Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of EP547 in Subjects With Cholestatic Pruritus Due to Primary Biliary Cholangitis or Primary Sclerosing Cholangitis
Phase: PHASE2
Conditions: Pruritus
Sponsor: Escient Pharmaceuticals, Inc

Offici al Title:  
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 t o E val uate t he Effects  
of E P 5 4 7 i n S u bjects wit h C h olestatic Pr urit us D ue t o Pri mar y Biliar y  
C h ola n gitis or Pri mar y Scler osi n g C h ola n gitis 
N C T N u m ber:  
N C T 0 5 5 2 5 5 2 0  
D oc u me nt D ate:  
 E P -5 4 7 -2 0 1 Pr ot oc ol, A me n d me nt 3. 0 ( 0 2 Oct o ber 2 0 2 3)  
 
 
 

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I n vesti g at or’s A gree me nt 
I h a ve r ea d t he pr ot oc ol f or E P- 5 4 7- 2 0 1 a n d a gree t o c o n d uct t he st u d y as o utli ne d. I a gree t o 
mai ntai n t he c o nfi de ntialit y  of all i nf or mati o n recei ve d or de v el o pe d i n c o n necti o n wit h t his 
pr ot oc ol.  
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri nte d Na me of I n v esti gat or 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of I n vesti gat or 
 
 
 
  
  
  
  
  
  
 
Date  
 
 

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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  
A me n d me nt 3. 0  
Gl o bal  
0 2  Oct o ber 2 0 2 3  
A me n d me nt 2. 3  
C o u ntr y -s pecific (Bel gi u m ) 
1 7 Marc h 2 0 2 3  
A me n d me nt 2. 2  
C o u ntr y -s pecific (S pai n ) 
0 3 Marc h  2 0 2 3  
A me n d me nt 2. 1  
C o u ntr y -s pecific (Fra nce ) 
1 5 Dece m ber 2 0 2 2 
A me n d me nt 2. 0  
Gl o bal  
2 0 A pril 2 0 2 2  
A me n d me nt 1. 0  
Gl o bal  
1 7 N o ve m ber 2 0 2 1 
Ori gi nal Pr ot oc ol  
N ot a p plica ble  
1 5 J u ne 2 0 2 1 
 
 
 

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2.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Escie nt P har mace uticals, I nc.  
N a me of I n vesti g ati o n al Pr o d uct: 
E P 5 4 7 Ta blet  
St u d y N u m ber:  
E P - 5 4 7- 2 0 1 
P h ase of De vel o p me nt:  
P hase 2  
Title of St u d y:  
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 t o E val uate t he Effects of E P 5 4 7 i n S u bjects 
wit h C h olestatic Pr urit us D ue t o Pri mar y Biliar y C h ola n gitis or Pri mar y Scler osi n g C h ola n gitis 
St u d y Ce nters:  
M ulti -ce nter st u d y t o be c o n d ucte d gl o ball y 
O bjecti ves:  
Pri mar y  
•  
T o assess t he efficac y of E P 5 4 7 c o m pare d t o place b o o n pr urit us as assesse d b y t he W orst Itc h 
N u meric  Rati n g Scale ( WI -N R S)  
Sec o n dar y  
•  
T o assess t he efficac y of E P 5 4 7 c o m pare d t o place b o o n t he f oll o wi n g: 
o  Pr urit us -relate d q ualit y of life usi n g t he 5-D Itc h Scale  
o  Pr urit us  se verit y usi n g t he Patie nt Gl o bal I m pressi o n of Se verit y ( P GI-S)  
o  O verall pr urit us res p o nse t o t hera p y usi n g t he Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI- C)  
•  
T o assess t he safet y a n d t olera bilit y of E P 5 4 7  
•  
T o assess t he p har mac o ki netics ( P K) of E P 5 4 7  
 
 
 

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se parate da ys, t he first d ose of st u d y dr u g is c o nsi dere d Da y 1. A ll ot her visits i n t he D o u ble-Bli n d 
Treat me nt Peri o d will ha ve a visit wi n d o w of ± 3 da y s. 
O pe n -La bel E xte nsi o n  Peri o d  
T he O pe n- La bel E xte nsi o n Peri o d will c o nsist of 2 st u d y visits ( Visit 7 [ Wee k 9] a n d Visit 8 
[ Wee k 1 2] ). D uri n g t his peri o d, all s u bjects w h o c o m plete t he D o u ble- Bli n d Treat me nt Peri o d a n d are 
still recei vi n g st u d y dr u g will recei ve o pe n-la bel 1 0 0 m g d oses of E P 5 4 7 . Visit  7 a n d Visit 8 will ha ve 
a visit wi n d o w of ± 3 da y s. 
Safet y F oll o w - U p Peri o d 
A n y s u bjec t w h o c o m pletes t he O pe n-La bel E xte nsi o n Peri o d or disc o nti n ues st u d y dr u g ( E P 5 4 7 or 
place b o) earl y will c o m plete a f oll o w- u p visit ( Visit 9) a p pr oxi matel y 2  wee ks ( ± 3  da ys) after t he last 
d ose of st u d y dr u g.  
N u m ber of S u bjects ( Pl a n ne d):  
A p pr o xi matel y 5 8 s u bjects wit h c h olestatic pr urit us d ue t o  P B C or P S C will be ra n d o mize d i n t he 
st u d y.  
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
S u bjects w h o h a ve a n e xcl usi o nar y res ult at Visit 1  ma y ha ve t hat assess me nt re peate d o nce at t he 
discreti o n of t he I n vesti gat or wit hi n t he scree ni n g wi n d o w a n d be e nr olle d if a re peat assess me nt is 
wit hi n t he i n dicate d ra n ge as s pecifie d bel o w f or partici pati n g i n t he st u d y.  
I ncl usi o n Criteria 
T o be eli gi ble f or st u d y partici pati o n, all s u bjects m ust meet all t he f oll o wi n g i ncl usi o n criteria:  
1.  A ge 1 8 t o 8 0 years, i ncl usi ve 
2.  Has e x perie nce d self-re p orte d dail y or near-dail y m o derate t o se vere pr urit us bef ore Scree ni n g  
3.  Ha s a mea n dail y WI-N R S sc ore i n dicati ve  of m o derate t o se vere pr urit us (sc ore ≥4) d uri n g 
Scree ni n g ( Da y - 7 t hr o u g h Da y  - 1); data fr o m at least 4 of t he 7 da ys are re q uire d t o be c o nsi dere d 
a n acce pta ble pr ofile  
4.  If c urre ntl y ta ki n g me dicati o ns t o treat t he c h olestatic dis or der  (i ncl u di n g o betic h olic aci d [ O C A ]), 
m ust be o n a sta ble d ose f or > 1 2 wee ks bef ore Scree ni n g a n d pla ns t o mai ntai n t he re gi me n 
t hr o u g h o ut t he st u d y 
5.  If c urre ntl y ta ki n g a fi brate, m ust be o n a sta ble d ose f or > 1 2 wee ks bef ore Scree ni n g a n d pla ns t o 
mai ntai n t he re gi me n t hr o u g h o ut t he st u d y  
6.  Eit her is n ot treate d wit h or has bee n o n a sta ble re gi me n wit h a n y me dicati o ns t o treat pr urit us  f or 
> 4  wee ks bef ore Scree ni n g  a n d pla ns t o mai ntai n t he re gi me n t hr o u g h o ut t he st u d y  
7.  If fe male, m ust ha v e a ne gati ve ser u m pre g na nc y te st at Scree ni n g a n d be willi n g t o n ot d o nate 
e g gs fr o m Scree ni n g u ntil t he last d ose of st u d y dr u g a n d:  
a. Is s ur gicall y sterile; or 
b.  Has bee n a me n orr h oeic f or ≥1 year wit h o ut a n alter nati ve me dical ca use ; or 

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c. If of c hil d beari n g p ote ntial 1, m ust a gree t o use at least 1 f or m of a n acce pta ble met h o d of 
c o ntrace pti o n fr o m Scree ni n g u ntil t he last d ose of st u d y dr u g . Acce pta ble birt h c o ntr ol 
met h o ds i ncl u de :  
•  
Barrier met h o ds of c o ntrace pti o n (e g, male c o n d o m, fe male c o n d o m, cer vical c a p or 
dia p hra g m, a n d c o ntrace pti ve s p o n ge) 
•  
C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n  
•  
Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n  
•  
Intra uteri ne de vice  
•  
Intra uteri ne h or m o ne releasi n g s yste m  
•  
B ilateral t u bal occl usi o n  
•  
V asect o mize d part ner  
•  
S e x ual a bsti ne nce (c o m plete se x ual a bsti ne nce defi ne d as refrai ni n g fr o m heter ose x ual 
i nterc o urse f or t he e ntire peri o d of ris k ass ociate d wit h st u d y dr u g), the relia bilit y of 
w hic h nee ds t o be e val uate d i n rela ti o n t o t he durati o n of t he cli nical st u d y a n d t he 
preferre d a n d us ual lifest yle of t he s u bject  
8.  M ust be a ble t o c o m m u nicate well wit h t he I n vesti gat or, u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t he st u d y, a n d u n dersta n d a n d pr o vi de writte n c o nse nt  
9.  F or s u bjects w it h c o nc o mita nt i nfla m mat or y b o wel disease (I B D): 
a. C ol o n osc o p y (if s u bject has a c ol o n) or ot her a p pr o priate e n d osc o pic pr oce d ure wit hi n 
1 8 m o nt hs of Da y 1 c o nfir mi n g n o d ys plasia or c ol orectal  ca ncer 
b.  S u bjects wit h Cr o h n’s d isease ( C D) m ust be i n re missi o n as defi ne d b y a Cr o h n’s Disease 
Acti vit y I n de x ( C D AI) < 1 5 0 at Scree ni n g 
c. S u bjects wit h ulcerati ve c olitis ( U C) m ust ha ve a Partial Ma y o Sc ori n g I n de x sc ore ≤3 
wit h n o i n di vi d ual s u b-sc ore e xcee di n g 1 p oi nt at Scree ni n g 
S u bjects wit h P B C m ust als o meet t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or st u d y partici pati o n: 
1 0.  D oc u me nte d hist or y of P B C t hat is c o nsiste nt wit h t he A merica n Ass ociati o n f or t he St u d y of 
Li ver Diseases (A A S L D ) Practice G ui deli nes  (Li n d or 2 0 1 9 ), defi ne d as ha vi n g ≥2 of t he f oll o wi n g 
3 fact ors u p o n dia g n osis: 
a. Hist or y of ele vate d al kali ne p h os p hatase ( A L P) le vels  
b.  Hist oric p ositi ve a nti mit oc h o n drial a nti b o d y ( A M A) or A M A - M 2 b y i m m u n ofl u oresce nce, 
enz y me li n ke d i m m u n os or be nt assa y ( E LI S A), or i m m u n o bl ot or if A M A is ne gati ve, 
p ositi ve f or P B C -s pecific a nti b odies (a nti - G P 2 1 0 a n d/ or a nti-S P 1 0 0)  
c. Li ver hist ol o g y at a n y p oi nt i n t i me c o nsiste nt wit h P B C  
1 1.  If c urre ntl y ta ki n g urs o de o x yc h olic aci d ( U D C A), m ust be o n a sta ble d ose of n ot m ore t ha n 
2 0 m g / k g/ da y f or ≥1 2 wee ks . If n ot c urre ntl y ta ki n g U D C A, m ust n ot be treate d wit h U D C A 
wit hi n 1 2 wee ks bef ore Scree ni n g or pla n t o be treate d wit h U D C A d uri n g t he st u d y 
 
1 W o me n of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are ferti le, f oll o wi n g me narc he a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile. Per ma ne nt sterili zati o n met h o ds i ncl u de h ysterect o m y, bilateral 
sal pi n gect o m y, a n d bilateral o o p h orect o m y. A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut 
a n alter nati ve me dical ca use.  

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S u bjects wit h P S C m ust als o meet all t he f oll o wi n g i ncl usi o n criteria  to be eli gi ble f or st u d y 
partici p ati o n: 
1 2.  D oc u me nte d hist or y of P S C base d o n eit her c h ola n gi o gra p h y (ie, ma g netic res o na nce 
c h ola n gi o pa ncreat o gra p h y, e n d osc o p ic retr o gra de c h ola n gi o pa ncreat o gra p h y, or perc uta ne o us 
tra ns he patic c h ola n gi o gra m) or if s mall d uct P S C , c o nfir me d b y t y pical hist ol o gic e vi de nce of P S C 
f or ≥1 year (E A S L 2 0 0 9 , C ha p ma n 2 0 1 0 )  
1 3.  If c urre ntl y ta ki n g U D C A, m ust be o n a sta ble d ose of n ot m ore t ha n 2 3 m g/ k g/ da y f or ≥1 2 wee ks. 
If n ot c urre ntl y ta ki n g U D C A, m ust n ot be treate d wit h U D C A wit hi n 1 2 wee ks bef ore Scree ni n g 
or pla n t o be treate d wit h U D C A d uri n g t he st u d y 
E xcl usi o n Criteria 
All s u bjects meeti n g a n y of t he f oll o w i n g criteria will be e xcl u de d fr o m t his st u d y:  
1.  Pr urit us is attri b ute d mai nl y t o a n y disease u nrelate d t o P B C or P S C  
2.  Pri or li ver tra ns pla nt or prese ntl y liste d f or tra ns pla ntati o n  
3.  Is recei vi n g o n g oi n g ultra vi olet B ( U V B) treat me nt or plas ma p heresis  or a nti ci pates recei vi n g s uc h 
treat me nts d uri n g t he st u d y 
4.  E vi de nce of c o m pe nsate d or dec o m pe nsate d cirr h osis base d o n A N Y of t he f oll o wi n g: 
a. Hist orical li ver bi o ps y de m o nstrati n g cirr h osis 
b.  Li ver stiff ness as assesse d b y a Fi br o Sca n ®  sc ore of ≥1 6. 9 k Pa f or s u bjects wit h P B C or 
≥1 4. 4 k Pa f or s u bjects wit h P S C wit hi n 6 m o nt hs of Scree ni n g  
c. Hist or y or prese nce of p ortal h y perte nsi o n  wit h c o m plicati o ns, i ncl u di n g k n o w n gastric or 
es o p ha geal varices , ascites, s p o nta ne o us bacterial perit o nitis, he patic e nce p hal o pat h y, 
hist or y of variceal blee ds, or relate d t hera pe utic or pr o p h ylactic i nter ve nti o ns (e g, n o n -
selecti ve beta bl oc kers bei n g use d t o pre ve nt c o m plicati o ns of p ortal h y perte nsi o n 
[ pr o pra n ol ol, na d ol ol, or car ve dil ol], i nserti o n of variceal ba n ds, tra nsj u g ular i ntra he patic 
p ort os yste mic s h u nt, or direct i ntra he patic p ort oca val s h u nt) 
5.  Hist or y of mali g na nc y of a n y or ga n s yste m, i ncl u di n g b ut n ot li mite d t o he pat ocell ular carci n o ma, 
c h ola n gi ocarci n o ma, a n d ga ll bla d der carci n o ma, treate d or u ntreate d, wit hi n t he past 5 years 
(l ocalize d s q ua m o us cell or basal cell carci n o ma of t he s ki n t hat ha ve bee n e xcise d or res ol ve d is 
n ot e xcl usi o nar y) 
6.  Alter nate ca uses of li ver diseases s uc h as he patic sarc oi d osis, alc o h olic li ver disease, hist ol o g y 
c o nfir me d a ut oi m m u ne he patitis, o verla p he patitis, or n o nalc o h olic steat o he patitis ( N A S H) , or 
u nc o ntr olle d viral he patitis  as defi ne d i n Secti o n 1 2. 9   
7.  Prese nce of d oc u me nte d sec o n dar y scler osi n g c h ola n gitis (e g, isc h e mic c h ola n gitis, rec urre nt 
pa ncreatitis, i ntra d uctal st o ne disease, se vere bacterial c h ola n gitis, s ur gical or bl u nt a b d o mi nal 
tra u ma, rec urre nt p y o ge nic c h ola n gitis, c h ole d oc h olit hiasis, t o xic scler osi n g c h ola n gitis d ue t o 
c he mical a ge nts, or a n y ot her ca use of sec o n dar y scler osi n g c h ola n gitis) o n pri or cli nical 
i n vesti gati o ns 
8.  I mm u n o gl o b uli n G 4 (I g G 4) > 4 × u p per li mit of n or mal ( U L N) at Scree ni n g or e vi de nce of s yste mic 
I g G 4-relate d disease 
9.  C urre nt e vi de nce of cli nicall y si g nifica nt hi g h -gra de strict ures or prese nce of biliar y ste nt at 
Scree ni n g 
1 0.  Hist or y of r ec urre nt bacterial c h olan gitis or rece nt epis o de wit hi n 3 m o nt hs bef ore Scree ni n g  
1 1.  E n d osc o pic i nter ve nti o ns wit h t hera pe utic i nte nt s uc h as biliar y d uct dilati o n wit hi n 3 m o nt hs 
bef ore  Scree ni n g or pla n ne d  d uri n g t he st u d y  
1 2.  Hist or y of si g nifica nt s mall b o wel resecti o n or s h ort b o we l s y n dr o me 

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1 3.  Prese nce of  a c o nc o mita nt  disease or a hist or y of a n y me dical c o n diti o n t hat, i n t he o pi ni o n of t he 
I n vesti gat or, c o ul d p ose u n d ue ris k t o t he s u bject, i m pe de c o m pleti o n of t he st u d y pr oce d ures, or 
w o ul d c o m pr o mise t he vali dit y of t he st u d y meas ure me nts  
1 4.  Cli nicall y rele va nt me dical hist or y, p h ysical e xa mi nati o n, vital si g n, sta n dar d 1 2- lea d 
electr ocar di o gra m ( E C G), c he mistr y, he mat ol o g y, uri nal ysis, or c oa g ulati o n res ults at Scree ni n g 
be y o n d w hat is e x pecte d f or s u bjects wit h a c h olestatic dis or der t hat w o ul d place t he s u bject at 
u n d ue ris k as dee me d b y t he I n vesti gat or  
1 5.  Has  a n y of t he f oll o wi n g la b orat or y res ults at Scree ni n g:  
a. T otal bilir u bi n > 2. 0 m g/ d L ; t otal bilir u bi n >2. 0 m g/ d L  is acce pta ble f or s u bjects wit h 
me dicall y d oc u me nte d Gil bert’s  s y n dr o me if direct bilir u bi n is < 0. 3 m g/ d L 
b.  Ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) > 5 × U L N  
c. A L P > 1 0 × U L N  
d.  I nter nati o nal n or malize d rati o (I N R) > 1. 3 
e. Platelet c o u nt < 1 5 0, 0 0 0/ µ L  
f. Uri ne al b u mi n t o creati ni ne rati o ≥3 0 m g/ g 
1 6.  Esti mate d gl o mer ular filtrati o n rate < 6 0 m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t he C hr o nic Ki d ne y 
Disease E pi de mi ol o g y C olla b orati o n e q uati o n at Scree ni n g 
1 7.  Hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) or p ositi ve f or HI V i nfecti o n at Scree ni n g 
1 8.  Si g nifica nt hist or y of a b use of dr u gs, s ol ve nts, or m o derate alc o h ol c o ns u m pti o n (≥1  ser vi n g or 
u nit/ da y o n a vera ge f or w o me n a n d ≥2 ser vi n gs or u nits/ da y o n a vera ge f or me n ; 
1 u nit = 1 2 o u nces [ 3 5 0 m L] of 5 % alc o h ol beer, 5 o u nces  [ 1 5 0 m L] of 1 2 % wi ne, or 1. 5 o u nces 
[ 4 5 m L] of 8 0  pr o of distille d s pirits) i n t he past 2 years bef ore Scree ni n g  
1 9.  Has recei ve d a pr o hi bite d me dicati o n wit hi n 2 wee ks or 5 half- li ves of Da y 1, w hic he ver is l o n ger, 
as descri be d i n Secti o n  8. 4. 1   
2 0.  Partici pati o n i n a n y cli nical st u d y wit h a n i n vesti gati o nal or a p pr o ve d dr u g/ de vice wit hi n 3 0 da ys 
bef ore Scree ni n g or is pla n ni n g t o partici pate i n a n ot her cli nical st u d y wit h a n i n vesti ga ti o nal or 
a p pr o ve d dr u g/ de vice w hile e nr olle d i n t his st u d y  
2 1.  Hist or y of k n o w n or s us pecte d h y perse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g  
2 2.  Fe male w h o is pre g na nt, n ursi n g, or i nte n ds t o bec o me pre g na nt d uri n g t he st u d y  
2 3.  Is directl y affiliate d wit h t he st u d y at t he st u d y site or is a n i m me diate fa mil y me m ber (s p o use, 
pare nt, c hil d, or si bli n g; bi ol o gical or le gall y a d o pte d) of pers o n nel directl y affiliate d wit h t he 
st u d y at t he st u d y site 
2 4.  Is e m pl o ye d b y Escie nt P har mace uticals, I nc., (t hat is a n e m pl o yee, te m p orar y c o ntract w or ker, or 
desi g nee res p o nsi ble f or t he c o n d uct of t he st u d y) or is a n i m me diate fa mil y me m ber of a n 
e m pl o yee of Escie nt P har mace uticals, I nc.  
2 5.  S u bject is, i n t he o pi ni o n of t he I n vesti gat or, n ot s uita ble t o partici pate i n t he st u d y  

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C o nfi de ntial 
Pa g e 1 2 of 1 2 8 
St u d y Dr u g M ateri als a n d M a n a ge me nt:  
St u d y Dr u gs  
F or t he D o u ble- Bli n d Treat me nt Peri o d, ta blets c o ntai n i n g 2 5 m g or 7 5 m g of E P 5 4 7  or place b o will 
be s u p plie d i n a wa y t o e ns ure t he st u d y bli n d. F or t he O pe n- La bel E xte nsi o n Peri o d, ta blets c o ntai ni n g 
2 5 m g or 7 5 m g  of E P 5 4 7  will be s u p plie d . S u bjects recei vi n g E P 5 4 7 will ta ke o ne 2 5-m g a n d o ne 
7 5- m g E P 5 4 7 ta blet per d ose (f or a t otal d ose of 1 0 0 m g) a n d s u bjects recei vi n g place b o will ta ke 
2 place b o ta blets  per d ose . 
St u d y Dr u g Pac ka gi n g a n d La beli n g 
F or t he D o u ble- Bli n d Treat me nt Peri o d, st ud y dr u g kits eac h c o ntai ni n g 2 ta blets per d ose a n d 
pac ka ge d i nt o blister car d/wallets will be la bele d wit h a u ni q ue n u m ber a n d will be s u p plie d t o st u d y 
sites i n a bli n de d ma n ner.  
St u d y dr u g kits  f or t he O pe n- La bel E xte nsi o n Peri o d will be pac ka ge d a n d la bele d si milarl y as t h ose 
f or t he D o u ble-Bli n d Treat me nt Peri o d b ut will be s u p plie d t o t he sites i n a n u n bli n de d ma n ner. 
St u d y Dr u g St ora ge 
T he st u d y dr u g ta blets s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure, 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F), 
wit h e xc ursi o ns all o we d bet wee n 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F). 
St u d y Dr u g A d mi nistrati o n  
Eac h st u d y dr u g d ose, c o ntai ni n g 2 ta blets, is t o be a d mi nistere d orall y as i ntact ta blets (s wall o we d 
w h ole, n ot c he we d or cr us he d), a n d ta ke n wit h water. D oses are t o be a d mi nistere d dail y at 
a p pr o xi matel y t he sa me ti me of da y a fter a fast of at least 8 h o urs.  
St u d y Dr u g Dis pe nsi n g a n d Acc o u nta bilit y 
S u bjects will c o m plete d osi n g rec or ds, w hic h will be re vie we d at eac h st u d y visit b y st u d y site staff.  
S u bjects s h o ul d be i nstr ucte d t o retai n t he st u d y dr u g kit (i ncl u di n g blister car ds/ wallets), e ve n if 
e m pt y, a n d t o ret ur n it a n d a n y re mai ni n g st u d y dr u g t o t he st u d y site at t heir ne xt visit or t o a direct -t o-
patie nt c o urier  ser vice. T he st u d y site staff s h o ul d perf or m st u d y dr u g acc ou nta bilit y a n d, if a p plica ble, 
f oll o w- u p wit h t he s u bject t o retrie ve a n y re mai ni n g st u d y dr u g t hat has  n ot bee n ret ur ne d.  
Ke y St u d y Pr oce d ures a n d Effic ac y, P h ar m ac o d y n a mic, S afet y, a n d P K E v al u ati o ns: 
At s pecific visits o utli ne d i n t he Sc he d ule of Asses s me nts (A p pe n di x A ), s u bjects will u n der g o 
efficac y, p har mac o d y na mic ( P D), safet y, a n d P K assess me nts.  
Ke y St u d y Pr oce d ures 
F asti n g Re q uire me nts 
S u bjects s h o ul d fast f or at least 8 h o urs bef ore eac h d ose of st u d y  dr u g a n d bef ore st u d y visits t hat 
re q uire a bl o o d sa m ple f or assess me nt of c he mistr y, P K ( pre d ose), or c o m pleti o n of q uesti o n naires. 
Water is acce pta ble i n t he m or ni n g of st u d y visits t o e ns ure t he s u bject is h y drate d f or la b orat or y 
sa m ple c ollecti o n.  
Di sc o nti n u ati o n of St u dy Dr u g  
S u bjects w h o ter mi nate treat me nt wit h st u d y dr u g earl y , re gar dless of t he reas o n, will  c o m plete t he 
earl y st u d y ter mi nati o n e val uati o ns as s o o n as p ossi ble after t he last d ose of st u d y dr u g, i deall y wit hi n 
2 da ys after t he last  d ose of st u d y dr u g. 

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W he ne ver p ossi ble, s u bjects s h o ul d re mai n i n t he st u d y a n d c o m plete t he re mai ni n g st u d y visits a n d 
assess me nts e ve n w he n st u d y dr u g has bee n disc o nti n ue d.  S u bjects w h o disc o nti n ue st u d y dr u g f or a n y 
reas o n a n d c o nti n ue wit h t he st u d y visits as pla n ne d t hr o u g h t he Wee k 1 2 visit ( partici pati n g o nl y i n 
efficac y a n d safet y, b ut n ot P K  meas ures) will  partici pate i n t he Safet y F oll o w- U p Visit if t he last d ose 
of st u d y dr u g was a d mi nistere d less t ha n 2 wee ks bef ore t he Wee k 1 2  visit t o e ns ure t hat at least 
2 wee ks  of f oll o w-u p data are c ollecte d f or all ra n d o mize d s u bjects.  
If a s u bject disc o nti n ues st u d y dr u g a n d c h o oses n ot t o c o m plete all of t he re mai ni n g st u d y visits, t he 
s u bject will ha ve a F oll o w-U p Visit a p pr o xi matel y 2 wee ks ( ± 3 da ys ) after t he last d ose of st u d y dr u g 
if at least 2 wee ks of f oll o w - u p data ha ve n ot alrea d y bee n c ollecte d . If a s u bject fails t o atte n d t he 
f oll o w- u p visit a n d has n ot wit h dra w n c o nse nt , all reas o na ble eff orts will be ma de t o c o ntact t he 
s u bject t o e ns ure t hat he/s he is i n satisfact or y healt h. All c o ntacts a n d c o ntact atte m pts must be 
d oc u me nte d i n t he s u bject’s me dical rec or d. 
Efficac y a n d P har mac o d y na mic Assess me nts  
Efficac y e val uati o ns, i ncl u di n g patie nt- re p orte d assess me nts of pr urit us  ( WI-N R S), pr urit us-r elate d 
q ualit y of life ( 5 -D Itc h Scale), pr urit us se verit y ( P GI-S) , o verall res p o nse t o t hera p y ( P GI-C), slee p 
dist ur ba nce ( P R O MI S S h ort F or m – Slee p Dist ur ba nce ), fati g ue (D- FI S), a n d o verall q ualit y of life 
( E Q- 5 D- 3L) will be assesse d.  
P D assess me nts, i n cl u di n g bl o o d a n d/ or uri ne sa m pli n g f or ge n ot y pi n g ( o pti o nal), pr urit us- relate d 
bi o mar kers ( bile aci ds  a n d he me meta b olites) , ki d ne y-relate d bi o mar kers, a n d f ut ure a nal ysis will als o 
be assesse d.  
All efficac y a n d P D assess me nts will be perf or me d as i n dicate d i n t he Sc he d ule of Assess me nts 
(A p pe n di x A ). 
Q uesti o n n aires  
A t Visit 1 ( Scree ni n g ) bef ore c o m pleti n g t he dail y WI -N R S f or Da y - 1 4, s u bjects will recei ve trai ni n g 
o n h o w t o res p o n d t o q uesti o n naires. Sites wil l re vie w t he res p o nses fr o m eac h s u bject at least t wice a 
wee k t o e ns ure pr o per c o m plia nce.  
W orst Itc h N u meric Rati n g Scale  ( WI-N R S) :  
S u bjects will be as ke d t o rate t he  se verit y of t heir w orst le vel of itc hi n g i n t he past 2 4 h o urs i n t he 
m or ni n g, a n d at t he sa me ti me of da y, usi n g t he WI -N R S. T he WI -N R S is a n 1 1 -p oi nt scale ra n gi n g 
fr o m 0 ( N o Itc hi n g) t o 1 0 ( W orst Itc hi n g I ma gi na ble) (P ha n 2 0 1 2 ) a n d re q uires a p pr o xi m atel y 
1 mi n ute t o c o m plete. Hi g her sc ores i n dicate greater itc h se verit y . Itc hi n g se verit y sc ores c ollecte d via 
t he WI- N R S ha ve bee n cate g orize d i n t he literat ure as mil d ( < 4), m o derate ( ≥4 t o < 7), or se vere ( ≥7) 
(Fis h ba ne 2 0 2 0 , Hirsc hfiel d 2 0 2 0 , Le v y 2 0 2 0 , Sta n der 2 0 2 0 ). A n e xa m ple of t he WI - N R S is i ncl u ded 
i n A p pe n di x B . 
S u bjects will be i nstr ucte d t o c o m plete t he WI -N R S dail y , i n t he m or ni n g, a n d at t he sa me ti me of da y, 
be gi n ni n g at Da y - 1 4 t o t he F oll o w- U p Visit. F or da ys t hat c oi nci de wit h a st u d y visit (f or Visit 2 a n d 
be y o n d), t he WI- N R S is t o be c o m plete d bef ore t he visit.  
T he W I-N R S sc ores fr o m Da y - 7 t hr o u g h Da y - 1 will be a vera ge d t o get her t o c o nfir m c o m plia nce a n d 
deter mi ne s u bject eli gi bilit y f or c o nti n ue d partici pati o n re gar di n g pr urit us se nsati o n. T he a vera ge 
WI -N R S sc ore usi n g t he dail y val ues fr o m t he wee k bef ore t he first d ose of st u d y dr u g ( Visit 2 
[Da y  1]) will ser ve as t he baseli ne sc ore.  T he 7 dail y WI -N R S sc ores pri or t o Visit 6 ( Wee k 6) will be 
a vera ge d t o get her f or pri mar y e n d p oi nt a nal yses. D ata fr o m at least 4  of t he 7 da ys f or eac h wee k are 
re q uire d t o be c o nsi dere d a n acce pta ble pr ofile. 

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5 -D Itc h Scale:  
T he 5 - D Itc h Scale was de vel o pe d as a brief b ut m ulti di me nsi o nal q uesti o n naire desi g ne d f or prurit us 
t hat meas ures c ha n ges o ver ti me (El ma n 2 0 1 0 ). T he 5 di me nsi o ns are de gree, d urati o n, directi o n, 
disa bilit y, a n d distri b uti o n. It re q uires a p pr o xi matel y 1 t o 2 mi n utes t o c o m plete, a n d sc ores ca n ra n ge 
bet wee n 5 ( n o pr urit us) a n d 2 5 ( m ost se vere pr urit us). T he sc ores of eac h of t he 5 d o mai ns are 
ac hie ve d se p aratel y a n d t he n s u m me d t o get her t o o btai n a t otal 5-D sc ore. A n e xa m ple of t he 5- D Itc h 
Scale is i ncl u de d i n A p pe n di x C . 
Patie nt Gl o bal I m pressi o n of Se verit y ( P GI -S):  
T he P GI -S was vali date d i n w o me n wit h stress ur i nar y i nc o nti ne nce, b ut ma y be use d t o rate t he 
se verit y of ot her s pecific c o n diti o ns (Yalci n 2 0 0 3 ). F or t his q uesti o n naire, t he s pecific c o n diti o n t o be 
rate d is pr urit us. S u bjects will be as ke d t o rate t he se verit y of t heir pr urit us i n t he past 7 da ys usi n g a 
4- p oi nt scale fr o m N o ne t o Se vere. T he P GI- S re q uires less t ha n 1 mi n ute t o c o m plete. A n e xa m ple of 
t he P GI- S is i ncl u de d i n A p pe n di x D .  
Patie nt G l o bal I m pressi o n of C ha n ge ( P GI-C) :  
S u bjects will be as ke d t o rate t heir  i m pressi o n of o verall c ha n ge i n pr urit us i n t he past 7 da ys c o m pare d 
t o bef ore t he y starte d ta ki n g st u d y dr u g usi n g t he P GI -C. T he P GI -C is a 7 - p oi nt scale ra n gi n g fr o m 
M uc h I m pr o ve d t o M uc h W orse a n d re q uires a p pr o xi matel y 1 m i n ute t o c o m plete (G u y 1 9 7 6 ). Hi g her 
sc ores i n dicate less i m pr o ve me nt i n pr urit us . A n e xa m ple of t he P GI -C is i ncl u de d i n A p pe n di x E . 
Patie nt -Re p orte d O utc o mes I nf or mati o n S yste m ( P R O MI S ) S h ort F or m – Slee p Dist ur ba nce:  
T he P R O MI S S h ort F or m – Slee p Dist ur ba nce is a n 8 -ite m i nstr u me nt t hat assesses self -re p orte d 
perce pti o ns of slee p q ualit y, slee p de pt h, a n d rest orati o n ass ociate d wit h slee p , i ncl u di n g percei ve d 
diffic ulties a n d c o ncer ns wit h getti n g t o slee p or sta yi n g aslee p, as well as perce pti o ns of t he a de q uac y 
of a n d satisfacti o n wit h slee p  (Healt h Meas ures 2 0 2 1 ). S u bjects will be as ke d t o a ns wer eac h ite m usi n g 
a 5- p oi nt scale.  T he scale ta kes a p pr o xi matel y 1 t o 2 mi n utes t o c o m plete.  A n e xa m ple of t he P R O MI S 
S h ort F or m – Slee p Dist ur ba nce is i ncl u de d i n A p pe n di x  F.  
Fati g ue I m pact Scale f or Dail y A d mi nistrati o n ( D-FI S):  
T he D - FI S, w hic h was a da pte d fr o m t he ori gi nal Fati g ue I m pact Scale (Sc hie hser 2 0 1 3 ), is a vali date d, 
self-re p ort scale t hat meas ures t he i m pact of fati g ue o n a bilit y t o f u ncti o n o ver t he past da y  b y ha vi n g 
partici pa nts rate 8 ite ms o n a scale fr o m 0 ( N o Pr o ble m) t o 4 ( Extre me P r o ble m). Sc ores ra n ge fr o m 
0 t o 3 2 wit h a hi g her sc ore reflecti n g a hi g her i m pact of fati g ue (Fis k 2 0 0 2 ). T he scale ta kes 
a ppr o xi matel y 2 t o 3 mi n utes t o c o m plete. A n e xa m ple of t he D- FI S is i ncl u de d i n  A p pe n di x G . 
3- Le vel E ur o Q ol- 5 D ( E Q-5 D - 3L):  
T he E Q - 5 D- 3 L is a wi del y used q ualit y of life i nstr u me nt de vel o pe d i n E ur o pe t hat i ncl u des 1 q uesti o n 
f or eac h of t he f oll o wi n g 5 q ualit y of life di me nsi o ns: m o bilit y, self -care, us ual acti vities, 
pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n  (Her d ma n 2 0 1 1 ). T he E Q- 5 D- 3 L als o i ncl u des a vis ual a nal o g 
scale, b y w hic h res p o n de nts ca n re p ort t heir percei ve d healt h stat us wit h a gra de ra n gi n g fr o m 0 (t he 
w orst p oss i ble healt h stat us) t o 1 0 0 (t he best possi ble healt h stat us).  T he q uesti o n naire ta kes 
a p pr o xi matel y 1 t o 2 mi n utes t o c o m plete. A n e xa m ple of t he E Q - 5 D- 3L is i ncl u de d i n A p pe n di x  H. 
Bl o o d a n d Uri ne S a m pli n g f or P h ar m ac o dy n a mic Assess me nts  
Bl o o d sa m ples f or ge n ot y pi n g ( o pti o nal) a n d pr urit us -relate d bi omar kers ( bile aci ds  a n d he me 
meta b olites)  a n d bl o o d a n d uri ne sa m pl es f or f ut ure a nal ysis will be assesse d.  Sa m ples f or ge n ot y pi n g 
a n d f ut ure a nal ysis  ma y be st ore d f or u p t o 1 0 years after c o m pleti o n of t he st u d y.  

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Al g orit h m f or M o nit ori n g a n d I nterr u pti n g St u d y Dr u g f or Tre at me nt -E mer ge nt He p at ocell ul ar 
DI LI S i g n als i n S u bjects wit h a N or m al A L T B aseli ne V al ue  
Tre at me nt - 
E mer ge nt A L T  
Bilir u bi n  
Li ver -Rel ate d 
S y m pt o ms  
Acti o n  
A L T ≥5 × U L N  
N or mal  
Gil bert ’s s y n dr o me or he m ol ysis: N o 
c ha n ge i n baseli ne  t otal bilir u bi n 
N o ne 
R e peat bl o o d tests a n d 
m o nit or f or s y m pt o ms . 
A L T ≥8 × U L N  
N or mal or ele vate d  
N o ne or 
prese nt 
Interr u pt st u d y dr u g 
a n d re peat bl o o d tests. 
St u d y dr u g ca n be 
restarte d if a n ot her 
eti ol o g y ( n ot 
he pat ocell ular i nj ur y) is 
i de ntifie d a n d 
a b n or malities ret ur n t o 
baseli ne  le vels. 
A L T ≥3 × U L N  
T otal bilir u bi n ≥2 × baseli ne  
Gil bert ’s s y n dr o me or he m ol ysis: 
direct bilir u bi n > 2 × baseli ne  if 
baseli ne > 0. 5 m g/ d L 
N o ne or 
prese nt 
A L T ≥5 × U L N  
N or mal or ele vate d  
Prese nt  
A L T = ala ni ne a mi n otra nsferase ; DI LI = dr u g i n d uce d li ver i nj ur y ; U L N = u p per li mit of n or mal . 
T he a l g orit h m f or m o nit ori n g a n d i nterr u pti n g st u d y dr u g f or treat me nt-e mer ge nt he pat ocell ular DI LI 
si g nals i n s u bjects wit h a n ele vate d A L T baseli ne val ue is pr o vi de d i n t he ta ble bel o w. 
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g S t u d y Dr u g f or T re at me nt - Emer ge nt He p at ocell ul ar 
DI LI S i g n als i n S u bjects wit h a n E le v ate d A L T B aseli ne V al ue  
Tre at me nt -
E mer ge nt A L T  
Bilir u bi n  
Li ver- Rel ate d 
S y m pt o ms  
Acti o n  
A L T ≥3 × 
baseli ne  
N or mal  
Gil bert ’s s y n dr o me or he m ol ysis: N o 
c ha n ge i n baseli ne t otal bilir u bi n 
N o ne 
R e peat bl o o d tests a n d 
m o nit or f or s y m pt o ms . 
A L T ≥5 × 
baseli ne  
N or mal or ele vate d  
N o ne or 
prese nt 
Interr u pt st u d y dr u g 
a n d re peat bl o o d tests. 
St u d y dr u g ca n be 
restarte d if a n ot her 
eti ol o g y ( n ot 
he pat ocell ular i nj ur y) is 
i de ntifie d a n d 
a b n or malities ret ur n t o 
baseli ne le vels . 
A L T ≥2 × 
baseli ne  
T otal bilir u bi n ≥2 × baseli ne 
Gil bert ’s s y n dr o me or he m ol ysis: 
direct bilir u bi n > 2 × baseli ne if 
baseli ne > 0. 5 m g/ d L 
N o ne or 
prese nt 
A L T ≥2 × 
baseli ne  
N or mal or ele vate d  
Prese nt  
A L T = ala ni ne a mi n otra nsferase ; DI LI = dr u g i n d uce d li ver i nj ur y . 
M o nit ori n g f or C h olestatic I nj ur y 
T he a l g orit h m f or m o nit ori n g a n d i nterr u pti n g st u d y dr u g f or treat me nt-e mer ge nt c h olestatic DI LI 
si g nals is pr o vi de d i n t he ta ble bel o w.  
 
 

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as t he c urre nt st u d y, val ues t his rece nt will n ot li kely be a vaila ble i n m ost cases. I n s uc h i nsta nces, t he 
I n vesti gat or ca n refer t o t he baseli ne val ue ( pri or t o starti n g st u d y dr u g) a n d e val uate t he c ha n ge. I n 
cases of A KI w here a n eti ol o g y is i de ntifie d, t he re p orte d A E ter m s h o ul d reflect t he eti ol o g y f or t he 
i m pair me nt of re nal f u ncti o n (e g, A KI d ue t o h y p o v ole mia). 
A d diti o nall y, all a b n or mal c o m plete bl o o d c o u nt, ser u m creati ni ne , B U N, a n d uri ne al b u mi n  t o 
creati ni ne rati o  val ues d uri n g t he D o u ble- Bli n d Treat me nt P eri o d a n d O pe n-La bel Treat me nt Peri o d 
are t o be f oll o we d as dee me d cli nicall y necessar y b y t he I n vesti gat or. 
P har mac o ki netic Assess me nts  
Bl o o d sa m pli n g f or P K of E P 5 4 7 will be c ollecte d pre d ose a n d 
 
p ost d ose at Visits 2 a n d 5 ( Da y 1 a n d Wee k 3) a n d pre d ose at Visit s 3, 4, a n d 6 ( Wee k s 1, 2, a n d  6) t o 
a nal yze E P 5 4 7 c o nce ntrati o ns; t he meta b olite pr ofile ma y als o be a nal yze d fr o m t hese sa m ples.  
E n d p oi nts:  
T he p ri mar y efficac y e n d p oi nt is t he c ha n ge fr o m baseli ne i n W I-N R S at Wee k 6.  
T he s ec o n dar y efficac y e n d p oi nts  are: 
•  
C ha n ge fr o m baseli ne i n 5- D Itc h Scale   
•  
T he pr o p orti o n of s u bjects wit h i m pr o ve me nt i n pr urit us as defi ne d b y P GI- C  
•  
T he pr o p orti o n of s u bjects wit h i m pr o ve me n t i n pr urit us se verit y fr o m baseli ne as defi ne d b y 
c ha n ge i n P GI-S  
•  
T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI - N R S ≥2 fr o m baseli ne  
•  
T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI - N R S ≥3 fr o m baseli ne  
•  
T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI - N R S ≥4 fr o m baseli ne  
•  
T he pr o p orti o n of s u bjects wit h WI -N R S < 4  
St atistic al Met h o ds:  
T he pri mar y efficac y e n d p oi nt , as meas ure d as t he wee kl y mea n of t he dail y WI -N R S sc ore , will be 
a nal yze d usi n g a mi xe d effects m o del f or re peate d meas ures ( M M R M) base d o n t he data fr o m all  visits 
u p t o Visit 6 ( Wee k 6). T he m o del will i ncl u de treat me nt, t y pe of c h olesta tic disease ( P B C, P S C), 
wee k, a n d treat me nt b y wee k i nteracti o n as fi xe d effects, a n d baseli ne WI -N R S sc ore as a c o variate. 
T he treat me nt effect will be t he c o ntrast bet wee n E P 5 4 7 a n d place b o least-s q uares ( L S) mea ns.  Testi n g 
of h y p ot hesis is 2-si de d at a 5 % t y pe I err or le vel. 
T he pri mar y a nal ysis of t he pri mar y e n d p oi nt of c ha n ge fr o m baseli ne i n WI- N R S will i ncl u de all 
o bser ve d data ( wee kl y WI- N R S sc ores c o nsi dere d n o n -miss i n g) wit h n o data i m p utati o ns, u n der t he 
ass u m pti o n of missi n g at ra n d o m ( M A R).  

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Pa g e 1 9 of 1 2 8 
T h e efficac y a n d P D e n d p oi nts a b o ve will be f urt her e val uate d d uri n g t he O pe n -La bel E xte nsi o n 
Peri o d. S u m maries of c ha n ge o ver ti me will e val uate b ot h c ha n ge fr o m baseli ne ( Visit 2 [ Da y 1]) a n d 
c ha n ge fr o m t he i nitiati o n of t he O pe n - La bel E xte nsi o n Peri o d ( Visit 6 [ Wee k 6]). 
Safet y data will be s u m marize d se paratel y f or t he D o u ble- Bli n d Treat me nt Peri o d a n d O pe n- La bel 
E xte nsi o n Peri o d b y ra n d o mize d D o u ble- Bli n d treat me nt recei ve d.  
A n i nteri m a nal ysis ma y  be c o n d ucte d t o s u p p ort b usi ness decisi o ns. T he pri mary a nal ysis will be  
c o n d ucte d after t he last s u bject ra n d o mize d has c o m plete d t he D o u ble - Bli n d Treat me nt Peri o d t o 
deter mi ne w het her t he pri mar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n WI- N R S at Wee k 6 is 
statisticall y si g nifica nt. T he fi nal a nal ysis will be c o n d ucte d whe n all ra n d o mize d s u bjects ha ve  
c o m pleted t he O pe n- La bel E xte nsi o n Peri o d or are disc o nti n ue d fr o m t he st u d y, a n d t he fi nal data base 
is l oc ke d. 
S a m ple Size C o nsi der ati o ns:  
Ass u mi n g a sta n dar d de viati o n of 2. 5 p oi nts, a sa m ple size of 2 6 s u bjects per treat me nt gr o u p pr o vi des 
a p pr o xi matel y  
% p o wer t o detect a differe nce of  
 p oi nts bet wee n E P 5 4 7 a n d place b o wit h res pect 
t o t he c ha n ge i n wee kl y mea n of t he dail y WI -N R S sc ore base d o n a 2-si de d, 2-sa m ple c o m paris o n of 
mea ns at t he 5 % si g nifica nce le vel. Wit h a n a ntici pate d earl y wit h dra wal rate of a p pr o xi matel y 1 0 %, 
t he pla n ne d e nr oll me nt of 2 9 s u bjects per treat me nt gr o u p will e ns ure t hat at least 2 6 s u bjects c o m plete 
t he 6 wee ks of d o u ble- bli n d  treat me nt. 
 

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Pa ge 2 0 of 1 2 8 
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
TI T L E P A G E  ................................................................................................................ 1 
P R O T O C O L HI S T O R Y  .................................................................................................................. 4 
2.  
S Y N O P SI S  ................................................................................................................... 6 
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  ............... 2 0 
T A B L E O F C O N T E N T S  ............................................................................................................... 2 0 
LI S T O F T A B L E S  ......................................................................................................................... 2 5 
LI S T O F FI G U R E S  ....................................................................................................................... 2 5 
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ............................. 2 6 
5.  
I N T R O D U C TI O N ...................................................................................................... 3 0 
5. 1.  
C h olestatic Pr urit us  ..................................................................................................... 3 0 
5. 2.  
Mas -Relate d G Pr otei n - C o u ple d Rece pt or X 4 ........................................................... 3 0 
5. 3.  
E P 5 4 7 a n d St u d y Rati o nale ........................................................................................ 3 1  
5. 4.  
E P 5 4 7 D ose Rati o nale ................................................................................................ 3 2  
5. 5.  
S u m mar y of Be nefits a n d Ris ks ................................................................................. 3 3  
5. 5. 1.  
Be nefit S u m mar y  ........................................................................................................ 3 3 
5. 5. 2.  
Ris k S u m mar y a n d Miti gati o n Strate g y  ..................................................................... 3 3 
5. 5. 3.  
O verall Be nefit: Ris k C o ncl usi o n  ................................................................................ 3 4 
6.  
T RI A L O BJ E C TI V E S A N D P U R P O S E  .................................................................... 3 4 
6. 1.  
Pri mar y O bjecti ve  ....................................................................................................... 3 4 
6. 2.  
Sec o n dar y O bj ecti ves  ................................................................................................. 3 4 
6. 3.  
E x pl orat or y O bjecti ves ............................................................................................... 3 4  
7.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 5 
7. 1.  
O verall St u d y Desi g n .................................................................................................. 3 5  
7. 1. 1.  
Scree ni n g Peri o d  ......................................................................................................... 3 5 
7. 1. 2.  
D o u ble- Bli n d Treat me nt Peri o d  ................................................................................. 3 6 
7. 1. 3.  
O pe n - La b el E xte nsi o n Peri o d ..................................................................................... 3 6 
7. 1. 4.  
Safet y F oll o w- U p Peri o d ............................................................................................ 3 6  
7. 2.  
E n d of St u d y ............................................................................................................... 3 6  
7. 3.  
N u m ber of S u bjects .................................................................................................... 3 6  

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7. 4.  
D ose A dj ust me nt Criteria  ........................................................................................... 3 6 
7. 5.  
Criteria f or St u d y Ter mi nati o n  ................................................................................... 3 6 
8.  
S E L E C TI O N A N D WI T H D R A W A L O F S U BJ E C T S  .............................................. 3 7 
8. 1.  
S u bject I n cl usi o n Criteria  ........................................................................................... 3 7 
8. 2.  
S u bject E xcl usi o n Criteria  .......................................................................................... 3 9 
8. 3.  
St u d y Restricti o ns ....................................................................................................... 4 1  
8. 4.  
C o nc o mita nt Me dicati o ns ........................................................................................... 4 1  
8. 4. 1.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  ......................................................................... 4 2 
8. 5.  
Re m o val of S u bjects fr o m T hera p y or Assess me nt .................................................... 4 3  
8. 5. 1.  
Disc o n ti n uati o n of St u d y Dr u g ................................................................................... 4 3 
8. 5. 2.  
Disc o nti n uati o n fr o m t he St u d y .................................................................................. 4 4  
8. 5. 3.  
Safet y Criteria f or St u d y Dr u g I nterr u pti o n ................................................................ 4 5  
9.  
T R E A T M E N T O F S U BJ E C T S  .................................................................................. 4 5 
9. 1.  
Treat me nt Assi g n me nt  ................................................................................................ 4 5 
9. 2.  
Treat me nt C o m plia nce  ................................................................................................ 4 5 
9. 3.  
Ra n d o mizati o n a n d Bli n di n g ...................................................................................... 4 6  
9. 3. 1.  
Ra n d o mizati o n ............................................................................................................ 4 6  
9. 3. 2.  
Bli n di n g ...................................................................................................................... 4 6  
9. 3. 2. 1.  
E mer ge nc y U n bli n di n g  ............................................................................................... 4 6 
9. 3. 2. 2.  
U n bli n di n g f or Re g ulat or y Re p orti n g ......................................................................... 4 6  
9. 4.  
St u d y Visits  ................................................................................................................. 4 7 
9. 4. 1.  
Scree ni n g Peri o d  ......................................................................................................... 4 7 
9. 4. 1. 1.  
Visit 1 ( Da y - 2 8 t o Da y - 1) ......................................................................................... 4 7 
9. 4. 2.  
D o u ble- Bli n d Treat me nt Peri o d  ................................................................................. 4 8 
9. 4. 2. 1.  
Visit 2 ( Da y 1) ............................................................................................................ 4 8  
9. 4. 2. 2.  
Visit 3 ( Wee k 1)  .......................................................................................................... 5 0 
9. 4. 2. 3.  
Visit 4 ( Wee k 2)  .......................................................................................................... 5 0 
9. 4. 2. 4.  
Visit 5 ( Wee k 3)  .......................................................................................................... 5 1 
9. 4. 2. 5.  
Visit 6 ( Wee k 6)  .......................................................................................................... 5 1 
9. 4. 3.  
O pe n -La b el E xte nsi o n  ................................................................................................ 5 2 
9. 4. 3. 1.  
Visit 7 ( Wee k 9)  .......................................................................................................... 5 2 
9. 4. 3. 2.  
Visit 8 ( Wee k 1 2) ........................................................................................................ 5 3  
9. 4. 4.  
Safet y F oll o w- U p Peri o d ............................................................................................ 5 4  

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9. 4. 4. 1.  
Safet y F oll o w- U p Visit ( Visit 9)  ................................................................................ 5 4 
9. 4. 5.  
Earl y St u d y Ter mi nati o n Visit  .................................................................................... 5 4 
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  ........................................... 5 5 
1 0. 1.  
St u d y Dr u gs ................................................................................................................ 5 5  
1 0. 2.  
St u d y Dr u g Pac ka gi n g a n d La beli n g .......................................................................... 5 5  
1 0. 3.  
St u d y Dr u g St ora ge ..................................................................................................... 5 6  
1 0. 4.  
St u d y Dr u g A d mi nistrati o n......................................................................................... 5 6  
1 0. 4. 1.  
I nstr u cti o ns f or Misse d D ose(s) .................................................................................. 5 6 
1 0. 5.  
St u d y Dr u g Dis pe nsi n g a n d Acc o u nta bilit y ............................................................... 5 6  
1 0. 6.  
St u d y Dr u g Ha n dli n g a n d Dis p osal ............................................................................ 5 6  
1 0. 7.  
Pr o d uct Q ualit y C o m plai nts ....................................................................................... 5 7  
1 1.  
E F FI C A C Y A N D P H A R M A C O D Y N A MI C A S S E S S M E N T S  ................................ 5 7 
1 1. 1.  
Q uesti o n naires ............................................................................................................ 5 7  
1 1. 1. 1.  
W orst Itc h N u meric Rati n g Scale ( WI -N R S)  ............................................................. 5 7 
1 1. 1. 2.  
5- D Itc h Scal e  ............................................................................................................. 5 8 
1 1. 1. 3.  
Patie nt Gl o bal I m pr essi o n of Se verit y ( P GI- S)  .......................................................... 5 8 
1 1. 1. 4.  
Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI- C)  ........................................................... 5 8 
1 1. 2.  
Bl o o d a n d Uri ne Sa m pli n g f or P har mac o d y na mic Assess me nts ............................... 5 9  
1 1. 3.  
Bl o o d a n d Uri ne Sa m pli n g f or A nal ysis of Ki d ne y- Relate d Bi o mar kers  .................. 5 9 
1 1. 4.  
Hei g ht ......................................................................................................................... 5 9  
1 2.  
S A F E T Y A S S E S S M E N T S  ........................................................................................ 5 9 
1 2. 1.  
A d verse E v e nts  ........................................................................................................... 6 0 
1 2. 1. 1.  
Defi niti o n of a n A d verse E ve nt .................................................................................. 6 0  
1 2. 1. 2.  
Deter mi ni n g Se verit y of A d verse E v e nts ................................................................... 6 0  
1 2. 1. 3.  
Deter mi ni n g Ca usalit y of A d verse E v e nts ................................................................. 6 1  
1 2. 1. 4.  
Rec or di n g A d verse E ve nts ......................................................................................... 6 1  
1 2. 1. 4. 1.  
S pecial I nstr ucti o ns f or Rec or di n g A d verse E ve nts i n t he e C R F ............................... 6 1  
1 2. 1. 5.  
A d verse E v e nts of S peci al I nt erest  ............................................................................. 6 2 
1 2. 2.  
Seri o us A d verse E v e nts .............................................................................................. 6 3  

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Pa ge 2 3 of 1 2 8 
1 2. 2. 1.  
Defi niti o n of a Seri o us A d verse E ve nt ....................................................................... 6 3  
1 2. 2. 2.  
Re p orti n g Seri o us A d verse E ve nts ............................................................................. 6 3  
1 2. 2. 3.  
Re p orti n g Seri o us a n d U ne x pecte d A d vers e E ve nts Assesse d as Relate d ................. 6 4  
1 2. 2. 4.  
Pre g na nc y  ................................................................................................................... 6 4 
1 2. 3.  
Data M o nit ori n g C o m mittee  ....................................................................................... 6 4 
1 2. 4.  
Me dical Hist or y  .......................................................................................................... 6 5 
1 2. 5.  
Vital Si g ns  .................................................................................................................. 6 5 
1 2. 6.  
P h ysical E xa mi nati o ns ................................................................................................ 6 5  
1 2. 7.  
Sta n dar d 1 2- Lea d Electr ocar di o gra ms  ....................................................................... 6 5 
1 2. 8.  
La b orat or y E v al uati o ns of Safet y ............................................................................... 6 5  
1 2. 9.  
Ot her La b or at or y E val u ati o ns ..................................................................................... 6 6  
1 2. 1 0.  
Tra nsie nt Elast o gra p h y ............................................................................................... 6 6  
1 2. 1 1.  
Partial Ma y o Sc ori n g I n d e x ( S u bjects wit h Ulcerati ve C olitis O nl y)  ........................ 6 7 
1 2. 1 2.  
Cr o h n’s Disease A cti vit y I n d e x ( C D AI) ( S u bjects wit h Cr o h n’s Disease 
O nl y) ........................................................................................................................... 6 7  
1 2. 1 3.  
S u bject Safet y G ui deli nes ........................................................................................... 6 7  
1 2. 1 3. 1.  
P ote ntial Si de Effects  .................................................................................................. 6 7 
1 2. 1 3. 2.  
O ver d ose ..................................................................................................................... 6 7  
1 2. 1 3. 3.  
M o nit ori n g a n d Ma na ge me nt of P ote ntial Dr u g-I n d uce d Li ver I nj ur y ...................... 6 7  
1 2. 1 3. 4.  
O bser vati o n f or Ac ute Ki d ne y I nj ur y ......................................................................... 6 9  
1 3.  
P H A R M A C O KI N E TI C S A S S E S S M E N T  ................................................................. 7 0 
1 4.  
S T A TI S TI C S  .............................................................................................................. 7 0 
1 4. 1.  
A nal ysis Sets  ............................................................................................................... 7 1 
1 4. 2.  
Esti ma n d  ..................................................................................................................... 7 1 
1 4. 3.  
E n d p oi nts .................................................................................................................... 7 2  
1 4. 3. 1.  
Pri mar y Efficac y E n d p oi nt ......................................................................................... 7 2  
1 4. 3. 2.  
Sec o n dar y Efficac y E n d p oi nts .................................................................................... 7 2  
1 4. 3. 3.  
E x pl orat or y E n d p oi nts ................................................................................................ 7 2  
1 4. 4.  
Sa m ple Size C o nsi derati o ns  ....................................................................................... 7 2 
1 4. 5.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................ 7 2 
1 4. 6.  
S u bject Dis p ositi o n  ..................................................................................................... 7 2 
1 4. 7.  
St u d y Dr u g Usa ge a n d C o m plia nce ............................................................................ 7 3  
1 4. 8.  
Efficac y a n d P har m ac o d y na mic A nal ysis  .................................................................. 7 3 

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Pa ge 2 4 of 1 2 8 
1 4. 8. 1.  
A nal ysis of t he Pri mar y E n d p oi nt: C ha n ge fr o m Baseli ne i n W orst Itc h 
N u meric Rati n g Scale ( WI -N R S) at Wee k 6  .............................................................. 7 3 
1 4. 8. 2.  
A nal ysis of Sec o n dar y a n d P har mac o d y na mic E n d p oi nts ......................................... 7 3  
1 4. 8. 3.  
Pri mar y a n d Se nsiti vit y A nal yses t o A d dress Missi n g Data i n t he Pri mar y 
A nal ysis ...................................................................................................................... 7 4  
1 4. 9.  
Safet y A nal ysis  ........................................................................................................... 7 4 
1 4. 1 0.  
P har mac o ki netic A n al ysis  .......................................................................................... 7 4 
1 4. 1 1.  
S u b gr o u p A nal yses ..................................................................................................... 7 4  
1 4. 1 2.  
M ulti ple C o m paris o n/ M ulti plicit y  .............................................................................. 7 4 
1 4. 1 3.  
Pla n ne d I nteri m, Pri mar y, a n d Fi nal A n al ysis ............................................................ 7 5  
1 5.  
Q U A LI T Y C O N T R O L A N D D A T A M A N A G E M E N T  ........................................... 7 5 
1 5. 1.  
Data Q ualit y Ass ur a nce  .............................................................................................. 7 5 
1 5. 2.  
Data Ma na g e me nt  ....................................................................................................... 7 5 
1 5. 3.  
M o nit ori n g .................................................................................................................. 7 6  
1 5. 4.  
C o nfi de ntialit y a n d A u diti n g ...................................................................................... 7 6  
1 5. 5.  
Case Re p ort F or ms  ..................................................................................................... 7 6 
1 5. 6.  
S o urce D oc u m e nts ...................................................................................................... 7 7  
1 5. 7.  
Rec or ds Rete nti o n  ....................................................................................................... 7 7 
1 5. 8.  
I nf or me d C o nse nt ....................................................................................................... 7 7 
1 5. 9.  
Et hical C o n d uct of t he St u d y ...................................................................................... 7 8  
1 5. 1 0.  
I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee ...................................... 7 8 
1 6.  
S T U D Y M A N A G E M E N T  ......................................................................................... 7 8 
1 6. 1.  
Pr ot oc ol De viati o ns .................................................................................................... 7 8  
1 6. 2.  
P u blicati o ns ................................................................................................................. 7 9  
1 6. 3.  
C ha n ge i n St u d y Site Staff .......................................................................................... 7 9  
1 7.  
LI S T O F R E F E R E N C E S  ............................................................................................ 8 0 
A P P E N DI X  A.  S C H E D U L E O F A S S E S S M E N T S  ................................................................... 8 3 
A P P E N DI X  B.  W O R S T I T C H N U M E RI C R A TI N G S C A L E ( WI -N R S)  ................................ 8 7 
A P P E N DI X  C.  5- D I T C H S C A L E  ............................................................................................. 8 8 
A P P E N DI X  D.  P A TI E N T G L O B A L I M P R E S SI O N O F S E V E RI T Y ( P GI -S)  ........................ 8 9 
A P P E N DI X  E.  P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E ( P GI -C)  ........................... 9 0 

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A P P E N DI X  I. S U M M A R Y O F C H A N G E S B Y A M E N D M E N T  ............................................ 9 5 
 
LI S T O F T A B L E S  
Ta ble 1:  
E mer ge nc y C o ntact I nf or mati o n ................................................................................... 5  
Ta ble 2:  
A b bre viati o ns a n d S pec i alist Ter ms ........................................................................... 2 6 
Ta ble  4: 
E P - 5 4 7- 2 0 1 Treat me nt Assi g n me nts .......................................................................... 4 5 
Ta ble  5: 
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g St u d y Dr u g f or Treat me nt-
E mer ge nt He p at ocell ular DI LI Si g nals i n S u bjects wit h a N or mal A L T 
B aseli ne Val ue  ............................................................................................................ 6 8 
Ta ble  6: 
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g St u d y Dr u g f or Treat me nt-
E mer ge nt He p at ocell ular DI LI Si g nals i n S u bjects wit h a n Ele vate d A L T 
Baseli ne Val ue  ............................................................................................................ 6 8 
Ta ble  7: 
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g St u d y Dr u g f or Treat me nt-
E mer ge nt C h olestatic DI LI Si g nals  ............................................................................ 6 9 
 
LI S T O F FI G U R E S  
Fi g ure 1:  
E P - 5 4 7- 2 0 1 St u d y Desi g n .......................................................................................... 3 5 
 

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4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 2:  
A b bre vi ati o ns a n d S peci alist T er ms  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
4 P B  
4- p he n yl b ut yrate 
A A S L D  
A merica n Ass ociati o n f or t he St u d y of Li ver Diseases  
A E  
a d verse e ve nt 
A E SI  
a d verse e ve nt s of s pecial i nterest 
A KI  
ac ute ki d ne y i nj ur y 
A L P  
al kali ne p h os p hatase 
A L T  
ala ni ne a mi n otra nsferase  
A M A  
a nti mit oc h o n drial a nti b o d y 
A N C O V A  
a nal ysis of c o varia nce 
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A S T  
as partate a mi n otra nsferase  
A T C  
A nat o mic T hera pe utic C he mistr y  
B C R P  
breast ca ncer resista nce pr otei n  
B U N  
bl o o d urea nitr o ge n 
C D  
Cr o h n’s disease 
C D AI  
Cr o h n’s Disease Acti vit y I n de x 
C F R  
C o de of Fe deral Re g ulati o ns 
C N S  
ce ntral ner v o us s yste m 
C O VI D - 1 9 
c or o na vir us disease 2 0 1 9 
C P K  
creati ne p h os p h o ki nase 
C R O  
C o ntract Researc h Or ga nizati o n  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
C Y P  
c yt oc hr o me P 4 5 0  
D DI  
dr u g- dr u g i nteracti o n  
D- FI S  
Fati g ue I m pact Scale f or Dail y A d mi nistrati o n  
DI LI  
dr u g- i n d uce d li ver i nj ur y 
D M C  
Data M o nit ori n g C o m mittee  
D N A  
de o x yri b o n ucleic aci d 
D R T  
Data Re vie w Tea m  

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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
E C G  
electr ocar di o gra m 
e C R F 
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure 
E LI S A  
enz y me li n ke d i m m u n os or be nt assa y 
E Q - 5 D- 3 L 
3- Le vel E ur o Q ol- 5 D 
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
G C P  
G o o d Cli nical Practice  
G G T  
ga m ma -gl uta m yltra nsf erase 
H A V  
he patitis A vir us  
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
H D L -c 
hi g h- de nsit y li p o pr otei n c h olester ol 
H E E N T  
hea d, e yes, ears, n ose, t hr oat  
h E R G  
h u ma n et her-à- g o- g o-relate d ge ne 
H E V  
he patitis E vir us 
H I V 
h u ma n i m m u n o deficie nc y vir us  
I B D 
i nfla m mat or y b o wel disease 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I g G 4 
i m m u n o gl o b uli n G 4 
I g M 
i m m u n o gl o b uli n M 
I N R 
i nter nati o nal n or malize d rati o 
IR B  
I nstit uti o nal Re vie w B oar d 
I W R S 
I nteracti ve We b Res p o nse S yste m 
K DI G O  
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes 
L D H  
lactate de h y dr o ge nase 
L D L -c 
l o w-de nsit y li p o pr otei n c h olester ol  
L S  
least-s q uares 
M A R  
missi n g at ra n d o m 

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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M M R M  
mi xe d effects m o del f or re peate d meas ures  
M R G P R  
mas -relate d G pr otei n -c o u ple d rece pt or 
N A S H  
n o nalc o h olic steat o he patitis 
N K  
nat ural killer  
O A T 1  
or ga nic a ni o n tra ns p orter  1 
O A T 3  
or ga nic a ni o n tra ns p orter  3 
O C A  
o betic h oli c aci d 
P B C  
pri mar y biliar y c h ola n gitis  
P D  
p har mac o d y na mic 
P FI C 1  
pr o gressi ve fa milial i ntra he patic c h olestasis t y pe 1 
P GI - C 
Patie nt Gl o bal I m pressi o n of C ha n ge 
P GI - S 
Patie nt Gl o bal I m pressi o n of Se verit y  
P K  
p har mac o ki netics 
P O  
o ral 
P P  
Per Pr ot oc ol  
P Q C  
pr o d uct q ualit y c o m plai nt 
P R O  
p atie nt-re p orte d outc o mes  
P R O MI S  
Patie nt - Re p orte d O utc o mes I nf or mati o n S yste m 
P S C  
pri mar y scler osi n g c h ola n gitis  
P T  
pr ot hr o m bi n ti me  
Q C  
q ualit y c o ntr ol  
Q D  
o nce dail y  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S A R S -C o V - 2 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
S M Q  
Sta n dar dize d Me d D R A Q uer y  
T 4  
t h yr o xi ne 
T E  
tra nsie nt elast o gra p h y 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T S H  
t h yr oi d-sti m ulati n g h or m o ne 

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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
U C  
ulcerati ve c olitis  
U D C A  
urs o de o x yc h olic aci d 
U L N  
u p per li mit of n or mal  
U V B  
ultra vi olet B  
W B C  
w hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n 
WI -N R S  
W orst Itc h N u meric Rati n g Scale  

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5.  
I N T R O D U C TI O N 
5. 1.  
C h olest atic Pr urit us  
Patie nts wit h c h olestatic li ver disease, s uc h as pri ma r y biliar y c h ola n gitis ( P B C) a n d pri mar y 
scler osi n g c h ola n gitis ( P S C), ofte n s uffer fr o m c hr o nic itc h or pr urit us t hat is e x perie nce d b y u p 
t o 7 0 % t o 8 0 % of t hese p atie nts o ver t he c o urse of t heir disease (Mittal 2 0 1 6 ).  
Patie nts w it h c h olestatic pr urit us ha ve diffic ult y c o pi n g wit h t he i nte nse itc hi n g a n d de vel o p 
ass ociate d stress. Pr urit us has a cli nicall y mea ni n gf ul ne gati ve effect o n patie nts’ q ualit y of life, 
slee p, fati g ue, e m oti o nal state, a n d s ocial relati o ns (Bassari 2 0 1 5 , I bra hi m 2 0 1 6), a n d c o ntri b utes 
t o t he de vel o p me nt of s ki n a n d s oft tiss ue lesi o ns a n d/ or i nfecti o ns (Oze n 2 0 1 8 ).  
T he pat h o p h ysi ol o g y of c h olestatic pr urit us is n ot f ull y u n derst o o d a n d t he itc h-ca usi n g 
pr urit o ge n(s) a n d t heir c o g nate rece pt or(s) ha ve re mai ne d lar gel y el usi ve. C h olestatic pr urit us is 
ofte n n o nres p o nsi ve t o st a n dar d p har mac ol o gic al treat me nts, i ncl u di n g a nti hista mi nes, a n d 
i nstea d re q uires p h ysicall y re m o vi n g t he ca us ati ve o bstr ucti o n (s uc h as gallst o nes), drai ni n g t he 
bile, or tra ns pla nti n g t he li ver t o alle viate itc h (Ber gasa 2 0 1 4 ). Beca us e t hese pr oce d ures are 
ofte n hi g hl y effecti ve, t h e res p o nsi ble pr urit o ge ns are h y p ot hesize d t o ori gi nate fr o m t he li ver 
a n d bile. N u mer o us ca n di date pr urit o ge ns are pres e nt i n bile a n d u pre g ulate d i n c h olestatic 
patie nts, i ncl u di n g o pi oi ds, l ys o p h os p hati dic aci d, bilir u bi n, a n d bile aci ds. T hera pies tar geti n g 
t hese mec ha nis ms, s uc h as o pi oi d a nta g o nists, rifa m pici n, ileal bile aci d tra ns p orter i n hi bit ors, 
a n d bile aci d - bi n di n g r esi ns li ke c h olest yra mi ne, are fr o ntli ne t hera p y f or c h olestatic pr urit us 
(Bassari 2 0 1 5 , Mittal 2 0 1 6 ); h o we ver, effi cac y is v aria ble a n d p atie nts are p o orl y ma na ge d wit h 
t hese me dicati o n s (Bassari 2 0 1 5 , Mittal 2 0 1 6 ).  
Alt h o u g h a variet y of i nt er ve nti o ns ha ve b ee n e x pl ore d, t he n ee d f or i m pr o ve d treat me nt of 
c h olestatic pr urit us re m ai ns hi g h. T heref ore, de v el o p me nt of a d diti o nal safe a n d effecti ve, 
mec ha nisticall y base d  t h era pe utic o pti o ns f or t his c o n diti o n is esse ntial. 
5. 2.  
M as -Rel ate d G P r otei n-C o u ple d Rece pt or  X 4  
Mas -relat e d G pr otei n- c o u ple d rece pt ors ( M R G P Rs) re prese nt a fa mil y of 8 h u ma n 
c he m ose ns or y m ulti- li ga n d rece pt ors t hat resi de c hiefl y i n barrier tiss ues s uc h as se ns or y n e ur o ns 
a n d cl osel y ass ociat e d l ocal i m m u ne cells. T he y act as a first -li ne i n nat e s ur veilla nce s yste m f or 
earl y detecti o n of a variet y of e n d o ge n o us a n d e x o ge n o us p ote ntiall y offe nsi ve sti m uli.  
M R G P R X 4 is e x presse d i n a s u bset of d orsal r o ot ga n glia ne ur o ns, s ki n se ns or y 
affere nts,  de n dritic cells, mela n oc ytes, a n d p ol y m or p h o n uclear le u k oc ytes, a n d has bee n 
de m o nstrate d t o be a rece pt or rele va nt t o c h ol estatic pr urit us (Mei xi o n g 2 0 1 9a , Mei xi o n g 2 0 1 9 b , 
Y u 2 0 1 9 ) ( data o n file). Alt h o u g h m ost, if n ot all c o m p o ne nts of bile acti v ate M R G P R X 4 t o 
var yi n g de gr ees, bile aci ds a n d bilir u bi n i n partic ular are str o n g a g o nists of M R G P R X 4 ( data o n 
file), a n d t heir s ki n acc u m ulati o n i n ass ociati o n wit h pr uritic c h olestatic diseases i m plicates 
M R G P R X 4 i n t his disease stat e. Se veral e x peri me nts ha ve bee n c o n d ucte d a n d p u blis he d i n 
s u p p ort of t his, i ncl u di n g o bser vati o ns t hat ac ute i njecti o n of bile aci ds res ults i n pr urit us i n b ot h 
mice a n d h u ma ns, a n d bile aci d- m o d ulati n g t hera p y is effecti ve i n c o ntr olli n g patie nt pr urit u s 
(Mei xi o n g 2 0 1 9a , Mei xi o n g 2 0 1 9 b , Y u 2 0 1 9 ). Si milarl y, bilir u bi n has bee n de m o nstrate d t o pla y 
a r ole i n pr urit us, a n d i n vitr o i n vesti gati o n of bilir u bi n a n d meta b olites b y t he S p o ns or has 

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s h o w n t hat a n u m ber of h e me meta b olites i n a d diti o n t o bilir u bi n ca n acti vate M R G P R X 4 as 
effecti vel y as bile aci ds ( data o n file).  
It has b ee n r e p orte d t h at 4- p he n yl b ut yrate ( 4 P B), a dr u g a p pr o v e d i n Ja pa n t o treat or nit hi ne 
tra nscar b a m ylase d eficie nc y, relie ve d i ntracta ble itc h i n patie nts wit h pro gre ssi ve fa milial 
i ntra he patic c h ol estasis t y pe 1 ( P FI C 1) (Hase g a w a 2 0 1 4 ). T his is a rare, i n herite d li ver diseas e 
ca use d b y m utati o ns i n A T P 8 B 1, a tra ns me m bra ne pr otei n t hat me diates t he tra nsl ocati o n of 
p h os p h oli pi ds, a n d is c haracterize d b y se v ere c h ol estasis a n d s ustai ne d i ntracta ble itc h. W hile 
4 P B t hera p y ha d n o be neficial eff ect o n li ver f u ncti o n i n t he patie nts wit h P FI C 1, d oses of 
3 5 0 t o 5 0 0 m g/ k g/ da y s h owe d si g nifica nt re d u cti o n of i ntracta ble itc h. 4 P B is als o a n a nta g o nist 
of M R G P R X 4 t hat ca n bl oc k acti vati o n b y bile aci ds, bilir u bi n, a n d ot her M R G P R X 4 a g o nists 
( data o n file). T h us, M R G P R X 4 a nta g o nis m b y 4 P B is p ote ntiall y t he u n derl yi n g mec ha nis m of 
its a ntipr uritic effect i n patie nts wit h P FI C 1  a n d ma y t heref ore c o nstit ute preli mi nar y  cli nical 
pr o of of c o n ce pt f or M R G P R X 4 i n hi biti o n i n c h olestatic pr urit us.  
T hese data s u g g est t hat i n hi biti o n of M R G P R X 4 ma y re d uce or alle viat e pr urit us i n patie nts w h o  
ha ve a  b uil d- u p of bile aci ds a n d/ or he me meta b olites a n d s u p p orts i n vesti gati o n of M R G P R X 4 
bl oc kers i n patie nts wit h c h olestatic pr urit us. 
5. 3.  
E P 5 4 7  a n d St u d y R ati o n ale  
E P 5 4 7 is a p ote nt s mall-m olec ule i n verse a g o nist of M R G P R X 4 u n der de v el o p me nt as a n orall y 
a d mi nistere d t hera p y f or c h olestatic pr urit us . 
Cli nical safet y a n d p har mac o ki netics ( P K ) of E P 5 4 7 are bas e d o n t he res ults fr o m 
St u d y E P - 5 4 7- 1 0 1, a first-i n- h u ma n ra n d o mize d, P hase 1 cli nical st u d y of oral si n gle a n d 
m ulti ple dail y d oses of E P 5 4 7 i n health y s u bjects, i n s u bjects wit h c h olestatic dis or ders wit h 
pr urit us, a n d i n he m o dial ysis s u bjects wit h ure mic pr urit us . 
 
. E P 5 4 7 has  bee n  teste d i n 6 6  i n di vi d uals, wit h 
2 4 treate d wit h a m ulti ple d ose re gi me n (ie, dail y d oses of E P 5 4 7 o ver 7 da ys) as f oll o ws b y 
p o p ulati o n:  
•  He alt h y s u bjects:  3 0 s u bjects recei ve d si n gle d oses of 2 5 m g t o 6 7 5 m g a n d 
1 8 s u bjects recei ve d 2 5, 7 5, or 2 2 5 m g as a m ulti ple d ose re gi me n. A n a d diti o nal 
5 s u bjects recei ve d si n gle 7 5- m g d oses u n der fe d a n d faste d c o n diti o ns.  
•  S u bjects wit h a c h olest atic dis or der:  5 s u bjects recei ve d a 7 5- m g si n gle d ose a n d 
2 s u bjects recei ve d a 3 0 m g m ulti ple d ose re gi me n.  
•  S u bjects wit h ure mic pr urit us : 6 s u bje cts recei ve d a 7 5- m g si n gle d ose; 4 of t hese 
s u bjects als o recei ve d a 2 0  m g m ulti ple d ose re gi me n.  
E P 5 4 7 P K  wa s hi g hl y pre dicta ble, s h o we d str o n g d ose li nearit y, a n d s u p p orts o nce dail y ( Q D) 
d osi n g. All d oses teste d t o date acr oss t he 3  p o p ulati o ns were w ell t olerate d  wit h n o safet y 
si g nals. T he a bse nce of s afet y si g nals , i n c o nj u ncti o n wit h fa v ora ble P K pr ofiles, s u p p ort f urt her 
i n vesti gati o n of E P 5 4 7 i n s u bjects wit h c h olestatic pr urit us i n t his P hase 2 cli nical st u d y. 
St u d y E P - 5 4 7- 2 0 1 is desi g ne d t o e val uate t h e effects of E P 5 4 7 o n re d uci n g t he se nsati o n of 
pr urit us o ver 6 wee ks i n a p pr o xi matel y 5 8 s u bjects dia g n ose d wit h c h olestatic pr urit us d ue t o 
P B C or P S C. Beca use pr o m pt a nti pr uritic acti o n is e x pecte d gi ve n t h e mec ha nis m of acti o n of 
E P 5 4 7 via its direct effect o n t he M R G P R X 4 rece pt or, a relati vel y s h ort d urati o n of treat me nt t o 

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( A KI) (e g, ‘ bl o o d ur ea i n creas e d’ or ‘ pr otei n uri ne prese nt’ a d v erse e ve nts [ A Es] as i de ntifie d b y 
t he Sta n dar dize d M e dical Dicti o nar y f or Re g ul at or y Acti vities [ Me d D R A] Q uer y [ S M Q] ‘ A c ute 
re nal f ail ure’) will be c o nsi dere d A Es  of s p ecial i nteres t ( A E SI, Secti o n  1 2. 1. 5 ). S u bjects will be 
cl osel y m o nit ore d f or o bser vati o ns of A KI, a n d st u d y dr u g ma y be i nterr u pte d f or s u bjects w h o 
e x perie n ce el e vati o ns i n ser u m creati ni ne le vels acc or di n g t o t he al g orit h m descri be d i n 
Secti o n  1 2. 1 3. 4 . 
5. 5. 3.  
O ver all Be nefit: Ris k C o ncl usi o n  
O vera ll, t he safet y meas ures t o be e m pl o ye d a n d t he cli nical e x perie nce t o date wit h E P 5 4 7 
s u g gest mi ni mal ris k t o s u bjects partici pati n g i n St u d y E P- 5 4 7- 2 0 1. Alt h o u g h a variet y of 
i nter ve nti o ns f or c h olestatic pr urit us ha ve bee n e x pl ore d, t here is c urre ntl y n o me dicati o n 
a p pr o ve d f or t his i n dicati o n i n a d ults, a n d t he nee d f or i m pr o ve d treat me nts re mai ns hi g h. 
T heref ore, d e vel o p me nt of a d diti o nal safe a n d eff ecti ve, mec h a nisticall y base d t hera pe utic 
o pti o ns f or t his c o n diti o n is esse ntial. If deter mi ne d t o be effecti ve i n t his st u d y, E P 5 4 7 ma y 
ulti matel y ha ve t he p ote ntial t o offer s u bsta ntial relief f or patie nts s ufferi n g fr o m c h olestatic 
pr urit us, i ncl u di n g t h ose e nr olle d i n t his st u d y. C o nsi deri n g all a vaila ble safet y i nf or mati o n a n d 
meas ures ta k e n t o mi ni miz e ris k t o s u bjects, t he o verall be nefit-ris k pr ofile of E P 5 4 7 is dee me d 
t o be acce pta ble f or t he c o n d uct of St u d y E P- 5 4 7- 2 0 1. 
6.  
T RI A L O B J E C TI V E S A N D P U R P O S E  
6. 1.  
Pri m ar y O bjecti ve 
•  T o assess t he efficac y of E P 5 4 7 c o m pare d t o place b o o n pr urit us as assess e d b y t he 
W orst Itc h N u meric Rati n g Scale ( WI -N R S)  
6. 2.  
Sec o n d ar y O bjecti ves  
•  T o assess t he efficac y of E P 5 4 7 c o m pare d t o place b o o n t he f oll o wi n g: 
− Pr urit us -relate d q ualit y of life usi n g t he 5 -D Itc h S cale  
− Pr urit us se verit y usi n g t he Patie nt Gl o bal I m pressi o n of Se verit y ( P GI-S)  
− O verall pr urit us r es p o nse t o t hera p y usi n g t he Patie nt Gl o bal I m pressi o n of 
C ha n ge ( P GI- C)  
•  T o assess t he saf et y a n d t olera bilit y of E P 5 4 7 
•  T o  assess t he P K of E P 5 4 7  
6. 3.  
E x pl or at or y O bjecti ve s 

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7. 1. 2.  
D o u ble -Bli n d Tre at m e nt Peri o d  
T he D o u ble- Bli n d Treat me nt Peri o d will c o nsist of 5 st u d y visits ( Visits 2, 3, 4, 5, a n d 6 [ Da y 1 
a n d Wee k s 1, 2, 3, a n d 6]). D uri n g t his peri o d, all s u bjects w h o meet eli gi bilit y re q uire me nts will 
be e nr olle d i nt o t he st u d y a n d ra n d o mize d t o recei ve d o u ble- bli n d, P O , Q D d oses of E P 5 4 7 or 
place b o f or 6  wee ks be gi n ni n g o n Visit 2 ( Da y 1). S u bjects will be ra n d o mize d t o recei ve eit her 
1 0 0 m g d oses of E P 5 4 7 or place b o i n a 1: 1 rati o. Ra n d o mizati o n will be c o n d ucte d ce ntrall y via 
a n I nter acti ve We b Res p o nse S yste m (I W R S) a n d stratifie d base d o n t y pe of c h ol estatic diseas e 
( P B C, P S C). Visit 2 ( Da y 1) will n ot ha ve a visit wi n d o w; h o we ver, for t h e dece ntralize d m o d el , 
e nr oll me nt/ra n d o mizati o n a n d t he first d ose of st u d y dr u g ma y be se p arate d b y u p t o 1 0 
a d diti o nal cale n dar da ys t o all o w f or h o me deli ver y of st u d y dr u g. W he n 
e nr oll me nt/ra n d o mizati o n a n d first d ose of st u d y dr u g are o n s e parate da ys, t he first d ose of 
st u d y dr u g is c o nsi dere d Da y 1. All ot her visits i n t he D o u ble-Bli n d Treat m e nt Peri o d will ha ve a 
visit wi n d o w of ± 3 d a ys. 
7. 1. 3.  
O pe n -L a bel E xte nsi o n Per i o d 
T he O pe n - L a bel E xte nsi o n Peri o d will c o nsist of 2 st u d y visits ( Visit 7 [ Wee k 9] a n d Visit 8 
[ Wee k 1 2]). D uri n g t his peri o d, all s u bjects w h o c o m plete t he D o u ble-Bli n d Treat me nt Peri o d 
a n d are still recei vi n g st u d y dr u g wil l recei v e o pe n-la bel 1 0 0 m g d oses of E P 5 4 7. Visit 7 a n d 
Visit 8 will ha ve a visit wi n d o w of ± 3 da ys. 
7. 1. 4.  
S afet y F oll o w- U p Peri o d  
A n y s u bject w h o c o m pletes t he O pe n- L a bel E xte nsi o n Peri o d or disc o nti n ues st u d y dr u g ( E P 5 4 7 
or place b o) earl y will c o m plete a f oll o w- u p visit ( Visit 9) a p pr o xi m atel y 2 wee ks ( ± 3 d a y s) aft er 
t he last d ose of st u d y dr u g. 
7. 2.  
E n d of St u d y  
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e st u d y if he/s he has c o m plete d all p hases of t he 
st u d y, i ncl u di n g t he last st u d y visit (ie, t he F oll o w-U p Visit [ Visit 9] ). 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast st u d y visit of t he last s u bject i n t he st u d y 
gl o ball y. 
7. 3.  
N u m ber of S u bjects  
A p pr o xi matel y 5 8 s u bjects wit h c h olestatic pr urit us d ue t o P B C or P S C will be ra n d o mize d i n 
t he st u d y.  
7. 4.  
D ose A dj ust me nt Criteri a  
D osa ges f or st u d y dr u g s h o ul d be mai ntai ne d c o nsta nt d uri n g t he st u d y. H o we ver, d osi n g of 
st u d y dr u g ma y be i nterr u pte d or disc o nti n ue d d u e t o safet y fi n di n gs. Refer t o Secti o n  8. 5  f or 
g ui da nce o n ma n d at or y disc o nti n uati o n of st u d y dr u g d ue t o se vere a n d rel ate d A E s. 
7. 5.  
Criteri a f or St u d y Ter mi n ati o n  
T he S p o ns or ma y ter mi n ate t he st u d y at a  st u d y site at a n y ti me (e g, G o o d Cli nical Practice 
[ G C P] n o nc o m plia nce or p o or st u d y data q ualit y ). If i nstr ucte d b y t he S p o ns or or desi g nee, t h e 

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I n v esti gat or m ust i m ple me nt t he ter mi nati o n i n a ti mefra me t o e ns ure s u bject safet y a n d 
well - bei n g. Refer t o Secti o n  8. 5. 2  ( Disc o nti n uati o n fr o m t he St u d y) f or i nstr ucti o ns f or s u bjects 
w h ose partici pati o n fr o m t he st u d y is disc o nti n ue d. 
T he I n vesti gat or a n d/ or S p o ns or ( or desi g nee) m ust n otif y t he I nstit uti o nal Re vie w 
B oar d/I n de pe n d e nt Et hics C o m mittee ( I R B/I E C) of disc o nti n uati o n of a site or t he st u d y a n d t he 
reas o n f or d oi n g s o. 
8.  
S E L E C TI O N A N D WI T H D R A W A L O F  S U B J E C T S 
S u bjects w h o ha ve a n e x cl usi o nar y res ult at Visit 1 ma y ha ve t hat ass ess me nt re peate d o nce at 
t he discreti o n of t he I n v esti gat or wit hi n t he scree ni n g wi n d o w a n d be e nr olle d if a re peat 
assess me nt is wit hi n t he i n dicate d ra n g e as s pecifi e d bel o w f or p artici pati n g i n t he st u d y. 
8. 1.  
S u bject I ncl usi o n Criteri a  
T o be eli gi ble f or st u d y p artici pati o n, all s u bjects m ust meet all t he f oll o wi n g i ncl usi o n criteria: 
1.  A ge 1 8 t o 8 0 years, i ncl usi ve 
2.  Has e x perie nce d self -re p orte d dail y or near-d ail y m o derate t o se v er e pr urit us bef ore 
Scree ni n g  
3.  Has a mea n d ail y WI -N R S sc ore i n dicati ve of m o d erate t o se v ere pr urit us (s c ore  ≥4) 
d uri n g Scree ni n g ( Da y - 7 t hr o u g h Da y - 1); d ata fr o m at least 4 of t he 7 da ys are re q uire d 
t o be c o nsi dere d a n acce pta ble pr ofile  
4.  If c urre ntl y ta ki n g me dicati o ns t o treat t he c h olest atic dis or der (i n cl u di n g o betic h olic aci d 
[O C A ]), m ust be o n a sta ble d ose f or > 1 2 wee ks  bef ore Scree ni n g a n d pla ns t o mai ntai n 
t he re gi me n t hr o u g h o ut t he st u d y 
5.  If c urre ntl y ta ki n g a fi br ate, m ust be o n a sta ble d ose f or > 1 2 wee ks b ef ore Scree ni n g a n d 
pla ns t o mai ntai n t he re gi me n t hr o u g h o ut t he st u d y 
6.  Eit her is n ot treate d wit h or has bee n o n a sta ble re gi me n wit h a n y me dicati o ns t o treat 
pr urit us f or > 4  w ee ks bef ore Scree ni n g  a n d pla ns t o mai ntai n t he re gi me n t hr o u g h o ut t he 
st u d y 
7.  If fe mal e, m ust ha ve a n e gati ve ser u m pre g n a nc y t est at Scree ni n g a n d be willi n g t o n ot 
d o nate e g gs fr o m Scree ni n g u ntil after t he last d os e of st u d y dr u g a n d:  
a. Is s ur gi call y sterile; or 
b.  Has bee n a me n orr h oeic f or ≥1 year wit h o ut a n alter nati ve me dical ca us e ; or 
c. If of c hil d beari n g p ote nti al2, m ust a gree t o us e at least 1 f or m of a n acce pta ble 
me t h o d of c o ntrace pti o n fr o m Scree ni n g u ntil t he last d ose of st u d y dr u g. Acce pt a ble 
birt h c o ntr ol met h o ds i ncl u de :  
 
2 W o me n of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile. Per ma ne nt sterili zati o n met h o ds i ncl u de h ysterect o m y, bilateral 
sal pi n gect o m y, a n d bilateral o o p h orect o m y. A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut 
a n alter nati ve me dical ca use.  

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•  Barrier met h o ds of c o ntrace pti o n (e g, m ale c o n d o m, fe male c o n d o m, cer vi cal ca p 
or dia p hra g m, a n d c o ntrace pti ve s p o n ge) 
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n 
•  Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n  
•  Intr a uteri ne d e vice  
•  I ntr a uteri ne h or m o ne r eleasi n g s yste m 
•  B ilateral t u bal occl usi o n 
•  V asect o mize d p art ner  
•  Se x ual a bsti ne nce (c o m plete se x ual a bsti ne n ce defi ne d as refrai ni n g fr o m 
heter ose x u al  i nterc o urs e f or t he e ntire p eri o d of ris k ass ociate d wit h st u d y dr u g), 
t he relia bilit y of w hic h n ee ds t o be e v al uate d i n relati o n t o t he d urati o n of t he 
cli nical st u d y a n d t he preferre d a n d usual lifest yle of t he s u bject  
8.  M ust be a ble t o c o m m u nicate w ell wit h t he I n v esti gat or, u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t h e st u d y, a n d u n dersta n d a n d pr o vi de writte n c o nse nt  
9.  F or s u bjects wit h c o n c o mita nt i nfla m mat or y b o wel disease ( I B D): 
a. C ol o n osc o p y (if s u bject has a c ol o n) or ot her a p pr o priate e n d os c o pic pr o ce d ure 
wit hi n 1 8 m o nt hs of Da y 1 c o nfir mi n g n o d ys plasia or c ol orectal  ca ncer  
b.  S u bjects wit h Cr o h n’s disease ( C D) m ust be i n re missi o n as defi ne d b y a Cr o h n’s 
Disease A cti vit y I n de x ( C D AI) < 1 5 0 at Scree ni n g  
c. S u bjects wit h ulcerati ve c olitis ( U C) m ust ha ve a Partial Ma y o Sc ori n g I n d e x sc ore 
≤3 wit h n o i n di vi d ual s u b-sc ore e xcee di n g 1 p oi nt at Scree ni n g  
S u bjects wit h P B C m ust als o meet t he f oll o wi n g i ncl usi o n criteri a t o be eli gi ble f or st u d y 
partici pati o n:  
1 0.  D oc u me nte d hist or y of P B C t hat is c o nsiste nt wit h t he A merica n Ass ociati o n f or t he 
St u d y of Li ver Diseases ( A A S L D ) Practice G ui deli nes  (Li n d or 2 0 1 9 ), defi ne d as ha vi n g 
≥2 of t he f oll o wi n g 3 fact ors u p o n dia g n osis: 
a. Hist or y of ele vate d al kali ne p h os p hatase ( A L P) le vels  
b.  Hist oric p ositi ve a nti mit oc h o n drial a nti b o d y ( A M A) or A M A - M 2 b y 
i m m u n ofl u oresce nce, en z y me li n ke d i m m u n os or be nt assa y ( E LI S A), or i m m u n o bl ot 
or if A M A is ne gati ve, p ositi ve f or P B C -s pecific a nti b odies (a nti - G P 2 1 0 a n d/ or 
a nti- S P 1 0 0)  
c. Li ver hist ol o g y at a n y p oi nt i n ti me c o nsiste nt wit h P B C  
1 1.  If c urre ntl y ta ki n g urs o de o x yc h olic aci d ( U D C A), m ust be o n a sta ble d ose of n ot m ore 
t ha n 2 0 m g/ k g/ da y f or ≥1 2 wee ks. If n ot c urre ntl y ta ki n g U D C A, m ust n ot be treate d 
wit h U D C A wit hi n 1 2 wee ks bef ore Scree ni n g or pla n t o be treate d wit h U D C A d uri n g 
t he st u d y 

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S u bjects wit h P S C m ust als o meet all t he f oll o wi n g i ncl usi o n criteria  t o be eli gi ble f or st u d y 
par tici pati o n: 
1 2.  D oc u me nte d hist or y of P S C base d o n eit her c h ola n gi o gra p h y (ie, ma g n etic res o na nce 
c h ola n gi o pa ncr eat o gr a p h y, e n d osc o pic retr o gra d e c h ola n gi o pa ncreat o gra p h y, or 
perc uta n e o us tra ns he p atic  c h ola n gi o gra m) or if s mall d uct P S C, c o nfir me d b y t y pical 
hist ol o gic e vi de nce of P S C f or ≥1 year (E A S L 2 0 0 9 , C ha p ma n 2 0 1 0 )  
1 3.  If c urre ntl y ta ki n g U D C A, m ust be o n a sta ble d ose of n ot m ore t ha n 2 3 m g/ k g/ da y f or 
≥1 2 wee ks. If n ot c urr e ntl y ta ki n g U D C A, m ust n ot be treate d wit h U D C A wit hi n 
1 2 wee ks  bef ore Scree ni n g or pla n t o be treate d wit h U D C A d uri n g t he st u d y 
8. 2.  
S u bject E xcl usi o n Criteri a  
All s u bjects meeti n g a n y of t he f oll o wi n g criteri a will be e xcl u de d fr o m t his st u d y: 
1.  Pr urit us is attri b ute d mai nl y t o a n y disease u nrel ate d t o P B C or P S C  
2.  Pri or li ver tra ns pla nt or prese ntl y liste d f or tra ns pl a ntati o n  
3.  Is recei vi n g o n g oi n g ultra vi olet B ( U V B ) treat me nt or plas ma p heresis  or a ntici pates 
recei vi n g s uc h tr eat ments d uri n g t he st u d y 
4.  E vi de nce of c o m pe nsate d or dec o m pe ns ate d cirr h osis base d o n A N Y of t h e f oll o wi n g: 
a. Hist orical li ver bi o ps y de m o nstrati n g cirr h osis 
b.  Li ver stiff ness as assesse d b y a Fi br o Sca n ®  sc ore of ≥1 6. 9 k Pa f or s u bjects wit h 
P B C or ≥1 4. 4 k Pa f or s u b jects wit h P S C wit hi n 6 m o nt hs of Scree ni n g 
c. Hist or y or prese n ce of p ortal h y perte nsi o n wit h c o m plicati o ns, i ncl u di n g k n o w n 
gastric or es o p h a geal v arices, ascites, s p o nta n e o us bact erial p erit o nit is, he patic 
e nce p h al o pat h y, hist or y of variceal blee ds, or relate d t hera pe utic or pr o p h ylactic 
i nter ve nti o ns (e g, n o n-sel ecti ve beta bl oc k ers bei n g use d t o pre ve nt c o m pli cati o ns 
of p ortal h y perte nsi o n [ pr o pra n ol ol, na d ol ol, or car ve dil ol], i nserti o n of var iceal 
ba n ds, tra nsj u g ular i ntra h e patic p ort os yste mic s h u nt, or direct i ntra he p atic 
p ort oca val s h u nt) 
5.  Hist or y of mali g na nc y of a n y or ga n s yste m, i ncl u di n g b ut n ot li mite d t o he pat ocell ular 
carci n o ma, c h ola n gi ocar ci n o ma, a n d gall bla d der carci n o ma, treate d or u ntreate d, wit hi n 
t he past 5 years (l ocalize d s q ua m o us cell or basal cell carci n o ma of t he s ki n t hat ha ve 
bee n e x cise d or r es ol ve d is n ot e xcl usi o nar y)  
6.  Alter nate ca uses of li ver diseases s uc h as h e patic s arc oi d osis, alc o h olic li ver disease, 
hist ol o g y c o nfir me d a ut oi m m u ne he patitis , o verla p he patitis, or n o nalc o h olic 
steat o he patitis ( N A S H), or u nc o ntr olle d viral he p atitis  as defi ne d i n Secti o n  1 2. 9  
7.  Prese nce of d oc u me nte d sec o n dar y s cler osi n g c h ola n gitis (e g, isc h e mic c h ola n gitis, 
rec urre nt pa n creatitis, i ntra d uctal st o ne disease, se vere bacteri al c h ola n gitis, s ur gical or 
bl u nt a b d o mi nal tra u ma, rec urre nt p y o ge nic c h ola n gitis, c h ole d oc h olit hiasis, t o xic 
scler osi n g c h ola n gitis d ue t o c he mical a g e nts, or a n y ot her ca us e of sec o n d ar y scler osi n g 
c h ola n gitis) o n pri or cli nical i n vesti gati o ns 

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8.  I m m u n o gl o b uli n G 4 (I g G 4) > 4 × u p p er li mit of n or mal ( U L N) at Scree ni n g or e vi de nce 
of s yste mic I g G 4-r elate d disease 
9.  C urre nt e vi de nce of cli nicall y si g nifica nt hi g h - gra de strict ures or prese n ce of biliar y ste nt 
at Scree ni n g  
1 0.  Hist or y of rec urre nt b act erial c h ola n gitis or rece nt e pis o de wit hi n 3 m o nt hs bef ore 
Scree ni n g  
1 1.  E n d osc o pic i nter ve nti o ns wit h t hera pe utic i nte nt s uc h as biliar y d uct dilati o n wit hi n 
3 m o nt hs bef ore Scr ee ni n g or pla n ne d d uri n g t he st u d y 
1 2.  Hist or y of si g nifica nt s mall b o wel resecti o n or s h ort b o wel s y n dr o me 
1 3.  Prese nce of  a c o n c o mita nt  disease or a hist or y of a n y me dical c o n diti o n t hat, i n t he 
o pi ni o n of t he I n v esti gat or, c o ul d p ose u n d ue ris k t o t he s u bject, i m pe de c o m pleti o n of 
t he st u d y pr oce d ur es, or w o ul d c o m pr o mise t he v ali dit y of t he st u d y meas ure me nts 
1 4.  C li nicall y rele va nt me dical hist or y, p h ysical e xami nati o n, vital si g n, sta n dar d 1 2- lea d 
electr ocar di o gr a m ( E C G), c he mistr y, he mat ol o g y, uri nal ysis, or c oa g ulati o n res ults at 
Scree ni n g be y o n d w hat is e x pecte d f or s u bjects wit h a c h olestatic dis or der t hat w o ul d 
place t he s u bject at u n d u e ris k as dee m e d b y t he I n vesti gat or  
1 5.  Has a n y of t he f oll o wi n g la b orat or y res ults at Scree ni n g:  
a. T otal bilir u bi n > 2. 0 m g/ d L ; t otal bilir u bi n >2. 0 m g/ d L  is acce pta ble f or s u bj ects wit h 
me dicall y d oc u me nte d  Gil bert’s s y n dr o me if direct bilir u bi n is < 0. 3 m g/ d L 
b.  Ala ni ne a mi n otra nsf eras e ( A L T) or as partate a mi n otra nsferase ( A S T) > 5 × U L N  
c. A L P > 1 0 × U L N  
d.  I nter nati o nal n or malize d rati o (I N R) > 1. 3 
e. Platelet c o u nt < 1 5 0, 0 0 0/ µ L 
f. Uri ne al b u mi n t o creati ni ne rati o ≥3 0 m g/ g  
1 6.  Esti mate d gl o mer ular filtrati o n rate < 6 0 m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t he C hr o nic 
Ki d ne y Disease E pi de mi ol o g y C olla b orati o n e q uati o n at Scree ni n g 
1 7.  Hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) or p ositi ve f or H I V i nfecti o n at 
Scree ni n g  
1 8.  Si g nifica nt hist or y of a b use of dr u gs, s ol ve nts, or m o dera te al c o h ol c o ns u m pti o n 
(≥1  ser vi n g or u nit/ da y o n a vera g e f or w o me n a n d ≥2 ser vi n gs or u nits/ da y o n a vera g e 
f or me n; 1 u nit = 1 2 o u nces [ 3 5 0 m L] of 5 % alc o h ol beer, 5 o u nces [ 1 5 0 m L] of 1 2 % 
wi ne, or 1. 5 o u nces [ 4 5 m L] of 8 0  pr o of distille d s pirits) i n t he past 2  years bef ore 
Scree ni n g  
1 9.  Has recei ve d a pr o hi bite d me dicati o n wit hi n 2 wee ks or 5 half-li ves of Da y 1, w hic he ver 
is l o n ger, as descri be d i n Secti o n  8. 4. 1   
2 0.  Partici pati o n i n a n y cli nical st u d y wit h a n i n vesti gati o nal or a p pr o v e d dr u g/ de vice wit hi n 
3 0 da ys bef or e Scree ni n g or is pla n ni n g t o partici pate i n a n ot her cli nical st u d y wit h a n 
i n vesti gatio nal or a p pr o v e d dr u g/ de vice w hile  e nr olle d i n t his st u d y  
2 1.  Hist or y of k n o w n or s us p ecte d h y perse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g  

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2 2.  Fe male w h o is pre g na nt, n ursi n g, or i nte n ds t o bec o me pre g na nt d uri n g t he st u d y  
2 3.  Is dir ectl y affiliate d wit h t he st u d y at t he st u d y site or is a n i mme diate fa mil y me m ber 
(s p o use, par e nt, c hil d, or si bli n g; bi ol o gical or le gall y a d o pte d) of p ers o n nel directl y 
affiliate d wit h t he st u d y at t he st u d y site  
2 4.  Is e m pl o ye d b y Escie nt P har mace uticals, I nc., (t hat is a n e m pl o yee, te m p orar y c o ntract 
w or ker, or desi g nee res p o nsi ble f or t he c o n d uct of t he st u d y) or is a n i m me diate fa mil y 
me m ber of a n e m pl o yee of Escie nt P har mace uticals, I nc.  
2 5.  S u bject is, i n t he o pi ni o n of t he I n vesti gat or, n ot s uita ble t o partici pate i n t he st u d y  
8. 3.  
St u d y  Restricti o ns  
D uri n g partici pati o n i n t he st u d y, s u bjects m ust a d here t o t he f oll o wi n g restricti o ns fr o m 
Scree ni n g t o t he e n d of t he D o u ble- Bli n d T reat me nt Peri o d u nless s u bject safet y is 
c o m pr o mise d: 
•  D o n ot use a n y dr u gs of a b use 
•  D o n ot use a n y i n vesti gati o nal a ge nts a n d/ or de vi ces 
•  D o n ot ta ke a n y ne w pres cri be d me dicati o n, u nless d o ne s o i n c o ns ultati o n wit h t he 
Me dical M o nit or 
•  Mai ntai n c urre nt d os e a n d re gi me n of all prescri b e d me dicati o n , u nless c h a n ge d i n 
c o ns ultati o n wit h t he Me dical M o nit or 
•  D o n ot u n der g o U V B treat me nt or plas ma p he resis  
•  D o n ot c ha n ge caffei ne i nta ke ha bits  
•  D o n ot a d d or c h a n ge t he fre q ue n c y, d ose, or ti me of a d mi nistrati o n of dr u gs t hat ma y 
ca use se d ati o n  
•  If r o uti nel y ta ki n g a bile aci d se q uestra nt (e g, c h olest yra mi ne, c olesti p ol, or 
c olese vela m), h ol d t he m or ni n g d ose u ntil 2 h o urs after st u d y dr u g a d mi nistrati o n. If 
t he bile aci d se q uestr a nt baseli ne d osi n g re gi me n d oes n ot all o w f or a 2- h o ur h ol d, 
h ol d d osi n g of t hese me dicati o ns f or a mi ni m u m of 1 h o ur after st u d y dr u g 
a d mi nistrati o n. Alter nati vel y, ta ke t he bil e aci d se q u estra nt at least 4 h o urs pri or t o 
st u d y dr u g a d mi nistrati o n  
•  If ta ki n g a ntaci ds (e g, al u mi n u m h y dr o xi de, calci u m car b o nate, m a g nesi u m 
car b o nat e, s o di u m bicar b o nate), wit h h ol d d osi n g of t hese me dicati o ns at least 4 h o urs 
pri or a n d 4 h o urs after eac h st u d y dr u g a d mi nistrati o n 
8. 4.  
C o nc o mit a nt Me dic ati o ns  
S u bjects are t o f oll o w t he me dicati o n restricti o ns o utli ne d i n t he i ncl usi o n a n d e xcl usi o n criteria 
(Secti o n  8. 1  a n d Secti o n  8. 2 ) a n d s u bject restricti o ns (Secti o n 8. 3 ) d uri n g t he st u d y. D osa ges f or 
c o nc o mita nt me dicati o ns are t o r e mai n c o nsta nt d uri n g t he st u d y u nless nee de d f or s u bject safet y  
a n d i nstr ucte d ot her wis e b y t he I n vesti gat or or a treati n g p h ysicia n. 

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8. 5.  
Re m o v al of S u bjects fr o m T her a p y or Assess me nt  
If a s u bject disc o nti n ues st u d y dr u g a n d/ or is wit h dra w n fr o m t he st u d y, t he reas o n will be 
rec ord e d o n t he e C R F p a ge a n d t he S p o ns or will be n otifie d pr o m ptl y. 
8. 5. 1.  
Disc o nti n u ati o n of St u d y Dr u g  
St u d y dr u g ma y  be disc o nti n ue d i n t he f oll o wi n g i nsta nces: 
•  A E  
•  Wit h dra wal of c o nse nt 
•  L ost t o f oll o w- u p 
•  Pr ot oc ol de viati o n 

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•  I n v esti gat or decisi o n 
•  S p o ns or decisi o n 
•  Pr e g na nc y d uri n g t he st u d y ( Secti o n  1 2. 2. 4 ) 
•  Criteria met fr o m dr u g-i n d uce d li ver i nj ur y ( DI LI ) m o nit ori n g t o disc o nti n ue st u d y 
dr u g ( Secti o n  1 2. 1 3. 3 ) 
•  Ot her  
If a s u bject e x peri e nces a n A E t hat is 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 ) Gra d e 4 or hi g her, t he st u d y dr u g m ust be disc o nti n ue d. A E gra di n g f or se verit y usi n g 
C T C A E  criteria is descri be d i n  Secti o n  1 2. 1. 2 .  
S u bjects w h o ter mi nate treat me nt wit h st u d y dr u g earl y , re gar dless of t he reas o n, will  c o m plete 
t he earl y st u d y ter mi nati o n e val uati o ns as s o o n as p ossi ble after t he last d ose of st u d y dr u g, 
i deall y wit hi n 2 da ys after t he last d ose of st u d y dr u g. 
W he ne v er p ossi ble, s u bjects s h o ul d re mai n i n t he st u d y a n d c o m plete t he re mai ni n g st u d y visits 
a n d assess me n ts e v e n w h e n st u d y dr u g has bee n disc o nti n ue d. S u bjects w h o disc o nti n ue st u d y 
dr u g f or a n y reas o n a n d c o nti n ue wit h t he st u d y visits as pla n ne d t hr o u g h t he Wee k 1 2 visit 
( partici pati n g o nl y i n effi cac y a n d saf et y, b ut n ot P K  meas ures) will  partici pate i n the Safet y 
F oll o w- U p Visit if t he last d ose of st u d y dr u g was a d mi nistere d less t ha n 2 wee ks bef ore t he 
Wee k 1 2 visit t o e ns ure t hat at least 2 wee ks of f oll o w- u p data are c ollecte d f or all ra n d o mize d 
s u bjects.  
If a s u bject disc o nti n ues st u d y dr u g a n d c h o oses n ot t o c o m plete all of t he re mai ni n g st u d y visits, 
t he s u bject will ha ve a F oll o w- U p Visit a p pr o xi matel y 2 wee ks ( ± 3 da y s) after t he last d ose of 
st u d y dr u g if at least 2 w ee ks of f oll o w- u p d ata ha ve n ot alrea d y b ee n c ollecte d. If a s u bject fails 
t o atte n d t he f oll o w- u p visit a n d has n ot wit h dra w n c o nse nt, all reas o na ble eff orts will be ma d e 
t o c o ntact t he s u bject t o e ns ure t hat he/s he is i n satisfact or y healt h. All c o ntacts a n d c o ntact 
atte m pts m ust be d oc u me nte d i n t he s u bject’s me dical rec or d.  
8. 5. 2.  
Disc o n ti n u ati o n fr o m t he St u d y 
S u bjects ma y disc o nti n ue fr o m t he st u d y at a n y ti me f or a n y of t h e f oll o wi n g reas o ns: 
•  Deat h  
•  Wit h dra wal of c o nse nt  
•  L ost t o f oll o w- u p 
•  Ter mi nati o n of t he st u d y b y t he S p o ns or or at t he re q uest of a re g ulat or y a g e nc y or a n 
I R B or I E C 
•  Ot her  
A s u bject 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 t heir f ut ure me dical care b y t he p h ysi cia n or at t he i nstit uti o n. If a s u bject wit h dra ws 
c o nse nt, n o f urt her e val u ati o n s h o ul d be perf or m e d, a n d n o a d diti o nal data s h o ul d be c ollecte d. 
T he S p o ns or ma y retai n a n d c o nti n ue t o use a n y d ata c ollecte d b ef ore s uc h wit h dra wal of 

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c o nse nt. T he I n v esti gat or s h o ul d ma ke a reas o na bl e atte m pt t o d oc u me nt t he s pecific reas o n w h y 
c o nse nt was wit h dr a w n.  
8. 5. 3.  
S afet y Crit eri a f o r S t u d y Dr u g I nterr u pti o n 
St u d y dr u g d osi n g will be i nterr u pte d f or all s u bjects if 3 s u bjects de vel o p A E s meeti n g C T C A E 
G ra de 3 or hi g her t hat ar e c o nsi der e d relat e d t o st u d y dr u g b y t he I n vesti gat or a n d/ or S p o ns or. 
A E gra di n g f or s e veri t y usi n g C T C A E criteria is descri be d i n Secti o n  1 2. 1. 2 . All e ve nts wit h a 
C T C A E Gra de of 3 or hi g her will be re vi e we d b y t he D ata M o nit ori n g C o m mittee ( D M C) 
(Secti o n  1 2. 3 ) t o i n de pe n de ntl y deter mi ne e v e nt relate d ness a n d pr o vi de rec o m me n dati o ns t o t he 
S p o ns or. 
9.  
T R E A T M E N T O F S U B J E C T S  
9. 1.  
Tre at me nt Assi g n me nt  
F or t he D o u bl e- Bli n d Treat me nt Peri o d, eli gi ble s u bjects will be ce ntrall y assi g ne d t o 
ra n d o mize d st u d y dr u g ( 1 0 0 m g d oses of E P 5 4 7 or place b o i n a 1: 1 rati o) usi n g a n I W R S a n d 
stratifie d base d o n t y pe of c h olestatic diseas e ( P B C, P S C). D uri n g t he O pe n- La bel E xte nsi o n 
Peri o d, all eli gi ble s u bjects will recei ve 1 0 0 m g d oses of E P 5 4 7 ( n o ra n d o mizati o n). E P - 5 4 7- 2 0 1 
treat me nt assi g n me nts b y st u d y peri o d are prese nt e d i n Ta ble  4. 
T a ble 4: 
E P - 5 4 7- 2 0 1 Tre at m e nt Assi g n me nts  
St u d y Peri o d  
St u d y D a ys  
A p pr o x. N o. 
of S u bj ects 
Tre at me nt 
Desi g n ati o n 
St u d y Dr u g D ose Re gi me n  
Scree ni n g  
Da y - 2 8 t o 
Da y  - 1 
5 8 
N ot 
a p plica ble 
N o ne 
6- Wee k, 
D o u ble -Bli n d 
Tre at me nt  
Da y 1 t o Da y 4 2 
 
2 9 
100 mg E P547  
O ne  2 5 m g E P 5 4 7 ta blet a n d  
O ne  75 m g E P 5 4 7 ta blet P O Q D  
2 9 
Place b o  
T w o place b o ta blets P O Q D  
6- Wee k, 
O pe n -L a bel 
E xte nsi o n 
Da y 4 3 t o Da y 8 5 
5 8 
100 mg E P547  
O ne 2 5 m g E P 5 4 7 ta blet a n d  
O ne 7 5 m g E P 5 4 7 ta blet P O Q D  
2- Wee k S afet y 
F oll o w -U p  
2 wee ks after last 
st u d y dr u g d ose 
5 8 
N ot 
a p plica bl e 
N o ne 
P O = oral; Q D = o nce dail y.  
Sites will re q uest t he all ocate d r a n d o mizati o n a n d kit n u m bers i n a d va nce of d osi n g via I W R S .  
9. 2.  
Tre at me nt C o m pli a nce  
T he I n vesti gat or s h o ul d assess t he s u bject’s c o m plia nce wit h d osi n g of st u d y dr u g b y c o u nti n g 
ret ur ne d st u d y dr u g ta bl ets a n d re vie wi n g t he s u bj ect’s d osi n g rec or ds as i n dicate d i n t he 
Sc he d ule of Assess me nts (A p pe n di x A ).  

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If t he I n vesti gat or h as c o ncer ns a b o ut a s u bject’s d osi n g c o m plia nce, t he I n vesti gat or s h o ul d 
disc uss t his wit h t he s u bject, assess t h e reas o ns f or n o nc o m plia nce a n d t he li keli h o o d t hat t he 
s u bject will re mai n n o nc o m plia nt, a n d n otif y t he S p o ns or acc or di n gl y. 
9. 3.  
R a n d o miz ati o n a n d Bli n di n g  
9. 3. 1.  
R a n d o miz ati o n 
All s u bjects w h o meet eli gi bilit y re q uire me nts  will be e nr olle d i nt o t he st u d y a n d ra n d o mize d t o 
recei v e d o u ble- bli n d, P O, Q D d oses of E P 5 4 7 or place b o f or 6 wee ks be gi n ni n g at Visit 2 
( Da y 1). S u bjects will be ra n d o mize d t o recei ve eit her 1 0 0 m g d oses of E P 5 4 7 or place b o i n a 
1: 1 rati o. Ra n d o mizati o n will be c o n d ucte d ce ntrall y via I W R S a n d stratifie d base d o n t y pe of 
c h olestatic disease  ( P B C, P S C). 
All s u bjects w h o c o m plete t he D o u ble- Bli n d Treat me nt Peri o d a n d are still recei vi n g st u d y dr u g 
will recei ve o p e n -la bel 1 0 0 m g d oses of E P 5 4 7 d uri n g t he O pe n- L a bel E xte nsi o n Peri o d. 
9. 3. 2.  
Bli n di n g  
T he S p o ns or, Me dical M o nit or, C o ntract Researc h Or ga nizati o n ( C R O) st aff, I n v esti gat ors, site 
staff, a n d s u bjects will  be bli n de d t o s u bject’s assi g ne d treat me nt d uri n g t he D o u ble- Bli n d 
T reat me nt Peri o d of t h e st u d y u ntil t he data base is l oc ke d e xce pt f or C R O or ve n d or staff 
i n v ol ve d i n t he a nal ysis of P K sa m ples or safet y re p orti n g t o re g ulat or y a ge ncies . 
T o a d dress b usi ness nee ds, a li mite d n u m ber of st u d y tea m me m bers a n d s e ni or sta ke h ol ders 
c o m prisi n g t he i nter nal Data  Re vie w T ea m ( D RT) ma y c o n d uct a n d re vi e w a n i nteri m a n al ysis 
of u n bli n de d data fr o m t h e D o u ble- Bli n d Treat me nt Peri o d  (Secti o n  1 4. 1 3 ). T he rest of t he 
ce ntral st u d y a n d pr oj ect tea m me m bers will re mai n bli n de d. 
T reat me nt wit h 1 0 0 m g d oses of E P 5 4 7 d uri n g t he O pe n - La b el E xte nsi o n Peri o d will be 
c o n d ucte d i n a n u n bli n de d ma n n er.  
9. 3. 2. 1.  
E m er ge nc y U n bli n di n g  
If a n e m er ge n c y u n bli n di n g d uri n g t he D o u ble- Bli n d Treat me nt Peri o d is re q uire d, t he s u bject’s 
treat me nt assi g n me nt may be u n bli n de d t hr o u g h I W R S b y t he I n v esti gat or . If a treat me nt 
assi g n me nt is u n bli n de d, t he s u bject will be disc o nti n ue d fr o m ra n d o mize d treat me nt.  
Bli n di n g c o des s h o ul d o nl y be br o ke n i n e mer ge nc y sit uati o ns f or reas o ns of s u bject safet y a n d 
w he n k n o wle d ge of t he tr eat me nt assi g n me nt will i m pact t he cli nical ma na ge me nt of t he s u bject . 
E ver y reas o na ble atte m pt s h o ul d be ma de t o c o m plete t he p ost- treat me nt e v al uati o n pr oce d ures 
pri or t o u n bli n di n g as k n o wle d ge of t he treat me nt ar m c o ul d i nfl ue nce s u bject as sess me nt.  
I n all e mer g e nc y cases, t he reas o ns a n d rati o nal e f or u n bli n di n g will be d oc u me nte d i n writi n g 
a n d mai ntai ne d i n t he st u d y file. 
9. 3. 2. 2.  
U n bli n di n g f or Re g ul at or y Re p orti n g 
Access t o r a n d o mizati o n c o des a n d c orres p o n di n g treat me nt assi g n me nt will als o b e ma de 
a vaila ble t hr o u g h t he I W R S s yste m t o t he a p pr o priate i n di vi d ual(s) res p o nsi ble f or u n bli n di n g 
s us pecte d u ne x p ecte d seri o us a d verse reacti o ns f or re p orti n g t o t he Re g ulat or y A uth orities.  

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9. 4.  
St u d y Visits  
S u bjects s h o ul d fast f or at least 8 h o urs bef ore eac h d ose of st u d y dr u g a n d bef ore st u d y visits 
t hat re q uire a bl o o d sa m ple f or assess me nt of c he mistr y, P K  ( pre d ose), or c o m pleti o n of 
q uesti o n naires. T he d ate, ti me, a n d t y pe of a n y s n ac k or meal pr o vi de d at t he site will be 
rec or d e d. Water is acce pt a ble i n t he m or ni n g of st u d y visits t o e ns ure t he s u bject is h y drate d f or 
la b orat or y sa m ple c ollecti o n. 
Q u esti o n naires t o be c o m plete d at t he site s h o ul d be a d mi nistere d i n a q uiet, pri vate place at t he 
st u d y site bef ore all ot her sc he d ule d pr o ce d ures. 
F or t he h y bri d m o del, Visits 1, 2, 6, a n d 8 ( Scree ni n g, Da y 1, Wee k 6, a n d Wee k 1 2)  a n d earl y 
ter mi nati o n (if a p plica ble) m ust be c o m plete d at t h e st u d y site. All ot her st u d y visits ma y be 
c o n d ucte d r e m otel y, w here all o we d p er re g ulat or y/l ocal re q uire me nts. F or t h e dece ntralize d 
m o del, all visits will be c o n d ucte d re m otel y.  
F or r e m ote visits f or b ot h t he h y bri d a n d dece ntrali ze d m o dels, t he h o me healt h n urse visit at t he 
s u bject’s h o me or w or k  a n d t he tele me dici ne visit wit h t he st u d y site staff f or a gi ve n st u d y visit 
ma y be c o n d uct e d o n diff ere nt da ys b ut m ust be wit hi n t he all o wa ble visit wi n d o w. T he h o me 
healt h n urse will c o m plet e t he st u d y assess me nts t hat t he site is p h ysicall y u na ble t o c o m plete 
re m otel y (e g, bl o o d a n d l a b sa m ple c ollecti o n, vital si g ns, E C Gs) ; t he site will c o m plete all ot her 
st u d y assess me nts re m otel y d uri n g t he tele me dici ne visit. A d diti o nal i nf or mati o n  f or c o n d ucti n g 
re m ote visits will be pr o vi de d i n st u d y- s pecific ma n ual(s).  
St u d y pr oce d ures are liste d f or eac h visit i n t he f oll o wi n g secti o ns a n d s u m marize d i n t he 
Sc he d ule of Assess me nts  (A p pe n di x A ). Furt her d etails re g ar di n g efficac y a n d P D , safet y, a n d 
P K  assess me nts  are l ocat e d i n Secti o ns  1 1 , 1 2 , a n d 1 3 , res pecti vel y.  
9. 4. 1.  
Scree ni n g Peri o d  
9. 4. 1. 1.  
Visit 1 ( D a y - 2 8 t o D a y - 1) 
D uri n g t he Scree ni n g Peri o d, s u bjects will u n der g o assess me nts t o deter mi ne t heir st u d y 
eli gi bilit y. S u bjects will be scree ne d a n d s h o ul d meet all i ncl usi o n criteria a n d n o ne of t he 
e xcl usi o n criteria t o b e e nr olle d i n t he st u d y. A n y q uesti o ns re gar di n g el i gi bilit y ma y be 
disc usse d wit h t he Me dical M o nit or.  
T he f oll o wi n g assess me nts ma y be c o n d ucte d o v er m ore t ha n 1 da y b ut m ust be c o m plete d 
bet wee n D a y - 2 8 a n d Da y - 1: 
•  C o m pleti o n of i nf or me d c o nse nt bef ore perf or ma nce of a n y st u d y pr oce d ures or 
assess me nts  
•  Me dical hist or y  
•  Hei g ht  
•  Assess me nt of baseli ne c o nc o mita nt me dicati o ns, i ncl u di n g:  
− All me dicati o ns  ta ke n wit hi n 1 4 da ys bef ore Scree ni n g  
− Me dicati o ns ta ke n t o treat a c h olestatic dis or der wit hi n 1 2 wee k s bef ore 
Scree ni n g  

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− Me dicati o ns k n o w n t o i m pact pr urit us wit hi n 4 wee ks bef ore Scree ni n g  
•  Assess me nt  of A E s  
•  Partial Ma y o Sc ore (f or s u bjects wit h U C o nl y) 
•  C D AI (f or s u bjects wit h C D o nl y) 
•  P h ysical e xa m i nati o n 
•  Vital si g ns  
•  Sta n dar d 1 2- lea d E C G 
•  Tra nsie nt ela st o gr a p h y ( T E; Fi br o Sca n; if a n eli gi ble hist orical T E is n ot a vaila ble 
wit hi n 6 m o nt hs of Scree ni n g ) 
•  La b orat or y assess me nts :  
− Uri nal ysis  
− HI V, he p atiti s A vir us ( H A V), he p atitis B vir us ( H B V ), he patitis C vir us ( H C V ), 
a n d he patitis E vir us ( H E V) ser ol o g y 
− Ser u m pre g na n c y test (fe males o nl y) 
− C he mistr y  a n d he mat ol o g y  
− C oa g ulati o n 
− I g G 4 
•  Eli gi bilit y c hec k  
•  Recei ve  q uesti o n nair e trai ni n g (t o be c o n d ucte d bef ore  c o m pleti n g t he d ail y WI -N R S 
f or Da y - 1 4) 
S u bjects will be i nstr ucte d t o c o m plete  t he WI -N R S dail y , i n t he m or ni n g, a n d at t he sa me ti me 
of da y, be gi n ni n g at Da y - 1 4 t o t he Safet y F oll o w- U p Visit.  F or da ys t hat c oi nci de wit h a st u d y 
visit (f or Visit 2 a n d be y o n d), t he WI-N R S is t o be c o m plete d bef ore t he st u d y visit.  
Scree ni n g  res ults will be re vie we d b y t h e I n vesti g at or t o deter mi ne t he s u bj ect’s eli gi bilit y. 
S u bjects w h o are c o nfir me d t o be eli gi ble will be as ke d t o ret ur n t o t he sit e f or Visit 2 ( Da y 1) 
f or e nr oll me nt a n d ra n d o mizati o n.  
9. 4. 2.  
D o u ble -Bli n d Tre at m e nt Peri o d  
9. 4. 2. 1.  
Visit 2 ( D a y 1)  
S u bjects w h o c o nti n ue t o meet st u d y eli gi bilit y re q uire me nts will be e nr oll e d a n d ra n d o mize d 
d uri n g Visit 2 ( Da y 1).  
S u bjects will u n der g o t he f oll o wi n g pr oce d ures at Visit 2 ( Da y 1): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Da y - 1 4 t o t he m or ni n g 
pri or t o t his visit  

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•  Q uesti o n naires: 
− 5- D Itc h Scal e  
− P GI - S 
 
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Vital si g ns  
•  Sta n dar d 1 2- lea d E C G 
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y) 
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y  a n d he mat ol o g y 
− C oa g ulati o n 
− Bile aci ds  a n d he me met a b olites  
− Retai ne d sa m ples f or f ut ure a nal ysis ( bl o o d a n d uri ne)  
− Ge n ot y pi n g ( o pti o nal) 
− T h yr oi d h or m o nes: t h yr oi d-sti m ulati n g h or m o ne ( T S H) a n d free t h yr o xi ne (T 4 ) 
•  Bl o o d sa m ple dra w f or P K assess me nt pre d os e a n d 
 
p ost d ose 
•  Eli gi bilit y c hec k  
•  Ra n d o mizati o n t o 1 0 0 m g E P 4 5 7 or place b o i n a 1: 1 rati o via I W R S  
•  Dis pe nse d o u ble- bli n d st u d y dr u g  
F or t he d ece ntr alize d m o del , e nr oll me nt/ra n d o mizati o n a n d t he first d ose of st u d y dr u g ma y be 
se parat e d b y u p t o 1 0 a d diti o nal cale n dar d a ys t o all o w f or h o me deli ver y of st u d y dr u g. If 
e nr oll me nt/ra n d o mizati o n is  c o n d ucted o n a se p arate da y  t ha n d osi n g, t he eli gi bilit y c hec k 
s h o ul d als o be c o n d ucte d d uri n g t he sa me da y as e nr oll me nt/ra n d o mizati o n. A d diti o nall y, 
c o nfir mati o n t hat WI - N R S has bee n c o m plete d d ail y a n d assess me nts of c o n c o mita nt me dicati o n 
usa ge a n d A E s are t o b e c o n d ucte d o n b ot h da ys ( ie, date of e nr oll me nt/ra n d o mizati o n  a n d date 
of first d ose) . All ot her assess me nts liste d a b o ve are t o be c o n d u cte d o n t he date of first d ose 
o nl y. 

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U p o n c o m pleti o n of t he assess me nts liste d a b o ve, d o u ble- bli n d st u d y dr u g is t o b e a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.   
9. 4. 2. 2.  
Visit 3 ( Wee k 1 )  
T he f oll o wi n g assess me nts will be perf or me d d uri n g Visit 3 ( Wee k 1) : 
•  C o nfir m t hat t he WI -N R S  has bee n c o m plete d d ail y fr o m Visit 2 ( Da y 1) t o t he 
m or ni n g pri or t o t his visit  
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt  of A Es 
•  Vital si g ns  
•  La b orat or y assess me nts :  
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y  
− C oa g ulati o n 
•  Bl o o d sa m ple dra w f or P K assess me nt pre d os e  
U p o n c o m pleti o n of t he assess me nts liste d a b o ve, d o u ble- bli n d st u d y dr u g is t o be a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.  
9. 4. 2. 3.  
Visit 4 ( Wee k 2 )  
T he f oll o wi n g assess me nts will be perf or me d d uri n g Visit 4 ( Wee k 2): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Visit 3 ( Wee k 1) t o t he 
m or ni n g pri or t o t his vis it  
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt  of A Es 
•  Vital si g ns 
•  La b orat or y assess me nts :  
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y  
− C oa g ulati o n 
•  Bl o o d sa m ple dra w f or P K assess me nt pre d os e  
U p o n c o m pleti o n of t he assess me nts liste d a b o ve, d o u ble- bli n d st u d y dr u g is t o be a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.  

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9. 4. 2. 4.  
Visit 5 ( Wee k 3 ) 
S u bjects will u n der g o t he f oll o wi n g assess me nt s at Visit 5 ( Wee k 3): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Visit 4 ( Wee k 2) t o t he 
m or ni n g pri or t o t his visit  
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Vital si g ns  
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y) 
− Ur i nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n 
− Retai ne d sa m ples f or f ut ure a nal ysis  ( bl o o d a n d uri ne) 
•  Bl o o d sa m ple dra w f or P K assess me nt pre d os e a n d 
 
p ost d ose 
•  C ollect st u d y dr u g kits  a n d assess st u d y dr u g acc o u nta bilit y a n d c o m plia nce 
•  Dis pe nse d o u ble- bli n d st u d y dr u g  
U p o n c o m pleti o n of t he assess me nts liste d a b o ve, d o u ble- bli n d st u d y dr u g is t o be a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.  
9. 4. 2. 5.  
Visit 6 ( Wee k 6 )  
S u bjects will u n der g o t he f oll o wi n g assess me nt s at Visit 6 ( Wee k 6 ): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Visit 5 ( Wee k 3) t o t he 
m or ni n g pri or t o t his visit  
•  Q uesti o n naires: 
− 5- D Itc h Scal e  
− P GI - C 
− P GI - S 
•  Asses s me nt of c o nc o mita nt medicati o n usa ge  

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•  Assess me nt of A E s  
•  Partial Ma y o Sc ore (f or s u bjects wit h U C o nl y) 
•  C D AI (f or s u bjects wit h C D o nl y) 
•  Vital si g ns  
•  Sta n dar d 1 2- lea d E C G 
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y) 
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n 
− Bile aci ds  a n d he me met a b olites  
− Retai ne d sa m ples f or f ut ure a nal ysis  ( bl o o d a n d uri ne) 
− T h y r oi d h or m o nes: T S H a n d free T 4 
•  Bl o o d sa m ple dra w f or P K assess me nt pre d os e  
•  C ollect st u d y dr u g kits  a n d assess st u d y dr u g acc o u nta bilit y a n d c o m plia nce 
•  Dis pe nse o pe n- l a bel st u d y dr u g  
U p o n c o m pleti o n of t he assess me nts liste d a b o ve, o pe n- la bel st u d y dr u g is t o be a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.  
9. 4. 3.  
O pe n - L a bel E xte nsi o n 
9. 4. 3. 1.  
Visit 7 ( Wee k 9 )  
S u bjects will u n der g o t he f oll o wi n g assess me nts at Visit 7 ( Wee k 9 ): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Visit 6 ( Wee k 6) t o t he 
m or ni n g pri or t o t his visit  
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Vital si g ns  
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y)  
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 

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− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n 
− Retai ne d sa m ples f or f ut ure a nal ysis  ( bl o o d a n d uri ne) 
•  C ollect st u d y dr u g kits a n d assess st u d y dr u g acc o u nta bilit y a n d c o m plia nce 
•  Dis pe nse o pe n- l a bel st u d y dr u g  
U p o n c o m pleti o n of t he assess me nts liste d a b o ve, o pe n- la bel st u d y dr u g is t o be a d mi nistere d 
orall y as i ntact ta blets  (s wall o we d w h ole, n ot c h e we d or cr us he d), a n d ta k e n wit h water.   
9. 4. 3. 2.  
Visit 8 ( Wee k 1 2 ) 
S u bjects will u n der g o t he f oll o wi n g assess me nts at Visit 8 ( Wee k 1 2 ): 
•  C o nfir m t hat t he WI - N R S has bee n c o m plete d d ail y fr o m Visit 7 ( Wee k 9) t o t he 
m or ni n g pri or t o t his visit  
•  Q uesti o n naires: 
− 5- D Itc h Scal e  
− P GI - C 
− P GI - S 
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Partial Ma y o Sc ore (f or s u bjects wit h U C o nl y) 
•  C D AI (f or s u bjects wit h C D o nl y) 
•  P h ysical e xa mi nati o n  
•  Vital si g ns  
•  Sta n dar d 1 2- lea d E C G 
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y ) 
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n 
− Retai ne d sa m ples f or f ut ure a nal ysis  ( bl o o d a n d uri ne) 

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− T h yr oi d h or m o nes: T S H a n d free T 4 
•  C ollect st u d y dr u g kits a n d assess st u d y dr u g acc o u nta bilit y a n d c o m plia nce  
9. 4. 4.  
S afet y F oll o w- U p Peri o d  
9. 4. 4. 1.  
S afet y F oll o w- U p Visit  ( Visit 9) 
S u bjects will u n der g o t he f oll o wi n g assess me nts at t he Safet y F oll o w -U p Visit, a p pr o xi matel y 
2 wee ks after t he last d os e of st u d y dr u g: 
•  C o nfir m t hat t he WI -N R S has bee n c o m plete d d ail y fr o m t he last visit t o t he m or ni n g 
pri or t o t his visit  
•  Q uesti o n naires: 
•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Vital si g ns  
•  Sta n d ar d 1 2-lea d E C G  
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y) 
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n 
9. 4. 5.  
E arl y St u d y Ter mi n ati o n Visit  
S u bjects w h o disc o nti n ue fr o m t he st u d y earl y s h o ul d ha ve t he Ea rl y St u d y Ter mi nati o n Visit 
c o n d ucte d as s o o n as p ossi ble after t he last d ose of st u d y dr u g, i deall y wit hi n 2 da ys after t he l ast 
d ose of st u d y dr u g. S u bjects will u n der g o t he f oll o wi n g assess me nts d uri n g t he Earl y St u d y 
Ter mi nati o n Visit:  
•  C o nfir m t hat t he  WI -N R S ha s bee n c o m plete d d ail y fr o m t he pre vi o us visit t o t he 
m or ni n g pri or t o t his visit  
•  Q uesti o n naires: 

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•  Assess me nt of c o nc o mita nt me dicati o n usa ge  
•  Assess me nt of A E s  
•  Partial Ma y o Sc or e (f or s u bjects wit h U C o nl y) 
•  C D AI (f or s u bjects wit h C D o nl y) 
•  P h ysical e xa mi nati o n  
•  Vital si g ns  
•  Sta n dar d 1 2- lea d E C G 
•  La b orat or y assess me nts :  
− Uri ne pre g n a nc y test (fe males o nl y) 
− Uri nal ysis  
− Ki d ne y- rel ate d bi o mar kers ( bl o o d a n d uri ne) 
− C he mistr y a n d he mat ol o g y 
− C oa g ulati o n  
− T h yr oi d h or m o nes: T S H a n d free T 4 
•  C ollect st u d y dr u g kits  a n d assess st u d y dr u g acc o u nta bilit y a n d c o m plia nce 
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
1 0. 1.  
St u d y Dr u g s 
F or t he D o u bl e- Bli n d Treat me nt Peri o d, ta blets c o ntai n i n g 2 5 m g or 7 5 m g of E P 5 4 7 or p lace b o 
will be s u p plie d i n a wa y t o e ns ure t he st u d y bli n d. F or t he O p e n- L a bel E xt e nsi o n Peri o d, ta blets 
c o ntai ni n g 2 5 m g or 7 5 m g  of E P 5 4 7 will be s u p plie d . S u bjects recei vi n g E P 5 4 7 will ta ke o ne 
2 5- m g a n d o ne 7 5- m g E P 5 4 7 ta blet per d ose (f or a t otal d ose of 1 0 0 m g) a n d s u bjects recei vi n g 
place b o will ta ke 2 place b o ta blets per d ose.  
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
F or t he D o u bl e- Bli n d Treat me nt Peri o d, st u d y dr u g kits eac h c o ntai ni n g 2 ta blets per d ose a n d 
pac ka g e d i nt o blister car d/ wallets will be l a bele d wit h a u ni q ue n u m ber a n d will be s u p plie d t o 
st u d y sites i n a bli n de d ma n ner.  
St u d y dr u g kits  f or t he O pe n-La b el E xte nsi o n Peri o d will be pac ka g e d a n d la bele d si milarl y as 
t h ose f or t he D o u ble-Bli n d Treat me nt Peri o d b ut will be s u p plie d t o t he site s i n a n u n bli n de d 
ma n ner.  

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1 0. 3.  
St u d y Dr u g St or a ge  
T he st u d y dr u g ta blets s h o ul d be st ore d at c o ntr oll e d r o o m te m perat ure, 2 0° C t o 2 5° C ( 6 8° F t o 
7 7° F), wit h e x c ursi o ns all o we d bet wee n 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F). 
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
Eac h st u d y dr u g d ose, c o ntai ni n g 2 ta blets, is t o be a d mi nistere d orall y as i ntact ta blets 
(s wall o we d w h ole, n ot c he we d or cr us he d), a n d t a ke n wit h water. D oses are t o be a d mi nistere d 
dail y at a p pr o xi matel y t h e sa me ti me of da y after a fast of at least 8 h o urs.  
1 0. 4. 1.  
I nstr ucti o ns f or Misse d D ose(s)  
S u bjects s h o ul d be i nstr ucte d t hat if t he y f or g et t o ta ke a d ose, t he y ca n ta k e t he d ose wit hi n 
8 h o urs of t he n or mal d osi n g ti me; ot her wise, t he y s h o ul d ta ke t heir ne xt d ose at t he re g ul ar ti me 
o n t he f oll o wi n g da y. If t he s u bject v o mits t he ta blet s, he/s he s h o ul d be i nstr ucte d n ot t o ta ke 
a d diti o nal ta blet s o n t he sa me da y b ut t o ta ke t he n e xt d ose at t he re g ular ti me o n t he f oll o wi n g 
da y. S u bjects s h o ul d be i nstr ucte d t o c o ntact t he I n vesti gat or if t he y miss 2 or m ore c o ns ec uti ve 
d oses.  
1 0. 5.  
St u d y Dr u g Dis pe nsi n g a n d Acc o u nt a bilit y  
S u bjects will c o m plete d osi n g rec or ds, w hic h will be re vie w e d at eac h st u d y visit b y st u d y site 
staff. 
S u bjects s h o ul d be i nstr ucte d t o retai n t he st u d y dr u g kit (i ncl u di n g blister car ds/ wallets) , e v e n if 
e m pt y, a n d t o ret ur n it a n d a n y re mai ni n g st u d y dr u g t o t he st u d y site at t heir ne xt visit or t o a 
direct -t o-patie nt c o urier s er vice. T h e st u d y site staff s h o ul d perf or m st u d y dr u g acc o u nt a bilit y 
a n d, if a p plica ble, f oll o w- u p wit h t he s u bject t o retrie ve a n y re mai nin g st u d y dr u g t hat has  n ot 
bee n ret ur ne d.  
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p os al  
St u d y dr u g will be se nt t o t he st u d y site u n der a p pr o priate st ora g e c o n diti o ns. U p o n recei pt of 
st u d y dr u g, st u d y site staff ar e t o o pe n t he s hi p me nt, a n d verif y t hat t he a m o u nt a n d i de ntit y of 
t he c o nte nts matc h t hat state d i n t he e ncl ose d s hi p pi n g f or m. T he S p o ns or ( or desi g nee) is t o be 
n otifie d i m me diatel y a b o ut a n y irr e g ularities, discre pa nci es, or da ma g e.  
All st u d y dr u g will be pr o vi de d f or use o nl y i n t his st u d y a n d is n ot t o be use d f or a n y ot h er 
p ur p ose. T he st u d y site staff will mai ntai n a f ull rec or d of st u d y dr u g acc o u nta bilit y as descri be d 
i n Secti o n  1 0. 5 .  
T o s u p p ort re m ote st u d y visits  f or t he h y bri d a n d dece ntralize d m o dels, t he use of a direct-t o-
patie nt c o urier s er vice t o tra ns p ort st u d y dr u g bet wee n t he st u d y site or ce ntral dr u g de p ot a n d 
t he s u bject’s h o me ma y b e arr a n ge d. T h e c o uri er will be as ke d t o c ollect t he st u d y dr u g kit 
dis pe nse d b y t he st u d y site staff or ce ntral dr u g de p ot a n d deli ver it t o t he s u bject’s h o me. T he 
c o urier ma y als o be as k e d t o  c ollect t he use d st u d y dr u g kit wit h a n y u n use d st u d y dr u g fr o m t he 
s u bject t o be ret ur n e d t o t he site or ce ntral dr u g de p ot f or acc o u nta bilit y a n d rec o nciliati o n. 
C hai n of c ust o d y of t he st u d y dr u g tra ns p ort will be d oc u me nte d. A d diti o nal st u d y dr u g ha n dli n g 
a n d dis p osal i nf or mati o n f or re m ote visits will be pr o vi de d i n st u d y- s pecifi c ma n ual(s). 

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Pa ge 5 8 of 1 2 8 
S u bjects will be i nstr ucte d t o c o m plete t he WI -N R S dail y , i n t he m or ni n g, a n d at t he sa me ti me 
of da y, be gi n ni n g at Da y - 1 4 t o t he F oll o w- U p Visit. F or da ys t hat c oi nci d e wit h a st u d y visit 
(f or Visit 2 a n d be y o n d), t he WI- N R S is t o be c o m plete d bef ore t he visit.  
T he WI -N R S sc ores fr o m Da y - 7 t hr o u g h Da y -1 will  be a vera g e d t o get her t o c o nfir m 
c o m plia nce a n d  d eter mi n e s u bject eli gi bilit y f or c o nti n ue d partici pati o n re gar di n g pr urit us 
se nsati o n. T he a ver a g e WI- N R S sc or e usi n g t he dail y val ues fr o m t he w ee k bef ore t he first d ose 
of st u d y dr u g ( Visit 2 [ D a y 1]) will ser v e as t he b aseli ne sc ore. T he 7 d ail y WI -N R S sc ores pri or 
t o Visit 6 ( We e k 6) will be a ver a ge d t o get h er f or pri mar y e n d p oi nt a nal yses. D ata fr o m at least 
4 of t he 7 da ys f or eac h wee k are r e q uire d t o be c o nsi dere d a n acce pta ble pr ofile.  
1 1. 1. 2.  
5- D Itc h Sc ale  
T he 5 - D Itc h S cale w as d e vel o pe d as a brief b ut m ulti di me nsi o nal q uesti o n naire desi g ne d f or 
pr urit us t hat meas ures c h a n ges o ver ti me (El ma n  2 0 1 0). T he 5 di me nsi o ns are de gree, d urati o n, 
directi o n, disa bilit y, a n d distri b uti o n. It re q uires a p pr o xi matel y 1 t o 2 mi n utes t o c o m plete, a n d 
sc ores ca n ra n g e bet w ee n 5 ( n o pr urit us) a n d 2 5 ( m ost se vere pr urit us). T he sc ores of eac h of t he 
5 d o mai ns are ac hie ve d s e parat el y a n d t he n s u m m e d t o get her t o o btai n a t otal 5- D sc ore. A n 
e xa m ple of t he 5 -D Itc h Scale is i ncl u de d i n A p pe n di x C . 
1 1. 1. 3.  
P atie nt Gl o b al I m pressi o n of Se verit y  ( P GI-S)  
T he P GI -S was vali dat e d i n w o me n wit h stress uri nar y i nc o nti ne nce, b ut ma y be use d t o rate t he 
se verit y of ot her s p ecific c o n diti o ns (Yalci n 2 0 0 3 ). F or t his q uesti o n naire, t he s pecific c o n diti o n 
t o be rate d is pr urit us. S u bjects will be as ke d t o rat e t he se verit y of t heir pr urit us i n t he past 
7 da ys usi n g a 4- p oi nt scale fr o m N o n e t o Se vere. T he P GI - S re q uires less t ha n 1 mi n ute t o 
c o m plete. A n e x a m ple of t he P GI - S is i ncl u de d i n A p pe n di x D .  
1 1. 1. 4.  
P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI-C)  
S u bjects will be as ke d t o rate t heir  i m pressi o n of o verall c ha n g e i n pr urit us i n t he past 7 da ys 
c o m pare d t o bef ore t h e y starte d ta ki n g st u d y dr u g usi n g t he P GI- C. T h e P GI -C is a 7 -p oi nt scale 
ra n gi n g fr o m M uc h I m pr o ve d t o M uc h W ors e a n d re q uires ap pr o xi matel y 1 mi n ute t o c o m plete 
(G u y 1 9 7 6 ). Hi g her sc or es i n dicate less i m pr o ve me nt i n pr urit us. A n e xa m ple of t he P GI-C is 
i ncl u de d i n A p pe n di x E . 

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1 1. 2.  
Bl o o d a n d Uri ne  S a m pli n g f or P h ar m ac o d y n a mic Assess me nts  
Bl o o d sa m pl es f or ge n ot y pi n g ( o pti o nal) a n d pr urit us- relate d bi o mar k ers ( bile aci ds a n d he me 
meta b olites)  a n d bl o o d a n d uri ne sa m ples f or f ut ure a nal ysis will be assess e d.  Sa m ples f or 
ge n ot y pi n g a n d f ut ure a n al ysis ma y be st ore d f or u p t o 1 0 years after c o m pleti o n of t he st u d y. 
1 1. 3.  
Bl o o d a n d Uri ne S a m pli n g f or A n al ysis of Ki d ne y -Rel ate d 
Bi o m ar kers  
Bl o o d will be c ollecte d f or a nal ysis of ki d ne y- relate d bi o mar kers s uc h as c ystati n- C a n d 
ne utr o p hil gelati nase- ass ociate d li p ocali n . 
Uri ne will be c ollect e d f or a nal y sis of ki d ne y-relat e d bi o mar kers s u c h as cl usteri n, c ystati n - C, 
ki d ne y i nj ur y m olec ule- 1, N- acet yl- β- D- gl uc os a mi ni dase, ne utr o p hil gelati nase-ass o ciate d 
li p ocali n, a n d oste o p o nti n.  
1 1. 4.  
Hei g ht  
Hei g ht will be meas ure d wit h n o s h oes.  
1 2.  
S A F E T Y A S S E S S M E N T S   
Safet y  e val uati o ns, i ncl u di n g A Es, c o nc o mita nt me dicati o ns, me dical hist or y, vital si g ns, 
p h ysical e xa mi nati o ns, sta n dar d 1 2-l ea d E C Gs, la b orat or y e v al uati o ns of safet y, a n d disease-
s pecific ass ess me nts ( Partial Ma y o Sc ore f or s u bjects wit h U C a n d C D AI f or s u bjects wit h C D) 
will be perf or me d as i n dicate d i n t he Sc he d ul e of Assess me nts ( A p pe n di x A ).  
F or t he d ece ntr alize d m o del, t he I n vesti gat or ma y re q uire t he s u bject t o ha v e a n i n- pers o n 
c o ns ultati o n wit h a p h ysicia n after virt uall y c o n d u cti n g safet y assess me nts, if dee me d necessar y.  

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1 2. 1.  
A d verse E ve nts  
1 2. 1. 1.  
Defi niti o n of a n A d verse E ve nt  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a s u bject a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot necess aril y ha ve a ca us al relati o ns hi p wit h t his 
treat me nt. A n A E ca n t heref or e be a n y u nfa v ora bl e or u ni nte n de d si g n (i ncl u di n g a cli nicall y 
si g nifica nt a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use 
of a  me dici nal (i n v esti gati o nal) pr o d u ct.  
Me dical c o n diti o ns prese nt at baseli ne t hat w orse n i n se verit y or fre q ue nc y after e x p os ure t o 
st u d y dr u g are c o nsi dere d treat me nt-e mer ge nt AE s ( T E A Es). Pla n ne d h os pital a d missi o ns or 
s ur gical pr oce d ures f or a n ill ness or a disease t hat e xiste d bef ore a d mi nistrati o n of st u d y dr u g, 
a n d f or w hic h t h e c o n diti o n has n ot w orse ne d si nce starti n g st u d y dr u g, are n ot t o be c o nsi dere d 
T E A Es/treat me nt -e mer g e nt seri o us A Es (S A Es ). E ve nts wit h emer ge n c y r o o m visits t hat are less 
t ha n 2 4 h o urs will als o n ot be c o nsi dere d S A Es  u nless t he y meet o ne of t h e criteri a liste d i n 
Secti o n  1 2. 2. 1 . 
Cli nicall y si g nifica nt a b n or mal la b orat or y tests, 1 2- lea d E C G ass ess me nts, or vital si g n res ults 
ma y, i n t he o pi ni o n of t he I n vesti gat or, c o nst it ute a n A E. H o w e ver, w h e ne ver p ossi ble, t he 
u n derl yi n g dia g n osis s h o ul d be liste d i n lie u of ass ociate d a b n or m al res ults . A b n or malities 
dee me d n ot cli nicall y si g nifica nt b y t he I n vesti gat or s h o ul d n ot be re p orte d as A E s. 
1 2. 1. 2.  
Deter mi ni n g Se verit y of A d verse  E ve nts  
A Es m ust be gra de d f or s e verit y (ie, i nte nsit y) usi n g C T C A E , versi o n 5. 0 (H H S 2 0 1 7 ). A 
se verit y cat e g or y of mil d, m o derate, se v ere, life-t hreate ni n g, or d eat h, as d efi ne d bel o w, m ust be 
e ntere d o n t he A E e C R F. It s h o ul d be n ote d t h at t he ter m “se v ere” use d t o gra de i nte nsit y is n ot 
s y n o n y m o us wit h t he ter m “seri o us”. T he assess me nt of  se verit y is ma de re gar dl ess of t he 
relatio ns hi p t o st u d y dr u g or of t he seri o us n ess of t he A E. W he n re p orti n g A E s, refere n ce s h o ul d 
be ma de t o t he C T C A E ma n ual f or g ui da n ce o n a p pr o priate gra di n g.  
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 ni 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  
(e g, pre p ari 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, a n d ma n a gi n g m o ne y). 
Gra de  3: 
Se vere or m e 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 life (e g, bat hi n g, dressi n g a n d 
u n dressi n g, fee di n g s elf , usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot 
be dri d de n ). 
Gra de  4: 
Life -t hreate ni n g c o nse q u e nces, ur g e nt i nter ve nti o n i n dicate d. 
Gra de  5: 
Deat h rel ate d t o A E.  

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All C T C A E Gra de 3 or hi g her m ust be re p ort e d t o t he S p o ns or or desi g nee usi n g t he 
S A E/ A E SI/ Gr a de 3 + R e p ort F or m, acc or di n g t o t he ti meli nes descri be d f or S A Es i n 
Secti o n  1 2. 2. 2 . 
1 2. 1. 3.  
Deter mi ni n g C a us alit y of A d verse E ve nts  
Ca usalit y refers t o t he rel ati o ns hi p of t he e ve nt t o t he st u d y dr u g ( E P 5 4 7 or place b o) . T h e 
I nv esti gat or will assess t he ca usalit y of t he e ve nt acc or di n g t o t he f oll o wi n g criteria:  
•  N ot rel at e d – A reacti o n f or w hic h s ufficie nt data e xist t o i n dicate t hat t he eti ol o g y is 
u nrelate d t o t he st u d y dr u g. 
•  Rel ate d  – A r eacti o n t hat f oll o ws a reas o n a ble te m p oral se q ue n ce fr o m a d mi nistrati o n of 
st u d y dr u g; t hat f oll o ws a k n o w n or e x pecte d res p o nse patter n t o t he st u d y dr u g, w hic h 
ma y or ma y n ot reas o na bl y ha ve bee n pr o d uce d b y a n u m ber of ot her fact ors i ncl u di n g 
u n derl yi n g disease, c o m plicati o ns, c o nc o mita nt dr u gs, or c o nc urre nt treat me nts; a n d/ or 
t hat c o ul d n ot be reas o n a bl y e x plai ne d b y ot her fact ors s uc h as u n derl yi n g disease, 
c o m plicati o ns, c o nc o mita nt dr u gs, or c o n c urre nt treat me nts; a n d/ or disa p p ears or 
decreases o n cessati o n or re d ucti o n i n st u d y dr u g d ose; a n d/ or rea p pears or w orse ns w he n 
t he st u d y dr u g is a d mi nistere d. 
1 2. 1. 4.  
Rec or di n g A d verse E ve nts  
All A Es m ust be rec or d e d i n t he s o urce d oc u m e nts a n d i n t he e C R Fs pr o vi de d b y t he S p o ns or 
fr o m t he si g ni n g of t he I nf or me d C o nse nt F or m (I C F) u ntil t he e n d of st u d y partici pati o n. A E s 
will be assesse d f or li keli h o o d of ca usal relati o ns hi p t o t he st u d y dr u g ( E P 5 4 7 or place b o) a n d 
se verit y.  
T he ne w o nset of si g ns, s y m pt o ms, or ot her fi n di n gs t hat occ ur bef ore  si g ni n g of t he I C F will be 
ca pt ure d as me dical hist or y ( Secti o n  1 2. 4 ).  
1 2. 1. 4. 1.  S peci al I nstr ucti o ns f or Rec or di n g A d verse E v e nts i n t he e C R F  
Di a g n osis vers us Si g ns a n d S y m pt o ms  
If a dia g n osis is k n o w n at t he ti me of re p orti n g, t his s h o ul d be rec or d e d i n t he e C R F rat her t ha n 
t he i n di vi d ual si g ns a n d s y m pt o ms (e g, rec or d o nl y he patitis rat her t ha n ele vate d tra nsa mi nas es, 
bilir u bi n, a n d ja u n dice). H o we ver, if a c o nst ellati o n of si g ns a n d/ or s y m pt o ms ca n n ot be 
me dicall y c har acterize d as a si n gle dia g n osis or s y n dr o me at t he ti me o f re p orti n g, eac h 
i n di vi d ual e ve nt s h o ul d be rec or de d as a n S A E or A E o n t he e C R F. If a dia g n osis is s u bse q ue ntl y 
esta blis he d, it s h o ul d be re p orte d as f oll o w- u p a n d s h o ul d re place t h e i n di vi d ual si g ns a n d/ or 
s y m pt o ms as t he e ve nt ter m o n t he e C R F, u nless t he si g ns/s y m pt o ms are cli nicall y si g nifica nt. 
A d verse E ve nts Occ urri n g Sec o n d ar y t o Ot her E ve nts  
I n g e ner al, AE s occ urri n g sec o n dar y t o ot her e ve nts (e g, cli nical se q uel ae or a cas ca d e of e v e nts) 
s h o ul d be i de ntifie d b y t heir pri mar y ca use. F or e x a m ple, i f severe v o miti n g is k n o w n t o res ult i n 
de h y drati o n, it is s ufficie nt t o rec or d o nl y v o miti n g as a n A E o n t he e C R F. H o we ver, me dicall y 
si g nifica nt AEs occ urri n g sec o n dar y t o a n i nitiati n g e ve nt t hat are se parate d i n ti me s h o ul d be 
rec or d e d as i n de p e n de nt eve nts o n t he e C R F. F or e xa m ple, if se v ere v o miti n g lea ds t o ac ute 
re nal f ail ure, b ot h e ve nts s h o ul d be rec or de d o n t h e e C R F. 

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relate d ness f or all A E s wit h C T C A E Gra de 3 or hi g her. T he D M C will als o meet o n a n a d h o c 
basis w he n  at least 3 A E s of C T C A E Gra de 3 or hi g her ha ve accr ue d or w h e n t here h as bee n  a 
si n gle C T C A E Gra de 4 or hi g her. Base d o n re vie w of t he data, t he D M C will pr o vi de 
rec o m me n dati o ns t o t he S p o ns or o n w het her t he n at ure, fre q ue n c y, a n d/ or s e verit y of A Es 
ass ociate d wit h st u d y dr u g  warr a nt m o dificati o n t o t he st u d y pr ot oc ol, s us pe nsi o n of d osi n g, or 
st u d y ter mi nati o n. 
1 2. 4.  
Me dic al Hist or y  
T he I n vesti gat or will c oll ect a n d r e vie w t he s u bject’s me dical hist or y t o e val uate t he s u bject’s 
eli gi bilit y f or st u d y partici pati o n. T he ne w o ns et of si g ns, s y m pt o ms, or ot her fi n di n gs t hat occ ur 
fr o m bef or e si g ni n g of t he I C F will be ca pt ure d as me dical hist or y .  
1 2. 5.  
Vit al Si g ns  
Vital si g ns , i ncl u di n g sitti n g s yst olic a n d diast olic bl o o d press ure, p ulse rate , o x y ge n sat urati o n, 
b o d y te m perat ur e, a n d r es pir at or y rate, will be meas ure d after at least 5 mi n utes of rest. Vital 
si g ns are t o be perf or me d pre d ose if t he d os e is a d mi nistere d at t he site. 
Vital si g ns als o i ncl u de b o d y wei g ht, w hic h s h o ul d be meas ure d wit h n o s h oes o n a n d usi n g a 
cali brate d s cale t hr o u g h o ut t he st u d y. 
1 2. 6.  
P h ysic al E x a mi n ati o ns  
P h ysical e xa mi nati o ns will i ncl u de , b ut are n ot li mite d t o , a n assess me nt of ge neral a p peara n ce, 
s ki n, H E E N T ( hea d, e yes, ears, n ose, t hr o at), m usc ul os keletal, t h yr oi d/e n d ocri ne, car di o vasc ul ar, 
c hest/l u n g, ne ur ol o gic, a b d o me n, a n d e xtre mities/ ge neral b o d y s yste ms. S y m pt o m directe d 
p h ysical e xa mi nati o ns t o assess cli nicall y si g nifica nt c ha n ges fr o m Scree ni n g  or a n y ne w si g ns 
or s y m pt o ms ma y be c o n d u cte d at ot her vis its as d eter mi ne d b y t he I n v esti gat or base d o n s u bject 
c o m plai nt. 
F or t he d ece ntr alize d m o del, t he I n vesti gat or, assiste d b y t he m o bile n urse, will c o n d uct p h ysical 
e xa mi nati o ns per pr ot oc ol via tele me dici ne d uri n g a vi de oc o nfere n ce sessi o n.  
1 2. 7.  
St a n d ar d  1 2 - Le a d Electr oc ar di o gr a ms  
T wel ve -lea d E C Gs ar e t o be perf or me d wit h s u bjects i n a s u pi ne p ositi o n after at least 5  mi n utes 
of rest . A n E C G is t o be perf or me d pre d os e if t he d ose is a d mi nistere d at t h e site. 
1 2. 8.  
L a b or at or y E v al u ati o ns of S afet y  
Sa m ples f or t he f ol l o wi n g la b orat or y tests will be c ollecte d after a n o v er ni g ht fast (at least 
8 h o urs): 
•  C he mistr y: s o di u m, al b u mi n, A L P, bicar b o nate, calci u m, bile aci ds, c orrecte d 
calci u m, c hl ori de, t otal a n d direct bilir u bi n, A S T, A L T, B U N, urea, creati ni ne, 
ma g nesi u m, p h os p h or us, p otassi u m, creati ne p h os p h o ki nase ( C P K), gl uc os e, t otal 
c h olester ol, tri gl yceri des, hi g h- de nsit y li p o pr otei n c h olester ol ( H D L -c), l o w- de nsit y 
li p o pr otei n c h olester ol (L D L -c), lactate d e h y dr o ge nase ( L D H), ga m ma -
gl uta m yltra nsferas e  ( G G T), a n d t otal pr otei n 

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•  He mat ol o g y: he m o gl o bi n, he mat ocrit, w hite bl o o d cell ( W B C) c o u nt wit h differe ntial 
(l y m p h oc ytes, ne utr o p hils, m o n oc ytes, e osi n o p hils, a n d bas o p hils), re d bl o o d cell 
c o u nt, pl atelet c o u nt, a n d platelet v ol u me . If a s u bj ect de vel o ps l y m p h o pe ni a, bl o o d 
l y m p h oc ytes will be teste d t o assess p o p ulati o ns of circ ulati n g T cells (i ncl u di n g 
C D 4 + a n d C D 8 + s u bt y pes), B cells, a n d nat ural killer ( N K ) cells.  
•  Uri nal ysis: le u k oc yte est erase, nitr ites, p H, pr otei n, s pecific gra vit y, gl uc ose, occ ult 
bl o o d, ket o nes, bilir u bi n, ur o bili n o ge n, al b u mi n , creati ni ne, s o di u m, c hl ori de, a n d 
p otassi u m; micr osc o pic a nal ysis is t o be perf or me d o nl y if pr otei n, le u k oc yte 
esterase, bl o o d or nitrite is p ositi v e 
•  C oa g ulati o n: acti vate d partial t hr o m b o plasti n ti me  (a P T T), I N R, a n d pr o t hr o m bi n 
ti me ( P T)  
•  Pre g na nc y testi n g: re q uir e d f or all fe males; ser u m test at Scree ni n g ( Visit 1) a n d uri ne 
test f or all ot her visits w here pre g na n c y testi n g is re q uire d 
•  T h yr oi d f u ncti o n tests: T S H a n d free T 4 
T he uri ne pr e g na nc y t est f or fe mal e s u bjects will be c o n d ucte d l o call y; all ot her pla n ne d 
la b orat or y e v al uati o ns of safet y will be c o n d u cte d at a ce ntral la b orat or y. D etails f or sa m ple 
c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt will be pr o vi de d i n t he La b orat or y Ma n ual. 
1 2. 9.  
Ot her L a b or at or y E v al u ati o n s 
Sa m ples f or t he f oll o wi n g la b orat or y tests will be c ollecte d after a n o v er ni g ht fast  (at least 
8 h o urs) :  
•  I g G 4 
•  Ser ol o g y: HI V, H A V, H B V, H C V , a n d H E V 
Per e xcl usi o n criteri o n 6 , s u bjects wit h u nc o ntr olle d viral he patitis are n ot eli gi ble t o partici pate 
i n t his st u d y. Acti ve H A V i nfecti o n is defi ne d as a p ositi ve res ult f or i m m u n o gl o b uli n M (I g M) 
a nti-H A V or H A V ri b o n ucleic aci d ( R N A). C urre nt c hr o nic H B V i nfecti o n is defi ne d as a 
p ositi ve res ult f or he patitis B s urface a nti ge n (H Bs A g ) or H B V de o x yri b o n ucleic aci d ( D N A ). 
C urre nt c hr o nic H C V i nf ecti o n is defi ne d as a p ositi ve res ult f or H C V a nti b o d y a n d H C V R N A 
at Scree ni n g. If H C V is c ure d, a ne g ati ve H C V R N A c o nfir me d wit hi n 1 year pri or t o Scree ni n g 
will be re q uire d. A cti ve H E V i nfecti o n is defi n e d as a p ositi ve res ult f or I g M a nti -H E V or H E V 
R N A.  
A ll ser ol o g y la b orat or y e val uati o ns will be c o n d ucte d at a ce ntral la b orat or y. Details f or sa m ple 
c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt will be pr o vi de d i n t he La b orat or y Ma n ual. 
1 2. 1 0.  
Tr a nsie nt El ast o gr a p h y  
Tra nsie nt elast o gr a p h y ( Fi br o Sca n T E) is a vali date d, n o ni n vasi ve tec h ni q ue use d t o assess 
he patic stiff ness  (C or p ec h ot 2 0 1 6 ) t hat will be use d t o deter mi ne s u bject eli gi bilit y base d o n 
e xcl usi o n criteri o n 4 . If an eli gi ble  hist orical T E wit hi n 6 m o nt hs of Scree ni n g  is n ot a vaila ble, 
T E pr oce d ures will be c o n d ucte d at st u d y sites wit h t he a p pr o priat e e q ui p m e nt a n d b y a de q u atel y 
trai ne d st u d y site staff. S c he d uli n g of t he T E ass ess me nt s h o ul d be wit hi n t he Scree ni n g wi n d o w 
( Da y - 2 8 t o D a y -1).  

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1 2. 1 1.  
P arti al M a y o Sc ori n g I n de x ( S u bjects wit h Ulcer ati ve C olitis  O nl y)  
T he Partial Ma y o Sc ori n g I n d e x is a n o n-i n vasi ve q uesti o n naire use d as a n o utc o me meas ure f or 
cli nical st u dies assessi n g t hera pies f or U C (Le wis 2 0 0 8 ). T he i n de x is c o m p ose d of 3 cat e g ories 
( Blee di n g, St o ol Fre q ue n c y, a n d P h ysicia n Assess me nt) t hat are eac h rate d fr o m 0 t o 3 a n d 
s u m me d t o gi ve a t otal sc ore t hat ra n g es fr o m 0 t o 9. T he Partial Ma y o Sc ori n g I n de x will be 
use d t o m o nit or disease sta bilit y d uri n g t he c o urse of t he st u d y. 
1 2. 1 2.  
Cr o h n’s Dise ase Acti vit y I n de x  ( C D AI) ( S u bjects wit h Cr o h n’s 
Dise ase O nl y)  
T he C D AI is a c o m p osite i nstr u me nt use d f or e val uati n g t he disease se v erit y  of C D  t hat is sc ore d 
o n a scale fr o m 0 t o 1 1 0 0 a n d i ncl u des a b d o mi nal pai n, ge neral well - bei n g, c o m plicati o ns, 
a b d o mi nal mass, a ne mia, a n d wei g ht c ha n g e. S u bjects wit h C D ca n be di vi de d i nt o 
as y m pt o matic re missi o n ( C D AI < 1 5 0), mil d-t o- m o derate C D ( 1 5 0  t o 2 1 9), m o derate-t o-s e vere 
C D ( 2 2 0 t o 4 5 0), a n d se v ere-f ul mi na nt disease ( > 4 5 0) (C he n 2 0 1 8 ). T h e C D AI will be use d t o 
m o nit or disease sta bilit y d uri n g t he c o urse of t he st u d y. 
1 2. 1 3.  
S u bject S afet y G ui deli nes  
1 2. 1 3. 1.  
P ote nti al Si de Effects  
Safet y res ults fr o m t he P hase 1 St u d y E P- 5 4 7- 1 0 1 di d n ot re veal a n y s afet y tre n ds, a n d t here 
were n o T E A Es assess e d as e x pect e d wit h t he use of E P 5 4 7. Refer  t o t he I n vesti gat or’s Br oc h ure 
f or a d diti o nal E P 5 4 7 i nf or mati o n re gar di n g p ote nti al si de effects.   
1 2. 1 3. 2.  
O ver d ose  
N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o ver d ose of E P 5 4 7. A d diti o nall y, t here is 
n o s pecific a nti d ote t o E P 5 4 7. I n a case of o verd ose, a p pr o priat e s u p p orti ve meas ures s h o ul d be 
e m pl o ye d.  
1 2. 1 3. 3.  
M o nit ori n g a n d M a n a ge m e nt of P ote nti al Dr u g -I n d uce d Li ver I nj ur y 
S u bjects will be assesse d  f or p ote ntial DI LI d uri n g b ot h t he D o u ble- Bli n d Treat me nt Peri o d a n d 
O pe n - La b el E xte nsi o n Peri o d acc or di n g t o t he c o nse ns us g ui deli nes f or cli nical trials i n a d ults 
wit h c h r o nic c h olestatic li ver disease (Pal mer 2 0 2 0 ). M o nit ori n g, i nterr u pti n g, a n d st o p pi n g r ules 
base d o n m ulti ples of U L N , t hres h ol d val ues, bas eli ne val ues , a n d/ or na d ir val ues of A L T , A S T, 
A L P , a n d t otal bilir u bi n a n d li ver‐r elate d s y m pt o ms are descri be d i n t he al g orit h ms for 
treat me nt-e mer ge nt he p at ocell ular a n d c h ol estatic DI LI si g nals pres e nte d b el o w.   
Ele vate d A L P val ues s h o ul d be c o nfir me d t o be of he patic  ori gi n wit h G G T. E xa m ples of li ver‐
relate d s y m pt o ms i ncl u de se ver e fati g ue, n a usea, ne w o nset of or w orse ni n g of pr urit us, ri g ht 
u p per q ua dr a nt pai n, i m m u n ol o gic reacti o n (e g, ras h, > 5 % e osi n o p hilia), a n d he patic 
dec o m p e nsati o n. If t h e al g orit h m calls f or re p eat bl o o d tests, t he tests are t o be perf or me d wit hi n 
2 t o 5 cale n dar d a ys  aft er recei pt of l a b orat or y v al ues b y t he site f or he p at o cell ular DI LI si g nals 
a n d wit hi n 7 t o 1 0 cale n d ar da ys after recei pt of la b orat or y v al ues b y t he sit e f or c h ol estatic DI LI 
si g nals. A L T, A S T, A L P, a n d t otal bilir u bi n, at a mi ni m u m, will be assesse d as part of t h e re p eat 
bl o o d tests. 

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M o nit ori n g f or H e pat ocell ular I nj ur y 
T he a l gorit h m f or m o nit ori n g a n d i nterr u pti n g st u d y dr u g f or treat me nt-e mer ge nt  he pat ocell ular  
DI LI si g nals i n s ubjects wit h a n or mal A L T bas eli n e val ue is pr o vi de d i n Ta ble  5. 
T a ble 5: 
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g St u d y Dr u g f or Tre at me nt -
E m er ge nt He p at ocell ul ar DI LI Si g n als i n S u bjects wit h a N o r m al A L T 
B ase li ne V al ue 
Tre at me nt -
E mer ge nt A L T  
Bilir u bi n  
Li ver -Rel ate d 
S y m pt o ms  
Acti o n  
A L T ≥5 × U L N  
N or mal  
Gil bert ’s s y n dr o me or he m ol ysis: N o 
c ha n ge i n baseli ne t otal bilir u bi n 
N o ne 
R e peat bl o o d tests a n d 
m o nit or f or s y m pt o ms . 
A L T ≥8 × U L N  
N or mal or ele vate d  
N o ne or 
prese nt 
Interr u pt st u d y dr u g 
a n d re peat bl o o d tests. 
St u d y dr u g ca n be 
restarte d if a n ot her 
eti ol o g y ( n ot 
he pat ocell ular i nj ur y) is 
i de ntifie d a n d 
a b n or malities ret ur n t o 
baseli ne  le vels. 
A L T ≥3 × U L N  
T otal bilir u bi n ≥2 × baseli ne 
Gil bert ’s s y n dr o me or he m ol ysis: 
direct bilir u bi n > 2 × baseli ne if 
baseli ne > 0. 5 m g/ d L 
N o ne or 
prese nt 
A L T ≥5 × U L N  
N or mal or ele vate d  
Prese nt  
A L T = ala ni ne a mi n otra nsferase ; DI LI = dr u g i n d uce d li ver i nj ur y ; U L N = u p per li mit of n or mal . 
T he a l g orit h m f or m o nit ori n g a n d i nterr u pti n g st u d y dr u g f or treat me nt-e mer ge nt he pat ocell ular 
DI LI si g nals i n s u bject s wit h a n ele vate d A L T baseli ne val ue is pr o vi de d i n Ta ble  6. 
T a ble 6:  
Al g orit h m f or M o nit ori n g a n d I nterr u pti n g S t u d y D r u g f or T re at me nt-
E m er ge nt H e p at ocell ul ar DI LI Si g n als i n S u bjects wit h a n E le v ate d A L T 
B aseli ne V al ue 
Tre at me nt -
E mer ge nt A L T  
Bilir u bi n  
Li ver -Rel ate d 
S y m pt o ms  
Acti o n  
A L T ≥3 × 
baseli ne  
N or mal  
Gil bert ’s s y n dr o me or he m ol ysis: N o 
c ha n ge i n baseli ne t otal bilir u bi n 
N o ne 
Re peat bl o o d tests a n d 
m o nit or f or s y m pt o ms . 
A L T ≥5 × 
baseli ne  
N or mal or ele vate d  
N o ne or 
prese nt 
I nterr u pt st u d y dr u g 
a n d re peat bl o o d tests. 
St u d y dr u g ca n be 
restarte d if a n ot her 
eti ol o g y ( n ot 
he pat ocell ular i nj ur y) is 
i de ntifie d a n d 
a b n or malities ret ur n t o 
baseli ne le vels . 
A L T ≥2 × 
baseli ne  
T otal bilir u bi n ≥2 × baseli ne 
Gil bert ’s s y n dr o me or he m ol ysis: 
direct bilir u bi n > 2 × baseli ne if 
baseli ne > 0. 5 m g/ d L 
N o ne or 
prese nt 
A L T ≥2 × 
baseli ne  
N or mal or ele vate d  
Prese nt  
A L T = ala ni ne a mi n otra nsferase ; DI LI = dr u g i n d uce d li ver i nj ur y . 

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1 4. 1.  
A n al ysis Sets  
T he f oll o wi n g a nal ysis sets will be c o nsi dere d: 
•  F ull A n al ysis Set : All s u bjects w h o are ra n d o mize d a n d ta ke at least 1 d os e of 
ra n d o mize d st u d y dr u g will be i ncl u de d i n t he F ull A nal ysis Set ( F A S). S u bjects i n 
t he F A S will be a nal y ze d acc or di n g t o ra n d o mize d treat me nt assi g n me nt. If a s u bject 
is i nc orrectl y stratifie d (ie, ra n d o mize d acc or di n g t o a n i nc orrect stratificati o n), t he 
s u bject will be a nal yze d u n der t he ra n d o mize d treat me nt f or t he strat u m rec or de d i n 
t he I W R S. All efficac y a n d P D  a nal yses will be b ase d o n t he F A S.  
•  Per Pr ot oc ol Set : T he P er Pr ot oc ol ( P P) Set is a s u bset of t he F A S c o nt ai ni n g 
s u bjects w h o meet st u d y eli gi bilit y re q uire me nts a n d ha ve n o pr ot oc ol de vi ati o ns t hat 
mi g ht i m pact t he assess me nt of efficac y meas ure me nts. S u bjects will be a nal yze d 
acc or di n g t o r a n d o mi ze d treat me nt assi g n me nt. T h e P P Set will be use d  f or 
se nsiti vit y a nal yses relati n g t o efficac y a n d P D . T he t y pe of pr ot oc ol d e viati o ns 
g o ver ni n g e xcl usi o n fr o m t he P P Set will be deter mi ne d pri or t o data bas e l oc k a n d 
pri mar y a nal ysis, a n d will be detaile d  i n t he S A P. 
•  S afet y A n al ysis Set : All s u bjects w h o are ra n d o mize d a n d ta k e at least 1 d ose of 
ra n d o mize d st u d y dr u g will be i ncl u de d i n t he Safet y A nal ysis Set. Safet y anal yses 
will be base d u p o n treat me nt act uall y recei ve d.  
•  P K Set : All s u bjects w h o recei v e at least 1 d ose of E P 5 4 7 a n d pr o vi de a d e q uate 
bl o o d sa m ples f or bi oa nal ysis will be i ncl u de d i n t he P K Set. 
1 4. 2.  
Esti m a n d  
C o nsiste nt wit h t he I nter nati o nal C o nfere n ce o n Har m o nisati o n (I C H) E 9 ( R 1) a d de n d u m o n 
esti ma n ds a n d se nsiti vit y a nal ysis i n cli nical trials t o t he g ui deli ne o n statistical pri nci ples f or 
cli nical trials (F D A 2 0 2 1 ), t he defi niti o n of t he attri b utes of t he pri mar y esti ma n d of t his st u d y is 
pr o vi de d i n t his secti o n. 
T he pri mar y esti ma n d of t he st u d y is t o assess t he differe n ce i n se v erit y of pr urit us i n s u bjects 
wit h c h olestatic pr urit us d ue t o P B C or P S C treate d wit h E P 5 4 7 or place b o, as meas ure d b y 
c ha n ge i n w ee kl y a v era g e WI -N R S after 6 w ee ks of ra n d o mize d treat me nt, re gar dl ess of 
treat me nt disc o nti n uati o n a n d use of pr o hi bite d a n d/ or resc ue m e dicati o ns. 
T he p o p ulati o n tar gete d b y t he scie ntific q uesti o n is defi ne d via t he i ncl usi o n a n d e xcl usi o n 
criteria as part of t he pr ot oc ol. A ke y as p ect of eli gi bilit y is t hat s u bjects m ust ha ve 
m o derate -t o-s e ver e pr urit us at baseli ne, as defi ne d as a mea n d ail y WI -N R S sc ore of at least 4.  
T he pri mar y e n d p oi nt t o be o btai ne d f or eac h s u bject i n t his st u d y t o a d dress t he scie ntific 
q uesti o n is t he mea n wee kl y WI- N R S sc ore at Wee k 6.  
Pre mat ure disc o nti n uati o n fr o m st u d y dr u g a n d us e of pr o hi bite d a n d/ or res c ue me dicati o ns are 
t he pri mar y p ote ntial i nterc urr e nt e ve nts t hat c o ul d occ ur. T h e treat me nt p olic y strate g y is use d 
f or t he pri mar y esti ma n d, c o nsiste nt wit h t he i nte nt-t o-treat pri nci ple. 

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1 4. 3.  
E n d p oi nts  
1 4. 3. 1.  
Pri m ar y Effic ac y  E n d p oi nt  
T he p ri mar y efficac y  e n d p oi nt is t he c ha n ge fr o m baseli ne i n WI-N R S at Wee k 6.  
1 4. 3. 2.  
Sec o n d ar y Effic ac y E n d p oi nts  
T he sec o n d ar y efficac y e n d p oi nts are: 
•  C ha n ge fr o m bas eli ne i n 5- D Itc h Scal e   
•  T he pr o p orti o n of s u bjects wit h i m pr o ve me nt i n pr urit us as defi ne d b y P GI -C  
•  T he pr o p orti o n of s u bjects wit h i m pr o ve me nt i n pr urit us se verit y fr o m baseli ne as 
defi ne d b y c h a n ge i n P GI -S  
•  T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI- N R S ≥2 fr o m baseli ne  
•  T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI- N R S ≥3 fr o m baseli ne  
•  T he pr o p orti o n of s u bjects wit h a re d ucti o n i n WI- N R S ≥4 fr o m baseli ne  
•  T he pr o p orti o n of s u bjects wit h WI- N R S < 4  
1 4. 3. 3.  
E x pl or at or y E n d p oi nts  
E x pl orat or y e n d p oi nts i ncl u de: 
1 4. 4.  
S a m ple Size C o nsi der ati o ns  
Ass u mi n g a sta n dar d de viati o n of 2. 5 p oi nts, a sa m ple size of 2 6 s u bjects per treat me nt gr o u p 
pr o vi des a p pr o xi matel y  
% p o wer t o det ect a differe nce of 
 E P 5 4 7 a n d 
place b o wit h res p ect t o t he c ha n g e i n wee kl y mea n of t he dail y WI- N R S sc ore base d o n a 
2-si de d, 2-sa m ple c o m p aris o n o f mea ns at t he 5 % si g nifica nce le v el. Wit h a n a ntici pate d earl y 
wit h dra wal r ate of a p pr o xi matel y 1 0 %, t he pla n ne d e nr oll me nt of 2 9 s u bjects per treat me nt 
gr o u p will e ns ure t hat at least 2 6 s u bjects c o m plet e t he 6 wee ks of d o u ble- bli n d treat me nt. 
1 4. 5.  
De m o gr a p hi c a n d B aseli ne C h ar acteristics  
De m o gra p hic d ata a n d b aseli ne c haracteristics f or t he F A S, P P, a n d Safet y A nal ysis Sets will be 
s u m marize d b y treat me nt gr o u p a n d o verall usi n g descri pti ve statistics.  
1 4. 6.  
S u bject Dis p ositi o n  
Dis p ositi o n of s u bjects will be s u m ma rize d b y treat me nt gr o u p a n d o verall. C o m pleti o n stat us 
a n d reas o ns f or disc o nti n uati o n will als o be s u m marize d.  

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T he n u m ber a n d p erce nta ge of s u bjects i n eac h a n al ysis set will be s u m marize d.  
1 4. 7.  
St u d y Dr u g Us a ge a n d C o m pli a nce  
C o m plia nce rate  d uri n g eac h treat me nt peri o d  will be c o m p ute d f or eac h s u bject a n d will be 
s u m marize d f or t h e Safet y A nal ysis Set usi n g s u m mar y statistics b y treat me nt gr o u p a n d o verall. 
D urati o n of treat me nt will als o be s u m marize d b y tr eat me nt gr o u p f or t he Safet y A nal ysis S et.  
1 4. 8.  
Effic a c y a n d P h ar m ac o d y n a mic A n al ysis  
Efficac y a n d P D  a n al yses will be b ase d o n t he F A S. T he pri mar y a n d sec o n dar y e n d p oi nt 
a nal yses will als o be r e peate d i n t he P P Set as s u p p orti ve a nal yses. 
All efficac y a n d P D e n d p oi nts will be f urt her e val uate d d uri n g t he O p e n - L a bel E xte nsi o n Peri o d. 
S u m maries of c ha n ge o v er ti me will e val uate b ot h c ha n ge fr o m baseli ne ( Visit 2 [ Da y 1]) a n d 
c ha n ge fr o m t he i nitiati o n of t he O pe n- La bel E xte nsi o n Peri o d ( Visit 6 [ Wee k 6]).  
F or WI -N R S , a wee kl y s c ore will be det er mi ne d b ase d o n t he a v era g e of all a vaila ble dail y 
sc ores of t he wee k. T he a vera ge WI - N R S sc ore usi n g t he dail y val ues fr o m t he wee k b ef ore t he 
first d ose of st u d y dr u g will ser ve as t he bas eli ne sc ore. F or a n y gi v e n wee k, if m ore t ha n 3 d ail y 
sc ores are missi n g, t he w ee kl y sc or e is c o nsi dere d missi n g. 
All c ha n ges fr o m baseli n e e n d p oi nts are d efi ne d as a bs ol ute c ha n ge. F or s elect e n d p oi nts, 
perce nt c ha n ge fr o m bas eli ne b y wee k will als o be s u m marize d.  
1 4. 8. 1.  
A n al ysi s of t he Pri m ar y E n d p oi nt: C h a n ge f r o m B aseli ne i n W orst Itc h N u m eric 
R ati n g Sc ale ( WI- N R S ) at Wee k 6  
WI -N R S data  will be a n al yze d usi n g a mi xe d effects m o del f or re p eate d m eas ures ( M M R M) 
base d o n t he data fr o m all visits u p t o Visit 6 ( Wee k 6). T he m o del will i ncl u de treat me nt, t y pe 
of c h olestatic diseas e  ( P B C, P S C), wee k, a n d treat me nt b y wee k i nteracti o n as fi xe d effects, a n d 
baseli ne WI -N R S sc ore as a c o vari ate. T he treat m e nt effect will be t he c o ntrast bet wee n E P 5 4 7 
a n d place b o l east-s q uares ( L S) mea ns.  T he L S mea ns, treat me nt effect esti mate, 9 5 % c o nfi d e nce 
i nter val, a n d p-v al ue will be prese nt e d.  Testi n g of h y p ot hesis is 2-si de d at a 5 % t y pe I err or le v el. 
1 4. 8. 2.  
A n al ysis of Sec o n d ar y a n d P h ar m ac o d y n a mic E n d p oi nts  
All efficac y a n d P D  e n d p oi nts descri be d i n Secti o ns  1 4. 3. 2  a n d 1 4. 3. 3  will be s u m marize d . 
E n d p oi nts t hat are defi n e d as c o nti n u o us varia bles will be a nal yze d usi n g a si milar m o del as 
descri be d f or t he pri mar y efficac y e n d p oi nt if t he y are c ollecte d at m ulti ple p ost- baseli ne vis its; 
ot her wise, t he y will be a nal yze d usi n g a nal ysis of c o varia n ce ( A N C O V A) a dj uste d f or 
ra n d o mizati o n strata a n d baseli ne meas ure me nts of t he res p o nse p ara meter of i nterest. Ot her 
e n d p oi nts defi ne d as r es p o nse pr o p orti o ns will be a nal yze d usi n g a C o c hra n- Ma ntel -Hae nszel 
test stratifie d b y ra n d o mi zati o n strata.  
S pecificall y f or WI - N R S, data s u m maries will prese nt sc ores, c h a n ge fr o m baseli ne, a n d 
res p o nse pr o p orti o ns b y wee k. Per ce nt c h a n ge fr o m baseli ne b y wee k will als o be s u m marize d. 

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1 4. 8. 3.  
Pr i m ar y a n d Se nsitivit y A n al yses t o A d dress Missi n g D at a i n t he Pri m ar y 
A n al ysis 
T he pri mar y a n al ysis of t he pri mar y e n d p oi nt of c ha n ge fr o m b aseli ne i n WI- N R S  will i ncl u de 
all o bser ve d dat a ( wee kl y WI- N R S sc ores c o nsi d ere d n o n-missi n g) wit h n o data i m p utati o ns, 
u n der t he ass u m pti o n of missi n g at ra n d o m ( M A R).  
As a se nsiti vit y a nal ysis, t he pri mar y e n d p oi nt will als o be a nal yze d wit h m ulti ple i m p utati o n 
pr oce d ur es (R u bi n 1 9 8 7 ). T he S A P will pr o vi de f ull detail of t he met h o d ol o gies t hat will be 
use d. 
1 4. 9.  
S afet y A n al ysis  
T he Safet y A n al ysis Set  will be use d f or t he s u m maries of t he safet y data acc or di n g t o t he 
treat me nt recei ve d. Safet y data will be s u m marize d se parat el y f or t he D o u ble-Bli n d Treat me nt 
Peri o d a n d O pe n- La b el E xte nsi o n Peri o d b y ra n d o mize d D o u ble- Bli n d treat me nt recei v e d. 
T he safet y a n d t olera bilit y of E P 5 4 7 will be assesse d b y c o m pari n g t he fre q ue nc y, ca usalit y, a nd 
se verit y of A Es, as well as treat me nt disc o nti n uati o ns d ue t o A Es. A Es will be c o de d usi n g t he 
Me d D R A b y S yste m O r g a n C lass a n d preferre d ter m. A Es t hat be gi n after t he first 
a d mi nistrati o n of st u d y dr u g, or e xisti n g A Es t hat w orse n after t he first d ose of st u d y dr u g , are 
c o nsi dere d T E A Es . All A E  s u m maries will i ncl u de T E A Es, a n d all AE s will be prese nte d i n 
listi n gs. 
T he W orl d H ealt h Or ga nizati o n ( W H O ) D R U G Dicti o nar y will be use d t o cate g orize ver bati m 
descri pti o ns of n o n-st u d y dr u g i nt o t he A nat o mic T hera p e utic C he mistr y ( A T C) classificati o n 
s yste m. C ha n ges i n vital si g ns, sta n dar d 1 2-lea d E C Gs , la b orat or y e v al uati o ns, a n d disease-
s pecific ass ess me nts ( Partial Ma y o Sc ore f or s u bjects wit h U C a n d C D AI f or s u bjects wit h C D) 
will be s u m marize d b y tr eat me nt gr o u p.  
1 4. 1 0.  
P h ar m ac o ki netic A n al ysis  
A descri pti ve s u m mar y of o bser ve d plas m a c o nce ntrati o ns of E P 5 4 7 will be dis pla ye d b y ti me 
a n d b y treat me nt gr o u p. T he plas ma c o n ce ntrati o ns  will be a nal yze d i n t he P K Set.  
1 4. 1 1.  
S u b gr o u p A n al yses  
T he pri mar y efficac y e n d p oi nt a n d selecte d sec o n dar y efficac y e n d p oi nts will be a nal yze d b ase d 
o n a ge, ge n d er, r ace/ et h nicit y, c h olestatic li ver disease  t y pe ( P B C or P S C), prese nce of 
c o m or bi dities (ie, I B D, C D, a n d/ or U C) , O C A use at baseli ne ( y es or n o),  or ot her 
de m o gra p hic/ bas eli ne c h aract eristics , as a p pr o priate. A d diti o nal details will be pr o vi de d i n t he 
S A P.  
1 4. 1 2.  
M ulti ple C o m p aris o n/ M ulti plicit y  
T his is t he first st u d y t o e x pl ore t he efficac y of E P 5 4 7 f or m ore t ha n 7 d a ys . T he fa mil y wise 
err or rate will be c o ntr olle d f or t he pri mar y efficac y e n d p oi nt at α = 5 %. All ot her effi cac y 
varia bles will be teste d at t he 0. 0 5 le vel of s i g nifica nce wit h o ut m ulti plicit y a dj ust me nt. 

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1 4. 1 3.  
Pl a n ne d I nteri m , Pri m ar y, a n d Fi n al A n al ysis  
T o a d dress b u si ness nee ds, a n i nteri m a nal ysis ma y be c o n d ucte d after a p pr o xi matel y 5 0 % of 
ra n d o mize d s u bjects ha v e c o m plete d 4 w ee ks of ra n d o mize d treat me nt. O nl y a li mite d n u m ber of 
st u d y tea m me m bers a n d se ni or ma na ge m e nt sta ke h ol ders c o m prisi ng t he i nter nal D R T w o u l d 
re vie w t he res ults of t he i nteri m a nal ysis of u n bli n de d data fr o m t he D o u ble-Bli n d Treat me nt 
Peri o d. T he i nteri m a nal ysis w o ul d e val uate t he effect of  E P 5 4 7 o n WI-N R S , select sec o n d ar y 
e n d p oi nts, a n d safet y.  
A d diti o nal details a b o ut t he i nteri m a nal ysis, if a p plica ble, will be pr o vi de d i n t he S A P , w hic h is 
t o be fi nalize d bef ore  t h e data base l oc k a n d u n bli n di n g of t he st u d y data, as a p plica ble. T he S A P  
will be a me n de d if e m er gi n g data fr o m t he c o m plete d i nteri m a nal ysis lea d s t o s u bsta ntial 
c ha n ge i n t he st u d y pr ot o c ol t hat has si g nifica nt i m pact o n t he statistical a nal yses. 
T he pri mar y a n al ysis will be c o n d ucte d after t h e last s u bject ra n d o mize d h as c o m plete d t he 
D o u ble- Bli n d Treat me nt Peri o d t o deter mi ne w het her t he pri mar y effi cac y e n d p oi nt of c ha n ge 
fr o m baseli ne i n WI-N R S at Wee k 6 is statisticall y si g nifica nt. Details re g ar di n g t he pri mar y 
a nal ysis pr oce d ures, i ncl u di n g data base l oc k a n d u n bli n di n g pr oce d ures, will be fi nalize d pri or t o 
a nal ysis. 
T he fi nal a n al ysis will be c o n d ucte d w h e n all ra n d o mize d s u bjects ha ve c o m plete d t he 
O pe n - La b el E xte nsi o n Peri o d or ar e disc o nti n ue d fr o m t he st u d y, a n d t he fi nal data base is 
l oc ke d.  
1 5.  
Q U A LI T Y C O N T R O L  A N D D A T A  MA N A G E M E N T  
1 5. 1.  
D at a Q u alit y Ass ur a nce  
T he f oll o wi n g meas ur es will be i m ple me nte d t o e ns ure acc urac y, c o nsiste n c y, c o m plete ness, a n d 
relia bilit y of data: 
•  I n v esti gat or disc ussi o ns 
•  Site i nitiati o n trai ni n g  
•  Earl y site visits f oll o wi n g e nr oll me nt  
•  R o uti ne site ma na ge me nt  
•  O n g oi n g site c o m m u nicati o n a n d trai ni n g 
•  Peri o dic site m o nit ori n g  
•  Re vie w of t he e C R F a gai nst s o urce data f or all s u bjects  
•  Data ma na g e me nt q ualit y c o ntr ol ( Q C ) c h ec ks  
•  Statistical Q C c hec ks  
1 5. 2.  
D at a M a n a ge me nt  
Base d o n t he fi nal e C R F, a data bas e will be  desi g ne d a n d b uilt t o meet U S F o o d a n d Dr u g 
A d mi nistrati o n ( F D A ): 2 1 C o de of Fe d eral Re g ulati o ns ( C F R) 1 1 re q uire me nts. A D ata 

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Ma na ge me nt Pla n will be writte n s pecif yi n g t he pr oce d ures t hat will be use d f or me dical c o di n g, 
S A E rec o nciliati o n, Q C, la b orat or y dat a, a n d dat a clea ni n g t hat will occ ur f or t he st u d y. A Data 
Vali dati o n Pla n  will be writte n a n d e dit c hec ks will be pr o gra m me d a n d vali date d.  
1 5. 3.  
M o nit ori n g  
M o nit ori n g visits will be c o n d ucte d b y re pres e ntati ves of t he S p o ns or acc or di n g t o t he I C H 
G ui deli ne f or G C P, a n d a p plica ble re gi o nal re g ulati o ns a n d g ui deli nes.  
A m o nit or ( or m o nit ors) will re vie w a n d verif y pr ot oc ol c o m plia nce wit h a f oc us o n A E/ S A E 
re p orti n g, e C R F dat a, s o urce d oc u m e ntati o n, I C Fs, a n d a n y ot her st u d y-rel ate d d oc u me ntati o n, 
i ncl u din g re vie w of site p har mac y pr oce d ures, dr u g acc o u nta bilit y d oc u me ntati o n, a n d dr u g 
st ora ge facilities a n d rec or ds. 
M o nit ori n g will be o n a n o n g oi n g basis. Bef ore  data base l oc k, 1 0 0 % e C R F data verifi cati o n will 
be perf or me d a g ai nst t he s o urce d oc u m e nts. T he  I n vesti gat or will a gree t o t he m o nit or(s) ma ki n g 
peri o dic site visits d uri n g t he st u d y. T he m o nit or(s) a n d t he st u d y site staff will a gree u p o n t he 
ti mi n g of t hese visits. 
1 5. 4.  
C o nfi de nti alit y a n d A u diti n g  
T he I n vesti gat or, t he S p o ns or, a n d t he S p o ns or’s re prese nt ati ves will preser ve t he c o nfi de ntialit y 
of all s u bjects partici pati n g i n t his st u d y, i n acc or da nce wit h I C H G C P, l o cal re g ulati o ns, a n d 
i nstit uti o nal re q uire me nts. T he st u d y s u bject n u m ber will be use d t o i de ntif y s u bjects o n t he 
e C R Fs a n d ot her st u d y-r elate d d oc u me nts s u b mitte d t o t he S p o ns or ( or desi g nee) . D oc u m e nts 
t hat are n ot s u b mitte d t o t he S p o ns or (e g, I C Fs) s h o ul d be ke pt i n strict c o nfi de nce b y t he 
i n vesti gati ve staff. 
I n c o m plia nce wit h I C H G C P, it is re q uire d t hat t he I n vesti gat or a n d i nstit uti o n per mit 
a ut h orize d r e pres e ntati ves of t he S p o ns or, t he I R B /I E C, t he U S F D A, a n d ot her a p pr o pri ate 
re g ulat or y a ut h orit y or h ealt h a ut h orit y i ns pect ors direct access t o all st u d y-relate d sites, s o urce 
data, d oc u me nts, a n d re p orts f or verifi cati o n of st u d y rec or ds a n d data. Direct access is t he 
per m issi o n t o e xa mi ne, a nal yze, verif y, a n d re pr o d uce a n y rec or ds a n d re p orts t hat are i m p orta nt 
t o t he e val uati o n of a cli nical st u d y. T he I n vesti gat or is o bli gate d t o i nf or m a n d o btai n c o nse nt 
fr o m t he s u bject to per mit t hese re pr ese ntati ves t o ha ve access t o t heir st u d y -relate d rec or ds f or 
t his verificati o n. A n y part y (e g, d o mestic a n d f orei g n re g ulat or y a ut h orities, S p o ns ors, a n d 
a u dit ors) wit h direct access s h o ul d ta ke all reas o na ble preca uti o ns wit hi n t he c o n strai nts of t he 
a p plica ble r e g ulat or y r e q uire me nt(s) t o mai ntai n t he c o nfi de ntialit y of s u bj ects.  
1 5. 5.  
C ase Re p ort  F or ms  
e C R Fs will be use d  f or t his st u d y. Site pers o n nel will recei ve trai ni n g o n e C R F c o m pleti o n. Eac h 
e C R F is t o be re vie w e d a n d a p pr o ve d b y t he I n vesti gat or.  
D uri n g peri o dic m o nit or i n g visits, t he I n vesti gat or will ma ke t he e C R Fs a v aila ble t o t he st u d y 
m o nit or s o t hat he or s he ma y verif y t he d ata e ntri es wit h t he s o urce d o c u me ntati o n. 

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1 5. 6.  
S o urce  D oc u me nts  
T he I n vesti gat or will pre pare a n d m ai ntai n a de q u ate a n d acc urate s o urce d oc u me nts (e g , me dical 
rec or ds, 1 2-lea d E C G res ults, a n d ra w data c ollecti o n f or ms) t o rec or d all o bser vati o ns a n d ot her 
perti ne nt data f or eac h s u bject e nr olle d  i nt o t he st u d y. T he data rec or d e d o n t he e C R Fs will be 
deri ve d fr o m t hes e s o urce d oc u me nts. T he I n v esti g at or will e ns ure t hat dat a o n t he e C R Fs a n d 
c o m plete d q ueries are acc urate, c o nsiste nt wit h s o urce d oc u m e ntati o n, a n d s u b mitte d t o t he 
S p o ns or i n a ti mel y ma n ner. T he I n v esti gat or will als o e ns ure t hat all dat a o n re q uire d st u d y l o gs 
are acc urate a n d ke pt u p t o date. 
1 5. 7.  
Rec or ds Rete nti o n  
T he I n vesti gat or m ust mai ntai n esse ntial st u d y d oc u me nts ( pr ot oc ol a n d a me n d me nts, c o m plete d 
e C R Fs, s o urce d o c u me nt ati o n, si g ne d I C Fs, rele v a nt c orres p o n de nce a n d a p pr o vals, a n d all ot her 
s u p p orti n g d oc u me ntati o n) u ntil n otifie d b y t he S p o ns or. S u bject i de ntificati o n c o des (s u bject 
na mes a n d c orres p o n di n g st u d y n u m bers) will be retai ne d f or t his sa me p eri o d a n d st ore d 
se parat el y. C ust o d y of t he rec or ds ma y be tra nsferre d t o a n ot her res p o nsi ble part y, acce pt a ble t o 
t he S p o ns or, w hic h a gr ees t o a bi de b y t he rete nti o n p olicies. Writte n n otice of tra nsfer m ust be 
s u b mitte d t o t he S p o ns or. T he I n vesti gat or m ust c o ntact t he S p o ns or bef ore dis p osi n g of a n y 
st u d y rec or ds. 
All cli nical st u d y d oc u me n ts m ust be retai ne d i n acc or da n ce wit h t he I C H E 6 g ui deli ne a n d i n 
c o m plia nce wit h l ocal data rete nti o n re q uire me nts.   
1 5. 8.  
I nf or me d C o nse nt  
Writte n i nf or me d c o ns e nt will be o btai ne d fr o m eac h s u bject bef ore a n y st u d y- relate d pr oce d ures 
are perf or m e d . T he I n v es ti gat or has a n et hical a n d le gal res p o nsi bilit y t o e ns ure eac h s u bject 
bei n g c o nsi dere d f or i ncl usi o n i n t he st u d y is gi ve n a f ull e x pla nati o n of t h e st u d y. T he 
I n v esti gat or, or his/ her d esi g nee, s hall i nf or m eac h s u bject, i n writi n g, of all as pects pertai ni n g t o 
partici pati o n i n t he st u d y, i ncl u di n g ( b ut n ot li mite d t o) ai ms, met h o ds, a ntici pate d be n efits, a n d 
p ote ntial ris ks . S u bjects will ha ve t he 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 h et her t o partici pate . S u bjects s h o ul d u n dersta n d t hat t he y are free t o ref use t o 
partici pate i n, or t o wit h dra w fr o m, t he st u d y at a n y ti me wit h o ut prej u dice or l oss of me dical 
care t o w hi c h t he y are ot her wise e ntitle d . Eac h s u bject m ust pers o nall y si g n a n d date a 
st u d y-s pecific I C F t o be a s u bject i n t he st u d y. T he I C F m ust be c o u ntersi g ne d b y t he site 
I n v esti gat or ( or d esi g nee) w h o c o n d uct e d t he i nf or me d c o nse nt disc ussi o n. T his will be 
d oc u me nte d o n a writte n I C F. Eac h I C F will i ncl u de t he ele me nts re q uire d b y U S 2 1 C F R 5 0 a n d 
I C H E 6, Secti o n  4. 8. T he I n v esti gat or a grees t o o btai n a p pr o val fr o m t he S p o ns or or desi g nee of 
a n y writte n i nf or me d c o nse nt f or use i n t he st u d y bef ore s u b missi o n t o t he I R B/I E C. 
Eac h s u bject w h o pr o vi des writte n i nf or me d c o nse nt f or t he st u d y ( b y si g ni n g a n d dati n g t he 
I CF), will be gi ve n a c o p y of t he si g ne d I C F. T h e ori gi nal will be ke pt i n t he s u bject’s me dical 
rec or d or st u d y c hart as p er mitte d b y t he i nstit uti o n. T he I C F 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 v aila ble t hat ma y be rele v a nt t o t he s u bject’s c o nse nt. A n y 
re vise d writte n I C F s h o ul d recei v e I R B/I E C a p pr o val i n a d va nce of use. T h e s u bject 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 h at ma y be rele v a nt t o t he 

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s u bject’s willi 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.  
It is i m p orta nt t o o btai n c o m plete f oll o w- u p f or all s u bjects. E ver y atte m pt s h o ul d be ma de t o 
u n derta ke all pr ot oc ol- s p ecifie d ass ess me nts a n d c o m plete t he e C R Fs e xce pt f or t h ose su bjects  
w h o s pecificall y wit h dra w c o nse nt f or release of s uc h i nf or mati o n. 
1 5. 9.  
Et hic al C o n d uct of t he St u d y  
T his st u d y s hall be c o n d ucte d i n acc or da n ce 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 H elsi n ki a n d t hat are c o nsiste nt wi t h G C P, I C H g ui deli nes, ot her a p plica ble 
re g ulat or y r e q uire me nts ( e g, l ocal re q uire me nts), t he st u d y pr ot oc ol, a n d w here a p plica ble, 
S p o ns or a n d/ or C R O sta n dar d o per ati n g pr oce d ures. 
1 5. 1 0.  
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee  
T he I n vesti gat or will n ot be gi n t he st u d y u ntil t he pr ot oc ol a n d I C F h a ve bee n a p pr o ve d b y t he 
a p pr o priate i n d e pe n de nt I R B /I E C. A n y a me n d m e nts t o t he pr ot oc ol m ust als o be a p pr o ve d i n 
writi n g b y t he S p o ns or a n d I R B /I E C, bef ore  i m ple me ntati o n b y t he I n vesti gat or, e xce pt w here 
necessar y t o eli mi nate a n i m me diate hazar d t o s u bjects. 
All I R B /I E C c orr es p o n de nce, i ncl u di n g pr o gress re p orts, will be retai ne d o n file at t he site. 
1 6.  
S T U D Y M A N A G E M E N T  
1 6. 1.  
Pr ot oc ol  De vi ati o ns  
T he I n vesti gat or is n ot per mitte d t o de viate fr o m t he pr ot oc ol i n a n y maj or wa y wit h o ut pr o per 
n otificati o n t o t he S p o ns or ( or desi g nee). O nl y t h e S p o ns or ma y re vise t he pr ot oc ol. A n y c ha n g e 
i n st u d y c o n d uct c o nsi dere d necessar y b y t h e I n vesti gat or will be ma de o nl y after c o ns ultati o n 
wit h t he S p o ns or, w h o will t he n iss ue a f or mal pr ot oc ol re visi o n t o i m ple me nt t he c ha n ge a n d 
o btai n re g ulat or y a p pr o v al. T he o nl y e xce pti o n is w he n t he I n vesti gat or c o nsi ders a s u bject’s 
safet y t o be c o m pr o mise d if i m me diate acti o n is n ot ta ke n. 
I n t he e ve nt of a n i m p orta nt de viati o n fr o m t he pr ot oc ol, t he I n v esti gat or or desi g nee m ust 
c o ntact t he S p o ns or or r e prese ntati ve at t he earliest p ossi ble ti me . T his will all o w a n earl y j oi nt 
decisi o n re gar di n g t he s u bject’s c o nti n uati o n i n t he st u d y.  
E xa m ples of i m p orta nt pr ot oc ol de viati o ns i ncl u de t he f oll o wi n g: 
•  S u bject di d n ot gi ve a p pr o priate i nf or me d c o nse nt 
•  I n cl usi o n or e xcl usi o n criteria n ot satisfie d 
•  N o n -per mitte d c o n c o mita nt me dicati o ns t hat ma y mea ni n gf ull y i m pact effi cac y or s afet y 
o utc o mes 
•  Mea ni n gf ul d osi n g err or 
•  Ra n d o mizati o n err or 

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T he I n vesti gat or a n d S p o ns or will b ot h d oc u me nt t his decisi o n. T he I R B /I E C will be i nf or me d of 
all i m p orta nt pr ot oc ol de viati o ns b y t he I n v esti gat or i n acc or da nce wit h est a blis he d pr oce d ures. 
1 6. 2.  
P u blic ati o ns  
N o p u blicati o n of t he res ults s hall ta ke place wit h o ut t he S p o ns or’s writte n c o nse nt. All 
p u blicati o n or prese ntati o n ri g hts f or t he fi n di n gs of t he cli nical i n vesti gati o n u n der t his pr ot oc ol 
s hall be g o ver ne d b y t h e a p pr o priate t er ms of t he cli nical researc h a gree me nt bet wee n t he 
I n v esti gat or, t he i n vesti g ati onal site, a n d t he S p o ns or. 
1 6. 3.  
C h a n ge i n St u d y Site St aff  
If t he Pri nci pal I n v esti gat or at a site is u na ble t o c o nti n ue t he st u d y, a n ot her s uita ble pers o n will 
be desi g nate d as t h e I n vesti gat or, a n d d oc u m e ntati o n testif yi n g t o t his will be s u b mitte d t o 
S p o ns or or its desi g nee wit hi n 1 0 da ys, w h o m ust a p pr o ve t he c h a n ge al o n g wit h t he I R B /I E C 
bef ore t h e st u d y ca n be c o nti n ue d at t hat i n vesti gati ve site. 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 8 0 of 1 2 8 
1 7.  
LI S T O F R E F E R E N C E S  
 
Bassari R, K oea J B. Ja u n dice Ass ociate d Pr uritis: A Re vie w of Pat h o p h ysi ol o g y a n d Treat me nt. 
W orl d J Gastr oe nt er ol. 2 0 1 5; 2 1( 5): 1 4 0 4- 1 3. 
 
Ber gasa N V. Pr urit us of C h olestasis. I n: Carste ns E, A ki ya ma T, e dit ors. It c h: Mec ha nis ms a n d 
Treat me nt. Fr o ntiers i n N e ur oscie n ce . B oca R at o n ( F L): C R C Press; 2 0 1 4. p. 6 1- 8 8. 
 
B o u d o ulas S, L us h R M, Mc Call N A, et al. Plas ma Pr otei n Bi n di n g of P he n ylacetate a n d 
P he n yl b ut yrate, T w o N o vel A nti ne o plastic A ge nts. T her Dr u g M o nit. 1 9 9 6; 1 8( 6): 7 1 4- 2 0. 
 
C ha p ma n R, Fe ver y J, K all o o A, et al. Dia g n osis a n d Ma na ge m e nt of Pri mar y Scler osi n g 
C h ola n gitis. He pat ol o g y. 2 0 1 0; 5 1( 2): 6 6 0- 7 8. 
 
C he n M, S he n B. O ver vie w of Dia g n osis a n d M e dical Treat me nt of I nfla m mat or y B o wel 
Diseases.  I nter ve nti o nal I nfla m mat or y B o wel Dis ease: E n d osc o pic M a na g e me nt a n d Tre at me nt 
of C o m plicati o ns: Aca de mic Press; 2 0 1 8. p. 1- 1 5. 
 
C o r pec h ot C. Utilit y of N o ni n vasi ve Mar k ers of Fi br osis i n C h olestatic Li ver Diseas es. Cli n 
Li ver Dis. 2 0 1 6; 2 0( 1): 1 4 3- 5 8. 
 
E A S L. E A S L Cli nical Practice G ui d eli nes: Ma na g e me nt of C h olestatic Li ver Dis eas es. J 
He pat ol. 2 0 0 9; 5 1( 2): 2 3 7- 6 7. 
 
El ma n S, H y na n L S, Ga briel V, et al. T he 5 -D Itc h Scale: A Ne w M eas ure of Pr urit us. Br J 
Der mat ol. 2 0 1 0; 1 6 2( 3): 5 8 7- 9 3. 
 
F D A. G ui da n ce f or I n d ustr y: E 9( R 1) Statistical Pri nci ples f or Cli nical Trials: A d de n d u m: 
Esti ma n ds  a n d Se nsiti vit y A nal ysis i n Cli nical Trials. F D A Mar yla n d;  2 0 2 1. p. 1- 1 9. 
 
Fis h ba ne S, Mat h ur V, G er mai n MJ, et al. Ra n d o mize d C o ntr olle d Trial of Difeli kefali n f or 
C hr o nic Pr urit us i n He m o dial ysis Patie nts. Ki d ne y I nt Re p. 2 0 2 0; 5( 5): 6 0 0- 1 0. 
 
Fis k J D, D o ble S E. C o nstr ucti o n a n d Vali dati o n of a Fati g ue I m pact Scal e f or Dail y 
A d mi nistrati o n ( D - FI S). Q ual Life Res. 2 0 0 2; 1 1( 3): 2 6 3- 7 2. 
 
G u y W. E C D E U Assess me nt Ma n ual f or Ps yc h o p har mac ol o g y. G u y W, e dit or. R oc k ville, M D: 
U S De part me nt of H ealt h, E d ucati o n, a n d Welfare P u blic Healt h Ser vice Alc o h ol, Dr u g A b use, 
a n d Me ntal Healt h A d mi nistrati o n; 1 9 7 6. 
 
Hase ga wa Y, H a yas hi H, Na oi S, et al. I ntracta ble Itc h R elie ve d b y 4- P he n yl b ut yrate T hera p y i n 
Patie nts wit h Pr o gressi ve Fa milial I ntra h e patic C h olestasis T y pe 1. Or p ha n et J Rare Dis. 
2 0 1 4; 9: 8 9. 
 
Healt h Meas ur es. P R O MI S Slee p  Dist ur ba nce Sc ori n g Ma n ual 2 0 2 1 [ u p date d Fe b 1 9, 2 0 2 1. 1-
1 3]. 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 8 1 of 1 2 8 
 
Her d ma n M, G u d e x C, Ll o y d A, et al. De vel o p me nt a n d Preli mi nar y Testi n g of t he Ne w Fi ve-
Le vel Versi o n of E Q- 5 D ( E Q - 5 D-5 L). Q ual Life Res. 2 0 1 1; 2 0( 1 0): 1 7 2 7- 3 6. 
 
H H S. C o m m o n Ter mi n ol o g y Criteria f or A d v erse E ve nts ( C T C A E) Versi o n 5. 0. 2 0 1 7. p. 1- 1 5 5. 
 
Hirsc hfiel d G, K o w dle y K, S hiff ma n M, et al., e dit ors. E N H A N C E: Safet y a n d Efficac y of 
Sela del par i n Patie nts wit h Pri mar y Biliar y C h ola n gitis ( P B C) – A P hase 3 I nter nati o nal, 
Ra n d o mize d, Place b o -C o ntr olle d St u d y ( L O 1 1). A merica n Ass o ciati o n f or t he St u d y of Li ver 
Diseases; 2 0 2 0; Virt ual.  
 
I bra hi m M K, Els ha hi d A R, El Baz T Z, et al. I m pact of Urae mic Pr urit us o n Q ualit y of Life 
A m o n g E n d Sta ge Re nal Disease Patie nts o n Dial ysis. J Cli n Dia g n Res. 2 0 1 6; 1 0( 3): W C 0 1- 5. 
 
K DI G O. Ki d n e y Diseas e: I m pr o vi n g Gl o bal O ut c o mes ( K DI G O) A c ute Ki d ne y I nj ur y W or k 
Gr o u p. K DI G O Cli nical Practice G ui deli ne f or A c ute Ki d ne y I nj ur y. Ki d ne y I nter n ati o nal 
S u p ple me nt. 2 0 1 2; 2: 1- 1 3 8. 
 
Le v y C, Ke n dric k S, B o wl us C, et al., e dit ors. G LI M M E R trial: A 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 of Li neri xi bat, a n I n hi bit or of t he Ileal Bile Aci d Tra ns p orter, i n t he 
Treat me nt of C h olestatic Pr urit us i n Pri mar y Biliar y C h ola n gitis ( L P 3 8). A merica n Ass o ciati o n 
f or t he St u d y of Li ver Diseases; 2 0 2 0; Virt ual. 
 
Le wis J D, C h uai S, Ness el L, et al. Use of t h e N o ni n vasi ve C o m p o ne nts of t he Ma y o Sc ore t o 
Assess Cli nical Res p o nse i n Ulcerati ve C olitis. I nfla m m B o wel Dis. 2 0 0 8; 1 4( 1 2): 1 6 6 0- 6. 
 
Li n d or K D, B o wl us C L, B o yer J, et al. Pri mar y Biliar y C h ola n gitis: 2 0 1 8 Practice G ui da nce 
fr o m t he A merica n Ass o ciati o n f or t he St u d y of Li ver Diseases. He pat ol o g y. 2 0 1 9; 6 9( 1): 3 9 4-
4 1 9. 
 
Mei xi o n g J, Vasa v da C, Gree n D, et al. I d e ntificati o n of a Bilir u bi n Rece pt or t hat Ma y Me diate a 
C o m p o ne nt of C h olestatic Itc h. Elife. 2 0 1 9 a; 8: 1- 2 5. 
 
Mei xi o n g J, Vasa v da C, S n y der S H, et al. M R G P R X 4 is a G Pr otei n- C o u ple d Rece pt or 
Acti vate d b y Bile Aci ds t hat Ma y C o ntri b ute t o C h olestatic Pr urit us. Pr oc N atl Aca d Sci U S A. 
2 0 1 9 b; 1 1 6( 2 1): 1 0 5 2 5- 3 0. 
 
Mittal A. C h olestatic It c h Ma na ge me nt. C urr Pr o bl Der mat ol. 2 0 1 6; 5 0: 1 4 2- 8. 
 
Na ka n o S, Osa k a S, Sa b u Y, et al. Eff ect of F o o d o n t he P har mac o ki netics a n d T hera pe utic 
Efficac y of 4 - P he n yl b ut yrate i n Pr o gressi ve Fa milial I ntra he p atic C h olestasis. Sci Re p. 
2 0 1 9; 9( 1): 1 7 0 7 5. 
 
Oze n N, C i nar FI, As ki n D, et al. Ure mic Pr urit us a n d Ass ociate d Fact ors i n He m o dial ysis 
Patie nts: A M ulti - Ce nter St u d y. Ki d ne y Res Cli n Pract. 2 0 1 8; 3 7( 2): 1 3 8- 4 7. 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 8 2 of 1 2 8 
Pal mer M, Re ge v A, Li n d or K, et al. C o nse ns us G ui deli nes: Best Practices f or Detecti o n, 
Assess me nt a n d Ma na g e me nt of S us pecte d Ac ut e Dr u g-I n d u ce d Li ver I nj ur y Occ urri n g D uri n g 
Cli nical Trials i n A d ults wit h C hr o nic C h olestatic Li ver Diseas e. Ali me nt P har mac ol T her. 
2 0 2 0; 5 1( 1): 9 0- 1 0 9. 
 
P ha n  N Q, Bl o me C, Fritz F, et al. Assess me nt of Pr urit us I nt e nsit y: Pr o s pecti ve St u d y o n 
Vali dit y a n d Relia bilit y of t he Vis ual A nal o g ue Scale, N u merical Rati n g Scale a n d V er bal 
Rati n g Scale i n 4 7 1 Patie nts wit h C hr o nic Pr urit us. Acta Der m Ve nere ol. 2 0 1 2; 9 2( 5): 5 0 2- 7. 
 
R u bi n D B. M ulti ple I m p utati o n f or N o nres p o ns e i n S ur ve ys. Ne w Y or k Wile y; 1 9 8 7. 
 
Sc hie hser D M, A y ers C R, Li u L, et al. Vali dati o n of t he M o difie d Fati g ue I m pact Scale i n 
Par ki ns o n's disease. Par ki ns o nis m Relat Dis or d. 2 0 1 3; 1 9( 3): 3 3 5- 8. 
 
Sta n der S, Y osi p o vitc h G, Le gat FJ, et al. Trial of Ne m oliz u ma b i n M o derate-t o- Se vere Pr uri g o 
N o d ularis. N E n gl J Me d. 2 0 2 0; 3 8 2( 8): 7 0 6- 1 6. 
 
Tal wal kar J A, S o ut o E, J or ge nse n R A, et al. Nat ural Hist or y of Pr urit us i n Pri mar y Biliar y 
Cirr h o sis. Cli n Gastr oe nter ol He pat ol. 2 0 0 3; 1( 4): 2 9 7- 3 0 2. 
 
Yalci n I, B u m p R C. Vali dati o n of T w o Gl o bal I m pressi o n Q uesti o n naires f or I nc o nti ne nce. A m 
J O bstet G y nec ol. 2 0 0 3; 1 8 9( 1): 9 8- 1 0 1. 
 
Y u H, Z ha o T, Li u S, et al. M R G P R X 4 is a N o vel Bile Aci d Rece pt or i n C h ol estatic Itc h. 
bi o R xi v. 2 0 1 9: 6 3 3 4 4 6. 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 3 of 1 2 8 
A P P E N DI X  A.  S C H E D U L E O F A S S E S S M E N T S   
Assess me nt  
Scree ni n g  
D o u ble -Bli n d Tre at me nt  
O pe n -L a bel 
E xte nsi o n  
F oll o w -
U p  
E arl y 
St u d y 
Ter m  
N otes  
Visit  
Visit 1 a Visit 2  
Da y 1  
Visit 3   
Wee k 1   
Visit 4  
Wee k 2  
Visit 5  
Week 3  
Visit 6  
Week 6  
Visit 7  
Week 9  
Visit 8   
Week 1 2  
Visit 9  
St u d y D a y  
Da ys -2 8 
t o -1  
Da y 1  
Da y 8  
Da y 1 5  Da y 2 2  Da y 4 3  Da y 6 4  
 
Da y 8 5  2 wee ks 
( ±3 day s) 
after last 
d ose  
≤2 da ys 
after last 
d ose  
Visit Wi n d o w  
N o ne  
N o ne b ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s 
Visit T y pe f or  
H y bri d M o del c 
Site o nl y  
Site 
o nl y  
Site or  
Re m ote  
Site or  
Re m ote  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
 
Ge ner al Assess m e nts  
I nf or me d c o nse nt   
X  
 
 
 
 
 
 
 
 
 
 
Me dical hist or y   
X  
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
Meas ure d wit h n o s h oes.  
HI V, H A V, H B V, 
H C V , H E V 
ser ol o g y  
X  
 
 
 
 
 
 
 
 
 
 
I g G 4 
X  
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y c hec k   
X  
X  
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n  via 
I W R S 
 
X  
 
 
 
 
 
 
 
 
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o 1 0 0 m g  
E P 4 5 7 or place b o.  
Dis pe nse st u d y 
dr u g / a d mi nister 
d ose  
 
X  
 
 
X  
X  
X  
 
 
 
A d mi nister st u d y dr u g Q D as i ntact ta blets wit h water.  
F or re m ote visits, st u d y dr u g dis pe nsi n g will be 
c o n d ucte d b y a direct -t o-patie nt c o urier  ser vice. 
C ollect st u d y dr u g / 
assess st u d y dr u g 
acc o u nta bilit y a n d 
c o m plia nce  
 
 
 
 
X  
X  
X  
X  
 
X  
F or re m ote visits, st u d y dr u g c ollecti o n will be 
c o n d ucte d b y a direct -t o-patie nt c o urier  ser vice. 
P r o vi de 
q uesti o n naire 
trai ni n g  
X  
 
 
 
 
 
 
 
 
 
T o be c o n d ucte d bef ore c o m pleti n g t he dail y WI -N R S 
f or Da y -1 4 . 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 4 of 1 2 8 
Assess me nt  
Scree ni n g  
D o u ble -Bli n d Tre at me nt  
O pe n -L a bel 
E xte nsi o n  
F oll o w -
U p  
E arl y 
St u d y 
Ter m  
N otes  
Visit  
Visit 1 a Visit 2  
Da y 1  
Visit 3   
Wee k 1   
Visit 4  
Wee k 2  
Visit 5  
Week 3  
Visit 6  
Week 6  
Visit 7  
Week 9  
Visit 8   
Week 1 2  
Visit 9  
St u d y D a y  
Da ys -2 8 
t o -1  
Da y 1  
Da y 8  
Da y 1 5  Da y 2 2  Da y 4 3  Da y 6 4  
 
Da y 8 5  2 wee ks 
( ±3 day s) 
after last 
d ose  
≤2 da ys 
after last 
d ose  
Visit Wi n d o w  
N o ne  
N o ne b ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s 
Visit T y pe f or  
H y bri d M o del c 
Site o nl y  
Site 
o nl y  
Site or  
Re m ote  
Site or  
Re m ote  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
 
Effic ac y  Assess m e nts  
WI -N R S  
X   
X  
X  
X  
X  
X  
X  
X  
X  
X  
T o be c o m plete d dail y, i n t he m or ni n g, a n d at t he sa me 
ti me of da y , fr o m Da y -1 4 t o t he Safet y F oll o w -U p 
Visit . F or da ys t hat c oi nci de wit h a st u d y visit (f or 
Visit 2 a n d be y o n d), it is t o be c o m plete d bef ore t he 
visit.   
5 -D  Itc h Scale  
 
X  
 
 
 
X  
 
X  
X  
X  
 
P GI -C  
 
 
 
 
 
X  
 
X  
 
X  
 
P GI -S  
 
X  
 
 
 
X  
 
X  
 
X  
 
P h ar m ac o d y n a mic  Assess m e nts   
Bile aci ds a n d 
he me m eta b olites  
 
X  
 
 
 
X  
 
 
 
 
 
Retai ne d sa m ples 
f or f ut ure a nal ysis   
 
X  
 
 
X  
X  
X  
X  
 
 
Bl o o d a n d uri ne s a m ples ma y be st ore d f or u p t o 
1 0  years after t he c o m pleti o n of t he st u d y. See t he 
L a b orat or y M a n ual f or c ollecti o n details.  
Ge n ot y pi n g  
( o pti o nal) 
 
X  
 
 
 
 
 
 
 
 
Ki d ne y -relate d 
bi o mar kers  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d a n d u ri ne will be c ollecte d f or a nal ysis of 
ki d ne y -relate d bi o mar kers as descri be d i n Secti o n  1 1. 3 .  
S afet y  Assess m e nts   
Partial Ma y o Sc ore  
X  
 
 
 
 
X  
 
X  
 
X  
T o be c o m plete d f or s u bjects wit h U C.  
C D AI  
X  
 
 
 
 
X  
 
X  
 
X  
T o be c o m plete d f or s u bjects wit h C D. 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 5 of 1 2 8 
Assess me nt  
Scree ni n g  
D o u ble -Bli n d Tre at me nt  
O pe n -L a bel 
E xte nsi o n  
F oll o w -
U p  
E arl y 
St u d y 
Ter m  
N otes  
Visit  
Visit 1 a Visit 2  
Da y 1  
Visit 3   
Wee k 1   
Visit 4  
Wee k 2  
Visit 5  
Week 3  
Visit 6  
Week 6  
Visit 7  
Week 9  
Visit 8   
Week 1 2  
Visit 9  
St u d y D a y  
Da ys -2 8 
t o -1  
Da y 1  
Da y 8  
Da y 1 5  Da y 2 2  Da y 4 3  Da y 6 4  
 
Da y 8 5  2 wee ks 
( ±3 day s) 
after last 
d ose  
≤2 da ys 
after last 
d ose  
Visit Wi n d o w  
N o ne  
N o ne b ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s 
Visit T y pe f or  
H y bri d M o del c 
Site o nl y  
Site 
o nl y  
Site or  
Re m ote  
Site or  
Re m ote  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
 
T E ( Fi br o Sca n)  
X  
 
 
 
 
 
 
 
 
 
If an eli gi ble  hist orical T E wit hi n 6  m o nt hs of 
Scree ni n g is n ot a vaila ble, T E pr oce d ures will be 
c o n d ucte d at st u d y sites. Sc he d uli n g of t he T E 
assess me nt s h o ul d be wit hi n t he Scree ni n g wi n d o w . 
Ser u m pre g na nc y 
testi n g 
X  
 
 
 
 
 
 
 
 
 
Re q uire d f or all fe males.  
Uri ne pre g na nc y 
testi n g 
 
X  
 
 
X  
X  
X  
X  
X  
X  
Re q uire d f or all fe males.  
P h ysical 
e xa mi nati o n 
X  
 
 
 
 
 
 
X  
 
X  
S y m pt o m directe d p h ysical e xa mi na ti o ns t o assess 
cli nicall y si g nifica nt c ha n ges fr o m Scree ni n g or a n y 
ne w si g ns or s y m pt o ms ma y be c o n d ucte d at ot her 
visits as deter mi ne d b y t he I n vesti gat or base d o n 
s u bject c o m plai nt (Secti o n  1 2. 6 ).  
Sta n dar d  1 2 -lea d 
E C G  
X  
X  
 
 
 
X  
 
X  
X  
X  
T o be perf or me d i n a s u pi ne p ositi o n after ≥5  mi n utes 
of rest.  
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I ncl u des sitti n g s yst olic a n d diast olic bl o o d press ure, 
p ulse rate, o x y ge n sat urati o n, b o d y te m perat ure, a n d 
res pirat or y rate, meas ure d after ≥5 mi n utes of rest. 
Als o i ncl u des wei g ht, w hic h s h o ul d be mea s ure d wit h 
n o s h oes o n a n d usi n g a cali brate d scale t hr o u g h o ut t he 
st u d y. 
C he mistr y, 
he mat ol o g y, a n d 
uri nal ysis  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dra w n after a n o ver ni g ht fast ( ≥8 h o urs) a n d pre d ose 
as a p plica ble. Refer t o Secti o n  1 2. 8  f or c he mistr y, 
he mat ol o g y, a n d uri nal ysis assess me nts.  
C oa g ulati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Refer t o Secti o n  1 2. 8  f or c oa g ulati o n assess me nts.  
T h yr oi d h or m o nes  
 
X  
 
 
 
X  
 
X  
 
X  
Refer t o Secti o n  1 2. 8  f or t h yr oi d h or m o ne assess me nts.  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial  
Pa ge 8 6 of 1 2 8 
Assess me nt  
Scree ni n g  
D o u ble -Bli n d Tre at me nt  
O pe n -L a bel 
E xte nsi o n  
F oll o w -
U p  
E arl y 
St u d y 
Ter m  
N otes  
Visit  
Visit 1 a Visit 2  
Da y 1  
Visit 3   
Wee k 1   
Visit 4  
Wee k 2  
Visit 5  
Week 3  
Visit 6  
Week 6  
Visit 7  
Week 9  
Visit 8   
Week 1 2  
Visit 9  
St u d y D a y  
Da ys -2 8 
t o -1  
Da y 1  
Da y 8  
Da y 1 5  Da y 2 2  Da y 4 3  Da y 6 4  
 
Da y 8 5  2 wee ks 
( ±3 day s) 
after last 
d ose  
≤2 da ys 
after last 
d ose  
Visit Wi n d o w  
N o ne  
N o ne b ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s ± 3  da y s 
Visit T y pe f or  
H y bri d M o del c 
Site o nl y  
Site 
o nl y  
Site or  
Re m ote  
Site or  
Re m ote  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
Site or  
Re m ote  
Site 
o nl y  
 
C o nc o mita nt 
me dicati o ns   
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
Rec or d all me dicati o ns ta ke n wit hi n 1 4 da ys bef ore 
Scree ni n g a n d me dicati o ns ta ke n t o treat a c h olestatic 
dis or der a n d a n y pr urit us wit hi n 1 2 wee ks a n d 4 wee ks, 
res pecti vel y, bef ore Scree ni n g. 
A E assess me nt  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
T o be d oc u me nte d fr o m t he si g ni n g of t he I nf or me d 
C o nse nt F or m u ntil t he e n d of st u d y partici pati o n.  
P h ar m ac o ki netic  Assess m e nts   
A E = a d verse e ve nt; C D = Cr o h n’s d isease; C D AI = Cr o h n’s Disease Acti vit y I n de x; 
; 
E C G  = electr ocar di o gra m; 
; H A V = he patitis A vir us; H B V = he patitis B vir us; H C V = he patitis C vir us; H E V = he patitis E 
vir us ; HI V = h u ma n i m m u n o deficie nc y vir us; I g G 4 = i m m u n o gl o b uli n G 4 ; I W R S = I nteracti ve We b Res p o nse S yste m ; P GI -C = Patie nt Gl o bal I m pressi o n of 
C ha n ge; P GI -S = Patie nt Gl o bal I m pressi o n of Se verit y; P K  = p har mac o ki netic; 
; T E = tra nsie nt 
elast o gra p h y; Q D = o nce dail y; Ter m  = ter mi nati o n; U C = ulcerati ve c olitis; WI-N R S  = W orst Itc h N u meric Rati n g Scale.  
S u bjects s h o ul d fast f or at least 8 h o urs bef ore eac h d ose of st u d y dr u g a n d bef ore st u d y da ys t hat re q uire a bl o o d sa m ple f or assess me nt of c he mistr y , P K  
( pre d ose), or c o m pleti o n of q uesti o n naires.  
a Visit 1 ( Scree ni n g) ma y be c o n d ucte d o ver m ore t ha n 1 da y b ut m ust be c o m plete d bet wee n Da y -2 8  a n d Da y -1.  
b F or t he dece ntralize d m o del , e nr oll me nt/ra n d o mizati o n a n d t he first d ose of st u d y dr u g ma y be se parate d b y u p t o 1 0 a d diti o nal cale n dar da ys t o all o w f or 
h o me deli ver y of st u d y dr u g.  If e nr oll me nt/ra n d o mizati o n is c o n d ucte d o n a se parate da y t ha n d osi n g, t he eli gi bilit y c hec k s h o ul d als o be c o n d ucte d d uri n g t he 
sa me da y as e nr oll me nt/ra n d o mizati o n. A d diti o nall y, c o nfir mati o n t hat WI-N R S has bee n c o m plete d dail y a n d assess me nts of c o nc o mita nt me dicati o n usa ge 
a n d A Es are t o be c o n d ucte d o n b ot h da ys (ie, date of e nr oll me nt/ra n d o mizati o n a n d date of first d ose). All ot her assess me nts liste d are t o be c o n d ucte d o n t he 
date of first d ose o nl y.  
c F or t he h y bri d m o del, Visits 1, 2, 6, a n d 8 ( Scree ni n g, Da y 1, Wee k 6, a n d Wee k 1 2) a n d  earl y ter mi nati o n (if a p plica ble) m ust be c o m plete d at t he st u d y site. 
All ot her st u d y visits ma y be c o n d ucte d re m otel y, w here all o we d per re g ulat or y/l oc al re q uire me nts. F or t he dece ntralize d m o del, all visits will be c o n d ucte d 
re m otel y.  
F or re m ote visit s f or b ot h t he h y bri d a n d dece ntralize d m o dels, t he h o me healt h n urse visit at t he s u bject's h o me or w or k a n d t he tele me dici n e visit wit h t he 
st u d y site staff f or a gi ve n st u d y visit ma y be c o n d ucte d o n differe nt da ys b ut m ust be wit hi n t he all o wa ble visit  wi n d o w. T he h o me healt h n urse will c o m plete 
t he st u d y assess me nts t hat t he site is p h ysicall y u na ble t o c o m plete re m otel y (e g, bl o o d a n d la b sa m ple c ollecti o n, vital si g ns, E C Gs); t he site will c o m plete all 
ot her st u d y assess me nts re m ot el y d uri n g t he tele me dici ne visit. A d diti o nal i nf or mati o n f or c o n d ucti n g re m ote visits will be pr o vi de d i n st u d y -s pecific 
ma n ual(s).  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 8 8 of 1 2 8 
A P P E N DI X  C.  5- D I T C H S C A L E  
1. D ur ati o n:  D uri n g t he last 2 wee ks, h o w ma n y h o urs a da y ha v e y o u bee n itc hi n g? 
 
Less t ha n 6 hrs/ da y  
1  
6 -1 2 hrs/ da y  
2 
1 2 -1 8 hrs/ da y  
3 
1 8 -2 3 hrs/ da y  
4 
All da y  
5 
2. De gree:  Pleas e rate t h e i nte nsit y of y o ur itc hi n g o ver t he past 2 w ee ks. 
 
N ot prese nt  
1  
Mil d  
2 
M o derate  
3 
Se vere  
4 
U n beara ble  
5 
3. Directi o n:  O v er t he p ast 2 wee ks has y o ur itc hi n g g otte n better or w ors e c o m pare d t o t he 
pre vi o us m o nt h? 
 
C o m pletel y 
res ol ve d 
1  
M uc h better, b ut 
still prese nt 
2 
Little bit better, 
b ut still prese nt  
3 
 
U nc ha n ge d 
4 
 
Getti n g w orse  
5 
4. Dis a bilit y:  Rate t he i m pact of y o ur itc hi n g o n t he f oll o wi n g acti vities o ver t he last 2 wee ks. 
 
 
 
Slee p  
 
 
Ne ver  
affects slee p 
1  
 
Occasi o nall y 
dela ys  
falli n g aslee p 
2 
 
Fre q ue ntl y  
dela ys falli n g 
aslee p 
3 
Dela ys falli n g aslee p  
a n d occasi o nall y 
wa kes me u p  
at ni g ht 
4 
Dela ys falli n g  
aslee p a n d fre q ue ntl y 
wa kes me u p  
at ni g ht 
5 
 
 
 
 
 
 
 
 
 
 
Leis ure/  
S oci al  
 
 
N/ A  
Ne ver  
affects  
t his acti vit y 
1 
Rarel y  
affects  
t his acti vit y 
2 
Occasi o nall y 
affects  
t his acti vit y 
3 
Fre q ue ntl y  
affects  
t his acti vit y 
4 
Al wa ys  
affects  
t his acti vit y 
5 
H o use w o r k/ 
Err a n ds  
 
 
1  
 
2  
 
3  
 
4  
 
5  
W or k/  
Sc h o ol  
 
 
1  
 
2  
 
3  
 
4  
 
5  
5. Distri b uti o n:  Mar k w het her  itc hi n g has bee n pres e nt i n t he f oll o wi n g parts of y o ur b o d y o ver 
t he last 2 wee ks. If a b o d y part is n ot liste d, c h o ose t he o ne t hat is cl osest a nat o micall y. 
 
 
 
 
 
 
 
Hea d/ Scal p  
Face  
C hest  
A b d o me n  
Bac k  
B utt oc ks  
T hi g hs  
L o wer Le gs  
T o ps of Feet/ T oes  
 Prese nt  
  
 
 
 
S oles  
Pal ms  
T o ps of Ha n ds/ Fi n gers  
F orear ms  
U p per Ar ms  
P oi nts of C o ntact w/ Cl ot hi n g    
  (e g, waist ba n d, u n d er gar me nt) 
Gr oi n  
 Prese nt  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 8 9 of 1 2 8 
A P P E N DI X  D.  P A TI E N T G L O B A L I M P R E S SI O N O F S E V E RI T Y  ( P GI-S)  
 
H o w w o ul d y o u rate t he se verit y of y o ur itc h i n t he past 7 da ys?  
 
N o ne  
Mil d  
M o derate 
Se vere  
 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 0 of 1 2 8 
A P P E N DI X  E. P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E ( P GI-C)  
 
 
 
C o m pare d t o bef ore y o u starte d ta ki n g t he st u d y dr u g , h o w w o ul d yo u rate y o ur  
itc h i n t he past 7 da ys: 
C hec k  o ne o nl y:  
 
 
M uc h I m pr o ve d  
 
M o deratel y  I m pr o ve d 
 
Mi ni mall y I m pr o ve d  
 
N o C ha n ge  
 
Mi ni mall y W orse  
 
M o deratel y  W orse  
 
M uc h W orse  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 1 of 1 2 8 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 2 of 1 2 8 
 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 3 of 1 2 8 
 
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 4 of 1 2 8 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 7 of 1 2 8 
Secti o n  
A m e n d m e nt 2. 0 
A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
• 
Pr o ges t o ge n o nl y h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n 
of o v ulati o n  
• 
I ntra uteri ne de vice 
• 
I ntra uteri ne h or m o ne releasi n g 
s yste m 
• 
Bilateral t u bal occl usi o n 
• 
Vasect o mize d part ner  
• 
Se x ual a bsti ne nce (c o m plete se x ual 
a bsti ne nce defi ne d as refrai ni n g  fr o m 
heter ose x ual i nterc o urse f or t he e ntire 
peri o d of ris k ass ociate d wit h st u d y 
dr u g), t he relia bilit y of w hic h nee ds t o 
be e val uate d i n relati o n  t o t he d urati o n 
of t he cli nical st u d y a n d t he preferre d 
a n d us ual lifest yle of t he s u bject  
 Effecti ve met h o ds of c o ntrace pti o n 
i ncl u de barrier met h o ds of c o ntrace pti o n 
(e g, male c o n d o m, fe male c o n d o m, 
cer vical ca p or dia p hra g m, a n d 
c o ntrace pti ve s p o n ge)  
• 
Vasect o mize d part ner  
• 
Se x ual a bsti ne nce (c o m plete se x ual 
a bsti ne nce defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse f or t he e ntire peri o d 
of ris k ass ociate d wit h st u d y dr u g), t he 
relia bilit y of w hic h nee ds t o be e val uate d i n 
relati o n t o t he d urati o n of t he cli nical st u d y 
a n d t he preferre d a n d us ual lifest yle of t he 
s u bject  
1W o m e n of c hil d be ari n g p ote nti al are 
defi ne d as t h ose w h o are fertile, f oll o wi n g 
m e n arc he a n d u ntil bec o mi n g 
p ost m e n o p a us al  u nless per m a ne ntl y 
sterile. Per m a ne nt sterilizati o n m et h o ds 
i ncl u de h ysterect o m y, bil ater al 
s al pi n gect o m y, a n d bil ater al 
o o p h orect o m y. A p ost m e n o p a us al st ate is 
defi ne d as n o m e nses f or 1 2 m o nt hs 
wit h o ut a n alter n ati ve m e dic al c a use.  
S y n o psis (I ncl usi o n Criteria)  
8. 1 S u bject I ncl usi o n Criteria  
8. If male a n d is n ot s ur gicall y sterile f or 
at least 3 m o nt hs, m ust be willi n g t o n ot 
d o nate s per m a n d m ust a gree t o use a 
barrier met h o d of c o ntrace pti o n (e g, 
c o n d o m) d uri n g i nterc o urse a n d at least 
1 ot her acce pta ble c o ntrace pti ve 
meas ure (e g, h or m o nal c o ntrace pti ves, 
i ntra uteri ne de vice, fe male s ur gical 
sterilizati o n, or a bsti ne nce) fr o m 
Scree ni n g t hr o u g h 3 0  da ys  after t he last 
d ose of st u d y dr u g  
Delete d text  
T he c o ntrace pti ve re q uire me nts 
were c ha n ge d i n acc or da nce wit h 
t he Cli nical Trial Facilitati o n 
Gr o u p rec o m me n dati o ns relate d t o 
c o ntrace pti o n a n d pre g na nc y 
testi n g gi ve n t he u nli kel y ris k of 
h u ma n terat o ge nicit y/fet ot o xicit y 
as deter mi ne d fr o m rece ntl y 
c o m plete d n o ncli nical st u dies.  
 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 8 of 1 2 8 
Secti o n  
A m e n d m e nt 2. 0 
A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
S y n o psis (I ncl usi o n Criteria)  
8. 1 S u bject I ncl usi o n Criteria  
1 2 . If c urre ntl y ta ki n g urs o de o x yc h olic 
aci d ( U D C A), m ust be treate d f or 
≥1  year, a n d  m ust be o n a sta ble d ose of 
n ot m ore t ha n 2 0 m g/ k g/ da y f or ≥1 2 
wee ks. If n ot c urre ntl y ta ki n g U D C A, 
m ust n ot be treate d wit h U D C A wit hi n 
1 2 wee ks bef ore Scree ni n g or pla n t o be 
treate d wit h U D C A d uri n g t he st u d y 
1 1 . If c urre ntl y ta ki n g urs o de o x yc h olic acid 
( U D C A), m ust be o n a sta ble d ose of n ot 
m ore t ha n 2 0 m g/ k g/ da y f or ≥1 2 wee ks. If 
n ot c urre ntl y ta ki n g U D C A, m ust n ot be 
treate d wit h U D C A wit hi n 1 2 wee ks bef ore 
Scree ni n g or pla n t o be treate d wit h U D C A 
d uri n g t he st u d y  
D urati o n of U D C A treat me nt was 
dec rease d fr o m 1 year t o 1 2 wee ks 
t o increase eli gi bilit y f or 
partici pati o n i nt o t he st u d y wit h o ut 
i m pacti n g safety.  
S y n o psis (I ncl usi o n Criteria)  
8. 1 S u bject I ncl usi o n Criteria  
1 4 . If c urre ntl y ta ki n g U D C A, m ust be 
treate d f or ≥1 year, a n d m ust be o n a 
sta ble d ose of n ot m ore t ha n 2 3 
m g/ k g/ da y f or ≥1 2 wee ks. If n ot 
c urre ntl y ta ki n g U D C A, m ust n ot be 
treate d wit h U D C A wit hi n 1 2 wee ks 
bef ore Scree ni n g or pla n t o be treate d 
wit h U D C A d u ri n g t he st u d y 
1 3 . If c urre ntl y ta ki n g U D C A, m ust be o n a 
sta ble d ose of n ot m ore t ha n 2 3 m g/ k g/ da y 
f or ≥1 2 wee ks. If n ot c urre ntl y ta ki n g 
U D C A, m ust n ot be treate d wit h U D C A 
wit hi n 1 2 wee ks bef ore Scree ni n g or pla n t o 
be treate d wit h U D C A d uri n g t he st u d y  
D urati o n of U D C A treat me nt was 
decrease d fr o m 1 year t o 1 2 wee ks 
t o increas e eli gi bilit y f or 
partici pati o n i nt o t he st u d y wit h o ut 
i m pacti n g safety.  
S y n o psis ( E xcl usi o n Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
1 5. Has  a n y of t he f oll o wi n g la b orat or y 
res ults at Scree ni n g:  
a. 
T otal bilir u bi n > U L N ; t otal bilir u bi n 
> U L N  is acce pta ble for s u bjects 
wit h me dicall y d oc u me nte d 
Gil bert’s s y n dr o me if direct 
bilir u bi n is < 0. 3  m g/ d L  
1 5.  Has  a n y of t he f oll o wi n g la b orat or y 
res ults at Screeni n g:  
a. 
T otal bilir u bi n > 2 . 0 m g/ d L; t otal 
bilir u bi n > 2 . 0 m g/ d L is acce pta ble f or 
s u bjects wit h me dicall y d oc u me nted 
Gil bert’s s y n dr o me if direct bilir u bi n is 
< 0. 3  m g/ d L  
T o f urt her all o w f or E P 2 6 2 t o be 
e val uate d i n a st u d y p o p ulati o n t hat 
is mea ni n gf ull y m ore c haracteristic 
of t he br oa der p o p ulati o n of pre -
cirr h otic patie nts wit h P B C a n d 
P S C wit h o ut i m pacti n g s u bject 
safet y. 
S y n o psis ( E xcl usi o n Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
1 6.  Esti mate d gl o mer ular filtrati o n rate 
< 9 0  m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y 
t he C hr o nic Ki d ne y Disease 
E pi de mi ol o g y C olla b orati o n e q uati o n at 
Scree ni n g  
1 6.  Esti mate d gl o mer ular filtrati o n rate 
< 6 0  m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t he 
C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n e q uati o n at Scree ni n g  
T o f urt her all o w f or E P 2 6 2 t o be 
e val uate d i n a st u d y p o p ulati o n t hat 
is mea ni n gf ull y m ore c haracteristic 
of t he br oa der p o p ulati o n of p re-
cirr h otic patie nts wit h  P B C a n d 
P S C wit h o ut i m pacti n g s u bject 
safet y. 
S y n o psis ( E xcl usi o n Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
2 3. P ositi ve se vere ac ute res pirat or y 
s y n dr o me c or o na vir us 2 ( S A R S C o V 2) 
re verse tra nscri pti o n p ol y merase c hai n 
reacti o n ( R T P C R) test at Scre e ni n g  
 
Delete d text  
Testi n g f or S A R S -C o V -2 was 
re m o ve d gi ve n rece nt 
a d va nce me nts i n t he pre ve nti o n  
a n d treat me nt of t he vir us.  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 9 9 of 1 2 8 
Secti o n  
A m e n d m e nt 2. 0 
A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
S y n o psis ( W orst Itc h 
N u meric Rati n g Scale 
[ WI-N R S ]) 
1 1. 1. 1  W orst Itc h N u meric 
Rati n g Scale ( WI -N R S)  
 
T he a vera ge WI -N R S sc ore usi n g t he 
dail y val ues fr o m t he wee k bef ore t he 
first d ose of st u d y dr u g ( Visit 2 [ Da y 1]) 
will ser ve as t he baseli ne sc ore. T he 
dail y WI -N R S sc ores fr o m Da y 3 6 
t hr o u g h Da y 4 3 will be a vera ge d 
t o get her f or pri mar y e n d p oi nt a nal yses. 
T he  a vera ge WI-N R S sc ore usi n g t he dail y 
val ues fr o m t he wee k bef ore t he first d ose of 
st u d y dr u g ( Visit 2 [ Da y 1]) will ser ve as t he 
baseli ne sc ore. T he 7  dail y WI -N R S sc ores 
pri or t o  Visit 6 ( Wee k 6)  will be a vera ge d 
t o get her f or pri mar y e n d p oi nt a nal yses. 
Usi n g t he 7 da ys pri or t o Visit 6 
( Wee k 6) i nstea d of a defi ne d 
ra n ge of dates f or t he pri mar y 
e n d p oi nt a nal yses all o ws f or m ore 
fle xi bilit y as t he date ra n ge ma y 
c ha n ge de pe n di n g o n w he n t he 
sc he d ule d visit is c o n d ucte d d uri n g 
t he visit wi n d o w. 
5. 3  E P 5 4 7  a n d St u d y  
Rati o nale  
Cli nical safet y a n d p har mac o ki netics 
( P K) of E P 5 4 7 are base d o n t he 
preli mi nar y  res ults fr o m St u d y 
E P -5 4 7 -1 0 1, a first -i n-h u ma n 
ra n d o mize d, P hase 1 cli nical st u d y of 
oral si n gle a n d m ulti ple dail y d oses of 
E P 5 4 7 i n healt h y s u bjects, i n  s u bjects 
wit h c h olestatic dis or ders wit h pr urit us, 
a n d i n he m o dial ysis s u bjects wit h 
ure mic pr urit us.  
Cli nical safet y a n d p har mac o ki netics ( P K) of 
E P 5 4 7 are base d o n t he res ults fr o m St u d y 
E P -5 4 7 -1 0 1, a first -i n-h u ma n ra n d o mize d, 
P hase 1 cli nical st u d y of  oral si n gle a n d 
m ulti ple dail y d oses of E P 5 4 7 i n healt h y 
s u bjects, i n s u bjects wit h c h olestatic 
dis or ders wit h pr urit us, a n d i n he m o dial ysis 
s u bjects wit h ure mic pr urit us. 
“ Preli mi nar y” was re m o ve d as t he 
P hase 1 St u d y E P -5 4 7 -1 0 1 is 
c o m plete a n d t he res ul ts are fi nal. 
5. 4  E P 5 4 7 D ose Rati o nale  
T here were n o preli mi nar y  safet y or 
t olera bilit y iss ues o bser ve d i n t he 
c h olestatic pr urit us p o p ulati o n i n t he 
7 5 -m g si n gle a n d 3 0-m g  m ulti ple d ose 
e val uati o ns. 
T here were n o safet y or t olera bilit y iss ues 
o bser ve d i n  t he c h olestatic pr urit us 
p o p ulati o n i n t he 7 5 -m g si n gle a n d 3 0 -m g  
m ulti ple d ose e val uati o ns.  
“ Preli mi nar y” was re m o ve d as t he 
P hase 1 St u d y E P -5 4 7 -1 0 1 is 
c o m plete a n d t he res ults are fi nal.  
5. 5 S u m mar y of Be nefits a n d 
Ris ks  
Ne w secti o n a d de d  
5 . 5. S u m m ar y  of Be nefits a n d Ris ks  
5. 5. 1.  
Be nefit S u m m ar y  
T his st u d y is i n vesti g ati n g a p ote nti al 
be nefit of E P 5 4 7 t o relie ve or lesse n 
c h olest atic itc h , w hic h m a y als o be 
ass oci ate d wit h a n i m pr o ve m e nt i n 
f ati g ue, q u alit y of slee p, a n d o ver all 
q u alit y of l ife. E P 5 4 7 is n ot i nte n de d t o 
i m pr o ve a s u bject’s c h olest atic li ver 
dise ase.  
5. 5. 2.  
Ris k S u m m ar y a n d Miti g ati o n 
Str ate g y  
T his c ha n ge reflects t he Fre nc h 
E t hics C o m mittee re q uire me nt t o 
i ncl u de a be nefit:ris k a nal ysis.  

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A m e n d m e nt 2. 0 
A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
‘ pr otei n uri ne prese nt’ a d verse e ve nts 
[A Es ] as i de ntifie d b y t he St a n d ar dize d 
Me dic al Dicti o n ar y f or Re g u l at or y 
Acti vities [ Me d D R A] Q uer y [ S M Q] 
‘ Ac ute re n al f ail ure’) will be c o nsi dere d 
A Es  of s peci al i nterest ( A E SI, Secti o n 
1 2. 1. 5). S u bjects will be cl osel y m o nit ore d 
f or o bser v ati o ns of A KI, an d st u d y dr u g 
m a y be i nterr u pte d f or s u bjects w h o 
e x perie nce ele v ati o ns i n ser u m cre ati ni ne 
le vels acc or di n g t o t he al g orit h m 
descri be d i n Secti o n 1 2. 1 3 . 4.   
5. 5. 3.  
O ver all Be nefit: Ris k C o ncl usi o n  
O ver all, t he s afet y m e as ures t o be 
e m pl o ye d a n d t he cli nic a l e x perie nce t o 
d ate wit h E P 5 4 7 s u g gest mi ni m al ris k t o 
s u bjects partici p ati n g i n St u d y E P -5 4 7 -
2 0 1. Alt h o u g h a v ariet y of i nter ve nti o ns 
f or c h olest atic pr urit us h a ve bee n 
e x pl ore d, t here is c urre ntl y n o m e dic ati o n 
a p pr o ve d f or t his i n dic ati o n i n a d ults, a n d 
t he nee d f or i m pr o ve d tre at m e nts re m ai ns 
hi g h. T heref ore, de vel o p m e nt of 
a d diti o n al s afe a n d effecti ve, 
m ec h a nistic all y b ase d t her a pe utic o pti o ns 
f or t his c o n diti o n is esse nti al. If 
deter mi ne d t o be effecti ve i n t his st u d y, 
E P 5 4 7 m a y ulti m atel y h a ve t he p ote nti al 
t o offer s u bst a nti al relief f or p atie nts 
s ufferi n g fr o m c h olest atic pr urit us, 
i ncl u di n g t h ose e nr olle d i n t his st u d y. 
C o nsi deri n g all a v ail a ble s afet y 
i nf or m ati o n a n d m e as ures t a k e n t o 
mi ni mize ris k t o s u bjects, t he o ver all 
be nefit -ris k pr ofile o f E P 5 4 7 is dee m e d t o 
be acce pt a ble f or t he c o n d uct of St u d y 
E P -5 4 7 -2 0 1 . 

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A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
7. 2 E n d of St u d y  
Ne w secti o n a d de d  
7. 2.  E n d of St u d y  
A s u bject is c o nsi dere d t o h a ve c o m plete d 
t he st u d y if he/s he h as c o m plete d all 
p h ases of t he st u d y, i ncl u di n g t he l ast 
st u d y visit (ie, t he F oll o w-U p Visit 
[ Visit 9]).   
T he e n d of t he st u d y is defi n e d as t he d ate 
of t he l ast st u d y visit of t he l ast s u bject i n 
t he st u d y gl o b all y. 
T his c h a n ge reflects t he A N S M 
re q uire me nt t o defi ne t he e n d of 
st u d y i n t he pr ot oc ol.  

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A m e n d m e nt 2. 0 
A m e n d m e nt 3. 0  
Re as o n f or C h a n ge  
1 2. 1 3. 1 P ote ntial Si de Effects  
(Previ o usly 1 2. 1 4. 1 i n 
A me n d me nt 2. 0 ) 
Preli mi nar y safet y res ults fr o m t he 
P hase  1 St u d y E P -5 4 7 -1 0 1 di d n ot 
re veal a n y safet y tre n ds, a n d t here were 
n o T E A Es assesse d as e x pecte d wit h t he 
use of E P 5 4 7. Refer t o t he I n vesti gat or’s 
Br oc h ure f or a d diti o nal E P 5 4 7 
i nf or mati o n re gar di n g p ote ntial si de 
effects.  
S afet y res ults fr o m t he P hase 1 St u d y 
E P -5 4 7 -1 0 1 di d n ot re veal a n y safet y tre n ds, 
a n d t here  were n o T E A Es assesse d as 
e x pecte d wit h t he use of E P 5 4 7. Refer t o t he 
I n vesti gat or’s Br oc h ure f or a d diti o nal E P 5 4 7 
i nf or mati o n re gar di n g p ote ntial si de effects.  
“ Preli mi nar y” was re m o ve d as t he 
P hase 1 St u d y E P -5 4 7 -1 0 1 is 
c o m plete a n d t he res ults are fi n al. 
1 5. 9 Et hical C o n d uct of t he 
St u d y  
Ne w secti o n a d de d  
1 5. 9.  
Et hic al C o n d uct of t he St u d y  
T his st u d y s h all be c o n d ucte d i n 
acc or d a nce wit h t he et hic al pri nci ples t h at 
h a ve t heir ori gi n i n t he Decl ar ati o n of 
Helsi n ki a n d t h at are c o nsiste nt wit h G C P, 
I C H g ui deli nes, ot her a p plic a ble 
re g ul at or y re q uire m e nts (e g, l oc al 
re q uire m e nts), t he st u d y pr ot oc ol, a n d 
w here a p plic a ble, S p o ns or a n d/ or C R O 
st a n dar d o per ati n g pr oce d u res.  
T his c ha n ge reflects t he Fre nc h 
E t hics C o m mittee re q uire me nt t o 
i ncl u de refere nces t o t he 
Declarati o n of Helsi n ki a n d G o o d 
Cli nical Practice.  
A p pe n di x A.  Sc he d ule o f 
Assess me nts  
S A R S -C o V -2 R T -P C R testi n g w as t o be 
c o m plete d at Vi sit 1 
S A R S -C o V -2 R T -P C R testi n g w as re m ove d 
fr o m Visit 1  a n d t he defi niti o ns f or S A R S -
C o V - 2 a n d  R T -P C R were re m ove d fr o m t he 
list of a b brevi ati o ns i n t he t a ble f o ot n otes.  
Testi n g f or S A R S -C o V -2 was 
re m o ve d gi ve n rece nt 
a d va nce me nts i n t he pre ve nti o n  
a n d treat me nt of t he vir us. 
A p pe n di x E.  Patie nt Gl o bal 
I m pressi o n o f C ha n ge 
( P GI-C)  
C hec k o ne b o x  o nl y:  
C hec k o ne o nl y:  
Re vise d t o better reflect t he 
i nf or mati o n prese nte d. 
 
 
 

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S u m m ar y of C h a n ges f or A m e n d m e nt 2 . 0 D ate d 2 0 A pril 2 0 2 2 
Pr ot oc ol E P- 5 4 7- 2 0 1 was a me n de d t o i ncrease o p p ort u nities f or re m ote visits t o ease s u bject b ur de n ass ociate d wit h partici p ati n g i n 
t his cli nical st u d y. Pre vi o usl y, s u bjects were a ble t o atte n d st u d y visits at a p h ysical st u d y site as well as re m otel y ( h y bri d m o del) 
w here all o we d per re g ulat or y/l ocal re q uire m e nts. A me n d me nt 2. 0 i ntr o d uces a n ot her o pti o n t hat all o ws all visits t o be c o n d ucte d 
re m otel y at a virt ual site ( dece ntralize d m o del) w h ere all o w e d per re g ulat or y/l ocal re q uire me nts . C ha n ges t o s u p p ort t he dece ntralize d 
m o del i ncl u de: 
•  Re visi n g Visit 2 ( Da y 1) f or s u bjects partici pati n g i n t he dece ntralize d m o d el s o t hat e nr oll me nt/ ra n d o mizati o n a n d first d ose 
ca n occ ur o n diff ere nt d a ys t o all o w ti me f or st u d y dr u g t o be deli vere d t o a s u bject’s h o me  
•  Clarif yi n g t hat hist orical Fi br osca n ®  ass ess me nts wit hi n  6 m o nt hs of Scree ni n g are per mitte d t o assess eli gi bilit y  
•  All o wi n g tra ns p ort of st u d y dr u g fr o m a ce ntral dr u g de p ot t o t he s u bject’s h o me t o strea mli ne dr u g tra ns p ort f or re m ote visits  
•  Re m o vi n g t he nee d t o use a sta di o meter t o meas ure hei g ht as t his de vice m a y n ot be rea dil y a vaila bl e f or use at re m ote visits   
Refi ne me nts t o t he statistical ass u m pti o ns all o we d f or a re d ucti o n i n sa m ple size fr o m 6 2 s u bjects t o 5 8 s u bjects f or a n al ysis of t he 
pri mar y e n d p oi nt. T he e nr oll me nt tar get f or s u bjects wit h c h olestatic pr urit us d ue t o P B C a n d t he e nr oll me nt ca p f or s u bjects recei vi n g 
treat me nt wit h o betic h olic aci d at b aseli ne were re m o ve d as t he y are n ot re q uire d t o esta blis h pr o of- of-c o nce pt a n d ma y li mit t he 
a bilit y of t he data t o i nf or m t he p o p ulati o n c haracteristics of s u bse q ue nt cli nical st u dies. St u d y dr u g st ora ge c o n diti o ns were als o 
u p date d t o matc h i nstr ucti o ns o n t he la belli n g. 
N ota b le c ha n g es ar e i ncl u de d bel o w i n t he s u m mar y ta ble. Re vise d te xt i n A me n d me nt 2. 0 is u n derli ne d, a n d te xt delete d fr o m t he 
A me n d me nt 1. 0 is cr osse d o ut i n t he ta ble bel o w. Italici ze d te xt is use d t o descri be a c ha n g e. Mi n or/e dit orial c ha n ges are n ot liste d 
i n di vi d uall y i n t he s u m mar y ta ble.  
Secti o n  
A m e n d m e nt 1. 0  
A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
Gl o bal  
site visit  
st u d y visit   
 
Gl o bal  
F oll o w -u p visit w as referre d t o by n a me 
a n d n ot assi g ne d a visit n u m ber.  
T he foll o w -u p visit is n o w als o referre d t o 
as Visit 9 . 
A visit n u m ber f or t he f oll o w-u p 
visit was assi g ne d f or 
c o m plete ness a n d c o nsiste nc y wit h 
t he na mi n g c o n ve nti o n of t he ot her 
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A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
S y n o psis ( Met h o d ol o g y 
Fi g ure)  
7. 1.  O verall St u d y Desi g n  
( Fi g ure 1) 
Ne w f o ot n ote.  
a F or t he dece ntr alize d m o del , 
e nr oll m e nt/r a n d o miz a ti o n a n d t he first 
d ose of st u d y dr u g m a y  be se p ar ate d b y 
u p t o 1 0 a d diti o n al c ale n d ar d a ys t o all o w 
f or h o m e deli ver y of st u d y dr u g. W he n 
e nr oll m e nt/r a n d o miz ati o n a n d first d ose 
of st u d y dr u g are o n se p ar ate d a ys, t he 
first d ose of st u d y dr u g is c o nsi dered D a y 
1.  
Te xt was a d de d t o all o w ti me t o 
tra ns p ort st u d y dr u g bet wee n t he 
ce ntral dr u g de p ot a n d t he 
s u bject’s h o me after ra n d o mizati o n 
f or s u bjects partici pati n g i n t he 
dece ntralize d m o del . 
S y n o psis ( D o u ble -Bli n d 
Treat me nt Peri o d)  
7. 1. 2.  D o u ble -Bli n d 
Treat me nt Peri o d  
Visit 2 ( Da y 1) will n ot ha ve a visit 
wi n d o w; all ot her visits i n t he D o u ble-
Bli n d Treat me nt Peri o d will ha ve a visit 
wi n d o w of ± 3 da ys.  
Visit 2 ( Da y 1) will n ot ha ve a visit 
wi n d o w; h o we ver, f or t he dece ntr alize d 
m o del , e nr oll m e nt/r a n d o miz ati o n a n d t he 
first d ose of st u d y dr u g m a y be se p ar ate d 
b y u p t o 1 0 a d diti o n al c ale n d ar d a ys t o 
all o w f or h o m e deli ver y of st u d y dr u g. 
W he n e nr oll m e nt/r a n d o miz ati o n a n d 
first d ose of st u d y dr u g are o n se p ar ate 
d a ys, t he first d ose of st u d y dr u g is 
c o nsi dere d D a y 1. A ll ot her visits i n t he 
D o u ble -Bl i n d Treat me nt Peri o d will ha ve a 
visit wi n d o w of ± 3 da ys.  
Te xt was a d de d t o all o w ti me t o 
tra ns p ort st u d y dr u g bet wee n t he 
ce ntral dr u g de p ot a n d t he 
s u bject’s h o me after ra n d o mizati o n 
f or s u bjects partici pati n g i n t he 
dece ntralize d m o del . 
S y n o psis ( D o u bl e-Bli n d 
Treat me nt Peri o d)  
7. 1. 2.  D o u ble -Bli n d 
Treat me nt Peri o d  
S u bjects are t o ret ur n t o t he site t o 
c o m plete sc he d ule d assess me nts. 
H o we ver, a h o me healt h n urse visit t o t he 
s u bject’s h o me a n d a tele healt h visit t o 
c o m m u nicate wit h st u d y site staff usi n g 
tec h n ol o g y (e g, s mart p h o ne or c o m p uter) 
i n lie u of a site visit ma y be per mitte d at 
certai n visits if t he s u bject is u na ble t o visit 
t he site b ut is willi n g t o c o nti n ue i n t he 
st u d y. 
Delete d text.  
T he te xt was delete d i n t his secti o n 
a n d a re vise d versi o n was i ncl u de d 
earlier i n t he s y n o psis a n d 
pr ot oc ol.  

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A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
S y n o psis ( N u m ber of 
S u bjects [Pla n ne d ]) 
7. 2.  N u m ber of S u bjects  
A p pr o xi matel y  6 2  s u bjects wit h c h olestatic 
pr urit us d ue t o P B C or P S C will be 
ra n d o mize d i n t he st u d y. At least 5 2 
s u bjects wit h c h olestatic pr urit us d ue t o 
P B C will be ra n d o mize d. T he n u m ber of 
s u bjects recei vi n g treat me nt wit h 
o betic h olic aci d ( O C A) at baseli ne will be 
ca p pe d at a p pr o xi matel y 1 0 s u bjects.  
A p pr o xi matel y  58 s u bjects wit h c h olestatic 
pr urit us d ue t o P B C or P S C will be 
ra n d o mized i n t he st u d y.  
Refi ne me nts t o t he statistical 
ass u m pti o ns all o we d f or a s maller 
sa m ple size f or a nal ysis of t he 
pri mar y e n d p oi nt.  
E nr oll me nt ca ps a n d tar gets f or 
vari o us p o p ulati o ns were re m o ve d 
as t he y are n ot re q uire d t o esta blis h 
pr o of -of -c o nce pt a n d m a y li mit t he 
a bilit y of t he data t o i nf or m t he 
p o p ulati o n c haracteristics of 
s u bse q ue nt cli nical st u dies. 
S y n o psis ( E xcl usi o n 
Criteria)  
8. 2.  S u bject E xcl usi o n 
Criteria  
4.  E vi de nce of c o m pe nsate d or 
dec o m pe nsate d cirr h osis base d o n A N Y of 
t he f oll o wi n g: 
a. Hist orical li ver bi o ps y de m o nstrati n g 
cirr h osis 
b.  Li ver stiff ness as assesse d b y a 
Fi br o Sca n ®  sc ore of ≥1 6. 9 k Pa f or 
s u bjects wit h P B C or ≥1 4. 4 k Pa f or 
s u bjects wit h P S C  
4.  E vi de nce of c o m pe nsate d or 
dec o m pe nsate d cirr h osis base d o n A N Y of 
t he f oll o wi n g: 
a. Hist orical li ver bi o ps y de m o nstrati n g 
cirr h osis 
b.  Li ver stiff ness as assesse d b y a 
Fi br o S ca n ®  sc ore of ≥1 6. 9 k Pa f or s u bjects 
wit h P B C or ≥1 4. 4 k Pa f or s u bjects wit h 
P S C wit hi n 6 m o nt hs of Scree ni n g  
All o wi n g Fi br osca n ®  t o be 
c o n d ucte d wit hi n 6 m o nt hs bef ore 
Da y 1 will i ncrease eli gi bilit y f or 
partici pati o n i nt o t he st u d y wit h o ut 
i m pacti n g safet y a n d is c o m m o nl y 
use d i n cli nical st u dies.  
S y n o psis ( St u d y Dr u g 
St ora ge)  
1 0. 3.  St u d y Dr u g St ora ge  
T he st u d y dr u g ta blets s h o ul d be st ore d at 
c o ntr olle d r o o m te m perat ure, 2 0° C t o 2 5° C 
( 6 8° F t o 7 7° F). 
T he st u d y dr u g ta blets s h o ul d be st ore d at 
c o ntr olle d r o o m te m perat ure, 2 0° C t o 2 5° C 
( 6 8° F t o 7 7° F), wit h e xc ursi o ns all o we d 
bet wee n 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F) . 
St u d y dr u g st ora ge c o n diti o ns were 
u p date d t o matc h i nstr ucti o ns o n 
t he la belli n g.  
S y n o psis ( St u d y Dr u g 
Dis pe nsi n g a n d 
Acc o u nta bilit y ) 
1 0. 5.  St u d y  Dr u g 
Dis pe nsi n g a n d 
Acc o u nta bilit y  
S u bjects s h o ul d be i nstr ucte d t o retai n t he 
st u d y dr u g kit (i ncl u di n g blister 
car ds/ wallets), e ve n if e m pt y, a n d t o ret ur n 
it a n d a n y re mai ni n g st u d y dr u g t o t he 
st u d y site at t heir ne xt visit. 
S u bjects s h o ul d be i nstr uc te d t o retai n t he 
st u d y dr u g kit (i ncl u di n g blister 
car ds/ wallets), e ve n if e m pt y, a n d t o ret ur n 
it a n d a n y re mai ni n g st u d y dr u g t o t he st u d y 
site at t heir ne xt visit or t o a direct -t o-
p atie nt c o urier  ser vice. 
T he te xt was u p date d t o all o w 
tra ns p ort of st ud y dr u g kits 
bet wee n t he s u bject’s h o me a n d 
t he ce ntral dr u g de p ot usi n g a 
c o urier t o better s u p p ort re m ote 
visits.  

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A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
S y n o psis ( Disc o nti n uati o n 
of St u d y Dr u g ) 
8. 5. 1.  Disc o nti n uati o n of 
St u d y Dr u g  
If t he s u bject is u na ble t o visit t he site b ut 
is willi n g t o c o nti n ue i n t he st u d y, a h o me 
healt h n urse visit t o t he s u bject’s h o me a n d 
a tele healt h visit t o c o m m u nicate  wit h 
st u d y site staff usi n g tec h n ol o g y (e g, 
s mart p h o ne or c o m p uter) i n lie u of a site 
visit ma y be per mitte d at certai n visits.  
Delete d text.  
T he te xt was delete d as t his 
a me n d me nt all o ws f or m ore 
o p p ort u nities t o c o n d uct visits 
re m otel y, re gar dless of 
di sc o nti n uati o n stat us. 
S y n o psis ( W orst Itc h 
N u meric Rati n g Scale 
[WI -N R S ]:) 
1 1. 1. 1.  W orst Itc h N u meric 
Rati n g Scale ( WI -N R S)  
1 4. 8.  Efficac y a n d 
P har mac o d y na mic A nal ysis  
T he a vera ge WI N R S sc ore usi n g t he dail y 
val ues fr o m t he wee k bef ore 
ra n d o mizati o n will ser ve as t he baseli ne 
sc ore. 
T he a vera ge WI N R S sc ore usi n g t he dail y 
val ues fr o m t he wee k bef ore t he first d ose 
of st u d y dr u g ( Visit 2 [ D a y 1]) wi ll ser ve 
as t he baseli ne sc ore. 
Gi ve n t hat e nr oll me nt/ 
ra n d o mizati o n a n d first d ose of 
st u d y dr u g ma y occ ur o n differe nt 
da ys f or s u bjects partici pati n g i n 
t he dece ntralize d m o del , t he te xt 
was re vise d t o clarif y h o w t he 
baseli ne sc ore will be calc ulate d.  
S y n o psis ( A d verse E ve nts 
of S pecial I nterest ) 
S y n o psis ( O bser vati o n f or 
Ac ute Ki d ne y I nj ur y ) 
1 2. 1. 5.  A d verse E ve nts of 
S pecial I nterest  
1 2. 1 4. 4.  O bser vati o n f or 
Ac ute Ki d ne y I nj ur y  

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Pa ge 1 1 2 of 1 2 8  
Secti o n  
A m e n d m e nt 1. 0  
A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
9. 4.  St u d y Visits  
A p pe n di x A.  Sc he d ule of 
Assess me nts  
 
Ne w text.  
F or t he h y bri d m o del, Visits 1 , 2, 6, a n d 8 
( Scree ni n g, D a y 1, Wee k 6, a n d Wee k 1 2) 
a n d e arl y ter mi n ati o n (if a p plic a ble) 
m ust be c o m plete d at t he st u d y site. All 
ot her st u d y visits m a y be c o n d ucte d 
re m otel y, w here all o we d per 
re g ul at or y/l oc al re q uire m e nts. F or t he 
dece ntr alize d m o del,  all visits will be 
c o n d ucte d re m otel y.  
F or re m ote visits f or b ot h t he h y bri d a n d 
dece ntr alize d m o dels, t he h o m e he alt h 
n urse visit at t he s u bject's h o m e or w or k 
a n d t he tele m e dici ne visit wit h t he st u d y 
site st aff f or a gi ve n st u d y visit m a y be 
c o n d ucte d o n differe nt d a ys b ut m ust be 
wit hi n t he all o w a ble visit wi n d o w. T he 
h o m e he alt h n urse  will c o m plete t he 
st u d y assess m e nts t h at t he site is 
p h ysic all y u n a ble t o c o m plete re m otel y 
(e g, bl o o d a n d l a b s a m ple c ollecti o n, vit al 
si g ns, E C Gs); t he site will c o m plete all 
ot her st u d y assess m e nts re m otel y d uri n g 
t he tele m e dici ne visit. A d diti o n al 
i nfor m ati o n f or c o n d ucti n g re m ote visits 
will be pr o vi de d i n st u d y -s pe cific 
m a n u al(s).  
A d de d w hic h visits ca n c o n d ucte d 
re m otel y f or t he h y bri d a n d 
dece ntralize d m o del s as well as 
w hic h assess me nts t he h o me healt h 
n urse a n d st u d y site are res p o nsi ble 
f or re m ote visits for b ot h t he 
h y bri d a n d dece ntralize d m o dels 
f or c o m plete ness. 
9. 4. 1. 1.  Visit 1 ( Da y -2 8 t o 
Da y -1)  
•  
Tra nsie nt elast o gra p h y ( T E; 
Fi br o Sca n)  
Tra nsie nt elast o gra p h y ( T E; Fi br o Sca n ; if 
a n eli gi ble hist oric al T E is n ot a v ail a ble 
wit hi n 6 m o nt hs of Scree ni n g ) 
All o wi n g Fi br osca n ®  t o be 
c o n d ucte d wit hi n 6 m o nt hs bef ore 
Da y 1 will i ncrease eli gi bilit y f or 
partici pati o n i nt o t he st u d y wit h o ut 
i m pacti n g safet y a n d is c o m m onl y 
use d i n cli nical s t u dies. 

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Secti o n  
A m e n d m e nt 1. 0  
A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
9. 4. 2. 1.  Visit 2 ( Da y 1)  
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Ne w text.  
F or t he dece ntr alize d m o del , 
e nr oll m e nt/r a n d o miz ati o n a n d t he first 
d ose of st u d y dr u g m a y be se p ar ate d b y 
u p t o 1 0 a d diti o n al c ale n d ar d a ys t o all o w 
f or h o m e deli ver y of st u d y dr u g. If 
e nr oll m e nt/r a n d o miz ati o n is c o n d ucte d 
o n a se p ar ate d a y t h a n d osi n g, t he 
eli gi bilit y c hec k s h o ul d als o be c o n d ucte d 
d uri n g t he s a m e d a y as 
e nr oll m e nt/r a n d o miz ati o n. A d diti o n all y, 
c o nfir m ati o n t h at WI -N R S h as bee n 
c o m plete d d ail y a n d assess m e nts of 
c o nc o mit a nt m e dic ati o n us a ge a n d A Es 
are t o be c o n d ucte d o n b ot h d a ys (ie, d ate 
of e nr oll m e nt/r a n d o miz ati o n a n d d ate of 
first d ose). All ot her assess m e nts liste d 
a b o ve are t o be c o n d ucte d o n t he d ate of 
first d ose o nl y. 
T he sc he d ul e of assess me nts was 
re vise d t o acc o u nt f or t he 
c o m pleti o n of 
e nr oll me nt/ra n d o mizati o n a n d first 
d ose of st u d y dr u g o n differe nt 
cale n dar da ys f or s u bjects 
partici pati n g i n t he dece ntralize d 
m o del . 
1 0. 6.  St u d y Dr u g Ha n dli n g 
a n d Dis p osal  
W here all o we d, t o s u p p ort h o me  visits b y 
a h o me healt h n urse , t he use of a direct-t o-
patie nt c o urier ser vice t o tra ns p ort st u d y 
dr u g bet wee n t he st u d y site a n d s u bject’s 
h o me ma y be arra n ge d  at certai n visits. 
T he c o urier will be as ke d t o c ollect t he 
st u d y dr u g kit dis pe nse d b y t he st u d y site 
staff a n d deli ver it t o t he s u bject’s h o me. 
T he c o urier ma y als o be as ke d t o c ollect 
t he use d st u d y dr u g kit wit h a n y u n use d 
st u d y dr u g fr o m t he s u bject t o be ret ur ne d 
t o t he site f or acc o u nta bilit y wit h  
rec o nciliati o n t o be c o m plete d by t he st u d y 
site staff.  
T o s u p p ort re m ote  st u d y visits  f or t he 
h y bri d a n d dece ntr alize d m o dels , t he use 
of a direct -t o-patie nt c o urier ser vice t o 
tra ns p ort st u d y dr u g bet wee n t he st u d y site 
or ce ntr al dr u g de p ot  a n d t he s u bject’s 
h o me ma y be arra n ge d. T he  c o urier will be 
as ke d t o c ollect t he st u d y dr u g kit dis pe nse d 
b y t he st u d y site staff or ce ntr al dr u g 
de p ot  a n d deli ver it t o t he s u bject’s h o me. 
T he c o urier ma y als o be as ke d t o c ollect t he 
use d st u d y dr u g kit wit h a n y  u n use d st u d y 
dr u g fr o m t he s u bject t o be ret ur ne d t o t he 
site or ce ntr al dr u g de p ot  f or 
acc o u nta bilit y a n d rec o nciliati o n. 
A d diti o n al st u d y dr u g h a n dli n g a n d 
dis p os al i nf or m ati o n f or re m ote visits will 
be pr o vi de d i n st u d y -s pecific m a n u al(s). 
T he te xt was  u p date d t o all o w 
tra ns p ort of st u d y dr u g bet wee n t he 
ce ntral dr u g de p ot a n d t he 
s u bject’s h o me t o better s u p p ort 
re m ote visits. 

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C o nfi de ntial 
Pa ge 1 1 4 of 1 2 8  
Secti o n  
A m e n d m e nt 1. 0  
A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
1 1. 4.  Hei g ht  
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Hei g ht will be meas ure d usi n g a 
sta di o meter wit h n o s h oes.  
Hei g ht will be m eas ure d wit h n o s h oes. 
T he met h o d i n  w hic h hei g ht is t o 
be meas ure d was re m o ve d as 
sta di o meters ma y n ot be rea dil y 
a vaila ble f or use at re m ote visits.   
1 2.  Safet y Assess me nts  
Ne w text.  
F or t he dece ntr alize d m o del, t he 
I n vesti g at or m a y re q uire t he s u bject t o 
h a ve a n i n-pers o n c o ns ult ati o n wit h a 
p h ysici a n after virt u all y c o n d ucti n g 
s afet y assess m e nts, if dee m e d necess ar y. 
All o wi n g t he I n vesti gat or t o 
re q uire t he s u bject t o ha ve a n i n -
pers o n c o ns ultati o n wit h a 
p h ysicia n f or a n y s u bject after 
virt uall y c o n d ucti n g safet y 
assess me nts f or t he de ce ntralize d 
m o del was a d de d t o e ns ure s u bject 
safet y. 
1 2. 1. 2.  Deter mi ni n g 
Se verit y of A d verse E ve nts  
Ne w text.  
All C T C A E Gr a de 3 or hi g her m ust be 
re p orte d t o t he S p o ns or or desi g nee  usi n g 
t he S A E/ A E SI/ Gr a de 3 + Re p ort F or m , 
acc or di n g t o t he ti m eli nes descri be d f or 
S A Es i n Secti o n  1 2. 2. 2 . 
Re p orti n g re q uire me nts f or 
C T C A E Gra de 3 or hi g her was 
s pecifie d as the D M C will ma ke a 
deter mi nati o n of relate d ne ss f or all 
C T C A E G ra de 3 or hi g her . 
1 2. 6.  P h ysical E xa mi nati o ns  Ne w text.  
F or t he dece ntr alize d m o del, t he 
I n vesti g at or, assiste d b y t he m o bile 
n urse, will c o n d uct p h ysic al e x a mi n ati o ns 
per pr ot oc ol vi a tele m e dici ne d uri n g a 
vi de oc o nfere nce sessi o n. 
T he l o gistics f or c o n d ucti n g t he 
p h ysical e xa m f or t he dece ntralize d 
m o del was a d de d f or 
c o m plete ness.  
1 2. 1 0.  Tr a nsie nt 
Elast o gra p h y  
T E pr oce d ures will be c o n d ucte d at st u d y 
sites wit h t he a p pr o priate e q ui p me nt a n d 
b y a de q uatel y trai ne d st u d y sit e staff.  
If an eli gi ble  hist oric al T E wit hi n 6 
m o nt hs of D a y  1 is n ot a v ail a ble,  T E 
pr oce d ures will be c o n d ucte d at st u d y  sites 
wit h t he a p pr o priate e q ui p me nt a n d b y 
a de q uatel y trai ne d st u d y site staff. 
Sc he d uli n g of t he T E assess m e nt s h o ul d 
be wit hi n t he  Scree ni n g wi n d o w ( D a y -2 8 
t o D a y -1).  
A ll o wi n g hist orical Fi br osca n®  
assess me nts a n d e x pa n di n g t he 
Fi br osca n ®  assess me nt wi n d o w t o 
6 m o nt hs bef ore Scree ni n g  will 
ease o verall b ur de n a n d sc he d uli n g 
c o nstrai nts. 

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Pa ge 1 1 5 of 1 2 8  
Secti o n  
A m e n d m e nt 1. 0  
A m e n d m e nt 2 . 0 
Re as o n f or C h a n ge  
1 4. 9. Safet y A nal ysis  
C ha n ges i n vital si g ns, sta n dar d 1 2 lea d 
E C Gs, la b orat or y e val uati o ns, a n d disease -
s pecific assess me nts ( Partial Ma y o Sc ore 
f or s u bjects wit h U C a n d C D AI f or 
s u bjects wit h C D) will be c o m pare d acr oss 
d oses a n d t o place b o . 
C ha n ges i n vital si g ns, sta n dar d 1 2 lea d 
E C Gs, la b orat or y e val uati o ns, a n d disease -
s pecific assess me nts ( Partial Ma y o Sc ore 
f or s u bjects wit h U C a n d C D AI f or s u bjects 
wit h C D) wi ll be s u m m arize d b y 
tre at m e nt gr o u p. 
T he te xt was c orrecte d t o reflect 
t he i nte n de d a nal ysis of safet y 
data . 
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Next text.  
A d de d  w hic h visits c a n c o n d ucte d re m otely 
f or t he hy bri d m o del. 
A d de d w hic h visits ca n be 
c o n d ucted re m otel y f or t he h y bri d 
m o del  f or c o m plete ness. 
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Ne w text.  
If a hist oric al T E wit hi n 6 m o nt hs of 
D a y  1 is n ot a v ail a ble, T E pr oce d ures will 
be c o n d ucte d at st u d y sites. Sc he d uli n g of 
t he T E assess m e nt s h o ul d be wit hi n t he 
Scree ni n g wi n d o w.  
A ll o wi n g hist orical Fi br osca n®  
assess me nts a n d e x pa n di n g t he 
Fi br osca n ®  assess me nt wi n d o w t o 
6 m o nt hs bef ore Scree ni n g  will 
ease o verall b ur de n a n d sc he d uli n g 
c o nstrai nts. 
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Ne w text.  
F or re m ote vi sits, st u d y dr u g dis pe nsi n g 
will be c o n d ucte d b y a direct -t o-p atie nt 
c o urier ser vice.  
A d de d t o reflect st u d y dr u g 
dis pe nsi n g pr oce d ures f or re m ote 
visits.  
A p pe n di x A.  Sc he d ule of 
Assess me nts  
Ne w text.  
F or re m ote visits, st u d y dr u g c ollecti o n 
will be c o n d ucte d b y a direct -t o-p atie nt 
c o urier ser vice.  
A d de d t o reflect st u d y dr u g 
c ollecti o n pr oce d ures f or re m ote 
visits.  
 
 
 

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C o nfi de ntial 
Pa ge 1 1 6 of 1 2 8  
S u m m ar y of C h a n ges f or A m e n d m e nt 1 . 0 D ate d 1 7 N o ve m ber 2 0 2 1 
Pr ot oc ol E P - 5 4 7- 2 0 1 was a me n de d t o  i m ple me nt c ha n ges t o t he st u d y p o p ulati o n, i ncl u de a d diti o nal safet y m o nit ori n g, a n d 
i nc or p orate o p erati o nal c ha n ges , w hic h i ncl u de t h e f oll o wi n g:  
St u d y P o p ul ati o n C h a n ges  
•  M o difie d t he i ncl usi o n/e xcl usi o n criteria t o refi ne s u bject selecti o n b y e x cl u di n g s u bjects wit h c o m pe nsate d cirr h osis, 
i m paire d re n al f u ncti o n, m o derate al c o h ol c o ns u m pti o n, a p ositi ve se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
(S A R S - C o V- 2) test, a n d acti ve he p atitis  A vir us ( H A V) or  h e patitis E vir us ( H E V) i nfecti o ns  
C h a n ges t o S afet y M o nit ori n g 
•  A d d e d i n di vi d ual a n d o verall st u d y st o p pi n g criteria  
•  A d d e d scr ee ni n g assess m e nts f or cirr h osis ( Fi br os ca n ® ), S A R S - C o V- 2, H A V , a n d H E V  
•  A d de d t h yr oi d-sti m ulati n g h or m o ne a n d free t h yr o xi ne m o nit ori n g 
•  I n cl u de d a Data M o nit ori n g C o m mittee  t o i n de pe n de ntl y deter mi ne a d v erse e ve nt  relat e d ness a n d a d vise t he S p o ns or 
re gar di n g p ote ntial m o dificati o ns t o t he st u d y pr ot oc ol, s us pe nsi o n of d osi n g, or st u d y ter mi nati o n 
•  A d de d t otal l y m p h oc yte c o u nt m o nit ori n g a n d a d diti o nal bl o o d l y m p h oc yte p o p ulati o n assess me nts f or s u bjects w h o 
de vel o p l y m p h o pe nia 
•  Re q ueste d t hat I n vesti gat ors atte m pt t o c ollect a bl o o d p har mac o ki netic s a m ple at a n u nsc he d ule d visit as part of seri o us 
a d verse e ve nt f oll o w- u p t o assess dr u g le vels at t h e ti me of t he e ve nt 
•  A d de d t hat all a b n or mal c o m plete bl o o d c o u nt, ser u m creati ni ne, bl o o d urea nitr o ge n, a n d uri n e al b u mi n t o creati ni ne rati o 
val ues d uri n g treat me nt b e f oll o we d as d ee me d cli nicall y necess ar y b y t he I n vesti gat or  
O per ati o n al C h a n ges 
•  Re m o ve d patie nt i nter vie ws, gl o bal meta b ol o mic a nal ysis, a ut ota xi n, l ys o p h os p hati d ic aci d, a n d c yt o ki nes mar kers fr o m 
t he st u d y as t hese p har m ac o d y namic assess me nts are n ot re q uire d t o esta blis h earl y pr o of of c o n ce pt 
•  Re m o ve d t he C hil d- P u g h assess me nt as it is n o l o n ger rel e va nt gi ve n t hat p atie nts wit h cirr h osis are n o l o n ger eli gi ble f or 
st u d y partici pati o n  
•  R e placed dail y d osi n g di aries wit h d osi n g rec or ds t o all o w m ore fle xi bilit y i n rec or di n g s u bject d osi n g 
•  A d de d i nstr ucti o ns f or us e of a direct -t o-p atie nt c o u rier ser vi ce t o s u p p ort dr u g dis pe nsi n g d uri n g h o me healt h n urse visits 

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Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 1 7 of 1 2 8  
N o ta ble ad mi nistrati ve c ha n ges a n d t y p o gra p hical err ors are i ncl u d e d bel o w i n t he s u m mar y ta ble. Re vise d te xt i n A me n d me nt 1. 0 is 
u n derli ne d, a n d te xt del ete d fr o m t he ori gi nal versi o n is cr osse d o ut i n t he ta ble bel o w. Italicize d te xt is use d t o descri be a c ha n ge. 
Mi n or/e dit orial c ha n ges are n ot liste d i n di vi d uall y i n t he s u m mar y ta ble.  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
Gl o bal  
I ncl u de d p atie nt i ntervie ws, gl o b al 
met a b ol o mic a n alysis, a ut ot axi n,  
lys o p h os p h ati dic aci d, a n d cyt oki nes 
m arkers (e g, i nterle uki n 8 [I L -8], t u m or 
necr osis f act or al p h a [ T N F -α]) as p art of 
t he p h ar m ac o dy n a mic assess me nts 
Re m ove d p atie nt i ntervie ws, gl o b al 
met a b ol o mic a n alysis, a ut ot axi n, 
lyso p h os p h ati dic aci d , a n d cyt oki nes 
m arkers (e g, i nterle uki n 8 [I L -8], t u m or 
necr o sis f act or al p h a [ T N F-α]) fr o m t he 
list of p h ar m ac o dy n a mic assess me nts  
G i ve n t hat t he pri mar y p ur p ose of 
E P -5 4 7 -2 0 1 is t o esta blis h earl y 
pr o of of c o nce pt, t he se 
p har mac o d y na mi c assess me nts 
ha ve bee n re m o ve d  b ut ma y be 
i nc or p orate d i nt o a f ut ure st u d y. 
S y n o psis ( D o u ble -Bli n d 
Treat me nt Peri o d)  
7. 1. 2 D o u ble -Bli n d 
Treat me nt Peri o d  
H o we ver, a h o me healt h n urse visit t o t he 
s u bject’s h o me a n d a tele healt h visit t o 
c o m m u nicate wit h st u d y site staff usi n g 
tec h n ol o g y (e g, s mart p h o ne or c o m p uter) 
i n lie u of a site visit ma y be per mitte d o n a 
case b y case basis if t he s u bject is u na ble 
t o visit t he site b ut is willi n g t o c o nti n ue i n 
t he st u d y. 
H o we ver, a h o me healt h n urs e visit t o t he 
s u bject’s h o me a n d a tele healt h visit t o 
c o m m u nicate wit h st u d y site staff usi n g 
tec h n ol o g y (e g, s mart p h o ne or c o m p uter) 
i n lie u of a site visit ma y be per mitte d at 
certai n visits if t he s u bject is u na ble t o visit 
t he site b ut is willi n g t o c o nti n ue i n t he 
st u d y. 
Usi n g “case -b y -case basis” f or 
all o wi n g alter nati ve visit t y pes i n 
lie u of a site visit was re m o ve d as 
it was t h o u g ht t o disc o ura ge t heir 
use . Beca use healt h n urs e visits are 
feasi ble o nl y at s pecific visits 
base d o n t he re q uire d pr oce d ures, 
t his clarificati o n was a d de d t o t he 
pr ot oc ol.  
S y n o psis (I ncl usi o n 
Criteria)  
8. 1 S u bject I ncl usi o n 
Criteria  
3. Has a mea n dail y WI -N R S sc ore 
i n dicati ve of m o derate t o se vere pr urit us 
(sc ore ≥4) as rec or de d usi n g a st u d y iss ue d 
electr o n ic de vice or a p plicati o n (a p p) 
d uri n g Scree ni n g ( Da y -7 t hr o u g h Da y  -1); 
data fr o m at least 4 of t he 7 da ys ar e 
re q uire d t o be c o nsi dere d a n acce pta ble 
pr ofile  
3. Has a mea n dail y WI -N R S sc ore 
i n dicati ve of m o derate t o se vere pr urit us 
(sc ore ≥4) d uri n g Sc ree ni n g ( Da y -7 
t hr o u g h Da y -1); data fr o m at least 4 of t he 
7 da ys are re q uire d t o be c o nsi dere d a n 
acce pta ble pr ofile  
T he s pecificit y of usi n g a st u d y -
iss ue d electr o nic de vice or a p p was 
re m o ve d t o all o w m ore fle xi bilit y 
f or h o w q uesti o n naire res ults are t o 
be rec or de d.  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 1 8 of 1 2 8  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
S y n o psis ( E xcl usi o n 
Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
4. Hist or y or prese nce of dec o m pe nsate d 
cirr h osis as e vi de nce d b y k n o w n p ortal 
h y perte nsi o n  wit h c o m plicati o ns, i ncl u di n g 
k n o w n gastric or es o p ha geal varices, 
ascites, s p o nta ne o us bacterial perit o nitis, 
he patic e nce p hal o pat h y, hist or y of variceal 
blee ds, m o derate t o se vere he patic 
i m pair me nt ( C hil d P u g h Class es B or C), 
or relate d t hera pe utic or  pr o p h ylactic 
i nter ve nti o ns (e g, n o n selecti ve beta 
bl oc kers bei n g use d t o pre ve nt 
c o m plicati o ns of p ortal h y perte nsi o n 
[ pr o pra n ol ol or car ve dil ol], i nserti o n of 
variceal ba n ds, tra nsj u g ular i ntr a he patic 
p ort os yste mic s h u nt or direct i ntra he patic 
p ort oca va l s h u nt) 
4.  E vi de nce of c o m pe nsate d or 
dec o m pe nsate d cirr h osis base d o n A N Y of 
t he f oll o wi n g: 
a. Hist orical li ver bi o ps y de m o nstrati n g 
cirr h osis 
b.  Li ver stiff ness as assesse d b y a 
Fi br o Sca n ®  sc ore of ≥1 6. 9 k Pa f or 
s u bjects wit h P B C or ≥1 4. 4 k Pa f or 
s u bjects wit h P S C 
c Hist or y or prese nce of p ortal 
h y perte nsi o n  wit h c o m plicati o ns, 
i ncl u di n g k n o w n gastric or es o p ha geal 
varices, ascites, s p o nta ne o us bacterial 
perit o nitis, he patic e nce p hal o pat h y, 
his t or y of variceal blee ds, or relate d 
t hera pe utic or pr o p h ylactic i nter ve nti o ns 
(e g, n o n -selecti ve beta bl oc kers bei n g 
use d t o pre ve nt c o m plicati o ns of p ortal 
h y perte nsi o n [ pr o pra n ol ol , na d ol ol,  or 
car ve dil ol], i nserti o n of variceal ba n ds, 
tra nsj u g ular i ntra he patic p ort os yste mic 
s h u nt, or direct i ntra he patic p ort oca val 
s h u nt) 
E xcl usi o n criteri o n 4 was re vise d 
t o e xcl u de cirr h otic s u bjects wit h 
C hil d -P u g h A  (ie, c o m pe nsate d 
cirr h osis) t o i ncrease s u bject 
safet y, a n d all o w f or t he use of 
Fi br osca n as a n o n -i n vasi ve 
assess me nt of cirr h osis.   
S y n o psi s ( E xcl usi o n 
Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
1 5. Has  a n y of t he f oll o wi n g la b orat or y 
res ults at Scree ni n g:  
b.  T otal bilir u bi n > 2 × U L N; t otal 
bilir u bi n > 2 × U L N is acce pta ble f or 
Gil bert’s s y n dr o me if fracti o nated a n d 
direct bilir u bi n < 5 0 %  
1 5. Has  a n y of t he f oll o wi n g la b orat or y 
res ults at Scree ni n g:  
b.  T otal bilir u bi n > U L N; t otal bilir u bi n 
> U L N is acce pta ble f or s u bjects wit h 
me dicall y d oc u me nte d Gil bert’s 
s y n dr o me if direct bilir u bi n is 
< 0. 3  m g/ d L  
E xcl usi o n criter i o n 1 5a was 
u p date d t o e xcl u de s u bjects w h o 
ha ve t otal bilir u bi n > U L N  t o 
i ncrease s u bject safet y b ut all o w 
t h ose wit h d oc u me nte d Gil bert’s 
s y n dr o me w h o ha ve direct 
bilir u bi n < 0. 3 m g/ d L t o be a ble t o 
partici pate.  
S y n o psis ( E xcl usi o n 
Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
1 6. Esti mate d gl o mer ular filtrati o n rate 
< 6 0  m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t he 
C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n e q uati o n at Scree ni n g  
1 6. Esti mate d gl o mer ular filtrati o n rate 
< 9 0  m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t he 
C hr o nic Ki d ne y Disease  E pi de mi ol o g y 
C olla b orati o n e q uati o n at Scree ni n g  
E xcl usi o n criteri o n 1 6 was re vise d 
t o e xcl u de s u bjects wit h esti m ate d 
gl o mer ular filtrati o n rate 
< 9 0  m L/ mi n/ 1. 7 3 m 2 t o i ncrease 
s u bject safet y. 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 1 9 of 1 2 8  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
S y n o psis ( E xcl usi o n 
Criteria)  
8. 2 S u bject E xcl usi o n 
Criteria  
1 8. Si g nifica nt hist or y of a b use of dr u gs, 
s ol ve nts, or alc o h ol (> 3  ser vi n gs or 
u nit s/ da y o n a vera ge; 1 u nit  = 1 2  o u nces 
[ 3 5 0 m L] of 5 % alc o h ol beer, 5 o u nces 
[ 1 5 0 m L] of 1 2 % wi ne, or 1. 5 o u nces 
[ 4 5 m L] of 8 0  pr o of distille d s pirits) i n t he 
past 2 years bef ore Scree ni n g  
1 8. Si g nifica nt hist or y of a b use of dr u gs, 
s ol ve nts, or m o derate alc o h ol c o ns u m pti o n 
(≥1  ser vi n g or u nit/ da y o n a vera ge f or 
w o me n a n d ≥2 ser vi n gs or u nits/ da y o n 
a vera ge f or me n ; 1 u nit  = 1 2  o u nces 
[ 3 5 0 m L] of 5 % alc o h ol be er, 5  o u nces 
[ 1 5 0 m L] of 1 2 % wi ne, or 1. 5 o u nces 
[ 4 5 m L] of 8 0  pr o of distille d s pirits) i n t he 
past 2  years bef ore Scree ni n g  
E xcl usi o n criteri o n 1 8 was re vise d 
t o e xcl u de s u bjects wit h m o derate 
alc o h ol c o ns u m pti o n  t o i ncrease 
s u bject safet y. 
S y n o psis ( E xc l usi o n 
C riteria) 
8. 2 S u bject E xcl usi o n 
Criteria  
Ne w text  
2 3. P ositi ve se vere ac ute res pirat or y 
s y n dr o me c or o na vir us 2 ( S A R S-C o V -2) 
re verse tra nscri pti o n- p ol y merase c hai n 
reacti o n ( R T-P C R) test at Scre e ni n g 
S u bjects w h o test p ositi ve f or 
S A R S -C o V- 2 will be  e xcl u de d 
fr o m partici pati n g i n t he st u d y. 
S y n o psis ( St u d y Dr u g 
Dis pe nsi n g a n d 
Acc o u nta bilit y)  
1 0. 5 St u d y Dr u g Dis pe nsi n g 
a n d Acc o u nta bilit y 
S u bjects will rec or d ta blet self
a d mi nistrati o n dail y i n a d osi n g diar y t hat 
will be re vie we d at eac h st u d y visit b y 
st u d y site staff. 
S u bjects will c o m plete d osi n g rec or ds, 
w hic h will be re vie we d at eac h st u d y visit 
b y st u d y site staff.  
Dail y d osi n g diaries were re place d 
wit h d osi n g rec or ds t o all o w m ore 
fle xi bilit y i n rec or di n g s u bject 
d osi n g.  
S y n o psis ( Disc o nti n ua ti o n 
of St u d y Dr u g)  
8. 5. 1 Disc o nti n uati o n of 
St u d y Dr u g  
If t he s u bject is u na ble t o visit t he site b ut 
is willi n g t o c o nti n ue i n t he st u d y, a h o me 
healt h n urse visit t o t he s u bject’s h o me a n d 
a tele healt h visit t o c o m m u nicate wit h 
st u d y site staff usi n g tec h n ol o g y (e g, 
s mart p h o ne or c o m p uter) i n lie u of a site 
visit ma y be per mitte d  o n a case b y case 
basis . 
If t he s u bject is u na ble t o visit t he site b ut 
is willi n g t o c o nti n ue i n t he st u d y, a h o me 
healt h n urse visit t o t he s u bject’s h o me a n d 
a tele healt h visit t o c o m m u nicate wit h 
st u d y site staff usi n g tec h n ol o g y (e g, 
s mart p h o ne or c o m p uter) i n lie u of a site 
visit ma y be per mitte d  at certai n visits. 
Usi n g “case -b y -case basis” f or 
all o wi n g alter nati ve visit t y pes i n 
lie u of a site visit was re m o ve d as 
it was t h o u g ht t o disc o ura ge t heir 
use . Beca use healt h n urs e visits are 
feasi ble o nl y at s pecific visits 
base d o n t he re q uire d pr oce d ures , 
t his clarificati o n was a d de d t o t he 
pr ot oc ol . 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 2 0 of 1 2 8  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
S y n o psis ( Q uesti o n naires)  
1 1. 1 Q uesti o n naires  
Re p o nses t o all q uesti o n naires a d mi nistere d 
t hr o u g h o ut t he st u d y will be rec or de d usi n g 
a st u d y iss ue d electr o nic de vice or a p p. At 
Visit 1 ( Scree ni n g) bef ore c o m pleti n g t he 
dai l y WI-N R S f or Da y -1 4, s u bjects will 
recei ve trai ni n g o n h o w t o use t he 
electr o nic de vice or a p p  t o res p o n d t o 
q uesti o n naires. Sites will re vie w t he 
res p o nses fr o m eac h s u bject at least t wice a 
wee k t o e ns ure pr o per c o m plia nce. All 
s u bjects w h o were gi ve n a st u d y iss ue d 
de vice, i ncl u di n g t h ose w h o fail Scree ni n g, 
will be re q uire d t o ret ur n it t o t he site o nce 
t heir partici pati o n i n t he st u d y is c o m plete. 
At Visit 1 ( Scree ni n g) bef ore c o m pleti n g 
t he dail y WI-N R S f or Da y -1 4, s u bjects 
will recei ve trai ni n g o n  h o w t o res p o n d t o 
q uesti o n naires. Sites will re vie w t he 
res p o nses fr o m eac h s u bject at least t wice a 
wee k t o e ns ure pr o per c o m plia nce.  
T he s pecificit y of usi n g a st u d y -
iss ue d electr o nic de vice or a p p was 
re m o ve d t o all o w m ore fle xi bilit y 
f or h o w q uesti o nnaire res ults are t o 
be rec or de d.  
S y n o psis ( W orst Itc h 
N u meric Rati n g Scale 
[ WI-N R S])  
1 1. 1. 1  W orst Itc h N u me ric 
Rati n g Scale ( WI -N R S)  
S u bjects will be i nstr ucte d t o c o m plete t he 
WI -N R S dail y, i n t he m or ni n g, a n d at t he 
sa me ti me of da y, usi n g t heir st u d y iss ue d 
electr o nic de vice or a p p be gi n ni n g at 
Da y  -1 4 t o t he F oll o w -U p Visit.  
S u bjects will be i nstr ucte d t o c o m plete t he 
WI -N R S dail y, i n t he m or ni n g, a n d at t he 
sa me ti me of da y, be gi n ni n g at Da y -1 4 t o 
t he F oll o w-U p Visit.  
S y n o psis (W orst Itc h 
N u meric Rati n g Scale 
[WI -N R S ]) 
1 1. 1. 1  W orst Itc h N u meric 
Rati n g Scale ( WI -N R S)  
T he WI -N R S sc ores fr o m Da y -7 t hr o u g h 
Da y -1 will be a vera ge d t o get her t o c o nfir m 
c o m plia nce wit h t he st u d y iss ue d electr o nic 
de vice or a p p a n d deter mi ne s u bject 
eli gi bilit y f or c o nti n ue d partici pati o n 
re gar di n g pr urit us se nsati o n. 
T he WI -N R S sc ores fr o m D a y -7 t hr o u g h 
Da y -1 will be a vera ge d t o get her t o c o nfir m 
c o m plia nce a n d deter mi ne s u bject 
eli gi bilit y f or c o nti n ue d partici pati o n 
re gar di n g pr urit us se nsati o n. 
S y n o psis ( O bser vati o n f or 
Ac ute Ki d ne y I nj ur y ) 
1 2. 1 4. 4  O bser vati o n f or 
Ac ute Ki d ne y I nj ur y  
 
Ne w text 
A d diti o nall y, all a b n or mal c o m plete bl o o d 
c o u nt, ser u m creati ni ne, B U N, a n d uri ne 
al b u mi n t o creati ni ne rati o val ues d uri n g 
t he D o u ble-Bli n d Treat me nt Peri o d a n d 
O pe n -La bel Treat me nt Peri o d are t o be 
f oll o we d as dee me d cli nicall y necessar y b y 
t he In vesti gat or.  
A d de d t o rei nf orce t he i m p orta nce 
of a ti mel y res p o nse f or a n y 
co m plete bl o o d c o u nt, ser u m 
creati ni ne, B U N, or uri ne al b u mi n 
val ue  d uri n g treat me nt . 

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 2 1 of 1 2 8  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
5. 4  E P 5 4 7 D ose Rati o nale  
7. 3  D ose A dj ust me nt 
Crit eria  
D osa ges f or st u d y dr u g s h o ul d be 
mai ntai ne d c o nsta nt d uri n g t he st u d y. 
T here are n o pres pecifie d safe t y criteria or 
P K criteria f or st o p pi n g d oses f or 
i n di vi d ual s u bjects.  
D osa ges f or st u d y dr u g s h o ul d be 
mai ntai ne d c o nsta nt d uri n g t he st u d y. 
H o we ver, d osi n g of st u d y dr u g ma y be 
i nterr u pte d or disc o nti n ue d d ue t o safet y 
fi n di n gs. Refer t o Secti o n 8. 5  f or g ui da nce 
o n ma n dat or y disc o nti n uati o n of st u d y dr u g 
d ue t o se vere a n d r elate d a d verse e ve nts 
( A Es). 
In di vi d ual s u bject a n d st u d y 
st o p pi n g criteria were a d de d t o t he 
pr ot oc ol t o e n ha nce ge neral 
o versite of safet y.  
8. 5. 1  Disc o nti n uati o n of 
St u d y Dr u g  
Ne w t ext.  
If a s u bject e x perie nces a n A E t hat is 
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) G ra de 4 or hi g her, t he 
st u d y dr u g m ust be disc o nti n ue d. A E 
gra di n g f or se verit y usi n g C T C A E criteria 
is descri be d i n Secti o n 1 2. 1. 2. 
In di vi d ual s u bject a n d s t u d y 
st o p pi n g criteria were a d de d t o t he 
pr ot oc ol t o e n ha nce ge neral 
o versite of safet y.  
8. 5. 3  Safet y Criteria f or 
St u d y Dr u g I nterr u pti o n  
Ne w secti o n.  
8, 5. 3 S afet y Criteri a f or St u d y Dr u g 
I nterr u pti o n 
St u d y dr u g d osi n g will be i nterr u pte d f or 
all s u bjects if 3 s u bjects de vel op A Es  
meeti n g C T C A E G ra de 3 or hi g her t hat are 
c o nsi dere d  relate d t o st u d y dr u g b y t he 
I n vesti gat or a n d/ or S p o ns or. A E gra di n g 
f or se verit y usi n g C T C A E criteria is 
descri be d i n Secti o n 1 2. 1. 2.  All e ve nts wit h 
a C T C A E G ra de of 3 or hi gher will be 
re vie we d b y t he Data M o nit ori n g 
C o m mittee ( D M C) ( Secti o n  1 2. 3 ) t o 
i n de pe n de ntl y deter mi ne e ve nt relate d ness 
a n d pr o vi de rec o m me n dati o ns t o t he 
S p o ns or.  

E P - 5 4 7- 2 0 1 Pr ot oc ol, A me n d me nt 3. 0  ( 0 2 Oct o ber  2 0 2 3)  
 
Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 1 2 2 of 1 2 8  
Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
9. 2  Treat me nt C o m plia nce  
T he I n vesti gat or s h o ul d assess t he s u bject’s 
c o m plia nce wit h d osi n g of st u d y dr u g b y 
c o u nti n g ret ur ne d st u d y dr u g ta blets a n d 
re vie wi n g t he s u bject’s dail y d osi n g diar y 
as i n dicate d i n t he Sc he d ule of 
Assess me nts (A p pe n di x A ). 
 
 
T he I n vesti gat or s h o ul d ass ess t he s u bject’s 
c o m plia nce wit h d osi n g of st u d y dr u g b y 
c o u nti n g ret ur ne d st u d y dr u g ta blets a n d 
re vie wi n g t he s u bject’s d osi n g rec or ds as 
i n dicate d i n t he Sc he d ule of Assess me nts 
(A p pe n di x A ). 
Dail y d osi n g diaries were re place d 
wit h d osi n g rec or ds t o al l o w m ore 
fle xi bilit y i n rec or di n g s u bject 
d osi n g.  
9. 4. 1. 1  Visit 1 (Da y -2 8 t o 
Da y -1)  
Ne w text.  
•  
Tra nsie nt elast o gra p h y ( T E; 
Fi br o Sca n)  
•  
S A R S -C o V -2 R T -P C R test  
T E a n d S A R S -C o V -2 R T -P C R 
testi n g were a d de d at Scree ni n g t o 
t he pr ot oc ol. 
9. 4. 1. 1  Visit 1 (Da y -2 8 t o 
Da y -1)  
-   HI V, he patitis B vir us ( H B V),  a n d  
he patitis C v ir us ( H C V) ser ol o g y 
 
-     HI V, he patitis A vir us ( H A V), 
he patitis B vir us ( H B V), he patitis C 
vir us ( H C V) , a n d he patitis E vir us 
( H E V) ser ol o g y 
T he e xcl usi o n of s u bjects wit h 
u nc o ntr olle d viral he patitis was 
e x pa n de d t o i ncl u de acti ve 
he patitis A a n d he pati tis E 
i nfecti o ns. 
9. 4. 1. 1  Visit 1 ( Da y -2 8 t o 
Da y -1)  
•  
Recei ve trai ni n g f or t he st u d y iss ue d 
electr o nic de vice or a p p (t o be 
c o n d ucte d bef ore c o m pleti n g t he dail y 
WI -N R S f or Da y -1 4)  
S u bjects will be i nstr ucte d t o c o m plete t he 
WI -N R S dail y, i n t he m or ni n g,  a n d at t he 
sa me ti me of da y, usi n g t heir st u d y iss ue d 
electr o nic de vice or a p p be gi n ni n g at 
Da y  -1 4 t o t he Safet y F oll o w -U p Visit.  
•  
Recei ve q uesti o n naire trai ni n g (t o be 
c o n d ucte d bef ore c o m pleti n g t he dail y 
WI -N R S f or Da y -1 4)  
S u bjects will be i nstr ucte d t o c o m plete t he 
WI -N R S dail y, i n t he m or ni n g, a n d at t he 
sa me ti me of da y, be gi n ni n g at Da y -1 4 t o 
t he Safet y F oll o w-U p Visit.  
T he s pecificit y of usi n g a st u d y -
iss ue d electr o nic de vice or a p p was 
re m o ve d t o all o w m ore fle xi bilit y 
f or h o w q uesti o n naire res ults are t o 
be rec or de d.  
9. 4. 2. 1  Visit 2 ( Da y 1)  
9. 4. 2. 5 Visit 6 ( Wee k 6)  
9. 4. 3. 2  Visit 8 ( Wee k 1 2)  
9. 4. 5  Earl y St u d y 
Ter mi nati o n Vi sit 
1 2. 8 La b orat or y E val uati o ns 
of Safet y  
Ne w text  
-  
T h yr oi d h or m o nes: T S H a n d free T 4  
T S H a n d free T 4 m o nit ori n g were 
a d ded t o t he pr ot oc ol t o i ncrease 
s u bject safet y. 

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Secti o n  
Ori gi n al  
A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
1 0. 6  St u d y Dr u g Ha n dli n g 
a n d Dis p osal  
Ne w text  
W here all o we d, t o s u p p ort h o me visits b y a 
h o me healt h n urse, t he use of a direct -t o-
patie nt c o urier ser vice t o tra ns p ort st u d y 
dr u g bet wee n t he st u d y site a n d s u bject’s 
h o me ma y be arra n ge d at certai n visits. T he 
c o urier will be as ke d t o c ollect t he st u d y  
dr u g kit dis pe nse d b y t he st u d y site staff 
a n d deli ver it t o t he s u bject’s h o me. T he 
c o urier ma y als o be as ke d t o c ollect t he 
use d st u d y dr u g kit wit h a n y u n use d  st u d y 
dr u g fr o m t he s u bject t o be ret ur ne d t o t he 
site f or acc o u nta bilit y wit h rec o nciliati o n t o 
be c o m plete d b y t he st u d y site staff. C hai n 
of c ust o d y of t he st u d y dr u g tra ns p ort will 
be d oc u me nte d.  
A direct -t o-patie nt c o urier ser vice 
ma y be pr o vi de d t o s u p p ort dr u g 
dis pe nsi n g d uri n g h o me healt h 
n urse visits . 
1 2. 1. 2  Deter mi ni n g Se verit y 
of A d verse E ve nts  
A Es m ust be gra de d f or se verit y (ie, 
i nte nsit y) usi n g 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) . 
A Es m ust be gra de d f or se verit y (ie, 
i nte nsit y) usi n g 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  ( H H S 2 0 1 7). 
T he h y perli n k f or t he C T C A E 
criteria was re place d wit h a 
refere nce a n d t he C T C A E criteria 
versi o n was s pecifie d t o all o w f or 
easier refere nci n g of t he criteria.  
1 2. 2. 2  Re p orti n g Seri o us 
A d verse E ve nts  
T o re p ort a n S A E, c o m plete t he st u d y -
s pecific Seri o us  A d verse E ve nt Re p ort 
(S A E R)  F or m electr o ni call y i n t he 
electr o nic data ca pt ure ( E D C) s yste m f or 
t he st u d y. 
T o re p ort a n S A E, c o m plete t he st u d y -
s pecific S A E/ A E SI Re p ort F or m 
electr o nicall y i n t he electr o nic data ca pt ure 
( E D C) s yste m f or t he st u d y. 
T he na me of t he S A E R F O R M was 
c ha n ge d t o S A E/ A E SI Re p ort 
F O R M t o reflect its c urre nt na mi n g 
c o n ve nti o n. 
1 2. 2. 2  Re p orti n g Seri o us 
A d verse E ve nts  
A n y s u p p orti n g d oc u me ntati o n (e g, 
me dical rec or ds) se nt t o C o va nce wit h t he 
S A E R F or m m ust ha ve s u bject i de ntif yi n g 
i nf or mati o n (e g, s u bject na mes, s u bject 
a d dre sses, a n d me dical rec or ds n u m ber) 
re dacte d b y t he site. 
A n y s u p p orti n g d oc u me ntati o n (e g, 
me dical rec or ds) se nt t o C o va nce wit h t he 
S A E/ A E SI  Re p ort  F or m m ust ha ve s u bject 
i de ntif yi n g i nf or mati o n (e g, s u bject na mes, 
s u bject a d dresses, a n d me dical rec or ds 
n u m ber) re dacte d b y t he site.  
T he na me of t he S A E R F O R M was 
c ha n ge d t o S A E/ A E SI Re p ort 
F O R M t o reflect its c urre nt na mi n g 
c o n ve nti o n. 
1 2. 2. 3  Re p orti n g Seri o us 
a n d U ne x pecte d A d verse 
E ve nts Assesse d as Relate d  
1 2. 2. 3.  Re p orti n g Seri o us a n d 
U ne x pecte d A d verse  E ve nts  
1 2. 2. 3.  Re p orti n g Seri o us a n d 
U ne x pecte d A d verse E ve nts Assesse d as 
Rel ate d  
T he title of Secti o n 1 2. 2. 3 was 
re vise d t o better reflect t he t y pes of 
A Es t hat re q uire re p orti n g i n t his 
secti o n. 

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A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
1 2. 3  Data M o nit ori n g 
C o m mittee  
Ne w secti o n 
1 2. 3 D at a M o nit ori n g C o m mittee  
T he D M C is a n i n de pe n de nt gr o u p of 
e xter nal e x perts w h o will re vie w safet y 
data d uri n g t he c o n d uct of t he st u d y, as 
o utli ne d i n t he D M C c harter. T he D M C 
will ma ke a deter mi nati o n of relate d ness 
f or all A Es wit h C T C A E G ra de 3 or hi g her. 
T he D M C will als o meet o n a n a d h oc basis 
w he n at least 3 A Es of C T C A E G ra de 3 or 
hi g her ha ve accr ue d or w he n t here has bee n 
a si n gle C T C A E G ra de 4 or hi g her. Base d 
o n re vie w of t he data, t he D M C will 
pr o vi d e rec o m me n dati o ns t o t he S p o ns or 
o n w het her t he nat ure, fre q ue nc y, a n d/ or 
se verit y of A Es ass ociate d wit h st u d y dr u g 
warra nt m o dificati o n t o t he st u d y pr ot oc ol, 
s us pe nsi o n of d osi n g, or st u d y ter mi nati o n. 
T he D M C was a d de d t o 
i n de pe n de ntl y deter mi ne A E 
relate d ness a n d a d vise t he S p o ns or 
re gar di n g p ote ntial m o dificati o ns 
t o t he st u d y pr ot oc ol, s us pe nsi o n of 
d osi n g, or st u d y ter mi nati o n.  
1 2. 8  La b orat or y E val uati o ns 
of Safet y  
He mat ol o g y: he m o gl o bi n, he mat ocrit, 
w hite bl o o d cell ( W B C) c o u nt t otal a n d 
differe nt ial), re d bl o o d cell c o u nt, platelet 
c o u nt, a n d pl atelet v ol u me 
He mat ol o g y: he m o gl o bi n, he mat ocrit, 
w hite bl o o d cell ( W B C) c o u nt wit h 
differe ntial (l y m p h oc ytes, ne utr o p hils, 
m o n oc ytes, e osi n o p hils, a n d bas o p hils ), re d 
bl o o d cell c o u nt, platelet c o u nt, a n d platelet 
v ol u me . If a s u bject de vel o ps l y m p h o pe nia, 
bl o o d l y m p h oc ytes will be teste d t o assess 
p o p ulati o ns of circ ulati n g T cells (i ncl u di n g 
C D 4 + a n d C D 8 + s u bt y pes), B cells, a n d 
nat ural killer ( N K ) cells. 
T otal l y m p h oc yte c o u nt  
m o nit ori n g  a n d a d diti o nal bl o o d 
l y m p h oc yte p o p ulati o n 
assess me nt s f or s u bjects w h o 
de vel o p l y m p h o pe nia were a d de d 
t o t he pr ot oc ol t o i ncrease s u bject 
safet y. 

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A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
1 2. 9  Ot her La b orat or y 
E val uati o ns  
•  
Ser ol o g y: HI V, H B V, H C V  
Per e xcl usi o n criteri o n 6, s u bjects wit h 
u nc o ntr olle d viral he patitis are n ot eli gi ble 
t o partici pate i n t his st u d y. C urre nt c hr o nic 
H B V i nfecti o n is defi ne d as a p ositi ve 
res ult f or he patitis B s urface a nti ge n 
( H Bs A g) or H B V de o x yri b o n ucleic aci d 
( D N A). C urre nt c hr o nic H C V i nfecti o n is 
defi ne d as a p ositi ve res ult f or H C V 
a nti b o d y a n d H C V ri b o n ucleic aci d (R N A ) 
at Scre e ni n g. If H C V is c ure d, a ne gati ve 
H C V R N A c o nfir me d wit hi n 1 year pri or t o 
Scree ni n g will be re q uire d.  
•  
Ser ol o g y: HI V, H A V, H B V, H C V , 
a n d H E V 
Per e xcl usi o n criteri o n 6 , s u bjects wit h 
u nc o ntr olle d viral he patitis are n ot eli gi ble 
t o partici pate i n t his st u dy. Acti ve H A V 
i nfecti o n is defi ne d as a p ositi ve res ult f or 
im m u n o gl o b uli n M  (I g M) a nti-H A V or 
H A V ri b o n ucleic aci d ( R N A). C urre nt 
c hr o nic H B V i nfecti o n is defi ne d as  a 
p ositi ve res ult f or he patitis B s urface 
a nti ge n ( H Bs A g) or H B V de o x yri b o n ucleic 
aci d ( DN A). C urre nt c hr o nic H C V 
i nfecti o n is defi ne d as a p ositi ve res ult f or 
H C V a nti b o d y a n d H C V R N A at 
Scree ni n g. If H C V is c ure d, a ne gati ve 
H C V R N A c o nfir me d wit hi n 1  year pri or t o 
Scree ni n g will be re q uire d.  Acti ve H E V 
i nfecti o n is defi ne d as a p ositi ve result f or 
I g M a nti-H E V or H E V R N A.  
T he e xcl usi o n of s u bjects wit h 
u nc o ntr olle d viral he patitis was 
e x pa n de d t o i ncl u de acti ve 
he patitis A a n d he patitis E  
i nfecti o ns t o i ncrease s u bject 
safet y. 
1 2. 1 0  Tra nsie nt 
Elast o gra p h y  
Ne w text  
1 2. 1 0 Tr a nsie nt El ast o gr a p h y  
Tra nsie nt elast o gra p h y ( Fi br o Sca n T E) is a 
vali date d, n o ni n vasi ve tec h ni q ue use d t o 
assess he patic stiff ness  ( C or pec h ot 2 0 1 6) 
t hat will be use d t o deter mi ne s u bject 
eli gi bilit y base d o n e xcl usi o n criteri o n 4 . 
T E pr oce d ures will be c o n d ucte d at st u d y 
sites wit h t he a p pr o priate e q ui p me nt a n d b y 
a de q uatel y trai ne d st u d y site staff.  
T E testi n g was a d de d at Scree ni n g 
t o t he pr ot oc ol t o e xcl u de s u bjects 
wit h e vi de nce of cirr h osis . 
1 2. 9  C hil d -P u g h 
Assess me nt    
1 2. 9 C hil d P u g h Assess m e nt  
T he C hil d P u g h sc ore i s use d t o assess t he 
pr o g n osis of c hr o nic li ver disease, 
partic ularl y cirr h osis ( P u g h 1 9 7 3, L uce y 
1 9 9 7). T he sc ore uses 5 cli nical meas ures 
of li ver disease (t otal bilir u bi n, ser u m 
al b u mi n, P T or I N R, ascites, a n d he patic 
e nce p hal o pat h y), eac h sc ore d 1  t o 3, wit h 3 
Delete d text  
T he C hil d -P u g h assess me nt was 
re m o ve d as it is n o l o n ger rele va nt 
gi ve n t hat pat ie nts wit h cirr h osis 
are n o l o n ger eli gi ble f or st u d y 
partici pati o n.  

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A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
i n dicati n g m ost se vere. C hr o nic li ver 
disease is classifie d i nt o C hil d P u g h Class 
A t o Class C as i n dicate d i n Ta ble 5, a n d 
will be use d t o deter mi ne s u bject eli gi bilit y 
f or e xcl usi o n criteri o n 4. 
T a ble  5:  C hil d P u g h Sc ori n g  S yste m  
F a ct o r  
P oi nts 
1 
2 
3 
Bilir u bi n 
( m g/ d L) 
< 2  
2- 3 
> 3  
Al b u mi n 
( g/ d L) 
> 3. 5  
3. 5 -2. 8  
< 2. 8  
Pr ot hr o m bi
n ti me (sec 
pr ol o n g e d)  
or I N R  
0- 3 
4- 6 
> 6  
< 1. 7  
1. 7 -2. 3  
> 2. 3  
Ascites  
N o n e  
Mil d  
M o d erate
Se v ere  
He p atic 
E n ce p h al o
p at h y  
N o n e  
Gra d e 1 
or 2  
Gra d e 3 
or 4  
I N R = i nter n ati o n al n or malize d rati o. 
T he C hil d P u g h sc ore is calc ulate d b y 
a d di n g t he sc ores f or t he 5 fact ors a n d ca n 
ra n ge fr o m 5 t o 1 5. C hil d P u g h sc ore class 
is eit her A (a sc ore of 5 t o 6), B ( 7 t o 9), or 
C ( 1 0 or a b o ve). Dec o m pe nsati o n i n dicates 
cirr h osis wit h a C hil d P u g h sc ore of 7 or 
m ore ( Class  B). T his le vel has bee n t he 
acce pte d criteri o n f or listi n g f or li ver 
tra ns pla ntati o n ( P u g h 1 9 7 3, L uce y 1 9 9 7). 

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A m e n d m e nt 1. 0  
Re as o n f or C h a n ge  
1 2. 1 1  S A R S -C o V -2 Testi n g  Ne w secti o n 
1 2. 1 1 S A R S -C o V -2 Testi n g  
S u bjects will be teste d f or S A R S -C o V -2 
( C O VI D-1 9) at Scree ni n g via R T -P C R test. 
A p ositi ve test res ult f or C O VI D -1 9 will 
e xcl u de t he s u bject fr o m e nr olli n g i n t he 
st u d y, e ve n if t he s u bject is as y m pt o matic, 
re gar dless of vacci nati o n stat us. 
S A R S -C o V- 2 R T -P C R testi n g will 
be c o n d ucte d at Scree ni n g a n d 
s ubjects w h o test p ositi ve f or t he 
vir us will be e xcl u de d fr o m 
partici pati n g i n t he st u d y t o 
i ncrease s u bject safet y.  
1 3  P har mac o ki netics 
Assess me nt  
Ne w text  
I n t he e ve nt of a n S A E, t he I n vesti gat or 
s h o ul d c ollect, if at all p ossi ble, a bl o o d P K 
sa m ple at a n u nsc he d ule d visit as part of 
S A E f oll o w -u p.  
I n vesti gat ors are t o atte m pt t o 
c ollect a bl o o d P K sa m ple at a n 
u nsc he d ule d visit as part of S A E 
f oll o w-u p  t o assess dr u g le vels at 
t he ti me of t he e ve nt. 
1 7  List of Refere nces  
P u g h R N, M urra y
L y o n I M, Da ws o n J L, et 
al. Tra nsecti o n of t he Oes o p ha g us f or 
Blee di n g Oes o p ha geal Varices. Br J S ur g. 
1 9 7 3; 6 0( 8): 6 4 6 9.  
L uce y M R, Br o w n K A, E vers o n G T, et al. 
Mi ni mal Criteria f or Place me nt of A d ults 
o n t he Li ver Tra ns pla nt Waiti n g List: A 
Re p ort of  a Nati o nal C o nfere nce Or ga nize d 
b y t he A merica n S ociet y of Tra ns pla nt 
P h ysicia ns a n d t he A merica n Ass ociati o n 
f or t he Stu d y of Li ver Diseases. Li ver 
Tra ns pl S ur g. 1 9 9 7; 3( 6): 6 2 8 3 7.  
C or pec h ot C. Utilit y of N o ni n vasi ve 
Mar kers of Fi br osis i n C h olest atic Li v er 
Diseases. Cli n Li ver Dis. 2 0 1 6; 2 0( 1): 1 4 3 -
5 8.  
H H S. 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. 
2 0 1 7. p. 1 -1 5 5 . 
Refere nces f or C hil d -P u g h sc ori n g 
were re m o ve d as t his assess m e nt is 
n o l o n ger bei n g c o n d ucte d a n d t he 
refere nce f or tra nsie nt elast o gra p h y 
was a d de d f or t his ne wl y a d de d 
assess me nt.  T he h y perli n k f or t he 
C T C A E criteria was re place d wit h 
a refere nce . 
 
A p pe n di x A. Sc he d ule of 
Assess me nts   
I ncl u de d p atie nt i ntervie ws, gl o b al 
met a b ol o mic a n alysis, a ut ot axi n, 
lys o p h os p h ati dic aci d, a n d cyt oki ne 
m arkers.  
M e nti o n e d  use of a n  electr o nic device or 
a p p f or c o m pleti n g q uesti o n n aires.  
Re m ove d p atie nt  i ntervie ws, gl o b al 
met a b ol o mic a n alysis, a ut ot axi n, 
lys o p h os p h ati dic aci d, a n d cyt oki ne 
m arkers.  
A d de d H A V, H E V, S A R S -C o V -2  
R T -P C R, a n d T E ( Fi br o Sc a n) testi n g t o 
Visit 1 .  
A d de d t hyr oi d h or m o ne testi n g t o Visits 2, 
6, 8 a n d e arly ter mi n ati o n . 
Re m ove d me n ti o n of a n  electr o nic device 
or a p p f or c o m pleti n g q uesti o n n aires.  
C ha n ges were ma de t o reflect e dits 
descri be d f or earlier secti o ns of t he 
pr ot oc ol.  

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