Randomized Double-Blind Study of Nitazoxanide Compared to Placebo in Subjects With HBeAG-Negative Chronic Hepatitis B Virologically Suppressed for at Least Twelve Months on Tenofovir Disoproxil Fumarate, Tenofovir Alafenamide or Entecavir
Phase: PHASE2
Conditions: Chronic Hepatitis B
Sponsor: Romark Laboratories L.C.

 
 
 
R A N D O MI Z E D D O U B L E- B LI N D S T U D Y O F NI T A Z O X A NI D E 
C O M P A R E D T O P L A C E B O I N S U B J E C T S WI T H H B E A G- N E G A TI V E 
C H R O NI C H E P A TI TI S B VI R O L O G I C A L L Y S U P P R E S S E D F O R A T 
L E A S T T W E L V E M O N T H S O N T E N O F O VI R DI S O P R O XI L 
F U M A R A T E, T E N O F O VI R A L A F E N A MI D E O R E N T E C A VI R  
 
P R O T O C O L N O. R M 0 8- 2 0 0 1 
 
St u d y S p o ns or: 
 
T he R o mar k I nstit ute f or Me dical Researc h 
 
 
 
C urre nt Versi o n: 
v 4. 0 I nc or p orati n g A me n d me nts 1, 2, a n d 3 
 
Re places: 
v 1. 0 ( Ori gi nal) 
v 2. 0 A me n d me nt 1, Date d 1 0 A pril 2 0 1 9 
v 3. 0 A me n d me nt 2, Date d 1 3 J u ne 2 0 1 9 
 
Effecti ve Date:  Ja n uar y 2, 2 0 2 0 
 
 
T his st u dy will be c o n d ucte d i n c o m pli a nce wit h t his pr ot oc ol, c urre nt I nter n ati o n al C o u ncil f or 
H ar m o nis ati o n G o o d Cli nic al Pr actice (I C H G C P), U nite d St ates ( U S) C o de of Fe der al 
Re g ul ati o ns ( C F R) a p plic a ble t o  cli nic al st u dies ( 4 5 C F R P art 4 6, 2 1 C F R 5 0, 2 1 C F R P art 
3 1 2), a n d a p plic a ble re g ul at ory re q uire me nts.  

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
2 
C O N FI D E N TI A L 
I N V E S TI G A T O R’ S A G R E E M E N T 
C O N FI D E N TI A LI T Y 
T he i nf or mati o n i n t his pr ot o c ol is pr o vi de d t o y o u, as a n I n vesti gat or or c o ns ulta nt, f or re vie w 
b y y o u, y o ur staff, a n d a n a p plica ble i nstit uti o nal re vie w c o m m ittee.  B y acce pti n g t his 
d oc u me nt, y o u a gree t hat i nf or ma ti o n c o ntai ne d herei n will be co nsi dere d c o nfi de ntial a n d will 
n ot be discl ose d t o ot hers, wit h o ut w ritte n a ut h orit y fr o m T he R o mar k I nstit ute f or Me dical 
Researc h, e xce pt t o t he e xte nt  necessar y t o o btai n: (a) I nstit uti o nal Re vie w B oar d a p pr o val a n d 
( b) i nf or me d c o nse nt fr o m t h ose pers o ns t o w h o m t he i n vesti gatio nal me dici nal pr o d uct will be 
a d mi nistere d. 
A P P R O V A L O F FI N A L P R O T O C O L 
M y si g nat ure bel o w c o nstit utes a gree me nt wit h t his pr ot oc ol.  I  a m pr o vi di n g t he necessar y 
ass ura nces t hat t his st u d y w ill be c o n d ucte d b y me a n d m y staff acc or di n g t o all sti p ulati o ns of 
t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntiality, a n d i n c o m plete acc or da nce wit h 
all a p plica ble re g ulati o ns i nc l u di n g c urre nt G o o d Cli nical Practice g ui deli nes a n d t he et hical 
g ui deli nes set b y t he W orl d Me dic al Asse m bl y ( Declarati o n of He lsi n ki, last a me n d me nt i n 
F ortaleza, Brazil Oct o ber 2 0 1 3).  F urt her m ore, m y si g nat ure bel o w i n dicates t hat s o urce 
d oc u me nts will be a vaila ble f or  re vie w b y t he S p o ns or or t heir desi g nate d re prese ntati ve. 
 
Pri nci pal I n vesti gat or Si g nat ure: 
 
 
 
Pri nci pal I n vesti gat or  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Pri nt na me:  
 
 
 
 
 
 
 
 
 
 
Wit h t he si g nat ure bel o w, t he S p o ns or a p pr o ves of t his pr ot oc ol .   
 
S p o ns or Si g nat ure: 
 
 
 
T he R o mar k I nstit ute f or Me dical Researc h  
 
 
 
 
 
 
Date 
 
Pri nt na me:  
 
 
 
 
 
 
 
 
 
 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
3 
C O N FI D E N TI A L 
1.  
S Y N O P SI S 
Title:   Ra n d o mize d D o u ble- Bli n d St u d y of Nitaz o xa ni de C o m pare d t o Place b o i n S u bjects Wit h 
H Be A g- Ne gati ve C hr o nic He pati tis B Vir ol o gicall y S u p presse d f or at Least T wel ve M o nt hs o n 
Te n of o vir Dis o pr o xil F u marate, Te n of o vir Alafe na mi de or E nteca v ir 
St u d y N u m ber:  
R M 0 8- 2 0 0 1 
I N D N u m ber:  1 4 3, 3 2 9 
I n dic ati o n:  
Treat me nt of he patitis B e a nti ge n ( H Be A g) ne gati ve c hr o nic he patitis B ( C H B). 
Desi g n:   
Ra n d o mize d d o u ble- bli n d place b o-c o ntr olle d d ose-ra n ge-fi n di n g trial. 
N u m ber of S u bjects:  4 8. 
P o p ul ati o n:   A d ults (at least 2 1 years of a ge) wit h H Be A g ne gati ve C H B vir ol o gicall y 
s u p presse d f or at least 1 2 m o nths o n te n of o vir dis o pr o xil f u mar ate ( T D F), te n of o vir alafe na mi de 
( T A F) or e nteca vir ( E T V). 
R a n d o mi z ati o n:   1: 1: 1: 1 ( 1 2 s u bjects per gr o u p). 
St u d y D ose a n d A d mi nistr ati o n:   
Gr o u p 1:  Place b o f or 1 2 wee ks. 
Gr o u p 2:  6 0 0 m g nitaz o xa ni de ( N T Z) o nce dail y f or 1 2 wee ks. 
Gr o u p 3:  6 0 0 m g N T Z t wice dail y f or 1 2 wee ks. 
Gr o u p 4:  9 0 0 m g N T Z t wice dail y f or 1 2 wee ks. 
All s u bjects will c o nti n ue T D F, T A F or E T V t hera p y t hr o u g h o ut t he st u d y. 
N T Z 3 0 0 m g e xte n de d release ta blets a n d matc hi n g place b o ta blet s will be a d mi nistere d i n 
d o u ble- bli n d fas hi o n orall y wit h f o o d. 
After 1 2 wee ks, s u bjects will c o n ti n ue treat me nt wit h t he sa me treat me nt re gi me n if t he y ha ve 
ac hie ve d a n y decli ne i n q ua ntitati ve he patitis B s urface a nti ge n ( H Bs A g) fr o m Baseli ne t o Wee k 
1 2. St o p pi n g r ules are pr o vi de d base d u p o n mea n c ha n ge i n q ua nt itati ve ( q H Bs A g) res p o nse. 
O bjecti ves:   
T o e val uate safet y, effecti ve ness, a n d p har mac o ki netic- p har mac o d y na mic 
( P K/ P D) relati o ns hi ps ass ociate d wit h t hree differe nt N T Z treat me nt re gi me ns a d de d t o T D F, 
T A F or E T V i n treati n g C H B. 
Pri m ar y Effic ac y P ar a meter:   Mea n c ha n ge i n H Bs A g fr o m Baseli ne t o Wee k 1 2. 
Sec o n d ar y Effic ac y P ar a meters: 
i.  S ustai ne d H Bs A g l oss wit h hepatitis B vir us ( H B V) de o x yri b o n ucleic aci d ( D N A) 
s u p pressi o n 2 4 wee ks after e n d of treat me nt wit h N T Z a n d T D F, TA F or E T V. 
ii  C ha n ge i n q H Bs A g fr o m Baseli ne t o differe nt ti me p oi nts o n treat me nt. 
iii.  H Bs A g l oss. 
i v.  H Bs A g ser oc o n versi o n. 
v.  H B V D N A s u p pressi o n. 
vi.  C ha n ge fr o m Baseli ne i n Fi br osis 4 ( FI B- 4) sc ore. 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
4 
C O N FI D E N TI A L 
vii. C ha n ge fr o m Baseli ne i n Fi br osca n ® sc ore. 
S afet y P ar a meters:   A d verse e ve nts, la b orat or y safet y tests 
Bi ol o gic al S a m ples:   Bl o o d a n d uri ne sa m ples c ollected at Scree ni n g, Baseli ne ( Da y 1), Da y 3, 
Wee ks 1, 2, 4, 8, 1 2, 1 6, 2 0, 2 4 a n d e ver y 1 2 wee ks t hereafter d uri n g treat me nt a n d at off-
treat me nt f oll o w- u p Wee ks 4, 8, 1 2, 2 4 a n d 4 8. 
St u d y Ce nter:   
Nati o nal U ni versit y Hos pital of Si n ga p ore 
Scree ni n g Peri o d:   
A u g ust 2 0 1 9 t hr o u g h A pril 2 0 2 0 
 
 
 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
5 
C O N FI D E N TI A L 
2.  
S T U D Y S C H E M A 
 
 
 
 
 
 
 
 
 
Baseli ne 
(ra n d o mizati o n t o 1 of 4 treat me nt gr o u ps) 
Wee k 9 6 
Wee k 7 2 
Wee k 4 8 
Wee k 2 4 
Wee k 1 2 
( pri mar y efficac y a nal ysis) 
N o H Bs A g decli ne 
fr o m baseli ne 
A n y H Bs A g decli ne 
fr o m baseli ne 
H Bs A g l oss 
H Bs A g decli ne fr o m 
baseli ne   
< 0. 5 l o g 1 0 I U/ m L 
H Bs A g decli ne fr o m 
baseli ne   
≥0. 5 l o g 1 0 I U/ m L 
H Bs A g l oss 
H Bs A g decli ne fr o m 
baseli ne   
< 1 l o g 1 0 I U/ m L 
H Bs A g decli ne fr o m 
baseli ne   
≥1 l o g 1 0 I U/ m L 
H Bs A g l oss 
H Bs A g decli ne fr o m 
baseli ne   
< 2 l o g 1 0 I U/ m L 
H Bs A g decli ne fr o m 
baseli ne   
≥2 l o g 1 0 I U/ m L 
H Bs A g l oss 
H Bs A g- p ositi ve 
H Bs A g l oss 
C o nti n ue treat me nt re gi me n u ntil 
H Bs A g- ne gati ve f or 2 4 wee ks, t he n st o p 
N T Z a n d NrtI, t he n 4 8 wee ks off-
treat me nt f oll o w- u p 
Disc o nti n ue N T Z, c o n ti n ue NrtI t hera p y 
wit h 1 2 wee ks off-t reat me nt f oll o w- u p 
Scree ni n g 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
6 
C O N FI D E N TI A L 
T A B L E O F C O N T E N T S 
I N V E S TI G A T O R’ S A G R E E M E N T ............................................................................................... 2 
1.  
S Y N O P SI S ...................................................... ............................................................. 3 
2.  
S T U D Y S C H E M A ....................................................................................................... 5  
T A B L E O F C O N T E N T S ................................................................................................................. 6  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ................ ............... 9 
4.  
I N T R O D U C TI O N ...................................................................................................... 1 1 
4. 1.  
C hr o nic He patitis B ........................................... ......................................................... 1 1 
4. 2.  
Nitaz o xa ni de ............................................................................................................... 1 1  
4. 2. 1.  
A nti viral Acti vit y of N T Z i n Cell C ult ures .................... ............................................ 1 1 
4. 2. 2.  
Cli nical E x perie nce wit h N T Z .................................. .................................................. 1 2 
4. 2. 2. 1.  
O verall Cli nical E x perie nce ................................... ..................................................... 1 2 
4. 2. 2. 2.  
Cli nical E x perie nce i n C H B .................................... ................................................... 1 3 
4. 3.  
Rati o nale f or t he St u d y ............................................................................................... 1 3  
5.  
S T U D Y O BJ E C TI V E S .............................................................................................. 1 3  
6.  
S T U D Y D E SI G N ....................................................................................................... 1 4  
7.  
S U BJ E C T S E L E C TI O N ............................................. ................................................ 1 6 
7. 1.  
I ncl usi o n Criteria ........................................................................................................ 1 6 
7. 2.  
E xcl usi o n Criteria ....................................................................................................... 1 6  
8.  
R A N D O MI Z A TI O N .................................................................................................. 1 7  
9.  
S T U D Y P R O C E D U R E S .............................................. .............................................. 1 7 
9. 1.  
Pre-st u d y E val uati o n ( Da y - 3 1 t o 1) ........................... ................................................ 1 7 
9. 2.  
Baseli ne ( Da y 1) ......................................................................................................... 1 8  
9. 3.  
E val uati o ns D uri n g Treat me nt .................................. .................................................. 2 0 
9. 4.  
F oll o w- u p After E n d of Treat me nt wit h N T Z/ Place b o ............. ................................. 2 1 
9. 5.  
U nsc he d ule d Visit ....................................................................................................... 2 2  
9. 6.  
St u d y Me dicati o n Disc o nti n uati o n a n d Wit h dra wal Criteria ...... ............................... 2 2 
9. 7.  
Resc ue T hera p y .......................................................................................................... 2 3  
9. 8.  
Vir ol o g y Testi n g a n d Pla n f or  M o nit ori n g Resista nce ............................................... 2 3 
1 0.  
D A T A M A N A G E M E N T ............................................... ............................................ 2 4 
1 0. 1.  
Electr o nic Data E ntr y ......................................... ........................................................ 2 4 
1 0. 2.  
Pr ot oc ol De viati o ns .................................................................................................... 2 4  
1 0. 3.  
Data Q ualit y Ass ura nce ........................................ ...................................................... 2 4 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
7 
C O N FI D E N TI A L 
1 1.  
S T A TI S TI C A L C O N SI D E R A TI O N S .................................... ................................... 2 5 
1 1. 1.  
Sa m ple Size Calc ulati o n ....................................... ...................................................... 2 5 
1 1. 2.  
Efficac y Varia bles ...................................................................................................... 2 5  
1 1. 3.  
Res p o nse Defi niti o ns .......................................... ........................................................ 2 5 
1 1. 4.  
Statistical Met h o d ol o g y .............................................................................................. 2 5  
1 1. 4. 1.  
Efficac y A nal yses ....................................................................................................... 2 5  
1 1. 4. 2.  
Safet y A nal yses ............................................... ........................................................... 2 6 
1 2.  
I N V E S TI G A TI O N A L P R O D U C T S .......................................................................... 2 7 
1 2. 1.  
I de ntit y of I n vesti gati o nal Pr o d ucts ............................................................................ 2 7  
1 2. 2.  
Pac ka gi n g a n d La beli n g ........................................ ...................................................... 2 7 
1 2. 3.  
Dr u g Acc o u nta bilit y ........................................... ........................................................ 2 8 
1 2. 4.  
S u bject C o m plia nce a n d Dis all o we d Me dicati o ns ..................................................... 2 8  
1 3.  
A D V E R S E E V E N T S ................................................ .................................................. 2 8 
1 3. 1.  
Defi niti o ns .................................................................................................................. 2 9  
1 3. 2.  
Cli nical A d verse E ve nts ............................................................................................. 2 9  
1 3. 3.  
Re p orti n g Re q uire me nt ......................................... ...................................................... 3 0 
1 3. 4.  
Me dicati o n M o dificati o n/ Wit h dra wal D ue t o A d verse E ve nt ....... ............................. 3 0 
1 3. 5.  
Me dicati o n Err ors ....................................................................................................... 3 1  
1 4.  
DI S C O N TI N U A TI O N ............................................................................................... 3 1  
1 5.  
R E T E N TI O N O F R E C O R D S .......................................... .......................................... 3 1 
1 6.  
M O NI T O RI N G T H E S T U D Y .......................................... ......................................... 3 2 
1 7.  
I N F O R M E D C O N S E N T ............................................................................................ 3 2 
1 8.  
E T HI C S ........................................................ .............................................................. 33  
1 8. 1.  
St u d y-s pecific Desi g n C o nsi derati o ns .......................... .............................................. 3 3 
1 8. 2.  
I n vesti gat or Res p o nsi bilities ....................................................................................... 3 3 
1 8. 3.  
I nstit uti o nal Re vie w B oar d ......................................................................................... 3 3 
1 8. 4.  
Pri vac y of Pers o nal Data ............................................................................................ 3 5  
1 9.  
D A T A C O N FI D E N TI A LI T Y, DI S C L O S U R E O F D A T A, A N D 
P U B LI C A TI O N ................................................... ....................................................... 3 5 
2 0.  
D A T A A N D R E P O R T R E Q UI R E M E N T S .................................. ............................. 3 6 
2 1.  
C O N T A C T I N F O R M A TI O N .................................................................................... 3 6  
2 2.  
LI S T O F R E F E R E N C E S ............................................................................................ 3 7  
2 3.  
A P P E N DI C E S ............................................................................................................ 3 9  

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
8 
C O N FI D E N TI A L 
2 3. 1.  
A p pe n di x I: Maj or C Y P 2 C 8 S u bstrates ..................................................................... 3 9  
2 3. 2.  
A p pe n di x II: Sc he d ule of St u d y Visits a n d Pr oce d ures .............................................. 4 0  
2 3. 3.  
A p pe n di x III: T o xicit y Gra di n g f or A d ult A d verse E ve nts ........................................ 4 2  
2 3. 4.  
A p pe n di x I V: List of Esse ntial D o c u me nts f or t he I n vesti gati ve Site ........................ 5 4  
2 3. 5.  
A p pe n di x V: Pr ot oc ol Re visi o n Hist or y ..................................................................... 5 6  
 
LI S T O F T A B L E S 
Ta ble 1:  
A b bre viati o ns ................................................................................................................ 9  
Ta ble 2:  
C o ntact I nf or mati o n ........................................... ......................................................... 3 6 
Ta ble 3:  
Maj or C Y P 2 C 8 S u bstrates .......................................................................................... 3 9  
Ta ble 4:  
Sc he d ule of Assess me nts ....................................... ..................................................... 4 0 
Ta ble 5:  
Di visi o n of AI D S Ta 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, P u blis h Date: J ul y 2 0 1 7 .............................................. 4 2  
Ta ble 6:  
Pr ot oc ol Re visi o n Hist or y ........................................................................................... 5 6  
 
 
 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
9 
C O N FI D E N TI A L 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S 
T a ble 1:  
A b bre vi ati o ns 
A b bre vi ati o n  
Ter m 
A F P 
al p ha-fet o pr otei n 
A L T 
ala ni ne a mi n otra nsferase  
A S T 
as partate a mi n otra nsferase  
BI D 
t wice dail y 
B U N 
bl o o d urea nitr o ge n  
ccc D N A  
c o vale ntl y cl ose d circ ular viral D N A 
C H B 
c hr o nic he patitis B 
C P K 
creati ne p h os p h o ki nase 
C R F 
case re p ort f or m  
C T P 
C hil d- T urc otte- P u g h 
D N A 
de o x yri b o n ucleic aci d 
E D C 
electr o nic data c ollecti o n  
E T V 
e nteca vir 
G C P  
G o o d Cli nical Practice  
G G T 
ga m ma gl uta m yl tra nsferase  
H Bc A g  
H B V c ore a nti ge n  
H Bcr A g  
H B V c ore-relate d a nti ge n 
H Be A g  
He patitis B e a nti ge n  
H Bs A g  
He patitis B s urface a nti ge n  
H B V 
He patitis B vir us  
H C C 
he pat ocell ular carci n o ma 
H C V 
He patitis C Vir us  
H D V 
He patitis D vir us  
HI V 
h u ma n i m m u n o deficie nc y vir us  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I g M 
I m m u n o gl o b uli n M 
I N R 
i nter nati o nal n or malize d rati o 
I R B 
i nstit uti o nal re vie w b oar d  
I U D 
i ntra uteri ne de vice 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
1 0 
C O N FI D E N TI A L 
A b bre vi ati o n  
Ter m 
N T Z 
nitaz o xa ni de 
P T 
pr ot hr o m bi n ti me 
Q D 
o nce dail y 
q H Bs A g  
q ua ntitati ve H Bs A g 
T A F 
te n of o vir alafe na mi de 
T D F 
te n of o vir dis o pr o xil f u marate  

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
Ja n uar y 2, 2 0 2 0 
 
 
1 1 
C O N FI D E N TI A L 
4.  
I N T R O D U C TI O N 
4. 1.  
C hr o nic He p atitis B 
He patitis B vir us ( H B V) is a partiall y d o u ble-stra n de d de o x yri b o n ucleic aci d ( D N A) vir us 
bel o n gi n g t o t he He pa d na vi ri dae fa mil y of vir uses. 
C hr o nic he patitis B ( C H B) i nfec ti o n re mai ns a maj or p u blic healt h pr o ble m, affecti n g m ore t ha n 
2 5 0 milli o n pe o ple w orl d wi de. T he se patie nts ha ve a hi g her ris k of de vel o pi n g se vere li ver 
diseases s uc h as cirr h osis, li v er fail ure, or he pat ocell ular ca rci n o ma (W orl d Healt h Or ga nizati o n, 
2 0 1 8 ). 
C urre ntl y a vaila ble t hera pies f o r C H B i ncl u de n ucle osi de/ n ucle oti de re verse tra nscri ptase 
i n hi bit ors ( NrtIs) a n d pe g ylated i nterfer o n.  T hese t hera pies d o n ot eli mi nate t he c o vale ntl y 
cl ose d circ ular viral D N A (ccc D N A ), w hic h f u ncti o ns as a n o nre plicati ve mi nic hr o m os o me a n d 
persists t hr o u g h o ut t he lifes pa n of i nfecte d he pat oc ytes, a n d t heref ore, t he g oals of treat me nt are 
s ustai ne d s u p pressi o n of H B V D N A a n d re missi o n of li ver disease.  W hile si x NrtIs ha ve bee n 
a p pr o ve d b y t he U. S. F D A f or treat me nt of C H B (te n of o vir dis o pr o xil f u marate ( T D F), te n of o vir 
alafe na mi de ( T A F), e nteca vir ( E T V), la mi v u di ne, a def o vir a n d te l bi v u di ne), T D F, T A F a n d E T V 
are t he preferre d NrtIs f or treat me nt ( L o k et al, 2 0 1 6; Terra ult et al, 2 0 1 8). 
Res p o nse rates f or patie nts wit h he patitis B e a nti ge n ( H Be A g) ne gati ve C H B e nr olle d i n 
ra n d o mize d cli nical trials of T D F, T A F or E T V are as f oll o ws (Terra ult et al, 2 0 1 8 ): 
H B V D N A s u p pressi o n (le ss t ha n 6 0 I U/ m L)  
9 0 t o 9 3 %. 
ala ni ne a mi n otra nsferase  ( A L T) n or malizati o n  7 6 t o 8 8 %. 
L oss of he patitis B s urface a nti ge n ( H Bs A g)   
less t ha n 1 %. 
L o n g-ter m a d mi nistrati o n of NrtIs  is sta n dar d of care f or H Be A g- ne gati ve C H B beca use it 
re d uces li ver-relate d c o m plicati o ns b y s u p pressi n g viral re plicati o n.  T he best a n d safest st o p pi n g 
r ule is H B V D N A s u p pressi o n wit h loss of H Bs A g.  L oss of H Bs A g is ass ociate d wit h re d uce d 
ris k of he patic dec o m pe nsati o n a n d i m pr o ve d s ur vi val ( Terra ult et al, 2 0 1 6; Sari n et al, 2 0 1 6; 
E ur o pea n Ass ociati o n f or t he  St u d y of t he Li ver, 2 0 1 7).  I n t his c o nte xt, a treat me nt f or C H B t hat 
c o ul d i n d uce l oss of H Bs A g lea di n g t o f u ncti o nal c ure is nee de d . 
4. 2.  
Nit az o x a ni de 
Nitaz o xa ni de ( N T Z) is a t hiaz oli de a nti-i nfecti ve wit h i n vitr o acti vit y a gai nst parasites, 
a naer o bic bacteria, a n d vir uses ( A n ders o n a n d C urra n, 2 0 0 7 ). 
Ali nia ® N T Z f or Oral S us pe nsi o n ( patie nts 1 year of a ge a n d ol der) a n d Ali nia N T Z Ta blets 
( patie nts 1 2 years a n d ol der) are mar kete d i n t he U nite d States  f or t he treat me nt of diarr hea 
ca use d b y Gi ar di a l a m bli a  or Cry pt os p ori di u m p arv u m .  Ali nia f or Oral S us pe nsi o n a n d Ali nia 
Ta blets ha ve n ot bee n s h o w n t o be  s u peri or t o place b o f or t he treat me nt of diarr hea ca use d b y 
Cry pt os p ori di u m p arv u m  i n h u ma n i m m u n o deficie nc y vir us (HI V)-i nfecte d or i m m u n o defici e nt 
patie n ts ( R o mar k, 2 0 1 7). 
4. 2. 1.  
A nti vir al Acti vit y of N T Z i n Cell C ult ures 
Tiz o xa ni de, t he acti ve meta b olite of N T Z, has bee n s h o w n t o p os sess a nti viral acti vit y i n cell 
c ult ure a gai nst a br oa d ra n ge of  vir uses i ncl u di n g i nfl ue nza A a n d B vir uses, parai nfl ue nza 

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( Se n dai) vir us, res pirat or y s y ncytial vir us ( R S V ) A- 2, ca ni ne cor o na vir us S- 3 7 8, r ota vir us, 
n or o vir us, he patitis C vir us ge n ot y pes 1a a n d 1 b, Ja pa nese e nce p halitis vir us, de n g ue fe ver 
vir us- 2, yell o w fe ver vir us, he pa titis B vir us, a n d HI V.  T he wi de s pectr u m of a nti viral acti vit y 
s u g gests a cell- me diate d effect rat her t ha n a s pecific viral ta r get ( R ossi g n ol, 2 0 1 4). 
I n cell c ult ure, tiz o xa ni de su p presses H B V D N A i n a d ose- de pe n d e nt ma n ner ( E C 5 0 = 0. 1 5 µ M) 
a n d acts s y ner gisticall y wit h l a mi v u di ne, a def o vir di pi v o xil, T D F a n d E T V.  U nli ke c urre ntl y 
a vaila ble t hera pies, tiz o xa ni d e als o s u p presses H Be A g a n d H Bs A g  i n a d ose- de pe n de nt ma n ner 
at c o nce ntrati o ns si milar t o t h os e re q uire d t o s u p press H B V D N A  ( K or ba et al., 2 0 0 8; 
R o mar k data o n file). 
Rece nt st u dies ha ve s h o w n t hat N T Z i n hi bits H B V tra nscri pti o n f r o m ccc D N A b y i nterferi n g 
wit h t he i nteracti o n bet wee n H B V  re g ulat or y pr otei n x ( H B x) a n d t he h ost pr otei n, 
da ma ge-s pecific- D N A- bi n di n g pr otei n 1 ( D D B 1) ( Se ki ba et al., 2 0 1 9). 
4. 2. 2.  
Cli nic al E x perie nce wit h N T Z 
4. 2. 2. 1.  
O ver all Cli nic al E x perie nce  
N T Z has bee n mar kete d f or  diarr heal disease ca use d b y Gi ar di a  or Cry pt os p ori di u m  i n t he 
U nite d States si nce 2 0 0 3.  I n Lati n A merica, I n dia, Ba n gla des h a n d E g y pt t he dr u g is mar kete d 
as a br oa d-s pectr u m a nti parasitic a ge nt.  It is esti mate d t hat m ore t ha n 3 0 0 milli o n patie nts ha ve 
bee n e x p ose d t o N T Z w orl d wi de w it h t he us ual a d ult d ose bei n g 50 0 m g t wice dail y f or t hree 
da ys.  N o si g nifica nt dr u g-relate d A Es ha ve bee n re p orte d i n p o st- mar keti n g e x perie nce. 
O ver 6, 0 0 0 s u bjects ha ve bee n treat e d wit h N T Z i n cli nical tria ls, i ncl u di n g 1, 7 6 0 s u bjects 
1 2 years of a ge a n d ol der w h o ha ve bee n e x p ose d t o t he N T Z 3 0 0 m g e xte n de d release ta blets 
(as m o n ot hera p y, n = 1, 2 7 2, or i n c o m bi nati o n wit h oselta mi vir, n = 4 8 8).  Of t he 1, 7 6 0 s u bjects, 
1, 3 7 4 were gi ve n a d ose of 6 0 0 m g t wice dail y f or 5 da ys.  T he m ost c o m m o nl y (at least 2 % of 
treate d s u bjects) re p orte d a d verse e ve nts ( A Es) re gar dless of c a usalit y assess me nt were: diarr hea 
( 6. 4 %), c hr o mat uria ( 4. 7 %), hea dac he ( 3. 5 %), na usea ( 3. 1 %), a b d o mi nal pai n/a b d o mi nal pai n 
u p per ( 3 %), br o nc hitis ( 2. 7 %), a n d v o miti n g ( 2. 3 %).  I n t he pla ce b o-c o ntr olle d trials, t he rates of 
occ urre nce of A Es di d n ot differ si g nifica ntl y fr o m t h ose of place b o e xce pt f or c hr o mat uria 
( 4. 7 % vs 0. 2 %).  Less t ha n 1 % of su bjects disc o nti n ue d t hera p y beca use of A Es. 
Ot her cli nical st u dies of N T Z i m me diate-release ta blets, oral s us pe nsi o n, or ot her f or m ulati o ns 
ha ve bee n c o n d ucte d i n m ore t ha n 4, 2 5 0 s u bjects.  T he d ose was t y picall y 5 0 0 m g t o 1 5 0 0 m g 
t wice dail y f or a d ults a n d a d olesce nts at least 1 2 years of a ge  or 7. 5 m g/ k g/ da y f or c hil dre n u n der 
1 2 years of a ge, a n d t he d urati o n of  treat me nt was t y picall y 3 t o 1 4 da ys. 
T he pr o d uct has bee n st u die d f or  l o n ger d urati o ns i n s u bjects wit h ac q uire d i m m u ne deficie nc y 
s y n dr o me ( AI D S) a n d cr y pt os p ori di osis, a n d i n s u bjects wit h c hro nic he patitis C.  A t otal of 
6 6 0 s u bjects e nr olle d i n t hese l o n g-ter m st u dies recei ve d N T Z f or m ore t ha n 1 m o nt h 
( ma xi m u m of 1, 5 2 8 da ys), of w hich 4 1 1 were treate d f or greater t ha n 3 m o nt hs, m ostl y at a d ose 
ra n ge of 5 0 0 m g t o 1 3 5 0 m g t wice dail y.  I n 3 1 5 s u bjects wit h chr o nic he patitis C, N T Z was 
a d mi nistere d at d oses ra n gi n g fr o m 5 0 0 m g t o 1 3 5 0 m g t wice dail y wit h f o o d f or u p t o 5 2 wee ks. 
T he A Es ass ociate d wit h l o n g-te r m use of N T Z were pri maril y relate d t o t he gastr oi ntesti nal ( GI) 
tract wit h mil d t o m o derate a n d tra nsie nt a b d o mi nal pai n, diarrhea, hea dac he a n d na usea bei n g 
t he m ost c o m m o n A Es re p orte d.  Mil d a n d tra nsie nt yell o w disc olorati o n of t he uri ne a n d sclera 

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ha ve als o bee n re p orte d, partic ularl y i n s u bjects recei vi n g d os es of at least 1, 0 0 0 m g BI D f or 
e xte n de d d urati o ns. 
4. 2. 2. 2.  
Cli nic al E x perie nce i n C H B 
R ossi g n ol a n d Brec h ot descri be d t he res ults of a n o pe n la bel, p il ot cli nical trial i n E g y pt i n 
9 s u bjects wit h c hr o nic C H B wit h o ut  cirr h osis.  All were H Bs A g p ositi ve a n d t w o were H Be A g 
p ositi ve.  O n bi o ps y, i nfla m mat or y gra di n g ra n ge d fr o m 2 t o 6/ 1 8 a n d fi br osis sta gi n g ra n ge d 
fr o m 1 t o 3/ 6.  N T Z 5 0 0 m g i m me di ate release ta blets were a d mi n istere d orall y t wice dail y wit h 
f o o d f or u p t o 4 8 wee ks.  N T Z was well t olerate d wit h occasi o nal mil d t o m o derate si de effects 
pri maril y relate d t o t he gastr o i ntesti nal tract, i ncl u di n g diarr hea a n d e pi gastric pai n.  
T hese a d verse e ve nts were tra n sie nt a n d res ol ve d d uri n g t hera p y; n o ne re q uire d disc o nti n uati o n 
of treat me nt.  T here were n o la b orat or y a b n or malities t hat were  dee me d t o be relate d t o 
treat me nt.  H B V D N A beca me u n detecta ble (less t ha n 3 8 I U/ m L) i n t he ser u m of 8 of t he 
9 s u bjects ( 8 9 %) after 4 t o 2 0 wee k s of N T Z treat me nt.  T he t w o s u bjects w h o were H Be A g 
p ositi ve beca me H Be A g ne gati ve after 4 a n d 1 6 wee ks of treat me n t, res pecti vel y.  T hree of t he 
9 s u bjects ( 3 3 %) beca me H Bs A g ne gati ve; t w o of t he m after 8 wee ks a n d o ne after 4 8 wee ks of 
treat me nt.  T he s u bject wit h the later res p o nses ( 2 0 wee ks t o u n detecta ble H B V D N A, 1 6 wee ks 
t o H Be A g ne gati ve, a n d 4 8 wee ks t o H Bs A g ne gati ve) was treate d wit h 5 0 0 m g N T Z o nl y o nce 
dail y ( R ossi g n ol a n d Brec h ot, 2 0 1 9 ). 
A brief re p ort of t he ni ne cas es descri be d a b o ve al o n g wit h t hr ee ot her case re p orts was re vie we d 
b y R ossi g n ol a n d Keeffe i n 2 0 0 8.  T w o of  t hese a d diti o nal t hree cases were H Be A g- p ositi ve 
patie nts i n E g y pt, a n d eac h recei v e d N T Z 5 0 0 m g i m me diate relea se ta blets orall y t wice dail y.  
B ot h beca me H Be A g ne gati ve a n d e x perie nce d decli nes i n ser u m H B V D N A wit h o ne of t he 
t w o cleari n g ser u m H B V D N A.  T he t hir d case was a 6 0 year- ol d male i n t he U nite d States wit h 
H Be A g p ositi ve c hr o nic he patitis B w h o ha d recei ve d la mi v u di ne 1 0 0 m g dail y f or t w o years 
a n d t he n a def o vir 1 0 m g dail y f or  o ne year wit h o ut res p o nse.  NT Z 5 0 0 m g t wice dail y was 
a d de d t o c o nti n ue d a def o vir f or a t otal of t w o years of c o m bi nati o n t hera p y.  T his patie nt 
de vel o pe d n or mal A L T, u n detecta ble ser u m H B V D N A, ne gati ve H Be A g a n d ne gati ve H Bs A g 
a n d ha d d oc u me nte d ser oc o n versi o n t o a nti b o d y t o H Bs A g (a nti- H Bs).  N o safet y data were 
re p orte d f or t hese three case re p orts ( R ossi g n ol a n d Keeffe, 2 0 0 8 ).  K ol ozi et al, als o re p orte d 
t w o of t hese cases i n a n a bstract, b ut n o safet y data was pr o vi de d ( K ol ozi et al., 2 0 0 8 ). 
4. 3.  
R ati o n ale f or t he St u d y 
T here is a nee d f or a ne w treat me nt of C H B t hat pr o vi des a f u nc ti o nal c ure wit h s u p pressi o n of 
H B V D N A a n d l oss of H Bs A g.  N T Z  i n hi bits re plicati o n of H B V i n vitr o b y mea ns of a n o vel 
mec ha nis m.  It is u ni q ue i n t ha t it i n hi bits H B V tra nscri pti o n fr o m ccc D N A a n d s u p presses H B V 
D N A w hile als o s u p pressi n g H Be A g a n d H Bs A g.  T his st u d y will e v al uate t he effect of differe nt 
d oses of N T Z o n q ua ntitati ve H Bs A g i n a n eff ort t o i de ntif y a d osa ge re gi me n f or f urt her 
de vel o p me nt wit h t he o bjecti v e of i n d uci n g l oss of H Bs A g. 
5.  
S T U D Y O B J E C TI V E S 
T his ra n d o mize d c o ntr olle d trial  is desi g ne d t o e val uate safet y, effecti ve ness a n d 
p har mac o ki netic- p har mac o d y na mic ( P K/ P D) relati o ns hi ps ass ociate d wit h t hree differe nt N T Z 
treat me nt re gi me ns a d de d t o T D F, T A F or E T V i n treati n g C H B. 

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6.  
S T U D Y D E SI G N 
T he st u d y will be a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d desi g n.  F ort y-ei g ht s u bjects 
will be selecte d acc or di n g t o t he i ncl usi o n a n d e xcl usi o n crite ria liste d bel o w.  U p o n e nr oll me nt 
i n t he st u d y, s u bjects will be ra n d o mize d t o o ne of t he f oll o win g treat me nt gr o u ps ( 1 2 s u bjects 
per gr o u p):  
• 
Gr o u p 1: P L A C E B O 
S u bjects will ta ke t hree pl ace b o ta blets t wice dail y. 
• 
Gr o u p 2: 6 0 0 m g N T Z o nce dail y ( Q D). 
S u bjects will ta ke t w o N T Z 3 0 0 m g e xte n de d release ta blets a n d o ne place b o ta blet i n t he 
m or ni n g a n d t hree place b o ta blets i n t he e ve ni n g. 
• 
Gr o u p 3: 6 0 0 m g N T Z t wice dail y ( BI D). 
S u bjects will ta ke t w o N T Z 3 0 0 m g e xte n de d release ta blets a n d o ne place b o ta blet t wice dail y. 
• 
Gr o u p 4: 9 0 0 m g N T Z BI D. 
S u bjects will ta ke t hree N T Z 3 0 0 m g e xte n de d release ta blets t w ice dail y. 
N T Z a n d place b o ta blets will be a d mi nistere d orall y wit h f o o d.  All s u bjects will c o nti n ue T D F, 
T A F or E T V t hera p y t hr o u g h o ut t he st u d y. 
After 1 2 wee ks, s u bjects will c o n ti n ue treat me nt wit h t he sa me treat me nt re gi me n if t he y ha ve 
ac hie ve d a n y decli ne i n  q ua ntitati ve H Bs A g (q H Bs A g) fr o m Baseli ne t o Wee k 1 2.  T he s u bjects 
will disc o nti n ue treat me nt wit h t he i n vesti gati o nal me dicati o n ( N T Z a n d/ or place b o) d ue t o: 
• 
A d verse e ve nts 
• 
Wit h dra w n c o nse nt 
• 
N o nc o m plia nce 
• 
T he s u bject fails t o ac hie ve a n y decli ne i n q H Bs A g fr o m Baseli n e t o Wee k 1 2, at least a 
0. 5 l o g 1 0 decli ne fr o m Baseli ne t o Wee k 2 4, at least a 1 l o g1 0 decli ne fr o m Baseli ne t o 
Wee k 4 8, at least a 2 l o g
1 0 decli ne fr o m Baseli ne t o Wee k 7 2 or H Bs A g l oss at Wee k 9 6. 
• 
T he s u bject e x perie nces H Bs A g l oss wit h H B V D N A s u p pressi o n mai ntai ne d o n 
treat me nt f or 2 4 wee ks (c o ns oli dati n g t hera p y).  T D F, T A F or E TV t hera p y will als o be 
disc o nti n ue d. 
S u bjects will ret ur n t o t h e cli nic at Da y 3, Wee ks 1, 2, 4, 8, 1 2, 1 6, 2 0, 2 4 a n d e ver y 1 2 wee ks 
t hereafter d uri n g t he treat me nt peri o d.  Bl o o d sa m ples will be c ollecte d at eac h visit f or 
la b orat or y a n d/ or ser ol o g y tests.  Bl o o d sa m ples f or tr o u g h (j ust pri or t o d osi n g) plas ma le vels of 
NrtI a n d tiz o xa ni de will be c ollecte d at Baseli ne a n d eac h sc he d ule d visit w hile o n t hera p y. 
S u bjects will ret ur n t o t he cli nic f or off-treat me nt f oll o w- u p at 4, 8 a n d 1 2 wee ks f oll o wi n g t he 
e n d of treat me nt wit h i n vesti ga ti o nal me dicati o n ( N T Z a n d/ or place b o).  I n t he e ve nt t hat a 
s u bject has s ustai ne d H Bs A g l oss wit h H B V D N A s u p pressi o n at t he Wee k 1 2 f oll o w- u p visit, 
t hat s u bject will ret ur n f or a d diti o nal f oll o w- u p visits 2 4 a n d 4 8 wee ks after t he e n d of treat me nt. 
T he st u d y will be u n bli n de d t o t he S p o ns or ( R o mar k) a n d Me dical  M o nit or after all s u bjects 
ha ve c o m plete d 1 2 wee ks of treat me nt a n d c o m plete data is c olle cte d t hr o u g h t hat ti me p oi nt f or 

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a nal ysis of safet y a n d t he pri mar y efficac y para meter ( mea n c ha n ge i n q H Bs A g at Wee k 1 2).  
T he i n vesti gat ors, s u bjects a n d cli nical m o nit ors will re mai n b li n de d t hr o u g h o ut t he st u d y. 
R ati o n ale f or st u dy desi g n:   I n vitr o data s u g gest t hat N T Z ma y be effecti ve i n i n d uci n g l oss of 
H Bs A g i n patie nts wit h C H B.  Cell c ult ure st u dies ha ve s h o w n t hat c o m bi nati o ns of N T Z wit h 
t he NrtIs, la mi v u di ne, a def o vir di p o v o xil, T D F a n d E T V are s y ner gistic i n i n hi biti n g H B V 
re plicati o n.  T he NrtIs are p o orl y effecti ve i n pr o d uci n g H Bs A g l oss or ser oc o n versi o n, a n d 
t heref ore, patie nts m ust re mai n o n c hr o nic t her a p y i n or der t o mai ntai n s u p pressi o n of H B V 
D N A.  Wit h t his bac k gr o u n d, t his st u d y is desi g ne d t o e val uate w het her t he c o m bi nati o n of N T Z 
pl us T D F, T A F or E T V is s u peri or  t o T D F, T A F or E T V al o ne i n red uci n g q ua ntitati ve ser u m 
H Bs A g.  T D F, T A F or E T V were sel ecte d f or use i n t his st u d y bec a use t he y are wi del y use d f or 
treati n g C H B a n d beca use of t heir pote nc y i n re d uci n g ser u m H B V  D N A a n d s u peri or resista nce 
pr ofiles.  T his st u d y is a P ha se 2 st u d y, a n d t heref ore, t he n um ber of s u bjects per treat me nt ar m 
is l o w.  T his st u d y is desi g ne d to pr o vi de data, i ncl u di n g d ose -ra n ge-fi n di n g data, t o deter mi ne 
w het her N T Z re d uces q H Bs A g a n d t o g ui de f ut ure de vel o p me nt of N T Z i n treati n g C H B 
i nfecti o n. 
R ati o n ale f or d ose a n d d u r ati o n of tre at me nt:  T he d ose of T D F, T A F or E T V use d i n t his st u d y 
is t he sta n dar d d ose a p pr o ve d b y the F D A a n d ot her re g ulat or y a ut h orities.  T he d oses of N T Z 
were selecte d base d u p o n safet y, t olera bilit y a n d p har mac o ki net ics data fr o m pri or cli nical 
e x perie nce wit h nitaz o xa ni de.  E xt e n de d release ta blets a d mi nistere d t wice dail y will be use d t o 
ac hie ve stea d y state plas ma c o nce n trati o ns of tiz o xa ni de a b o ve t he c o nce ntrati o ns re q uire d t o 
i n hi bit H Bs A g i n cell c ult ures.  While it is e x pecte d t hat t his  a p pr oac h will be o pti mal, a 6 0 0 m g 
o nce dail y re gi me n will als o be use d t o e val uate effecti ve ness.   T w o differe nt d oses ( 6 0 0 m g a n d 
9 0 0 m g) will be use d i n t wice dail y re gi me ns. T hese d oses are l o wer t ha n d oses t hat ha ve bee n 
use d wit h o ut safet y iss ues i n c li nical trials i n v ol vi n g l o n g-ter m (at least 4 8 wee ks) treat me nt of 
s u bjects wit h c hr o nic he patitis C or AI D S-relate d cr y pt os p ori diosis.  D oses of 1, 0 0 0 t o 1, 3 5 0 m g 
N T Z t wice dail y ha ve bee n ass ociat e d wit h gastr oi ntesti nal si de  effects (e. g., e pi gastric pai n, 
diarr hea) t hat ma ke t h ose re gi me ns diffic ult t o a d mi nister f or l o n g d urati o ns, a n d t heref ore, a 
ma xi m u m N T Z d ose of 9 0 0 m g t wice dail y has bee n selecte d. 
T he d urati o n of treat me nt t o t he pri mar y e n d p oi nt ( 1 2 wee ks) is  desi g ne d t o pr o vi de a relati vel y 
q uic k deter mi nati o n re gar di n g w het her N T Z i n d uces a mea ni n gf ul re d ucti o n of q H Bs A g.  
S u bjects will be all o we d t o c o nti n ue treat me nt be y o n d 1 2 wee ks if t he y are s h o wi n g pr o gressi ve 
decli nes i n q H Bs A g or if t he y e x perie nce H Bs A g l oss.  T he st o p p i n g r ules re q uire 
disc o nti n uati o n of t he i n vesti gati o nal me dicati o n i n t he e ve nt t hat a s u bject fails t o ac hie ve a n y 
decli ne i n q H Bs A g fr o m Base li ne t o Wee k 1 2, at least a 0. 5 l o g 10 decli ne fr o m Baseli ne t o 
Wee k 2 4, at least a 1 l o g
1 0 decli ne fr o m Baseli ne t o Wee k 4 8, at least a 2 l o g1 0 decli ne fr o m 
Baseli ne t o Wee k 7 2 or H Bs A g l o ss at Wee k 9 6.  T he ge nerall y acce pte d st o p pi n g r ule f or 
pe gi nterfer o n is less t ha n a 1 l o g 1 0 decli ne of H Bs A g at Wee k 1 2.  The st o p pi n g r ules f or t his 
st u d y were selecte d beca use ( 1) t here is i ns ufficie nt i nf or matio n re gar di n g t he p ote ntial q H Bs A g 
res p o nse patter ns t o N T Z a n d ( 2) use of N T Z f or d urati o ns l o n ger t ha n 1 2 wee ks has n ot bee n 
ass ociate d wit h si g nifica nt saf et y iss ues.  S u bjects ac hie vi n g H Bs A g l oss a n d H B V D N A 
s u p pressi o n will c o nti n ue treat me nt wit h t he i n vesti gati o nal medicati o n a n d NrtI u ntil t he y ha ve 
mai ntai ne d H Bs A g l oss a n d H B V D N A s u p pressi o n f or 2 4 wee ks o n t reat me nt (c o ns oli dati n g 
t hera p y).  T he e xte n de d d urati o n of treat me nt f or s u bjects s h o wi n g res p o nse t o treat me nt is 
desi g ne d t o all o w s u bjects t o c o n ti n ue treat me nt if t he y are e xperie nci n g be nefit wit h res pect t o 

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q H Bs A g.  It als o all o ws f or c ollecti o n of data re gar di n g t he d u rati o n of treat me nt f or f ut ure 
cli nical de vel o p me nt. 
7.  
S U B J E C T S E L E C TI O N 
T he criteria f or i ncl usi o n a n d e xcl usi o n are defi ne d bel o w: 
7. 1.  
I ncl usi o n Criteri a 
1.  A ge at least 2 1 years. 
2.  C H B vir us i nfecti o n (ser u m H Bs A g- p ositi ve f or at least 6 m o nt hs  or ser u m H Bs A g 
p ositi ve a n d ne gati ve i m m u n o gl o b uli n M (I g M) a nti b o dies t o H B V c ore a nti ge n (I g M 
a nti- H Bc). 
3.  H Be A g ne gati ve. 
4.  Vir ol o gicall y s u p presse d ( H B V D N A less t ha n t he l o wer li mit of q ua ntitati o n) f or at least 
1 2 m o nt hs o n T D F, T A F or E T V t hera p y. 
5.  Q ua ntitati ve H Bs A g greater t ha n 1 0 0 I U/ m L. 
6.  A L T bel o w 1. 5 ti mes t he u p per li mit of n or mal. 
7.  A ble t o c o m pl y wit h t he  st u d y re q uire me nts. 
7. 2.  
E xcl usi o n Criteri a 
1.  U na ble t o ta ke oral me dicati o ns. 
2.  Fe males w h o are pre g na nt, breas t-fee di n g or n ot usi n g birt h c o ntr ol.  A d o u ble barrier 
met h o d, oral birt h c o ntr ol pills a d mi nistere d f or at least 2 m o nt hl y c ycles pri or t o st u d y 
dr u g a d mi nistrati o n, a n i ntra uteri ne de vice (I U D), or me dr o x y pr o gester o ne acetate 
a d mi nistere d i ntra m usc ularl y f or a mi ni m u m of o ne m o nt h pri or t o st u d y dr u g 
a d mi nistrati o n are acce pta ble met h o ds of birt h c o ntr ol f or i ncl usi o n i nt o t he st u d y.  I n 
a d diti o n, fe male s u bjects s h o ul d ha ve a Baseli ne pre g na nc y test  a n d s h o ul d a gree t o 
c o nti n ue a n acce pta ble met h o d of birt h c o ntr ol f or t he d urati o n  of t he st u d y (i ncl u di n g 
f oll o w- u p) if se x uall y acti ve. 
3.  A n y i n vesti gati o nal dr u g t hera p y wit hi n 3 0 da ys pri or t o e nr oll me nt. 
4.  Ot her ca uses of li ver disease. 
5.  C o-i nfecti o n wit h HI V, he patitis C  vir us ( H C V) or he patitis D vir us ( H D V) base d o n a n 
e nz y me i m m u n oassa y ( EI A). 
6.  Hist or y of alc o h olis m or wit h a n a lc o h ol c o ns u m pti o n of greater t ha n 4 0 g per da y. 
7.  Cli nicall y u nsta ble. 
8.  A n y c o nc o mita nt c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or w o ul d precl u de 
e val uati o n of res p o nse or ma ke it  u nli kel y t hat t he c o nte m plated c o urse of t hera p y a n d 
f oll o w- u p c o ul d be c o m plete d. 

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9.  Hist or y of h y perse nsiti vit y or i nt olera nce t o N T Z or a n y of t he  e xci pie nts c o m prisi n g t he 
N T Z ta blets. 
1 0.  He pat ocell ular carci n o ma. 
1 1.  Dec o m pe nsate d li ver disease i ncl u di n g hist or y of ascites, blee di n g es o p ha geal varices, 
p ortal h y perte nsi o n or he pa tic e nce p hal o pat h y. 
1 2.  Fi br o Sca n ® sc ore greater t ha n 1 1 or hist or y of cirr h osis o n li v er bi o ps y. 
1 3.  Creati ni ne cleara nce < 6 5 ml/ mi n ut e ( b y t he C oc kcr oft- Ga ult e q uati o n usi n g i deal b o d y 
wei g ht). 
1 4.  Hist or y of cli nicall y rele va nt ps yc hiatric disease, seiz ures, c e ntral ner v o us s yste m 
d ysf u ncti o n, se vere pre-e xisti n g car diac, re nal, pat h ol o gic b o n e fract ure or ot her ris k 
fact ors f or oste o p or osis, he mat ol o gical disease or me dical ill ness t hat i n t he i n vesti gat or's 
o pi ni o n mi g ht i nterfere wit h t hera p y. 
1 5.  Mali g na nt disease wit hi n 3 years of trial e ntr y. 
1 6.  R he u mat ol o gical c o n diti o ns, i nfla m mat or y b o wel disease or ps ori asis re q uiri n g or 
a ntici pate d t o re q uire bi ol o gica l/i m m u n os u p pressi ve t hera pies. 
1 7.  S u bjects ta ki n g or a ntici pate d t o nee d me dicati o ns c o nsi dere d t o be maj or C Y P 2 C 8 
s u bstrates (see Secti o n 2 3. 1 ). 
8.  
R A N D O MI Z A TI O N 
A n i n de pe n de nt t hir d part y will pr e pare a master ra n d o mizati o n list a n d mai ntai n t he mas ki n g of 
t he st u d y.  S u bjects w h o q ualif y f or the st u d y will be assi g ne d  t o treat me nt usi n g ce ntralize d 
ra n d o mizati o n pr oce d ures stratifie d b y q H Bs A g (less t ha n 3, 3 to 4, greater t ha n 4 l o g 1 0 I U/ m L) 
a n d NrtI t hera p y ( T D F, T A F or E T V ).  T he treat me nt n u m bers will a p pear o n t he me dicati o n kits 
c o ntai ni n g t he mas ke d st u d y me dicati o n.  T he ra n d o mizati o n list  will be mas ke d t o st u d y 
partici pa nts i ncl u di n g S p o ns or, I n vesti gat ors, st u d y m o nit ors, s u bjects a n d la b orat or y pers o n nel.  
U n mas ki n g f or a n y i n di vi d ual s u bj ect will occ ur o nl y if necessi tate d b y e mer ge nc y a n d 
k n o wle d ge of t he me dicati o n bei n g ta ke n will i nfl ue nce t he me dical ma na ge me nt of t he s u bject.  
F urt her m ore, if t he e ve nt warra nts s u b missi o n of a safet y re p or t t o re g ulat or y a ut h orities, t he n 
t he s u bject’s treat me nt assi g n me nt will be u n mas ke d f or c o m pleti o n of t he re p ort.  If a s u bject is 
l ost t o f oll o w u p or disc o nti n ues t he st u d y pri or t o t he assessme nt at wee k 1 2, a n a d diti o nal 
s u bject ma y be e nr olle d i n t he sa me treat me nt gr o u p. 
9.  
S T U D Y P R O C E D U R E S 
T he sc he d ule of st u d y pr oce d ures f or eac h visit are s u m marize d i n Secti o n 2 3. 2  a n d are 
descri be d bel o w. 
9. 1.  
Pre-st u d y E v al u ati o n ( D a y - 3 1 t o 1) 
Bef ore scree ni n g, s u bjects will be  i nf or me d of t he nat ure of t he st u d y, a n d writte n c o nse nt m ust 
be o btai ne d pri or t o partici pati o n. After o btai ni n g i nf or me d c o nse nt, t he f oll o wi n g pr oce d ures 
will be carrie d o ut: 

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1.  C o m plete me dical hist or y 
2.  P h ysical e xa mi nati o n, i ncl u di n g hei g ht, b o d y wei g ht a n d vital s tatistics 
3.  Uri ne pre g na nc y test f or all fe males of c hil d- beari n g p ote ntial  
4.  Re vie w c o nc o mita nt me dicati o ns 
5.  C ollecti o n of bl o o d sa m ple f or se r ol o gical tests f or q H B V D N A, q H Bs A g, q A nti- H Bs, 
H Be A g, a nti- H Be, I g M a nti- H Bc, a nti- HI V, a nti- H C V a n d a nti- H D V.  
6.  C ollecti o n of a bl o o d sa m ple f or la b orat or y tests i ncl u di n g he mo gl o bi n, he mat ocrit, 
c o m plete bl o o d c o u nt (t otal a n d d iffere ntial), platelet c o u nt, pr ot hr o m bi n ti me ( P T), 
i nter nati o nal n or malize d ratio (I N R), ra n d o m/faste d bl o o d s u gar , t otal c h olester ol, 
hi g h- de nsit y li p o pr otei n, tri gl yceri des, al b u mi n, ir o n, ferriti n, as partate a mi n otra nsferase 
( A S T), A L T, ga m ma gl uta m yl tra nsferase ( G G T), creati ne p h os p h o ki nase ( C P K), 
al kali ne p h os p hatase, bilir u bi n (t otal/ direct), bl o o d urea nitro ge n ( B U N), creati ni ne, 
s o di u m, p otassi u m, c hl ori de, an d al p ha-fet o pr otei n ( A F P). 
7.  C ollecti o n of uri ne sa m ple f or r o uti ne uri nal ysis (a p peara nce, gl uc ose, pr otei n a n d 
bl o o d). 
8.  Calc ulati o n of creati n i ne cleara nce b y t he C oc kcr oft- Ga ult e q uati o n usi n g i deal b o d y 
wei g ht. 
9.  Fi br o Sca n ® test. 
1 0.  Ultras o n o gra p h y f or he pat ocell ula r carci n o ma ( H C C) scree ni n g. 
1 1.  C o nfir mati o n t hat t he s u bject sat isfies all i ncl usi o n/e xcl usi o n criteria. 
9. 2.  
B aseli ne ( D a y 1) 
At Baseli ne, t he f oll o wi n g pr oce d ures will be carrie d o ut: 
1.  P h ysical e xa mi nati o n, i ncl u di n g b o d y wei g ht a n d vital statistic s. 
2.  Uri ne pre g na nc y test f or all fe males of c hil d- beari n g p ote ntial . 
3.  Re vie w c o nc o mita nt me dicati o ns. 
4.  C ollecti o n of a bl o o d sa m ple f or  q H B V D N A, q H Bs A g, q A nti- H Bs, HBe A g, a nti- H Be 
a n d a nti- HI V (a nti- HI V is o nl y f or s u bjects at hi g h ris k of c o n tracti n g HI V acc or di n g t o 
t he discreti o n of t he i n vesti gat or). 
5.  C ollecti o n of a bl o o d sa m ple t o be st ore d f or e x pl orat or y a nal y ses of H B V R N A, H B V 
c ore-relate d a nti ge n ( H Bcr A g) , q A nti- H Bc, q ua ntitati ve ccc D N A, H Bs fra g me nts, 
H Bs A g-a nti- H Bs i m m u ne c o m ple x, i m m u n ol o gical st u dies a n d/ or h ost D N A (t o assess 
relati o ns hi ps wit h vir ol o gic res p o nse). 
6.  C ollecti o n of a bl o o d sa m ple f or la b orat or y tests i ncl u di n g he mo gl o bi n, he mat ocrit, 
c o mplete bl o o d c o u nt (t otal a n d d iffere ntial), platelet c o u nt, P T, I N R, al b u mi n, A S T, 
A L T, G G T, C P K, al kali ne p h os p hatase, bilir u bi n (t otal/ direct), B U N, creati ni ne, s o di u m, 
p otassi u m, c hl ori de, a n d A F P. 

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7.  C ollecti o n of bl o o d sa m ples f or t r o u g h (j ust pri or t o d osi n g) plas ma le vels of NrtI a n d 
tiz o xa ni de. 
8.  C ollecti o n of a uri ne sa m ple f or  r o uti ne uri nal ysis (a p peara nce, gl uc ose, pr otei n a n d 
bl o o d). 
9.  O btai n a 1 2-lea d electr ocar di o gra m ( E C G). 
1 0.  I nstr uct t he s u bject re gar di n g: 
a. A d mi nistrati o n of st u d y me dicati o n. 
b.  Use of birt h c o ntr ol.  Fe male s u bjects of c hil d beari n g p ote ntia l, if se x uall y acti ve, 
will be i nstr ucte d t o c o nti n ue a n acce pta ble met h o d of birt h c o ntr ol f or t he d urati o n 
of t he st u d y a n d f or o ne m o nt h p ost-treat me nt.  Acce pta ble met h o ds of birt h c o ntr ol 
i ncl u de  a  d o u ble  barrier  met h o d,  oral  birt h  c o ntr ol  pills,  a n  IU D,  or 
me dr o x y pr o gester o ne acetate a d mi nistere d i ntra m usc ularl y. 
c. St u d y visits.  S u bjects will be pr o vi de d i nstr ucti o ns f or ret ur ni n g t o t he cli nic f or 
st u d y visits. 
d.  See ki n g e mer ge nc y care or c o nt acti n g t he st u d y p h ysicia n or n ur se.  S u bjects m ust 
be  i nstr ucte d  t o  see k  e mer ge nc y  me dical  care  or  c o ntact  t he  st u d y  p h ysicia n  or 
n urse if he/s he de vel o ps a n y of t he f oll o wi n g s y m pt o ms d uri n g t he st u d y (treat me nt 
peri o d or off-treat me nt f oll o w- u p peri o d). 
 C A L L 9 1 1 ( U nite d States) or L O C A L E M E R G E N C Y S E R VI C E S ( o utsi de 
t he U nite d States) O R H O S PI T A L O R C O N T A C T S T U D Y P H Y SI CI A N I F 
Y O U H A V E: 
 Tr o u ble breat hi n g i ncl u d i n g s h ort ness of breat h. 
 Se vere pai n i n y o ur c hest , s h o ul der or bell y. 
 C A L L S T U D Y N U R S E O R P H Y SI CI A N I F Y O U E X P E RI E N C E: 
 Fe ver t hat d oes n ot g o a wa y or gets hi g her. 
 Feeli n g ver y wea k or tire d. 
 U n us ual ( n ot n or mal) m uscle pai n. 
 Tr o u ble breat hi n g. 
 St o mac h pai n or na usea a n d v o miti n g. 
 Feeli n g c ol d, es peciall y i n y o ur ar ms a n d le gs. 
 Feeli n g dizz y or li g ht- hea de d. 
 Fast or irre g ular heart beat. 
 Yell o wi n g of e yes or sclera. 
 Br o w n or dar k uri ne. 
 C o nf usi o n. 
 Ti g ht ness i n y o ur t hr oat or c hest, ras h (es peciall y hi ves) or itc hi ness. 

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 L oss of a p petite f or se veral da ys or l o n ger. 
 B o wel m o ve me nts (st o ol s) t ur n li g ht i n c ol or. 
1 1.  Ra n d o mizati o n (see Secti o n 8 ). 
At t he Baseli ne visit, s u bjects will be ra n d o ml y assi g ne d t o o n e of t he f oll o wi n g 
treat me nt gr o u ps: 
Gr o u p 1:  P L A C E B O - S u bjects will r ecei ve t hree place b o ta blets t wice dail y wit h 
f o o d i n a d diti o n t o c o nti n ui n g TD F, T A F or E T V t hera p y. 
Gr o u p 2:  6 0 0 m g N T Z Q D - S u bjects will recei ve t w o N T Z 3 0 0 m g e xte n de d 
release ta blets a n d o ne place b o ta blet i n t he m or ni n g a n d t hree place b o ta blets i n t he 
e ve ni n g wit h f o o d i n a d diti o n t o c o nti n ui n g T D F, T A F or E T V t he ra p y. 
Gr o u p 3:  6 0 0 m g N T Z BI D - S u bject s will recei ve t w o N T Z 3 0 0 m g e xte n de d 
release ta blets a n d o ne place b o ta blet t wice dail y wit h f o o d i n a d diti o n t o c o nti n ui n g 
T D F, T A F or E T V t hera p y. 
Gr o u p 4:  9 0 0 m g N T Z BI D - S u bjects will recei ve t hree N T Z 3 0 0 m g e xte n de d 
release ta blets t wice daily wit h f o o d i n a d diti o n t o c o nti n ui n g  T D F, T A F or E T V 
t hera p y. 
S u bjects will be gi ve n a 4- wee k s u p pl y of me dicati o n a n d i nstr u cti o ns o n 
a d mi nistrati o n of t he st u d y me dicati o n. T he N T Z a n d place b o ta b lets ( yell o w) m ust 
be a d mi nistere d wit h f o o d.  T D F, T A F  or E T V ta blets s h o ul d be ad mi nistere d dail y at 
t he sa me ti me eac h da y.  T he first d ose of st u d y me dicati o n s h oul d be ta ke n i n t he 
cli nic u n der t he o bser vati o n of t he i n vesti gat or. 
9. 3.  
E v al u ati o ns D uri n g Tre at me nt 
S u bjects will ret ur n t o t he cli nic f or e val uati o n at Da y 3, a n d Wee ks 1, 2, 4, 8, 1 2, 1 6, 2 0, 2 4 a n d 
e ver y 1 2 wee ks t hereafter d uri n g treat me nt.  Visit wi n d o ws will be ± 1 da y t hr o u g h Wee k 4 a n d 
± 3 da ys t hereafter.  T he f oll o wi n g e val uati o ns will be perf or me d: 
1.  A brief p h ysical e xa mi nati o n i ncl u di n g b o d y wei g ht a n d vital st atistics 
2.  A uri ne pre g na nc y test f or all fe males of c hil d- beari n g p ote ntial (e xce pt f or Da y 3) 
3.  Re vie w c o nc o mita nt me dicati o ns 
4.  C ollecti o n of bl o o d sa m ple f or q H B V D N A, q H Bs A g, q A nti- H Bs, H Be A g, a nti- H Be a n d a nti-
HI V (a nti- HI V is o nl y f or s u bject s at hi g h ris k of c o ntracti n g HI V acc or di n g t o t he discreti o n 
of t he i n vesti gat or) 
5.  C ollecti o n  of  bl o o d  sa m ple  t o  be  s t ore d  f or  e x pl orat or y  a nal yses  of  H B V  R N A,  H Bcr A g, 
q A nti- H Bc,  q ua ntitati ve  ccc D N A,  H Bs   fra g me nts,  H Bs A g-a nti- H Bs  im m u ne  c o m ple x, 
i m m u n ol o gical st u dies a n d/ or h ost D N A (t o assess relati o ns hi ps wit h vir ol o gic res p o nse) 
6.  C ollecti o n  of  bl o o d  sa m ple  f or  la b orat or y  safet y:  he m o gl o bi n,  h e mat ocrit,  c o m plete  bl o o d 
c o u nt,  (t otal  a n d  differe ntial),  platelet  c o u nt,  P T,  I N R,  A S T, A L T,  G G T,  C P K,  al kali ne 
p h os p hatase, bilir u bi n t otal/ dir ect, al b u mi n, B U N, creati ni ne, s o di u m, p otassi u m, c hl ori de, a n d 
A F P (e xce pt f or Da y 3). 

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7.  C ollecti o n  of  bl o o d  sa m ples  f or tr o u g h  (j ust  pri or  t o  d osi n g)  plas ma  le vels  of  NrtI  a n d 
tiz o xa ni de. 
8.  C ollecti o n of a uri ne sa m ple f or  r o uti ne uri nal ysis (a p peara nce, gl uc ose, pr otei n a n d bl o o d) 
(e xce pt f or Da y 3). 
9.  O btai n a 1 2-lea d E C G ( Wee k 1 2 a n d e n d of treat me nt visits o nl y) . 
1 0.  Fi br o Sca n ® testi n g (at  e n d of treat me nt o nl y). 
1 1.  Ultras o n o gra p h y f or H C C scr ee ni n g (e ver y 6 m o nt hs). 
1 2.  Re vie w of a d verse e ve nts/si de effects. 
1 3.  Re vie w  of  c o m plia nce,  c ollecti o n  of  a n y  u n use d  me dicati o ns  fr o m  t he pre vi o us visit, a n d 
dis pe nse ne w s u p pl y of st u d y me dicati o n. 
9. 4.  
F oll o w- u p After E n d of Tre a t me nt wit h N T Z/ Pl ace b o 
S u bjects will ret ur n t o t he c li nic f or f oll o w- u p e val uati o n 4, 8 a n d 1 2 wee ks after t he e n d of 
treat me nt wit h t he i n vesti gati o nal me dicati o n ( N T Z/ place b o).  In t he e ve nt t hat a s u bject has 
s ustai ne d H Bs A g l oss wit h H B V D N A s u p pressi o n at t he Wee k 1 2 f oll o w- u p visit, t hat s u bject 
will als o ret ur n f or a d diti o nal f oll o w- u p visits at 2 4 a n d 4 8 w ee ks after t he e n d of treat me nt. 
T he f oll o wi n g e val uati o ns will be perf or me d d uri n g eac h f oll o w- u p visit: 
1.  Brief p h ysical e xa mi nati o n i nc l u di n g b o d y wei g ht a n d vital statistics. 
2.  Re vie w c o nc o mita nt me dicati o ns. 
3.  C ollecti o n of bl o o d sa m ple f or q H B V D N A, q H Bs A g, q A nti- H Bs, H Be A g, a nti- H Be 
a n d a nti- HI V (a nti- HI V is o nl y f or s u bjects at hi g h ris k of c o n tracti n g HI V acc or di n g 
t o t he discreti o n of the i n vesti gat or). 
4.  C ollecti o n of bl o o d sa m ple t o be s t ore d f or e x pl orat or y a nal yses of H B V R N A, 
H Bcr A g, q A nti- H Bc, q ua ntitati ve c cc D N A, H Bs fra g me nts, H Bs A g-a n ti- H Bs 
i m m u ne c o m ple x, i m m u n ol o gical st u dies a n d/ or h ost D N A (t o assess relati o ns hi ps 
wit h vir ol o gic res p o nse). 
5.  C ollecti o n of bl o o d sa m ple f or la b orat or y safet y: he m o gl o bi n, h e mat ocrit, c o m plete 
bl o o d c o u nt, (t otal a n d differe ntia l), platelet c o u nt, P T, I N R, A S T, A L T, G G T, C P K, 
al kali ne p h os p hatase, bilir u bi n t o tal/ direct, al b u mi n, B U N, creati ni ne, s o di u m, 
p otassi u m, c hl ori de, a n d A F P. 
6.  C ollecti o n of uri ne sa m ple f or r o uti ne uri nal ysis (a p peara nce, gl uc ose, pr otei n a n d 
bl o o d). 
7.  Fi br o Sca n ® testi n g (at e n d of f oll o w- u p o nl y). 
8.  Ultras o n o gra p h y f or H C C scr ee ni n g (e ver y 6 m o nt hs). 
9.  Re vie w of a d verse e ve nts/si de effects. 
All a d vers e e ve nts m ust be f oll o we d u p u ntil t he y res ol ve or ha ve sta bilize d (e ve n be y o n d t he 
f oll o w- u p visit dates pr o vi de d a b o ve). 

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9. 5.  
U nsc he d ule d Visit 
S u bjects ret ur ni n g t o t he cli nic  f or a n u nsc he d ule d visit d ue to a d verse e ve nts will be e val uate d at 
t he discreti o n of t he I n vesti gat or as is me dicall y warra nte d.  Tests a n d/ or pr oce d ures perf or me d 
at t his visit ma y i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g : 
1.  P h ysical e xa mi nati o n, i ncl u di n g b o d y wei g ht a n d vital statistic s. 
2.  Re vie w of c o m plia nce wit h st u d y me dicati o n. 
3.  Re vie w c o nc o mita nt me dicati o ns. 
4.  C ollecti o n of bl o o d sa m ple f or q H B V D N A, q H Bs A g, q A nti- H Bs, H Be A g, a nti- H Be a n d 
a nti- HI V (a nti- HI V is o nl y f or  s u bjects at hi g h ris k of c o ntracti n g HI V acc or di n g t o t he 
discreti o n of t he i n vesti gat or). 
5.  C ollecti o n of bl o o d sa m ple f or la b orat or y safet y: he m o gl o bi n, h e mat ocrit, c o m plete bl o o d 
c o u nt, (t otal a n d differe ntial) , platelet c o u nt, P T, I N R, A S T, A L T, G G T, C P K, al kali ne 
p h os p hatase, bilir u bi n t otal/ dir ect, al b u mi n, B U N, creati ni ne, s o di u m, p otassi u m, c hl ori de, 
a n d A F P. 
6.  C ollecti o n of uri ne sa m ple f or r o uti ne uri nal ysis (a p peara nce, gl uc ose, pr otei n a n d bl o o d). 
7.  Re vie w of a d verse e ve nts/si de effects. 
9. 6.  
St u d y Me dic ati o n Disc o nti n u ati o n a n d Wit h dr a w al Criteri a 
Treat me nt wit h t he i n vesti gati o nal me dicati o n ( N T Z/ place b o) wil l be disc o nti n ued f or i n di vi d ual 
s u bjects f or t he f oll o wi n g reas o ns: 
1.  S u bject wit h dra ws c o nse nt. 
2.  A  s u bject  m ust  disc o nti n ue  st u d y  me dicati o n  f or  t he  f oll o wi n g  m e dical  or  a d mi nistrati ve 
reas o ns [reas o ns f or disc o nti n uin g m ust be rec or de d i n t he case  re p ort f or m ( C R F)]: 
 Vi olati o n of eli gi b ilit y criteria. 
 Material de viati o n fr o m t he trea t me nt pla n s pecifie d i n t he pr ot oc ol. 
 Pr o gressi o n of t he disease w hic h i n t he o pi ni o n of t he i n vesti g at or precl u des f urt her 
partici pati o n. 
 W o me n w h o bec o me pre g na nt. 
3.  A n a d verse e ve nt dee me d s uffi cie ntl y se vere t o re q uire st u d y  disc o nti n uati o n.  T hese i ncl u de: 
 Gra de 2 or hi g her ras h at leas t p ossi bl y relate d t o st u d y dr u g. 
 Gra de 3 or 4 ac ute s yste mic aller gic reacti o n. 
 Gra de 2 ser u m creati ni ne c o nsi d ere d at least p ossi bl y relate d t o t he st u d y dr u g b y t he 
i n vesti gat or, or Gra de 3 or 4 protei n uria o n uri nal ysis, c o nfir me d b y retesti n g. 
 Gra de 2 v o miti n g t hat persists des pite a nti-e metics, or Gra de 3  or hi g her v o miti n g. 
 Gra de 3 or hi g her diarr hea at l east p ossi bl y relate d t o st u d y d r u g. 

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 Treat me nt-e mer ge nt ele vati o n of A L T greater t ha n 2 x baseli ne, i n c o m bi nati o n wit h 
eit her bilir u bi n greater t ha n 2 x t he u p per li mit of n or mal ( U L N ) or I N R greater t ha n 1. 5 x 
U L N or ser u m al b u mi n l ess t ha n  t he l o wer li mit of n or mal ( L L N), c o nfir me d b y 
retesti n g. 
 A n y Gra de 4 A E or c o nfir me d a b n or malit y (e xce pt f or A S T/ A L T ele vati o ns) c o nsi dere d 
at least p ossi bl y relat e d t o t he st u d y dr u g. 
 Cli nical si g ns of he patic dec o m pe nsati o n. 
 Q Tc F pr ol o n gati o n ( Q Tc F greater  t ha n 5 0 0 msec, or i ncrease fr o m baseli ne greater t ha n 
6 0 msec) at a n y ti me p oi nt , c o nfir me d b y re peat E C G. 
4.  S u bject is: 
 H Bs A g p ositi ve wit h n o decli ne i n q H Bs A g fr o m Baseli ne at Wee k 1 2. 
 H Bs A g p ositi ve wit h less t ha n a 0. 5 l o g 1 0 decli ne i n q H Bs A g fr o m Baseli ne at Wee k 2 4. 
 H Bs A g p ositi ve wit h less t ha n a 1 l o g 1 0 decli ne i n q H Bs A g fr o m Baseli ne at Wee k 4 8. 
 H Bs A g p ositi ve wit h less t ha n a 2 l o g 1 0 decli ne i n q H Bs A g fr o m Baseli ne at Wee k 7 2. 
 H Bs A g p ositi ve at Wee k 9 6. 
5.  H Bs A g l oss wit h H B V D N A s u p pre ssi o n mai ntai ne d o n treat me nt f or 2 4 wee ks 
(c o ns oli dati n g t hera p y). 
I M P O R T A N T: T D F, T A F or E T V t hera p y will o nl y be disc o nti n ue d after a s u bject e x perie nces 
s ustai ne d H Bs A g l oss wit h HB V D N A s u p pressi o n f or 2 4 wee ks o n t reat me nt (c o ns oli dati n g 
t hera p y).  Ot her wise, s u bjects will c o nti n ue T D F, T A F or E T V t hera p y after disc o nti n ui n g t he 
i n vesti gati o nal me dicati o n ( N T Z/ place b o). 
9. 7.  
Resc ue T her a p y 
A d diti o nal H B V t hera p y ma y be i nitiate d at t he discreti o n of t h e i n vesti gat or i n t he f oll o wi n g 
circ u msta nces: 
 He patitis B flare defi ne d as a b r u pt rise i n A L T greater t ha n 1 0x u p per li mit of n or mal. 
 E vi de nce of li ver dec o m pe nsati o n wit h bilir u bi n greater t ha n 2 x  u p per li mit of n or mal, 
pr ol o n gati o n of P T greater t ha n 1 sec o n d ass ociate d wit h he pati tis B reacti vati o n, c o nfir me d 
b y re peate d test wit hi n 4 wee ks a part. 
 E vi de nce of cli nical li ver dec o m pe nsati o n wit h de vel o p me nt of ascites, e nce p hal o pat h y, 
variceal blee di n g. 
9. 8.  
Vir ol o g y Testi n g a n d Pl a n f or M o nit ori n g Resist a nce 
A ce ntral la b orat or y will perf or m all cli nical vir ol o g y testi n g .  All vir ol o gic assess me nts will be 
perf or me d usi n g a n F D A-a p pr o ve d or F D A-cleare d assa ys.  Q ua ntit ati ve H Bs A g will be 
deter mi ne d via a c he mil u mi nes ce nt i m m u n oassa y.  I n t he case of vir ol o gic fail ure o n treat me nt 
( q ua ntifia ble H B V D NA after bei n g less t ha n L L O Q), ge n ot y pes a n d p he n ot y pes of Baseli ne a n d 
vir ol o gic fail ure is olates will  be deter mi ne d, a n d ne wl y e mer ged dr u g resista nce-ass ociate d 
s u bstit uti o ns/ m utati o ns will be i de ntifie d. 

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1 0.  
D A T A M A N A G E M E N T 
1 0. 1.  
Electr o nic D at a E ntr y 
Data will be tra nscri be d fr o m s o urce d oc u me nts i nt o a n electr o n ic data ca pt ure ( E D C) s yste m. 
T he res p o nsi ble st u d y m o nit or(s)  will verif y data, w hic h ca n be perf or me d re m otel y or at t he 
cli nical st u d y site.  T he I n vesti gat or will e ns ure t hat t he dat a rec or de d are acc urate a n d c o m plete.  
Q ueries e mer gi n g d uri n g data clea ni n g will be ge nerate d wit hi n t he E D C s yste m b y data 
ma na ge me nt or cli nical researc h ass ociates. T he I n vesti gat or or  his/ her desi g nee will a ns wer t he 
q ueries a n d u p date t he s o urce data, if nee de d.  
A d verse e ve nts a n d c o m or bi d c o n diti o ns will be c o de d b y data ma na ge me nt usi n g t he latest 
versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A); me dicati o ns will be 
c o de d b y data ma na ge me nt usi n g t he  W orl d Healt h Or ga nizati o n ( WH O) D R U G dicti o nar y. 
After t he Last S u bject Last Vis it ( L S L V) has ta ke n place, t he data base will be clea ne d as 
necessar y.  As s o o n as t he data base  is c o nsi dere d clea n, it will be l oc ke d.  T he l oc ke d data base 
will be use d i n t he fi nal statist ical a nal ysis f or st u d y re p orti n g.  Meas ures will be u n derta ke n t o 
pr otect s u bject data ha n dle d d uri n g i ns pecti o ns a gai nst discl os ure t o u na ut h orize d t hir d parties.  
S u bject c o nfi de ntialit y will be mai ntai ne d at all ti mes. 
1 0. 2.  
Pr ot oc ol De vi ati o ns 
Pr ot oc ol de viati o ns will be d oc u me nte d b y t he I n vesti gat or, re p orte d t o t he i nstit uti o nal re vie w 
b oar d (I R B) as a p pr o priate, a n d als o re vie we d b y t he assi g ne d c li nical researc h ass ociate ( C R A). 
De viati o ns will be re p orte d i n t he cli nical trial ma na ge me nt s yste m. Eac h de viati o n will be 
classifie d as maj or or mi n or acc or di n g t o t he f oll o wi n g defi nit i o ns: 
Maj or pr ot oc ol de viati o n:  A de viati o n t hat has a n i m pact o n s u bject safet y, ma y s u bsta ntiall y 
alter ris ks t o s u bjects, ma y ha ve a n effect o n t he i nte grit y of  t he st u d y data, or ma y affect t he 
s u bject’s willi n g ness t o partici pate i n t he st u d y. 
Mi n or pr ot oc ol de viati o n:  All  ot her pr ot oc ol de viati o ns. 
1 0. 3.  
D at a Q u alit y Ass ur a nce 
T he acc urac y a n d relia bilit y of t he st u d y data will be ass ure d b y t he selecti o n of q ualifie d 
I n vesti gat ors a n d a p pr o priate stu d y ce nters, re vie w of pr ot oc ol  pr oce d ures wit h t he I n vesti gat or 
a n d ass ociate d pers o n nel pri or t o t he st u d y, a n d b y peri o dic m onit ori n g visits b y t he S p o ns or.  
Writte n i nstr ucti o ns will be pr o vi de d f or c ollecti o n, pre parati o n, a n d s hi p me nt of sa m ples. 
T he m o nit or will re vie w t he s o urce data f or acc urac y a n d c o m ple te ness, a n d a n y discre pa ncies 
will be res ol ve d wit h t he I n vest i gat or or desi g nee, as a p pr o priate. 
T he S p o ns or will be e ntitle d t o i n s pect a n d a u dit t he facilities use d i n t he cli nical a n d la b orat or y 
parts of t he st u d y, as well as t o ma ke a n o n y mize d c o pies of all  t he data files pertai ni n g t o t he 
st u d y.  Si milar pr oce d ures ma y als o be c o n d ucte d b y a ge nts of an y re g ulat or y b o d y, eit her as part 
of a nati o nal G o o d Cli nical Practice ( G C P) c o m plia nce pr o gra m o r t o re vie w t he res ults of t his 
st u d y i n s u p p ort of a re g ulat ory s u b missi o n.  T he I n vesti gat or s h o ul d i m me diatel y n otif y t he 
S p o ns or if t he y ha ve bee n c o ntac te d b y a re g ulat or y a ge nc y c o ncer ni n g a n u pc o mi n g i ns pecti o n. 

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1 1.  
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 1. 1.  
S a m ple Size C alc ul ati o n 
T he st u d y is desi g ne d t o e val uat e t he safet y a n d efficac y of t h ree differe nt N T Z treat me nt 
re gi me ns c o m pare d t o place b o as a d d- o n t hera p y t o T D F, T A F or ET V i n re d uci n g q ua ntitati ve 
H Bs A g (i n or der t o select a d ose f or f ut ure cli nical trials). 
A st u de nt's t-test wit h a 0. 0 5 t w o -si de d si g nifica nce le vel will ha ve 9 0 % p o wer t o detect t he 
differe nce bet wee n a mea n c ha n ge of 0. 5 l o g 1 0 f or o ne treat me nt  gr o u p a n d n o c ha n ge f or t he 
ot her treat me nt gr o u p w he n si g ma (c o m m o n sta n dar d de viati o n) is 0. 3 3 a n d t he sa m ple size i n 
eac h gr o u p is 1 0.  A sa m ple size of 1 2 per gr o u p was selecte d i n or der t o all o w f or t he p ossi bilit y 
of u p t o 2 n o n-e val ua ble s u bjects  per gr o u p ( d ue t o dr o p- o ut, etc.). 
1 1. 2.  
Effic ac y V ari a bles 
Pri mar y Efficac y Para meter:  T he  mea n c ha n ge i n q H Bs A g fr o m Baseli ne t o Wee k 1 2. 
Sec o n dar y Efficac y Para meters: 
i.  S ustai ne d H Bs A g l oss wit h s u p pressi o n of H B V D N A f or 2 4 wee ks after t he e n d of 
treat me nt. 
ii.  C ha n ge i n q H Bs A g fr o m Baseli ne t o differe nt ti me p oi nts o n treat me nt. 
iii  H Bs A g l oss. 
i v.  H Bs A g ser oc o n versi o n. 
v.  H B V D N A s u p pressi o n. 
vi.  C ha n ge fr o m Baseli ne i n Fi br osis 4 ( FI B- 4) sc ore. 
vii. C ha n ge fr o m Baseli ne i n Fi br o Sca n ®  sc ore. 
1 1. 3.  
Res p o nse Defi niti o ns 
H Bs A g L oss:  H Bs A g bel o w t he l o wer li mit of detecti o n. 
H Bs A g ser oc o n versi o n:  L oss of H Bs A g a n d gai n of a nti- H Bs. 
H B V D N A s u p pressi o n:  H B V D N A less t ha n l o wer li mit of q ua ntita ti o n; tar get n ot detecte d. 
1 1. 4.  
St atistic al Met h o d ol o g y 
T he statistical met h o d ol o g y is  descri be d briefl y bel o w a n d will be descri be d i n detail i n t he 
Statistical A nal ysis Pla n. 
1 1. 4. 1.  
Effic ac y A n al yses 
T he st u d y will be u n bli n de d t o t he S p o ns or ( R o mar k) a n d Me dical  M o nit or f or a nal ysis of 
efficac y a n d safet y data after all  s u bjects ha ve c o m plete d 1 2 wee ks of treat me nt a n d c o m plete 
data is c ollecte d t hr o u g h t hat ti me p oi nt.  T he i n vesti gat ors, s u bjects a n d m o nit ors will re mai n 
bli n de d t hr o u g h o ut t he st u d y. 

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Efficac y a nal yses will be ba se d o n a p o p ulati o n c o nsisti n g of all s u bjects ra n d o ml y assi g ne d t o 
t he st u d y (“i nte nt-t o-treat” p o p ulati o n).  I n t he e ve nt t hat t here are si g nifica nt n u m bers of 
s u bjects w h o fail t o c o m plete t he st u d y, vi olate t he pr ot oc ol, or are n o nc o m plia nt wit h t he st u d y 
me dicati o n, efficac y a nal yses wi ll als o be c o n d ucte d f or a p o p ulati o n e xcl u di n g t hese s u bjects 
(“ per pr ot oc ol p o p ulati o n”). 
Pri mar y effi cac y a nal yses will be  c o n d ucte d as f oll o ws:  F or eac h N T Z treat me nt gr o u p, t he 
mea n c ha n ge i n q H Bs A g fr o m Baseli ne t o Wee k 1 2 will be c o m pare d  t o t hat of t he place b o 
treat me nt gr o u p. 
Sec o n dar y efficac y a nal yses will be c o n d ucte d as f oll o ws: 
 F or eac h of t he t hree N T Z gr o u ps , t he pr o p orti o n of s u bjects wit h s ustai ne d s u p pressi o n of 
H B V D N A a n d H Bs A g l oss at 2 4 wee k s after t he e n d of treat me nt will be c o m pare d t o t he 
pr o p orti o n f or t he place b o treat me nts gr o u p. 
 F or eac h N T Z d ose gr o u p a n d f or eac h st u d y ti me p oi nt, t he c ha n ge i n q H Bs A g fr o m 
Baseli ne will be c o m pare d t o t he  c ha n ge i n q H Bs A g f or t he placeb o treat me nt gr o u p. 
 F or eac h of t he t hree N T Z gr o u ps a n d f or eac h st u d y ti me p oi nt,  t he pr o p orti o n of s u bjects 
wit h H Bs A g l oss will be c o m pa re d t o t he pr o p orti o n f or t he place b o treat me nts gr o u p. 
 F or eac h of t he t hree N T Z gr o u ps a n d f or eac h st u d y ti me p oi nt,  t he pr o p orti o n of s u bjects 
wit h H Bs A g ser oc o n versi o n will be c o m pare d t o t he pr o p orti o n f o r t he place b o treat me nts 
gr o u p. 
 F or eac h of t he t hree N T Z gr o u ps a n d f or eac h st u d y ti me p oi nt,  t he pr o p orti o n of s u bjects 
wit h q ua ntifia ble H B V D N A at Base li ne w h o e x perie nce d H B V D N A su p pressi o n will be 
c o m pare d t o t he pr o p orti o n f or  t he place b o treat me nts gr o u p. 
 F or eac h N T Z d ose gr o u p a n d f or eac h st u d y ti me p oi nt, t he mea n  c ha n ge i n Fi br osis 4 
( FI B- 4) sc ore fr o m Baseli ne will be c o m pare d t o t he c ha n ge f or t he place b o treat me nt gr o u p. 
 F or eac h N T Z d ose gr o u p, t he mea n c ha n ge i n Fi br o Sca n ®  sc ore fr o m Baseli ne t o e n d of 
treat me nt a n d t o e n d of off-treat me nt f oll o w- u p will be c o m pared t o t he c ha n ge f or t he 
place b o treat me nt gr o u p. 
Mea ns will be c o m pare d b y t w o-si d e d st u de nt’s t tests, α = 0. 0 5 .  N o n para metric data will be 
a nal yze d usi n g t he Wilc o x o n ra n k s u m ( Ma n n- W hit ne y) test.  Pr o p orti o ns will be c o m pare d 
usi n g a t w o-si de d Fis her’s E xact test, α = 0. 0 5.  I n t he setti n g of a n earl y P hase 2 st u d y, n o 
a dj ust me nts f or m ulti plicit y are pla n ne d. 
1 1. 4. 2.  
S afet y A n al yses 
All ra n d o mize d s u bjects w h o recei ve t he st u d y me dicati o n will b e assesse d f or dr u g safet y. 
Safet y a nal yses will be d o ne descri pti vel y. 

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1 2.  
I N V E S TI G A TI O N A L P R O D U C T S 
1 2. 1.  
I de ntit y of I n vesti g ati o n al Pr o d ucts 
N T Z 3 0 0 m g e xte n de d release ta bl ets ma n ufact ure d f or R o mar k La b orat ories, L. C. b y Xcelie nce 
I nc., Ta m pa, Fl ori da. Eac h ta blet is a yell o w, r o u n d, c o n ve x, fil m-c oate d, bi-la yer ta blet f or oral 
a d mi nistrati o n, eac h ta blet c o ntai ns 3 0 0 m g of N T Z a n d t he i nac ti ve i n gre die nts. 
T he st u d y me dicati o ns will be pr o vi de d b y t he st u d y s p o ns or. 
1 2. 2.  
P ac k a gi n g a n d L a beli n g 
All st u d y me dicati o n will be pa c ka ge d a n d la bele d b y t he st u d y s p o ns or a n d its c o ntract ors.  
N T Z a n d place b o ta blets will pac ka ge d i n w hite 3 0cc H D P E b ottles, eac h c o ntai ni n g 3 0 ta blets.  
T he b ottles will be st ore d at r o o m te m perat ure.  D o n ot st ore a b o ve 2 5º C a n d pr otect fr o m 
m oist ure.  T he b o x a n d b ottles will bear a la bel wit h t he f oll o wi n g i nf or mati o n: 
E xter n al B o x L a bel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n vesti gat or Na me 
 
1 8 0 Ta blets  
 
 
 
 
 
R M 0 8- 2 0 0 1  
 
 
 
 
 
 
 
Treat me nt # 
L ot # 
 
 
 
 
 
Nitaz o xa ni de/ Pl ace b o 3 0 0 m g Ta blets 
E X P Date  Ta ke o ne ta blet fr o m b ottle A, B, a n d C b y m o ut h eac h m or ni n g wit h f o o d, a n d 
  
  
ta ke o ne ta blet fr o m b ottle D, E, a n d F b y m o ut h eac h e ve ni n g wit h f o o d.   
 
 
 
 
 
 
 
 
“ F or cli nical trial use o nl y ” 
 
 
 
 
 
 
D o n ot st ore ab o ve 2 5⁰ C.  Pr otect fr o m m oist ure.   
St u d y S p o ns or: T he R o mar k I nstit ute f or Me dical Researc h 
 
 
I n di vi d u al B ottle L a bel ( A M D oses) 
3 0 Ta blets  
 
 
 
 
 
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Treat me nt # 
L ot # 
 
 
 
 
 
Nitaz o xa ni de/ Pl ace b o 3 0 0 m g Ta blets    
  
B ottle # ( A- C) 
 
 
 
 
 
Ta ke o ne ta blet b y m o ut h eac h m or ni n g wit h f o o d. 
 
 
 
 
 
 
 
 
“ F or cli nical trial use o nl y ” 
 
 
 
 
 
 
D o n ot st ore ab o ve 2 5⁰ C.  Pr otect fr o m m oist ure.   
St u d y S p o ns or: T he R o mar k I nstit ute f or Me dical Researc h 
 

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C O N FI D E N TI A L 
I n di vi d u al B ottle L a bel ( P M D oses) 
3 0 Ta blets  
 
 
 
 
 
R M 0 8- 2 0 0 1  
 
 
 
 
 
 
 
Treat me nt # 
L ot # 
 
 
 
 
 
Nitaz o xa ni de/ Pl ace b o 3 0 0 m g Ta blets    
  
B ottle # ( D- F) 
 
 
 
 
 
Ta ke o ne ta blet b y m o ut h eac h e ve ni n g wit h f o o d. 
 
 
 
 
 
 
 
 
“ F or cli nical trial use o nl y ” 
 
 
 
 
 
 
D o n ot st ore ab o ve 2 5⁰ C.  Pr otect fr o m m oist ure.   
St u d y S p o ns or: T he R o mar k I nstit ute f or Me dical Researc h 
 
 
S u bjects will be pr o vi de d wit h a n i nf or mati o n car d c o ntai ni n g t he na me, a d dress, a n d tele p h o ne 
n u m ber of t he best c o ntact  if t he y ha ve q uesti o ns. 
1 2. 3.  
Dr u g Acc o u nt a bilit y 
Me dicati o n s u p plies will be dis p e nse d at Baseli ne ( Da y 1) a n d e ver y 4 t o 1 2 wee ks d uri n g t he 
treat me nt peri o d, de pe n di n g o n t he visit sc he d ule.  S u bjects will be as ke d t o ret ur n a n y u n use d 
s u p plies at eac h visit. 
T he i n vesti gat or is re q uire d t o mai ntai n a de q uate rec or ds of t h e dis p ositi o n of all st u d y dr u g, 
i ncl u di n g dates, q ua ntit y a n d use b y s u bject.  U n use d s u p plies m ust be ret ur ne d t o t he S p o ns or or 
destr o ye d i n acc or da nce wit h i nstit uti o nal pr oce d ures i n effect  at t he st u d y site. 
1 2. 4.  
S u bject C o m pli a nce a n d Dis all o we d Me dic ati o ns 
S u bject c o m plia nce wit h t he pr ot oc ol will be c hec ke d b y t he I n v esti gat or a n d rec or de d i n t he 
C R F at eac h visit. 
S u bjects will be c o nsi dere d n o n-c o m plia nt if t he y ha ve misse d m ore t ha n 2 0 % of t he d oses of t he 
st u d y me dicati o n or if t he y ta ke a n y a nti viral dr u g acti ve a gai nst H B V ot her t ha n t he 
i n vesti gati o nal me dicati o n, T D F, T A F a n d E T V.  
D uri n g t he acti ve treat me nt c o urse of t he st u d y, c o nc o mita nt us e of me dicati o ns c o nsi dere d 
maj or C Y P 2 C 8 s u bstrates ( Secti o n 2 3. 1 ) are pr o hi bite d.  S u bjects are als o pr o hi bite d fr o m ta ki n g 
a n y ot her i n vesti gati o nal me dicati o n d uri n g t he st u d y. 
1 3.  
A D V E R S E E V E N T S 
T he ter m “a d verse e ve nt” is de fi ne d f or p ur p oses of t his st u d y as a n y u n wa nte d p h ysical, 
ps yc h ol o gical or be ha vi oral c ha n ge e x perie nce d b y a s u bject d ur i n g t he c o urse of t he st u d y a n d 
after ta ki n g t he first d ose of s t u d y me dicati o n re gar dless of its se verit y or relati o n t o t he st u d y.  
A d verse e ve nts ma y i ncl u de s y m pt o ms, si g ns, u ne x pecte d w orse ni n g of pre-e xisti n g c o n diti o ns, 
cli nicall y si g nifica nt c ha n ges i n la b orat or y values, diseases a n d s y n dr o mes, a n d si g nifica nt a n d 
u ne x pecte d fail ures of p har mac ol o gical acti o n of ot her me dicati o ns.  S y m pt o ms of C H B will n ot 
be re p orte d as a d verse e ve nts. 

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C O N FI D E N TI A L 
A d verse e ve nts will be rec or de d o n t he a p pr o priate E D C f or ms t hr o u g h o ut t he st u d y, a n d t he 
se verit y of eac h a d verse e ve nt will be gra de d o n a f o ur- p oi nt scale: mil d, m o derate, se vere, or 
life-t hreate ni n g ( See Secti o n 2 3. 3 ).  T he d urati o n of t he a d verse e ve nt a n d relati o ns hi p t o t he 
st u d y dr u g will als o be rec or de d.  All a d verse e ve nts m ust be f oll o we d u ntil t heir res ol uti o n or 
sta bilizati o n e ve n be y o n d t he pla n ne d st u d y peri o d. 
1 3. 1.  
Defi niti o ns 
T he f oll o wi n g defi niti o ns will a p pl y t o t he re p orti n g of a d vers e e ve nts: 
1.  Seri o us A d verse E ve nt: A n y a d verse e x perie nce occ urri n g at a n y d ose t hat is fatal or 
life  t hreate ni n g;  re q uires  i n- patie nt  h os pitalizati o n  or  pr ol o ngati o n  of  a n  e xisti n g 
h os pitalizati o n; is a persiste nt  si g nifica nt disa bilit y/i nca pacit y; is a c o n ge nital a n o mal y 
or birt h defect; or is a n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be life-
t hreate ni n g, or re q uire h os pitalizati o n b ut, base d u p o n a p pr o priate me dical j u d g me nt, 
ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d a b o ve. 
2.  U ne x pecte d A d verse E ve nt: A n y a d verse e x perie nce t hat is n ot i d e ntifie d i n nat ure, 
se verit y,  or  fre q ue nc y  i n  t he  I n vesti gat or's  Br oc h ure  f or  N T Z  o r  t he  res pecti ve 
prescri bi n g i nf or mati o n f or T D F, T A F or E T V. 
3.  Se verit y  of  a d verse  e ve nts  will  be  assesse d  b y  t he  I n vesti gat or  usi n g  t he  T o xicit y 
Gra di n g Scale Ta bles pr o vi de d i n Secti o n 2 3. 3 ( deri ve d a n d a da pte d fr o m “ Di visi o n of 
AI D S Ta ble f or Gra di n g t he Se verit y of A d ult a n d Pe diatric A d ve rse E ve nts,” Versi o n 
2. 1, P u blis h Date: J ul y 2 0 1 7) 
4.  Ca usalit y (relati o ns hi p t o treat me nt) will be assesse d as f oll o ws: 
T he I n vesti gat or will assess ca u sal relati o ns hi p bet wee n I n vesti gati o nal Pr o d uct a n d eac h 
a d verse e ve nt a n d a ns wer “ yes ” or “ n o” t o t he q uesti o n, “ D o y o u  c o nsi der t hat t here is a 
reas o na ble p ossi bilit y t hat t he e ve nt ma y ha ve bee n ca use d b y t he I n vesti gati o nal Pr o d uct?” 
U n der d o u ble- bli n d treat me nt c o n diti o ns, it s h o ul d be ass u me d t hat all s u bjects ar e ta ki n g t he test 
dr u g. 
1 3. 2.  
Cli nic al A d verse E ve nts 
At t he ti me of eac h ret ur n vis it, t he s u bject will be q uesti o ned re gar di n g t he occ urre nce a n d 
nat ure of a n y a d verse e ve nts.  All e ve nts m us t be rec or de d i n the s u bjects' me dical rec or ds a n d i n 
t he E D C s yste m.  A n y s u bject affecte d will be e xa mi ne d b y t he In vesti gat or as dee me d necessar y 
t o ascertai n t he c o urse of t he eve nt a n d a n y resi d ual effects.  
All m o derate a n d se vere a d verse e ve nts will be re vie we d b y t he Pri nci pal I n vesti gat or w h o will 
deter mi ne usi n g his/ her best cli n ical j u d g me nt w het her t he y warra nt t he s u bject t o be 
disc o nti n ue d fr o m t he st u d y.  T he S p o ns or will be n otifie d i m me diatel y if a s u bject is 
disc o nti n ue d fr o m t he st u d y.  F or  all a d verse e ve nts t hat re q uire t he s u bject t o be disc o nti n ue d 
fr o m t he st u d y, rele va nt cli nical assess me nts a n d la b orat or y tests will be re peate d as cli nicall y 
i n dicate d u ntil fi nal res ol uti o n or sta bilizati o n of t he e ve nt(s). 
All s u bjects will be i nstr ucte d t o c o ntact t he I n vesti gat or, I n vesti gat or's assista nts, or cli nical 
pers o n nel s h o ul d t he s u b ject ha ve a n y seri o us a d verse e x perie nces.  Seri o us a d verse e ve nts, 

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C O N FI D E N TI A L 
i ncl u di n g deat h re gar dless of t he ca use, m ust be re p orte d t o t h e S p o ns or i m me diatel y ( wit hi n 2 4 
h o urs of t he i ni tial re p ort). 
A seri o us e ve nt re q uiri n g i m me d iate n otificati o n b y tele p h o ne is a n e ve nt t hat: 
 res ults i n deat h 
 is life t hreate ni n g  
 re q uires i n patie nt h os pitalizatio n or pr ol o n gati o n  of a n e xistin g h os pitalizati o n 
 is a persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 is a c o n ge nital a n o mal y/ birt h defect 
 a n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be lif e-t hreate ni n g, or re q uire 
h os pitalizati o n  b ut,  base d  u p o n  a p pr o priate  me dical  j u d g me nt,  m a y  je o par dize  t he 
s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o preve nt o ne of t he o utc o mes 
liste d a b o ve. 
A n o ver d ose is defi ne d as a n y i nt e nti o nal or u ni nte nti o nal c o ns u m pti o n of t he dr u g b y a n y r o ute 
t hat e xcee ds t he hi g hest d ose state d i n t he I n vesti gat or's Br och ure, a p pr o ve d pr o d uct la beli n g 
(f or T D F, T A F or E T V) or i n a n i n vesti gati o nal pr ot oc ol, w hic hever d ose is lar ger.  O ver d oses 
wit h o ut a n ass ociate d a d verse  e ve nt s h o ul d be rec or de d, b ut n ot re p orte d as a n ad verse e ve nt. 
1 3. 3.  
Re p orti n g Re q uire me nt 
T he Pri nci pal I n vesti gat or i s re q uire d t o n otif y T he R o mar k I nstit ute f or Me dical Researc h 
( S p o ns or) wit hi n 2 4 h o urs of learni n g of a n y u ne x pecte d, fatal,  or life-t hreate nin g e x perie nce a n d 
all u n us ual, alar mi n g, or seri o us  reacti o ns t o me dicati o n re gardless of a n y o pi ni o ns as t o t he 
ca use/effect relati o ns hi p.  All seri o us a d verse e ve nts will als o be re p orte d t o t he I R B.  A d verse 
e ve nts s h o ul d be re p orte d t o: 
T he R o mar k I nstit ute f or Me dical Researc h  
Me dical Affairs 
  
  
 
 
1 3. 4.  
Me dic ati o n M o dific ati o n/ Wit h dr a w al D ue t o A d verse E ve nt 
If a se vere a d verse reacti o n or la b orat or y a b n or malit y de vel o ps d uri n g c o m bi nati o n t hera p y, t he 
d ose s h o ul d be m o difie d or disc o nti n ue d, at t he discreti o n of t he I n vesti gat or a n d i n acc or da nce 
wit h t he a p pr o ve d pr o d uct la be li n g f or T D F, T A F or E T V, u ntil the a d verse reacti o n a bates.  
If i nt olera nce persists after the d ose has bee n a dj uste d, t he s t u d y me dicati o n s h o ul d be 
disc o nti n ue d. 

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1 3. 5.  
Me dic ati o n Err ors 
A me dicati o n err or is defi ne d as a n y pre ve nta ble e ve nt relate d t o d osi n g i nstr ucti o ns, pr o d uct 
la beli n g, or pac ka gi n g t hat ca uses or lea ds t o i na p pr o priate medicati o n use or s u bject har m w hile 
t he me dicati o n is i n t he c o ntr ol of t he i n vesti gati ve site or su bject.  Me dicati o n err ors w hic h 
res ult i n a d verse e ve nts s h o uld be rec or de d a n d re p orte d as a d v erse e ve nts.  All ot her me dicati o n 
err ors s h o ul d be re p orte d t o t he  st u d y S p o ns or t hr o u g h t he Me dical Affairs de part me nt wit hi n 
7 da ys of i de ntifica ti o n b y t he site. 
1 4.  
DI S C O N TI N U A TI O N 
T he st u d y ma y be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces: 
1.  T he S p o ns or reser ves t he ri g ht  t o disc o nti n ue t he st u d y at a n y ti me.  
2.  A d verse e ve nt listi n gs will be pr o d uce d f or safet y m o nit ori n g a t least o nce e ver y t w o wee ks 
d uri n g recr uit me nt.  T he data will be teste d t o deter mi ne if t h ere are greater t ha n 2 0 % of t he 
s u bjects w h o ha ve ha d at least Gra de 3 a d verse e ve nts c o nsi dered b y t he I n vesti gat or t o be 
relate d t o t he st u d y dr u g ( defi ne d b y t he T o xicit y Gra di n g Scale Ta bles pr o vi de d i n Secti o n 
2 3. 3 ). 
If greater t ha n 2 0 % of t he s u bjects ha ve at least o ne Gra de 3 or Gra de 4 a d verse e ve nt c o nsi dere d 
t o be relate d t o t he st u d y dru g b y t he st u d y Me dical M o nit or, t he n t he st u d y m ust be st o p pe d a n d 
t he I nstit uti o nal Re vie w B oar ds, l ocal re g ulat or y a ut h orities an d F D A’s Di visi o n of A nti viral 
Dr u g Pr o d ucts will be n otifie d.  All safet y a n d acti vit y data w ill be s u b mitte d t o t he F D A i n a 
ti mel y ma n ner. 
1 5.  
R E T E N TI O N O F R E C O R D S 
Esse ntial D oc u me nts ( E Ds) are  d oc u me nts t hat i n di vi d uall y a n d c ollecti vel y per mit e val uati o n of 
t he c o n d uct of a trial a n d q ualit y of t he data pr o d uce d.  T he y de m o nstrate t he c o m plia nce of t he 
I n vesti gat or, S p o ns or, a n d m o nit or wit h t he G C P sta n dar ds a n d wit h all a p plica ble re g ulat or y 
re q uire me nts. 
I n c o m plia nce wit h t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H)/ G C P g ui deli nes, t he 
I n vesti gat or/i nstit uti o n will mai ntai n all C R Fs a n d all E D C s o urce f or ms a n d s o urce d oc u me nts 
t hat s u p p ort t he data c ollecte d fr o m eac h s u bject, as well as all st u d y d oc u me nts as s pecifie d i n 
I C H/ G C P Secti o n 8, Esse ntial D oc u me nts f or t he C o n d uct of a Clinical Trial, a n d all st u d y 
d oc u me nts as s pecifie d b y t he a p pl ica ble re g ulat or y re q uire me nt(s).  A list of t hese d oc u me nts is 
f o u n d i n Secti o n 2 3. 4 : List of Esse ntial D oc u me nt f or t he I n vesti gati ve Site.  T he 
I n vesti gat or/i nstit uti o n will ta ke meas ures t o pre ve nt acci de ntal or pre mat ure destr ucti o n of t hese 
d oc u me nts. 
Esse ntial d oc u me nts liste d i n Secti o n 2 3. 4  m ust be retai ne d f or t he d urati o n re q uire d b y 
a p plica ble re g ulat or y a ut h orities or u ntil t he S p o ns or i nf or ms t he I n vesti gat or/i nstit uti o n t hese 
d oc u me nts are n o l o n ger nee de d. 
If it bec o mes necessar y f or t he S p o ns or or t he a p pr o priate re g ulat or y a ut h orit y t o re vie w a n y 
d oc u me ntati o n relati n g t o t his st u d y, t he I n vesti gat or m ust per mit access t o s uc h re p orts. 

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T he S p o ns or is res p o nsi ble f or or ga nizi n g a n d mai ntai ni n g t he T rial Master File w hic h is a clear 
d oc u me ntati o n of t he c o urse of t he st u d y. 
1 6.  
M O NI T O RI N G T H E S T U D Y 
M o nit ori n g will be c o n d ucte d b y t he  S p o ns or a n d/ or a c o ntract researc h or ga nizati o n ( C R O) 
acc or di n g t o t he S p o ns or’s sta n dar d o perati n g pr oce d ures.  Site  visits will be c o n d ucte d b y t he 
S p o ns or at re g ular i nter vals  t o c o n d uct i ns pecti o ns. 
A n y data tra nscri be d i nt o t he E D C s yste m will be 1 0 0 % s o urce ve rifie d. 
T he I n vesti gat or will gra nt re prese ntati ves of t he S p o ns or's cl i nical o perati o ns tea m a n d q ualit y 
tea m, as well as re g ulat or y a ge ncies a n d et hical c o m mittees access t o i ns pect facilities a n d 
rec or ds (i ncl u di n g s u bject c harts) rele va nt t o t his st u d y a n d a grees t o assist t he m o nit ors i n t heir 
acti vities, if re q ueste d. 
T he data fr o m t his st u d y will  n ot be m o nit ore d b y a n i n de pe n de nt data m o nit ori n g c o m mittee. 
1 7.  
I N F O R M E D C O N S E N T 
Eac h s u bject m ust gi ve writte n c o nse nt acc or di n g t o l ocal re q ui re me nts after t he nat ure of t he 
st u d y has bee n f ull y e x plai ne d.  T he i nf or me d c o nse nt f or m (I C F) m ust be si g ne d bef ore 
perf or ma nce of a n y st u d y-relate d acti vit y.  T he i nf or me d c o nse n t f or m will be a p pr o ve d b y b ot h 
t he S p o ns or a n d b y t he re vie wi n g I R B.  T he y will be i n acc or da nce wit h pri nci ples t hat 
ori gi nate d i n t he Declarati o n of  Helsi n ki, c urre nt I C H a n d G C P g ui deli nes, a p plica ble re g ulat or y 
re q uire me nts, a n d S p o ns or p olic y. 
Bef ore e nr oll me nt i n t he st u d y, t he I n vesti gat or or a n a ut h oriz e d me m ber of t he i n vesti gati o nal 
staff m ust e x plai n t o p ote ntial s u bjects t he ai ms, met h o ds, reas o na bl y a ntici pate d be nefits, a n d 
p ote ntial hazar ds of t he st u d y, a n d a n y disc o mf ort partici pati o n i n t he st u d y ma y e ntail.  S u bjects 
will be i nf or me d t hat t heir part ici pati o n is v ol u ntar y a n d t hat t he y ma y wit h dra w c o nse nt t o 
partici pate at a n y ti me.  T he y w ill be i nf or me d t hat c h o osi n g not t o partici pate will n ot affect t he 
care he/s he will recei ve.  Fi nall y, t he y will be t ol d t hat t he I n vesti gat or will mai ntai n a s u bject 
i de ntificati o n re gister f or t he p ur p oses of l o n g-ter m f oll o w- u p if nee de d a n d t hat t heir rec or ds 
ma y be accesse d b y healt h a ut h orities a n d a ut h orize d S p o ns or st aff wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject , t o t he e xte nt per mitte d b y t he a p plica ble la w(s) or re g ulati o ns.  
B y si g ni n g t he I C F s u bjects are  a ut h orizi n g s uc h access, a n d a gree t o all o w t he st u d y p h ysicia n 
t o re-c o ntact t he s u bject f or t he p ur p ose of o btai ni n g c o nse nt f or a d diti o nal safet y e val uati o ns, if 
nee de d. 
T he s u bject will be gi ve n s uffi cie nt ti me t o rea d t he I C F a n d t he o p p ort u nit y t o as k q uesti o ns.  
After t his e x pla nati o n a n d bef o re e ntr y i nt o t he st u d y, c o nse nt s h o ul d be a p pr o priatel y rec or de d 
b y mea ns of t he s u bject's pers o na ll y date d si g nat ure.  After ha vi n g o btai ne d t he c o nse nt, a c o p y 
of t he I C F m ust be gi ve n t o t he s u bject. 
If t he s u bject is u na ble t o rea d or write, a n i m partial wit ness s h o ul d be prese nt f or t he e ntire 
i nf or me d c o nse nt pr ocess ( w hich i ncl u des rea di n g a n d e x plai ni n g  all writte n i nf or mati o n) a n d 
s h o ul d pers o nall y date a n d si g n t he I C F after t he oral c o nse nt of t he s u bject is o btai ne d, if 
per mitte d b y l ocal la w.  

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C O N FI D E N TI A L 
T he c o nse nt f or ms m ust be si g ne d pri or t o t he perf or ma nce of a n y st u d y relate d acti vit y. 
Si g ne d I C Fs m ust re mai n i n t he s u bject's file(s) a n d be a vaila b le f or verificati o n b y 
re prese ntati ves of R o mar k, t he IR B, a n d F D A/rele va nt re g ulat or y  a ge ncies at a n y ti me. 
1 8.  
E T HI C S 
T he cli nical trial will be perf or me d i n acc or da nce wit h t he g ui deli nes set b y t he W orl d Me dical 
Asse m bl y ( Declarati o n of Helsi n ki, last a me n d me nt i n F ortaleza,  Brazil, Oct o ber 2 0 1 3).  Pri or 
writte n a p pr o val of t he st u d y pr ot oc ol a n d of t he i nf or me d c o ns e nt f or m will be o btai ne d fr o m 
t he a p pr o priate l ocal Me dical Et hics Re vie w B oar d. 
1 8. 1.  
St u d y-s pecific Desi g n C o nsi der ati o ns 
P ote ntial s u bjects will be f ull y i nf or me d of t he ris ks a n d re q u ire me nts of t he st u d y a n d d uri n g t he 
st u d y s u bjects will be gi ve n a n y ne w i nf or mati o n t hat ma y affect t heir decisi o n t o c o nti n ue 
partici pati o n.  T he y will be t ol d t hat t heir c o nse nt t o partici pate i n t he st u d y is v ol u ntar y a n d ma y 
be wit h dra w n at a n y ti me wit h n o reas o n gi ve n a n d wit h o ut pe nalt y or l oss of be nefits t o w hic h 
t he y w o ul d ot her wise be e ntitle d.  O nl y s u bjects w h o are f ull y a ble t o u n dersta n d t he ris ks, 
be nefits, a n d p ote ntial A Es of t he st u d y, a n d pr o vi de t heir c o n se nt v ol u ntaril y will be e nr olle d. 
1 8. 2.  
I n vesti g at or Res p o nsi bilities 
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he cli nical st u d y is perf or me d i n acc or da nce 
wit h t he pr ot oc ol, c urre nt I nter nati o nal C o u ncil f or Har m o nisat i o n (I C H) g ui deli nes o n G C P, a n d 
a p plica ble re g ulat or y a n d c o u nt r y s pecific re q uire me nts. 
G o o d Cli nical Practice is a n i nter nati o nal et hical a n d scie ntific q ualit y sta n dar d f or desi g ni n g, 
c o n d ucti n g, rec or di n g, a n d re p orti n g  st u dies t hat i n v ol ve t he partici pati o n of h u ma n s u bjects.  
C o m plia nce wit h t his sta n dar d pr o vi des p u blic ass ura nce t hat t he ri g hts, safet y, a n d well bei n g of 
st u d y s u bjects are pr otecte d, c o nsiste nt wit h t he pri nci ples t hat ori gi nate d i n t he Declarati o n of 
Helsi n ki, a n d t hat t he cli ni cal st u d y data are cre di ble. 
1 8. 3.  
I nstit uti o n al Re vie w B o ar d 
Bef ore t he start of t he st u d y, t he I n vesti gat or ( or S p o ns or w he re re q uire d) will pr o vi de t he I R B 
wit h c urre nt a n d c o m plete c o pi es of t he f oll o wi n g d oc u me nts: 
 Fi nal pr ot oc ol a n d, if a p plica ble, a me n d me nts. 
 S p o ns or-a p pr o ve d I C F (a n d a n y ot her writte n materials t o be pr o vi de d t o t he s u bjects). 
 I n vesti gat or’s Br oc h ure ( or e q ui vale nt i nf or mati o n) a n d a d de n da. 
 S p o ns or-a p pr o ve d s u bject r ecr uiti n g materials. 
 I nf or mati o n  o n  c o m pe nsati o n  f or  st u d y-relate d  i nj uries  or  pa y me nt  t o  s u bjects  f or 
partici pati o n i n t he s t u d y, if a p plica ble. 
 I n vesti gat or’s  c urric ul um  vitae  or  e q ui vale nt  i nf or mati o n  ( u nle ss  n ot  re q uire d,  as 
d oc u me nte d b y I R B). 

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C O N FI D E N TI A L 
 I nf or mati o n  re gar di n g  f u n di n g,  na me  of  t he  S p o ns or,  i nstit uti o nal  affiliati o ns,  ot her 
p ote ntial c o nflicts of i nteres t, a n d i nce nti ves f or s u bjects. 
 A n y ot her d oc u me nts t hat t he I R B re q uests t o f ulfill its o bli ga ti o n. 
T his st u d y will be u n derta ke n o nl y after t he I R B has gi ve n f ull  a p pr o val of t he fi nal pr ot oc ol, 
a me n d me nts (if a n y), t he I C F, a p p lica ble recr uiti n g materials, a n d s u bject c o m pe nsati o n 
pr o gra ms, a n d t he S p o ns or has recei ve d a c o p y of t his a p pr o val.   T his a p pr o val letter m ust be 
date d a n d m ust clearl y i de ntif y t he I R B a n d t he d oc u me nts bei n g  a p pr o ve d. 
D uri n g t he st u d y, t he I n vesti gat or  ( or S p o ns or w here re q uire d) will se n d t he f oll o wi n g 
d oc u me nts a n d u p dates t o t he I R B f or t heir re vie w a n d a p pr o val,  w here a p pr o priate:  
 Pr ot oc ol a me n d me nts. 
 Re visi o n(s) t o I C F a n d a n y ot her writte n materials t o be pr o vi d e d t o s u bjects. 
 If a p plica ble, ne w or re vise d su bject recr uiti n g materials a p pr o ve d b y t he S p o ns or. 
 Re visi o ns  t o  c o m pe nsati o n  f or  st u d y-relate d  i nj uries  or  pa y me nt   t o  s u bjects  f or 
partici pati o n i n t he s t u d y, if a p plica ble. 
 I n vesti gat or’s Br oc h ure a d de n da or ne w e diti o n(s). 
 S u m maries of t he stat us of t he s t u d y at i nter vals sti p ulate d i n g ui deli nes of t he I R B (at 
least a n n uall y). 
 Re p orts of A Es t hat are seri o us , u nliste d, a n d ass ociate d wit h t he i n vesti gati o nal dr u g. 
 Ne w i nf or mati o n t hat ma y a d versel y affect t he safet y of t he s u b jects or t he c o n d uct of 
t he st u d y. 
 De viati o ns  fr o m  or  c ha n ges  t o  t he  pr ot oc ol  t o  eli mi nate  i m me dia te  hazar ds  t o  t he 
s u bjects. 
 Re p ort of deat hs of s u bjects u n der t he I n vesti gat or’s care. 
 N otificati o n if a ne w I n vesti gat or is res p o nsi ble f or t he st u d y  at t he site. 
 A n n ual  I N D  U p date  Re p ort,  S h ort  Ter m  St u d y  S pecific  Safet y  S u m m ar y  a n d  Li ne 
Listi n gs, w here a p plica ble. 
 A n y ot her re q uire me nts of t he I R B. 
F or all pr ot oc ol a me n d me nts (e xcl u di n g t he o nes t hat are p urel y  a d mi nistrati ve, wit h n o 
c o nse q ue nces f or s u bjects, data or st u d y c o n d uct), t he a me n d me n t a n d a p plica ble i nf or me d 
c o nse nt f or m a n d asse nt f or m re visi o ns m ust be s u b mitte d pr o m pt l y t o t he I R B f or re vie w a n d 
a p pr o val bef ore i m ple me ntati o n of  t he c ha n ge(s), e xce pt w he n necessar y t o eli mi nate i m me diate 
hazar d t o t he st u d y s u bjects.  If a de viati o n fr o m, or a c ha n ge  t o t he pr ot oc ol was i m ple me nte d t o 
eli mi nate a n i m me diate hazar d t o st u d y s u bjects, t he n t he i m ple me nte d de viati o n or c ha n ge, t he 
reas o ns f or it, a n d, if a p pr o priate, t he pr ot oc ol a me n d me nt s h o ul d be s u b mitte d t o t he I R B as 
s o o n as p ossi ble. 
T he re-a p pr o val of t he cli nical st u d y b y t he I R B s h o ul d be d oc u me nte d i n writi n g. 

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C O N FI D E N TI A L 
At t he e n d of t he st u d y, t he I n vest i gat or ( or S p o ns or w here re quire d) will n otif y t he I R B a b o ut 
t he st u d y c o m pleti o n. 
1 8. 4.  
Pri v ac y of Pers o n al D at a 
T he c ollecti o n a n d pr ocessi n g of pe rs o nal data fr o m s u bjects e nr olle d i n t his st u d y will be 
li mite d t o t h ose data t hat are necessar y t o i n vesti gate t he safet y, q ualit y, a n d utilit y of t he 
i n vesti gati o nal st u d y dr u g(s) use d i n t his st u d y. 
T hese data m ust be c ollecte d a n d pr ocesse d wit h a de q uate preca u ti o ns t o e ns ure c o nfi de ntialit y 
a n d c o m plia nce wit h a p plica ble da ta pri vac y pr otecti o n la ws a n d re g ulati o ns.  A p pr o priate 
tec h nical a n d or ga nizati o nal measures t o pr otect t he pers o nal d ata a gai nst u na ut h orize d 
discl os ures or access, acci de ntal or u nla wf ul destr ucti o n, or a cci de ntal l oss or a lterati o n m ust be 
p ut i n place.  S p o ns or pers o n nel w h os e res p o nsi bilities re q uire  access t o pers o nal data a gree t o 
kee p t he i de ntit y of st u d y s u bjects c o nfi de ntial. 
T he i nf or me d c o nse nt o btai ne d fr o m t he s u bject i ncl u des e x plici t c o nse nt f or t he pr ocessi n g of 
pers o nal data a n d f or t he I n vesti g at or t o all o w direct access t o his or her ori gi nal me dical rec or ds 
f or st u d y-relate d m o nit ori n g, a u dit, I R B re vie w, a n d re g ulat or y i ns pecti o n.  T his c o nse nt als o 
a d dresses t he tra nsfer of t he data t o ot her e ntities a n d t o ot h er c o u ntries. 
1 9.  
D A T A C O N FI D E N TI A LI T Y, DI S C L O S U R E O F D A T A, A N D P U B LI C A TI O N 
Data ge nerate d f or t he st u d y s h o ul d be st ore d b y t he I n vesti gat or i n a li mite d-access file area a n d 
be accessi ble o nl y t o re prese ntati ves of t he st u d y site, R o mar k , t he I R B, a n d F D A/rele va nt 
re g ulat or y a ge ncies.  Me dical i nfor mati o n res ulti n g fr o m a s u bj ect’s partici pati o n i n t his st u d y 
ma y be gi ve n t o t he s u bject’s per s o nal p h ysicia n or t o t he a p pro priate me dical pers o n nel 
res p o nsi ble f or t he s u bject’s welfare.   
N o i nf or mati o n t hat ca n be relate d t o a s pecific i n di vi d ual s u bject ma y be release d or use d i n a n y 
fas hi o n wit h o ut t he sig ne d writte n c o nse nt of t hat s u bject.  Al l re p orts a n d c o m m u nicati o ns 
relati n g t o st u d y s u bjects will i de ntif y s u bjects o nl y b y i nitials a n d s u bject i de ntificati o n n u m ber.  
T he I n vesti gat or will kee p c o m pl ete s u bject i de ntificati o n f or p ur p oses of l o n g-ter m f oll o w- u p, if 
nee de d.  T his i nf or mati o n will be treate d wit h strict a d here nce  t o pr ofessi o nal sta n dar ds of 
c o nfi de ntialit y. 
Site pers o n nel will e n ter data relati n g to eac h s u bject’s parti ci pati o n i n t he st u d y i nt o t he E D C 
s yste m pr o vi de d b y t he S p o ns or.  I n t he E D C s yste m, i de ntificati o n n u m bers a n d i nitials will be 
use d t o i de ntif y s u bjects.  S u bj ect na mes will n ot be use d i n t he C R Fs.  Ma na ge me nt of data 
fr o m t he E D C s yste m a n d t he pro d ucti o n of t he cli nical st u d y re p ort will be t he res p o nsi bilit y of 
t he S p o ns or.  Access t o t he data base will be restricte d t o e m plo yees w h o ha ve bee n trai ne d t o use 
t he s yste m.  Access t o t he E D C s yste m a n d st u d y re p ort will be li mite d t o t he I R B, F D A or ot her 
re g ulat or y a ge ncies a n d t he S p o ns or. 
Prese ntati o n a n d/ or p u blicati o n of t he res ults of t he st u d y is e nc o ura ge d pr o vi de d t hat T he 
R o mar k I nstit ute f or Me dical R esearc h is n otifie d i n a d va nce of  t he a ut h or's i nte nt a n d is gi ve n 
t he o p p ort u nit y t o re vie w t he ma n uscri pt or a bstract 4 5 da ys pri or t o its s u b missi o n f or 
prese ntati o n at a scie ntific  meeti n g or f or p u blicati o n i n a scie ntific j o ur nal.  T he I n vesti gat ors 
will ha ve c o m plete a ut o n o m y r e gar di n g t he c o nte nt a n d w or di n g o f a n y a bstracts, prese ntati o ns, 

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3 8 
C O N FI D E N TI A L 
R ossi g n ol J F. Nitaz o xa ni de: A firs t-i n-class br oa d-s pectr u m a nti viral a ge nt. A nti viral Res 
2 0 1 4; 1 1 0: 9 4- 1 0 3. 
R ossi g n ol J F, Brec h ot C. A pil ot cl i nical trial of nitaz o xa ni de i n t he treat me nt of c hr o nic 
he patitis B. He pat ol C o m m 2 0 1 9; 6: 7 4 4- 7 4 7. 
R ossi g n ol J F, Keeffe E B. T hiaz oli d es: a ne w class of dr u gs f or t he treat me nt of c hr o nic he patitis 
B a n d C. F ut ure Micr o bi ol 2 0 0 8; 3: 5 3 9- 5 4 5. 
Sari n S K, K u mar M, La u G K, A b bas Z, C ha n H L, C he n CJ et al.  Asia n- Pacific cli nical practice 
g ui deli nes o n t he ma na ge me nt  of he patitis B: a 2 0 1 5 u p date. He pat ol I nt 2 0 1 6; 1 0: 1- 9 8. 
Se ki ba K, Ots u ka M, O h n o M, Ya ma ga mi M, Kis hi ka wa T, et al.  I n hi biti o n of H B V 
tra nscri pti o n fr o m ccc D N A wit h nitaz o xa ni de b y tar geti n g t he H BX- D D B 1 i nteracti o n. Cell M ol 
Gastr oe nter ol He pat ol 2 0 1 9; 7: 2 9 7- 3 1 2. 
Terra ult N A, Bz o wej N H, C ha n g K- M, H wa n g J P, J o nas M M, M ura d M H . A merica n 
Ass ociati o n f or t he St u d y of L i ver Diseases.  A A S L D g ui deli nes f or treat me nt of c hr o nic 
he patitis B. He pat ol o g y 2 0 1 6; 6 3: 2 6 1- 2 8 3. 
Terra ult N A, L o k A S F, Mc Ma h o n BJ, C ha n g K M, H wa n g J P, et al. U p date o n pre ve nti o n, 
dia g n osis a n d treat me nt of c hr o nic he patitis B: A A S L D 2 0 1 8 he pa titis B g ui da nce. He pat ol o g y 
2 0 1 8; 6 7: 1 5 6 0- 1 5 9 8. 
W orl d Healt h Or ga nizati o n. He patitis B Fact S heet. J ul y 1 8, 2 0 1 8.  Accesse d at: 
htt p:// w w w. w h o.i nt/ ne ws-r o o m/fact -s heets/ detail/ he patitis- b.  Accesse d date: Fe br uar y 5, 2 0 1 9. 
 
 

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C O N FI D E N TI A L 
2 3.  
A P P E N DI C E S 
2 3. 1.  
A p pe n di x I: M aj or C Y P 2 C 8 S u bstr ates 
T a ble 3:  
M aj or C Y P 2 C 8 S u bstr ates 
Ge neric N a me 
Br a n d N a me(s) 
T her a pe utic Use a n d/ or Dr u g Cl ass 
A m o di a q ui ne  
B A S O Q UI N, C A M O Q UI N, F L A V O Q UI N  
A nti malarial 
Ceri v ast ati n ( aci d, p are nt)  
B A Y C O L * 
A nti h y perli pi de mic, H M G- C o A re d uctase 
i n hi bit or 
D a pr o d ust at ( G S K 1 2 7 8 8 6 3)  
* * 
A ntia ne mic, pr ol yl h y dr o x ylase i n hi bit or 
D as a b u vir ( A B T- 3 3 3)  
E X VI E R A 
A nti viral, N S B 5 i n hi bit or 
E n z al ut a mi de  
X T A N DI 
A ntica ncer, a ntia n dr o ge n 
M o ntel u k ast  
SI N G U L AI R 
A ntiast h matic, L T R A 
Pi o glit az o ne  
A C T O S 
A nti dia betic, P P A R- γ a g o nist 
Re p a gli ni de  
N O V O N O R M, P R A N DI N 
A nti dia betic, me gliti ni de a nal o g 
S o urce: Bac k ma n et al., 2 0 1 6 . 
* O nl y a vaila ble o utsi de of U S. 
* * C urre ntl y liste d as i n vesti ga ti o nal o nl y a n d n ot y et gra nte d a tra de na me b y t he ma n ufact urer. 

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4 0 
C O N FI D E N TI A L 
2 3. 2.  
A p pe n di x II: Sc he d ule of St u d y Visits a n d Pr oce d ures 
T a ble 4:  
Sc he d ule of Assess me nts 
 
 
Tre at me nt Peri o d 
F oll o w- u p Peri o d 
 
  
D a y 
Wee k 
E ver y 1 2 
Wee ks 
T here after 
Wee k 
 
S C R E E N  
1  
3  
1  
2  
4  
8  
1 2  
1 6  
2 0  
2 4 
4  
8  
1 2  
2 4 2
4 8 2
I nf or me d c o nse nt 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w i ncl usi o n/e xcl usi o n criteria 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m i ncl u di n g wei g ht, vital 
si g ns 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
Uri ne pre g na nc y test 1 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Re vie w c o nc o mita nt me dicati o ns 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Bl o o d sa m ple f or viral ser ol o g y 3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ple f or viral ser ol o g y 4 
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
Bl o o d sa m ple f or e x pl orat or y a nal yses  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
x  
x  
x  
x 
Bl o o d sa m ple f or P K ( pre- d ose) 
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
 
 
 
 
 
Bl o o d sa m ple f or safet y tests 
x  
x  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
Uri ne c ollecti o n f or uri nal ysis 
x  
x  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
x 
Fi br osca n ®  
x5 
 
 
 
 
 
 
 
 
 
 
 
 
x5
 
 
x5 
 
x5 
Ultras o n o gra p h y H C C scree ni n g 
x 6 
 
 
 
 
 
 
 
 
 
 
x6 
x6
x 6 
x6 
x6 
x6 
x6 
Electr ocar di o gra m 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
x7 
 
 
 
 
 
 
Ra n d o mizati o n 
  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d verse e ve nts 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Dis pe nse dr u gs & acc o u nta bilit y 
  
x  
  
  
  
x  
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1 F or w o me n of c hil d beari n g p ote ntial o nl y. 
2 Wee k 2 4 a n d 4 8 f oll o w- u ps are o nl y re q uire d if s u bjects ha ve s ustai ne d H Bs A g l oss wit h H B V D N A s u p pressi o n at t he Wee k 1 2 off-treat me nt f oll o w- u p visit. 
3 Tests perf or me d o n Scree ni n g sam ple will i ncl u de q H B V D N A, q H B s A g, a nti- H Bs, H Be A g, a nti- H Be, I g M a nti- H Bc, a nti- H C V, a nti- H DV, a nti- HI V. 
4 Tests perf or me d will i ncl u de: q H B V D N A, q H Bs A g, q A nti- H Bs, H BeA g, a nti- H Be, a n d a nti- HI V (a nti- HI V is o nl y f or s u bjects at hi g h ris k of c o ntracti n g HI V acc or di n g t o t he 
discreti o n of t he  i n vesti gat or). 
5 Fi br o Sca n ® will be perf or me d at Scree ni n g, t he e n d- of-treat me nt visit, a n d at t he last off-treat me nt f oll o w- u p visit (eit her 1 2 or 4 8 wee ks after e n d of treat me nt). 
6 Ultras o n o gra p h y f or H C C will be perf or me d at Scree ni n g a n d e ver y 6 m o nt hs d uri n g t he st u d y. 
7 A 1 2-lea d E C G will be o btai ne d at Baseli ne, Wee k 1 2 a n d at e n d  of treat me nt o nl y. 
 

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5 5 
C O N FI D E N TI A L 
a. I nf or me d c o nse nt f or m ( all versi o ns), a n y ot her writte n i nf or mati o n, a d vertise me nt 
f or s u bject recr uit me nt (if use d). 
4.  Fi na ncial a gree me nt bet wee n t he I n vesti gat or/i nstit uti o n a n d t h e S p o ns or f or t he trial. 
5.  Si g ne d a gree me nts bet wee n i n v ol ve d parties: 
a. Fi na ncial Discl os ure of I n vesti gat or/i nstit uti o n a n d s p o ns or. 
b.  C o nfi de ntial Discl os ure A gree me n t of I n vesti gat or/i nstit uti o n an d S p o ns or. 
6.  Date d, d oc u me nte d a p pr o val/fa v ora b le o pi ni o n of I R B of t he f ollo wi n g: 
a. Pr ot oc ol a n d a n y a me n d me nts. 
b.  E D C s yste m (if a p plica ble). 
c. I nf or me d c o nse nt f or m a n d a n y re visi o ns. 
d.  A n y ot her writte n i nf or mati o n t o be  pr o vi de d t o ot her s u bjects. 
e. A d vertise me nt f or s u bject recr uit me nt (if use d). 
f. S u bject c o m pe nsati o n (if a n y). 
g.  A n y ot her d oc u me nts gi ve n a p pr o val. 
h.  C o nti n ui n g re vie w of t he trial. 
7.  I nstit uti o nal Re vie w B oar d c o m p ositi o n. 
8.  Re g ulat or y n otice of Pri nci pal I n vesti gat or a n d s u b-I n vesti gat o rs, F D A F or m 1 5 7 2. 
9.  C urric ul u m vitae a n d/ or ot her r ele va nt d oc u me nts e vi de nci n g q ua lificati o ns of 
I n vesti gat or a n d s u b-I n vesti gat ors. 
1 0.  N or mal val ues/ra n ges a n d u p dates f or me dical/ la b orat or y/tec h nical pr oce d ures 
a n d/ or tests i ncl u de d i n t he pr ot oc ol. 
1 1.  Me dical/la b orat or y tec h nical p r oce d ures/tests a n d u p dates: 
a. Certificati o n or 
b.  Accre ditati o n or 
c. Esta blis he d q ualit y c o ntr ol a n d/ or e xter nal q ualit y assess me nt or 
d.  Ot her vali dati o n ( w here re q uire d). 
1 2.  S hi p pi n g rec or ds f or i n vesti gati o nal pr o d uct(s) a n d trial-relat e d materials. 
1 3.  Site i nitiati o n m o nit ori n g re p ort. 
1 4.  Rele va nt c o m m u nicati o ns ot her t ha n site visits: 
a. Letters/e mails. 
b.  Meeti n g n otes. 
c. N otes of tele p h o ne calls. 
1 5.  Si g ne d i nf or me d c o nse nt f or ms. 
1 6.  S o urce d oc u me nts. 
1 7.  Si g ne d, date d, a n d c o m plete d E D C f or ms t o i ncl u de d oc u me ntati o n  of E D C f or m 
c orrecti o ns. 
1 8.  N otificati o n b y ori gi nati n g I n vest i gat or t o S p o ns or of seri o us a d verse e ve nts a n d 
relate d re p orts. 

Pr ot oc ol R M 0 8- 2 0 0 1 v 4. 0 
 
 
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5 7 
C O N FI D E N TI A L 
 is t he  
 we b p ortal.  It deli vers real-ti me access t o s o urce data, 
a n d e na bles a ut h orize d  S p o ns or pers o n nel t o i nsta ntl y re vie w, clea n a n d a nal yze st u d y data. 
T he site staff will use 
 as t he y meet wit h st u d y s u bjects a n d perf or m st u d y 
pr oce d ures.    C o m p uterize d  data  clea ni n g  c hec ks  will  be  use d  i n a d diti o n  t o  ma n ual  re vie w, 
i ncl u di n g listi n gs re vie w, t o c hec k f or discre pa ncies a n d t o e n s ure c o nsiste nc y a n d c o m plete ness 
of t he data. If t he 
 s yste m is n ot a vaila ble f or a n y reas o n, s o urce data ma y 
be ca pt ure d o n pa per a n d tra nscri be d t o t he 
 s yste m at a later ti me. T he 
res p o nsi ble st u d y m o nit or(s) will verif y data, w hic h ca n be per f or me d re m otel y or at t he cli nical 
st u d y site.  T he I n vesti gat or will e ns ure t hat t he data rec or de d are acc urate a n d c o m plete.  
Q ueries e mer gi n g d uri n g data cl ea ni n g will be ge nerate d b y data  ma na ge me nt or cli nical researc h 
ass ociates i n 
.  T he I n vesti gat or or his/ her desi g nee will a ns wer t he q ueries 
a n d u p date t he s o ur ce data, if nee de d. ” 
t o  
“ Data will be tra nscr i be d fr o m s o urce d oc u me nts i nt o a n electr onic data ca pt ure ( E D C) s yste m. 
T he res p o nsi ble st u d y m o nit or(s) will verif y data, w hic h ca n be  perf or me d re m otel y or at t he 
cli nical st u d y site.  T he I n vesti g at or will e ns ure t hat t he data rec or de d are acc urate a n d 
c o m plete.  
Q ueries e mer gi n g d uri n g data cl ea ni n g will be ge nerate d wit hi n t he E D C s yste m b y data 
ma na ge me nt or cli nical researc h ass ociates. T he I n vesti gat or or  his/ her desi g nee will a ns wer t he 
q ueries a n d u p date t he s o urce data, if nee de d.” 
 
Delete d: “ All listi n gs, s u m mar ies a n d a nal yses will be pr o d uce d usi n g S A S Statistical S oft ware 
( S A S I nstit ute, I nc., Car y, N C).” 
C ha n ge 5: 
Secti o n 9. 2, P ack a gi n g a n d L a beli n g  
C ha n ge d te xt fr o m: 
“ M o nt hl y s u p plies of me dicati o n will be pac ka ge d f or eac h patie nt i n u nit- d ose d blister car ds. 
T he blister car ds will be st ore d i n a c o ntr olle d e n vir o n me nt of  2° C t o 2 5° C wit h e xc ursi o ns u p 
t o 4 0° C all o we d.  Eac h blister car d will bear a la bel wit h t he f oll o wi n g i nf or mati o n: 
I n vesti gat or na me 
Patie nt n u m ber 
Wee k X X - X X 
N u m ber of ta blets 
I nstr ucti o ns f or d osi n g 
Pr ot oc ol n u m ber 
Ca uti o n: Ne w Dr u g – Li mite d b y Fe deral La w t o I n vesti gati o nal U se 
D O N O T U S E B E Y O N D E N D O F S T U D Y 
K E E P O U T O F R E A C H O F C HI L D R E N 
I nstr ucti o ns f or st ora ge 
A d dress of t he S p o ns or” 
t o: 
“ N T Z a n d place b o ta blets will pa c ka ge d i n w hite 3 0cc H D P E b ottl es, eac h c o ntai ni n g 3 0 
ta blets.  T he b ottles will be st ore d at r o o m te m perat ure a n d will bear a la bel wit h t he f oll o wi n g 
i nf or mati o n: 
I n vesti gat or na me 
Patie nt n u m ber 
Wee k X X - X X 
3 0 ta blets 
Ta ke 3 ta blets orall y wit h f o o d i n t he m or ni n g a n d i n t he e ve ni n g 
R M 0 8- 2 0 0 1 
Ca uti o n: Ne w Dr u g – Li mite d b y Fe deral La w t o I n vesti gati o nal U se 

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5 9 
C O N FI D E N TI A L 
C ha n ge 1 5 
Secti o n 1 2. 4, u p date d title t o rea d: “ S u bject C o m plia nce a n d Di sall o we d Me dicati o ns” a n d 
a d de d t he f oll o wi n g: “ D uri n g t h e acti ve treat me nt c o urse of t he st u d y, c o nc o mita nt use of 
me dicati o ns c o nsi dere d maj or C Y P 2 C 8 s u bstrates ( A p pe n di x I) are  pr o hi bite d.  S u bjects are 
als o pr o hi bite d fr o m ta ki n g a n y ot her i n vesti gati o nal me dicati o n d uri n g t he st u d y.”    
C ha n ge 1 6 
Secti o n 9. 1 (Ite m # 7), Secti o n 9. 2 (Ite m # 8), Secti o n 9. 3 (Ite m  # 8), Secti o n 9. 4 (Ite m # 6) a n d 
Secti o n 9. 5 (Ite m # 6): Uri ne a p peara nce was a d de d t o cli nical l a b orat or y testi n g. 
Acti o n:  
A re vise d pr ot oc ol versi o n 3. 0 date d J u ne 1 3, 2 0 1 9 was ge nerate d. 
A me n d me nt 3 
 
P ur p ose: 
Re vise pr ot oc ol defi ne d st o p pi n g r ules, a n d ot her mi n or c ha n ges . 
C ha n ge 1 
Secti o n 1, secti o n 6, secti o n 9. 6 (ite m # 4): Re vise d st o p pi n g r ules. 
C ha n ge 2  
Secti o n 1: A d de d st u d y ce nter a n d scree ni n g peri o d.  
C ha n ge 3  
Secti o n 2: U p date d t he st u d y sc he ma. 
C ha n ge 4  
Secti o n 4. 2. 2. 2: C ha n ge d “ …treate d wit h 5 0 0 m g nitaz o x a ni de o nl y o nce dail y …” t o  
“ …treate d wit h 5 0 0  m g N T Z o nl y o nce dail y …”.   
C ha n ge d “ …re vie we d b y R ossi g n ol a n d Keeffe i n 2 0 0 9” t o “ …re vie w e d b y R ossi g n ol a n d 
Keeffe i n 2 0 0 8”   
C ha n ge 5 
Secti o n 8: A d de d, “If a s u bject  is l ost t o f oll o w u p or disc o nti n ues t he st u d y pri or t o t he 
assess me nt at wee k 1 2, a n a d diti o nal s u bject ma y be e nr olle d i n  t he sa me treat me nt gr o u p.” 
C ha n ge 6  
Secti o n 9. 1 (Ite m # 5): C ha n ge d H B V D N A t o q H B V D N A a n d  H Bs A G t o q H Bs A g. 
C ha n ge 7  
Secti o n 9. 1 (Ite m # 5), secti o n 9. 2 (Ite m # 4): C ha n ge d a nti- H Bs t o q A nti- H Bs. 
C ha n ge 8 
Secti o n 9. 2 (Ite m # 1 1): Re m o ve d “ …f or 1 2 wee ks …” fr o m t he Gr o u p  3 a n d 4 d osi n g 
i nstr ucti o ns a n d a d de d “ … wit h f o o d …” t o t he Gr o u p 2 d osi n g i nstr ucti o ns. 
C ha n ge 9 
Secti o n 1 2. 3: A d de d t he f oll o wi n g italicize d la n g ua ge, “ …e ver y 4 t o 1 2 wee ks d uri n g t he 
treat me nt peri o d, de pe n di n g o n t he visit sc he d ule.” 
C ha n ge 1 0  
Secti o n 2 1: Re m o ve d 
 as sec o n d Me dical M o nit or. 
C ha n ge 1 1 
Secti o n 2 3. 3: A d de d “( Ta ble 5)” a n d re m o ve d “ … o n t he f oll o wi n g pa ges”.  A d de d “ Ta ble 5” 
a n d re m o ve d “ …t he ne xt pa ge”. 
C ha n ge 1 2 
A me n d me nt 2 S u m mar y of C ha n ges (Ite m # 3): C ha n ge d “ … Baseli ne a n d W ee k 1” t o 
“ … Baseli ne a n d visits t hr o u g h o ut t he st u d y”. 
Acti o n: 
A re vise d pr ot oc ol versi o n 4. 0 date d Ja n uar y 2, 2 0 2 0 was ge nera te d.