A Randomized, Partially Double-Blind, Four-Period, Four-Treatment, Crossover Study Investigating the Placebo-Corrected Effects of a Therapeutic Dose (100 mg) and a Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval in Healthy Male and Female Subjects
Phase: PHASE1
Conditions: Duchenne and Becker Muscular Dystrophy, Polycytemia Vera
Sponsor: Italfarmaco

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
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Italfar mac o S. p. A. 
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C o nfi de ntial  
P a ge 1  of 6 7  
A me n d me nt I  
 
 
 
I T A L F A R M A C O S. p. A. 
 
P R O T O C O L 2 0 0 1 4 8   
It alf ar m ac o S. p. A. st u d y n u m ber:  I T F/ 2 3 5 7/ 5 4 
I N D n u m ber: 
 
E u dr a C T n u m ber: 2 0 2 0 -0 0 3 1 0 5 -6 3  
  
 
A R A N D O MI Z E D, P A R TI A L L Y D O U B L E -B LI N D, F O U R -P E RI O D, F O U R -
T R E A T M E N T, C R O S S O V E R S T U D Y I N V E S TI G A TI N G T H E P L A C E B O -
C O R R E C T E D E F F E C T S O F A T H E R A P E U TI C D O S E ( 1 0 0  m g ) A N D A 
S U P R A T H E R A P E U TI C D O S E ( 3 0 0 m g ) O F I T F 2 3 5 7 ( GI VI N O S T A T) A N D 
M O XI F L O X A CI N O N Q T/ Q T C I N T E R V A L I N H E A L T H Y M A L E A N D F E M A L E 
S U B J E C T S  
 
 
C o ntr act Rese a rc h Or g a niz ati o n:  
S y ne os H ealt h Cli ni q ue i nc.  
( « S y ne os H ealt h  »)  
2 5 0 0, r ue Ei nstei n  
Q ué bec ( Q ué b ec)  
Ca na da, G 1 P 0 A 2  
Tel.: 1 -4 1 8 -5 2 7 -4 0 0 0  
S p o ns or:  
Italfar mac o S.p. A.   
C o ntact p oi nt:  
Via dei La v orat ori 5 4  
2 0 0 9 2 Ci nisell o Balsa m o  
Mila n, Ital y  
Tel.: + 3 9  0 2 6 4 4 3 1  
Fa x: + 3 9 0 2 6 4 4 3 3 5 5 4
 
 
 
 
 
 
 
       Re gistere d office:  
 
 
 
 
 
 
 
       Viale F u lvi o Testi, 3 3 0  
 
 
 
 
 
 
 
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       Tel. : + 3 9 0 2 6 4 4 3 1 
 
C O N FI D E N TI A L  
T his d oc u me nt is strictl y c o nfi de ntial. It was de vel o pe d f or Italfar mac o S. p. A. b y S y ne os H ealt h  a n d m ust n ot b e 
discl ose d t o a t hir d part y, wit h t he e xce pti o n of re g ulat or y a ge ncies a n d st u d y a u dit pers o n nel wit h o ut t he  e x presse d, 
writte n c o nse nt of Italfar mac o S. p. A . T he st u d y will be c o n d ucte d acc or di n g t o t he I nter nati o nal C o nfere nce o n 
Har m o nisa ti o n (I C H) Tri partite G ui deli ne E 6 ( R 1/ R 2): G o o d Cli nical Practice a n d U nite d States ( U S) C o de of 
Fe deral Re g ulati o ns ( C F R) a p plica ble t o cli nical st u dies, i ncl u di n g 2 1 C F R P arts 5 0, 5 6, a n d 3 1 2 . 
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A me n d me nt I  
Pr ot oc ol Hist oric al File  
Versi o n 
n u m ber  
Brief descri pti o n/s u m m ar y of c h a n ges  
D ate  
Fi nal   
Si g ne d versi o n . 
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A me n d me nt  I Versi o n s u b mitte d t o t he I E C . 
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C h a n ges i ncl u de d i n A me n d me nt I :  
C ha n ges h a ve b ee n ma d e t o a me n d t he d urati o n of s o me of t he o n-st u d y restricti o ns. T hese 
c ha n ges ha v e bee n ma de a p plie d t o:  
- 
Pa ge 1 6 , st u d y restricti o ns u n der s ecti o n 2. S y n o psis of Pr ot oc ol . T he first 5 b ullete d  p oi nts  
ha ve bee n c ha n ge d as f oll o ws:  
 "Prescri pti o n me dicati o n fr o m 1 4 da ys pri or t o t h e first d osi n g u ntil after t he last 
P K bl o o d sa m ple c ollecti o n of t he st u d y” n o w rea d s “Prescri pti o n me dicati o n fr o m 
1 4 da ys pri or t o t he first d osi n g u ntil st u d y e xit”  
 “ O T C pr o d ucts fr o m 7 d a ys pri or t o t he first d osi n g u ntil after t h e last P K bl o o d 
sa m ple c ollecti o n of t he st u d y” n o w rea d “ O TC pr o d ucts fr o m 7 da ys pri or t o t he 
first d osi n g u ntil st u d y e xit” 
 “ Nat ural h ealt h pr o d ucts fr o m 7 da ys pre d ose u ntil after t he last P K bl o o d sa m ple 
c ollecti o n of t he st u d y” n o w rea d s “Nat ur al healt h pr o d ucts fr o m 7 da ys pri or t o t he 
first d osi n g u ntil stu d y e xit”  
 “ A de p ot i njecti o n or a n i m pla nt of a n y dr u g wit hi n 3 m o nt hs pri or t o t he first 
d osi n g” n o w rea d s “ A d e p ot i njecti o n or a n i m pla nt of a n y dr u g wit hi n 3 m o nt hs 
pri or t o t he first d osi n g u ntil st u d y e xit”  
 “ St. J o h n´s w ort fr o m 3 0 da ys pri or t o t he first d osi n g u ntil after t he last P K bl o o d 
sa m ple c ollecti o n of t he st u d y” n o w rea ds “ St. J o h n´s w ort a n d a n y dr u gs k n o w n 
t o i n d uce or i n hi bit he patic dr u g meta b olis m fr o m 3 0 da ys pri or t o t he first d osi n g 
u ntil st u d y e xit”  
- 
Pa ges 4 1  t o 42 , st u d y restricti o ns u n der secti o n 9. 8 St u dy Restricti o ns . T he t hir d b ullet 
p oi nt o n pa ge 4 1 , secti o n 9. 8. 1 F o o d a n d Fl ui ds, n o w rea d s “( …) fr o m 7 da ys pri or t o first 
d osi n g u ntil st u d y e xit”, a n d t he first se nte nce o n pa ge 4 2 , secti o n 9. 8. 2 T o b acc o, Alc o h ol 
a n d Illicit  Dr u gs , n o w rea d s “( …) u ntil st u d y e xit.” 
 
Clarificati o n s ha ve  b ee n ma de o n pre vi o us a n d c o nc o mita nt me dicati o ns restricti o ns; t hese 
c ha n ges ha v e bee n ma de t o:  
- 
Pa ge 1 4 , e x cl usi o n criteria 1 8 u n der secti o n 2. Sy n o psis of Pr ot oc ol. P oi nt b) of criteri o n 
1 8) n o w rea ds “( …) wit h t he e x ce pti o n of t he occasi o nal use of a ceta mi n o p he n [ u p t o 2 g 
dail y] ( …) .” T h eref ore, criteria 1 9 w hic h e x plai ne d t he occasi o nal us e of aceta mi n o p he n 
has bee n d elete d, a n d criteria 2 0 w hic h d escri b e t he restri cti o ns of plas ma d o nati o n  
bec o mes n o w criteria 1 9.   
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C o nfi de ntial  
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A me n d me nt I  
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Pa ge 3 5 , e x cl usi o n criteria 1 8 u n der secti o n 8. 3 Excl usi o n Criteri a. P oi nt b) of criteri o n 
1 8) n o w rea ds “( …) wit h t he e x ce pti o n of t he oc casi o nal use of aceta mi n o p he n [ u p t o 2 g 
dail y] ( …) .” T h eref ore, criteria 1 9 w hic h e x plai n e d t he occasi o nal us e of aceta mi n o p he n 
has bee n d elete d, a n d criteria 2 0 w hic h d escri b e t he restri cti o ns of plas ma d o nati o n 
bec o mes n o w criteria 1 9.   
- 
Pa ge 1 6 , st u d y restricti o ns u n der secti o n 2. Sy n o psis of Pr ot oc ol : 
 B ullet p oi nt 5 has bee n c ha n ge d fr o m “ St. J o h n´s w ort fr o m 3 0 d a ys pri or t o t he 
first d osi n g u ntil aft er t h e last P K bl o o d sa m ple c ollecti o n of t he st u d y” t o  “ St. 
J o h n´s w ort a n d a n y dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g meta b olis m fr o m 
3 0 da ys pri or t o t he first d osi n g u ntil st u d y e xit .” 
  B ullet p oi nt 1 0 has bee n a d de d “ S oft or har d dr u gs or a n y t o bacc o or nic oti ne 
pr o d ucts fr o m scree ni n g u ntil st u d y e xit .”   
- 
Pa ge s 4 1  t o 4 2, st u d y restricti o ns u n der secti o n 9. 8 St u dy Restricti o ns, secti o n 9. 8. 1 F o o d 
a n d Fl ui ds, b ullet p oi nt 4 has bee n  a d de d o n pa ge 4 2 a n d rea ds “ St J o h n’s w ort a n d a n y 
dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g m eta b olis m fr o m 3 0 da ys pri or t o first d osi n g 
u ntil st u d y e xit .” 
- 
Pa ge 4 2 , secti o n 9. 8. 3 c o nc o mita nt me dicati o ns, t he first se nte nce n o w rea ds “( …) a n d 
de p ot i njecti o n or i m pla nt of a n y dr u g, f or t he peri o d of ti me s pecifi e d i n e x cl usi o n criteri o n 
1 8) u ntil st u d y e xit .”  
 
T he uri nar y p h ar mac o ki netic para m eters w ere u p d ate d a n d n o w i ncl u d e: A e 0 -t, Rma x , TR ma x , a n d 
Clr.  T heref ore c h a n ges are br o u g ht t o:  
 Pa ge 1 9 , p h ar mac o ki netics  u n der Secti o n 2, Sy n o psis of Pr ot oc ol   
 Pa ges 5 6 -5 7  uri ne P K para meters u n d er Secti o n 1 2. 2  
As a res ult of t he a b o ve c ha n ges, a d diti o nal a b bre viati o ns a n d defi niti o n of ter ms ha ve bee n 
a d de d or u p dat e d; c ha n ges ha ve bee n br o u g ht t o:  
 Pa ges 2 0 -2 2  u n der Secti o n 3 List of A b brevi ati o ns a n d Defi niti o n of Ter ms  
 Pa ge 5 6  u n d er Secti o n 1 2. 1 Pl as m a P K P ar a meters
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C o nfi de ntial  
P a ge 5  of 6 7  
A me n d me nt I  
Si g n at ure P a ge  
C o ntr act Rese a rc h Or g a niz ati o n  ( C R O) 
S y ne os H ealt h Cli ni q ue i nc.  
 
Si g nat ure  
Date  ( X X-M M M -2 0 2 0)  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
( pri nte d na me a n d title)  
 
 
 
 
 
 
El e ctr o ni c all y si g n e d b y:
R e a s o n: I a m a c c e pti n g t h e t er m s of s er vi c e
D at e: S e p 2 9, 2 0 2 0 1 6: 4 2 E D T
2 9- S e p- 2 0 2 0
P P D
P P D
P P D
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Italfar mac o S. p. A. 
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C o nfi de ntial  
P a ge 6  of 6 7  
A me n d me nt I  
Si g n at ure p a ge  
Q u alifie d I n vesti g at or 
I (as Q u alifie d I n vesti gat or) ha ve caref ull y rea d a n d u n derst o o d all secti o n s of t his st u d y pr ot oc ol 
Fi nal V ersi o n d ate d 2 0 -J U L-2 0 2 0  a n d a gree t hat it c o ntai ns all necessar y i nf or mati o n re q uir e d t o 
c o n d uct t his st u d y.  
I a gree t o s u per vise all as pects of t he pr ot oc ol a n d t o c o n d uct t he st u d y acc or di n g t o t his pr ot oc ol 
(i ncl u di n g a n y a me n d me nts) a n d i n acc or da nce wit h t he cli nical site’s Sta n dar d O perati n g 
Pr oce d ures ( S O Ps), I C H G o o d Cli nical Practice ( G C P), all ot her a p plica bl e re g ulati o ns,  
i ncl u di n g t he Fe deral F o o d, Dr u g a n d C os metic Act, U. S. a p plica ble C o d e of Fe deral 
Re g ulati o ns (title 2 1), a n d a n y I E C re q ui re me nts relati ve t o cli nical st u dies a n d t he 
rec o m me n dati o ns lai d d o w n i n t he m ost rece nt versi o n of t he Declarati o n of Helsi n ki. 
I will n ot ma ke c ha n ges t o t he pr ot oc ol bef ore c o ns ulti n g wit h It alfar m ac o S. p. A. or i m ple me nt 
pr ot oc ol c ha n ges wit h o ut I n d e pe n de nt Et hics C o m mittee  (I E C) a p pr o val e xce pt t o eli mi nate a n 
i m me diate ris k t o s u bjects. I a gree t o a d mi nister st u d y dr u g o nl y t o s u bjects u n der m y pers o nal 
s u per visi o n or t he s u per visi o n of a s u b-i n vesti gat or. I will n ot s u p pl y t he i n vesti gati o nal dr u g t o 
a n y p ers o n n ot a ut h orize d t o recei ve it. S u bject i d e ntit y will n ot be discl ose d t o t hir d parties or 
a p pear i n a n y st u d y re p orts or p u blicati o ns.  
It is f urt h er a gree d t h at t he details of t his trial a n d all i nf or mati o n pr o vi de d t o me b y Italfar mac o 
S. p. A. o r S y ne os H ealt h will be hel d i n t he strictest c o nfi de nce a n d will n ot be re veale d f or a n y 
reas o n wit h o ut writte n a ut h orizati o n fr o m Italfar m ac o S. p. A. e x ce pt t o t h ose w h o are t o 
partici pate i n t he c o n d u ct of t he trial.  
I a gree t hat all data, t he case re p ort f or ms a n d all materials pr o vi de d f or t he c o n d uct of t he trial 
are t he pr o pert y of It alfar mac o S. p. A. u nless s pecifie d ot her wise i n writi n g.  It is u n derst o o d t hat 
Italfar mac o S. p. A. will utiliz e t he i nf or mati o n deri ve d fr o m t his trial i n vari o us wa ys, s uc h as f or 
s u b missi o n t o g o ver n me nt re g ul at or y a ge ncies, re q uire d i nter nal r e p orts a n d prese ntat i o ns 
wit h o ut vi olati n g patie nt/ s u bject c o nfi de ntialit y i n a n y wa y. 
I f urt her a gree t hat Italfar mac o S. p. A. or its re pres e ntati ves will be per mitte d access i n 
accor da nce wit h c urre nt G o o d Cli nical Practice G ui deli nes, t o all data ge nerate d b y t his trial a n d 
t he s o urce d o c u me nts fr o m w hic h case re p ort f or m data were ge nerate d. 
 
 
Si g nat ure  
 
Date  ( X X-M M M -2 0 2 0)  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
( pri nte d na me  a n d title)  
 
El e ctr o ni c all y si g n e d b y:
R e a s o n: I a m a c c e pti n g t h e t er m s of s er vi c e
D at e: S e p 2 9, 2 0 2 0 2 3: 3 1 E D T
S e p 2 9, 2 0 2 0
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P a ge 7  of 6 7  
A me n d me nt I  
1.  
F acilities a n d Res p o nsi ble St aff  
1. 1  
Cli nic al Rese arc h F acilities  
T his st u d y will be c o n d u cte d b y S y n e os Healt h at t he f oll o wi n g facilit y:  
2 5 0 0, r ue Ei nstei n  
Q ué bec ( Q ué b ec), Ca n a d a, G 1 P 0 A 2  
Tel.: 1 -4 1 8 -5 2 7 -4 0 0 0  
Scree ni n g a n d/ or ret ur n visits (if a n y) ma y als o be perf or me d at t he M o ntréal S y ne os H ealt h 
facilit y: 
5 1 6 0, b o ul. Décarie, s uite 8 0 0  
M o ntréal ( Q u é bec), Ca na da, H 3 X 2 H 9  
Tel .: 1-5 1 4 -4 8 5 -7 5 0 0  
1. 2  
Bi o me dic al  L a b or at or y F acilit ies 
Bi o me dical  la b orat or y testi n g will be perf or me d b y t he f oll o wi n g la b orat ories: 
Bir o n Me dic al La b orat or y i nc.  
4 1 0 5 -F, b o ul. Matte  
Br ossar d ( Q ué b ec), Ca na da, J 4 Y 2 P 4  
Tel.: 1 -5 1 4 -8 6 6 -6 1 4 6  
S y ne os H ealt h  
2 5 0 0, r ue Ei nstei n  
Q ué bec ( Q ué b ec), Ca n a d a, G 1 P 0 A 2  
Tel.: 1 -4 1 8 -5 2 7 -4 0 0 0  
S y ne os H ealt h  
5 1 6 0, b o ul. Décarie, s uite 8 0 0  
M o ntréal ( Q u é bec), Ca na da, H 3 X 2 H 9  
Tel.: 1 -5 1 4 -4 8 5 -7 5 0 0  
If a n ot her bi o me di cal la b orat or y is use d, t his will be d oc u me nte d a n d a n ne x e d t o t he pr ot oc ol. 
1. 3  
E C G Ce ntr al C ore L a b or at or y  
E R T  
1 5 0 Alle ns Cree k R d  
R oc hester, N Y 1 4 6 1 8  
U S A  
Tel.: 1 - 5 8 5 -2 9 5 -7 6 1 0  
, M D P h D 
  
Tel.: 
 
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A me n d me nt I  
1. 4  
Cli nic al P h ar m ac ol o g y a n d Re g ul at or y Aff airs   
S y ne os H ealt h  
2 5 0 0, r ue Ei nstei n  
Q ué bec ( Q ué b ec), Ca n a d a, G 1 P 0 A 2  
Tel. : 1 -4 1 8 -5 2 7 -4 0 0 0  
, P h. D.  
 
, P h. D . 
 
1. 5  
Bi o a n al ytic al F acilit y  
S y ne os H ealt h  
2 5 0 0, r ue Ei nstei n  
Q ué bec ( Q ué b ec), Ca n a d a, G 1 P 0 A 2  
Tel. : 1 -4 1 8 -5 2 7 -4 0 0 0  
, B. S. 
 
 
P P D
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A me n d me nt I  
T a ble of C o nte nts  
1.  
F A CI LI TI E S A N D R E S P O N SI B L E S T A F F  ................................................................................. 7  
1. 1  
C LI NI C A L R E S E A R C H F A CI LI TI E S  ........................................................................................................................ 7  
1. 2  
B I O M E DI C A L L A B O R A T O R Y F A CI LI TI E S  .............................................................................................................. 7  
1. 3  
E C G  C E N T R A L C O R E L A B O R A T O R Y  ................................................................................................................... 7  
1. 4  
C LI NI C A L P H A R M A C O L O G Y A N D R E G U L A T O R Y A F F AI R S  ................................................................................... 8  
1. 5  
B I O A N A L Y TI C A L F A CI LI T Y  .................................................................................................................................. 8  
2.  
S Y N O P SI S O F P R O T O C O L  ........................................................................................................ 1 1  
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 O F T E R M S  ................................................ 2 0  
4.  
S C H E D U L E O F E V E N T S  ............................................................................................................. 2 3  
5.  
I N T R O D U C TI O N .......................................................................................................................... 2 5  
 2 5  
5. 2  
M O XI F L O X A CI N B A C K G R O U N D IN F O R M A TI O N  ................................................................................................. 2 6  
 2 7  
6.  
O B J E C TI V E S  ................................................................................................................................. 3 1  
7.  
S T U D Y D E SI G N  ............................................................................................................................ 3 1  
8.  
S T U D Y P O P U L A TI O N  ................................................................................................................. 3 1  
8. 1  
S A M P L E S I Z E ..................................................................................................................................................... 3 1  
8. 2  
IN C L U SI O N C RI T E RI A  ........................................................................................................................................ 3 2  
8. 3  
E X C L U S I O N C RI T E RI A  ....................................................................................................................................... 3 3  
9.  
C LI NI C A L P R O C E D U R E S  .......................................................................................................... 3 5  
9. 1  
S C R E E NI N G P R O C E D U R E S  .................................................................................................................................. 3 5  
9. 2  
S T U D Y P R O C E D U R E S  ......................................................................................................................................... 3 6  
9. 3  
C O N FI N E M E N T S A N D W
A S H O U T  ........................................................................................................................ 3 6  
9. 4  
R A N D O MI Z A TI O N A N D B LI N DI N G  ...................................................................................................................... 3 7  
9. 5  
S T U D Y M E DI C A TI O N S  ....................................................................................................................................... 3 9  
9. 6  
D R U G S U P P LI E S A N D A C C O U N T A BI LI T Y  ............................................................................................................ 3 9  
9. 7  
S T U D Y T R E A T M E N T S A D MI NI S T R A TI O N ............................................................................................................ 4 0  
9. 8  
S T U D Y R E S T RI C TI O N S  ....................................................................................................................................... 4 1  
9. 9  
S A M P L E C O L L E C TI O N A N D P R O C E S SI N G  ........................................................................................................... 4 2  
9. 1 0  S U BJ E C T M O NI T O RI N G  ...................................................................................................................................... 4 4  
9. 1 1  S T U D Y E XI T P R O C E D U R E S ( EN D O F T RI A L V I SI T/ EA R L Y T E R MI N A TI O N V I SI T) ................................................ 4 8  
9. 1 2  F O L L O W -U P T E L E P H O N E C A L L ( DA Y 1 2 ± 2  D A Y S ): ........................................................................................... 4 8  
9. 1 3  D A T A C O L L E C TI O N A N D E V A L U A TI O N  ............................................................................................................. 4 9  
9. 1 4  S U BJ E C T W
I T H D R A W A L A N D R E P L A C E M E N T  .................................................................................................... 4 9  
9. 1 5  A D V E R S E E V E N T S A N D A D V E R S E R E A C TI O N S  .................................................................................................. 5 0  
9. 1 6  P R E G N A N C Y  ...................................................................................................................................................... 5 3  
9. 1 7  O V E R D O S E  ........................................................................................................................................................ 5 4  
9. 1 8  R E P O R T A B L E D I S EA S E  ...................................................................................................................................... 5 4  
9. 1 9  P R E M A T U R E T E R MI N A TI O N O F T H E S T U D Y  ....................................................................................................... 5 5  
1 0.  
A N A L Y TI C A L M E T H O D O L O G Y  ............................................................................................. 5 5  
1 1.  
S T U D Y E N D P OI N T S  .................................................................................................................... 5 5  
1 2.  
P H A R M A C O KI N E TI C A N D S T A TI S TI C A L A N A L Y S E S  ..................................................... 5 6  
1 2. 1  P L A S M A P K  P A R A M E T E R S  ................................................................................................................................ 5 6  
1 2. 2  U RI N E P K  P A R A M E T E R S  ................................................................................................................................... 5 6  
1 2. 3  A N A L Y SI S P O P U L A TI O N S ................................................................................................................................... 5 7  
1 2. 4  S T A TI S TI C A L A N A L Y S E S  ................................................................................................................................... 5 8  
C CI
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 0  of 6 7  
A me n d me nt I  
1 3.  
R E G U L A T O R Y C O N SI D E R A TI O N S A N D Q U A LI T Y A S S U R A N C E  .................................. 6 2  
1 3. 1  IN D E P E N D E N T E T HI C S C O M MI T T E E A P P R O V A L O F P R O T O C O L A N D O T H E R S T U D Y D O C U M E N T S  ..................... 6 2  
1 3. 2  C O M P LI A N C E ..................................................................................................................................................... 6 3  
1 3. 3  P R O T O C O L D E VI A TI O N S  .................................................................................................................................... 6 3  
1 3. 4  F I N A N CI A L D I S C L O S U R E A N D O B LI G A TI O N S  ..................................................................................................... 6 3  
1 3. 5  Q U A LI T Y A S S U R A N C E P R O G R A M  ...................................................................................................................... 6 4  
1 3. 6  IN V E S TI G A T O R D O C U M E N T A TI O N  ..................................................................................................................... 6 4  
1 3. 7  A U DI T S , IN S P E C TI O N S A N D M O NI T O RI N G  .......................................................................................................... 6 4  
1 4.  
C O N FI D E N TI A LI T Y A N D R E T E N TI O N O F S T U D Y R E C O R D S  ........................................ 6 5  
1 5.  
R E F E R E N C E S  ............................................................................................................................... 6 7  
 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 1  of 6 7  
A me n d me nt I  
2.  
S y n o psis of Pr ot oc ol  
Pr oject N o.:  
S y ne os Healt h pr oj ect n u m ber: 2 0 0 1 4 8   
Italfar mac o S. p. A. st u d y n u m ber: I T F/ 2 3 5 7/ 5 4 
I N D n u m ber: 
 
E u dra C T n u m ber: 2 0 2 0 -0 0 3 1 0 5 -6 3  
St u d y Title:  
A R A N D O MI Z E D, P A R TI A L L Y D O U B L E -B LI N D, F O U R -P E RI O D, F O U R -
T R E A T M E N T, C R O S S O V E R S T U D Y I N V E S TI G A TI N G T H E P L A C E B O -
C O R R E C T E D E F F E C T S O F A T H E R A P E U TI C D O S E ( 1 0 0 m g ) A N D A 
S U P R A T H E R A P E U TI C D O S E ( 3 0 0 m g ) O F I T F 2 3 5 7 ( GI VI N O S T A T) A N D 
M O XI F L O X A CI N O N Q T/ Q T C I N T E R V A L I N  H E A L T H Y M A L E A N D 
F E M A L E S U BJ E C T S  
St u d y Dr u g:  
G i vi n ostat (I T F 2 3 5 7) 
St u d y P h ase a n d T y pe:  
P hase 1  -  T h or o u g h Q T/ Q T c St u d y  
St u d y O bjecti ve s: 
Pri mar y o bj ecti ve : 
 
T o e val uate t he effect of a t her a pe utic d ose a n d a s u prat hera p e utic d ose 
of  I T F 2 3 5 7 o n t he Q T/Q T c i nter val.  
Sec o n dar y o bj ecti ves : 
 
T o e val uate t he effect of a  si n gle oral t hera pe utic (T)  a n d a 
s u prat hera pe utic d ose ( S T) of I T F 23 5 7  o n ot her E C G para meters ( heart 
rate [ H R], [ P R], Q R S i nter vals a n d T-wa ve m or p h ol o g y).  
 
T o e val uate  t he p har mac o ki netic ( P K) para meters of t w o d oses ( 1 0 0 m g 
a n d 3 0 0 m g)  of I T F 2 3 5 7 a n d  meta b olites : I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, 
I T F 2 5 6 3 a n d I T F 2 95 5 gl uc ur o ni de .  
 
T o e val uate  t he safet y a n d t olera bilit y of t w o d oses ( 1 0 0 m g a n d 3 0 0 m g) 
of  I T F 2 3 5 7.  
St u d y Desi g n:  
T his will b e a si n gle ce ntre, ra n d o mize d, partiall y d o u ble -bli n d, si n gle d ose, 
place b o -correcte d , 1 2-se q ue nc e, 4-peri o d,  cr oss o ver st u d y u n der fasti n g 
c o n diti o ns.  
S u bjects:  
U p  t o 3 4  s u bj ects t o e ns ure 2 8 e val ua ble healt h y a d ult, males or  fe males, ≥ 1 8 a n d 
≤ 5 5  years of a ge , n o n -s m o ker. 
R a n d o miz ati o n a n d 
Bli n di n g:   
Treat me nts T  (thera pe utic) , S T (su prat hera pe utic) , a n d P (p lace b o) will be 
pre p are d i n di vi d uall y b y t he u n bli n de d  tea m at t he site p har mac y, acc or di n g t o t he 
ra n d o mizati o n sc he d ule, a n d will lea ve t he p har mac y r o o m bli n de d, s o t hat t he 
bli n de d  site tea m c o ul d a d mi nister t he m t o t he s u bj ects.  
O n t he c o ntrar y n o bli n di n g will be nee de d wit h treat me nt M (m o xifl o xaci n) . T o  
mai ntai n bli n di n g f or s u bj ect s w h o recei ve M i n P eri o d s 1, 2 a n d 3, s u bj ects will 
be ra n d o mize d t o o ne of 1 2 treat me nt se q ue nces. T h e E C G Ce ntral C ore 
La b orat or y  E C G A nal yst , will be bli n de d t o treat me nt, st u d y peri o d, ti me p oi nt of 
E C G rec or di n g , a n d s u bj ect details s uc h as la b orat or y res ults a n d ad verse eve nts  
( A Es). 
I ncl usi o n Criteri a:  
S u bj ects m ust meet all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:  
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 2  of 6 7  
A me n d me nt I  
1)  Male or fe male, n o n -s m o ker ( n o use of t o bacc o or nic oti ne pr o d ucts wit hi n 
3  m o nt hs  pri or t o scree ni n g), ≥1 8 a n d ≤5 5 years of a ge, wit h B MI > 1 8. 5 a n d 
< 3 0. 0  k g/ m 2 a n d b o d y wei g ht ≥5 5  k g  a n d ≤1 0 0 k g f or  fe mal es a n d b o d y 
wei g ht ≥6 0 k g a n d ≤1 0 0 k g f or males. 
2)  Healt h y as defi ne d b y:  
a) T he a bse nce of cli nicall y si g nifica nt ill ness a n d maj or s ur ger y wit hi n 
4  wee ks pri or t o d osi n g. S u bj ects v o miti n g wit hi n 2 4 h o urs pre -d ose will 
be caref ull y e val uate d f or u pc o mi n g ill ness/ disease.  I ncl usi o n pre-d osi n g 
of t he patie nt i n t he st u d y is at t he discreti o n of t he I n vesti gat or, 
de pe n di n g o n his/ her cli nical j u d ge me nt.  
b)  T he a bse nce of cli nicall y si g nifica nt hist or y of ne ur ol o gical, e n d ocri nal, 
car di o vasc ular, p ul m o nar y, he mat ol o gical, i m m u n ol o gic, ps yc hiatric, 
gastr oi ntesti nal, re nal, he patic, a n d meta b olic disease.  
3)  N o n -c hil d beari n g p ote ntial fe male defi ne d as:  
a) P ost -me n o pa usal fe male (a bse nce of me nses f or 1 2  m o nt hs pri or t o t he 
first st u d y dr u g a d mi nistrati o n, bilateral o o p h orect o m y or h ysterect o m y 
wit h bilateral o o p h orect o m y at least 6 m o nt hs pri or t o t he first st u d y 
dr u g a d mi nistrati o n); or  
b)  S ur gica ll y sterile fe male ( h yst erect o m y or t u bal li gati o n at l east 
6  m o nt hs pri or t o dr u g a d mi nistrati o n).  
4)  Fe males of c hil d beari n g p ote ntial w h o are  se x uall y acti ve wit h a male part ner 
m ust b e willi n g t o use o ne of t he f oll o wi n g acce pta ble c o ntrace pti ve met h o ds  
t hr o u g h o ut t he st u d y a n d f or at least 9 0 da ys after t he last st u d y dr u g 
a d mi nistrati o n:  
a) S i m ulta ne o us use of i ntra-uteri ne c o ntrace pti ve de vice, wit h o ut h or m o ne 
release s yste m place d at least 4 wee ks pri or t o st u d y dr u g a d mi nistrati o n, 
a n d c o n d o m f or t he m ale part ner ; 
b)  S i m ulta ne o us use of dia p hra g m or cer vical ca p wit h i ntra va gi nall y 
a p plie d s per mici de a n d male c o n d o m f or t he male part ner, st arte d at least 
2 1 da ys pri or t o st u d y dr u g a d mi nistrati o n .  
5)  Male s u bj ects w h o are n ot vas ect o mize d f or at least 6 m o nt hs, a n d w h o are 
se x uall y acti ve wit h a fe male part ner of c hil d beari n g p ote nti al (c hil d beari n g 
p ote ntial fe males are defi ne d as w o me n t hat are neit her p ost -me n o pa usal n or 
s ur gicall y sterile) m ust be willi n g t o use o ne of t he f oll o wi n g acce pta ble 
c o ntrace pti ve met h o ds fr o m t he first st u d y dr u g a d mi nistrati o n u ntil at least 
9 0 da ys after t he last st u d y dr u g a d mi nistrati o n:  
a) S i m ulta ne o us use of a male c o n d o m a n d, f or t he fe male part ner, 
h or m o nal c o ntrace pti ves use d si nce at least 4 wee ks or i ntra -uteri ne 
c o ntrac e pti ve de vice place d si nce at least 4 wee ks;  
b)  S i m ulta ne o us use of a male c o n d o m a n d, f or t he fe male part ner, a 
dia p hra g m or cer vical ca p wit h i ntra va gi nall y a p plie d s per mici de.  
6)  Male s u bj ects (i ncl u di n g me n w h o ha ve ha d a vasect o m y) wit h a pre g na nt 
part ner m ust a gree t o use a c o n d o m fr o m t he first st u d y dr u g a d mi nistrati o n 
u ntil at least 9 0 da ys after t he last st u d y dr u g a d mi nistrati o n.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 3  of 6 7  
A me n d me nt I  
7)  Male s u bj ects m ust be willi n g n ot t o d o nate s per m u ntil 9 0 da ys f oll o wi n g 
t he last st u d y dr u g a d mi nistrati o n. 
8)  Fe male s u bj ect s m ust be willi n g n ot t o d o nate o v ules u ntil 9 0 da ys f oll o wi n g 
t he last st u d y dr u g a d mi nistrati o n. 
9)  S u bj ect’s writte n i nf or me d c o nse nt o btai ne d pri or t o a n y st u d y -relate d 
pr oce d ure;  
1 0)  Willi n g ness a n d ca pa bilit y t o c o m pl y wit h t he re q uire me nts of t he st u d y a n d  
abilit y t o u n dersta n d t he st u d y pr oce d ures a n d t he ris ks i n v ol ve d.  
1 1)  Willi n g t o ta ke o ut de nt ures a n d m o ut h pierci n gs f or st u d y pr oce d ures.  
E xcl usi o n Criteri a:  
S u bj ects t o w h o m a n y of t he f oll o wi n g a p plies will be e xcl u de d fr o m t he st u d y:  
1)  A n y cli nicall y si g nifica nt a b n or malit y at p h ysical e xa mi nati o n, cli nicall y 
si g nifica nt a b n or mal la b orat or y test res ults or p ositi ve test f or HI V, he p atitis 
B, or he patitis C f o u n d d uri n g me dical scree ni n g.  
2)  Cli nicall y si g nifica n t vital si g n a b n or malities ( s yst olic bl o o d press ure l o wer 
t ha n 9 0 or o ver 1 4 0 m m H g, di ast olic bl o o d press ure l o wer t ha n 6 0 or o ver 
9 0  m m H g, or heart rate less t ha n 4 0  or o ver 1 0 0 b p m ) at scre e ni n g . F or 
eli gi bilit y p ur p oses, n ot t he mea n val ue, b ut t he t w o si n gle meas ure me nts 
will b e c o nsi dere d.  
3)  A n y of t he f oll o wi n g a b n or malities  o n 1 2 -lea d E C G at scree ni n g: P R ( P R 
i nter val) ˃ 2 1 0  msec;  Q R S ( Q R S c o m ple x) ˃ 1 2 0 msec;  Q T c F ( Fri dericia’s 
c orrecte d Q T i nter val) ˃ 4 5 0 msec; a n y a b n or malit y of  car diac r h yt h m ot her 
t ha n si n us arr h yt h mia; a b n or malit y of T -wa ve m or p h ol o g y t hat will i m pair 
t he a bilit y t o meas ure t he Q T i nter val relia bl y. T he a vera ge d val ue of t hree 
E C G s 5 mi n utes a part fr o m ea c h ot her  will be use d ; e val uati o ns ha ve  t o be 
use d f or t he e val uati o n of t he Q T c i nter val re q ueste d b y t his e xcl usi o n 
criteria.  
4)  S u bj ects wit h hist or y of s ustai ne d a n d n o n -s ustai ne d car diac arr h yt h mias 
( E C G de m o nstrate d), s u bj ects wit h a fa mil y hist or y of s u d de n car diac deat h 
a n d s u bj ects wit h a hist or y of a d diti o nal ris k fact ors f or t ors a de de p oi ntes 
(T d P ), heart fail ure, h y p o kale mia, a n d l o n g Q T s y n dr o me (L Q T S ).  
5)  A n y of t he f oll o wi n g a b n or mal la b orat or y test val ues at scre e ni n g a n d 
baseli ne Da y  -1  of P eri o d 1 . 
a) Platelet c o u nt < 1 2 5  x 1 0 9/ L 
b)  A bs ol ute ne utr o p hil c o u nt < 1. 2  x 1 0 9/ L  
6)  S u bj ects w h o ha ve car di o vasc ular c o n diti o n s uc h as, b ut n ot li mite d t o 
u nsta ble isc he mic heart diseas e, N Y H A Class III/I V left ve ntric ular fail ure, 
ac ute isc he mic heart disease i n t he last year pri or t o st u d y s cree ni n g, w hic h 
ma y i m pact t he safet y of t he s u bj ect or t he e val uati o n of t he res ult of t he 
st u d y acc or di n g t o t he I n vesti gat or's j u d g me nt; car di o vasc ul ar c o n diti o ns 
s h o ul d be discar de d base d o n t he res ults o btai ne d o n t he E C G, me dical 
e xa mi nati o n a n d r o uti ne la b test.  
7)  P ositi ve uri ne dr u g scree n, alc o h ol breat h test or u ri ne c oti ni ne test at 
scree ni n g or at baseli ne ( Da y -1) . 
8)  Hist or y of a na p h yla xis reacti o n or cli nicall y si g nifica nt dr u g h y perse nsiti vit y 
reacti o n (e.g. , a n gi oe de ma, St e ve ns -J o h ns o n s y n dr o me, Ac ute Ge neralize d 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 4  of 6 7  
A me n d me nt I  
E xa nt he mat o us P ust ul osis, Dr u g -i n d uce d h y perse nsiti vit y s y n dr o me, Dr u g-
i n d uce d ne utr o pe nia). 
9)  Hist or y of aller gic reacti o ns t o  I T F 2 3 5 7, hist o ne deacet ylase  (H D A C ) 
i n hi bit ors, or ot her relate d dr u gs, m o xifl o xaci n, ot her q ui n ol o nes, or t o a n y 
e xci pie nt i n t he f or m ulati o n.  
1 0)  P osit i ve preg na nc y test at scre e ni n g or  at baseli ne ( Da y -1).  
1 1)  S u bj ects wit h a s or bit ol i nt olera nce or s or bit ol mala bs or pti o n or ha ve fr uct ose 
i nt olera nce.  
1 2)  C urre nt or rece nt ( wit hi n 3 m o nt hs of st u d y dr u g a d mi nistrati o n) cli nicall y 
si g nifica nt gastr oi ntesti nal disease t hat ca n i nterfere wit h dr u g a bs or pti o n. 
1 3)  Gastr oi ntesti nal s ur ger y t hat i nterferes wit h p h ysi ol o gical a bs or pti o n a n d 
m otilit y (i.e., gastric b y pass, d u o de nect o m y) or gastric ba n ds.  
1 4)  Hist or y of si g nifica nt alc o h ol a b use wit hi n 1 year pri or t o scree ni n g or 
reg ular use of alc o h ol wit hi n 6 m o nt hs pri or t o t he scree ni n g visit ( m ore t ha n 
1 4 u nits of alc o h ol per wee k [ 1 u nit = 1 5 0 m L of wi ne, 3 6 0 m L of beer, or 
4 5  m L of 4 0 % alc o h ol]).  
1 5)  Hist or y of si g nifica nt dr u g a b use wit hi n 1 year pri or t o scree ni n g or use of 
s oft dr u gs (s uc h as marij ua na) wit hi n 3 m o nt hs pri or t o t he scree ni n g visit or 
har d dr u gs (s uc h as c ocai ne, p he nc ycli di ne [ P C P], crac k, o pi oi d deri vati ves 
i ncl u di n g her oi n, a n d a m p heta mi ne deri vati ves) wit hi n 1 year pri or t o 
scree ni n g. 
1 6)  Use of I T F 2 3 5 7 f or a me dical c o n diti o n or i n t he c o nte xt of a n ot her cli nical 
trial wit hi n a peri o d of 3 0 da ys pri or t o t he first d osi n g. 
1 7)  P artici pati o n i n a cli nical rese arc h st u d y i n v ol vi n g t he a d mi nistrati o n of a n 
i n vesti gati o nal or mar kete d dr u g or de vice wit hi n 3 0 da ys pri or to t he first 
d osi n g, a d mi nistrati o n of a bi ol o gical pr o d uct i n t he c o nte xt of a cli nical 
researc h st u d y wit hi n 9 0 da ys pri or t o t he first d osi n g, or c o nc o mita nt 
partici pati o n i n a n i n vesti gati o nal st u d y i n v ol vi n g n o dr u g or de vice 
a d mi nistrati o n.  
1 8)  Use of me d icati o ns f or t he ti mefra mes s pecifie d bel o w, wit h t he e xce pti o n of 
me dicati o ns e xe m pte d b y t he I n vesti gat or o n a case -b y -case basis beca use 
t he y are j u d ge d u nli kel y t o affect t he p har mac o ki netic pr ofil e of t he st u d y 
dr u g or s u bj ect safet y (e. g., t o pical dr u g pr o d ucts wit h o ut si g nifica nt 
s yste mic a bs or pti o n):  
a) Prescri pti o n me dicati o ns wit hi n 1 4 da ys pri or t o t he first d osi n g;  
b)  O ver -t he-c o u nter ( O T C) pr o d ucts a n d nat ural healt h pr o d ucts (i ncl u di n g 
her bal re me dies, h o me o pat hic a n d tra diti o nal me dici nes, pr o bi ot ics, f o o d 
s u p ple me nts s uc h as vita mi ns, mi nerals, a mi n o aci ds, esse nti al fatt y 
aci ds, a n d pr otei n s u p ple me nts use d i n s p orts) wit hi n 7 da ys pri or t o t he 
first d osi n g , wit h t he e xce pti o n of t he occasi o nal use of acet a mi n o p he n 
( u p t o 2 g dail y) ;  
c) De p ot i nj ec ti o n or i m pla nt of a n y dr u g wit hi n 3 m o nt hs pri or t o t he first 
d osi n g;  
d)  A n y dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g meta b olis m 
(i ncl u di n g St. J o h n’s w ort) wit hi n 3 0 da ys pri or t o t he first d osi n g.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 5  of 6 7  
A me n d me nt I  
1 9)  D o nati o n of plas ma wit hi n 7 da ys pri or t o d osi n g. D o na ti o n or l oss of bl o o d 
(e xcl u di n g v ol u me dra w n at s cree ni n g) of 5 0 m L t o 4 9 9 m L of bl o o d wit hi n 
3 0 da ys, or m ore t ha n 4 9 9 m L wit hi n 5 6 da ys pri or t o t he first d osi n g.  
2 0)  Breast -fee di n g s u bj ect. 
2 1)  I na bilit y t o be ve ni p u nct ure d a n d/ or t olerate cat heter ve n o us access; 
2 2)  I na bilit y or diffic ult y t o s wall o w ta blets or s us pe nsi o n. 
2 3)  A n y reas o n w hic h, i n t he o pi ni o n of t he I n vesti gat or, w o ul d pre ve nt t he 
s u bj ect fr o m partici pati n g i n t he st u d y. 
2 4)  Hist or y or prese nce of ot her diseases, meta b olic d ysf u ncti o ns, p h ysical 
e xa mi nati o n fi n di n gs, or a n y cli nicall y rele va nt a b n or mal la b orat or y val ue at 
scree ni n g s u g gesti n g a n u n k n o w n disease a n d re q uiri n g f urt her cli nical 
i n vesti gati o n or w hic h ma y i m pact t he safet y of t he s u bj ect or t he e val uati o n 
of t he res ult of t he st u d y ac c or di n g t o t he I n vesti gat or's j u d g me nt . 
Scree ni n g Pr o ce d ures:  
De m o gra p hic data, me dical a n d me dicati o n hist ories,  c o m plete p h ysical 
e xa mi nati o n, b o d y meas ure me nts , s u pi ne vital si g ns ( bl o o d press ure [ B P], heart 
rate [H R],  res pirat or y rate [ R R], a n d oral te m perat ure [ O T]), 1 2 -lea d E C G , fasti n g 
safet y la b orat or y assess me nts: i ncl u di n g he mat ol o g y , bi oc he mistr y , c oa g ulati o n 
(pr ot hr o m bi n ti me [ P T ] a n d partial t hr o m b o plasti n [P T T ]) a n d uri nal ysis,  
ser ol o g y ( h u ma n i m m u n o defi cie nc y vir us [ HI V], he patitis B a n d C tests), uri ne 
pre g na nc y test, uri ne c ot i ni ne test, alc o h ol breat h test, uri ne dr u g scree n , a d verse 
e ve nts ( A Es)  m o nit ori n g,  a n d c o nc o mita nt me dicati o ns.  
C o nfi ne me nts a n d 
W as h o ut:  
F or eac h peri o d, s u bj ects will be c o nfi ne d f or at least 1 2  h o urs  bef ore d osi n g u ntil 
after t he 7 2  h o ur p ost -d ose  assess me nts.  
T here will be a was h o ut peri o d of 7 da ys or m ore bet wee n d oses.  
St u d y D ur ati o n:  
T he st u d y d urati o n  i ncl u di n g t he scree ni n g peri o d will be a p pr o xi matel y  8  wee ks.  
St u d y Tre at me nts 
A d mi nistr ati o ns:  
Si n gle oral d ose i n eac h peri o d as f oll o ws:  
 
T hera pe utic d ose ( T) of  I T F 2 3 5 7 1 0 0 m g: a d mi nistere d as 1 x 1 0  m L of 
I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n + 2 x 1 0 m L of matc hi n g place b o oral  
s us pe nsi on (sa me a p peara nce a n d taste of I T F 2 3 5 7 ) u n der fasti n g 
c o n diti o ns ( 3 0 m L i n t otal, f or a t otal I T F 2 3 5 7 d ose of 1 0 0 m g) . 
 
S u prat hera pe utic d ose ( S T) of  I T F 2 3 5 7 3 0 0 m g: a d mi nistere d as 3  x 1 0 m L 
of I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n u n der fasti n g c o n d iti o ns (3 0 m L i n 
t otal, f or a t otal I T F 2 3 5 7 d ose of 3 0 0 m g).  
 
Place b o ( P) : a d mi nistere d as 3  x 1 0 m L of matc hi n g place b o oral 
s us pe nsi o n (sa me a p peara nce a n d taste of I T F 2 3 5 7) a d mi nistere d u n der 
fasti n g c o n diti o ns (3 0 m L i n t otal).  
 
M o xifl o xaci n ( M) : m o xiflo xa ci n 4 0 0 m g ta blet a d mi nistere d as 1 x 4 0 0 m g 
ta blet u n der fasti n g c o n diti o ns.  
N o f o o d will be all o we d fr o m at least 1 0  h o urs bef ore d osi n g u nti l at least 4 h o urs 
after d osi n g wit h t he e xce pti o n of o ne piece of ca n d y f or ea c h s u bj ect after eac h 
d osi n g  d ue t o  t he bitter taste of t he st u d y dr u g.   
E xce pt f or water gi ve n wit h st u d y me dicati o n, n o fl ui ds will be all o we d fr o m 
1  h o ur bef ore d osi n g u ntil 1  h o ur p ost -d ose.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 6  of 6 7  
A me n d me nt I  
S u bj ects will be ra n d o mize d t o recei ve st u d y treat me nt i n o ne of t he 1 2  f oll o wi n g 
se q ue nces:  
 
Se q ue nce  
Peri o d 1  
Peri o d 2  
Peri o d 3  
Peri o d 4  
1  
T  
S T  
P  
M  
2  
S T  
M  
T  
P  
3  
P  
T  
M  
S T  
4  
M  
P  
S T  
T  
5  
S T  
P  
T  
M  
6  
P  
M  
S T  
T  
7  
T  
S T  
M  
P  
8  
M  
T  
P  
S T  
9  
P  
T  
S T  
M  
1 0  
T  
M  
P  
S T  
1 1  
S T  
P  
M  
T  
1 2  
M  
S T  
T  
P  
 
St u d y Restricti o ns:  
S u bj ects will be as ke d t o refrai n fr o m usi n g pr o d ucts t hat ma y p ote ntiall y affect 
t heir safet y a n d/ or t he P K  pr ofile of t he st u d y dr u g. Mai n st u d y restricti o ns 
i ncl u de: 
 
P rescri pti o n me dicati o n fr o m 1 4 da ys pri or t o t he first d osi n g u ntil st u d y 
e xit;  
 
O T C p r o d ucts fr o m 7 da ys pri or t o t he first d osi n g u ntil st u d y e xit;    
 
N at ural healt h pr o d ucts fr o m 7  da ys pri or t o t he first d osi n g  u ntil st u d y 
e xit;  
 
A  de p ot i nj ecti o n or a n i m pla nt of a n y dr u g wit hi n 3 m o nt hs pri or t o t he 
first d osi n g u ntil st u d y e xit ; 
 
St. J o h n’s w ort  a n d a n y dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g 
meta b olis m fr o m 3 0 da ys pri or t o t he first d osi n g u ntil st u d y e xit;   
 
F o o d c o ntai ni n g p o p p y see ds wit hi n 2 4 h o urs pri or t o a d missi o n of eac h 
peri o d;  
 
F o o d or be vera ges c o ntai ni n g xa nt hi ne deri vati ves or xa nt hi ne -relate d 
c o m p o u n ds or e ner g y dri n ks fr o m 4 8 h o urs pre -d ose  (f or s u bj ects w h o 
re g ularl y c o ns u me lar ge a m o u nts i.e. ≥ 5 c u ps of c offee/ da y  t he 
restricti o n will be fr o m o ne wee k pre-d ose)  u ntil after t he last P K  bl o o d 
sa m ple c ollecti o n of eac h peri o d ; 
 
F o o d or be vera ges c o ntai ni n g gra pefr uit, starfr uit, p o me gra nate, 
pi nea p ple, or p o mel o fr o m 7  da ys pre -d ose u ntil after t he last P K  bl o o d 
sa m ple c ollecti o n of eac h peri o d ; 
 
A lc o h ol-base d pr o d ucts fr o m 2 4 h o urs pri or t o a d missi o n u ntil after t he 
last P K  bl o o d sa m ple c ollecti o n  of eac h peri o d ; 
 
S oft or  h ar d dr u gs or a n y t o bacc o or nic oti ne pr o d ucts fr o m scree ni n g 
u ntil  st u d y e xit. 
F or safet y reas o ns, s u bj ects will be re q uire d t o re mai n i n a s u pi ne or se mi-
recli ne d p ositi o n  a n d a v oi d sle e pi n g f or t he first 4 h o urs after dr u g a d mi nistrati o n.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 7  of 6 7  
A me n d me nt I  
Bl o o d S a m ple C ollecti o n  
f or P h ar m ac o ki netic  
A n al ysis : 
I T F 2 3 5 7 a n d meta b olites : I T F2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3,  I T F 2 9 5 5 
gl uc ur o ni de, a n d m o xifl o xaci n will be q ua ntifie d f or P K a nal yses.  
A t otal of 1 9  bl o o d sa m ples will be c ollecte d i n eac h peri o d: pre -d ose a n d 0. 5, 1, 
1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 6, 7 , 8, 1 2, 2 4, 3 6, 4 8 , 6 0 a n d 7 2 h o urs p ost -d ose  ( 6 m L f or 
eac h sa m pli n g ti me f or st u d y treat me nts S, S T, a n d P; 3  m L f or st u d y treat me nt 
M) .   
I T F 2 3 5 7 plas ma le vels will be of i nterest t o c orrelate wit h p har mac o d y na mic 
( P D) effect. T heref ore, o nl y bl o o d sa m ples f or st u d y treat me nts I T F 2 3 5 7 a n d 
m o xifl o x aci n will be a nal yze d.  
Sa m ples fr o m s u bj ects i n t he place b o treat me nt will be sa ve d f or a nal ysis if 
nee de d.  
I T F 2 3 5 7 will be a nal yzed  i n all s u bj ects, h o we ver, I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, 
I T F 2 5 6 3 a n d I T F 2 9 5 5 gl uc ur o ni de  will o nl y be a nal yz e d i n a s u b gr o u p of 
1 2  e val ua ble su bj ects ( t he sa me p o p ulati o n f or w h o m uri ne s a m ples will be 
a nal yz e d)  as n o effect fr o m t he meta b olites is e x pecte d o n t he Q T c  res ults. T he 
sa m ples t hat w o ul d  n ot be a nal yz e d  will be ke pt fr oze n u ntil bi oa nal ysis res ults 
are o btai ne d, if wit hi n t hese res ults a n y i n dicati o n of a p ossi ble effect is f o u n d, all 
sa m ples w o ul d be f urt her st u die d.  
Uri ne S a m ple C ollecti o n 
f or P h ar m ac o ki netic 
A n al ysis:  
I T F 2 3 5 7 a n d meta b olites : I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3 a n d I T F 2 9 5 5 
gl uc ur o ni de be q ua ntifie d f or P K a nal ysis  i n t he sa me s u b gr o u p of 1 2 e val ua ble 
s u bj ects t hat will als o ha ve t he a nal ysis of meta b olites d o ne i n bl o o d sa m ples .  
Uri ne sa m ples will be c ollecte d  i n all s u bj ects at 5 ti mes or ti me i nter vals  d u ri n g 
treat me nt wit h T, S T, a n d P : s p ot pre-d ose ( wit hi n 2 h o urs b ef ore d osi n g), 0 -8 
h o urs, 8 -2 4  h o urs, 2 4 -4 8 h o urs, a n d 4 8 -7 2 h o urs p ost -d ose.   
B ef ore starti n g bi oa nal ysis, t he bi ostatisticia n  will ra n d o ml y select 1 2 e val ua ble 
s u bj ects f or w h o m uri n e a n d bl o o d sa m ples will be a nal yze d  f or I T F 2 3 5 7 
meta b olit es. T he rest of t he sa m ples will be ke pt fr oze n f or f urt her a nal ysis i n 
case a n y i n dicati o n is f o u n d of a p ossi ble effect of t he meta b olites o n t he Q T c 
a nal ysis.  
C o nti n u o us E C G 
E v al u ati o n:  
T he car di o d y na mic assess me nt will be  perf or me d t hr o u g h 1 2 -lea d E C Gs 
e xtracte d fr o m c o nti n u o us rec or di n gs at pre -s pecifie d ti me p oi nts, paire d wit h P K 
sa m ples. 
F or eac h peri o d , c o nti n u o us 1 2-lea d E C G rec or di n gs will be perf or me d fr o m o ne 
h o ur pri or t o d osi n g u ntil a p pr o xi matel y 3 6 h o urs p ost -d ose. T he 1 2 -lea d H olter 
a n d E C G e q ui p me nt will be s u p plie d a n d s u p p orte d b y E R T. All E C G data will 
be c ollec te d usi n g Gl o bal I nstr u me ntati o n ( Ma nli us, N Y, U S A) M 1 2 R E C G 
c o nti n u o us 1 2 -lea d di gital rec or der. T he c o nti n u o us 1 2-lea d di gital E C G data will 
be s t ore d o nt o S D me m or y car ds. 1 2-lea d E C Gs will be e xtra cte d fr o m t he 
c o nti n u o us rec or di n gs at pre -d eter mi ne d ti me p oi nts as defi ne d bel o w, a n d will b e 
meas ure d ce ntrall y b y E R T.  
At t he E C G c ore la b orat or y, u p t o 1 0 re plicate E C Gs will be e xtracte d at eac h o f 
t he f oll o wi n g ti me p oi nts, pair e d wit h P K deter mi nati o ns, o n Da ys 1 a n d 2, i n 
eac h treat me nt peri o d: 3 ti me p oi nts pri or t o d osi n g ( -4 5, -3 0 , a n d -1 5 mi n utes) 
a n d 0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 6, 7, 8, 1 2, 2 4, a n d 3 6 h o urs p ost -d ose. S u bj ects 
will b e s u pi nel y resti n g f or at least 1 0 mi n utes bef ore a n d 5 mi n utes after eac h 
ti me p oi nt, w he ne ver p ossi ble.  W he n E C G e xtracti o ns c oi nci de wit h vital si g ns 
meas ure me nts  a n d bl o o d dra ws, pr oce d ures will be carrie d o ut i n t h at or der . 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 8  of 6 7  
A me n d me nt I  
S u bject S afet y : 
I n P eri o ds 1, 2 a n d 3,  a brief p h ysical e xa mi nati o n will be perf or me d at c hec k-i n 
o n Da y -1, a n d a p pr o xi matel y 2 4 a n d 7 2 ( Da y 4) h o urs p ost -d ose. I n P eri o d 4, a 
brief p h ysical e xa mi nati o n will be perf or me d at c hec k -i n o n Da y -1 a n d 
a p pr o xi matel y 2 4 h o urs p ost -d ose.  
B o d y wei g ht : at c hec k-i n o n Da y -1 f or eac h peri o d.  
S u pi ne B P, H R, R R, a n d O T:  pre -d ose a n d  a p pr o xi matel y 2,  3, 6, 1 2 a n d 2 4 h o urs 
p ost -d ose f or eac h peri o d.  
1 2 -lea d E C G (safet y): pre -d os e a n d  a p pr o xi matel y 2,  3, 6, 1 2 a n d 2 4 h o urs p o st-
d ose f or eac h peri o d.  
Alc o h ol br eat h test, uri ne c oti ni ne test,  uri ne dr u g scree n a n d ser u m pre g na nc y 
test: at c hec k -i n o n Da y -1 f or eac h peri o d.  
Fast in g safet y la b orat or y asses me nts i ncl u di n g h e mat ol o g y, bi oc he mistr y , 
c o a g ulati o n ( P T a n d P T T), a n d uri nal ysis: at  c hec k -i n o n  Da y  -1,  2 4 a n d 7 2 ( Da y 
4) h o urs p ost -d ose f or eac h peri o d.   
Me dical s ur veilla nce: S u bj ects will be m o nit ore d t hr o u g h o ut t he st u d y b y t he 
cli nical staff f or A Es  a n d c o nc o mita nt me dicati o ns. I n eac h peri o d, an 
I n vesti gat or or S u b -i n vesti gat or, will  be o n site f or dr u g a d mi nistrati o n a n d u ntil 4 
h o urs  p ost -d ose, a n d a vaila ble o n call f or t he re mai n der of t he st u d y.  
St u d y E xit 
Pr o ce d ures / E n d of Tri al 
Visit/ E arl y Ter mi n ati o n 
Visit : 
C o m plete p h ysical e xa mi nati o n,  fasti n g safet y la b orat or y ass ess me nts i ncl u di n g 
he mat ol o g y, bi oc he mistr y , c o a g ulati o n (P T a n d P T T)  a n d uri nal ysis,  s u pi ne vital  
si g ns [ B P, H R, R R a n d O T], 1 2 -lea d E C G, uri ne pre g na nc y t est, A Es  m o nit ori n g , 
a n d c o nc o mita nt me dicati o ns.  
F oll o w -u p Tele p h o ne C all  
( D a y 1 2 ± 2 d a ys): 
A f oll o w -u p tele p h o ne call will be ma de t o all s u bj ects t o m o nit or o n g oi n g A Es or 
t o c hec k f or p ossi ble A Es o n Da y 1 2 ± 2 da ys after d osi n g i n P eri o d 4.  
A n al ytic al M et h o d:  
T he Bi oa nal ytical Di visi o n of S y ne os Healt h will a nal yze I T F 2 3 5 7, I T F 2 3 7 4,  
I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3, a n d I T F 2 9 5 5 gl uc ur o ni de, i n plas ma a n d uri ne 
sa m ples, a n d m o xifl o xaci n i n plas ma sa m ples usi n g vali date d met h o ds.   
St u d y E n d p oi nts:   
Pri mar y e n d p oi nt : 
 
T he pri mar y e n d p oi nt f or t he car di o d y na mic E C G assess me nt is t he 
place b o -c orrecte d c ha n ge fr o m -baseli ne Q T c F ( Δ Q T c F).  
Sec o n dar y e n d p oi nts : 
 
C ha n ge -fr o m-baseli ne Q T c F, P R, Q R S, a n d heart rate ( H R) ( Δ Q T c F, 
Δ P R, Δ Q R S, a n d Δ H R)  
 
Place b o -c orrecte d Δ P R, Δ Q R S a n d Δ H R ( Δ Δ P R, Δ Δ Q R S, a n d Δ Δ H R)  
 
Cate g orical o utliers f or Q T c F, H R, P R, a n d Q R S  
 
Fre q ue nc y of treat me nt e mer ge nt c ha n ges of T -wa ve m or p h ol o g y a n d U -
wa ve prese nce  
 
T he P K e n d p oi nts will i ncl u de t he plas ma a n d uri ne P K para meters f or 
I T F 2 3 5 7, I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3, I T F 2 9 5 5 gl uc ur o ni de, 
a n d m o xifl o xaci n (as descri be d i n t he P har mac o ki netics secti o n).  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 1 9  of 6 7  
A me n d me nt I  
 
Safet y a n d t olera bilit y t o I T F 2 3 5 7 will be e val uate d t hr o u g h t he 
assess me nt of a d verse e ve nts (i.e., seri o us ness, se verit y, r elati o ns hi p t o 
t he st u d y me dicati o n, o utc o me, d urati o n, a n d ma na ge me nt), vital si g ns, 
E C G , a n d cli nical la b orat or y p ara meters. 
P h ar m ac o ki netics:  
P ara meters f or plas ma P K: A U C 0 -t, A U C 0 -1 2, A U C 0 -i nf, Resi d ual area, Cma x , Tma x , 
T ½  el, a n d K el, C L/ F, a n d V d/ F. 
P ara meters f or u ri ne P K: A e 0-t, R ma x , T R ma x , a n d C lr. 
St atistic al A n al yses:  
Car di o d y na mic E C G assess me nt : 
T he pri mar y a nal ysis will be base d o n c o nce ntrati o n -Q T c  m o deli n g of t he 
relati o ns hi p bet wee n plas ma c o nce ntrati o ns of I T F 2 3 5 7 a n d c ha n ge-fr o m-baseli ne 
Q T c F ( Δ Q T c F) wit h t he i nte nt t o e xcl u de a n effect of pla ce b o -c orrecte d Δ Q T c F 
( Δ Δ Q T c F) >1 0 msec at cli nic all y rele va nt plas ma le vels.  
I n a d diti o n, t he effects of I T F 2 3 5 7 o n t he place b o -c orrecte d ∆Q T c F, Δ H R, Δ P R, 
a n d Δ Q R S ( ∆∆Q T c F, Δ Δ H R, Δ Δ P R, a n d Δ Δ Q R S) will be e val uate d at e ac h p ost -
d osi n g ti me p oi nt (' b y ti me p oi nt' a nal ysis). A n a nal ysis of c ate g orical o utliers 
will b e perf or me d f or c ha n ges i n Q T c F, H R, P R, Q R S , T-wa ve m or p h ol o g y a n d 
U -wa ve prese nce.  
Assa y se nsiti vit y will be e val uate d b y c o nce ntrati o n -Q T c a nal ysis of t he effect o n 
∆Δ Q T c F of m o xifl o xaci n usi n g a si milar m o del as f or t he pri mar y a nal ysis. Assa y 
se nsiti vit y will be dee me d as met if t he sl o pe of the c o nce ntrati o n -Q T c 
relati o ns hi p/ Δ Q T c F is statistic all y si g nifica nt at 1 0 % le vel of si g nifica nce i n a 2-
si de d test a n d t he pre dicte d Q T effect (i.e. t he l o wer b o u n d of t he 2 -si de d 9 0 % 
c o nfi de nce i nter val  [ CI] of Δ Δ Q T c F) is a b o ve 5  msec at t he o bser ve d ge o metric 
mea n C ma x  of 4 0 0 m g m o xifl o xaci n.  
P har mac o ki netic assess me nt : 
I n di vi d ual a n d mea n plas ma c o nce ntrati o n vers us ti me c ur ves will be prese nte d 
f or b ot h li near a n d se mi-l o g sc ales. Descri pti ve statistics (arit h metic a n d 
ge o metric mea ns, sta n dar d de viati o n [ S D], c oefficie nt of variati o n [ C V %], 
mi ni m u m [ Mi n], ma xi m u m [ Ma x], a n d me dia n) of t he plas ma c o nce ntrati o ns 
vers us ti me will be prese nte d as well f or t he p har mac o ki neti c para meters.  
Safet y assess me nts : 
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) will be ta b ulat e d b y treat me nt f or 
all s u bj ects w h o were d ose d ( Safet y P o p ulati o n) . C ha n ges fr o m baseli ne val ues i n 
vital s i g ns, E C G, a n d cli nical l a b orat or y para meters will be e val uate d a n d 
ta b ulate d b y st u d y treat me nt. Safet y a n d t olera bilit y data will be re p orte d usi n g 
descri pti ve statistics. De m o gra p hic para meters will be s u m marize d descri pti vel y.  
A d verse e ve nts  of s pecial i nterest : 
T he rates of a d verse e ve nts of s pecial i nterest ( A E SI) s h o ul d be c o m pare d i n t he 
treat me nt a n d c o ntr ol peri o d. S u b gr o u p a nal yses s h o ul d be c o n d ucte d i n ter ms of 
a ge, ge n der, pre -e xisti n g car diac disease, electr ol yte dist ur ba nces a n d 
c o nc o mita nt me dicati o ns.  
Details of statistical a nal yses will be de vel o pe d i n a Statisti cal A nal ysis Pla n 
( S A P) t hat will be pre pare d after c o m pleti o n of t he fi nal pr ot oc ol. 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 0  of 6 7  
A me n d me nt I  
3.  
List of A b bre vi ati o ns a n d  Defi niti o n of Ter ms  
A D R  
a d verse dr u g r eacti o n  
A E  
ad verse eve nt  
A E SI  
a d verse e ve nts of s p ecial i nterest  
Ae 0 -t 
c u m ulati ve uri nar y e x creti o n fr o m ti me zer o t o t i me t 
A L T  
A la ni ne A mi n otra nsferas e  
A MI S  
A nal ytical Met h o d ol o g y I nf or mati o n S heet  
A S T  
A s partate A mi n otra nsferase  
A U C  
area u n d er  t he cur ve  
b.i. d . 
t wice a da y  
B MI  
b o d y mass i n de x  
B P  
b l o o d p ress ure 
CI  
co nfi de nce inter val  
C F R  
C o de of Fe d eral Re g ul ati o ns  
Clr  
re nal cleara nce 
Cl / F 
a p pare nt t otal b o d y cl eara nce 
C ma x  
m a xi m u m p las ma co nce ntrati o n  
C R F  
C ase R e p ort F or m  
C T A  
Cli nical Trial A p plicati o n  
C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts  
C T M S  
Cli nical Trial Ma na ge me nt S yst e m  
C V  
coeff i cie nt of v ariati o n 
C Y P  
cyt o c hr o me P 4 5 0  
D N A  
de o x yri b o n ucleic aci d  
E D C  
electr o nic d ata c a pt ure  
E C G  
electr ocar di o gra m 
E M A  
E ur o pea n Me dici nes A ge nc y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b orat or y Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
H Bs A g  
h e patitis B s urface a nti ge n  
H C V  
h e patitis C vir us  
H D A C  
hist o ne d eacet ylas e  
H D L  
h i g h-de ns it y li p o pr otei n 
H E E N T  
h ea d, e yes, ears, n ose, a n d thr oat  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 1  of 6 7  
A me n d me nt I  
h E R G  
h u ma n et her -g o -g o -relate d ge n e 
HI V  
h u ma n i m m u n o deficie nc y v ir us 
H R  
heart r ate  
I C F 
I nf or me d C o nse nt F or m 
I B 
I n v esti gat or’s Br oc h ure 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use  
I C 5 0 
c o nce ntr ati o n at w hic h 5 0 % i n hi biti o n o bser ve d  
I D 
ide ntificati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee  
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
intra ve n o us  
K el 
eli mi nati o n rate c o nsta nt 
k g  
k il o gra m 
L  
liter 
L D L  
l o w-de nsit y li p o pr otei n  
LI M S  
La b orat or y I nf or mati o n Ma na ge me nt S yste m  
L Q T S  
l o n g Q T s y n dr o m e 
M  
m o xifl o x aci n  
m A R C  
mit oc h o n drial a mi d o xi me  re d uci n g c o m p o ne nts 
Ma x.  
m a xi m u m 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M D M A  
3, 4 -met h yle n e di o x y m et h a m p heta mi ne  
m g  
m illi gra m 
Mi n.  
m i ni m u m 
mi n  
m i n ute 
m L  
m illiliter 
m m H g  
m illi meters of Merc ur y 
N O L  
N o O bjecti o n Letter  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O T  
oral te m perat ure  
O T C  
o ver -t he-c o u nter  
P  
place b o  
P C P  
p he nc ycli di ne  
P D  
p har mac o d y n a mic(s)  
P K  
p har mac o ki netic(s)  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 2  of 6 7  
A me n d me nt I  
P R  
P R i nter val of t he E C G  
P T T  
partial t hr o m b o plasti n t i me 
P T  
pr ot hr o m bi n t i me 
Q A  
q ualit y a ss ur a nce 
Q C  
q ualit y c o ntr ol  
Q R S  
Q R S i nter val of t he E C G  
Q T  
Q T i nter val of t he E C G  
Q Tc F  
Fri deri cia’s c orrecte d Q T i nter val  
R ma x  
ma xi m u m rate of uri nar y e x creti o n  
R R  
R R i nter val of t he E C G  
R R  
res pirat or y rate 
S A E  
seri o us a d vers e e v e nt 
S A P  
Statistical A nal ysis Pla n  
S A R S  
se vere ac ute res pirat or y s y n dr o me 
S D  
sta n dar d de viati o n  
S E  
sta n dar d err or 
S O P  
Sta n dar d O perati o n Pr oce d ure  
S T  
s u prat hera p e utic d ose 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T  
t hera pe utic d os e 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T d P  
t orsa de de poi ntes  
t.i. d 
t hree ti mes a da y 
T 1/ 2 el 
eli mi nati o n h alf-Lif e  
T ma x  
ti me of ma xi m u m co nce ntrati o n  
T R ma x  
ti me of ma xi mal uri nar y ex creti o n  
U S  
U nite d States  
V d/ F  
a p pare nt v ol u me of distri b uti o n  
W B C  
w hite bl o o d c ell 
∆ 
c ha n ge f r o m baseli ne 
∆∆ 
place b o -c orrecte d c ha n ge fr o m b aseli ne  
 
 
 
 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 3  of 6 7  
A me n d me nt I  
4.  
Sc he d ule of E ve nts  
 
P R O C E D U R E  
Scree ni n g  
D  -2 8  
Peri o ds 1, 2, 3 a n d 4  
St u d y E xit / E arl y 
Ter mi n ati o n 1 
 
D -1  
D 1  
D 2  
D 3  
D 4  
F oll o w -u p 
Tele p h o ne 
C all ( D a y 
1 2 ± 2 d a ys)  
I nf o r m C o nse nt F or m 
X  
 
 
 
 
 
 
 
I ncl usi o n a n d e xcl usi o n 
criteri a c hec k 2 
 
X  
 
 
 
 
 
 
R a n d o miz ati o n 2 
 
X  
 
 
 
 
 
 
De m o gr a p hic D at a 3 
X  
 
 
 
 
 
 
 
M e dic al a n d M e dic ati o n 
Hist ories  
X  
 
 
 
 
 
 
X  
Re vie w a n d M o nit ori n g of 
A Es , a n d C o nc o mit a nt 
M e dic ati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
P h ysic al E x a mi n ati o n 4 
X  
X  
 
X  
 
X  
X  
 
B o d y M e as ure me nts 
( Hei g ht, Wei g ht, a n d B MI) 
X  
X 5 
 
 
 
 
 
 
S u pi ne Vit al Si g ns ( B P, H R, 
R R, O T)  
X  
 
X 6 
X 6 
 
 
X  
 
1 2 -le a d S afet y E C G 
X  
 
X 7 
X 7 
 
 
X  
 
C o nti n u o us E C G ( H olter 
M o nit o ri n g)  
 
 
X 8 
X 8 
 
 
 
 
He m at ol o g y  
X  
X 9 
 
X 9 
 
X 9 
X  
 
Bi oc he mistr y  
X  
X 9 
 
X 9 
 
X 9 
X  
 
C o a g ul ati o n  
X  
X 9 
 
X 9 
 
X 9 
X  
 
Ser ol o g y ( HI V a n d 
He p atitis B a n d C)  
X  
 
 
 
 
 
 
 
Uri n al ysis  
X  
X 9 
 
X 9 
 
X 9 
X  
 
Uri ne Dr u g Scree n  
X  
X  
 
 
 
 
 
 
Uri ne C oti ni ne Test   
X  
X  
 
 
 
 
 
 
Alc o h ol B re at h Test  
X  
X  
 
 
 
 
 
 
Ser u m Pre g n a nc y Tes t 
 
X  
 
 
 
 
 
 
Uri ne Pre g n a nc y Test  
X  
 
 
 
 
X  
X  
 
C o nfi ne me nt 1 0 
 
X  
X  
X  
X  
X  
 
 
St u d y Tre at me nt 
A d mi nistr ati o n (I T F 2 3 5 7 [ T 
or S T], M o xifl o x aci n [ M] or 
Pl ace b o [ P]) 1 1 
 
 
X  
 
 
 
 
 
Pl as m a P K S a m ples 1 2 
 
 
X  
X  
X  
X  
 
 
Uri ne P K S a m ples 1 3 
 
 
X  
X  
X  
X  
 
 
1  
St u d y pr oce d ures  perf or me d o n Da y 4 of P eri o d 4 will ser ve as st u d y e xit pr oce d ures. Earl y ter mi nati o n 
pr oce d ures will be perf or me d as s o o n as p ossi ble after s u bj ect wit h dra wal , al wa ys wit hi n 1 4 da ys after last 
partici pati o n of t he s u bj ect i n t he st u d y . If cli nicall y si g nifica nt a b n or mal res ults are f o u n d o n t he la b orat or y 
assess me nts perf or me d d uri n g St u d y E xit/ Earl y T er mi nati o n, t he s u bj ect will be i n vite d t o t he site cli nic a gai n 
t o re p eat a b n or mal para meters.   
2  
Ra n d o mizati o n, i ncl usi o n a n d e xcl usi o n criteria c hec k t o be perf or me d at c hec k -i n o n Da y -1 of P eri o d  1.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 4  of 6 7  
A me n d me nt I  
3  
De m o gra p hic data i ncl u di n g: a ge, se x, race, a n d et h nicit y.  
4  
A c o m plete p h ysical e xa mi nati o n  (hea d, e yes, ears, n ose, t hr oat ( H E E N T), nec k (i ncl u di n g t h yr oi d), c hest, 
l u n gs, a b d o me n, bac k, l y m p h n o des, m usc ul os keletal, der mat ol o gical, car di o vasc ular/ peri p heral vasc ular, a n d 
ge neral ne ur ol o gical e xa mi nati o n ) will be perf or me d at scre e ni n g a n d at st u d y e xit. I n P eri o ds 1, 2 a n d 3, a brief 
p h ysical e xa mi nati o n will be perf or me d at c hec k -i n o n Da y -1, a n d a p pr o xi matel y 2 4  ( Da y 2) a n d  7 2 ( Da y 4) 
h o urs p ost -d ose.  I n P eri o d 4, a brief p h ysical e xa mi nati o n will be perf or me d at c hec k-i n o n Da y -1 a n d 
a p pr o xi matel y 2 4 h o urs p ost -d ose. A bri ef p h y sical e xa mi nati o n will c o nsist of: H E E N T, c hest, l u n gs, 
a b d o me n, der mat ol o gical, car di o vasc ular/ peri p heral vasc ular, a n d areas of n ote elicite d fr o m t he s u bj ect . 
5  
B o d y wei g ht , will b e deter mi ne d at c hec k -i n o n Da y -1 of ea c h peri o d.  
6  
S u pi ne v ital si g ns ( B P, H R, R R a n d O T): pre -d ose ( Da y 1), a n d a p pr o xi matel y 2,  3 , 6, 1 2 , a n d 2 4  h o urs  p ost -
d ose . Vital si g ns will be matc he d t o t he 1 2 -lea d safet y E C G. Bl o o d press ure meas ure me nt: t w o meas ures 
perf or me d after at least 5 mi n utes of resti n g i n s u pi ne p ositi o n, meas ures 2  mi n utes  a part fr o m eac h ot her .  
7  
1 2 -lea d safet y E C G: pre-d ose  ( Da y 1) a n d a p pr o xi matel y 2, 3 , 6 , 1 2 , a n d 2 4  h o urs p ost -d ose. 1 2 -lea d safet y 
E C G will be matc he d t o vital si g ns.  
8  
C o nti n u o us E C G: S u bj ects will be c o nti n u o usl y m o nit ore d fr o m  a p pr o xi matel y 1 h o ur pre -d ose  ( Da y 1) u ntil 
a p pr o xi matel y 3 6 h o urs p ost -d ose. E xtracti o n ti me p oi nts f or E C G are: -4 5, -3 0 a n d -1 5 mi n utes pre -d ose a n d 
0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 6,  7,  8, 1 2, 2 4, a n d 3 6 h o urs p ost -d ose. T he E C G e xtracti o n ti me p oi nts will be 
paire d  wit h P K deter mi nati o ns.  S u bj ects will be s u pi nel y resti n g f or at least 1 0 mi n utes bef ore a n d 5 mi n utes 
after eac h ti me p oi nt, w he ne ver p ossi ble.   
9  
Fasti n g safet y la b orat or y assess me nts (i.e., bi oc he mistr y, he mat ol o g y, uri nal ysis  a n d c oag ulati o n ): at c hec k-i n 
o n  Da y -1 , a n d 2 4  ( Da y 2) a n d 7 2  ( Da y 4 ) h o urs p ost-d ose .  
1 0  S u bj ects will be c o nfi ne d fr o m at l east 1 2 h o urs pre -d ose o n Da y -1 u ntil after 7 2 h o ur  p ost -d ose assess me nts o n 
Da y 4 . 
1 1  St u d y dr u g a d mi nistrati o n s h o ul d be d oc u me nte d al o n g wit h c o nfir mati o n of t he t otal d ose bei n g a d mi nistere d . 
1 2  Bl o o d sa m ples  f or I T F 2 3 5 7 a n d meta b olites, a n d m o xifl o xaci n P K : pre-d ose a n d 0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 
6, 7, 8, 1 2, 2 4, 3 6, 4 8 , 6 0 a n d 7 2 h o urs p ost -d ose  ( 6 m L f or eac h sa m pli n g ti me f or st u d y treat me nts S, S T, a n d 
P; 3  m L f or st u d y treat me nt M).   
1 3  Uri ne sa m ples  f or P K: s p ot pre-d ose ( wit hi n 2 h o urs bef ore d osi n g), 0 -8 h o urs, 8 -2 4 h o urs, 2 4 -4 8 h o urs, a n d 4 8 -
7 2 h o urs p ost -d ose.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 5  of 6 7  
A me n d me nt I  
5.  
I ntr o d ucti o n 
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
C o nfi de ntial  
P a ge 2 6  of 6 7  
A me n d me nt I  
5. 2  
M o xifl o x aci n B ac k gr o u n d I nf or m ati o n  
M o xifl o x aci n is a s y nt h etic fl u or o q ui n ol o ne wit h a br oa d s pectr u m of acti vit y a n d a bact erici dal 
m o de of acti o n.  M o xifl o x aci n is i n dicate d f or t he treat me nt  of a d ults wit h bacterial i nf ecti o ns 
ca use d b y s usc e pti ble strai ns of t he desi g nate d mi cr o or ga nis ms f or w hic h treat me nt is 
a p pr o priate. T h e rec o m m e n de d d ose f or m o xifl o xaci n is 4 0 0 m g o nce dail y f or all i n dicati o ns. 
T he d urati o n of t hera p y a n d r o ute of a d m i nistrati o n is de pe n de nt u p o n t he t y p e a n d se verit y of 
i nfecti o n.2   
T he bacterici dal acti o n res ults fr o m t he i nterfere nce of m o xifl o x aci n  wit h bacterial 
t o p ois o merases II ( D N A g yrase) a n d I V.2 
M o xifl o x aci n pr ol o n gs t he Q Tc i nter val, a n effect t hat is belie ve d t o occ ur t hr o u g h i n hi bit i o n of 
t he IKr h E R G c ha n n el i n t he car di ac m y oc yte. 3   
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 7  of 6 7  
A me n d me nt I  
M o xifl o x aci n gi ve n as a n oral ta blet is well a bs or be d fr o m t he gastr oi ntesti nal tract. T he a bs o l ute 
bi oa vaila bilit y of m o xifl o x aci n is a p pr o xi matel y 9 0 %. F oll o wi n g oral a d mi nistrati o n, pea k 
plas ma c o nce ntrati o n is attai ne d i n 1 t o 3 h o urs. Plas ma c o nce ntrati o ns i ncrease pr o p orti o natel y 
wit h d ose u p t o t he hi g hest d ose teste d ( 1 2 0 0 m g si n gle oral d ose). 2   
M o xifl o x aci n is a p pr o xi matel y 5 0 % b o u n d t o s er u m pr otei ns, i n de pe n de nt of dr u g c o nce ntrati o n. 
M o xifl o x aci n is meta b olize d via gl uc ur o ni d e a n d s ulfate c o nj u gati o n. T he c yt oc hr o m e P 4 5 0  
s yste m is n ot i n v ol ve d i n m o xifl o x aci n meta b olis m, a n d is n ot affect e d b y m o xifl o x aci n. 
M o xifl o x aci n is eli mi nate d fr o m plas ma b y first -or der pr o cess. T he m ea n ( ± S D) eli mi nati o n 
half -life fr o m plas ma is 1 2 ± 1. 3 ho urs. 2   
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
C o nfi de ntial  
P a ge 2 8  of 6 7  
A me n d me nt I  
5. 3. 2  
P ositi ve C o ntr ol Selecti o n  
M o xif l o x aci n 4 0 0 m g has bee n sele cte d as a p ositi ve dr u g c o ntr ol t o esta blis h assa y s e nsiti vit y as 
m o xifl o x aci n is a re versi ble bl oc ker of t h e ra pi d c o m p o ne nt of t he dela ye d rectifier, p ot assi u m 
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 2 9  of 6 7  
A me n d me nt I  
c urre nt of t h e car diac K +  c ha n nel. A cc or di n gl y, i n cli nical p har mac ol o g y st u dies, t he a g gre gate 
mea n pr ol o n gati o n of t he Q Tc i nter val at t he e x pecte d ti me of pea k pl as ma c o nce ntr ati o ns after a 
si n gle oral d ose of 4 0 0 m g m o xifl o x aci n was 7 ± 2 3 msec. 2  He nce, m o xifl o x aci n has bee n wi del y 
use d as a p ositi ve c o ntr ol a ge nt i n st u dies e val uati n g effect s of i n vesti gati o nal pr o d ucts o n 
Q T .2 ,7 ,8 ,9    
C CI
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 0  of 6 7  
A me n d me nt I  
5. 3. 5  
R ati o n ale f or t he St u d y P o p ul ati o n  
I n t he re pr o d ucti ve t o xicit y st u dies, n o a d verse effects were o bser ve d i n fertilit y st u dies i n rats 
a n d i n e m br y o -fetal t o xicit y st u dies b ot h i n rats a n d i n ra b bits. H o we ver,  t here are n o a de q uat e 
a n d well -c o ntr olle d st u di es wit h I T F 2 3 5 7 i n pre g n a nt w o me n. T heref ore, n o n -pre g na nt, n o n -
lactati n g fe males will be i ncl u de d i n t he st u d y. I n a d diti o n, fe males of c hil d beari n g p ote ntial will 
be i ncl u de d if t he y use a p pr o priate met h o ds of c o ntrace pti o n.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 1  of 6 7  
A me n d me nt I  
6.  
O bjecti ves  
Pri mar y o bje cti ve : 
 T o e val uate t he effect of a t hera p e utic d ose a n d a s u prat hera p e utic d ose of I T F 2 3 5 7 o n 
t he Q T/ Q Tc i nter val. 
Sec o n dar y o bje cti ves : 
 T o e val uate t he effect of a si n gle oral t hera pe utic a n d s u prat hera pe utic d os e of I T F 23 5 7 
o n ot her E C G para meters ( H R, P R, Q R S i nter vals a n d T-wa v e m or p h ol o g y).  
 T o e val uate t he P K p ara meters of t w o d oses ( 1 0 0 m g a n d 3 0 0  m g) of I T F 2 3 5 7 a n d its 
meta b olites: I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3 a n d I T F 2 95 5  gl u c ur o ni de.  
 T o e val uate t he s afet y a n d t olera bilit y of t w o d oses  (1 0 0 m g a n d 3 0 0 m g)  of I T F 2 3 5 7.   
7.  
St u d y Desi g n  
T his will be a si n gle ce ntre, ra n d o mize d, partiall y d o u ble -bli n d, s i n gle d ose, place b o-c orrecte d, 
1 2 -se q ue nce, 4 -peri o d,  cr oss o ver st u d y u n d er fasti n g c o n diti o ns.   
8.  
St u d y P o p ul ati o n  
8. 1  
S a m ple Size  
It is pla n ne d t o e nr ol up  t o 3 4  healt h y a d ults t o e ns ure 2 8 s u bjects  wit h e val ua ble data .  
8. 1. 1  
S a m ple Size C o nsi der ati o ns f or Ass a y Se nsiti vit y  
C CI
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 2  of 6 7  
A me n d me nt I  
8. 2  
I ncl usi o n Criteri a 
S u bjects e nr olle d i n t his st u d y will be me m bers of t he c o m m u nit y at lar ge . T he recr uit me nt 
a d vertise me nts ma y use  vari o us me dia t y pes (e. g., ra di o, ne ws pa p er, t he cli nical site We b site 
a n d v ol u nteer dat a base). S u bjects m ust meet all of t he f oll o wi n g criteria t o be i ncl u de d i n t he 
st u d y: 
1)  Male or fe m ale, n o n -s m o ker ( n o use of t o bacc o or nic oti ne pr o d ucts wit hi n 3 m o nt hs pri or t o 
scree ni n g), ≥1 8 a n d ≤5 5 years of a ge, wit h B MI > 1 8. 5 a n d < 3 0. 0 k g/ m 2 a n d b o d y wei g ht 
≥5 5  k g a n d ≤1 0 0 k g f or fe males  a n d b o d y wei g ht ≥6 0 k g a n d ≤1 0 0 k g f or males   
2)  Healt h y as defi ne d b y:  
a)  T he a bse n ce of cli nicall y si g nifica nt ill ness a n d  m aj or  s ur ger y wit hi n 4 wee ks pri or t o 
d osi n g. S u bjects v o miti n g wit hi n 2 4 h o urs pre -d ose will be caref ull y e val u ate d f or 
u pc o mi n g ill ness/ disease. I n cl usi o n pre -d osi n g  of t he patie nt i n t he st u d y  is at t he 
discreti o n of t he I n v esti gat or , de pe n di n g o n his/ her  cli nical j u d ge me nt. 
b)  T he a bse n ce of cli nicall y si g nifica nt hist or y of ne ur ol o gical, e n d ocri nal, car di o vasc ular, 
p ul m o nar y, h e mat ol o gi cal, i m m u n ol o gic, ps yc hi atric, gastr oi ntesti nal, re n al, he patic, a n d  
meta b olic disease.  
3)  N o n -c hil d beari n g p ot e ntial fe male d efi ne d as:  
a)  P ost -me n o pa usal fe male (a bse nce of me ns es f or 1 2 m o nt hs pri or t o t he first st u d y dr u g 
a d mi nistrati o n, bilateral o o p h orect o m y or h ysterect o m y wit h bilateral o o p h orect o m y at 
least 6 m o nt hs pri or t o t he first st u d y dr u g a d mi nistrati o n); or 
b)  S ur gicall y sterile fe male ( h ysterect o m y or t u b al li gati o n at least 6 m o nt hs pri or t o dr u g 
a d mi nistrati o n).  
4)  Fe males of c hil d beari n g p ote ntial w h o are s e x uall y acti ve wit h a male part ner m ust be 
willi n g t o use o ne of t he f oll o wi n g acce pt a ble c o ntrace pti ve met h o ds t hr o u g h o ut t he st u d y 
a n d f or at least 9 0 da ys after t he last st u d y dr u g a d mi nistrati o n:  
a)  S i m ulta ne o us use of i ntra-uteri ne c o ntr ace pti ve de vice, wit h o ut h or m o ne release s yste m 
place d at least 4 wee ks pri or t o st u d y dr u g a d mi nistrati o n, a n d c o n d o m f or t he male 
pa rt ner; 
b)  S i m ulta ne o us use of dia p hra g m or cer vical ca p wit h i ntra va gi nall y a p plie d s per mici de 
a n d male c o n d o m f or t he male part ner, starte d at l east 2 1 da ys pri or t o st u d y dr u g 
a d mi nistrati o n ;  
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 3  of 6 7  
A me n d me nt I  
5)  Male s u bjects w h o are n ot vasect o mize d f or at least 6 m o nt hs, a n d w h o are se x uall y acti ve 
wit h a fe male p art ner of c hil d beari n g p ote ntial (c hil d beari n g p ot e ntial fe m ales are defi ne d as 
w o me n t hat are n eit her p ost -me n o pa usal n or s ur gi call y sterile) m ust be willi n g t o use o ne of 
t he f oll o wi n g acce pta ble c o ntrace pti ve met h o ds fr o m t he first st u d y dr u g a d mi nistrati o n u ntil 
at least 9 0 da ys aft er t he l ast st u d y dr u g a d mi nistrati o n:  
a)  S i m ulta ne o us use of a male c o n d o m a n d, f or t he fe male part n er, h or m o nal c o ntrace pti ves 
use d si nce at least 4 wee ks or i ntra -uteri ne c o ntrace pti ve de vice place d si nce at least 
4  wee ks;  
b)  S i m ulta ne o us use of a male c o n d o m a n d, f or t he fe male part n er, a dia p hra g m or cer vical 
ca p wit h i ntra va gi nall y a p plie d s per mici de.  
6)  Male s u bjects (i ncl u di n g me n w h o ha ve h a d a vas ect o m y) wit h a pre g na nt part ner m ust a gree 
t o use a c o n d o m fr o m t he first st u d y dr u g a d mi nistrati o n u ntil at least 9 0 da ys after t he last 
st u d y dr u g a d mi nistrati o n. 
7)  Male s u bjects m ust be willi n g n ot t o d o nate s per m u ntil 9 0 da ys f oll o wi n g t he last st u d y dr u g 
a d mi nistrati o n.  
8)  Fe male s u bjects m u st be willi n g n ot t o d o nate o v ules u ntil 9 0 da ys f oll o wi n g t he last st u d y 
dr u g a d mi nistrati o n.  
9)  S u bject’s writte n i nf or me d  c o nse nt o btai ne d pri or t o a n y st u d y-relate d pr oce d ure. 
1 0)  Willi n g ness a n d ca pa bilit y t o c o m pl y wit h t he re q uire me nts of t he st u d y a n d  abi lit y t o 
u n dersta n d t he st u d y pr oce d ures a n d t he ris ks i n v ol ve d.  
1 1)  Willi n g t o ta ke o ut de nt ures a n d m o ut h pierci n gs f or st u d y pr oce d ures.  
8. 3  
E xcl usi o n Criteri a  
S u bjects t o w h o m a n y of t he f oll o wi n g a p plies will be e x cl u de d fr o m t he st u d y:  
1)  A n y cli nicall y si g nifica nt a b n or malit y at p h ysi cal e x a mi nati o n, cli nicall y si g nifica nt 
a b n or mal la b orat or y test res ults or p ositi ve test f or HI V, he p atitis B, or he p atitis C f o u n d 
d uri n g me dical scree ni n g.  
2)  Cli nicall y si g nifica nt vital si g n a b n or malities (s yst olic bl o o d press ure l o wer t ha n 9 0 or o ver 
1 4 0 m m H g, diast olic bl o o d press ure l o w er t ha n 6 0 or o ver 9 0 m m H g, or heart rate less t ha n 
4 0  or o ver 1 0 0 b p m) at scree ni n g . F or eli gi bilit y p ur p oses, n ot t he mea n val ue, b ut t he t w o 
si n gle meas ure me nts will be c o nsi dere d.  
3)  A n y of t he f oll o wi n g a b n or malities o n 1 2 -lea d E C G at scree ni n g. P R ( P R i nter val) ˃ 2 1 0 
msec; Q R S ( Q R S c o m ple x) ˃ 1 2 0 msec;  Q Tc F ˃ 4 5 0 msec; a n y a b n or m alit y of car di ac 
r h yt h m ot her t h a n si n us arr h yth mia; a b n or malit y of T -wa v e m or p h ol o g y t hat will i m pair t he 
a bilit y t o meas ur e t he Q T i nter val relia bl y. T he a v era ge d v al ue of t hr ee E C G s 5 mi n utes 
a part fr o m eac h ot h er will be use d; e val uati o ns ha ve t o be use d f or t he e val uati o n of t he Q Tc 
i nter val re q u este d b y t his e x cl usi o n criteria. 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 4  of 6 7  
A me n d me nt I  
4)  S u bjects wit h hist or y of s ustai ne d a n d n o n -s ustai n e d car di ac arr h yt h mias ( E C G 
de m o nstrate d), s u bjects wit h a fa mil y hist or y of s u d de n car di ac deat h a n d s u bjects wit h a 
hist or y of a d diti o nal ris k fact ors f or T d P, heart fail u re, h y p o kale mia, L Q T S).  
5)  A n y of t he f oll o wi n g a b n or mal la b orat or y te st v al ues at scree ni n g or at b aseli ne ( Da y -1)  of 
Peri o d 1 : 
a)  Platelet c o u nt < 1 2 5  x 1 0 9/ L 
b)  A bs ol ute ne utr o p hil c o u nt < 1. 2  x 1 0 9/ L  
6)  S u bjects w h o ha ve car di o vasc ular c o n diti o n s uc h as, b ut n ot li mite d t o u nsta ble isc he mic 
heart diseas e, N Y H A Class III/I V left ve ntric ular fail ure, ac ut e isc he mic heart disease i n t he 
last year pri or t o st u d y scree ni n g, w hic h ma y i m pact t he safet y of t h e su bject or t he 
e val uati o n of t he res ult of t he st u d y acc or di n g t o t he I n vesti gat or's j u d g me nt; car di o vasc ular 
c o n diti o ns s h o ul d be discar de d bas e d o n t he res ults o btai ne d o n t he E C G, me dical 
e x a mi nati o n a n d r o uti ne la b test.  
7)  P ositi ve uri ne dr u g scree n,  alco h ol breat h test or uri ne c oti ni ne test at scree ni n g or at b aseli ne 
( Da y -1) . 
8)  Hist or y of a na p h yla xis reacti o n or cli nicall y si g nifica nt dr u g h y perse nsiti vit y reacti o n (e .g. , 
a n gi o e de ma, Ste ve ns -J o h ns o n s y n dr o me, Ac ute Ge neralize d E x a nt he mat o us P ust ul osis, 
Dr u g -i n d uce d h y p erse nsiti vit y s y n dr o m e, Dr u g-i n d uce d ne utr o p e nia). 
9)  Hist or y of aller gic reacti o ns t o I T F 2 3 5 7, hist o ne deacet yl ases ( H D A C) i n hi bit ors, or ot her 
relate d dr u gs, m o xifl o x aci n, ot her q ui n ol o nes, or t o a n y e x ci pie nt i n t he f or m ulati o n. 
1 0)  P ositi ve pr e g na n c y test at scree ni n g or at baseli ne ( Da y -1).  
1 1)  S u bjects wit h a s or bit ol i nt olera nce or s or bit ol mala bs or pti o n or ha ve fr uct ose i nt olera nce.  
1 2)  C urre nt or rece nt ( wit hi n 3 m o nt hs of st u d y dr u g a d mi nistrati o n) cli nicall y si g nifica nt 
gastr oi ntesti nal diseas e t hat ca n i nterfere wit h dr u g a bs or pti o n.  
1 3)  Gastr oi ntesti nal s ur ger y t hat i nterferes wit h p h ysi ol o gical a bs or pti o n a n d m otilit y (i.e., 
gastri c b y pass, d u o de n ect o m y) or gastric ba n ds.  
1 4)  Hist or y of si g nifica nt alc o h ol a b use wit hi n 1 year pri or t o scree ni n g or r e g ular use of al c o h ol 
wit hi n 6 m o nt hs pri or t o t he scree ni n g visit ( m ore t ha n 1 4 u nits of alc o h ol per wee k [ 1 u nit = 
1 5 0 m L of wi n e, 3 6 0 m L of beer, or 4 5 m L of 4 0 % alc o h ol]).  
1 5)  Hist or y of si g nifica nt dr u g a b us e wit hi n 1 year pri or t o scree ni n g or use of s of t dr u gs (s uc h as 
marij ua na) wit hi n 3 m o nt hs pri or t o t he scree ni n g visit or har d dr u gs (s uc h as c ocai n e, 
p he nc ycli di ne [ P C P], crac k, o pi oi d deri vati ves i ncl u di n g her oi n, a n d a m p heta mi ne 
deri vati ves) wit hi n 1 year pri or t o scree ni n g.  
1 6)  Use of I T F 2 3 5 7 f or a me dical c o n diti o n or i n t he c o nte xt of a n ot her cli nical trial wit hi n a 
peri o d of 3 0 da ys pri or t o t he first d osi n g.  
1 7)  Partici pati o n i n a cli nical researc h st u d y i n v ol vi n g t he a d mi nistrati o n of a n i n vesti gati o nal or 
mar kete d dr u g or de vic e wit hi n 3 0 da ys pri or t o t h e first d osi n g, a d mi nistrati o n of a 
bi ol o gical pr o d u ct i n t he c o nte xt of a cli nical researc h st u d y wit hi n 9 0 da ys pri or t o t he first 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 5  of 6 7  
A me n d me nt I  
d osi n g, or c o n c o mita nt partici pati o n i n a n i n vesti gati o nal st u d y i n v ol vi n g n o dr u g or de vice 
a d mi nistrati o n.  
1 8)  Use of me dic ati o ns f or t he ti mefra mes s p ecifie d b el o w, wit h t he e x ce pti o n of me dicati o ns 
e x e m pte d b y t he I n v esti gat or o n a case -b y -cas e basis beca use t he y are j u d ge d u nli kel y t o 
affect t he p har m ac o ki neti c pr ofile of t he st u d y dr u g or s u bject safet y (e. g., t o pical d r u g 
pr o d ucts wit h o ut si g nifica nt s yste mic a bs or pti o n):  
a)  P rescri pti o n me dicati o ns wit hi n 1 4 da ys pri or t o t h e first d osi n g; 
b)  O T C  pr o d ucts (wit h t he e x ce pti o n of t he occasi o nal use of aceta mi n o p he n [u p t o 2 g 
dail y ]) a n d nat ur al healt h pr o d ucts (i ncl u di n g h er b al re me dies, h o me o p at hic a n d 
tra diti o nal me dici nes, pr o bi otics, f o o d s u p ple me nts s uc h as vita mi ns, mi nerals, a mi n o 
aci ds, esse ntial f att y aci ds, a n d pr otei n s u p ple me nts use d i n s p orts) wit hi n 7 da ys pri or t o 
t he first d osi n g;  
c)  D e p ot i njecti o n or i m pla nt o f a n y dr u g wit hi n 3 m o nt hs pri or t o t he first d osi n g; 
d)  A n y dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g meta b olis m (i ncl u di n g St. J o h n’s 
w ort ) wit hi n 3 0 da ys pri or t o t he first d osi n g.  
1 9)  D o nati o n of plas ma wit hi n 7 da ys pri or t o d osi n g. D o nati o n or l oss of bl o o d (e x cl u di n g 
v ol u me dra w n at scree ni n g) of 5 0 m L t o 4 9 9 m L of bl o o d wit hi n 3 0 da ys, or m ore t ha n 
4 9 9  m L wit hi n 5 6 da ys pri or t o t he first d osi n g.  
2 0)  Breast -fee di n g s u bject. 
2 1)  I n a bilit y t o be ve ni p u n ct ure d a n d/ or t olerate cat heter ve n o us access; 
2 2)  I n a bilit y or diffic ult y t o s wall o w ta blets or s us pe nsi o n. 
2 3)  A n y reas o n w hi c h, i n t he o pi ni o n of t he I n v esti gat or, w o ul d pre ve nt t he s u bject fr o m 
partici pati n g i n t he st u d y.   
2 4)  Hist or y or pre se n ce of ot her diseases, m eta b olic d ysf u ncti o ns, p h ysic al e xa mi nati o n fi n di n gs, 
or a n y cli nicall y rele va nt a b n or mal la b orat or y val u e at scree ni n g s u g gesti n g a n u n k n o w n 
disease a n d re q uiri n g f urt her cli nical i n vesti gati o n or w hic h ma y i m pact t he safet y of t he 
s u bject or t he e v al uati o n of t he res ult of t he st u d y acc or di n g t o t he I n vesti gat or's j u d g me nt . 
9.  
Cli nic al Pr oce d ures  
U nless ot her wise s pecifie d, pr oce d ures, data c ollecti o n a n d e val uati o n will be c o n d ucte d as per 
t he cli nical site S O Ps . 
9. 1  
Scree ni n g Pr oce d ur es  
S u bjects m ust pr o vi de writte n i nf or me d c o nse nt pri or t o i nitiati o n of a n y scree ni n g pr oce d ures. 
S u bjects pr o vi de writte n c o nse nt t o ge neral scree ni n g pr oce d ures, w hic h are n ot st u d y s pecific, 
t he c o nse nt t o t h ose pr oce d ures is o btai ne d o n a ge neral c o nse nt d oc u me nt differe nt fr o m t he 
st u d y s pecific I nf or m C o nse nt F or m (I C F).  
T he s u bjects  pr o vi de writte n i nf or m e d c o nse nt t o p artici pate in t he st u d y, a n d he nce t he st u d y 
s pecific I C F m ust be si g n e d a nd date d b y t h e s u bject a n d t he I n vesti gat or, b ef ore p artici pati o n t o 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 6  of 6 7  
A me n d me nt I  
st u d y-s pecific pr oce d ures i ncl u di n g a n y st u d y-s pecific scree ni n g pr oce d ures. B ot h I C F f or ms 
m ust be c o m plete d pri or t o starti n g a n y pr oce d ures.    
S t u d y s p ecific s cree ni n g pr oce d ures will be perf or me d wit hi n 2 8 da ys prec e di n g a d m i nistrati o n 
of st u d y me dicati o n , a n d will  c o nsist o f: d e m o gra p hic data  i ncl u di n g a ge, s e x, race, a n d 
et h nicit y, me dical a n d m e dicati o n hist ories, c o m plete p h ysic al e xa mi nati o n , b o d y meas ure me nts , 
s u pi ne vital si g ns ( B P, H R, R R , a n d O T), 1 2 -lea d E C G,  fasti n g s afet y la b orat or y asses me nts 
i ncl u di n g he mat ol o g y , bi oc he mistr y , c oa g ulati o n  ( P T a n d PT T)  a n d uri nal ysis,  ser ol o g y (HI V, 
he patitis B a n d C tests), uri ne pre g n a nc y test, uri n e c oti ni ne test, alc o h ol br eat h test, uri ne dr u g 
scree n, A Es m o nit ori n g, a n d c o nc o mita nt me dicati o ns.   
D uri n g t h e scree ni n g peri o d, f or  eli gi bilit y p ur p oses, a b n or mal la b orat or y or vital si g ns res ults 
ma y b e re p eate d o n ce if a b n or mal res ult is o bser ve d at t he i nitial rea di n g. M ore o ver, 
a b n or malities f o u n d i n t he E C G  ma y nee d t o b e c o nfir me d b y re p eate d meas ure me nts  ( us uall y i n 
tri plicate).  
I n t he e ve nt t hat t he p artici pati o n of a s u bject i n t h e st u d y is dela ye d, a n d t h e scree ni n g 
pr oce d ures ma y bec o me o ut date d , t he s u bject will t he n be scree n -faile d, a nd  re-scree n e d a gai n, 
u n der a ne w scree ni n g n u m ber a n d si g ni n g a ne w I C F. T he scree ni n g pr oce d ures will t he n be 
re peat e d.  
Eac h patie nt will be i de ntifie d i n t he st u d y b y a p atie nt I D n u m ber. O nce assi g ne d, t he I D s u bject 
n u m ber m ust n ot be re us e d f or a n y ot h er patie nt. If t he patie nt fails t o be e nr olle d , t he reas o n f or 
scree ni n g fail ure m ust be rec or de d a n d will be d o c u me nte d i n t he s o urce d ata.   
9. 2  
St u d y Pr oce d ures  
9. 2. 1  
C hec k -i n ( D a y -1)  
Re vie w of i ncl usi o n a n d e x cl usi o n criteria  ( Peri o d 1 o nl y) e x ce pt f or E C G a n d  v ital si g ns t hat 
will be meas ure d b ef ore d osi n g o n Da y 1 , c o nfi ne me nt , ra n d o mizati o n ( Peri o d 1 o nl y), re vie w 
a n d m o nit ori n g of A Es a n d c o nc o mita nt me dicati o ns, brief p h ysical e xa m i nati o n, b o d y wei g ht, 
fasti n g safet y la b orat or y assess me nts i ncl u di n g he mat o l o g y, bi oc he mistr y, c oa g ulati o n (P T a n d 
P T T ) a n d uri nal ysis, uri ne dr u g scree n, uri n e c oti ni ne scree n, alc o h ol breat h test a n d ser u m 
pre g na nc y t est . 
9. 2. 2  
St u d y D a ys 1 t hr o u g h 4  
Re vie w a n d m o nit ori n g of A E s a n d c o n c o mita nt me dicati o ns, ph ysi cal e xa mi nati o n  ( Da y 2 a n d 
Da y 4) , s u pi ne v ital si g ns ( Da y 1 a n d Da y 2), 1 2-lea d safet y E C G ( Da y 1 a n d Da y 2), c o nti n u o us 
E C G  ( Da y 1 a n d Da y 2), fasti n g safet y la b orat or y assess me nts i ncl u di n g he mat ol o g y, 
bi oc he mistr y, c oa g ulati o n  (P T a n d P T T ) a n d uri n al ysis  (Da y 2 a n d D a y 4), Uri ne pre g n a nc y test 
( Da y 4), c o nfi ne me nt, st u d y treat me nt  a d mi nistrati o n  ( Da y 1), plas ma P K sa m ple c ollecti o n a n d 
uri ne  P K sa m ple c ollecti o n .  
9. 3  
C o nfi ne me nts a n d W as h o ut  
F or eac h peri o d, s u bjects will be c o nfi ne d f or at least 1 2  h o urs  bef ore d osi n g u ntil after t he 
7 2  h o ur p ost -d ose assess me nts .  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 7  of 6 7  
A me n d me nt I  
T here will be a was h o ut of 7 da ys or m ore  b et wee n d oses. T he  was h o ut peri o d ma y be i n crease d 
f or l o gistical c o nsi derati o ns. Partici pati o n of  eac h s u bject i n t his st u d y i ncl u di n g t he scree ni n g 
pe ri o d s h o ul d last a p pr o xi matel y 8  w ee ks.  
9. 4  
R a n d o miz ati o n a n d Bli n di n g  
S u bjects will be a d mi nistere d eac h tr eat me nt acc or di n g t o t he 4 -p eri o d , 1 2 -se q ue nce, bl o c k 
ra n d o mizati o n sc he me. S u bjects will be ra n d o mize d t o recei ve st u d y treat me nt i n o ne of t he 
1 2  f oll o wi n g se q u e nces: 
 
Se q ue nce  
Peri o d 1  
Peri o d 2  
Peri o d 3  
Peri o d 4  
1  
T  
S T  
P  
M  
2  
S T  
M  
T  
P  
3  
P  
T  
M  
S T  
4  
M  
P  
S T  
T  
5  
S T  
P  
T  
M  
6  
P  
M  
S T  
T  
7  
T  
S T  
M  
P  
8  
M  
T  
P  
S T  
9  
P  
T  
S T  
M  
1 0  
T  
M  
P  
S T  
1 1  
S T  
P  
M  
T  
1 2  
M  
S T  
T  
P  
 
I T F 2 3 5 7 (t h era p e utic [ T] a n d s u prat hera pe utic [ S T] d ose, a n d place b o [P ]) will be a d mi nistere d 
i n a d o u ble-bli n de d fas hi o n.  
 
Treat me nts T, S T, a n d P will be pre pare d i n di vi d uall y b y t he u n bl i n de d tea m at t he site 
p har mac y , acc or di n g t o t he ra n d o mizati o n sc he d ule, a n d will lea ve t he p har mac y r o o m bli n de d,  
s o t hat t he bli n de d site tea m c o ul d a d mi nister t he m t o t he s u bjects.  
 
O n t he c o ntrar y n o bli n di n g will be nee de d wit h t reat me nt M.  
 
T he E C G Ce ntral C ore La b orat or y E C G A n al yst, will be bli n de d t o treat me nt, st u d y peri o d, ti me 
p oi nt of E C G rec or di n g, a n d s u bject details s uc h as la b orat or y res ults a n d A Es . 
9. 4. 1  
St u d y Tre at me nts T, S T, P  a n d M  
 T hera p e utic d ose ( T) of  I T F 2 3 5 7 1 0 0 m g: a d mi nistere d as 1 x 1 0  m L  of I T F 2 3 5 7 1 0 
m g/ m L oral s us pe nsi o n + 2 x 1 0 m L of mat c hi n g place b o oral  s us pe nsi o n (s a me 
a p peara nce a n d taste as I T F 2 3 5 7 ) u n der fasti n g c o n diti o ns (3 0 m L i n t otal, f or a t otal 
I T F 2 3 5 7 d ose of 1 0 0 m g). 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 8  of 6 7  
A me n d me nt I  
 S u prat hera p e utic d ose ( S T) of  I T F 2 3 5 7 3 0 0 m g: a d mi nistere d as 3  x 1 0 m L of I T F 2 3 5 7 
1 0  m g/ m L oral s us pe nsi o n u n der fasti n g c o n diti o ns ( 3 0 m L i n t otal, f or a t otal I T F 2 3 5 7 
d ose of 3 0 0 m g).  
 Place b o ( P) : a d mi nistere d as 3  x 1 0 m L of matc hi n g place b o oral s us pe nsi o n (sa me 
a p peara nce a n d taste of I T F 2 3 5 7 ) a d mi nistered u n der fasti n g c o n diti o ns (3 0  m L i n t otal).  
 
S p o ns or, s u bjects,  In v esti gat ors,  t h e cli nical pers o n nel i n v ol ve d i n t he c ollecti o n, m o nit ori n g, 
re visi o n, or e val uati o n of a d verse e ve nts, or pers o n nel w h o c o ul d ha ve a n i m pact o n t he o utc o me 
of t he st u d y will be bli n d e d wit h res pect t o t he s u bject’s treat me nt assi g n me nt (I T F 2 3 5 7 [ T a n d 
S T]) a n d place b o [ P]). Bli n di n g will be mai ntai ne d u ntil t he st u d y h as bee n fi nalize d, t he 
data base h as bee n v erifie d, a n d all pr ot oc ol vi olati o ns ha ve bee n deter mi ne d. All pers o n nel 
i n v ol ve d directl y i n t he st u d y s hall be u n a ware of t he treat me nt assi g ne d t o t he s u bjects u ntil t he 
data base h as bee n cl ose d.  T he E C G Ce ntral C ore La b orat or y’s  E C G A nal yst , w h o is differe nt 
fr o m t h ose w h o will e val uate la b orat or y assess me nts a n d A Es, will be bli n de d wit h res pect t o t he 
s u bject’s treat me nt assi g n me nt (i ncl u di n g m o xifl o x aci n ar m) , st u d y peri o d, ti me p oi nt of E C G 
rec or di n g a n d s u bject det ails. 
T he u n bli n de d tea m at site will c o m prise t he d esi g nate d p har mac y pers o n nel at t he cli nical site 
n ot directl y i n v ol ve d wit h t he cli nical as pects of t he trial  w h o  will pre pare a nd dis pe nse t he st u d y 
me dicati o n, will be a ware of t he ra n d o mizati o n c o de. T he st u d y dr u g a n d pl ace b o will ha v e t he 
sa me vis ual a p peara n ce i n or der t o a v oi d c o m pr o misi n g t he st u d y bli n di n g. 
I n t he e ve nt of a n e mer ge nc y, a n d o nl y w he n t he k n o wle d ge of t he tr eat me nt assi g n me nt is 
dee me d ess e ntial f or t he s u bject´s care, a n e n vel o pe f or eac h s u bject c o ntai ni n g his/ her treat me nt 
assi g n me nt will be a v aila ble fr o m cli nical pers o n nel i n v ol ve d wit h t he pre p arati o n of t he st u d y 
me dicati o n. T he Q ualifie d I n v esti gat o r or ot her d esi g nee  d ele gat e d b y t he Q u ali fie d I n vesti gat or 
will ma ke e ver y eff ort t o c o ntact t he S p o ns or pri or t o u n bli n di n g a s u bject’s treat me nt 
assi g n me nt a n d will rec or d t he date, ti me, a n d reas o n f or t he u n bli n di n g i n t he st u d y s o urce 
d oc u me nts.  T he Q ualifie d In v esti gat or  or desi g nee  s h o ul d i m me diatel y i nf or m t he st u d y m o nit or 
t hat a treat me nt c o d e has bee n o pe n e d. O nce t he st u d y treat me nt  has bee n u n bli n de d f or a gi ve n 
s u bject, t hat s u bject will be defi niti vel y wit h dra w n fr o m t he st u d y.  
T he p har mac y  pers o n n el will pr o vi de t o  t he Bi oa nal ytical Di visi o n of S y ne os Healt h a list of 
s u bject n u m bers t o be a n al yze d, s o t hat o nl y sa m ples fr o m treat me nts T, S T , a n d M 
( m o xifl o x aci n) will be a nal yze d. Because bl o o d sa m ples fr o m p lace b o will n ot be a nal yz e d 
u nle ss nee de d, a n d m o xifl o x aci n will be a d mi nistere d i n a n o pe n -la bel basis, a f ull bli n di n g of 
bi oa nal ytical staff will n ot be c o m pletel y e ns ure d.  
T he ra n d o mizati o n c o de will n ot be a vaila ble t o t he Bi oa nal ytical Di visi o n of S y ne os H ealt h  
u ntil t he cli nical a n d a nal ytical p h ases of t he st u d y ha ve bee n c o m plete d.  
9. 4. 2  
St u d y Tre at me nt M  
St u d y t reat me nt M ( m o xifl o x aci n) is s u p plie d as a ta blet f or m ulati o n w hile st u d y treat me nts T, 
S T (t hera pe utic a n d s u pr at hera p e utic d oses of I T F 2 3 5 7) a n d P  ( matc hi n g pl ace b o) are s u p plie d 
as oral  s us pe nsi o n f or m ulati o ns. T he p ositi ve c o ntr ol, st u d y treat me nt M ( m o xifl o x aci n) will be 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 3 9  of 6 7  
A me n d me nt I  
a d mi nistere d o n a n o pe n la bel basis. T he use of a d o u ble -bli n de d p ositi ve c o ntr ol is n ot 
ma n dat or y, 6  pr o vi de d t hat t he rea di n g of E C Gs is perf or me d i n a bli n de d ma n ner as d escri b e d 
a b o ve.  
9. 5  
St u d y Me dic ati o ns  
Tre at me nt  
St u d y Me dic ati o n  
 
Tre at me nt T: T her a pe utic d ose of 
I T F 2 3 5 7 1 0 0 m g  
 
 I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n –  1 4 0 
m L/ b ottle  
 Place b o oral s us pe nsi o n –  1 4 0 m L/ b ottle  
A d mi nistere d as 1 x 1 0  m L of I T F 2 3 5 7 1 0 m g/ m L 
oral s us pe nsi o n + 2 x 1 0  m L of mat c hi n g pl ace b o 
oral s us pe nsi o n (sa me a p peara n ce a n d taste of 
I T F 2 3 5 7 o ne) u n der fasti n g c o n diti o ns (3 0 m L i n 
t otal, f or a t otal I T F 2 3 5 7 d ose of 1 0 0 m g). 
 
Tre at me nt S T: S u pr at her a pe utic 
d ose of I T F 2 3 5 7 3 0 0 m g  
 I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n –  1 4 0 
m L/ b ottle  
A d mi nistere d as 3  x 1 0 m L of I T F 2 3 5 7 1 0 m g/ m L 
oral s us pe nsi o n u n der fasti n g c o n diti o ns ( 3 0 m L i n 
t otal, f or a t otal I T F 2 3 5 7 d ose of 3 0 0 m g).  
 
Tre at me nt P: Pl ace b o  
 
 Place b o oral s us pe nsi o n –  1 4 0 m L/ b ottle  
A d mi nistere d as 3  x 1 0 m L of mat c hi n g pl ace b o oral 
s us pe nsi o n (sa me a p p eara nce a n d taste of I T F 2 3 5 7 
o ne) a d mi nistere d u n d er fasti n g c o n diti o ns ( 3 0 m L i n 
t otal). 
 
Tre at me nt M: M o xifl o x aci n  
( P ositi v e C o ntr ol)   
 
M o xifl o x aci n h y dr oc hl ori de 4 0 0 m g ta blet  
A d mi nistere d as 1 x 4 0 0 m g ta blet u n der fasti n g 
c o n diti o ns.  
9. 6  
Dr u g S u p plies a n d Acc o u nt a bilit y  
It is t he res p o nsi bilit y of t he S p o ns or t o e ns ure t hat st u d y me dicati o n pr o vi de d f or t his st u d y are 
ma n ufact ur e d u n der G o o d Ma n ufact uri n g Practice ( G M P) a n d are s uita ble f or h u ma n us e. T he 
S p o ns or is res p o nsi ble t o s hi p a s ufficie nt a m o u nt of d osa ge u nits t o all o w t he cli nical site t o 
mai ntai n a n a p p r o pri ate s a m pli n g f or t h e st u d y. St u d y me dicati o n will be st ore d at t he cli nic al 
site as per a p plica ble re q uire me nts.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 0  of 6 7  
A me n d me nt I  
M o xifl o x aci n will be p urc ha sed  dir ectl y b y S y n e os Healt h a n d rela bel e d f or cli nical use at t he 
site p har mac y.  
T he me dicati o ns will be st ore d i n a l oc ke d, e n vir o n me ntall y -c o ntr olle d me dicati o n r o o m wit h 
restricte d access. C o ntai ner(s) will be ar a la bel c o ntai ni n g at least t he na me of t he st u d y dr u g, l ot 
a n d/ or batc h n u m ber, a n d ma n ufact uri n g a n d/ or e x pir y/r etest date.  
I n di vi d ual d oses f or eac h s u bject a n d peri o d will b e dis pe nse d at t he cli nical site, as per 
a p pr o priate S O P. I n di vi d ual d oses will be dis pe nse d  acc or di n g t o t he ra n d o mizati o n sc he me a n d 
a p pr o priate s yri n ges will be la bele d  wit h at least t he st u d y n u m ber , t he peri o d n u m ber a n d t he 
s u bject n u m ber/s pare n u m ber.  
All st u d y dr u g recei ve d at t he site will be i n ve nt orie d a n d acc o u nte d f or t hr o u g h o ut t he st u d y a n d 
t he res ult rec or de d i n t he dr u g acc o u nt a bilit y/rete nti o n rec or d acc or di n g t o t he cli nical site 
a p pr o priate S O P.   
Treat me nt c o m plia nce f or eac h p eri o d a n d s u bject s h o ul d be rec or de d i n t he Cli nical Trial 
Ma na ge me nt S yste m ( C T M S ) a n d re p ort e d i n t he C R F .  
9. 7  
St u d y Tre at me nts  A d mi nistr ati o n  
S u bjects will be re q uire d n ot t o wear de nt ur es or oral pierci n gs at t he ti me of d osi n g.  
T he I T F 2 3 5 7 a n d Place b o oral s us pe nsi o ns will be a d mi nistere d b y mea ns of gra d uat e d d osi n g 
s yri n ges f or oral use. Bef ore use, t he I T F 2 3 5 7 a n d P lace b o oral s us pe nsi o n m ust be s ha ke n f or at 
least 3 0 sec o n ds b y r otati n g t he b ottle b y 1 8 0° a n d t he h o m o ge n eit y s h o ul d be vis uall y verifie d. 
F or treat me nt T, 1 x 1 0 m L of t he I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n a n d 2 x 1 0 m L of t he 
matc hi n g pla ce b o oral s us pe nsi o n ( 3 0 m L i n t otal , f or a t otal I T F 2 3 5 7 d ose of 1 0 0 m g) will be 
wit h dra w n wit h  s uita ble 1 0 m L oral s yri n ge s pr o vi de d wit h t he st u d y me di cati o ns. T hree 
se parat e s yri n ges will be pre pare d, 1 wit h 1 0 m L of I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n  a n d 2 
wit h 1 0 m L of matc hi n g place b o  oral s us pe nsi o n eac h . T h e pre p arati o n of t he s yri n ges will be 
d o ne a n d d oc u me nt e d at t he site p har mac y. T h e s yri n ges will be pac k a ge d i n a plastic ba g a n d 
gi ve n t o t he bli n de d p ers o n nel at t he cli nical site f or t heir a d mi nist rati o n t o t he patie nts. F or 
a d mi nistrati o n p ur p oses, t he c o nte nts of eac h of t h e 3  s yri n ges will be  tra nsferre d t o t he sa me 
glass.   
F or treat me nt S T, 3 x 1 0 m L of I T F 2 3 5 7 1 0 m g/ m L oral s us pe nsi o n ( 3 0 m L i n t otal, f or a t otal 
I T F 2 3 5 7 d ose of 3 0 0 m g) will be  wit h dra w n wit h s uita ble 1 0 m L oral s yri n ges pr o vi de d wit h t he 
st u d y me dicati o ns. T hree se parat e s yri n ges will be pre pare d, 3 wit h 1 0 m L of I T F 2 3 5 7 oral 
s us pe nsi o n eac h. T h e pre parati o n of t he s yri n ges will be d o ne a n d d oc u me nte d at t he site 
p har mac y. T h e s yri n ges will be pac ka ge d i n a plastic ba g a n d gi ve n t o t he bli n de d pers o n nel at 
t he cli nical site f or t heir a d mi nistrati o n t o t he patie nts. F or a d mi nistrati o n p ur p oses, the  c o nte nts 
of eac h of t he 3 s yri n ges will be tra nsferre d t o t he sa me gl ass. 
F or trea t me nt P, 3 x 1 0 m L of t he m atc hi n g place b o oral s us pe nsi o n ( 3 0 m L i n t otal) will be 
wit h dra w n wit h s uita ble 1 0 m L oral s yri n ges pr o vi de d wit h t he st u d y me di cati o ns. T hree 
se parat e s yri n ges will be pre pare d, 3 wit h 1 0 m L of matc hi n g pl ace b o  oral s us pe nsi o n eac h.T h e 
pre parati o n of t he s yri n ges will be d o ne a n d d oc u me nte d at t he site p har m ac y. T he s yri n ges will 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 1  of 6 7  
A me n d me nt I  
be pac k a ge d i n a plastic ba g a n d gi ve n t o t he bli n de d pers o n nel at t he cli nical site f or t heir 
a d mi nistrati o n t o t he patie nts. F or a d mi nistrati o n p ur p o ses, the c o nte nts of eac h of t h e 3 s yri n ges 
will be tra nsferre d t o t he sa me gl ass.  
F or treat me nts T, S T  a n d P, t he s u bjects will dri n k all t he s us pe nsi o n  i m me diatel y after t he 
c o nte nts of t he 3 s yri n ges is tra nsferre d t o t he sa m e gl ass . T he glass will t he n be ri nse d t wice 
wit h 1 0 5  m L of water a n d t he ri nse dr u n k (t otal of 2 1 0  m L of water).  
F or treat me nt s T, S T a n d P t he c o m plete pre parati o n a n d d osi n g pr oce d ure m ust be c o m plete d:  
 
 wit hi n 1 h o ur b y t he ti me of starti n g of st u d y me di cati o ns s yri n ges pre p arat i o n 
 wit hi n 2 mi n utes b y t he ti me t he st u d y me dicati o n is tra nsferre d t o t he sa m e gl ass. 
 
F or treat me nt M, t he ta bl et will be a d mi nistere d wit h 2 4 0 m L of wat er a n d a ha n d a n d m o ut h 
c hec k will be p erf or m e d t o e ns ure c o ns u m pti o n of t he  me dicati o n. Ti me of d osi n g will  be set 
e q ual t o t he ti me w he n ta blet is a d mi nistere d.  
9. 8  
St u d y Restricti o ns  
9. 8. 1  
F o o d a n d Fl ui ds  
N o f o o d will be all o we d fr o m at least 1 0 h o urs bef ore d osi n g u nti l at least 4 h o urs after d osi n g 
wit h t he e x ce pti o n of o ne piece of ca n d y f or  eac h s u bject  after eac h d osi n g d ue t o  t he bitter taste 
of t he st u d y dr u g.    
S u bjects will be i n a fasti n g state b ef ore safet y l a b orat or y assess me nts i ncl u di n g he mat ol o g y, 
bi oc he mistr y, c oa g ulati o n ( P T a n d P T T) a n d uri n al ysis.   
Meals will be sta n dar di ze d a n d si milar i n  c o m p ositi o n bet wee n peri o ds.  
E x ce pt f or water gi v e n wit h st u d y me di cati o n, n o fl ui ds will be all o we d f or  1  h o ur bef ore d osi n g 
u ntil 1  h o ur p ost -d ose.  Water will be pr o vi de d a d li bit u m  at all ot her ti mes.  
I n a d diti o n, s u bjects will be re q uir e d t o a bstai n fr o m: 
 F o o d c o ntai ni n g p o p p y s ee ds wit hi n 2 4 h o urs pri or t o a d missi o n of eac h p eri o d;  
 F o o d or be v era ges c o ntai ni n g x a nt hi ne deri vati ves or xa nt hi ne -relate d c o m p o u n ds or 
e ner g y dri n ks fr o m 4 8 h o urs pre -d os e (f or s u bj ects w h o re g ularl y c o ns u me lar ge a m o u nts 
i.e. ≥ 5 c u ps of c offee/ d a y  t he restricti o n will be fr o m o ne wee k pre-d os e)  u ntil after t he 
last P K bl o o d sa m ple c ollecti o n of eac h peri o d ; 
 N at ural healt h pr o d ucts (i ncl u di n g her bal re m e dies, h o me o pat hic a n d tra diti o nal 
me dici nes, pr o bi otics, f o o d s u p ple m e nts s uc h as vita mi ns, mi nerals, a mi n o aci ds, 
esse ntial fatt y aci ds, a n d pr otei n s u p ple me nts use d i n s p orts) fr o m 7  da ys pri or t o first 
d osi n g  u ntil st u d y e xit ;  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 2  of 6 7  
A me n d me nt I  
 St J o h n ’s w ort a n d a n y dr u gs k n o w n t o i n d uce or i n hi bit he patic dr u g met a b olis m fr o m 
3 0 da ys p ri or t o first d osi n g u ntil st u d y e xit ; 
 F o o d or be v era ges c o ntai ni n g gra p efr uit, starfr uit, p o me gra nate, pi n ea p ple, or p o mel o 
fr o m 7  da ys pri or t o d osi n g u ntil after t he last p har mac o ki netic bl o o d sa m ple c ollecti o n  of 
eac h p eri o d . 
9. 8. 2  
T o b acc o, Alc o h ol, a n d Illi cit Dr u gs  
S u bjects will be re q uire d t o a bstai n fr o m usi n g s oft or har d dr u gs or a n y t o b acc o or ni c oti ne 
pr o d ucts fr o m scree ni n g u ntil st u d y e xit.   
C o ns u m pti o n of alc o h ol -base d pr o d ucts will be pr o hi bite d fr o m 2 4  h o urs pri or t o  a d missi o n u ntil 
after t he l ast  p har mac o ki netic bl o o d sa m ple  c ollecti o n of eac h peri o d.  
9. 8. 3  
C o nc o mit a nt Me dic ati o ns  
S u bjects will be re q uire d t o a v oi d  usi n g pres cri pti o n a n d O T C  me dicati o ns , a n d de p ot i njecti o ns 
or i m pla nt of a n y dr u g  f or t he peri o d of ti me s p ecifie d i n e xcl usi o n criteri o n  1 8)  u ntil  st u d y e xit . 
N o c o nc o mita nt dr u g t hera p y will be all o we d d uri n g t he st u d y e x ce pt o ne(s) re q uire d f or t he 
me dical ma na ge m e nt of a n a d vers e e v e nt. A n y c o nc o mita nt me dicati o n use ot her t ha n t he 
occasi o nal use of aceta mi n o p he n  ( u p t o 2  g d ail y)  will be e val uate d o n a case -b y -case basis b y 
t he I n v esti gat or or a S u b -i n vesti gat or. All c o n c o mita nt me dicati o n use will be d oc u me nte d fr o m 
scree ni n g t hr o u g h st u d y e xit/earl y ter mi nati o n. 
9. 8. 4  
P ost ur e a n d P h ysic al A cti vit y  
S u bjects will be re q uire d t o re mai n i n a s u pi ne or se mi-recli ne d p ositi o n b ut a v oi d  slee pi n g f or 
t he first 4 h o urs after st u d y treat me nt a d mi nistrati o n. H o we ver, fail ure of s u bjects t o c o m pl y wit h 
t hese re q uir e me nts d oes n ot c o nstit ute a de viati o n fr o m t he pr ot oc ol if it is me dicall y n ecess ar y, 
re q uire d f or pr oce d ures, or t o g o t o t he bat hr o o m. W he n a p pr o priate, s u bjects will be 
acc o m pa ni e d b y a staff me m ber w hile wal ki n g . Vi g or o us acti vit y will be pr o hi bite d at all ti mes 
d uri n g t he c o nfi ne me nt.  
9. 8. 5  
Ot her Rest ricti o ns  
D uri n g t h e peri o d f or w hic h s u bjects are weari n g a H olter  m o nit or, access t o la pt o p, i P o d, cell 
p h o ne, b o o ks or T V will be restricte d a n d c o ntr oll e d. I n a d diti o n, fe mal e partici pa nts will be 
re q uire d t o eit her re m o v e t heir bra if a n y, or wear a bra wit h n o u n der wire, s uc h as s p orts bra. If 
fe male partici pa nts prefer n ot t o wear a bra, it will nee d t o be re m o ve d bef ore t he place me nt of 
electr o des f or t he c o nti n u o us rec or di n g of t h eir heart r h yt h m. I n b ot h cas es, if partici pa nt c h o ose s 
n ot t o wear a bra or wear a wireless bra, it m ust be f or t he d urati o n of t h e e nt ire rec or di n g. 
9. 9  
S a m ple C ollecti o n a n d Pr o cessi n g  
D uri n g t h e st u d y, all sa m ples will be c ollecte d a n d pr ocesse d acc or di n g t o t he ve n d or -s p ecific 
S O P. At t he e n d of t he st u d y a n d after st u d y re p ort ela b orati o n, sa m ples o btai ne d f or cli nical 
la b orat or y ass ess me nts a n d f or P K a nal ysis will be destr o ye d .  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 3  of 6 7  
A me n d me nt I  
9. 9. 1  
Bl o o d S a m ples  
I n eac h p eri o d a t otal of 1 9  bl o o d  sa m ples will be dra w n fr o m eac h s u bj ect f or P K a nal yses . 
Bl o o d sa m ples f or t he m eas ure m e nt of I T F 2 3 5 7 a n d meta b olites: I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, 
I T F 2 5 6 3, I T F2 9 5 5  gl uc ur o ni de , a n d m o xif o x aci n  will be c ollecte d . O nl y sa m ples fr o m s u bjects 
w h o recei ve  I T F 2 3 5 7 a n d m o xifl o x aci n will be a nal yze d, sa m ples fr o m s u bjects w h o recei ve  
place b o will be sa v e d f or a nal ysis if n ee de d.  
Sa m ples will be c ollecte d pre -d ose  a n d 0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 6,  7,  8, 1 2, 2 4, 3 6, 4 8 , 6 0 
a n d 7 2 h o urs p ost -d ose  ( 6 m L f or eac h sa m pli n g ti me f or st u d y tr eat me nts S, S T, a n d P; 3  m L f or 
st u d y treat me nt M).  
I T F 2 3 5 7 will be q ua ntifi e d i n all s u bjects a d mi nistere d wit h t he st u d y dr u g w hile t he meta b olites 
will be q ua ntifie d o nl y i n a ra n d o mize d gr o u p of 1 2 s u bjects, as n o effect fr o m t he meta b olites is 
e x pecte d o n t he Q Tc res ults. T he sa m ples t hat w o ul d n ot be a nal yze d will be ke pt fr oze n u ntil 
bi oa nal ysis res ults are o btai ne d, if  wit hi n t hese res ults a n y i n dicati o n of a p ossi ble effect is 
f o u n d, all sa m ples w o ul d be f urt her st u die d. Bl o o d dra ws will be perf or me d after t he 1 5 -mi n ute 
s u pi nel y resti n g peri o d ar o u n d eac h ti me p oi nt f or E C G e xtracti o n. T he ti me t olera nce wi n d o w 
f or bl oo d sa m ples c ollect e d d uri n g t he c o nfi n e me nt peri o d will be ± 1 0  mi n ute s f or all sa m ples. 
Sa m ple c ollecti o ns d o ne o utsi de t he pre -defi ne d ti me wi n d o ws will n ot be c o nsi dere d as pr ot oc ol 
de viati o ns si nce act u al  p ost -d ose sa m pli n g ti mes will be use d f or p har ma c o ki netic a n d statistical 
a nal ys es.  A dea d -v ol u me i ntra ve n o us  cat h eter will be use d f or bl o o d c ollecti o n t o a v oi d m ulti ple 
s ki n p u nct ures, w he n a p pr o priate. Ot her wise, bl o o d sa m ples will be c ollect e d b y dir ect 
ve ni p u nct ure.   
T he t otal v ol u me of bl o o d i ncl u di n g t hat c ollect e d f or eli gi bilit y a n d safet y p ur p oses s h o ul d n ot 
e x cee d 4 3 5  m L  f or t he w h ole st u d y.  
Bef ore starti n g bi oa n al ysis, t he bi ostatisticia n will ra n d o ml y s elect 1 2 e val u ble s u bjects f or 
plas ma meta b olite a nal ysis. T hese will be t he sa m e 1 2  e valua bl e s u bjects r a n d o mel y s electe d f or 
uri nar y meta b olte a nal ysis.  
Plas ma sa m ples will be c ollecte d a n d pr ocesse d as per  t he A nal ytical Met h o d ol o g y I nf or mati o n 
S heet  ( A MI S). 
9. 9. 2  
Uri ne S a m ple C ollecti o n  
D uri n g tr eat me nt wit h T, S T , a n d P , u ri ne will be c ollecte d fr o m eac h s u bj ect at 5 ti mes or ti me 
i nter vals: s p ot pre-d ose ( wit hi n 2 h o urs bef ore d osi n g), 0 -8 h o urs, 8 -2 4 h o urs, 2 4 -4 8 h o urs, a n d 
4 8 -7 2 h o urs p ost -d ose.  
Uri ne sa m ples will be c ollecte d fr o m all s u bjects, b ut o nl y u ri ne sa m ples fr o m 1 2 ra n d o mize d 
s u bjects will be use d f or t he P K a nal yses of I T F 2 3 5 7 a n d meta b olites: I T F 2 3 7 4, I T F 2 3 7 5, 
I T F 2 4 4 0, I T F 2 5 6 3, a n d I T F 2 9 5 5 gl uc ur o ni de. T h e rest of t he s a m ples will be ke pt fr oze n f or 
f urt her a n al ysis i n case a n y i n dicati o n is f o u n d of a p ossi ble effect of t he m etab olites o n t he Q Tc 
a nal ysis.  
If a s u bject ca n n ot v oi d his or her bla d der wit hi n 3 0  mi n utes bef ore d osi n g, a sa m ple fr o m earlier 
t hat m or ni n g ma y be us e d as t he pre-d ose sa m ple. V oi ds t hat occ ur wit hi n t he ti me i nter val will 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 4  of 6 7  
A me n d me nt I  
be p o ole d, a n d s u bjects will be as ke d t o v oi d t heir bla d der  wit hi n  3 0  mi n utes bef ore t he  e n d of 
eac h c ollecti o n i nter val, s o t hat eac h n e w i nter val will be gi n wit h a n e m pt y bla d der. A n y uri n e 
v oi de d b y s u bjects at t he i ntersecti o n ( wit hi n 1 0  mi n utes) of t w o i nter vals will be i ncl u de d  i n t he 
earlier s a m ple. A n y uri ne v oi de d b y s u bjects b ut n ot c ollecte d will be d oc u me nte d.  
Bef ore starti n g bi oa n al ysis, t he bi ostatisticia n will ra n d o ml y s elect 1 2 e val u ble s u bjects f or 
uri na ry meta b olite a n al ysis. T hese will be t he sa m e e val ua bl e s u bjects ra n d o mel y selecte d f or 
plas ma meta b olte a nal ysis.  
Uri ne  sa m ples will be c ollecte d a n d pr ocesse d as p er  t he A MI S.  
9. 1 0  S u bject M o nit ori n g  
S u bjects will be m o nit ore d t hr o u g h o ut t he st u d y b y t he cli nical staff f or A Es . I n eac h p eri o d, a n 
I v esti gat or or S u b -i n vesti gat or will be  o n site f or dr u g a d mi nistrati o n a n d  u ntil  4 h o urs p ost -d ose, 
a n d a vaila ble o n call f or t he re mai n der of t he st u d y. If necessar y, a n I n vesti gat or or desi g nee ,  at 
t he cli nical site or a healt hcare pr ofessi o nal i n a n ear b y h os pital will a d mi nister treat me nt f or  a n y 
a d verse e ve nt(s). A cras h  cart or e mer ge n c y ba g c o ntai ni n g t he necessar y resc ue material a n d 
a p pr o priate m e dicati o ns will be a vaila ble i n t he  cli nic t o all o w ra pi d i nter v e nti o n i n case of 
e mer ge n c y.  
Safet y p ara meters, i ncl u di n g  la b orat or y res ults a n d E C G, will be assesse d b y a n I n vesti gat or or 
S u b -i n vesti gat or, usi n g t he cli nical site's criteri a f or bi o me dical la b orat or y a n d E C G acce pta nce 
ra n ges as s u g geste d g ui d eli nes i n ma ki n g t he me dical assess me nt. 
Sc he d ule d safet y m eas ur e m e nts will be re peate d acc or di n g t o t he cli nical site S O Ps or u p o n 
re q uest fr o m an I n vesti gat or or S u b-i n vesti gat or. A n y a b n or mal r e peat e d meas ure me nt will be 
e val uate d b y a n I n vesti gat or or S u b -i n vesti gat or a n d re peat e d if j u d ge d necessar y. F urt her acti o n 
ma y b e ta ke n u p o n  a n I n vesti gat or  or S u b -i n vesti gat or’s re q u est. 
S u bjects will be a d vise d t o n otif y t heir h ealt h care pr ofessi o nal(s) (e. g., p h ysicia n, de ntist, a n d/ or  
p har macist) t hat t he y are partici pati n g i n a  cli nical researc h st u d y o n a dr u g calle d I T F 2 3 5 7 
( Gi vi n ostat), w hic h is bei n g de v el o pe d b y Italfar m ac o S. p. A. f or p ote ntial cli nical use i n patie nts 
s ufferi n g fr o m M usc ular D ystr o p hies i n cl u di n g D uc he n ne a n d Bec ker M us c ular D ystr o p h y, a n d 
c hr o nic m yel o pr oliferati ve ne o plas ms i ncl u di n g P ol yc yt he mi a Vera, b ef ore ta ki n g a n y me dici n es 
or u n der g oi n g a n y me di cal pr oce d ure.  
9. 1 0. 1  Vit al Si g ns  
B P, H R, R R, a n d O T will be meas ure d i n a  s u pi ne p ositi o n at: scree ni n g, pre -d ose a n d 
a pr o xi matel y 2, 3, 6, 1 2 a n d 2 4  h o urs p ost -d ose f or eac h p eri o d,  a n d at st u d y e xit . Vi tal si g ns 
will be matc he d t o t he safet y E C G  (at scree ni n g, pre -d ose a n d a p pr o xi matel y 2,  3, 6, 1 2 , a n d 
2 4  h o urs p ost -d ose f or eac h peri o d , a n d at st u d y e xit ). W he n vital si g ns meas ure me nts c oi nci d e 
wit h  E C G or  bl o o d dra w , t he assess me nts will  be perf or me d i n t he f oll o wi n g or der: E C G,  v ital 
si g ns, a n d bl o o d dra w . Uri ne c ollecti o n ti me p oi nts will n ot be pri or itize d o ver safet y a n d ot her 
P K assess me nts.   
F or t he me as ure me nt of B P , t w o meas ures perf or me d after at least 5 mi n utes of resti n g i n s u pi ne 
p ositi o n s h o ul d be ta ke n 2  mi n utes  a part fr o m eac h ot her.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 5  of 6 7  
A me n d me nt I  
9. 1 0. 2  S afet y E C G   
S u pi ne 1 2 -lea d E C G will be perf or me d at scree ni n g , pre -d ose a n d a p pr o xi matel y 2, 3, 6, 1 2 a n d 
2 4 h o urs p ost -d ose f o r eac h peri o d, a n d at st u d y e xit . Safet y E C G will be matc he d t o vital si g ns 
(at scree ni n g, pre -d ose a n d  2,  3, 6, 1 2 a n d 2 4 h o urs p ost -d ose f or eac h p eri o d, a n d at st u d y e xit). 
W he n  E C G c oi nci des wit h vital si g ns  meas ure me nt s or  bl o o d dra w , t he ass ess me nts will be 
perf or me d i n t he f oll o wi n g or der: E C G, vital si g ns, a n d bl o o d dra w . Uri ne c ollecti o n ti me p oi nts 
will n ot be pri ortiz e d o ver safet y a n d ot h er P K ass ess me nts.   
9. 1 0. 3  C o nti n u o us E C G  Rec o r di n g  
T he car di o d y n a mic  assess me nt will be perf or me d t hr o u g h 1 2 -l ea d E C Gs e xtracte d fr o m 
c o nti n u o us rec or di n gs at pre -s pecifie d ti me p oi nts, paire d wit h P K sa m ples. 
C o nti n u o us 1 2 -lea d E C G rec or di n gs will be perf or me d fr o m o ne h o ur pri or t o d osi n g i n eac h 
treat me nt peri o d t o 3 6  h o urs p ost -d ose. T he  1 2 -l ea d H olter a n d E C G e q ui p me nt will be s u p plie d 
a n d s u p p orte d b y E R T. All E C G data will be c ollecte d usi n g Gl o bal I nstr u me ntati o n ( Ma nli us, 
N Y, U S A) M 1 2 R E C G c o nti n u o us 1 2 -lea d di gital rec or der. T h e c o nti n u o us 1 2 -lea d di gital E C G 
data  will be st ore d o nt o S D me m or y car ds. 1 2 -lea d E C Gs will be e xtracte d fr o m t he c o nti n u o us 
rec or di n gs at pre-d eter mi ne d ti me p oi nts as defi ne d i n Secti o n 4 . Sc he d ule of E ve nts, a n d will be 
meas ure d ce ntrall y b y E R T.  
S u bjects will be s u pi nel y resti n g f or at least 1 0 mi n utes pri or t o a n d 5 mi n utes after eac h  ti me 
p oi nt f or E C G e xtracti o ns, w he ne ver  p ossi ble.  S u bjects will be re q uire d t o a v oi d p ost ural 
c ha n ges d uri n g t hes e E C G rec or di n gs.  
W he n ti me p oi nts f or E C G e xtracti o ns c oi nci de wit h vital si g ns meas ure me nts , a n d bl o o d dra ws, 
pr oce d ures will be carrie d o ut i n t h at or der . Uri ne c ollecti o n ti me p oi nts will n ot be pri ortiz e d 
o ver safet y a n d ot her P K assess me nts.   
At t he E C G c ore la b orat or y, u p t o 1 0 r e plicate E C Gs will be e xtracte d at eac h of t he f oll o wi n g 
ti me p oi nts o n Da y 1 i n e ac h treat me nt peri o d: 3 ti me p oi nts pri or t o d osi n g ( -4 5, -3 0 a n d 
- 1 5  mi n utes) a n d 0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5, 4, 5, 6, 7, 8, 1 2, 2 4, a n d 3 6 h o urs p ost -d ose.  
T he f oll o wi n g pri nci pals will be f oll o we d i n E R T’s c ore la b orat or y:  
 
 E C G a nal ysts are bli n de d t o t he s u bject, visit a n d treat me nt all ocati o n  
 Baseli ne a n d o n -tr eat me nt E C Gs f or a partic ul ar s u bject will be o ver -rea d o n t he sa me 
lea d a n d will be a n al yze d b y t he sa m e rea der  
 T he pri mar y a n al ysis lea d is lea d II.  If lea d II is n ot a nal yza ble, t he n pri mar y lea d of 
a nal ysis will be c ha n ge d t o a n ot her lea d f or t he e ntire s u bj ect data set.  
T he f oll o wi n g is a brief descri pti o n of E C G a nal ysis met h o ds utilize d b y E R T’s c ore la b orat or y.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 6  of 6 7  
A me n d me nt I  
9. 1 0. 3. 1  T Q T Pl us E C G E xtr acti o n Tec h ni q ue  
Te n 1 4 -sec o n d di gital 1 2-lea d E C G traci n gs will be e xtracte d fr o m t he c o nti n u o us H olter 
rec or di n gs usi n g t he ‘ T QT Pl us met h o d’, a c o m p uter -assiste d a n d statistical pr ocess utilize d b y 
E R T. T he met h o d e na bles e xtracti o n of E C Gs wit h t he l o west H R varia bilit y a n d n oise wit hi n 
t he pr ot oc ol-s pecifie d e xtracti o n ti me wi n d o w (e. g., t he H R a n d Q T c h a n ges fr o m beat -t o-b eat i n 
t he ra n ge of < 1 0 %). At e ac h pr ot oc ol-s p ecifie d ti me p oi nt, 1 0 E C G re plicates will be e xtracte d 
fr o m a 5-mi n ute “ E C G wi n d o w” (t y picall y, t he last 5 mi n utes of t he 1 5 -mi n ute peri o d w he n t he 
s u bject is mai ntai ne d i n a s u pi ne or se mi-rec u m be nt q uiet p ositi o n). 
9. 1 0. 3. 2  E x pert -Precisi o n Q T A n al ysis  
E x pert -precisi o n Q T a n al ysis will be perf or me d o n all a nal yza ble ( n o n -artifact) b eats i n t he 1 0 
E C G re plicates. Statistical q ualit y c o ntr ol pr oce d ures are use d t o re vie w a n d assess all beats a n d 
i de ntif y “ hi g h ” a n d “l o w ” c o nfi de n ce beats usi n g se veral criteria, i ncl u di n g: 
 
 Q T or Q Tc v al ues e x cee di n g or bel o w certai n t hres h ol ds ( bi ol o gicall y u nli kel y).  
 R R val ues e x cee di n g or bel o w cert ai n t hres h ol ds ( bi ol o gicall y u nli kel y).  
 Ra pi d c ha n ges i n Q T, Q Tc or R R fr o m beat t o beat.  
Mea s ure me nts of all pri mar y E C G para meters ( Q T, Q Tc, R R) i n all rec or de d beats of all 
re plicates t hat are d ee me d “ hi g h c o nfi de nce” is perf or me d usi n g C O M P A S s oft ware.  All l o w 
c o nfi de nce beats are re vi e we d ma n u all y a n d a dj u dic ate d usi n g p ass -fail criteria. T h e fi nal Q C 
assess me nt i s perf or m e d b y a car di ol o gist. T he beats f o u n d acce pta ble b y ma n ual re vie w  are 
i ncl u de d i n t he a nal ysis. T he me dia n Q T, Q Tc, a n d R R val ue fr o m eac h e xtracte d re plicate is 
calc ulate d, a n d t he n t he mea n of all a v aila ble me dia ns fr o m a n o mi nal ti me p oi nt is use d as t he 
s u bject’s re p orta ble val u e at t hat ti me p oi nt. 
Cate g orical T -wa ve m or p h ol o g y a n al ysis a n d t h e meas ure me nt of P R a n d Q R S i nter vals will be 
perf or me d m a n uall y i n 3 of t he 1 0 E C G  re plicates at eac h ti me p oi nt. Eac h fi d ucial p oi n t ( o nset 
of P -wa ve, o ns et of Q -w a ve, offs et of S -wa v e, a n d offset of T -wa ve) is electr o nicall y mar ke d.  
 
F or T -wa ve m or p h ol o g y a n d U -w a ve prese nce, treat me nt -e mer ge nt c ha n ges will be assesse d, 
i.e., c ha n ges n ot pr ese nt at baseli ne. F or eac h cate g or y of T -wa ve m or p h ol o g y a n d of U -wa ves, 
t he cate g or y will be dee me d as prese nt if o bser ve d i n a n y re plicates at t he ti me p oi nt. F or 
baseli ne, t he cate g or y will be dee me d as prese nt if o bser ve d i n a n y re plicates fr o m all ti me p o i nts 
t hat c o nstit ute baseli ne. T he T -wa v e m or p h ol o g y cate g ories are d escri b e d as f oll o ws.  
 
T a ble 1:  
T -w a ve m or p h ol o g y a n d U -w a ve prese nce c ate g ories ( assesse d m a n u all y)  
C ate g or y  
Descri pti o n  
N or mal T -wa ve  
A n y p ositi ve T -wa ve n ot meeti n g a n y criteri o n bel o w  
Flat T -wa ve  
T a m plit u de < 1 m m (eit her p ositi ve or ne gati ve) i ncl u di n g flat 
is oelectric li ne 
N otc he d T -wa ve ( +)  
Prese nce of n otc h(es) of at least 0. 0 5 m V a m plit u de o n asce n di n g or 
desce n di n g ar m of t he p ositi ve T -wa ve  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 7  of 6 7  
A me n d me nt I  
C ate g or y  
Descri pti o n  
Bi p hasic  
T -wa ve t hat c o ntai ns a sec o n d c o m p o ne nt wit h a n o p p osite p hase t hat is 
at least 0. 1 m V dee p ( b ot h p ositi ve/ ne gati ve a n d ne gati ve/ p ositi ve a n d 
p ol y p hasic T -wa ves i ncl u de d)  
N or mal T -wa ve ( -) 
T a m plit u de t hat is ne gati ve, wit h o ut bi p hasic T -wa ve or n otc hes  
N otc he d T -wa ve ( -) 
Prese nce of n otc h(es) of at least 0. 0 5 m V a m plit u de o n desce n di n g or 
asce n di n g ar m of t he ne gati ve T -wa ve  
U -wa ves  
Prese nce of a b n or mal U -wa ves  
9. 1 0. 4  P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e x a mi nati o n wi ll be perf or m e d at scree ni n g a n d at st u d y e xit. A c o m plete 
p h ysical e x a mi nati o n i ncl u des assess me nts of t he f oll o wi n g: hea d, e yes, ears, n ose, t hr oat 
( H E E N T), n ec k  (i n cl u di n g t h yr oi d), c hest, l u n gs, a b d o me n,  bac k, l y m p h n o des,  m usc ul os keletal, 
der mat ol o gi cal, c ar di o vasc ular/ peri p heral vas c ular, a n d ge ne ral ne ur ol o gi cal e xa mi nati o n. 
I n Peri o ds 1, 2 a n d 3, a brief p h ysical e xa mi nati o n will be perf or me d at c hec k-i n o n Da y -1, a n d 
a p pr o xi matel y 2 4 a n d 7 2 ( Da y 4) h o urs p ost -d ose. I n Peri o d 4, a brief p h ysical e xa mi nati o n will 
be perf or me d at c h ec k -i n o n Da y -1 a n d a p pr o xi matel y 2 4 h o urs p ost -d ose. A brief p h ysic al 
e x a mi nati o n i ncl u des assess me nts of t he f oll o wi n g: H E E N T, c hest, l u n gs, a b d o me n, 
der mat ol o gi cal, c ar di o vasc ular/ peri p heral vas c ular, a n d areas of n ot e elicit e d fr o m t he s u bject . 
B o d y meas ure me nts  i ncl u di n g b o d y hei g ht, b o d y wei g ht a n d B MI will be meas ure d at scree ni n g. 
B o d y wei g ht will be meas ure d  at c h ec k-i n ( Da y -1)  f or eac h peri o d.  
9. 1 0. 5  Dr u g , Alc o h ol , a n d C oti ni ne  Scree n  
A uri ne dr u g scree n (a m p heta mi nes, met ha m p heta mi nes, bar bit urates, be nz o diaze p i nes, 
tetra h y dr oca n na bi n ol, c o cai ne, o piates, P C P, M D M A, met ha d o ne), a n alc o h ol breat h test , a n d a 
uri ne c oti ni ne test,  will  be perf or me d at  scree ni n g. A uri ne dr u g scree n, a n alc o h ol breat h test , 
a n d a uri ne c oti ni ne test a n d will als o be perf or me d bef ore  d osi n g of eac h p eri o d.  
9. 1 0. 6  Pre g n a nc y Test  
A uri ne  pre g n a nc y test will be perf or me d  at scree ni n g a n d at st u d y e xit, a n d a ser u m pre g na nc y 
test will be perf or me d at c hec k -i n of eac h peri o d.  
9. 1 0. 7  L a b or at or y Assess me nts  
9. 1 0. 7. 1  
He m at ol o g y  
Fasti n g h e mat ol o g y will be perf or me d at scree ni n g, bef ore d osi n g of eac h peri o d (at c hec k -i n or 
i n t he m or ni n g of Da y -1), 2 4  (Da y 2)  a n d 7 2  ( Da y 4) h o urs  p ost -d ose , a n d at st u d y e xit. T he 
f oll o wi n g will be assess e d: c o m plete bl o o d c o u nt wit h differe ntial, he m o gl o bi n, a n d he mat ocrit.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 8  of 6 7  
A me n d me nt I  
9. 1 0. 7. 2  
Bi oc he mist r y  
Fasti n g b i oc he mistr y will be perf or me d at scree ni n g, bef ore  d osi n g of eac h p eri o d (at c h ec k-i n or  
in t he m or ni n g of Da y -1 ), 2 4 (Da y 2) a n d 7 2  ( Da y 4) h o urs p ost -d ose , a n d  at st u d y e xit. T he 
f oll o wi n g will be assess e d: c h olester ol [t otal, L D L a n d H D L], tri gl yceri des, al b u mi n, al kali ne 
p h os p hatase, A S T, A L T, urea, c yst ati n C,  calci u m, c hl ori de, gl uc ose, p h os p h or us, p otassi u m, 
creati ni ne, s o di u m, t otal bilir u bi n,  a n d t otal  pr otei n.  
9. 1 0. 8  C o a g ul ati o n  
Fasti n g c oa g ulati o n will be p erf or me d at scree ni n g, bef ore  d osi n g of eac h peri o d (at c h ec k-i n or  
in t he m or ni n g of Da y -1 ), 2 4 (Da y 2) a n d 7 2  ( Da y 4) h o urs  p ost -d ose, a n d  at st u d y e xit. T he 
f oll o wi n g will be assess e d: P T a n d P T T . 
9. 1 0. 8. 1  
Ser ol o g y  
Ser ol o g y will be perf or m e d at scree ni n g. T he f oll o wi n g will be ass esse d: HI V a nti ge n a n d 
a nti b o d y, he p atitis B s urface a nti ge n ( H Bs A g), a n d he patitis C vir us ( H C V) a nti b o d y.  
9. 1 0. 8. 2  
Uri n al ysis  
Fasti n g u ri nal ysis will be perf or me d at scree ni n g a n d bef ore d osi n g of eac h peri o d (at c hec k -i n 
or i n t he m or ni n g of Da y -1), 2 4 a n d 7 2  h o urs p ost -d ose , a n d at st u d y e xit. T he f oll o wi n g will be 
assesse d: macr osc o pic e x a mi nati o n, p H, s pecific gra vit y, pr otei n, gl uc ose, k et o nes, bilir u bi n, 
occ ult bl o o d, nitrite, ur o bili n o ge n, a n d le u k oc ytes. U nless ot her wise s pecifi e d, micr osc o pic 
e x a mi nati o n will be perf or me d o n a b n or mal fi n di n gs.  
9. 1 1  St u d y E xit Pr oce d ures  (E n d of T ri al V isit/E arl y T er mi n ati o n V isit)  
T his visit is perf or me d a t t he e n d of t he s u bject partici pati o n i n t he trial, u p on c o m pleti o n o n 
Da y  4 of Peri o d  4 . St u d y pr oce d ures perf or me d o n Da y 4 of Peri o d 4 will s er ve as st u d y e xit 
pr oce d ures. T his visit is als o perf or m e d i n case of earl y ter mi nati o n or wit h dra wals, i n t his case, 
st u d y pr oce d ures will be d o ne t he sa me da y of wi t h dra wal or as s o o n as p ossi ble b ut al wa ys 
wit hi n 1 4 da ys after last partici pati o n of t he s u bject i n t he st u d y . If cli nicall y si g nifica nt 
a b n or mal res ults are f o u n d o n t he la b orat or y assess me nts perf or me d d uri n g St u d y E xit/ Earl y 
Ter mi nati o n, t he s u bject wi ll be i n vite d t o t he site cli nic a gai n t o re p eat a b n or mal para m eters. 
T he f oll o wi n g pr oce d ures s h o ul d be perf or m e d: c o m plete p h ysic al e xa mi nati o n, fasti n g safet y 
la b orat or y ass ess me nts i ncl u di n g he m at ol o g y, bi oc he mistr y, c o a g ulati o n ( P T a n d P T T) , a n d 
uri nal ysis,  s u pi ne vital si g ns [ B P, H R, R R a n d O T], 1 2 -lea d E C G, uri ne pre g na n c y test, A Es 
m o nit ori n g, a n d c o n c o mita nt me dicati o ns .  
9. 1 2  F oll o w -u p Tele p h o ne C all ( D a y 1 2 ± 2 d a ys): 
A f oll o w -u p tele p h o ne call will be ma de t o all s u bjects t o m o nit or o n g oi n g A Es or  t o c hec k f or 
p ossi ble A Es  o n Da y 1 2 ± 2 da ys  after d osi n g i n Peri o d 4.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 4 9  of 6 7  
A me n d me nt I  
9. 1 3  D at a C ollecti o n a n d E v al u ati o n  
S u bjects' pers o nal i nf or m ati o n will be st ore d i n a n electr o nic d ata ca pt ure ( E D C) s yste m 
(I nitiat or ™ or Al p ha d as® ). All cli nical ra w data will be rec or de d pr o m ptl y, acc uratel y, a n d 
le gi bl y; eit her dir ectl y i nt o t he E D C s yste m as e-s o urce dat a or i n deli bl y o n pa per (e. g., ra w data 
s heets w he n el ectr o nic d ata ca pt ur e is n ot p ossi ble). A detaile d list of t he t y p e (electr o nic or 
pa per) a n d l ocati o n f or all s o urc e data will be i ncl u de d i n t he Trial Master File. W he n rec or de d 
electr o nicall y, Cas e Re p ort F or ms will be electr o nicall y ge nerate d aft er war ds. All ra w dat a will 
be c o nser ve d i n or der t o mai ntai n data i nte grit y. T he Q ualifie d I n v esti gat or a n d desi g nee h a ve  
t he res p o nsi bilit y of e ns uri n g t he c o m plete ness a n d acc urac y of t he cli nical data.  
All la b orat or y res ults pr o vi de d b y Bir o n bi o me dical la b orat or y will be st or e d i n I n La b ( Cli nical 
La b orat or y I nf or mati o n Ma na ge me nt S yste m). I nitiat or ™, Al p ha das® , a n d I n La b are vali date d 
a n d are C o d e of Fe deral Re g ulati o ns ( C F R) part 1 1 c o m plia nt a p plicati o ns.   
Cli nical data ma na ge me nt will be perf or me d i n acc or da nce wit h a p plica bl e S y ne os sta n dar ds a n d 
data cle a ni n g pr oce d ures t o e n s ure t he i nte grit y of t he data, e.g ., rem o vi n g err ors a n d 
i nc o nsiste ncies i n t he dat a. A d vers e e ve nts a n d c o nc o mita nt me dicati o n ter ms will be c o de d 
usi n g t he  Me dic al Dicti o nar y f or Re g ul at or y Acti vities (Me d D R A ). 
9. 1 4  S u bject Wit h dr a w al a n d Re pl ace me nt  
S u bjects will be a d vise d t hat t he y are free t o wit h dra w fr o m t he st u d y at a n y ti me. O ver t he 
c o urse of t he st u d y, t he S p o ns or a n d t he I n v esti gat or or a S u b -i n vesti gat or ma y  wit h dr a w a n y 
s u bject fr o m t he st u d y f or o ne of t he reas o ns d escri be d bel o w; s u bject wit h dra wal will be d o ne i n 
acc or da nce wit h t he  cli nical site’s  S O P : 
o  safet y reas o n; 
o  n o n -c o m plia nce wit h pr ot oc ol re q uire me nts;  
o  sig nifica nt pr ot o c ol de viati o n;  
o  p ositi ve alc o h ol breat h test, c oti ni ne test, dr u g scree n, or pre g n a nc y test;  
o  v o miti n g wit hi n 4  h o urs  after d osi n g;  
o  m ar ke d pr ol o n gati o n of t he Q T/ Q Tc i nt er val (i ncreases i n Q T/ Q T c t o > 5 0 0 ms or of   > 6 0 
ms o ver baseli ne) ; 
o  u n bli n di n g of s u bjects treat me nt  
 
He mat ol o g y , bi o c he mistr y , c o a g ulati o n ( P T a n d P T T), a n d uri nal ysis res ults will be re vie we d b y 
a n I n vesti gat or or S u b -i n vesti gat or pri or  t o d osin g; s u bjects will be wit h dra w n fr o m t he st u d y if 
it is dee me d t hat t he s u bject’s safet y ma y be at ris k o n t he basis of t hese test res ults. 
S u bjects e x cl u de d fr o m d osi n g i n o ne peri o d as per criteria liste d a b o ve, ma y be i n vite d t o 
partici pate i n s u bse q ue nt  peri o ds of t he st u d y if dee me d a p pr o priate b y t he I n v esti gat or a n d 
a p pr o priate fr o m a statistical sta n d p oi nt (i.e. w o ul d per mit a de q uate st atistical c o m paris o n). 
H o we ver, s u bjects wit h p ositi ve alc o h ol, c oti ni ne, dr u g s cree n, or pre g na n c y test  a n d s u bject s 
wit h dra w n d ue t o u n bli n di n g of t he st u d y treat me nt,  will be defi niti vel y wit h dra w n fr o m t he 
st u d y.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 0  of 6 7  
A me n d me nt I  
S u bjects w h o wit h dra w or are wit h dra w n fr o m t he st u d y aft er d osi n g will n ot be re place d. 
H o we ver, i n t he e ve nt t h at t he n u m ber of dr o p -o uts e x cee ds i nitia l e x pectati o ns, s u bjects w h o 
wit h dra w or are wit h dr a w n mi g ht be re place d  at t he discreti o n of t he S p o ns or . S uc h re place me nt 
res ulti n g i n d osi n g m ore s u bjects t ha n pla n ne d i n t his pr ot oc ol w o ul d be d oc u me nte d i n a 
pr ot oc ol a me n d me nt.  
S u bjects w h o wit h dra w or are wit h dra w n will be as ke d t o re mai n at t he cli nic u ntil t he 
I n v esti gat or or S u b -i n vesti gat or a grees  t hat t he s u bject is fi ne a n d ca n be disc har ge d. As s o o n as 
s u bject wit h dra wal is c o nfir me d, bl o o d sa m pli n g will be st o p pe d. A P K bl o o d dra w ma y b e 
c ollecte d at t he ti me of wit h dra wal if dee me d re q uire d b y t h e I n vesti gat or.  St u d y e xit 
pr oce d ures /earl y t er mi nati o n visit  will be perf or m e d at t he ti me of wit h dra wal fr o m t he st u d y or 
as s o o n as p ossi ble t hereafter.   
9. 1 5  A d verse E ve nts  a n d A d verse Re acti o ns  
A d verse E ve nt : 
A n A E  is “a n y u nt o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d w hi c h d oes n ot necess aril y ha v e a ca usal rel ati o ns hi p 
wit h t his treat me nt (I nt er nati o nal C o nfere nce o n Har m o nisati o n [I C H] E 2 A).” St u d y dr u g i ncl u des 
b ot h t he i n vesti gati o nal dr u g u n der e v al uati o n a n d t he c o m p arat or dr u g or place b o. M e dical 
c o n diti o ns t hat were prese nt bef ore st arti n g st u d y dr u g are o nl y c o nsi d ere d A Es if t he y w ors e n 
after t he s u bject has start e d t he st u d y dr u g.  
A d verse D r u g Re acti o n :  
I n t he pre-a p pr o val cli nic al e x perie nce wit h a ne w me dici nal pr o d uct: “all n o xi o us a n d u ni nte n de d 
res p o nses t o a me dici nal pr o d uct relate d t o a n y d ose s h o ul d be c o nsi dere d a n A d verse Dr u g 
Reacti o n ( A D R).” T h e p hrase “res p o nses t o a me dical pr o d uct” mea ns t hat a ca usal rel ati o ns hi p 
bet wee n a me di cal pr o d uct a n d a n A E is at least a reas o na bl e p ossi bilit y, i.e., t he relati o ns ca n n ot 
be r ule d o ut.  
U ne x pecte d A d ve rse Dr u g Re acti o n : 
A n u ne x pecte d A D R is a n A D R, t he nat ur e or se verit y of w h ic h is n ot c o nsiste nt wit h t he 
a p plica ble pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure f or a n u na p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct) . 
9. 1 5. 1  Seri o us A d verse E ve nt ( S A E)  
A S A E is a n y e ve nt t hat meets a n y of t he f oll o wi n g criteria:  
 Deat h  
 Lif e -t hreate nin g  
 I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
 Persiste nt or si g nifica nt disa bilit y/i nca pacit y  
 C o n ge nital a n o mal y/ birt h defect i n t he offs pri n g of a s u bject  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 1  of 6 7  
A me n d me nt I  
 Ot her: I m p orta nt me dic al e ve nts 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 pitaliz ati o n, ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g m e nt, 
t he y ma y j e o par dize t he s u bject a n d ma y re q uire m e 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 i n t his defi niti o n. E x a m ple s of s uc h e v e nts are: 
o  
I nte nsi v e treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m 
o  
Bl o o d d ys crasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n  
o  
De vel o p me nt of dr u g d e pe n de nc y or dr u g a b us e  
A S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R) is referre d t o a n A D R t hat 
c o m plies wit h b ot h t he defi niti o ns of “seri o us” a n d “ u ne x pecte d.”  
A n y a b n or m al la b orat or y test res ults felt t o be cli nicall y si g nifi ca nt i n t he me dical a n d scie ntific 
j u d g me nt of t h e In v esti gat or  are t o be rec or de d as A Es or S A Es. S u bject’s he mat ol o gical 
para meters, i n partic ular platelet c o u nts, s h o ul d be caref ull y m o nit ore d. S u bjects s h o ul d f urt her be 
caref ull y m o nit ore d f or si g ns of gastr oi ntesti nal A E’s a n d, if necessar y.  
9. 1 5. 2  Rec or di n g of A d verse E ve nts  
A Es will be rec or de d a n d e val uate d f or t heir seri o us ness, se verit y, a n d relati o ns hi p t o t he st u d y 
me dicati o n. A d vers e e ve nts will be c ollecte d a n d d oc u me nte d d uri n g t he c o urse of t he st u d y, 
fr o m I C F si g nat ur e u ntil a peri o d of 1 2 ± 2  da ys  f oll o wi n g t he last st u d y dr u g a d mi nistrati o n.  
A d verse e ve nts will be f oll o we d -u p u ntil c o m plete res ol uti o n, or u ntil t he I n vesti gat or j u d ges it 
t o be safe t o disc o nti n ue f oll o w-u p. T he relati o ns hi p t o t he st u d y m e dica ti o n will be classifie d b y 
t he In v esti gat or acc or d i n g secti o n 9. 1 5. 4 .  
9. 1 5. 3  Assess me nt of Se verit y  
T he se verit y of A Es will be  assesse d a n d gra d e d acc or di n g t o t he m ost rece ntl y p u blis he d 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A E ( C T C A E).   
9. 1 5. 4  Assess m e nt of Rel ati o ns hi p t o t he St u d y Dr u g  
T he relati o ns hi p wit h t he st u d y dr u g s h o ul d be assesse d as:  
 relate d t o st u d y dr u g;  
 n ot relate d t o st u d y dr u g;  
 u n k n o w n.   
 
T he assess me nt of t he rel ati o ns hi p of a n a d verse e ve nt wit h t he a d mi nistrati o n of st u d y dr u g i s a 
cli nical decisi o n base d o n all a vaila ble i nf or mati o n at t he ti me of t he c o m pleti o n of t he C R F.  
 A n assess me nt of “ Rel ate d” i n dicates t hat t here is a reas o n a ble s us pici o n t hat t he A E is 
ass ociate d wit h t he use of t he st u d y dr u g.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 2  of 6 7  
A me n d me nt I  
 A n assess me nt of “ N ot relate d” w o ul d i ncl u de t he e xiste nce of a clear alter nati ve 
e x pla nati o n, or n o n -pla usi bilit y.  
 A n assess me nt “ U n k n o w n” i n dicates t here is n ot a reas o na bl e s us pici o n t hat t he A E is 
ass ociate d wit h t he use of t he st u d y dr u g a n d at t h e sa me ti me t here is n ot t he e xiste nce of 
a clear alter nati ve e x pla nati o n or n o n -pla usi bilit y. I n t his case, I n v esti gat or has t o c ollect 
all p ossi ble i nf or mati o n i n or der t o assess t he relati o ns hi p wit h t he st u d y dr u g, 
partic ularl y i n cas e of S A Es.  
9. 1 5. 5  Seri o us A d verse E ve nts Re p orti n g  
A n y S A E t hat o cc urs after a s u bject has si g ne d t h e I nf or me d C o nse nt F or m m ust b e re p orte d b y 
t he I n v esti gat or t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of its occ urre n ce. 
T he I n vesti gat or m ust n otif y t he S p o ns or of t he S A E b y c o m pleti n g t he w or d ve rsi o n of t he S A E 
re p orti n g f or m a n d e-maili n g t he p df versi o n t o t he a d dress es s pecifi e d bel o w. 
Seri o us a d verse e ve nt r e p orts m ust be ma de w het her or n ot t he I n v esti gat or c o nsi ders t he e ve nt 
t o be relate d t o t he i n vesti gati o nal dr u g. 
T he I n vesti gat ors are re q uire d t o c o m plete t he S A E F or m. S ufficie nt d etails m ust be pr o vi de d t o 
all o w f or a c o m plete me dical assess me nt of t he S A E a n d i n de pe n de nt d eter mi nati o n of p ossi ble 
ca usalit y. T he I n v esti gat ors are o bli ge d t o p urs u e a n d pr o vi de a d di ti o nal i nf or mati o n as 
re q ueste d b y It alfar m ac o S. p. A. or its desi g nee. T h e n otificati o n m ust be directe d t o: 
Italfar mac o S. p. A. 
C or p orate Dr u g Safet y  
Via dei La v orat ori, 5 4  
2 0 0 9 2 Ci nisell o Balsa m o ( MI), Ital y  
P h o ne:
Fa x: 
Fa x ( bac k -u p):
M o bile:
e-mail: dr u g -safet y @italf ar mac o. c o m 
 
T he sa me pr o ce d ure m ust be a p plie d t o t he S A E f oll o w -u p i nf or mati o n.  
9. 1 5. 6  S us pecte d, U ne x pecte d, Seri o us A d ve rse Dr u g Re acti o ns  
9. 1 5. 6. 1  
F at al o r L if e-t hre ate ni n g S eri o us, U ne x pecte d A d verse D r u g R e acti o ns 
T he S p o ns or  is res p o nsi ble f or n otif yi n g re g ulat or y a ge ncies of fatal or life-t hreate ni n g seri o us, 
u ne x pecte d a d vers e dr u g reacti o ns ( b y tel e p h o ne, facsi mile tra ns missi o n or i n writi n g) as s o o n as 
p ossi ble, b ut n o later t ha n 7 cale n dar da ys after bec o mi n g a ware of t h e i nf or mati o n. 
A d diti o nall y, wit hi n 8 da ys after ha vi n g i nf or me d t he a ge nc y(i es), a c o m plete re p ort m ust be 
s u b mitte d, i ncl u di n g a n assess me nt of t he i m p orta nce a n d i m plicati o n of a n y fi n di n gs. S y n e os 
Healt h  will ha n dle n otificati o ns t o t he Ca na dia n re g ul a t or y a ge n c y o n be h alf of t he S p o ns or. 
C CI
P P D
P P D
P P D
P P D

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 3  of 6 7  
A me n d me nt I  
It is t he res p o nsi bilit y of t he cli nical site t o re p ort as s o o n as p ossi ble, b ut n o later t ha n 7 cale n dar 
da ys after first k n o wle d ge b y t h e I n vesti gat or, fatal or life-t hreate ni n g seri o us, u ne x pecte d 
a d verse dr u g react i o ns t o t he I E C res p o nsi ble f or t he st u d y. 
9. 1 5. 6. 2  
Ot her S us pecte d, U ne x pecte d, S eri o us A d verse D r u g R e actio ns  
T he S p o ns or is res p o nsi ble f or n otif yi n g re g ulat or y a ge ncies of all ot her s us pecte d, u ne x pecte d, 
seri o us a d vers e dr u g reacti o ns t hat are neit her fatal n or life-t hreate ni n g as s o o n as p ossi ble, b ut 
n o later t ha n 1 5  cale n dar da ys after bec o mi n g a ware of t he i nf or mati o n. S y ne os Healt h  will 
ha n dle n otificati o ns t o t he Ca na dia n re g ulat or y a ge nc y o n be h alf of t he S p o ns or .  
It is t he res p o nsi bilit y of t he cli nical site t o re p ort t o t he I E C res p o nsi ble f or t he st u d y all ot her 
s us pecte d, u ne x pecte d, s eri o us a d vers e dr u g reacti o ns t hat are neit her fatal n or life -t hreate ni n g, 
as s o o n as p ossi ble, b ut n o later t ha n 1 5  cale n dar da ys after firs t k n o wle d ge b y t he I n vesti gat or. 
9. 1 5. 7  A d verse E ve nts of S peci al I nterest  
A E SI are re q uire d t o be re p orte d b y t he i n vesti gat or t o t he S p o ns or i m me diatel y (i.e., n o m ore 
t ha n 2 4 h o urs after lear ni n g of t he e ve nt). A E SI f or t his st u d y i ncl u de t he f oll o wi n g:   
 T orsa de de p oi ntes  
 S u d de n deat h  
 Ve ntric ular t ac h ycar dia  
 Ve ntric ular fi brillati o n a n d fl utter  
 P ost -d ose s y nc o p e   
 Seiz ures  
W hic h are t o be classifi e d as A E SI  i n t he C R F a n d will be rec or de d fr o m I C F si g nat ure a n d 
t hr o u g h o ut t he st u d y peri o d u ntil st u d y c o m pleti o n  (foll o w -u p tele p h o ne call). W he n t hese 
e ve nts are i de ntifie d t he y s h o ul d be e x a mi ne d cl osel y f or ot her ris ks fact ors, a n d e val uati o n a n d 
t he nee d f or e val u ati o n b y a car di ac s pecialist will be disc usse d b y t he I n v esti gat or a n d t h e 
S p o ns or  
9. 1 6  Pre g n a nc y  
I n t he e ve nt a d os e d fe m ale s u bject ( or t h e fe m ale part ner of a d ose d mal e s u bject, w he n 
a p plica ble) b ec o mes pre g na nt d uri n g t he treat me nt p hase or t hr o u g h 3 m o nt hs after t he last d ose 
of st u d y dr u g, t his pr e g n a nc y m ust be re p orte d t o t he site pers o n nel i m me diatel y.  
T he I n vesti gat or is r eq uir e d t o re p ort wit hi n 2 4 h o urs t he pre g na nc y, usi n g t he Pre g n a nc y 
N otificati o n F or m, t o Italfar mac o C or p orate Dr u g Safet y b y m aili n g t o t he f oll o wi n g e -mail 
a d dress:  
Italfar mac o C or p orate Dr u g Safet y:  dr u g -safet y @italfar mac o. c o m 
If n otificati o n ca n n ot b e ma de via t hese mea ns d u e t o tec h nical deli ver y pr o ble ms, i nitial 
n otificati o n ma y b e ma de b y tele p h o n e or b y fa x, usi n g t he f oll o wi n g n u m bers:  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 4  of 6 7  
A me n d me nt I  
Italfar mac o C or p orate Dr u g Safet y:   
P h o ne: 
Fa x: 
Fa x ( bac k -u p):
 
F oll o w -u p i nf or mati o n r e gar di n g t h e c o urse a n d o utc o me of t he pre g na nc y wit h a n o nset wit hi n 
t he a b o ve defi ne d ti me fra me, will be d oc u me nte d (after o bt ai ni n g t he c o ns e nt of t he fe m ale 
part ner, w h e n a p plica ble) as per site’s S O P. A n y pre mat ure t er mi nati o n s h o ul d be re p orte d, a n d 
t he stat us of t he m ot her a n d c hil d s h o ul d be re p ort e d t o t he s p o ns or after deli ver y. If t he o utc o me 
of t he pre g n a nc y me ets t he criteri a f or classificati o n as a n S A E, re p orti n g  of t he e ve nt t o t he I E C 
a n d re g ulat or y a ge n c y(ies) will be perf or me d as p er site’s S O P.  
A n y s u bject w h o bec o mes pre g na nt d uri n g t he st u d y will be i m me diatel y wit h dra w n.  
9. 1 7  O ver d ose  
I n ge neral, a dr u g o v er d ose i n a cli nical st u d y is defi ne d as t he acci de ntal or i nte nti o nal use of a 
dr u g or me dici ne i n a n a m o u nt e x cee di n g t he pr ot oc ol defi ne d d ose. T h e I n vesti gat or m ust 
i m me diatel y n otif y t he S p o ns or of a n y occ urre nce of o ver d ose wit h st u d y dr u g. 
A n y o v er d ose or i nc orrect a d mi nistrati o n of st u d y dr u g s h o ul d be rec or de d i n t he C T M S  a n d 
re p orte d o n t he rele v a nt st u d y dr u g a d mi nistrati o n Case Re p ort F or m ( C R F) a n d t he Pr ot oc ol 
D e viati o n C R F. A Es ass ociate d wit h a n o ver d ose or i nc orrect a d mi nistrati o n of st u d y dr u g 
s h o ul d be re p orte d o n t he rele va nt A d v erse E v e nt C RF. N o safet y dat a relat e d t o o ver d osi n g of 
I T F 2 3 5 7 are a vaila ble. 
A n y i nsta n ce of o ver d ose (s us pecte d or c o nfir me d, wit h a n d wit h o ut a n A E) m ust be re p orte d t o 
t he S p o ns or wit hi n 2 4 h o urs a n d, o nl y i n case of A Es, it m ust be f ull y d oc u me nte d as a S A E. 
Details of a n y si g ns or s y m pt o ms a n d t heir ma na ge me nt s h o ul d be rec or de d i n t he S A E F or m 
i ncl u di n g details of a n y a nti d ote or s yste matic tr eat me nt a d mi nistere d. A n y si g ns or s y m pt o ms of 
o ver -d osa ge will be treate d s y m pt o maticall y.   
 
A n y ot her sit uati o ns p u tti n g t he s u bject at ris k of a n a d verse reacti o n, s uc h as mis use a n d a b use, 
me dicati o n err ors, s us pe ct of tra ns missi o n of i nfecti ve a ge nts m ust be re p orte d t o t he S p o ns or 
wit hi n 2 4 h o urs a n d be f ull y d oc u me nte d as a S A E.  
Me d D R A  f or c o di n g e v e nt a n d W H O Dr u g Dicti o nar y f or c o di n g c o nc o mita nt me dicati o ns will 
be use d wit hi n t he Italfar mac o safet y d ata bas e.   
9. 1 8  Re p ort a ble Dise ase  
I n t he cas e a s u bject h as or ma nifests a n y cli nical si g ns c haract eristic of a re p orta ble disease or 
c o n dit i o n (e. g., HI V, t u b erc ul osis, S A R S), it is t he res p o nsi bilit y of t he Q ualifie d I n vesti gat or or 
desi g nee  t o n otif y t he P u blic Healt h a ut h orities wit hi n 4 8  h o urs  after bec o mi n g a ware of t he 
i nf or mati o n. 
C CI
P P D
P P D
P P D

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 5  of 6 7  
A me n d me nt I  
9. 1 9  Pre m at ure Ter mi n ati o n of t he St u d y  
T he st u d y ma y b e pre m at urel y t er mi nate d b y t he  Q ualifie d  I n vesti gat or f oll o wi n g c o ns ultati o n 
wit h t he S p o ns or, b y t he S p o ns or or b y t he re g ulat or y a ut h orities. F oll o wi n g a d ecisi o n t o 
disc o nti n ue t he trial, t he Q ualifie d I n vesti gat or or desi g nee will pr o m ptl y i nf or m t he acti v e st u d y 
s u bjects a n d t he I E C r es p o nsi ble f or t his trial, stati n g t he reas o ns f or disc o nti n uati o n of t he st u d y 
a n d, f urt her m ore, a d vise t he m i n writi n g of a n y p ote ntial ris ks t o t he healt h of st u d y s u bjects or 
ot her pers o ns. It is t he S p o ns or’s res p o nsi bili t y t o re p ort t he pre mat ure ter mi nati o n of t he st u d y 
t o t he re g ulat or y a ut h orit y(ies), w he n re q uir e d b y t he a p plica ble re g ulat or y re q uire me nt(s). T he  
Ca na dia n re g ul at or y a ge nc y m ust be i nf or me d of pre mat ure t er mi nati o n wit hi n 1 5 da ys , pr o vi de d 
wit h t he reas o ns f or t he trial disc o nti n uati o n a n d of a n y p ote ntial ris ks t o t he healt h of st u d y 
s u bjects or ot her pers o ns. S y ne os H ealt h  ma y n otif y t he Ca n a dia n re g ulat or y a ge nc y o n b e half of 
t he S p o ns or u p o n his re q uest.   
1 0.  A n al ytic al Met h o d ol o g y  
W he n a p plica ble, sa m ples will be tra ns p orte d t o t he bi oa nal ytical f acilit y i n at least t w o se parate 
s hi p me nts, wit h eac h set of ali q u ots i n se parate s hi p me nts. O nce t he bi oa n al ytical la b orat or y 
c o nfir ms recei pt of t he first s hi p me nt, t he sec o n d set of ali q u ots ma y b e se nt. T he sa m ples s h o ul d 
be pac k e d o n s ufficie nt dr y ic e t o kee p t h e m fr oze n f or at least 7 2 h o urs.  
T he Bi oa n al yti cal Di visi o n of S y ne os H ealt h will a nal yze I T F 2 3 5 7, I T F 2 3 7 4, I T F 2 3 7 5, 
I T F 2 4 4 0, I T F 2 5 6 3, a n d I T F2 9 5 5  gl uc ur o ni de , i n plas ma a n d urine sa m ples, a n d m o xifl o x aci n i n 
plas ma sa m ples usi n g v ali date d met h o ds.   
A nal yst a n d Wats o n LI M S ( La b orat or y I nf or mati o n Ma na ge me nt S yste m) will be use d at 
differe nt ste ps of t he a n al ysis.  
T he bi oa nal ytical w or k i n s u p p ort of t he st u d y will be c o n d ucte d i n  c o m plia nce wit h t he G C P, 
usi n g t he S O Ps i n place i n t he Bi oa nal ytical Di visi o n  of S y ne os H ealt h. T h ese S O Ps are i n 
acc or da nce wit h a p plica ble re g ulati o ns i n t he i n d ustr y: G ui deli nes o n Bi oa nal ytical Met h o d 
Vali dati o n, G o o d La b orat or y Practice ( G L P), a n d G ui deli ne f or G C P I C H E 6 ( R 2).  
Sa m ples fr o m s u bjects i ncl u de d i n t he P har mac o ki netic P o p ulati o n (see secti o n 1 2. 3. 3 ) a n d fr o m 
s u bjects w h o were wit h dra w n fr o m t he st u d y d u e t o a d verse e ve nts,  or v o miti n g e pis o des, will be 
a nal yze d.  
1 1.  St u d y E n d p oi nts  
Pri mar y e n d p oi nt : 
 
 T he pri mar y e n d p oi nt f or t he car di o d y na mic E C G assess me nt is t he place b o -c orrecte d 
c ha n ge fr o m -bas eli ne Q Tc F ( Δ Q T c F).  
 
Sec o n da r y e n d p oi nts: 
 
 C ha n ge -fr o m-baseli ne Q Tc F, P R, Q R S, a n d heart rate ( H R) ( Δ Q Tc F, Δ P R, Δ Q R S, a n d 
Δ H R)  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 6  of 6 7  
A me n d me nt I  
 Place b o -c orrecte d Δ P R, Δ Q R S a n d Δ H R ( Δ Δ P R, Δ Δ Q R S, a n d Δ Δ H R)  
 Cate g orical o utliers f or Q Tc F, H R, P R, a n d Q R S  
 Fre q u e nc y of treat me nt e mer ge nt c ha n ges of T -wa v e m or p h ol o g y a n d U -wa ve pres e nce  
 T he P K e n d p oi nts will i ncl u de t he plas ma a n d uri ne P K para met ers f or I T F 2 3 5 7, 
I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3, I T F 2 9 5 5 gl uc ur o ni d e, a n d m o xifl o x aci n (as 
descri be d i n t he P har m ac o ki netics secti o n).  
 Safet y a n d t olera bilit y t o I T F 2 3 5 7 will be e v al uate d t hr o u g h t he assess me nt of a d verse 
e ve nts (i.e., seri o us ness, se verit y, relati o ns hi p t o t he st u d y me dicati o n, o utc o me, d urati o n, 
a n d ma na ge m e nt), vital si g ns, E C G, a n d cli nical la b orat or y p ara met ers . 
1 2.  P h ar m a c o ki netic a n d St atistic al A n al yses  
P har mac o ki netic a n al ysis will be perf or me d usi n g P h oe ni x ®  Wi n N o nli n
® . I nfere ntial statistical 
a nal ys es will  be p erf or me d usi n g S A S ®  acc or di n g t o F D A  a n d E M A g ui deli nes . 
1 2. 1  Pl as m a P K P ar a meters  
T he f oll o wi n g p h ar mac o ki netic para met ers will be calc ul ate d b y sta n dar d n o n -c o m part me ntal 
met h o ds f or I T F 2 3 5 7 a n d meta b olites: I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0, I T F 2 5 6 3 a n d I T F2 9 5 5  
gl uc ur o ni d e , a n d m o xifl o x aci n i n plas ma:  
1)  
A U C 0 -t: area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o t he last meas ura ble  
c o nce ntr ati o n  
2)  
A U C 0 -1 2: area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 1 2 h o urs 
3)  
A U C 0 -i nf: area u n der t he c o nce ntr ati o n-ti me c ur ve fr o m ti me zer o t o i nfi nit y 
(e xtra p olate d)  
4)  
C ma x : ma xi m u m o bser ve d c o nce ntr ati o n  
5)  
Resi d ual area: calc ulat e d as 1 0 0 *( 1 - A U C 0 -t / A U C0 -i nf) 
6)  
T ma x : ti me of o bser ve d C ma x 
7)  
T ½ el : eli mi nati o n half-life 
8)  
K el: eli mi nati o n rate c o nsta nt 
9)  
C L/ F: a p p are nt t otal b o d y cl eara nce, calc ul ate d as D ose/ A U C0 -i nf 
1 0)  
V d/ F: a p pare nt v ol u me of distri b uti o n, calc ulate d as D ose/ K el x A U C 0 -i nf 
1 2. 2  Uri ne P K P a r a meters  
T he f oll o wi n g P K  p ara m eters will be calc ulate d f or  I T F 2 3 5 7 a n d meta b olites I T F 2 3 7 4, I T F 2 3 7 5, 
I T F 2 4 4 0, I T F 2 5 6 3 a n d I T F2 9 5 5  gl uc ur o ni de  I T F 2 9 5 5 i n uri ne:  
1)  Ae 0 -t: C u m ulati ve uri nar y e x creti o n fr o m ti me zer o t o ti me t, calc ulate d as t he s u m of t he 
a m o u nts e x crete d o ver eac h c ollecti o n i nter val. T h e a m o u nt e x crete d i n uri n e f or eac h 
ti me i nter val is calc ulate d as t he uri ne c o n ce ntr ati o n m ulti plie d b y t he uri ne v ol u me. 
2)  R ma x : Ma xi m u m rate of uri nar y e x creti o n, calc ulat e d b y di vi di n g t he a m o u nt of dr u g 
e x crete d i n eac h c ollecti o n i nter val b y t h e ti me o ver w hic h it was c ollecte d  
3)  T R ma x : Ti me of R ma x , calc ulate d as t he mi d p oi nt of t he c ollecti o n i nter val d uri n g w hic h 
R ma x  occ urre d   
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 7  of 6 7  
A me n d me nt I  
4)  Clr : Re nal cleara n ce, cal c ulate d as A e 0 -t / A U C0 -t ( plas ma) 
A d diti o nal P K  a nal ysis ma y b e perf or me d. U p o n S p o ns or's re q u est, p har mac o ki netic re p eats 
mi g ht be perf or me d acc or di n g t o S y ne os Healt h’s S O P. If re -ass a ys are re q ueste d f or 
p har mac o ki ne tic reas o ns, fi nal res ults will i ncl u de re-ass a y val ues, w hile res ults wit h ori gi nal 
val ues will be prese nt e d i n a n a p pe n di x of t he cli nical st u d y re p ort as s u p p orti ve data.    
1 2. 3  A n al ysis P o p ul ati o ns  
1 2. 3. 1  S afet y P o p ul ati o n  
T he Safet y P o p ulati o n will i ncl u de all s u bjects w h o recei v e at least 1 d ose of st u d y dr u g 
(t hera p e utic a n d s u pr at hera pe utic d oses of I T F 2 3 5 7, m o xifl o x aci n, or place b o). 
1 2. 3. 2  Q T/ Q Tc P o p ul ati o n  
T he Q T/ Q Tc P o p ulati o n will i ncl u de all s u bjects i n t he Safet y P o p ulat i o n wit h meas ure me nts at 
baseli ne as w ell as o n -treat me nt wit h at least o ne p ost-d ose ti me p oi nt wit h a vali d Δ Q Tc F val u e. 
T he Q T/ Q Tc P o p ulati o n will be use d f or t he b y -ti me p oi nt a n d cate g ori cal a nal ys es of t he 
car di o d y na mic E C G p ara meters.  
1 2. 3. 3  P h ar m a c o ki net ic P o p ul ati o n  
T he P K p o p ulati o n will i ncl u de all s u bjects c o m pl eti n g at least 3 peri o ds, i ncl u di n g at least T, 
S T, a n d M a n d f or w h o m t he P K pr ofile ca n b e a d e q uatel y c h aracterize d.  T he p har mac o ki netic 
p o p ulati o n will be use d f or calc ulati o n of P K para mete rs a n d statsitical a nal yses. 
A n y s u bject wit h pre -d os e c o nce ntrati o ns will be e x cl u de d fr o m t he P K a n d statistical a nal ysis 
f or t he res p ecti ve a nal yte f or t he c o n cer ne d peri o d if t he pre-d os e c o nce ntrati o n is great er t ha n 
5 % of t he C ma x  val ue of t hat peri o d f or t hat s u bject.  
Data fr o m s u bje cts w h o e x perie nce d e mesis d uri n g t he sa m pli n g i nter val a n d w h o were n ot 
wit h dra w n as per criteri o n esta blis he d u n der secti o n 9. 1 4  ma y  b e e val u ate d after c o m pleti o n of 
t he P K a nal ysis.  
A n y s u bject w h o e x perie nce d e mesis wit hi n 2 ti mes me dia n T ma x  of t he c urre nt st u d y will be 
e x cl u de d fr o m t he statistical a nal ysis.  
Data ( c o n ce ntr ati o ns a n d P K para meters) fr o m s u bjects e x cl u de d d ue t o a pre -d ose c o nce ntrati o n 
greater t ha n 5 % of t h eir C ma x  or fr o m s u bjects wit h dra w n d ue t o a d verse e v e nts or v o miti n g 
e pis o des will be prese nt e d b ut e x cl u de d fr o m descri pti ve statistics f or t he c o ncer ne d p eri o d.  
1 2. 3. 4  P h ar m a c o ki netic  C o nce ntr ati o n P o p ul ati o n  
T he P K c o nce ntrati o n p o p ulati o n will i ncl u de all s u bjects w h o recei ve a d ose of I T F 2 3 5 7 or 
m o xifl o x aci n a n d pr o vi de at least o ne e val ua ble P K c o nce ntr ati o n f or  I T F 2 3 5 7 or m o xifl o x aci n.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 8  of 6 7  
A me n d me nt I  
1 2. 3. 5  P K / Q Tc P o p ulati o n  
T he P K/ Q Tc P o p ulati o n will i ncl u de all s u bjects w h o are i n b ot h t he Q T/ Q Tc a n d P K  
C o nce ntrati o n  p o p ulati o ns wit h at least o ne pair of p ost -d ose P K a n d Q Tc F data fr o m t he sa m e 
ti me p oi nt as well as s u bjects i n t he Q T/ Q Tc p o p ul ati o n w h o recei ve d place b o. T he P K/ Q Tc 
P o p ulati o n will be use d f or t he c o nce ntrati o n -Q Tc a nal ysis. P K/ Q Tc P o p ulati o n will be defi ne d 
f or I T F 2 3 5 7 a n d f or m o xifl o x aci n.   
1 2. 4  St atistic al A n al yses  
Details of statistical a nal ys es will be d e vel o pe d i n a S A P  t hat will be pre pare d aft er c o m pleti o n 
of t he fi nal pr ot oc ol . 
1 2. 4. 1  C ar di o d y n a mic E C G A ssess me nt 
T he pri mar y a n al ysis will be base d o n c o n ce ntr ati o n -Q Tc m o deli n g of t he relati o ns hi p bet wee n 
plas ma c o nce ntrati o ns of I T F 23 5 7  a n d c ha n ge-fr o m-baseli ne Q Tc F ( Δ Q Tc F) wit h t he i nte nt t o 
e x cl u de a n effect of pla ce b o -c orrect e d Δ Q T c F ( Δ Δ Q Tc F) > 1 0 msec at cli nicall y rele va nt plas ma 
le vels. I n a d diti o n, t he effects of I T F 23 5 7  o n t he place b o -c orrecte d ∆Q Tc F, Δ H R, Δ P R, a n d 
Δ Q R S ( ∆∆Q Tc F, Δ Δ H R, Δ Δ P R, a n d Δ Δ Q R S) will be e val uate d  at eac h p ost -d osi n g ti me p oi nt 
(' b y ti me p oi nt' a nal ysis). A n a nal ysis of cate g orical o utliers will be perf or me d f or c h a n ges i n 
Q Tc F, H R, P R, Q R S, T -wa ve m or p h ol o g y a n d U -wa ve prese n ce.  
Assa y s e nsiti vit y will be e val uate d b y c o nce ntr ati o n -Q Tc  a n al ysis of t he effect o n ∆Δ Q Tc F of 
m o xifl o x aci n usi n g a si milar m o del as f or t he pri mar y a nal ysis. Assa y s e nsiti vit y will be dee me d 
as met if t he sl o pe of t he c o nce ntr ati o n -Q Tc relati o ns hi p/ Δ Q Tc F is statisticall y si g nifica nt at 
1 0 % le vel of si g nifica n ce i n a 2-si de d test a n d t he pre dicte d Q T effect (i.e. t he l o wer b o u n d of 
t he 2-si de d 9 0 % CI  of Δ Δ Q Tc F) is a b o ve 5  ms ec at t he o bser ve d ge o metri c mea n C ma x  of 4 0 0 
m g m o xifl o x aci n.  
Ge neral met h o d ol o g y : 
All statistical a nal ysis of t he st u d y will be perf or m e d us i n g t he statistical s oft ware S A S f or 
Wi n d o ws Versi o n 9. 4 or ne wer ( S A S I nstit ute, I n c., Car y, N C). I n all calc ul ati o ns, zer o will be 
s u bstit ute d f or c o nce ntr ati o ns bel o w t he q ua ntificati o n li mit of t he assa y. Data c ollecte d fr o m all 
ra n d o mize d s u bjects will be prese nt e d i n data listi n gs. B ot h a bs ol ute val ues a n d c ha n ge-fr o m-
baseli ne val ues f or eac h s u bject will be gi v e n w here a p plica ble. All c o nti n u o us data will be liste d 
wit h t he sa me precisi o n as will be prese nte d i n t he data base. Data listi n gs will be s o rte d b y 
treat me nt, s u bject I D, a n d ti me p oi nt. Missi n g val ues will be re prese nte d b y a n e m pt y cell a n d n o 
i m p utati o n will be ma de. 
F or all des cri pti ve statistics of c o nti n u o us E C G para meters, data will be s u m marize d i ncl u di n g 
n u m ber of s u bjects ( n), mea n, me dia n, S D, S E, 9 0 % CI, Mi n, a n d M a x b y treat me nt a n d ti me 
p oi nt. F or all m o deli n g res ults of t he b y -ti me-p oi nt a nal ysis of c ha n ge -fr o m-baseli ne val ues of 
c o nti n u o us E C G para met ers, n, L S m ea n, S E, a n d 9 0 % CI will be i ncl u de d. M o deli n g res ults of 
t he b y-time p oi nt a n al ysis of place b o -c orrecte d c h a n ge -fr o m-baseli ne will als o i ncl u de L S mea n, 
S E, a n d 9 0 % CI. M ea n a n d me dia n val ues will be r o u n de d t o t he nearest te nt h. S D, S E, a n d CI 
will be r o u n de d t o t he nearest h u n dre dt h. F or t he c o nce ntr ati o n -Q Tc a nal ysis,  2 deci mal places 
will be s h o w n f or all effect esti mates f or all res ults w hic h ha ve a n a bs ol ute val ue greater t ha n 
0. 0 5. Eac h effect esti mate wit h a n a bs ol ute val ue  ≤  0. 0 5 will be dis pla ye d wit h 2 si g nifica nt 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 5 9  of 6 7  
A me n d me nt I  
fi g ures. T he CI of t he effect esti mate will displa y 1 m ore deci mal place t ha n t he effect esti mate. 
S E a n d P  val ues will be re p orte d wit h 4 di gits a n d P  val ues  <  0. 0 0 0 1 will be re p orte d as  <  0. 0 0 0 1. 
De grees of free d o m ( df ), a n d t-val ue will be re p ort e d t o t he nearest te nt h a n d nearest h u n dre dt h, 
res pecti vel y. Cate g orical data will be s u m marize d 2 wa ys, b y s u bject a n d b y ti me p oi nt. S u bject 
data will be s u m marize d usi n g t he c o u nt of disti nct s u bjects t hat fall i nt o t he cate g or y a n d t he 
perce nt a ge of t h e t otal n u m ber of s u bjects. Ti me p oi nt data will be s u m marize d usi n g t he c o u nt 
of t he assess me nts t hat fall i nt o t he cate g or y a n d t he perce nta ge of t he t otal n u m ber of 
assess me nts. Perce nt a ges will be r o u n de d u p or d o w n t o t he ne xt i nte ger perce nta ge. P o p ulati o n 
c o u nts (eit her n u m ber of s u bjects or n u m ber of ti me p oi nts at t he assess me nt) f or eac h tr eat me nt 
gr o u p will be use d as t he de n o mi nat or i n t he calc ul ati o n of perce nta ges u nless ot her wise 
s pecifie d. 
Baseli ne :  
F or all c o nti n u o us E C G para meters fr o m eac h p eri o d, baseli ne will be t he a vera ge of t he deri ve d  
E C G i nter vals fr o m t he 3 E C G ti me p oi nts ( -4 5, -3 0, a n d -1 5 mi n utes) pri or t o treat me nt 
a d mi nistrati o n o n Da y 1 i n eac h p eri o d f or t he res p ecti ve peri o d. F or T -wa v e m or p h ol o g y a n d U -
wa ve prese nce  i n eac h peri o d, baseli ne i ncl u des fi n di n gs o bser v e d i n a n y of t he re plicates fr o m 
t he 3 ti me p oi nts pri or t o d osi n g o n Da y 1 i n eac h peri o d f or t he res pecti ve peri o d. 
C o nce ntrati o n -Q Tc a nal ysis ( pri mar y a nal ysis) : 
T he relati o ns hi p bet wee n  plas ma c o nce ntrati o ns  of I T F 2 3 5 7 a n d c h a n ge-fr o m-baseli ne Q Tc F 
( Δ Q Tc F) be q ua ntifie d usi n g a li near mi x e d-effects m o deli n g a p pr oac h. T h e  m o del will i ncl u de 
Δ Q Tc F as t he d e pe n de nt varia ble, plas ma c o nce ntrati o ns  of I T F 2 3 5 7, as t h e e x pla nat or y v ariate 
( 0 f or place b o), ce ntere d baseli ne Q Tc F (i.e., b aseli ne Q Tc F f or i n di vi d ual s u bject mi n us t he 
p o p ulati o n mea n baseli ne Q Tc F f or all s u bjects i n t he sa me treat me nt peri o d) as a n a d diti o nal 
c o variate, treat me nt ( acti ve  =  1 or place b o  =  0), ti me (i.e., n o mi nal p ost -d ose ti me p oi nt) as fi x e d 
effects, a n d  ra n d o m  effects o n t he  inter ce pt a n d sl o pe per s u bject ( Gar nett et al. 2 0 1 8).1 1  
T he de grees of free d o m of esti mates will be deter mi ne d b y t he Ke n war d -R o ger met h o d. Fr o m 
t he m o del, t he sl o pe (i.e., t he re gressi o n para met er f or c o nce ntrati o ns of I T F 2 3 5 7a n d t he 
treat me nt effect-s p ecific i nterce pt ( d efi ne d as t h e differe n ce b et wee n acti v e a n d place b o) will be 
esti mate d t o get h er wit h t he 2 -si de d 9 0 % CI. T h e esti mates f or t he ti me effect will be re p orte d 
wit h de grees of free d o m a n d S E.  
T he ge o metric mea n of t he i n di vi d ual C ma x  val ues f or s u bjects i n eac h of t h e acti ve d ose gr o u ps 
will be deter mi ne d. T he pre dicte d effect a n d its 2 -si de d 9 0 % CI f or Δ Δ Q Tc F at t his ge o metric 
mea n C ma x will be o btai ne d. If t he u p p er b o u n d of t he 2 -si de d 9 0 % CI (e q ui vale nt t o t he u p per 
b o u n d of t he 1 -si de d 9 5 % CI) of t he pre dicte d Q Tc effect ( ∆∆Q Tc F) is bel o w 1 0 msec at 
cli nicall y rele va nt plas m a le vels, it will be c o ncl u de d t hat I T F 2 3 5 7, d o es n ot ca use cli nicall y 
rele va nt Q T c i nter val pr ol o n gati o n wit hi n t he o bser ve d plas ma c o n ce ntr ati o n ra n ges. 
T o e val uate t he a de q u ac y of m o del fit wit h res pect t o t he ass u m pti o n of li nearit y, t he o bs er ve d 
Δ Q Tc F val ues a dj uste d b y p o p ulati o n ti me effect esti mate d fr o m t he  m o del will be use d. T hese 
i n di vi d ual place b o-a dj ust e d Δ Q Tc Fi, k ( Δ Δ Q Tc Fi, k) val ues e q u al t he o bser ve d i n di vi d ual 
Δ Q Tc Fi, k f or s u bject a d mi nistere d wit h I T F 2 3 5 7 or place b o at ti me p oi nt k mi n us t he esti mate d 
p o p ulati o n mea n place b o effect at ti me p oi nt k (i .e., ti me effect). A q ua ntile pl ot, i.e. pl ot of t he 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 0  of 6 7  
A me n d me nt I  
q ua ntiles ( deciles) of o bs er ve d I T F 2 3 5 7 c o nce ntr ati o ns a n d t he mea n place b o -a dj uste d Δ Q T c F 
( Δ Δ Q T c F) a n d 9 0 % CI at t he me dia n c o nce ntrati o n wit hi n eac h decile will be gi v e n. T he 
re gressi o n li ne prese nti n g t he m o del-pre dict e d Δ Δ Q Tc F (as d escri be d b y T or n øe et al ., 2 0 1 1) 
will be a d de d t o e val u ate t he fit of a li near m o d el a n d vis ualize t he c o nce ntrati o n -res p o ns e 
relati o ns hi p.1 2F or e val uati o n of t he H R -c orrecte d Q T i nter val, a scatter pl ot a n d q ua ntile pl ot of 
Q Tc F a n d R R i nter vals b y treat me nt wit h re gressi o n li ne a n d a li near mi x e d -effects li ne ( 9 0 % 
CI), res pecti vel y, als o will be gi ve n. 
 
 
 
C CI
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
C o nfi de ntial  
P a ge 6 1  of 6 7  
A me n d me nt I  
B y -ti me poi nt a nal ysis (s ec o n dar y a nal ysis) :  
T he a nal ysis f or Q Tc F  will be base d o n a li near mi x e d -effects m o del wit h Δ Q Tc F as t he 
de pe n de nt varia ble, peri o d, se q ue nce, ti me ( i.e., n o mi nal  p ost -d ose ti me p oi nt), treat me nt 
(t hera p e utic a n d s u pr at hera pe utic d oses of I T F 2 3 5 7, m o xifl o x aci n, a n d place b o), a n d ti me-b y -
treat me nt i nteracti o n as fi x e d effects, a n d bas eli ne Q Tc F as a c o v ariate. A n u nstr uct ure d 
c o varia n ce matri x will be s pecifie d f or t he re p eate d meas ures at p ost -d os e ti me p oi nts f or s u bject 
wit hi n treat me nt peri o d. If t he m o del wit h u nstr uct ure d c o varia nce matri x  fails t o c o n ver ge, ot her 
c o varia n ce matri x s uc h as c o m p o u n d s y m metr y a n d a ut ore gressi ve will be c o nsi dere d. T h e 
m o del will als o i ncl u de a s u bject -s pecifi c ra n d o m effect. If t he fi x e d effects f or peri o d a n d/ or 
se q ue nce s h o ul d pr o ve t o be n o n-si g nifica nt (that is, if t he p -val ue > 0. 1), t h ese effects ma y b e 
re m o ve d fr o m t he m o d el a n d t he a nal ysis will be re peate d wit h o ut t h ose c o variates. Fr o m t his 
a nal ysis, t he L S me a n, S E, a n d 2 -si de d 9 0 % CI will be calc ulate d f or t he c o ntrast “I T F 2 3 5 7 
vers us place b o” f or eac h d ose of I T F 2 3 5 7 at eac h p ost -d ose ti me p oi nt, se paratel y.  
F or H R, P R, a n d Q R S i nter vals, t he a n al ysis will b e base d o n t he c ha n ge -fr o m-baseli ne p ost -
d osi n g val ues ( Δ H R, Δ P R, a n d Δ Q R S). T he sa me ( b y -ti me p oi nt a nal ysis) m o del will be use d as 
descri be d f or Q Tc F. T h e L S mea n, S E, a n d 2-si de d 9 0 % CI fr o m t he statistical m o deli n g f or 
b ot h c ha n ge fr o m -baseli n e a n d place b o -c orrecte d c ha n ge -fr o m-b aseli ne val ues will be liste d i n 
t he ta bles a n d gra p hicall y dis pla ye d. 
Cate g orical a n al ysis :  
T he a nal ysis res ults f or cate g orical o utliers will be base d o n treat me nt e mer ge nt e ve nts (i.e., ne w 
fi n di n gs c o m pare d t o bas eli ne); T-wa v e m or p h ol o g y a n d prese n ce of U -wa ves will be 
s u m marize d i n fre q ue nc y ta bles wit h c o u nts perce nta ges f or b ot h n u m ber of s u bjects a n d n u m ber 
of ti me p oi nts. F or cate g orical o utliers, t he n u m ber ( perce nta ge) of s u bjects as well as ti me p oi nts 
w h o ha d i ncreases i n a bs ol ute treat me nt e mer ge nt Q Tc F v al ues > 4 5 0 a n d ≤4 8 0 msec, > 4 8 0 a n d 
≤5 0 0 msec, or > 5 0 0 msec, a n d c h a n ges fr o m pre -d ose baseli ne of > 3 0 a n d ≤ 6 0 msec, or > 6 0 
msec; i ncrease i n P R fr o m pre -d ose bas eli ne > 2 5 % t o a P R > 2 1 0 msec; i ncrease  i n Q R S fr o m 
pre -d ose b aseli ne > 2 5 % t o a Q R S > 1 2 0 msec; decrease i n H R fr o m pre -d ose baseli ne > 2 5 % t o a 
H R < 5 0 b p m; a n d i ncrease i n H R fr o m  pre -d os e b aseli ne > 2 5 % t o a H R > 1 0 0 b p m will be 
deter mi ne d. F or T -w a ve m or p h ol o g y a n d U -wa v e prese nce, treat me nt -e mer ge nt c ha n ges will be 
assesse d, i.e., c h a n ges n ot prese nt at baseli ne. F or eac h cate g or y of T -wa ve m or p h ol o g y a n d of 
U -wa v es, t he cat e g or y will be dee me d as prese nt if o bser ve d i n a n y re plicat es at t he ti me p oi nt . 
1 2. 4. 2  P h ar m a c o ki netic Assess me nt  
I n di vi d ual a n d m ea n plas ma c o nce ntr ati o n vers us ti me c ur ves will be pres e nte d f or b ot h li near 
a n d se mi -l o g s cales. Des cri pti ve statistics (arit h metic a n d ge o metri c mea ns, S D, C V % , Mi n, 
M a x , a n d me dia n) of t he plas ma c o nce ntrati o ns vers us ti me will be prese nte d as well f or t he 
p har mac o ki netic p ara m eters.  N o i nfere ntial statistical a nal ysis of dat a is pla n ne d.  
C CI
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 2  of 6 7  
A me n d me nt I  
1 2. 4. 3  S afet y A ssess me nts 
T E A Es will be ta b ulate d b y tre at me nt f or all s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g 
(safet y p o p ulati o n). C ha n ges fr o m baseli ne v al ues i n vital si g ns, E C G, a n d cli nical la b orat or y 
para meters will be e val u ate d a n d ta b ulate d b y st u d y treat me nt. Safet y a n d t olera bilit y data will 
be re p ort e d usi n g d escri pti ve statistics. De m o gra p hic para met ers will be s u m marize d  
descri pti vel y. N o i nfere ntial statistical a nal ysis of data is pla n ne d.  
1 2. 4. 4  A d vers e E ve nts of S peci al I nterest  
T he rates of t hese A E SI  s h o ul d be c o m pare d i n t he treat me nt a n d c o ntr ol peri o d. S u b gr o u p 
a nal ys es s h o ul d be c o n d u cte d i n ter ms of a ge, ge n der, pre -e x isti n g car di ac disease, electr ol yt e 
dist ur ba nces a n d c o nc o mita nt me dicati o ns.  
1 3.  Re g ul at or y C o nsi der ati o ns a n d Q u alit y Ass ur a nce  
1 3. 1  I n de pe n de nt Et hics C o m mittee A p pr o v al of Pr ot oc ol a n d Ot her St u d y D oc u me nts  
T he Q ualifie d I n v esti gat or a grees t o pr o vi de t he I E C wit h all a p pr o priate d oc u me nts, i ncl u di n g a 
c o p y of t he pr ot oc ol/a m e n d me nts, I C Fs, a d vertisi n g te xt (if a n y), I n v esti gat or’s Br oc h ure (if a n y) 
a n d a n y ot her writte n i nf or mati o n pr o vi de d t o st u d y s u bjects. T h e trial will n ot be gi n u ntil t he 
I E C f a v o ura bl e writte n a p pr o vals f or t he a b o ve-m e nti o ne d st u d y d oc u m e nts  ha ve bee n o btai ne d . 
A writte n i nf or me d c o ns e nt i n c o m plia nce wit h I C H G ui deli ne f or G C P E 6 ( R 2) a n d U S Title 2 1 
C o de of Fe d eral Re g ul ati o ns ( C F R) Part 5 0 s hall b e o btai ne d fr o m eac h s u bject bef ore e nt eri n g 
t he st u d y or perf or mi n g a n y u n us ual or n o n-r o uti n e pr oce d ure t hat i n v ol ves ris k t o t he s u bject. 
T he ori gi nal si g n e d a n d d ate d I C F will be k e pt i n the cli nical bi n der  at S y ne os  Healt h a n d a c o p y 
will be gi ve n t o t he s u bject.   
I n t he e ve nt t hat t he pr ot oc ol is a me n de d, t he re vise d pr ot oc ol m ust be a p pr o ve d b y t he I E C pri or 
t o its i m ple me ntati o n, u nless t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects of t he 
trial, i n s uc h cases a n otificati o n will be se nt t o t he I E C for t heir i nf or m ati o n, b ut n o a p pr o val is 
e x pecte d. If a re vise d I C F is i ntr o d uce d d uri n g t h e st u d y, eac h s u bject’s f urt her c o nse nt m ust be 
o btai ne d. T he ne w v ersi o n of t he I C F m ust be a p pr o ve d b y t he I E C, pri or t o s u bse q ue ntl y 
o btai ni n g eac h s u bject’s c o ns e nt. 
T he Q ualifie d I n v esti gat or a n d t he S p o ns or’s re prese ntati ve m ust si g n t he pr ot oc ol a n d its 
a me n d me nts (if a n y) bef ore i nitiati n g t he st u d y.  
It is t he S p o ns or’s r es p o nsi bilit y t o s u b mit t he pr ot oc ol a n d its a me n d me nts (if a n y), a n d t h e 
I C Fs t o re g ulat or y a ut h orities w he n necess ar y.  
U p o n c o m pleti o n of t he st u d y, t he Q u alifie d In vesti gat or, w here a p plica bl e, s h o ul d i nf or m t he 
i nstit uti o n; t he Q ualifie d I n v esti gat or/i nstit uti o n s h o ul d pr o vi de t he I R B/I E C wit h a s u m mar y of 
t he st u d y’s o utc o me a n d t he S p o ns or a n d re g ulat or y a ut h orit y(i es) wit h a n y re p orts re q uir e d . 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 3  of 6 7  
A me n d me nt I  
1 3. 2  C o m pli a nce  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, G C P ,  a n d all a p plica ble 
re g ulati o ns, i ncl u di n g t he Fe deral F o o d, Dr u g a n d C os metic Act, U. S. a p plica ble C o de of 
Fe deral Re g ulati o ns (title 2 1), a n d a n y I E C re q uire me nts relati ve t o cli nical st u dies. T he st u d y 
will als o be c o n d ucte d i n c o m plia nce wit h t he rec o m me n dati o ns lai d d o w n i n t he m ost rece nt 
versi o n of t he Declarati o n of Helsi n ki, wit h t he e x ce pti o n t hat re gistrati o n of s uc h P hase 1 trials 
i n a p u blicl y accessi ble d ata base is n ot ma n dat or y. As re q uire d b y t h e Ca na dia n re g ulat or y 
a ge nc y, a Cli nical Tria l A p plicati o n ( C T A) will be s u b mitte d bef ore t he be gi n ni n g of t he st u d y 
a n d a N o O bje cti o n Letter ( N O L) m ust be recei ve d pri or t o d osi n g.   
1 3. 3  Pr ot oc ol D e vi ati o ns  
T he I n vesti gat or or d esi g nee m ust d oc u me nt a n d e x plai n i n t he s u bject’s s o urce d oc u m e ntati o n 
a n y d e viati o n fr o m t he a p pr o ve d pr ot oc ol. T he I n vesti gat or m a y i m ple me nt a de viati o n fr o m, or 
a c ha n ge of, t he pr ot o c ol t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects wit h o ut pri or 
I R B/I E C a p pr o v al. As s o o n as p ossi ble after s uc h a n occ urre n ce, t he i m ple mente d de viati o n or 
c ha n ge, t he reas o ns f or it, a n d a n y pr o p ose d pr ot o c ol a me n d me nts s h o ul d be s u b mitte d t o t he 
I R B/I E C f or re vie w a n d a p pr o val, t o t he S p o ns or f or a gree me nt, a n d t o t he re g ulat or y 
a ut h orities, as a p plica ble.  
A si g nifica nt de viati o n fr o m t he pr ot oc ol is a n u ni nte n de d or u na ntici pat e d de part ure fr o m t he 
pr oce d ures or pr o cesses a p pr o ve d b y t he S p o ns or a n d t h e I R B/I E C a n d a gree d t o b y t he 
In v esti gat or. A si g nifica nt de viati o n occ urs w h e n t here is n o n -a d here nce t o t he pr ot oc ol b y t h e 
s u bject or i nvesti gat or t h at res ults i n a si g nifica nt, a d diti o nal ris k t o t he s u bject. Si g nifica nt 
de viati o ns ca n i ncl u de n o n -a d here nce t o i ncl usi o n or e x cl usi o n criteria, or n o n -a d here nce t o I C H 
G C P g ui deli nes or F D A/ C o m pete nt A ut h orities re g ulati o ns, a n d will lea d t o  t he s u bject bei n g 
wit h dra w n fr o m t he st u d y.  
Pr ot oc ol de viati o ns will be d oc u me nte d b y t he st u d y site staff, t he i n vesti gat or, a n d t he cli nical 
m o nit or t hr o u g h o ut t he c o urse of t he st u d y. Q ualifie d In v esti gat or will be n otifie d i n writi n g b y 
t he m o nit or of de viati o ns. T he I R B/I E C s h o ul d be n otifie d of all  pr ot oc ol de viati o ns i n a ti mel y 
ma n ner, as a p plica ble.  
1 3. 4  Fi n a nci al Discl os ure a n d O bli g ati o ns  
I n v esti gat ors are re q uir e d t o pr o vi de fi na ncial discl os ure i nf or mati o n t o all o w t he S p o ns or t o 
s u b mit t he c o m plete a n d acc urate certificati o n or discl os ure state me nts re q uire d u n der FD A 2 1 
C F R 5 4. I n a d diti o n, t he I n v esti gat or m ust pr o vi de t o t he S p o ns or a c o m mit me nt t o pr o m ptl y 
u p date t his i nf or mati o n if a n y rele v a nt c ha n ges occ ur d uri n g t he c o urse of t he i n vesti ga ti o n a n d 
f or 1 year f oll o wi n g t he c o m pleti o n of t he st u d y.  
T he S p o ns or is n ot fi na nciall y res p o nsi ble f or f urt her testi n g or treat me nt of a n y me dical 
c o n diti o n t hat ma y be d etecte d d uri n g t he s cree ni n g pr ocess. I n a d diti o n, i n t he a bse nce of 
s pecific arra n ge me nts, t he S p o ns or is n ot fi na nciall y res p o nsi ble f or f urt her treat me nt of t he 
s u bject’s disease 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 4  of 6 7  
A me n d me nt I  
1 3. 5  Q u alit y Ass ur a nce Pr o g r a m  
S y ne os H ealt h  has esta blis he d Q ualit y C o ntr ol ( Q C) a n d Q ualit y Ass ura n ce ( Q A) s yste ms wit h 
writte n S O Ps t o e ns ure t hat t he st u d y will be c o n d ucte d a n d  dat a will be ge nerate d, rec or de d, a n d 
re p orte d i n c o m plia n ce wit h t he pr ot oc ol, G C P, a n d a p plica ble re g ulat or y re q uire me nts. A 
ri g or o us Q C pr o gra m is a p plie d t o e ns ure acc urac y of all data a n d re p orts. Q A o versees a 
c o m ple me ntar y r is k-b ase d pr o gra m of a u dits t o ass ure c o m plia nce wit h a p plica ble re g ulati o ns 
a n d S y ne os Healt h 's pr escri pti ve d oc u me ntati o n. 
1 3. 6  I n vesti g at or D oc u me nt ati o n 
Pri or t o be gi n ni n g t he st u d y, t he Q ualifie d I n vesti gat or will be as ke d t o c o m pl y wit h I C H G C P 
E 6  ( R 2) 8. 2 b y pr o vi di n g t he f oll o wi n g ess e ntial d oc u me nts, i ncl u di n g b ut n ot li mite d t o: 
 I R B/I E C a p pr o v al 
 U S F D A 1 5 7 2 F or m  
 Pr ot oc ol si g nat ure p a ge a n d I n v esti gat or Br oc h ure o ri gi nall y si g ne d b y t he Q ualifie d 
In v esti gat or   
 C urric ul u m vitae f or t he In v esti gat or s partici pati n g  i n t he st u d y 
 Fi na ncial discl os ur e i nf or mati o n t o all o w t he S p o ns or or desi g nee t o s u b mit c o m plete 
a n d acc urate certificati o n or discl os ure state me nts re q uire d u n d er I C H G C P E 6 (R 2). I n 
a d diti o n, t he In v esti gat ors m ust pr o vi de t o t he S p o ns or a c o m mit me nt t o pr o m ptl y 
u p date t his i nf or mati o n if a n y rele va nt c ha n ges occ ur d uri n g t he c o urse of t he 
i n vesti gati o n a n d f or 1 year aft er t he c o m pleti o n of t he st u d y.  
 I R B/I E C-a p pr o ve d i nf or me d c o nse nt, sa m ples of site a d vertise me nts f or recr uit me nt f or  
t his st u d y, a n d a n y ot her writte n i nf or mati o n re gar di n g t his st u d y t hat is t o be pr o vi de d 
t o t he s u bject or le gal g u ar dia n 
 La b orat or y certificati o ns a n d n or mal ra n ges f or a n y l ocal la b orat ories us e d b y t he site, i n 
acc or da nce wit h G C P  
1 3. 7  A u dits, I ns pecti o ns a n d M o nit ori n g  
I n acc or da n ce wit h t he pri nci ples of G C P a n d G L P, t he st u d y ma y be i ns p ecte d b y re g ulat or y 
a ut h orities, t he S p o ns or a n d S y ne os H ealt h, i n s uc h case, t he Q ualifie d I n v esti gat or  or desi g nee  
will pr o vi de direct a ccess t o a ll st u d y rec or ds. M ore o ver, t he  S p o ns or is e ntitle d t o access  
i nf or mati o n a b o ut t he stat us of t he st u d y  a n d t o r e vie w t he ori gi nal  d oc u me nts of t he st u d y  a n d t o 
c o n d uct st u d y relate d m o nit ori n g acti vities . 
I n t he e ve nt of a n a u dit/I ns pecti o n, t he Q ualifie d I n vesti gat or a gre es t o all o w t he S p o ns or, 
re pres e ntati ves of t he S p o ns or, or a re g ulat or y a ge nc y (e. g., F D A or ot h er re g ulat or y a ge nc y) 
access t o all st u d y rec or ds. T he Q ualifie d I n v esti gat or  or desi g nee  s h o ul d pr o m ptl y n otif y t he 
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 5  of 6 7  
A me n d me nt I  
S p o ns or of a n y i ns pecti o n sc he d ule d b y a n y re g ul at or y a ut h orities a n d pr o m ptl y f or war d c o pies 
of a n y i ns pecti o n re p orts recei v e d t o t he S p o ns or. 
T he st u d y will be m o nit ore d  b y S p o ns or’ s dele gat es acc or di n g t o G C P g ui deli nes. T he cli nical 
m o nit or, as a re prese ntati ve of t he S p o ns or, has t h e o bli gat i o n t o f oll o w t he st u d y cl osel y. I n 
d oi n g s o, t he m o nit or will visit t he Q ualifie d I n v esti gat or a n d st u d y site at p eri o dic i nter vals, i n 
a d diti o n t o mai ntai ni n g necessar y tele p h o ne a n d letter c o ntact.  A site visit will be hel d pri or t o 
i nitiati o n of patie nt e nr ol me nt. T he pr ot oc ol, s o urce d oc u me nts, st u d y dr u g s u p plies a n d rele va nt 
pr oce d ures will be e x plai ne d t o t he Q ualifie d I n v esti gat or’s a n d his/ her staff i n detail at t he site 
visit. D uri n g t he st u d y, t he st u d y m o nit or will visit t he site r e g ularl y t o c hec k, t he c o m plete ness 
of patie nt rec or ds, t he a d here nce t o t he pr ot oc ol a n d t o G C P, t he pr o gress of e nr ol me nt, a n d als o 
t o e ns ure t hat st u d y m e dicati o n is bei n g st or e d, dis pe nse d a n d acc o u nte d f or acc or di n g t o 
s pecificati o ns. T he Q ualifie d In vesti gat or a n d ke y trial pers o n nel m ust be a vaila ble t o assist t he 
m o nit or d uri n g t hese visits.  
T he I n vesti gat or m ust gi ve t he m o nit or access t o rele va nt h os pital or cli nical rec or ds, t o c o nfir m 
a d here n ce t o t he pr ot oc ol . N o i nf or mati o n i n t hese rec or ds a b o ut t he i de ntit y of t he p atie nts will 
lea ve t he st u d y ce ntre. M o nit ori n g sta n dar d pr oce d ures re q uir e f ull verifi cati o n f or t he prese n ce 
of i nf or me d c o ns e nt, a d h ere nce t o t he i ncl usi o n/e x cl usi o n criteria, d oc u me ntati o n of S A Es a n d 
t he rec or di n g of pri mar y effic ac y a n d s afet y v aria bles.  T he I n vesti gat or is r es p o nsi ble f or 
c o m pleti n g t he s o ur ce d o c u me nts e x pe diti o usl y t o ca pt ure all t he rele va nt i nf or mati o n, w hile t he 
m o nit or is res p o nsi ble f or re vie wi n g t he m a n d clarif yi n g a n y data  q u eries  
All as pects of t he st u d y wi ll be caref ull y m o nit or e d, b y t h e S p o ns or or its desi g nee, f or 
c o m plia nce wit h a p plica ble g o v er n me nt r e g ulati o n wit h res pect t o c urre nt G C P a n d c urre nt 
sta n dar d o perati n g pr oce d ures. 
1 4.  C o nfi de nti alit y a n d Rete nti o n of St u d y Rec or ds  
T his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat is c o nfi de ntial a n d ma y 
n ot be discl ose d t o t hir d parties. Pers o ns t o w h o m t his st u d y pr ot oc ol is discl ose d m ust be 
i nf or me d t hat all t he i nf or mati o n herei n is c o nfi d e ntial a n d ma y n ot b e f urt her di v ul ge d. T hese 
restricti o ns will a p pl y as well t o all f ut ure c o m m u nicati o ns if dee me d pri vile ge d or c o nfi de ntial. 
P u blicati o n of t he st u d y res ults ma y o nl y be all o we d wit h writte n per missi o n fr o m t he S p o ns or.  
All i nf or mati o n o n a s u bject o btai ne d d uri n g  t he c o n d uct of t he st u d y w ill be ke pt c o nfi de ntial. 
S u bjects will be i de ntifie d b y  an  a n o n y mize d  i de ntifier o n all sa m ples a n d st u d y rec or ds 
pr o vi de d t o  t he S p o ns or or desi g n ee . I n c o m plia nce wit h I C H G C P, t he S p o ns or’s a ut h orize d 
re pres e ntati ves, m o nit or(s), a u dit or(s), I EC, a n d re g ulat or y a ut h orit y(i es) will be gra nte d direct 
access t o t he s u bject’s ori gi nal trial -relate d rec or ds f or verifi cati o n of cli nical trial pr oce d ures 
a n d/ or data, 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 
ap plica ble la ws a n d re g ul ati o ns. C o nse nt  fr o m t he s u bject f or discl os ure of s uc h i nf or mati o n will 
be o btai ne d i n  writi n g i n t he I C F. I n a d diti o n, s h o ul d a s u bject re q uir e me dical care or 
h os pitaliz ati o n d uri n g t he c o urse of t he st u d y, t he cli nical site ma y c o ntact t he treati n g p h ysicia n 
wit h t he  s u bject’s c o nse nt, e x ce pt t hat c o nse nt ma y n ot be re q ueste d if t h ere is a n e mer ge nc y 
sit uati o n. If t he res ults of t he st u d y are p u blis he d, t he s u bject’s i de ntit y will re mai n c o nfi d e ntial.  
C CI

2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 6  of 6 7  
A me n d me nt I  
T he S p o ns or a n d t he I n v esti g at or s h all arc hi v e t he c o nte nt of t he cli nical trial master file f or at 
least 2 5 years after t h e e n d of t he cli nical st u d y, i n a wa y t hat e ns ures it is rea dil y a v aila ble a n d 
accessi ble, u p o n re q uest, t o t he c o m pete nt a ut h orities. H o we ver, t he me dical files  of s u bjects 
s hall be arc hi v e d i n acc or da nce wit h nati o nal la w. After t he arc hi vi n g peri o d, t he S p o ns or will be 
c o ntacte d t o deter mi ne w het her t he st u d y rec or ds will be f or war de d t o t he S p o ns or, destr o ye d or 
ke pt at t he cli nical site or a n ot her facilit y f o r a l o n ger peri o d of ti me at t he S p o ns or's e x pe nse. 
T he I n vesti gat or will n ot be all o we d t o p u blis h fi n di n gs fr o m t his st u d y wit h o ut pri or writte n 
c o nse nt of t he S p o ns or.  
 
 
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2 0 0 1 4 8  - I T F/ 2 3 5 7/ 5 4 - I N D:  
 - E u dra C T: 2 0 2 0 -0 0 3 1 0 5 -6 3  
Italfar mac o S. p. A. 
2 9 -S E P -2 0 2 0  
 
 
C o nfi de ntial  
P a ge 6 7  of 6 7  
A me n d me nt I  
1 5.  Refere nces  
1  
Gi vi n ostat ( I T F 23 5 7). I n vesti gat or  Br oc h ure. Italfar mac o  S. p. A. E diti o n N o. 2 1 . 0 
Versi o n Date d 2 9 M a y  2 0 2 0 . 
2  
A vel o x, Pr o d uct M o n o gra p h. Versi o n re vise d Fe br uar y  1 8, 2 0 2 0 . Dr u g Pr o d uct Data bas e, 
Healt h Ca na da. A vaila bl e o nli ne at: htt p:// w w w. hc -sc. gc. ca/ d h p-
m ps/ pr o d p har ma/ data bas d o n/i n de x _e. ht ml.  
3  
C he n X et al. Q T pr ol o n gati o n a n d pr oarr h yt h mia b y m o xifl o x aci n: c o nc or da nce of 
precli nical m o dels i n rel ati o n t o cli nical o utc o me. Br J P h ar m ac ol. 2 0 0 5  N o v; 1 4 6 ( 6): 
7 9 2 – 7 9 9.  
4  
I nter nati o nal C o nfere nce o n Har m o nisati o n, E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nterv al 
Pr ol o n gati o n a n d Pr oarr h yt h mic P ote ntial f or N o n -A ntiarr h yt h mic Dr u gs, i n Pr ocee di n gs 
of t he I nter n ati o nal C o nfere nce o n Har m o nisati o n: I C H T o pic Oct o ber 2 0 0 5. A vaila ble 
o nli ne at: 
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E 1 4 _ G ui deli ne. p df  
5  
C D E R –  C B E R G ui da nce f or I n d ustr y E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nter val 
Pr ol o n gati o n a n d Pr oarr h yt h mic P ote ntial f or N o n -A ntiarr h yt h mic Dr u gs , Oct o ber 2 0 0 5.  
6  
C D E R –  C B E R E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nter v al Pr ol o n gati o n a n d 
Pr oarr h yt h mic P ote ntial f or N o n -A ntiarr h yt h mic Dr u gs —  Q uesti o ns a n d A ns wers ( R 3) 
G ui da nce f or I n d ustr y, J u ne 2 0 1 7.  
7  
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p hase. Cli n P h ar m ac ol T her . 2 0 1 5 A pr; 9 7( 4): 3 2 6– 3 5. d oi: 1 0. 1 0 0 2/c pt. 6 0.  
8  
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9  
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1 0  
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1 4  
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Version dated: 21-OCT-2020 
 
Annex to Amended Protocol 200148 Dated 29-SEP-2020 – Clinical Facilities 
 
 
 
Clinical Laboratories 
The following Biomedical Laboratories will be used: 
CDL Laboratories 
5990 Chemin de la Côte-des-neiges 
Montréal (Québec), Canada, H3S 1Z5 
Tel.: 1-514-344-8022 
Syneos Health 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Syneos Health 
5160, boul. Décarie, suite 800 
Montréal (Québec), Canada, H3X 2H9 
Tel.: 1-514-485-7500 
If another biomedical laboratory is used, this will be documented and annexed to the 
protocol.