An Open-Label Phase 2a Study Evaluating the Safety and Efficacy of Combination Treatment With 2 Weeks of the Non-Nucleoside Inhibitor CDI 31244 Plus 6 Weeks of Sofosbuvir/Velpatasvir in Subjects With Chronic Hepatitis C Genotype 1 Infection
Phase: PHASE2
Conditions: Chronic Hepatitis C
Sponsor: Cocrystal Pharma, Inc.



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P R O T O C O L S Y N O P SI S  
Title : A n O pe n-L a bel P hase 2a St u d y E val uati n g t he Safet y a n d Effic ac y of C o m bi nati o n 
Tr eat me nt wit h 2 Wee ks of t he N o n -N ucle osi d e I n hi bit or C D I-3 1 2 4 4 Pl us 6 Wee ks of 
S of os b u vir/ V el p at as vir i n S u bje cts wit h C hr o nic H e patitis C Ge n ot y pe 1 I nfecti o n.  
Dise ase : 
C hr o nic he patitis C vir us ( H C V) i nfecti o n.  
O bj ecti ves : 
T he pri mar y o bjecti ve of t his st u d y is t o e val uat e t he safet y, t olera bilit y, a n d preli mi nar y effic ac y 
of tr eat me nt wit h 2 wee ks of C DI -3 1 2 4 4 pl us 6 we e ks of s of os b u vir/ vel p at as vir ( S O F/ V E L) i n 
s u bje cts wit h c hr o nic H C V ge n ot y p e 1 i nfe cti o n. Sec o n dar y o bjecti ves i ncl u de: a) e val uati n g t he 
vir al ki netics of cir c ulati n g H C V R N A d uri n g a n d aft e r treat me nt wit h C DI-3 1 2 4 4 pl us 
S O F/ V E L, a n d b) e val uati n g t he p har mac o ki netics of C DI -3 1 2 4 4 d uri n g treat me nt wit h C DI - 
3 1 2 4 4 pl us S O F/ V E L.  
St u d y Desi g n : 
T his is a n o pe n -la bel p hase 2a st u d y t o e val uat e t he safet y, t olera bilit y, a n d preli mi nar y effic ac y 
of  tr eat me nt wit h 2 wee ks of a n or al n o n-n u cle osi d e i n hi bit or C DI -3 1 2 4 4 c o m bi ne d wit h 6 
wee ks of S O F/ V E L i n a d ult s u bjects wit h c hr o nic H C V ge n ot y pe 1 vir us i nfe cti o n.  
S u m m a r y of S u bj ect Eli gi bilit y Crit e ri a : 
I ncl usi o n Crit eria: 
•  
A ge ≥ 1 8 ye ars at  scr ee ni n g. 
•  
D o c u me nt e d c hr o nic H C V i nfecti o n base d o n a n y of t he  f oll o wi n g: 
− 
A nti -H C V a nti b o d y p ositi vit y f or at least 6 m o nt hs pri or t o st u d y e nr oll me nt,  or  
− 
H C V ge n ot y pe r es ults f or at least 6 m o nt hs pri or t o st u d y e nr oll me nt,  or 
− 
H C V R N A p r ese nt i n plas ma b y a se nsiti ve a n d s p ecific assa y f or at least 6 m o nt hs pri or 
t o st u d y e nr oll me nt, or  
− 
Hist ol o gic e vi de nce of c hr o nic H C V  i nfe cti o n. 
•  
H C V ge n ot y pe 1a or 1 b i nfecti o n b y H C V ge n ot y pi n g perf or me d at scree ni n g. ( N ot e:  N o 
m or e t ha n f o ur s u bjects  wit h H C V ge n ot y pe 1 b will be  e nr olle d).  
•  
Ser u m H C V R N A > 1, 0 0 0 I U/ m L d uri n g  scree ni n g. 
•  
M ust ha ve a pri mar y car e pr o vi der(s) f or me dical  ma na ge me nt.  
•  
A bse nce of a d va nc e d fi br osis or cirr h osis b y li ver bi o ps y, fi br osca n ( < 8 k Pa) or 
Fi br o T est/ Fi br o S ur e ( F 2 or l o wer) wit hi n 1 year of scree ni n g. If t he prece di n g fi br osis 
t ests ar e n ot a vaila ble, Fi br o T est/ Fi br o S ure will be d o ne at scree ni n g. 

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•  
Fe males of c hil d be ari n g p ot e ntial m ust ha ve a ne g ati ve ser u m pre g na nc y t est at  scree ni n g 
a n d a gr ee t o use a me dicall y r elia ble met h o d of c o ntrace pti o n u ntil st u d y c o m pleti o n. 
Effecti ve c o ntr ace pti o n met h o ds i ncl u de: t ot al a bsti ne nce ( w he n lifest yle or se x ual 
orie nt ati o n of t he s u bject pr ecl u des i nt erc o urse wit h a male part ner); fe male st erilizati o n; 
barrier met h o ds of c o ntr ace pti o n ( dia p hra g m or cer vical/ va ult ca ps wit h s per mici dal 
f o a m, gel, cr ea m, or va gi nal s u p p osit or y); use of oral, i nject e d, or i m pla nt e d h or m o nal 
c o ntr ace pti o n or ot her f or ms t hat ha ve c o m p ara ble effic ac y (fail ure rat e < 1 %); or 
place me nt of a n i ntr a ut eri ne  de vice or i ntra ut eri ne  s yst e m. 
•  
Male s u bjects m ust be willi n g t o a bst ai n fr o m het er ose x ual i nt erc o urse or use a  c o n d o m 
wit h s per mici de t hr o u g h o ut t he st u d y  peri o d. 
•  
Be willi n g t o ha ve bl o o d sa m ples st ore d f or f ut ure  researc h. 
•  
A vaila ble f or at least 3 0 wee ks  f or st u d y partici pati o n.  
•  
Writt e n i nf or me d c o nse nt m ust be o bt ai ne d bef ore a n y st u d y pr o ce d ure is perf or me d. 
E xcl usi o n  Crit eria : 
•  
N ursi n g or pr e g na nt.  
•  
Acti ve he patitis B vir us ( H B V) i nfecti o n, defi ne d as p ositi ve he patitis B s urface a nti g e n 
( H Bs A g) at scr eeni n g. If s u bject is ne gati ve f or b ot h H Bs A g a n d he patitis B s urfa ce 
a nti b o d y ( H Bs A b), b ut he patitis B c ore a nti b o d y ( H Bc A b) -p ositi ve, plas ma H B V D N A 
le vels will be c he c ke d a n d s u bje ct e xcl u d e d if H B V D N A is det ect e d.  
•  
H u ma n i m m u n o deficie nc y vir us ( HI V)  i nfecti o n.  
•  
Hist or y of use of a n y H C V dir e ct -acti n g a nti viral t hera p y. 
•  
Cli nicall y si g nific a nt ill ness ot her t ha n H C V t hat ma y i nt erfere wit h s u bject treat me nt, 
assess me nt, safet y, or c o m plia nce wit h t he pr ot o c ol i n t he j u d g me nt of t he  i n vesti gat or. 
•  
P ositi ve uri ne scr ee n f or a m p het a mi nes or  c o cai ne.  
•  
K n o w n c urr e nt her oi n, m or p hi ne, or met ha d o ne us e. C urre nt narc otic us e ot her t ha n 
met ha d o ne is acc e pt a ble if me dicall y i n dic at e d ( d oc u me nt e d i n me dical rec or ds) a n d 
pr escri be d b y a p h ysicia n.  
•  
S u bst a nce a b use, i ncl u di n g alc o h ol a b use, w hic h i n t he o pi ni o n of t he i n vesti g at or  is 
li kel y t o i nt erfer e wit h me dicati o n a d here nce or st u d y c o m plia nce.  
•  
Gastr oi nt esti nal dis or der t hat c o ul d i nt erfere wit h t he a bs or pti o n of t he st u d y dr u g (e. g., 
str uct ur al defect, di gesti ve fail ure or e nz y me deficie ncies wit h t he e xce pti o n of la ct ose 
i nt oler a nce) a n d/ or hist or y of bariatric s ur ger y. 
•  
P o or ve n o us access i nt erferi n g wit h re q uire d st u d y bl o o d  c ollecti o n.  
•  
Si g nifica nt hist or y of dr u g aller g y (s uc h as a na p h yla xis or he pat ot o xicit y) t o t he st u d y 
me dicati o ns.  
•  
Hist or y of cli nic all y si g nifica nt c hr o nic li ver dis ease d ue t o ot her eti ol o g y (e. g., 
he m o c hr o mat osis, a ut oi m m u ne he patitis, Wils o n’s disease, α 1 -a ntitr y psi n deficie nc y,  

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alc o h olic li ver dise ase, k n o w n great er t ha n m o derat e n o n -alc o h olic st eat o he patitis, a n d 
t o xi n e x p os ur es). 
•  
Use of her bal/ nat ur al r e me dies f or p ot e ntial be nefit t o t he li ver wit hi n 3 0 da ys bef ore 
st u d y e ntr y.  
•  
Tr eat me nt wit h a mi o dar o ne wit hi n 1 8 0 da ys bef ore st u d y  e ntr y.  
•  
Tr eat me nt wit h di g o xi n wit hi n 3 0 da ys bef ore st u d y  e ntr y. 
•  
Tr eat me nt wit h rifa b uti n, rifa m pi n, rifa pe nti ne, p he n yt oi n, p he n o bar bit al, St. J o h n’s w ort, 
car ba maz e pi ne, o xcar baze pi ne, r os u vast ati n, or at or vast ati n wit hi n 1 0 da ys bef ore st u d y 
e ntr y. H o we ver, s wit c hi n g t o a n ot her st ati n is  acce pt a ble.  
•  
C hr o nic s yst e mic tr eat me nt wit h eit her c ortic ost er oi ds ( > 1 0 m g dail y pre d nis o ne 
e q ui vale nt) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys bef ore st u d y e ntr y. 
I n hale d st er oi ds ar e per mitt e d per I n vesti g at or’s discreti o n.  
•  
Scr ee ni n g or baseli ne E C G wit h cli nical l y si g nific a nt fi n di n gs. 
•  
Q T c F ( Q T i nt er val c orr ect e d usi n g Fri dericia's f or m ula) > 4 5 0 msec at  scree ni n g. 
•  
Cli nicall y si g nific a nt he mat ol o gical a n d bi o c he mic al val ues at scree ni n g t hat ma y 
i nt erfer e wit h s u bject tr eat me nt, assess me nt, safet y, or c o m plia nc e wit h t he pr ot o c ol i n 
t he j u d g me nt of t he i n vesti gat or, i ncl u di n g: 
− 
A bs ol ut e ne utr o p hil c o u nt ( A N C) < 1, 0 0 0  cells/ m m 3. 
− 
He m o gl o bi n le vel < 1 0  g/ d L. 
− 
Plat elet c o u nt < 1 0 0, 0 0 0  cells/ m m 3. 
− 
Esti mat e d gl o mer ular filtrati o n rat e (e G F R) < 3 0 m L/ mi n/ 1. 7 3  m2. 
− 
A L T or A S T le vel ≥ 5 ti mes u p per li mit of n or mal ( U L N). 
− 
Dir ect bilir u bi n le vel ≥1. 5 ti mes  U L N.  
•  
Hist or y of he pat o cell ular car ci n o ma  ( H C C). 
•  
Hist or y of mali g na nt dis ease wit hi n pre vi o us 5 ye ars (e xce pt f or a de q uat el y treat e d basal 
cell car ci n o ma).  
•  
Hist or y of cli nic all y si g nifica nt m y o pat h y. 
I n vesti g ati o n al Dr u g: 
C DI - 3 1 2 4 4 
St u d y Dr u g D oses a n d R o ut e of A d mi nistr ati o n : 
•  
C DI -3 1 2 4 4 ( 5 0  m g)  
•  
S of os b u vir 4 0 0 m g/ vel pat as vir 1 0 0 m g  ( E pcl usa) 
St u d y dr u g ( C DI -3 1 2 4 4 a n d s of os b u vir/ vel pat as vir [ S O F/ V E L]) will be pr o vi de d as ca ps ules 
( C DI-3 1 2 4 4) or t a blets ( S O F/ V E L) i n b ottles. S u bjects will be i nstr uct e d t o t a ke 8 ca ps ules of 
C DI -3 1 2 4 4 ( 4 0 0 m g t ot al d ose) a n d 1 t a blet of S O F/ V E L o nce dail y wit h at least 8 o z. of plai n  

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wat er i n t he m or ni n g u p o n a wa ke ni n g. D uri n g t he peri o d of S O F/ V E L treat me nt al o ne, s u bjects 
will be i nstr uct e d t o t a ke 1 t a blet o nce dail y.  
P r oce d u res : 
•  
Scr ee ni n g e val uati o ns will o cc ur bet wee n 7 a n d 4 2 da ys bef ore i nitial st u d y dr u g 
a d mi nistr ati o n.  
•  
Da y 1 is t he da y of baseli ne ( pr e -st u d y dr u g) assess me nts a n d t he first da y of st u d y dr u g 
a d mi nistr ati o n. Cli nic visits will o cc ur at scree ni n g a n d baseli ne a n d t hr o u g h wee k 3 0 
(i. e., 2 4 wee ks aft er c o m pleti o n of treat me nt) f or all s u bjects. 
•  
Safet y e val u ati o ns will c o nsist of vit al si g ns, p h ysical e xa mi nati o n, electr o car di o gr a m 
( E C G), a n d a d diti o nal cli nic al a n d la b orat or y dat a. A d verse e ve nts will be c ollect e d 
t hr o u g h 4 wee ks aft er c o m pleti o n of treat me nt f or all  s u bjects. 
•  
T he pri mar y a n d sec o n d ar y effic ac y o ut c o mes will be meas ure d t hr o u g h o ut t he st u d y 
peri o d b y plas ma H C V R N A.  
•  
P har mac o ki netic ( P K) par a met ers will be assesse d t hr o u g h plas ma C DI - 3 1 2 4 4, 
s of os b u vir, G S-3 3 1 0 0 7 (s of os b u vir met a b olit e), a n d vel pat as vir c o nce ntrati o ns at Da y 1 
( pr e-d ose) a n d at 0 ( pr e -d ose), 1, 2, 4, 6, 8, 1 2, a n d 2 4 h o urs aft er da y 1 4  d osi n g. 
•  
Vi r al ki netics ( V K) will be assess e d t hr o u g h plas ma H C V R N A le vels o bt ai ne d at 2, 4, 
a n d 6 h o urs aft er Da y 1  d osi n g. 
•  
T he t ot al st u d y d ur ati o n is 3 0 wee ks. 
P ri m a r y a n d Sec o n d ar y Effic ac y  E n d p oi nts: 
Pri mar y efficac y  e n d p oi nt:  
•  
Pr o p orti o n of s u bjects w h o ac hie ve  s ust ai ne d vir ol o gic res p o nse 1 2 wee ks aft er 
c o m pleti o n of tr eat me nt  ( S V R 1 2). 
Sec o n dar y efficac y e n d p oi nts:  
•  
Pr o p orti o n of s u bjects w h o ac hie ve s ust ai ne d vir ol o gic res p o nse 2 4 wee ks aft er 
c o m pleti o n of tr eat me nt  ( S V R 2 4). 
•  
Ti me t o ac hie ve H C V R N A le vels bel o w  t he l o wer li mit of q ua ntificati o n ( L L O Q). 
•  
Pr o p orti o n of s u bjects wit h H C V R N A < L L O Q aft er Da y 7 a n d Da y 1 4 of C DI - 3 1 2 4 4 
pl us S O F/ V E L  tr eat me nt. 
•  
Pr o p orti o n of s u bjects wit h H C V R N A < L L O Q aft er Da y 7 a n d Da y 1 4, of C DI - 3 1 2 4 4 
pl us S O F/ V E L tr eat me nt b y ge n ot y pe 1a or  1 b.  
E x pl or at or y e n d p oi nts ( usi n g st or e d bl o o d) will i n cl u de:  

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•  
I m m u n ol o gic, vir ol o gic, a n d h ost ge netic/ pr ot e o mic pre dict ors of res p o nse t o t hera p y. 
•  
Effect of t her a p y o n peri p her al mar kers of T cell  a cti vati o n.  
S a m ple Si ze, P o we r, a n d N u m ber of Si tes: 
•  
A t ot al of 1 2 s u bjects wit h tr eat me nt -naï ve c hr o nic H C V ge n ot y pe 1 (eit her 1a or 1 b)  is 
c o nsist e nt wit h t he n u m ber of s u bjects i n pr o of-of -c o nce pt pil ot st u dies t hat e val uat e 
n o vel t her a pies f or H C V vir e mia (a n d c ure) i n patie nts wit h c hr o nic H C V  i nfecti o n.  
•  
Sit e: I nstit ut e of H u ma n Vir ol o g y (I H V), U ni versit y of Mar yla n d, Balti m ore,  M D.  
Re m o v al of S u bj ects fr o m St u d y Dr u g or Assess me nt:  
A s u bject m ust pr e mat ur el y dis c o nti n ue st u d y dr u g u n der a n y of t he f oll o wi n g circ u mst a nces:  
•  
T he s u bject wis hes st u d y d r u g t o be disc o nti n ue d f or a n y reas o n. 
•  
T he i n vesti gat or wis hes t he s u bject t o disc o nti n ue st u d y dr u g, es peciall y b ut n ot li mit e d 
t o t he i n vesti g at or c o ncl u di n g t hat f urt her treat me nt p uts t he s u bje ct at u nacce pt a ble ris k 
or st u d y  n o nc o m plia nce.  
•  
T he s u bject  de vel o ps a c o n diti o n or be gi ns a t hera p y t hat w o ul d ha ve e xcl u de d e ntr y i nt o 
t he st u d y. 
•  
T he s u bject pr e mat ur el y fails effic ac y base d o n a n y of t he f oll o wi n g crit eria, w hic h m ust 
be c o nfir me d b y a r e peat t est wit hi n 7  da ys:  
− H C V R N A > L L O Q aft er 2 c o nsec uti ve H C V R N A val ues <  L L O Q.  
− Gr eat er t ha n 1 l o g 1 0 i ncrease i n H C V R N A fr o m na dir.  
Resist a nce ass a y t est will be o bt ai ne d f or all s u bje cts dis c o nti n ui n g st u d y dr u g 
pr e mat ur el y d ue t o lac k of effic ac y.  
•  
T he s u bject has e vi de nce of a se vere dr u g aller g y s uc h as  a na p h yla xis. 
•  
A n a d verse e ve nt wit h a Di visi o n of AI D S ( D AI D S) T a ble f or “ Gra di n g t he Se verit y  of 
A d ult a n d Pe diatric A d verse E ve nts” gra de 3 or great er t o xicit y t hat is relat e d t o st u d y 
dr u g i n t he j u d g me nt of t he  i n vesti gat or. 
A s u bject has t he ri g ht t o disc o nti n ue st u d y dr u g treat me nt at a n y ti me f or a n y reas o n wit h o ut 
pr ej u dice t o f ut ur e me dical car e b y t he i n vesti gat or or ot her p h ysicia n at t he i nstit uti o n. A 
s u bje ct w h o disc o nti n ues st u d y dr u g s h o ul d c o m plet e all sc he d ule d st u d y visits pr ovi de d t h at 
wri tte n c o nse nt t o d o s o h as n ot bee n wit h dr a w n. S u bjects w h o pre mat urel y disc o nti n ue st u d y 
dr u g ma y be r e plac e d.  
A s u bject m ust be wit h dr a w n fr o m t he st u d y (a n d dis c o nti n ue a n y st u d y dr u g) if t he s u bje ct 
r e q uests s uc h st u d y disc o nti n uati o n. T he reas o n f or wit h dra wal m ust be rec or de d i n t he s u bject’s 

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case r e p ort f or m ( C R F). If p ossi ble, t he s u bject s h o ul d c o m plet e t he e val uati o ns f or t he st u d y 
wee k 6 visit pr ovi de d t h at writte n c o ns e nt t o d o s o h as n ot bee n wit h dr a w n . S u bje cts w h o 
wit h dr a w fr o m t he st u d y ma y be r e place d.  
Ret re at me nt:  
S u bjects w h o ha ve vir ol o gic fail ur e d uri n g t he 6 -wee k st u d y dr u g treat me nt peri o d, defi ne d as 
eit her H C V R N A > L L O Q aft er 2 c o nsec uti ve H C V R N A val ues < L L O Q or > 1 l o g 1 0 i ncrease 
i n H C V R N A fr o m na dir, will be disc o nti n ue d fr o m st u d y dr u g treat me nt ( Secti o n 5. 3. 1). T hese 
s u bje cts will r ecei ve a d diti o nal tr eat me nt (“retreat me nt ”) wit h s of os b u vir/ vel pat as vir/ 
v o xila pr e vir ( S O F/ V E L/ V O X) 4 0 0 m g/ 1 0 0 m g/ 1 0 0 m g o nce dail y f or 1 2 wee ks wit h a d diti o nal 
f oll o w-u p t hr o u g h 1 2 wee ks aft er ce ssati o n of treat me nt ( S V R 1 2). 
S u bjects w h o c o m plet e t he 6 -wee k tr eat me nt peri o d will be c o nsi dere d t o ha ve vir ol o gic 
(tr eat me nt) fail ur e if t he y ha ve det ect a ble H C V R N A at t he ne xt st u d y visit a n d t hereaft er 
t hr o u g h o ut t he st u d y. T hese s u bjects will re cei ve a d diti o nal treat me nt (“retreat me nt ”) wit h 
s of os b u vir/ vel pat as vir/ v o xila pr e vir ( S O F/ V E L/ V O X) 4 0 0 m g/ 1 0 0 m g/ 1 0 0 m g o nce dail y f or 1 2 
wee ks wit h a d diti o nal f oll o w -u p t hr o u g h 1 2 wee ks aft er cessati o n of treat me nt ( S V R 1 2).  
St atistic al A n al ysis : 
Safet y a n d effic ac y will be ass ess e d o n a n i nt e nt -t o-treat basis f or all s u bjects w h o ha ve recei ve d 
st u d y dr u g. Dat a will be s u m mariz e d usi n g descri pti ve st atistics ( n u m ber of patie nts, mea n, 
me dia n, st a n dar d de viati o n, mi ni m u m a n d ma xi m u m) f or c o nti n u o us varia bles a n d fre q ue nc y 
a n d per ce nt a ges f or cat e g orical varia bles. Ti me t o ac hie ve H C V R N A le vels L L O Q will als o be 
s u m marize d usi n g descri pti ve st atistics. E x pl orat or y e n d p oi nts will be ass esse d usi n g descri pti ve 
st atistics. T he i nci de nce of all r e p ort e d a d verse e ve nts  ( A Es) a n d treat me nt-relat e d A Es will  be 
t a b ulat e d. A Es will be classifie d b y s yst e m or ga n class a n d preferre d t er m usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities  ( Me d D R A). 
S p o ns or : C o cr yst al P har ma, I nc. 

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T A B L E O F C O N T E N T S  
P R O T O C O L  S Y N O P SI S.  .......................................................................................................... 2  
T A B L E O F  C O N T E N T S  ........................................................................................................... 8  
LI S T  O F  A B B R E VI A TI O N S  ....................................................................................................1 1  
1.
I N T R O D U C TI O N ............................................................................................................. 1 4
1.1. Bac k gr o u n d a n d  St u d y Rati o nale  .................................................................................. 1 4 
1. 1. 1.  C hr o nic  He patitis  C ................................................................................................ 1 4 
1. 1. 2.  S of os b u vir/ V el p at as vir  ........................................................................................... 1 5 
1. 1. 3 .  C DI - 3 1 2 4 4 .............................................................................................................1 6  
1.2. Ris k/ Be nefit  Assess me nt ............................................................................................... 1 8 
2.
O BJ E C TI V E S  .................................................................................................................... 2 0
3.
I N V E S TI G A TI O N A L P L A N  ............................................................................................ 2 1  
3.1. S u m mar y of  St u d y Desi g n  ............................................................................................ 2 1 
3.2. O utli ne of  Visit  Sc he d ule  .............................................................................................. 2 1 
3. 2. 1.  Scr ee ni n g a n d  Baseli ne  E val uati o ns ........................................................................ 2 1 
3. 2. 2.  A d diti o nal  St u d y E val u ati o ns  ................................................................................. 2 3 
4.
DI S C U S SI O N O F  D E SI G N  ............................................................................................... 2 9 
5.
S T U D Y P O P U L A TI O N  .................................................................................................... 3 1 
5.1. I ncl usi o n Crit eria ......................................................................................................... 3 1 
5.2. E xcl usi o n  Crit eria  ........................................................................................................ 3 2 
5.3. Re m o val of S u bjects fr o m St u d y Dr u g  or  Assess me nt  .................................................. 3 3 
5. 3. 1.  St u d y Dr u g  Dis c o nti n u ati o n  .................................................................................... 3 3 
5. 3. 2.  S u bject Wit h dr a w al fr o m  t he St u d y ........................................................................ 3 4 
5. 4  Retr eat me nt  ................................................................................................................... 3 4 
5. 5  St u d y St o p pi n g R ules  ..................................................................................................... 3 5 
6.
T R E A T M E N T S  ................................................................................................................. 3 6
6.1. S u bject  Assi g n me n t ...................................................................................................... 3 6 
6.2. Met h o d of Assi g n me nt  t o Tr eat me nt  ............................................................................ 3 6 
6.3. Mat erials  a n d S u p plies  ................................................................................................. 3 6 
6. 3. 1.  F or m ulati o n, Pac ka gi n g,  a n d La beli n g  .................................................................... 3 6 

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6. 3. 2.  St or a ge a n d Ha n dli n g  ............................................................................................. 3 6 
6. 3. 3.  Fi nal Dis p ositi o n of  Cli nical  S u p plies  ..................................................................... 3 6 
6.4. D osa ge  A d mi nistr ati o n  ................................................................................................. 3 7 
6.5. Bli n di n g  ....................................................................................................................... 3 7 
6.6. C o nc o mit a nt  T her a p y  ................................................................................................... 3 7 
7.
A D V E R S E E V E N T  R E P O R TI N G  .................................................................................... 3 9 
7.1. Defi niti o n of  A d verse  E ve nt  ......................................................................................... 3 9 
7. 1. 1.  Re p orti n g Pr o ce d ur es f or All  A d vers e  E ve nts  ......................................................... 3 9 
7. 1. 2.  A d vers e  E ve nt  Se verit y  .......................................................................................... 4 0 
7. 1. 3.  A d vers e E ve nt Relati o ns hi p t o  St u d y Dr u g  ............................................................. 4 0 
7. 1. 4.  Seri o us  Ad verse E v e nt Defi nitio n a n d  Re p orti n g  Pr oce d ures  .................................  4 1  
7. 1. 5.  La b or at or y  T e sts ..................................................................................................... 4 2 
7. 1. 6.  Safet y  M o nit ori n g  ................................................................................................... 4 2 
8.
Q U A LI T Y C O N T R O L A N D  Q U A LI T Y  A S S U R A N C E  ................................................... 4 3 
9.
D A T A  A N A L Y SI S  M E T H O D S  ........................................................................................ 4 4 
9.1. Det er mi nati o n of  Sa m ple  Size  ...................................................................................... 4 4 
9.2. Mai n  Efficac y  Varia ble  ................................................................................................ 4 4 
9. 2. 1.  Q ua ntit ati ve Plas ma H C V  Le vels ............................................................................ 4 4 
9.3. Safet y  Varia bles  ........................................................................................................... 4 4 
9.4. F ut ur e Use o f St or e d  S peci me ns  ................................................................................... 4 4 
9.5. St atistical a n d  A nal ytical Pla ns ..................................................................................... 4 5 
9. 5. 1.  Ge ner al  C o nsi der ati o ns  ........................................................................................... 4 5 
9. 5. 2.  Ha n dli n g of  Missi n g  Dat a  ....................................................................................... 4 5 
9. 5. 3.  S u bject  Dis p ositi o n  ................................................................................................. 4 5 
9. 5. 4.  S u bject  C har act eristics  ............................................................................................ 4 5 
9. 5. 5.  Tr eat me nt  C o m plia nce  ............................................................................................ 4 5 
9. 5. 6.  Efficac y  A nal yses  ................................................................................................... 4 5 
9. 5. 7.  Safet y  A nal ys es  ...................................................................................................... 4 6 
9. 5. 8.  P har mac o ki netic  A nal ys es  ...................................................................................... 4 6 
9. 5. 9.  P har mac o ki netic/ P har mac o d y na mic  A nal ysis  ......................................................... 4 6 
9. 5. 1 0.  I nt eri m A nal ys es  ................................................................................................... 4 6 
1 0.
A D MI NI S T R A TI V E,  ET HI C A L,  A N D  R E G U L A T O R Y  C O N SI D E R A TI O N S  ................4 7  
10.1. Et hical  Re vie w  ........................................................................................................... 4 7 

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10.2. 
Re g ulat or y  Co nsi derati o ns  ......................................................................................... ..4 7  
1 0. 2. 1.  I n vesti gator  I nf or mati o n ......................................................................................... 4 8 
1 0. 2. 2.  Pr ot o c ol A me n d me nts a n d  St u d y T er mi n ati o n.  ....................................................... 4 8 
1 0. 2. 3.  Pr ot o c ol  De viati o ns  ................................................................................................ 4 8 
1 0. 2. 4.  St u d y D o c u me nt ati o n, Pri vac y, a n d  Re c or ds  Ret e nti o n  ........................................... 4 8 
10.3. 
St u d y Fi n a n c es  ........................................................................................................... .4 9  
10.4. 
P u blicati o ns ................................................................................................................ . 4 9  
1 1.
R E F E R E N C E S  ................................................................................................................ .5 0  
A P P E N DI X  A.  S C H E D U L E  O F  E V E N T S  ............................................................................. 5 2 
A P P E N DI X  B.  P R O T O C O L  SI G N A T U R E  P A G E  ................................................................ 5 5 
LI S T O F T A B L E S  
T a ble 1:  
St u d y Dr u g Tr eat me nt  a n d Pac ka gi n g  ..................................................................... 3 6 
T a ble 2:  
Me dicati o ns t hat ar e Pr o hi bit e d or t o be Use d  wit h  Ca uti o n ..................................... 3 8 
LI S T O F FI G U R E S  
Fi g ur e 1:  
Ill ustr ati o n of St u d y Desi g n  .................................................................................... 2 1 

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LI S T O F A B B R E VI A TI O N S  
 
 
A B B R E VI A TI O N  
D E FI NI TI O N  
A E  
a d vers e e ve nt  
A L T  
ala ni ne a mi n otr a nsf er ase  
A N C  
a bs ol ut e ne utr o p hil c o u nt  
A S T  
as partate a mi n otr a nsf er ase  
A U C  
ar ea u n der t he plas ma c o nc e ntr ati o n-ti me c ur ve 
B P  
bl o o d pr ess ur e  
C B C  
c o m plet e bl o o d c o u nt  
C K  
cr eati ne ki nas e 
C ma x  
ma xi m u m plas ma c o nc e ntr ati o n of dr u g  
C mi n  
mi ni m u m plas ma c o nc e ntr ati o n of dr u g  
C R F  
case r e p ort f or m 
D A A  
dir ect -a ct i n g a nti vir al 
D AI D S  
Di visi o n of AI D S  
D DI  
dr u g -dr u g i nt er a cti o n  
D N A  
de o x yri b o n ucleic a ci d  
E C 5 0  
c o nc e ntr ati o n of a n i n hi bit or w her e t he r es p o ns e ( or bi n di n g) of dr u g is 
r e d uc e d b y half 
E C G  
electr ocar di o gr a m 
e G F R  
esti mat e d gl o mer ular filtr ati o n r ate 
E O T 
e n d of tr eat me nt  
E O T - C 
e n d of tr eat me nt wit h C DI - 3 1 2 4 4 
E O T -S V  
e n d of tr eat me nt wit h s of os b u vir a n d vel patas vir  
F D A  
( U S) F o o d a n d Dr u g A d mi nistr ati o n 
G C P  
G o o d Cli nical Pr a ctice  
G L P  
G o o d La b Pra ctic e  
G T  
ge n ot y p e  
H Bc A b  
he patitis B c or e a nti b o d y  
H Bs A b 
he patitis B s urfa ce a nti b o d y  
H Bs A g  
he patitis B s urfa ce a nti ge n  

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A B B R E VI A TI O N  
D E FI NI TI O N  
H B V  
he patitis B vir us  
H C C  
he pat oc ell ular car ci n o ma  
h C G  
h u ma n c h ori o nic g o na d otr o pi n  
H C V  
he patitis C vir us  
HI P A A  
Healt h I ns ur a nc e P orta bilit y a n d Ac c o u nta bili t y Act 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
heart r ate  
I C5 0  
T he half ma xi mal i n hi bit or y c o nc e ntr ati o n ( of dr u g)  
I C H 
I nt er nati o nal C o nf er e nc e o n Har m o nisati o n 
I H V 
I nstit ut e of H u ma n Vir ol o g y 
I L 2 8 B 
i nt erle u ki n 2 8 B 
I N R 
i nt er nati o nal n or maliz e d r ati o 
I RB 
I nstit uti o nal R e vie w B oar d 
I T T 
i nt e nt-t o-tr eat 
L C -M S  
li q ui d c hr o mat o gr a p h y– mass s pectr o metr y  
L L O Q  
l o wer li mit of q ua ntificati o n 
M A D  
m ulti ple asc e n di n g d os e  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
M C V  
mea n c ell v ol u me  
N NI  
n o n- n ucle osi de  i n hi bit or 
P  
p uls e r ate  
P B M C  
peri p her al bl o o d m o n o n u clear cells  
P C R  
p ol y mer ase c hai n r ea cti o n  
P D  
p har ma c o d y na mics  
P- g p  
P- gl yc o pr ot ei n  
P K  
p har ma c o ki netics 
P T  
pr ot hr o m bi n ti me  
P T T  
partial t hr o m b o plasti n ti me  
P W  
p ost -tr eat me nt wee k 
Q T c F  
Q T i nter val c orr ect e d usi n g Fri dericia's f or m ula  
R  
r es pir at or y r ate 
R A V  
r esista nc e-ass ociate d varia nts  

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A B B R E VI A TI O N  
D E FI NI TI O N  
R B C  
r e d bl o o d c ell 
R N A  
ri b o n ucleic a ci d 
S A D  
si n gle asc e n di n g d os e 
S A E  
seri o us a d vers e e ve nt 
S O F  
s of os b u vir 
S O T  
start of tr eat me nt 
S V R  
s ustai ne d vir ol o gic r es p o ns e 
S V R 4  
s ustai ne d vir ol o gic r es p o ns e, 4 wee ks after tr eat me nt  
S V R 1 2  
s ustai ne d vir ol o gic r es p o ns e, 1 2 wee ks after tr eat me nt  
S V R 2 4  
s ustai ne d vir ol o gic r es p o ns e, 2 4 wee ks after tr eat me nt  
T  
T e m p er at ur e  
t ½ 
mea n eli mi nati o n h alf-lif e ( of dr u g) 
tma x  
ti me t o ma xi m u m c o nc e ntr ati o n ( of dr u g) 
U L N  
u p per li mit of n or mal  
U S  
U nit e d States  
V E L  
vel patas vir  
V K  
vir al ki netics  
V O X  
v o xila pr e vir 
W  
wee k  
W H O  
W orl d H ealt h Or ga nizati o n  

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1.  
I N T R O D U C TI O N 
1. 1.  
B ac k gr o u n d a n d St u d y  R ati o n ale 
1. 1. 1.  
C hr o nic He p atitis  C 
C hr o nic he patitis C vir us ( H C V) i nfecti o n afflicts a p pr o xi mat el y 1 % of t he gl o bal p o p ulati o n, 
wit h a n esti mat e d pr e vale nc e of 7 1 milli o n pers o ns ( P olaris O bser vat or y H C V C olla b orat ors 
2 0 1 7). It is o ne of t he maj or ca uses of c hr o nic li ver disease, lea di n g t o cirr h osis, he patic 
dec o m pe nsati o n, a n d he pat o cell ular carci n o ma ( H C C) ( L y et al., 2 0 1 2; West br o o k a n d 
D us hei k o, 2 0 1 4). C hr o nic he patitis C is a n i n d ole nt disease c haract eriz e d b y persist e nt li ver 
i nfla m mati o n, le a di n g t o li ver cirr h osis in a b o ut 1 0 t o 2 0 % of patie nts o ver a c o urse of 2 0 t o 3 0 
years of i nfecti o n ( West br o o k a n d D us hei k o, 2 0 1 4). T he W orl d Healt h Or ga nizati o n ( W H O) 
esti mat es t hat 4 0 0, 0 0 0 a n n ual deat hs are attri b ut e d t o H C V i nfecti o n, mai nl y d ue t o 
c o m plicati o ns of cirr h osis a nd H C C ( W orl d Healt h Or ga nizati o n 2 0 1 7).  
T he a d ve nt of safe a n d hi g hl y effecti ve direct -acti n g a nti viral ( D A A) t hera p y has re v ol uti o nize d 
t he tr eat me nt of c hr o nic he patitis C i nfecti o n. C o m bi nati o n D A As are s u bst a ntiall y bett er i n 
att ai ni n g c ur e t ha n earlie r i nt erfer o n-base d re gi me ns. S ust ai ne d vir ol o gic res p o nse at 1 2 wee ks 
( S V R 1 2), defi ne d, as a bse nce of H C V R N A i n plas ma 1 2 wee ks aft er cessati o n of H C V t hera p y, 
is s y n o n y m o us wit h c ur e. Ac hie vi n g S V R has be e n ass o ciat e d wit h re versal of li ver fi br osis, a n d 
r e d ucti o n i n ris k of he p atic dec o m p e nsati o n, H C C, a n d li ver-relat e d m ort alit y ( Vel dt et al., 
2 0 0 7).  U n der e xisti n g H C V tr eat me nt g ui deli nes, rec o m me n dati o ns are t o treat f or d urati o n  of  
8- 1 2 wee ks of c o m bi nati o n D A A t her a p y, w hic h res ults i n hi g h rat es o f S V R acr oss vari o us viral 
a n d h ost c har act eristics ( K o hli et al., 2 0 1 4; A A S L D/I D S A H C V G ui da nce Pa nel, 2 0 1 5; 
E ur o pea n Ass o ciati o n f or t he St u d y of t he Li ver  2 0 1 7). 
W hile m ost patie nts wit h c hr o nic H C V i nfecti o n are treat e d f or 1 2 wee ks, t w o re gi me ns are 
rec o m me n de d f or a s h ort er 8 -wee k tr eat me nt peri o d. Le di pas vir/s of os b u vir ( Har v o ni) ca n be 
use d f or 8 wee ks i n H C V ge n ot y p e 1 patie nts w h o are treat me nt naï ve, wit h o ut cirr h osis, n o n - 
blac ks, n ot i nfect e d wit h HI V, a n d w h ose bas eli ne H C V R N A le vel is < 6 mill i o n I U/ m L – a 
s u bset of t he H C V p o p ulati o n wit h a ver y g o o d treat me nt res p o nse ( K o w dle y et al., 2 0 1 4; 
A A S L D/I D S A H C V G ui da nce Pa nel 2 0 1 5). T he m ore rece nt F D A -a p pr o ve d gleca pre vir/ 
pi br e nt as vir ( Ma v yr et), a fi xe d d ose c o m bi nati o n of N S 3/ 4 A pr ot ease i n hi bit or a n d N S 5 A 
i n hi bit or, ca n be use d f or 8 wee ks t o treat patie nts wit h D A A-naï ve H C V ge n ot y pes 1 -6 wit h o ut 
cirr h osis base d o n dat a s h o wi n g hi g h S V R rat es i n t his p o p ulati o n ( Ze uze m et al., 2 0 1 8).  
T he hi g h c ost of H C V dr u gs is a barrier t o treat me nt f or ma n y  patie nts.  Ins ura nc e pr o vi ders 
oft e n use a ris k str atificati o n m o del t o pri oritize w h o s h o ul d recei ve treat me nt, ge nerall y fa v ori n g 
t h ose wit h cirr h osis (fi br osis sc or e of F 4) o ver t h ose wit h o ut ( C h ua a n d K ottilil, 2 0 1 7). T his 
str at e g y t e n ds t o e xcl u d e treat me nt f or y o u n ger, less a d va nce d H C V -i nfe ct e d pe o ple w h o 
c o m prise t he b ul k of t he u ntr eat e d H C V e pi de mic.  O ne wa y t o miti gat e t his c ost iss u e is  t he 

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de vel o p me nt of a safe a n d effecti ve r e gi me n t hat s h ort e ns t he c urre nt d urati o n of treat me nt. 
S h ort er d ur ati o n of t her a p y c o ul d als o e n ha nc e treat me nt a d here nce ( E m ma n uel et al., 2 0 1 7).  
Se ver al cli nic al st u dies ha ve e val uat e d treati n g patie nts wit h H C V i nfecti o n f or less t ha n 8 wee ks 
d ur ati o n, wit h mi xe d r es ults ( E m ma n uel et al., 2 0 1 7). T he S Y N E R G Y st u d y e val uat e d 5 0 
tr eat me nt-naï ve H C V ge n ot y pe 1 patie nts treat e d f or 4 wee ks wit h eit her a 3 -dr u g re gi me n 
(s of os b u vir, le di pas vir, N S 3/ 4 A pr ot ease i n hi bit or G S-9 4 5 1) or 4 -dr u g re gi me n (s of os b u vir, 
le di pas vir, G S-9 4 5 1, a n d n o n -n ucle osi de i n hi bit or [ N NI] G S - 9 6 6 9) ( K o hli et al., 2 0 1 5). T h o u g h 
well t oler at e d, b ot h tr eat me nts r es ult e d i n e xcessi v e rela pses a n d l o w c ure rat es – S V R rat es of 
4 0 % ( 1 0/ 2 5) i n t he 3 -dr u g gr o u p, a n d 2 0 % ( 5/ 2 5) i n t he 4 -dr u g gr o u p. I n c o ntrast, t he L E P T O N 
st u d y e val uat e d patie nts w h o wer e eit her treat me nt-naï ve or pre vi o usl y treat e d -H C V ge n ot y pes  
1- 3 wit h or wit h o ut cirr h osis. D ur ati o n of t hera p y was 4 or 6 wee ks f or treat me nt -naï ve patie nts 
wit h o ut cirr h osis, 6 wee ks f or tr eat me nt -naï ve patie nts wit h cirr h osis, a n d 6 or 8 wee ks f or 
pr e vi o usl y tr eat e d patie nts wit h or wit h o ut cirr h osis ( Ga ne et al,. 2 0 1 6). A p pr o xi mat el y 4/ 1 5 
( 2 7 %) tr eat me nt-naï ve ge n ot y pe 1 patie nts wit h o ut cirr h osis treat e d f or 4 wee ks ac hie ve d 
S V R 1 2, w hile 1 4/ 1 5 ( 9 3. 3 %) patie nts treat e d f or 6 wee ks ac hie ve d S V R 1 2. T hese ultr as h ort 
tr eat me nt st u dies ha d se ver al li mit ati o ns, i ncl u di n g s mall sa m ple sizes a n d i ncl usi o n of patie nts 
mai nl y wit h H C V ge n ot y pe 1 i nfecti o n ( E m ma n u el et al., 2 0 1 7).  
1. 1. 2.  
S of os b u vi r/ Vel p at as vi r 
S of os b u vir/ vel p at as vir ( E pcl usa) is t he first fi xe d -d ose c o m bi nati o n dr u g t o be a p pr o ve d b y t he 
F D A f or t he tr eat me nt of all H C V ge n ot y pes. S of os b u vir i n hi bits H C V N S 5 B R N A -de pe n d e nt 
R N A p ol y mer ase i n hi bit or, w hile vel pat as vir i n hi bits H C V re plic ati o n b y bi n di n g t o t he N S 5 A 
pr ot ei n ( Gr ei g 2 0 1 6).  B ot h N S 5 A a n d N S 5 B are e sse ntial f or H C V re plicati o n.  I n p has e 3 
st u dies t hat e val uat e d tr eat me nt-naï ve a n d treat me nt -e x perie nce d patie nts wit h or wit h o ut 
c o m pe nsat e d cirr h osis ( A S T R A L -1 t hr o u g h -3), s of os b u vir/ vel pat as vir ( S O F/ V E L) treat me nt f or 
1 2 wee ks r es ult e d i n S V R r at es r a n gi n g fr o m 9 5 t hr o u g h 9 9 % ( Fel d et al., 2 0 1 5; F ost er et al., 
2 0 1 5). A m o n g H C V patie nts wit h dec o m pe ns at e d cirr h osis ( A S T R A L -4), S V R 1 2 rat es were  als o 
acce pt a bl y hi g h ( 8 3 %) if S O F/ V E L was t a ke n f or 1 2 wee ks wit h o ut ri ba viri n, a n d hi g her ( 9 4 %) 
if t a ke n wit h ri ba viri n ( C urr y et al., 2 0 1 5).  T he m ost c o m m o n a d verse e ve nts ( A Es), o cc urri n g 
i n ≥ 1 0 % of S O F/ V E L-tr eat e d s u bjects, were hea d ac he a n d fati g u e ( E pcl usa [ U. S. pac ka ge 
i ns ert] 2 0 1 7). A n esti mat e d 0. 2 % of s u bjects recei vi n g 1 2 wee ks of S O F/ V E L treat me nt 
dis c o nti n ue d dr u g d ue t o A Es ( C urr y et al., 2 0 1 5; Fel d et al., 2 0 1 5; F ost er et al., 2 0 1 5; E pcl usa 
[ U. S. pac ka ge i nsert] 2 0 1 7). 
S of os b u vir/ vel p at as vir gi ve n f or 1 2 wee ks i n A S T R A L 1 -4 was als o ass o ciat e d wit h hi g h S V R 
r at es des pit e t he pr ese nce of pr etr eat me nt N S 5 A or N S 5 B resist a nce -ass o ciat e d varia nts ( R A Vs); 
i n t h ose patie nts wit h pr etr eat me nt R A Vs, S V R 1 2 was ac hie ve d i n 1 0 0 % ( 8 5/ 8 5) wit h N S 5 B 
R A Vs a n d 9 7 % ( 4 3 7/ 4 5 2) wit h N S 5 A R A Vs ( C urr y et al., 2 0 1 5; Fel d et al., 2 0 1 5; F ost er et al., 
2 0 1 5). S of os b u vir/ vel pa t as vir has ma n y fa v ora ble c haract eristics t hat ma y ma k e it a n i deal 
c o m p o ne nt of a n ultr as h ort D A A r e gi me n.  

Pr ot o c ol C DI -3 1 2 4 4 -P 2 -0 0 1  
C O N FI D E N TI A L  
1 6  
Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
1. 1. 3. 
C DI - 3 1 2 4 4 
C DI -3 1 2 4 4 is a n i n vesti gati o nal a ge nt t hat is a n o vel, hi g hl y p ot e nt, selecti ve N NI of t he H C V 
R N A -de pe n de nt R N A p ol y mer as e a n d w it h e xcelle nt a nti viral acti vit y acr oss all ge n ot y pes 
( C o cr yst al P har ma, I nc., dat a o n file). C DI-3 1 2 4 4 is desi g ne d t o deli ver hi g h dr u g 
c o nce ntr ati o ns t o t he li ver a n d is hi g hl y sele cti ve a gai nst H C V p ol y merase wit h n o rele va nt i n 
vitr o effects a gai nst h u ma n D N A a n d R N A p ol y merases ( C o cr yst al P har ma, I nc., dat a o n file). 
I n t he P hase 1 b p orti o n of t he st u d y t hat e val uat e d patie nts wit h H C V ge n ot y p e 1 ( St u d y n o. 
C DI - 3 1 2 4 4-P 1 -0 0 1), C DI -3 1 2 4 4 at a t ot al dail y d ose of 4 0 0 m g (eit her 2 0 0 m g t wice dail y or 
4 0 0 m g o nce dail y) or 6 0 0 m g f or 7 da ys res ult e d i n mea n H C V R N A viral l o a d re d ucti o ns of  3. 0 
l o g1 0 I U/ m L b y 4 8 h o urs.  C DI-3 1 2 4 4 as a o nce a da y m o n ot hera p y res ult e d i n great er me a n 
H C V R N A vir al l o a d decli ne c o m par e d t o dasa b u vir ( 0. 9 5 l o g 1 0) t he o nl y a p pr o ved N NI 
( P o c kr os 2 0 1 3).  As s uc h, C DI-3 1 2 4 4 is a str o n g ca n di dat e t o c o m bi ne wit h S O F/ V E L t o 
e val uat e its p ot e ntial as a hi g hl y effecti ve a n d safe ultras h ort D A A  re gi me n. 
T he p har mac o ki netics of C DI -3 2 1 4 4 ha ve bee n st u die d i n si n gle a n d m ulti ple asc e n di n g d o ses i n 
healt h y a n d H C V -i nfect e d s u bje cts ( St u d y n o. C DI- 3 1 2 4 4-P 1 -0 0 1).  Aft er a d mi nistrati o n of 
si n gle d oses r a n gi n g fr o m 2 0 m g t o 4 0 0 m g t o healt h y s u bjects u n der fast e d c o n diti o ns, t he mea n 
C DI -3 2 1 4 4 plas ma c o nce ntr ati o ns a n d val ues f or ma xi m u m plas ma c o nce ntrati o n ( C ma x ) a n d 
ar ea u n der t he c ur ve t o i nfi nit y ( A U C 0- ∞) i ncrease d i n a d ose-relat e d ma n ner wit h a mea n 
eli mi nati o n half-life (t ½) at t he hi g her d oses ra n gi n g fr o m 2. 9 1 t o 1 2. 6 h o urs.  A d mi nistrati o n of 
a 2 0 0 m g d ose wit h a st a n dar d hi g h fat/ hi g h c al orie meal a p peare d t o decrease t he rat e b ut n ot 
t he e xt e nt of a bs or pti o n. Aft er a d mi nistrati o n of 2 0 0 m g or 4 0 0 m g o nce dail y f or 7 da ys t o 
healt h y s u bjects, t her e was a d ose -r elat e d i ncreas e i n Cma x a n d A U C 0- 2 4 wit h mea n t ½ o n da y 7  of  
1 4. 0 hr ( 2 0 0 m g gr o u p) a n d 7. 6 2 hr ( 4 0 0 m g gr o u p), c o nsist e nt wit h t hat aft er a si n gle d ose.  
A d mi nistr ati o n of 2 0 0 m g t wice a da y a n d 4 0 0 m g a n d 6 0 0 m g o nce dail y t o H C V -i nfect e d 
s u bje cts r es ult e d i n d ose-r elat e d i ncr eases i n Cma x a n d A U C f or t he d osi n g i nt er val — A U C 0- 1 2 
f or t wice dail y a n d A U C0- 2 4 f or o nce dail y. T he me a n t ½ ra n ge d fr o m 1 5. 8 t o 1 9. 8 h o urs, hi g her 
t ha n t hat f or healt h y s u bjects. T he A U C a n d Cma x aft er d osi n g f or 7 da ys were a b o ut 1. 5- t o 3- 
f ol d hi g her i n H C V-i nfe ct e d s u bjects w he n c o m pare d wit h a healt h y p o p ulati o n f or si milar d ose 
le vels ( 2 0 0 m g a n d 4 0 0 m g) f oll o wi n g ac ut e ( da y 1) a n d e xt e n de d e x p os ure ( da y 7), a n d t he 
mea n t ½ was l o n ger, s u g gesti n g a p ossi bl y l o wer cleara nce i n H C V -i nfect e d s u bje cts. 
T he met a b olis m of C DI -3 1 2 4 4 was i n vesti gat e d i n h u ma ns  usi n g plas ma sa m ples c ollect e d fr o m 
healt h y v ol u nt eers w h o partici pat e d i n t he C DI -3 1 2 4 4 P hase 1 st u d y ( St u d y n o. C DI - 3 1 2 4 4-P 1 - 
0 0 1). T he plas ma s a m ples o n da y 7 o bt ai ne d fr o m h u ma n s u bjects a d mi nist ere d 4 0 0 m g C DI - 
3 1 2 4 4 wer e a nal yz e d f or t he pr ese nce of  met a b olit es usi n g li q ui d c hr o mat o gra p h y – mass 
s pectr o metr y ( L C-M S) a nal ysis. Met a b olit es were str uct urall y c haract eriz e d base d o n t heir 
r et e nti o n ti mes, acc ur at e mass, a n d t he c haract eristics of t heir fra g me nt i o ns.  C DI-3 1 2 4 4 was 
o ne of t he m ost a b u n da nt cir c ulati n g e ntities i n t he h u ma n plas ma base d o n relati ve a b u n da nce 
meas ur e d b y hi g h -r es ol uti o n M S pea k area ( 2 3-2 7 %). Ni ne met a b olit es of C DI -3 1 2 4 4 were 
c har act erize d i n h u ma n plas ma.  T he t hree m ost pr o mi ne nt met a b olit es were M 4 0 2 or M 9  

Pr ot o c ol C DI -3 1 2 4 4 -P 2 -0 0 1  
C O N FI D E N TI A L  
1 7  
Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
 
( m olec ular mass 4 0 2; 2 0 % a b u n da nce) f or me d b y N-deal k ylati o n of C DI -3 1 2 4 4; M 5 0 2 or M 7 
( m olec ular mass 5 0 2; 2 3-3 2 % a b u n da nce), a n O -deal k ylati o n met a b olit e als o see n i n rat a n d d o g 
plas ma; a n d M 6 7 8 or M 2 ( m olec ular mass 6 7 8; 1 8 -2 5 % a b u n da nc e), a gl uc ur o ni d e c o nj u gat e of  
M 7. T her e wer e 3 ot her met a b olit es > 1 % relati ve a b u n da nce — M 4 1 8 or M 5 ( m ole c ular mass 
4 1 8; 1 -5 % a b u n d a nce), a n o xi dati o n a n d N -deal k ylati o n met a b olit e als o see n i n rat plas ma; 
M 4 8 8 or M 8 ( m olec ular mass 4 8 8; 2 % a b u n da nce) a n O -deal k ylati o n met a b olit e al s o see n i n d o g 
plas ma; a n d M 7 9 8 or M 1 2 ( m olec ular mass 7 9 8; 4 % a b u n d a nce), a gl uc ur o ni de c o nj u gat e of 
C DI -3 1 2 4 4 als o see n i n r at a n d d o g plas ma. All of t hese mai n h u ma n met a b olit es were 
r e pr ese nt e d i n r at a n d/ or d o g plas ma t a ke n fr o m t he 1 4-da y ( G o o d La b or at or y Practice) G L P 
t o xic ol o g y st u dies. 
Base d o n i n vitr o r eacti o n p he n ot y pi n g, C DI -3 1 2 4 4 met a b olis m w as pri maril y me diat e d b y 
C Y P 3 A 4 ( < 2 % r e mai ni n g o ver 6 0 mi n ut es i nc u bati o n) wit h a lesser c o ntri b uti o n fr o m C Y P 2 C 8 
( 6 0-8 5 % r e mai ni n g). C Y Ps 1 A 2, 2 B 6, 2 C 9,  2 C 1 9, a n d 2 D 6 s h o we d mi ni mal or n o C DI - 3 1 2 4 4 
t ur n o ver. C he mical i n hi biti o n de m o nstrat e d i n hi biti o n of C DI-3 1 2 4 4 met a b olis m ra n gi n g 
bet wee n 1 7 t o 5 3 % b y selecti ve i n hi bit ors f or C Y Ps 2 B 6, 2 C 8, 2 C 9, 2 C 1 9, 2 D 6 a n d 3 A 4, w hile 
t he i n hi bit or f or C Y P 1 A 2 ha d n o effect. C ollecti vel y, t he res ults of t hese t w o a p pr o ac hes 
i n dicat e t hat t he C Y P met a b olis m of C DI 3 1 2 4 4 is br o a dl y base d acr oss t he maj or h u ma n C Y Ps 
wit h t he e xc e pti o n of C Y P 1 A 2, a n d s u g g ests mi ni mal li keli h o o d t hat C DI -3 1 2 4 4 w o ul d be 
i n v ol ve d i n a C Y P i n hibiti o n -me diat e d dr u g -dr u g i nt eracti o n.  
A n  i n  vitr o  st u d y  e val uat e d  t he  met a b olic  st a bilit y  of  C DI-3 1 2 4 4,  s of os b u vir,  a n d 
vel pat as vir al o ne a n d i n c o m bi nati o n usi n g cr y o preser ve d h u ma n he pat o c yt es. N o met a b olic 
t ur n o ver was o bser ve d wit h vel pat as vir, c o nsist e nt wit h t he re p ort e d mi ni mal met a b olic t ur n o ver 
of t his c o m p o u n d i n h u ma ns. I nc u bati o ns of eit her C DI -3 1 2 4 4 or s of os b u vir wit h h u ma n 
he pat o c yt es e x hi bit e d e xt e nsi ve met a b olic t ur n o ver.  Met a b olic t ur n o ver dat a wit h C DI - 3 1 2 4 4 
a n d s of os b u vir i n tri ple c o m bi nati o n wit h vel p at as vir pr o d uce d 2 0 % a n d 3 0 % re d ucti o ns i n t heir 
clear a nc e val ues, r es pecti vel y. Ge ner all y, l o w -le vel d ecreases i n t he met a b olic t ur n o ver of C DI- 
3 1 2 4 4 a n d s of os b u vir wer e f o u n d i n t his i n vitr o st u d y, w hic h i n relati o n t o t he nor mal varia bilit y 
of dr u g plas ma c o nce ntr ati o ns i n h u ma ns, a n d t he ma n y ot her pr o cesses affe cti n g dr u g 
dis p ositi o n ar e n ot e x pect e d t o tr a nslat e i nt o P K e x p os ure c ha n ges i n viv o i n patie nts. 
T he uri nar y e xcr eti o n of C DI -3 1 2 4 4 o ver 1 2 0 h o urs was st u die d i n 3 0 healt h y s u bjects f oll o wi n g 
si n gle or al d oses ( 2 0, 5 0, 1 0 0, 2 0 0 a n d 4 0 0 m g) u n der b ot h fasti n g a n d fe d c o n diti o ns ( St u d y n o. 
C DI - 3 1 2 4 4-P 1 -0 0 1). F or t h ose s u bjects/c o h orts i n w hic h uri ne c o nce ntrati o ns were a b o ve t he 
l o wer li mit of q ua ntit ati o n, uri nar y excreti o n acc o u nt e d f or < 0. 0 1 % of t he d ose. T his i n dic at es 
t hat met a b olis m is t he pri mar y r o ut e of eli mi nati o n of C DI- 3 1 2 4 4. 
I n st u dies i n h u ma n li ver micr os o mes, C DI-3 1 2 4 4 ha d l o w direct i n hi bit or y p ot e nc y f or C Y P 2 B 6 
(I C5 0 = 3 3 µ M), C Y P 2 C 8 (I C 5 0 = 2 0 µ M),  C Y P 2 C 9 (I C 5 0 = 1 4 µ M) a n d C Y P 2 C 1 9 (I C 5 0 = 2. 1  
µ M) a n d mi ni mal le vels of dir ect i n hi biti o n ( ≤1 8 % at 1 0 µ M) f or C Y P 1 A, C Y P 2 D 6, a n d 
C Y P 3 A.  N o e vi de nce of ti me -de p e n de nt i n hi biti o n was o bser ve d.  T he mea n t ot al C ma x o n da y 7  

Pr ot o c ol C DI -3 1 2 4 4 -P 2 -0 0 1  
C O N FI D E N TI A L  
1 8  
Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
 
aft er a d mi nistr ati o n of 4 0 0 m g o nce dail y t o H C V -i nfect e d s u bjects  was 5 3 0 ng/ m L, e q ui vale nt 
t o 0. 8 5 µ M ( St u d y n o. C DI- 3 1 2 4 4-P 1 -0 0 1). Base d o n 9 9. 2 % bi n di n g -t o-plas ma pr ot ei n, t his 
r e pr ese nts a n u n b o u n d c o nce ntr ati o n of 0. 0 0 6 8 µ M. T he ass o ciat e d A U C rati o f or t he m ost 
se nsiti ve C Y P ( C Y P 2 C 1 9; I C 5 0 = 2. 1 µ M → Ki = 1. 0 5) is 1. 0 0 3, be l o w t he t hres h ol d of 1. 0 2 t hat 
i n dicat es t he nee d f or a cli nical D DI ( dr u g-dr u g i nt eracti o n) st u d y. C DI -3 1 2 4 4 is t heref ore 
u nli kel y t o i n hi bit a n y of t he C Y P 4 5 0 e nz y mes.  
T he p ot e ntial i n hi bit or y effects of C DI -3 1 2 4 4 were st u die d o n a ra n ge of h u ma n tra ns p o rt ers 
i ncl u di n g P-g p ( P -gl yc o pr ot ei n), B C R P, O C T 2, O A T 1, O A T 3, O A T P 1 B 1, O A T P 1 B 3, O C T 1, 
a n d M R P 2. C DI -3 1 2 4 4 s h o we d i n hi bit or y acti vit y f or O A T 3, O A T P 1 B 1 a n d O A T P 1 B 3 
tr a ns p ort ers t hat di d n ot i n dicat e p ot e ntial f or D DI. 
T he a ntici pat e d u n b o u n d C DI -3 1 2 4 4 C ma x  c o nce ntrati o n, 0. 0 0 6 8 µ M, f or t he 4 0 0 m g d ose i n t his 
pr o p ose d st u d y ( calc ulat e d da y 7 P hase 1 b st u d y P K dat a) is t hree or ders of ma g nit u de l o wer 
t ha n t he c o nce ntr ati o n ( 1 0 µ M) t hat s h o we d p ot e ntial C Y P 2 B 6 i n d u cti o n. C o nse q u e ntl y, n o 
i n d ucti o n-me diat e d i m pact of C DI -3 1 2 4 4 o n t he e x p os ure t o s u bstrat es of t hese C Y P e nz y mes is 
pr e dict e d. H o we ver, si nce S O F a n d V E L are C Y P 2 B 6 s u bstrat es ( E pcl usa [ U. S. pac ka ge i nsert] 
2 0 1 7), t he p ot e ntial f or r e d uce d e x p os ure t o b ot h dr u gs s h o ul d be assesse d b y m o nit ori n g of 
p las ma c o nce ntr ati o ns. 
C DI -3 1 2 4 4 is a s u bstr at e of P -g p, w hic h ma y p ose s o me D DI p ot e ntial wit h dr u gs t hat are P - g p 
i n hi bit ors. 
M or e det aile d i nf or mati o n a b o ut C DI -3 1 2 4 4 ca n be f o u n d i n t he I n vesti gat or’s Br o c h ure.  
T he pri mar y o bjecti ve of t he c urr e nt st u d y  is t o e val uat e t he effect of 2 wee ks of t he hi g hl y 
p ot e nt N NI C DI -3 1 2 4 4 c o m bi ne d wit h 6 wee ks of S O F/ V E L treat me nt o n S V R rat es i n H C V 
ge n ot y pe 1 -i nfect e d s u bje cts. I n a d diti o n, t he st u d y will als o e val uat e ki netics of circ ulati n g 
H C V R N A d uri n g tr eat me nt , a n d t he p har mac o ki netics of C DI-3 1 2 4 4 d uri n g treat me nt.  
1. 2.  
Ris k/ Be nefit  Assess me nt  
T he m ost c o m m o n si de effects i n t he p hase 1a st u d y of healt h y v ol u nt eers recei vi n g C DI - 3 1 2 4 4 
wer e hea dac hes ( 2/ 3 0 s u bjects, or 7 %) i n t he si n gle asce n di n g d ose c o h ort a n d d ys ge usia ( 2/ 1 2 
s u bje cts, or 1 7 %) i n t he m ulti ple asce n di n g d ose c o h ort ( C o cr yst al P har ma, I nc., dat a o n file).  
O ne healt h y v ol u nt eer (r ecei vi n g a si n gle d ose of C DI -3 1 2 4 4 1 0 0 m g) e x perie nce d a gra de 4 A E 
t o xicit y r elat e d t o a n ele vat e d cr eati ne ki nase ( C K) that o cc urre d o n st u d y da y 4 aft er d osi n g a n d 
was j u d ge d b y t he i n vesti gat or t o be r elat e d t o st u d y dr u g. C K -M B val ues were n or mal. T his A E 
was n ot ass o ciat e d wit h si g ns a n d s y m pt o ms of m y o pat h y, a n d res ol ve d at f oll o w -u p t esti n g o n 
da y 1 4. It is n ot e w ort h y  t hat t he s u bject ha d a si milar as y m pt o matic gra de 4 t o xicit y of ele vat e d 
C K t hat was j u d ge d t o be r elat e d t o st u d y dr u g i n a pri or o pe n -la bel st u d y wit h a n i n vesti gati o nal 
t yr osi ne ki nase i n hi bit or. T he m ost c o m m o n si de effe cts i n t he P hase 1 b st u d y of s u bjects wit h 
c hr o nic H C V ge n ot y pe 1 i nfe cti o n r ecei vi n g C DI -3 1 2 4 4 2 0 0 m g t wic e dail y, 4 0 0 m g o nce dail y,  

Pr ot o c ol C DI -3 1 2 4 4 -P 2 -0 0 1  
C O N FI D E N TI A L  
1 9  
Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
 
or 6 0 0 m g o nce dail y f or 7 da ys wer e hea dac he ( 4/ 1 6 s u bjects, 2 5 %) a n d nasal c o n g esti o n ( 2/ 1 6 
s u bje cts, 1 2 %). 
T he A E dat a f or S O F/ V E L ( E pcl usa) i n pa tie nts wit h o ut cirr h osis or wit h c o m p e nsat e d cirr h osis 
wer e deri ve d fr o m t hr ee P hase 3 cli nical trials ( A S T R A L - 1, -2, a n d -3) t hat e val uat e d 1 0 3 5 
s u bje cts i nfect e d wit h ge n ot y p e 1-6 H C V, wit h o ut cirr h osis or wit h c o m pe nsat e d cirr h osis.  
S u bjects r ecei ve d S O F/ V E L f or 1 2 wee ks. T he m ost c o m m o n A Es t hat were j u d ge d t o be relat e d 
t o st u d y dr u g i n patie nts r ecei vi n g S O F/ V E L were hea d ac he ( 2 2 %), fati g ue ( 1 5 %), na usea ( 9 %), 
ast he nia ( 5 %) a n d i ns o m nia ( 5 %) ( E pcl us a [ U. S. pac ka ge i nsert] 2 0 1 7). M ost of t hese A Es were  
mil d i n i nt e nsit y. T he pr o p orti o n of s u bjects w h o per ma ne ntl y dis c o nti n ue d treat me nt d ue t o A Es 
was 0. 2 % f or s u bjects r ecei vi n g S O L/ V E L f or 1 2 wee ks ( E pcl usa [ U. S. pac ka ge i ns ert] 2 0 1 7). I n 
A S T R A L -1, is olat e d, as y m pt o matic C K ele vati o ns ≥1 0 ti mes U L N were re p ort e d i n 1 % of 
s u bje cts tr eat e d wit h S O F/ V E L a n d n o s u bje cts treat e d wit h plac e b o f or 1 2 wee ks; a m o n g 
s u bje cts tr eat e d wit h S O F/ V E L, si milar C K ele vati o ns ( ≥ 1 0 ti mes U L N) were re p ort e d i n 2 % of 
s u bje cts i n A S T R A L-2 a n d 1 % of s u bjects i n A S T R A L - 3. 
He patitis B vir us ( H B V) r eacti vati o n has be e n re p ort e d i n H C V/ H B V c oi nfect e d patie nts w h o 
wer e r ecei vi n g or ha d c o m plet e d tr eat me nt wit h H C V D A As, a n d w h o were n ot recei vi n g H B V 
ther a p y. H B V r eacti vati o ns wer e c har act erize d b y a n a br u pt i ncreas e i n H B V re plic ati o n a n d 
wer e acc o m pa nie d i n s o me cases b y ac ut e he patitis (i. e., i ncreases i n ser u m a mi n otra nsferase 
le vels) a n d, i n r ar e cases, li ver fail ur e a n d deat h ( Bers off-Mat c ha et al ., 2 0 1 7; E pcl usa [ U. S. 
pac ka ge i nsert] 2 0 1 7).  As s uc h, t he c urre nt st u d y will e xcl u de patie nts wit h acti ve H B V 
i nfecti o n. I n patie nts r ecei vi n g a mi o dar o ne, c o a d mi nistrati o n of S O F-c o nt ai ni n g re gi me ns ca n 
ca use seri o us s y m pt o matic br a d yc ar dia res ulti n g i n pace ma ker i nt er ve nti o n a n d fat al car diac 
arr est (t he latt er wit h use of Har v o ni [le di pas vir -s of os b u vir] ( E pcl us a [ U. S. pac ka ge i nsert] 
2 0 1 7). Br a d ycar dia has ge ner all y o cc urre d wit hi n h o urs t o da ys, b ut cases ha ve bee n o bser ve d u p 
t o 2 wee ks aft er i nitiatin g H C V tr eat me nt. Patie nts als o t a ki n g bet a -bl o c ker dr u gs, or t h ose wit h 
u n derl yi n g car diac c o m or bi dities or a d va nce d li ver disease, ma y be at i ncrease d ris k f or 
s y m pt o matic br a d ycar dia wit h c o a d mi nistrati o n of a mi o dar o ne. D ue t o t his c o ncer n, patie nts 
r ecei vi n g a mi o d ar o ne wit hi n 1 8 0 da ys bef ore st u d y e ntr y or are e x pect e d t o recei ve a mi o dar o ne 
d uri n g t he st u d y peri o d will be e xcl u de d fr o m t he c urre nt st u d y. Fi nall y, t here is als o a p ot e ntial 
ris k f or s u bjects t o de vel o p m ulticlass dr u g resist a nce if treat me nt i n t his st u d y is u ns u ccessf ul.  
T her e is a p ot e ntial be nefit f or st u d y partici pa nts of viral s u p pressi o n a n d era dicati o n (c ure) of 
H C V. Ac hie vi n g c ur e wit h S O F/ V E L a n d ot her D A As has res ult e d i n re versal of li ver fi br osis, 
as well as r e d ucti o ns i n li ver -r elat e d m ort alit y, H C C, a n d li ver dec o m p e nsati o n ( West br o o k a n d 
D us hei k o, 2 0 1 4). Dat a gat her e d fr o m t his st u d y ma y als o lea d t o t he e ve nt ual de vel o p me nt of a 
ne w safe a n d effecti ve tr eat me nt t hat s u bst a ntiall y s h ort e ns t he c urre nt c o urse of treat me nt f or 
patie nts wit h c hr o nic H C V i nfe cti o n.  

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2.  
O B J E C TI V E S  
•  T he pri mar y o bjecti ve of t his st u d y is t o assess t he safet y, t olera bilit y, a n d 
pr eli mi nar y effica c y of s h ort d urati o n c o m bi nati o n treat me nt wit h C DI -3 1 2 4 4 pl us 
S O F/ V E L i n s u bjects wit h c hr o nic H C V ge n ot y p e 1 i nfecti o n. 
•  Safet y ( a n d t oler a bilit y) will be e val uat e d usi n g a d verse e ve nt, p h ysical e xa mi nati o n 
(i ncl u di n g vit al si g ns), electr o car di o gra m ( E C G), a n d cli nic al la b orat or y dat a. 
P har mac o ki netics will be e val uat e d b y plas ma c o nce ntrati o ns of C DI -3 1 2 4 4, S O F, 
G S -3 3 1 0 0 7 a n d V E L. Vir al ki netics will be e val uat e d b y serial plas ma H C V  le vels. 
•  Efficac y will be e val uat e d b y H C V R N A le vels b y t he f oll o wi n g pri mar y a n d 
sec o n dar y e n d p oi nts:  
Pri mar y efficac y e n d p oi nt:  
•  Pr o p orti o n of s u bjects w h o ac hie ve s ust ai ne d vir o l o gic res p o nse 1 2 wee ks aft er 
c o m pleti o n of tr eat me nt  ( S V R 1 2). 
Sec o n dar y efficac y e n d p oi nts:  
•  Pr o p orti o n of s u bjects w h o ac hie ve s ust ai ne d vir ol o gic res p o nse 2 4 wee ks aft er 
c o m pleti o n of tr eat me nt  ( S V R 2 4). 
•  Ti me t o ac hie ve H C V R N A le vels bel o w t he l o wer li mit of q ua ntificati o n  ( L L O Q). 
•  Pr o p orti o n of s u bjects wit h H C V R N A < L L O Q aft er Da y 7 a n d Da y 1 4 of  C DI - 
3 1 2 4 4 pl us S O F/ V E L  tr eat me nt. 
•  Pr o p orti o n of s u bjects wit h H C V R N A < L L O Q aft er Da y 7 a n d Da y 1 4 of  C DI - 
3 1 2 4 4 pl us S O F/ V E L tr eat me nt b y g e n ot y p e 1a or  1 b.  
E x pl or at or y e n d p oi nts ( usi n g st or e d bl o o d) will i n cl u de:  
•  I m m u n ol o gic, vir ol o gic, a n d h ost ge netic/ pr ot e o mic pre dict ors of res p o nse t o t hera p y. 
•  Effect of t her a p y o n peri p heral mar kers of T cell  a cti vati o n.  

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3.  
I N V E S TI G A TI O N A L P L A N  
3. 1.  
S u m m ar y of St u d y  Desi g n  
T hi s is a si n gle ce nt er, o pe n-la bel p hase 2a st u d y t o e val uat e t he safet y, t olera bilit y, a n d 
pr eli mi nar y effica c y of tr eat me nt wit h 2 wee ks of a n oral N NI C DI -3 1 2 4 4 c o m bi ne d wit h 6 
wee ks of S O F/ V E L i n a d ult s u bjects wit h c hr o nic H C V ge n ot y pe 1 vir us i nfe cti o n . O ne sit e is 
pla n ne d t o partici pat e: I nstit ut e of H u ma n Vir ol o g y (I H V), U ni versit y of Mar yla n d, Balti m ore, 
M D. Cli nic visits will o cc ur at scr ee ni n g a n d baseli ne, a n d t hr o u g h st u d y wee k 3 0. A d verse 
e ve nts will be c olle ct e d t hr o u g h st u d y wee k 3 0.  
Safet y e v al u ati o ns will c o nsist of a d vers e e ve nt, p h ysic al e xa mi nati o n (i ncl u di n g vit al si g ns), 
E C G, a n d cli nical la b or at or y dat a. Effic ac y a n d vir al ki netics will be e val uat e d b y H C V R N A 
le vels. P har ma c o ki netics will be e val uat e d b y plas ma C DI-3 1 2 4 4, S O F, G S - 3 3 1 0 07 a n d V E L 
c o nce ntr ati o ns.  
Fi g ure  1: 
Ill ust r ati o n of St u d y Desi g n  
3. 2.  
O utli ne of Visit  Sc he d ule  
Als o see Sc he d ule of E ve nts, A p pe n di x A . 
 
3. 2. 1.  
Scre e ni n g a n d B aseli ne  E v al u ati o ns 
 
3. 2. 1. 1.  
Scre e ni n g E v al u ati o ns ( D a y – 4 2 t o  - 7) 
T he f oll o wi n g scr ee ni n g assess me nts m ust be d o ne  t o det er mi ne s u bject eli gi bilit y. Writt e n 
c o nse nt will be o bt ai ne d bef or e c o n d ucti n g a n y st u d y pr o ce d ures.  
•  Scr ee n f or i ncl usi o n/e xcl usi o n crit eria (see Secti o n  5 ). 
•  Me dical  hist or y.  
•  P h ysic al e xa mi nati o n, i ncl u di n g wei g ht, hei g ht, a n d vit al si g ns ( bl o o d pre ss ure, 
r es pir at or y r at e, heart r at e, a n d t e m perat ure). 
•  Met a b olic pa nel (ser u m c o nce ntrati o ns of s o di u m, p ot assi u m, c hl ori d e, t ot al  bilir u bi n, 
al kali ne p h os p hat ase, ala ni ne tra nsa mi nase [ A L T], as part at e tra nsa mi nas e [ A S T], 
bl o o d ur ea nitr o ge n [ B U N], creati ni ne, uric aci d, c alci u m, gl uc ose, t ot al pr ot ei n, 
al b u mi n, c h olest er ol, li pase, creati ne ki nase  [ C K]). 

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•  C o m plet e bl o o d c o u nt [ he m o gl o bi n, he mat o crit, er yt hr o c yt e c o u nt ( R B C), mea n cell 
v ol u me ( M C V), se g me nt e d ne utr o p hils, l y m p h o c yt es, m o n o c yt es, e osi n o p hil s, 
bas o p hils, plat elets, cell  m or p h ol o g y].  
•  C o a g ulati o n ( C o a g ulati o n: pr ot hr o m bi n ti me [ P T], partial t hr o m b o plasti n ti me [ P T T], 
i nt er nati o nal n or malize d r ati o [I N R]). 
•  1 2- lea d electr o car di o gr a m ( E C G). 
•  Fi br o T est/ Fi br o S ur e t est, if n o assess me nt of li ver fi br o sis b y bi o ps y, fi br osca n, or 
Fi br o T est/ Fi br o S ur e has bee n c o n d uct e d wit hi n 1 year of  scree ni n g. 
•  He patitis B s urface a nti ge n ( H Bs A g), he patitis B s urfa ce a nti b o d y ( H Bs A b), a n d 
he patitis B c or e a nti b o d y ( H Bc A b). He patitis B D N A P C R will be d o ne if p ositi ve 
for H Bc A b b ut ne gati ve f or b ot h H Bs A g a n d  H Bs A b.  
•  H u ma n i m m u n o deficie nc y vir us ( HI V)  a nti b o d y.  
•  Plas ma H C V R N A  le vel. 
•  H C V  ge n ot y pi n g. 
•  Uri ne t o xic ol o g y scr ee n (f or a m p het a mi nes a n d  c o cai ne).  
•  Ser u m bet a h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y t est f or fe ma les of 
c hil d beari n g p ot e ntial ( defi ne d as a w o ma n w h o is p h ysi ol o gicall y ca pa ble of 
bec o mi n g  pr e g na nt).  
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
3. 2. 1. 2.  
B aseli ne E v al u ati o ns a n d First D ose of St u d y Dr u g ( D a y  1) 
Scr ee ni n g t ests ( e. g., sele ct la b or at ories) m ust b e a vaila ble bef ore t he s u bject is eli gi ble f or st u d y 
partici pati o n. O nce scr ee ni n g is c o m plet e d a n d t he s u bject meets all eli gi bilit y crit eria, t he 
s u bje ct will o bt ai n bas eli ne e val u ati o ns.  St u d y dr u g a d mi nistrati o n ma y o cc ur aft er c o m pleti o n 
of all basel i ne pr o ce d ur es. 
B ef ore St u d y Dr u g A d mi nist r ati o n:  
•  Re vie w eli gi bilit y crit eria a n d c o nfir m eli gi bilit y of  s u bject. 
•  O bt ai n c o m plet e me dic al  hist or y.  
•  P h ysic al e xa mi nati o n, i ncl u di n g wei g ht a n d vit al si g ns ( bl o o d press ure  [ B P], 
r es pir at or y r at e [ R], heart r at e [ H R], a n d t e m perat ure [ T]). 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n 
•  1 2- lea d E C G.  

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•  Plas ma H C V R N A  le vel. 
•  Met a b olic pa nel.  
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Uri ne bet a h C G pr e g na nc y t est f or fe males of c hil d beari n g  p ot e ntial. 
•  Bl o o d f or P A X ge ne R N A a n d D N A  a nal ysis.  
•  I L 2 8 B ge n ot y pi n g. 
•  Bl o o d f or H C V r esist a nc e assa ys.  
•  Bl o o d sa m ple f or meas ur e me nt of plas ma c o nce ntrati o ns of C DI -3 1 2 4 4, S O F,  G S - 
3 3 1 0 0 7 a n d  V E L.  
•  Bl o o d f or st or a ge of plas ma, ser u m, a n d peri p heral bl o o d m o n o n uclear cells 
( P B M Cs) f or f ut ur e r esear c h p ur p oses. 
St u d y Dr u g A d mi nist r ati o n ( a n d P ost -St u d y Dr u g Assess me nt):  
•  A d mi nist er first d ose of C DI -3 1 2 4 4 a n d  S O F/ V E L.  
•  Dis p e nse st u d y dr u g s u p pl y (re mai n der of 7 - da y s u p pl y). 
•  Rei nf or ce st u d y dr u g i nstr ucti o n: s u bjects are t o t a ke 8 C DI -3 1 2 4 4 ca ps ules a n d 1 
t a blet of S O F/ V E L u p o n a wa ke ni n g wit h at least 8 o z. of plai n wat er.  
•  Plas ma H C V le vels at 2, 4, a n d 6 h o urs aft er first d ose of st u d y  dr u g. 
•  Dis p e nse St u d y Dr u g  Diar y.  
•  C ollect a d vers e e ve nt  i nf or mati o n 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
3. 2. 2.  
A d diti o n al St u d y  E v al u ati o ns 
 
3. 2. 2. 1.  
D a ys 2 a n d 3  Visits  
•  O bt ai n i nt er val me dical  hist or y.  
•  O bt ai n wei g ht a n d vit al si g ns ( B P, R, H R,  T).  
•  Plas ma H C V R N A  le vel. 
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 

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•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  ca ps ules/t a blets.  
3. 2. 2. 2.  
D a y 7  Visit  
•  O bt ai n i nt er val me dical  hist or y.  
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  
•  Plas ma H C V R N A  le vel. 
•  Uri ne bet a h C G pr e g na nc y t est f or fe males of c hi l d beari n g p ot e ntial. 
•  Met a b olic pa nel.  
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Bl o o d f or P A X ge ne R N A  a nal ysis.  
•  Bl o o d f or st or a ge of plas ma, ser u m, a n d  P B M Cs.  
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  ca ps ules/t a blets.  
•  Dis p e nse st u d y dr u g s u p pl y ( 7 - da y s u p pl y). 
3. 2. 2. 3.  
D a y 1 0  Visit  
•  O bt ai n i nt er val me dical  hist or y.  
•  C o n d uct wei g ht a n d vit al si g ns ( B P, R, H R,  T).  
•  Plas ma H C V R N A  le vel. 
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  ca ps ules/t a blets.  
3. 2. 2. 4.  
D a y 1 4  Visit  
T his da y is t he e n d of tr eat me nt wit h C DI -3 1 2 4 4 f or all s u bjects.  
S u bjects will be as ke d t o dela y t heir st u d y dr u g o n da y 1 4 u ntil t heir st u d y vi sit t o acc o m m o dat e 
P K sa m pli n g f or plas ma C DI -3 1 2 4 4, S O F, G S -3 3 1 0 0 7, a n d V E L le vels.  
•  O bt ai n i nt er val me dical  hist or y.  

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Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  
•  Bl o o d sa m ple f or meas ur e me nt of plas ma c o nce ntrati o ns of C DI -3 1 2 4 4, S O F,  G S - 
3 3 1 0 0 7, a n d V E L at 0 ( pr e -d ose), 1, 2, 4, 6, 8, a n d 1 2 h o urs aft er  d osi n g.  
•  Plas ma H C V R N A  le vel. 
•  Uri ne bet a h C G pr e g na nc y t est f or fe males of c hil d beari n g  p ot e ntial. 
•  Met a b olic pa nel.  
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Bl o o d f or st or a ge of plas ma, ser u m, a n d  P B M Cs.  
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  ca ps ules/t a blets.  
•  Dis p e nse st u d y dr u g s u p pl y ( 2 8 -da y s u p pl y of  S O F/ V E L).  
3. 2. 2. 5.  
D a y 1 5  Visit  
•  Bl o o d sa m ple f or meas ur e me nt of plas ma C DI -3 1 2 4 4, S O F, G S -3 3 1 0 0 7, a n d V E L 
c o nce ntr ati o n ( a p pr o xi mat el y 2 4 hr aft er da y 1 4  d osi n g). 
3. 2. 2. 6.  
Wee k 3 Visit ( ± 2  d a ys) 
•  O bt ai n i nt er val me dical  hist or y.  
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  
•  Plas ma H C V R N A  le vel. 
•  Bl o o d sa m ple f or meas ur e me nt of plas ma c o nce ntrati o ns of C DI -3 1 2 4 4, S O F,  G S - 
3 3 1 0 0 7, a n d  V E L.  
•  Met a b olic pa nel.  
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 

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C O N FI D E N TI A L  
2 6  
Versi o n 3 . 0: Ma y 2 2 , 2 0 1 8 
 
 
 
•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  ca ps ules/t a blets.  
3. 2. 2. 7.  
Wee k 6 Visit ( ± 3  d a ys) 
T his visit descri bes assess me nts f or t heir e n d of treat me nt visit.  
•  O bt ai n c o m plet e me dic al  hist or y.  
•  C o n d uct c o m plet e p h ysica l e xa mi nati o n, i ncl u di n g wei g ht a n d vit al si g ns ( B P, R, 
H R,  T).  
•  Plas ma H C V R N A  le vel. 
•  Bl o o d sa m ple f or meas ur e me nt of plas ma c o nce ntrati o ns of C DI -3 1 2 4 4, S O F,  G S - 
3 3 1 0 0 7, a n d  V E L.  
•  Uri ne bet a h C G pr e g na nc y t est f or fe males of c hil d beari n g  p ot e ntial. 
•  Met a b ol ic pa nel. 
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Uri nal ysis.  
•  Bl o o d f or P A X ge ne R N A  a nal ysis.  
•  Bl o o d f or st or a ge of plas ma, ser u m, a n d  P B M Cs.  
•  1 2- lea d E C G.  
•  E val uat e Patie nt Diar y a n d n u m ber of use d a n d u n use d  t a blets. 
•  C ollect a d vers e e ve nt  i nf or mati o n. 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n 
F or all s u bjects w h o t er mi nat e st u d y dr u g pre mat urel y, c o nti n ue d assess me nts s h o ul d o cc ur if 
c o nse nt t o d o s o h as n ot bee n wit h dr a w n . F or s u bjects w h o t er mi nat e t he st u d y earl y, t he s u bje ct 
s h o ul d c o m plet e t he e val u ati o ns for t he st u d y wee k 6 visit pr ovi de d t h at writte n c o nse nt t o d o s o 
h as n ot bee n wit h dr a w n . 
3. 2. 2. 8.  
Wee k 8, 1 0, a n d 1 4 Visits ( ± 3  d a ys) 
T his visit descri bes p ost -tr eat me nt assess me nts f or all s u bje cts. 
•  O bt ai n i nt er val me dical  hist or y.  
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  

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•  Plas ma H C V R N A  le vel. 
•  H C V r esist a nce assa y if H C V R N A > 1, 0 0 0  I U/ m L. 
•  Met a b olic pa nel ( wee k 1 0 o nl y).  
•  C o m plet e bl o o d c o u nt ( wee k 1 0  o nl y).  
•  C o a g ulati o n ( wee k 1 0 o nl y).  
•  Bl o o d f or st or a ge of  plas ma, ser u m, a n d  P B M Cs.  
•  C ollect a d vers e e ve nt i nf or mati o n ( wee k 8 a n d 1 0  o nl y).  
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
3. 2. 2. 9.  
Wee k 1 8 Visit ( ± 7  d a ys) 
T his visit descri bes assess me nts f or S V R 1 2, t he pri mar y e n d p oi nt of t he st u d y.  
•  O bt ai n i nt er val me dical  hist or y. 
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  
•  Plas ma H C V R N A  le vel. 
•  H C V r esist a nce assa y if H C V R N A > 1, 0 0 0  I U/ m L. 
•  Met a b olic pa nel.  
•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Bl o o d f or st or a ge of plas ma,  ser u m, a n d P B M Cs.  
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
3. 2. 2. 1 0.  Wee k 3 0 Visit ( ± 1 4  d a ys) 
T his visit descri bes assess me nts f or e n d of st u d y f or all s u bjects.  
•  O bt ai n c o m plet e me dic al  hist or y.  
•  C o n d uct c o m plet e p h ysical e xa mi nati o n, i ncl u di n g wei g ht a n d vit al si g ns ( B P, R, 
H R,  T).  
•  Plas ma H C V R N A  le vel. 
•  H C V r esist a nce assa y if H C V R N A > 1, 0 0 0  I U/ m L. 
•  Met a b olic pa nel.  

Pr ot o c ol C DI -3 1 2 4 4 -P 2 -0 0 1  
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•  C o m plet e bl o o d  c o u nt. 
•  C o a g ulati o n.  
•  Bl o o d f or st or a ge of plas ma, ser u m, a n d  P B M Cs.  
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
3. 2. 2. 1 1.  Ret re at me nt Visits ( ±  7 d a ys) 
T his descri bes assess me nts d uri n g r etr eat me nt wit h st a n dar d of care re gi me n usi n g 
S O F/ V E L/ V O X f or 1 2 wee ks. St u d y visits at i nitiati o n of retreat me nt, 4 -wee ks aft er i nitiati o n of 
r etr eat me nt, at t he e n d of t he 1 2-wee k retreat me nt peri o d, at 4 wee k s aft er c o m pleti o n of 
tr eat me nt, a n d at 1 2 wee ks aft er c o m pleti o n of treat me nt. 
•  O bt ai n i nt eri m me dical  hist or y.  
•  C o n d uct t ar get e d p h ysical e xa mi nati o n (if nee de d), i ncl u di n g wei g ht a n d vit al si g ns 
( B P, R, H R, T).  
•  Plas ma H C V R N A  le vel. 
•  Met a b olic pa nel.  
•  C o m pl et e bl o o d c o u nt. 
•  C ollect a d vers e e ve nt i nf or mati o n (e xc e pt at 1 2 wee ks aft er c o m pleti o n of  treat me nt). 
•  C ollect c o nc o mit a nt me dicati o n  i nf or mati o n. 
S O F/ V E L/ V O X ( 4 -wee k s u p pl y) will be dis pe nse d at i nitiati o n of retreat me nt a n d at 4 wee ks 
aft er i nitiati o n of r etr eat me nt (r e mai ni n g 8-wee k s u p pl y). All b ottles a n d u n use d pills will be 
r et ur ne d b y s u bjects t o t he st u d y t ea m b y t he e n d of t he retreat me nt peri o d visit. T he m ost rece nt 
la bs f or eac h s u bje ct ( plas ma H C V R N A le vels, met a b olic pa nel, a n d c o m plet e bl o od c o u nt) will 
be use d f or t he p ur p ose of t he s u bject’s pre -S O F/ V E L/ V O X bas eli ne.  

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4.  
DI S C U S SI O N O F  D E SI G N  
T his is a si n gle ce nt er, o pe n -la bel p hase 2a st u d y t o e val uat e t he safet y, t olera bilit y, a n d 
pr eli mi nar y effica c y of tr eat me nt wit h 2 wee ks of a n oral  N NI C DI -3 1 2 4 4 c o m bi ne d wit h 6 
wee ks of S O F/ V E L i n a d ult s u bjects wit h c hr o nic H C V ge n ot y pe 1 vir us i nfe cti o n. T his desi g n 
all o ws t he m ost dir ect assess me nt of t he safet y a n d preli mi nar y efficac y of C DI -3 1 2 4 4 c o m bi ne d 
wit h S O F/ V E L i n t his patie nt p o p ulati o n.  
D ose : T he use of c o m bi ne d C DI-3 1 2 4 4 wit h S O F/ V E L is u n k n o w n. C DI -3 1 2 4 4 is a n 
i n vesti gati o nal a ge nt t hat is a n o vel, p ot e nt, a n d selecti ve N NI of t he H C V vir al R N A 
p ol y mer ase. C DI -3 1 2 4 4 has bee n e val uat e d i n a p hase 1a/ 1 b ra n d o mize d, place b o -c o ntr olle d, 
d o u ble- bli n d st u d y i n v ol vi n g b ot h healt h y v ol u nt eers a n d patie nts wit h c hr o nic H C V i nfecti o n 
( St u d y n o. C DI- 3 1 2 4 4-P 1 -0 0 1). T he p hase 1a p orti o n of t he st u d y was c o n d uct e d i n healt h y 
v ol u nt eers a n d i n v ol ve d t w o parts: a si n gle asc e n di n g d ose ( S A D) a n d a m ulti ple asce n di n g d ose 
( M A D) p hase. I n t he S A D p hase, 4 0 healt h y v ol u nt eers ( 3: 1 rati o C DI-3 1 2 4 4: plac e b o) were 
e nr olle d. S u bjects r ecei ve d si n gle d oses of C DI -3 1 2 4 4 (c o h orts of 2 0 m g, 5 0 m g, 1 0 0 m g, 2 0 0 
m g, a n d 4 0 0 m g).  I n t he M A D p hase, 1 6 healt h y v ol u nt e ers were e nr olle d a n d ra n d o mize d i nt o 
3 gr o u ps t o r ecei ve st u d y dr u g o nce dail y f or 7 da ys; 6 s u bjects recei ve d C DI -3 1 2 4 4 2 0 0 m g; 6 
r ecei ve d C DI-3 1 2 4 4 4 0 0 m g; a n d 4 r ecei ve d place b o. Res ults of t he p hase 1a healt h y v ol u nt eer 
S A D/ M A D st u d y s h o we d t hat n o se ri o us A Es wer e re p ort e d a n d n o disc o nti n uati o ns d ue t o A Es 
o cc urr e d. O ne healt h y v ol u nt eer (r ecei vi n g a si n gle d ose of C DI -3 1 2 4 4 1 0 0 m g) ha d a gra de 4 
t o xicit y A E r elat e d t o a n ele vat e d C K t hat o cc urre d o n st u d y da y 4 a n d was j u d ge d b y t he 
i n vesti gat or t o be ass o ciat e d wit h st u d y dr u g. T his A E was n ot ass o ciat e d wit h si g ns a n d 
s y m pt o ms, a n d r es ol ve d o n f oll o w-u p t esti n g o n da y 1 4. C K -M B was n or mal. It is n ot e w ort h y 
t hat t he s u bje ct ha d a si milar as y m pt o matic gra de 4 t o xicit y of ele vat e d C K i n a pri or st u d y 
i n v ol vi n g a n i n vesti gati o nal t yr osi ne ki nase i n hi bit or. T he A E i nci de nc e rat es i n t he S A D p hase 
wer e 2 3 % f or t he C DI -3 1 2 4 4 gr o u ps c o m bi ne d a n d 5 0 % f or t he place b o gr o u p; i n t he M A D 
p hase, A E i nci de nce r at es wer e 2 5 % f or t he C DI -3 1 2 4 4 gr o u ps c o m bi ne d a n d 5 0 % f or t he 
place b o gr o u p.  
T he p hase 1 b p orti o n of t he st u d y e nr olle d 2 0 treat me nt -naï ve s u bjects wit h H C V ge n ot y p e 1 a n d 
a n H C V R N A vir al l o a d ≥ 5 l o g 1 0 I U/ m L. T his st u d y ha d 3 d ose-escalati o n p hases i n v ol vi n g t he 
f oll o wi n g C DI-3 1 2 4 4 r e gi me ns: ( 1) 2 0 0 m g t wic e dail y f or 7 da ys ( n = 3), ( 2) 4 0 0 m g o nce dail y 
f or 7 da ys ( n = 7), a n d ( 3) 6 0 0 m g o nce dail y f or 7 da ys ( n = 6).  F o ur s u bjects recei ve d pla ce b o. 
O ne s u bje ct o n 4 0 0 m g Q D was wit h dr a w n aft er a si n gle d ose a n d was n ot i ncl u de d i n t he 
P K/ P D a nal ysis. T her e we r e n o seri o us A Es re p orte d or disc o nti n uati o ns d ue t o A Es. A d verse 
e ve nt i nci de nce r at es wer e 7 5 % f or t he c o m bi ne d C DI -3 1 2 4 4 gr o u ps a n d 1 0 0 % f or t he place b o 
gr o u p. I n a d diti o n, si milar decli nes i n H C V R N A viral l o a d wit hi n 4 8 h o urs aft er i nitiati o n of 
tr eat me nt ( 3-l o g) wer e o bser ve d i n t he C DI-3 1 2 4 4 4 0 0 m g t ot al dail y d ose c o h orts ( 2 0 0 m g 
t wice dail y, 4 0 0 m g o nce dail y) a n d 6 0 0 m g c o h ort. N o s yst e mic ac c u m ulati o n of C DI- 3 1 2 4 4 

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was o bser ve d aft er 7 -da y tr eat me nt. T his dat a s u p p orts t he use of C DI -3 1 2 4 4 4 0 0  m g as t he 
ma xi m u m dail y d ose i n t he c urr e nt st u d y t o ac hie ve ma xi mal re d ucti o n i n vir al l o a d w hile 
mi ni mizi n g C DI -3 1 2 4 4 e x p os ur e.  
S of os b u vir/ vel p at as vir ( E pcl usa) is a n F D A -a p pr o ve d fi xe d -d ose c o m bi nati o n of s of os b u vir, a n 
H C V n ucle oti de a nal o g N S 5 B p ol y m erase i n hi bit or, a n d vel p at as vir, a n H C V N S 5 A re plic ati o n 
c o m ple x i n hi bit or. T his c o m bi nati o n was a p pr o ve d b y t he F D A i n 2 0 1 6 a n d is i n dic at e d f or t he 
tr eat me nt of ( a) a d ult patie nts wit h c hr o nic H C V g e n ot y pe 1 t hr o u g h 6, b ot h wit h a n d wit h o ut 
cirr h osis, an d ( b) a d ult patie nts wit h dec o m pe ns at e d cirr h osis f or use i n c o m bi nati o n wit h 
ri ba viri n. T he r ec o m me n d e d d ur ati o n of treat me nt is 1 2 wee ks. T he prese nt st u d y will use t he 
fi xe d d ose c o m bi nati o n f or a peri o d of 6 wee ks. 
Safet y E n d p oi nts : T he safet y assess me nts use d i n t his trial are st a n dar d ass ess me nts f or P hase 2a 
st u dies e val uati n g t he safet y of r e peat e d d osi n g. 
Efficac y E n d p oi nts : Assess me nt of q ua ntit ati ve H C V R N A i n plas ma is t he st a n dar d pr o ce d ure 
f or det er mi ni n g effe cti ve ness of H C V t hera p y (i ncl u di n g c ure at S V R 1 2). B ot h pri mar y a n d 
sec o n dar y efficac y e n d p oi nts use q ua ntit ati ve H C V R N A le vels as t he mai n assess me nt meas ure. 
A d diti o nal ass ess me nts i n t he c urr e nt st u d y (e. g., assa ys t o det ect resist a nce -ass o ciat e d varia nts 
a gai nst N S 5 A a n d N S 5 B, a n d v ir al ki netic assa ys) are als o st a n dar d me as ures i n trials of H C V 
t her a pies t hat a d d a d diti o nal val ue. 
Le n gt h of Assess me nt : Effic ac y assess me nts will be e val uat e d t hr o u g h 2 4 wee ks f oll o wi n g 
c o m pleti o n of tr eat me nt. T his peri o d s pa ns a t ot al of 3 0 wee ks f or  all s u bjects. T he 6 -wee k 
peri o d of c o m bi nati o n C DI - 3 1 2 4 4-S O F/ V E L t hera p y is necessar y t o det er mi ne w het her H C V 
c ur e is p ossi ble wit h d ur ati o ns s h ort er t ha n c urre ntl y a p pr o ve d re gi me ns. A bse nce of H C V 
vir e mia aft er 1 2 wee ks of c o m pleti o n of t hera p y is t he st a n dar d f or det er mi nati o n of c ure.  

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5.  
S T U D Y  P O P U L A TI O N  
T he i n vesti gat ors partici pati n g i n t his st u d y ha ve e x pertise i n t he dia g n osis a n d ma na ge me nt of 
patie nts wit h H C V. T he partici pati n g ce nt er is t he I nstit ut e of H u ma n Vir ol o g y, U ni versit y of 
Mar yla n d,  Balti m or e, M D. S u bjects will be recr uit e d fr o m i n vesti gat or a n d s u bi n vesti gat or 
( ass o ciat e i n vesti gat or) cli nical pr actic es a n d referri n g p h ysicia ns. 
I n vesti gat ors will dia g n ose s u bjects wit h H C V bas e d o n hist or y, p h ysic al e xa mi nati o n, a n d 
la b or at or y st u dies. I ncl usi o n crit eria f or t his st u d y i ncl u de patie nts (a ge ≥ 1 8 years) wit h c hr o nic 
H C V ge n ot y pe 1a or 1 b. A ma xi m u m of 4 s u bjects wit h ge n ot y pe 1 b will be e nr olle d.  
Partici p ati o n i n t his st u d y is v ol u nt ar y. T he nat ure of t he st u d y will be f ull y e x plai ne d t o eac h 
s u bje ct d uri n g t he i nf or me d c o nse nt pr o cess. T he s u bjects will ha ve t he o p p ort u nit y t o as k 
q uesti o ns. A n i nf or me d c o nse nt d o c u me nt will t he n be si g ne d b y t he s u bject a n d t he pers o n 
perf or mi n g t he c o nse nt disc ussi o n, a n d ret ai ne d b y t he i n vesti g at or acc or di n g t o G o o d Cli nic al 
Pr actice ( G C P). All d o c u me nts will be ret ai ne d b y t he i n vesti gat or acc or di n g t o G C P. A c o p y 
of t he si g ne d i nf or me d c o nse nt d o c u me nt will be gi ve n t o t he s u bject.  
Eli gi bilit y f or e nr oll me nt will be base d o n t he res ults of s cree ni n g f or t he f oll o wi n g i ncl usi o n a n d 
e xcl usi o n crit eria.  
5. 1.  
I ncl usi o n Criteri a  
Patie nts ma y be i ncl u de d i n t he st u d y o nl y if t he y meet all of t he f oll o wi n g crit eria:  
1.  A ge ≥ 1 8 ye ars at  scr ee ni n g. 
2.  D o c u me nt e d c hr o nic H C V i nfecti o n base d o n a n y of t he  f oll o wi n g: 
•  A nti -H C V a nti b o d y p ositi vit y f or at least 6 m o nt hs pri or t o st u d y  e nr oll me nt.  
•  H C V ge n ot y pe r es ults f or at least 6 m o nt hs i m me diat el y pri or t o st u d y  e nr oll me nt.  
•  H C V R N A pr ese nt i n plas ma b y a se nsiti ve a n d s p ecific assa y f or at least 6  m o nt hs 
pri or t o st u d y  e nr oll me nt. 
•  Hist ol o gic e vi de nce of c hr o nic H C V  i nfe cti o n. 
3.  H C V ge n ot y pe 1a or 1 b i nfecti o n b y H C V ge n ot y pi n g perf or me d at scree ni n g. ( N ot e:  N o 
m or e t ha n f o ur s u bjects wit h H C V ge n ot y pe 1 b will be  e nr olle d).  
4.  Ser u m H C V R N A > 1, 0 0 0 I U/ m L d uri n g  scree ni n g. 
5.  M ust  ha ve a pri mar y car e pr o vi der(s) f or me dical  ma na ge me nt.  
6.  A bse nce of a d va nc e d fi br osis or cirr h osis b y li ver bi o ps y, fi br osca n ( < 8 k Pa) or 
Fi br o T est/ Fi br o S ur e ( F 2 or l o wer) wit hi n 1 year of scree ni n g. If t he prece di n g fi br osis 
t ests ar e n ot a vaila ble, Fi br oT est/ Fi br o S ure will be d o ne at  scree ni n g. 
7.  Fe males of c hil d be ari n g p ot e ntial m ust ha ve a ne g ati ve ser u m pre g na nc y t est at  scree ni n g 
a n d a gr ee t o use a me dicall y r elia ble met h o d of c o ntrace pti o n u ntil st u d y  c o m pleti o n.  

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Effecti ve c o ntr ace pti o n met h o ds i ncl u de: t ot al a bsti ne nce ( w he n lifest yle or se x ual 
orie nt ati o n of t he s u bject pr ecl u des i nt erc o urse wit h a male part ner); fe male st erilizati o n; 
barrier met h o ds of c o ntr ace pti o n ( dia p hra g m or cer vical/ va ult ca ps wit h s per mici dal 
f o a m, gel, cr ea m, or va gi nal s u pp osit or y); use of oral, i nject e d, or i m pla nt e d h or m o nal 
c o ntr ace pti o n or ot her f or ms t hat ha ve c o m p ara ble effic ac y (fail ure rat e < 1 %); or 
place me nt of a n i ntr a ut eri ne de vice or i ntra ut eri ne s yst e m.  
8.  Male s u bjects m ust be willi n g t o a bst ai n fr o m het er ose x ual  i nt erc o urse or use a c o n d o m 
wit h s per mici de t hr o u g h o ut t he st u d y  peri o d. 
9.  Be willi n g t o ha ve bl o o d sa m ples st ore d f or f ut ure  researc h. 
1 0.  A vaila ble f or at least 3 0 wee ks f or st u d y  partici pati o n.  
1 1.  Writt e n i nf or me d c o nse nt m ust be o bt ai ne d bef ore a n y st u d y pr o ce d ure is  perf or me d.  
 
5. 2.  
E xcl usi o n  Criteri a  
Patie nts meeti n g a n y of t he f oll o wi n g crit eria will n ot be eli gi ble t o partici pat e i n t he st u d y:  
1.  N ursi n g or pr e g na nt.  
2.  Acti ve he patitis B vir us ( H B V) i nfecti o n, defi ne d as p ositi ve he patitis B s urface a nti g e n 
( H Bs A g) at scr ee ni n g. If s u bject is ne gati ve f or b ot h H Bs A g a n d he patitis B s urfa ce 
a nti b o d y ( H Bs A b), b ut he patitis B c ore a nti b o d y ( H Bc A b) -p ositi ve, plas ma H B V D N A 
le vels will be c he c ke d a n d s u bje ct e xcl u d e d if H B V D N A det ect e d.  
3.  H u ma n i m m u n o deficie nc y vir us ( HI V)  i nfecti o n. 
4.  Hist or y of use of a n y H C V dir e ct -acti n g a nti viral t hera p y. 
5.  Cli nicall y si g nific a nt ill ness ot her t ha n H C V t hat ma y i nt erfere wit h s u bject treat me nt, 
assess me nt, safet y, or c o m plia nce wit h t he pr ot o c ol i n t he j u d g me nt of t he  i n vesti gat or. 
6.  P ositi ve  uri ne scr ee n f or a m p het a mi nes or  c o cai ne.  
7.  K n o w n c urr e nt her oi n, m or p hi ne, or met ha d o ne us e. C urre nt narc otic us e ot her t ha n 
met ha d o ne is acc e pt a ble if me dicall y i n dic at e d ( d oc u me nt e d i n me dical rec or ds) a n d 
pr escri be d b y a p h ysicia n.  
8.  S u bst a nce a b use, i ncl u di n g alc o h ol a b use, w hic h i n t he o pi ni o n of t he i n vesti g at or  is 
li kel y t o i nt erfer e wit h me dicati o n a d here nce or st u d y c o m plia nce.  
9.  Gastr oi nt esti nal dis or der t hat c o ul d i nt erfere wit h t he a bs or pti o n of t he st u d y dr u g (e. g., 
str uct ur al defect, di gesti ve fail ure or e nz y me deficie ncies wit h t he e xce pti o n of la ct ose 
i nt oler a nce) a n d/ or hist or y of bariatric s ur ger y. 
1 0.  P o or ve n o us access i nt erferi n g wit h re q uire d st u d y bl o o d  c ollecti o n.  
1 1.  Si g nifica nt hist or y of dr u g aller g y (s uc h as a na p h yla xis or he pat ot o xicit y) t o t he st u d y 
me dicati o ns.  
1 2.  Hist or y of cli nic all y si g nifica nt c hr o nic li ver dis ease d ue t o ot her eti ol o g y (e. g., 
he m o c hr o mat osis, a ut oi m m u ne he patitis, Wils o n’s disease, α 1 -a ntitr y psi n deficie nc y,  

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alc o h olic li ver dise ase, k n o w n great er t ha n m o derat e n o n -alc o h olic st eat o he patitis, a n d 
t o xi n e x p os ur es). 
1 3.  Use of her bal/ nat ur al r e me dies f or p ot e ntial be nefit t o t he li ver wit hi n 3 0 da ys bef ore 
st u dy e ntr y.  
1 4.  Tr eat me nt wit h a mi o dar o ne wit hi n 1 8 0 da ys bef ore st u d y  e ntr y.  
1 5.  Tr eat me nt wit h di g o xi n wit hi n 3 0 da ys bef ore st u d y  e ntr y.  
1 6.  Tr eat me nt wit h rifa b uti n, rifa m pi n, rifa pe nti ne, p he n yt oi n, p he n o bar bit al, St. J o h n’s w ort, 
car ba maz e pi ne, o xcar baze pi ne, r os u v ast ati n, or at or vast ati n wit hi n 1 0 da ys bef ore st u d y 
e ntr y. H o we ver, s wit c hi n g t o a n ot her st ati n is  acce pt a ble.  
1 7.  C hr o nic s yst e mic tr eat me nt wit h eit her c ortic ost er oi ds ( > 1 0 m g dail y pre d nis o ne 
e q ui vale nt) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da y s bef ore st u d y e ntr y. 
I n hale d st er oi ds ar e per mitt e d per I n vesti g at or’s discreti o n.  
1 8.  Scr ee ni n g or baseli ne electr o car di o gra m ( E C G) wit h cli nic all y si g nifica nt  fi n di n gs. 
1 9.  Q T c F ( Q T i nt er val c orr ect e d usi n g Fri dericia's f or m ula) > 4 5 0 msec at  scree ni n g. 
2 0.  Cli nica ll y si g nific a nt he mat ol o gical a n d bi o c he mic al val ues at scree ni n g t hat ma y 
i nt erfer e wit h s u bject tr eat me nt, assess me nt, safet y, or c o m plia nc e wit h t he pr ot o c ol i n 
t he j u d g me nt of t he i n vesti gat or, i ncl u di n g: 
•  A bs ol ut e ne utr o p hil c o u nt ( A N C) < 1, 0 0 0  cells/ m m 3. 
•  He m o gl o bi n le vel < 1 0  g/ d L. 
•  Plat elet c o u nt < 1 0 0, 0 0 0  cells/ m m 3. 
•  Esti mat e d gl o mer ular filtr ati o n rat e (e G F R) < 3 0 m L/ mi n/ 1. 7 3  m2. 
•  A L T or A S T le vel ≥ 5 ti mes u p per li mit of n or mal  ( U L N). 
•  Dir ect bilir u bi n le vel ≥1. 5 ti mes  U L N.  
2 1.  Hist or y of he pat o cell ular car ci n o ma ( H C C). 
2 2.  Hist or y of mali g na nt dis ease wit hi n pre vi o us 5 ye ars (e xce pt f or a de q uat el y treat e d basal 
cell car ci n o ma).  
2 3.  Hist or y of cli nic all y si g nifica nt  m y o pat h y. 
 
5. 3.  
Re m o v al of S u bjects f r o m St u d y Dr u g or  Ass ess me nt  
5. 3. 1.  
St u d y Dr u g  Disc o nti n u ati o n 
A s u bject m us t pr e mat ur el y dis c o nti n ue st u d y dr u g u n der a n y of t he f oll o wi n g 
cir c u mst a nces:  
•  T he s u bject wis hes st u d y dr u g t o be disc o nti n ue d f or a n y  reas o n. 
•  T he i n vesti gat or wis hes t he s u bje ct t o disc o nti n ue st u d y dr u g, es peciall y b ut n ot 
li mit e d t o t he i n vesti g at or c oncl u di n g t hat f urt her treat me nt p uts t he s u bject at 
u nac ce pt a ble ris k or st u d y  n o nc o m plia nce.  

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•  T he s u bject de vel o ps a c o n diti o n or be gi ns t hera p y t hat w o ul d ha ve e xcl u de d e ntr y 
i nt o st u d y. 
•  T he s u bject pr e mat ur el y fails effic ac y ( “ vir ol o gic fail ure”) base d  o n a n y of t he t w o 
f oll o wi n g crit eria, w hic h m ust be c o nfir me d b y a re peat t est wit hi n 7 da ys:  
− H C V R N A > L L O Q aft er 2 pri or c o nsec uti ve H C V R N A val ues <  L L O Q.  
− Gr eat er t ha n 1 l o g 1 0 i ncrease i n H C V R N A fr o m na dir.  
•  T he s u bject has e vi de nce of a se vere dr u g aller g y s uc h as si g ns of  a na p h yla xis. 
•  A n A E t hat is Di visi o n of AI D S ( D AI D S) T a ble f or Gra di n g t he Se verit y of A d ult 
a n d Pe diatric A d verse E ve nts gra de 3 or great er t o xicit y t hat is relat e d t o st u d y dr u g 
i n t he j u d g me nt of t he i n vesti gat or. 
A s u bject has t he  ri g ht t o disc o nti n ue st u d y dr u g treat me nt at a n y ti me f or a n y reas o n wit h o ut 
pr ej u dice t o f ut ur e me dical car e b y t he i n vesti gat or or ot her p h ysicia n at t he i nstit uti o n. A 
s u bje ct w h o disc o nti n ues st u d y dr u g s h o ul d c o m plet e all sc he d ule d st u d y visits pr ovi de d t h at 
writte n c o nse nt t o d o s o h as n ot bee n wit h dr a w n . S u bjects w h o pre mat urel y disc o nti n ue st u d y 
dr u g ma y be r e plac e d.  
5. 3. 2.  
S u bj ect Wit h dr a w al f r o m t he  St u d y  
A s u bject m ust be wit h dr a w n fr o m t he st u d y (a n d dis c o nti n ue a n y st u d y dr u g) if t he s u bje ct 
r e q uests s uc h st u d y disc o nti n uati o n. T he reas o n f or wit h dra wal m ust be rec or de d i n t he s u bject’s 
case r e p ort f or m ( C R F). If p ossi ble, t he s u bject s h o ul d c o m plet e t he e val uati o ns f or st u d y wee k 
1 2 visit pr ovi de d t h at writte n c o ns e nt t o d o s o h as n ot bee n wit h dr a w n . S u bjects w h o wit h dra w 
fr o m t he st u d y ma y be r e plac e d. 
5. 4  
Retre at me nt  
S u bjects w h o ha ve vir ol o gic (tr eat me nt) fail ure d uri n g t he 6 -wee k st u d y dr u g treat me nt peri o d, 
defi ne d as eit her H C V R N A > L L O Q aft er 2 c o nse c uti ve H C V R N A val ues < L L O Q or > 1 l o g 1 0 
i ncr ease i n H C V R N A fr o m na dir, will be dis c o nti n ue d fr o m st u d y dr u g treat me nt ( Secti o n 
5. 3. 1). T hese s u bjects will r ec ei ve a d diti o nal treat me nt (“retreat me nt ”) wit h st a n dar d of care 
r e gi me n usi n g s of os b u vir/ vel pat as vir/ v o xila pre vir ( S O F/ V E L/ V O X) 4 0 0 m g/ 1 0 0 m g/ 10 0 m g 
o nce dail y f or 1 2 wee ks wit h a d diti o nal f oll o w -u p t hr o u g h 1 2 wee ks aft er cessati o n of treat me nt 
( S V R 1 2). 
S u bjects w h o c o m plet e t he 6 -wee k tr eat me nt peri o d will be c o nsi dere d t o ha ve vir ol o gic 
(tr eat me nt) fail ur e if t he y ha ve det ect a ble H C V R N A at t he ne xt st u d y visit a n d t hereaft er 
t hr o u g h o ut t he st u d y. T hese s u bjects will re cei ve a d diti o nal treat me nt (“retreat me nt ”) wit h 
st a n dar d of car e r e gi me n usi n g s of os b u vir/ vel pat as vir/ v o xila pre vir ( S O F/ V E L/ V O X) 4 0 0 m g/ 
1 0 0 m g/ 1 0 0 m g o nce dail y f or 1 2 wee ks wit h  a d diti o nal f oll o w -u p t hr o u g h 1 2 wee ks aft er 
cessati o n of tr eat me nt ( S V R 1 2).  

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S u bjects  recei vi n g retr eat me nt will ha ve st u d y  visits at 4-wee ks  aft er initiati o n  of retreat me nt , at 
t he en d  of the  1 2-wee k  retr eat me nt pe ri o d, at 4 wee ks aft er co m pl eti o n of treat me nt (S V R 4),  a nd  
at 1 2 wee ks aft er c om p leti o n of tr eat me nt (S V R 1 2).   Pr o ce d ur es d urin g  retreat me nt are det aile d 
i n S e cti o n 3. 2. 2. 1 1. 
H C V  resist a nce assa ys  will be o bt ai ne d  i n b ot h  su bjects  wit h vir ol o gic (treat me nt) fail ur e d uri n g 
st u d y dr u g tr eat me nt or  in t he  p ost-tr eatm e nt f ol lo w -u p peri o d. 
5. 5  
St u d y  Sto p pi n g  R ules  
T he st u d y will be st o p pe d if 3 s u bjects (eit her d uri n g t he treat me nt peri o d or f oll o w- up)  are 
vir ol o gi c  (tr e at m e nt) f ail ur es/r el a ps e. I n t his sit uati o n, s u bjects recei vi n g C DI- 3 1 2 4 4 will be 
d is c o nti n ued fr om C DI -3 1 2 4 4. S u bjects recei vin g S O F/ V E L w ill co nti n u e to recei ve S O F/ V E L 
t o c om plet e a 1 2  w ee k co urs e of  tr eat ment.  

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6.  
T R E A T M E N T S  
6. 1.  
S u bject  Assi g n me nt  
T his is a n o pe n -la bel st u d y a n d all eli gi ble patie nts will recei ve 2 wee ks of C DI-3 1 2 4 4 treat me nt  
c o nc urr e nt wit h 6 wee ks of S O F/ V E L treat me nt.  
6. 2.  
M et h o d of Assi g n me nt t o  Tre at me nt  
T his is a n o pe n -la bel st u d y. 
 
6. 3.  
M ateri als a n d  S u p plies  
6. 3. 1.  
F o r m ul ati o n, P ac k a gi n g, a n d  L a beli n g  
St u d y dr u g will be pr o vi de d t o t he s u bject i n b ottles fr o m t he i n vesti gat or t hr o u g h t he 
partici pati n g h os pit al’s o ut patie nt p har ma c y d uri n g vari o us ti mes t hr o u g h t he st u d y peri o d. C DI - 
3 1 2 4 4 is pr o vi de d as 5 0 m g ca ps ules ( C o cr yst al P har ma, I nc.). E pcl usa ( S O F 4 0 0 m g/ V E L 1 0 0 
m g) is c o m mer ciall y a vaila ble as a fi xe d -d ose si n gle c o m bi nati o n t a blet ( Gilea d Scie nces, I nc.).  
T a ble  1: 
St u d y Dr u g Tre at me nt a n d  P ac k a gi n g 
 
Tre at me nt  
St u d y Dr u g  
Fr e q ue nc y  
P ac k a gi n g  
4 0 0 m g C DI - 3 1 2 4 4 
Ei g ht ( 5 0 m g) ca ps ules  
O nc e dail y  
B ottle  
E pcl usa ( S O F/ V E L)  
O ne 4 0 0 m g/ 1 0 0 m g ta blet  
O nc e dail y  
B ottle  
St u d y dr u g b ottle  will c o nt ai n t he f oll o wi n g i nf or mati o n:  
•  A pr eca uti o nar y st at e me nt t hat t he i n vesti g ati o nal pr o d uct is f or li mit e d  use.  
•  L ot  n u m ber. 
•  St or a ge c o n diti o ns.  
•  St at e me nt r e gar di n g dat e f or rea nal ysis or  ret est. 
6. 3. 2.  
St or a ge a n d  H a n dli n g  
T he st u d y dr u g will be pr o vi de d t o s u bjects i n b ottles. C DI-3 1 2 4 4 s h o ul d be st ore d at c o ntr olle d 
r o o m t e m per at ur es bet wee n 2 0º a n d 2 5 º C ( 6 8-7 7 º F). E pcl usa ( S O F/ V E L) s h o ul d be st ore d 
bel o w 3 0 ° C ( 8 6 º F). N o ot her s pecial ha n dli n g is re q uire d. S u bjects will be i nstr uct e d t o ret ur n 
b ottle s a n d a n y u n use d st u d y dr u g t o t he i n vesti gat or at s pecifie d st u d y visits.  
6. 3. 3.  
Fi n al Dis p ositi o n of Cli nic al  S u p plies  
At t he e n d of t he st u d y, fi nal st u d y dr u g s u p pl y a n d acc o u nt a bilit y rec or ds will be rec o ncile d as 
t o dr u g s hi p pe d, dr u g c o ns u me d, a n d dr u g re mai ni n g. A n y discre pa ncies n ot e d will be 
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S u bject acc o u nt a bilit y f or st u d y dr u g will be e ns ur e d t hr o u g h s u bject i nt er vie ws ( d uri n g visits), 
diaries, a n d st u d y dr u g r ec o nciliati o n at select e d visits bef ore dis pe nsi n g dr u g s u p pl y f or t he ne xt 
vi sit i nt er val. At select e d cli nic visits, s u bjects will be as ke d t o ret ur n a n y u n use d st u d y dr u g t o 
t he st u d y sit e. Fi nal dr u g acc o u nt a bilit y rec o nciliati o n will be perf or me d at t he s u bject visit 
o cc urri n g at t he e n d of t her a p y or at earl y disc o nti n uati o n.  U n use d st u d y dr u g will be destr o ye d.  
6. 4.  
D os a ge A d mi nistr ati o n  
F oll o wi n g i nitial d osi n g o n da y 1, t he i n vesti gat or will pr o vi de t he s u bje ct wit h t he re mai n der of 
t he 7-da y st u d y dr u g s u p pl y t o c o nti n ue o n t he f oll o wi n g da y. S u bje cts will recei ve a n a d diti o nal  
7- da y s u p pl y of st u d y dr u g fr o m t he i n vesti gat or at da y 7 st u d y visit. O n da y 1 4 visit, all s u bje cts 
will r ecei ve a n a d diti o nal 2 8 -da y s u p pl y of S O F/ V E L t o c o m plet e t heir 6 -wee k treat me nt 
r e gi me n. 
S u bjects will be i nstr uct e d t o t a ke st u d y dr u g ( 8 ca ps ules  C DI -3 1 2 4 4 pl us 1 t a blet S O F/ V E L, or 
1 t a blet of S O F/ V E L) wit h at least 8 o z. of plai n w at er o nce dail y i n t he m or ni n g t hr o u g h o ut t he 
tr eat me nt peri o d. S u bjects will be as k e d t o dela y t heir d ose of st u d y dr u g o n da y 1 4 u ntil t heir 
st u d y visit t o all o w f or a pr e-d ose bl o o d dra w f or plas ma C DI -3 1 2 4 4 c o nce ntrati o ns.  
T he i n vesti gat or is r es p o nsi ble f or e x plai ni n g t he c orrect use of t he st u d y dr u g t o t he s u bject, 
verif yi n g t hat i nstr ucti o ns ar e f oll o we d pr o perl y, mai nt ai ni n g acc urat e rec or ds of st u d y dr u g 
dis p e n si n g, a n d c ollecti o n of all u n use d st u d y dr u g, i ncl u di n g e m pt y dr u g pac ka gi n g.  
S u bjects will be i nstr uct e d t o c o nt act t he i n vesti gat or as s o o n as p ossi ble if a c o m plai nt or 
pr o ble m wit h t he st u d y dr u g or dr u g deli ver y s yst e m e xists, s o t hat t he sit uati o n c a n be assesse d.  
6. 5.  
Bli n di n g  
T his is a n o pe n -la bel st u d y. B ot h t he s u bje cts a n d select e d st u d y pers o n nel wit h direct c o nt act 
wit h t he s u bje ct will k n o w w hic h st u d y dr u g ( C DI -3 1 2 4 4, S O F/ V E L) is a d mi nist ere d.  
6. 6.  
C o nc o mit a nt  T her a p y  
Dr u gs t hat ar e i n d ucers of P -g p a n d/ or m o derat e -t o-p ot e nt i n d ucers of C Y P 2 B 6, C Y P 2 C 8, or 
C Y P 3 A 4 ( e. g., rifa m pi n, St. J o h n's w ort, car ba maz e pi ne) ma y si g nifica ntl y d ecrease plas ma 
c o nce ntr ati o ns of C DI -3 1 2 4 4, S O F or V E L, le a di n g t o p ot e ntiall y re d uce d t hera pe utic effect of 
C DI -3 1 2 4 4 a n d E pcl usa ( E pcl us a pac ka ge i nsert, 2 0 1 7). Vel pat as vir is a n i n hi bit or of dr u g 
tr a ns p ort ers P-g p, br east ca ncer r esist a nce pr ot ei n ( B C R P), O A T P 1 B 1, O A T P 1 B 3, a n d 
O A T P 2 B 1. As a r es ult, c o a d mi nistr ati o n of E pcl us a ( S O F/ V E L) or C DI -3 1 2 4 4 wit h dr u gs t hat 
ar e s u bstr at es of t hese tr a ns p ort ers ma y i ncrease t he e x p os ure of s uc h dr u gs. Treat me nt wit h t he 
f oll o wi n g dr u gs is eit her pr o hi bit e d or t o be use d wit h ca uti o n d ue t o t he p ot e ntial f or dr u g- dr u g 
i nt er acti o ns t hat ma y r es ult i n r e d uce d dr u g efficac y or i ncrease ris k of A Es. S u bje cts recei vi n g 
a pr o hi bit e d me dicati o n d uri n g t he st u d y s h o ul d be disc o nti n ue d fr o m st u d y dr u g.  

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T a ble 2 is n ot all -i ncl usi ve a n d t he use of ot her c o nc o mit a nt me dic ati o ns s h o ul d be d o ne wit h 
ca uti o n base d o n ris k of p ot e ntial dr u g -dr u g i nt eracti o ns. Q uesti o ns a b o ut use of st u d y dr u g wit h 
c o nc o mit a nt me dicati o ns n ot list e d i n T a ble 2 ca n be dire ct e d t o t he s p o ns or.  
T a ble  2: 
M e dic ati o ns t h at are P r o hi bite d or t o be Use d wit h  C a uti o n 
 
Dr u g Cl ass  
Pr o hi bite d A ge nts  
Cli nic al C o m me nt  
A ntiarr h yt h mics  
a mi o dar o ne 
C oa d mi nistr ati o n of a mi o dar o ne wit h S O F 
ma y r es ult i n s eri o us s y m pt o matic 
br a d ycar dia. T he mec ha nis m is u n k n o w n.  
A ntiarr h yt h mics  
di g o xi n  
C oa d mi nistr ati o n of S O F/ V E L ma y i ncr ease 
t he c o nc e ntr ati o n of di g o xi n. 
A ntic o n v ulsa nts  
car ba ma z e pi ne, p hen yt oi n 
p he n o bar bital, 
o xcar ba ze pi ne 
C oa d mi nistr ati o n is e x p ect e d t o decr eas e 
c o nc e ntr ati o n of b ot h S O F a n d V E L, lea di n g 
t o r e d uc e d t her a pe utic eff ect of S O F/ V E L. 
A nti m yc o ba ct erials  
rifa b uti n, rifa m pi n, 
rifa pe nti ne 
C oa d mi nistr ati o n is e x p ect e d t o decr eas e 
c o nc e ntr ati o n of b ot h S O F a n d V E L, lea di n g 
t o r e d uc e d t her a pe utic eff ect of S O F/ V E L. 
Her bal S u p ple me nts  
St. J o h n’s w ort 
(Hy peric u m perf or at u m ) 
C oa d mi nistr ati o n of S O F/ V E L wit h St. J o h n’s 
w ort, a P -g p i n d u c er, is n ot r ec o m me n de d d u e 
t o decr eas e d c o nc e ntr ati o n of S O F a n d V E L. 
H M G -C o A R e d uctas e 
I n hi bit ors 
r os u vastati n, at or vastati n 
C oa d mi nistr ati o n ma y si g nifica ntl y i ncr eas e 
c o nc e ntr ati o n of r os u vastati n a n d at or vastati n, 
w hic h is ass ociat e d wit h i ncr ease d ris k of 
m y o pat h y, i ncl u di n g r ha b d o m y ol ysis.  
Dr u g Cl ass  
Use wit h C a uti o n  
Cli nic al C o m me nt  
A nta ci ds  
T u ms, Ma al o x, etc.  
A nta ci d a n d S O F/ V E L a d mi nistr ati o n s h o ul d 
be s e par ate d b y 4 hr t o a v oi d decr eas e d 
c o nc e ntr ati o n of V E L.  
H 2 -r ec e pt or a nta g o nists 
nizati di ne, fa m oti di ne, 
ci meti di ne, r a niti di ne 
H 2 -r ec e pt or anta g o nists ma y b e a d mi nist er e d 
si m ulta ne o usl y wit h or 1 2 h o urs a part fr o m 
S O F/ V E L at d os e t hat d oes n ot e x c ee d d os e 
c o m par a ble t o fa m oti di ne 4 0 m g t wic e dail y.  
Pr ot o n -p u m p i n hi bit ors  
de xla ns o pr a z ole, 
es o me pr a z ole, la ns o pr a z ole,  
o me pr a z ole, pa nt o pr a z ole, 
r a be pra z ole 
C oa d mi nistr ati o n of pr ot o n -p u m p i n hi bit ors is 
n ot r ec o m me n d e d. If me dicall y nec essar y t o 
c oa d mi nister, S O F/ V E L s h o ul d b e 
a d mi nist er e d wit h f o o d a n d 4 hr bef or e 
o me pr a z ole 2 0 m g. Us e of ot her pr ot o n - p u m p 
i n hi bit ors has n ot bee n st u die d wit h 
S O F/ V E L.  

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7.  
A D V E R S E E V E N T  R E P O R TI N G  
7. 1.  
Defi niti o n of A d verse  E ve nt  
F or p ur p oses of t his trial, a n A E will be defi ne d as a n y ne w u nfa v ora ble or u ni nt e n d e d si g n, 
s y m pt o m, or diseas e or c ha n ge of a n e xisti n g c o n diti o n, w hic h o cc urs d uri n g or aft er treat me nt, 
w het he r or n ot c o nsi der e d tr eat me nt-r elat e d. If cli nicall y si g nific a nt la b orat or y val ues lea d t o or 
ar e ass o ciat e d wit h cli nical s y m pt o m(s), t he dia g n osis s h o ul d be re p ort e d as a n A E. Lac k of dr u g 
effect is n ot a n A E i n cli nical trials beca use t he p ur p ose of t he  cli nical trial is t o est a blis h dr u g 
effect. 
Pri or t o e nr oll me nt, st u d y sit e pers o n nel will n ot e t he o cc urre nce a n d nat ure of eac h s u bject’s 
me dical c o n diti o n(s) i n t he a p pr o priat e secti o n of t he C R F. D uri n g t he re mai n der of t he st u d y, 
sit e pers o n nel will a gai n n ot e a n y c ha n g e i n t he c o n diti o n(s) a n d t he o cc urre nce a n d nat ure of 
a n y a d verse e ve nts.  
If a s u bject e x perie nces a n A E aft er t he i nf or me d c o nse nt d o c u me nt is si g ne d (e ntr y) b ut t he 
s u bje ct is ne ver assi g ne d t o tr eat me nt (e nr oll me nt), t he e ve nt will o nl y be re p ort e d if t he 
i n vesti gat or belie ves t hat t he e ve nt ma y ha ve bee n ca use d b y a pr ot o c ol pr o ce d ure. 
All A Es o cc urri n g aft er t he s u bject has e nt ere d t he st u d y (t hat is, aft er t he i nf or me d c o nse nt 
d o c u me nt is si g ne d) m ust be r ec or de d i n t he C R F. If t h e st u d y dr u g is disc o nti n u e d f or a s u bject, 
st u d y sit e pers o n nel m ust r e p ort a n d clearl y d o c u me nt t he circ u mst a nces a n d dat a le a di n g t o a n y 
s uc h dis c o nti n u ati o n, usi n g desi g nat e d C R Fs. F or A Es, t he s u bject s h o ul d be f oll o we d u ntil t he 
e ve nt r es ol ves or st a biliz es, wit h fr e q ue nc y of f oll o w -u p at t he discreti o n of t he i n vesti gat or.  
I n cases w her e t he i n vesti gat or n otices a n u na ntici pat e d be nefit t o t he s u bje ct, st u d y sit e 
pers o n nel s h o ul d e nt er “ u ne x p ect e d be nefit ” wit h t he act ual e ve nt t er m (f or e xa m ple, t he  
c o m plet e act ual t er m w o ul d be “ u ne x pe ct e d be nefit — sle e pi n g l o n ger”). 
Cases of pr e g na nc y t hat o cc ur d uri n g mat er nal or pat er nal e x p os ures t o st u d y dr u g s h o ul d be 
r e p ort e d f or tr ac ki n g p ur p oses. Dat a o n fet al o ut c o me a n d breastfe e di n g are c ollect e d f or 
r e g ulat or y r e p orti n g a n d dr u g safet y e val uati o n. 
7. 1. 1.  
Re p orti n g P r oce d u res f o r All A d ve rse  E ve nts  
I n vesti gat ors ar e r es p o nsi ble f or m o nit ori n g t he safet y of s u bjects w h o ha ve e nt ere d t his st u d y 
a n d n oti n g a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be c o ns i d ere d a n u na ntici pat e d 
be nefit t o t he s u bject. T he i n vesti g at or is res p o nsi ble f or a p pr o priat e me dical c are of s u bjects 
d uri n g t he st u d y.  
T he i n vesti gat or r e mai ns r es p o nsi ble f or f oll o wi n g, t hr o u g h a n a p pr o priat e healt h care o pti o n, 
A Es t hat ar e seri o us or t hat ca use d t he s u bject t o disc o nti n u e t he st u d y.  T he s u bject s h o ul d be  

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f oll o we d u ntil t he e ve nt is r es ol ve d or e x plai ne d. Fre q ue nc y of f oll o w-u p is left t o t he discreti o n 
of t he i n vesti gat or.  
A d vers e e ve nt i nf or mati o n will be c olle ct e d  t hr o u g h 4 wee ks aft er t he c o m pleti o n of 
tr eat me nt f or all s u bjects. S u bje cts w h o dis c o nti n u e st u d y dr u g at a n y ti me will ha ve A Es 
c ollect e d t hr o u g h 4 wee ks aft er t he last st u d y dr u g d ose, pr o vi de d c o ns e nt t o c o ntin u e i n t he 
st u d y has n ot bee n wit h dr a w n. 
T he i n vesti gat or is r es p o nsi ble f or assessi n g a n d rec or di n g all a d verse e x perie nces. E ac h a d vers e 
e x perie nce will be r ec or de d a n d classifie d f or i nt e nsit y, seri o us ness, a n d ca usalit y. All A Es eit her 
o bser ve d b y t he i n vesti g at or or r e p ort e d b y t he s u bject will be rec or de d re gar dless of ca usalit y.  
T he i n vesti gat or will f oll o w t he s u bject u ntil a n A E res ol ves or st a bilizes.  
It is t he r es p o nsi bilit y of t he sit e i n vesti gat or t o re p ort A Es t o t he I R B t hat c o nstit ut e Re p orta ble 
Ne w I nf or mati o n wit hi n 5 w or ki n g da ys of i de ntificati o n as per l o cal I R B re q uire me nts.  
7. 1. 2.  
A d verse E ve nt  Se verit y  
T he Di visi o n of AI D S ( D AI D S) T a ble f or “ Gra di n g t he Se verit y of A d ult a n d Pe diatric A d verse 
E ve nts” versi o n 2. 1 ( Mar c h 2 0 1 7) will be use d t o assess a n d gra de A E se verit y, i ncl u di n g 
la b or at or y a b n or malities j u d g e d t o be cli nicall y si g nific a nt. If t he e x perie nc e is n ot c o vere d i n 
t he D AI D S crit eria, t he f oll o wi n g g ui deli nes s h o ul d be use d t o gra de se verit y: 
-  Mil d ( gr a de 1): Mil d s y m pt o ms ca usi n g n o or mi ni mal i nt erfere nce wit h us u al s o cial a n d 
f u ncti o nal a cti vities wit h i nt er ve nti o n n ot i n dicat e d. 
-  M o der at e ( gr a de 2): M o der at e s y m pt o ms ca usi n g great er t ha n mi ni mal i nt erfere nc e wit h 
us ual s o cial a n d f u ncti o nal acti vities wit h i nt er ve nti o n  i n dicat e. 
-  S e ver e ( gr a de 3): Se ver e s y m pt o ms ca usi n g i na bilit y t o perf or m us ual s o cial a n d f u ncti o nal 
acti vities wit h i nt er ve nti o n or h os pit alizati o n  i n dic at e d. 
-  Life -t hreat e ni n g ( gr a de 4): P ot e ntiall y life-t hreat e ni n g s y m pt o ms ca usi n g i na bilit y t o perf or m 
basic self - car e f u ncti o ns wit h i nt er ve nti o n i n dicat e d t o pre ve nt per ma ne nt i m pair me nt, 
persist e nt dis a bilit y, or deat h.  
T he t er m “se ver e” is a me as ur e of i nt e nsit y a n d a s e vere A E is n ot necessaril y seri o us.  
 
7. 1. 3.  
A d verse E ve nt Rel ati o ns hi p t o St u d y  Dr u g  
T he r elati o ns hi p o f a n A E t o t he st u d y dr u g s h o ul d be base d o n t he j u d g me nt of t he i n vesti gat or 
a n d assesse d usi n g t he f oll o wi n g t he g ui d eli nes:  
-  Defi nit el y: Pr e vi o usl y k n o w n t o xicit y of a ge nt; or a n e ve nt t hat f oll o ws a reas o na ble 
t e m p or al se q ue nce fr o m a d mi nistr ati o n of t he dr u g; t hat f oll o ws a k n o w n or e x pect e d 
r es p o nse patt er n t o t he s us pect e d dr u g; t hat is c o nfir me d b y st o p pi n g or re d uci n g t he d osa ge 
of t he dr u g; a n d t hat is n ot e x plai ne d b y a n y ot her reas o na ble  h y p ot hesis.  
-  Pr o ba bl y: A n e ve nt t hat f oll o ws a r eas o na ble t e m p oral se q ue nce fr o m a d mi nistrati o n of t he 
dr u g; t hat f oll o ws a k n o w n or e x pect e d res p o nse patt er n t o t he s us pect e d dr u g; t hat is 
c o nfir me d b y st o p pi n g or r e d uci n g t he d osa ge of t he dr u g; a n d t hat is u nli k el y t o  be  

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e x plai ne d b y t he k n o w n c har act eristics  of t he s u bje ct’s cli nical st at e or b y ot her 
i nt er ve nti o ns. 
-  P ossi bl y: A n e ve nt t hat f oll o ws a r eas o na ble t e m p oral se q ue nce fr o m a d mi nistrati o n of t he 
dr u g; t hat f oll o ws a k n o w n or e x pect e d res p o nse patt er n t o t hat s us pect e d dr u g; b ut t hat  c o ul d 
r ea dil y ha ve be e n pr o d uce d b y a n u m ber of ot her  fact ors. 
-  U nr elat e d: A n e ve nt t hat ca n be det er mi ne d wit h c ert ai nt y t o ha ve n o relati o ns hi p t o t he 
st u d y dr u g. 
7. 1. 4.  
Seri o us A d ve rse E ve nt Defi niti o n a n d Re p orti n g  P r oce d u res  
A n y A E t hat meets t he defi niti o n of s eri o us n ot e d bel o w a n d o cc urs i n a s u bject d uri n g t he 
c o urse of t he st u d y m ust be r e p ort e d t o t he s p o ns or b y t ele p h o ne wit hi n 2 4 h o urs of t he 
i n vesti gat or bec o mi n g a war e of t he e ve nt. I n a d diti o n, a seri o us a d verse e ve nt ( S A E) f or m m ust 
be c o m plet e d b y t he i n vesti gat or a n d fa xe d t o t he st u d y s p o ns or wit hi n 2 4 h o urs of t he 
i n vesti gat or bec o mi n g a war e of t he e ve nt: 
   Maria L uz Pasc ual, M D; C o cr yst al P har ma, I nc., fa x ( 4 0 4) 6 0 1 - 1 4 3 1; ( 4 0 4) 7 4 5- 8 2 5 1 
I n a d diti o n, t he sit e i n vesti gat or m ust re p ort S A Es t o t heir l o cal I R B i n acc or da nce wit h t he 
I R B’s st a n d ar d o per ati n g pr o ce d ur es a n d p olicies. 
A n S A E is defi ne d as a n A E t hat s u g gests a si g nifica nt hazar d or si de effect, re gar dless of t he 
r elati o ns hi p t o st u d y dr u g.  A n S A E i ncl u d es, b ut ma y n ot be li mit e d t o, a n y e ve nt t hat: 
•  
Re s ults i n de at h.  
•  
Is life-t hr eat e ni n g. T his defi niti o n i m plies t hat t he s u bje ct, i n t he vie w of t he i n vesti gat or, 
is at i m me diat e ris k of deat h fr o m t he e ve nt. It d o es n ot i ncl u de a n e ve nt t hat, ha d it 
o cc urr e d i n a m or e seri o us f or m, mi g ht ha ve ca use d  deat h . 
•  
Re q uir es i n patie nt h os pit alizati o n or pr ol o n gs e xisti n g  h os pit aliz ati o n.  
•  
Res ults i n persist e nt or si g nifica nt  disa bilit y/i nca pa cit y.  
•  
Res ults i n a c o n ge nit al a n o mal y or birt h defect. T his seri o us crit eri o n a p plies if a s u bject 
e x p ose d t o a n i n vesti gati o na l pr o d uct gi ves birt h t o a c hil d wit h a c o n ge nit al a n o mal y or 
birt h  defect.  
Me dical a n d s cie ntific j u d g me nt will be e xercis e d i n deci di n g w het her classific ati o n of a n A E as 
seri o us is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p ort a nt me dical e ve nts t hat ma y n ot be 
i m me diat el y life-t hr eat e ni n g or r es ult i n deat h or h os pit aliz ati o n, b ut ma y je o par dize t he s u bject 
or r e q uir e i nt er ve nti o n t o pr e ve nt o ne of t he o ut c o mes list e d i n t he defi niti o n a b o ve. T hese 
s h o ul d als o us uall y be c o nsi der e d seri o us. E xa m ples of s uc h e ve nts i ncl u de aller gic 
br o nc h os pas m r e q uiri n g i nt e nsi ve tr eat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d ys crasias 
or c o n v ulsi o ns t hat d o n ot r es ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n d e nce or a b use.  

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Seri o us a d verse e ve nts o cc urri n g aft er a s u bject is dis c o nti n ue d fr o m t he st u d y will o nl y be 
r e p ort e d if t he i n vesti gat or belie ves t hat t he e ve nt ma y ha ve bee n ca use d b y t he st u d y dr u g or a 
pr ot o c ol pr o ce d ur e.  
F or t he p ur p ose of e x pe dit e d r e p orti n g t o re g ulat or y a ge ncies, t he s p o ns or will be res p o nsi ble f or 
r e p orti n g a n y A E t hat is s eri o us, u ne x pect e d, a n d belie ve d t o be relat e d t o st u d y dr u g. A n A E or 
s us pect e d a d vers e r eacti o n is c o nsi der e d “ u ne x pect e d” if it is n ot c o nsist e nt wit h t he ris k 
i nf or mati o n descri be d i n t he ge ner al i n vesti g ati o nal pla n, i n vesti gat or br o c h ure, or else w here i n 
t he c urr e nt i n vesti gati o nal ne w dr u g a p plic ati o n. F or e xa m ple, u n d er t his defi niti o n, he patic 
necr osis w o ul d be u ne x pect e d ( b y virt ue of great er se verit y) if t he i n vesti gat or br o c h ure or 
i n vesti gati o nal dr u g a p plicati o n r eferr e d o nl y t o ele vat e d he patic e nz y mes or he patitis. Si milarl y, 
cer e br al t hr o m b o e m b olis m a n d cer e br al vasc ulitis w o ul d be u ne x p ect e d ( b y virt ue of great er 
s pecificit y) if t he i n vesti gat or br o c h ur e or i n vesti g ati o nal dr u g a pplicati o n list e d o nl y “cere bral 
vasc ular acci de nts. ”  
7. 1. 5.  
L a b or at o r y Tests  
Cli nical la b or at or y t ests will be perf or me d at t he ti mes s pecifie d i n t he St u d y Sc he d ule (see 
A p pe n di x A). All cli nical la b or at or y ass ess me nts will be a nal yz e d t hr o u g h t he partici p ati n g 
sit e’s l o cal la b or at or y or desi g ne e. 
La b or at or y val ues t hat fall o utsi de a cli nicall y acce pt e d refere nce ra n ge or val ues t hat differ 
si g nifica ntl y fr o m pr e vi o us val ues m ust be f urt her e val uat e d b y t he i n vesti g at or. I n vesti gat ors 
m ust d o c u me nt t heir r e vie w of eac h la b orat or y re p ort b y si g ni n g or i nitiali n g a n d dati n g eac h 
r e p ort. 
Cli nicall y si g nific a nt la b or at or y a b n or malities will be re p ort e d as A Es.  
 
7. 1. 6.  
S afet y  M o nit ori n g 
T he s p o ns or or desi g nees will m o nit or safet y dat a t hr o u g h o ut t he c o urse of t he st u d y. T he  
s p o ns or will r e vie w S A Es wit hi n ti me fra mes ma n dat e d b y re g ulat or y re q uire me nts a n d will 
r e vie w tr e n ds, la b or at or y a nal yt es, a n d A Es at peri o dic i nt er vals. 

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8.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y  A S S U R A N C E  
T he i n vesti gat or a gr ees t o be r es p o nsi ble f or i m ple me nti n g a n d mai nt ai ni n g q ualit y c o ntr ol a n d 
q ualit y ass ur a nc e s yst e ms t o e ns ur e t hat trials are c o n d uct e d a n d dat a are ge nerat e d, d o c u me nt e d, 
a n d r e p ort e d i n c o m plia nc e wit h t he pr ot o c ol, acce pt e d st a n dar ds of G C P, a n d all a p plic a ble 
fe der al, st at e, a n d l o cal laws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he cli nic al st u d y.  
T he i n vesti gat or als o a gr ees t o c o n d uct t he st u d y i n a n efficie nt a n d dili ge nt ma n ner a n d i n 
c o nf or ma nce wit h t his pr ot o c ol; ge ner all y ac ce pt e d st a n dar d of G C P; a n d all a p plic a ble fe d eral, 
st at e, a n d l o cal la ws, r ules a n d r e g ulati o ns relati n g t o t he c o n d uct of t he cli nic al st u d y.  
T he i n vesti gat or m ust all o w st u d y -r elat e d m o nit ori n g, a u dits, a n d i ns p ecti o n b y t he I R B, s p o ns or 
( or desi g nee), g o ver n me nt r e g ulat or y a ge ncies, a n d, if a p plica ble, U ni versit y c o m plia nce a n d 
q ualit y ass ur a nc e gr o u ps of all trial -r elat e d d o c u me nts a n d pr o ce d ures. 
T he i n vesti gat or s hall pr e par e a n d mai nt ai n ac c urat e st u d y d o c u me nt ati o n i n c o m plia nce wit h 
G C P st a n dar ds a n d a p plica ble fe d er al, st at e, a n d l o cal la ws,  r ules a n d re g ulati o ns. 

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9.  
D A T A A N A L Y SI S  M E T H O D S  
9. 1.  
Deter mi n ati o n of S a m ple  Si ze  
N o f or mal sa m ple size calc ulati o ns wer e d o ne. A t ot al of 1 2 s u bjects wit h treat me nt -naï ve 
c hr o nic H C V ge n ot y pe 1 ( eit her 1a or 1 b) is c o nsist e nt wit h t he n u m ber of s u bjects i n p r o of-of - 
c o nce pt pil ot st u dies t hat e val uat e n o vel t hera pies f or H C V vire mia (a n d c ure) i n patie nts wit h 
c hr o nic H C V i nfecti o n.  
9. 2.  
M ai n Effic ac y  V ari a ble  
9. 2. 1.  
Q u a ntit ati ve Pl as m a H C V  Le vels  
H C V ge netic mat erial ( R N A) t esti n g uses p ol y merase c hai n reacti o n ( P C R) t o  i de ntif y a n acti ve 
he patitis C i nfe cti o n. H C V q ua ntit ati ve t esti n g (als o calle d viral l o a d) is t he st a n dar d meas ure 
use d bef or e a n d d uri n g tr eat me nt t o assess t he be nefit of treat me nt (as well as t o me as ure viral 
ki netics).  
9. 3.  
S af et y  V ari a bles  
Safet y e val u at i o ns will i ncl u de c olle cti o n of a d verse e ve nt, p h ysical e xa mi nati o n, vit al si g n, 
E C G, a n d cli nical la b or at or y dat a. La b orat or y dat a will i ncl u de e val uati o n of:  
•  He mat ol o g y: he m o gl o bi n, he mat o crit, er yt hr o c yt e c o u nt ( R B C), mea n cell v ol u me 
( M C V), se g me nt e d ne utr o p hils, l y m p h o c yt es, m o n o c yt es, e osi n o p hils, bas o p hils, 
plat elets, cell m or p h ol o g y, r etic ul o c yt e  c o u nt. 
•  Met a b olic pa nel: Ser u m c o nce ntrati o ns of s o di u m, p ot assi u m, c hl ori d e, t ot al bilir u bi n, 
al kali ne p h os p hat ase, ala ni ne tra nsa mi nase ( A L T), as part at e tra nsa mi nas e ( A S T),  bl o o d 
ur ea nitr o ge n ( B U N), cr eati ni ne, uric aci d, calci u m, gl uc ose, t ot al pr ot ei n, al b u mi n, 
c h olest er ol, li pase, cr eati ne ki nase  ( C K). 
•  C o a g ulati o n: pr ot hr o m bi n ti me ( P T), partial t hr o m b o plasti n ti me ( P T T), i nt er nati o nal 
n or maliz e d r ati o  (I N R). 
•  Ser u m a n d uri ne bet a h C G pr e g na nc y t est o n fe males of c hil d be ari n g  p ot e ntial.  
•  Uri nal ysis:  s pecific gr a vit y, p H, pr ot ei n, gl uc ose, bl o o d, le u k o c yt e  est erase. 
9. 4.  
F ut ure Us e of St ore d  S peci me ns  
Cert ai n bi ol o gic s a m ples f or t his st u d y will be st ore d at t he i n vesti gati ve sit e ( U ni versit y of 
Mar yla n d, I nstit ut e of H u ma n Vir ol o g y) wit h t he s u bject’s c o ns e nt a n d as a p pr o ve d b y t he l o cal 
I R B. T hese sa m ples will be de-i d e ntifie d a n d use d t o researc h i m m u ne res p o ns e t o he patitis C, 
its c o m plicati o ns, a n d ot her c on diti o ns f or w hic h i n di vi d uals wit h he p atitis C are at i ncrease d 
ris k t o i m pr o ve tr eat me nt. C o cr yst al P har ma I nc. will be pr o vi d e d wit h a c o de-li n k t hat will 
all o w li n ki n g t he r es ults fr o m t he bi ol o gic al s p eci me ns wit h p he n ot y pic s u bje ct dat a w hile 
mai nt ai ni n g t he bli n d of t he i de ntit y of t he s u bje ct.  D uri n g t he c o n d uct of t he st u d y, a s u bject  

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ca n c h o ose t o wit h dr a w c o nse nt t o ha ve t hese o pti o nal bi ol o gic al s p eci me ns st ore d f or f ut ure 
r esear c h, i n w hic h cas e t he s peci me ns will be destr o ye d. 
9. 5.  
St atistic al a n d A n al ytic al  Pl a ns  
9. 5. 1.  
Ge ner al  C o nsi de r ati o ns 
Efficac y a nal ys es will be d o ne o n a n i nt e nt -t o-treat (I T T) basis usi n g t he f ull a nal ysis p o p ulati o n. 
T he f ull a nal ysis p o p ulati o n will i ncl u de all s u bjects w h o ha ve recei ve d st u d y dr u g. T he a nal ysis 
of safet y var ia bles will als o i ncl u de all s u bjects w h o recei ve st u d y dr u g. 
All varia bles will be s u m mariz e d b y descri pti ve st atistics. T he st atistics f or c o nti n u o us varia bles 
will i ncl u de mea n, me dia n, st a n dar d de viati o n, a n d n u m ber of o bser vati o ns.  Cat e g oric al 
varia b les will be t a b ulat e d usi n g fr e q ue ncies a n d perce nt a ges. 
9. 5. 2.  
H a n dli n g of Missi n g  D at a  
Missi n g dat a will n ot be i m p ut e d f or safet y a nal ys es. F or effica c y a nal ys es, s o me missi n g val ues 
ma y be i m p ut e d usi n g t he last o bser vati o n carrie d f or war d met h o d.  
9. 5. 3.  
S u bj ect  Dis p ositi o n 
St u d y s u bject dis p ositi o n will be s u m mariz e d. S u bjects w h o disc o nti n ue d st u d y dr u g 
pr e mat ur el y or wit h dr e w fr o m t he st u d y will be s u m marize d a n d list e d, wit h reas o n f or earl y 
t er mi nati o n/ wit h dr a wal. 
9. 5. 4.  
S u bj ect  C h ar act e ristics  
De m o gr a p hic a n d ot her ba seli ne c har act eristics will be s u m marize d b y treat me nt gr o u p. 
 
9. 5. 5.  
T re at me nt  C o m pli a nce 
Tr eat me nt c o m plia nce will be e val uat e d b y visits. T his will i ncl u de t he dat e t he st u d y dr u g was 
dis p e nse d, t he n u m ber of ca ps ules/t a blets dis pe nse d, a n d t he n u m ber of t a ble ts a n d ca ps ules 
r et ur ne d. 
9. 5. 6.  
Effic ac y  A n al yses  
 
9. 5. 6. 1.  
Effic ac y  A n al yses  
Dat a will be s u m marize d usi n g descri pti ve st atistics ( n u m ber of patie nts, mea n, me dia n, st a n dar d 
de viati o n, mi ni m u m a n d ma xi m u m) a n d f or c o nti n u o us varia bles a n d fre q ue nc y a n d perce nt a ges 
f or cat e g orical varia bles. Ti me t o ac hie ve H C V R N A le vels ( bel o w L L O Q) a n d viral ki netics 
will als o be s u m marize d usi n g descri pti ve st atistics. E x pl orat or y e n d p oi nts will be assesse d usi n g 
descri pti ve  st atistics. 
F or t he pri mar y efficac y o bjecti ve, we e x pect S V R 1 2 t o 7 0 % or hi g her i n t his st u d y. If t he tr ue 
s u p pr essi o n r at e ( S V R) is 7 0 %, we will be a ble t o esti mat e t he pr o ba bilit y of s u p pressi o n t o 
wit hi n a p pr o xi mat el y ± 1. 9 6[(. 7)( 1 -. 7)/ 1 2] 1/ 2 = 0. 2 6 base d o n a 9 5 % c o nfi de nce i nt er val. 

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9. 5. 7.  
S afet y  A n al yses 
Tr eat me nt - emer ge nt a d verse e ve nts ar e defi ne d as a d vers e e ve nts o cc urri n g aft er t he first d ose of 
st u d y dr u g u ntil 1 2 wee ks aft er t he last d ose of st u d y dr u g. T he i nci de nce of all re p ort e d A Es a n d 
tr eat me nt-r elat e d A Es will be t a b ulat e d b y treat me nt gr o u p. A Es will be classifie d b y s yst e m 
or ga n class a n d pr eferr e d t er m usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). 
A Es will be list e d a n d s u m marize d b y treat me nt gr o u p, Me d D R A preferre d t er m, se verit y, 
seri o us ness, a n d r elati o ns hi p t o st u d y dr u g. I n t he e ve nt of m ulti ple o cc urre nces of t he sa me A E 
wit h t he sa me pr eferr e d t er m i n o ne s u bje ct, t he A E will be c o u nt e d o nce as t he w orst 
o cc urr e nce. T he i nci d e nce of A Es will be t a b ulat e d b y s yst e m or ga n class a n d treat me nt gr o u p. 
A Es lea di n g t o pr e mat ur e disc o nti n uati o n of st u d y dr u g or wit h dra wal fr o m t he st u d y will be 
s u m marize d a n d list e d i n t he sa me ma n ner. 
S u m mar y st atistics f or act ual val ues a n d f or c ha n g e fr o m baseli ne will be s u m marize d f or 
la b or at or y r es ults b y tr eat me nt gr o u p a n d sc he d ule d visit. S u bje cts wit h la b orat or y val ues o utsi de 
of t he n or mal r efer e nce r a n ge at a n y p ost baseli ne assess me nt will be i de ntifie d. F or vit al si g ns, 
descri pti ve st atistics will be use d t o s u m marize t he mea n a bs ol ut e val u es a n d c ha n ge fr o m 
baseli ne. P h ysical e xa mi nati o n fi n di n gs a n d c ha n g es fr o m bas eli ne will be s u m marize d f or eac h 
patie nt i n dat a listi n gs o nl y.  
9. 5. 8.  
P h a r m ac o ki netic  A n al yses  
Plas ma c o nce ntr ati o n -ti me pr ofiles of C DI-3 1 2 4 4, S O F, G S -3 3 1 0 0 7, a n d V E L will be 
det er mi ne d o ver a 2 4 -h o ur ti me peri o d o n da y 1 4 at t he f oll o wi n g ti me i nt er vals: 0 ( pre -d ose), 1, 
2, 4, 6, 8, 1 2, a n d 2 4 h o urs aft er d osi n g. A sa m ple will als o be c ollect e d bef ore t he first d ose o n 
da y 1.  
T he f oll o wi n g p har mac o ki netic par a met ers will be c o m p ut e d f or eac h patie nt usi n g  
n o n -c o m part me nt al a nal ysis : ma xi m u m plas ma c o nce ntrati o n ( C ma x), mi ni m u m plas ma 
c o nce ntr ati o n ( C mi n), ti me t o ma xi m u m c o nce ntrati o n (t ma x), a n d area u n der t he plas ma 
c o nce ntr ati o n-ti me c ur ve fr o m 0 t o 2 4 h o urs ( A U C 0- 2 4). 
I n di vi d u al s u bject plas ma c o nce ntr ati o ns a n d p har mac o ki netic para met ers will be list e d a n d will 
be s u m marize d b y descri pti ve st atistics. I n di vi d ual s u bje ct a n d mea n plas ma c o nce ntrati o n -ti me 
dat a will be pr ese nt e d gr a p hicall y.  
9. 5. 9.  
P h a r m ac o ki netic/ P h a r m ac o d y n a mic  A n al ysis  
Relati o ns hi ps bet wee n t he c ha n ge fr o m baseli ne i n  l o g 1 0 R N A at da y 1 4 a n d C mi n a n d A U C 0- 
2 4 will be e xa mi ne d gr a p hicall y. If s u g gest e d b y t he gra p hs, a p pr o priat e P K/ P D m o dels will be 
fit t o t he dat a. 
9. 5. 1 0.  
I nt eri m A n al ys es 
N o i nt eri m a nal yses ar e pla n ne d f or t his st u d y.  

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1 0.  
A D MI NI S T R A TI V E, E T HI C A L, A N D  R E G U L A T O R Y 
C O N SI D E R A TI O N S  
T he i n vesti gat or is r es p o nsi ble f or pr ese nti n g t he ris ks a n d be nefits of st u d y partici p ati o n t o t he 
s u bje ct i n si m ple t er ms usi n g t he i nf or me d c o nse nt d o c u me nt. T he i n vesti gat or will e ns ure t hat 
writt e n i nf or me d c o ns e nt is o bt ai ne d fr o m eac h s u bject or le gall y a ut h orize d re prese nt ati ve b y 
o bt ai ni n g t he a p pr o priat e si g nat ur es a n d dat es o n t he i nf or me d c o nse nt d o c u me nt bef ore t he 
perf or ma nc e of pr ot o c ol e val uati o ns or pr o ce d ures.  
1 0. 1.  
Et hic al  Re vie w  
T he i n vesti gat or will pr o vi de t he s p o ns or or i ts desi g nee wit h d o c u me nt ati o n of t he I R B a p pr o val 
of t he pr ot o c ol a n d t he i nf or me d c o ns e nt d o c u me nt bef ore t he st u d y ma y be gi n at t he 
i n vesti gati ve sit e. T he na me a n d a d dr ess of t he re vie wi n g I R B are pr o vi d e d i n t he i n vesti g at or 
file. 
T he i n vesti gat or will s u p pl y t he f oll o wi n g t o t he i n vesti g ati ve sit e’s I R B:  
•  Pr ot o c ol a n d  a me n d me nts.  
•  I nf or me d c o nse nt d o c u me nt a n d u p dat es. 
•  I n vesti gati o nal Ne w Dr u g A p plic ati o n.  
•  Rele va nt c urric ula vit ae, if  re q uire d. 
•  Re q uir e d safet y a n d S A E  r e p orts. 
•  A n y a d diti o nal s u b missi o ns  re q uir e d b y t he sit e’s I R B. 
T he i n vesti gat or m ust pr o vi de t he f oll o wi n g d o c u me nt ati o n t o t he s p o ns or, if a p plica ble:  
•  T he I R B peri o dic ( e. g., q uart erl y, a n n ual) rea p pr o val of t he  pr ot o c ol. 
•  T he I R B a p pr o vals of a n y a me n d me nts t o t he pr ot o c ol or re visi o ns t o  t he i nf or me d 
c o nse nt  d o c u me nt. 
•  T he I R B r ecei pt of safet y a n d S A E re p orts, as  a p pr o priat e. 
1 0. 2.  
Re g ul at or y  C o nsi der ati o ns 
T his st u d y will be c o n d uct e d i n acc or da nce wit h t he pr ot o c ol a n d et hical pri nci ples st at e d i n t he 
2 0 1 3 versi o n of t he Declar ati o n of Helsi n ki or t he a p plica ble g ui deli nes o n G C P, a n d all 
a p plica ble fe der al, st at e, a n d l o cal la ws, r ules, a n d re g ulati o ns.  
All dat a r ec or de d i n t he C R F f or s u bjects partici pati n g i n t his st u d y will be tra nscri be d fr o m 
me dical r ec or ds. Aft er r ea di n g t he pr ot o c ol, t he i n vesti g at or will si g n t he pr ot o c ol si g nat ure 
pa ge a n d r et ur n it t o t he s p o ns or or desi g nee.  

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I n vesti g at or I nf o r m ati o n 
T he c o nt act i nf or mati o n a n d q ualificati o ns of t he pri nci pal i n vesti g at or a n d s u bi n vesti gat ors 
( ass o ciat e i n vesti gat ors), a n d na me a n d a d dress of t he researc h fa cilities are i ncl u de d i n t he 
i n vesti gat or file. 
1 0. 2. 2.  
P r ot oc ol A me n d me nts a n d St u d y  Ter mi n ati o n  
A n y i n vesti gat or -i nitiat e d c ha n ges t o t he pr ot o c ol ( wit h t he e xc e pti o n of c ha n g es t o eli mi nat e a n 
i m me diat e hazar d t o a st u d y s u bje ct) m ust be a p pr o ve d b y t he s p o ns or pri or t o see ki n g a p pr o val 
fr o m t he I R B, a n d bef or e i m ple me nti n g. 
T he i n vesti gat or is r es p o nsi ble f or e nr olli n g s u bje cts w h o ha ve met pr ot o c ol eli gi bilit y crit eria. 
I m p ort a nt pr ot o c ol de viati o ns m ust be re p ort e d t o t he s p o ns or a n d t he l o cal I R B i n acc or da nce 
wit h I R B p olicies.  
T he s p o ns or ma y t er mi nat e t he st u d y at a n y ti me. T he I R B m ust be a d vise d i n writi n g of st u d y 
c o m pleti o n or earl y t er mi nati o n.  
1 0. 2. 3.  
P r ot oc ol De vi ati o ns 
A pr ot o c ol de viati o n is a n y c ha n ge, di ver ge nc e, or de part ure fr o m t he st u d y desi g n or pr o ce d ures 
defi ne d i n t he pr ot o c ol or I nt er nati o nal C o nfere nce o n Har m o nisati o n G o o d Cli nic al Practice 
(I C H G C P). A pr ot o c ol de viati o n ma y be eit her o n t he part of t he s u bje ct, t he i n vesti g at or, or t he 
st u d y sit e st aff. As a r es ult of de viati o ns, c orrecti ve acti o ns are t o be de vel o pe d b y t he sit e a n d 
i m ple me nt e d pr o m ptl y. I m p ort a nt pr ot o c ol de viati o ns are a s u bset of pr ot o c ol de viati o ns t hat 
mi g ht si g nifica ntl y affect t he c o m plet e ness, acc urac y, a n d/ or relia bilit y of t he st u d y dat a or t hat 
mi g ht si g nifica ntl y affect a s u bject's ri g hts, safet y, or well bei n g. F or e xa m ple, i m p ort a nt pr ot o c ol 
de viati o ns mi g ht i ncl u de e nr olli n g s u bjects i n vi olati o n of ke y eli gi bilit y crit eria desi g ne d t o 
e ns ur e a s pecific s u bject p o p ulati o n or faili n g t o  c ollect dat a necessar y t o i nt er pret pri mar y 
e n d p oi nts, as t his ma y c o m pr o mis e t he scie ntific val ue of t he trial.  
It is t he r es p o nsi bilit y of t he sit e i n vesti gat or t o use c o nti n u o us vi gila nc e t o i de ntif y a n d re p ort 
de viati o ns t hat c o nstit ut e Re p ort a ble Ne w  I nf or mati o n t o t he I R B wit hi n 5 w or ki n g da ys of 
i de ntific ati o n of t he pr ot o c ol de viati o n as per l o cal I R B re q uire me nts. T he sit e i n vesti gat or is 
r es p o nsi ble f or k n o wi n g a n d a d heri n g t o t he re vie wi n g I R B re q uire me nts. 
1 0. 2. 4.  
St u d y D oc u me nt ati o n, Pri v ac y, a n d Rec o r ds Rete nti o n  
G o ver n me nt a ge nc y r e g ulati o ns a n d dire cti ves re q uire t hat all st u d y d o c u me nt ati o n pert ai ni n g t o 
t he c o n d uct of a cli nical trial m ust be ret ai ne d b y t he i n vesti gat or f or a mi ni m u m of 2 ye ars ( or 
l o n ger if r e q uir e d b y t he l o cal I R B). 
T o pr ot ect  t he safet y of partici pa nts i n t he st u d y a n d t o e ns ure acc urat e, c o m plet e, a n d relia ble 
dat a, t he i n vesti gat or will kee p r ec or ds of la b orat or y t ests, cli nic al n ot es, a n d s u bject me dic al 
r ec or ds i n t he s u bject files as ori gi nal s o urce d o c u me nts f or t he st u d y. If re q uest e d, t he 

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i n vesti gat or will pr o vi d e t he a p plica ble re g ulat or y a ge ncies a n d a p plic a ble I R B wit h direct 
access t o ori gi nal s o ur ce d o c u me nts.  
Rec or ds c o nt ai ni n g s u bje ct me dical i nf or mati o n m ust be ha n dle d i n acc or da nce wit h t he 
r e q uir e me nts of the Healt h I ns ur a nce P ort a bilit y a n d Acc o u nt a bilit y Act ( HI P A A) Pri vac y R ule 
a n d c o nsist e nt wit h t he t er ms of t he s u bject a ut h orizati o n c o nt ai ne d i n t he i nf or me d c o nse nt 
d o c u me nt f or t he st u d y. Car e s h o ul d be t a ke n t o e ns ure t hat s uc h rec or ds are n ot s hare d  wit h a n y 
pers o n or f or a n y p ur p ose n ot c o nt e m plat e d b y t he i nf or me d c o ns e nt d o c u me nt. F urt her m ore, 
C R Fs a n d ot her d o c u me nts s h o ul d be c o m plet e d i n strict acc or da nce wit h t he i nstr ucti o ns 
pr o vi de d b y t he s p o ns or, i ncl u di n g t he i nstr ucti o ns re gar di n g t he c o di n g of s u bje ct i de ntities.  
1 0. 3.  
St u d y  Fi n a nces  
T his st u d y is fi na nce d b y C o cr yst al P har ma, I nc.  
 
1 0. 4.  
P u blic ati o ns  
Ke y desi g n ele me nts of t his pr ot o c ol will be p ost e d i n a p u blicl y acc essi ble dat a base s uc h as 
cli nicaltrials. g o v. Neit her t he c o m plet e n or a n y part of t he res ults of t he st u d y carrie d o ut u n der 
t his pr ot o c ol, n or a n y of t he i nf or mati o n pr o vi de d b y t he s p o ns or f or t he p ur p oses of perf or mi n g 
t he st u d y, will be p u blis he d or passe d o n t o a n y t hir d part y wit h o ut t he c o nse nt of t he st u d y 
s p o ns or. A n y i n vesti g at or i n v ol ve d wit h t his st u d y is o bli gat e d t o pr o vi de t he s p o ns or wit h 
c o m plet e t est r es ults a n d all dat a deri ve d fr o m t he st u d y.  

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1 1.  
R E F E R E N C E S  
A A S L D/I D S A H C V G ui da nce Pa nel. ( 2 0 1 5) He patitis C g ui da nce: A A S L D -I D S A 
r ec o m me n dati o ns f or t esti n g, ma na gi n g, a n d treati n g a d ults i nfect e d wit h he p atitis C vir us. 
He pat ol o g y 6 2( 3): 9 3 2 - 9 5 4. 
Bers off -Mat c ha SJ, Ca o K, Jas o n M, et al. ( 2 0 1 7) He patitis B Vir us Reacti vati o n Ass o ciat e d 
Wit h Dir ect -Acti n g A nti vir al T her a p y f or C hr o nic He patitis C Vir us: A Re vie w of Cases 
Re p ort e d t o t he U. S. F o o d a n d Dr u g A d mi nistrati o n A d verse E ve nt Re p orti n g S yst e m. A n n 
I nt er n Me d 1 6 6( 1 1): 7 9 2 - 7 9 8. 
C h u a J V, K ottilil S. ( 2 0 1 7) Ar e we neari n g t he e n d i n t he fi g ht a gai nst he patitis C ? E x pert Re v 
Gastr o e nt er ol He pat ol 1 1( 6): 4 9 9 - 5 0 0. 
C urr y M P, O' Lear y J G, Bz o wej N, et al. ( 2 0 1 5) S of os b u vir a n d Vel pat as vir f or H C V i n Patie nts 
wit h Dec o m pe ns at e d Cirr h osis. N E n gl J M e d 3 7 3( 2 7): 2 6 1 8 - 2 6 2 8. 
E m ma n u el B, Wils o n E M, O' Brie n T R, K ottilil S, La u G. ( 2 0 1 7) S h ort e ni n g t he d urati o n of 
t her a p y f or c hr o nic he patitis C i nfecti o n. La ncet Gastr o e nt er ol He pat ol 2( 1 1): 8 3 2 - 8 3 6. 
E pcl usa [ U. S. pac ka ge i ns ert] ( 2 0 1 7) Gilea d Scie nces I nc. F ost er Cit y C A.  
E ur o pea n Ass o ciati o n f or t he St u d y of t he Li ver. ( 2 0 1 7) E A S L Rec o m me n dati o ns o n Treat me nt 
of He patitis C 2 0 1 6. J He pat ol 6 6( 1): 1 5 3 - 1 9 4. 
Fel d JJ, Jac o bs o n I M, Héz o de C, et al. ( 2 0 1 5) S of os b u vir a n d Vel p at as vir f or H C V Ge n ot y pe 1, 
2, 4, 5, a n d 6 I nfecti o n. N E n gl J Me d 3 7 3( 2 7): 2 5 9 9 - 2 6 0 7. 
F ost er G R, Af d hal N, R o berts S K, et al. ( 2 0 1 5) S of os b u vir a n d Vel pat as vir f or H C V Ge n ot y pe 2 
a n d 3 I nfecti o n. N E n gl J Me d 3 7 3( 2 7): 2 6 0 8 -2 6 1 7.  
Ga ne EJ, Sc h wa be C, H yla n d R H, et al. ( 2 0 1 6) Efficac y of t he C o m bi nati o n of S of os b u vir, 
Vel pat as vir, a n d t he N S 3/ 4 A Pr ot ease I n hi bit or G S -9 8 5 7 i n Treat me nt -Nai ve or Pre vi o usl y 
Tr eat e d Patie nts Wit h He patitis C Vir us Ge n ot y pe 1 or 3 I nfecti o ns. Gastr o e nt er ol o g y 1 5 1( 3): 
4 4 8- 4 5 6 e 1.  
Gr ei g S L. ( 2 0 1 6) S of os b u vir/ Vel pat as vir: A Re vie w i n C hr o nic He patitis C. Dr u gs 7 6( 1 6): 1 5 6 7 - 
1 5 7 8. 
K o hli A, Katt a k uz h y S, Si d hart ha n S, et al. ( 2 0 1 5) F o ur -Wee k Direct -Acti n g A nti viral Re gi me ns 
i n N o ncirr h otic Patie nts Wit h He patitis C Vir us Ge n ot y pe 1 I nfecti o n: A n O pe n-La bel, 
N o nr a n d o mize d Trial. A n n I nt er n Me d 1 6 3( 1 2): 8 9 9 - 9 0 7. 
K o hli A, S haffer A, S her ma n A, K ottilil S. ( 2 0 1 4) Treat me nt of he patitis C: a s yst e matic re vie w. 
J A M A 3 1 2( 6): 6 3 1 - 6 4 0. 

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K o w dle y K V, G or d o n S C, Re d d y K R, et al. ( 2 0 1 4) Le di pas vir a n d s of os b u vir f or 8 or 1 2 wee ks 
f or c hr o nic H C V wit h o ut cirr h osis. N E n gl J Me d 3 7 0( 2 0): 1 8 7 9 - 1 8 8 8. 
L y K N, Xi n g J, Kle ve ns R M, Jiles R B, War d J W, H ol m ber g S D. ( 2 0 1 2) T he i ncreasi n g b ur de n 
of m ort alit y fr o m vir al he patitis i n t he U nit e d St at es bet wee n 1 9 9 9 a n d 2 0 0 7. A n n I nt er n Me d 
1 5 6( 4): 2 7 1 - 2 7 8. 
P o c kr os PJ. ( 2 0 1 3) N o n -n ucle osi de a nal o g ue p ol y meras e i n hi bit ors i n de vel o p me nt. Cli n Li ver 
Dis 1 7( 1): 1 2 3 - 1 2 8. 
P olaris O bse r vat or y H C V C olla b or at ors. ( 2 0 1 7) Gl o bal pre vale nce a n d ge n ot y pe distri b uti o n of 
he patitis C vir us i nfecti o n i n 2 0 1 5: a m o delli n g st u d y. La ncet Gastr o e nt er ol He pat ol 2( 3): 1 6 1 - 
1 7 6. 
Vel dt BJ, Heat hc ot e EJ, We de me yer H, et al. ( 2 0 0 7) S ust ai ne d vir ol o gic res p o nse a n d cli nical 
o ut c o mes i n patie nts wit h c hr o nic he patitis C a n d a d va nc e d fi br osis. A n n I nt er n Me d 1 4 7( 1 0): 
6 7 7- 6 8 4. 
West br o o k R H, D us hei k o G. ( 2 0 1 4) Nat ural hist or y of he patitis C. J He pat ol 6 1( 1 S u p pl): S 5 8 - 
6 8. 
W orl d Healt h Or ga nizati o n. ( 2 0 1 7) He pa titis C Fa ct S heet. U p dat e d Oct o ber 2 0 1 7, W H O; 
Ge ne va, S wit zerla n d.  
Ze uze m S, F ost er G R, Wa n g S, et al. ( 2 0 1 8) Gle ca pre vir -Pi br e nt as vir f or 8 or 1 2 Wee ks i n H C V 
Ge n ot y pe 1 or 3 I nfe cti o n. N E n gl J M e d 3 7 8( 4): 3 5 4 - 3 6 9. 

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S u bj ects r ecei vi n g r etr eat m e nt will h a ve st u d y visits at 4 wee ks aft er i niti ati o n of r etr eat m e nt, at t h e e n d of t h e 1 2 -wee k r etr eat m e nt peri o d, at 4 wee ks aft er 
c o m pl eti o n of tr eat m e nt ( S V R 4), a n d at 1 2 wee ks aft er c o m pl eti o n of tr eat m e nt ( S V R 1 2). Pr oce d ur es d uri n g r etr eat m e nt ar e deta il e d i n Secti o n 3. 2. 2. 1 1. 

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Pr ot o c ol  C DI - 3 1 2 4 4-P 2 - 0 0 1 
C O N FI D E N TI A L  
 
 
 
A P P E N DI X  B.  P R O T O C O L SI G N A T U R E  P A G E  
B y si g ni n g t his pr ot o c ol, t he i n vesti gat or a grees t o c o n d uct t he st u d y i n acc or da nce wit h t he 
pr ot o c ol, ge ner all y ac ce pt e d st a n dar ds of g o o d cli nical practice, a n d all a p plica ble fe deral, st at e, 
a n d l o cal la ws, r ules, a n d r e g ulati o ns relati n g t o t he c o n d uc t of t he cli nical st u d y. I n a d diti o n, t he 
i n vesti gat or a gr ees t o pr o vi de t he s p o ns or wit h acc urat e fi na ncial i nf or mati o n t o all o w t he 
s p o ns or t o s u b mit c o m plet e a n d acc ur at e certificati o n a n d discl os ure st at e me nts as re q uire d b y 
F D A r e g ulati o ns.  
B y si g ni n g  t his pr ot o c ol, t he s p o ns or a grees t o be res p o nsi ble f or i m ple me nti n g a n d mai nt ai ni n g 
q ualit y c o ntr ol a n d q ualit y ass ur a nce s yst e ms wit h writt e n pr o ce d ures t o e ns ure t hat t he trials are 
c o n d uct e d a n d dat a ar e ge ner at e d, d o c u me nt e d, a n d re p ort e d i n c o m plia nce wit h t he pr ot o c ol, 
acce pt e d st a n dar ds of g o o d cli nical pr actice, a n d all a p plic a ble fe deral, st at e, a n d l o cal la ws, 
r ules, a n d r e g ulati o ns r elati n g t o t he c o n d uct of t he st u d y. 
 
 
 
 
I n vesti gat or’s Si g nat ur e 
Pri nt Na m e  
Dat e  
I n vesti gat or’s Si g nat ur e 
Pri nt  Na m e  
Dat e  
 
 
Sit e A d dr ess a n d T el e p h o n e  
 
 
S p o ns or’s  Si g nat ur e  
Dat e