Conditions: Irritable Bowel Syndrome With Diarrhea
Keywords: IBS-D BAM
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study will evaluate the possibility of a differential effect of eluxadoline on altered bowel function in Irritable Bowel Syndrome with Diarrhea (IBS-D) participants with and without evidence of Bile Acid Malabsorption (BAM).

Detailed description:

Arms:
arm 1: IBS-D participants with evidence of Bile Acid Malabsorption (BAM) treated with eluxadoline 100 mg oral tablets twice daily (BID) with food for 4 weeks. arm 2: IBS-D participants without evidence of BAM treated with eluxadoline 100 mg oral tablets BID with food for 4 weeks.

Interventions: intervention 1: Eluxadoline
Intervention descriptions: intervention 1: Eluxadoline 100 mg oral tablets BID with food.

Protocol document:
Prot_000.pdf: 
 
     
   
   
  
         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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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 .


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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.


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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.


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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.


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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. 


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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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
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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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.


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El u xa d oli ne
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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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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,


El u xa d oli ne
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 .


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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.


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9 0
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
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 1


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 2


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 3


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 4


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 5


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 6


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 7


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 8


El u xa d oli ne
Pr ot oc ol 3 0 3 0 -4 0 1 -0 0 2
9 9


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

SAP_001.pdf: 
 
   
 
 
 
         NCT03441581 
 
Study ID: 3030-401-002 
 
 
Title: 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) 
 
                Statistical Analysis Plan Date: March 20, 2020 


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1.0 
TITLE PAGE 
 
 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) 
STATISTICAL ANALYSIS PLAN  
Final 1.0:   26 Feb 2018 
Amendment 1: 20 March 2020 
 
 
 
 
 
Confidentiality Statement 
This document is the property of Allergan, Inc., and may not -- in full or part -- be passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, Inc. 


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2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
TABLE OF CONTENTS .................................................................................................................. 2 
3.0 
LIST OF ABBREVIATIONS ........................................................................................................... 4 
4.0 
INTRODUCTION ............................................................................................................................ 6 
5.0 
OBJECTIVES ................................................................................................................................. 10 
6.0 
PARTICIPANT POPULATIONS .................................................................................................. 11 
6.1 
sCREENED Population .................................................................................................... 11 
6.2 
enrolled pOPULATION ................................................................................................... 11 
6.3 
MODIFIED Intent-to-Treat Population ............................................................................ 11 
6.4 
Safety Population .............................................................................................................. 11 
7.0 
PARTICIPANT DISPOSITION ..................................................................................................... 12 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................ 13 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................ 14 
9.1 
Extent of Exposure ........................................................................................................... 14 
9.2 
Measurement of Treatment Compliance ........................................................................... 14 
10.0 
EFFICACY ANALYSES ............................................................................................................... 15 
10.1 
Primary Efficacy Parameter .............................................................................................. 15 
10.2 
Secondary Efficacy Parameters ........................................................................................ 15 
11.0 
SAFETY ANALYSES .................................................................................................................... 16 
11.1 
Adverse Events ................................................................................................................. 16 
11.2 
Clinical Laboratory Parameters ........................................................................................ 17 
11.3 
Vital Signs ........................................................................................................................ 20 
11.4 
Electrocardiogram (ECG) ................................................................................................. 20 
12.0 
HEALTH OUTCOMES ANALYSES ............................................................................................ 21 
13.0 
INTERIM ANALYSIS ................................................................................................................... 22 
14.0 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 23 
15.0 
STATISTICAL SOFTWARE ......................................................................................................... 24 
16.0 
DATA HANDLING CONVENTIONS .......................................................................................... 25 
16.1 
Visit Time Windows ......................................................................................................... 25 
16.2 
Derived Variables ............................................................................................................. 25 
16.3 
Repeated or Unscheduled Assessments of Safety Parameters .......................................... 26 
16.4 
Missing Date of the Last Dose of STudy Treatment......................................................... 26 


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16.5 
Missing Severity Assessment for Adverse Events ............................................................ 27 
16.6 
Missing Causal Relationship to stuyd drug for Adverse Events ....................................... 27 
16.7 
Missing Date Information for Adverse Events ................................................................. 27 
16.8 
Missing Date Information for Prior or Concomitant Medications .................................... 28 
16.9 
Character Values of Clinical Laboratory Parameters ........................................................ 30 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................................... 32 
18.0 
REFERENCES ............................................................................................................................... 33 
 
 


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3.0 
LIST OF ABBREVIATIONS  
7αC4                                  7a-hydroxy-4-cholesten-3-one 
AE 
adverse event 
BAM                                  bile acid malabsorption 
BP                                      blood pressure 
BSFS                                  Bristol Stool Form Scale 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ETO                                   end of treatment 
ET                                      early termination 
mITT 
modified intent to treat 
IBS                                     irritable bowel syndrome 
IBS-D                                 irritable bowel syndrome with diarrhea 
IBS-Quality of Life            IBS-Quality of Life 
PCS 
potentially clinically significant 
PK                                      pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Le Système International d’Unités (International System of Units) 
TEAE 
treatment-emergent adverse event 


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Summary of Changes from the Final SAP: 
Date 
Section 
Description 
03/16/2020 
16.2 Derived Variables  
IBS-QOL conversion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
final protocol of Study 3030-401-002 dated 19 Oct 2017 and the most recent amendment 
dated 17 Apr 2019. Specifications of tables, figures, and data listings are contained in a 
separate document. The SAP for pharmacokinetic will be prepared separately. 
Study 3030-401-002 is a Phase 4, non-randomized, open-label, parallel-group, cohort 
controlled trial to evaluate the efficacy, safety, tolerability and pharmacokinetics of 
eluxadoline in participants meeting the Rome IV criteria for IBS-D with and without 
evidence of BAM. This study will be comprised of a 0 to 2-week screening period, a 2 to 
3-week pretreatment period, a 4-week open-label treatment period during which time 
participants will receive eluxadoline 100 mg BID, and a 2-week post-treatment safety 
follow-up.  
There will be 24 participants enrolled in the study, 12 with evidence of BAM and 12 
without evidence of BAM. Cohort 1consists of IBS-D participants with evidence of BAM 
treated with eluxadoline 100 mg oral tablets BID with food. Cohort 2 consists of IBS-D 
participants without evidence of BAM treated with eluxadoline 100 mg oral tablets BID 
with food. The 100 mg BID dose selected for this trial is consistent with US and global 
labeling for eluxadoline in IBS-D. This non-randomized design is considered most 
appropriate since the cohort assignment will be based on the determination of BAM 
status. As far as possible, the 2 cohorts will be matched by age, gender and severity of 
historic symptoms based on the investigator's discretion. 
The total duration of the study is up to 11 weeks, which includes: screening period (1-2 
weeks), pretreatment period (2-3 weeks), 4-week open-label treatment period, and 2-
week post-treatment follow-up period. A total of 6 study visits are planned for each 
participant: Screening, Week -3 to -4 (Visit 1); Pretreatment, Week -3 to -2 (Visit 2); Day 
1 (Visit 3; first administration of study drug); Week 2 (Visit 4; Week 2 of treatment), 
may be done by telephone; Week 4 (Visit 5; end of treatment/early termination); Week 6 
(Visit 6; post-treatment follow-up), may be done by telephone The end of the study is 
defined as the date of Visit 6. The schedule of evaluations for Study 3030-401-002 is 
presented in Table 4-1.   


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Table 4-1: Schedule of Activities (SoA) 


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5.0 
OBJECTIVES 
The primary objectives of this study are to evaluate the efficacy of eluxadoline 100 mg 
BID in IBS-D participants with evidence of BAM compared to IBS-D participants 
without evidence of BAM and to evaluate the safety and tolerability of eluxadoline 100 
mg BID in IBS-D participants with evidence of BAM and in IBS-D participants without 
evidence of BAM. The secondary objectives of this study are to further evaluate the 
efficacy of eluxadoline 100 mg BID in IBS-D participants with evidence of BAM 
compared to IBS-D participants without evidence of BAM and to evaluate the population 
PK of eluxadoline in IBS-D participants with and without evidence of BAM. 


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6.0 
PARTICIPANT POPULATIONS 
The analysis populations will consist of participants as defined below. 
6.1 
SCREENED POPULATION 
All screened participants who sign informed consent. 
6.2 
ENROLLED POPULATION 
All participants in Screened Population who meet the eligibility criteria and enter the 
open-label treatment period (on Day 1, Visit 3). 
6.3 
MODIFIED INTENT-TO-TREAT POPULATION 
All participants in Enrolled Population with ≥ 1 postbaseline assessment for Bristol Stool 
Form Scale (BSFS). 
6.4 
SAFETY POPULATION 
 All participants who received ≥ 1 dose of study treatment. 


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7.0 
PARTICIPANT DISPOSITION 
The number of participants in 3 study populations (Enrolled, mITT, and Safety) will be 
summarized overall, by participant group (BAM or Non-BAM) and overall for the 
Screened Population. 
The number of screen failures (ie, participants who enter the Screening Period and the 
Pretreatment but not enter the open-label treatment period (on Day 1, Visit 3)) and 
participants ineligible for enrollment, along with the associated reasons for failure, will 
be tabulated overall. Screened participants who are not enrolled will also be listed with 
the reasons for exclusion. 
The number and percentage of participants who complete the open-label Treatment 
Period and Post-treatment Period and of participants who prematurely discontinue during 
the same period will be presented by participant group and overall for Enrolled 
Population. The reasons for premature discontinuation from the open-label study period 
or Post-treatment Period as recorded in the eCRF will be summarized (number and 
percentage) by participant group for the Enrolled Population. All participants who 
prematurely discontinue during the open-label Treatment Period or Post-treatment Period 
will be listed by discontinuation reason for the Enrolled Population. 
 
 


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8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters (age; sex; race; ethnicity), baseline characteristics (weight; 
height) will be summarized descriptively by participant group (BAM or Non-BAM) for 
the Safety population. Continuous variables will be summarized by number of 
participants and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants. 
Abnormalities in participants’ medical and surgical histories will be coded using the 
MedDRA (Medical Dictionary for Regulatory Activities, version 20 or newer). The 
number and percentage of participants with abnormalities in medical and surgical 
histories in each system organ class and preferred term will be summarized by participant 
group for the Safety Population. 
 
All prescription drugs, herbal products, vitamins, minerals, and over-the-counter 
medications taken within 30 days prior to the open-label treatment period will be 
recorded as prior medications. All medications taken after beginning open-label treatment 
and through the early termination or follow-up visit will be recorded as concomitant 
therapy. The use of all prior and concomitant medications is to be recorded on the 
participant’s electronic case report form (eCRF) at each visit along with the reason the 
medication was taken. 
Prior and concomitant medications will be listed by participant group with the drug 
names and Anatomical Therapeutic Chemical classification codes based on the data 
collected in the eCRF. 
The World Health Organization (WHO) Drug Dictionary, version March 2017 or newer, 
will be used to classify prior and concomitant medications by therapeutic class and drug 
name. 
 
 
 


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9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
EXTENT OF EXPOSURE 
Exposure to the study treatment for the Safety Population during the treatment period will 
be summarized for treatment duration, calculated as the number of days from the date of 
the first dose of study treatment to the date of the last dose of study treatment, inclusive. 
Descriptive statistics (number of participants, mean, SD, median, minimum, and 
maximum) will be presented by participant group (BAM or Non-BAM). 
Patient-years, defined as exposure to the study treatment in years, will be summarized by 
participant group for the Safety Population. 
9.2 
MEASUREMENT OF TREATMENT COMPLIANCE 
Dosing compliance for a specified period is defined as the number of tablets taken by a 
participant during that period divided by the number of tablets prescribed for the same 
period multiplied by 100. This information will be obtained from Study Treatment 
Record of the participant’s electronic case report form. 
Descriptive statistics for study drug compliance will be presented by participant group for 
each period between 2 consecutive visits, as well as for the whole treatment period (Visit 
4 to Visit 5), for the Safety Population. 


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10.0 
EFFICACY ANALYSES 
The efficacy of eluxadoline will be based on eDiary measures related to improvements in 
IBS-D signs and symptoms. Participants will be required to access the eDiary each 
evening, preferably at the same time each day, to record daily IBS symptoms. 
The efficacy analyses will be based on the mITT Population. Baseline for efficacy based 
on eDiary measures will be determined for the respective scores average over 14 days 
prior to the first dose of study treatment. Baseline for efficacy based on study visit 
measures (IBS-QoL and 7αC4) will be the last assessment before the first dose of study 
treatment. Continuous variables will be summarized by number of participants and mean, 
SD, median, minimum, and maximum values. Categorical variables will be summarized 
by number and percentage of participants. All efficacy endpoints will be summarized by 
participant group (BAM or Non-BAM). 
10.1 
PRIMARY EFFICACY PARAMETER 
The primary efficacy parameter will be the change from baseline in average BSFS score 
over 4 weeks of treatment period. The participant-reported BSFS is a 1 to 7 scale where 1 
corresponds to a hard stool and 7 corresponds to watery stool. For each participant, all 
available (non-missing) postbaseline BSFS score of the treatment period will be used to 
calculate the average BSFS score.       
10.2 
SECONDARY EFFICACY PARAMETERS 
The secondary efficacy parameter will be: 
• Change from baseline in the 4-week average of daily bowel movement frequency 
during the treatment period; 
• Change from baseline in the 4-week average of daily worst abdominal pain scores 
during the treatment period; 
• Change from baseline in the 4-week average of daily bloating during the 
treatment period; 
• Change from baseline in the 4-week average of number of daily urgent bowel 
movements during the treatment period; 
• The proportion of participants with any fecal incontinence during the treatment 
period; 
• Change from baseline in IBS-QoL total score at the end of the treatment period; 
Change from baseline in serum 7αC4 levels at the end of the treatment period.. 
 


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11.0 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety Population. The safety parameters 
will include adverse events (AEs), clinical laboratory and vital signs. For each safety 
parameter of the clinical laboratory and vital sign parameters, the last non-missing safety 
assessment before the first dose of study treatment will be used as the baseline for all 
analyses of that safety parameter. Continuous variables will be summarized by number of 
participants and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants. 
11.1 
ADVERSE EVENTS 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 20 or newer. 
An AE will be considered a treatment-emergent adverse event (TEAE) if it was present 
after the first dose of study treatment or was present before the date of the first dose of 
study treatment and increased in severity after the first dose of study treatment. If more 
than 1 AE was reported before the first dose of study treatment and coded to the same 
preferred term, the AE with the greatest severity will be used as the benchmark for 
comparison with the AEs occurring during the study. An AE that occurs after the date of 
the last protocol-defined study visit (or last contact date if last study visit is missing) will 
not be counted as a TEAE. 
The incidence of participants reporting TEAEs in each participant group will be tabulated 
by system organ class (SOC) and preferred term; by SOC, preferred term, and severity; 
and by SOC, preferred term, and relationship to the study drug. If more than 1 event 
occurs with the same preferred term for the same participant, the participant will be 
counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to the study drug. 
The distribution of TEAEs by SOC and preferred term, severity, and relationship to study 
drug will be summarized by participant group. 
In addition, the incidence of serious adverse events and events that caused death, if any, 
will be summarized by participant group, SOC, and preferred term. 
A listing of participants who discontinued because of an AE(s) and a listing of 
participants with serious AEs and participants who died (if any) will be presented. 
AEs during the Post-treatment Period will also be included in the listings. 


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11.2 
CLINICAL LABORATORY PARAMETERS 
Descriptive statistics for clinical laboratory values (in SI units) at baseline, at end-of-
treatment, changes from the baseline to end-of-treatment will be presented by participant 
group for the following laboratory parameters: 


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Table 11.2–1. 
Criteria for Potentially Clinically Significant Laboratory Tests 


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11.3 
VITAL SIGNS 
Vital signs to be assessed include systolic and diastolic blood pressure (BP), pulse rate, 
respiration rate and weight. 
Descriptive statistics for BP (systolic and diastolic), pulse rate, respiration rate and 
weight will be presented by participant group and for all participants at baseline, end-of-
treatment, and for changes from baseline to end-of-treatment.  
Blood pressure and pulse rate values will be regarded as PCS if they meet both the 
observed value criteria and the change from baseline value criteria. Weight values will be 
regarded as PCS if they meet either high or low change from baseline value criterion. The 
number and percentage of participants who have PCS post-baseline vital sign values will 
be tabulated by participant group. The percentages will be calculated relative to the 
number of participants who have available baseline values and at least 1 post-baseline 
assessment. The numerator will be the total number of participants with available non-
PCS baseline values and at least 1 PCS postbaseline value. 
 A supportive listing of participants with PCS end-of-study vital sign values will be 
provided, including the participant number and baseline and end-of-treatment values, for 
the Safety Population. In this listing, any participant with PCS value (if any) during the 
Post-treatment Period will also be included. Criteria for PCS vital sign parameters is 
provided below in Table 10.3-1.  
Table 11.3–1. 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteria 
Observed Value 
Change From Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a A postbaseline value is considered potentially clinically significant if it meets both the observed-value 
and the change-from-baseline criteria. 
bpm = beats per minute. 
11.4 
ELECTROCARDIOGRAM (ECG) 
ECG assessment is unavailable in this study. 


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12.0 
HEALTH OUTCOMES ANALYSES 
The health outcome data are unavailable in this study.  


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13.0 
INTERIM ANALYSIS 
No interim analysis will be conducted 


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14.0 
DETERMINATION OF SAMPLE SIZE 
The total sample size for this study is 24 participants (12 participants with BAM and 12 
participants without BAM). No formal sample size estimation will be calculated because 
the sample size for this study is not based on statistical consideration. 


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15.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux 
operating system. 


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16.0 
DATA HANDLING CONVENTIONS 
16.1 
VISIT TIME WINDOWS 
 
Table 16.1–1 presents the visits assigned for efficacy and safety analyses and the 
corresponding range of treatment days (window) during which an actual visit may occur. 
Table 16.1–1. 
Visit Time Windows 
Derived Visit 
Scheduled Visit Daya 
Window 
Visit 1 (Screening) 
 
 
Visit 2 (Pre-treatment) 
 
 
Visit 3 (Baseline) 
Day 1 
Days ≤ 1 
Visit 4 
Day 15 
Days [2, 21] 
Visit 5 (End of 
Treatmentb) 
Day 29 
Days >=22 and last dose day +1 
Visit 6 
Day 33  
Days>=last dose day + 2 
a 
Relative to the date of the first dose of treatment period. Day 1 = the date of the first dose of study treatment. 
There is no Day 0. 
b 
Presented in analysis tables for safety parameters, including but not limited to clinical laboratory values and vital 
signs. 
If the assessment date (if the assessment date is unavailable, use visit date instead) is on 
or after the date of the first dose of study treatment, the study day is calculated by 
assessment date – date of the first dose of study treatment + 1. If the assessment date is 
before the date of the first dose of study treatment, the study day is calculated by 
assessment date – date of the first dose of study treatment. Therefore, a negative day 
indicates a day before the start of the study treatment. 
If a participant has 2 or more visits within the same window, the last visit with a non-
missing value will be used for analysis. 
 
 
 
 
16.2 
DERIVED VARIABLES 
During the open-label treatment period, participants will record via the eDiary their daily 
IBS-D symptoms. The average values of non-missing postbaseline will be derived for the 
following variables: 


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The primary endpoint:  BSFS score; 
The secondary endpoints: the worst abdominal pain score, the worst abdominal bloating 
score, the number of bowel movements and the number of urgent bowel movements. 
Only non-missing postbaseline values will be used to calculate the average values. 
Imputation will not be applied to missing records. The denominator should be adjusted 
accordingly when average values are calculated.  
The IBS-QOL is composed of 34 items scored on a 1-5 scale, where lower item scores 
indicate greater quality of life. All items are reversed prior to derivation of composite 
scores; thus, higher IBS-QOL total scores indicate greater quality of life. The 
transformation formula used for the IBS-QOL total score is 
Score = 100 × 
sum of all items – lowest possible derived score 
possible sum range 
 
 
 
Items 
Lowest/Highest 
Possible Derived Score 
Possible Sum 
Range 
IBS-QOL total score 
All items 
34, 170 
136 
If 7 or more items are missing, the total score will be set to missing; otherwise, the total score will be calculated 
using the mean score of the non-missing items to replace the missing item. 
All items reversed prior to derivation of overall and subscale scores: reversed score = 6 – original score. 
 
 
16.3 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a participant has repeated assessments before the start of the first treatment, the results 
from the final non-missing assessment made prior to the start of the study treatment will 
be used as baseline. If end-of-treatment assessments are repeated or if unscheduled visits 
occur, the last non-missing postbaseline assessment will be used as the end-of-treatment 
assessment for generating summary statistics. However, all postbaseline assessments will 
be used for PCS value determinations, and all assessments will be presented in the data 
listings. 
16.4 
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT 
When the date of the last dose of study treatment is missing for a participant in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all 
efforts are made it is still missing, the last available dosing record date will be used as the 
last dose date. 


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16.5 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started before the date of the first dose of study 
treatment, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of study treatment, an intensity of severe will 
be assigned. The imputed values for severity assessment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
16.6 
MISSING CAUSAL RELATIONSHIP TO STUYD DRUG FOR 
ADVERSE EVENTS 
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
16.7 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 


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16.8 
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS 


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17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
There are no changes to the analyses specified in the latest protocol (dated 19 Oct 2017). 


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18.0 
REFERENCES 
N/A