Clinical trial NCT05130047
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
Start date: 2021-12-01; Completion date: 2022-11-08
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, (NGM282), 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM).

Detailed description:
This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, NGM282, 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM). Thirty patients will receive either aldafermin (NGM282) or placebo, not both. The study includes a 7 to 28-day long prescreen period and a 28-day long treatment period for a maximum study duration of 56 days. Bowel pattern will be assessed by patient-recorded daily bowel pattern diaries. Serum 7-alpha C4 (C4) and fibroblast growth factor 19 (FGF-19) and fecal bile acids will be measured at baseline and Day 14 and Day 28 of treatment. Safety will be assessed through regular monitoring of adverse events, clinical laboratory results, 12-lead ECGs, physical examinations, and vital signs.

Arms: arm 1: Aldafermin (NGM282) is an investigational medication. It is an engineered analog of FGF-19 which reduces synthesis of bile acids and diarrhea caused by elevated bile acids. Participants receive aldafermin (NGM282) 1 mg given by subcutaneous injection once daily for 28 days. arm 2: A placebo looks exactly like the study drug but contains no active ingredients. It is used to learn if the effects seen are truly from the study drug. Participants receive placebo solution matching aldafermin (NGM282) given by subcutaneous injection once daily for 28 days.
Interventions: intervention 1: Aldafermin intervention 2: Placebo
Intervention descriptions: intervention 1: 1 mg solution intervention 2: Aldafermin placebo solution

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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 


C o nfi de ntial  
Pa ge 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  
 
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 
 
 


C o nfi de ntial  
Pa ge 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  
 
 
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 . 


C o nfi de ntial  
Pa ge 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  
 
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  


C o nfi de ntial  
Pa ge 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  
 
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. 


C o nfi de ntial  
Pa ge 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  
 
 
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  


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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 


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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  
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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.  


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•  
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:  


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Pr ot oc ol N u m ber 2 1 -0 0 9 3 4 8  
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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