Clinical trial NCT02903966
Conditions: Colitis, Ulcerative
Keywords: Tolerability GSK2982772 Safety Pharmacokinetics RIP1 kinase inhibitor Ulcerative colitis Pharmacodynamics
Sponsor: GlaxoSmithKline
Start date: 2016-11-15; Completion date: 2019-06-17
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is the first experience with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active ulcerative colitis (UC). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 mg or placebo three times daily for 42 days (Part A) followed by open label with GSK298772 60 mg three times daily for 42 days (Part B). In addition to pharmacokinetics (PK), a number of experimental and clinical endpoints will be employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy in subjects with active UC. Although no formal hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of action and potential for clinical efficacy of GSK2982772 in UC. Within 30 Days of screening visit, subjects will be randomized to receive either GSK2982772 60 mg or placebo orally three times daily for 42 Days (6 weeks) in a 2:1 ratio in Part A study. Subjects who complete the Part A study will move to open label Part B study to receive GSK2982772 60 mg three times daily for an additional 42 Days (6 weeks). After the open label (Part B) treatment period, subjects will enter the Follow-up period which lasts for 28 Days (+/- 3 Days) post the last administration of study medication. The total duration of participation in the study will be approximately 20 Weeks from screening to the last study visit.

Detailed description:

Arms: arm 1: Subjects will receive GSK2982772 60 mg orally three times daily (approximately 8 hours apart) for 42 days (6 weeks). arm 2: Subjects will receive placebo orally three times daily (approximately 8 hours apart) for 42 days (6 weeks). arm 3: Subjects from GSK2982772 and placebo arm who complete Part A study will move to Part B open-label extension phase. All subjects will receive GSK2982772 60 mg three times daily (approximately 8 hours apart) for 42 days (6 weeks).
Interventions: intervention 1: GSK2982772 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2982772 is available as a 30 mg white to almost white, round film coated tablet which will be administered as two tablets three times a day as directed. intervention 2: Placebo is available as a white to almost white, round film coated tablet which will be administered as two tablets three times a day as directed.

Protocol documents:
Prot_001.pdf: 
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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
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P P D
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P P D


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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


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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
 
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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
 
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C O N FI D E N TI A L
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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
 
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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
 
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C O N FI D E N TI A L
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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 
 
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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
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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:
 
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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.
 
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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.  
 
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2 0 1 5 N 2 5 1 7 5 8 _ 0 1
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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.
 
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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.
 
 
 
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2 0 1 5 N 2 5 1 7 5 8 _ 0 1
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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. 
 
 
 
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C O N FI D E N TI A L
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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
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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.
 
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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.
 
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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


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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.
 
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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”. 
 
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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
 
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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*
 
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
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.
 
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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.
 
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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.
 
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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.
 
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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 
 
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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 
 
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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.
 
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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.
 
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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
 
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C O N FI D E N TI A L
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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
 
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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
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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.
 
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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 
 
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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


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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.
 
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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.
 
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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
 
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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.
 
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
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.
 
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
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.
 
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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

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
202152
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 202152: 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.
Compound Number 
:
GSK2982772
Effective Date 
:
18-Jul-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 202152.

This RAP is intended to describe the interim and final analyses required for the 
study.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author’s Name and Functional Area: 
15-JUL-2019
Principal Statistician (II Clinical Statistics)
15-JUL-2019
Statistics Manager (II Clinical Statistics)
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
202152
2
RAP Team Review Confirmation:
(Email)
Reviewer
Date
Principal Programmer/Analyst (Clinical 
Programming)
16-JUL-2019
16-JUL-2019
Operations and Science Lead (II Global Clinical 
& Data Operations)
16-JUL-2019
Clinical Investigational Lead, Discovery 
Medicine
 
16-JUL-2019
Director, CPMS
Project Physician Lead, iiTA
16-JUL-2019
Senior Medical Director, GCSP SERM
16-JUL-2019
15-JUL-2019
Data Quality Lead (II Global Clinical & Data 
Operations)
Clinical Statistics and Clinical Programming Line Approvals:
(PharmaTMF signoff)
Approver
Date
18-JUL-2019
Snr Statistical Director (II Clinical Statistics)
18-JUL-2019
Programming Manager (II Clinical Programming)
 
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CONFIDENTIAL
202152
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Analyses.....................................................................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................13
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................15
5.2.1.
Derivations and Handling of Missing Baseline Data.....................17
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates, Other Strata and Subgroups............................17
5.5.
Multiple Comparisons and Multiplicity .........................................................17
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
6.1.1.
Study Population Summary Measure...........................................18
7.
SAFETY ANALYSES .............................................................................................20
7.1.
Adverse Events Analyses ...........................................................................20
7.1.1.
Adverse Event Summary Measures.............................................20
7.2.
Clinical Laboratory Analyses.......................................................................21
7.2.1.
Clinical Laboratory Summary Measures ......................................21
7.3.
Other Safety Analyses ................................................................................22
7.3.1.
Summary Measures.....................................................................22
7.4.
Other Safety Analyses ................................................................................23
8.
EFFICACY .............................................................................................................24
8.1.
Efficacy Endpoints ......................................................................................24
8.1.1.
Population of Interest...................................................................25
8.1.2.
Statistical Analyses / Methods .....................................................25
8.1.2.1.
Statistical Methodology Specification..........................25
8.1.2.1.1
Continuous Endpoints ................................................25
8.1.2.1.2
Binary Endpoints ........................................................26
8.2.
Exploratory Efficacy Analyses.....................................................................27
8.2.1.
Responder Across Endpoints.......................................................27
 
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8.2.2.
Probabilities of Success...............................................................27
8.3.
Exploratory Pharmacodynamic / Efficacy Analyses.....................................28
9.
PHARMACOKINETIC ANALYSES.........................................................................28
9.1.
Pharmacokinetic Analyses..........................................................................28
9.1.1.
Endpoint / Variables.....................................................................28
9.1.1.1.
Drug Concentration Measures....................................28
9.1.2.
Population of Interest...................................................................29
9.2.
Population PK Analyses..............................................................................29
9.3.
Pharmacokinetic/Pharmacodynamic Analyses............................................29
10. BIOMARKER ANALYSES......................................................................................30
10.1.
Biomarker/Target Engagement/Pathway Engagement/ 
Transcriptomics Analyses...........................................................................30
10.1.1.
Endpoint / Variables.....................................................................30
10.1.2.
Population of Interest...................................................................31
10.1.3.
Statistical Analyses / Methods .....................................................31
10.1.3.1.
Statistical Methodology Specification..........................31
11. REFERENCES.......................................................................................................36
12. APPENDICES........................................................................................................37
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................37
12.1.1.
Exclusions from Per Protocol Population .....................................37
12.2.
Appendix 2: Schedule of Activities ..............................................................38
12.2.1.
Protocol Defined Schedule of Events...........................................38
12.3.
Appendix 3: Assessment Windows .............................................................42
12.3.1.
Definitions of Assessment Windows for Analyses........................42
12.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................43
12.4.1.
Study Phases ..............................................................................43
12.4.1.1.
Study Phases for Concomitant Medication .................43
12.4.2.
Treatment Emergent Flag for Adverse Events .............................43
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................44
12.5.1.
Reporting Process .......................................................................44
12.5.2.
Reporting Standards....................................................................44
12.5.3.
Reporting Standards for Pharmacokinetic....................................45
12.6.
Appendix 6: Derived and Transformed Data ...............................................46
12.6.1.
General........................................................................................46
12.6.2.
Study Population..........................................................................46
12.6.3.
Safety ..........................................................................................47
12.6.4.
Efficacy........................................................................................48
12.6.5.
Biomarker ....................................................................................53
12.7.
Appendix 7: Reporting Standards for Missing Data.....................................54
12.7.1.
Premature Withdrawals................................................................54
12.7.2.
Handling of Missing Data.............................................................54
12.7.2.1.
Handling of Missing and Partial Dates ........................54
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................55
12.8.1.
Laboratory Values........................................................................55
12.8.2.
ECG.............................................................................................56
12.8.3.
Vital Signs....................................................................................56
 
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12.9.
Appendix 9: Abbreviations & Trade Marks ..................................................57
12.9.1.
Abbreviations...............................................................................57
12.9.2.
Trademarks .................................................................................58
12.10. Appendix 10: List of Data Displays..............................................................59
12.10.1. Data Display Numbering..............................................................59
12.10.2. Mock Example Shell Referencing ................................................59
12.10.3. Deliverables.................................................................................59
12.10.4. Study Population Tables..............................................................60
12.10.5. Safety Tables...............................................................................63
12.10.6. Safety Figures .............................................................................71
12.10.7. Efficacy Tables ............................................................................72
12.10.8. Efficacy Figures ...........................................................................77
12.10.9. Pharmacokinetic Tables...............................................................83
12.10.10.Pharmacokinetic Figures .............................................................84
12.10.11.Pharmacodynamic and/or Biomarker Tables ...............................87
12.10.12.Pharmacodynamic and/or Biomarker Figures ..............................90
12.10.13.ICH Listings .................................................................................95
12.10.14.Non-ICH Listings........................................................................103
12.11. Appendix 11: Example Mock Shells for Data Displays ..............................109
12.12. Appendix 12: NONMEM datafile specification...........................................110
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the CSR for Protocol 202152:
Revision Chronology:
2015N251758_00
23-MAY-2016
Original
2015N251758_01
20-APR-2017
Protocol Amendment 1 - Change in dosing regimen from 60 
mg BID to 60 mg TID, updates to Inclusion criteria 3 and 6 
and Exclusion criteria 3, 9, 21 and 22, allowance for 
rescreening, and addition of suicidality stopping criteria plus 
some minor protocol clarifications and administrative changes.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Two interim analyses (IA) were 
planned. The decision whether the
first IA will be conducted was to be 
based on the recommendation of 
the DRC review to assess futility 
based on 6 weeks of treatment, or 
when an appropriate number have 
completed 6 weeks of treatment, 
whichever is earliest. The purpose 
of the first IA would be to assess 
whether to stop the study for futility 
and, if appropriate, to perform a 
sample size re-estimation. The 
second IA will occur when an 
appropriate number have
completed 12 weeks of treatment. 
The purpose of the second IA would 
be to assess whether to stop the 
study for futility.
A formal IA at 6 weeks will no 
longer be conducted based 
recommendations of the DRC. 
The DRC data review of the 6 
week data concluded that there 
was insufficient evidence to stop 
for futility and recommended a 
single IA to be conducted when 
an appropriate number of 
subjects have completed 12 
weeks of treatment. This DRC 
data review will be considered in 
replacement of the first IA.
Endpoints for the 3-domain partial 
Mayo, 3-domain Mayo clinical 
response and 3-domain Mayo 
clinical remission are not specified 
in the protocol. 
Relevant definitions and required 
summaries was added to the 
RAP. 
The landscape for UC has 
changed since the protocol was 
developed. 
The total score for the Mayo is 
The RAP uses the Total Mayo 
To match terminology used in the 
 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
called the complete Mayo in the 
Protocol.
Score terminology.
FDA’s Ulcerative Colitis: Clinical 
Trial Endpoints Guidance for 
Industry document.
The scoring algorithm for the 
Modified Riley Scale in Table 7 of 
the protocol has an error where 
reverse labelling was used for the 
Historical Characteristics for mild 
and moderate disease activity. 
The RAP details the correct MRS 
scores as provided by Robarts 
(central reader). 
To fix an error in the protocol.
Further details can be found in 
the Protocol Note to File #4 
dated 24 May 2018. 
No endpoint and derivations for the 
Robarts Histology Index (RHI) was 
explicitly mentioned in the protocol. 
The protocol endpoints section 
states: Change from baseline on 
histologic severity including but not 
limited to MRS and Geboes. 
Robarts will also provide GSK with 
the RHI alongside the MRS and 
Geboes.
Relevant definitions for the RHI 
and required summaries were 
added to the RAP
To enable analysis of the RHI 
data.  
GSK2982772 plasma 
concentrations will be summarised 
descriptively by day and nominal 
sampling time (Pre-dose on Day 43
and at 1, 2, 4, and 6 hours post 
dose on Days 1 and 43 and trough 
on Day 85 or Early Withdrawal).
The predicted trough 
concentration at 7am on Day 43 
will be calculated using the 
observed pre-dose concentration 
at the time of the PK sample (see 
Section 9.1.1.1 for calculations)
The predicted Day 43 trough 
concentration will be used in 
PK/PD assessments instead of 
the observed Day 43 Pre-Dose 
concentration
Since the half-life of 
GSK2982772 is short (2-3h), the 
duration of time between the Day 
43 clinic visit and the usual 
dosing time (assumed to be 7am 
for all subjects) may result in the 
reported “pre-dose” 
concentration being lower than 
the true “trough concentration”
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To investigate the safety and tolerability 
of 60 mg three times daily doses of 
GSK2982772 in subjects with moderate 
to severe ulcerative colitis.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, heart rate, 
respiratory rate, and body temperature).

12-Lead ECG monitoring.
Secondary Objectives
Secondary Endpoints

To investigate the preliminary efficacy of 
60 mg three times daily doses of 
GSK2982772 in achieving mucosal 
healing after 6 and 12 weeks of treatment 
in subjects with active ulcerative colitis.

The proportion of subjects who achieve an absolute 
Mayo endoscopy subscore of 0 or 1 at Days 43 
(Week 6) and 85 (Week 12).

Change from baseline in mucosal appearance 
determined by Ulcerative Colitis Endoscopic Index of 
 
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Objectives
Endpoints
Severity (UCEIS).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
biomarkers of disease activity in subjects 
with active ulcerative colitis.

Change from baseline in markers which may include, 
but are not limited to, mean CRP and faecal 
calprotectin (FCP).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
histologic disease activity in subjects with 
active ulcerative colitis.

Change from baseline in histologic severity, including 
but not limited to Modified Riley Score and Geboes 
Index.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 in 
achieving clinical response and remission 
after 6 and 12 weeks of treatment in 
subjects with active ulcerative colitis.

The proportion of subjects who achieve clinical 
response defined as reduction by ≥3 points or ≥30% 
improvement from baseline complete Mayo score, 
along with a decrease in the rectal bleeding score of 
≥1 point, at Days 43 (Week 6) and 85 (Week 12).

The proportion of subjects who achieve clinical 
remission defined as a complete Mayo score of 2 
points or lower, with no individual subscore exceeding 
1 point, at Days 43 (Week 6) and 85 (Week 12).

To investigate the preliminary efficacy of 
60 mg three times daily doses of 
GSK2982772 in achieving symptomatic 
clinical remission after 6 and 12 weeks of 
treatment in subjects with active 
ulcerative colitis.

Change from baseline in partial Mayo score.

To investigate the plasma concentrations 
of GSK2982772 following 60 mg three 
times daily in subjects with active 
ulcerative colitis.

Pre-dose plasma concentrations of GSK2982772 at 
Day 43 (Week 6). 

Post-dose plasma concentrations of GSK2982772 on 
Days 1 and 43 (Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week 12).
Exploratory Objectives
Exploratory Endpoints

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
expression of inflammatory biomarkers in 
mucosal tissue biopsies in subjects with 
active ulcerative colitis.

Change from baseline in inflammatory markers which 
may include, but are not limited to IL-1, IL-6, IL-8, 
MMP3, TNFα, IFNγ.

To investigate pathway and target 
engagement following 60 mg three times
daily doses of GSK2982772 in blood and 
colon biopsy tissue.

Pharmacology biomarker endpoints may include, but 
are not limited to the following, pre-dose at Days 1, 
43 (Week 6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and data permit:
o
Target Engagement Assay RiP1 (TEAR1) in 
blood and colon tissue.

Phosphorylated or total RIP1, MLKL, RIP3, cleaved 
and total caspase 3 and 8 signatures in colon biopsy 
tissue.

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the colon tissue 

Pre-dose GSK2982772 and possible drug-related 
material concentrations, as well as specific distribution 
within tissue if feasible, in colon biopsies at Days 43 
(Week 6) and 85 (Week 12), as evaluable samples 
 
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Objectives
Endpoints
after 60 mg three times daily doses of 
GSK2982772.
and data permit.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
quality of life in subjects with active 
ulcerative colitis.

Change from baseline in Inflammatory Bowel Disease 
Questionnaire (IBDQ).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in the blood in subjects 
with active ulcerative colitis.

Transcriptomic analysis of mRNA isolated from blood 
Days 1 and 43 (Week 6) and trough on Day 85 (Week 
12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in colon tissue biopsies 
in subjects with active ulcerative colitis.

Transcriptomic analysis of mRNA isolated from colon 
tissue biopsies at Screening, and Days 43 (Week 6) 
and trough on Day 85 (Week 12).
 
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2.3.
Study Design
Overview of Study Design and Key Features
Key assessments:
Safety assessments, PK samples, Mayo score, Modified Riley Scale, 
Geboes Index, IBDQ and PD samples
Design Features

This is a multicentre, randomized, double-blind (sponsor-unblinded), placebo-
controlled (Part A) study with an open label extension (Part B). 

Investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with active UC.
Study Duration 
and Dosing

Each participant will participate in the study for approximately 20 weeks. This 
includes a screening period up to 30 days, an 84-day (12 week) treatment period, 
and a 28-day follow-up period after the last dose.

Within 30 days of the screening visit (defined as day of consent signing), eligible 
participants enter a 2-part treatment phase as follows with study treatment starting 
on study day 1:
o
Part A: Approximately 36 participants are randomly assigned to receive either 
GSK2982772 60 mg three times daily (TID) or placebo TID for 42 days (6 
weeks) in a 2:1 ratio.
o
Part B: All participants who complete Part A move on to receive open label 
treatment of GSK2982772 60 mg TID for an additional 42 days (6 weeks).  

Treatment duration is a total of 84 days (12 weeks) inclusive of Parts A and B.

Participants are followed-up for 28 days (4 weeks) after the last dose in Part B. 

Prior to amendment 01 being effective in each country, participants were randomly 
assigned to receive either: 

Part A: GSK2982772 60 mg two times daily (BID) or placebo BID for 42 days 
(6 weeks) in a 2:1 ratio. 

Part B: Open label treatment for all participants who have completed Part A
of GSK2982772 60 mg BID for an additional 42 days (6 weeks).  
Time & Events

Refer to Appendix 2: Schedule of Activities.

During the 84-day (12 week) treatment period, participants attend the clinical for 
visits on Days 1, 15, 29, 43, 57, 71 and 85. 

At specific visits, participants must not take treatment prior to their scheduled 
treatment. 

On Days 8, 22, 36, 50, 64 and 78 participants were to be contacted by telephone 
and asked about their general health. 

Participants are given a diary card at every visit and asked to record daily study 
 
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Overview of Study Design and Key Features
medication, concomitant medication and adverse events. 
Treatment 
Assignment

At Screening a unique CRF number (Subject Number) is assigned.

Participants who meet screening eligibility criteria and complete pre-treatment 
assessments are randomised through an Interactive Response Technology 
System (IRTS). The IRTS confirms the participant’s CRF number (Subject 
Number) and provides the randomisation number.

The randomisation number is generated by Clinical Statistics, prior to the start of 
the study, using validated internal software.  Once assigned, this randomisation
number must not be reassigned to any other participant in the study.

The randomisation is centrally controlled by the IRTS.

Approximately 36 participants were randomised in a 2:1 ratio to receive 
GSK2982772 60mg TID or Placebo TID in Part A. 

Any participant that is re-screened outside of the allowed screening window at the 
approval of the GSK Medical Monitor, must be assigned a new unique Subject 
Number.
Interim Analysis

An internal GSK Safety Review Team (SRT) reviews blinded safety data at 
appropriate intervals during the study and an internal GSK Data Review 
Committee (DRC) reviews unblinded safety, inflammatory biomarkers, clinical and 
mechanistic data at appropriate intervals during the study in accordance with the 
DRC Charter.

Two interim analyses were planned in the protocol to facilitate decision making 
regarding the subsequent clinical development of GSK2982772 for UC.

Interim Analysis #1: 

Was planned to occur either on the recommendation of the DRC, or when an 
appropriate number have completed 6 weeks of treatment, whichever is 
earliest. 

The purpose was to assess whether to stop the study for futility and, if 
appropriate, to perform a sample size re-estimation. 

Interim Analysis #2:

Was planned to occur when an appropriate number of participants have 
completed 12 weeks of treatment. 

The purpose was to assess whether to stop the study for futility.  

A formal interim analysis at 6 weeks will no longer be conducted based on review 
of recruitment information and recommendation by the DRC. The DRC instead 
recommended a single interim analysis to be conducted when an appropriate 
number of participants have completed 12 weeks of treatment.

The DRC data review of the 6 week data concluded that there was insufficient 
evidence to stop for futility and recommended a single interim analysis to be 
conducted when an appropriate number of participants have completed 12 weeks 
of treatment. 

This DRC data review will be considered in replacement of the first interim 
analysis.
2.4.
Statistical Analyses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 60mg tid following 12 weeks of treatment. No formal statistical hypotheses 
will be conducted to assess this objective. 
 
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If appropriate, comparisons between the GSK2982772 arm and the placebo arm will be 
made to investigate the secondary pharmacodynamic, mechanistic and efficacy 
objectives. Trends over time will be investigated for both treatment arms along with 
associations between each of the parameters. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Two interim analyses were planned to be conducted during the study.  Additionally, two 
review teams monitor data on an ongoing basis for routine pharmacovigilance and 
decision making regarding the subsequent clinical development of GSK2982772 for UC.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT) 
which includes members of the GSK2982772 project team, reviews blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
Once an appropriate number of participants have completed Day 43 (Week 6), mucosal 
healing will be reviewed in an unblinded manner by the DRC consisting of the GSK 
study physician, the study statistician, the study pharmacokineticist, the PRR DPU Head, 
EDL and SRT Leader or designees on an ongoing basis.  A physician external to the 
GSK2982772 project team may also be involved in the data review. Additional 
inflammatory biomarkers, clinical and mechanistic endpoints (e.g. target engagement) 
may be reviewed if available. No other member of the GSK core study team will be 
unblinded to this data. The primary purpose of these reviews is to monitor mucosal 
healing rates.  On review of mucosal healing data, the review group may recommend an 
interim analysis of key clinical and mechanistic data is first conducted prior to any 
decision to terminate the study for futility.  A data review charter identifies the specific 
GSK individuals involved; outline in detail the activities of this review and how the 
integrity of the study will be maintained.
The timing of Interim Analysis #1 in the protocol was either on the recommendation of 
the DRC to assess futility based on 6 weeks of treatment, or when an appropriate number 
have completed 6 weeks of treatment, whichever is earliest.  The purpose of Interim 
Analysis #1 would be to assess whether to stop the study for futility and, if appropriate, to 
perform a sample size re-estimation.  The timing of Interim Analysis #2 was to occur 
when an appropriate number have completed 12 weeks of treatment.  The purpose of the 
Interim Analysis #2 was to assess whether to stop the study for futility.  
A formal interim analysis at 6 weeks will no longer be conducted based on review of 
recruitment information and recommendation by the DRC. The DRC data review of the 6 
week data concluded that there was insufficient evidence to stop for futility and 
recommended a single interim analysis be conducted when an appropriate number of 
participants have completed 12 weeks of treatment. This DRC data review will be 
considered in replacement of the first interim analysis.
 
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3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed per RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects

Comprises of all participants who were screened for 
the study.

Selected Study 
Population
Safety

Comprise of all participants who receive at least one 
dose of study treatment.

Study Population

Safety

Efficacy

PD

Biomarker
Pharmacokinetic

Participants in the ‘Safety’ population who received an 
active dose and for whom a GSK2982772 
pharmacokinetic sample was obtained and analysed.

PK
Per Protocol (PP)

All participants in the Safety population who comply 
with the protocol.

Protocol deviations that would exclude participants 
from the PP population are defined in Section 4.1
(Protocol Deviations) and Appendix 1: Protocol
Deviation Management and Definitions for Per 
Protocol Population).

Efficacy: Mayo only
PP + Completers

All participants in the PP population who also 
complete the study (Parts A, B and Follow-up) [1]

Efficacy: Mayo only
Refer to Appendix 10: List of Data Displays which details the population used for each display.
[1] Completion of the study as defined from the eCRF study conclusion page. 
Note: All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
 
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Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan Version 3, dated 14th June
o Data will be reviewed instream prior to unblinding and freezing the database to 
ensure all important deviations are captured and categorised on the protocol 
deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
One subject was randomised to a BID regimen before the protocol was amended. Per 
instructions in the protocol, data will be summarised in tables and figures by treatment 
(GSK2982772 60mg or Placebo) irrespective of dosing regimen received (BID or TID). 
Data will be listed per treatment and dosing regimen received (BID or TID). Some key 
safety endpoints will be summarised by both randomised treatment and period treatment, 
details are provided in Appendix 9.
Should a participant receive the wrong medication at any point during the study in error, 
that participant will be treated as having received GSK2982772 60mg TID for the 
duration of the study.   
Randomised Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description in 
tables/non-PK figures
Order 
in TF 
Description in 
Listings/PK figures
Order in 
Listing
A
GSK2982772 60mg BID 
(Double-blind)
GSK2982772 60mg 
2
GSK2982772 60mg 
BID
3
C
GSK2982772 60mg TID 
(Double-blind)
GSK2982772 60mg 
2
GSK2982772 60mg 
TID
4
P
Placebo BID (Double-blind)
Placebo 
1
Placebo BID
1
Q
Placebo TID (Double-blind)
Placebo 
1
Placebo TID
2
 
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Period Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description in tables
Order 
in TF 
Description in 
Listings
Order in 
Listing
A
GSK2982772 60mg BID 
(Double-blind)
GSK2982772 60mg 
2
GSK2982772 60mg 
DB BID
3
B
GSK2982772 60mg BID 
(Open-label)
GSK2982772 60mg 
2
GSK2982772 60mg 
OL BID
5
C
GSK2982772 60mg TID 
(Double-blind)
GSK2982772 60mg 
2
GSK2982772 60mg 
DB TID
4
D
GSK2982772 60mg TID 
(Open-label)
GSK2982772 60mg 
2
GSK2982772 60mg 
OL TID
6
P
Placebo BID (Double-blind)
Placebo 
1
Placebo DB BID
1
Q
Placebo TID (Double-blind)
Placebo 
1
Placebo DB TID
2
Treatment comparisons will be displayed as follows using the descriptors as specified:

GSK2982772 60mg vs Placebo.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. Triplicate assessments at a timepoint will be averaged. An 
additional period baseline will be determined for vital signs, ECGs and clinical labs.
Unless otherwise stated, if baseline data is missing, no derivation will be performed and 
baseline will be set to missing.
For tables summarising from Day 43 (Part B), all data recorded on day 43 will be used as 
baseline and if this result is missing then there is no part B baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used 
in Data Display
Period 
Baseline 
Used in Data 
Display
Screening 
(-30)
Screening (-
7 to 30)
Day 1 
(Pre-Dose)
Day 1 
Primary: Safety 
Vital Signs[1,2]
X
X
Day 1
(Pre-Dose)
Day 43
12-Lead ECG [2]
X[3]
X
Screening
or
Day 1 
(Pre-Dose)
Day 43
Clinical Laboratory 
Values including CRP 
[2,4]
X
X
Day 1
(Pre-Dose)
Day 43
 
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Parameter
Study Assessments Considered as Baseline
Baseline Used 
in Data Display
Period 
Baseline 
Used in Data 
Display
Screening 
(-30)
Screening (-
7 to 30)
Day 1 
(Pre-Dose)
Day 1 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)
X
X
Day 1 
(Pre-Dose)
Secondary
Mayo Score [5]
X
Screening
UCEIS
X
Screening
Modified Riley 
X
Screening
Geboes Index
X
Screening
RHI
X
Screening
FCP
X
X
Screening
Exploratory
Blood Sample: PK 
X
Day 1 
Blood Sample: 
Exploratory 
Biomarkers, Target 
Engagement and 
mRNA Expression 
X
Day 1 
(Pre-Dose)
Biopsy Tissue: PK, 
Inflammatory 
Biomarkers, mRNA 
Expression, Target 
Engagement and 
Pathway Marker 
X
Screening
IBDQ
X
Day 1 
(Pre-Dose)
NOTES:

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for that time point.
1: Vital sign measurements include Blood Pressure, Heart Rate, Respiratory Rate, and Body Temperature.
2: Where both screening and pre-dose are available, the value closest to first dose will be used.
3: ECG recordings will be performed in triplicate at screening. The mean of the triplicate measurements should be used.
4: Clinical Laboratory measurements include Clinical Chemistry (which includes CRP), Haematology and Urinalysis.
5: Includes Total Mayo, Partial Mayo and 3-domain Mayo Scores.
 
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5.2.1.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
Log-Transformed Change from 
Baseline (Loge Change)
= Loge (Visit) – loge (Baseline).
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 5.2. Baseline Definitions will be used 
for derivations for endpoints / parameters. 

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all the change from baseline displays. 
5.3.
Multicentre Studies
There are no planned adjustments for multiple centres or regions due to the size of the 
study. Enrolment will be presented by country. For all other analyses, all sites, countries 
and regions will be pooled.
5.4.
Examination of Covariates, Other Strata and Subgroups
There are no planned subgroup analyses to be conducted on this study.
Category
Details
Strata
Not applicable for this study
Covariates
Baseline measure will be included as a covariate
5.5.
Multiple Comparisons and Multiplicity
Overall, no adjustments will be made for multiple comparisons or multiplicity across 
different endpoints.
The process to reduce the false discovery rate for the transcriptomic analyses of mRNA
expression is detailed in Section 10.1.3.1. 
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
12.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
12.2
Appendix 2: Schedule of Activities
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
12.5
Appendix 5: Data Display Standards & Handling Conventions
 
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Section
Component
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Reporting Standards for Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance
12.9
Appendix 9: Abbreviations & Trademarks
12.10
Appendix 10: List of Data Displays
12.11
Appendix 11: Example Mock Shells for Data Displays
12.12
Appendix 12: NONMEM datafile specification
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Table 2 below and  Appendix 10: List of 
Data Displays.
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
6.1.1.
Study Population Summary Measure
Population analyses will be presented (summarised in tables and listed) by randomised 
treatment group only. 
Table 2
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition for the Subject Conclusion Record
Y
Treatment Status and Reasons for Discontinuation of Study 
Treatment
Y
Y
Screen Status and Reason for Screen Failure
Y
Y
Subjects by Country and Site ID
Y
Reasons for Subject Withdrawal
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
 
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Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Populations Analysed
Study Populations 
Y
Exclusion from Any Population
Y
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y [1]
Ulcerative Colitis Baseline Characteristics [2]
Y
Y
Prior/Current Medical Conditions and Concomitant Medications [3]
Medical Conditions
Y
Y
Concomitant Medications [4]
Y
Y
Cardiovascular Risk Factors 
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
Study Drug Accountability 
Y
NOTES:

Y = Yes display generated.
1: Listing of race.
2: Baseline characteristics including: Baseline Mucosal Appearance at Endoscopy Mayo Subscore, Baseline Total 
Mayo Score, Baseline Partial Mayo Score, Baseline 3-domain Mayo Score, Baseline UCEIS Total Score, Baseline 
Modified Riley Scale , Baseline FCP, Baseline FCP category, Baseline concomitant medications for UC
(Glucocorticoids only, Immunosuppressants only, Glucocorticoids and immunosuppressants, No glucocorticoids or 
immunosuppressants), Baseline Prednisone dose, Family History of Premature Coronary Artery Disease and History of 
Tobacco Use.
3: Separate summaries for Current and Past Medical Conditions/Cardiovascular Risk Factors/Concomitant Medications.
4: The ingredients of concomitant medications will be reviewed by the clinical and medical team to determine baseline 
use of Glucocorticoids, Immunosuppressants and Prednisone.
 
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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Table 3 below and Appendix 12: List of Data Displays.
7.1.1.
Adverse Event Summary Measures
AE data will be summarised in tables and figures by the following: 

Part A by randomised treatment;

Parts A, B and follow-up by randomised treatment; 

Parts A, B and follow-up by period treatment (i.e. treatment participant actually 
received). 
AE data will be presented in data listings by the following: 

Parts A, B and follow-up by period treatment (i.e. treatment participant actually 
received). 
Table 3
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AE by Maximum Intensity by SOC and PT
Y
All Drug-Related AEs by Maximum Intensity by SOC and PT
Y
Common (>=10%) AEs / Drug-Related AEs by Overall Frequency
Y
Y [1]
Common (>=10%) Non-serious AEs by SOC and PT (Number of Subjects and 
Occurrences)
Y
All AEs
Y
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
Serious and Other Significant AEs
Serious AEs by SOC and PT (Number of Subjects and Occurrences)
Y
Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
AEs Leading to Permanent Discontinuation of Study Treatment or Withdrawal 
from Study 
Y
Y
Reasons for Considering as a Serious AE
Y
Possible Suicidality-Related AE (PSRAE)
Y
 
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NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents L related to any displays of individual participant observed raw data.
1: Plot of common AEs and relative risk will be generated.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. Table 4 provides an overview of the planned analyses with further detail being 
presented in Appendix 10: List of Data Displays.
7.2.1.
Clinical Laboratory Summary Measures
Clinical Laboratory data will be summarised in tables and figures by the following: 

Parts A, B and Follow-up by randomised treatment;

Parts A, B and Follow-up by period treatment (i.e. treatment participant actually 
received). 
Clinical Laboratory data will be presented in data listings by the following:  

Parts A and B and follow-up by period treatment (i.e. treatment participant actually 
received). 
Table 4
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Results 
Y
Chemistry Lipids Results [1] 
Y [2]
Worst Case Chemistry Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline
Y
Worst Case Lipids Results Relative to NR Criteria Post-
Baseline Relative to Baseline [1]
Y
Lipids Outside of the Normal Range [1]
Y
Hematology
Hematology Results
Y
Worst Case Hematology Results Relative to PCI Criteria 
Post-Baseline Relative to Baseline
Y
 
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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Urinalysis
Urine Concentration 
Y
Worst Case Urinalysis Results (Discrete or Character 
Values) Post-Baseline Relative to Baseline
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
Scatter Plot of Maximum Versus Baseline for ALT
Y
Scatter Plot of Maximum ALT Versus Maximum Total 
Bilirubin
Y
All Laboratory [3]
All Laboratory Data for Subjects with Any Value of PCI
Y
Laboratory Data with Character Results
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents L related to any displays of individual participant observed raw data.
1: Lipids parameters = LDL Cholesterol, HDL Cholesterol, Total Cholesterol, Triglycerides and Cholesterol/HDL ratio
2: Percentage changes from baseline. 
3: Chemistry, Hematology and Urinalysis will be considered.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Table 5 below and Appendix 10: List of Data Displays.
7.3.1.
Summary Measures
Non-laboratory safety results will be summarised in tables and figures by the following: 

Parts A, B and Follow-up by randomised treatment; 

Parts A, B and Follow-up by period treatment (i.e. treatment participant actually 
received). 
Non-laboratory safety results will be presented in data listings by the following:  

Parts A and B and follow-up by period treatment (i.e. treatment participant actually 
received). 
 
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Table 5
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings 
Y
ECG Values1
Y
Maximum QTc Values Post-Baseline Relative to 
Baseline by Category1
Y
Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category1
Y
All ECG Values for Subjects with Any Value of PCI1
Y
Vital Signs
Vital Signs 
Y
Worst Case Vital Signs Results by PCI Criteria Post-
Baseline Relative to Baseline
Y
All Vital Signs for Subjects with Any Value of PCI
Y
C-SSRS V4
C-SSRS Suicidal Ideation and Behaviour Data 
Y 
NOTES:
1. ECGs change from baseline are to be produced for change from screening (average triplicate) and change from 
baseline

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.
7.4.
Other Safety Analyses
If any of the following events are recorded in the eCRF as a CV event during the study,
posthoc patient profile listings will be generated per IDSL and provided to the GCSP 
department:

Arrhythmias, Congestive heart failure, Cerebrovascular events stroke (CVA) and 
Transient ischemic attack (TIA), Deep vein thrombosis (DVT)/Pulmonary 
embolism (PE), Myocardial Infarction/Unstable Angina, Peripheral arterial 
thromboembolism, Pulmonary Hypertension, Revascularisation, Valvopathy.
 
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8.
EFFICACY
8.1.
Efficacy Endpoints
Table 6 below provides an overview of the planned efficacy analyses, with full details of 
data displays being available in Appendix 10: List of Data Displays.  
Table 6
Overview of Planned Efficacy Analyses
Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L[1]
T
F
F
L
T
F
L[1]
T
F
F
L
Mayo –Endoscopy Response
Mucosal Appearance 
at Endoscopy Mayo 
Subscore 
Y
Y
Proportion Achieving 
Mayo Endoscopy 
Remission 
C
C
C
Y
Y
Y
Mayo – Clinical Response and Remission 
Proportion Achieving 
Mayo Clinical 
Response 
C
C
C
Y
Y
Y
Proportion Achieving 
Mayo Clinical 
Remission
C
C
C
Y
Y
Y
Proportion Achieving 
3-domain Mayo 
Clinical Response 
C
C
C
Y
Y
Y
Proportion Achieving 
3-domain Mayo 
Clinical Remission
C
C
C
Y
Y
Y
Mayo – Symptomatic Clinical Remission 
Total
Y
Y
Y
C
C
C
Y
Y
Y
Partial Mayo
Y
Y
Y
C
C
C
Y
Y
Y
3-domain Mayo 
Y
Y
Y
C
C
C
Y
Y
Y
UCEIS – Mucosal Healing 
UCEIS Total Score
Y
Y
Y
C
C
C
Y
Y
Y
UCEIS – Remission 
Proportion Achieving 
UCEIS Remission 
C
C
C
Y
Y
Y
Biomarkers of Disease Activity
CRP
Y
Y
Y
C
C
C
Y
Y
Y
FCP [2]
Y
Y
Y
C
C
C
Y
Y
Y
Histologic Disease Activity
Modified Riley Scale 
Y
Y
Y
C
C
C
Y
Y
Y
Geboes Index Total 
Score
Y
Y
Y
C
C
C
Y
Y
Y
RHI Total Score
Y
Y
Y
C
C
C
Y
Y
Y
 
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Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L[1]
T
F
F
L
T
F
L[1]
T
F
F
L
Quality of Life
IBDQ Domains [3]
Y
Y
Y
Y
IBDQ Total Score
Y
Y
Y
C
C
C
Y
Y
Y
Subject Symptom Diary Cards
Diary Card [4]
Y
Y
NOTES:
T = Table, F = Figure, L = Listing, Y = Yes display generated, C = conditional 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
Individual = Represents FL related to any displays of individual participant observed raw data.
1.
Listing of the RAW SAS output from the statistical modelling. 
2.
FCP will be log-transformed before determining change from baseline.
3.
IBDQ domains: Bowel Symptoms, Systemic Systems, Emotional Function and Social Function. 
4.
Data from diary cards will be transcribed into the eCRF for the 5 days prior to the following visits: Screening, 
Day 15, Day 29, Day 43, Day 85 and EW.
8.1.1.
Population of Interest 
Analyses of the Mayo will be based on the Safety, PP and PP + Completers populations 
respectively. 
All other efficacy analyses will be based on the Safety Population only.
8.1.2.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
All efficacy data will be summarised for Parts A, B and Follow-up (if applicable) by 
randomised treatment. 
Unless otherwise specified, endpoints / variables defined will be summarised using 
descriptive statistics, graphically presented (where appropriate) and listed.
8.1.2.1.
Statistical Methodology Specification
8.1.2.1.1
Continuous Endpoints
Secondary and Exploratory Endpoint(s)

Change from baseline in Total and 3-domain Mayo Score at Day 43 pre-dose and Day 85.

Change from baseline in Partial Mayo Score at Day 15, Day 29, Day 43 pre-dose and Day 85.

Change from baseline in UCEIS Total Score at Day 43 pre-dose and Day 85.

Change from baseline Modified Riley Scale at Day 43 pre-dose and Day 85.

Change from baseline Geboes Index Total Score at Day 43 pre-dose and Day 85.

Change from baseline RHI Score at Day 43 pre-dose and Day 85.

Change from baseline in CRP at Day 43 pre-dose and Day 85.

Change from baseline in Log-transformed FCP at Day 15, Day 29, Day 43, Day 57, Day 71 and Day 85.

Change from baseline in IBDQ Total Score at Day 43 pre-dose and Day 85.
 
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Model Specification

Continuous endpoints will be statistically analyzed using a Mixed Models Repeated Measures (MMRM) 
approach. 

Terms fitted in the MMRM model will include:
o
Fixed Category                           : Treatment, Day, Treatment*Day
o
Fixed Continuous Covariates     : Baseline Score, baseline*Day
o
Repeated Effect                         : Day

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting 
for bias in the estimated variance-covariance of the fixed effects will be used. 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the 
REPEATED line with a subject=SUBJID option.
o
In the event that this model fails to converge, alternative correlation structures may be 
considered such as CS or AR(1). 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.

Other covariates maybe explored, if deemed appropriate for sensitivity analyses.
Model Checking & Diagnostics

MMRM model assumptions will be applied, but appropriate adjustments may be made based on the 
data.

Distributional assumptions underlying the MMRM model will be examined by obtaining a normal 
probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking the 
normality assumption and constant variance assumption of the model respectively) to gain confidence 
that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be explored using 
appropriate transformed data.
Model Results Presentation - Untransformed

Point estimates and corresponding 95% confidence intervals will be constructed for the treatment 
differences (GSK2982772 60mg tid- Placebo), using the residual error from the repeated measures 
model.

Plots of LS means and 95% confidence intervals from the model will be generated for each treatment 
group by time.

For log-transformed data the adjusted back-transformed geometric means and CV will be presented.
Model Results Presentation -  Log transformed

Adjusted geometric means, the mean difference between each dose (test) and the placebo (reference) at 
each timepoint and associated 95% confidence interval will be constructed using the residual variance

The treatment ratios and 95% CI will be calculated by back-transforming the difference between the least 
square means and associated 95% CI
Sensitivity and Supportive Statistical Analyses

Non-parametric analyses may be conducted if the normality assumption does not hold.

Analyses using different covariance structures may be explored if the unstructured covariance matrix 
does not converge.
8.1.2.1.2
Binary Endpoints
Secondary and Exploratory Endpoint(s)

Proportion of participants achieving a Mayo endoscopy remission at Day 43 pre-dose and Day 85.

Proportion of participants achieving Mayo clinical response and 3-domain Mayo clinical response at Day 
43 pre-dose and Day 85.
 
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
Proportion of participants achieving Mayo clinical remission and 3-domain Mayo clinical remission at Day 
43 pre-dose and Day 85.

Proportion of participants achieving an UCEIS remission at Day 43 pre-dose and Day 85.
Model Specification

Binary efficacy endpoints will be statistically analysed using a Generalised Estimating Equations (GEE) 
model.

GEE modelling will only be performed if at least 30% response rate at Day 85 for any one treatment 
group.

The model will be fitted using an unstructured covariance structure of the correlated responses.

Terms fitted in the GEE model will include:
Fixed Categorical
: Treatment group, Visit, Treatment group * Visit Interaction
Repeated
: Visit
Model Results Presentation

Binary endpoints will be summarised using counts and proportions of participants achieving a response by 
treatment group.

Point estimates and corresponding 95% confidence intervals will be constructed using contrasts for the 
treatment group by visit interaction.

Plots of the point estimates and 95% confidence intervals from the model will be generated for each 
treatment group by time.

If a minimum 30% response rate at Day 85 for any one treatment group is not achieved, the display should 
be created with ‘Insufficient data to produce GEE analysis’ printed in the main body of the display.
8.2.
Exploratory Efficacy Analyses
8.2.1.
Responder Across Endpoints 
For appraisal of trends across secondary efficacy endpoints, a nine-panel plot for each 
participant with a single panel for each of the following efficacy endpoints will be 
produced:  

Mayo Endoscopy Remission

UCEIS Total Score,

FCP,

CRP,

Modified Riley Scale Total Score

Geboes Index Total Score, 

Total Mayo Score, 

Partial Mayo Score

3-domain Mayo Score.
8.2.2.
Probabilities of Success 
Probabilities of success may be determined, based on the data observed in the study, 
where the definition of success will be dependent on the endpoint. For example, what is 
the probability that we would observe a certain proportion of Mayo Endoscopic 
Remission (0 or 1) (i.e., comparatory rate), based on the data that we have observed in 
this study.
 
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A Bayesian approach will be employed to determine a 95% credible confidence interval 
around the observed probability of success with a flat Beta (1, 1) prior. Any such 
analyses will be done by GSK II Clinical Statistics after unblinding of the interim data 
and thus will be deemed post-hoc.
8.3.
Exploratory Pharmacodynamic / Efficacy Analyses
If deemed appropriate, the relationship between the biopsy biomarkers and efficacy 
endpoints will be explored further using multivariate statistical methods and/or Bayesian 
methodology as recommended by the GSK PCPS Experimental Medicine working group. 
The consistency in the changes over time between the endpoints will also be assessed.  
Any such analyses will be defined after unblinding of the interim data and thus will be 
deemed post-hoc.
9.
PHARMACOKINETIC ANALYSES
9.1.
Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
PK plasma and biopsy tissue Concentration data for GSK2982772 will be summarised 
and listed, no statistical analysis will be conducted. Summary statistics of GSK2982772 
concentration by Day (1, 43, and 85) and nominal blood sampling time will be 
determined. PK blood samples are taken pre-dose on Day 43 and post-dose on Days 1 
and Day 43 at the following time points: 1, 2, 4, and 6 hours and trough on Day 85 or 
Early Withdrawal.
PK data will be summarised for Parts A and B by randomised treatment. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Standards for Pharmacokinetic).
Table 7
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed 
Log-transformed 
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Pharmacokinetic 
Plasma Drug concentration 
Y
Y[1][2]
Y[1]
Y
Biopsy Tissue Drug 
concentration 
Y
Y[1][2]
Y[1]
Y
 
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NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Summary = represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = represents FL related to any displays of individual participant observed raw data.  
1:  Linear and Semi-Log plots will be created on the same display.
2: Separate Mean (± SE) and Median plots will be generated.
Since the half-life of GSK2982772 is short (2-3h), the duration of time between the Day 
43 clinic visit and the usual dosing time may result in the reported “pre-dose” 
concentration being lower than the true “pre-dose” or trough concentration (e.g. if the 
usual dose time was 7am and the clinic visit was 10am the “pre-dose” sample collected at 
10 am would be approximately ½ that of the true “trough” concentration assuming a 3 
hour half-life).  Therefore, the predicted “trough” concentration will be calculated using 
the following equation-
where

Ctrough = predicted trough concentration prior to usual dosing time 

Cpredose = observed “pre-dose” concentration collected at the clinic 

t = time in hours between pre-dose blood sample collection and time of dosing 
(assumed to be 7am) 

ke = elimination rate constant (0.693/ t½), (t½ assumed to be 2.5h) 
9.1.2.
Population of Interest 
The PK analyses will be based on the Pharmacokinetic population, unless otherwise 
specified.
9.2.
Population PK Analyses
GSK2982772 plasma concentrations from this study may be included in a cross-study 
population pharmacokinetic (Pop PK) analysis. If deemed appropriate to conduct a Pop
PK analysis, a NONMEM datafile will be generated. The details for the dataset 
specifications are provided in Appendix 12. 
9.3.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between GSK2982772 predicted trough concentration and the following 
variables will be explored graphically: 
Target engagement from the corresponding blood/biopsy tissue sample;
Change from baseline in continuous efficacy endpoints (Total Mayo Score, Partial 
Mayo Score, 3-domain Mayo Score, UCEIS Total Score, Modified Riley Scale
Score, Geboes Index Total Score, RHI Score, CRP and FCP. 
 
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Box plot of GSK2982772 concentrations in participants not achieving a Mayo Endoscopy 
Remission and participants achieving a Mayo Endoscopy Remission.
10.
BIOMARKER ANALYSES
10.1.
Biomarker/Target Engagement/Pathway Engagement/ 
Transcriptomics Analyses
10.1.1.
Endpoint / Variables
Table 8
Overview of Planned Analyses
Endpoint 
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Exploratory Biomarkers
Inflammatory 
biomarkers in biopsy 
tissue1
Y
Y
Y
Y
Y
Y
Y
Y
Pathway and Target Engagement
Pathway and target 
engagement in blood2
Y
Y
Y
Y
Y3
Y
Pathway and target 
engagement in biopsy 
tissue2
Y
Y
Y
Y
Y
Y
Transcriptomics 
mRNA 
expression from 
blood[3][4]
Y
Y
Y
Y
Y
Y
mRNA expression from 
biopsy tissue[3][4]
Y
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data
1: Markers including but not limited to:  IL-1, IL-6, IL-8, MMP-3, TNFα and IFNy 
2: TEAR1, phosphorylated or total RIP1, MLKL, and RIP3, cleaved and total caspase 3 and caspase 8 signatures 
in blood and biopsy tissue if sample quantity and data allow.
3: mRNA expression of inflammatory gene transcripts including but not limited to: IL-4, IL-10, IL-17, IL-21, IL-22, 
IL-23, TNF and IFNγ.
4: Data to be analysed by the GSK II Statistics and Programming Team Post-SAC.
Scatter plots of Target Engagement and blood/biopsy tissue biomarkers for Day 43 and 
Day 85 will also be produced.  
 
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If deemed appropriate, the relationship between Target Engagement and the blood/biopsy 
tissue biomarkers will be explored further using multivariate statistical analyses. The 
consistency in the changes over time between the endpoints will also be assessed.  Any 
such analyses will be defined after unblinding of the data and thus deemed post-hoc.
10.1.2.
Population of Interest
The pharmacodynamic/biomarker analyses will be based on the Safety population, unless 
otherwise specified.
10.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
Biomarker data will be summarised for Parts A and B combined by randomised 
treatment. 
10.1.3.1.
Statistical Methodology Specification
Exploratory Inflammatory Biomarkers
Endpoints

Change from baseline on log transformed inflammatory biomarkers in biopsy tissue on Day 43 pre-dose 
and Day 85: Loge Change = Loge (Visit) – loge (Baseline).
Markers include but not limited to: IL-1, IL-6, IL-8, MMP-3, TNFα and IFNy.
Model Specification

Endpoints will be statistically analyzed using a mixed model repeated measures (MMRM) approach. 

Terms fitted in the MMRM model will include:
o
Fixed Category                           : Treatment, Day, Treatment*Day
o
Fixed Continuous Covariates     : Baseline Score, baseline*Day
o
Repeated Effect                          : Day

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting 
for bias in the estimated variance-covariance of the fixed effects will be used. 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the 
REPEATED line with a subject=SUBJID option.
Model Checking & Diagnostics

For the MMRM, model assumptions will be applied, but appropriate adjustments may be applied based 
on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, this will be 
explored. For example, the SCORING=4 option could be used in the MIXED statement, which makes 
SAS use Fisher scoring for the first 4 iterations. If the convergence problem cannot be resolved, the 
unstructured covariance matrix will be replaced by ANTE (1) covariance structure in combination with a 
 
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random participant effect.
o
If this model fails to converge, alternative correlation structures may be considered such 
as CS or AR (1). 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.

Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking 
the normality assumption and constant variance assumption of the model respectively) to gain
confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be explored 
using appropriate transformed data.
Presentation of results

Adjusted geometric means, the mean difference between each dose (test) and the placebo (reference) 
at each timepoint and associated 95% confidence interval will be constructed using the residual 
variance.

The treatment ratios and 95% CI will be calculated by back-transforming the difference between the 
least square means and associated 95% CI.

Percentage change from baseline at each timepoint will be calculated from the adjusted geometric 
means using the formula 100% x (exp (adj mean)- 1).
Pathway and Target Engagement 
Endpoints

Log Ratio = Log (free TEAR1) – log (total TEAR1). 
Model Specification

A mixed effect model will be fitted with randomised treatment, time (i.e. planned relative time) and 
randomised treatment * time as a fixed effect and participant as a random effect.  Baseline log ratio will 
be fitted as a continuous covariate along with Baseline log ratio* time.

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting 
for bias in the estimated variance-covariance of the fixed effects will be used. 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the 
REPEATED line with a subject=SUBJID option.
Model Checking

For the MMRM, model assumptions will be applied, but appropriate adjustments may be applied based 
on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, this will be 
explored. For example, the SCORING=4 option could be used in the MIXED statement, which makes 
SAS use Fisher scoring for the first 4 iterations. If the convergence problem cannot be resolved, the 
unstructured covariance matrix will be replaced by ANTE (1) covariance structure in combination with a 
random participant effect.

If this model fails to converge, alternative correlation structures may be considered such as CSH or CS. 

Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking
the normality assumption and constant variance assumption of the model respectively) to gain 
confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be explored 
using appropriate transformed data.
 
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Pathway and Target Engagement 
Presentation of Results

Adjusted geometric means, the mean difference between each dose (test) and the placebo (reference) 
at each timepoint and associated 95% confidence interval will be constructed using the residual 
variance.

The treatment ratios and 95% CI will be calculated by back-transforming the difference between the 
least square means and associated 95% CI.

Percentage target engagement at each timepoint will be calculated from the adjusted geometric means 
using the formula: 100% x (exp (ln (v2 / v1) + 1) 

percentage target engagement = (1 – engagement ratio) * 100.
Transcriptomics – Fold Change Analysis

The log2 normalised copy numbers (also referred to as log2(intensity)) received from the normalised 
process will be listed and summarised appropriately by randomised treatment.

As the data will be log2 transformed prior to the analysis, the randomised treatment effects will be 
expressed as ratios after back transformation to the original scale. These ratios can be converted from 
randomised treatment ratios to fold change values as follows:  

If ratio ≥ 0 then fold change = ratio

If ratio <0 then fold change = -1/ratio
Endpoint(s)

Log2(intensity) mRNA expression of inflammatory gene transcripts 
Model Specification

Endpoints will be statistically analyzed using a linear repeated measure mixed effects model. 

Terms fitted in the linear repeated measures mixed effects model will include:
o
Fixed Category                          : Treatment, Visit, Treatment * Visit
o
Random Effect                           : Participant
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments may be applied based on the data.

In the unlikely circumstance that there are convergence problems with the analysis, this will be 
explored. 

If this model fails to converge, alternative correlation structures may be considered such as CSH or CS. 

Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking 
the normality assumption and constant variance assumption of the model respectively) to gain 
confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be explored 
using appropriate transformed data.
Presentation of Results

For each probeset analysed adjusted means with corresponding 95% CI and fold changes with 
corresponding 95% CI’s can be outputted. The fold change is derived from the ratio of the back-
transformed estimate of the difference between adjusted means.

Plots of LS means and 95% confidence intervals from the model will be generated for each treatment 
by time. Additionally, plots of differences and 95% confidence intervals for the comparison between the 
treatment groups will be generated.

For each comparison subsets of probesets will be identified based on an appropriate fold-change, for 
example, fold changes >1.5 or <-1.5. The proportion of probesets with fold changes >1.5 or <-1.5 will 
 
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Transcriptomics – Fold Change Analysis
be summarised in a frequency table.

Exploratory graphical reporting on the back-transformed scale can include:

Log2 (intensity) plotted against time point separately for individual participants, grouped by 
randomised treatment group

Adjusted mean intensity and 95 CI% plotted by treatment group and time point.
Transcriptomics - MicroArray RNA Analysis

MicroArray RNA will be extracted and hybridised using a balanced batch design by Epistem. An 
appropriate microarray platform will be determined at the time of hybridisation, to allow for 
improvements in technology. The quality of the data will be assessed and then normalised using 
appropriate methodologies and software.

Microarray mRNA data will be normalised using gcRMA or RMA in Array Studio v5.0 or later. After 
normalisation, the data will be quality assessed and any samples deemed as QC fails will be excluded 
from any further analysis. This quality assessment will involve looking for outlying signals in both the 
normalised expression data and the MAS5 QC metrics generated from each sample. If any samples 
are excluded, the remaining data will be re-normalised. The output from the normalisation will be log2
transformed mRNA intensity data (measured in arbitrary units).

Microarray data consists of expression values (log2-transformed) derived from individual probesets 
designed against coding regions of individual genes. More than one probeset can exist per gene. This 
analysis will be conducted at the probeset level.

To identify the most robustly expressed probesets, the data can be filtered to remove low intensity 
probesets, low quality and control probe sets prior to analysis. This could be done simply by excluding 
all probesets where all observations are <6 (on the log2 scale). Note it has been observed empirically 
that when you get below 100 (6.6 on the log2 scale) you are into the noise of the assay. Other more 
stringent methods of filtering the data could be used. In total, there are 53,617 probesets that could be 
analysed. 

To compare the expression value for each probeset, the following linear repeated measures mixed 
effects model will be fitted to each probeset that passes any pre-filtering, with log2 (intensity) as the 
response variable. Randomised Treatment by visit, randomised treatment and visit will be fitted as fixed 
effects and participant as a random effect. Example SAS code is given below: 
proc mixed data=data; 
ods output covparms=cov lsmeans=lse estimates=Compare;
class subjid treatment visit; 
model lgintensity= treatment visit treatment*visit /ddfm=kr;
repeated visit / subject=subjid type=un;  
lsmeans treatment*visit / diff cl alpha=0.05; 
run; 

For each probeset analysed adjusted means with corresponding 95% CI and fold changes with 
corresponding 95% CI’s can be outputted. The fold change is derived from the ratio of the back-
transformed estimate of the difference between adjusted means.
 
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Transcriptomics - MicroArray RNA Analysis

Where appropriate, particularly with microarray data, multiple testing will be considered using the 
Benjamini-Hochberg correction (Benjamini, Y; J Royal Stat Soc 1995;57:289-300) to calculate FDR 
adjusted p-values. Proc Multtest incorporating the FDR adjusted p-value option is SAS is used to 
convert the raw p-values from the proc mixed code above into the FDR adjusted p-values based on the 
Benjamini-Hochberg correction. Example code to generate the FDR adjusted p-values is given below:
data pvalues (keep = probsid label probt rename=(probt=raw_p));
     set compare;
run;
proc multtest pdata=pvalues fdr out=FDRres noprint;
run;

Where the FDRes dataset will include the following columns:
p-values
Test
Raw
False Discovery Rate
1
0.2828
0.9243
2
0.9437
0.9437
3
0.0350
0.6305
etc.

Appropriate outputs will be created containing all the results for the relevant comparisons for all 
analysed probesets. A summary may be generated, including probeset ID, gene ID, time point, adjusted 
means with corresponding 95% CI for each randomised treatment group, Benjamini-Hochberg FDR 
adjusted p-value and fold changes corresponding 95% CI from each comparison. Note that probeset ID 
is required if there is more than one probeset per gene.  

For each comparison subsets of probesets will be identified based on an appropriate fold-change, for 
example, fold changes >1.5 or <-1.5. The proportion of probesets with fold changes >1.5 or <-1.5 will 
be summarised in a frequency table.

The outputs should be reviewed by the study team and the pre-agreed subset of biologically relevant 
probesets will be reported within the CSR. If based on the fold-changes observed other probesets, 
which were not pre-specified in the RAP, are deemed relevant then these should be interpreted with 
caution. 

Exploratory graphical reporting on the back-transformed scale can include:

Log2 (intensity) plotted against time point separately for individual participants, grouped by 
randomised treatment group

Adjusted mean intensity and 95 CI% plotted by randomised treatment group and time point.
 
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Transcriptomics – Microarray Percentage Inhibition Analysis

The log2 normalised data is back transformed and the percentage inhibition is derived on a participant
level on the back transformed data for each probeset. The percentage inhibition will be determined for 
each probeset per participant, where it is defined as the reduction from baseline. For example: 
Day X – baseline = -40% would be a 40% reduction (i.e. -40% change from baseline) which in turn is 
defined as a 40% inhibition. So, the percentage inhibition would be calculated as:
[ (Day x – Baseline) / Baseline] * -100 = % inhibition

A subset of probesets may be identified and individual participant mRNA intensities and percentage 
inhibitions may be listed, summarised and plotted appropriately for each selected probeset. The 
selected probesets will be statistically analysed appropriately, and the output from the mixed effects 
model summarised. The probeset, gene or gene description will be included in the outputs.

To compare the percentage inhibition for each selected probeset, the following linear repeated 
measures mixed effects model will be fitted to each selected probeset, with percentage inhibition as the 
response variable. Randomised Treatment by visit, randomised treatment and visit will be fitted as fixed 
effects and participant as a random effect. Example SAS code is given below:
proc mixed data=data; 
class subjid treatment visit; 
model perinhibit= treatment visit treatment*visit /ddfm=kr;
repeated visit / subject=subjid type=un;  
lsmeans treatment*visit / diff cl alpha=0.05; 
run; 
11.
REFERENCES
Guyatt, G, Mitchell A, Irvine E J, Singer J, Williams N, Goodacre R, and Tomkins C;
A New Measure of Health Status for Clinical Trials in Inflammatory Bowel Disease. 
Gastroenterology. 1989; 96:804-10
 
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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion #9 – Informed Consent: Informed Consent not available at site or Patient 
did not sign or date
02
Inclusion #2 – Eligibility: Other medical conditions
03
Inclusion #3 – Eligibility: Confirmed diagnosis of UC
04
Inclusion #4 – Eligibility: Total Mayo score and endoscopy subscore
05
Inclusion #5 – Eligibility: Stable concurrent medication
06
Inclusion #6 – Eligibility: Prior treatment
07
Incorrect randomisation or study unblinding procedures
A participant meeting any of the following criteria will be reviewed for exclusion from 
the Per Protocol population:
Number
Exclusion Description
08
Exclusion #17 – Concomitant Medication
 
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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Procedures
Screening (-30)
Screening (-7 to -30)
Treatment Period18
Early 
Withdrawal
19
Follow Up 
(3)20
PART A
PART B
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, 
temperature)
X
X4
X
X
X4
X
X
X
X
X
12-lead ECG3
X
X4
X
X
X4
X
X
X
X
X
Concomitant medication review & 
AE reporting/SAEs5
X--------------------------------------------------------------------------------------------------------------
PROs/Questionnaires/Disease Assessments and Procedures
Columbia Suicide Severity Rating 
X
X4
X4
X
X
 
 
 
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Procedures
Screening (-30)
Screening (-7 to -30)
Treatment Period18
Early 
Withdrawal
19
Follow Up 
(3)20
PART A
PART B
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Scale (C-SSRS)
IBDQ6
X4
X4
X
X
UCEIS, Modified Riley, Geboes 
Index
X-------X7
X4
X
X
Mayo Score (including 
sigmoidoscopy and biopsy)
X-----X7
X4, 8
X
X9
Partial Mayo Score
X-----X7
X
X
X4
X
X
Study Treatment
Randomisation
X
Study medication (three times 
daily)10
X----------------------------------------XX---------------------------------------X11
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
Collection of diary cards
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, Hep B, Hep C Ab, C. 
Difficile toxin 
X
FSH & estradiol (if applicable)
X
Serum pregnancy test (WCBP 
only)
X
 
 
 
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Procedures
Screening (-30)
Screening (-7 to -30)
Treatment Period18
Early 
Withdrawal
19
Follow Up 
(3)20
PART A
PART B
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Urine pregnancy test (WCBP 
only)12
X4
X
X
X4
X
X
X
X
X
Haematology, chemistry, 
urinalysis 
X
X4
X
X13
X4
X13
X13
X
X
X
Faecal calprotectin14
X
X
X
X
X
X
X
X
X
Blood sample for exploratory 
biomarkers and TE15
X4
X4
X
X
PK blood samples GSK298277216
X
X4
X
X
Biopsies for PK, inflammatory 
biomarkers, mRNA, TE & pathway 
marker analysis
X-------X7
X4
X
X8
Pharmacogenetic sample (PGx)17
X
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only and if stopping criteria are met.
4.
Pre-dose.  
5.
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be 
recorded from the time a participant consents to participate in the study up to and including any follow-up.  AEs will be collected from the start of Study Treatment until the follow-
up contact.
6.
PRO assessments should be conducted before any tests, procedures or assessments to avoid influencing the participants’ perception.
 
 
 
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7.
Sigmoidoscopy may be performed at any time during the screening window as an additional visit (if required) up to Day -7 in order for central reading confirmation of Mayo Score 
for inclusion.  If a shorter window is required (e.g., within Day -3 to Day -7), this will be permitted as long as it has been confirmed with the sponsor and central reader that results 
of the Mayo endoscopy score will be available before end of screening window.  Histological disease (e.g., UCEIS, MRS and Geboes Index) along with Mayo score assessments 
will also be completed.
8.
Sigmoidoscopy may be performed on a separate day within the Day 43 visit window allowance (3 days).  A separate visit to perform sigmoidoscopy is only allowed to 
accommodate scheduling.  This separate visit should be done before the full Day 43 visit where PK, clinical laboratory tests and all other required Day 43 procedures are 
performed.  Participants must not take their study medication at home in the morning before the sigmoidoscopy procedure and also the morning before the full Day 43 visit, if 
being done on a separate day. Dispensing of study medication must be done at the 2nd visit (if separate visits are performed).
9.
Biopsy only required at Early Withdrawal visit if after at least 14 days of treatment and prior to Day 43 or if after Day 57 and prior to Day 85.
10. Participants must take study medication three times a day approximately 8 hours apart. Exact time of dosing to be recorded in diary cards. On Day 43 and 85, participants must 
not take their study medication at home in the morning. Participant will complete specified pre-dose assessments and then will be administered their morning dose of medication 
at site on Day 43.  On Day 85, participants are no longer receiving study medication.
11. In Part A, participants will be randomised 2:1 to GSK2982772 60 mg or placebo three times daily for 42 days.  At the Day 43 visit, all participants who have completed Part A, will 
move in to Part B open label treatment with GSK2982772 60 mg three times daily for 42 days.
12. If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
13. Urinalysis not required on Days 29, 57 and 71.
14. Participants can provide a faecal sample at any time during the screening window and up to 48 hours prior to any visit where FCP is being collected.  Please see laboratory 
manual for full details on sample handling and procedure.
15. Blood samples for exploratory biomarkers and Target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
16. PK blood samples for GSK2982772 will be taken pre-dose on Day 43. Post-dose serial PK samples will be taken on Days 1 and Day 43 at the following time points: 1, 2, 4, and 6 
hours and trough on Day 85 or Early Withdrawal.
17. A PGx blood sample is collected at the baseline visit (Day 1), after the participant has been randomized and provided informed consent for genetic research.  If the sample is not 
collected at the baseline visit, it can be collected at any time during the study after randomization.
18. Visit windows during the treatment period are relative to Day 1.
19. If a participant withdraws from the study, every effort will be made for the participant to complete an Early Withdrawal visit prior to the Follow Up visit.
20. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
 
 
 
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12.3.
Appendix 3: Assessment Windows
12.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits.
 
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12.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
12.4.1.
Study Phases
Treatment phases will be defined for Part A and Part B of the study. Therefore,
assessments and events will be classified according to the time of occurrence relative to 
study treatment start date and the Day 43 visit.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
On-Treatment (Part A)
Study Treatment Start Date < Date ≤ Day 43 Visit Date
On-Treatment (Part B)
Day 43 Visit Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
12.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
Post-Treatment
Any medication that is started >= Study Treatment Stop Date +1
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
12.4.2.
Treatment Emergent Flag for Adverse Events
Treatment State
Definition
AE = Pre-Treatment
If AE onset date is before treatment start date:
= AE Onset Date < Study Treatment Start Date
AE = On-Treatment
If AE onset date is on or after treatment start date and on or before treatment stop date:
= Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date +1
AE = Post-Treatment
If AE onset date is after the treatment stop date:
= AE Start Date > Study Treatment Stop Date +1
AE Onset Time 
Since 1st Dose 
(Days)
If Treatment Start Date ˃ AE Onset Date: 
= AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date: 
= AE Onset Date - Treatment Start Date +1
Missing otherwise.
AE Duration (Days) 
AE Resolution Date – AE Onset Date + 1
AE = Drug-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.
 
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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area for Interim Analysis 
HARP Server
UK1SALX00175
HARP Area
arenv \ arprod \ gsk2982772 \ mid202152 \ interim1 
QC Spreadsheet
arenv \ arwork \ gsk2982772 \ mid202152 \ interim1 \ documents
Reporting Area for Final Reporting
HARP Server
UK1SALX00175
HARP Area
arenv \ arprod \ gsk2982772 \ mid202152 \ final
QC Spreadsheet
arenv \ arwork \ gsk2982772 \ mid202152 \ final \ documents
Analysis Datasets 

Analysis datasets will be created per Integrated Data Standards Library (IDSL) GSK A&R dataset 
standards.
Generation of RTF Files

RTF files will be generated for all tables at the time of the SAC.
12.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx:

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Participant level listings will not be provided in the main body of the GSK Clinical Study Report. All 
participant level listings will be located in the modular appendices as ICH or non-ICH listings.
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.
 
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
Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

For all safety data:

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.

For efficacy data:

Early withdrawal visit will be included in all summary tables, figures and listings

Early withdrawal visit will be assigned to closest planned study assessment following withdrawal i.e. 
for data collected from biopsies at the Day 43 visit or Day 85 visit
Descriptive Summary Statistics
Continuous Data
N, n, mean, median, SD, SE, min, max
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

Placebo in graphs to be shown in Black and GSK2982772 in Green
12.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings

Refer to IDSL PK Display Standards.

Refer to IDSL Statistical Principle 6.06.1.

Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/PK/PD 
File

PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology 
Modelling and Simulation function mayl be created according to the data 
specification detailed in Appendix 12: NONMEM datafile Specification.
 
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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance (PCI) 
summary tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date –First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.6.2.
Study Population
Demographics
Date of Birth 

Only the year of birth will be captured, and therefore the date of birth is then derived as follows:
Year of birth = YYYY → Date of birth = 30th June YYYY
Age

Calculated as the integer part of (date of screening  – date of birth)
       Age = integer part (date of study day 1   – 30th June YYYY)

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Race category 

White: ‘White: Arabic/North African Heritage’ and ‘White: White/Caucasian/European Heritage’, or both 
of these, but no other category checked.

African descent: ‘African American/African Heritage’, and no other category checked.

Asian: ‘Asian – Central/South Asian Heritage’, ‘Asian – East Asian Heritage’, ‘Asian – Japanese 
Heritage’, and ‘Asian – South East Asian Heritage’, or any combination of these, but no other category 
checked.

Other: Any combination that has not been categorized above (‘mixed race’).
Treatment Compliance

Participant compliance will be based on the number of expected tablets to be taken and the number 
actually taken and will depend on whether a participant was taking investigational product (two tablets) 
twice a day or three times a day. 

Treatment compliance will be calculated based on the formula:  

Treatment Compliance = (Total tablets taken/total tablets expected to be taken) *100

Total tablets taken = (Total number of Tablets Dispensed-Total Tablets Returned) 

Total Tablets expected to be taken is duration of exposure*4 (see derivation below) for BID 
participants and *6 for TID participants.
 
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Demographics

Note compliance will only be calculated for participants who took at least one dose (i.e. number of 
tablets taken is >=1).
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  

Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula: Cumulative Dose = Total Tablets taken*60.
Concomitant Medications

The following information will be added to the baseline characteristics table: 

Concomitant Medications for UC: Participants will be categorized into one of 4 groups based on 
their ongoing prior concomitant medications: 

Glucocorticoids only,

Immunosuppressants only,  

Glucocorticoids and immunosuppressants and 

No glucocorticoids or immunosuppressants.

Prednisone dose (or equivalent): Summary statistics will be presented.

Glucocorticoids, Immunosuppressants and Prednisone will be identified by review of GSK drug terms by 
clinical and medical team.
12.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value then do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 
 
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Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of decimal places in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x ‘becomes x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
12.6.4.
Efficacy
Clinical Efficacy
Mayo
The Mayo is a 12-point scoring system used to assess UC disease activity based 4 subscores:
, 
 and
 The following table 
describes how each subscore is composed: 
Subscore
Score
The following endpoints for the Mayo score are to be considered using the following algorithms: 

Mayo Endoscopy Remission:  Participants with a score or or  on the
subscore.

Total Mayo Score: the total score of all 4 domain subscores -
and 

Partial Mayo Score: the total score of the 3 domain subscores -
and 
 
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Clinical Efficacy

3-domain Mayo Score: the total score of the 3 domain subscores:
and 

Mayo Clinical Response: ≥3 points or ≥30% improvement from baseline in total Mayo score, along with 
a decrease in the
subscore of ≥1 point. 
o
i.e., ( < change from baseline in total mayo score <=
OR % change from baseline in total 
mayo score <=
) AND change from baseline in
subscore <=
.

3-domain Mayo Clinical Response: ≥2 points or ≥30% improvement from baseline in partial Mayo score, 
along with a decrease in the 
subscore of ≥1 point or a
 subscore of
or . 
o
i.e., ( < change from baseline in partial mayo score <=
OR % change from baseline in 
partial mayo score <=
) AND (change from baseline in 
subscore <=
OR 
 subscore of  or ). 

Mayo Clinical Remission: Total Mayo score of 2 points or lower, with no individual subscore exceeding 1 
point.
o
i.e.,
<= total mayo score <=
AND
 subscore =  or AND
subscore =  or  AND
 subscore =
or  AND
 
subscore = or . 

3-domain Mayo Clinical Remission: At least one point decrease in
 subscore from 
Baseline to achieve a
 subscore of  or  and
subscore =  and
 subscore of or .
o
i.e. (
 subscore  or  AND change from baseline in
subscore <= 
) AND 
subscore of  AND
subscore =  or 
.
Clinical Efficacy 
UCEIS
The UCEIS is used as an additional tool to assess disease activity based on endoscopic
, 
and
. The following table describes how the UCEIS is scored:
Descriptor (score most
severe lesions)
Likert scale anchor points
Definition
 
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Clinical Efficacy
The following endpoint for the UCEIS is to be considered at each visit: 

UCEIS Total Score:  Sum of all likert scale anchor points scores. 

UCEIS Remission: Participants with a score or 0 or 1 on the UCEIS Total Score.
Geboes
The Geboes Index is divided in 6 grades: architectural changes [grade 0], chronic inflammatory infiltrate [grade 1], 
lamina propria neutrophils and eosinophils [grade 2], neutrophils in epithelium [grade 3], crypt destruction [grade 
4] and erosions or ulcerations [grade 5], and each grade of the score is divided in 4 or 5 subcategories. 
Grade
Subgrade
0
Structural (architectural change)
0.0
No abnormality
0.1
Mild abnormality
0.2
Mild or moderate diffuse or multifocal 
abnormalities
0.3
Severe diffuse or multifocal abnormalities
1
Chronic inflammatory infiltrate
1.0
No increase
1.1
Mild but unequivocal increase
1.2
Moderate increase
1.3
Marked increase
2
Lamina propria eosinophils and 
neutrophils (to be graded separately)
2.0
No increase
2.1
Mild but unequivocal increase
2.2
Moderate increase
2.3
Marked increase
3
Neutrophils in epithelium
3.0
None
3.1
<5% crypts involved
3.2
=<50% crypts involved
3.3
>=50% crypts involved
4
Crypt destruction
4.0
None
4.1
Probable – local excess of neutrophils in part 
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Clinical Efficacy
4.2
Probable – marked attenuation
4.3
Unequivocal crypt destruction
5
Erosion or ulcerative
5.0
No erosion, ulceration, or granulation tissue
5.1
Recovering epithelium plus adjacent 
inflammation
5.2
Probable erosion – focally stripped
5.3
Unequivocal erosion
5.4
Ulcer or granulation tissue
The following endpoint for the Geboes is to be considered at each relevant visit: 

Geboes Index Total Score:  Sum of the all the subgrades (i.e. Structural (architectural change) = 0.2 is a 
score of 2, Chronic inflammatory infiltrate = 1.1 is scored as a 1 etc.).

Robarts Histology Index (RHI)
The RHI will be provided by Robarts as an additional tool to measure histologic disease activity. 
The RHI Score is a continuous score, ranging from 0-33 with higher scores indicating more severe disease.
For the frequency table of RHI Score the following cut-points will be used: 

Remission: Score <=6, 

Low: Scores >6-<12, 

Moderate/Severe Score: > = 12
Modified Riley Scale
The Modified Riley Scale (MRS) is a 4-point scale (none, mild, moderate and severe) which scores histologic 
activity based on localization and quantification of neutrophils in the mucosa. A single modified riley scale score is 
collected at each relevant visit.  
Activity 
Histological Characteristics
None 
0
Normal biopsy or inactive colitis
Mild
1 
Lamina propria neutrophils only = Scattered 
individual neutrophils
2 
Lamina propria neutrophils only = Patchy 
collections of neutrophils
3 
Lamina propria neutrophils only = Diffuse 
neutrophils infiltrate
Moderate
4 
Cryptitis/crypt abscesses = <25% crypts involved
5 
Cryptitis/crypt abscesses = 25%- 74% crypts 
involved
6 
Cryptitis/crypt abscesses = >=75% crypts 
involved
Severe
7
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Clinical Efficacy
Faecal Calprotectin (FCP)
FCP, a protein biomarker, is measured from the faecal samples. The raw FCP data is highly variable and 
therefore data should be log-transformed before a change from baseline is calculated. 
For the frequency table of FCP categories the following cut-points will be used: 

<250, 

>= 250 and 

>=1000.
C-Reactive Protein (CRP)
CRP will be provided as a clinical chemistry parameter in the Clinical Laboratory dataset.
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ is a 32-item Inflammatory Bowel Disease-specific health related quality of life instrument evaluating 
general activities of daily living, intestinal function, social performance, personal interactions, and emotional 
status. Each item is presented on seven-point scale with higher representing better functioning. 
The IBDQ items are grouped into four domains with a total score for each being calculated as follows:

Bowel symptoms (10 items): Sum items 1, 5, 9, 13, 17, 20, 22, 24, 26, 29

Systemic Symptoms (5 items): Sum items 2, 6, 10, 14, 18.

Emotional Function (12 items): Sum items 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32

Social Function (5 items): Sum items 4, 8, 12, 16 and 28
The IBDQ Total Score is calculated as follows:

IBDQ Total Score:  Sum of all 32-items. 
Subject Symptom Diary Cards
Participants will be given a diary card at each visit. The number of stools, stool frequency score and rectal 
Bleeding Score will be transcribed into the eCRF for the 5 days prior to the following visits: Screening, Day 15, 
Day 29, Day 43, Day 85 and EW. 
The stool frequency score is on a 4-point scale as follows: 

0 = Normal

1 = 1-2 stools/day more than normal

2 = 3-4 stools/day more than normal

3 = >=4 stools/day more than normal 
The rectal bleeding score is on a 4-point scale as follows: 

0 = No blood seen

1 = Streaks of blood with stool less than half the time

2 = Obvious blood with stool most of the time 
 
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Clinical Efficacy

3 = Blood alone passed.
The average score and maximum score be considered for both stool frequency and rectal bleeding over the 5 
days prior to at each visit: 

Average Score: [Sum of scores over 5 prior days] / [number of prior days with a score available] 

Maximum Score: Maximum (i.e. highest) score collected over 5 prior days. 
The average score will be considered for number of stools over the 5 days prior to at each visit: 

Average Score: [Sum of number of stools over 5 prior days] / [number of prior days with a stool data 
available] 
12.6.5.
Biomarker
TEAR
Target Engagement

Ratio = free / total

Target Engagement = 100 – (ratio post/ratio baseline) * 100))

BIOMARK dataset:
BICAT = TRIPK1 (total) or FRIPK1 (free) and BITESTCD = CONC 
 
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12.7.
Appendix 7: Reporting Standards for Missing Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion was defined as one who has completed all phases of the 
study including the follow-up visit. 

Withdrawn participants may be replaced in the study at the discretion of the 
investigator.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
12.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:

These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:

Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.

Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will be used for 
the month

If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

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12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
µmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
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12.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
≤ 479 
≥ 480 
≤ 499
≥ 500 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 30 
<60
msec
≥60 
12.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
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12.9.
Appendix 9: Abbreviations & Trade Marks
12.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
AIC
Akaike's Information Criteria
BID
Twice a day
CI
Confidence Interval
CRF
Case Report Form
CRP
C-Reactive Protein
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DB
Double-Blind
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
DRC
Data Review Committee
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FCP
Faecal Calprotectin
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GEE
Generalised Estimating Equations
GSK
GlaxoSmithKline
IA
Interim Analysis
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
IRTS
Interactive Response Technology System
ITT
Intent-To-Treat
Kg
Kilogram
mmol
Millimole
MMRM
Mixed Model Repeated Measures
MRS
Modified Riley Scale
NR
Normal Range
OL
Open-Label
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PopPK
Population PK
PP
Per Protocol
 
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Abbreviation
Description
PP
Per Protocol
PSRAE
Possible Suicidality-Related Adverse Event
PT
Preferred Term
QC
Quality Control
QTcB
Bazett’s QT Interval Corrected for Heart Rate
QTcF
Frederica’s QT Interval Corrected for Heart Rate
RAMOS
Randomization & Medication Ordering System 
RAP
Reporting & Analysis Plan
RHI
Robarts Histology Index
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SE
Standard Error
SOC
System Organ Class
SOP
Standard Operation Procedure
SRT 
Safety Review Team
TA
Therapeutic Area
TEAR1
Target Engagement Assay RIP1
TFL
Tables, Figures & Listings 
TID
Three times a day
UC
Ulcerative Colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
ULN
Upper Limit of Normal
12.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
RandALL
MedDRA
NONMEM
SAS
 
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12.10.
Appendix 10: List of Data Displays
12.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.16
NA
Efficacy
2.1 to 2.41
2.1 to 2.44
Safety
3.1 to 3.56
3.1 to 3.7
Pharmacokinetic
4.1 
4.1 to 4.28
Pharmacodynamic and / or Biomarker
6.1 to 6.11
6.1 to 6.19
Section
Listings
ICH Listings
1 to 42
Other Listings
43 to 83
12.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.10.3.
Deliverables
Delivery [Priority] [1]
Description
IA SAC [X]
Interim Analysis Statistical Analysis Complete
SAC [X]
Final Statistical Analysis Complete
SAC2 [X]
Post-Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
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12.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record by Randomised Treatment 
ICH E3, FDAAA, EudraCT
Footnote: Add footnote : Note: 
“Subjects” is used to refer to 
“Participants” in all data displays to 
reflect GSK Display Standards
IA SAC[1],
SAC [1]
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
1.3.
All Subjects
ES6
Summary of Screening Status and Reasons for Screen Failure
by Randomised Treatment
Journal Requirements
IA SAC [1], 
SAC [1]
1.4.
All Subjects
NS1
Summary of Number of Subjects by Country and Site ID by 
Randomised Treatment
EudraCT/Clinical Operations
IA SAC [1], 
SAC [1]
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations by Randomised 
Treatment
ICH E3
IA SAC [1], 
SAC [1]
Population Analysed
1.6.
Safety
SP1
Summary of Study Populations by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
1.7.
Safety
SP2 / 
SP2A
Summary of Exclusions from the PP and PP + Completers
Population
IDSL
IA SAC [1], 
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.8.
Safety
DM1 
Summary of Demographic Characteristics by Randomised 
Treatment
ICH E3, FDAAA, EudraCT
If height and weight are collected 
only at baseline, then display in this 
demographic summary. Otherwise 
display height and weight with the 
vital signs data. 
IA SAC [1], 
SAC [1]
1.9.
All Subjects
DM11
Summary of Age Ranges by Randomised Treatment
EudraCT
IA SAC [1], 
SAC [1]
1.10.
Safety
DM5
Summary of Race and Racial Combinations by Randomised 
Treatment
ICH E3, FDA, FDAAA, EudraCT
IA SAC [1], 
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
Safety
DM1
Summary of Ulcerative Colitis Baseline Characteristics by 
Randomised Treatment
To include:
Baseline Mucosal Appearance at 
Endoscopy Mayo Subscore, Baseline 
Total Mayo Score,
Baseline Partial Mayo Score Baseline 
3-domain Mayo Score, Baseline UCEIS 
Total Score, Baseline Modified Riley 
Scale Score,
Baseline FCP, 
Baseline FCP category, 
Baseline Concomitant Medications for 
UC (Glucocorticoids only, 
Immunosuppressants only, 
Glucocorticoids and 
Immunosuppressants, No 
Glucocorticoids or 
Immunosuppressants, 
Baseline Prednisone dose,
Family History of Premature Coronary 
Artery Disease and History of Tobacco 
Use.
Include the footnote:
Note: Glucocorticoids and 
Immunosuppressants were identified by 
review of all ingredients by clinical and 
medical team.
IA SAC[1],
SAC [1]
Prior/Current Medical Conditions and Concomitant Medications
1.12.
Safety
MH4
Summary of Current/Past Medical Conditions by Randomised 
Treatment
ICH E3 
Separate summaries for Current & 
Past conditions, if collected.
IA SAC [1], 
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.13.
Safety
MH1 
Summary of Current/Past Cardiovascular Risk Factors by 
Randomised Treatment
ICH E3
Separate summaries for Current & 
Past, if collected
IA SAC [1], 
SAC [1]
1.14.
Safety
CM1
Summary of Prior Medications by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
1.15.
Safety
CM1
Summary of Concomitant Medications by Randomised 
Treatment
ICH E3
IA SAC [1], 
SAC [1]
Exposure and Treatment Compliance
1.16.
Safety
EX1 / 
EX5
Summary of Exposure to Study Treatment by Randomised 
Treatment
ICH E3
IA SAC [1], 
SAC [1]
12.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Part A only) by 
Randomised Treatment
ICH E3
Include total column across all 
intensities
IA SAC [1], 
SAC [1]
3.2.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Parts A, B and 
Follow-up) by Randomised Treatment
ICH E3
Include total column across all 
intensities
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Parts A, B and 
Follow-up) by Period Treatment
ICH E3
Include total column across all 
intensities
IA SAC[1], 
SAC [1]
3.4.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term (Part A only) by Randomised Treatment
IA SAC[1],
SAC [1]
3.5.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term (Parts A, B and Follow-up) by Randomised 
Treatment
IA SAC[1],
SAC [1]
3.6.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term (Parts A, B and Follow-up) by Period Treatment
IA SAC[1],
SAC [1]
3.7.
Safety
AE3
Summary of Common (>=10%) Adverse Events by Overall 
Frequency (Part A only) by Randomised Treatment
ICH E3
Common defined as >= 10% within 
either randomised treatment group
IA SAC [1], 
SAC [1]
3.8.
Safety
AE3
Summary of Common (>=10%) Adverse Events by Overall 
Frequency (Parts A, B and Follow-up) by Randomised 
Treatment
ICH E3
Common defined as >= 10% within 
either randomised treatment group
IA SAC[1], 
SAC [1]
3.9.
Safety
AE3
Summary of Common (>=10%) Adverse Events by Overall 
Frequency (Parts A, B and Follow-up) by Period Treatment
ICH E3
Common defined as >= 10% within 
either randomised treatment group
IA SAC[1], 
SAC [1]
3.10.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity and System Organ Class and Preferred Term (Part A 
only) by Randomised Treatment
ICH E3
Include total column across all 
intensities
IA SAC [1], 
SAC [1]
3.11.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity and System Organ Class and Preferred Term (Parts A, 
B and Follow-up) by Randomised Treatment
ICH E3
Include total column across all 
intensities
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.12.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity and System Organ Class and Preferred Term (Parts A,
B and Follow-up) by Period Treatment
ICH E3
Include total column across all 
intensities
IA SAC [1], 
SAC [1]
3.13.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) (Part A only) by Randomised Treatment
FDAAA, EudraCT
IA SAC [1], 
SAC [1]
3.14.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) (Parts A, B and Follow-up) by Randomised 
Treatment
FDAAA, EudraCT
IA SAC [1], 
SAC [1]
3.15.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) (Parts A, B and Follow-up) by Period 
Treatment
FDAAA, EudraCT
IA SAC [1], 
SAC [1]
3.16.
Safety
AE3
Summary of Common (>=10%) Drug-Related Adverse Events 
by Overall Frequency (Part A only) by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.17.
Safety
AE3
Summary of Common (>=10%) Drug-Related Adverse Events 
by Overall Frequency (Parts A, B and Follow-up) by 
Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.18.
Safety
AE3
Summary of Common (>=10%) Drug-Related Adverse Events 
by Overall Frequency (Parts A, B and Follow-up) by Period 
Treatment
ICH E3
IA SAC [1], 
SAC [1]
Serious and Other Significant Adverse Events
3.19.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
(Part A only) by Randomised Treatment
FDAAA, EudraCT
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.20.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
(Parts A, B and Follow-up) by Randomised Treatment
FDAAA, EudraCT
IA SAC [1],
SAC [1]
3.21.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
(Parts A, B and Follow-up) by Period Treatment
FDAAA, EudraCT
IA SAC [1], 
SAC [1]
3.22.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
(Part A only) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.23.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study
(Parts A, B and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.24.
Safety
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study
(Parts A, B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
Laboratory: Chemistry 
3.25.
Safety
LB1
Summary of Chemistry Changes from Baseline (Parts A, B and 
Follow-up) by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.26.
Safety
LB1
Summary of Chemistry Changes from Period Baseline (Parts A, 
B and Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.27.
Safety 
LB1
Summary of Lipids Percentage Changes from Baseline (Parts A, 
B and Follow-up) by Randomised Treatment
Lipids parameters = LDL 
Cholesterol, HDL Cholesterol, Total 
Cholesterol, Triglycerides and 
Cholesterol/HDL ratio
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.28.
Safety 
LB1
Summary of Lipids Percentage Changes from Period Baseline 
(Parts A, B and Follow-up) by Period Treatment
Lipids parameters = LDL 
Cholesterol, HDL Cholesterol, Total 
Cholesterol Triglycerides and 
Cholesterol/HDL ratio
IA SAC[1],
SAC [1]
3.29.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline (Parts A, B and Follow-up) by 
Randomised Treatment
ICH E3 (i.e. treatment emergent)
IA SAC [1], 
SAC [1]
3.30.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Period Baseline (Parts A, B and 
Follow-up) by Period Treatment
ICH E3 (i.e. treatment emergent)
IA SAC [1], 
SAC [1]
3.31.
Safety
LB17
Summary of Worst Case Lipids Results by NR Criteria Post-
Baseline Relative to Baseline (Parts A, B and Follow-up) by 
Randomised Treatment
Lipids parameters = LDL 
Cholesterol, HDL Cholesterol, Total 
CholesterolTriglycerides and 
Cholesterol/HDL ratio
IA SAC [1], 
SAC [1]
3.32.
Safety
LB17
Summary of Worst Case Lipids Results by NR Criteria Post-
Baseline Relative to Period Baseline (Parts A, B and Follow-up) 
by Period Treatment
Lipids parameters = LDL 
Cholesterol, HDL Cholesterol, Total 
Cholesterol, Triglycerides and 
Cholesterol/HDL ratio
IA SAC [1], 
SAC [1]
Laboratory: Hematology
3.33.
Safety
LB1
Summary of Hematology Changes from Baseline (Parts A, B 
and Follow-up) by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.34.
Safety
LB1
Summary of Hematology Changes from Period Baseline (Parts 
A, B and Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.35.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline (Parts A, B and Follow-up) by 
Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.36.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Period Baseline (Parts A, B and 
Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
Laboratory: Urinalysis
3.37.
Safety
LB1
Summary of Urine Concentration Changes from Baseline (Parts 
A, B and Follow-up) by Randomised Treatment 
ICH E3
IA SAC [1], 
SAC [1]
3.38.
Safety
LB1
Summary of Urine Concentration Changes from Period Baseline 
(Parts A, B and Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.39.
Safety
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline (Parts A, 
B and Follow-up) by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.40.
Safety
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Period Baseline 
(Parts A, B and Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
Laboratory: Hepatobiliary (Liver)
3.41.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting (Parts A, 
B and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.42.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting (Parts A, 
B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
3.43.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (Parts A, B 
and Follow-up) by Randomised Treatment
IDSL
IASAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.44.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (Parts A, B 
and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
ECGs
3.45.
Safety
EG1
Summary of ECG Findings (Parts A, B and Follow-up) by 
Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.46.
Safety
EG1
Summary of ECG Findings (Parts A, B and Follow-up) by Period 
Treatment
IDSL
IA SAC [1], 
SAC [1]
3.47.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category (Parts A, B and Follow-up) by 
Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.48.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Screening by Category (Parts A, B and Follow-up) by 
Randomised Treatment
Change relative to average of 
screening triplicates
SAC[1]
3.49.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Period Baseline by Category (Parts A, B and Follow-up) by 
Period Treatment
IDSL
IA SAC [1], 
SAC [1]
3.50.
Safety
EG2
Summary of Change from Baseline in ECG Values (Parts A, B 
and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.51.
Safety
EG2
Summary of Change from Screening in ECG Values (Parts A, B 
and Follow-up) by Randomised Treatment
Change relative to average of 
screening triplicates
SAC [1]
3.52.
Safety
EG2
Summary of Change from Period Baseline in ECG Values (Parts 
A, B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
3.53.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category (Parts A, B and Follow-up) by 
Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.54.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Screening by Category (Parts A, B and Follow-up) by 
Randomised Treatment
Change relative to average of 
screening triplicates
SAC [1]
3.55.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Period Baseline by Category (Parts A, B and Follow-
up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
Vital Signs
3.56.
Safety
VS1
Summary of Change from Baseline in Vital Signs (Parts A, B 
and Follow-up) by Randomised Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.57.
Safety
VS1
Summary of Change from Period Baseline in Vital Signs (Parts 
A, B and Follow-up) by Period Treatment
ICH E3
IA SAC [1], 
SAC [1]
3.58.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline (Parts A, B and Follow-up) by 
Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.59.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Period Baseline (Parts A, B and 
Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
 
 
 
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12.10.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk
(Part A only) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.2.
Safety
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk 
(Parts A, B and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.3.
Safety
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk 
(Parts A, B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
Laboratory
3.4.
Safety
LIVER14
Scatter Plot of Maximum Versus Baseline for ALT (Parts A, B 
and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.5.
Safety
LIVER14
Scatter Plot of Maximum Versus Period Baseline for ALT (Parts 
A, B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
3.6.
Safety
LIVER9
Scatter Plot of Maximum ALT Versus Maximum Total Bilirubin 
ALT (Parts A, B and Follow-up) by Randomised Treatment
IDSL
IA SAC [1], 
SAC [1]
3.7.
Safety
LIVER9
Scatter Plot of Maximum ALT Versus Maximum Total Bilirubin 
(Parts A, B and Follow-up) by Period Treatment
IDSL
IA SAC [1], 
SAC [1]
 
 
 
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12.10.7.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Mayo – Endoscopy Response
2.1.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in
Mucosal Appearance at Endoscopy Mayo Subscore (Parts A
and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.2.
Safety
EFF_T2b
Frequency Table of Mucosal Appearance at Endoscopy Mayo 
Subscore (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.3.
Safety
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Endoscopy Remission (Parts A and B) by Randomised 
Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.4.
PP
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Mucosal Appearance at Endoscopy Mayo Subscore (Parts A 
and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.5.
PP
EFF_T2b
Frequency Table of Mucosal Appearance at Endoscopy Mayo 
Subscore (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.6.
PP
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Endoscopy Remission (Parts A and B) by Randomised 
Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.7.
PP + 
Completers
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Mucosal Appearance at Endoscopy Mayo Subscore (Parts A 
and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.8.
PP + 
Completers
EFF_T2b
Frequency Table of Mucosal Appearance at Endoscopy Mayo 
Subscore (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.9.
PP + 
Completers
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Endoscopy Remission (Parts A and B) by Randomised 
Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
Mayo – Clinical Response and Remission
2.10.
Safety
EFF_T2a
Frequency Table of Subjects Achieving Mayo Clinical Response, 
3-domain Clinical Response, Mayo Clinical Remission and 3-
Domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.11.
Safety
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Clinical Response, 3-domain Mayo Clinical Response, Mayo 
Clinical Remission and 3-domain Mayo Clinical Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.12.
PP
EFF_T2a
Frequency Table of Subjects Achieving Mayo Clinical Response, 
3-domain Clinical Response, Mayo Clinical Remission and 3-
Domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.13.
PP
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Clinical Response, 3-domain Mayo Clinical Response, Mayo 
Clinical Remission and 3-domain Mayo Clinical Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.14.
PP + 
Completers
EFF_T2a
Frequency Table of Subjects Achieving Mayo Clinical Response, 
3-domain Clinical Response, Mayo Clinical Remission and 3-
Domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.15.
PP + 
Completers
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving Mayo 
Clinical Response, 3-domain Mayo Clinical Response, Mayo 
Clinical Remission and 3-domain Mayo Clinical Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
Mayo – Symptomatic Clinical Remission  
2.16.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Total, Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.17.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in Total, 
Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.18.
PP
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Total, Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.19.
PP
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in Total, 
Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.20.
PP + 
Completers
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Total, Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.21.
PP + 
Completers
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in Total, 
Partial and 3-domain Mayo Scores (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
UCEIS – Mucosal Healing 
2.22.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
UCEIS Total Score (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in UCEIS 
Total Score (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
UCEIS – Remission 
2.24.
Safety
EFF_T2a
Frequency Table of Subjects Achieving UCEIS Remission (Parts 
A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.25.
Safety
EFF_T3
GEE Point Estimate and 95% CI for Subjects Achieving UCEIS 
Remission (Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
Biomarkers of Disease Activity
2.26.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in CRP 
(Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.27.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in CRP 
(Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.28.
Safety
EFF_T2b
Frequency Table of FCP Categories (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.29.
Safety
EFF_T1
Summary Statistics for Actual and Log-Transformed Change 
from Baseline in FCP (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.30.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Log-transformed Change from 
Baseline in FCP (Parts A and B) by Randomised Treatment
Include related estimated adjusted 
geometric means and treatment 
differences
IA SAC [1], 
SAC [1]
Histologic Disease Activity
2.31.
Safety
EFF_T2b
Frequency Table of Modified Riley Scale Categories (Parts A 
and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.32.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Modified Riley Scale Score (Parts A and B) by Randomised 
Treatment
IA SAC [1], 
SAC [1]
2.33.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in 
Modified Riley Scale Score (Parts A and B) by Randomised 
Treatment
IA SAC [1], 
SAC [1]
2.34.
Safety
EFF_T2b
Frequency Table of RHI Categories (Parts A and B) by 
Randomised Treatment
IA SAC [1], 
SAC [1]
2.35.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in RHI 
Score (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.36.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in RHI 
Score (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.37.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
Geboes Index Total Score (Parts A and B) by Randomised 
Treatment
IA SAC [1], 
SAC [1]
2.38.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in 
Geboes Index Total Score (Parts A and B) by Randomised 
Treatment
IA SAC [1], 
SAC [1]
Quality of Life
2.39.
Safety
EFF_T1
Summary Statistics for Actual and Change from Baseline in 
IBDQ Domain Scores and Total Score (Parts A and B) by 
Randomised Treatment 
SAC [1]
2.40.
Safety
EFF_T4
Adjusted Mean (95% CI) of the Change from Baseline in IBDQ 
Total Score (Parts A and B) by Randomised Treatment
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Symptom Diary Cards
2.41.
Safety
EFF_T1
Summary Statistics of Average and Maximum Stool Frequency 
Score over 5 days from Subject Symptom Diary (Parts A and B) 
by Randomised Treatment
Include Average and Maximum 
Stool Frequency Score, Average 
and Maximum Rectal Bleeding 
Score and Average Number of 
Stools.
SAC [1]
12.10.8.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Mayo
2
Safety
EFF_F1
Individual Subject Profiles for Subjects Achieving Mayo 
Endoscopy Remission, Total Mayo Score, Partial Mayo Score, 
3-domain Mayo Score, Mayo Clinical Response, 3-domain Mayo 
Clinical Response, Mayo Clinical Remission and 3-domain 
Clinical Remission over Time (Parts A and B) by Randomised 
Treatment
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2
Safety
EFF_F4
Proportion of Subjects Achieving Mayo Endoscopy Remission 
and over Time (Parts A and B) by Randomised Treatment
Line graph with randomised 
treatment on the same plot
IA SAC [1], 
SAC [1]
2.3.
Safety
EFF_F3
Odds Ratio and 95% CI for Proportion of Subjects Achieving 
Mayo Endoscopy Remission (Parts A and B) by Randomised 
Treatment 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.4.
Safety
EFF_F4
Proportion of Subjects Mayo Clinical Response, 3-domain Mayo 
Clinical Response, Mayo Clinical Remission and 3-domain 
Clinical Remission over Time (Parts A and B) by Randomised 
Treatment  
Separate pages for each endpoint.
Line graph with randomised 
treatment on the same plot.
IA SAC [1], 
SAC [1]
2.5.
Safety
EFF_F3
Odds Ratio and 95% CI for Achieving Mayo Clinical Response, 
3-domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Clinical Remission over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint. 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.6.
Safety
EFF_F2
Mean (SE) Total, Partial and 3-domain Mayo Scores over Time 
(Parts A and B) by Randomised Treatment  
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.7.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in Total, 
Partial and 3-domain Mayo Scores over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint.
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.8.
PP
EFF_F1
Individual Subject Profiles for Subjects Achieving Mayo 
Endoscopy Remission, Total Mayo Score, Partial Mayo Score, 
3-domain Mayo Score, Mayo Clinical Response, 3-domain Mayo 
Clinical Response, Mayo Clinical Remission and 3-domain 
Clinical Remission over Time (Parts A and B) by Randomised 
Treatment
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.9.
PP
EFF_F4
Proportion of Subjects Achieving Mayo Endoscopy Remission 
and over Time (Parts A and B) by Randomised Treatment
Line graph with randomised 
treatment on the same plot
IA SAC [1], 
SAC [1]
2.10.
PP
EFF_F3
Odds Ratio and 95% CI for Proportion of Subjects Achieving 
Mayo Endoscopy Remission (Parts A and B) by Randomised 
Treatment 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.11.
PP
EFF_F4
Proportion of Subjects Mayo Clinical Response, 3-domain Mayo 
Separate pages for each endpoint.
IA SAC [1], 
 
 
 
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79
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Clinical Response, Mayo Clinical Remission and 3-domain 
Clinical Remission over Time (Parts A and B) by Randomised 
Treatment  
Line graph with randomised 
treatment on the same plot.
SAC [1]
2.12.
PP
EFF_F3
Odds Ratio and 95% CI for Achieving Mayo Clinical Response, 
3-domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Clinical Remission over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint. 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.13.
PP
EFF_F2
Mean (SE) Total, Partial and 3-domain Mayo Scores over Time 
(Parts A and B) by Randomised Treatment  
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.14.
PP
EFF_F3
Point Estimates and 95% CI of Change from Baseline in Total, 
Partial and 3-domain Mayo Scores over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint.
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.15.
PP + 
Completers
EFF_F1
Individual Subject Profiles for Subjects Achieving Mayo 
Endoscopy Remission, Total Mayo Score, Partial Mayo Score, 
3-domain Mayo Score, Mayo Clinical Response, Mayo Clinical 
Remission and 3-domain Clinical Remission over Time (Parts A 
and B) by Randomised Treatment
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.16.
PP + 
Completers
EFF_F4
Proportion of Subjects Achieving Mayo Endoscopy Remission 
and over Time (Parts A and B) by Randomised Treatment
Line graph with randomised 
treatment on the same plot
IA SAC [1], 
SAC [1]
2.17.
PP + 
Completers
EFF_F3
Odds Ratio and 95% CI for Proportion of Subjects Achieving 
Mayo Endoscopy Remission (Parts A and B) by Randomised 
Treatment 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.18.
PP + 
Completers
EFF_F4
Proportion of Subjects Mayo Clinical Response, 3-domain Mayo 
Clinical Response, Mayo Clinical Remission and 3-domain 
Clinical Remission over Time (Parts A and B) by Randomised 
Separate pages for each endpoint.
Line graph with randomised 
treatment on the same plot.
IA SAC [1], 
SAC [1]
 
 
 
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80
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment  
2.19.
PP + 
Completers
EFF_F3
Odds Ratio and 95% CI for Achieving Mayo Clinical Response, 
3-domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Clinical Remission over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint. 
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
2.20.
PP + 
Completers
EFF_F2
Mean (SE) Total, Partial and 3-domain Mayo Scores over Time 
(Parts A and B) by Randomised Treatment  
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.21.
PP + 
Completers
EFF_F3
Point Estimates and 95% CI of Change from Baseline in Total, 
Partial and 3-domain Mayo Scores over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint.
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
UCEIS
2.22.
Safety
EFF_F1
Individual Subject Profiles for UCEIS Total Score over Time
(Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.23.
Safety
EFF_F2
Mean (SE) UCEIS Total Score over Time (Parts A and B) by 
Randomised Treatment  
IA SAC [1], 
SAC [1]
2.24.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in UCEIS 
Total Score over Time (Parts A and B) by Randomised 
Treatment  
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.25.
Safety
EFF_F4
Proportion of Subjects Achieving UCEIS Clinical Remission over 
Time (Parts A and B) by Randomised Treatment  
Line graph with randomised 
treatment on the same plot.
IA SAC [1], 
SAC [1]
2.26.
Safety
EFF_F3
Odds Ratio and 95% CI for Achieving UCEIS Clinical Remission 
over Time (Parts A and B) by Randomised Treatment  
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one treatment 
group.
IA SAC [1], 
SAC [1]
 
 
 
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81
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers of Disease Activity 
2.27.
Safety
EFF_F1
Individual Subject Profiles for CRP and FCP over Time (Parts A 
and B) by Randomised Treatment
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.28.
Safety
EFF_F2
Mean (SE) CRP over Time (Parts A and B) by Randomised 
Treatment  
IA SAC [1], 
SAC [1]
2.29.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in CRP 
over Time (Parts A and B) by Randomised Treatment  
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.30.
Safety
EFF_F2
Mean (SE) FCP over Time (Parts A and B) by Randomised 
Treatment  
IA SAC [1], 
SAC [1]
2.31.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in log-
transformed FCP over Time (Parts A and B) by Randomised 
Treatment  
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
Histologic Disease Activity
2.32.
Safety
EFF_F1
Individual Subject Profiles for Modified Riley Scale Score over 
Time (Parts A and B) by Randomised Treatment
Separate pages for each endpoint. 
IA SAC [1], 
SAC [1]
2.33.
Safety
EFF_F2
Mean (SE) Modified Riley Scale Score over Time (Parts A and 
B) by Randomised Treatment  
Separate pages for each endpoint.
IA SAC [1], 
SAC [1]
2.34.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in 
Modified Riley Scale Score over Time (Parts A and B) by 
Randomised Treatment  
Separate pages for each endpoint.
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.35.
Safety
EFF_F1
Individual Subject Profiles for RHI Total Score over Time (Parts 
A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.36.
Safety
EFF_F2
Mean (SE) RHI Total Score over Time (Parts A and B) by 
Randomised Treatment  
IA SAC [1], 
SAC [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.37.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in RHI
Total Score over Time (Parts A and B) by Randomised 
Treatment  
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
2.38.
Safety
EFF_F1
Individual Subject Profiles for Geboes Index Total Score over 
Time (Parts A and B) by Randomised Treatment
IA SAC [1], 
SAC [1]
2.39.
Safety
EFF_F2
Mean (SE) Geboes Index Total Score over Time (Parts A and 
B) by Randomised Treatment  
IA SAC [1], 
SAC [1]
2.40.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in Geboes 
Index Total Score over Time (Parts A and B) by Randomised 
Treatment  
Grey dashed line at y=0. 
IA SAC [1], 
SAC [1]
Quality of Life
2.41.
Safety
EFF_F1
Individual Subject Profiles for IBDQ Total Score over Time 
(Parts A and B) by Randomised Treatment
Separate pages for each endpoint. 
SAC [1]
2.42.
Safety
EFF_F2
Mean (SE) IBDQ Total Score over Time (Parts A and B) by 
Randomised Treatment  
SAC [1]
2.43.
Safety
EFF_F3
Point Estimates and 95% CI of Change from Baseline in IBDQ 
Total Score over Time (Parts A and B) by Randomised 
Treatment  
Grey dashed line at y=0. 
SAC [1]
Responder Across Efficacy Endpoints
2.44.
Safety
EFF_F4
Individual Subject Profile Plot of Efficacy Endpoints over Time 
(Parts A and B) by Randomised Treatment
Separate pages for each Subject 
9 panel plot with a panel for: 
(order change following IA)
Top Row: Total Mayo Score, Partial 
Mayo Score, 3-domain Mayo Score
IA SAC [1]
SAC [1]
 
 
 
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83
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Middle Row: Mayo Endoscopy 
Remission, Mayo Rectal Bleed,
UCEIS Total Score,
Bottom Row: Geboes Index Total 
Score, FCP, CRP
12.10.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK concentration data 
4.1.
PK
PK01
Summary of GSK2982772 Concentration-Time Data (ng/mL)
Separate summaries for blood and 
biopsy tissue samples. 
Pre-dose: Day 43, Post-dose: Day 1 
and 43 at 1, 2, 4 and 6 hours.
IA SAC [1]
SAC [1]
Summary of GSK2982772 Predicted Trough Concentrations
(ng/mL)
Predicted trough Day 43
 
 
 
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12.10.10. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual PK Concentration
4.1.
Mean/Median Concentration
4.2.
PK
PKCF2
Mean (SE) Plot: GSK2982772 Concentrations versus Time
(Linear) on Day 1 and Day 43 (60 mg TID only)
IA SAC [1]
SAC [1]
4.3.
Trough Concentration 
4.4.
PK
GSK2982772 Observed pre-dose Concentration Data vs Day (60 
TID only)
Separate pages for plasma
Spaghetti Plot of individual trough 
concentrations vs day.
IA SAC [1]
SAC [1]
4.5.
PK
GSK2982772 Observed Pre-Dose Concentration Data vs Day
Plot of individual trough 
concentrations vs day overlaid 
with box and whisker plot.
IA SAC [1]
SAC [1]
4.6.
PK
PD_F1
Scatter Plot GSK2982772 Observed Pre-Dose Plasma
Concentration Versus Biopsy Pre-Dose Tissue Concentration
X axis – Plasma
Y axis – Biopsy
IA SAC [1]
SAC [1]
PK/PD
4.7.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Pre-Dose Concentrations
Versus Individual Pre-Dose % Target Engagement 
Separate pages sample type 
(Plasma/Biopsy)
X axis – PK concentration,
Y axis – TE
IA SAC [1]
SAC [1]
 
 
 
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202152
85
Pharmacokinetic: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.8.
PK
PD_F1
Box Plots of GSK2982772 Day 43 Predicted Trough 
Concentration for participants not achieving Mayo Endoscopy 
Remission and for participants achieving Mayo Endoscopy 
Remission 
Separate pages sample type 
(predicted trough /Biopsy)
X axis – Non Mayo Endoscopy 
Remission / Mayo Endoscopy 
Remission
Y axis – PK Conc
IA SAC [1]
SAC [1]
4.9.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in Total Mayo 
Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.10.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in Partial Mayo 
Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.11.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in 3-domain Mayo 
Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.12.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in UCEIS Total 
Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.13.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in Modified Riley 
Scale Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.14.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in RHI  
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.15.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in Geboes Index 
Total Score 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.16.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in CRP
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter
IA SAC [1]
SAC [1]
4.17.
PK
PD_F1
Scatter Plot of Individual GSK2982772 Predicted Trough 
Concentration Versus Change from Baseline in FCP
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
IA SAC [1]
SAC [1]
4.18.
PK
PD_F1
Scatter Plot of GSK2982772 Pre-Dose Concentration Versus 
Pre-Dose TEAR 1 % Target Engagement 
Separate pages sample type 
(Blood/Biopsy)
X axis – PK Trough 
concentration,
Y axis – TE
SAC [1]
 
 
 
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12.10.11. Pharmacodynamic and/or Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Biomarkers
6.1.
Safety
PD_T1
Summary Statistics for Actual and Percentage Change from 
Baseline in Biopsy Tissue Inflammatory Biomarkers (Parts A and 
B) 
One page for each cell 
type/measure by visit/time and 
treatment
SAC [1]
6.2.
Safety
PD_T2
Adjusted Mean (95% CI) of Percentage Change from Baseline in 
Biopsy Tissue Inflammatory Biomarkers (Parts A and B) 
One page for each cell 
type/measure by visit/time and 
treatment/dosing regimen
SAC [1]
Pathway and Target Engagement
6.3.
Safety
EFF_T1
Summary Statistics for Observed TEAR1 % Target Engagement 
(Parts A and B) 
Separate summaries for sample 
type (Blood/Biopsy)
% Target Engagement by visit/time
SAC [1]
6.4.
Summary Statistics for Predicted  TEAR1 % Target Engagement 
based on predicted GSK2982772 trough concentrations (Parts A 
and B)
6.5.
Safety
PD_T3
Adjusted Mean (95% CI) of TEAR1 % Target Engagement in 
Blood (Parts A and B) by Randomised Treatment
SAC [1]
6.6.
Safety
PD_T3
Adjusted Mean (95% CI) of TEAR1 % Target Engagement in 
Biopsy Tissue (Parts A and B) by Randomised Treatment
SAC [1]
6.7.
Safety
EFF_T1
Summary Statistics of Pathway Engagement (Parts A and B) by 
Randomised Treatment
Separate summaries for sample 
type (Blood/Biopsy)
SAC [1]
6.8.
Safety
PD_T3
Adjusted Mean (95% CI) of Pathway Engagement in Blood 
(Parts A and B) by Randomised Treatment
SAC [1]
6.9.
Safety
PD_T3
Adjusted Mean (95% CI) of Pathway Engagement in Biopsy 
Tissue (Parts A and B) by Randomised Treatment
SAC [1]
 
 
 
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
mRNA Expression 
6.10.
Safety
PD_T4
Summary of mRNA Expression of Inflammatory Gene 
Transcripts (Parts A and B) by Randomised Treatment
Separate summaries for sample 
type (Blood/Biopsy)
qPCR – micarray dataset
SAC2 [1]
6.11.
Safety
PD_T5
Frequency Table Summarising the Number of Probe Sets with 
Various Fold Change (Parts A and B) by Randomised Treatment
Separate summaries for sample 
type (Blood/Biopsy).
Use cut-offs 1.5 and -1.5 initially.  
Change to -1.25 and 1.5 if no one 
achieves the initial cut-offs
SAC2 [1]
6.12.
Safety
PD_T6
Summary of Adjusted Mean Fold Changes in mRNA Expression 
of Inflammatory Gene Transcripts (Parts A and B) by 
Randomised Treatment
Separate summaries for sample 
type (Blood/Biopsy).
If Adj Mean FC lies between -1 and 
1 then do not include on table
SAC2 [1]
6.13.
Safety
Summary of Analysis for Microaray mRNA Intensity Data in 
Blood  
GSK to produce 
Only to be produced for significant 
probsets based on adjusted p-values.
If Adj Mean FC lies between -1 and 1 
then do not include on table
SAC2 [1]
6.14.
Safety
Summary of mRNA Percentage Inhibition of Inflammatory 
Gene Transcripts in Blood 
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
SAC2 [1]
 
 
 
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.15.
Safety
Summary of Analysis for Microaray mRNA Percentage Inhibition 
Data in Blood  
GSK to produce 
Only to be produced for significant 
probsets based on adjusted p-values.
If Adj Mean FC lies between -1 and 1 
then do not include on table
SAC2 [1]
 
 
 
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90
12.10.12. Pharmacodynamic and/or Biomarker Figures
Pharmacodynamic and or Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Biomarkers
6.1.
Safety
EFF_F1
Individual Subject Profiles for Biopsy Tissue Inflammatory 
Biomarkers over Time (Parts A and B) by Randomised 
Treatment
Separate pages for each endpoint.
SAC [1]
6.2.
Safety
EFF_F3
Point Estimates and 95% CI for Percentage Change from 
Baseline in Biopsy Tissue Inflammatory Biomarkers over Time 
(Parts A and B) by Randomised Treatment
SAC [1]
Pathway and Target Engagement
6.3.
Safety
EFF_F1
Individual Subject Profiles for TEAR1 % Target Engagement 
(Parts A and B) by Randomised Treatment
Separate pages sample type 
(Blood/Biopsy)
Panel plot, line colours by treatment 
group, subjid as cell header
SAC [1]
6.4.
Safety
EFF_F3
Point Estimates and (95% CI) TEAR1 % Target Engagement in 
Blood (Parts A and B) by Randomised Treatment
SAC [1]
6.5.
Safety
EFF_F3
Point Estimates and (95% CI) TEAR1 % Target Engagement in 
Biopsy Tissue (Parts A and B) by Randomised Treatment
SAC [1]
6.6.
Safety
PD_F1
Scatter Plot of TEAR 1 % Target Engagement in Blood Versus 
TEAR1 % Target Engagement in Biopsy Tissue by Randomised 
Treatment 
SAC [1]
 
 
 
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91
Pharmacodynamic and or Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.7.
PK
PD_F1
Scatter Plot of TEAR 1 % Target Engagement 
Versus Proportion Achieving Mayo Endoscopy Remission 
Randomised Treatment
Separate pages sample type 
(Blood/Biopsy)
X axis – PK concentration,
Y axis – Efficacy Parameter 
SAC2 [1]
6.8.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in Total Mayo Score by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type (blood/ 
Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.9.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in Partial Mayo Score by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type (blood/ 
Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.10.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in 3-domain Mayo Score by Randomised 
Treatment
Separate pages for each biomarker 
parameter and sample type (blood/ 
Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
 
 
 
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92
Pharmacodynamic and or Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.11.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in UCEIS Total Score by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type (blood/ 
Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.12.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in Modified Riley Scale Score by Randomised 
Treatment
Separate pages for each biomarker 
parameter and sample type (blood/ 
Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.13.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in RHI by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type 
(blood/Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
 
 
 
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93
Pharmacodynamic and or Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.14.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in Geboes Index Total Score by Randomised 
Treatment
Separate pages for each biomarker 
parameter and sample type 
(blood/Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.15.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in CRP by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type 
(blood/Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
6.16.
Safety
PD_F1
Scatter Plot of TEAR1 % Target Engagement Versus Change 
from Baseline in FCP by Randomised Treatment
Separate pages for each biomarker 
parameter and sample type 
(blood/Biopsy)
X axis – Target Engagement,
Y axis – Efficacy Parameter 
Different markers for each 
randomised treatment group
SAC2 [1]
mRNA Expression
6.17.
Safety
EFF_F1
Individual Subject Profiles for mRNA Expression of Inflammatory 
Gene Transcripts (Parts A and B) by Randomised Treatment
Separate pages for each gene and 
sample type (blood/Biopsy).
SAC2 [1]
 
 
 
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94
Pharmacodynamic and or Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.18.
Safety
PD_F2
Adjusted Mean Intensities for mRNA Expression of Inflammatory 
Gene Transcripts (Parts A and B) by Randomised Treatment
Separate pages for each gene and 
sample type (blood/biopsy). 
. 
SAC2 [1]
6.19.
Safety
PD_F3
Adjusted Mean (95% CI) Fold Change in mRNA Expression of 
Inflammatory Gene Transcripts (Parts A and B) by Randomised 
Treatment
Separate pages for each gene and 
sample type (blood/biopsy). 
Include band from FC -1 to 1, 
transparency 0.5
SAC2 [1]
 
 
 
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12.10.13. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All Subjects
ES7
Listing of Reasons for Screen Failure by Randomised Treatment
Journal Guidelines
IA SAC [1]
SAC [1]
2.
Safety
ES2 
Listing of Reasons for Study Withdrawal by Randomised 
Treatment
ICH E3
IA SAC [1]
SAC [1]
3.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation by 
Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]1]
4.
Safety
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken 
During the Study by Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]
5.
Safety
TA1 
Listing of Planned and Actual Treatments
IDSL
IA SAC [1]
SAC [1] [1]
Protocol Deviations
6.
Safety
DV2
Listing of Important Protocol Deviations by Randomised 
Treatment
ICH E3
IA SAC [1]
SAC [1]
7.
Safety
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
by Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]1]
Populations Analysed
8.
Safety
SP3
Listing of Subjects Excluded from Any Population by 
Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
9.
Safety
DM2 / DM4
Listing of Demographic Characteristics by Randomised 
Treatment
ICH E3
IA SAC [1]
SAC [1]
10.
Safety
DM9 / DM10
Listing of Race by Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
11.
Safety
DM2
Listing of Ulcerative Colitis Baseline Characteristics by 
Randomised Treatment
To include:
Baseline Mucosal Appearance at 
Endoscopy Mayo Subscore, Baseline 
Total Mayo Score, 
Baseline Partial Mayo Score Baseline 
3-domain Mayo Score, Baseline UCEIS 
Total Score, Baseline Modified Riley 
Scale Score 
Baseline FCP, 
Baseline FCP category, 
Baseline Concomitant Medications for 
UC (Glucocorticoids only, 
Immunosuppressants only, 
Glucocorticoids and 
Immunosuppressants, No 
Glucocorticoids or 
Immunosuppressants, 
Baseline Prednisone dose,
Family History of Premature Coronary 
Artery Disease and History of Tobacco 
Use.
Include the footnote:
Note: Glucocorticoids and 
Immunosuppressants were identified by 
review of all ingredients by clinical and 
medical team.
IA SAC [1]
SAC [1]
Prior, Current and Concomitant Medications
12.
Safety
MH2
Listing of Medical Conditions by Randomised Treatment
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
13.
Safety
CP_CM3 
Listing of Concomitant Medications by Randomised Treatment
IDSL
IA SAC [1]
SAC [1]
Exposure and Treatment Compliance
14.
Safety
EX3 / EX4
Listing of Exposure Data by Randomised Treatment
ICH E3
IA SAC [1]
SAC [1]
15.
Safety 
COMP3A/ 
COMP3B
Listing of Drug Accountability Data by Randomised Treatment
IA SAC [1]
SAC [1]
Adverse Events
16.
Safety
AE9CP
Listing of All Adverse Events by Period Treatment
ICH E3
IA SAC [1]
SAC [1]
17.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events by 
Period Treatment
ICH E3
IA SAC [1]
SAC [1]1]
18.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
IA SAC [1]
SAC [1]]
Serious and Other Significant Adverse Events
19.
Safety
AE9CPa
Listing of Fatal Serious Adverse Events by Period Treatment
ICH E3
IA SAC [1]
SAC [1]
20.
Safety
AE9CPa
Listing of Non-Fatal Serious Adverse Events by Period 
Treatment
ICH E3
IA SAC [1]
SAC [1]
21.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
by Period Treatment 
ICH E3
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
22.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Period 
Treatment
ICH E3
IA SAC [1]
SAC [1]
23.
Safety
AE9CP
Listing of Other Significant Adverse Events by Period Treatment
ICH E3
IA SAC [1]
SAC [1] [1]
24.
Safety
PSRAE1
Listing of Possible Suicidality-Related Adverse Event Data: 
Event and Description (Section 1- Section 2) by Period 
Treatment
IDSL
IA SAC [1]
SAC [1]
25.
Safety
PSRAE2
Listing of Possible Suicidality-Related Adverse Event Data: 
Event and Description (Sections 1- Section 2) by Period 
Treatment
IDSL
IA SAC [1]
SAC [1]1]
26.
Safety
PSRAE3
Listing of Possible Suicidality-Related Adverse Event Data: 
Possible Cause(s) (Section 3) by Period Treatment
IDSL
IA SAC [1]
SAC [1]
27.
Safety
PSRAE4
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 4) by Period Treatment
IDSL
IA SAC [1]
SAC [1]1]
Hepatobiliary (Liver)
28.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events by Period Treatment
IDSL
IA SAC [1]
SAC [1]]
29.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events by Period Treatment
IDSL
IA SAC [1]
SAC [1] [1]
All Laboratory
30.
Safety
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance by Period Treatment
ICH E3
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
31.
Safety
LB5 
Listing of Laboratory Values of Potential Clinical Importance by 
Period Treatment
IA SAC [1]
SAC [1] [1]
32.
Safety
LB14
Listing of Laboratory Data with Character Results by Period 
Treatment
ICH E3
IA SAC [1]
SAC [1]]
33.
Safety
UR2A
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance by Period Treatment
ICH E3
IA SAC [1]
SAC [1]
34.
Safety
LB5 
Listing of Lipids Outside of the Normal Range by Period 
Treatment
Lipids parameters = LDL 
Cholesterol, HDL Cholesterol, Total 
Cholesterol Triglycerides and
Cholesterol/HDL ratio
Include fasted status
IA SAC [1]
SAC [1]
ECG
35.
Safety
EG3*
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance by Period Treatment (including 
manually corrected values)
IDSL EG3 plus extra columns for 
Manually Calculated QTcB and 
QTcF.  Highlighted provided QTc 
value
See 203168 Listing 89 for shell
Include absolute PCI subjects.
Footnote: H=High absolute, L= Low 
absolute.
* Provided QTc 
IA SAC [1]
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
36.
Safety
EG3*
Listing of All ECG Changes for Subjects with a Value of 
Potential Clinical Importance by Period Treatment (including 
manually corrected values)
Include change from baseline or 
change from screening PCI 
subjects. 
IDSL EG3 plus extra columns for 
Manually Calculated QTcB and 
QTcF.  Highlighted provided QTc 
value
Footnote:  H=High change from 
baseline value, L= Low change from 
baseline value
* Provided QTc
IA SAC [1]
SAC [1]
37.
Safety
EG3 
Listing of ECG Values of Potential Clinical Importance by Period 
Treatment (including manually corrected values)
"Include absolute PCIs. 
IDSL EG3 plus extra columns for 
Manually Calculated QTcB and 
QTcF.  Highlighted provided QTc 
value
Footnote: H=High absolute, L= Low 
absolute."
* Provided QTc
IA SAC [1]
SAC [1]]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
38.
Safety
EG3
Listing of ECG Changes of Potential Clinical Importance by 
Period Treatment (including manually corrected values)
"Include change from baseline 
PCIs. 
IDSL EG3 plus extra columns for 
Manually Calculated QTcB and 
QTcF.  Highlighted provided QTc 
value
Footnote: H=High change, L= Low 
change."
IA SAC [1]
SAC [1]
39.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding by Period Treatment
IDSL
IA SAC [1]
SAC [1]
40.
Safety
EG5 
Listing of Abnormal ECG Findings by Period Treatment
IDSL
IA SAC [1]
SAC [1]
Vital Signs
41.
Safety
VS4 / VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance by Period Treatment
IDSL
IA SAC [1]
SAC [1]
42.
Safety
VS4 / VS5
Listing of Vital Signs of Potential Clinical Importance by Period 
Treatment
IDSL
IA SAC [1]
SAC [1]
 
 
 
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12.10.14. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
CSSRS
43.
Safety
ECSSRS4
Listing of C-SSRS Suicidal Ideation and Behaviour Data by 
Period Treatment
IA SAC [1]
SAC [1]
44.
Safety
ECSSRS5
Listing of C-SSRS Suicidal Behaviour Details by Period 
Treatment
IA SAC [1]
SAC [1]
PK
45.
PK
PK07
Listing of GSK2982772 Pharmacokinetic Concentration-Time 
Data
Separate listings for Blood and 
Biopsy data
IA SAC [1]
SAC [1]
Efficacy
46.
Safety
LS2
Listing of Individual Mayo Subscores by Randomised 
Treatment
IA SAC [1]
SAC [1]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
47.
Safety
LS2
Listing of Mayo Data by Randomised Treatment
Actual and Change from Baseline 
in Total Mayo, Partial Mayo and 3-
domain Mayo Scores.
Proportion of Subjects Achieving 
Endoscopy Remission, Mayo 
Clinical Response, 3-domain Mayo 
Clinical Response, Mayo Clinical 
Remission and 3-domain Mayo 
Clinical Remission.
Add variables which determine if 
the subjects are in the PP and /or 
PP + Completers Population.
IA SAC [1]
SAC [1]
48.
Safety
LS2
Listing of Individual UCEIS Scores by Randomised Treatment
IA SAC [1]
SAC [1]
49.
Safety
LS2
Listing of UCEIS Data by Randomised Treatment
Actual and Change from Baseline 
in UCEIS Total Score 
Proportion of Subjects Achieving 
UCEIS Remission 
IA SAC [1]
SAC [1]
50.
Safety
LS2
Listing of Actual and Change from Baseline in CRP by 
Randomised Treatment
IA SAC [1]
SAC [1]
51.
Safety
LS2
Listing of Actual and Log-transformed Change from Baseline in 
FCP by Randomised Treatment
IA SAC [1]
SAC [1]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
52.
Safety
LS2
Listing of Actual and Change from Baseline in Modified Riley 
Scale Score by Randomised Treatment
IA SAC [1]
SAC [1]
53.
Safety 
LS2
Listing of Actual and Change from Baseline in RHI Score by
Randomised Treatment
IA SAC [1]
SAC [1]
54.
Safety 
LS2
Listing of Actual and Change from Baseline in Geboes Index 
Total Score by Randomised Treatment
IA SAC [1]
SAC [1]
55.
Safety 
LS2
Listing of Actual and Change from Baseline in IBDQ Domains 
and Total Score by Randomised Treatment
SAC [1]
56.
Safety
EFF_L1
Listing of Subject Symptom Diary Card Data by Randomised 
Treatment
Use the decodes specified in RAP 
Section 12.6.4 and not codelist 
defined in FCEORS.
SAC [1]
57.
Safety
n/a
Raw SAS output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Endoscopic Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
58.
PP
n/a
Raw SAS output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Endoscopic Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
59.
PP + 
Completers
n/a
Raw SAS output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Endoscopic Remission 
(Parts A and B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
 
 
 
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106
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
60.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Clinical Response. 3-
domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
61.
PP
n/a
Raw SAS Output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Clinical Response. 3-
domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
62.
PP + 
Completers
n/a
Raw SAS Output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving Mayo Clinical Response. 3-
domain Mayo Clinical Response, Mayo Clinical Remission and 
3-domain Mayo Clinical Remission (Parts A and B) by 
Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]
63.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Total, Partial and 3-
domain Mayo Scores (Parts A and B) by Randomised 
Treatment
IA SAC [1]
SAC [1]
64.
PP
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Total, Partial and 3-
domain Mayo Scores (Parts A and B) by Randomised 
Treatment
IA SAC [1]
SAC [1]
65.
PP + 
Completers
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Total, Partial and 3-
domain Mayo Scores (Parts A and B) by Randomised 
Treatment
IA SAC [1]
SAC [1]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
66.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in UCEIS Total Score 
(Parts A and B) by Randomised Treatment
IA SAC [1]
SAC [1]
67.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for GEE 
Analysis for Subjects Achieving UCEIS Remission (Parts A and 
B) by Randomised Treatment
GEE modelling will only be 
performed if at least 30% response 
rate at Day 85 for any one 
treatment group.
IA SAC [1]
SAC [1]]
68.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in CRP (Parts A and B) 
by Randomised Treatment
IA SAC [1]
SAC [1]
69.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Log-Transformed FCP 
(Parts A and B) by Randomised Treatment 
IA SAC [1]
SAC [1]
70.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Modified Riley Scale 
Score (Parts A and B) by Randomised Treatment
IA SAC [1]
SAC [1]
71.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in RHI Score (Parts A 
and B) by Randomised Treatment
IA SAC [1]
SAC [1]
72.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in Geboes Index Total 
Score (Parts A and B) by Randomised Treatment
IA SAC [1]
SAC [1]]
73.
Safety
n/a
Raw SAS Output of Statistical Analysis Results for MMRM 
Analysis of the Change from Baseline in IBDQ Total Score 
(Parts A and B) by Randomised Treatment
SAC [1]
 
 
 
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108
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarker
74.
Safety
PD_L1
Listing of Inflammatory Biomarkers in Biopsy Tissue by 
Randomised Treatment
SAC [1]
75.
Safety
PD_L2
Listing of TEAR1 Concentrations % Target Engagement and 
Pathway Engagement by Randomised Treatment
Separate listings for Blood and 
Biopsy Tissue
SAC [1]
76.
Safety
PD_L3
Listing of mRNA Expression of Inflammatory Gene Transcripts 
by Randomised Treatment
Separate listings for Blood and 
Biopsy Tissue
SAC [1]
77.
Safety
n/a
Raw SAS Output of Statistical Analysis of Biopsy Tissue 
Inflammatory Biomarkers (Parts A and B) by Randomised 
Treatment
SAC [1]
78.
Safety
n/a
Raw SAS Output of Statistical Analysis of TEAR1 % Target 
Engagement in Blood (Parts A and B) by Randomised 
Treatment
SAC [1]
79.
Safety
n/a
Raw SAS Output of Statistical Analysis of TEAR1 % Target 
Engagement in Biopsy Tissue (Parts A and B) by Randomised 
Treatment
SAC [1]
80.
Safety
n/a
Raw SAS Output of Statistical Analysis of Pathway 
Engagement in Blood (Parts A and B) by Randomised 
Treatment
SAC [1]
81.
Safety
n/a
Raw SAS Output of Statistical Analysis of Pathway 
Engagement in Biopsy Tissue (Parts A and B) by Randomised 
Treatment
SAC [1]
82.
Safety
n/a
Raw SAS Output of Statistical Analysis of mRNA Expression in 
Blood (Parts A and B) by Randomised Treatment
SAC2 [1]
83.
Safety
n/a
Raw SAS Output of Statistical Analysis of mRNA Expression in 
Biopsy Tissue (Parts A and B) by Randomised Treatment
SAC2 [1]
 
 
 
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12.11.
Appendix 11: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
 
 
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12.12.
Appendix 12: NONMEM datafile specification
GSK to produce based on 203176 dataspec file
 
 
 
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