f or f utilit y 
a n d, if a p pr o priate, t o perf or m a sa m ple size re -esti mati o n.  T his i nteri m a nal ysis ma y 
als o facilitate decisi o n ma ki n g re gar di n g t he s u bse q ue nt cli nical de vel o p me nt of 
G S K 2 9 8 2 7 7 2 f or U C. 
T he ti mi n g of I nteri m A nal y sis # 2 will occ ur w he n a n a p pro priate n u m ber ha ve 
c o m plete d 1 2 wee ks of treat me nt.  T he p ur p ose of t he I nteri m A nal ys is w o ul d be t o 
assess w het her t o st o p t he st u d y  f or f utilit y.  T his i nteri m a nal ysis ma y als o facilitate 
decisi o n ma ki n g re gar di n g t he s u bse q ue nt cli nical de vel o p me nt of G S K 2 9 8 2 7 7 2 f or U C. 
9. 3.
K e y  El e m e nt s of An al y si s Pl a n
9. 3. 1.
Pri m ar y  An al y s e s
All safet y e val uati o ns will be base d o n t he Safet y p o p ulati o n.  Cli nical i nter pretati o n will 
be base d o n t he re vie w a n d dis pla ys of a d verse e ve nts, cli nical la b orat or y  val ues, vital 
si g n meas ure me nts a n d 1 2 -lea d E C G m o nit ori n g.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 5
Safet y  data c ollecte d i n Part A a n d Part B of t he st u d y will be c o m bi ne d a n d s u m marise d 
acc or di n g t o treat me nt recei ve d f or t he first si x wee ks of treat me nt a n d o verall. If 1 2 or 
m ore s u bjects are ra n d o mise d t o a BI D re gi me n (i.e. , ≥4 place b o a n d ≥8 G S K 2 9 8 2 7 7 2 6 0 
m g BI D) t he n treat me nt recei ve d will ta ke i nt o acc o u nt d osi n g fre q ue nc y f or 
G S K 2 9 8 2 7 7 2, ot her wise treat me nt will be irres pecti ve of d osi n g fre q ue nc y .
9. 3. 2.
S e c o n d ar y  An al y s e s
Efficac y , P D a n d bi o mar ker data will be s u m marise d f or Part A, a n d s u p p orti n g 
s u m maries a n d a nalys es, as a p pr o priate, will be s u m marise d f or Part A a n d Part B 
c o m bi ne d, acc or di n g t o treat me nt recei ve d.  
C o m paris o ns bet wee n treat me nt gr o u ps o n a n y c ha n ges o bser ve d will be c o n d ucte d f or 
t he sec o n dar y e n d p oi nts if dee me d a p pr o priate, e. g., c ha n ges i n t he mea n tar get 
e n ga ge me nt a n d c ha n ges i n i nfla m mat or y  mar kers be statisticall y  a nal yze d usi n g a
M M R M a nal y sis c o m pari n g G S K 2 9 8 2 7 7 2 wit h place b o at eac h ti me p oi nt. T he 
pr o p orti o n of s u bjects ac hi e vi n g Ma yo E n d osc o p y  Re missi o n ( Sc ores of 0 or 1), will be 
statisticall y a nalys e d usi n g a G E E m o del c o m pari n g G S K 2 9 8 2 7 7 2 wit h place b o at eac h 
ti me p oi nt if a p pr o priate. Si milar a nal y ses will be c o n d ucte d f or ot her sec o n dar y 
e n d p oi nts if dee me d a p pr o priate.
T he relati o ns hi p bet wee n eac h of t he mec ha nistic e n d p oi nts a n d als o wit h t he cli nical 
e n d p oi nts ma y als o be gra p hically prese nte d a n d a nal yse d usi n g a n a p pr o priate statistical 
m o del i de ntif y i n g a ny tre n ds. T he m o del will deter mi ne w het her t he mec ha nistic effect 
si g nifica ntly e x plai ns or pre dicts t he effect o n t he ot her mec ha nistic or cli nical e n d p oi nts 
(e. g., Ma yo E n d osc o p y S c ores). T his ma y be c o n d ucte d t hr o u g h c o m pari n g statistical 
m o dels i nc or p orati n g differe nt e x pla nat or y  ter ms (i.e., mec ha nistic e n d p oi nts) wit h t he 
‘ n ull’ m o del ( n o mec ha nistic e n d p oi nts); or if dee me d a p pr o priate, m ulti variate statistical 
met h o ds ma y  als o be a p plie d t o deter mi ne t he relati o ns hi p bet wee n t he ke y e n d p oi nts. 
T he c o nsiste nc y  i n t he c ha n ges o ver ti me bet wee n t he e n d p oi nts will als o be assesse d. 
9. 3. 3.
Ot h er A n al y s e s
I n a d diti o n, base d o n t he data t hat we o bser ve i n t he st u d y, pr o ba bilities of s uccess will 
be deter mi ne d, w here t he defi niti o n of s uccess will be de pe n de nt o n t he e n d p oi nt. F or 
e xa m ple, w hat is t he pr o ba bilit y  t hat we w o ul d o bser ve a certai n pr o p orti o n of Ma y o 
E n d osc o pic Re missi o n ( 0 or 1) (i.e., c o m parat or y  rate), base d o n t he data t hat we ha ve 
o bser ve d i n t he st u d y.
G S K 2 9 8 2 7 7 2 plas ma c o nce ntrati o ns will be s u m marise d descri pti vel y  b y da y a n d 
n o mi nal sa m pli n g ti me.  
F urt her details re gar di n g t he statistical a nal y sis will be o utli ne d i n t he Re p orti n g a n d 
A nal y sis Pla n ( R A P).
9. 3. 3. 1.
E x pl or at or y  An al y s e s
All e x pl orat or y  e n d p oi nts will be descri pti vel y s u m marize d, gra p hically prese nte d a n d 
liste d a p pr o priately.  F urt her details c a n be f o u n d i n t he R A P.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 6
1 0.
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S
1 0. 1.
P o sti n g of I nf or m ati o n o n P u bli cl y  Av ail a bl e Cli ni c al Tri al 
R e gi st er s
St u d y  i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a vaila ble cli nical trial 
re gisters bef ore e nr oll me nt of s u bjects b e gi ns.
1 0. 2.
R e g ul at or y  a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
Pri or t o i nitiati o n of a site, G S K will o btai n fa v o ura ble o pi ni o n/a p pr o val fr o m t he 
a p pr o priate re g ulat or y a ge nc y t o c o n d uct t he st u d y i n acc or da nce wit h IC H G o o d Cli nical
Practice ( G C P) a n d a p plica ble c o u ntr y -s pecific re g ulat or y re q uire me nts.
T he st u d y  will be c o n d ucte d i n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts, 
a n d wit h G S K p olic y.
T he st u d y  will als o be c o n d ucte d i n acc or da nce wit h IC H G o o d Cli nical Pract ice ( G C P), 
all a p plica ble s u bject pri vac y re q uire me nts, a n d t he g ui di n g pri nci ples of t he c urre nt 
versi o n of t he Declarati o n of Helsi n ki.  T his i ncl u des, b ut is n ot li mite d t o, t he f oll o wi n g:

I RB/I E C re vie w a n d fa v ora ble o pi ni o n/a p pr o val of t he st u d y  pr ot oc ol a n d 
a me n d me nts as a p plica ble

I n vesti gat or re p orti n g re q uire me nts (e. g. re p orti n g of A Es/ S A Es/ pr ot oc ol 
de viati o ns t o I R B/I E C)

G S K will pr o vi de f ull details of t he a b o ve pr oce d ures, eit her ver ball y, i n writi n g, 
or b ot h .

Si g ne d i nf or me d c o nse nt m ust be o btai ne d f or eac h s u bject pri or t o partici pati o n 
i n t he st u d y.

T he I E C/I R B, a n d w here a p plica ble t he re g ulat or y a ut h orit y, a p pr o ve t he cli nical 
pr ot oc ol a n d all o pti o nal assess me nts, i ncl u di n g ge netic researc h.  

O pti o nal assess me nts (i ncl u di n g t h ose i n a se parate pr ot oc ol a n d/ or u n der se parate 
i nf or me d c o nse nt) a n d t he cli nical pr ot oc ol s h o ul d be c o nc urre ntly s u b mitte d f or 
a p pr o val u nless re g ulati o n re q uires se parate s u b missi o n.  

A p pr o val of t he o pti o nal assess me nts ma y  occ ur after a p pr o val is gra nte d f or t he 
cli nical pr ot oc ol w here re q uire d b y re g ulat or y  a ut h orities.  In t his sit uati o n, 
writte n a p pr o val of t he cli nical pr ot oc ol s h o ul d state t hat a p pr o val of o pti o nal 
assess me nts is bei n g deferre d a n d t he st u d y , wit h t he e xce pti o n of t he o pti o nal 
assess me nts, ca n be i nitiate d.
1 0. 3.
Q u alit y C o ntr ol ( St u d y  M o nit ori n g)

I n acc or da nce wit h a p plica ble re g ulati o ns i ncl u di n g G C P, a n d G S K pr oce d ures, 
G S K m o nit ors will c o ntact t he site pri or t o t he start of t he st u d y  t o re vie w wit h t he 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 7
site staff t he pr ot oc ol, st u d y re q uire me nts, a n d t heir res p o nsi bilities t o satisf y 
re g ulat or y, et hical, a n d G S K re q uire me nts.  

W he n re vie wi n g data c ollecti o n pr oce d ures, t he disc ussi o n will als o i ncl u de 
i de ntificati o n, a gree me nt a n d d oc u me ntati o n of data items f or w hic h t he C R F will 
ser ve as t he s o urce d oc u me nt.
G S K will m o nit or t he st u d y  a n d site acti vit y t o verif y t hat t he:

Data are a ut he ntic, acc urate, a n d c o m plete.

Safet y  a n d ri g hts of s u bjects are bei n g pr otecte d.

St u d y  is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y  
ot her st u d y  a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
T he I n vesti gat or a n d t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d oc u me nts
1 0. 4.
Q u alit y A s s ur a n c e

T o e ns ure c o m plia nce wit h G C P a n d all a p plica ble re g ulat or y  re q uire me nts, G S K 
ma y  c o n d uct a q ualit y ass ura nce assess me nt a n d/ or a u dit of t he site rec or ds, a n d 
t he re g ulat or y a ge ncies ma y c o n d uct a re g ulat or y i ns pecti o n at a n y ti me d uri n g or 
after c o m pleti o n of t he st u d y. 

I n t he e ve nt of a n assess me nt, a u dit or i ns pecti o n, t he In vesti gat or (a n d i nstit uti o n) 
m ust a gree t o gra nt t he a d vis or(s), a u dit or(s) a n d i ns pect or(s) direct access t o all 
rele va nt d oc u me nts a n d t o all ocate t heir ti me a n d t he ti me of t heir staff t o disc uss 
t he c o n d uct of t he st u dy, a n y fi n di n gs/rele va nt iss ues a n d t o i m ple me nt a n y 
c orrecti ve a n d/ or pre ve ntati ve acti o ns t o a d dress a n y  fi n di n gs/iss ues i de ntifie d.
1 0. 5.
St u d y a n d Sit e Cl o s ur e

U p o n c o m pleti o n or pre mat ure disc o nti n ua ti o n of t he st u d y, t he G S K m o nit or will 
c o n d uct site cl os ure acti vities wit h t he I n vesti gat or or site staff, as a p pr o priate, i n 
acc or da nce wit h a p plica ble re g ulati o ns i ncl u di n g G C P, a n d G S K Sta n dar d 
O perati n g Pr oce d ures.

G S K reser ves t he ri g ht t o te m p orari l y s us pe n d or pre mat urely disc o nti n ue t his 
st u d y at a ny ti me f or reas o ns i ncl u di n g, b ut n ot li mite d t o, safet y  or et hical iss ues 
or se vere n o n -c o m plia nce. F or m ultice nter st u dies, t his ca n occ ur at o ne or m ore 
or at all sites.  

If G S K deter mi nes s uc h actio n is nee de d, G S K will disc uss t he reas o ns f or ta ki n g 
s uc h acti o n wit h t he I n vesti gat or or t he hea d of t he me dical i nstit uti o n ( w here 
a p plica ble).  W he n feasi ble, G S K will pr o vi de a d va nce n otificati o n t o t he 
I n vesti gat or or t he hea d of t he me dical i nstit uti o n, w here a p plica ble, of t he 
i m pe n di n g acti o n.

If t he st u d y is s us pe n de d or pre mat urel y disc o nti n ue d f or safety reas o ns, G S K will 
pr o m ptl y  i nf or m all I n vesti gat ors, hea ds of t he me dical i nstit uti o ns ( w here 
a p plica ble) a n d/ or i nstit uti o n(s) c o n d ucti n g t he st u d y. G S K will als o pr o m ptl y 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 8
i nf or m t he rele va nt re g ulat or y a ut h orities of t he s us pe nsi o n or pre mat ure 
disc o nti n uati o n of t he st u d y  a n d t he reas o n(s) f or t he acti o n.  

If re q uire d by a p plica ble re g ulati o ns, t he I n vesti gat or or t he hea d of t he me dical 
i nstit uti o n ( w here a p plica ble) m ust i nf or m t he IR B/I E C pr o m ptl y a n d pr o vi de t he 
reas o n f or t he s us pe nsi o n or pre mat ure disc o nti n uati o n.
1 0. 6.
R e c or d s R et e nti o n

F oll o wi n g cl os ure of t he st u d y , t he I n vesti gat or or t he hea d of t he me dical 
i nstit uti o n ( w here a p plica ble) m ust mai ntai n all site st u d y  rec or ds (e xce pt f or 
t h ose re q uire d by l ocal re g ulati o ns t o be mai ntai ne d else w here), i n a safe a n d 
sec ure l ocati o n.  

T he rec or ds m ust be mai ntai ne d t o all o w eas y a n d ti mel y  retrie val, w he n nee de d 
(e. g., f or a G S K a u dit or re g ulat or y i ns pecti o n) a n d m ust be a vaila ble f or re vie w 
i n c o nj u ncti o n wit h assess me nt of t he facility, s u p p orti n g s ys te ms, a n d rele va nt 
site staff.  

W here per mitte d b y l ocal la ws/re g ulati o ns or i nstit uti o nal p olic y, s o me or all of 
t hese rec or ds ca n be mai ntai ne d i n a f or mat ot her t ha n har d c o py (e. g., micr ofic he, 
sca n ne d, electr o nic); h o we ver, ca uti o n nee ds t o be e xercise d bef ore s uc h acti o n is 
ta ke n. 

T he I n vesti gat or m ust e ns ure t hat all re pr o d ucti o ns are le gi ble a n d are a tr ue a n d 
acc urate c o p y of t he ori gi nal a n d meet accessi bilit y a n d retrie val sta n dar ds, 
i ncl u di n g re-ge nerati n g a har d c o p y, if re q uire d.  F urt her m ore, t he I n vesti gat or 
m ust e ns ure t here is a n acce pta ble bac k-u p of t hese re pr o d ucti o ns a n d t hat a n 
acce pta ble q ualit y c o ntr ol pr ocess e xists f or ma ki n g t hese re pr o d ucti o ns.

G S K will i nf or m t he I n vesti gat or of t he ti me peri o d f or retai ni n g t hese rec or ds t o 
c o m pl y wit h all a p plica ble re g ulat or y re q uire me nts.  T he mi ni m u m rete nti o n ti me 
will meet t he strictest sta n dar d a p plica ble t o t hat site f or t he st u d y, as dictate d b y 
a n y i nstit uti o nal re q uire me nts or l ocal la ws or re g ulati o ns, G S K 
sta n dar ds/ pr oce d ures, a n d/ or i nstit uti o nal re q uire me nts. 

T he I n vesti gat or m ust n otif y  G S K of a n y c ha n ges i n t he arc hi val arra n ge me nts, 
i ncl u di n g, b ut n ot li mite d t o, arc hi val at a n off-site facilit y or tra nsfer of 
o w ners hi p of t he rec or ds i n t he e ve nt t he I n vesti gat or is n o l o n ger ass ociate d wit h 
t he site.
1 0. 7.
Pr o vi si o n of St u d y  R e s ult s t o I n v e sti g at or s, P o sti n g of 
I nf or m ati o n o n P u bli c all y Av ail a bl e Cli ni c al Tri al s R e gi st er s 
a n d P u bli c ati o n
W here re q uire d b y a p plica ble re g ulat or y  re q uire me nts, a n I n vesti gat or si g nat or y will be 
i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort.  T he I n vesti gat or will be pr o vi de d 
reas o na ble access t o statistical ta bles, fi g ures, a n d rele va nt re p orts a n d will ha ve t he 
o p p ort u nit y  t o re vie w t he c o m plete st u d y res ults at a G S K site or ot her m ut uall y-
a greea ble l ocati o n.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
6 9
G S K will a ls o pr o vi de t he I n vesti gat or wit h t he f ull s u m mar y of t he st u dy res ults.  T he 
I n vesti gat or is e nc o ura ge d t o s hare t he s u m mar y res ults wit h t he st u d y s u bjects, as 
a p pr o priate.
G S K will pr o vi de t he I n vesti gat or wit h t he ra n d o mizati o n c o des f or t heir site o nl y after 
c o m pleti o n of t he f ull statistical a nal ysis.
T he pr oce d ures a n d ti mi n g f or p u blic discl os ure of t he res ults s u m mar y  a n d f or 
de vel o p me nt of a ma n uscri pt f or p u blicati o n will be i n acc or da nce wit h G S K P olic y .
A ma n uscri pt will be pr o gresse d f or p u bli cati o n i n t he scie ntific literat ure if t he res ults 
pr o vi de i m p orta nt scie ntific or me dical k n o wle d ge.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 0
1 1.
R E F E R E N C E S
C he n H, Y u K D, X u G Z. Ass ociati o n bet wee n Varia nt Y 4 0 2 H i n A ge- Relate d Mac ular 
De ge nerati o n ( A M D) S usce pti bilit y  Ge ne C F H a n d Treat me nt Res p o nse of A M D: A 
Meta -A nal ys is. Pl o S O N E 2 0 1 2; 7: e 4 2 4 6 4
D o n deli n ger Y, A g uileta M A, G o osse ns V, D u b uiss o n C, Gr o otja ns S, Dejar di n E et al.  
RI P K 3 c o ntri b utes t o T N F R 1 -me diate d RI P K 1 ki nase -de pe n de nt a p o pt osis i n c o n diti o ns 
of cI A P 1/ 2 de pleti o n or T A K 1 ki nase i n hi biti o n.  Cell De at h a n d Differe nti ati o n , 
2 0 1 3; 2 0: 1 3 8 1 - 9 2.
D o ur mas h ki n R R, Da vies H, Wells C, S ha h D, Price A, O’ M orai n C et al.  E pit helial 
patc h y necr osis i n Cr o h n’s disease.  H u m a n P at h ol o gy, 1 9 8 3; 1 4: 6 4 3 - 8.
D u prez L , Ta ka has hi N, Va n Ha u wer meire n F, Va n de n driessc he B, G o osse ns V, 
Va n de n Ber g he T et al.  RI P ki nase -de pe n de nt necr osis dri ves let hal s ys te mic 
i nfla m mat or y res p o nse s yn dr o me.  I m m u nity, 2 0 1 1; 3 5: 9 0 8 - 1 8.
Fea ga n B G, C ha n de N, Mac D o nal d J K.  Are t here a n y differe nces i n t he efficac y a n d 
safety of differe nt f or m ulati o ns of Oral 5 -A S A use d f or i n d ucti o n a n d mai nte na nce of 
re missi o n i n ulcerati ve c olitis?  E vi de nce fr o m C oc hra ne re vie ws. I nfl a m m B o wel Dis. 
2 0 1 3 A u g; 1 9( 9): 2 0 3 1 -4 0.
Fratila O C, Craci u n C Ultrastr uct ural e vi de nce of m uc osal heali n g af ter i nfli xi ma b i n 
patie nts wit h ulcerati ve c olitis. J Gastr oi ntesti n L i ver Dis. 2 0 1 0 J u n; 1 9( 2): 1 4 7- 5 3.
Ge b oes K, Ri d dell R, Ost A, Je nsfelt B, Perss o n T, L öf 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 ve c olitis. G ut , 2 0 0 0 
Se p; 4 7( 3): 4 0 4 - 9.
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 2.  I n vesti gat or Br oc h ure f or 
G S K 2 9 8 2 7 7 2.  Re p ort Date 2 7 -J A N- 2 0 1 7.
G ori n M B.  Ge netic i nsi g hts i nt o a ge -relate d mac ular de ge nerati o n: C o ntr o versies 
a d dressi n g ris k, ca usalit y, a n d t hera pe utics. M o. As pects Me d . 2 0 1 2; 3 3: 4 6 7- 4 8 6.
G ü nt her C, Marti ni E, Witt k o pf N, A ma n n K, Wei g ma n n B, Ne u ma n n H et al.  
Cas pase -8 re g ulates T N F --i n d uce d e pit helial necr o pt osis a n d ter mi nal ileitis.  N at ure,
2 0 1 1; 4 7 7: 3 3 5 - 9.
Hatc her R A, Tr ussell J,  Nels o n A L, Cates W Jr, Ste wart F, K o wal D et al. C o ntr ace ptive 
Tec h n ol o gy . 2 0t h e diti o n.  Atla nta, Ge or gia: Ar de nt Me dia, I nc., 2 0 1 1: 5 0.  Ta ble 3 2.
H u m p hries F, Ya n g S, Wa n g B, M o y na g h P N.  RI P ki nases: ke y decisi o n ma kers i n cell 
deat h a n d i n nate i m m u nit y .  Cell De at h & Differ , 2 0 1 5; 2 2: 2 2 5- 2 3 6.
Ja mes LP, Letzi g L, Si m ps o n P M, Ca p parelli E, R o berts D W, Hi ns o n J A, Da ver n TJ, Lee 
W M. P har mac o ki netics of Aceta mi n o p he n - A d d uct i n A d ults wit h Aceta mi n o p he n 
O ver d ose a n d Ac ute Li ver Fail ure . Dru g Met a b Dis p os 2 0 0 9; 3 7: 1 7 7 9 - 1 7 8 4.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 1
Ofe n gei m D a n d Y ua n J.  Re g ulati o n of RI P 1 ki nase si g nali n g at t he cr ossr oa ds of 
i nfla m mati o n a n d cell deat h.  N at ure Revie ws M olec ul ar Cell Bi ol o gy , 2 0 1 3; 1 4: 7 2 7 - 3 6.
Re geli n g A, I mha n n F, V ol ders H H, Bl o kzijl T, Bl o ks V W , Weers ma R K et al.  H S P A 6 
is a n ulcerati ve c olitis s usce pti bilit y fact or t hat is i n d uce d b y ci garette s m o ke a n d pr otects 
i ntesti nal e pit helial cells b y sta bilizi n g a nti-a p o pt otic Bcl-X L. Bi oc hi m Bi o p h y s Acta. 
2 0 1 6 Ja n 2 6. Pii: S 0 9 2 5 -4 4 3 9( 1 6) 3 0 0 1 7 - 5. 
Rei ni sc h W, Sa n d b or n WJ, H o m mes D W, D' Hae ns G, Ha na uer S, Sc hrei ber S et al. 
A dali m u ma b f or i n d ucti o n of cli nical re missi o n i n m o deratel y t o se verel y acti ve 
ulcerati ve c olitis: res ults of a ra n d o mise d c o ntr olle d trial. G ut . 2 0 1 1 J u n; 6 0( 6): 7 8 0- 7. 
Rile y  S A, Ma ni V, G o o d ma n MJ, D utt S, Her d M E. Micr osc o pic acti vit y  i n ulcerati ve 
c olitis: w hat d oes it mea n? G ut . 1 9 9 1; 3 2: 1 7 4- 1 7 8.
Sa n d b or n WJ, Fea ga n B G, Mara n o C, Z ha n g H, Stra uss R, J o ha n ns J, A de d o k u n OJ et al; 
P U R S UI T- Mai nte na nce St u d y  Gr o u p.  S u bc uta ne o us g oli m u ma b mai ntai ns cli nical 
res p o nse i n patie nts wit h m o derate-t o-se vere ulcerati ve c olitis. G astr oe nter ol o gy . 2 0 1 4 
Ja n; 1 4 6( 1): 9 6- 1 0 9.  
Sa n d b or n WJ, va n Assc he G, Rei nisc h W, C ol o m bel J F, D' Hae ns G, W olf D C et al. 
A dali m u ma b i n d uces a n d mai ntai ns cli nical re mis si o n i n patie nts wit h m o derate-t o-
se vere ulcerati ve c olitis. G astr oe nter ol o gy . 2 0 1 2 Fe b; 1 4 2( 2): 2 5 7- 6 5.
Sei deli n J B, C os k u n M, Vai ner B, Riis L , S oe n der gaar d C, Nielse n O H et al.  
E R K c o ntr ols e pit helial cell deat h rece pt or si g nali n g a n d cell ular F LI C E -li ke i n hi bit or y 
pr otei n (c -F LI P) i n ulcerati ve c olitis.  J o ur n al of M olec ul ar Me dici ne, 2 0 1 3; 9 1: 8 3 9 - 4 9.
Sei deli n J B. Re g ulati o n of a ntia p o pt otic a n d c y t o pr otecti ve pat h wa ys i n c ol o nic e pit helial 
cells i n ulcerati ve c olitis. Sc a n d J G astr oe nter ol . 2 0 1 5; 5 0 S u p pl 1: 1 - 2 9. 
Si p os F, M ol nár B, Zá g o ni T, Berczi L , T ulassa y Z.  Gr o wt h i n e pit helial cell 
pr oliferati o n a n d a p o pt osis c orrelates s pecificall y  t o t he i nfla m mati o n acti vit y of 
i nfla m mat or y b o wel diseases: ulcerati ve c olitis s h o ws s pecific p 5 3- a n d E G F R 
e x press i o n alterati o ns.  Dis C ol o n Rect u m . 2 0 0 5 A pr; 4 8( 4): 7 7 5- 8 6.
Tra vis S, Sc h nell D, Krzes ki P, A br ue M T, Alt ma n D G, C ol o m bel J F et al.  De vel o pi n g 
a n i nstr u me nt t o assess e n d osc o pic se verit y  of ulcerati ve c olitis: t he Ulcerati ve C olitis 
E n d osc o pic I n de x of Se v erit y ( U C EI S). G ut , 2 0 1 2 A pr; 6 1( 4): 5 3 5- 4 2.
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 ( F D A). 
( 2 0 1 2) G ui da nce f or I n d ustr y: Dr u g I nteracti o n St u dies – St u d y  Desi g n, Data A nalys is, 
I m plicati o ns f or D osi n g, a n d La beli n g Rec o m men dati o ns. Ce nter f or Dr u g E val uati o n 
a n d Researc h, 1 0 9 0 3 Ne w Ha m ps hire A ve n ue, Sil ver S pri n g, M D 2 0 9 9 3. 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ U C M 2 9 2 3 6 2. p df
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 2
Vitali R, Str o nati L , Ne gr o ni A, Di Nar d o G, Pier d o menic o M, Del Gi u dice E et al.  Fecal 
H M G B 1 is a n o vel mar ker of i ntesti nal m uc osal i nfla m mati o n i n pe diatric i nfla m mat or y  
b o wel disease.  A meric a n J o ur n al of G astr oe nter ol o gy., 2 0 1 1; 1 0 6: 2 0 2 9 - 4 0.
Wa n g L, D u F, Wa n g X. T N F- al p ha i n d uces t w o disti nct cas pase - 8 acti vati o n pat h wa ys. 
Cell , 2 0 0 8; 1 3 3( 4): 6 9 3- 7 0 3.
Welz P S, W ullaert A, Vla ntis K, K o n d ylis V, Fer na n dez -Maja da V, Er m olae va M et al.  
F A D D pre ve nts RI P 3 -me diate d e pit helial cell necr osis a n d c hr o nic i ntesti nal 
i nfla m mati o n.  N at ure, 2 0 1 1; 4 7 7: 3 3 0 - 4.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 3
1 2.
A P P E N DI C E S
1 2. 1.
A p p e n di x 1 – A b br e vi ati o n s a n d Tr a d e m ar k s
A b br e v i ati o n s
5 -A S A
5 -a mi n osalic ylates
A D A
A nti- dr u g A nti b o dies
A E
A d verse E ve nt
A L T
Ala ni ne a mi n otra nsferase ( S G P T)
A M D
A ge -relate d mac ular de ge nerati o n
A S T
As partate a mi n otra nsferase ( S G O T)
A U C
Area u n der c o nce ntrati o n- ti me c ur ve
BI D
T wice a da y
CI
C o nfi de nce I nter val
C K D -E PI
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
C L
S y ste mic Cleara nce
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n
C N S
Ce ntral ner v o us s ys te m
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C R F 
Case Re p ort F or m
C R P
C- Reacti ve Pr otei n
C- S S R S
C ol u m bia S uici de Se verit y  Rati n g Scale
C V
Car di o vasc ular
C Y P
C y t oc hr o me P
D N A
De o x yri b ose N ucleic Aci d
D P U
Disc o ver y  Perf or ma nce U nit
D R C
Data Re vie w C o m mittee
E C G
Electr ocar di o gra m
E D L
Earl y De vel o p me nt Lea d
E M A
E ur o pea n Me dici nes A ge nc y
E T C O 2
E n d -ti dal Car b o n Di o xi de
F C P
Faecal Cal pr otecti n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F R P
Fe males of Re pr o d ucti ve P ote ntial
F S H
F ollicle Sti m ulati n g H or m o ne
F Ti H
First Ti me i n H u ma n
G C P
G o o d Cli nical Practice
G E E
Ge neralise d Esti mati n g E q uati o ns
G F R
Gl o mer ular Filtrate Rate
G S K
Gla x o S mit h Kli ne
H Bc A b
He patitis B C ore A nti b o d y
H Bs A g
He patitis B S urface A nti ge n
h C G
H u ma n C h ori o nic G o na d otr o pi n
HI V
H u ma n I m m u n o deficie nc y  Vir us
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 4
H R T
H or m o ne Re place me nt T hera p y
I B
I n vesti gat or Br oc h ure
I B D
I nfla m mat or y B o wel Disease
I C H
I nter nati o nal C o nfere nce o n Har mi nisati o n
I D SL
I nte grate d Data Sta n dar ds L i brar y
I E C
I n de pe n de nt Et hics C o m mittee
I F N
I nterfer o n
I g G
I m m u n o gl o b uli n ga m ma
I L
I nterle u ki n
I P
I n vesti gati o nal Pr o d uct
I RB
I nstit uti o nal Re vie w B oar d
I R T S
I nteracti ve Res p o nse Tec h n ol o g y S yste m
K g
Kil o gra m
L
Litre
L D L
L o w De nsit y  Li p o pr otei n
M C H
Mea n c or p usc ular hae m o gl o bi n
M C V
Mea n C or p usc ular V ol u me
M C H C
Mea n c or p usc ular hae m o gl o bi n c o nce ntrati o n
M D M A
3, 4 -met h y le ne di o x y-met ha m p heta mi ne
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vit y
m g
Milli gra m
m L
Millilitre
M L K L
Mi xe d
li nea ge ki nase d o mai n-li ke pr otei n
m m
Milli meter
m m ol
Milli m ole
M M P
Matri x metall o p pr otei nase
M M R M
Mi xe d -effect M o del Re peat Meas ure me nts
M R S
M o difie d Rile y  Scale
msec
millisec o n d
M S D
Mes o -Scale Disc o ver y
M S D S
Material Safet y Data S heet
M T X
Met h otre xate
N F -B
N uclear fact or ka p pa -li g ht-c hai n-e n ha ncer of acti vate d B 
cells
N H S
Nati o nal Healt h Ser vice
N O A E L
N o A d verse Effect Le vel
N O N M E M
N o n L i near Mi xe d Effect M o del
N S AI D
N o n -ster oi dal a nti-i nfla m mat or y dr u g y
N TI
Narr o w t hera pe utic i n de x
P C R
P ol y merase C hai n Reacti o n
P D
P har mac o d y na mic
P G A
P h y sicia n’s Gl o bal Assess me nt of Disease
P- g p
P- gl yc o pr otei n
P G x
P har mac o ge netic
P K
P har mac o ki netic
P P D
T u berc uli n P urifie d Pr otei n Deri vati ve
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 5
P P L
Pr oject P h y sicia n Lea d
P R O
Patie nt re p orte d o utc o me
P R R
Patter n Rec o g niti o n Rece pt or
P S R A E
P ossi ble S uici dalit y  Relate d A d verse E ve nt
P T S I VI V T
Platf or m Tec h n ol o g y  a n d Scie nce I n vitr o/I n vi v o 
Tra nslati o n
Q Tc
Electr ocar di o gra m Q T i nter val c orrecte d f or heart rate
Q Tc B
Electr ocar di o gra m Q T i nter val c orrecte d f or heart rate usi n g 
Bazett’s f or m ula
Q Tc F
Electr ocar di o gra m Q T i nter val c orrecte d f or heart rate usi n g 
Fri dericia’s f or m ula
R & D
Researc h a n d De vel o p me nt
R A P
Re p orti n g a n d A nal ys is Pla n
R B C
Re d Bl o o d Cell
R C T
Ra n d o mise d cli nical trials
RI P 1
Rece pt or -i nteracti n g pr otei n- 1
RI P 3
Rece pt or -i nteracti n g pr otei n- 3
R N A
Ri b o n ucleic Aci d
S A E
Seri o us A d verse E ve nt
S G O T
Ser u m Gl uta mic O xal oacetic Tra nsa mi nase
S G P T
Ser u m Gl uta mic P y r u vic Tra nsa mi nase
SI B
S uici dal I deati o n Be ha vi o ur
S O P
Sta n dar d O perati n g Pr oce d ure
S p O 2
Peri p heral Ca pillar y  O xy ge n Sat urati o n
S R M
St u d y  Refere nce Ma n ual
S R T
Safet y  Re vie w Tea m
T B
T u berc ul osis
T E A R
Tar get E n ga ge me nt Assa y RI P 1
TI
Ter mi nal ile u m
TI D
T hree ti mes a da y
T L R
T oll -li ke rece pt or
T N F
T u m or necr osis fact or
T T S
Tec h nical Ter ms of S u p pl y
U C
Ulcerati ve c olitis
U K
U nite d Ki n g d o me
U L N
U p per Li mit of N or mal
V
V ol u me of Distri b uti o n
V A S
Vis ual A nal o g ue Scale
W C B P
W o me n of C hil d beari n g P ote ntial
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 6
Tr a d e m ar k I nf or m ati o n
Tr a d e m ar k s of t h e Gl a x o S mit h Kli n e 
gr o u p of c o m p a ni e s
Tr a d e m ar k s n ot o w n e d b y t h e 
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
N O N E
Me d D R A
Q ua nti F E R O N
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 7
1 2. 2.
A p p e n di x 2: Li v er S af et y  R e q uir e d Acti o n s a n d F oll o w u p 
A s s e s s m e nt s
P hase II li ver c he mistr y  st o p pi n g criteria ha ve bee n desi g ne d t o ass ure s u bject safet y a n d 
t o e val uate li ver e ve nt eti ol o g y (i n ali g n me nt wit h t he F D A pre mar keti n g cli nical li ver 
safety g ui da nce). 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ul at or yI nf or mati o n/ G ui d
a nces/ U C M 1 7 4 0 9 0. p df.
P h ase II li ver c he mistr y st o p pi n g criteri a a n d re q uire d f oll o w u p assess me nts 
Li v er C h e mi str y St o p pi n g Crit eri a – Li v er St o p pi n g E v e nt
A L T -a b s ol ut e
A L T 5x U L N
A L T I n cr e a s e
A L T 3x U L N p ersists f or 4 w e eks
Bilir u bi n 1, 2
A L T 3x U L N a n d bilir u bi n 2x U L N ( > 3 5 % dir ect bilir u bi n)
I N R2
A L T 3x U L N a n d I N R > 1. 5, if I N R m e as ur e d
C a n n ot M o nit or
A L T 3x U L N a n d c a n n ot b e m o nit or e d w e ekly f or 4 w e eks
S y m pt o m ati c 3
A L T  3x U L N ass oci at e d wit h sy m pt o ms ( n e w or w ors e ni n g) b eli ev e d t o b e 
r el at e d t o liv er i nj ury or hy p ers e nsitivity
R e q uir e d A cti o n s a n d F oll o w u p A s s e s s m e nt s f oll o wi n g A N Y Li v er St o p pi n g E v e nt
A cti o n s
F oll o w U p A s s e s s m e nt s

I m m e di at el y disc o nti n u e  st u dy tr e at m e nt 

R e p ort t h e ev e nt t o G S K wit hi n 2 4 h o ur s

C o m pl et e t h e liv er ev e nt C R F a n d c o m pl et e a n 
S A E d at a c oll ecti o n t o ol if t h e ev e nt als o m e ets 
t h e crit eri a f or a n S A E2

P erf or m liv er ev e nt f oll o w u p ass ess m e nts 

M o nit or t h e s u bj ect u nti l liv er c h e mistri es
r es olv e, st a biliz e, or r et ur n t o wit hi n b as eli n e 
(s e e M O NI T O RI N G b el o w)

D o n ot r e st art/r e c h all e n g e s u bj ect wit h st u dy 
tr e at m e nt u nl ess all o w e d p er pr ot oc ol a n d G S K 
M e dic al G ov er n a nc e a p pr ov al i s gr a nt e d

If r est art/r ec h all e n g e n ot all o w e d p er pr ot o c ol 
or n ot gr a nt e d , p er m a n e ntly disc o nti n u e st u dy 

Vir a l h e p atitis s er ol o gy4

Bl o o d s a m pl e f or p h ar m ac oki n etic ( P K) 
a n alysis, o bt ai n e d wit hi n 2 d ays  aft er 
l ast d os e5

S er u m cr e ati n e p h os p h oki n as e ( C P K) 
a n d l act at e d e hy dr o g e n as e ( L D H).

Fr acti o n at e bilir u bi n, if t ot al 
bilir u bi n 2x U L N

O bt ai n c o m pl et e bl o o d c o u nt wit h 
diff er e nti al t o ass ess e osi n o p hili a

R ec or d t h e a p p e ar a nc e or w ors e ni n g of 
cli nic al sy m pt o ms of liv er i nj ury, or 
hy p ers e nsitivity, o n t h e A E r e p ort f or m

R ec or d us e of c o nc o mit a nt m e dic ati o ns 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 8
tr e at m e nt a n d m ay c o nti n u e s u bj ect i n t h e st u dy 
f or a ny pr ot oc ol s p ecifi e d f oll o w u p ass ess m e nts 
M O NI T O RI N G:
F or bilir u bi n or I N R crit eri a:

R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n ) a n d p erf or m 
liv er ev e nt f oll o w u p ass ess m e nts wit hi n  2 4 hr s

M o nit or s u bj ects t wic e w e ekly u ntil liv er 
c h e mistri es r es olv e, st a biliz e or r et ur n t o wit hi n 
b as eli n e 

A s p eci alist or h e p at ol o gy c o ns ult ati o n is 
r ec o m m e n d e d
F or All ot h er crit eri a: 

R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n) a n d p erf or m 
liv er ev e nt f oll o w u p ass ess m e nts wit hi n  2 4 -7 2 
hr s 

M o nit or s u bj ects w e ekly u ntil liv er c h e mistri es 
r es olv e, st a biliz e or r et ur n t o wit hi n b as eli n e
o n t h e c o nc o mit a nt m e dic ati o ns r e p ort 
f or m i ncl u di n g ac et a mi n o p h e n, h er b al 
r e m e di es, ot h er ov er t h e c o u nt er 
m e dic ati o ns .

R ec or d alc o h ol us e o n t h e liv er ev e nt 
alc o h ol i nt ak e c as e r e p ort f or m
F or bilir u bi n or I N R crit eri a:

A nti -n ucl e ar a nti b o dy, a nti -s m o ot h 
m uscl e a nti b o dy, Ty p e 1 a nti- liv er 
ki d n ey micr os o m al a nti b o di es, a n d 
q u a ntit ativ e t ot al i m m u n o gl o b uli n G 
(I g G or g a m m a gl o b uli ns).

S er u m ac et a mi n o p h e n a d d uct H P L C 
ass ay ( q u a ntifi es p ot e nti al 
ac et a mi n o p h e n c o ntri b uti o n t o liv er 
i nj ury i n s u bj ects wit h d efi nit e or lik ely 
ac et a mi n o p h e n us e i n t h e pr ec e di n g 
w e ek [J a m es, 2 0 0 9]). N O T E: n ot 
r e q uir e d i n C hi n a

Liv er i m a gi n g ( ultr as o u n d, m a g n etic 
r es o n a nc e, or c o m p ut eris e d 
t o m o gr a p hy) a n d / or liv er bi o psy t o 
ev al u at e liv er dis e as e ; c o m pl et e Liv er 
I m a gi n g a n d/ or Liv er Bi o psy C R F 
f or ms.
1.
S er u m bilir u bi n fr acti o n ati o n s h o ul d b e p erf or m e d if t esti n g is av ail a bl e. If s er u m bilir u bi n fr acti o n ati o n is n ot 
i m m e di at ely av ail a bl e, disc o nti n u e st u dy tr e at m e nt f or t h at s u bj ect if A L T 3x U L N a n d bilir u bi n 2x U L N.. 
A d diti o n ally, if s er u m bilir u bi n f r acti o n ati o n t esti n g is u n av ail a bl e, r e c or d pr e s e n c e of d et e ct a bl e uri n ar y 
bilir u bi n o n di p sti c k , i n dic ati n g dir ect bilir u bi n el ev ati o ns a n d s u g g esti n g liv er i nj ury. 
2.
All ev e nts of A L T 3x U L N a n d bilir u bi n 2x U L N ( > 3 5 % dir ect bilir u bi n) or A L T 3x U L N a n d I N R > 1. 5, if I N R 
m e as ur e d w hic h m ay i n dic at e s ev er e liv er i nj ury ( p ossi bl e ‘ Hy’s L a w’), m u st b e r e p ort e d a s a n S A E ( e x cl u di n g 
st u di e s of h e p ati c i m p air m e nt or cirr h o si s) ; I N R m e as ur e m e nt is n ot r e q uir e d a n d t h e t hr es h ol d v al u e st at e d 
will n ot a p ply t o s u b j ects r ec eivi n g a ntic o a g ul a nts
3.
N e w or w ors e ni n g sy m pt o ms b eli ev e d t o b e r el at e d t o liv er i nj ury (s uc h as f ati g u e, n a us e a, v o miti n g, ri g ht u p p er 
q u a dr a nt p ai n or t e n d er n ess, or j a u n dic e) or b eli ev e d t o b e r el at e d t o hy p ers e nsitivity (s uc h as f ev er, r as h or 
e osi n o p hili a)
4.
I ncl u d es: H e p atitis A I g M a nti b o dy; H e p atitis B s urf ac e a nti g e n a n d H e p atitis B C or e A nti b o dy (I g M); H e p atitis C 
R N A; Cyt o m e g al ovir us I g M a nti b o dy;  E pst ei n -B arr vir al c a psi d a nti g e n I g M a nti b o dy ( or if u n av ail a bl e, o bt ai n 
h et er o p hil e a nti b o d y or m o n os p ot t esti n g);  H e p atitis E I g M a nti b o dy 
5.
P K s a m pl e m ay n ot b e r e q uir e d f or s u bj ects k n o w n t o b e r ec eivi n g pl ac e b o or n o n -G S K c o m p ar at or tr e at m e nts.)  
R ec or d t h e d at e/ti m e of t h e P K bl o o d s a m pl e dr a w a n d t h e d at e/ti m e of t h e l ast d os e of st u dy tr e at m e nt pri or t o 
bl o o d s a m pl e dr a w o n t h e C R F. If t h e d at e or ti m e of t h e l ast d os e is u ncl e ar, pr ovi d e t h e s u bj ect’s b est 
a p pr oxi m ati o n. If t h e d at e/ti m e of t h e l ast d os e c a n n ot b e a p pr oxi m at e d O R a P K s a m pl e c a n n ot b e c oll ect e d i n 
t h e ti m e p eri o d i n dic at ed a b ov e, d o n ot o bt ai n a P K s a m pl e. I nstr ucti o ns f or s a m pl e h a n dli n g a n d s hi p pi n g ar e i n 
t h e l a b or at ory m a n u al.  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
7 9
1 2. 3.
A p p e n di x 3: Pr e d ni s ol o n e a n d 5- A S A E q ui v al e nt D o s e 
T a bl e s
Dr u g N a me
D ose E q ui v ale nt t o 1 m g Or al Pre d nis o ne
C ortis o ne acetate
H y dr oc ortis o ne
Pre d nis ol o ne
Met h y l pre d nis ol o ne
Tria mci n ol o ne
De xa met has o ne
5 m g
4 m g
1 m g
0. 8 m g
0. 8 m g
0. 1 5 m g
Dr u g N a me
D ose E q ui v ale nt t o 2 0 m g Or al Pre d nis o ne
Uceris E R
9 m g
Dr u g N a me
D ose E q ui v ale nt t o 5 -A S A
S ulfasalazi ne
2 -4 g ( 0. 8 – 1. 6 g m 5 -A S A)
Balsalazi de
2 -6. 7 5 g ( 0. 7 – 2. 4 g m 5 -A S A)
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 0
1 2. 4.
A p p e n di x 4 - G e n eti c R e s e ar c h
G e n eti c s – B a c k gr o u n d
Nat urall y occ urri n g ge netic variati o n ma y  c o ntri b ute t o i nter-i n di vi d ual varia bilit y i n 
res p o nse t o me dici nes, as well as a n i n di vi d ual's ris k of de vel o pi n g s pecific diseases. 
Ge netic fact ors ass ociate d wit h disease c haracteristics ma y  als o be ass ociate d wit h 
res p o nse t o t hera py, a n d c o ul d hel p t o e x plai n s o me cli nical st u d y o utc o mes. F or 
e xa m ple, ge netic varia nts ass ociate d wit h a ge- relate d mac ular de ge neratio n ( A M D) are 
re p orte d t o acc o u nt f or m uc h of t he ris k f or t he c o n diti o n [G ori n , 2 0 1 2] wit h certai n 
varia nts re p orte d t o i nfl ue nce treat me nt res p o nse [ C he n , 2 0 1 2]. T h us, k n o wle d ge of t he 
ge netic eti ol o g y  of disease ma y better i nf or m u n dersta n di n g of disease a n d t he 
de vel o p me nt of me dici nes. A d diti o nall y , ge netic varia bilit y ma y i m pact t he 
p har mac o ki netics (a bs or pti o n, distri b uti o n, meta b olis m, a n d eli mi nati o n), or 
p har mac o d y n a mics (relati o ns hi p bet wee n c o nce ntrati o n a n d p har mac ol o gic effects or t he 
ti me c o urse of p har mac ol o gic effects) of a s pecific me dici ne a n d/ or cli nical o utc o mes 
(efficac y a n d/ or safety) o bser ve d i n a cli nical st u d y.
G e n eti c R e s e ar c h O bj e cti v e s a n d A n al y s e s
T he o bjecti ves of t he ge netic researc h are t o i n vesti gate t he relati o ns hi p bet wee n ge netic 
varia nts a n d: 

Res p o nse t o me dici ne, i ncl u di n g G S K 2 9 8 2 7 7 2 or a n y c o nc o m ita nt me dici nes;

Ulcerati ve c olitis s usce pti bilit y , se verity, a n d pr o gressi o n a n d relate d c o n diti o ns
G S K 2 9 8 2 7 7 2 is a n o vel first -i n-class asset bei n g i ntr o d uce d t o patie nts wit h acti ve U C 
f or t he first ti me. C urre ntl y its mec ha nis m of acti o n is n ot f ull y c haracterise d n or 
u n derst o o d. 
S pecific ge nes ma y  be st u die d t hat e nc o de t he dr u g tar gets, or dr u g mec ha nis m of acti o n 
pat h wa y s, dr u g meta b olizi n g e nz y mes, dr u g tra ns p orters or w hic h ma y u n der pi n a d verse 
e ve nts, disease ris k or dr u g res p o nse. T hese ca n di da te ge nes ma y i ncl u de a c o m m o n set 
of A D M E ( A bs or pti o n, Distri b uti o n, Meta b olis m a n d E xcreti o n) ge nes t hat are st u die d t o 
deter mi ne t he relati o ns hi p bet wee n ge ne varia nts or treat me nt res p o nse a n d/ or t olera nce. 
I n a d diti o n, c o nti n ui n g researc h ma y i de ntif y ot her e nz y mes, tra ns p orters, pr otei ns ore 
rece pt ors t hat ma y be i n v ol ve d i n res p o nse t o G S K 2 9 8 2 7 7 2. T he ge nes t hat ma y c o de f or 
t hese pr otei ns ma y als o be st u die d. Ge n o me-wi de sca ns i n v ol vi n g a lar ge n u m ber of 
p ol y m or p hic mar kers (e. g. si n gle n ucle oti de p o l ym or p his ms) at defi ne d l ocati o ns i n t he 
ge n o me, ofte n c orrelate d wit h a ca n di date ge ne, ma y  be st u die d t o deter mi ne t he 
relati o ns hi p bet wee n ge netic varia nts a n d treat me nt res p o nse or t olera nce. T his a p pr oac h 
is ofte n e m pl o ye d w he n a defi niti ve ca n di date ge ne d oes n ot e xist a n d/ or t he p ote ntial 
ge netic effects are n ot well u n derst o o d.
Ge netic data ma y  be ge nerate d w hile t he st u d y is u n der wa y or f oll o wi n g c o m pleti o n of 
t he st u d y.  Ge netic e val uati o ns ma y i ncl u de f oc use d ca n di date ge ne a p pr oac hes a n d/ or 
e xa mi nati o n of a lar ge n u m ber of ge netic varia nts t hr o u g h o ut t he ge n o me ( w h ole ge n o me 
a nal ys es). Ge netic a nal ys es will utilize data c ollecte d i n t he st u d y  a n d will be li mite d t o 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 1
u n dersta n di n g t he o bjecti ves hi g hli g hte d a b o ve.  A nal y ses ma y be perf or me d usi n g data 
fr o m m ulti ple cli nical st u dies t o i n vesti gate t hese researc h o bjecti ves.
If a p plica ble a n d ge netic researc h is c o n d ucte d, ap pr o priate descri pti ve a n d/ or statistical 
a nal ys is met h o ds will be use d t o e val uate p har mac o ge netic data i n t he c o nte xt of t he 
ot her cli nical data . A detaile d descri pti o n of a n y pla n ne d a nalys es will be d oc u me nte d i n 
a Re p orti n g a n d A nal ys is Pla n ( R A P) pri or t o i nitiati o n of t he a nalys is. Pla n ne d a nalys es 
a n d res ults of ge netic i n vesti gati o ns will be re p orte d eit her as part of t he c li nical R A P a n d 
st u d y re p ort, or i n a se parate ge netics R A P a n d re p ort, as a p pr o priate.
St u d y P o p ul ati o n
A n y  s u bject w h o is e nr olle d i n t he st u d y ca n partici pate i n ge netic researc h.  A n y s u bject 
w h o has recei ve d a n all o ge neic b o ne marr o w tra ns pla nt m ust b e e xcl u de d fr o m t he 
ge netic researc h.
St u d y A s s e s s m e nt s a n d Pr o c e d ur e s
A ke y  c o m p o ne nt of s uccessf ul ge netic researc h is t he c ollecti o n of sa m ples d uri n g 
cli nical st u dies. C ollecti o n of sa m ples, e ve n w he n n o a pri ori h y p ot hesis has bee n 
i de ntifie d, ma y e na ble f ut ure ge netic a nalys es t o be c o n d ucte d t o hel p u n dersta n d 
varia bilit y  i n disease a n d me dici ne res p o nse.  

A 6 ml bl o o d sa m ple will be ta ke n f or De o x yri b o n ucleic aci d ( D N A) e xtracti o n. 
A bl o o d sa m ple is c ollecte d at t he baseli ne visit, after t he s u bject has bee n 
ra n d o mize d a n d pr o vi de d i nf or me d c o nse nt f or ge netic researc h. I nstr ucti o ns f or 
c ollecti o n a n d s hi p pi n g of t he ge netic sa m ple are descri be d i n t he la b orat or y 
ma n ual. T he D N A fr o m t he bl o o d sa m ple ma y  u n derg o q ualit y  c o ntr ol a nal yses t o 
c o nfir m t he i nte grit y of t he sa m ple. If t here are c o ncer ns re gar di n g t he q ualit y  of 
t he sa m ple, t he n t he sa m ple ma y be destr o ye d. T he bl o o d sa m ple is ta ke n o n a 
si n gle occasi o n u nless a d u plicate sa m ple is re q uire d d ue t o a n i na bility t o utilize 
t he ori gi nal sa m ple.  
T he ge netic sa m ple is la belle d ( or “c o de d”) wit h t he sa me st u d y s pecific n u m ber use d t o 
la bel ot her sa m ples a n d data i n t he st u d y.   T his n u m ber ca n be trace d or li n ke d bac k t o 
t he s u bject b y t he I n vesti gat or or site staff. C o de d sa m ples d o n ot carr y pers o nal 
i de ntifiers (s uc h as na me or s ocial sec urit y n u m ber). 
T he nee d t o c o n d uct P G x a nal ys is ma y be i de ntifie d after a st u d y ( or set of st u dies) of 
G S K 2 9 8 2 7 7 2 has bee n c o m plete d a n d t he st u d y  data re vie we d. I n s o me cases, t he 
sa m ples ma y n ot be st u die d.
Sa m ples will be st ore d sec urel y a n d ma y be ke pt f or u p t o 1 5 years after t he last s u bject 
c o m pletes t he st u d y, or G S K ma y destr o y t he sa m ples s o o ner.  G S K or t h ose w or ki n g 
wit h G S K (f or e xa m ple, ot her researc hers) will o nl y  use sa m ples c ollecte d fr o m t he st u d y 
f or t he p ur p ose state d i n t his pr ot oc ol a n d i n t he i nf or me d c o nse nt f or m.  Sa m ples ma y be 
use d as part of t he de vel o p me nt of a c o m pa ni o n dia g n ostic t o s u p p ort t he G S K me dici nal 
pr o d uct.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 2
S u bjects ca n re q uest t heir sa m ple t o be destr o ye d at a n y  ti me.
I nf or m e d C o n s e nt
S u bjects w h o d o n ot wis h t o partici pate i n t he ge netic researc h ma y  still partici pate i n t he 
st u d y.  Ge netic i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y bl o o d bei n g ta ke n.
S u bj e ct Wit h dr a w al fr o m St u d y
If a s u bject w h o has c o nse nte d t o partici pate i n ge netic researc h wit h dra ws fr o m t he 
cli nical st u d y f or a n y reas o n ot her t ha n bei n g l ost t o f oll o w- u p, t he s u bject will be gi ve n a 
c h oice of o ne of t he f oll o wi n g o pti o ns c o ncer ni n g t he ge netic sa m ple, if alrea d y 
c ollecte d:

C o nti n ue t o partici pate i n t he ge netic researc h i n w hic h case t he ge netic D N A 
sa m ple is retai ne d

Disc o nti n ue partici pati o n i n t he ge netic researc h a n d destr o y  t he ge netic D N A 
sa m ple 
If a s u bject wit h dra ws c o nse nt f or ge netic researc h or re q uests sa m ple destr ucti o n f or a n y 
reas o n, t he I n vesti gat or m ust c o m plete t he a p pr o priate d oc u me ntati o n t o re q uest sa m ple 
destr ucti o n wit hi n t he ti mefra me s pecifie d b y G S K a n d mai ntai n t he d oc u me ntati o n i n 
t he site st u d y rec or ds. 
Ge n ot y pe data ma y  be ge nerate d d uri n g t he st u d y  or after c o m pleti o n of t he st u d y a n d 
ma y  be a nalyz e d d uri n g t he st u d y or st ore d f or f ut ure a nalys is. 

If a s u bject wit h dra ws c o nse nt f or ge netic researc h a n d ge n oty pe data has n ot bee n 
a nal yz e d, it will n ot be a nal yze d or use d f or f ut ure researc h.  

Ge netic data t hat has bee n a nal yz e d at t he ti me of wit h dra w n c o nse nt will 
c o nti n ue t o be st ore d a n d use d, as a p pr o priate. 
S cr e e n a n d B a s eli n e F ail ur e s
If a sa m ple f or ge netic researc h has bee n c ollecte d a n d it is deter mi ne d t hat t he s u bject 
d oes n ot meet t he e ntr y  criteria f or partici pati o n i n t he st u d y, t he n t he I n vesti gat or s h o ul d 
i nstr uct t he s u bject t hat t heir ge netic sa m ple will be destr oye d. N o f or ms are re q uire d t o 
c o m plete t his pr ocess as it will be c o m plete d as part of t he c o nse nt a n d sa m ple 
rec o nciliati o n pr ocess.  I n t his i nsta nce a sa m ple destr ucti o n f or m will n ot be a vaila ble t o 
i ncl u de i n t he site files.
Pr o vi si o n of St u d y R e s ult s a n d C o nfi d e nti alit y  of S u bj e ct’ s G e n eti c D at a
G S K ma y  s u m marize t he ge netic researc h res ults i n t he cli nical st u d y re p ort, or 
se paratel y a n d ma y p u blis h t he res ults i n scie ntific j o ur nals. 
G S K ma y  s hare ge netic researc h data wit h ot her scie ntists t o f urt her scie ntific 
u n dersta n di n g i n ali g n me nt wit h t he i nf or me d c o nse nt. G S K d oes n ot i nf or m t he s u bject, 
fa mil y me m bers, i ns urers, or e m pl o yers of i n di vi d ual ge n ot ypi n g res ults t hat are n ot 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 3
k n o w n t o be rele va nt t o t he s u bject’s me dical care at t he ti me of t he st u d y , u nless 
re q uire d by la w. T his is d ue t o t he fact t hat t he i nf or mati o n ge nerate d fr o m g e netic 
st u dies is ge nerally preli mi nar y i n nat ure, a n d t heref ore t he si g nifica nce a n d scie ntific 
vali dit y  of t he res ults are u n deter mi ne d.  F urt her, data ge nerate d i n a researc h la b orat or y 
ma y  n ot meet re g ulat or y re q uire me nts f or i ncl usi o n i n cli nical care.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 4
1 2. 5.
A p p e n di x 5: D efi niti o n of a n d Pr o c e d ur e s f or R e c or di n g, 
E v al u ati n g, F oll o w -U p a n d R e p orti n g of A d v er s e E v e nt s
1 2. 5. 1.
D efi niti o n of A d v er s e E v e nt s
A d verse E ve nt Defi niti o n:

A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject, te m p orally 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.

N O T E: A n A E 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 (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d uct.
E ve nts meeti n g A E defi niti o n i ncl u de:

A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) 
or ot her safet y assess me nts (e. g., E C Gs, ra di ol o gical sca ns, vital si g ns 
meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, a n d felt t o be cli nicall y  
si g nifica nt i n t he me dical a n d scie ntific j u d ge me nt of t he I n vesti gat or.

E xacer bati o n of a c hr o nic or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.

Ne w c o n diti o ns detecte d or dia g n ose d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt pri or t o t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pec te d i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
treat me nt or a c o nc o mita nt me dicati o n ( o ver d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless t his is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self-
har mi n g i nte nt.  T his s h o ul d be re p orte d re gar dless of se q uelae).

" Lac k of efficac y" or "fail ure of e x pecte d p har mac ol o gical acti o n" per se will n ot be 
re p orte d as a n A E or S A E.  H o we ver, t he si g ns a n d s ym pt o ms a n d/ or cli nical 
se q uelae res ulti n g fr o m lac k of efficac y will be re p orte d if t he y f ulfil t he defi niti o n 
of a n A E or S A E.

T he si g ns a n d 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  will 
be re p orte d if t he y  f ulfil t he defi niti o n of a n A E or S A E.  Als o, "lac k of efficac y" or 
"fail ure of e x pecte d p har mac ol o gical acti o n" als o c o nstit utes a n A E or S A E.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 5
E ve nts N O T meeti n g defi niti o n of a n A E i ncl u de:

A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are 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.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of 
t he disease/ dis or der bei n g st u die d, u nless m ore se vere t han e x pecte d f or t he s u bject’s 
c o n diti o n.

Me dical or s ur gical pr oce d ure (e. g., e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E.

Sit uati o ns w here a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A ntici pate d da y -t o-d a y  fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.
1 2. 5. 2.
D efi niti o n of S eri o u s A d v er s e E v e nt s
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n not be a n S A E e ve n if seri o us 
c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , 
deat h d ue t o pr o gressi o n of disease, etc).
Seri o us A d verse E ve nt ( S A E) is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, 
at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
N O T E:
T he ter m 'life -t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e ve nt.  It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heticall y  mi g ht ha ve cause d deat h, if it were m ore se vere.
c.
Re q uires h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n
N O T E:

I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or 
o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h y sicia n’s 
office or o ut -patie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are 
A Es.  If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, 
t he e ve nt is seri o us.  W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o ul d be c o nsi dere d seri o us.

H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 6
d.
Res ults i n dis a bilit y/i nc a p acit y
N O T E:

T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y  t o c o n d uct 
n or mal life f u ncti o ns.

T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea , i nfl ue nza, 
a n d acci de ntal tra u ma (e. g. s prai ne d a n kle) w hic h ma y  i nterfere or pre ve nt e ver yd a y  
life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n
e.
Is a c o n ge nit al a n o m al y/ birt h defect
f.
Ot her sit u ati o ns:

Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y  n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he a b o ve defi niti o n.  T hese s h o ul d als o be c o nsi dere d 
seri o us.

E xa m ples of s uc h e ve nts are i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y  
or dr u g a b use
g.
Is ass oci ate d wit h li ver i nj ur y a n d i m p aire d li ver f u ncti o n defi ne d as:

A L T 3 x U L N a n d t otal bilir u bi n * 2 x U L N ( > 3 5 % direct), o r

A L T 3 x U L N a n d I N R * * > 1. 5.
* Ser u m bilir u bi n fracti o nati o n s h o ul d be perf or me d if testi n g is a vaila ble; if u na vaila ble, 
meas ure uri nar y  bilir u bi n via di pstic k.  If fracti o nati o n is u na vaila ble a n d A L T 3 x U L N 
a n d t otal bilir u bi n 2 x U L N, t he n t he e ve nt is still t o be re p orte d as a n S A E.
* * I N R testi n g n ot re q uire d per pr ot oc ol a n d t he t hres h ol d val ue d oes n ot a p pl y  t o 
s u bjects recei vi n g a ntic oa g ula nts.  If I N R meas ure me nt is o btai ne d, t he val ue is t o be 
rec or de d o n t he S A E f or m.

Refer t o A p pe n di x 2 f or t he re q uire d li ver c he mistr y f oll o w-u p i nstr ucti o ns
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 7
1 2. 5. 3.
D efi niti o n of C ar di o v a s c ul ar E v e nt s
C ar di o v asc ul ar E ve nts ( C V) Defi niti o n:
I n vesti gat ors will be re q uire d t o fill o ut t he s pecific C V e ve nt pa ge of t he C R F f or t he 
f oll o wi n g A Es a n d S A Es:

M y ocar dial i nfarcti o n/ u nsta ble a n gi na

C o n gesti ve heart fail ure

Arr h yt h mias

Val v ul o pat h y

P ul m o nar y  h yperte nsi o n

Cere br o vasc ular e ve nts/str o ke a n d tra nsie nt isc he mic attac k

Peri p heral arterial t hr o m b oe m b o lis m

Dee p ve n o us t hr o m b osis/ p ul m o nar y  e m b olis m

Re vasc ularizati o n
1 2. 5. 4.
R e c or di n g of A E s a n d S A E s
A Es a n d S A E Rec or di n g:

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y  of t he In vesti gat or t o re vie w all 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y , a n d dia g n ostics re p orts) 
relati ve t o t he e ve nt.

T he I n vesti gat or will t he n rec or d all rele va nt i nf or mati o n re gar di n g a n A E/ S A E i n 
t he C R F

It is n ot acce pta ble f or t he I n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical 
rec or ds t o G S K i n lie u of c o m pleti o n of t he G S K, A E/ S A E C R F pa ge.

T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are 
re q ueste d by G S K.  I n t his i nsta nce, all s u bject i de ntifiers, wit h t he e xce pti o n of t he 
s u bject n u m ber, will be bli n de d o n t he c o pies of t he me dical rec or ds pri or t o 
s u b missi o n of t o G S K.

T he I n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n.  I n s uc h cases, t he dia g n osis will be 
d oc u me nte d as t he A E/ S A E a n d n ot t he i n di vi d ua l si g ns/s ym pt o ms.

S u bject -c o m plete d Val ue E vi de nce a n d O utc o mes q uesti o n naires a n d t he c ollecti o n 
of A E data are i n de pe n de nt c o m p o ne nts of t he st u d y .

Res p o nses t o eac h q uesti o n i n t he Val ue E vi de nce a n d O utc o mes q uesti o n naire will 
be treate d i n acc or da nce wit h sta n dar d sc ori n g a n d statistical pr oce d ures detaile d b y 
t he scale’s de vel o per.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 8

T he use of a si n gle q uesti o n fr o m a m ulti di me nsi o nal healt h s ur ve y  t o desi g nate a 
ca use- effect relati o ns hi p t o a n A E is i na p pr o priate.
1 2. 5. 5.
E v al u ati n g A E s a n d S A E s
A s s e s s m e nt o f I nt e n sit y
T he I n vesti gat or will ma ke a n assess me nt of i nte nsit y  f or eac h A E a n d S A E re p orte d 
d uri n g t he st u d y a n d will assi g n it t o o ne of t he f oll o wi n g cate g ories:

Mil d:  A n e ve nt t hat is easil y  t olerate d b y t he s u bject, ca usi n g mi ni mal disc o mf ort 
a n d n ot i nterferi n g wit h e ver y d a y  acti vities.

M o derate:  A n e ve nt t hat is s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal 
e ver yd a y  acti vities

Se vere:  A n e ve nt t hat pre ve nts n or mal e ver y d a y  acti vities. - a n A E t hat is assesse d 
as se vere will n ot be c o nf use d wit h a n S A E. Se verit y  is a cate g or y utilize d f or rati n g 
t he i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.

A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least o ne of t he pre -defi ne d 
o utc o mes as descri be d i n t he defi nit i o n of a n S A E.
A s s e s s m e nt of C a u s alit y

T he I n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y treat me nt a n d 
t he occ urre nce of eac h A E/ S A E.

A "reas o na ble p ossi bilit y " is mea nt t o c o n ve y t hat t here are facts/e vi de nce or 
ar g u me nts t o s u g ges t a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d 
o ut.

T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.

Alter nati ve ca uses, s uc h as nat ural hist or y  of t he u n derl yi n g diseases, c o nc o mita nt 
t hera py, ot her ris k fact ors, a n d 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 will be c o nsi dere d a n d i n vesti gate d.

T he I n vesti gat or will als o c o ns ult t he I n vesti gat or Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n t he deter mi nati o n of his/ her assess me nt.

F or eac h A E/ S A E t he I nvesti 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 E/ 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 w he n a n S A E has occ urre d a n d t he I n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o G S K.  H o we ver, it is ver y i m p ort a nt 
t h at t he I n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or e ver y e ve nt 
pri or t o t he i niti al tr a ns missi o n of t he S A E d at a t o G S K.

T he I n vesti gat or ma y  c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n, a me n di n g t he S A E data c ollecti o n t o ol acc or di n gly.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
8 9

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 me nts.
F oll o w -u p of A E s a n d S A E s

T he I n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as ma y  be i n dicate d or as re q ueste d b y G S K t o 
el uci date as f ull y as p ossi ble t he nat ure a n d/ or ca usalit y of t he A E or S A E.

T he I n vesti gat or is o bli gate d t o assi st.  T his ma y i ncl u de a d diti o nal la b orat or y tests 
or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns or c o ns ultati o n wit h ot her healt h 
care pr ofessi o nals.

If a s u bject dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w- u p 
peri o d, t he I n ves ti gat or will pr o vi de G S K wit h a c o p y of a n y p ost-m orte m fi n di n gs, 
i ncl u di n g hist o pat h ol o g y.

Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d C R F.

T he I n vesti gat or will s u b mit a n y  u p date d S A E data t o G S K wit hi n t he desi g nate d 
re p orti ng ti me fra mes.
1 2. 5. 6.
R e p orti n g of S A E s t o G S K
S A E re p orti n g t o G S K vi a electr o nic d at a c ollecti o n t o ol

Pri mar y  mec ha nis m f or re p orti n g S A Es t o G S K will be t he electr o nic data c ollecti o n 
t o ol

If t he electr o nic sys te m is u na vaila ble f or greater t ha n 2 4 h o urs, t he site will use t he 
pa per S A E data c ollecti o n t o ol a n d fa x it t o t he Me dical M o nit or.

Site will e nter t he seri o us a d verse e ve nt data i nt o t he electr o nic s ys te m as s o o n as it 
bec o mes a vaila ble.

T he I n vesti gat or will be re q uire d t o c o nfir m re vie w of t he S A E ca usalit y  b y tic ki n g 
t he ‘re vie we d’ b o x at t he b ott o m of t he e C R F pa ge wit hi n 7 2 h o urs of s u b missi o n of 
t he S A E.

After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol (e. g., 
I nF or m s ys te m) will be ta ke n off-li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o 
e xisti n g data

If a site recei ves a re p ort of a ne w S A E fr o m a st u d y s u bject or recei ves u p date d data 
o n a pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n 
off -li ne, t he site ca n re p ort t his inf or mati o n o n a pa per S A E f or m or t o t he Me dical 
M o nit or b y  tele p h o ne.

C o ntacts f or S A E recei pt ca n be f o u n d at t he be gi n ni n g of t his pr ot oc ol o n t he 
S p o ns or/ Me dical M o nit or C o ntact I nf or mati o n pa ge.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 0
1 2. 6.
A p p e n di x 6: M o difi e d Li st of Hi g hl y  Eff e cti v e M et h o d s f or 
A v oi di n g Pr e g n a n c y  i n F R P a n d C oll e cti o n of Pr e g n a n c y 
I nf or m ati o n
1 2. 6. 1.
M o difi e d Li st of Hi g hl y Eff e cti v e M et h o d s f or A v oi di n g Pr e g n a n c y  
i n F e m al e s of R e pr o d u cti v e P ot e nti al ( F R P)
T he list d oes n ot a p pl y  t o F R P wit h sa me se x part ners or f or s u bjects w h o are a n d will 
c o nti n ue t o be a bsti ne nt fr o m pe nile- va gi nal i nterc o urse o n a l o n g ter m a n d persiste nt 
basis, w he n t his is t heir preferre d a n d us ual lifest yle. Peri o dic a bsti ne nce (e. g. cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n met h o ds) a n d wit h dra wal a re n ot acce pta ble 
met h o ds of c o ntrace pti o n.
C o ntrace pti ve s u b der mal i m pla nt
1.
I ntra uteri ne de vice or i ntra uteri ne sys te m
2.
C o m bi ne d estr o ge n a n d pr o gest o ge n oral c o ntrace pti ve [ Hatc her , 2 0 1 1])
3.
I njecta ble pr o gest o ge n [Hatc her , 2 0 1 1]
4.
C o ntrace pti ve va gi nal ri n g [ Hatc her , 2 0 1 1]
5.
Perc uta ne o us c o ntrace pti ve patc hes [ Hatc her , 2 0 1 1]
6.
Male part ner sterilizati o n wit h d oc u me ntati o n of az o os per mia pri or t o t he fe male 
s u bject's e ntr y i nt o t he st u d y, a n d t his male is t he s ole part ner f or t hat s u bject 
[Hatc her , 2 0 1 1]. T he d oc u me ntati o n o n male sterilit y  ca n c o me fr o m t he site 
pers o n nel’s: re vie w of s u bject’s me dical rec or ds, me dical e xa mi nati o n an d/ or se me n 
a nal ys is, or me dical hist or y i nter vie w pr o vi de d by her or her part ner.
T hese all o we d met h o ds of c o ntrace pti o n are o nl y  effecti ve w he n use d c o nsiste ntl y, 
c orrectl y a n d i n acc or da nce wit h t he pr o d uct la bel. T he I n vesti gat or is res p o nsi ble f or 
e ns uri n g t hat s u bjects u n dersta n d h o w t o pr o perly use t hese met h o ds of c o ntrace pti o n
C o ntr ace pti ve re q uire me nts f or m ale s u bjects wit h fe m ale p art ners of re pr o d ucti ve 
p ote nti al ( w he n a p plic a ble).
Male s u bjects wit h fe male part ners of c hil d beari n g p ote ntial m ust c o m pl y  wit h t he 
f oll o wi n g c o ntrace pti o n re q uire me nts fr o m t he ti me of first d ose of st u dy m e dicati o n 
u ntil 9 0 da y s after t he last d ose of st u d y me dicati o n.
1.
Vasect o m y wit h d oc u me ntati o n of az o os per mia. T he d oc u me ntati o n o n male sterilit y 
ca n c o me fr o m t he site pers o n nel’s: re vie w of s u bject’s me dical rec or ds, me dical 
e xa mi nati o n a n d/ or se me n a nal ys is, or me dical hist or y i nter vie w.
2.
Male c o n d o m pl us part ner use of o ne of t he c o ntrace pti ve o pti o ns bel o w t hat meets 
t he S O P effecti ve ness criteria i ncl u di n g a < 1 % rate of fail ure per ye ar, as state d i n 
t he pr o d uct la bel:

C o ntrace pti ve s u b der mal i m pla nt

I ntra uteri ne de vice or i ntra uteri ne sys te m
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 1

C o m bi ne d estr o ge n a n d pr o gest o ge n oral c o ntrace pti ve [ Hatc her , 2 0 1 1] 

I njecta ble pr o gest o ge n [Hatc her , 2 0 1 1]

C o ntrace pti ve va gi nal ri n g [ Hatc her , 2 0 1 1]

Perc uta ne o us c o ntrace pti ve patc hes [ Hatc her , 2 0 1 1]
T hese all o we d met h o ds of c o ntrace pti o n are o nl y  effecti ve w he n use d c o nsiste ntl y, 
c orrectl y a n d i n acc or da nce wit h t he pr o d uct la bel. T he I n vesti gat or is res p o nsi ble f or 
e ns uri n g t hat s u bjects u n dersta n d h o w t o pr o perl y use t hese met h o ds of c o ntrace pti o n.
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat s u bjects u n dersta n d h o w t o pr o perl y use 
t hese met h o ds of c o ntrace pti o n.
1 2. 6. 2.
C oll e cti o n of Pr e g n a n c y  I nf or m ati o n

I n vesti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male s u bject, w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y

I nf or mati o n will be recor de d o n t he a p pr o priate f or m a n d s u b mitte d t o G S K wit hi n 2 
wee ks of lear ni n g of a s u bject's pre g na nc y .

S u bject will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y . T he 
I n vesti gat or will c ollect f oll o w u p i nf or mati o n o n m ot her a n d i nfa nt, w hic h will be 
f or war de d t o G S K.  Ge nerally, f oll o w - u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 
wee ks be y o n d t he esti mate d deli ver y  date. 

A n y  ter mi nati o n of pre g na nc y will be re p orte d, re gar dless of fetal stat us ( prese nce or 
a bse nce of a n o malies) or i n dicati o n f o r pr oce d ure.

W hile pre g na nc y  itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o m plicati o n or electi ve ter mi nati o n of a pre g na nc y will be re p orte d as a n A E or 
S A E.

A s p o nta ne o us a b orti o n is al wa y s c o nsi dere d t o be a n S A E a n d will be re p orte d as 
suc h.  

A n y  S A E occ urri n g as a res ult of a p ost-st u d y pre g na nc y w hic h is c o nsi dere d 
reas o na bly relate d t o t he st u d y  treat me nt b y t he I n vesti gat or, will be re p orte d t o G S K 
as descri be d i n A p pe n di x 5 .  W hile t he In vesti gat or is n ot o bli gate d t o acti vel y  see k 
t his i nf or mati o n i n f or mer st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h 
s p o nta ne o us re p orti n g.
A n y fe m ale s u bject w h o bec o mes pre g n a nt w hile p artici p ati n g 

Will disc o nti n ue st u d y  me dicati o n or be wit h dra w n fr o m t he st u d y

I n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y fe male part ner of a 
male st u d y  s u bject w h o bec o mes pre g na nt w hile partici pati n g i n t his st u d y a n d u p t o 
9 0 da y s after t he last d ose of st u d y me dicati o n.  T his a p plies o nl y t o s u bjects w h o are 
ra n d o mize d t o recei ve st u d y me dicati o n. 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 2

After o btai ni n g t he necessar y  si g ne d i nf or me d c o nse nt fr o m t he fe male part ner 
directl y , t he I n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o priate f or m 
a n d s u b mit it t o G S K wit hi n 2 wee ks of lear ni n g of t he part ner’s pre g na nc y.

Part ner will als o be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y .  
I nf or mati o n o n t he stat us of the m ot her a n d c hil d will be f or war de d t o G S K. 

Ge nerall y , f oll o w- u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t he esti mate d 
deli ver y  date.  A ny t er mi nati o n of t he pre g na nc y will be re p orte d re gar dless of fetal 
stat us ( prese nce or a bse nce of a n o malies) or i n dicati o n f or pr oce d ure.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1 
C O N FI D E N TI A L
 
 
 
2 0 2 1 5 2
 
 9 3
 
 
1 2. 7.  
A p p e n di x 7:  Pr ot o c ol A m e n d m e nt C h a n g e s 
Pr ot o c ol A m e n d m e nt 1 ( 2 0- A P R- 2 0 1 7) fr o m t h e ori gi n al pr ot o c ol ( 2 3- M A Y- 2 0 1 6) 
W here t he A me n d me nt A p plies 
T his a me n d me nt a p plies t o all s u bjects w h o w ill partici pate i n t his st u d y i n all c o u ntries. 
S u m m ar y of Pr ot oc ol A me n d m e nt C h a n ges wit h R ati o n ale 
C ha n ge i n d osi n g re gi me n fr o m 6 0 m g BI D t o 6 0  m g TI D, u p dates t o I ncl usi o n criteria 3 
a n d 6 a n d E xcl usi o n criteria 3, 9, 2 1 a n d 2 2, a ll o wa nce f or rescree ni n g a n d a d diti o n of 
s uici dalit y sto p pi n g criteria. 
Gla x o S mit h Kli ne D oc u me nt N u m ber of I n vesti gat or Br oc h ure G S K 2 9 8 2 7 7 2 has bee n 
u p date d t o 2 0 1 4 N 2 0 4 1 2 6 _ 0 2 t hr o u g h o ut t he d oc u me nt. Ot her mi n or pr ot oc ol 
clarificati o ns a n d a d mi nist rati ve c ha n ges are als o pr o vide d i n t his a me n d me nt. 
List of S pecific C h a n ges  (b ol d  i n dicates te xt a d de d a n d stri ket hr o u g h i n dicates te xt 
re m o ve d): 
A ut h ors 
A ut h or (s):
 
 
 
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n:  
R ol e 
N a m e  
D ay Ti m e P h o n e N u m b er a n d 
e m ail a d dr ess 
Aft er- h o urs 
P h o n e/ C ell/ 
P a g er N u m b er 
F ax N u m b er  
Sit e A d dr ess 
Pri m ary 
M e dic al 
M o nit or  
 
 
 
 
T el       
 
E m ail   
 
 
T el: 
 
M o bil e:
 
E m ail:  
 
M o bil e   
 
 
 
M o bil e:  
 
N/ A  
 
G S K St o c kl e y 
P ar k W e st, 1- 3 
Ir o n brid g e 
R o a d, 
U x bri d g e, 
Mi d dl e s e x, 
U B 1 1 1 B T, U K 
P att er n  
R ec o g niti o n  
R ec e pt or D P U,  
U P 4 4 4 0  
1 2 5 0 S  
C oll e g evill e, P A  
1 9 4 2 6  
 
P P D
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
P P D
P P D
P P D
P P D
P P D
P P D
P P
D
P P D
P P D

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 4
S ec o n d ary 
M e dic al 
M o nit or
 
M o bil e: +
E m ail 
T el: 
M o bil e: 
E m ail:
M o bil e: 
 
M o bil e: 
N A
1 2 5 0 S. 
C oll e g e vill e 
R d.
C oll e g e vill e P A 
1 9 4 2 6, U S A
Cyt oki n e
C h e m oki n e
D P U, G S K,
G u n n els W o o d
R o a d,
St ev e n a g e,
S G 1 2 N Y, U K
S A E 
c o nt act  
i nf or m ati o n 
M e dic al 
M o nit or as 
a b ov e
S y n o psis a n d Secti o n 2. 1 St u d y R ati o n ale
T he pri m ar y o bjecti ve of t his st u d y h as n ot c h a n ge d wit h a me n d me nt 0 1; h o we ver 
t he d osi n g re gi me n d oes c h a n ge t o G S K 2 9 8 2 7 7 2 ( 6 0 m g t hree ti mes d ail y f or b ot h 
P arts A a n d B).
T he pri mar y  o bjecti ve will be t o i n vesti gate t he safet y a n d t olera bilit y of re peat oral d oses 
of G S K 2 9 8 2 7 7 2 6 0 m g or place b o t wicet hree ti mes dail y  f or 4 2 da ys ( Part A) f oll o we d 
b y  o pe n la bel wit h G S K 2 9 8 7 7 2 6 0 m g t wicet hree ti mes dail y f or 4 2 da ys ( Part B). I n 
a d diti o n t o p har mac o ki netics ( P K), a n u m ber of e x peri me ntal a n d cli nical e n d p oi nts will 
be e m pl o y e d t o o btai n i nf or mati o n o n t he p har mac o d y na mics ( P D), a n d preli mi nar y  
efficac y i n s u bjects wit h acti ve U C. Alth o u g h n o f or mal h y p ot hesis will be teste d, t hese 
e n d p oi nts will e na ble a br oa der u n dersta n di n g of t he mec ha nis m of acti o n a n d p ote ntial 
f or cli nical efficac y of G S K 2 9 8 2 7 7 2 i n U C, b y ma ki n g f ull use of t he i nf or mati o n 
o btai ne d fr o m eac h s u bject e nr olle d.
S y n o psis a n d Secti o n 3 O bjecti ves a n d E n d p oi nts
O bj e cti v e s
E n d p oi nt s
Pri m ar y

T o i nv esti g at e t h e s af ety a n d t ol er a bility 
of 6 0 m g t wic et hr e e ti m e s d aily d os es of 
G S K 2 9 8 2 7 7 2 i n s u bj ects wit h activ e 
ulc er ativ e c olitis.

A dv ers e ev e nts.

Cli nic al l a b or at ory v al u es (cli nic al 
c h e mistry, h a e m at ol o gy a n d uri n alysis).

Vit al si g n m e as ur e m e nts ( bl o o d pr ess ur e, 
h e art r at e, r es pir at ory r at e, a n d b o dy 
t e m p er at ur e).

1 2 -L e a d E C G m o nit ori n g.
S e c o n d ar y

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g m uc os al 
h e ali n g aft er 6 a n d 1 2 w e eks of 
tr e at m e nt i n s u bj ects wit h activ e 

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
a n a bs ol ut e M ay o e n d osc o py s u bsc or e 
of 0 or 1 at D ays 4 3 ( W e ek 6) a n d 8 5 
( W e ek 1 2).

C h a n g e fr o m b as eli n e i n m uc os al 
 
P P D
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
P P D
P P D
P P D
P P D
P P D
P P D
P P
D

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 5
O bj e cti v e s
E n d p oi nt s
ulc er ativ e c olitis.
a p p e ar a nc e d et er mi n e d by Ulc er ativ e 
C olitis E n d osc o pic I n d ex of S ev erity 
( U C EI S).

T o i nv esti g at e t h e eff ect of 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 o n bi o m ark ers of dis e as e 
activity i n s u bj ects wit h activ e ulc er ativ e 
c olitis.

C h a n g e fr o m b as eli n e i n m ark ers w hic h 
m ay i ncl u d e, b ut ar e n ot li mit e d t o, m e a n 
C R P a n d f a ec al c al pr ot ecti n ( F C P).

T o i nv esti g at e t h e eff ect of 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 o n hist ol o gic dis e as e 
activity i n s u bj ects wit h activ e ulc er ativ e 
c olitis.

C h a n g e fr o m b as eli n e i n hist ol o gic 
s ev erity, i ncl u di n g b ut n ot li mit e d t o 
M o difi e d Ril ey Sc or e a n d G e b o es I n d ex.

T o i nv esti g at e t h e eff ect of 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g cli nic al 
r es p o ns e a n d r e missi o n aft er 6 a n d 1 2 
w e eks of tr e at m e nt i n s u bj ects wit h 
activ e ulc er ativ e c olitis.

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r es p o ns e d efi n e d as r e d ucti o n by 
≥3 p oi nts or ≥3 0 % i m pr ov e m e nt fr o m 
b as eli n e c o m pl et e M ay o sc or e, al o n g 
wit h a d ecr e as e i n t h e r ect al bl e e di n g 
sc or e of ≥1 p oi nt, at D ays 4 3 ( W e ek 6) 
a n d 8 5 ( W e ek 1 2).

T h e pr o p orti o n of s u bj ects w h o ac hi ev e 
cli nic al r e missi o n d efi n e d as a c o m pl et e 
M ay o sc or e of 2 p oi nts or l o w er, w it h n o 
i n divi d u al s u bsc or e exc e e di n g 1 p oi nt, at 
D ays 4 3 ( W e ek 6) a n d 8 5 ( W e ek 1 2).

T o i nv esti g at e t h e pr eli mi n ary effic acy of 
6 0 m g t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 i n ac hi evi n g sy m pt o m atic 
cli nic al r e missi o n aft er 6 a n d 1 2 w e eks of 
tr e at m e nt in s u bj ects wit h activ e 
ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n p arti al M ay o 
sc or e.

T o i nv esti g at e t h e pl as m a c o nc e ntr ati o ns 
of G S K 2 9 8 2 7 7 2 f oll o wi n g 6 0 m g 
t wicet hree ti mes d aily i n s u bj ects wit h 
activ e ulc er ativ e c olitis.

Pr e- d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 at D ay 4 3 ( W e ek 6). 

P ost -d os e pl as m a c o nc e ntr ati o ns of 
G S K 2 9 8 2 7 7 2 o n D ays 1 a n d 4 3 ( W e ek 
6) at 1, 2, 4 a n d 6 h o urs.

Tr o u g h c o nc e ntr ati o ns o n D ay 8 5 ( W e ek 
1 2).
E x pl or at or y

T o i nv esti g at e t h e eff ect of 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 2 2 o n ex pr essi o n of 

C h a n g e fr o m b as eli n e i n i nfl a m m at ory 
m ark ers w hic h m ay i ncl u d e, b ut ar e n ot 
li mit e d t o I L- 1, I L- 6, I L-8, M M P 3, T N F α, 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 6
O bj e cti v e s
E n d p oi nt s
i nfl a m m at ory bi o m ark ers i n m uc os al 
tiss u e bi o psi es i n s u bj ects wit h activ e 
ulc er ativ e c olitis.
I F Nγ.

T o i nv esti g at e p at h w ay a n d t ar g et 
e n g a g e m e nt f oll o wi n g 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 i n bl o o d a n d c ol o n bi o psy 
tiss u e.

P h ar m ac ol o gy bi o m ark er e n d p oi nts m ay 
i ncl u d e, b ut ar e n ot li mit e d t o t h e 
f oll o wi n g, pr e- d os e at D ays 1, 4 3 ( W e ek 
6) a n d tr o u g h o n D ay 8 5 ( W e ek 1 2), as 
a p plic a bl e a n d if ev al u a bl e s a m pl es a n d 
d at a p er mit:
o
T ar g et E n g a g e m e nt Ass ay RI P 1 
( T E A R 1) i n bl o o d a n d c ol o n 
tiss u e.
o
P h os p h oryl at e d or t ot al RI P 1, 
M L K L, RI P 3, cl e av e d a n d t ot al 
c as p as e 3 a n d c as p as e 8 
si g n at ur es i n col o n tiss u e.

T o i nv esti g at e t h e c o nc e ntr ati o n of 
G S K 2 9 8 2 7 7 2 a n d p ossi bl e dr u g -r el at e d 
m at eri al, as w ell as s p ecific distri b uti o n 
wit hi n tiss u e if f e asi bl e, i n t h e c ol o n 
tiss u e aft er 6 0 m g t wicet hree ti mes
d aily d os es of G S K 2 9 8 2 7 7 2.

Pr e- d os e G S K 2 9 8 2 7 7 2 a n d p ossi bl e 
dr u g -r el at e d m at eri al c o nc e ntr ati o ns, as 
w ell as s p ecific distri b uti o n wit hi n tiss u e 
if f e asi bl e, i n c ol o n bi o psi es at D ays 4 3 
( W e ek 6) a n d 8 5 ( W e ek 1 2), as 
ev al u a bl e s a m pl es a n d d at a p er mit.

T o i nv esti g at e t h e eff ect of 6 0 
t wicet hree ti mes d ail y d os es of 
G S K 2 9 8 2 7 7 2 o n q u ality of lif e i n s u bj ects 
wit h activ e ulc er ativ e c olitis.

C h a n g e fr o m b as eli n e i n I nfl a m m at ory 
B o w el Dis e as e Q u esti o n n air e (I B D Q).

T o i nv esti g at e t h e eff ect of 6 0 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 o n g e n e ex pr essi o n i n t h e 
bl o o d s u bj ects wit h activ e ulc er ativ e 
c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol at e d fr o m bl o o d D ays 1 a n d 4 3 
( W e ek 6) a n d tr o u g h o n D ay 8 5 ( W e ek 
1 2).

T o i nv esti g at e t h e eff ect of 6 0 m g 
t wicet hree ti mes d aily d os es of 
G S K 2 9 8 2 7 7 2 o n g e n e ex pr essi o n i n 
c ol o n tiss u e bi o psi es i n s u bj ects wit h 
activ e ulc er ativ e c olitis.

Tr a nscri pt o mic a n alysis of m R N A 
is ol at e d fr o m c ol o n tiss u e bi o psi es at 
Scr e e ni n g, a n d D ays 4 3 ( W e ek 6) a n d 
tr o u g h o n D ay 8 5 ( W e ek 1 2).
S y n o psis a n d Secti o n 4. 1 O ver all Desi g n
Sc he m atic a d de d. 
A m e n d me nt 0 1:
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 7
S y n o psis Tre at me nt Ar ms a n d D ur ati o n
Part A:  A p pr o xi matel y  3 6 s u bjects w h o ha ve c o m plete d scree ni n g assess me nts a n d are 
eli gi ble will be ra n d o mize d i n a 2: 1 rati o (acti ve t o place b o) t o o ne of t he f oll o wi n g st u d y  
treat me nts f or 4 2 d a y s:
G S K 2 9 8 2 7 7 2 6 0 m g t wicet hree ti mes dail y ( B TI D) 
Place b o t wicet hree ti mes dail y  ( BTI D) 
Part B:  Is a 6 wee k o pe n la bel e xte nsi o n w here all s u bjects w h o ha ve c o m plete d Part A 
will recei ve 6 0 m g G S K 2 9 8 2 7 7 2 t wicet hree ti mes dail y  ( BTI D ) f or 4 2 da ys.
Pri or t o a me n d me nt 0 1 bei n g effecti ve i n e ac h c o u ntr y, s u bjects h a ve bee n 
r a n d o mise d i n a 2: 1 r ati o ( acti ve t o pl ace b o) t o o ne of t he f oll o wi n g tre at me nts f or 
P art A:
G S K 2 9 8 2 7 7 2 6 0 m g t wice d ail y ( BI D) x 4 2 d a ys
Pl ace b o t wice d ail y ( BI D) x 4 2 d a ys
P art B: A 6 wee k o pe n l a bel e xte nsi o n w here all s u bjects w h o h a ve c o m plete d P art 
A recei ved 6 0 m g G S K 2 9 8 2 7 7 2 t wice d ail y ( BI D) f or 4 2 d a ys.
S y n o psis a n d Secti o n 4. 3 T y pe a n d N u m ber of S u bjects
A s ufficie nt n u m ber of s u bjects will be scree ne d s o t hat a p pr o xi matel y 3 0 - 3 6 s u bjects 
wit h acti ve U C will be ra n d o mise d i nt o t he st u d y  o n a TI D re gi me n. Pri or t o pr ot oc ol 
a me n d me nt 0 1 bei n g a p pr o ve d i n e ac h c o u ntr y, n o m ore t h a n 1 8 s u bjects will be 
r a n d o mise d i nt o t he st u d y o n a BI D re gi me n . S h o ul d t he dr o p o ut rate i n Part A [ Da y 1 
t hr o u g h 4 3 ( Wee k 6)] be hi g her t ha n a ntici pate d, or t he sa m ple size re vie w warra nts a n 
i ncrease i n ra n d o mise d s u bjects, a d diti o nal or re place me nt s u bjects ma y be ra n d o mise d 
( u p t o a n o ver all t ot al ma xi m u m of 4 8 6 0 ) i nt o t he st u d y at t he discreti o n of t he S p o ns or.  
S u bjects w h o disc o nti n ue partici pati o n d uri n g t he o pe n la bel p hase i n Part B [( Da y  4 3 
( Wee k 6) t hr o u g h Da y 8 5 ( Wee k 1 2)] will n ot be re place d.
Secti o n 4. 2. 2 Tre at me nt Peri o d
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 8
S u bjects will be ra n d o ml y assi g ne d t o eit her G S K 2 9 8 2 7 7 2 6 0 m g or place b o orall y  
t wicet hree ti mes dail y  (a p pr o xi matel y 8 1 2 h o urs a part) f or 4 2 da y s ( 6 wee ks) i n a 2: 1 
rati o i n Part A.  All s u bjects will m o ve t o o pe n la bel i n Part B t o recei ve G S K 2 9 8 2 7 7 2 6 0 
m g t wicet hree ti mes dail y  (a p pr o xi matel y8 1 2 h o urs a part) f or a n a d diti o nal 4 2 da y s ( 6 
wee ks).  Treat me nt d urati o n is a t otal of 8 4 da ys ( 1 2 wee ks) i ncl usi ve of Parts A a n d B.  
S u bjects t h at were r a n d o mise d pri or t o pr ot oc ol a me n d me nt 0 1 bei n g a p pr o ve d i n 
eac h c o u ntr y were r a n d o ml y assi g ne d t o eit her G S K 2 9 8 2 7 7 2 6 0 m g or pl ace b o 
or all y t w o ti mes d ail y ( a p pr o xi m atel y 1 2 h o urs a p art) f or 4 2 d a ys f oll o we d b y 
G S K 2 9 8 2 7 7 2 6 0 m g BI D f or 4 2 d a ys.
D uri n g t he 8 4 da y  ( 1 2 wee k) treat me nt peri o d, s u bjects will atte n d t he cli nical site f or 
visits o n Da y s 1, 1 5, 2 9, 4 3, 5 7, 7 1 a n d 8 5.  At s pecific visits, s u bjects m ust n ot ta ke 
st u d y treat me nt pri or t o t heir sc he d ule d visit (see Secti o n 7. 1).  O n Da ys 8, 2 2, 3 6, 5 0, 6 4 
a n d 7 8 eac h s u bject will be c o ntacte d b y tele p h o ne a n d a s ke d a b o ut t heir ge neral healt h,
st u d y me dic ati o n c o m pli a nce a n d di ar y c ar d c o m pleti o n. S u bjects will be gi ve n a 
diar y  car d at eac h of t he visits w hic h will t he y will be i nstr ucte d t o rec or d t heir dail y 
st u d y me dicati o n a n d c o nc o mita nt me dicati o n a d mi nistrati o n a n d a n y a d verse e ve nts.
Secti o n 4. 5 D ose J ustific ati o n
T he i niti al selecti o n of t he 6 0 m g BI D d ose t o bebei n g teste d i n t his st u d y is base d o n t he 
safety, P K, a n d P D data fr o m t he First Ti me i n H u ma n ( F Ti H) st u d y, 2 0 0 9 7 5.  
G S K 2 9 8 2 7 7 2 a d mi nistere d at 6 0 m g BI D f or 1 4 da y s was well t olerate d a n d n o safety 
c o ncer ns were i de ntifie d. A BI D d osi n g re gi me n was i niti all y selecte d o ver a Q D d osi n g 
re gi me n d ue t o t he s h ort half-life of G S K 2 9 8 2 7 7 2 i n h u ma ns ( ~ 2 h).  Base d o n 
preli mi nar y  P K/ P D m o delli n g fr o m t he si n gle d ose asce n di n g part of st u d y 2 0 0 9 7 5, a 6 0 
m g BI D d ose w as is pre dicte d t o ha ve o n a vera ge 9 5 % RI P 1 tar get e n ga ge me nt a n d 
a p pr o xi matel y 9 0 % of s u bjects will ha ve > 9 0 % tar get e n ga ge me nt at Cmi n usi n g a n o vel 
i n-h o use e x - vi v o P D/t ar get e n g a ge me nt ass a y base d s olel y o n t he T N F p at h w a y 
w hic h is belie ve d t o be a ke y c o m p o ne nt of t he RI P 1 p at h w a y.
H o we ver, b ase d o n fi n al P K/ P D m o delli n g fr o m t he f ull re pe at d ose p art of t he 
St u d y 2 0 0 9 7 5 ( u p t o 1 2 0 m g BI D), a 6 0 m g BI D d ose is n o w pre dicte d t o h a ve o n 
a ver a ge 9 9 % RI P 1 t ar get e n g a ge me nt i n bl o o d a n d a p pr o xi m atel y 9 0 % of s u bjects 
will h a ve > 8 5 % t ar get e n g a ge me nt at C mi n .  T his is l o wer t h a n o ur t ar get of 
ac hie vi n g > 9 0 % t ar get e n g a ge me nt i n at le ast 9 0 % of s u bjects at C mi n .  T heref ore, a 
6 0 m g TI D c o h ort is n o w be i n g pr o p ose d.
T he C mi n v al ues at 6 0 m g TI D are pre dicte d t o be a p pr o xi m atel y 3. 5 f ol d hi g her t h a n 
f or 6 0 m g BI D.  Usi n g t he fi n al P K/ P D, a 6 0 m g TI D d ose is pre dicte d t o h a ve o n 
a ver a ge 9 9 % RI P 1 t ar get e n g a ge me nt i n bl o o d a n d a p pr o xi m atel y 9 0 % of s u bjects
will h a ve > 9 6 % t ar get e n g a ge me nt at C mi n .  N o data is c urre ntl y  a vaila ble a b o ut t he 
distri b uti o n of G S K 2 8 9 2 7 7 2 i nt o gastr oi ntesti nal ( GI) tiss ue.  H o we ver, if bl o o d 
c o nce ntrati o n is re prese ntati ve of t he c o nce ntrati o n at t he site of acti o n, a 6 0 m g BI D 
d ose re gi me n s h o ul d pr o vi de s ufficie nt RI P 1 tar get e n ga ge me nt t o esta blis h pr o of of 
mec ha nis m.
I n a d diti o n, bec a use of t he s h ort h alf-life, a m o difie d rele ase f or m ul ati o n is n o w 
bei n g de vel o pe d wit h t he ai m t o pr o vi de a o nce d ail y d osi n g re gi me n.  B y i ncre asi n g 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
9 9
t he fre q ue nc y of d osi n g t o t hree ti mes d ail y ( TI D) wit h t he c urre nt i m me di ate 
rele ase f or m ul ati o n, t his will m ore cl osel y m atc h t he P K, s afet y a n d effic ac y pr ofile 
of a preferre d o nce d ail y m o difie d rele ase f or m ul ati o n.
T he s afet y of i ncre asi n g t he d ose fre q ue nc y t o 6 0 m g TI D is j ustifie d b ase d o n 
n o ncli nic al s afet y fi n di n gs t o d ate wit h G S K 2 9 8 2 7 7 2. It is a ntici p ate d t h at a h u m a n 
d ose of 6 0 m g TI D ( 1 8 0 m g/ d a y) will pr o d uce A U C ( 0-2 4) a n d C m a x v al ues of 
a p pr o xi m atel y 9. 9 u g. h/ m L a n d 0. 8 u g/ m L, res pect i vel y, w hic h are a p pr o xi m atel y 
1/ 5 t h a n d 1/ 1 5 t h of t he ge n der -a ver a ge d A U C ( 4 8. 4 u g. h/ m L) a n d C m a x ( 1 2. 3 u g/ m L) 
ac hie ve d i n t he 1 3 wee k m o n ke y st u d y at t he n o a d verse effect le vel ( N O A E L) d ose 
of 3 0 m g/ k g/ d a y. Ple ase see G S K 2 9 8 2 7 7 2 I B [ Gl a x o S mit h Kli ne D o c u me nt N u m ber 
2 0 1 4 N 2 0 4 1 2 6 _ 0 2].
As of 0 3 A pr 2 0 1 7, a t ot al of a p pr o xi m atel y 9 3 s u bjects acr oss 4 cli nic al st u dies h a ve 
bee n r a n d o mise d t o recei ve G S K 2 9 8 2 7 7 2. I n St u d y 2 0 0 9 7 5, G S K 2 9 8 2 7 7 2 
a d mi nistere d u p t o 1 2 0 m g BI D f or 1 4 d a ys a n d w as well t oler ate d a n d n o s afet y 
c o ncer ns were i de ntifie d. A t ot al of 9 s u bjects h a d recei ve d 1 2 0 m g BI D i n t h at 
st u d y.  Ple ase see G S K 2 9 8 2 7 7 2 I B [ Gl a x o S mit h Kli ne D oc u me nt N u m ber 
2 0 1 4 N 2 0 4 1 2 6 _ 0 2]. I n t he o n g oi n g P h ase 2 a st u dies i n Ps ori asis [( Ps O); St u d y 
2 0 3 1 6 7] a n d R he u m at oi d Art h ritis [( R A); St u d y 2 0 3 1 6 8], a t ot al of 2 6 s u bjects h a ve 
bee n r a n d o mise d t o G S K 2 9 8 2 7 7 2 6 0 m g BI D. N o s u bjects h a ve bee n r a n d o mise d 
yet t o t his st u d y ( St u d y 2 0 2 1 5 2).  G S K 2 9 8 2 7 7 2 w as well t oler ate d a n d n o dr u g -
rel ate d S A Es h a ve bee n re p orte d.  I n St u d y 2 0 3 1 6 7, t here w as a de at h of a 1 9 ye ar 
ol d m al e s u bject d ue t o a n acci de nt al o ver d ose wit h 3, 4 -met h yle ne di o x y -
met h a m p het a mi ne ( M D M A) t h at w as n ot c o nsi dere d dr u g rel ate d b y t he Pri nci p al 
I n vesti g at or ( PI).  
T heref ore, it is pre dicte d t hat a d ose of G S K 2 9 8 2 7 7 2 6 0 m g BI D ma y  be cli nicall y 
efficaci o us i n s u bjects wit h U C.
It is a ntici pate d t hat a h u ma n d ose of 6 0 m g BI D will pr o d uce A U C( 0-2 4) a n d C ma x val ues 
of a p pr o xi matel y  9 u g. h/ m L a n d 1 u g/ m L, res pecti vel y, w hic h are a p pr o xi matel y 1/ 6t h  
a n d 1/ 1 2 t h of t he ge n der -a vera ge d A U C ( 4 8. 4 u g. h/ m L ) a n d Cma x ( 1 2. 3 u g/ m L) ac hie ve d 
i n t he 1 3 wee k m o n ke y st u d y at t he N O A E L d ose of 3 0 m g/ k g/ da y.  Please see 
G S K 2 9 8 2 7 7 2 I B [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 1].  
Secti o n 5. 1 I ncl usi o n Criteri a
3.
S u bject has ha d a c o nfir me d dia g n osis of acti ve U C, as d oc u me nte d b y c o m plete 
dia g n ostic c ol o n osc o p y t o t he ter mi nal ile u m ( TI) wit h bi o ps y  at least perf or me d 3 
m o nt hs pri or t o scree ni n g.  If di a g n ostic c ol o n osc o p y w as n ot perf or me d t o t he TI, 
it m ust be d oc u me nted b y t he PI t h at t he s u bject h as diff use i nfl a m m ati o n fr o m 
t he rect u m e xte n di n g pr o xi m all y t o t he c ol o n i n a c o nti n u o us a n d u nif or m w a y.
6.
S u bject is nai ve t o a n y  bi ol o gical t hera pies f or U C.
O R
S u bject ma y  ha ve ha d pre vi o us e x p os ure t o a si n gle a nti-T N F bi ol o gic a ge nt w hic h 
was disc o nti n ue d f or reas o ns ot her t ha n pri mar y  n o n-res p o nse m ore t ha n 8 wee ks ( or 
5 half li ves w hic he ver is l o n ger) pri or t o first d ose.  
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 0
O R
S u bject m a y h a ve h a d pre vi o us e x p os ure t o a si n gle bi ol o gic a ge nt (e. g., 
ve d oliz u m a b) i n t he c o nte xt of a pre vi o us cli nic al tri al.  T he bi ol o gic a ge nt m ust 
h a ve bee n disc o nti n ue d m ore t h a n 8 wee ks ( or 5 h alf li ves w hic he ver is l o n ger) 
pri or t o first d ose.  
N ote:  E x p os ure t o a si n gle bi ol o gic a ge nt is n ot re q uire d i n a d diti o n t o I ncl usi o n 
# 4 a n d # 5 a b o ve.
Fe m ales : 
A fe male s u bject is eli gi ble t o partici pate if s he is n ot pre g na nt (as c o nfir me d b y  a 
ne gati ve ser u m h u ma n c h ori o nic g o na d otr o p hi n [ h C G] test), n ot lactati n g, a n d at least 
o ne of t he f oll o wi n g c o n diti o ns a p plies:
a.
N o n -re pr o d ucti ve p ote ntial as defi ne d as i n A p pe n di x 6:
Pre -me n o p a us al fe m ales wit h o ne of t he f oll o wi n g:

D oc u me nte d t u b al li g ati o n

D oc u me nte d h yster osc o pic t u b al occl usi o n pr oce d ure wit h f oll o w- u p 
c o nfir m ati o n of bil ater al t u b al occl usi o n 

H ysterect o m y

D oc u me nte d Bil ater al O o p h orect o m y

P ost me n o p a us al defi ne d as 1 2 m o nt hs of s p o nt a ne o us a me n orr he a i n 
q uesti o n a ble c ases a bl o o d s a m ple w it h si m ult a ne o us f ollicle sti m ul ati n g 
h or m o ne ( F S H) a n d estr a di ol le vels c o nsiste nt wit h me n o p a use (refer t o 
l a b or at or y refere nce r a n ges f or c o nfir m at or y le vels).  Fe m ales o n 
h or m o ne re pl ace me nt t her a p y ( H R T) a n d w h ose me n o p a us al st at us is i n 
d o u bt will be re q uire d t o use o ne of t he hi g hl y effecti ve c o ntr ace pti o n 
met h o ds (see A p pe n di x 6) if t he y wis h t o c o nti n ue t heir H R T d uri n g t he 
st u d y.  Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir m ati o n of 
p ost -me n o p a us al st at us pri or t o st u d y e nr ol me nt.
Secti o n 5. 2 E xcl usi o n Criteri a
3.
S u bject wit h pre vi o us s mall b o wel or c ol o nic s ur ger y ( wit h e xce pti o n of
a p pe n dect o m y) , hist ol o gical e vi de nce of c ol o nic d y s plasia or b o wel strict ure.
9.
Q Tc > 4 5 0 msec or Q Tc > 4 8 0 msec f or s u bjects wit h b u n dle bra nc h bl oc k at 
scree ni n g a n d Da y - 1.
2 1. T he s u bject has partici pate d i n a cli nical trial a n d has recei ve d a n i n vesti gati o nal 
pr o d uct wit hi n 3 0 da y s or 5 half-li ves, w hic he ver is l o n ger bef ore t he first d ose of 
st u d y me dicati o n, or pla ns t o ta ke part i n a n ot her cli nical trial ( n ot i ncl usi ve of a n y 
U C re gistr y st u d y w here n o st u d y me dic ati o n is bei n g a d mi nistere d) at t he sa me 
ti me as partici pati n g i n t his cli nical trial.
2 2. Hae m o gl o bi n < 1 0 g/ d L ; hae mat ocrit < 3 0 %, w hite bl o o d cell c o u nt ≤3, 0 0 0/ m m 3 ( ≤3. 0 
x 1 0 9/ L) or ≥1 4, 0 0 0/ m m 3 ( ≥1 4 x 1 0 9/ L); platelet c o u nt ≤ 1 0 0, 0 0 0/ µ L  ( ≤1 0 0 x 1 09/ L); 
a bs ol ute ne utr o p hil c o u nt ≤3 1. 5 x 1 0 9/ L; l ym p h oc y te c o u nt < 1 x 1 09/ L.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 1
Secti o n 5. 3 Scree ni n g/ B aseli ne/ R u n -i n F ail ures
S u bjects c a n be re -scree ne d o nl y o n a p pr o v al of t he G S K Me dic al M o nit or a n d o nl y 
o nce.  Re -scree ni n g is all o we d w he n a s u bject f aile d i ncl usi o n/e xcl usi o n criteri a or 
s o me ot her scree ni n g c o n diti o n i niti all y ( prefer a bl y bef ore perf or mi n g 
si g m oi d osc o p y), b ut t he I n vesti g at or belie ves t here is a re as o n a ble pr o b a bilit y t h at 
t he s u bject w o ul d be eli gi ble if re-scree ne d. 
Secti o n 5. 4. 1 I n di vi d u al S afet y St o p pi n g Criteri a
St u d y  me dicati o n will be disc o nti n ue d i n t he e ve nt of a n y of t he f oll o wi n g:

If a s u bject e x perie nces a seri o us or se vere cli nicall y si g nifica nt A E t hat i n t he 
cli nical j u d ge me nt of t he I n vesti gat or, after c o ns ultati o n wit h t he me dical m o nit or, 
is p ossi bl y, pr o ba bly or defi nitel y relate d t o i n vesti gati o nal pr o d uct.

T he s u bject bec o mes pre g na nt.

T he s u bject i nitiates treat me nt wit h a n y pr o hi bite d me dicati o n f or t he treat me nt of 
U C as liste d i n Secti o n 6. 1 1. 2.

T he s u bject de vel o ps a seri o us o p p ort u nistic or at y pical i nfecti o n.

If a ny of t he li ver c he mistr y st o p pi n g criteria ( Secti o n 5. 4. 3), Q Tc st o p pi n g 
criteria ( Secti o n 5. 4. 4), or Hae mat ol o gic st o p pi n g criteria ( Secti o n 5. 4. 5) are met.

T he s u bject e x perie nces a n y si g ns of s uici d al i de ati o n or be h a vi o ur ( Secti o n 
7. 3. 7).
Secti o n 5. 4 Wit h dr a w al/ St o p pi n g Criteri a
S u bjects ma y  be wit h dra w n fr o m t he st u d y for a n y  of t he f oll o wi n g reas o ns:

A s u bject ma y  wit h dra w fr o m st u d y treat me nt at a n y ti me at his/ her o w n re q uest, 
or ma y  be wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safet y, 
be ha vi o ural or a d mi nistrati ve reas o ns.  If a s u bject wit h dra w s fr o m t he st u d y, 
he/s he ma y  re q uest destr ucti o n of a n y sa m ples ta ke n, a n d t he I n vesti gat or m ust 
d oc u me nt t his i n t he site st u d y  rec or ds.  T he reas o n f or wit h dra wal s h o ul d be 
d oc u me nte d i n t he C R F.

T he S p o ns or’s re q uest, f or reas o ns s uc h as si g nifica nt pr o t oc ol de viati o ns or 
s u bject s afet y c o ncer n (a n d after disc ussi o n wit h t he In vesti gat or).

If a s u bject is wit h dra w n fr o m st u d y treat me nt, t his s u bject is als o c o nsi dere d t o 
be wit h dra w n fr o m t he st u d y .

St u d y  is ter mi nate d b y t he S p o ns or.
Secti o n 5. 4. 5 H ae m a t ol o gic St o p pi n g R ules
St u d y  treat me nt will be st o p pe d f or a s u bject if a n y of t he f oll o wi n g hae mat ol o gical 
st o p pi n g criteria is met:

Hae m o gl o bi n < 9 g/ d L ( 5. 5 8 m m ol/ L) or a n a bs ol ute decrease of  ≥3 g/ d L fr o m 
baseli ne ( pre -d ose Da y  1)
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 2

Ne utr o p hils < 1 × 1 0 9/ L

L y m p h oc y tes < 0. 5 × 1 09/ L

Platelets < 5 0 × 1 0 9/ L
Secti o n 6. 1 I n vesti g ati o n Pr o d uct a n d Ot her St u d y Tre at me nt
St u d y Tr e at m e nt
Pr o d uct n a m e:
G S K 2 9 8 2 7 7 2
Pl ac e b o
D os a g e f or m:
T a bl et
T a bl et
U nit d os e 
str e n gt h(s)/ D os a g e 
l ev el(s):
3 0 m g
N A
R o ut e of A d mi nistr ati o n 
F or or al us e o nly
F or or al us e o nly
D o si n g i n str u cti o n s 
( wit h a m e n d m e nt 0 1):
T a k e T W O t a bl et s t hr e e 
ti m e s a d a y a s dir e ct e d 
b y y o ur p h y si ci a n
T a k e T W O t a bl et s t hr e e 
ti m e s a d a y a s dir e ct e d 
b y y o ur p h y si ci a n
D osi n g i nstr ucti o ns ( pri or 
t o a m e n d m e nt 0 1):
T ak e T W O t a bl ets i n t h e 
M O R NI N G a n d T W O 
t a bl ets i n t h e E V E NI N G as 
dir ect e d
T ak e T W O t a bl ets i n t h e 
M O R NI N G a n d T W O 
t a bl ets i n t h e E V E NI N G as 
dir ect e d
P hysic al d escri pti o n:
W hit e t o al m ost w hit e, 
r o u n d, fil m c o at e d t a bl et
W hit e t o al m ost w hit e, 
r o u n d, fil m c o at e d t a bl et
S o urc e of pr oc ur e m e nt
St u dy m e dic ati o n is 
s u p pli e d by 
Gl ax o S mit h Kli n e
Pl ac e b o is s u p pli e d by 
Gl ax o S mit h Kli n e
Secti o n 6. 4 Bli n di n g
S p o ns or u n bli n de d refers o nl y  t o t he Data Re vie w C o m mittee ( D R C) c o nsisti n g of t he 
G S K st u d y p h ysicia n Pr oject P h ysici a n Le a d ( P P L), t he st u d y statisticia n, t he st u d y 
p har mac o ki neticist, Patter n Rec o g niti o n Rece pt or ( P R R) Disc o ver y  Perf or ma nce U nit 
( D P U) Hea d, t he Earl y De vel o p me nt Lea der ( E D L), t he Safety Re vie w Tea m ( S R T) 
lea der, or t heir desi g nees o n a n o n g oi n g basis.
Secti o n 6. 7 C o m pli a nce wit h St u d y Tre at me nt A d mi nistr ati o n
W he n s u bjects self- a d mi nister st u d y treat me nt(s) at h o me, c o m plia nce wit h G S K 2 9 8 2 7 7 2 
a n d place b o will be assesse d a n d d oc u me nte d t hr o u g h t he re vie w of t he s u bject’s diar y  
car d a n d q uer yi n g t he s u bject d uri n g t he site visits.  A rec or d of t he n u m ber of 
G S K 2 9 8 2 7 7 2 or place b o ta blets dis pe nse d t o a n d ta ke n b y eac h s u bject m ust be 
mai ntai ne d a n d rec o ncile d wit h st u d y  treat me nt a n d c o m plia nce rec or ds.  Treat me nt start 
a n d st o p dates, i ncl u di n g dates f or treat me nt dela ys a n d/ or d ose re d ucti o ns will als o be 
rec or de d i n t he st u d y di ar y c ar ds a n d t he C R F.
Secti o n 6. 8 Tre at me nt of St u d y Tre at me nt O ver d ose
F or t his st u d y , a n y d ose of G S K 2 9 8 2 7 7 2 >1 2 0 1 8 0 m g dail y will be c o nsi dere d a n 
o ver d ose.  G S K d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.  T he 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 3
I n vesti gat or will use cli nical j u d ge me nt t o treat a n y o ver d ose as a n d w he n t he y are ma de 
a ware of t his.
Secti o n 6. 1 1. 2 Pr o hi bite d Me dic ati o ns a n d N o n - Dr u g T her a pies
T a ble 2
T h er a p y
Ti m e p eri o d
A c h a n g e i n d os e of 5 -A S A
4 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2)
A c h a n g e i n d os e of p uri n e a n al o g u e
1 2 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2)
A c h a n g e i n d os e of M T X
1 2 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2).
Gr e at er t h a n 2 0 m g/d ay or al pr e d nis ol o n e ( or 
e q uiv al e nt c ortic ost er oi d) or a c h a n g e i n d os e 
of c ortic ost er oi d.
2 w e eks pri or t o si g m oi d osc o py u ntil aft er t h e 
f oll o w u p visit ( D ay 1 1 2).
A c h a n g e i n d os e or fr e q u e ncy of t o pic al 
(r ect al) c ortic ost er oi ds or t o pic al (r ect al) 5-A S A.
4 w e eks pri or t o first d os e ( D ay 1) u ntil aft er 
t h e f oll o w u p visit ( D ay 1 1 2).
Ex p os ur e t o m or e t h a n o n e a nti -T N F bi ol o gic 
t h er a py i ncl u di n g b ut n ot li mit e d t o a nti-T N F 
bi ol o gics, i nflixi m a b, a d ali m u m a b, a n d 
g oli m u m a b.
E x c e pti o n :  Ex p os ur e t o a si n gl e a nti-T N F -
bi ol o gic f or w hic h t h e s u bj ect t h e s u bj ect 
disc o nti n u e d f or a r e as o n ot h er t h a n pri m ary 
n o n -r es p o ns e.
C a n n ot h av e b e e n ex p os e d t o m or e t h a n 1 
a nti -T N F bi ol o gic or b e o n bi ol o gic t h er a py at 
a ny ti m e d uri n g t h e st u dy.
I n t h e c as e of a si n gl e a nti-T N F bi ol o gic f or 
w hic h t h e s u bj ect disc o nti n u e d f or a r e as o n 
ot h er t h a n pri m ary n o n -r es p o ns e, t h e s u bj ect 
m ust n ot b e o n f or 8 w e eks or 5 ½ h alf liv es 
( w hic h ev er is l o n g er) pri or t o first d os e u ntil 
aft er t h e f oll o w u p visit ( D ay 1 1 2).  
Bi ol o gic t h er a pi es E x p o s ur e t o a si n gl e 
bi ol o gi c t h er a py f or t h e tr e at m e nt of U C ( ot h er 
t h a n a nti-T N F a s d et ail e d a b o v e), i n cl u di n g
b ut n ot li mit e d t o v e d oliz u m a b. 
E x c e pti o n :  v e d oliz u m a b pr e vi o u sl y 
a d mi ni st er e d i n a cli ni c al tri al s etti n g.
C a n n ot h av e b e e n o n at a ny ti m e, e x c e pt f or 
v e d oliz u m a b i n a cli ni c al tri al s etti n g 
w h er e it m u st h a v e b e e n di s c o nti n u e d f or 
8 w e e k s or 5 h alf li v e s ( w hi c h e v er i s 
l o n g er) pri or t o fir st d o s e.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 4
Secti o n 7. 1 Ti me a n d E ve nts T a ble
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
Sit e Visit
X
X
X
X
X
X
X
X
X
X
X
P h o n e c all
X
X
X
X
X
X
G e n er al/ S af et y A s s e s s m e nt s a n d Pr o c e d ur e s
I nf or m e d C o ns e nt
X
S u bj ect D e m o gr a p hy
X
F ull m e dic al hist ory 1
X
I ncl usi o n/ Excl usi o n Crit eri a
X
F ull p hysic al ex a m 2
X
X 
X
X
Bri ef p hysic al ex a m
X 4
X
X
X 4
X
X
Vit al si g ns ( B P, H R, R R, t e m p er at ur e)
X
X 4
X
X
X 4
X
X
X 
X
X
1 2 -l e a d E C G3
X
X 4
X
X
X 4
X
X
X 
X
X
C o nc o mit a nt m e dic ati o n r evi e w & A E 
r e p orti n g/ S A Es5
X ------------------------------------------------------------------------------------------------------------------------------------------X
P R O s/ Q u e sti o n n air e s/ Di s e a s e A s s e s s m e nt s a n d Pr o c e d ur e s
C ol u m bi a S uici d e S ev erity R ati n g 
Sc al e ( C -S S R S)
X
X 4
X 4
X 
X
I B D Q6
X 4
X 4
X 
X
U C EI S, M o difi e d Ril ey, G e b o es
X -------X 7
X 4
X
X
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 5
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
M ay o Sc or e (i ncl u di n g si g m oi d osc o py 
a n d bi o psy)
X -----X 7
X 4, 8
X 
X 9
P arti al M ay o Sc or e
X -----X 7
X
X
X 4
X 
X
St u d y Tr e at m e nt
R a n d o mis ati o n
X
St u dy m e dic ati o n ( t wic et hr e e ti m e s 
d aily) 10
X ----------------------------------------------------------X X -------------------------------------------------------X 11
Dis p e nsi n g of st u dy m e dic ati o n
X
X
X
Dis p e nsi n g of di ary c ar ds
X
X
X
X
X
X
C oll ecti o n of di ary c ar ds
X
X
X
X
X
X
L a b or at or y ( S af et y) A s s e s s m e nt s a n d Pr o c e d ur e s
T B, HI V, H e p B, H e p C A b, C. Difficil e 
t oxi n 
X
F S H & estr a di ol  (if a p plic a bl e)
X
S er u m pr e g n a ncy t est ( W C B P o nly)
X
Uri n e pr e g n a ncy t est ( W C B P o nly) 12
X 4
X
X
X 4
X
X
X 
X
X
H a e m at ol o gy, c h e mistry, uri n alysis 
X
X 4
X
X 13
X 4
X 13
X 13
X 
X
X
F a ec al c al pr ot ecti n 14
X 
X
X
X
X
X
X
X 
X
Bl o o d s a m pl e f or ex pl or at ory 
X 4
X 4
X 
X
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 6
Pr o c e d ur e s
S cr e e ni n g (- 3 0)
S cr e e ni n g (- 7 t o - 3 0)
Tr e at m e nt P eri o d 18
E arl y Wit h dr a w al 1 9
F oll o w U p ( 3) 2 0
P A R T A
P A R T B
D a y 1 
D a y 8 ( 3)
D a y 1 5 ( 3)
D a y 2 2 ( 3)
D a y 2 9 ( 3)
D a y 3 6 ( 3)
D a y 4 3 ( 3)
( w e ek 6)
D a y 5 0 ( 3)
D a y 5 7 ( 3)
D a y 6 4 ( 3)
D a y 7 1 ( 3)
D a y 7 8 ( 3)
D a y 8 5 ( + 2)
( w e ek 1 2)
bi o m ark ers a n d T E 15
P K bl o o d s a m pl es G S K 2 9 8 2 7 7 2 16
X
X 4
X 
X
Bi o psi es f or P K, i nfl a m m at ory 
bi o m ark ers, m R N A, T E & p at h w ay 
m ark er a n alysis
X -------X 7
X 4
X 
X 8
P h ar m ac o g e n etic s a m pl e ( P Gx) 17
X
F o ot n ot es:
1.
F ull m e dic al hist ory (i ncl u d es p ast a n d c urr e nt c o n diti o ns, m e dic ati o n hist ory, s u bst a nc e us a g e, a n d f a mily hist ory of pr e m at ur e C V dis e as e).
2.
F ull p hysic al ex a m (i ncl u d es h ei g ht/ w ei g ht at scr e e ni n g, h ei g ht n ot m e as ur e d at l at er ti m e p oi nts).
3.
Tri plic at e E C G t o b e p erf or m e d at scr e e ni n g o nly.
4.
Pr e -d os e.  
5.
A ny S A Es ass ess e d as r el at e d t o st u dy p artici p ati o n ( e. g., pr ot oc ol -m a n d at e d pr oc e d ur es, i nv asiv e t ests, or c h a n g e i n existi n g t h er a py) or r el at e d t o a G S K pr o d uct will b e 
r ec or d e d fr o m t h e ti m e a s u bj ect c o ns e nts t o p artici p at e i n t h e st u dy u p t o a n d i ncl u di n g a ny f oll o w-u p.  A Es will b e c oll ect e d fr o m t h e st art of St u dy Tr e at m e nt u ntil t h e f oll o w -u p 
c o nt act.
6.
P R O ass ess m e nts s h o ul d b e c o n d uct e d b ef or e a ny t est s, pr oc e d ur es or ass ess m e nts t o av oi d i nfl u e nci n g t h e s u bj ects’ p erc e pti o n.
7.
Si g m oi d osc o py m ay b e p erf or m e d at a ny ti m e d uri n g t h e scr e e ni n g wi n d o w as a n a d diti o n al visit (if r e q uir e d) u p t o D ay -7 i n or d er f or c e ntr al r e a di n g c o nfir m ati o n of M ay o Sc or e 
f or i ncl usi o n.  If a s h ort er wi n d o w i s r e q uir e d ( e. g., wit hi n D a y -3 t o D a y -7), t hi s will b e p er mitt e d a s l o n g a s it h a s b e e n c o nfir m e d wit h t h e s p o n s or a n d c e ntr al r e a d er 
t h at r e s ult s of t h e M a y o e n d o s c o p y s c or e will b e a v ail a bl e b ef or e e n d of t h e s cr e e ni n g wi n d o w.   Hist ol o gic al dis e as e ( e. g., U C EI S, M R S a n d G e b o es I n d ex) al o n g wit h 
M ay o sc or e ass ess m e nts will als o b e c o m pl et e d.
8.
Si g m oi d osc o py m ay b e p erf or m e d o n a s e p ar at e d ay wit hi n t h e D ay 4 3 visit wi n d o w all o w a nc e ( 3 d ays).  A s e p ar at e visit t o p erf or m s i g m oi d osc o py is o nly all o w e d t o 
acc o m m o d at e sc h e d uli n g.  T his s e p ar at e visit s h o ul d c a n b e d o n e b ef or e or aft er t h e f ull D ay 4 3 visit w h er e P K, cli nic al l a b or at ory t ests a n d all ot h er r e q uir e d D ay 4 3 pr oc e d ur es 
ar e p erf or m e d.  S u bj ects m ust n ot t ak e t h eir s t u dy m e dic ati o n at h o m e i n t h e m or ni n g b ef or e t h e si g m oi d osc o py pr oc e d ur e a n d als o t h e m or ni n g b ef or e t h e f ull D ay 4 3 visit, if 
b ei n g d o n e o n a s e p ar at e d ay. Dis p e nsi n g of st u dy m e dic ati o n m ust b e d o n e at t h e 2 n d visit (if s e p ar at e visits ar e p erf or m e d).
9.
Bi o psy o nly r e q uir e d at E arly Wit h dr a w al visit if aft er at l e ast 1 4 d ays of tr e at m e nt a n d pri or t o D ay 4 3 or if aft er D ay 5 7 a n d pri or t o D ay 8 5.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 7
1 0.
S u bj ects m ust t ak e st u dy m e dic ati o n t wic et hr e e ti m e s a d ay a p pr oxi m at ely 1 2 8 h o urs a p art. Ex act ti m e of d osi n g t o b e r ec or d e d i n di ary c ar ds. O n D ay 4 3 a n d 8 5, s u bj ects m ust 
n ot t ak e t h eir st u dy m e dic ati o n at h o m e i n t h e m or ni n g. S u bj ects will c o m pl et e s p ecifi e d pr e -d os e ass ess m e nts a n d t h e n will b e a d mi nist er e d t h eir m or ni n g d os e of m e dic ati o n at 
sit e o n D ay 4 3. O n D ay 8 5, s u bj ects ar e n o l o n g er r ec eivi n g st u dy m e dic ati o n.
1 1.
I n P art A, s u bj ects will b e r a n d o mis e d 2: 1 t o G S K 2 9 8 7 2 2 6 0 m g or pl ac e b o t wic et hr e e ti m e s d aily f or 4 2 d ays.  At t h e D ay 4 3 visit, all s u bj ects w h o h av e c o m pl et e d P art A, will 
m ov e i n t o P art B o p e n l a b el tr e at m e nt wit h G S K 2 9 8 2 7 7 2 6 0 m g t wic et hr e e ti m e s d aily f or 4 2 d ays.
1 2.
If uri n e pr e g n a ncy t est is p ositiv e, a c o nfir m at ory s er u m pr e g n a ncy t est m ust b e p erf or m e d.
1 3.
Uri n alysis n ot r e q uir e d o n D ays 2 9, 5 7 a n d 7 1.
1 4.
S u bj ects c a n pr ovi d e a f a ec al s a m pl e at a ny ti m e d uri n g t h e scr e e ni n g wi n d o w a n d u p t o 4 8 h o urs pri or t o a ny visit w h er e F C P is b ei n g c oll ect e d.  Pl e as e s e e l a b or at ory m a n u al 
f or f ull d et ails o n s a m pl e h a n dli n g a n d pr oc e d ur e.
1 5.
Bl o o d s a m pl es f or ex pl or at ory bi o m ark ers a n d T ar g et e n g a g e m e nt.  S e e l a b or at ory m a n u al f or f ull d et ails o n s a m pl e c oll ecti o n, h a n dli n g a n d s hi p m e nt.
1 6.
P K bl o o d s a m pl es f or G S K 2 9 8 2 7 7 2 will b e t ak e n pr e -d os e o n D ay 4 3. P ost -d os e s eri al P K s a m pl es will b e t ak e n o n D ays 1 a n d D ay 4 3 at t h e f oll o wi n g ti m e p oi nts: 1, 2, 4, a n d 6 
h o urs a n d tr o u g h o n D ay 8 5 or E arly Wit h dr a w al.
1 7.
A P Gx bl o o d s a m pl e is c oll ect e d at t h e b as eli n e visit ( D ay 1), aft er t h e s u bj ect h as b e e n r a n d o miz e d a n d pr ovi d e d i nf or m e d c o ns e nt f or g e n etic r es e arc h.  If t h e s a m pl e is n ot 
c oll ect e d at t h e b as eli n e visit, it c a n b e c oll ect e d at a ny ti m e d uri n g t h e st u dy aft er r a n d o miz ati o n.
1 8.
Visit wi n d o ws d uri n g t h e tr e at m e nt p eri o d ar e r el ativ e t o D ay 1.
1 9.
If a s u bj ect wit h dr a ws fr o m t h e st u dy, ev ery eff ort will b e m a d e f or t h e s u bj ect t o c o m pl et e a n E arly Wit h dr a w al visit pri or t o t h e F oll o w U p visit.
2 0.
F oll o w -u p visit s h o ul d b e c o m pl et e d 2 8 d ays ( 3 d ays) aft er t h e l ast d os e of st u dy m e dic ati o n.
 
 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 8
Secti o n 7. 3. 5 Electr oc ar di o gr a m ( E C G)

Tri plicate 1 2 -lea d E C Gs will be o btai ne d at scree ni n g a n d si n gle 1 2-lea d E C Gs 
o btai ne d at e ver y  ti me p oi nt d uri n g t he st u dy usi n g a n E C G mac hi ne t hat 
a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc ( F or 
B) i nter vals.  A m a n u al o ver re a d is als o all o we d. Refer t o Secti o n 5. 4. 4 f or Q Tc 
wit h dra wal criteria a n d a d diti o nal Q Tc rea di n gs t hat ma y  be necessar y.
Secti o n 7. 3. 7 S uici d al Ris k M o nit ori n g
S u bjects bei n g treate d wit h G S K 2 9 8 2 7 2 2 s h o ul d be m o nit ore d a p pr o priatel y  f or s uici dal 
i deati o n a n d be ha vi o ur or a ny ot her u n us ual c ha n ges i n be ha vi o ur. C o nsi derati o n s h o ul d 
be gi ve n t o disc o nti n ui n g G S K 2 9 8 2 7 7 2 i n s u bjects w h o e x perie nce si g ns of s uici dal 
i deati o n or be ha vi o ur.  St u d y me dic ati o n m ust be i m me di atel y disc o nti n ue d i n a A ll 
s u bjects wh o e x perie nce si g ns of s uici d al i de ati o n or be h a vi o ur .
Secti o n 7. 4. 2. 1 M a y o Sc ore
T a ble 4 
Si g n/ S y m pt o m
S c or e
Secti o n 9. 1. 1 S a m ple Size Ass u m pti o ns
T he st u d y  is n ot p o were d t o detect pre-defi ne d differe nces. A p pr o xi matel y  3 0 -3 6 s u bjects 
will be ra n d o mise d i nt o t he st u d y  t o eit her G S K 2 9 8 2 7 7 2 or place b o i n a 2: 1 rati o. Pri or 
t o pr ot oc ol a me n d me nt 0 1 bei n g a p pr o ve d i n e ac h c o u ntr y, s u bjects will be 
r a n d omise d i nt o t he st u d y t o eit her G S K 2 9 8 2 7 7 2 6 0 m g BI D or pl ace b o i n a 2: 1 
r ati o. O ver all u p t o 4 8 s u bjects will be r a n d o mise d i nt o t he st u d y t o eit her a BI D or 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or 
i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
2 0 1 9 N 4 2 5 8 9 3 _ 0 0
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 0 9
TI D re gi me n i n a 2: 1 r ati o of G S K 2 9 8 2 7 7 2 or pl ace b o res pecti vel y.
T a ble 8
s u m m arises t he t ot al pla n ne d s a m ple sizes f or BI D a n d TI D re gi me ns. S h o ul d t he 
dr o p o ut rate i n Part A [ Da y  1 t hr o u g h 4 3 ( Wee k 6)] be hi g her t ha n a ntici pate d, a d diti o nal 
or re place me nt s u bjects ma y  be ra n d o mise d ( u p t o a n o ver all t ot al ma xi m u m of 6 0 4 8 ) 
i nt o t he st u d y at t he discreti o n of t he S p o ns or.  S u bjects w h o disc o nti n ue partici pati o n 
d uri n g t he o pe n la bel p hase i n Part B [( Da y  4 3 ( Wee k 6) t hr o u g h Da y 8 5 ( Wee k 1 2)] will 
n ot be re place d.
T a bl e 8
S u m m ar y  of T ot al S a m pl e Si z e b y D o si n g R e gi m e n
N u m b er R a n d o mi s e d t o 
G S K 2 9 8 2 7 7 2 6 0 m g BI D or 
Pl a c e b o BI D
N u m b er R a n d o mi s e d t o 
G S K 2 9 8 2 7 7 2 6 0 m g TI D or 
Pl a c e b o 6 0 m g
R e vi s e d 
M a x 
T ot al 
S a m pl e 
Siz e
T ot al + 
A d diti o n al/ 
R e pl a c e m e nt 
S u bj e ct s
0 - 6
3 0 - 36
3 6
4 8
7 - 1 2
3 0 - 36
4 2
5 4
1 2 - 18
3 0 - 36
4 8
6 0
T he pri mar y  o bjecti ve of t he st u d y is safet y a n d t olera bilit y, w here t here will be u p t o 2 4 
s u bjects ra n d o mise d t o G S K 2 9 8 2 7 7 2 6 0 m g TI D, a n d u p t o 1 2 s u bjects r a n d o mise d t o 
G S K 2 9 8 2 7 7 2 6 0 m g BI D i n Part A. Usi n g a Ba yesia n a p pr oac h t o deter mi ne t he 
c o nfi de nce i nter val ar o u n d a n o bser ve d safet y e ve nt, we w o ul d ass u me a flat Beta ( 1, 1) 
pri or, a n d if we were t o o bser ve o ne safet y e ve nt i n 2 4 2 0 t he n t he p osteri or distri b uti o n 
w o ul d be Beta ( 2, 2 4), as o utli ne d bel o w i n Fi g ure 4. 
Secti o n 9. 1. 2 S a m ple Size Se nsi ti vit y
A sa m ple size se nsiti vit y  a nalys is has bee n c o n d ucte d o n t he pri mar y e n d p oi nt t o 
i n vesti gate t he differe nt safety e ve nt rates. If t he n u m ber of s u bjects w h o c o m plete t he 1 2 
wee ks is l o wer t ha n 2 4 i n t he G S K 2 9 8 2 7 7 2 6 0 m g TI D gr o u p, t he n t he tr ue i nci de nce 
rates of t he safety e ve nts t hat c o ul d n ot be r ule d o ut (as o utli ne d i n Secti o n 9. 1. 1) w o ul d 
c ha n ge.  T hese c ha n ges are o utli ne d i n Ta ble 9 .
Secti o n 9. 1. 3 S a m ple Size R E -esti m ati o n of A dj ust me nt
A f or mal sa m ple size re -esti mati o n will be c o n d ucte d at t he pla n ne d I nteri m A nal yses 
wit h t he p ur p ose of t he assessi n g t he pr o ba bilit y of ac hie vi n g a cli nicall y mea ni n gf ul 
i ncrease i n pre-deter mi ne d cli nical e n d p oi nts o ver place b o at t he e n d of t he st u d y .  T he 
sa m ple size ma y nee d t o be re-esti mate d if hi g her v aria bilit y or differi n g place b o mea ns 
are o bser ve d o n t hese e n d p oi nts.  A rec o m me n de d i ncrease i n sa m ple size a b o ve 6 0 4 8
ra n d o mise d s u bjects w o ul d re q uire a pr ot oc ol a me n d me nt.
Secti o n 9. 2. 2 I nteri m A n al ysis
O nce a n a p pr o priate n u m ber of s u bjects ha ve c o m plete d Da y  4 3 ( Wee k 6), m uc osal 
heali n g will be re vie we d i n a n u n bli n de d ma n ner b y  t he Data Re vie w C o m mittee, 
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 1 0
c o nsisti n g of t he G S K st u d y p h ysicia nPr oject P h ysici a n Le a d ( P P L) , t he st u d y 
statisticia n, t he st u dy p har mac o ki neticist, t he P R R D P U Hea d, E D L a n d S R T Lea der or 
desi g nees o n a n o n g oi n g basis.  A p h y sicia n e xter nal t o t he G S K 2 9 8 2 7 7 2 pr oject tea m 
ma y  als o be i n v ol ve d i n t he data re vie w. A d diti o nal i nfla m mat or y bi o mar kers, cli nical 
a n d mec ha nistic e n d p oi nt s (e. g. tar get e n ga ge me nt) ma y be re vie we d if a vaila ble. N o 
ot her me m ber of t he G S K c ore st u d y tea m will be u n bli n de d t o t his data. T he pri mar y 
p ur p ose of t hese re vie ws will be t o m o nit or m uc osal heali n g rates.  O n re vie w of m uc osal 
heali n g data, t he re vie w gr o u p ma y  rec o m me n d a n i nteri m a nal ysis of ke y cli nical a n d 
mec ha nistic data is first c o n d ucte d pri or t o a n y decisi o n t o ter mi nate t he st u d y  f or f utilit y.  
A data re vie w c harter will i de ntif y  t he s pecific G S K i n di vi d uals i n v ol ve d; o utli ne i n 
detail t he a cti vities of t his re vie w a n d h o w t he i nte grit y  of t he st u d y will be mai ntai ne d.
Secti o n 9. 3. 1 Pri m ar y A n al yses
Safet y  data c ollecte d i n Part A a n d Part B of t he st u d y will be c o m bi ne d a n d s u m marise d 
acc or di n g t o treat me nt recei ve d f or t he first si x wee ks o f treat me nt a n d o verall. If 1 2 or 
m o re s u bjects are r a n d o mise d t o a BI D re gi me n (i.e. ≥4 pl ace b o a n d ≥8 
G S K 2 9 8 2 7 7 2 6 0 m g BI D) t he n tre at me nt recei ve d will t a ke i nt o acc o u nt d osi n g 
fre q ue nc y f or G S K 2 9 8 2 7 7 2, ot her wise tre at me nt will be irres pecti ve of d osi n g
fre q ue nc y.
Secti o n 1 1
Refere nces
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 4 N 2 0 4 1 2 6 _ 0 1 0 2 .  In vesti gat or Br oc h ure f or 
G S K 2 9 8 2 7 7 2.  Re p ort Date 0 8- M A R - 2 0 1 62 7 -J A N - 2 0 1 7.
Secti o n 1 2. 1
A p pe n di x 1 – A b bre vi ati o ns a n d Tr a de m ar ks
h C G
H u m a n C h ori o nic G o n a d otr o pi n
L D L
L o w De nsit y Li p o pr otei n
M C V
Me a n C or p usc ul ar V ol u me
M D M A
3, 4 -met h yle ne di o x y -met h a m p het a mi ne
P P L
Pr oject P h ysici a n Le a d
S G O T
Ser u m Gl ut a mic O x al o acetic Tr a ns a mi n ase
S G P T
Ser u m Gl ut a mic P yr u vic Tr a ns a mi n ase
TI
Ter mi n al ile u m
TI D
T hree ti mes d ail y
Secti o n 1 2. 3 A p pe n di x 3: Pre d nis ol o ne a n d 5 -A S A E q ui vale nt D ose Ta bles
Dr u g N a me
D ose E q ui v ale nt t o 1 m g Or al Pre d nis o ne
C ortis o ne acetate
H y dr oc ortis o ne
Pre d nis ol o ne
Met h y l pre d nis ol o ne
Tria mci n ol o ne
5 m g
4 m g
1 m g
0. 8 m g
0. 8 m g
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0

2 0 1 5 N 2 5 1 7 5 8 _ 0 1
C O N FI D E N TI A L
2 0 2 1 5 2
1 1 1
De xa met has o ne
0. 1 5 m g
Dr u g N a me
D ose E q ui v ale nt t o 2 0 m g Or al Pre d nis o ne
Uceris E R
9 m g
Dr u g N a me
D ose E q ui v ale nt t o 5 -A S A
S ulf as al azi ne
2 -4 g ( 0. 8 – 1. 6 g m 5 -A S A)
B als al azi de
2 -6. 7 5 g ( 0. 7 – 2. 4 g m 5 -A S A)
Secti o n 1 2. 4 A p pe n di x 4 – Ge netic Rese arc h
G S K 2 9 8 2 7 7 2 is a n o vel first -i n-cl ass asset bei n g i ntr o d uce d t o p atie nts wit h acti ve 
U C f or t he first ti me. C urre ntl y its mec h a nis m of acti o n is n ot f ull y c h ar acterise d 
n or u n derst o o d. 
S pecific ge nes m a y be st u die d t h at e nc o de t he dr u g t ar gets, or dr u g mec h a nis m of 
acti o n p at h w a ys, dr u g met a b olizi n g e nz y mes, dr u g tr a ns p orters or w hic h m a y 
u n der pi n a d verse e ve nts, dise ase ris k or dr u g res p o nse. T hese c a n di d ate ge nes m a y 
i ncl u de a c o m m o n set of A D M E ( A bs or pti o n, Distri b uti o n, Met a b olis m a n d 
E xcreti o n) ge nes t h at are st u die d t o deter mi ne t he rel ati o ns hi p bet wee n ge ne 
v ari a nts or tre at me nt res p o nse a n d/ or t oler a nce. I n a d diti o n, c o nti n ui n g rese arc h 
m a y i de ntif y ot her e nz y mes, tr a ns p orters, pr otei ns ore rece pt ors t h at m a y be 
i n v ol ve d i n res p o nse t o G S K 2 9 8 2 7 7 2. T he ge nes t h at m a y c o de f or t hese pr otei ns 
m a y als o be st u die d. Ge n o me - wi de sc a ns i n v ol vi n g a l ar ge n u m ber of p ol y m or p hic 
m a r kers (e. g. si n gle n ucle oti de p ol y m or p his ms) at defi ne d l oc ati o ns i n t he ge n o me, 
ofte n c orrel ate d wit h a c a n di d ate ge ne, m a y be st u die d t o deter mi ne t he rel ati o ns hi p 
bet wee n ge netic v ari a nts a n d tre at me nt res p o nse or t oler a nce. T his a p pr o ac h is 
ofte n e m pl o ye d w he n a defi niti ve c a n di d ate ge ne d oes n ot e xist a n d/ or t he p ote nti al 
ge netic effects are n ot well u n derst o o d.  
Ge netic data ma y  be ge nerate d w hile t he st u d y is u n der wa y or f oll o wi n g c o m pleti o n of 
t he st u d y.  Ge netic e val uati o ns ma y  i ncl u de f oc use d ca n di date ge ne a p pr oac hes a n d/ or 
e xa mi nati o n of a lar ge n u m ber of ge netic varia nts t hr o u g h o ut t he ge n o me ( w h ole ge n o me 
a nal ys es). Ge netic a nal ys es will utilize data c ollecte d i n t he st u d y  a n d will be li mite d t o 
u n dersta n di n g t he o bjecti ves hi g hli g hte d a b o ve.  A nal y ses ma y be perf or me d usi n g data 
fr o m m ulti ple cli nical st u dies t o i n vesti gate t hese researc h o bjecti ves.
If a pplic a ble a n d ge netic rese arc h is c o n d ucte d, A a p pr o pri ate descri pti ve a n d/ or 
statistical a nal ysis met h o ds will be use d t o e v al u ate p h ar m ac o ge netic d at a i n t he 
c o nte xt of t he ot her cli nic al d at a . A detaile d descri pti o n of a ny pla n ne d a nal yses will be 
d oc u me n te d i n a Re p orti n g a n d A nalys is Pla n ( R A P) pri or t o i nitiati o n of t he a nalys is. 
Pla n ne d a nal ys es a n d res ults of ge netic i n vesti gati o ns will be re p orte d eit her as part of t he 
cli nical R A P a n d st u d y re p ort, or i n a se parate ge netics R A P a n d re p ort, as a p pr o priate.
 
2 0 1 9 N 4 2 5 8 9 3 _ 0 0