Conditions: Pruritus
Keywords: Pruritus Itch Primary Biliary Cholangitis Primary Sclerosing Cholangitis PACIFIC EP547
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: no

Brief summary:
This phase 2 trial will evaluate the effects of EP547 in subjects with cholestatic pruritus due to Primary Biliary Cholangitis (PBC) or Primary Sclerosing Cholangitis (PSC)

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: EP547 intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily intervention 2: Once daily

Protocol document:
Prot_000.pdf: 
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  


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 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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C o nfi de ntial 
Pa g e 1 3 of 1 2 8 
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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C o nfi de ntial 
Pa g e 1 4 of 1 2 8 
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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Pa g e 1 6 of 1 2 8 
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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Pa g e 1 8 of 1 2 8 
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).  


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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C o nfi de ntial 
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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C o nfi de ntial 
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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Pa ge 2 1 of 1 2 8 
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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Pa ge 2 2 of 1 2 8 
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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C o nfi de ntial 
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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Pa ge 2 6 of 1 2 8 
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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Escie nt P har mace uticals, I nc.  
C o nfi de ntial 
Pa ge 4 9 of 1 2 8 
•  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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C o nfi de ntial 
Pa ge 5 0 of 1 2 8 
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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C o nfi de ntial 
Pa ge 5 1 of 1 2 8 
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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C o nfi de ntial 
Pa ge 5 2 of 1 2 8 
•  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 o nfi de ntial 
Pa ge 5 3 of 1 2 8 
− 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) 


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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C o nfi de ntial 
Pa ge 5 4 of 1 2 8 
− 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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C o nfi de ntial 
Pa ge 5 5 of 1 2 8 
•  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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C o nfi de ntial 
Pa ge 5 6 of 1 2 8 
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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C o nfi de ntial 
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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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 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 2. 0 
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 
st u d y visits. 




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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  
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 1. 0  
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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C o nfi de ntial 
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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C o nfi de ntial 
Pa ge 1 1 3 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. 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. 


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 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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C o nfi de ntial 
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 


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 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. 


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 3 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  
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. 


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 4 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  
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. 


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 5 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  
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.  


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 6 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  
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). 


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 7 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  
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.  


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 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  
 

SAP_001.pdf: 
Official Title: 
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 
NCT Number: 
NCT05525520 
Document Date: 
Statistical Analysis Plan EP-547-201 Version 1.0; 01 May 2024 
 
 
 


Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
Page 1 of 51 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Escient Pharmaceuticals, Inc. 
EP-547-201 
 
 
 
 
 
 
Protocol Title: 
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 
Protocol Version 
and Date: 
Amendment: 3.0; 02 October 2023 
Sponsor: 
Escient Pharmaceuticals, Inc. 
10578 Science Center Drive, Suite 250  
San Diego, CA 92121 USA 
Prepared By: 
Document 
Version and Date 
Version 1.0; 01 May 2024 
 
 


Escient Pharmaceuticals, Inc.
Statistical Analysis Plan
EP-547-201
Version 1.0; 01 May 2024
Confidential
Page 2 of 51
STATISTICAL ANALYSIS PLAN APPROVAL
Sponsor:
Escient Pharmaceuticals, Inc.
Clinical Protocol Number:
EP-547-201
Protocol Title:
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
Document File and Name:
Escient_EP-547-201_SAP_v1.0_2024-05-01.pdf
Document Version and 
Effective Date:
Version 1.0; 01 May 2024
Approved By:
, MS
, Biometrics and 
Data Analytics
Escient Pharmaceuticals, Inc.
, PhD
, Head of Clinical 
Development
Escient Pharmaceuticals, Inc.
, Biostatistics
Emanate Biostats, Inc.
Emanate Biostats, Inc.
, MS
, Biometrics and
, Biostatistics
Emanate Biostats Inc
, PhD
, Head of Clinical
Emanate Biostats Inc


Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
Page 3 of 51 
 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN APPROVAL ........................................................ 2 
TABLE OF CONTENTS ............................................................................................... 3 
TABLE OF TABLES .................................................................................................... 5 
TABLE OF FIGURES ................................................................................................... 5 
ABBREVIATIONS ....................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................. 9 
2. 
STUDY OBJECTIVES .......................................................................................... 9 
2.1 
Primary Study Objective ................................................................................. 9 
2.2 
Secondary Study Objectives............................................................................ 9 
2.3 
Exploratory Objectives .................................................................................... 9 
3. 
INVESTIGATIONAL PLAN .............................................................................. 10 
3.1 
Overall Study Design .................................................................................... 10 
3.2 
Schedule of Assessments .............................................................................. 11 
3.3 
Treatments ..................................................................................................... 11 
3.3.1 
Treatments Administered ....................................................................... 11 
3.3.2 
Prohibited Concomitant Medications .................................................... 12 
3.3.3 
Method of Assigning Subjects to Treatment Groups ............................. 12 
3.3.4 
Blinding Procedures ............................................................................... 13 
3.4 
Efficacy and Safety Variables ....................................................................... 13 
3.4.1 
Efficacy Variables .................................................................................. 13 
3.4.2 
Pharmacodynamic Variables ................................................................. 18 
3.4.3 
Safety Variables ..................................................................................... 19 
3.4.4 
Pharmacokinetic Variables .................................................................... 23 
3.5 
Data Quality Assurance ................................................................................. 23 
4. 
STATISTICAL METHODS ................................................................................ 23 
4.1 
General Methodology .................................................................................... 23 
4.1.1 
Reporting Conventions .......................................................................... 24 
4.1.2 
Definition of Baseline ............................................................................ 24 
4.1.3 
Summarization by Visit ......................................................................... 25 
4.1.4 
Data Handling Rules .............................................................................. 25 
4.1.5 
Standard Calculations ............................................................................ 26 
4.2 
Analysis Sets ................................................................................................. 26 
4.3 
Study Subjects ............................................................................................... 27 
4.3.1 
Disposition of Subjects .......................................................................... 27 
4.3.2 
Protocol Deviations ................................................................................ 28 
4.4 
Efficacy and Pharmacodynamic Evaluation ................................................. 28 


Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
Page 4 of 51 
 
4.4.1 
Datasets Analyzed .................................................................................. 28 
4.4.2 
Demographic and Other Baseline Characteristics ................................. 28 
4.4.3 
Primary Efficacy Endpoint Analysis Methods ...................................... 30 
4.4.4 
Secondary Endpoint Analysis Methods ................................................. 31 
4.4.5 
Exploratory Endpoint Analysis Methods ............................................... 32 
4.4.6 
Sensitivity Analysis of Efficacy Endpoints ........................................... 33 
4.4.7 
Statistical/Analytical Issues ................................................................... 34 
4.4.8 
EP547 Plasma Concentrations ............................................................... 37 
4.4.9 
Pharmacokinetic Analysis ...................................................................... 37 
4.5 
Safety Evaluation .......................................................................................... 37 
4.5.1 
Extent of Exposure ................................................................................. 37 
4.5.2 
Measurements of Treatment Compliance .............................................. 38 
4.5.3 
Adverse Events ...................................................................................... 39 
4.5.4 
Deaths, Other Serious Adverse Events, and Adverse Events of Special 
Interest 40 
4.5.5 
Clinical Laboratory Evaluation .............................................................. 40 
4.5.6 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 42 
4.6 
Determination of Sample Size....................................................................... 45 
4.7 
Changes in the Conduct of the Study or Planned Analyses .......................... 45 
5. 
REFERENCE LIST ............................................................................................. 45 
 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations ................................................................................... 6 
Table 2 
EP-547-201 Treatment Assignments ......................................................... 12 
 
TABLE OF FIGURES 
Figure 1 
EP-547-201 Study Design ......................................................................... 10 
 
 
 


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ABBREVIATIONS 
Table 1 
List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIC 
Akaike’s information criterion 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AR 
First-Order Autoregressive 
AST 
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
B2M 
Beta-2-microglobulin 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CDCA 
Chenodeoxycholic acid 
CA 
Cholic acid 
CLU 
Clusterin 
CM 
Composite measure 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease 2019 
CRO 
Contract Research Organization 
CS 
Compound symmetry 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CysC 
Cystatin-C 
DCA 
Deoxycholic acid 
DILI 
Drug-induced liver injury 
D-FIS 
Fatigue Impact Scale for Daily Administration 
DMC 
Data Monitoring Committee 
DRT 
Data Review Team 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EQ-5D-3L 
3-Level EuroQol-5D 
FC 
Fold change  
GCA 
Glycocholic acid 
GDCA 
Glycodeoxycholic acid 


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Abbreviation 
Definition 
GCDCA 
Glycochenodeoxycholic acid 
GLCA 
Glycolithocholic acid 
GUDCA 
Glycoursodeoxycholic acid 
HEENT 
Head, eyes, ears, nose, throat 
IBD 
Inflammatory bowel disease 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IL-31 
Interleukin-31 
IPD 
Important Protocol Deviation 
IWRS 
Interactive Web Response System 
KIM-1 
Kidney injury molecule-1 
LCA 
Lithocholic acid 
LLOQ 
Lower limit of quantification 
LS 
Least-square 
LSMD 
Least-square mean difference 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputations 
MMRM 
Mixed effects model for repeated measures 
NAG 
N-acetyl-β-D-glucosaminidase 
NGAL 
Neutrophil gelatinase-associated lipocalin 
OCA 
Obeticholic acid 
OLE 
Open-Label Extension 
OPN 
Osteopontin 
PBC 
Primary Biliary Cholangitis 
PD 
Pharmacodynamic 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetics 
PROMIS 
Patient-Reported Outcomes Information System 
PSC 
Primary Sclerosing Cholangitis 
Q1 
1st quartile (25th percentile) 
Q3 
3rd quartile (75th percentile) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Query 
TCA 
Taurocholic acid 
TCDCA 
Taurochenodeoxycholic acid 
TDCA 
Taurodeoxycholic acid 
TE 
Transient elastography 


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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
TLCA 
Taurolithocholic acid 
TTF3 
Trefoil Factor 3 
TUDCA 
Tauroursodeoxycholic acid 
UC 
Ulcerative colitis 
uCR 
Urine creatinine  
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
VEGF 
Vascular endothelial growth factor 
WHO 
World Health Organization  
WI-NRS 
Worst Itch Numeric Rating Scale 
 
 


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1. INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide comprehensive and 
detailed descriptions of the statistical methods and presentation of data collected for 
Escient Pharmaceuticals, Inc. Protocol EP-547-201 (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). 
Descriptions of planned analyses are provided in order to avoid post hoc decisions that 
may affect the interpretation of the statistical analysis. The statistical methods applied 
in the design and planned analyses of this study are consistent with the International 
Council for Harmonisation (ICH) guideline Statistical Principles for Clinical Trials 
(E9) (1998) and Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials (E9[R1], Rev 1) (2021).  
This SAP will be finalized prior to data analysis and before treatment unblinding and 
database lock to provide comprehensive details of the tables and listings to be presented 
in the Clinical Study Report (CSR). Any changes between the statistical methods 
provided in the clinical study protocol and this SAP will be explained herein; any 
changes or deviations from this SAP relative to the final analysis will be fully 
documented in the CSR. Minor changes or deviations from the templates for tables and 
listings need not be documented in the CSR. 
2. STUDY OBJECTIVES 
2.1 
Primary Study Objective 
The primary objective of this study is to assess the efficacy of EP547 compared to 
placebo on pruritus as assessed by the Worst Itch Numeric Rating Scale (WI-NRS). 
2.2 
Secondary Study Objectives 
The secondary objectives of this study are: 
 To assess the efficacy of EP547 compared to placebo on the following: 
o Pruritus-related quality of life using the 5-D Itch Scale 
o Pruritus severity using the Patient Global Impression of Severity 
(PGI-S) 
o Overall pruritus response to therapy using the Patient Global Impression 
of Change (PGI-C) 
 To assess the safety and tolerability of EP547 
 To assess the pharmacokinetics (PK) of EP547 
2.3 
Exploratory Objectives 
 
 


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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
EP-547-201 is a randomized, double-blind, placebo-controlled study to evaluate the 
effects of EP547 on pruritus over 6 weeks in subjects with cholestatic pruritus due to 
primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Where 
allowed per regulatory/local requirements, subjects will be able to attend study visits at 
a physical study site as well as remotely (hybrid model) or at a virtual site where all 
visits will be conducted remotely (decentralized model). For both the hybrid and 
decentralized models, a home health nurse visit at the subject’s home or work and a 
telemedicine visit with the study site staff (e.g., smartphone or computer) will be 
arranged to conduct procedures for each remote study visit. 
The study includes a Screening Period of up to 4 weeks to assess subject eligibility; a 
6-week Double-Blind Treatment Period; a 6-week Open-Label Extension (OLE) 
Period; and a 2-week Safety Follow-Up Period after administration of the last dose of 
study drug (EP547 or placebo). Approximately 58 subjects with cholestatic pruritus due 
to PBC or PSC will be randomized to receive either 100 mg doses of EP547 or placebo 
orally (PO) QD in a 1:1 ratio. In the Open-Label Extension Period, all subjects will 
receive 100 mg doses of EP547. Details of the study design are presented in Figure 1.  
Figure 1 
EP-547-201 Study Design 
 
 
PO = oral, QD = once daily. 
a For the decentralized model, enrollment/randomization and the first dose of study drug may be 
separated by up to 10 additional calendar days to allow for home delivery of study drug. When 
enrollment/randomization and first dose of study drug are on separate days, the first dose of study 
drug is considered Day 1. 
b Any subject who completes the Open-Label Extension Period or discontinues study drug (EP547 or 
placebo) early will complete a follow-up visit approximately 2 weeks (±3 days) after the last dose of 
study drug. 
Enroll/
Randomize
Visit 2a
Day 1
Placebo PO QD
Screening
Visit 1
Days -28 to -1
Visit 3
Week 1
Visit 5
Week 3
Follow-Up 
Visit 6
Week 6
Screening 
Period
Double-Blind 
Treatment Period
Safety Follow-Up 
Period
100 mg EP547 PO QD
Open-Label
Extension Period
100 mg EP547 PO QD
Visit 7
Week 9
Visit 8
Week 12
Visit 4
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Visit 9b


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The Screening Period will consist of one study visit (Visit 1). During this period, 
subjects will undergo assessments to determine study eligibility. Visit 1 (Day -28 to 
Day -1) may be conducted over more than one day but must be completed between Day 
-28 and Day -1. 
The Double-Blind Treatment Period will consist of five study visits (Visits 2, 3, 4, 5, 
and 6 [Day 1 and Weeks 1, 2, 3, and 6]). During this period, all subjects who meet 
eligibility requirements will be enrolled into the study and randomized to receive 
double-blind, PO, QD 100 mg doses of EP547 or placebo for 6 weeks beginning on 
Visit 2 (Day 1). Visit 2 (Day 1) will not have a visit window; however, for the 
decentralized model, enrollment/randomization and the first dose of study drug may be 
separated by up to 10 additional calendar days to allow for home delivery of study drug. 
When enrollment/randomization and first dose of study drug are on separate days, the 
first dose of study drug is considered Day 1. All other visits in the Double-Blind 
Treatment Period will have a visit window of ±3 days. 
For the hybrid model, Visits 1, 2, 6, and 8 (Screening, Day 1, Week 6, and Week 12) 
and early termination (if applicable) must be completed at the study site. All other study 
visits may be conducted remotely, where allowed per regulatory/local requirements. 
For the decentralized model, all visits will be conducted remotely. 
For remote visits for both the hybrid and decentralized models, the home health nurse 
visit at the subject’s home or work and the telemedicine visit with the study site staff 
for a given study visit may be conducted on different days but must be within the 
allowable visit window. The home health nurse will complete the study assessments 
that the site is physically unable to complete remotely (e.g., blood and lab sample 
collection, vital signs, electrocardiograms [ECGs]); the site will complete all other 
study assessments remotely during the telemedicine visit.  
The Open-Label Extension Period will consist of two study visits (Visit 7 [Week 9] and 
Visit 8 [Week 12]). During this period, all subjects who complete the Double-Blind 
Treatment Period and are still receiving study drug will receive open-label 100 mg 
doses of EP547. Visit 7 and Visit 8 will have a visit window of ±3 days. 
Any subject who completes the Open-Label Extension Period or discontinues study 
drug (EP547 or placebo) early will complete a Follow-Up Visit (Visit 9) approximately 
2 weeks (±3 days) after the last dose of study drug. 
3.2 
Schedule of Assessments 
For the complete schedule of assessments, refer to Appendix A of the clinical study 
protocol. 
3.3 
Treatments 
3.3.1 Treatments Administered 
Tablets containing 25 mg or 75 mg of EP547 or placebo will be supplied in a way to 
ensure the study blind. For the Open-Label Extension Period, tablets containing 25 mg 
and 75 mg of EP547 will be supplied. Subjects receiving EP547 will take one 25 mg 


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and one 75 mg EP547 tablet per dose (for a total dose of 100 mg) and subjects receiving 
placebo will take two placebo tablets per dose.  
Each study drug dose, containing two tablets, is to be administered orally as intact 
tablets (swallowed whole, not chewed or crushed), and taken with water. Doses are to 
be administered daily at approximately the same time of day after a fast of at least eight 
hours. 
EP-547-201 treatment assignments by study period are presented in Table 2. 
Table 2 
EP-547-201 Treatment Assignments 
Study Period  
Study Days 
Approx. No. 
of Subjects 
Treatment 
Designation 
Study Drug Dose 
Regimen 
Screening  
Day -28 to Day -1 
58 
Not applicable 
None 
6-Week, Double-
Blind Treatment  
 
Day 1 to Day 42 
 
29 
100 mg EP547 
One 25 mg EP547 
tablet and One 75 mg 
EP547 tablet PO QD 
29 
Placebo 
Two placebo tablets 
PO QD 
6-Week, Open-
Label Extension  
Day 43 to Day 85 
58 
100 mg EP547 
One 25 mg EP547 
tablet and One 75 mg 
EP547 tablet PO QD 
2-Week Safety 
Follow-Up  
2 weeks after last 
study drug dose 
58 
Not applicable 
None 
PO = oral; QD = once daily. 
3.3.2 Prohibited Concomitant Medications 
Subjects taking immunosuppressant/immunomodulating agents may not receive live, 
attenuated vaccines during participation in this study. Medications with known 
nephrotoxic potential (e.g., aminoglycosides, contrast dye, bisphosphonates, and 
nonsteroidal anti-inflammatory drugs) are prohibited from use during the study as are 
some medications that are substrates for BCRP, OAT1, CYP2B6, or CYP2C8, or 
inhibitors of OAT3. Table 3 of the clinical study protocol lists examples of excluded 
medications that are substrates for BCRP, OAT1, CYP2B6 or CYP2C8, or inhibitors 
of OAT3. If a subject receives a prohibited concomitant medication during the study, 
the Investigator, in consultation with the Medical Monitor, may interrupt or discontinue 
study drug as warranted for reasons of protecting subject safety. 
3.3.3 Method of Assigning Subjects to Treatment Groups 
All subjects who meet eligibility requirements will be enrolled into the study and 
randomized to receive double-blind, PO, QD doses of EP547 or placebo for 6 weeks 
beginning at Visit 2 (Day 1). Subjects will be randomized to receive either 100 mg 
doses of EP547 or placebo in a 1:1 ratio. Randomization will be conducted centrally 
via an Interactive Web Response System (IWRS) and stratified based on type of 
cholestatic disease (PBC or PSC). 
All subjects who complete the Double-Blind Treatment Period and are still receiving 
study drug will receive open-label 100 mg doses of EP547 during the Open-Label 
Extension Period. 


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3.3.4 Blinding Procedures 
The Sponsor, Medical Monitor, Contract Research Organization (CRO) staff, 
Investigators, site staff, and subjects will be blinded to subject’s assigned treatment 
during the Double-Blind Treatment Period of the study until the database is locked 
except for CRO or vendor staff involved in the analysis of PK samples or safety 
reporting to regulatory agencies. 
To address business needs, a limited number of study team members and senior 
stakeholders comprising the internal Data Review Team (DRT) may conduct and 
review an interim analysis of all accumulated data including unblinded data from the 
Double-Blind Treatment Period (see Section 4.4.7.3). The rest of the central study and 
project team members will remain blinded. 
Treatment with 100 mg doses of EP547 during the Open-Label Extension Period will 
be conducted in an unblinded manner. 
If an emergency unblinding during the Double-Blind Treatment Period is required, the 
subject’s treatment assignment may be unblinded through IWRS by the Investigator. If 
a treatment assignment is unblinded, the subject will be discontinued from randomized 
treatment. Blinding codes should only be broken in emergency situations for reasons of 
subject safety and when knowledge of the treatment assignment will impact the clinical 
management of the subject. Every reasonable attempt should be made to complete the 
post-treatment evaluation procedures prior to unblinding as knowledge of the treatment 
arm could influence subject assessment. 
In all emergency cases, the reasons and rationale for unblinding will be documented in 
writing and maintained in the study file. 
Access to randomization codes and corresponding treatment assignment will also be 
made available through the IWRS system to the appropriate individual(s) responsible 
for unblinding suspected unexpected serious adverse reactions for reporting to the 
Regulatory Authorities. 
3.4 
Efficacy and Safety Variables 
3.4.1 Efficacy Variables 
3.4.1.1 
Primary Efficacy Variable 
The primary efficacy endpoint is the change from baseline in WI-NRS at Week 6. 
Subjects will be asked to rate the severity of their worst level of itching in the past 24 
hours in the morning, and at the same time of day, using the WI-NRS. The WI-NRS is 
an 11-point scale ranging from 0 (No Itching) to 10 (Worst Itching Imaginable) (Phan 
2012) and requires approximately 1 minute to complete. Higher scores indicate greater 
itch severity. Itching severity scores collected via the WI-NRS have been categorized 
in the literature as mild (<4), moderate (≥4 to <7), or severe (≥7) (Fishbane 2020, 
Hirschfield 2020, Levy 2020, Stander 2020).  


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Subjects will be instructed to complete the WI-NRS daily, in the morning, and at the 
same time of day, beginning at Day -14 to the Follow-Up Visit. For days that coincide 
with a study visit (for Visit 2 and beyond), the WI-NRS is to be completed before the 
visit. 
For WI-NRS, a weekly score will be determined based on the average of all available 
daily scores of the week. Weekly scores will be calculated for Week 1 through Week 6 
of the Double-Blind Treatment Period and Week 7 through Week 12 of the Open-Label 
Extension Period. During the Safety Follow-up Period, weekly scores for Week 13 and 
Week 14 will be derived, when available. 
The average WI-NRS score using the daily values from the week before the first dose 
of study drug (including the WI-NRS score captured on study day 1 of dosing) will 
serve as the baseline score.  
For subjects who complete the nominal Week 6 visit, the weekly WI-NRS scores for 
both the Double-Blind Treatment Period and Open-Label Extension Period will be 
anchored to the nominal Week 6 visit date with the following considerations applied:  
 Within the Double-Blind Treatment Period, analysis of Week 6 will be the 7 
days leading up to the nominal Week 6 date (including the nominal Week 6 visit 
date WI-NRS score). Each preceding analysis visit will be the 7 prior days.  
 Within the Open-Label Extension Period, analysis of Week 7 will be the first 7 
days after the nominal Week 6 visit date or start date of open-label dosing, 
whichever is later; for subjects who participate in the decentralized model, there 
may be a gap between the nominal Week 6 visit and open-label dosing due to 
drug shipment considerations. Subsequent analysis visits will be counted using 
the next 7 days. The Week 6 WI-NRS score will be used as the Initiation of 
OLE score. 
The Safety Follow-up Period will be anchored to the nominal Week 12 visit date. Week 
13 will be the first 7 days after the nominal Week 12 visit date and Week 14 will be 
derived using the next 7 days. 
For subjects who early terminate during the Double-Blind Treatment Period, the 
subject’s first day of dosing (i.e., study day 1) will be the anchor date for weekly 
analysis visit derivations. Week 1 will be study days 2 through 8 and subsequent weekly 
analysis visits will be the next 7 days, deriving all applicable analysis visits until early 
termination.  
The following additional general considerations will be applied in deriving the weekly 
WI-NRS scores:  
 No WI-NRS daily score is to be utilized in more than one analysis visit 
derivation. 
 For weeks where 7 calendar days are available for a given week, there must be 
4 non-missing daily scores to compute the weekly score; if more than 3 daily 
scores are missing, the weekly score is considered missing. 


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 For weeks where less than 7 calendar days are available for a given week due 
to visit anchoring rules, at least 57% of the daily scores for the available 
calendar days must be reported, maintaining the same rate of reported scores as 
seen for a full week (i.e., 4 out of 7 days). If 6 calendar days are available for a 
given week, 4 non-missing daily scores are required. If 4 or 5 calendar days are 
available for a given week, 3 non-missing daily scores are required. If less than 
4 calendar days are available for a given week, the weekly score will be 
considered missing. 
A bi-weekly WI-NRS score will be calculated for exploratory analysis. The average 
WI-NRS score using the daily values from the 14 days before the first dose of study 
drug (including the WI-NRS score captured on the study day 1 of dosing) will serve as 
the baseline bi-weekly score.  
Bi-weekly WI-NRS scores for Week 2, Week 4, and Week 6 in the Double-Blind 
Treatment Period and Week 8, Week 10, Week 12 in the Open-Label Extension Period 
and Week 14 in the Safety Follow-up Period will be calculated following the same 
general guidelines as the weekly WI-NRS scores, applied to a bi-weekly derivation 
(e.g., requiring 8 non-missing daily scores in 14 calendar days). For intervals shorter 
than 14 calendar days due to visit anchoring rules, at least 57% of the daily scores for 
the available calendar days must be reported for a bi-weekly score to be computed.  The 
Change from OLE summary will be relative to the bi-weekly score prior to the Initiation 
of OLE (e.g., Week 6). 
3.4.1.2 
Secondary Efficacy Variables 
All efficacy assessments will be performed as indicated in the Schedule of Assessments 
(Appendix A) of the clinical study protocol. Secondary efficacy endpoints include the 
following: 
 Change from baseline in 5-D Itch Scale 
 The proportion of subjects with improvement in pruritus as defined by PGI-C 
 The proportion of subjects with improvement in pruritus severity from baseline 
as defined by change in PGI-S 
 The proportion of subjects with a reduction in WI-NRS ≥2 from baseline 
 The proportion of subjects with a reduction in WI-NRS ≥3 from baseline 
 The proportion of subjects with a reduction in WI-NRS ≥4 from baseline 
 The proportion of subjects with WI-NRS <4 
5-D Itch Scale 
The 5-D Itch Scale was developed as a brief but multidimensional questionnaire 
designed for pruritus that measures changes over time (Elman 2010). The 5 dimensions 
are degree, duration, direction, disability, and distribution. It requires approximately 1 
to 2 minutes to complete. For analysis purposes, the single-item domain scores 


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(duration, degree and direction) are equal to the value indicated by the response choice, 
with a range of 1 to 5. The disability domain includes four items that assess the impact 
of itching on daily activities: sleep, leisure/social activities, housework/errands and 
work/school. The score for the disability domain is achieved by taking the highest score 
on any of the four categories. For the distribution domain, 16 body parts are listed to 
determine the distribution of itching over the last two weeks; the number of affected 
body parts is tallied (for a potential sum of 0 to 16) and the sum is sorted into five 
scoring thresholds: a sum of 0 to 2 is assigned a score of 1; a sum of 3 to 5 is assigned 
a score of 2; a sum of 6 to 10 is assigned a score of 3; a sum of 11 to 13 is assigned a 
score of 4, and a sum of 14 to 16 is assigned a score of 5. The scores of each of the 5 
domains are achieved separately and then summed together to obtain a total 5-D score, 
ranging from 5 (no pruritus) to 25 (most severe pruritus). 
PGI-C 
Subjects will be asked to rate their impression of overall change in pruritus in the past 
7 days compared to before they started taking study drug using the PGI-C. The PGI-C 
is a 7-point scale ranging from “Much Improved” to “Much Worse” and requires 
approximately 1 minute to complete (Guy 1976). Higher scores indicate less 
improvement in pruritus. For analysis purposes, subjects that report a change in their 
itch of “Minimally Improved” or better will be considered as being a responder for 
“improvement in pruritus” efficacy considerations.  
PGI-S 
The PGI-S was validated in women with stress urinary incontinence, but may be used 
to rate the severity of other specific conditions (Yalcin 2003). For this questionnaire, 
the specific condition to be rated is pruritus. Subjects will be asked to rate the severity 
of their pruritus in the past 7 days using a 4-point scale from “None” to “Severe.” The 
PGI-S requires less than 1 minute to complete. For analysis purposes, subjects that 
report a positive shift in their categorical assessment of itch compared to their baseline 
level (e.g., “Severe” at Visit 2 [Day 1] with a shift to “Moderate” at Visit 6 [Week 6]), 
will be considered a responder for “improvement in pruritus.” 
WI-NRS 
Details on the WI-NRS are described in Section 3.4.1.1. 
3.4.1.3 
Exploratory Efficacy Variables 


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3.4.3 Safety Variables 
Safety evaluations, including adverse events (AEs), concomitant medications, medical 
history, vital signs, physical examinations, standard 12-lead ECGs, laboratory 
evaluations of safety, and disease-specific assessments (Partial Mayo Score for subjects 
with ulcerative colitis [UC] and Crohn’s Disease Activity Index [CDAI] for subjects 
with Crohn’s disease [CD]) will be performed as indicated in the Schedule of 
Assessments (Appendix A) of the clinical study protocol. For the decentralized model, 
the Investigator may require the subject to have an in-person consultation with a 
physician after virtually conducting safety assessments, if deemed necessary. 
3.4.3.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable or unintended sign (including 
a clinically significant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product. All AEs are recorded 
in the source documents and in the electronic case report forms (eCRFs) provided by 


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the Sponsor from the signing of the Informed Consent Form (ICF) until the end of study 
participation. 
Medical conditions present at baseline that worsen in severity or frequency after 
exposure to study drug are considered treatment-emergent AEs (TEAEs). Planned 
hospital admissions or surgical procedures for an illness or a disease that existed before 
administration of study drug, and for which the condition has not worsened since 
starting study drug, are not to be considered TEAEs/treatment-emergent serious AEs 
(SAEs). Events with emergency room visits that are less than 24 hours will also not be 
considered SAEs unless they meet one of the criteria listed in Section 12.2.1 of the 
clinical study protocol. 
Clinically significant abnormal laboratory tests, 12-lead ECG assessments, or vital sign 
results may, in the opinion of the Investigator, constitute an AE. However, whenever 
possible, the underlying diagnosis should be listed in lieu of associated abnormal 
results. Abnormalities deemed not clinically significant by the Investigator should not 
be reported as AEs. 
Subjects will be assessed for potential drug-induced liver injury (DILI) during both the 
Double-Blind Treatment Period and Open-Label Extension Period according to the 
consensus guidelines for clinical trials in adults with chronic cholestatic liver disease 
(Palmer 2020). Monitoring, interrupting, and stopping rules based on multiples of upper 
limit of normal (ULN), threshold values, baseline values, and/or nadir values of 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), and total bilirubin and liver‐ related symptoms are described in the 
algorithms for treatment-emergent hepatocellular and cholestatic DILI signals in 
Section 12.13.3 of the clinical study protocol. 
Adverse events are graded for severity (i.e., intensity) using the U.S. Department of 
Health and Human Services Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0 (HHS 2017). All AEs will be assessed for relationship to study 
drug based upon the definitions provided in Section 12.1.3 of the clinical study 
protocol. 
Any clinically meaningful new, worsening from baseline, or abnormal laboratory 
findings or symptoms suggestive of acute kidney injury (AKI) (e.g., ‘blood urea 
increased’ or ‘protein urine present’ AEs as identified by the Standardized Medical 
Dictionary for Regulatory Activities [MedDRA] Query [SMQ] ‘acute renal failure’) 
will be considered AEs of special interest (AESI). 
An SAE is any untoward medical occurrence, that at any dose: 
 Results in death; 
 Is life-threatening, i.e., the subject is, in the opinion of the Investigator, at 
immediate risk of death from the event as it occurred (it does not include an 
event that, had it occurred in a more severe form, might have caused death); 
 Requires hospital admission or prolongs hospitalization. Planned hospital 
admissions or surgical procedures for an illness or a disease that existed before 
administration of study drug, and for which the condition has not worsened 


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since starting study drug, are not to be considered SAEs. Emergency room visits 
that are less than 24 hours will also not be considered SAEs; 
 Results in persistent or significant disability or incapacity; 
 Is a congenital anomaly/birth defect; or 
 Is a medically significant event that, based on appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
3.4.3.2 
Safety Laboratory Parameters 
Samples for the following laboratory tests will be collected after an overnight fast (at 
least 8 hours): 
 Chemistry: sodium, albumin, ALP, bicarbonate, calcium, bile acids, corrected 
calcium, chloride, total and direct bilirubin, AST, ALT, blood urea nitrogen, 
urea, creatinine, magnesium, phosphorus, potassium, creatine phosphokinase, 
glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, 
low-density 
lipoprotein 
cholesterol, 
lactate 
dehydrogenase, 
gamma-
glutamyltransferase, and total protein 
 Hematology: hemoglobin, hematocrit, white blood cell counts with differential 
(lymphocytes, neutrophils, monocytes, eosinophils, and basophils), red blood 
cell count, platelet count, and platelet volume. If a subject develops 
lymphopenia, blood lymphocytes will be tested to assess populations of 
circulating T cells (including CD4+ and CD8+ subtypes), B cells, and natural 
killer cells. 
 Urinalysis: leukocyte esterase, nitrites, pH, protein, specific gravity, glucose, 
occult blood, ketones, bilirubin, urobilinogen, albumin, creatinine, sodium, 
chloride, and potassium; microscopic analysis is to be performed only if protein, 
leukocyte esterase, blood or nitrite is positive 
 Coagulation: activated partial thromboplastin time, international normalized 
ratio, and prothrombin time 
 Pregnancy testing: required for all females; serum test at Screening (Visit 1) and 
urine test for all other visits where pregnancy testing is required 
 Thyroid function tests: thyroid-stimulating hormone and free thyroxine  
The urine pregnancy test for female subjects will be conducted locally; all other planned 
laboratory evaluations of safety will be conducted at a central laboratory.  
3.4.3.3 
Vital Signs 
Vital signs, including sitting systolic and diastolic blood pressure, pulse rate, oxygen 
saturation, body temperature, and respiratory rate, will be measured after at least 5 


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minutes of rest. Vital signs are to be performed pre-dose if the dose is administered at 
the site. 
Vital signs also include body weight, which should be measured with no shoes on and 
using a calibrated scale throughout the study. 
3.4.3.4 
Physical Examinations 
Physical examinations will include, but are not limited to, an assessment of general 
appearance, skin, head, eyes, ears, nose, throat (HEENT), musculoskeletal, 
thyroid/endocrine, 
cardiovascular, 
chest/lung, 
neurologic, 
abdomen, 
and 
extremities/general body systems. Symptom directed physical examinations to assess 
clinically significant changes from Screening or any new signs or symptoms may be 
conducted at other visits as determined by the Investigator based on subject complaint. 
Any clinically significant findings will be recorded as medical history (prior to first 
dose) or adverse events (post first dose). 
For the decentralized model, the Investigator, assisted by the mobile nurse, will conduct 
physical examinations per protocol via telemedicine during a videoconference session. 
3.4.3.5 
Standard 12-Lead Electrocardiograms 
Twelve-lead ECGs are to be performed with subjects in a supine position after at least 
5 minutes of rest.  
3.4.3.6 
Partial Mayo Scoring Index (Subjects with Ulcerative Colitis Only) 
The Partial Mayo Scoring Index is a non-invasive questionnaire used as an outcome 
measure for clinical studies assessing therapies for UC (Lewis 2008). The index is 
composed of 3 categories (Bleeding, Stool Frequency, and Physician Assessment) that 
are each rated from 0 to 3 and summed to give a total score that ranges from 0 to 9. The 
Partial Mayo Scoring Index will be used to monitor disease stability during the course 
of the study. 
3.4.3.7 
Crohn’s Disease Activity Index (Subjects with Crohn’s Disease Only) 
The CDAI is a composite instrument used for evaluating the disease severity of CD that 
is scored on a scale from 0 to 1100 and includes abdominal pain, general well-being, 
complications, abdominal mass, anemia, and weight change. Subjects with CD can be 
divided into asymptomatic remission (CDAI <150), mild-to-moderate CD (150 to 219), 
moderate-to-severe CD (220 to 450), and severe-fulminant disease (>450) (Chen 2018). 
The CDAI will be used to monitor disease stability during the course of the study. 
3.4.3.8 
Other Safety Screening Assessments 
During the Screening Period, subjects will undergo assessments to determine their 
study eligibility. The following additional safety assessments not already described 
above are to be performed at Screening:  
 Samples for the following laboratory tests will be collected after an overnight 
fast (at least 8 hours): immunoglobulin G4 and serology (human 


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immunodeficiency virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, 
and hepatitis E virus) 
 Transient elastography (TE): FibroScan TE. If an eligible historical TE within 
6 months of Screening is not available, TE procedures will be conducted at 
study sites with the appropriate equipment and by adequately trained study site 
staff. Scheduling of the TE assessment should be within the Screening window 
(Day -28 to Day -1). 
 SARS-CoV-2 Testing (Only required prior to protocol amendment version 3.0): 
Subjects will be tested for SARS-CoV-2 (coronavirus disease 2019 [COVID-
19]) at Screening via reverse transcription-polymerase chain reaction test. A 
positive test result for COVID-19 will exclude the subject from enrolling in the 
study, even if the subject is asymptomatic, regardless of vaccination status. 
3.4.4 Pharmacokinetic Variables 
Blood sampling for PK of EP547 will be collected pre-dose and 
 
 
 to analyze EP547 concentrations; the metabolite profile may 
also be analyzed from these samples. The PK will be evaluated based on plasma 
concentrations of EP547 and potential metabolite profile. 
In the event of an SAE, the Investigator should collect, if at all possible, a blood PK 
sample at an unscheduled visit as part of SAE follow-up. 
3.5 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS® software, version 9.4 
or higher, on a PC or server-based platform. Additional validated software may be used 
to generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated 
by a second statistical programmer or biostatistician. At a minimum, validation of 
programs will consist of a review of the program log, review of output or dataset format 
and structure, and independent confirmatory programming to verify output results or 
dataset content. Additionally, all outputs will undergo a review by a senior level team 
member before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 
checks, and other programmatic testing procedures. All findings will be forwarded to 
the project data manager for appropriate action and resolution. 
4. STATISTICAL METHODS 
4.1 
General Methodology 
Data will be analyzed by Emanate biostatistics personnel. Statistical analyses will be 
reported with tables and listings, presented in rich text format, and using recommended 


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ICH numbering. Output specifications for all tables and listings will be in conformance 
with guidelines specified by the ICH in Appendix 7 of the Electronic Common 
Technical Document Specification (Apr 2003). 
4.1.1 Reporting Conventions 
In general, tables will be summarized by treatment group and overall. Summaries will 
be presented for both the Double-Blind Treatment Period and the Open-Label 
Extension Period separately. Tables summarizing data from the Open-Label Extension 
Period will summarize subjects by randomized treatment from the Double-Blind 
Treatment Period as well as by all subjects combined. In general, all data collected and 
any derived data will be presented in subject data listings, for all enrolled subjects. 
Listings will be ordered by site, subject number, treatment group, and assessment or 
event date. The treatment group presented in listings will be based on the planned 
assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population 
sample size (N), number of subjects with available data (n), mean, SD, median, first 
(Q1) and third (Q3) quartiles, minimum, and maximum values. Categorical variables 
will be summarized by the population size (N), number of subjects with available data 
(n), number of subjects in each category, and the percentage of subjects in each 
category. Unless otherwise noted, the denominator to determine the percentage of 
subjects in each category will be based on the number of subjects with available data. 
Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the eCRF or as provided 
within an external file) and are outlined as follows: 
 The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
 Measures of variability (e.g., SD, SE) will be rounded to two more decimal 
places than the precision of the variable of summarization; and 
 Minimum and maximum values will be presented using the same precision as 
the variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above, 
or assessed for the most appropriate presentation based on the underlying data. 
Statistical significance testing will be two-sided and performed using α=0.05. P-values 
will be reported for all statistical tests, rounded to four decimal places. P-values less 
than 0.0001 will be displayed as “<0.0001”; p-values greater than 0.9999 will be 
displayed as “>0.9999”.  
4.1.2 Definition of Baseline 
Baseline will be defined as follows:  


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 For WI-NRS analysis, the average WI-NRS score using the daily values from 
the week before the first dose of study drug (Visit 2 [Day 1]) will serve as the 
baseline score. The WI-NRS value reported on Visit 2 [Day 1] is to be collected 
prior to the study visit according to the clinical study protocol and will be used 
in the baseline derivation. Day -6 through Day 1 will reflect the seven days of 
data reporting to be utilized.  
 
, the average WI-NRS score 
using the daily values from the 14 days before the first dose of study drug 
(including the WI-NRS score captured on the study day 1 of dosing) will serve 
as the baseline bi-weekly score. 
 For all other study assessments, baseline is the last pre-treatment value available 
prior to the first dose of study drug. 
Change from baseline summaries of the Open-Label Extension Period will utilize the 
same baseline definition derived in the Double-Blind Treatment Period. Change from 
the initiation of OLE will also be summarized for the Open-Label Extension Period 
summaries; change from the initiation of OLE will compare OLE assessments with the 
subject’s Week 6 [Visit 6] reported assessment or last available measurement in the 
event Week 6 is not reported.  
4.1.3 Summarization by Visit 
Assessments that are collected only at study visits (i.e., all study assessments except 
WI-NRS) are to be summarized by study visit and will be based on the nominal, 
scheduled visit label as reported on the eCRF.  
Subjects who discontinue from the study early will have their assessments conducted 
at the early termination visit mapped and summarized with the next scheduled nominal 
visit, according to the schedule of events, based on the last visit completed per protocol. 
Any subject who completes the Open-Label Extension Period or discontinues study 
drug (EP547 or placebo) early will complete a Follow-Up Visit (Visit 9) approximately 
2 weeks (±3 days) after the last dose of study drug. The Follow-Up Visit may be 
summarized in both the Double-Blind Treatment Period and Open-Label Extension 
Period summaries, based on the treatment period of participation at the time of study 
termination or completion and as warranted by available data. 
Data collected at unscheduled visits will not be included in by-visit summaries, but will 
be considered when endpoint derivations potentially include multiple visits (e.g., 
determination of baseline value, determination of worst post-baseline value, etc.). All 
data will be included in subject listings. 
For details on WI-NRS analysis visits, see Section 3.4.1.1.  
4.1.4 Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 1.0”) will be summarized with the sign suppressed in summary tables, 


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using the numeric value reported. Data will display on subject listings to include the 
sign. 
4.1.5 Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on subject data listings, where study day 
will be determined as: 
 The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
 The assessment/event date minus the date of first dose of study drug, plus one, 
if the assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
 Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
o Later date – earlier date + 1, if the earlier date is on or after the reference 
date of interest (e.g., date of first dose of study drug); or 
o Later date – earlier date, if the earlier date is prior to the reference date 
of interest. 
 Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12). 
 Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25. 
 Change from Baseline: Change from baseline will be calculated as the post 
baseline value minus the baseline value.  
 Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
4.2 
Analysis Sets 
The analysis sets are defined as follows for the Double-Blind Treatment Period:  
 Full Analysis Set: All subjects who are randomized and take at least 1 dose of 
randomized study drug will be included in the Full Analysis Set. Subjects in the 
Full Analysis Set will be analyzed according to randomized treatment 
assignment. If a subject is incorrectly stratified (i.e., randomized according to 
an incorrect stratification), the subject will be analyzed under the randomized 
treatment for the stratum recorded in the IWRS. All efficacy and PD analyses 
will be based on the Full Analysis Set. 


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 Per Protocol Set: The Per Protocol Set is a subset of the Full Analysis Set 
containing subjects who meet study eligibility requirements and have no 
protocol deviations that might impact the assessment of efficacy measurements. 
Subjects will be analyzed according to randomized treatment assignment. The 
Per Protocol Set will be used for sensitivity analyses relating to efficacy and 
PD. Protocol deviations that qualify for exclusion from the Per Protocol Set 
include: 
o Deviations of inclusion/exclusion criteria 
o Non-permitted concomitant medications that may meaningfully impact 
efficacy outcomes (e.g., receipt of prohibited and/or a rescue medication 
qualifying as an intercurrent event) 
o Meaningful dosing and/or randomization error(s) 
o Any other important protocol deviation deemed by the Sponsor to 
warrant exclusion from the Per Protocol set 
Any protocol deviations that govern exclusion from the Per Protocol Set will be 
determined prior to database lock and primary analysis. 
 Safety Analysis Set: All subjects who are randomized and take at least 1 dose 
of randomized study drug will be included in the Safety Analysis Set. Safety 
analyses will be based upon treatment actually received. 
 PK Set: All subjects who receive at least 1 dose of EP547 and provide adequate 
blood samples for bioanalysis will be included in the PK Set. 
Data summaries to be presented on both the Safety Analysis Set and the Full Analysis 
Set will only be produced on both analysis sets if there is a difference in the population 
groups. 
An Open-Label Extension Analysis Set will be determined as all subjects who complete 
the Double-Blind Treatment Period and receive at least one dose of study drug in the 
Open-Label Extension Period and will be used to summarize all available data collected 
in both the Double-Blind and Open-Label Extension Periods. 
4.3 
Study Subjects 
4.3.1 Disposition of Subjects 
Subject disposition will be summarized for all randomized subjects by treatment group 
and over all subjects combined, separately for the Double-Blind Treatment Period and 
Open-Label Extension Period. Summaries will include the number and percentage of 
subjects in each analysis set, completing treatment within each study treatment period, 
completing the study, and the reason for discontinuation from each treatment period 
and the overall study. Subject disposition during the Double-Blind Treatment Period 
will also be summarized separately for each study site for all randomized subjects. 


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The number and percentage of subjects randomized by geographic region, country and 
site will be presented by treatment group and over all randomized subjects in the 
Double-Blind Treatment Period. 
The number and percentage of screen failures will be presented by screen failure reason, 
based on the total number of subjects screened. 
4.3.2 Protocol Deviations 
Important Protocol Deviations (IPDs) will be summarized by treatment group and over 
all subjects combined for the Full Analysis Set. Important Protocol Deviations are 
identified by the Sponsor and are defined in the ICH guideline Structure and Content 
of Clinical Study Reports – Questions and Answers (E3[R1], 2013) as a subset of 
protocol deviations that might significantly affect the completeness, accuracy, and/or 
reliability of the study data or that might significantly affect a subject’s rights, safety, 
or well-being.  
All IPDs will be determined and appropriately categorized prior to database lock and 
prior to breaking the blind of the treatment group assignments. The number and 
percentage of subjects with any IPDs as well as the number and percentage of subjects 
with IPDs within each category will be presented. A listing of important protocol 
deviations will be provided.  
4.4 
Efficacy and Pharmacodynamic Evaluation 
4.4.1 Datasets Analyzed 
All efficacy and PD summaries will be based on the Full Analysis Set; select efficacy 
summaries will also be produced on the Per Protocol Set. In general, the Double-Blind 
Treatment Period summaries will summarize subjects by treatment group; the Open-
Label Extension Period will summarize subjects by randomized treatment from the 
Double-Blind Treatment Period as well as by all subjects combined. A data listing of 
subjects excluded from the Full Analysis Set or Per Protocol Set, to include the reason 
for exclusion, will be presented. The efficacy and PD endpoints will be further 
evaluated during the Open-Label Extension Period with descriptive statistics for the 
Open-Label Extension Analysis Set; summaries of change over time will evaluate both 
change from baseline and change from the initiation of OLE.  
4.4.2 Demographic and Other Baseline Characteristics 
Demographic variables including age, sex, ethnicity and race will be summarized by 
treatment group and over all subjects combined for the Safety Analysis Set, Full 
Analysis Set, Per Protocol Set, PK Set, and the Open-Label Extension Analysis Set. 
Demographics will be also analyzed by the stratum factor, cholestatic liver disease type. 
Age will be summarized using descriptive statistics. Sex, ethnicity, and race will be 
summarized with the number and percentage of subjects in each parameter category. 
Age, ethnicity and race will also be presented in the subgroup categories described in 
Section 4.4.7.8 with the number and percentage of subjects in each subgroup category. 


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Baseline characteristics include medical history, itch history, disease characteristics, 
transient elastography (FibroScan TE), estimated glomerular filtration rate (eGFR) 
height, weight, and body mass index (BMI). Body mass index will be calculated as: 
weight (kg) / [height (cm) / 100]2. Baseline characteristics will be summarized for the 
Full Analysis Set by treatment group and over all subjects combined. Height, weight, 
BMI, Fibroscan, and eGFR at baseline will be summarized using descriptive statistics. 
Baseline eGFR will also be presented categorically by the subgroups (<90 vs ≥ 90 
mL/min/1.73 m2) described in Section 4.4.7.8 with the number and percentage of 
subjects in each subgroup summarized. 
Baseline disease characteristics to be summarized include time since initial cholestatic 
disease diagnosis, type of cholestatic disease, presence of inflammatory bowel disease 
(IBD), type of IBD, use of obeticholic acid (OCA), and use of UDCA at baseline. Time 
since initial cholestatic disease diagnosis (in years) is calculated as the informed 
consent date – the date of diagnosis divided by 365.25. Time since initial cholestatic 
disease diagnosis will be summarized using descriptive statistics. Type of cholestatic 
disease, presence and type of IBD, baseline/concurrent OCA and baseline/concurrent 
UDCA use will be summarized with the number and percentage of subjects in each 
parameter category. 
Itch history will be summarized for the Full Analysis Set with the number and 
percentage of subjects in each parameter category of the following itch history 
questions:  
 Did the subject have significant itch or periods of consistent itch prior to liver 
disease diagnosis? (Yes / No) 
 Is the itch worse during the: Day / Night / No Difference 
 Itch Frequency (Daily / Near-Daily / Other) 
 Does Itch Interfere with Sleep (Yes / No) 
 Areas of Body that are Itchy (Face / Chest / Abdomen / Back / Limbs / Palms / 
Soles / Scalp / Other Body Area) 
 Secondary Lesions Present (Yes / No) 
 Itch More Prominent in Different Seasons (Yes / No) 
 Season(s) Where Itch is Worse (Winter / Spring / Summer / Autumn) 
 Circumstances that Aggravate Itching (Heat / Cold / Stress / Eating / Physical 
Activity / Showering / Clothing / Menstrual Period / Other) 
 Subject Tried Treatment in the Past? (Yes / No) 
 Did Past Treatment Help? (Yes / No) 
Baseline height, weight, BMI, Fibroscan, eGFR, disease characteristics, and itch history 
summarizations will be repeated for the Safety Analysis Set, Per Protocol Set, PK Set, 


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and for the Open-Label Extension Analysis Set. Baseline characteristics of height, 
weight, BMI, Fibroscan, eGFR, and disease characteristics will be also analyzed by the 
stratum factor, cholestatic liver disease type. 
Medical history conditions will be mapped to preferred terms and system organ classes 
using MedDRA, version 25.0. Frequency counts and percentages to summarize subjects 
reporting abnormal medical history by system organ class will be presented for the Full 
Analysis Set. 
4.4.3 Primary Efficacy Endpoint Analysis Methods 
The primary estimand is the difference in means between treatment groups in the 
weekly WI-NRS score at Week 6 for all subjects in the Full Analysis Set. The treatment 
policy strategy for addressing intercurrent events will be used for the primary estimand; 
data collected following use of prohibited and/or rescue medications or for subjects 
who prematurely discontinue from study drug use will be reported in the analysis. The 
WI-NRS data will be analyzed using a mixed effects model for repeated measures 
(MMRM) based on the data from weekly scores up to Visit 6 (Week 6) in the Double-
Blind Treatment Period. The model will include treatment, type of cholestatic disease 
(PBC, PSC), week, and treatment by week interaction as fixed effects, and the baseline 
WI-NRS weekly score as a covariate. The unstructured covariance model will be used. 
In the event the computational algorithm fails to converge, the following structures will 
be 
executed: 
heterogeneous 
Toeplitz, 
Toeplitz, 
heterogeneous 
First-Order 
Autoregressive [AR(1)], AR(1), heterogeneous compound symmetry (CS), and CS. 
The covariance structure converging to the best fit, as determined by Akaike’s 
information criterion (AIC), will be used. The Kenward-Roger approximation will be 
used to calculate the denominator degrees of freedom for the test of fixed effects. The 
null hypothesis to be tested is that there is no difference between EP547 and Placebo: 
H0:  µA = µB; 
Where µA and µB represent the mean values for EP547 and Placebo, respectively. The 
alternate hypothesis to be tested is that the treatment group means differ: 
H1:  µA ≠ µB; 
Testing of the hypothesis is 2-sided at a 5% type I error level. Estimates of least-square 
(LS) means, standard error, and 95% CIs will be presented by treatment group. In 
addition, the LS mean difference (LSMD) of the comparison between EP547 and 
placebo, the standard error of the difference, and 95% CI of the difference will be 
presented. 
Percent change from baseline will also be analyzed in the Double-Blind Treatment 
Period and Open-Label Extension Period. Descriptive statistics will be provided for 
weekly WI-NRS scores in the Double-Blind Treatment Period and Open-Label 
Extension Period summaries, to include the observed weekly value, change from 
baseline, percent change from baseline, change from initiation of OLE and percent 
change from initiation of OLE (in OLE-specific summaries). Initiation of the OLE is 
considered the Visit 6 (Week 6) average score, or the last available weekly score if 
Week 6 is not reported. In addition, a categorical summary of WI-NRS by itch severity 
(mild as defined as <4, moderate as defined as 4 to <7, and severe as defined as ≥7) will 


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be provided for each week. Normality assumptions will be assessed for appropriateness. 
If any are violated and inhibit the interpretation of the results, appropriate data 
transformations or non-parametric analyses will be performed in addition to other 
planned sensitivity analyses to support the interpretation of the treatment effect. If the 
model does not converge under the covariance structure testing methods, a reduced 
model restricted to select analysis visits (i.e., Week 1, Week 2, Week 3, and Week 6) 
or analysis of covariance (ANCOVA) model (with treatment group as a fixed effect and 
the randomization strata type of cholestatic disease [PBC, PSC] and covariate 
adjustment for baseline WI-NRS score) may be explored post-hoc.   
4.4.4 Secondary Endpoint Analysis Methods 
Analysis of secondary endpoints will be performed on the Full Analysis Set. Treatment 
group comparisons will be tested at the 5% significance level without multiplicity 
adjustment.  
4.4.4.1 
5-D Itch Scale 
The change from baseline in 5-D Itch Scale total score will be analyzed using an 
ANCOVA model with fixed effects for treatment group and randomization strata (type 
of cholestatic disease [PBC, PSC]) and covariate adjustment for baseline 5-D total 
score. Descriptive statistics will be presented for values and changes from baseline for 
all post baseline visits where data was scheduled to be collected. The LS means and SE 
will be presented for all treatment groups. The LSMD and their SEs, 95% CIs, and p-
value to test for a difference between EP547 to placebo at Week 6 will also be presented 
for the Double-Blind Treatment Period. Descriptive statistics will also be presented for 
individual component scores. 
Descriptive statistics will be presented for the Open-Label Extension Period to include 
change from baseline and change from initiation of OLE. 
4.4.4.2 
Responder PGI-C Analysis  
The proportion of subjects with improvement at Week 6 will be compared among 
treatment groups using a Cochran-Mantel-Haenszel (CMH) chi-square test, stratified 
by the type of cholestatic disease (PBC, PSC). The PGI-C responses at each visit in the 
Double-Blind Treatment Period (i.e., Week 6) and Open-Label Extension Period (i.e., 
Week 12) will also be presented with the number and percentage of subjects in each 
response category by treatment group along with two-sided 95% Clopper-Pearson exact 
CIs. Proportional endpoints (PGI-C, PGI-S and WI-NRS) will be analyzed using the 
number of patients in each treatment group with non-missing data at each visit (i.e., 
observed values) as the denominator for percentages for the Double-Blind Treatment 
Period and Open-Label Extension Period summaries. 
4.4.4.3 
Responder PGI-S Analysis 
The PGI-S improvement in pruritus severity will be analyzed using the same statistical 
methodologies as the PGI-C analysis described in Section 4.4.4.2. The proportion of 
subjects with improvement in pruritus at Week 12 relative to their initiation of OLE 
value will also be summarized.  


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4.4.4.4 
Responder WI-NRS Analysis  
The proportion of responders in WI-NRS will be analyzed using the same statistical 
methodologies as the PGI-C analysis described in Section 4.4.4.2. The proportion of 
subjects with a reduction in WI-NRS score of ≥2, ≥3 and ≥4 when compared to baseline 
and those with WI-NRS score <4 will be assessed at each analysis visit during the 
Double-Blind Treatment Period and Open-Label Extension Period to include the Safety 
Follow-Up weeks. The proportion of subjects within each WI-NRS category will also 
be assessed relative to their initiation of OLE value for visits in the Open-Label 
Extension Period and Safety Follow-Up visits.  
4.4.5 Exploratory Endpoint Analysis Methods 


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4.4.6 Sensitivity Analysis of Efficacy Endpoints 
Sensitivity analyses of the primary endpoint will be conducted to better assess the 
impact of intercurrent events on the efficacy conclusions. The intercurrent events of 
interest include receipt of prohibited and/or rescue medications while on study and early 
withdrawal of study drug. The treatment policy strategy will be used for the primary 
estimand.  
The while on treatment strategy will be used as a sensitivity analysis to further explore 
the intercurrent event of prohibited and/or rescue medication usage. The difference in 
means between treatment groups in the weekly WI-NRS score at the last visit prior to 
receipt of prohibited and/or rescue medications (or the last derived weekly WI-NRS 
score, for those who never require prohibited and/or rescue medication) will be 
presented during the Double-Blind Treatment Period. For those subjects that receive a 
prohibited and/or rescue medication, any WI-NRS scores reported after the receipt of 
medication will be excluded from the analysis. 
Determination of intercurrent events based on use of a prohibited and/or rescue 
medication will be based on review of the Concomitant Medication eCRF. Before study 
unblinding, the sponsor will review all reported concomitant medications, including on-
study changes to background medications, to determine which qualify as an intercurrent 
event for prohibited or rescue medication usage. This external assessment will be 
documented in the study files and integrated into the sensitivity analysis. 
The analysis of the primary efficacy endpoint will be analyzed for the Full Analysis Set 
using multiple imputations (MI) assuming data missing at Week 6 to be missing at 
random (MAR) (Section 4.4.7.2), and for the Per Protocol Set using observed data. 
Treatment group comparisons will use the methodology described in Section 4.4.3 for 
sensitivity analysis of the primary endpoint.  


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Secondary and PD endpoint analyses during the Double-Blind Treatment Period will 
be repeated for the Per Protocol Set as supportive analyses.   
4.4.7 Statistical/Analytical Issues 
4.4.7.1 
Adjustments for Covariates 
The MMRM or ANCOVA model (depending on the endpoint) to compare treatment 
groups during Double-Blind Treatment Period will include a covariate adjustment for 
the baseline parameter value of interest.  
4.4.7.2 
Handling of Dropouts or Missing Data 
Treatment groups will be compared for observed and change from baseline in weekly 
WI-NRS score during the Double-blind Treatment Period using a MMRM to include 
fixed effects for treatment, type of cholestatic disease (PBC, PSC), week, and treatment 
by week interaction, with the relevant baseline value included as a covariate. A similar 
model will be used for the exploratory analysis of bi-weekly WI-NRS scores, replacing 
the week score with a bi-weekly score in the model. 
As a sensitivity analysis of the primary endpoint, subjects missing data will be imputed 
using MI methodology using the subjects in the Full Analysis Set. The MI will be 
performed under the assumption data is missing at random (MAR) using the model 
defined in the primary analysis. Using the general methodology described in Ouyang 
(2017), the following imputations will be applied:  
 Intermittent missing value(s) arising prior to a discontinuation event (i.e., 
discontinuation of randomized treatment or early permanent dropout) are 
imputed using the Markov Chain Monte Carlo (MCMC) option in SAS PROC 
MI by treatment group assuming nonmonotone missing, a seed of 671982, 500 
burn-in iterations, 100 iterations between imputations, and a non-informative 
prior. The MAR assumption is reasonable for intermittent missing values as the 
values of the endpoint before and after the intermittent missing value are known. 
The imputation of the intermittent missing data will be accomplished using the 
MCMC option in SAS PROC MI to impute intermittent missing data without a 
monotone missing pattern, prior to performing imputations of values following 
the discontinuation event.  
 Missing data following a discontinuation event will then be imputed by 
treatment group under the assumption of MAR using the regression option from 
the monotone statement of SAS PROC MI. The baseline and post-baseline 
derived weekly visits during the Double-Blind Treatment Period will be used in 
the regression option to impute the missing values.  
 The MI methods described above will be used to generate 30 imputed datasets. 
Data will be analyzed using the primary MMRM model for the observed and 
imputed data; observed and change from baseline values to each post-baseline 
week visit will be calculated based on observed and imputed data.  


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 Results from the analysis of each of the 30 imputed datasets will be combined 
using Rubin’s imputation rules (Rubin 1987) through SAS PROC 
MIANALYZE to produce pooled LS mean estimates of treatment difference. 
For assessment of responder endpoints, subjects with missing data at the time point of 
interest will not be analyzed (i.e., PGI-C, PGI-S and WI-NRS); only observed values 
will be used. 
4.4.7.3 
Planned Interim, Primary, and Final Analyses and Data Monitoring 
To address business needs, an interim analysis may be conducted after approximately 
50% of randomized subjects have completed 4 weeks of randomized treatment. Only a 
limited number of study team members and senior management stakeholders 
comprising the internal DRT would review the results of the interim analysis of 
unblinded data from the Double-Blind Treatment Period. The interim analysis would 
evaluate the effect of EP547 on WI-NRS, select secondary endpoints, and safety. 
The primary analysis will be conducted after the last subject randomized has completed 
the Double-Blind Treatment Period to determine whether the primary efficacy endpoint 
of change from baseline in WI-NRS at Week 6 is statistically significant. Details 
regarding the primary analysis procedures, including database lock and unblinding 
procedures, will be finalized prior to analysis. 
The final analysis will be conducted when all randomized subjects have completed the 
Open-Label Extension Period or are discontinued from the study, and the final database 
is locked. 
The Data Monitoring Committee (DMC) is an independent group of external experts 
who will review safety data during the conduct of the study, as outlined in the DMC 
charter. The DMC will make a determination of relatedness for all AEs with CTCAE 
Grade 3 or higher. The DMC will also meet on an ad hoc basis when at least 3 AEs of 
CTCAE Grade 3 or higher have accrued or when there has been a single CTCAE Grade 
4 or higher. Based on review of the data, the DMC will provide recommendations to 
the Sponsor on whether the nature, frequency, and/or severity of AEs associated with 
study drug warrant modification to the study protocol, suspension of dosing, or study 
termination. 
4.4.7.4 
Multicenter Studies 
This is a multicenter study to be conducted globally. Efficacy data collected from all 
study sites will be pooled for data analysis. The effect of study site on the efficacy 
analysis results may be explored post-hoc, as needed. 
4.4.7.5 
Multiple Comparisons/Multiplicity 
This is the first study to explore the efficacy of EP547 for more than 7 days. The 
familywise error rate will be controlled for the primary efficacy endpoint at an alpha of 
5%. All other efficacy endpoints will be tested at the 0.05 level of significance without 
multiplicity adjustment.  


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4.4.7.6 
Use of an “Efficacy Subset” of Subjects 
The primary efficacy analysis will be performed on the Full Analysis Set; the Per 
Protocol Set will be utilized as a sensitivity analysis. The Per Protocol Set will exclude 
subjects with protocol deviations that might impact the assessment of efficacy 
measurements. 
4.4.7.7 
Active-Control Studies Intended to Show Equivalence 
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products. 
4.4.7.8 
Examination of Subgroups 
The primary efficacy endpoint and select secondary efficacy endpoints will be analyzed 
based on: 
 Age (< 65 years of age vs ≥ 65 years of age) 
 Gender (Male vs Female) 
 Race (White vs All Other Races) 
 Ethnicity (Hispanic or Latino vs Not Hispanic or Latino) 
 Cholestatic liver disease type (PBC or PSC) 
 Prescence of IBD (Yes or No) 
 IBD Type (CD or UC) 
 OCA use at baseline (Yes or No) 
 Geographic region (North America vs Europe/Rest of the World) 
 Baseline itch severity (moderate/WI-NRS <7 vs severe/WI-NRS ≥7) 
 Any improvement in PGI-C (Week 6 for Double-Blind Treatment Period; Week 
12 for Open-Label Extension Period [Open-Label Extension Analysis Set only]) 
The primary and select secondary efficacy endpoints to include the WI-NRS responder 
analysis will be analyzed for the subgroups using the Full Analysis Set and the Open-
Label Extension Analysis Set. Separate summaries will be presented for each subgroup 
category.   
Select safety analysis defined in Section 4.5.3 and 4.5.5 will be analyzed by the 
following subgroups:  
 Cholestatic liver disease type (PBC or PSC) 
 Baseline eGFR (<90 vs ≥90 mL/min/1.73 m2) 


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A summary of subject disposition will also be provided by each subgroup. 
Demographic and baseline characteristics will be further explored by the stratum factor, 
cholestatic liver disease type. Summaries by subgroup will only be produced if there 
are at least 5 subjects in the category of interest for each treatment group. Additional 
subgroup analyses may be performed post-hoc, as appropriate. 
4.4.8 EP547 Plasma Concentrations 
Raw plasma concentration values will be summarized for the PK Set by treatment group 
and sampling time point in the Double-Blind Treatment Period using descriptive 
statistics, to include the geometric mean and CV (%). The geometric CV is calculated 
as 100*sqrt[exp(σ2)-1], where σ2 is the variance of the log-transformed data. For 
summaries of plasma concentrations, BLQ values will be set to missing. The number 
and percentage of subjects with BLQ values will be summarized by time point and 
treatment group.  
4.4.9 Pharmacokinetic Analysis 
Pharmacokinetic analysis will be based on analysis of the EP547 concentration data as 
outlined in Section 4.4.8. 
4.5 
Safety Evaluation 
Safety analyses during the Double-Blind Treatment Period will be carried out for the 
Safety Analysis Set, to include all subjects who receive at least one dose of study drug. 
Safety analyses during the Double-Blind Treatment Period and Open-Label Extension 
Period will be summarized for the Open-Label Extension Analysis Set, to include all 
subjects who receive at least one dose of study drug during open-label participation. 
Safety data will be summarized separately for the Double-Blind Treatment Period and 
Open-Label Extension Period by randomized Double-Blind treatment received; a 
summary of all subjects combined within each study treatment period will also be 
provided. Subjects who do not complete the study, for whatever reason, will have all 
available data up until the time of termination included in the analysis. For safety 
analysis presented by study visit, the baseline value will be defined as described in 
Section 4.1.2 to include a Change from Baseline and Change from Initiation of OLE 
assessment. 
4.5.1 Extent of Exposure 
Extent of exposure to study treatment will be summarized by treatment group separately 
for each study treatment period as well as over the entire study participation. The 
duration of exposure will be presented in days and calculated as the date of last dose of 
study drug of the respective study treatment period minus the date of first dose of study 
drug of the respective study treatment period, plus one. For the purposes of defining the 
start of the Open-Label Extension Period, the on-site dose from the Week 6 Study Drug 
Administration (On-site) eCRF will be considered the start of OLE dosing for the 
duration of exposure calculation in the Open-Label Extension Period. The Open-Label 
Extension Period summary will also include a summary of duration of exposure across 
all study participation (both study treatment periods). 


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As dosing includes receipt of a 25 mg and 75 mg tablet for each daily dose totaling 100 
mg of study drug, the total number of tablets received in each study treatment period 
will be determined based on treatment period dosing ranges as described in Section 
4.5.2 (Treatment Compliance) and dosing will be based on the number of tablets 
received with the following derivation: 
 Subjects reporting an even number of tablets will have their total dose received 
(mg) calculated as: (total tablets taken during study treatment period divided 
by 2) multiplied by 100. 
 Subjects reporting an odd number of tablets (i.e., there was an incomplete 
dosing day) will have their total dose received (mg) calculated as: (the floor of 
[total tablets taken during study treatment period divided by 2] multiplied by 
100) + 25 mg. 
Duration of exposure and total dose received (mg) will be summarized using descriptive 
statistics. The Open-Label Extension Period summary will also include a summary of 
total dose received for EP547 across both study treatment periods for those randomized 
to EP547. 
4.5.2 Measurements of Treatment Compliance 
Compliance to the study treatment regimen will be summarized by treatment group, 
separately for each study treatment period as well as over the entire study participation. 
Compliance will be determined based on tablet count entries made on the Study Drug 
Dispensing and Accountability eCRF pages. Expected dosing will be based on the on-
site dosing administration: 
 The expected tablet dosing for Double-Blind Treatment Period is considered to 
be the on-site dose from Day 1 to the Treatment Completion or Treatment 
Discontinuation Date on the End of Treatment (Double-Blind eCRF), plus 1. 
The number of dosing days is then multiplied by two to account for two tablets 
of EP-547 or placebo taken each day.  
 The expected tablet dosing for Open-Label Extension Period is considered to be 
the on-site dose from the Week 6 Study Drug Administration (On-site) eCRF to 
the Treatment Completion or Treatment Discontinuation Date on the End of 
Treatment (Open-Label eCRF), plus 1. The number of dosing days is then 
multiplied by two to account for two tablets of EP-547 taken each day.   
The actual number of doses (tablets) received will be determined based on the number 
of tablets taken reported on the Study Drug Dispensing and Accountability eCRF. The 
number of tablets taken in the Double-Blind Treatment Period and Open-Label 
Extension Period will be assessed based on the defined treatment period windows 
(using the date ranges calculated in the expected dosing derivation) and the kit dispense 
dates. 
Treatment compliance will then be calculated as the actual number of tablets taken 
divided by the expected number of tablets taken, multiplied by 100 for each treatment 
period and overall.  


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The number and percentage of subjects who are < 80% compliant and ≥ 80% compliant 
within each treatment group will be summarized separately for each study treatment 
period, as well as for overall study participation. 
4.5.3 Adverse Events 
Treatment-emergent adverse events are defined as those AEs with onset after the first 
dose of study drug or existing events that worsened after the first dose during the study. 
Treatment-emergent AEs will be summarized by treatment group separately for each 
study treatment period and overall, within each study treatment period. An overall 
TEAE summary, incidence of TEAEs by system organ class and preferred term, and 
summary of the most frequently-occurring TEAEs will also be presented for both 
periods combined (i.e., overall study) for the Safety Analysis Set and the Open-Label 
Extension Analysis Set. Adverse events will be considered treatment-emergent relative 
to the study treatment period where the onset of the AE occurred; any TEAE that begins 
in the Double-Blind Treatment Period will be considered treatment-emergent in the 
Double-Blind Treatment Period only. The same logic is to be applied to the Open-Label 
Extension assessment; the Week 6 Study Drug Administration (On-site) entry will be 
considered the start of Open-Label Extension dosing for assessing treatment-
emergence.  Events reported with a partial onset date (e.g., month and year are reported 
but the day is missing) will be considered to be treatment-emergent in both treatment 
periods if it cannot be confirmed that the event onset was prior to the first dose of study 
drug for a specific treatment period based on the available date entries. Events with date 
and time present will be compared against the treatment start date and time to determine 
treatment-emergence. 
Verbatim terms on case report forms will be mapped to preferred terms and system 
organ classes using MedDRA, version 25.0.   
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 
organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term. Inclusion criteria assessments for frequency-related 
summaries will be made separately for each study treatment period and study overall. 
Summaries of the following types will be presented: 
 Overall summary of number of unique TEAEs and treatment-emergent SAEs 
and subject incidence of TEAEs meeting various criteria; 
 Subject incidence of TEAEs by MedDRA system organ class and preferred 
term; 
 Subject incidence of the most frequently-occurring TEAEs (i.e., TEAEs 
occurring in ≥ 10% of the Safety Analysis Set or Open-Label Extension 
Analysis Set) by MedDRA preferred term; 
 Subject incidence of TEAEs by CTCAE severity grade, MedDRA system organ 
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 Subject incidence of TEAEs by relationship to study drug, MedDRA system 
organ class, and preferred term;  
 Subject incidence of TEAEs of Special Interest by MedDRA system organ class 
and preferred term; 
 Subject incidence of the most frequently-occurring TEAEs related to study drug 
(i.e., related TEAEs occurring in ≥ 10% of the Safety Analysis Set or Open-
Label Extension Analysis Set) by MedDRA preferred term; 
 Subject incidence of CTCAE grade 3 or higher TEAEs related to study drug by 
MedDRA system organ class and preferred term; and 
 Subject incidence of SAEs by MedDRA system organ class and preferred term. 
A summary by safety subgroups of interest (type of cholestatic disease and baseline 
eGFR) described in Section 4.4.7.8 will be provided for the overall AE summary and 
subject incidence of TEAEs by MedDRA system organ class and preferred term for the 
Double-Blind Treatment Period, Open-Label Extension Period, and study overall. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), 
subjects experiencing more than one TEAE will be counted only once. In the summary 
of TEAEs by severity grade, subjects will be counted once at the highest severity 
reported at each level of summarization; in the summary of TEAEs by relationship, 
subjects will be counted once at the closest relationship to study drug. Related events 
include those reported as “Related” to study drug; events considered not related are 
those reported as “Not Related” to study drug.  
Adverse event data will be presented in data listings by subject, treatment group, and 
event. Serious AEs and AEs leading to discontinuation of the study drug will be 
presented in separate data listings. 
4.5.4 Deaths, Other Serious Adverse Events, and Adverse Events of Special Interest 
All deaths during the study will be listed by subject, to include the primary cause of 
death. Serious AEs and AEs of Special Interest, including those that led to withdrawal, 
or interruption of the study drug, will be provided in separate subject data listings.  
4.5.5 Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data analyzed by the 
central laboratory and presented in conventional units. All data will be included in by-
subject data listings. Laboratory measurements identified as abnormal (i.e., outside the 
normal range) will also be listed separately by subject, laboratory test, and unit. In 
addition, normal ranges provided by the central laboratory will be presented in a 
separate listing. 
Clinical laboratory measurements, including serum chemistry, hematology, 
coagulation, and thyroid function tests, will be summarized by treatment group and all 
subjects combined for each study treatment period. Descriptive statistics will be 
presented for observed values and changes from baseline at each visit where parameters 


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were scheduled to be collected per the clinical study protocol. A summary by safety 
subgroups of interest (type of cholestatic disease and baseline eGFR) described in 
Section 4.4.7.8 will be provided for the univariate summaries of chemistry and 
hematology using the Safety Analysis Set and Open-Label Extension Analysis Set. 
Change from the initiation of OLE will also be presented in the Open-Label Extension 
Period summaries. 
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” 
with respect to the parameter-specific reference ranges (i.e., below the lower limit of 
the normal range, within the normal range, or above the upper limit of the normal 
range). Three-by-three contingency tables will be presented for each laboratory 
parameter to summarize the shift from the baseline category to the worst post-baseline 
measurement within each treatment period, defined as the value numerically farthest 
outside of the normal range across all post-baseline visits through the end of each study 
treatment period and the study overall. Shift from the initiation of OLE value to the 
worst post-OLE value will also be provided for the Open-Label Extension Period. 
Summary results will include the count and percentage of subjects within each shift 
category and treatment group separately for each study treatment period and the study 
overall. 
Where applicable, hematology, chemistry and coagulation results for select parameters 
will be assigned a toxicity grade based on the U.S. Department of Health and Human 
Services CTCAE, version 5.0 (HHS 2017). If criteria for a grade includes a quantitative 
component and a clinical intervention component, the clinical intervention component 
will be ignored where it cannot be programmatically addressed using available data and 
only the quantitative portion of the criteria will be considered. If the quantitative criteria 
for grading are equivalent for two grades and the differentiation is described by clinical 
interventions, the clinical intervention component will not be considered and the 
highest CTCAE grade will be assigned. Similarly, death related to AE (i.e., Grade 5) 
cannot be determined with available laboratory-based data collection and, thus, will not 
be summarized as a category. Laboratory parameters that include multiple sets of 
criteria for each direction (e.g., separate criteria for potassium measures to assess 
hyperkalemia and hypokalemia) will be summarized separately to reflect each set of 
criteria. 
Five-by-five contingency tables will be presented for lab tests where toxicity grading 
can be applied, to summarize the shift from the baseline grade to the worst post-baseline 
grade within each study treatment period and the study overall. Grades will be presented 
as none (Grade 0; i.e., measurements did not meet any CTCAE criteria for Grades 1 
through 4), mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening 
(Grade 4). Shift from the initiation of OLE value to the worst post-OLE value will also 
be provided for the Open-Label Extension Period. Summary results will include the 
count and percentage of subjects within each shift category, analyzed separately for 
each study treatment period. 
The clinical study protocol includes algorithms for monitoring and interrupting study 
drug for treatment-emergent hepatocellular and cholestatic DILI signals based on ALT, 
ALP and total bilirubin values. A shift from baseline in ALT or ALP values to select 
treatment-emergent DILI signal criteria will be summarized for each study period and 
the study overall. 


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Subjects with post-baseline ALT values will be assessed for shift from Baseline ALT 
to the following DILI criteria:  
Normal Baseline ALT: 
 Any Instance of ALT ≥ 3 x ULN and Total Bilirubin ≥ 2 x Baseline 
 Any Instance of ALT ≥ 5 x ULN 
 Any Instance of ALT ≥ 8 x ULN 
Elevated Baseline ALT (ALT > ULN at Baseline): 
 Any Instance of ALT ≥ 2 x Baseline and Total Bilirubin ≥2× Baseline 
 Any Instance of ALT ≥ 3 x Baseline 
 Any Instance of ALT ≥ 5 x Baseline 
Subjects with post-baseline ALP values will be assessed for shift from Baseline ALP 
to the following DILI criteria:  
 Any Instance of ALP ≥ 2 x Baseline and Total Bilirubin ≥ 2 x Baseline 
 Any Instance of ALP ≥ 3 x Baseline 
Summary results will include the count and percentage of subjects within each shift 
category, analyzed separately for each study treatment period and the study overall. 
Subjects qualifying in any of the above ALT or ALP treatment-emergent DILI criteria 
will be presented in a data listing to include ALT (or ALP), baseline and treatment-
emergent total bilirubin, baseline and treatment-emergent direct bilirubin, Gilbert 
Syndrome status, and any treatment-emergent AEs reported at the time of the treatment-
emergent lab date.  
The clinical study protocol also includes algorithms for monitoring and interrupting 
study drug for treatment-emergent acute deterioration of kidney function based on 
laboratory parameters or clinical symptoms. Any increase in serum creatinine by ≥0.3 
mg/dL from baseline and any increase in serum creatinine to ≥1.5 x baseline will be 
summarized for each study period and the study overall. 
4.5.6 Vital Signs, Physical Findings, and Other Observations Related to Safety 
4.5.6.1 
Vital Signs 
Vital sign parameter measurements will be summarized by treatment group for each 
study treatment period. Descriptive statistics will be presented for results and change 
from baseline at each visit where parameters were scheduled to be collected. Change 
from the initiation of OLE will also be presented in the Open-Label Extension Period 
summary. 


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4.5.6.2 
12-Lead Electrocardiogram 
Twelve-Lead ECG interval parameters will be summarized by treatment group for each 
study treatment period. Descriptive statistics will be presented for observed values and 
changes from baseline at each visit where parameters were scheduled to be collected. 
Change from the initiation of OLE will also be presented in the Open-Label Extension 
Period summaries. 
Twelve-lead ECG will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” or “abnormal, clinically significant.” Three-by-three 
contingency tables will be presented to summarize the shift from the baseline category 
to the worst post-baseline value of each study treatment period and study overall. Shift 
from the initiation of OLE value to the worst post-OLE value will also be provided for 
the Open-Label Extension Period. Summary results will include the count and 
percentage of subjects within each shift category and treatment group for each study 
treatment period and study overall. 
Prolonged QTc intervals will be summarized as QTc measurements (msec) that are 
>450, >480, and >500 at each visit where ECG is routinely collected per the clinical 
study protocol. Change from baseline categories will also be summarized for 
measurements that represent a change >30 or >60 relative to the baseline value. Change 
from the initiation of OLE will also be presented in the Open-Label Extension Period 
summary. Summary results will include the percentage of subjects within each category 
and treatment group for each study treatment period. 
4.5.6.3 
Physical Examination 
Any clinically significant findings from the physical examination assessment will be 
reported on the Medical History form (prior to first dose) or Adverse Events form (post 
first dose). A separate subject listing of physical examination results will not be 
provided.  
4.5.6.4 
Crohn’s Disease Activity Index (Crohn’s Disease Subjects Only) 
Crohn’s Disease Activity Index total criteria point counts will be summarized by 
treatment group for each study treatment period for the subset of study subjects with 
CD. Descriptive statistics will be presented for results and change from baseline at each 
visit where parameters were scheduled to be collected. Change from the initiation of 
OLE will also be presented in the Open-Label Extension Period summary. 
Additionally, the assignment of the CDAI scores into the disease severity categories of 
“asymptomatic remission (CDAI <150),” “mild-to-moderate CD (150 to 219),” 
“moderate-to-severe CD (220 to 450),” and “severe-fulminant disease (>450).” Four-
by-four contingency tables will be presented to summarize the shift from the baseline 
category to the Week 6 and Week 12 categories (Open-Label Extension Period 
summary) for each study treatment period. For the Open-Label Extension Period 
summary, change from initiation of OLE to Week 12 will also be provided. Summary 
results will include the count and percentage of subjects within each shift category and 
treatment group for each study treatment period. 


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4.5.6.5 
Partial Mayo Scoring Index (Ulcerative Colitis Subjects Only) 
The Partial Mayo Scoring Index questionnaire categories (Bleeding, Stool Frequency, 
and Physician Assessment) and the total index score will be summarized by treatment 
group for each study treatment period for the subset of study subjects with Ulcerative 
Colitis. Summary results will include the count and percentage of subjects within each 
shift category and treatment group for each study visit where the questionnaire was 
collected. 
Additionally, the total index score will be summarized as four-by-four contingency 
tables to present the shift from the baseline category to the Week 6 and Week 12 
categories (Open-Label Extension Period summary) for each study treatment period. 
For the Open-Label Extension Period summary, change from Initiation of OLE to Week 
12 will also be provided. Summary results will include the count and percentage of 
subjects within each shift category and treatment group for each study treatment period. 
4.5.6.6 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Global 
B3, version March 2022. Medications entered on the eCRF will be mapped to 
Anatomical Therapeutic Chemical (ATC) drug class (level 4) and drug name. The ATC 
drug class level 3 term is provided if level 4 is not available, and the ATC drug class 
level 2 term is provided if level 3 and level 4 are not available. 
Prior and concomitant medications will be summarized separately and the study phase 
of each medication will be determined programmatically based on medication start and 
end dates. A prior medication is defined as any medication administered prior to the 
date of the first dose of study drug. A concomitant medication is defined as any 
medication administered on or after the date of the first dose of study drug. A 
medication may be defined as both prior and concomitant, and may occur in both study 
treatment periods based on reported start and end dates. If it cannot be determined 
whether a medication was received prior to the start of study drug dosing due to partial 
or missing medication start and/or end dates, it will be considered a prior medication. 
Likewise, if it cannot be determined whether a medication was received after the start 
of study drug dosing, it will be considered concomitant. 
For both prior and concomitant medications summaries, the number and percentage of 
subjects receiving any medication will be summarized by treatment group, as will the 
number and percentage receiving any medication by ATC drug class and generic drug 
name. Concomitant medications will be summarized separately for the Double-Blind 
Treatment Period and Open-Label Extension Period. Prior medications will be 
summarized for the Full Analysis Set. Subjects reporting use of more than one 
medication at each level of summarization (any medication received, ATC class, and 
generic drug name) will be counted only once. The ATC class terms will be displayed 
by descending order of incidence, as will generic drug names within each ATC class. 
Subjects receiving UDCA as part of their allowed treatment regimen will have the 
medication reported on the Prior and Concomitant Medication CRF for summarization 
in each applicable table.  The study phase during which each medication was received 
(e.g., prior, concomitant, or both) will be presented on the listing of prior and 
concomitant medications, as well the study treatment period in which the medication 


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was received (e.g., Double-Blind Treatment Period, Open-Label Extension Period, or 
both). A listing of those concomitant medications that are prohibited and/or rescue 
medications and are to be considered intercurrent events for the primary estimand will 
also be provided.  
4.6 
Determination of Sample Size 
Assuming a standard deviation of 2.5 points, a sample size of 26 subjects per treatment 
group provides approximately 
% power to detect a 
 
EP547 and placebo with respect to the change in weekly mean of the daily WI-NRS 
score based on a 2-sided, 2-sample comparison of means at the 5% significance level. 
With an anticipated early withdrawal rate of approximately 10%, the planned 
enrollment of 29 subjects per treatment group will ensure that at least 26 subjects 
complete the 6 weeks of double-blind treatment. 
4.7 
Changes in the Conduct of the Study or Planned Analyses 
There were no changes to the study conduct or planned analyses identified within the 
development of this SAP, relative to the descriptions provided within the clinical study 
protocol. 
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Palmer M, Regev A, Lindor K, et al. Consensus Guidelines: Best Practices for 
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Prurigo Nodularis. N Engl J Med. 2020;382(8):706-16. 
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Incontinence. Am J Obstet Gynecol. 2003;189(1):98-101. 
 
 


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Version 1.0; 01 May 2024 
 
 
 
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Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
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Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
Page 49 of 51 
 


Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
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Escient Pharmaceuticals, Inc. 
Statistical Analysis Plan 
EP-547-201 
Version 1.0; 01 May 2024 
 
 
 
Confidential 
Page 51 of 51