Clinical trial NCT02240108
Conditions: Crohn's Disease
Keywords: Crohn's Disease Rifaximin Clinical remission with endoscopic response Inflammatory Bowel Disease
Sponsor: Bausch Health Americas, Inc.
Start date: 2014-10-28; Completion date: 2017-10-06
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine the efficacy of rifaximin DR also referred to as Extended Intestinal Release (EIR) tablets vs. placebo for the induction of clinical remission and endoscopic response following 16 weeks of treatment in participants presenting with active moderate Crohn's disease. A key secondary objective is to evaluate clinical and endoscopic remission following an additional 36 weeks of treatment.

Detailed description:
RECD3126 is a double-blind, placebo-controlled, parallel-group, multicenter, multiregional, 52-week study to assess the efficacy and safety of rifaximin DR tablets for the induction of clinical remission and endoscopic response at 16 weeks followed by clinical and endoscopic remission after 52 weeks of continuous therapy in participants with active moderate Crohn's disease.

Participants will be randomized in a 1:1 allocation to rifaximin or placebo at the beginning of the treatment period and will maintain treatment assignment throughout the duration of the study. Ileocolonoscopy will be performed on all participants at baseline, between Weeks 16 and 17 (end of the Induction Phase), and following completion of the 36-week Long Term Treatment Phase (Week 52).

Arms: arm 1: Participants will receive rifaximin EIR 400 milligrams (mg) tablets orally twice daily for 52 weeks. arm 2: Participants will receive placebo matching to rifaximin EIR tablets orally twice daily for 52 weeks.
Interventions: intervention 1: Rifaximin EIR intervention 2: Placebo
Intervention descriptions: intervention 1: Rifaximin EIR tablets will be administered per the dose and schedule specified in the arm. intervention 2: Placebo matching to rifaximin EIR tablets will be administered per the dose and schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
R E C D 3 1 2 6  
Versi o n Dat e: 1 4J ul 2 0 1 4  
S ali x P h a r m a c e uti c als,  I n c. 
C R P -7 1  
C o nfi de nti al  
P a ge 1  of 1 0 3  
T his pr ot oc ol c o ntai ns c o nfi de ntial i nf or mati o n a b o ut a pr o d uct pr o vi de d b y Sali x P har ma ce uticals, I nc. T his 
i nf or mati o n is pr o vi de d f or t he e xcl usi ve use of t he I n vesti gat ors partici pati n g i n t his st u d y. A n y a n d all c o nfi de ntial 
i nf or mati o n c o ntai ne d herei n ma y n ot be discl ose d t o a n y ot her pers o n or part y wit h o ut t he pri or writte n c o nse nt of 
Sali x P har mace utica ls, I nc. 
C LI NI C A L R E S E A R C H P R O T O C O L  
A D o u ble -B li n d, Pl ace b o-C o ntr olle d, P ar allel -Gr o u p, M ultice nter, M ultire gi o n al, O ne 
Ye ar St u d y t o Assess t h e Effic ac y a n d S afet y of T wice D ail y Or al Rif a xi mi n Del a ye d 
Rele ase T a blets f or I n d ucti o n of Cli nic al Re missi o n wit h E n d osc o pic Res p o nse at 1 6 Wee ks 
f oll o w e d b y Cli nic al a n d E n d osc o pic Re missi o n at 5 2 Wee ks i n S u bjects wit h Acti ve 
M o der ate Cr o h n’s Dise ase  
Pr ot oc ol I D:  
R E C D 3 1 2 6  
I N D N u m ber: 
1 1 5, 6 3 8 
E u dr a C T N u m ber:  
2 0 1 4- 0 0 1 6 4 5- 2 4 
Cli nic al P h ase:  
3 
Tre at me nt Re gi me n:  
R ifa xi mi n Dela ye d Release ( D R) Ta blets 8 0 0 m g BI D or Place b o 
BI D  
I n dic ati o n: 
M o derate Cr o h n’s Diseas e  
S p o ns or:  
S ali x P har mace uticals, I n c. 
8 5 1 0 C ol o n na de Ce nter Dri ve 
Ralei g h, N ort h Car oli na, U S A 2 7 6 1 5 
St u d y Direct or:  
 
 
Sali x P har mace uticals, I n c.  
 
 
Me dic al M o nit or:  
 
 
S ali x P har mace uticals, I n c.  
 
Pri nci p al I n vesti g at or: 
M ultice nter  
Pr ot oc ol D at e:  
1 4J ul 2 0 1 4  
N C T #: N C T 0 2 2 4 0 1 0 8


RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
Page 2 of 103 
 
 
 
SIGNATURE PAGE 
 
A Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Multiregional, One   
Year Study to Assess the Efficacy and Safety of Twice Daily Oral Rifaximin Delayed 
Release Tablets for Induction of Clinical Remission with Endoscopic Response at 16 Weeks 
followed by Clinical and Endoscopic Remission at 52 Weeks in Subjects with Active 
Moderate Crohn's Disease 
 
 
This study protocol has been reviewed and approved by the undersigned persons. It is confirmed 
that the information and guidance given in this protocol complies with scientific principles, the 
guidelines of Good Clinical Practices, the Declaration of Helsinki in the latest relevant version 
and the applicable legal and regulatory requirements. 
 
 
 
 
 
 
Salix Pharmaceuticals, Inc. 
)Jg1rj y 
Date 
I . w;rn!M,,U,c, 
 
1 
 
 
 
('1- 
 
 
Date 
 
Salix Pharmaceuticals, Inc. 
Study Director: 
7 '>/ 


R E C D 3 1 2 6  
Versi o n Dat e: 1 4J ul 2 0 1 4  
S ali x P h a r m a c e uti c als,  I n c. 
C R P -7 1  
C o nfi de nti al  
P a ge 3  of 1 0 3  
 
 
 
R E C D 3 1 2 6 I n vesti g at o r Pr ot o c ol A gree me nt  
 
I a gree: 
•  T o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t he st u d y at t his site. 
•  T o c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d m e nts, a n d wit h a n y 
ot her st u d y c o n d uct pr oce d ures pr o vi d e d b y t he S p o ns or, Sali x P har mace uticals, I n c.  ( Sali x). 
•  N ot t o i m ple me nt a n y de viati o ns fr o m or c ha n ges t o t he pr ot oc ol wit h o ut a gree me nt fr o m t he 
S p o ns or a n d pri or re vi e w a n d writte n a p pr o v al fr o m t he I nstit uti o nal Re vie w 
B oar d/I nstit uti o nal Et hics C o m mittee (I R B/I E C), e x ce pt w here n ecess ar y t o eli mi nate a n 
i m me diate hazar d t o t he s u bjects, or f or a d mi nistrati ve as pects of t h e st u d y ( w here per mitte d 
b y all a p plica ble r e g ulat or y  r e q uire me nts). 
•  T hat I a m t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he i n vesti gati o nal dr u g(s), as 
descri be d i n t his pr ot oc ol a n d a n y ot her i nf or mati o n pr o vi de d b y t he S p o ns or i ncl u di n g,  b ut 
n ot li mite d t o t he f oll o wi n g: t he c urre nt i n vesti gat or’s br oc h ure or e q ui vale nt d oc u me nt 
pr o vi de d b y Sali x a n d a p pr o ve d pr o d uct la b el, if  a p plica ble.  
•  T hat I a m a w are of, a n d will c o m pl y wit h, “ g o o d c li nical practices” ( G C P) a n d all a p plica ble 
re g ulat or y re q uir e me nts. 
•  T o e ns ur e t hat all pers o ns assisti n g m e wit h t he st u d y are a d e q uatel y i nf or me d a b o ut t he 
i n vesti gati o nal dr u g(s) a n d of t heir st u d y-relate d d uties a n d f u ncti o ns as d escri be d i n t he 
pr ot oc ol.  
•  T o peri o dic o n -site m o nit ori n g of t he case re p ort f or ms ( C R Fs) a n d s o urce d oc u me nts b y 
Sali x or desi g nee a n d t o o n -site i ns pecti o n of C R Fs a n d s o urce d oc u me nts b y a p pr o priate 
re g ulat or y a ut h orities, i ncl u di n g b ut n ot li mite d t o t he U nite d States ( U S) Fo o d a n d Dr u g 
A d mi nistrati o n ( F D A), l ocal g o ver ni n g re g ulat or y b o dies, a n d I R B/I E C  i ns pect ors. 
•  T hat I ha ve b ee n i nf or me d t hat certai n re g ulat or y a ut h orities re q uire t h e S p o ns or t o o btai n 
a n d s u p pl y d etails a b o ut t he i n vesti gat or’s o w ners hi p i nterest i n t he S p o ns or or st u d y dr u g, 
a n d m ore ge n erall y a b o ut his/ her fi na ncial ties wit h t he S p o ns or. Sali x will use a n d  discl ose 
t he i nf or mati o n s olel y f or t he p ur p ose of c o m pl yi n g wit h re g ulat or y re q uire me nts. 
He nce I:  
–  A gree t o s u p pl y Sali x wit h a n y i nf or mati o n re gar di n g o w ners hi p i nterest a n d  fi na ncial 
ties (i ncl u di n g t h ose of m y s p o use a n d de pe n d e nt c hil dre n);  
–  A gree t o pr o m ptl y u p dat e t his i nf or mati o n if a n y rele va nt c h a n ges o cc ur d uri n g  t he 
c o urse of t he st u d y a n d f or 1 year f oll o wi n g c o m pleti o n of t he st u d y;  a n d  
–  A gree t hat Sali x ma y dis cl ose t his i nf or mati o n a b o ut s uc h o w ners hi p i nterests a n d 
fi na ncial ties t o re g ulat or y a ut h orities. 
 
 
 
I n vesti g at or N a me [ Pri nt]  
I n vesti g at or Si g n at ure 
 
D ate  


R E C D 3 1 2 6  
Versi o n Dat e: 1 4J ul 2 0 1 4  
S ali x P h a r m a c e uti c als,  I n c. 
C R P -7 1  
C o nfi de nti al  
P a ge 4  of 1 0 3  
 
 
 
S Y N O P SI S  
 
P R O T O C O L TI T L E:  
A D o u ble -Bli n d, Place b o -C o ntr olle d, Parallel -Gr o u p, M ultice nter, 
M ultire gi o nal, O n e Year St u d y t o Ass ess t he Effi cac y a n d Safet y of 
T wice Dail y Oral Rifa xi mi n Dela ye d Releas e Ta blets f or I n d ucti o n 
of Cli nical Re missi o n wit h E n d osc o pic Res p o nse at 1 6 Wee ks 
f oll o we d b y Cli nical a n d E n d osc o pic Re missi o n at 5 2 Wee ks i n 
S u bjects wit h Acti ve M o derate Cr o h n’s Diseas e  
P R O T O C O L N U M B E R:  R E C D 3 1 2 6  
S P O N S O R:  
Sali x P har mace uticals, I n c.  
T R E A T M E N T:  
Treat me nt A: Rifa xi mi n Dela ye d Release ( D R) Oral Ta blets 8 0 0 
m g BI D a d mi nistere d c o nti n u o usl y wit h o ut d ose -a dj ust me nt f or 5 2 
wee ks  
Treat me nt B: Matc hi n g place b o BI D a d mi nistere d c o nti n u o usl y 
wit h o ut d ose -a dj ust me nt f or 5 2 wee ks  
P RI M A R Y O B J E C TI V E:  T o deter mi ne t he efficac y of Rifa xi mi n D R 8 0 0 m g BI D vs. 
place b o f or t he i n d ucti o n of cli nical re missi o n a n d e n d osc o pic 
res p o nse f oll o wi n g 1 6 w ee ks of treat me nt i n s u bjects prese nti n g 
wit h acti ve m o derat e Cr o h n’s disease.  
K E Y S E C O N D A R Y 
O B J E C TI V E:  
A ke y sec o n d ar y o bjecti ve is t o e val uate cli nical a n d e n d osc o pic 
re missi o n f oll o wi n g a n a d diti o nal 3 6-wee k l o n g ter m treat me nt 
p hase of Rifa xi mi n D R 8 0 0 m g BI D vs. place b o.  
S T U D Y D E SI G N:  
R E C D 3 1 2 6 is a d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p, 
m ultice nter, m ultire gi o nal, 5 2 -wee k st u d y t o assess t he efficac y 
a n d safet y of Rifa xi mi n D R ta blets f or t he i n d ucti o n of cli nical 
re missi o n a n d e n d osc o pi c res p o nse at 1 6 wee ks f oll o we d b y 
cli nical a n d e n d osc o pi c re missi o n after 5 2 wee ks of c o nti n u o us 
t hera p y i n s u bjects wit h acti ve m o derate Cr o h n’s disease. S u bjects 
will be eli gi ble if t he y h a ve acti ve, m o derate disease defi ne d b y a 
Cr o h n’s disease A cti vit y I n d e x ( C D AI) sc ore of ≥ 2 2 0 a n d ≤ 4 5 0 
p oi nts at scree ni n g, a n d e v i de nce of acti ve ile oc ol o nic Cr o h n’s 
disease defi n e d b y a Si m ple E n d osc o pic Sc ore f or Cr o h n’s disease 
( S E S-C D) of ≥ 7 o n baseli ne ile oc ol o n osc o p y as assesse d b y 
bli n de d ce ntral rea di n g. Eli gi ble s u bjects will c o m plete a 2 - t o 3- 
wee k Scr ee ni n g Peri o d, a 5 2 -wee k Treat me nt Peri o d c o nsisti n g of 
a 1 6-wee k I n d ucti o n P hase a n d 3 6 -Wee k L o n g T er m Treat me nt 
P hase, a n d a 2 -wee k F oll o w -u p Peri o d. S u bjects will be 
ra n d o mize d i n a 1: 1 all ocati o n t o Rifa xi mi n D R 8 0 0 m g BI D or 
place b o at t he b e gi n ni n g of t he treat me nt p er i o d a n d will mai ntai n 


P a ge 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
treat me nt assi g n me nt t hr o u g h o ut t he d urati o n of t he st u d y. 
Ile o c ol o n osc o p y will be perf or me d o n all s u bjects at baseli ne 
( bet wee n Visits 1 a n d 2), bet wee n Wee ks 1 6 a n d 1 7 (e n d of t he 
I n d u cti o n P hase), a n d f oll o wi n g c o m pleti o n of t he 3 6-wee k L o n g 
Ter m Treat me nt P hase ( Wee k 5 2) t o assess t he effects of treat me nt 
o n t he de gree of m uc osal heali n g. S u bjects will be assesse d d uri n g 
cli nic visits w hic h are sc he d ule d at Wee ks 0 ( b aseli ne), 2, 4, 8, 1 2, 
a n d 1 6; t he n  e ver y f o ur wee ks t hr o u g h Wee k 5 2. All s u bjects will 
be re q uir e d t o c o m plete a dail y diar y. All s u bjects will c o m plete a 
2 -wee k (st u d y dr u g free) F oll o w -u p Peri o d f oll o wi n g c o m pleti o n 
of t he 5 2 -wee k Treat me nt Peri o d, a n d will ret ur n t o t he cli nic f or 
fi nal assess me nts ( E n d -of -St u d y [ E O S] visit; Wee k 5 4). See 
Fi g ure  1.  
S T U D Y D U R A TI O N:  
Per S u bject: 2 - t o 3-wee k Scree ni n g Peri o d, 5 2 -wee k Treat me nt 
Peri o d, a n d a 2 -w ee k F oll o w -u p Peri o d. T he ma xi m u m d urati o n of 
s u bject partici pati o n will be 5 7 wee ks. 
S U B J E C T 
P O P U L A TI O N:  
S u bjects wit h acti ve, m o derate disease defi ne d b y a C D AI sc ore of  
≥ 2 2 0 a n d ≤ 4 5 0 p oi nts at scree ni n g, a n d e vi de n ce of acti ve 
ile oc ol o nic Cr o h n’s disease defi ne d b y a S E S-C D sc ore of ≥ 7 as 
deter mi ne d fr o m b aseli ne ile oc ol o n osc o p y.  
N U M B E R O F 
S U B J E C T S:  
A p pr o xi matel y 6 6 0 t otal: 3 3 0 t o Treat me nt A ( 8 0 0 m g Rifa xi mi n 
D R BI D) a n d 3 3 0 t o Treat me nt B ( Place b o BI D)  
N U M B E R O F C E N T E R S:  A p pr o xi matel y 2 0 0  
L O C A TI O N:  
U nite d States, Ca na da, R ussia, Israel a n d c o u ntries i n E ur o pe  
C O -P RI M A R Y 
E F FI C A C Y E N D P OI N T:  
T here will be t w o c o -pri mar y m eas ures of efficac y ass esse d d uri n g 
t he I n d u cti o n of Cli nical Re missi o n a n d E n d osc o pic Res p o nse 
P hase. T he first c o -pri mar y e n d p oi nt is:  
•  Cli nical S y m pt o m Re missi o n defi ne d b y ( 1) t he t otal n u m ber  of 
li q ui d/ ver y s oft st o ols f or t he 7 da ys pri or t o t he Wee k 1 6 visit 
bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n a b d o mi nal pai n 
rati n g of ≤ 1 (fr o m C D AI Ite m 2) o n eac h da y f or t he 7 da ys 
pri or t o t he Wee k 1 6  visit.  
T he sec o n d c o -pri mar y e n d p oi nt is:  
•  E n d osc o pic Res p o nse defi ne d as a ≥ 3 -p oi nt decrease i n t he 
S E S -C D fr o m baseli ne t o t he S E S -C D sc ore o btai ne d bet wee n 
Wee k 1 6 a n d Wee k 1 7. S E S -C D sc ores will be calc ulate d fr o m 
ce ntrall y-rea d di gital vi d e o of ile oc ol o n osc o pies p erf or me d at  


P a ge 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
baseli ne a n d bet w ee n Wee k 1 6 a n d Wee k 1 7.  
K E Y C O -S E C O N D A R Y 
E N D P OI N T:  
T here will be t w o k e y c o -sec o n dar y e n d p oi nts of efficac y ass esse d 
d uri n g t he L o n g T er m Treat me nt P hase. T he first is:  
 
•  Cli nical s y m pt o m re missi o n defi ne d b y ( 1) t he t ot al n u m ber  of 
li q ui d/ ver y s oft st o ols f or t he 7 da ys pri or t o t he Wee k 5 2 visit 
bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n a b d o mi nal pai n 
rati n g of ≤ 1(fr o m C D AI Ite m 2) o n eac h da y f or t he 7 da ys 
pri or t o t he Wee k 5 2  visit.  
T he sec o n d is:  
 
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 at 
Wee k 5 2. S E S -C D sc ores will be calc ulate d fr o m ce ntrall y - 
rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at Wee k 5 2  
S E C O N D A R Y 
E N D P OI N T S:  
T he f oll o wi n g s ec o n dar y e n d p oi nts will be assesse d:  
 
•  I n d u cti o n of cli nical re missi o n defi ne d as a C D AI sc ore of less 
t ha n 1 5 0 p oi nts at Wee k 1 6.  
•  Pr o p orti o n of s u bjects wit h S E S -C D sc ore of 0 at Wee k  5 2.  
•  Cli nical re missi o n defi ne d as a C D AI sc ore of l ess t ha n  1 5 0 
p oi nts at p ost -baseli ne  visits.  
•  C ha n ge fr o m bas eli ne i n S E S -C D sc ore at Wee k 1 6 a n d  Wee k 
5 2.  
•  Cli nical s y m pt o m re missi o n o ver ti me: T he t otal n u m ber of 
li q ui d/ ver y s oft st o ols f or t he 7 da ys pri or t o eac h cli nic visit 
bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n a b d o mi nal pai n 
rati n g of ≤ 1(fr o m C D AI Ite m 2) o n eac h da y f or t he last 7 
da ys pri or t o eac h cli nic visit i n ≥ 8 0 % of t he st u d y visits 
d uri n g t he 5 2 -Wee k Treat me nt P hase, i ncl u di n g Wee k  5 2.  
•  Ti me t o l oss of C D AI r es p o nse defi ne d b y a C D AI sc ore of  ≥ 
1 5 0 p oi nts d uri n g t he L o n g Ter m Treat me nt P hase.  
 
•  Ti me u ntil d ura ble res p o nse t o t he li q ui d/ ver y s oft st o ol 
c o m p o ne nt of t he c o -pri mar y e n d p oi nt d uri n g t he  5 2 -Wee k 
Treat me nt  P hase.  


P a ge 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Ti me u ntil d ura ble res p o nse t o t he a b d o mi nal pai n c o m p o ne nt 
of t he c o -pri mar y e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt 
P hase.  
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he a b d o mi nal pai n 
c o m p o ne nt of t he c o -pri mar y e n d p oi nt at p ost -baseli ne ti me 
p oi nts.  
•  Pr o p orti o n of s u bj ects wit h res p o nse t o t he li q ui d/ ver y s oft 
st o ol c o m p o ne nt of t he c o-pri mar y e n d p oi nt at p ost -baseli ne 
ti me p oi nts.  
•  Pr o p orti o n of s u bjects w h o ac hie ve cli nical re missi o n b y t he 
C D AI e n d p oi nt at p ost -b aseli ne ti me  p oi nts.  
•  Perce nta ge of s u bjects w h o ac hie ve cli nical res p o nse at p ost - 
baseli ne ti me p oi nts. Cli nical res p o nse is defi ne d as a  re d u cti o n 
of at least 1 0 0 p oi nts fr o m t he baseli ne C D AI  sc ore. 
•  Ti me t o cli nical res p o nse base d o n Wee k 1 6 c o -pri mar y 
e n d p oi nts.  
S A F E T Y E N D P OI N T S:  
•  I n ci de nce, i nte nsit y, a n d t y pes of a d vers e e v e nts ( A Es). 
•  C ha n ges fr o m bas eli ne i n t he la b orat or y p ara met ers 
( he mat ol o g y, cli nical c h e mistr y, uri nal ysis).  
•  C ha n ges fr o m bas eli ne i n vital si g n  meas ure m e nts.  
O T H E R E N D P OI N T S:  
E x pl orat or y assess me nts will i ncl u de: 
•  C haracterizati o n of st o ol micr o bi ota at baseli ne a n d after  1 6 
a n d 5 2 wee ks of  treat me nt. 
 Baseli ne a n d p ost -treat me nt bacteri al D N A is olate d 
fr o m st o ol f or 1 6 S r R N A ge n e a m plificati o n.  
 Descri pti ve c h aracterizati o n of bacteri a i n st o ol  b y:  
•  Is olati o n a n d i d e ntificati o n of selecte d Gra m - 
ne gati ve a n d Gra m -p ositi ve  bacteria.  
•  Resista nce t o select e d a nti bi otics, i ncl u di n g 
rifa xi mi n a n d rifa m pi n. 
•  Ge n o mic pr ofili n g of pre g na n e X rece pt or ( P X R) i n  bl o o d.  
•  P o p ulati o n p har mac o ki netics of  rifa xi mi n. 


Page 8 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
SAMPLE SIZE: 
The information below provides the background information for 
sample size determination for the induction of clinical remission 
with endoscopic response at 16 weeks followed by clinical and 
endoscopic remission at 52 weeks. For placebo, the expected rates 
are based on data from a Phase 2 study (RETIC 03/06) conducted 
in subjects with active moderate Crohn’s disease. The rates for 
Rifaximin DR are based on the assumption that Rifaximin DR will 
provide a somewhat higher induction of remission rate. 
Expected rates for induction of clinical remission with endoscopic 
response at Week 16 are 40% for placebo and 55% for Rifaximin 
DR. 
Based on a significance level of 5% (alpha 0.05), a sample size of 
approximately 240 subjects per treatment group will have at least 
90% power to test the hypothesis that Rifaximin DR is superior to 
placebo for each co-primary endpoint considered individually. 
Approximately 80% power is available to detect significant 
differences between Rifaximin DR and placebo for each of the co- 
primary endpoints. 
For the long term treatment phase, a 15% treatment effect is 
expected for both clinical symptom and endoscopic remission at 
Week 52. Based on this assumption and testing at a significance 
level of 5% (alpha 0.05), a sample size of approximately 210 
subjects per treatment group will have at least 90% power to test 
the key secondary efficacy hypothesis that Rifaximin DR is 
superior to placebo when each key co-secondary endpoint is 
considered individually. In addition, approximately 80% power is 
available to detect significant differences between Rifaximin DR 
and placebo for each of the key co-secondary endpoints. 
An additional consideration for sample size determination is the 
application of an inflation factor of 20% to account for drop-out 
rates during the Induction and Long Term Treatment Phases of the 
study. This consideration suggested that 330 subjects per treatment 
group would be required at study entry. 


P a ge 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
T a ble of C o nte nts  
SI G N A T U R E  P A G E  ......................................................................................................................2  
R E C D 3 1 2 6 I N V E S TI G A T O R  P R O T O C O L  A G R E E M E N T  ...................................................3  
S Y N O P SI S  ......................................................................................................................................4  
LI S T  O F  A B B R E VI A TI O N S  .....................................................................................................1 4  
1. 0  
I N T R O D U C TI O N............................................................................................................1 7  
1. 1  
Disease Bac k gr o u n d a n d Scie ntific Rati o nale f or t he Use of Rifa xi mi n D R i n  
Cr o h n’s  Disease  .....................................................................................................1 7  
1. 2  
C urre nt T her a p y f or  Cr o h n’s  Disease  ....................................................................1 9  
1. 3  
Rifa xi mi n  D R  Bac k gr o u n d  ....................................................................................2 0  
1. 4  
Cli nical E x perie nce  wit h  Rifa xi mi n  .......................................................................2 0  
1. 5  
St u d y  Rati o nale  ......................................................................................................2 3  
1. 6  
Pri mar y E n d p oi nt De v el o p me nt f or t he  U nite d  States  ...........................................2 4  
2. 0  
O B J E C TI V E S  A N D  E N D P OI N T S  ................................................................................2 8  
2. 1  
O bjecti ves  ..............................................................................................................2 8  
2. 1. 1  
Pri mar y  O bjecti ve  .................................................................................2 8  
2. 1. 2  
Sec o n dar y  O bjecti ves  ............................................................................2 8  
2. 2  
E n d p oi nts  ...............................................................................................................2 8  
2. 2. 1  
Pri mar y  Efficac y  E n d p oi nts  ..................................................................2 8  
2. 2. 2  
Ke y  Sec o n dar y  E n d p oi nts  .....................................................................2 9  
2. 2. 3  
Sec o n dar y  Efficac y  E n d p oi nts  ..............................................................2 9  
2. 2. 4  
Safet y  E n d p oi nts  ...................................................................................3 0  
2. 2. 5  
E x pl orat or y  Ass ess me nts  ......................................................................3 0  
3. 0  
I N V E S TI G A TI O N A L P L A N  .........................................................................................3 1  
3. 1  
O ver vie w of  St u d y  Desi g n  .....................................................................................3 1  
3. 2  
Rati o nale f or Pr o p ose d  St u d y  Desi g n  ....................................................................3 2  
3. 3  
Treat me nt  Assi g n me nt/ Ra n d o mizati o n  .................................................................3 2  
3. 4  
Pr oce d ures f or Brea ki n g  t he Bli n d  .........................................................................3 3  
4. 0  
S E L E C TI O N A N D WI T H D R A W A L  O F  S U B J E C T S  ................................................3 4  
4. 1  
I n cl usi o n Criteria  ...................................................................................................3 4  
4. 2  
E x cl usi o n  Criteria  ..................................................................................................3 5  
4. 3  
C o nc o mita nt  T hera pies  ..........................................................................................3 7  
4. 3. 1  
Per mitte d  T hera p y  .................................................................................3 7  
4. 3. 2  
Pr o hi bite d  T hera p y  ................................................................................3 8  


P a ge 1 0  of 1 0 3  
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S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
4. 4  
Fe males of  Re pr o d u cti ve  P ote ntial  ........................................................................3 8  
4. 5  
Pre mat ure  S u bject Disc o nti n uati o n  ........................................................................3 9  
4. 6  
St u d y  C o ntact  I nf or m ati o n .....................................................................................3 9  
5. 0  
T R E A T M E N T  O F  S U B J E C T S  ......................................................................................4 1  
5. 1  
F or m ulati o n  a n d S u p pl y .........................................................................................4 1  
5. 2  
Pac ka gi n g  ...............................................................................................................4 1  
5. 3  
La b eli n g  .................................................................................................................4 1  
5. 4  
St ora ge a n d H a n dli n g  .............................................................................................4 2  
5. 5  
D osi n g a n d  D osi n g  Sc h e d ule  .................................................................................4 2  
5. 6  
Rati o nale f or  D ose  Selec ti o n .................................................................................4 2  
5. 7  
St u d y  Dr u g  Acc o u nta bilit y  ....................................................................................4 2  
5. 8  
Assess me nt  of  C o m plia nce  ....................................................................................4 3  
6. 0  
S T U D Y P R O C E D U R E S  A N D  A S S E S S M E N T S  ..........................................................4 4  
6. 1  
St u d y Sc h e d ule b y  Treat me nt Visit  ........................................................................4 4  
6. 1. 1  
Visit 1: Scree ni n g ( Da y – 2 1 t o  Da y  -1 4)  ...............................................4 4  
6. 1. 2  
Visit 2: Baseli ne/ Ra n d o mizati o n, Wee k  0/ Da y  1 ..................................4 5  
6. 1. 3  
Visits 3, 4, 5, 6: Wee ks 2, 4, 8, 1 2 / Da ys 1 4, 2 8, 5 6, 8 4 ( ± 3  da ys)  ......4 5  
6. 1. 4  
Visit 7: Wee k 1 6/ Da y 1 1 2 ( ±  3 da ys)  ....................................................4 6  
6. 1. 5  
Visits 8, 9, 1 0, 1 1, 1 2, 1 3, 1 4, 1 5: Wee ks 2 0, 2 4, 2 8, 3 2, 3 6, 4 0,  4 4,  
4 8 / Da ys 1 4 0, 1 6 8, 1 9 6, 2 2 4, 2 5 2, 2 8 0, 3 0 8, 3 3 6 ( ±  3  da ys)  ...............4 7  
6. 1. 6  
Visit 1 6: E n d of Treat me nt ( E O T) Visit, Wee k 5 2/ Da y 3 6 4 ( ±  3  
da ys)  ......................................................................................................4 7  
6. 1. 7  
Visit 1 7: E n d of St u d y ( E O S) Visit, Wee k 5 4/ Da y 3 7 8 ( ±  3  da ys)  .......4 8  
6. 1. 8  
U nsc he d ule d  Visit  .................................................................................4 8  
6. 1. 9  
Dail y Di ar y ( a n d/ or ot her  s u bject-c ollecte d data)  .................................4 9  
6. 2  
Assess me nt  of  Efficac y  ..........................................................................................4 9  
6. 2. 1  
Cr o h n’s Disease A cti vit y I n d e x  ( C D AI) Sc ore  .....................................4 9  
6. 2. 2  
Si m ple E n d osc o pic Sc ore f or Cr o h n’s  Disease  ( S E S-C D)  ...................4 9  
6. 2. 3  
I nfla m mat or y B o wel Dis ease Q u esti o n naire  (I B D Q) ...........................5 0  
6. 2. 4  
W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q u esti o n naire  f or 
Cr o h n's  Diseas e  ( W P AI-C D)  ................................................................5 0  
6. 3  
Assess me nt  of  Safet y  .............................................................................................5 0  
6. 3. 1  
Cli nical  La b orat or y  T ests  ......................................................................5 0  
6. 3. 2  
Assess me nt of I nfla m mati o n Mar kers  ..................................................5 1  
6. 3. 3  
St o ol Sa m ple C ollecti o n  a n d Testi n g  ....................................................5 2  
6. 3. 4  
Uri ne a n d Ser u m  Pre g na nc y  T ests  ........................................................5 3  


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C R P -7 1  
C o nfi de nti al  
 
 
6. 3. 5  
Safet y M o nit ori n g f or  C. difficile  ..........................................................5 3  
6. 3. 6  
A d verse  E v e nts ......................................................................................5 3  
6. 3. 7  
P h ysical  E x a mi nati o n  ............................................................................5 3  
6. 3. 8  
Vital  Si g n Assess me nts  .........................................................................5 4  
6. 3. 9  
Electr ocar di o gra m  ( E C G) .....................................................................5 4  
6. 4  
Ot her  Assess me nts  .................................................................................................5 4  
6. 4. 1  
Me dical Hist or y  .....................................................................................5 4  
6. 5  
P har mac o ki netics  ...................................................................................................5 4  
7. 0  
S A F E T Y  R E P O R TI N G ...................................................................................................5 5  
7. 1  
O perati n g Defi niti o ns f or  Assessi n g  Safet y  ...........................................................5 5  
7. 1. 1  
A d verse  E v e nt  .......................................................................................5 5  
7. 1. 2  
Seri o us  A d verse  E ve nt  ..........................................................................5 6  
7. 2  
Cli nical La b or at or y A b n or malities a n d Ot her A b n or mal Assess me nts as  A Es  
a n d S A Es  ................................................................................................................5 7  
7. 3  
Met h o d, Fre q u e nc y, a n d Ti me Peri o d f or Det ecti n g A Es  a n d S A Es  .....................5 7  
7. 3. 1  
T he Ti me Peri o d f or D et ecti n g a n d Re p orti n g of A Es  a n d S A Es  .........5 8  
7. 3. 2  
P ost -St u d y  S A Es  ...................................................................................5 8  
7. 4  
D oc u me nti n g A Es  a n d S A Es  .................................................................................5 8  
7. 5  
F oll o w -u p of A Es a n d S A Es  ..................................................................................5 9  
7. 6  
Pr o m pt Re p orti n g of S A Es t o  Sali x  P har mace uticals  ............................................5 9  
7. 7  
Pre g n a nc y  R e p orti n g  ..............................................................................................5 9  
7. 8  
Tra ns missi o n of S A E Re p ort F or ms a n d Pre g n a nc y  N otificati o n F or ms  ..............6 0  
7. 9  
Re g ulat or y Re p orti n g Re q uire me nts  f or S A Es  ......................................................6 0  
8. 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  ...........................................................................6 1  
8. 1  
Ra n d o mizati o n  .......................................................................................................6 1  
8. 2  
Deter mi nati o n of  Sa m ple  Size  ...............................................................................6 1  
8. 3  
A nal ysis  P o p ulati o ns  ..............................................................................................6 2  
8. 4  
S u bject  Dis p ositi o n  ................................................................................................6 2  
8. 5  
De m o gra p hic a n d Baseli ne  C haracteristics  ...........................................................6 2  
8. 6  
A nal ysis  Met h o ds ...................................................................................................6 3  
8. 6. 1  
Pri mar y  Efficac y  A nal ysis  ....................................................................6 3  
8. 6. 2  
Sec o n dar y  Efficac y  A n al ys es  ................................................................6 5  
8. 6. 3  
Safet y  A nal ys es  .....................................................................................6 7  
8. 6. 4  
E xte nt of E x p os ure a n d  Treat me nt  C o m plia nce  ...................................6 7  
8. 6. 5  
A d verse  E v e nts ......................................................................................6 7  
8. 6. 6  
Cli nical  La b orat or y  Ass ess me nts  ..........................................................6 7  


P a ge 1 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
8. 6. 7  
Vital  Si g ns  .............................................................................................6 8  
8. 6. 8  
C o nc o mita nt  Me dicati o ns  .....................................................................6 8  
8. 6. 9  
P h ysical  E x a mi nati o ns  ..........................................................................6 8  
8. 6. 1 0  
Electr ocar di o gra m  .................................................................................6 8  
8. 7  
Statistical a n d  A nal ytical  Iss ues.............................................................................6 9  
8. 7. 1  
A dj ust me nt  f or C o variates  ....................................................................6 9  
8. 7. 2  
Ha n dli n g of Dr o p o uts or  Missi n g  Data  .................................................6 9  
8. 7. 3  
I nteri m A nal yses a n d Data  M o nit ori n g  .................................................7 0  
8. 7. 4  
M ultice nter  St u dies  ...............................................................................7 0  
8. 7. 5  
M ulti ple  C o m paris o ns/ M ulti plicit y  .......................................................7 0  
8. 7. 6  
Use of a n Efficac y S u bset  of  S u bjects  ..................................................7 0  
8. 7. 7  
E x pl orati o n of t he Effects of Vari o us Pr o g n ostic Fact ors  o n  
Efficac y  .................................................................................................7 0  
8. 7. 8  
Criteria f or St o p pi n g  t he St u d y  .............................................................7 1  
9. 0  
S T U D Y  A D MI NI S T R A TI O N .........................................................................................7 2  
9. 1  
I n v esti gat or I nf or mati o n a n d Trai ni n g ...................................................................7 2  
9. 2  
M o nit ori n g  .............................................................................................................7 2  
9. 3  
A u dits  .....................................................................................................................7 2  
1 0. 0  
E T HI C A L A N D  L E G A L A S P E C T S  .............................................................................7 3  
1 0. 1  
I nstit uti o nal Re vie w B oar d/ I n d e pe n d e nt Et hics C o m mittee (I R B/I E C) 
A p pr o val  ................................................................................................................7 3  
1 0. 2  
S u bject I nf or mati o n a n d  I nf or me d C o nse nt  ...........................................................7 4  
1 0. 3  
St u d y a n d Site Cl os ure  or  Disc o nti n uati o n  ............................................................7 4  
1 0. 3. 1  
St u d y  Disc o nti n uati o n  ...........................................................................7 5  
1 0. 3. 2  
St u d y  Site  Disc o nti n uati o n  ....................................................................7 5  
1 0. 4  
Ha n dli n g a n d  Rec or d  Kee pi n g  ...............................................................................7 6  
1 0. 4. 1  
Case Re p ort F or ms a n d Data base  Pr ocessi n g  .......................................7 6  
1 0. 4. 2  
S o urce  D oc u m e nts  ................................................................................7 6  
1 0. 4. 3  
S u bject  Trac ki n g  ...................................................................................7 6  
1 0. 4. 4  
St u d y  Files  .............................................................................................7 6  
1 0. 4. 5  
Data  Ma n a ge me nt  .................................................................................7 6  
1 0. 5  
C o nfi de ntialit y  .......................................................................................................7 6  
1 0. 6  
Rec or d  Rete nti o n  ...................................................................................................7 7  
1 0. 7  
Fi na nci n g  a n d I ns ura n ce ........................................................................................7 7  
1 0. 7. 1  
Fi na nce  ..................................................................................................7 7  
1 0. 7. 2  
I ns ura nce a n d I n d e m nificati o n ..............................................................7 8  


P a ge 1 3  of 1 0 3  
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S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
1 0. 8  
P u blicati o n  P olic y  ..................................................................................................7 8  
1 0. 9  
O w ners hi p  ..............................................................................................................7 8  
1 1. 0  
R E F E R E N C E S  .................................................................................................................7 9  
A p pe n di x 1: O verall Ti me a n d E ve nts Sc he d ul e  ...............................................................8 3  
A p pe n di x 2: Cr o h n’s Disease A cti vit y  I n d e x ( C D AI) .......................................................8 4  
A p pe n di x 3:  Brist ol St o ol F or m Scale  ( B S F S) .................................................................8 5  
A p pe n di x 4: Si m ple E n d osc o pic Sc ore f or Cr o h n’s Disease ( S E S -C D) D efi niti o ns of  
S E S -C D  Varia bles  .................................................................................................8 6  
A p pe n di x 5: I nfla m mat or y B o wel Disease  Q uesti o n naire  (I B D Q) ...................................8 7  
A p pe n di x 6: W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q uesti o n naire  ( W P AI: C D) ....9 8  
A p pe n di x 7: S u bject Dail y  Di ar y  Rec or di n g  ...................................................................1 0 1  
A p pe n di x 8: I deal B o d y Mass of N or mal A d ults ( Me n  &  W o me n)  ................................1 0 2  


P a ge 1 4  of 1 0 3  
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S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
LI S T O F A B B R E VI A TI O N S  
 
A b bre vi ati o n  
Defi niti o n  
5 -A S A  
5 -A mi n osalic ylic Aci d  
A E  
A d verse E v e nt  
A L T  
Ala ni ne A mi n otra nsferas e  
A S T  
As partate A mi n otra nsferase  
A U C  
Area U n der t he Plas ma C o nce ntrati o n -ti me C ur ve 
BI D  
T w o Ti mes a Da y  
B S F S  
Brist ol St o ol F or m Scale  
C. difficile  
Cl ostri di u m difficile  
C D  
Cr o h n’s Disease  
C D AI  
Cr o h n’s Disease A cti vit y I n d e x  
C D EI S  
Cr o h n’s Disease E n d os c o pic I n d e x of Se verit y  
C L SI  
Cli nical La b or at or y Sta n dar ds I nstit ute  
C ma x  
Ma xi m u m O bser ve d Plas ma C o nce ntrati o n  
C M H  
C oc hra n -Ma nt el -Hae nszel  
C R F  
Case Re p ort F or m  
C R P  
C -Reacti ve Pr otei n  
D N A  
De o x yri b o n ucleic Aci d  
D S M -5  
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, 5t h. E diti o n  
D R  
Dela ye d Release  
E C G  
Electr ocar di o gra m  
E. C oli  
Esc heric hi a c oli  
E D C  
Electr o nic D ata Ca pt ure  
EI A  
E nz y m e I m m u n oassa y 
EI R  
E xte n de d I ntesti nal Release  
E M A  
E ur o pea n Me dici nes A ge nc y  
E O S  
E n d of St u d y  
E O T  
E n d of Treat me nt  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practices  
GI  
Gastr oi ntesti nal  
H b A 1c  
He m o gl o bi n A 1 c  


Page 15 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
Abbreviation 
Definition 
HDPE 
High Density Polyethylene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
IBS 
Irritable Bowel Syndrome 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IL 
Interleukins 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-9 
Matrix Metalloproteinase-9 
NASH 
Non-alcoholic Steatohepatitis 
NC 
North Carolina 
NF-kB 
Nuclear Factor kappa-light-chain-enhancer of activated B Cells 
PCR 
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PSAP 
Pharmacokinetics Statistical Analysis Plan 
PXR 
Pregnane X Receptor 
rCRT 
Clinical Remission Rate Treatment 
rCRP 
Clinical Remission Rate Placebo 
RNA 
Ribonucleic Acid 
ROC 
Receiver Operating Characteristics 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 


P a ge 1 6  of 1 0 3  
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S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
A b bre vi ati o n  
Defi niti o n  
S E S -C D  
Si m ple E n d osc o pic Sc ore f or Cr o h n’s Dis ease  
S D  
Sta n dar d De viati o n  
tc d B 
C. difficile T o xi n B  
T ma x  
Ti me of Ma xi m u m O bser ve d Plas ma C o nce ntrati o n  
T N B S  
Tri nitr o be nze ne S ulf o nic Aci d  
T N F α  
T u m or Necr osis Fact or al p ha  
U L N  
U p per Li mit of N or mal  
U S  
U nite d States  
W P AI: C D  
W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q u esti o n naire - Cr o h n’s 
Disease  
W H O  
W orl d Healt h Or ga nizati o n  


P a ge 1 7  of 1 0 3  
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S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
1. 0  
I N T R O D U C TI O N 
 
1. 1  
Dise ase B ac k gr o u n d a n d Scie ntific R ati o n ale f or t he Use of Rif a xi mi n D R  i n 
Cr o h n’s  Dise ase  
 
Cr o h n’s disease ( C D) is a c hr o nic, rela psi n g, re mitti n g, s yste mic disease w hic h ma y res ult i n 
tra ns m ural i nfla m mati o n of t he gastr oi ntesti nal tract. T he i nci de n ce a n d pre vale nce rates f or 
C D i n Ca ucasia n pe o ple i n N ort her n E ur o p e a n d N ort h A merica are n ot e d i n Ta ble 1.  
 
T a ble 1: E pi de mi ol o g y of Cr o h n’s Dise ase  
Fact or  
Cr o h n’s disease  
I n ci de nce per 1 0 0, 0 0 0  
1 -6  
Pre vale nce per 1 0 0, 0 0 0  
1 0 -1 0 0  
Racial I nci de n ce  
Hi g h i n Ca ucasia ns  
Et h nic I n ci de nce  
Hi g h i n J e wis h pe o ple  
Ge n der  
Sli g ht fe male pre p o n dera nce  
A ge of O nset  
1 5 -2 5 ( pea k)  
5 5 -6 5 ( 2 n d s maller pea k)  
Refere nce ( 1)  
Cr o h n’s disease ma y aff ect a n y part of t h e ali me ntar y tract, b ut mai nl y affects t he ile u m ( 3 0 - 
4 0 %), ile oc ol o nic r e gi o n ( 4 0 -5 5 %) or c ol o n ( 1 5 -2 5 %). Gastr oi ntesti nal s y m pt o ms are 
deter mi ne d b y t he a n at o mical l ocati o n a n d t he se verit y of t he diseas e a n d i ncl u de:  
 
•  Ge ner al ma nifestati o ns: f ati g ue, l oss of a p petite,  fe ver. 
•  B o wel s pecific s y m pt o ms: irre g ul ar b o w el m o ve me nts, m uc us a n d / or bl o o d i n st o ols, 
c hr o nic r ec urre nt diarr hea, rec urre nt a b d o mi nal pai n, a b d o mi nal te n der ness, na usea, 
wei g ht l oss, peria nal  diseases.  
•  Strict ures a n d fist ulae, w hic h ma y l ea d t o o bstr ucti o ns, a bscesses a n d mala bs or pti o n.  
•  E xtrai ntesti nal ma nifestati o ns: prese nt i n u p t o 3 0 % of C D patie nts a n d i ncl u de 
art hr o pat hies, b o ne d e mi neralizati o n, s ki n lesi o ns, oc ular ma nifestati o ns, he patic  diseases.  
 
Se verit y of  disease ge ner all y is assess e d b y b ot h n o n -i n vasi ve a n d i n vasi ve meas ures. T h e 
Cr o h n’s disease A cti vit y I n d e x ( C D AI) sc ore is a wei g ht e d, c o m p osite i n de x of ei g ht ite ms 
(st o ol fre q ue n c y, se verit y of a b d o mi nal pai n, de gree of ge n eral well-bei n g, prese nce or  
a bse nce of e xtrai ntesti nal ma nifestati o ns i ncl u di n g fist ula, use or n o n use of a nti diarr heal 
a ge nts, prese n ce or a bse n ce of a b d o mi nal mass, h e mat ocrit a n d b o d y wei g ht). Sc ores ra n ge 
fr o m 0 t o a p pr o xi matel y 6 0 0 wit h hi g her s c ores i n dicati n g greater diseas e se verit y. Cli nical 
(as y m pt o matic) re missi o n is defi ne d as a s c ore of ≤ 1 5 0 p oi nts. Mil d-t o-m o derate disease a n d 
se vere disease are d efi ne d b y sc ores of >  1 5 0 t o ≤ 4 5 0, a n d >  4 5 0 p oi nts, res pecti vel y. ( See 
A p pe n di x 2: Cr o h n’s  Disease A cti vit y I n d e x ). 


P a ge 1 8  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
 
T he Si m ple E n d osc o pic Sc ore f or Cr o h n’s diseas e ( S E S -C D) is a vali date d i nstr u me nt 
reflecti n g a n e n d osc o pist’s gl o bal a p praisal of m u c osal lesi o ns i n Cr o h n’s disease. T he S E S- 
C D gr a des lesi o ns b y l ocati o n (ile u m, ri g ht  c ol o n, tra ns verse c ol o n, left c ol o n a n d rect u m) 
usi n g ulcer size, e xte nt of ulcer ate d s urface, e xte nt of affecte d s urface, a n d prese nce/t y p e of 
narr o wi n g. ( See A p pe n di x 4: Si m ple E n d osc o pic Sc ore f or Cr o h n’s Diseas e ( S E S -C D ) 
Defi niti o ns of S E S -C D Varia bles ). 
 
T he disease c o urse is varia ble wit h s o me patie nts e x perie nci n g a ver y mil d disease wit h 
i nfre q ue nt flare-u ps w hile ot hers ma y s uffer fr o m m ore se vere diseas e wit h fre q ue nt 
h os pitalizati o n s. E pi de mi ol o gical st u dies s h o w t hat o ver 1 year fr o m dia g n osis, 1 0-3 0 % of 
patie nts ha ve at least o ne e x acer bati o n; 6 7 -7 3 % of patie nts ha ve a c hr o nic i nter mitte nt c o urse; 
a n d 2 7 % a n d 2 9 % of pati e nts de vel o p strict ures or pe netrati n g diseas e, res p ecti vel y ( 2 -6). F or 
refr act or y C D or C D c o m plicate d b y p erf orati o n, i ntesti nal o bstr ucti o n, ste n osis or fist ulae, 
patie nts fre q ue ntl y r e q uir e b o wel s ur ger y ( 3; 6 -8).  
 
C o nsi dera ble cli nical a n d e x peri me ntal e vi de nce e xists t o de m o nstrate t hat a n altere d i m m u ne 
res p o nse t o c o m me nsal e nteric bact eria i n a ge neti call y s us ce pti ble h ost pla ys a k e y r ole b ot h 
i n t he de vel o p me nt a n d p ersiste nce of t he i ntesti nal i nfla m mati o n prese nt i n C D ( 9-1 1).  
Rece nt e vi de n ce i n dicat es t he prese nce of c haract eristic c ha n ges i n t he bi ostr uc t ure of t he 
fecal micr o bi ota i n C D patie nts ( 1 2). A d diti o nall y, fecal micr o bi ota of C D patie nts is 
u nsta ble o ver ti me as c o m pare d wit h healt h y s u bj ects ( 1 3), wit h i ncrease d E nter o bact eria a n d 
decrease d d e nsit y of b e n eficial bacteria s u c h as Fir mic utes (i n partic ular F. pr a us nitzii ), 
Bifi d o b acteri a , a n d L act o b acilli ( 1 3-1 6). F urt h er m ore, t he c orrelati o n bet wee n t he 
q ua ntificati o n of E. c oli i n ileal bi o psies a n d t he e xte nt of disease acti vit y i n C D patie nts, 
c o u ple d wit h t he a bilit y of C D -ass ociat e d E. c oli t o de m o nstrate pat h o ge n-li ke a d here nt a n d 
i n vasi ve be ha vi ors i n c ult ure d cells, s u p p ort t he r ole of E. c oli i n t he i nfla m mat or y pr ocess 
( 1 7; 1 8). 
 
Rifa xi mi n is a n oral, mi ni mall y a bs or b e d, n o n -s yste mic, a nti bacteri al a ge nt t hat e x erts its 
acti vit y i n t he i ntesti nal l u me n. B y decreasi n g t h e tri g gers of i m m u ne acti v ati o n as well as 
e nteric i nfla m mat or y res p o nse, rifa xi mi n ma y re d uce t he u nc o ntr olle d i m m u ne res p o nse t o 
e nteric bacteria, wit h o ut t he safet y c o ncer ns ass oci ate d wit h s yste mic br oa d s pectr u m 
a nti bi otics, i ncl u di n g metr o ni daz ole a n d ci pr ofl o x aci n. 
 
T he use of rif a xi mi n i n t he treat me nt of C D is s u p p orte d b y rece nt micr o bi ol o gic a n d 
p har mac o d y n a mic e vi de nce w hic h s u g gests b ot h a nti bacterial a n d a nti -i nfl a m mat or y eff ects 
as mec ha nis ms of acti o n as o ut li ne d bel o w: 


P a ge 1 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
A nti b acteri al eff ect a n d i m p act o n i ntesti n al mi cr o bi ot a:  
 
•  Rifa xi mi n is acti ve a gai nst t he bacteria t hat h a ve b ee n i n vesti gate d as p ossi ble pat h o ge nic 
a ge nts f or C D.  
•  Rifa xi mi n i n d uces i n e nter oa g gr e gati ve a n d e nter ot o xi ge nic E. c oli a l oss of vir ule nce 
fact ors s uc h as e nter ot o xi ns, s urface a d hesi o n fact ors a n d matri x metall o pr otei nase-9 
( M M P-9), a n d c h a n ges i n e pit helial cell p h ysi ol o g y ass o ciate d wit h c h a n ges i n b acteri al 
attac h me nt/i nter nalizati o n  ( 1 9; 2 0). 
•  Rifa xi mi n di d n ot alter t he o verall str uct ure of h u ma n c ol o nic micr o bi ota, b ut ca use d a n 
i ncreas e i n c o nce ntrati o ns of Bifi d o bacteri u m, At o p o bi u m a n d F. pra us nitzii, all be neficial 
bacteria, as s h o w n b y a s u p p or ti ve i n vitr o st u d y usi n g a c o nti n u o us c ult ure c ol o nic m o del 
s yste m t o a nal yze t he i m pact of rifa xi mi n a d mi nistrati o n o n t he fecal micr o bi ota of 
patie nts affecte d b y c ol o nic acti ve C D  ( 2 1). 
 
H ost eff ects of Rif a xi mi n:  
 
•  Rifa xi mi n affects bacteri al tra nsl oca ti o n t o mese nteric l y m p h n o d es ( 2 2). 
•  Rifa xi mi n i n d uce d a d o w n -re g ulati o n of pr o-i nfla m mat or y c yt o ki nes i n b ot h i n vitr o 
( 2 0; 2 1) e x peri me nts a n d a ni mal m o dels [tri nitr o be nze ne s ulf o nic aci d ( T N B S)-i n d uce d 
c olitis]. Rifa xi mi n -i n d uce d i n hi biti o n of c yt o ki ne pr o d ucti o n pr otecte d a ni mals a gai nst t he 
de vel o p me nt of c olitis  ( 2 3). 
•  Data i n dicate t hat t he a nti -i nfla m mat or y acti vit y of rifa xi mi n is d ue t o its g ut-s pecific 
h u ma n pre g na n e -X -rece pt or ( P X R) acti vati o n ( 2 3). Rifa xi mi n acti vati o n of P X R i n d uces 
t he i n hi bitio n of n uclear f act or ka p p a -li g ht-c hai n -e n ha ncer of acti vate d B cells ( N F -κ B) 
me diate d e x pressi o n of pr o -i nfla m mat or y fact ors ( 2 4; 2 5). T he d o w n-re g ulati o n of N F-κ B 
tar get ge nes is c o u pl e d wit h a n i m pr o ve me nt i n cli nical s y m pt o ms of c olitis ( 2 6). 
 
1. 2  
C urre nt T her a p y f or C r o h n’s  Dise ase  
 
T here is c urre ntl y n o c ur e f or C D. T he c h oice of t hera p y de p e n ds o n t he a n at o mical l ocati o n 
of t he disease, disease se verit y, a n d g oals of t hera p y w hic h i n cl u de i n d ucti o n a n d 
mai nte na nce of cli nical r e missi o n, treat me nt of i nfecti o us a n d ot her c o m plicati o ns ass ociate d 
wit h t he disease, a n d a v oi di n g h os pitalizati o ns a n d s ur geries. C urre nt treat me nts f or C D 
i ncl u de 5-a mi n osalic ylat e ( 5 -A S A) c o m p o u n ds, gl uc oc ortic oi ds, i m m u ne m o d ulat ors ( 6 - 
merca pt o p uri n e, met h otr e x ate, azat hi o pri ne), bi ol o gic res p o nse m o d ulat ors ( T u m or Necr osis 
Fact or al p ha ( T N F α ) i n hi bit ors), a n d a nti bi otics.  F or mil d t o m o derate C D, t w o a p pr oac hes 
t o t hera p y ar e use d i n t he o ut patie nt setti n g. Ste p-u p t hera p y is a gra de d t h era p y t hat i nitiall y 
u ses less p ote nt me dicati o ns ( wit h fe wer a d verse effects) s uc h as t h e 5-A S A dr u gs. If 
res p o nse is i na de q u ate, m ore p ote nt me dicati o ns s uc h as t he i m m u n o m o d ulat ors a n d bi ol o gics  


Page 20 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
are added. Top-down therapy begins with more potent therapies earlier in the course of the 
disease. Induction of remission for patients in an acute flare is typically achieved using 5- 
ASA drugs, antibiotics (see below), and/or a glucocorticoid. Patients with severe or 
fulminant disease are treated aggressively with available pharmacologic agents, bowel rest, 
parenteral nutrition, and intravenous glucocorticoids. 
 
Antibiotics, primarily metronidazole and ciprofloxacin, are used to treat complications of CD 
such as perianal disease, small intestinal bacterial overgrowth, postoperative infections, toxic 
colitis, and secondary infections such as Clostridium difficile (C. difficile). Given the 
association between enteric bacteria and CD as noted above, antibiotics have been evaluated 
as primary therapy for active CD. Metronidazole, a broad spectrum antibiotic with activity 
against enteric anaerobes, and ciprofloxacin, a broad spectrum antibiotic with activity against 
aerobic bacteria, have been investigated in several randomized, controlled trials. Results from 
these trials show that metronidazole given alone or with ciprofloxacin for 12 to 16 weeks is 
better than placebo, and comparable to methylprednisolone and sulfasalazine at reducing the 
CDAI score in patients with mild to moderate CD; however, it has been less effective than 
methylprednisolone at inducing clinical remission (26-29). Ciprofloxacin administered alone 
for up to 6 weeks has shown similar efficacy to mesalazine at inducing clinical remission 
(56% and 55%) in patients with mild to moderate disease. Early clinical evidence indicates 
that metronidazole may be more effective in patients with colonic disease (27;30-32). 
Metronidazole was more effective than steroids at reducing symptoms of CD including 
abdominal pain, diarrhea, fever, and general well-being (22). A retrospective review of 
patients with CD receiving rifaximin 600 mg/day for a median duration of 16.6 weeks 
demonstrated clinical improvements in CDAI score (33). While the efficacy of antibiotics 
supports the hypothesis that colonic flora contribute to the etiology of CD, both 
metronidazole and ciprofloxacin are potent broad spectrum antibiotics with significant side 
effect profiles and high systemic exposures. 
 
1.3 
Rifaximin DR Background 
 
Rifaximin Delayed Release (Rifaximin DR) tablets contain a new pharmaceutical formulation 
that has been designed to release the active drug following passage through the stomach, and 
to achieve a homogeneous distribution of rifaximin in the intestinal tract. The intent of the 
formulation is to provide uniform coverage of the active drug in the intestinal lumen, and to 
maximize contact with the intestinal mucosa. 
 
1.4 
Clinical Experience with Rifaximin 
 
A summary of the clinical studies conducted with rifaximin are provided in the Investigator’s 
Brochure. 


P a ge 2 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
Rifa xi mi n D R ta blets were descri be d as E xte n de d I ntesti nal Release ( Rifa xi mi n EI R) ta blets 
i n pre vi o usl y c o n d u cte d st u dies. T he release des cri pt or was c ha n ge d t o ‘ del a ye d rel ease’ t o 
reflect c o n ve nti o nal sta n dar d d osa ge f or m ter mi n ol o g y a n d t he release rate of t he dr u g 
pr o d uct fr o m t he f or m ulati o n.  
 
T hree p h ar mac o ki n etic st u dies wit h Rifa xi mi n EI R 4 0 0 m g ta blets ( R E TI C/ 0 1/ 0 6, 
R E TI C/ 0 2/ 0 6 a n d R E TI C -P K/ 0 0 4/ 2 0 0 9) a n d o ne s u p p orti ve st u d y wit h a n 8 0 0 m g sac het 
f or m ulati o n ( C CR U -0 1 5 1 4) ha ve bee n c o m plete d t o assess bi oa vaila bilit y.  
 
R E TI C/ 0 1/ 0 6 was a n o p e n la bel, ra n d o mize d cr oss -o ver st u d y t hat assess e d t he effect of a 
hi g h -f at brea kfast o n t he bi oa vaila bilit y of a si n gle 1 2 0 0 m g d ose of Rifa xi mi n EI R (ta blet 
f or m ulati o n), c o m par e d t o t he faste d state i n healt h y v ol u nteers. Ei g ht ee n s u bjects ( 9 males 
a n d 9 fe males) were r a n d o mize d. All s u bjects recei ve d t he treat me nt b ot h i n fasti n g sit uati o n 
a n d after f o o d. T he was h -o ut peri o d bet wee n t he t w o treat me nts was 8 d a ys. A d mi nistrati o n 
i n t he faste d a n d f e d state pr o d uce d si milar res ults i n ter ms of mea n Cma x  (sta n dar d de vi ati o n 
[ S D]) [ 5. 1 ( 3. 8) a n d 4. 4 ( 2. 9) n g/ m L, res pecti vel y], mea n A U Ct [ 1 1. 3 ( 8. 8) a n d 1 0. 2 ( 6. 0) 
n g· h/ m L, r es pecti vel y] a n d me dia n T ma x  ( 1 a n d 1. 5 h o urs, res pecti vel y). I n a d diti o n, t he 
a d mi nistrati o n of Rifa xi mi n EI R wit h f o o d di d n ot affect t he uri nar y e x creti o n, w hic h 
re pres e nte d < 0. 0 2 % of t he d ose i n b ot h c o n diti o ns. T he l o w s yste mic a bs or pti o n was 
c o nfir me d b y a st u d y i n healt h y s u bjects ( N = 9) a d mi nistere d Rifa xi mi n EI R 8 0 0 m g (sac het) 
as a si n gl e d ose ( C C R U -0 1 5 1 4).  
 
T he ver y l o w a bs or pti o n of rifa xi mi n was als o o bser ve d i n patie nts wit h acti ve C D 
( R E TI C/ 0 2/ 0 6). Ei g htee n patie nts wit h acti ve C D ( Har v e y Bra ds ha w i n de x of ≤ 7) a n d n o 
c o nc o mita nt t reat me nt wit h ot her a nti bi otics (fr o m t he wee k b ef ore scree ni n g), or oral a n d 
rectal ster oi ds (l ess t ha n 3 0 da ys pri or t o scree ni n g) recei ve d a si n gle oral d ose of 1 2 0 0 m g ( 3 
x 4 0 0 m g) Rifa xi mi n EI R ta blets. Rifa xi mi n pea k c o nce ntrati o n i n plas ma was reac h e d o n 
a vera ge at 1. 8 h o urs. T h e C ma x  ( S D) a vera ge d 1 1. 8 ( 1 0. 3) n g/ m L a n d mea n A U C0 -t ( S D) was 
4 7. 8 ( 3 0. 9) n g· h/ m L.  
 
A n o pe n -la bel st u d y w as perf or me d t o assess t he bi oa vaila bilit y of a re peat d ose of 1 2 0 0 m g 
( 3 x 4 0 0 m g) Rifa xi mi n EI R ta blets a d mi nistere d t wice dail y (t otal dail y d ose 2 4 0 0 m g) f or 7 
da ys i n 1 2 ( 1 0 e val ua bl e) acti ve C D patie nts ( R E TI C -P K/ 0 0 4/ 2 0 0 9). O n Da ys 1 a n d 7, o nl y 
t he m or ni n g d ose was a d mi nistere d. S yste mic e x p os ure t o rifa xi mi n was l o w after b ot h si n gle 
[ Cma x  ( S D) = 7. 8 ( 3. 5) n g/ m L; AU C 0 -t ( S D) = 3 4. 6 ( 1 9. 4) n g. h/ m L] a n d re peat d osi n g [ Cma x  
( S D) = 6. 1 ( 2. 4) n g/ m L; A U C0 -t ( S D) = 4 1. 4 ( 1 7. 4) n g. h/ m L). Stea d y-state was reac he d b y 
Da y 3 of m ulti ple d osi n g wit h a mi ni mal e xte nt of acc u m ulati o n ( R C = 1. 4 2). T he a m o u nt of 
rifa xi mi n e x crete d i n uri ne (c u m ulati ve uri n ar y e x creti o n ra n gi n g fr o m 0. 0 0 8 t o 0. 0 1 3 6 % of 
t he a d mi nistere d d ose) c o nfir me d t he l o w a bs or pti o n.  
 
T w o P hase 2 pil ot/ pr o of of c o nce pt st u dies ( G R A C E 0 1 a n d G R A C E 0 2), a n d a P hase 2 d ose - 
ra n ge fi n di n g st u d y ( R E TI C/ 0 3/ 0 6) ha v e bee n co m plete d; a sac het d os a ge f or m of Rifa xi mi n  


P a ge 2 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
EI R w as use d i n G R A C E 0 1 a n d 0 2, a n d t he prese nt f or m ulati o n was use d i n R E TI C/ 0 3/ 0 6. 
G R A C E 0 1 was a place b o c o ntr olle d st u d y i n 8 3 mil d t o m o derate C D patie nts t hat e val uate d 
Rifa xi mi n EI R 8 0 0 m g Q D a n d BI D vers us place b o; G R A C E 0 2 was a n u n c o ntr olle d st u d y 
t hat e val uate d Rifa xi mi n EI R 8 0 0 m g Q D a n d BI D. Efficac y was e val uat e d pri maril y b y t he 
rate of cli nical re missi o n defi ne d as C D AI sc ore <  1 5 0 p oi nts after 1 2 wee ks of t hera p y.  
Gi ve n t he s mall n u m ber of patie nts i n b ot h st u dies, a n d t he u nc o ntr olle d d esi g n of G R A C E 
0 2, neit her st u d y m et t he pri mar y e n d p oi nt; data di d s u p p ort p ote ntial efficac y i n t he 8 0 0 m g 
BI D re gi me n.  
 
T he c urr e nt ta blet f or m ul ati o n of Rifa xi mi n EI R w as e val uate d i n a P hase II d ose ra n ge 
fi n di n g st u d y i n 4 0 2 patie nts wit h a n ac ute flare of C D ( R E TI C/ 0 3/ 0 6). Patie nts wit h a C D AI 
bet wee n 2 2 0 a n d 4 0 0 p oi nts were r a n d o mize d t o 4 treat me nt gr o u ps: Rifa xi mi n EI R 4 0 0 m g 
t wice a da y, Rif a xi mi n EI R 8 0 0 m g BI D, Rifa xi mi n EI R 1 2 0 0 m g BI D or place b o BI D f or 1 2 
wee ks. Patie nts w h o ac hie ve d cli nical re missi o n at t he e n d of t he treat me nt peri o d, defi ne d as 
C D AI s c ore < 1 5 0 p oi nts, were a d mitte d t o a 3 -m o nt h f oll o w -u p p hase. Pati e nts were all o we d 
t o c o nti n ue sta ble d oses of oral 5-A S A, merca pt o p uri ne, azat hi o pri ne, a n d/ or met h otre x ate as 
c o nc o mita nt t hera pies t hr o u g h o ut t he st u d y ( u p t o 1 2 wee ks), w hile t h e use of a nti bi otics a n d 
oral, i ntra ve n o us, a n d rectal ster oi ds was n ot per m itte d. 
 
As a d d -o n t her a p y ( 8 3 % of e nr olle d patie nts w ere treate d wit h sta ble d oses of 5 -A S A a n d/ or 
met h otre x ate, azat hi o pri ne a n d mer ca pt o p uri ne), Rifa xi mi n EI R 8 0 0 m g t wi ce a d a y was 
statisticall y s u peri or t o pl ace b o i n i n d uci n g cli nical re missi o n ( C D AI <  1 5 0 p oi nts) after 1 2 
wee ks of t hera p y ( p = 0. 0 0 7) a n d mai ntai ni n g re missi o n f or t hree m o nt hs aft er Rifa xi mi n EI R 
was st o p pe d ( p = 0. 0 2).  
 
Hea dac he ( 6 % of patie nts), C D s y m pt o ms ( 6 % of patie nts), na usea ( 4 % of patie nts), 
flat ule nce ( 2 % of p atie nts), nas o p har y n gitis ( 2 % of patie nts), a n d fe ver ( 2 % of patie nts) were 
t he m ost c o m m o nl y re p orte d dr u g-relate d A Es. O ne case of C. difficile i nfecti o n was 
dia g n ose d 2 0 da ys after t he e n d of t he treat me nt p eri o d i n a patie nt w h o recei ve d Rifa xi mi n 
EI R 8 0 0 m g t wice d ai l y. A s u d de n deat h d uri n g t h e f oll o w-u p peri o d, ca use d b y ac ute 
massi ve bilateral p ul m o nar y e de m a, was re p orte d i n a patie nt wit h pree xisti n g c o n c o mita nt 
arr h yt h mia. T he d eat h w as assesse d as u nli kel y relate d t o t he st u d y dr u g. N o cli nicall y 
si g nifica nt c ha n ges i n t he res ults of safet y la b orat or y tests w ere o bs er ve d i n a n y st u d y gr o u p.  
 
I n a d diti o n t o t he st u dies n ote d a b o ve f or Rifa xi mi n EI R, rifa xi mi n has bee n st u die d i n 
a p pr o xi matel y 5 0 0 0 s u bjects i n m ulti ple cli nical st u dies i n irrita ble b o wel disease ( I B S) ( N = 
1 1 0 3); a n d i n ot her t her a pe utic areas i ncl u di n g treat me nt of tra velers’ diarr hea ( N = 5 9 3), 
tra velers’ diarr h ea pr o p h yl a xis ( N = 8 2 0), ac ute h e patic e n ce p hal o pat h y ( N = 1 5 2), a n d 
rec urre nce of h e patic e n ce p hal o pat h y ( N = 3 4 8). I n a d diti o n, t here is o ver 2 0 years of p ost- 
mar keti n g e x perie nce wit h t he dr u g.  


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1.5 
Study Rationale 
 
Crohn’s disease is a chronic, relapsing, remitting, systemic disease which may result in 
transmural inflammation of the gastrointestinal tract. Bacteria might be involved in the 
development and persistence of inflammation in patients with CD. Rifaximin has been shown 
to induce in enteroaggregative and enterotoxigenic E. coli a loss of virulence factors such as 
enterotoxins, surface adhesion factors and MMP-9, and changes in epithelial cell physiology 
associated with changes in bacterial attachment/internalization. Rifaximin DR is an oral, 
minimally absorbed, non-systemic, antimicrobial agent that exerts its effects on bacteria in the 
intestinal lumen. By decreasing the triggers of immune activation as well as enteric 
inflammatory response, rifaximin may reduce the uncontrolled immune response to enteric 
bacteria, without the safety concerns associated with systemic broad spectrum antibiotics.  In 
a large Phase 2 dose-ranging study, a Rifaximin EIR regimen of 800 mg twice daily for 12 
weeks induced remission in patients with mild to moderate CD, and was generally well 
tolerated.  Given the need for safe and effective alternatives to immunomodulator and 
biologic therapy for CD in patients with mild to moderate disease, this Phase 3 trial will be 
conducted to assess the viability of Rifaximin DR for the treatment of CD. 
 
Rifaximin is a semisynthetic antibiotic of the rifamycin class. Rifaximin is, however, unique 
in this class due to its gut-targeted activity and minimal systemic absorption. In vitro, 
rifaximin binds to the beta subunit of the bacterial DNA-dependent RNA polymerase to 
inhibit bacterial RNA synthesis, resulting in its classification as a broad spectrum antibiotic. 
However, in vivo, rifaximin does not appear to affect to a clinically significant extent the 
numbers or diversity of the endogenous enteric bacteria at therapeutic doses that have been 
tested. 
 
The clinical experience with rifaximin is extensive, having been commercially available since 
1987 following its initial approval in Italy. Today rifaximin is approved and in use in over 35 
countries for a number of gastrointestinal (GI) indications which are responsive to its gut- 
targeted effects. There are more than 800 publications involving rifaximin in the scientific 
literature, including approximately 100 preclinical and approximately 200 clinical study 
reports. Rifaximin has also been extensively studied in controlled clinical studies with a total 
of approximately 5,000 subjects enrolled. Two clinical development programs have resulted 
in approvals in many of the markets in North America and Europe and include treatment of 
travelers’ diarrhea and the prevention of overt hepatic encephalopathy recurrence. 
Additionally, there is positive data from prophylaxis of travelers’ diarrhea (PRO3 study, Salix 
data on file) and C. difficile infection studies (Study RFCL3001, Salix data on file). Rifaximin 
possesses a strong safety record and adverse events are well-characterized, generally mild, 
and similar to placebo. 
Crohn’s disease is the fourth major development program that has been undertaken with 
rifaximin. Rifaximin DR has been developed in order to provide a formulation of rifaximin 


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that exerts its targeted effects on bacteria throughout the small and large intestinal lumens. By 
decreasing the triggers of immune activation as well as enteric inflammatory response, 
rifaximin may reduce the uncontrolled immune response to enteric bacteria, without the safety 
concerns associated with systemic broad spectrum antibiotics.  The rationale for Rifaximin 
DR in the treatment of CD is based on its three plausible mechanisms of action. Rifaximin 
affects gut bacteria and reduces bacterial products that negatively affect the host. It may also 
up-regulate gut detoxification mechanisms and decrease the inflammatory response 
mechanisms of the host to bacterial products. Bacteria have been purported to be involved in 
the development and persistence of inflammation in patients with CD. Finally, rifaximin 
impacts both the bacterial and host response and the bacteria host interface. It has been shown 
to induce in enteroaggregative and enterotoxigenic E. coli a loss of virulence factors such as 
enterotoxins, surface adhesion factors and MMP-9, and changes in epithelial cell physiology 
associated with changes in bacterial attachment/internalization. 
Rifaximin DR presents a unique paradigm in the treatment of mild to moderate CD. The 
proposed dosing for Rifaximin DR will remain constant from the induction phase through the 
long term treatment phase with no reduction in dose required. Unlike biologic or 
corticosteroid therapy, there is no known suppression of the host immune system associated 
with the use of Rifaximin DR. In a large Phase 2 dose-ranging study, the delayed release 
formulation of rifaximin (also called Rifaximin EIR) 800 mg, taken twice daily for 12 weeks 
induced remission in patients with mild to moderate CD, and was generally well tolerated. 
1.6 
Primary Endpoint Development for the United States 
 
The primary endpoint for this study was developed in collaboration with the United States 
(US) Food and Drug Administration (FDA). In discussions with Salix, the FDA has indicated 
that use of the CDAI as the primary endpoint in CD trials will no longer be acceptable. It is 
now recommended that a co-primary endpoint for CD studies, as defined during the 
Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT II) 
meeting, be used to assess clinically meaningful outcomes for both symptoms and changes in 
the appearance of the inflamed ileocolonic mucosa. 
 
After further discussions with the FDA and several key opinion leaders regarding the best 
way to meet these recommendations, Salix developed responder criteria based on the 
validated Short CDAI (34) and data from a previous CD study conducted with rifaximin 
(Phase 2 dose-range finding study RETIC/03/06). Symptoms included in the short CDAI 
were “abdominal pain” and “diarrhea frequency”. 
 
Assuming that a CDAI score of < 150 points always reflects the true disease activity of 
clinical remission in Crohn’s disease, Salix developed a symptom index for Crohn’s disease 
to assess a clinically significant “symptomatic response.” The following points were used to 
assess symptomatic activity in Crohn’s disease when a CDAI score of < 150 points is 
considered the “gold standard”: 


P a ge 2 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
 
•  Se nsiti vit y e v al uates h o w well a test is at detecti n g a p ositi ve res p o nse, i.e., s y m pt o m 
re missi o n. 
•  S pecificit y esti mates h o w li kel y s u bjects wit h o ut cli nical re missi o n (i.e., C D AI s c ore of ≥ 
1 5 0 p oi nts) ca n be c orrectl y r ule d o ut bas e d o n t he  test. 
•  Acc ur ac y meas ures h o w c orrect a dia g n ostic test i de ntifies a n d e x cl u des a gi ve n c o n diti o n 
(e. g., C DAI < 1 5 0  p oi nts).  
Usi n g t he p oi nts o utli ne d a b o ve, t he le v el of t he s y m pt o m meas ures (li q ui d/ ver y s oft st o ols 
a n d a b d o mi nal pai n) w er e deter mi ne d t o be s uffici e nt t o defi ne s y m pt o matic re missi o n.  
 
A n a nal ysis of t he data fr o m t he P hase 2 C D st u d y c o n d ucte d wit h rifa xi mi n was perf or me d 
i n or der t o deter mi ne li q ui d/ ver y s oft st o ol c o u nts f or s u bjects w h o ha d cli nical re missi o n a n d 
s u bjects w h o di d n ot ac hi e ve cli nical re missi o n base d o n a C D AI sc ore of < 1 5 0 p oi nts. T he 
recei v er o perati n g c haracteristics ( R O C) c ur ve a nal ysis f or t he dia g n osis of cli nical re missi o n 
b y li q ui d/ ver y s oft st o ol c o u nts s h o we d a n area u n der t he R O C c ur v e val u e of 0. 7 9. T he area 
u n der t he R O C c ur v e val ue i n dicate d t hat li q ui d/ ver y s oft st o ol c o u nt ha d g o o d acc urac y i n 
pre dict i n g cli nical re missi o n base d o n a C D AI s c ore of < 1 5 0 p oi nts. S u bse q ue ntl y, t he 
n u m ber of li q ui d/ ver y s oft st o ols was use d t o i de ntif y t he c ut -p oi nts t hat res ulte d i n t he 
o pti mal bala nce of s e nsiti vit y, s p ecificit y a n d acc urac y f or pre di cti n g a C D AI sc ore of < 1 5 0 
p oi nts. T he data i n dicate d a c ut p oi nt of 1 0 as o pti mal. T h us, f or li q ui d/ ver y s oft st o ols, 
s u bjects wit h a wee kl y t otal of 1 0 or less will be cl assifie d as res p o n d ers. 
 
A d diti o nal a nal ysis pr o d uce d a r es p o n der defi niti o n f or a b d o mi nal pai n. A res p o n der f or 
a b d o mi nal pai n is base d o n a dail y rati n g (sc ore) of ≤1.  
 
A res p o n der, base d o n t h e Sali x e n d p oi nt, will meet t he criteria f or li q ui d/ ver y s oft st o ols 
A N D a b d o mi nal pai n i n a gi v e n wee k.  
 
T he Si m ple E n d osc o pic Sc ore f or Cr o h n's Dis eas e ( S E S -C D) w as c h os e n as t he vali date d 
meas ure me nt of e n d osc o pic a p peara nce beca use it c orrel ate d well wit h t he m ore c o m ple x 
Cr o h n's Disease E n d osc o pic I n d e x of Se verit y ( C D EI S). W hile t he C D EI S has bee n use d f or 
e n d osc o pic sc ori n g of C D lesi o ns f or 2 0 years, it is n o t c o m m o nl y us e d i n cli nical practice 
beca use it is c o m plicate d a n d ti me -c o ns u mi n g ( 3 5). Sali x has deter mi ne d t hat a decreas e i n 
t he S E S-C D sc ore of at l east 3 p oi nts is cli nicall y mea ni n gf ul base d o n t he a nal ysis of t he 
S O NI C trial d ata i n Cr o h n’s disease ( 3 6).  T heir a nal ysis i ncl u de d a n e val u ati o n of 
e n d osc o pic r es p o nse i n p atie nts wit h baseli ne S E S -C D sc ores of ≥ 7 , a n d c o ncl u de d t hat 
e n d osc o pic r es p o nse ( d efi ne d as a decrease fr o m baseli ne i n S E S -C D sc ore of at least 5 0 % 
after 2 6 w ee ks of treat me nt) c o ul d pre dict patie nts m ost li kel y t o ac hie ve c ortic oster oi d -free 
cli nical re missi o n after 5 0 wee ks of treat me nt. T h e pr o p ose d 3 -p oi nt c h a n ge i n S E S -C D i n 
t his st u d y is c o nsiste nt wit h t he res ults of t he S O NI C a n al ysis i n pre dicti n g c ortic oster oi d -free 
cli nical re missi o n a n d reflects a n a p pr o xi mate 5 0 % re d ucti o n i n t he mi ni m u m  S E S -C D  


P a ge 2 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
baseli ne sc or e at st u d y e ntr y of 7. W hereas e n d osc o pic res p o nse, d efi ne d as a re d ucti o n i n  t h e 
S E S -C D sc ore of at least 3 p oi nts, reflects a cli nicall y si g nifica nt i m pr o ve me nt i n ile oc ol o nic 
i nfla m mati o n, t here ma y still be i nfla m mati o n prese nt. E n d osc o pic re missi o n has bee n 
defi ne d as a n a bse n ce or near a bs e nce of e n d os c o picall y e vi de nt i nfla m mati o n as reflect e d i n 
S E S -C D sc ore of 0 t o 2  ( 3 7). 
 
I n or der t o f ull y ass ess f or t he prese n ce of ile oc ol o nic Cr o h n’s disease a n d calc ulate a n 
acc ur ate S E S -C D sc or e, t he e n d osc o pist m ust atte m pt t o i nt u bate a n d vis ualize t he ter mi nal 
ile u m i n or der t o deter mi ne prese n ce a n d e xte nt of disease d uri n g eac h ile o c ol o n osc o p y. T o 
re d uce t h e p ote ntial f or bias or varia bilit y i n e n d os c o p y s c ori n g, bli n de d ce ntral rea di n g will 
be utilize d t o deter mi ne t he S E S -C D sc ores f or all ile oc ol o n osc o pies o btai n e d d uri n g t he 
st u d y. As s uc h, e ver y eff ort m ust be ma de at eac h pr oce d ure t o f ull y vis u alize eac h se g me nt 
of t he ter mi nal ile u m a n d c ol o n t o facil itate ce ntral rea di n g of t he rec or de d pr oce d ures. T he 
rate of wit h dr a wal of t h e c ol o n osc o pe d uri n g t he pr oce d ure s h o ul d als o be s ufficie ntl y sl o w as 
t o all o w f or a de q u ate vis ualizati o n a n d sc ori n g of eac h se g m e nt i n t he vi de o rec or di n g b y a 
ce ntral r ea d er.  Strict ures t hat d o n ot per mit f urt her passa ge of t h e c ol o n osc o pe s h o ul d be 
a n n otate d as  s uc h. 
 
T he c o -pri mar y efficac y e n d p oi nts f or i n d ucti o n of cli nical re missi o n wit h  e n d osc o pic 
res p o nse are defi ne d b y  
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 1 6 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 1 6  visit.  
•  E n d osc o pic res p o ns e defi ne d as  a ≥ 3-p oi nt decrease i n t he S E S -C D fr o m baseli ne t o t he 
S E S -C D sc ore o btai ne d bet wee n Wee k 1 6 a n d Wee k 1 7. S E S -C D sc ores will be 
calc ulate d fr o m ce ntrall y-rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at baseli ne a n d 
bet wee n Wee k 1 6 a n d Wee k  1 7.  
Si mil arl y, t here will be t w o ke y c o -s ec o n dar y e n d p oi nts of efficac y assess e d d uri n g t he L o n g 
Ter m Treat me nt  P hase.  
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 5 2 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 5 2  visit.  
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 at Wee k 5 2. S E S -C D sc ores will 
be calc ul ate d fr o m ce ntrall y -r ea d di gital vide o of ile oc ol o n osc o pies perf or me d at Wee k  5 2.  
I n t he P h ase 3 st u dies Sali x is c o n d ucti n g, t hese e n d p oi nts will be e val uate d f or 
res p o nsi ve ness (i.e., d e m o nstrate t he a bilit y t o det ect cli nicall y mea ni n gf ul c ha n ge i n diseas e 
acti vit y i n de x es of C D, f or e x a m ple f ull C D AI) a n d vali dit y (i.e., de m o nstrate c orrelati o ns  


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with other measures of disease activity indexes of CD). These attributes are consistent with 
recommendations in the published FDA Guidance for Industry on the use of patient-reported 
outcomes (2009) (38). 


P a ge 2 8  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
2. 0  
O B J E C TI V E S A N D  E N D P OI N T S  
 
2. 1  
O bjecti ves  
 
2. 1. 1  
Pri m ar y  O bjecti v e  
 
T o deter mi ne t he effi cac y of Rif a xi mi n D R 8 0 0 m g BI D vs. place b o o n t he i n d ucti o n of 
cli nical re missi o n a n d e n d osc o pic res p o nse f oll o wi n g 1 6 wee ks of treat me nt i n s u bjects 
prese nti n g wit h acti ve m o derate Cr o h n’s  diseas e.  
2. 1. 2  
Sec o n d ar y  O bjecti ves  
 
A ke y sec o n d ar y o bjecti ve is t o e val uate cli nical a n d e n d osc o pic re missi o n f oll o wi n g a n 
a d diti o nal 3 6 -wee k L o n g Ter m Treat me nt P hase of Rifa x i mi n D R 8 0 0 m g BI D vs. place b o. 
T he sec o n d ar y o bjecti ves of t his st u d y are t he f oll o wi n g:  
•  Assess t he safet y of Rifa xi mi n D R f oll o wi n g a 1 6 -wee k i n d ucti o n, a n d a n a d diti o nal 3 6 - 
wee k L o n g T er m Treat me nt P hase (i.e., u p t o 5 2 wee ks of treat me nt f or eli gi ble  s u bjects). 
•  Assess t he p o p ulati o n p har mac o ki netics of Rifa xi mi n  D R.  
•  C haracterize t he gastr oi ntesti nal micr o bi ota fr o m st o ol sa m ples, a n d a nti bi otic resista nce 
fr o m bacteria c ult ure d fr o m st o ol sa m ples bef ore a n d after treat me nt wit h Rifa xi mi n D R.  
•  E val uate t he effects of Rifa xi mi n D R treat me nt o n i n dices of healt h  o utc o m es.  
•  Assess t he eff ects of Rifa xi mi n D R treat me nt o n bi ol o gical (i nfl a m mat or y) mar kers  of 
disease.  
2. 2  
E n d p oi nts  
 
2. 2. 1  
Pri m ar y Effic ac y  E n d p oi nts  
T here will be t w o c o -pri mar y m eas ures of effic ac y f or I n d ucti o n of Cli nical Re missi o n a n d 
E n d osc o pic Res p o nse. T he first c o -pri mar y e n d p oi nt is:  
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 1 6 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 1 6  visit.  
T he sec o n d c o -pri mar y e n d p oi nt is:  
 
•  E n d osc o pic res p o ns e defi ne d as a ≥ 3 -p oi nt decrease i n t he S E S -C D fr o m baseli ne t o t he 
S E S -C D sc ore o bta i ne d bet wee n Wee k 1 6 a n d Wee k 1 7. S E S-C D sc ores will be 
calc ulate d fr o m ce ntrall y-rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at baseli ne a n d 
bet wee n Wee k 1 6 a n d Wee k  1 7.  


P a ge 2 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
F or t he d ail y st o ol data, t he n u m ber of d ail y li q ui d/ ver y s oft st o ols wit h a c o nsiste nc y of a 
Brist ol St o ol F or m Scale [ B S F S] sc ore of T y pe 6 or T y p e 7 will be assess e d usi n g t he 
i nf or mati o n rec or de d b y t he s u bject via a n el ectr o nic diar y s yste m. T he n u m ber of 
li q ui d/ ver y s oft st o ols i n a gi v e n wee k will be cal c ulate d as f oll o ws: 
( N u m ber of li q ui d/ ver y s oft st o ols d uri n g t hat wee k ÷ N u m ber of da ys wit h n o n- 
missi n g assess me nts d uri n g t hat w ee k) × 7  
 
2. 2. 2  
Ke y Sec o n d ar y  E n d p oi nts  
 
T he ke y sec o n dar y e n d p oi nt is cli nical a n d e n d osc o pic re missi o n. T w o ke y c o -sec o n d ar y 
e n d p oi nts of efficac y will assess t his e n d p oi nt d uri n g t he L o n g T er m Treat me nt P hase. T he 
first is: 
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 5 2 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 5 2  visit.  
T he sec o n d is:  
 
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 a t Wee k 5 2. S E S-C D sc ores will 
be calc ul ate d fr o m ce ntrall y -r ea d di gital vi de o of ile oc ol o n osc o pies perf or me d at Wee k 5 2.  
2. 2. 3  
Sec o n d ar y Effic ac y  E n d p oi nts  
 
•  I n d u cti o n of cli nical r e missi o n defi ne d as a C D AI Sc ore of less t ha n 1 5 0 p oi nts at 
Wee k 1 6.
 
•  Cli nical s y m pt o m r e missi o n o ver ti me: T he t otal n u m ber of li q ui d/ ver y s oft st o ols f or t he 
7 da ys pri or t o eac h cli nic visit bei n g ≤ 1 0; A N D ( 2) a n a b d o mi nal pai n rati n g of ≤ 1 o n 
eac h d a y f or t he l ast 7 da ys pri or t o eac h cli nic visit i n ≥ 8 0 % of t he st u d y  visits d uri n g t he 
5 2 -Wee k Treat me nt Peri o d, i ncl u di n g Wee k  5 2.  
•  Ti me u ntil d ura ble res p o nse (see Secti o n 8. 6. 2) t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of 
t he c o-pri mar y e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt  Peri o d.  
•  Ti me u ntil d ura ble res p o nse ( See Secti o n  8. 6. 2) t o t he a b d o mi nal pai n c o m p o ne nt of t he 
c o-pri mar y e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt  Peri o d.  
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he c o -pri mar y 
e n d p oi nt at p ost -baseli ne ti me  p oi nts.  
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of t he  c o- 
pri mar y e n d p oi nt at p ost -baseli ne ti me  p oi nts.  
•  C ha n ge fr o m bas eli ne i n S E S -C D sc ore at Wee k 1 6 a n d Wee k  5 2.  
•  Pr o p orti o n of s u bjects wit h S E S -C D sc ore of 0 at Wee k  5 2.  


P a ge 3 0  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Pr o p orti o n of s u bjects w h o ac hie ve cli nical re missi o n b y t he C D AI e n d p oi nt at p ost - 
baseli ne ti me  p oi nts.  
•  Ti me t o l oss of C D AI res p o nse defi ne d b y a C D AI sc ore of ≥ 1 5 0 p oi nts d uri n g t he L o n g 
Ter m Treat me nt  P hase.  
•  Perce nta ge of s u bjects w h o ac hie ve cli nical res p o nse at p ost -baseli ne ti me p oi nts. Cli nical 
res p o nse is defi n e d as a r e d ucti o n of at least 1 0 0 p oi nts fr o m t he baseli ne C D AI s c ore. 
•  Ti me t o cli nical re missi o n base d o n a b d o mi nal pai n a n d li q ui d st o ol c o m p o ne nts of t he  c o- 
pri mar y  e n d p oi nts.  
•  Ti me t o cli nical re missi o n base d o n C D AI <  1 5 0.  
•  C ha n ge fr o m bas eli ne i n i n dices of healt h o utc o m es (I nfla m mat or y B o w el Disease 
Q uesti o n naire [I B D Q], W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q u esti o n naire  f or 
Cr o h n's Disease [ W P AI -C D]) at p ost -baseli ne ti me  p oi nts.  
•  C ha n ge fr o m bas eli ne i n mar kers of i nfl a m mati o n (e. g. C R P, i nterle u ki ns, c yt o ki nes,  fecal 
cal pr otecti n) at p ost-baseli ne ti me  p oi nts.  
2. 2. 4  
S af et y  E n d p oi nts  
 
•  I n ci de nce, i nte nsit y, a n d t y pes of a d vers e e v e nts ( A Es). 
•  C ha n ges fr o m bas eli ne i n t he la b orat or y p ara met ers ( he mat ol o g y, cli nical  c he mistr y, 
uri nal ysis).  
•  C ha n ge fr o m bas eli ne i n vital si g n  meas ure me nts.  
2. 2. 5  
E x pl or at or y  Assess me nts  
 
E x pl orat or y assess me nts will i ncl u de:  
•  C haracterizati o n of st o ol micr o bi ota at baseli ne a n d after 1 6 a n d 5 2 wee ks of  treat me nt. 
 Baseli ne a n d p ost -treat me nt bacteri al D N A is olate d fr o m st o ol f or 1 6 S r R N A ge ne 
a m plificat i o n. 
 Descri pti ve c h aracterizati o n of bacteri a i n st o ol  b y:  
•  Is olati o n a n d i d e ntificati o n of selecte d Gra m-n e gati ve a n d Gra m -p ositi ve 
bacteria.  
•  Resista nce t o select e d a nti bi otics, i ncl u di n g rifa xi mi n a n d  rifa m pi n. 
•  Ge n o mic pr ofili n g of pr e g na n e X rece pt or ( P X R) i n  bl o o d.  
•  P o p ulati o n p har mac o ki netics of  rifa xi mi n. 


P a ge 3 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
3. 0  
I N V E S TI G A TI O N A L P L A N  
 
3. 1  
O ver vie w of St u d y  Desi g n  
 
R E C D 3 1 2 6 is a d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p, m ultice nt er, m ultire gi o nal, 
5 2 -wee k st u d y t o assess t he effi cac y a n d safet y of Rifa xi mi n D R ta blets f or t he i n d ucti o n of 
cli nical re missi o n a n d e n d osc o pic res p o nse at 1 6 wee ks f oll o we d b y cli nical a n d e n d osc o pic 
re missi o n after 5 2 w ee ks of c o nti n u o us t hera p y i n s u bjects wit h acti ve m o d erate Cr o h n’s 
disease. S u bjects wit h acti ve, m o derate disease defi ne d b y a C D A I sc ore of ≥ 2 2 0 a n d ≤ 4 5 0 
p oi nts at scree ni n g, a n d e vi de nce of acti ve ile oc ol o nic Cr o h n’s disease d efi ne d b y a mi ni m u m 
S E S -C D of 7 deter mi ne d d uri n g b aseli ne ile oc ol o n osc o p y will be eli gi ble f or t he st u d y.  
Eli gi ble s u bjects will c o m plete a 2 - t o 3-w ee k Sc ree ni n g Peri o d, a 5 2-wee k Treat me nt Peri o d 
c o nsisti n g of a 1 6 -wee k I n d ucti o n P hase a n d 3 6 -Wee k L o n g T er m Treat me nt P hase, a n d a 2 - 
wee k F oll o w -u p Peri o d. S u bjects w h o s uccessf ull y c o m plet e t he 2 - t o 3-w ee k Scree ni n g 
Peri o d a n d q ualif y base d o n C D AI a n d S E S -C D sc ores will e nter t he 5 2 -wee k Treat me nt 
Peri o d of t he trial a n d will be ra n d o mize d i n a 1: 1 all ocati o n t o Rifa xi mi n D R 8 0 0 m g BI D or 
place b o. Ra n d o mize d s u bjects will ha ve s u bse q ue nt ile oc ol o n osc o pies c o n d ucte d at t he e n d 
of t he I n d ucti o n P hase ( b et wee n Wee ks 1 6 a n d 1 7), a n d f oll o wi n g c o m pleti o n of t he 3 6 -wee k 
L o n g T er m Treat me nt P hase ( Wee k 5 2) t o assess t he effects of treat me nt o n t he de gree of 
m uc osal heali n g. Assess me nts of efficac y a n d safet y will be p erf or m e d d uri n g cli nic visits at 
Wee ks 0 ( basel i ne), 2, 4, 8, 1 2, a n d 1 6; t he n e ver y f o ur wee ks t hr o u g h Wee k 5 2. All s u bjects 
will c o m plete a 2 -wee k (st u d y dr u g free) F oll o w -u p Peri o d f oll o wi n g c o m pleti o n of t he 5 2 - 
wee k Tr eat me nt Peri o d, a n d will ret ur n t o t he cli nic f or fi nal ass ess me nts ( E n d -of -St u d y 
[ E O S] visit; Wee k 5 4). See Fi g ur e 1. 


P a ge 3 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
Fi g ure 1 Desi g n Sc he m atic  
 
3. 2  
R ati o n ale f or Pr o p ose d St u d y Desi g n  
 
T he desi g n of St u d y R E C D 3 1 2 6 i ncl u di n g t he 5 2 -wee k Treat me nt Peri o d asses si n g b ot h 
i n d ucti o n of cli nical re missi o n wit h e n d osc o pic res p o nse at Wee k 1 6 a n d cli nical re missi o n 
wit h e n d osc o pic re missi o n at Wee k 5 2, t he c o -pri mar y e n d p oi nts selecte d f or i n d ucti o n a n d 
t he c o-meas ures of efficac y f or t he L o n g T er m Treat me nt p hase are  c o nsiste nt wit h re g ulat or y 
g ui da n ce ( F D A m eeti n g a d vice/ mi n utes wit h Sali x/ Alfa Wasser ma n n), a n d t he cli nical 
ma na ge me nt of p atie nts wit h Cr o h n’s disease.  
 
E n d p oi nt de vel o p me nt is pr o vi de d i n Sec ti o n 1. 6. 
 
3. 3  
Tre at me nt  Assi g n me nt/ R a n d o miz ati o n  
 
S u bjects w h o s uccessf ull y c o m plet e t he Scree ni n g Peri o d will e nter t he Treat me nt Peri o d a n d 
will be ra n d o mize d i n a 1: 1 all ocati o n t o o ne of  t w o treat me nt gr o u ps f or t h e d urati o n of t he 
st u d y as assi g ne d b y t h e mea ns of ce ntralize d electr o nic ra n d o mizati o n s yst e m. 
Ra n d o mizati o n will be stratifie d b y st u d y ce nter wit hi n a c o u ntr y. Treat me nt gr o u ps are as 
f oll o ws: 
 
•  Treat me nt  A:  
Rifa xi mi n D R Ta bl ets 8 0 0 m g BI D  
•  Treat me nt  B:  
Place b o BI D  


Page 33 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
3.4 
Procedures for Breaking the Blind 
 
Only in the case of an emergency, when knowledge of the study drug is essential for the 
clinical management or welfare of the subject, will the investigator be allowed to unblind a 
subject’s treatment assignment. To discuss breaking of the blind or to break the blind, please 
contact the study manager at Salix Pharmaceuticals, Inc. by using the following contact 
information: 
 
 
Clinical Project Manager 
Rifaximin DR RECD3126 Study 
Salix Pharmaceuticals, Inc. 
8510 Colonnade Center Drive 
Raleigh, NC 27615 
 
 
 
For sites outside the USA and Canada: 
See your Study Reference Manual for your country specific 
information. 
 
 
If the investigator breaks the blind for an individual subject, the reason must be recorded on 
the CRF and the subject will be removed from the study. 


P a ge 3 4  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
4. 0  
S E L E C TI O N A N D WI T H D R A W A L O F  S U B J E C T S  
 
4. 1  
I ncl usi o n Criteri 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 if he/s h e meets all of t h e f oll o wi n g 
criteria:  
1.  
S u bject is ≥ 1 8 years of a ge at Scree ni n g.  
2.  
S u bject is male or  fe male. 
Fe males of c hil d beari n g (re pr o d u cti ve) p ote ntial m ust ha ve a ne gati ve s er u m pre g n a nc y 
test at scree ni n g a n d a gr ee t o use a n acce pt a ble met h o d of c o ntrace pti o n t hr o u g h o ut 
t heir partici pati o n i n t he st u d y. Acce pta ble m et h o ds of c o ntrace pti o n i ncl u de d o u ble 
barrier m et h o ds (c o n d o m wit h s per mici dal jell y or a dia p hra g m wit h s per mi ci de), 
h or m o nal met h o ds (e. g., oral c o ntrace pti ves, pat c hes or me dr o x y pr o gester o ne acetate), 
or a n i ntra uteri n e de vice (I U D) w it h a d oc u me nte d fail ure rate of less t ha n 1 % per year. 
A bsti ne nce or p art ner(s) wit h a vasect o m y ma y be c o nsi dere d a n acce pta bl e met h o d of 
c o ntrace pti o n at t he discr eti o n of t he i n vesti gat or.  
N O T E: Fe m ales w h o ha v e bee n s ur gi call y sterilize d (e. g., h yster ect o m y) or w h o are 
p ost me n o pa usal (t otal cessati o n of me nses f or > 1 year) will n ot be c o nsi dere d “fe males 
of c hil d beari n g p ote ntial ”.  
3.  
S u bject has m o derate, n o n -fist ulizi n g Cr o h n’s disease i n t he ile u m a n d/ or c ol o n as 
defi ne d b y a C D AI sc or e of ≥ 2 2 0 a n d ≤ 4 5 0 p oi nts pri or t o ra n d o mizati o n; a n d a S E S - 
C D sc ore of ≥7. T h e S E S -C D sc ore will be calc ulate d usi n g t he bas eli ne 
ile oc ol o n osc o p y p erf or m e d d uri n g t he Scree ni n g Peri o d.  
N O T E: E n d osc o pists fr o m t he Ce ntral E n d osc o p y La b orat or y will deter mi ne w het her 
t he s u bject meets t he S E S-C D i ncl usi o n criteri o n. E n d osc o pists perf or mi n g t he 
pr oce d ur es s h o ul d e ns ure t hat all areas of t he c ol o n, i ncl u di n g t he ter mi nal ile u m, are 
a de q uatel y vis ualize d as t o e ns ure t hat a ce ntral rea der ca n ma ke a deter mi nati o n of t he 
S E S -C D sc ore base d o n t he vi de o rec or di n g of t he pr oce d ure. Strict ures t hat d o n ot 
per mit f urt her p assa ge of t he c ol o n osc o pe s h o ul d be a n n otate d as s uc h.  
4.  
D uri n g t h e Scree ni n g Peri o d, t he s u bject has t he f oll o wi n g a vera ge d ail y s c ores  f or 
a b d o mi nal pai n a n d a v e r a ge n u m ber of li q ui d/ ver y s oft st o ols : 
•  A n a ver a ge dail y sc ore of > 1. 5 f or a b d o mi nal pai n (fr o m C D AI It e m 2);  a n d 
•  A n a ver a ge dail y c o u nt of > 1. 5 f or li q ui d/ ver y s oft st o ols (fr o m C D AI  It e m 
1). Li q ui d/ ver y s oft st o ol will be defi ne d as a c o nsiste nc y of T y pe 6 or T y p e 7 o n t he 
B S F S.  
5.  
S u bject is ca pa ble of u n d ersta n di n g t he re q uire me nts of t he st u d y, is willi n g t o c o m pl y 
wit h all st u d y pr oce d ures, a n d de m o nstrates a bilit y t o c o m pl y wit h t he st u d y  electr o ni c  


P a ge 3 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
s yste ms (i ncl u di n g access t o Wi-Fi) re q uire d t o rec or d Cr o h n’s diseas e s y m pt o ms a n d 
C D AI c o m p o ne nts.  
6.  
S u bject u n dersta n ds t he l a n g u a ge of t h e i nf or me d c o nse nt f or m (I C F), a n d is  ca p a ble 
a n d willi n g t o si g n t he i nf or me d c o nse nt f or m. 
4. 2  
E xcl usi o n  Criteri 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 he/s he m eets a n y of t he f oll o wi n g 
criteria:  
 
1.  
S u bject has a dia g n osis of ulcerati ve or i n deter mi n ate  c olitis. 
2.  
S u bject has a dia g n osis of Celiac  Disease.  
3.  
S u bject has ha d b o wel s ur ger y wit hi n 1 2 wee ks pri or t o scree ni n g a n d/ or has s ur ger y 
pla n ne d or dee me d li kel y f or Cr o h n's disease d uri n g t he st u d y  peri o d.  
4.  
S u bject has h a d m or e t ha n o ne s e g me ntal c ol o nic resecti o n (i.e. m ore t ha n  o ne of t he 
f oll o wi n g: ri g ht he mic olect o m y, left he mic olect o m y, tra ns verse c olect o m y, ile o cecal 
resecti o n, si g m oi d c olect o m y).  
5.  
S u bject has prese n ce of a n ile ost o m y or  c ol ost o m y. 
6.  
S u bject has k n o w n fi x e d s y m pt o matic ste n osis/strict ure of t he s mall or l ar ge b o wel.  
7.  
S u bject has ha d m ore t ha n 3 s mall b o wel resecti o ns, or s y m pt o ms ass ociate d wit h  s h ort 
b o wel  s y n dr o me. 
8.  
S u bject has c urr e nt e vi de nce of  perit o nitis.  
9.  
S u bject ha d hist or y or e vi de nce of c ol o nic m uc osal  d ys plasia.  
1 0.  
S u bject ha d hist or y or e vi de nce of  a de n o mat o us c ol o nic p ol y ps t hat ha ve n ot bee n 
re m o ve d. N O T E: S u bjects ca n n ot be e nr olle d if a n y a d e n o mat o us p ol y p(s) re m o ve d 
d uri n g t he s cree ni n g ile o c ol o n osc o p y has e vi de n ce of d ys plasia or  mali g na nc y.  
1 1.  
S u bject has e vi de nce of h e patic d ysf u ncti o n, viral h e patitis, or c urre nt or c hr o nic 
hist or y of li ver disease i n cl u di n g n o n -alc o h olic steat o he patitis ( N A S H) as well as  li ver 
f u ncti o n tests ( L F Ts) wit h val ues ≥ 1. 5 ti mes t he u p per li mit of n or mal ( U L N) f or a n y 
of t he f oll o wi n g L F Ts: al a ni ne a mi n otra nsferas e ( A L T), as partate a mi n otra nsferas e 
( A S T), al kali ne p h os p hat ase, or bilir u bi n (e x ce pt is olate d ele vati o n of u n c o nj u gate d 
bilir u bi n d ue t o Gil bert’s S y n dr o me) at  Scree ni n g.  
N O T E: La b or at or y tests nee de d f or eli gi bilit y as relate d t o I ncl usi o n a n d E x cl usi o n 
criteria ca n be re peate d o nce bef ore c o nsi deri n g a s u bject a Scree ni n g fail ure. 
1 2.  
S u bject has dia betes ( T y pe 1 or T y pe 2) t hat is p o orl y c o ntr olle d i n t he o pi ni o n of t he 
i n vesti gat or, or has h a d a n H b A 1c >  1 2 % wit hi n 3 m o nt hs pri or t o Scree ni n g or at t he 
Scree ni n g  Visit.  


P a ge 3 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
1 3.  
S u bject has hist or y of t h e f oll o wi n g c o n diti o ns per Dia g n ostic a n d Statistical Ma n ual  of  
Me ntal Dis or ders, 5t h e diti o n  ( D S M-5):  
•  a maj or ps yc hiatric dis or der (i ncl u di n g maj or de pressi o n or  ps yc h osis)  
•  alc o h ol or s u bsta nce a b use wit hi n 2 4 m o nt hs pri or t o si g ni n g t he i nf or me d  c o nse nt  
1 4.  
S u bject has a hist or y of s eiz ure  dis or ders.  
1 5.  
S u bject has re nal disease ma nifeste d b y ele v ati o ns i n ser u m creati ni ne a n d/ or bl o o d 
urea nitr o ge n c o nce ntrati o ns of ≥1. 5 ti mes t he  U L N.  
1 6.  
S u bject has u nsta ble car di o vasc ular or p ul m o nar y disease, cate g orize d b y a w or se ni n g 
i n t he disease c o n diti o n t hat re q uires a c ha n ge i n treat me nt or me dical care wit hi n 3 0 
da ys pri or t o  ra n d o mizati o n. 
1 7.  
S u bject has a n acti ve m ali g na n c y wit hi n t he last 5 years (e x ce pti o ns: basal cell 
carci n o mas of t he s ki n, or if fe male, i n sit u cer vic al carci n o ma t hat has bee n s ur gicall y 
e x cise d). 
1 8.  
S u bject has d o nate d bl o o d or bl o o d pr o d ucts wit hi n t he past 4 wee ks pri or t o 
ra n d o mizati o n. 
1 9.  
S u bject has k n o w n varicella, her pes z oster, or ot h er se vere viral i nfecti o n wit hi n 6 
wee ks of ra n d o mizati o n. 
2 0.  
S u bject has k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V)  i nfecti o n. 
2 1.  
S u bject has a p ositi ve st o ol test f or Y ersi ni a e nter oc olitic a , C a m pyl o b acter jej u ni , 
S al m o nell a , S hi ge lla, o v u m a n d parasites, a n d/ or Cl ostri di u m difficile . N O T E: Res ults 
of st o ol tests m ust be c o nfir me d as ne gati ve pri or t o  ra n d o mizati o n. 
2 2.  
S u bject has a hist or y of t u berc ul osis i nfecti o n a n d/ or has recei ve d treat me nt f or  a 
t u berc ul osis i nfecti o n. If s u bject has ha d a pre vi o us p ositi ve test f or t u berc ul osis 
a nti ge n t h e n t he y m ust ha ve a c urre nt ne gati ve c h est X -ra y t o b e eli gi ble.  
2 3.  
S u bject use d a n y bi ol o gi c (e. g., T N F α i n hi bit or, n ataliz u ma b, or si milar dr u gs)  wit hi n 
1 2 wee ks pri or t o  ra n d o mizati o n. 
2 4.  
S u bject is u n willi n g t o be ta pere d off c ortic oster oi ds b y Wee k 8 of t h e Treat me nt 
Peri o d or t he s u bject is k n o w n b y t he I n vesti gat or t o be ster oi d de pe n d e nt. N O T E: Use 
of oral c ortic ost er oi ds f or t he treat me nt of acti ve Cr o h n’s disease is per mitte d at st u d y 
e ntr y. Per mitte d me dicati o ns are: pre d nis o n e if t he d ose is ≤ 2 0 m g ( or e q ui v ale nt) per 
da y or b u des o ni de if t he d ose is ≤ 9 m g/ da y. T he s u bject m ust be ta pere d off t he 
c ortic oster oi ds as n ote d  a b o ve. 
2 5.  
S u bject use d c ycl os p ori n e, tacr oli m us, sir oli m us, m yc o p h e n olate m ofetil, or si milar 
dr u gs wit hi n 8 wee ks pri or t o  ra n d o mizati o n. 
2 6.  
S u b ject use d a n y oral or i ntra ve n o us a nti bi otic i ncl u di n g rifa xi mi n, rifa m pi n or a n y 
dr u gs i n t he rifa m yci n gr o u p, wit hi n 4 wee ks pri or t o t he scree ni n g  visit.  


P a ge 3 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
2 7.  
S u bject ha d rect al a d mi nistrati o n of 5 -A S A or c ortic oster oi d 
e ne mas/f oa ms/s u p p osit ories wit hi n 2 wee ks pri or t o scree ni n g  visit.  
2 8.  
S u bjects use d t u be or e nt eral fee di n g, a n ele me ntal diet, or pare nteral ali me ntati o n 
wit hi n  2 wee ks pri or t o Scree ni n g Visit. N ote: diet ar y s u p ple me nts (e. g. B o ost,  E ns ure) 
are all o we d.  
2 9.  
S u bjects w h o are pla n ni n g t o be gi n ta ki n g pr o bi oti cs or si milar s u p ple me nts at or after 
t he Scree ni n g Visit, or s u bjects w h o be ga n usi n g t hese s u p ple me nts wit hi n 2 wee ks 
pri or t o t he Scree ni n g Visit. N O T E: T hese s u p ple me nts are all o w e d if t he s u bject has 
bee n o n a sta ble d os e f or 2 wee ks or m ore pri or t o t he Scree ni n g Visit a n d t he s u bject 
pla ns t o re mai n o n t hat d ose t hr o u g h o ut t he st u d y. T he s u bject s h o ul d n ot i ntr o d uce 
a n y n e w pr o bi otics or si milar s u p ple me nts f or t he d urati o n of t he st u d y. Pri or a n d 
c urre nt use of pr o bi otics or si milar s u p ple me nts will be rec or d e d i n t he s u bject’s  s o urce 
d oc u me nts a n d  e C R F.  
3 0.  
S u bject is c urre ntl y recei vi n g warfari n or ot her 4 -h y dr o x yc o u mari ns at t he Scree ni n g 
Visit, or has pla ns t o i nitiate t he me dicati o n at a n y ti me d uri n g t he  st u d y. 
3 1.  
S u bject, if fe male, is c urr e ntl y pre g na nt or h as pla ns t o bec o me pre g n a nt at a n y ti me 
d uri n g t he st u d y, has a p ositi ve pre g n a nc y test at scree n i n g or is breast -fee di n g. 
3 2.  
 S u bject has a hist or y of s e nsiti vit y t o rifa xi mi n, rifa m pi n, rifa m yci n a nti micr o bial 
a ge nts, or a n y of t he c o m p o ne nts of Rifa xi mi n  D R.  
3 3.  
S u bject has use d a n y i n v esti gati o nal pr o d u ct wit hi n 3 0 da ys pri or t o ra n d o mizati o n, or 
d uri n g t he st u d y. 
3 4.  
S u bject has a n y c o nc urre nt ill ness, disa bilit y or circ u msta nce t hat ma y affect t he 
i nter pretati o n of cli nical data, c o ul d ca use n o nc o m plia nce wit h treat me nt or visits or 
ot her wise c o ntr ai n dicates partici pati o n i n t his st u d y i n t he o pi ni o n of t he i n vesti gat or. 
 
4. 3  
C o nc o mit a nt  T her a pies  
 
4. 3. 1  
Per mitte d  T her a p y  
 
S u bjects will be all o we d t o c o nti n ue o n t he f oll o wi n g Cr o h n’s disease -relat e d c o nc o mita nt 
me dicati o ns d uri n g t h e st u d y.  
 
•  Oral 5 -A S A dr u gs, if o n a sta ble d ose f or at least 2 wee ks pri or t o t he s c ree ni n g visit (sa m e 
d osa ge t o be mai ntai ne d t hr o u g h o ut t he  trial). 
•  A nti diarr heals ( e. g., l o pera mi de) will be ass esse d at eac h  visit.  
•  Merca pt o p uri n e, azat hi o pri ne, met h otre x ate, if sta ble d ose f or at least 8 w ee ks pri or t o  t he 
scree ni n g visit (sa me d os a ge t o be mai ntai ne d t hr o u g h o ut t he  trial). 


P a ge 3 8  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Oral ster oi ds (first 8 wee ks of Treat me nt Peri o d o nl y): Pre d nis ol o ne or pre d nis o ne at  d oses 
of ≤ 2 0 m g ( or e q ui vale nt) per da y, or a b u des o ni d e d ose of ≤ 9 m g per d a y are per mitte d. 
S u bjects m ust be a ble t o be ta pere d off ster oi ds b y Wee k 8 of t he Treat me nt  Peri o d.  
4. 3. 2  
Pr o hi bite d  T her a p y  
 
Use of t he f oll o wi n g me dicati o ns is pr o hi bite d wit hi n t he i ncl usi o n/e x cl usi o n s pecifie d pre - 
st u d y ti me-fr a mes a n d t hr o u g h o ut t he st u d y u nless ot her wise n ote d: 
 
•  C ortic oster oi ds: Pare nter al a n d rectal ster oi ds are pr o hi bite d fr o m t he scree ni n g visit 
t hr o u g h t he e n d of t he st u d y. 
•  A n y oral or i ntra v e n o us a nti bi otic. N O T E: A s h ort c o urse of a nti bi otic  t o treat ac ut e 
c o n diti o ns (e. g., si n usitis, uri nar y tract i nfecti o n) is  per mitte d.  
•  Use of a n y dr u g fr o m t he rifa m yci n class at a n y ti me d uri n g st u d y partici pati o n, i ncl u di n g 
rifa xi mi n, rifa m pi n, rifa pe nti ne, a n d rifa b uti n. C urre nt i nter nati o nal tra d e n a mes of 
rifa xi mi n i ncl u de: Alfa N or mi x, C oli di mi n, Fa xi n or m, Fl o n or m, L or m y x, N or mi x, Refer o, 
Rifac ol, Rifa x -A w, Rifa xa n -A w, S pira xi n, Tar ga x a n, Ti xtar, Ti xteller, Xifa x a n, Xifa x a nta, 
a n d Za xi ne.  
•  A n y bi ol o gicals ( e. g., T N F α i n hi bit or, nataliz u ma b, or si milar  dr u gs)  
•  C ycl os p ori ne, tacr oli m us, sir oli m us, m yc o p h e n olate m ofetil, or si milar  dr u gs  
•  Rectal a d mi nistrati o n of 5 -A S A or c ortic oster oi d  e ne mas/f oa ms/s u p p osit ories.  
•  Use of t u be or e nter al fee di n g, ele m e ntal diet, or p are nteral  ali me ntati o n.  
•  I ntr o d u cti o n of a n y ne w pr o bi otics or si milar s u p ple me nts d uri n g t he st u d y. 
•  T he i ntr o d ucti o n of a n y n e w me dicati o n f or t he treat me nt of Cr o h n’s diseas e is  pr o hi bite d, 
u nless t he me dicati o n is r e q uire d i n t he I n v esti gat or’s o pi ni o n as resc u e me dicati o n. 
S u b jects recei vi n g r esc ue me dicati o n will be c o nsi dere d treat me nt fail ures b ut s h o ul d 
re mai n i n t he st u d y. 
All c o nc o mita nt me dicati o ns, i ncl u di n g t h ose ta ke n 3 0 da ys pri or t o scree ni n g visit, will be 
d oc u me nte d ( dr u g n a me, start a n d st o p dates, a n d i n dicati o n ) i n t he c o nc o mita nt me dicati o n 
secti o n of t he C R F. 
4. 4  
Fe m ales of Re pr o d ucti v e  P ote nti al  
If a f e male s u bject bec o mes pre g na nt w hile p artici pati n g i n t his st u d y, t he st u d y dr u g will be 
i m me diatel y disc o nti n ue d a n d t he s u bject will be f oll o we d u ntil t he o utc o me of t he pre g n a nc y 
is k n o w n. T he pre g n a nc y will be re p orte d t o Sali x usi n g t he g ui deli nes pr o vi de d i n 
Sec ti o n 7. 7 a n d Secti o n 7. 8.  


P a ge 3 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
4. 5  
Pre m at ure S u bject  Disc o nti n u ati o n  
S u bjects will be e nc o ura ge d t o c o m plete t he st u d y; h o we v er, t he y ma y v ol u ntaril y wit h dra w 
at a n y ti me. S u bjects wit h dra w n fr o m t he st u d y will n ot be re place d.  
 
A s u bject ma y be disc o nti n ue d fr o m st u d y dr u g treat me nt a n d/ or t he st u d y f or t he f oll o wi n g 
reas o ns: 
 
•  Occ urre nce of a n A E a n d/ or S A E, w hic h s u g gests a n u nacce pta ble ris k t o t he s u bject,  i n 
t he j u d g me nt of t he i n v esti gat or, i ncl u di n g w ors e ni n g of t he disease u n der st u d y. 
•  Pre g n a nc y (s ee Sec ti o n 7. 7 f or f urt her det ails).  
•  S u bject re q uest t o  wit h dra w.  
•  S p o ns or decisi o n t o ter mi nate t he  st u d y. 
F or all cases of pre mat ur e wit h dra wal fr o m t he st u d y liste d a b o ve or a n y ot her, t he 
i n vesti gat or m ust pr o vi de t he reas o n f or disc o nti n uati o n o n t he a p pr o priat e C R F pa ge. T he 
i nvesti g at or s h o ul d m a ke every atte m pt t o o bt ai n E n d of Tre at m e nt a n d E n d of St u dy 
assess m e nts, i ncl u di n g ile oc ol o n osc o py.  
 
If treat me nt wit h i n vesti gati o nal st u d y dr u g h as bee n pre mat urel y disc o nti n ue d, t he E n d of 
Treat me nt ass ess me nts will be c o m plete d, a n d a n atte m pt s h o ul d be ma de t o ha ve t he s u bject 
f oll o we d f or 1 4 d a ys after last a d mi nistrati o n of st u d y dr u g t o p erf or m t he E n d of St u d y 
assess me nts.  
 
If a s u bject pre mat ur el y disc o nti n ues treat me nt wit h i nvesti gati o nal dr u g at a n y ti me d ue t o  a n 
A E or S A E, t he E n d of Treat me nt assess me nts will be c o m plete d, a n d a n atte m pt s h o ul d be 
ma de t o ha ve t he s u bject f oll o we d at least 1 4 da ys t o perf or m t he E n d of St u d y ass ess me nts, 
or u ntil res ol uti o n or sta bilizati o n of t he c o n diti o n res ulti n g i n wit h dra w al h as bee n 
c o nfir me d.  
 
T he I n vesti gat or ma y dis c o nti n ue i n di vi d ual s u bjects fr o m t he st u d y at a n y ti me d uri n g t he 
st u d y. T he i n vesti gat or m ust pr o vi de t he reas o n f or disc o nti n uati o n o n t he a p pr o priate C R F 
pa ge.  
4. 6  
St u d y C o nt act  I nf or m ati o n 
 
T he i n vesti gat or ma y dee m it necessar y t o perf or m s pecial tests, t o h os pitalize t he s u bject, or 
t o prescri be n e w dr u gs. I n t he e ve nt t he i n vesti gat or nee ds t o c o ns ult wit h a Sali x 
re pres e ntati ve, pleas e c o ntact: 
 
Cli nical Pr oject Ma na ger 
Rifa xi mi n D R R E C D 3 1 2 6 St u d y 
Sali x P har mace uticals, I n c.  
8 5 1 0 C ol o n na de Ce nter Dri ve  


Page 40 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
Raleigh, NC 27615 
 
 
 
For sites outside the USA and Canada: 
See your Study Reference Manual for your country specific 
information. 


P a ge 4 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
5. 0  
T R E A T M E N T O F  S U B J E C T S  
 
5. 1  
F or m ul ati o n a n d  S u p pl y  
 
St u d y dr u g will be s u p plie d b y Sali x as ta blets c o ntai ni n g 4 0 0 m g Rifa xi mi n D R or matc hi n g 
place b o.  
 
Rifa xi mi n D R will be s u p plie d as pi n k, c oate d, o v al, bic o n ve x ta blets. Eac h Rifa xi mi n D R 
ta blet will c o ntai n 4 0 0 m g Rifa xi mi n a n d t he f oll o wi n g i nacti ve i n gre die nts: c oll oi dal silic o n 
di o xi de, cr oscar mell ose s o di u m, dis o di u m e detate, h y pr o mell ose, m a g nesi u m stearate, 
met hacr ylic aci d a n d et h yl acr ylate c o p ol y m er, micr ocr ystalli ne cell ul ose, pr o p yle n e gl yc ol, 
re d ir o n o xi de E 1 7 2, talc, a n d tita ni u m di o xi de. 
 
Matc hi n g place b o will be s u p plie d as ta blets t hat are i de ntical i n a p p eara nce t o Rifa xi mi n D R 
ta blets wit h i nacti ve i n gr e die nts. T he c o m p o ne nts use d i n t he ma n ufacturi n g of t he m atc hi n g 
place b o ta bles are: calci u m p h os p hate, c oll oi dal silic o n di o xi de, c or n starc h, dis o di u m 
e detate, h y pr o m ell ose, ma g n esi u m stearat e, micr o cr ystalli ne cell ul ose, pr o p yle n e gl yc ol, re d 
ir o n o xi de E 1 7 2, a n d tita ni u m di o xi de. 
 
A d diti o nal de tails are pr o vi de d i n t he Rifa xi mi n I B ( 3 9). 
 
5. 2  
P ac k a gi n g  
 
Sali x will s u p pl y d o u ble -bli n d st u d y dr u g i n hi g h de nsit y p ol yet h yle ne ( H D P E) b ottles. Eac h 
b ottle will c o ntai n st u d y dr u g f or 3 2 da ys of t hera p y.  
5. 3  
L a beli n g  
 
T he c o nte nts of t he la b el will be i n acc or d a nce wit h all a p plica ble re g ulat or y re q uire me nts 
a n d i n t he official la n g u a ge f or eac h c o u ntr y. Eac h la bel ma y i ncl u de, b ut is n ot li mite d t o, t he 
f oll o wi n g i nf or mati o n. 
 
•  Fe deral la w stat e me nt: Ca uti o n Ne w Dr u g -Li mite d b y U nite d States La w t o I n v esti gati o nal 
Use ( U S  o nl y)  
•  St u d y n u m b er:  R E C D 3 1 2 6  
•  Q ua ntit y  
•  D osi n g i nstr ucti o ns: Ta k e 2 ta blets b y m o ut h 2 ti mes a da y, a p pr o xi matel y e v er y 1 2  h o urs.  
•  St ora ge i nf or mati o n: St ore ta blets at 2 0 -2 5° C ( 6 8 -7 7° F); e x c ursi o ns per mitte d t o 1 5 -3 0° C 
( 5 9-8 6° F).  
•  Na me , a d dr ess, a n d tele p h o ne n u m ber of t he s p o ns or, c o ntract researc h or ga nizati o n or 
i n vesti gat or 
•  St u d y dr u g, l ot n u m ber, a n d e x pirati o n or re -test date  


P a ge 4 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  S pace f or rec or di n g visit n u m ber, date dis pe nse d, a n d date  ret ur ne d 
•  S pace f or rec or di n g s u bject n u m ber a n d s u bj ect  i nitials 
•  S pace f or rec or di n g i n vesti gat or  na me  
•  " F or cli nical trial use o nl y" or si milar w or di n g  
•  " Kee p o ut of r eac h of c hil dre n"  
5. 4  
St or a ge a n d  H a n dli n g  
 
All st u d y me dicati o n will be ke pt i n a sec ure st ora ge area wit h li mite d access. T he sec ure 
st ora ge ar ea will be mai ntai ne d u n der c o ntr olle d te m perat ure c o n diti o ns at 2 0-2 5° C ( 6 8 - 
7 7° F); e x c ursi o ns ar e per mitte d t o 1 5 t o 3 0° C ( 5 9 t o 8 6° F).  
5. 5  
D osi n g a n d D osi n g  Sc he d ule  
 
St u d y m e dicati o n will be d ose d orall y as t w o ta blets t wice a da y ( m or ni n g a n d e ve ni n g, 
a p pr o xi matel y 1 2 h o urs a part) wit h or wit h o ut f o o d f or 5 2 wee ks.  
5. 6  
R ati o n ale f or D ose  Selecti o n  
 
T he c urr e nt ta blet f or m ul ati o n of Rifa xi mi n EI R was e val uate d i n a P hase II d ose ra n ge 
fi n di n g st u d y i n 4 0 2 s u bjects wit h a n ac ut e flare of C D ( R E TI C/ 0 3/ 0 6). Patie nts wit h a C D AI 
bet wee n 2 2 0 a n d 4 0 0 p oi nts were r a n d o mize d t o 4 treat me nt gr o u ps: Rifa xi mi n EI R 4 0 0 m g 
t wice a da y, Rif a xi mi n RI R 8 0 0 m g BI D, Rifa xi mi n EI R 1 2 0 0 m g BI D or place b o BI D f or 1 2 
wee ks. S u bjects w h o ac hie ve d cli nical re missi o n at t he e n d of t he treat me nt peri o d, defi ne d as 
C D AI s c ore <  1 5 0 p oi nts, were a d mitte d t o a 3 -m o nt h f oll o w -u p p hase. S u bjects were 
all o we d t o c o nti n ue sta bl e d oses of oral 5 -A S A, m erca p t o p uri ne, azat hi o pri ne, a n d/ or 
met h otre x ate as c o nc o mita nt t hera pies t hr o u g h o ut t he st u d y ( u p t o 1 2 w ee ks), w hile t he use of 
a nti bi otics a n d oral, i ntra ve n o us, a n d rectal ster oi ds were n ot per mitte d. As a d d -o n t hera p y 
( 8 3 % of e nr olle d s u bjects were tr eate d wit h sta ble d oses of 5 -A S A a n d/ or met h otre x ate, 
azat hi o pri ne a n d merca pt o p uri ne), Rifa xi mi n EI R 8 0 0 m g t wice a da y w as statisticall y 
s u peri or t o place b o i n i n d uci n g cli nical re missi o n ( C D AI <  1 5 0 p oi nts) after 1 2 wee ks of 
t hera p y ( p = 0. 0 0 7), a n d mai ntai ni n g re missi o n f or t hree m o nt hs aft er Rifa xi mi n EI R was 
st o p pe d ( p = 0. 0 2). I n a d diti o n, t he safet y a n d t olera bilit y of t he Rifa xi mi n EI R 8 0 0 m g BI D 
re gi me n i n t his st u d y was acce pta ble t o warra nt f urt her i n vesti gati o n. Bas e d o n t hese data, a 
d ose of 8 0 0 m g  t wi ce a d a y was selecte d f or f urt h er de vel o p me nt.  
5. 7  
St u d y Dr u g  Acc o u nt a bilit y  
 
O nl y a ut h orize d site pers o n nel ma y dis pe ns e st u d y dr u g. D oc u me ntati o n of i n vesti gati o nal 
dr u g or ders, rec or ds of st u d y dr u g recei pt, dis pe nsi n g, a n d o n g oi n g st u d y dr u g i n ve nt or y will 
be e x a mi ne d a n d rec o ncile d t hr o u g h o ut t he st u d y. O nl y s u bjects e nr olle d i n t he st u d y ma y 
recei v e st u d y dr u g, i n acc or da nce wit h all a p plica ble re g ulat or y re q uire m e nts. 


P a ge 4 3  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
St u d y dr u g rec o nciliati o n will be c o n d ucte d d uri n g m o nit ori n g visits t o e ns ure a p pr o priate 
recei pt, st ora ge, dis pe nsi n g, a n d d o c u me ntati o n of ret ur ne d st u d y dr u g. U p o n c o m pleti o n of 
t he st u d y, t his material will be s u bjecte d t o fi nal i ns pecti o n a n d rec o nciliati o n. 
 
T he f oll o wi n g i nf or mati o n will be d oc u me nte d re gar di n g st u d y dr u g:  
 
•  S u bject  n u m ber.  
•  S u bject  i nitials. 
•  Dis pe nsi n g dat e a n d q ua ntit y of  ta blets. 
•  I nitials of st u d y staff dis p e nsi n g dr u g.  
•  Ret ur n date a n d q u a ntit y of dr u g ret ur n e d b y  s u bj ect. 
•  C o m plia nce ( %) i n ta ki n g t he st u d y dr u g at eac h  visit.  
•  Start a n d st o p dates of st u d y  dr u g.  
 
5. 8  
Assess me nt of  C o m pli a nce  
 
After st u d y dr u g is dis pe nse d, t he i n vesti gat or or his/ her re prese ntati ve will c o u nt t he u n use d 
st u d y dr u g ta blets t hat w ere r et ur ne d b y the s u bj ect at eac h visit t o assess c o m plia nce. St u d y 
dr u g c o m plia nce will be rec or d e d i n t he s u bject's s o urce d oc u m e ntati o n a n d C R F. If t he 
s u bject f or gets t o ret ur n u n use d st u d y dr u g at a visit, t he n c o m plia nce will be c o nfir me d after 
direct q uesti o ni n g o f t he s u bject. T he i n vesti gat or's j u d g me nt of c o m plia n ce will be acce pte d. 
Atte m pts t o o btai n u n use d st u d y dr u g s h o ul d be m a de at s u bse q u e nt visits or b y t he 
c o ncl usi o n of t he s u bject’s partici pati o n i n t he trial.  


P a ge 4 4  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
6. 0  
S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S  
 
A sc he d ule of assess me nts t o be perf or me d d uri n g t he st u d y is pr o vi de d i n A p pe n di x 1:  
O verall Ti me a n d E ve nts Sc he d ule.  F or t his st u d y, Da y 1 s hall be defi ne d as t he da y of 
ra n d o mizati o n/ baseli ne. 
 
S u bjects will be pr o vi de d b o wel pre p f or use pri or t o t he ile oc ol o n osc o pies. T he b o wel pre p 
will be dis pe nse d b y st u d y staff at Visits 1, 7, a n d 1 6.  
6. 1  
St u d y Sc he d ule b y T re at me nt Visit  
 
6. 1. 1  
Visit 1: Scree ni n g ( D a y – 2 1 t o D a y  -1 4)  
 
Scree ni n g e v al uati o ns m ust be gi n n o less t ha n 1 4 da ys pri or t o t he Baseli ne Visit ( Visit 2). 
T he f oll o wi n g pr oce d ures will occ ur d uri n g t his visit:  
 
•  I nf or me d c o ns e nt si g n e d b y t he s u bject pri or t o perf or mi n g a n y st u d y e val u ati o ns or 
pr oce d ur es.  
•  Assi g n s u bject  i de ntificati o n. 
•  Me dical hist or y a n d de m o gr a p hic i nf or mati o n s h o ul d be rec or de d. A p pr o xi mate date  of 
i nitial dia g n osis a n d o nset of s y m pt o ms of Cr o h n’s disease s h o ul d be d o c u me nte d.  
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns.  
•  I n cl usi o n/ E x cl usi o n criteria re vie w t o e ns ure s u bj ect q ualifies f or t he st u d y. 
•  F ull p h ysical e x a mi nati o n i ncl u di n g diseas e s pecific e x a mi nati o n (i ncl u di n g ass ess me nts 
f or a b d o mi nal mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease b ase d o n C D AI  –  
see A p pe n di x 2). 
•  Vital si g ns (t o i ncl u de m eas ure m e nt of hei g ht a n d  wei g ht).  
•  Electr ocar di o gra m.  
•  Safet y l a b orat or y t ests i ncl u di n g ser u m pre g na n c y test ( he mat ol o g y, bl o o d c he mistr y,  a n d 
uri nal ysis).  
•  St o ol c ollecti o n a n d pr ocessi n g N O T E: T his sa m ple is c ollecte d i n part t o a d dress 
E x cl usi o n Criter i o n 2 1. Micr o bi ol o g y res ults re q uire d f or e ntr y m ust be recei ve d bef ore 
ra n d o mizati o n. If t he s u bject ca n n ot pr o d u ce a s a m ple d uri n g t he visit, t he s u bject will be 
iss ue d a c ollecti o n kit a n d as ke d t o c ollect a s p eci me n at h o me, refri gerate it i m me diatel y 
a n d ret ur n it t o t he cli nic a mi ni m u m of 7 da ys pri or t o visit  2.  
•  Pr o vi de s u bject i nstr ucti o n f or dail y diar y  c o m pleti o n.  
•  Sc he d ule el i gi bilit y/ b aseli ne ile oc ol o n osc o p y a n d pr o vi de b o wel pre p.  


P a ge 4 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  S u bjects w h o ac hie ve t h e q ualif yi n g C D AI sc ore s h o ul d ha ve t he baseli ne il e oc ol o n osc o p y 
(f or eli gi bilit y S E S-C D sc ore)  p erf or me d n o later t ha n Da y  -5.  
•  Sc he d ule Visit  2  
6. 1. 2  
Visit 2: B aseli ne/ R a n d o miz ati o n, Wee k 0/ D a y  1  
 
T he Baseli ne/ Ra n d o mizati o n Visit will be perf or me d o n Da y 1. T h ere is n o Da y 0 i n t his 
pr ot oc ol. T he f oll o wi n g assess me nts are t o be c o m plete d at Visit 2:  
 
Pri or t o d osi n g:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  I n cl usi o n/ E x cl usi o n re vie w t o e ns ure s u bj ect c o nti n ues t o q ualif y f or t he st u d y 
•  Vital si g ns a n d  wei g ht  
•  Disease a n d s y m pt o m dri ve n p h ysi cal e x a mi nati o n (i ncl u di n g ass ess me nts f or a b d o mi nal 
mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease base d o n C D AI –  see A p pe n di x 
2)  
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y,  uri nal ysis)  
•  Uri ne pre g n a nc y  test 
•  Bl o o d dra w pri or t o first d ose a d mi nistrati o n f or i nfla m mat or y mar kers, P X R a n d  P K  
•  St o ol a n d bl o o d c ollecti o ns f or l o n g -ter m st ora ge 
•  I B D Q a n d W P AI-C D  
•  Diar y C o m plia nce  C hec k  
•  Ra n d o mizati o n  
After first d ose assess me nts:  
 
•  St u d y dr u g dis pe nsi n g - first d ose t o be ta ke n at t h e cli nic u n der o bs er vati o n. T he e x act 
ti me of d ose a d mi nistrati o n s h o ul d be  rec or d e d. 
•  Sc he d ule Visit  3  
6. 1. 3  
Visits 3, 4, 5, 6: Wee ks 2, 4, 8, 1 2 / D a ys 1 4, 2 8, 5 6, 8 4 ( ± 3  d a ys)  
 
T he f oll o wi n g assess me nts are t o be c o m plet e d:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  


P a ge 4 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Disease a n d s y m pt o m dri ve n p h ysi cal e x a mi nati o n (i ncl u di n g ass ess me nts f or a b d o mi nal 
mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease base d o n C D AI –  see A p pe n di x 
2)  
•  St u d y dr u g c ollecti o n a n d dis pe nsi n g. N O T E: At Visit 3 n o st u d y dr u g is c ollecte d  or 
dis pe nse d.  
•  Rec or d ti me a n d dat e of m ost rece nt d ose of st u d y dr u g. T his i nf or mati o n m ust be 
o btai ne d fr o m t he s u bject a n d s h o ul d be his/ her best rec ollecti o n of w h e n t he y t o o k  t heir 
m ost rece nt  d ose.  
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y,  uri nal ysis)  
•  Bl o o d dra w f or P K ( Visit 6 o nl y f or  P K)  
•  C D AI assess me nt ( C D AI sc ore will be calc ulate d b y E D C  s yste m) 
•  Re vie w d osi n g a n d diar y  c o m plia nce  
•  Sc he d ule t he ne xt st u d y  visit  
 
6. 1. 4  
Visit 7: Wee k 1 6/ D a y 1 1 2 ( ± 3  d a ys)  
 
T he f oll o wi n g assess me nts are t o be c o m plet e d at Visit  7:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  
•  Electr ocar di o gra m  
•  F ull p h ysical e x a mi nati o n i ncl u di n g diseas e s pecific e x a mi nati o n (i ncl u di n g ass ess me nts 
f or a b d o mi nal mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease b ase d o n C D AI –  
see A p pe n di x 2). 
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y,  uri nal ysis)  
•  Uri ne pre g n a nc y  test 
•  Bl o o d f or i nfla m mat or y  mar ke rs 
•  St o ol c ollecti o n a n d pr ocessi n g. N O T E: If t he s u bject ca n n ot pr o d u ce a s a m ple d uri n g t he 
visit, t he s u bject will be iss ue d a c ollecti o n kit a n d as ke d t o c ollect a s p eci me n at h o me, 
refri gerate it i m me diatel y, a n d bri n g it t o t he cli nic as s o o n as p ossi b le. 
•  St o ol a n d Bl o o d c ollecti o ns f or L o n g -ter m St ora ge  
•  C D AI assess me nt ( C D AI sc ore will be calc ulate d b y E D C  s yste m) 
•  I B D Q a n d W P AI-C D  
•  Re vie w d osi n g a n d diar y  c o m plia nce  
•  St u d y dr u g c ollecti o n a n d  dis pe nsi n g  


P a ge 4 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Sc he d ule ile oc ol o n osc o p y a n d dis p e nse b o wel pre p f or  ile oc ol o n osc o p y 
•  Ile o c ol o n osc o p y t o be p erf or me d wit hi n 7 da ys after Visit 7.  
•  All Visit 7 pr oce d ures t o be c o m plete d pri or t o b e gi n ni n g b o we l pre p.  
•  Sc he d ule Visit  8  
 
6. 1. 5  
Visits 8, 9, 1 0, 1 1, 1 2, 1 3, 1 4, 1 5: Wee ks 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8 / D a ys  1 4 0,  
1 6 8, 1 9 6, 2 2 4, 2 5 2, 2 8 0, 3 0 8, 3 3 6 ( ± 3 d a ys)  
 
T he f oll o wi n g assess me nts are t o be c o m plet e d:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  
•  Disease a n d s y m pt o m dri ve n p h ysi cal e x a mi nati o n (i ncl u di n g ass ess me nts f or a b d o mi nal 
mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease base d o n C D AI –  see A p pe n di x 
2)  
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y, uri n al ysis) wit h uri ne pre g na nc y t est 
at Visit 1 0 ( Wee k 2 8) a n d Visit 1 3 ( Wee k 4 0) o nl y; bl o o d dra w f or P K at Visit 1 5  o nl y  
•  At Visit 1 5 o nl y: Rec or d ti me a n d date of m ost rece nt d ose of st u d y dr u g. T his 
i nf or mati o n m ust be o btai ne d fr o m t he s u bject a n d s h o ul d be his/ her best rec ollecti o n of 
w he n t he y t o o k t heir m ost rece nt  d ose.  
•  C D AI assess me nt ( C D AI sc ore will be calc ulate d b y E D C  s yste m) 
•  I B D Q a n d W P AI-C D at Visit 1 0 ( Wee k 2 8) a n d Visit 1 3 ( Wee k 4 0)  o nl y  
•  Re vie w d osi n g a n d diar y  c o m plia nce  
•  St u d y dr u g c ollecti o n a n d  dis pe nsi n g  
•  Sc he d ule t he ne xt st u d y visit ( Visit 1 5 s h o ul d occ ur i n t he  m or ni n g)  
 
6. 1. 6  
Visit 1 6: E n d of Tre at me nt ( E O T) Visit, Wee k 5 2/ D a y 3 6 4 ( ± 3  d a ys)  
 
T he s u bject’s fi nal d os e of st u d y dr u g will be t he e ve ni n g bef ore Visit 1 6. T he f oll o wi n g 
assess me nts are t o b e c o m plete d at t his visit:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  
•  Electr ocar di o gra m  
•  F ull p h ysical e x a mi nati o n i ncl u di n g diseas e s pecific e x a mi nati o n (i ncl u di n g ass ess me nts 
f or a b d o mi nal mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease b ase d o n C D AI  –  
see A p pe n di x 2). 


P a ge 4 8  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y, uri n al ysis) i ncl u di n g bl o o d f or 
ser u m pre g na nc y test a n d i nfla m mat or y m ar kers  
•  St o ol c ollecti o n a n d pr ocessi n g. N O T E: If t he s u bject ca n n ot pr o d u ce a s a m ple d uri n g t he  
visit, t he s u bject will be iss ue d a c ollecti o n kit a n d as ke d t o c ollect a s p eci me n at h o me, 
refri gerate it i m me diatel y, a n d bri n g it t o t he cli nic as s o o n as p ossi ble.  
•  St o ol a n d Bl o o d c ollecti o ns f or L o n g -ter m St ora ge  
•  C D AI assess me nt ( C D AI sc ore will be c alc ulate d b y E D C  s yste m) 
•  I B D Q a n d W P AI-C D  
•  Re vie w d osi n g a n d diar y  c o m plia nce  
•  C ollect u n use d st u d y  dr u g  
•  Sc he d ule ile oc ol o n osc o p y a n d dis p e nse b o wel pre p f or  ile oc ol o n osc o p y 
•  Ile o c ol o n osc o p y t o be c o n d ucte d wit hi n 7 da ys aft er Visit 1 6.  
•  All Visit 1 6 pr oce d ures t o be c o m plete d pri or t o b e gi n ni n g b o w el  pre p.  
•  Sc he d ule Visit 1 7,  E O S  
6. 1. 7  
Visit 1 7: E n d of St u d y ( E O S) Visit, Wee k 5 4/ D a y 3 7 8 ( ± 3  d a ys)  
 
T he f oll o wi n g assess me nts are t o be c o m plet e d:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  
•  Electr ocar di o gra m  
•  Safet y l a b orat or y t ests ( h e mat ol o g y, bl o o d c h e mistr y,  uri nal ysis)  
 
6. 1. 8  
U nsc he d ule d  Visit  
 
T he i n vesti gat or ma y perf or m a n u nsc h e d ule d visit at a n y ti me d uri n g t he st u d y at his/ her 
discreti o n. Assess me nts perf or me d at a n  u nsc h e d ule d visit s h o ul d be s y m pt o m directe d. At a 
mi ni m u m t he f oll o wi n g assess me nts s h o ul d be perf or me d:  
 
•  A d verse e ve nts a n d c o nc o mita nt  me dicati o ns  
•  Vital si g ns a n d  wei g ht  
•  S y m pt o m dri ve n p h ysi cal  e x a mi nati o n  
•  Safet y l a b orat or y t ests as a p pr o priate ( he mat o l o g y, bl o o d c he mistr y, uri nal ysis)  


P a ge 4 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
6. 1. 9  
D ail y Di ar y ( a n d/ or ot her s u bject -c ollecte d  d at a)  
 
Electr o nic s yste m diaries will be utilize d t o c ollect s u bject’s res p o nses t o t h e C D AI q uesti o ns 
(A p pe n di x 2: Cr o h n’s Disease A cti vit y I n de x ). Eac h s u bject will be i nstr ucte d o n t he use of 
t he Electr o nic diar y s yst e m. S u bjects will be pr o vi de d sec ure access i nstr ucti o ns t o t he 
Electr o nic diar y s yste m d uri n g t h e Scree ni n g Visit.  
6. 2  
Assess me nt of  Effic ac y  
 
Efficac y e n d p oi nts ar e pr ese nte d i n Sec ti o n 2. 2. A nal yses of efficac y e n d p oi nts are descri be d 
i n Secti o n 8. 6. 1 . 
6. 2. 1  
Cr o h n’s Dise ase Acti vit y I n de x ( C D AI)  Sc ore  
 
T he C D AI sc ore is a w ei g hte d, c o m p osite i n de x of ei g ht ite ms (st o ol fre q u e nc y, se verit y of 
a b d o mi nal pai n, de gree of ge ner al well -bei n g, pres e nce or a bse n ce of e xtrai ntesti nal 
ma nifestati o ns i ncl u di n g fist ula, use or n o n -use of a nti diarr heal a ge nts,  prese nce or a bse n ce  of 
a b d o mi nal mass, he mat o crit a n d b o d y wei g ht). Sc ores ra n ge fr o m 0 t o a p pr o xi matel y 6 0 0 
wit h hi g her s c ores i n dicati n g greater disease se v erit y. Cli nical (as y m pt o matic) re missi o n is 
defi ne d as a sc or e of ≤ 1 5 0 p oi nts. Mil d -t o-m o derate disease a n d se vere dis ease are d efi ne d 
b y sc ores of > 1 5 0 t o ≤ 4 5 0, a n d > 4 5 0 p oi nts, res pecti vel y. T he C D AI s c ori n g s yste m ca n be 
f o u n d i n A p pe n di x 2: Cr o h n’s Disease A cti vit y I n de x . C D AI will be e v al uate d at all cli nic 
vis its f or t he st u d y. C D AI s c ore will be calc ulat e d b y E D C s yste m. 
6. 2. 2  
Si m ple E n d osc o pic Sc ore f or Cr o h n’s Dise ase  ( S E S-C D)  
 
T he S E S -C D is a vali date d i nstr u me nt reflecti n g a n e n d osc o pist’s gl o bal a p praisal of m uc osal 
lesi o ns i n Cr o h n’s disease. T he S E S-C D gra d es  lesi o ns b y l ocati o n (ile u m, ri g ht c ol o n, 
tra ns verse c ol o n, left c ol o n a n d rect u m) usi n g ulcer size, e xte nt of ulcerate d s urface, e xte nt of 
affecte d s urf ace, a n d pr es e nce/t y pe of n arr o wi n g. T he S E S -C D ca n be f o u n d i n A p pe n di x 4 . 
Vi de o rec or di n gs of ile oc ol o n osc o pies will be re vi e we d, a n d S E S -C D sc ores will be 
calc ulate d b y bli n de d ce ntral la b orat or y e n d osc o pists f or t he st u d y. T h e i n de pe n de nt ce ntral 
e n d osc o p y rea ders a n d t h e ce ntr al e n d osc o p y la b orat or y will n ot be ass ociate d wit h a n y 
i nstit uti o n c o n d ucti n g t he st u d y. 
I n or der t o f ull y ass ess f or t he prese n ce of ile oc ol o nic Cr o h n’s disease a n d calc ulate a n 
acc ur ate S E S -C D sc or e, t he e n d osc o pist m ust atte m pt t o i nt u bate a n d vis ualize t he ter mi nal 
ile u m i n or der t o deter mi ne prese n ce a n d e xte nt of disease d uri n g eac h ile o c ol o n osc o p y. T o 
re d uce t h e p ote ntial f or bias or varia bilit y i n e n d os c o p y s c ori n g, bli n de d ce ntral rea di n g will 
be utilize d t o deter mi ne t he S E S -C D sc ores f or all ile oc ol o n osc o pies o btai n e d d uri n g t he 
st u d y. As s uc h, e ver y eff ort m ust be ma de at eac h pr oce d ure t o f ull y vis u alize eac h se g me nt 
of t he ter mi nal ile u m a n d c ol o n t o facilitate ce ntral rea di n g of t he rec or de d pr oce d ures. T he 
rate of wit h dr a wal of t h e c ol o n osc o pe d uri n g t he pr oce d ure s h o ul d als o be s ufficie ntl y sl o w as 
t o all o w f or a de q u ate vis ualizati o n a n d sc ori n g of eac h se g m e nt i n t he vi de o rec or di n g b y a  


P a ge 5 0  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
ce ntral r ea d er. Strict ures t hat d o n ot per mit f urt her passa ge of t h e c ol o n osc o pe s h o ul d be 
a n n otate d as s uc h.  
6. 2. 3  
I nfl a m m at or y B o w el Dise ase Q uesti o n n aire (I B D Q) 
 
T he I B D Q is a vali dat e d 3 2 -ite m q uesti o n naire wit h 4 di me nsi o ns t hat assess b o wel f u ncti o n, 
e m oti o nal stat us, s yste mic s y m pt o ms, a n d s ocial f u ncti o n. T he I B D Q ca n  b e self - 
a d mi nistere d. T he t otal s c ore o n t he i n de x ra n ges fr o m 3 2 -2 2 4, wit h hi g h er sc ores i n dicati n g 
better q ualit y of life. A relati vel y g o o d c orrel ati o n e xists bet wee n t he I B D Q a n d t he C D AI (r  
= -0. 6 7; P < 0. 0 0 1). St u dies ha ve bee n perf or me d i n patie nt s wit h i nfla m mat or y Cr o h n's 
disease, b ut t here is n o p u blis he d data o n I B D Q s c ores of p atie nts wit h pri maril y fist ulizi n g 
Cr o h n's diseas e. See A p p e n di x 5: I nfla m mat or y B o wel Disease Q uesti o n naire.  
 
6. 2. 4  
W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q uesti o n n aire f or Cr o h n's 
Dise ase  ( W P AI-C D)  
 
T he W P AI -C D is a q u esti o n naire t hat assesses t h e effect of Cr o h n’s disease o n a patie nt’s 
a bilit y t o w or k a n d p erf or m re g ular acti vities. T he W P AI -C D has discri mi n ati ve vali dit y  a n d 
re pr o d uci bilit y i n Cr o h n’s disease. I n a d diti o n, e v al uati ve vali dit y a n d res p o nsi ve ness t o 
cli nicall y mea ni n gf ul c ha n ges i n t he W P AI -C D sc ores ha ve b ee n esta blis he d f or Cr o h n's 
disease. W P AI -C D o utc o mes are e x presse d as i m pair me nt perce nta ges, wit h hi g her n u m bers 
i n dicati n g gr eater i m pair me nt a n d less pr o d ucti vit y (i.e. w orse o ut c o mes). D o mai ns 
e val uate d are c urr e nt e m pl o y me nt, w or k h o urs misse d d ue t o Cr o h n’s disease, w or k h o urs 
misse d f or ot her r eas o ns, h o urs act uall y w or k e d, d e gree t h at Cr o h n’s diseas e a ffecte d 
pr o d ucti vit y w hile w or ki n g, a n d d e gree t hat Cr o h n’s disease affecte d re g ular acti vities. See 
A p pe n di x 6: W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q uesti o n naire: Cr o h n’s  Disease.  
6. 3  
Assess me nt of  S af et y  
 
Safet y e n d p oi nt s are pres e nte d i n Secti o n 2. 2. 4. Safet y assess me nts will i ncl u de t he 
f oll o wi n g: 
 
•  A Es, b ot h re p orte d a n d  o bser ve d  
•  Vital si g n meas ur e me nts (seate d bl o o d press ure, p ulse a n d oral  te m perat ure) 
•  R o uti ne he mat ol o g y a n d bl o o d c he mistr y tests a n d  uri nal ysis  
•  Electr ocar di o gra ms  
 
6. 3. 1  
Cli nic al L a b or at or y  Tests  
 
T he f oll o wi n g cli nical la b orat or y tests are t o be p erf or me d d uri n g t he st u d y a n d will be 
a nal yze d b y a ce ntral, lice nse d cli nical la b orat or y (e x ce pt f or t he uri n e pre g na nc y tests ). At 
t he i n vesti gat or’s discreti o n, a d diti o nal bl o o d ma y be c ollecte d f or cli nical l a b orat or y tests 


P a ge 5 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
(i.e., he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis) base d o n patie nt re p orte d si g ns a n d 
s y m pt o ms or pre vi o us cli nical la b orat or y test res ults. 
 
Res ults fr o m la b orat or y s peci me ns c ollect e d d uri n g t he Scree ni n g Visit m ust be recei ve d b y 
t he site pri or t o Visit 2 ( Baseli ne/ Ra n d o mizati o n). 
 
T he cli nical la b or at or y p ara meters t o  be e v al uate d are as f oll o ws:  
 
•  He m at ol o g y : He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt wit h 
differe ntial, a n d platelet  c o u nt.  
•  Bl o o d c he mistr y : Ala ni n e a mi n otra nsferase, as partate a mi n otra nsferase, al kali ne 
p h os p hatase, t otal bilir u bi n (e x ce pt i n is olate d ele vati o n of u nc o nj u gate d bilir u bi n), bl o o d 
urea nitr o ge n, creati ni ne, uric aci d, el ectr ol ytes, lactate de h y dr o ge nas e, cal ci u m, al b u mi n, 
gl uc ose, c h olester ol, a n d  tri gl yceri des. 
•  Uri n al ysis : R o uti ne uri ne a n al ysis (i ncl u di n g b ut n ot li mite d t o w hite bl o o d cell c o u nt, re d 
bl o o d cell c o u nt, a n d pr otei n). If t here are a n y p ositi ve fi n di n gs, micr osc o pic e x a mi nati o n 
s h o ul d be perf or m e d t o q ua ntif y t he res ults. 
•  St o ol : St o ol testi n g will be perf or me d d uri n g t he scree ni n g p eri o d t o i de ntif y t he prese nce 
of e nteric i nf ecti o ns (e. g. Yersi nia e nter oc olitica, Ca m p yl o bact er jej u ni, Sal m o nella, 
S hi gella, o v u m a n d parasite a n d/ or Cl ostri di u m difficile) a n d a ne gati ve test m ust be 
c o nfir me d f or s u bjects pri or t o  ra n d o mizati o n. 
6. 3. 2  
Assess me nt of I nfl a m m ati o n  M ar kers  
 
Bl o o d sa m ples f or d eter mi nati o n of i nfla m mat or y mar k ers will be c ollect e d at Visit 2 
( Bas eli ne/ Ra n d o mizati o n), Visit 7, a n d Visit 1 6 ( E O T). Bl o o d sa m ples will be c ollecte d i n 
ser u m-se parati n g t u bes t o c ollect ser u m f or i nfla m mat or y mar kers. After all o wi n g bl o o d t o 
cl ot f or a p pr o xi matel y 3 0 mi n utes, t he sa m ples will be ce ntrif u ge d at 1 3 0 0 g t o se parate t h e 
bl o o d cells fr o m ser u m. Ser u m sa m ples will be s hi p pe d a m bie nt ( C R P) or fr oze n ( ot her 
i nfla m mat or y m ar kers) t o t he ce ntral la b orat or y f or i nfla m mat or y mar k er t esti n g. T he 
prese nce of i nfla m mat or y mar k ers ( w hic h ma y i n cl u de C R P, I L -1 β, I L -2, I L -6, I L -1 2, I L -1 3, 
T N F -α a n d e n d ot o xi n) will be a nal yze d usi n g a p article base d C yt o metric Bea d Arra y 
i m m u n oassa y at t he ce ntr al la b orat or y. 
Bl o o d sa m pl es f or d eter mi nati o n of Pre g n a ne X Rece pt or ( P X R) ge n ot y pi n g will be c ollecte d 
at Visit 2. 
•  Bl o o d, Bl o o d Pl as m a, a n d Ser u m f or St or a ge : Bl o o d, bl o o d plas ma, a n d ser u m 
sa m ples will be c ollecte d at Visit 2 ( Baseli ne/ Ra n d o mizati o n), Visit 7, a n d Visit 1 6 
( E O T). Sa m ples will be st ore d at ≤ -2 0° C at t he cli nical site a n d s hi p pe d o n dr y ice  a n d 
st ore d l o n g-ter m at ≤ -7 0° C. T hese sa m ples ma y b e use d f or e x pl orat or y a n al yses 
( p ote ntiall y i ncl u di n g a d diti o nal i nfla m mat or y mar kers or P X R ge n ot y pi n g) t o be  


P a ge 5 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
detaile d i n s u bse q ue nt site -s pecifi c a me n d me nts or s u b-st u dies. S u bjects will be a d vise d 
of a n d m ust c o nse nt t o bl o o d a n d bl o o d plas ma c ollecti o n f or st ora ge.  
 
6. 3. 3  
St o ol S a m ple C ollecti o n a n d  Testi n g  
 
St o ol sa m ple c ollecti o n  s h o ul d be perf or me d f or t he f oll o wi n g visits: Scree ni n g, Visit 7, a n d 
Visit 1 6 ( E O T). Fr es h st o ol sa m ples will be c ollecte d at eac h of t he a b o ve visits w he ne ver 
p ossi ble. If t h e s u bject ca n n ot pr o d uce a s a m ple d uri n g t he visit, t he s u bject will be iss ue d a 
c ollecti o n kit a n d as ke d t o c ollect a s peci me n at h o me, refri gerat e it i m me diatel y, a n d bri n g it 
t o t he cli nic as s o o n as p ossi ble. St o ol sa m ples will be ali q u ote d i nt o 2-m L p ol y pr o p yle n e 
cr y o vials, st ore d at ≤ -2 0° C at t he cli nical site, s hi p pe d o n dr y  ice a n d st ore d l o n g ter m at ≤ - 
7 0° C. St o ol sa m ples will be use d f or t h e f oll o wi n g:  
•  S af et y Testi n g f or C. difficile : A st o ol sa m ple f or a nal ysis of C. difficile f or T o xi ns A & 
B will be c ollect e d at Scr ee ni n g, Visit 7, a n d Visit 1 6. Testi n g will be perf or me d b y 
e nz y me i m m u n oassa y ( EI A). 
•  St o ol sa m ples testi n g p ositi ve f or C. difficile T o xi n B will be c ult ure d a n d  teste d 
f or resista nce t o select a nti bi otics. 
•  Fec al C al pr otecti n I m m u n o ass a y : A st o ol sa m ple f or ass a y of fecal cal pr otecti n will be 
c ollecte d at S cr ee ni n g, Visit 7, a n d Visit 1 6. St o ol sa m ples will be c ollecte d i n sterile 
s peci me n c u ps a n d st or e d i m me diatel y at ≤ -2 0º C. Sa m ples will be s hi p pe d fr oze n o n dr y 
ice t o t he ce ntr al la b orat or y f or testi n g. Testi n g will be perf or m e d b y i m m u n oassa y. 
•  Micr o bi ot a C h ar acteri z ati o n : S usce pti bilit y Testi n g: I n a s u bs et of t he st u d y p o p ulati o n 
(a p pr o xi matel y 1 0 %), t he s usce pti bilit y of t he st o ol micr o bi ota t o rifa xi mi n, rifa m pi n, a n d 
ot her select e d a nti bi otics of cli nical i nterest will be c haracterize d. St o ol sa m ples will be 
i n oc ulate d o nt o vari o us me dia t o i de ntif y or ga nis ms. St o ol c ult ures will i de ntif y a n d 
is olate yeast as well as s electe d bacteria, c h ose n t o i nc or p orate t h e m ost pre vale nt s pecies 
of i ntesti nal bacteria. Bacteria will be  i de ntifie d a n d c haracterize d b y m or p h ol o g y a n d 
p h ysical tests, wit h i de ntit y c o nfir me d wit h m olec ular i de ntificati o n s yste ms. Yeast will 
be i de ntifie d if pres e nt i n st o ol, b ut will n ot be teste d f urt her. Bacteri al se nsiti vit y testi n g 
will be perf or me d b y br ot h micr o dil uti o n ( per Cli nical La b orat or y Sta n dar ds I nstit ute 
( C L SI) d o c u me nt M 7-A 8) f or aer o bic b acteri a a n d b y a gar dil uti o n f or a n aer o bic bacteria 
usi n g cli nicall y r ele va nt a nti bi otics. D u plicate sa m ples of all is olates a n d st o ol ali q u ots 
will be st o re d t o all o w f or p ote ntial f ut ure a n al ysis.  
•  Micr o bi ot a C h ar acteri z ati o n : C o m p ositi o n, Di versit y, D N A Se q ue n ci n g: I n a s u bset of 
t he st u d y p o p ulati o n (a p pr o xi matel y 1 0 %), t he i ntesti nal micr o bi ota fr o m st o ol sa m ples 
will be c haracterize d i n ter ms of c o m p ositi o n a n d di versit y, as well as se q u e nci n g f or 
s pecific or ga nis ms of i nterest. Bacterial D N A will be is olate d fr o m fecal sa m ples, a n d t he 
h y per -varia ble r e gi o ns of t he 1 6 S r R N A ge ne will be a m plifie d usi n g t w o -ste p P C R 
se q ue nci n g tec h n ol o g y. All st o ol sa m ples a n d D N A is olates will be st ore d t o all o w f or 
p ote ntial f ut ure  a n al ysis.  


P a ge 5 3  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  L o n g -ter m st o r a ge f or f ut ure e x pl or at or y a n al ysis. S u bjects m ust be a d vise d of a n d 
pr o vi de c o n se nt t o t his st o ol c ollecti o n f or st ora ge. A d diti o nal s u bst u dies ma y b e defi n e d 
i n t he f ut ure. 
6. 3. 4  
Uri ne a n d Ser u m Pre g n a nc y  Tests  
 
Ser u m pre g na n c y tests will be perf or me d f or all fe males of c hil d beari n g p ot e ntial a n d t h ose 
w h o ha ve ha d a t u bal li gati o n at Vis it 1 ( Scree ni n g) a n d Visit 1 6 ( E O T). Uri ne pre g n a nc y 
tests will be perf or me d f or all fe males of c hil d beari n g p ote ntial a n d t h os e w h o ha ve ha d a 
t u bal li gati o n at Visit 2 ( Baseli ne/ Ra n d o mizati o n) pri or t o ra n d o mizati o n a n d at Visit 7, Visit 
1 0, a n d Visit 1 3 . T he Visits 1 a n d 2 pre g na nc y t ests m ust be c o nfir me d as n e gati ve bef ore t he 
a d mi nistrati o n of st u d y dr u g.  
6. 3. 5  
S af et y M o nit ori n g f or C.  difficile  
 
St o ol sa m ples m ust be c ollecte d a n d teste d f or C. difficile T o xi n B ge ne (tc d B) usi n g real - 
ti me p ol y m eras e c h ai n reacti o n ( P C R) met h o d f or a n y s u bject w h o has w orse ni n g, ac ute 
diarr hea a n d a b d o mi nal p ai n d uri n g t he st u d y, d efi ne d b y:  
 
•  S u bject ha d at least 3 u nf or me d (l o ose or w ater y) st o ols i n t he last 2 4 h o urs. 
A N D  
•  S u bject has at least 1 ot h er si g n of e nteric i nfecti o n prese nt, s uc h as fe v er, na usea/l oss of 
a p petite, v o miti n g, se ver e a b d o mi nal pai n or  disc o mf ort.  
•  St o ol sa m ples testi n g p ositi ve f or C. difficile T o xi n B, will be c ult ure d a n d teste d 
f or resista nce t o select a nti bi otics. 
All p ositi v e test res ults will be rec or d e d as a n a d verse e ve nt.  
 
6. 3. 6  
A d verse  E ve nts  
 
T he i n vesti gat or is res p o nsi ble f or t he detecti o n a n d d oc u me ntati o n of e ve nts t hat meet t he 
defi niti o n of a n a d verse e ve nt ( A E) or s eri o us a d v erse e v e nt ( S A E) as pr o vi de d i n t his 
pr ot oc o l ( Secti o n 7. 0). Assess me nts of occ urre nces of A Es or S A Es s h o ul d be c o n d ucte d 
d uri n g eac h st u d y visit or as re p orte d b y t h e s u bject o utsi de of sc he d ule d visits. I n or d er t o 
f ulfill i nter nati o nal safet y re p orti n g o bli gati o ns, t he i n vesti gat or s h o ul d i ncl u de i n his or her 
assess me nt a n y A Es r es ulti n g fr o m st u d y p artici pati o n re gar dless of relati o n t o st u d y dr u g 
(e. g., c o m plicati o ns res ulti n g fr o m t he ta ki n g of a bl o o d sa m ple). 
6. 3. 7  
P h ysic al  E x a mi n ati o n  
 
A f ull p h ysi cal e x a mi nati o n w ill be perf or me d d uri n g Visit 1, Visit 7, a n d Visit 1 6 ( E O T). A 
s y m pt o m-direct e d p h ysical e x a mi nati o n will be perf or me d at ot her visits. All p h ysical e x a ms 
will i ncl u de t he assess me nts re q uire d f or C D AI calc ulati o n.  


Page 54 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
6.3.8 
Vital Sign Assessments 
 
Vital sign assessments (sitting blood pressure, pulse, and temperature) will be performed at 
each clinic visit. Vital signs will be measured after the subject has been seated for 5 minutes. 
Weight will be measured at each clinic visit. Height will only be collected at Visit 1. 
6.3.9 
Electrocardiogram (ECG) 
 
A standard 12 lead ECG (at rest) will be performed on all subjects at Visits 1, 7, 16 and 17. 
The baseline ECG obtained at Visit 1 will be performed in triplicate (i.e., three 12-lead ECGs 
obtained 3 minutes apart). A print out of the ECG reports must be available in the source 
documentation. The investigator will evaluate if the patient should enter the study based on 
any findings on ECG. 
6.4 
Other Assessments 
 
6.4.1 
Medical History 
 
Each subject’s relevant medical history is to be recorded in source documents and the 
appropriate CRF pages. Medical history (including past enteric infections) will include a 
detailed history of the subjects CD (e.g., date of onset, surgical history, location of disease, 
etc.). 
6.5 
Pharmacokinetics 
 
Samples will be collected at Visit 2, at Visit 6, and at Visit 15. Collection and recording of 
the date and time of the last dose administered prior to the visit is required at each visit in 
order to most accurately estimate rifaximin exposure. Steady-state rifaximin concentrations 
are anticipated for collections at Visits 6 and 15. 
 
Statistical analysis (including exploratory data analysis and population modeling) will be 
described in detail in the Pharmacokinetics Statistical Analysis Plan (PSAP) document. The 
PSAP will be finalized prior to the pharmacokinetic analysis. 


P a ge 5 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
7. 0  
S A F E T Y  R E P O R TI N G  
 
Sali x mai ntai ns a r o b ust p har mac o vi gila nce s yste m c o m prise d of a g o ver n a nce fra me w or k 
a n d sta n dar d o p erati n g pr oce d ures s u p p orti n g a s yste matic pr ocess f or re vi e w, e val u ati o n,  a n d 
ma na ge me nt of acc u m ul ati n g safet y data f r o m cli nical trials a n d ot her s o urces t o: 
 
•  I d e ntif y a p ote ntial ne w safet y si g nal; 
•  E ns ure t hat a n i n vesti gati o nal pr o d uct’s ris ks are a de q uatel y assess e d a n d  c o m m u nicate d 
t o i n vesti gat ors, I R Bs/I E Cs, a n d re g ulat or y b o dies d uri n g cli nical de vel o p m e nt.  
•  F or t his st u d y, safet y m o nit ori n g acti vities will i ncl u de b ut are n ot li mite d  t o: 
•  Re vie w a n d e v al uati o n of si n gle S A E o cc urre nces i n real -ti me as re p orte d t hr o u g h t h e 
S A E re p orti n g pr ocess as o utli ne d i n t his secti o n of t he  pr ot oc ol;  
•  Re vie w a n d e v al uati o n, i n real -ti me, of o n e or m ore occ urre n ces of a n u nc o m m o n S A E 
t hat is n ot c o m m o nl y ass ociate d wit h pr o d uct e x p os ure;  
•  Fi n di n gs a n d/ or saf et y d ata o btai ne d d uri n g t his st u d y will pr o vi de i nf or m ati o n f or t he 
o verall re vi e w of safet y t hat is c o n d ucte d b y Sali x o n a r o uti ne basis. Sali x will re p ort 
e x pe diti o usl y a n y fi n di n gs fr o m cli nical trials ( o n g oi n g or c o m plete d), e pi d e mi ol o gical 
st u dies, p o ole d a nal ysis of m ulti ple st u dies, a n d fi n di n gs fr o m a ni mal or i n vitr o testi n g 
t hat s u g gest a sig nifica nt ris k i n h u ma ns e x p ose d t o t he st u d y  pr o d uct.  
Safet y d ata c ollecti o n f or t his st u d y b e gi ns at t he ti me of t he s u bject’s si g ni n g of t he i nf or me d 
c o nse nt acc or di n g t o t he o perati n g defi niti o ns defi ne d i n t his secti o n of t he pr ot oc ol. T he 
i n vesti gat or is r es p o nsi ble f or t he d etecti o n a n d d o c u me ntati o n of e ve nts t h at meet t he 
defi niti o n of a n u na ntici p ate d pr o ble m (refer t o t he pr ot oc ol Secti o n 1 0. 1), A E or S A E.  
7. 1  
O per ati n g Defi niti o ns f or Assessi n g  S afet y  
 
7. 1. 1  
A d verse  E ve nt  
 
A n A E is a n y u nt o war d me dical oc c urre n ce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a st u d y pr o d uct a n d w hic h d oes n ot necessaril y h a ve a ca us al relati o ns hi p wit h 
t he treat me nt. 
 
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 (t hat c o ul d i ncl u de a cli nicall y 
si g nifica nt a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease t e m p orall y ass ociate d wit h t he 
use of a st u d y pr o d uct, wit h o ut a n y j u d g m e nt a b o ut ca usalit y (i.e., w het her or n ot c o nsi dere d 
relate d t o t he st u d y pr o d u ct). 
 
A n A E d oes i ncl u de t he f oll o wi n g: 


P a ge 5 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  E x acer bati o n or w orse ni n g of a pre -e xisti n g ill ness. N O T E: if t he pre -e xisti n g ill ness is 
t he disease u n der st u d y, t he n “e x acer bati o n” refers t o a n u n e x pecte d w ors e ni n g fr o m t he 
c o n diti o n at  baseli ne.  
•  I n crease i n fr e q ue nc y or i nte nsit y of a pre -e xisti n g e pis o dic e ve nt or  c o n diti o n.  
•  C o n diti o n detecte d or dia g n ose d after st u d y pr o d u ct a d mi nistrati o n e ve n t h o u g h it ma y 
ha ve bee n pres e nt pri or t o t he start of t he  st u d y. 
•  S y m pt o m ass o ciate d wit h disease n ot pre vi o usl y re p orte d b y t he s u bject. 
A n A E d oes n ot i ncl u de t he f oll o wi n g: 
•  Me dical or s ur gical pr oce d ures ( e. g., s ur ger y, e n d osc o p y, t o ot h e xtracti o n, tra nsf usi o n) as 
e ve nt ter ms; t he c o n diti o n t hat le d t o t he pr oce d ure is t he A E if it meets t he defi niti o n of a n 
A E.  
•  Sit uati o ns w here a n u nt o war d me dical occ urre n ce has n ot occ urre d (e. g., h os pitalizati o n 
f or c os metic el ecti ve s ur ger y; a n d s ocial a n d/ or c o n ve nie nce a d missi o ns).  
•  O ver d ose of eit her st u d y pr o d uct or c o n c urre nt me dicati o n wit h o ut a n y si g ns or  s y m pt o ms. 
•  S y m pt o ms ass ociate d wit h disease, w hic h are c o nsiste nt wit h t he s u bject’s us ual cli nical 
c o urse; u nless t he s u bject e x perie nces w orse ni n g of t heir s y m pt o m(s) or t he s y m pt o m(s) 
meet t he criteri a f or a n  S A E.  
7. 1. 2  
Seri o us A d verse  E ve nt  
 
A S A E is a n y A E, occ urri n g at a n y d os e, w hic h res ults i n a n y of t he f oll o wi n g o utc o mes 
(“ Occ urri n g at a n y d ose” d oes n ot i m pl y t h at t he s u bject recei ve d st u d y pr o d uct): 
 
•  Res ults i n  deat h  
•  Is life t hreate ni n g 
N O T E : Lif e-t hr eate ni n g mea ns t hat t he s u bject w as, i n t he vie w of t he i n v esti gat or or 
s p o ns or, at i m me diate ris k of deat h at t he ti me of t he e ve nt. T his defi niti o n d oes n ot refer 
t o a n e ve nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h if it were m ore se vere. 
 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g  h o s pitalizati o n 
N O T E : 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 h er seri o us criteria, t he e ve nt is 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 t o be a n A E. “I n -patie nt” h os pitalizati o n mea ns t he s u bject has 
bee n f or m all y a d mitte d t o a h os pital f or me dical reas o ns. T his ma y or ma y n ot be 
o ver ni g ht. It d o es n ot i ncl u de prese ntati o n at a cas ualt y or e mer g e nc y r o o m.  


P a ge 5 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o  c o n d uct 
n or mal life  f u ncti o ns. 
N O T E: T he ter m disa bilit y mea ns a s u bsta ntial disr u p ti 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 n ce s uc h as u n c o m plicate d hea dac he, na us ea, v o miti n g, diarr hea, 
i nfl ue nza, or acci de ntal tr a u ma (e. g., s prai ne d a n kl e) t hat ma y i nterfere or pre ve nt 
e ver y da y lif e 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.  
•  A c o n ge nital a n o mal y or birt h defect i n t he offs pri n g of a s u bject w h o recei ve d st u d y 
pr o d uct.  
•  I m p ort a nt me dical e v e nts t hat d o n ot res ult i n deat h, are n ot life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a n S A E w h e n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o p ar dize t he s u bject a n d ma y re q uire me di cal or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  
N O T E : E x a m ples of s uc h me dical e ve nts i ncl u de aller gic br o n c h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y or 
dr u g a b use.  
 
A d diti o nall y, a n a d v erse e ve nt meeti n g a n y of t h e seri o us o utc o mes pre vi o usl y defi n e d a b o ve 
t hat is assesse d b y t he i n vesti gat or as res ulti n g fr o m st u d y partici pati o n (re gar dless of 
relati o ns hi p t o st u d y dr u g) s h o ul d be treate d as a S A E f or t his pr ot oc ol (e. g., c o m plicati o ns 
res ulti n g fr o m t he ta ki n g of a bl o o d sa m ple or perf or ma nce of a pr ot oc ol re q uire d pr oce d ure). 
 
Me dical a n d sci e ntific j u d g me nt s h o ul d be use d i n deci di n g w het her pr o m pt re p orti n g is 
a p pr o priate i n case  of e v e nts t hat d o n ot meet t he seri o us criteria a b o ve.  
7. 2  
Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts as A Es 
a n d  S A Es  
 
A b n or mal la b orat or y fi n di n gs (e. g., cli nical c h e mistr y, he mat ol o g y, a n d uri nal ysis) or ot her 
a b n or mal assess me nts ( e. g., a b n or mal fi n di n gs d uri n g e x a mi nati o ns or E C G m o nit ori n g) t hat 
are j u d ge d b y t he i n v esti gat or as cli nic all y si g nific a nt m ust be rec or de d  as A Es or S A Es if 
t he y meet t he defi niti o n of a n A E or S A E. T h e i n vesti gat or s h o ul d e x ercise his or her 
me dical a n d scie ntific j u d g me nt i n deci di n g w h et her a n a b n or mal la b orat or y fi n di n g or ot her 
a b n or mal assess me nt (i n cl u di n g E C G m o nit ori n g) is cli nicall y si g nifica nt.  
7. 3  
Met h o d, Fre q ue nc y, a n d Ti me Peri o d f or Detecti n g A Es a n d  S A Es  
 
At eac h visit, after t he s u bject has ha d a n o p p ort u nit y t o s p o nta ne o usl y me nti o n a n y 
pr o ble ms, t he i n vesti gat or s h o ul d i n q uire a b o ut A Es b y as ki n g t he f oll o wi n g sta n dar d 
q uesti o ns:  


Page 58 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
1. "Have you had any (other) medical problems since your last visit/assessment?" 
2. "Have you taken any new medicines, other than those given to you in this study, since 
your last visit/assessment?" 
7.3.1 
The Time Period for Detecting and Reporting of AEs and SAEs 
 
The Time Period for Detecting and Reporting of AEs and SAEs is from the time of informed 
consent through study completion/withdrawal, including the follow-up period. 
7.3.2 
Post-Study SAEs 
 
Investigators are not obligated to actively seek SAE information in former study participants, 
but investigators are encouraged to notify Salix of any SAEs occurring at any time after a 
subject has discontinued or terminated study participation that they judge may reasonably be 
related to study treatment or study participation. 
7.4 
Documenting AEs and SAEs 
 
All AEs that occur after the subject has signed the ICF and during the course of the study, 
regardless of causality or seriousness, will be assessed and recorded in the subject’s medical 
records and in the CRF. In addition, SAEs must be documented on the paper SAE Report 
Form. 
 
A separate paper SAE Report Form should be used for each SAE. However, if at the time of 
initial reporting, multiple SAEs are present that are temporally and/or clinically related, they 
may be reported on the same SAE Report Form. 
 
The investigator should attempt to establish a diagnosis for the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and SAE and not the individual signs/symptoms. 
 
For clinically significant abnormal laboratory findings or other abnormal assessments meeting 
the definition of an AE or SAE, a diagnosis, if known (or clinical signs and symptoms if 
diagnosis is unknown), should be recorded by the investigator. If a diagnosis is unknown and 
clinical signs and symptoms are not present, then the abnormal finding should be recorded. 
When documenting as an SAE on the SAE Report Form, relevant laboratory data should 
either be recorded in the ‘Details of Relevant Assessments’ section of the SAE Report Form 
(including the reference range and units) or copies of the laboratory report (with reference 
ranges and units) should be sent with the SAE Report Form. 
 
The SAE Report Form should be completed as thoroughly as possible and signed by the 
investigator or his/her designee before transmittal to Salix Product Safety or Designee. It is 
very important that the investigator provide his/her assessment of causality to study product 
at the time of initial SAE reporting. 


P a ge 5 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
7. 5  
F oll o w -u p of A Es a n d  S A Es  
 
All A Es, re gar dl ess of seri o us ness, m ust 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 t he s u bject is l ost t o f oll o w-u p. T he 
i n vesti gat or is r es p o nsi ble t o e ns ure t hat f oll o w-u p i ncl u des a n y s u p ple me ntal i n vesti gati o ns 
as ma y b e i n dicate d t o el uci date as c o m plet el y as practical t he n at ure a n d/ or ca usalit y of t he 
A E. T his ma y i ncl u d e 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 x a mi nati o ns, rele va nt h os pital rec or ds (i.e. dis c h ar ge s u m mar y), or c o ns ult ati o n wit h ot her 
healt h car e pr of essi o nals.  
 
Sali x ma y re q u est t hat t he i n vesti gat or perf or m or arra n ge f or t h e 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. 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 p e ri o d, Sali x s h o ul d be pr o vi de d 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. 
 
F or S A Es, ne w or u p date d i nf or mati o n s h o ul d be rec or de d o n t h e ori gi nall y c o m plete d pa per 
S A E Re p ort F or m a n d all c ha n ges si g ne d a n d date d b y t he I n vesti gat or  or d esi g nee. B y 
si g ni n g t he S A E Re p ort F or m, t he i n vesti gat or or desi g nee attests t o t he acc urac y a n d 
c o m plete ness of t he d ata a n d t hat he/s he has re vie we d a n d a p pr o ve d t he re p ort bei n g 
s u b mitte d. T he i n vesti gati o nal sites I R B/I E C m ust be n otifie d a b o ut SA Es i n acc or d a nce 
wit h t he re q uire me nts of t he g o v er ni n g I R B/I E C.  
7. 6  
Pr o m pt Re p orti n g of S A Es t o S ali x  P h ar m ace utic als  
 
S A Es m ust be re p orte d pr o m ptl y t o Sali x Pr o d uct Safet y or Desi g n ee o nce t he i n vesti gat or 
deter mi nes t hat t he e v e nt meets t he pr ot oc ol defi n iti o n of a S A E. 
 
Pr o m pt re p orti n g of a S A E re q uires:  
 
•  C o m pleti o n a n d tra ns missi o n of t he S A E Re p ort F or m t o Sali x Pr o d uct Safet y or Desi g nee 
via fa x wit hi n 2 4 h o urs of t he i n vesti gat or’s k n o wle d ge of t he e v e nt. I n parallel, a 
c orres p o n di n g A E wit h t he S A E details s h o ul d be e ntere d i nt o t he A E  C R F.  
•  Pr o m pt re p orti n g of a d diti o nal i nf or mati o n f or pre vi o usl y re p orte d S A Es s h o ul d f oll o w  t he 
sa me re p orti n g ti mefr a m e as i nitial re p orts. I n a d diti o n, t he c orres p o n di n g A E i n t he A E 
C R F (as a p plica bl e) s h o ul d be u p date d t o e ns ure all data p oi nts d oc u me nte d i n t he A E 
C R F are ali g ne d wit h t he matc hi n g d ata p oi nts o n t he pa per S A E Re p ort  F or m.  
7. 7  
Pre g n a nc y  Re p orti n g  
 
Pre g n a ncies d etecte d i n s u bjects assi g n e d t o st u d y treat me nt s h o ul d be pr o m ptl y re p ort e d t o 
Sali x Pr o d uct Safet y or Desi g n ee via fa x as s o o n as t he i n vesti gat or is n otifie d usi n g t he Sali x 
Pre g n a nc y N otificati o n F or m. If a f e male s u bject bec o mes pre g na nt f oll o wi n g assi g n me nt t o 
st u d y treat me nt, t he st u d y pr o d u ct will be i m me diatel y disc o nti n ue d a n d t h e s u bject will be 


P a ge 6 0  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
f oll o we d u ntil t he o utc o me of t he pre g n a nc y is k n o w n. ( Refer t o t he ‘ Fe m ales of 
Re pr o d ucti ve P ote ntial’ Sec ti o n 4. 4). 
 
Sali x Pr o d uct Safet y or Desi g n ee s h o ul d be n otifie d via fa x of a n y u p dates o n t he stat us of t he 
pre g na nc y as s o o n as t he i nf or mati o n bec o mes a v aila ble b y u p d ate a n d/ or a me n d me nt of t he 
i nitial pre g na n c y n otificati o n f or m. 
 
Alt h o u g h pr e g na nc y occ urri n g i n a cli nical st u d y 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 n c y, f or me di cal reas o ns, will be 
rec or d e d as a n A E or S A E a n d f oll o we d as s u c h. 
7. 8  
Tr a ns missi o n of S A E Re p ort F or ms a n d Pre g n a nc y N otific ati o n  F or ms  
 
C o m plete d S A E Re p ort F or ms a n d c o m plet e d Pre g n a nc y N otificati o n F or ms s h o ul d be 
tra ns mitte d via t he c o u ntr y s p ecific fa x n u m bers liste d i n t he S A E F or m C o m pleti o n 
G ui deli nes w hic h ar e pr o vi de d i n t he St u d y Refere nce Ma n ual.  
 
F or q uesti o ns re gar di n g S A E a n d / or Pre g na n c y re p orts, c o u ntr y s pecific p h o ne n u m bers are 
liste d i n t he S A E F or m C o m pleti o n G ui deli nes w hic h are pr o vi de d i n t he St u d y Refere n ce 
Ma n ual.  
7. 9  
Re g ul at or y Re p orti n g Re q uire me nts f or  S A Es  
 
T he i n vesti gat or, or r es p o nsi ble pers o n per l ocal re q uire me nts, m ust c o m pl y wit h t he 
a p plica ble l ocal re g ulat or y r e q uire me nts relate d t o t he re p orti n g of S A Es a n d e x pe dite d safet y 
re p orts t o re g ulat or y a ut h orities a n d t heir I R B/I E C. 


P a ge 6 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
8. 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
 
A detaile d statistical a nal ysis pla n will be pre p are d f or t his st u d y. T he pla n will c o ntai n a 
disc ussi o n of t he statistical met h o ds, a descri pti o n of t he c o m p utati o nal al g orit h ms a n d data 
ha n dli n g c o n v e nti o ns, a n d s pecificati o ns f or t h e d ata s u m maries a n d listi n gs. It will be 
fi nalize d bef ore d ata base l oc k. 
8. 1  
R a n d o miz ati o n  
 
S u bjects w h o s uccessf ull y c o m plet e t he Scree ni n g Peri o d will e nter t he Treat me nt Peri o d a n d 
will be ra n d o mize d i n a 1: 1 all ocati o n t o o ne of t w o treat me nt gr o u ps f or t h e d urati o n of t he 
st u d y as assi g ne d b y t h e mea ns of ce ntralize d electr o nic ra n d o mizati o n s yst e m. 
Ra n d o mizati o n will be stratifie d b y st u d y ce nter wit hi n a c o u ntr y. Treat me nt gr o u ps are as 
f oll o ws: 
 
•  Treat me nt  A:  
Rifa xi mi n D R 8 0 0 m g  BI D  
•  Treat me nt  B:  
Place b o BI D  
8. 2  
Deter mi n ati o n of S a m ple  Size  
 
T he i nf or mati o n bel o w pr o vi des t he bac k gr o u n d i nf or mati o n f or sa m ple si ze deter mi nati o n 
f or t he i n d ucti o n of cli nical re missi o n wit h e n d osc o pic res p o nse at 1 6 wee ks f oll o we d b y 
cli nical a n d e n d osc o pi c r e missi o n at 5 2 wee ks. F or place b o, t he e x pecte d rates are base d o n 
data fr o m a P has e 2 st u d y ( R E TI C 0 3/ 0 6) c o n d ucte d i n s u bjects wit h acti ve m o derate  Cr o h n’s 
disease. T he rates f or Rifa xi mi n D R are base d o n t he ass u m pti o n t hat Rifa xi mi n D R will 
pr o vi de a s o me w h at hi g h er i n d ucti o n of re missi o n  rate. 
 
E x pecte d rates f or i n d u cti o n of cli nical re m issi o n wit h e n d osc o pic res p o ns e at Wee k 1 6 are 
4 0 % f or place b o a n d 5 5 % f or Rifa xi mi n D R.  
 
Base d o n a si g nifica n ce l e vel of 5 % (al p ha 0. 0 5), a sa m ple size of a p pr o xi matel y 2 4 0 s u bjects 
per treat me nt gr o u p will ha ve at least 9 0 % p o wer t o test t he h y p ot hesis t hat Rifa xi mi n D R is 
s u peri or t o place b o f or eac h c o-pri mar y e n d p oi nt c o nsi dere d i n di vi d uall y. A p pr o xi matel y 
8 0 % p o wer is a v aila ble t o detect si g nifica nt differe nces bet w ee n Rifa xi mi n D R a n d place b o 
f or b ot h c o-pri mar y e n d p oi nts.  
 
F or t he L o n g T er m Tr eat me nt P hase, a 1 5 % treat me nt effect is e x pecte d f or b ot h cli nical 
s y m pt o m a n d e n d osc o pi c re missi o n at Wee k 5 2. Base d o n t his ass u m pti o n a n d testi n g at a 
si g nifica n ce le v el of 5 % (al p ha 0. 0 5), a sa m ple size of a p pr o xi matel y 2 1 0 s u bjects per 
treat me nt gr o u p will ha v e at least 9 0 % p o w er t o t est t he ke y sec o n d ar y effi cac y h y p ot hesis 
t hat Rifa xi mi n D R is s u peri or t o place b o w he n eac h ke y c o-s ec o n d ar y e n d p oi nt is c o nsi dere d 
i n di vi d uall y. I n a d diti o n, a p pr o xi matel y 8 0 % p o wer is a v aila ble t o detect si g nifi ca nt 
differe n ces b et wee n Rif a xi mi n D R a n d place b o f or eac h of t he ke y c o -sec o n dar y e n d p oi nts.  


P a ge 6 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
A n a d diti o nal c o nsi derati o n f or sa m ple size deter mi nati o n is t he a p plicati o n of a n i nflati o n 
fact or of 2 0 % t o acc o u nt f or dr o p-o ut rates d uri n g t he I n d u cti o n a n d L o n g T er m Treat me nt 
P hases of t he st u d y. T his c o nsi derati o n s u g geste d t hat 3 3 0 s u bjects per treat me nt gr o u p 
w o ul d be re q uir e d at st u d y e ntr y.  
8. 3  
A n al ysis P o p ul ati o ns 
I nte nt-t o-Tre at (I T T)  P o p ul ati o n  
T he I T T p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o ta ke at least o ne d ose of st u d y 
dr u g.  
 
Per Pr ot oc ol ( P P) P o p ul ati o n will i ncl u de all s u bjects i n t he I T T P o p ulati o n wit h t he 
e x ce pti o n of t h ose w h o f aile d t o meet I ncl usi o n Criteria 3 a n d 4; or met E x cl usi o n Criteria 1, 
2, 1 3 or 1 4.  
 
T he a nal yses of baseli ne c haracteristics a n d efficac y will be per f or me d f or t he I T T 
P o p ulati o n. T he pri mar y efficac y a n al ysis als o will be perf or m e d o n t he P P P o p ulati o n as a 
se nsiti vit y a nal ysis. All safet y a n al ys es will be perf or me d o n t he I T T P o p ul ati o n. 
8. 4  
S u bject  Dis p ositi o n  
 
S u bject dis p ositi o n will be s u m marize d b y treat me nt a n d st u d y p has e a n d will i ncl u de t he 
n u m ber of s u bjects e nt er e d i n t he st u d y; n u m ber a n d perce nt a ge of s u bjects w h o c o m plete d or 
pre mat urel y disc o nti n ue d (classifie d b y reas o ns f or pre mat ure disc o nti n uati o n); t he n u m ber of 
s u bjects e ntere d i n t he st u d y at eac h st u d y site; a n d t he n u m ber a n d perce nta ge of s u bjects 
w h o c o m plete d or disc o nti n ue d at eac h st u d y site.  
8. 5  
De m o gr a p hic a n d B aseli ne  C h ar acteristics  
 
De m o gra p hic a n d baseli n e c har acteristics will be s u m marize d descri pti vel y b y treat me nt 
gr o u p. Bas eli ne will be d efi ne d as t he l ast assess me nts pri or t o i nitiati n g t he Treat me nt 
Peri o d. T he f oll o wi n g d e m o gra p hi c a n d bas eli ne disease c h aracteristics will be s u m marize d: 
 
De m o gr a p hics : 
 
•  A ge ( years) = ( dat e of i nf or me d c o nse nt si g ne d –  d ate of  birt h)/ 3 6 5. 2 5;  
•  A ge gr o u p ( < 6 5, > = 6 5);  
•  Se x  ( male/fe male); 
•  Et h nicit y ( His pa nic or Lati n o/ n ot His pa nic or  Lati n o);  
•  Race ( A m erica n I n dia n or Alas ka n N ati ve, Asia n, Blac k or Af ri ca n-A merica n, Nati ve 
Ha waiia n or Ot her Pacific Isla n der, W hite, a n d Ot her); s u bjects w h o i de ntif y m ore  t h a n 
o ne race will be cate g ori ze d as  “ Ot her”;  


P a ge 6 3  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  Hei g ht  (c m); 
•  Wei g ht  ( k g); 
•  B o d y mass i n de x ( k g/ m 2) = ( Wei g ht i n k g)/ ( Hei g ht i n  m) 2;  
•  Re gi o n ( U S/ Rest Of  W orl d).
 
B aseli ne c h ar acteristi cs:  
 
All baseli ne s u bject c h ar acteristics i ncl u di n g de m o gra p hic data ( o utli ne d a b o ve), baseli ne 
C D AI a n d S E S -C D sc ores, d urati o n of t he disease ( years), l ocati o n of disease, pre vi o us 
ster oi d use ( d ose, d ur ati o n), pre vi o us s ur ger y f or C D, s m o ki n g hist or y ( n o ns m o ker/e x - 
s m o ker/s m o ker), bas eli ne C R P a n d fecal cal pr otecti n val ues will be s u m marize d b y treat me nt 
ar m. Baseli ne c o m para bilit y will be assesse d via d escri pti ve meas ures, e. g., b y c o m p ari n g 
mea ns, 9 5 % c o nfi de nce i nter vals a n d pr o p orti o ns.  
8. 6  
A n al ysis  Met h o ds  
 
T he p hrases ‘statistical a nal ysis’ or ‘a n al ysis’ will be use d t o mea n i nfe re ntial a nal ysis (s u c h 
as perf or mi n g tests of si g nifica nce, re p orti n g p -v al ues a n d c o nfi d e nce i nter vals). W he n n o 
i nfere ntial a n al ysis will b e perf or me d, t he p hrases ‘ descri pti ve a n al ysis’ or ‘ descri pti ve 
statistics’ will be use d (f or i nsta nce, pr o d u ci n g su m mar y ta bl es of mea ns, sta n dar d de viati o ns, 
perce nt a ges of res p o n ders). All efficac y a n al ys es will be c o n d ucte d o n I T T a n d P P 
p o p ulati o ns. All efficac y a nal ys es will a dj ust f or c o u ntr y.  
8. 6. 1  
Pri m ar y Effic ac y A n al ysis  
I n d ucti o n P h ase  
T here will be t w o c o -pri mar y m eas ures of efficac y ass esse d d uri n g t he I n d ucti o n P hase. T he 
first c o-pri mar y e n d p oi nt is:  
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 1 6 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 1 6  visit.  
T he sec o n d c o -pri mar y e n d p oi nt  is: 
 
•  E n d osc o pic res p o ns e defi ne d as a ≥3 -p oi nt decreas e i n t he S E S -C D fr o m baseli ne t o t he 
S E S -C D sc ore o btai ne d bet wee n Wee k 1 6 a n d Wee k 1 7. S E S -C D sc ores will be 
calc ulate d fr o m ce ntrall y-rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at baseli ne a n d 
bet wee n Wee k 1 6 a n d Wee k  1 7.  
F or eac h e n d p oi nt, t he n ull h y p ot hesis H 0: π R -π P = 0 vers us t he alter n ati ve H A: π R -π P ≠0 is of 
i nterest, w her e π R is t he bi n o mial para meter f or i n d ucti o n of re missi o n/res p o nse f or t he 


P a ge 6 4  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
Rifa xi mi n D R gr o u p, a n d π P is t he bi n o mial para meter f or i n d ucti o n of re missi o n/res p o nse 
f or t he place b o gr o u p. S u bjects w h o re q uire t he i nitiati o n of resc ue me di cati o n a n d/ or s ur ger y 
f or C D will be c o nsi der e d treat me nt fail ures fr o m t he date of t he i ntr o d u cti o n of t he resc ue 
me dicati o n a n d/ or s ur ger y, r e gar dl ess of t heir ac t u al res p o nse dat a. T he C o c hra n-M a ntel - 
Hae nszel ( C M H) test, str atifie d b y c o u ntr y, will b e use d t o test t he h y p ot hesis. Eac h n ull 
h y p ot hesis of n o differ e n ce will be rej ecte d if t he res ulti n g p -val u e f or t he res pecti ve 
statistical test is less t ha n 0. 0 5. Si g nifica nce f or t h e i n d ucti o n clai m will o nl y be d eclare d if 
b ot h n ull h y p ot h eses ar e rejecte d. As s uc h, t he o v erall T y pe I err or rat e will be mai ntai ne d at 
t he 5 % le vel wit h o ut a dj ust me nt f or m ulti ple c o m paris o ns.  
If it is e vi de nt t hat t he res p o nse variable is c o nf o u n de d wit h s o me of t he bac k gr o u n d 
varia bles, t he n l o gistic re gr essi o n will be perf or me d usi n g t he b ac k gr o u n d varia bles as 
c o variates. T h e diff ere n ces bet wee n t his a dj uste d a nal ysis a n d t he pre vi o us u na dj uste d 
a nal ysis will be n ote d, a n d t he i m p act of s uc h differe nces will be disc usse d.  
 
T he pri mar y efficac y a n al ysis will be re peate d o n t he P P p o p ulati o n t o assess t he r o b ust ness 
of t he res ults of t he pri m ar y o utc o me.  
 
L o n g Ter m Tre at me nt P h ase  
 
T here will be t w o k e y c o -sec o n dar y e n d p oi nts of efficac y ass esse d d uri n g t he L o n g T er m 
Treat me nt P hase. T h e first is:  
 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or 
t he 7 da ys pri or t o t he Wee k 5 2 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a bd o mi nal pai n rati n g of ≤ 1 (fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 5 2  visit.  
T he sec o n d is:  
 
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 at Wee k 5 2. S E S -C D sc ores will 
be calc ul ate d fr o m ce ntrall y -r ea d di gital vi de o of ile oc ol o n osc o pies perf or me d at Wee k 5 2.  
F or eac h e n d p oi nt, t he n u m ber a n d pr o p orti o n of s u bjects wit h cli nical a n d e n d os c o pic 
re missi o n will be s u m marize d b y treat me nt gr o u p f or t he I T T P o p ulati o n. 
F or eac h e n d p oi nt, t he n ull h y p ot hesis H 0: π R -π P = 0 vers us t he alter n ati ve H A: π R -π P ≠0 is  of 
i nterest, w her e π R is t he bi n o mial para meter f or re missi o n f or t he Rifa xi mi n D R gr o u p, a n d 
π P is t he bi n o mial para meter f or re missi o n f or t he place b o gr o u p. S u bjects w h o re q uire t h e 
i nitiati o n of resc ue me dicati o n a n d/ or s ur ger y f or C D will be c o nsi dere d treat me nt fail ures 
fr o m t he date of t h e i ntr o d ucti o n of t he resc u e me dicati o n a n d/ or sur ger y, re gar dless of t h eir 
act ual res p o ns e data.  T h e C oc hra n -M a ntel -H ae ns zel ( C M H) test, stratifie d b y c o u ntr y, will 
be use d t o test t he h y p ot hesis. Eac h n ull h y p ot h esis of n o differe nce will be rejecte d if t he 
res ulti n g p-v al ue f or t h e r es pecti ve statis tical test is less t ha n 0. 0 5. Si g nifica nce f or cli nical  


P a ge 6 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
a n d e n d osc o pic re missi o n will o nl y b e declare d if b ot h n ull h y p ot h eses are rejecte d. As s uc h, 
t he o verall T y pe I err or rate will be mai ntai ne d at t he 5 % le vel wit h o ut a dj ust me nt f or 
m ulti ple c o m paris o ns.  
 
If it is e vi de nt t hat t he res p o nse varia ble is c o nf o u n de d wit h s o me of t he bac k gr o u n d 
varia bles, t he n l o gistic re gr essi o n will be perf or me d usi n g t he b ac k gr o u n d varia bles as 
c o variates. T h e diff ere n ces bet wee n t his a dj uste d a nal ysis a n d t he pre vi o us u na dj uste d 
a nal ysis will be n ote d, a n d t he i m pact of s uc h differe nces will be disc usse d.  
8. 6. 2  
Sec o n d ar y Effic ac y  A n al yses  
 
A nal ysis of bi n ar y e n d p oi nts will be base d o n t he  met h o ds o utli ne d a b o ve f or t he pri mar y 
efficac y a n al ysis.  
 
F or ti me u ntil d ura ble r es p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of t he c o -pri mar y 
e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt P hase, a res p o nse will be c o nsi dere d d ura bl e if it 
starte d at Wee k 4 a n d l aste d t hr o u g h Wee k 5 2. A res p o nse is defi ne d as t otal n u m ber of 
li q ui d/ ver y s oft st o ols f or t he 7 da ys pri or t o t he visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1). T h e 
e n d p oi nt is t he n t he ti me w he n t he d ura ble res p o ns e be ga n, or t h e first wee k of res p o nse t hat  
be ga n t he stri n g of c o ns ec uti ve visits wit h res p o nse t hr o u g h Wee k 5 2. It is w ort h re mar ki n g 
t hat t his e n d p oi nt w o ul d n ot be defi ne d f or a s u bject w h o d oes n ot ha ve a d ura ble res p o nse, s o 
we c o nsi der i nstea d t he ti me of t he last visit at w hic h res p o nse was  ac hie ve d. F or e x a m ple, if 
a s u bject is cate g orize d as a res p o n der at Wee k 5 2, t he n a d ura ble res p o nse was n ot ac hie v e d. 
If a s u bject is cate g orize d as a res p o n d er at Wee k 2 0, t he n a d ura ble res p o nse starte d o n Wee k  
2 4. Ti me u ntil d ura ble res p o nse will be a nal yz e d b y t he K ol m o g or o v -S mir n o v test. Ti me 
u ntil d ura ble res p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he c o -pri mar y e n d p oi nt d uri n g 
t he 5 2-Wee k Treat me nt P hase is a nal yze d si milarl y. A res p o nse is defi n e d as a b d o mi nal pai n 
rati n g of ≤ 1(fr o m C D AI Ite m 2) o n eac h da y f or t he 7 da ys pri or t o t he visit.  
C ha n ge fr o m bas eli ne i n c o nti n u o us o utc o mes (f or e x a m ple, t he c ha n ge fr o m baseli ne i n t he 
S E S -C D at Wee k 1 6) will be a nal yz e d b y fitti n g fi x e d effects li near m o dels t o t he data. A n 
i nitial m o del wit h ter ms f or treat me nt, c o u ntr y, b aseli ne, a n d baseli ne b y treat me nt i nteracti o n 
will be fitte d.  T he i nteracti o n ter m will be teste d at a 0. 1 0 le vel.  A n o n -si g nifica nt 
i nteracti o n will res ult i n dr o p pi n g t he ter m fr o m t he m o del i n s u bse q ue nt a nal yses. If t he fi n al 
m o del i n v ol ves heter o ge ne o us sl o pes, t he n t he a n al ysis will i ncl u de o verall pl ots of baseli ne 
vers us c ha n ge fr o m b aseli ne b y tr eat me nt gr o u ps, a n d pl ots of t he esti mate d re gressi o n li nes. 
Treat me nt diff ere n ces will be esti mate d a n d teste d at 2 5t h, 5 0t h a n d 7 5t h perce ntiles of t he 
baseli ne  val ue.  
Ti me t o e ve nt data (f or e x a m ple, ti me t o cli nical re missi o n) will be a nal yze d b y K a pla n -Mei er 
a nal ysis ( P R O C LI E F T T E S T i n S A S/ S T A T) stratifie d b y c o u ntr y. A d diti o nall y, t he c ha n ge 
fr o m baseli ne i n c o nti n u o us o utc o mes meas ure d at m ulti ple p ost -baseli ne ti me p oi nts will be 
a nal yze d l o n git u di nall y usi n g a mi x e d m o del. M o dels will i ncl u de fi x e d effects f or b aseli ne  


P a ge 6 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
val ue, c o u ntr y, tr ea t me nt, wee k a n d t h e treat me nt b y w ee k i nteracti o n a n d all o w f or ra n d o m 
s u bject eff ects. Tr eat me nt a n d wee k will eac h be fit as cate g orical varia bl es. M o dels will be 
fit usi n g S A S Pr oc Mi x e d ass u mi n g a c o m p o u n d s y m metric c orrelati o n str uct ure all o wi n g f or 
h eter o ge n e o us varia n ces b y w ee k. T he Ke n w ar d -R o gers a p pr oac h f or c o m p uti n g 
de n o mi nat or de gr ees of free d o m will be use d t o acc o u nt a p pr o priatel y f or p o oli n g of wit hi n - 
a n d bet wee n -s u bject v ari a nce esti mates. Least s q u ares mea ns wit h 9 5 % c o nfi de nce i nter vals 
will be prese nte d f or eac h treat me nt * wee k cr oss -classificati o n. T he basic S A S c o de will 
f oll o w t he str uct ure bel o w:  
 
pr oc mi xe d ; 
class treat me nt c o u ntr y wee k s u bjectI D;  
m o del Y = baseli ne c o u ntr y tr eat me nt wee k treat me nt * wee k/ d df m = K e n w ar d R o ger s ol uti o n; 
ra n d o m i nt/ s u bject =s u bjectI D t y pe = V C; 
ls mea ns treat me nt * wee k/st derr; 
r u n ; 
 
Esti mate a n d c o ntrast state me nts will be i ncl u de d t o c o m pare t he mea n c h a n ge fr o m baseli ne 
a vera ge d o ver all wee ks f or t he treat me nt c o m paris o n.  
 
T o deter mi ne w h et her t h e declarati o n of res p o nse base d o n t he c o -pri mar y e n d p oi nts f or 
i n d ucti o n parallels t he patter n of C D AI sc ores, S p ear ma n c orrelati o n a nal yses will be a p plie d 
t o C D AI s c ores wit h t he occ urr e nce or n o n-o cc urre nce of res p o nse b ase d o n t he c o -pri mar y 
e n d p oi nts ( Yes or N o). Wilc o x o n ra n k -s u m test will be c o n d ucte d t o c o m pare c h a n ges i n t he 
C D AI s c ores b et wee n res p o n ders a n d n o n -res p o n d ers t o t he c o-pri mar y e n d p oi nts.  
 
T he W or k Pr o d ucti vit y a n d Acti vit y I m pair m e nt Q uesti o n naire: C r o h n’s disease ( W P AI: C D) 
is a n i nstr u me nt wit h 6 q uesti o ns t hat will be use d t o assess t he effect of C D o n s u bjects’ 
w or k ha bits. A c o p y of t h e W P AI: C D q uesti o n naire is pr o vi de d i n A p pe n di x 6.  
 
W P AI: C D o utc o mes ar e e x presse d as i m pair me nt perce nt a ges, w it h hi g her n u m bers 
i n dicati n g gr eater i m pair me nt a n d less pr o d ucti vit y, i.e., w orse o utc o mes. T he f o ur W P AI: 
C D o utc o me sc ores are c o m p ute d as f oll o ws:  
 
•  % w or k ti me misse d d ue t o C D =  1 0 0 * Q 2/( Q 2 + Q 4)  
•  % i m pair me nt w hile w or ki n g d ue t o C D =  1 0 0 * Q 5/ 1 0  
•  % o verall w or k i m pair me nt =  1 0 0 *[ Q 2/( Q 2 + Q 4) +[( 1 -Q 2/( Q 2 + Q 4)] *( Q 5/ 1 0)]  
•  % acti vit y i m pair me nt d u e t o C D =  1 0 0 * Q 6/ 1 0  
T he I B D Q Gl o bal Sc or e is t he s u m of 3 2 res p o nses, eac h ra n gi n g fr o m 1 t o 7, t h us t he Gl o bal 
Sc ore ra n ges fr o m 3 2 t o 2 2 4; a hi g her sc ore i n dicati n g  a b etter q ualit y of life. A c o p y of t he 
I B D Q q u esti o n naire is pr o vi de d i n A p pe n di x 5. 


P a ge 6 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
C ha n ges fr o m bas eli ne i n t he f o ur W P AI: C D a n d I B D Q Gl o bal Sc ore o ut c o mes will be 
a nal yze d b y t h e met h o ds o utli ne d a b o ve f or c o nti n u o us o utc o mes.  
8. 6. 3  
S af et y  A n al yses  
 
Safet y e val uati o ns will b e base d o n t he i nci d e nce, i nte nsit y a n d t y pes of A Es, a n d c ha n ges i n 
vital si g ns, cli nical la b or at or y res ults, p h ysical e x a m a n d electr ocar di o gra ms. C o nc o mita nt 
me dicati o n, e x p os ure t o st u d y me dicati o n a n d treat me nt c o m plia nce will be s u m marize d 
descri pti vel y.  
8. 6. 4  
E xte nt of E x p os ure a n d Tre at me nt  C o m pli a nce  
 
T he n u m ber of s u bjects a d mi nistere d st u d y dr u g, t he d urati o n of e x p os ure t o st u d y dr u g, a n d 
c o m plia nce data will be s u m marize d descri pti vel y.  
8. 6. 5  
A d verse  E ve nts  
 
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y A cti vities 
( Me d D R A) c o di n g dicti o nar y. Treat me nt-e mer ge nt A Es will be defi ne d as a n y e ve nt wit h a 
start date occ urri ng o n or after Visit 2 ( D a y 1) or, if pre -e xisti n g, w orse ni n g after Visit 2 ( D a y 
1).  
 
T he i nci de nce of treat me nt -e mer ge nt A Es will be s u m marize d b y b o d y s yste m a n d  Me d D R A 
preferre d t er m. If a s u bject re p orts t he sa m e A E m ore t ha n o nce, t he n t hat s u bject wil l o nl y 
be c o u nte d o nce f or t h e s u m mar y of t hat A E, usi n g t he m ost se vere  i nte nsit y. 
 
Treat me nt -e mer ge nt A Es will be s u m marize d as f oll o ws:  
 
•  All treat me nt -e mer ge nt  A Es;  
•  All treat me nt -e mer ge nt A Es b y i nt e nsit y; 
•  All treat me nt -e mer ge nt A Es relate d t o st u d y dr u g;  
•  All treat me nt -e mer ge nt S A Es;  a n d  
•  All treat me nt -e mer ge nt A Es t hat le d t o pre mat ure disc o nti n uati o n of st u d y  dr u g.  
 
8. 6. 6  
Cli nic al L a b or at or y  Assess me nts  
 
La b orat or y v al ues will be s u m marize d at baseli ne a n d at eac h ti me p oi nt. I n a d diti o n, c ha n ges 
fr o m baseli ne t o last visit will be s u m marize d. 
 
A s u m mar y of s hifts fr o m baseli ne t o fi nal e val u ati o n will be gi ve n f or eac h treat me nt gr o u p 
f or eac h par a meter. T he n or mal ra n ge f or eac h p ara meter will be use d t o create cate g ories of 
l o w, n or mal, or hi g h. A n y r es ult hi g her t ha n U L N or l o wer t ha n t he l o w er li mit of n or mal 
( L L N) will be cate g orize d as hi g h or l o w res pecti vel y, a n d a n y res ult wit hi n t he l o wer a n d 


Page 68 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
upper limits of normal will be categorized as normal. The number and percentage of subjects 
in each treatment group in each shift category from baseline to final evaluation will be shown 
for each parameter. 
 
All potentially clinically significant values for clinical laboratory tests will be assessed by the 
investigator. Out of range laboratory values that may be potentially clinically significant will 
be flagged for review. 
8.6.7 
Vital Signs 
 
Vital sign measurements will be summarized at baseline and at each time point. In addition, 
changes from baseline to last visit in vital sign measurements will be summarized. For each 
summary the number, mean, median, standard deviation, minimum, and maximum values will 
be presented by treatment and study phase. 
8.6.8 
Concomitant Medications 
 
Concomitant medications taken from screening and during the study will be categorized by 
World Health Organization (WHO) classification for therapeutic class and drug name and 
summarized by number and percentage of subjects. 
8.6.9 
Physical Examinations 
 
Physical examination data will be presented in a data listing. 
 
8.6.10 
Electrocardiogram 
 
ECG parameters will be summarized by treatment group using descriptive statistics. In order 
to assess the QT interval data, corrected QT (QTc) values will be calculated based on the 
following three methods. 
 
1) Fridericia’s correction: QTc=QT/RR0.33, 
 
2) Bazett’s Correction: QTc=QT/RR0.5 , 
And 
3) Correction based on linear regression techniques: Based on the data from 
baseline study population, the intercept(a) and slope (b) will be estimated 
separately for males and females using the equation QT=a+b(1-RR). Those 
estimates will be used to calculate the corrected QT values at post baseline 
time points. 


P a ge 6 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
Q Tc i nter val d ata at p ost -baseli ne visits will t he n be s u m marize d descri pti vel y b y ce ntral 
te n de nc y tec h ni q ues. I n a d diti o n, t he fre q ue nc y c o u nts a n d perce nta ges b y treat me nt gr o u p 
f or t he f oll o wi n g cat e g ories will be pr o vi de d:  
 
> 4 5 0 wit h Bas eli ne  < = 4 5 0,  
 
> 4 8 0 wit h Bas eli ne  < = 4 8 0,  
 
> 5 0 0 wit h Bas eli ne < = 5 0 0, 
I n creases fr o m baseli ne > 3 0 a n d 
I n creases fr o m baseli ne > 6 0. 
8. 7  
St atistic al a n d A n al ytic al  Iss ues 
 
8. 7. 1  
A dj ust me nt f or  C o v ari ates  
 
Efficac y a nal ys es will be a dj uste d f or c o u ntr y a n d baseli ne val ues.  
 
8. 7. 2  
H a n dli n g of Dr o p o uts or Missi n g  D at a  
 
Missi n g data will be ha n dle d usi n g t he W orst Case a nal ysis met h o d f or t he pri mar y a n d ke y 
sec o n dar y e n d p oi nts. I n t he W orst Case a nal ysis, s u bjects wit h fe wer t ha n 4 da ys of diar y 
data i n a gi ve n w ee k will be c o nsi dere d n o n -res p o n ders f or t hat w ee k. A d diti o nall y, s u bjects 
wit h missi n g S E S -C D data will be classifie d n o n -res p o n der f or t hat meas ure i n t hat wee k. 
 
T he f oll o wi n g t hr ee s e nsiti vit y a nal yses will be c o n d ucte d t o a d dress t he i m pact of missi n g 
data o n t he pri mar y a n d ke y s ec o n dar y e n d p oi nts:  
 
L ast O bser v ati o n C arri e d F or w ar d ( L O C F) A n al ysis : I n t he first a nal ysis, missi n g val ues 
will be re place d wit h t he last pre vi o us n o n -missi n g val u e. T he bas eli ne val ues will n ot be 
carri e d f or w ar d.  
 
M ulti ple I m p ut ati o n A n al ysis : I n t he s ec o n d a n al ysis, missi n g val u es will be fille d i n b y t he 
m ulti ple i m p utati o n met h o d w hic h i n v ol ves t he f oll o wi n g disti nct p hases:  
 
•  T he missi n g data will be fille d i n t o ge nerate c o m plete data sets usi n g S A S/ S T A T 
pr oce d ur e P R O C  MI;
 
•  T he c o m plete dat a sets will be a nal yze d usi n g P R O C L O GI S TI C i n  S A S/ S T A T;  
•  T he a b o ve t w o ste ps will be re peate d 5  ti mes; 
•  T he res ults fr o m t he c o m plete data sets will be c o m bi ne d f or statistical i nfere nce  usi n g 
S A S/ S T A T pr oce d ure P R O C  MI A N A L Y Z E.
 


P a ge 7 0  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
O bser ve d C ase A n al ysis : I n t he t hir d a n al ysis, s u bjects are e x cl u de d fr o m t he a nal ysis if t he 
s u bject has i ns ufficie nt d ata t o be deter mi ne d as a res p o n der or n o n-resp o n der i n a gi ve n 4 - 
wee k ass ess me nt peri o d. T his a nal ysis is n ot base d o n t he I T T p o p ulati o n a n d, t heref ore, 
i nter pretati o n of r es ults fr o m t his a nal ysis re q uires s u bsta ntial ca uti o n. T his is beca use t he 
s u bjects w h o res p o n de d i n t he res pecti ve treat me nt gr o u ps ma y h a ve differe nt distri b uti o ns 
f or bac k gr o u n d c h aracteristics. T h us, a d diti o nal a nal ysis ma y be u n d erta k e n b y t he us e of 
statistical met h o ds w hic h pr o vi de a dj ust me nt f or b ac k gr o u n d c h aracteristics. 
8. 7. 3  
I nteri m A n al yses a n d D at a M o nit ori n g  
 
N o i nteri m a nal yses are pla n ne d f or t his st u d y.  
 
8. 7. 4  
M ultice nter  St u dies  
 
Ce nters will be p o ole d wit hi n c o u ntries f or t he ass ess me nt of c o u ntr y effects.  
 
8. 7. 5  
M ulti ple  C o m p aris o ns/ M ulti plicit y  
 
T he st u d y h as a si n gle pri mar y e n d p oi nt as t he pri mar y h y p ot hesis, t heref ore n o m ulti plicit y 
a dj ust me nt is nee de d t o t he o verall si g nifica n ce le vel of 0. 0 5. A d diti o nall y, t he cli nical trial 
will be pr o vi di n g data f or t w o se parat e i n dicati o ns (i n d ucti o n a n d l o n g ter m treat me nt) wit h 
eac h i n dicati o n ha vi n g its o w n se parate e n d p oi nt. O n t hat basis, n o m ulti plicit y a dj ust me nt is 
nee de d t o t he o v erall si g nifica nce l e vel of 0. 0 5 p er i n dicati o n beca us e c o n cl usi o ns will be 
reac h e d i n de pe n d e ntl y f or i n d ucti o n a n d se paratel y f or l o n g t er m treat me nt. 
 
T he c o m plete e v al uati o n of cli ni cal efficac y i n t his st u d y re q uires t he st u d y of m ulti ple ke y 
sec o n dar y effi cac y v aria bles c ollecte d at n u mer o us ti me p oi nts. It is t heref ore necessar y t o 
pr o perl y a n d s e nsiti vel y c o ntr ol t he pr o ba bilit y of ma ki n g err o ne o us c o ncl usi o ns base d s olel y 
u p o n c o m p o u n di n g t he li keli h o o d of a t y p e I err or. T he iss ue of m ulti plicit y of s ec o n dar y 
meas ure me nts will be ha n dle d b y statistical testi n g of t hes e o utc o mes i n a hierarc hical 
fas hi o n. T he or d er of s ec o n dar y e n d p oi nts f or t he I n d u cti o n a n d L o n g Ter m Treat me nt 
P hases are d escri b e d i n Secti o ns  2. 2. 2  a n d 2. 2. 3. Si g nifica n ce tests will be c o n d ucte d u ntil a 
n o n -si g nifica nt p-val ue is f o u n d ( p > 0. 0 5). O nce a n o n -si g nifica nt p-val ue occ urre d, all 
s u bse q ue nt si g nifica nce tests will be c o nsi dere d e x pl orat or y i n  nat ure.  
8. 7. 6  
Use of a n Effic ac y S u bset of  S u bjects  
 
T he pri mar y efficac y e n d p oi nt will be a nal yze d usi n g t he I T T P o p ulati o n.  
 
8. 7. 7  
E x pl or ati o n of t he Eff ects of V ari o us Pr o g n ostic F a ct ors o n  Effic ac y  
 
T his st u d y is n ot f or mall y i nte n de d  t o o btai n d ata o n t he i nfl ue nce of de m o gra p hic a n d 
baseli ne disease c haracteristics (e. g., ge n der, race, a ge, a n d re gi o n ( U S/ R O W)) o n efficac y 
o utc o mes b y t he e x plicit desi g n or ra n d o mizati o n. H o we ver, t he p ote ntial i nfl ue nce of t hese  


Page 71 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
factors in efficacy outcomes will be investigated by pooled analysis across the two identical 
studies (RECD3125 and RECD3126, reference: FDA ISE guidance document). 
8.7.8 
Criteria for Stopping the Study 
 
It is expected that the study will be terminated when the enrollment goals are reached. It is 
not anticipated that the study will be stopped early for any reason. 


P a ge 7 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
9. 0  
S T U D Y  A D MI NI S T R A TI O N  
 
9. 1  
I n vesti g at or I nf or m ati o n a n d Tr ai ni n g  
 
T he i n vesti gat ors a n d ess e ntial s u p p ort staff will be trai ne d b y Sali x ( or desi g nee) i n re gar ds 
t o G o o d Cli nical Practices ( G C Ps) a n d all as pects of pr ot oc ol e x ec uti o n. It is t he 
res p o nsi bilit y of t he i n vesti gat or t o trai n a n cillar y st u d y staff. 
9. 2  
M o nit ori n g  
 
T his st u d y will be m o nit ore d b y Sali x ( or desi g nee), i n acc or da n ce wit h G C Ps a n d a p plica ble 
re g ulati o ns. B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o peri o dic, o n -site m o nit ori n g of 
all a p pr o priate st u d y d oc u me ntati o n.  
 
T he pr o gress of t he st u d y will be m o nit ore d b y peri o dic o n -site visits a n d fre q ue nt 
c o m m u nicati o ns bet wee n t he Sali x ( or desi g nee) a n d t he i n vesti gat or (eit her b y p h o n e, fa x, 
e mail, or p ost).  
 
D uri n g t h ese c o ntacts, t he m o nit or will:  
 
•  C hec k a n d ass ess t he pr o gr ess of t he  st u d y. 
•  Re vie w st u d y d ata  c ollecte d.  
•  C o n d uct s o urce d oc u me nt  verificati o n.  
•  I d e ntif y a n y iss ues a n d a d dress t heir res ol uti o n. 
T he o bjecti ves of m o nit ori n g pr o ce d ures are t o verif y t h at data are a ut h e ntic, acc urate, a n d 
c o m plete; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr otecte d; a n d t h at t he st u d y is 
c o n d ucte d i n acc or d a nce wit h t he c urre ntl y a p pr o v e d pr ot oc ol (a n d a n y a me n d me nts), G C Ps, 
a n d all a p plica ble re g ulat or y re q uire m e nts.  
9. 3  
A u dits  
 
At its discreti o n, Sali x ( or desi g n ee) ma y c o n d u ct a q ualit y ass ura nce a u dit of t his st u d y. If 
s uc h a n a u dit occ urs, t he i n vesti gat or a grees t o all o w t he a u dit or direct access t o all rele va nt 
d oc u me nts a n d t o sc he d ule his/ her ti me a n d t he ti me of his/ her staff t o per mit meeti n gs wit h 
t he a u dit or t o disc uss fi n di n gs a n d a n y rele v a nt iss ues. 
 
I n a d diti o n, re g ulat or y a ge ncies ma y c o n d u ct a re g ulat or y i ns pecti o n of t his st u d y. If s u c h a n 
i ns pecti o n occ urs, t he i n v esti gat or a grees t o all o w t he i ns pect or direct access t o all rele va nt 
d oc u me nts a n d t o sc he d ule his/ her ti me a n d t he ti me of his/ her staff t o p er mit meeti n gs wit h 
t he i ns pect or t o disc uss fi n di n gs a n d a n y rele v a nt iss ues. T he i n vesti gat or will n otif y Sali x 
i m me diatel y w h e n a Re g ulat or y A ge nc y n otifies t he site of a n i ns pecti o n. 


P a ge 7 3  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
1 0. 0  
E T HI C A L A N D L E G A L  A S P E C T S  
 
T he i n vesti gat or a n d t he st u d y staff are res p o nsi bl e f or c o n d ucti n g t his st u d y i n acc or d a nce 
wit h t he a p plica ble pri nci ples w hic h h a ve t heir ori gi ns i n t h e D eclarati o n of Helsi n ki, I C H, 
G C Ps, a n d all ot her a p plica ble la ws a n d re g ul ati o ns.  
1 0. 1  
I nstit uti o n al Re vie w B o ar d/ I n de pe n de nt Et hics C o m mittee (I R B/I E C) A p pr o v a l 
 
T his pr ot oc ol, t he i nf or me d c o nse nt f or m, rele v a nt s u p p orti n g i nf or mati o n, a n d all t y p es of 
s u bject recr uit me nt or a d vertise me nt i nf or mati o n m ust be a p pr o ve d b y t he a p pr o priate 
I R B/I E C bef ore t he st u d y is i nitiate d. A n y a me n d me nts t o t he pr ot oc ol m ust als o be 
a p pr o ve d, w h ere n ecessar y, b y t he I R B/I E C pri or t o i m ple me nti n g c ha n ges i n t he st u d y.  
D oc u me ntati o n of t hese a p pr o vals m ust be pr o vi d e d t o t he s p o ns or pri or t o t he i nitiati o n of 
t he a me n d me nt. 
 
T he i n vesti gat or’s r es p o nsi bilities re gar di n g t he I R B/I E C are as f oll o ws:  
 
•  O btai n I R B/I E C a p pr o v al of t he pr ot oc ol, i nf or me d c o nse nt f or m, a n d a n y  a d vertise me nts 
f or s u bject r ecr uit me nt pri or t o t heir use.  
•  O btai n I R B/I E C a p pr o v al f or a n y pr ot oc ol a m e n d me nts a n d re visi o ns t o t he  i nf or me d 
c o nse nt d oc u me nt bef ore  i m ple me nti n g t he c h a n ges.  
•  Pr o vi de t he I R B/I E C wit h a n y re q uire d i nf or mati o n bef ore or d uri n g t he  st u d y. 
•  S u b mit pr o gress r e p orts t o t he I R B/I E C, as re q uire d, d uri n g t he c o n d uct of t he st u d y; 
re q uest re-re vi e w a n d a p pr o val of t he st u d y, as nee de d; pr o vi de c o pi es of all I R B/I E C  re- 
a p pr o vals a n d rele va nt c o m m u nicati o n t o t he  s p o ns or. 
•  N otif y t he I R B/I E C wit hi n 1 0 da ys ( u nless re q uire d s o o ner b y I R B/I E C) of all seri o us a n d 
u ne x pecte d A Es relat e d t o t he st u d y me dicati o ns t hat are re p orte d t o y o u b y t he s p o ns or. 
T he i n vesti gat or is res p o nsi ble f or u p dati n g t h e I R B/I E C o n t he pr o gress of t he st u d y a n d 
of a n y c ha n ges ma de t o t he pr ot oc ol at least o n ce a year or at re g ular i nter v als as dee me d 
a p pr o priate. T h e i n vesti gat or m ust als o kee p t he I R B/I E C i nf or me d of a n y A Es, acc or di n g 
t o t he I R B/I E C p olic y. 
 
N otif yi n g Sali x wit hi n 2 4 h o urs of a w are n ess a n d t he I R B/I E C wit hi n i n 1 0 da ys ( u nless 
re q uire d s o o n er b y I R B/I E C) of all u na ntici pate d pr o ble ms i n v ol vi n g ris k t o s u bjects or 
ot hers. F or t he p ur p oses of t his st u d y, a n U n a ntici p ate d Pr o ble m is defi ne d as a n y 
i nci de nt, e x perie nce, or o utc o me t h at meets all of t he f oll o wi n g criteri a: 
•  U ne x pecte d i n nat ure, s e verit y, or fre q ue nc y (i.e. n ot descri be d i n st u d y -rel ate d d oc u me nts 
s uc h as t he I R B-a p pr o ve d pr ot oc ol or c o ns e nt f or m, t he i n vesti gat ors br o c h ure,  etc.)  
•  Relate d or p ossi bl y r elate d t o partici pati o n i n t he researc h (i.e. p ossi bl y rel ate d mea ns  t here 
is a reas o na bl e p ossi bilit y t hat t he i nci d e nt e x perie nce, or o ut c o me ma y ha ve bee n ca use d 
b y t he pr oce d ures i n v ol ve d i n t he  researc h) 


P a ge 7 4  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
•  S u g gests t hat t he res ear c h places s u bjects or ot h ers at greater ris k of har m (i ncl u di n g 
p h ysical, ps yc h ol o gi cal, ec o n o mic, or s oci al har m).  
1 0. 2  
S u bject I nf or m ati o n a n d I nf or me d  C o nse nt  
 
T he i n vesti gat or is res p o nsi ble f or o btai ni n g writte n i nf or me d c o ns e nt fr o m eac h i n di vi d ual 
partici pati n g i n t his st u d y after a de q uat e e x pla nati o n i n la y ma n’s t er ms re gar di n g t h e nat ure 
of t he st u d y, al o n g w it h t he ai ms, met h o ds, o bjecti ves, a n d a n y p ote ntial ris ks. T he i nf or me d 
c o nse nt f or m m ust be a p pr o priatel y si g n e d a n d d ate d b y t he s u bject or t he s u bject’s le gall y 
a ut h orize d re pres e ntati ve a n d t he pers o n o btai ni n g t he c o nse nt (if re q uire d b y t he I R B/I E C)  
pri or t o c o n d ucti n g/ o btai ni n g a n y st u d y -relate d assess me nts i ncl u di n g t he disc o nti n uati o n of 
a n y m e dicati o ns pr o hi bite d f or t he st u d y.  
 
If t he i nf or me d c o nse nt f or m is a me n de d d uri n g t he st u d y, t he i n vesti gat or m ust f oll o w all 
a p plica ble r e g ulat or y r e q uir e me nts pertai ni n g t o a p pr o val of t he a m e n de d i nf or me d c o ns e nt 
f or m b y t h e I R B/I E C a n d use of t he a me n d e d d oc u me nt (i ncl u di n g f or o n g oi n g s u bjects). 
 
T he i nf or me d c o ns e nt f or m s hall als o c o ntai n t he s u bject's a ut h orizati o n f or t he use a n d 
discl os ure of his/ her pr ot ecte d healt h i nf or mati o n ( P HI) i n c o n necti o n wit h t he st u d y. T he 
a ut h orizati o n s hall i ncl u de at a mi ni m u m a clear d escri pti o n of t he f oll o wi n g: t he d urati o n of 
t he a ut h orizati o n, t he s u bject's ri g ht of access t o t he P HI ( or a n y s us pe nsi o n t here of duri n g t he 
c o urse of t he st u d y), t y p e of i nf or mati o n t o be use d/ discl ose d i n t he st u d y, t he na mes or 
classes of parties t hat ma y use or discl ose t he P HI, t he p ur p ose of t he us e/ discl os ure of P HI, 
t he e xte nt of t he s u bject's ri g ht t o re v o k e t he a ut h orizati o n, t he e xte nt t o w hic h partici pati o n i n 
t he st u d y is c o n diti o ne d o n si g ni n g t he a ut h orizati o n, a n d t he p ote ntial f or re-discl os ure of 
P HI.  
T he ori gi nal a n d a n y a me n de d si g n e d a n d date d i nf or me d c o nse nt f or ms m ust be retai ne d at 
t he st u d y site; a n d a c o p y m ust be gi ve n t o t he s u bject or s u bject’s le gall y a ut h orize d 
re pres e ntati ve(s). 
1 0. 3  
St u d y a n d Site Cl os ure or  Disc o nti n u ati o n  
 
U p o n c o m pleti o n of t he st u d y, t he f oll o wi n g acti vities, w he n a p plica ble, m ust be c o n d ucte d 
b y t he m o nit or i n c o nj u n cti o n wit h t he i n ves ti gat or, as a p pr o priate: 
 
•  Ret ur n of all st u d y d ata t o Sali x ( or  desi g nee).  
•  Data clarificati o ns a n d/ or  res ol uti o ns. 
•  Acc o u nti n g, rec o nciliati o n, a n d fi nal dis p ositi o n of use d a n d u n use d st u d y dr u g  a n d 
place b o.  
•  Re vie w of site st u d y rec or ds f or  c o m plete ness.  


P a ge 7 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
I n a d diti o n, Sali x reser ves t he ri g ht t o te m p oraril y s us pe n d or pre mat urel y disc o nti n ue t his 
st u d y eit her at a si n gle site or at all sites at a n y ti m e a n d f or a n y reas o n. If s uc h acti o n is 
ta ke n, Sali x will disc uss t his wit h t he i n vesti gat or (i ncl u di n g t he reas o ns f or ta ki n g s uc h 
acti o n) at t hat ti me. Sali x will pr o m ptl y i nf or m all ot her i n vesti gat ors a n d/ or i nstit uti o ns 
c o n d ucti n g t h e st u d y if t h e st u d y is s us pe n d e d or t er mi nate d f or s afet y reas o ns, a n d will als o 
i nf or m t he re g ulat or y a ut h orities of t he s us pe nsi o n or ter mi nati o n of t he st u d y a n d t h e 
reas o n(s) f or t he acti o n. If re q uire d b y a p plica ble re g ul ati o ns, t he i n vesti gat or m ust i nf or m t he 
I R B/I E C pr o m ptl y a nd pr o vi de t he reas o n f or t he s us pe nsi o n or  ter mi nati o n. 
1 0. 3. 1  
St u d y  Disc o nti n u ati o n  
 
S h o ul d t he i n vesti gat or, Sali x, t he F D A or l ocal re g ul at or y a ut h orities bec o me a ware of 
c o n diti o ns arisi n g d uri n g t he c o n d uct of t his st u d y t hat ma y w arra nt t he cessati o n of t he  st u d y, 
s uc h acti o n ma y be ta k e n. Pri or t o s uc h acti o n, c o ns ultati o n bet wee n Sali x, t he i n vesti gat or, 
a n d, as a p pr o priate, t he F D A a n d/ or l ocal re g ulat or y a ut h orities will ta ke place. C o n diti o ns 
t hat ma y r es ult i n t he ter mi nati o n of t he st u d y or parts t here of i ncl u de, b ut are n ot li mite d t o, 
t he f oll o wi n g: 
 
•  T he disc o ver y of a n u ne x pecte d, seri o us, or u nacce pta ble ris k t o t he s u bjects e nr olle d i n 
t he st u d y 
•  A decisi o n o n t he part of Sali x t o alter, s us pe n d, or disc o nti n ue t he de vel o p me nt of t he 
i n vesti gati o nal pr o d uct  
1 0. 3. 2  
St u d y Site  Disc o nti n u ati o n  
 
T he st u d y site ca n be dis c o nti n ue d at t he re q u est of Sali x, t he i n vesti gat or, or b y t he F D A or 
l ocal re g ulat or y a ut h orities. 
 
C o n diti o ns t hat ma y w arr a nt disc o nti n uati o n of t he st u d y site i ncl u de, b ut are  n ot li mite d t o, 
a n y of t he f oll o wi n g:  
 
•  Fail ure of t he i n vesti gat or t o accr ue s u bjects i nt o t he st u d y at a n acce pta bl e  rate. 
•  Fail ure of t he i n vesti gat or t o c o m pl y wit h G C Ps a n d/ or a p plica ble c urre nt  re g ul ati o ns. 
•  S u b missi o n of k n o wi n gl y f alse i nf or mati o n fr o m t he researc h facilit y t o t h e s p o ns or, F D A, 
or ot her re g ul at or y  a ut h orities.  
•  I ns ufficie nt a d h ere n ce t o pr ot oc ol re q uire m e nts a n d pr oce d ures.  
If t he st u d y is pre mat ur el y disc o nti n ue d, all st u d y data m ust be ret ur n e d t o Sali x or desi g nee. 
I n a d diti o n, t he site m ust c o n d uct fi nal dis p ositi o n of all use d a n d u n use d st u d y dr u gs i n 
acc or d a nce wit h Sali x pr oce d ures f or t he st u d y. St u d y ter mi nati o n a n d f oll o w -u p will be 
perf or me d i n c o m plia nce wit h G C P a n d a p plica ble re g ulati o ns.  


P a ge 7 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
Fi na ncial c o m pe nsati o n t o i n vesti gat ors a n d/ or i nstit uti o ns will be i n acc or d a nce wit h t he 
a gree m e nt esta blis he d bet wee n t he i n vesti gat or a n d Sali x.  
1 0. 4  
H a n dli n g a n d Rec or d  Kee pi n g  
 
1 0. 4. 1  
C ase Re p ort F or ms a n d D at a b ase Pr ocessi n g  
 
S u bject data will be c ollecte d i n a n electr o nic C R F usi n g Electr o ni c Data C a pt ure ( E D C). 
T he E D C s yst e m will be Part 1 1 c o m plia nt a n d will ha ve a d oc u me nt e d a u dit trail f or all 
c ha n ges ma d e t o t he electr o nic C R F . 
 
T he I n vesti gat or or d esi g nee m ust e nter all re q uire d s u bject data usi n g t he s pecifie d dat a 
c ollecti o n met h o d defi ne d b y Sali x. T he I n v esti gat or m ust si g n a n d date a declarati o n o n t he 
electr o nic C R F attesti n g t o his/ her res p o nsi bilit y f or t he q ualit y of all data e ntere d a n d t hat t he 
data re prese nts a c o m plet e a n d acc urate rec or d of eac h s u bject's p artici pati o n i n t he st u d y.  
Electr o nic case r e p ort f or m data will be pr o vi de d t o t he I n v esti gat or at t he e n d of t he st u d y 
a n d will nee d t o be r etai n e d  b y t h e I n vesti gat or.  
1 0. 4. 2  
S o urce  D oc u me nts  
 
S o urce d oc u me nts c o nsist of, b ut are n ot li mite d t o, i n -patie nt h os pital c harts, cli nic n otes, 
o ut -patie nt rec or ds, ori gi nal test res ults, la b orat or y dat a, w or ks heets, dr u g acc o u nta bilit y 
rec or ds, i nf or me d c o ns e nt f or ms, etc. S o urce d o c u me nts m ust be a vaila ble f or re vie w a n d 
i ns pecti o n d uri n g o n-site m o nit ori n g of t he st u d y b y Sali x, t heir desi g nees, I R B/I E C, a n d/ or 
a p pr o priate re g ulat or y a ut h orities.  
1 0. 4. 3  
S u bject  Tr ac ki n g  
 
A dr u g acc o u nta bilit y l o g, s u bject i de ntifi cati o n  l o g (t o be retai n e d b y t he i n vesti gat or o nl y), 
a n d s u bject scr ee ni n g/e nr oll me nt l o g will be use d t o trac k s u bject p artici pati o n i n t he st u d y.  
1 0. 4. 4  
St u d y  Files  
 
T he i n vesti gati o nal ce nter will mai ntai n a s pecial st u d y file. T his file is s u bject t o re vie w a n d 
i ns pecti o n as descri b e d u n der Secti o n 9. 2 a n d Secti o n 9. 3  of t his pr ot oc ol.  
1 0. 4. 5  
D at a  M a n a ge me nt  
 
Data ma na ge me nt will be perf or me d i n acc or d a nce wit h t he sta n dar d o p erati n g pr oce d ures of 
Sali x or its desi g nee.  
1 0. 5  
C o nfi de nti alit y  
 
A n o n y mit y of s u bjects p artici pati n g i n t his st u d y will be mai ntai ne d. O nl y s u bject i nitials a n d 
s u bject n u m ber will be o n a n y st u d y d o c u me nts s u b mitte d t o t he s p o ns or. E ver y eff ort will be  


P a ge 7 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
ma de t o mai ntai n t he c o nfi de ntialit y of d o c u me nts t hat i de ntif y t he s u bject b y na m e (e. g., 
si g ne d i nf or me d c o nse nt d oc u me nt, la b orat or y re p orts, cli nic c harts), e x ce pt t o t he e xte nt 
necessar y t o all o w a u d iti n g b y t he F D A, or ot her re g ul at or y a ut h orities. S h o ul d t he na me 
a n d/ or a d dr ess of a s u bject partici pati n g i n t his trial be o n a d oc u m e nt s u b mitte d t o t he F D A, 
or ot her re g ul at or y a ut h orities (e. g., la b orat or y re p ort), t he na me a n d/ or a d dress will be 
c o mpletel y bl o c ke d o ut a n d re place d wit h t he s u bject i nitials a n d n u m ber.  
 
T he i n vesti gat or a n d ot her st u d y site pers o n nel will kee p c o nfi de ntial a n y i nf or mati o n 
pr o vi de d b y Sali x (i ncl u di n g t his pr ot oc ol) relate d t o t his st u d y a n d all data a n d rec or ds 
ge n era t e d i n t he c o urs e of c o n d ucti n g t he st u d y, a n d will n ot use t he i nf or mati o n, data, or 
rec or ds f or a n y p ur p ose ot her t ha n c o n d ucti n g t he st u d y. T hes e restricti o ns d o n ot a p pl y t o: 
( 1) i nf or mati o n w hic h b ec o mes p u blicl y a vaila ble t hr o u g h n o fa ult of t he i n vesti gat or or st u d y 
site pers o n nel; ( 2) i nf or m ati o n w hic h it is necessar y t o discl ose i n c o nfi d e nce t o a n I R B/I E C 
s olel y f or t he e val u ati o n of t he st u d y; ( 3) i nf or mati o n w hic h it is necessar y t o discl ose i n 
or der t o pr o vi de a p pr o pri ate me dical care t o a st u d y s u bject, or ( 4) st u d y res ults w hic h ma y be 
p u blis he d as descri be d i n Sec ti o n 1 0. 8. If a writte n c o ntract f or t he c o n d u ct of t he st u d y w hic h 
i ncl u des c o nfi de ntialit y pr o visi o ns i nc o nsiste nt wit h t his state me nt is e x ec ute d, t hat c o ntract’s 
c o nfi de ntialit y pr o visi o ns s hall a p pl y rat her t ha n t his  state me nt. 
1 0. 6  
Rec or d  Rete nti o n  
 
Esse ntial d oc u me nts as d escri be d a b o ve s h o ul d be retai ne d f or o ne of t h e f oll o wi n g ti me 
peri o ds:  
 
•  At least 2 years after a p pr o val of t he last mar k eti n g  a p plicati o n,  
O R  
 
•  At least 2 years h a ve el a pse d si nce t he f or mal disc o nti n uati o n of cli nical d e vel o p me nt of 
t he i n vesti gati o nal pr o d u ct.  
T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger p eri o d h o we ver if re q uire d b y a p plica ble 
re g ulat or y r e q uire me nts (i.e., l ocal or c o u ntr y-s pecific re g ulati o ns) or b y a n a gree m e nt wit h 
t he s p o ns or. It is t he res p o nsi bilit y of Sali x t o i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n 
t hese d oc u me nts n o l o n ger nee d t o b e ret ai ne d. It is t he i n vesti gat or res p o nsi bilit y t o n otif y 
Sali x if t he y m o ve or retire s o t hat d oc u me nt st ora ge ca n b e a d dresse d.  
1 0. 7  
Fi n a nci n g a n d  I ns ur a nce 
 
1 0. 7. 1  
Fi n a nce  
 
T he st u d y is s u p p orte d b y Sali x.  


Page 78 of 103 
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Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
10.7.2 
Insurance and Indemnification 
 
Documentation of product liability insurance is on file at Salix and is available upon request. 
 
10.8 
Publication Policy 
 
An Institution and/or the investigator shall have the right, consistent with academic standards, 
to publish or present the results of the study, provided such publication or presentation does 
not disclose confidential information or other proprietary trade secrets of Salix. Salix will 
work with the protocol development team to identify a lead author for manuscript 
development. The manuscript authors will be determined by the amount of effort and 
participation each investigator contributes towards the study design, the conduct of the study 
and the analysis of the study data. Prior to any publication, presentation or other disclosure, 
the institution and/or investigator will submit the manuscript of any proposed publication 
(including abstracts, or presentation to a journal, editor, meeting, seminar, or other third 
party) to Salix at least sixty (60) days before publication, and Salix shall have the right to 
review and comment upon the proposed publication. Upon sponsor's request, publication will 
be delayed up to ninety (90) additional days to enable Salix to secure adequate intellectual 
property protection of property of Salix that could be affected by said publication. Salix shall 
have the right to require the deletion of any trade secret, or proprietary or confidential 
information of sponsor. Any publication or disclosure by the Institution and/or Investigator 
shall give appropriate credit to Sponsor. Where title is not retained by the publisher, title to 
and the right to determine the disposition of any copyrightable material, first produced or 
composed in the performance of the study, shall remain with the Institution and/or 
investigator. With respect to such materials, the Institution and/or investigator hereby grants 
to Salix an irrevocable, royalty-free, nonexclusive right to reproduce, translate, and use any 
such copyrighted material for its own research and commercial purposes. Investigator 
acknowledges and agrees that the study data and results may be disclosed by Salix to other 
clinical investigators, the FDA, and other regulatory authorities. 
10.9 
Ownership 
 
All data and records provided by Salix or generated during the study (other than a subject’s 
medical records) and all inventions discovered during the course of conducting the study are 
the property of Salix. If a written agreement is executed by the parties for the conduct of the 
study, which includes ownership provisions inconsistent with this statement, the ownership 
provisions contained in the written agreement between the parties shall control. 


Page 79 of 103 
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CRP-71 
Confidential 
 
 
 
11.0 
REFERENCES 
 
Reference List 
 
(1) Stenson WF. Inflammatory Bowel Disease. In: Yamada T, Alpers DH, Laine L, Owyang 
C, Powell D, editors. Textbook of Gastroenterology. 2 ed. Philadelphia: Lippincott, 
Williams, and Wilkins; 1999. p. Table 81-1:1776. 
 
(2) Penner RM, Madsen KL, Fedorak RN. Postoperative Crohn's disease. Inflamm Bowel 
Dis 2005 Aug;11(8):765-77. 
 
(3) Nos P, Domenech E. Postoperative Crohn's disease recurrence: a practical approach. 
World J Gastroenterol 2008 Sep 28;14(36):5540-8. 
 
(4) Aratari A, Papi C, Leandro G, Viscido A, Capurso L, Caprilli R. Early versus late surgery 
for ileo-caecal Crohn's disease. Aliment Pharmacol Ther 2007 Nov 15;26(10):1303-12. 
 
(5) Lemann M. Review article: can post-operative recurrence in Crohn's disease be 
prevented? Aliment Pharmacol Ther 2006 Oct;24 Suppl 3:22-8. 
 
(6) Terdiman JP. Prevention of postoperative recurrence in Crohn's disease. Clin 
Gastroenterol Hepatol 2008 Jun;6(6):616-20. 
 
(7) Rutgeerts P, Van AG, Vermeire S, D'Haens G, Baert F, Noman M, et al. Ornidazole for 
prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, 
placebo-controlled trial. Gastroenterology 2005 Apr;128(4):856-61. 
 
(8) Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in 
Crohn's disease. Ann Surg 2000 Jan;231(1):38-45. 
 
(9) 
In: Yamada T, editor. Textbook of Gastroenterology. 2 ed. 1999. p. Table 81-1:1776. 
 
(10) Scaldaferri F, Fiocchi C. Inflammatory bowel disease: progress and current concepts of 
etiopathogenesis. Journal of digestive diseases 2007 Nov;8(4):171-8. 
 
(11) Sartor RB. Microbial influences in inflammatory bowel diseases. [Review] [213 refs]. 
Gastroenterology 2008 Feb;134(2):577-94. 
 
(12) Swidsinski A, Loening-Baucke V, Herber A. Mucosal flora in Crohn's disease and 
ulcerative colitis - an overview. J Physiol Pharmacol 2009 Dec;60 Suppl 6:61-71. 
 
(13) Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y. Active Crohn's disease 
and ulcerative colitis can be specifically diagnosed and monitored based on the 
biostructure of the fecal flora. Inflamm Bowel Dis 2008 Feb;14(2):147-61. 


Page 80 of 103 
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Confidential 
 
 
 
(14) Seksik P, Rigottier-Gois L, Gramet G, Sutren M, Pochart P, Marteau P, et al. Alterations 
of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. Gut 
2003 Feb;52(2):237-42. 
 
(15) Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, et al. Low 
counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 2009 
Aug;15(8):1183-9. 
 
(16) Scanlan PD, Shanahan F, Marchesi JR. Culture-independent analysis of desulfovibrios in 
the human distal colon of healthy, colorectal cancer and polypectomized individuals. 
FEMS Microbiol Ecol 2009 Aug;69(2):213-21. 
 
(17) Mangin I, Bonnet R, Seksik P, Rigottier-Gois L, Sutren M, Bouhnik Y, et al. Molecular 
inventory of faecal microflora in patients with Crohn's disease. FEMS Microbiol Ecol 
2004 Oct 1;50(1):25-36. 
 
(18) Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, et al. Culture 
independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia 
coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving 
the ileum. ISME J 2007 Sep;1(5):403-18. 
 
(19) Barnich N, Carvalho FA, Glasser AL, Darcha C, Jantscheff P, Allez M, et al. CEACAM6 
acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in 
Crohn disease. J Clin Invest 2007 Jun;117(6):1566-74. 
 
(20) Brown EL, Xue Q, Jiang ZD, Xu Y, DuPont HL. Pretreatment of epithelial cells with 
rifaximin alters bacterial attachment and internalization profiles. Antimicrob Agents 
Chemother 2010 Jan;54(1):388-96. 
 
(21) Jiang ZD, Ke S, DuPont HL. Rifaximin-induced alteration of virulence of diarrhoea- 
producing Escherichia coli and Shigella sonnei. Int J Antimicrob Agents 2010 
Mar;35(3):278-81. 
 
(22) Maccaferri S, Vitali B, Klinder A, Kolida S, Ndagijimana M, Laghi L, et al. Rifaximin 
modulates the colonic microbiota of patients with Crohn's disease: an in vitro approach 
using a continuous culture colonic model system. J Antimicrob Chemother 2010 
Dec;65(12):2556-65. 
 
(23) Fiorucci S, Distrutti E, Mencarelli A, Barbanti M, Palazzini E, Morelli A. Inhibition of 
intestinal bacterial translocation with rifaximin modulates lamina propria monocytic cells 
reactivity and protects against inflammation in a rodent model of colitis. Digestion 
2002;66(4):246-56. 
 
(24) Ma X, Shah YM, Guo GL, Wang T, Krausz KW, Idle JR, et al. Rifaximin is a gut- 
specific human pregnane X receptor activator. J Pharmacol Exp Ther 2007 
Jul;322(1):391-8. 


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(25) Mencarelli A, Migliorati M, Barbanti M, Cipriani S, Palladino G, Distrutti E, et al. 
Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on 
detoxification pathways in intestinal epithelial cells. Biochem Pharmacol 2010 Dec 
1;80(11):1700-7. 
 
(26) Cheng J, Shah YM, Ma X, Pang X, Tanaka T, Kodama T, et al. Therapeutic role of 
rifaximin in inflammatory bowel disease: clinical implication of human pregnane X 
receptor activation. J Pharmacol Exp Ther 2010 Oct;335(1):32-41. 
 
(27) Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, et al. Double 
blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 1991 
Sep;32(9):1071-5. 
 
(28) Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, et al. An antibiotic 
regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial 
of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996 Feb;91(2):328-32. 
 
(29) Ursing B, Alm T, Barany F, Bergelin I, Ganrot-Norlin K, Hoevels J, et al. A comparative 
study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative 
Crohn's disease study in Sweden. II. Result. Gastroenterology 1982 Sep;83(3):550-62. 
 
(30) Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Croitoru K, et al. 
Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized 
controlled trial. Gastroenterology 2002 Jul;123(1):33-40. 
 
(31) Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and 
metronidazole for active Crohn's disease. Can J Gastroenterol 1998 Jan;12(1):53-6. 
 
(32) Colombel JF, Lemann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas JL, et al. A 
controlled trial comparing ciprofloxacin with mesalazine for the treatment of active 
Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires 
Digestives (GETAID). Am J Gastroenterol 1999 Mar;94(3):674-8. 
 
(33) Shafran I, Burgunder P. Adjunctive antibiotic therapy with rifaximin may help reduce 
Crohn's disease activity. Dig Dis Sci 2010 Apr;55(4):1079-84. 
 
(34) Thia K, Faubion WA, Jr., Loftus EV, Jr., Persson T, Persson A, Sandborn WJ. Short 
CDAI: development and validation of a shortened and simplified Crohn's disease activity 
index. Inflamm Bowel Dis 2011 Jan;17(1):105-11. 
 
(35) Sipponen T, Nuutinen H, Turunen U, Farkkila M. Endoscopic evaluation of Crohn's 
disease activity: comparison of the CDEIS and the SES-CD. Inflamm Bowel Dis 2010 
Dec;16(12):2131-6. 
 
(36) Ferrante M, Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, et al. 
Validation of endoscopic activity scores in patients with Crohn's disease based on a post 
hoc analysis of data from SONIC. Gastroenterology 2013 Nov;145(5):978-86. 


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(37) Moskovitz D, Daperno M, Van Assche G, Baert F, Gevers A, Sostegni R, et al. Defining 
and validating cut-offs for the Simple Endocopic Score for Crohn's Disease. 
Gastroenterology 2007;132:S1097. 
 
(38) Guidance for Industry. Patient-reported outcome measures: use in medical product 
development to support labeling claims. FDA Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices 
and Radiological Health (CDRH). 2009. 
 
(39) Rifaximin Investigator's Brochure. 2013. 


P a ge 8 3 of 1 0 3  
 
 
R E C D 3 1 2 6  
S ali x P h ar m ace utic als,  I nc. 
Versi o n  D ate:  1 4 J ul 2 0 1 4  
C R P -7 1  
C o nfi de nti al  
A P P E N DI X 1: O V E R A L L TI M E A N D E V E N T S S C H E D U L E  
 
S T U D Y A S S E S S M E N T S  
Scree ni n g 
Peri o d  
 
Tre at me nt Peri o d  
F oll o w -U p 
Peri o d  
U nsc he  
d ul e d 
Visit  
St u d y Visit  
Visit 1  
Visit 2  
Visit 3, 4, 5, 6  
Visit 7  
Visit 8, 9, 1 0, 1 1, 1 2, 1 3, 1 4, 1 5,  
Visit 1 6 
( E O T) 
Visit 1 7 
( E O S) 
 
St u d y Wee k  
 
0  
2, 4, 8 a n d 1 2  
1 6  
2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8  
5 2  
5 4  
 
St u d y D a y  
-2 1 t o – 1 4  
1  
1 4, 2 8, 5 6, 8 4 
( ± 3 d) 
1 1 2 ( ± 3 d)  
1 4 0, 1 6 8, 1 9 6, 2 2 4, 2 5 2, 2 8 0, 3 0 8, 3 3 6 
( ± 3 d) 
3 6 4 ( ± 3 d)  
3 7 8 ( ± 3 d)  
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
Assi g n S u bject I de ntificati o n  
X  
 
 
 
 
 
 
 
Me dical Hist or y a n d De m o gra p hics  
X  
 
 
 
 
 
 
 
A d verse E ve nts a n d C o nc o mita nt  
Me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
I ncl usi o n/ E xcl usi o n Criteria 
X  
X  
 
 
 
 
 
 
Vital Si g ns, Wei g ht, a n d P h ysical 
E xa mi nati o n a 
X (i ncl u de 
hei g ht)  
X  
X  
X  
X  
X  
X ( Vit al Si g ns a n d 
Wei g ht O nl y)  
X  
Electr ocar di o gra m  
X (tri plicat e) 
 
 
X  
 
X  
X  
 
Pre g na n c y Test  
X (ser u m) 
X ( uri ne) 
 
X ( uri ne) 
X ( uri ne) ( V 1 0 a n d V 1 3 o nl y) 
X (ser u m) 
 
 
Safet y La b orat or y Tests b 
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d Sa m ple f or I nfla m mat or y 
Mar kers a n d P X R ( V 2 o nl y)  
 
X  
 
X  
 
X  
 
 
P har mac o ki netic Bl o o d Sa m ple  
 
X  
X ( V 6 o nl y)  
 
X ( V 1 5 o nl y)  
 
 
 
St o ol C ollecti o n a n d Pr ocessi n g  
X  
 
 
X  
 
X  
 
 
St o ol/ Bl o o d f or L o n g -ter m St ora g e 
 
X  
 
X  
 
X  
 
 
C D AI assess me nt calc ulate d b y E D C  
X  
 
X  
X  
X  
X  
 
 
Ile oc ol o n osc o p y ( S E S-C D) c 
X  
 
 
X  
 
X  
 
 
I B D Q a n d W P AI-C D  
 
X  
 
X  
X ( V 1 0 a n d V 1 3 o nl y)  
X  
 
 
Electr o nic Dail y Diar y  
I nstr ucti o ns/ C o m pleti o n 
X  
X  
X  
X  
X  
X  
 
 
Ra n d o mizati o n  
 
X  
 
 
 
 
 
 
Dis pe nse St u d y Dr u g  
 
X ( 1st d ose at 
cli nic)  
X (e xce pt V 3)  
X  
X  
 
 
 
St u d y Dr u g C ollecti o n/ C o m plia nce  
 
 
X  
X  
X  
X  
 
 
a. 
Perf or m a f ull p h ysical e xa mi nati o n at Scree ni n g ( Visit 1), pri or t o t he L o n g Ter m Tr eat me nt P hase ( Visit 7), a n d at E n d of Treat me nt ( Visit 1 6); perf or m disease a n d s y m pt o m dri ve n p h ysical e xa mi nati o n 
(i n cl u di n g assess me nts f or a b d o mi nal mass a n d e xtrai ntesti nal ma nifestati o ns of Cr o h n’s disease base d o n C D AI –  see A p pe n di x 2) at ot her visits.  
b.  
I n cl u di n g C. Difficile safet y testi n g as descri be d i n Secti o n 6. 3. 5  
c. 
T h e b aseli n e ile oc ol o n osc o p y will be perf or me d bet wee n Da y -1 2 a n d Da y -5; it will pr o vi de t he baseli ne S E S -C D, a n d will be use d t o assess I ncl usi o n Criteri o n # 3. B o wel pre p will be dis pe nse d at Visit 1. 
Ile oc ol o n osc o p y t o be  c o m plete d wit hi n 7  da ys  after Visit  7  a n d  Visit  1 6.  B o wel  pre p will  be  dis pe nse d at Visit  7  a n d Visit  1 6,  clea nsi n g re gi me n t o be gi n  after Visit  7  a n d Visit  1 6  assess me nts. 


R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
A P P E N DI X 2: C R O H N’ S DI S E A S E A C TI VI T Y I N D E X ( C D AI)  
P a ge 8 4  of 1 0 3  
 
 
 
 
D A Y  
-7  
-6  
-5  
-4  
-3  
-2  
-1  
7 d a y  T otal  
1.  N u m ber of li q ui d  or  ver y  
X 2  =  
s oft st o ols * 
 
 
2.  A b d o mi nal  p ai n  
X 5  =  
 
0 = n o ne, 1 = mil d, 2 = m o derate, 3 = se vere  
 
3.  Ge ner al  well  b ei n g  
X 7  =  
 
0 = ge nerall y well, 1 = sli g htl y u n der par, 2 = p o or, 3 = ver y p o or, 4 = terri ble  
4.  E xtrai ntesti nal ma nifestati o ns s u bject h as n o w  (c h ec k A L L t h at a p pl y) 
Art hritis/art hral gia   
Iritis/ u veitis  
Er yt h e ma n o d os u m/ p y o d er ma ga n gre n os u m/ a p ht h o us st o matitis  
A n al fiss ure, fist ula or a bscess  
Ot h er fist ula  
Fe ver o ver 3 7. 8 °C ( 1 0 0 °F) d uri n g p ast wee k  
T otal  c h ec ke d  
X 2 0  =  
b o xes  
 
5.  A nti diarr heal dr u gs i n t h e last 7  da ys  
N o = 0, Yes  =  1  
X 3 0  =  
 
 
6.  A b d o mi nal  Mass  
N o n e = 0, Q u esti o n a ble = 2, Defi nite  =  5  
X 1 0 =  
 
 
7.  He mat ocrit ( %, r o u n de d t o w h ole  n u m ber ) 
Male  
4 7  - 
=  
or  Fe male  
4 2  - 
X 6  =  
8.  B o d y  Wei g ht  Calc ulati o n * *  
If ne g ative, e nter 0  
I d eal Wei g ht  
k g  
 
 
mi n us  Act u al  Wei g ht  
k g  
 
 
=  
÷ I d eal Wei g ht  =  
X 1 0 0  =  
 
 
(r o u n de d t o w h ole n u m ber * * *) 
T O T A L C D AI =   
 
* Gra de d usi n g t he Brist ol St o ol F or m Scale ( A p pe n di x  3)  
* * See A p pe n di x 8 f or calc ulati o ns of I deal B o d y  W ei g ht  
* * * If calc ulate d val ue > -1 0, rec or d – 1 0 ( ma xi m u m l o wer li mit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


P a ge 8 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
A P P E N DI X 3: B RI S T O L S T O O L F O R M S C A L E ( B S F S)  
 
 
 
 
 


P a ge 8 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
A P P E N DI X 4: SI M P L E E N D O S C O PI C S C O R E F O R C R O H N’ S DI S E A S E ( S E S -C D) 
D E FI NI TI O N S O F S E S -C D V A RI A B L E S  
 
 
S E S -C D Sc ori n g F or m  
 
 
 
Da per n o M, D’ Hae ns G, Va n Assc he G, et.al. D e v el o p me nt a n d vali dati o n of a ne w a n d si m ple 
e n d osc o pic acti vit y sc or e f or Cr o h n’s diseas e: t he S E S -C D. Gastr oi ntest E n d osc 2 0 0 4; 6 0: 5 0 5 - 
5 1 2.  
 
 


P a ge 8 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 
A P P E N DI X 5: I N F L A M M A T O R Y B O W E L DI S E A S E Q U E S TI O N N AI R E (I B D Q)  
 


P a ge 8 8  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 8 9  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 0  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 1  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 2  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 3  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 4  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 5  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 6  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


P a ge 9 7  of 1 0 3  
R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
 
 
 


Page 98 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
APPENDIX 6: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE (WPAI: CD) 
 
Work Productivity and Activity Impairment Questionnaire: 
Crohn’s Disease V2.0 (WPAI: CD) 
 
 
 
The following questions ask about the effect of your CROHN’S DISEASE on your ability 
to work and perform regular activities. Please fill in the blanks or circle a number, as 
indicated. 
 
1. Are you currently employed (working for pay)? 
  
NO  
YES 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your CROHN’S DISEASE? Include hours you missed on 
sick days, times you went in late, left early, etc., because of your CROHN’S 
DISEASE. Do not include time you missed to participate in this study. 
 
  
 HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
  
HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
  
HOURS (If “0”, skip to question 6.) 


Page 99 of 103 
RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
 
 
 
 
 
 
 
 
 
5. During the past seven days, how much did your CROHN’S DISEASE affect your 
productivity while you were working? 
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual. If CROHN’S DISEASE affected your work only a little, choose a 
low number. Choose a high number if CROHN’S DISEASE affected your work a 
great deal. 
Consider only how much CROHN’S DISEASE affected 
productivity while you were working. 
 
CROHN’S 
DISEASE had 
no effect on my 
work 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CROHN’S 
DISEASE 
completely 
prevented me 
from working 
 
CIRCLE A NUMBER 


RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
Page 100 of 103 
 
 
 
6. During the past seven days, how much did your CROHN’S DISEASE affect your 
ability to do your regular daily activities, other than work at a job? 
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If CROHN’S DISEASE affected your activities only a little, 
choose a low number. Choose a high number if CROHN’S DISEASE affected your 
activities a great deal. 
 
Consider only how much CROHN’S DISEASE affected your ability 
to do your regular daily activities, other than work at a job. 
 
CROHN’S 
DISEASE had 
no effect on my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CROHN’S 
DISEASE 
completely 
prevented me 
from doing my 
daily activities 
 
 
 
WPAI: CD V2.0 (US English) 
CIRCLE A NUMBER 
 
 
 
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure. 
PharmacoEconomics 1993; 4(5):353-365. 


R E C D 3 1 2 6  
Versi o n D ate: 1 4 J ul 2 0 1 4  
S ali x P h ar m ace utic als,  I nc. 
C R P -7 1  
C o nfi de nti al  
P a ge 1 0 1  of 1 0 3  
 
 
 
A P P E N DI X 7: S U B J E C T D AI L Y DI A R Y R E C O R DI N G  
 
T he f oll o wi n g will be ca pt ure d dail y i n t he electr o nic diar y s yste m.  
 
Usi n g t he Brist ol St o ol F or m Scale pr o vi de d (s ee A p pe n di x 3), please rec or d t he  T otal  N u m ber 
of Li q ui d/ ver y s oft St o ols ( T y p e 6 or 7) y o u h a d  t o da y.     
 
 
H o w w o ul d y o u rate y o ur A b d o mi nal Pai n t o da y?  
 0 = n o ne  
 1 =  mil d  
 2 =  m o derate  
 3 =  se vere 
 
H o w w o ul d y o u rate y o ur Ge neral Well Bei n g t o d a y?  
 0 = ge ner all y  well  
 1 = sli g htl y u n d er  p ar  
 2 =  p o or  
 3 = ver y  p o or  
 4 =  terri ble 
 
Di d y o u use a n y A nti diarr heal Dr u gs t o d a y?  
 0 = N o  
 1 = Yes  
 
Di d y o u e x perie n ce ha v e a n y ele vat e d te m perat ure (fe ver) of m ore t ha n 3 7. 8 de grees Celsi us 
de gree C elsi us ( 1 0 0 de gr ees Fa hre n h eit) t o da y?  
 0 = N o  
 1 = Yes  


RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
Page 102 of 103 
 
 
 
APPENDIX 8: IDEAL BODY MASS OF NORMAL ADULTS (MEN & WOMEN) 
 
Ideal Body Mass of Normal Adults - MEN 
Actual Height 
Standard Weight in Clothing 
Inches with one inch heels 
Centimeters with 2.5 cm 
heels 
Pounds in indoor clothing 
weighing 5 pounds 
Kilograms in indoor clothing 
weighing 2.3 kg 
62 
157.5 
136 
61.7 
62.5 
158.8 
137 
62.1 
63 
160 
138 
62.6 
63.5 
161.3 
139 
63 
64 
162.6 
140 
63.5 
64.5 
163.8 
141.3 
64.1 
65 
165.1 
142.5 
64.6 
65.5 
166.4 
143.8 
65.2 
66 
167.6 
145 
65.8 
66.5 
168.9 
146.5 
66.4 
67 
170.2 
148 
67.1 
67.5 
171.5 
149.5 
67.8 
68 
172.7 
151 
68.5 
68.5 
174 
152.5 
69.2 
69 
175.3 
154 
69.8 
69.5 
176.5 
155.5 
70.5 
70 
177.8 
157 
71.2 
70.5 
179.1 
158.5 
71.9 
71 
180.3 
160 
72.6 
71.5 
181.6 
161.8 
73.4 
72 
182.9 
163.5 
74.1 
72.5 
184.2 
165.3 
75 
73 
185.4 
167 
75.7 
73.5 
186.7 
169 
76.6 
74 
188 
171 
77.5 
74.5 
189.2 
172.8 
78.4 
75 
190.5 
174.5 
79.1 
75.5 
191.8 
176.8 
80.2 
76 
193 
179 
81.2 


RECD3126 
Version Date: 14Jul2014 
Salix Pharmaceuticals, Inc. 
CRP-71 
Confidential 
Page 103 of 103 
 
 
 
Ideal Body Mass of Normal Adults – WOMEN 
 
Actual Height 
Standard Weight in Clothing 
Inches with one inch heels 
Centimeters with 2.5 cm 
heels 
Pounds in indoor clothing 
weighing 5 pounds 
Kilograms in indoor clothing 
weighing 2.3 kg 
58.0 
147.3 
115.0 
52.2 
58.5 
148.6 
116.0 
52.6 
59.0 
149.9 
117.0 
53.1 
59.5 
151.1 
118.3 
53.6 
60.0 
152.4 
119.5 
54.2 
60.5 
153.7 
120.8 
54.8 
61.0 
154.9 
122.0 
55.3 
61.5 
156.2 
123.5 
56.0 
62.0 
157.5 
125.0 
56.7 
62.5 
158.8 
126.5 
57.4 
63.0 
160.0 
128.0 
58.0 
63.5 
161.3 
129.5 
58.7 
64.0 
162.6 
131.0 
59.4 
64.5 
163.8 
132.5 
60.1 
65.0 
165.1 
134.0 
60.8 
65.5 
166.4 
135.5 
61.4 
66.0 
167.6 
137.0 
62.1 
66.5 
168.9 
138.5 
62.8 
67.0 
170.2 
140.0 
63.5 
67.5 
171.5 
141.5 
64.2 
68.0 
172.7 
143.0 
64.9 
68.5 
174.0 
144.5 
65.5 
69.0 
175.3 
146.0 
66.2 
69.5 
176.5 
147.5 
66.9 
70.0 
177.8 
149.0 
67.6 
70.5 
179.1 
150.5 
68.3 
71.0 
180.3 
152.0 
68.9 
71.5 
181.6 
153.5 
69.6 
72.0 
182.9 
155.0 
70.3 
 

SAP_001.pdf: 
Salix Pharmaceuticals, Inc. 
Product: Rifuximin 
Statistical Analysis Plan: Rifuximin Delayed Release 
NCT#: NCT02240108 
Master Statistical Analysis Plan 
for 
Rifaximin Delayed Release Studies in Subjects with Active Moderate Crohn's 
Disease including 
RECD3125 and RECD3126 
Version: 1.0 
Version Date: January 3, 2019 
Prepared by: 
Date: 
EDETEK, Inc. 
Confidential 
Pagel of28 
Final: January 3, 2019 


Salix Pharmaceuticals, Inc. 
Product: Rifaximin                                                                       Statistical Analysis Plan: Rifaximin Delayed Release 
 Confidential                                                             Page 2 of 28                                         Final: January 3, 2019 
 
 
Table 1. A List of Applicable Studies Covered by This SAP 
Protocol 
Number 
 
Treatment groups  
Indication 
Phase 
Protocol Title 
RECD3125 
Rifaximin DR 
Tablets 800 mg BID 
Vs  
Placebo BID 
Crohn’s Disease 
3 
A Double-Blind, Placebo-Controlled, 
Parallel-Group, Multicenter, 
Multiregional, One Year Study to 
Assess the Efficacy and Safety of Twice 
Daily Oral Rifaximin Delayed Release 
Tablets for Induction of Clinical 
Remission with Endoscopic Response at 
16 Weeks followed by Clinical and 
Endoscopic Remission at 52 Weeks in 
Subjects with Active Moderate Crohn’s 
Disease 
RECD3126 
Rifaximin DR 
Tablets 800 mg BID 
Vs  
Placebo BID 
Crohn’s Disease 
3 
A Double-Blind, Placebo-Controlled, 
Parallel-Group, Multicenter, 
Multiregional, One 
Year Study to Assess the Efficacy and 
Safety of Twice Daily Oral Rifaximin 
Delayed 
Release Tablets for Induction of Clinical 
Remission with Endoscopic Response at 
16 Weeks 
followed by Clinical and Endoscopic 
Remission at 52 Weeks in Subjects with 
Active Moderate Crohn’s Disease 


Sali x P har mace uticals, I nc.  
Pr o d uct:  Rifa xi mi n                                                                       Statistical A nal ysis Pla n: Rifa xi mi n Dela ye d Release  
 C o nfi de ntial                                                             P a ge 3  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
 
Ta ble of C o nte nts  
1  
T A BL E O F A B B R E VI A TI O N S  .................................................................................................................... 5  
2  
I N T R O D U C TI O N ..................................................................................................................................... 8  
3  
O BJ E C TI V E S  ........................................................................................................................................... 8  
3. 1 Pri m ar y O bj ecti v e  ................................................................................................................................ 8  
3. 2 S ec o n d ary O bj ectiv e  ........................................................................................................................... 8  
4  
E N D P OI N T S  ........................................................................................................................................... 9  
4. 1 Pri m ar y Effic acy E n d p oi nt  ................................................................................................................... 9  
4. 2 K e y S ec o n d ar y E n d p oi nts  .................................................................................................................... 9  
4. 3 S ec o n d ary Effic ac y E n d p oi nts  ........................................................................................................... 1 0  
4. 4 S af et y E n d p oi nts  ............................................................................................................................... 1 1  
5  
S T U D Y O V E R VI E W  ............................................................................................................................... 1 1  
5. 1 St u dy D esi g n  ...................................................................................................................................... 1 1  
6  
T R E A T M E N T D E S C RI P TI O N  .................................................................................................................. 1 4  
7  
S T A TI S TI C AL A N AL Y SI S M E T H O D S  ....................................................................................................... 1 4  
7. 1 G e n er al C o nsi d er ati o ns  ..................................................................................................................... 1 4  
7. 2 R a n d o miz ati o n a n d U n bli n di n g  ......................................................................................................... 1 4  
7. 3 S a m pl e Siz e  ....................................................................................................................................... 1 5  
7. 4 I nt eri m A n al ys es a n d D at a M o nit ori n g  ............................................................................................. 1 5  
7. 5 A n alysis P o p ul ati o n  ........................................................................................................................... 1 5  
7. 6 D e m o gr a p hics a n d St u dy S u m m ary  .................................................................................................. 1 6  
7. 6. 1 S u bj ect Dis p ositi o n  ..................................................................................................................... 1 6  
7. 6. 2 D e m o gr a p hics a n d B as eli n e Dis e as e C h ar act eristics  ................................................................. 1 6  
7. 6. 3 Pr ot oc ol D evi ati o ns  .................................................................................................................... 1 7  
7. 6. 4 M e dic al Hist or y  .......................................................................................................................... 1 7  
7. 7 Effic acy A n al ysis  ................................................................................................................................ 1 7  
7. 7. 1 Pri m ary Effic ac y A n al ysis  ............................................................................................................ 1 7  
7. 7. 2 S ec o n d ar y Effic acy A n al ysis  ....................................................................................................... 1 9  
7. 8 S af et y A n al ys es  ................................................................................................................................. 2 2  
7. 8. 1 Ext e nt of Ex p os ur e  ..................................................................................................................... 2 2  
7. 8. 2 Tr e at m e nt C o m pli a nc e a n d M o dific ati o ns  ................................................................................ 2 2  
7. 8. 3 A dv ers e Ev ets  ............................................................................................................................. 2 3  


Sali x P har mace uticals, I nc.  
Pr o d uct:  Rifa xi mi n                                                                       Statistical A nal ysis Pla n: Rifa xi mi n Dela ye d Release  
 C o nfi de ntial                                                             P a ge 4  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
7. 8. 4 Cli nic al L a b or at ory Ev al u ati o ns  .................................................................................................. 2 4  
7. 8. 5 Pri or a n d C o nc o mit a nt M e dic ati o ns  .......................................................................................... 2 5  
7. 8. 6 Vit al Si g n M e as ur e m e nts  ........................................................................................................... 2 5  
7. 8. 7 P hysic al Ex a m  ............................................................................................................................. 2 5  
7. 8. 8 El ectr oc ar di o gr a m ( E C G)  ............................................................................................................ 2 5  
7. 9 Cli nic al bi ol o gy  .................................................................................................................................. 2 6  
7. 1 0 St a tistic al a n d a n alytic al iss u es ....................................................................................................... 2 6  
7. 1 0. 1 H a n dli n g of Dr o p o uts or Missi n g D at a  ..................................................................................... 2 6  
7. 1 0. 2 L ast O bs erv ati o n C arri e d F or w ar d (L O C F) A n alysis  .................................................................. 2 6  
7. 1 0. 3 I m p ut ati o n R ul es f or P arti al or Missi n g D at es  ......................................................................... 2 6  
7. 1 1 M ulti plicit y  ...................................................................................................................................... 2 7  
8  
C H A N G E S F R O M P R O T O C OL -S P E CI FI E D A N AL Y S E S  ............................................................................ 2 8  
 
 
 


Salix Pharmaceuticals, Inc. 
Product: Rifaximin                                                                       Statistical Analysis Plan: Rifaximin Delayed Release 
 Confidential                                                             Page 5 of 28                                         Final: January 3, 2019 
 
 
1 TABLE OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
BID 
Two Times a Day 
BSFS 
Bristol Stool Form Scale 
CDAI 
Crohn’s Disease Activity Index 
CDEIS 
Crohn’s Disease Endoscopic Index of Severity 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
DNA 
Deoxyribonucleic Acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th. 
Edition 
DR 
Delayed Release 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
HbA1c 
Hemoglobin A1c 


Salix Pharmaceuticals, Inc. 
Product: Rifaximin                                                                       Statistical Analysis Plan: Rifaximin Delayed Release 
 Confidential                                                             Page 6 of 28                                         Final: January 3, 2019 
 
HIV 
Human Immunodeficiency Virus 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IL 
Interleukins 
IND 
Investigational New Drug 
ITT 
Intent-to-Treat 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
Non-alcoholic Steatohepatitis 
NF-kB 
Nuclear Factor kappa-light-chain-enhancer of activated B 
Cells 
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PSAP 
Pharmacokinetics Statistical Analysis Plan 
PXR 
Pregnane X Receptor 
rCRT 
Clinical Remission Rate Treatment 
rCRP 
Clinical Remission Rate Placebo 


Salix Pharmaceuticals, Inc. 
Product: Rifaximin                                                                       Statistical Analysis Plan: Rifaximin Delayed Release 
 Confidential                                                             Page 7 of 28                                         Final: January 3, 2019 
 
RNA 
Ribonucleic Acid 
ROC 
Receiver Operating Characteristics 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SD 
Standard Deviation 
ULN 
Upper Limit of Normal 
US 
United States 
WPAI:CD 
Work Productivity and Activity Impairment Questionnaire - 
Crohn’s Disease 
WHO 
World Health Organization 
 
 
 
 
 


Sali x P har mace uticals, I nc.  
Pr o d uct:  Rifa xi mi n                                                                       Statistical A nal ysis Pla n: Rifa xi mi n Dela ye d Release  
 C o nfi de ntial                                                             P a ge 8  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
2  I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o pr o vi de details of t he statistical 
a nal ys es t hat ha v e bee n o utli ne d wit hi n t he pr ot oc ols of Rifa xi mi n dela ye d releas e st u dies 
i ncl u di n g R E C D 3 1 2 5  a n d R E C D 3 1 2 6 . T he sc o pe of t his pla n i ncl u des t he fi nal a nal ysis. A n y 
c ha n ges t o t he met h o ds d escri be d i n t his S A P will be d oc u me nte d i n eac h cli nical st u d y  
re p ort ( C S R). 
3  O B J E C TI V E S   
3. 1 Pri m a r y O bjecti ve   
•  T o deter mi ne t he efficac y of Rifa xi mi n D R 8 0 0 m g BI D vs. place b o o n t he i n d ucti o n of 
cli nical re missi o n a n d e n d osc o pic res p o nse f oll o wi n g 1 6 wee ks of treat me nt i n s u bjects 
p rese nti n g wit h acti ve m o derate Cr o h n’s disease. 
3. 2 Sec o n d ar y O bjecti ve  
A ke y sec o n d ar y o bjecti ve is t o e val uate cli nical a n d e n d osc o pic re missi o n f oll o wi n g a n 
a d diti o nal 3 6 -wee k L o n g Ter m Treat me nt P hase of Rifa xi mi n D R 8 0 0 m g BI D vs. place b o. T h e 
sec o n dar y o bj ecti ves of t his st u d y ar e t he f oll o wi n g: 
•  Assess t he safet y of Rifa xi mi n D R f oll o wi n g a 1 6 -wee k i n d ucti o n, a n d a n a d diti o nal 3 6 -
wee k L o n g T er m Treat me nt P hase (i.e., u p t o 5 2 wee ks of treat me nt f or eli gi ble s u bjects).  
•  Assess t he p o p ulati o n p har mac o ki n etics of Rifa xi mi n D R.  
•  C haracterize t he gastr oi ntesti nal micr o bi ota fr o m st o ol sa m ples, a n d a nti bi otic resista nce 
fr o m bacteria c ult ure d fr o m st o ol sa m ples bef ore a n d after treat me nt wit h Rifa xi mi n D R. 
•  E val uate t he effects of Rifa xi mi n D R treat me nt o n i n dices of healt h o utc o m es. 
•  Assess t he eff ects of Rifa xi mi n D R treat me nt o n bi ol o gical (i nfl a m mat or y) mar kers of 
disease.  
T his a p plies t o  b ot h R E C D 3 1 2 5 a n d R E C D 3 1 2 6 . 


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4  E N D P OI N T S  
4. 1 Pri m a r y Effi c ac y E n d p oi nt   
T here will be t w o c o-pri mar y m eas ur es of efficac y f or I n d ucti o n of Cli nical Re missi o n a n d  
E n d osc o pic Res p o nse : 
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or  
t he 7 da ys pri or t o t he Wee k 1 6 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he  
Wee k 1 6 visit.  
•  E n d osc o pic res p o ns e defi ne d as a ≥ 3 -p oi nt decrease i n t he S E S -C D fr o m baseli ne t o t he  
S E S -C D sc ore o btai ne d bet wee n Wee k 1 6 a n d Wee k 1 7. S E S -C D sc ores will be  
calc ulate d fr o m ce ntrall y -rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at baseli ne 
a n d bet wee n Wee k 1 6 a n d Wee k 1 7.  
F or t he d ail y st o ol data, t he n u m ber of d ail y li q ui d/ ver y s oft st o ols wit h a c o nsiste nc y of a  Brist ol 
St o ol F or m Scale [ B S F S] sc ore of T y p e 6 or T y p e 7 will be assesse d usi n g t he  i nf or mati o n 
rec or d e d b y t he s u bject via a n electr o nic diar y s yst e m. T he n u m ber of li q ui d/ ver y s oft st o ols i n a 
gi ve n w ee k will be calc ul ate d as f oll o ws:  
( N u m ber of li q ui d/ ver y s oft st o ols d uri n g t hat wee k ÷ N u m ber of da ys wit h  n o n -
missi n g  assess me nts d uri n g t hat w ee k) × 7  
4. 2 K e y Sec o n d ar y  E n d p oi nts   
T he ke y sec o n dar y e n d p oi nt is cli nical a n d e n d osc o pic re missi o n. T w o ke y c o -sec o n d ar y 
e n d p oi nts of efficac y will assess t his e n d p oi nt d uri n g t he L o n g -T er m  Treat me nt P hase.  
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or  
t he 7 da ys pri or t o t he Wee k 5 2 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he 
Wee k 5 2 visit.  
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 at Wee k 5 2. S E S -C D sc ores will  
be calc ul ate d fr o m ce ntrall y -r ea d di gital vi de o of ile oc ol o n osc o pies perf or me d at Wee k 
5 2.  


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4. 3 Sec o n d ar y Effic ac y  E n d p oi nts  
•  I n d u cti on of cli nical r e missi o n defi ne d as a C D AI Sc ore of less t ha n 1 5 0 p oi nts at  Wee k 
1 6.  
•  Cli nical s y m pt o m r e missi o n o ver ti me: T he t otal n u m ber of li q ui d/ ver y s oft st o ols f or t he  
7 da ys pri or t o eac h cli nic visit bei n g ≤ 1 0; A N D ( 2) a n a b d o mi nal pai n rati n g of ≤ 1 o n  
eac h d a y f or t he l ast 7 da ys pri or t o eac h cli nic visit i n ≥ 8 0 % of t he st u d y visits d uri n g 
t he 5 2 -Wee k Treat me nt Peri o d, i ncl u di n g Wee k 5 2.  
•  Ti me u ntil d ura ble res p o nse (see Secti o n 7 . 2) t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of 
t he c o-pri mar y e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt Peri o d.  
•  Ti me u ntil d ura ble res p o nse ( See Secti o n 7 . 2) t o t he a b d o mi nal pai n c o m p o ne nt of t he 
c o-pri mar y e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt Peri o d.  
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he c o-pri mar y  
e n d p oi nt at p ost -baseli ne ti me p oi nts.  
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of t he c o -
pri mar y  e n d p oi nt at p ost -baseli ne ti me p oi nts.  
•  C ha n ge fr o m bas eli ne i n S E S -C D sc ore at Wee k 1 6 a n d Wee k 5 2.  
•  Pr o p ort i o n of s u bjects wit h S E S-C D sc ore of 0 at Wee k 5 2.  
•  Pr o p orti o n of s u bjects w h o ac hie ve cli nical re missi o n b y t he C D AI e n d p oi nt at p ost -
baseli ne  ti me p oi nts. 
•  Ti me t o l oss of C D AI res p o nse defi ne d b y a C D AI sc ore of  1 5 0 p oi nts d uri n g t he L o n g  
Ter m Treat me nt P hase.  
•  Perce nta ge of s u bjects w h o ac hie ve cli nical res p o nse at p ost -baseli ne ti me p oi nts. 
Cli nical  res p o nse is defi n e d as a re d ucti o n of at least 1 0 0 p oi nts fr o m t he baseli ne C D AI 
sc ore. 
•  Ti me t o cli nical re missi o n base d o n a b d o mi nal pai n a n d li q ui d st o ol c o m p o ne nts of t he 
c o-pri mar y  e n d p oi nts.  
•  Ti me t o cli nical re missi o n base d o n C D AI < 1 5 0.  


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•  C ha n ge fr o m bas eli ne i n i n dices of healt h o utc o m es (I nfla m mat or y B o w el Disease  
Q uesti o n naire [I B D Q], W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q u esti o n naire f or  
C r o h n's Disease [ W P AI-C D]) at p ost -baseli ne ti me p oi nts.  
•  C ha n ge fr o m bas eli ne i n mar kers of i nfl a m mati o n (e. g. C R P, i nterle u ki ns, c yt o ki nes, 
fecal cal pr otecti n) at p ost -baseli ne ti me p oi nts.  
4. 4 S afet y  E n d p oi nts   
 
•  I n ci de nce, i nte nsit y, a n d t y pes of a d vers e e v e nts ( A Es).  
•  C ha n ges fr o m bas eli ne i n t he la b orat or y p ara met ers ( he mat ol o g y, cli nical c he mistr y,  
uri nal ysis).  
•  C ha n ge fr o m bas eli ne i n vital si g n meas ure me nts.  
5   S T U D Y O V E R VI E W   
5. 1 St u d y Desi g n   
R E C D 3 1 2 5 a n d R E C D 3 1 2 6  a d o u ble-bli n d, place b o -c o ntr olle d, parallel-gr o u p, m ultice nter, 
m ultire gi o nal,  5 2 -w ee k st u d ies t o assess t he efficac y a n d safet y of Rifa xi mi n D R ta blets f or t he 
i n d ucti o n of cli nical re missi o n a n d e n d osc o pic res p o nse at 1 6 wee ks f oll o w e d b y cli nical a n d 
e n d osc o pic r e missi o n after 5 2 wee ks of c o nti n u o us t hera p y i n s u bjects wit h acti ve m o derate 
Cr o h n’s  disease. S u bjects wit h acti ve, m o derat e disease defi n e d b y a C D AI s c ore of ≥ 2 2 0 a n d ≤ 
4 5 0 p oi nts at scree ni n g, a n d e vi de nce of acti ve ile oc ol o nic Cr o h n’s disease defi ne d b y a 
mi ni m u m  S E S -C D of 7 deter mi ne d d uri n g bas eli ne ile oc ol o n osc o p y will be eli gi ble f or t he 
st u d y. Eli gi ble s u bjects will c o m plete a 2 - t o 3-w ee k Scree ni n g Peri o d, a 5 2 -wee k Treat me nt 
Peri o d  c o nsisti n g of a 1 6 -wee k I n d ucti o n P hase a n d 3 6 -Wee k L o n g Ter m Treat me nt P hase, a n d 
a 2-wee k F oll o w -u p Peri o d. S u bjects w h o s uccessf ull y c o m plete t h e 2 - t o 3-wee k Scree ni n g  
Peri o d a n d q ualif y base d o n C D AI a n d S E S -C D sc ores will e nter t he 5 2 -wee k Treat me nt  Peri o d 
of t he trial a n d will be r a n d o mize d i n a 1: 1 all ocati o n t o Rifa xi mi n D R 8 0 0 m g BI D or  pl ace b o. 
Ra n d o mize d s u bjects will ha ve s u bse q ue nt ile oc ol o n osc o pies c o n d ucte d at t he e n d  of t he 
I n d u cti o n P hase ( bet w ee n Wee ks 1 6 a n d 1 7), a n d f oll o wi n g c o m pleti o n of t he 3 6-wee k  L o n g 
Ter m Treat me nt P hase ( Wee k 5 2) t o assess t he effects of tre at me nt o n t he de gree of  m uc osal 
heali n g. Assess me nts of efficac y a n d s afet y will b e perf or me d d uri n g cli nic visits at  Wee ks 0 


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( baseli ne), 2, 4, 8, 1 2, a n d 1 6; t he n e ver y f o ur wee ks t hr o u g h Wee k 5 2. All s u bjects will 
c o m plete a 2 -w ee k (st u d y dr u g free) F oll o w -u p Peri o d f oll o wi n g c o m pleti o n of t he 5 2 -wee k 
Treat me nt Peri o d a n d  will ret ur n t o t he cli nic f or fi nal assess me nts ( E n d -of -St u d y  [ E O S] visit; 
Wee k 5 4). See Fi g ure 1.  


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Fi g ure 1 Desi g n Sc he m atic  
 


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6  T R E A T M E N T  D E S C RI P TI O N  
T here are t w o tr eat me nt gr o u ps as liste d bel o w. All treat me nts will be a d mi nistere d t wice d ail y at 
m or ni n g a n d e ve ni n g.  T h e d urati o n of t he treat me nt is 5 2  wee ks.    
•  Treat me nt A: Rifa xi mi n D R Ta blets 8 0 0 m g BI D  
•  Treat me nt B: Place b o BI D  
7  S T A TI S TI C A L A N A L Y SI S M E T H O D S  
7. 1 Ge ner al C o nsi der ati o ns  
All data f or e nr olle d s u bjects will be prese nt e d i n data listi n gs b y s u bject n u m be r. 
C o nti n u o us data will be descri be d usi n g des cri pti ve statistics: n u m ber of o bser vati o ns ( n), mea n,  
sta n dar d de viati o n ( S T D), me dia n, mi ni m u m, a n d ma xi m u m. Fre q ue ncies a n d perce nt a ges will 
be  use d f or s u m marizi n g discrete ( cate g orical) d ata. W he n cate g ori cal data are prese nte d, t he 
perce nt  will be s u p pr esse d w he n t he c o u nt is zer o. T he de n o mi nat or f or all perce nt a ges, u nless 
ot her wise  s pecifie d, will be t he n u m ber of s u bjects i n t he s pecifie d a n al ysis p o p ulati o n. 
F or t h ose s u m mar y ta bl es i n w hic h b aseli ne a n d c ha n ge fr o m b aseli ne meas ure me nts will be  
prese nte d, t he b aseli ne is defi ne d s u bject t o eac h s pecific a n al ysis.  
Safet y d ata will be a n al yze d usi n g t he o bser v e d d ata. Missi n g val ues will n ot be i m p ute d u nless  
o t her wise state d. 
If a d diti o nal a nalyses are re q uire d t o s u p ple me nt t he pla n ne d a n al ys es descri be d i n t his S A P after  
data base l oc k, t h e y ma y be perf or me d a n d will be i de ntifie d i n t he C S R.  
Statistical a nal yses a n d s u m maries will be perf or me d usi n g S A S ® Versi o n 9. 3 or great er or ot her  
vali dat e d statistical s oft ware as re q uir e d.  
7. 2 R a n d o mi z ati o n a n d U n bli n di n g  
S u bjects w h o s uccessf ull y c o m plet e t he Scree ni n g Peri o d will e nter t he Tr eat me nt Peri o d a n d  
will be ra n d o mize d i n a 1: 1 all ocati o n t o o ne of t w o treat me nt  gr o u ps f or t h e d urati o n of t he  
st u d y as assi g ne d b y t h e mea ns of ce ntralize d electr o nic ra n d o mizati o n s yst e m. Ra n d o mizati o n 
will be stratifie d b y st u d y ce nter wit hi n a c o u ntr y.  


Salix Pharmaceuticals, Inc. 
Product: Rifaximin                                                                       Statistical Analysis Plan: Rifaximin Delayed Release 
 
 Confidential                                                             Page 15 of 28                                         Final: January 3, 2019 
 
Only in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of the subject, will the investigator be allowed to unblind a subject’s 
treatment assignment. If the investigator breaks the blind for an individual subject, the reason 
must be recorded on the CRF and the subject will be removed from the study. 
7.3 Sample Size  
For sample size justification, reference corresponding study protocols. 
Originally planned sample sizes per arm for each of the studies are listed below: 
Study 
Treatment A: Rifaximin DR 
Tablets 800 mg BID 
Treatment B: Placebo BID 
RECD3125 
330 
330 
RECD3126 
330 
330 
 
Both studies will be terminated early therefore the actual sample size may vary.  
7.4 Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
7.5 Analysis Population  
The Intent to Treat (ITT) population will include all randomized subjects who take at least one 
dose of study drug. 
The analyses of baseline characteristics, efficacy and safety will be performed for the ITT 
Population. 


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 7. 6 De m o gr a p hics a n d St u d y S u m m ar y  
7. 6. 1 S u bject Dis p ositi o n   
S u bject dis p ositi o n will be s u m marize d b y treat me nt a n d st u d y p has e a n d will i ncl u de t he  
n u m ber of s u bjects e nt er e d i n t he st u d y; n u m ber a n d perce nt a ge of s u bjects w h o c o m plete d or  
pre mat urel y disc o nti n ue d (classifie d b y reas o ns f or pre mat ure disc o nti n uati o n); t he n u m ber of  
s u bjects e ntere d i n t he st u d y at eac h st u d y site; a n d t he n u m ber a n d perce nta ge of s u bjects w h o 
c o m plete d or disc o nti n ue d at eac h st u d y site.  
 7. 6. 2 De m o gr a p hics a n d B aseli ne Dise ase C h ar acteristics  
De m o gra p hic a n d baseli n e c har acteristics will be s u m marize d descri pti vel y b y treat me nt  gr o u p. 
Baseli ne will be defi ne d as t he last assess me nts pri or t o i nitiati n g t he Treat me nt  P eri o d. T he 
f oll o wi n g de m o gr a p hic a n d baseli ne disease c haracteristics will be s u m marize d: 
7. 6. 2. 1 De m o gr a p hics    
•  A ge ( years) = ( dat e of i nf or me d c o nse nt si g ne d –  d ate of birt h)/ 3 6 5. 2 5;  
•  A ge gr o u p ( < 6 5, > = 6 5);  
•  Se x ( male/fe male);  
•  Et h nicit y ( His pa nic or Lati n o / n ot His pa nic or Lati n o); 
•  Race ( A m erica n I n dia n or Alas ka n N ati ve, Asia n, Blac k or Afri ca n -A merica n, Nati ve  
Ha waiia n or Ot her Pacific Isla n der, W hite, a n d Ot her); s u bjects w h o i de ntif y m ore t h a n  
o ne race will be cate g ori ze d as “ Ot her”;  
•  Hei g ht ( c m);  
•  Wei g ht ( k g); 
•  B o d y mass i n de x ( k g/ m 2) = ( Wei g ht i n k g)/ ( Hei g ht i n m) 2;  
•  Re gi o n ( U S/ Rest Of W orl d).  
7. 6. 2. 2 B aseli ne Dise ase C h ar act eristics  
Baseli ne disease c har acteristics liste d bel o w will be s u m marize d descri pti vel y b y treat me nt 
gr o u p a n d o ver all usi n g t he I T T p o p ulati o n.  


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•  D e m o gra p hic d ata ( o utli ne d a b o ve)  
•  B aseli ne C D AI a n d S E S -C D sc ores  
•  D urati o n of t he diseas e ( years)  
•  L ocati o n of diseas e  
•  P re vi o us ster oi d use ( d os e, d urati o n) 
•  P re vi o us s ur ger y f or C D 
•  S m o ki n g hist or y ( n o ns m o ker/ e xs m o ker/s m o ker)  
7. 6. 3 Pr ot oc ol De vi ati o ns   
All pr ot oc ol de viati o ns will be liste d b y s u bj ect.  
7. 6. 4 Me dic al Hist or y  
All c urre nt me dical c o n diti o n a n d/ or ot her si g nifica nt me dical hist or y will be c o de d usi n g 
Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) Versi o n 2 1. 0, liste d b y treat me nt, 
re p orte d ter m, S yste m Or ga n Class, a n d Preferre d Ter m i n a s u bject dat a listi n g. 
7. 7 Effic ac y A n al ysis  
T he p hrases ‘st atistical a nal ysis’ or ‘a n al ysis’ will be use d t o mea n i nfere ntial a nal ysis (s u c h  as 
perf or mi n g tests of si g nifica nce, re p orti n g p -v al ues a n d  c o nfi de n ce i nter v als). W he n n o  
i nfere ntial a n al ysis will b e perf or me d, t he p hrases ‘ descripti ve a n al ysis’ or ‘ desc ri pti ve statistics’ 
will be use d (f or i nsta nce, pr o d uci n g s u m mar y ta bles  of mea ns, sta n dar d de viati o ns,  perce nta ges 
of res p o n ders). All efficac y a nal yses will be c o n d ucte d o n I T T p o p ulati o n. All efficac y a n al ys es 
will a dj ust f or c o u ntr y.  
7. 7. 1 Pri m ar y Effi c ac y A n al ysis   
 7. 7. 1. 1 I n d ucti o n P h ase  
T here will be t w o c o -pri mar y m eas ur es of efficac y ass esse d d uri n g t he I n d ucti o n P hase. T he  first 
c o-pri mar y e n d p oi nt is:  
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or  
t he 7 da ys pri or t o t he Wee k 1 6 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 


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a b d o mi nal pai n rati n g of ≤ 1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he  
Wee k 1 6 visit.  
T he sec o n d c o -pri mar y e n d p oi nt is:  
•  E n d osc o pic res p o ns e defi ne d as a ≥3 -p oi nt decreas e i n t he S E S -C D fr o m baseli ne t o t he  
S E S -C D sc ore o btai ne d bet wee n Wee k 1 6 a n d Wee k 1 7. S E S -C D sc ores will be  
calc ulate d fr o m ce ntrall y -rea d di gital vi de o of ile o c ol o n osc o pies perf or me d at baseli ne 
a n d bet wee n Wee k 1 6 a n d Wee k 1 7.  
F or eac h e n d p oi nt, t he n ull h y p ot hesis H 0: π R -π P = 0 v ers us t he alter n ati ve H A: π R -π P = 0 is of  
i nterest, w her e π R is t he bi n o mial para meter f or i n d ucti o n of re missi o n/res p o nse f or t he 
Rifa xi mi n D R gr o u p, a n d π P is t he bi n o mial para meter f or i n d ucti o n of re missi o n/res p o nse for 
t he place b o gr o u p. S u bjects w h o re q uire t he i nitiati o n of resc ue m e dicati o n a n d/ or s ur ger y f or 
C D will be c o nsi dere d tr eat me nt fail ures fr o m t he date of t he i ntr o d ucti o n of t he resc u e  
me dicati o n a n d/ or s ur ger y, r e gar dl ess of t heir act u al res p o nse dat a. T he C o c hra n -M a ntel -
Hae nszel ( C M H) test, str atifie d b y c o u ntr y, will b e use d t o test t he h y p ot hesis. Eac h n ull  
h y p ot hesis of n o differ e n ce will be rej ecte d if t he res ulti n g p -val u e f or t he res pecti ve  statistical 
test is less t ha n 0. 0 5. Si g nifica nce f or t he i n d ucti o n clai m will o nl y be declare d if b ot h n ull 
h y p ot hes es ar e rejecte d. As s uc h, t he o verall T y p e I err or rate will be mai ntai ne d at  t he 5 % le v el 
wit h o ut a dj ust me nt f or m ulti ple c o m paris o ns.  
7. 7. 1. 2 L o n g Ter m Tr e at me nt P h ase  
T here will be t w o k e y c o -sec o n dar y e n d p oi nts of efficac y ass esse d d uri n g t he L o n g T er m  
Treat me nt P hase. T h e first is:  
•  Cli nical s y m pt o m r e missi o n defi ne d b y ( 1) t he t ot al n u m ber of li q ui d/ ver y s oft st o ols f or  
t he 7 da ys pri or t o t he Wee k 5 2 visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1); A N D ( 2) a n 
a b d o mi nal pai n rati n g of ≤ 1 (fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he  
Wee k 5 2 visit.  
T he sec o n d is:  
•  E n d osc o pic re missi o n defi ne d as a S E S -C D sc ore of ≤ 2 at Wee k 5 2. S E S -C D sc ores will  
be calc ul ate d fr o m ce ntrall y -r ea d di gital vi deo of ile oc ol o n osc o pies perf or me d at Wee k 
5 2.  


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Pr o d uct:  Rifa xi mi n                                                                       Statistical A nal ysis Pla n: Rifa xi mi n Dela ye d Release  
 
 C o nfi de ntial                                                             P a ge 1 9  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
F or eac h e n d p oi nt, t he n u m ber a n d pr o p orti o n of s u bjects wit h cli nical a n d e n d osc o pic  re missi o n 
will be s u m marize d b y tr eat me nt gr o u p.  
F or eac h e n d p oi nt, t he n ull h y p ot hesis H 0: π R -π P = 0 vers us t he alter n ati ve H A : π R-π P ≠0 is of  
i nterest, w her e π R is t he bi n o mial para meter f or re missi o n f or t he Rifa xi mi n D R gr o u p, a n d π P is 
t he bi n o mial para meter f or re missi o n f or t he place b o gr o u p. S u bjects w h o re q uire t he i nitiati o n 
of resc u e me dicati o n a n d/ or s ur ger y f or C D will  be c o nsi dere d treat me nt fail ures  fr o m t he date of 
t he i ntr o d ucti o n of t he resc ue me dicati o n a n d/ or s ur ger y, re gar dl ess of t heir act ual res p o nse dat a. 
T he C oc hra n -Ma ntel -H ae nszel ( C M H) test, stratifie d b y c o u ntr y, will  be us e d t o test t he 
h y p ot hesis. Eac h n ull h y p ot hesis of n o differe nce will be rejecte d if t h e  res ulti n g p-val ue f or t he 
res pecti ve statistical test is less t ha n 0. 0 5. Si g nifica nce f or cli nical a n d e n d osc o pic re missi o n will 
o nl y be d eclar e d if b ot h n ull h y p ot heses are reject e d. As s uc h,  t he o verall T y pe I err or rate will 
be mai ntai ne d at t he 5 % l e vel wit h o ut a dj ust me nt f or  m ulti ple c o m paris o ns.  
If it is e vi de nt t hat t he res p o nse varia ble is c o nf o u n de d wit h s o me of t he bac k gr o u n d vari a bles, 
t he n l o gistic re gressi o n will be perf or me d usi n g t he bac k gr o u n d varia bl es as  c o vari ates. T he 
differe n ces b et wee n t his a dj uste d a nal ysis a n d t he pre vi o us u na dj uste d  a nal ysis will be n ote d, 
a n d t he i m pact of s uc h differ e nces will be disc usse d.  
7. 7. 2 Sec o n d ar y Effic ac y A n al ysis  
 7. 7. 2. 1  Bi n ar y o utc o mes  
A nal ysis of bi n ar y e n d p oi nts will be base d o n t he met h o ds o utli ne d a b o ve f or t he pri mar y  
efficac y a n al ysis . It i ncl u des: 
•  I n d u cti o n of cli nical r e missi o n defi ne d as a C D AI Sc ore of less t ha n 1 5 0 p oi nts at Wee k 
1 6.  
•  Cli nical s y m pt o m r e missi o n o ver ti me: T he t otal n u m ber of li q ui d/ ver y s oft st o ols f or t he  
7 da ys pri or t o eac h cli nic visit bei n g ≤ 1 0; A N D ( 2) a n a b d o mi nal pai n rati n g of ≤ 1 o n  
eac h d a y f or t he l ast 7 da ys pri or t o eac h cli nic visit i n ≥ 8 0 % of t he st u d y visits d uri n g 
t he 5 2 -Wee k Treat me nt Peri o d , i ncl u di n g Wee k 5 2. 
•  Pr o p orti o n of s u bjects wit h res p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he c o -pri mar y  
e n d p oi nt at p ost -baseli ne ti me p oi nts.  


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•  Pr o p orti o n of s u bjects wit h res p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of t he c o -
pri mar y  e n d p oi nt at p o st-baseli ne ti me p oi nts.  
•  Pr o p orti o n of s u bjects wit h S E S -C D sc ore of 0 at Wee k 5 2.  
•  Pr o p orti o n of s u bjects w h o ac hie ve cli nical re missi o n b y t he C D AI e n d p oi nt at p ost -
baseli ne  ti me p oi nts. 
•  Perce nta ge of s u bjects w h o ac hie ve cli nical res p o nse at p ost -baseli n e ti me p oi nts. 
Cli nical  res p o nse is defi n e d as a re d ucti o n of at least 1 0 0 p oi nts fr o m t he baseli ne C D AI 
sc ore. 
7. 7. 2. 2 Ti me t o d ur a bl e res p o nse  
T i me u ntil d ura ble res p o nse e n d p oi nts i ncl u de:  
•  Ti me u ntil d ura ble res p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o n e nt of t he c o-pri mar y 
e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt Peri o d.  
•  Ti me u ntil d ura ble res p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he  c o -pri mar y e n d p oi nt 
d uri n g t he 5 2 -Wee k Tr eat me nt Peri o d.  
F or ti me u ntil d ura ble r es p o nse t o t he li q ui d/ ver y s oft st o ol c o m p o ne nt of t he c o-pri mar y  
e n d p oi nt d uri n g t he 5 2 -Wee k Treat me nt P hase, a res p o nse will be c o nsi dere d d ura bl e if it  starte d 
at Wee k 4 a n d laste d t hr o u g h Wee k 5 2. A res p o ns e is defi ne d as t otal n u m ber of  li q ui d/ ver y s oft 
st o ols f or t he 7 da ys pri or to t he visit bei n g ≤ 1 0 (fr o m C D AI Ite m 1). T he  e n d p oi nt is t he n t he 
ti me w he n t he d ura ble res p o nse be ga n, or t h e first wee k of res p o nse t hat b e ga n t h e stri n g of 
c o nsec uti ve visits wit h res p o nse t hr o u g h Wee k 5 2. It is w ort h re mar ki n g  t hat t his e n d p oi nt w o uld 
n ot be defi ne d f or a s u bject w h o d oes n ot ha ve a d ura ble res p o nse, s o  we c o nsi der i nstea d t he 
ti me of t he last visit at w hic h res p o nse w as ac hi e v e d. F or e x a m ple, if a s u bject is cate g orize d as a 
res p o n der at Wee k 5 2, t he n a d ura bl e res p o ns e was n ot ac hieve d.  
If a s u bject is cate g orize d as a res p o n d er at Wee k 2 0, t he n a d ura ble res p o nse starte d o n Wee k 
2 4.  
Ti me u ntil d ura ble res p o nse will be a nal yz e d b y t he K ol m o g or o v -S mir n o v test. Ti me  u ntil 
d ura ble r es p o nse t o t he a b d o mi nal pai n c o m p o ne nt of t he c o -pri m ar y e n d p oi nt d uri n g t he 5 2-


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Wee k Treat me nt P hase is a nal yze d si milarl y. A res p o nse is defi ne d as a b d o mi nal pai n  rati n g of ≤ 
1(fr o m C D AI It e m 2) o n eac h d a y f or t he 7 d a ys pri or t o t he visit.   
 7. 7. 2. 3  C o nti n u o us o utc o mes   
C ha n ge f or m bas eli ne f or t he c o nti n ues o utc o mes i ncl u de:  
•  C ha n ge fr o m bas eli ne i n S E S -C D sc ore at Wee k 1 6 a n d Wee k 5 2.  
•  C ha n ge fr o m bas eli ne i n i n dices of healt h o utc o m es (I nfla m mat or y B o w el Disease  
Q uesti o n naire [I B D Q], W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q u esti o n naire f or  
Cr o h n's Disease [ W P AI -C D]) at p ost -baseli ne ti me p oi nts.  
•  C ha n ge fr o m bas eli ne i n mar kers of i nfl a m mati o n (e. g. C R P, i nterle u ki ns, c yt o ki nes, 
fecal cal pr otecti n) at p ost -baseli ne ti me p oi nts.  
C ha n ge fr o m bas eli ne i n c o nti n u o us o utc o mes will be a nal yz e d b y f itti n g fi x e d effects li near 
m o dels t o t he data. A n  i nitial m o del wit h ter ms f or treat me nt, c o u ntr y, b aseli ne, a n d baseli ne b y 
treat me nt i nteracti o n will be fitte d. T he i nteracti o n ter m will be teste d at a 0. 1 0 le vel. A n o n -
si g nifica nt i nter acti o n will res ult i n dr o p pi n g t he t er m fr o m t he m o del i n s u bse q ue nt a nal yses. If 
t he fi nal m o del i n v ol ves heter o ge n e o us sl o pes, t he n t he a nal ysis will i ncl u de o verall pl ots of 
baseli ne  vers us c ha n ge fr o m baseli ne b y treat me nt gr o u ps, a n d pl ots of t he esti mate d re gressi o n  
li nes. 
Treat me nt diff ere n ces will be esti mate d a n d teste d at 2 5t h, 5 0t h a n d 7 5t h perce ntiles of t he  
baseli ne val ue.  
T he W or k Pr o d ucti vit y a n d Acti vit y I m pair m e nt Q uesti o n naire: Cr o h n’s disease ( W P AI: C D)  is 
a n i nstr u me nt wit h 6 q uesti o ns t hat will be use d  t o assess t he effect of C D o n s u bjects’ w or k 
ha bits.  
W P AI: C D o utc o mes ar e e x presse d as i m pair me nt perce nt a ges, wit h hi g her n u m bers  i n dicati n g 
gr eater i m pair me nt a n d l ess pr o d ucti vit y, i.e., w orse o utc o mes. T he f o ur W P AI:  C D o utc o me 
sc ores are c o m p ute d as f oll o ws: 
•  % w or k ti me misse d d ue t o C D = 1 0 0 * Q 2/( Q 2 + Q 4)  
•  % i m pair me nt w hile w or ki n g d ue t o C D = 1 0 0 * Q 5/ 1 0  
•  % o verall w or k i m pair me nt = 1 0 0 *[ Q 2/( Q 2 + Q 4) +[( 1 -Q 2/( Q 2 + Q 4)] *( Q 5/ 1 0)]  


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 C o nfi de ntial                                                             P a ge 2 2  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
•  % acti vit y i m pair me nt d u e t o C D = 1 0 0 * Q 6/ 1 0  
T he I B D Q Gl o bal Sc or e is t he s u m of 3 2  res p o nses, eac h ra n gin g fr o m 1 t o 7, t h us t he Gl o bal  
Sc ore ra n ges fr o m 3 2 t o 2 2 4; a hi g her sc ore i n dicati n g a b etter  q ualit y of life.  
  7. 7. 2. 4 Ti me t o e ve nt   
Ti me t o e ve nt relate d e n d p oi nts i ncl u de: 
•  Ti me t o cli nical re missi o n base d o n a b d o mi nal pai n a n d li q ui d st o ol c o m p o ne nts of 
t he c o-pri mar y  e n d p oi nts.  
•  Ti me t o cli nical re missi o n base d o n C D AI < 1 5 0.  
•  Ti me t o l oss of C D AI res p o nse defi ne d b y a C D AI sc ore of  1 5 0 p oi nts d uri n g t he 
L o n g  T er m Treat me nt P hase.  
Ti me t o e ve nt data (f or e x a m ple, ti me t o cli n ical re missi o n) will be a nal yze d b y K a pla n-Mei er  
a nal ysis ( P R O C LI E F T T E S T i n S A S/ S T A T) stratifie d b y c o u ntr y.  
If t he pri mar y effi cac y e n d p oi nts are n ot statisticall y si g nifica nt, des cri pti ve a nal ysis will be 
perf or me d f or all sec o n d ar y efficac y e n d p oi nts.  
  
 7. 8 S afet y A n al yses  
7. 8. 1 E xte nt of E x p os ure   
T he n u m ber of s u bjects a d mi nistere d st u d y dr u g  a n d t he d urati o n of e x p os ure t o st u d y dr u g will 
be s u m marize d descri pti vel y  b y tr eat me nt gr o u p ( n, mea n, me dia n, S D, mi ni m u m, a n d ma xi m u m 
val ues).  E xte nt of e x p os ure is defi ne d as last d ose of st u d y dr u g –  first d ose of st u d y dr u g + 1. 
7. 8. 2 T re at me nt C o m pli a nce  a n d M o dific ati o ns  
Treat me nt c o m plia nce f or t he rifa xi mi n use will be calc ul ate d usi n g t h e f oll o wi n g al g orit h m:  
Perce nt o verall c o m plia n ce f or t h e rifa xi mi n use will be calc ulate d as: 1 0 0 *(t otal n u m ber of 
ta blets dis pe nse d –  t otal n u m ber of ta blets ret ur ne d)/(4  x t otal e xte nt of e x p os ure [as defi ne d i n 
Secti o n 7 .8 . 1. a b o ve]). 


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C o m plia nce will be defi n e d f or a s u bject as t he recei pt of at least 8 0 % a n d n o m ore t ha n 1 2 0 % of 
t he e x pecte d ta blets.   
Calc ulate d o ver all c o m plia nce a n d c o m plia nce will be s u m marize d descri pti vel y b y treat me nt 
gr o u p ( n,  mea n, me di a n, S D, mi ni m u m, a n d ma xi m u m val ues).  T he n u m b er a n d perce nt of 
c o m plia nt a n d  n o nc o m plia nt s u bjects base d o n t he calc ulate d o v erall c o m pli a nce will be 
s u m marize d b y treat me nt gr o u p.  
7. 8. 3 A d verse E vets  
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y A cti vities  ( Me d D R A) 
c o di n g dicti o nar y. Treat me nt -e mer ge nt A Es will  be defi ne d as a n y e v e nt wit h a  start date 
occ urri n g o n or after Visit 2 ( Da y 1) or, if pre -e xisti ng, w orse ni n g after Visit 2 ( Da y  1).  
7. 8. 3. 1 Tre at me nt -E mer ge nt A d verse E v e nts  
A  n o n -fatal A E is c o nsi dere d as a treat me nt e mer ge nt a d vers e e ve nt ( T E A E), if t he start date of 
t he A E is wit hi n t he peri o d of first d ose date of st u d y me dicati o n a n d last d ose date of st u d y 
me dicati o n pl us fi ve da ys .  A fatal A E is c o nsi dere d T E A E if t he start date of t he A E is wit hi n 
t he peri o d of first d ose d ate of st u d y me dicati o n a n d last d ose of st u d y me dicati o n pl us 3 0 da ys. 
T he i nci de nce of treat me nt -e mer ge nt A Es will be s u m ma rize d b y b o d y s yste m a n d Me d D R A  
preferre d t er m. If a s u bject re p orts t he sa m e A E m ore t ha n o n ce, t he n t hat s u bject will o nl y be 
c o u nte d o nce f or t he s u m mar y of t hat A E, usi n g t h e m ost se vere i nte nsit y.  
I n case of i nc o m plete or missi n g A E dates, t he sta n dar d Sali x esti mati o n r ule for A Es will be 
f oll o we d i n or der t o det er mi ne w het her a n A E s h o ul d be c o nsi dere d treat m e nt-e mer ge nt. If t he 
A E cate g or y still ca n’t be deter mi ne d, t he A E will be c o nsi dere d as T E A E. T he o nset dates 
re p orte d i n t he C R F will be prese nt e d i n t he listi n gs. 
Tre at me nt-e mer ge nt A Es will be s u m marize d as f oll o ws:  
•  All treat me nt -e mer ge nt A Es;  
•  All treat me nt -e mer ge nt A Es b y i nte nsit y;  
•  All treat me nt -e mer ge nt A Es relate d t o st u d y dr u g;  
•  All treat me nt -e mer ge nt S A Es; a n d  


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•  All treat me nt -e mer ge nt A Es t hat le d t o pre mat ure disc o nti n uati o n of st u d y dr u g.  
7. 8. 3. 2 Tre at me nt -E mer ge nt A d verse E v e nts  b y I nte nsit y  
A d verse e ve nts ar e cate g orize d f or se verit y b y t he i n vesti gat or as “ Mil d”, “ M o derate” or 
“ Se vere”. T he fre q u e nc y of T E A Es b y i nte nsit y will be s u m marize d b y b o d y s yste m, a n d 
preferre d t er m, o ver all a n d b y treat me nt gr o u p.  T E A Es wit h missi n g i nte nsit y will be c o nsi dere d 
‘ Se vere’ i n t he ta b ular s u m maries b ut data listi n gs will s h o w se verit y liste d as missi n g.  I n case 
of m ulti ple T E A Es f or t he sa me b o d y s yste m a n d preferre d t er m f or t he s a me s u bject, o nl y t he 
T E A E wit h t he ma xi m u m i nte nsit y will be c o u nte d i n t he ta ble.   
7. 8. 3. 3 Tre at me nt -E mer ge nt A d verse E v e nts  Rel ate d t o St u d y Dr u g  
Relate d A Es ar e t he A Es wit h “relate d ” f or ca usalit y. T E A Es wit h missi n g relati o ns hi p t o st u d y 
dr u g will be c o nsi dere d “relate d” i n t he t a b ular s u m maries b ut data listi n gs will s h o w 
relati o ns hi p as missi n g. 
  7. 8. 3. 4 All Tre at me nt -E mer ge nt Seri o us A d verse E ve nts  b y I nte nsit y  
A n y A E re p orte d as seri o us i n C R F will be re p orte d a s a S A E. T he cli nical data base will be 
rec o ncile d wit h t he seri o us a d verse e ve nt data b as e (fr o m t he Sali x Safet y de part me nt) b ef ore 
data base l oc k.  
All treat me nt -e mer ge nt S A Es will be s u m marize d b y b o d y s yste m a n d preferre d t er m, o verall 
a n d b y tr eat me nt gr o u p. 
7. 8. 3. 5 Tre at me nt -E mer ge nt A d verse E v e nts Le a di n g t o St u d y Pre m at ure 
Disc o nti n u ati o n  
All T E A Es t hat le d t o s u bject disc o nti n uati o n fr o m t he st u d y will be s u m marize d a n d liste d 
se parat el y.  
7. 8. 4 Cli nic al L a b or at or y E v al u ati o ns  
La b orat or y v al ues will be s u m marize d at baseli ne a n d at eac h ti me p oi nt. I n a d diti o n, c ha n ges  
fr o m baseli ne t o last visit will be s u m marize d. 
All p ote ntiall y cli nicall y si g nifica nt v al ues f or cli nical la b orat or y tests will be assesse d b y t he  
i n vesti gat or. O ut of ra n ge la b orat or y v al ues t hat ma y b e p ote ntia ll y cli nicall y si g nifica nt will be 
fla g ge d f or re vie w. 


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7. 8. 5 Pri or a n d C o nc o mit a nt Me dic ati o ns  
Pri or me dicati o ns are d efi ne d as me dicati o ns t hat st o p pri or t o t he first d ose of st u d y dr u g. 
C o nc o mita nt me dicati o ns are defi ne d as me di cati o ns t hat ( 1) start bef ore t he first d ose of st u d y 
dr u g a n d ar e c o nti n ui n g at t he ti me of t he first d ose of st u d y dr u g, or ( 2) start o n or after t he date 
of t he first d ose of st u d y dr u g.  
Pri or a n d c o nc o mita nt m e dicati o ns w ill be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) 
Dr u g E n ha nce d Dicti o nar y (Mar c h 2 0 1 8 Versi o n)  a n d liste d b y re p orte d ter m a n d A nat o mical 
T hera p e utic Class ( A T C) classificati o n. Me dicati o ns will be liste d b y s u bject i ncl u di n g t he start 
a n d e n d dates,  or w het her it is o n g oi n g, d os e, u nit , a n d i n dicati o n.  
7. 8. 6 Vit al Si g n Me as ure me nts  
Vital si g n meas ur e me nts will be s u m marize d at baseli ne a n d at eac h ti me p oi nt. F or eac h  
s u m mar y t he n u m b er, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m val ues will  be 
prese nte d b y tr eat me nt a n d st u d y p hase.  
7. 8. 7 P h ysic al E x a m  
P h ysical e x a mi nati o n data will be liste d.  
7. 8. 8 E lectr oc ar di o gr a m ( E C G) 
E C G para meters will be s u m marize d b y treat me nt gr o u p usi n g des cri pti ve statistics. I n or der  t o 
assess t he Q T i nter v al data, c orr ecte d Q T ( Q Tc) v al ues will be calc ul ate d b ase d o n t he f oll o wi n g 
met h o ds.  
1) Fri dericia’s c orr ecti o n: Q Tc = Q T/ R R 0. 3 3,  
2) Ba zett’s C orr ecti o n: Q Tc = Q T/ R R 0. 5 , 
Q Tc i nter val d ata at p ost -baseli ne visits will t he n be s u m marize d descri pti vel y b y ce ntral  
te n de nc y tec h ni q ues. I n a d diti o n, t he fre q ue nc y c o u nts a n d perce nta ges b y treat me nt gr o u p f or 
t he f oll o wi n g cate g ori es will be pr o vi de d: 
> 4 5 0 wit h Bas eli ne < = 4 5 0,  
> 4 8 0 wit h Bas eli ne < = 4 8 0,  
> 5 0 0 wit h Bas eli ne < = 5 0 0,  


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 C o nfi de ntial                                                             P a ge 2 6  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
I n creases fr o m baseli ne > 3 0 a n d  
I n creases fr o m baseli ne > 6 0. 
7. 9 Cli nic al bi ol o g y  
O nl y a p orti o n of cli nical bi ol o g y data will be a vaila ble at t he ti me of data b ase l oc k. Fi nal 
cli nical bi ol o g y a n al ysis/s u m mar y o ut p uts will be ge n erat e d w he n all cli nical bi ol o g y data are  
a vaila ble.  
 7. 1 0 S t atistic al a n d a n al ytic al iss u es  
7. 1 0. 1 H a n dli n g of D r o p o uts or M issi n g D at a   
Missi n g data will be ha n dle d usi n g t he W orst -Cas e  a nal ysis met h o d f or t he pri mar y a n d ke y  
sec o n dar y e n d p oi nts. I n t he W orst -Case  a nal ysis, s u bjects wit h fe wer t ha n 4 da ys of diar y  d ata i n 
a gi v e n wee k will be c o nsi dere d n o n -res p o n ders f or t hat wee k. A d diti o nall y, s u bjects wit h 
missi n g S E S -C D data will be classifie d n o n -res p o n der f or t hat meas ure i n t hat wee k. 
T he f oll o wi n g t hr ee s e nsiti vit y a nal yses will be c o n d ucte d t o a d dress t he i m pact of missi n g  dat a 
o n t he pri mar y a n d k e y sec o n dar y e n d p oi nts:  
7. 1 0. 2 L ast O bser v ati o n C arrie d F or w ar d ( L O C F) A n al ysis  
I n t he first a nal ysis, missi n g val ues will be re place d wit h t he last pre vi o us n o n -missi n g val ue. 
T he baseli ne v al ues will n ot be  carrie d f or war d.  
 
7. 1 0. 3 I m p ut ati o n R ules f or P arti al or Missi n g D ates  
I m p utati o n of p artial dates will be ma de f or A E o nset a n d st o p dates, start a n d e n d dates of 
c o nc o mita nt me dicati o n, start date of s u bse q u e nt a ntica ncer t h era p y, d ate of i nitial dia g n osis a n d 
deat h date. If dates are c o m pletel y missi n g, n o  i m p utati o n will be ma de. F or a n y p artial date wit h 
missi n g year, n o i m p utati o n will be  ma de.  
T he ge neral r ule f or i m p utati o n is:  
•  If o nl y d a y is missi n g, t h e n t he 1 5t h of t he m o nt h will be use d. 
•  If o nl y year is prese nt, t h e n J u ne 3 0t h will be use d. 


Sali x P har mace uticals, I nc.  
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 C o nfi de ntial                                                             P a ge 2 7  of 2 8                                          Fi nal : J a n uar y 3, 2 0 1 9 
 
If s uc h i m p utati o n date f or i nitial dia g n osis is o n or after d ate of first d ose, t he n date of first d ose 
–  1 will be use d. If s uc h i m p ute d date f or s u bse q u e nt a ntica ncer t hera pies  is bef ore d ate of last 
d ose, t he n date of l ast d ose + 1 will be use d.  If t he i m p ute d date is f or a n A E start date a n d is i n 
t he sa me year a n d m o nt h as b ut bef ore t h e first d ose date, t he n t he first d ose date will be use d, or 
if t he i m p ute d A E start d ate is after t h e A E e n d d ate, t he n t he A E e n d d ate will be use d. If t he 
i m p ute d date is f or a n A E start date a n d is i n t he sa me year a n d m o nt h as b ut after t he last d ose  
date + 3 0 da ys, t he n t h e last d ose date + 3 0 d a ys will be use d.  
If t he i m p ute d date is f or a n A E e n d dat e a n d is aft er t he deat h date, t he n t h e deat h dat e will be 
use d, or if t he i m p ute d A E e n d date is bef ore t he A E start date, t he n t he A E start  date will be 
use d.  
E ver y eff ort will be ma d e t o o btai n c o m plete dates f or dea t hs. If b ot h m o nt h a n d da y are missi n g 
f or deat h d ate or a d eat h date is t otall y missi n g, d o n ot i m p ute a n d ce ns or t he s u bject s ur vi val 
ti me. If d eat h year a n d m o nt h are a v aila ble b ut da y is missi n g, t he f oll o wi n g al g orit h m will be 
use d:  
•  If m m y y y y f or last c o ntact date = m m y y y y f or d eat h date, set deat h date t o t he da y after 
t he last c o ntact date. 
•   If m m y y y y f or last c o ntact date < m m y y y y f or d eat h date, set deat h date t o t he first da y 
of t he deat h m o nt h.  
•  If m m y y y y f or last c o ntact date > m m y y y y f or d eat h date, data err or a n d d o n ot i m p ute. 
7. 1 1 M ulti plicit y  
T he st u d y h as a si n gle pri mar y e n d p oi nt as t he pri mar y h y p ot hesis, t heref ore n o m ulti plicit y  
a dj ust me nt is nee de d t o t he o verall si g nifica n ce le vel of 0. 0 5. A d d iti o nall y, t he cli nical trial will 
be pr o vi di n g d ata f or t w o se parat e i n dicati o ns (i n d ucti o n a n d l o n g ter m treat me nt) wit h  eac h 
i n dicati o n ha vi n g its o w n se parat e e n d p oi nt. O n t h at basis, n o m ulti plicit y a dj ust me nt is nee de d 
t o t he o verall si g nifi ca nce le vel of 0. 0 5 per i n dicati o n beca use c o ncl usi o ns will be reac h e d 
i n de pe n de ntl y f or i n d ucti o n a n d se par atel y f or l o n g ter m treat me nt. 


Sali x P har mace uticals, I nc.  
Pr o d uct:  Rifa xi mi n                                                                       Statistical A nal ysis Pla n: Rifa xi mi n Dela ye d Release  
 
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8  C H A N G E S F R O M P R O T O C O L -S P E CI FI E D A N A L Y S E S  
 Beca use b ot h st u dies will be ter mi nate d earl y a n d f or t he p ur p ose of  a b bre viate d C S R o ri gi nall y pla n ne d 
e val uati o ns t hat will n ot be perf or me d  i ncl u de: 
A d diti o n al a n alysis of Sec o n d ary Effic a cy E n d p oi nts :  
•  L o n git u di nal a nal ysis usi n g a mi x e d m o del of t he c ha n ge fr o m baseli ne i n c o nti n u o us 
o utc o mes meas ure d at m ulti ple p ost -baseli ne ti me p oi nts.  
•  Deter mi nati o n w het her t he  declarati o n of res p o nse base d o n t he c o -pri mar y e n d p oi nts f or  
i n d ucti o n parallels t he patter n of C D AI sc ores 
•  
C o m paris o n of c ha n ges i n t he C D AI sc ores bet wee n res p o n ders a n d n o n -res p o n ders t o 
t he c o-pri mar y e n d p oi nts via Wilc o x o n ra n k -s u m test 
 A n alysis E x pl or at ory E n d p oi nt s:  
•  C haracterizati o n of st o ol micr o bi ota at baseli ne a n d after 1 6  a n d 5 2 wee ks of treat me nt.  
o  Baseli ne a n d p ost -treat me nt bacteri al D N A is olate d fr o m st o ol f or 1 6 S r R N A 
ge n e a m plificati o n.  
o  Descri pti ve c h aracterizati o n of bacteri a i n st o ol b y:  
 Is olati o n a n d i d e ntificati o n of selecte d Gra m ne gati ve a n d Gra m -p ositi ve 
bacteria.  
 Resista nce t o select e d a nti bi otics, i ncl u di n g  rifa xi mi n a n d rifa m pi n.   
•  Ge n o mic pr ofili n g of pr e g na n e X r ece pt or ( P X R) i n bl o o d.  
•  P o p ulati o n p har mac o ki netics of rifa xi mi n.  
Cli nic al L a b or at ory Assess m e nts:  
•  A s u m mar y of s hifts fr o m baseli ne t o fi nal e val u ati o n f or eac h treat me nt gr o u p f or eac h 
para meter.  
Electr oc ar di o gr a m  
•  Q T corr ecti o n base d o n li near re gressi o n tec h ni q ues 
T hese c h a n ges will be d o c u me nte d i n t he Cli nical St u d y R e p ort