Clinical trial NCT05492318
Conditions: Drug-Drug Interaction Heathy Volunteer
Keywords: PK Pharmacokinetics Givinostat Midazolam Dabigatran
Sponsor: Italfarmaco
Start date: 2022-03-21; Completion date: 2022-05-24
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective:

1. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose pharmacokinetics (PK) of intravenous or oral midazolam.
2. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose PK of oral dabigatran etexilate.

Secondary objective:

To assess the safety and tolerability of concomitant administration of givinostat plus midazolam and dabigatran etexilate.

Detailed description:
This study was planned as a phase I, open-label, 3-part, fixed-sequence, nonrandomized study in healthy male and female subjects. The study evaluated the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport with intravenous or oral midazolam and with oral dabigatran etexilate.

More precisely, the study aimed at assessing the potential (inhibitory or inducing) effect of givinostat on the PK of midazolam IV, on the PK of oral midazolam and on the PK of dabigatran etexilate.

The study lasted from Day 1 to Day 20. Subjects were confined from Day -1 to Day 20. On Days 6 and 17, single doses of 1 mg midazolam IV and 75 mg dabigatran etexilate, were administered 1 hour after the planned morning time of givinostat administration. On day 1, however, drugs were not administered 1h after gininostat.

On Days 7 and 18, a single oral dose of 2.5 mg midazolam oral solution was administered 1 hour after the planned morning time of givinostat administration.

On day 2, however, the drugs were not administered 1h after gininostat.

From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening.

On Day 19, only the morning dose was administered.

The following assessments were performed:

* Blood collection for pharmacokinetic analysis on Days 1 to 4, 6 to 9 and 17 to 20.
* Vital signs measurements (BP, PR and RR) on Days 1, 2, and 4 to 19.
* 12-lead ECG on Days 3 to 19.
* Blood collection for laboratory tests (hematology, biochemistry and coagulation on Days 4 and 9 and hematology on Days 6, 12, 15 and 18). Subjects were discharged from BlueClinical Phase I in the morning of Day 20 if allowed by the investigator based on their medical condition. The following procedures were performed:
* Physical examination.
* Collection of body weight.
* Vital signs measurements (BP, PR, RR and body temperature).
* 12-lead ECG.
* Safety laboratory assessments (hematology, biochemistry, coagulation and urinalysis).
* Serum pregnancy test for all female subjects. Subjects returned to the site 10 to 14 days after the end of study to undergo additional assessments as required per protocol.

The total duration of Part 1 for each subject was up to approximately 8 weeks from Screening to Follow-up visit, divided as follows:

* Screening: up to 21 days
* Treatment Period: Days 1 to 20
* Safety follow-up visit: 12±2 days

Arms: arm 1: On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.
Interventions: intervention 1: Givinostat 10 mg/mL intervention 2: Midazolam 1mg/ml IV intervention 3: Midazolam 2.5 mg oromucosal solution intervention 4: Dabigatran etexilate 75 mg oral hard capsules
Intervention descriptions: intervention 1: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Days 1, 2, 6, 7, 17 and 18), and twice a day (50 mg as oral suspension), in the morning and in the evening, from the Day 4 to Day 18. On Day 19, only the morning dose was administered. intervention 2: Midazolam 1 mg/ml, solution for intravenous administration. Midazolam 1mg/ml IV, single dose, was administered on Days 1, 6 and 17, 1 hour after the planned morning time of givinostat administration. Midazolam IV were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose. intervention 3: Dose: 2.5 mg oromucosal solution. Midazolam 2.5 mg single oral solution was administered on Days 2, 7 and 18, 1 hour after the planned morning time of givinostat administration.

Oral midazolam (and dabigatran etexilate) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose.

Oral midazolam (and dabigatran etexilate) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before midazolam and dabigatran dosing until 2 hours postdose. Water was provided ad libitum at all other times. Midazolam (and dabigatran etexilate) were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose. intervention 4: Dose: 75 mg; Dosage form: hard capsules On Days 1, 6 and 17, dabigatran etexilate 75 mg was administered (with midazolam 1mg IV) 1 hour after the planned morning time of givinostat administration.

Dabigatran etexilate (and midazolam) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose Oral dabigatran etexilate (and oral midazolam) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before dabigatran (and midazolam) dosing until 2 hours postdose. Water was provided ad libitum at all other times. Dabigatran etexilate (and Midazolam) was administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.

Protocol documents:
Prot_000.pdf: 
 
 
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
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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  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
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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  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
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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  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  
 
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D at e: 2 9 N O V 2 0 2 1  
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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 
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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  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 
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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  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  
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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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D at e: 2 9 N O V 2 0 2 1  
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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 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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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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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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− 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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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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P a g e  1  of 1 3 7  
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
S T U D Y TI T L E:  
A n O pe n -l a bel, Si n gle-ce nter, 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 he Effect 
of Gi vi n ost at o n t he P h ar m ac o ki netics of Mi d az ol a m a n d D a bi g atr a n, t he Effect of 
Cl arit hr o m yci n o n t he P h ar m ac o ki netics of Gi vi n ost at a n d t he P h ar m ac o ki netics of Si n gle 
a n d M ulti ple D oses of Gi vi n ost at.  
 
 
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  of S A P : 2 4 M A R 2 0 2 2  
 
 
S u perse des Versi o n:  N o ne  
Date of S u perse de d Versi o n:  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 writte n a ut h ori z ati o n fr o m 
 
or t he S p o ns or o f t his st u d y. 
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E u dr a C T N o: 2 0 2 1 - 00 5 7 5 6 - 11  
P a g e  2  of 1 3 7  
1.
SI G N A T U R E P A G E
1. 1.  
Cli nic al Rese ar c h U nit  
, P har m D, M S c, P h D 
He a d of P har mac o metrics  
 
 
....................................................... 
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  
1. 2.  
S p o ns or’s Re pr ese nt ati ve  
, M D 
Cli nic al R & D Dire ct or  
Italfar ma c o S. p. A. 
....................................................... 
Si g nat ure  
....................... 
Date  
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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 - 00 5 7 5 6 - 11  
P a g e  3  of 1 3 7  
2.
C O N T E N T S A N D A B B R E VI A TI O N S
2. 1.  
T a ble of C o nte nts  
1.
SI G N A T U R E P A G E  ...................................................................................................... 2  
1. 1.  C LI NI C A L R E S E A R C H U NI T  ..................................................................................... 2  
1. 2.  S P O N S O R ’S R E P R E S E N T A TI V E  ................................................................................ 2  
2.
C O N T E N T S A N D A B B R E VI A TI O N S  ........................................................................ 3  
2. 1.  T A B L E O F C O N T E N T S  .............................................................................................. 3  
2. 2.  L I S T O F A B B R E VI A TI O N S  ........................................................................................ 5  
3.
I N T R O D U C TI O N .......................................................................................................... 8  
4.
S T U D Y O B J E C TI V E S  .................................................................................................. 8  
4. 1.  P RI M A R Y  ................................................................................................................. 8  
4. 2.  S E C O N D A R Y  ............................................................................................................ 8  
5.
I N V E S TI G A TI O N A L P L A N ........................................................................................ 8  
5. 1.  S T U D Y D E SI G N  ....................................................................................................... 8  
R ati o n al f or St u dy Desi g n  ............................................................................ 8  
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  ................................. 9  
5. 2.  S T U D Y P L A N  ........................................................................................................... 9  
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 netics of I ntr av e n o us a n d Or al  Mi d az ol a m  ........................................... 9  
5. 3.  N U M B E R O F P A R TI CI P A N T S A N D S A M P L E S I Z E E S TI M A TI O N  ............................... 1 0  
P art 1  ......................................................................................................... 1 0  
5. 4.  R A N D O MI Z A TI O N  .................................................................................................. 1 0  
5. 5.  B LI N DI N G  .............................................................................................................. 1 1  
5. 6.  S T A TI S TI C A L H Y P O T H E SI S .................................................................................... 1 1  
P art 1  ......................................................................................................... 1 1  
6.
S T U D Y A S S E S S M E N T S  ............................................................................................. 1 2  
6. 1.  S A F E T Y A S S E S S M E N T S  ......................................................................................... 1 2  
Me dic al Hist ory  ......................................................................................... 1 2  
P hysic al Ex a mi n ati o n  ................................................................................ 1 2  
Wei g ht, Hei g ht a n d B o dy M ass I n dex ........................................................ 1 2  
Vit al Si g ns  .................................................................................................. 1 3  
1 2 L e a d Electr oc ar di o gr a m  ....................................................................... 1 3  
L a b or at ory S afety T ests  ............................................................................. 1 3  
A dv erse Ev e nts  ........................................................................................... 1 5  
Pre vi o us a n d C o nc o mit a nt Me dic ati o ns  .................................................... 1 6  
6. 2.  P H A R M A C O KI N E TI C A S S E S S M E N T S  ...................................................................... 1 6  
Bl o o d S a m pli n g f or P h ar m ac oki netic Assess me nts  ................................... 1 6  
Pl as m a P h ar m ac oki netic P ar a meters  ....................................................... 1 7  
7.
S T U D Y E N D P OI N T S  .................................................................................................. 1 8  
7. 1.  P RI M A R Y  ............................................................................................................... 1 8  
7. 2.  S E C O N D A R Y  .......................................................................................................... 1 8  
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E u dr a C T N o: 2 0 2 1 - 00 5 7 5 6 - 11  
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8.
A N A L Y SI S P O P U L A TI O N S  ...................................................................................... 1 9  
8. 1.  P A R T 1  .................................................................................................................. 1 9  
P art 1 S afety A n alysis P o p ul ati o n  ............................................................. 1 9  
P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n ............................................ 1 9  
P art 1 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 ns  ............................................................................................................. 1 9  
9.
D A T A R E VI E W / T R A N S F O R M A TI O N  ................................................................. 2 0  
9. 1.  D A T A M A N A G E M E N T  ........................................................................................... 2 1  
9. 2.  A C C E P T A N C E O F D A T A ......................................................................................... 2 1  
9. 3.  D A T A T R A N S F O R M A TI O N ( C DI S C) ...................................................................... 2 1  
1 0.
S T A TI S TI C A L M E T H O D S  ........................................................................................ 2 3  
1 0. 1.  G E N E R A L C O N SI D E R A TI O N S ............................................................................... 2 3  
1 0. 2.  S U BJ E C T S ’ D I S P O SI TI O N ..................................................................................... 2 3  
1 0. 3.  P R O T O C O L D E VI A TI O N S  ..................................................................................... 2 4  
1 0. 4.  P L A S M A P H A R M A C O KI N E TI C C O N C E N T R A TI O N S ............................................... 2 4  
1 0. 5.  P L A S M A P H A R M A C O KI N E TI C P A R A M E T E R S  ....................................................... 2 4  
1 0. 6.  D R U G -D R U G IN T E R A C TI O N C O M P A R A TI V E B I O A V AI L A BI LI T Y S T A TI S TI C A L 
A N A L Y SI S  ........................................................................................................................ 2 5  
P art 1  ....................................................................................................... 2 5  
1 0. 7.  S A F E T Y D A T A A N A L Y SI S  ................................................................................... 2 6  
1 1.
P R E S E N T A TI O N O F R E S U L T S  ............................................................................... 2 6  
1 1. 1.  S T A TI S TI C A L O U T P U T S P E CI FI C A TI O N  ............................................................... 2 6  
1 1. 2.  P L A N N E D T A B L E S , F I G U R E S, A N D S U BJ E C T D A T A L I S TI N G S ............................. 2 7  
I n-te xt T a bles a n d Fi g ures ....................................................................... 2 7  
T a bles, Fi g ures a n d Gr a p hs Referre d t o B ut N ot I ncl u de d i n t he T e xt ( Secti o n 
1 4 of C S R)  ............................................................................................................... 3 4  
List of S u bje ct D at a Listi n gs ( Se cti o n 1 6. 2 of C S R)  ................................ 4 3  
1 2.
R E F E R E N C E S  ............................................................................................................. 4 7  
1 3.
A P P E N DI C E S  ............................................................................................................... 4 8  
A P P E N DI X  A.  P L A N N E D T A B L E S , F I G U R E S, A N D S U BJ E C T D A T A L I S TI N G S ............... 4 8  
A. 1.  I n-te xt T a bles a n d Fi g ures –  F or C S R Sy n o psis  ............................................. 4 8  
A. 2.  I n-te xt T a bles a n d Fi g ures –  F or C S R B o dy T ext  ........................................... 6 1  
A. 3.  T a bles, Fi g ures a n d Gr a p hs Referre d t o B ut N ot I ncl u de d i n t he T e xt ( Secti o n 1 4 
of C S R)  .................................................................................................................... 8 1  
A. 4.  List of S u bje ct D at a Listi n gs ( Se cti o n 1 6. 2 of C S R)  ...................................... 1 0 2  
1 4.
A N N E X E S  ................................................................................................................... 1 3 7  
P P D


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St ati sti c al A n al y si s Pl a n  
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 - 00 5 7 5 6 - 11  
P a g e  5  of 1 3 7  
2. 2.  
List of A b br e vi ati o ns  
α  
T y pe I Err or ( Si g nifica nce Le vel)  
A b  
A nti b o d y  
A Da M  
A nal ysis Data M o del  
A Da MI G  
A nal ysis Data M o del I m ple me ntati o n G ui de 
A D P C  
A nal ysis Data P har ma c o ki netic C o nce ntrati o ns  
A D P P  
A nal ysis Data P har ma c o ki netic Para meters  
A D S L  
S u bje ct -Le vel A nal ysis  
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 m ea n  
Arit h metic  Mea n  
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 C he mic al  
A U C  
Area U n der t he C o nc e ntrati o n Vers us  Ti me C ur ve  
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 w it h Q ua ntifia ble C o nc e ntrati o ns 
A U C 0 -∞  
A U C fr o m Ti me Zer o t o I nfi nit y  
A U C 0 -τ,ss 
A U C C orres p o n di n g t o t he D osi n g I nter val, at Ste a d y State  
A U R C 0 -t 
Area U n der t he Uri nar y E xcreti o n Rate C ur ve fr o m Ti me 0 t o t he Last Rate  
% 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 -∞
B D S  
Basic Data Str uct ure  
B L Q  
Bel o w  t he Li mit of Q ua ntific ati o n  
B MI  
B o d y Mass I n de x  
b p m  
Be ats Per Mi n ute  
C 0 
Pre -d ose C o nce ntrati o n  
CI  
C o nfi de nc e I nter val  
Cl  
T otal B o d y Cle ara nce  
C K  
Cre ati ne Ki nase  
Cl/ F  
T otal B o d y Cle ara nce Affecte d b y t he Bi oa vaila bilit y Fa ct or  
Cl R  
Re nal Cle ara nc e  
Cl R / F 
Re nal Cle ara nc e Affe cte d b y t he Bi oa vaila bilit y Fa ct or  
C l ast 
Last Q ua ntifia ble C o nce ntrati o n  
C m a x  
Ma xi m u m O bser ve d C o nce ntrati o n  
C m a x,ss  
Ma xi m u m O bser ve d Plas ma C o nc e ntrati o n at Ste a d y State  
Cr C L  
Cre ati ni ne Cle ara nce  
C S P  
Cli nic al St u d y Pr ot oc ol  
C S R  
Cli nic al St u d y Re p ort  
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  
D r u g-D r u g Intera cti o n  
D M 
De m o gra p hics  
E C G  
Electr ocar di o gra m  
F  
Bi oa vaila bilit y Fa ct or  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G G T  
Ga m ma -Gl uta m yltra nsferase  
G L P  
G o o d La b orat or y Practic es  
P P D


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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 - 00 5 7 5 6 - 11  
P a g e  6  of 1 3 7  
G m ea n  
Ge o metric  Mea n  
G M R  
Ge o metric Le ast S q uare Mea ns Rati o  
G C V %  
Ge o metric C oefficie nt of Variati o n  
G S D  
Ge o metr ic Sta n dar d De viati o n 
H 0 
N ull H y p ot hesis  
H 1 
Alter nati ve H y p ot hesis  
H Bs A g  
He patitis B S urfac e A nti ge n  
h C G  
H u ma n C h ori o nic G o na d otr o pi n  
H C V A b  
He patitis C Vir us A nti b o dies  
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 nfere nc e o n Har m o nizati o n  
I N R 
I nter nati o nal N or malize d Rati o 
I S C V % 
I ntra-S u bject C oefficie nt of Variati o n  
I V 
I ntra ve n o us 
L C -M S/ M S 
Li q ui d C hr o mat o gra p h y wit h Ta n de m Mass S pectr o metr y  
L D H  
La ctate De h y dr o ge nase  
L L O Q  
L o wer Li mit of Q ua ntific ati o n  
L S me a ns  
Le ast S q uare Mea ns  
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 S E  
Mea n S q uare Err or  
M W  
M ole c ular W ei g ht  
N C A  
N o n -C o m part me ntal A nal ysis  
P C  
P har ma c o ki netic C o nce ntrati o ns  
P C L  
Pr ot oc ol Clarific ati o n Letter  
P -g p
P -Gl yc o pr otei n
P P
P har ma c o ki netic Para meters
P T
Me d D R A  Preferre d Ter m
Q Tc F
C orre cte d Q T Inter val b y Fri dericia
R B C
Re d Bl o o d Cell
R D W -C V
C oefficie nt Variati o n of t he Re d Cell Dist ri b uti o n Wi dt h
R S Q
G o o d ness of Fit f or t he Ter mi nal Eli mi nati o n P hase
rtf
Ric h Te xt File
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 eri o us A d verse Re a cti o 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 A S  
Statistic al A nal ysis S oft ware  
S B P  
S yst olic Bl o o d Press ure  
S D  
Sta n dar d De viati o n  
S D T M   
St u d y Data Ta b ulati o n M o del  
S D T MI G  
St u d y Data Ta b ulati o n M o del I m ple me ntati o n G ui de 
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  
T E A E   
Tr e at me nt -E mer ge nt A d verse E ve nts  
T F Ls   
Ta bles, Fi g ures a n d Listi n gs  
T m a x  
Ti me t o Ma xi m u m O bser ve d C o nce ntrati o n  
T m a x ,ss  
Ti me t o Ma xi m u m O bser ve d C o nce ntrati o n at Ste a d y State  
P P D


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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 - 00 5 7 5 6 - 11  
P a g e  7  of 1 3 7  
T O S T  
T w o O ne -Si de d T -Tests  
T S H 
T h yr oi d -Sti m ulati n g H or m o ne  
t0 
Ti me of D os in g  (t = 0 h) 
t½  
A p pare nt Ter mi nal Eli mi nati o n Half -Life  
U L O Q  
U p per Li mit of Q ua ntificati o n  
V D  
A p pare nt V ol u me of Distri b uti o n  
V D / F 
A p pare nt V ol u me of Distri b uti o n Affe cte d b y t he Bi oa vaila bilit y Fa ct or ( F)  
W B C  
W hite Bl o o d Cell  
W H O  
W orl d Healt h Or ga nizati o n  
λ z 
A p pare nt Ter mi nal Eli mi nati o n Rate C o nsta nt  
τ 
D osi n g I nter val  
P P D


I T F/ 2 3 5 7/ 55  
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St ati sti c al A n al y si s Pl a n  
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  
 
P a g e  8  of 1 3 7  
3.
I N T R O D U C TI O N
T his Statistic al A nal ysis Pla n ( S A P) details t he statistic al met h o d ol o g y t o be use d i n  a nal y sin g  st u d y
data a n d o utli nes t he statistic al pr o gra m mi n g s pecific ati o ns f or t he T a bles, F i g ures a n d L isti n gs
( T F Ls). T his d oc u me nt descri bes t he varia bles a n d p o p ulati o ns , a ntici pate d data tra nsf or mati o n a n d
ma ni p ulati o ns a n d ot her details of t he a nal ysis n ot pr o vi de d i n t he Cli nic al St u d y Pr ot oc ol ( C S P).
T he  d escri be d a nal yses are base d o n t he fi nal C S P versi o n 1. 0, date d 2 9 N O V 2 0 2 1  [ 1] a n d a Pr ot oc ol
Clarific ati o n Letter ( P C L) date d 2 5 F E B 2 0 2 2 . T his S A P was  fi nalize d pri or t o data base l oc k a n d
c o n d uct of t he statistic al a nal yses. F or ea c h part of t he st u d y a t t he ti me of t he Bli n d Re vie w
Pr oc ess, a Data Bli n d Re vie w Pr ocess Mi n ute will be pre pare d a n d attac he d t o t his d oc u me nt
(A n ne x 1 ).
A d diti o nal p har ma c o ki netic a n d statistic al a nal ysis ma y be perf or me d t o s u p ple me nt t he pla n ne d
a nal yses descri be d i n t his S A P . These s u p ple me ntal a nal yses will be i de ntifie d  a n d prese nte d i n t he
Cli nic al St u d y Re p ort ( C S R) .
4.
S T U D Y O B J E C TI V E S
4. 1.  
Pri m ar y  
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 mac o ki netics of i ntra ve n o us (I V) a n d oral mi da z ola m ( Part 1).
2.
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 os tat 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).
4. 2.  
S e c o n d ar y  
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).
5.
I N V E S TI G A TI O N A L P L A N
5. 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 
f e male s u bjects. 
St u d y parts ma y be c o n d ucte d c o nc o mita ntl y.  
R ati o n al f or  St u d y Desi g n  
T he rati o nal f or st u d y desi g n detaile d  i n t he C S P [ 1]. 
I n Part 1, t he per petrat or dr u g -dr u g i ntera cti o n ( D DI)  p ote ntial of gi vi n ostat as i n hi bit or a n d i n d uc er 
of c yt oc hr o me P 4 5 0 ( C Y P) 3 A a n d P -gl yc o pr otei n ( P -g p) a cti vit y will be e val uate d . 
P P D


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St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  9  of 1 3 7  
 
 
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  
 
5. 1. 2. 1.  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  
 
A d ose of 5 0 m g gi vi n ostat will be a d mi nistere d t wice-dail y  t o s u bje cts i n or der t o ma xi mize t he 
p ossi bilit y t o i de ntif y a D DI wit h mi da z ola m a n d da bi gatra n ete xilate . 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 uci n g effe ct will assesse d o n Da ys 1 7 t o 2 0 [ 1]. 
 
Rati o nale f or S u bstrates D ose  
 
T o a cc ess a D DI at C Y P 3 A 4 le vel , a t hera pe utic si n gle-d ose of 1 m g mi da z ola m I V, a n d 2. 5 m g  
si n gle-d ose of oral mi da z ola m will be a d mi nistere d , i n t he prese nt st u d y. 
T o a cc ess a D DI at P -g p le vel, a  t hera pe utic si n gle-d ose of 7 5 m g da bi gatra n will be a d mi nister e d  
[ 1]. 
 
Rati o nale f or Per petrat or a n d S u bstrates A d mi nistrati o n Sc he d ule  
 
I n or der t o p ote ntiate t he 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 a n d 
da bi gatra n a d mi nistrati o n  will oc c ur 1 h o ur after t he gi vi n ostat m or ni n g d ose o n Da ys 6, 7, 1 7 a n d 
1 8 [ 1]. 
 
 
5. 2.  
St u d y Pl a n  
 
 
P art 1 –  I n hi bit or y a n d I n d uci n g Effe ct of Or al Gi vi n ost at o n t h e Si n gle D ose 
P h ar m ac o ki n etics of I ntr a ve n o us a n d Or al Mi d az ol a m  
 
S u bje cts will be c o nfi ne d i n Bl ue Cli nic al P hase I 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 y s 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 nister e 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 bje cts will re mai n faste d u ntil at least 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 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 gatr a 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.  
Mi 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 os e . 
 
T he f oll o wi n g assess me nts will be perf or me d:  
- 
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 ( bl o o d press ure [ B P ], p ulse rate [ P R ] a n d res pirat or y rate [R R ]) 
o n Da ys 1, 2, a n d 4 t o 1 9.  
P P D


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V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 0  of 1 3 7  
- 
1 2 -le a d ele ctr oc ar di o gra m ( E C G ) o n Da ys 3 t o 1 9.  
- 
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 Bl ue Cli nic al P hase I i n 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 dic al 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 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 o c 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 cts will ret ur n t o Bl ue Cli nic al P hase I 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 cree ni n g t o 
F oll o w -u p visit, di vi de d as 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  
 
5. 3.  
N u m b er of P artici p a nts  a n d S a m ple S ize Esti m a ti o n 
 
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 fift y-f o ur (5 4 ) 
he alt h y male a n d fe male s u bje cts are pla n ne d t o be e nr olle d as f oll o ws:  
- 
Part 1: t we nt y-si x (2 6 ) s u bje cts 
- 
Part 2: t we nt y (2 0 ) s u bje cts 
- 
Part 3: ei g ht ( 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 art 1  
 
Mi da z ola m : Ass u mi n g a n I ntra-S 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 -∞, 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 nce 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 bjects 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 bjects will be e nrolle 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 -∞, a 
tr ue ge o metric me a 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 
r ati o of Cm a 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 ults i n at le ast 8 0 % p o wer. Ac c o u nti n g f or earl 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.  
 
5. 4.  
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.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 1  of 1 3 7  
 
5. 5.  
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.  
 
5. 6.  
St atistic al  H y p ot hesis  
 
 
P art 1  
 
Part 1 of t he  st u d y is desi g ne d t o: 
1.  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 mac o ki netics of I V a n d oral mi da z ola m.  
2.  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 mac o ki netics of oral da bi gatr a n ete xilate. 
 
As i n a c c or da nc e wit h F D A G ui da nc e o n D DI st u dies [ 2], assess me nt of D DI will be  base d u p o n t he 
9 0 % c o nfi de nc e i nter val ( CI ) f or t he Ge o metric Le ast S q uare Me a ns ( L Sm ea ns) Ratio ( G M R) f or 
t he pri mar y p har ma c o ki netic para meters.  
 
T his met h o d is e q ui vale nt t o t w o o ne -si de d t-tests ( T O S T) wit h t he n ull h y p ot hesis ( H0) of n o n -
c o m para ble bi oa vaila bilit y at t he 5 % si g nific a nce le vel ( α = 0. 0 5).  
 
F or mi da z ola m, a ss u mi n g a ma xi m u m 2 0 % differe nc e bet we e n mi da z ola m c o-a d mi nistere d wit h 
gi vi n ostat a n d a d mi nistere d al o ne , t he i nter val h y p ot heses f or c o m para ble bi oa vaila bilit y  c a n be 
f or m ulate d as: 
 
 
 
H 0:   𝜇T
𝜇R
⁄
< 0 .8 0    or   𝜇T
𝜇R
⁄
> 1 .2 5  
v ers us   H 1:   
0 .8 0 ≤𝜇T
𝜇R
⁄
≤1 .2 5  
 
w here μ T  a n d μ R  are t he Ge o metric L S m e a ns f or mi da z ola m c o-a d mi nistere d wit h gi vi n ostat a n d 
a d mi nistere d al o ne , res pe cti vel y.  
 
He nce, t he h y p ot hesis is t o s h o w c o m para ble bi oa vaila bilit y  b y reje cti n g t he H 0 of n o n -c o m par a ble 
bi oa vaila bilit y , i.e., t he de cisi o n of c o m para ble bi oa vaila bilit y  is ma de base d o n w het her t he 9 0 % CI 
of t he mi da z ola m c o -a d mi nistere d wit h gi vi n ostat -t o-mi da z ola m a d mi nistere d al o ne  G M R is wit hi n 
8 0. 0 0  –  1 2 5. 0 0 %  [2 ]. 
 
F or da bi gatra n, ass u mi n g a ma xi m u m 2 5. 3 8 % differe nc e bet we e n mi da z ola m c o-a d mi nister e d wit h 
gi vi n ostat a n d a d mi nistere d al o ne, t he i nter val h y p ot heses f or c o m para ble bi oa vail a bilit y c a n be 
f or m ulate d as: 
 
H 0:   𝜇T
𝜇R
⁄
< 0 .7 4 6 2    or   𝜇T
𝜇R
⁄
> 1 .3 4 0 2  
v ers us   H 1:   
0 .7 4 6 2 ≤𝜇T
𝜇R
⁄
≤1 .3 4 0 2  
 
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I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 2  of 1 3 7  
w here μ T  a n d μ R  are t he Ge o metric L S m e a ns f or da bi gatra n c o-a d mi nistere d wit h gi vi n ostat a n d 
a d mi nistere d al o ne, res pe cti vel y.  
 
He nce, t he h y p ot hesis is t o s h o w c o m para ble bi oa vaila bilit y  b y reje cti n g t he H 0 of n o n -c o m par a ble 
bi oa vaila bilit y , i.e., t he de cisi o n of c o m para ble bi oa vaila bilit y  is ma de base d o n w het her t he 9 0 % CI 
of t he da bi gatra n c o -a d mi nistere d wit h gi vi n ostat -t o-da bi gatra n a d mi nistere d al o ne  G M R is wit hi n 
7 4. 6 2 –  1 3 4. 0 2 %  [2 ]. 
 
6.  
S T U D Y A S S E S S M E N T S  
 
F or e a c h st u d y part, a  s u m mar y of pr oce d ures f or st u d y assess me nts are prese nte d i n S ecti o n 2 of 
t he C S P ( St u d y Fl o w-C hart a n d St u d y Desi g n Dia gra m)  [1 ]. 
 
6. 1.  
S af et 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.  
 
S afet y a ssess 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 d verse e ve nt ( 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 n s relate d t o s u bject safet y. 
 
Me dic ati o ns will be me nti o ne d ac c or di n g t o t he W orl d He alt h Or ga nizati o n ( W H O) A nat o mic al 
T hera pe utic C he mical ( A T C) classific ati o n s yste m.  
 
 
M e dic al Hist or y  
 
Me dic 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 healt 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 gical, ps yc hiatric, dr u g a n d s ur gic al hist or y, or a n y ot her diseases or 
dis or ders.  
 
Me dic 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), versi o n 2 4. 1  or hi g her.  
 
A d verse e ve nts relate d t o me dic al hist or y will be i de ntifie d.  
 
 
P h ysic al E x a mi n ati o n  
 
P h ysic al e xa mi nati o n at scre 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 
ne c 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; car dia c 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.  
 
 
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 o d y mass i n de x ( B MI ) will be re c or de d i n t he 
ele ctr o nic c ase re p ort f or m ( 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 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 3  of 1 3 7  
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. 
 
Vit al Si g ns  
 
Vital si g ns will i ncl u de:  
- 
S yst olic bl o o d press ure ( S B P).  
- 
Diast olic bl o o d press ure ( D B P) . 
- 
P ulse rate  ( P R). 
- 
Res pirat or y rate ( R R ). 
- 
B o d y te m perat ure.  
 
 
1 2 Le a d Ele ctr oc ar di o gr a m  
 
A 1 2 -le a d E C G will be perf or me d  prefera bl y bef ore t he bl o o d c olle cti o n . T he c orre cte d Q T i nter val 
b y Fri dericia (Q Tc F ) will be a nal yze d.  
 
 
L a b or at or y S afet y Tests  
 
T he f oll o wi n g la b orat or y para meters will be teste d:  
- 
He mat ol o g y:  
- 
Re d bl o o d c ell ( R B C) c o u nt.  
- 
W hite bl o o d c ell ( W B C) c o u nt.  
- 
W B C differe ntial c o u nt:  
- 
Ne utr o p hils.  
- 
E osi n o p hils.  
- 
Bas o p hils.  
- 
L y m p h oc ytes.  
- 
M o n oc ytes.  
- 
He m o gl o bi n.  
- 
Mea n c or p usc ular v ol u me ( M C V).  
- 
Mea n c or p usc ular he m o gl o bi n ( M C H).  
- 
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n ( M C H C).  
- 
C oefficie nt variati o n of t he re d c ell distri b uti o n wi dt h ( R D W -C V).  
- 
He mat ocrit . 
- 
Platelet c o u nt.  
- 
Mea n platelet v ol u me.  
- 
C oa g ulati o n:  
- 
Pr ot hr o m bi n rate.  
- 
Pr ot hr o m bi n ti me.  
- 
Pr ot hr o m bi n ti me –  i nter nati o nal n or malize d rati o (I N R). 
- 
Acti vate d partial t hr o m b o plasti n ti me (a P T T).  
- 
Ge ne ral bi oc he mistr y:  
- 
T otal bilir u bi n.  
- 
Dire ct bilir u bi n.  
- 
I n dire ct bilir u bi n. 
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I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 4  of 1 3 7  
- 
Al kali ne p h os p hatase ( A L P).  
- 
A m ylase.  
- 
As partate a mi n otra nsferase ( A S T).  
- 
Ala ni ne a mi n otra nsferase ( A L T).  
- 
La ctate de h y dr o ge nase ( L D H).  
- 
C ystati n  C . 
- 
C -re acti ve pr otei n. 
- 
Ga m ma -gl uta m yltra nsferase ( G G T).  
- 
Cre ati ni 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.  
- 
Calci u m.  
- 
Ma g nesi u m.  
- 
Gl uc ose.  
- 
Cre ati ni ne.  
- 
Urea.  
- 
T h yr oi d -sti m ulati n g h or m o ne (T S H ). 
- 
Esti mate d creati ni ne cleara nce  ( CrC L ). 
- 
Viral Ser ol o g y:  
- 
H u ma n I m m u n o deficie nc y Vir us ( HI V):  
- 
HI V -1 (a nti -HI V -1 A b).  
- 
HI V -2 (a nti -HI V -2 A b).  
- 
He patitis B ( H Bs A g)  
- 
He patitis C (a nti-H C V A b).  
- 
Beta -h u ma n c h ori o nic g o na d otr o pi n ( beta -h C G) pre g na nc y tests:  
- 
S er u m.  
- 
Uri ne.  
- 
Uri nal ysis:  
- 
p H.  
- 
S pe cific 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.  
- 
Micr osc o p y.  
- 
Dr u gs -of -a b use uri ne test: 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 5  of 1 3 7  
- 
Ca n na bi n oi ds.  
- 
O piates.  
- 
C oc ai ne.  
- 
A m p heta mi nes.  
- 
Be nz o dia ze pi nes.  
- 
Et ha n ol uri ne test.  
- 
C oti ni ne uri ne test.  
- 
F ollicle -sti m ulati n g h or m o ne ( F S H) test. 
- 
S e vere Ac ute Res pirat or y S y n dr o me C or o na vir us 2 ( S A R S -C o V -2) dia g n ostic tests.  
 
 
A d verse E ve nts  
 
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  a n d p h ysic al e xa mi nati o n 
will be re p orte d as A Es.  
 
Tr e at me nt -e mer ge nt A Es ( 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 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 ve sti 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 tre at me nt a d mi nistere d i n t hat peri o d. 
 
T he f oll o wi n g i nf or mati o n will be use d f or t he descri pti o n of t he A Es:  
- 
Re p orte d Ter m.  
- 
Me dic al Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) S yste m Or ga n Class ( S O C) 
c o di n g. 
- 
Me d D R A Preferre d Ter m ( P T) c o di n g.  
- 
Start date a n d ti me.  
- 
E n d date a n d ti me.  
- 
S eri o us ness.  
- 
S e verit y:  
- 
Mil d.  
- 
M o derate.  
- 
S e vere.  
- 
Relati o ns hi p (c a usalit y)  f or ea c h tre at me nt a d mi nistrate d , per part. 
- 
Re as o na bl y P ossi ble.  
- 
N ot Re as o na bl y P ossi ble.  
- 
U n k n o w n.  
- 
Acti o n ta ke n:  
- 
D ose I ncrease d.  
- 
D ose N ot C ha n ge d.   
- 
D ose Rate Re d uc e d.  
- 
D ose Re d uce d.  
- 
Dr u g I nterr u pte d.  
- 
Dr u g Wit h dra w n.  
- 
N ot A p plic a ble.  
- 
U n k n o w n.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
P a g e  1 6  of 1 3 7  
-
C o nc o mita nt me dic ati o n.
-
O utc o me:
-
Fatal.
-
N ot Re c o vere d / N ot Res ol ve d.
-
Re c o vere d / Res ol ve d.
-
Re c o vere d / Res ol ve d wit h Se q uelae.
-
Re c o veri n g / Res ol vi n g.
-
U n k n o w n.
-
M ost re c e nt st u d y treat me nt ta ke n.
-
Last d osi n g date.
6. 2.  
Pr e vi o us a n d C o nc o mit a nt M e dic ati o ns 
A pr e 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 to first d osi n g. 
A c o nc o mita nt m e dicati o n is a n y me dic ati o n o n g oi n g or initiate d after first d osi n g.  
F or all stu d y parts, t he use of a n y me dic ati 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 m e dici nes s uc h as St J o h n’s W ort, h o me o pat hic pr e parati o ns, vita mi ns, a n d 
mi nerals) is f or bi d den fr o m 2 8 da ys or w it hi n 5 half-li ves of the m e dici nal pr o d uct, w hic he ver is 
l o n ger, pri or to a d missi o n u p t o last sam ple for p h ar mac o ki netics assess me nt, e xc e pt for m e dic ati o ns 
f or the tre at me nt of 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 to a d missi o n u ntil the e n d of stu 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 pe ri o d of m e dic ati o n restricti o n m ust be 
r e c or de d i n t he e C R F. If c o nc o mita nt m e dic ati o n is o n g oi n g at the foll 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. 
F or e a c h  st u d y part, pre vi o us a n d c o nc o mita nt me dicati o ns use d b y st u d y partici pa nts d uri n g t he 
st u d y a n d t heir j u d ge d i m pact o n t he p har mac o ki netic assess me nt will be liste d i n t he res pecti ve 
Data Bli n d Re vie w Meeti n g/ Pr ocess Mi n ute ( A n ne x 1 ).  
C o nc o mita nt m e dic ati o ns will be c o de d a c c or di n g t o t he W H O A T C c lassific ati o n s yste m. 
P h ar m ac o ki n etic A ssess me nts 
Bl o o d S a m pli n g f or P h ar m ac o ki netic A ssess me nts 
I n e a c h st u d y part, w hile s u bject is c o nfi ned at the c li nical researc h u nit, bl o o d sa m ples will be ta ke n 
pr efera bl y via a n i n d welli n g ca n n ula pl ac e d i n a v ein of an u p per li m b of the s u bje ct. Duri n g 
a m b ulat or y visits, bl o o d sa m ples will be ta ke n b y direct ve ni p u nct ure. 
T he act ual ti me of a ll p ha r ma c o ki netic bl o o d dra ws will b e rec or de d a n d re p orte d f or all s u bje cts. 
T he pr e- d ose bl o o d sa m ple w ill be c olle cte d wit hi n 3 0 mi n utes bef ore d osi n g. 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 the sche d ule d sa m pli n g ti me. Gre ater d e viati o ns 
will be re p orte d as a p r ot oc ol de viati o n a n d its ca use w ill be rec or de d. 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 7  of 1 3 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 dr a 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.  
 
 will c arr y o ut t he deter mi nati o n of plas ma le vels of gi vi n ostat a n d its 
meta b olites  (I T F 2 3 7 4, I T F 2 3 7 5, I T F 2 4 4 0 a n d I T F 2 5 6 3), mi da z ola m, 1-h y dr o x y mi da z ola m a n d t otal 
a n d fre e da bi gatra n 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 ctices 
( G L P), usi n g a pre vi o usl y vali date d li q ui d c hr o mat o gra p h y wit h ta n dem mass s pectr o metr y ( L C -
M S/ M S) a nal ytic al met h o d.  
 
T he pla n ne d l o wer li mit of q ua ntific ati o n ( L L O Q) a n d u p per li mit of q ua ntific ati o n ( U L O Q) f or:  
- 
gi vi n ostat are 1  a n d 1 0 0 n g/ m L . 
- 
gi vi n ostat meta b olite I T F 2 3 7 4 are 1  a n d 1 0 0 n g / m L. 
- 
gi vi n ostat meta b olite I T F 2 3 7 5 are 1  a n d 1 0 0 n g/ m L . 
- 
gi vi n ostat meta b olite I T F 2 4 4 0 are 1 0  a n d 5 0 0  n g/ m L . 
- 
gi vi n ostat meta b olite I T F 2 5 6 3  are 2  a n d 1 2 5  n g/ m L . 
- 
mi da z ola m are 1 0 0  a n d 1 0 0 0 0 0 p g/ m L . 
- 
1 -h y dr o x y mi da z ola m are 1 0 0  a n d 5 0 0 0 0 p g/ m L . 
- 
t otal da bi gatra n are 1  a n d 4 0 0 n g/ m L . 
- 
free da bi gatra n are 1  a n d 4 0 0 n g/ m L . 
L L O Q re prese nts a val ue l o wer t ha n or e q ual t o 1/ 2 0 of esti mate d C ma x  val ue. A n y a dj ust me nt t o t his 
r a n ge will be d oc u me nte d i n t he st u d y s pecific Bi oa nal ytic al Re p ort, w hic h will su perse de t he 
i n dic ate d ra n ge. 
 
6. 2. 1. 1.  P art 1  
 
A t otal of o ne h u n dre d a n d  se ve ntee n (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 mi da z ola m  I V, 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.  
- 
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 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 mi da z ola m  I V 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 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 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 nistr ati 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.  
 
 
 
Pl as m a P h ar m ac o ki n etic P ar a meters  
 
T he f oll o wi n g p har ma c o ki netic para meters will be deri ve d b y sta n dar d n o n -c o m part me ntal a nal ys is 
( N C A) met h o ds fr o m t he si n gle-d ose plas ma c o nce ntrati o n v ers us ti me pr ofiles, f or: 
- 
Part 1 : 
- 
mi da z ola m . 
- 
1 -h y dr o x y mi da z ola m . 
- 
t otal da bi gatra n. 
P P D
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  1 8  of 1 3 7  
- 
free da bi gatra n. 
 
 
P ar a meter  
Descri pti o n  
C m a x  
Ma xi m u m o bser ve d c o nc e ntrati o n, dire ctl y o btai ne d fr o m t he o bser ve d 
c o nc e ntrati o n v ers us ti me pr ofile. 
T m a x  
Ti me of oc c urre nce of ma xi m u m o bser ve d c o nc e ntrati o n.  
A U C 0 -t 1 
Area u n der t he c o nc e ntrati o n v ers us ti me c ur ve ( A U C) fr o m ti me of d osi n g 
(t = 0 h) t o t he ti me of t he last meas ura ble c o nc e ntrati o n (tlast), calc ulate d b y 
t he li ne ar-u p/l o g -d o w n tra pe z oi dal met h o d.  
A U C 0 -∞ 
T otal A U C e xtra p olate d t o i nfi nit y, c alc ulate d as A U C 0 −t +
C l a st
λ z , w here Clast 
is t he last me as ura ble c o nce ntrati o n a n d λz is t he a p pare nt ter mi nal 
eli mi nati o n rate c o nsta nt. 
% A U C
e xtra p 
Perc e nta ge of A U C 0 -∞ d ue t o e xtra p olati o n fr o m t he ti me of t he last 
me as ura ble c o nc e ntrati o n (t last) t o i nfi nit y, i.e., resi d ual are a, calc ulate d as 
1 0 0 ∙
A U C 0 −∞−A U C 0 −t
A U C 0 −∞
. 
λ z 
A p pare nt first or der eli mi nati o n rate c o nsta nt ass ociate d wit h t he ter mi nal 
(l o g-li ne ar) p orti o n of t he c o nce ntrati o n vers us ti me c ur ve. T he para meter is 
esti mate d b y li ne ar least s q uare re gressi o n a nal ysis usi n g t he last t hre e ( or 
m ore) n o n -zer o c o nc e ntrati o ns.  
t½  
A p pare nt ter mi nal eli mi nati o n half -life, calc ulate d as 
𝜇𝜇(2 )
λ z . 
1 I n P art 1 , f or mi d az ol a m a n d its met a b olite t he l ast s a m pli n g ti me c orres p o n ds t o 2 4 h o urs, a n d f or t ot al a n d free 
d a bi g atr a n t he l ast s a m pli n g ti me c orres p o n ds t o 7 2 h o urs . 
 
T he u p per a n d t he l o wer ti me p oi nts a n d t he n u m ber of ti me p oi nts use d f or λ z esti mati o n, as well as 
t he g o o d ness of fit f or t he ter mi nal eli mi nati o n p hase ( R S Q), will be re p orte d.  
N o val ues of λ z, A U C0 -∞, % A U Ce xtra p a n d t ½  will be re p orte d f or c ases w here λ z c a n n ot be relia bl y 
deter mi ne d.  
 
7.  
S T U D Y E N D P OI N T S  
 
7. 1.  
Pri m ar y  
 
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 g i vi n ostat ( Part 1). 
 
7. 2.  
S e c o n d ar y  
 
1.  I nci de nc e a n d se verit y of A Es; c ha n ges i n vital si g ns, p h ysic al e xa mi nati o n, 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 daz 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).  
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
P a g e  1 9  of 1 3 7  
8.
A N A L Y SI S P O P U L A TI O N S
8. 1.  
T he a nal ysis p o p ulati o ns are de fi ne d i n ac c or da nce w it h t he C S P  [ 1].
F or eac h st u d y part, t he s u bjects t o be i ncl u de d i n eac h a nal ysis p o p ulati o n will be re p orte d i n t he 
res pecti ve Data Bli n d Re vie w Pr ocess Mi n ute ( A n ne x 1 ).
F or eac h st u d y part, e x pla nati o n of t he reas o ns f or e xcl usi o n of s u bjects fr o m a n y a nal ysis  
p o p ulati o n will be pr o vi de d i n t he res pecti ve Data Bli n d Re vie w Pr ocess Mi n ute ( A n ne x 1 ) a n d i n 
t he C S R.
T he list of s u bjects w h o c o m plete eac h st u d y part will be prese nte d i n A n ne x 2 ,.
P art 1 
P art 1 S afet y A n al ysis P o p ul ati o n 
All s u bjects w h o recei ve at least o ne d ose of a n I M P i n Part 1 of t he st u d y will c o nstit ute t he Part 1 
Safet y A nal ysis P o p ulati o n. 
Part 1 safet y data a nal ysis will be perf or me d f or all s u bjects i n t he Part 1 Safet y A nal ysis P o p ulati o n. 
P art 1 P h ar m ac o ki netic A n al ysis P o p ul ati o n 
Part 1 P har mac o ki netic A nal ysis P o p ulati o n will i ncl u de all s u bjects e nr olle d i n Part 1 of t he st u d y, 
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 least o ne 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. 
T he f oll o wi n g reas o ns j ustif y t he e xcl usi o n of t he p har mac o ki netic data of a s u bject fr o m t he Part 1 
p har mac o ki netic a nal ysis p o p ulati o n: 
-
Pr ot oc ol vi olati o n c o nsi dere d t o ha ve a p ote ntiall y rele va nt effect o n t he p har ma c o ki netic
res ults of t he st u d y.
N O T E: T h e se  pr ot oc ol vi ol ati o ns  will be re p orte d i n t he D at a Bli n d Re vie w Pr ocess Mi n ute  
(A n ne x 1 ), a n d t heir i m p act will be as sesse d at t he ti me of p h ar m ac oki netic a n alysis. 
-
S u bje ct e x perie nc e d v o miti n g or diarr hea.
N O T E: S u bjects t h at e x perie nc e d v o miti n g or di arr h oe a  d uri n g t h is st u dy p art w ill be 
re p orte d i n t he D at a Bli n d Re vie w Pr oc ess  Mi n ut e (A n nex 1 ), a n d t heir ex cl usi o n will be 
assesse d at t he ti me of p h ar m ac oki netic a n alysis.  
-
S u bje ct wit h pre -d ose c o nce ntrati o n > 5 % of t he C ma x  val ue of t he c orres p o n di n g
p har mac o ki netic pr ofile.
N O T E: T his e x cl usi o n will be assesse d at t he ti me of p h ar m ac oki netic a n alysis . 
-
S u bje ct wit h lac k of a n y me as ura ble c o nc e ntrati o ns or o nl y ver y l o w plas ma  c o nce ntrati o ns.
N O T E: T his e x cl usi o n will be ass esse d at t he ti me of p h ar m ac oki netic a n alysis.  
P art 1 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 s 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 0  of 1 3 7  
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 nter a 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.  
 
8. 1. 3. 1.  P art 1 I n hi bit or y Effe ct of Gi vi n ost at o n Mi d az ol a m I V A n al ysis P o p ul ati o n  
 
P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n Mi da z ola m I V A nal ysis P o p ulati o n will i ncl u de all 
s u bje cts fr o m t he Part 1 P har ma c o ki netic A nal ysis P o p ulati o n w h o are e x pe cte d t o pr o vi de 
e val ua ble p har mac o ki netic data f or mi da z ola m I V a d mi nistere d al o ne ( Da y 1) a n d c o -a d mi nister e d 
wit h gi vi n ostat ( Da y 6), wit h o ut de viati o ns affe cti n g p har ma c o ki netic i nter pretati o n.  
 
8. 1. 3. 2.  P art 1 I n hi bit or y Effe ct of Gi vi n ost at o n Or al Mi d az ol a m A n al ysis P o p ul ati o n  
 
P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n Oral Mi da z ola m A nal ysis P o p ulati o n will i ncl u de all 
s u bje cts fr o m t he Part 1 P har ma c o ki netic A nal ysis P o p ulati o n w h o are e x pe cte d t o pr o vi de 
e val ua ble p har mac o ki netic data f or oral mi da z ola m a d mi nistere d al o ne ( Da y 2) a n d c o -a d mi nister e d 
wit h gi vi n ostat ( Da y 7), wit h o ut de viati o ns affe cti n g p har ma c o ki netic i nter pretati o n.  
 
8. 1. 3. 3.  P art 1 In hi bit or y Effe ct of Gi vi n ost at o n D a bi g atr a n A n al ysis P o p ul ati o n  
 
P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n Da bi gatra n A nal ysis P o p ulati o n will i ncl u de all s u bje cts 
fr o m t he Part 1 P har mac 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 da bi gatra n a d mi nistere d al o ne ( Da y 1) a n d c o -a d mi nistere d wit h gi vi n ostat 
( Da y 6), wit h o ut de viati o ns affe cti n g p har ma c o ki netic i nter pretati o n. 
 
8. 1. 3. 4.  P art 1 I n d uci n g Effe ct of Gi vi n ost at o n Mi d az ol a m I V A n al ysis P o p ul ati o n  
 
I n d uci n g E ffe ct of Gi vi n ostat o n Mi da z ola m I V A nal ysis P o p ulati o n will i ncl u de all s u bje cts fr o m 
t he Part 1 P har ma c o ki netic A nal ysis P o p ulati o n w h o are e x pe cte d t o pr o vi de e val ua ble 
p har mac o ki netic data f or mi da z ola m I V a d mi nistere d al o ne ( Da y 1) a n d c o -a d mi nistere d  wit h 
gi vi n ostat ( Da y 1 7), wit h o ut de viati o ns affecti n g p har mac o ki netic i nter pretati o n.  
 
8. 1. 3. 5.  P art 1 I n d uci n g Effe ct of Gi vi n ost at o n Or al Mi d az ol a m A n al ysis P o p ul ati o n  
 
I n d uci n g Effe ct of Gi vi n ostat o n Oral Mi da z ola m A nal ysis P o p ulati o n will i ncl u de all s u bje c ts fr o m 
t he Part 1 P har ma c o ki netic A nal ysis P o p ulati o n w h o are e x pe cte d t o pr o vi de e val ua ble 
p har mac o ki netic data f or oral mi da z ola m a d mi nistere d al o ne ( Da y 2) a n d c o -a d mi nistere d wit h 
gi vi n ostat ( Da y 1 8 ), wit h o ut de viati o ns affecti n g p har mac o ki netic i nterpretati o n.  
 
8. 1. 3. 6.  P art 1 I n d uci n g Effe ct of Gi vi n ost at o n D a bi g atr a n A n al ysis P o p ul ati o n  
 
I n d uci n g Effe ct of Gi vi n ostat o n Da bi gatra n A nal ysis P o p ulati o n will i ncl u de all s u bje cts fr o m t he 
Part 1 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 ma c o ki netic 
data f or da bi gatra n a d mi nistere d al o ne ( Da y 1) a n d c o -a d mi nistere d wi t h gi vi n ostat ( Da y 1 7 ), 
wit h o ut de viati o ns affecti n g p har mac o ki netic i nter pretati o n.  
 
9.  
D A T A R E VI E W / T R A N S F O R M A TI O N  
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 1  of 1 3 7  
9. 1.  
D at a M a n a ge me nt  
 
Data ha n dli n g will be c o n d ucte d i n ac c or da nc e wit h t he Cli nic al Data Ma na ge me nt secti o n of t he 
C S P a n d t he Data Ma na ge me nt Pla n de vel o pe d s pecific all y f or t his st u d y.   
 
9. 2.  
Ac ce pt a nc e of D at a  
 
F or e a c h st u d y part, T F Ls ma y start bei n g pr o gra m me d pri or t o or d uri n g t he c o urse of t he trial. 
H o we ver, t he pr o gra m mi n g of a nal ysis datasets a n d T F Ls will o nl y be c o ncl u de d a n d q ualit y -
c o ntr olle d after data base s oft l oc k. O nl y a u dite d data release d b y t he bi oa nal ytic al la b or at or y will be 
use d f or pr o gra m mi n g t he fi nal a nal ysis datasets a n d T F Ls.    
 
9. 3.  
D at a Tr a nsf or m ati o n ( C DI S C)  
 
Bef ore perf or mi n g t he statistic al a nal ysis, all data c olle cte d ( m ulti ple s o urc es) will be i nte grate d i nt o 
a c o m m o n re p osit or y, usi n g S A S ®  versi o n 9. 4 or hi g her .  
 
F or sta n dar dizati o n a n d s u b missi o n p ur p ose, all data will be tra nsf or me d ac c or di n g t o Cli nic al Data 
I nterc ha n ge Sta n dar ds C o ns orti u m ( C DI S C):  
- 
St u d y Data Ta b ulati o n M o del ( S D T M) versi o n 1. 4  or hi g her . 
- 
S D T M  I m ple me ntati o n G ui de ( S D T MI G) versi o n 3. 2  or hi g her . 
- 
T he f oll o wi n g a nal ysis datasets will be ge nerate d ( A nal ysis Data M o del [ A Da M] versi o n 
2. 1  or hi g her ; A Da M I m ple me ntati o n G ui de [ A Da MI G], versi o n 1.2  or hi g her ) t o s u p p ort 
t he res ults a n d ease t he pr o gra m mi n g a cti vities d uri n g t he statistic al a nal ysis:  
- 
S u bje ct -Le vel A nal ysis Dataset ( A D S L). 
- 
A nal ysis Data P har ma c o ki netic C o nce ntrati o ns ( A D P C) . 
- 
A nal ysis Data P har ma c o ki netic Para meters ( A D P P) . 
- 
A nal ysis Data A d verse E ve nts ( A D A E).  
- 
A nal ysis Data Vital Si g ns ( A D V S).  
- 
A nal ysis Data Electr o car di o gra m Para meters ( A D E G).  
- 
A nal ysis Data La b orat or y Test Res ults ( A D L B).  
 
F or t he sc o pe of t his trial, c o nsi deri n g t he pri mar y a n d sec o n dar y o bje cti ves, si x (6 ) Basic Data 
Str uct ure ( B D S) d o mai ns will be ge nerate d: A D P C, A D P P, A D A E, A D V S , A D E G a n d A D L B . 
T hese si x datasets pl us A D S L will be u p date d f or e ac h part.  T hese d o mai ns will s u p p ort t he 
descri pti ve statistic al a nal yses of t he p har mac o ki netic c o nc e ntrati o ns , t he p har mac o ki netic 
par a meters  a n d safet y.  
 
A D S L –  S u bje ct -Le vel A nal ysis Dataset  
T his a nal ysis d o mai n will c o ntai n: ge neral data a b o ut t he s u bje cts (i.e., a ge, se x a n d rac e), pla n ne d 
a n d a ct ual all oc ate d treat me nt  a nal ysis, a n d start a n d e n d dates of tre at me nt a nal ysis peri o d. T he 
ori gi n of t hese data will pri maril y be t he De m o gra p hics ( D M)  a n d E x p os ure ( E X) S D T M d o mai ns.  
Besi des t his i nf or mati o n, t he f oll o wi n g varia bles will be deri ve d:  
- 
S afety P o p ul ati o n Fl a g  –  S u bje cts i ncl u de d i n t he S afet y A nal ysis P o p ulati o n.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 1  –  S u bje cts i ncl u de d i n t he Part 1 
P har ma c o ki netic A nal ysis P o p ulati o n.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 1 –  S u bje cts i ncl u de d i n t he Part 1 
I n hi bit or y Effe ct of Gi vi n ostat o n Mi da z ola m I V A nal ysis P o p ulati o n.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 2  of 1 3 7  
- 
Dr u g -Dr u g I nter acti o n A n alys is Set P o p ul ati o n Fl a g 2 –  S u bje cts i ncl u de d i n t he Part 1 
I n hi bit or y Effe ct of Gi vi n ostat o n Oral Mi da z ola m A nal ysis P o p ulati o n. 
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 3  –  S u bje cts i ncl u de d i n t he Part 1 
I n hi bit or y Effe ct of Gi vi n ostat o n Da bigatra n A nal ysis P o p ulati o n.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 4  –  S u bje cts i ncl u de d i n t he Part 1 
I n d uci n g Effe ct of Gi vi n ostat o n Mi da z ola m I V A nal ysis P o p ulati o n.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 5  –  S u bje cts i ncl u de d i n t he Part 1 
I n d uci n g Effe ct of Gi vi n ostat o n Oral Mi da z ola m A nal ysis P o p ulati o n.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 6  –  S u bje cts i ncl u de d i n t he Part 1 
I n d uci n g Effe ct of Gi vi n ostat o n Da bi gatra n A nal ysis P o p ulati o n.  
- 
C o m pleters P o p ul ati o n Fl a g  –  S u bje cts w h o c o m plete d t he treat me nt p eri o d. 
 
A D P C –  A nal ysis Data P har mac o ki netic C o nce ntrati o ns  
T his is a B D S dataset t hat will c o ntai n t he c o nce ntrati o ns f or ea c h s u bject, per tre at me nt  a nal ysis, 
per a nal yte/ meta b olite,  a n d per ti me p oi nt.  
T he ori gi n of t hese data will pri maril y be t he E X a n d P har ma c o ki netic C o nce ntrati o ns ( P C) S D T M 
d o mai ns a n d A D S L A Da M d o mai n.  
Besi des t his i nf or mati o n, t he f oll o wi n g varia bles will be deri ve d:  
- 
P h ar m ac o ki netic A n alysis Set P o p ul ati o n Fl a g 1.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 1  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 2  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 3.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 4.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 5.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 6.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 2.   
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 7.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 3.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 4 . 
 
A D P P –  A nal ysis Data P har mac o ki netic Para meters  
T his is a B D S dataset t hat will c o ntai n t he N C A p har ma c o ki netic para meters ( plas ma a n d uri ne) f or 
e a c h s u bje ct , per treat me nt  a nal ysis a n d per a nal yte/ meta b olite . 
Besi des t he ori gi nal p har ma c o ki netic para meter val ue, t he dataset will c o ntai n t he l n-tra nsf or me d 
val ue t hat is necessar y t o a p pl y f or t he s pe cifie d statistic al m o del(s).  
T he ori gi n of t hese data will pri maril y be t he D M a n d P har ma c o ki netic Para meters ( P P) S D T M 
d o mai ns.  
Besi des t his i nf or mati o n, t he f oll o wi n g varia bles will be deri ve d:  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 1.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 1.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Se t P o p ul ati o n Fl a g 2. 
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 3.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 4.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 5.  
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 6.  
- 
P h ar m ac oki netic A n a lysis Set P o p ul ati o n Fl a g 2. 
- 
Dr u g -Dr u g I nter acti o n A n alysis Set P o p ul ati o n Fl a g 7.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 3.  
- 
P h ar m ac oki netic A n alysis Set P o p ul ati o n Fl a g 4 . 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 3  of 1 3 7  
 
 
 
A D A E –  A nal ysis Data A d verse E ve nts Dataset  
T his is a n O C C D S dataset t hat will c o ntai n t he a d verse e ve nts f or ea c h s u bject.  
T he ori gi n of t hese data will pri maril y be t he A d verse E ve nts ( A E) S D T M d o mai n a n d A D S L 
A Da M d o mai n.  
 
A D V S –  A nal ysis Data Vital Si g ns Dataset  
T his is a B D S dataset t hat will c o ntai n t he vital si g ns res ults f or e ac h s u bje ct, per treat me nt  a nal ysis 
a n d per ti me p oi nt.  
T he ori gi n of t hese data will pri maril y be t he Vital Si g ns ( V S) S D T M d o mai n a n d A D S L A Da M 
d o mai n.  
 
A D E G –  A nal ysis Data Electr ocar di o gra m Para meters Dataset  
T his i s a B D S dataset t hat will c o ntai n t he electr ocar di o gra m f or ea c h s u bject, per treat me nt  a nal ysis 
a n d per ti me p oi nt.  
T he ori gi n of t hese data will pri maril y be t he E C G Test Res ults ( E G) S D T M d o mai n a n d A D S L 
A Da M d o mai n.  
 
A D L B –  A nal ysis Data La b orat or y Test Res ults Dataset  
T his is a B D S dataset t hat will c o ntai n t he safet y la b orat or y test res ults f or e a c h s u bje ct  a n d per 
tr e at me nt a nal ysis.  
T he ori gi n of t hese data will pri maril y be t he La b orat or y Test Res ults ( L B) S D T M d o mai n a n d 
A D S L A Da M d o mai n.  
 
1 0.  
S T A TI S TI C A L M E T H O D S  
 
1 0. 1.  
Ge n er al C o nsi de r ati o ns  
 
Esti mati o n of t he p har ma c o ki netic para meters a n d dr u g -dr u g i nteracti o n c o m parati ve bi oa vaila bilit y  
a nal ysis will be c o n d ucte d o n P h oe ni x ®  Wi n N o nli n
®  versi o n  8. 2 or hi g her ( Certara U S A I nc, 
Pri nc e t o n, NJ). All ot her statistic al a nal ysis will be c o n d ucte d o n S A S®  versi o n 9. 4 or hi g her.  
 
Statistic al a nal yses a n d p har ma c o ki netic a nal yses will be perf or me d i n a cc or da nce wit h  t he U. S. 
F D A  g ui da nc es  [ 2, 3] a n d Bl ue Cli nic al a p plic a ble Sta n dar d O perati n g Pr oc e d ures ( S O Ps) . 
 
U nless s pecifie d ot her wise, c o nti n u o us varia bles will be s u m marize d wit h t he f oll o wi n g descri pti ve 
statistics: n u m ber of o bser vati o ns (n ), me a n, sta n dar d de viati o n ( S D), mi ni m u m, me dia n a n d 
ma xi m u m val ue s. Cate g orical data will be s u m marize d wit h fre q ue ncies a n d perc e nta ges. 
F or s u bje ct s’ c haracteristics a n d safet y a nal yses, missi n g data will n ot be re pla ce d; descri pti ve 
statistics a n d statistic al a nal ysis will be perf or me d base d o n t he a vaila ble data o nl y.  All data 
r e c or de d o n disc o nti n ue d s u bjects will be liste d.  
 
1 0. 2.  
S u bjects’ Dis p ositi o n  
 
T he n u m ber of s u bje cts w h o c o m plete d ea c h st u d y part as well as s u bje cts w h o wit h dre w 
pr e mat urel y fr o m t he st u d y will be s u m marize d b y c o m pleti o n stat us a n d reas o n f or wit h dra wal. 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
P a g e  2 4  of 1 3 7  
1 0. 3.  
1 0. 4.  
S u bje cts w h o pre mat urel y wit h dr e w fr o m the stu d y will be liste d. 
T he n u m ber o f s u bje cts i ncl u de d in e a c h a nal ysis p o p ulati o n will be s u mmarize d, f or ea c h st u d y 
part. 
Pr ot oc ol D e vi ati o ns 
D uri n g t he res pe cti ve Data B li n d Re vie w P r ocess, all pr ot oc ol de viati o ns t hat oc c urre d d urin g ea c h 
st u d y part will be a ssesse d i n ter ms of their p ot e ntial im pa ct o n t he p ha r ma c o ki netic a nal ysis. T he 
res ult of t his assess me nt will be re p orte d i n t he res pecti ve Data Bli n d Re vie w Pr ocess Mi n ute 
(A n ne x 1 ). 
Pl as m a P h ar m ac o ki n etic C o n ce ntr ati o ns 
F or e a c h st u d y part ( Part 1, Part 2 a n d Part 3) , f or t he s u bje cts i ncl u de d i n t he res pecti ve 
p har mac o ki netic a nal ysis p o p ulati o n, descri pti ve statistics [ n, ge o metric m e a n ( Gmea n ), arit h metic 
me a n ( Am ea n ), S D, ge o m etric S D ( G S D) , c oefficie nt o f va riati o n ( C V %), ge o metric C V % ( G C V %), 
t w o-si de d 9 5 % C I of the A m ea n  a n d G mea n , me dian, mi ni m u m a n d ma xi m u m] of the pl as ma 
c o nc e ntrati o ns will be pr ese nte d f or ea c h ti me p oi nt, b y a nal yte, a n d b y a d mi nistrati o n da y. 
C o nc e ntrat i o ns bel o w the L L O Q w ill be ta ke n as missi n g f or the calc ulati o n of t he l o g-tra nsf or me d 
statistics a n d as zer o f or the c alc ulati o n of the re mai ni n g s u m mar y statistics. 
F or e a c h st u d y part ( Part 1, Part 2 a n d Part 3) , i n di vi d ual ( per s u bject) a n d G mea n  (i ncl u di n g 9 5 % 
CIs) plas ma c o nc e ntrati o n v ers us ti me pr ofile w ill be g ra p hic all y dis pla ye d i n b ot h li ne ar a n d se mi-
l o garit h mic scales: 
-
F or pl otti n g i n di vi d ual data i n li ne ar scale, c o nc e ntrati o ns bel o w t he L L O Q will be
s u bstit ute d b y zer o.
-
F or pl otti n g G m ea n  data i n li ne ar scale, c o nc e ntrati o ns bel o w t he L L O Q will be s u bstit ute d
b y missi n g.
-
F or pl otti n g data i n se mi -l o garit h mic scale, c o nc e ntrati o ns bel o w t he L L O Q bef ore t ma x ,
will be s u bstit ute d b y ½ of t he L L O Q val ue. After t ma x , c o nc e ntrati o ns bel o w t he L L O Q
will be c o nsi dere d as missi n g . H o we ver, i n c ase of t w o or m ore c o nsec uti ve c o nc e ntrati o ns
bel o w t he L L O Q, t he first val ue will be re pla ce d b y ½ of t he L L O Q val ue a n d t he ne xt
val ues will be c o nsi dere d as missi n g.
Gr a p hic prese ntati o n of i n di vi d ual data will be base d o n act ual bl o o d sa m pli n g ti me,  e xc e pt f or pr e-
d ose sa m pli n g ti me w hic h will be ass u me d as t 0. 
C o nc e ntrati o n data fr o m n o n -e val ua ble peri o ds will be liste d a n d gra p hic all y re prese nte d se paratel y. 
1 0. 5.  
Pl as m a P h ar m ac o ki n etic P ar a meters  
F or e a c h st u d y part, plas ma p har ma c o ki netic para meters will be c alc ulate d f or t he res pe cti ve 
p har mac o ki netic a nal ysis p o p ulati o n.  
F or e a c h st u d y part, 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 
plas ma p har mac o ki netic para meters a n d descri pti ve st atistics ( n, Gmea 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 A mea n  a n d G mea n , me dia n, mi ni m u m a n d ma xi m u m) , will be 
pr ese nte d b y i n vesti gati o nal pr o d uct.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 5  of 1 3 7  
 
If a gi ve n p har mac o ki netic para meter c o ul d n ot be relia bl y deter mi ne d f or m ore t ha n ⅓ of t he 
s u bje cts, o nl y t he mi ni m u m a n d ma xi m u m val ues will be prese nte d, a n d t he ot her descri pti ve 
statistics will be o mitte d f or t hat para meter.  
 
Missi n g p har ma c o ki netic  para meter data will n ot be i m p ute d.  
 
 
1 0. 6.  
Dr u g -Dr u g I nte r acti o n C o m p ar ati ve Bi o a v ail a bilit y St atistic al A n al ysis  
 
 
P art 1  
 
F or mal statistic al a nal ysis of p har mac o ki netic data will be perf or me d t o c hara cterize t he f oll o wi n g 
p har mac o ki netic i ntera cti o ns:  
1.  A nal ysis of t he p ote ntial i n hi bit or y effe ct of oral gi vi n ostat o n t he si n gle -d ose 
p har mac o ki netics of mi da z ola m I V: 
C m a x  a n d A U C 0 -t of mi da z ola m a n d 1 -h y dr o x y mi da z ola m w he n mi da z ola m I V is 
a d mi nistere d al o ne ( Da y 1 ) a n d c o-a d mi nistere d wit h gi vi n ostat ( Da y 6 ) will be t he pri mar y 
p har mac o ki netic para meters f or t he assess me nt of t he p ote ntial i n hi bit or y effect of oral 
gi vi n ostat o n  t he si n gle-d ose p har mac o ki netics of mi da z ola m I V. 
2.  A nal ysis of t he p ote ntial i n d uci n g effect of oral gi vi n ostat o n t he si n gle -d ose 
p har mac o ki netics of mi da z ola m I V: 
C m a x  a n d A U C 0 -t of mi da z ola m a n d 1 -h y dr o x y mi da z ola m w he n mi da z ola m I V is 
a d mi nistere d al o ne  ( Da y 1) a n d c o-a d mi nistere d wit h gi vi n ostat ( Da y 1 7) 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 p ote ntial i n d uci n g eff ect of 
oral gi vi n ostat o n t he si n gle -d ose p har ma c o ki netics of mi da z ola m I V. 
3.  A nal ysis of t he p ote ntial i n hi bit or y 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 mi da z ola m : 
C m a x  a n d A U C 0 -t of mi da z ola m a n d 1 -h y dr o x y mi da z ola m w he n oral mi da z ola m is 
a d mi nistere d al o ne ( Da y 2 ) a n d c o-a d mi nistere d wit h gi vi n ostat ( Da y 7) will be t he pri mar y 
p har mac o ki netic para meters f or t he assess me nt of t he p ote ntial i n hi bit or y effect of oral 
gi vi n ostat o n t he si n gle -d ose p har mac o ki netics of oral mi da z ola m . 
4.  A nal ysis of t he p ote ntial i n d uci n g effect of oral gi vi n ostat o n t he si n gl e -d ose 
p har mac o ki netics of oral mi da z ola m : 
C m a x  a n d A U C 0 -t of mi da z ola m a n d 1 -h y dr o x y mi da z ola m w he n oral mi da z ola m is 
a d mi nistere d al o ne ( Da y 2) a n d c o -a d mi nistere d wit h gi vi n ostat ( Da y 1 8 ) 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 p ote ntial i n d uci n g eff ect or al 
gi vi n ostat o n t he si n gle -d ose p har mac o ki netics of oral mi da z ola m . 
5.  A nal ysis of t he p ote ntial i n hi bit or y 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:  
C m a x  a n d A U C 0 -t 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 nister e d al o ne  
( Da y 1) a n d c o-a d mi nistere d wit h gi vi n ostat ( Da y 6 ) will be t he pri mar y p har mac o ki netic 
para meters f or t he assess me nt of t he p ote ntial i n hi bit or y 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 gatra n p har ma c o ki netic . 
6.  A nal ysis of t he p ote ntial i n d uci n g effect 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:  
C m a x  a n d A U C 0 -t 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 nister e d al o ne 
( Da y 1) a n d c o-a d mi nistere d wit h gi vi n ostat ( Da y 1 7 ) will be t he pri mar y p har mac o ki netic 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 6  of 1 3 7  
para meters f or t he assess me nt of t he p ote ntial 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 ma c o ki netics of oral da bi gatra n.  
 
F or e a c h of t he a b o ve c o m parati o n of i nterest, a n a nal ysis of varia nc e ( 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 ma c o ki netic para meters. A li ne ar mi xe d effe cts m o del will be 
a p plie d, usi n g Tr eat me nt as fi xe d effe ct, assesse d at a t w o o ne -si de d 5 % si g nifica nce 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 le ast s q uare me a ns rati os ( G M R) of t he 
Test -t o-Refere nc e 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 ( mi da z ola m I V, oral mi da z ola m, a n d da bi gatr a n 
ete xilate) c o -a d mi nistere d wit h gi vi n ostat as t he Test a n d a d mi nistere d 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 . T he 9 0 % CI  f or me dia n T ma x  
diff ere nce will be calc ulate d b y a n e xa ct as y m metric met h o d.  
 
1 0. 7.  
S af et y D at a A n al ysis  
 
S afet y a n d t olera bilit y data will be liste d b y st u d y part, treat me nt, st u d y ti me p oi nt a n d s u bje ct 
n u m ber 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 st u d y ti me p oi nt. 
 
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 bas eli 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.  
 
F or cl i nic al la b orat or y data a n d vital si g ns data, o ut of ra n ge val ues will be fla g ge d as “ H” ( Hi g h) or 
“ L” ( L o w) i n t he D ata L isti n gs if t he para meter is o utsi de t he n or mal ra n ge.  
T he E C G res ults will be liste d per s u bje ct. A n y c o m me nt o n a b n or mal res ults will  als o be pr o vi de d.  
A b n or malities i n p h ysic al e xa mi nati o n, E C G, cli nic al la b orat or y tests a n d vital si g ns will be 
classifie d i n ter ms of cli nic al si g nific a nc e. Cli nic all y si g nific a nt a b n or malities will be re p orte d as  
a d verse e ve nts  (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 , versi o n 2 4 .1  or hi g her , a n d 
classifie d b y S O C a n d P T.  
 
All oc c urri n g T E A Es will be assi g ne d t o t he last tre at me nt a d mi nistere d. A se parate listi n g of 
S eri o us A d verse E ve nts ( S A Es ) will be  prese nte d , if a p plic a ble. 
 
I nci de nc e a n d fre q ue ncy  of 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 ea c h 
i n vesti gati o nal pr o d uct a n d o verall . 
 
1 1.  
P R E S E N T A TI O N O F R E S U L T S  
 
1 1. 1.  
St atistic al O ut p ut S pe cific ati o n  
 
Ta bles will be ge nerate d as Ric h Te xt Files ( *.rtf) fr o m S A S® . 
Fi g ures a n d A nal ysis O ut p uts will be ge nerate d as *. d oc x files, e x p orte d fr o m P h oe ni x Wi n N o nli n ®  
a n d/ or S A S ® . 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 7  of 1 3 7  
I n-te xt Ta bles a n d Fi g ures will prefera bl y be pre pare d i n p ortrait f or mat. Listi n gs will prefer a bl y be 
pr e pare d i n la n dsca pe f or mat. 
 
T he C S R will be writte n ac c or di n g t o Bl ue Cli nic al S O Ps a n d te m plates f or re p orti n g 
bi oa vaila bilit y/ bi oe q ui vale nc e trials.  
 
1 1. 2.  
Pl a n n e d T a bles, Fi g u res, a n d S u bje ct D at a Listi n gs  
 
T he pla n ne d T a bles, F i g ures, a n d In di vi d ual D ata L isti n gs f or t he C S R are liste d bel o w.  
 
 
I n-te xt T a bles a n d Fi g u res 
 
F or C S R S y n o psis:  
 
T he f oll o wi n g  Ta bles will be pr o d uce d f or dire ct i nserti o n i n t he S y n o psis of t he C S R:  
 
 
Title  
P A R T 1  
Mi da z ola m: S u m mar y Statistics of t he P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of 
Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect)  
1 -H y d r o x y mi da z ola m: S u m mar y Statistics of t he P har mac o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of Mi da z ola m I V a n d 
Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effe ct)  
M i da z ola m: S u m mar y Statistics of t he P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of 
Or al Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 
7 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effe ct)  
1 -H y dr o x y mi da z ola m: S u m mar y Statistics of t he P har mac o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of Oral Mi da z ola m 
a n d Gi vi n ostat ( Da y 7 –  P ote ntial I n hi bit or y Effect, a n d Da y 1 8 –  P ote ntial I n d uci n g Eff ect) 
T otal Da bi gatra n: S u m mar y Statistics of t he P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of Da bi gatra n 
Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g 
Effect)  
Fr e e Da bi gatra n: S u m mar y Statistics of t he P har mac o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of Da bi gatra n 
Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g 
Effect)  
Mi da z ola m: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he P har mac o ki netics of Mi da z ola m I V: 
T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uare Me a ns, Ge o metric Le ast 
S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d A U C 0 -t 
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect of Gi vi n ostat o n t he P har ma c o ki netics of 
Mi da z ola m I V: T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
Mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har mac o ki netics of Mi da z ola m I V: 
T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uare Me a ns, Ge o met ric Le ast 
S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d A U C 0 -t 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 8  of 1 3 7  
Title  
1 -H y dr o x y mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har ma c o ki netics of 
Mi da z ola m I V: T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
Mi da z ola m: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he P har mac o ki netics of Oral 
Mi da z ola m: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric Le ast S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect of Gi vi n ostat o n t he P har ma c o ki netics of Oral 
Mi da z ola m: T otal I ntra -S u bje ct C oeffi cie nt of Variati o n, Ge o metric Le ast S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
Mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har mac o ki netics of Oral Mi da z ola m: 
T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uare Me a ns, Ge o metric Le ast 
S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d A U C 0 -t 
1 -H y dr o x y mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har ma c o ki netics of Oral 
Mi da z ola m T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric Le ast S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
T otal Da bi gatra n: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he P har ma c o k i netics of 
Da bi gatra n Ete xilate: T otal I ntra -S u bject C oefficie nt of Variati o n, Ge o metric Le ast S q uar e 
Mea ns, Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or 
C m a x  a n d A U C 0 -t 
Fr e e Da bi gatra n: P ote ntial I n hi bit or y Effe ct of G i vi n ostat o n t he P har ma c o ki netics of Da bi gatr a n 
Ete xilate: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric Least S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
T otal Da bi gatra n: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har ma c o ki netics of Da bi gatr a n 
Ete xilate: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric Least S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n di n g 9 0 % C o nfi de nce I nter val f or C ma x  a n d 
A U C 0 -t 
Fr e e Da bi gatra n: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har ma c o ki netics of Da bi gatr a n 
Ete xilate: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric Least S q uare Mea ns, 
Ge o metric Le ast S q uare Mea ns Rati o a n d C orres p o n d i n g 9 0 % C o nfi de nce I nter val f or Cma x  a n d 
A U C 0 -t 
 
 
 
 
 
 
T he f oll o wi n g  Fi g ures will be pr o d uce d f or direct i nserti o n i n t he S y n o psis of t he C S R:  
 
Le ge n d  
P A R T 1  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of Mi da z ola m I V a n d 
Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g E ffe ct). A –  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  2 9  of 1 3 7  
Le ge n d  
Li near S cale; B –  S e mi -L o garit h mic Sc ale  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of 
Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial 
I n d uci n g Effe ct). A –  Li near Sc ale; B –  S e mi -L o garit h mic S cale  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of Oral Mi da z ola m 
a n d Gi vi n ostat ( Da y 7 –  P ote ntial I n hi bit or y Effect, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect). A –  
Li near S cale; B –  S e mi -L o garit h mic Sc ale  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr of iles 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of Oral 
Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial I n hi bit or y Effect, a n d Da y 1 8 –  P ote ntial I n d uci n g 
Effect). A –  Li near S cale; B –  S e mi -L o garit h mic Sc ale  
T otal Da bi gatr a n: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of 
Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial 
In d uci n g Effe ct). A –  Li near Sc ale; B –  S e mi -L o garit h mic S cale  
Fr e e Da bi gatra n: Ge o metric Me a n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of 
Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial 
I n d uci n g Effe ct). A –  Li near Sc ale; B –  S e mi -L o garit h mic S cale  
 
F or C S R B o d y Te xt:  
 
T he f oll o wi n g Ta bles a n d Fi g ures will be pr o d uc e d f or dire ct i nserti o n i n t he b o d y te xt of t he C S R:  
 
I n-te xt T a bles 
Title  
P A R T 1  
Ta ble 1. A.   
St u d y Fl o w -C hart –  Part 1  
Ta ble 1. B.   
I de ntit y of I n vesti gati o nal Pr o d ucts –  Part 1  
Ta ble 1. C.   
S u m mar y of E x p os ure t o Tre at me nt –  Part 1  
Ta ble 1. D.   
S u m mar y of S u bje cts Dis p ositi o n –  Part 1  
Ta ble 1. E. 1.   
S u m mar y of De m o gra p hic Data of P har ma c o ki netic A nal ysis P o p ulati o ns  
Ta ble 1. E. 2.   
S u m mar y of De m o gra p hic Data of 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 ns –  Effe ct of Gi vi n ost at o n Mi da z ola m I V  
Ta ble 1. E. 3.   
S u m mar y of  De m o gra p hic Data of 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 ns –  Effe ct of Gi vi n ost at o n Oral 
Mi da z ola m  
Ta ble 1. E. 4.   
S u m mar y of De m o gra p hic Data of 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 ns –  Effe ct  of Gi vi n ost at o n Da bi gatra n 
Ete xilate  
Ta ble 1. F. 1.   
Mi da z ola m: S u m mar y Statistics of t he P har ma c o ki netic Para meters 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect)  
Ta ble 1. F. 2.   
1 -H y dr o x y mi da z ola m: S u m mar y Statistics of t he P har mac o ki netic 
Para meters F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d 
C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ot e ntial 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 0  of 1 3 7  
I n-te xt T a bles 
Title  
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect)  
Ta ble 1. G. 1.   
Mi da z ola m: S u m mar y Statistics of t he P har ma c o ki netic Para meters 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -
A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect)  
T a ble 1. G. 2.   
1 -H y dr o x y mi da z ola m: S u m mar y Statistics of t he P har mac o ki netic 
Para meters F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d 
C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote nti al I n d uci n g Effect)  
Ta ble 1. H. 1.   
T otal Da bi gatra n: S u m mar y Statistics of t he P har ma c o ki netic Para meters 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect)  
Ta ble 1. H. 2.   
Fre e Da bi gatra n: S u m mar y Statistics of t he P har mac o ki netic Para meters 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect)  
Ta ble 1.I. 1.   
Mi da z ola m: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Mi da z ola m I V: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1.I. 2.   
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect of Gi vi n ostat o n t he 
P har ma c o ki netics of Mi da z ola m I V: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1.J. 1.   
Mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har mac o ki netics 
of Mi da z ola m I V: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric 
Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns Rati o a n d 
C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1.J. 2.   
1 -H y dr o x y mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of M i da z ola m I V: T otal I ntra-S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. K. 1.   
Mi da z ola m: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Oral Mi da z ola m: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. K. 2.   
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect of Gi vi n ostat o n t he 
P har ma c o ki netics of Oral Mi da z ola m: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. L. 1.   
Mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he P har mac o ki netics 
of Oral Mi da z ola m: T otal I ntra -S u bje ct C oefficie nt of Variati o n, Ge o metric 
Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns Rati o a n d 
C orres p o n di n g 9 0 % C o nfi d e nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. L. 2.   
1 -H y dr o x y mi da z ola m: P ote ntial I n d uci n g Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Oral Mi da z ola m: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 1  of 1 3 7  
I n-te xt T a bles 
Title  
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. M. 1.   
T otal Da bi gatra n: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Da bi gatra n Ete xilate: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. M. 2.   
Fre e Da bi gatra n: P ote ntial I n hi bit or y Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Da bi gatra n Ete xilate: T otal I ntra-S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. N. 1.   
T otal Da bi gatra n: P ote ntial I n d ucti o n Effe ct of Gi vi n ostat o n t he 
P har ma c o ki netics of Da bi gatra n Ete xilate: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. N. 2.   
Fre e Da bi gatra n: P ote ntial I n d ucti o n Effect of Gi vi n ostat o n t he 
P har ma c o ki netics of Da bi gatra n Ete xilate: T otal I ntra -S u bje ct C oefficie nt of 
Variati o n, Ge o metric Le ast S q uare Mea ns, Ge o metric Least S q uare Mea ns 
Rati o a n d C orres p o n di n g 9 0 % C o nfi de nc e I nter val f or C ma x  a n d A U C 0 -t 
Ta ble 1. O. 1.   
S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts ( T E A Es) –  All T E A Es  
Ta ble 1. O. 2.  
S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts ( T E A Es) –  Dr u g -R elate d 
T E A Es  
Ta ble 1. O. 3 .  
S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts ( T E A Es) –  
I n hi biti o n/I n d ucti o n Dr u g -R elate d T E A Es 
 
I n-te xt Fi g ur es 
Le ge n d  
P A R T 1  
Fi g ure 1. A. 1.  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o n e ( Da y 1) a n d C o -
A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y 
Effect, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near S c ale  
Fi g ure 1. A. 2.  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o n e ( Da y 1) a n d C o -
A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y 
Effect, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Se mi -L o garit h mic S cale  
Fi g ure 1. B. 1.  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n 
Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne 
( Da y 1) a n d C o-A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near 
S c ale  
Fi g ure 1. B. 2.  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n 
Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne 
( Da y 1) a n d C o-A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Se mi -
L o garit h mic Sc ale  
Fi g ure 1. C. 1.  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi d a z ola m Al o ne ( Da y 2) a n d C o -
A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect) –  Li near S cale  
Fi g ure 1. C. 2.  
Mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 2  of 1 3 7  
I n-te xt Fi g ur es 
Le ge n d  
Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -
A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d ucin g Effect) –  S e mi -
L o garit h mic Sc ale  
Fi g ure 1. D. 1.  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n 
Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne 
( Da y 2) a n d C o-A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7  –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect) –  Li near 
S c ale  
Fi g ure 1. D. 2.  
1 -H y dr o x y mi da z ola m: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n 
Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne 
( Da y 2) a n d C o-A d m i nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect) –  Se mi -
L o garit h mic Sc ale  
Fi g ure 1. E. 1.  
T otal Da bi gatra n: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  
Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1) a n d C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near 
S c ale  
Fi g ure 1. E. 2.  
T otal Da bi gatra n: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  
Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1) a n d C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Se mi -
L o garit h mic Sc ale  
Fi g ure 1. F. 1.  
Fre e Da bi gatra n: Ge o metric Me a n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  
Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1) a n d C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near 
S c ale  
Fi g ure 1. F. 2.  
Fre e Da bi gatra n: Ge o metric Me a n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  
Ti me Pr ofiles F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1) a n d C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  
P ote ntial I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Se mi -
L o garit h mic Sc ale  
Fi g ure 3. A. 4.   
Gi vi n ostat: Ge o metric Mea n ( 9 5 % CI) Plas ma C o nc e ntrati o n Vers us  Ti me 
Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistrati o n of Gi vi n ostat ( Da y 9  t o Da y 
1 3) –  S e mi -L o garit h mic Sc ale  
Fi g ure 3. A. 5.  
Gi vi n ostat: Ge o metric Mea n ( 9 5 % CI) Tr o u g h Plas ma C o nc e ntrati o n Vers us  
Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistrati o n of Gi vi n ostat ( Da y 9  
t o Da y 1 3) –  Li near S c ale  
Fi g ure 3. B. 1.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e n trati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li ne ar S cale  
Fi g ure 3. B. 2.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  S e mi -L o garit h mic 
S c ale  
Fi g ure 3. B. 3.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) Plas ma 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 3  of 1 3 7  
I n-te xt Fi g ur es 
Le ge n d  
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. B. 4.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Se mi -L o garit h mic S cale  
Fi g ure 3. B. 5.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) Tr o u g h Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. C. 1.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li ne ar S cale  
Fi g ure 3. C. 2.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  S e mi -L o garit h mic 
S c ale  
Fi g ure 3. C. 3.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5) : Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. C. 4.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Se mi -L o garit h mic S cale  
Fi g ure 3. C. 5.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) Tr o u g h Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. D. 1.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n osta t –  Li ne ar S cale  
Fi g ure 3. D. 2.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  S e mi -L o garit h mic 
S c ale  
Fi g ure 3. D. 3.   
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. D. 4.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Se mi -L o garit h mic S cale  
Fi g ure 3. D. 5.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) Tr o u g h Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. E. 1.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofi le F oll o wi n g Si n gle-D ose ( Da y 1) a n d 
M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li ne ar S cale  
Fi g ure 3. E. 2.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d 
M ult i ple-D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  S e mi -L o garit h mic 
S c ale  
Fi g ure 3. E. 3.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) Plas ma 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 4  of 1 3 7  
I n-te xt Fi g ur es 
Le ge n d  
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. E. 4.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Se mi -L o garit h mic S cale  
Fi g ure 3. E. 5.  
Gi vi n ostat Me ta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) Tr o u g h Plas ma 
C o nc e ntrati o n Vers us  Ti me Pr ofile F oll o wi n g M ulti ple -D ose A d mi nistr ati o n 
of Gi vi n ostat ( Da y 9  t o Da y 1 3) –  Li near S cale  
Fi g ure 3. F. 1.  
Gi vi n ostat: Ge o metric Mea n ( 9 5 % CI) of Uri nar y E xcreti o n Vers us  Ti me 
Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -D ose ( Da y 1 3) 
A d mi nistrati o n of Gi vi n ostat –  Li near Sc ale  
Fi g ure 3. F. 2.  
Gi vi n ostat: Ge o metric Mea n ( 9 5 % CI) of C u m ulati ve A m o u nt Uri nar y 
E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -
D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near Sc ale  
Fi g ure 3. G. 1.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric M e a n ( 9 5 % CI) of Uri nar y 
E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -
D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near Sc ale  
Fi g ure 3. G. 2.  
Gi vi n ostat Meta b olite (I T F 2 3 7 4): Ge o metric Mea n ( 9 5 % CI) of C u m ulati ve 
A m o u nt Uri nar y  E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 
1) a n d M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near S cale  
Fi g ure 3. H. 1.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) of Uri nar y 
E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -
D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near Sc ale  
Fi g ure 3. H. 2.  
Gi vi n ostat Meta b olite (I T F 2 3 7 5): Ge o metric Mea n ( 9 5 % CI) of C u m ulati ve 
A m o u nt Uri nar y E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 
1) a n d  M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near S cale  
Fi g ure 3.I. 1.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) of Uri nar y 
E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -
D ose ( Da y 1 3) A d mi nistrati o n of  Gi vi n ostat –  Li near Sc ale  
Fi g ure 3.I. 2.  
Gi vi n ostat Meta b olite (I T F 2 4 4 0): Ge o metric Mea n ( 9 5 % CI) of C u m ulati ve 
A m o u nt Uri nar y E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 
1) a n d M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near S c ale 
Fi g ure 3.J. 1.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) of Uri nar y 
E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g Si n gle -D ose ( Da y 1) a n d M ulti ple -
D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near Sc ale  
Fi g ure 3.J. 2.  
Gi vi n ostat Meta b olite (I T F 2 5 6 3): Ge o metric Mea n ( 9 5 % CI) of C u m ulati ve 
A m o u nt Uri nar y E xcreti o n Vers us  Ti me Pr ofile F oll o wi n g  Si n gle -D ose ( Da y 
1) a n d M ulti ple -D ose ( Da y 1 3) A d mi nistrati o n of Gi vi n ostat –  Li near S cale  
 
 
T a bles, Fi g u res a n d Gr a p hs Refer re d t o B ut N ot I ncl u d e d i n t h e Te xt ( S e cti o n 1 4 of C S R)  
 
At le ast t he f oll o wi n g Ta bles a n d Fi g ures s h o ul d be pr o d uc e d f or Se cti o n 1 4 of t he C S R.  
If ne c essar y, a d diti o nal Ta bles a n d Fi g ures s h o ul d be pre pare d. 
 
T he f oll o wi n g Ta bles a n d Fi g ures will be c o m pile d i n a d oc u me nt, t o be c o nsi dere d as S ecti o n 1 4 
( Ta bles, Fi g ures a n d Gra p h Referre d T o B ut N ot I ncl u de d i n t he Te xt) of t he C S R. 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 5  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. P A R T 1  
1 4. 1. 1. D E M O G R A P HI C D A T A –  P A R T 1  
1 4. 1. 1. 1.  
De m o gr a p hic D at a –  P art 1 S afet y A n al ysis P o p ul ati o n  
1 4. 1. 1. 2.  
De m o gr a p hic D at a –  P art 1 P h ar m ac o ki netic A n al ysis P o p ul ati o n  
1 4. 1. 1. 3.  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n hi bit or y Effe ct of Gi vi n ost at o n 
Mi d az ol a m I V  
1 4. 1. 1. 4.  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I nhi bit or y Effe ct of Gi vi n ost at o n 
Or al Mi d az ol a m  
1 4. 1. 1. 5.  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n hi bit or y Effe ct of Gi vi n ost at o n 
D a bi g atr a n  
1 4. 1. 1. 6.  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n 
Mi d az ol a m I V  
1 4. 1. 1. 7.  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n 
Or al Mi d az ol a m  
1 4. 1. 1. 8 .  
De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n 
D a bi g atr a n  
1 4. 1. 1. 9 .  
S u bjects Pr e m at ur el y Disc o nti n ue d Afte r First D osi n g  
 
 
1 4. 1. 2. P H A R M A C O KI N E TI C D A T A –  P A R T 1  
1 4. 1. 2. 1.  
De vi ati o ns fr o m Bl o o d S a m pli n g Sc he d ule  
1 4. 1. 2. 1. 1.  
De viati o ns fr o m Bl o o d S a m pli n g Sc he d ule  
1 4. 1. 2. 1. 2.  
Missi n g Bl o o d S a m ples  
1 4. 1. 2. 1. 3.  
Ot her I m p orta nt Pr ot oc ol De viati o ns  
1 4. 1. 2. 2.  
Pl as m a C o n ce ntr ati o ns  
1 4. 1. 2. 2. 1.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1)  
1 4. 1. 2. 2. 2.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Mi da z ol a m I V a n d 
Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 2. 3.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Mi da z ol a m I V a n d 
Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 2. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1)  
1 4. 1. 2. 2. 5.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Mi da z ol a m I V a n d 
Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 2. 6.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Mi da z ol a m I V a n d 
Gi vi n ostat ( Da y 1 7)  
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St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 6  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. 2. 2. 7.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2)  
1 4. 1. 2. 2. 8.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d 
Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 2. 9.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d 
Gi vi n ostat ( Da y 1 8)  
1 4. 1. 2. 2. 1 0.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2)  
1 4. 1. 2. 2. 1 1.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d 
Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 2. 1 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d 
Gi vi n ostat ( Da y 1 8)  
1 4. 1. 2. 2. 1 3.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma  
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1)  
1 4. 1. 2. 2. 1 4.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d 
Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 2. 1 5.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d 
Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 2. 1 6.  
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of P las ma 
C o nc e ntrati o ns F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 
1)  
1 4. 1. 2. 2. 1 7.  
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d 
Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 2. 1 8.  
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of Plas ma 
C o nc e ntrati o ns F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d 
Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 3.  
P h ar m ac o ki n etic P ar a meters  
1 4. 1. 2. 3. 1.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1)  
1 4. 1. 2. 3. 2.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g C o -A d mi nistrati o n of  Mi da z ola m I V a n d Gi vi n ostat 
( Da y 6) 
1 4. 1. 2. 3. 3.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat 
( Da y 1 7) 
1 4. 1. 2. 3. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of Mi da z ola m I V 
Al o ne ( Da y 1)  
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St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 7  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. 2. 3. 5.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nist rati o n of Mi da z ola m I V 
a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 3. 6.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V 
a n d Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 3. 7.  
Mi da z ola m: I n di vi d ual  Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2)  
1 4. 1. 2. 3. 8.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat 
( Da y 7) 
1 4. 1. 2. 3. 9.  
Mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of P har ma c o ki netic 
Para meters F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat 
( Da y 1 8) 
1 4. 1. 2. 3. 1 0.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m 
Al o ne ( Da y 2)  
1 4. 1. 2. 3. 1 1.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Oral 
Mi da z ola m a n d Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 3. 1 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Oral 
Mi da z ola m a n d Gi vi n ostat ( Da y 1 8)  
1 4. 1. 2. 3. 1 3.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of Da bi gatra n 
Ete xilate Al o ne ( Da y 1)  
1 4. 1. 2. 3. 1 4.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n 
Ete xilate a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 3. 1 5.  
T otal Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n 
Ete xilate a n d Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 3. 1 6.   
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g A d mi nistrati o n of Da bi gatra n 
Ete xilate Al o ne ( Da y 1)  
1 4. 1. 2. 3. 1 7.  
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n 
Ete xilate a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 3. 1 8.  
Fre e Da bi gatra n: I n di vi d ual Data a n d Descri pti ve Statistics of 
P har ma c o ki netic Para meters F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n 
Ete xila te a n d Gi vi n ostat ( Da y 1 7) 
1 4. 1. 2. 3. 1 9.  
Mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 6) -t o-
Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or C
ma x  
1 4. 1. 2. 3. 2 0.  
Mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 6) -t o-
Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 2 1.  
1 -H y dr o x y mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
6) -t o-Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or C
ma x  
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St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 8  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. 2. 3. 2 2.  
1 -H y dr o x y mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d G i vi n ostat ( Da y 
6) -t o-Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C
0 -t 
1 4. 1. 2. 3. 2 3.  
Mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 1 7) -t o-
Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or C
ma x  
1 4. 1. 2. 3. 2 4.  
Mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 1 7) -t o-
Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C
0 -t 
1 4. 1. 2. 3. 2 5.  
1 -H y dr o x y mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
1 7) -t o-Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or C
ma x  
1 4. 1. 2. 3. 2 6.  
1 -H y dr o x y mi da z ola m: Mi da z ola m I V C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
1 7) -t o-Mi da z ola m I V Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C
0 -t 
1 4. 1. 2. 3. 2 7.  
Mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat ( Da y 7) -t o-
Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 2 8.  
Mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat ( Da y 7) -t o-
Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 2 9.  
1 -H y dr o x y mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat 
( Da y 7)-t o-Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 3 0.  
1 -H y dr o x y mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat 
( Da y 7)-t o-Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 3 1.  
Mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat ( Da y 1 8) -t o-
Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 3 2.  
Mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat ( Da y 1 8) -t o-
Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 3 3.  
1 -H y dr o x y mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat 
( Da y 1 8)-t o-Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 3 4.  
1 -H y dr o x y mi da z ola m: Oral Mi da z ola m C o -A d mi nistere d a n d Gi vi n ostat 
( Da y 1 8)-t o-Oral Mi da z ola m Al o ne ( Da y 2) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 3 5.  
T otal Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
6) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 3 6.  
T otal Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
6) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 3 7.  
Fre e Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
6) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual  Rati os f or C ma x  
1 4. 1. 2. 3. 3 8.  
Fre e Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
6) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 3 9.  
T otal Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
1 7) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 4 0.  
T otal Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
1 7) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 3. 4 1.  
Fre e Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y 
1 7) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or C ma x  
1 4. 1. 2. 3. 4 2.  
Fre e Da bi gatra n: Da bi gatra n Ete xilate C o -A d mi nistere d a n d Gi vi n ostat ( Da y  
1 7) -t o-Da bi gatra n Ete xilate Al o ne ( Da y 1) I n di vi d ual Rati os f or A U C 0 -t 
1 4. 1. 2. 4.  
L o g -Li n e ar Re gressi o n P ar a mete rs f or λ z Esti m ati o n  
1 4. 1. 2. 4. 1.  
Mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1)  
1 4. 1. 2. 4. 2.  
Mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n F oll o wi n g 
C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6)  
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St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  3 9  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. 2. 4. 3.  
Mi da z ola m: L o g -Li near Re gressi o n  Para meters f or λ z Esti mati o n F oll o wi n g 
C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 4. 4.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1)  
1 4. 1. 2. 4. 5.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 4. 6.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2. 4. 7.  
Mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2)  
1 4. 1. 2. 4. 8.  
Mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n F oll o wi n g 
C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 4. 9.  
Mi da z ola m: L o g -Li near Re gres si o n Para meters f or λ z Esti mati o n F oll o wi n g 
C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 1 8)  
1 4. 1. 2. 4. 1 0.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2)  
1 4. 1. 2. 4. 1 1.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 4. 1 2.  
1 -H y dr o x y mi da z ola m: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d m i nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 1 8) 
1 4. 1. 2. 4. 1 3.  
T otal Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
1 4. 1. 2. 4. 1 4.  
T otal Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 4. 1 5.  
T otal Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 
1 7)  
1 4. 1. 2. 4. 1 6.  
Fre e Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
1 4. 1. 2. 4. 1 7.  
Fre e Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate C o -A d mi nistere d a n d 
Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 4. 1 8.  
Fre e Da bi gatra n: L o g -Li near Re gressi o n Para meters f or λ z Esti mati o n 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate C o -A d mi nistere d a n d 
Gi vi n ostat ( Da y 1 7)  
 
 
1 4. 1. 3. S A F E T Y D A T A –  P A R T 1  
1 4. 1. 3. 1.  
A d verse E ve nts  
1 4. 1. 3. 1. 1.  
Pre -Tre at me nt A d verse E ve nts  
1 4. 1. 3. 1. 2.  
Tr e at me nt -E mer ge nt A d verse E ve nts (I)  
1 4. 1. 3. 1. 3.  
Tr e at me nt -E mer ge nt A d verse E ve nts (II)  
1 4. 1. 3. 2.  
Vit al Si g ns  
1 4. 1. 3. 2. 1.  
Descri pti ve Statistics of Vital Si g ns Para meters  
1 4. 1. 3. 2. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of Vital Si g ns Para meters  
1 4. 1. 3. 2. 3.  
S hifts i n Vital Si g ns Para meters  
1 4. 1. 3. 3.  
1 2 -Le a d E C G  
1 4. 1. 3. 3. 1.  
Descri pti ve Statistics of 1 2 -Le a d E C G Para meters  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 0  of 1 3 7  
E n d -of -Te xt 
T a bles  
Title  
1 4. 1. 3. 3. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of 1 2 -Lea d E C G Para meters  
1 4. 1. 3. 3. 3.  
S hifts i n 1 2 -Le a d E C G Para meters  
1 4. 1. 3. 4.  
He m at ol o g y  
1 4. 1. 3. 4. 1.  
Descri pti ve Statistics of He mat ol o g y Para meters  
1 4. 1. 3. 4. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of He mat ol o g y Para meters  
1 4. 1. 3. 4. 3.  
S hifts i n He mat ol o g y Para meters  
1 4. 1. 3. 5.  
Bi oc h e mistr y  
1 4. 1. 3. 5. 1.  
Descri pti ve Statistics of Bi oc he mistr y Para meters  
1 4. 1. 3. 5. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of Bi oc he mistr y Para meters  
1 4. 1. 3. 5. 3.  
S hifts i n Bi oc he mistr y Para meters  
1 4. 1. 3. 6.  
C o a g ul ati o n  
1 4. 1. 3. 6. 1.  
Descri pti ve Statistics of C oa g ulati o n Para meters  
1 4. 1. 3. 6. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of C oa g ulati o n Para meters  
1 4. 1. 3. 6. 3.  
S hifts i n C oa g ulati o n Para meters  
1 4. 1. 3. 7.  
Uri n al ysis  
1 4. 1. 3. 7. 1.  
Descri pti ve Statistics of Uri nal ysis Para meters  
1 4. 1. 3. 7. 2.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of Uri nal ysis Para meters  
1 4. 1. 3. 7. 3.  
S hifts i n Uri nal ysis Para meters  
1 4. 1. 3. 8.  
B o d y Wei g ht  
1 4. 1. 3. 8. 1.  
Descri pti ve Statistics of B o d y W ei g ht  
1 4. 1. 3. 8. 2.  
Descri pti ve Statistics of B o d y W ei g ht –  Male S u bjects  
1 4. 1. 3. 8. 3.  
Descri pti ve Statistics of B o d y W ei g ht –  Fe male S u bjects  
1 4. 1. 3. 8. 4.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of B o d y W ei g ht  
1 4. 1. 3. 8. 5.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of B o d y W ei g ht –  Male 
S u bje cts  
1 4. 1. 3. 8. 6.  
Descri pti ve Statistics of C ha n ge fr o m Baseli ne of B o d y W ei g ht –  Fe male 
S u bje cts  
 
 
 
 
E n d -of -Te xt 
Fi g u r es  
Title  
1 4. 1. P A R T 1  
1 4. 1. 2. P H A R M A C O KI N E TI C D A T A –  Part 1  
1 4. 1. 2. 5.  
Pl as m a C o n ce ntr ati o n  Vers us  Ti me Pr ofiles of All S u bje cts  
1 4. 1. 2. 5. 1.  
Mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) –  Li near Sc ale  
1 4. 1. 2. 5. 2.  
Mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 5. 3.  
Mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 1 7)  
1 4. 1. 2 . 5. 4.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) –  Li near 
S c ale  
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V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 1  of 1 3 7  
E n d -of -Te xt 
Fi g u r es  
Title  
1 4. 1. 2. 5. 5.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts F oll o wi n g  C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 
6)  
1 4. 1. 2. 5. 6.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts F oll o wi n g C o -A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 
1 7)  
1 4. 1. 2. 5. 7.  
Mi da z ola m: Plas ma C o nc e n trati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) –  Li near Sc ale  
1 4. 1. 2. 5. 8.  
Mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7)  
1 4. 1. 2. 5. 9.  
Mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 1 8)  
1 4. 1. 2. 5. 1 0.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) –  
Li near S cale  
1 4. 1. 2. 5. 1 1.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts  F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat 
( Da y 7) 
1 4. 1. 2. 5. 1 2.  
1 -H y dr o x y mi da z ola m: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All 
S u bje cts F oll o wi n g C o -A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat 
( Da y 1 8) 
1 4. 1. 2. 5. 1 3.  
T otal Da bi gatra n: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bjects 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) –  Li ne ar 
S c ale  
1 4. 1. 2. 5. 1 4.  
T otal Da bi gatra n: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bjects 
F oll o wi n g C o -A d mi ni strati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6) 
1 4. 1. 2. 5. 1 5.  
T otal Da bi gatra n: Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles of All S u bjects 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 
1 7)  
1 4. 1. 2. 5. 1 6.  
Fre e Da bi gatra n: P las ma C o nce ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) –  Li ne ar 
S c ale  
1 4. 1. 2. 5. 1 7.  
Fre e Da bi gatra n: Plas ma C o nce ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6)  
1 4. 1. 2. 5. 1 8.  
Fre e Da bi gatra n: Plas ma C o nce ntrati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g C o -A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 
1 7)  
1 4. 1. 2. 6.  
I n di vi d u al Pl as m a C o nc e ntr ati o n Vers us  Ti me Pr ofiles  
1 4. 1. 2. 6. 1.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of 
Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 
1 7 –  P ote ntial I n d uci n g Effe ct) –  Li near S cale  
1 4. 1. 2. 6. 2.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -A d mi nistrati o n of 
Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 
1 7 –  P ote ntial I n d uci n g Effe ct) –  S e mi -L o garit h mic S cale  
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I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 2  of 1 3 7  
E n d -of -Te xt 
Fi g u r es  
Title  
1 4. 1. 2. 6. 3.  
1 -H y dr o x y mi da z ol a m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y 
Effect, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near S c al e 
1 4. 1. 2. 6. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Mi da z ola m I V a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y 
Effect, a n d Da y 1 7 –  P ote ntia l I n d uci n g Effect) –  Se mi -L o garit h mic S cale  
1 4. 1. 2. 6. 5.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of 
Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 
1 8 –  P ote ntial I n d uci n g Effe ct) –  Li near S cale  
1 4. 1. 2. 6. 6.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -A d mi nistrati o n of 
Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial I n hi bit or y Effe ct, a n d Da y 
1 8 –  P ote ntial I n d uci n g Effe ct) –  S e mi -L o garit h mic S cale  
1 4. 1. 2. 6. 7.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -
A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 8 –  P ote n tial I n d uci n g Effect) –  Li near S cale  
1 4. 1. 2. 6. 8.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m Al o ne ( Da y 2) a n d C o -
A d mi nistrati o n of Oral Mi da z ola m a n d Gi vi n ostat ( Da y 7 –  P ote ntial 
In hi bit or y Effe ct, a n d Da y 1 8 –  P ote ntial I n d uci n g Effect) –  S e mi -
L o garit h mic Sc ale  
1 4. 1. 2. 6. 9.  
T otal Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  Li near S cale  
1 4. 1. 2. 6. 1 0.  
T otal Da b i gatra n: I n di vi d ual Plas ma C o nc e ntrati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  S e mi -
L o garit h mic Sc ale  
1 4. 1. 2. 6. 1 1.  
Fre e Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -A d mi nistr ati o n 
of Da bi gatra n Ete xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial I n hi bit or y Eff e ct, 
a n d Da y 1 7 –  P ote ntial I n d uci n g Effe ct) –  Li ne ar S cale  
1 4. 1. 2. 6. 1 2.  
Fre e Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n  Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate Al o ne ( Da y 1) a n d C o -
A d mi nistrati o n of Da bi gatra n Et e xilate a n d Gi vi n ostat ( Da y 6 –  P ote ntial 
I n hi bit or y Effe ct, a n d Da y 1 7 –  P ote ntial I n d uci n g Effect) –  S e mi -
L o garit h mic Sc ale  
 
 
 
 
 
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I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 3  of 1 3 7  
 
List of S u bject D at a Listi n gs ( S e cti o n 1 6. 2 of C S R)  
 
T he f oll o wi n g Data Listi n gs will be pr o d uc e d f or Se cti o n 1 6. 2. S u bje ct Data Listi n gs of t he C S R.  
 
If ne c essar y, a d diti o nal Data Listi n gs s h o ul d be pre pare d. 
 
Listi n g N o.  
Title  
1 6. 2. S U BJ E C T S D A T A LI S TI N G  
1 6. 2. 1. Part 1  
1 6. 2. 1. 1.   
S u bject Dis p ositi o n  
1 6. 2. 1. 1. 1.  
S u bje ct Dis p ositi o n  
1 6. 2. 1. 2.   
Pr ot oc ol De vi ati o ns  
1 6. 2. 1. 2. 1.  
Bl o o d S a m pli n g Ti mes De viati o ns  
1 6. 2. 1. 2. 2.  
Ot her Pr ot oc ol De viati o ns  
1 6. 2. 1. 3.   
E xcl u d e d D at a fr o m t h e P h ar m ac o ki n etic A n al ysis  
1 6. 2. 1. 3. 1.  
Plas ma C o nc e ntrati o ns  
1 6. 2. 1. 3. 1. 1.  
Mi da z ola m: I n di vi d ual Data of Plas ma C o nc e ntrat i o ns F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 3. 1. 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data of Plas ma C o nc e ntrati o ns F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 3. 1. 3.  
Mi da z ola m: I n di vi d ual Data of Plas ma C o nc e ntrati o ns F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 3. 1. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Data of Plas ma C o nc e ntrati o ns F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 3. 1. 5.  
T otal Da bi gatra n: I n di vi d ual Data of Plas ma C o nc e ntrati o ns F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 3. 1. 6.  
Fre e Da bi gatra n: I n di vi d ual Data of Plas ma C o nc e ntrati o ns F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 3. 2.  
Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles  
1 6. 2. 1. 3. 2. 1.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V –  Li near S cale  
1 6. 2. 1. 3. 2. 2.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Mi da z ola m I V –  S e mi -L o garit h mic S c ale  
1 6. 2. 1. 3. 2. 3.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V –  Li ne ar S cale  
1 6. 2. 1. 3. 2. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Mi da z ola m I V –  S e mi -L o garit h mic 
S c ale  
1 6. 2. 1. 3. 2. 5.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m –  Li near Scale  
1 6. 2. 1. 3. 2. 6.  
Mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Ver s us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m –  S e mi -L o garit h mic S cale  
1 6. 2. 1. 3. 2. 7.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m –  Li near S cale  
1 6. 2. 1. 3. 2. 8.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me 
Pr ofiles F oll o wi n g A d mi nistrati o n of Oral Mi da z ola m –  Se mi -L o garit h mic 
S c ale  
1 6. 2. 1. 3. 2. 9.  
T otal Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gat ra n Ete xilate –  Li near Sc ale  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 4  of 1 3 7  
Listi n g N o.  
Title  
1 6. 2. 1. 3. 2. 1 0.  
T otal Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate –  S e mi -L o garit h mic Sc ale  
1 6. 2. 1. 3. 2. 1 1.  
Fre e Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate –  Li near Sc ale  
1 6. 2. 1. 3. 2. 1 2.  
Fre e Da bi gatra n: I n di vi d ual Plas ma C o nc e ntrati o n Vers us Ti me Pr ofiles 
F oll o wi n g A d mi nistrati o n of Da bi gatra n Ete xilate –  S e mi -L o garit h mic Sc ale 
1 6. 2. 1. 4.   
De m o gr a p hic a n d Ot h e r B aseli n e D at a  
1 6. 2. 1. 4. 1.  
De m o gra p hic Data  
1 6. 2. 1. 4. 2.  
Fertilit y/ C o ntra c e pti o n  
1 6. 2. 1. 4. 2. 1.  
Fe male Fertilit y/ C o ntra c e pti o n  
1 6. 2. 1. 4. 2. 2.  
Male Fertilit y/ C o ntra c e pti o n  
1 6. 2. 1. 4. 3.  
Dr u gs of A b use, Et ha n ol a n d C oti ni ne  
1 6. 2. 1. 4. 4.  
Viral Ser ol o g y at Scre e ni n g  
1 6. 2. 1. 4. 5.  
Pre vi o us a n d C o nc o mita nt Me dic ati o n  
1 6. 2. 1. 4. 6.  
S A R S -C O V -2 Test  
1 6. 2. 1. 5.   
C o m pli a nc e  
1 6. 2. 1. 5. 1.  
I n vesti gati o nal Pr o d uct A d mi nistrati o n 
1 6. 2. 1. 6.  
I n di vi d u al P h ar m ac o ki netic D at a  
1 6. 2. 1. 6. 1.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Data F oll o wi n g A d mi nistrati o n of 
Mi da z ola m I V  
1 6. 2. 1. 6. 1. 1.  
Mi da z ola m: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g A d mi nistrati o n 
of Mi da z ola m I V  
1 6. 2. 1. 6. 1. 2.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 6. 1. 3.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g A d mi nistrati o n 
of Mi da z ola m I V  
1 6. 2. 1. 6. 1. 4.  
Mi da z ola m: D oc u me ntati o n of Statistic al A nal ys is F oll o wi n g A d mi nistr ati o n 
of Mi da z ola m I V  
1 6. 2. 1. 6. 1. 4. 1.  
Mi da z ola m: N o n -C o m part me ntal A nal ysis O ut p ut  
1 6. 2. 1. 6. 1. 4. 2.  
Mi da z ola m: N o n -C o m part me ntal A nal ysis Pl ots  
1 6. 2. 1. 6. 1. 4. 3.  
Mi da z ola m: P ote ntial I n hi bit or y Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 1. 4. 4.  
Mi da z ola m: P ote ntial I n d ucti o n Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Data F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 6. 2. 1.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g 
A d mi nistrati o n Mi da z ola m I V  
1 6. 2. 1. 6. 2. 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 6. 2. 3.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 6. 2. 4.  
1 -H y dr o x y mi da z ola m: D oc u me ntati o n of Statistic al A nal ysis F oll o wi n g 
A d mi nistrati o n of Mi da z ola m I V  
1 6. 2. 1. 6. 2. 4. 1.  
1 -H y dr o x y mi da z ola m: N o n -C o m part me ntal A nal ysis O ut p ut  
1 6. 2. 1. 6. 2. 4. 2.  
1 -H y dr o x y mi da z ola m: N o n -C o m part me ntal A nal ysis Pl ot s 
1 6. 2. 1. 6. 2. 4. 3.  
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect A nal ysis O ut p ut  
1 6. 2. 1. 6. 2. 4. 4.  
1 -H y dr o x y mi da z ola m: P ote ntial I n d ucti o n Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 3.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Data F oll o wi n g A d mi nistrati o n of 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 5  of 1 3 7  
Listi n g N o.  
Title  
Oral Mi da z ola m  
1 6. 2. 1. 6. 3. 1.  
Mi da z ola m: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g A d mi nistrati o n 
of Oral Mi da z ola m  
1 6. 2. 1. 6. 3. 2.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 6. 3. 3.  
Mi da z ola m: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g A d mi nistrati o n 
of Oral Mi da z ola m  
1 6. 2. 1. 6. 3. 4.  
Mi da z ola m: D oc u me ntati o n of Statistic al A nal ysis F oll o wi n g A d mi nistr ati o n 
of Oral Mi da z ola m  
1 6. 2. 1. 6. 3. 4. 1.  
Mi da z ola m: N o n -C o m part me ntal A nal ysis O ut p ut  
1 6. 2. 1. 6. 3. 4. 2.  
Mi da z ola m: N o n -C o m part me ntal A nal ysis Pl ots  
1 6. 2. 1. 6. 3. 4. 3.  
Mi da z ola m: P ote ntial I n hi bit or y Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 3. 4. 4.  
Mi da z ola m: P ote ntial I n d ucti o n Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 4.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Data F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 6. 4. 1.  
1 -H y dr o x y mi da z ola m: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g 
A d mi nistrati o n Oral Mi da z ola m  
1 6. 2. 1. 6. 4. 2.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 6. 4. 3.  
1 -H y dr o x y mi da z ola m: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 6. 4. 4.  
1 -H y dr o x y mi da z ola m: D oc u me ntati o n of Statistic al A nal ysis F oll o wi n g 
A d mi nistrati o n of Oral Mi da z ola m  
1 6. 2. 1. 6. 4. 4. 1.  
1 -H y dr o x y mi da z ola m: N o n -C o m part me ntal A nal ysis O ut p ut  
1 6. 2. 1. 6. 4. 4. 2.  
1 -H y dr o x y mi da z ola m: N o n -C o m part me ntal A nal ysis Pl ots  
1 6. 2. 1. 6. 4. 4. 3.  
1 -H y dr o x y mi da z ola m: P ote ntial I n hi bit or y Effect A nal ysis O ut p ut 
1 6. 2. 1. 6. 4. 4. 4.  
1 -H y dr o x y mi da z ola m: P ote ntial I n d ucti o n Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 5.  
T otal Da bi gatra n: I n di vi d ual P har ma c o ki netic Data F oll o wi n g A d mi nistr ati o n 
of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 5. 1.  
T otal Da bi ga tra n: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 5. 2.  
T otal Da bi gatra n: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 5. 3.  
T otal Da bi gatra n: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 5. 4.  
T otal Da bi gatra n: D oc u me ntati o n of Statistic al A nal ysis F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 5. 4. 1.  
T otal Da bi gatra n: N o n -C o m part me n tal A nal ysis O ut p ut 
1 6. 2. 1. 6. 5. 4. 2.  
T otal Da bi gatra n: N o n -C o m part me ntal A nal ysis Pl ots  
1 6. 2. 1. 6. 5. 4. 3.  
T otal Da bi gatra n: P ote ntial I n hi bit or y Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 5. 4. 4.  
T otal Da bi gatra n: P ote ntial I n d ucti o n Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 6.  
Fre e Da bi gatra n: I n di vi d ual P har ma c o ki netic Data F oll o wi n g A d mi nistr ati o n 
of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 6. 1.  
Fre e Da bi gatra n: I n di vi d ual Dr u g C o nc e ntrati o n Data F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 6. 2.  
Fre e Da bi gatr a n: I n di vi d ual P har ma c o ki netic Para meters F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 6  of 1 3 7  
Listi n g N o.  
Title  
1 6. 2. 1. 6. 6. 3.  
Fre e Da bi gatra n: I n di vi d ual P har ma c o ki netic Pr ofiles F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 6. 4.  
Fre e Da bi gatra n: D oc u me ntati o n of Statistic al A nal ysis F oll o wi n g 
A d mi nistrati o n of Da bi gatra n Ete xilate  
1 6. 2. 1. 6. 6. 4. 1.  
Fre e Da bi gatra n: N o n -C o m part me ntal A nal ysis O ut p ut  
1 6. 2. 1. 6. 6. 4. 2.  
Fre e Da bi gatra n: N o n -C o m part me ntal A nal ysis Pl ots  
1 6. 2. 1. 6. 6. 4. 3.  
Fre e Da bi gatra n: P ote ntial I n hi bit or y Effe ct A nal ysis O ut p ut  
1 6. 2. 1. 6. 6. 4. 4.  
Fre e Da bi gatra n: P ote ntial I n d ucti o n Effect A nal ysis O ut p ut  
1 6. 2. 1. 7.  
A d verse E ve nt Listi n gs ( E ac h S u bject)  
1 6. 2. 1. 7. 1.  
Pre -Tre at me nt A d verse E ve nts  
1 6. 2. 1. 7. 2.  
Tr e at me nt -E mer g e nt A d verse E ve nts  
1 6. 2. 1. 7. 3.  
S eri o us A d verse E ve nts (I)  
1 6. 2. 1. 8.   
Listi n gs of L a b or at or y Me as u re me nts b y S u bject  
1 6. 2. 1. 8. 1.  
N or mal Ra n ge of La b orat or y Val ues  
1 6. 2. 1. 8. 2.  
He mat ol o g y (I)  
1 6. 2. 1. 8. 3.  
He mat ol o g y (II)  
1 6. 2. 1. 8. 4.  
Bi oc he mistr y (I)  
1 6. 2. 1. 8. 5.  
Bi oc he mistr y (II)  
1 6. 2. 1. 8. 6.  
Bi oc he mistr y (III)  
1 6. 2. 1. 8. 7.  
Bi oc he mistr y (I V)  
1 6. 2. 1. 8. 8.  
Bi oc he mistr y ( V)  
1 6. 2. 1. 8. 9.  
C oa g ulati o n  
1 6. 2. 1. 8. 1 0.  
Uri nal ysis  
1 6. 2. 1. 8. 1 1.  
Uri ne Micr osc o p y  
1 6. 2. 1. 8. 1 2.  
Pre g na nc y Test  
1 6. 2. 1. 8. 1 3.  
A d diti o nal ( N ot Pla n ne d) La b orat or y S afet y Tests  
1 6. 2. 1. 9.   
Vit al Si g ns  
1 6. 2. 1. 1 0.   
1 2 -Le a d E C G  
 
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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  
 
 
P a g e  4 7  of 1 3 7  
1 2.  
R E F E R E N C E S  
 
[ 1] I T F/ 2 3 5 7/ 5 5 Cli nic al St u d y Pr ot oc ol, Versi o n 1. 0 , 2 9 N O V 2 0 2 1  
[ 2] 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 Tra ns p orter-Me diate d Dr u g I ntera cti o ns G ui da nc e f or I n d ustr y ( 2 0 2 0).  
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  4 8  of 1 3 7  
1 3.  
A P P E N DI C E S  
 
A P P E N DI X A.  Pl a n n e d T a bles, Fi g u res, a n d S u bje ct D at a Listi n gs  
 
A. 1.  
I n-te xt T a bles a n d Fi g u res –  F or C S R S y n o psis  
 
A. 1. 1.  
P art 1  
 
 
S Y N O P SI S T A B L E S ( 1 ) 
 
Mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6 –  
P ot e nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect ) 1 
 
 
S Y N O P SI S T A B L E S ( 2 ) 
 
1 -H y d r o x y mi d az ol a m : S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a mete rs F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effect ) 1 
 
 
1 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
Mi d az ol a m I V Al o n e  
( D a y 1) 
( n = x x ) 
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6 ) 
( n = x x ) 
Mi d az ol a m I V 
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
λ z ( 1/ h) 
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
t½  ( h) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( Gm e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis  
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his ta ble will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or  P art 1 
P h ar m ac oki netic  A n alysis P o p ul ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d f or o ne 
or m ore s u bje cts i n t he P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n , t he p h ar m ac oki netic p ar a meter s h o ul d 
be f oll o we d by t he  # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a meter (s)> , n =x x , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct  < , a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  4 9  of 1 3 7  
S Y N O P SI S T A B L E S ( 3 ) 
 
Mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ot e nti al 
I n hi bit or y Effe ct, a n d D a y 1 8 –  P ote nti al I n d u ci n g Effe ct) 2 
 
 
S Y N O P SI S T A B L E S ( 4 ) 
 
1 -H y d r o x y mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a mete rs F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect)  2 
 
 
2 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
Or al Mi d az ol a m Al o n e 
( D a y 2) 
( n = x x ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 7)  
( n = x x ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 8)  
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
λ z ( 1/ h) 
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
t½  ( h) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( G m e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis 
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p u l ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d 
f or o ne or m ore s u bje cts i n t he P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n, t he p h ar m ac oki netic p ar a meter 
s h o ul d be f oll o we d by t he # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a mete r(s) >, n =xx , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct <, a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 0  of 1 3 7  
S Y N O P SI S T A B L E S ( 5 ) 
 
T ot al D a bi g atr a n: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d Gi vi n ost at 
( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d uci n g Effe ct)  3 
 
 
S Y N O P SI S T A B L E S ( 6 ) 
 
Fr ee D a bi g atr a n: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d Gi vi n ost a t 
( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d uci n g Effe ct)  3 
 
 
3 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
D a bi g atr a n Ete xil ate Al o ne 
( D a y 1) 
( n = x x ) 
D a bi g atr a n Ete xil ate  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6 ) 
( n = x x ) 
D a bi g atr a n Ete xil ate   
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7 ) 
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %) 
x x. x x ( x x. x %)  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
λ z ( 1/ h) 
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
x. x x x ( x x. x %)  
t½  ( h) 
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
x x. x x ( x x. x %)  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( G m e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis 
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a bl e will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d 
f or o ne or m ore s u bje cts i n t he P art 1 P h ar m ac oki netic A n alys is P o p ul ati o n, t he p h ar m ac oki netic p ar a meter 
s h o ul d be f oll o we d by t he # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a meter(s) > , n =xx , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct <, a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 1  of 1 3 7  
S Y N O P SI S T A B L E S ( 7 ) 
 
Mi d az ol a m: P ote nti al I n hi bit or y Effe ct 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 I V: T ot al 
I nt r a-S u bj e ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, Ge o metric Le ast S q u ar e 
M e a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi d e n ce I nte r v al f or C m a x  a n d A U C 0 -t 4 
 
 
S Y N O P SI S T A B L E S ( 8 ) 
 
1 -H y d r o x y mi d az ol a m : P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of Mi d az ol a m 
I V: T ot al I nt r a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, Ge o metric Le ast 
S q u are M e a ns  R ati o  a n d C or res p o n di n g 9 0 % C o nfi de n c e I nte r v al  f or C m a x  a n d A U C 0 -t 4 
 
 
4 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Mi d az ol a m I V  
Al o n e ( D a y 1)  
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Mi daz ola m I V C o -A d mi nistere d wit h Gi vi n ostat ( Da y 6) a n d t he 
Ge o metric L S mea ns of Mi daz ola m of I V Al o ne ( Da y 1)   
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he  res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe c t of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of mi d az ol a m I V, perf or me d o n t he P ote nti al I n hi bit ory Effe ct of Givi n ost at 
o n Mi d az ol a m I V A n alysis P o p ul ati o n . 
  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 2  of 1 3 7  
S Y N O P SI S T A B L E S ( 9 ) 
 
Mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t h e P h ar m ac o ki netics of Mi d az ol a m I V: T ot al 
I nt r a-S u bj e ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, Ge o metric Le ast S q u ar e 
M e a ns  R ati o  a n d C o rr es p o n di n g 9 0 % C o nfi d e n ce I nte r v al  f or C m a x  a n d A U C 0 -t 5 
 
 
S Y N O P SI S T A B L E S ( 1 0 ) 
 
1 -H y d r o x y mi d az ol a m: P ote nti al I n d u ci n g 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 
I V: T ot al I nt r a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, Ge o metric Le ast 
S q u are M e a ns  R ati o  a n d C or res p o n di n g 9 0 % C o nfi de n c e I nte r v al  f or C m a x  a n d A U C 0 -t 5 
 
 
5 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Mi d az ol a m I V  
Al o n e ( D a y 1)  
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7 ) 
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Mi daz ola m I V C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 7) a n d t he 
Ge o metric L S mea ns of Mi daz ola m of I V Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe c t of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of mi d az ol a m I V, perf or me d o n t he P ote nti al I n d ucti o n Effect of Givi n ost at 
o n Mi d az ol a m I V A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 3  of 1 3 7  
S Y N O P SI S T A B L E S ( 1 1 ) 
 
Mi d az ol a m: P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t he P h ar m ac o ki n etics of Or al Mi d az ol a m: 
T ot al I nt r a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, Ge o metric Le ast S q u are 
M e a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi d e n ce I nte r v al  f or C m a x  a n d A U C 0 -t 6 
 
 
S Y N O P SI S T A B L E S ( 1 2 ) 
 
1 -H y d r o x y mi d az ol a m: P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of Or al 
Mi d az ol a m: T ot al I ntr a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are M e a ns, Ge o metric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v a l f or C m a x  a n d A U C 0 -t 6 
 
 
6 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Or al Mi d az ol a m  
Al o n e ( D a y 2 ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 7 ) 
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Oral Mi daz ola m C o -A d mi nistere d wit h Gi vi n ostat ( Da y 7) a n d t he 
Ge o metric L S mea ns of Oral Mi daz ola m Al o ne ( Da y 2 )  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of o r al m i d az ol a m, perf or me d o n t he P ote nti al I n hi bit ory Effe ct of 
Givi n ost at o n Or al Mi d az ol a m A n alysis P o p ul ati o n.  
  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 4  of 1 3 7  
S Y N O P SI S T A B L E S ( 1 3 ) 
 
Mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t h e P h ar m ac o ki netics of Or al Mi d az ol a m: T ot al 
I nt r a-S u bj e ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, Ge o metric Le ast S q u ar e 
M e a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi d e n ce I nte r v al  f or C m a x  a n d A U C 0 -t 7 
 
 
S Y N O P SI S T A B L E S ( 1 4 ) 
 
1 -H y d r o x y mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t he P h ar m ac o ki n etics of Or al 
Mi d az ol a m  T ot al I ntr a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are M e a ns, Ge o metric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 7 
 
 
7 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Or al Mi d az ol a m  
Al o n e ( D a y 2 ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 8 ) 
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Oral Mi daz ola m C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 8) a n d t he 
Ge o metric L S mea ns of Oral Mi daz ola m Al o ne ( Da y 2)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble wil l prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of o r al m i d az ol a m, perf or me d o n t he P ote nti al I n d ucti o n Effe ct of 
Givi n ost at o n Or al Mi d az ol a m A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 5  of 1 3 7  
S Y N O P SI S T A B L E S ( 1 5 ) 
 
T ot al D a bi g atr a n : P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of D a bi g atr a n 
Et e xil at e : T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e Me a ns, Ge o met ric 
Le ast  S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 8 
 
 
S Y N O P SI S T A B L E S ( 1 6 ) 
 
Fr ee  D a bi g atr a n : P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of D a bi g atr a n 
Et e xil at e : T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e Me a ns, Ge o met ric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 8 
 
 
8 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
D a bi g atr a n Ete xil ate 
Al o n e ( D a y 1)  
D a bi g atr a n Ete xil ate 
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6) 
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Da bi gatra n Ete xilate C o -A d mi nistere d wit h Gi vi n ostat ( Da y 6) a n d t he 
Ge o metric L S mea ns of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of d a bi g atr a n ete xil ate , perf or me d o n t he P o te nti al I n hi bit ory Effe ct of 
Givi n ost at o n D a bi g atr a n Ete xil ate A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 6  of 1 3 7  
S Y N O P SI S T A B L E S ( 1 7 ) 
 
T ot al D a bi g atr a n : P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t h e P h ar m ac o ki netics of D a bi g atr a n 
Et e xil at e: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e Me a ns, Ge o met ric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 9 
 
 
S Y N O P SI S T A B L E S ( 1 8 ) 
 
Fr ee D a bi g atr a n : P ote nti al I n d u ci n g Eff ect of Gi vi n ost at o n t he P h ar m ac o ki n etics of D a bi g atr a n 
Et e xil at e: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e Me a ns, Ge o met ric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 9 
 
 
9 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
D a bi g atr a n Ete xil ate 
Al o n e ( D a y 1)  
D a bi g atr a n Ete xil ate 
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Da bi gatra n Ete xilate C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 7) a n d t he 
Ge o metric L S mea ns of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T hi s t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of d a bi g atr a n ete xil ate , perf or me d o n t he P ote nti al I n d ucti o n Effect of 
Givi n ost at o n D a bi g atr a n Ete xil ate A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 7  of 1 3 7  
S Y N O P SI S FI G U R E S  (1 9 ) 
 
Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effect) . A –  Li n e ar 
S c ale; B –  S e mi -L o g arit h mic S c ale  
 
 
S Y N O P SI S FI G U R E S ( 2 0 ) 
 
1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V 
a n d  Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al In d u ci n g  Effect) . A –  
Li n e ar Sc ale; B –  S e mi -L o g arit h mic S c ale  
 
 
Pl ot t he v al ues of mi d az ol a m or its met a b olite pl as m a c o nc e ntr ati o n s (< u nits C > ) o n t he y axis a g ai nst ti me 
( h) o n t he x axis. 
L a bel x axis wit h ‘ Ti me ( h)’ a n d y axis wit h ‘ Mi d az ol a m C o nc e ntr ati o n ( < u nits C > )’ or ‘ 1-
Hy dr oxy mi d az ol a m C o nc e ntr ati o n ( < u nits C > )’. 
M arks o n t he x axis s h o ul d be fr o m ti me 0 t o 2 4 h, at i nterv als of 4 h o urs, or m ulti ples.  
Pl as m a c o nc e ntr ati o ns m arks f or e ac h bl o o d s a m pli n g sc he d ule d ti me p oi nt s h o ul d be i n (i)  b or dere d circles 
(i n bl ac k c ol or) wit h o ut fill f or Mi d az ol a m I V Al o ne ( D ay 1), (ii) s oli d fill circles (i n d ark bl ue c ol or) f or t he 
Mi d az ol a m I V C o -A d mi nist e re d wit h Givi n ost at ( D ay 6) a n d (iii) s oli d fill s q u are (i n d ark re d c ol or) f or t he 
Mi d az ol a m I V C o -A d mi nist e re d wit h Givi n ost at ( D ay 1 7 ). 
 
T hese g ui deli nes s h o ul d be a p plie d o n ev ery Fi g ure pr o d uc e d f or p h ar m ac oki netic res ults of t his st u dy.  
 
N ote: T hese fi g ures will prese nt t he ge o metric me a n c o nce ntr ati o n v ers us ti me pr ofiles c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n.  
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 8  of 1 3 7  
S Y N O P SI S FI G U R E S ( 2 1 ) 
 
Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect) . A –  Li n e ar 
S c ale; B –  S e mi -L o g arit h mic S c ale  
 
 
S Y N O P SI S FI G U R E S ( 2 2 ) 
 
1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al 
Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 8 –  P ot e nti al I n d uci n g 
Eff e ct) . A –  Li ne ar S c ale; B –  S e mi -L o g arit h mic S c ale  
 
 
Pl ot t he v al ues of mi d az ol a m or its met a b olite pl as m a c o nc e ntr ati o n s (< u nits C > ) o n t he y axis a g ai nst ti me 
( h) o n t he x axis. 
L a bel x axis w it h ‘ Ti me ( h)’ a n d y axis wit h ‘Mi d az ol a m C o nc e ntr ati o n ( < u nits C > )’ or ‘ 1-
Hy dr oxy mi d az ol a m C o nc e ntr ati o n ( < u nits C > )’. 
M arks o n t he x axis s h o ul d be fr o m ti me 0 t o 2 4 h, at i nterv als of 4 h o urs, or m ulti ples.  
Pl as m a c o nc e ntr ati o ns m arks f or e ac h bl o o d s a m pl i n g sc he d ule d ti me p oi nt s h o ul d be i n (i) b or dere d circles 
(i n bl ac k c ol or) wit h o ut fill f or Or al Mi d az ol a m  Al o ne ( D ay 2 ), (ii) s oli d fill circles (i n d ark bl ue c ol or) f or 
t he Or al Mi d az ol a m  C o -A d mi nist e re d wit h Givi n ost at ( D ay 7 ) a n d (iii) s oli d fill s q u are (i n d ark re d c ol or) 
f or t he Or al Mi d az ol a m  C o -A d mi nist e re d wit h Givi n ost at ( D ay 1 8).  
 
T hese g ui deli nes s h o ul d be a p plie d o n ev ery Fi g ure pr o d uc e d f or p h ar m ac oki netic res ults of t his st u dy.  
 
N ote: T hese fi g ures will prese nt t he ge o metric me a n c o nce ntr ati o n v ers us ti me pr ofiles c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n . 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  5 9  of 1 3 7  
S Y N O P SI S FI G U R E S ( 2 3 ) 
 
T ot al D a bi g atr a n: Ge o metric M e a n ( 9 5 % C I) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e 
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect) . A –  
Li n e ar Sc ale; B –  S e mi -L o g arit h mic S c ale  
 
 
S Y N O P SI S FI G U R E S ( 2 4 ) 
 
Fr ee D a bi g atr a n: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e 
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect) . A –  
Li n e ar Sc ale; B –  S e mi-L o g arit h mic S c ale  
 
 
Pl ot t he v al ues of t ot al or free d a bi g atr a n  pl as m a c o nc e ntr ati o n s (< u nits C > ) o n t he y axis a g ai nst ti me ( h) o n 
t he x axis. 
L a bel x axis wit h ‘ Ti me ( h)’ a n d y axis wit h ‘ T ot al D a bi g atr a n  C o nc e ntr ati o n ( < u nits C > )’ or ‘Fre e 
D a bi g atr a n  C o nc e ntr ati o n ( < u nits C > )’. 
M arks o n t he x axis s h o ul d be fr o m ti me 0 t o 7 2  h, at i nterv als of 4 h o urs, or m ulti ples.  
Pl as m a c o nc e ntr ati o ns m arks f or e ac h bl o o d s a m pli n g sc he d ule d ti me p oi nt s h o ul d be i n (i)  b or dere d circles 
(i n bl ac k c ol or) wit h out fill f or D a bi g atr a n Ete xil ate Al o n e ( D ay 1), (ii) s oli d fill circles (i n d ark bl ue c ol or) 
f or t he D a bi g atr a n Ete xil ate C o -A d mi nist e re d wit h Givi n ost at ( D ay 6) a n d (iii) s oli d fill s q u are (i n d ark re d 
c ol or) f or t he D a bi g atr a n Ete xil ate C o -A d mi nist e re d w it h Givi n ost at ( D ay 1 8). 
 
T hese g ui deli nes s h o ul d be a p plie d o n ev ery Fi g ure pr o d uc e d f or p h ar m ac oki netic res ults of t his st u dy.  
 
N ote: T hese fi g ures will prese nt t he ge o metric me a n c o nce ntr ati o n v ers us ti me pr ofiles c alc ul ate d f or t he 
P art 1 P h ar m ac oki net ic A n alysis P o p ul ati o n. 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 0  of 1 3 7  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 1  of 1 3 7  
A. 2.  
I n-te xt T a bles a n d Fi g u res –  F or C S R B o d y Te xt  
 
A. 2. 1.  
P art 1  
 
  
  
T a ble 1. A.  St u d y F l o w-C h art  –  P art 1  
 
N ote: T o be c a pt ure d fr o m t he Cli nic al St u dy Pr ot oc ol ( C SP ) a n d A me n d me nts.  
 
 
T a ble 1. B.  I d e ntit y of I n vesti g ati o n al Pr o d ucts –  P art 1  
 
N ote: T o be ge ner ate d by t he Me dic al Writi n g ( M W ). 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 2  of 1 3 7  
T a ble 1. C.  S u m m ar y of E x p os ur e t o Tr e at me nt  –  P art 1  
 
Tr e at me nt  
St u d y D a y  
N u m b er of 
S u bj ects  
 
Mi da z ola m (I V) 1 m g + Da bi gatra m 7 5 m g  
Da y 1  
x x  
Mi da z ola m ( Oral) 2. 5 m g  
Da y 2  
x x  
Gi vi n ostat 5 0 m g b.i. d.  
Da ys 4  –  5  
x x  
Mi da z ola m (I V) 1 m g + Da bi gatra m 7 5 m g + Gi vi n ostat 5 0 m g b.i. d.  
Da y 6  
x x  
Mi da z ola m ( Oral) 2. 5 m g + Gi vi n ostat 5 0 m g b.i. d.  
Da y 7  
x x  
Gi vi n ostat 5 0 m g b.i. d.  
Da ys 8  –  1 6  
x x  
Mi da z ola m (I V) 1 m g + Da bi gatra m 7 5 m g + Gi vi n ostat 5 0 m g b.i. d.  
Da y 1 7  
x x  
Mi da z ola m ( Oral) 2. 5 m g + Gi vi n ostat 5 0 m g b.i. d.  
Da y 1 8  
x x  
Gi vi n ostat 5 0 m g  
Da y 1 9  
x x  
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 3  of 1 3 7  
T a ble 1. D.  S u m m ar y of S u bje ct s Dis p ositi o n  –  P art 1  
 
Dis p ositi o n  
N u m b er of 
S u bj ects  
 
R a n d o mize d  
x x  
Disc o nti n ue d after First D osi n g  
x x  
    Re as o n  
 
- < Re as o n >  
x x  
P art 1 S af et y A n al ysis P o p ul ati o n  
x x  
P art 1 P h ar m ac o ki n etic A n al ysis P o p ul ati o n  
x x  
P art 1 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 ns  
 
    I n hi bit or y Effe ct of Gi vi n ost at o n Mi d az ol a m I V A n al ysis P o p ul ati o n  
x x  
    I n hi bit or y Effe ct of Gi vi n ost at o n Or al Mi d az ol a m A n al ysis P o p ul ati o n  
x x  
    I n hi bit or y Effe ct of Gi vi n ost at o n D a bi g atr a n A n al ysis P o p ul ati o n  
x x  
    I n d uci n g Effect of Gi vi n ost at o n Mi d az ol a m I V A n al ysis P o p ul ati o n  
x x  
    I n d uci n g Effect of Gi vi n ost at o n Or al Mi d az ol a m A n al ysis P o p ul ati o n  
x x  
    I n d uci n g Effect of Gi vi n ost at o n D a bi g atr a n A n al ysis P o p ul ati o n  
x x  
C o m plet e d P art 1 of St u d y  
x x  
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 4  of 1 3 7  
T a ble 1. E.  
  
 
 
T a ble 1. E. 1.  S u m m ar y of De m o gr a p hic D at a of P h ar m ac o ki netic A n al ysis P o p ul ati o ns  
 
 
 
 
De m o gr a p h y  
P ar a meter  
P h ar m ac o ki n etic A n al ysis 
P o p ul ati o n  
 
 
A ge ( ye ars)  
n  
x x  
 
Mea n  
x x  
 
S D  
x x. x  
 
Me dia n  
x x  
 
Mi ni m u m  
x x  
 
Ma xi m u m  
x x  
S e x, n ( %)  
n  
x x  
 
Male  
x x ( x x. x %)  
 
Fe male  
x x ( x x. x %)  
Ra c e, n ( %)  
n  
x x  
 
< Ra c e >  
x x ( x x. x %)  
W ei g ht ( k g)  
n  
x x  
 
Mea n  
x x. x  
 
S D  
x x. x x  
 
Me dia n  
x x. x  
 
Mi ni m u m  
x x. x  
 
Ma xi m u m  
x x. x  
Hei g ht ( c m)  
n  
x x  
 
Mea n  
x x x  
 
S D  
x x. x  
 
Me dia n  
x x x  
 
Mi ni m u m  
x x x  
 
Ma xi m u m  
x x x  
B o d y Mass I n de x ( k g/ m 2) 
n  
x x  
 
Mea n  
x x. x  
 
S D  
x x. x x  
 
Me dia n  
x x. x  
 
Mi ni m u m  
x x. x  
 
Ma xi m u m  
x x. x  
 
 
n –  N u m ber of S u bjects; S D –  Sta n dar d De viati o n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 5  of 1 3 7  
T a ble 1. E. 2.  S u m m ar y of De m o gr a p hic D at a of Dr u g -Dr u g I nter 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 ns –  Effect of Gi vi n ost at o n Mi d az ol a m I V 1 1 
 
T a ble 1. E. 3.  S u m m ar y of De m o gr a p hic D at a of Dr u g -Dr u g I nter 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 ns –  Effect of Gi vi n ost at o n Or al Mi d az ol a m
1 1 
 
T a ble 1. E. 4.  S u m m ar y of De m o gr a p hic D at a of Dr u g -Dr u g I nter 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 ns –  Effect of Gi vi n ost at o n D a bi g atr a n Ete xil ate  1 1 
 
 
1 1 T o be ge ner ate d as f oll o ws:  
  
 
De m o gr a p h y  
P ar a meter  
I n hi bit or y E ffe ct 
I n d uci n g Eff ect  
 
A ge ( ye ars) 
n  
x x  
x x  
 
Mea n  
x x  
x x  
 
S D  
x x. x  
x x. x  
 
Me dia n  
x x  
x x  
 
Mi ni m u m  
x x  
x x  
 
Ma xi m u m  
x x  
x x  
S e x, n ( %)  
n  
x x  
x x  
 
Male  
x x ( x x. x %)  
x x ( x x. x %)  
 
Fe male  
x x ( x x. x %)  
x x ( x x. x %)  
Ra c e, n ( %)  
n  
x x  
x x  
 
< Ra c e >  
x x ( x x. x %)  
x x ( x x. x %)  
W ei g ht ( k g)  
n  
x x  
x x  
 
Mea n  
x x. x  
x x. x  
 
S D  
x x. x x  
x x. x x  
 
Me dia n  
x x. x  
x x. x  
 
Mi ni m u m  
x x. x  
x x. x  
 
Ma xi m u m  
x x. x  
x x. x  
Hei g ht ( c m)  
n  
x x  
x x  
 
Mea n  
x x x  
x x x  
 
S D  
x x. x  
x x. x  
 
Me dia n  
x x x  
x x x  
 
Mi ni m u m  
x x x  
x x x  
 
Ma xi m u m  
x x x  
x x x  
B o d y Mass I n de x ( k g/ m 2) n  
x x  
x x  
 
Mea n  
x x. x  
x x. x  
 
S D  
x x. x x  
x x. x x  
 
Me dia n  
x x. x  
x x. x  
 
Mi ni m u m  
x x. x  
x x. x  
 
Ma xi m u m  
x x. x  
x x. x  
 
n –  N u m ber of S u bjects; S D –  Sta n dar d De viati o n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 6  of 1 3 7  
T a ble 1. F.  
 
 
T a ble 1. F. 1.  Mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effect) 1 2 
 
 
T a ble 1. F. 2.  1 -H y d r o x y mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a mete rs F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effec t) 1 2 
 
 
1 2 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
Mi d az ol a m I V Al o n e  
( D a y 1) 
( n = x x ) 
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6)  
( n = x x ) 
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %) 
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %) 
[ x x. x x –  x x. x x]  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
λ z ( 1/ h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
t½  ( h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( G m e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis  a n d 9 5 % c o nfi de nce i nter val 
of t he G m e a n  wit hi n s q uare brac kets  
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or P art 1 
P h ar m ac oki netic A n alysis P o p ul ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d f or o ne 
or m ore s u bje cts i n t he P art 1 P h ar m ac oki n etic A n alysis P o p ul ati o n, t he p h ar m ac oki netic p ar a meter s h o ul d 
be f oll o we d by t he # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a meter(s) > , n =x x , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct <, a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 7  of 1 3 7  
T a ble 1. G.  
 
 
T a ble 1. G. 1.  Mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect ) 1 3 
 
 
T a ble 1. G. 2.  1 -H y d r o x y mi d az ol a m: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a mete rs F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect) 1 3 
 
 
1 3 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
Or al Mi d az ol a m Al o n e 
( D a y 2) 
( n = x x ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 7)  
( n = x x ) 
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 8)  
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %) 
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
λ z ( 1/ h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %) 
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
t½  ( h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( G m e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis a n d 9 5 % c o nfi de nce i nter val 
of t he G m e a n  wit hi n s q uare brac kets  
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d 
f or o ne or m ore s u bje cts i n t he P art 1 P h ar m acoki netic A n alysis P o p ul ati o n, t he p h ar m ac oki netic p ar a meter 
s h o ul d be f oll o we d by t he # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a meter(s) > , n =xx , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct <, a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 8  of 1 3 7  
T a ble 1. H.  
 
T a ble 1. H. 1.  T ot al D a bi g atr a n: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e  
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect) 1 4 
 
 
T a ble 1. H. 2.  Fr ee D a bi g atr a n: S u m m ar y St atistics  of t h e P h ar m ac o ki n etic P ar a meters F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e  
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y  Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect) 1 4 
 
 
1 4 T o be ge ner ate d as f oll o ws:  
P ar a m et er ( u nit)  
D a bi g atr a n Ete xil ate Al o ne 
( D a y 1) 
( n = x x ) 
D a bi g atr a n Ete xil ate  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6)  
( n = x x ) 
D a bi g atr a n Ete xil ate  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
( n = x x ) 
 
C m a x  (< u nits C > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
T m a x  ( h) 
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
x x. x x ( x x. x x –  x x. x x)  
A U C 0 -t (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
A U C 0 - (< u nits A > ) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
% A U C
e xtra p ( %) 
x x. x x ( x x. x %) 
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
λ z ( 1/ h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
t½  ( h) 
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
x x. x x ( x x. x %)  
[ x x. x x –  x x. x x]  
 
n  –  N u m ber  of  S u bjects  
Val ues are ge o metric mea n ( G m e a n ) wit h ge o metric c oefficie nt of variati o n ( G C V %) wit hi n pare nt hesis a n d 9 5 % c o nfi de nce i nter val 
of t he G m e a n  wit hi n s q uare brac kets  
T m a x  val ues  are me dia n  wit h  ra n ge bet wee n  pare nt heses  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he s u m m ary st atistics of t he p h ar m ac oki netic p ar a meters c alc ul ate d f or t he 
P art 1 P h ar m ac oki netic A n alysis P o p u l ati o n. I n c ase a p h ar m ac oki netic p ar a meter c o ul d n ot be c alc ul ate d 
f or o ne or m ore s u bje cts i n t he P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n, t he p h ar m ac oki netic p ar a meter 
s h o ul d be f oll o we d by t he # sy m b ol a n d acc o m p a nie d by a f o ot n ote: ‘ # F or < P ar a mete r(s) >, n =xx , f or 
<I nvesti g ati o n al Pr o d uct >  pr o d uct <, a n d n =xx, f or <I nv esti g ati o n al Pr o d uct > pr o d uct > ’. 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  6 9  of 1 3 7  
T a ble 1.I.  
  
  
   
 
  
 
   
 
 
T a ble 1.I. 1.  Mi d az ol a m: P ote nti al I n hi bit or y Effe ct 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 I V: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t  1 5 
 
 
T a ble 1.I. 2.  1 -H y d r o x y mi d az ol a m: P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
Mi d az ol a m I V: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 4 
 
 
1 5 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Mi d az ol a m I V  
Al o n e ( D a y 1)  
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Mi daz ola m I V C o -A d mi nistere d wit h Gi vi n ostat ( Da y 6) a n d t he 
Ge o metric L S mea ns of Mi daz ola m of I V Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of mi d az ol a m I V, perf or me d o n t he P ote nti al I n hi bit ory Effe ct of Givi n ost at 
o n Mi d az ol a m I V A n alysis P o p ul at i o n. 
  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 0  of 1 3 7  
T a ble 1. J.  
  
  
   
 
  
 
   
 
 
T a ble 1. J. 1.  Mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
Mi d az ol a m I V: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 6 
 
 
T a ble 1. J. 2.  1 -H y d r o x y mi d az ol a m: P ote nti al I n d u ci n g 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 I V: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 6 
 
 
1 6 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Mi d az ol a m I V  
Al o n e ( D a y 1)  
Mi d az ol a m I V  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Mi daz ola m I V C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 7) a n d t he 
Ge o metric L S mea ns of Mi daz ola m of I V Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will  prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of mi d az ol a m I V, perf or me d o n t he P ote nti al I n d ucti o n Effect of Givi n ost at 
o n Mi d az ol a m I V A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 1  of 1 3 7  
T a ble 1. K.  
  
  
   
 
  
 
   
 
 
T a ble 1. K. 1.  Mi d az ol a m: P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t he P h ar m ac o ki n etics of Or al 
Mi d az ol a m: T ot al I ntr a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are M e a ns, Ge o metric 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 1 7 
 
 
T a ble 1. K. 2.  1 -H y d r o x y mi d az ol a m: P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics 
of Or al Mi d az ol a m: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 7 
 
 
1 7 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Or al Mi d az ol a m  
Al o n e ( D a y 2)  
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 7)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Oral Mi daz ola m C o -A d mi nistere d wit h Gi vi n ostat ( Da y 7) a n d t he 
Ge o metric L S mea ns of Oral Mi daz ola m Al o ne ( Da y 2)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of or al mi d az ol a m , perf or me d o n t he P ote nti al I n hi bit ory Effe ct of 
Givi n ost at o n Or al Mi d az ol a m A n alysis P o p ul ati o n.  
  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 2  of 1 3 7  
T a ble 1. L.  
  
  
   
 
  
 
   
 
 
T a ble 1. L. 1.  Mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t h e P h ar m ac o ki netics of Or al 
Mi d az ol a m: T ot al I ntr a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are M e a ns, Ge o metr ic 
Le ast S q u are Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d A U C 0 -t 1 8 
 
 
T a ble 1. L. 2.  1 -H y d r o x y mi d az ol a m: P ote nti al I n d u ci n g Effect of Gi vi n ost at o n t he P h ar m ac o ki n etics of 
Or al Mi d az ol a m: T ot al I ntr a -S u bject C oefficie nt of V ari ati o n, Ge o metric Le ast S q u are Me a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 8 
 
 
1 8 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
Or al Mi d az ol a m  
Al o n e ( D a y 2)  
Or al Mi d az ol a m  
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 8)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Oral Mi daz ola m C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 8) a n d t he 
Ge o metric L S mea ns of Oral Mi daz ola m Al o ne ( Da y 2)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of or al mi d az ol a m , perf or me d o n t he P ote nti al I n d ucti o n Effe ct of 
Givi n ost at o n Or al Mi d az ol a m A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 3  of 1 3 7  
T a ble 1. M.  
  
  
   
 
  
 
   
 
 
T a ble 1. M. 1.  T ot al D a bi g atr a n : P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
D a bi g at r a n Ete xil ate: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 9 
 
 
T a ble 1. M. 2.  Fr ee D a bi g atr a n : P ote nti al I n hi bit or y Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
D a bi g at r a n Ete xil ate: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etr ic Le ast S q u ar e Me a ns R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 1 9 
 
 
1 9 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
D a bi g atr a n Ete xil ate 
Al o n e ( D a y 1)  
D a bi g atr a n Ete xil ate 
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 6)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Da bi gatra n Ete xilate C o -A d mi nistere d wit h Gi vi n ostat ( Da y 6) a n d t he 
Ge o metric L S mea ns of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his  t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n hi bit ory effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of d a bi g atr a n ete xil ate , perf or me d o n t he P ote nti al I n hi bit ory Effe ct of 
Givi n ost at o n D a bi g atr a n Ete xil ate A n alysis P o p ul ati o n.  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 4  of 1 3 7  
T a ble 1. N.  
  
  
   
 
  
 
   
 
 
T a ble 1. N. 1.  T ot al D a bi g atr a n : P ote nti al I n d u cti o n Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
D a bi g at r a n Ete xil ate: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 2 0 
 
 
T a ble 1. N. 2.  Fr ee D a bi g atr a n : P ote nti al I n d u cti o n Effe ct of Gi vi n ost at o n t h e P h ar m ac o ki netics of 
D a bi g at r a n Ete xil ate: T ot al I ntr a -S u bje ct C oefficie nt of V ari ati o n, Ge o metric Le ast S q u ar e M e a ns, 
Ge o m etric Le ast S q u ar e Me a ns  R ati o  a n d C orr es p o n di n g 9 0 % C o nfi de nc e I nter v al  f or C m a x  a n d 
A U C 0 -t 2 0 
 
 
2 0 T o be ge ner ate d as f oll o ws:  
 
  
Ge o metric L S me a ns  
  
  
P ar a m et er  
T ot al  
I S C V % 
D a bi g atr a n Ete xil ate 
Al o n e ( D a y 1)  
D a bi g atr a n Ete xil ate 
C o -A d mi nister e d wit h 
Gi vi n ost at ( D a y 1 7)  
G M R ( %)  
9 0 % CI  
 
C m a x  
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
A U C 0 -t 
x x. x  
x x. x x  
x x. x x  
x x. x x  
x x. x x –  x x. x x  
 
Ge o metric L S mea ns  val ues  are gi ve n  i n < u nits C >  f or C m a x  a n d < u nits A >  f or A U C  
G M R c orres p o n ds t o t he rati o of t he Ge o metric L S mea ns of Da bi gatra n Ete xilate C o -A d mi nistere d wit h Gi vi n ostat ( Da y 1 7) a n d t he 
Ge o metric L S mea ns of Da bi gatra n Ete xilate Al o ne ( Da y 1)  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
N ote: T his t a ble will prese nt t he res ults of t he a n alysis of t he p ote nti al i n d ucti o n effe ct of or al givi n ost at o n 
t he si n gle-d ose p h ar m ac oki netics of d a bi g atr a n ete xil ate , perf or me d o n t he P ote nti al I n d ucti o n Effect of 
Givi n ost at o n D a bi g atr a n Ete xil ate A n alysis P o p ul ati o n.  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 5  of 1 3 7  
T a ble 1. O.   
T a ble 1. O. 1.  S u m m ar y of Tr e at me nt -E me r ge nt A d verse E ve nts ( T E A Es) –  All T E A Es  
 
 
M i d az ol a m 
( n =  x x ) 
D a bi g atr a n  
( n =  x x ) 
Gi vi n ost at  
( n = x x ) 
T ot al  
( N =  x x ) 
 N u m b er of S u bjects { Nr. of T E A Es} 
( % of S u bj ects) 
x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %) x x { x x} ( x x %)  
 
M e d D R A  
S yste m  Or g a n  Cl ass  ( S O C) 
   Pr ef err e d  Ter m  ( P T) 
 < T E A Es S O C >  
x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  
   < T E A Es S O C >  
x x { x x } ( x x %)  x x { x x } ( x x %)  x x { x x } ( x x %)  x x { x x } ( x x %)  
 
 
 
 
 
<I nsert as ma n y r o ws as de e me d 
ne c essar y >  
 
 
 
 
  
S e verit y  
   Mil d  
x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  
   M o d er ate  
x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  
   S e ver e  
x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  x x { x x} ( x x %)  
 Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 6  of 1 3 7  
T a ble 1. O. 2.  S u m m ar y of Tr e at me nt -E me r ge nt A d verse E ve nts ( T E A Es) –  Dr u g -R el ate d  T E A Es  
 
Tr e at me nt Gr o u ps  
S u bstr ates Al o n e   
( n = x x ) 
Ste a d y -S t ate 
B uil d -U p   
( n =  x x ) 
 
Tr e at me nt I de ntific ati o n   
M i d az ol a m D a bi g atr a n  
T ot al  
Gi vi n ost at  
 
 
 
 
 
 
N u m b er of S u bjects { Nr. of T E A Es} ( % of 
S u bj ects)  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
 
 
M e d D R A  
S yste m  Or g a n  Cl ass  ( S O C) 
   Pr ef err e d  Ter m  ( P T) 
< T E A Es S O C >  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
 
   < T E A Es S O C >  
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
 
 
 
 
 
 
<I nsert as ma n y r o ws as dee me d nec essar y >  
 
 
 
 
 
 
 
 
 
 
 
S e verit y  
   Mil d  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
   M o d er ate  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
   S e ver e  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
 
 
 
 
 
 
 
Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities  
Dr u g -relate d T E A Es  are t h ose w hic h ca usalit y was assesse d as “ Reas o na bl y P ossi ble” b y t he I n vesti gat or.  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 7  of 1 3 7  
T a ble 1. O. 3.  S u m m ar y of Tr e at me nt -E me r ge nt A d verse E ve nts ( T E A Es) –  I n hi biti o n/I n d u cti o n Dr u g -
R el at e d  T E A Es  
 
Tr e at me nt Gr o u ps  
I n hi biti o n Effect  
( n = x x ) 
I n d ucti o n Effect  
( n = x x ) 
Tr e at me nt 
I d e ntific ati o n  
M i d az ol a m D a bi g atr a n  Gi vi n ost at  T ot al  M i d az ol a m D a bi g atr a n  Gi vi n ost at  T ot al  
 
 
 
 
 
 
 
N u m b er of 
S u bj ects { Nr. of 
T E A Es} ( % of 
S u bj ects)  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
 
M e d D R A  
S yste m  Or g a n  Cl ass  ( S O C) 
   Pr ef err e d  Ter m  ( P T) 
 
< T E A Es S O C >  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
   < T E A Es S O C >  
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x 
{ x x } 
( x x %) 
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x { x x } 
( x x %) 
x x 
{ x x } 
( x x %) 
 
 
 
 
 
 
 
 
 
 
 
 
 
<I nsert as ma n y 
r o ws as dee me d 
ne c essar y >  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S e verit y  
 
   Mil d  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
   M o d er ate  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
   S e ver e  
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
x x { x x} 
( x x %) 
 
 
 
 
 
 
 
Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities  
Dr u g -relate d T E A Es  are t h ose w hic h ca usalit y was assesse d as “ Reas o na bl y P ossi ble” b y t he I n vesti gat or.  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 8  of 1 3 7  
  
 
 
 
Fi g u r e 1. A. 1.  Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V 
a n d  Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect)  –  Li ne ar 
S c ale  
 
Fi g u r e 1. A. 2.  Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o ne ( D a y 1) a n d C o -A d mi nistr at i o n of Mi d az ol a m I V 
a n d  Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect)  –  S e mi -
L o g arit h mic S c ale  
 
 
 
 
Fi g u r e 1. B. 1.  1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti m e 
Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of 
Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ot e nti al I n d uci n g 
Eff e ct)  –  Li n e ar Sc ale  
 
Fi g u r e 1. B. 2.  1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n V ers us Ti m e 
Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of 
Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ot e nti al I n d uci n g 
Eff e ct)  –  S e mi -L o g arit h mic Sc ale  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  7 9  of 1 3 7  
 
 
 
Fi g u r e 1. C. 1.  Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al 
Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 8 –  P ot e nti al I n d ucin g  
Eff e ct)  –  Li n e ar Sc ale  
 
Fi g u r e 1. C. 2.  Mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al 
Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 8 –  P ot e nti al I n d uci n g 
Eff e ct)  –  S e mi -L o g arit h mic Sc ale  
 
 
 
 
Fi g u r e 1. D. 1.  1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti m e 
Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al 
Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 8 –  P ot e nti al I n d uci n g 
Eff e ct)  –  Li n e ar Sc ale  
 
Fi g u r e 1. D. 2.  1 -H y d r o x y mi d az ol a m: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti m e 
Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al 
Mi d az ol a m a n d Gi vi n ost at ( D a y 7 –  P ot e nti al I n hi bit or y Effect, a n d D a y 1 8 –  P ot e nti al I n d uci n g 
Eff e ct)  –  S e mi -L o g arit h mic Sc ale  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 0  of 1 3 7  
 
 
 
 
Fi g u r e 1. E. 1.  T ot al D a bi g atr a n: Ge o metric M e a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me 
Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ot e nti al 
I n d uci n g Effect)  –  Li ne ar S c ale  
 
Fi g u r e 1. E. 2.  T ot al D a bi g atr a n: Ge o metric M e a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me 
Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ot e nti al 
I n d uci n g Eff ect)  –  S e mi -L o g arit h mic S c ale  
 
 
 
 
 
Fi g u r e 1. F. 1.  Fr ee D a bi g atr a n: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n 
Et e xil at e a n d Gi vi n o st at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d u ci n g Eff ect)  –  
Li n e ar Sc ale  
 
Fi g u r e 1. F. 2.  Fr ee D a bi g atr a n: Ge o metric Me a n ( 9 5 % CI) Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles 
F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n 
Et e xil at e a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d u ci n g Eff ect)  –  
S e mi -L o g arit h mic Sc ale  
 
 
N ote:  T o be pr o d uc e d ac c or di n g t o t he g ui deli nes est a blis he d f or t he Sy n o psis Fi g ure.  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 1  of 1 3 7  
A. 3.  
T a bles, Fi g u res a n d Gr a p hs Refer re d t o B ut N ot I ncl u d e d i n t h e Te xt ( S e cti o n 1 4 of C S R)  
 
A. 3. 1.  
P art 1  
 
1 4. 1.  P A R T 1  
 
1 4. 1. 1.  D E M O G R A P HI C D A T A  –  P A R T 1  
 
1 4. 1. 1. 1.  De m o gr a p hic D at a –  P art 1 S afet y A n al ysis P o p ul ati o n  2 
 
1 4. 1. 1. 2.  De m o gr a p hic D at a –  P art 1 P h ar m ac o ki netic A n al ysis P o p ul ati o n  2 
 
1 4. 1. 1. 3.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n hi bit or y Effect of Gi vi n ost at o n Mi d az ol a m I V 2 
 
1 4. 1. 1. 4.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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  –  I n hi bit or y Effect of Gi vi n ost at o n Or al Mi d az ol a m 2 
 
1 4. 1. 1. 5.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n hi bit or y Effect of Gi vi n ost at o n D a bi g atr a n 2 
 
1 4. 1. 1. 6.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n Mi d az ol a m I V 2 
 
1 4. 1. 1. 7.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n Or al Mi d az ol a m 2 
 
1 4. 1. 1. 8.  De m o gr a p hic D at a –  P art 1 Dr u g -Dr u g I nter 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 –  I n d uci n g Effe ct of Gi vi n ost at o n D a bi g atr a n 2 
 
 
2 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Se x  
R ace  
A ge  
( ye ars) 
Hei g ht  
(c m) 
Wei g ht  
( k g) 
B MI  
( k g/ m2) 
 
< S u bject I D >  
< M ale / 
Fe male >  
< R ace >  
x x  
x x x  
x x. x  
x x. x  
 
 
 
 
 
 
 
<I ns ert as ma n y r o ws as dee me d necessar y >  
 
 
n  
x x  
x x  
x x  
x x  
 
 
M ea n  
x x  
x x x  
x x. x  
x x. x  
 
 
S D  
x x . x 
x x . x 
x x. x x  
x x. x x  
 
 
M e dia n  
x x  
x x x  
x x. x  
x x. x  
 
 
Mi ni m u m  
x x  
x x x  
x x. x  
x x. x  
 
 
M a xi m u m  
x x  
x x x  
x x. x  
x x. x  
 
B MI  –  B o d y  Mass  I n de x; n –  N u m ber of S u bjects; S D –  Sta n dar d De viati o n   
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 2  of 1 3 7  
1 4. 1. 1. 9.  S u bjects Pr e m at ur el y Disc o nti n ue d Afte r First D osi n g  
 
S u bject N o.  
Ti m e of Dis c o nti n u ati o n  
L ast T re at m e nt  
A d mi nistere d  
Re as o n f or Dis c o nti n u ati o n  
 
< S u bject I D >  
< Da y # >  
< Treat me nt >  
< R eas o n >  
 
 
 
 
<I ns ert as ma n y r o ws as dee me d necessar y >  
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 3  of 1 3 7  
1 4. 1. 2.  P H A R M A C O KI N E TI C D A T A  –  P A R T 1  
 
1 4. 1. 2. 1.  De vi ati o ns fr o m Bl o o d S a m pli n g Sc he d ule  
 
1 4. 1. 2. 1. 1.  De vi ati o ns fr o m Bl o o d S a m pli n g Sc he d ule  
 
S u bject N o.  
D a y of 
D os e  
T re at m e nt  
A n al yte  
Pl a n ne d 
Ti m e  
( h: mi n) 
De vi ati o n  
( h: mi n) Re as o n f or De vi ati o n  
 
< S u bject >  
< Da y # >  
< Treat me nt >  
< A nal yte >  < Pla n ne d 
bl o o d 
s a m pli n g 
ti me > 
< De viati o n 
ti me > 
< R eas o n f or de viati o n (e. g. Diffic ult y 
wit h bl o o d s a m pli n g / S u bject 
u na vaila ble at s c he d ule d ti me) >  
 
 
 
 
 
 
 
<I ns ert as ma n y r o ws as dee me d necessar y >  
 
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
1 4. 1. 2. 1. 2.  Missi n g Bl o o d S a m ples  
 
S u bject N o.  
D a y of 
D os e  
T re at m e nt  
A n al yte  
Pl a n ne d Ti m e  
( h: mi n) 
Re as o n f or Missi n g Bl o o d S a m ple  
 
< S u bject I D >  < Da y # >  
< Treat me nt >  
< A nal yte >  
< Pla n ne d bl o o d 
s a m pli n g ti me > 
< R eas o n f or missi n g bl o o d s a m ple >  
 
 
 
 
 
 
<I ns ert as 
ma n y r o ws as 
dee me d 
necess ar y >  
 
 
 
 
 
 
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
1 4. 1. 2. 1. 3.  Ot h er I m p ort a nt Pr ot oc ol De vi ati o ns  
 
S u bject N o.  
D a y of 
D os e  
T re at m e nt  
A n al yte  
C ate g or y  
Des cri pti o n  
 
 
< S u bject I D >  
< Da y # >  
< Treat me nt >  
< A nal yte >  < De viati o n 
cate g or y > 
< Des cri pti o n of de viati o n >  
 
 
 
 
 
 
<I ns ert as ma n y 
r o ws as dee me d 
necess ar y >  
 
 
 
 
 
 
 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 4  of 1 3 7  
1 4. 1. 2. 2.  Pl as m a C o n ce ntr ati o ns  
 
1 4. 1. 2. 2. 1.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) 3 
 
1 4. 1. 2. 2. 2.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
C o -A d mi nistr ati o n of Mi d az ol a m  I V a n d  Gi vi n ost at ( D a y 6) 3 
 
1 4. 1. 2. 2. 3.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7) 3 
 
 
1 4. 1. 2. 2. 4.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o ne ( D a y 1) 3 
 
1 4. 1. 2. 2. 5.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6)  3 
 
1 4. 1. 2. 2. 6.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7 ) 3 
 
 
 
1 4. 1. 2. 2. 7.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) 3 
 
1 4. 1. 2. 2. 8.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 3 
 
1 4. 1. 2. 2. 9.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e ntr ati o ns F oll o wi n g 
C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 3 
 
 
1 4. 1. 2. 2. 1 0.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) 3 
 
1 4. 1. 2. 2. 1 1.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 3 
 
1 4. 1. 2. 2. 1 2.  1 -H y d r o x y mi d az ol a m : I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o nc e nt r ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 3 
 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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  
 
 
 
P a g e  8 5  of 1 3 7  
1 4. 1. 2. 2. 1 3.  T ot al D a bi g atr a n : I n di vi d u al D at a a n d Descri pti ve St atistic s of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate  Al o n e ( D a y 1) 3 
 
1 4. 1. 2. 2. 1 4.  T ot al D a bi g atr a n : I n di vi d u al D at a a n d Descri pti ve St atistics of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d  Gi vi n ost at ( D a y 6) 3 
 
1 4. 1. 2. 2. 1 5.  T ot al D a bi g atr a n : I n di vi d u al D at a a n d Descri pti ve St atistics of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d  Gi vi n ost at ( D a y 1 7) 3 
 
 
1 4. 1. 2. 2. 1 6.  Fr ee  D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o n e ( D a y 1) 3 
 
1 4. 1. 2. 2. 1 7.  Fr ee  D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g C o -A d mi nistr at i o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 6) 3 
 
1 4. 1. 2. 2. 1 8.  Fr ee  D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of Pl as m a C o n ce ntr ati o ns 
F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 1 7) 3 
 
 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  8 6  of 1 3 7  
3 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Pre -d os e  
 Ti m e P ost -D os e ( h)  
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
< S u bject I D >  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
n  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
G me a n  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
A me a n  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
G S D ( < u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
S D ( < u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
G C V %  
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
C V %  
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
G me a n  9 5 % CI L o wer  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
G me a n  9 5 % CI U p per  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
A me a n  9 5 % CI L o wer  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
A me a n  9 5 % CI U p per  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
M e dia n  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
Mi ni m u m  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
M a xi m u m  (< u nits C > ) 
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
n –  N u m ber of S u bjects; G m e a n –  Ge o metric Mea n; A m e a n –  Arit h metic Mea n; G S D –  Ge o metric Sta n dar d De viati o n; S D –  Sta n dar d De viati o n; G C V % –  Ge o metric C oefficie nt of 
Variati o n; C V % –  C oefficie nt of Variati o n; G m e a n  9 5 % CI L o wer –  L o wer Li mit of t he 9 5 % C o nfi de nce I nter val f or t he Ge o metric Mea n; G m e a n  9 5 % CI U p per –  U p per Li mit of t he 
9 5 % C o nfi de nce I nter val f or t he Ge o metric Mea n; A m e a n  9 5 % CI L o wer –  L o wer Li mit of t he 9 5 % C o nfi de nce I nter val f or t he Arit h metic Mea n; A m e a n  9 5 % CI U p per –  U p per Li mit 
of t he 9 5 % C o nfi de nce I nter val f or t he Arit h metic Mea n.  
B L Q  –  Bel o w  t he Li mit  of  Q ua ntificati o n  ( L L O Q = < L L O Q >  < u nits C > ) of  t he assa y (ta ke n as missi n g f or t he calc ulati o n of l o g-tra nsf or me d statistics a n d as zer o f or t he calc ulati o n 
of t he re mai ni n g s u m mar y statistics)  
N D –  N ot D o ne  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T h ese  t a bles will prese nt t he i n divi d u al d at a a n d descri ptiv e  st atistics of t he pl as m a c o nc e ntr ati o ns  of t he  P art 1 P h ar m ac oki netic A n alysis 
P o p ul ati o n.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  8 7  of 1 3 7  
1 4. 1. 2. 3.  P h ar m ac o ki n etic P ar a meters  
1 4. 1. 2. 3. 1.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki netic P ar a meters  
F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o ne ( D a y 1) 3 
1 4. 1. 2. 3. 2.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki netic P ar a met ers  
F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6) 3 
1 4. 1. 2. 3. 3.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve S t atistics of P h ar m ac o ki netic P ar a meters  
F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7) 3 
1 4. 1. 2. 3. 4.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y  1) 3 
1 4. 1. 2. 3. 5.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6) 3 
1 4. 1. 2. 3. 6.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7) 3 
1 4. 1. 2. 3. 7.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki netic P ar a met ers  
F oll o w i n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) 3 
1 4. 1. 2. 3. 8.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki netic P ar a met ers  
F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 3 
1 4. 1. 2. 3. 9.  Mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St a tistics of P h ar m ac o ki netic P ar a met ers  
F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 3 
1 4. 1. 2. 3. 1 0.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) 3 
1 4. 1. 2. 3. 1 1.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 3 
1 4. 1. 2. 3. 1 2.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 3 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  8 8  of 1 3 7  
1 4. 1. 2. 3. 1 3.  T ot al D a bi g atr a n: I n di vi d u al D at a a n d Descri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et e rs F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) 3 
1 4. 1. 2. 3. 1 4.  T ot al D a bi g atr a n: I n di vi d u al D at a a n d Descri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 6) 3 
1 4. 1. 2. 3. 1 5.  T ot al D a bi g atr a n: I n di vi d u al D at a a n d Descri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 1 7) 3 
1 4. 1. 2. 3. 1 6.  Fr ee D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) 3 
1 4. 1. 2. 3. 1 7.  Fr ee D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 6) 3 
1 4. 1. 2. 3. 1 8.  Fr ee D a bi g atr a n: I n di vi d u al D at a a n d Desc ri pti ve St atistics of P h ar m ac o ki n etic 
P ar a m et ers  F oll o wi n g C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 1 7) 3 
4 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
C m a x  
(< u nits C > ) 
T m a x  
( h) 
A U C 0 -t 
(< u nits A > ) 
A U C 0 - 
(< u nits A > ) 
% A U C
e xtr a p 
( %) 
λ z 
( 1/ h) 
t1/ 2  
( h) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
n  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
G me a n  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
A me a n  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
G S D  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
S D  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
G C V %  
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
C V %  
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
x x. x
G me a n  9 5 % CI L o wer  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
G me a n  9 5 % CI U p per  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
A me a n  9 5 % CI L o wer  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
A me a n  9 5 % CI U p per  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
M e dia n  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
Mi ni m u m  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
M a xi m u m  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x. x x x
x x. x x
n –  N u m ber of S u bjects; G m e a n –  Ge o metric Mea n; A m e a n –  Arit h metic Mea n; G S D –  Ge o metric Sta n dar d De viati o n; S D –  Sta n dar d 
De viati o n; G C V % –  Ge o metric C oefficie nt of Variati o n; C V % –  C oefficie nt of Variati o n; G m e a n  9 5 % CI L o wer –  L o wer Li mit of t he 
9 5 % C o nfi de nce I nter val f or t he Ge o metric Mea n; G m e a n  9 5 % CI U p per –  U p per Li mit of t he 9 5 % C o nfi de nce I nter val f or t he 
Ge o metric Mea n; A
m e a n  9 5 % CI L o wer –  L o wer Li mit of t he 9 5 % C o nfi de nce I nter val f or t he Arit h metic Mea n; A m e a n  9 5 % CI U p per 
– U p per Li mit of t he 9 5 % C o nfi de nce I nter val f or t he Arit h metic Mea n.
N C  –  N ot  Calc ulate d
Pr o gr a m:  < S A S Pr o gra m >
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >
N ote: T hese  t a bles will prese nt t he i n divi d u al d at a a n d descri ptiv e st atistics of t he p h ar m ac oki netic 
p ar a meters c alc ul ate d f or P art 1 P h ar m ac oki netic A n alysis P o p ul ati o n.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  8 9  of 1 3 7  
1 4. 1. 2. 3. 1 9.  Mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-Mi d az ol a m I V 
Al o n e ( D a y 1)  I n di vi d ual R ati os f or Cm a x  5 
1 4. 1. 2. 3. 2 0.  Mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-Mi d az ol a m I V 
Al o n e ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 5
1 4. 1. 2. 3. 2 1.  1 -H y d r o x y mi d az ol a m : Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-
Mi d az ol a m I V Al o n e ( D a y 1) I n di vi d u al R ati os f or Cm a x  5 
1 4. 1. 2. 3. 2 2.  1 -H y d r o x y mi d az ol a m : Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-
Mi d az ol a m I V Al o n e ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 5
5 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Mi d az ol a m I V 
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 6)  
(< u nits > ) 
Mi d az ol a m I V Al o ne 
( D a y 1) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 4. 1. 2. 3. 2 3.  Mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-Mi d az ol a m I V 
Al o n e ( D a y 1) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 2 4.  Mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-Mi d az ol a m I V 
Al o n e ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 6
1 4. 1. 2. 3. 2 5.  1 -H y d r o x y mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-
Mi d az ol a m I V Al o n e ( D a y 1) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 2 6.  1 -H y d r o x y mi d az ol a m: Mi d az ol a m I V C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-
Mi d az ol a m I V Al o n e ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 6
6 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Mi d az ol a m I V 
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 1 7)  
(< u nits > ) 
Mi d az ol a m I V Al o ne 
( D a y 1) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 0  of 1 3 7  
1 4. 1. 2. 3. 2 7.  Mi d az ol a m: Or al Mi d az ol a m  C o -A d mi niste r e d a n d  Gi vi n ost at ( D a y 7 )-t o-Or al Mi d az ol a m  
Al o n e ( D a y 2 ) I n di vi d u al R ati os f or Cm a x  5 
1 4. 1. 2. 3. 2 8.  Mi d az ol a m: Or al Mi d az ol a m  C o -A d mi niste r e d a n d  Gi vi n ost at ( D a y 7 )-t o-Or al Mi d az ol a m  
Al o n e ( D a y 2 ) I n di vi d u al R ati os f or A U C0 -t 5
1 4. 1. 2. 3. 2 9.  1 -H y d r o x y mi d az ol a m: Or al Mi d az ol a m  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 7 )-t o-Or al 
Mi d az ol a m  Al o n e ( D a y 2 ) I n di vi d u al R ati os f or C m a x  5 
1 4. 1. 2. 3. 3 0.  1 -H y d r o x y mi d az ol a m: Or al Mi d az ol a m  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 7 )-t o-Or al 
Mi d az ol a m  Al o n e ( D a y 2 ) I n di vi d u al R ati os f or A U C0 -t 5
5 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Or al Mi d az ol a m  
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 7 ) 
(< u nits > ) 
Or al Mi d az ol a m  Al o ne 
( D a y 2 ) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 4. 1. 2. 3. 3 1.  Mi d az ol a m: Or al Mi d az ol a m  C o -A d mi niste r e d a n d  Gi vi n ost at ( D a y 1 8 )-t o-Or al 
Mi d az ol a m  Al o n e ( D a y 2 ) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 3 2.  Mi d az ol a m: Or al Mi d az ol a m  C o -A d mi niste r e d a n d  Gi vi n ost at ( D a y 1 8)-t o-Or al 
Mi d az ol a m Al o n e ( D a y 2) I n di vi d u al R ati os f or A U C0 -t 6
1 4. 1. 2. 3. 3 3.  1 -H y d r o x y mi d az ol a m: Or al Mi d az ol a m  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 1 8 )-t o-Or al 
Mi d az ol a m  Al o n e ( D a y 2 ) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 3 4.  1 -H y d r o x y mi d az ol a m: Or al Mi d az ol a m  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 1 8 )-t o-Or al 
Mi d az ol a m  Al o n e ( D a y 2 ) I n di vi d u al R ati os f or A U C 0 -t 6
6 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
Or al Mi d az ol a m  
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 1 8 ) 
(< u nits > ) 
Or al Mi d az ol a m  Al o ne 
( D a y 2 ) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 1  of 1 3 7  
1 4. 1. 2. 3. 3 5.  T ot al D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 6) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or Cm a x  5 
1 4. 1. 2. 3. 3 6.  T ot al D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 6) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 5
1 4. 1. 2. 3. 3 7.  Fr ee D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1)  I n di vi d u al R ati os f or Cm a x  5 
1 4. 1. 2. 3. 3 8.  Fr ee D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 6) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 5
5 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
D a bi g atr a n Ete xil ate  
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 6)  
(< u nits > ) 
D a bi g atr a n Ete xil ate  Al o ne 
( D a y 1) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 4. 1. 2. 3. 3 9.  T ot al D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 1 7) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 4 0.  T ot al D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 1 7) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 6
1 4. 1. 2. 3. 4 1.  Fr ee D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or Cm a x  6 
1 4. 1. 2. 3. 4 2.  Fr ee D a bi g atr a n : D a bi g atr a n Ete xil ate  C o -A d mi niste re d a n d  Gi vi n ost at ( D a y 1 7) -t o-
D a bi g at r a n Ete xil ate  Al o ne ( D a y 1) I n di vi d u al R ati os f or A U C 0 -t 6
6 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
D a bi g atr a n Ete xil ate  
C o -A d mi nistere d a n d  
Gi vi n ost at ( D a y 1 7)  
(< u nits > ) 
D a bi g atr a n Ete xil ate  Al o ne 
( D a y 1) 
(< u nits > ) 
R ati o  
( %) 
< S u bject I D >  
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 2  of 1 3 7  
1 4. 1. 2. 4.  L o g -Li n e ar Re gressi o n P ar a mete rs f or λ z Esti m ati o n  
1 4. 1. 2. 4. 1.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g A d mi nistr ati o n 
of Mi d az ol a m I V Al o ne ( D a y 1) 6 
1 4. 1. 2. 4. 2.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6)  6 
1 4. 1. 2. 4. 3.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7) 6 
1 4. 1. 2. 4. 4.  1 -H y d r o x y mi d az ol a m : L o g-Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) 6 
1 4. 1. 2. 4. 5.  1 -H y d r o x y mi d az ol a m : L o g-Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6) 6 
1 4. 1. 2. 4. 6.  1 -H y d r o x y mi d az ol a m : L o g-Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7) 6 
1 4. 1. 2. 4. 7.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g A d mi nistr ati o n 
of Or al Mi d az ol a m Al o ne ( D a y 2) 6 
1 4. 1. 2. 4. 8.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 6 
1 4. 1. 2. 4. 9.  Mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 6 
1 4. 1. 2. 4. 1 0.  1 -H y d r o x y mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) 6 
1 4. 1. 2. 4. 1 1.  1 -H y d r o x y mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7) 6 
1 4. 1. 2. 4. 1 2.  1 -H y d r o x y mi d az ol a m: L o g -Li n e ar Re gr essi o n P ar a meters f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8) 6 
1 4. 1. 2. 4. 1 3.  T ot al D a bi g atr a n: L o g -Li n e ar Re gressi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate  Al o ne ( D a y 1) 6 
1 4. 1. 2. 4. 1 4.  T ot al D a bi g atr a n : L o g-Li n e ar Re gressi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d  Gi vi n ost at ( D a y 6) 6 
1 4. 1. 2. 4. 1 5.  T ot al D a bi g atr a n : L o g-Li n e ar Re gressi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d  Gi vi n ost at ( D a y 1 7) 6 
1 4. 1. 2. 4. 1 6.  Fr ee D a bi g atr a n: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z E sti m ati o n F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) 6 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 3  of 1 3 7  
1 4. 1. 2. 4. 1 7.  Fr ee D a bi g atr a n: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 6) 6 
1 4. 1. 2. 4. 1 8.  Fr ee D a bi g atr a n: L o g -Li n e ar Re gr essi o n P ar a mete rs f or λ z Esti m ati o n F oll o wi n g C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate C o -A d mi nister e d a n d  Gi vi n ost at ( D a y 1 7) 6 
6 T o be ge ner ate d as f oll o ws:  
S u bject N o.  
L o wer T LI N  
( h) 
U p per T LI N  
( h) 
N o . of Ti m e P oi nts 
R S Q  
< S u bject I D >  
x x. x x
x x. x x
x x  
x .x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
L o wer  T LI N  –  L o wer  Ti me  P oi nt  Use d  i n Re gressi o n  A nal ysis ; U p per  T LI N  –  U p per  Ti me  P oi nt  Use d  i n Re gressi o n  A nal ysis ; 
R S Q  –  G o o d ness of Fit f or t he Ter mi nal Eli mi nati o n P hase  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 4  of 1 3 7  
1 4. 1. 2. 5.  Pl as m a  C o n ce ntr ati o n  Vers us  Ti me Pr ofiles of All S u bje cts 
1 4. 1. 2. 5. 1.  Mi d az ol a m : Pl as m a  C o n ce ntr ati o n  Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1)  –  Li ne ar S c ale  
1 4. 1. 2. 5. 2.  Mi d az ol a m: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6 ) 
1 4. 1. 2. 5. 3.  Mi d az ol a m: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  C o -
A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7)  
1 4. 1. 2. 5. 4.  1 -H y d r o x y mi d az ol a m : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y  1) –  Li ne ar S c ale  
1 4. 1. 2. 5. 5.  1 -H y d r o x y mi d az ol a m : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  
C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 6)  
1 4. 1. 2. 5. 6.  1 -H y d r o x y mi d az ol a m : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  
C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  Gi vi n ost at ( D a y 1 7)  
1 4. 1. 2. 5. 7.  Mi d az ol a m: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) –  Li n e ar S c ale  
1 4. 1. 2. 5. 8.  Mi d az ol a m: Pl a s m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7)  
1 4. 1. 2. 5. 9.  Mi d az ol a m: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts F oll o wi n g  C o -
A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8)  
1 4. 1. 2. 5. 1 0.  1 -H y d r o x y mi d az ol a m: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) –  Li n e ar S c ale  
1 4. 1. 2. 5. 1 1.  1 -H y d r o x y mi d az ol a m : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g  C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 7)  
1 4. 1. 2. 5. 1 2.  1 -H y d r o x y mi d az ol a m : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bje cts 
F oll o wi n g  C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d  Gi vi n ost at ( D a y 1 8)  
1 4. 1. 2. 5. 1 3.  T ot al D a bi g atr a n : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) –  Li n e ar Sc ale  
1 4. 1. 2. 5. 1 4.  T ot al D a bi g atr a n : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g  
C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 6)  
1 4. 1. 2. 5. 1 5.  T ot al D a bi g atr a n : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g  
C o -A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 1 7)  
1 4. 1. 2. 5. 1 6.  Fr ee D a bi g atr a n : Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) –  Li n e ar Sc ale  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 5  of 1 3 7  
1 4. 1. 2. 5. 1 7.  Fr ee D a bi g atr a n: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g  C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 6)  
1 4. 1. 2. 5. 1 8.  Fr ee D a bi g atr a n: Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles of All S u bjects F oll o wi n g  C o -
A d mi nistr ati o n of D a bi g atr a n Ete xil ate a n d  Gi vi n ost at ( D a y 1 7 ) 
N ote: T hese F i g ures will be e xtr acte d fr o m P h oe nix®  Wi n N o nli n
®  8. 2 or hi g her . 
1 4. 1. 2. 6.  I n di vi d u al Pl as m a  C o nc e ntr ati o n  Vers us  Ti me Pr ofile s 
1 4. 1. 2. 6. 1.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effect)  –  Li n e ar  S c ale  
1 4. 1. 2. 6. 2.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me  Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effect)  –  Se mi -
L o g arit h mic S c ale  
1 4. 1. 2. 6. 3.  1 -H y d r o x y mi d az ol a m : I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e nti al I n d u ci n g Effec t) –  Li n e ar S c ale  
1 4. 1. 2. 6. 4.  1 -H y d r o x y mi d az ol a m : I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Mi d az ol a m I V Al o n e ( D a y 1) a n d C o -A d mi nistr ati o n of Mi d az ol a m I V a n d  
Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ot e n ti al I n d u ci n g Effect)  –  Se mi -
L o g arit h mic S c ale  
1 4. 1. 2. 6. 5.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect)  –  Li n e ar S c ale  
1 4. 1. 2. 6. 6.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect)  –  Se mi -
L o g arit h mic S c ale  
1 4. 1. 2. 6. 7.  1 -H y d r o x y mi d az ol a m : I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P ot e nti al I n d u ci n g Effect ) –  Li n e ar S c ale  
1 4. 1. 2. 6. 8.  1 -H y d r o x y mi d az ol a m : I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of Or al Mi d az ol a m Al o n e ( D a y 2) a n d C o -A d mi nistr ati o n of Or al Mi d az ol a m a n d 
Gi vi n ost at ( D a y 7 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 8 –  P o te nti al I n d u ci n g Effect)  –  Se mi -
L o g arit h mic S c ale  
1 4. 1. 2. 6. 9.  T ot al D a bi g atr a n : I n di vi d u al Pl as m a C o nc e ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e  
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect)  –  Li ne ar 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 6  of 1 3 7  
S c ale  
1 4. 1. 2. 6. 1 0.  T ot al D a bi g atr a n: I n di vi d u al Pl as m a C o nc e ntr ati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e  
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect)  –  S e mi -
L o g arit h mic S c ale  
1 4. 1. 2. 6. 1 1.  Fr ee D a bi g atr a n: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me F oll o wi n g A d mi nistr ati o n 
of D a bi g atr a n Ete xil ate Al o n e ( D a y 1) a n d C o-A d mi nistr ati o n of D a bi g atr a n Ete xil ate  a n d Gi vi n ost at 
( D a y 6 –  P ote nti al I n hi bit or y Effe ct, a n d D a y 1 7 –  P ote nti al I n d uci n g Effe ct)  –  Li ne ar S c ale  
1 4. 1. 2. 6. 1 2.  Fr ee D a bi g atr a n: I n di vi d u al Pl as m a C o n ce ntr ati o n  Vers us  Ti me Pr ofiles F oll o wi n g 
A d mi nistr ati o n of D a bi g atr a n Ete xil ate Al o ne ( D a y 1) a n d C o -A d mi nistr ati o n of D a bi g atr a n Ete xil at e  
a n d Gi vi n ost at ( D a y 6 –  P ote nti al I n hi bit or y Effect, a n d D a y 1 7 –  P ote nti al I n d u ci n g Effect)  –  S e mi -
L o g arit h mic S c ale  
N ote: T hese fi g ures will be e xtr acte d fr o m P h oe nix®  Wi n N o nli n
®  8. 2 or hi g her . A fi g ure will be pr o d uc e d f or 
e ac h s u bject i ncl u de d i n t he p h ar m ac oki netic a n alysis p o p ul ati o n. 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 7  of 1 3 7  
1 4. 1. 3.  S A F E T Y D A T A  –  P A R T 1  
1 4. 1. 3. 1.  A d verse E ve nts  
1 4. 1. 3. 1. 1.  Pr e -Tr e at me nt A d verse E ve nts  
S u bject N o.  
S O C  
Me d D R A P T  
( Re p orte d T er m) 
S A E ?  
( Yes/ N o) 
A d vers e E ve nt D ate a n d Ti m e  
M a xi m al 
Se verit y  
C a us alit y  
Me dic ati o n  
Re q uire d ?  
O utc o m e  
St art  
E n d  
< S u bject 
I D > 
< S O C >  
< T E A E i n M e d D R A P T > 
( < T E A E re p orte d ter m >) 
< Yes / N o >  D D M M M Y Y Y Y -
h h: m m >  
D D M M M Y Y Y Y -
h h m m >  
< M a xi mal 
Se verit y of t he 
A E >  
< C a usalit y of 
t he A E > 
< Yes/ N o >  
< O utc o me of 
t he A E > 
<I ns ert as ma n y r o ws as dee me d necessar y > 
S O C –  S yste m Or ga n Class; Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities ; P T –  Preferre d Ter m; S A E –  Seri o us A d verse E ve nt 
N K  –  N ot  K n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 8  of 1 3 7  
1 4. 1. 3. 1. 2.  Tr e at me nt -E mer ge nt A d verse E ve nts (I)  
S u bject N o.  
D a y of D ose  
T re at m e nt  
S O C  
Me d D R A P T  
( Re p orte d T er m) 
S A E ?  
( Yes/ N o) 
L ast T re at m e nt  
D ate a n d Ti m e  
A d vers e E ve nt D ate a n d Ti m e  
St art  
St art  
< S u bject I D >  
< Da y  # >  
< Treat me nt >  
< S O C >  
< T E A E i n M e d D R A P T > 
( < T E A E re p orte d ter m >) 
< Yes / N o >  
< D D M M M Y Y Y Y 
h h: m m >  
< D D M M M Y Y Y Y 
h h: m m >  
< D D M M M Y Y Y Y 
h h: m m >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
S O C –  S yste m Or ga n Class; Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities ; P T –  Preferre d Ter m; S A E –  Seri o us A d verse E ve nt 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 4. 1. 3. 1. 3.  Tr e at me nt -E mer ge nt A d verse E ve nts (II)  
S u bject N o.  
D a y of D ose  
T re at m e nt  
S O C  
Me d D R A P T  
( Re p orte d T er m) 
M a xi m al Se verit y  
C a us alit y  
Me dic ati o n  
Re q uire d ?  
O utc o m e  
< S u bject I D >  
< Da y  # >  
< Treat me nt >  
< S O C >  
< T E A E i n M e d D R A P T > 
( < T E A E re p orte d ter m >) 
< M a xi mal Se verit y 
of t he T E A E >  
< C a usalit y of t he 
T E A E >  
< Yes/ N o >  
< O utc o me of t he 
T E A E >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
S O C –  S yste m Or ga n Class; Me d D R A –  Me dical Dicti o nar y f or Re g ulat or y Acti vities ; P T –  Preferre d Ter m; S A E –  Seri o us A d verse E ve nt 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  9 9  of 1 3 7  
1 4. 1. 3. 2.  Vit al Si g ns  
1 4. 1. 3. 2. 1.  Descri pti ve St atistics of Vit al Si g ns P ar a meters 9 
1 4. 1. 3. 2. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of Vit al Si g ns P ar a mete rs 
9 
1 4. 1. 3. 2. 3.  S hifts i n Vit al Si g ns P ar a mete rs  1 0 
1 4. 1. 3. 3.  1 2 -Le a d E C G  
1 4. 1. 3. 3. 1.  Descri pti ve St atistics of 1 2 -Le a d E C G P ar a mete rs 9 
1 4. 1. 3. 3. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of 1 2 -Le a d E C G P ar a mete rs 9 
1 4. 1. 3. 3. 3.  S hifts i n 1 2 -Le a d E C G P ar a mete rs 1 0 
1 4. 1. 3. 4.  He m at ol o g y  
1 4. 1. 3. 4. 1.  Descri pti ve St atistics of He m at ol o g y P ar a meters 9 
1 4. 1. 3. 4. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of He m at ol o g y P ar a meters 9 
1 4. 1. 3. 4. 3.  S hif ts i n He m at ol o g y P ar a mete rs 1 0 
1 4. 1. 3. 5.  Bi oc h e mistr y  
1 4. 1. 3. 5. 1.  Descri pti ve St atistics of Bi oc h e mistr y P ar a meters 9 
1 4. 1. 3. 5. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of Bi oc h e mistr y P ar a meters 
9 
1 4. 1. 3. 5. 3.  S hifts i n Bi oc he mistr y P ar a mete rs 1 0 
1 4. 1. 3. 6.  C o a g ul ati o n  
1 4. 1. 3. 6. 1.  Descri pti ve St atistics of C o a g ul ati o n P ar a mete rs 9 
1 4. 1. 3. 6. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of C o a g ul ati o n P ar a meters 
9 
1 4. 1. 3. 6. 3.  S hifts i n C o a g ul ati o n P ar a meters 1 0 
1 4. 1. 3. 7.  Uri n al ysis  
1 4. 1. 3. 7. 1.  Descri pti ve St atistics of Uri n al ysis P ar a mete rs 9 
1 4. 1. 3. 7. 2.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of Uri n al ysis P ar a mete rs 9 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 0  of 1 3 7  
1 4. 1. 3. 7. 3.  S hifts i n Uri n al ysis P ar a meters 1 0 
9 T o be ge ner ate d as f oll o ws:  
P ar a m eter  
T re at m e nt  
St u d y D a y  Pr ot oc ol Ti m e  
n  Me a n  S D  S E  Me di a n  Mi ni m u m  M a xi m u m  
< Para meter ( u nit) >  < Treat me nt >  < Da y >  
< Pr ot oc ol Ti me >  x x  x. x x x  x. x x x  x. x x x  x. x x x  
x. x x x
x. x x x
< Pr ot oc ol Ti me >  
< Pr ot oc ol Ti me >  
< Pr ot oc ol Ti me >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
n  –  n u m ber  of  s u bjects; S D  –  Sta n dar d  De viati o n; S E –  Sta n dar d Err or  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 0 T o be ge ner ate d as f oll o ws:  
P ar a m eter  
St u d y D a y  
Pr ot oc ol Ti m e  
Cl assific ati o n  
Nr. of S u bjects  
B as eli ne  
P ost -B as eli ne 
Ass ess m e nt  
< Para meter ( u nit) >  < Da y >  
< Pr ot oc ol Ti me >  
< L o w/  
N or mal/  
Hi g h >  
< L o w/  
N or mal/  
Hi g h >  
x x  
< Pr ot oc ol Ti me >  
< L o w/  
N or mal/  
Hi g h >  
< L o w/  
N or mal/  
Hi g h >  
x x  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 1  of 1 3 7  
1 4. 1. 3. 8.  B o d y Wei g ht  
1 4. 1. 3. 8. 1.  Descri pti ve St atistics of B o d y Wei g ht  9 
1 4. 1. 3. 8. 2.  Descri pti ve St atistics of B o d y Wei g ht  –  M ale S u bje cts  9 
1 4. 1. 3. 8. 3.  Descri pti ve St atistics of B o d y Wei g ht –  Fe m ale S u bje cts  9 
1 4. 1. 3. 8. 4.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of B o d y Wei g ht  9 
1 4. 1. 3. 8. 5.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of B o d y Wei g ht –  M ale S u bjects  9 
1 4. 1. 3. 8. 6.  Descri pti ve St atistics of C h a n ge fr o m B aseli ne of B o d y Wei g ht –  Fe m ale  S u bje cts  9 
9 T o be ge ner ate d as f oll o ws:  
Visit  
n  
Me a n  
S D  
S E  
Me di a n  
Mi ni m u m  
M a xi m u m  
< Da y >  
x x  
x. x x x
x. x x x
x. x x x
x. x x x
x. x x x
x. x x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
n  –  n u m ber  of  s u bjects; S D  –  Sta n dar d  De viati o n; S E –  Sta n dar d Err or  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  L 
P a g e  1 0 2  of 1 3 7  
A. 4.  
List of S u bject D at a Listi n gs ( S e cti o n 1 6. 2 of C S R)  
A. 4. 1.  
P art 1  
1 6. 2.  S U B J E C T S D A T A LI S TI N G S  
1 6. 2. 1.  P A R T 1  
1 6. 2. 1. 1.  S u bject Dis p ositi o n  
1 6. 2. 1. 1. 1.  S u bject Dis p ositi o n  
Scree ni n g 
N o.  
D ate I C F Si g ne d  S u bject 
Eli gi ble ?  
S u bject Gi ve n 
a n U ni q ue 
S u bject N o. ?  
U ni q ue S u bject N o.  I ncl usi o n Criteri a 
N ot Met  
E xcl usi o n Criteri a 
Met  
Ot her Re as o n f or 
N o n -Eli gi bilit y  
Re as o n f or 
N o n -
R a n d o miz ati o n  
< Scree ni n g 
n u m ber >  
< D D M M M Y Y Y Y >  < Yes/ N o >  < Yes/ N o >  
< U ni q ue S u bject 
N o >  
< List all i ncl usi o n 
criteria t hat were 
n ot met >  
< List all e xcl usi o n 
criteria t hat were 
met >  
< List ot her reas o ns 
f or n o n-eli gi bilit y >  
< List reas o n f or 
n o n -ra n d o mizati o n > 
<I ns ert as ma n y r o ws as dee me d necessar y >  
I C F –  I nf or me d C o nse nt  F or m  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 3  of 1 3 7  
1 6. 2. 1. 2.  Pr ot oc ol De vi ati o ns  
1 6. 2. 1. 2. 1.  Bl o o d S a m pli n g Ti mes De vi ati o ns  
S u bject N o.  
T re at m e nt  
S a m pli n g Ti m e p oi nt  
S a m pli n g D ate a n d Ti m e  
De vi ati o n Re as o n  
Sc he d ule d/ T ar get  
Act u al  
< S u bject I D >  
< Treat me nt >  
< Sc he d ule d Ti me or 
u ns c he d ule d >  
< D D M M M Y Y Y Y 
h h: m m >  
< D D M M M Y Y Y Y 
h h m m >  
< R eas o n f or de viati o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 6. 2. 1. 2. 2.  Ot h er Pr ot oc ol De vi ati o ns  
S u bject N o.  Pr ot oc ol 
P h as e  
T re at m e nt  
C ate g or y  
Des cri pti o n  
Cl assific ati o n  
< S u bject I D >  < Pr ot oc ol 
P has e # >  
< Treat me nt >  
< De viati o n 
C ate g or y >  
< Des cri pti o n of t he de viati o n >  
<I m p orta nt / N ot i m p orta nt >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 4  of 1 3 7  
1 6. 2. 1. 3.  E xcl u d e d D at a fr o m t h e P h ar m ac o ki n etic A n al ysis 
1 6. 2. 1. 3. 1.  Pl as m a  C o n ce ntr ati o ns  
1 6. 2. 1. 3. 1. 1.  Mi d az ol a m:  I n di vi d u al D at a of Pl as m a  C o n ce ntr ati o ns  F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V 9 
1 6. 2. 1. 3. 1. 2.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a of Pl as m a C o nc e ntr ati o ns F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V 9 
1 6. 2. 1. 3. 1. 3.  Mi d az ol a m: I n di vi d u al D at a of Pl as m a C o n ce ntr ati o ns F oll o wi n g A d m i nistr ati o n of Or al Mi d az ol a m 9 
1 6. 2. 1. 3. 1. 4.  1 -H y d r o x y mi d az ol a m: I n di vi d u al D at a of Pl as m a C o nc e ntr ati o ns F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m 
9 
1 6. 2. 1. 3. 1. 5.  T ot al D a bi g atr a n: I n di vi d u al D at a of Pl as m a C o nc e ntr ati o ns F oll o wi n g A d mi nistr ati o n of D a bi g at r a n Et e xil at e 9 
1 6. 2. 1. 3. 1. 6.  Fr ee D a bi g atr a n: I n di vi d u al D at a of Pl as m a C o n ce ntr ati o ns F oll o wi n g A d mi nistr ati o n of D a bi g atr a n Ete xil at e 
9 
9 T o be ge ner ate d as f oll o ws:  
S u bject N o.  D a y  of 
D osi n g  
I n vesti g ati o n al 
Pr o d uct  
Pre -d os e  
 Ti m e P ost -D os e ( h)  
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
x. x x
< S u bject 
I D > 
< Da y  # >  
<I n vesti gati o nal 
Pr o d uct >  
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
x x. x x
<I ns ert as ma n y r o ws as dee me d necessar y >  
B L Q  –  Bel o w  t he Li mit  of  Q ua ntificati o n  ( L L O Q = < L L O Q >  < u nits C > ) of  t he assa y 
N D  –  N ot  D o ne  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 5  of 1 3 7  
1 6. 2. 1. 3. 2.  Pl as m a  C o n ce ntr ati o n  Vers us  Ti me Pr ofile s 
1 6. 2. 1. 3. 2. 1.  Mi d az ol a m: I n di vi d u al Pl as m a  C o n ce ntr ati o n  Vers us  Ti me Pr ofiles  F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V –  Li n e ar S c ale  
1 6. 2. 1. 3. 2. 2.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V –  S e mi -
L o g arit h mic S c ale   
1 6. 2. 1. 3. 2. 3.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V –  
Li n e ar Sc ale  
1 6. 2. 1. 3. 2. 4.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V –  
S e mi -L o g ar it h mic Sc ale  
1 6. 2. 1. 3. 2. 5.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m –  Li n e ar 
S c ale  
1 6. 2. 1. 3. 2. 6.  Mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m –  S e mi -
L o g a rit h mic S c ale   
1 6. 2. 1. 3. 2. 7.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m –  
Li n e ar Sc ale  
1 6. 2. 1. 3. 2. 8.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m –  
S e mi -L o g arit h mic Sc ale   
1 6. 2. 1. 3. 2. 9.  T ot al D a bi g atr a n: I n di vi d u al Pl as m a C o nc e ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g at r a n Ete xil at e –  
Li n e ar Sc ale  
1 6. 2. 1. 3. 2. 1 0.  T ot al D a bi g atr a n: I n di vi d u al Pl as m a C o nc e ntr ati o n Vers us  Ti m e Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g at r a n Ete xil at e –  
S e mi -L o g arit h mic Sc ale   
1 6. 2. 1. 3. 2. 1 1.  Fr ee D a bi g atr a n: I n di vi d u al Pl as m a C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g at r a n Ete xil at e –  
Li n e ar Sc ale  
1 6. 2. 1. 3. 2. 1 2.  Fr ee D a bi g atr a n: I n di vi d u al Pl as m a  C o n ce ntr ati o n Vers us  Ti me Pr ofiles F oll o wi n g A d mi nistr ati o n of D a bi g at r a n Ete xil at e –  
S e mi -L o g arit h mic Sc ale   
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 6  of 1 3 7  
N ote: T hese F i g ures will be e xtr acte d fr o m P h oe nix®  Wi n N o nli n
®  8. 2  or hi g her . A fi g ure will be pr o d uc e d f or e ac h s u bje ct wit h d at a e x cl u de d fr o m 
t he p h ar m ac oki netic a n alysis.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 7  of 1 3 7  
1 6. 2. 1. 4.  De m o gr a p hic a n d O t h e r B aseli n e D at a  
1 6. 2. 1. 4. 1.  De m o gr a p hic D at a  
S u bject N o.  
D ate I C F Si g ne d  
D ate of Birt h  
Se x  
R ace  
A ge  
( ye ars) 
Hei g ht  
(c m) 
Wei g ht  
( k g) 
B MI  
( k g/ m2) 
< S u bject I D >  
< D D M M M Y Y Y Y >  < M M M Y Y Y Y >  
< M/ F >   < R ace >  
x x  
x x x  
x x. x
x x. x
<I ns ert as ma n y r o ws as dee me d necessar y >  
I C F –  I nf or me d C o nse nt  F or m; B MI  –  B o d y  Mass  I n de x; M –  Male; F –  Fe male  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 8  of 1 3 7  
1 6. 2. 1. 4. 2.  Fe rtilit y/ C o ntr ac e pti o n 
1 6. 2. 1. 4. 2. 1.  Fe m ale Fe rtilit y/ C o ntr ace pti o n  
S u bject N o.  
C hil d be ari n g P ote nti al ?  
If Yes, Birt h C o ntr ol Met h o d B re ast Fee di n g ?  
C o m me nts  
< S u bject I D >  
< Yes/ N o >  
< Birt h C o ntr ol M et h o d >  
< Yes/ N o >  
< C o m me nts >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
1 6. 2. 1. 4. 2. 2.  M ale Fertilit y/ C o ntr ac e pti o n  
S u bject N o.  
Se x u all y Acti ve ?  
A grees t o Us e C o n d o m ?  
Fe m ale p art ner a grees t o us e a 
hi g hl y eff ecti ve m et h o d of 
c o ntr ace pti o n ?  
A gree n ot t o d o n ate s per m 
f r o m first d os e a d mi nistr ati o n 
u ntil at le ast 9 0 d a ys after t he 
l ast st u d y dr u g a d mi nistr ati o n ? 
C o m me nts  
< S u bject I D >  
< Yes/ N o >  
< Yes/ N o >  
< Yes/ N o >  
< Yes/ N o >  
< C o m me nts >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 0 9  of 1 3 7  
1 6. 2. 1. 4. 3.  Dr u gs of A b use, Et h a n ol a n d C oti ni ne  
S u bject N o.  
I n vesti g ati o n al 
Pr o d uct  
D ate  a n d Ti m e  
A m p het a mi nes  B e nz o di a ze pi nes  C oc ai ne  
C a n n a bi n oi ds  O pi ates  
Et h a n ol  
C oti ni ne  
< S u bject I D >  <I n vesti gati o nal 
Pr o d uct >  
< D D M M M Y Y Y Y 
h h: m m >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
< P ositi ve / 
Ne gati ve >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 0  of 1 3 7  
1 6. 2. 1. 4. 4.  Vir al S er ol o g y at Sc re e ni n g  
S u bject N o.  
Act u al D ate  a n d Ti m e  
Pr ot oc ol P h as e  
HI V -1 & HI V -2  
He p atitis B  
He p atitis C  
< S u bject I D >  
< D D M M M Y Y Y Y 
h h: m m >  
< Pr ot oc ol P has e >  
< Q ualitati ve Val ue >  
< Q ualitati ve Val ue >  
< Q ualitati ve Val ue >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
HI V  –  H u ma n  I m m u n o deficie nc y Vir us  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 1  of 1 3 7  
1 6. 2. 1. 4. 5.  Pr e vi o us a n d C o nc o mit a nt Me dic ati o n  
S u bject N o.  
T re at m e nt  
Dr u g N a m e  
[ A T C C o de] I n dic ati o n 
P h ar m ace utic al 
F or m  
D os e ( u nits)  
Fre q ue nc y  
R o ute  
D ate a n d Ti m e  
St art  
E n d  
< S u bject I D >  < Treat me nt >  < Ge neric na me 
[ X X X X X X X] > 
< T hera pe utic 
i n dicati o n > 
< P har mace utical 
F or m >  
< D os e ( u nits) >  < Fre q ue nc y >  < R o ute >  
< D D M M M Y Y Y Y >  < D D M M M Y Y Y Y 
or O n g oi n g >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
A T C –  A nat o mical T hera pe utic C he mical 
N K  –  N ot  K n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 2  of 1 3 7  
1 6. 2. 1. 4. 6.  S A R S -C O V -2 Test  
S u bject N o.  
Act u al D ate  
Pr ot oc ol P h as e  
Res ult  
If U nsc he d ule d, Re as o n 
< S u bject I D >  
< D D M M M Y Y Y Y >  
< Pr ot oc ol P has e >  
< N ot detecta ble, Detecta ble, 
I nc o ncl usi ve > 
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y > 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or a ny of t he e v al u ati o ns . 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 3  of 1 3 7  
1 6. 2. 1. 5.  C o m pli a nc e 
1 6. 2. 1. 5. 1.  I n vesti g ati o n al Pr o d u ct A d mi nistr ati o n 
S u bject N o.  
D ate  
Act u al  
Cl oc k Ti m e  
I n vesti g ati o n al 
Pr o d uct  
D os e ( u nits)  
I n vesti g ati o n al 
Pr o d uct 
F or m ul ati o n  
R o ute of 
A d mi nistr ati o n  
H a n ds a n d  
M o ut h C hec k ?  
1 5 0 m L of  
w ater t a ke n ?  C o m me nts  
< S u bject I D >  
< D D M M M Y Y
Y Y/ N/ A >  
< h h: m m/ N/ A >  <I n vesti gati o nal 
Pr o d uct >  
< D os e ( u nits) >  < F or m ulati o n >  < R o ute >  
< Yes/ N o/ N/ A >  < Yes/ N o/ N/ A >  < C o m me nts >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
N/ A –  N ot A p plica ble  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 4  of 1 3 7  
1 6. 2. 1. 6.  I n di vi d u al P h ar m ac o ki netic D at a  
1 6. 2. 1. 6. 1.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic D at a F oll o wi n g A d mi nistr ati o n of Mi d az ol a m I V 
1 6. 2. 1. 6. 1. 1.  Mi d az ol a m: I n di vi d u al Dr u g C o n ce ntr ati o n D at a F oll o wi n g A d mi nistr ati o n of Mi d az ol a m 
I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se ct i o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 1 . t o 1 4. 1. 2. 2. 3 .’ 
1 6. 2. 1. 6. 1. 2.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt he r i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 . 1. t o 1 4. 1. 2. 3 .3 .’ 
1 6. 2. 1. 6. 1. 3.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic Pr ofiles F oll o wi n g A d mi nistr ati o n of Mi d az ol a m 
I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 . 1. t o 1 4. 1. 2. 6 .2 .’ 
1 6. 2. 1. 6. 1. 4.  Mi d az ol a m: D oc u me nt ati o n of St atistic al A n al ysis F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V 
1 6. 2. 1. 6. 1. 4. 1.  Mi d az ol a m: N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 1. 4. 2.  Mi d az ol a m: N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 1. 4. 3.  Mi d az ol a m: P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 1. 4. 4.  Mi d az ol a m: P ote nti al I n d u cti o n Effect A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h o e nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 5  of 1 3 7  
1 6. 2. 1. 6. 2.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic D at a F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V 
1 6. 2. 1. 6. 2. 1.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Dr u g C o n ce ntr ati o n D at a F oll o wi n g A d mi nistr ati o n 
Mi d az ol a m I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 4 . t o 1 4. 1. 2. 2. 6 .’ 
1 6. 2. 1. 6. 2. 2.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n 
of Mi d az ol a m I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 .4 . t o 1 4. 1. 2. 3 .6 .’ 
1 6. 2. 1. 6. 2. 3.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic Pr ofiles F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V 
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 .3 . t o 1 4. 1. 2. 6 .4 .’ 
1 6. 2. 1. 6. 2. 4.  1 -H y d r o x y mi d az ol a m: D oc u me nt ati o n of St atistic al A n al ysis F oll o wi n g A d mi nistr ati o n of 
Mi d az ol a m I V 
1 6. 2. 1. 6. 2. 4. 1.  1 -H y d r o x y mi d az ol a m: N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 2. 4. 2.  1 -H y d r o x y mi d az ol a m: N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 2. 4. 3.  1 -H y d r o x y mi d az ol a m: P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 2. 4. 4.  1 -H y d r o x y mi d az ol a m: P ote nti al I n d u cti o n Effect A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h oe nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 6  of 1 3 7  
1 6. 2. 1. 6. 3.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic D at a F oll o wi n g A d mi nistr ati o n of Or al Mi d az ol a m  
1 6. 2. 1. 6. 3. 1.  Mi d az ol a m: I n di vi d u al Dr u g C o n ce ntr ati o n D at a F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 7 . t o 1 4. 1. 2. 2. 9 .’ 
1 6. 2. 1. 6. 3. 2.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m  
N ote: T he f ol l o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 .7 . t o 1 4. 1. 2. 3 .9 .’ 
1 6. 2. 1. 6. 3. 3.  Mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic Pr ofiles F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m  
N ote: T he f oll o wi n g se nte nce  s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 .5 . t o 1 4. 1. 2. 6 .6 .’ 
1 6. 2. 1. 6. 3. 4.  Mi d az ol a m: D oc u me nt ati o n of St atistic al A n al ysis F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m  
1 6. 2. 1. 6. 3. 4. 1.  Mi d az ol a m: N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 3. 4. 2.  Mi d az ol a m: N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 3. 4. 3.  Mi d az ol a m: P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 3. 4. 4.  Mi d az ol a m: P ote nti al I n d u cti o n Effect A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h oe nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 7  of 1 3 7  
1 6. 2. 1. 6. 4.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic D at a F oll o wi n g A d mi nistr ati o n of Or al 
Mi d az ol a m  
1 6. 2. 1. 6. 4. 1.  1 -H y d r o x y mi d az ol a m: I n di vi d u al Dr u g C o n ce ntr ati o n D at a F oll o wi n g A d mi nistr ati o n 
Or al Mi d az ol a m  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 1 0 . t o 1 4. 1. 2. 2. 1 2 .’ 
1 6. 2. 1. 6. 4. 2.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic P ar a meters F oll o wi n g A d mi nistr ati o n 
of Or al Mi d az ol a m  
N o te: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 .1 0 . t o 1 4. 1. 2. 3 .1 2 .’ 
1 6. 2. 1. 6. 4. 3.  1 -H y d r o x y mi d az ol a m: I n di vi d u al P h ar m ac o ki n etic Pr ofiles F oll o wi n g A d mi nistr ati o n of 
Or al Mi d az ol a m  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 .7 . t o 1 4. 1. 2. 6 .8 .’ 
1 6. 2. 1. 6. 4. 4.  1 -H y d r o x y mi d az ol a m: D oc u me nt ati o n of St atistic al A n al ysis F oll o wi n g A d mi nistr ati o n of 
Or al Mi d az ol a m  
1 6. 2. 1. 6. 4. 4. 1.  1 -H y d r o x y m i d az ol a m: N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 4. 4. 2.  1 -H y d r o x y mi d az ol a m: N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 4. 4. 3.  1 -H y d r o x y mi d az ol a m: P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 4. 4. 4.  1 -H y d r o x y mi d az ol a m: P ote nti al I n d u cti o n Effect A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h oe nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 8  of 1 3 7  
1 6. 2. 1. 6. 5.  T ot al D a bi g atr a n: I n di vi d u al P h ar m ac o ki netic D at a F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
1 6. 2. 1. 6. 5. 1.  T ot al D a bi g atr a n: I n di vi d u al Dr u g C o nc e ntr ati o n D at a F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 1 3 . t o 1 4. 1. 2. 2. 1 5 .’ 
1 6. 2. 1. 6. 5. 2.  T ot al D a bi g atr a n: I n di vi d u al P h ar m ac o ki netic P ar a meter s F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 .1 3 . t o 1 4. 1. 2. 3 .1 5 .’ 
1 6. 2. 1. 6. 5. 3.  T ot al D a bi g atr a n: I n di vi d u al P h ar m ac o ki netic Pr ofile s F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 .9 . t o 1 4. 1. 2. 6 .1 0 .’ 
1 6. 2. 1. 6. 5. 4.  T ot al D a bi g atr a n: D oc u me nt ati o n of St atistic al A n al ys is F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
1 6. 2. 1. 6. 5. 4. 1.  T ot al D a bi g atr a n : N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 5. 4. 2.  T ot al D a bi g atr a n : N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 5. 4. 3.  T ot al D a bi g atr a n : P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 5. 4. 4.  T ot al D a bi g atr a n : P ote nti al I n d u cti o n Effe ct A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h oe nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 1 9  of 1 3 7  
1 6. 2. 1. 6. 6.  Fr ee D a bi g atr a n: I n di vi d u al P h ar m ac o ki n etic D at a F oll o wi n g A d mi nistr ati o n of D a bi g at r a n 
Et e xil at e  
1 6. 2. 1. 6. 6. 1.  Fr ee D a bi g atr a n: I n di vi d u al Dr u g C o nc e ntr ati o n D at a F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 2. 1 6 . t o 1 4. 1. 2. 2. 1 8 .’ 
1 6. 2. 1. 6. 6. 2.  Fr ee D a bi g atr a n: I n di vi d u al P h ar m ac o ki n etic P ar a mete rs F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 3 .1 6 . t o 1 4. 1. 2. 3 .1 8 .’ 
1 6. 2. 1. 6. 6. 3.  Fr ee D a bi g atr a n: I n di vi d u al P h ar m ac o ki n etic Pr ofiles F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
N ote: T he f oll o wi n g se nte nce s h o ul d be i nserte d i n t his se cti o n: ‘ N o f urt her i nf or m ati o n is pr ovi de d; refer t o 
se cti o ns 1 4. 1. 2. 6 . 11 . t o 1 4. 1. 2. 6 .1 2 .’ 
1 6. 2. 1. 6. 6. 4.  Fr ee D a bi g atr a n: D oc u me nt ati o n of St atistic al A n al ysis F oll o wi n g A d mi nistr ati o n of 
D a bi g at r a n Ete xil ate  
1 6. 2. 1. 6. 6. 4. 1.  Fr ee D a bi g atr a n : N o n -C o m p art me nt al A n al ysis O ut p ut  
1 6. 2. 1. 6. 6. 4. 2.  Fr ee D a bi g atr a n : N o n -C o m p art me nt al A n al ysis Pl ots  
1 6. 2. 1. 6. 6. 4. 3.  Fr ee D a bi g atr a n : P ote nti al I n hi bit or y Effe ct A n al ysis O ut p ut  
1 6. 2. 1. 6. 6. 4. 4.  Fr ee D a bi g atr a n : P ote nti al I n d u cti o n Effe ct A n al ysis O ut p ut  
N ote: T he d oc u me nt ati o n of st atistic al a n alysis will be e xtr acte d P h oe nix ®  Wi n N o nli n
®  8. 2 or hi g her.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 0  of 1 3 7  
1 6. 2. 1. 7.  A d verse E ve nt Listi n gs ( E ac h S u bject)  
1 6. 2. 1. 7. 1.  Pr e -Tr e at me nt A d verse E ve nts  7 
1 6. 2. 1. 7. 2.  Tr e at me nt -E mer ge nt A d verse E ve nts 7 
7 T o be ge ner ate d as f oll o ws:  
S u bject N o.  D a y of 
D os e  
T re at m e nt  Re p orte d 
T er m  
Seri o us ?  
M a xi m al  
Se verit y  
C a us alit y  Acti o n 
T a ke n  
Me dic ati o n 
Re q uire d ?  O utc o m e  
A d vers e 
E ve nt St art 
D ate a n d 
Ti m e  
A d vers e 
E ve nt E n d  
D ate a n d 
Ti m e  
C o m me nts  
< S u bject 
I D > 
< Da y # >  
<I n vesti gati
o nal 
Pr o d uct >  
< A E 
R e p orte d 
T er m >  
< Yes/ N o >  < Mil d, 
M o derate or 
Se vere >  
< N ot 
R eas o na bl y 
P ossi ble or 
R eas o na bl y 
P ossi ble >  
< D os e 
I ncreas e d, 
D os e N ot 
C ha n ge d, 
D os e R ate 
R e d uce d, 
D os e 
R e d uce d, 
Dr u g 
I nterr u pte d, 
Dr u g 
Wit h dra w n, 
N ot 
A p plica ble 
or 
U n k n o w n >  
< Yes or 
N o >  
< Fatal, N ot 
R ec o vere d / 
N ot 
R es ol ve d, 
R ec o vere d / 
R es ol ve d, 
R ec o vere d / 
R es ol ve d 
wit h 
Se q uelae, 
R ec o veri n g 
/ R es ol vi n g 
or 
U n k n o w n >  
< D D M M M
Y Y Y Y 
h h: m m >  
< D D M M M
Y Y Y Y 
h h m m or 
O n g oi n g >  
< C o m me nts
>  
<I ns ert as ma n y r o ws as dee me d necessar y >  
N K  –  N ot  K n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “I nv esti g ati o n al Pr o d uct ” c ol u m n will o nly be ge ner ate d f or T a ble 1 6. 2. 1. 7. 2.  If a n A dverse Eve nt is rel ate d t o M e dic al Hist ory, t h at 
i nf or m ati o n will be re p orte d i n ‘ C o m me nts’. T he “ C o m me nts ” c ol u m n will o nly be ge ner ate d if t here are re p orte d  c o m me nts f or t he a dverse e ve nts . 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 1  of 1 3 7  
1 6. 2. 1. 7. 3.  S e ri o us A d ve rse E ve nts  (I) 
S u bject N o.  
T re at m e nt  
Re p orte d T er m  
Re as o n f or Seri o us ness  
Det ails  
< S u bject I D >  
< Treat me nt >  
< A E R e p orte d T er m >  
< R eas o n >  
< S A E details >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 2  of 1 3 7  
1 6. 2. 1. 8.  Listi n g s of L a b or at or y Me as u re me nts b y S u bject 
1 6. 2. 1. 8. 1.  N or m al R a n ge of L a b or at or y V al ues  
N or m al R a n ge  
Fe m ale  
M ale  
C ate g or y  
A n al yte  
A ge  
U nits  
L L N  
U L N  
L L N  
U L N  Q u alit ati ve  
< C ate g or y >  
< La b orat or y A nal yte >  
< A ge i nter val >  
< U nits >  
< L o wer 
Li mit >  
< U p per 
Li mit >  
< L o wer 
Li mit >  
< U p per 
Li mit >  
< Q ualitati ve 
Val ues >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L L N  –  L o wer  Li mit  N or mal ; U L N  –  U p per  Li mit  N or mal  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
. 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 3  of 1 3 7  
1 6. 2. 1. 8. 2.  He m at ol o g y (I)  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
S u bject N o.  Act u al D ate  
a n d Ti m e  
Pr ot oc ol 
P h as e  
He m o gl o bi n  
( g/ d L) 
R B C  
( 1 0 ^ 1 2/ L) 
He m at ocrit  
( %) 
M C V  
(f L) 
M C H  
( p g) 
M C H C  
( g/ d L) 
R D W -C V  
( %) 
T ot al 
W B C  
( 1 0 ^ 9/ L) 
If 
U ns c he d ule d, 
Re as o n  
< S u bject I D >  < D D M M M Y
Y Y Y 
h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
R B C –  Re d Bl o o d Cell; M C V –  Mea n C or p usc ular V ol u me; 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 nce ntrati o n; R D W -C V –  
C oefficie nt Variati o n of t he Re d Cell Distri b uti o n Wi dt h; W B C –  W hite Bl o o d Cell  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 4  of 1 3 7  
1 6. 2. 1. 8. 3.  He m at ol o g y (II)  
S u bject N o.  Act u al D ate  
a n d Ti m e  
Pr ot oc ol 
P h as e  
Ne utr o p hils  
( 1 0 ^ 9/ L) 
E osi n o p hils  
( 1 0 ^ 9/ L) 
B as o p hils  
( 1 0 ^ 9/ L) 
L y m p h oc ytes  
( 1 0 ^ 9/ L) 
M o n oc ytes  
( 1 0 ^ 9/ L) 
Pl atelets  
( 1 0 ^ 9/ L) 
Me a n Pl atelet 
V ol u m e  
(f L) 
If 
U ns c he d ule d, 
Re as o n  
< S u bject I D >  < D D M M M Y
Y Y Y h h: m m >  
< Pr ot oc ol 
P has e >  
x x  
x x  
x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 5  of 1 3 7  
1 6. 2. 1. 8. 4.  Bi oc h e mistr y (I)  
S u bject N o.  
Act u al D ate  
a n d Ti m e  
Pr ot oc ol P h as e  A S T  
(I U/ L) 
A L T  
(I U/ L) 
G G T  
(I U/ L) 
L D H  
(I U/ L) 
A L P  
(I U/ L) 
C K  
(I U/ L) 
If U nsc he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y
Y Y h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 6  of 1 3 7  
1 6. 2. 1. 8. 5.  Bi oc h e mistr y (II)  
S u bject N o.  
Act u al D ate  
a n d Ti m e  
Pr ot oc ol P h as e  Cre ati ni ne  
( m g/ d L) 
e G F R  
Ure a  
( m g/ d L) 
S o di u m  
( m m ol/ L) 
P ot assi u m  
( m m ol/ L) 
C alci u m 
( m g/ d L) 
If U nsc he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y
Y Y h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 7  of 1 3 7  
1 6. 2. 1. 8. 6.  Bi oc h e mistr y (III)  
S u bject N o.  
Act u al D ate  
a n d Ti m e  
Pr ot oc ol P h as e  M a g nesi u m 
( m g/ d L) 
Gl uc os e  
( m g/ d L) 
T ot al 
C h olester ol  
( m g/ d L) 
T ri gl yceri des  
( m g/ d L) 
Al b u mi n  
( g/ d L) 
T ot al Pr otei n  
( g/ d L) 
If 
U ns c he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y
Y Y h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 8  of 1 3 7  
1 6. 2. 1. 8. 7.  Bi oc h e mistr y (I V)  
S u bject N o.  
Act u al D ate  
a n d Ti m e  
Pr ot oc ol P h as e  Uric Aci d  
( m g/ d L) 
T ot al Bilir u bi n  
( m g/ d L) 
Direct 
Bilir u bi n  
( m g/ d L) 
I n direct 
Bilir u bi n  
( m g/ d L) 
T S H  
( mI U/ L) 
C hl ori de  
( m m ol/ L) 
If 
U ns c he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y
Y Y h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 2 9  of 1 3 7  
1 6. 2. 1. 8. 8.  Bi oc h e mistr y ( V)  
S u bject N o.  
Act u al D ate  
a n d Ti m e  
Pr ot oc ol P h as e  A m yl as e  
( g/ d L) 
L D L 
C h olester ol  
( m g/ d L) 
H D L 
C h olester ol  
( m g/ d L) 
F S H  
( m g/ d L) 
C -Re acti ve
Pr otei n
C yst ai n C  
If 
U ns c he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y
Y Y h h m m >  
< Pr ot oc ol 
P has e >  
x x  
x x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 0  of 1 3 7  
1 6. 2. 1. 8. 9.  C o a g ul ati o n  
S u bject N o.  
Act u al D ate  a n d 
Ti m e  
Pr ot oc ol P h as e  
Pr ot hr o m bi n R ate  
( %) 
Pr ot hr o m bi n Ti m e  
(s ec) 
I N R 
a P T T  
(s ec) 
If U nsc he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y Y Y 
h h: m m >  
< Pr ot oc ol P has e >  
x x  
x x. x
x. x x
x x. x
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
I N R –  I nter nati o nal N or malize d Rati o; a P T T –  Acti vate d Partial T hr o m b o plasti n Ti me  
L  –  L o w;  H  –  Hi g h;  C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 1  of 1 3 7  
1 6. 2. 1. 8. 1 0.  Uri n al ysis  
S u bject 
N o.  
Act u al 
D ate  a n d 
Ti m e  
Pr ot oc ol 
P h as e  
p H  
S pecific  
Gr a vit y  Pr otei n  
He m o gl o bi n  Gl uc os e  
Ket o nes  
Bilir u bi n  
Nitrites  
Ur o bili n o ge n  
If 
U ns c he d ule d, 
Re as o n  
< S u bject 
I D > 
< D D M M
M Y Y Y Y 
h h: m m >  
< Pr ot oc o
l P has e > x x. x
x. x x x
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< Q ualitati ve 
Val ue >  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h; N C R  –  N ot  Cli nicall y  Rele va nt;  C R  –  Cli nicall y  Rele va nt;  R U  - Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters.  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 2  of 1 3 7  
1 6. 2. 1. 8. 1 1.  Uri n e Micr osc o p y  
S u bject N o.  
Act u al D ate  a n d 
Ti m e  
Pr ot oc ol P h as e  
S q u a m o us 
E pit heli al Cells  
(/ u L) 
E r yt hr oc ytes 
(/ u L) 
L e u k oc ytes 
(/ u L) 
O bs er v ati o ns  
If U nsc he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y Y Y 
h h: m m >  
< Pr ot oc ol P has e >  
< Q ualitati ve 
Val ue >  
x x  
x x  
< O bs er vati o ns >  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
L  –  L o w;  H  –  Hi g h; C R  –  Cli nicall y  Rele va nt;  N C R  –  N ot  Cli nicall y  Rele va nt;  R U  –  Rele va nce  U n k n o w n  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters. 
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 3  of 1 3 7  
1 6. 2. 1. 8. 1 2.  Pr e g n a nc y Test  
S u bject N o.  
Act u al D ate  a n d Ti m e  Pr ot oc ol P h as e  
M atri x  
Res ult  
If U nsc he d ule d, 
Re as o n  
< S u bject I D >  
< D D M M M Y Y Y Y 
h h: m m >  
< Pr ot oc ol P has e >  
< Ser u m or Uri ne >  
< P ositi ve or Ne gati ve >  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y > 
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he of t he e v al u ati o ns . 
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 4  of 1 3 7  
1 6. 2. 1. 8. 1 3.  A d diti o n al ( N ot Pl a n ne d) L a b or at or y S afet y Tests  
S u bject N o.  
Act u al D ate a n d 
Ti m e  
Pr ot oc ol P h as e  
I n vesti g ati o n al 
Pr o d uct  
P ar a m eter  
Res ults  
Re as o n  
< S u bject I D >  
< D D M M M Y Y Y Y 
h h m m >  
< Pr ot oc ol P has e >  
<I n vesti gati o nal 
Pr o d uct >  
< Para meter >  
< R es ults >  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
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I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 5  of 1 3 7  
1 6. 2. 1. 9.  Vit al Si g ns  
S u bject N o.  Sc he d ule d 
Ti m e  
Act u al D ate 
a n d Ti m e  
Pr ot oc ol 
P h as e  
T re at m e nt  
S B P 
( m m H g) 
D B P 
( m m H g) 
P uls e R ate  
( be ats/ mi n) 
B o d y 
T e m per at ure  
(º C) 
Res pir at or y 
R ate  
( be ats/ mi n) 
If 
U ns c he d ule d,  
Re as o n  
< S u bject I D >  < Sc he d ule d 
Ti me or 
U ns c he d ule d >  
< D D M M M Y
Y Y Y h h: m m >  
< Pr ot oc ol 
P has e >  
< Treat me nt >  
x x  
x x  
x x  
x x  
x x  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
S B P –  S yst olic Bl o o d Press ure; D B P –  Diast olic Bl o o d Press ure  
L –  L o w;  H –  Hi g h;  C R –  Cli nicall y  Rele va nt;  N C R –  N ot  Cli nicall y  Rele va nt  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or o ne of t he e v al u ate d p ar a meters. 
P P D


I T F/ 2 3 5 7/ 55  
V er si o n: < V er si o n >  
D at e: < D D M M M Y Y Y Y >  
Cli ni c al St u d y R e p ort  
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 - 00 5 7 5 6 - 11  
P a g e  1 3 6  of 1 3 7  
1 6. 2. 1. 1 0.  1 2 -Le a d E C G  
S u bject N o.  
Sc he d ule d 
Ti m e  
Act u al D ate 
a n d Ti m e  
Pr ot oc ol P h as e  T re at m e nt  
Q T c F  
( ms ec) 
Res ult  
If A b n or m al, 
Re as o n  
If A b n or m al, 
Cli nic all y 
Si g nific a nt ?  
If 
U ns c he d ule d,  
Re as o n  
< S u bject I D >  
< Sc he d ule d 
Ti me or 
U ns c he d ule d >  
< D D M M M Y Y
Y Y h h: m m >  
< Pr ot oc ol 
P has e >  
< Treat me nt >  
x x x  
< A b n or mal/ 
N or mal >  
< R eas o n f or 
bei n g 
c o nsi dere d 
a b n or mal >  
< Yes / N o >  
< R eas o n >  
<I ns ert as ma n y r o ws as dee me d necessar y >  
Pr o gr a m:  < S A S Pr o gra m >  
E xec uti o n  D ate/ Ti me:  < d d M M M y y y y H H: M M >  
N ote: T he “If U nsc he d ule d, Re as o n ” c ol u m n will o nly be ge ner ate d if t here is a n U nsc he d ule d Re as o n f or a ny  of t he e v al u ati o ns . 
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I T F/ 2 3 5 7/ 55  
V er si o n: 1. 0  
D at e: 2 4 M A R 2 0 2 2  
St ati sti c al A n al y si s Pl a n  
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 - 00 5 7 5 6 - 11   
P a g e  1 3 7  of 1 3 7  
1 4.
A N N E X E S
A n ne x 1 : Data Bli n d Re vie w Pr oc ess Mi n ute –  Part 1  
A n ne x 2 : List of S u bjects D ose d –  Part 1  
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