Open-label, Single-center Study in Healthy Subjects to Investigate the Effect of Oral Givinostat on Pharmacokinetics (PK) of Intravenous and Oral Midazolam and Oral Dabigatran Etexilate (PART 1)
Phase: PHASE1
Conditions: Drug-Drug Interaction, Heathy Volunteer
Sponsor: Italfarmaco

 
 
C LI NI C A L S T U D Y  P R O T O C O L  
 
S T U D Y TI T L E:  
A n O pe n -l a bel, Si n gle-ce nter St u d y i n He alt h y S u bjects t o I n vesti g ate t he Effect            
of Or al Gi vi n ost at o n t he Si n gle D ose P h ar m ac o ki netics ( P K) of I ntr a ve n o us                   
or Or al Mi d az ol a m a n d Or al D a bi g atr a n Ete xil at e  
 
Pr ot oc ol c o de:  I T F/2 3 5 7 /5 5  
  
T y pe:  I nter ve nti o nal, P har mac o ki n eti c a n d Dr u g -Dr u g 
I nteracti o n Trial 
 
 
E u dra C T N o.:  2 0 2 1 -0 0 5 7 5 6 -1 1  
  
Versi o n:  1. 0  
Date:  2 9 N O V 2 0 2 1  
S u perse des versi o n:  N o ne  
Date:  N ot a p plic a ble  
  
S p o ns or:  I T A L F A R M A C O S. p. A 
Via dei L a v orat ori, 5 4  
2 0 0 9 2 Ci nisell o B alsa m o ( MI), It al y  
wit h its re gist ere d offi ce at  
Viale F ul vi o Testi, 3 3 0,  
Mila n ( MI), Ital y  
w w w.italfar ma c o. c o m  
P h o ne: + 3 9 0 2 6 4 4 3 1   
Fa x: + 3 9 0 2 6 4 4 3 4 6  
  
Cli nic al P har m ac ol o g y U nit:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O N FI D E N TI A LI T Y DI S C L AI M E R  
T his d oc u me nt is c o nfi de nti al a n d is a v ail a ble f or re vie w t o i n vesti g at o rs, re g ul at or y 
b o dies a n d st u d y a u dit pers o n nel. N o p art of t his d oc u me nt m a y be use d, p u blis he d, 
c o pie d or ot her wise discl ose d wit h o ut pri or writt e n a ut h oriz ati o n fr o m Bl ue C li nic al 
L d a.  or t he S p o ns or of t his st u d y.  
 
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2  of 5 7  
 
1  
S T U D Y  S U M M A R Y  
 
St u d y T itle:  
A n O pe n -l a b el, Si n gle-c e nte r, T hr ee -p art St u d y i n He alt h y 
S u bjects t o I n vesti g ate t h e Effect of Gi vi n ost at o n t he 
P h ar m ac o ki n etics of Mi d az ol a m a n d D a bi g atr a n, t he Effe ct of 
Cl arit hr o m yci n o n t he  P h ar m ac o ki n etics of Gi vi n ost at  a n d t h e 
P h ar m ac o ki n etics of Si n gle a n d M ulti ple D oses of Gi vi n ost at . 
St u d y T y pe:  
I nter ve nti o nal, P har ma c o ki netic a n d Dr u g-Dr u g I ntera cti o n Trial . 
St u d y C o de:  
I T F/ 2 3 5 7/ 5 5 
E u dr a C T/I N D N o.  
2 0 2 1 -0 0 5 7 5 6 -1 1/ 1 2 6 5 9 8  
P hase:  
P hase I.  
S p o ns or:  
Italfar ma c o S. p. A. 
Cli nic al P har ma c ol o g y 
U nit:  
 
 
 
 
 
 
 
 
 
 
Pri nci pal I n vesti gat or:  
Marle ne F o nsec a, M D  
mf o nsec a @ bl uecli nic al. pt  
I n vesti gati o nal 
P r o d ucts: 
I T F 2 3 5 7/ Gi vi n ostat * 1 0 m g/ m L or al s us pe nsi o n ( 1 4 0 m L/ b ottle). 
* Gi vi n ostat is us e d t o i n dicate t he w h ole st u d y dr u g na me gi vi n ostat 
h y dr oc hl ori de m o n o h y drate.  T he d os a ges/c o nce ntrati o ns of t he st u d y dr u g are 
e x press e d as gi vi n ostat h y dr oc hl ori de m o n o h y drat e. 
Mi da z ola m A ur o bi n d o 1 m g/ ml s ol uti o n f or i nje cti o n/i nf usi o n or re ctal 
a d mi nistrati o n . 
Mi da z ola m 2. 5 m g or o m uc osal s ol uti o n ( B uc c ola m
® ). 
Da bi gatra n ete xilate 7 5 m g har d c a ps ules ( Pra da xa ® ). 
 
Ba c k gr o u n d 
i nf or mati o n a n d trial 
r ati o nale: 
I n vitr o data s h o we d t hat g i vi n ostat (I T F 2 3 5 7) ma y ha ve a p ote ntial f or 
dr u g -dr u g i ntera cti o n ( D DI) at le vel of C Y P 3 A -me diate d meta b olis m 
a n d P-gl yc o pr otei n ( P -g p) tra ns p ort.  
I n t he c urre nt st u d y, t he per petrat or D DI p ote ntial of g i vi n ostat as 
i n hi bit or a n d i n d uc er of C Y P 3 A a n d P-g p a cti vit y will be e val uate d i n 
Part 1, b y deter mi ni n g t he i m pa ct of g i vi n ostat o n t he p har ma c o ki netics 
of mi da z ola m (se nsiti ve i n de x C Y P 3 A s u bstrate) a n d da bi gatra n 
ete xilate ( P-g p s u bstrate). T he per petrat or D DI p ote ntial of g i vi n ostat 
at t he le vel of C Y P 3 A acti vit y will be e val uate d f oll o wi n g oral (effe ct 
at b ot h i ntesti nal a n d he patic C Y P 3 A) a n d i ntra ve n o us ( mai nl y he patic 
C Y P 3 A) mi da z ola m a d mi nistrati o n.   
 
Pri mar y O bje cti ves:  
1.  T o assess t he  p ote ntial  i n hi bit or y a n d i n d uci n g effect of oral 
gi vi n ostat o n t he si n gle d ose p har ma c o ki netics of i ntra ve n o us a n d 
oral mi da z ola m ( Part 1).  
2.  T o assess t he p o te ntial i n hi bit or y a n d i n d uci n g effect of oral 
gi vi n ostat o n t he si n gle d ose p har ma c o ki netics of oral da bi gat ra n 
ete xilate ( Part 1). 
 
S e c o n dar y O bje cti ves:  
1.  T o assess t he safet y a n d t olera bilit y of c o nc o mita nt a d mi nistrati o n of 
gi vi n ostat pl us mi da z ola m a n d da bi gatra n ete xilate ( Part 1).  
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3  of 5 7  
 
Pri mar y E n d p oi nt  
1.  Mi da z ola m a n d da bi gatra n plas ma c o nc e ntrati o ns a n d t here of 
deri ve d p har mac o ki netic para meters al o ne a n d i n c o m bi nati o n wit h 
Gi vi n ostat ( Part 1).  
S e c o n dar y E n d p oi nts  
1.  I nci de nc e a n d se verit y of a d verse e ve nts ( A Es); c ha n ges i n vital 
si g ns, p h ysic al e xa mi nati o n , ele ctr oc ar di o gra m ( E C G) a n d cli nic al 
la b orat or y tests f oll o wi n g a d mi nistrati o n 
of 
mi da z ola m a n d 
da bi gatra n ete xilate al o ne a n d i n c o m bi nati o n wit h gi vi n ostat ( Par t 
1).  
St u d y Desi g n:  
T his is a n o pe n -la bel, 3-part, fi xe d-se q ue nce, n o n -ra n d o mize d st u d y i n 
he alt h y male a n d fe male s u bje cts.  
A s u m mar y of pr oc e d ures a n d a n o ver vie w of st u d y desi g n are 
prese nte d i n S ecti o n 2 ( Fl o w -C hart a n d Desi g n Dia gra m) . 
St u d y parts ma y be c o n d ucte d c o nc o mita ntl y.  
S a m ple Size:  
T o e ns ure e n o u g h s u bje cts wit h e val ua ble data c o m plete e a c h St u d y 
part, a t otal of 5 4 he alt h y male a n d fe male s u bjects are pla n ne d t o be 
e nr olle d as f oll o ws:  
− 
Part 1: 2 6 s u bje cts  
− 
Part 2: 2 0 s u bje cts 
− 
Part 3: 8 s u bje cts  
Ea c h s u bject will partici pate i n o ne st u d y part o nl y.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4  of 5 7  
 
I ncl usi o n Criteria: 
F or all s u bje cts:  
1.  S u bje ct’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. 
2.  Male or fe male s u bject , ≥1 8 a n d ≤5 5 years of a ge , at t he ti me of 
si g ni n g t he i nf or me d c o nse nt. 
3.  B o d y mass i n de x ( B MI) of 1 8. 5 t o 3 2. 0 k g/ m 2 i ncl usi ve, 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 1 0 k g f or males.  
4.  N o n -s m o ker or e x-s m o ker (i.e. s o me o ne w h o a bstai ne d fr o m usi n g 
t o ba c c o- or nic oti ne -c o ntai ni n g pr o d ucts f or at least 3 m o nt hs pri or 
t o S cre e ni n g). 
5.  N o cli nic all y rele va nt diseases.  
6.  N o m aj or s ur ger y wit hi n 4 we e ks pri or t o d osi n g.  
7.  N o cli nic all y rele va nt a b n or malities o n p h ysic al e xa mi nati o n.  
8.  N o cli nic all y rele va nt a b n or malities o n 1 2 -le a d E C G.  
9.  N o cli nic all y rele va nt a b n or malities o n cli nic al la b orat or y tests.  
1 0.  Ne gati ve test res ults f or a nti -H u ma n I m m u n o deficie nc y vir us 1 a n d 
2 a nti b o dies (a nti -HI V -1 A b a n d a nti -HI V -2 A b), He patitis B s urfa ce 
a nti ge n ( H Bs A g) a n d a nti-He patitis C vir us a nti b o dies (a nti -
H C V A b).  
1 1.  Fe male s u bje cts are eli gi ble if t he y are of n o n -c hil d be ari n g p ote ntial 
or a gre e t o use a n o n -h or m o nal hi g hl y effe cti ve c o ntrac e pti ve 
met h o d fr o m 2 8 da ys pri or t o S cre e ni n g u ntil at le ast 9 0 d a ys after 
t he last st u d y dr u g a d mi nistrati o n. N o nc hil d be ari n g p ote ntial fe male 
is defi ne d as: 
a) Me n o pa usal, i.e. n o me nses f or ≥ 1 2 m o nt hs wit h o ut a n 
alter nati ve me dic al c a use ot her t ha n me n o pa use , a n d a hi g h 
f ollicle-sti m ulati n g h or m o ne ( F S H) le vel. 
b)  Pre -me n o pa usal fe male wit h h ystere ct o m y, bilateral 
sal pi n ge ct o m y a n d/or bilateral o o p h ore ct o m y.  
A n o n -h or m o nal hi g hl y effe cti ve c o ntrac e pti ve met h o d is defi ne d as:  
a) I ntra uteri ne de vice. 
b)  Bilateral t u bal oc cl usi o n.  
c) T otal a bsti ne nc e of heter ose x ual i nterc o urse, i n ac c or da nce 
wit h t he lifest yle of t he s u bje ct.  
d)  Vasect o mize d part ner, w h o has re cei ve d me dical assess me nt of 
t he s ur gic al s ucc ess, or cli nic all y dia g n ose d i nfertile part ner. 
1 2.  Male s u bje cts w h o are se x uall y acti ve wit h a fe male part ner of 
c hil d be ari n g p ote ntial ( pre g na nt or n o n -pre g na nt) m ust use 
c o ntrac e pti o n (c o n d o m) fr o m i n vesti gati o nal pr o d uct a d mi nistrati o n 
u p t o at le ast 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 .  
1 3.  Male s u bje cts m ust e ns ure t hat his n o n -pre g na nt fe male part ner of 
c hil d be ari n g p ote ntial a grees t o c o nsiste ntl y a n d c orrectl y use f or 
t he sa me peri o d a hi g hl y effecti ve met h o d of c o ntra ce pti o n (see 
S e cti o n 8. 3. 3 ). 
1 4.  Male s u bje cts 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. 
1 5.  Willi n g ness a n d c a 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 a bilit y t o u n dersta n d t he stu d y pr oce d ures a n d t he ris ks 
i n v ol ve d. 
E xcl usi o n Criteria:  
S u bje cts t o w h o m a n y of t he f oll o wi n g criteria a p pl y will be e xcl u de d 
fr o m t he st u d y: 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5  of 5 7  
 
At Scree ni n g  
1.  Pre vi o us use of gi vi n ostat.  
2.  Hist or y of a na p h yla xis re acti o n or cli nicall y si g nific a nt dr u g 
h y perse nsiti vit y re acti o n (e. g., a n gi oe de ma, Ste ve ns -J o h ns o n 
s y n dr o me, a c ute ge neralize d e xa nt he mat o us p ust ul osis, dr u g-
i n d uc e 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). 
3.  K n o w n hist or y of h y perse nsiti vit y a n d/ or aller gic re acti o ns t o 
gi vi n ostat,  hist o ne de a c et ylases ( H D A C) i n hi bit ors or t o a n y 
e xci pie nt i n t he f or m ulati o n. 
4.  Hist or y of s or bit ol i nt olera nc e, s or bit ol mala bs or pti o n or fr uct ose 
i nt olera nce.  
5.  A n y me dic al c o n diti o n (e. g. gastr oi ntesti nal, re nal or he patic, 
i ncl u di n g pe ptic ulc er, i nfla mmat or y b o wel disease or pa ncreatitis) 
or s ur gic al c o n diti o n (e. g. c h olec yste ct o m y, gastre ct o m y) t hat ma y 
affe ct dr u g p har mac o ki netics (a bs or pti o n, distri b uti o n, m eta b olis m 
or e xcreti o n) or s u bject safet y.  
6.  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 wer t ha n 6 0 or o ver 9 0 m m H g, or p ulse rate l o wer 
t ha n 5 0 or o ver 1 0 0 b p m. 
7.  Q Tc F ˃ 4 5 0 msec.  
8.  S u bje cts wit h hist or y of car diac arr h yt h mias ( d oc u me nte d ), fa mil y 
hist or y of s u d de n c ar dia c de at h or hist or y of a d diti o nal ris k fa ct o rs 
f or t orsa des-de -p oi ntes (e. g. he art fail ure, h y p o kale mia , l o n g Q T 
s y n dr o me). 
9.  Ha vi n g a n esti mate d gl o mer ular filtrati o n (e G F R) < 8 0 m L/ mi n, 
base d o n creati ni ne cleara nc e c alc ulati o n b y t he C oc kcr oft -Ga ult 
f or m ula a n d n or malize d t o a n a vera ge s urfa ce are a of 1. 7 3 m 2.  
1 0.  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:  
a) Platelet c o u nt bel o w t he l o wer li mit of t he n or mal ra n ge ( L L N)  
b)  T otal w hite bl o o d c ells c o u nt bel o w t he L L N  
c) He m o gl o bi n bel o w t he L L N  
d)  Tri gl yc eri des a b o ve t he u p per li mit of n or mal ra n ge ( U L N) 
e) P otassi u m or ma g nesi u m bel o w t he L L N  
1 1.  P ositi ve uri ne alc o h ol, dr u gs -of -a b use or c oti ni ne scree n test s. 
1 2.  P ositi ve ser u m pre g na nc y test.  
1 3.  If w o ma n, s he is bre ast-fee di n g. 
1 4.  Hist or y of alc o h ol a b use wit hi n 1 ye ar pri or t o scre e ni n g or re g ular 
use of alc o h ol wit hi n 6 m o nt hs pri or t o t he scre e ni n g visit (i.e. m or e 
t ha n 1 4 u nits of alc o h ol per we e k f or males or  m ore t ha n 7 u nits f or 
fe males). 
1 5.  Hist or y of dr u g a b use wit hi n 1 ye ar pri or t o scre e 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 scre e ni n g 
visit or har d dr u gs [s uc h as c oc ai 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 ye ar pri or t o scree ni n g.  
1 6.  Partici pati o n i n a n y cli nic al trial wit hi n t he pre vi o us 2 m o nt hs.  
1 7.  P artici pati o n i n m ore t ha n 2 cli nical trials wit hi n t he pre vi o us 1 2 
m o nt hs.  
1 8.  Bl o o d d o nati o n or si g nific a nt bl o o d l oss ( ≥ 4 5 0 m L) d ue t o a n y 
re as o n or ha d plas ma p heresis wit hi n t he pre vi o us 2 m o nt hs. 
1 9.  Vei ns u ns uita ble f or i ntra ve n o us p u nct ure o n eit her ar m.  
2 0.  Di ffic ult y i n s wall o wi n g c a ps ules, ta blets or s us pe nsi o ns. 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  6  of 5 7  
 
2 1.  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 bje ct fr o m partici pati n g i n t he st u d y. 
At A d missi o n t o Tre at me nt Peri o d  
2 2.  A n y cli nic all y rele va nt a b n or malities o n cli nic al la b orat or y tests.  
2 3.  P ositi ve uri ne alc o h ol, dr u gs -of -a b use or c oti ni ne scree n test s. 
2 4.  P ositi ve uri ne pre g na nc y test.  
2 5.  P ositi ve or i nc o ncl usi ve S A R S -C o V -2 test pri or t o a d missi o n.  
2 6.  Use of prescri pti o n or n o n -prescri pti o n me dici nal pr o d ucts wit hi n 2 8 
da y s or wit hi n 5 -half -li ves of t he me dici nal pr o d uct, w hic he ver is 
l o n ger. 
2 7.  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 bje ct fr o m partici pati n g i n t he st u d y. 
F or P art 1 s u bjects : 
At Scree ni n g  
2 8.  K n o w n hist or y of h y perse nsiti vit y a n d / or aller gic re acti o ns t o 
mi da z ola m, ot her be nz o dia ze pi nes, da bi gatra n ete xilate or t o a n y 
e xci pie nt of t he f or m ulati o ns.  
2 9.  Cli nic all y rele va nt hist or y of i m paire d res pirat or y f u ncti o n, 
o bstr ucti ve sle e p a p ne a, m yast he nia gra vis, res pirat or y arrest a n d/ or 
c a r dia c arrest.  
3 0.  Hist or y of gla uc o ma.  
3 1.  Prese nce of res pirat or y fail ure.  
3 2.  Prese nce of a cti ve cli nicall y si g nific a nt ble e di n g. 
3 3.  Lesi o n or c o n diti o n c o nsi dere d t o p ose a si g nifica nt ris k fa ct or f or 
maj or ble e di n g i ncl u di n g, b ut n ot li mite d t o: c urre nt or rec e nt 
gastr oi ntesti nal ulc erati o n, mali g na nt ne o plas ms, rec e nt brai n or 
s pi nal i nj ur y, re ce nt brai n, s pi nal or o p ht hal mic s ur ger y, re c e nt 
i ntra cra nial he m orr ha ge , k n o w n or s us pecte d es o p ha geal  varices, 
arteri o ve n o us malf or mati o ns, vasc ular a ne ur ys ms or maj or 
i ntras pi nal or i ntra cere bral vasc ular a b n or malities. 
3 4.  Prese nce of a me dic al c o n diti o n re q uiri n g a ntic oa g ula nt tre at me nt.  
At A d m issi o n t o Tre at me nt Peri o d 
3 5.  Tr e at me nt wit h a ntic oa g ula nts wit hi n 2 8 da ys or 5 dr u g half -li ves, 
w hic he ver is l o n ger, bef ore a d missi o n . 
 
S cre e ni n g Pr oce d ures:  
T he healt h y stat us will be deter mi ne d b y t he f oll o wi n g pre -st u d y 
assess me nts:  
-  C olle cti o n of de m o gra p hic data, me dic al hist or y, a n d me dic ati o n 
hist or y.  
-  C o m plete p h ysic al e xa mi nati o n, b o d y meas ure me nts a n d vital si g ns 
[ bl o o d press ure ( B P), p ulse  rate (P R ), res pirat or y rate ( R R), a n d 
b o d y te m perat ure].  
-  E C G.  
-  Fasti n g safet y la b orat or y assess me nts:  
▪ 
He mat ol o g y [c o m plete bl o o d c o u nt: re d bl o o d c o u nt ( R B C), 
w hite bl o o d c ell ( W B C) (i ncl u di n g differe ntial c o u nt), 
he m o gl o bi n, me a n c or p usc ular he m o gl o bi n ( M C H), me a n 
c or p usc ular he m o gl o bi n c o nce ntrati o n ( M C H C), me a n 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  7  of 5 7  
 
c or p usc ular v ol u me ( M C V), re d c ell distri b uti o n wi dt h, 
he mat ocrit, platelets a n d me a n platelet v ol u me].  
▪ 
Bi oc he mistr y [t otal bilir u bi n, dire ct a n d i n direct bilir u bi n, 
al kali ne p h os p hatase ( A L P), a m ylase, ala n i ne a mi n otra nsferase 
( A L T), as partate a mi n otra nsferase ( A S T), lactate 
de h y dr o ge nase ( L D H), c ystati n C, C -re acti ve pr otei n ( C R P), 
ga m ma -gl uta m yltra nsferase ( G G T), creati ne ki nase  ( C K), t otal 
pr otei n, al b u mi n, uric aci d, tri gl yc eri des, t otal c h olester ol, l o w -
de nsit y li p o pr otei n c h olester ol ( L D L -C), hi g h -de nsit y 
li p o pr otei n c h olester ol ( H D L-C), s o di u m, p otassi u m, c hl ori de, 
c alci u m, ma g nesi u m, gl uc ose, cre ati ni ne, ure a a n d t h yr oi d -
sti m ulati n g h or m o ne ( T S H)]. 
▪ 
C oa g ulati o n [ pr ot hr o m bi n ti me, pr ot hr o m bi n rate, i nter nati o nal 
n or malize d rati o (I N R) a n d acti vate d partial t hr o m b o plasti n 
ti me (a P T T)].  
▪ 
Uri nal ysis.  
-  Viral ser ol o g y ( HI V, he patitis B a n d C tests).  
-  S er u m pre g na nc y test.  
-  Uri ne c oti ni ne, alc o h ol a n d dr u g scre e n test.  
-  F S H test.  
Tr e at me nts:  
Part 1 : O n Da ys 1, 6 a n d 1 7, si n gle d oses of mi da z ola m 1 m g i. v a n d 
da bi gatra n ete xilate 7 5 m g, will be a d mi nistere d 1 h o ur after t he 
pla n ne d (as per Da y 4) m or ni n g ti me of gi vi n ostat a d mi nistrati o n.  
O n Da ys 2, 7 a n d 1 8, a si n gle oral d ose of mi da z ola m 2. 5 m g oral 
s ol uti o n will be a d mi nistere d 1 h o ur after t he pla n ne d (as per Da y 4) 
m or ni n g ti me of gi vi n ostat a d mi nistrati o n.  
Fr o m Da y 4 t o Da y 1 8, gi vi n ostat 5 0 m g as oral s us pe nsi o n will be 
a d mi nistere d  t wic e a da y, i n t he m or ni n g a n d i n t he e ve ni n g. O n Da y 
1 9, o nl y t he m or ni n g d ose will be a d mi nistere d.  
Mi da z ola m a n d da bi gatra n ete xilate will be a d mi nistere d f oll o wi n g a n 
o ver ni g ht fasti n g of at least 8 h o urs a n d s u bjects will re mai n faste d 
u ntil at le as t 3  h o urs p ost -d ose. Oral mi da z ola m a n d da bi gatra n 
ete xilate will be a d mi nistere d wit h 1 5 0 m L of water. E xce pt f or water 
gi ve n wit h t he i n vesti gati o nal pr o d ucts, n o fl ui ds will be all o we d fr o m 
1 h o ur bef ore mi da z ola m a n d da bi gatra n d osi n g u ntil 2 h o urs p os t 
d ose. W ater will be pr o vi de d a d li bit u m at all ot her ti mes.  
M i da z ola m a n d da bi gatra n ete xilate will be a d mi nistere d wit h t he 
s u bje cts i n a se mi-re c u m be nt p ositi o n. S u bje cts will re mai n se mi-
re c u m be nt u ntil at le ast 3 h o urs p ost -d ose.  
C o nfi ne me nt:  
S u bje ct s will be c o nfi ne d at t he cli nic al u nit fr o m Da y -1 of e ac h Part 
t o t he m or ni n g of Da y 2 0 i n Part 1. 
C o nc o mita nt 
Tr e at me nts a n d St u d y 
Restricti o ns:  
T he use of a n y me dicati o ns i ncl u di n g O ver -t he-C o u nter ( O T C) 
pr o d ucts (i ncl u di n g her bal me dici nes s uc h as St  J o h n’s W ort, 
h o me o pat hic pre parati o ns, vita mi ns, a n d mi nerals) is f or bi d de n fr o m 
2 8 da ys  or wit hi n 5 half -li ves of t he me dici nal pr o d uct, w hic he ver is 
l o n ger, pri or t o a d missi o n  u p t o last sa m ple f or p har mac o ki netics 
assess me nt, e xce pt f or me dic ati o ns f or  t he treat me nt of a d verse e ve nts 
( A Es). 
Use or t he c o ns u m pti o n of a n y met h yl xa nt hi nes -c o ntai ni n g pr o d ucts 
(e. g., c offee, tea, c h oc olate, or c ola) is pr o hi bite d fr o m 4 8 h o urs pri or 
t o a d missi o n u ntil t he e n d-of -st u d y, i.e. u ntil t he last sa m ple c olle cti o n 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  8  of 5 7  
 
f or p har ma c o ki netic assess me nt.  Use or the c o ns u m pti o n of alc o h olic 
be vera ges is pr o hi bite d fr o m 7 2 h o urs pri or t o a d missi o n a n d u ntil t he 
e n d-of -st u d y. S u bje cts will als o be a d vise d t o a bstai n fr o m stre n u o us 
p h ysic al a cti vit y wit hi n 4 8 h o urs pri or t o bl o o d c olle cti o n f or cli nic al 
la b orat or y tests. 
S u bje cts will be re q ueste d t o a bstai n fr o m c o ns u mi n g pi ne a p ple, 
S e ville ora n ge, p o mel o, p o me gra nate, starfr uit or gra pefr uit pr o d ucts 
(fres h, ca n ne d, or fr oze n) fr o m 7 da ys pri or t o a d missi o n u ntil t he e n d-
of -st u d y. 
W hile c o nfi ne d, partici pa nts will re cei ve a sta n dar dize d diet at 
sc he d ule d ti mes t hat d o n ot c o nflict wit h ot her st u d y-relate d a cti vities. 
Bl o o d S a m pli n g  f or 
P har ma c o ki netics 
Assess me nt : 
Part 1 : A t otal of 1 1 7 bl o o d sa m ples will be c olle cte d as f oll o ws : 
− 
1 3 bl o o d sa m ples of 3 m L e ac h  will be c ollecte d i n K 2-E D T A 
c olle cti o n t u bes at pre -d ose a n d at 2 mi n utes, 0. 2 5, 0. 5, 0. 7 5, 1, 2, 3, 
4, 6, 9, 1 2 a n d 2 4 h o urs after t he a d mi nistrati o n of i ntra ve n o us 
mi da z ola m,  o n Da ys 1, 6 a n d 1 7, f or t he deter mi nati o n of 
mi da z ola m a n d 1 -h y dr o x y mi da z ola m plas ma c o nc e ntrati o ns.  
− 
1 1 bl o o d sa m ples of 3 m L e ac h  will be c ollecte d i n K 2-E D T A 
c olle cti o n t u bes at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2 a n d 2 4 h o urs after 
t he a d mi nistrati o n of oral mi da z ola m, o n Da ys 2, 7 a n d 1 8, f or t he 
deter mi nati o n of mi da z ola m a n d 1 -h y dr o x y mi da z ola m plas ma 
c o nc e ntrati o ns. T he 2 4 -h o ur bl o o d c olle cti o n f oll o wi n g i ntra ve n o us 
mi da z ola m will be ass u me d as t he pre -d ose sa m pli n g f or oral 
mi da z ola m.  
− 
1 5 bl o o d sa m ples of 4 m L e ac h  will be c ollecte d i n K 2E D T A 
c olle cti o n t u bes at pre -d ose a n d at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2, 
2 4, 3 6, 4 8 a n d 7 2 h o urs after t he a d mi nistrati o n of da bi gatra n 
ete xilate,  o n Da ys 1, 6 a n d 1 7 , f or t he deter mi nati o n of t otal a n d 
free da bi gatra n plas ma c o nce ntrati o ns. 
P har ma c o ki netic 
Assess me nts:  
T he f oll o wi n g para meters will be esti mate d f or mi da z ola m, 1 -
h y dr o x y mi da z ola m, t otal da bi gatra n, free da bi gatra n, f oll o wi n g si n gle 
d oses of t he pare nt dr u g:  
-  M a xi m u m o bser ve d plas ma c o nce ntrati o n ( C ma x );  
-  T i me of oc c urre nce of Cma x  (tma x );  
-  A rea u n der t he plas ma c o nc e ntrati o n vers us ti me c ur ve ( A U C) fr o m 
pre -d ose (ti me zer o) t o t he last sa m pli n g ti me wit h q ua ntifia ble 
c o nc e ntrati o ns ( A U C 0 -t);  
-  A U C fr o m ti me zer o t o i nfi nit y ( A U C 0 -∞);  
-  R esi d ual area or perc e nta ge of e xtra p olate d part of 
A U C 0 -∞ 
( % A U Ce xtrap);  
-  A p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ z); a n d a p par e nt 
ter mi nal eli mi nati o n half-life (t1/ 2). 
Ot her P K para meters will be calc ulate d, if c o nsi dere d a p pr o priate a n d 
j ustifie d at t he ti me of t he P K a nal ysis. 
 
S afet y Assess me nts:  
Cli nic all y si g nific a nt a b n or malities i n la b orat or y safet y tests, vital si g ns, 
1 2 -le a d E C G, p h ysic al e xa mi nati o n a n d a n y ot her rele va nt safet y 
varia bles will be re p orte d as A Es.  
T he f oll o wi n g safet y e n d p oi nts will be c o nsi dere d:  
-  Tr e at me nt -e mer ge nt A Es ( T E A Es) after I M P a d mi nistrati o n.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L  
 or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  9  of 5 7  
 
-  Tr e at me nt -e mer ge nt Seri o us A Es ( S A Es).  
-  T E A Es le a di n g t o pre mat ure st u d y disc o nti n uati o n.  
Statistic al Met h o ds:  
P art 1:  
A p pr o priate descri pti ve statistics will be use d t o s u m marize plas ma 
c o nc e ntrati o ns a n d P K para meters. F or mal statistic al a nal ysis of P K 
data will be perf or me d t o c haracterize t he P K i ntera cti o ns:  
-  A n alysis of t h e effect of gi vi n ost at o n mi d az ol a m P K: C ma x  a n d 
A U C 0 -2 4 of mi daz ola m a n d h y dr o x y -mi da z ola m w he n it is 
a d mi nist ere d al o ne a n d c o -a d mi nis tere d wit h gi vi n ostat will 
be t he pri mar y p har mac o ki n eti c para met ers f or t he assess me nt 
of t he effe ct of gi vi n ostat o n mi daz ola m P K.  
-  A n alysis of t h e effect of gi vi n ost at o n d a bi g atr a n P K:  C ma x  a n d 
A U C 0 -7 2 of t otal a n d free da bi gatr a n w he n da bi g atra n ete xil at e 
is a d mi nist ere d al o ne a n d c o-a d mi nistere d wit h gi vi n ostat will 
be t he pri mar y p har mac o ki n eti c para met ers f or t he assess me nt 
of t he effe ct of gi vi n ostat o n da bi gatr a n.  
A n a nal ysis of varia nce ( A N O V A) will be perf or me d o n t he l n-
tra nsf or me d pri mar y p har mac o ki netic para meters. A li near mi xe d 
effe cts m o del will be a p plie d, usi n g Tre at me nt as fi xe d effe cts, 
assesse d at a t w o o ne -si de d 5 % si g nific a nc e le vel ( α = 0. 0 5). S u bject 
will be i ncl u de d as ra n d o m effect.  Ge o metric me a ns rati os ( G M R ) a n d 
c orres p o n di n g 9 0 % c o nfi de nce i nter vals ( CI) will be calc ulate d f or t he 
l n-tra nsf or me d pri mar y p har mac o ki netic para meters, usi n g s u bstrates 
al o ne as t he refere nce.  
Wilc o x o n si g ne d ra n k test will be use d t o test f or t he differe nce i n t
ma x.  
Pla n ne d Trial 
Ti me li nes: 
E x pe cte d d urati o n of e nr ol me nt: 1 m o nt h  
E x pe cte d F SI: Marc h 2 0 2 2  
E x pe cte d L S L V: A pril 2 0 2 2  
Trial Pr oc e d ures:  
S e e Fl o wc hart  
St u d y E xit 
Pr oc e d ures/ E n d of Trial 
Visit/ Earl y Ter mi nati o n 
Visit  
At t he e n d -of -st u d y (i.e., at t he sc he d ule d disc har ge or i n c ase of 
e arlier disc o nti n uati o n), s u bje cts will u n der g o: p h ysical e xa mi nati o n, 
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 a n d uri nal ysis, vital si g ns ( B P, P R , R R a n d b o d y 
te m perat ure), 1 2-le a d E C G, wei g ht a n d, if fe male, ser u m pre g na nc y 
test. A Es will be m o nit ore d . 
F oll o w -u p Visit ( Da y 
1 2 after E o S ± 2 da ys)  
F or e a c h st u d y Part, a f oll o w -u p visit will be ma de t o all s u bje cts w h o 
re cei ve d at least o ne d ose of t he i n vesti gati o nal pr o d uct f or safet y 
assess me nts [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 a n d c oa g ulati o n ( o nl y i n Part 1), vit al si g ns ( B P, P R , R R 
a n d b o d y te m perat ure), 1 2 -lea d E C G a n d, if fe male, uri ne  pre g na nc y 
test] a n d t o m o nit or o n g oi n g A Es or t o c he c k f or p ossi ble A Es o n Da y 
1 2 ± 2 da ys after t he E o S.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 0  of 5 7  
 
2  
F L O W -C H A R T A N D S T U D Y D E SI G N DI A G R A M  
 
2. 1  
St u d y Fl o w -C h art  –  P art 1  
 
 
Scree ni n g  A d missi o n  
Tre at m e nt P eri o d  
S af et y 
F oll o w -u p  
D A Y S  
– 2 1 t o – 3  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
2 0  
( E o S1) 
1 0 -1 4 
Da ys after 
E o S  
I nf or m e d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gr a p hic d at a 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dic al hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selecti o n crit eri a verific ati o n  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysic al e x a mi n ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
P h ysic al e x a mi n ati o n u p d at e  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o d y hei g ht, wei g ht a n d B MI 3 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
Vit al si g ns 4  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -le a d s af et y E C G5 
X  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
He m at o l o g y 
X  
X  
 
 
 
X  
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
X  
X  
Bi oc he mist r y 6 
X  
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
Uri n al ysis  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
C o a g ul ati o n  
X  
X  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
Vir al ser ol o g y ( HI V a n d He p atitis 
B a n d C)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri ne dr u g, c oti ni ne a n d alc o h ol 
scree n 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P re g n a nc y t es t7 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
F S H t est ( p ost -m e n o p a us al o nl y)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S A R S -C o V -2 t est 8 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gi vi n ost at a d mi nist r ati o n
9 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
   X  
 
 
Mi d az ol a m i. v. a d mi nist r ati o n  
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
Mi d az ol a m or al a d mi nist r ati o n  
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
D a bi g at r a n et e xil at e 
A d mi nist r ati o n  
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
Bl o o d s a m pli n g f or mi d az ol a m 
P K 1 0 
 
 
X  
X  
X  
 
 
X  
X  
X  
 
 
 
 
 
 
 
 
X  
X  
X  
 
 
Bl o o d s a m pli n g f or d a bi g at r a n 
et e xil at e P K 1 1 
 
 
X  
X  
X  
X  
 
X  
X  
X  
X  
 
 
 
 
 
 
 
X  
X  
X  
X  
 
Ti m e i n cli nic  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
A E m o nit ori n g  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 1  of 5 7  
 
 
Scree ni n g  A d missi o n  
Tre at m e nt P eri o d  
S af et y 
F oll o w -u p  
D A Y S  
– 2 1 t o – 3  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
2 0  
( E o S1) 
1 0 -1 4 
Da ys after 
E o S  
P ri or a n d c o nc o mit a nt m e dic ati o n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
E n d -of -st u d y is defi ne d as t he last st u d y pr oce d ure o n Da y 2 0 or at earl y dis c o nti n uati o n of s u bjects a d mi nistere d at least o ne d os e  of i n vesti gati o nal pr o d uct. 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 bject wit h dra wal, wit hi n 1 0 -1 4 da ys after last partici pati o n of t he s u bject i n t he st u d y, w he ne ver 
p ossi ble. 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 s afet y tests perf or me d d uri n g e n d -of -st u d y s afet y ass ess me nts, t he s u bject will be 
i n vite d t o repeat si g nifica nt a b n or mal la b orat or y res ults.   
2 
De m o gra p hic data i ncl u di n g a ge, s e x a n d race.  
3 
O nl y b o d y wei g ht will be deter mi ne d at a d missi o n a n d e n d -of -st u d y. 
4 
Bl o o d press ure, p uls e rate, res pirat or y rate a n d b o d y te m perat ure will be assesse d at scree ni n g, a d missi o n, e n d-of -st u d y a n d f oll o w-u p. O n D a ys 1, 2, 6, 7, 1 7 a n d 1 8 
bl o o d press ure, p uls e rate a n d res pirat or y rate will be assess e d bef ore mi daz ola m a d mi nistrati o n a n d 0. 5, 1, 2, 4, 8 a n d 1 2 h o urs p ost -d os e. O n D a ys 4, 5, 8 -1 6 a n d 
1 9, bl o o d press ure a n d p uls e rate will be ass ess e d pri or t o eac h gi vi n ostat m or ni n g d os e. B o d y te m perat ure will als o be assesse d o nce dail y, i n t he m or ni n g, d uri n g 
t he c o nfi ne me nt peri o d as part of t he C O VI D -1 9 c o nti n ge nc y pla n .  
5 
Fr o m Da y 4 t o Da y 1 9, a n E C G will be o btai ne d a p pr o xi matel y at 5 h o urs after t he a d mi nistrati o n  of  gi vi n ostat m or ni n g d os e. B as eli ne E C G will be o btai ne d o n 
Da y 3 at a p pr o xi matel y  t he s a me ti me. E C G will als o be o btai ne d at s cree ni n g, a d missi o n, e n d-of -st u d y a n d f oll o w-u p.  
6 
T he f oll o wi n g bi oc he mistr y para meters will be ass ess e d at all ti me p oi nts: t otal bilir u bi n, direct a n d i n direct bilir u bi n, A L P , A L T, A S T, L D H, G G T, creati ne ki nas e, 
s o di u m, p otassi u m, c hl ori de, calci u m, ma g nesi u m, gl uc ose, creati ni ne a n d urea. T otal c h olester ol, L D L -C , H D L-C , tri gl yceri d es, a m ylase, c-reacti ve pr otei n, 
c ystati n C,  t otal pr otei n, al b u mi n, uric aci d, T S H will be ass esse d at s cree ni n g a n d e n d-of -st u d y.  
7 
T he pre g na nc y test will be perf or me d i n s er u m at  s cree ni n g a n d e n d of st u d y, a n d i n uri ne at a d missi o n a n d f oll o w -u p.  
8 
S A R S -C o V -2 test t o be perf or me d pri or t o a d missi o n t o treat m e nt peri o d.  
9 
Fr o m Da y 4 a n d Da y 1 8 gi vi n ostat 5 0 m g as oral s us pe nsi o n will be a d mi nistere d t wice a da y, i n t he m or ni n g a n d i n t he e ve ni n g. O n Da y 1 9, o nl y t he m or ni n g d os e 
will be a d mi nistere d.  
1 0 
Bl o o d s a m ples f or P K ass ess me nt of mi daz ola m a n d 1 -h y dr o x y mi daz ola m f oll o wi n g i ntra ve n o us mi daz ola m will be c ollecte d o n Da ys 1, 6 a n d 1 7 at pre -d os e a n d at 
2 mi n utes, 0. 2 5, 0. 5, 0. 7 5, 1, 2, 3, 4, 6, 9, 1 2 a n d 2 4 h o urs after t he a d mi nistrati o n of i ntra ve n o us mi daz ola m. Bl o o d s a m ples f or P K ass ess me nt of mi daz ola m a n d 1 -
h y dr o x y mi daz ola m f oll o wi n g oral mi daz ola m will be c ollecte d o n Da ys 2, 7 a n d 1 8 at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2 a n d 2 4 h o urs p ost -d os e. T he 2 4 -h o ur bl o o d 
c ollecti o n f oll o wi n g i ntra ve n o us mi daz ola m will be ass u me d as t he pre -d os e s a m pli n g f or oral mi daz ola m.  
1 1 
Bl o o d s a m ples f or P K ass ess me nt of da bi gatra n (t otal a n d free) will be c ollecte d o n Da ys 1, 6 a n d 1 7 at pre -d os e a n d at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2, 2 4, 3 6, 4 8 a n d 
7 2 h o urs p ost -d os e. 
 
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n  
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 2  of 5 7  
 
2. 2  
St u d y D i a gr a m –  P art 1  
 
 
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 3  of 5 7  
 
3  
A D MI NI S T R A TI V E I N F O R M A TI O N  
 
Cli nic al S ite: 
 
 
 
 
 
 
 P ort u gal 
P h o ne: 
 
 
 
Cli nic al P h ar m ac ol o g y Dir e ct or:  
, M D, P h D 
Bl ue C li nic al P hase I 
 
 
Pri n ci p al I n vesti g at or:  
Marle ne F o nsec a, M D  
 
mf o nsec a @ bl uecli nic al. pt  
 
P h ar m ac o ki n etics:  
, P har m D, P h D 
 
 
 
D at a M a n a ge me nt , St atistics a n d Re p orti n g : 
 
 
,
 
 
Cli nic al P at h ol o g y:  
 
 
 
 
  
Bi o a n al ysis ( Pl as m a a n d Uri n e Dr u g Ass a ys):  
 
 
 
 
S p o ns or Dr u g S afet y M a n a ger : 
Italfar ma c 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: + 3 9 0 2 6 4 4 3 2 5 0 6  
Fa x: + 3 9 0 2 6 6 1 0 6 5 3 8  
Fa x ( ba c k -u p): + 3 9 0 2 6 4 4 3 2 9 5 5  
M o bile: + 3 9 3 9 3 3 3 2 1 4 0 0 0 4  
e -mail: dr u g -safet y @italfar ma c o.c o m 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 4  of 5 7  
 
M ateri o Vi gil a n ce a n d P h ar m ac o vi gil a n c e U nit:  
  
  
  
 
 
 
 
 
S p o ns or’s Cli nic al R & D M a n a ge r:  
 
Italfar ma c o S. p. A. 
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: + 3 9 0 2 6 4 4 3 
 
e -mail: 
 
 
S p o ns or’s Cli nic al R & D Dir ect or –  M e dic al E x pe rt:  
 
Italfar ma c o S. p. A. 
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: + 3 9 0 2 6 4 4 3 
 
e -mail: 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 5  of 5 7  
 
4  
SI G N A T U R E P A G E S  
 
4. 1  
Cli nic al Rese ar c h U nit  
 
We a gree t o c o n d uct t he st u dy i n c o m pli a nc e wit h t his Pr ot oc ol, De cl ar ati o n of Helsi nki, 
G o o d Cli nic al P r actic e ( G C P) g ui deli nes a n d t he a p plic a ble re g ul at ory re q uire me nts.  
 
 
Marle ne F o nsec a, M D  
Pri nci pal I n vesti gat or  
 
mf o nsec a @ bl uecli nic al. pt  
....................................................... 
Si g nat ure  
....................... 
Date  
 
 
 
 
 
, M D, P h D 
Cli nic al P har ma c ol o g y Direct or  
  
 
....................................................... 
Si g nat ure  
....................... 
Date  
 
 
4. 2  
S p o ns or’s R e pr ese nt ati ve / S p o ns or Me dic al E x p e rt 
 
O n be h alf of t he S p o ns or, I  a gree t o c o m ply wit h t he  pr oce d ures a n d S p o ns or’s 
res p o nsi bilities defi ne d i n t he Pr ot oc ol, w hic h h as bee n c o m pile d i n o bserv ati o n of t he  
De cl ar ati o n of Helsi nki, G o o d Cli nic al P r actic e ( G C P) g ui deli nes a n d a p plic a ble  
re g ul at ory re q uire me nts. 
 
 
 
Cli nic al R & D Dire ct or  
Italfar ma c o S. p. A. 
 
....................................................... 
Si g nat ure  
....................... 
Date  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 6  of 5 7  
 
5  
C O N T E N T S A N D A B B R E VI A TI O N S  
5. 1  
T a ble of C o nte nts  
 
1  S T U D Y S U M M A R Y  ........................................................................................................... 2  
2  F L O W -C H A R T A N D S T U D Y D E SI G N DI A G R A M  ................................................... 1 0  
2. 1  
S T U D Y F L O W -C H A R T –  P A R T 1  .............................................................................. 1 0  
2. 2  
S T U D Y D I A G R A M –  P A R T 1  .................................................................................... 1 2  
3  A D MI NI S T R A TI V E I N F O R M A TI O N  .......................................................................... 1 3  
4  SI G N A T U R E P A G E S ....................................................................................................... 1 5  
4. 1  
C LI NI C A L R E S E A R C H U NI T  .................................................................................... 1 5  
4. 2  
S P O N S O R ’S R E P R E S E N T A TI V E / SP O N S O R M E DI C A L E X P E R T  .................................. 1 5  
5  C O N T E N T S A N D A B B R E VI A TI O N S  .......................................................................... 1 6  
5. 1  
T A B L E O F C O N T E N T S  ............................................................................................. 1 6  
5. 2  
L I S T O F A B B R E VI A TI O N S  ........................................................................................ 1 9  
6  I N T R O D U C TI O N ............................................................................................................. 2 2  
6. 1  
B A C K G R O U N D O N H D A C  IN HI BI T O R S  ................................................................... 2 2  
6. 2  
B A C K G R O U N D O N G I VI N O S T A T ............................................................................. 2 3  
6. 3  
S T U D Y R A TI O N A L  .................................................................................................. 2 4  
6. 3. 1  
R ati o n al f or t he St u dy Desi g n  ................................................................. 2 4  
6. 3. 2  
R ati o n al f or D ose Sele cti o n a n d Tre at me nt D ur ati o n  ............................ 2 4  
6. 4  
B E N E FI T -R I S K A S S E S S M E N T  .................................................................................. 2 5  
7  S T U D Y O B J E C TI V E S  ..................................................................................................... 2 6  
7. 1  
P RI M A R Y  ................................................................................................................ 2 6  
7. 2  
S E C O N D A R Y  ........................................................................................................... 2 6  
8  I N V E S TI G A TI O N A L P L A N........................................................................................... 2 6  
8. 1  
S T U D Y D E SI G N  ....................................................................................................... 2 6  
8. 2  
S T U D Y P L A N  ........................................................................................................... 2 6  
8. 2. 1  
Scree ni n g Pr oc e d ures  ............................................................................. 2 6  
8. 2. 2  
A d missi o n t o Tre at me nt Peri o d  .............................................................. 2 7  
8. 2. 3  
P art 1 - I n hi bit ory a n d I n d uci n g Effe ct of Or al Givi n ost at o n t he Si n gle 
D ose P h ar m ac oki n etics of I ntr ave n o us a n d Or al Mi d az ol a m  ............................... 2 7  
8. 2. 4  
F oll o w -u p Visit  ....................................................................................... 2 8  
8. 3  
S T U D Y R E S T RI C TI O N S  ............................................................................................ 2 8  
8. 3. 1  
Lifestyle a n d Diet ary Restricti o ns  .......................................................... 2 8  
8. 3. 2  
Pre vi o us a n d C o nc o mit a nt Me dic ati o n  .................................................. 2 9  
8. 3. 3  
C o ntr ace pti o n Re q uire me nts  .................................................................. 2 9  
8. 4  
M E A S U R E S T O M I NI MI Z E B I A S ............................................................................... 3 0  
8. 4. 1  
R a n d o miz ati o n  ........................................................................................ 3 0  
8. 4. 2  
Bli n di n g  .................................................................................................. 3 0  
9  S T U D Y P O P U L A TI O N  ................................................................................................... 3 0  
9. 1  
R E C R UI T M E N T A N D S C R E E NI N G P R O C E D U R E S  ...................................................... 3 0  
9. 2  
IN C L U SI O N C RI T E RI A  ............................................................................................. 3 1  
9. 3  
E X C L U SI O N C RI T E RI A  ............................................................................................ 3 2  
1 0  S U B J E C T’ S P R E M A T U R E S T U D Y DI S C O N TI N U A TI O N A N D S T U D Y 
T E R MI N A TI O N  .................................................................................................................... 3 4  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 7  of 5 7  
 
1 0. 1  
S U BJ E C T ’S P R E M A T U R E D I S C O N TI N U A TI O N .......................................................... 3 4  
1 1  I N V E S TI G A TI O N A L P R O D U C T S ............................................................................... 3 5  
1 1. 1  
ID E N TI T Y O F IN V E S TI G A TI O N A L P R O D U C T S  .......................................................... 3 5  
1 1. 2  
IN V E S TI G A TI O N A L P R O D U C T S S U P P LI E S ................................................................ 3 5  
1 1. 3  
S T O R A G E A N D R E T U R N O F IN V E S TI G A TI O N A L P R O D U C T S  .................................... 3 6  
1 1. 4  
IN V E S TI G A TI O N A L P R O D U C T S A D MI NI S T R A TI O N  .................................................. 3 6  
1 1. 4. 1  
Tre at me nt C o m pli a nc e  ........................................................................... 3 7  
1 2  S T U D Y A S S E S S M E N T S  ................................................................................................. 3 7  
1 2. 1  
P H A R M A C O KI N E TI C A S S E S S M E N T S  ........................................................................ 3 7  
1 2. 1. 1  
Bl o o d S a m pli n g f or P h ar m ac oki netic Assess me nts  ................................ 3 7  
1 2. 1. 2  
Uri ne S a m pli n g f or P h ar m ac oki netic Assess me nts  ................................ 3 8  
1 2. 1. 3  
S a m ple  Pr oc essi n g, St or a ge a n d Tr a nsfer  ............................................. 3 8  
1 2. 1. 4  
Bi o a n alytic al Met h o ds  ............................................................................ 3 8  
1 2. 1. 5  
I nc urre d S a m ples Re a n alysis .................................................................. 3 8  
1 2. 2  
G E N E R A L S A F E T Y A S S E S S M E N T S  .......................................................................... 3 9  
1 2. 2. 1  
Me dic al Hist ory  ...................................................................................... 3 9  
1 2. 2. 2  
P hysic al Ex a mi n ati o n  ............................................................................. 3 9  
1 2. 2. 3  
Wei g ht, Hei g ht a n d B o dy M ass I n dex ..................................................... 3 9  
1 2. 2. 4  
Vit al Si g ns  ............................................................................................... 3 9  
1 2. 2. 5  
1 2 -L e a d Ele ctr oc ar di o gr a m  ................................................................... 3 9  
1 2. 2. 6  
L a b or at ory S afety T ests  .......................................................................... 3 9  
1 2. 3  
T O T A L B L O O D V O L U M E  ......................................................................................... 4 1  
1 3  A D V E R S E E V E N T S D E FI NI TI O N S A N D R E P O R TI N G R E Q UI R E M E N T S  ........ 4 1  
1 3. 1. 1  
Ex pe dite d Re p orti n g  ............................................................................... 4 1  
1 4  S T U D Y E N D P OI N T S  ....................................................................................................... 4 2  
1 4. 1  
P RI M A R Y E N D P OI N T S  ............................................................................................. 4 2  
1 4. 2  
S E C O N D A R Y E N D P OI N T S  ........................................................................................ 4 3  
1 5  S T A TI S TI C A L M E T H O D O L O G Y A N D A N A L Y SI S  ................................................. 4 3  
1 5. 1  
S A M P L E S I Z E D E T E R MI N A TI O N  .............................................................................. 4 3  
1 5. 2  
S T A TI S TI C A L A N A L Y SI S P L A N  ............................................................................... 4 3  
1 5. 3  
A N A L Y SI S P O P U L A TI O N S  ....................................................................................... 4 3  
1 5. 3. 1  
S afety P o p ul ati o n  .................................................................................... 4 3  
1 5. 3. 2  
P h ar m ac oki netic A n alysis P o p ul ati o n  .................................................... 4 4  
1 5. 3. 3  
Dr u g -Dr u g I nter acti o n C o m p ar a ble Bi o av ail a bility A n alysis P o p ul ati o n
 
4 4  
1 5. 4  
S U BJ E C T S ’ C H A R A C T E RI S TI C S  ............................................................................... 4 4  
1 5. 5  
P H A R M A C O KI N E TI C A N A L Y SI S  .............................................................................. 4 4  
1 5. 5. 1  
P art 1  ...................................................................................................... 4 4  
1 5. 6  
S A F E T Y D A T A A N A L Y SI S  ....................................................................................... 4 5  
1 6  D A T A C O L L E C TI O N, M O NI T O RI N G A N D R E T E N TI O N  ..................................... 4 5  
1 6. 1  
D A T A C O L L E C TI O N  ................................................................................................ 4 5  
1 6. 1. 1  
C ase Re p ort F or ms  ................................................................................. 4 6  
1 6. 1. 2  
S o urce D oc u me nts  .................................................................................. 4 6  
1 6. 2  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ................................................... 4 6  
1 6. 2. 1  
Q u ality C o ntr ol  ....................................................................................... 4 6  
1 6. 2. 2  
M o nit ori n g  .............................................................................................. 4 6  
1 6. 2. 3  
S o urce D oc u me nt Verific ati o n  ................................................................ 4 7  
1 6. 2. 4  
A u diti n g a n d I ns pecti o n  .......................................................................... 4 7  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 8  of 5 7  
 
1 6. 3  
R E T E N TI O N A N D A R C HI VI N G O F D O C U M E N T S ....................................................... 4 7  
1 6. 4  
F I N A L S T U D Y R E P O R T  ............................................................................................ 4 7  
1 7  G E N E R A L S T U D Y A D MI NI S T R A TI O N  ..................................................................... 4 8  
1 7. 1  
R E G U L A T O R Y A N D E T HI C A L A S P E C T S ................................................................... 4 8  
1 7. 1. 1  
Re vie w a n d A p pr ov al by t he I n de pe n de nt Et hics C o m mitte e  ................. 4 8  
1 7. 1. 2  
S u bje ct I nf or m ati o n a n d C o nse nt  ........................................................... 4 8  
1 7. 1. 3  
Re vie w a n d A p pr ov al by Re g ul at ory A ut h orities .................................... 4 8  
1 7. 1. 4  
I ns ur a nc e, I n de m nity a n d C o m pe ns ati o n ............................................... 4 8  
1 7. 1. 5  
C o m pli a nc e St ate me nt  ............................................................................ 4 9  
1 7. 1. 6  
I nv esti g at or St ate me nt ............................................................................ 4 9  
1 7. 1. 7  
Dele g ati o n of I nvesti g at or D uties  ........................................................... 4 9  
1 7. 2  
C O N DI TI O N S F O R M O DI F YI N G / AM E N DI N G T H E P R O T O C O L  ................................... 4 9  
1 7. 3  
D O C U M E N T S F O R S T U D Y INI TI A TI O N  ..................................................................... 4 9  
1 7. 4  
O W N E R S HI P O F D A T A , DI S C L O S U R E A N D C O N FI D E N TI A LI T Y  ................................. 4 9  
1 8  R E F E R E N C E S  .................................................................................................................. 5 0  
1 9  A P P E N DI C E S  ................................................................................................................... 5 2  
1 9. 1  
A P P E N DI X 1  - A D V E R S E E V E N T S A N D P R E G N A N C Y C O N SI D E R A TI O N S  ................. 5 2  
1 9. 1. 1  
A dv erse Ev e nts - Defi niti o ns  ................................................................... 5 2  
1 9. 1. 2  
Pr oc e d ures f or Rec or di n g, Ev al u ati o n, D oc u me nt ati o n a n d Re p orti n g  5 3  
1 9. 1. 3  
Pre g n a nc y  ............................................................................................... 5 6  
 
 
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  1 9  of 5 7  
 
 
5. 2  
List of A b br e vi ati o ns  
 
A D R  
A d verse Dr u g Rea cti o n  
A E  
A d verse E ve nt  
A L P  
Al kali ne P h os p hatase  
A L T  
Ala ni ne A mi n otra nsferase  
A mt C U M  
C u m ulati ve a m o u nt of dr u g e xcrete d i n uri ne  
A N O V A  
A nal ysis of Varia nce  
a P T T  
Acti vate d Partial T hr o m b o plasti n Ti me  
A S T  
As partate A mi n otra nsferase  
A T C  
A nat o mic T hera pe utic Class  
A U C  
Area U n der t he Plas ma C o nc e ntrati o n -Ti me C ur ve  
A U C 0 -2 4 
A U C fr o m ti me zer o t o 2 4 h o urs  
A U C 0 -7 2 
A U C fr o m ti me zer o t o 7 2 h o urs  
A U C 0 -t 
A U C fr o m Ti me Zer o t o Last Sa m pli n g Ti me wit h Q ua ntifia ble C o nc e ntr ati o ns  
A U C 0 -τ,ss 
A U C d uri n g a D osi n g I nter val at stea d y state  
A U C 0 -∞ 
A U C fr o m T i me Zer o t o I nfi nit y 
% A U C
e xtra p 
Resi d ual Area or Perc e nta ge of E xtra p olate d Part of A U C 0 -∞ 
A U R C 0 -tl ast 
Area u n der t he uri ne e xcreti o n c ur ve fr o m ti me zer o t o last o bser ve d 
c o nc e ntrati o n 
β -h C G  
Beta H u ma n C h ori o nic G o na d otr o pi n  
B M D  
Be c ker M usc ular D ystr o p h y  
B MI  
B o d y Mass I n de x  
B P  
Bl o o d Press ure  
C EI C  
C o missã o de Étic a para a I n vesti ga çã o Clí nic a  
 
 
( P ort u g uese Et hics C o m mitte e f or Cli nic al Researc h) 
CI   
C o nfi de nc e I nter val  
C L ss/ F 
A p pare nt t otal b o d y cle ara nc e at ste a d y state  
C m a x  
Ma xi m u m O bser ve d Plas ma C o nc e ntrati o n  
C m a x,ss  
Ma xi m u m O bser ve d Plas ma C o nce ntrati o n at stea d y state
 
 
Cr C L   
Cre ati ni ne Cle ara nce  
C L R / F 
A p pare nt re nal cleara nc e  
C S R  
Cli nic al St u d y Re p ort  
C T C L  
C uta ne o us T Cell L y m p h o ma  
C tr o u g h 
Pre -d ose Plas ma C o nce ntrati o n  
C V %  
C oefficie nt of Variati o n  
C Y P  
C yt oc hr o me P 4 5 0  
D B P  
Diast olic Bl o o d Press ure  
D DI  
Dr u g -Dr u g I ntera cti o n  
D M D  
D uc he n ne M usc ular D ystr o p h y  
D N A  
De o x yri b o n ucleic Aci d  
E C G  
Electr ocar di o gra m  
e C R F  
Electr o nic Case Re p ort F or m  
e C T D  
Electr o nic C o m m o n Te c h nic al D oc u me nt  
e G F R  
Esti mate d Gl o mer ular Filtrati o n  
E o S  
E n d -of -St u d y  
E M A  
E ur o pe a 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  
F S H  
F ollicle Sti m ulati n g H or m o ne  
G C P  
G o o d Cli nic al Pra ctic e  
G G T  
Ga m ma -Gl uta m yltra nsferase  
G L P  
G o o d La b orat or y Practic e  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 0  of 5 7  
 
G M P  
G o o d Ma n ufa ct uri n g Practic e  
G M R  
Ge o metric Le ast S q uare Mea ns Rati o  
H Bs A g  
He patitis B S urfac e A nti ge n  
H C V  
He patitis C Vir us  
H D A C  
Hist o ne De ac et ylases  
H D L -C  
Hi g h -De nsit y Li p o pr otei n C h olester ol  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I N F A R M E D 
A ut ori da de Na ci o nal d o Me dic a me nt o e Pr o d ut os de Sa ú de I. P.  
 
 
( P ort u g uese Nati o nal A ut h orit y of Me dici nes a n d Healt h Pr o d ucts)  
I N R 
I nter nati o nal N or malize d Rati o 
I S C V % 
I ntras u bje ct C oefficie nt of Variati o n  
L D H  
La ctate De h y dr o ge nase  
L D L -C  
L o w -De nsit y Li p o pr otei n C h olester ol  
L L N  
L o wer Li mit of t he N or mal  
L L O Q  
L o wer Li mit of Q ua ntific ati o n  
M C H  
Mea n C or p usc ular He m o gl o bi n  
M C H C  
Mea n C or p usc ular He m o gl o bi n C o nc e ntrati o n  
M C V  
Mea n C or p usc ular V ol u me  
Me d D R A  
Me dic al Dicti o nar y f or Re g ulat or y Acti vities  
m R N A  
Messe n ger Ri b o n ucleic Aci d  
O T C  
O ver -T he -C o u nter  
P C P  
P he nc ycli di ne  
P C R  
P ol y merase C hai n R e acti o n  
P -g p  
P -gl yc o pr otei n  
P K  
P har ma c o ki netic  
P T   
Me d D R A Preferre d Ter m  
P T C L  
Peri p heral T -cell L y m p h o ma  
P R  
P ulse  Rate  
Q Tc F  
C orre cte d Q T i nter val b y Fre dericia  
R B C  
Re d Bl o o d Cell  
R E C %  
Perc e nta ge of dr u g re c o vere d i n uri ne  
R m a x  
Ma xi m u m uri nar y e xcreti o n rate  
R R  
Res pirat or y Rate  
S A E  
S eri o us A d verse E ve nt  
S A P  
Statistic al A nal ysis Pla n  
S A R S -C o V -2  S e vere Ac ute Res pirat or y S y n dr o me C or o na vir us 2  
S B P  
S yst olic Bl o o d Press ure  
S D  
Sta n dar d De viati o n  
S E   
Sta n dar d Err or  
S O C  
Me d D R A S yste m Or ga n Class  
S O P  
Sta n dar d O perati n g Pr oc e d ure  
S U S A R  
S us pecte d U ne x pe cte d S eri o us A d verse Re acti o n  
T E A E  
Tr e at me nt -E mer ge nt A d verse E ve nts  
T M F  
Trial Master File  
tm a x  
Ti me t o Ma xi m u m O bser ve d C o nce ntrati o n  
tm a x,ss  
Ti me of oc c urre nce of C ma x,ss  
t um a x  
Ti me t o R m a x  
t1/ 2  
A p pare nt Ter mi nal Eli mi nati o n Half -Life  
U A R  
U ne x pecte d A d verse Rea cti o n  
U L O Q  
U p per Li mit of Q ua ntificati o n  
U L N  
U p per Li mit of N or mal  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 1  of 5 7  
 
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 Cell  
λ z  
A p pare nt Ter mi nal Eli mi nati o n Rate C o nsta nt  
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 2  of 5 7  
 
6  
I N T R O D U C TI O N 
 
I T F 2 3 5 7 ( Gi vi n ostat h y dr oc hl ori de m o n o h y drate ) is a n orall y a cti ve h y dr o xa mic aci d 
deri vati ve t hat is bei n g de vel o pe d b y Italfar ma c o S. p. A. i n t he tre at me nt of D uc he n ne 
M usc ular D ystr o p h y ( D M D) a n d Be c ker M usc ular D ystr o p h y ( B M D) as a n oral 
s us pe nsi o n f or m ulati o n. 
 
6. 1  
B ac k gr o u n d o n H D A C I n hi bit ors  
 
Zi nc i o n de pe n de nt hist o ne de ac et ylases ( H D A Cs ) are a class of 1 1 is oe nz y mes ass ociate d 
wit h n u mer o us n ucle ar re press or c o m ple xes t hat, o nc e recr uite d t o s pecific sites of 
e uc hr o mati n, mai ntai n n ucle os o me hist o nes i n a state of de a cet ylati o n s o t hat D N A 
re mai ns ti g htl y b o u n d a n d i nac cessi ble t o tra nscri pti o n fact ors f or ge ne e x pressi o n. I n 
c o ntrast, i n hi biti o n of H D A C res ults i n h y perac et ylati o n of t hese hist o nes a n d all o ws t he 
u nra veli n g of D N A s ufficie nt f or t he bi n di n g of tra nscri pti o n fa ct ors a n d t he s y nt hesis of 
m R N A. H o we ver,  h ist o ne de ac et ylases als o dea cet ylate n o n-hist o ne s u bstrates i n t he 
c yt os ol. F or i nsta nc e,  re g ulati o n of pr otei n f u ncti o ns t hr o u g h re versi ble l ysi ne a cet ylati o n 
i n v ol ves a gr o wi n g n u m ber of pr otei ns. A re p ort i n dicates t hat m ore t ha n 3, 6 0 0 critic al 
l ysi ne resi d ues are  ac et ylate d i n m ore t ha n 1, 7 5 0 pr otei ns i n v ol ve d i n t he re g ulati o n of 
b ot h n ucle ar a n d  c yt o plas mic f u ncti o ns of t he cell [C h o u d har y 2 0 0 9 ]. 
 
A ge nts t hat i n hi bit H D A C a cti vit y var y i n  str uct ure a n d e xa m ples of selecti ve i n hi bit ors of 
s pecific H D A Cs are als o re p orte d i n t he literat ure [Wa n g 2 0 0 9; Pa n  2 0 1 2 ]. 
I n vesti gati o ns of i n hi bit ors of H D A C ha ve f oc use d mai nl y i n mali g na nt c ells. M ost t u m or 
c ells s ur vi ve a n d pr oliferate b y s u p pressi n g e x pressi o n of pr o -a p o pt otic ge nes a n d t his  
me c ha nis m is re verse d b y i n hi biti o n of H D A C. F urt her m ore, o nc o ge nic pr otei ns are a ble 
t o efficie ntl y re cr uit H D A C e nz y mes f or mi n g m ulti -pr otei n c o m ple xes acti n g as 
re press ors o n t h ose pr o m oter re gi o ns n or mall y c o ntr olle d b y t he wil d-t y pe tra nscri pti o n 
fa ct or. 
T he fi n di n g t hat a berra nt H D A C acti vit y oc c urs wi del y i n c a ncer has pr o vi de d a rati o nale 
f or usi n g H D A C i n hi bit ors as a p ote ntial treat me nt wit h t hera pe utic be nefits a n d a n 
u n pre ce de nte d  l o w t o xicit y f or n or mal c ells a n d sele cti vit y f or t u m or cells [K ha n O  2 0 1 2; 
Mar ks 2 0 1 0 ]. 
A pa n H D A C i n hi bit or, V ori n ostat ( Z oli nza; s u ber o yl a nili de h y dr o xa mic: S A H A) is 
alrea d y  a p pr o ve d f or c uta ne o us T cell L y m p h o ma ( C T C L). R o mi de psi n (Ist o da x) a n 
i n hi bit or wit h differe nt s pecificit y f or H D A C is oe nz y mes, a n d of differe nt c he mical class 
c o m pare d t o  V ori n ostat, has als o bee n a p pr o ve d f or  C T C L a n d f or peri p heral T -c ell 
l y m p h o ma ( P T C L). M ore rec e ntl y Beli n ostat ( Bele o da q) a n d Pa n o bi n ostat ( Far y da k), 
ot her H D A C i n hi bit ors,  ha ve be e n a p pr o ve d f or rela pse d or refract or y P T C L a n d f or t he 
tre at me nt of rela pse d a n d refract or y m ulti ple m yel o ma i n c o m bi nati o n wit h Velc a de 
( B orte z o mi b) a n d De xa met has o ne ( Dec a dr o n), res pecti vel y. 
Gi vi n ostat is a n orall y a cti ve h y dr o xa mic aci d deri vati ve p ossessi n g a p ote nt  H D A C 
i n hi bit or y a cti vit y a n d p ossi bl y t he a nti-t u m oral pr o perties t y pic al of t his class of 
i n hi bit ors. T heref ore, its use f or t he treat me nt of mali g na ncies i n ge neral a n d t he 
he mat ol o gic al o nes i n partic ular a p pears t o be well j ustifie d.  
 
I n vitr o, t he c o nce ntrati o ns of H D A C i n hi bit ors re q uire d t o i n d uc e cell de at h are i n t he 
micr o m olar or hi g her ra n ge; i n a ni mals, si milar circ ulati n g c o nc e ntrati o ns are nee de d f or  
t u m or re gressi o n. A n u ne x pecte d a n d se e mi n gl y para d o xic al pr o pert y of H D A C i n hi biti o n 
is t he re d ucti o n of i nfla m mati o n, partic ularl y i n m o dels of a ut oi m m u ne diseases a n d 
i nfla m mati o n. T his ad diti o nal effect is e xerte d at c o nc e ntrati o ns/ d oses w hic h are 
si g nific a ntl y i nferi or t o t he t u m orici dal o nes a n d is d ue t o t he i n hi biti o n of pr o-
i nfla m mat or y c yt o ki ne ge ne e x pressi o n [Le o ni 2 0 0 2; Nis hi da 2 0 0 4 ]. S e veral st u dies i n 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 3  of 5 7  
 
vitr o a n d i n viv o s u p p ort t he c o nce pt t hat i n hi biti o n of H D A C is als o a strate g y t o re d uce 
t he pr o d ucti o n a n d a cti vit y of pr o -i nfla m mat or y c yt o ki nes [S uli ma n 2 0 1 2 ]. T he a nti-
i nfla m mat or y a cti vities of a n u m ber of H D A C i n hi bit ors, a m o n g t he m V ori n ostat 
( S A H A), gi vi n ostat  a n d Da ci n ostat ( L A Q 8 2 4) ha ve bee n descri be d [Le o ni ; Br o g d o n 
2 0 0 7; Le o ni 2 0 0 5; Carta 2 0 0 6 ]. Re c e nt e vi de nc e als o i n dic ates t hat t he i n hi biti o n of 
H D A C  e nz y mes le a ds t o pr of o u n d c ha n ges i n t he  e pi ge netic pr o gra m me of i m m u ne c ells. 
T h us, t he  dere g ulate d re acti vit y a n d li ne a ge c o m mit me nt of c ells of t he i n nate a n d  
a da pti ve i m m u ne  s yste m f o u n d i n a variet y of i nfla m mat or y-relate d diseases ca n be 
re verte d t o n or mal b y H D A C i n hi biti o n [S we et 2 0 1 2; Di narell o 2 0 1 1 ]. T he 
af ore me nti o ne d a nti-i nfla m mat or y a n d im m u ne -m o d ulati n g a cti vities are t he basis of t he 
p ote ntial use of gi vi n ostat  i n a n u m ber of diseases, s uc h as r he u mat ol o gic al dis or ders, 
Graft Vers us H ost Disease, a n d  selecte d o nc o he mat ol o gical c o n diti o ns. Fi nall y, t he a nti-
i nfla m mat or y pr o perties of gi vi n ostat  ass ociate d wit h its a nti -fi br otic a n d pr o-re ge nerati ve 
a cti vities are t he basis f or t he  de vel o p me nt of t his c o m p o u n d i n D M D  [Mi netti  2 0 0 6; 
C ol ussi 2 0 0 8; C ol ussi 2 0 0 9; Ie z zi 2 0 0 4; Mal 2 0 0 1; Ne b bi os o 2 0 0 9 ]. 
 
6. 2  
B ac k gr o u n d o n Gi vi n ost at  
 
Gi vi n ostat has bee n teste d i n a n u m ber of cli nic al st u dies. T hr e e maj or i n dic ati o ns ha ve 
be e n e x pl ore d s o far wit h gi vi n o stat i n c o m plete d or o n g oi n g trials: (i) i nfla m mat or y 
diseases, (ii) o nc ol o g y a n d (iii) m usc ular d ystr o p hies.  
Cli nic al e x perie nc e wit h gi vi n ostat i n h u ma ns i ncl u des 2 1  s p o ns ore d cl ose d trials a n d 
c o m passi o nate use pr o gra m a n d 4 o n g oi n g trials. T he t otal e x p ose d p o p ulati o n is 6 5 5 
patie nts i n gi vi n ostat a n d 2 3 0 patie nts i n gi vi n ostat or pla c e b o ( o n g oi n g d o u ble -bli n d 
trials). 
 
Gi vi n ostat is well a bs or be d after oral a d mi nistrati o n a n d plas ma c o nce ntrati o ns i ncre ase i n 
a d ose pr o p orti o nal ma n ner. T he a p pare nt ha lf-life after oral a d mi nistrati o n is 
a p pr o xi matel y 6 -8 h o urs wit h a ti me of occ urre nce of ma xi m u m o bser ve d plas ma 
c o nc e ntrati o n (t m a x ) at 2-3 h o urs p ost d ose. Stea d y state le vels are a c hie ve d after 5 -7 da ys 
of c o nti n u o us d osi n g.  
B o d y wei g ht was i de ntifie d as c o variate of cleara nc e. A n i ncrease of 1 0 k g i n b o d y wei g ht 
i n patie nts wei g hi n g fr o m 1 0 k g t o 3 0 k g res ulte d i n re d ucti o n of ma xi m u m o bser ve d 
plas ma c o nce ntrati o n ( C m a x ) a n d are a u n der t he c ur ve ( A U C ) bet wee n 2 0 a n d 3 0 % o n 
a vera ge, w hile i n patie nts wei g hi n g fr o m 3 0 k g t o 7 0 k g t he re d ucti o n was  
bet we e n 1 0 -1 5 %. A hi g h fat sta n dar d me al sli g htl y affe cte d t he p har ma c o ki netics of 
gi vi n ostat res ulti n g i n i ncre ase d plas ma c o nce ntrati o ns (a b o ut 4 0 % i ncrease i n gi vi n ostat 
A U Cs a n d a b o ut 2 0 % i ncrease i n C ma x ) a n d i n a sli g ht dela y i n a bs or pti o n. 
 
T he m ost c o m m o n a d verse e ve nts ( A Es) o bser ve d were t hr o m b oc yt o pe nia as well as 
gastr oi ntesti nal t o xicities. A Es were ge nerall y mil d t o m o derate a n d re versi ble u p o n 
dis c o nti n uati o n of st u d y dr u g. T he ma xi m u m a d mi nistere d d ose was a si n gle d ose of 
6 0 0  m g i n he alt h y v ol u nte ers a n d u p t o 4 0 0 m g o nce per we e k i n patie nts wit h m ulti ple 
m yel o ma. D oses u p t o a p pr o xi matel y 1 0 0 m g b.i. d. were ge nerall y well t olerate d i n a d ults. 
A t hi g her d oses of gi vi n ostat, tra nsie nt re d ucti o ns i n he mat ol o gic al para meters 
( partic ularl y platelets), diarr he a , na usea a n d v o miti n g were o bser ve d.  
N o seri o us a d verse e ve nts ( S A Es) oc c urre d t hr o u g h o ut t he st u d y peri o d i n a n y of t he 
st u dies wit h he alt h y vol u nte ers.  
O verall, tre at me nt wit h gi vi n ostat  of b ot h he alt h y v ol u nteers a n d patie nts di d n ot s h o w  
cli nic all y me a ni n gf ul c ha n ges f or a n y of t he meas ure d c he mistr y para meters, wit h t he  
e xc e pti o n of a tra nsie nt a n d sli g ht i ncre ase i n ser u m creati ni ne le vels o bser ve d i n o nl y o ne  
st u d y i n Cr o h n’s disease patie nts. 
T here was n o e vi de nce of ge neral s yste mic t o xicit y refle cte d b y c ha n ges i n vital si g ns i n 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 4  of 5 7  
 
t he st u die d p o p ulati o ns. Is olate d c ases of pal pitati o n a n d ta c h ycar dia ha ve be e n re p orte d 
i n gi vi n ostat  tre ate d patie nts. T here is n o i n dic ati o n t hat t h ose mi g ht be c a usall y ass ociate d 
wit h  gi vi n ostat . Fi nall y, des pite s o me e pis o des of Q Tc pr ol o n gati o n were re p orte d, n o 
e ve nts of  cli nical c o ncer n or d ose relate d tre n d were se e n.  
I n a de dic ate d  Q T/ Q Tc ( T Q T) st u d y, preli mi nar y data s u g gest t hat after g i vi n ostat 
a d mi nistrati o n i n si n gle d oses of 1 0 0 m g (t hera pe utic d ose) or 3 0 0 m g (s u prat hera pe utic 
d ose) t o he alt h y s u bjects, g i vi n ostat e xerte d a d ose -de pe n de nt effe ct o n he art rate, w hic h 
was cli nic all y rele va nt f or t he s u prat hera pe utic d ose ( 3 0 0 m g) o nl y.  T he effect see n o n 
1 0 0 m g is of n o cli nic al c o ncer n. Gi vi n ostat  c a use d pr ol o n gati o n of t he Q Tc i nter val, f or 
t he s u prat hera pe utic d ose ( 3 0 0 m g) o nl y. T he pea k effect was se e n at 5 h o urs p ost -d ose 
f or b ot h g i vi n ostat teste d d oses. Gi vi n ostat  di d n ot ha ve a cli nic all y rele va nt effect o n t he 
he art rate or Q R S i nter vals.  
O verall, n o s u bje cts re p orte d Q Tc F > 4 8 0 ms or Δ Q Tc F > 6 0 ms. T here was o nl y o ne 
s u bje ct a d mi nistere d wit h t he s u prat hera peutic d ose ( 3 0 0 m g) of g i vi n ostat wit h Q Tc F 
>  4 5 0 a n d ≤  4 8 0 ms at o ne ti me p oi nt.  
 
F urt her details o n gi vi n ostat, i ncl u di n g a s u m mar y of t he res ults of t he n o ncli nic al a n d 
cli nic al st u dies alrea d y a vaila ble, are prese nte d i n t he res pecti ve I n vesti gat or’s Br oc h ur e 
[Gi vi n ostat I B ].  
 
6. 3  
St u d y R ati o n al  
 
6. 3. 1  
R ati o n al f or t he St u d y  Desi g n  
 
I n vitr o data s h o we d t hat gi vi n ostat ma y ha ve a p ote ntial f or dr u g -dr u g i ntera cti o n ( D DI) 
at le vel of c yt oc hr o me P 4 5 0 ( C Y P )3 A -me diate d meta b olis m a n d P -gl yc o pr otei n ( P -g p) 
tra ns p ort. 
I n t he c urre nt st u d y, t he per petrat or D DI p ote ntial of gi vi n ostat as i n hi bit or a nd i n d uc er of 
C Y P 3 A a n d P -g p a cti vit y will be e val uate d i n Part 1, b y deter mi ni n g t he i m pa ct of 
gi vi n ostat o n t he p har ma c o ki netics of mi da z ola m (se nsiti ve i n de x C Y P 3 A s u bstrate) a n d 
da bi gatra n ete xilate ( P -g p s u bstrate). T he per petrat or D DI p ote ntial of gi v i n ostat at t he 
le vel of C Y P 3 A a cti vit y will be e val uate d f oll o wi n g oral (effe ct at b ot h i ntesti nal a n d 
he patic C Y P 3 A) a n d i ntra ve n o us ( mai nl y he patic C Y P 3 A) mi da z ola m a d mi nistrati o n.   
 
6. 3. 2  
R ati o n al f or D ose  S electi o n  a n d Tr e at me nt D u r ati o n  
 
P art 1  
 
Rati o nale  f or Gi vi n ostat D ose a n d Tre at me nt D urati o n as Per petrat or 
 
Ac c or d i n g t o t he F D A G ui da nc e o n Cli nic al Dr u g I nteracti o n St u dies [F D A G ui da nc e 
2 0 2 0 ], t he d oses of t he per petrat or dr u g use d i n D DI st u dies s h o ul d ma xi mize t he 
p ossi bilit y of i de ntif yi n g a D DI. T he use of t he ma xi m u m d ose a n d t he s h ortest d osi n g 
i nter val of t he per petrat or u n der t he i nte n de d c o n diti o ns is re c o m me n de d. Acc or di n g t o 
Gi vi n ostat I n vesti gat or’s Br oc h ure [ Gi vi n ostat I B ], t his c orres p o n ds t o 5 0 m g t wic e-dail y.  
T he treat me nt d urati o n s hall all o w a p pr o priate i n hi bit or y effe ct ( us ua ll y ne ar ste a d y-state) 
a n d i n d ucti o n effe ct (i.e., a b o ut 2 we e ks of dail y dr u g a d mi nistrati o n, a c c or di n g t o t he 
F D A G ui da nc e o n D DI st u dies [F D A G ui da nc e 2 0 2 0 ]. T h us, t he i n hi bit or y effect will be 
assesse d o n Da ys 6 t o 9 a n d t he i n d ucti o n effect will assesse d o n Da ys 1 7 t o 2 0.  
T o mai ntai n a de q uate i n hi biti o n/i n d ucti o n of P -g p a n d C Y P 3 A, g i vi n ostat s h o ul d be 
c o nti n ue d f or 4 – 5 half -li ves of t he s u bstrate wit h l o n ger half-life ( da bi gatra n), i.e., at least 
u p t o 4 8 h o urs after da bi gatra n ete xilate a d mi nistrati o n o n Da y 1 7.  
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 5  of 5 7  
 
Rati o nale f or S u bstrates D ose  
 
Ac c or di n g t o t he F D A G ui da nc e o n D DI st u dies [ F D A G ui da nc e 2 0 2 0 ], t he t hera pe utic 
d ose m ost li kel y t o de m o nstrate a D DI s h o ul d be use d.  
I ntra ve n o us mi da z ola m is us uall y a d mi nistere d i n d oses u p t o 2 m g i ntra ve n o us as a 
s u bstrate of he patic C Y P 3 A [F u hr, 2 0 1 9 ]. I n t he prese nt st u d y, a 1 m g i ntra ve n o us d ose is 
pla n ne d.  
Mi da z ola m i n t he f or m of oral s ol uti o n is us uall y a d mi nistere d i n d oses u p t o 5 m g as a 
s u bstrate of i ntesti nal C Y P 3 A [F u hr, 2 0 1 9 ]. I n t he prese nt st u d y, a 2. 5 m g si n gle d ose is 
pla n ne d.  
Da bi gatra n  is us uall y a d mi nistere d i n d oses u p t o 1 5 0 m g as a pr o be f or i ntesti nal P-g p 
a cti vit y [F u hr, 2 0 1 9 ]. I n t he prese nt st u d y, a 7 5 m g si n gle d ose is pla n ne d. 
 
Rati o nale f or P er petrat or a n d S u bstrates A d mi nistrati o n S c he d ule: 
 
D DI st u dies e val uati n g t he effect of p ote ntial i n hi bit ors a n d i n d uc ers o n s u bstrate 
e x p os ure ha ve use d si m ulta ne o us d osi n g of per petrat or a n d s u bstrate/ victi m, as well as 
sta g gere d d osi n g, wit h t he s u bstrate bei n g a d mi nistere d bet we e n 1 a n d 4 h o urs after t he 
per petrat or d ose o n t he da y of c oa d mi nistrati o n. As a ge neral r ule, s u bstrates s hall be 
a d mi nistere d i n a ti mi n g t hat ai ms t o c a pt ure ma xi mal P -g p a n d C Y P 3 A i n hi biti o n b y t he 
per petrat or.  
Mi da z ola m oral s ol uti o n is a bs or be d ra pi dl y a n d c o m pletel y, a c hi e vi n g C ma x  at 0. 5 h o urs 
[B uc c ola m ®  S m P C ]. Da bi gatra n ete xilate p har mac o ki netic pr ofile i n plas ma is 
c hara cterize d b y a ra pi d i ncre ase i n c o nce ntrati o ns wit h C ma x  attai ne d wit hi n 0. 5 t o 2. 0 
h o u rs [Pra da xa ®  S m P C ].  
C o nsi deri n g a T m a x  ar o u n d 2 h o urs f or g i vi n ostat a n d t he p har mac o ki netic pr ofile of t he 
s u bstrates, t he a d mi nistrati o n of t he s u bstrates will oc c ur 1 h o ur after t he g i vi n ostat 
m or ni n g d ose o n Da ys 6, 7, 1 7 a n d 1 8.    
  
6. 4  
Be n efit -Ris k Assess me nt  
 
As t his cli nic al p har mac ol o g y st u d y is n ot c o n d ucte d i n t he tar get p o p ulati o n f or 
gi vi n ostat, t here are n o a ntici pate d cli nical be nefits f or partici pa nts be y o n d t he t h or o u g h 
me dic al c he c k -u p w hic h ea c h s u bje ct will u n der g o pri or t o re cei vi n g t he i n vesti gati o nal 
pr o d ucts a n d at t he e n d of t he st u d y.  
 
T he pre vi o us cli nic al e x perie nc e i n dicates t hat  gi vi n ostat is  well t olerate d at t he teste d 
d oses i n he alt h y  v ol u nte ers or patie nt s wit h c hr o nic i nfla m mat or y diseases, or wit h D M D 
w here d ose -relate d platelets c o u nt re d ucti o n a n d diarr he a were t he m ost fre q ue ntl y 
re p orte d A Es. 
As far as patie nts wit h o nc o -he mat ol o gic al c o n diti o ns are c o nc er ne d, gi vi n ostat  see ms t o 
ha ve  m ore pr of o u n d e ffe cts o n b o ne marr o w cell-li nes. O verall, t here has be e n n o ot her 
maj or safet y c o ncer n i n t he patie nt p o p ulati o n teste d.   
T here is e xte nsi ve e x perie nc e wit h mi da z ola m a n d da bi gatra n as pr o bes a n d wit h 
clarit hr o m yci n as per petrat or i n D DI st u dies wit h he alt h y s u bje cts. T he pla n ne d d oses a n d 
tre at me nt d urati o n f oll o w a sta n dar d a p pr oac h a n d are  e x pe cte d t o be safe a n d well -
t olerate d b y he alt h y s u bje cts a n d t o all o w a de q uate de m o nstrati o n of D DI. 
   
S u bje cts will be ke pt u n der me dical s u per visi o n d uri n g t he st u d y . S afet y assess me nts will 
i ncl u de p h ysic al e xa mi nati o n, vital si g ns, 1 2-le a d electr ocar di o gra m ( E C G ) a n d cli nic al 
la b orat or y safet y tests . D ue t o t he k n o w n effects of gi vi n ostat o n b o ne -marr o w cell -li nes, 
he mat ol o g y para meters will be fre q ue ntl y m o nit ore d d uri n g t he st u d y.  
S u bje ct’s t otal v ol u me of bl o o d wit h dra w n d uri n g t he st u d y, i ncl u di n g t he v ol u me 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 6  of 5 7  
 
re q uire d f or safet y tests, will be a p pr o xi matel y 4 7 7  m L i n Part 1. T he t otal bl o o d d o nati o n 
ma y be hi g her if re pe at bl o o d sa m ples are re q uire d.  
 
 
7  
S T U D Y  O B J E C TI V E S  
 
7. 1  
Pri m ar y  
 
1.  T o assess t he p o te ntial i n hi bit or y a n d i n d uci n g effe ct of oral gi vi n ostat o n t he si n gle 
d ose p har mac o ki netics of i ntra ve n o us a n d oral mi da z ola m ( Part 1).  
2.  T o assess t he p o te ntial i n hi bit or y a n d i n d uci n g effe ct of oral gi vi n ostat o n t he si n gle 
d ose p har mac o ki netics of oral da bi gatra n ete xilate ( Part 1).  
 
7. 2  
S e c o n d ar y  
 
1.  T o assess t he safet y a n d t olera bil it y of c o nc o mita nt a d mi nistrati o n of gi vi n ostat pl us 
mi da z ola m a n d da bi gatra n ete xilate ( Part 1).  
 
 
8  
I N V E S TI G A TI O N A L P L A N 
 
 
8. 1  
St u d y D esi g n 
 
T his is a p hase I,  o pe n -la bel, 3-part, fi xe d -se q ue nc e, n o n-ra n d o mize d st u d y i n he alt h y 
male a n d fe male s u bjects.  
A s u m mar y of pr oc e d ures a n d a  st u d y desi g n dia gra m are prese nte d i n S ecti o n 2  (St u d y 
F l o w-C hart  a n d S t u d y D esi g n D ia gra m).  
St u d y parts ma y be c o n d ucte d c o nc o mita ntl y.  
 
8. 2  
St u d y Pl a n  
 
8. 2. 1  
S c re e ni n g Pr oce d u res  
 
T he healt h y stat us will be deter mi ne d b y t he f oll o wi n g pre -st u d y assess me nts:  
-  C olle cti o n of de m o gra p hic data, me dic al hist or y, a n d me dic ati o n hist or y.  
-  C o m plete p h ysic al e xa mi nati o n, wei g ht a n d hei g ht a n d vital si g ns [ bl o o d press ur e 
( B P), p ulse rate (P R ), res pirat or y rate ( R R), a n d b o d y te m perat ure]. 
-  1 2 -le a d E C G. 
-  Fasti n g safet y la b orat or y assess me nts:  
▪ 
H e mat ol o g y [c o m plete bl o o d c o u nt : re d bl o o d cell (R B C ), w hite bl o o d 
c ell ( W B C ) (i ncl u di n g differe ntial c o u nt), he m o gl o bi n, me a n c or p usc ular 
he m o gl o bi n ( M C H ), me a n c or p usc ular he m o gl o bi n c o nce ntrati o n 
(M C H C ), me a n c or p usc ular v ol u me ( M C V ), re d cell distri b uti o n wi dt h, 
he mat ocrit, platelets  a n d me a n platelet v ol u me ]. 
▪ 
B i oc he mistr y [t otal bilir u bi n, dire ct a n d i n direct bilir u bi n, al kali ne 
p h os p hatase  ( A L P), a m ylase, ala ni ne a mi n otra nsferase ( A L T ), as partate 
a mi n otra nsferase ( A S T ), lactate de h y dr o ge nase (L D H ), c ystati n C, C -
re acti ve pr otei n (C R P ), ga m ma -gl uta m yltra nsferase ( G G T ), cre ati ne 
ki nase, t otal pr otei n, al b u mi n, uric a ci d, tri gl yc eri des, t otal c h olester ol, 
l o w-de nsit y li p o pr otei n  c h olester ol (L D L -C) , hi g h -de nsit y li p o pr otei n 
c h olester ol (H D L -C) , s o di u m, p otassi u m, c hl ori de, c alci u m, ma g nesi u m,  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 7  of 5 7  
 
gl uc ose, cre ati ni ne, ure a  a n d t h yr oi d-sti m ulati n g h or m o ne (T S H )]. 
▪ 
C oa g ulati o n [ pr ot hr o m bi n ti me , pr ot hr o m bi n rate, i nter nati o nal 
n or malize d rati o  (I N R) a n d acti vate d partial t hr o m b o plasti n  ti me (a P T T)].  
▪ 
Uri nal ysis.  
-  Viral ser ol o g y [ a nti-H u ma n I m m u n o deficie nc y vir us 1 a n d 2 a nti b o dies (a nti-
HI V -1 A b a n d a nti -HI V -2 A b), He patitis B s urfa ce a nti ge n ( H Bs A g) a n d a nti -
He patitis C vir us a nti b o dies (a nti -H C V A b) ]. 
-  S er u m  pre g na nc y test.  
-  Uri ne c oti ni ne, alc o h ol a n d dr u g scre e n test.  
-  F ollicle sti m ulati n g h or m o ne ( F S H) test.  
 
8. 2. 2  
A d missi o n t o Tre at me nt Pe ri o d  
 
I n e a c h part, t he f oll o wi n g pr oce d ures will be perf or me d d uri n g a d missi o n t o tre at me nt 
peri o d ( Da y -1):  
 
- 
C olle cti o n of b o d y wei g ht  a n d p h ysic al e xa mi nati o n . 
- 
Vital si g ns me as ure me nts ( B P, P R , R R a n d b o d y te m perat ure). 
- 
1 2 -le a d E C G. 
- 
S afet y la b orat or y assess me nts [ he mat ol o g y, bi oc he mistr y a n d c oa g ulati o n ( o nl y o n 
Part 1)].  
- 
Uri ne dr u g a n d alc o h ol scree n.  
- 
Uri ne c oti ni ne test.  
- 
Uri ne pre g na nc y test f or all fe male s u bje cts. 
- 
S A R S -C o V -2 test.  
 
 
8. 2. 3  
P art 1 - In hi bit or y a n d In d u ci n g E ffect of O r al G i vi n ost at o n t h e S i n gle D ose 
P h ar m ac o ki n etics of Intr a ve n o us a n d O r al M i d az ol a m 
 
S u bje cts will be c o nfi ne d 
 fr o m Da y – 1 t o Da y 2 0.  
 
O n Da ys 1, 6 a n d 1 7, si n gle d oses of mi da z ola m 1 m g i. v a n d da bi gatra n ete xilate 7 5  m g, 
will be a d mi nistere d 1 h o ur after t he pla n ne d m or ni n g ti me of gi vi n ostat a d mi nistrati o n.  
O n Da ys 2, 7 a n d 1 8, a si n gle oral d ose of mi da z ola m 2. 5 m g oral s ol uti o n will be 
a d mi nistere d 1 h o ur after t he pla n ne d m or ni n g ti me of gi vi n ostat a d mi nistrati o n.  
Fr o m Da y 4 t o Da y 1 8, gi vi n ostat 5 0 m g as oral s us pe nsi o n will be a d mi nistere d t wic e a 
da y, i n t he m or ni n g a n d i n t he e ve ni n g. O n Da y 1 9, o nl y t he m or ni n g d ose will be 
a d mi nistere d . 
Mi da z ola m a n d da bi gatra n ete xilate will be a d mi nistere d f oll o wi n g a n o ver ni g ht fasti n g of 
at le ast 8 h o urs a n d s u bjects will re mai n faste d u ntil at le ast 3  h o urs p ost -d os e. Oral 
mi da z ola m a n d da bi gatra n ete xilate will be a d mi nistere d wit h 1 5 0 m L of water. E xc e pt f or 
water gi ve n wit h t he i n vesti gati o nal pr o d ucts, n o fl ui ds will be all o we d fr o m 1 h o ur bef ore 
mi da z ola m a n d da bi gatra n d osi n g u ntil 2 h o urs p ost d ose. W ater will  be pr o vi de d a d 
li bit u m at all ot her ti mes. 
M i da z ola m a n d da bi gatra n ete xilate will be a d mi nistere d wit h t he s u bje cts i n a se mi-
re c u m be nt p ositi o n. S u bje cts will re mai n se mi-re c u m be nt u ntil at le ast 3  h o urs p ost -d ose.  
 
T he f oll o wi n g assess me nts will be perf or me d  [see Se cti o n 2. 1  ( St u d y Fl o w-C hart –  
Part  1)] : 
- 
Bl o o d c olle cti o n f or p har ma c o ki netic a nal ysis o n Da ys 1 t o 4, 6 t o 9 a n d 1 7 t o 2 0.  
- 
Vital si g ns me as ure me nts  (B P, P R  a n d R R) o n  Da ys 1 , 2 , a n d 4 t o 1 9 . 
- 
1 2 -le a d E C G o n Da ys 3 t o 1 9. 
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 8  of 5 7  
 
- 
Bl o o d c olle cti o n f or  la b orat or y tests ( he mat ol o g y, bi oc he mistr y a n d c oa g ulati o n 
o n Da ys 4 a n d 9 a n d he mat ol o g y o n Da ys 6 , 1 2, 1 5 a n d 1 8). 
S u bje cts will be disc har ge d fr o m 
 in t he m or ni n g of Da y 2 0  if all o we d 
b y t he i n vesti gat or base d o n t heir me dical c o n diti o n. T he f oll o wi n g pr oc e d ures will be 
perf or me d:  
- 
P h ysic al e xa mi nati o n.  
- 
C olle cti o n of b o d y wei g ht.  
- 
Vital si g ns me as ure m e nts (B P, P R , R R a n d b o d y te m perat ure). 
- 
1 2 -le a d E C G. 
- 
S afet y la b orat or y assess me nts ( he mat ol o g y, bi oc he mistr y , c oa g ulati o n  a n d 
uri nal ysis ). 
- 
S er u m  pre g na nc y test f or all fe male s u bje cts.  
 
S u bje ct s will  ret ur n t o 
 1 0 t o 1 4 da ys after t he e n d of st u d y  t o u n der g o 
a d diti o nal assess me nts as re q uire d per pr ot oc ol.  
 
T he t otal d urati o n of Part 1 f or ea c h s u bject will be u p t o a p pr o xi matel y 8  we e ks fr o m 
S cre e ni n g t o F oll o w -u p visit, di vi de d a s f oll o ws: 
− S cre e ni n g: u p t o 2 1  da ys  
− Tr e at me nt Peri o d: Da ys 1 t o 2 0  
− S afet y f oll o w -u p visit: 1 2 ± 2 da ys  
 
 
8. 2. 4  
F oll o w -u p Visit  
 
I n e a c h st u d y part, a f oll o w-u p visit will oc c ur 1 2  ± 2 da ys after t he e n d of st u dy or 
pre mat ure st u d y disc o nti n uati o n : 
- t o perf or m 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 a n d 
c oa g ulati o n ( o nl y i n Part 1), vital si g ns ( B P, P R, R R a n d b o d y te m perat ure), 1 2 -
le a d E C G a n d, if fe male, uri ne  pre g na nc y test  
- t o m o nit or o n g oi n g A Es or t o c he c k f or p ossi ble A Es. 
 
8. 3  
St u d y Restricti o ns  
 
T he st u d y c o n diti o ns will be sta n dar dize d i n or der t o mi ni mize t he varia bilit y of all fact ors 
i n v ol ve d e xc e pt t hat of t he bei n g teste d.  
 
T o a v oi d p ossi ble ne gati ve effe cts o n t he meas ure me nt of plas ma dr u g c o nc e ntrati o ns 
a n d/ or o n s u bje cts’ safet y, se vera l restricti o ns will be i m ple me nte d, as descri be d i n t he 
ne xt secti o ns.  
 
8. 3. 1  
Lifest yle a n d Diet ar y Restricti o ns  
 
W hile c o nfi ne d, partici pa nts will re cei ve a sta n dar dize d diet at sc he d ule d ti mes t hat d o n ot 
c o nflict wit h ot her st u d y -relate d a cti vities.  
F o o d a n d fl ui d i nta ke will be c o ntr olle d f or all s u bje cts as descri be d i n S ecti o n 8. 2. 3  (f or 
Part 1 ).  
 
S u bje cts will be re q ueste d t o a bstai n fr o m c o ns u mi n g pi ne a p ple, S e ville ora n ge, p o mel o, 
p o me gra nate, starfr uit or gra pefr uit pr o d ucts (fres h, c a n ne d, or fr oze n) fr o m 7 da ys pri or 
t o a d missi o n u ntil t he e n d-of -st u d y. 
 
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  2 9  of 5 7  
 
C he wi n g g u m will n ot be all o we d d uri n g c o nfi ne me nt.  
 
S u bje cts will be a d vise d t hat t he y s h o ul d, wit hi n 4 8 h o urs pri or t o a d missi o n a bstai n fr o m 
c o ns u mi n g a n y f o o d or be vera ges c o ntai ni n g p o p p y see ds, be c a use it ma y re n der p ositi ve 
t he uri ne dr u gs-of -a b use tests. S u bjects will als o be a d vise d t o a v oi d i n d o or s paces 
c o nta mi nate d wit h t o ba cc o or c a n na bi n oi ds s m o ke, be ca use i t ma y re n der p ositi ve t he 
dr u gs -of -a b use tests.  
Use or t he c o ns u m pti o n of a n y met h yl xa nt hi nes -c o ntai ni n g pr o d ucts (e. g., c offe e, te a, 
c h oc olate, or c ola) is pr o hi bite d fr o m 4 8 h o urs pri or t o a d missi o n u ntil t he e n d -of -st u d y, 
i.e. u ntil t he last sa m ple c olle cti o n f or p har mac o ki netic assess me nt. 
 
Use or t he c o ns u m pti o n of alc o h olic be vera ges is pr o hi bite d fr o m 7 2 h o urs pri or t o 
a d missi o n a n d u ntil t he e n d -of -st u d y. T hr o u g h o ut t he st u d y, i n c ase of a n y d o u bt a b o ut 
alc o h ol c o ns u m pti o n, a n alc o h ol test ma y be perf or me d if re q ueste d b y t he i n vesti gat or.  
 
Use of t o bac c o pr o d ucts is n ot all o we d fr o m 3 m o nt hs pri or t o scree ni n g u ntil t he e n d -of -
st u d y. 
 
S u bje cts will be a d vise d t o a bstai n fr o m stre n u o us p h ysical a cti vit y wit hi n 4 8 h o urs pri or 
t o bl o o d c olle cti o n f or cli nic al la b orat or y tests.  
 
8. 3. 2  
Pr e vi o us a n d C o nc o mit a nt Me dic ati o n  
 
A pre vi o us me dicati o n is a n y me dic ati o n f or w hic h t he e n d date is pri or t o first d osi n g.  
A c o nc o mita nt me dicati o n is a n y me dic ati o n o n g oi n g or i nitiate d after first d osi n g.  
 
T he use of a n y m e dicati o ns i ncl u di n g O ver -t he-C o u nter ( O T C) pr o d ucts (i ncl u di n g her bal 
me dici nes s uc h as St J o h n’s W ort, h o me o pat hic pre parati o ns, vita mi ns, a n d mi nerals) is 
f or bi d de n fr o m 2 8 da ys  or wit hi n 5 half -li ves of t he me dici nal pr o d uct, w hic he ver is 
l o n ger, pri or  t o a d missi o n  u p t o last sa m ple f or p har mac o ki netics assess me nt, e xc e pt f or 
me dic ati o ns f or t he tre at me nt of a d verse e ve nts ( A Es).  
 
I n st u d y Part 1 , t he use of a ntic oa g ula nts is f or bi d de n wit hi n 2 8 da ys or 5 dr u g half-li ves, 
w hic he ver is l o n ger, pri or t o a d missi o n  u ntil t he e n d of st u d y.  
 
A n y me dic ati o n ( pre vi o us or c o nc o mita nt) ta ke n wit hi n t he peri o d of me dic ati o n 
restricti o n m ust be rec or de d i n t he electr o nic c ase re p ort f or m ( e C R F). If c o nc o mita nt 
me dic ati o n is o n g oi n g at t he f oll o w-u p visit , n o e n d date will be pr o vi de d i n t he e C R F.  
 
8. 3. 3  
C o ntr ace pti o n Re q uir e me nts  
 
O nl y n o n pre g na nt fe males c a n be a d mitte d t o t he st u d y a n d w o me n m ust n ot be c o me 
pre g na nt d uri n g t he st u d y a n d u ntil at le ast 9 0 da ys after t he last st u d y dr u g 
a d mi nistrati o n . 
 
A w o ma n is n ot c o nsi dere d of c hil d beari n g p ote ntial if s he:  
- Is i n a p ost-me n o pa u sal state. 
N O T E: A p ost -me n o p a us al st ate is defi ne d as 1 2 c o nsec utiv e m o nt hs wit h n o 
me nses wit h o ut a n alter n ativ e me dic al c a use, c o nfir me d by a F S H test.  
- Pre -me n o pa usal fe male wit h d oc u me nte d h ystere ct o m y, bilateral sal pi n gect o m y or 
bilateral o o p h ore ct o m y.  
 
Fe male s u bje cts of c hil d be ari n g p ote ntial will ha ve t o ta ke a p pr o priate meas ures t o 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 0  of 5 7  
 
pre ve nt pre g na nc y fr o m at le ast 2 8 da ys pri or t o Scree ni n g  u ntil 9 0 da ys after t he last 
st u d y dr u g a d mi nistrati o n.  
It is t he partici pa nt’s res p o nsi bilit y t o n otif y t he cli nic al researc h u nit if a pre g na nc y 
oc c urs fr o m t he e n d of t heir st u d y partici pati o n u ntil 9 0 da ys after t he last st u d y dr u g 
a d mi nistrati o n . 
 
T he ac c e pta ble c o ntrac e pti ve meas ures  are t he f oll o wi n g:  
- I ntra uteri ne de vice. 
- Bilateral t u bal oc cl us i o n. 
- T otal a bsti ne nc e of heter ose x ual i nterc o urse, i n ac c or da nce wit h t he lifest yle of t he 
s u bje ct. 
- Vasect o mize d part ner, w h o has re cei ve d me dical assess me nt of t he s ur gical s uccess, 
or cli nic all y dia g n ose d i nfertile part ner  
 
T he n ot a cc e pta ble c o ntra ce pti ve me as ures  are t he f oll o wi n g:  
- 
H or m o nal c o ntra ce pti o n.  
- 
Male or fe male c o n d o m wit h or wit h o ut s per mici de.  
- 
Ca p, dia p hra g m or s p o n ge wit h s per mici de.  
- 
Peri o dic a bsti ne nce (e. g., c ale n dar, o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n 
met h o ds).  
- 
Wit h dra wal (c oit us i nterr u pt us).  
 
Male s u bje cts w h o are se x uall y acti ve wit h a fe male part ner of c hil d be ari n g p ote ntial 
( pre g na nt or n o n-pre g na nt) m ust use c o ntrac e pti o n (c o n d o m) fr o m i n vesti gati o nal pr o d uct 
a d mi nistrati o n u p t o at le ast 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. 
Male s u bje cts m ust e ns ure t hat his n o n -pre g na nt fe male part ner of c hil d beari n g p ote ntial 
a grees t o c o nsiste ntl y a n d c orrectl y use f or t he sa me peri o d o ne of t he f oll o wi n g hi g hl y 
effe cti ve met h o ds of c o ntrac e pti o n:  
- Pr o ges t o ge n-o nl y h or m o nal c o ntra ce pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
( oral, i nje cta ble, i m pla nta ble). 
- C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrac e pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n ( oral, i ntra va gi nal, tra ns der mal).  
- I ntra uteri ne de vice. 
- I ntra uteri ne h or m o ne-rele asi n g s yste m.  
- Bilateral t u bal oc cl usi o n.  
Male s u bje cts 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. 4  
M e as ur es t o Mi ni mize Bi as  
 
8. 4. 1  
R a n d o miz ati o n  
 
T his is a fi xe d se q ue nc e st u d y. Ra n d o mizati o n is n ot a p plic a ble. 
 
8. 4. 2  
Bli n di n g  
 
T he st u d y will be c o n d ucte d as o pe n la bel. Bli n di n g pr oce d ures are n ot a p plic a ble.  
 
 
9  
S T U D Y P O P U L A TI O N  
 
9. 1  
Re cr uit me nt a n d S cr e e ni n g P r oce d u res 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 1  of 5 7  
 
 
St u d y  s u bje cts will be recr uite d 
’s p o ol of he alt h y v ol u nte ers , 
a c c or di n g t o t he a p plica ble sta n dar d o perati n g pr oce d ures  ( S O Ps). 
 
S u bje cts will be scree ne d bet we e n Da ys -2 1  t o -3  ( b ot h i ncl usi ve) of e a c h st u d y part t o 
c o nfir m t hat t he y meet t he s u bje ct sele cti o n criteria.  
 
Pri or t o a n y scree ni n g assess me nt, t he I n vesti gat or ( or a n a p pr o priate dele gate) will o btai n 
i nf or me d c o nse nt fr o m ea c h s u bject i n a cc or da nce wit h t he pr oce d ures descri be d i n 
S e cti o n 1 7. 1. 2  ( S u bject I nf or mati o n a n d C o nse nt). T he assess me nts t o be perf or me d at 
S cre e ni n g are descri be d i n Se cti o n 8. 2. 1 ). 
T he res ults of tests perf or me d at scre e ni n g m ust be k n o w n b y t he i n vesti gat or pri or t o 
s u bje ct’s a d missi o n t o t he cli nic al rese arc h site.  
 
S u bje cts w h o meet all t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria at t he 
scree ni n g visit of e a c h st u d y part ma y be eli gi ble f or partici pati o n i n t h e res pecti ve  st u d y 
part . C o nti n ue d eli gi bilit y will be assesse d u p o n a d missi o n t o t he cli nic al rese arc h site, 
pri or t o t he first st u d y dr u g a d mi nistrati o n.  
 
S u bje cts will rec ei ve a u ni q ue s u bject n u m ber u p o n e nr ol me nt i n t he st u d y. S u bje ct 
n u m bers will be all oc ate d se q ue ntiall y i n t he or der i n w hic h t he s u bje cts are e nr olle d. T he 
s u bje ct n u m ber will e ns ure i de ntificati o n u ntil t he F oll o w -u p visit. S u bje cts will be 
i de ntifie d o n all st u d y d oc u me ntati o n b y t heir s u bject n u m ber o nl y. A list i de ntif yi n g t he 
s u bje cts b y s u bje ct n u m ber will be ke pt i n t he Site Master File. 
 
9. 2  
I n cl usi o n C rite ri a 
 
S u bje cts m ust me et t he f oll o wi n g criteria t o be eli gi ble f or e nr ol me nt i nt o t he trial.  
F or all s u bje cts:  
 
1.  S u bje ct’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. 
2.  Male or fe male s u bject, ≥1 8 a n d ≤5 5 years of a ge, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt. 
3.  B o d y mass i n de x ( B MI) of 1 8. 5 t o 3 2. 0 k g/ m 2 i ncl usi ve, 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 1 0 k g f or males.  
4.  N o n -s m o ker or e x-s m o ker (i.e. s o me o ne w h o a bstai ne d fr o m usi n g t o ba c c o- or 
nic oti ne -c o ntai ni n g pr o d ucts f or at le ast 3 m o nt hs pri or t o S cre e ni n g).  
5.  N o cli nic all y rele va nt diseases.  
6.  N o m aj or s ur ger y wit hi n 4 we e ks pri or t o d osi n g.  
7.  N o cli nic all y rele va nt a b n or malities o n p h ysic al e xa mi nati o n.  
8.  N o cli nic all y re le va nt a b n or malities o n 1 2-le a d E C G.  
9.  N o cli nic all y rele va nt a b n or malities o n cli nic al la b orat or y tests.  
1 0.  Ne gati ve test res ults f or a nti -H u ma n I m m u n o deficie nc y vir us 1 a n d 2 a nti b o dies 
(a nti-HI V -1 A b a n d a nti -HI V -2 A b), He patitis B s urfa c e a nti ge n ( H Bs A g) a n d a nti -
He patitis C vir us a nti b o dies (a nti -H C V A b).  
1 1.  Fe male s u bje cts are eli gi ble if t he y are of n o n -c hil d be ari n g p ote ntial or a gre e t o use a 
n o n -h or m o nal hi g hl y effe cti ve c o ntrac e pti ve met h o d fr o m 2 8 da ys pri or t o S cree ni n g 
u ntil at le ast 9 0 da ys a fter t he last st u d y dr u g a d mi nistrati o n. N o nc hil d be ari n g 
p ote ntial fe male is defi ne d as:  
a) Me n o pa usal, i.e. n o me nses f or ≥ 1 2 m o nt hs wit h o ut a n alter nati ve me dic al 
c a use ot her t ha n me n o pa use , a n d a hi g h F S H le vel . 
b)  Pre -me n o pa usal fe male wit h d oc u me nte d  h ystere ct o m y, bilateral 
sal pi n ge ct o m y a n d/ or bilateral o o p h ore ct o m y. 
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 2  of 5 7  
 
A n o n -h or m o nal effe cti ve c o ntrac e pti ve met h o d is defi ne d as:  
a) I ntra uteri ne de vice.  
b)  Bilateral t u bal oc cl usi o n.  
c) T otal a bsti ne nc e of heter ose x ual i nterc o urse, i n ac c or da nce wit h t he lifest yle of 
t he s u bje ct. 
d)  Vasect o mize d part ner, w h o has re cei ve d me dical assess me nt of t he s ur gical 
s ucc ess, or cli nic all y dia g n ose d i nfertile part ner. 
1 2.  Male s u bje cts w h o are se x uall y acti ve wit h a fe male part ner of c hil d be ari n g p ote ntial 
( pre g na nt or n o n-pre g na nt) m ust use c o ntrac e pti o n (c o n d o m) fr o m i n vesti gati o nal 
pr o d uct a d mi nistrati o n u p t o at le ast 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.  
1 3.  Male s u bje cts m ust e ns ure t hat his n o n -pre g na nt fe male part ner of c hil d beari n g 
p ote ntial a grees t o c o nsiste ntl y a n d c orrectl y use f or t he sa me peri o d a hi g hl y 
effe cti ve met h o d of c o ntra ce pti o n (see  S ecti o n 8. 3. 3 ). 
1 4.  Male s u bje cts 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. 
1 5.  Willi n g ness a n d c a 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 a bilit 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. 
 
9. 3  
E xcl usi o n Crite ri a  
 
S u bje cts t o w h o m a n y of t he f oll o wi n g criteria a p pl y will be e xcl u de d fr o m t he st u d y:  
 
At Scree ni n g  
 
1.  Pre vi o us use of gi vi n ostat.  
2.  Hist or y of a na p h yla xis re acti o n or cli nicall y si g nific a nt dr u g h y perse nsiti vit y re acti o n 
(e. g., a n gi oe de ma, Ste ve ns-J o h ns o n s y n dr o me, ac ute ge neralize d e xa nt he mat o us 
p ust ul osis, dr u g -i n d uc e d h y perse nsiti vit y s y n dr o me, dr u g-i n d uc e d ne utr o pe nia). 
3.  K n o w n hist or y of h y perse nsiti vit y a n d/ or aller gic re acti o ns t o gi vi n ostat, hist o ne 
de a cet ylases ( H D A C) i n hi bit ors or t o a n y e xci pie nt i n t he f or m ulati o n.  
4.  Hist or y of s or bit ol i nt olera nc e, s or bit ol mala bs or pti o n or fr uct ose i nt olera nce.  
5.  A n y me dic al c o n diti o n (e. g. gastr oi ntesti nal, re nal or he patic, i ncl u di n g pe ptic ulc er, 
i nfla m mat or y b o wel disease or pa ncreatitis) or s ur gic al c o n diti o n (e. g. 
c h ole c ystect o m y, gastrect o m y) t hat ma y affe ct dr u g p har ma c o ki netics (a bs or pti o n, 
distri b uti o n, meta b olis m or e xcreti o n) or s u bject safet y.  
6.  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 oli c bl o o d press ure 
l o wer t ha n 6 0 or o ver 9 0 m m H g, or p ulse  rate l o wer t ha n 5 0 or o ver 1 0 0 b p m. 
7.  Q Tc F ˃ 4 5 0 msec.  
8.  S u bje cts wit h hist or y of car diac arr h yt h mias ( d oc u me nte d), fa mil y hist or y of s u d de n 
c ar dia c deat h or hist or y of a d diti o nal ris k fact ors f or t orsa des -de -p oi ntes (e. g. he art 
fail ure, h y p o kale mia , l o n g Q T s y n dr o me). 
9.  Ha vi n g a n esti mate d gl o mer ular filtrati o n (e G F R) < 8 0 m L/ mi n, base d o n cre ati ni ne 
cle ara nce calc ulati o n b y t he C oc kcr oft -Ga ult f or m ula a n d n or malize d t o a n a vera ge 
s urfac e area of 1. 7 3 m2.   
1 0.  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:  
a) Platelet c o u nt bel o w t he l o wer li mit of t he n or mal ra n ge ( L L N)  
b)  T otal w hite bl o o d c ells c o u nt bel o w t he L L N  
c) He m o gl o bi n bel o w t he L L N  
d)  Tri gl yc eri des a b o ve t he u p per li mit of n or ma l ra n ge ( U L N) 
e) P otassi u m or ma g nesi u m bel o w t he L L N  
1 1.  P ositi ve uri ne alc o h ol, dr u gs -of -a b use or c oti ni ne scree n tests.  
1 2.  P ositi ve ser u m pre g na nc y test.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 3  of 5 7  
 
1 3.  If w o ma n, s he is bre ast-fee di n g. 
1 4.  Hist or y of alc o h ol a b use wit hi n 1 ye ar pri or t o scre e ni n g or re g ular use of alc o h ol 
wit hi n 6 m o nt hs pri or t o t he scre e ni n g visit (i.e. m ore t ha n 1 4 u nits of alc o h ol per 
we e k f or males or m ore t ha n 7 u nits f or fe males).  
1 5.  Hist or y of dr u g a b use wit hi n 1 ye ar pri or t o scre e 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 oc ai ne, p he nc ycli di ne ( P C P), cra c 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 ye ar pri or t o scre e ni n g.  
1 6.  Partici pati o n i n a n y cli nic al tr ial wit hi n t he pre vi o us 2 m o nt hs. 
1 7.  Partici pati o n i n m ore t ha n 2 cli nical trials wit hi n t he pre vi o us 1 2 m o nt hs.  
1 8.  Bl o o d d o nati o n or si g nific a nt bl o o d l oss ( ≥ 4 5 0 m L) d ue t o a n y reas o n or ha d 
plas ma p heresis wit hi n t he pre vi o us 2 m o nt hs.  
1 9.  Vei ns u ns uit a ble f or i ntra ve n o us p u nct ure o n eit her ar m.  
2 0.  Diffic ult y i n s wall o wi n g c a ps ules, ta blets or s us pe nsi o ns.  
2 1.  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 bject fr o m 
partici pati n g i n t he st u d y.  
 
At A d missi o n t o Tre at me nt Peri o d  
 
2 2.  A n y cli nic all y rele va nt a b n or malities o n cli nic al la b orat or y tests.  
2 3.  P ositi ve uri ne alc o h ol, dr u gs -of -a b use or c oti ni ne scree n tests.  
2 4.  P ositi ve uri ne pre g na nc y test.  
2 5.  P ositi ve or i nc o ncl usi ve S A R S -C o V -2 test pri or t o a d missi o n.  
2 6.  Use of prescri pti o n or n o n -prescri pti o n me dici nal pr o d ucts wit hi n t he pre vi o us 2 8 
da ys or wit hi n 5 -half -li ves of t he me dici nal pr o d uct, w hic he ver is l o n ger. 
2 7.  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 bject fr o m 
partici pati n g i n t he st u d y. 
 
F or P art 1 s u bjects:  
 
At Scree ni n g  
 
2 8.  K n o w n hist or y of h y perse nsiti vit y a n d/ or aller gic re acti o ns t o mi da z ola m, ot her 
be nz o dia ze pi nes, da bi gatra n ete xilate or t o a n y e xci pie nt of t he f or m ulati o ns.  
2 9.  Cli nic all y rele va nt hist or y of i m paire d res pirat or y f u ncti o n, o bstr ucti ve sle e p a p ne a, 
m yast he nia gra vis, res pirat or y arrest a n d/ or c ar dia c arrest.  
3 0.  Hist or y of gla uc o ma.  
3 1.  Prese nce of res pirat or y fail ure.  
3 2.  Prese nce of acti ve cli nicall y si g nific a nt ble e di n g.  
3 3.  Lesi o n or c o n diti o n c o nsi dere d t o p ose a si g nifica nt ris k fa ct or f or maj or blee di n g 
i ncl u di n g, b ut n ot li mite d t o: c urre nt or re ce nt gastr oi ntesti nal ulc erati o n, mali g na nt 
ne o plas ms, rec e nt brai n or s pi nal i nj ur y, rec e nt brai n, s pi nal or o p ht hal mic s ur ger y , 
re ce nt i ntra cra nial he m orr ha ge , k n o w n or s us pe cte d es o p ha ge al varices, 
arteri o ve n o us malf or mati o ns, vasc ular a ne ur ys ms or maj or i ntras pi nal or i ntrac ere bral 
vasc ular a b n or malities.  
3 4.  Prese nce of a me dic al c o n diti o n re q uiri n g a ntic oa g ula nt tre at me nt.  
 
A t A d missi o n t o Tre at me nt Peri o d 
 
3 5.  Tr e at me nt wit h a ntic oa g ula nts wit hi n 2 8 da ys or 5 dr u g half -li ves, w hic he ver is 
l o n ger, bef ore a d missi o n. 
 
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 4  of 5 7  
 
1 0  
S U B J E C T’ S P R E M A T U R E S T U D Y DI S C O N TI N U A TI O N A N D S T U D Y 
T E R MI N A TI O N  
 
1 0. 1  
S u bject’s Pre m at u re Disc o nti n u ati o n  
 
Ac c or di n g  t o t he De clarati o n of Helsi n ki a n d t he G o o d Cli nic al Pra ctice ( G C P) 
re q uire me nts iss ue d b y t he I nter nati o nal C o nfere nc e o n Har m o nizati o n (I C H), a s u bje ct 
ma y wit h dra w  t he c o nse nt a n d a ba n d o n t he st u d y at his/ her re q uest, at a n y ti me, 
irres pecti ve of t he reas o n.  
 
T he i n vesti gat or or S p o ns or ma y wit h dra w a s u bje ct at a n y ti me if it is deter mi ne d t heir 
c o nti n ui n g i n t he st u d y ma y res ult i n a si g nific a nt safet y ris k t o t he s u bje ct or if t heir 
be ha vi o ur is deleteri o us t o t he st u d y e n vir o n me nt.  
O ver t he c o urse of t he st u d y t he I n vesti gat or ma y wit h dra w a n y s u bje ct f or t he f oll o wi n g 
re as o ns:  
− Oc c urre nc e of a S A E.  
− Cli nic all y si g nific a nt st u d y tre at me nt -relate d c ha n ges i n safet y para meters t hat are 
c o nsi dere d u na cc e pta ble b y t he I n vesti gat or a n d/ or t he S p o ns or . 
− Si g nific a nt pr ot oc ol vi olati o n.  
− S u bje ct re cei ve d/re q uire d a n y c o nc o mita nt me dic ati o n at a ti mefra me i n w hic h, 
a c c or di n g t o t he I n vesti gat or, ma y i nterfere wit h t he p har ma c o ki netics or safet y of 
st u d y dr u gs. 
− P ositi ve pre g na nc y test (if w o ma n).  
− Diffic ult y i n c olle cti n g bl o o d.  
− A n y ot her c o n diti o n t hat i n t he I n vesti gat or’s a n d/ or S p o ns or’s o pi ni o n n o l o n ger 
j ustifies or per mits a safe partici pati o n of t he s u bject i n t he st u d y. 
 
 
As s o o n as s u bje ct’s wit h dra wal is c o nfir me d, bl o o d sa m pli n g f or p har mac o ki netic 
assess me nts s h o ul d be st o p pe d.  
 
I n t he e ve nt of a pre mat ure wit h dra wal after d osi n g, t he s u bje ct will be re q ueste d t o 
c o m plete a safet y assess me nt at t he ti me of dis c o nti n uati o n ( or as s o o n as p ossi ble after 
t he ti me of disc o nti n uati o n). S u bjects wit h dra w n f or safet y re as o ns will be as ke d t o 
re mai n i n t he cli nical site u ntil t he I n vesti gat or a gre es t hat t he s u bje ct ca n be safel y 
disc har ge d.  
 
Re as o ns f or a pre mat ure wi t h dra wal m ust be cle arl y d oc u me nte d i n t he s u bje ct’s me dic al 
re c or ds a n d i n t he e C R F. I n c ase of m ulti ple reas o ns, safet y relate d iss ues s h o ul d be 
i n dic ate d as t he pri mar y re as o n if a p plic a ble. I n vesti gat ors m ust atte m pt t o c o nta ct 
s u bje cts w h o f ail t o atte n d sc he d ule d visits b y tele p h o ne, e -mail, etc., t o e xcl u de t he 
p ossi bilit y of a n A E bei n g t he c a use. S h o ul d t his be t he case, t he A E m ust be d oc u me nte d, 
re p orte d a n d f oll o we d u p as descri be d i n t his Pr ot oc ol. 
 
I n c ase of wit h dra wal d ue t o A E, t he I n vesti gat or will i nstit ute t he a p pr o priate f oll o w -u p 
i n vesti gati o ns i n a c c or da nce wit h t he a cc e pte d sta n dar ds of me dic al c are, i ncl u di n g tests at 
t he ti me of wit h dra wal. A n y s u bje ct wit h dra w n d uri n g t he st u d y d ue t o a n y A E will be 
f oll o we d u p w here ver p ossi ble u ntil res ol uti o n or u ntil t h e i n vesti gat or belie ves t hat t here 
will be n o f urt her c ha n ge. T his ma y i n v ol ve a d diti o nal visits, w h ose i nf or mati o n m ust be 
cle arl y d oc u me nte d i n t he s u bject’s me dical rec or ds.  
 
S u bje cts wit h dra w n after t he first d ose a d mi nistrati o n will n ot be re plac e d.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 5  of 5 7  
 
 
 
1 1  
I N V E S TI G A TI O N A L P R O D U C T S 
 
1 1. 1  
Id e ntit y  of In vesti g ati o n al P r o d ucts 
 
Gi vi n ost at  
Na me of t he Pr o d uct: I T F 2 3 5 7/ Gi vi n ostat * 1 0 m g/ m L or al s us pe nsi o n ( 1 4 0 m L/ b ottle) 
 * Gi vi n ostat is us e d t o i n dicate t he w h ole st u d y dr u g na me gi vi n ostat h y dr oc hl ori de m o n o h y drate. 
T he d os a ges/c o nce ntrati o ns of t he st u d y dr u g are e x press e d as gi vi n ostat h y dr oc hl ori de 
m o n o h y drate  
R o ute/ m o de of a d mi nistrati o n: Orall y , wit h o ut water 
Ma n ufact urer:  Italfar mac o S p A, viale F. Testi 3 3 0 –  2 0 1 2 6 Mila n , Ital y (fi nal 
la belli n g/ pa c ka gi n g a n d rele ase f or cli nic al use). 
 
Mi d az ol a m (I V) 
Na me of t he Pr o d uct: Mi da z ola m A ur o bi n d o 1 m g/ ml s ol uti o n f or i nje cti o n/i nf usi o n or 
re ctal a d mi nistrati o n  
R o ute/ m o de of a d mi nistrati o n: I ntra ve n o usl y 
Mar keti n g A ut h oriz ati o n H ol der: A ur o bi n d o P har ma B. V.  
 
Mi d az ol a m (Or al ) 
Na me of t he Pr o d uct: B uc c ola m ®  2. 5 m g or o m uc osal s ol uti o n   
R o ute/ m o de of a d mi nistrati o n: Orall y wit h 1 5 0 m L of water  
Mar keti n g A ut h orizati o n H ol der: La b orat ori os Les vi, S. L.  
 
 
D a bi g atr a n  ete xil ate 
Na me of t he Pr o d uct: Pra da xa ®  7 5 m g har d c a ps ules  
R o ute/ m o de of a d mi nistrati o n: Orall y wit h 1 5 0 m L of water  
Mar keti n g A ut h orizati o n H ol der: B oe hri n ger I n gel hei m I nter nati o nal G m b H  
 
 
T he batc h n u m ber  of e ac h pr o d uct  will be i ncl u de d i n t he fi nal  Cli nic al S t u d y R e p ort 
( C S R). Als o , t he Gi vi n ostat c ertific ate of a nal ysis will be i ncl u de d i n t he fi nal C S R. 
 
1 1. 2  
I n vesti g ati o n al Pr o d u cts S u p plies 
 
T he S p o ns or will be res p o nsi ble f or e ns uri n g t hat g i vi n ostat is ma n ufa ct ure d u n der G o o d 
Ma n ufact uri n g Pra ctice ( G M P) a n d is pr o vi de d i n a de q uate q ua ntities f or t he st u d y.  
 
Gi vi n ostat will be s u p plie d b y t he S p o ns or as f oll o ws: la bele d a n d se ale d w hite c art o o n 
b o x e a c h c o ntai ni n g o ne la bele d  m ulti d ose b ottle of 1 4 0 m L Gi vi n ostat 1 0 m g/ m L or al 
s us pe nsi o n. T he la bel  will i ncl u de at least  t he f oll o wi n g i nf or mati o n: na me of t he st u d y 
dr u g, batc h n u m ber, a n d  e x pir y  date.  
At 
I, a n d ac c or di n g t o t he a p plic a ble S O Ps, t he P har ma cist will pre par e 
t he i n di vi d ual d oses of Gi vi n ostat f or e a c h s u bject a n d d osi n g ti me usi n g 5 m L or al 
s yri n ges. T he si n gle c o ntai ners will be la bele d i n ac c or da nc e wit h t he a p plica ble la ws a n d 
re g ulati o ns. 
A sa m ple of t he la bel will be pr o vi de d i n t he C S R.  
 
Mi da z ola m  a n d da bi gatra n will be o btai ne d fr o m t he c o m mercial s o urc es.  
At 
, t he P har ma cist will la bel, pre pare a n d dis pe nse t he res pecti ve 
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 7  of 5 7  
 
1 1. 4. 1  
Tr e at me nt C o m pli a n ce  
 
A d mi nistrati o n of I n vesti gati o nal Me dici nal Pr o d ucts (I M Ps) will o nl y be perf or me d b y 
a ut h orize d cli nic al researc h staff a n d, i n c ase of gi vi n ostat, oral mi da z ola m , a n d 
da bi gatra n will be f oll o we d b y a n  oral ca vit y a n d ha n d ( w her e a p plic a ble) c he c k i n or der 
t o c o nfir m t he s wall o wi n g of t he pr o d uct.  
 
U p o n dis pe nsi n g me dic ati o n, t he cli nic al researc h staff will re c or d t he relate d i nf or mati o n 
o n t he a p plic a ble s o urce d oc u me nts, t o all o w i n vesti gati o nal pr o d uct ac c o u nta bilit y a n d 
e va l uati o n of s u bject c o m plia nce. 
 
 
1 2  
S T U D Y A S S E S S M E N T S  
 
S u bje cts  w h o ha ve v ol u ntaril y si g ne d writte n i nf or me d c o nse nt ma y start t he f oll o wi n g 
trial pr oc e d ures a cc or di n g t o t he fl o w-c hart ( Se cti o n 2 ). All t he res ults will be re p orte d i n 
t he a p pr o priate C R F secti o ns a n d all s o urce d oc u me nts will be arc hi ve d i n t he s u bject file 
at t he trial site. 
 
 
 
1 2. 1  
P h ar m ac o ki n etic Assess me nts  
 
1 2. 1. 1  
Bl o o d S a m pli n g f or P h ar m ac o ki netic A ssess me nts 
 
P art 1  
 
A t otal of 1 1 7 bl o o d sa m ples will be c olle cte d as f oll o ws:  
 
− T hirte e n ( 1 3) bl o o d sa m ples of 3 m L ea c h will be c olle cte d i n K 2-E D T A c olle cti o n 
t u bes at pre-d ose a n d at 2 mi n utes, 0. 2 5, 0. 5, 0. 7 5, 1, 2, 3, 4, 6, 9, 1 2 a n d 2 4 h o urs 
after t he a d mi nistrati o n of i ntra ve n o us mi da z ola m, o n Da ys 1, 6 a n d 1 7, f or t he 
deter mi n ati o n of mi da z ola m a n d 1 -h y dr o x y mi da z ola m plas ma c o nc e ntrati o ns.  
− Ele ve n ( 1 1) bl o o d sa m ples of 3 m L ea c h will be c olle cte d i n K 2-E D T A c olle cti o n 
t u bes at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2 a n d 2 4 h o urs after t he a d mi nistrati o n of or al 
mi da z ola m, o n Da ys 2, 7 a n d 1 8, f or t he deter mi nati o n of mi da z ola m a n d 1 -
h y dr o x y mi da z ola m plas ma c o nce ntrati o ns. T he 2 4 -h o ur bl o o d c olle cti o n f oll o wi n g 
i ntra ve n o us mi da z ola m will be ass u me d as t he pre-d ose sa m pli n g f or oral mi da z ola m.  
− Fifte e n ( 1 5) bl o o d sa m ples of 4 m L e ac h wil l be c ollecte d i n K 2-E D T A c olle cti o n 
t u bes at pre-d ose a n d at 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 1 0, 1 2, 2 4, 3 6, 4 8 a n d 7 2 h o urs after 
t he a d mi nistrati o n of da bi gatra n ete xilate, o n Da ys 1, 6 a n d 1 7, f or t he deter mi nati o n 
of t otal a n d fre e da bi gatra n plas ma c o nc e ntrati o ns.  
 
 
I n e a c h st u d y part, while s u bject is c o nfi ne d at t he cli nical researc h u nit, bl o o d sa m ples 
will be ta ke n prefera bl y via a n i n d welli n g c a n n ula pla ce d i n a vei n of a n u p per li m b of t he 
s u bje ct. D uri n g a m b ulat or y visits, bl o o d sa m ples will be ta ke n b y dire ct ve ni p u nct ure. 
 
T he act ual ti me of all p har ma c o ki netic bl o o d dra ws will be rec or de d a n d re p orte d f or all 
s u bje cts. T he p ost -d ose bl o o d sa m ples will be c olle cte d wit hi n ± 3 mi n utes fr o m t he 
sc he d ule d sa m pli n g ti me. Gre ater de viati o ns will be re p orte d as a pr ot oc ol de viati o n a n d 
its ca use will be re c or de d. 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 8  of 5 7  
 
 
I n c ase bl o o d sa m pli n g f or p har ma c o ki netics a n d ot her pr oc e d ures c oi nci de i n ti me, bl o o d 
dra ws will ha ve pri orit y u nless ot her pr oc e d ures are ne cessar y f or ass uri n g s u bje ct’s 
safet y. 
T he date a n d act ual ti me of uri ne c olle cti o n start a n d c o m pleti o n will be re c or de d a n d 
re p orte d f or all s u bje cts.  
 
1 2. 1. 2  
S a m ple P r oc essi n g, S t or a ge a n d T r a nsfer 
 
Bl o o d  a n d uri ne  sa m ples f or p har mac o ki netic a nal ysis will be c olle cte d a n d pr oc esse d as 
per t he a nal ytic al met h o d ol o g y i nstr ucti o ns pr o vi de d  b y  t he bi oa nal ytic al la b orat ory .  
 
S a m ples will be la bele d wit h self -a d hesi ve pre-pri nte d la bels s uita ble t o wit hsta n d 
free zi n g tem perat ures. La bels s h o ul d be ar t he f oll o wi n g mi ni m u m i nf or mati o n:  
− La bels of bl o o d sa m ple t u bes: pr ot oc ol c o de, s u bje ct n u m ber,  sa m ple n u m ber, st u d y 
da y, sa m ple ti me p oi nt, st u d y part, matri x t y pe, a n d o ne of t he  state me nts “f or I V  
mi da z ola m a n d meta b olite  assa y” / “f or oral  mi da z ola m a n d meta b olite  assa y”/“f or 
da bi gatra n t otal  a n d fre e assa y”  (Part 1 ).  
− La bels of plas ma ali q u ots: pr ot oc ol c o de, s u bject n u m ber, sa m ple n u m ber, st u d y da y, 
sa m ple ti me p oi nt, ali q u ot series, st u d y part , matri x t y pe, a n d o ne of t he state me nts 
“f or I V mi da z ola m a n d meta b olite  assa y ”/ “f or oral mi daz ola m a n d meta b olite  
assa y”/ “f or da bi gatra n t otal  a n d fre e assa y ” ( Part 1 ). 
− La bels of uri ne c ollecti o n c o ntai ners: pr ot oc ol c o de, s u bject n u m ber, st u d y da y/ da y 
i nter val, sc he d ule d sa m ple i nter val , matri x t y pe a n d state me nt.  
− La bels of uri ne ali q u ots: pr ot oc ol c o de, s u bje ct n u m ber, st u d y da y/ da y i nter val, 
sc he d ule d sa m ple i nter val, ali q u ot series, matri x t y pe ( uri ne)  a n d state me nt . 
At a gree d ti mes, sa m ples will be tra nsferre d t o t he bi oa nal ytic al la b orat or y, wit h ea c h 
series of ali q u ots i n se parate s hi p me nts. T he bl o o d sa m ples will be pa c ke d i n dr y ice f or 
tra ns p ort a n d n o i nterr u pti o n of t he free ze c ycle is all o we d. T he te m perat ure i n t he b o x 
d uri n g t he tra ns p ort will be m o nit ore d. O nc e t he bi oa nal ytic al la b orat or y c o nfir ms re cei pt 
of t he first s hi p me nt, t he sec o n d series of ali q u ots will be se nt, if re q uire d. F or all 
s hi p me nts, t he la b orat or y s h o ul d ac k n o wle d ge i n writi n g t he rec ei p t of sa m ples i n g o o d 
c o n diti o n.  
 
1 2. 1. 3  
Bi o a n al ytic al M et h o d s 
 
T he plas ma  or uri ne  le vels of ea c h a nal yte  will be deter mi ne d  b y t he bi oa nal ytical 
la b orat or y i de ntifie d i n S ecti o n 3  i n a cc or da nc e wit h t he a p plic a ble pri nci ples of G o o d 
La b orat or y Pra ctice ( G L P), usi n g pre vi o usl y vali date d a nal ytic al met h o d s.  
 
T he l o wer ( L L O Q) a n d u p per ( U L O Q) li mits of t he q ua ntific ati o n ra n ge will be pr o vi de d 
i n t he a nal ytic al met h o d d oc u me ntati o n. 
 
Details of t he met h o ds use d a n d t he res ults o btai ne d will be gi ve n i n t he bi oa nal ytical 
re p ort. 
 
1 2. 1. 4  
I n c ur re d S a m ples Re a n al ysis 
 
I n or der t o esta blis h t he re pr o d uci bilit y of t he assa y, 1 0 % of t he first 1 0 0 0 sa m ples a n d 
5 % of t he n u m ber of sa m ples e xce e di n g 1 0 0 0 sa m ples will be re a nal yze d [E M A 
G ui deli ne 2 0 1 1; F D A G ui da nc e 2 0 1 8] . B ot h t he ori gi nal a n d re plicate val ues will be 
prese nte d i n t he bi oa nal ytic al re p ort, wit h t he perce nt differe nc e bet wee n t he t w o val ues. 
T he ori gi nal val ue will be t he o ne use d f or p har mac o ki netic a nal ysis.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  3 9  of 5 7  
 
 
1 2. 2  
Ge n er al S afet y Assess me nts  
 
S u bje cts’ safet y will be m o nit ore d d uri n g t he st u d y. A s u m mar y of safet y pr oce d ures is 
prese nte d i n S ecti o n 2. 1  (St u dy F l o w-C h art  –  P art 1 ).  
 
S afet y assess me nts will i ncl u de pre -st u d y me dical hist or y, p h ysic al e xa mi nati o n, vital 
si g ns, 1 2-le a d E C G, cli nic al la b orat or y tests a n d A E m o nit ori n g. A d diti o nal safet y 
me as ure me nts ma y be perf or me d at t he discreti o n of t he i n vesti gat or f or re as o ns relate d t o 
s u bje ct safet y. 
 
1 2. 2. 1  
M e dic al Hist or y  
 
Me d ic al hist or y will c o ver all rele va nt past or prese nt i nf or mati o n relate d t o s u bject’s 
he alt h at t he ti me of i nf or me d c o nse nt si g nat ure.  
Me dic al hist or y at scre e ni n g will i ncl u de past or prese nt rele va nt car di o vasc ular, 
res pirat or y, re nal, ge nit o uri nar y, gastr oi ntesti nal, he patic, he mat ol o gic al, i m m u n ol o gic al, 
e n d ocri ne, der mat ol o gic al, m usc ul os keletal, ne ur ol o gic al, ps yc hiatric, dr u g a n d s ur gical 
hist or y , or a n y ot her diseases or dis or ders.  
 
1 2. 2. 2  
P h ysic al E x a mi n ati o n  
 
P h ysic al e xa mi nati o n at sc re e ni n g a n d e n d -of -st u d y will i ncl u de: ge neral a p pe ara nc e; 
s ki n; he a d a n d nec k; t h ora x a n d a b d o me n; p ul m o nar y a usc ultati o n; c ar diac a usc ultati o n; 
a b d o me n pal pati o n; li m bs; brief ne ur ol o gic al e xa mi nati o n.  
 
1 2. 2. 3  
Wei g ht, Hei g ht a n d B o d y M ass I n de x  
 
T he b o d y hei g ht a n d wei g ht val ues as well as t he B MI will be re c or de d i n t he e C R F , a n d 
will be deter mi ne d  at S cree ni n g. O nl y b o d y wei g ht will be deter mi ne d  als o at a d missi o n 
a n d e n d-of -st u d y. 
 
T he s u bje cts’ b o d y wei g ht will prefera bl y be me as ure d usi n g t he sa me wei g hi n g scale f or 
all s u bje cts a n d t hr o u g h o ut t he st u d y. T he wei g hi n g scale s h o ul d ha ve a pre cisi o n of at 
le ast 0. 5 k g. 
 
1 2. 2. 4  
Vit al Si g ns  
 
Vital si g ns will  be perf or me d as sc he d ule d i n Se cti o n 2. 1  (St u dy Fl o w -C h art –  P art 1 ), 
a n d i ncl u de rest s yst olic bl o o d press ure ( S B P), diast olic bl o o d press ure ( D B P), P R , R R  
a n d b o d y te m perat ure.  
W he n vital si g ns rec or di n gs c oi nci de wit h a bl o o d dra w, t he y s h o ul d prefera bl y be  
perf or me d bef ore t he bl o o d c olle cti o n.  
 
1 2. 2. 5  
1 2 -Le a d Ele ctr oc ar di o gr a m  
 
1 2 -le a d E C G will be perf or me d as sc he d ule d  i n S ecti o n 2. 1  (St u dy Fl o w -C h art –  P art 1 ). 
W he n E C G re c or di n gs c oi nci de wi t h a bl o o d dra w, t he y s h o ul d prefera bl y be perf or me d 
bef ore t he bl o o d c ollecti o n.  
 
1 2. 2. 6  
L a b or at or y S afet y Tests  
 
La b orat or y safet y test will be perf or me d as sc he d ule d i n S e cti o n 2. 1  (St u dy Fl o w -C h art –  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 0  of 5 7  
 
P art 1 ). A d diti o nal or u nsc he d ule d la b orat or y safet y tests ma y be perf or me d if dee me d 
ne c essar y f or a n a p pr o priate s u bje ct’s safet y ma na ge me nt.  
 
 
 
 
 P ort u gal) will perf or m t he he mat ol o g y, 
bi oc he mistr y, c oa g ulati o n, viral ser ol o g y, uri nal ysis a n d ser u m pre g na nc y tests.  
Alc o h ol , dr u gs -of -a b use , c oti ni ne a n d pre g na nc y uri ne tests will be perf or me d at 
 
S A R S -C o V -2 dia g n ostic test usi n g p ol y merase c hai n re acti o n ( P C R) te c h n ol o g y  will be 
perf or me d at o ne of t he  
P ort u gal fa cilities .  
 
All sa m ples will be pr o perl y la bele d f or c orrect i de ntific ati o n. T he refere nce ra n ges will 
be pr o vi de d i n t he st u d y files  (e. g. T M F a n d I F) t o get her wit h t he descri pti o n of t he 
la b orat or y met h o ds use d. 
 
T he i n vesti gat or will assess t he cli nic al si g nific a nc e of res ults of la b orat or y i n vesti gati o ns 
o utsi de t he n or mal ra n ges. All c ha n ges fr o m scree ni n g t hat are o bser ve d at a n y ti me 
d uri n g t he st u d y a n d me et t he re q uisites f or cli nic al si g nific a nce will be rec or de d as A Es.  
 
 
 
He mat ol o g y:  
− R B C c o u nt, W B C c o u nt wit h differe ntial ( ne utr o p hil, e osi n o p hil, bas o p hil, 
l y m p h oc yte a n d m o n oc yte), he m o gl o bi n, M C V, M C H, M C H C, R B C distri b uti o n 
wi dt h, he mat ocrit, platelet s a n d me a n platelet v ol u me. 
C oa g ulati o n:  
− Pr ot hr o m bi n rate , p r ot hr o m bi n ti me, I N R, a P T T . 
Bi oc he m istr y: 
− T otal, dire ct a n d i n dire ct bilir u bi n, A L P, a m ylase, A S T, A L T , L D H, c ystati n C, C -
re acti ve pr otei n, G G T, C K, t otal pr otei n, al b u mi n, uric a ci d, tri gl yc eri des, t otal 
c h olester ol, L D L-C , H D L-C , s o di u m, p otassi u m, c hl ori de, c alci u m, ma g nesi u m, 
gl uc ose, cre ati ni ne, ure a a n d T S H . 
N O T E: Cre ati ni ne cle ar a nc e ( Cr C L ) will be esti m ate d at scree ni n g by usi n g t he 
C oc k cr oft -G a ult f or m ul a: Cr C L  m ale = [( 1 4 0 -a ge) x ( wei g ht i n k g)] / [(ser u m Cr 
m g/ d L) x ( 7 2)]; Cr C L  fe m ale = 0. 8 5 x ( Cr C L m ale) a n d n or m alize d t o a n av er a ge 
s urf ac e are a of 1. 7 3 m 2:  CrC L  n or m alize d = Cr C L  x 1. 7 3/ B S A.  
B o dy S urf ac e Are a ( B S A) = ( wei g ht 0. 4 2 5 [i n k g] × hei g ht 0. 7 2 5 [i n c m]) × 0. 0 0 7 1 8 4 
 
Viral ser ol o g y:  
− a nti-HI V -1 A b, a nti -HI V -2 A b, H Bs A g a n d a nti -H C V A b.  
 
Pre g na nc y test:  
− β -h C G  ser u m pre g na nc y test will be perf or me d b y a ut o mate d i m m u n oassa y usi n g t he 
bi oc he mistr y bl o o d sa m ple.  
− U ri ne pre g na nc y test will be perf or me d  usi n g a q ualitati ve c hr o mat o gra p hic 
i m m u n oassa y β -h C G  kit.  
 
Uri nal ysis:  
− p H, s pecific gra vit y, pr otei n, he m o gl o bi n, gl uc ose, ket o nes, bilir u bi n, nitrites, 
ur o bili n o ge n a n d micr osc o p y . 
P P D
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 1  of 5 7  
 
 
C oti ni ne, a lc o h ol a n d dr u g scre e n test (ca n na bi n oi ds, o piates, c ocai ne, a m p heta mi nes, a n d 
be nz o dia ze pi nes).  
 
F S H test will be perf or me d t o c o nfir m t he p ost -me n o pa usal stat us of fe male of n o n -
c hil d be ari n g p ote ntial.   
 
1 2. 3  
T ot al Bl o o d V ol u me  
 
P art 1  
 
T he t otal v ol u me of bl o o d t o be ta ke n per s u bject d uri n g Part 1  is as f oll o ws: 
 
 
T otal v ol u me of bl o o d c olle cte d c o ul d be differe nt if la b orat or y test re -c he c ks are 
perf or me d f or safet y reas o ns.  
 
 
1 3  
A D V E R S E E V E N T S D E FI NI TI O N S A N D R E P O R TI N G R E Q UI R E M E N T S  
 
T he a d o pte d  defi niti o ns  a n d t he met h o ds of assess me nt, d oc u me ntati o n a n d ma na ge me nt  
of a d verse e ve nts ca n be f o u n d i n A p pe n di x 1 . 
  
 
1 3. 1. 1  
E x p e dite d R e p orti n g  
 
A n y S A E t hat oc c urs after a s u bject has si g ne d t he I nf or me d C o nse nt F or m a n d u p t o t he 
f oll o w-u p visit (re gar dless of relati o ns hi p t o st u d y dr u g/c o m parat or)  m ust be re p orte d b y 
t he I n vesti gat or t o t he S p o ns or ( Dr u g safet y Ma na ger) a n d 
 
 -wit hi n 2 4 h o urs of le ar ni n g of its 
oc c urre nc e.  
T he I n vesti gat or m ust n otif y t he S p o ns or ( Dr u g S afet y Ma na ger) a n d 
 
 - of t he S A E b y c o m pleti n g t he w or d 
Pr oce d ure  
S a m ple  
Bl o o d  
v ol u m e per 
s a m ple ( m L) 
N u m ber of 
bl o o d s a m ples 
per s u bject  
T ot al 
v ol u m e per 
s u bject ( m L) 
La b orat or y tests  
He mat ol o g y  
3  
1 0  
3 0  
 
C oa g ulati o n  
1. 8  
6  
1 0. 8  
 
Bi oc he mistr y (i ncl u di n g 
pre g na nc y a n d F S H tests, if 
fe male, a n d viral s er ol o g y ) 
5  
6  
3 0  
 
C ystati n C  
5  
2  
1 0  
Bi oa nal ysis  
P K da bi gatra n (t otal a n d free)  
4  
4 5  
1 8 0  
Bi oa nal ysis  
P K mi daz ola m a n d meta b olite 
(I V) 
3  
3 9  
1 1 7  
Bi oa nal ysis  
P K mi daz ola m a n d meta b olite 
( oral) 
3  
3 3  
9 9  
T otal v ol u me of bl o o d c ollecte d  
4 7 6. 8  
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 2  of 5 7  
 
versi 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 dresses s pecifie d 
bel o w.  
S eri o us a d verse e ve nt re p orts m ust be ma de w het her or n ot t he I n vesti ga t 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 details m ust be 
pr o vi de d t o all o w f or a c o m plete me dic al assess me nt of t he S A E a n d i n de pe n de nt 
deter mi nati o n of p ossi ble ca usalit y. T he I n vesti gat ors are o bli ge d t o p urs ue a n d pr o vi de 
a d diti o nal i nf or mati o n as re q ueste d b y Italfar ma c o S. p. A. or its desi g ne e  a n d 
. T he n otificati o n m ust 
be directe d t o:  
 
  
  
  
  
 
 
 
 
 
A n d  
 
S p o ns or’s Dr u g Safet y Ma na ger:  
Italfar ma c 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: + 3 9 0 2 6 4 4 3 2 5 0 6  
Fa x: + 3 9 0 2 6 6 1 0 6 5 3 8  
Fa x ( ba c k -u p): + 3 9 0 2 6 4 4 3 2 9 5 5  
M o bile: + 3 9 3 9 3 3 3 2 1 4 0 0 0 4  
e -mail: dr u g -safet y @italfar ma c o.c o m 
 
 
T he sa me pr oc e 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.  
 
All S us pecte d U ne x pe cte d S eri o us A d verse Re acti o ns ( S U S A Rs) s hall be e x pe ditel y 
re p orte d t o I N F A R M E D a n d C EI C. E x pe ditel y me a ns t hat a n y fatal or life-t hre ate ni n g 
S U S A R will be re p orte d wit hi n 7 da ys of k n o wle d ge (i.e., 7 da ys after t he S p o ns or  - Dr u g 
S afet y Ma na ger a n d 
 was first a ware of t he rea cti o n) a n d all ot her 
S U S A Rs will be re p orte d wit hi n 1 5 da ys of k n o wle d ge.  
 
S p o ns or - Dr u g Safet y Ma na ger - will be res p o nsi ble f or t he e x pe diti n g re p ort of S U S A Rs 
t o I N F A R M E D via E u dr a Vi gila nc e cli nic al trials m o d ule ( E V C T M), a n d f or pr o vi di n g 
 wit h t he res pecti ve c o p y of t he C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dic al Scie nc es ( CI O M S) f or m. 
will be res p o nsi ble f or re p orti n g S U S A Rs 
t o C EI C via e mail (c eic @c eic. pt ). 
 
 
1 4  
S T U D Y E N D P OI N T S  
 
1 4. 1  
Pri m ar y E n d p oi nts  
 
1.  Mi da z ola m a n d da bi gatra n plas ma c o nc e ntrati o ns a n d t here of deri ve d p har mac o ki netic 
P P D
P P D
P P D
P P D
P P D
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 3  of 5 7  
 
para meters al o ne a n d i n c o m bi nati o n wit h Gi vi n ostat ( Part 1).  
  
1 4. 2  
S e c o n d ar y E n d p oi nts  
 
1 . I nci de nc e a n d se verit y of a d verse e ve nts ( A Es); c ha n ges i n vital si g ns, p h ysic al 
e xa mi nati o n , electr ocar di o gra m ( E C G) a n d cli nic al la b orat or y tests f oll o wi n g 
a d mi nistrati o n of mi da z ola m a n d da bi gatra n ete xilate al o ne a n d i n c o m bi nati o n wit h 
gi vi n ostat ( Part 1).  
 
 
 
1 5  
S T A TI S TI C A L M E T H O D O L O G Y A N D A N A L Y SI S  
 
1 5. 1  
S a m ple Size Deter mi n ati o n  
 
P art 1  
 
Mi da z ola m : Ass u mi n g a n I ntras u bje ct C oefficie nt of Variati o n (I S C V %) of ≤2 3 % f or 
mi da z ola m C m a x , A U C0 -t a n d A U C 0 -∞ [E pistat us ®  S m P C ], a tr ue ge o metric mea ns rati o 
( mi da z ola m wit h vs wit h o ut gi vi n ostat) of 1. 0 0, a si g nific a nc e le vel (al p ha err or) of 5 %, 
a n d a defa ult n o -effe ct b o u n dar y of 8 0. 0 0 % t o 1 2 5. 0 0 %, a sa m ple of 2 0 e val ua ble s u bje cts 
res ults i n at le ast 8 0 % p o wer. Ac c o u nti n g f or e arl y -ter mi nati o n s u bje cts, a sa m ple size of 
2 6 s u bje cts will be e nr olle d.  
 
Da bi gatra n : Ass u mi n g a n I S C V % of a p pr o x i matel y 3 0 % f or da bi gatra n C ma x , A U C0 -t a n d 
A U C 0 -∞ [Li, Xi n, et al. 2 0 2 0 ], a tr ue ge o metric mea ns rati o ( da bi gatra n wit h vs wit h o ut 
gi vi n ostat) of 1. 0 0, a si g nific a nc e le vel (al p ha err or) of 5 %, a n d t hat t he t w o -si de d 9 0 % 
c o nfi de nc e i nter val ( CI ) f or t he ge o metric me a ns rati o of Cma x , A U C0 -t a n d A U C 0 -∞ will lie 
wit hi n 7 4. 6 2 % t o 1 3 4. 0 2 %, a sa m ple of 2 0 e val ua ble s u bje cts res ult s i n at le ast 8 0 % 
p o wer. Ac c o u nti n g f or e arl y -ter mi nati o n s u bjects, a sa m ple size of 2 6 s u bje cts will be 
e nr olle d. 
 
1 5. 2  
St atistic al A n al ysis Pl a n  
 
A detaile d Statistic al A nal ysis Pla n ( S A P) will be pre pare d a n d fi nalize d pri or t o t he 
a nal ysis.  
 
Esti mati o n of p har ma c o ki netic para meters a n d statistic al a nal yses o n p har ma c o ki netic 
data will be c o n d ucte d usi n g P h oe ni x ®  Wi n N o nli n
®  8. 2  or hi g her  ( Certara U S A I nc, 
Pri nc et o n, NJ) a n d S A S ®  9. 4  or hi g her . T he ot her a nal yses will use S A S®  9. 4  or hi g her.  
 
1 5. 3  
A n al ys is P o p ul ati o ns  
 
1 5. 3. 1  
S afet y P o p ul ati o n  
 
All s u bje cts w h o r ec ei ve d at le ast o ne d ose of i n vesti gati o nal pr o d uct will c o nstit ute t he 
safet y p o p ulati o n. 
 
S afet y data a nal ysis will be perf or me d f or all s u bje cts i n t he safet y a nal ysis p o p ulati o n.   
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 4  of 5 7  
 
1 5. 3. 2  
P h ar m ac o ki n etic A n al ysis P o p ul ati o n  
 
F or e a c h st u d y part, a P har ma c o ki netic A nal ysis P o p ulati o n will be defi ne d.  
Ea c h P har ma c o ki netic A nal ysis P o p ulati o n will i ncl u de all s u bje cts w h o are e x pecte d t o 
pr o vi de e val ua ble p har mac o ki netic data f or at le ast o n e I M P, wit h o ut de viati o ns affe cti n g 
p har mac o ki netic i nter pretati o n.  
 
1 5. 3. 3  
Dr u g -Dr u g I nte r acti o n C o m p ar a ble Bi o a v ail a bilit y  A n al ysis P o p ul ati o n  
 
F or e a c h c o m parati o n of i nterest t o assess a p ote ntial dr u g -dr u g i ntera cti o n, a Dr u g -Dr u g 
I ntera cti o n C o m para ble Bi oa vaila bilit y A nal ysis P o p ulati o n will be defi ne d.  
Ea c h Dr u g -Dr u g I ntera cti o n C o m para ble Bi oa vaila bilit y A nal ysis P o p ulati o n will i ncl u de 
all s u bje cts fr o m t he P har ma c o ki netic A nal ysis P o p ulati o n w h o are e x pecte d t o pr o vi de 
e val ua ble p har mac o ki netic data f or a n I M P a d mi nistere d al o ne a n d c o -a d mi nistere d wit h 
a n ot her I M P, wit h o ut de viati o ns affecti n g p har mac o ki netic i nter pretati o n.  
 
1 5. 4  
S u bjects’ C h ar acte ristics  
 
S u bje ct dis p ositi o n will be s u m marize d. T he de m o gra p hic, ba c k gr o u n d a n d baseli ne data 
will be prese n te d descri pti vel y f or ea c h st u d y p o p ulati o n. 
 
T he pr ot oc ol vi olati o ns will be liste d per s u bject, descri bi n g t he nat ure of t he vi olati o n. 
S u bje cts faili n g t o c o m plete t he st u d y (as well as t he ti me a n d reas o ns f or disc o nti n uati o n) 
will be dis pla ye d.  
 
Me di c al hist or y will be referre d i n a cc or da nc e wit h t he Me dic al Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) 2 4 .1  or hi g her. Me dic ati o ns will be me nti o ne d a cc or di n g t o t he 
a nat o mic t hera pe utic class ( A T C ) classificati o n s yste m.  
 
1 5. 5  
P h ar m ac o ki n etic A n al ysis  
 
F or t he s u bje cts i ncl u de d i n t he p har ma c o ki netic a nal ysis p o p ulati o n, descri pti ve statistics 
[ n u m ber of o bser vati o ns ( n), ge o metric me a n ( Gmea n ), arit h metic me a n ( Amea n ), sta n dar d 
de viati o n ( S D), ge o metric S D ( G S D), c oefficie nt of variati o n ( C V %) , ge o metric C V % 
( G C V %), t w o-si de d 9 5 % CI of t he arit h metic a n d ge o metric me a ns, me dia n, mi ni m u m 
a n d ma xi m u m] of t he plas ma c o nce ntrati o ns will be prese nte d b y i n vesti gati o nal pr o d uct.  
 
I n di vi d ual plas ma c o nc e ntrati o n ti me pr ofiles will be dis pla ye d gra p hicall y o n a li near -
li ne ar scale a n d se mi-l o garit h mic scale. Gmea n  plas ma c o nc e ntrati o ns -ti me c ur ves i ncl u di n g 
9 5 % CIs will be dis pla ye d b y tre at me nt peri o d.  
 
Ot her P K para meters ma y be c alc ulate d f or t he plas ma c o nc e ntrati o n -ti me pr ofiles, if 
c o nsi dere d a p pr o priate a n d j ustifie d at t he ti me of t he P K a nal ysis.  
 
F or t he s u bje cts i ncl u de d i n t he p har ma c o ki netic a nal ysis p o p ulati o n, i n di vi d ual 
p har mac o ki netic para meters a n d descri pti ve statistics ( n, G mea n , Ame a n , S D, G S D, C V %, 
G C V %, t w o -si de d 9 5 % CI of t he arit h metic a n d ge o metric me a ns, me dia n, mi ni m u m a n d 
ma xi m u m) will be prese nte d b y i n vesti gati o nal pr o d uct.  
 
1 5. 5. 1  
P art 1    
 
A p pr o priate descri pti ve statistics will be use d t o s u m marize plas ma c o nce ntrati o ns a n d P K 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 5  of 5 7  
 
para meters.  F or mal statistic al a nal ys is of P K data will be perf or me d t o c haracterize t he P K 
i ntera cti o ns: 
- 
A nal ysis of t he effect of gi vi n ostat o n mi da z ola m P K: C m a x  a n d A U C 0 -2 4 of 
mi da z ola m a n d h y dr o x y -mi da z ola m w he n it is a d mi nistere d al o ne a n d c o -
a d mi nistere d wit h gi vi n ostat will be t he pri mar y p har ma c o ki netic para meters f or 
t he assess me nt of t he effe ct of gi vi n ostat o n mi da z ola m P K. 
- 
A nal ysis of t he effect of gi vi n ostat o n da bi gatra n P K: C ma x  a n d A U C 0 -7 2 of t otal 
a n d fre e da bi gatra n w he n da bi gatra n ete xilate is a d mi nistere d al o ne a n d c o -
a d mi nistere d wit h gi vi n ostat will be t he pri mar y p har ma c o ki netic para meters f or 
t he assess me nt of t he effe ct of gi vi n ostat o n da bi gatra n. 
A n a nal ysis of varia nce ( A N O V A) will be perf or me d o n t he l n-tra nsf or me d pri mar y 
p har mac o ki netic para meters. A li near mi xe d effe cts m o del will be a p plie d, usi n g 
Tr e at me nt as fi xe d effe cts, assesse d at a t w o o ne -si de d 5 % si g nific a nce le vel ( α = 0. 0 5). 
S u bje ct will be i ncl u de d as ra n d o m effect . Ge o metric me a ns rati os ( G M R ) a n d 
c orres p o n di n g 9 0 % CI will be c alc ulate d f or t he l n -tra nsf or me d pri mar y p har mac o ki netic 
para meters, usi n g s u bstrates al o ne as t he refere nce.  
Wilc o x o n si g ne d ra n k test will be use d t o test f or t he differe nce i n t
ma x . 
 
 
1 5. 6  
S afet y D at a A n al ysis  
 
S afet y a n d t olera bilit y data will be liste d a n d s u m marize d descri pti vel y b y  st u d y part, 
tre at me nt a n d s u bject n u m ber. 
 
At e a c h ti me p oi nt, a bs ol ute val ues of safet y varia bles  a n d c ha n ge fr o m baseli ne  will be 
s u m marize d wit h me a n, me dia n, S D, S E, mi ni m u m, a n d ma xi m u m val ues. T he n u m ber of 
a vaila ble o bser vati o ns a n d a bs ol ute o ut -of -ra n ge val ues will be prese nte d. Val ues o utsi de 
t he i n vesti gat or’s n or mal ra n ge will be fla g ge d i n t he listi n g. 
 
T he occ urre nce of cli nical A Es will be m o nit ore d t hr o u g h o ut t he st u d y.  
Cli nic all y si g nific a nt a b n or malities i n la b orat or y safet y tests, vital si g ns , E C G a n d 
p h ysic al e xa mi nati o n will be re p orte d as A Es.  
 
A Es will be ta b ulate d a n d s u m marize d a cc or di n g t o t he Me d D R A 2 4 .1  or hi g her, a n d 
classifie d b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T). T he f oll o wi n g 
i nf or mati o n rec or de d or c o m p ute d is use d f or t he descri pti o n of t he A Es: re p orte d Ter m; 
S O C a n d P T b y Me d D R A c o di n g;  start date, start ti me, e n d date an d e n d ti me;  
seri o us ness; se verit y; relati o ns hi p (c a usalit y); a cti o n ta ke n; c o nc o mita nt me dic ati o n; 
o utc o me; m ost re c e nt st u d y treat me nt ta ke n; last d osi n g date. 
 
A se parate listi n g of S A Es will be prese nte d, if a p plica ble.  
 
I nci de nc e a n d fre q ue nc y of tre at me nt-e mer ge nt a d verse e ve nts ( T E A Es ) will be 
s u m marize d descri pti vel y b y S O C a n d P T f or Test a n d Refere nc e pr o d ucts a n d o verall, f or 
all s u bje cts w h o were d ose d ( Safet y p o p ulati o n).  
 
 
1 6  
D A T A C O L L E C TI O N, M O NI T O RI N G A N D R E T E N TI O N  
 
1 6. 1  
D at a C olle cti o n  
 
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 6  of 5 7  
 
1 6. 1. 1  
C ase Re p ort F or ms  
 
Sta n dar dize d e C R Fs will be p r o d uc e d usi n g Vie d oc™ s oft ware pa c ka ge (Vie d oc 
Te c h n ol o gies A B , U p psala, S we de n). All st u d y data will be rec or de d i nt o t he e C R Fs, 
e xc e pt f or plas ma dr u g c o nc e ntrati o ns, w hic h will be directl y i m p orte d i nt o t he fi nal st u d y 
data base.  
T he rec or d i n e C R F is pe rf or me d b y t he cli nical rese arc h staff, e xc e pt f or safet y 
la b orat or y res ults w hic h will be i m p orte d t o e C R F b y t he 
s Cli nic al Data 
Ma na ge me nt de part me nt.   
 
e C R Fs will  be c o m plete d f or ea c h s u bject w h o pr o vi de d i nf or me d c o nse nt a cc or di n g t o 
t he a p plic a ble S O Ps a n d t he st u d y e C R F c o m pleti o n g ui deli nes. F or s u bje cts w h o met t he 
sele cti o n criteria at scree ni n g a n d a d missi o n, data will be f ull y re c or de d i nt o t he e C R F, 
i ncl u di n g e n d-of -st u d y safet y assess me nts. F or s u bje cts w h o ha ve si g ne d t he i nf or me d 
c o nse nt b ut di d n ot me et t he selecti o n criteria, data will o nl y be partiall y rec or de d i nt o t he 
e C R Fs.  
 
Cli nic al researc h staff will perf or m q ualit y c o ntr ol of data e ntere d i nt o t he e C R Fs pri or t o 
st u d y m o nit ori n g a cti vities. e C R Fs will b e ele ctr o nic all y si g ne d off b y t he Pri nci pal 
I n vesti gat or after t he data base is c o nsi dere d cle a n.  
 
1 6. 1. 2  
S o ur c e D oc u me nts  
 
St u d y data will be re c or de d o n s o urc e d oc u me nts. S o urce d oc u me nts will be verifie d f or 
c o m plete ness a n d a cc ura c y b y 
. Data fr o m s o urce d oc u me nts 
will be tra nscri be d, w here ne c essar y, i nt o t he e C R Fs b y t he dele gate d cli nical rese arc h 
staff.  
T he  cli nic al researc h u nit will retai n all s o urce d oc u me nts.  
T he s o urce d oc u me nts m ust be ke pt i n or der a n d u p -t o-date s o t he y al wa ys refle ct t he 
latest o bser vati o ns o n t he s u bjects e nr olle d i n t he st u d y.  
 
Data o n s u bjects c olle cte d o n e C R Fs d uri n g t he trial will be d oc u me nte d i n a n a n o n y m o us 
fas hi o n a n d t he s u bject will o nl y be i de ntifie d b y t he s u bje ct n u m ber a n d b y his/ her  partial 
date of birt h. All t he i nf or mati o n re q uire d b y t he pr ot oc ol s h o ul d be pr o vi de d a n d a n y 
o missi o ns re q uire e x pla nati o n. All e C R Fs m ust be c o m plete d e x pe diti o usl y after t he 
s u bje ct’s visit. T he C R O will pr o vi de t he st u d y site wit h e C R F a n d t he g ui deli nes f or t he 
e C R F c o m pilati o n f or e a c h patie nt. T he i n vesti gat or m ust mai ntai n s o urc e d oc u me nts f or 
e a c h s u bje ct i n t he st u d y. All i nf or mati o n o n e C R Fs m ust be trac e a ble t o t hese s o urc e 
d oc u me nt s, w hic h are ge nerall y mai ntai ne d i n t he s u bject's file.  
 
1 6. 2  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nc e  
 
1 6. 2. 1  
Q u alit y C o ntr ol  
 
T he st u d y will be c o n d ucte d a n d s u b mitte d t o q ualit y c o ntr ol t o ass ure data i nte grit y, i n 
a c c or da nc e wit h a p plica ble S O Ps a n d I C H G C P re q uire me nts. T hese S O Ps re q uire q ualit y 
c o ntr ol o n t he f oll o wi n g pr ocesses: me dical writi n g, s o urc e d oc u me nts a n d e C R F data 
e ntr y c o m pleti o n a n d a cc urac y, data ma na ge me nt a n d st u d y re p orti n g.  
 
1 6. 2. 2  
M o nit ori n g  
 
T he m o nit ori n g will be d o ne at t he trial site b y a n i n de p e n de nt st u d y m o nit or. A site 
i nitiati o n visit will be hel d pri or t o i nitiati o n of s u bje ct e nr ol me nt. D uri n g t he st u d y, t he 
P P D
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I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 8  of 5 7  
 
E ur o pe a n electr o nic C o m m o n Te c h nical D oc u me nt (e C T D) f or mat s pecificati o ns a n d i n 
a c c or da nc e wit h t he a p plic a ble S O Ps. T he p har mac o ki netic a nal ysis will be i ncl u de d i n 
t he i nte grate d C S R. 
 
 
1 7  
G E N E R A L S T U D Y A D MI NI S T R A TI O N  
 
1 7. 1  
Re g ul at or y a n d E t hic al As pe cts  
 
1 7. 1. 1  
Re vie w a n d A p p r o v al b y t he I n d e p e n de nt Et hics C o m mittee  
 
T his pr ot oc ol, i nf or me d c o nse nt f or m s, details of s u bje ct c o m pe nsati o n a n d a n y s u bje ct 
re cr uiti n g materials will be s u b mitte d t o C EI C –  Et hics C o m mitte e f or Cli nic al R esearc h 
( A ve ni da d o Brasil, Lis b oa, P ort u gal) f or e val uati o n a n d a p pr o val, pri or t o t he start of t he 
st u d y. T he a p pr o ve d d oc u me nts m ust be file d i n t he st u d y files ( T M F a n d I F).  
T he st u d y will n ot start u ntil t he C EI C has a p pr o ve d t he d oc u me nts. T he letter of t he 
C EI C a p pr o val will be a p pe n de d t o t he fi nal C S R.  
 
1 7. 1. 2  
S u bject Inf or m ati o n a n d C o nse nt  
 
Writte n i nf or me d c o nse nt will be o btai ne d fr o m ea c h pr os pe cti ve s u bject i n writi n g pri or 
t o t he start of t he st u d y.  
 
Ea c h pr os pe cti ve partici pa nt will rec ei ve a f ul l e x pla nati o n of t he o bje cti ves, pr oc e d ur es, 
restricti o ns a n d p ote ntial ha zar ds of t he st u d y b y t he I n vesti gat or . O nc e t his i nf or mati o n is 
pr o vi de d t o t he s u bje ct, t he pr os pecti ve partici pa nt is re q uire d t o rea d t he i nf or me d 
c o nse nt f or m a n d as k a n y q uesti o ns a b o ut its c o nte nts. After t he p h ysicia n i n c har ge has 
t he c o n victi o n t hat t he s u bje ct is a ware of t he i m plic ati o ns of partici pati n g i n t he st u dy, t he 
s u bje ct will c o nfir m his/ her willi n g ness t o partici pate b y si g ni n g a n d dati n g t he i nf or me d 
c o nse nt f or m. 
S u bje cts will  rec ei ve a c o p y of s u bje ct i nf or mati o n a n d si g ne d i nf or me d c o nse nt f or m a n d 
will  be ass ure d t hat t he y ma y disc o nti n ue fr o m t he st u d y at a n y ti me a n d f or a n y re as o n  
wi t h o ut a n y prej u dic e. A s u bje ct scree ni n g l o g t o d oc u me nt t he  s u bje cts e nteri n g t he 
scree ni n g p hase m ust be mai ntai ne d at trial site a n d arc hi ve d i n t he I n vesti gat or File.  
I n c ase of a me n d me nts t o t he i nf or me d c o nse nt f or m d uri n g t he st u d y, a re ne we d written 
a n d si g ne d c o nse nt m ust be o btai ne d fr o m e a c h s u bje ct still partici pati n g i n t he st u d y.  
 
S u bject I nf or m ati o n a n d C o nse nt f or S A R S -C o V -2 testi n g  
 
S A R S -C o V -2 testi n g will be perf or me d pri or t o a d missi o n t o tre at me nt peri o d a n d 
w he ne ver dee me d a p pr o priate t hr o u g h o ut t he st u d y. A s pe cific writte n i nf or me d c o nse nt 
will be o btai ne d fr o m ea c h pr os pecti ve s u bje ct i n writi n g.   
 
1 7. 1. 3  
Re vie w a n d A p p r o v al b y Re g ul at or y A ut h orities  
 
T he st u d y will be s u b mitte d t o t he re vie w a n d a p pr o val of I N F A R M E D, I. P. ( P ort u g uese 
Nati o nal C o m pete nt A ut h orit y) ac c or di n g t o r ules i n f orce. T he letter of t he I N F A R M E D 
a p pr o val will be a p pe n de d t o t he fi nal C S R . 
 
1 7. 1. 4  
I ns u r a n ce, In d e m nit y a n d C o m pe ns ati o n  
 
It is t he S p o ns or’s res p o nsi bilit y t o g uara nte e s ufficie nt i ns ura nce c o vera ge f or t his st u d y 
s h o ul d a n y seri o us e ve nts or de at hs res ult dire ctl y or n ot fr o m t he e xec uti o n of t he prese nt 
P P D

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V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  4 9  of 5 7  
 
pr ot oc ol.  
T he prese nt article is n ot t o be i nter prete d as e n ga gi n g t he  S p o ns or’s res p o nsi bilit y i n t he 
e ve nt of fa ult or ne gli ge nc e of t he s u bje cts, i n vesti gat ors, or a n y pers o ns or e m pl o yees 
u n der t he c o ntr ol of 
 
 
1 7. 1. 5  
C o m pli a nc e S t ate me nt 
 
T he st u d y will be c o n d ucte d a cc or di n g t o t his pr ot oc ol , t he c urre nt versi o n of t he 
De clarati o n of Helsi n ki , I C H G C P , E M A re g ulati o ns a n d a p plic a ble P ort u g uese la ws a n d 
re g ulati o ns. 
 
1 7. 1. 6  
I n vesti g at or St ate me nt 
 
F D A 1 5 7 2 f or m, State me nt of I n vesti gat or ( Title 2 1, C F R Part 3 1 2), c o m plete d a n d 
si g ne d b y t he Pri nci pal I n vesti gat or, will be ke pt o n file a n d will be a vaila ble u p o n 
re q uest. 
 
1 7. 1. 7  
Dele g ati o n of I n vesti g at or D uties  
 
T he Pri nci pal I n vesti gat or is res p o nsi ble t o ass ure t hat all staff i n v ol ve d i n t he st u d y are 
a de q uatel y q ualifie d, trai ne d a n d i nf or me d a b o ut t he pr o t oc ol, a n y pr ot oc ol a me n d me nt, 
t he st u d y tre at me nts, a n d all t heir assi g ne d st u d y-relate d d uties. 
T he Pri nci pal I n vesti gat or m ust mai ntai n a d oc u me nt wit h t he i de ntific ati o n of s u b -
i n vesti gat ors a n d ot her pers o n nel t o w h o m he dele gates si g nific a nt st u d y-r elate d d uties. 
 
1 7. 2  
C o n diti o ns f or M o dif yi n g/ A me n di n g t h e P r ot oc ol 
 
All s u bsta ntial pr ot oc ol m o dific ati o ns m ust be s u b mitte d t o C EI C a n d I N F A R M E D bef or e 
t he y c a n be i m ple me nte d. A me n d me nt t hat eli mi nates a n a p pare nt i m me diate ris k t o 
s u bje cts ca n be i m ple me nte d bef ore a p pr o val, b ut C EI C a n d I N F A R M E D ha ve t o be 
i nf or me d a b o ut s uc h m o dificati o n as s o o n as p ossi ble.  
A d mi nistrati ve c ha n ges (e. g., re plac e me nt of a st u d y m o nit or, a d dress c ha n ge) t hat ha ve 
n o i m pa ct o n t he st u d y c o n d uct a n d/ or safet y of t he v ol u nte ers  s h o ul d be n otifie d t o C EI C 
a n d I N F A R M E D b ut d o n ot re q uire a p pr o val.  
 
1 7. 3  
D oc u me nts f or S t u d y Initi ati o n  
 
T he f oll o wi n g d oc u me nts, at mi ni m u m, ha ve t o be a vaila ble pri or t o scre e ni n g: c urric ula 
vita e of all t he cli nic al staff, C EI C a p pr o val of t he fi nal versi o n of t he Cli nic al St u d y 
Pr ot oc ol, i nf or me d c o nse nt f or m a n d writte n s u bje ct i nf or mati o n,  refere nc e safet y 
i nf or mati o n, writte n a p pr o val b y I N F A R M E D, st u d y i ns ura nce p olic y, a n d list of n or mal 
ra n ges of cli nic al la b orat or y tests. 
 
1 7. 4  
O w n e rs hi p of d at a, d iscl os ur e a n d c o nfi d e nti alit y 
 
T he I n vesti gat or/
 ma y n ot p u blis h t he data c olle cte d d uri n g  t his st u d y i n a n y 
f or m, e xce pt wit h t he writte n per missi o n of t he S p o ns or. I n c ase of p u blic ati o n, 
c o nfi de ntialit y of t he st u d y v ol u nte ers will be mai ntai ne d.  
B y si g ni n g t he pr ot oc ol, t he i n vesti gat ors a n d t heir c o -w or kers a c ce pt t o s u b mit a n y 
i nte n de d co m m u nic ati o n (a bstract, pa per or oral prese ntati o n) t o t he S p o ns or re as o na bl y i n 
a d va nce (at le ast 3 0 w or ki n g da ys f or a n a bstra ct or oral prese ntati o n a n d 6 0 w or ki n g da ys 
f or a ma n uscri pt). T his is t o all o w t he S p o ns or t o re vie w t he c o m m u nic ati o ns f or a ccura c y 
P P D
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V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 0  of 5 7  
 
a n d c o nfi de ntialit y, t o pr o vi de a n y rele va nt s u p ple me ntar y i nf or mati o n a n d t o all o w 
esta blis h me nt of c o -a ut h ors hi p a n d i n n o wa y has t o be i nte n de d as a restricti o n of t he 
s p o ns or t o t he i n vesti gat ors’ ri g ht t o p u blis h t he res ults of t he st u d y. I n c a se t he S p o ns or 
i de ntifies s pe cific ne e d/ o p p ort u nit y t o pate nt a n y of t he st u d y fi n di n gs, t he I n vesti gat or 
will all o w a si x m o nt h ti me -wi n d o w bet we e n his s u b missi o n t o t he S p o ns or a n d t he 
i nte n de d p u blic ati o n a n d act ual s u b missi o n/c o m m u nic ati o n t o t hir d parties, i n or der t o 
all o w t he S p o ns or t o u n derta ke a p pr o priate pate nti n g ste ps.  
 
 
1 8  
R E F E R E N C E S  
 
[ Br o g d o n 2 0 0 7] Br o g d o n J L, X u Y, S za b o SJ, et al. Hist o ne de ac et ylase acti vities are 
re q uire d f or i n nate i m m u ne c ell c o ntr ol of T h 1 b ut n ot T h 2 effe ct or c ell f u nctio n. Bl o o d 
2 0 0 7; 1 0 9( 3), 1 1 2 3 -1 1 3 0.  
[ B uc c ola m®  S u m mar y of Pr o d uct C hara cteristics 2 0 1 1] B uc c ola m 2. 5 m g or o m uc osal 
s ol uti o n, re vise d 0 8/ 2 0 2 1, La b orat ori os Les vi, S. L..  
[ Carta 2 0 0 6] Carta S, Tassi S, S e mi n o C, et al. Hist o ne dea c et ylase i n hi bit ors pre ve nt 
e x oc yt osis of i nterle u ki n -1 β -c o ntai ni n g secret or y l ys os o mes: r ole of micr ot u b ules. Bl o o d 
2 0 0 6; 1 0 8( 5), 1 6 1 8 -1 6 2 6.  
[ C h o u d har y 2 0 0 9] C h o u d har y C, K u mar C, G na d F, et al. L ysi ne a cet ylati o n tar gets 
pr otei n c o m ple xes a n d c o -re g ulates maj or c ell ular f u ncti o ns. S cie nc e 2 0 0 9; 3 2 5( 5 9 4 2), 
8 3 4 -8 4 0.  
[ C ol ussi 2 0 0 8] C ol ussi C, M ozzetta C, G urt ner A, et al. H D A C 2 bl oc ka de b y nitric o xi de 
a n d hist o ne de ac et ylase i n hi bit ors re veals a c o m m o n tar get i n D uc he n ne m usc ular 
d ystr o p h y tre at me nt. P N A S 2 0 0 8; 1 0 5( 4 9), 1 9 1 8 3 -1 9 1 8 7.  
[ Di narell o 2 0 1 1] Di narell o C A. Bl o o d 2 0 1 1; 1 1 7( 1 4), 3 7 2 0-3 7 3 2.  
[ E berl 2 0 0 7] E berl S, Re n ner B, Ne u bert A, et al. R ole of p-gl yc o pr otei n i n hi biti o n f or 
dr u g i nteracti o ns: e vi de nce fr o m i n vitr o a n d p har mac oe pi de mi ol o gic al st u dies. Cli n 
P har ma c o ki net. 2 0 0 7; 4 6, 1 0 3 9 -4 9.  
[ E M A G ui deli ne 2 0 1 1] E ur o pe a n Me dici nes A ge nc y ( E M A). G ui deli ne o n bi oa nal ytic al 
met h o d vali dati o n, D oc. Ref.: E M E A/ C H M P/ E W P/ 1 9 2 2 1 7/ 2 0 0 9 Re v. 1 C orr. 2, L o n d o n, 
2 1 J ul y, 2 0 1 1.  
[ E pistat us®  S u m mar y of Pr o d uct C haracteristics]  
[ F D A Gui da nc e 2 0 1 8] F o o d a n d Dr u g A d mi nistrati o n ( F D A), G ui da nc e f or I n d ustr y, 
Bi oa nal ytic al Met h o d Vali dati o n ( 2 0 1 8).  
[ F D A G ui da nc e 2 0 2 0] F o o d a n d Dr u g A d mi nistrati o n ( F D A), Cli nic al Dr u g I nteracti o n 
St u dies - C yt oc hr o me P 4 5 0 E nz y me - a n d Tr a ns p orter-Me diate d Dr u g I nteracti o ns 
G ui da nc e f or I n d ustr y ( 2 0 2 0).  
[ F u hr 2 0 1 9] F u hr U, Hsi n C H, Li X, et al. Assess me nt of p har mac o ki netic dr u g -dr u g 
i ntera cti o ns i n h u ma ns: I n vi v o pr o be s u bstrates f or dr u g meta b olis m a n d dr u g tra ns p ort 
re visite d. A n n ual re vie w of p har ma c ol o g y a n d t o xic ol o g y 2 0 1 9; 5 9, 5 0 7 -5 3 6.  
[ Gi vi n ostat I B] Gi vi n ostat (I T F 2 3 5 7) I n vesti gat or’s Br oc h ure, e diti o n n o. 2 2. 0, 
2 0J A N 2 0 2 1, Italfar mac o S. p. A.  
[Ie z zi 2 0 0 4] Ie z zi S, Pa d o va M D, S erra C, et al. De ac et ylase i n hi bit ors i ncrease m uscle 
c ell size b y pr o m oti n g m y o blast re cr uit me nt a n d f usi o n t hr o u g h i n d ucti o n of f ollistati n. 
De v Cell 2 0 0 4; 6( 5), 6 7 3 -6 8 4.  
P P D

I T F/ 2 3 5 7/ 5 5 
V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 1  of 5 7  
 
[ Ka petas 2 0 2 1] Ka petas AJ, A b u hel wa A Y, S oric h MJ, et al. E vi de nce-Base d G ui deli nes 
f or Dr u g I ntera cti o n St u dies: M o del-I nf or me d Ti me C o urse of I ntesti nal a n d He patic 
C Y P 3 A 4 I n hi biti o n b y Clarit hr o m yci n. A A P S J 2 0 2 1; 2 3( 5), 1 0 4.  
[ K ha n O 2 0 1 2] Ka n O, La T ha n g ue N B. H D A C i n hi bit ors i n c a ncer bi ol o g y: e mer gi n g 
me c ha nis ms a n d cli nical a p plic ati o ns. I m m u n o Cell Bi ol 2 0 1 2; 9 0( 1), 8 5-9 4.  
[ Le o ni 2 0 0 2] Le o ni F, Zalia ni A, Bert oli ni G, et al. T he a ntit u m or hist o ne de a c et ylase 
i n hi bit or s u ber o yla nili de h y dr o xa mic aci d e x hi bits a ntii nfla m mat or y pr o perties via 
s u p pressi o n of c yt o ki nes. Pr oc Natl Aca d Sci U S A 2 0 0 2; 9 9, 2 9 9 5 – 3 0 0 0.  
[ Le o ni 2 0 0 5] Le o ni F, F ossati G, Le wis E C, et al. T he hist o ne de ac et ylase i n hi bit or 
I T F 2 3 5 7 re d uc es pr o d ucti o n of pr o-i nfla m mat or y c yt o ki nes i n vitr o a n d s yste mic 
i nfla m mati o n i n vi v o. M ol Me d 2 0 0 5; 1 1( 1 -1 2), 1 -1 5.  
[ Li 2 0 2 0] Li X, Li u L, X u B, et al. Bi oe q ui vale nc e a n d p har mac o d y na mics of a ge neric 
da bi gatra n ete xilate c a ps ule i n he alt h y C hi nese s u bje cts u n der fasti n g a n d fe d c o n diti o ns. 
P har ma c ol Res Pers pe ct 2 0 2 0; 8( 2), e 0 0 5 9 3.  
[ Mal 2 0 0 1] Mal A, St ur ni ol o M, S c hiltz R L, et al. A r ole f or hist o ne dea c et ylase H D A C 1 
i n m o d ulati n g t he tra nscri ptio nal a cti vit y of M y o D: i n hi biti o n of t he m y o ge nic pr o gra m. 
E M B O J 2 0 0 1; 2 0( 7), 1 7 3 9 -1 7 5 3.  
[ Mar ks 2 0 1 0] Mar ks P A. T he cli nic al de vel o p me nt of hist o ne de ac et ylase i n hi bit ors as 
tar gete d a ntic a nc er dr u gs. E x pert O pi n I n vesti g Dr u gs 2 0 1 0; 1 9( 9), 1 0 4 9 -1 0 6 6.  
[ Minetti 2 0 0 6] Mi netti G C, C ol ussi C, A da mi R, et al. F u ncti o nal a n d m or p h ol o gic al 
re c o ver y of d ystr o p hic m uscles i n mic e tre ate d wit h de acet ylase i n hi bit ors. Nat Me d 2 0 0 6; 
1 2( 1 0), 1 1 4 7 – 1 1 5 0.  
[ Ne b bi os o 2 0 0 9] Ne b bi os o A, Ma nz o F, Mic eli M, et al. S electi ve class II H D A C 
i n hi bit ors i m pair m y o ge nesis b y m o d ulati n g t he sta bilit y a n d a cti vit y of H D A C-M E F 2 
c o m ple xes. E M B O Re p 2 0 0 9; 1 0( 7), 7 7 6 -7 8 2.  
[ Nis hi da 2 0 0 4] Nis hi da A, Hi da ka K, Ka n dra T, et al. I ncre ase d E x pressi o n of I nterle u ki n-
3 6, a Me m ber of t he I nterle u ki n -1 C yt o ki ne Fa mil y, i n I nfla m mat or y B o wel Disease. 
I nfla m m B o wel Dis 2 0 1 6; 2 2( 2), 3 0 3-3 1 4.  
[ Pa n 2 0 1 2] Pa n H, Jia n g yi n g C, W e nfa n g X. S ele cti ve Hist o ne De ac et ylase I n hi bit ors. 
A nti -Ca nc er A ge nts i n Me dici nal C he mistr y 2 0 1 2; 1 2( 3), 2 4 7 -2 7 0.  
[ Pe nsa k 2 0 1 9] Pe nsa k S R, R ojas-Fer na n de z C. 4 β -H y dr o x yc h olester ol as a n E n d o ge n o us 
Bi o mar ker f or C Y P 3 A Acti vit y: Literat ure Re vie w a n d Critic al E val uati o n. J Cli n 
P har ma c ol ol 2 0 1 9; 5 9( 5), 6 1 1 -6 2 4.  
[ Pra daxa ®  S u m mar y of Pr o d uct C hara cteristics 2 0 0 9] Pra da xa 7 5 m g har d c a ps ules, 
re vise d 0 6/ 2 0 2 1, B oe hri n ger I n gel hei m I nter nati o nal G m b H. 
[ S uli ma n 2 0 1 2] S uli ma n B A, X u D, Willia ms B R G. H D A Ci: m ole c ular me c ha nis ms a n d 
t hera pe utic i m plic ati o ns i n t he i n nate i m m u ne s yste m. I m m u n ol Cell Bi ol 2 0 1 2; 9 0( 1), 2 3-
3 2.  
[ S we et 2 0 1 2] S weet MJ, S ha kes pear M R, Ka mal N A, et al. H D A C i n hi bit ors: m o d ulati n g 
le u k oc yte differe ntiati o n, s ur vi val, pr oliferati o n a n d i nfla m mati o n. I m m u n ol Cell Bi ol 
2 0 1 2; 9 0( 1), 1 4 -2 2.  
[ W a n g 2 0 0 9] W a n g H, D y m oc k B W. Ne w pate nte d hist o ne de ac et ylase i n hi bit ors. E x pert 
O pi n T her Pat 2 0 0 9; 1 9, 1 7 2 7 -1 7 5 7.  
 
 
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V er si o n: 1. 0  
D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 2  of 5 7  
 
1 9  
A P P E N DI C E S  
 
1 9. 1  
A p pe n di x 1  - A d verse E ve nts a n d Pr e g n a nc y C o nsi de r ati o ns  
  
1 9. 1. 1  
A d verse E ve nts - Defi niti o ns  
 
T he defi niti o ns are i n a cc or da nce wit h t he I C H-E 2 A, Directi ve 2 0 0 1/ 2 0/ E C, a n d t he 
E ur o pe a n C o m missi o n Detaile d G ui da nc e 2 0 1 1/ C 1 7 2/ 0 1.  
 
A d verse E ve nt ( A E)  - a n y u nt o war d me dic al occ urre nc e i n a patie nt or cli nical 
i n vesti gati o n s u bje ct a d mi nistere d a p har mac e utical pr o d uct a n d w hic h d oes n ot 
ne c ess aril y ha ve t o ha ve a ca usal relati o ns hi p wit h t his tre at me nt.  
A n A E ca n t heref ore be a n y u nfa v ora ble  a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use 
of a me dici nal pr o d uct,  w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.  
 
E xa m ples of e ve nts t hat me et A E defi niti o n:  
–  
A n y si g n/s y m pt o m prese nte d d uri n g t he c o urse of t he st u d y or re p orte d wit hi n a 
re as o na ble ti me after last dr u g a d mi nistrati o n. 
–  
A n y a b n or mal la b orat or y  test res ults or ot her safet y assess me nts c o nsi dere d cli nic all y 
si g nific a nt i n t he me dic al j u d g me nt of t he i n vesti gat or. 
–  
I ncre ase i n fre q ue nc y/se verit y of a pre -e xisti n g c o n diti o n.  
–  
A n y ne w c o n diti o n detecte d/ dia g n ose d d uri n g t he st u d y c o n d ucti o n, i ncl u di n g  t h ose 
pre vi o usl y prese nt b ut u n k n o w n u ntil t he n.  
–  
A n y c o n diti o n res ulti n g fr o m a s us pecte d dr u g -dr u g i ntera cti o n.  
–  
O ver d ose, mis use, a n d a b use of t he st u d y treat me nt. St u d y tre at me nt err ors m ust be 
d oc u me nte d i n t he st u d y treat me nt pa ge of t he e C R F.  
 
A d ver se Dr u g Re acti o n ( A D R) - all n o xi o us a n d u n inte 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 a d mi nistere d.  
T he defi niti o n i m plies a reas o na ble p ossi bilit y of a ca usal relati o ns hi p bet wee n t he e ve nt 
a n d t he I M P. T his me a ns t hat t here are facts ( e vi de nc e) or ar g u me nts t o s u g gest a ca usal 
relati o ns hi p. 
 
U n e x p ecte d A d verse Re acti o n ( U A R)  - a n a d verse re a cti o n, t he nat ure or se verit y of 
w hic h is n ot c o nsiste nt wit h t he a p plic a ble pr o d uct i nf or mati o n ( Refere nce Safet y 
I nf or mati o n: I n vesti gat or’s Br oc h ure or S m P C ).  
 
S e ri o us A d ve rse E ve nt ( S A E)  - a n y u nt o war d me dic al oc c urre nc e or effect, t hat, at a n y 
d ose:  
–  
res ults i n de at h; 
–  
is life t hre ate ni n g; 
N O T E: T he ter m refers t o a n e ve nt i n w hic h t he p atie nt w as at risk of de at h at 
t he ti me of t he e ve nt; it d oes n ot refer t o a n ev e nt w hic h hy p ot hetic ally mi g ht 
h av e c a use d de at h if it were m ore sev ere.  
–  
re q uires h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pit alizati o n;  
N O T E: T his a p plies if h os pit al a d missi o n or pr ol o n g ati o n of e xisti n g 
h os pit aliz a ti o n is a res ult of t he a dv erse ev e nt. 
–  
res ults i n persiste nt or si g nific a nt disa bilit y/i nc a pacit y; 
N O T E: T his me a ns a s u bst a nti al disr u pti o n of a pers o n’s a bility t o c o n d uct 
n or m al life f u ncti o ns, i.e. t he a dv erse ev e nt res ult s i n a si g nific a nt, persiste nt or 
per m a ne nt c h a n ge, i m p air me nt, d a m a ge or disr u pti o n i n t he st u dy p artici p a nt’s 
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D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 3  of 5 7  
 
b o dy f u ncti o n/str uct ure, p hysic al activities a n d/ or q u ality of life.  
–  
is a c o n ge nital a n o mal y/ birt h defect; 
N O T E: T o  be  c o nsi dere d if t here is a s us pici o n t h at t he e x p os ure t o a me dici n al 
pr o d uct pri or t o c o nc e pti o n or d uri n g pre g n a nc y m ay h ave res ulte d i n a n 
a dv erse o utc o me i n t he c hil d.  N ot all c o n ge nit al a n o m alies h ave cli nic al 
c o nse q ue nc e a n d c a n be c o nsi dere d e ve n n or m al v ari a nts. F urt her m ore, n ot all 
ge netic c o n diti o ns h a ve a dr u g rel ate d eti ol o gy . T o c o nfir m if a c o n ge nit al 
a n o m aly or a ge netic c o n diti o n is t o be cl assifie d as S A E, t he I m p ort a nt Me dic al 
Ev e nt ( I M E) list1 s h oul d be c o ns ulte d .  
–  
is a n i m p orta nt me dic al e ve nt t hat re q uires i nter ve nti o n t o pre ve nt o ne of t he a b o ve. 
N O T E: Me dic al a n d scie ntific j u d g me nt s h o ul d be e xercise d i n i m p ort a nt 
me dic al ev e nts t h at m ay n ot be i m me di ately life t hre ate ni n g, res ult i n de at h or 
h os pit aliz ati o n, b ut m ay je o p ar dize t he s u bje ct or m ay re q uire i nterve nti o n t o 
prev e nt o ne of t he a b ov e liste d. As a b ov e, t he I M E list s h o ul d be c o ns ulte d. 
 
A pre -pla n ne d h os pitalizati o n s h o ul d n ot be c o nsi dere d a n S A E.  
 
A S us p ecte d U n e x p ecte d S e ri o us A d ve rse Re acti o n ( S U S A R)  is referre d t o a n A D R 
t h at 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. ”  
 
O ve r d ose  
I n ge neral, a dr u g o ver d ose i n a cli nic al st u d y is defi ne d as t he a cci 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 xc ee di n g t he pr ot oc ol defi ne d d ose. T he 
I n vesti gat or m ust i m me diatel y n otif y t he S p o ns or ( Dr u g S afet y Ma na ger) a n d 
- Materi o Vi gila nce a n d P har ma c o vi gila nc e U nit - of a n y occ urre nce of 
o ver d ose wit h I n vesti gati o nal Me dici nal Pr o d ucts.  
A n y i nsta nc e 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 to t he S p o ns or ( Dr u g S afet y Ma na ger) a n d 
 - Materi o Vi gila nc e 
a n d P har mac o vi gila nc e U nit wit hi n 2 4 h o urs a n d, o nl y i n c ase of A Es, it m ust be f ull y 
d oc u me nte d as a S A E f oll o wi n g t he m o dalit y re p ort at  para gra p h 1 3 . 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 treat 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 matic all y.  
A n y ot her sit uati o ns p utti n g t he s u bje ct at ris k of a n a d verse rea cti o n, s uc h as mis use  a n d 
a b use, me dicati o n err ors, s us pect 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 ( Dr u g Safet y Ma na ger) a n d 
- Materi o Vi gila nc e a n d 
P har ma c o vi gila nce U nit - 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 f oll o wi n g 
t he m o dalit y re p ort at para gra p h 1 3. 
  
1 9. 1. 2  
Pr oce d u res f or Re c or di n g, E v al u ati o n , D oc u me nt ati o n  a n d Re p orti n g  
 
T he peri o d of o bser vati o n f or t he c olle cti o n of me dic al occ urre nces e xte n ds fr o m t he ti me 
w he n t he s u bject gi ves I nf or me d C o nse nt u ntil t he f oll o w-u p visit . Me dic al oc c urre nc es 
re p orte d fr o m scree ni n g u ntil t he first st u d y dr u g a d mi nistrati o n s h o ul d be re porte d as 
“ pre-treat me nt a d verse e ve nts”.  
 
T E A Es are defi ne d as A Es n ot prese nt pri or t o first a d mi nistrati o n of i n vesti gati o nal 
 
1 E ur o pea n M e dici nes A ge nc y ( E M A). I ncl usi o n/e xcl usi o n criteria f or t he “I m p orta nt M e dical 
E ve nts ” list, D oc. R ef.: E M A/ 1 2 6 9 1 3/ 2 0 2 1 , 1 8 Marc h 2 0 2 1 , accesse d at: 
htt ps:// w w w.e ma.e ur o pa.e u/ d oc u me nts/ ot her/e u dra vi gila nce -i ncl usi o n/e xcl usi o n-criteria -i m p orta nt-
me dical -e ve nts -list _e n. p df 
 
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D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 4  of 5 7  
 
pr o d uct, or A Es prese nt bef ore first a d mi nistrati o n of i n vesti gati o nal pr o d uct t hat w orse n 
after t he s u bje ct re cei ves t he first  d ose of i n vesti gati o nal pr o d uct. T E A Es t hat oc c ur after 
a d mi nistrati o n of i n vesti gati o nal pr o d uct d uri n g t he was h o ut of a gi ve n peri o d will be 
assi g ne d t o t he treat me nt a d mi nistere d i n t hat peri o d.  
 
F oll o w -u p of A Es a n d S A Es still o n g oi n g at e n d -of -st u d y or 3 0 da ys after pre mat ure st u d y 
disc o nti n uati o n f or a gi ve n s u bject (if n o e n d -of -st u d y has bee n perf or me d) will be 
e xte n de d u ntil fi nal res ol uti o n or u ntil it is me dic all y j ustifia ble t o st o p f urt her f oll o w-u p 
(e. g. a c hr o nic c o n diti o n has bee n rea c he d) or, f or S A Es, u ntil sta bili zati o n or u ntil t he 
e ve nt is ot her wise e x plai ne d. 
 
If t he i n vesti gat or be c o mes a ware of an  S A E i n a st u d y s u bje ct after t he e n d of t he peri o d 
of o bser vati o n, he/s he m ust c o m m u nic ate t his t o t he S p o ns or ( Dr u g S afety M a n a ger) a n d 
 - M ateri o Vi gil a nc e a n d P h ar m ac ovi gil a nc e U nit - i n or der t o m ut uall y 
a gree o n f urt her meas ures a n d a p pr o priate re p orti n g.  Relate d S A Es M U S T be c olle cte d 
a n d re p orte d re gar dless of t he ti me ela pse d fr o m t he last st u d y dr u g a d mi nistrati o n, e ve n if 
t he st u d y has bee n cl ose d. 
 
All A Es, i ncl u di n g S A Es, will be c ollecte d i nt o t he e C R Fs. T he o utc o me of all A Es t hat 
are o n g oi n g at t he e n d -of -st u d y e val uati o n will be rec or de d i n t he e C R F as re c o veri n g/ 
res ol vi n g, n ot re c o vere d/ n ot res ol ve d or u n k n o w n. T he f oll o w-u p i nf or mati o n of t hese 
A Es will o nl y be re c or de d i n t he s o urc e d oc u me nts. F or S A Es, t he f oll o w -u p i nf or mati o n 
will als o be c o m m u nic ate d t o t he S p o ns or ( Dr u g S afety M a n a ger) a n d 
- 
M ateri o Vi gil a nc e a n d P h ar m ac ovi gil a nc e U nit - f or t he p ur p ose of u p dati n g t he dr u g 
safet y data base. 
Data c ollecte d i n t he s o urc e d oc u me nts f or all A Es after t he e n d -of -st u d y e val uati o n will 
n ot be re p orte d i n t he C S R.  
 
All A Es s h o ul d be re c or de d i n t he e C R F after bei n g f ull y d oc u me nte d b y t he i n vesti gat or, 
i n ter ms of: 
  
a)  S e ri o us ness: yes or n o (see criteria f or S A E a b o ve)  
 
b)  S e verit y  
T he i n vesti gat or will c ate g orize t he se verit y of t he A E as f oll o ws:  
–  
Mil d:  A n e ve nt t hat is as y m pt o matic or, if s y m pt o matic, is easil y t olerate d b y t he 
s u bje ct a n d d oes n ot i nterfere wit h dail y acti vities; me dic ati o n  n ot  us uall y  
i n dic ate d. 
N ote: S elf -me dicati o n s h o ul d be assesse d o n t he a p pr o priate ness of its  cli nic al 
i n dic ati o n. 
–  
M o der ate:  A n e ve nt t hat c a uses disc o mf ort a n d i nterferes wit h dail y a cti vities; 
me dic ati o n  p ossi bl y i n dic ate d.  
–  
Se v ere:  A n i nt olera ble e ve nt t hat pre ve nts us ual dail y acti vities; me dic ati o n  
us uall y i n dic ate d.  
If a n A E has m ulti ple aspe cts, t he o ne wit h t he hi g hest se verit y will be gra de d.  
 
c) O utc o me:  
E ve nt o utc o me s h o ul d be assesse d as f oll o ws:  
− F at al :  De at h as a res ult of a n a d verse e ve nt. 
− N ot Re c ov ere d / N ot Res olv e d :  T he e ve nt has n ot i m pr o ve d or re c o vere d. 
− Re c ov ere d / Res olv e d : T he e ve nt has i m pr o ve d or rec u perate d. 
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D at e: 2 9 N O V 2 0 2 1  
I T F 2 3 5 7/Gi vi n o st at 1 0 m g/ m L   
or al s u s p e n si o n   
E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 5  of 5 7  
 
− Re c ov ere d / Res olv e d wit h Se q uel ae : T he s u bject has rec o vere d b ut retai ne d 
pat h ol o gic al c o n diti o ns res ulti n g fr o m t he pri or dise ase or i nj ur y.  
− Re c ov eri n g / Res olvi n g : T he e ve nt is i m pr o vi n g. 
− U nk n o w n : N ot k n ow n, n ot o bser ve d, n ot re c or de d, or ref use d.  
 
d)  Rel ati o ns hi p t o t he i n vesti g ati o n al pr o d u ct ( or c a us alit y  assess me nt ) 
Me dic al j u d g me nt s h o ul d be use d b y t he i n vesti gat or t o deter mi ne t he c a usalit y base d 
o n all a vaila ble i nf or mati o n a n d c o nsi deri n g (i) te m p ora l relati o ns hi p wit h me dici nal 
pr o d uct a d mi nistrati o n, (ii) patter n of re acti o n/ bi ol o gic al pla usi bilit y, (iii) de -
c halle n ge a n d re -c halle n ge, (i v) c o nf o u n di n g fact ors (e. g. c o nc o mita nt me dic ati o n, 
rele va nt me dic al hist or y). 
 
Ca usalit y will be assesse d as:  
–  
R e as o n a bly P ossi ble : T here are fa cts, e vi de nce or ar g u me nts t hat s u g gest a 
c a usal relati o ns hi p.  
A reas o na ble te m p oral relati o ns hi p e xists bet we e n t he A E o nset a n d 
i n vesti gati o nal pr o d uct a d mi nistrati o n t hat c a n n ot be rea dil y e x plai ne d b y t he 
s u bje ct’s cli nic al state or c o nc o mita nt t hera pies. F urt her m ore, t he A E a p pears 
wit h s o me de gree of certai nt y t o be relate d, base d o n t he k n o w n t hera pe utic a n d 
p har mac ol o gic a cti o ns or A E pr ofile of t he i n vesti gati o nal pr o d uct. I n c ase of 
c essati o n or re d ucti o n of t he d o se t he A E ma y a bate or res ol ve, a n d it ma y 
re a p pe ar u p o n re-c halle n ge.   
–  
N ot Re as o n a bly P ossi ble: E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n 
t he i n vesti gati o nal pr o d uct.  
T he e ve nt is cle arl y/ m ost pr o ba bl y c a use d b y ot her eti ol o gies s uc h a n u n derl yi n g 
c o n diti o n, t hera pe utic i nter ve nti o n or c o nc o mita nt me dicati o n; or t he dela y 
bet we e n dr u g a d mi nistrati o n a n d t he o nset of t he a d verse e ve nt is i nc o m pati ble 
wit h a c a usal relati o ns hi p; or t he e ve nt starte d bef ore t he first d ose.   
F or S A Es, a n alter nati ve c a use m ust be pr o vi de d (e. g., pre e xisti n g c o n diti o n, 
u n derl yi n g disease, i nterc urre nt i ll ness, or c o nc o mita nt me dic ati o n). 
 
Ar g u me nts f or Re as o n a bly p ossi ble  
Ar g u me nts f or N ot re as o n a bly 
p ossi ble  
•  
A pla usi ble ti me bet wee n dr u g 
e x p os ure a n d a d verse e ve nt o nset . 
•  
T he e ve nt is c o nsiste nt wit h t he 
k n o w n p har mac ol o g y of t he dr u g.  
•  
T he e ve nt c a n be attri b ute d t o t he 
dr u g class.  
•  
E vi de nc e t hat t he e ve nt is 
re pr o d uci ble w he n t he dr u g is re-
i ntr o d uc e d. 
•  
A n i n dic ati o n of d ose -res p o nse (i.e. 
gre ater a d verse effect if t he d ose is 
i ncrease d, s maller if d ose is 
di mi nis he d).  
•  
T he e ve nt is t y pic all y dr u g -relate d 
a n d i nfre q ue nt i n t he ge neral 
p o p ulati o n n ot  e x p ose d t o dr u gs (e. g. 
•  
N o pla usi ble ti me bet wee n dr u g 
e x p os ure a n d a d verse e ve nt o nset 
(e. g. pre-tre at me nt cases, dia g n osis 
of c a nc er or c hr o nic disease wit hi n 
da ys/ we e ks of dr u g a d mi nistrati o n; 
a n aller gic rea cti o n we e ks after 
disc o nti n uati o n of t he dr u g).  
•  
C o nti n uati o n of t he e ve nt des pite t he 
wit h dra wal of t he me dicati o n, 
c o nsi deri n g t he p har ma c ol o gic al 
pr o perties of t he c o m p o u n d (e. g. 
after 5 half -li ves) a n d t he nat ure of 
t he e ve nt. 
•  
A  me dic all y s o u n d  alter nati ve 
eti ol o g y (e. g. sit uati o ns w here ot her 
dr u gs or u n derl yi n g diseas es a p pe ar 
t o pr o vi de a m ore li kel y e x pla nati o n 
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h y perse nsiti vit y re acti o ns li ke 
Ste ve ns -J o h ns o n s y n dr o me). 
•  
N o me dic all y s o u n d alter nati ve 
eti ol o gies t hat c o ul d e x plai n t he 
e ve nt (e. g. pree xisti n g c o n diti o ns, or 
c o-me dicati o n).  
f or t he o bser ve d e ve nt t ha n t he dr u g 
c o nc er ne d). 
 
T he i n vesti gat or ma y c ha n ge his o pi ni o n of c a usalit y i n li g ht of f oll o w -u p 
i nf or mati o n a n d u p date c a usalit y assess me nt. 
 
–  
U nk n o w n:  I n dic ates t here is n ot a re as o na ble s us pici o n t hat t he a d verse e ve nt is 
ass ociate d wit h t he use of t he i n vesti gati o nal pr o d uct a n d at t he sa me ti me t here 
is n ot t he e xiste nc e of a cle ar alter nati ve e x pla nati o n or n o n-pla usi bilit y. I n t his 
c ase, I n vesti gat or has t o c olle ct 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 I M P, partic ularl y i n c ase of Seri o us A d verse E ve nts. 
 
e) Acti o n t a ke n o n i n vesti g ati o n al pr o d u ct : 
Acti o n ta ke n wit h st u d y tre at me nt s h o ul d be gra de d as f oll o ws:  
− D ose I ncre ase d:  A me dic ati o n sc he d ule was m o difie d b y a d diti o n; eit her b y 
c ha n gi n g t he fre q ue nc y, stre n gt h or a m o u nt.  
− D ose N ot C h a n ge d :  A me dic ati o n sc he d ule was mai ntai ne d. 
− D ose R ate Re d uce d :  A me dic ati o n sc he d ule was m o difie d b y re d uci n g t he r ate 
at w hic h t he d ose was gi ve n, wit h o ut re d uci n g t he t otal d ose a d mi nistere d. 
− D ose Re d uc e d : A me dic ati o n sc he d ule was m o difie d b y s u btra cti o n; eit her b y 
c ha n gi n g t he fre q ue nc y, stre n gt h or a m o u nt.  
− Dr u g I nterr u pte d:  A 
me dic ati o n sc he d ule 
was 
m o difie d b y te m p oraril y 
termi nati n g a prescri be d re gi me n of me dicati o n.  
− Dr u g Wit h dr a w n : -A me dic ati o n sc he d ule was m o difie d t hr o u g h ter mi nati o n of 
a prescri be d re gi me n of me dic ati o n.  
− N ot A p plic a ble:  Acti o n is n ot rele va nt i n t he c urre nt c o nte xt.  
− U nk n o w n:  N ot k n o w n, n ot o bser ve d, n ot  rec or de d, or ref use d. 
 
T he e x p ecte d/ u n e x p ecte d st at us  s h o ul d be e val uate d a n d assesse d b y t he S p o ns or ( Dr u g 
S afety M a n a ger) , base d o n t he refere nc e safet y i nf or mati o n ( R SI) a vaila ble f or Gi vi n ostat 
si nc e e x pe cte d ness i n P har ma c o vi gila nc e refers strictl y to t he i nf or mati o n liste d or 
me nti o ne d i n t he a p plic a ble refere nce safet y i nf or mati o n a n d n ot t o e ve nts t hat mi g ht be 
a ntici pate d fr o m k n o wle d ge of t he p har mac ol o gic al pr o perties of a s u bsta nc e or be ca use it 
was f oresee a ble d ue t o t he healt h stat us (e. g., a ge, me dical hist or y) of t he st u d y s u bje cts.  
 
1 9. 1. 3  
Pr e g n a nc y  
 
T he i n vesti gat or m ust re p ort a n y pre g na nc y t o t he S p o ns or ( Dr u g S afety M a n a ger) a n d 
 - M ateri o Vi gil a nc e a n d P h ar m ac ovi gil a nc e U nit -wit hi n t he sa me 
ti meli nes as t he S A E, b ut a pre g na nc y is n ot per se  a S A E.  
Pre g na nc y i n  a  v ol u nte er  or i n a ma le v ol u nteer’s part ner  s hall be f oll o we d-u p t o 
deter mi ne its o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details of birt h, 
prese nc e or a bse nc e of a n y birt h defects, c o n ge nital a n o malies, or mater nal a n d/ or 
ne w b or n c o m plic ati o ns. If t he o utc o me of t he pre g na nc y me et s t he criteria f or i m me diate 
classific ati o n of a S A E ( e. g. s p o nta ne o us or ele cti ve a b orti o n –  a n y c o n ge nital a n o mal y 
dete cte d i n a n a b orte d fet us is t o be d oc u me nte d; still birt h; ne o natal deat h; c o n ge nital 
a n o mal y), t he i n vesti gat or will re p ort t he e ve nt b y c o m pleti n g a S A E f or m.   
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E u dr a C T N o: 2 0 2 1 -0 0 5 7 5 6 -1 1  
 
 
 
Pa ge  5 7  of 5 7  
 
A n y s u bje ct 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.  
I n c ase of pre g na nc y of a fe male v ol u nte er or of t he part ner of a male v ol u nteer , v ol u nte er 
s h o ul d be i nstr ucte d t o n otif y t he i n vesti gat or if, after c o m pleti o n of t he st u d y, it is 
deter mi ne d t hat t he y be ca me 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.  
N ote 1: T o c o nfir m if a c o n ge nit al a n o m aly or a ge netic c o n diti o n is t o be cl assifie d as 
S A E, t he I M E lis t2 s h o ul d be c o ns ulte d. 
N ote  2 : A n i n d uce d a b orti o n wit h o ut me dic al re as o ns is n ot c o nsi dere d a n S A E.  
 
 
 
2 E ur o pea n M e dici nes A ge nc y ( E M A). I ncl usi o n/e xcl usi o n criteria f or t he “I m p orta nt M e dical 
E ve nts ” list, D oc. R ef.: E M A/ 1 2 6 9 1 3/ 2 0 2 1 , 1 8 Marc h 2 0 2 1 , accesse d at: 
htt ps:// w w w.e ma.e ur o pa.e u/ d oc u me nts/ ot her/e u dra vi gila nce -i ncl usi o n/e xcl usi o n-criteria -i m p orta nt-
me dical -e ve nts -list _e n. p df 
 
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