A Randomized, Double-Blind, Placebo Controlled Trial of Aldafermin (NGM282) for Treatment of Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)
Phase: PHASE2
Conditions: Chronic Diarrhea, Irritable Bowel Syndrome With Diarrhea, Bile Acid Malabsorption, Bile Acid Diarrhea, Bile Acid Malabsorption Syndrome Type II, Functional Diarrhea
Sponsor: Michael Camilleri, MD

 
 
A R a n d o miz e d, D o u bl e -Bli n d, Pl ac e b o 
C o ntr oll e d Tri al of Al d af er mi n ( N G M 2 8 2) f or 
Tr e at m e nt of C hr o nic Di arr h e a D u e t o Bil e Aci d 
M al a bs or pti o n ( B A M)  
 
N C T 0 5 1 3 0 0 4 7  
 
9/ 2 9/ 2 0 2 2  

C o nfi de ntial  
Pa ge 1  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
A R a n d o mize d, D o u ble -Bli n d, Pl ace b o C o ntr olle d Tri al  of Al d afer mi n 
( N G M 2 8 2) f or Tre at me nt of C hr o nic Di arr he a D ue t o Bile Aci d 
M al a bs or pti o n ( B A M)  
 
 
 
 
 
 
 
 
Mic hael Ca milleri, M. D.  
 
 
 
 
 
Ma y o Cli nic  
 
 
 
 
 
2 0 0 First Street S W  
 
 
 
 
 
R oc hester, Mi n nes ota  5 5 9 0 5  
 
 
 
 
 
Tele p h o ne: 
 
 
 
 
 
 
E mail: ca milleri. mic hael @ ma y o.e d u  
 
 
 
 
 
 
 
St u d y N u m ber:  
2 1 -0 0 9 3 4 8  
 
C o m p o u n d Na me:  
Al dafer mi n ( N G M 2 8 2)  
I N D 
I n vesti gat or-hel d I N D  
Letter of cr oss -refere nce f or I N Ds 
 a n d 
 hel d b y N G M  
 
De vel o p me nt P hase:  
II   
 
Versi o n Date of Pr ot oc ol:  
 Versi o n 6 . 0: Se pte m ber 2 9 t h, 2 0 2 2  
 
 
 
 
C o nfi de nti alit y  St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of N G M Bi o p har mace uticals,  I nc. U na ut h orize d 
distri b uti o n,  c o p yi n g,  or  discl os ure  is strictl y pr o hi bite d  u nless  re q uire d b y  a p plica ble  la w. Pers o ns  
recei vi n g t his i nf or mati o n m ust  be  n otifie d  t hat it is c o nfi de ntial  a n d ma y  n ot  be  f urt her distri b ute d,  
c o pie d, or discl ose d.  
 
 
 
 
P R O T O C O L  HI S T O R Y  
 
D oc u m e nt  
A m e n d m e nt  T y pe  
D ate  
Ori gi nal , Versi o n 1 . 0 
N ot  a p plica ble 
A u g ust 3 1, 2 0 2 1  
First pr ot oc ol re visi o n , Versi o n  2. 0  
N ot a p plica ble  
Se pte m ber 1 5, 2 0 2 1  
Sec o n d pr ot oc ol re visi o n , Versi o n  3. 0  
N ot a p plica ble  
Oct o ber 7, 2 0 2 1  
T hir d pr ot oc ol re visi o n , Versi o n  4. 0  
A me n d me nt 1  
Fe br uar y 9 , 2 0 2 2 
F ort h pr ot oc ol re visi o n, Versi o n 5. 0  
A me n d me nt 2  
A pril 2 0, 2 0 2 2  
F ift h pr ot oc ol re visi o n, Versi o n 6  
A me n d me nt 2  
Se pte m ber 2 9 t h, 2 0 2 2 

C o nfi de ntial  
Pa ge 2  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
P R O T O C O L  S Y N O P SI S  
 
Pr ot oc ol  Title  
A Ra n d o mize d, D o u ble -Bli n d, Place b o C o ntr olle d Trial of Al dafer mi n ( N G M 2 8 2) 
f or Treat me nt of C hr o nic Diarr hea D ue t o Bile Aci d Mala bs or pti o n (( B A M)  
St u d y  N u m ber  
2 1 -0 0 9 3 4 8  
De v el o p me nt  P hase  
P hase  II 
St u d y  Ce nter  
Ma y o  Cli nic,  R oc h ester,  Mi n nes ota,  U S A  
A bstract  
Bile aci d mala bs or pti o n ( B A M), als o k n o w n as bile aci d diarr hea ( B A D), is a c o n diti o n 
c h aracterize d b y e xcessi ve bi os y nt hesis of bile aci ds or i na bilit y t o rea bs or b s ufficie nt 
bile aci ds i n t he ter mi nal ile u m ( 1, 2). T his res ults i n u na bs or be d bile aci ds i n t he c ol o n 
lea di n g t o i ncrease d c ol o nic secreti o n of fl ui d, t here b y ca usi n g diarr hea. B A M/ B A D 
c o ntri b utes t o s y m pt o ms i n a s u bset of i n di vi d uals wit h Irrita ble b o wel s y n dr o me (I B S), 
w hic h is t he m ost c o m m o n l o wer gastr oi ntesti nal ( GI) dis or der t hat affects 1 1 % of a d ults 
(3 ). C urre ntl y, I B S a n d s u b gr o u ps diarr hea-pre d o mi na nt I B S (I B S -D), a n d I B S -
c o nsti pati o n (I B S -C), are defi ne d b y s y m pt o ms al o ne. A part fr o m ce ntral h y per vi gila nce 
a n d ps yc h ol o gical dist ur ba nces i n I B S ( 4 ), 4 8 % of I B S-D patie nts ha ve accelerate d 
c ol o nic tra nsit, 2 1 % ha ve i ncrease d rectal se nsati o n ( 5 ), a n d 2 5-3 3 % of I B S -D patie nts 
ha v e a b n or mal bile aci d ( B A) s y nt hesis or e xcreti o n ( 6 ). Al dafer mi n ( N G M 2 8 2) is a n 
a n al o g of fi br o blast gr o wt h fact or 1 9 ( F G F 1 9), a p ote nt i n hi bit or of bile aci d ( B A) 
s y nt hesis i n a ni mals a n d h u ma ns. 
H y p ot hesis  
Al dafer mi n re d uces bile aci d s y nt hesis a n d fecal e xcreti o n of bile aci ds a n d n or malizes 
s y m pt o ms of c ol o nic d ysf u ncti o n i n B A M/ B A D wit h i ncrease d fecal B A e xcreti o n.  
S pecific Ai m  
T his si n gle -ce nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y is  desi g ne d t o  
c o m pare  effects of al dafer mi n, 1 m g a n d place b o S Q dail y , o n b o wel f u ncti o ns,  he p atic 
s y nt hesis a n d fecal e xcreti o n of bile aci ds i n patie nts wit h diarr hea ass ociate d wit h bile 
aci d mala bs or pti o n  ( B A M). 
N u m ber  of S u bjects  
A p pr o xi matel y  3 6  patie nts wit h la b orat or y c o nfir me d B A M  will  be  e nr olle d. 
St u d y  D urati o n  
T he st u d y i ncl u des a ma xi m u m 2 8 -da y prescree n peri o d a n d a 2 8 -da y treat me nt peri o d 
f or a ma xi m u m d urati o n of  5 6  da ys.  
St u d y  P o p ulati o n  
I ncl usi o n criteri a : 
1.  A ge d  1 8  t o 7 5  years,  i ncl usi ve at Visit 1 S cree n . 
2.  Cli nical  dia g n osis  of  f u ncti o nal diarr hea or I B S wit h diarr hea  acc or di n g t o  R o me  III 
or I V criteria  at Visit 1 Scree n . 
3.  Cli nical la b orat or y e vi de nce of B A M ( 2 0-2 2) , wit h at least o ne of t he f oll o wi n g 
res ults rec or de d i n t heir past me dical hist or y: 
•  
Ser u m C 4 ≥ 5 2 n g/ m L  
•  
Fecal B A > 2 3 3 7 µ m oles / 4 8 h o urs  
•  
T otal fecal B A > 1 0 0 0 µ m oles / 4 8 h o urs + 4 % pri mar y B A  
•  
Fecal p ri mar y B A > 1 0 % / 4 8 h o urs 
 
4.  B o d y  mass  i n de x ( B MI) 1 8. 0  t o 4 5 . 0 k g/ m 2, i ncl usi ve at Visit 1 Scree n  
 
5.    U n dersta n ds t he st u d y pr oce d ures, is willi n g a n d a ble t o c o m pl y wit h t he st u d y 
pr oce d ures, a n d is a ble t o gi ve i nf or me d c o nse nt  
 
6.     If treate d wit h a n y of t he f oll o wi n g me dicati o ns, d osi n g m ust be sta ble f or 3 0  da ys 
pri or t o Visit 1 Scree n . Patie nt m ust a gree t o mai ntai n t he sa me d ose of 
me dicati o n t hr o u g h o ut t he st u d y:  
•  Tric yclic a nti de pressa nts, selecti ve ser ot o ni n re u pta ke i n hi bit ors  
( S S RIs), ser ot o ni n a n d n ore pi ne p hri ne re u pta ke i n hi bit ors ( S N RIs).  
•  Bile aci d se q uestra nts s uc h as c olesti p ol, c h olest yra mi ne  a n d 
c olese vela m . 
 
7.     Patie nts m ust use o ne hi g hl y effecti ve met h o d of c o ntrace pti o n f or 3 0 da ys bef ore 

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t he st u d y t hr o u g h 9 0 da ys after st u d y c o m pleti o n f or males a n d t hr o u g h 3 0 da ys 
after st u d y c o m pleti o n f or fe males. Hi g hl y effecti ve met h o ds of c o ntrace pti o n 
i ncl u de: 
•  Oral, i m pla nta ble, s u bder mal or i njecta ble h or m o nal c o ntrace pti ves  
•  Sta n dar d i ntra uteri ne de vice or va gi nal ri n g  
•  Male or fe male c o n d o ms a n d dia p hra g ms use d wit h s per mici de  
•  A bsti ne nce fr o m heter ose x ual i nterc o urse  
•  Fe male part ners e xcl usi vel y se x uall y acti ve wit h a s ur gicall y sterilize d 
male part ner  
•  Fe males w h o are s ur gicall y sterile pri or h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect o m y) or p ost me n o pa usal  ( defi ne d 
as: 1 2  c o nsec uti ve  m o nt hs  wit h  n o  me nses) are n ot c o nsi dere d t o be of 
c hil d beari n g p ote ntial  
 
E xcl usi o n criteri a:  
1.     Pre g na nt or lactati n g  
 
2.    Str u ct ural or meta b olic diseases/c o n diti o ns t hat affect t he gastr oi ntesti nal s yste m  
 
3.    Use of t he f oll o wi n g me dicati o ns at least 1 4  da ys pri or t o Visit 1 t hr o u g h o ut  t he 
d urati o n of t he treat me nt peri o d   
•  Patie nts ma y elect t o wit h dra w fr o m  bile aci d se q uestra nts s uc h as 
c olesti p ol, c h olest yra mi ne  a n d c olese vela m  or t he y ma y c o nti n ue b ut 
t he y m ust c o nti n ue at t he sa me d ose t hr o u g h o ut t he st u d y.  
•  GI me dicati o ns i ncl u di n g:  
•  A nti -na usea a ge nts i ncl u di n g tri met h o be nza mi de, pr o met hazi ne, 
pr oc hl or perazi ne, di me n h y dri nate, h y dr o x yzi ne  
•  Os m otic la xati ve a ge nts i ncl u di n g lact ul ose, s or bit ol or P E G s ol uti o ns 
as Mirala x a n d Gl yc ola x  
•  Pr o ki netic a ge nts i ncl u di n g te gaser o d, met ocl o pra mi de, pr ucal o pri de, 
d o m per i d o ne, er yt hr o m yci n, clarit hr o m yci n a n d azit hr o m yci n. 
•  5-H T 3 a nta g o nists i ncl u di n g al osetr o n, o n da nsetr o n, tr o pisetr o n  
•  
Patie nts ma y use Ga b a pe nti n  if t he y are o n a sta ble d ose, w hic h is n ot 
greater t ha n 1 2 0 0 m g  a da y.  
•  Dr u gs wit h a k n o w n p har mac ol o gical acti vit y at 5 -H T 4, 5 -H T 2 b or 
5 -H T 3 rece pt ors i ncl u di n g te gaser o d, o n da nsetr o n, gra nisetr o n a n d 
tr o pisetr o n  
•  All n arc otics i ncl u di n g c o dei ne, m or p hi ne, a n d pr o p o x y p he ne, eit her 
al o ne or i n c o m bi nati o n  
•  A nti -c h oli ner gics i ncl u di n g dic ycl o mi ne, h y osc ya mi ne, 
pr o pa nt heli ne.  
•  A nti m uscari nics  
•  Tra ma d ol  
•  Pe p per mi nt oil  
•  S yste mic a nti bi otics a n d a nti bi otics directe d at c ol o nic fl ora 
i ncl u di n g rifa xi mi n a n d metr o ni daz ole 
 
 

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5 .    Cli nicall y rele v a nt c ha n ges i n dietar y, lifest yle, or e xercise re gi me n wit hi n 3 0  
       da ys  pri or t o Visit 1 Scree n a n d t hr o u g h o ut t he d urati o n of t he st u d y  
 
6 .    A n y  c ol o nic  or  maj or  a b d o mi nal  s ur ger y i ncl u di n g bariatric  s ur ger y, gastric  
ba n di n g, st o m ac h s ur ger y  a n d  i ntesti nal or c ol o nic s ur ger y.  Pr o ce d ures  s uc h as 
a p pe n dect o m y, c h olec ystect o m y, h ysterect o m y, caesarea n secti o n, or 
p ol y pect o m y are  all o we d as  l o n g as t he y ha ve  occ urre d at least 3 m o nt hs pri or  t o 
Visit 1 Scree n.  
 
7 .    .Hist or y  of  c ol orectal  ca ncer,  i nfla m mat or y b o wel  disease,  di vertic ulitis,  isc he mic 
c olitis, micr osc o pic c olitis  or  celiac disease  
 
8 .     Hist or y of or ga nic a b n or malities of t he GI tract, i ntesti nal o bstr ucti o n, strict ure,  
t o xic me gac ol o n, GI perf orati o n, or i m paire d i ntesti nal circ ulati o n. 
 
9 .     Ot her GI diseases s uc h as GI blee di n g  or ulcerati o ns  
 
1 0 .    Hist or y of cere br o vasc ular disease i ncl u di n g str o ke, TI A, ac ute c or o nar y 
s y n dr o me, m y ocar dial i nfarcti o n or u nsta ble a n gi na 
 
1 1 .    Cli nicall y si g nifica nt car diac  hist or y or prese nce of electr ocar di o gra m ( E C G)  
fi n di n gs at Visit 1  Scree n:  
o  A b n or mal  heart  rate < 4 0 or  >  1 0 0  beats  per mi n ute  
o  Q Tc  i nter val > 4 7 0  millisec o n ds  ( ms) 
o  Q R S  i nter val ≥ 1 1 0  ms  
o  P R  i nter val ≥ 2 2 0  ms  
 
1 2 .    He patic d ysf u ncti o n i ncl u di n g a b n or mal ser u m ala ni ne  a mi n otra nsferase [ A L T] or 
as partate tra nsa mi nase [ A S T] > 3 × u p per li mit of  n or mal  [ U L N]); t otal direct  
bilir u bi n >  2  ×  U L N,  or  al kali ne  p h os p hatase  > 2 ×  U L N  at Visit 1 Scree n  
 
1 3 .    Cli nicall y si g nifica nt re nal i ns ufficie nc y i ncl u di n g ser u m creati ni ne > 2. 5 m g/ d L at 
Visit 1 Scree n  
 
1 4 .   Hist or y  of  se v ere hea d i nj ur y  or  hist or y  of  seiz ures 
 
1 5 .    H ist or y of s uici de atte m pt or  a h os pitalizati o n f or  a maj or  ps yc hiatric c o n diti o n 
wit hi n  1  year  pri or t o Visit 1 Scree n . At Visit 1 Scree n  or d uri n g t he o pti o nal 
re m ote c o nse nt a n d eli gi bilit y re vie w, partici pa nts will c o m plete t he H os pital 
A n xiet y a n d De pressi o n q uesti o n naire. If eit her sc ore f or a n xiet y or de pressi o n 
i n di vi d uall y e xcee ds 8, t he sc ore will be disc usse d. T he patie nt will be  a n d a d vise d 
w het her t o partici pate or w het her t o see t heir pri mar y care p h ysicia n.  
 
1 6 .    Hist or y of alc o h ol use dis or der or s u bsta nce use dis or der wit hi n 2 years of Visit 1 
Scree n.  
 
1 7 .    Si g nifica nt hist or y or cli nical ma nifestati o n of a n y e n d ocri ne, aller gic,  
der mat ol o gical,  he patic,  re nal, he mat ol o gical,  p ul m o nar y,  GI,  ne ur ol o gical  or 
ps yc hiatric dis or der, mali g na nc y ( wit h t he e xce pti o n of treate d basal cell  
carci n o mas), or a n y ot her c o n diti o n  t hat w o ul d  pre ve nt  t he i n di vi d ual fr o m 
partici pati n g  i n t he st u d y d ue  t o ris k t o t he scie ntific vali dit y of st u d y assess me nts 
or t o pers o nal well -bei n g of t he   patie nt .   
 
1 8 .   Partici pate d i n a n ot her cli nical st u d y t hat i ncl u des a n i n vesti gati o nal dr u g or a 
bi ol o gic t hera p y wit hi n 3 0  da ys  or  5  half -li ves, w hic he ver ti me  peri o d  is 
l o n ger, pri or  t o Visit 1 Scree n . 

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Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
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Criteria f or E val u ati o n:  
B o wel p atter n:  
Assesse d b y patie nt -rec or de d dail y b o wel patter n diaries 
 
Bi o m ar k ers:  
Meas ure me nts of fasti n g ser u m C 4 a n d F G F -1 9 will be u n derta ke n at baseli ne, Da y 1 4 
a n d Da y 2 8.  
 
P h ar m ac o ki netics  ( P K): 
Tr o u g h c o nce ntrati o ns of al dafer mi n will be deter mi ne d b y a vali date d P K la b orat or y 
assa y perf or me d at a bi oa nal ytical C R O, Fr o nta ge La b o rat ories, at baseli ne, Da y 1 4 a n d 
Da y 2 8 . 
 
S afet y : 
Safet y will be assesse d t hr o u g h re g ular m o nit ori n g of a d verse  e ve nts, cli nical 
la b orat or y res ults, safet y 1 2-lea d E C Gs, p h ysical e xa mi nati o ns,  a n d  vital  si g ns. 
St u d y E n d p oi nts  
Pri m ar y E n d p oi nts:  
•  
C ha n ge i n fasti n g ser u m C 4 le vels fr o m Baseli ne t o Da y 2 8    
•  
C ha n ge i n st o ol c o nsiste nc y fr o m Baseli ne t o Da y 2 8  
 
Sec o n d ar y E n d p oi nts:  
•  
St o ol c o nsiste nc y base d o n Brist ol St o ol F or m Scale, B S F S  
o  
A bs ol ute c ha n ge i n st o ol c o nsiste nc y fr o m baseli ne t o  Da y 1 4 a n d Da y 
2 8 of treat me nt  
o  
A vera ge dail y st o ol c o nsiste nc y sc ore at D a y  1 4  a n d D a y  2 8  of 
treat me nt 
•  
Ma xi m u m a b d o mi nal pai n sc ore rate d b y patie nt usi n g an 1 1 -p oi nt scale , 0 t o 1 0 
i ncl usi ve wit h 0 as n o ne a n d 1 0 as w orst i ma gi na ble pai n  
•  
A bs ol ute c ha n ge i n a b d o mi nal pai n fr o m baseli ne t o Da y 1 4 a n d Da y 2 8 of 
treat me nt 
•  
N u m ber of b o wel m o ve me nts  per wee k  
•  
C ha n e i n t otal fecal bile aci d c o nce ntrati o n bet wee n baseli ne a n d Da y 2 8  
•  
Pr o p orti o n of fecal secret or y ( C D C A+  D C A) bile aci d as meas ure d i n a si n gle, 
ra n d o m st o ol sa m ple b y a vali date d la b orat or y assa y. 
•  
 P r o p orti o n of fecal pri mar y  ( C D C A + C A)  bile aci d as meas ure d i n  
a si n gle, ra n d o m st o ol sa m ple b y a vali date d la b orat or y assa y. 
•  
T otal fecal bile aci d c o nce ntrati o n i n a si n gle, ra n d o m st o ol sa m ple as meas ure d 
b y a vali date d la b orat or y assa y.  
•  
T otal al dafer mi n c o nce ntrati o n i n ser u m as meas ure d b y a vali date d la b orat or y 
assa y  
 
Statistical  Met h o ds  
S a m ple  size: 3 0 patie nts, 1 5 i n place b o gr o u p, 1 5 i n al dafer mi n treat me nt gr o u p . 
 
St atistic al  a n al ys es: Effects of treat me nt will be c o m pare d usi n g I nte nt -t o-Treat 
pri nci ples usi n g A N C O V A wit h B MI, ge n der a n d baseli ne fasti n g C 4 as c o va riates. 
A d verse e v e nts ( A Es) will be liste d a n d s u m marize d b y s yste m or ga n class a n d  
preferre d ter m, as well as acc or di n g t o se verit y a n d ca usalit y/relati o ns hi p t o st u d y  
treat me nt. O bser ve d val ues f or cli nical la b orat or y tests, vital si g ns a n d safet y 1 2 -
lea d E C Gs will b e s u m marize d b y treat me nt. O bser ve d val ues will b e classifie d 
as n or mal, a b n or malit y t hat is n ot cli nicall y si g nifica nt, a n d cli nicall y si g nifica nt  
a b n or malit y b y treat me nt Res ults  of  ot her  safet y assess me nts  will  be  liste d a n d 
s u m marize d as a p pr o priate.  
 
St atistic al p o wer:  Base d o n t he pri or o pe n -la bel st u d y, t he pr o p ose d sa m ple size of 1 5 
per gr o u p has ~ 8 0 % p o wer ( 2 -si de d α = 0. 0 5) t o detect cli nicall y rele v a nt effect sizes i n 
ser u m C 4 a n d st o ol c o nsiste nc y . 
 
A ntici p ate d res ults a n d si g nific a nce: Al dafer mi n will re d uce ser u m  C 4 a n d perce nt  

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fecal pri mar y bile aci ds i n a ra n d o m st o ol sa m ple; preli mi nar y data will be o btai ne d 
re g ar di n g efficac y o n st o ol fre q ue nc y a n d st o ol c o nsiste nc y i n B A M/ B A D wit h hi g h B A 
e x creti o n. 

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1.  IN T R O D U C TI O N  
1. 1.  Si g nific a nce of t he Pr o ble m  
 
Bile aci d mala bs or pti o n ( B A M), als o k n o w n as bile aci d diarr hea ( B A D), is a c o n diti o n c haracterize d b y 
e xcessi ve bi os y nt hesis of bile aci ds or i na bilit y t o rea bs or b s ufficie nt bile aci ds i n t he ter mi nal ile u m ( 1, 2). 
T his res ults i n u na bs or be d bil e aci ds i n t he c ol o n lea di n g t o i ncrease d c ol o nic secreti o n of fl ui d, t here b y 
ca usi n g diarr hea. B A M/ B A D c o ntri b utes t o s y m pt o ms i n a s u bset of i n di vi d uals wit h irrita ble b o wel s y n dr o me 
(I B S), w hic h is t he m ost c o m m o n l o wer gastr oi ntesti nal ( GI) dis or der.  
 
I B S affects ~ 1 1 % a n d I B S-D affects ~ 5 % of t he U S p o p ulati o n ( 3 ) a n d ofte n i m pairs q ualit y of life ( 5). 
B A M/ B A D affects a p pr o xi matel y o ne t hir d of i n di vi d uals wit h I B S -D. I B S is c urre ntl y defi ne d b y s y m pt o ms 
(i.e., a b d o mi nal disc o mf ort ass ociate d wit h b o wel dist ur ba nces) i n t he a bse nce of or ga nic disease o n r o uti ne 
testi n g. T here is a lar ge b o d y of e vi de nce t hat I B S-D s y m pt o ms are ma nifestati o ns of  c ol o nic tra nsit, m uc osal 
i m m u ne f u ncti o n, visceral h y perse nsiti vit y, a n d ce ntral ner v o us s yste m ( C N S) h y per vi gila nce (4 ,8 ,9 ). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: F X R : far nes oi d X rece pt or; F G F 1 9 : fi br o blast gr o wt h fact or 1 9; F G F R 4 : F G F rece pt or 
4; G p B A R 1 : G pr otei n c o u ple d bile aci d rece pt or 1; K L B : kl ot h o B; L R H 1: li ver rece pt or h o m ol o g-1; 
T G R 5 = G p B A R 1  
 
 A gra p hical re prese ntati o n of t he e nter o he patic circ ulati o n of bile aci ds ( 1 0 ) s u m marizes t he pi v otal c he mical 
ste ps i n t he c o ntr ol of bile aci d s y nt hesis t hat is critical t o i m pact bile aci d diarr hea. B As are rea bs or be d i n t he 
ile u m, acti vate F X R, a n d i ncrease F G F-1 9 s y nt hesis. F G F -1 9 t he n bi n ds t o t he  F G F R -4 a n d kl ot h o β rece pt ors 
t o decrease C 4 a n d s u bse q ue nt he patic B A s y nt hesis. I n B A M, B As are rea bs or be d, b ut F G F-1 9 re mai ns l o w, 
or t here are m utati o ns wit hi n t he F G F R -4 or kl ot h o β rece pt ors t hat d o n ot i n hi bit he patic B A s y nt hesis. B As 
t hat e nter the c ol o n bi n d t o t he G P B A R 1 rece pt or a n d ca use i ncrease d c ol o nic tra nsit a n d secreti o n.   

C o nfi de ntial  
Pa ge 8  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
 
 
A s yste m atic re vie w a n d met a -
a n al ysis  (1 1 ) s h o we d a n a vera ge 2 8 % 
of I B S -D p atie nts h a ve e vi de nce of 
i ncre ase d B A s y nt hesis or fec al B A  
e xcreti o n.    
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 2  
E x peri me nt al T her a pies f or B A M/ B A D  
 
A pri or o pe n -l a bel st u d y of t he B A se q uestra nt, C olese vela m, i n 1 2 patie nts wit h I B S-D a n d hi g h fecal bile 
aci d e xcreti o n de m o nstrate d  bi ol o gical rele va nce of i ncrease d fecal B A e xcreti o n ( 1 2 ).   
 
 
Effects of c olese vel a m o n se q uestrati o n of bile aci d 
( met h a n ol extr acti o n of st o ol rele ase d t he bile aci ds 
s h o wi n g t h at i ncre ase d a m o u nts were b o u n d) a n d re d uce d 
st o ol f or m.  C olese vela m i m pr o ve d st o ol c o nsiste nc y, 
se q uesteri n g a n d i nacti vati n g B A (s h o w n b y i ncrease d 
B A i n st o ol after met ha n ol e xtracti o n).  
 
 

C o nfi de ntial  
Pa ge 9  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
 
 
 
O n t he ot her ha n d, a ra n d o mize d, c o ntr olle d trial wit h 
c olese vela m, 1. 8 7 5 g bi d, of 4 wee ks’  d urati o n ( 1 3 ) 
di d n ot si g nifica ntl y i m pact s y m pt o ms (st o ol 
fre q ue nc y a n d c o nsiste nc y) alt h o u g h t here was 
e vi de nce of bi ol o gical efficac y, wit h si g nifica nt 
c ha n ges i n se q uestere d fecal t otal B A e xcreti o n ( P < 
. 0 0 1) a n d ser u m le vels of C 4 a n d F G F 1 9 ( b ot h P < 
. 0 0 1), a nd wit h a mea n i ncrease i n fecal le vel of 
de o x yc h olic aci d ( 1 0 %; P = 0. 0 7) c o m pare d t o 
place b o.  
 
 
Effects of c olese vel a m  o n st o ol fre q ue nc y a n d 
c o nsiste nc y i n patie nts wit h I B S -D a n d B A D i n 
ra n d o mize d c o ntr olle d st u d y 
 
 
T he F X R a g o nist, tr o pife x or , has bee n teste d i n a s mall m ultice nter st u d y, ra n d o mize d cr oss o ver st u d y i n 
patie nts wit h pri mar y B A M/ B A D ( 1 4 ). Tr o pife x or 6 0 μ g o nce dail y ha d acce pta ble safet y a n d t olera bilit y. 
Effects o n c ha n ges i n F G F 1 9 a n d C 4 s h o we d effecti ve tar get e n ga ge me nt; h o we ver, hi g her d oses ma y be 
re q uire d t o o bser ve st o ol fre q ue nc y c ha n ges. O n t he ot her ha n d, sl o wi n g of asce n di n g c ol o n e m pt yi n g s u g gests 
t hera pe utic p ote ntial of tr o pife x or i n patie nts wit h pri mar y B A M/ B A D.  
 
 
 
 
 
 
 
 
 
 
Ef fect of tr o pife x or o n gastr oi ntesti nal tra nsit i n t he si n gle ce nter s u b-st u d y. A, Asce n di n g c ol o n 
e m pt yi n g T 1/ 2 ( n  = 8) o n Da y 1 2 of eac h p hase. Lef t pa nel s h o ws a statisticall y si g nifica nt (p  = 0. 0 3 6) sl o wi n g 
of t he mea n asce n di n g c ol o n e m pt yi n g wit h tr o pife x or vs. place b o o n Da y 1 2. Ri g ht pa nel s h o ws t he asce n di n g 
c ol o nic T 1/ 2 i n i n di vi d ual patie nts.  
 
 
 
 
 

C o nfi de ntial  
Pa ge 1 0  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
6 -et h yl C D C A or o betic h olic aci d  
is a n ot her F X R a g o nist t hat has 
als o bee n teste d f or i di o pat hic 
B A M/ B A D ( 1 5 ).  O betic h olic aci d 
sti m ulates F G F-1 9, re d uces bile 
aci d s y nt hesis a n d pr o d uces 
cli nical be nefits i n bile aci d 
diarr hea .  
 
 
 
 
 
S u m m ar y: Pri or cli nic al tri als i n s m all n u m bers of p artici p a nts s u g gest p ote nti al effic ac y of bile aci d 
se q uestr ati o n as well as bi ol o gic al b ut n ot cli nic al effic ac y wit h e x peri me nt al me dic ati o ns wit h p ote nti al 
f or effic ac y t h o u g h i ncre ases i n F G F-1 9, t he fee d b ac k re g ul at or of he p atic bile aci d s y nt hesis  
 
 
1. 3  Al d afer mi n  
 
Al dafer mi n ( N G M 2 8 2) is a rec o m bi na nt pr otei n wit h 9 5. 4 % of its 1 9 0 a mi n o aci ds i de ntical t o fi br o blast 
gr o wt h fact or 1 9 ( F G F 1 9) a n d wit h si milar bi n di n g affi nit y t o F G F R 4 a n d K L B c o -rece pt or o n h u ma n 
he pat oc ytes. T he m olec ule al dafer mi n mi mics t he acti o ns of F G F 1 9 o n bile aci d s y nt hesis b y decreasi n g t he 
ge ne e x pressi o n i n h u ma n he pat oc ytes of C Y P 7 A 1 w hic h is res p o nsi ble f or catal yzi n g t he rate li miti n g ste p of 
c h olester ol c o n versi o n t o bile aci ds. T his has bee n de m o nstrate d b y  a ra pi d a n d d ose -de pe n de nt re d ucti o n i n 
le vels of ser u m 7-al p ha-h y dr o x y -4 -c h oleste n -3 -o ne ( C 4), a ke y i nter me diate meta b olite of C Y P 7 A 1 -me diate d 
bile aci d s y nt hesis i n mice a n d h u ma ns ( 1 6 -1 8) . 
 
T h is i n vesti gat or-i nitiate d stu d y will be c o n d ucte d u n der a n i n vesti gat or-hel d I N D 
wit h a L etter of 
A ut h orizati o n  fr o m N G M Bi o p har mace uticals, I nc. base d u p o n t he e xisti n g al dafer mi n I N Ds 
 a n d 
  A pri or st u d y of al dafer mi n  (N G M 2 8 2 ) was c o n d ucte d a fe w years a g o i n patie nts wit h f u ncti o nal 
c o nsti pati o n u n der I N D  
 
 
I n t his pri or st u d y ( 19 ), we s h o we d t here was a d ose relate d effect of al dafer mi n o n c ol o nic tra nsit i n patie nts 
wit h f u ncti o nal c o nsti pati o n, wit h si g nifica nt effect o n c ol o nic tra nsit ( partic ularl y asce n di n g c ol o n e m pt yi n g) 
a n d bo wel fre q ue nc y wit h t he 1 m g d ose of al dafer mi n i n c o ntrast t o t he sti m ulati o n wit h t he 6  m g d ose:  
 
 
 
 
 
 
 

C o nfi de ntial  
Pa ge 1 1  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
  
D at a L S M (S E M)  
Pl ace b o 
( P L A) 
n = 1 0  
N G M 2 8 2  
1 m g,  
n = 1 0  
N G M 2 8 2  
6 m g,  
n = 1 1  
P  
A N O V A  
N G M 2 8 2  
1 m g vs P L A  
N G M 2 8 2  
6 m g vs 
P L A  
G E T 1/ 2  , mi n 
1 3 2. 4 ( 7. 4)  
9 7. 8 ( 7. 2) 
9 4. 5 ( 8. 1)  
0. 0 0 2  
0. 0 0 3  
0. 0 0 1  
C T G C 2 4  
2. 0 3  ( 0. 1 6) 
2. 3 5  ( 0. 1 8) 
3. 3 0  ( 0. 2 9) 
<  0. 0 0 1  
0. 0 7 0  
<  0. 0 0 1  
C T G C 4 8  
3. 3 6 ( 0. 2 9)  
4. 2 9  ( 0. 2 2) 
4. 6 6  ( 0. 1 3) 
<  0. 0 0 1  
0. 0 0 1  
<  0. 0 0 1  
A C T 1/ 2, h 
2 0. 0 ( 2. 9)  
1 6. 7 ( 1. 8)  
1 2. 2 ( 1. 6)  
0. 0 4 9  
0. 3 0 0  
0. 0 1 5  
# B M/ wee k  
5. 1 (0. 5)  
8. 0 ( 0. 7)  
1 5. 1 (2. 3)  
<  0. 0 0 1  
0. 1 7 8  
<  0. 0 0 1  
Fasti n g C 4 n g/ m L  
2 7. 7 ( 7. 9)  
9. 5 ( 4. 3)  
2. 6 ( 1. 9)  
0. 8 9  
0. 9 8  
0. 7 2  
Δ Fasti n g C 4 o n R x  
mi n us pre -R x, n g/ m L  
5. 9 ( 5. 2)  
-2. 9 ( 4. 0)  
-8. 3 ( 2. 3)  
0. 0 5 6  
0. 1 2  
0. 0 1 8  
 
 
 
 
 
2.   S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
 
2. 1  Pri m ar y  O bjecti ve  
T o c o m pare wit h a ra n d o mize d trial ( n = 1 5 per treat me nt gr o u p), effects of Al dafer mi n, 1 m g a n d place b o S Q 
treat me nt, o n b o wel f u ncti o ns,  he patic s y nt hesis a n d fecal e xcreti o n of bile aci ds i n patie nts wit h diarr hea 
ass ociate d wit h bile aci d mala bs or pti o n.  
 
 
2. 2  
St u d y E n d p oi nts  
 
Pri m ar y E n d p oi nt s 
1.  C ha n ge i n fasti n g ser u m C 4 le vels fr o m Baseli ne t o Da y 2 8    
 
2.  C ha n ge i n st o ol c o nsiste nc y base d o n t he Brist ol St o ol F or m Scale, B S F S fr o m 
Baseli ne t o Da y 2 8   
 
Sec o n d ar y E n d p oi nt s 
 
1.  St o ol c o nsiste nc y base d o n Brist ol St o ol F or m Scale, B S F S  
a. A bs ol ute c ha n ge i n st o ol c o nsiste nc y fr o m baseli ne t o Da y 1 4 a n d Da y 2 8 of 
treat me nt.  
 
b.  A vera ge dail y st o ol c o nsiste nc y sc ore at D a y 1 4  a n d D a y 2 8  of treat me nt  

C o nfi de ntial  
Pa ge 1 2  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
2.  Ma xi m u m a b d o mi nal pai n sc ore rate d b y patie nt usi n g a n 1 1 -p oi nt scale, 0 t o 1 0 i ncl usi ve 
wit h 0 as n o ne a n d 1 0 as w orst i ma gi na ble a b d o mi nal pai n . 
 
3.   A bs ol ute c ha n ge i n a b d o mi nal pai n fr o m baseli ne t o Da y 1 4 a n d Da y 2 8 of treat me nt.  
 
4.  N u m ber of b o wel m o ve me nts  per  wee k  
 
5.  C ha n ge i n t otal fecal bile aci d c o nce ntrati o n bet wee n baseli ne a n d Da y 2 8.  
 
6.  Pr o p orti o n of fecal secret or y  ( C D C A +  D C A) bile aci d as me as ure d i n a si n gle, ra n d o m st o ol 
sa m ple b y a vali date d la b orat or y assa y. 
 
7.   P r o p orti o n of fecal pri mar y ( C D C A + C A)  bile aci d as meas ure d i n a si n gle, ra n d o m st o ol 
sa m ple b y a vali date d la b orat or y assa y. 
 
8.  T otal fecal bile aci d c o nce ntrati o n i n a si n gle, ra n d o m st o ol sa m ple as meas ure d b y a vali date d 
la b orat or y assa y. 
 
9.  T otal al dafer mi n c o nce ntrati o n i n ser u m as meas ure d b y a vali dat e d la b orat or y assa y  
 
3.  S T U D Y  D E SI G N  
 
3. 1  
O ver vie w  
T his si n gle -ce nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y is desi g ne d t o  e val uate  t he effects of 
al dafer mi n  o n  dail y b o wel patter n , fasti n g ser u m C 4 a n d F G F-1 9 a n d fecal bile aci d e xcreti o n i n a ra n d o m st o ol 
sa m ple i n patie nts wit h B A M/ B A D.  T he st u d y i ncl u des a scree ni n g p eri o d ( u p t o 2 8  da ys ) a n d t w o 1 4-da y 
treat me nt p eri o ds f or a ma xi m u m  d urati o n of u p t o 5 6  da ys. E li gi ble patie nts  will be  ra n d o mize d i nt o 2 bl oc ks, 
t h ose sta yi n g of bile aci d se q uestra nts a n d t h ose n ot ta ki n g t he m, a n d  stratifie d b y ge n der a n d B MI , we 
a ntici pate 9 0 % fe male a n d 7 5 % B MI > 3 0 k g/ m 2.  A sc he matic dia gra m  of  t he st u d y desi g n is s h o w n bel o w . 
 
 
 
 
 
 
 
 
 
 
 
 
 

C o nfi de ntial  
Pa ge 1 3  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 1. 1 Re m ote C o nse nt a n d Eli gi bilit y Re vie w  ( o pti o n al) 
 
T his is a n o pti o n al  presc he d ule d p h o ne call or researc h e -c o ns ult f or patie nts. T he patie nts will recei ve a 
pac ket at t heir h o me c o ntai ni n g t he st u d y c o nse nt f or m, st u d y q uesti o n naire, t he 7 -da y b o wel patter n diar y, a n d 
a st o ol kit wit h i nstr ucti o ns o n h o w t o c ollect a si n gl e, ra n d o m st o ol sa m ple. T he patie nt a n d a st u d y tea m 
me m ber will re vie w t he i nf or me d c o nse nt. A de q uate  ti me f or q uesti o ns a n d disc ussi o n will be all o we d. T he 
patie nt  ca n si g n, date a n d ti me t he c o nse nt f or m wit h eit her t he E lectr o nic C o nse nt T ec h n ol o g y -D oc u Si g n  or 
t he pa per f or m w hic h nee ds t o be place d  i n a pre pai d a d dresse d e n vel o pe t o maile d bac k t o t he st u d y tea m 
me m ber w he n t his re vie w is o ver.  O nce t he st u d y tea m recei ves t his si g ne d c o p y, t he y will si g n t he c o nse nt 
f or m, ma ke a har d c o p y t o be ret urne d t o t he patie nt a n d place a c o p y i n t he patie nt’s me dical rec or d.  
 
F or t he eli gi bilit y re vie w, t he patie nt will be as ke d t heir a p pr o xi mate hei g ht a n d wei g ht a n d t he n c o m plete  o ne  
of t he t hree sta n dar d q uesti o n naires wit h t he st u d y tea m me m ber o ver t he p h o ne call or e-c o ns ult.  T he  
q uesti o n naire  is t he H os pital a n d A n xiet y De pressi o n q uesti o n naire ( H A Ds) a n d i ncl u de d i n t he pr ot oc ol 
a p pe n dices . The patie nt will be as ke d t o si g n, date, a n d place t he m i n t he pre pai d e n vel o pe. T he st u d y tea m 
me m ber will  re vie w t he b o wel patter n diar y wit h t he patie nt t o rec or d i n f or at least 7 da ys pri or t o Visit 3.  
T he st o ol c ollecti o n i nstr ucti o ns a n d ti mi n g will als o be re vie we d s o t he st o ol c ollecti o n ca n be br o u g ht i n at 
Visit 3.  A st u d y p h ysicia n will t he n as k t he patie nt ge neral q uesti o ns a b o ut t heir c urre nt healt h, past me dical 
hist or y, c urre nt me dicati o ns/s u p ple me nts a n d re vie w t he patie nt’s q uesti o n naire a ns wers wit h t he m.  T he t his 
p oi nt t he st u d y p h ysicia n will disc uss eli gi bilit y criteria wit h t he patie nt.  If t he st u d y p h ysicia n belie ves t he 
patie nt is eli gi ble f or t he st u d y, pr o hi bite d a n d resc ue me dicati o ns will be disc usse d wit h t he m. If t he st u d y 
p h ysicia n belie ves t he patie nt d oes n ot meet eli gi bilit y criteria, t hat will als o be disc usse d wit h t he pati e nt.  T he 
patie nt will still be as ke d t o se n d t he pa per c o nse nt f or m if y o u di d n ot use D oc u Si g n a n d q uesti o n naires bac k 
t o t he st u d y tea m. e ve n if t he y d o n ot q ualif y s o t he st u d y tea m ca n rei m b urse t he m f or t heir ti me.    
 
Al dafer mi n St u d y Desi g n  
Scree n  
Visit  
Wit hi n  
4 w e e ks 
VI SI T: 1  
B aseli ne Testi n g  
 1) Eli gi bilit y, pre g n a nc y test  
2) R a n d o m st o ol s a m ple  
3) Bl o o d ( D N A, C 4 , F G F 1 9 , p k) 
4) 1 wee k st o ol di ar y c ollecte d  
5) Me dic ati o n pic k u p  
 
 
5  
D a y 1  
2  
    D a y 2 8 ± 3  
Tre at me nt Testi n g  
1) R a n d o m st o ol s a m ple  
2) Bl o o d ( C 4 , F G F 1 9 , p k) 
3) 2 wee k st o ol di ar y c ollecte d 
4) U n use d m e dic ati o n ret ur ne d  
4 -wee k Tre at me nt wit h  
Al d afer mi n/ Pl ace b o      
Wit hi n  
1 w e e k 
D a y 1 4 ± 2  
I nteri m Tre at m e nt Testi n g 
1 ) R a n d o m st o ol s a m ple 
2) Bl o o d ( C 4 , F G F 1 9 , p k) 
3) 2 wee k st o ol di ar y c ollecte d 
4) Me dic ati o n pic k u p  
 
4  
3  

C o nfi de ntial  
Pa ge 1 4  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
F or patie nts w h o ha ve c o m plete d t his re m ote co nse nt  a n d eli gi bilit y re vie w, t he a b o ve acti vities will n ot be 
re peate d at Visit 1 Scree n e xce pt t heir act ual hei g ht a n d wei g ht will be meas ure d w he n t he y c o me i n f or Visit 
1.  
 
3. 2  
Visit 1 Scree n  
 
T he patie nt will fast f or 1 2 h o urs  a n d a v oi da nce of alc o h ol f or 2 4 h o urs bef ore t he visit  if t he y wis h t o ha ve 
t heir scree ni n g safet y bl o o ds dra w n. T he patie nt a n d a st u d y tea m me m ber will re vie w t he i nf or me d c o nse nt. 
A de q uate  ti me f or q uesti o ns a n d disc ussi o n  will be all o we d. T he patie nt will be gi ve n a si g ne d har d c o p y of 
t he i nf or me d c o nse nt a n d a c o p y will be place d i n t he patie nt’s electr o nic me dical hist or y.  A st u d y p h ysicia n 
will re vie w t he st u d y’s eli gi bilit y criteria , t he patie nt’s me dical hist or y a n d perf or m a p h ysical e xa mi nati o n.  
Hei g ht, wei g ht a n d vital si g ns ( p ulse, bl o o d press ure , res pirati o n rate a n d te m perat ure) will be o btai ne d. If t he 
patie nt d oes n ot ha ve a pri or la b orat or y assess me nt t o c o nfir m t he prese nce of B A M/ B A D  ( 2 0-2 2)  , a s mall 
v ol u me bl o o d sa m ple will be dra w n t o test f or ser u m C 4.  Bl o o d a n d uri ne will be o btai ne d f or r o uti ne safet y 
la bs of he mat ol o g y, c he mistr y, li pi d pa nel a n d a di pstic k uri nal ysis.  A 1 2 -lea d electr ocar di o gra m ( E C G) will 
be perf o r me d. T he patie nt will c o m plete t hree sta n dar d  q uesti o n naires, t he S h ort B o wel Disease q uesti o n naire 
(s h ort B D Q), , t he H os pital a n d A n xiet y De pressi o n q uesti o n naire a n d t he Q ualit y -of -Life  q uesti o n naire; t hese 
q uesti o n naires are i ncl u de d i n t he pr ot oc ol a p pe n dices. T he patie nt will be gi ve n a b o wel patter n diar y t o 
rec or d i n f or at least 7 da ys pri or t o Visit 2; t he diar y pa ge is i ncl u de d i n t he pr ot oc ol a p pe n dices.  T he patie nt 
will be gi ve n a st o ol kit t o c ollect a si n gle, ra n d o m st o ol sa m ple t o bri n g i n at Visit 3 . 
 
If a patie nt elects t o wit h dra w fr o m ta ki n g s o me pr o hi bite d me dicati o ns, a 1 4 -da y was h o ut will be 
re q uire d after w hic h t he patie nt ma y pr ocee d wit h la b orat or y tests, b o wel patter n diar y a n d st o ol 
c ollecti o n. 
 
Visit 1 acti vities ma y be c o m bi n e d wit h Visit 2 f or greater c o n ve nie nce if t he patie nt has n ot ta ke n a n y of t he 
pr o hi bite d me dicati o ns wit hi n 2 wee ks.  
 
3. 3  
Visit 2 Pre -R a n d o miz ati o n  
 
T he patie nt will ret ur n after a t wel ve-h o ur fast  a n d a v oi da nce of alc o h ol f or 2 4 h o urs . V ital si g ns will be 
o btai ne d. Bl o o d will be o btai ne d f or D N A, C 4 , F G F -1 9  a n d p k a nal ysis . Bl o o d will be o btai ne d f or r o uti ne 
safet y la bs of he mat ol o g y, c he mistr y, li pi d pa nel if patie nt  di d n ot ha ve t he m o n Visit 1 Scree n.  Uri ne will be 
o btai ne d f or a pre g na nc y test f or fe males of c hil d -beari n g p ote ntial.  
 
Visit 2 ma y be c o m bi ne d wit h Visit 3 f or greater c o n ve nie nce if re q ueste d b y patie nt. 
 
 
3. 4  
Visit 3 R a n d o miz ati o n  
 
V ital si g ns will be o btai ne d. T he patie nt will be as ke d a b o ut a n y c ha n ges i n eli gi bilit y criteria, c o nc o mita nt 
me dicati o ns a n d a d verse e ve nts. T he patie nt will bri n g i n a si n gle, ra n d o m st o ol sa m ple a n d will be gi ve n a 
ne w st o ol c ollecti o n kit t o bri n g i n a sa m ple at t he next visit. T he patie nt will ret ur n t he b o wel patter n diar y 

C o nfi de ntial  
Pa ge 1 5  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
a n d recei ve a ne w b o wel patter n diar y. St u d y me dicati o n, eit her al dafer mi n or place b o, will be dis pe nse d.  A 
n urse will de m o nstrate pr o per s u bc uta ne o us i njecti o n i nt o t he a b d o me n a n d o bser ve  t he patie nt self -a d mi nister 
t he first d ose of t he st u d y me dicati o n. D osi n g i nstr ucti o ns a n d p ote ntial si de effect s will be re vie we d.  Patie nts 
will be i nstr ucte d t o self-a d mi nister al dafer mi n/ matc he d place b o as a s u bc uta ne o us i njecti o n  i nt o t he a b d o me n 
at h o me at a  si milar ti me eac h da y, prefera bl y i n t he e ve ni n g, after di n ner a n d bef ore be d, f or 4 wee ks. 
Al dafer mi n/ place b o s yri n ges will be e q uili brate d t o r o o m te m perat ure pri or t o use ; t his re q uires a b o ut 1 5 t o 3 0 
mi n utes at r o o m te m perat ure . T he al dafer mi n/ place b o s yri n ge m ust be self -i njecte d wit hi n a n h o ur of bei n g 
re m o ve d fr o m t he refri gerat or. If t he s yri n ge is left at r o o m te m perat ure f or l o n ger t ha n a n h o ur, it m ust be 
discar de d i nt o a pr o vi de d re d s har ps c o ntai ner a n d a re place me nt s yri n ge use d. T he al dafer mi n/ place b o 
s yri n ges are pr o vi de d as kits wit h f o ur a d diti o nal s yri n ges. A d diti o nal or re place me nt st u d y me dicati o n 
s yri n ges are a vaila ble. Patie nts m ust rec or d ti me of d osi n g i n t he b o wel patter n diar y.  
 
3. 5  
Visit 4 I nteri m Tre at me nt Test i n g 
 
A b o ut t w o wee ks later, t he patie nt will ret ur n after a t wel ve-h o ur fast  a n d a v oi da nce of alc o h ol f or 2 4 h o urs . 
T he patie nt will be as ke d a b o ut a n y c ha n ges i n eli gi bilit y criteria, st u d y me dicati o n d osi n g, c o nc o mita nt 
me dicati o ns a n d a d verse e ve nts. V ital si g ns will be o btai ne d. T he patie nt will t ur n i n a n y re mai ni n g st u d y 
me dicati o n a n d recei ve a ne w s u p pl y. T he patie nt will bri n g i n a si n gle, ra n d o m st o ol sa m ple  a n d  will be 
gi ve n a ne w st o ol c ollecti o n kit t o bri n g i n a sa m ple at t he ne xt visit. T he patie nt will ret ur n t he b o wel patter n 
diar y a n d recei ve a ne w b o wel patter n diar y.  Bl o o d will be o btai ne d f or C 4 ,  F G F 1 9  a n d p k a nal ysis . Uri ne 
will be o btai ne d f or a pre g na nc y test f or fe males of c hil d -beari n g p ote ntial.    
 
3. 6  
Visit 5 E n d of St u d y Testi n g  
 
A b o ut t w o wee ks later, t he patie nt will ret ur n after a t wel ve-h o ur  fast a n d a v oi da nce of alc o h ol f or 2 4 h o urs . 
T he patie nt will be as ke d a b o ut a n y c ha n ges i n eli gi bilit y criteria, st u d y me dicati o n d osi n g, c o nc o mita nt 
me dicati o ns a n d a d verse e ve nts. Wei g ht a n d v ital si g ns will be o btai ne d. T he patie nt will ha ve a n i nter vie w 
a n d a brief p h ysical e xa m b y a  st u d y p h ysicia n. T he patie nt will be as ke d t o c o m plete t he Q ualit y -of - Life 
( Q o L) q uesti o n naire o nce m ore. Bl o o d a n d uri ne will be o btai ne d f or r o uti ne safet y la bs of he mat ol o g y, 
c he mistr y, li pi d pa nel a n d a di pstic k uri nal ysis . If t here is a cli nicall y si g nifica nt c ha n ge i n a n y la b test res ult, 
t he test will be re peate d i n 3 0 da ys’ ti me t o e ns ure t he res ult has ret ur ne d t o pre-st u d y me dicati o n le vels. A 1 2 -
lea d electr ocar di o gra m ( E C G) will be perf or me d. T he patie nt will ret ur n an y re mai ni n g st u d y me dicati o n. T he 
patie nt will t ur n i n a  si n gle, ra n d o m st o ol sa m ple. T he patie nt will ret ur n t he b o wel patter n diar y . Bl o o d will 
be o btai ne d f or C 4 , F G F 1 9  a n d  p k a nal ysis .  
 
3. 7  St u d y Desi g n R ati o n ale  
 
B A M/ B A D is i ncreasi n gl y rec o g nize d as a s u bt y pe of I B S -D ( 1 1 , 27 ).  I n a n o pe n-la bel st u d y ( 12 ), we 
i de ntifie d be neficial effects of c olese vela m i n t he treat me nt of I B S s y m pt o ms i n patie nts wit h hi g h t otal fecal 
B A e xcreti o n ( >  2 0 0 0 µ m oles/ 4 8 h), ele vate d pri mar y bile aci ds ( >  4 %) wit h ele vate d t otal fecal bile aci ds ( >  
1, 0 0 0 µ m ol/ 4 8 h) , or pri mar y bile aci ds > 1 0 % / 4 8 h, ele vate d C 4 ( > 4 0 n g/ m L), a n d decrease d F G F 1 9 ( < 8 0 
p g/ m L).   
 
 

C o nfi de ntial  
Pa ge 1 6  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
4.  S T U D Y  P O P U L A TI O N  
4. 1  
N u m b er of P atie nt s 
A p pr o xi matel y  3 6  patie nts wit h B A M/ B A D irrita ble b o wel s y n dr o me -diarr hea  will be  e nr olle d. 
 
4. 2  
I ncl usi o n Criteri a  
Patie nts  m ust meet A L L of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i nt o t he  st u d y: 
 
1.  A ge d  1 8  t o 7 5  years,  i ncl usi ve at Visit 1 S cree n. 
2.  Cli nical dia g n osis of f u ncti o nal diarr hea or I B S wit h diarr hea  acc or di n g t o R o me III or I V criteria at 
Visit 1 Scree n.  
3.  Cli nical la b orat or y e vi de nce of B A M  ( 2 0-2 2) , wit h at least o ne of t he f oll o wi n g res ults rec or de d i n 
t heir past me dical hist or y: 
•  
Ser u m C 4 ≥ 5 2 n g/ m L  
•  
Fecal B A > 2 3 3 7 µ m oles / 4 8 h o urs  
•  
T otal fecal B A > 1 0 0 0 µ m oles / 4 8 h o urs + 4 % pri mar y B A  
•  
Fecal p ri mar y B A > 1 0 % / 4 8 h o urs 
 
4.  B o d y  mass  i n de x ( B MI) 1 8. 0  t o 4 5. 0  k g/ m 2, i ncl usi ve at Visit 1 Scree n  
 
5.    U n dersta n ds t he st u d y pr oce d ures, is willi n g a n d a ble t o c o m pl y wit h t he st u d y pr oce d ures, a n d is 
a ble t o gi ve i nf or me d c o nse nt 
 
6.    If treate d wit h a n y of t he f oll o wi n g me dicati o ns, d osi n g m ust be sta ble f or 3 0 da ys pri or t o Visit 1 
Scree n. Patie nt m ust a gree t o mai ntai n t he sa me d ose of me dicati o n t hr o u g h o ut t he st u d y:  
•  
Tric yclic a nti de pressa nts, selecti ve ser ot o ni n re u pta ke i n hi bit ors ( S S RIs) a n d  ser ot o ni n a n d 
n ore pi ne p hri ne re u pta ke i n hi bit ors ( S N RIs).  
•  
Bile Aci d se q uestra nts s uc h as c olesti p ol, c h olest yra mi ne a n d c olese vela m .  
 
7.  Patie nts m ust use o ne hi g hl y effecti ve met h o d of c o ntrace pti o n f or 3 0 da ys bef ore t h e st u d y 
t hr o u g h 9 0 da ys after st u d y c o m pleti o n f or males a n d t hr o u g h 3 0 da ys after st u d y 
c o m pleti o n f or fe mal es. Hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de  
•  Oral, i m pla nta ble, s u bder mal or i njecta ble h or m o n al c o ntrace pti ves  
•  Sta n dar d i ntra uteri ne d e vice or va gi nal ri n g 
•  Male or fe m ale c o n d o ms a n d dia p hra g ms use d wit h s per mici de  
•  A bsti ne nce fr o m heter os e x ual i nterc o urse  
•  Fe male p art ners e xcl usi v el y se x uall y acti ve wit h a s ur gicall y sterilize d mal e part ner  
•  Fe males w h o are s ur gicall y sterile  pri or h ysterect o m y, bilateral sal pi n gect o m y, or 
bilateral o o p h orect o m y) or p ost me n o pa usal ( defi ne d as: 1 2 c o nsec uti ve m o nt hs wit h n o 
me nses) are n ot c o nsi dere d t o be of c hil d beari n g p ote ntial  

C o nfi de ntial  
Pa ge 1 7  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
4. 3  
E xcl usi o n  Criteri a  
Patie nts  w h o  meet  A N Y of t he  f oll o wi n g e xcl usi o n criteria  will n ot  be  eli gi ble  f or e nr oll me nt i nt o t he 
st u d y: 
 
1.  Pre g na nt or lactati n g  
 
2.  Str uct ural or meta b olic diseases/c o n diti o ns t hat affect t he gastr oi ntesti nal s yste m  
 
3.  Use of t he f oll o wi n g me dicati o ns at least 1 4  da ys pri or t o Visit 1 t hr o u g h o ut t he d urati o n of t he 
treat me nt peri o d:   
 
•  Patie nts ma y elect t o wit h dra w fr o m bile aci d se q uestra nts s uc h as c olesti p ol, 
c h olest yra mi ne a n d c olese vela m  or t he y ma y c o nti n ue b ut t he y m ust c o nti n ue at t he sa me 
d ose t hr o u g h o ut t he st u d y.  
 
•  GI me dicati o ns i ncl u di n g:  
•  A nti -na usea a ge nts i ncl u di n g tri met h o be nza mi de, pr o met hazi ne, pr oc hl or perazi ne, 
di me n h y dri nate, h y dr o x yzi ne  
•  Os m otic la xati ve a ge nts i ncl u di n g lact ul ose, s or bit ol or P E G s ol uti o ns as Mirala x a n d 
Gl yc ola x  
•  Pr o ki netic a ge nts i ncl u di n g te gaser o d, met ocl o pra mi de, pr ucal o pri de, d o m peri d o ne, 
er yt hr o m yci n, clarit hr o m yci n a n d azit hr o m yci n.  
•  
5 -H T 3 a nta g o nists i ncl u di n g al osetr o n, o n da nsetr o n, t r o pisetr o n.  
•  
Patie nts ma y use Ga ba pe nti n if t he y are o n a sta ble d ose, w hic h is n ot greater t ha n 1 2 0 0 m g a 
da y.  
 
•  Dr u gs wit h a k n o w n p har mac ol o gical acti vit y at 5 -H T 4, 5 -H T 2 b or 5 -H T 3 rece pt ors 
i ncl u di n g te gaser o d, o n da nsetr o n, gra nisetr o n a n d tr o pisetr o n  
 
•  All narc otics i ncl u di n g c o dei ne, m or p hi ne, a n d pr o p o x y p he ne, eit her al o ne or i n 
c o m bi nati o n 
•  A nti -c h oli ner gics i ncl u di n g dic ycl o mi ne, h y osc ya mi ne, pr o pa nt heli ne.  
•  A nti m uscari nics  
•  Tra ma d ol  
•  Pe p per mi nt oil  
•  S yste mic a nti bi otics a n d a nti bi otics directe d at c ol o nic fl ora i ncl u di n g rifa xi mi n a n d 
metr o ni daz ole  
 
 
5.  Cli nicall y rele va nt c ha n ges i n dietar y, lifest yle, or e xercise re gi me n wit hi n 3 0 da ys pri or t o Visit 1 
Scree n a n d t hr o u g h o ut t he d urati o n of t he st u d y  
6.    A n y c ol o nic or maj or a b d o mi nal s ur ger y i ncl u di n g bariatric s ur ger y, gastric ba n di n g, st o mac h 

C o nfi de ntial  
Pa ge 1 8  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
s ur ger y a n d i ntesti nal or c ol o nic s ur ger y.  Pr oce d ures s uc h as a p pe n dect o m y, c h olec ystect o m y, 
h ysterect o m y, caesarea n secti o n, or p ol y pect o m y are all o we d as l o n g as t he y ha ve occ urre d at least 
3 m o nt hs pri or t o Visit 1 Scree n.  
 
7.   Hist or y of c ol orectal ca ncer , i nfla m mat or y b o wel disease, di vertic ulitis, isc he mic c olitis, 
micr osc o pic c olitis or celiac disease  
 
8.   Hist or y of or ga nic a b n or malities of t he GI tract, i ntesti nal o bstr ucti o n, strict ure, t o xic me gac ol o n, 
GI perf orati o n, or i m paire d i ntesti nal circ ula ti o n. 
 
9.   Ot her GI diseases s uc h as GI blee di n g or ulcerati o ns  
 
1 0. Hist or y of cere br o vasc ular disease i ncl u di n g str o ke, TI A, ac ute c or o nar y s y n dr o me, m y ocar dial 
i nfarcti o n or u nsta ble a n gi na 
 
1 1. Cli nicall y si g nifica nt car diac hist or y or prese nce of ele ctr ocar di o gra m ( E C G)  fi n di n gs at Visit 1  
Scree n:  
1.  A b n or mal heart rate < 4 0 or > 1 0 0 beats per mi n ute  
2.  Q Tc i nter val > 4 7 0 millisec o n ds ( ms)  
3.  Q R S i nt er val ≥ 1 1 0 ms  
4.  P R i nter val ≥ 2 2 0 ms  
 
1 2. He patic d ysf u ncti o n i ncl u di n g a b n or mal ser u m ala ni ne a mi n otra nsferase [ A L T] or as partate 
tra nsa mi nase [ A S T] > 3 × u p per li mit of n or mal [ U L N]); t otal direct bilir u bi n > 2 × U L N, or 
al kali ne p h os p hatase > 2 × U L N at Visit 1 Scree n  
 
1 3. Cli nicall y si g nifica nt re nal i ns ufficie nc y i ncl u di n g ser u m creati ni ne > 2. 5 m g/ d L at Visit 1 Scree n  
 
1 4. Hist or y of se vere hea d i nj ur y or hist or y of seiz ures  
 
1 5. Hist or y of s uici de atte m pt or a h os pitalizati o n f or a maj or ps yc hiatric c o n diti o n wit hi n 1 year pri or 
t o Visit 1 Scree n. At Visit 1 Scree n or d uri n g t he o pti o nal re m ote c o nse nt a n d eli gi bilit y re vie w , 
partici pa nts will c o m plete t he H os pital A n xiet y a n d De pressi o n q uesti o n naire. If eit her sc ore f or 
a n xiet y or de pressi o n i n di vi d uall y e xcee ds 8, t he sc ore will be disc usse d. T he patie nt will be  a n d 
a d vise d w het her t o partici pate or w het her t o see t heir pri mar y care p h ysicia n.  
 
1 6. Hist or y of alc o h ol use dis or der or s u bsta nce use dis or der wit hi n 2 years of Visit 1 Scree n.  
 
1 7. Si g nifica nt hist or y or cli nical ma nifestati o n of a n y e n d ocri ne, all er gic, der mat ol o gical, he patic, 
re nal, he mat ol o gical, p ul m o nar y, GI, ne ur ol o gical or ps yc hiatric dis or der, mali g na nc y ( wit h t he 
e xce pti o n of treate d basal cell carci n o mas), or a n y ot her c o n diti o n  t hat w o ul d pre ve nt t he 
i n di vi d ual fr o m partici pati n g i n t he st u d y d ue t o ris k t o t he scie ntific vali dit y of st u d y assess me nts 
or t o pers o nal well -bei n g of t he  patie nt.  
1 8 .  Partici pate d i n a n ot her cli nical st u d y t hat i ncl u des a n i n vesti gati o nal dr u g or a bi ol o gic t hera p y wit hi n 

C o nfi de ntial  
Pa ge 1 9  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
3 0 da ys or 5 half -li ves, w hic he ver ti me peri o d is l o n ger,  pri or t o Visit 1 Scree n  
 
4. 4  
P atie nt  Wit h dr a w al  a n d  Re pl ace me nt  
 
If a patie nt is pre g na nt, t he patie nt  will be wit h dra w n fr o m st u d y treat me nt   i m me diatel y. 
 
A patie nt ma y be wit h dra w n f or a n y  treat me nt relate d a d verse e ve nt or cli ni call y si g nifica nt fi n di n gs i n 
cli nical la bs or  ot her  vital  si g ns  t hat are dee me d b y  t he in vesti gat or t o p ose  a n u nacce pta ble  ris k t o t he 
patie nt . If t he st u d y is i nterr u pte d d ue t o a n y of t he criteria liste d a b o ve, t he patie n t ma y u n der g o 
u nsc he d ule d assess me nts t o e val uate his/ her stat us. A d diti o nal s u bse q ue nt visits ma y be  re q uire d t o assess 
e ve nt o utc o mes.    
 
St u d y treat me nt ma y be disc o nti n ue d, i nterr u pte d or d ose re d uce d f or a n y gra de 3 a d verse e ve nt t hat is 
p ossi bl y or pr o ba bl y relate d t o st u d y treat me nt. St u d y treat me nt will be disc o nti n ue d f or a n y gra de 4 
a d verse e ve nt t hat is p ossi bl y or pr o ba bl y relate d t o st u d y treat me nt  
 
Patie nts  ma y  als o be  disc o nti n ue d fr o m  t he st u d y at a n y ti me  f or a n y of t he f oll o wi n g reas o ns: 
•  A d verse  e ve nt 
•  Deat h  
•  L ost  t o f oll o w-u p  
•  I n vesti gat or decisi o n  
•  Pre g na nc y  
•  Pr ot oc ol  de viati o n  
•  St u d y  ter mi nate d b y S p o ns or  
•  Wit h dra wal  b y  s u bject 
 
A patie nt ma y be wit h dra w n fr o m t he st u d y at a n y ti me d ue t o t he f oll o wi n g a d verse e ve nts  base d o n t he 
k n o w n safet y pr ofile a n d mec ha nis m of t he dr u g : 
•  De h y drati o n re q uiri n g h os pitalizati o n  
•  A la b orat or y res ult of t otal c h olester ol a n d tri gl yceri des > 2 x U L N  
•  Aller gic reacti o n re q uiri n g h os pitalizati o n  
 
A patie nt  ma y be wit h dra w n fr o m t he st u d y at a n y ti me d ue t o t he f oll o wi n g a d verse e ve nts:  
•  
A la b orat or y res ult of A L T or A S T > 3 x U L N, t otal direct bilir u bi n > 2 x U L N or ser u m 
creati ne > 2. 5 U L N  
•  
A b n or mal car diac fi n di n gs s uc h as a cli nicall y si g nifica nt a b n or mal heart rate or  r h yt h m, 
left b u n dle bra nc h bl oc k wit h Q R S i nter val > 1 1 0 msec  or first -de gree A V bl oc k  wit h P R 
i nter val > 2 2 0 msec.  
 
A patie nt  ma y be wit h dra w n b y t he in vesti gat or or t he sp o ns or if e nr oll me nt i n  the st u d y is dee me d 
i na p pr o priate, t he st u d y pla n is vi olate d, or f or a d mi nistrati ve a n d/ or safet y  reas o ns. 
 
A patie n t ma y elect t o disc o nti n ue st u d y partici pati o n at a n y ti me f or a n y reas o n wit h o ut  prej u dice  t o his/ her  

C o nfi de ntial  
Pa ge 2 0  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
f ut ure me dical care  b y t he  p h ysicia n or  at t he i nstit uti o n. T he in vesti gat or will  d oc u me nt  t he s pecific reas o n 
w h y  c o nse nt was wit h dra w n.  
 
4. 5  
Ter mi n ati o n  of  t he Cli nic al St u d y  
 
T he sp o ns or has t he ri g ht t o ter mi nate t his  st u d y at a n y ti me. Reas o ns f or ter mi nati n g t he st u d y ma y i ncl u de, 
b ut are  n ot li mite d t o, t he  f oll o wi n g: 
 
•  
T he i nci de nce or se verit y of a d verse e ve nts ( A Es) i n t his or ot her st u dies i n dicates a  
p ote ntial  healt h hazar d t o  s u bjects. S pecificall y, t he st u d y will be st o p pe d if fi ve or m ore 
patie nts re p ort de h y drati o n re q uiri n g h os pitalizati o n or aller gic reacti o n re q uiri n g 
h os pitalizati o n  
•  
Patie nt  e nr oll me nt  is u nsatisfact or y  
•  
U p o n  re q uest of  healt h  or re g ulat or y  a ut h orities 
 
T he sp o ns or will n otif y t he in vesti gat or if t he st u d y is place d o n h ol d or if t he sp o ns or deci des  t o disc o nti n ue 
t he st u d y. Healt h a ut h orities, re g ulat or y a ut h orities, a n d I n de pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal 
Re vie w B oar ds (I R Bs) will be i nf or me d a b o ut t he ter mi nati o n of  t he st u d y i n acc or da nce wit h a p plica ble 
re g ulati o ns. 
 
5.  
I N V E S TI G A TI O N A L M E DI CI N A L  P R O D U C T  
5. 1.  I de ntit y of  t he I n vesti g ati o n al Me dici n al  Pr o d ucts  
St u d y treat me nts i ncl u de a p har mace utical f or m of t he acti ve s u bsta nce bei n g teste d , al dafer mi n,   a n d a 
matc he d place b o  bei n g use d as a  refere nce. 
5. 2.  Dr u g  Acc o u nt a bilit y,  Dis pe nsi n g,  a n d  Destr ucti o n  
T he st u d y p har macist will mai ntai n acc urate rec or ds of recei pt of all st u d y  treat me nt materials. I n a d diti o n, 
acc urate rec or ds will be ke pt re gar di n g w he n a n d h o w m uc h  st u d y treat me nt is dis pe nse d a n d use d b y eac h 
s u bject. Reas o ns f or de viati o n fr o m t he e x pecte d   dis pe nsi n g re gi me n als o m ust be rec or de d. St u d y treat me nt 
will be rec o ncile d . T he st u d y p har macist will  pr o vi de access t o st u d y  treat me nt a n d st u d y treat me nt rec or ds as 
re q uire d f or rec o nciliati o n t o be  ti mel y c o m plete d. 
 
At t he c o ncl usi o n of t he st u d y, a n y use d a n d u n use d st u d y treat me nt c o ntai ners will be ret ur ne d   t o t he sp o ns or 
or desi g nee, or destr o ye d, after data re vie w is c o m plete, as per sp o ns or  i nstr ucti o ns. If n o s u p plies re mai n, t his 
fact will be d oc u me nte d i n p har mac y pr o d uct acc o u nta bilit y rec or ds. 
 
 
5. 3.  A d mi nistr ati o n  of  I n vesti g ati o n al Me dici n al  Pr o d ucts  
 
U n bli n de d  p har mac y  pers o n nel will  be  res p o nsi ble f or pr o vi di n g  al dafer mi n or  place b o  t o bli n de d  st u d y 
pers o n nel f or dis pe nsi n g as per t he ra n d o mizati o n sc he me. St u d y treat me nt will be  dis pe nse d  t o s u bjects i n a 

C o nfi de ntial  
Pa ge 2 1  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
bli n de d ma n ner.  
 
Patie nts will self-a d mi nistere d st u d y treat me nt b y s u bc uta ne o us i njecti o n i nt o t he a bd o me n  o nce dail y at 
a p pr o xi matel y t he sa me cl oc k ti me eac h da y d uri n g t he treat me nt p eri o d. Patie nts  will be c o u nsele d o n t he 
i m p orta nce of a d mi nisteri n g st u d y treat me nt as i nstr ucte d a n d of rec or di n g t he ti me of eac h d ose acc uratel y i n 
t he patie nt ’s b o wel patter n diar y t hr o u g h o ut t he treat me nt p eri o d.  
5. 4.  C o m pli a nce  
 
As t his is a m ulti ple -d ose st u d y, treat me nt c o m p lia nce will be assesse d f or eac h a d mi nistrati o n of  st u d y 
treat me nt. C o m me nts will be rec or de d if t here are a n y de viati o ns fr o m pla n ne d st u d y treat me nt a d mi nistrati o n 
pr oce d ures.  
 
5. 5.  R a n d o miz ati o n  
 
Patie nts  w h o c o m plete scree ni n g assess me nts a n d meet all eli g i bilit y criteria will be assi g ne d a u ni q ue  
ra n d o mizati o n i de ntificati o n n u m ber  at t he ti me of  st u d y treat me nt a d mi nistrati o n.  O nce  a ra n d o mizati o n 
n u m ber  has bee n  all ocate d t o  a s u bject, it ma y n ot be  assi g ne d  t o a n ot her patie nt.  
 
D E SI G N:   Ra n d o mize d place b o -c o ntr ol trial base d usi n g B L O C K R A N D O MI Z A TI O N  s o t hat e q ual 
n u m bers of patie nts are ra n d o mize d t o place b o a n d al dafer mi n  1 m g  i n t w o bl oc ks: 
a.  P ati e nts O F F bil e aci d s e q u estr a nts  
b.  P ati e nts O N bil e aci d s e q u estr a nts.  
 
Ra n d o mize d tre at me nt  assi g n me nt will be c o nsi dere d bli n de d as per t he f oll o wi n g: T he ra n d o mizati o n 
assi g n me nts will  be a vaila ble t o t he st u d y p har mac y staff t hat is pre pari n g t he st u d y treat me nt, w h o will n ot be   
i n v ol ve d i n a n y ot her as pect  of t he  st u d y i ncl u di n g a d mi nistrati o n of  t he st u d y treat me nt. Ra n d o mizati o n  
assi g n me nts will n ot be  ma de  a vaila ble  t o t he patie nts or st u d y staff res p o nsi ble f or t he m o nit ori n g a n d 
e val uati o n of safet y assess me nts.  
 
I n t he a bse nce of a me dical e mer ge nc y, t he bli n de d ra n d o mizati o n f or t his st u d y will n ot be re veale d t o t he 
Pri nci pal I n vesti gat or a n d st u d y tea m u ntil  all data  are e ntere d  i n t he data base, e dit c hec ks   are perf or me d, 
q ueries  cl ose d, a n d t he data base is officiall y  l oc ke d. 
 
Brea ki n g t he bli n d  is e x pressl y f or bi d de n e xce pt i n t he e ve nt  of  a me dical  e mer ge nc y  w here   t he i de ntit y of t he 
st u d y treat me nt m ust be  k n o w n  i n or der t o pr o perl y treat t he patie nt . I n t he e ve nt of a  me dical  e mer ge nc y, it is 
re q ueste d t hat t he in vesti gat or  c o ntact t he s p o ns or pri or t o brea ki n g t he bli n d. If brea ki n g t he  bli n d is re q uire d 
beca use of a me dical e mer ge nc y, t he treat me nt i de ntit y w o ul d be re veale d b y  t he in vesti gat or or desi g nee, f or 
t hat patie nt  o nl y. Reas o ns f or treat me nt u n bli n di n g  m ust be clearl y e x plai ne d a n d d oc u me nte d.  
 
5. 6.  Pri or  a n d  C o nc o mit a nt  Me dic ati o ns  
 

C o nfi de ntial  
Pa ge 2 2  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A n y  me dicati o n  (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) or 
vacci nes t hat a patie nt uses  fr o m 3 0 da ys pri or t o Visit 1 Scree n t hr o u g h o ut t he st u d y m ust be  rec or de d al o n g 
wit h  reas o n f or use, d ose a n d fre q ue nc y a n d dates of use. 
 
 
5. 7.  Resc ue  Me dic ati o n  
 
Beca use t he st u d y i ncl u des place b o treat me nt a n d is a p pr o xi matel y 5 6 da ys l o n g, l o pera mi de ma y be use d as a 
resc ue me dicati o n e xce pt  wit hi n 4 8 h o urs of a st o ol c ollecti o n.  T he ma xi m u m d ose of l o pera mi de all o we d is 4 
m g i n a 2 4 -h o ur peri o d.  T he use of l o pera mi de as a resc ue me dicati o n m ust be rec or de d i n t he b o wel patter n 
diar y . 
 
 
6.  
S T U D Y  A S S E S S M E N T S  A N D  P R O C E D U R E S  
 
6. 1.  Scree ni n g  a n d  Eli gi bilit y  
 
Patie nt  eli gi bilit y will be assesse d base d o n pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria. 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 p ote ntial  patie nt s meet all eli gi bilit y criteria.  
 
Scree ni n g pr oce d ures m ust be c o m plete d wit hi n 2 8 da ys pri or t o  i nitiati o n of st u d y me dicati o n.  
 
At t he Visit 1  Scree n  or d uri n g t he o pti o nal re m ote c o nse nt a n d eli gi bilit y re vie w , p ote ntial patie nts  will ha ve a 
detaile d ver bal prese ntati o n of t he  nat ure, p ur p ose, r is ks, a n d re q uire me nts of t he st u d y i n a d diti o n t o recei vi n g 
detaile d writte n  i nf or mati o n. Patie nts  will  ha ve  a de q uate  o p p ort u nit y  t o as k t he a p pr o priate pers o n  of  t he st u d y 
tea m (ie, Pri nci pal I n vesti gat or or desi g nee)  a b o ut a n y as pect  of t he  st u d y. If a patie n t deci des  t hat he/s he is 
willi n g t o partici pate i n t he st u d y, he/s he will be as ke d t o si g n t he i nf or me d c o nse nt f or m. T he cli nical 
pers o n nel o btai ni n g writte n c o nse nt fr o m t he patie n t will als o si g n t he f or m t o c o nfir m c o nse nt has bee n 
o btai ne d. O nce si g ne d, t he ori gi nal c o nse nt will be mai ntai ne d f or t he st u d y rec or ds a n d a si g ne d c o p y gi ve n t o 
t he patie nt.  A c o p y will be sca n ne d i nt o t he patie nt’s electr o nic me dical rec or d. T he in vesti gat or w ill verif y 
t hat i nf or me d c o nse nt has bee n o btai ne d fr o m eac h patie nt pr i or t o t he patie nt  u n der g oi n g  a n y st u d y -relate d 
pr oce d ures.  
Visit 1 Scree n c o nsist s of:  
•  
C o m plete  me dical  hist or y  
•  
P h ysical e xa mi nati o n, i ncl u di n g hei g ht, wei g ht, a n d vital si g ns ( heart rate, bl o o d press ure,  
te m perat ure a n d res pirati o n rate) 
•  
Safet y  1 2 -lea d E C G  
•  
Cli nical la b orat or y tests : T he sta n dar d C o m pre he nsi ve Meta b olic Pa nel  w hic h i ncl u des 
calci u m, creati ni ne, s o di u m, p otassi u m, al b u mi n, al kali ne p h os p hatase, t otal bilir u bi n, 
car b o n di o xi de, c hl ori de, gl uc ose, t otal pr otei n, B U N, A S T, a n d A L T.  He mat ol o g y 
i ncl u des a C B C wit h differe ntial.  A li pi d pa nel i ncl u di n g t otal c h olester ol, H D L, L D L a n d 
tri gl yceri des will be perf or me d. A nal ysis of t he uri ne will be c o m plete d b y a sta n dar d uri ne 
di pstic k met h o d wit h micr osc o p y.  

C o nfi de ntial  
Pa ge 2 3  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
•  
Uri ne h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y test (f or fe males of  
c hil d beari n g  p ote ntial)  
 
6. 2.  A d verse E ve nt  
 
A n  A E  is a n y u nt o war d  me dical  occ urre nce  t hat d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he st u d y 
treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d uct, w het her  or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.  
A d verse  e ve nts  ca n i ncl u de, b ut are  n ot  li mite d t o, a n y of  t he f oll o wi n g: 
•  
U nfa v ora ble  c ha n ges  i n ge neral c o n diti o n 
•  
S u bjecti ve  or  o bjecti ve  si g ns/s y m pt o ms 
•  
C o nc o mita nt  disease  or  acci de nts 
•  
Cli nicall y  rele va nt a d verse  c ha n ges  i n la b orat or y para meters o ver  t he c o urse  of  t he st u d y 
•  
Pre -e xisti n g c o n diti o ns  t hat w orse n  i n se verit y, i ncrease i n fre q ue nc y, or  ha ve  ne w  
si g ns/s y m pt o ms 
 
 
6. 3  Seri o us  A d verse  E ve nt  
A n  A E  s h o ul d be  classifie d as a n S A E  if it meets o ne  of t he  f oll o wi n g criteria: 
 
Fatal:  
T he  A E res ulte d  i n deat h. 
 
Life -t hreate ni n g: 
 
T he A E place d t he s u bject at i m me diate ris k of deat h. T his classificati o n  
d oes n ot a p pl y t o a n A E t hat h y p ot heticall y mi g ht ca use deat h if it were  
m ore  se vere. 
 
H os pitalizati o n:  
T he A E re q uire d or pr ol o n ge d a n e xisti n g i n patie nt h os pitalizati o n.  
H os pitalizati o ns f or electi ve me dical or s ur gical pr oce d ures or 
treat me nts  pla n ne d bef ore t he si g ni n g of i nf or me d c o nse nt i n t he 
st u d y or r o uti ne c hec k-u ps  are n ot S A Es b y  t his defi niti o n. 
 
Disa bli n g/  
i nca pacitati n g: 
T he A E res ulte d i n a persiste nt or si g nifica nt i nca pacit y or 
s u bsta ntial   disr u pti o n  of  t he s u bject’s a bilit y t o c o n d uct n or mal 
life f u ncti o ns. 
 
C o n ge nital a n o mal y or  
birt h  defect:  
A n a d verse o utc o me i n a c hil d or fet us of a s u bject e x p ose d t o t he 
st u d y   treat me nt bef ore c o nce pti o n or d uri n g  pre g na nc y.  
 

C o nfi de ntial  
Pa ge 2 4  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
Me dicall y  si g nifica nt: 
T he A E di d n ot meet a n y of t he a b o ve criteria b ut c o ul d ha ve je o par dize d 
t he patie nt a n d mi g ht ha ve re q uire d me dical or s ur gical i nter ve nti o n t o 
pre ve nt  o ne  of  t he o utc o mes  liste d a b o ve or  i n v ol ves s us pecte d 
tra ns missi o n via a  me dici nal  pr o d uct of  a n i nfecti o us  a ge nt. 
 
T he Pri nci pal I n vesti gat or will pr o m ptl y re vie w all i nf or mati o n rele va nt t o t he safet y of t he i n vesti gati o nal 
dr u g a n d n otif y t he F D A of a n y u ne x pecte d fatal or life -t hreate ni n g s us pecte d a d verse reacti o n as s o o n as 
p ossi ble, b ut n o later t ha n 7 cale n dar da ys after recei pt of t he i nf or mati o n. T he Pri nci pal I n vesti gat or will als o 
n otif y t he F D A i n a n I N D safet y re p ort of p ote ntial seri o us ris ks, as s o o n as p ossi ble, b ut i n n o case later t ha n 
1 5 cale n dar da ys after t he Pri nci pal I n vesti gat or deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g.  
 
Electi ve  h os pitalizati o n  a n d/ or s ur ger y f or clearl y pree xisti n g  c o n diti o ns  (i.e., a s ur ger y t hat has   bee n 
sc he d ule d pri or t o t he patie nt ’s e ntr y i nt o t he st u d y) will n ot be re p orte d as a n S A E. All  ot her h os pitalizati o ns, 
i ncl u di n g electi ve h os pitalizati o ns f or a n y c o n diti o n t hat was n ot pree xisti n g,  will be re p orte d as a n S A E.  
 
A n y  S A E  t hat is o n g oi n g  w he n  t he patie nt  c o m pletes  t he st u d y or  disc o nti n ues  t he st u d y will  be  f oll o we d b y  t he 
I n vesti gat or u ntil t he e ve nt res ol ves,  sta bilizes, or  ret ur ns t o baseli ne  stat us. 
 
 
6. 4  
A d verse E ve nt Se verit y  
 
T he se verit y of eac h A E will be assesse d at t he o nset b y a p h ysicia n. W he n rec or di n g  t he o utc o me of t he A E 
t he ma xi m u m se verit y of t he A E e x perie nce d will als o be rec or de d.  T he  se verit y of  eac h A E  will  be  gra de d  
acc or di n g t o t he C o m m o n Ter mi n ol o g y Criteria  f or A d verse  E ve nts  (C T C A E)  versi o n 5. 0:  
 
Gra de  1:  
Mil d;  as y m pt o matic  or  mil d  s y m pt o ms; cli nical  or  dia g n ostic  o bser vati o ns  
o nl y; i nter ve nti o n n ot  i n dicate d. 
 
Gra de  2:  
M o derate; mi ni mal, l ocal or n o n -i n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge -a p pr o priate  i nstr u me ntal acti vities of dail y  li vi n g. 
 
Gra de  3:  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g, li miti n g  
self-care acti vities of dail y li vi n g ( i.e., pre pari n g meals, s h o p pi n g f or 
gr oceries  or  cl ot hes, usi n g t he tele p h o ne,  ma na gi n g  m o ne y) . 
 
Gra de  4:  
Life -t hreate ni n g c o nse q ue nces,  ur ge nt  i nter ve nti o n i n dicate d. 
Gra de  5:  
Deat h  relate d t o A E  
 
6. 5  A d verse E ve nt Rel ati o ns hi p  
 
T he  in vesti gat or  is o bli gate d  t o assess t he ca usal  relati o ns hi p bet wee n  t he st u d y  treat me nt a n d eac h occ urre nce 
of a n A E. T he A E ca usal relati o ns hi p t o st u d y  treat me nt m ust be c haracterize d as  o ne  of t he  f oll o wi n g 
cate g ories:  

C o nfi de ntial  
Pa ge 2 5  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
N ot Relate d:  
T he A E d oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of 
t he st u d y treat me nt, d oes n ot a bate u p o n disc o nti n uati o n of the st u d y treat me nt, 
d oes n ot f oll o w a k n o w n or h y p ot hesize d ca use -effect relati o ns hi p, a n d (if 
a p plica ble) d oes n ot rea p pear w he n t he st u d y treat me nt is rei ntr o d uce d, 
f urt her m ore, t here ma y e xist a clear alter nati ve me dical e x pla nati o n (e. g., 
u n derl yi n g di sease state) or ass ociati o n wit h st u d y pr oce d ure or c o n d uct . 
 
U nli kel y Relate d:   
T he te m p oral ass ociati o n bet wee n t he A E a n d t he st u d y treat me nt is s uc h t hat  
t he st u d y treat me nt is n ot  li kel y t o ha ve a n y reas o na ble ass ociati o n wit h t he 
A E.  
 
P ossi bl y Relate d:  
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he  
st u d y treat me nt a n d f oll o ws a k n o w n or e x pecte d res p o nse t o t he st u d y 
treat me nt b ut c o ul d ha ve als o bee n pr o d uce d b y a n u m ber of ot her fact ors. 
 
Pr o ba bl y Relate d:  
T h e A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he  st u d y 
treat me nt a n d ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n c haracteristics  of  t he 
patie nt ’s cli nical  state, e n vir o n me ntal,  or  t o xic fact ors, or  ot her  m o des  of  t hera p y 
a d mi nistere d  t o t he patie nt. 
 
Relate d:  
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he  st u d y 
treat me nt, a bates u p o n disc o nti n uati o n of t he st u d y treat me nt, f oll o ws a k n o w n  or  
h y p ot hesize d  ca use -effect relati o ns hi p,  a n d (if a p pr o priate) rea p pear s w he n  t he 
st u d y treat me nt is rei ntr o d uce d. 
 
 
T he Pri nci pal I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he ca usal 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 p y, a n d ot her ris k fact ors, as  well as t he te m p oral relati o ns hi p 
of t he e ve nt t o t he st u d y treat me nt a d mi nistrati o n s h o ul d be  c o nsi dere d a n d i n vesti gate d. T he Pri nci pal 
In vesti gat or s h o ul d c o ns ult t he I B a n d t he Pr o d uct I nf or mati o n   of mar kete d pr o d ucts wit hi n t he st u d y 
treat me nt class, w he n a p plica ble. F or eac h A E, t he  Pri nci pal 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 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 Pri nci pal 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; 
h o we ver,  t he Pri nci pal I n vesti gat or s h o ul d al wa ys ma ke a n i nitial assess me nt of ca usalit y f or e ver y e ve nt .  T he 
Pri nci pal I n vesti gat or ma y c ha n ge his/ her o pi ni o n of  ca usalit y base d o n s u bse q ue nt recei pt o f i nf or 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. 
 
A n y  S A E  t hat is o n g oi n g  w he n  t he s u bject c o m pletes  t he st u d y or  disc o nti n ues  t he st u d y will  be f oll o we d b y  
t he Pri nci pal I n vesti gat or u ntil t he e ve nt res ol ves, sta bilizes, or  ret ur ns t o baseli ne  stat us. 
 
6. 6  Cli nic al L a b or at or y  Tests  
 
Cli nical safet y la b orat or y tests will be perf or me d at t he st u d y site at Visit 1 Scree n or Visit 2  a n d Visit 5 E n d 
of St u d y. T hese tests i ncl u de t he C o m pre he nsi ve Meta b olic Pa nel , calci u m, creati ni ne, s o di u m, p otassi u m, 

C o nfi de ntial  
Pa ge 2 6  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
al b u mi n, al kali ne p h os p hatase, t otal bilir u bi n, car b o n di o xi de, c hl ori de, gl uc ose, t otal pr otei n, B U N, A S T, a n d 
A L T.  He mat ol o g y i ncl u des a C B C wit h differe ntial.  A li pi d pa nel i ncl u di n g t otal c h olester ol, H D L, L D L a n d 
tri gl yceri des will be perf or me d. A na l ysis of t he uri ne will be c o m plete d b y a sta n dar d uri ne di pstic k met h o d 
wit h micr osc o p y.   T he in vesti gat or will t he la b orat or y re p ort, d oc u me nt t he re vie w, a n d  rec or d a n y cli nicall y 
rele va nt c ha n ges as A E s. 
 
 
 
6. 7  Electr oc ar di o gr a ms  
 
Si n gle  1 2 -lea d E C Gs  will be  rec or de d wit h  s u bjects i n a s u pi ne p ositi o n  at Visit 1 Scree n a n d Visit 5 E n d of 
St u d y.  A d diti o nal  E C Gs  ma y  be  ta ke n at a n y ot her  ti mes, if dee me d  necessar y  b y  t he in vesti gat or .  All  E C G  
traci n gs will  be  re vie we d b y  t he Pri n ci pal I n vesti gat or  or  desi g nee.  
 
 
6. 8  
Assess me nt  of  A b d o mi n al P ai n, St o ol  Fre q ue nc y  a n d  C o nsiste nc y  
 
Patie nts will c o m plete a dail y b o wel patter n diar y t hr o u g h o ut t he st u d y t o rec or d a n d assess t he ir m ost se vere 
a b d o mi nal pai n o n a n 1 1 -p oi nt scale a n d ti mi n g of eac h b o wel m o ve me nt, c o nsiste nc y base d o n Brist ol st o ol 
f or m scale, ease of passa ge, a n d se nse of c o m plete ness of e vac uati o n.  Ease of st o ol passa ge was als o assesse d 
base d o n a 7 -p oi nt scale ( 1: ma n ual disi m pacti o n; 2: e ne ma nee d e d; 3: strai ni n g nee de d; 4: n or mal; 5: ur ge nt 
w/ o pai n; 6: ur ge nt w/ pai n; 7: i nc o nti ne nt).   T he Brist ol st o ol scale a n d a sa m ple diar y pa ge are i ncl u de d i n t he 
pr ot oc ol a p pe n dices.   
 
 
6. 9  Assess me nt of Bile Aci d Ki netics  
 
Assess me nt of B A s y nt hesis a n d f ecal e xcreti o n ( u ni q uel y a vaila ble i n U S A at Ma y o Cli nic) : 
 
Ser u m 7 -hy dr oxy -4 -c h oleste n-3 -o ne ( 7 -H C O or C 4)  meas ures he patic c h olester ol s y nt hesis a n d is a 
vali date d met h o d f or B A M/ B A D ( 1 8, 1 9).  Ser u m C 4 (ref. 2 0, assa y base d o n ref. 2 1) is p ositi vel y c o rrelate d 
wit h fecal B A e xcreti o n [r s =  0. 6 1, p < 0. 0 0 1 ( 4)].  
 
Ser u m fi br o bl ast gr o wt h f act or 1 9 ( F G F 1 9) , a meas ure of fee d bac k re g ulati o n of B A s y nt hesis ( 2 2), will be 
meas ure d b y E LI S A ( R & D S yste ms, Mi n nea p olis, M N).      
 
Fec al B A excreti o n : Usi n g H P L C/ta n de m mass s pectr o metr y, we a da pte d a met h o d ( 2 3) t o meas ure fecal t otal 
a n d i n di vi d ual B As i n a R A N D O M st o ol sa m ple.  We ha ve pre vi o usl y s h o w n t hat fecal t otal B A ( 4), a n d 
secret or y pri mar y a n d sec o n dar y B As [c he n o de o x yc h olic ( C D C A) a n d de o x yc h olic a ci ds ( D C A)] are hi g her 
i n I B S-D, w hereas C D C A is decrease d a n d n o n -secret or y lit h oc h olic aci d i ncrease d i n I B S-C ( 2 4)].  T otal 
fecal bile aci ds a n d pri mar y C D C A will be meas ure d. 
 
6. 1 0  Assess me nt of Al d afer mi n P h ar m ac o ki netics  
Tr o u g h c o nce ntrati o ns of al da fer mi n will be deter mi ne d b y a vali date d P K la b orat or y assa y perf or me d at a 
bi oa nal ytical C R O, Fr o ntier La b orat ories, usi n g ser u m sa m ples o btai ne d at baseli ne, Da y 1 4 a n d Da y 2 8.  

C o nfi de ntial  
Pa ge 2 7  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
A n o n y mize d s er u m sa m ples will be pr o vi de d f or p k a nal ysis. T he sa m ples will be la belle d wit h a de -
i de ntifie d st u d y n u m ber t hat ca n n ot be li n ke d t o t he patie nt’s i de ntit y wit h o ut use of a ke y w hic h will be ke pt 
i n a pass w or d-pr otecte d sec ure ser ver at Ma y o accessi ble o nl y t o t he st u d y tea m.  
 
Sa m ples will be st ore d at Fr o ntier La b o rat ories o nl y u ntil t he p k a nal ysis is perf or me d w hic h m ust be d o ne i n a 
reas o na ble a m o u nt of ti me. After perf or mi n g t he p k a nal ysis, Fr o ntier La b orat ories will discar d t he sa m ples. 
 
7.  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
 
7. 1  S a m ple Size a n d St atistic al P o wer  
 
B ase d o n t he e n d p oi nts of i nterest i n patie nts wit h bile aci d diarr hea [ 1 2], t he pr o p ose d sa m ple sizes ha ve 
~ 8 0 % p o wer ( 2 -si de d α = 0. 0 5) t o detect cli nicall y rele va nt effect sizes i n ser u m C 4 a n d st o ol f or m (e x presse d 
as detecta ble differe nce [ Δ] i n 2 gr o u ps :   
 
T a ble 1: Detect a ble differe nces b ase d o n 8 0 % p o wer  i n patie nts wit h B A D n ot  recei vi n g B A se q uestra nt 
Res p o nse  
Me a n ( S D)  
Detect a ble ∆a bs ol ute wit h n = 9 per gr o u p  
Ser u m C 4 n g/ m L  
7 2. 3 ( 4 5. 6)  
6 4. 1 ( 1. 3 4 * S D or 8 9 % of baseli ne mea n)  
% fecal pri mar y B A  
1 5. 7 ( 2 0)  
2 8. 1 ( 1. 7 9 * S D or 1 7 9 % of baseli ne mea n)  
# B Ms per wee k  
1 5. 1 ( 7. 1)  
1 0. 0 ( 1. 4 1 * S D or 6 6 % of baseli ne mea n)  
St o ol f or m ( B S F S 1 -7 scale)  
4. 4 ( 1. 1 2)  
1. 5 8 ( 1. 4 1 * S D or 3 5. 9 % of baseli ne mea n)  
 
 
Base d o n o ur pre vi o us o pe n -la bel st u d y de m o nstrati n g effects of a bile aci d se q uestra nt (c olese vela m) as a 
t y pical baseli ne res ults f or patie nts o n bile aci d se q uestra nts: 
 
T a ble 2: Detect a ble differe nces b ase d o n 8 0 % p o wer  i n patie nts wit h B A D recei vi n g B A se q uestra nt 
Res p o nse  
Me a n ( S D)  
Detect a ble ∆a bs ol ute wit h n = 6 per gr o u p  
Ser u m C 4 n g/ m L  
1 1 2. 5 ( 5 0. 6)  
9 0. 8 ( 1. 7 9 * S D or  8 0. 7 % of baseli ne mea n )  
% fecal pri mar y B A  
2. 7 ( 7. 4)  
1 3. 3 ( 1. 8 0 * S D or 4 9 2 % of baseli ne mea n)  
# B Ms per wee k  
2 1. 7 ( 7. 1)  
1 2. 7 5 ( 1. 8 0 * S D or  5 8. 8 % of baseli ne mea n)  
St o ol f or m ( B S F S 1 -7 scale)  
4. 6 ( 0. 6)  
1. 0 8 ( 1. 8 0 * S D or 2 3. 5 % of baseli ne mea n)  
 
7. 2  
St atistic al A n al ysis  
 
Effects of treat me nt will be c o m pare d usi n g I nte nt -t o-Treat pri nci ples usi n g A N C O V A wit h B MI, ge n der a n d 
baseli ne fasti n g C 4 as c o variates.  I n or der t o reac h 3 0 s u bjects, accr ual will be set at 3 6 t o re place a n y 
v ol u nteer(s) w h o wit h dra w pri or t o ta ki n g le ss t ha n 1 da y of d osi n g. A n y S u bject w h o recei ves m ore t ha n 1 

C o nfi de ntial  
Pa ge 2 8  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
da y of d osi n g will be c o nsi der c o m plete d usi n g t he I nte nt -t o-Treat a nal ysis.  
 
Pri mar y en d p oi nts are cha n ge i n fasti n g ser u m C 4 le vels fr o m baseli ne t o Da y 2 8  a n d c ha n ge i n st o ol 
c o nsiste nc y bas e d o n Brist ol St o ol F or m Scale, B S F S  fr o m baseli ne t o Da y 2 8.  
 
Sec o n dar y e nd p oi nts  are  
•  
A bs ol ute c ha n ge i n st o ol c o nsiste nc y fr o m baseli ne t o Da y 1 4 a n d Da y 2 8 of treat me nt  
•  
A vera ge dail y st o ol c o nsiste nc y sc ore at Da y 1 4  a n d D a y 2 8  of treat me nt  
•  
Ma xi m u m a b d o mi nal pai n sc ore rate d b y patie nt usi n g a n 1 1 -p oi nt scale, 0 t o 1 0 i ncl usi ve wit h 0 as 
n o ne a n d 1 0 as w orst i ma gi na ble pai n  
•  
A bs ol ute c ha n ge i n a b d o mi nal pai n fr o m baseli ne t o Da y 1 4 a n d Da y 2 8 of treat me nt  
•  
N u m ber of b o wel m o ve me nt s per wee k 
•  
C ha n ge i n t otal fecal bile aci d c o nce ntrati o n bet wee n baseli ne a n d Da y 2 8  
•  
Pr o p orti o n of fecal secret or y ( C D C A + D C A) bile aci d as meas ure d i n a si n gle, ra n d o m st o ol sa m ple 
b y a vali date d la b orat or y assa y.  
•  
 Pr o p orti o n of fecal pri mar y  ( C D C A + C A ) bile aci d as meas ure d i n  
a si n gle, ra n d o m st o ol sa m ple b y a vali date d la b orat or y assa y.  
•  
T otal fecal bile aci d c o nce ntrati o n i n a si n gle, ra n d o m st o ol sa m ple as meas ure d b y a vali date d 
la b orat or y assa y. 
•  
T otal al dafer mi n c o nce ntrati o n i n ser u m as meas ure d  b y a vali date d la b orat or y assa y  
 
A d verse e ve nts ( A Es) will be liste d a n d s u m marize d b y s yste m or ga n class a n d  preferre d ter m, as well as 
acc or di n g t o se verit y a n d ca usalit y/relati o ns hi p t o st u d y   treat me nt.  
 
O bser ve d val ues f or cli nical la b orat or y tests, vital si g ns a n d safet y 1 2 -lea d E C Gs will be s u m marize d  
b y treat me nt. O bser ve d val ues will be classifie d as  n or mal, a b n or malit y t hat is n ot cli nicall y si g nifica nt, a n d 
cli nicall y si g nifica nt  a b n or malit y b y tre at me nt. 
 
 
8.  
E T HI C A L  C O N SI D E R A TI O N S  
8. 1.  Et hic al  C o n d uct  of t he St u d y  
 
T his  st u d y will  be  c o n d ucte d  i n acc or da nce  wit h  t he et hical  pri nci ples  t hat ha ve  t heir ori gi n  i n t he Declarati o n 
of Helsi n ki a n d t hat are c o nsiste nt wit h G C P, I nter nati o nal C o u ncil f or  Har m o nisati o n (I C H) g ui deli nes, a n d 
ot her a p plica ble re g ulat or y re q uire me nts ( i.e., l ocal re q uire me nts). 
 
8. 2.  I nstit uti o n al Re vie w B o ar d A p pr o v al 
 
Bef ore i nitiati n g a st u d y, t he Pri nci pal I n vesti gat or m ust ha ve writte n a n d date d a p pr o val fr o m t he  I R B/I E C f or 
the  st u d y pr ot oc ol,  writte n  I C F, s u bject recr uit me nt materials  a n d pr oce d ures  (i.e., a d vertise me nts  or  
we bsites),  a n d a n y ot her writte n  i nf or mati o n t o be  pr o vi de d  t o s u bjects. 
 
A p pr o val fr o m t he c o m mittee m ust be d oc u me nte d i n a letter t o t he Pri nci pal I n vesti gat or s pecif yi n g t he   

C o nfi de ntial  
Pa ge 2 9  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
pr ot oc ol n u m ber, pr ot oc ol versi o n, d oc u me nts re vie we d, a n d t he date o n w hic h t he c o m mittee  met  a n d gra nte d 
t he a p pr o val. 
 
All d oc u me nts s u bject t o re vi e w d uri n g t he st u d y, i ncl u di n g a n y m o dificati o ns ma de t o t he  pr ot oc ol  after 
recei pt of I R B  a p pr o val,  m ust  als o be  s u b mitte d t o t he c o m mittee  f or a p pr o val pri or  t o i m ple me ntati o n. T he 
Pri nci pal I n vesti gat or m ust als o pr o vi de peri o dic re p orts as re q uire d a n d pr o m ptl y re p ort i m p orta nt safet y 
i nf or mati o n (ie, S A Es) a n d pr ot oc ol vi olati o ns, as a p pr o priate, t o t he I R B. 
 
As  part  of  t he Pri nci pal I n vesti gat or’s  writte n  a p plicati o n  t o t he I R B, he  s h o ul d pr o vi de   t he c o m mittee wit h a 
c urre nt c o p y of t he I B. If t he I B is u p date d d uri n g t he st u d y, t he  I n vesti gat or s h o ul d s u p pl y a n u p date d c o p y t o 
t he c o m mittee. 
 
 
8. 3  
Desi g n ati o n  of  a n  I n de pe n de nt M o nit or  
 
Dr. 
 P h D ( Ma y o Cli nic) will ser ve as i n de pe n de nt m o nit or t o perf or m a n i n de pe n de nt 
re vie w of o n g oi n g safet y. I n acc or d a nce wit h I R B revie w, we s h all ask Dr.  
 t o c o nstit ute a n i n de pe n de nt 
D S M B if re q uire d.  
 
As a s p o ns or -i n vesti gator st u d y, t he st u d y will be m o nit ore d a n n uall y b y t he Ma y o Office of Researc h 
Re g ulat or y S u p p ort.  
 
8. 4  
S afet y  Re vie w  Pl a n  
St u d y  pr o gress  a n d safet y will  be  re vie we d q uarterl y  (a n d m ore fre q ue ntl y,  if nee de d).  Pr o gress  re p orts 
i ncl u di n g patie nt recr uit me nt, rete nti o n/attriti o n, a n d A Es will be pr o vi de d t o t he  I n de pe n de nt M o nit or e ver y 
year. A n a n n ual re p ort will be c o m pile d a n d will i ncl u de a list a n d  s u m marizati o n of  A Es.  I n a d diti o n, t he 
a n n ual re p ort will  a d dress: 
1.  W het her  A E  rates are c o nsiste nt  wit h  pre -st u d y ass u m pti o ns;  
2.  Reas o n  f or dr o p o uts  fr o m t he st u d y; 
3.  W het her  all partici pa nts  met  e ntr y criteria; 
4.  W het her c o nti n uati o n of t he st u d y is j ustifie d o n t he basis t hat a d diti o nal data are nee de d  t o 
acc o m plis h t he state d ai ms of  t he st u d y; a n d 
 
5.  C o n diti o ns w here b y  t he st u d y mi g ht  be  ter mi nate d pre mat urel y  (i.e.,, v ol u ntar y dr o p o ut  of  
>  4 0 %  of  c o h ort). 
 
T he a n n ual re p ort will be re vie we d b y t he in de pe n de nt m o nit or a n d will be f or war de d t o t he I R B  o n a n a n n ual 
basis.  
8. 5  
I nf or me d C o nse nt  
 
T he in vesti gat or will f ull y i nf or m t he patie nt  of all perti ne nt as pects of t he st u d y, i ncl u di n g t he  a p pr o val  of  t he 

C o nfi de ntial  
Pa ge 3 0  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
st u d y b y  t he I R B. Bef ore  i nf or me d c o nse nt  ma y  be o btai ne d,  t he in vesti gat or  or a desi g nee s h o ul d pr o vi de  t he 
patie nt  a m ple ti me a n d o p p ort u nit y  t o i n q uire a b o ut details  of t he  st u d y a n d t o deci de w het her or  n ot t o 
partici pate.  
 
Pri or t o a patie nt ’s partici pati o n i n t he st u d y, t he I R B-a p pr o ve d I C F m ust be si g ne d a n d  pers o nall y date d b y 
t he patie nt  a n d b y t he pers on w h o c o n d ucte d t he i nf or me d c o nse nt  disc ussi o n.   
 
T he writte n I C F a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o patie nt s s h o ul d be re vise d w he ne ver 
i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he patie nt ’s c o nse nt. A n y re vise d 
writte n I C F or st u d y materials t o be a vaila ble a n d/ or s u p plie d t o patie nts  s h o ul d recei ve t he I R B’s a p pr o val i n 
a d va nce of use. T he patie nt  will be i nf or me d i n a  ti mel y ma n ner if ne w i nf or mati o n bec o mes a vaila ble t hat 
ma y be rele va nt t o t he s u bject’s  wil li n g ness t o c o nti n ue partici pati o n i n t he st u d y. T he c o m m u nicati o n of t his 
i nf or mati o n s h o ul d be  d oc u me nte d.  
 
8. 6  
C o nfi de nti alit y  
 
All i nf or mati o n ge nerate d i n t his st u d y is c o nsi dere d hi g hl y c o nfi de ntial a n d m ust n ot be  discl ose d  t o a n y 
pers o n  or e ntit y n ot  directl y  i n v ol ve d wit h t he  st u d y. 
 
Pri or  t o st u d y partici pati o n,  t he in vesti gat or  s hall i nf or m t he patie nt  t hat t he m o nit or(s),  sp o ns or  re prese ntati ves, 
a u dit or(s), I R B, a n d t he re g ulat or y a ut h orities will be gra nte d direct access  t o t he patie nt ’s ori gi nal me dical 
rec or ds f or verificati o n of cli nical st u d y pr oce d ures a n d/ or data, a n d t hat, b y si g ni n g a writte n I C F, t he patie nt  
is a ut h orizi n g s uc h access. 
 
I n a d diti o n, pri or  t o st u d y partici pati o n,  t he patie nt  m ust  be  i nf or me d t hat t he rec or ds i de ntif yi n g t he patie nt  will 
n ot be ma de p u blicl y a vaila ble; if t he res ults of t he st u d y are p u blis he d, t he  patie n t’s i de ntit y will re mai n 
c o nfi de ntial. 
8. 7  
Pr ot oc ol  C o m pli a nce  
 
T he Pri nci pal I n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y  t he re g ulat or y  
a ut h orities (if a p plica ble) a n d t hat was  a p pr o ve d  b y  t he I R B.  
 
T he Pri nci pal I n vesti gat or s h o ul d n ot i m ple me nt a n y de viati o n fr o m, or c ha n ges t o, t he pr ot oc ol wit h o ut  pri or 
re vie w a n d d oc u me nte d  a p pr o val  fr o m t he I R B of  a n ame n d me nt, e xce pt w here necessar y t o eli mi nate 
i m me diate hazar d(s) t o st u d y patie nt s or w he n t he c ha n ge i n v ol ves o nl y l o gistical or a d mi nistrati ve as pects of 
t he st u d y (i.e., c ha n ge i n m o nit or, c ha n ge of tele p h o ne n u m ber).  
 
W he n a n i m p orta nt de viati o n fr o m t he pr ot oc ol is dee me d necessar y f or a n i n di vi d ual patie n t, t he Pri nci pal  
In vesti gat or m ust d eter mi ne t he i m pact of t he de viati o n o n  t he patie nt ’s partici pati o n a n d/ or t he assess me nt of 
safet y or efficac y i n t he st u d y. A n y si g nifica nt pr ot oc ol  de viati o ns  affecti n g  patie nt  eli gi bilit y a n d/ or safet y 
m ust  be  re p orte d b y  t he Pri nci pal I n vesti gat or or site dele gate t o t he I R B a n d re g ulat or y a ut h orities, as 
a p plica ble, pri or t o  i m ple me ntati o n. 
 

C o nfi de ntial  
Pa ge 3 1  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
T he  Pri nci pal I n vesti gat or  s h o ul d d oc u me nt  a n d e x plai n a n y de viati o n  fr o m t he a p pr o ve d pr ot oc ol.  

C o nfi de ntial  
Pa ge 3 2  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
R E F E R E N C E S  
1.  Ca milleri M, Vija y var gi ya, P. T he r ole of bile aci ds i n c hr o nic diarr hea. A m J Gastr oe nter ol. 2 0 2 0 
Oct; 1 1 5( 1 0): 1 5 9 6 -1 6 0 3.  
 
2.  Vija y var gi ya P, Ca m illeri M. U p date o n bile aci d mala bs or pti o n: fi nall y rea d y f or pri me ti me? C urr 
Gastr oe nter ol Re p. 2 0 1 8 Mar 2 6; 2 0( 3): 1 0.  
 
3 .  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 1 2 -2 1    P MI D 2 2 4 2 6 0 8 7  
 
4 .   Ma yer E A, Tillisc h K. T he brai n-g ut a xis i n a b d o mi nal pai n s y n dr o mes. A n n u Re v Me d 2 0 1 1; 6 2: 3 8 1 -9 6   
P M C 3 8 1 7 7 1 1  
 
5 .  Ca milleri M, Mc Ki nzie S, B usci gli o I, L o w P A, S weetser S, B urt o n D, Ba xter K, R y ks M, Zi ns meister A R.  
Pr os pecti ve st u d y of m ot or, se ns or y, ps yc h ol o gical a n d a ut o n o mic f u ncti o ns i n 1 1 9 patie nts wit h irrita ble b o wel 
s y n dr o me.  Cli n Gastr oe nter ol He pat ol 2 0 0 8; 6: 7 7 2-7 8 1   P M C 2 4 9 5 0 7 8  
 
6 .  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, D yer R B, La msa m J, Zi ns meister A R.  
I ncrease d B A 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 5, e 3    P M C 3 5 6 5 4 2 9  
 
7 .  M ö n ni kes H. Q ualit y of life i n patie nts wit h irritable b o wel s y n dr o me. J Cli n Gastr oe nter ol 
2 0 1 1; 4 5( S u p pl.): S 9 8 -1 0 1    P MI D 2 1 6 6 6 4 2 8  
 
8 .  Ca milleri M.  Peri p heral mec ha nis ms i n irrita ble b o wel s y n 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    
P MI D 2 3 0 9 4 7 2 4  
 
9 .  S piller R C. Is I B S ca use d b y i nfecti o us diarr hea? Nat Cli n Pract Gastr oe nter ol He pat ol 2 0 0 7; 4: 6 4 2-3    
P MI D 1 7 9 8 4 9 8 3      
 
1 0 .  Ca milleri M. P h ysi ol o gical u n der pi n ni n gs of irrita ble b o wel s y n dr o me: ne ur o h or m o nal mec ha nis ms. J 
P h ysi ol 2 0 1 4; 5 9 2( Pt 1 4): 2 9 6 7 -8 0     P M C 4 2 1 4 6 5 3  
 
1 1.  Vale nti n N, Ca milleri M, Alta yar O, Vija y var 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 hea i n f u ncti o nal gastr oi ntesti nal dis or ders wit h diarr hea: a s yste matic 
re vie w a n d m eta-a nal ysis. G ut. 2 0 1 5 Se p 7. pii: g utj nl -2 0 1 5 -3 0 9 8 8 9. d oi: 1 0. 1 1 3 6/ g utj nl -2 0 1 5 -3 0 9 8 8 9. 
[ E p u b a hea d of pri nt] 
 
1 2 .  Ca milleri M, Ac osta A, B usci gli o I, B ol di n g h A, D yer R B, Zi ns meister A R, L ue ke A, Gra y A, D o nat o LJ. 
Effect of c olese vela m o n faecal bile aci ds a n d b o wel f u ncti o ns i n diarr h oea -pre d o mi na nt irrita b le b o wel 
s y n dr o me. Ali me nt P har mac ol T her 2 0 1 5; 4 1: 4 3 8-4 8  
 
1 3 .  Vija y var gi ya P, Ca milleri M, Carls o n P, et al. Effects of C olese vela m o n B o wel S y m pt o ms, Bi o mar kers, a n d 

C o nfi de ntial  
Pa ge 3 3  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
C ol o nic M uc osal Ge ne E x pressi o n i n Patie nts w it h Bile Aci d Diarr hea i n a Ra n d o mize d Trial. Cli n Gastr oe nter ol 
He pat ol 2 0 2 0; 1 8: 2 9 6 2 – 7 0  
 
1 4 .  Ca milleri M, N or d S L, B urt o n D, O d u ye b o I, Z ha n g Y, C he n J, I m K, B ha d P, Ba d ma n M K, 
Sa n ders D S, Walters J R F. Ra n d o mise d cli nical trial: si g nifica nt bi oc he mical a n d c ol o nic tra nsit effects 
of t he far nes oi d X rece pt or a g o nist tr o pife x or i n p atie nts wit h pri mar y bile aci d diarr h o ea. Ali me nt 
P har mac ol T her 2 0 2 0; 5 2: 8 0 8 -2 0  
 
1 5.   Walters J R F, J o h nst o n I M, N ol a n J D, Vassie C, Pr uza ns ki M E, S ha pir o D A. T he res p o nse of 
patie nts wit h bile aci d diarr h oea t o t he far ne s oi d X rece pt or a g o nist o betic h olic aci d. Ali me nt 
P har mac ol T her 2 0 1 5; 4 1: 5 4 -6 4  
 
1 6 .  L u o J , K o B , Elli ott M , et al. A n o nt u m ori ge nic varia nt of F G F 1 9 treats c h olestatic li ver disease. Sci Tr nsl 
Me d 2 0 1 4; 6: 2 4 7ra 1 0 0  
 
1 7 .  Z h o u M, Wa n g X, P h u n g V, et al. Se parati n g t u m ori ge nicit y fr o m bile aci d re g ulat or y acti vit y f or e n d ocri ne 
h or m o ne F G F 1 9. Ca ncer Res 2 0 1 4; 7 4: 3 3 0 6 -1 6  
 
1 8 .  Z h o u M, Lear ne d R M, R ossi SJ, et al. E n gi neere d fi br o blast gr o wt h fact or 1 9 re d uces li ver i nj ur y a n d 
res ol ves scler osi n g c h ola n gitis i n M dr 2-deficie nt mice . He pat ol o g y 2 0 1 6; 6 3: 9 1 4-2 9   
 
1 9 .  O d u ye b o I, Ca milleri M, Nels o n A D, K he ma ni D, Li n ker N or d S, B usci gli o I, B urt o n D, R h ote n D, 
R y ks M, Carls o n P, D o nat o L, L ue ke A, Ki m K, R ossi SJ, Zi ns meister A R.  Effects of N G M 2 8 2, a n 
F G F 1 9 v aria nt, o n c ol o nic tra nsi t a n d b o wel f u n cti o n i n f u ncti o nal c o nsti pati o n: a ra n d o mize d p has e 2 
trial.  A m J Gastr oe nter ol 2 0 1 8; 1 1 3: 7 2 5-3 4  
 
2 0.  Vija y var gi ya, P a n d Ca milleri, M. C urre nt practice i n t he dia g n osis of bile aci d diarr hea. Gastr o 2 0 1 9; 
1 5 6( 5): 1 2 3 3 -1 2 3 8. d oi: 1 0. 1 0 5 3/j. g astr o. 2 0 1 8. 1 1. 0 6 9. 
 
2 1.  Vija y var gi ya, P. et al.  C o m bi ne d fasti n g ser u m C 4 a n d pri mar y bile aci ds fr o m a si n gle st o ol sa m ple t o 
dia g n ose bile aci d diarr hea  Gastr o 2 0 2 0; 1 5 9( 5): 1 9 5 2 -1 9 5 4. d oi: 1 0. 1 0 5 3/j. gastr o. 2 0 2 0. 0 7. 0 0 1.  
 
2 2.  D o nat o, L. et al. Descri pti o n of a nal ytical met h o d a n d cli nical utilit y of meas uri n g ser u m 7 -al p ha -h y dr o x y -4 -
c h oleste n -3 -o ne ( 7a C 4) b y mass s pectr o metr y.   Cli nic Bi oc he m  2 0 1 8 Fe b; 5 2: 1 0 6 -1 1 1. d oi: 
1 0. 1 0 1 6/j.cli n bi oc he m. 2 0 1 7. 1 0. 0 0 8.   
 
2 3 .  Sa uter G H, M ü nzi n g W, v o n Ritter C, Pa u m gart ner G. B A 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 -9      
 
2 4 .  Br y d o n W G, N y hli n H, East w o o d M A, Merric k M V. Ser u m 7 al p ha -h y dr o x y -4 -c h oleste n -3 -o ne a n d sele n o -
h o m oc h ol ylta uri ne ( Se H C A T) w h ole b o d y rete nti o n i n t he assess me nt of B A i n d uce d diarr h oea. E ur J 
Gastr oe nter ol He pat ol 1 9 9 6; 8: 1 1 7 -2 3         
 
2 5 .  Ca milleri M, Na dea u A, Tre mai ne WJ, 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 B A 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  

C o nfi de ntial  
Pa ge 3 4  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
2 6 .  Gäl ma n C, Ar vidss o n I, A n geli n B, R u dli n g M. M o nit ori n g he patic c h olester ol 7al p ha -h y dr o x ylase acti vit y 
b y assa y of t he sta ble B A i nter me diate 7al p ha -h y dr o x y -4 -c h oleste n -3 -o ne i n peri p heral bl o o d. J Li pi d Res 
2 0 0 3; 4 4: 8 5 9 -6 6     
 
2 7 .  Walters J R, Taslee m A M, O mer O S, Br yd o n W G, De w T, Le R o u x C W. A ne w mec ha nis m f or B A 
diarr hea: defecti ve fee d bac k i n hi biti o n of B A bi os y nt hesis. Cli n Gastr oe nter ol He pat ol 2 0 0 9; 7: 1 1 8 9 -9 4  
 
2 8 .  Ta gliac ozzi D, M ozzi A F, Casetta B, Bert ucci P, Ber nar di ni S, Di Ili o C, Ur ba ni A, Fe derici G. Q uantitati ve 
a nal ysis of B As i n h u ma n plas ma b y li q ui d c hr o mat o gra p h y -electr os pra y ta n de m mass s pectr o metr y: a si m ple 
a n d ra pi d o ne -ste p met h o d. Cli n C he m La b Me d 2 0 0 3; 4 1: 1 6 3 3-4 1      
 
2 9 .  S hi n A, Ca milleri M, Vija y var gi ya P, B usci gli o I, B urt o n D, R y ks M, Rh ote n D, L ue ke A, Sae n ger A, 
Girt ma n A, Zi ns meister A R.  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 B As, a n d c ol o nic 
tra nsit i n patie nts wit h irrita ble b o wel s y n dr o me. Cli n Gastr oe nter ol He pat ol 2 0 1 3; 1 1: 1 2 7 0-5       
 
3 0 .  Ca milleri M, B usci gli o I, Ac osta A, S hi n A, Carls o n P, B urt o n D, R y ks M, R h ote n D, La msa m J, L ue ke A, 
D o nat o LJ, Zi ns meister A R. Effect of i ncrease d bile aci d s y nt 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 -3 0   
 
3 1 .  Talley NJ, P hilli ps S F, Wilt ge n C M, Zi ns meister A R, Melt o n LJ 3r d. Assess me nt of f u ncti o nal 
gastr oi ntesti nal disease: t he b o wel disease q uesti o n naire. Ma y o Cli n Pr oc 1 9 9 0; 6 5: 1 4 5 6 -7 9     
 
3 2 .  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 s y 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 -1 1   
 
3 3 .  Zi g m o n d A S, S nait h R P. T he h os pital a n xiet y a n d de pressi o n scale. Acta Ps yc hiatr Sca n d 1 9 8 3; 6 7: 3 6 1-7 0   
 
3 4 .  L o n gstret h G F, Th 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: 1 4 8 0 -9 1     
 
3 5 .  Bes k o w L M, B ur ke W, Merz J F, Barr P A, Terr y S, Pe nc hasza de h V B, G osti n L O, G wi n n M, K h o ur y MJ. 
I nf or me d c o nse nt f or p o p ulati o n-base d researc h i n v ol vi n g ge netics. J A M A 2 0 0 1; 2 8 6: 2 3 1 5-2 1   
 
 
 

C o nfi de ntial  
Pa ge 3 5  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A P P E N DI X I : B O W E L P A T T E R N DI A R Y  
 
 
 
 
 
D ail y Di ar y: D a y 1
If y o u h a d n o b o wel m o v e m e nt s t o d a y, pl e a s e c h e c k t hi s b o x:
Pl e a s e r at e y o ur m o st s e v er e a b d o mi n al p ai n o v er t h e l a st 2 4 h o ur s,
_ _ _ _ _ _ _ _ _
o n a t e n- p oi nt s c al e wit h 0 = n o p ai n, 1 0 = wor st i m a gi n a bl e p ai n
Pl e a s e r e c or d t h e ti m e t h e st u d y m e di c ati o n wa s i nj e ct e d   _ _ _ _ _ _: _ _ _ _ _ _ p m  
1
H ar d l u mp s
1
Ma n u al Di si mp a cti o n
1
N o
2
L u mp y s a u s a g e
2
En e ma n e e d e d
2
Y e s
3
Cr a c k e d s a u s a g e
3
Str ai ni n g n e e d e d
4
S mo ot h s a u s a g e
4
N or mal
5
S oft l u mp s
5
Ur g e nt w o/ p ai n
6
Mu s h y
6
Ur g e nt w / p ai n
7
w at er y
7
I n c o nti n e nt
a m
1
p m
a m
2
p m
a m
3
p m
a m
4
p m
a m
5
p m
a m
6
p m
a m
7
p m
N o
Y e s
( c o m pl et e b el o w)
E ve nt
Mil d  /  M o d er at e  /  S e ver e
 
R e s ol ve d  /  O n g oi n g
E ve nt
Mil d  /  M o d er at e  /  S e ver e
R e s ol ve d  /  O n g oi n g
E ve nt
Mil d  /  M o d er at e  /  S e ver e
R e s ol ve d  /  O n g oi n g
N o
Y e s
( c o m pl et e b el o w)
M e di c ati o n
M e di c ati o n
D o s e
D o s e
Ti m e( s)
Ti m e( s)
T a k e n a n y m e di c ati o n s ot h er t h a n t h o s e y o u r o uti n el y u s e ?
hr.
mi n
hr.
mi n
A n y u n u s u al n e g ati v e e v e nt s t o d a y ?
hr.
mi n
hr.
mi n
hr.
mi n
hr.
hr.
mi n
mi n
D at e
Di d y o u f e el li k e y o u 
c o m pl et el y e m pti e d y o ur 
b o w el s ?
D e s cri b e t h e 
c o n si st e n c y of b o w el 
m o v e m e nt
D e s cri b e t h e e a s e of 
p a s s a g e of b o w el 
m o v e m e nt

C o nfi de ntial  
Pa ge 3 6  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A P P E N DI X II : S H O R T B O W E L DI S E A S E Q U E S TI O N N AI R E  
 
I n t he p ast 1 2 m o nt hs, ha ve y o u e x peri e nce d t h e f oll o wi n g? 
 
 
 
 
 
 
Q U E S T I O N  
Y E S  
N O  
1.  2 or l ess t h a n 2 b o w el m o v e m e nts/ w e e k  
 
 
2.  E x c essi v e str ai ni n g or s e ns ati o n of i n c o m pl et e e v a c u ati o n of st o ol o n 
m or e t h a n 2 5 % of o c c asi o ns  
 
 
3.  L u m p y st o ols o n m or e t h a n 2 5 % of o c c asi o ns  
 
 
At l e a st 3 m o nt hs of c o nti n u o us or r e c urr e nt s y m pt o ms of: 
 
4.  A b d o mi n al p ai n or dis c o mf ort r eli e v e d b y d ef e c ati o n  
 
5.  A b d o mi n al p ai n or dis c o mf ort ass o ci at e d wit h a c h a n g e i n st o ol fr e q u e n c y  
 
6.  A b d o mi n al p ai n or dis c o mf ort ass o ci at e d wit h a c h a n g e i n st o ol c o nsist e n c y  
 
 
 
 
 
 
7.  M or e t h a n 3 b o w el m o v e m e nts p er d a y  
 
 
8.  L o os e w at er y st o ols  
 
 
9.  Bl o ati n g  
 
 
1 0.  S w all o wi n g diffi c ulti es  
 
 
1 1.  U p p er a b d o mi n al p ai n aft er m e als m or e t h a n o n c e a m o nt h  
 
 
1 2.  A b d o mi n al bl o ati n g aft er m e als  
 
 
1 3.  N a us e a r e g ul arl y m or e t h a n o n c e a m o nt h  
 
 
1 4.  V o miti n g r e g ul arl y m or e t h a n o n c e a m o nt h 
 
 
1 5.  H e art b ur n r e g ul arl y m or e t h a n o n c e a w e e k  
 
 
1 6.  A ci d r efl u x r e g ul arl y m or e t h a n o n c e a w e e k  
 
 
 
 
 
Si g n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
D ate _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 

C o nfi de ntial  
Pa ge 3 7  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A P P E N DI X I II : H O S PI T A L a n d A N XI E T Y D E P R E S SI O N Q U E S TI O N N AI R E 
 
Please rea d eac h ite m a n d circle  t he re pl y w hic h best descri bes h o w y o u ha ve bee n feeli n g d uri n g t he past wee k.  D o n’t 
de v ote t o o m uc h ti me t o y o ur res p o nses; y o ur i m me diate reacti o n will pr o ba bl y be m ore acc urate t ha n a l o n g t h o u g ht-o ut  
res p o nse. 
 
1.  I feel te nse or ‘ w o u n d u p’ : 
 
M ost of t he ti me  
A l ot of t he ti me  
Occasi o nall y  
N ot at all  
 
2.  I still e nj o y t he t hi n gs I use d t o e nj o y : 
 
Defi nitel y as m uc h  
N ot q uite s o m uc h  
O nl y a little  
Har dl y at all  
 
3.  I get a fri g hte ne d feeli n g, as if s o met hi n g a wf ul is a b o ut t o ha p pe n :  
 
Ver y defi nitel y a n d q uite ba dl y  
Yes, b ut n ot t o o ba dl y  
A little, b ut it d oes n’t w orr y me  
N ot at all  
 
4.  I ca n la u g h a n d see t he f u n n y si de of t hi n gs : 
 
As m uc h as I al wa ys c o ul d  
N ot q uite s o m uc h n o w  
Defi nitel y n ot s o m uc h n o w  
N ot at all  
 
5.  W orr yi n g t h o u g hts g o t hr o u g h m y mi n d :  
 
A great d eal of t he ti me  
A l ot of t he ti me  
Fr o m ti me t o ti me  
O nl y occasi o nall y  
 
6.  I feel c heerf ul : 
 
N ot at all  
N ot ofte n  
S o meti mes  
M ost of t he ti me  
 
7.  I ca n sit at ease a n d feel rela x e d : 
 
Defi nitel y  
Us uall y  
N ot ofte n  
N ot at all  
 
 
 

C o nfi de ntial  
Pa ge 3 8  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
8.  I feel as if I a m sl o we d d o w n : 
 
Nearl y all t he ti me  
Ver y ofte n  
S o meti mes  
N ot at all  
 
9.  I get a fri g hte ne d feeli n g, li ke ‘ b utterflies i n t he st o mac h’ : 
 
N ot at all  
Occasi o nall y  
Q uite ofte n  
Ver y ofte n  
 
1 0.   I ha ve l ost i nterest i n m y a p peara nce : 
 
Defi nitel y  
I d o n’t ta ke as m uc h care as I s h o ul d 
I ma y n ot ta ke q uite as m uc h care 
I ta ke j ust as m uc h care as e ver 
 
1 1.  I feel restless as if I ha v e t o be o n t he m o ve : 
 
Ver y m uc h i n dee d  
Q uite a l ot  
N ot v er y m uc h  
N ot at all 
 
1 2.  I l o o k f or war d wit h e nj o y me nt t o t hi n gs : 
 
As m uc h as I e v er di d  
Rat her less t ha n I use d t o  
Defi nitel y less t ha n I use d t o  
Har dl y at all  
 
1 3.  I get s u d de n feeli n gs of pa nic : 
 
Ver y ofte n i n dee d  
Q uite ofte n  
N ot v er y ofte n  
N ot at all  
 
1 4.  I ca n e nj o y a g o o d b o o k or T V pr o gra m :  
 
Ofte n  
S o meti mes  
N ot ofte n  
Ver y sel d o m  
 
 
 
 
 
 
 
 

C o nfi de ntial  
Pa ge 3 9  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A P P E N DI X I V  : Q U A LI T Y of LI F E Q U E S TI O N N AI R E 
 
 
 
 
Q u alit y of Lif e Q u e sti o n n air e  
 
 
P L E A S E R E A D T HI S C A R E F U L L Y  
 
O N T H E F O L L O WI N G P A G E S Y O U WI L L FI N D S T A T E M E N T S C O N C E R NI N G B O W E L  
P R O B L E M S (I R RI T A B L E B O W E L S Y N D R O M E) A N D H O W T H E Y A F F E C T Y O U . 
 
F O R E A C H S T A T E M E N T , P L E A S E C H O O S E T H E R E S P O N S E T H A T A P P LI E S B E S T T O Y O U  
 A N D  CI R C L E  T H E N U M B E R O F Y O U R R E S P O N S E . 
 
IF Y O U A R E U N S U R E A B O U T H O W T O R E S P O N D T O A S T A T E M E N T , P L E A S E GI V E T H E B E S T  
R E S P O N S E Y O U C A N . T H E R E A R E N O RI G H T O R W R O N G R E S P O N S E S .  
 
 
 
 
 
 
 
 
 
T he I B S -Q O L was de vel o pe d b y D o nal d L. Patric k, P h. D. at T he U ni versit y of Was hi n gt o n, D o u glas A. 
Dr oss ma n, M D at T he U ni versit y of N ort h Car oli na, N o vartis P har mace uticals C or p orati o n, a n d 
N o vartis P har ma A G. A ut h ors h ol d j oi nt c o p yri g ht o ver t he I B S -Q O L a n d all its tra nslati o ns.

C o nfi de ntial  
Pa ge 4 0  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
A b o ut h o w y o u feel  
 
Please t hi n k a b o ut y o ur life o ver t he p ast m o nt h (l ast 3 0 d a ys)  a n d l o o k at t he state me nts bel o w.  Eac h 
state me nt has fi ve differe nt res p o nses.  F or eac h state me nt, please circle t he res p o nse t hat best descri bes y o ur 
feeli n gs. 
 
Q 1.  
I feel hel pless beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 2.  
I a m e m barrasse d b y t he s mell ca use d b y m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 3.  
I a m b ot here d b y h o w m uc h time I s pe n d o n t he t oilet. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 4.  
I feel v ul nera ble t o ot her ill nesses beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 5.  
I feel fat/ bl oate d beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 6.  
I feel li ke I' m l osi n g c o ntr ol of m y life beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 7.  
I feel m y life is less e nj o ya ble beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  

C o nfi de ntial  
Pa ge 4 1  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 8.  
I feel u nc o mf orta ble w he n I tal k a b o ut m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 9.  
I feel de presse d a b o ut m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 1 0.  
I feel is olate d fr o m ot hers beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 1 1.  
I ha ve t o watc h t he a m o u nt of f o o d I eat beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 1 2.  
Beca use of m y b o wel pr o ble ms, se x ual acti vit y is diffic ult f or me. ( Ple ase circle o ne n u m ber)  
 
(If n ot a p plic a ble, ple ase circle “ N O T A T A L L ”) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 1 3.  
I feel a n gr y t hat I ha ve b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 1 4.  
I feel li ke I irritate ot hers beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 

C o nfi de ntial  
Pa ge 4 2  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
Q 1 5.  
I w orr y t hat m y b o wel pr o ble ms will get w orse. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 1 6.  
I feel irrita ble beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 1 7.  
I w orr y t hat pe o ple t hi n k I e xa g gerate m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 1 8.  
I feel I get less d o ne beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 1 9.  
I ha ve t o a v oi d stressf ul sit uati o ns beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 0.  
M y b o wel pr o ble ms re d uce m y se x ual desire. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 1.  
M y b o wel pr o ble ms li mit w hat I ca n wear. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 2.  
I ha ve t o a v oi d stre n u o us acti vit y beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  

C o nfi de ntial  
Pa ge 4 3  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 3.  
I ha ve t o watc h t he ki n d of f o o d I eat beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 4.  
Beca use of m y b o wel pr o ble ms, I ha ve diffic ult y bei n g ar o u n d pe o ple I d o n ot k n o w well. ( Ple ase circle 
o ne n u m ber)  
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 2 5.  
I feel sl u g gis h beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 2 6.  
I feel u nclea n beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 2 7.  
L o n g tri ps a re diffic ult f or me beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 2 8.  
I feel fr ustrate d t hat I ca n n ot eat w he n I wa nt beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne 
n u m ber)  
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
Q 2 9.  
It is i m p orta nt t o be near a t oilet beca use of m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  

C o nfi de ntial  
Pa ge 4 4  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2  
 
 
Q 3 0.  
M y life re v ol ves ar o u n d m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 3 1.  
I w orr y a b o ut l osi n g c o ntr ol of m y b o wels. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 3 2.  
I fear t hat I w o n't be a ble t o ha ve a b o wel m o ve me nt. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 3 3.  
M y b o wel pr o ble ms are affecti n g m y cl osest relati o ns hi ps. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
A G R E A T D E A L  
 
Q 3 4.  
I feel t hat n o o ne u n dersta n ds m y b o wel pr o ble ms. ( Ple ase circle o ne n u m ber) 
 
 
1  
N O T A T A L L  
 
 
2  
S LI G H T L Y  
 
 
3  
M O D E R A T E L Y  
 
 
4  
Q UI T E A BI T  
 
 
5  
E X T R E M E L Y  
 
 
 
 
 

C o nfi de ntial  
Pa ge 4 5  
 of 7 2  
Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
Pr ot oc ol Date: - Se pte m ber 2 9 . 2 0 2 2