Conditions: Duchenne and Becker Muscular Dystrophy Polycytemia Vera
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: yes

Brief summary:
The study will evaluate the effect of a therapeutic dose and a supratherapeutic dose of ITF2357 on the QT/QTc interval.

Detailed description:

Arms:
arm 1: Participants will receive a single dose of ITF2357 100 mg administered as 10 milliliters (mL) of ITF2357 10 milligrams per milliliter (mg/mL) oral suspension and 20 mL of placebo matched to ITF2357 oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence. arm 2: Participants will receive a single dose of ITF2357 300 mg administered as 30 mL of ITF2357 10 mg/mL oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence. arm 3: Participants will receive a single dose of placebo matched to ITF2357 administered as 30 mL oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence. arm 4: Participants will receive a single dose of moxifloxacin 400 mg tablet under fasting conditions on Day 1 of respective period as per the assigned treatment sequence.

Interventions: intervention 1: ITF2357 10 mg/mL intervention 2: ITF2357 10 mg/mL intervention 3: Placebo intervention 4: Moxifloxacin Hydrochloride intervention 5: Placebo
Intervention descriptions: intervention 1: Dose: 100 mg (administered as 10 mL); Dosage form: suspension; Route of administration: oral intervention 2: Dose: 300 mg (administered as 30 mL); Dosage form: suspension; Route of administration: oral intervention 3: Dose: 20 mL; Dosage form: suspension; Route of administration: oral intervention 4: Dose: 400 mg; Dosage form: tablet; Route of administration: oral intervention 5: Dose: 30 mL; Dosage form: suspension; Route of administration: oral

Protocol document:
Prot_000.pdf: 
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C o nfi de ntial  
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I T A L F A R M A C O S. p. A. 
 
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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  
 
 
 
 
 
 
 
       2 0 1 2 6 Mila n, Ital y  
 
 
 
 
 
 
 
       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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Versi o n 
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Brief descri pti o n/s u m m ar y of c h a n ges  
D ate  
Fi nal   
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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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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 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)  
 
 
 
 
 
 
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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)  
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( 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
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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  
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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  
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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  
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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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S y ne os H ealt h  
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Q ué bec ( Q ué b ec), Ca n a d a, G 1 P 0 A 2  
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, 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  
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, B. S. 
 
 
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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  
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 - 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.  
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 - 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
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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:  
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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
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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 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.  
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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 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: 
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Ef ficac y/ E 1 4/
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  
Dar p o B., Be ns o n C., D ota C., et al 2 0 1 5. Res ults fr o m t he I Q -C S R C pr os pecti ve st u d y 
s u p p ort re place me nt of t he t h or o u g h Q T st u d y b y Q T assess me nt i n t he earl y cli nical 
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  
Fl oria n J. A., T or n øe C. W., Br u n da ge R. et al 2 0 1 1. P o p ulati o n p har mac o ki netic a n d 
c o nce ntr ati o n -Q Tc m o dels f or m o xifl o x aci n : p o ole d a nal ysis of 2 0 t h or o u g h Q T st u dies. 
J Cli n P h ar m ac ol , 5 1( 8): 1 1 5 2– 1 1 6 2, 2 0 1 1.  
9  
Dar p o B., 2 0 1 0. T he t h or o u g h Q T/ Q T c st u d y 4 years after t he i m ple me ntati o n of t he I C F 
E 1 4 g ui da n ce. Br J P h ar m ac ol . 2 0 1 0 J a n; 1 5 9( 1): 4 9– 5 7.  
1 0  
Fer ber, G., M. Z h o u a n d B. Da r p o. Detecti o n of Q Tc effects i n s mall st u dies--
i m plicati o ns f or re placi n g t he t h or o u g h Q T st u d y. A n n als of n o ni nv asive 
electr oc ar di ol o gy , 2 0 1 5; 2 0( 4): 3 6 8– 7 7.  
1 1  
Gar nett C, B o n ate P L, D a n g Q, Fer ber G, H ua n g D, Li u J, et al. Scie ntific w hite pa per o n 
c o nce nt rati o n-Q Tc m o deli n g. [ p u blis he d c orrecti o n a p pears i n J P h ar m ac o ki net 
P h ar m ac o dy n . 2 0 1 8; 4 5( 3): 3 9 9]. J P h ar m ac oki net P h ar m ac o dy n . 2 0 1 8; 4 5( 3): 3 8 3– 3 9 7.  
1 2  
T or n øe C W, Gar nett C E, Wa n g Y, Fl oria n J, Li M, G o b b ur u J V. Creati o n of a k n o wle d ge 
ma na ge me nt s yste m f or Q T a nal yses. J Cli n P h ar m ac ol . 2 0 1 1; 5 1( 7): 1 0 3 5– 1 0 4 2.  
1 3  
Cle vela n d W S. R o b ust l ocall y wei g hte d re gressi o n a n d s m o ot hi n g scatter pl ots. J A m St at 
Ass oc . 1 9 7 9; 7 4( 3 6 8): 8 2 9– 8 3 6.  
1 4  
H ur vic h C M, Si m o n off J S, a n d Tsai C L. S m o ot hi n g para meter selecti o n i n n o n para metri c 
re gressi o n usi n g a n i m pr o ve d A kai ke I nf or mati o n Criteri o n. J R St at S oc S eries B St at 
Met h o d ol . 1 9 9 8; 6 0( 2): 2 7 1– 2 9 3.  
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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. 
 

SAP_001.pdf: 
 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 1  of 4 4  
 
 
 
St atistic al A n al ysis Pl a n  
 
 
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 X I F L O X A CI N O N Q T/ Q Tc 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 . 
 
S p o ns or St u d y N o. 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  
S y ne os He alt h Cli ni q ue Inc. Pr oject N o.  2 0 0 1 4 8  
 
Fi nal Versi o n: 2 . 0 ( A me n d me nt I) 
Date: 1 1 -J U N-2 0 2 1  
 
C o ntract Researc h Or ga 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  
 
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 
 
Re gistere d office:  
Viale F ul vi o Testi, 3 3 0  
2 0 1 2 6 Mila n, Ital y.  
 
 
C O N FI D E N TI A L  
T his d oc u m e nt c o nt ai ns c o nfi d e nti al i nf or m ati o n of It alf ar m ac o S. p. A.  A ny vi e wi n g or discl os ur e of s uc h 
i nf or m ati o n t h at is n ot a ut h oriz e d i n writi n g by It alf ar m ac o S. p. A. is strictly pr o hi bit e d.  S uc h inf or m ati o n 
m ay b e us e d s ol ely f or t h e p ur p os e of r evi e wi n g or p erf or mi n g t his st u dy.  
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Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 3  of 4 4  
 
R E VI SI O N HI S T O R Y  
Versi o n  
D ate  
S u m m ar y of Re visi o ns  
Re vise d B y  
Fi nal 1. 0  
2 1 -S E P -2 0 2 0  
N A –  Ori gi nal versi o n  
 
A me n d me nt I  2 6 -A P R -2 0 2 1  
See bel o w f or a 
descri pti o n of c ha n ges  
 
 
C h a n ges i ncl u de d i n A me n d me nt I:  
T he c ha n ges fr o m S A P T e xt Fi nal 1. 0 are as b el o w:  
1.  A b bre viati o n f or C last, Clr, a n d Rma x  were a d de d t o t he List of A b bre viati o ns.  
2.  St u d y pr ot oc ol u p date d t o Pr ot oc ol A me n d me nt 1 i n Secti o n 1.  
3.  Secti o n 3. 3  Treat me nt D escri pti o n is re vise d a n d ela b orate d m ore f or better clarit y of 
treat me nt a d mi nistrati o n. 
4.  W H O D R U G t he m ost c urre nt versi o n will be use d t o classif y all pri or a n d c o nc o mita nt 
me dicati o n. T his c ha n ge will reflect i n secti o n 8. 5 . 
5.  Pr oce d ure of wei g ht ass es s me nt has bee n a d d e d i n secti o n 8. 6  as f oll o ws:  
T hree w ei g hts of t he t hree s yri n ges will be i ncl u de d i n C R F a n d S D T M ( 9 wei g hts t otal, 
f or e ver y d osi n g): 
- La bele d e m pt y s yri n ge wit h ti p ca p    
- S yri n ge fille d wit h 1 0 m L wit h ti p ca p    
- E m pt y s yri n ge wi t h ti p ca p p ost-d ose   
T he act ual n u m ber of ta blet ta ke n f or M o xifl o x aci n will als o be i ncl u de d i n C R F.  
Se parate listi n g f or eac h treat me nt will be pr o vi de d wit h t otal d ose a d mi nistere d.  
6.  N o P h ysical e x a mi nati o n listi n g a n d s u m mar y will be pr o vi de d. T his c h a n ge will reflect 
i n secti o n 9. 1 . Als o, i n t his secti o n clarificati o n has bee n a d de d re gar di n g h o w data o n 
b o d y me as ure me nts will be prese nt e d.  
7.  Secti o n 9. 2. 1 clarificati o ns a d de d re gar di n g A E SI rec or di n g a n d h o w t he d ata will be 
prese nte d.  
8.  Secti o n 9. 3 , [P T a n d P T T] has bee n a d de d  t o cl arif y c o a g ulati o n  para meters  as per 
pr ot oc ol.  
9.  Me d D R A
®   t he m ost c urre nt versi o n will be use d t o classif y all me dical hist or y a n d 
a d verse e ve nts. T his c ha n ge will reflect i n secti o n 8. 4  a n d 9. 2 . 
1 0.  Tri plicate E C G will be p erf or me d at scree ni n g. T he a vera ge d v al ue of t hr ee Q Tc will be 
i ncl u de d i n S T D M. T his c ha n ge will be reflecte d i n secti o n 9. 5.  Als o, i n t his secti o n 
clarificati o n has bee n a d de d re gar di n g h o w t he data of t he E C Gs will be prese nte d.   
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Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 4 of 44 
 
TABLE OF CONTENTS 
 
SIGNATURES ....................................................................................................................... 2 
REVISION HISTORY........................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................... 4 
LIST OF ABBREVIATIONS ................................................................................................ 6 
1. 
Introduction ................................................................................................................. 9 
2. 
Study Objectives ........................................................................................................ 10 
2.1 
Primary Objective .................................................................................................. 10 
2.2 
Secondary Objectives ............................................................................................ 10 
3. 
Study Design ............................................................................................................. 11 
3.1 
General Design ...................................................................................................... 11 
3.2 
Study Procedures ................................................................................................... 11 
3.3 
Treatment Description ........................................................................................... 11 
3.4 
Confinement and Washout .................................................................................... 12 
3.5 
Sample Size ........................................................................................................... 12 
3.6 
Randomization and Blinding ................................................................................. 12 
3.7 
Subject Withdrawal and Replacement ................................................................... 13 
4. 
Change From the Protocol ......................................................................................... 15 
5. 
Primary and Secondary Parameters ........................................................................... 16 
6. 
Analysis Populations ................................................................................................. 17 
6.1 
Safety Population ................................................................................................... 17 
6.2 
QT/QTc Population ............................................................................................... 17 
6.3 
Pharmacokinetic Population .................................................................................. 17 
6.4 
PK/QTc Population ................................................................................................ 18 
7. 
Interim Analyses ........................................................................................................ 19 
8. 
Study Population and Exposure ................................................................................ 20 
8.1 
Subject Disposition ................................................................................................ 20 
8.2 
Protocol Deviations ............................................................................................... 20 
8.3 
Demographics and Baseline Characteristics .......................................................... 20 
8.4 
Medical History ..................................................................................................... 20 
8.5 
Prior and Concomitant Medications ...................................................................... 20 
8.6 
Study Drug Administration ................................................................................... 21 
9. 
Safety Analyses ......................................................................................................... 22 
9.1 
Physical Examination Findings ............................................................................. 22 
9.2 
Adverse Events ...................................................................................................... 22 
9.2.1 
Adverse Events of Special Interest ................................................................ 24 
9.3 
Laboratory Parameters ........................................................................................... 24 


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 5  of 4 4  
 
9. 4  
V ital Si g ns ............................................................................................................. 2 5  
9. 5  
1 2 -Lea d Safet y E C G  .............................................................................................. 2 6  
1 0.  
Car di o d y n a mic E C G Ass ess me nt  ............................................................................. 2 7  
1 0. 1  E C G a n d P har mac o ki neti c Sa m ple C ollecti o n  ...................................................... 2 7  
1 0. 2  Statistical Met h o ds ................................................................................................. 2 7  
1 0. 2. 1  
Ge neral Met h o d ol o g y  .................................................................................... 2 7  
1 0. 2. 2  
Baseli ne  .......................................................................................................... 2 8  
1 0. 2. 3  
Q T C orrecti o n Met h o ds  ................................................................................. 2 8  
1 0. 3  A nal ysis  ................................................................................................................. 2 9  
1 0. 3. 1  
C o nce ntrati o n -Q Tc A nal ysis ( Pri mar y A nal ysis)  .......................................... 2 9  
 3 0  
 3 0  
1 0. 4  Assa y Se nsiti vit y  ................................................................................................... 3 1  
1 0. 5  B y -Ti me P oi nt A nal ysis  ........................................................................................ 3 1  
1 0. 6  Cate g orical A n al ysis  .............................................................................................. 3 2  
1 0. 7  Ter mi n ol o g y a n d Defi niti o ns: Place b o -c orrecte d Δ Q Tc F a n d Place b o -a dj uste d 
Δ Q Tc F ( Δ Δ Q Tc F)  ................................................................................................. 3 3  
1 0. 8  Sa m ple Siz e C o nsi derati o ns f or Assa y Se nsiti vit y  ................................................ 3 4  
1 1.  
P har mac o ki netic A n al ys es ......................................................................................... 3 5  
1 1. 1  Ha n dli n g of t he Bel o w t h e L o wer Li mit of Q u a ntitati o n ( B L Q) a n d t he N o 
Re p orta ble C o nce ntr ati o n Val ues  .......................................................................... 3 5  
1 1. 2  Ha n dli n g of t he Differe n ce Bet wee n t he Sc he d ule d a n d t he Act ual Sa m pli n g 
Ti mes  ..................................................................................................................... 3 5  
1 1. 3  P har mac o ki netic Para meters  .................................................................................. 3 5  
1 1. 3. 1  
Plas ma P har mac o ki netic Para meters  ............................................................. 3 5  
1 1. 3. 2  
Uri ne P har ma c o ki netic Para meters  ................................................................ 3 7  
1 1. 4  Statistical A nal yses  ................................................................................................ 3 7  
1 2.  
Perce nta ges a n d D eci mal Places  ............................................................................... 3 9  
1 3.  
Ha n dli n g of Missi n g Dat a  ......................................................................................... 4 0  
1 4.  
Data Ha n dli n g  ............................................................................................................ 4 1  
1 5.  
S oft ware t o be Us e d  .................................................................................................. 4 2  
1 6.  
A p pe n di x A: Earl y Precisi o n Q T A nal ysis  ............................................................... 4 3  
1 7.  
Refere n ce List  ............................................................................................................ 4 4  
 
 
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Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 6 of 44 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
Ae0-t 
Cumulative Urinary Excretion From Time Zero to Time t 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Ander the Curve 
AUC0-t 
Area under the concentration-time curve from time zero 
AUC0-12 
Area under the concentration-time curve from time zero to 12 hours 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
(extrapolated) 
BP 
Blood Pressure 
bpm 
Beats per minute 
CL/F 
Total body clearance, calculated as Dose/AUC0-inf 
CI 
Confidence Interval 
CL 
Renal Clearance 
Clast 
The last measurable concentration 
Clr 
Renal clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for AE 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EPQT 
Early Precision QT analysis technique (formerly High Precision QT) 
FDA 
Food and Drug Administration 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IC50 
Concentration at Which 50% Inhibition Observed 
INR 
International Normalized Ratio 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 7 of 44 
 
IV 
Intravenous 
Kel 
Elimination rate constant 
kg 
Kilogram 
L 
Liter 
LDL 
Low-density lipoprotein 
LLN 
Lower Limit of Normal 
LOESS 
Locally weighted scatter plot smoothing 
LS 
Least squares 
Max. 
Maximum 
MDMA 
3,4-methylenedioxymethamphetamine 
mg 
Milligram 
Min. 
Minimum 
min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
ms 
Millisecond 
OT 
Oral temperature 
OTC 
Over-the-Counter 
PCP 
Phencyclidine 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
PR Interval of the ECG 
PTT 
Partial Thromboplastin Time 
PT 
Prothrombin Time/Preferred Term 
Q-Q 
Quantile-quantile 
QRS 
QRS interval of the ECG 
QT 
QT Interval of the ECG 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
Rmax 
Maximum rate of urinary excretion 
RR 
RR interval of the ECG 
Rsq 
r-squared 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 8 of 44 
 
SD 
Standard Deviation 
SE 
Standard Error 
SOP 
Standard Operation Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TdP 
Torsade de Pointes 
T½ el 
Half-Life 
Tmax 
Time of Maximum Concentration 
TRmax 
Time of Maximal Urinary Excretion 
TQT 
Thorough QT 
ULN 
Upper Limit of Normal 
Vd/F 
Apparent volume of distribution, calculated as Dose/Kel x AUC0-inf 
WBC 
White Blood Cell 
∆ 
Change From baseline 
∆∆ 
Placebo-corrected or Placebo-adjusted Change From Baseline 
 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 9 of 44 
 
1. 
Introduction 
This analysis plan (SAP) is intended to give a detailed description of the summaries and the 
analyses that will be generated for the present study by Syneos Health or a designee. Analyses 
specified in this plan are based on Italfarmaco S.p.A., Study Protocol No. ITF/2357/54 
(Amendment I) dated 29 SEP, 2020 (Syneos Project No. 200148). Cardiodynamic 
electrocardiogram (ECG), safety, tolerability, pharmacokinetic (PK) and pharmacodynamics 
(PD) analyses will all be described. 
This document defines the populations to be analyzed and provides full details of the statistical 
analyses, data displays, and algorithms to be used for data derivations to aid in the production of 
the statistical output and the statistical section of the cardiac safety report in regard to 
electrocardiogram (ECG) and concentration-QTc analyses. Relevant subject characteristics as 
well as the electrocardiographic parameters that will be evaluated are described along with the 
specific statistical methods. 
The plan may change due to unforeseen circumstances and any changes made after the plan has 
been finalized will be documented. If additional analyses are required to supplement the planned 
analyses described in the SAP, the changes and justification for the changes will be outlined in a 
SAP amendment and in the clinical study report (CSR). No change will be made without prior 
approval of the study sponsor. No revision to the SAP is required for changes that do not affect 
the statistical analysis methods, definitions, or rules defined in this document.  
When applicable, all methodology and related processes will be conducted according to Syneos' 
standard operating procedures (SOPs) as appropriate. Protocol deviations occurring during the 
study will be listed. 
Shells for all statistical tables, figures and listings referred to in this SAP will be displayed in a 
separate document. 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 10 of 44 
 
2. 
Study Objectives 
2.1 
Primary Objective  
 To evaluate the effect of a therapeutic dose and a supratherapeutic dose of ITF2357 on 
the QT/QTc interval. 
The evaluation will be done on the QTc interval corrected for heart rate (HR) using the 
Fridericia method (QTcF). 
2.2 
Secondary Objectives  
 To evaluate the effect of a single oral therapeutic (T) and a supratherapeutic dose (ST) of 
ITF2537 on other ECG parameters: heart rate (HR), PR interval, QRS intervals and T-
wave morphology. 
 To evaluate the pharmacokinetic (PK) parameters of two doses (100 mg and 300 mg) of 
ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563 and ITF2955 
glucuronide.  
 To evaluate the safety and tolerability of two doses (100 mg and 300 mg) of ITF2357. 
 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 11 of 44 
 
3. 
Study Design 
3.1 
General Design 
This will be a single centre, randomized, partially double-blind, single dose, placebo-corrected, 
12-sequence, 4-period, crossover study under fasting conditions.  
3.2 
Study Procedures 
The study will comprise of a Screening visit, Day -1 (check-in), study Day 1 through to Day 4, 
Study Exit /Early Termination, and a Follow-up call (Day 12 ± 2 days). Each of the 4 periods 
will be separated by a washout of 7 days or more. The duration of subject participation, including 
screening period, for each subject should last approximately 8 weeks. 
The overall schedule of procedures and assessments is provided in the protocol. 
3.3 
Treatment Description 
Treatment T – Therapeutic dose of ITF2357 100 mg (ITF2357 10 mg/mL oral suspension –  
 
140 mL/bottle and Placebo oral suspension – 140 mL/bottle). 
Treatment T will be administered as 1 x 10 mL of the ITF2357 10 mg/mL oral suspension and 2 
x 10 mL of the matching placebo oral suspension (30 mL in total, for a total ITF2357 dose of 
100 mg), it will be withdrawn with suitable 10 mL oral syringes provided with the study 
medications. Three separate syringes will be prepared, 1 with 10 mL of ITF2357 10 mg/mL oral 
suspension and 2 with 10 mL of matching placebo oral suspension each. The preparation of the 
syringes will be done and documented at the site pharmacy. The syringes will be packaged in a 
plastic bag and given to the blinded personnel at the clinical site for their administration to the 
patients. For administration purposes, the contents of each of the 3 syringes will be transferred to 
the same glass. The administration will be done under fasting conditions.  
Treatment ST – Supratherapeutic dose of ITF2357 300 mg (ITF2357 10 mg/mL oral suspension 
– 140 mL/bottle). 
Treatment ST will be administered as 3 x 10 mL of ITF2357 10 mg/mL oral suspension (30 mL 
in total, for a total ITF2357 dose of 300 mg), it will be withdrawn with suitable 10 mL oral 
syringes provided with the study medications. Three separate syringes will be prepared, 3 with 
10 mL of ITF2357 oral suspension each. The preparation of the syringes will be done and 
documented at the site pharmacy. The syringes will be packaged in a plastic bag and given to the 
blinded personnel at the clinical site for their administration to the patients. For administration 
purposes, the contents of each of the 3 syringes will be transferred to the same glass. The 
administration will be done under fasting conditions.  
Treatment P – Placebo (Placebo oral suspension – 140 mL/bottle). 
Treatment P will be administered as 3 x 10 mL of the matching placebo oral suspension (30 mL 
in total), it will be withdrawn with suitable 10 mL oral syringes provided with the study 
medications. Three separate syringes will be prepared, 3 with 10 mL of matching placebo oral 


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 1 2  of 4 4  
 
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, t he 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.  T he a d mi nistrati o n will be d o n e 
u n der fasti n g c o n diti o ns.  
F or Treat me nts T, S T, a n d P, t he st u d y me dicati o n will be pre pare d wit h i n 1 h o ur of d osi n g. 
A d diti o nall y, s u bjects will dri n k all s us pe nsi o n i m me diatel y ( wit hi n 2 mi n utes) after t he c o nte nts 
of t he 3 s yri n ges is tra nsf erre d t o t he s a me glass. 
Tre at me nt M –  M o xifl o x aci n ( P ositi ve 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).  
Treat me nt M will be a d mi nistere d o n a n o pe n la bel basis, as 1 x 4 0 0 m g ta blet u n der fasti n g 
c o n diti o ns  wit h 2 4 0 m L of water .  
3. 4  
C o nfi ne me nt 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.  
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 
peri o d s h o ul d last a p pr o xi matel y 8 w ee ks . 
3. 5  
S a m ple Size  
It is pla n ne d t o e nr ol u p t o 3 4 s u bjects t o e ns ure 2 8 s u bjects wit h e val ua ble data.  
3. 6  
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  se q ue nces, d escri b e d i n Ta ble 1  b el o w:  
 
 
C CI


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 13 of 44 
 
Table 1 Study Treatment Sequence 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
1 
T 
ST 
P 
M 
2 
ST 
M 
T 
P 
3 
P 
T 
M 
ST 
4 
M 
P 
ST 
T 
5 
ST 
P 
T 
M 
6 
P 
M 
ST 
T 
7 
T 
ST 
M 
P 
8 
M 
T 
P 
ST 
9 
P 
T 
ST 
M 
10 
T 
M 
P 
ST 
11 
ST 
P 
M 
T 
12 
M 
ST 
T 
P 
ITF2357 (therapeutic [T] and supratherapeutic [ST] dose, and placebo [P]) will be administered 
in a double-blinded fashion.  
Treatments T, ST, and P will be prepared individually by the unblinded team at the site 
pharmacy, and will leave the pharmacy blinded, so that the blinded site team could administer 
them to the subjects.  
On the contrary, no blinding will be needed with Treatment M.  
The ECG Central Core Laboratory ECG Analyst, will be blinded to treatment, study period, time 
point of ECG recording, and subject details such as laboratory results and AEs. 
3.7 
Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or a Sub-investigator may withdraw any 
subject from the study for one of the reasons described below; subject withdrawal will be done in 
accordance with the clinical site’s SOP: 
 safety reason; 
 non-compliance with protocol requirements; 
 significant protocol deviation; 
 positive alcohol breath test, cotinine test, drug screen, or pregnancy test; 
 vomiting within 4 hours after dosing; 
 marked prolongation of the QT/QTc interval (increases in QT/QTc to >500 ms or 
of  >60 ms over baseline); 
 unblinding of subjects treatment. 


 
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Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
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Hematology, biochemistry, coagulation (prothrombin time [PT] and partial thromboplastin time 
[PTT]), and urinalysis results will be reviewed by the Investigator or Sub-investigator prior to 
dosing; subjects will be withdrawn from the study if it is deemed that the subject’s safety may be 
at risk on the basis of these test results. 
Subjects excluded from dosing in one period as per criteria listed above, may be invited to 
participate in subsequent periods of the study if deemed appropriate by the Investigator and 
appropriate from a statistical standpoint (i.e. would permit adequate statistical comparison). 
However, subjects with positive alcohol, cotinine, drug screen, or pregnancy test and subjects 
withdrawn due to unblinding of the study treatment, will be definitively withdrawn from the 
study.  
Subjects who withdraw or are withdrawn from the study after dosing will not be replaced. 
However, in the event that the number of drop-outs exceeds initial expectations, subjects who 
withdraw or are withdrawn might be replaced at the discretion of the Sponsor. Such replacement 
resulting in dosing more subjects than planned in this protocol would be documented in a 
protocol amendment. 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or Sub-investigator agrees that the subject is fine and can be discharged. As soon as 
subject withdrawal is confirmed, blood sampling will be stopped. A PK blood draw may be 
collected at the time of withdrawal if deemed required by the Investigator. Study exit 
procedures/early termination visit will be performed at the time of withdrawal from the study or 
as soon as possible thereafter.  


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
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4. 
Change From the Protocol 
No changes in planned analyses were done compared to the protocol. 


 
Statistical Analysis Plan 
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Project No. 200148 (Sponsor Study number ITF/2357/54) 
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5. 
Primary and Secondary Parameters 
The primary and secondary parameters for the study are summarized as: 
Primary parameters:  
 The primary parameter for the cardiodynamic ECG assessment is the placebo-corrected 
change from-baseline QTcF (ΔQTcF). 
Secondary parameters:  
 Change-from-baseline QTcF, PR, QRS, and heart rate (HR) (ΔQTcF, ΔPR, ΔQRS, and 
ΔHR); 
 Placebo-corrected ΔPR, ΔQRS and ΔHR (ΔΔPR, ΔΔQRS, and ΔΔHR); 
 Categorical outliers for QTcF, HR, PR, and QRS; 
 Frequency of treatment emergent changes of T-wave morphology and U-wave presence 
 
Plasma and urine PK parameters for ITF2357, ITF2374, ITF2375, ITF2440, ITF2563, 
ITF2955 glucuronide, and moxifloxacin: 
Parameters for plasma PK: AUC0-t, AUC0-12, AUC0-inf, Residual area, Cmax, Tmax, T½ el, 
and Kel, CL/F, and Vd/F; 
Parameters for urine PK: Ae0-t, Rmax, TRmax, and Clr. 
 
Parameters for Safety and tolerability include the assessment of adverse events (i.e., 
seriousness, severity, relationship to the study medication, outcome, duration, and 
management), vital signs, ECG, and clinical laboratory parameters. 


 
Statistical Analysis Plan 
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Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
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6. 
Analysis Populations 
Study populations will include: Safety population, QT/QTc population, Pharmacokinetic 
population, Pharmacokinetic concentration population and PK/QTc population.  
When determining data availability for the study populations, the following aspects are to be 
considered (but not to be limited to) : inclusion and exclusion criteria, acceptable times for visit 
dates and measurements, compliance with treatment, the nature and quality of the data, 
withdrawal and any protocol deviation. Any decision for excluding data from the final data set 
will be provided with a detailed explanation and will be properly recorded and dated with 
Sponsor’s approval. The final responsibility of deciding which subjects are to be included or 
excluded lies with the Investigator, and/or the Sponsor. 
The analysis of safety and tolerability parameters will be based on the safety population detailed 
in Section 6.1 below. The analysis of cardiodynamic ECG parameters will be based the QT/QTc 
population detailed in Section 6.2 below. The analysis of PK parameters will be based on the PK 
population detailed in Section 6.3 below. PT/QTc population will be detailed in Section 6.4 
below. 
6.1 
Safety Population 
The Safety Population will be defined as all subjects who receive at least 1 dose of study drug 
(therapeutic and supratherapeutic doses of ITF2357, moxifloxacin, or placebo). 
6.2 
QT/QTc Population 
The QT/QTc Population will be defined as all subjects in the Safety Population with 
measurements at baseline as well as on-treatment with at least one post-dose time point with a 
valid ΔQTcF value. The QT/QTc Population will be used for the by-time point and categorical 
analyses of the cardiodynamic ECG parameters. 
6.3 
Pharmacokinetic Population 
The PK population will de defined as all subjects completing at least 3 periods, including at least 
Treatments T, ST, and M and for whom the PK profile can be adequately characterized. The PK 
population will be used for calculation of PK parameters and statistical analyses. 
Any subject with pre-dose concentrations will be excluded from the PK and statistical analysis 
for the respective analyte for the concerned period if the pre-dose concentration is greater than 
5% of the Cmax value of that period for that subject. 
Data from subjects who experienced emesis during the sampling interval and who were not 
withdrawn may be evaluated after completion of the PK analysis.  
Data (concentrations and PK parameters) from subjects excluded due to a pre-dose concentration 
greater than 5% of their Cmax or from subjects withdrawn due to adverse events or vomiting 
episodes will be presented but excluded from descriptive statistics for the concerned period.  


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 18 of 44 
 
Any subject who experienced emesis within 2 times median Tmax of the current study will be 
excluded from the statistical analysis. 
Pharmacokinetic Concentration Population 
The PK concentration population will be defined as all subjects who receive a dose of ITF2357 
or moxifloxacin and provide at least one evaluable PK concentration for ITF2357 or 
moxifloxacin. 
6.4 
PK/QTc Population 
The PK/QTc Population will be defined as all subjects who are in both the QT/QTc and PK 
Concentration populations with at least one pair of post-dose PK and QTcF data from the same 
time point as well as subjects in the QT/QTc population who received placebo. The PK/QTc 
Population will be used for the concentration-QTc analysis. PK/QTc Population will be defined 
for ITF2357 and for moxifloxacin. 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
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7. 
Interim Analyses 
No formal interim analysis is planned. 
However, a preliminary analysis using PK data will be done after the bioanalytical phase is 
completed. The PK parameters will be calculated using nominal sampling times as actual 
sampling times will not be available for these preliminary analyses. Only descriptive statistics of 
PK parameters will be calculated and provided. 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
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8. 
Study Population and Exposure 
No inferential analysis will be done. Only observed data will be used. 
8.1 
Subject Disposition 
Subject disposition will be summarized by treatment and overall (frequency and the percentage 
of subjects). Subject completion and discontinuation information will be listed. In addition, 
subjects who were dismissed from a period or who did not complete a dosing period will also be 
presented in this listing, including absence/early discontinuation reason, date and time of 
discontinuation. 
8.2 
Protocol Deviations 
The protocol deviations will be summarized by the categorized deviations and listed by subject, 
for the safety population. 
8.3 
Demographics and Baseline Characteristics 
The descriptive statistics (mean, median, standard deviation [SD], minimum [Min], maximum 
[Max], and sample size) will be calculated for continuous variables (age, body weight, height 
and body mass index [BMI]) considering last results (scheduled or unscheduled) obtained at 
screening. Frequency counts and percentages will be tabulated for categorical variables (age 
group, sex, ethnicity, and race). Results will be presented summarized by treatment and overall 
for the safety population (overall) and for PK population. All demographic characteristics will be 
listed by subject. 
8.4 
Medical History 
Medical history at screening will be listed by subject and summarized by treatment group for the 
safety population. The Medical Dictionary for Regulatory Activities (MedDRA®)will be used to 
classify all medical history findings by System Organ Class (SOC) and Preferred Term (PT). The 
MedDRA dictionaries used on the study will be updated to the current versions every 6 months 
to coincide with the dictionary updates cycles. 
8.5 
Prior and Concomitant Medications 
The use of prior and/or concomitant medication will be monitored throughout the study and 
listed by subject for the safety population. The World Health Organization Drug Dictionary will 
be used to classify all medication reported as from screening through study exit/early 
termination. The most current version will be used throughout the trial.  
Prior and concomitant medications will be listed and the Anatomical Therapeutic Code (ATC) 
will be included.  


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 21 of 44 
 
8.6 
Study Drug Administration 
The study drug administration details (including sequence, period, treatment received, total dose 
administered, start and end date/time of administration) will be listed by subject and by treatment 
for the safety population.  
In order to calculate treatment compliance, three weights of the three syringes will be included in 
CRF and SDTM (9 weights total, for every dosing): 
- Labeled empty syringe with tip cap     
- Labeled syringe filled with 10 mL with tip cap    
- Labeled empty syringe with tip cap post-dose    
 
The actual number of tablets taken for Moifoxacin will also be included in CRF. Separate listing 
for each treatment will be provided with total dose administered and compliance calculation. 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 22 of 44 
 
9. 
Safety Analyses 
Safety data will be evaluated for the safety population through the assessment of AEs, AESIs, 
laboratory parameters (hematology, biochemistry, coagulation, and urinalysis), safety ECG, 
clinical signs and symptoms from physical examination, and vital signs assessments. Treatment-
Emergent Adverse Events (TEAEs), laboratory values, and vital signs, will be summarized by 
treatment and overall, changes from baseline values in vital signs, ECG and clinical laboratory 
parameters will be evaluated and tabulated. Safety and tolerability data will be reported using 
descriptive statistics, it will be listed or summarized but will not be subjected to inferential 
analysis. 
Schedule safety measurements will be repeated according to the clinical site SOPs or upon 
request from an Investigator or Sub-investigator. Any abnormal repeated measurement will be 
evaluated by an Investigator or sub- investigator and repeated if judged necessary. Results from 
repeated / unscheduled tests will not be included in the summary statistics unless the repeat was 
required (and documented as such) due to technical reasons or an invalid initial result. 
9.1 
Physical Examination Findings 
A complete physical examination will be performed at screening and at study exit. For Periods 1, 
2, and 3, a brief physical examination will be performed at check-in (Day -1), and approximately 
24 (Day 2), and 72 (Day 4) hours post dose. For Period 4, a brief physical examination will be 
performed at check-in (Day -1), and 24 hours post dose. 
The complete physical examination includes assessments of the following: head, eyes, ears, nose, 
throat (HEENT), neck (including thyroid), chest, lungs, abdomen, back, lymph nodes, 
musculoskeletal, dermatological, cardiovascular/peripheral vascular, and general neurological 
examination. 
The brief physical examination includes assessments of the following: HEENT, chest, lungs, 
abdomen, dermatological, cardiovascular/peripheral vascular, and areas of note elicited from the 
subject.  
 
Body measurements including body height, body weight and BMI will be measured at screening. 
Body weight will be measured at check-in (Day -1) for each period. The data of body 
measurements for screening are included in the demographic data listing of the SAP, while for 
the other visits only weight is collected and this information is included in the CRF. 
Any abnormal findings judged to be clinically significant (CS) will be documented as medical 
history or as an AE, depending upon time of observation whether noted at screening, prior to 
dosing or after dosing, as appropriate. 
9.2 
Adverse Events 
AEs will be recorded and evaluated for their seriousness, severity, and relationship to the study 
medication. Adverse events will be collected and documented during the course of the study, 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 23 of 44 
 
from ICF signature until a period of 12±2 days following the last study drug administration, and 
they will be followed-up until complete resolution, or until the Investigator judges it to be safe to 
discontinue follow-up.  
Treatment-emergent AEs and non-TEAEs (those occurring prior to administration of study 
medication or that first occurred prior to study drug administration and did not worsen in 
frequency or severity) will be listed. TEAEs will be defined as AEs that occur on or after the 
date and time of study drug administration, or those that first occur pre-dose but worsen by 
increase in occurrence or severity after study drug administration.  
The incidence of TEAEs will be summarized using the safety population. The updated version of 
MedDRA® dictionary will be used to classify all AEs reported during the study by SOC and PT. 
Incidence of subjects who experienced TEAEs will be presented by treatment and overall, SOC, 
PT, by Investigator-assessed relationship and also by severity. Each subject may only contribute 
once to each of the incidence rates, for a TEAE following a given treatment, regardless of the 
number of occurrences; the highest severity or highest relationship will be presented, as 
appropriate. In each table, SOC will be presented in descending order of overall incidence rate in 
terms of frequency of subjects and then in frequency of events (alphabetical order will be used in 
case of equal rates). For each SOC, PT will be presented the same way.  
Incidence of TEAEs (number of events) will also be presented by treatment and overall, by SOC, 
and PT, by Investigator-assessed relationship and severity. 
Frequency of subjects experiencing Serious Treatment Emergent Adverse Events and Suspected 
Unexpected Serious Adverse Drug Reactions; and the number of events would be also 
summarized per treatment and overall. Also, these events and Serious Adverse Events will be 
listed per subject. 
The severity of AEs will be assessed and graded according to the most recently published 
National Cancer Institute Common Terminology Criteria for AE (CTCAE).  
The relationship of an AE or SAE to the study drug will be assessed according to the study 
protocol as: 
 Related to study drug;  
 Not related to study drug;  
 Unknown.  
 
The assessment of the relationship of an adverse event with the administration of study drug is a 
clinical decision based on all available information at the time of the completion of the CRF. 
 An assessment of “Related” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study drug.  
 An assessment of “Not related” would include the existence of a clear alternative 
explanation, or non-plausibility. 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 24 of 44 
 
 An assessment “Unknown” indicates there is not a reasonable suspicion that the AE is 
associated with the use of the study drug and at the same time there is not the existence of 
a clear alternative explanation or non-plausibility. In this case, Investigator has to collect 
all possible information in order to assess the relationship with the study drug, particularly 
in case of SAEs. 
9.2.1 Adverse Events of Special Interest 
Adverse events of special interest (AESIs) for this study will include the following: 
 Torsade de pointes; 
 Sudden death; 
 Ventricular tachycardia; 
 Ventricular fibrillation and flutter; 
 Post-dose syncope ; 
 Seizures. 
Which are to be classified as AESI in the CRF and will be recorded from ICF signature and 
throughout the study period until study completion. When these events are identified they should 
be examined closely for other risks factors, and evaluated. Also the need for evaluation by a 
cardiac specialist will be discussed by the Investigator and the Sponsor. 
Incidence of AESIs (number of events) will also be presented by treatment and overall for 
severity and relationship and by treatment and overall for age, gender, pre-existing cardiac 
disease, electrolyte disturbances and concomitant medications. 
9.3 
Laboratory Parameters 
Clinical laboratory (hematology, biochemistry, coagulation [PT and PTT], and urinalysis) results 
will be obtained at screening, before dosing of each period (at check-in or in the morning of Day 
-1), 24 (Day 2) and 72 (Day 4) hours post-dose, and at study exit. 
Hematology parameters include the following: complete blood count with differential, 
hemoglobin, and hematocrit.  
Biochemistry parameters include the following: cholesterol (total, low-density lipoprotein [LDL] 
and high-density lipoprotein [HDL]), triglycerides, albumin, alkaline phosphatase, aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], urea, cystatin C, calcium, chloride, 
glucose, phosphorus, potassium, creatinine, sodium, total bilirubin, and total protein. 
Coagulation parameters include the following: PT and PTT. 
Urinalysis parameters include the following: macroscopic examination, pH, specific gravity, 
protein, glucose, ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes. Unless 
otherwise specified, microscopic examination will be performed on abnormal findings.  


 
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Project No. 200148 (Sponsor Study number ITF/2357/54) 
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Human Immunodeficiency Virus (HIV) antigen and antibody, Hepatitis B surface antigen 
(HBsAg), and Hepatitis C (HCV) antibody detection will be performed at screening. 
A urine pregnancy test will be performed at screening and at study exit, and a serum pregnancy 
test will be performed at check-in of each period. 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, phencyclidine [PCP], 3,4-methylenedioxy-
methamphetamine [MDMA], methadone), an alcohol breath test, and a urine cotinine test, will 
be performed at screening. A urine drug screen, an alcohol breath test, and a urine cotinine test 
and will also be performed before dosing of each period. 
Listings of all clinical laboratory results will be provided with the abnormal values flagged with 
"L" (below normal) and "H" (above normal) for continuous parameters, and “A” (abnormal) for 
categorical parameters, including the evaluation of the abnormal result as clinically significant or 
not clinically significant. 
Clinically significant laboratory abnormalities will be recorded as AEs or SAEs and identified as 
Grade 3 to 4 laboratory test results graded according to numeric laboratory test criteria in the 
latest version of Common Technical Criteria for Adverse Events (CTCAE version 5.0) if 
available, otherwise according to the latest version of Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events Corrected will be provided. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) for each clinical laboratory 
test (continuous variables) will be presented by treatment and overall. Change from baseline for 
hematology, biochemistry, coagulation, and urinalysis will be presented. Baseline is defined as 
the last assessment prior to dosing with study drug in that same treatment period (i.e. baseline 
measurements must have been collected prior to administration of study drug in that treatment 
period). The unscheduled results will not be included in the summary tables. The repeated 
laboratory test performed due to safety reasons, after a clinically significant abnormal results is 
obtained, will be considered as follow-up and analyzed as such. For categorical variable 
(urinalysis test), the number of subjects (frequency and percentage) will be tabulated by results 
(e.g., negative, positive, trace …). A summary table of shifts from baseline to study exit will be 
provided. Results from repeat tests will not be included in the summary statistics unless the 
repeat was required (and documented as such) due to technical reasons or an invalid initial result. 
9.4 
Vital Signs 
Blood pressure (BP), heart rate (HR), respiratory rate (RR), and oral temperature (OT) will be 
measured in a supine position at: screening, pre-dose, and approximately 2, 3, 6, 12, and 
24 hours post-dose for each period, and at study exit. Vital signs will be matched to the safety 
ECG (at screening, pre-dose, and approximately 2, 3, 6, 12, and 24 hours post-dose for each 
period, and at study exit). When vital signs measurements coincide with ECG or blood draw, the 
assessments will be performed in the following order: ECG, vital signs, and blood draw. Urine 
collection timepoints will not be prioritized over safety and other PK assessments.  


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 26 of 44 
 
For the measurement of BP, 2 measures performed after at least 5 minutes of resting in supine 
position should be taken 2 minutes apart from each other. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) will be presented overall 
for baseline and study exit and by the associated current treatment for on-study measurements 
and for each vital sign measurement. Descriptive statistics for change from baseline to study exit 
for on-study measurements will also be presented. Baseline will be defined as the last results 
(scheduled or unscheduled) obtained prior to drug administration in each period. Unscheduled 
results will not be included in the summary tables otherwise. Results from post-dose repeat tests 
will not be included in the summary statistics unless the repeat was required (and documented as 
such) due to technical reasons or an invalid initial result.  
A table summarizing the descriptive statistics, a table showing shift of results (low, normal and 
high) from baseline to post dose and a listing of all vital signs results will be provided. 
9.5 
12-Lead Safety ECG 
Supine 12-lead ECG will be performed at screening (triplicate ECG will be performed at 
screening. The averaged value of three QTc will be included in STDM), pre-dose, and 
approximately 2, 3, 6, 12, and 24 hours post-dose for each period and at study exit. Safety ECG 
will be matched to vital signs (at screening, pre-dose, and 2, 3, 6, 12, and 24 hours post-dose for 
each period, and at study exit). When ECG coincides with vital signs measurements or blood 
draw, the assessments will be performed in the following order: ECG, vital signs, and blood 
draw. Urine collection timepoints will not be prioritized over safety and other PK assessments 
The standard ECG parameters will be measured, including ventricular heart rate (VR), PR 
interval, QRS interval, QT interval, QTcB interval (Bazett’s formula correction), and QTcF 
interval (Fridericia’s formula correction). The QTcF interval will be used for clinical evaluations. 
A table summarizing the descriptive statistics, a table showing shift of results (normal, abnormal 
non-significant (NCS) and abnormal clinically significant (CS)) from baseline to post dose and a 
listing of all ECG results will be presented. 
 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 27 of 44 
 
10. Cardiodynamic ECG Assessment 
10.1 ECG and Pharmacokinetic Sample Collection 
The cardiodynamic assessment will be performed through 12-lead ECGs extracted from 
continuous recordings at prespecified time points, paired with PK samples. 
Continuous 12-lead ECG recordings will be performed from 1 hour prior to dosing in each 
treatment period to 36 hours post-dose. At the ECG core laboratory, up to 10 replicate ECGs will 
be extracted at each of the following time points on Day 1 in each treatment period: 3 time points 
prior to dosing (−45, −30, and −15 minutes) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 
36 hours post-dose. 
Subjects will be supinely resting for at least 10 minutes prior to and 5 minutes after each time 
point for ECG extractions, whenever possible. Subjects will be required to avoid postural 
changes during these ECG recordings. 
The 12-lead Holter and ECG equipment will be supplied and supported by ERT. All ECG data 
will be collected using Global Instrumentation (Manlius, NY, USA) Ml2R ECG continuous 12-
lead digital recorder. The continuous 12-lead digital ECG data will be stored onto SD memory 
cards. 12-lead ECGs will be extracted from the continuous recordings at pre-determined time 
points as defined in the study protocol, and will be measured centrally by ERT. 
ECG intervals will be measured by the core laboratory in a blinded manner using the Early 
Precision QT technique (EPQT) (see Appendix A for more details). The ECG database will be 
locked before any statistical analysis is undertaken. 
Blood samples for PK determination will be drawn at the same time points in each period (i.e., 
pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose) immediately 
after the ECG extractions and additionally at 48, 60, and 72 hours post-dose. ITF2357 plasma 
levels will be of interest to correlate with pharmacodynamic effect. Therefore, only blood 
samples for study treatments ITF2357 and moxifloxacin will be analyzed. Samples from subjects 
in the placebo treatment will be saved for analysis if needed. ITF2357 will be analyzed in all 
subjects, however, ITF2374, ITF2375, ITF2440, ITF2563 and ITF2955 glucuronide will only be 
analyzed in a subgroup of 12 evaluable subjects (the same population for whom urine samples 
will be analyzed) as no effect from the metabolites is expected on the QTc results. The samples 
that would not be analyzed will be kept frozen until bioanalysis results are obtained, if within 
these results any indication of a possible effect is found, all samples would be further studied. 
10.2 Statistical Methods 
10.2.1 General Methodology 
All statistical analyses will be performed using the statistical software SAS® for Windows 
Version 9.4 or higher (SAS Institute, Inc., Cary, NC). In all calculations, zero will be substituted 
for concentrations below the quantification limit of the assay. Data collected from all randomized 
subjects will be presented in data listings. Both absolute values and change-from- baseline values 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 28 of 44 
 
for each subject will be given where applicable. All continuous data will be listed with the same 
precision as will be presented in the database. Data listings will be sorted by treatment, subject 
ID, and time point. Missing values will be represented by an empty cell and no imputation will 
be made. 
For all descriptive statistics of continuous ECG parameters (i.e., HR, PR, QRS, and QTcF), data 
will be summarized including number of subjects (n), mean, median, standard deviation (SD), 
standard error (SE), 90% confidence interval (CI), minimum, and maximum by treatment and 
time point. For all modeling results of the by-time-point analysis of change-from-baseline values 
of continuous ECG parameters, n, least squares (LS) mean, SE, and 90% CI will be included. 
Modeling results of the by-time point analysis of placebo-corrected change-from-baseline will 
also include LS mean, SE, and 90% CI. Mean and median values will be rounded to the nearest 
tenth. SD, SE, and CI will be rounded to the nearest hundredth. For the concentration-QTc 
analysis, 2 decimal places will be shown for all effect estimates for all results which have an 
absolute value greater than 0.05. Each effect estimate with an absolute value ≤ 0.05 will be 
displayed with 2 significant figures. The CI of the effect estimate will display 1 more decimal 
place than the effect estimate. SE and P values will be reported with 4 digits and P 
values < 0.0001 will be reported as < 0.0001. Degrees of freedom (df), and t-value will be 
reported to the nearest tenth and nearest hundredth, respectively. Categorical data will be 
summarized 2 ways, by subject and by time point. Subject data will be summarized using the 
count of distinct subjects that fall into the category and the percentage of the total number of 
subjects. Time point data will be summarized using the count of the assessments that fall into the 
category and the percentage of the total number of assessments. Percentages will be rounded up 
or down to the next integer percentage. Population counts (either number of subjects or number 
of time points at the assessment) for each treatment group will be used as the denominator in the 
calculation of percentages unless otherwise specified 
10.2.2 Baseline 
For all continuous ECG parameters from each period, baseline is defined as the average of the 
measured ECG intervals from the 3 ECG time points (−45, −30, and −15 minutes) prior to 
treatment administration on Day 1 for the respective period. For T-wave morphology and U-
wave presence in each period, baseline includes findings observed in any of the replicates from 
the 3 time points prior to dosing on Day 1 for the respective period. 
10.2.3 QT Correction Methods 
The QT and RR value for each beat will be used for HR correction.  
The Fridericia's correction (QTcF) is defined as QTcF (ms) = QT (ms)/[RR(ms)/1000]1/3. 
For evaluation of the HR-corrected QT interval, a scatter plot and quantile plot of QTcF and RR 
intervals by treatment with a regression line and a linear mixed-effects line (90% CI), 
respectively, also will be given. 


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 2 9  of 4 4  
 
1 0. 3  A n al ysis  
1 0. 3. 1  C o nce ntr ati o n -Q T c A n al ysis ( Pri m a r y A n al 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 Δ Q T c F will 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 he m o del will i ncl u de Δ Q Tc F as t he de pe n d e nt 
varia ble, plas ma c o nce ntrati o n of I T F 2 3 5 7 as t he e x pla nat or y variate ( 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 ua l 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 wit hi n t he sa me treat me nt p eri o d) as a n a d diti o nal c o variate, treat me nt 
(acti ve  =  1 or pla ce 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 i nterc e pt a n d sl o pe per s u bject ( Gar nett et al ).  
A n u nstr uct ure d c o varia n ce matri x will be s pecifie d f or t he ra n d o m effects. If c o n ver ge nce 
ca n n ot be ac hie ve d e ve n after a p pr o priat e res cali n g of t he c o nce ntrati o ns, t he ra n d o m effect o n 
t he sl o pe a n d i nterce pt will be dr o p pe d, i n t his or der, u ntil c o n ver ge nce is a c hie ve d. T he d e grees 
of free d o m ( df ) esti mates will be deter mi ne d b y t h e 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 meter f or c o nce ntrati o n I T F 2 3 5 7) a n d t he treat me nt effect-
s pecific i nterce pt ( defi ne d as t he differe nce bet w ee n acti ve a n d place b o) will be esti mate d 
t o get her wit h t he 2-si de d 9 0 % CI. T h e esti mates f or t he ti me effects will be re p orte d wit h df  a n d 
S E.  
T he ge o metric mea n of t he i n di vi d ual Cma 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 i.e., sl o pe 
esti mate  × c o nce ntr ati o n  + treat me nt effect -s pecifi c i nterce pt) 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 ( Δ Δ Q T c F  is bel o w 1 0 ms at cli nicall y rele va nt plas ma 
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 Tc prol o n gati o n 
wit hi n t he o bser ve d plas ma c o nce 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 dual place b o -a dj ust e d Δ Q Tc F i, k ( Δ Δ Q Tci, k) val ues e q ual t he o bs er 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 q ua ntiles 
( deciles) of o bser 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 Tc F ( Δ Δ Q Tc F) 
a n d 9 0 % CI at t he me dia n c o nce ntr ati o n wit hi n eac h decile will be gi ve n. T he re gressi o n li ne 
prese nti n g t he m o del -pre dicte d Δ Δ Q Tc F (as des cri be d b y T or n øe et al ) will be a d de d t o e val uate 
t he fit of a li near m o d el a n d vis ualize t he c o nce ntr ati o n-res p o nse relati o ns hi p.  
 
 
 
 
T he S A S c o de f or t h e c o nce ntrati o n -Q Tc a n al ysis is as f oll o ws.  
P R O C MI X E D D A T A = P K P D met h o d =re ml;  
C L A S S S U BJI D TI M E;  
C CI


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 3 0  of 4 4  
 
M O D E L D Q Tc = T R T C O N C TI M E C B A S E/ s ol uti o n cl n oi nt al p ha = 0. 1 al p ha p = 0. 1 C O V B 
D D F M = K R;  
R A N D O M I N T C O N C /t y p e = U N S U BJ E C T = S U BJI D s;  
R U N;  
W here P K P D  =  P K/ Q Tc p o p ulati o n, S U BJI D  = s u bject n u m ber, T R T  = treat me nt (acti ve  =  1 or 
place b o  =  0), TI M E  =  n o mi nal p ost -d ose ti me p oi nt, C O N C =  plas ma c o nce ntrati o n of I T F 2 3 5 7, 
C B A S E  = ce ntere d baseli ne Q Tc F, a n d D Q Tc  =  Δ Q Tc F.  
N ote: E S TI M A T E state me n ts will be i ncl u de d f or t he pre dicti o n of t he effect i n eac h of t he 
acti ve d ose gr o u ps . 
C CI


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 3 1  of 4 4  
 
1 0. 4  Ass a y  Se nsiti vit y  
T he a nal ysis t o s h o w ass a y s e nsiti vit y will be als o base d o n t he c o n ce ntr ati o n -Q Tc a n al ysi s of 
t he effect o n Δ ∆Q Tc F of 4 0 0 m g oral 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. T h at is, t he relati o ns hi p bet wee n m o xifl o x aci n plas ma c o nce ntr ati o n a n d ∆Q Tc F will be 
i n vesti gate d b y li near mi x e d-effects m o deli n g. T h e m o del will i nc l u de Δ Q Tc F as t h e de pe n d e nt 
varia ble, m o xifl o x aci n plas ma c o nce ntrati o n as t h e e x pla nat or y v aria ble ( 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 at eac h p ost -d ose ti me p oi nt 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 ( m o xifl o x aci n  =  1 or place b o  =  0) a n d ti me (i.e., p ost -d ose ti me p oi nt) as 
fi x e d effects, a n d a ra n d o m i nterce pt a n d sl o pe p er s u bject (Ga r nett et al). T he ge o metric mea n of 
t he i n di vi d ual Cma x  val ues f or s u bjects recei vi n g t he si n gle d os e of 4 0 0 m g m o xifl o x aci n 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 (i.e., sl o pe esti mate × 
c o nce ntr ati o n + treat me nt effect-s pecifi c i nterce pt) at t his ge o m etric mea n C ma x  will be o btai ne d.  
If t he sl o pe of t he c o nce ntrati o n-Q Tc ( ∆Q Tc F) f or m o xifl o x aci n is statisticall y si g nifica nt at 1 0 % 
le vel f or 2-si de d t est a n d t he l o wer b o u n d of t he 2-si de d 9 0 % CI of t he pre dicte d effect of 
∆∆Q Tc F is a b o ve 5 ms at t he ge o m etric mea n C ma x  f or 4 0 0 m g m o xifl o x aci n, assa y se nsiti vit y 
will be dee me d t o ha v e b ee n de m o nstrat e d.  
1 0. 5  B y -Ti me P oi nt A n al ysis  
T he b y -ti me p oi nt 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 d e nt varia bl e, peri o d, se q ue n ce, 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 d ose of I T F 2 3 5 7, s u prat hera pe utic d ose of I T F 2 3 5 7, m o xifl o xaci n, a n d place b o) a n d 
ti me-b y -tr eat me nt i nteracti o n as fi x e d effects, a n d baseli ne Q Tc F as a c o variate. 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 a n u nstr uct ure d c o v aria n ce matri x fails t o c o n ver ge, 
ot her c o varia nce matrices s uc h as c o m p o u n d s y m metr y a n d a ut or e gressi ve will be c o nsi dere d. 
T he m o del will als o i ncl u de a s u bject -s p ecific 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 n ce s h o ul d pr o ve t o be n ot si g nifi ca nt (i.e., if t he P val ue >  0. 1), t hese 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 re p eate d wit h o ut t h ose c o variates. Fr o m t his a nal ysis, 
t he L S mea 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” ( Δ Δ Q Tc F) 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 parat el y.  
F or H R, P R, a n d Q R S i nter val, t he a n al ysis will be base d o n t he c h a 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 om t he statistical m o deli n g f or 
b ot h c ha n ge -fr o m-bas eli ne 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 
ta bles a n d gra p hi call y dis pla ye d. 
T he S A S c o de f or t h e b y -ti me p oi nt a nal ysis f or Q Tc F is as f oll o ws. 
C CI


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 32 of 44 
 
PROC MIXED DATA=ECG; 
CLASS SUBJID TREAT TIME PERIOD SEQUENCE; 
MODEL DQTc=BASE TREAT TIME TREAT*TIME PERIOD SEQUENCE/DDFM=KR;  
random intercept / SUBJECT =SUBJID type=UN; 
REPEATED TIME / SUBJECT = PERIOD*SUBJID type = un; 
LSMEANS TREAT*TIME/CL DIFF ALPHA=0.1;  
RUN; 
Where ECG = QT/QTc population, SUBJID = subject identifier, TREAT = treatment (therapeutic 
dose of ITF2357, supratherapeutic dose of ITF2357, moxifloxacin, and placebo), 
TIME = nominal post-dose time point, BASE = baseline QTcF, PERIOD = period, 
SEQUENCE = sequence, and DQTc = ΔQTcF. 
10.6 Categorical Analysis 
The analysis results for categorical outliers will be based on treatment-emergent events (i.e., new 
findings compared to baseline); T-wave morphology and presence of U-waves will be 
summarized in frequency tables with counts and percentages for both number of subjects and 
number of time points. Subject data will be summarized using the count of distinct subjects that 
fall into the category and the percentage of the total number of subjects. Time point data will be 
summarized using the count of time points at which the assessments fall into the category and the 
percentage of the total number of time points at which assessments are performed. Counts (either 
number of subjects or number of time points) for each treatment group will be used as the 
denominator in the calculation of percentages unless otherwise specified. 
A subject or time point will be determined as an outlier if the following criteria (which are 
assessed separately) are met for the ECG intervals (Table 2). 
Table 2 
Criteria for determining a subject or time point outlier 
ECG 
interval 
Categorical outlier criteria 
QTcF 
Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline (new 
onset) 
Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new 
onset) 
Treatment-emergent value of > 500 ms when not present at baseline (new onset) 
Increase of QTcF from baseline of > 30 and ≤ 60 ms 
Increase of QTcF from baseline > 60 ms 
PR 
Increase of PR from baseline > 25% resulting in PR > 210 ms 
QRS 
Increase of QRS from baseline > 25% resulting in QRS > 120 ms 
HR 
Decrease of HR from baseline >25% resulting in HR < 50 bpm 
Increase of HR from baseline >25% resulting in HR > 100 bpm 


 
Statistical Analysis Plan 
Italfarmaco S.p.A. 
Project No. 200148 (Sponsor Study number ITF/2357/54) 
11-JUN-2021 (Final 2.0) 
 
Page 33 of 44 
 
All outliers will be summarized for each treatment group on the basis of incidence rates. A 
subject will be counted only once for a particular outlier event if the subject experiences more 
than 1 episode of that event. The total number of time points will be based on the number of 
observed time points across all subjects within a treatment group. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, 
i.e., changes not present at baseline. For each category of T-wave morphology and of U-waves, 
the category will be deemed as present if observed in any replicates at the time point. 
The T-wave morphology and U-wave presence categories are described as follows (Table 3). 
Table 3 
T-wave morphology and U-wave presence categories (assessed manually) 
Category 
Description 
Normal T-wave (+) 
Any positive T-wave not meeting any criterion below. 
Flat T-wave 
T-amplitude < 1 mm (either positive or negative), including flat isoelectric 
line. 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave. 
Biphasic 
T-wave that contains a second component with an opposite phase that is at 
least 0.1 mV deep (both positive/negative and negative/positive and 
polyphasic T-waves included). 
Normal T-wave (-) 
T-amplitude that is negative, without biphasic T-wave or notches. 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave. 
U-waves 
Presence of abnormal U-waves. 
10.7 Terminology and Definitions: Placebo-corrected ΔQTcF and Placebo-adjusted 
ΔQTcF (ΔΔQTcF) 
Change-from-baseline QTcF (QTcF) will be used as the dependent variable in the 
concentration-QTc analysis and in the by-time point analysis.  
By-time point analysis 
Placebo-corrected ΔQTcF (ΔΔQTcF) 
 In the by-time point analysis on the QTcF interval, LS mean, SE, and 2-sided 90% CI of 
QTcF and QTcF will be calculated for each active dose group and moxifloxacin 
group, as well as on placebo group for ΔQTcF at each post-dose time point. 
Concentration-QTc analysis 
Placebo-corrected ΔQTcF (ΔΔQTcF) 
 In the concentration-QTc analysis, the term placebo-corrected ΔQTcF (ΔΔQTcF) will be 
used for the model-predicted effect across concentrations on a population level. 


 
Statistical A nal ysis Pla n  
Italfar mac o S. p. A. 
Pr oj ect N o.  2 0 0 1 4 8 ( S p o ns or St u d y n u m ber I T F/ 2 3 5 7/ 5 4)  
1 1 -J U N-2 0 2 1 ( Fi nal 2. 0)  
 
P a ge 3 4  of 4 4  
 
 Defi niti o n : M o del-pre dicte d mea n Δ Q T c F i n eac h acti ve d ose gr o u p mi n us m o del -
pre dicte d me a n Δ Q T c F i n t he place b o gr o u p, w hic h e q uals sl o pe esti mate × 
c o nce ntr ati o n + treat m e nt effect -s pecifi c i nterce pt.  
 
Pl ac e b o -a dj uste d Δ Q Tc F ( Δ Δ Q Tc F)  
 I n t he c o nce ntrati o n-Q Tc a nal ysis, t he t er m place b o -a dj uste d Δ Q T c F ( Δ Δ Q Tc F) will be 
use d t o ill ustrate t he u n derl yi n g d ata o n b ot h s u bject a n d p o p ulati o n le vels.  
 Defi niti o n f or t he esti m ate d pl ace b o -a dj uste d Δ Q T c F o n a s u bject level:  o bser ve d Δ Q Tc F 
f or eac h s u bject ( o n acti v e d ose gr o u p or m o xifl o xaci n gr o u p or place b o gr o u p) mi n us t he 
esti mate d ti me effect (i.e., t he m o del -pre dict e d mea n Δ Q Tc F i n t he place b o gr o u p).  
  
 Defi niti o n f or t he esti m ate d pl ace b o -a dj uste d Δ Q T c F ter m o n a p o p ul ati o n level:  t he 
a vera ge of i n di vi d uall y esti mate d place b o -a dj uste d Δ Q Tc F val ues at t he ass ociate d 
me dia n plas ma c o nce ntrati o n wit hi n eac h c o nce ntr ati o n decile.  
1 0. 8  S a m ple Size C o nsi der ati o ns f or Ass a y Se nsiti vit y  
C CI


 
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11. Pharmacokinetic Analyses 
11.1 Handling of the Below the Lower Limit of Quantitation (BLQ) and the No 
Reportable Concentration Values 
During PK and statistical analyses, drug concentrations BLQ of an assay will be considered as 
zero except when they occur between two non-BLQ concentrations where they will be 
considered as missing during PK calculations and estimations. A sample with a no reportable 
value occurring prior to the dosing for a given period will be replaced by zero. For tabulation, 
graphical representation and calculation purposes, all samples with no reportable value observed 
after dosing will be set to missing.  
11.2 Handling of the Difference Between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK 
samples will be recorded using the electronic data capture. For all sampling times, the actual 
sampling times will be calculated as the difference between the sample collection actual clock 
time and the actual clock time of dosing. The actual post-dose sampling times expressed in hours 
and rounded off to three decimal digits will be used to calculate the PK parameters, except for 
pre-dose samples occurring prior to dosing, which will always be reported as zero (0.000), 
regardless of the time difference. In the PK section of the report, scheduled sampling times will 
be presented in concentration tables and mean graphs while actual times are presented for the 
individual graphs. A listing of the actual times for PKs will be provided for PK samples. 
11.3 Pharmacokinetic Parameters  
11.3.1 
 Plasma Pharmacokinetic Parameters 
For PK analysis of ITF2357 and its metabolites (ITF2374, ITF2375, ITF2440, ITF2563, 
ITF2955 glucuronide), and moxifloxacin for each period, a total of 19 blood samples will be 
collected from each subject at pre-dose (baseline) and 0.500, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 
4.00, 5.00, 6.00, 7.00, 8.00, 12.0, 24.0, 36.0, 48.0, 60.0, and 72.0 hours post-dose. 
Only samples from subjects who receive ITF2357 and moxifloxacin will be analyzed, samples 
from subjects who receive placebo will be saved for analysis if needed. 
ITF2357 will be quantified in all subjects administered with the study drug while the metabolites 
will be quantified only in a randomized group of 12 subjects, as no effect from the metabolites is 
expected on the QTc results. Before starting bioanalysis, the biostatistician will randomly select 
12 evaluble subjects for plasma metabolite analysis. These will be the same 12 evaluable 
subjects randomely selected for urinary analysis. The samples that would not be analyzed will be 
kept frozen until bioanalysis results are obtained, if within these results any indication of a 
possible effect is found, all samples would be further studied using a similar analysis method.  
Blood draws will be performed after the 15-minute supinely resting period around each time 
point for ECG extraction. The time tolerance window for blood samples collected during the 
confinement period will be ±10 minutes for all samples. Sample collections done outside the pre-


 
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defined time windows will not be considered as protocol deviations since actual post-dose 
sampling times will be used for pharmacokinetic and statistical analyses. A dead-volume 
intravenous catheter will be used for blood collection to avoid multiple skin punctures, when 
appropriate. Otherwise, blood samples will be collected by direct venipuncture.  
Plasma concentrations for ITF2357 and its metabolites, and moxifloxacin will be used to 
calculate the following PK parameters by standard non compartmental methods: 
AUC0-t 
Area under the concentration-time curve from time zero to the last 
measurable concentration, calculated using the trapezoidal method. 
AUC0-12 
Area under the concentration-time curve from time zero to 12 hours, 
calculated using the trapezoidal method. 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
(extrapolated), calculated as AUC0-t + Clast/Kel, where Clast is the last 
measurable concentration. 
Cmax 
Maximum observed plasma concentration. 
Residual area 
Residual area, calculated as 100*(1- AUC0-t / AUC0-inf). 
Tmax 
Time of observed Cmax. 
T½ el 
Elimination half-life, calculated as ln(2)/Kel. 
Kel 
Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed concentration 
versus time profile in the terminal elimination phase. Best fit method will be 
used to calculate the Kel from at least 3 concentration data points excluding 
the Cmax. Rsq adjusted, the goodness of fit statistic for the terminal 
elimination phase, adjusted for the number of points used in the estimation of 
Kel must be ≥ 0.8. If the Kel cannot be measured (e.g.: fewer than 3 non-zero 
concentrations in the terminal elimination phase or Rsq adjusted < 0.8), the 
PK parameters derived from Kel will not be reported for that individual PK 
profile (AUC0-inf, Residual area, and T½ el). The timepoint where ln-linear 
Kel calculation begins (Kel Lower) and the actual sampling time of the last 
measurable concentration used to estimate the Kel (Kel Upper), as well as the 
Rsq adjusted for the ln-linear regression for the calculation of the elimination 
rate constant will be reported. 
CL/F 
Apparent total body clearance, calculated as Dose/AUC0-inf. 
Vd/F 
Apparent volume of distribution, calculated as Dose/Kel x AUC0-inf. 


 
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11.3.2 
Urine Pharmacokinetic Parameters 
Urine samples will be collected in all subjects at 5 times or time intervals during treatment with 
Treatments T, ST, and P: spot pre-dose (within 2 hours before dosing), 0.00 -8.00 hour, 8.00-
24.0 hours, 24.0-48.0 hours, and 48.0-72.0 hours post-dose. Before starting analysis, the 
biostatistician will randomly select 12 evaluable subjects for whom urine and blood samples for 
metabolite analysis will be analyzed; the rest of the samples will be kept frozen and analyzed 
similarly later on if after obtaining bioanalysis results, further analysis will be needed. 
The following PK parameters will be calculated for ITF2357 and its metabolites ITF2374, 
ITF2375, ITF2440, ITF2563, and ITF2955 glucuronidein urine:  
Ae0-t 
Cumulative urinary excretion from time zero to time t, calculated as the sum 
of the amounts excreted over each collection interval. The amount excreted 
in urine for each time interval is calculated as the urine concentration 
multiplied by the urine volume. 
Rmax 
Maximum rate of urinary excretion, calculated by dividing the amount of 
drug excreted in each collection interval by the time over which it was 
collected. 
TRmax 
Time of Rmax, calculated as the midpoint of the collection interval during 
which Rmax occurred. 
Clr 
Renal clearance, calculated as Ae0-t/AUC0-t (plasma) 
Additional PK analysis may be performed. Upon Sponsor's request, pharmacokinetic repeats 
might be performed according to Syneos Health’s SOP. If re-assays are requested for 
pharmacokinetic reasons, final results will include re-assay values, while results with original 
values will be presented in an appendix of the clinical study report as supportive data. 
Some PK parameters may not be calculated for all or some subjects, at the discretion of the 
Syneos pharmacokineticist, if the concentration data is not deemed to be amenable to evaluation. 
Explanations for PK parameters that could not be estimated will be provided in the report. 
11.4 
Statistical Analyses  
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales for ITF2357 and its metabolites, and moxifloxacin. Descriptive statistics 
(arithmetic and geometric means, SD, CV%, Min, Max, and median) of the plasma 
concentrations versus time will be presented as well for the PK parameters, except Tmax, and  
T½ el. 
 
The Tmax and T½ el data will be summarized by treatment with number of observations, mean, 
SD, CV, Min, median, and Max. 


 
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Whenever a PK parameter can be calculated for only one period for a subject, the subject will be 
excluded from the statistical analysis involving this parameter. However, data from the available 
period will be included in the descriptive statistics. 
Additional PK statistical analyses may be performed as warranted.  
 
 


 
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12. Percentages and Decimal Places 
If not otherwise specified, the following rules will be applied, with the exception of PK tables 
and listings described below: 
Percentages will be presented to one decimal point. 
Percentages equal to 0 or 100 will be presented as such without a decimal point. 
Minimum and maximum will be presented with the same precision as the original values and, 
mean, standard deviation, and median will be presented with one more decimal place than the 
original values. 
All digits will be used for pharmacokinetic and statistical PK calculations. For PK tables and 
listings, the final reportable results or data will be presented by rounding off to two decimal 
digits, except for the following situations (this applies to individual data and descriptive 
statistics): 
Kel and Rsq adjusted data: rounded off to four decimal digits. 
Pharmacokinetic parameters related to time such as Tmax, must be reported with the same 
precision as the actual sampling time: rounded off to 3 decimal digits. 
Concentration versus time data, as well as Cmax: reported as they appear in corresponding dataset. 


 
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13. Handling of Missing Data  
For safety,  
 If an AE is recorded with an onset date corresponding to a dosing day, but the time is 
missing, then the AE will be assigned to the treatment phase planned treatment with a 
dosing planned that day. 
 If an AE is recorded with an onset date that does not correspond to a dosing day, but the 
time is missing, then the AE will be assigned to the treatment phase planned treatment that 
covers the AE onset day. 
 If an AE is recorded with an onset date where day and time are both missing, then the AE 
allocation to a treatment phase planned treatment will be done on a case by case basis 
considering available information (e.g. AE onset date, AE end date, AE comments, subject 
disposition). 
For PK, only observed data will be used in the data analysis except for concentration values BLQ 
as described in Section 11.3. No attempt will be made to extrapolate or interpolate estimates for 
missing data. 
For Holter, Data listings will be sorted by treatment, subject ID, and time point. Missing values 
will be represented by an empty cell and no imputation will be made, as described in section 10.2.1. 
 
 


 
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11-JUN-2021 (Final 2.0) 
 
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14. Data Handling 
The PK plasma concentrations, safety, and tolerability data will be received as SAS® datasets 
from the Syneos data management facility. Screening failures and ineligible volunteer’s data 
(subject disposition) will be received from the clinical site as source data. 
 
 


 
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15. Software to be Used 
PK analysis will be performed using Phoenix WinNonlin® version 8.0 or higher, which is 
validated for bioequivalence/bioavailability studies by inVentiv. The safety data tables and 
listings, as well as PK tables and listings will be created using SAS®, release 9.2 or a higher 
version. PK figures will be created using R version 3.5 (or higher).  The CSR will be created 
using Microsoft® Office Word 2010, or a higher version. 


 
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16. Appendix A: Early Precision QT Analysis 
Twelve-lead ECGs will be extracted in up to 10 replicates from each nominal time point 
prespecified in the protocol. The median value of each parameter from the set of evaluable beats 
in each extracted replicate will be calculated, and then the mean of all available medians 
(minimum 3 medians) from the nominal time point will be used as the subject’s reportable value 
at that time point. 
Early Precision QT analysis (formerly High Precision QT analysis) will be performed on all 
analyzable (non-artifact) beats in the 10 ECG replicates (1 replicate consists of one 14 second 
ECG). Statistical quality control procedures will be used to review and assess all beats and 
identify “high” and “low” confidence beats using several criteria including: 
 QT or QTc values exceeding or below certain thresholds (biologically unlikely); 
 RR values exceeding or below certain thresholds (biologically unlikely); 
 Rapid changes in QT, QTc, or RR from beat to beat. 
Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) in all 
recorded beats of all replicates will be performed using the iCOMPAS software. All beats that 
are deemed “high confidence” will not be reviewed by an ERT cardiac safety specialist. All low 
confidence beats will be reviewed manually by an ERT cardiac safety specialist and adjudicated 
using pass-fail criteria. The beats found acceptable by manual review will be included in the 
analysis. The beats confirmed to meet fail criteria will not be included in the analysis. 
For the purpose of measuring PR and QRS intervals and to assess T-wave morphology and 
presence of U-waves, the TQT Plus algorithm will select the 3 ECG replicates with the highest 
quality score from the ECG extraction window. These 3 ECGs will be analyzed using a semi-
automated process to determine these parameters. If 3 consecutive usable beats cannot be 
identified in at least 2 of the 3 replicates, then all beats in all replicates will be reviewed for that 
time point using a manual analysis. 
If manual analysis is required, then all beats in a minimum of 3 replicates will be reviewed using 
the iCOMPAS software. The ERT cardiac safety specialist will review all usable beats in Lead II 
(or an alternate lead) for each replicate and will review and/or adjust the fiducial placements 
(onset of P, onset of Q, offset of S, and offset of T-wave that were electronically marked) of each 
waveform and also document the T wave morphology and the presence of U-waves for each 
beat. A replicate will only be reported if it has 3 approved, usable beats. 


 
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17. Reference List 
 Darpo B., Benson C., Dota C., et al 2015. Results from the IQ-CSRC prospective study 
support replacement of the thorough QT study by QT assessment in the early clinical 
phase. Clin Pharmacol Ther. 2015 Apr;97(4):326–35. doi: 10.1002/cpt.60. 
 Ferber, G., M. Zhou and B. Darpo. Detection of QTc effects in small studies--
implications for replacing the thorough QT study. Annals of noninvasive 
electrocardiology, 2015; 20(4): 368–77. 
 Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. [Published correction appears in J Pharmacokinet 
Pharmacodyn. 2018;45(3):399]. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
 Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-1042. 
 Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat 
Assoc. 1979;74(368):829-836. 
 Hurvich CM, Simonoff JS, and Tsai CL. Smoothing parameter selection in nonparametric 
regression using an improved Akaike Information Criterion. J R Stat Soc Series B Stat 
Methodol. 1998;60(2):271-293. 
 Darpo B, Benson C, Dota C, et al. Results From the IQ-CSRC Prospective Study Support 
Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase. 
Clin Pharmacol Ther. 2015;97(4):326-335. 
 Ferber G, Zhou M, and Darpo B. Detection of QTc Effects in Small Studies--Implications 
for Replacing the Thorough QT Study. Ann Noninvasive Electrocardiol. 2015;20(4):368-
377.