3030-401-002: An Open-Label Pilot Study of Eluxadoline in Participants With Irritable Bowel Syndrome With Diarrhea (IBS-D) Who Have Evidence of Bile Acid Malabsorption (BAM)
Phase: PHASE4
Conditions: Irritable Bowel Syndrome With Diarrhea
Sponsor: Allergan

 
     
   
   
  
         N C T 0 3 4 4 1 5 8 1  
 
St u d y I D: 3 0 3 0 -4 0 1 -0 0 2  
 
 
Titl e:  A n  O p e n -L a b el  Pil ot  St u d y  of  El u x a d oli n e  i n  P arti ci p a nt s  wit h Irrit a bl e 
B o w el  S y n dr o m e  wit h  Di arr h e a (I B S -D)  W h o  H a v e  E vi d e n c e  of  Bil e  A ci d 
M al a b s or pti o n ( B A M)  
 
                                Pr ot o c ol  D at e:  A pril   1 7,  2 0 1 9 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1
Title P a ge
Pr ot oc ol Title: 3 0 3 0 -4 0 1 -0 0 2: A n O pe n -L a bel Pil ot St u d y of El u x a d oli ne i n P artici p a nts 
wit h Irrit a ble B o wel S y n dr o me wit h Di arr he a (I B S -D) W h o H a ve E vi de nce of Bile Aci d 
M al a bs or pti o n ( B A M)
A m e n d me nt N u m ber: 2
Brief Pr ot oc ol Title: 3 0 3 0 -4 0 1 -0 0 2 E L X B A M St u d y
Pr o d uct: El u x a d oli ne
S p o ns or N a me a n d Le g al Re gistere d A d dress:
Aller g a n S ales, 5 Gir al d a F ar ms, M a dis o n, 
N J 0 7 9 4 0, U nite d St ates; Aller g a n Li mite d, 1st F l o or M arl o w I nter n ati o n al, T he P ar k w a y, 
M arl o w, B uc ki n g h a ms hire S L 7, 1 Y L Aller g a n S ales, 5 Gir al d a F ar ms, M a dis o n, N J 0 7 9 4 0, 
U nite d St ates
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s): I ND 7 9, 2 0 1 4
E mer ge nc y Tele p h o ne N u m ber: Refer t o t he st u d y c o nt act s p a ge
S A E Re p orti n g F a x N u m ber/ E m ail:
B usi ness U nit/ 
Or g a niz ati o n 
E m ail
F a x
Aller ga n 
P har mace uticals
A p pr o v al D ate: 1 7 A pril 2 0 1 9
A me n d me nt 1 Date: 0 5 J u ne 2 0 1 8
Ori gi nal Pr ot oc ol Date: 1 9 Oct o ber 2 0 1 7
S p o ns or Si g n at or y:
Si g nat ures of t he s p o ns or si g nat ories are c ollecte d o n t he pr ot oc ol a p pr o val f or m.
V P, Cli nical De vel o p me nt – GI  
T hera p y Area Hea d

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges Ta ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A m e n d me nt 2
1 7 A pril 2 0 1 9
A me n d me nt 1
0 5 J u ne 2 0 1 8
Ori gi nal Pr ot oc ol
1 9 Oct o ber 2 0 1 7
P ur p ose of A me n d me nt
T he p ur p ose of Pr ot oc ol A me n d me nt 2 f or 3 0 3 0 -4 0 1 - 0 0 2 ( date d 1 7 A pril 2 0 1 9 ) is t o reflect t he 
defi niti o n of B A M base d o n t he m ost rece nt literat ure. 
T he f oll o wi n g is a s u m mar y  of c o nte nt-orie nte d c ha n ges t hat were ma de. Stri ket hr o u g h te xt 
de n otes te xt re m o ve d a n d b ol de d te xt de n otes a d de d te xt. A d diti o nal a d mi nistrati ve e dits were 
als o ma de, b ut n ot s pecificall y n ote d (e g, c orrecte d s pelli n g, p u nct uati o n, gra m mar, a b bre viati o n, 
a n d st yle err ors) i ncl u di n g gl o bal e dits re q uire d f or c o nsiste nc y.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3
T a ble 1 – 1 
S u m m ar y of C h a n ges i n Pr ot oc ol A me n d me nt 2
Secti o n N o. a n d 
N a me
Descri pti o n of C h a n ge
R ati o n ale
Title Pa ge
A d de d Aller ga n U K, Marl o w  S p o ns or A d dress t o facilitate 
i ncl usi o n of e x-U S sites i n t he st u d y
U p date t o ali g n wit h c urre nt Aller ga n sta n dar d
Secti o n 5. 4 Scie ntific 
Rati o nale f or St u d y 
Desi g n
U p date d wit h rati o nale f or use of b ot h ser u m 7 α C 4 testi n g a n d 
meas ure me nt of fecal bile aci ds t o deter mi ne B A M stat us.
T o u p date defi niti o n of B A M base d o n t he m ost rece nt 
literat ure
S y n o psis a n d Secti o n 6. 1 
I ncl usi o n Criteria
A me n de d I C 1. 0 1: Partici pa nt is a ma n or w o m a n a ge d 1 8 t o 6 5 7 5
years, i ncl usi ve, at scree ni n g.
A p pr o xi matel y 2 5 % of partici pa nts wit h c hr o nic 
diarr hea or diarr hea pre d o mi na nt irrita ble b o w el 
s y n dr o me are f o u n d t o ha ve bile aci d mala bs or pti o n. As 
t here is n ot a ge restricti o n i n de vel o pi n g bile aci d 
mala bs or pti o n, Aller ga n belie ve it is critical t o 
u n dersta n d h o w t his me dicati o n will affect t his 
partici pa nt p o p ulati o n .
S y n o psis a n d Secti o n 6. 1 
I ncl usi o n Criteria
A me n de d I C 2. 0 3: Pa rtici pa nts wit h e vi de nce of B A M
Partici pa nts m ust ha ve at le ast o ne of t he f oll o wi n g res ults fr o m 
fasti n g ser u m 7 α C 4 le vel ≥5 2. 5 n g/ m L at scree ni n g or wit hi n 1 
cale n dar year pri or t o scree ni n g.
 
f asti n g ser u m 7 a -h y dr o x y - 4-c h oleste n- 3-o ne ( 7 α C 4) le vel 
≥5 2. 5 n g/ m L
 
t ot al fec al bile aci ds   > 2 3 3 7 mi cr o m oles/ 4 8 h o urs  
 
pri m ar y bile aci ds ( fec al C A a n d C D C A) ≥1 0 % i n a 4 8 h 
fec al c ollecti o n
 
pri m ar y bile aci ds ( fec al C A a n d C D C A) ≥4 % wit h t ot al 
fec al bile aci d ≥ 1, 0 0 0 m icr o m oles/ 4 8 hr  
N ote: Partici pa nts ma y be e nr olle d as B A M p ositi ve wit h o ut ser u m 
7 α C 4 test res ults if t he y ha ve p ositi ve res ults fr o m 4 8 -h o ur 
meas ure me nt of t otal fecal bile aci ds w it hi n 1 cale n dar year pri or t o
T o u p date defi niti o n of B A M base d o n t he m ost rece nt 
literat ure

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
4
Secti o n N o. a n d 
N a me
Descri pti o n of C h a n ge
R ati o n ale
scree ni n g, defi ne d b y t otal fecal B A > 2 3 3 7 micr o m oles/ 4 8 h o urs.
S y n o psis a n d Secti o n 6. 1 
I ncl usi o n Criteria
A me n de d I C 2 . 0 4: Partici pa nts wit h o ut B A M
Partici pa nts m ust ha ve at le ast o ne of t he f oll o wi n g res ults fr o m 
fasti n g ser u m 7 α C 4 le vel ≤ 4 7. 1 n g/ m L at scree ni n g or wit hi n 1 
cale n dar year pri or t o scree ni n g. 
 
f asti n g ser u m 7 α C 4 le vel ≤ 4 7. 1 n g/ mL 
 
f asti n g ser u m 7 α C 4 le vels > 4 7. 1 n g/ m L b ut < 5 2. 5 n g/ m L 
wit h fec al bile aci ds t h at are ne g ati ve f or bile aci d 
m al a bs or pti o n (i.e. d o n ot meet criteri a 2. 0 3 b ase d o n fec al 
bile aci ds le vel)    
 
t ot al fec al bile aci ds ( B A) ≤2 3 3 7 m icr o m oles/ 4 8 h o urs  
 
pri m ar y bile aci ds ( fec al C A an d C D C A ) < 1 0 % i n a 4 8 h 
fec al c ollecti o n
 
pri m ar y bile aci ds ( fec al C A a n d C D C A) < 4 % wit h t ot al 
fec al bile aci d < 1, 0 0 0 micr o m oles / 4 8 hr
N ote: Partici pa nts ma y be e nr olle d as B A M ne gati ve wit h o ut ser u m 
7 α C 4 test res ults if t he y ha ve ne gati ve res ults fr o m 4 8 -h o ur 
meas ure me nt of t otal fecal B A w it hi n 1 cale n dar year pri or t o 
scree ni n g, defi ne d b y t otal fecal B A < 2 2 0 0 micr o m oles/ 4 8 h o urs. 
Partici pa nts wit h fasti n g ser u m 7 α C 4 le vels > 4 7. 1 n g/ m L b ut 
< 5 2. 5 n g/ m L ma y be e nr olle d as partici pa nts wit h o ut B A M if 
wit hi n 1 cale n dar year pri or t o scree ni n g visit t he y ha d ne gati ve 
res ults fr o m 4 8-h o ur meas ure me nts of t otal fecal B A.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5
Ta ble of C o nte nts
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble ....................................................................2
T a ble of C o nte nts ...........................................................................................................................5
T a ble of T a bles ...............................................................................................................................7
1. 
S y n o psis ............................................................................................................................8
2.  
Sc he d ule of Acti vities ( S o A) .........................................................................................1 3
3. 
I ntr o d ucti o n...................................................................................................................1 6
3. 1. 
St u d y  Rati o nale...............................................................................................................1 7
3. 2. 
Bac k gr o u n d .....................................................................................................................1 7
3. 3. 
Be nefit/ Ris k Assess me nt ................................................................................................1 8
4. 
O bjecti ves a n d E n d p oi nts ............................................................................................1 9
5. 
St u d y Desi g n ..................................................................................................................2 1
5. 1. 
O verall Desi g n ................................................................................................................2 1
5. 2. 
Partici pa nt a n d St u d y  C o m pleti o n..................................................................................2 2
5. 3. 
E n d of St u d y  Defi niti o n..................................................................................................2 3
5. 4. 
Scie ntific Rati o nale f or St u d y  Desi g n ............................................................................2 3
5. 5. 
J ustificati o n f or D ose...................................................................................................... 2 5
6. 
St u d y P o p ul ati o n ...........................................................................................................2 6
6. 1. 
I ncl usi o n Criteria ............................................................................................................2 6
6. 2. 
E xcl usi o n Criteria ...........................................................................................................2 8
6. 3. 
Lifest y le Restricti o ns ......................................................................................................3 0
6. 4. 
Scree n Fail ures ................................................................................................................3 0
7. 
Tre at me nts .....................................................................................................................3 2
7. 1. 
Treat me nts A d mi nistere d ................................................................................................3 2
7. 2. 
D ose M o dificati o n .......................................................................................................... 3 2
7. 3. 
Met h o d of Treat me nt Assi g n me nt.................................................................................. 3 2
7. 4. 
Bli n di n g/ Mas ki n g ...........................................................................................................3 3
7. 5. 
P re parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y................................................................3 3
7. 6. 
Treat me nt C o m plia nce.................................................................................................... 3 3
7. 7. 
C o nc o mita nt T hera p y .....................................................................................................3 3
7. 7. 1. 
Pr o hi bite d Treat me nts Bef ore a n d D uri n g t he St u d y ......................................................3 4
7. 7. 2. 
Per mitte d Treat me nts...................................................................................................... 3 4
7. 7. 3. 
Resc ue Me dici ne .............................................................................................................3 5
7. 8. 
Treat me nt after t he E n d of t he St u d y ..............................................................................3 6
8. 
Disc o nti n u ati o n/ Wit h dr a w al Criteri a .........................................................................3 7
8. 1. 
Disc o nti n uati o n of St u d y Treat me nt ...............................................................................3 7
8. 1. 1. 
Te m p orar y  Disc o nti n uati o n ............................................................................................3 8
8. 1. 2. 
Rec halle n ge .....................................................................................................................3 8

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
6
8. 2. 
Wit h dra wal fr o m t he St u d y .............................................................................................3 8
8. 3. 
L ost t o F oll o w U p ...........................................................................................................3 9
9. 
St u d y Assess me nts a n d Pr oce d ures............................................................................. 4 0
9. 1. 
Efficac y  Assess me nts .....................................................................................................4 3
9. 1. 1. 
Dail y  IB S S y m pt o ms ......................................................................................................4 4
9. 1. 2. 
Irrita ble B o wel Sy n dr o me -Q ualit y of Life Q uesti o n naire ..............................................4 4
9. 1. 3. 
Ser u m 7 α C 4 Le vel ..........................................................................................................4 4
9. 2. 
A d verse E ve nts ...............................................................................................................4 5
9. 2. 1. 
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E 
I nf or mati o n .....................................................................................................................4 5
9. 2. 2. 
Met h o d of Detecti n g A Es a n d S A Es
..............................................................................4 5
9. 2. 3. 
F oll o w -u p of A Es a n d S A Es ...........................................................................................4 6
9. 2. 4. 
Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es...............................................................4 6
9. 2. 5. 
Car di o vasc ular a n d Deat h E ve nts ...................................................................................4 6
9. 2. 6. 
Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es .............................................................................................4 7
9. 2. 7. 
Pre g na nc y ........................................................................................................................4 7
9. 2. 8. 
A d verse E ve nts of S pecial I nterest .................................................................................4 7
9. 2. 9. 
Me dicati o n Err ors
...........................................................................................................4 9
9. 3. 
Treat me nt of O ver d ose ...................................................................................................4 9
9. 4. 
Safet y  Assess me nts.........................................................................................................4 9
9. 4. 1. 
P h y sical E xa mi nati o ns ....................................................................................................4 9
9. 4. 2. 
Vital Si g ns....................................................................................................................... 4 9
9. 4. 3. 
Cli nical Safet y  La b orat or y Assess me nts ........................................................................5 0
9. 4. 4. 
S uici dal Ris k M o nit ori n g ................................................................................................5 0
9. 5. 
P har mac o ki netics ............................................................................................................5 0
9. 6. 
P har mac o d y na mics .........................................................................................................5 1
9. 7. 
Ge netics ..........................................................................................................................5 1
9. 8. 
Bi o mar ker s ......................................................................................................................5 1
9. 9.   
Healt h Ec o n o mics O R Me dical Res o urce Utilizati o n a n d Healt h 
Ec o n o mics....................................................................................................................... 5 1
1 0. 
St atistic al C o nsi der ati o ns ............................................................................................5 2
1 0. 1. 
Sa m ple Size Deter mi nati o n ...........................................................................................5 2
1 0. 2. 
P o p ulati o ns f or A nal y ses ................................................................................................5 2
1 0. 3. 
Statistical A nal y ses .........................................................................................................5 2
1 0. 3. 1. 
Ke y  Statistical Met h o d ol o g y...........................................................................................5 2
1 0. 3. 2. 
Efficac y  A nalys es ...........................................................................................................5 3
1 0 . 3. 3.
Safet y A nal ys es ...............................................................................................................5 4
1 0. 3. 4. 
P har mac o ki netic A nal y ses ..............................................................................................5 5
1 0. 3. 5. 
Ot her A nal ys es ................................................................................................................5 5
1 0. 3. 6. 
I nteri m A nalys es .............................................................................................................5 5
1 1. 
Refere nces ......................................................................................................................5 6

El u xa d oli ne
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7
1 2. 
A p pe n dices .....................................................................................................................5 9
1 2. 1. 
A p pe n di x 1: A b bre viati o ns a n d Tra de mar ks ..................................................................5 9
1 2. 3. 
A p pe n di x 3: St u d y  G o ver na nce C o nsi derati o ns.............................................................6 3
1 2. 4. 
A p pe n di x 4: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E val uati n g, F oll o w -u p, a n d Re p orti n g .........................................................6 7
1 2. 5. 
A p pe n di x 5: C o ntrace pti ve G ui da nce a n d C ollecti o n of 
Pre g na nc y  Inf or mati o n ...................................................................................................7 3
1 2. 6. 
A p pe n di x 6: L i ver Safety: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts ...................................................................................................................7 5
1 2. 7. 
A p pe n di x 7: Sta n dar d Disc o nti n uati o n Criteria ..............................................................7 8
1 2. 8. 
A p pe n di x 8: St u d y Ta b ular S u m mar y ............................................................................8 0
 
1 2. 1 0. 
A p pe n di x 1 0: S u m mar y  A da pte d fr o m G ui deli nes of t he U S 
M ulti -s ociet y Tas k F orce o n C ol orectal Ca ncer a n d Ot her 
C ol o n osc o p y  Re q uire me nts............................................................................................8 8
1 2. 1 1. 
A p pe n di x 1 1: Brist ol St o ol F or m Scale ( B S F S) .............................................................9 0
1 2. 1 3. 
Pr ot oc ol A me n d me nt 1 S u m mar y .................................................................................1 0 0
Ta ble of Ta bles
Ta ble 1- 1 
S u m mar y  of C ha n ges i n Pr ot oc ol A me n d me nt 1................................................ 3
Ta ble 5 - 1 
St u d y  Desi g n ..................................................................................................... 2 2
Ta ble 7- 1 
Treat me nts A d mi nistere d .................................................................................. 3 2
Ta ble 7 - 2 
Pr o hi bite d Treat me nts Bef ore a n d D uri n g t he St u d y ........................................ 3 4
Ta ble 1 0 - 1 
A nal y sis P o p ulati o ns ......................................................................................... 5 2
Ta ble 1 0 -2 
Statistical Met h o d ol o g y ..................................................................................... 5 3
Ta ble 1 0 - 3 
Pri mar y  Efficac y E n d p oi nt................................................................................ 5 3
Ta ble 1 0 -4 
Sec o n dar y  Efficac y E n d p oi nts .......................................................................... 5 4
Ta ble 1 2 - 1 
Pr ot oc ol -Re q uire d Safet y L a b orat or y Assess me nts.......................................... 6 2

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
8
1. 
S y n o psis
Pr ot oc ol Title: 3 0 3 0 -4 0 1 -0 0 2: A n O pe n -L a bel Pil ot St u d y of El u x a d oli ne i n P artici p a nts 
wit h Irrit a ble B o wel S y n dr o me wit h Di arr he a (I B S -D) W h o H a ve E vi de nce of Bile Aci d 
M al a bs or pti o n ( B A M)
Pr ot oc ol N u m ber: 3 0 3 0 -4 0 1 -0 0 2
Brief Title: 3 0 3 0 -4 0 1 -0 0 2 E L X B A M St u d y
St u d y P h ase: P hase I V
St u d y R ati o n ale:
El u xa d oli ne was a p pr o ve d f or t he treat me nt of a d ult patie nts wit h I B S -D b y  t he F D A a n d E M A 
i n 2 0 1 5 a n d 2 0 1 6 , res pecti vel y. Beca use t he P hase 3 c o nfir mat or y  st u dies of el u xa d oli ne f or I B S -
D were c o n d ucte d pri or t o t he iss ua nce of t he latest versi o n of t he R o me criteria ( R o me I V) a n d 
pri or t o t he p u blicati o n of t he fi nal E M A g ui deli ne o n irrita ble b o wel s yn dr o me ( I B S), t hese 
st u dies di d n ot pr os pecti vel y  e xcl u de patie nts wit h e vi de nce of B A M. Baseli ne c haracteristics of 
t he P hase 3 I B S-D patie nt p o p ulati o n de m o nstrate d a hi g h pre vale nce of b ot h o besit y  a n d pri or 
c h olec ystect o my. Gi ve n t he k n o w n ass ociati o n of hi g her b o d y  mass i n de x (B MI ) wit h B A M a n d 
t hat c h olec ystect o my is a k n o w n ris k fact or f or B A M it is c o ncei va ble t hat s o me p orti o n of 
partici pa nts e nr olle d i n t h ose st u dies ma y  ha ve ha d e vi de nce of B A M. Si nce t he el u xa d oli ne 
P hase 3 I B S -D st u dies di d n ot e val uate partici pa nt’s bile aci d a bs or pti o n stat us, it is u n k n o w n 
w het her t he effecti ve ness of el u xa d oli ne ma y be differe nt i n patie nts wit h e vi de nce of B A M. It is 
p ossi ble t hat t he o verall effects of el u xa d oli ne c o ul d ha ve bee n dil ute d b y a s u bset of n o n -
res p o nsi ve partici pa nts s ufferi n g fr o m B A M f or w h o m a bile aci d se q uestra nt mi g ht ha ve bee n a 
m ore a p pr o priate treat me nt o pti o n. 
T he g oal of t he prese nt st u d y  is t heref ore t o e val uate t he p ossi bilit y of a differe ntial effect of 
el u xa d oli ne o n altere d b o wel f u ncti o n i n I B S - D partici pa nts wit h a n d wit h o ut e vi de nce of B A M. 
T he o verall h y p ot hesis of t his st u d y  is t hat t he efficac y of el u xa d oli ne is greater i n partici pa nts
wit h o ut e vi de nce of B A M c o m pare d t o t h ose wit h e vi de nce of B A M.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9
O bjecti ves a n d E n d p oi nt s
T he pri mar y  a n d sec o n dar y st u d y o bjecti ves a n d t heir c orres p o n di n g e n d p oi nts are liste d i n t he 
ta ble bel o w.
O bjecti ves
E n d p oi nts
Pri mar y
 
T o e val uate t he efficac y of el u xa d oli ne 1 0 0 m g 
BI D i n I B S -D partici pa nts wit h e vi de nce of B A M 
c o m pare d t o I B S-D partici pa nts wit h o ut e vi de nce 
of B A M
 
C ha n ge fr o m baseli ne i n a vera ge B S F S sc ore o ver 
4 we e ks of treat me nt peri o d
 
T o e val uate t he safet y a n d t olera bilit y of 
el u xa d oli ne 1 0 0 m g BI D i n I B S -D partici pa nts 
wit h e vi de nce of B A M a n d i n I B S -D partici pa nts 
wit h o ut e vi de nce of B A M
 
E val uati o n of a d verse e ve nts, cli nical la b orat or y 
tests, vital si g ns, p h ysical e xa mi nati o ns
Sec o n dar y
 
T o f urt her e val uate t he efficac y of el u xa d oli ne 
1 0 0 m g BI D i n I B S -D partici pa nts wit h e vi de nce of 
B A M c o m pare d t o I B S -D partici pa nts wit h o ut 
e vi de nce of B A M
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of dail y 
b o w el m o ve me nt fre q ue nc y d uri n g t he treat me nt 
peri o d
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of dail y 
w orst a b d o mi nal pai n sc ores d uri n g t he treat me nt 
peri o d
 
C ha n ge fr o m baseli ne i n t he 4- wee k a vera ge of dail y 
bl oati n g d uri n g t he treat me nt peri o d
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of 
n u m ber of dail y ur ge nt b o w el m o ve me nts d uri n g t he 
treat me nt peri o d
 
T he pr o p orti o n of partici pa nts wit h a n y fecal 
i nc o nti ne nce d uri n g t he treat me nt peri o d
 
C ha n ge fr o m baseli ne i n I B S -Q O L sc ore at t he e n d 
of t he treat me nt peri o d
 
C ha n ge fr o m baseli ne i n ser u m 7 α C 4 le vels at t he 
e n d of t he treat me nt peri o d
 
T o e val uate t he p o p ulati o n P K of el u xa d oli ne i n 
I B S-D patie nts wit h a n d wit h o ut e vi de nce of B A M
 
P o p ulati o n p har mac o ki netic para meters of 
el u xa d oli ne deter mi ne d fr o m plas ma c o nce ntrati o n 
data e xtra p olate d fr o m drie d bl o o d sa m ple a nal ysis
7 α C 4 = 7a -h y dr o x y - 4-c h oleste n- 3-o ne; B A M = bile aci d mala bs or pti o n; BI D = t wice dail y; B S F S = Brist ol St o ol 
F or m  Scale; I B S- D = irrita ble b o wel s y n dr o me wit h diarr hea; I B S-Q O L = irrita ble b o wel s y n dr o me -q ualit y of 
life; P K = p har mac o ki netics .
O ver all St u d y Desi g n:
T his P hase I V st u d y  will use a n o pe n-la bel, parallel- gr o u p, c o h ort-c o ntr olle d desi g n i n 
partici pa nts meeti n g t he R o me IV criteria f or I B S -D wit h a n d wit h o ut e vi de nce of B A M. 
Partici pa nts will be assi g ne d t o 1 of 2 c o h orts base d o n t heir B A M stat us. As far as p ossi ble t he 
2 c o h orts will be matc he d b y a ge, ge n der a n d se verit y of s ym pt o ms.
1.
C o h ort 1: I B S -D partici pa nts wit h e vi de nce of B A M treate d wit h el u xa d oli ne 1 0 0 m g oral 
ta blets t wice daily ( BI D ) wit h f o o d.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 0
2.
C o h ort 2: I B S -D partici pa nts wit h o ut e vi de nce of B A M treate d wit h el u xa d oli ne 1 0 0 m g oral 
ta blets BI D wit h f o o d.
St u d y Desi g n
Peri o d 
Scree ni n g a
Pretre at m e nt a
O pe n -L a bel Tre at me nt
P ost -Tre at m e nt
D ur ati o n
0- 2 w ee ks 
2- 3 w ee ks
4 w ee ks
2 w ee ks
Wee k
Scree ni n g 
Pretreat me nt 
Baseli ne 
Wee k 2
b
Wee k 4
( E O T/ E T)
Wee k 6
b
( F oll o w-u p)
St u d y 
Visit 
1
2
3
4
5
6
St u d y D a y
1 
1 5 ( ± 2) 
2 9 ( ± 2) 
Visit 5 + 1 4 da ys 
(± 7 )
7 α C 4 = 7a -h y dr o x y - 4-c h oleste n- 3-o ne; B A = bile aci d
a
Scree ni n g a n d pretreat me nt peri o ds ma y be c o m bi ne d . if res ults of fasti n g ser u m 7 α C 4 test or 4 8-h o ur fecal B A 
c ollecti o n c o n d ucte d wit hi n 1 cale n dar year fr o m scree ni n g are a vaila ble at t he ti me of t he c o m bi ne d visit or 
res ults fr o m fasti n g ser u m 7 α C 4 test are a vaila ble pri or t o t he start of st u d y treat me nt..
b
M a y  be d o ne o ver t he p h o ne.
T he t otal d urati o n of st u d y partici pati o n f or eac h part ici pa nt will be u p t o 1 1 wee ks.   
Ke y i ncl usi o n criteri a:
1.
A d ult me n or w o me n a ge d 1 8 t o 7 5 ye ars i ncl usi ve wit h a dia g n osis of I B S - D per R o me I V 
criteri a.
2.
Partici pa nts wit h e vi de nce of B A M m ust ha ve at least o ne of t he f oll o wi n g at scree ni n g or 
wit hi n 1 ca le n dar ye ar pri or t o scree ni n g :

fasti n g ser u m 7a -h y dr o x y - 4-c h oleste n- 3-o ne ( 7 α C 4) le vel ≥5 2. 5 n g/ m L

t otal fecal bile aci ds   > 2 3 3 7 micr o m oles/ 4 8 h o urs  

pri mar y  bile aci ds (fecal C A a n d C D C A) ≥1 0 % i n a 4 8 h fecal c ollecti o n

pri mar y  bile aci ds (fecal C A a n d C D C A) ≥4 % wit h t otal fecal bile aci d ≥ 1, 0 0 0 
micr o m oles/ 4 8 hr  
3.
.Partici pa nts wit h o ut B A M m ust ha ve at least o ne of t he f oll o wi n g at scree ni n g or wit h i n 1 
cale ndar y ear pri or t o scree ni n g :

fasti n g ser u m 7 α C 4 le vel ≤ 4 7. 1  n g/ m L 

fasti n g ser u m 7 α C 4 le vels > 4 7. 1 n g/ m L b ut < 5 2. 5 n g/ m L wit h  fecal bile aci ds t hat are 
ne gati ve f or bile aci d mala bs or pti o n (i.e. d o n ot meet criteria 2. 0 3 base d o n fecal bile 
aci ds le vel)    

t otal fecal bile aci ds ( B A) ≤2 3 3 7 micr o m oles/ 4 8 h o urs  

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 1

pri mar y  bile aci ds (fecal C A a n d C D C A) < 1 0 % i n a 4 8 h fecal c ollecti o n

pri mar y  bile aci ds (fecal C A a n d C D C A) < 4 % wit h t otal fecal bile aci d < 1, 0 0 0 
micr o m oles / 4 8 hr
4.
A n a vera ge dail y Brist ol St o ol F or m Scale ( B S F S ) sc ore ≥ 5. 0 or ≥ 2 5 % of diar y  e ntr y d a y s 
wit h a B S F S sc ore of 6 or 7 d uri n g t he 1 4 da y s pri or t o Da y 1.
5.
W o me n of c hil d b eari n g p ote ntial m ust use h or m o nal or d o u ble barrier c o ntrace pti o n or 
mai ntai n a m o n o ga m o us relati o ns hi p wit h a vasect o mize d male part ner fr o m t he date of 
i nf or me d c o nse nt u ntil 2 4 h o urs after fi nal d ose of st u d y dr u g. 
6.
C o m plete d t he electr o nic diar y ( e Diar y) o n ≥1 0 of t he 1 4 da y s pri or t o Da y  1.
7.
H as n ot use d l o pera mi de resc ue me dicati o n o n > 3 of t he 1 4 da y s pri or t o Da y 1. 
Ke y e xcl usi o n criteri a:
1.
A dia g n o sis of I B S wit h a s u bt ype of irrita ble b o wel s y n dr o me wit h c o nsti pati o n (I B S- C), 
mi xe d I B S, or u ns u bt y pe d I B S per R o me I V criteria.
2.
D oes n ot ha ve a gall bla d der.
3.
K n o w n or s us pecte d biliar y  d uct o b str ucti o n, or s p hi ncter of O d di disease or d ysf u ncti o n. 
(Partici pa nts wit h a hist or y  of gallst o nes ma y be e nr olle d).
4.
H ist or y of alc o h olis m, alc o h ol a b use or alc o h ol a d dicti o n, or dri n ks m ore t ha n 3 alc o h olic 
be vera ges per da y .
5.
H ist or y of pa ncreatitis; str uct ural diseases of t he pa ncreas, i ncl u di n g k n o w n or s us pecte d 
pa ncreatic d uct o bstr ucti o n.
6.
H ist or y of mil d, m o derate, or se vere he patic i m pair me nt acc or di n g t o C hil d-P u g h 
classificati o n. H ist or y or c urre nt dia g n osis of i nfla m mat or y or i m m u ne-me diate d 
gastr oi ntesti nal ( GI ) dis or ders .
7.
C eliac disease or a p ositi ve ser o l o gical test f or celiac disease.
8.
K n o w n lact ose or fr uct ose i nt olera nce ass ociate d wit h diarr hea, a b d o mi nal pai n or 
disc o mf ort, t hat c o ul d c o nf o u n d assess me nts i n t he st u d y.
9.
W o me n
w h o are c urre ntl y pre g na nt or n ursi n g, or pla n t o bec o me pre g na nt or n urse d uri n g 
t he st u d y.
1 0. K n o w n aller gies or h y perse nsiti vit y  t o o pi oi ds.
N u m ber of P artici p a nt s:
T here will be 2 4 partici pa nts e nr olle d i n t he st u d y , 1 2 partici pants wit h e vi de nce of B A M a n d 
1 2 partici pa nts wit h o ut e vi de nce of B A M. 
N u m ber of Sites: 
T he st u d y  will be c o n d ucte d at 1 st u d y site i n t he U nite d States.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 2
Tre at me nt Gr o u ps a n d St u d y D ur ati o n:
T he t otal d urati o n of t he st u d y  is u p t o 1 1 wee ks, w hic h i ncl u des: scree ni n g peri o d ( 0 - 2 wee ks), 
pretreat me nt peri o d ( 2 -3 wee ks), 4 -wee k o pe n -la bel treat me nt peri o d, a n d 2-wee k p ost -treat me nt 
safety f oll o w-u p peri o d .

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 3
2. 
Sc he d ule of Acti vities ( S o A)

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 4

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 5

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 6
3. 
I ntr o d ucti o n
Irrita ble b o wel s yn dr o me (I B S) is o ne of t he m ost c o m m o n a n d m ost wi del y  st u die d f u ncti o nal 
gastr oi ntesti nal dis or ders ( F GI D; L o n gstret h 2 0 0 6 ; C he y  2 0 1 5). I B S is c haracterize d by 
a b d o mi nal pai n ass ociate d wit h altere d b o wel m o ve me nt s y m pt o ms a n d is s u bcate g orize d base d 
o n st o ol patter ns ( Dr oss ma n 2 0 0 6 ). F o ur differe nt s u bt ypes are defi ne d w hic h i ncl u de I B S wit h: 
diarr hea (I B S -D), c o nsti pati o n (I B S -C), b ot h c o nsti pati o n a n d diarr hea (I B S -M), or u ns pecifie d 
(I B S-U). As a n F GI D, I B S lac ks a n u n derl yi n g or ga nic ca use (s uc h as a str uct ural, i nfla m mat or y , 
or bi oc he mical a b n or malit y ) a n d is dia g n ose d pri maril y base d o n patie nts’ s ym pt o m re p orts per 
t he R o me Dia g n ostic Criteria f or F u ncti o nal Gastr oi ntesti nal Dis or ders ( R o me). T he gl o bal 
pre vale nce of I B S is esti mate d t o be 1 1. 2 % (L o vell 2 0 1 2 ; C he y  2 0 1 5). I B S is ass ociate d wit h 
si g nifica nt i m pair me nt i n q ualit y of life a n d hi g h rates of c o m or bi d c o n diti o ns (Gral ne k 2 0 0 0 ), 
w hic h i m p o ses a si g nifica nt s oci oec o n o mic b ur de n t o s ociet y (H ulisz 2 0 0 4 ; Paré 2 0 0 6 ). 
T he pat h o p h ys i ol o g y of I B S is n ot c o m pletel y u n derst o o d b ut is t h o u g ht t o be m ultifact orial, 
wit h ge netics, a b n or mal g ut m otilit y , visceral h yperse nsiti vit y , psyc h os ocial distress, altere d g ut 
micr o bi o me, a n d brai n -g ut i nteracti o n pla y i n g i m p orta nt r oles i n its de vel o p me nt 
(Ca milleri 2 0 1 2 ; C he y  2 0 1 5). Im p orta nt t o t he diarr heal s u bt ype of I B S, it is i ncreasi n gl y 
rec o g nize d t hat bile aci d mala bs or pti o n ( B A M) ma y be a p ote ntial ca use of c hr o nic diarr hea 
(Aziz 2 0 1 5 ; Baj or 2 0 1 5 ; Ca milleri 2 0 1 5 ; Vale nti n 2 0 1 6 ). I n B A M, t he fail ure t o a de q uately 
rea bs or b c o nj u gate d bile salts i n t he ter mi nal ile u m lea ds t o e xcess bile aci ds e nteri n g t he c ol o n 
w here t he y  sti m ulate c ol o nic secreti o n a n d m otilit y (Ca milleri 2 0 1 4 ). Sy m pt o ms of B A M prese nt 
as water y diarr hea, bl oati n g, fecal ur ge nc y a n d fecal i nc o nti ne nce, w hic h cl osel y o verla p t he 
s ym pt o ms of f u ncti o nal diarr hea a n d I B S -D ( Isla m 2 0 1 2 ). Rece nt e vi de nce s u g gests t hat u p t o 
1/ 3 of patie nts w h o meet t he R o me criteria f or I B S -D ha ve e vi de nce of B A M base d pri maril y o n 
7 5Sele ni u m -h o m oc h olic aci d ta uri ne ( Se H C A T) rete nti o n testi n g ( We dla ke 2 0 0 9 ; Aziz 2 0 1 5 ; 
Baj or 2 0 1 5 ). O verall, I B S-D patie nts wit h a n d wit h o ut e vi de nce of B A M a p pear hi g hl y si milar i n 
de m o gra p hic c haracteristics a n d assess me nts of well -bei n g, e xce pt t hat patie nts wit h B A M te n d 
t o ha ve hi g her B MIs (Ca milleri 2 0 1 4a ; Aziz 2 0 1 5 ). 
T he p ote ntial o verla p of I B S -D a n d B A M ma y  ha ve i m p orta nt i m plicati o ns f or cli nical practice, 
es peciall y if a n altere d treat me nt c o urse w o ul d be c o nsi dere d. Re c o g nizi n g t his, t he m ost rece nt 
versi o n of t he R o me dia g n ostic criteria f or I B S -D iss ue d i n 2 0 1 6 ( R o me I V) n o w rec o m me n ds 
a n asses s me nt of B A M stat us as a p ote ntial ca use of c hr o nic, water y diarr hea ( Lac y  2 0 1 6). F or 
patie nts wit h e vi de nce of B A M, a bile aci d se q uestra nt ma y be a n a p pr o priate treat me nt o pti o n, 
at least f or t he diarr heal s y m pt o ms, t h o u g h p o or t olera bilit y a n d c o m plia nce ca n be pr o ble matic 
f or t he m ost ec o n o mical bile aci d bi n di n g a ge nt c h olest yra mine ( Ca milleri 2 0 1 4 ). T he p ote ntial 
I B S-D/ B A M o verla p als o has i m plicati o ns f or cli nical researc h, partic ularl y if a pr o d uct bei n g 
de vel o pe d f or I B S -D has a differe nt be nefit -ris k pr ofile i n patie nts wit h e vi de nce of B A M. S uc h 
a sit uati o n c o ul d lea d t o a n u n deresti mate of a pr o d uct’s real effecti ve ness i n I B S -D, es peciall y if 
a lar ge pr o p orti o n of patie nts i n a st u d y ha ve o verla p pi n g B A M a n d are u nres p o nsi ve t o 
treat me nt. T o eli mi nate t his p ossi bilit y, t he Se pte m ber 2 0 1 4 E M A g ui deli ne 
( C P M P/ EW P/ 7 8 5/ 9 7/ Re v. 1) o n t he de vel o p me nt of dr u gs f or I B S rec o m me n ds e xcl u di n g 
patie nts wit h B A M fr o m I B S -D st u dies.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 7
3. 1. 
St u d y R ati o n ale
El u xa d oli ne was a p pr o ve d f or t he treat me nt of a d ult patie nts wit h I B S -D b y  t he F D A a n d E M A 
i n 2 0 1 5 a n d 2 0 1 6 , res pecti vel y. Beca use t he P hase 3 c o nfir mat or y st u dies of el u xa d oli ne f or I B S -
D were c o n d ucte d pri or t o t he iss ua nce of t he latest versi o n of t he R o me criteria ( R o me I V) a n d 
pri or t o t he p u blicati o n of t he fi nal E M A g ui deli ne o n I B S, t hese st u dies di d n ot pr os pecti vel y 
e xcl u de patie nts wit h e vi de nce of B A M. Baseli ne c haracteristics of t he P hase 3 I B S -D patie nt 
p o p ulati o n de m o nstrate d a hi g h pre vale nce of b ot h o besit y  a n d pri or c h olec ystect o my. Gi ve n t he 
k n o w n ass ociati o n of hi g her B M I wit h B A M (Ca milleri 2 0 1 4a ; Aziz 2 0 1 5 ) a n d t hat 
c h olec ystect o my is a k n o w n ris k fact or f or B A M ( Walters 2 0 1 0 ), it is c o ncei va ble t hat s o me 
p o rti o n of partici pa nts e nr olle d i n t h ose st u dies ma y ha ve ha d e vi de nce of B A M. Si nce t he 
el u xa d oli ne P hase 3 I B S -D st u dies di d n ot e val uate partici pa nt’s bile aci d a bs or pti o n stat us, it is 
u n k n o w n w het her t he effecti ve ness of el u xa d oli ne ma y  be differe nt i n patie nts wit h e vi de nce of 
B A M. It is p ossi ble t hat t he o verall effects of el u xa d oli ne c o ul d ha ve bee n dil ute d b y  a s u bset of 
n o n -res p o nsi ve patie nts s ufferi n g fr o m B A M f or w h o m a bile aci d se q uestra nt mi g ht ha ve bee n a 
m ore a p pr o priate treat me nt o pti o n. 
T he g oal of t he prese nt st u d y  is t heref ore t o e val uate t he p ossi bilit y of a differe ntial effect of 
el u xa d oli ne o n altere d b o wel f u ncti o n i n I B S -D partici pa nts wit h a n d wit h o ut e vi de nce of B A M. 
T he o verall h y p ot hesis of t his st u d y  is t hat t he efficac y of el u xa d oli ne is greater i n partici pa nts
wit h o ut e vi de nce of B A M c o m pare d t o t h ose wit h e vi de nce of B A M.
3. 2. 
B ac k gr o u n d
El u xa d oli ne is a l ocall y  acti ve mi xe d m u -o pi oi d rece pt or (µ O R ) a g o nist, ka p pa -o pi oi d rece pt or 
( κ O R) a g o nist, a n d delta-o pi oi d rece pt or ( δ O R) a nta g o nist wit h l o w oral bi oa vaila bilit y. 
El u xa d oli ne has bee n a p pr o ve d f or t he treat me nt of a d ult patie nts wit h I B S -D i n t he U nite d 
States, t he E ur o pea n U ni o n, a n d Ca na da, a m o n g ot her re gi o ns. El u xa d oli ne has gastr oi ntesti nal 
(GI ) tra nsit i n hi biti n g acti vit y t hat is c o nsiste nt wit h its pri mar y p har mac ol o gical pr ofile as a 
µ O R a g o nist. T he mi xe d p har mac ol o gical pr ofile of el u xa d oli ne ma y  miti gate t he ris k of 
c o nsti pati o n effects t hr o u g h u n o p p ose d µ O R a g o nis m as see n wit h a ge nts s uc h as l o pera mi de, 
t hr o u g h a nta go nis m of t he δ O R ( Wa de 2 0 1 2 ). 
El u xa d oli ne has bee n de m o nstrate d t o be effecti ve i n treati n g t he a b d o mi nal pai n a n d diarr heal 
s ym pt o ms of patie nt s wit h I B S-D wit h a n acce pta ble ris k pr ofile ( El u xa d oli ne In vesti gat or’s 
Br oc h ure). T he efficac y  a n d safety i n I B S -D patie nts was c o nfir me d i n 2 ra n d o mize d, 
m ultice nter, m ulti nati o nal, d o u ble -bli n d, place b o -c o ntr olle d P ha se 3 st u dies i n a t otal of 
2 4 2 6 pat ie nts meeti n g t he R o me III criteria f or I B S-D (st u dies I B S -3 0 0 1 a n d I B S -3 0 0 2; 
Le m b o 2 0 1 6 a n d VI B E R ZI ™ PI 2 0 1 7 ). T he pri mar y  e n d p oi nt of t he P hase 3 st u dies was defi ne d 
b y  t he si m ulta ne o us i m pr o ve me nt i n t he dail y w orst a b d o mi nal pai n sc ore b y ≥3 0 % c o m pare d 
wit h baseli ne wee kl y a vera ge a n d a re d ucti o n i n t he Brist ol St o ol F or m Scale ( B S F S) t o < 5 o n at 
least 5 0 % of da ys wit hi n a 1 2-wee k treat me nt peri o d ( F D A e n d p oi nt) a n d a 2 6 -wee k treat me nt 
peri o d ( E M A e n d p oi nt).

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 8
3. 3. 
Be nefit/ Ris k Assess me nt
El u xa d oli ne 1 0 0 m g t wice dail y ( BI D) de m o nstrate d si g nifica ntl y greater c o m p osite res p o n der 
rates as c o m pare d wit h place b o o ver 1 2 wee ks a n d 2 6 wee ks of treat me nt. El u xa d oli ne 7 5 m g 
BI D de m o nstrate d si g nifica ntl y  greater res p o n der rates t ha n place b o o ver 1 2 wee ks i n b ot h 
st u dies, a n d greater res p o n der rates t ha n place b o o ver 2 6 wee ks of treat me nt i n st u d y IB S 3 0 0 2, 
b ut n ot i n st u d y  IB S 3 0 0 1 ( Le m b o 2 0 1 6 , VI B E R ZI P I 2 0 17 ). T he treat me nt effect of el u xa d oli ne 
o ver place b o was o bser ve d wit hi n t he first wee k a n d was mai ntai ne d t hr o u g h o ut t he 2 6 -wee k 
assess me nt peri o d. 
Ot her a b d o mi nal s y m pt o ms a n d meas ures of b o wel f u ncti o n were als o si g nifica ntl y  i m pr o ve d 
wit h el u xa d oli ne treat me nt as c o m pare d wit h place b o. Lo n git u di nal a nal ys es de m o nstrate d t hat 
dail y  a b d o mi nal disc o mf ort sc ores were si g nifica ntl y l o wer t ha n place b o f or b ot h t he 7 5 m g a n d 
1 0 0 m g el u xa d oli ne gr o u ps t hr o u g h Wee k 2 6. Dail y  bl oati n g sc ores were si gnifica ntl y  l o wer 
t ha n place b o wit h el u xa d oli ne 1 0 0 m g after Wee k 1 2 ( Wee ks 1 6, 2 0, 2 4, a n d 2 6). Ris ks f or 
fre q ue nc y of b o wel m o ve me nts a n d ur ge nc y e pis o des were als o si g nifica ntl y l o wer t ha n place b o 
f or b ot h el u xa d oli ne d oses t hr o u g h Wee k 2 6 of treat me nt. A d diti o nall y , b ot h d oses of 
el u xa d oli ne were si g nifica ntl y s u peri or t o place b o wit h res pect t o t he e n d p oi nts of a de q uate 
relief of I B S sy m pt o ms, sc ores f or gl o bal s y m pt o ms, a n d sc ores o n t he I B S -Q ualit y  of Life 
q uesti o n naire. El u xa d oli ne was si g nifica ntl y s u peri or t o place b o i n all s u b p o p ulati o ns e x pl ore d 
(Le m b o 2 0 1 6 ).
I n cli nical st u dies, el u xa d oli ne ha d a fa v ora ble t olera bilit y pr ofile wit h l o w rates of 
pre d o mi na ntl y  GI A Es. T he m ost c o m m o nl y re p orte d A Es were c o nsti pati o n, nausea, a n d 
a b d o mi nal pai n. A p pr o xi matel y 5 0 % of c o nsti pati o n e ve nts occ urre d wit hi n t he first 2 wee ks of 
treat me nt, wit h m ost cases bei n g of mil d t o m o derate i nte nsit y . 
I nfre q ue nt, me dically i m p orta nt ris ks re p orte d wit h el u xa d oli ne i n cli nical st u dies wer e ( 1) mil d 
tra nsie nt pa ncreatitis or ra pi dl y re versi ble ele vati o n of tra nsa mi nases ass ociate d wit h a b d o mi nal 
pai n, b ot h c o nsiste nt wit h s p hi ncter of O d di ( S O) s pas m or biliar y sl u d ge, a n d ( 2) pa ncreatitis 
ass ociate d wit h hea v y alc o h ol c o ns u m pti o n. S o me of t hese e ve nts le d t o brief h os pitalizati o ns, 
b ut all ha d fa v ora ble o utc o mes wit h n o se q uelae. T here were 1 3 cases t hat were a dj u dicate d as 
S O s pas m wit h a n o verall occ urre nce rate of 0. 5 8 %. C h olec y stec t o my stat us was k n o w n i n 1 2 of 
t he 1 3 patie nts, a n d all 1 2 patie nts w here stat us was k n o w n ha d n o gall bla d der. I n t he 
p ost mar keti n g setti n g, se vere cases of ac ute pa ncreatitis, s o meti mes fatal, were o bser ve d 
f oll o wi n g t he use of el u xa d oli ne i n patie nts wit h o ut a gall bla d der. Beca use of t his, use of 
el u xa d oli ne i n patie nts wit h o ut a gall bla d der is c o ntrai n dicate d. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of el u xa d oli ne ma y  be f o u n d i n t he In vesti gat or’s B r oc h ure (I B) a n d/ or pac ka ge 
i nsert.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
1 9
4. 
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
Pri mar y
 
T o e val uate t he efficac y of el u xa d oli ne 1 0 0 m g 
BI D i n I B S -D partici pa nt s wit h e vi de nce of B A M 
c o m pare d t o I B S-D partici pa nt s wit h o ut e vi de nce 
of B A M
 
C ha n ge fr o m baseli ne i n a vera ge B S F S sc ore o ver 
4 we e ks of treat me nt peri o d
 
T o e val uate t he safet y a n d t olera bilit y of 
el u xa d oli ne 1 0 0 m g BI D i n I B S -D partici pa nt s 
wit h e vi de nce of B A M a n d i n I B S -D partici pa nt s 
wit h o ut e vi de nce of B A M
 
E val uati o n of a d verse e ve nts, cli nical la b orat or y 
tests, vital si g ns, p h ysical e xa mi nati o ns
Sec o n dar y
 
T o f urt her e val uate t he efficac y of el u xa d oli ne 
1 0 0 m g BI D i n I B S -D partici pa nts wit h e vi de nce of 
B A M c o m pare d t o I B S -D partici pa nts wit h o ut 
e vi de nce of B A M
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of dail y 
b o w el m o ve me nt fre q ue nc y d uri n g t he treat me nt 
peri o d
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of dail y 
w orst a b d o mi nal pai n sc ores d uri n g t he treat me nt 
peri o d
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of dail y 
bl oati n g d uri n g t he treat me nt peri o d
 
C ha n ge fr o m baseli ne i n t he 4 -wee k a vera ge of 
n u m ber of dail y ur ge nt b o w el m o ve me nts d uri n g t he 
treat me nt peri o d
 
T he pr o p orti o n of partici pa nt s wit h a n y fecal 
i nc o nti ne nce d uri n g t he treat me nt peri o d
 
C ha n ge fr o m baseli ne i n I B S -Q O L sc ore at t he e n d 
of t he treat me nt pe ri o d
 
C ha n ge fr o m baseli ne i n ser u m 7 α C 4 le vels at t he 
e n d of t he treat me nt peri o d
 
T o e val uate t he p o p ulati o n P K of el u xa d oli ne i n 
I B S-D patie nts wit h a n d wit h o ut e vi de nce of B A M.
 
P o p ulati o n p har mac o ki netic para meters of 
el u xa d oli ne deter mi ne d fr o m plas ma c o nce ntrati o n 
data e xtra p olate d fr o m drie d bl o o d sa m ple a nal ysis
7 α C 4 = 7a -h y dr o x y - 4-c h oleste n- 3-o ne; B A M = bile aci d mala bs or pti o n; BI D = t w ice dail y; B S F S = Brist ol St o ol 
F or m  Scale; I B S-D = irrita ble b o w el s y n dr o me wit h diarr hea; I B S-Q O L = irrit a ble b o wel s y n dr o me -q ualit y of 
life; P K = p har mac o ki netics
Cli nic al H y p ot heses
T he p ote ntial i ncl usi o n of partici pa nt s wit h e vi de nce of B A M i n t he el u xa d oli ne P hase 3 st u dies
of I B S -D c o ul d ha ve le d t o a n u n deresti mati o n of el u xa d oli ne’s effects o n I B S -D, es peciall y if 
t he partici pa nt s’ B A M re prese nte d t he pri mar y ca use of t heir diarr heal sy m pt o ms. H o we ver, 
gi ve n its mec ha nis m of acti o n as a mi xe d μ O R/ κ O R a g o nist a n d δ O R a nta g o nist, el u xa d oli ne 
s h o ul d res ult i n re d uce d i ntesti nal m otilit y a n d secreti o ns irres pecti ve of a n y u n derl yi n g eti ol o g y 
(s uc h as u na bs or be d l u mi nal bile aci ds d ue t o B A M). It is t heref ore h yp ot hesize d t hat 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 0
el u xa d oli ne will ha ve si milar p har mac o d y n a mic effect s t o i ncrease st o ol c o nsiste nc y i n I B S-D 
partici pa nts wit h a n d wit h o ut e vi de nce of B A M. 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 1
5. 
St u d y Desi g n
5. 1. 
O ver all Desi g n
T his is a P hase 4, o pe n -la bel, parallel-gr o u p, c o h ort c o ntr olle d st u d y t o e val uate t he efficac y, 
safety, t olera bility a n d p har mac o ki net ics of el u xa d oli ne i n partici pa nt s meeti n g t he R o me I V 
criteria f or I B S-D wit h a n d wit h o ut e vi de nce of B A M. T hi s st u d y will be c o m prise d of a 
0 t o 2- wee k scree ni n g peri o d, a 2 t o 3- wee k pretreat me nt peri o d, a 4 -wee k o pe n -la bel treat me nt 
peri o d d uri n g w hic h ti me partici pa nt s will recei ve el u xa d oli ne 1 0 0 m g BI D, a n d a 2 -wee k 
p ost -treat me nt safet y f oll o w-u p. 
T here will be 2 4 partici pa nt s e nr olle d i n t he st u d y, 1 2 wit h e vi de nce of B A M a n d 1 2 wit h o ut
e vi de nce of B A M. 

C o h ort 1: I B S -D partici pa nt s wit h e vi de nce of B A M treate d wit h el u xa d oli ne 1 0 0 m g oral 
ta blets BI D wit h f o o d

C o h ort 2: I B S -D partici pa nt s wit h o ut e vi de nce of B A M treate d wit h el u xa d oli ne 1 0 0 m g 
oral ta blets BI D wit h f o o d
As far as p ossi ble, t he 2 c o h orts will be matc he d b y  a ge, ge n der a n d se verit y of hist oric 
s ym pt o ms base d o n t he i n vesti gat or's discreti o n. E val uati o n of I B S -D s y m pt o ms d uri n g t he 
pretreat me nt peri o d will esta blis h t he baseli ne of I B S -D se verit y  a n d will c o nti n ue f or t he 
d urati o n of t he st u d y. Meas ure me nts of st o ol c o nsiste nc y sc ores a n d ot her I B S-D si g ns a n d 
s ym pt o ms will be meas ure d dail y usi n g a n electr o nic diar y (e Diar y).
After scree ni n g pr oce d ures ha ve bee n perf or me d ( u p t o 2 wee ks), eli gi ble partici pa nt s will enter 
a p retreat me nt peri o d of 2 t o 3 wee ks. At t he be gi n ni n g of t he p retreat me nt peri o d partici pa nt s 
will recei ve i nstr ucti o ns f or c o m pleti n g t he e Diar y t o c ollect dail y i nf or mati o n relate d t o t heir 
I B S-D s y m pt o ms i ncl u di n g st o ol c o nsiste nc y  (B S F S ), w orst a b d o mi nal pai n, a b d o mi nal 
bl oati n g, b o wel m o ve me nt fre q ue nc y , resc ue me dicati o n usa ge, n u m ber of e pis o des of ur ge nc y  
i n a da y, a n d n u m ber of e pis o des of fecal i nc o nti ne nce , if a n y. At t he c o ncl usi o n of t he 
pretreat me nt peri o d, partici pa nt s w h o meet t he st ud y  e ntry criteria relate d t o st o ol c o nsiste nc y , 
e Diar y c o m plia nce, a n d resc ue l o pera mi de use will be e nr olle d t o recei ve a 4-wee k o pe n -la bel 
el u xa d oli ne 1 0 0 m g BI D treat me nt.
Partici pa nt s e nr olle d i n t he t reat me nt p eri o d will ret ur n t o t he st u d y site f or st u d y visits at 
Wee k
2, Wee k
4 (e n d -of -treat me nt st u d y visit), a n d f or a p ost-treat me nt f oll o w-u p st u d y  visit at 
Wee k
6. Tele p h o ne c o ntacts ma y  be ma de t o partici pa nt s i n lie u of a n o n-site visit at Wee k 2. A 
c o m plete sc he d ule of acti vities ( S o A) is pr o vi de d i n Secti o n 2 . Partici pa nt s w h o disc o nti n ue 
fr o m t he st u d y bef ore t he Wee k 4 visit s h o ul d ret ur n t o t he st u d y  site t o c o m plete t he early 
ter mi nati o n assess me nts as s o o n as p ossi ble after st o p pi n g t he st u d y dr u g.
D uri n g t he o pe n -la bel treat me nt peri o d, partici pa nts will rec or d via t he e Diar y  t heir dail y I B S-D 
s ym pt o ms i ncl u di n g st o ol c o nsiste nc y ( B S F S), w orst a b d o mi nal pai n, a b d o mi nal bl oa ti n g, b o wel 
m o ve me nt fre q ue nc y , resc ue me dicati o n usa ge, n u m ber of e piso des of ur ge nc y  i n a da y, a n d 
n u m ber of e pis o des of fecal i nc o nti ne nce, if a ny.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 2
T he act ual e Diar y  data e ntere d by t he partici pa nt s will n ot be pr o vi de d t o t he i n vesti gati ve site 
staff at a ny ti me d uri n g t he st u d y t o pre ve nt a n y p ote ntial bias i n s u bse q ue nt partici pa nt e ntries. 
H o we ver, peri o dic n otificati o ns will be ge nerate d t o i nf or m t he i n vesti gat or of partici pa nt s’
o n g oi n g c o m plia nce wit h e Diar y  e ntries a n d t o alert i n vesti gat ors if partici pa nt s ha ve 
e x perie nce d e pis o des of c o nsti pati o n or ha ve re q uire d e xcessi ve l o pera mi de resc ue me dicati o n 
f or ac ute treat me nt of u nc o ntr olle d diarr hea.
T he t otal d urati o n of t he st u d y  is u p t o 1 1 wee ks, w hic h i ncl u des: scree ni n g peri o d (0 - 2 wee ks), 
pr etreat me nt peri o d ( 2 -3 wee ks), 4 -wee k o pe n -la bel treat me nt peri o d, a n d 2-wee k p ost -treat me nt 
f oll o w-u p peri o d. A t otal of 6 st u d y visits are pla n ne d f or eac h partici pa nt :
 
Scree ni n g, Wee k -3 t o - 5 ( Visit 1) pri or t o Baseli ne visit
 
Pretreat me nt, Wee k -3 t o -2 ( Visit 2) pri or t o Baseli ne visit
 
Da y  1 ( Visit 3; first a d mi nistrati o n of st u d y dr u g)
 
Wee k 2 ( Visit 4;
Wee k 2 of treat me nt), ma y  be d o ne b y tele p h o ne
 
Wee k 4 ( Visit 5;
en d of treat me nt/earl y  ter mi nati o n)
 
Wee k 6 ( Visit 6; p ost -treat me nt f oll o w-u p) 
T he st u d y  desi g n is prese nte d i n Ta ble 5 – 1 .
T a ble 5 – 1 
St u d y Desi g n
Peri o d 
Scree ni n g a
Pretre at m e nt a
O pe n -L a bel Tre at me nt
P ost -Tre at m e nt
D ur ati o n
0- 2 w ee ks 
2- 3 w ee ks
4 w ee ks
2 w ee ks
Wee k
Scree ni n g 
Pretreat me nt 
Baseli ne 
Wee k 2
b
Wee k 4
( E O T/ E T)
Wee k 6
b
( F oll o w-u p)
St u d y 
Visit 
1
2
3
4
5
6
St u d y D a y
1 
1 5 ( ± 2) 
2 9 ( ± 2) 
Visit 5 + 1 4 da ys
(± 7 )
7 α C 4 = 7a -h y dr o x y - 4-c h oleste n- 3-o ne ; B A = bile aci d
a
Scree ni n g a n d pretreat me nt peri o ds ma y be c o mbi ne d if res ults of fasti n g ser u m 7 α C 4 test or 4 8 -h o ur fecal B A 
c ollecti o n c o n d ucte d wit hi n 1 cale n dar year fr o m scree ni n g are a vaila ble at t he ti me of t he c o m bi ne d visit or 
res ults fr o m fasti n g ser u m 7 α C 4 test are a vaila ble pri or t o t he start of st u d y treat me nt.
b
M a y  be d o ne o ver t he p h o ne.
5. 2. 
P artici p a nt a n d St u d y C o m pleti o n
A ma xi m u m of 2 4 partici pa nt s, 1 2 partici pa nt s wit h e vi de nce of B A M a n d 1 2 partici pa nt s 
wit h o ut e vi de nce of B A M will recei ve st u d y treat me nt s uc h t hat a p pr o xi matel y 2 4 e val ua ble 
partici pa nt s c o m plete t he st u d y.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 3
5. 3. 
E n d of St u d y Defi niti o n
T he e n d of t he st u d y is defi ne d as t he date of Visit 6 ( p ost -treat me nt f oll o w-u p visit).
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all peri o d s of t he 
st u d y i ncl u di n g post -treat me nt f oll o w-u p visit.
5. 4. 
Scie ntific R ati o n ale f or St u d y Desi g n
T his is a n o pe n -la bel, c o h ort c o ntr olle d st u d y desi g ne d t o e val uate t he c o m parati ve effects of 
el u xa d oli ne o n t he altere d b o wel f u ncti o n i n I B S -D partici pa nts wit h a n d wit h o ut e vi de nce of 
B A M. T his n o n -ra n d o mize d desi g n is c o nsi dere d m ost a p pr o priate si nce t he c o h ort assi g n me nt 
will be base d o n t he deter mi nati o n of B A M stat us.
A pri mar y  fact or i n t he desi g n of t his st u dy is t he mec ha nis m b y w hic h e vi de nce of B A M will be 
esta blis he d a n d d oc u me nte d i n t he patie nt p o p ulati o n. B ot h t he R o me I V criteria a n d E M A 
g ui deli ne f or I B S s u g gest t hat t he res ults fr o m a t hera pe utic st u d y wit h a bile aci d bi n di n g a ge nt 
ca n be a n a p pr o priate s urr o gate gi ve n t hat t hese a ge nts ha v e bee n s h o w n t o i m pr o ve st o ol 
passa ge a n d st o ol c o nsiste nc y  i n patie nts wit h B A M (W o n g 2 0 1 2 ; Baj or 2 0 1 5 ). W hile e m piric 
st u dies of se q uestra nts s uc h as c h olest yr a mi ne or c olese vela m ha ve t he a d va nta ge of bei n g 
cli nicall y a p plica ble, t he y pr o vi de o nl y i n direct e vi de nce of B A M si nce t hese a ge nts ca n ha ve 
n o ns pecific effects t o a meli orate diarr hea of ot her ca uses ( Ca milleri 2 0 1 5 ). A d diti o nall y, 
t hera pe utic st u dies of c h olest y ra mi ne are ha m pere d b y t olera bilit y a n d c o m plia nce iss ues o wi n g 
t o its p o or palata bilit y a n d p ote ntial si de effects, w hile st u dies of t he ne wer a ge nt c olese vela m 
are ha m pere d b y its e x pe nse ( Ca milleri 2 0 1 4 ).
M o st p ote ntiall y  direct dia g n ostic tests of B A M are li mite d i n t heir a vaila bilit y a n d/ or cli nical 
practicalit y. T he m ost defi niti ve test is t he meas ure me nt of fecal bile aci ds i n a 4 8 -h o ur st o ol 
c ollecti o n . Meas ure me nt of fecal bile aci ds is a direct meas ure
of e xcess bile aci ds e nteri n g t he 
c ol o n. Pri mar y  fecal bile aci ds [C he n o de o x yc h olic aci d ( C D C A) a n d c h olic aci d ( C A)] are 
si g nifica ntly hi g her i n patie nts wit h B A M a n d c orrelate wit h st o ol fre q ue nc y a n d c o nsiste nc y
(S hi n 2 0 1 3 , W o n g 2 0 1 2 ). A p ote ntial alter nati ve, t he n uclear me dici ne Se H C A T test w hic h 
meas ures bile aci d rete nti o n is m ore cli nicall y practical b ut d oes re q uire 2 se parate cli nical visits 
t o deter mi ne Se H C A T rete nti o n after a wee k. W hile Se H C A T testi n g has bee n t he pri mar y  
meas ure b y w hic h t he o verla p of B A M a n d I B S-D has bee n i de ntifie d, it is n ot a p pr o ve d f or use 
i n t he U nite d States a n d is n ot wi del y a vaila ble i n t he rest of t he w orl d (Isla m 2 0 1 2 ). T otal fecal 
bile aci ds > 2 3 3 7 μ m ol/ 4 8 hr is t he g ol d sta n dar d f or B A M dia g n osis i n c o u ntries w here 
Se H C A T rete nti o n is n ot a vaila ble (S hi n 2 0 1 3 ).
T he t y pical pr o p orti o n of pri mar y  fecal bile aci ds i n healt h y v ol u nteers is ~ 0. 2 %. Patie nts wit h 
B A M ha ve hi g her st o ol wei g ht c o m pare d t o t h ose wi t h c hr o nic diarr hea wit h o ut B A M or healt hy 
v ol u nteers ( Vija y var gi ya 2 0 1 8 ). T he se nsiti vit y  a n d s pecificity of t he fecal bi o mar kers of B A M
are liste d i n Ta ble 5- 2 . T heref ore, ele vate d pri mar y  B A al o ne or i n c o m bi nati o n wit h t otal fecal 
bile aci ds of ≥1 0 0 0 μ m ol/ 4 8 hr ha ve a si milar dia g n ostic acc urac y  as t otal fecal B A al o ne of
> 2 3 3 7 μ m ol/ 4 8 hr i n det ecti n g ele vate d f ecal wei g ht i n patie nts wit h B A M . Statistical a nal y sis 
has de m o nstrate d n o si g nifica nt differe nce bet wee n t he R O C c ur ve t o esti mate ele vate d fecal 
wei g ht f or eit her t otal B A or ele vate d pri mar y fecal B A ( p = 0. 1 3). After i ncreasi n g t he pri ma r y 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 4
B A c ut off t o 1 0 % or hi g her wit h t otal fecal B A ≥1 0 0 0 µ m ol/ 4 8 hr , t here was n o si g nifica nt gai n 
i n eit her se nsiti vit y ( 4 1 %) or s pecificit y ( 9 7 %) c o m pare d t o t he l o wer c ut off of pri mar y B A 
≥4 % wit h t otal fecal B A ≥1, 0 0 0 μ m ol/ 4 8 hr (Vija y var gi ya 2 0 1 8 ). 
T heref ore, e ve n at t he l o wer c ut off val ues of ≥4 %, pri mar y  fecal bile aci ds are i n dicati ve of B A D 
e ve n t h o u g h t he t otal fecal B A ma y be o nl y 1 0 0 0 μ m ol/ 4 8 hr. 
H o we ver, i n a n a nal y sis of 9 8 6 patie nts w ho u n der we nt 4 8 h o ur fecal B A e val uati o n f or c hr o nic 
diarr hea, 2 6 % of patie nts ha d ele vate d t otal fecal bile aci ds w hereas 4 6 % of patie nts ha d fecal 
pri mar y  bile aci ds ≥1 0 %, i n dicati n g t hat meas uri n g t otal fecal bile aci ds al o ne will miss a 
s u b gr o u p of patie nts w h o ha ve feat ures of B A M ( Vija y var gi ya 2 0 1 8) .
E vi de nce has s u g geste d t hat meas ure me nt of ser u m 7 α- h y dr o x y- 4- c h oleste n - 3-o ne ( 7 αC 4 test) 
ma y als o be a n effecti ve i n dicat or of B A M. Ser u m 7 α C 4 is a s urr o gate f or he patic B A sy nt hesis 
rate a n d has bee n dem o nstrate d t o be ele vate d i n patie nts wit h B A M ( E us ufzai 1 9 9 3 ) a n d i n 
s o me patie nts wit h I B S-D ( O d u nsi -S hi y a n ba de 2 0 1 0 ; W o n g 2 0 1 2 ). T he use of ser u m 7 α C 4 t o 
dia g n ose B A M has bee n vali date d a gai nst Se H C A T testi n g a n d was de m o nstrate d t o ha ve 
a p pr o xi matel y 9 0 % se nsiti vit y a n d 7 9 % s pecificit y (Sa uter 1 9 9 9 ). T he fasti n g ( 6 -1 0 a m) ser u m 
7 α C 4 test is c o nsi dere d m ost i deal beca use of its si m plicit y, as c ollecti o n of bl o o d f or 7 α C 4 
a nal ys is ca n occ ur as part of t he r o uti ne scree ni n g pr ocess f or t he st u d y. T he a nalys is of ser u m 
7 α C 4 le vels re q uires a li q ui d c hr o mat o gra p h y- ta n de m mass s pectr o metr y ( L C-M S/ M S) met h o d 
w hic h is c urre ntl y  a vaila ble (Ca milleri 2 0 0 9 ; Ca milleri 2 0 1 4a ). F urt her, ser u m 7 α C 4 was 
de m o nstrate d t o ha ve hi g h p ositi ve a n d ne gati ve pre dicti ve val ues ma ki n g it attracti ve as a 
dia g n ostic test of B A M. T heref o re, in t his st u d y , B A M stat us will be deter mi ne d b y t he prese nce 
of at least o ne of t he para meters liste d i n Ta ble 5- 2 . 
T he sa m ple size is base d pri maril y o n cli nical c o nsi derati o ns, i ncl u di n g t he desire t o mi ni mize 
t he n u m ber of p ote ntial cli nical sites gi ve n t he p ossi ble nee d t o utilize a researc h la b orat or y f or 
a nal ys is of scree ni n g ser u m 7 α C 4 sa m ples. W hile n ot statisticall y p o were d, t he st u d y sa m ple is 
c o nsi dere d s ufficie nt t o c haracterize t he effects of el u xa d oli ne o n t he altere d b o wel f u ncti o n of 
I B S-D patie nts wit h B A M a n d t o q ualitati vel y  e val uate w het her t hese patie nts res p o n d 
differe ntl y t o el u xa d oli ne treat me nt.
T he d urati o n of treat me nt was c h ose n t o be c o nsiste nt wit h cli nic al practice i n I B S, w here a 
1- m o nt h t hera pe utic st u d y of a ne w a ge nt is c o m m o n a n d is s u p p orte d b y  res ults of t he P hase 3 
st u dies w hic h s h o we d t hat a patie nt’s res p o nse t o el u xa d oli ne treat me nt o ver t he first m o nt h is 
reas o na bly pre dicti ve of res p o nsi ve ness o ver l o n ger d urati o ns. T he p ost -treat me nt peri o d is 
i nte n de d t o all o w f or a n off-treat me nt assess me nt of safety.
T he st u d y  will e nr oll a n I B S-D p o p ulati o n si milar t o t hat e nr olle d i n t he P hase 3 st u dies of 
el u xa d oli ne. Partici pa nt s will meet t he R o me I V criteria f or I B S -D, w hic h differs fr o m t he 
R o me III criteria use d i n t he P hase 3 st u dies pri maril y  i n eli mi nati n g a b d o mi nal disc o mf ort as a 
disti nct e ntit y  fr o m a b d o mi nal pai n i n t he defi niti o n of I B S -D ( Lac y  2 0 1 6). E vi de nce of B A M 
will be deter mi ne d b y a scree ni n g ser u m 7 α C 4 val ue ≥5 2. 5 n g/ m L, w hic h has pre vi o usl y bee n 
utilize d as a dia g n ostic c ut off f or B A M base d o n t his val ue bei n g greater t ha n t he 9 5 t h perce ntile 
of ser u m 7 α C 4 val ues fr o m 1 8 4 healt h y  c o ntr ols (Vija y var gi ya 2 0 1 7 ). 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 5
I n or der t o ha ve c o m para ble treat me nt gr o u ps, t he c o h orts will be matc he d t o t he hi g hest e xte nt 
p ossi ble b y  a ge, ge n der a n d se verity of hist oric s y m pt o ms base d o n t he i n vesti gat or's discreti o n.
I m pr o ve me nts i n b o wel s y m pt o ms will be meas ure d d uri n g t he st u d y. St o ol c o nsiste nc y is a 
hi g hl y se nsiti ve efficac y mar ker, ma ki n g it i deally s uita ble t o detect p ote ntial differe nces i n 
res p o nsi ve ness t o treat me nt a m o n g partici pa nt s wit h a n d wit h o ut e vi de nce of B A M. T he pri mar y 
o utc o me meas ure f or t his st u d y  will t heref ore be c ha n ges fr o m baseli ne i n st o ol c o nsiste nc y 
sc ores o ver t he 4-wee k treat me nt peri o d. C ha n ges fr o m baseli ne are c o nsi dere d m ore a p pr o priate 
t ha n m o nt hl y  res p o n der defi niti o ns gi ve n t he s mall pil ot nat ure of t his st u d y. 
T a ble 5- 2 
C urre nt a n d f ut ure a n d bile aci d di arr he a ( B A D) di a g n ostic tests 
Di a g n ostic 
Test 
F asti n g 
ser u m C 4 
T ot al fec al B A 
Pri m ar y B A > 4 % + t ot al 
fec al B A  
Fec al pri m ar y B A > 1 0 % 
W h at d oes it 
me as ure
He patic bile 
aci d s y nt hesis
T otal fecal bile 
aci d e xcrete d 
fr o m t he c ol o n
A m o u nt of bile aci ds wit h 
secret or y p ote ntial wit h t otal 
fecal B A e xcreti o n
A m o u nt of bile aci ds t hat 
are directl y s y nt hesize d 
fr o m t he li ver wit h 
secret or y p ote ntial
Di a g n ostic 
C ut offs 
> 5 2. 5 n g/ m L 
> 2, 3 3 7 
μ m ol/ 4 8 h
Pri mar y B A ≥4 % + t otal 
fecal B A ≥1, 0 0 0 μ m ol/ 4 8 h
≥1 0 % Pri mar y B A
Se nsiti vit y 
rel ati ve t o 
fec al wei g ht 
> 4 0 0 g/ 4 8 h
1 5 %
5 9 %
4 6 %
4 9 %
S pecificit y 
rel ati ve t o 
fec al wei g ht 
> 4 0 0 g/ 4 8 h
8 6 %
9 2 %
9 7 %
9 1 %
S o urce: Vija y var gi ya 2 0 1 8
5. 5. 
J ustific ati o n f or D ose
T he 1 0 0 m g BI D d ose selecte d f or t his st u d y is c o nsiste nt wit h U S a n d gl o bal la beli n g f or 
el u xa d oli ne i n IB S -D. 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 6
6. 
St u d y P o p ul ati o n
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
6. 1. 
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:
1. 
A ge / Se x
1. 0 1 
Partici pa nt is a ma n or w o ma n a ge d 1 8 t o 7 5 ye ars, i ncl usi ve, at s cree ni n g.
2. 
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2. 0 2 
Partici pa n t has a dia g n osis of I B S wit h pre d o mi na nt diarr hea (I B S -D) defi n e d b y t he 
R o me I V criteria as > ¼ ( 2 5 %) of b o wel m o ve me nts wit h B S F S sc ore of 6 or 7 a n d 
< ¼ ( 2 5 %) of b o wel m o ve me nts wit h B S F S sc ore of 1 or 2.
2. 0 3 
Partici pa nt s wit h e vi de nce of B A M: Partici pa nt s m ust ha ve at least o ne of t he 
f oll o wi n g at scree ni n g or wit hi n 1 cale n dar year pri or t o scree ni n g.
 
fasti n g ser u m 7a -h y dr o x y - 4-c h oleste n- 3-o ne ( 7 α C 4) le vel ≥5 2. 5 n g/ m L
 
t otal fecal bile aci ds   > 2 3 3 7 micr o m oles/ 4 8 h o urs  
 
pri mar y  bile aci ds (fecal C A a n d C D C A) ≥1 0 % i n a 4 8 h fecal c ollecti o n
 
pri mar y  bile aci ds (fecal C A a n d C D C A) ≥4 % wit h t otal fecal bile aci d ≥ 
1, 0 0 0 micr o m oles/ 4 8 hr  

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 7
2. 0 4 
Partici pa nt s wit h o ut B A M: Partici pa nt s m ust ha ve at least o ne of t he f oll o wi n g at 
scree ni n g or w it hi n 1 cale n dar year pri or t o s cree ni n g. 
 
fasti n g ser u m 7 α C 4 le vel ≤ 4 7. 1  n g/ m L 
 
fasti n g ser u m 7 α C 4 le vels > 4 7. 1 n g/ m L b ut < 5 2. 5 n g/ m L wit h  fecal bile 
aci ds t hat are ne gati ve f or bile aci d mala bs or pti o n (i.e. d o n ot meet criteria 
2. 0 3 base d o n fecal b ile aci ds le vel)    
 
t otal fecal bile aci ds ( B A) ≤2 3 3 7 micr o m oles/ 4 8 h o urs  
 
pri mar y  bile aci ds (fecal C A a n d C D C A) < 1 0 % i n a 4 8 h fecal c ollecti o n
 
pri mar y  bile aci ds (fecal C A a n d C D C A) < 4 % wit h t otal fecal bile aci d 
< 1, 0 0 0 micr o m oles / 4 8 hr
2. 0 5 
Partici pa nt meets t he c ol o n osc o p y  re q uire me nts defi ne d i n A p pe n di x 1 0
Secti o n 1 2. 1 0 , w hic h are m o difie d fr o m t he S u m mar y  of t he U S-M ulti -S ociet y  Tas k 
F orce o n C ol orectal Ca ncer a n d ot her C ol o n osc o p y  Re q uire me nts
2. 0 6 
Partici pa nt has a n a vera ge dail y  B S F S sc ore ≥ 5. 0 or at l east 2 5 % of da ys of diar y 
e ntr y wit h a B S F S sc ore of 6 or 7 d uri n g t he 1 4 da y s pri or t o Da y 1 of st u d y 
treat me nt
3 . 
C o ntr ace pti ves
3. 0 1 
A se x uall y  acti ve w o ma n of c hil d beari n g p ote ntial ( W O C B P), as defi ne d i n 
A p pe n di x 5, Secti o n 1 2. 5 m ust a gree t o f oll o w t he c o ntrace pti ve g ui da nce gi ve n i n 
A p pe n di x 5, Secti o n 1 2. 5 fr o m t he date s he pr o vi de s i nf or me d c onse nt u ntil 
2 4 h o urs after her fi nal d ose of st u d y dr u g.
4 . 
I nf or me d C o nse nt
4 . 0 1 
Partici pa nt m ust si g n a n i nf or me d c o nse nt f or m (I C F) bef ore t he i nitiati o n of a n y 
st u d y-relate d pr oce d ures i n dicati n g t hat he or s he u n dersta n ds t he p ur p ose of a n d 
pr oce d ures re q uire d f or t he st u d y a n d is willi n g t o partici pate i n t he st u d y.
5 . 
Ot her
5 . 0 1 
Partici pa nt has c o m plete d t he e D iar y o n at least 1 0 of t he 1 4 da ys pri or t o Da y 1 of 
st u d y treat me nt.
5 . 0 2 
Partici pa nt has n ot use d l o pera mi de resc ue me dicati o n o n m ore t ha n 3 da y s i n t he 
1 4 da y s pri or t o Da y  1 of st u d y treat me nt (see Secti o n 7. 7. 3 ).

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 8
6. 2. 
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
1. 
Me dic al C o n diti o ns
1. 0 1 
Partici pa nt has a dia g n osis of I B S wit h a s u bt y pe of I B S wit h c o nsti pati o n , mi xe d I B S, or 
u ns u bt y pe d I B S b y t he R o me I V criteria.
1. 0 2 
Partici pa nt d oes n ot ha ve a gall bla d der.
1. 0 3 
Partici pa nt s wit h k n o w n or s us pecte d biliar y d uct o bstr ucti o n, or s p hi ncter of O d di 
disease or d ys f u ncti o n. Partici pa nt s wit h a hist or y of gallst o nes ma y be e nr olle d.
1. 0 4 
Partici pa nt has a hist or y  of alc o h olis m, alc o h ol a b use or alc o h ol a d dicti o n, or dri n ks 
m ore t h a n 3 alc o h olic be vera ges per da y.
1. 0 5 
Partici pa nt has a hist or y  of pa ncreatitis; str uct ural diseases of t he pa ncreas, i ncl u di n g 
k n o w n or s us pecte d pa ncreatic d uct o bstr ucti o n.
1. 0 9 
Partici pa nt has d oc u me nte d hist or y  of mil d, m o derate, or se vere he patic i m pair me nt 
acc or di n g t o C hil d -P u g h classificati o n.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
2 9
1. 1 0 
Partici pa nt has a hist or y  or c urre nt dia g n osis of i nfla m mat or y or i m m u ne- me diate d GI 
dis or ders i ncl u di n g i nfla m mat or y  b o wel disease (ie, Cr o h n’s disease, ulcerati ve c olitis, 
micr osc o pic c olitis).
1. 1 3 
Partici pa nt has celiac disease or a p ositi ve ser ol o gical test f or celiac disease, a n d t he 
c o n diti o n has n ot bee n r ule d o ut b y  e n d osc o pic bi o ps y.
1. 1 5 
Partici pa nt has a hist or y  of a micr o bi ol o gically d oc u me nte d (ie, st o ol c ult ure or me dical 
hist or y ) GI i nfecti o n wit hi n 3 m o nt hs pri or t o scree ni n g.
2. 
Pri or/ C o nc o mit a nt T her a p y
2. 0 1 
Partici pa nt use d a pr ot oc ol -s pecifie d pr o hi bite d me dicati o n or faile d t o meet t he sta ble -
d ose re q uire me nts of certai n me dicati o ns (see Secti o n 7. 7. 1 )
2. 0 2 
Partici pa nt has pre vi o usl y  recei ve d el u xa d oli ne.
4 . 
Ot her
4 . 0 1
Fe male partici pa nt s w h o are c urre ntly pre g na nt or n ursi n g, or pla n t o bec o me pre g na nt or 
n urse d uri n g t he cli nical st u d y .

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3 0
4 . 0 2 
Partici pa nt has k n o w n aller gies or h y perse nsiti vit y t o o pi oi ds. Na usea a n d v o miti n g i n 
res p o nse t o o pi oi d treat me nt are n ot hy perse nsiti vit y reacti o ns. Partici pa nt s w h o ha ve ha d 
pri or mil d, o pi oi d -i n d uce d pr urit us i n t he a bse nce of de m o nstra ble aller gic der matitis, 
a n gi oe de ma, a n d lar yn geal e de ma are eli gi ble f or t he st u d y .
R ati o n ale f or I ncl usi o n a n d E xcl usi o n Criteri a
T he eli gi bilit y  criteria defi ne d i n t he pr ot oc ol are i nte n de d t o e ns ure e nr oll me nt of a n I B S-D 
partici pa nt p o p ulati o n c o nsiste nt wit h t he a p pr o ve d gl o bal la beli n g of el u xa d oli ne as well as 
all o wi n g f or t he selecti ve i ncl usi o n of partici pa nts wit h o verla p pi n g B A M base d o n sta n dar d 
dia g n ostic met h o d ol o g y . T he eli gi bilit y criteria a n d s pecific dia g n ostic scree ni n g pr oce d ures are 
i nte n de d t o e xcl u de ot her p ote ntial eti ol o gies of t he partici pa n t’s I B S-D s y m pt o ms a n d, 
c o nsiste nt wit h gl o bal la beli n g, t o e xcl u de p artici pa n ts w h o ma y be at i ncrease d ris k of 
e x perie nci n g certai n A Es ass ociate d wit h el u xa d oli ne, s uc h as c o nsti pati o n, S O s pas m, or 
pa ncreatitis. T he i ncl usi o n criteria relate d t o e Diar y e ntries are i nte n de d t o e ns ure partici pa nt s 
ha ve s ufficie nt baseli ne diar y  data a n d diarr heal sy m pt o ms of a s ufficie nt i nte nsit y t o detect a 
treat me nt differe nce wit h el u xa d oli ne.
6. 3. 
Lifest yle Restricti o ns
N o lifest y le restricti o ns are re q uire d.
6. 4. 
Scree n F ail ures
Scree n fail ures are defi ne d as partici pa nt s w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y  e ntere d i n t he st u d y t o recei ve st u d y treat me nt. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nt s t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o 
res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p hy, 
scree n fail ure details, eli gi bilit y criteria, a n d a ny seri o us a d verse e ve nt ( S A E).

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3 1
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ures) m a y  b e
rescree ne d.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3 2
7. 
Tre at me nt s
St u d y  treat me nt is defi ne d as a ny i n vesti gati o nal treat me nt(s), mar kete d pr o d uct(s), place b o, or 
me dical de vice (s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u d y 
pr ot oc ol.
7. 1. 
Tre at me nt s A d mi nistere d
T a ble 7 – 1
Tre at m e nts A d mi nistere d
St u d y Tre at me nt N a me
El u xa d oli ne
D os a ge F or m ul ati o n
fil m-c oate d ta blet
U nit D ose Stre n gt h(s)/ D os a ge Le vel(s)
1 0 0 m g BI D
R o ute of A d m i nistr ati o n
Oral
D osi n g I nstr ucti o ns
O ne ta blet t wice a da y t o be ta ke n wit h f o o d
M a n uf act urer
Aller ga n
7. 2. 
D ose M o dific ati o n
N o d ose m o dificati o n will be all o we d .
Retre at me nt Criteri a
N o retreat me nt will be all o we d .
7. 3. 
Met h o d of Tre at me nt Assi g n me nt
T his is a n o pe n -label, parallel -gr o u p st u d y . El u xa d oli ne 1 0 0 m g BI D will be a d mi nistere d t o all 
partici pa nt s i n t he st u d y after t he y are q ualifie d base d o n meeti n g all eli gi bilit y criteria.
Partici pa nt s will be stratifie d i nt o 2 c o h orts: I B S -D partici pa nts wit h e vi de nce of B A M a n d 
I B S-D partici pa nt s wit h o ut e vi de nce of B A M. As far as p ossi ble, t he 2 c o h orts will be matc he d 
b y  a ge, ge n der a n d se verit y of hist oric s y m pt o ms base d o n t he i n vesti gat or's discreti o n. St u d y  
partici pa nts w h o ha ve disc o nti n ue d t he st u d y ma y n ot be re place d.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3 3
7. 4. 
Bli n di n g/ M as ki n g
O pe n -l a bel, N o 
Bli n di n g at Site Le vel
T his is a n o pe n -la bel st u d y; p ote ntial bias will be re d uce d b y t he f oll o wi n g ste ps: 
matc hi n g n o n -B A M partici pa nt s t o B A M partici pa nts b y  eli gi bilit y criteria f ulfilled 
d uri n g baseli ne peri o d
7. 5. 
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
T he i n vesti gat o r or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y treat me nt recei ve d a n d a n y discre pa ncies are re p orte d a n d 
res ol ve d bef ore use of t he st u d y treat me nt.
1.
O nl y  partici pa nt s e nr olle d i n t he st u d y may recei ve st u d y treat me nt , a n d o nl y a ut h orize d site 
staff ma y s u p ply or a d mi nister st u d y treat me nt.
7. 6. 
Tre at me nt C o m pli a nce
Treat me nt c o m plia nce will be assesse d at t he st u d y site b y pill c o u nts. T his re vie w will be 
d oc u me nte d i n t he s o urce d oc u me nts.
7. 7. 
C o nc o mit a nt T her a p y
All prescri pti o n dr u gs, her bal pr o d ucts, vita mi ns, mi nerals, a n d o ver -t he-c o u nter me dicati o ns 
ta ke n wit h i n 3 0 d a y s pri or t o t he o pe n-la bel treat me nt peri o d will be rec or de d as pri or 
me dicati o ns. It will als o be deter mi ne d w hic h pri or me dicati o ns were prescri be d or ta ke n 
o ver -t he-c o u nter b y p artici pa nts f or t he treat me nt of I B S -D. 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
3 4
All me dicati o ns ta ke n after be gi n ni n g o pe n -la bel treat me nt a n d t hr o u g h t he early ter mi nati o n or 
f oll o w-u p visit will be rec or de d as c o nc o mita nt t hera p y. T he u se of all pri or a n d c o nc o mita nt 
me dicati o ns is t o be rec or de d o n t he partici pa nt ’s electr o nic case re p ort f or m (e C R F) at eac h visit 
al o n g wit h t he reas o n t he me dicati o n wa s ta ke n. A n y c ha n ges i n c o nc o mita nt me dicati o ns will 
als o be rec or de d o n t he partici pa n t’s e C R F. T he mi ni m u m re q uire me nt is t hat dr u g na me a n d t he 
dates of a d mi nistrati o n are t o be rec or de d. 
A n y  c o nc o mita nt me dicati o n dee me d necessary f or t he welfare of t he partici pa nt d uri n g t he 
st u d y ma y be gi ve n at t he discreti o n of t he i n vesti gat or. H o we ver, it is t he res p o nsi bilit y of t he 
i n vesti gat or t o e ns ure t hat details re gar di n g t he me dicati o n are rec or de d i n full i n t he s o urce 
d oc u me nts as well as i n t he e C R F.
7. 7. 1. 
Pr o hi bite d Tre at me nts Bef ore a n d D uri n g t he St u d y
Partici pa nts m ust disc o nti n ue a n y of t he me dicati o ns liste d i n t he ta ble bel o w f or t he s pecifie d 
peri o d pri or t o Da y  1. T hese me dicati o ns are pr o hi bite d for t he d urati o n of t he st u d y . Ot her 
me dicati o ns bei n g use d at scree ni n g ma y  be c o nti n ue d.
7. 7. 2. 
Per mitte d Tre at me nts
A n y  me dicati o n or vacci ne (i ncl u di n g o ver-t he-c o u nter or prescri pti o n me dici nes, vita mi ns ,
a n d/ or her bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves 
d uri n g t he st u d y m ust be rec or de d al o n g wit h :

I n dicati o n

D ates of a d mi nistrati o n i ncl u di n g start a n d e n d dates

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y

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T hera p y c o nsi dere d necessar y f or t he partici pa nt’s welfare ma y  be gi ve n at t he discreti o n of t he 
i n vesti gat or. If t he per missi bilit y of a s pecific me dicati o n/treat me nt is i n q uesti o n, please c o ntact 
t he s p o ns or.
T he s p o ns or or desi g nee s h o ul d be c o ntacte d if t here are a ny q uesti o ns re gar di n g c o nc o mita nt or 
pri or t hera p y.
7. 7. 3. 
Resc ue Me dici ne
L o pera mi de h y dr oc hl ori de ma y  be use d as resc ue me dicati o n f or ac ute treat me nt of diarr hea
d uri n g t he pretreat me nt a n d o pe n -la bel treat me nt peri o ds. L o pera mi de resc ue me dicati o n use will 
be rec or de d b y t he partici pa nt i n t he e Diar y.

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7. 8. 
Tre at me nt a fter t he E n d of t he St u d y
N ot a p plica ble .

El u xa d oli ne
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8. 
Disc o nti n u ati o n/ Wit h dr a w al Criteri a
Pre mat ure disc o nti n uati o n of t he st u d y  will occ ur w he n a partici pa nt ceases partici pati o n i n t he 
st u d y, re gar dless of circ u msta nces, bef ore t he c o m pleti o n of t he st u d y visits a n d pr oce d ures.
N otificati o n of earl y  partici pa nt disc o nti n uati o n fr o m t he st u d y a n d t he reas o n f or st u d y 
disc o nti n uati o n will be se nt t o t he s p o ns or a n d will be clearl y d oc u me nte d o n t he e C R F.
Reas o ns f or pre mat ure disc o nti n uati o n fr o m t he st u d y treat me nt a n d/ or t he st u d y  ma y i ncl u de t he 
f oll o wi n g:
 
A d verse e ve nt
 
Deat h
 
Lac k of efficac y
 
L ost t o f oll o w -u p
 
N o n- c o m plia nce wit h st u d y dr u g
 
Ot her
 
P h y sicia n de cisi o n
 
Pre g na nc y
 
Pr ot oc ol de viati o n
 
Site ter mi nate d b y s p o ns or
 
Wit h dra wal b y  s u bject
W he n a partici pa nt
disc o nti n ues st u d y treat me nt, t he reas o n(s) f or treat me nt disc o nti n uati o n s hall 
be rec or de d b y t he i n vesti gat or o n t he rele va nt pa ge of t he e C R F. W he ne v er p ossi ble, all 
e nr olle d pa rtici pa nts w h o pre mat urely disc o nti n ue st u d y treat me nt will u n der g o al l E O T/ E T visit 
assess me nts.
It is vital t o o btai n f oll o w-u p data o n a n y p artici pa nt disc o nti n ui n g st u d y  treat me nt beca use of a n 
A E or S A E . I n e ver y case, eff orts m ust be ma de t o u n derta ke pr ot oc ol -s pecifie d safet y f oll o w-u p 
pr oce d ures u ntil res ol uti o n or sta bilizati o n.
8. 1. 
Disc o nti n u ati o n of St u d y Tre at me nt
Partici pa nts m ust pre mat urel y  disc o nti n ue st u d y treat me nt f or reas o ns of safet y i ncl u di n g: 
 
a n S A E c o nsi de re d b y t he i n vesti gat or or t he sp o ns or t o be p ossi bl y  relate d or relate d t o 
i n vesti gati o nal pr o d uct,
 
a n A E of s pe cial i nterest ( S O s pas m, pa ncreatitis, se vere c o nsti pati o n) see 
Secti o n 9. 2. 8. 1 ,
 
pre g na nc y , see Secti o n 9. 2. 7 ,

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 
si g ns of dr u g-i n d uce d li ver i nj ur y ( DI LI), see A p pe n di x 6, Secti o n 1 2. 6 .
Partici pa nt s ma y pre mat urel y  disc o nti n ue st u d y treat me nt f or reas o ns of safet y i ncl u di n g:
 
t he prese nce of i nte nti o nal o ver d ose or i nte nti o nal mis use per in vesti gat or discreti o n,
 
a n A E i n dicati ve of a ce ntral ner v o us s ys te m (C N S ) o pi oi d effect, e g, pi n p oi nt p u pils, 
l oss of c o nsci o us ness, deliri u m, se dati o n or s o m n ole nce, e u p h oric, a n xi o us or de presse d 
m o o d, t hat i n t he o pi ni o n of t he i n vesti gat or or t he sp o ns or is p ossi bl y  relate d or relate d 
t o t he i n vesti gati o nal pr o d uct,
 
a vital si g n, a n d/ or la b orat or y a b n or malit y j u d ge d t o be cli nicall y si g nifica nt b y t he 
in vesti gat or a n d t hat i n t he o pi n i o n of t he in vesti gat or or t he s p o ns or is p ossi bl y  relate d 
or relate d t o t he i n vesti gati o nal pr o d uct,
 
a n i nt olera ble A E ( defi ne d as a n A E t hat s u bjecti vel y w o ul d ca use a partici pa nt t o
c o nsi der st u d y wit h dra wal),
 
a n a bse nce of b o wel m o ve me nts f or ≥ 3 c o nsec uti ve da y s, see Secti o n 9. 2. 8. 1 , base d o n 
res p o nses rec or de d via e Diar y.
 
t he use of a n e xcessi ve a m o u nt of l o pera mi de resc ue me dicati o n see Secti o n 7. 7. 3 .
 
t he occ urre nce of a n y ot her A E t hat i n t he o pi n i o n of t he in vesti gat or or t he s p o ns or is 
p ossi bl y  relate d or relate d t o t he st u d y treat me nt t hat re prese nts a cli nically si g ni fica nt 
safety ris k t o t he partici pa nt.
See t he sc he d ule of acti vities (Secti o n 2 ) f or data t o be c ollecte d at t he ti me of treat me nt 
disc o nti n uati o n a n d f oll o w -u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d .
8. 1. 1. 
Te m p or ar y Disc o nti n u ati o n
Te m p orar y  disc o nti n uati o ns are n ot all o we d.
8. 1. 2. 
Rec h alle n ge
Rec halle n ge is n ot all o we d .
8. 2. 
Wit h dr a w al fr o m t he St u d y
1.
A partici pa nt m a y  wit h dra w fr o m t he st u dy at a n y ti me at his/ her o w n re q uest, or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral,
c o m plia nce, or a d mi nistrati ve reas o ns .
2.
If t he partici pa nt wit h dra ws c o nse nt f or discl osure of f ut ure i nf or mati o n, t he s p o ns or ma y  
retai n a n d c o nti n ue t o use a ny data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt .
3.
If a partici pa nt wit h dra ws fr o m t he st u d y , he/s he ma y re q uest destr ucti o n of a ny sa m ples 
ta ke n a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he site st u d y  rec or ds.
4.
See t he S o A f or data t o be c ollecte d at t he ti me of st u d y disc o nti n uati o n a n d f oll o w -u p a n d 
f or a ny f urt her e val uati o ns t hat nee d t o be c o m plete d .

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8. 3. 
L ost t o F oll o w U p
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.

El u xa d oli ne
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9. 
St u d y Assess me nts a n d Pr oce d ures
 
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A.
 
Pr ot oc ol wai ver s or e xe m pti o ns are n ot all o we d.
 
I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y  u p o n 
occ urre nce or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
treat me nt.
 
A d here nce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A , is 
esse ntial a n d re q uire d f or st u d y c o n d uct.
 
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nt s meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble. 
 
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of t he I C F ma y  be utilize d f or scree ni n g or baseli ne 
p u r p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol-s pecifie d criteria a n d were perf or me d 
wit hi n t he ti me fra me defi ne d i n t he S o A .
Scree ni n g (Visit 1 )
Partici pa nt s will u n der g o a scree ni n g visit t o deter mi ne eli gi bilit y t o pr ocee d i n t he st u d y. T his 
visit ma y  be c o m bi ne d wit h t he p retreat me nt v isit if res ults fr o m a fasti n g ser u m 7 α C 4 test or 
4 8 -h o ur fecal B A c ollecti o n, c o n d ucte d wit hi n 1 cale n dar ye ar pri or t o scree ni n g, are a vaila ble at 
t he ti me of t he c o m bi ne d visit or res ults fr o m fasti n g se r u m 7 α C 4 test are a vaila ble pri or t o t he 
start of st u d y treat me nt. T he scree ni n g visit will occ ur a p pr o xi matel y 2 t o 3 wee ks bef ore t he 
first d ose of st u d y dr u g (if c o m bi ne d wit h pretreat me nt visit) a n d n o m ore t ha n 5 wee ks bef ore 
t he first d ose of st u dy d r u g, if t he partici pa nt re q uires a n a d diti o nal wee k f or eac h (scree ni n g a n d 
pretreat me nt pr oce d ures). 
Bef ore u n der g oi n g s cree ni n g pr oce d ures, all p ote ntial partici pa nt s will be i nf or me d of t heir 
pri vac y  ri g hts a n d will si g n a n I CF. Partici pa nt s will ha ve t he o p p ort u nit y t o ha ve a ny q uesti o ns 
a ns were d bef ore si g ni n g t he IC F. T he i n vesti gat or m ust a d dress all q uesti o ns raise d b y t he 
partici pa nt . T he i n vesti gat or will als o si g n t he I C F. After si g ni n g t he I C F, t he partici pa nt will 
u n der g o t he scree ni n g assess m e nts a n d pr oce d ures list e d i n t he S o A , i ncl u di n g fasti n g ser u m 
7 α C 4 testi n g (if necessar y) a n d cli nical la b orat or y testi n g (ser u m c he mistr y, he mat ol o g y), t o 
deter mi ne eli gi bilit y . T he i ncl usi o n a n d e xcl usi o n criteria re q uire me nts will be verifie d f or t he 
partici pa nt . Co nc o mita nt me dicati o n a n d me dical hist or y , i ncl u di n g hist or y s pecifically relate d t o 
I B S-D, vital si g ns a n d wei g ht will be rec or de d a n d a p h y sical e xa mi nati o n will be perf or me d. 
Hei g ht will be meas ure d o nl y  at scree ni n g. 

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A ser u m pre g na nc y  test will als o be perf or me d f or all w o me n u nless t he y are s ur gically sterile or 
t here is a d oc u me nte d hist or y of t heir p ost me n o pa usal stat us. If t he pre g na nc y test is p ositi ve, t he 
partici pa nt is n ot eli gi ble t o e nter t he st u dy. 
Eli gi ble partici pa nt s will be i nstr ucte d t o ret ur n t o t he st u d y site i n 1 t o 2 wee ks f or t he 
pre treat me nt visit.
Pretre at me nt ( Visit 2 )
T his visit ma y  be c o m bi ne d wit h t he scree ni n g visit if res ults fr o m a fasti n g ser u m 7 α C 4 test or 
4 8 -h o ur fecal B A c ollecti o n, c o n d ucte d wit hi n 1 cal e n dar ye ar pri or t o scree ni n g, are a vaila ble at 
t he ti me of t he c o m bi ne d visit or res ults fr o m fasti n g ser u m 7 α C 4 test are a vaila ble pri or t o t he 
start of st u d y treat me nt. After scree ni n g pr oce d ures ha ve bee n perf or me d, eli gi ble partici pa nt s 
will e nter t he pre treat me nt peri o d. Partici pa nt s will u n der g o t he p retreat me nt v isit a n d 
p r oce d ures liste d i n t he S o A. T he p retreat me nt v isit will occ ur a p pr o xi matel y 2 t o 3 wee ks 
bef o re t he first d ose of st u d y dr u g.
T he i ncl usi o n a n d e xcl usi o n criteria, me dical hist or y, c o nc o mita nt me dicati o ns, a n d A Es will be 
re vie we d, vital si g ns a n d wei g ht will be meas ure d a n d rec or de d. Partici pa nt s will recei ve 
i nstr ucti o ns o n t he use of resc ue l o pera mi de.
Partici pa nt s will be pr o vi de d wit h t he e Diar y  de vice a n d i nstr ucte d o n t he use of t he e Diar y
s yste m t o rec or d t heir I B S-D s y m pt o ms a n d i nf or mati o n relate d t o t heir b o wel f u ncti o ni n g (e g, 
b o wel m o ve me nt fre q ue nc y , ur ge nc y a n d e pis o des of i nc o nti ne nce) o n a dail y basis. 
A d diti o nall y, partici pa nt s will be i nstr ucte d t o rec or d i n t he e Diar y t heir use of l o pera mi de 
resc ue me dicati o n f or t he ac ute treat me nt of u nc o ntr olle d diarr hea.
Partici pa nt s will be eli gi ble f or partici pati o n i n t he st u d y t o recei ve a n o pe n-la bel st u d y treat me nt 
if t he y meet all 3 of t he f oll o wi n g re q uire me nts:
 
C o m plia nt i n c o m pleti n g t he e Diar y o n at least 1 0 of t he 1 4 da y s i m me diatel y pri or t o 
e nr oll me nt i nt o o pe n-la bel treat me nt peri o d of t he st u d y ; a n d
 
Ha ve a n a vera ge dail y  B S F S sc ore ≥ 5 . 0 or at least 2 5 % of d a y s of diar y e ntr y wit h a 
B S F S sc ore of 6 or 7 d uri n g t he 1 4 da y s pri or t o Da y 1 of st u d y treat me nt, a n d
 
T he use of resc ue me dicati o n o n n o m ore t ha n 3 da ys d uri n g t he 1 4 da ys pri or t o 
e nr oll me nt i n t he o pe n -la bel treat me nt peri o d as detaile d i n Secti o n 7. 7. 3 .

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B aseli ne
D ay 1 ( Visit 3)
O n Da y  1, partici pa nt s w h o were dee me d eli gi ble d uri n g t he pretreat me nt peri o d will be 
dis pe nse d st u d y  treat me nt (el u xa d oli ne 1 0 0 m g BI D).
O pe n -L a bel Tre at me nt Peri o d
D uri n g t he treat me nt peri o d, partici pa nt s will u n der g o t he assess me nts a n d pr oce d ures liste d i n 
t he S o A.

El u xa d oli ne
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4 3
Wee k 2 ( Visit 4)
Partici pa nt s will ret ur n t o t he st u d y site at Wee k 2 ( ± 2 da ys) of t he st u d y treat me nt. 
 
 
 
E n d -of -Tre at me nt/ E arly Ter mi n ati o n ( Visit 5)
Partici pa nt s will ret ur n t o t he st u d y site at Wee k 4 ( ± 2 da ys) after t he c o m pleti o n of t he 
treat me nt peri o d. 
 
 
 
 
 
 
P ost -tre at me nt (Visit 6)
T o e ns ure partici pa nt safet y, a ma n dat or y p ost-treat me nt visit will be perf or me d 1 4 da ys after t he 
last d ose of st u d y dr u g f or partici pa nts t hat c o m plete t he o pe n -la bel treat me nt peri o d. 
 
 
 
 
 
 
 
 
9. 1. 
Effic ac y Assess me nts
T he efficac y  of el u xa d oli ne will be base d o n e Diar y meas ures relate d t o i m pr o ve me nts i n I B S-D 
si g ns a n d sy m pt o ms. Partici pa nt s will be re q uire d t o access t he e Di ar y eac h e ve ni n g, prefera bl y 
at t he sa me ti me eac h da y, t o rec or d dail y I B S s y m pt o ms. At t he start of t he pre treat me nt peri o d, 
partici pa nt s will recei ve f ull trai ni n g i n t he use a n d c o m pleti o n of t he dail y e Diar y.

El u xa d oli ne
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9. 1. 1. 
D ail y I B S S y m pt o ms
Partici pa nts will rec or d t he f oll o wi n g I B S-D si g ns a n d s y m pt o ms d uri n g t heir dail y  e Diar y e ntr y 
d uri n g t he pretreat me nt peri o d a n d t hr o u g h o ut t he 4 wee ks of t he o pe n-la bel treat me nt peri o d:
 
St o ol C o nsiste nc y : P artici pa nt s will be as ke d t o use t he B S F S t o rate t heir st o ol 
c o nsiste nc y m ost re prese ntati ve of t he past 2 4 h o urs. T he partici pa nt -re p orte d B S F S is a 
1 t o 7 scale w here 1 c orres p o n ds t o a har d st o ol a n d 7 c orres p o n ds t o water y st o ol 
(A p pe n di x 1 1 , Secti o n 1 2. 1 1 ; O' D o n nell 1 9 8 8 ):
1 = Se parate har d l u m ps li ke n uts ( diffic ult t o pass)
2 = Sa usa ge s ha pe d b ut l u m p y
3 = L i ke a sa usa ge b ut wit h crac ks o n s urface
4 = L i ke a sa usa ge or s na ke, s m o ot h a n d s oft
5 = S oft bl o bs wit h clear -c ut e d ges ( passe d easil y)
6 = Fl uff y  pieces wit h ra g ge d e d ges, a m us hy st o ol
7 = Water y , n o s oli d pieces (e ntirely li q ui d) 
 
W orst A b d o mi nal Pai n: P artici pa nt s will be as ke d t o rate t heir w orst a b d o mi nal pai n i n 
t he past 2 4 h o urs. T he partici pa nt -re p orte d w orst a b d o mi nal pai n i n t he past 2 4 h o urs 
will be rec or de d o n a 0 t o 1 0 scale, w here 0 c orres p o n ds t o n o pai n a n d 1 0 c orres p o n ds 
t o w orst i ma gi na ble pai n.
 
A b d o mi nal Bl oati n g: P artici pa nt s will be as ke d t o rate t heir a b d o mi nal bl oati n g i n t he 
past 2 4 h o urs. T he partici pa nt -re p orte d w orst a b d o mi nal bl oati n g i n t he past 2 4 h o urs 
will be rec or de d o n a 0 t o 1 0 scale, w here 0 c orres p o n ds t o n o bl oati n g a n d 1 0 
c orres p o n ds t o w orst i ma gi na ble bl oat i n g.
 
Fre q ue nc y , Ur ge nc y a n d I nc o nti ne nce: P artici pa nt s will be as ke d t o rec ord t he n u m ber 
of b o wel m o ve me nts, n u m ber of ur ge nt b o wel m o ve me nts, a n d n u m ber of e pis o des of 
fecal i nc o nti ne nce, o ver t he past 2 4 h o urs.
9. 1. 2.  
Irrit a ble B o wel S y n dr o me -Q u alit y of Life Q uesti o n n aire
T he i m pact of I B S o n partici pa nts’ q ualit y  of life will be assesse d usi n g t he I B S- Q ualit y  of Life 
(I B S-Q o L) q uesti o n naire (Dr oss ma n 2 0 0 0 ; Patric k 1 9 9 8 ; A p pe n di x 1 2 , Secti o n 1 2. 1 2 ). T he 
I B S-Q o L q uesti o n naire will be c o m plete d b y  partici pa nts at t he st u d y site at Baseli ne ( Da y 1)
pri or t o t he a d mi nistrati o n of st u d y  dr u g, a n d Wee k 4 ( or E T visit). T he q uesti o n naire will be 
c o m plete d at t he be gi n ni n g of t he a p plica ble st u d y visits bef ore all ot her e val uati o ns, es pecially 
disc ussi o n of A Es or t he partici pa nt ’s me dical c o n diti o n. 

El u xa d oli ne
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4 5
9. 2. 
A d verse E ve nts
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 4 , Secti o n 1 2. 4 .
A E s will be re p orte d by t he partici pa nt ( or, w he n a p pr o priate, by a care gi ver, s urr o gate, or t he 
partici pa nt’ s le gally a ut h orize d re prese ntati ve).
T he i n vesti gat or a n d a ny desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g
e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g u p A Es
t hat are seri o us, c o nsi dere d relate d t o t he st u dy treat me nt or st u d y pr oce d ures , or t hat ca use d t he 
partici pa nt t o disc o nti n ue t he st u d y (see Secti o n 8 ). 
9. 2. 1. 
Ti me P eri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E Inf or m ati o n
All A E s/ S A Es fr o m t he start of treat me nt u ntil t he f oll o w-u p visit will be c ollecte d at t he 
ti mep oi nts s pecifie d i n t he S o A (Secti o n 2 ), a n d as o bser ve d or re p orte d s p o nta ne o usl y by st u d y 
partici pa nts . A n y cli nicall y si g nifica nt a b n or malities persisti n g at t he e n d of t he st u d y will be 
f oll o we d u ntil t he A E has res ol ve d.
Me di cal occ urre nces t hat be gi n bef ore t he start of st u d y treat me nt b ut after o btai ni n g i nf or me d 
c o nse nt will be rec or de d o n t he Me dical Hist or y / C urre nt Me dical C o n diti o ns secti o n of t he 
eC R F , n ot t he A E secti o n.
All S A E s will be rec or de d a n d re p orte d t o t he sp o ns or or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x 4, Secti o n 1 2. 4 . T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o t he sp o ns or
wit hi n 2 4 h o urs of it bei n g a vaila ble.
I n vesti gat ors are n ot o bli gate d t o acti vely see k A E or S A E i nf or mati o n i n f or mer st u dy 
partici pa nt s. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after 
a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y 
relate d t o t he st u dy treat me nt or st u d y par tici pati o n, t he i n vesti gat or m ust pr o m ptl y n otif y t he 
sp o ns or .
T he met h o d of rec or di n g, e val uati n g , a n d assessi n g ca usalit y of A Es a n d S A E s a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 4 , 
Secti o n 1 2. 4 .
9. 2. 2.   
Met h o d of Detecti n g A E s a n d S A E s
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A E s a n d/ or S A Es. O pe n-e n de d a n d 
n o n -lea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nce s.

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9. 2. 3. 
F oll o w -u p of A E s a n d S A E s
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All A Es/ S A E s a n d n o n -seri o us A Es of s pecial i nterest (as defi ne d 
i n Secti o n 9. 2. 8 ) will be f oll o we d u ntil res ol uti o n, sta biliz ati o n, u ntil t he e ve nt is ot her wise
e x plai ne d, or t he partici pa nt is l ost t o f oll o w - u p (as defi ne d i n Secti o n 8. 3 ).
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dical l y i n dicate d or as re q ueste d b y t he s p o ns or t o 
el uci date t he na t ure a n d/ or ca usality of t he A E or S A E as f ull y as p ossi ble. T his ma y i ncl u de 
a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h 
ot her healt h care pr ofessi o nals.
If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p peri o d, t he 
i n vesti gat or will pr o vi de t he s p o ns or wit h a c o p y of a n y p ost m orte m fi n d i n gs i ncl u di n g 
hist o pat h ol o g y .
Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y c o m plete d C R F.
T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n.
9. 2. 4.   
Re g ul at or y Re p orti n g Re q uire me nts f or S A E s
 
Pr o m pt n otificati o n b y  t he i n vesti gat or t o t he sp o ns or of a n S A E is esse ntial s o t hat 
le gal o bli gati ons a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nt s a n d t he 
safety of a st u d y treat me nt u n der cli nical i n vesti gati o n are met. 
 
T he sp o ns or has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y  a ge ncies a b o ut t he safet y of a st u d y treat me nt u n der cli nical 
i n vesti gati o n. T he sp o ns or will c o m pl y  wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
relati n g t o safety re p orti n g t o t he re g ulat or y a ut h orit y, i nstit uti o nal re vie w b oar ds 
(IR B s)/i n de pe n de nt et hics c o m mittees (I E Cs), a n d i n vesti gat ors.
 
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A Rs) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d sp o ns or p olic y  a n d 
f or war de d t o i n vesti gat ors as necessar y.
 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m t he sp o ns or will 
re vie w a n d t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate 
acc ordi n g t o l ocal re q uire me nts .
9. 2. 5. 
C ar di o v asc ul ar a n d De at h E ve nts
N ot a p plica ble

El u xa d oli ne
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9. 2. 6. 
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot Q u alif yi n g as A E s
or S A Es
N ot a p plica ble
9. 2. 7. 
Pre g n a nc y
 
Details of all pre g na ncies i n fe male partici pa nt s will be c ollecte d after t he start of st u d y 
treat me nt a n d u ntil 3 0 da y s after t he last d ose.
9. 2. 8. 
A d verse E ve nts of S peci al I nterest
9. 2. 8. 1. 
A d verse E ve nt s of S peci al I nterest
A Es of s pecial i nterest are defi ne d as A Es of s p hi ncter of O d di s pas m, pa ncreatitis, a n d se vere 
c o nsti pati o n. T hese e ve nts m ust be re p orte d t o t he s p o ns or e x pe diti o usl y , as descri be d bel o w. 
Gi ve n t he μ -o pi oi d rece pt or a g o nis m of el u xa d oli ne, t here is a p ote ntial f or i ncrease d ris k of 
s p hi ncter of O d di s pas m, res ulti n g i n pa ncreatitis or he patic e nzy m e ele vati o n ass ociate d wit h 
ac ute a b d o mi nal pai n (e g, biliar y -t ype pai n), es peciall y  d uri n g t he first fe w wee ks of treat me nt, 
i n partici pa nt s ta ki n g el u xa d oli ne, partic ularl y i n partici pa nt s wit h o ut a gall bla dder. Pa ncreatitis, 
wit h or wit h o ut s p hi ncter of O d di s pas m has bee n re p orte d i n patie nts ta ki n g el u xa d oli ne, 
i ncl u di n g seri o us cases res ulti n g i n h os pitalizati o n, pri maril y i n patie nts wit h o ut a gall bla d der. 
Fatal cases ha ve als o bee n re p orte d i n patie nts wit h o ut a gall bla d der.
Partici pa nt s m ust be i nstr ucte d t o st o p t he st u d y treat me nt a n d see k me dical atte nti o n if t he y 
e x perie nce s y m pt o ms s u g gesti ve of s p hi ncter of O d di s pas m s uc h as ac ute w orse ni n g of 
a b d o mi nal pai n (e g, ac ute e pi gastric or biliar y [ie, ri g ht u p per q ua dra nt] pai n) t hat ma y ra diate t o 
t he bac k or s h o ul der, wit h or wit h o ut na usea a n d v o miti n g a n d/ or if t he y e x perie nce sy m pt o ms 
s u g gesti ve of pa ncreatitis s uc h as ac ute a b d o mi nal or e pi gastric pai n ra diati n g t o t he bac k.
C o nsti pati o n was t he m ost fre q ue nt A E re p orte d i n st u dies of el u xa d oli ne f or I B S-D. Per t he U S 
Prescri bi n g I nf or mati o n, el u xa d oli ne is t o be disc o nti n ue d i n partici pa nt s w h o de vel o p se vere 
c o nsti pati o n. T o e ns ure t he i n vesti gat or is ma de a ware of se vere c o nsti pati o n (ie, t he partici pa nt
is e x perie nci n g se vere disc o mf ort t hat se verely li mits or pre ve nts his/ her perf or ma nce of n or mal 
acti vities, or re prese nts a defi nite hazar d t o healt h t hat has or c o ul d res ul t i n h os pitalizati o n a n d 
prescri pti o n dr u g t hera p y) e pis o des , a n alert will be se nt t o t he in vesti gat or if a partici pa nt fails 
t o rec or d a b o wel m o ve me nt f or 3 c o nsec uti ve da ys i n his/her e Diar y . O nce n otifie d, t he 
in vesti gat or m ust c o ntact t he partici pa nt t o re vie w t he partici pa nt ’s stat us as s o o n as p ossi ble t o 
assess t he se verit y of his/ her c o nsti pati o n or t he prese nce of a ny se q uelae of c o nsti pati o n. E ver y  
atte m pt s h o ul d be ma de t o reac h t he st u d y partici pa nt wit hi n 2 4 h o urs. A n u nsc he d ule d visit t o 

El u xa d oli ne
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4 8
f urt her e val uate t he partici pa nt 's stat us s h o ul d be arra nge d if dee me d warra nte d b y t he 
in vesti gat or. T he st u d y  treat ment m ust be disc o nti n ue d if t he i n vesti gat or deter mi nes t hat se vere 
c o nsti pati o n is prese nt. 
If a partici pa nt is s us pecte d of e x perie nci ng pa ncreatitis, s p hi ncter of O d di s pas m, or se vere 
c o nsti pati o n, t he A E m ust be re p orte d t o t he sp o ns or's S A E mail b o x: I R- Cli nical -
S A E @aller ga n.c o m wit hi n 2 4 h o urs o n a n S A E F or m f or Cli nical Trials; i n t he a bse nce of 
sca n ni n g or e maili n g, t he S A E f or m ma y be fa xe d t o + 1 -7 1 4 -7 9 6 -9 5 0 4 .

El u xa d oli ne
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4 9
9. 2. 9. 
Me dic ati o n Err ors
Me dicati o n err or refers t o a n y u ni nte n de d err or i n t he d osi n g a n d/ or a d mi nistrati o n of t he st u d y 
treat me nt as per i nstr ucti o ns i n t he pr ot oc ol. Me dicati o n err ors ge nerally fall i nt o 4 cate g ories as 
f oll o ws:
 
Wr o n g st u d y dr u g/ de vice
 
W r o n g d ose (i ncl u di n g d osi n g re gi me n, stre n gt h, f or m, c o nce ntrati o n, a m o u nt)
 
W r o n g r o ute of a d mi nistrati o n
 
W r o n g p artici pa n t (ie, n ot a d mi nistere d t o t he i nte n de d p artici pant)
9. 3. 
Tre at me nt of O ver d ose
Please refer t o t he U S prescri bi n g i nf or mati o n ( VI B E R ZI PI 2 0 1 7 ) f or t he treat me nt t o be gi ve n 
i n case of o ver d ose.
9. 4. 
S afet y Assess me nts
Pla n ne d ti mep oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A .
9. 4. 1. 
P h ysic al E x a m i n ati o ns
 
A p h y sical e xa mi nati o n will c o nsist of a f ull re vie w of all b o d y s ys te ms (e xcl u di n g 
rectal a n d pel vic e xa mi nati o ns) s yste ms. 
 
In vesti gat ors s h o ul d pa y  s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
9. 4. 2. 
Vit al Si g ns
 
P ulse, res pirat or y  rate, a n d bl o o d press ure will be assesse d.

El u xa d oli ne
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5 0
 
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n a sitti n g p ositi o n wit h a 
c o m pletel y a ut o mate d de vice. Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d 
de vice is n ot a vaila ble.
 
Vital si g ns will be meas ure d after at least 5 mi n utes rest f or t he partici pa nt i n a q uiet 
setti n g wit h o ut distracti o ns (e g, tele visi o n, cell p h o nes). O ne rea di n g eac h of p ulse, 
res pirat or y rate, a n d bl o o d press ure will be ta ke n.
 
Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d as s pecifie d i n t he S o A .
9. 4. 3. 
C li nic al S afet y L a b or at or y Assess me nts
 
See A p pe n di x 2 , Secti o n 1 2. 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d 
t he S o A f or t he ti mi n g a n d fre q ue nc y. 
 
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. 
T he la b orat or y  re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y  si g nifica nt 
a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g 
d isease, u nless j u d ge d by t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he 
partici pa nt’ s c o n diti o n.
 
All la b orat or y  tests wit h val ues c o nsi dere d cli nicall y si g nifica ntly a b n or mal d uri n g 
partici pati o n i n t he st u d y  or wit hi n 2 wee ks after t he last d ose of st u d y treat me nt s h o ul d 
be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d 
cli nicall y si g nifica nt by t he i n vesti gat or or me dical m o nit or .
 
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d 
reas o na ble by t he i n vesti gat or, t he eti ol o g y s h o ul d be i de ntifie d a n d t he sp o ns or
n otifie d.
 
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , 
Secti o n 1 2. 2 , m ust be c o n d ucte d i n acc or da nce wit h t he S o A .
 
If la b orat or y val ues fr o m n o n -pr ot oc ol s pecifie d la b orat or y assess me nts 
perf or me d at t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n partici pa nt
ma na ge me nt or are c o nsi dere d cli nica ll y si g nifica nt b y t he i n vesti gat or (e g, S A E 
or A E or d ose m o dificati o n) , t he n t he res ults m ust be rec or de d i n t he e CR F.
9. 4. 4. 
S uici d al Ris k M o nit ori n g
S uici dal Ris k M o nit ori n g is n ot a p plica ble t o t his st u d y .
9. 5. 
P h ar m ac o k i netics

El u xa d oli ne
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5 1
9. 6. 
P h ar m ac o d y n a mics
T he p har mac o d y na mic effects of el u xa d oli ne o n t he altere d b o wel ha bits of I B S -D will be 
assesse d via efficac y assess me nts pre vi o usl y descri be d.
9. 7. 
Ge netics
Ge netics are n ot e val uate d i n t his st u d y .
9. 8. 
Bi o m ar k ers
Bi o mar kers are n ot e val uate d i n t his st u d y .
9. 9. 
He alt h Ec o n o mic s or Me dic al Res o urce Utiliz ati o n a n d He alt h 
Ec o n o mic s
Healt h ec o n o mics/ Me dical res o urce utilizati o n a n d healt h ec o n o mics para meters a re n ot 
e val uate d i n t his st u d y.

El u xa d oli ne
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5 2
1 0. 
St atistic al C o nsi der ati o ns 
1 0. 1. 
S a m ple Size Deter mi n ati o n
T he t otal sa m ple size f or t his st u d y is 2 4 partici pa nt s ( 1 2 partici pa nt s wit h B A M a n d 
1 2 partici pa nts wit h o ut B A M). N o f or mal sa m ple size esti mati o n will be calc ulate d beca use t he 
sa m ple size f or t his st u d y is n ot base d o n statistical c o nsi derati o n.
1 0. 2. 
P o p ul at i o ns f or A n al yses
T he a nal ys is p o p ulati o ns will c o nsist of partici pa nt s as defi ne d i n Ta ble 1 0 – 1 .
T a ble 1 0 – 1
A n al ysis P o p ul ati o ns
P o p ul ati o n
Defi niti o n
St u d y Tre at me nt
Scree ne d
All scree ne d partici pa nt s w h o si g n i nf or me d c o nse nt
—
E nr olle d
All partici pa nts i n Scree ne d P o p ulati o n w h o meet t he 
eli gi bilit y criteria a n d e nter t he o pe n-la bel treat me nt 
peri o d
A ssi g n me nt
M o difie d i nte nt -t o-
treat ( mI T T)
All partici pa nt s i n E nr olle d P o p ulati o n wit h 
≥1 p ost baseli ne assess me nt f or B S F S 
A ssi g n me nt
Safet y
All partici pa nt s w h o recei ve d ≥ 1 a d mi nistrati o n of st u d y 
treat me nt
Act ual recei ve d
B S F S = Brist ol St o ol F or m Scale
1 0. 3. 
St atistic al A n al yses
T he statistical a nal ys is pla n ( S A P) will be de vel o pe d a n d fi nalize d bef ore data base l oc k a n d will 
descri be t he partici pa nt p o p ulati o ns t o be i ncl u de d i n t he a nalys es, a n d pr oce d ures f or acc o u nti n g 
f or missi n g, u n use d, a n d s p uri o us data. T his secti o n is a s u m mar y of t he pla n ne d statistical 
a nal ys es of t he pri mar y a n d sec o n dar y e n d p oi nts.
1 0. 3. 1. 
Ke y St atistic al Met h o d ol o g y
T he met h o d ol o gies defi ne d i n Ta ble 1 0 – 2 a p pl y as s pecifie d t o i n di vi d ual e n d p oi nts. All efficac y 
e n d p oi nts will be s u m marize d b y partici pa nt c o h ort ( B A M or N o n -B A M) descri pti vel y.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 3
T a ble 1 0 – 2
St atistic al Met h o d ol o g y
M e t h o d ol o g y
Descri pti o n
Cate g orical c o u nts
 
N u m ber of partici pa nts i n i n di vi d ual cate g ories
o 
Partici pa nts wit h ≥ 1 q ualif yi n g e ve nt c o u nte d o nce per i n di vi d ual 
cate g or y
Cate g orical 
descri pti ves
 
N u m ber a n d perce nta ge of partici pa nts i n i n di vi d ual cate g ories
o 
Partici pa nts wit h ≥ 1 q ualif yi n g e ve nt c o u nte d o nce per i n di vi d ual 
cate g or y
 
[ O pti o nal] N 1 if perce nta ge de n o mi nat or ≠ n u m ber of partici pa nts i n t he 
p o p ulati o n (sta n dar d perce nta ge de n o mi nat or)
o 
N 1 = partici pa nts w it h n o n missi n g baseli ne val ue
P C S descri pti ves
 
N u m ber a n d perce nta ge of partici pa nts meeti n g P C S criteria
o 
Partici pa nts wit h ≥ 1 q ualif yi n g e ve nt c o u nte d o nce per P C S cate g or y 
 
Perce nta ge de n o mi nat or = n u m ber of partici pa nts wit h n o n missi n g baseli ne a n d 
≥1 n o n missi n g p ost baseli ne assess me nt
o 
U ne val ua ble assess me nts c o nsi dere d missi n g
E ve nt descri pti ves
 
N u m ber a n d perce nta ge of e ve nts i n i n di vi d ual cate g ories
o 
E ve nts c o u nte d i n di vi d uall y f or eac h i nsta nce
 
Perce nta ge de n o mi nat or = t otal n u m ber of e ve nts
S hift a nal ysis
 
N u m ber a n d perce nta ge of partici pa nts i n i n di vi d ual baseli ne a n d p ost baseli ne 
cate g ories
 
Perce nta ge de n o mi nat or = n u m ber of partici pa nts i n i n di vi d ual baseli ne 
cate g ories
 
N 1 = partici pa nts w it h n o n missi n g val ues at b ot h baseli ne a n d t he s pecifie d 
p ost baseli ne a nal ysis visit
C o nti n u o us 
descri pti ves
 
N 1, mea n, S D, me dia n, mi ni m u m, ma xi m u m
 
N 1 = partici pa nts w it h n o n missi n g val ue
C F B descri pti ves
 
C o nti n u o us descri pti ves f or baseli ne, p ost baseli ne, a n d C F B val ues
 
N 1 = partici pa nts w it h n o n missi n g val ues at b ot h baseli ne a n d t he s pecifie d 
p ost baseli ne a nal ysis visit
C F B = c ha n ge fr o m baseli ne; P C S = p ote ntiall y cli nicall y si g nifica nt
1 0. 3. 2. 
Effic ac y A n al yses
T he f oll o wi n g pri mar y  a n d sec o n dar y efficac y e n d p oi nts will be s u m marize d b y c o h ort ( B A M or 
N o n- B A M) f or t he m I T T p o p ulati o n. All ot her efficac y  e n d p oi nts a n d a nal yses will be defi ne d i n 
t he S A P.
Descri pti o ns i n Ta ble 1 0 – 3 a n d Ta ble 1 0 – 4 m a y  be li n ke d t o t he assess me nt(s) a n d/ or 
o bjecti ve(s).
T a ble 1 0 – 3 
Pri m ar y Effic ac y E n d p oi nt
E n d p oi nt
Descri pti o n
Ti mi n g
M e t h o d ol o g y
C ha n ge fr o m baseli ne i n a vera ge B S F S  
Treat me nt Peri o d 
Descri pti ve 

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 4
E n d p oi nt
Descri pti o n
Ti mi n g
M e t h o d ol o g y
sc ore o ver 4 wee ks of treat me nt peri o d
s u m mar y
N ote: A nal ysis visits will be i n t he S A P.
B S F S = Brist ol St o ol F or m Scale
T a ble 1 0 – 4
Sec o n d ar y Effic ac y E n d p oi nts
E n d p oi nt
Descri pti o n
Ti mi n g
M e t h o d ol o g y
C ha n ge fr o m baseli ne i n t he 4 -wee k 
a vera ge of dail y b o wel m o ve me nt 
fre q ue nc y d uri n g t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n t he 4 -wee k 
a vera ge of dail y w orst a b d o mi nal pai n 
sc ores d uri n g t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n t he 4 -wee k 
a vera ge of dail y worst a b d o mi nal pai n 
sc ores d uri n g t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n t he 4 -wee k 
a vera ge of ur ge nc y -free da ys i n a wee k 
d uri n g t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n t he 4 -wee k 
a vera ge of dail y bl oati n g sc ores d uri n g t he 
treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n I B S -Q O L sc ore at 
t he e n d of t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
C ha n ge fr o m baseli ne i n ser u m 7 α C 4 
le vels at t he e n d of t he treat me nt peri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
Pr o p orti o n of partici pa nts wit h a n y fecal 
i nco nti ne nce d uri n g t he treat me nt p eri o d
Treat me nt Peri o d 
Descri pti ve 
s u m mar y
N ote: A nal ysis visits will be i n t he S A P.
7 α C 4 = 7a -h y dr o x y - 4-c h oleste n- 3-o ne; I B S-Q O L = i rrita ble b o wel s y n dr o me -q ualit y of life
1 0. 3. 3. 
S afet y A n al yses
T he f oll o wi n g safet y cate g ories will be s u m marize d as a p pr o priate (e g, cate g orical or c o nti n u o us 
descri pti ves, s hift ta bles) f or t he safet y p o p ulati o n a n d will be f ull y defi ne d i n t he S A P.
 
Seri o us A d verse E ve nts
 
A d verse e ve nts
 
Cli nical la b o rat or y assess me nts
 
P ote ntial H y ’s la w cases
 
P ote ntial Dr u g I n d uce d Li ver I nj ur y  Cases

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 5
 
Vital si g ns i ncl u di n g wei g ht
 
P h y sical e xa mi nati o ns
1 0. 3. 4. 
P h ar m ac o ki netic A n al yses
1 0. 3. 5. 
Ot her A n al yses
N o ne
1 0. 3. 6. 
I nteri m A n al yses
N o i nteri m a nal ys is will be c o n d ucte d.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 6
1 1. 
Refere nces
Aziz I, M u mtaz S, B h ola h H, C h o w d h ur y F U, Sa n ders D S, F or d A C. Hi g h pre vale nce of 
i di o pat hic bile aci d diarr hea a m o n g patie nts wit h diarr hea-pre d o mi na nt irrita ble b o wel s y n dr o me 
base d o n R o me III criteria. Cli n Gastr oe nter ol He pat ol. 2 0 1 5; 1 3: 1 6 5 0 -1 6 5 5. 
Baj or A, T ör n bl o m H, R u dli n g M, U n g K A, Si mré n M. I ncrease d c ol o nic bile aci d e x p os ure: a 
rele va nt fact or f or sy m pt o ms a n d treat me nt i n I B S. G ut. 2 0 1 5; 6 4: 8 4 -9 2.
Ca milleri M, Na dea u A, Tre mai ne WJ, L a msa m J, B urt o n D, O d u nsi S, et al. Meas ure me nt of 
ser u m 7al p ha-h y dr o x y - 4-c h oleste n- 3-o ne ( or 7al p ha C 4), a s urr o gate test f or bile aci d 
mala bs or pti o n i n healt h, ileal disease a n d irrita ble b o wel s y n dr o me usi n g li q ui d c hr o mat o gra p h y -
ta n de m mass s pectr o metr y. Ne ur o gastr oe nter ol M otil. 2 0 0 9; 2 1: 7 3 4-e 4 3.
Ca milleri M. Peri p h eral mec ha nis ms i n irrita ble b o wel s yn dr o me. N E n gl J Me d. 
2 0 1 2; 3 6 7: 1 6 2 6 -1 6 3 5.
Ca milleri M. A d va nces i n u n dersta n di n g of bile aci d diarr hea. E x pert Re v Gastr oe nter ol He pat ol. 
2 0 1 4; 8( 1): 4 9 – 6 1.
Ca milleri M, B usci gli o I, Ac osta A, S hi n A, Carls o n P, B urt o n D, et al. Effect of i ncrease d bile 
aci d s ynt hesis or fecal e xcreti o n i n irrita ble b o wel s y n dr o me -diarr hea. A m J Gastr oe nter ol. 
2 0 1 4 ; 1 0 9: 1 6 2 1-1 6 3 0.
Ca milleri M. Bile Aci d Diarr hea: Pre vale nce, Pat h o ge ne sis, a n d T hera p y. G ut a n d Li ver. 
2 0 1 5; 9( 3): 3 3 2 -3 3 9.
C he y  W D, K urla n der J, Es wara n S. Irrita ble b o wel s yn dr o me: a cli nical re vie w. J A M A 
2 0 1 5; 3 1 3: 9 4 9 - 95 8.
Dr oss ma n D A, Patric k D L, W hite hea d W E, T o ner B B, Dia ma nt N E, H u Y, et al . F urt her 
vali dati o n of t he I B S- Q O L: a disease -s pecific q ualit y-of -life q uesti o nnaire. A m J Gastr oe nter ol 
2 0 0 0; 9 5: 9 9 9 -1 0 0 7 .
Dr oss ma n D A. T he f u ncti o nal gastr oi ntesti nal dis or ders a n d t he R o me III pr ocess. 
Gastr oe nter ol o g y . 2 0 0 6;1 3 0( 5): 1 3 7 7 -1 3 9 0.
E us ufzai S, A xels o n M, A n geli n B, Ei narss o n K. Ser u m 7 al p ha -h y dr o x y- 4-c h oleste n- 3- o ne 
c o nce ntrati o ns i n t he e val uati o n of bile aci d mala bs or pti o n i n patie nts wit h diarr h oea: c orrel ati o n 
t o Se H C A T test. G ut. 1 9 9 3;3 4: 6 9 8 – 7 0 1. 
F D A G ui da nce f or I n d ustr y , Dr u g-I n d uce d Li ver I nj ur y: Pre mar keti n g Cli nical E val uati o n, J ul y 
2 0 0 9
htt ps:// w w w.f da. g o v/ d o w nl oa ds/ dr u gs/ g ui da ncec o m plia ncere g ulat or yi nf or mati o n/ g ui da nces/ uc m
1 7 4 0 9 0. p df
Gral ne k I M, Ha y s R D, Kil b o ur ne A, Nali b off B, Ma yer E A. T he i m pact of irrita ble b o wel 
s yn dr o me o n healt h -relate d q ualit y of life. Gastr oe nter ol o g y. 2 0 0 0; 1 1 9:6 5 4 -6 6 0.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 7
H ulisz D. T he b ur de n of ill ness of irrita ble b o wel s y n dr o me: c urre nt c halle n ges a n d h o pe f or t he 
fut ure. J Ma na g Care P har m 2 0 0 4; 1 0: 2 9 9 -3 0 9.
Isla m R S, Di Baise J K. Bile aci ds: a n u n derrec o g nize d a n d u n dera p preciate d ca use of c hr o nic 
diarr hea. Practical Gastr oe nter ol 2 0 1 2; 3 6( 1 0): 3 2 -4 4. 
Lac y  B E, Meari n F, C ha n g L, C he y W D, Le m b o AJ, Si mre n M, S piller R. B o wel Dis or ders. 
Gastr oe nter ol. 2 0 1 6; 1 5 0: 1 3 9 3 – 1 4 0 7.
Le m b o AJ, Lac y  B E, Z uc ker ma n MJ, Sc he y R, D o ve LS, A n drae D A et al . El u xa d oli ne f or 
Irrita ble B o wel Sy n dr o me wit h Diarr hea. N E n gl J Me d. 2 0 1 6; 3 7 4( 3): 2 4 2 - 25 3.
L o n gstret h G F, T h o m ps o n W G, C he y  W D, H o u g ht o n L A, Meari n F, S piller R C . F u ncti o nal 
b o wel dis or ders. Gastr oe nter ol o g y . 2 0 0 6;1 3 0( 5): 1 4 8 0 -1 4 9 1.
L o vell R M, F or d A C. Gl o bal Pre vale nce of a n d Ris k Fact ors f or Irrita ble B o wel S y n dr o me: A 
Meta -a nal ysis. Cli n Gastr oe nter ol He pat ol. 2 0 1 2; 1 0( 7): 7 1 2 -7 2 1.
O d u nsi -S hi y a n ba de S T, Ca milleri M, Mc Ki nzie S, B u rt o n D, Carls o n P, B usci gli o I A et al .
Effects of c he n o de o x yc h olate a n d a bile ac i d se q uestra nt, c olese vela m, o n i ntesti nal tra nsit a n d 
b o wel f u ncti o n. Cli n Gastr oe nter ol He pat ol . 2 0 1 0; 8: 1 5 9 -1 6 5.
O' D o n nell L J D, Heat o n K W. Pse u d o-diarr hea i n t he irr ita ble b o wel s y n dr o me: patie nts’ rec or ds 
of st o ol f or m reflect tra nsit ti me w hile st o o l fre q ue nc y d oes n ot. G ut 1 9 8 8; 2 9:A 1 4 5 5 .
Paré P, Gra y  J, La m S, Bals ha w R, K h oras he h S, Bar bea u M et al. Healt h -relate d q uality of life, 
w or k pr o d ucti vit y , a n d healt h care res o urce utilizati o n of s u bjects wit h irrita ble b o wel sy n dr o me: 
baseli ne res ults fr o m L O GI C ( L o n git u di nal O utc o mes St u d y  of Gastr oi ntesti nal S ym pt o ms i n 
Ca na da), a nat uralistic st u d y . Cli n T her. 2 0 0 6; 2 8:1 7 2 6 -1 7 3 5.
Patric k D L, Dr oss ma n D A, Fre deric k I O, Di Cesare J, P u der K L. Q ualit y of life i n pers o ns wit h 
irrita ble b o wel sy n dr o me: de vel o p me nt a n d vali dati o n of a ne w meas ure. Di g Dis Sci 1 9 9 8; 
4 3: 4 0 0 - 41 1 .
Sa uter G H, M ü nzi n g W, v o n Ritter C, Pa u m gart ner G. Bile aci d mala bs or pti o n as a ca use of 
c hr o nic diarr hea: dia g n ostic val ue of 7al p ha -h y dr o x y - 4-c h oleste n- 3-o ne i n ser u m. Di g Dis Sci. 
1 9 9 9; 4 4 :1 4 -1 9.
S hi n A, Ca milleri M, Vija y var gi ya P, et al. B o wel f u ncti o ns, fecal u nc o nj u gate d pri mar y a n d 
sec o n dar y bile aci ds, a n d c ol o nic tra nsit i n patie nts wit h irrita ble b o wel sy n dr o me. Cli n 
Gastr oe nter ol He pat ol. 2 0 1 3; 1 1( 1 0): 1 2 7 0 -1 2 7 5.e 1.
Vale nti n N, Ca mil leri M, Alta yar O, Vija yvar gi ya P, Ac osta A, Nels o n A D, M ura d M H. 
Bi o mar kers f or bile aci d diarr h oea i n f u ncti o nal b o wel dis or der wit h diarr h oea: a s ys te matic 
re vie w a n d meta-a nal ys is. G ut. 2 0 1 6 Dec; 6 5( 1 2): 1 9 5 1 -1 9 5 9 .
VI B E R ZI ™ Prescri bi n g i nf or mati o n Aller g a n U S A, I nc. Ir vi ne, C A 9 2 6 1 2 2 0 1 5 ; 
htt ps:// dail y me d. nl m. ni h. g o v/ dail y m e d/ dr u gI nf o.cf m?seti d = 7 8 2 1 b d 4 0 -4c 8 4 -4 9 8 4 -9 5 1 b -
6 4 3 6ae 2 0 4 2 1a

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 8
Vija y var gi ya P, Ca milleri M, Carls o n P, L ue ke A, O' Neill J, B urt o n D et al. Perf or ma nce 
c haracteristics of ser u m C 4 a n d F G F 1 9 meas ure me nts t o e xcl u de t he dia g n osis of bile aci d 
diarr h oea i n I B S -diarr h oea a n d f u ncti o nal diarr h oea. Ali me nt P har mac ol T her. 
2 0 1 7 ; 4 6( 6): 5 8 1-5 8 8. 
Vija y var gi ya P, Ca milleri M, C he di d V, et al. A nal ysis of Fecal Pri mar y Bile Aci ds Detects 
I ncrease d St o ol Wei g ht a n d C ol o nic Tra nsit i n Patie nts Wit h C hr o nic F u ncti o nal Diarr hea. Cli n 
Gastr oe nter ol He pat ol. 2 0 1 8.
Wa de P R, Pal mer J M, Mc Ke n ne y  S, Ke ni gs V, C he valier K, M o ore B A, et al. M o d ulati o n of 
gastr oi ntesti nal f u ncti o n b y M u Delta, a mi xe d µ o pi oi d rece pt or a g o nist/ µ o pi oi d rece pt or 
a nta g o nist. Br J P har mac ol. 2 0 1 2 N o v ; 1 6 7( 5): 1 1 1 1-1 1 2 5. C orrecti o n t o title i n Br J P har mac ol. 
2 0 1 3 ; 1 6 8: 5 1 8.
Walters
J R. Defi ni n g pri mar y bile aci d diarr hea: ma ki n g t he dia g n osis a n d rec o g nizi n g t he 
dis or der. E x p Re v Gastr oe nter o l He pat ol. 2 0 1 0; 4( 5): 5 6 1-5 6 7.
We dla ke
L,  A’ Her n R, R ussell D, T h o mas K, Walters J R, A n dre ye v HJ. S yste matic re vie w: t he 
pre vale nce of i di o pat hic bile aci d mala bs or pti o n as dia g n ose d b y Se H C A T sca n ni n g i n patie nts 
wit h diarr h oea- pre d o mi na nt irrita ble b o wel s y n dr o me. Ali me nt P har mac ol . 2 0 0 9;3 0: 7 0 7 -7 1 7.
W o n g B S, Ca milleri M, Carls o n P, Mc Ki nzie S, B usci gli o I, B o n dar O
et al. I ncrease d bile aci d 
bi os y nt hesis is ass ociate d wit h irrita ble b o wel s y n dr o me wit h diarr hea. Cli n Gastr oe nter ol 
He pat ol. 2 0 1 2; 1 0: 1 0 0 9 -1 0 1 5.

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
5 9
1 2. 
A p pe n dices
1 2. 1. 
A p pe n di x 1: A b bre vi ati o ns a n d Tr a de m ar ks
7 α C 4
7a -h y dr o x y- 4-c h oleste n- 3- o ne
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C ta u
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve d uri n g t he d osi n g i nter val
B A
bile aci d
B A M
bile aci d mala bs or pti o n
BI D
t wice dail y
B MI
b o d y  mass i n de x
B S F S
Brist ol St o ol F or m Scale
C DI S C
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
C F B
c ha n ge fr o m baseli ne
C F R
C o de of Fe deral Re g ulati o ns
C L
a p pare nt cleara nce
C ma x
ma xi m u m plas ma c o nce ntrati o n
C mi n
mi ni m u m plas ma c o nce ntrati o n
C N S
ce ntral ner v o us s ys te m
C O N S O R T 
C o ns oli date d Sta n dar ds of Re p orti n g T rials
D B S
drie d bl o o d sa m ple
DI LI
dr u g i n d uce d li ver i nj ur y
e C R F
electr o nic case re p ort f or m
e Diar y
electr o nic diar y
E M A
E ur o pea n Me dici nes A ge nc y
E O T
e n d of treat me nt
E T
earl y ter mi nati o n
F D A
U S F o o d a n d Dr u g A d mi nistrati o n
F GI D
f u ncti o nal gastr oi ntesti nal dis or ders

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
6 0
F S H
f ollicle sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
GI
gastr oi ntesti nal
H R T
h or m o nal re place me nt t hera p y
I B
In vesti gat or ’s Br oc h ure
I B S
irrita ble b o wel sy n dr o me 
I B S- C
irrita ble b o wel sy n dr o me wit h c o nsti pati o n
I B S- D
irrita ble b o wel sy n dr o me wit h diarr hea
I B S- M
irrita ble b o wel sy n dr o me wit h c o nsti pati o n a n d diarr hea
I B S-Q O L 
irrita ble b o wel sy n dr o me -q ualit y  of life
I B S- U
irrita ble b o wel sy n dr o me ( u ns pecifie d)
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I N R
i nter nati o nal n or malize d rati o
I RB
I nstit uti o nal Re vie w B oar d
L C -M S/ M S 
li q ui d c hr o mat o gra p hy ta n de m -mass s pectr o metr y
mI T T
m o difie d i nte nt -t o-treat
N CI
Nati o nal Ca ncer I nstit ute
N O N M E M 
n o nli near mi xe d effects m o deli n g
P K
p har mac o ki netic
P T
pr ot hr o m bi n ti me
R o me
R o me Dia g n ostic Criteria f or F u ncti o nal Gastr oi ntesti nal Dis or ders
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
Se H C AT
7 5Sele ni u m -h o m oc h olic aci d ta uri ne
S O
s p hi ncter of O d di
S o A
sc he d ule of acti vities
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
half -life
tma x
ti me t o Cma x
U L N
u p per li mit of n or mal
V
a p pare nt v ol u me of distri b uti o n
W O C B P
w o ma n of c hil d beari n g p ote ntial

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
6 1
δ O R
delta -o pi oi d rece pt or
κ O R
ka p pa- o pi oi d rece pt or
µ O R
m u -o pi oi d rece pt or

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
6 2
1 2. 2. 
A p pe n di x 2: Cli nic al L a b or at or y Tests

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
6 3
1 2. 3. 
A p pe n di x 3: St u d y G o ver n a nce C o nsi der ati o ns
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:
 
C o nse ns us et hic al pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) i nter nati o nal et hical g ui deli nes
 
A p plica ble I CH G C P g ui deli nes
 
A p plica ble la ws a n d re g ulati o ns
 
T he pr ot oc ol, pr ot oc ol a me n d me nts, I CF , I B, a n d ot her rele va nt d oc u me nts ( e g,
a d vertise me nts) m ust be s u b mitte d t o a n IR B/I E C b y  t he i n vesti gat or a n d re vie we d a n d 
a p pr o ve d b y t he I RB/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 will re q uire I R B/IE C a p pr o val bef ore i m ple me ntati o n 
of c ha n ges ma de t o t he st u d y  desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate a n 
i m me diate hazar d t o st u d y partici pa nt s.
 
T he i n vesti gat or will be res p o nsi ble for t he f oll o wi n g:
o 
Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/ IE C 
a n n uall y or m ore fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, 
a n d pr oce d ures esta blis he d b y t he I R B/ IE C
o 
N otif y i n g t he I R B/I E C of S A Es or ot her si g nifica nt safety fi n di n gs as 
re q uire d by I RB/I E C pr oce d ures
o 
Pr o vi di n g o versi g ht of t he o verall c o n d uct of t he st u d y at t he site a n d 
a d here nce t o re q uire me nts of a p plica ble l ocal re g ulati o ns , f or e xa m ple 2 1 
C F R, I C H g ui deli nes, t he I R B/I E C, a n d E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or 
cli nical st u dies (if a p plica ble)
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u bin vesti gat ors will pr o vi de t he sp o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste d t o all o w t he sp o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities. I nvesti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u dy a n d f or 
1 y ear after c o m pleti o n of t he st u d y.
I nf or me d C o nse nt Pr ocess
 
T he i n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt or his/ her le gall y a ut h orize d re prese ntati ve a n d a ns wer all q uesti o ns 
re gar di n g t he st u dy. 
 
Partici pa nt s m ust be i nf or me d t hat t heir partici pati o n is v ol u n tar y. Partici pa nt s will be 
re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 

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2 1 C F R Part 5 0, l ocal re g ulati o ns, I C H g ui deli nes, Healt h I ns ura nce P orta bilit y  a n d 
Acc o u nta bilit y  Act (HI P A A ) re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u dy 
site. 
 
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date t he writte n c o nse nt 
was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he 
I CF.
 
Partici pa nt s m ust be re-c o nse nte d t o t he m ost c urre nt versi o n of t he I CF(s) d uri n g t heir 
partici pati o n i n t he st u d y . 
 
A c o p y of t he I CF(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orize d re p rese ntati ve. 
Partici pa nt s w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
D at a Pr otecti o n
 
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he sp o ns or . A n y partici pa nt rec or ds 
or datasets t hat are tra nsferre d t o t he sp o ns or will c o ntai n t he i de ntif ier o nl y; partici pa nt 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be 
tra nsferre d. 
 
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-relate d data will be use d 
b y the sp o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure 
m ust als o be e x plai ne d t o t he partici pa nt. 
 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y 
Cli nical Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he 
sp o ns or , b y  a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.
C o m mittees Str uct ure
P u blic ati o n P olic y
 
Aller ga n as t he s p o ns or has pr o prietar y  i nterest i n t his st u d y. A ut h ors hi p a n d ma n uscri pt 
c o m p ositi o n will reflect j oi nt c o o perati o n bet wee n t he i n vesti gat or a n d Aller ga n 
pers o n nel. A ut h ors hi p will be esta blis he d pri or t o t he writi n g of t he ma n uscri pt. 
 
T h e sp o ns or will c o m pl y  wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he sp o ns or will ge nerall y 
s u p p ort p u blicati o n of m ultice nter st u dies o nl y  i n t heir e ntirety a n d n ot as i n di vi d ual site 
data.
 
A ut h ors hi p will be deter mi ne d b y  m ut ual a gree me nt a n d i n li ne wit h Inter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts .

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Disse mi n ati o n of Cli nic al St u d y D at a
D at a Q u alit y Ass ur a nce
 
All partici pa nt data relati n g t o t he st u d y will be rec o rde d o n pri nte d or electr o nic C R F s
u nless tra ns mitte d t o t he sp o ns or or desi g nee electr o nicall y  (e g, la b orat or y data). T he 
i n vesti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect by 
p h y sically or electr o nicall y  si g ni n g t he C R F. 
 
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F. 
 
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi d e direct access t o s o urce data d oc u me nts. 
 
T he sp o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t hi s st u d y i ncl u di n g 
q ualit y  c hec ki n g of t he data. 
 
St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble 
fr o m s o urce d oc u me nts; t hat t he safet y a n d ri g hts of partici pa nt s are bei n g pr otecte d; 
a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d 
pr ot oc ol a n d a n y ot her st u d y a gree me nts, I CH G C P, a n d all a p plica ble re g ulat or y  
re q uire me nts. 
 
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C F s, pertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he i n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal 
re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be 
destr o y e d d uri n g t he re te nti o n peri o d wit h o ut t he writte n a p pr o val of t he sp o ns or . N o 
rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o 
t he sp o ns or . 
S o urce D oc u me nts
 
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate 
t he i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
 
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce 
d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be 
e x plai ne d. T he i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer 
rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dica l rec or ds m ust be a vaila ble.
 
S o urce d oc u me nts i ncl u de a partici pa nt’s me dical rec or ds, h os pital c harts, cli nic c harts, 
t he i n vesti gat or’s partici pa nt st u d y files, as well as t he res ults of dia g n ostic tests s uc h as 
ultras o u n d pr oce d ures a n d la b orat or y  tests. T he i n vesti gat or’s c o py of t he e C R F ser ves 
as part of t he i n vesti gat or’s rec or d of a partici pa nt’s st u d y -relate d data.

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St u d y a n d Site Cl os ure
T he sp o ns or or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y 
ti me f or a ny reas o n at t he s ole discreti o n of t he s p o ns or. T he st u d y site will be cl ose d u p o n st u d y 
c o m plet i o n. T he st u d y site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y s up plies 
ha ve bee n c ollecte d a n d t he st u d y-site cl os ure visit has bee n perf or me d.
T he i n vesti gat or ma y  i nitiate st u d y-site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.
Re as o ns f or t he earl y cl os ure of t he st u d y site by t he s p o ns or or i n vesti gat or ma y i ncl u d e b ut are 
n ot li mite d t o:
 
Fail ure of t he i n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he IR B/I E C 
or l ocal healt h a ut h orities, t he s p o ns or ’s pr oce d ures, or G C P g ui deli nes
 
I na de q uate recr uit me nt of partici pa nt s b y t he i n vesti gat or
 
Disc o nti n uati o n of f urt her st u d y treat me nt de vel o p me nt

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1 2. 4. 
A p pe n di x 4: A d verse E ve nts: Defi niti o ns a n d P r oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w -u p , a n d Re p orti n g
Defi niti o n of A E
A E Defi niti o n
 
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y partici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y treat me nt, w het her or n ot c o nsi dere d 
relate d t o t he st u d y treat me nt.
 
N O T E: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y  
ass ociate d wit h t he use of st u d y treat me nt.
A E of S peci al I nterest ( A E SI)
A n A E of s pecial i nterest (seri o us or n o nseri o us) is o ne of scie ntific a n d me dical c o ncer n 
s pecific t o t he sp o ns or’s st u d y  dr u g/ de vice or pr o gra m, w hic h warra nts o n g oi n g 
m o nit ori n g a n d ra pi d c o m m u nicati o n b y  t he i n vesti gat or t o t he s p o ns or. S uc h a n e ve nt 
mi g ht warra nt f urt her i n vesti gati o n i n or der t o c haracterize a n d u n dersta n d it.
T he f oll o wi n g A E SIs ha ve bee n i de nt ifie d f or t he st u d y treat me nt i n t his pr ot oc ol: S O
s pas m, pa ncreatitis, a n d se vere c o nsti pati o n.
 
If a partici pa nt is s us pecte d of e x perie nci n g a n A E SI  (i.e. pa ncreatitis, S O s pas m, or 
se vere c o nsti pati o n), t he A E m ust be re p orte d t o t he s p o ns or's S A E mail b o x: 
I R-Cli nical -S A E @aller ga n.c o m wit hi n 2 4 h o urs o n a n S A E F or m f or Cli nical Trials; 
i n t he a bse nce of sca n ni n g or e maili n g, t he S A E f or m ma y be fa xe d t o 
+ 1 -7 1 4 -7 9 6 -9 5 0 4.

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E ve nts M eeti n g t he A E D efi niti o n 
 
A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) 
or ot her safet y assess me nts ( e g, electr ocar di o gra ms [ E C G s], ra di ol o gical sca ns, vital 
si g ns meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d
cli nicall y si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he i n vesti gat or (ie,
n ot relate d t o pr o gressi o n of u n derl yi n g disease )
 
E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a nd/ or i nte nsit y  of t he c o n diti o n
 
Ne w c o n diti o n detecte d or dia g n ose d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of the st u d y
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
treat me nt or a c o nc o mita nt me dicati o n. Over d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self-
har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae.
 
Lac k of efficac y  or fail ure of e x pecte d p har mac ol o gical acti o n per se will n ot be 
re p orte d as a n A E or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y  
assess me nts. H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m 
lac k of efficac y will be re p orte d as A E s or S A E s if t he y f ulfil t he defi niti o n of a n A E 
or S A E.
E ve nts N O T Meeti n g t he A E D efi niti o n 
 
A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts t hat are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y  t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt ’s c o n diti o n
 
T h e disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or sy m pt o ms 
(clearl y defi ne d) of t he disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n 
e x pecte d f or t he partici pa nt ’s c o n diti o n
 
Me dical or s ur gical pr oce d ure ( e g, e n d osc o p y, a p pe n dect o my): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is t he A E
 
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital)
 
A ntici pate d da y -t o-d a y  fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n

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Defi niti o n of S A E
If a n e ve nt is n ot a n A E per t he defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met ( e g, h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , deat h d ue 
t o pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a. 
Res ults i n de at h
b. 
Is life t hre ate ni n g
T he ter m life t hre ate ni n g i n t he defi niti o n of seri o us refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, 
w hic h h y p ot heticall y mi g ht ha ve ca use d deat h, if it were m ore se vere.
c. 
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y  
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y  war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A E s. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us. W he n i n d o u b t as to w het her h os pitalizati o n occ urre d or was necessar y , t he AE 
s h o ul d be c o nsi dere d seri o us.
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n fr o m 
baseli ne is n ot c o nsi dere d a n A E.
d. 
Res ults i n persiste nt dis a bilit y/ i nc a p acit y
 
T he ter m disa bilit y  mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns.

T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, 
a n d acci de ntal tra u ma ( e g, s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt 
e ver yd a y  life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.
e. 
Is a c o n ge nit al a n o m al y/ birt h defect
f. 
Ot her sit u ati o ns:
 
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y 
n ot be i m me diatel y  life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y 
je o par dize the partici pa nt or ma y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y
be c o nsi dere d seri o us .

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E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y 
or dr u g a b use.
Rec or di n g a n A E a n d / or S A E
A E a n d S A E Rec or di n g
 
W he n a n A E/ S A E oc c urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all
d oc u me ntati o n ( e g, h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics 
re p orts) relate d t o t he e ve nt.
 
T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.
 
It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt ’s 
me dical rec or ds t o t he s p o ns or i n lie u of c o m pleti o n of t he A E/ S A E C R F pa ge.
 
T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are 
re q ueste d by t he s p o ns or. I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti o n 
of t he partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds 
bef ore s u b missi o n t o t he s p o ns or.

T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble , t he dia g n osis ( n ot 
t he i n di vi d ual si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E .
Assess me nt of I nte nsit y
MI L D 
A t y pe of a d verse e ve nt t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal 
treat me nt or t hera pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere 
wit h us ual acti vities of dail y li vi n g.
M O D E R A T E 
A t y pe of a d verse e ve nt t hat is us uall y alle viate d wit h a d diti o nal s pecific 
t hera pe utic i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of dail y 
li vi n g, ca usi n g disc o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of har m 
t o t he researc h partici pa nt.
S E V E R E 
A t y pe of a d verse e ve nt t hat i nterr u pts us ual acti vities of dail y li vi n g, or 
si g nifica ntl y affects cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic 
i nter ve nti o n.
A n e ve nt is defi ne d as seri o us w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi niti o n of a n S A E , N O T w he n it is rate d as se vere.

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Assess me nt of C a us alit y
 
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y treat me nt a n d 
eac h occ urre nce of eac h A E/ S A E.
 
A re as o n a ble p ossi bility of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce ,
a n d/or ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat h er t ha n a relati o ns hi p ca n n ot 
be r ule d o ut.
 
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.
 
Alter nati ve ca uses, s uc h as u n derl yi n g disease (s), c o nc o mita nt t hera py, a n d ot her 
ris k fact ors, as well as t he te m p oral relati o ns hi p of the e ve nt t o st u d y treat me nt 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.
 
T he i n vesti gat or will als o c o ns ult t he I B a n d/ or pr o d uct i nf o r mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.
 
F or eac h A E/ S A E , t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y .
 
T here ma y  be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he s p o ns or. H o we ver, it is 
ver y i m p ort a nt t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or 
e ver y e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a t o t he s p o ns or.
 
T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y  i n li g ht of f oll o w-u p 
i nfor mati o n a n d se n d a n S A E f oll o w -u p re p ort wit h t he u p date d ca usalit y  
assess me nt .

T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts.
Re p orti n g of S A E s
S A E R e p orti n g t o t he S p o ns or vi a a n E lectr o nic D at a C ollecti o n T o ol
 
T he p ri mar y mec ha nis m f or re p orti n g a n S A E t o t he s p o ns or will be t he electr o nic 
data c ollecti o n t o ol .
 
If t he electr o nic sys te m is u na vaila ble f or m ore t ha n 2 4 h o urs, t hen t he site will use 
t he pa per S A E data c ollecti o n t o ol (see ne xt secti o n).
 
T he s ite will e nter t he S A E data i nt o t he electr o nic s y ste m as s o o n as it bec o mes 
a vaila ble.
 
After t he st u d y is c o m plete d at t he site, t he electr o nic data c ollecti o n t o ol will be 
ta ke n off-li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data.
 
If t he site recei ves a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei ves 
u p date d data o n a pre vi o usl y  re p orte d S A E after t he electr o nic data c ollecti o n t o ol 

El u xa d oli ne
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7 2
has bee n ta ke n off -li ne, t hen t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m
(see ne xt secti o n) or t o t he s p o ns or b y  tele p h o ne.

C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he pr ot oc ol title pa ge.
S A E Re p orti n g t o t he S p o ns or vi a P a per C R F
 
Facsi mile tra ns missi o n of t he S A E pa per C R F is t he preferre d met h o d t o t ra ns mit 
t his i nf or mati o n t o t he s p o ns or.
 
I n rare circ u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y 
tele p h o ne is acce pta ble wit h a c o py of t he S A E data c ollecti o n t o ol se nt b y o ver ni g ht 
mail or c o urier ser vice. I nitial n otificati o n via tele p h o ne does n ot re place t he nee d f or 
t he i n vesti gat or t o c o m plete a n d si g n t he S A E C R F pa ges wit hin t he desi g nate d 
re p orti n g ti me fra mes.

C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he pr ot oc ol title pa ge.

El u xa d oli ne
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7 3

El u xa d oli ne
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7 4

El u xa d oli ne
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7 5

C O N FI D E N TI A L
El u xa d oli ne
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7 6

El u xa d oli ne
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7 7

El u xa d oli ne
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1 2. 7. 
A p pe n di x 7 : St a n d ar d Disc o nti n u ati o n Criteri a
C DI S C S u b missi o n V al ue
C DI S C Defi niti o n
A d verse e ve nt
A n y u nt o war d me dical occ urre nce i n a patie nt or 
cli nical i n vesti gati o n s u bject a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot 
necessaril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt. A n a d verse e ve nt ( A E) ca n t heref ore be 
a n y u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease 
te mp orall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o 
t he me dici nal (i n vesti gati o nal) pr o d uct. F or f urt her 
i nf or mati o n, see t he I C H G ui deli ne f or Cli nical 
Safet y Data Ma na ge me nt: Defi niti o ns a n d 
Sta n dar ds f or E x pe dite d Re p orti n g. [ M o difie d fr o m 
I C H E 2 A] S y n o n y ms: si de effect, a d verse 
e x perie nce. See als o seri o us a d verse e ve nt ( S A E), 
seri o us a d verse e x perie nce ( Cli nical Data 
I nterc ha n ge Sta n dar ds C o ns orti u m [ C DI S C]
gl ossar y)
C o m plete d
T o p ossess e ver y necessar y or n or mal part or 
c o m p o ne nt or ste p; ha vi n g c o me or bee n br o u g ht t o 
a c o ncl usi o n (Nati o nal Ca ncer I nstit ute [ N CI ])
Deat h
T he a bse nce of life or state of bei n g dea d ( N CI)
Lac k of efficac y
T he lac k of e x pecte d or desire d effect relate d t o a 
t hera p y ( N CI)
L ost t o f oll o w -u p
T he l oss or lac k of c o nti n uati o n of a s u bject t o 
f oll o w-u p
N o n -c o mplia nce wit h st u d y dr u g
A n i n dicati o n t hat a s u bject has n ot a gree d wit h or 
f oll o we d t he i nstr ucti o ns relate d t o t he st u d y 
me dicati o n ( N CI)
Ot her
Differe nt t ha n t he o ne(s) pre vi o usl y s pecifie d or 
me nti o ne d ( N CI)
P h y sicia n decisi o n
A p ositi o n, o pi ni o n or j u d g me nt reac he d after 
c o nsi derati o n b y a p h ysicia n wit h refere nce t o 
s u bject ( N CI)
Pre g na nc y
Pre g na nc y is t he state or c o n diti o n of ha vi n g a 
de vel o pi n g e m br y o or fet us i n t he b o d y ( uter us), 
after u ni o n of a n o v u m a n d s per mat oz o o n, d uri n g 
t he peri o d fr o m c o nce pti o n t o birt h. ( N CI)
Pr ot oc ol de viati o n
A n e ve nt or decisi o n t hat sta n ds i n c o ntrast t o t he 
g ui deli nes set o ut b y t he pr ot oc ol ( N CI)
Scree n fail ure
T he p ote ntial s u bject w h o d oes n ot meet o ne or 
m o re criteria re q uire d f or partici pati o n i n a trial

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C DI S C S u b missi o n V al ue
C DI S C Defi niti o n
Site ter mi nate d b y s p o ns or
A n i n dicati o n t hat a cli nical st u d y was st o p pe d at a 
partic ular site b y its s p o ns or ( N CI)
St u d y ter mi nate d b y s p o ns or
A n i n dicati o n t hat a cli nical st u d y was st o p pe d b y 
its s p o ns or ( N CI)
Wit h dra w al b y s u bject
A n i n dicati o n t hat a st u d y partici pa nt has re m o ve d 
itself fr o m t he st u d y (N CI)

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1 2. 8. 
A p pe n di x 8 : St u d y T a b ul ar S u m m ar y
P ar a m eter Gr o u p
P ar a m eter
V al ue
Trial i nf or mati o n 
Trial Title
3 0 3 0 -4 0 1 -0 0 2: A n O pe n -La bel Pil ot St u d y 
of El u xa d oli ne i n Partici pa nts wit h Irrita ble 
B o w el S y n dr o me wit h Diarr hea (I B S -D) 
W h o Ha ve E vi de nce of Bile Aci d 
Mala bs or pti o n ( B A M)
Cli nical St u d y S p o ns or
Aller ga n
Trial P hase Classificati o n
P hase 4
Trial I n dicati o n
I B S- D
Trial I n dicati o n T y pe
Treat me nt
Trial T y pe
Efficac y
Safet y
Trial Le n gt h
U p t o 1 1 w ee ks, w hic h i ncl u des: scree ni n g 
peri o d ( 0 -2 we e ks), pretreat me nt peri o d 
( 2-3 w ee ks), 4-wee k o pe n -la bel treat me nt 
peri o d a n d 2 -we e k p ost -treat me nt 
f oll o w-u p peri o d.
Pla n ne d C o u ntr y of I n vesti gati o nal Site 
U nite d States
Pla n ne d N u m ber of Partici pa nt s
2 4
F D A -Re g ulate d De vice St u d y I n dicat or 
N o
F D A -Re g ulate d Dr u g St u d y I n dicat or
N o
Pe diatric St u d y I n dicat or
N o
Partici pa nt 
i nf or mati o n
Dia g n osis Gr o u p
Partici pa nts wit h I B S-D w h o ha ve 
evi de nce of B A M
Healt h y Partici pa nt I n dicat or
N o
Pla n ne d Mi ni m u m A ge of Partici pa nts
1 8
Pla n ne d Ma xi m u m A ge of Partici pa nts 
6 5
Se x of Partici pa nts
B ot h
Sta ble Disease Mi ni m u m D urati o n
A dia g n osis of I B S f ulfille d f or t he last 
3 m o nt hs pri or t o s cree ni n g wit h s y m pt o m 
o nset at least 6 m o nt hs bef ore dia g n osis as 
defi ne d b y t he R o me I V criteria f or I B S.
Treat me nts 
I n vesti gati o nal T hera p y or Treat me nt
El u xa d oli ne
I nter ve nti o n Ty pe
Dr u g
P har mac ol o gical Class of I n vesti gati o nal
T hera p y
L ocall y acti ve mi xe d m u -o pi oi d rece pt or 
( µ O R) a g o nist, ka p pa-o pi oi d rece pt or 

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P ar a m eter Gr o u p
P ar a m eter
V al ue
( κ O R) a g o nist, a n d delta-o pi oi d rece pt or 
( δ O R) a nta g o nist.
D ose per A d mi nistrati o n
1 0 0 m g
D ose U nits
1 0 0 m g
D osi n g Fre q ue nc y
BI D
R o ute of A d mi nistrati o n
Oral
C urre nt T hera p y or Treat me nt
N o ne
A d de d o n t o E xisti n g Treat me nts
N o
C o ntr ol T y pe
N/ A
C o m parati ve Treat me nt Na me
N/ A
Trial desi g n 
St u d y T y pe
I nter ve nti o nal
I nter ve nti o n M o del
O pe n -La bel , pil ot
Pla n ne d N u m ber of Ar ms
1
Pla n ne d N u m ber of C o h orts
2
Trial is Ra n d o mize d
N o
Ra n d o mizati o n Q u otie nt
N/ A
Trial Bli n di n g Sc he ma
N o ne
Stratificati o n Fact or
Wit h a n d wit h o ut e vi de nce of B A M
A da pti ve Desi g n
N o
St u d y St o p R ules
Partici pa nts m ust pre mat urel y disc o nti n ue 
st u d y treat me nt f or reas o ns of safet y 
i ncl u di n g: 
 
a n S A E c o nsi dere d b y t he in vesti gat or 
or t he s p o ns or t o be p ossi bl y relate d or 
relate d t o i n vesti gati o nal pr o d uct,
 
a n A E of s pecial i nterest ( S O s pas m, 
pa ncreatitis , se vere c o nsti pati o n) 
 
pre g na nc y
 
si g ns of dr u g-i n d uce d li ver i nj ur y 
( DI LI) o utli ne d i n A p pe n di x 6
Secti o n 1 2. 6 , Li ver Safet y
Partici pa nts ma y pr e m at urel y disc o nti n ue 
st u d y treat me nt f or reas o ns of safet y 
i ncl u di n g:
 
t he prese nce of i nte nti o nal o verd ose or 
i nte nti o nal mis use per in vesti gat or 
discreti o n,

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Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
8 2
P ar a m eter Gr o u p
P ar a m eter
V al ue
 
a n A E i n dicati ve of a C N S o pi oi d 
effect, e g, pi n p oi nt p u pils, l oss of 
c o nsci o us ness, deliri u m, se dati o n or 
s o m n ole nce, e u p h oric, a n xi o us or 
de presse d m o o d, t hat i n t he o pi n i o n of 
t he in vesti gat or or t he s p o ns or is 
p ossi bl y relate d or relate d t o t he 
i n vesti gati o nal pr o d uct,
 
a vital si g n, a n d/ or la b orat or y 
a b n or malit y j u d ge d t o be cli nicall y 
si g nificant b y t he i n vesti gat or a n d t hat 
i n t he o pi ni o n of t he in vesti gat or or 
t he sp o ns or is p ossi bl y relate d or 
relate d t o t he i n vesti gati o nal pr o d uct,
 
a n i nt olera ble A E ( defi ne d as a n A E 
t hat s u bjecti vel y w o ul d ca use a 
partici pa nt t o c o nsi der st u d y 
wit h dra wal),
 
a n a bse nce of b o wel m o ve me nts f or 
≥3 c o nsec uti ve da ys, base d o n 
res p o nses rec or de d via e Diar y,
 
t he use of a n e xcessi ve a m o u nt of 
l o pera mi de resc ue me dicati o n,
 
t he occ urre nce of a n y ot her A E t hat i n 
t he o pi ni o n of t he in vesti gat or or t he 
sp o ns or is p ossi bl y relate d or relate d 
t o t he st u d y treat me nt t hat re prese nts a 
cli nicall y si g nifica nt safet y ris k t o t he 
partici pa nt .

El u xa d oli ne
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8 3

El u xa d oli ne
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8 4

El u xa d oli ne
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8 5

El u xa d oli ne
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8 6

El u xa d oli ne
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8 7

El u xa d oli ne
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8 8
1 2. 1 0. 
A p pe n di x 1 0 : S u m m ar y A d a pte d fr o m G ui deli nes of t he U S M ulti -
s ociet y T as k F orce o n C ol orect al C a ncer a n d Ot her C ol o n osc o p y 
Re q uire me nts
N ote: Partici pa nt m a y  be e nr olle d if n o f oll o w-u p c ol o n osc o p y  after p ol yp re m o val is d ue w hile 
partici pati n g i n t he st u d y.
1.
Partici pa nt s a ge 5 0 ye ars ( 4 0 years if Africa n A merica n) a n d ol der m ust ha ve ha d a 
c ol o n osc o p y wit h ne g ati ve fi n di n gs wi t hi n t he 1 0 years pri or t o t he scree ni n g v isit ( Visit 1).
2.
If t he m ost rece nt c ol o n osc o p y re veale d h yper plastic p ol y ps t hat were e ntirel y  re m o ve d, t he 
partici pa nt m a y  be e nr olle d, pr o vi de d t he c ol o n osc o p y was perf or med wit hi n 1 0 y ears pri or
t o t he scree ni n g visit ( Visit 1).
3.
If t he m ost rece nt c ol o n osc o p y re veale d 2 or fe wer s mall ( < 1 c m) a de n o mat o us p ol yps wit h 
t u b ular str uct ure wit h l o w gra de dys plasia a n d wit h o ut a p precia ble vill o us tiss ue, t he 
partici pa nt m a y  be e nr olle d, pr o vi de d t he c ol o n osc o p y was perf or me d wit hi n 5 years pri or t o 
t he scree ni n g visit ( Visit 1).
4.
Partici pa nt s w h o ha ve 1 first-de gree relati ve wit h c ol orectal ca ncer or a de n o mat o us p ol y ps 
dia g n ose d bef ore a ge 6 0 or 2 first- de gree relati ves wit h c ol orectal ca ncer dia g n ose d a t a ny 
a ge, m ust ha ve ha d a c ol o n osc o p y  wit h ne gati ve fi n di n gs 5 years bef ore t h e scree ni n g v isit 
( Visit 1). T his a p plies t o partici pa nt s w h o are 4 0 years or ol der a n d t o partici pa nt s yo u n ger 
t ha n 4 0 years, w h o are 1 0 or fe wer years fr o m t he a ge at w hic h t h eir y o u n gest relati ve was 
f o u n d t o ha ve 1 of t he af ore me nti o ne d c o n diti o ns.
5.
Partici pa nt s w h o ha ve 1 first-de gree relati ve wit h c ol orectal ca ncer or a de n o mat o us p ol y ps 
dia g n ose d at a ge 6 0 or ol der or 2 sec o n d -de gree relati ves wit h c ol orectal ca ncer dia g n ose d at 
a n y a ge, m ust ha ve ha d a c ol o n osc o p y  wit h ne gati ve fi n di n gs wit hi n 1 0 years pri or t o t he 
scree ni n g visit ( Visit 1). T his a p plies t o partici pa nt s w h o are 4 0 ye ars or ol der a n d t o 
partici pa nt s yo u n ger t ha n 4 0 y ears, w h o are 1 0 or fe wer years fr o m t he a g e at w hic h t heir 
y o u n gest relati ve was f o u n d t o ha ve 1 of t he af ore me nti o ne d c o n diti o ns.
Ot her C ol o n osc o p y Re q uire me nts:
Partici pa nt s of a ny a ge w h o ha ve alar m s y m pt o ms m ust ha ve ha d a c ol o n osc o p y wit h ne gati ve 
fi n di n gs after t he o nset of t he alar m sy m pt o ms a n d wit hi n 5 y ears pri or t o t he scree ni n g v isit 
( Visit 1). Alar m sy m pt o ms i ncl u de l o wer GI blee di n g (rectal blee di n g or he me -p ositi ve st o ol), 
ir o n-deficie nc y  a ne mia, a n d wei g ht l oss. (N ote: C urre nt u ne x plai ne d or cli nicall y  si g nifica nt 
alar m s y m pt o ms ar e e xcl usi o nar y.) T hese re q uire me nts are a da pte d base d o n rece nt G ui da nce o n 
C ol orectal Ca ncer Scree ni n g (Le vi n 2 0 0 8 ; Li e ber ma n 2 0 1 2 ; Qasee m 2 0 1 2 ).
Refere nces
Le vi n B, Lie ber ma n D A, Mc Farla n d B, A n dre ws K S, Br o o ks D, B o n d J et al . Scree ni n g a n d 
S ur veilla nce f or t he Earl y Detecti o n of C ol orectal Ca ncer a n d A de n o mat o us P ol yps, 2 0 0 8: A 
J oi nt G ui deli ne Fr o m t he A merica n Ca ncer S ociet y , t he U S M ulti-S ociet y T as k F orce o n 
C ol orectal Ca ncer, a n d t he A merica n C olle ge of Ra di ol o g y . Gastr oe nter ol o g y .
2 0 0 8; 1 3 4: 1 5 7 0 -1 5 9 5 .

El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
8 9
Lie ber ma n D A, Re x D K, Wi na wer SJ, Giar diell o F M, J o h ns o n D A, Le vi n T R. G ui deli nes f or 
C ol o n osc o p y  Sur veilla nce After Scree ni n g a n d P ol y pect o m y : A C o nse ns us U p date b y t he U S 
M ulti -S ociet y  Tas k F orce o n C ol orectal Ca ncer . G astr oe nter ol o g y. 2 0 1 2; 1 4 3: 8 4 4 – 8 5 7 .
Qasee m A, De n ber g T D, H o p ki ns Jr R H, H u m p hre y L L, Le vi ne J, S weet D E, S he kelle P .
Scree ni n g f or C ol orectal Ca ncer : A G ui da nce State me nt Fr o m t he A merica n C olle ge of 
P h y sicia ns. A n n I nter n Me d. 2 0 1 2; 1 5 6: 3 7 8 -3 8 6.

El u xa d oli ne
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1 2. 1 1. 
A p pe n di x 1 1: Brist ol St o ol F or m Sc ale ( B S F S)
T y p e 1 - S e p ar at e h ar d l u m p s li k e n ut s ( diffi c ult 
t o p a s s)
T y p e 2 - S a u s a g e s h a p e d b ut l u m p y
T y p e 3 - Li k e a s a u s a g e b ut wit h cr a c k s o n 
s urf a c e
T y p e 4 - Li k e a s a u s a g e or s n a k e, s m o ot h a n d 
s oft
T y p e 5 - S oft bl o b s wit h cl e ar -c ut e d g e s ( p a s s e d 
e a sil y)
T y p e 6 - Fl uff y pi e c e s wit h r a g g e d e d g e s, a 
m u s h y st o ol
T y p e 7 - W a t er y, n o s oli d pi e c e s ( e ntir el y li q ui d)

El u xa d oli ne
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1 2. 1 3. 
Pr ot oc ol A me n d me nt 1 S u m m ar y
Secti o n N o. a n d N a m e 
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 1 S y n o psis ( St u d y 
desi g n ta ble); Secti o n 2 
S O A; Secti o n 5. 1 
Ta ble 5- 1
A d diti o n of b ol de d te xt t o 
f o ot n ote (f o ot n ote a i n s y n o psis 
a n d f o ot n ote b i n S O A): 
Scree ni n g a n d Pretreat me nt 
peri o ds ma y be c o m bi ne d, if 
res ults of fasti n g ser u m 7 α C 4 test 
or 4 8 -h o ur fecal B A c ollecti o n 
c o n d ucte d wit hi n 1 cale n dar year 
fr o m Scree ni n g Visit are a vaila ble 
at t he ti me of t he c o m bi ne d visit 
or res ults fr o m f asti n g ser u m 
7 α C 4 test are a v ail a ble pri or t o 
t he st art of st u d y tre at me nt.
Secti o n 9 Scree ni n g Visit 1 
A d diti o n of b ol de d te xt: T his visit 
ma y be c o m bi ne d wit h t he 
pretreat me nt visit if res ults fr o m a 
fasti n g ser u m 7 α C 4 test or 
4 8 -h o ur fecal B A c ollecti o n, 
c o n d ucte d wit hi n 1 cale n dar year 
pri or t o scree ni n g, are a vaila ble at 
t he ti me of t he c o m bi ne d visit or 
res ults fr o m f asti n g ser u m 7 α C 4 
test are a v ail a ble pri or t o t he 
st art of st u d y tre at me nt. T he 
scree ni n g visit will occ ur 
a p pr o xi matel y 2 t o 3 w ee ks 
bef ore t he first d ose of st u d y dr u g 
(if c o mbi ne d wit h pretre at me nt 
visit) a n d n o m ore t ha n 5 wee ks 
bef ore t he first d ose of st u d y dr u g, 
if t he partici pa nt re q uires a n 
a d diti o nal wee k f or eac h, 
scree ni n g a n d pretreat me nt 
pr oce d ures).
T he ori gi nal pr ot oc ol all o w e d scree ni n g a n d 
pretreat me nt visits t o be c o m bi ne d f or 
partici pa nt w h o ha d hist orical res ults of 
fasti n g ser u m 7 α C 4 test or 4 8-h o ur fecal B A 
c ollecti o n a vaila ble wit hi n 1 cale n dar year 
fr o m scree ni n g. T he t ur nar o u n d f or 7 α C 4 
res ults use d t o be a p pr o xi matel y 2-3 wee ks. 
T he 7 α C 4 test res ults are n o w a vaila ble i n 
a p pr o xi matel y 1 wee k w hic h was a tri g ger t o 
all o w c o mbi ni n g Scree ni n g a n d Pretreat me nt 
f or all st u d y partici pa nts. T his will all o w 
fe wer visits f or s o me partici pa nts, decreasi n g 
t he partici pa nt b ur de n.   
Secti o n 9 Pretreat me nt 
( Visit 2)
A d diti o n of b ol de d te xt: T his visit 
ma y be c o m bi ne d wit h t he 
scree ni n g visit if res ults fr o m a 
fasti n g ser u m 7 α C 4 test or 
4 8 -h o ur fecal B A c ollecti o n, 
c o n d ucte d wit hi n 1 cale n dar year 
pri or t o scree ni n g, are a vaila ble at 
t he ti me of t he c o m bi ne d visit or 
res ults fr o m f asti n g ser u m 7 α C 4 
test are a v ail a ble pri or t o t he 
st art of st u d y tre at me nt.

El u xa d oli ne
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Secti o n N o. a n d N a m e 
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 5. 1
D urati o n of scree ni n g peri o d 
c ha n ge d t o 1 0 -2 w ee ks a n d 
defi ne d as Wee k - 3 t o -4 5 pri or 
t o B aseli ne Visit ( V 3, St u d y 
D a y 1)
T o c orrect i nacc urac y i n ori gi nal pr ot oc ol
Secti o n 7. 5
A d diti o n of b ol de d te xt descri bi n g 
destr ucti o n of test material: T he 
st u d y site m ust se n d a n y u n use d 
st u d y treat me nt t o t he ve n d or 
s pecifie d, f or destr ucti o n or h a ve 
st u d y dr u g destr o ye d per 
d oc u me nte d i nstit uti o n al 
st a n d ar ds of pr actice t h at h a ve 
bee n a p p r o ve d b y t he s p o ns or.
D ue t o D E A ha n dli n g restricti o ns a n d 
i nsti uti o n pr ocesses t he site is u na blet o ret ur n 
u n use d st u d y dr u g t o s p o ns or.  T he alter nati ve 
destr ucti o n pr ocess was a gree d u p o n a n d 
d oc u me nte d i n N ote t o file
Secti o n 9. 8. 2. 1 A Es of 
S pecial I n terest
A d diti o n of b ol de d te xt f or 
clarificati o n: O nce n otifie d, t he 
i n vesti gat or m ust c o ntact t he 
partici pa nt t o re vie w  t he 
partici pa nt’s stat us as s o o n as 
p ossi ble (e g, wit hi n 2 4 h o urs), t o 
assess t he se verit y of his/ her 
c o nsti pati o n or t he prese nce of 
a n y se q uelae of c o nsti pati o n. 
E ver y atte m pt s h o ul d be m a de 
t o re ac h t he st u d y p artici p a nt 
wit hi n 2 4 h o urs .
F or clarit y: Se vere c o nsti pati o n is a n a d verse 
e ve nt of s pecial i nterest a n d d ue to t he 
p ote ntial seri o us ness of t his c o n diti o n, 
i n vesti gat or's s h o ul d atte m pt t o reac h t he 
partici pa nt wit hi n a 2 4 h o ur peri o d. T he 
pre vi o us iterati o n of t his te xt all o w  f or 
i nter pretati o n of t he p hrase "as s o o n as 
p ossi ble", w hile t he a me n d me nt ma kes it 
clear t hat " E ver y atte m pt s h o ul d be ma de t o 
reac h t he st u d y partici pa nt wit hi n 2 4 h o urs".
Secti o n 1 2. 9 A p pe n di x 9 
T he s p o ns or c o ntact i nf or mati o n 
wa s u p date d. 
Pers o n nel c ha n ge at Aller ga n