Clinical trial NCT03905655
Conditions: Chronic Hepatitis B
Sponsor: Romark Laboratories L.C.
Start date: 2019-10-22; Completion date: 2021-10-11
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized controlled trial is designed to evaluate safety, effectiveness and pharmacokinetic-pharmacodynamic (PK/PD) relationships associated with three different Nitazoxanide (NTZ) treatment regimens added to Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF) or Entecavir (ETV) in treating Chronic Hepatitis B (CHB).

Detailed description:

Arms: arm 1: Three placebo tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy arm 2: Two 300 mg NTZ tablets and one placebo tablet administered orally in the morning and three placebo tablets in the evening in addition to continuing TDF, TAF or ETV therapy arm 3: Two 300 mg NTZ tablets and one placebo tablet administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy arm 4: Three 300 mg NTZ tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy
Interventions: intervention 1: Placebo Oral Tablet intervention 2: Nitazoxanide
Intervention descriptions: intervention 1: Number of placebo tablets administered orally depends on the arm intervention 2: Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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 
 
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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 
 
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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 


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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  


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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 
 
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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 
 
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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 
 
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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  
 
 
 
 
 
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 # ( 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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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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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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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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 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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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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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  
x  
x  
x  
x  
x  
x 
 
 
 
 
 
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. 




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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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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.