An Ascending Dose Tolerability Study and Pharmacokinetic Assessment in Healthy Male and Female Volunteers After Single & Multiple Oral Administration of DF2755A
Phase: PHASE1
Conditions: no Condition
Sponsor: Dompé Farmaceutici S.p.A

 
 
 
 
Pr ot oc ol Te m plate v 6. 0 2 3 0 5 1 6 
 
1/ 8 5 
 
 
 
C LI NI C A L T RI A L P R O T O C O L  
 
 
P r ot oc ol N° B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M 
E u dr a C T n° : 2 0 1 6- 0 0 3 6 2 9- 4 1 
  
V ersi o n n° 6. 0 - D ate: - 2 7- M A R- 2 0 1 8 
 
A n Asce n di n g D ose T oler a bilit y St u d y a n d P h ar m ac o ki netic Assess me nt i n He alt h y M ale a n d 
F e m ale V ol u nteers after Si n gle & M ulti ple Or al A d mi nistr ati o n of D F 2 7 5 5 A 
 
 
 
Versi o n  
M o dific ati o n  
A ut h or  
D ate  
A p plic ati o n  
1. 0  
Fi n al Versi o n  
E ur ofi ns O pti me d  
0 5 -O C T -2 0 1 6  
N A  
 
2. 0  
I nc o nsiste nc y bet wee n te xt a n d 
fl o w-c h art rectifie d  a n d 
esc al ati o n d ose pr oce d ure 
rectifie d 
E ur ofi ns O pti me d  
2 3 -N O V -2 0 1 6  
 
3. 0  
M a xi m u m d ose j ustifie d a n d 
d ur ati o n of c o ntr ace pti o n 
e xte n de d 
E ur ofi ns O pti me d  
3 0 -N O V -2 0 1 6  
 
4. 0  
C h a n ge ti mi n g le u k oc ytes 
s u bset f or l o gistic al re as o ns of 
l a b or at or y a n d i m ple me nt ati o n 
acc or di n g t o t he l ast A N S M 
re q uests: i m ple me nt ati o n 
st o p pi n g r ules; 
A d diti o n f e m ale i n all c o h ort; 
u p d ati n g c o ncer ni n g t he 
m o d alities of i m me di ate 
decl ar ati o n f or vi gil a nce d at a ; 
I m ple me nt ati o n ti me wi n d o w 
bet wee n all s u bjects of e ac h 
c o h ort; st art t he M A D after all 
of S A D c o h orts;  c h a n ge t he 
hi g hes t d ose of S A D f r o m 9 0 0 
m g t o 7 0 0  m g  a n d t he hi g hest 
d ose of M A D fr o m 4 0 0 bi d t o 
3 0 0 bi d ; e x pl a n ati o n a b o ut 
r a n d o miz ati o n f or first t w o 
s u bjects; i m ple me nt ati o n 
a b o ut c o ntr ace pti ve met h o d ; 
D ur ati o n of s u bjects f oll o w u p; 
a d di n g of p h ar m ac o ki netic 
pr ofile i n t he d o g; c h a n ge of 
m a n uf act urer  
E ur ofi ns 
O pti me d/ D o m pé 
F ar m ace utici s p a  
0 7 -A P R -2 0 1 7  
 
5. 0  
A  preli mi n ar y q u a ntit ati ve 
a n al ysis of met a b olites 
i de ntifie d will be pl a n ne d 
d uri n g t he S A D;  
I n or der t o pr ocee d fr o m S A D 
t o M A D, a s u bst a nti al 
E ur ofi ns 
O pti me d /D o m pé 
F ar m ace utici s p a  
2 4 -M A Y -2 0 1 7  
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 – 2 7/ M A R/ 2 0 1 8  
 
2 / 8 5  
Versi o n  
M o dific ati o n  
A ut h or  
D ate  
A p plic ati o n  
a me n d me nt t o t he pr ot oc ol  
wit h t he res ults of S A D p art of 
t he st u d y m ust be s u b mitte d t o 
A N S M . 
 
6. 0  
I n or der t o better q u alif y t he 
P D m ar kers a n d a d d collecti o n 
of bl o o d f or  P D m ar ker s 
(Le uc oc yte  s u bsets) d uri n g t he 
S A D, st arti n g fr o m t he sec o nd 
asce n di n g  d ose.  
I n or der t o e xte n d t he r a n ge of 
a ge a n d re d uce t he mi ni m u m 
n u m ber of e nr olle d w o me n i n 
S A D a n d M A D.  
I n or der t o m o dif y criteri a 6. 
E ur ofi ns 
O pti me d/ D o m pé 
F ar m ace utici s p a  
2 7 M A R 2 0 1 8  
 
 
 
 
« T his d oc u me nt is t he pr o pert y of t he S p o ns or a n d ma y n ot –  i n f ull or i n part –  be passe d o n, re pr o d uce d, 
p u blis he d or use d b y a ut h oriti es or ot her a p plica nts f or a p pr o val or re gistrati o n p ur p oses wit h o ut e x press per missi o n 
of t he S p o ns or. » 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 – 2 7/ M A R/ 2 0 1 8  
 
6 / 8 5  
S Y N O P SI S 
 
Title : 
A n As ce n di n g D ose T olera bilit y St u d y a n d P har mac o ki neti c Assess me nt i n Healt h y Mal e 
a n d Fe male  V ol u nteers  after Si n gle & M ulti ple Oral A d mi nistrati o n of D F 2 7 5 5 A  
St u d y pr o d uct  
D F 2 7 5 5 A  
Pr ot oc ol N o. : 
B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
S p o ns or:  
 
 
D O M P É  F A R M A C E U TI CI S. P. A  
Via Ca m p o di Pile s. p.a  
6 7 1 0 0 L’ A q uila –  Ital y 
N u m ber  
of  
st u d y 
ce nter s  
Si n gle ce nter st u d y  
Pri nci p al 
I n vesti g at or: 
Y ves D O N A Z Z O L O, M. D., M. Sc.  
E U R O FI N S O P TI M E D, GI E R E S –  Fra nce  
St u d y Desi g n:  
T he st u d y is a p hase I, si n gle ce nter, d o u ble -bli n d , place b o c o ntr olle d, ra n d o mize d, 
asce n di n g si n gle a n d re peate d d oses st u d y i n  healt h y male  a n d fe male v ol u nteers . 
T he desi g n c o nsists of a d o u ble bli n d c o m paris o n of t he test c o m p o u n d vers us place b o i n 
w hic h t he d ose is i ncrease d i n s uccessi ve treat me nt per i o ds.  
T he M u lti ple Asce n di n g D os e ( M A D) will be i nitiate d  o nl y after  t he a ut h orizati o n, fr o m 
A N S M of a s u bsta ntial a me n d me nt t hat will be prese nte d i n or der t o n otif y t he res ults of 
Si n gle Asce n di n g D ose ( S A D)  part of t he st u d y. Besi des i n or der t o deci de  t o m o ve 
f or war d fr o m S A D t o M A D, t he p har mac o ki netic data f or all d oses a d mi nistere d d uri n g 
S A D will be e val uate d (i.e. plas ma: q ua ntitati ve deter mi nati o n of D F 2 7 5 5 A b o u n d a n d 
u n b o u n d; q ualitati ve  a n d preli mi nar y  q ua ntitati ve  deter mi nati o n  of  k n o w n meta b o lites; 
uri ne a n d faeces: q ualitati ve a n d q ua ntitati ve deter mi nati o n  of pare nt c o m p o u n d a n d 
q ualitati ve  a n d preli mi nar y  q ua ntitati ve  i n vesti gati o n of k n o w n meta b olites).  
D ose will be escalate d i n or der t o ac hie ve e n o u g h safet y i nf or mati o n o n a n i nter val of 
d oses p ossi bl y e nc o m passi n g b ot h t he effecti ve d ose a n d t he ma xi m u m t olerate d d os e 
( defi ne d as t he hi g hest  d ose de v oi d of a n y cli nical si g ns/s y m pt o ms).  
 
P art A : Si n gle d oses of 5 0 m g oa d, 1 5 0 m g oad, 4 5 0 m g o a d or 7 0 0  m g oa d  of D F 2 7 5 5 A 
are pla n ne d t o be teste d i n healt h y  male a n d fe male  v ol u nteers.  
 
P art B : Re p eate d d oses of 1 0 0 m g bi d, 2 0 0 m g bi d or 3 0 0 m g bi d of D F 2 7 5 5 A are pla n ne d 
t o be teste d i n healt h y male a n d fe male v ol u nteers.  
St u d y O bjecti ves : 
Pri m ar y O bjecti ve:  
 
T o e val uate t he t olera bilit y a n d safet y of asce n di n g si n gle a n d re peate d d oses of  
D F 2 7 5 5 A i n healt h y a d ult mal e a n d fe male v ol u nteers.  
 
Sec o n d ar y O bjecti ves : 
 
T o deter mi ne t he p har mac o ki netics para meters of D F 2 7 5 5 A  
 
T o esta blis h a d ose c o nce ntrati o n -res p o nse relati o ns hi p o ver a wi de ra n ge of d oses 
i n or der t o select a narr o wer r a n ge of d ose a n d d osi n g re gi me n t o be s u bse q ue ntl y 
st u die d i n patie nts after si n gle a n d m ulti ple a d mi nistrati o n  
 
T o e val uate t he effect of asce n di n g si n gle a n d re peate d d oses o n t he 
p har mac o d y na mics para meters  
 
T o c o m pare meta b olites pat h wa y i n H u ma n wit h t he o ne o bser ve d i n a ni mals  
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 – 2 7/ M A R/ 2 0 1 8  
 
7 / 8 5  
I n vesti g ati o n al 
Tre at me nt : 
Na me of t he c o m p o u n d:         D F 2 7 5 5 A  
P har mace utical f or m:  
       Ca ps ule s of 5 0 m g , a n d 2 0 0 m g 
D ose per a d mi nistrati o n:            P art A:  5 0 m g oa d, 1 5 0 m g oa d, 4 5 0  m g oa d or 7 0 0  m g  oa d  
P art B:  1 0 0 m g bi d, 2 0 0 m g bi d or  3 0 0 m g bi d  
Ti mi n g f or a d mi nistrati o n:       P art A:  Si n gle oral d ose a d mi nistrati o n o n D 1 acc or di n g t o 
t he ra n d o mizati o n. T he ad mi nistrati o n will ta ke place at 
ar o u n d 8: 0 0 a m  wit h 2 0 0 
ml of ta p water, i n sitti n g 
p ositi o n , i n fasti n g c o n diti o ns. 
P art B:  Re peate d oral a d mi nistrati o n fr o m Da y 1 t o Da y 1 4. 
T he a d mi nistrati o n will ta ke place at ar o u n d 8: 0 0 a m a n d at 
ar o u n d 8: 0 0 p. m w it h 2 00 
ml of ta p water, i n sitti n g 
p ositi o n , i n fasti n g c o n diti o ns.  
 
Na me of t he c o m p o u n d:          Place b o  
P har mace utical f or m:  
        Matc hi n g ca ps ule  
D ose per a d mi nistrati o n:           N A  
Ti mi n g f or a d mi nistrati o n:       P art A:  Si n gle oral d ose a d mi nistrati o n o n D 1 acc or di n g t o 
t he ra n d o mizati o n. T he a d mi nistrati o n will ta ke place at 
ar o u n d 8: 0 0 a. m wit h 2 0 0 
ml of ta p water, i n sitti n g 
p ositi o n , i n fasti n g c o n diti o ns. 
P art B:  Re peate d oral a d mi nistrati o n fr o m Da y 1 t o Da y 1 4. 
T h e a d mi nistrati o n will ta ke place at ar o u n d 8: 0 0 a m a n d at 
ar o u n d 8: 0 0 p. m wit h 2 0 0 
ml of  ta p water, i n sitti n g 
p ositi o n, i n fasti n g c o n diti o ns.   
S u bjects : 
P art A:  Ei g ht healt h y male  a n d fe male  s u bj ects ( 6 acti ve a n d 2 place b o) will be i ncl u de d i n 
t he f o ur d ose le vel.  At least t w o healt h y fe male s u bj ects will be i ncl u de d i n eac h c o h ort . 
O ne of t h e m s h o ul d be all ocate d t o place b o. In t otal, 3 2 s u bjects  will be e nr olle d.  
 
P art B:  T wel ve healt h y male  a n d fe male  s u bj ects ( 9 acti ve a n d 3 place b o) will be i ncl u de d 
i n eac h d ose le vel.  B et wee n t hree a n d si x healt h y fe male s u bj ects will be i nc lu de d i n t he 
c o h ort . At least o ne of t he m s h o ul d be all ocate d t o place b o.  I n t otal, 3 6 s u bj ects will be 
e nr olle d.  
 
M ai n E v al u ati o n 
Criteri a:  
Pri m ar y e v al u ati o n criteri a:  
A E , vital si g ns, 1 2-lea d E C G, la b orat or y e xa ms. 
Sec o n d ar y e v al u ati o n criteri a:  
Meas ure me nt of p har mac o ki netics para meters: C ma x , tma x , λ z, t1/ 2, A U C 0 -last, A U Ci nf, V z/ F, 
C L/ F, Ae 0 -last, C LR , t otal a m o u nt i n faeces, pare nt: meta b olite(s) rati o. 
Meas ure me nt of C yt o ki ne I nfla m mati o n Mar kers  ( part B  o nl y)  a n d Le u k oc yte mar kers 
( C D 1 1 b &  C D 1 8 ), part A  e xc e pt f or first c o h ort  a n d part B . 
St u d y D ur ati o n :  
P art A:  
Scree ni n g wit hi n 2 1  da ys pr i or t o t he first a d mi nistrati o n. 
H os pitalizati o n a p pr o xi matel y f or 4  da ys ( D -1 m or ni n g t o D 4  m or ni n g) . Co nsi derati o n 
s h o ul d be gi ve n t o t he h os pitalizati o n after t he last d ose , i n f act it c o ul d be re vie w e d  acc or di n g 
t o P K para meters of t he c o m p o u n d after eac h d ose of S A D.  E x pecte d d urati o n : a p pr o xi matel y 
4  wee ks f or eac h partici pati n g s u bj ect . 
 
P art B:  
Scree ni n g wit hi n 2 1 da ys pri or t o t he first a d mi nistrati o n . 
H os pitalizati o n f or 1 7  da ys ( D -1 m or ni n g t o D 1 7 m or ni n g)  C o nsi derati o n s h o ul d be gi ve n 
t o t he h os pitalizati o n after t he last d ose , i n f act it c o ul d be re vie w e d  acc or di n g t o P K para met ers 
of t he c o m p o u n d after eac h d ose of M A D.  
E x pecte d d urati o n: a p pr o xi matel y 6  wee ks f or eac h p artici pati n g s u bj ect . 
 
St atistic s  
S a m ple size:  N o f or mal sa m ple size calc ulati o n was ma de. T he s u bj ects treate d wit h test 
pr o d uct a n d t he s u bj ects treate d wit h place b o are c o nsi dere d s ufficie nt t o detect dr u g 
effects a n d deter mi ne p har ma c o ki netic para meters bef ore es calati n g t o t he ne xt d ose le vel.  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 –  2 7/ M A R/ 2 0 1 8  
 
8 / 8 5  
T a ble 1:  S T U D Y F L O W C H A R T –  P A R T A : fr o m c o h ort 1 t o c o h ort 4 
Visit/ Peri o d
Scree ni n g
I ncl usi o n
E n d of st u d y visit
D a y
D- 2 1 t o D- 2
D- 1
D 1
D 2
D 3
D 4
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n criteria1
X
X
Pre vi o us Me dical / S ur gical Hist or y
X
Pri or/c o nc o mita nt me dicati o ns
X
X
X
X
X
X
P h ysical/ Me dical e xa mi n ati o ns
X
X
X
B o d y wei g ht, hei g ht
X
X
X
Hae mat ol o g y
X
X
X
X
He m ostasis
X
X
X
X
Bi oc he mistr y
X
X
X
X
Uri nal ysis
X
X
X
X
Ser ol o g y
X
Uri ne test f or dr u g a b use
X
X
Alc o h ol breat h test
X
X
A d missi o n
X
Disc har ge
X
Ra n d o mizati o n
X
St u d y Dr u g / Place b o A d mi nistrati o n 2
X
Vital si g ns : Bl o o d press ure / Heart rate 
/ Oral b o d y te m perat ure
X
X
X
X
X
1 2-lea d E C G rec or di n g 3
X
X
X
X
X
X
Bl o o d sa m ple f or P har mac o ki n etics
X
X
X
X
Bl o o d sa m ple f or P har mac o d y na mic 5
X
X
X 6
X 6
Uri ne c ollecti o n
X
X
X
X
X
Faeces c ollecti o n
X
X
X
X
X
A E c ollecti o n 4
Tre at me nt peri o d
 
1C o nfir mati o n of t h e I ncl usi o n/e xcl usi o n criteria pri or t o ra n d o mizati o n n u m ber assi g n me nt;   
2D ose: C o h ort 1, 2; 3 & 4;    Si n gle d ose i n t h e m or ni n g; All s u bjects will be i n fasti n g c o n diti o ns fr o m t h e e ve ni n g bef ore (at least 1 0 h, o ver ni g ht); 
3Safet y E C G;  
4All A Es will be re p orte d 
5 Starti n g o nl y fr o m t h e sec o n d asce n di n g d ose f or le uc oc ytes mar kers o nl y; 
6  T 4 8 h or T 7 2 h: ti me will be deter mi n e d aft er res ults of t h e first d ose a d mi nistere d. 
W he n E C G, vital si g ns a n d P K are re q uire d at t h e sa me ti me, t his s pecific or der will be f oll o we d: E C G first, t h e n vital si g ns, t he n a n d bl o o d sa m ple f or P K at t he e n d. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 –  2 7/ M A R/ 2 0 1 8  
 
9 / 8 5  
 
T a ble  2:   D E T AI LE D  F L O W C H A R T –  P A R T A   
Visit/ Peri o d 
I ncl usi o n
D a y
D- 1
D 4
T he oretic al ti me ( h)
Pre 
d ose
T 0
T 0, 5
T 1 
T 2 
T 3 
T 4 
T 5 
T 6 
T 7 
T 8 
T 9
T 1 0
T 1 2
T 1 6
T 2 4 
T 3 6 
T 4 0 
T 4 8 
T 6 0 
T 7 2
I ncl usi o n/ E xcl usi o n 
criteria
X
Pri or/c o nc o mita nt 
me dicati o ns
P h ysical/ Me dical 
e xa mi nati o ns
X
X
B o d y wei g ht; hei g ht  
X
X
Hae mat ol o g y
X
X
X
He m ostasis
X
X
X
Bi oc he mistr y
X
X
X
Uri nal ysis
X
X
X
Uri ne test f or dr u g 
a b use
X
Alc o h ol breat h test  
X
A d missi o n
X
Disc har ge
X
Ra n d o mizati o n
X
St u d y Dr u g 
A d mi nistrati o n
X
Bl o o d press ure / Heart 
rate / Oral B o d y 
T e m perat ure
X  
X
X  
X  
X
X
X  
X
X
1 2-lea d E C G rec or di n g  
X  
X
X  
X  
X  
X  
X  
X
X  
X
X
X
Bl o o d sa m ple f or 
P har mac o ki netics
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Bl o o d sa m ple f or 
P har mac o d y na mics
X
X  
X
X 1
X 1
Uri ne c ollecti o n
Faeces c ollecti o n
A E c ollecti o n
C ma x t he n C ma x + 3 h
D 2
D 3
Tre at me nt peri o d
D 1
X
X
X
X
X
X
X
X
X
X
 
1  T 4 8 h or T 7 2 h: ti me will be deter mi n e d aft er res ults of t h e first d ose a d mi nistere d  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6. 0 –  2 7/ M A R/ 2 0 1 8  
 
1 0  / 8 5  
 
T a ble  3:  S T U D Y F L O W C H A R T –  P A R T B : fr o m c o h ort 5 t o c o h ort 7 
Visit/ Peri o d
Scree ni n g 
I ncl usi o n
E n d of st u d y 
visit
D a y
D- 2 1 t o D- 2
D- 1  
D 1  
D 2  
D 3  
D 4  
D 5  
D 6  
D 7  
D 8  
D 9
D 1 0  
D 1 1  
D 1 2  
D 1 3  
D 1 4  
D 1 5  
D 1 6  
D 1 7
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n criteria1
X
X
Pre vi o us M e dical / S ur gical Hist or y
X
Pri or/c o nc o mita nt me dicati o ns
P h ysical/ Me dical e xa mi nati o ns
X
X  
X
X
X
X
X
X
B o d y wei g ht; hei g ht
X
X
X
Hae mat ol o g y 1
X
X
X
X
X
X
X
He m ostasis 1
X
X
X
X
X
X
X
Bi oc he mistr y 1
X
X
X
X
X
X
X
Uri nal ysis 1
X
X
X
X
X
X
X
Ser ol o g y
X
Uri ne test f or dr u g a b use
X
X
Alc o h ol breat h test
X
X
A d missi o n
X
Disc h ar ge
X
Ra n d o mizati o n
X
St u d y Dr u g / Place b o A d mi nistrati o n 3
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Bl o o d press ure / Heart rate / Oral b o d y 
te m perat ure
X
X  
X
X
X
X
X
X
1 2-lea d E C G rec or di n g
X
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
X  
X
X
Bl o o d sa m ple f or P har mac o ki netics
X  
X
X  
X
X  
X
X  
X  
X  
X
C yt o ki ne plas ma c ollecti o n
X
X
X
X  
X
Le u k oc ytes s u bsets bl o o d c ollecti o n
X
X  
X
Uri ne c ollecti o n
X  
X  
X
X  
X
X  
X
X  
X  
X  
X
Faeces c ollecti o n
X  
X  
X
X  
X
X  
X
X  
X  
X  
X
A E c ollecti o n 4
Tre at me nt peri o d
X 5
 
 
1C o nfir mati o n of t h e I ncl usi o n/e xcl usi o n criteria pri or t o ra n d o mizati o n n u m ber assi g n me nt;   
 
4All A Es will be re p orte d 
5Ti me wi n d o w fr o m D 5 t o D 7: T pre d ose et T c ma x 
 
W he n E C G, vital si g ns a n d P K are re q uire d at t h e sa me ti me, t his s pecific or der will be f oll o we d: E C G first, t h e n vital si g ns,a n d bl o o d sa m ple f or P K at t he e n d.  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 2  / 8 5  
T A B L E O F C O N T E N T S 
1.  
S CI E N TI FI C J U S TI FI C A TI O N A N D G E N E R A L D E S C RI P TI O N O F T H E R E S E A R C H  . 1 8  
1. 1.  I ntr o d ucti o n a n d b ac k gr o u n d ........................................................................................................ 1 8  
1. 2.  S u m m ar y of a v ail a ble res ults of n o n -cli nic al st u dies a n d cli nic al st u dies perti ne nt t o t he 
bi o me dic al rese arc h c o ncer ne d  ...................................................................................................... 1 8  
1. 2. 1.  
N o n cli nical st u dies  .................................................................................................................. 1 8  
1. 2. 1. 1.  
N o n cli nical pri mar y p har mac ol o g y  .................................................................................. 1 8  
1. 2. 1. 2.  
S afet y P har mac ol o g y ......................................................................................................... 2 0  
1. 2. 1. 3.  
P har mac o ki netics  .............................................................................................................. 2 0  
1. 2. 1. 4.  
T o xic ol o g y  ........................................................................................................................ 2 6  
1. 3.  S u m m ar y of t he p ote nti al ris k a n d be nefits t o h u m a n s u bjects  .................................................. 2 8  
1. 4.  Descri pti o n a n d j ustific ati o n f or t he d os a ge re gi me n  ................................................................... 2 8  
1. 5.  Et hic al c o nsi der ati o ns  ..................................................................................................................... 2 9  
1. 6.  Descri pti o n of t he p o p ul ati o n t o be st u die d  ................................................................................... 3 0  
1. 7.  Ref ere nces  ........................................................................................................................................ 3 0  
2.  
S T U D Y O B J E C TI V E S A N D  P U R P O S E  ...................................................................................... 3 0  
2. 1.  P ri nci p al o bjecti ve  ........................................................................................................................... 3 0  
2. 2.  Sec o n d ar y o bjecti ves  ....................................................................................................................... 3 0  
3.  
S T U D Y D E SI G N  ............................................................................................................................. 3 1  
3. 1.  E v al u ati o n criteri a  ........................................................................................................................... 3 1  
3. 1. 1.  
Pri mar y e n d p oi nt  ..................................................................................................................... 3 1  
3. 1. 2.  
Sec o n dar y e n d p oi nts  ................................................................................................................ 3 1  
3. 2.  Desi g n ................................................................................................................................................ 3 1  
3. 3.  Descri pti o n of t he me as ures t a ke n t o  mi ni mize a n d a v oi d bi as  ................................................... 3 2  
3. 3. 1.  
Ra n d o mizati o n  ......................................................................................................................... 3 2  
3. 3. 2.  
Bli n di n g  ................................................................................................................................... 3 2  
3. 3. 3.  
Ris k assess me nt, st u d y c o n d uct a n d met h o d of d ose escalati o n  .............................................. 3 2  
3. 3. 3. 1.  
N u m ber of s u bjects recei vi n g t he st u d y dr u g si m ulta ne o usl y  ........................................... 3 2  
3. 3. 3. 2.  
D ose Escalati o n  ................................................................................................................. 3 2  
3. 4.  E x pecte d d ur ati o n of s u bject p artici p ati o n  ................................................................................... 3 3  
3. 4. 1.  
Descri pti o n a n d d urati o n of trial peri o ds  ................................................................................. 3 3  
3. 4. 2.  
D urati o n of f oll o w -u p  .............................................................................................................. 3 4  
3. 5.  St o p pi n g r ules  .................................................................................................................................. 3 4  
3. 5. 1.  
St o p pi n g r ule a p plica ble at a n y ti me  ........................................................................................ 3 4  
3. 5. 2.  
St o p pi n g r ule f or a s u bject  ....................................................................................................... 3 4  
3. 5. 3.  
St o p pi n g r ules wit hi n a gr o u p  .................................................................................................. 3 4  
3. 5. 4.  
St o p pi n g r ule f or d ose escalati o n  ............................................................................................. 3 4  
3. 6.  Re m o v al of S u bjects f r o m T her a p y or Assess me nt  ...................................................................... 3 5  
3. 7.  Bli n d a n d pr oce d ures f or u n bli n di n g  ............................................................................................. 3 5  
3. 7. 1.  
C o di n g list  ................................................................................................................................ 3 6  
3. 7. 2.  
Brea ki n g t he bli n d  .................................................................................................................... 3 6  
4.  
S T U D Y P O P U L A TI O N  .................................................................................................................. 3 6  
4. 1.  S u bject i ncl usi o n criteri a  ................................................................................................................ 3 6  
4. 2.  S u bject n o n -i ncl usi o n criteri a......................................................................................................... 3 7  
4. 3.  S u bject I de n tific ati o n ...................................................................................................................... 3 8  
4. 3. 1.  
Scree ni n g n u m ber  .................................................................................................................... 3 8  
4. 3. 2.  
I ncl usi o n n u m ber ..................................................................................................................... 3 8  
4. 3. 3.  
Ra n d o mizati o n n u m ber  ............................................................................................................ 3 8  
4. 4.  S u bject wit h dr a w al c riteri a ............................................................................................................ 3 8  
4. 4. 1.  
Defi niti ve or te m p orar y st o p of a pers o n’s partici pati o n i n t he researc h  ................................. 3 8  
4. 4. 1. 1.  
List of wit h dra wal criteria  ................................................................................................. 3 8  
4. 4. 1. 2.  
Reas o ns f or wit h dra wal  ..................................................................................................... 3 8  
4. 4. 2.  
Defi niti ve or  te m p orar y st o p of a part or t he t otalit y of t he researc h ....................................... 3 8  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 3  / 8 5  
4. 4. 2. 1.  
D eci de d b y t he S p o ns or  ..................................................................................................... 3 8  
4. 4. 2. 2.  
Deci de d b y t he I n vesti gat or  ............................................................................................... 3 9  
4. 5.  P re m at ure disc o nti n u ati o n of s u bject  ............................................................................................ 3 9  
4. 5. 1.  
Data t o be c ollecte d, a n d ti me of rec or di n g of t hese data  ........................................................ 3 9  
4. 5. 2.  
Met h o ds of re place me nt ........................................................................................................... 3 9  
4. 5. 3.  
Met h o ds of f oll o w -u p of pre mat ure disc o nti n uati o ns  .............................................................. 3 9  
4. 6.  E xcl usi o n peri o d  .............................................................................................................................. 3 9  
5.  
S T U D Y P R O D U C T/ T R E A T M E N T  .............................................................................................. 4 0  
5. 1.  Descri pti o n of t he tre at me nt(s)  ....................................................................................................... 4 0  
5. 1. 1.  
P har mace ut ical f or m ................................................................................................................ 4 0  
5. 1. 2.  
U nit f or m, ma n ufact ure, pac ka gi n g a n d la belli n g  ................................................................... 4 0  
5. 1. 3.  
R o ute a n d m o de of a d mi nistrati o n  ........................................................................................... 4 2  
5. 2.  Acc o u nt a bilit y pr oce d ures f or t he i n vesti g ati o n al pr o d uct(s)  ..................................................... 4 2  
5. 2. 1.  
Res p o nsi bilities  ........................................................................................................................ 4 2  
5. 2. 2.  
Acc o u nta bilit y  .......................................................................................................................... 4 3  
5. 2. 3.  
Ret ur n a n d / or destr ucti o n of I M P  ........................................................................................... 4 3  
5. 3.  Me dic ati o n(s)/tre at me nt(s) per mitte d a n d n o per mitte d bef ore a n d/ or d uri n g t he tri al  .......... 4 3  
5. 4.  P r oce d ures of m o nit ori n g s u bject c o m pli a nce  .............................................................................. 4 3  
6.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C  ................................................................................ 4 4  
6. 1.  P h ar m ac o ki netic e n d p oi nts ............................................................................................................ 4 4  
6. 2.  S pecific ati o n of p h ar m ac o ki netic p ar a meters ............................................................................... 4 6  
6. 3.  Met h o ds a n d ti mi n g f or assessi n g, rec or di n g, a n d a n al ysi n g p h ar m ac o ki netic p ar a meters  .... 4 7  
6. 3. 1.  
C ollecti o n, treat me nt a n d st ora ge of bl o o d sa m ples  ................................................................ 4 7  
6. 3. 2.  
C ollecti o n, treat me nt a n d st ora ge of uri ne sa m ples  ................................................................. 5 0  
6. 3. 3.  
C ollecti o n, treat me nt a n d st ora ge of faeces sa m ples  ............................................................... 5 0  
6. 4.  A n al ytic al met h o ds  .......................................................................................................................... 5 1  
7.  
A S S E S S M E N T O F P H A R M A C O D Y N A MI C .............................................................................. 5 1  
7. 1.  C yt o ki ne I nfl a m m ati o n M ar ker a n al ysis  ...................................................................................... 5 1  
7. 2.  Le u k oc ytes s u bset bl o o d s a m ples  ................................................................................................... 5 2  
8.  
A S S E S S M E N T O F S A F E T Y  ......................................................................................................... 5 3  
8. 1.  S pecific ati o n of s afet y p ar a meters  ................................................................................................. 5 4  
8. 1. 1.  
Cli nical para meters  .................................................................................................................. 5 4  
8. 1. 1. 1.  
Bl o o d press ure a n d  heart rate  ............................................................................................ 5 4  
8. 1. 1. 2.  
P h ysical e xa mi nati o n ......................................................................................................... 5 4  
8. 1. 1. 3.  
B o d y wei g ht a n d hei g ht  ..................................................................................................... 5 4  
8. 1. 1. 4.  
Electr ocar di o gra m ( E C G)  ................................................................................................. 5 4  
8. 1. 2.  
Bi ol o gical para meters  .............................................................................................................. 5 4  
8. 1. 2. 1.  
R o uti ne la b orat or y o bser vati o ns  ........................................................................................ 5 4  
8. 1. 2. 2.  
Uri nal ysis  .......................................................................................................................... 5 5  
8. 1. 2. 3.  
Dr u g of a b use scree ni n g tests  ............................................................................................ 5 5  
8. 1. 2. 4.  
Ser ol o gies  .......................................................................................................................... 5 5  
8. 1. 3.  
Ot her para meters  ...................................................................................................................... 5 5  
8. 1. 3. 1.  
Alc o h ol breat h test  ............................................................................................................ 5 5  
8. 2.  St u d y P r oce d ure  .............................................................................................................................. 5 5  
8. 2. 1.  
Scree ni n g pr oce d ures  ............................................................................................................... 5 5  
8. 2. 2.  
Descri pti o n b y t y pe of visit  ...................................................................................................... 5 6  
8. 2. 3.  
Sa m ple d bl o o d v ol u me  ............................................................................................................ 6 0  
8. 3.  E v al u ati o n of A d verse E ve nt a n d S afet y I nf or m ati o n  ................................................................. 6 1  
8. 3. 1.  
Rec or di n g of a d verse e ve nts  .................................................................................................... 6 3  
8. 3. 2.  
A nal ysis of a d verse e ve nts  ....................................................................................................... 6 3  
8. 4.  P r oce d ures i n pl ace f or t he rec or di n g a n d n otific ati o n of seri o us a d verse e ve nts, S U S A R a n d 
ne w e ve nts  ......................................................................................................................................... 6 4  
Peri o dical Re p orti n g t o Re g ulat or y A ut h orities a n d I n vesti gat ors  .......................................................... 6 7  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 4  / 8 5  
8. 5.  T y pe a n d d ur ati o n of t he f oll o w -u p of s u bjects after a d verse e ve nts  ......................................... 6 7  
8. 6.  P R E G N A N C Y I N T H E C LI NI C A L T RI A L  ................................................................................ 6 7  
8. 7.  O V E R D O S E  ..................................................................................................................................... 6 8  
9.  
D A T A M A N A G E M E N T  ................................................................................................................. 6 8  
9. 1.  Defi niti o n of s o urce d at a  ................................................................................................................. 6 8  
9. 2.  S o urce d oc u me nt re q uire me nts  ...................................................................................................... 6 8  
9. 3.  Use a n d c o m pleti o n of  t he e C R F a n d  a d diti o n al re q uest  ............................................................ 6 8  
9. 3. 1. 1.  
Data c ollecti o n ................................................................................................................... 6 8  
9. 3. 1. 2.  
Res p o nsi bilities  ................................................................................................................. 6 8  
9. 3. 1. 3.  
Data Ma na ge me nt  ............................................................................................................. 6 9  
9. 4.  St u d y m o nit ori n g  ............................................................................................................................. 6 9  
9. 5.  Access t o d at a b y t he s u bjects  ......................................................................................................... 6 9  
1 0.  
S T A TI S TI C S  .................................................................................................................................... 7 0  
1 0. 1.  Descri pti o n of t he st atistic al me t h o ds ............................................................................................ 7 0  
1 0. 1. 1.  
Descri pti ve statistics  ................................................................................................................ 7 0  
1 0. 1. 1. 1.  
S u bj ect de m o gra p hic c haracteristics, me dical hist or y a n d dia g n oses  ............................... 7 0  
1 0. 1. 1. 2.  
Pre vi o us me dicati o ns ......................................................................................................... 7 0  
1 0. 1. 1. 3.  
Baseli ne s afet y para meters  ................................................................................................ 7 0  
1 0. 1. 1. 4.  
St u d y dr u g a n d c o nc o mita nt t hera p y  ................................................................................. 7 0  
1 0. 1. 1. 5.  
P har mac o ki netics  .............................................................................................................. 7 0  
1 0. 1. 2.  
A nal ysis of pri nci pal criteria .................................................................................................... 7 1  
1 0. 1. 2. 1.  
A d v erse e ve nt (f or eac h part)  ............................................................................................ 7 1  
1 0. 1. 2. 2.  
P h ysical e xa mi nati o n, E C G a n d vital si g ns (f or eac h part)  ............................................... 7 1  
1 0. 1. 2. 3.  
La b orat or y para meters (f or eac h part)  ............................................................................... 7 2  
1 0. 1. 1.  
A nal ysis of sec o n dar y criteria  .................................................................................................. 7 2  
1 0. 1. 1. 1.  
F or mal statistics f or p har mac o ki netic  ............................................................................... 7 2  
1 0. 1. 1. 2.  
C orrelati o n bet wee n p har mac o ki netic a n d p har mac o d y na mic para meters  ....................... 7 3  
1 0. 1. 2.  
Cale n dar f or a nal yses  ............................................................................................................... 7 3  
1 0. 2.  S a m ple size  ....................................................................................................................................... 7 3  
1 0. 3.  Le vel of si g nific a nce t o be use d  ...................................................................................................... 7 3  
1 0. 4.  I nteri m An al ysis  ............................................................................................................................... 7 3  
1 0. 5.  P r oce d ure f or acc o u nti n g, f or missi n g, u n use d, a n d s p uri o us d at a  ............................................ 7 3  
1 0. 6.  P r oce d ures f or re p orti n g a n y de vi ati o n(s) fr o m ori gi n al st atistic al pl a n  ................................... 7 4  
1 0. 7.  Selecti o n of s u bjects t o be i ncl u de d i n t he a n al yses  ...................................................................... 7 4  
1 1.  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  ................................................................................ 7 4  
1 1. 1.  Q u alit y Ass ur a nce  ........................................................................................................................... 7 4  
1 1. 2.  Q u alit y C o ntr ol  ................................................................................................................................ 7 4  
1 1. 3.  S p o ns or a u dits a n d i ns pecti o ns b y re g ul at or y a ge ncies  ............................................................... 7 4  
1 2.  
E T HI C S  ............................................................................................................................................ 7 4  
1 2. 1.  I nf or me d c o nse nt f or m .................................................................................................................... 7 4  
1 2. 2.  Et hics C o m mittee a n d C o m pete nt A ut h orities  ............................................................................. 7 5  
1 2. 3.  P r ot oc ol a me n d me nts  ...................................................................................................................... 7 5  
1 2. 4.  P r ot oc ol de vi ati o ns  .......................................................................................................................... 7 5  
1 3.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .......................................................................... 7 5  
1 3. 1.  Arc hi v al  ............................................................................................................................................ 7 5  
1 3. 2.  C o nfi de nti alit y  ................................................................................................................................. 7 5  
1 3. 3.  O w ners hi p of res ults  ........................................................................................................................ 7 5  
1 4.  
FI N A N CI N G A N D I N S U R A N C E  .................................................................................................. 7 6  
1 5.  
P U B LI C A TI O N  ............................................................................................................................... 7 6  
1 6.  
LI S T O F A P P E N DI C E S  ................................................................................................................. 7 6  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 5  / 8 5  
 
 
L I S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S 
 
 
Ge neral ter ms 
A N S M   
: 
A ge nce Nati o nale de séc urité d u mé dica me nt et des pr o d uits de 
sa nté 
c G C P  
: 
C urre nt G o o d Cli nical Practice  
C P P  
 
: 
C o mité de Pr otecti o n des Pers o n nes  
C R F  
 
: 
Case Re p ort F or m   
C R O   
: 
C o ntract Rresearc h Or ga nisati o n  
C S P  
 
: 
C o de de la Sa nté P u bli q ue  
C S R  
 
: 
Cli nical St u d y Re p ort   
C Q A   
: 
Cli nical Q ualit y Ass ura nce  
E C  
 
: 
Et hics c o m mittee  
E O S  
 
 
E n d Of St u d y Visit  
F D A  
 
: 
F o o d a n d Dr u g A d mi nistrati o n  
FI M  
 
: 
First i n me n  
G C P   
: 
G o o d Cli nical Practice  
G L P  
 
: 
G o o d la b orat or y practice  
I C H 
 
: 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I M P 
 
: 
I n vesti gati o nal Me dici nal Pr o d uct  
I R B/I E C 
: 
I nstit uti o nal re vie w b oar d / et hical re vie w b oar d 
Me d D R A  
: 
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N T E A E  
: 
N o n -Treat me nt E mer ge nt A d verse E ve nt  
PI  
 
: 
Pri nci pal I n vesti gat or  
O T R   
: 
O n T reat me nt Res p o nse 
S A D  
 
: 
Si n gle a d mi nistrati o n d ose  
S m P C   
: 
S u m mar y of Pr o d uct C haracteristics  
 
Safet y 
A E  
 
: 
A d verse E ve nt  
A R  
 
: 
A d verse Reacti o n  
L D 5 0   
: 
Me dia n Let hal D ose  
M T D   
: 
Ma xi m u m T olerate d D ose  
S A E  
 
: 
Seri o us A d verse E ve nt  
S A R  
 
: 
Seri o us A d verse Reacti o n  
S U S A R  
: 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T E A E   
: 
Treat me nt E mer ge nt A d verse E ve nt  
 
Me dical 
B P  
 
: 
Bl o o d press ure   
b p m  
 
: 
beats per mi n ute   
B W  
 
: 
B o d y Wei g ht  
E C G   
: 
Electr ocar di o gra m   

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 6  / 8 5  
H R  
 
: 
Heart Rate   
I V 
 
: 
I ntra ve n o us 
S B P  
 
: 
S yst olic Bl o o d Press ure   
 
Bi ol o gics 
A L T  
 
: 
Ala ni ne Le uci ne Tra nsferase  
A S T  
 
: 
Ala ni ne seri ne tra nsferase   
C H C   
: 
C hr o nic viral he patitis C  
C P K   
: 
Creati ne p h os p h o ki nase  
G G T   
: 
Ga m ma Gl uta m y 1 Tra nsferase   
H Bs  
 
: 
He patitis B s urface a nti ge n   
H C V   
: 
He patitis C vir us   
HI V  
 
: 
H u ma n I m m u n o deficie nc y Vir us  
HI V 1   
: 
H u ma n I m m u n o deficie nc y Vir us t y pe 1   
HI V 2   
: 
H u ma n I m m u n o deficie nc y Vir us t y pe 2   
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  
M C V   
: 
Mea n C or p usc ular V ol u me  
P N M  
P oli m or p h o n uclear le u k oc ytes  
R B C   
: 
Re d Bl o o d Cells  
W B C   
: 
W hite Bl o o d Cells   
 
Bi oa nal ysis 
A L Q  
L O Q   
: 
A b o ve li mit of q ua ntificati o n  
Li mit of q ua ntificati o n  
U L O Q  
U p per li mit of q ua ntificati o n  
   
P har mac o ki netics  
 
Ae  
A m o u nt e xcrete d i n uri ne 
Ae 0 -l ast 
C u m ulati ve uri nar y e xcreti o n u p t o t he fi nal uri nar y c ollecti o n 
i nter val 
A U C  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
A U C 0 -l ast 
 
A U C i nf 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o 
t o i nfi nit y 
A U C 0 -1 2 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o 
t o 1 2 h o urs p ost -d osi n g  
A U C 0 -2 4 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o 
t o 2 4 h o urs p ost -d osi n g  
A U C 0 -7 2 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o 
t o 7 2  h o urs p ost -d osi n g  
A U C τ 
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
wit hi n a 
1 2 -h o ur d osi n g i nter val at stea d y state  
C L/ F  
A p pare nt cleara nce   
C L R  
Re nal cleara nce  
C L ss/ F 
C L/ F at stea d y state  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 7  / 8 5  
C m a x  
Ma xi m u m plas ma c o nce ntrati o n  
C ss, a v 
A vera ge plas ma c o nce ntrati o n at stea d y state  
C ss, m a x 
Ma xi m u m plas ma c o nce ntrati o n at stea d y state  
C ss, mi n 
Meas ure d plas ma c o nce ntrati o n at t he e n d of t he d osi n g 
i nter val 
P K  
P har mac o ki netic(s)  
P T F %  
Pea k tr o u g h fl uct uati o n  
t½  
T er mi nal half -life 
tm a x  
Ti me of ma xi m u m plas ma c o nce ntrati o n  
tss, m a x 
Ti me t o ma xi m u m plas ma c o nce ntrati o n at stea d y state  
V d  
 
: 
A p pare nt v ol u me of distri b uti o n  
V dss  
 
: 
A p pare nt v ol u me of distri b uti o n at stea d y state  
z 
T er mi nal p hase rate c o nsta nt  
 
 
Data Ma na ge me nt & Statistics 
CI  
 
: 
C o nfi de nce I nter val  
D C F  
 
: 
Data Clarificati o n F or m  
D R F  
 
: 
Data Res ol uti o n F or m  
e C R F  
: 
Electr o nic Case Re p ort F or m  
G M  
Ge o metric mea n  
Mi n  
Mi ni m u m  
M a x  
Ma xi m u m  
N  
N u m ber  
S D  
 
: 
Sta n dar d De viati o n  
S E M   
: 
Sta n dar d Err or of t he Mea n     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
1 8  / 8 5  
1.  S CI E N TI FI C 
J U S TI FI C A TI O N 
A N D 
G E N E R A L 
D E S C RI P TI O N 
O F 
T H E 
R E S E A R C H 
1. 1.  
I ntr o d ucti o n a n d b ac k gr o u n d 
D F 2 7 5 5 A is a n o vel s mall m olec ular wei g ht selecti ve C X C R 1/ 2 (c he m o ki ne rece pt or 1 a n d 2) 
i n hi bit or, ai me d at pr o vi di n g a n oral t hera p y f or I nterstitial c ystitis/ bla d der pai n s y n dr o me (I C/ B P S) a n d 
ot her i nfla m mat or y or pai n-relate d c o n diti o ns. D F 2 7 5 5 A is a p ote nt a n d selecti ve all osteric m o d ulat or of 
b ot h C X C R 1 a n d C X C R 2 a n d i n hi bits C X C L- 1 a n d C X C L- 8 (I L- 8)-relate d h u ma n ne utr o p hil c he m ota xis 
w hile s h o wi n g selecti vit y o ver ot her c he m o ki nes. 
 
1. 2.  
S u m m ar y of a v ail a ble res ults of n o n-cli nic al st u dies a n d cli nic al st u dies perti ne nt t o t he 
bi o me dic al rese arc h c o ncer ne d 
 
1. 2. 1.  N o n cli nic al st u dies 
1. 2. 1. 1.  N o n cli nic al pri m ar y p h ar m ac ol o g y 
D F 2 7 5 5 A i n hi bits C X C R 1 a n d C X C R 2 si g nalli n g after I L- 8 bi n di n g, i n h u ma n p ol y m or p h o n uclear 
le u k oc ytes ( P M N Ls), b y a n o n-c o m petiti ve all osteric mec ha nis m of acti o n. Pre-i nc u bati o n of P M N Ls 
wit h D F 2 7 5 5 A at 1 µ M de m o nstrate d t hat D F 2 7 5 5 A i n hi bits I L- 8-i n d uce d G- pr otei n acti vati o n wit h o u t 
m o dif yi n g eit her t he n u m ber or t he affi nit y of t he rece pt ors. T he all osteric bi n di n g 
m o de 
was 
de m o nstrate d b y site-s pecific m uta ge nesis st u dies a n d s h o we d t hat D F 2 7 5 5 A i n d uces a n u nc o u ple d 
c o nf or mati o n t hat ca n n ot tra ns d uce t he I L- 8 si g nal. D F 2 7 5 5 A di d n ot affect t he mi grati o n of P M N Ls 
i n d uce d b y C 5a a n d f M L P or m o n oc yte mi grati o n i n d uce d b y C C L 2. Si milarl y, n o effect of D F 2 7 5 5 A 
was o bser ve d o n t he pr o d ucti o n of P G E 2 i n d uce d b y L P S. T hese res ults s u g gest t hat i n hi biti o n of I L- 8-
i n d uce d si g nalli n g is relate d t o C X C R 1/ 2 i n hi biti o n rat her t ha n ot her c he m o ki nes or c ycl o- o x y ge nase 
acti vit y. A pa nel scree n wit h D F 2 7 5 5 A at 1 0 µ M a gai nst a series of a dre ner gic, hista mi nic, m uscari nic, 
ne ur o ki ni n, o pi oi d a n d ser ot o ni ner gic rece pt ors re veale d n o i n hi bit or y pr o perties, w hile s pecific st u dies i n 
cell- base d assa ys i de ntifie d a n a g o nistic effect a gai nst t he ca n na bi n oi d rece pt or 2 ( C B 2) wit h a n E C 5 0 of 
1 7. 4 µ M b ut n o effects t o war ds t he C B 1 rece pt or, t he bra d y ki ni n rece pt ors B 1 or B 2 or d o pa mi ne 
rece pt or D 2 or D 3. 
D F 2 7 5 5 A i n hi bite d C X C L 1- a n d I L- 8-i n d uce d mi grati o n of h u ma n P M N Ls i n a c o nce ntrati o n- de pe n de nt 
ma n ner wit h I C 5 0 val ues of 2. 1 a n d 4. 2 n M f or C X C L 1 a n d I L- 8, res pecti vel y, Fi g ure 1. I n t he a bse nce 
of c he m o ki ne sti m ulati o n, D F 2 7 5 5 A di d n ot m o d ulate s p o nta ne o us mi grati o n. 
 
 
Fi g ure 1.  H u ma n P M N Ls were pre-i nc u bate d at 3 7° C f or 1 5 mi n wit h ve hicle or D F 2 7 5 5 A. h P M N Ls 
were t he n teste d f or t heir a bilit y t o mi grate i n res p o nse t o I L- 8 ( 1 n M) or C X C L 1 ( 1 0 n M). Data are 
e x presse d as Mea n ± S D of 5- 6 i n de p e n de nt e x peri me nts. S p o nta ne o us h P M N L mi grati o n was 7 ± 1 1. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 0  / 8 5  
 
1. 2. 1. 2.  S a f et y P h ar m ac ol o g y 
St u d y T y pe/ S pecies/ 
R o ute/ G L P St at us  
D ose 
Le vels  
Res ults  
Ne ur o be ha vi oral 
st u d y/ Rat/ Si n gle d ose oral/ G L P 
 
5 0 m g/ k g  
--- 
1 0 0 m g/ k g  
--- 
1 5 0 m g/ k g  
N O E L  
Res pirat or y f u ncti o n 
st u d y/ Rat/ Si n gle d ose oral/ G L P 
 
5 0 m g/ k g  
--- 
1 0 0 m g/ k g  
N O E L  
1 5 0 m g/ k g  
 res pirat or y rate ( 1 4. 5 %) at 1-3 h p ost d ose.  
Effects o n t he h E R G c ha n nel i n 
H E K cells/i n vitr o/ G L P  
 
1 0 µ M  
9 3. 0 9 ± 6. 6 6 % of c o ntr ol  
5 0 µ M  
9 8. 5 2 ±  1 0. 2 % of c o ntr ol  
1 0 0 µ M  
8 0. 9 0 ± 1. 4 7 % of c o ntr ol  
3 0 0 µ M  
9 1. 5 0 ± 1. 0 6 % of c o ntr ol  
1 0 0 0 µ M  
8 9. 1 8 ± 2. 7 4 % of c o ntr ol  
Car di o vasc ular effect i n 
a naest hetise d G ui nea pi gs after 
I V a d mi nistrati o n/ n o n-G L P .  
1 m g/ k g  
--- 
3 m g/ k g  
--- 
1 0 m g/ k g  
N O E L  
3 0 m g/ k g  
 tra nsie nt diast olic B P ( n o n-si g nifica nt) 
Car di o vasc ular a n d b o d y 
te m perat ure Tele metr y st u d y/ 
D o g/ Si n gle d ose oral/ G L P [ 2 6]  
3 0 m g/ k g  
--- 
7 5 m g/ k g  
N O E L  
1 2 5 m g/ k g  
 heart rate ( u p t o 5 2 %),  b o d y te m perat ure 
( u p t o 0. 7 ° C),   s yst olic ( 3-8 h p ost d ose),  
arterial press ure,  p ulse press ure,  R R, P R 
a n d  Q T.  
A b bre vi ati o ns : --- = n o n ote w ort h y fi n di n gs see n;  = i ncrease d;  = decrease d; H E K = H u ma n E m br y o nic Ki d ne y; h E R G = h u ma n 
et her-a-g o -g o -r elate d ge ne; N O E L = N o-o bser ve d -effect -le vel.  
1. 2. 1. 3.  P h ar m ac o ki netics 
P har mac o ki netics of 
D F 2 7 5 5 A 
were st u die d i n rats a n d 
mice after si n gle i. v. a n d oral 
a d mi nistrati o n; f urt her m ore, p har mac o ki netics were als o e val uate d after m ulti ple oral a d mi nistrati o ns i n 
rats a n d d o gs t o assess t he t o xicit y. Besi des, t he a bs or pti o n, distri b uti o n, meta b olis m a n d e xcreti o n after 
i. v. a n d p. o. of [1 4C] D F 2 7 5 5 A has bee n st u die d i n rats a n d, after p. o. a d mi nistrati o n i n d o gs. 
D F 2 7 5 5 A is al m ost c o m pletel y a bs or be d after oral a d mi nistrati o n i n rats a n d t he a bs ol ute 
bi oa vaila bilit y i n b ot h r ats a n d mice is hi g her t ha n 8 0 % .  
N o ge n der differe nces i n p har mac o ki netic pr ofile were o bser ve d i n all a ni mal s pecies. 
F oll o wi n g i ntra ve n o us a d mi nistrati o n, t he s yste mic cleara nce ra n ge d fr o m 2- 8 % of t he he patic 
bl o o d fl o w i n all s pecies . T he v ol u me of distri b uti o n at stea d y state ( Vss) was 0. 3- 0. 4 L/ K g i n all s pecies.  
After oral a d mi nistrati o n, plas ma le vels ge nerall y reac h e d ma xi mal val ues wit hi n 2 h i n rats a n d 
t he n decli nes i n a m o n o or bi p hasic ma n ner wit h ter mi nal eli mi nati o n half-li ves of 3- 8 h. Plas ma half-li ves 
were si milar after i ntra ve n o us a n d oral a d mi nistrati o n, s u g gesti n g t hat t he a bs or pti o n di d n ot i nterfere 
wit h t he eli mi nati o n rate of D F 2 7 5 5 A. 
 
I n t he male a n d fe male fertilit y a n d e m br y o-fetal de vel o p me nt c o m bi ne d st u d y wit h D F 2 7 5 5 A 
m o n o h y drate i n rats b y oral ga va ge, t he plas ma e x p os ure was meas ure d i n fe males o n da y 1 7 p ost-
c oit u m. 
At all d ose le vels t he pea k plas ma c o nce ntrati o n, C ma x , was reac he d at 1 h o ur after d osi n g. F or all 
gr o u ps t last was 2 4 h o urs, as t his was t he ti me p oi nt o n w hic h t he last sa m ple was ta ke n.  
O n Da y 1 7 p ost-c oit u m, t he C ma x  val ues a n d t he s yste mic e x p os ure, i n ter ms of A U Clast, i ncrease d wit h 
i ncreasi n g d ose i n a lar gel y d ose- pr o p orti o nal ma n ner. 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 2  / 8 5  
 
 
Fi g ure 4: Re pres e nt ati ve pr ofile s h o wi n g c o nce ntr ati o ns of r a di o acti vit y i n pl as m a o bt ai ne d fr o m f e m al e B e a gle d o gs 
f oll o wi n g a si n gle or al a d mi nist r ati o n of [ 1 4 C] D F 2 7 5 5 A at a t ar get d os e r ate of 4 0 m g free c o m p o u n d/ k g 
C o nce ntrati o ns of u nc ha n ge d D F 2 7 5 5 A (i.e. D F 2 7 5 5 Y) i n plas ma were als o deter mi ne d. Ma xi m u m mea n 
plas ma c o nce ntrati o ns of 1 2 7 a n d 1 9 4 μ g/ m L res pecti vel y, were meas ure d 3 0 mi n utes p ost d ose  ( Ta ble 
3) . 
T a ble 3: P h ar m ac o ki netic p ar a meters of r a di o acti vit y i n pl as m a a n d D F 2 7 5 5 free c o m p o u n d ( D F 2 7 5 5 Y) i n pl as m a 
f oll o wi n g a si n gle or al a d mi nist r ati o n of [ 1 4 C] D F 2 7 5 5 A t o m al e a n d fe m ale B e a gle d o gs at a t ar get d os e of 4 0 m g free 
c o m p o u n d/ k g 
P ar a meter  
M ale
 a 
Fe m ale  a 
R a di o acti vit y i n pl as m a  
D F 2 7 5 5 Y 
i n pl as m a  
R a di o acti vit y i n 
pl as m a  
D F 2 7 5 5 Y 
i n pl as m a  
t ma x ( h) 
0. 5  
0. 5  
0. 5  
0. 5  
C ma x  ( µ g e q ui v/ g)) 
1 1 6. 2  
1 2 7  
1 5 7. 7  
1 9 4  
A U C 0 -t ( µ g e q ui v∙h/ g) 
3 5 7. 7 8 3  
2 1 9. 6 3 7  
5 5 7. 6 9 3  
3 9 8. 9 4 1  
A U C 0 -i nf ( µ g e q ui v∙h/ g) 
4 0 6. 8 1 6  
2 2 0. 5 3 0  
6 3 7. 2 7 7  
3 9 9. 1 5 9  
k ( h – 1)  
0. 0 0 6 2 6  
0. 0 5 1 9  
0. 0 0 5 5 7  
0. 0 6 2 2  
t ½ ( h) 
1 1 0. 7  
1 3. 4  
1 2 4. 5  
1 1. 1  
a 
Res ults are base d o n a mea n of 3 a ni mals p er sa m pli n g ti me p oi nt  
 
N ote: Ra di oacti vit y val ues are e x presse d as µ g e q ui vale nts/ g a n d t he u nits f or D F 2 7 5 5 Y plas ma c o nce ntrati o ns are µ g/ m L  
 
T he differe nce bet wee n t he t w o meas ure me nts of t otal ra di oacti vit y a n d D F 2 7 5 5 A is d ue t o t he 
meta b olite l oa d. 
E xcreti o n of a d mi nistere d ra di oacti vit y was pre d o mi na ntl y via t he faecal r o ute, wit h mea ns of 5 7. 7 5 % 
a n d 5 6. 4 4 % of d ose o bser ve d fr o m 0 t o 1 6 8 h p ost- d ose, f or males a n d fe males, res pecti vel y. O ver t he 
sa me peri o d, ra di oacti vit y rec o vere d i n uri ne acc o u nte d f or mea ns of 2 6. 4 3 % a n d 3 1. 9 4 % of d ose, f or 
males a n d fe males, res pecti vel y. A n a d diti o nal 2. 8 % of ra di oacti vit y was meas ure d i n t he ca ge was hi n gs 
i n b ot h male a n d fe male gr o u ps ( Ta ble 4).  
T a ble 4: p h ar m ac o ki netic p ar a meters of r a di o acti vit y i n pl as m a a n d D F 2 7 5 5 free c o m p o u n d ( D F 2 7 5 5 Y) i n pl as m a 
f oll o wi n g a si n gle or al a d mi nist r ati o n of [ 1 4 C] D F 2 7 5 5 A t o m al e a n d fe m ale B e a gle d o gs at a t ar get d os e of 4 0 m g free 
c o m p o u n d/ k g. 
S a m pl e  
( 0 –  1 6 8 h)  
M e a n rec o ve ries ( % d ose) ± S D  
M ale ( n = 3)  
Fe m ale ( = 3)  
Uri ne  
2 6. 4 3 ± 2. 1 8  
3 1. 9 4 ± 3 . 4 7  
F aeces  
5 7. 7 5 ± 2. 8 2  
5 6. 4 4 ± 2. 1 4  
C a ge w as h  
2. 8 2 ± 0. 6 1  
2. 8 4 ± 0. 8 6  
T ot al  
8 7. 0 0 ± 3. 8 1  
9 1. 2 2 ± 1. 9 2  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 3  / 8 5  
 
 
 
A 
pr o p ose d 
meta b olic pat h wa y i n rat a n d d o g of 
D F 2 7 5 5 A is i de ntifie d f oll o wi n g si n gle oral 
a d mi nistrati o ns of ra di ola belle d c o m p o u n d [ 1 4 C] D F 2 7 5 5 A.   
Fr o m t he data i n vi v o i n rats a n d d o gs  it is p ossi ble  t o see t hat i n  plas ma, t he lar gest ra di o-c o m p o ne nt 
circ ulati n g was pare nt dr u g ( D F 2 7 5 5 A) acc o u nti n g f or > 8 3 % of t he sa m ple ra di oacti vit y at all ti mes u p t o 
2 4 h o urs i n t he rat a n d > 6 6 % of t he sa m ple ra di oacti vit y at all ti mes u p t o 2 4 h o urs i n t he d o g. N o 
meta b olite re prese nte d > 1 0 % of t he sa m ple ra di oacti vit y i n t he rat plas ma.  
O ne P hase II meta b olite was o bser ve d i n t he d o g plas ma –  
M 8 (a gl uc ur o ni de c o nj u gate), w hic h 
acc o u nte d f or 2- 1 0 % of sa m ple ra di oacti vit y. 
I n uri ne, o nl y o ne si n gle c o m p o ne nt, i n b ot h rat a n d d o g, re prese nte d > 1 0 % of t he a d mi nistered 
ra di oacti vit y ( M 2 i n t he fe male d o g (t otal 1 0. 7 % a d mi nistere d ra di oacti vit y). B ot h s pecies w o ul d a p pear 
t o c o ntai n ma n y meta b olites, wit h t he rat uri ne c o ntai ni n g s mall a m o u nts of pare nt D F 2 7 5 5 A i n a d diti o n 
t o se veral P hase I meta b olites M 2 ( o xi dati o n t h e n h y dr ol ysis), M 3 ( h y dr ol ysis) a n d M 4 ( o xi dati o n), all 
acc o u nti n g f or > 1 0 % of t he sa m ple ra di oacti vit y.  T he d o g uri ne c o ntai ne d ver y s mall c o nce ntrati o ns of 
pare nt D F 2 7 5 5 A i n a d diti o n t o f o ur meta b olites, eac h re prese nti n g > 1 0 % of t he sa m ple ra di oacti vit y; t w o 
P hase I meta b olites - M 2 ( o xi dati o n t he n h y dr ol ysis) a n d M 3 ( h y dr ol ysis) a n d t w o P hase II meta b olites 
M 7 (ta uri ne c o nj u gate) a n d M 8 ( gl uc ur o ni de c o nj u gate). 
I n rat faeces, t he lar gest ra di o-c o m p o ne nt was 
M 1 (a s ul p hate c o nj u gate of a P hase I h y dr ol yse d 
meta b olite) w hic h acc o u nte d f or a p pr o xi matel y 5 0 % of t he t otal a d mi nistere d ra di oacti vit y. Pare nt dr u g 
( D F 2 7 5 5 A) was als o o bser ve d, at c o nce ntrati o ns of > 1 2 % of t otal a d mi nistere d ra di oacti vit y. T he ot her 
n ota ble s pecies, acc o u nti n g f or > 1 0 % of a d mi nistere d a n d sa m ple ra di oacti vit y was a P hase I meta b olite 
M 2 ( o xi dati o n t he n h y dr ol ysis). T he lar gest c o m p o ne nt i n d o g faeces was a P hase II meta b olite M 7 
(ta uri ne c o nj u gate), acc o u nti n g f or > 2 5 % of t he t otal a d mi nistere d ra di oacti vit y ( > 6 0 % of t he sa m ple 
ra di oacti vit y). T he o nl y ot her c o m p o ne nt re prese nti n g > 1 0 % of sa m ple ra di oacti vit y was pare nt dr u g 
( D F 2 7 5 5 A) w hic h acc o u nte d f or a p pr o xi matel y 1 0 % of a d mi nistere d ra di oacti vit y. 
T here are s o me si milarities bet wee n t he t w o s pecies, i n ter ms of t he meta b olit es o bser ve d acr oss t he 
differe nt matrices. B ot h s pecies als o ge nerate b ot h P hase I a n d P hase II meta b olites. It w o ul d a p pear t hat 
t he rat ge nerates m ore P hase I meta b olites a n d t he d o g ge nerates s o me s pecies-s pecific P hase II 
c o nj u gates.  
Q ua ntitati ve w h ol e b o d y a ut ora di o gra p h y ( Q W B A) st u dies s h o w t hat [ 1 4 C] D F 2 7 5 5 A is fairl y ra pi d 
distri b ute d i nt o tiss ues w he n a d mi nistere d orall y t o b ot h al bi n o a n d partiall y pi g me nte d male rats a n d 
wi des prea d i n t he b o d y , a n d n o mela ni n bi n di n g is o bser ve d b y t he c o m p o u n d a n d/ or its meta b olites. T he 
ma xi m u m c o nce ntrati o ns of ra di oacti vit y i n t he vast maj orit y of tiss ues were ac hie ve d at 2 h a n d t he 
lar gest pr o p orti o n of d ose was rec o vere d i n 
 a n d 
 at 2 4 h. Ver y l o w 
c o nce ntrati o n were f o u n d  
 ra n gi n g fr o m 0. 9 9 6 1. 7 9 µ g/e q D F 2 7 5 5 A/ g of tiss ue after 2 h of 
a d mi nistrati o n i n al bi n o a n d partiall y pi g me nte d rats. I n dicati n g t hat t he c o m p o u n d d o n ot  
 
 rati o were 0. 0 3 i n a bi n o rats a n d 0. 0 4 i n partiall y pi g me nte d 
rats).   
Mater nal tiss ue distri b uti o n of t he ra di ola belle d c o m p o u n d [
1 4 C] D F 2 7 5 5 A i nt o pre g na nt fe male rats is 
c o m para ble wit h tiss ue distri b uti o n of  n ot ra di ola belle d c o m p o u n d D F 2 7 5 5 A i n male a n d fe male rats. 
T he ma xi m u m c o nce ntrati o ns of ra di oacti vit y were visi ble i n f oetal tiss ues at 6 h after t he a d mi nistrati o n 
a n d e xcrete d als o i nt o mil k, mea ni n g t hat p u ps w o ul d be e x p ose d t o t he c o m p o u n d. 
T he t o xic o ki netic of D F 2 7 5 5 A has bee n st u die d after re peate d a d mi nistrati o n ( 2 8 da ys) of 
D F 2 7 5 5 A i n rat at t he d ose of 3 0, 6 0 a n d 1 5 0 m g/ k g b.i. d. c orres p o n di n g t o 6 0, 1 2 0 a n d 3 0 0 m g/ k g/ da y.  
T he pl as ma c o nce ntrati o n ti me c ur ves dis pla ye d a clear d o u ble pea k patter n ass ociate d wit h t he 
t wice dail y d osi n g of D F 2 7 5 5 A (fi g ure 5). T he plas ma c o nce ntrati o ns of D F 2 7 5 5 A i ncrease d ra pi dl y after 
t he first a n d sec o n d d osi n g. T he pea k plas ma c o nce ntrati o n was deter mi ne d after t he first a n d t he sec o n d 
a d mi nistrati o n. After t he first d osi n g t he pea k plas ma c o nce ntrati o n was reac he d 1 or 2 h after d osi n g, 
after t he sec o n d d osi n g t he pea k plas ma c o nce ntrati o n was reac he d 4 h after d osi n g, i.e. 1 2 h. F or all 
C CI
C CI
C CI
C CI

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 7  / 8 5  
b o d y  te m perat ure, heart rate or E C G i nter vals f oll o wi n g oral d oses u p t o 7 5 m g/ k g i n c o nsci o us Bea gle 
d o gs, w hile t he hi g hest d ose of 1 2 5 m g/ k g pr o d uce d tr a nsie nt i ncrease i n heart rate a n d b o d y te m perat ure 
al o n g wit h l o wer s yst olic-, mea n arterial-, p ulse press ure as well as s h orter P R, R R, a n d Q T. T he d ose of 
7 5 m g/ k g was t he N O E L f or car di o vasc ular f u ncti o n i n t he d o g. 
Oral ga va ge t o xic ol o g y st u dies ha ve bee n c o n d ucte d wit h D F 2 7 5 5 A f or u p t o 4 wee ks d urati o n 
wit h 2 wee k rec o ver y peri o ds i n rats a n d d o gs. Ra n ge-fi n di n g st u dies of 7 da ys d urati o n were perf or me d 
i n rats a n d d o gs at d ose le vels of u p t o 8 0 0 a n d 9 0 0 m g/ k g/ da y, res pecti vel y. Fi n di n gs i n rats a n d d o gs 
were si milar; i n t he rat, at t he d ose of 8 0 0 m g/ k g/ da y, s u b d ue d be ha vi o ur, pil oerecti o n, bra d y p n oea a n d 
rales were o bser ve d al o n g wit h decrease d f o o d i nta ke. Micr osc o pic effects i ncl u de d mi xe d cell i nfiltrati o n 
a n d oe de ma of t he gla n d ular m uc osa of t he st o mac h, peri p ortal i nfla m mati o n i n t he li ver a n d de ge nerati ve 
c ha n ges i n t he pr o xi mal t u b ules, mai nl y at t he hi g her d ose le vel. Bi oc he mistr y fi n di n gs i ncl u de d 
i ncreases i n tra nsa mi nases, li pi ds a n d i n or ga nic p h os p h or us w hile hae mat ol o g y fi n di n gs i ncl u d e d 
i ncrease d platelet c o u nt, mea n c or p usc ular v ol u me a n d relati ve retic ul oc yte c o u nts. N ota ble fi n di n gs i n 
d o gs at t he 9 0 0 m g/ k g/ da y d ose le vel i ncl u de d s p ora dic i nsta nces of hae m orr ha ge ( disc ol o ure d ears a n d 
e yes; dar k or re d faeces), v o miti n g, diarr h oea, tre m ors a n d let har g y. F o o d i nta ke a n d b o d y wei g ht were 
als o re d uce d. Micr osc o pic fi n di n gs at t he hi g her d ose i ncl u de d oe de ma, c o n gesti o n a n d i nfla m mat or y 
i nfiltrati o n a n d de ge nerati o n of t he f u n d us m uc osa, d u o de n u m a n d ile u m. I n t he li ver, diff use or 
ce ntril o b ular he pat ocell ular h y pertr o p h y, si n gle cell necr osis or mi ni mal f ocal necr osis a n d diff use 
he pat ocell ular vac u olati o n a n d peri p ortal i nfla m mati o n 
were o bser ve d. I n t he ki d ne ys, t u b ular 
de ge nerati o n a n d re ge nerati o n a n d t u b ular dilati o n were o bser ve d. Bi oc he mical fi n di n gs i ncl u de d 
i ncrease d tra nsa mi nases, t otal bilir u bi n, urea, creati ni ne a n d c h olester ol a n d decrease d electr ol ytes, 
gl uc ose, t otal pr otei n a n d al b u mi n. Hae mat ol o g y fi n di n gs i ncl u de d 
W B C para meter alterati o ns a n d 
decrease d platelet c o u nts a n d decrease of t he pr ot hr o m bi n ti me. 
I n t he 2 8- da y re peate d d ose st u dies i n rats a n d d o gs, t o xicit y fi n di n gs were c o nsiste nt wit h t h ose 
o bser ve d i n t he ra n ge-fi n di n g st u dies. I n t he rat, D F 2 7 5 5 A was a d mi nistere d at d ose le vels of 6 0 t o 3 0 0 
m g/ k g/ da y ( BI D). N o m ortalit y occ urre d d uri n g t he st u d y a n d n o treat me nt-relate d effects were n ote d i n 
ter ms of f o o d c o ns u m pti o n, o p ht hal m osc o p y or uri ne para meters. At 3 0 0 m g/ k g/ da y, h u nc he d p ost ure a n d 
sli g ht sali vati o n were see n t o get her wit h a l o wer b o d y wei g ht gai n. T he sa me d ose le vel pr o d uce d sli g ht 
i ncreases i n tra nsa mi nases. Decrease d t otal pr otei n, t otal gl o b uli n a n d gl uc ose were see n al o n g wit h 
i ncrease d li pi ds. I ncrease d i n or ga nic p h os p h or us a n d decrease d p otassi u m a n d calci u m were als o see n, 
w hile decrease d urea a n d creati ni ne c o nce ntrati o ns were o bser ve d i n fe males. At hist o pat h ol o g y, mi xe d 
cell i nfiltrati o n, oe de ma, hae m orr ha ge a n d er osi o ns were n ote d i n t he GI tract b ut s h o we d n o d ose-
de pe n de nc y a n d were see n als o i n c o ntr ol a ni mals. C ha n ges re mi nisce nt of meta b olic a da pti o n were see n 
i n t he li ver a n d ki d ne ys c orrelate d wit h i ncrease d or ga n wei g ht a n d were f ull y re versi ble at rec o ver y. 
Sli g ht atr o p h y of t he t h y m us, diff use h y pertr o p h y of t he a dre nal c orte x a n d re d uce d secreti o n i n t he 
pr ostate, c oa g ulati n g gla n d a n d se mi nal vesicles were als o see n at 3 0 0 m g/ k g/ da y. Ot her fi n di n gs at 3 0 0 
m g/ k g/ da y i ncl u de d i ncrease d i nci de nce of s pla nc h nic hae mat o p oiesis a n d i ncrease d b o ne marr o w 
cell ularit y, c orrelati n g wit h decrease d R B C c o u nt, hae m o gl o bi n, hae mat ocrit a n d mea n c or p usc ular 
hae m o gl o bi n a n d i ncrease d relati ve  retic ul oc ytes; all t hese c ha n ges were re versi ble at rec o ver y. Sli g ht 
i ncreases i n W B Cs c orrelate d wit h t he i nfla m mat or y c ha n ges see n i n t he st o mac h. I n t he d o g, re peate d 
a d mi nistrati o n of D F 2 7 5 5 A at d os e le vels i n t he ra n ge 4 0 t o 2 0 0 m g/ k g/ da y was ge nerall y well t olerate d 
a n d n o effects o n b o d y wei g ht, f o o d c o ns u m pti o n, o p ht hal m osc o p y, E C G e xa mi nati o n or cli nical 
pat h ol o g y para meters were see n at a n y d ose. 
Macr osc o pic fi n di n gs i ncl u de d disc ol orati o n of t he 
ile ocaecal val ve a n d re d dis h f oci i n t he c ol o n, rect u m a n d p yl or us. U p o n micr osc o pic e xa mi nati o n, 
hae m orr ha ge or c o n gesti o n i n t he ile ocaecal val ve a n d/ or c ol o n as well as hae m orr ha ge, er osi o n, mi xe d 
cell i nfiltrati o n, a n d c o n gesti o n of t he p yl or us were  o bser ve d. Ce ntril o b ular he pat ocell ular h y pertr o p h y 
was o bser ve d i n fe males at mi d a n d hi g h d ose a n d c orrelate d wit h i ncrease d li ver wei g hts, b ut was n ot 
ass ociate d wit h a n y de ge nerati ve or i nfla m mat or y c ha n ges. I n b ot h s pecies, t he GI effects are si milar t o 
effects see n wit h ot her pr o pi o nic aci d deri vati ve a n d li kel y a class effect, w hile t he li ver a n d ki d ne y 
c ha n ges are c o nsi dere d t o re prese nt a n a da pti ve meta b olic p he n o me n o n a n d of li mite d t o xic ol o gical 
c o ncer n. T he d ose of 1 2 0 m g/ k g/ da y was c o nsi dere d t o be t he N O A E L f or re peate d 4 -wee k oral 
a d mi nistrati o n i n t he rat, w hile t he N O A E L i n t he d o g was 4 0 m g/ k g/ da y.  
Electr o n micr osc o p y i n vesti gati o n i n t he li ver of rats i n dicate d t he prese nce i n t he he pat oc ytes of 
areas of l o w electr o n- de nsit y a n d h o m o ge ne o us a p peara nce i nters perse d a m o n g t he mit oc h o n dria a n d 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 8  / 8 5  
ro u g h e n d o plas matic retic ul u m. H o we ver, n o i n dicati o n of cell ular or or ga nelles alterati o ns were 
o bser ve d. 
T he i n vitr o ge netic t o xicit y test f or bacterial m utati o ns ( A mes assa y) a n d c hr o m os o mal a berrati o ns 
i n h u ma n l y m p h oc ytes re veale d n o ge n ot o xic p ote ntial f or D F 2 7 5 5 A. N o e vi de nce of clast o ge nicit y or 
a ne u ge nicit y was f o u n d i n t he rat micr o n ucle us test f oll o wi n g a d mi nistrati o n of D F 2 7 5 5 A b y oral ga va ge 
u p t o t he ma xi m u m t olerate d d ose le vel of 3 0 0 m g/ k g/ da y.  
A male a n d fe male fertilit y st u d y c o m bi ne d wit h e m br y o-fetal de vel o p me nt st u d y wit h D F 2 7 5 5 A 
M o n o h y drate was d o ne i n rats b y oral ga va ge. Ni net y-si x male a n d ni net y-si x mai n fe male Wistar Ha n 
rats were assi g ne d t o f o ur d ose gr o u ps. T he test ite m was a d mi nistere d o nce dail y b y oral ga va ge at d oses 
of 5 0, 1 0 0 a n d 1 5 0 m g/ k g ( Gr o u ps 2, 3 a n d 4 res pecti vel y). T he rats of t he c o ntr ol gr o u p recei ve d t he 
ve hicle, water, al o ne. I n a d diti o n, fi ve satellite a ni mals (fe males o nl y) per treat me nt gr o u p a n d t hree 
satellite fe males i n t he c o ntr ol gr o u p were e x p ose d a n d use d f or t o xic o ki netic bl o o d sa m pli n g o n Da y 1 7 
p ost-c oit u m. Males were e x p ose d f or 4 3- 4 6 da ys, i.e. 2 wee ks pri or t o mati n g, d uri n g mati n g, a n d u p t o 
ter mi nati o n. Mate d fe males were e x p ose d f or 3 3- 4 6 da ys, i.e. d uri n g 2 wee ks pri or t o mati n g, d uri n g 
mati n g, a n d c o nti n ui n g u ntil Da y 1 7 p ost -c oit u m, i ncl usi vel y. Fe males wit h o ut e vi de nce of mati n g were 
d ose d u ntil o ne da y pri or t o e ut ha nasia.  
N o re pr o d ucti o n a n d de vel o p me ntal t o xicit y was o bser ve d u p t o a d ose le vel of 1 5 0 m g/ k g. A sli g ht, 
treat me nt relate d decrease i n b o d y wei g ht gai n was o bser ve d i n males treate d at 1 5 0 m g/ k g fr o m Da y 4 of 
treat me nt o n war ds, res ulti n g i n a p pr o xi matel y 5 % l o wer a bs ol ute b o d y wei g hts at t he e n d of treat me nt. 
As t his effect was ver y s mall a n d n o c o nc urre nt effect o n f o o d c o ns u m pti o n was n ote d, t his was 
c o nsi dere d n ot t o be a d verse.  
N o mater nal t o xicit y was o bser ve d i n fe males at a n y d ose gr o u ps.  
I n c o ncl usi o n t he N O A E L t o be c o nsi dere d f or t he calc ulati o n of t he ma xi m u m rec o m me n de d starti n g 
d ose ( M R S D) i n h u ma ns are:   
T O X 4 w ee k ( 2 8 d a y) a n d c orres p o n di n g e x p os ure le vels 
R A T: 
N O A E L 1 2 0 m g/ k g ( 6 0 m g/ k g b.i d.)  
C ma x ss    1 9 3  µ g/ m L  
A U C ss( 0- 2 4)   2 2 7 5  h * μ g/ m L  
D O G: 
N O A E L   4 0 m g/ k g ( 2 0 m g/ k g b.i d.)  
C ma x ss    1 8. 0 0 µ g/ m L  
A U Css ( 0- 2 4)  8 1. 7 5    h * μ g/ m L  
 
1. 3.  
S u m m ar y of t he p ote nti al ris k a n d be nefits t o h u m a n s u bjects 
St u d y s u bjects will n ot recei ve a n y direct t hera pe utic be nefit fr o m ta ki n g part i n t his st u d y.   
 
T he s u bjects e nr olle d i n t he prese nt st u d y bei n g healt h y are n ot e x pecte d t o deri ve a n y be nefit fr o m 
partici pati n g i n t he prese nt st u d y. D F 2 7 5 5 A is bei n g de vel o pe d f or a c hr o nic c o n diti o n, I C/ B P S, t hat as of 
t o da y lac ks effecti ve treat me nt. A gr o wi n g b o d y of e vi de nce s u g gest t hat m olec ules affecti n g t he I L- 8 –  
C X C R 1/ 2 a xis li ke D F 2 7 5 5 A c o ul d re prese nt a n o vel treat me nt o pti o ns. D F 2 7 5 5 A  e x hi bits a n o n -cli nical 
safet y a n d p har mac o ki netic pr ofile c o m pati ble wit h c hr o nic treat me nt, a n d t heref ore satisfies all criteria 
t o qualif y as a ca n di date f or cli nical st u dies i n patie nts wit h I C/ B P S.  As t o t he prese nt p hase I cli nical 
trial, a de q uate safet y mar gi ns base d u p o n t o xic ol o g y st u dies i n rats a n d d o gs, a sta g geri n g a p pr oac h t o 
d osi n g s u bjects at eac h d ose le vel, cl ose m o nit or i n g of cli nical c o n diti o ns of partici pa nts a n d a safet y 
m o nit ori n g c o m mittee t o be c o n ve ne d bet wee n eac h d ose le vel t o re vie w t he data of t he pre vi o us c o h ort 
a n d c o nfir m or select t he ne xt d ose f or e val uati o n , re prese nt a de q uate safet y meas ures t o e ns ure the safet y  
of trial partici pa nts.   
 
 
1. 4.  
Descri pti o n a n d j ustific ati o n f or t he d os a ge re gi me n  
D oses were calc ulate d usi n g t he b o d y s urface area c o n versi o n. T he calc ulate d ma xi m u m rec o m me n de d 
starti n g d ose ( M R S D) is 1 1 7 m g i n rats a n d 1 3 0 m g i n d o gs. Base d o n data a vaila ble f or t he rat, t he  
pr o p ose d M R S D is 5 0 m g/s u bj ect, 2 3 ti mes l o wer t ha n t he H E D at N O A E L. A s ge neral r ule t he h u ma n 
e q ui vale nt efficac y d ose is hi g her t ha n t he efficac y d ose o btai ne d i n a ni mals.   
 A pre dicti o n of t he h u ma n P K para meters a n d t he h u ma n e q ui vale nt p har mac ol o gical d ose of D F 2 7 5 5 A 
usi n g all o metric scale si m ulati o n has bee n carrie d o ut usi n g t he i nf or mati o n o n efficac y i n rats. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
2 9  / 8 5  
P har mac ol o gic H E D was calc ulate d usi n g t he esti mate d (scale d) h u ma n cleara nce a n d t he A U C t hat 
res ulte d i n p har mac ol o gical acti vit y. P har mac ol o gic H E D ra n ge d fr o m 7 7 t o 3 2 0 2 m g BI D (i.e. 1 4 4 - 6 4 0 4 
m g) de pe n di n g o n t he rat efficaci o us e x p os ure a n d pr ojecte d C L use d. C o nsi deri n g t hese res ults, t he d ose 
of 5 0 m g c o ul d be c o nsi dere d t he s uita ble first d ose i n h u ma n d ue t o t he fact t hat it is l o wer t ha n t he 
pr ojecte d h u ma n p har mac ol o gical e q ui vale nt d ose b y a fact or > 7 or > 1 0  if 7 or 1 0 m g/ k g are c o nsi dere d 
t he efficac y d oses i n rats, res pecti vel y.  
T hese res ults are i n a gree me nt, see a b o ve, wit h t he H E D calc ulate d fr o m t he 4- we e k oral t o xicit y st u d y i n 
rat were a p pl yi n g a safet y fact or of 2 3-f ol d t he starti n g d ose res ults t o be 5 0 m g.  
T o preser ve t he safet y of t he s u bjects after t he first c o h ort ( P K para meters per mitti n g) a P K si m ulati o n t o 
deter mi ne t he pre dicte d P K para meters at t he hi g her d ose/s will be perf or me d t o pre dicte d t he e x pecte d 
e x p os ure. 
 
 T he f oll o wi n g si n gle d oses are pla n ne d t o be a d mi nistere d i n Part A: 
 
T a ble 8 : D oses f or a d mi nistrati o n i n P art A 
Pr o p ose d D oses  
S A D  
H u m a n E q ui v ale nt d ose ( H E D) c o nsi deri n g 
t he m ore s e nsiti ve s pecies ( R A T) 
m g/ k g  
D ose 
m g/s u b j 
( 6 0 k g) 
D ose 
m g/ k g  
S afet y 
m ar gi n  
R ati o  
1 9. 4 4  
5 0  
0. 8 3  
2 3. 3 3  
 
 
1 5 0  
2. 5 0  
7. 7 8  
3  
 
4 5 0  
7. 5 0  
2. 5 9  
3  
 
7 0 0  
1 1. 6 7  
1. 6 7  
1. 5 5  
T he ma xi m u m d ose of 7 0 0 m g is i n t he ra n ge of t he p har mac ol o gical H E D a n d it is i n t he ra n ge of t he 
e x p os ure c o vere d b y t he t o xic ol o gical st u dies.   
 
T he first 
M A D c o h ort will be i nitiate d o nl y after t he a ut h orizati o n, fr o m A N S M of a s u bsta ntial 
a me n d me nt t hat will be prese nte d i n or der t o n otif y t he res ults of S A D part of t he st u d y.  
 
T he a ntici pate d d oses teste d i n Part B are t he f oll o wi n g: 
 
T a ble 9 : D oses f or a d mi nistrati o n i n P art B 
Pr o p ose d D oses  
M A D ( pr o p ose d 1 4 d a ys) b i. d.  
H u m a n E q ui v ale nt d ose ( H E D) c o nsi deri n g 
t he m ore s e nsiti ve s pecies ( R A T) 
m g/ k g  
D ose 
m g/s u b j 
( 6 0 k g) 
T ot al d ose 
d a y  
m g/s u bj  
D ose 
m g/ k g  
S afet y 
m ar gi n  
R ati o  
1 9. 4 4  
1 0 0  
2 0 0  
3. 3 3  
5. 8 3  
 
 
2 0 0  
4 0 0  
6. 6 7  
2. 9 2  
2  
 
3 0 0  
6 0 0  
1 0. 0 0  
1. 9 4  
1. 5  
T he a d mi nistere d d ose i n part B c o ul d be m o difie d acc or di n g t o t he res ults of t he part A. 
1. 5.  
Et hic al c o nsi der ati o ns 
T he st u d y will be perf or me d acc or di n g t o t he l ocal re g ulati o ns, t he rec o m me n dati o ns o n G o o d 
Cli nical Practice ( G C P) “I C H T o pic E 6, C P M P/I C H/ 1 3 5/ 9 5”, J ul y 1 9 9 6 i ncl u di n g p ost Ste p 4 errata, 
stat us Se pte m ber 1 9 9 7 a n d p ost Ste p errata (li n g uistic c orrecti o ns), J ul y 2 0 0 2 a n d acc or di n g t o  t he 
rele va nt g ui deli nes of t he Declarati o n of Helsi n ki. 
D ose Calc ulati o n: G ui da nce f or I n d ustr y - Esti mati n g t he Ma xi m u m Safe Starti n g D ose i n I nitial Cli nical 
Trials f or T hera pe utics i n A d ult Healt h y V ol u nteers - U. S. De part me nt of Healt h a n d H u ma n Ser vices - 
F o o d a n d Dr u g A d mi nistrati o n - Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R) J ul y 2 0 0 5  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 0  / 8 5  
T he cli nical st u d y will start u p o n recei pt of t he a p pr o val of b ot h t he Et hics C o m mittee “ C o mité d e 
Pr otecti o n des Pers o n nes ” ( C P P) a n d t he Fre nc h Healt h A ut h orities “ A ge nce Nati o nale de séc urité d u 
mé dica me nt et des pr o d uits de sa nté ” ( A N S M). 
 
1. 6.  
Descri pti o n of t he p o p ul ati o n t o be st u die d 
Part A: Ei g ht healt h y male a n d fe male s u bj ects ( 6 acti ve a n d 2 place b o) will be i ncl u de d i n t he f o ur d ose 
le vel. At least t w o healt h y fe male s u bjects will be i ncl u de d i n eac h c o h ort. O ne of t he m s h o ul d be 
all ocate d t o place b o. . I n t otal, 3 2 s u bjects will be e nr olle d. 
 
Part B: T wel ve healt h y male a n d fe male s u bj ects ( 9 acti ve a n d 3 place b o) will be i ncl u de d i n eac h d ose 
le vel. Bet wee n t hree a n d si x healt h y fe male s u bjects will be i ncl u de d i n t he c o h ort. At least o ne of t he m 
s h o ul d be all ocate d t o place b o.  .  
I n t otal, 3 6 s u bjects will be e nr olle d. 
 
F or b ot h parts, s u bj ects will be recr uite d fr o m v ol u nteers’ data base of t he cli nical u nit. Ne ws pa per 
a d vertise me nts, ra di o s p ots, p osters, maili n g, s pecific press i nserts, br oa dcast messa ge or cli nical u nit 
recr uit me nt we bsite ma y be use d. O nl y st u d y-s pecific recr uit me nt t o ols a p pr o ve d b y E C will be use d.  
 
1. 7.  
Ref ere nces 
- 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d of t he C o u ncil o n t he a p pr o xi mati o n of 
la ws re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he 
me m bers states relati n g t o t he 
i m ple me ntati o n of G C P i n t he c o n d uct of cli nical trials o n me dici nal pr o d ucts f or h u ma n use; 
 
- 
Declarati o n of Helsi n ki, 1 8t h W orl d Me dical Asse m bl y, Helsi n ki, Fi nla n d 1 9 6 4, as m o difie d i n 
F ortaleza ( 2 0 1 3); 
 
- 
C o de de la Sa nté P u bli q ue ( C S P); 
 
- 
A N S M g ui deli nes “ Esti mati o n of t he starti n g d ose, defi nit i o n of d ose pr o gressi o n a n d pr ot oc ol 
a d mi nistrati o n t o v ol u nteers” Se pte m ber 2 0 0 6 . 
 
2.  S T U D Y O B J E C TI V E S A N D P U R P O S E  
2. 1.  
P r i nci p al o bjecti ve 
T o e val uate t he t olera bilit y a n d safet y of asce n di n g si n gle a n d re peate d d oses of D F 2 7 5 5 A i n healt h y 
a d ult male a n d fe male v ol u nteers. 
2. 2.  
Sec o n d ar y o bjecti ves 
 
T o deter mi ne t he p har mac o ki netics para meters of D F 2 7 5 5 A  
 
T o esta blis h a d ose c o nce ntrati o n -res p o nse relati o ns hi p o ver a wi de ra n ge of d oses i n or der t o 
select a narr o wer ra n ge of d oses a n d d osi n g re gi me n t o be s u bse q ue ntl y st u die d i n patie nts after 
si n gle a n d m ulti ple a d mi nistrati o n 
 
T o e val uate t he effect s of asce n di n g si n gle a n d re peate d d oses o n t he p har mac o d y na mics 
para meters.  
 
T o c o m pare meta b olites pat h wa y i n h u ma n wit h t he o ne o bse r ve d i n a ni mals 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 1  / 8 5  
3.  S T U D Y D E SI G N 
3. 1.  
E v al u ati o n criteri a 
3. 1. 1.  P ri m ar y e n d p oi nt 
A E, vital si g ns, 1 2-lea d E C G, la b orat or y e xa ms. 
3. 1. 2.  Sec o n d ar y e n d p oi nts 
Meas ure me nt of p har mac o ki netics para meters: C
ma x , tma x , λz, t1/ 2, A U C0-last, A U C i nf, Vz/ F, C L/ F, Ae0-last, 
C L R , total a m o u nt i n faeces, pare nt: meta b olite(s) rati o. 
Meas ure me nt of C yt o ki ne I nfla m mati o n Mar kers [ C X C L 1( Gr o alfa), C X C L 2( Gr o beta); C X C L 5( E N A-
7 8), C X C L 6 ( G C P- 2), C X C L 8 (I L- 8 )] i n part B a n d Le u k oc yte s u bsets ( C D 1 1 b a n d C D 1 8) i n part A, 
e xce pt f or 1 st c o h ort a n d part B. 
3. 2.  
Desi g n 
T he st u d y is a p hase I, si n gle ce nter, d o u ble- bli n d, place b o c o ntr olle d, ra n d o mize d, asce n di n g si n gle a n d 
re peate d d oses st u d y i n healt h y male a n d fe male v ol u nteers. 
 
T he desi g n c o nsists of a d o u ble bli n d c o m paris o n of t he test c o m p o u n d vers us place b o i n w hic h t he d ose 
is i ncrease d i n s uccessi ve treat me nt peri o ds.  
T he M ulti ple Asce n di n g D ose ( M A D) has t o be starte d o nl y after t he e n d of all t he c o h orts of Si n gle 
Asce n di n g D ose ( S A D). Besi des i n or der t o deci de t o 
m o ve f or war d fr o m S A D t o 
M A D, t he 
p har mac o ki netic data f or all d oses a d mi nistere d d uri n g S A D will be e val uate d (i.e. plas ma: q ua ntitati ve 
deter mi nati o n of D F 2 7 5 5 A b o u n d a n d u n b o u n d; q ualitati ve a n d preli mi nar y q ua ntitati ve deter mi nati o n of 
k n o w n meta b olites; uri ne a n d faeces: q ualitati ve a n d q ua ntitati ve deter mi nati o n of pare nt c o m p o u n d a n d 
q ualitati ve a n d preli mi nar y q ua ntitati ve i n vesti gati o n of k n o w n meta b olites). 
D ose will be escalate d i n or der t o ac hie ve e n o u g h safet y i nf or mati o n o n a n i nter val of d oses p ossi bl y 
e nc o m passi n g b ot h t he effecti ve d ose a n d t he ma xi m u m t olerate d d ose ( defi ne d as t he hi g hest t d ose 
de v oi d of a n y cli nical si g ns/s y m pt o ms).  
 
Part A: Si n gle d oses of 5 0 m g oa d, 1 5 0 m g oa d, 4 5 0 m g oa d or 7 0 0 m g oa d of D F 2 7 5 5 A are pla n ne d t o 
be teste d i n healt h y v ol u nteers. 
 
Part B: Re peate d d oses of 1 0 0 m g bi d, 2 0 0 m g bi d or 3 0 0 m g bi d of D F 2 7 5 5 A are pla n ne d t o be teste d i n 
healt h y v ol u nteers. 
 
T he st u d y pla n is s h o w n i n Fi g ure 7 a n d 8. 
St u d y pr oce d ures are detaile d i n Secti o n 6 a n d 7. 
 
Fi g ure  7 -   St u d y pla n - P art A 
D- 2 1 
D- 2
D- 1
D 1
D 2
D 3
D 4
Arri val t o t h e 
c e nt er 
Tr e at m e nt 
A d mi ni str ati o n 
D e p a rt ur e fr o m 
t h e c e nt er 
Sel ecti o n 
A m b ul at ory Visit 
H os pit ali s ati o n
 
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 3  / 8 5  
- 
C o nc o mita nt t hera p y; 
- 
P h ysical e xa mi nati o n a b n or malities; 
- 
Vital si g ns a b n or malities; 
- 
E C G a b n or malities. 
 
F or d ose escalati o n, P har mac o ki netic data o n plas ma ( q ua ntitati ve deter mi nati o n of D F 2 7 5 5 A b o u n d a n d 
u n b o u n d; q ualitati ve a n d preli mi nar y q ua ntitati ve deter mi nati o n of k n o w n meta b olites), uri ne a n d faeces 
rec o ver y ( q ualitati ve a n d q ua ntitati ve deter mi nati o n of pare nt c o m p o u n d a n d q ualitati ve a n d preli mi nar y 
q ua ntitati ve i n vesti gati o n of k n o w n meta b olites) will be c o nsi dere d b y usi n g, f or eac h ne w d ose le vel, t he 
p har mac o ki netic res ults of t he pre vi o us d ose le vel i n or der t o re -esti mate t he safet y mar gi n base d o n t he 
a ni mal -h u ma n e x p os ure rati o. T his re -esti mati o n m ust be ta ke n i nt o acc o u nt w he n deci di n g w het her t o 
pr ocee d t o t he ne xt d ose le vel.  
T he e x p os ure d oes n ot e xcee d t he A U C of 1 0 0 0 µ g∙h/ m L . 
 
I de ntificati o n of n o n-acce pta ble ris ks or si g nifica nt pr o p orti o n of A Es wit h c o m m o n pat h ol o gical patter n 
ca n j ustif y t he m o dificati o n of t he d ose escalati o n desi g n. 
After m ut ual a gree me nt bet wee n t he S p o ns or a n d t he I n vesti gat or a n d if it is c o nsi dere d usef ul f or t he 
selecti o n of t he ne xt d ose le vel, t he treat me nt of a s pecific s u bject a n d/ or a c o h ort ma y be u n bli n de d 
bef ore t he ne xt d ose le vel of D F 2 7 5 5 A is a d mi nistere d. 
At t he e n d of t he telec o nfere nce meeti n g, the f oll o wi n g decisi o ns ca n be ta ke n:  
- 
D ose escalati o n will c o nti n ue as sc he d ule d; 
- 
A n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he f oll o wi n g d ose will be a d mi nistere d t o t he 
ne xt c o h ort; 
- 
A l o wer i nter me diate d ose, bet wee n t he c urre nt d ose a n d t he d ose a d mi nistere d i n t he pre vi o us 
c o h ort will be a d mi nistere d t o t he ne xt c o h ort;  
- 
T he c urre nt d ose will be re peate d i n t he ne xt c o h ort;  
- 
T he st u d y will be st o p pe d. 
 
Acc or di n g t o t he c o ncl usi o n of t his meeti n g, t he f or mal a gree me nt/ disa gree me nt t o m o ve t o a ne xt c o h ort 
will be si g ne d b y b ot h t he S p o ns or a n d t he I n vesti gat or.  
 
3. 4.  
E x pecte d d ur ati o n of s u bject p artici p ati o n 
3. 4. 1.  Descri pti o n a n d d ur ati o n of tri al peri o ds 
Part A: 
Scree ni n g wit hi n 2 1 da ys pri or t o t he first a d mi nistrati o n, 
H os pitalizati o n a p pr o xi matel y f or 4 da ys ( D- 1 m or ni n g t o D 4 m or ni n g). C o nsi derati o n s h o ul d be gi ve n t o 
t he h os pitalizati o n after t he last d ose, i n fact it c o ul d be re vie we d acc or di n g t o P K para meters of t he 
c o m p o u n d after eac h d ose of S A D. 
E x pecte d d urati o n: a p pr o xi matel y 4 wee ks f or eac h partici pati n g s u bject. 
 
Part B: 
Scree ni n g wit hi n 2 1 da ys pri or t o t he first a d mi nistrati o n, 
H os pitalizati o n a p pr o xi matel y f or 1 7 da ys ( D- 1 m or ni n g t o D 1 7 m or ni n g). C o nsi derati o n s h o ul d be gi ve n 
t o t he h os pitalizati o n after t he last d ose, i n fact it c o ul d be re vie we d acc or di n g t o P K para meters of t he 
c o m p o u n d after eac h d ose of M A D. 
E x pecte d d urati o n: a p pr o xi matel y 6 wee ks f or eac h partici pati n g s u bject. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 4  / 8 5  
3. 4. 2.  D ur ati o n of f oll o w- u p  
D uri n g t he last visit, s u bjects will u n der g o a c o m plete cli nical a n d bi ol o gical e xa mi nati o n, i de ntical 
t o t he e xa mi nati o n at t he start of t he st u d y. A Es will be rec or de d, a n d if t he y are o n- g oi n g a f urt her 
f oll o w- u p will be arra n ge d; f oll o w- u p will c o nti n ue u ntil t he e ve nt is res ol ve d or t he c o n diti o n is u nli kel y 
t o c ha n ge or t he s u bject is l ost t o f oll o w- u p (see secti o n 8. 5 ).  
 
3. 5.  
St o p pi n g r ules 
3. 5. 1.  St o p pi n g r ule a p plic a ble at a n y ti me 
I n case of occ urre nce of a S A E at least p ossi bl y relate d t o t he st u d y dr u g a d mi nistrati o n, t he safet y re vie w 
c o m mittee will deci de t o p ut t he st u d y o n h ol d, a n d will as k f or u n bli n di n g f or t he s u bject. If t he s u bj ect 
was treate d b y place b o, t he st u d y will be c o nti n ue d as pla n ne d per pr ot oc ol. If t he s u bject was recei vi n g 
D F 2 7 5 5 A, t he st u d y will be i m me diatel y i nterr u pte d a n d de pe n di n g o n t he nat ure a n d S A E res ol uti o n it 
s h o ul d be p ote ntiall y re-starte d after s u b missi o n a n d a p pr o val b y b ot h E C a n d C A of a s u bsta ntial 
a me n d me nt. 
3. 5. 2.  St o p pi n g r ule f or a s u bject 
D uri n g t he treat me nt peri o d, t he safet y a n d t olera bilit y will be e val uate d o n a n o n g oi n g basis, t he 
f oll o wi n g criteria will a p pl y t o st o p a s u bject:  
 
T he s u bject e x perie nces a n A E t hat pre ve nts hi m fr o m c o nti n ui n g i n t he st u d y,  
 
Si g nifica nt i ncrease (i.e. > 3 N) of A L T ( N bei n g t he u p per li mit of t he n or mal val ue), 
 
A b n or mal la b orat or y res ults wit h si m ulta ne o us i ncreases of t otal bilir u bi n ( > 2 N), A L T ( > 2 
N) a n d al kali ne p h os p hatases ( > 1. 5 N),  
 
T he s u bject de vel o ps a ser u m creati ni ne ≥ 2 ti mes t he U L N , 
 
S ust ai ne d Q Tc F val ue of > 5 0 0 msec c o nfir me d b y at least o ne re peat E C G, 
 
T he s u bject wit h dra ws c o nse nt,  
 
At t he re q uest of t he S p o ns or or at t he I n vesti gat or's re q uest (f or e xa m ple if t he I n vesti gat or 
c o nsi ders t hat t he s u bject's healt h is c o m pr o mise d b y re mai ni n g i n t he st u d y or t he s u bject is 
n ot s ufficie ntl y c o o perati ve). 
 
See als o Secti o n 3. 6 “ Re m o val of S u bjects fr o m T hera p y or Assess me nt”.  
 
3. 5. 3.  St o p pi n g r ules wit hi n a gr o u p 
D uri n g t he treat me nt peri o d, t he safet y a n d t olera bilit y will be e val uate d o n a n o n g oi n g basis, t he 
f oll o wi n g criteria will a p pl y t o st o p t he c o h ort :  
 
2 s u bjects e x perie nci n g se vere n o n seri o us A Es c o nsi dere d as at least p ossi bl y relate d t o t he 
stu d y dr u g,  
 
2 s u bjects e x perie nci n g a si g nifica nt i ncrease (i.e. > 5 N) of A L A T ( N bei n g t he u p per li mit of 
t he n or mal val ue), 
3. 5. 4.  St o p pi n g r ule f or d ose esc al ati o n 
T he safet y re vie w c o m mittee will deci de t o st o p t he d ose escalati o n as pla n ne d per pr ot oc ol i n case 
of occ urre nce o f:  
 
2 s u bjects e x perie nci n g se vere n o n seri o us A Es of t he sa me or ga n class a n d nat ure relate d t o 
t he st u d y dr u g,  
 
4 s u bjects (f or S A D) a n d 8 s u bj ects (f or M A D) e x perie nci n g st u d y dr u g relate d m o derate n o n 
seri o us A Es (t hat are c o nsi dere d directl y relate d to t he dr u g effect u nless t he y res ol ve d 
des pite t he c o nti n uati o n of t he treat me nt),  
 
2 s u bjects of t he gr o u p e x perie nce a si g nifica nt i ncrease (i.e. > 3 N) A L A T,  
 
2 s u bjects of t he gr o u p e x perie nce si m ulta ne o us i ncreases of t otal bilir u bi n ( > 2 N), A L A T ( > 
2 N) a n d al kali ne p h os p hatases ( > 1. 5 N),  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 5  / 8 5  
 
2 s u bjects has a s ustai ne d Q T c val ue > 5 0 0 ms (c o nfir me d b y a sec o n d E C G u n der strict 
resti n g p ositi o n), 
 
O ne s u bject prese nts a C ma x or A U C ( 0- 2 4 h) val ues res pecti vel y a b o ve 1 5 0 µ g/ m L a n d 1 0 0 0  
µ g/ m L * h,   
 
T he mea n C ma x  a n d A U C ( 0-2 4 h)   lea ds t o belie ve ta ki n g i nt o acc o u nt t he d ose i ncrease t hat Cma x 
or A U C ( 0-2 4 h) val ues of 1 2 5  µ g/ m L a n d 6 0 0  µ g/ m L * h will be o ver pass wit h t he f oll o wi n g 
pla n ne d hi g her d ose,  
 
I n M A D part t he mea n at  t he stea d y state Cma x  a n d A U C (τ)   lea ds t o belie ve ta ki n g i nt o 
acc o u nt t he d ose i ncrease t hat C ma x or A U C ( 0-2 4 h) val ues of 1 2 5 µ g/ m L a n d 8 0 0 µ g/ m L * h will 
be o ver pass wit h t he f oll o wi n g pla n ne d hi g her d ose,  
 
  
In o ne of t he cases liste d a b o ve, t he d ose gr o u p i n pr o gress will be st o p pe d a n d t he bli n d c o ul d be 
br o ke n. Re gar di n g  la b orat or y a n d Q Tc a b n or malities descri be d a b o ve, if u n bli n di n g c o nfir ms t hat at least 
t w o s u bjects prese nti n g t hese a b n or malities were recei vi n g t he acti ve dr u g t he d ose escalati o n will be 
st o p pe d.  
 
3. 6.  
Re m o v al of S u bjects f r o m T her a p y or Assess me nt 
I n acc or da nce wit h t he Declarati o n of Helsi n ki, s u bjects will be free t o wit h dra w fr o m t he st u d y at 
a n y ti me if t he y wis h s o, f or a n y reas o n s pecifie d or u ns pecifie d. 
 
T he f oll o wi n g reas o ns will be acce pte d f or st u d y disc o nti n uati o n:  
o  
Wit h dra wal of s u bject c o nse nt, or l oss t o f oll o w- u p, or i na bilit y t o re mai n u n der me dical 
o bser vati o n i ncl u di n g p ost st u d y e xa mi nati o n, 
o  
N o n-c o m plia nce or maj or de viati o n fr o m t he pr ot oc ol, 
o  
A p peara nce of a seri o us A E ( S A E), 
o  
Ne w si g nifica nt i nf or mati o n ( Fre nc h re g ulati o n : “fait n o u vea u”), a n y ne w fact c o ncer ni n g 
t he researc h or t he st u d y pr o d uct w hic h ma y j e o par dize t he partici pa nts’ safet y, a n d w hic h 
lea ds t he S p o ns or or I n vesti gat or t o ta ke a p pr o priate ur ge nt sec urit y decisi o n, 
o  
A n y ot her sit uati o n w here, i n t he o pi ni o n of t he I n vesti gat or, c o nti n uati o n of t he st u d y w o ul d 
n ot be i n t he i nterest of t he s u bj ect, 
o  
Disc o nti n uati o n of t he st u d y b y t he S p o ns or. 
 
S h o ul d a n y of t he s u bjects be wit h dra w n fr o m t he st u d y, t he S p o ns or’s re prese ntati ve a n d 
I n vesti gat or will disc uss t he p ossi bilit y of re place me nt. All s u bjects wit h dra wi n g f or reas o ns u nrelate d t o 
t he i n vesti gati o nal pr o d uct will ha ve t o be re place d. T he reas o n f or wit h dra wal will ha ve t o be rec or de d i n 
t he e-C R F  f or all wit h dra w n s u bjects. 
T he e- C R F  has t o be c o m plete d u p t o t he ti me of dr o p o ut. All dr o p o uts after t he first i nta ke of 
i n vesti gati o nal pr o d uct s h o ul d be gi ve n a p ost-st u d y assess me nt as a p pr o priate. T he pre mat ure 
ter mi nati o n f or m i n t he e- C R F m ust be c o m plete d f or all dr o p o uts. 
A ll data, i ncl u di n g a n y dr u g c o nce ntrati o ns fr o m a n y wit h dra w n s u bject, has t o be i ncl u de d i n t he 
fi nal re p ort. T hese data will o nl y be e val uate d if b ot h t he S p o ns or a n d t he I n vesti gat or a gree t hat it is 
vali d t o d o s o. 
S u bj ects wit h dra w n beca use of a d verse e x perie nces will u n der g o a p h ysical e xa mi nati o n a n d 
la b orat or y tests pla n ne d at t he f oll o w- u p visit. A f oll o w- u p of A Es will als o be u n derta ke n f or wit h dra w n 
s u bj ects. 
 
 
3. 7.  
Bli n d a n d pr oce d ures f or u n bli n di n g  
T his st u d y is a d o u ble bli n d st u d y. 
Ra n d o mizati o n will be perf or me d at D 1. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 6  / 8 5  
3. 7. 1.  C o di n g list 
T he a nal ytical ce ntre as well as t he I n vesti gat or a n d t he tea m a n d t he s u bj ects will be i n bli n d 
c o n diti o ns. 
F or eac h s u bject, ra n d o mizati o n e n vel o pes, c o ntai ni n g t he i de ntificati o n of t he treat me nt 
(e mer ge nc y e n vel o pes) will be s u p plie d b y E ur ofi ns O pti me d a n d ke pt i n a safe place o n site d uri n g t he 
w h ole cli nical st u d y peri o d.  
I n t he case of a p har mace utical pre parati o n is re q uire d, t he dec o di n g s yste m use d is a seale d c o di n g 
list t o be gi ve n t o t he E U R O FI N S- O P TI M E D p har ma cist. T he seale d c o di n g list s h o ul d be ke pt i n a safe 
place a n d accessi ble t o a n y pers o n a ut h orise d t o u n bli n d. 
T he i n vesti gat or, C R O staff (e xce pt t he P har macist a n d p har mac y assista nt i n c har ge of t he I P fi nal 
pac ka gi n g) a n d S p o ns or ’s cli nical trial tea m 
me m bers will n ot ha ve access t o t he ra n d o mizati o n 
(treat me nt/ pr o d uct) c o de e xce pt u n der certai n circ u msta nces.  
 
 
3. 7. 2.  Bre a ki n g t he bli n d 
 
T he c o de f or a n y st u d y partici pa nt s h o ul d o nl y be br o ke n b y t he I n vesti gat or or a ut h orise d pers o n i f 
it is a bs ol utel y necessar y.   
I n case of e mer ge nc y, f or a s u bj ect i n partic ular, t he c o de ma y be br o ke n t o ascertai n t he t y pe of 
treat me nt gi ve n t o st u d y p artici pa nt c o ncer ne d. If s o, t he I n vesti gat or ( or a pers o n desi g nate d fr o m his 
tea m) m ust write his na me, si g nat ure, date, t he n u m ber of t he partici pa nt c o ncer ne d, t he reas o n f or c o de 
brea ki n g a n d t he S p o ns or m ust be n otifie d wit hi n 2 4 h o urs a n d a f ull writte n e x pla nati o n m ust be 
pr o vi de d. 
T he c o de ma y als o be br o ke n b y t he Cli nical Q ualit y Ass ura nce ( C Q A) re prese ntati ve if t his 
i nf or mati o n has t o be pr o vi de d t o t he p h ysicia n i n c har ge of s u bjects treat me nts (i.e. at t he h os pital). I n 
t his case, t he c o de will be br o ke n usi n g t he seale d c o di n g list if a vaila ble or seale d e n vel o pe. T he 
i nf or mati o n res ulti n g fr o m c o de-brea ki n g (i.e., t he s u bject’s gr o u p assi g n me nt) will n ot be c o m m u nicate d 
t o eit her t he I n vesti gat or or t he S p o ns or. 
A c o p y of t he e mer ge nc y e n vel o pes will be s u p plie d als o t o t he S p o ns or. W hile t he I n vesti gat or 
( PI) will o perate u n der bli n d c o n diti o ns u ntil t he e n d of t he st u d y, t he S p o ns or ma y o pe n t he c o de f or a 
si n gle c o h ort, b ut o nl y after t he st u d y c o h ort has bee n c o m plete d a n d t he j oi nt (t o get her wit h t he PI) 
bli n de d decisi o n, a b o ut w het her or n ot t o c o nti n ue wit h t he pla n ne d d ose escalati o n, has bee n ta ke n.  
T he ra n d o mizati o n e n vel o pes s h o ul d n ot be o pe ne d b y t he I n vesti gat or at t he e n d of t he st u d y. 
I n case of S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R), t he S p o ns or Dr u g Safet y 
s h o ul d brea k treat me nt c o des bef ore re p orti n g o n a n e x pe dite d basis t he S U S A R t o t he C o m pete nt 
A ut h orities a n d t o t he Et hics C o m mittee c o ncer ne d. T he bli n di n g c o de s h o ul d be br o ke n o nl y f or t he 
s u bj ect c o ncer ne d wit h t hat S U S A R a n d treat me nt c o de s hall n ot be discl ose d t o I n vesti gat or staff a n d t o 
S p o ns or Cli nical De part me nt . A n a d diti o nal c o p y of t he I n di vi d ual e n vel o pes i de ntifie d wit h t he s u bj ect 
assi g n me nt n u m ber is st ore d b y D o m pé Dr u g Safet y. D o m pé Dr u g Safet y will u n mas k a patie nt treat me nt 
o nl y f or safet y reas o n or t o assess  re g ulat or y re p orta bilit y of a p ote ntial S U S A R a n d will d oc u me nt 
e n vel o pe o pe ni n g.  
 
 
4.  S T U D Y P O P U L A TI O N 
4. 1.  
S u bject i ncl usi o n criteri a 
F or eli gi bilit y i nt o t he trial, s u bjects m ust meet all t he f oll o wi n g i ncl usi o n criteria : 
 
1-  H ealt h y male s u bj ect, a ge d bet wee n 1 8 a n d 5 5 years i ncl usi ve; 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 7  / 8 5  
2-  H ealt h y fe male s u bject i nfertile or i n p ost me n o pa use f or at least t w o years, a ge d bet wee n 1 8 a n d 
6 0 years i ncl usi ve; 
3-  B o d y Mass I n de x ( B MI) bet wee n 1 8. 5 a n d 2 9. 9 k g/ m 2 incl usi ve a n d wei g ht ≤ 9 0 k g ; 
4-  C o nsi dere d as healt h y after a c o m pre he nsi ve cli nical assess me nt ( detaile d me dical hist or y a n d 
c o m plete p h ysical e xa mi nati o n); 
5-  N or mal Bl o o d Press ure ( B P) a n d Heart Rate ( H R) at t he scree ni n g visit after 1 0 mi n utes i n s u pi ne 
p ositi o n: 
o  9 0 m m H g ≤ S yst olic Bl o o d Press ure ( S B P) ≤ 1 4 0 m m H g or 1 5 0 m m H g f or s u bject > 
4 5 years, 
o  5 0 m m H g ≤ Diast olic Bl o o d Press ure (D B P ) ≤ 9 0 m m H g, 
o  4 0  b p m  H R  1 0 0 b p m, 
 Or c o nsi dere d N Cs b y i n vesti gat ors; 
6-  S m o ker < 5ci garettes per da y w h o st o p t otall y d uri n g t he st u d y  
7-  N or mal E C G rec or di n g o n a 1 2-lea d E C G at t he scree ni n g visit: 
o  
1 2 0 < P R < 2 1 0 ms,  
o  
Q R S < 1 2 0 ms,  
o  
Q T cf  4 3 0 ms f or male a n d < 4 5 0 ms f or fe male, 
o  
N o si g n of a n y tr o u ble of si n usal a ut o matis m, 
Or c o nsi dere d N Cs b y i n vesti gat ors; 
8-  N or mal oral te m perat ure 
o  3 6. 3° C < oral b o d y te m perat ure < 3 7. 5° C;  
9 - La b orat or y para meters 
wit hi n t he n or mal ra n ge of t he la b orat or y ( ha e mat ol o gical, bl o o d 
c he mistr y tests, uri nal ysis). I n di vi d ual val ues o ut of t he n or mal ra n ge ca n be acce pte d if j u d ge d 
cli nicall y n o n rele va nt b y t he I n vesti gat or; 
1 0-  N or mal dietar y ha bits; 
1 1-  A ble t o c o m m u nicate well wit h t he I n vesti gat or, u n dersta n d a n d c o m pl y wit h t he re q uire me nts of 
t he st u d y, a n d u n dersta n d a n d si g n a writte n i nf or me d c o nse nt pri or t o selecti o n; 
1 2-  C o vere d b y Healt h I ns ura nce S yste m a n d / or i n c o m plia nce wit h t he rec o m me n dati o ns of 
Nati o nal La w i n f orce relati n g t o bi o me dical researc h. 
 
4. 2.  S u bject n o n-i ncl usi o n criteri a 
S u bj ects meeti n g a n y of t he f oll o wi n g criteria will n ot be i ncl u de d i nt o t he trial : 
 
 
1-  S u b j ect has ha d a cli nicall y si g nifica nt ill ness i n t he si x wee ks bef ore scree ni n g i n t he o pi ni o n of 
t he I n vesti gat or; 
2-  S u b j ect has ha d a seri o us a d verse reacti o n or si g nifica nt h y perse nsiti vit y t o a n y dr u g, has a 
k n o w n cli nicall y si g nifica nt aller g y t o a nti-i nfla m mat or y dr u gs or c he micall y relate d c o m p o u n ds 
or has a cli nicall y si g nifica nt aller g y t o dr u gs, f o o ds or ot her materials (i n t he o pi ni o n of t he 
I n vesti gat or). H o we ver, s u bjects wit h mil d ha yfe ver ma y be i ncl u de d i n t he st u d y.  
3 - S u bj ect has use d prescri pti o n me dicati o n i n t he 1 4 da ys pri or t o d osi n g or o ver-t he-c o u nter 
pre parati o ns f or 7 da ys pri or t o d osi n g (i ncl u di n g vita mi n s u p ple me nts a n d her bal re me dies), wit h 
t he e xce pti o n of paraceta m ol w hic h will be all o we d d uri n g t he st u d y ( ma xi m u m 5 0 0 m g per 
a d mi nistrati o n, t otal dail y d ose ma xi m u m 2 gra ms). 
4-  S u b j ect has a si g nifica nt hist or y of dr u g/s ol ve nt a b use or a p ositi ve dr u gs of a b use ( D O A) test at 
a n y ti me d uri n g t he st u d y. 
5-  S u b j ect has a hist or y of alc o h ol a b use i n t he last 5 years or c urre ntl y dri n ks i n e xcess of 2 1 a n d 1 4 
u nits per wee k f or males a n d fe male, res pecti vel y, or has a p ositi ve alc o h ol breat h test ( A B T) at 
a n y ti me d uri n g t he st u d y. 
6 - S u bj ect is n ot willi n g t o refrai n fr o m caffei ne/ xa nt hi ne c o ntai ni n g pr o d ucts i n t he 4 8 h o urs pri or 
t o a d missi o n t o t he cli nical u nit o n Da y - 1 a n d f or t he d urati o n of t he resi de ntial peri o d. 
7 - S u bj ect w h o has a p ositi ve h u ma n i m m u n o deficie nc y vir us ( HI V) scree n, He patitis B scree n or 
He patitis C scree n. 
8 - S u bj ect has d o nate d bl o o d or bl o o d pr o d ucts (e. g., plas ma or platelets) wit hi n t he t hree m o nt hs 
pri or t o scree ni n g. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 8  / 8 5  
9-  S u b j ect w h o is n ot s uita ble t o partici pate i n t he st u d y i n t he o pi ni o n of t he I n vesti gat or; 
1 0-  S u bj ect w h o has partici pate d i n a n y cli nical st u d y wit h a n i n vesti gati o nal dr u g/ de vice wit hi n t hree 
m o nt hs pri or t o t he first da y of d osi n g.  
1 1-  S u bj ect w h o is i n t he e xcl usi o n peri o d fr o m a n ot her st u d y. 
1 2-  A d mi nistrati ve or le gal s u per visi o n; 
1 3-  S u bj ect w h o w o ul d recei ve 
m ore t ha n 4 5 0 0 e ur os as i n de m nities f or his partici pati o n i n 
bi o me dical researc h wit hi n t he 1 2 last m o nt hs, i ncl u di n g t he i n de m nities f or t he prese nt st u d y. 
 
4. 3.  S u bject I de ntific ati o n 
4. 3. 1.  Scree ni n g n u m ber 
T he scree ni n g n u m ber will be S a n d 3 di gits, f or e xa m ple: S 0 0 3. It will be a c hr o n ol o gic al n u m ber. T he 
scree ni n g n u m ber will be use d t hr o u g h o ut t he scree ni n g peri o d, u ntil s u bjects are ra n d o mize d. 
 
4. 3. 2.  I ncl usi o n n u m ber 
T he i ncl usi o n n u m ber will be c o m p ose d of 7 di gits, 3 f or t he n u m ber of ce ntre ( 0 0 1) a n d 4 f or t he 
i ncl usi o n n u m ber: fr o m 1 0 0 1 t o 1 0 3 2 f or part A a n d fr o m 2 0 0 1 t o 2 0 3 6 f or part B. It will be a 
c hr o n ol o gical n u m ber. 
 
4. 3. 3.   R a n d o miz ati o n n u m ber  
T he ra n d o mizati o n n u m ber will be t he sa me as t he i ncl usi o n n u m ber a n d t he treat me nt n u m ber.  
 
4. 4.  S u bject wit h dr a w al criteri a 
4. 4. 1.  Defi niti ve or te m p or ar y st o p of a pers o n’s p artici p ati o n i n t he rese arc h 
4. 4. 1. 1.  List of wit h dr a w al criteri a 
T he criteria of wit h dra wal c o ul d be seri o us a d verse e ve nts ( S A E) or A Es 
4. 4. 1. 2.  R e as o ns f or wit h dr a w al 
T he s u bjects ma y wit h dra w fr o m t he st u d y f or t he f oll o wi n g reas o ns: 
- 
t he s u bject wit h dra ws c o nse nt at a n y ti me a n d irres pecti ve of t he reas o n. 
- 
t he s u bj ect i nc urs a si g nifica nt pr ot oc ol vi olati o n t hat p uts t he safet y of t he s u bj ect or t he 
i nte grit y of t he data at ris k (t he defi niti o n of si g nifica nt is ma de c o nte m p ora ne o usl y b y t he 
I n vesti gat or). 
- 
at t he I n vesti gat or's re q uest (f or e xa m ple if t he I n vesti gat or c o nsi ders t hat t he s u bj ect's healt h is 
c o m pr o mise d b y re mai ni n g i n t he st u d y or t he s u bject is n ot s ufficie ntl y c o o perati ve). 
- 
at t he re q uest of t he S p o ns or. 
 
4. 4. 2.  Defi niti ve or te m p or ar y st o p of a p art or t he t ot alit y of t he rese arc h 
4. 4. 2. 1.  Deci de d b y t he S p o ns or  
T he S p o ns or ma y deci de pre mat ure disc o nti n uati o n of t he st u d y i n t he f oll o wi n g cases: 
- T he st u d y is n ot c o n d ucte d i n acc or da nce wit h t he pr oce d ures defi ne d i n t he a p pr o ve d pr ot oc ol (i.e. 
l o w rate of recr uiti n g - pr ot oc ol de viati o ns - fail ure t o e ns ure t he q ualit y of t he data c ollecte d); 
- Inf or mati o n o n t he I n vesti gati o nal Me dici nal Pr o d uct (I M P) / St u d y Pr o d uct t hat mi g ht c ha n ge t he 
c urre nt be nefit -ris k pr ofile of t he I M P or t hat w o ul d be s ufficie nt t o re q uire c ha n ges i n t he I M P 
a d mi nistrati o n or i n t he o verall c o n d uct of t he trial ; 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
3 9  / 8 5  
- Lef t at t he discreti o n of t he S p o ns or. 
4. 4. 2. 2.  Deci de d b y t he I n vesti g at or 
T he I n vesti gat or ma y s us pe n d or st o p t he researc h if i n his j u d g me nt t he partici pati n g s u bj ects are 
e x p ose d t o ris ks t hat are n ot et hicall y or scie ntificall y j ustifia ble a n d m ust n otif y i n writi n g t he S p o ns or of 
t his decisi o n pr o vi di n g t he reas o n t here of. 
If t he researc h is s us pe n de d f or safet y reas o ns, t he Healt h A ut h orities m ust be i m me diatel y n otifie d of t he 
s us pe nsi o n. I n t his case, t he st u d y ca n res u me after a n a me n d me nt is a p pr o ve d b y t he Healt h A ut h orities. 
If t he st u d y is st o p pe d, Et hics C o m mittee a n d Healt h A ut h orities s h o ul d be i nf or me d b y S p o ns or, wit hi n 
1 5 da ys after t he decisi o n is ta ke n. 
 
4. 5.  
P re m at ure disc o nti n u ati o n of  s u bject  
4. 5. 1.  D at a t o be c ollecte d, a n d ti me of rec or di n g of t hese d at a 
Eac h partici pa nt is free t o disc o nti n ue fr o m t he st u d y at a n y ti me, f or a n y reas o n. If a partici pa nt 
disc o nti n ues fr o m t he st u d y (re gar dless of t he reas o n f or a partici pa nt’s disc o nti n uati o n a n d re gar dless of 
t he partici pa nt’s stat us as e val ua ble or n ot e val ua ble), t he I n vesti gat or will i n dicate t he reas o n f or 
disc o nti n uati o n o n t he a p pr o priate e C R F pa ge. A f oll o w- u p visit will be pla n ne d b y t he I n vesti gat or. T he 
e xa ms sc he d ule d f or t he e n d- of-st u d y visit will be perf or me d.  
I n case of pre mat ure disc o nti n uati o n d ue t o A Es, t he I n vesti gat or will i n dicate t hat o n t he A E F or m of t he 
e C R F a n d i n t he S A E F or m, if a p pr o priate. Partici pa nts will be m o nit ore d u ntil res ol uti o n. 
 
4. 5. 2.  Met h o ds of re pl ace me nt 
A s u bj ect w h o pre mat urel y e n ds his/ her st u d y peri o d after t he start of t he baseli ne peri o d a n d w h o 
recei ve d treat me nt will be re place d. 
T he re place me nt s u bj ect will u n der g o t he c o m plete st u d y. He/s he will be gi ve n a n u m ber c orres p o n di n g 
t o t he n u m ber of t he s u bject bei n g re place d pl us 1 0 0 (i.e. f or t he s u bject n u m ber 1 0 0 4, t he re place me nt 
s u bj ect will recei ve t he n u m ber 1 1 0 4).  
S u bj ects w h o ha ve bee n wit h dra w n fr o m t he st u d y ca n n ot be re-i ncl u de d i n t he st u d y. T heir i ncl usi o n a n d 
treat me nt n u m ber m ust n ot be re- use d. 
 
4. 5. 3.  Met h o ds of f oll o w- u p of pre m at ure disc o nti n u ati o ns 
I n case of pre mat ure disc o nti n uati o n d ue t o A Es/ S A Es, f oll o w- u p will c o nti n ue u ntil t he e ve nt is res ol ve d 
or t he c o n diti o n is u nli kel y t o c ha n ge or t he s u bject is l ost t o f oll o w- u p (see secti o n 8. 5 ). 
 
4. 6.  
E xcl usi o n peri o d 
T he s u bjects i ncl u de d i n t his st u d y will be pr o hi bite d fr o m partici pati n g si m ulta ne o usl y i n ot her researc h.  
T he e xcl usi o n peri o d pla n ne d at t he e n d of t he researc h will be 3 m o nt hs. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 0  / 8 5  
5.  S T U D Y P R O D U C T/ T R E A T M E N T  
5. 1.  
Des cri pti o n of t he tre at me nt(s) 
5. 1. 1.  P h ar m ace utic al f or m 
Na me of t he c o m p o u n d:  
  
  
  
D F 2 7 5 5 A 
P har mace utical f or m :   
  
 
Ca ps ules of 5 0 m g a n d 2 0 0 m g     
D ose per a d mi nistrati o n: 
Part A:  5 0 m g oa d, 1 5 0 m g oa d, 4 5 0 m g oa d or 7 0 0 m g 
oa d  
Part B: 1 0 0 m g bi d, 2 0 0 m g bi d or 3 0 0 m g bi d 
 
N u m ber of ca ps ules / a d mi nistrati o n:  
1, 2, 3 or 6 ca ps ules per a d mi nistrati o n acc or di n g t o t he 
d ose le vel 
Ti mi n g f or a d mi nistrati o n: 
Part A: Si n gle oral d ose a d mi nistrati o n o n D 1 acc or di n g 
t o t he ra n d o mizati o n. T he a d mi nistrati o n will ta ke place 
at ar o u n d 8: 0 0 a. m wit h 2 0 0 ml of ta p water, i n sitti n g 
p ositi o n, i n fasti n g c o n diti o ns. 
Part B: Re peate d oral a d mi nistrati o n fr o m Da y 1 t o Da y 
1 4. T he a d mi nistrati o n will ta ke place at ar o u n d 8: 0 0 a. m 
a n d at ar o u n d 8: 0 0 p. m wit h 2 0 0 ml of ta p water, i n 
sitti n g p ositi o n, i n fasti n g c o n diti o ns. 
 
Na me of t he c o m p o u n d:  
  
  
  
Place b o 
P har mace utical f or m ulati o n:    
  
  
Matc hi n g ca ps ule of 5 0 m g a n d 2 0 0 m g 
D ose per a d mi nistrati o n:  
  
  
 
N A  
N u m ber of ta blets/ca ps ules / a d mi nistrati o n:  
1, 2, 3 or 6 ca ps ules per a d mi nistrati o n acc or di n g t o t he 
d ose le vel 
Ti mi n g f or a d mi nistrati o n: 
Part A: Si n gle oral d ose a d mi nistrati o n o n D 1 acc or di n g 
t o t he ra n d o mizati o n. T he a d mi nistrati o n will ta ke place 
at ar o u n d 8: 0 0 a. m wit h 2 0 0 ml of ta p water, i n sitti n g 
p ositi o n, i n fasti n g c o n diti o ns. 
Part B: Re peate d oral a d mi nistrati o n fr o m Da y 1 t o Da y 
1 4. T he a d mi nistrati o n will ta ke place at ar o u n d 8: 0 0 a. m 
a n d at ar o u n d 8: 0 0 p. m wit h 2 0 0 ml of ta p water, i n 
sitti n g p ositi o n, i n fasti n g c o n diti o ns. 
 
5. 1. 2.  U nit f or m, m a n uf act ure, p ac k a gi n g a n d l a belli n g 
T he ma n ufact ure of b ul k D F 2 7 5 5 A ca ps ules a n d b ul k matc hi n g place b o ca ps ules a n d t he pac ka gi n g is 
carrie d o ut, i n acc or da nce wit h G o o d Ma n ufact uri n g Practice at: 
 
S Y N E R L A B D E V E L O P P E M E N T 
C S 7 0 0 0 2 1, r ue C harles C o ul o m b  
4 5 0 7 7 Orléa ns Ce de x 2 - Fra nce 
S Y N E R L A B D E V E L O P P E M E N T   is a s u b-c o ntract or of E U R O FI N S O P TI M E D. 
 
IM P ( D F 2 7 5 5 A a n d matc hi n g place b o ca ps ules) will be s hi p pe d t o t he E U R O FI N S O P TI M E D 
P har mac y.  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 1  / 8 5  
L a belli n g st ora ge a n d dis pe nsati o n of D F 2 7 5 5 A ca ps ules a n d matc hi n g place b o ca ps ules, are c o n d ucte d 
i n acc or da nce wit h t he a p plica ble G o o d Cli nical Practices at  E U R O FI N S O P TI M E D P har mac y 
O P TI M E D E U R O FI N S 
1 r ue des Essarts 
3 8 6 1 0 GI E R E S 
 
T he A PI is ma n ufact ure d b y A M S A o n be half of D o m pé Far mace utici S. p. A. 
A M S A 
Via g. di Vitt ori o, 6 
2 2 1 0 0 C o m o, I T A L Y 
 
A tri partite q ualit y a gree me nt bet wee n D o m pé Far mace utici (t he c o ntract gi ver), E U R O FI N S O P TI M E D 
a n d S Y N E R L A B D E V E L O P P E M E N T ( b ot h c o ntract acce pt or) will be i n place f or t he G M P 
ma na ge me nt of a n y I M P ma n ufact uri n g acti vities.  
D F 2 7 5 5 A a n d matc hi n g place b o ca ps ules will be pac k a ge d i nt o blister of 1 0 ca ps ules. De pe n di n g of t he 
d oses, ca ps ules will be places i n e n vel o pe, eac h e n vel o pe c o ntai ni n g: Part A: 1, 3, 3 or 6 ca ps ules of 
D F 2 7 5 5 A or matc hi n g Place b o; Part B: 2, 1 or 2 ca ps ules of D F 2 7 5 5 A or matc hi n g Place b o.  
La bel f or blister: 
 
o  D F 2 7 5 5 A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o  P L A C E B O  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B P S 0 1 1 5 / O P 0 9 9 5 1 6. D O M  
E u dr a C T  N° 2 0 1 6 -0 0 3 6 2 9 -4 1  
Pr o m ot e ur :  
D O M P E  F A R M A C E U TI CI S. P. A  
Vi a S a nt a L uci a 6 –  2 0 1 2 2 Mil a n o –  It aly  
T el.: + 3 9 0 2 5 8 3 8 3 1 –  F ax: + 3 9 0 2 5 8 3 8 3 3 2 4  
I n v esti g at e ur :  
Dr Y v es D O N A Z Z OL O  
 
           
E ur ofi ns O pti m e d Cli nic al R es e arc h  
 
 
1 r u e d es Ess arts –  3 8 6 1 0 GI E R E S Fr a nc e  
 
Tr ait e m e nt  :  
D F 2 7 5 5 A –  g él ul es d e X X  m g  
  
 
1 blist er d e 1 0 g él ul es  
L ot n° : X X X X X X X X X X X       D at e d e p ér e m pti o n : M M/ Y Y Y Y   
 
P o ur a d mi nistr ati o n or al e  
A utilis er c o nf or m é m e nt a ux i n dic ati o ns d u pr ot oc ol e  
A c o ns erv er à u n e t e m p ér at ur e  n e d é p ass a nt p as 3 0 ° C  
P o ur r ec h erc h e s ur l a p ers o n n e h u m ai n e u ni q u e m e nt  
B P S 0 1 1 5 / O P 0 9 9 5 1 6. D O M  
E u dr a C T N° 2 0 1 6 -0 0 3 6 2 9 -4 1  
Pr o m ot e ur :  
D O M P E F A R M A C E U TI CI S. P. A  
Vi a S a nt a L uci a 6 –  2 0 1 2 2 Mil a n o –  It aly  
T el.: + 3 9 0 2 5 8 3 8 3 1 –  F ax: + 3 9 0 2 5 8 3 8 3 3 2 4  
I n v esti g at e ur :  
Dr Y v es D O N A Z Z OL O  
 
           
E ur ofi ns O pti m e d Cli nic al R es e arc h  
 
 
1 r u e d es Ess arts –  3 8 6 1 0 GI E R E S Fr a nc e  
 
Tr ait e m e nt  :  
D F 2 7 5 5 A PL A C E B O –  g él ul es d e X X  m g  
  
 
1 blist er d e  1 0 g él ul es  
L ot n° : X X X X X X X X X X X       D at e d e p ér e m pti o n : M M/ Y Y Y Y   
 
P o ur a d mi nistr ati o n or al e  
A utilis er c o nf or m é m e nt a ux i n dic ati o ns d u pr ot oc ol e  
A c o ns erv er à u n e t e m p ér at ur e n e d é p ass a nt p as 3 0 ° C  
P o ur r ec h erc h e s ur l a p ers o n n e h u m ai n e u ni q u e m e nt  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 2  / 8 5  
L a belli n g o perati o ns perf or me d b y t he E U R O FI N S O P TI M E D P har macist, will be i n c o m plia nce wit h 
E u dra Le x - V ol u me 4, E U G ui deli nes t o G o o d Ma n ufact uri n g Practice Me dici nal Pr o d ucts f or H u ma n 
a n d Veteri nar y Use - A n ne x 1 3.  
 
La bels f or u nitar y d oses will bear t he f oll o wi n g i nf or mati o n’s: 
 
B P S 0 1 1 5/ O P 0 9 9 5 1 6. D O M 
D o m pé f ar m ace utici s. p. a 
Dr Y ves D o nazz ol o  
Traite me nt : D F 2 7 5 5 A o u place b o 
N°  d u s uj et : 0 0 1 -X X X   
D ose  : X X m g s oit X  gél ules  
V oie d’a d mi nistrati o n  : orale 
A utiliser c o nf or mé me nt a u x i n dicati o ns d u pr ot oc ole 
 n°: P R E P 2 0 1 _ _ _ _ 
Date de pére m pti o n : _ _/ _ _/ _ _ _ _ 
A d mi nistrati o n de   D X T X  : _ _/ _ _/ _ _ _ _  
C o nser ver à u ne te m pérat ure ne dé passa nt pas 3 0° C 
P o ur rec herc he s ur l a pers o n ne h u m ai ne u ni q ue me nt 
 
 
T he a d dress a n d tele p h o ne n u m ber of t he mai n c o ntact f or i nf or mati o n o n t he pr o d uct, cli nical trial a n d 
f or e mer ge nc y c o ntact will be dis pla ye d o n st u d y car ds t hat s u bjects will ha ve bee n i nstr ucte d t o kee p i n 
t heir p ossessi o n at all ti mes. 
 
5. 1. 3.  R o ute a n d m o de of a d mi nistr ati o n 
F or Part A, D F 2 7 5 5 A will be a d mi nistere d orall y, at T 0 h (ar o u n d 8: 0 0 a. m), i n sitti n g p ositi o n, i n fasti n g 
c o n diti o ns, wit h 2 0 0 ml of ta p water.  
F or Part B, re peate d a d mi nistrati o ns will be perf or me d at T 0 h (ar o u n d 8: 0 0a. m) a n d at T 1 2 h (ar o u n d 
8: 0 0 p. m). F or eac h s u bj ect, t hese a d mi nistrati o ns will be perf or me d wit h a n a ut h orise d wi n d o w of ± 1 5 
mi n utes. 
Treat me nts will be a d mi nistere d u n der t he s u per visi o n of t he I n vesti gat or, i n t he Cli nical P har mac ol o g y 
U nit E U R O FI N S O P TI M E D.  
T he act ual ti me of dr u g a d mi nistrati o n will be d oc u me nte d i n t he s o urce d oc u me nts a n d re p orte d i n 
i n di vi d ual e C R F. 
 
5. 2.  
Acc o u nt a bilit y pr oce d ures f or t he i n vesti g ati o n al pr o d uct(s) 
 
5. 2. 1.  Res p o nsi bilities 
T he I n vesti gat or, t he p har macist or ot her pers o n nel all o we d t o st ore a n d dis pe nse I M P will be res p o nsi ble 
f or e ns uri n g t hat t he I n vesti gati o nal Treat me nt use d i n t he st u d y is sec urel y mai ntai ne d as s pecifie d b y t he 
S p o ns or a n d i n acc or da nce wit h t he a p plica ble re g ulat or y re q uire me nts. 
T he I M P will be dis pe nse d i n ac c or da nce wit h t he I n vesti gat or's prescri pti o n a n d it is t he I n vesti gat or's 
res p o nsi bilit y t o e ns ure t hat a n acc urate rec or d of I n vesti gati o nal Pr o d uct iss ue d a n d ret ur ne d is 
mai ntai ne d. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 3  / 8 5  
5. 2. 2.  A cc o u nt a bilit y 
Details of t he q ua ntities of eac h me dicati o n dis pe nse d will be e ntere d o nt o t he acc o u nta bilit y f or m. At t he 
e n d of t he st u d y, t he a m o u nt of eac h pr o d uct retai ne d (if re q uire d) i n t he Cli nical U nit a n d t he re mai ni n g 
a m o u nt (if a n y), will be ret ur ne d t o t he S p o ns or or destr o ye d after a fi nal rec o nciliati o n (if a gree d wit h t he 
S p o ns or ). A c o p y of t he f or m will t he n be se nt t o t he S p o ns or, t o get her wit h a n y re mai ni n g me dicati o n (if 
a gree d) (see secti o n 5. 2. 3 ). 
S pecific pr oce d ures f or t he I M P pre parati o n, dis pe nsati o n, st ora ge a n d destr ucti o n w he n re q uire d will be 
detaile d i n t he “ p har mac y ma n ual f or st u d y O P 0 9 9 5 1 6. D O M ”. T his d oc u me nt will be s u p plie d b y t he 
p har macist of E ur ofi ns O pti me d a n d a p pr o ve d b y t he s p o ns or, a part fr o m t he st u d y pr ot oc ol. 
 
5. 2. 3.  Ret ur n a n d / or destr ucti o n of I M P 
 
I n vesti gati o nal me dici nal pr o d uct rec o nciliati o n m ust be perf or me d at t he site b y t he I n vesti gat or ( or t he 
p har macist) a n d t he m o nit ori n g tea m usi n g t he a p pr o pri ate f or m c o u ntersi g ne d b y t he I n vesti gat or ( or t he 
p har macist) a n d t he m o nit ori n g tea m. T est materials (i ncl u di n g i n vesti gati o nal pr o d ucts a n d place b o) 
re mai ni n g at t he e n d of t he st u d y will be ret ur ne d t o t he S p o ns or or t heir re prese ntati ve, or destr o ye d o n 
be half of t he S p o ns or after a fi nal rec o nciliati o n of i n vesti gati o nal me dici nal pr o d uct.  
I n case of destr ucti o n, a writte n a ut h orizati o n f or destr ucti o n will be gi ve n b y t he cli nical trial tea m o nce 
t he i n vesti gati o nal me dici nal pr o d uct rec o nciliati o n is ac hie ve d. T his destr ucti o n will be perf or me d b y t he 
p har macist or dele gate d pers o n a n d a certificate of destr ucti o n will pr o vi de d.  
 
5. 3.  
Me dic ati o n(s)/tre at me nt(s) per mitte d a n d n o per mitte d bef ore a n d/ or d uri n g t he tri al 
 
N o c o nc o mita nt t hera p y ( prescri be d or n o n- prescri be d dr u g i ncl u de d O T C) will be all o we d d uri n g t he 
st u d y, e xce pt paraceta m ol ( ma xi m u m 5 0 0 m g per a d mi nistrati o n, t otal dail y d ose 
ma xi m u m 2 g). 
H o we ver, i n case of i nterc urre nt ill ness or e mer ge nc y, t he i n vesti gat or is all o we d t o use a n y ne e de d 
me dicati o n. 
T his m ust be d o ne wit h a partic ular atte nti o n t o t he a vaila ble p har mac ol o gical k n o wle d ge of t he gi ve n 
me dicati o n a n d p ossi ble i nteracti o n(s) wit h t he st u d y dr u g. I n case of i nta ke of a n y c o nc o mita nt 
me dicati o n d uri n g t he st u d y, t he f oll o wi n g i nf or mati o n m ust be n ote d i n t he rele va nt secti o n of t he e C R F:  
- Na me of t he treat me nt a n d its f or m, 
- Reas o ns f or prescri pti o n, 
- Date a n d ti me of start, 
- R o ute of a d mi nistrati o n, 
- Dail y d ose, 
- D urati o n of treat me nt. 
 
T he decisi o n t o wit h dra w t he s u bject ma y be ma de b y m ut ual a gree me nt bet wee n t he I n vesti gat or a n d t he 
S p o ns or. 
 
5. 4.  
P r oce d ures of m o nit ori n g s u bject c o m pli a nce 
A d mi nistrati o n will be perf or me d u n der me dical s u per visi o n. A m o ut h c o ntr ol will be perf or me d 
i m me diatel y after t he a d mi nistrati o n. 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 4  / 8 5  
6.  A S S E S S M E N T O F P H A R M A C O KI N E TI C  
Deri vati o n of P K para meters will be carrie d o ut b y P hi n C De vel o p me nt usi n g Wi n N o nli n
®  Pr ofessi o nal 
s oft ware ( Versi o n P h oe ni x 6. 4 –  P harsi g ht C or p orati o n –  M o utai n Vie w, Calif or nia –  U S A). A n o n-
c o m part me ntal a nal ysis a p pr oac h will be perf or me d. 
T he statistical a nal ysis will be carrie d o ut b y P hi n C de vel o p me nt usi n g t he S A S ®  pac ka ge (releas e 9. 4). 
In eac h part of t he st u d y, a first i nteri m P K a nal ysis wit h n o mi nal ti me p oi nts will be r u n after c o m pleti o n 
of eac h d ose le vel. After data base l oc k, a fi nal a nal ysis will be r u n wit h act ual ti me p oi nts. F or t he i nteri m 
a nal ysis, n o f or mal statisti cs will be prese nte d. 
After c o m pleti o n of t he bi oa nal ytical part of t he st u d y, a n electr o nic c o p y of t he q ualit y c hec ke d a n d 
vali date d data will be pr o vi de d t o P hi n C De vel o p me nt. 
 
6. 1.  
P h ar m ac o ki netic e n d p oi nts 
F or t he calc ulati o n of t he P K para meters a n d c hara cteristics t he f oll o wi n g r ules will be a p plie d:  
 
All t he plas ma c o nce ntrati o ns vali date d b y t he bi oa nal ytical la b orat or y a n d pr o vi de d t o t he 
p har mac o ki neticist will be use d f or t he P K a nal ysis. 
 
T he act ual bl o o d sa m pli n g ti me p oi nts relate d t o t he prece di n g a d mi nistrati o n will be use d if 
a vaila ble. Ot her wise, n o mi nal bl o o d sa m pli n g ti mes will be ta ke n i nt o acc o u nt. 
 
At ti me p oi nts i n t he la g-ti me bet wee n ti me zer o a n d t he first c o nce ntrati o n e q ual or a b o ve t he 
li mit of q ua ntificati o n ( L O Q), c o nce ntrati o ns bel o w L O Q will be set t o zer o ( 0). C o nce ntrati o ns 
bel o w L O Q bet wee n 2 c o nce ntrati o ns e q ual or a b o ve L O Q will be c o nsi dere d as missi n g data. 
Traili n g c o nce ntrati o ns bel o w L O Q will n ot be use d i n calc ulati o ns.  
 
F or plas ma c o nce ntrati o n a b o ve t he u p per li mit of q ua ntificati o n ( U L O Q) a n d re p orte d as a b o ve 
t he li mit of q ua ntificati o n ( A L Q) i n t he fi nal plas ma c o nce ntrati o n ta bles, A L Q will be re place d 
b y t he first meas ure me nt f or t he P K a nal ysis. 
 
N ot re p orte d c o nce ntrati o n ( N R) will be e xcl u de d fr o m t he P K a nal ysis. 
 
If pre- d ose c o nce ntrati o n is less t ha n or e q ual t o 5 % of C ma x  val ue i n a P K pr ofile, t he s u bject's 
data ca n be i ncl u de d i n all P K meas ure me nts a n d calc ulati o ns wit h o ut a n y a dj ust me nts. If t he pre-
d ose val ue is greater t ha n 5 % of C ma x , t he s u bject will be dr o p pe d fr o m all statistical e val uati o ns 
(a p plica ble o nl y at t he pre d ose o n da y 1). 
Acc or di n g t o t he st u d y part a n d t he da y of P K assess me nt, t he f oll o wi n g P K para meters of D F 2 5 7 7 Y 
b o u n d a n d u n b o u n d ( or relate d meta b olites) will be deri ve d fr o m D F 2 5 7 7 Y ( or relate d meta b olites) 
plas ma c o nce ntrati o ns f or eac h s u bj ect o n Da y 1 ( S A D a n d M A D parts) a n d o n Da y 1 4 ( M A D part): 
C m a x / Css, m a x T he o bser ve d ma xi m u m plas ma c o nce ntrati o n of D F 2 5 7 7 Y ( or meta b olites) meas ure d i n a 
s u bj ect after d osi n g i de ntifie d b y i ns pe cti o n of t he plas ma dr u g c o nce ntrati o n vers us (vs.) 
ti me data b y P h oe ni x Wi n N o nli n. 
C ss, mi n  
T he o bser ve d plas ma c o nce ntrati o n of D F 2 5 7 7 Y ( or meta b olites) meas ure d i n a s u bject at 
1 2 h p ost- d ose j ust bef ore t he sec o n d dail y d osi n g vers us (vs.) ti me data b y P h oe ni x 
Wi n N o nli n ( Da y 1 4 i n M A D part o nl y). 
C ss, a v 
T he a vera ge c o nce ntrati o n at stea d y-state defi ne d as t he rati o A U C 0- τ/τ ( Da y 1 4 i n M A D part 
o nl y). 
tm a x /tss, m a x T he ti me at 
w hic h C ma x  
was a p pare nt, i de ntifie d b y i ns pecti o n of t he plas ma dr u g 
c o nce ntrati o n vs. ti me data b y P h oe ni x Wi n N o nli n. 
tl a g 
T he ti me bef ore occ urre nce of t he first q ua ntifia ble plas ma c o ncetrati o n will als o be o btai ne d 
directl y fr o m t he c o nce ntrati o n-ti me data; it is t he ti me p oi nt i m me diatel y pri or t o t he first 
q ua ntifia ble plas ma c o nce ntrati o n. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 5  / 8 5  
λz  
T he ter mi nal plas ma eli mi nati o n rate-c o nsta nt will be esti mate d fr o m l o g-li near re gressi o n 
a nal ysis of t he ter mi nal p hase of t he plas ma c o nce ntrati o n vs. ti me pr ofile ( S A D part a n d 
M A D part Da y 1 4 o nl y). F or t he sl o pe of t he ter mi nal eli mi nati o n p hase t o be acce pte d as 
relia ble, t he f oll o wi n g criteria will be i m p ose d: 
 
a c oefficie nt r² ≥ 0. 9 0,  
 
a mi ni m u m of 3 data p oi nts, i ncl u di n g t he last meas ure d data p oi nt a n d e xcl u di n g 
C ma x , are a vaila ble f or t he re gressi o n. 
  
If t hese 2 criteria c o ul d n ot be met, t he sl o pe of t he ter mi nal eli mi nati o n p hase will be 
c o nsi dere d as n ot calc ula ble a n d all t he para meters deri ve d fr o m t his val ue ( A U C 0- , t1/ 2, …) 
will be re p orte d as n ot calc ula ble ( N C). 
t1/ 2 
t1/ 2 will be calc ulate d acc or di n g t o t he f oll o wi n g e q uati o n: t1/ 2 = l n 2/ λz  (S A D part a n d M A D 
part Da y 1 4 o nl y). 
A U C 0- τ  
T he area u n der t he c o nce ntrati o n  vs. ti me c ur ve o ver t he d osi n g i nter val will be calc ulate d 
usi n g a li near tra pez oi dal met h o d ( i.e. fr o m ti me zer o ( pre- d ose) t o 1 2 h p ost- d ose i n M A D 
part o nl y). 
A U C 0- 2 4  
T he area u n der t he c o nce ntrati o n  vs. ti me c ur ve fr o m ti me zer o ( pre- d ose) t o 2 4 h p ost- d ose 
will be calc ulate d usi n g a li near tra pez oi dal met h o d ( S A D part o nl y). 
A U C 0-t 
T he area u n der t he c o nce ntrati o n  vs. ti me c ur ve fr o m ti me zer o ( pre- d ose) t o t he ti me of last 
q ua ntifia ble c o nce ntrati o n will be calc ulate d usi n g a li near tra pez oi dal met h o d. 
A U C 0 - 
T he area u n der t he ser u m dr u g c o nce ntrati o n vs. ti me c ur ve fr o m ti me zer o t o i nfi nit y: 
[ A U C0-  = A U C 0-t + ( Ct/ ke), w here Ct = t he o bser ve d c o nce ntrati o n of dr u g f or t he last 
sa m ple o n t he P K pr ofile i n w hic h dr u g was detecte d, a n d ke as defi ne d a b o ve. T he 
perce nta ge of e xtra p olati o n of A U C 0-  s h o ul d n or mall y n ot e xcee d 2 0 % t o c o nsi der t he val ue 
as relia ble ( S A D part o nl y). 
f u 
Fracti o n of u n b o u n d i n plas ma 
Cl/ F 
T he a p pare nt v ol u me of t he ce ntral c o m part me nt cleare d of dr u g per u nit ti me will be 
esti mate d usi n g t he f or m ula ( D F 2 5 7 7 Y o nl y i n S A D part o nl y). 
Cl/ F = D ose / A U C 0-  
V d/ F 
T he a p pare nt v ol u me of distri b uti o n base d o n t he ter mi nal eli mi nati o n p hase. T he esti mate 
d oes n ot acc o u nt f or t he bi oa vaila bilit y ( F, as a fracti o n of 1) a n d is t heref ore n o mi nall y 
di vi de d b y t his val ue w he n dr u g is gi ve n via e xtra vasc ular r o utes ( D F 2 5 7 7 Y o nl y i n S A D 
part o nl y). 
V d/ F = Cl/ F / ke  
P T F   
T he pea k tr o u g h fl uct uati o n will be calc ulate d o n Da y 1 4 as t he f oll o wi n g rati o: 
[( Css, ma x –  Css, tr o u g h)/ Css, a v] 
w here C ss,tr o u g h is t he pre- d ose c o nce ntrati o n meas ure d o n t he da y of assess me nt. 
In t he M A D part, acc u m ulati o n rati os will be calc ulate d f or C ma x  a n d A U C0- τ bet wee n Da y 1 4 a n d Da y 1 
f or eac h c o m p o u n d. 
Pare nt t o meta b olite rati os will be calc ulate d f or C ma x  a n d all A U Cs. 
T he f oll o wi n g P K para meters of D F 2 5 7 7 Y ( or relate d meta b olites) will be deri ve d fr o m D F 2 5 7 7 Y ( or 
relate d meta b olites) uri ne c o nce ntrati o ns f or eac h: 
Ae  
A m o u nt of D F 2 5 7 7 Y ( or relate d meta b olites) meas ure d i n a gi ve n uri ne fracti o n: 
Ae = D F 2 5 7 7 Y ( or relate d meta b olites) c o nce ntrati o n meas ure d i n t he fracti o n × Uri nar y v ol u me of t he 
fracti o n 
fe 
Perce nta ge of t he d ose e xcrete d i n t he uri ne ( D F 2 5 7 7 Y o nl y) deter mi ne d o ver vari o us ti me 
i nter vals ( 2 4 h p ost- d ose a n d tlast i n S A D part; 1 2 a n d 2 4 h p ost- d ose o n Da y 1 i n M A D part). 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 6  / 8 5  
Cl R  
Re nal cleara nce deter mi ne d as t he rati o Ae 0-t/A U C 0-t wit h t = 2 4 h p ost- d ose a n d tlast i n S A D part 
a n d t = 1 2 a n d 2 4 h p ost- d ose o n Da y 1 i n M A D part 
 
6. 2.  
S pecific ati o n of p h ar m ac o ki netic p ar a meters 
Part A: 
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d fr o m D F 2 7 5 5 Y (t he aci d f or m of 
D F 2 7 5 5 A a n d f or meta b olites if a n y): 
- 
C ma x  ( n g/ m L);  
- 
tm a x ( h); 
- 
λ Z ; 
- 
t1/ 2( h):; 
- 
A U C 0- 2 4 ( h × n g/ m L); 
- 
A U C 0-t  ( h × n g/ m L); 
- 
A U C 0- ∞  ( h × n g/ m L); 
- 
f u 
- 
V Z /F ( D F 2 5 7 7 Y o nl y); 
- 
C L/ F ( D F 2 5 7 7 Y o nl y); 
- 
Ae 0 - 2 4 a n d A U C 0 -last; 
- 
fe0- 2 4 a n d fe 0-tlast; 
- 
C L R ; 
- 
T otal a m o u nt i n faeces; 
- 
Pare nt: meta b olite(s) rati o f or C ma x  a n d A U Cs.. 
 
Part B: 
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d fr o m D F 2 5 7 7 Y (t he aci d f or m of 
D F 2 7 5 5 A a n d f or meta b olites if a n y): 
Da y 1 
- 
C ma x  ( n g/ m L);  
- 
tm a x ( h); 
- 
tla g ( h); 
- 
λ Z ; 
- 
t1/ 2 ( h); 
- 
A U C 0- 1 2 (h × n g/ m L); 
- 
Ae 0- 1 2 a n d Ae 0- 2 4; 
- 
f u; 
- 
fe ( %); 
- 
C L R : re nal cleara nce; 
- 
Pare nt: meta b olite(s) rati o f or C ma x  a n d A U Cs. 
 
Da y 1 4 
- 
C ss, ma x ( n g/ m L);  
- 
tss, ma x ( h); 
- 
tla g ( h); Css, mi n ( n g/ m L): meas ure d plas ma c o nce ntrati o n at t he e n d of t he d osi n g i nter val; 
- 
λ Z : ter mi nal p hase rate c o nsta nt; 
- 
t1/ 2 ( h): ter mi nal half-life; 
- 
A U C 0 -τ ( h × n g/ m L); 
- 
C ss, a v ( n g/ m L); 
- 
f u; 
- 
Ae 0 -tlast; 
- 
T otal a m o u nt i n faeces; 
- 
Pare nt: meta b olite(s) rati o; 
- 
Acc u m ulati o n rati os f or C ma x  a n d A U C 0- 1 2. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 7  / 8 5  
 
 
6. 3.  
Met h o ds a n d ti mi n g f or assessi n g, rec or di n g, a n d a n al ysi n g p h ar m ac o ki netic p ar a meters 
6. 3. 1.  C ollecti o n, tre at me nt a n d st or a ge of bl o o d s a m ples 
Bl o o d sa m pli n g will be perf or me d f or D F 2 7 5 5 Y c o nce ntrati o n meas ure me nts at t he e xact ti me- p oi nts 
wit h a n a ut h orise d ti me- wi n d o w descri be d i n t he ta ble bel o w. 
W he n E C G, vital si g ns a n d P K are re q uire d at t he sa me ti me, t his s pecific or der will be f oll o we d: E C G 
first, t he n vital si g ns a n d bl o o d sa m ple f or P K at t he e n d. 
 
 
Part A : 
 
 
D a y  
S a m pli n g ti me  
S a m ple N°  
Ti me 
wi n d o w ( mi n) 
1  
T 0 ( pre -d ose)  
T 0 h 3 0 mi n  
T 1 h 0 0  
T 2 h  
T 3 h  
T 4 h  
T 5 h  
T 6 h  
T 7 h  
T 8 h  
T 9 h  
T 1 0 h  
T 1 2 h  
T 1 6 h  
P 0 0  
P 0 1  
P 0 2  
P 0 3  
P 0 4  
P 0 5  
P 0 6  
P 0 7  
P 0 8  
P 0 9  
P 1 0  
P 1 1  
P 1 2  
P 1 3  
 
+/ -1  
+/ -3  
+/ -3  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
2  
T 2 4 h  
T 3 6 h  
T 4 0 h  
P 1 4  
P 1 5  
P 1 6  
+/ -1 5  
+/ -1 5  
+/ -1 5  
3  
T 4 8 h  
T 6 0 h  
P 1 7  
P 1 8  
+/ -1 5  
+/ -1 5  
4  
T 7 2 h  
P 1 9  
+/ -1 5  
 
After t he deter mi nati o ns of D F 2 7 5 5 Y i n plas ma sa m ples d uri n g c o h ort 1 a n d acc or di n g t o res ults 
o btai ne d, t he bl o o d sa m pli n g ti mes a n d t he c ollecti o n peri o ds c o ul d be re vie we d t o o pti mize t he 
c ollecti o n ti mes wit h res pect t o t he P K pr ofile of D F 2 7 5 5 Y. 
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 8  / 8 5  
Part B : 
D a y  
S a m pli n g ti me  
S a m ple N°  
Ti me 
wi n d o w( mi n)  
1  
T 0 ( pre -d ose)  
T 0 h 3 0 mi n  
T 1 h 0 0  
T 2 h  
T 3 h  
T 4 h  
T 5 h  
T 6 h  
T 7 h  
T 8 h  
T 9 h  
T 1 0 h  
T 1 2 h  
T 1 6 h  
P 0 0  
P 0 1  
P 0 2  
P 0 3  
P 0 4  
P 0 5  
P 0 6  
P 0 7  
P 0 8  
P 0 9  
P 1 0  
P 1 1  
P 1 2  
P 1 3  
 
+/ -1  
+/ -3  
+/ -3  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
+/ -5  
2  
Pre -d ose/ T 2 4 h  D 1  
P 1 4  
+/ -1 5  
5  
T 0 ( pre -d ose) / T 2 4 h D 4 
T C ma x
1 
T 1 2 h  
T C ma x
1 
P 1 5  
P 1 6  
P 1 7  
P 1 8  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
6  
Pre -d ose/ T 2 4 h  D 5  
P 1 9  
+/ -1 5  
1 0  
T 0 ( pre -d ose) / T 2 4 h D 9  
T C ma x
1 
T 1 2 h  
T C ma x
1 
P 2 0  
P 2 1  
P 2 2  
P 2 3  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
1 1  
Pre -d ose/ T 2 4 h  D 1 0  
P 2 4  
+/ -1 5  
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
4 9  / 8 5  
D a y  
S a m pli n g ti me  
S a m pl e N° 
Ti me 
wi n d o w( mi n)  
1 4  
T 0 ( pre -d ose) / T 2 4 h D 1 3 
T 0 h 3 0 mi n  
T 1 h  
T 2 h  
T 3 h  
T 4 h  
T 5 h  
T 6 h  
T 7 h  
T 8 h  
T 9 h  
T 1 0 h  
T 1 2 h  
T 1 6 h  
P 2 5  
P 2 6  
P 2 7  
P 2 8  
P 2 9  
P 3 0  
P 3 1  
P 3 2  
P 3 3  
P 3 4  
P 3 5  
P 3 6  
P 3 7  
P 3 8  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
+/ -1 5  
1 5  
T 2 4 h  D 1 4  
T 3 6 h  
T 4 0 h  
P 3 9  
P 4 0  
P 4 1  
+/ -1 5  
+/ -1 5  
+/ -1 5  
1 6  
T 4 8 h  
T 6 0 h  
P 4 2  
P 4 3  
+/ -1 5  
+/ -1 5  
1 7  
T 7 2 h  
P 4 4  
+/ -1 5  
1T his ti me ( TC ma x ) will be deter mi ne d t ha n ks t o part A res ults. 
 
Bl o o d h a n dli n g pr oce d ures:  
A ca n n ula or direct ve ne p u nct ure will be use d t o c ollect bl o o d sa m ples. 6 m L  of bl o o d f or assa y of 
D F  2 7 5 5 Y a n d meta b olites (if a p plica ble) will be ta ke n i nt o lit hi u m he pari n vac utai ners. Bl o o d sa m ples 
w ill be ce ntrif u ge d wit hi n 1 5 mi n utes of c ollecti o n at 1 5 0 0 g at 4° C f or 1 0 mi n utes. Ar o u n d 3 m L of 
plas ma will be o btai ne d a n d, i m me diatel y after t he ce ntrif u gati o n, di vi de d e q uall y i nt o t w o ali q u ots. 
Plas ma sa m ples will be st ore d i m me diatel y at a p pr o xi matel y - 2 0° C i nt o pl us scre we d p ol y pr o p yle ne 
t u bes.  
Bl o o d s a m ples Tr a ns p ort:  
Sa m ples will be se nt t o D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories f or a nal ysis. T he s hi p me nt 
will be d o ne i n a dr y ice or u n der c o ntr olle d te m perat ure bet wee n - 1 5° C a n d - 2 5° C b y a s pecialize d 
carrier.  
T e m perat ures will be m o nit ore d usi n g data l o g ger d uri n g all tra ns p ort. T he first set will be se nt fr oze n 
se paratel y t o t he sec o n d o ne. 
D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories 
Via Ca m p o di Pile 
s. n.c L’ A q uila, Ital y 
atte nti o n t o Dr. ssa  Maria T eresa Mass ucci. 
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 0  / 8 5  
6. 3. 2.  C ollecti o n, tre at me nt a n d st or a ge of uri ne s a m ples 
Part A: 
Uri ne c ollecti o n will be perf or me d f or D F 2 7 5 5 Y a n d t w o meta b olites uri ne c o nce ntrati o n meas ure me nts , 
at t he f oll o wi n g ti me p oi nts:  ] D- 1 T- 2 4 h –  D 1 T 0 h( pre- d ose)], ] D 1 T 0 h –  D 1 T 6 h], ] D 1 T 6 h –  D 1 T 1 2 h], 
] D 1 T 1 2 h –  D 2 T 2 4 h], ] D 2 T 2 4 h –  D 3 T 4 8 h], ] D 3 T 4 8 h –  D 4 T 7 2 h]. 
 
Part B: 
Uri ne c ollecti o n will be perf or me d f or D F 2 7 5 5 Y a n d t w o meta b olites uri ne c o nce ntrati o n me as ure me nts , 
at t he f oll o wi n g ti me p oi nts: ] D- 1 T- 2 4 h –  D 1 T 0 h( pre- d ose)], ] D 1 T 0 h –  D 1 T 1 2 h], ] D 1 T 1 2 h –  D 2 T 2 4 h], 
]D 5 T 0 h –  D 6 T 2 4 h], ] D 1 0 T 0 h –  D 1 1 T 2 4h] , ] D 1 4 T 0h –  D 1 4 T 1 2 h], ] D 1 4 T 1 2 h –  D 1 5 T 2 4 h], ] D 1 5 T 2 4 h –  
D 1 6 T 4 8 h], ] D 1 6 T 4 8 h –  D1 7 T 7 2 h]. 
 
Uri ne h a n dli n g pr oce d ures:  
Uri ne will be c ollecte d f or P K a nal ysis fr o m 2 4 h o urs bef ore d osi n g o n Da y 1 u ntil 7 2 h o urs p ost- d ose i n 
C o h orts 1, 2, 3 a n d 4 ( S A D, P A R T A) a n d fr o m 2 4 h o urs bef ore d osi n g o n Da y 1 u ntil 4 0 8 h after t he 
first d ose i n C o h ort 5, 6 a n d 7 ( M A D, P A R T B). T he uri ne c ollecti o n i nter vals are detaile d a b o ve.  
S u bj ec ts will be as ke d t o v oi d t heir bla d ders pri or t o t he start of eac h c ollecti o n i nter val a n d t he start a n d 
st o p ti me of eac h c ollecti o n i nter val will be rec or de d i n t he C R F. 
Uri ne c ollecti o ns f or P K a nal ysis will be c ollecte d i nt o b ottles wit h o ut preser vati ve. F oll o wi n g 
c o m pleti o n of eac h uri ne c ollecti o n peri o d, uri ne p H will be meas ure d a n d t he wei g ht of eac h c ollecti o n 
will be rec or de d. T he c ollecti o n will be t h or o u g hl y mi xe d a n d o ne 5 m L ali q u ot will be  re m o ve d fr o m 
eac h c ollecti o n t o deter mi ne creati ni ne e x creti o n ( E ur ofi ns la b orat or y). T he n t w o ali q u ots of 5 m L will be 
ta ke n f or P K a nal ysis a n d st ore d at a p pr o xi matel y - 2 0° C i n st o p pe d p ol y pr o p yle ne t u bes.  
 
Uri ne s a m ples Tr a ns p ort:  
Sa m ples will be se nt t o D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories f or a nal ysis. T he s hi p me nt 
will be d o ne i n a dr y ice or u n der c o ntr olle d te m perat ure bet wee n - 1 5° C a n d - 2 5° C b y a s pecialize d 
carrier. T e m perat ures will be m o nit ore d usi n g data l o g ger  d uri n g all tra ns p ort. T he first set will be se nt 
fr oze n se paratel y t o t he sec o n d o ne. 
D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories 
Via Ca m p o di Pile 
s. n.c L’ A q uila, Ital y 
atte nti o n t o Dr.ssa  Maria Teresa Mass ucci 
 
6. 3. 3.  
C ollecti o n, tre at me nt a n d st or a ge of f aeces s a m ples 
Part A: 
Faeces c ollecti o n 
will be perf or me d f or 
D F 2 7 5 5 Y a n d t w o 
meta b olites faeces c o nce ntrati o n 
meas ure me nts, at t he f oll o wi n g ti me p oi nts: ] D- 1 T - 2 4 h –  D 1 T 0 h( pre- d ose)], ] D 1 T 0 h –  D 2 T 2 4 h], 
]D 2 T 2 4 h –  D 3 T4 8 h], ] D 3 T 4 8 h –  D 4 T 7 2h] . 
 
Part B: 
Faeces c ollecti o n 
will be perf or me d f or 
D F 2 7 5 5 Y a n d t w o 
meta b olites faeces c o nce ntrati o n 
meas ure me nts, at t he f oll o wi n g ti me p oi nts: ] D- 1 T- 2 4 h –  D 1 T 0 h( pre- d ose)],  ] D 1 T 0 h –  D 2 T 2 4 h], 
]D 5 T 0 h –  D 6 T 2 4 h], ] D 1 0 T 0 h –  D 1 1 T 2 4h] , ] D 1 4 T 0h –  D 1 5 T 2 4 h], ] D 1 5 T 2 4 h –  D 1 6 T 4 8 h], ] D 16 T 4 8 h –  
D 1 7 T 7 2 h]. 
 
 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 1  / 8 5  
 
F aeces h a n dli n g pr oce d ures:  
Faeces will be c ollecte d f or P K a nal ysis fr o m 2 4 h o urs bef ore d osi n g o n Da y 1 u ntil 7 2 h p ost d ose i n 
C o h orts 1, 2, 3 a n d 4 ( S A D) a n d fr o m 2 4 h o urs bef ore d osi n g o n Da y 1 u ntil 4 0 8 h after t he first d ose i n 
C o h ort 5, 6 a n d 7 ( M A D). T he faeces c ollecti o n i nter vals are detaile d a b o ve. 
After t he c ollecti o n of eac h faeces sa m ples, t he sa m ple will be wei g he d a n d h o m o ge nize d wit hi n 3 0 
mi n ute. T w o 1 0 g ali q u ots of eac h h o m o ge nise d sa m ple will be ta ke n. Eac h 1 0 g ali q u ot will be mi xe d 
w it hP h os p hate b uffere d sali n ( P B S) at P H = 7. 4 . T he faeces/ b uffer rati o s h o ul d be 1: 2 (e. g., 1 0 g 
faeces mi xe d wit h 2 0 m L b uffer). T he sa m ples ( 2 ali q u ots) will be st ore d at a p pr o xi matel y - 2 0° C i n 
st o p pe d p ol y pr o p yle ne t u bes.  
 
F aeces s a m ples Tr a ns p ort:  
Sa m ples will be se nt t o D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories f or a nal ysis. T he s hi p me nt 
will be d o ne i n dr y ice or u n der c o ntr olle d te m perat ure bet wee n - 1 5° C a n d - 2 5° C b y a s pecialize d carrier. 
T e m perat ures will be m o nit ore d usi n g dat a l o g ger d uri n g all tra ns p ort. T he first set will be se nt fr oze n 
se paratel y t o t he sec o n d o ne. 
D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories 
Via Ca m p o di Pile 
s. n.c L’ A q uila, Ital y 
atte nti o n t o Dr.ssa  Maria Teresa Mass ucci 
6. 4.  
A n al ytic al met h o ds 
Plas ma, uri ne a n d faeces sa m ples will be assa ye d t o deter mi ne t he c o nce ntrati o ns of D F 2 7 5 5 Y ( b o u n d 
a n d u n b o u n d plas ma sa m ple) acc or di n g t o D o m pé far mace utici S. p. A Bi oa nal ytical La b orat ories st u d y 
pla ns. T he sa m ples will be assa ye d wit h vali date d a nal ytical met h o ds. T he meta b olic pat h wa y will be als o 
st u die d t o i de ntif y t he p ote ntial meta b olites. 
 
 
7.  A S S E S S M E N T O F P H A R M A C O D Y N A MI C 
T he Assess me nt of P har mac o d y na mic will be perf or me d i n Part A ( o nl y f or le uc oc yte s u bsets ) starti n g 
fr o m t he sec o n d asce n di n g d ose a n d i n Part B of t he st u d y. 
7. 1.  
C yt o ki ne I nfl a m m ati o n M ar ker a n al ysis 
I nfla m mati o n C yt o ki nes :  
1.  C X C L 1 ( Gr o alfa) 
2.  C X C L 2 ( Gr o beta) ( Bi ora d) 
3.  C X C L 5 ( E N A- 7 8) 
4.  C X C L 6 ( G C P- 2) 
5.  C X C L 8 (I L- 8) 
will be a nal yze d fr o m bl o o d sa m ples. 
T he  met h o d ( Elisa) t hat will be use d f or t he deter mi nati o n of c yt o ki nes will be disc usse d i n t he fi nal 
re p ort. 
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 2  / 8 5  
Part B: 
D a y  
S a m pli n g ti me  
S a m ple N°  
Ti me 
wi n d o w( mi n)  
1  
T 0 ( pre -d ose ) 
Il1 0 0  
N A  
5  
T 0 ( pre -d ose)  
Il1 0 1  
+/ -1 5  
1 4  
T 0 ( pre -d ose)  
Il1 0 2  
+/ -1 5  
1 6  
T 4 8 h  
Il1 0 3  
+/ -1 5  
1 7  
T 7 2 h  
Il1 0 4  
+/ -1 5  
 
Bl o o d h a n dli n g pr oce d ures:  At eac h ti me p oi nt i n dicate d i n t he ta ble, a 1 0 m L bl o o d sa m ple s h o ul d be 
dra w n i nt o K 2 E D T A t u be. T his v ol u me is i n a d diti o n wit h t he o ne of t he assess me nt of p har mac o ki netic 
descri be d pre vi o usl y. After c ollecti o n, ge ntl y mi x t he bl o o d b y i n verti n g t he t u be fe w ti me f or c o m plete 
mi xi n g wit h a ntic oa g ula nt. St ore vac utai ner t u bes u pri g ht at 4º C u ntil ce ntrif u gati o n. Bl o o d sa m ples 
s h o ul d be ce ntrif u ge d wit hi n f o ur h o urs of bl o o d c ollecti o n. Ce ntrif u ge bl o o d sa m ples f or 1 5 mi n utes at 
1 0 0 0 g at 4° C. After ce ntrif u gati o n caref ull y tra nsfer t he plas ma la yer wit h a n a p pr o priate tra nsfer pi pette 
wit h o ut di st ur bi n g t he b uff y c oat la yer t o a clea n p ol y pr o p yle ne t u be. T o c o m plete re m o ve platelets a n d 
preci pitates, ce ntrif u ge a gai n f or 1 0 
mi n at 1 0 0 0 0 g at 4° C. Ali q u ot plas ma  i nt o 5 pre-la belle d 
p ol y pr o p yle ne t u bes. Eac h t u be will c o ntai n a p pr o xi matel y 7 0 0 μ L of plas ma. All sa m ple t u bes m ust be 
clearl y a n d a p pr o priatel y la belle d. T u bes will be ca p pe d i m me diatel y fr o m eac h ti me p oi nt a n d t he 
plas ma will be fr oze n i n a n u pri g ht p ositi o n at a p pr o xi matel y – 8 0° C f or st ora ge. 
  
 
Bl o o d s a m ples Tr a ns p ort: Sa m ples will be se nt t o la b orat or y H ô pital L y o n S u d f or a nal ysis of 
sec o n dar y o bjecti ve. T he s hi p me nt will be d o ne i n a dr y ice b y a s pecialize d carrier. T e m perat ures will be 
m o nit ore d usi n g data l o g ger d uri n g all tra ns p ort. F o ur sets will be se nt fr oze n se paratel y t o H ô pital L y o n 
S u d a n d o ne will be ke pt at E U R O FI N S O P TI M E D.  
7. 2.  
Le u k oc ytes s u bset bl o o d s a m ples 
Le u k oc ytes s u bset: C D 1 1 b a n d C D 1 8 will be a nal yse d o n P M N fr o m bl o o d sa m ples.  
 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 3  / 8 5  
Part A: 
D a y  
S a m pli n g ti me  
S a m ple N°  
Ti me 
wi n d o w( mi n)  
1  
T 0  ( pre-d ose)  
T C m a x  (ti me will be set 
after t he res ults of t he first 
d ose a d mi nistre d)  
T C m a x  + 3 h  (ti me will be 
deter mi ne d after t he 
res ults of t he first d ose 
a d mi nistre d) 
T 1 2 h  
C D 0 0  –  R S 0 0  
C D 0 1  –  R S 0 1  
 
 
C D 0 2  –  R S 0 2  
 
 
C D 0 3  –  R S 0 3  
N A  
+/ -5  
 
 
+/ -5  
2  
2 4 h   
C D 0 4  –  R S 0 4  
+/ -1 5  
3 or 4  
4 8 h or 7 2 h  
(ti me will be deter mi ne d 
after t he res ults of t he first 
d ose a d mi nistre d)  
C D 0 5  –  R S 0 5  
 
+/ -1 5  
Part B: 
D a y  
S a m pli n g ti me  
S a m ple N°  
Ti me 
wi n d o w( mi n)  
1  
T 0  ( pre-d ose)  
T C ma x  
C D 1 0  –  R S 1 0  
C D 1 1  –  R S 1 1       
 
+/ -5  
W i n d o w 
fr o m 5  t o 7 
T 0 ( pre -d ose) / 
T C ma x  
C D 1 2  –  R S 1 2  
C D 1 3  –  R S 1 3      
+/ -1 5  
+/ -1 5  
1 4  ( Last 
d ose)  
T 0  
T C ma x  
C D 1 4 –  R S 1 4  
+/ -1 5  
1 5  
T 2 4 h  
C D 1 5  –  R S 1 5    
+/ -1 5  
 
Bl o o d h a n dli n g pr oce d ures:  
- C D 1 1 b & C D 1 8:  at eac h ti me p oi nt i n dicate d i n t he ta ble, a 6 m L bl o o d sa m ple s h o ul d be dra w n i nt o a 
K 3 E D T A t u be. T his v ol u me is i n a d diti o n wit h t he o ne of t he assess me nt of p har mac o ki netic a n d f or 
c yt o ki nes descri be d pre vi o usl y.   
Sa m ple will be treate d at E ur ofi ns- O pti me d la b orat or y ( detaile d will be disc uss i n t he fi nal re p ort ) a n d 
wi ll be rea d at i m m u n ol o g y la b orat or y C H U de Gre n o ble b y a fl o w C yt o meter.   
S a m ples Tr a ns p ort: sa m ples will be s hi p pe d t o I m m u n ol o g y la b orat or y C H U de Gre n o ble at  4° C 
pr otecte d fr o m li g ht. 
 
 
8.  A S S E S S M E N T O F S A F E T Y 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 4  / 8 5  
8. 1.  
S pecific ati o n of s afet y p ar a meters 
8. 1. 1.  Cli nic al p ar a meters 
8. 1. 1. 1.  Bl o o d press ure a n d he art r ate 
Vital si g ns c o nsist of s yst olic ( S B P) a n d diast olic ( D B P) bl o o d press ures a n d heart rate.  
T he meas ure me nts s h o ul d be ma de after at least 1 0 mi n utes rest i n t he s u pi ne p ositi o n a n d after 2 mi n utes 
i n t he sta n di n g p ositi o n, bef ore ve ne p u nct ure w he n ti mes of eac h c oi nci de (e xce pt pre- d ose).  
 
8. 1. 1. 2.  P h ysic al e x a mi n ati o n 
A p h ysical e xa mi nati o n i ncl u di n g e val uati o n of mai n b o d y s yste ms/re gi o ns, i ncl u di n g: s ki n a n d m uc o us, 
ears/ n ose/t hr oat, p ul m o nar y, car diac, gastr o-i ntesti nal a n d ne ur ol o gical s yste ms. 
 
I n case of a b n or malit y, a c o m me nt will be rec or de d i n t he e C R F. 
8. 1. 1. 3.  B o d y wei g ht a n d hei g ht 
Meas ure me nts of b o d y wei g ht a n d hei g ht (at scree ni n g o nl y), will be d o ne d uri n g p h ysical e xa mi nati o n 
( w he n ti me of b o d y wei g ht meas ure me nt c oi nci des wit h p h ysi cal e xa mi nati o n) 
8. 1. 1. 4.  Electr oc ar di o gr a m ( E C G) 
T wel ve-lea d E C Gs will be rec or de d after at least 1 0 mi n utes i n s u pi ne p ositi o n usi n g a Cart o uc h 
Car di o nics ® De vice.  
E C Gs s h o ul d al wa ys be rec or de d bef ore t he P K sa m pli n g (if a n y), e xce pt pre- d ose.  
Eac h E C G c o nsists of a 1 0 sec o n d rec or di n g of t he 1 2 l ea ds si m ulta ne o usl y, lea di n g t o a 1 2-lea d E C G ( 2 5 
m m/s, 1 0 m m/ m V) pri nt- o ut wit h H R, P R, Q R S, Q T, Q T c a ut o matic c orrecti o n e val uati o n, i ncl u di n g date, 
ti me, n u m ber of t he s u bject, si g nat ure of t he researc h p h ysicia n, a n d at least 3 c o m ple xes f or eac h lea d. 
T he I n vesti gat or me dical o pi ni o n a n d a ut o matic val ues will be rec or de d i n t he e C R F. T his pri nt- o ut will 
be retai ne d at t he site le vel. 
 
8. 1. 2.  Bi ol o gic al p ar a meters 
8. 1. 2. 1.  R o uti ne l a b or at or y o bser v ati o ns 
Bef ore t he s u bject is all o we d t o e nter t he st u d y a f ull bi ol o gical test will be o btai ne d a n d t he a bse nce of 
cli nicall y si g nifica nt a b n or malities c o nfir me d b y t he I n vesti gat or. 
 
T he f ull bi ol o gical test c o m prises: 
Hae mat ol o g y:. T hese tests will be perf or me d as f oll o w: Hae m o gl o bi n, hae mat ocrit, Re d Bl o o d Cells 
(R B C), W hite Bl o o d Cells ( W B C), differe ntial c o u nt, platelet c o u nt, Mea n C or p usc ular V ol u me 
( M C V), Mea n C or p usc ular H ae 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). 
 
He m ostasis: P T, a P T T. 
 
Bi oc he mistr y:. T hese  tests will be perf or me d as f oll o w: Creati ni ne, fasti n g bl o o d gl uc ose, t otal pr otei ns, 
al b u mi n, gl o b uli n (al b u mi n/ gl o b uli n rati o), t otal c h olester ol, tri gl yceri des, L D H, meas ure d L D L, H D L, 
electr ol ytes (s o di u m, p otassi u m, c hl ori de, calci u m, p h os p h ore), uric aci d, ala ni ne seri ne tra nsferase 
( A S T), ala ni ne le uci ne tra nsferase ( A L T), Ga m ma Gl uta m yl Tra nsferase ( G G T), al kali ne p h os p hatases, 
urea, creati ne p h os p h o ki nase ( C P K), t otal a n d c o nj u gate d bilir u bi n. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 5  / 8 5  
8. 1. 2. 2.  U ri n al ysis  
T he uri nal ysis tests will be perf or me d b y E ur ofi ns- O pti me d. A p peara nce a n d c ol ors of uri ne m ust be 
re p orte d i n s o urce d oc u me nts.  
 
Se mi- q ua ntitati ve (" di pstic k") a nal ysis will be perf or me d f or t he f oll o wi n g para meters: p H, ket o ne 
b o dies, pr otei ns, gl uc ose, bl o o d, le u k oc ytes, ur o bili n o ge n, bilir u bi n, nitrite a n d s pecific de nsit y. If 
“ di pstic k” s h o ws a p ositi ve res ult f or a n y of t hese para meters, a q ua ntitati ve res ult will be perf or me d wit h 
s u p ple me ntar y a nal ysis: er yt hr oc ytes, e pit helial cells cells, e pit heli u m re nal cells, cr ytals, c yli n ders, 
m uc us a n d bacteria. 
 
8. 1. 2. 3.  Dr u g of a b use scree ni n g tests 
Dr u g of a b use scree ni n g tests will be perf or me d, at E ur ofi ns O pti me d, o n uri ne sa m ples.  
Scree ne d dr u gs are met ha m p heta mi nes/a m p heta mi nes, ca n na bis, c ocai ne, o piates, ecstas y. 
8. 1. 2. 4.  Ser ol o gies 
It will c o nsist of t he deter mi nati o n of: H Bs a nti ge n ( he patitis B a nti ge n), a nti H C V a nti b o d y, a nti HI V 1 
a n d 2 a nti b o dies. 
8. 1. 3.  Ot her p ar a meters 
8. 1. 3. 1.  Alc o h ol bre at h test 
A n alc o h ol breat h test will be perf or me d at t he ce ntre , at scree ni n g a n d D- 1 f or eac h part. T he test will be 
perf or me d usi n g t he alc o h ol breat h de vice ref 7 4 1 0 pl us Dra ger. 
 
8. 2.  
St u d y P r oce d ure  
8. 2. 1.  Scree ni n g pr oce d ures 
Scree ni n g pr oce d ures occ ur wit hi n 3 wee ks ( D- 2 1 t o D- 1) bef ore starti n g st u d y me dicati o n. 
 
S u bject e nr ol me nt –  Scree ni n g visit 
S u bj ects will be scree ne d wit hi n s u bject’s pa nel of E ur ofi ns O pti me d or recr uite d via a d vertise me nts if 
necessar y (i n t his case, t he a d vertise me nt has t o be s u b mitte d t o t he Et hics C o m mittee f or a p pr o val bef ore 
use ). 
De dicate d recr uit me nt officers will pr o p ose s u bjects t o partici pate i n t his st u d y. T he y will be first 
i nf or me d ver ball y a b o ut t he st u d y. T he n a n a p p oi nt me nt will be sc he d ule d at t he cli nical ce ntre (selecti o n 
visit). 
Bef ore a n y scree ni n g assess me nt is perf or me d, c o m plete a n d detaile d i nf or mati o n a b o ut t he ai m, t he 
c o nse q ue nces a n d t he c o nstrai nts of t he trial will be gi ve n b y a p h ysicia n, b ot h ver ball y a n d b y re vie wi n g 
t he i nf or mati o n leaflet a n d c o nse nt f or m. If s u bject a grees t o perf or m t he st u d y, he/s he will si g n t he 
I nf or me d C o nse nt f or m a n d a c o p y of t he i nf or mati o n leaflet a n d c o nse nt f orm will be gi ve n t o s u bjects.  
At t he scree ni n g visit, eac h s u bj ect will u n der g o a c o m plete me dical hist or y a n d a p h ysical e xa mi nati o n 
i ncl u di n g bl o o d press ure a n d heart rate meas ure me nts. T he s u bject will u n der g o t he f oll o wi n g tests a n d 
pr oce d ures: 
- A me dic al e xa mi nati o n i ncl u di n g a ge, et h nic ori gi n, alc o h ol, caffei ne a n d nic oti ne c o ns u m pti o ns, 
pre vi o us me dicati o n usa ge, s ur gical a n d me dical hist or y ; 
- A c o m plete p h ysical e xa mi nati o n i ncl u di n g hei g ht (c m), wei g ht ( k g) a n d B MI ( k g/ m²) ; 
- A n alc o h ol breat h test ; 
- B l o o d press ure ( S B P a n d D B P) a n d heart rate i n b ot h s u pi ne p ositi o n (after at least 1 0 mi n utes rest) 
a n d sta n di n g p ositi o n (after 2 mi n utes), usi n g a n a ut o matic s p h y g m o ma n o meter ; 
- E C G,  
- A bi ol o gical scree ni n g  test, i ncl u di n g: 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 6  / 8 5  
o  Ser ol o g y test: H Bs A g, a nti- H C V a nti b o d y, a nti- HI V 1 a n d 2 a nti b o dies, 
o  Uri ne dr u g scree n: 
meta m p heta mi nes/ a m p heta mi nes, ca n na bis, c ocai ne, o piates a n d 
ecstas y, 
o  H ae mat ol o g y, 
o  Hae m ostasis, 
o  Bi oc he mistr y, 
o  Uri nal ysis ( q ualitati ve). 
 
8. 2. 2.  Descri pti o n b y t y pe of visit 
Part A: 
D- 1 
- 
S u bj ect a d missi o n; 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
B o d y wei g ht 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
A E/ Pri or me dicati o n c hec k; 
- 
Alc o h ol breat h test; 
- 
Uri ne test f or dr u g a b use; 
- 
E C G; 
- 
Vi tal si g ns; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 
D 1  
 Bef ore a d mi nistr ati o n 
 
- 
Vital si g ns; 
- 
E C G; 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Bl o o d sa m pli n g ( Pre- d ose, P K, le u k oc ytes s u bsets (e xce pt f or 1 st c o h ort)). 
- 
U ri ne c ollecti o n 
- 
Faeces c ollecti o n 
 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Vital si g ns; 
- 
Bl o o d sa m pli n g ( P K, le u k oc ytes s u bsets (e xce pt f or 1 st c o h ort)); 
- 
U ri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 2  
- 
Vital si g ns; 
- 
La b orat or y safet y ( ha e mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
Bl o o d sa m pli n g ( P K, le u k oc ytes s u bset (e xce pt f or 1 st c o h ort)); 
- 
E C G; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n.  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 7  / 8 5  
 
D 3 
 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
Bl o o d sa m pli n g ( P K, le u k oc ytes s u bset (e xce pt f or 1 st c o h ort)); 
- 
E C G; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n.  
 
D 4 e n d of st u d y visit  
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
B o d y wei g ht  
- 
La b orat or y safet y ( ha e mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
E C G; 
- 
Vital si g ns; 
- 
Bl o o d sa m pli n g ( P K, le u k oc ytes s u bset, if n ot d o ne o n D 3 (e xce pt f or 1st c o h ort)) 
- 
U ri ne c ollecti o n; 
- 
Faeces c ollecti o n; 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
S u bj ect disc har ge. 
 
Part B: 
D- 1 
- 
S u bj ect a d missi o n; 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
B o d y wei g ht 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Alc o h ol breat h test; 
- 
Uri ne test f or dr u g a b use; 
- 
Vital si g ns; 
- 
E C G; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 1  
 Bef ore a d mi nistr ati o n 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
Vital si g ns; 
- 
E C G; 
- 
A E / C o nc o mita nt me dicati o n c hec k; 
- 
Bl o o d sa m pli n g ( P K , c yt o ki ne plas ma c o nce ntrati o n a n d le u k oc ytes s u bset); 
- 
U ri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K a n d le u k oc ytes s u bset); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
D 2  
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 8  / 8 5  
- 
E C G; 
- 
Bl o o d sa m pli n g f or P K; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
 
D 3 
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
 
D 4  
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
 
D 5  
 Bef ore a d mi nistr ati o n 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
Vital si g ns; 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Bl o o d sa m pli n g ( P K, c yt o ki ne plas ma c o nce ntrati o n a n d le u k oc ytes s u bset); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K  a n d le u k oc ytes s u bset); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 6  
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K  a n d le u k oc ytes s u bset if t he case) 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me). 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
5 9  / 8 5  
- 
B l o o d sa m pli n g (le u k oc ytes s u bset if t he case) 
- 
 
 
D 7  
 Bef ore a d mi nistr ati o n 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
Vital si g ns; 
- 
A E/ C o nc o mita nt me dicati o n c hec k. 
- 
Bl o o d sa m pli n g (le u k oc ytes s u bset if t he case) 
- 
 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G. 
- 
Bl o o d sa m pli n g (le u k oc ytes s u bset if t he case) 
 
 
D 8 
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
E C G. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me). 
 
D 9 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
 
D 1 0 
 Bef ore a d mi nistr ati o n 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
Vital si g ns; 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Bl o o d sa m pli n g f or P K; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g f or P K; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 1 1 
 Bef ore a d mi nistr ati o n 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g f or P K; 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
6 0  / 8 5  
 or al  a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me). 
 
D 1 2 –  D 1 3 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
 
D 1 4  
 Bef ore a d mi nistr ati o n 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
Vital si g ns; 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Bl o o d sa m pli n g ( P K, c yt o ki ne plas ma c o nce ntrati o n); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
 or al a d mi nistr ati o n i n f asti n g c o n diti o n. 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 1 5 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K  a n d le u k oc ytes s u bset) 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 1 6 
- 
A E/ C o nc o mita nt me dicati o n c hec k (a n y ti me); 
- 
Bl o o d sa m pli n g ( P K, c yt o ki ne plas ma c o nce ntrati o n); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n. 
 
D 1 7 e n d of st u d y visit 
- 
P h ysical a n d me dical e xa mi nati o n; 
- 
B o d y wei g ht 
- 
La b orat or y safet y ( hae mat ol o g y, bi oc he mistr y, hae m ostasis, uri nal ysis); 
- 
A E/ C o nc o mita nt me dicati o n c hec k; 
- 
Vital si g ns; 
- 
E C G; 
- 
Bl o o d sa m pli n g ( P K, c yt o ki ne plas ma c o nce ntrati o n); 
- 
Uri ne c ollecti o n; 
- 
Faeces c ollecti o n; 
- 
S u bj ect disc har ge. 
 
 
8. 2. 3.  S a m ple d bl o o d v ol u me 
T he t otal a m o u nt of bl o o d c ollecte d d uri n g t he st u d y will be a p pr o xi matel y: 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
6 1  / 8 5  
P art A ( C o h orts: 1 ) 
Tests  
N u m ber of 
S a m ples  
V ol u me  
( m L) 
T ot al 
( m L) 
Scree ni n g b i ol o g y  
1  
1 8 .7  
1 8 . 7 
St u d y bi ol o g y  
3  
1 0. 2  
3 0. 6  
P har mac o ki netics ( S A D)  
2 0  
6  
1 2 0  
T ot al v ol u me i n P art A  c o h ort 1   1 6 9 ,3  m L  
 
 
 
 
 
P art A ( C o h orts: 2, 3, 4 ) 
Tests  
N u m ber of 
S a m ples  
V ol u me 
( m L) 
T ot al 
( m L) 
Scree ni n g bi ol o g y  
1  
1 8 . 7 
1 8 . 7 
St u d y bi ol o g y  
3  
1 0. 2  
3 0. 6  
P har mac o ki netics ( S A D)  
2 0  
6  
1 2 0  
P har mac o d y na mics 
C D 1 1 b & C D 1 8  
6  
6  
3 6  
 
T ot al v ol u me i n P art A  c o h ort 2, 3, 4    2 0 5 . 3  m L  
 
 
 
 
 
P art B  ( C o h orts: 5, 6 a n d 7) 
Tests  
N u m ber of 
S a m ples  
V ol u me 
( m L) 
T ot al 
( m L) 
Scree ni n g bi ol o g y  
1  
1 8 .7  
1 8 .7  
St u d y bi ol o g y  
6  
1 0. 2  
6 1. 2  
P har mac o ki netics ( M A D)  
4 5  
6  
2 7 0  
P har mac o di na mics c yt o ki ne  
5  
1 0  
5 0  
P har mac o di na mics C D 1 1 b & C D 1 8   
6  
6  
3 6  
T ot al v ol u me i n P art B   4 3 5 . 9 m L  
 
 
 
8. 3.  
E v al u ati o n of A d verse E ve nt a n d S afet y I nf or m ati o n  
A d verse E ve nt ( A E), is defi ne d as a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n 
s u bj ect a d mi nistere d a p har mace utical pr o d uct, w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h 
t his treat me nt/ pr o d uct. A n A E ca n t heref ore be a n y u nfa v o ura 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), 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 
(i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct. 
A d verse Dr u g Re acti o n ( A D R), all u nt o war d a n d u ni nte n de d res p o nses t o a n I M P reas o na bl y relate d t o 
a n y d ose a d mi nistere d i.e. a n y A Es j u d ge d b y eit her t he I n vesti gat or or t he S p o ns or as ha vi n g a 
reas o na ble ca usal relati o ns hi p wit h t he I M P. T he e x pressi o n “reas o na ble ca usal relati o ns hi p” mea ns t o 
c o n ve y i n ge neral t hat t here is e vi de nce or ar g u me nt t o s u g gest a ca usal relati o ns hi p. T he defi niti o n 
c o vers als o me dicati o n err ors a n d uses o utsi de w hat is f oresee n i n t he pr ot oc ol, i ncl u di n g mis use a n d 
a b use of t he pr o d uct.   
Seri o us A d verse E ve nt or Re acti o n, a Seri o us A d verse E ve nt ( S A E) or Reacti o n ( S A R) is a n y u nt o war d 
me dical occ urre nce, i ncl u di n g i nterc urre nt pat h ol o g y, or effect t hat at a n y d ose:  
- 
Res ults i n deat h (a ca use of deat h s hall al wa ys be s pecifie d w he n k n o w n);  

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
6 2  / 8 5  
- 
Is life-t hreate ni n g (at t he ti me of t he e ve nt);  
N O T E: Life-t hre ate ni n g me a ns t h at t he p atie nt w as at i m me di ate risk of de at h fr o m t he re acti o n 
as it occ urre d, i.e., it d oes n ot i ncl u de a n eve nt w hic h hy p ot hetic ally mi g ht h ave c a use d de at h h a d 
it occ urre d i n a m ore severe f or m. 
- 
Re q uires i n patie nt  h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;  
N O T E: I n ge ner al, h os pit aliz ati o n me a ns t h at t he i n divi d u al re m ai ne d at t he h os pit al or 
e mer ge ncy w ar d f or o bserv ati o n a n d/ or tre at me nt ( us u ally i nv olvi n g a n over ni g ht st ay) t h at 
w o ul d n ot h ave bee n a p pr o pri ate i n t he p hysici a n's office or a n o ut- p atie nt setti n g. C o m plic ati o ns 
t h at occ ur d uri n g h os pit aliz ati o n are A Es. If a c o m plic ati o n pr ol o n gs h os pit aliz ati o n or f ulfills 
a ny ot her seri o us criteri a, t he eve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pit aliz ati o n ” 
occ urre d, t he eve nt s h o ul d be c o nsi dere d seri o us. 
- 
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y; 
N O T E: T his defi niti o n is n ot i nte n de d t o i ncl u de ex perie nces of rel atively mi n or me dic al 
si g nific a nce s uc h as u nc o m plic ate d he a d ac he, n a use a, v o miti n g, di arr he a, i nfl ue nz a, or 
acci de nt al tr a u m a (e. g., s pr ai ne d a nkle) w hic h m ay i nterfere or preve nt every d ay life f u ncti o ns, 
b ut d o n ot c o nstit ute a s u bst a nti al disr u pti o n. 
- 
Is a c o n ge nital a n o mal y or birt h defect; 
- 
Is a n i m p orta nt me dical e ve nt: a n i m p orta nt me dical reacti o n, t hat ma y n ot res ult i n deat h, be life-
t hreate ni n g or re q uire h os pitalizati o n, ma y be c o nsi dere d a S A E w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, it ma y je o par dize t he patie nt a n d ma y re q uire me dical or s ur gical i nter ve nti o n 
t o pre ve nt o ne of t he o utc o mes liste d a b o ve. Ex a m ples of s uc h me dic al eve nts i ncl u de aller gic 
br o nc h os p as m re q uiri n g i nte nsive tre at me nt i n a n e mer ge ncy r o o m or at h o me, bl o o d dyscr asi as 
or c o nv ulsi o ns t h at d o n ot res ult i n p atie nt h os pit aliz ati o n, or t he devel o p me nt of dr u g 
de pe n de ncy or dr u g a b use. 
Pre- pla n ne d h os pitalizati o n or h os pitalizati o n, lasti n g less t ha n 2 4 h, n ot ass ociate d 
wit h a n y 
det eri orati o n i n c o n diti o n are n ot c o nsi dere d t o be seri o us a d verse e ve nts. T hese e ve nts m ust be 
rec or de d i n t he A E pa ge of t he C R F w here a varia ble will be tic ke d t o i n dicate t hat t he y are n ot 
S A Es.  
 
U ne x pecte d a d verse re acti o n, a n u ne x pecte d a d verse reacti o n is a n a d verse reacti o n, w h ose nat ure, 
se verit y or o utc o me is n ot c o nsiste nt wit h t he a p plica ble 
me dici nal pr o d uct i nf or mati o n i.e. t he 
I n vesti gat or's Br oc h ure ( Refere nce Safet y I nf or mati o n) f or a n u na ut h orize d I M P or t he S u m mar y of 
Pr o d uct C haracteristics ( S m P C) f or a n a ut h orize d pr o d uct w hic h is bei n g use d acc or di n g t o t he ter ms a n d 
c o n diti o ns of t he mar keti n g a ut h orizati o n. E ve nts t hat are me nti o ne d i n t he I n vesti gat or Br oc h ure as 
occ urri n g wit h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g, b ut are 
n ot s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n are c o nsi dere d 
u ne x pecte d. 
 
S us pecte d u ne x pecte d seri o us u ne x pecte d a d verse re acti o n ( S U S A R) is defi ne d as a n a d verse reacti o n 
t hat is b ot h u ne x pecte d ( n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n) a n d meets t he defi niti o n 
of a Seri o us A d verse Reacti o n. T he deter mi nati o n of e x pecte d ness s h o ul d be ma de o n t he basis of t he I B 
( Refere nce Safet y I nf or mati o n). 
 
Ne w e ve nt ( f aits n o uve a ux) is defi ne d as ne w safet y data t hat ma y lea d t o a re-assess me nt of t he 
be nefit/ris k bala nce of t he i n vesti gati o nal me dici nal pr o d uct or of t he cli nical st u d y or t hat ma y be 
s ufficie nt t o lea d t o c ha n ges i n t he I M P a d mi nistrati o n, st u d y c o n d uct  or st u d y relate d d oc u me nts.  
I n cli nical st u d y i n v ol vi n g healt h y v ol u nteers, fatal a d verse e ve nts a n d e ve nts lea di n g t o h os pitalizati o n, 
p ote ntiall y relate d t o t he st u d y dr u g, of a s u bj ect e nr olle d i n t he st u d y is q ualifie d as ne w e ve nt. T he ne w 
e ve nt s hall i m me diatel y lea d t o disc o nti n uati o n of st u d y treat me nt a d mi nistrati o n t o a n y e nr olle d 
partici pa nts u ntil t heir safet y is g uara ntee d (t hr o u g h ur ge nt safet y meas ures). S u bj ects’  i nf or me d a n d 
writte n c o nse nt m ust be o btai ne d bef ore re-starti n g t he trial. T he ne w e ve nt ca n c orres p o n d t o S U S A R 
s us pici o n. I n t his case, t he e ve nt will be declare d t wice : as a S U S A R a n d as a ne w e ve nt. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
6 3  / 8 5  
U r ge nt s af et y me as ure (mes ures ur ge ntes de séc urité ) is a decisi o n ta ke n, b y t he S p o ns or or t he 
I n vesti gat or, f oll o wi n g t he occ urre nce of a ne w e ve nt li kel y t o i m pact o n t he safet y of t he st u d y s u bj ects. 
It ma y i ncl u de t he i m me diate disc o nti n uati o n of a cli nical trial or i m me diate acti o n o n t he st u d y c o n d uct, 
i n or der t o pr otect s u bjects fr o m a n y saf et y da n ger. 
 
 
8. 3. 1.  Rec or di n g of a d verse e ve nts 
A n y 
A E (i ncl u di n g la b orat or y test a b n or malities, i nterc urre nt ill nesses or i nj uries, a n d/ or st u d y 
pr oce d ures relate d A E) re p orte d s p o nta ne o usl y b y t he s u bjects, or o bser ve d b y t he I n vesti gat or, will be 
rec or de d acc or di n g t o t he pr oce d ures i n f orce at E U R O FI N S O P TI M E D. 
A n y u nt o war d me dical e ve nt, w hic h occ urs fr o m t he ti me of si g ne d I nf or me d C o nse nt t o t he ti me of I M P 
a d mi nistrati o n, will be classifie d as “ pre -d ose e ve nt”.  
A n y A E ( n o n-seri o us a n d seri o us) w hic h occ ur d uri n g t he c o urse of t he st u d y will be rec or de d i n t he 
C R F.  A n y pre-e xisti n g me dical c o n diti o ns or si g ns/s y m pt o ms prese nt i n a patie nt pri or t o t he start of t he 
st u d y (i.e., bef ore i nf or me d c o nse nt is si g ne d), s h o ul d be e ntere d i n t he baseli ne hist or y secti o n of t h e 
C R F.  
A n y u nt o war d me dical e ve nt w hic h occ urs wit hi n 3 0 da ys after t he c o m pleti o n of t he cli nical trial a n d 
t hat is p ossi bl y re p orte d b y t he I n vesti gat or t o E U R O FI N S O P TI M E D will be classifie d as a “ p ost-st u d y 
e ve nt”. 
La b orat or y, vital si g ns or E C G a b n or malities are t o be rec or de d as A E o nl y if: 
- 
S y m pt o matic, a n d/ or 
- 
Re q uiri n g eit her c orrecti ve treat me nt or cli nicall y si g nifica nt , a n d/ or 
- 
Lea di n g t o I M P/ n o n I M P disc o nti n uati o n or m o dificati o n of d osi n g, a n d/ or 
- 
F ulfilli n g a seri o us criteri o n, a n d/ or 
 
I n li ne wit h I C H E 2 A pr o visi o ns, alt h o u g h t he I n vesti gat or d oes n ot us uall y nee d t o acti vel y m o nit or 
s u bj ects f or a d verse e ve nts o nce t he trial has e n de d, if t he I n vesti gat or bec o mes a ware of a seri o us 
a d verse e ve nt occ urri n g t o a s u bj ect after t he treat me nt of t hat s u bject has e n de d, t he S A E s h o ul d be 
re p orte d b y t he I n vesti gat or t o t he S p o ns or. S uc h “cases” s h o ul d be re gar de d f or e x pe dite d re p orti n g 
p ur p oses as t h o u g h t he y were st u d y re p orts. T heref ore, a ca usalit y assess me nt ( b y t he I n vesti gat or a n d b y 
D o m pé) a n d deter mi nati o n of e x pecte d ness ( b y D o m pé) are nee de d f or a decisi o n o n w het her or n ot 
e x pe dite d re p orti n g is re q uire d. 
 
8. 3. 2.  A n al ysis of a d verse e ve nts 
T he I n vesti gat or will e val uate t he seri o us ness of a n y re p orte d a d verse e ve nt. 
 
T he I n vesti gat or will als o e val uate eac h e ve nt wit h re gar d t o its se verit y. T he se verit y of t he A Es will be 
deter mi ne d i n t he f oll o wi n g ma n ner: 
Mil d  
Gra de 1 - D oes n ot i nterfere wit h s u bject’s us ual f u ncti o n (a ware ness 
of s y m pt o ms  or si g ns, b ut easil y t olerate d [acce pta ble]).  
M o derate  
Gra de 2 - I nterferes t o s o me e xte nt wit h s u bject’s us ual f u ncti o n 
(e n o u g h disc o mf ort t o i nterfere wit h us ual acti vit y [ dist ur bi n g]). 
Se vere  
Gra de 3 
- I nterferes si g nifica ntl y 
wit h s u bjectt’s us ual f u ncti o n 
(i nca pacit y t o w or k or t o d o us ual acti vities [ u nacce pta ble]) 
 
T he I n vesti gat or will als o e val uate t he ca usalit y of t he st u d y treat me nt/ pr o d uct a n d a n y ot her treat me nts 
f or eac h A E, a n d will tra ns mit t he res ult of t his e val uati o n t o t he S p o ns or. T he p ossi ble relati o ns hi p 
bet wee n t he A E a n d t he st u d y pr o d uct/treat me nt will be q u ote d as f oll o wi n g: 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
6 4  / 8 5  
N o ne 
(I nterc urre nt 
E ve nt)  
A n e ve nt t hat is n ot a n d ca n n ot be relate d t o t he i n vesti gati o nal 
pr o d uct, e. g. patie nt is a passe n ger i n a r oa d traffic  acci de nt or s ur gical 
i nter ve nti o n perf or me d d uri n g t he st u d y, b ut pla n ne d bef ore patie nt 
e nr ol me nt i nt o t he st u d y  
U nli kel y (re m ote)  
Relati o ns hi p is n ot li kel y e. g. a cli nical e ve nt i ncl u di n g la b orat or y test 
a b n or malit y wit h te m p oral relati o ns hi p t o dr u g  a d mi nistrati o n w hic h 
ma kes a ca usal relati o ns hi p i m pr o ba ble a n d i n w hic h ot her dr u gs, 
c he micals or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns  
P ossi ble  
Relati o ns hi p ma y e xist, b ut c o ul d ha ve bee n pr o d uce d b y t he patie nt’s 
c o n diti o n or treat me nt or ot her ca use  
Pr o ba ble  
Relati o ns hi p is li kel y, t he 
A E a bates u p o n disc o nti n uati o n of 
i n vesti gati o nal pr o d uct  a n d ca n n ot be d ue t o t he patie nt’s c o n diti o n 
Hi g hl y Pr o ba ble  
Str o n g relati o ns hi p, t he e ve nt a bates 
u p o n 
disc o nti n uati o n 
of 
i n vesti gati o nal pr o d uct a n d, if a p plica ble, re -a p pears u p o n re peat 
e x p os ure 
N ot Assessa ble  
N ot p ossi ble t o assess, beca use of i ns ufficie nt e vi de nce, c o nflicti n g 
data or p o or d oc u me ntati o n.  
 
Als o t he S p o ns or will e val uate seri o us a d verse e ve nts w hic h are re p orte d b y t he I n vesti gat or, assessi n g 
ca usalit y wit h t he st u d y dr u g a n d a n y ot her treat me nts f or eac h S A E  a n d e x pecte d ness. 
S A Es f or w hic h t he I n vesti gat or or t he S p o ns or c o nsi der t hat a ca usal li n k wit h t he st u d y pr o d uct c o ul d 
reas o na bl y be e n visa ge d will be c o nsi dere d t o be s us pecte d a d verse effects. S h o ul d t he e val uati o ns of t he 
S p o ns or a n d t he I n vesti gat or differ wit h re gar d t o ca usalit y, t he n b ot h will be re p orte d i n t he declarati o n 
of s us pecte d a d verse effect. 
S A E c o nsi dere d “ P ossi ble”, “ Pr o ba ble” a n d “ Hi g hl y Pr o ba ble” relate d t o t he I M P treat me nt, if c o nsi dere d 
seri o us a n d u ne x pecte d, will be re p orte d t o a p pr o priate Re g ulat or y A ut h orities. 
 
8. 4.  
P r oce d ures i n pl ace f or t he rec or di n g a n d n otific ati o n of seri o us a d verse e ve nts, S U S A R a n d 
ne w e ve nts  
Re p orti n g pr oce d ure f r o m I n vesti g at or t o S p o ns or 
T he I n vesti gat or will n otif y t he S p o ns or wit h o ut dela y o n t he da y of a ware ness of a n y S A E. I n a d diti o n, 
t he I n vesti gat or will n otif y t he S p o ns or of A Es a n d a b n or mal a nal ysis res ults defi ne d i n t he para gra p h 
“ Descri pti o n of safet y e val uati o n para meters”.  
 
T he I n vesti gat or m ust: 
- 
n ote  i n t he partici pa nt's me dical file t he date o n w hic h he/s he bec o mes a ware of t he e ve nt (at a 
f oll o w- u p visit or a tele p h o ne c o ntact wit h t he partici pa nt or a t hir d pers o n, etc); 
- 
i m me di atel y i nf or m b y  e mail,  t he pers o n res p o nsi ble at S P O N S O R ( Pier A delc hi R uffi ni, M D 
m o bile + 3 9 3 4 6 8 7 4 5 9 0 8, piera delc hi.r uffi ni @ d o m pe.c o m ) a n d b y fa x or e- mail t he S P O N S O R 
P H A R M A C O VI GI L A N C E office, at t he f oll o wi n g a d dresses: Fa x n u m ber : + 3 9 0 2 3 6 0 2 6 9 1 3  
e mail: far mac o vi gila nza @ d o m pe.c o m;  
- 
c o m plete t he S A E f or m a n d se n d it b y fa x or e mail t o t he pers o ns res p o nsi ble desi g nate d a b o ve, 
i m me diatel y ( wit hi n 2 4 h o urs) after of bei n g i nf or me d of t his e ve nt, wit h o ut waiti n g f or t he 
res ults of t he cli nical o utc o me or of a d diti o nal i n vesti gati o ns; 
- 
pr o vi de t he pers o ns desi g nate d a b o ve, as it bec o mes a vaila ble, wit h a n y rele va nt i nf or mati o n 
(t o get her wit h tra nslati o n i nt o E n glis h la n g ua ge) t hat c o ul d c o ntri b ute t o t he clarificati o n of t he 
S A E a n d t o t he assess me nt of p ote ntial ris k f or t he st u d y s u bj ects a n d wit h a n o n y mise d c o pies of 
t he d oc u me nts w hic h pr o vi de a d diti o nal usef ul i nf or mati o n, s uc h as h os pital a d missi o n re p orts, 
re p orts of f urt her c o ns ultati o ns, la b orat or y test re p orts, re p orts of ot her e xa mi nati o ns ai di n g 
dia g n osis ( w here p ossi ble, t he res ults fr o m pre-treat me nt assess me nts s h o ul d be a p pe n de d f or 

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c o mparis o n wit h t he res ults o btai ne d u n der treat me nt), or t he a ut o ps y re p ort, if a ut o ps y is 
perf or me d; 
- 
i nf or m t he pers o ns desi g nate d a b o ve of t he o utc o me, if n ot pre vi o usl y re p orte d, a n d ot her 
rele va nt f oll o w u p i nf or mati o n of t he S A E as s o o n as p ossi ble, t hr o u g h a S A E f or m clearl y 
mar ke d as F oll o w U p; 
 
T he I n vesti gat or m ust als o re p ort all S A Es/ S A Rs i n t he e C R F b y filli n g i n t he A E f or m.   
If t he S A E is t he reas o n of s u bj ect dr o p- o ut fr o m t he st u d y, t he I n vesti gat or will detail t he reas o n f or s uc h 
a state me nt i n t he c o m me nt secti o n of t he f or m. 
 
T he mi ni m u m criteria t o be re p orte d are as f oll o ws: 
- 
a s us pecte d i n vesti gati o nal me dici nal pr o d uct; 
- 
a n i de ntifia ble s u bject (at least st u d y s u bject i de ntificati o n c o de n u m ber, ge n der, a ge, b ut n o 
s u bj ect i nitials);  
- 
a n A E assesse d as seri o us; 
- 
a n i de ntifia ble re p orti n g s o urce; 
- 
a n u ni q ue cli nical trial i de ntificati o n; 
- 
t he o pi ni o n of t he I n vesti gat or a b o ut t he ca usal relati o ns hi p bet wee n t he e ve nt a n d t he I M P. 
 
T he o utc o me of t he S A E s hall be classifie d as f oll o wi n g: 
- 
rec o vere d/res ol ve d; 
- 
rec o veri n g/res ol vi n g; 
- 
rec o vere d/res ol ve d wit h se q uelae; 
- 
n ot rec o vere d/ n ot res ol ve d; 
- 
fatal; 
- 
u n k n o w n. 
Details s h o ul d be gi ve n f or t he latter f o ur cate g ories. 
 
Re g ul at or y re p orti n g pr oce d ure fr o m S p o ns or t o Re g ul at or y A ut h orities 
T he S p o ns or will s u b mit t o t he C o m pete nt A ut h orit y ( A N S M) a n d t o t he Et hics C o m mittee w hic h ga ve 
its a p pr o val f or t he researc h t o ta ke place, all u ne x pecte d S A Rs w hic h t o o k place d uri n g t he researc h a n d 
li kel y t o be d ue t o t he teste d pr o d ucts ( S U S A R), ne w e ve nt or ur ge nt safet y meas ures. S U S A R s hall als o 
be electr o nicall y tra ns mitte d t o E u dra Vi gila nce C T M o d ule ( E V C T). 
 
S U S A R decl ar ati o n 
I n case of S U S A R re gar di n g a cli nical trial o n me dici nal pr o d ucts i n v ol vi n g healt h y v ol u nteers 
- 
Eac h S U S A R m ust t o be re p orte d i n a n i n di vi d ual ele ctr o nic e mail messa ge 
- 
It s h o ul d be se nt t o : declarati o ns usars @a ns m.sa nte.fr  a n d t o t he E C ( C P P) 
- 
T he s u bject li ne s h o ul d be writte n as f oll o ws : E C- V S S U S A R _ y y y y m m d d _ na me of t he 
s u bsta nce ( or trial c o d e n u m ber) _ W orl d wi de u ni q ue case i de ntificati o n n u m ber _ C T 
- 
T he f oll o wi n g d oc u me nt s h o ul d be attac he d t o t he messa ge : CI O M S f or m ( P D F f or mat)/file 
na me la belle d as f oll o ws : y y y y m m d d _ na me of s u bsta nce ( or trial c o de n u m ber) _ w orl d wi de 
u ni q ue case i de ntificati o n n u m ber _ C T _ C 
- 
A n ac k n o wle d ge me nt of recei pt will be a ut o maticall y se nt b y ret ur n e mail 
 
Treat me nt will be u n mas ke d b y S p o ns or Dr u g Safet y pri or t o s u b missi o n of a S U S A R t o Re g ulat or y 
A ut h orities a n d o nl y cases referre d t o acti ve treat me nt will be c o nsi dere d e x pe dita ble f or re g ulat or y 
re p orti n g, i n li ne wit h la w re q uire me nts. 
 
Decl ar ati o ns m ust be d o ne : 
- 
Wi t h o ut dela y (a n d i n n o case later t ha n se ve n da ys) : if t he e ve nt is fatal or life t hreate ni n g; t o be 
f oll o we d b y a n y rele va nt i nf or mati o n wit hi n ei g ht da ys. 

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- 
N o later t ha n fiftee n da ys if t he e ve nt is seri o us b ut neit her fatal n or life t hreate ni n g; t o be 
f oll o we d b y a n y rele va nt i nf or mati o n wit hi n ei g ht da ys. 
T he sa me ti meli nes a p pl y f or S U S A R electr o nic s u b missi o n via E V C T . 
 
 
Ne w e ve nt decl ar ati o n 
- 
It s h o ul d be se nt t o : aec-essaiscli ni q ues @a ns m.sa nte.fr  a n d t o t he E C ( C P P) 
- 
T he s u bj ect li ne s h o ul d be writte n as f oll o ws a n d i n Fre nc h : Fait n o u vea u/ v ol o ntaires sai ns/ n° 
essai/ D CI o u c o de s u bsta nce 
- 
T he te xt messa ge (i n E n glis h) s h o ul d i ncl u de: 
 E u dra C T n u m ber, 
 Trial title, 
 Trial c o de n u m ber, 
 Ne w e ve nt s u m mar y, 
 If a p plica ble, ur ge nt safet y meas ures ta ke n, all rele va nt i nf or mati o n 
A ne w e ve nt ma y be a fatal e ve nt or a n e ve nt lea di n g t o s u bject’s h os pi talizati o n, p ote ntiall y relate d t o t he 
dr u g st u d y. It ma y als o be a S U S A R: i n t his case, t he c orres p o n di n g e ve nt m ust be re p orte d t wice, b ot h as 
Ne w E ve nt a n d as S U S A R, t o rele va nt i n v ol ve d parties. 
Decl ar ati o ns m ust be d o ne : 
- 
Wit h o ut del a y  a n d t o be f oll owe d b y a n y rele va nt i nf or mati o n wit hi n ei g ht da ys.  
 
T he S p o ns or will e ns ure t hat s u bj ects i n v ol ve d i n t he st u d y will be i nf or me d of Ne w E ve nts as a p plica ble. 
T he ne w e ve nt s hall i m me diatel y lea d t o disc o nti n uati o n of st u d y treat me nt a d mi nistrati o n t o a n y e nr olle d 
partici pa nts u ntil t heir safet y is g uara ntee d (t hr o u g h ur ge nt safet y meas ures). After t he Ne w E ve nt 
e val uati o n b y t he S p o ns or, if s u bject’s safet y is g uara ntee, t he cli nical st u d y is re -starte d a n d su bjects’ 
i nf or me d a n d writte n c o nse nt m ust be o btai ne d pri or t o I M P a d mi nistrati o n. 
 
 
 
Ur ge nt s af et y me as ure decl ar ati o n 
- 
First b y p h o ne t o A N S M: gastr oe nter ol o g y de part me nt: Nat halie D u marcet: + 3 3( 0) 1 5 5 8 7 3 6 7 7 
- 
T he n b y e mail t o: a ms-essaiscli ni q ues @a ns m.sa nte.fr a n d t o t he E C ( C P P) 
- 
T he s u bject li ne s h o ul d be writte n as f oll o ws a n d i n Fre nc h : 
M U S/ n° essai/ D CI o u c o de 
s u bsta nce 
- 
T he te xt me ssa ge (i n E n glis h) s h o ul d i ncl u de t he details of t he ur ge nt safet y meas ure a n d t he 
acti o n pla n 
 
Decl ar ati o ns m ust be d o ne : 
- 
V er ball y wit h o ut del a y  a n d f oll o we d b y a re p ort wit hi n fiftee n da ys 
- 
T he declarati o n wit h o ut a n y dela y has t o be f oll o we d b y : 
 T he s u b missi o n of a s u bsta ntial m o dificati o n of t he cli nical st u d y wit hi n fiftee n da ys after 
t he i nitiati o n of t he ur ge nt safet y meas ure (i n or der t o s pecif y a te m p orar y cessati o n or t o 
ma ke s u bsta ntial m o dificati o n) 
Or  
 Declarati o n of a n a ntici pate d e n d of st u d y, wit hi n fiftee n da ys. 
 

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P eri o dic al Re p orti n g t o Re g ul at or y A ut h orities a n d I n vesti g at ors 
D o m pé Dr u g Safet y s hall be res p o nsi ble t o pre pare a n d s u b mit peri o dical safet y re p orts ( De vel o p me nt 
Safet y U p date Re p ort –  D S U R) t o rele va nt Re g ulat or y A ut h orities a n d Et hic C o m mittee, as a p plica ble.  
Per i o dical (si x m o nt hl y) li ne listi n g of S U S A Rs will be pr o vi de d t o I n vesti gat ors as well, mai ntai ni n g 
treat me nt i nf or mati o n bli n de d, as a p plica ble. 
 
T he S p o ns or will a ns wer t o a n y re q uest fr o m t he C o m pete nt A ut h orit y or Et hics C o m mittee c o ncer ni n g 
s uc h reacti o ns. 
T he S p o ns or P har mac o vi gila nce is res p o nsi ble f or all declarati o ns referre d t o safet y t o Et hics C o m mittee 
a n d Healt h A ut h orities. 
8. 5.  
T y pe a n d d ur ati o n of t he f oll o w- u p of s u bjects after a d verse e ve nts 
All A Es will be m o nit ore d b y t he I n vesti gat or u ntil a satisfact or y o utc o me is o btai ne d (i.e. t he e ve nt is 
res ol ve d or t he c o n diti o n is u nli kel y t o c ha n ge or t he s u bject is l ost t o f oll o w- u p). All cli nical a n d 
bi ol o gical e xa mi nati o ns j u d ge d necessar y b y t he I n vesti gat or will be c o nti n ue d u ntil ret ur n t o n or mal. T he 
I n vesti gat or will pr o vi de t he S p o ns or wit h c o pies of all e xa mi nati o n res ults a n d treat me nts li n ke d t o t he 
f oll o w- u p of A Es. 
8. 6.  
P R E G N A N C Y I N T H E C LI NI C A L T RI A L 
Pri or t o e nr ol me nt i n t he cli nical trial, v ol u nteers ‘ part ners  wit h c hil d beari n g p ote ntial m ust be a d vise d of 
t he i m p orta nce of a v oi di n g pre g na nc y fr o m t he ti me of i nf or me d c o nse nt si g nat ure u p t o 9 0 da ys after t he 
last I M P a d mi nistrati o n a n d of t he p ote ntial ris ks ass ociate d wit h a n u ni nte nti o nal pre g na nc y.  
 
A male partici pati n g t o t he st u d y ha ve t o a gree t o use a c o n d o m wit h s per mici de, o n t he ti me of i nf or me d 
c o nse nt si g nat ure, u p t o 9 0 da ys after t he last I M P a d mi nistrati o n. T he Pri nci pal I n vesti gat or or a dele gate 
m ust i nf or m a fe male se x ual part ner t o use at least o ne of t he f oll o wi n g relia ble met h o ds of c o ntrace pti o n: 
a. H or m o nal oral, i m pla nta ble, tra ns der mal, or i njecta ble c o ntrace pti ves  
b.  A n o n- h or m o nal i ntra uteri ne de vice [I U D] or fe male c o n d o m wit h s per mici de or c o ntrace pti ve 
s po n ge wit h s per mici de or dia p hra g m wit h s per mici de or cer vical ca p wit h s per mici de  
 
 D uri n g t he trial a n d wit hi n 3 0 da ys after t he last I M P a d mi nistrati o n , fe male s u bjects are t o be i nstr ucte d 
t o c o ntact t he I n vesti gat or i m me diatel y if t he y s us pect t he y mig ht be pre g na nt. I n t he sa me wa y, male 
s u bj ects w h o bec o me a ware t hat t he part ner mi g ht be pre g na nt, are t o be i nstr ucte d t o c o ntact t he 
I n vesti gat or i m me diatel y.  
T he I n vesti gat or m ust re p ort e ver y pre g na nc y o n a pre g na nc y re p ort f or m as s o o n as p ossi ble ( wit hi n 2 4 
h o urs of lear ni n g of t he pre g na nc y t o t he D o m pé Dr u g Safet y c o ntacts re p orte d at Para gra p h 8. 4, e ve n if 
n o A E has occ urre d, a n d f oll o w it t o ter m. If, h o we ver, t he pre g na nc y is ass ociate d wit h a n S A E (e g, if 
t he m ot her is h os pitalize d f or a n a d verse e ve nt), i n a d diti o n t o t he pre g na nc y re p ort f or m, a se parate S A E 
re p ort f or m m ust be file d as descri be d i n Secti o n 8. 4 wit h t he a p pr o priate seri o us criteri o n (e g, 
h os pitalizati o n) i n dicate d o n t he S A E re p ort f or m. Miscarria ge, still birt h a n d a n y malf or mati o n/ disease 
m ust be re p orte d as a S A E.  
A f or m pre pare d b y D o m p é will be utilize d t o ca pt ure all pre g na nc y-relate d i nf or mati o n u ntil t he birt h of 
t he c hil d. 
 
 

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8. 7.  
O V E R D O S E  
Cases of o ver d ose (acci de ntal or i nte nti o nal) w hic h ma y or ma y n ot res ult i n seri o us a d verse reacti o ns are 
t o be re p orte d t o S p o ns or Dr u g Safet y, f oll o wi n g t he sa me pr oce d ure f or S A E, wit hi n 2 4 h o urs fr o m t he 
I n vesti gat or’s k n o wle d ge of its occ urre nce. T his i ncl u des re p orts relate d t o dr u g i nta ke wit h s uici dal 
i nte nti o ns a n d c o nse q ue nt dr u g o ver d ose. 
O ver d ose, a n d s hall be re p orte d, e ve n if n ot ass ociate d wit h a d verse reacti o ns, wit hi n 2 4 h o urs, i n a S A E 
f or m, t o D o m pé P H A R M A C O VI GI L A N C E c o ntacts re p orte d at Para gra p h 8. 4 a n d t o D o m pé Me dical 
E x pert, w h o s h o ul d be c o ntacte d t o disc uss c orrecti ve treat me nt, if necessar y. 
 
 
 
9.  D A T A M A N A G E M E N T 
9. 1.  
Defi niti o n of s o urce d at a 
All e val uati o ns t hat are re p orte d i n electr o nic Case Re p ort F or m (e C R F) 
m ust be s u p p orte d b y 
a p pr o priatel y si g ne d i de ntifie d s o urce d oc u me ntati o n relate d t o b ut n ot li mite d t o: 
- 
S u bj ect i de ntificati o n, last partici pati o n t o a cli nical trial, 
me dical hist or y, pre vi o us a n d 
c o nc o mita nt me dicati o n; 
- 
P h ysical e xa mi nati o n, bl o o d press ure a n d heart rate, b o d y wei g ht, B MI, s u bject ha bits; 
- 
Dates a n d ti mes of st u d y dr u g a d mi nistrati o n; 
- 
P har mac o ki netic ti me p oi nts; 
- 
La b orat or y assess me nts, meals; 
- 
A Es. 
 
9. 2.  
S o urce d oc u me nt re q uire me nts 
Acc or di n g t o t he g ui deli nes o n G C P , t he M o nit ori n g T ea m m ust c hec k t he e C R F e ntries a gai nst t he 
s o urce d oc u me nts, e xce pt f or t he pre-i de ntifie d s o urce, data directl y rec or de d/e ncl ose d i n/t o t he C R F. T he 
I nf or me d C o nse nt F or m will i ncl u de a state me nt b y w hic h t he s u bject all o ws t he S p o ns or’s d ul y 
a ut h orize d pers o n nel, t he Et hics C o m mittee, a n d t he re g ulat or y a ut h orities t o ha ve direct access t o s o urce 
data w hic h s u p p orts t he data o n t he e C R F (e. g. s u bj ect's me dical file, a p p oi nt me nt b o o ks, ori gi nal 
la b orat or y rec or ds, etc.). T hese pers o n nel, b o u n d b y pr ofessi o nal secrec y, will n ot discl ose a n y pers o nal 
i de ntit y or pers o nal me dical i nf or mati o n. 
 
9. 3.  
Use a n d c om pleti o n of  t he e C R F a n d  a d diti o n al re q uest 
9. 3. 1. 1.  D at a c ollecti o n 
All cli nical data will be re p orte d electr o nicall y b y t he I n vesti gat or or a ut h orise d desi g nee o n a we b- base d 
e C R F. T his e C R F is s pecificall y desi g ne d f or t he st u d y a n d de vel o pe d b y t he Data 
Ma na ge me nt 
De part me nt of E ur ofi ns O pti me d usi n g Vie d oc versi o n 4., a vali date d Electr o nic Data Ca pt ure s yste m, 2 1 
C F R Part 1 1 c o m plia nt. 
S h o ul d a c orrecti o n be ma de, t he c orrecte d i nf or mati o n will be e ntere d i n t he e C R F a n d t he i nitial 
i nf or mati o n will be trac ke d i n t he a u dit trail. 
9. 3. 1. 2.  Res p o nsi bilities 
T he I n vesti gat or or a ut h orise d desi g nee is res p o nsi ble f or t he ti meli ness, c o m plete ness, a n d acc urac y of 
all o bser vati o ns a n d ot her data perti ne nt t o t he cli nical i n vesti gati o n i n t he e C R Fs. 
T he I n vesti gat or will e ns ure t hat all data are e ntere d pr o m ptl y ( wit hi n 2 da ys) after t he e val uati o n has 
occ urre d, i n acc or da nce wit h s o urce d oc u me nts a n d s pecific i nstr ucti o ns acc o m pa n yi n g t he e C R Fs , 
desi g ne d s pecificall y f or t he st u d y.  

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T he Data Ma na ge me nt De part me nt of E ur ofi ns O pti me d will pr o vi de all t o ols, i nstr ucti o ns, a n d trai ni n g 
necessar y t o c o m plete t he e C R F, a n d eac h user will be iss ue d a u ni q ue user na me a n d pass w or d.  
T he data ma na ge me nt of E ur ofi ns O pti me d will be res p o nsi ble f or data pr ocessi n g, i n acc or da nce wit h 
t he C R O data ma na ge me nt pr oce d ures.  
9. 3. 1. 3.  D at a M a n a ge me nt 
D uri n g t he st u d y, t hr o u g h re g ular data c ollecti o n a n d m o nit ori n g, cli nical data will be re p orte d i n t he 
e C R F. C o m p uterise d l o gic a n d/ or c o nsiste nc y c hec ks will be s yste maticall y a p plie d i n or der t o detect 
err ors or o missi o ns. Q ueries will be ge nerate d a n d s u b mitte d t hr o u g h t he electr o nic data ca pt ure ( E D C) 
s yste m t o t he i n vesti gat or sites f or res ol uti o n ( q ueries s h o ul d be a ns were d wit hi n 3 w or ki n g da ys, e xce pt 
cl ose t o t he data base l oc k peri o d, q ueries s h o ul d be a ns were d wit hi n 1 w or ki n g da y).  
C orrecti o n will be ma de eit her a ut o maticall y fr o m t he i m me diate c o m pleti o n or f oll o wi n g t he re vie w of 
t he data d uri n g t he E ur ofi ns O pti me d m o nit ori n g. A n a u dit trail, w hic h will be i nitiate d at t he ti me of t he 
first data e ntr y, all o ws trac ki n g all m o dificati o ns.  
T he Data Ma na ge me nt De part me nt of E ur ofi ns O pti me d ma y ge nerate a d diti o nal re q uests t o w hic h t he 
I n vesti gat or m ust res p o n d electr o nicall y b y c o nfir mi n g or m o dif yi n g t he data q uesti o ne d. T he re q uests 
wit h t heir res p o nses will be i m ple me nte d t o t he e C R Fs.  
Eac h ste p of t his pr ocess will be m o nit ore d t hr o u g h t he i m ple me ntati o n of i n di vi d ual pass w or ds a n d 
re g ular bac k u ps t o mai ntai n a p pr o priate data base access a n d t o e ns ure data base i nte grit y. 
W he n e C R Fs are c o m plete a n d all q ueries ha ve bee n a ns were d, t he I n vesti gat or has t o si g n t he e C R Fs . 
T he n e C R Fs are l oc ke d a n d n o m o dificati o n is p ossi ble a n y m ore.  
After i nte grati o n of all c orre cti o ns i n t he c o m plete set of data, t he data base will be l oc ke d a n d sa ve d 
bef ore bei n g release d f or statistical a nal ysis.  
After data base l oc k, a Patie nt Data Re p ort ( P D R) c o nsisti n g of t he creati o n of t he e ntire case b o o k f or a 
s u bj ect, i ncl u di n g t he a u dit trail, will be ge nerate d f or eac h s u bject i n . p df f or mat. T he i n vesti gat or a n d 
t he S p o ns or will recei ve t he P D Rs f or arc hi vi n g after t he l oc k of t he data base. All Data Ma na ge me nt 
acti vities will be descri be d i n a d oc u me nt, t he Data Ma na ge me nt Pla n. 
 
 
9. 4.  
St u d y m o nit ori n g 
E U R O FI N S O P TI M E D will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, G C P  a n d t he a p plica ble 
re g ulat or y re q uire me nts a n d t he c o ntract wit h t he S p o ns or. 
 T he I n vesti gat or is re q uire d t o e ns ure c o m plia nce wit h t he I n vesti gati o nal Pr o d uct sc he d ule, visit 
sche d ule a n d pr oce d ures re q uire d b y t he pr ot oc ol. T he I n vesti gat or a grees t o pr o vi de all i nf or mati o n 
re q ueste d i n t he C R F i n a n acc urate ma n ner acc or di n g t o t he i nstr ucti o ns pr o vi de d a n d t o e ns ure direct 
access t o s o urce d oc u me nts t o S p o ns or re prese ntati ves. 
T he S p o ns or is res p o nsi ble t o Healt h A ut h orities f or ta ki n g all reas o na ble ste ps t o e ns ure t he pr o per 
c o n d uct of t he st u d y as re gar ds et hics, pr ot oc ol c o m plia nce, i nte grit y a n d vali dit y of t he data rec or de d o n 
t he Case Re p ort F or ms. T h us, t he mai n d ut y of t he M o nit ori n g T ea m is t o hel p t he I n vesti gat or a n d t he 
S p o ns or mai ntai n a hi g h le vel of et hical, scie ntific, tec h nical a n d re g ulat or y q ualit y i n all as pects of t he 
st u d y. 
 
9. 5.  
Access t o d at a b y t he s u bjects 
I n c o nf or mit y wit h t he la w, a n y s u bjects w h o s o wis h ma y access a n y data c o ncer ni n g t he m, at t he e n d of 
t he researc h. T he y s h o ul d a d dress t heir re q uest i n writi n g t o t he I n vesti gat or, a n d will o btai n a res p o nse 
wit hi n 8 w or ki n g da ys. 
 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
7 0  / 8 5  
1 0.  S T A TI S TI C S  
1 0. 1.  Descri pti o n of t he st atistic al met h o ds 
T he statistical a nal ysis will c o nsist i n i n di vi d ual data listi n gs a n d descri pti ve statistics perf or me d b y 
E U R O FI N S O P TI M E D, usi n g t he S A S  c o m p uter pr o gra m (release 9. 3). 
A ll i n di vi d ual data f or all i ncl u de d s u bjects will be prese nte d i n data listi n gs, s orte d b y s u bj ect wit hi n 
st u d y pr o d uct/treat me nt gr o u p. 
De m o gra p hic a n d baseli ne c haracteristics data will be s u m marize d b y pr o d uct/treat me nt, c o h ort a n d visit 
da y w here c o nsiste nt. 
F or para meters wit h e val uati o n bef ore d osi n g a n d i n case of rec hec ke d val ue(s) f or o ne s u bject, o nl y t he 
last o bser vati o n will be use d i n descri pti ve statistics a n d deri vati o ns of ot her para meter val ues. After 
d osi n g, o nl y o bser vati o ns pla n ne d i n t he pr ot oc ol will be use d i n descri pti ve statistics. 
1 0. 1. 1.  Descri pti ve st atistics 
Descri pti ve statistics f or q ua ntitati ve para meters will be pr o vi de d usi n g mea n, Sta n dar d De viati o n ( S D), 
Sta n dar d Err or of t he 
Mea n ( S E M), 
mi ni m u m, 
me dia n, 
ma xi m u m, a n d n u m ber of o bser vati o ns; 
descri pti ve statistics f or q ualitati ve para meters will be pr o vi de d usi n g fre q ue ncies ( n) a n d perce nt 
fre q ue ncies ( %). Perce nt will be calc ulate d usi n g as de n o mi nat or t he act ual n u m ber of n o n- missi n g data. 
 
1 0. 1. 1. 1.  S u bject de m o gr a p hic c h ar acteristics, m e dic al hist or y a n d di a g n oses 
C o nti n u o us varia bles (a ge, hei g ht, wei g ht, B MI a n d q ualitati ve varia bles (race) will be s u m marize d i n 
descri pti ve statistics o n t he i ncl u de d s u bjects a n d/ or p har mac o ki netic p o p ulati o n, if rele va nt. 
Me dical hist or y will be liste d a n d s u m marize d b y s yste m or ga n class a n d preferre d ter m, if rele va nt 
( Me dical Dicti o nar y f or Re g ulat or y Acti vit y ( Me d D R A)). A b n or mal p h ysical fi n di n gs at baseli ne will be 
liste d. 
1 0. 1. 1. 2.  P re vi o us me dic ati o ns 
Pre vi o us me dicati o ns will be c o de d acc or di n g t o t he 
W orl d Healt h Or ga nizati o n- Dr u g Refere nce List 
( W H O- D R L). S u bjects w h o t o o k me dicati o ns t hat were st o p pe d bef ore t he first st u d y dr u g d osi n g will be 
liste d. 
1 0. 1. 1. 3.  B aseli ne s af et y p ar a meters 
I n di vi d ual safet y data (cli nical la b orat or y, vital si g ns) meas ure d bef ore t he first dr u g a d mi nistrati o n will 
be c hec ke d f or vali dit y of e ntra nce criteria, a n d a b n or malities 
will be d oc u me nte d. I n di vi d ual 
a b n or malities bef ore d osi n g will be fla g ge d i n data listi n gs a n d prese nte d al o n g wit h p ost- d ose 
meas ure me nts i n t he statistical a p pe n dices.  
1 0. 1. 1. 4.  St u d y dr u g a n d c o nc o mit a nt t her a p y 
Dr u g dis pe nsi n g i nf or mati o n a n d details of dr u g d osi n g (act ual pr o d ucts/treat me nt recei ve d, act ual d ose 
recei ve d, date a n d ti me of dr u g i nta ke) f or eac h s u bject will be liste d b y pr o d uct/treat me nt gr o u p. 
C o nc o mita nt treat me nts will be c o de d acc or di n g t o t he 
W orl d Healt h Or ga nizati o n- Dr u g Dicti o nar y 
( W H O- D D). S u bj ects w h o recei ve d c o nc o mita nt treat me nts al o n g wit h t he st u d y dr u g will be liste d b y 
st u d y pr o d uct/treat me nt gr o u p a n d s u bj ect. If rele va nt, c o nc o mit a nt me dicati o ns will als o be s u m marize d 
b y a nat o mic class a n d t hera pe utic class f or eac h treat me nt gr o u p a n d o verall s u bj ects, prese nti n g t he 
fre q ue nc y of s u bjects ( n) ta ki n g a gi ve n me dicati o n a n d t he n u m ber of occ urre nce of eac h me dicati o n. 
 
1 0. 1. 1. 5.  P h ar m ac o ki netics 
All descri pti ve statistics will be prese nte d i n de pe n de ntl y f or eac h part of t he st u d y. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
7 1  / 8 5  
In eac h part, i n di vi d ual D F 2 5 7 7 Y b o u n d a n d u n b o u n d ( or relate d meta b olites) plas ma c o nce ntrati o ns will 
be prese nte d b y d ose le vel a n d n o mi nal ti me p oi nts, w he n a p plica ble. 
Descri pti ve statistics f or t he plas ma c o nce ntrati o ns will be prese nte d as n u m ber of a vaila ble data ( N), 
mea n, sta n dar d de viati o n ( S D) a n d will be calc ulate d if at least 2/ 3 of t he plas ma val ues per ti me- p oi nt are 
a b o ve L O Q. F or descri pti ve statistics calc ulati o ns, c o nce ntrati o ns bel o w L O Q will be set t o zer o ( 0) if 
t he y are re p orte d bef ore t he first q ua ntifia ble sa m ple or c o nsi dere d as missi n g data if t he y are r e p orte d 
after t he first q ua ntifia ble data. 
I n di vi d ual deri ve d P K para meters will be prese nte d b y d ose le vel ( Escalati n g D ose Part). Descri pti ve 
statistics of t he P K para meters will be prese nte d as N, mea n, S D, sta n dar d err or ( S E), c oefficie nt of 
variati o n ( C V %), me dia n, mi ni m u m ( Mi n), ma xi m u m ( Ma x) val ues, a n d ge o metric mea n ( G M). 
I n t he ta bles of i n di vi d ual P K para meters, all t he de viati o ns fr o m pla n ne d a nal ysis will be me nti o ne d b y 
fla g gi n g t he a b n or mal res ults (e. g. t1/ 2 deter mi ne d wit h ter mi nal eli mi nati o n sl o pe w h ose r² is l o wer t ha n 
0. 9 0 will als o be fla g ge d). 
P ossi ble e xcl usi o n of fla g ge d P K para meters c o ul d be perf or me d if, i n t he j u d g me nt of t he 
p har mac o ki neticist, t he y are dee me d n ot t o be “ p har mac o ki neticall y rele va nt”. E xcl usi o n of P K 
para meters will be disc usse d i n t he P K res ults secti o n a n d als o disc usse d wit h S p o ns or. If data are 
e xcl u de d fr o m t he P K dataset, all s u bse q ue nt statistical a nal yses will be perf or me d t wice, o nce usi n g t he 
c o m plete a vaila ble P K dataset a n d o nce usi n g t he fi nal P K dataset as defi ne d b y t he p har mac o ki neticist. 
St u d y c o ncl usi o n will be a pri ori  base d o n t he fi nal dataset as defi ne d b y t he p har mac o ki neticist. 
In di vi d ual meas ure d plas ma c o nce ntrati o n vs. act ual ti me c ur ve will be pr o d uce d i n gra p hic f or eac h 
s u bj ect, f or ea c h d ose le vel o n b ot h li near/li near a n d l o g/li near scales w here a p plica ble. Si milarl y, mea n 
plas ma c o nce ntrati o n vs. ti me c ur ves will als o be pr o d uce d f or eac h d ose le vel. 
 
1 0. 1. 2.  A n al ysis of pri nci p al criteri a 
 
1 0. 1. 2. 1.  A d verse e ve nt (f or e ac h p art) 
A Es will be c o de d acc or di n g t o t he Me dical Dicti o nar y f or Re g ulat or y Acti vit y ( Me d D R A). T he y will be 
classifie d i nt o pre- defi ne d sta n dar d cate g ories acc or di n g t o c hr o n ol o gical criteria: 
- Treat me nt e mer ge nt A Es ( T E A E): A Es t hat occ urs f or t he first ti me or if prese nt bef ore w orse ne d 
d uri n g a n e x p os ure t o dr u g(s).  
- N o n-treat me nt e mer ge nt A Es ( N T E A E): A Es t hat occ urs bef ore t he st u d y dr u g a d mi nistrati o n (als o 
calle d “ pre -d ose e ve nt” see para gra p h 7. 3. 2).  
A n A E occ urri n g d uri n g t he r u n- o ut will be relate d t o t he last da y of treat me nt a d mi nistrati o n recei ve d. 
A Es will be i n di vi d uall y liste d per s u bject n u m ber, prese nti n g: assi g ne d treat me nt gr o u p ( or treat me nt 
recei ve d), ver bati m, Me d D R A Pri mar y S yste m Or ga n Class, Me d D R A L o west Le vel Ter m,  Me d D R A 
Preferre d Ter m, e mer ge nce ( yes or n o) date a n d ti me of o nset, date a n d ti me of last st u d y dr u g 
a d mi nistrati o n bef ore A E , d urati o n, ti me fr o m o nset si nce last st u d y dr u g a d mi nistrati o n, fre q ue nc y, 
se verit y a n d seri o us ness, relati o ns hi p t o st u d y dr u g, t he re q uire d acti o n ta ke n (e. g. c orrecti ve treat me nt, 
h os pitalisati o n) o utc o me a n d if it is a reas o n f or dr o p- o ut. 
T he n o n-treat me nt e mer ge nt A Es will be s u m marise d b y S yste m Or ga n Class a n d Preferre d T er m f or t he 
safet y set. 
T he treat me nt e mer ge nt A Es will be s u m marise d b y Pri mar y S yste m Or ga n Class, Preferre d T er m a n d 
treat me nt gr o u p f or t he safet y set. It will c o nsist i n t he e val uati o n of t he n u m ber of A Es a n d t he n u m ber 
of s u bjects re p orti n g t hese A Es. 
1 0. 1. 2. 2.  P h ysic al e x a mi n ati o n, E C G a n d vit al si g ns (f or e ac h p art) 
P h ysical e xa mi nati o n, E C Gs (i ncl u di n g Q Tc F) a n d vital si g ns rec or de d d uri n g t he st u d y will be 
i n di vi d uall y liste d a n d q ua ntitati ve para meters will be s u m marise d b y usi n g descri pti ve statistics. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
7 2  / 8 5  
F or vital si g ns a n d E C G para meters, val ues a n d cli nicall y p ote ntiall y si g nifica nt a b n or malities will be 
descri be d b y treat me nt a n d o verall, at scree ni n g, i ncl usi o n, baseli ne ( D 1 pre- d ose), eac h sc he d ule d 
assess me nt d uri n g treat me nt p hase a n d at t he e n d of t he st u d y. 
F or vital si g ns a n d E C G para meters, c ha n ge bet wee n t he val ue at baseli ne a n d t he val ue d uri n g at eac h 
sc he d ule d assess me nt d uri n g treat me nt p hase a n d at t he e n d of st u d y visit will be descri be d f or eac h 
para meter b y treat me nt a n d o verall. 
I n ge neral, a p pr o priate descri pti ve statistics acc or di n g t o t he nat ure of t he varia ble will be a p plie d: 
cate g orical varia bles will be prese nte d usi n g c o u nts a n d perce nta ge, w hilst c o nti n u o us varia bles will be 
prese nte d usi n g mea n, sta n dar d de viati o n ( S D), me dia n, mi ni m u m, ma xi m u m, c oefficie nt of variati o n 
( C V( %)) a n d n u m ber of s u bj ects. 
A p pr o priate i nfere ntial statistics, base d o n varia ble c haracteristics, will be a p plie d, if c o nsiste nt. 
 
1 0. 1. 2. 3.  L a b or at or y p ar a meters (f or e ac h p art) 
All la b orat or y val ues rec or de d d uri n g t he st u d y will be i n di vi d uall y liste d a n d fla g ge d f or val ues o utsi de 
refere nce ra n ges a n d f or cli nical rele va nce (assesse d b y i n vesti gat or). Q ua ntitati ve para meters will be 
s u m marise d b y descri pti ve statistics. 
Val ues, p ositi o n acc or di n g t o la b orat or y ra n ge a n d cli nical assess me nt will be descri be d at scree ni n g, 
baseli ne ( D- 1), d uri n g t he treat me nt p hase a n d at t he e n d of st u d y b y treat me nt f or st u dies a n d o verall. 
C ha n ge bet wee n t he val ue at baseli ne a n d t he val ue d uri n g treat me nt p hase a n d at t he e n d of st u d y visit 
will be descri be d f or eac h para meter b y treat me nt a n d o verall. 
All q ua ntitati ve a n d q ualitati ve uri nar y test res ults will be liste d, s orte d b y treat me nt f or st u dies i n parallel 
gr o u ps or b y se q ue nce f or cr oss o ver st u dies. 
Ser ol o g y, A B T a n d D O A test res ults will be liste d f or eac h s u bj ect. 
 
1 0. 1. 1.  A n al ysis of sec o n d ar y criteri a 
1 0. 1. 1. 1.  F or m al st atistics f or p h ar m ac o ki netic 
F or  D F 2 5 7 7 Y b o u n d a n d u n b o u n d a n d relate d meta b olites, t he h y p ot hesis t hat C ma x , A U C0- ∞ ( S A D part) 
or A U C 0-  ( M A D part) are d ose pr o p orti o nal will be f or mall y teste d usi n g a p o wer m o del a p pr oac h. A U C 
a n d C ma x  val ues, f or all d ose le vels, will be a nal yze d f or d ose pr o p orti o nalit y usi n g a nal ysis of varia nce 
tec h ni q ues. 
Data will be fitte d t o t he f oll o wi n g m o del: 
l o g( A U C or Cma x ) =  + [  x  l o g( D ose)] 
T his is us uall y referre d t o as a p o wer m o del beca use after e x p o ne ntiati o n: 
A U C 0- ∞ or Cm a x =  x D ose  
Pri or t o t he a nal ysis, t he ass u m pti o n of a li near relati o ns hi p bet wee n t he l o g A U C 0- ∞ ( Cm a x) a n d l o g- d ose 
will be teste d usi n g a nal ysis of varia nce b y partiti o ni n g t he s u ms of s q uares f or treat me nts i nt o t h ose f or 
li nearit y a n d de part ures fr o m li nearit y. If t he de part ures fr o m li nearit y are si g nifica nt t he n t he h y p ot hesis 
of d ose pr o p orti o nalit y is rejecte d a n d t he p o wer m o del a nal ysis will n ot be perf or me d. 
I n case, A U C0 -∞ c o ul d n ot be c o nsi dere d as relia ble i n a maj orit y of s u bjects (e. g. t o o lar ge perce nta ge of 
e xtra p olati o n, p o or q ualit y of ke deter mi nati o n), d ose pr o p orti o nalit y assess me nt will be perf or me d o n 
A U C 0-t val ues.  
T he esti mate o btai ne d f or  is a meas ure of d ose pr o p orti o nalit y. T he esti mate of  t o get her wit h its 9 0 % 
c o nfi de nce i nter val ( CI) ( l, u) will be prese nte d t o q ua ntif y t he de gree of n o n- pr o p orti o nalit y. 
T he d ose pr o p orti o nalit y will be c o nfir me d if t he 9 0 % CI of  (l, u) is c o ntai ne d c o m pletel y wit hi n t he 
f oll o wi n g critical re gi o n: 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
7 3  / 8 5  
 




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

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l o g(
)
2 5
.1
l o g(
1;
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l o g(
)8
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l o g(
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w here r, defi ne d as t he d ose rati o, is e q ual t o 
l
h
, h  bei n g t he hi g hest d ose a n d l t he l o west d ose. 
Assess me nt of t he d ose pr o p orti o nalit y will be perf or me d o n t he c o m plete d ose ra n ge. I n case of 
de part ures fr o m li nearit y or of ne gati ve c o ncl usi o n of d ose pr o p orti o nalit y o n t he c o m plete d ose, f urt her 
i n vesti gati o n usi n g t he sa me met h o d ol o g y mi g ht be d o ne o n a restrai ne d d ose ra n ge.  
T he statistical pac ka ge S A S ®  v. 9. 4 will be use d t o perf or m all statistical a nal yses. 
F or eac h part of t he st u d y a n d da y of P K assess me nt, t he i n di vi d ual A U C a n d C ma x  val ues will be 
prese nte d gra p hicall y b y d ose le vel. T he mea n A U C a n d C ma x  val ues al o n g wit h t he S D will als o be 
dis pla ye d gra p hicall y b y d ose le vel. 
 
1 0. 1. 1. 2.  C orrel ati o n 
bet wee n 
p h ar m ac o ki netic 
a n d 
p h ar m ac o d y n a mic 
p ar a meters 
T he relati o ns hi p bet wee n val ues of p har mac o d y na mic p ara meters ti me matc he d wit h D F 2 5 7 7 Y ( b o u n d 
a n d u n b o u n d) plas ma c o nce ntrati o ns will be first e val uate d b y vis ual i ns pecti o n of gra p hs relati n g 
p har mac o d y na mic para meters wit h D F 2 5 7 7 Y ( b o u n d a n d u n b o u n d) plas ma c o nce ntrati o ns.  
I n case of relia ble relati o ns hi ps, basic m o dels, s uc h as Ema x  m o del, will be first de vel o pe d. T he n, t he 
selecte d m o dels will be o pti mize d b y testi n g c o variate s uc h as B MI, a ge, etc. 
F urt her m o del de vel o p me nt mi g ht be d o ne de pe n di n g o n t he res ults of eac h m o delli n g. 
 
1 0. 1. 2.  C ale n d ar f or a n al yses 
N A  
 
1 0. 2.  S a m ple size 
N o f or mal sa m ple size calc ulati o n was ma de. T he s u bj ects treate d wit h test pr o d uct a n d t he s u bjects 
treate d wit h place b o are c o nsi dere d s ufficie nt t o detect dr u g effects a n d deter mi ne p har mac o ki netic 
para meters bef ore escalati n g t o t he ne xt d ose le vel.  
S A D c o h orts:  T hirt y -t w o (3 2)  healt h y v ol u nteers ( H V) + 4 reser ve s u bjects (t otal 3 6) will be e nr olle d t o 
ha ve 4 gr o u ps. T hree gr o u ps of ei g ht ( 8) male s u bjects a n d o ne gr o u p of 4 M + 4 F.  
 
M A D c o h orts: M A D c o h orts: T hirt y -si x ( 3 6) healt h y v ol u nteers ( H V) + 4 reser ve s u bjects (t otal 4 0) will 
be e nr olle d t o ha ve 3 gr o u ps. T w o gr o u ps of t wel ve ( 1 2) male s u bjects a n d gr o u p of 6 M + 6 F.  
 
1 0. 3.  Le vel of si g nific a nce t o be use d 
T he le vel of si g nifica nce will be fi xe d at 0. 0 5. 
T ests will be t w o-taile d wit h n o m ulti plicit y a dj ust me nt. 
 
1 0. 4.  I nteri m A n al ysis  
F or eac h part of t he st u d y, a n i nteri m P K a nal ysis o n D F 2 5 7 7 Y will be perf or me d after c o m pleti o n of 
eac h d ose le vel. T his a nal ysis will be d o ne o n a n o n y mize d data pr o vi de d b y t he bi oa nal ytical ce nter t o 
pre ve nt a n y vi olati o n of t he d o u ble bli n d c o n diti o n of t he st u d y. 
1 0. 5.  P r oce d ure f or acc o u nti n g, f or missi n g, u n use d, a n d s p uri o us d at a 
Missi n g data val ues will n ot be re place d. 

Pr ot oc ol N°  B P S 0 1 1 5  / O P 0 9 9 5 1 6. D O M  
 
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1 0. 6.  P r oce d ures f or re p orti n g a n y de vi ati o n(s) fr o m ori gi n al st atistic al pl a n 
T his pla n ma y be re vise d d uri n g t he st u d y t o acc o m m o date pr ot oc ol a me n d me nts a n d t o ma ke c ha n ges t o 
a da pt t o u ne x pecte d iss ues i n st u d y e xec uti o n a n d data c ollecti o n t hat c o ul d affect pla n ne d a nal yses. 
T hese re visi o ns will be base d o n re vie w of t he data, a n d a fi nal pl a n will be iss ue d pri or t o data base l oc k, 
if a p plica ble. 
 
1 0. 7.  Selecti o n of s u bjects t o be i ncl u de d i n t he a n al yses 
I n case of i nc orrect treat me nt assi g ne d, s u bjects will be a nal yse d i n t he treat me nt gr o u p t he y act uall y 
recei ve d. 
 
1 1.  Q U A LI T Y C O N T R O L A N D A S S U R A N C E 
1 1. 1.  Q u alit y Ass ur a nce 
T he st u d y will be carrie d o ut i n c o nf or mit y wit h le gal c o n diti o ns a n d Fre nc h re g ulati o ns, a n d wit h res pect 
t o G C P  (I C H E 6). T he Q ualit y Ass ura nce s yste m i n f orce at E U R O FI N S O P TI M E D will a p pl y, e xce pt 
f or a n y s pecific cla uses a d de d t o t he pr ot oc ol or s pecifie d i n writi n g b y t he S p o ns or bef ore t he start of t he 
st u d y. 
1 1. 2.  Q u alit y C o ntr ol 
T he mai n st u d y sta ges (c o here nce bet wee n s o urce a n d C R F f or: eli gi bilit y criteria, mai n e val uati o n 
criteria, A Es ) will be s u b mitte d t o a q ualit y c o ntr ol pr ocess. 
 
1 1. 3.  S p o ns or a u dits a n d i ns pecti o ns b y re g ul at or y a ge ncies 
T he st u d y ma y be s u bj ecte d t o o n-site a u dit visit b y t he S p o ns or a n d i ns pecti o n b y a p plica ble Re g ulat or y 
A ut h orities i n or der t o verif y t he st u d y is c o n d ucte d i n c o m plia nce wit h t he pri nci ples of G C P  a n d wit h 
t he st u d y pr ot oc ol. T he a u dit or/i ns pect ors will ha ve direct access t o me dical rec or ds, s o urce d oc u me nts, 
a n d all d oc u me nts a n d facilities rele va nt t o t he cli nical trial. 
T he I n vesti gat or a grees t o all o w t he a u dit ors/i ns pect ors t o ha ve direct access t o st u d y rec or ds f or re vie w, 
bei n g u n derst o o d t hat t his pers o n nel is b o u n d b y pr ofessi o nal secrec y, a n d as s uc h will n ot discl ose a n y 
pers o nal i de ntit y or pers o nal me dical i nf or mati o n. 
T he c o nfi de ntialit y of t he data verifie d a n d t he a n o n y mit y of t he s u bjects s h o ul d be res pecte d d uri n g t hese 
i ns pecti o ns. 
 
1 2.  E T H I C S 
1 2. 1.  I nf or me d c o nse nt f or m 
T he pers o ns partici pati n g i n t he st u d y will be selecte d d uri n g a scree ni n g visit. D uri n g t his meeti n g, t he 
st u d y o bjecti ves a n d met h o d ol o g y will be e x plai ne d. 
T he v ol u nteer s u bj ects will recei ve a s y nt hesis d oc u me nt e x plai ni n g t he re q uire me nts of researc h, t he title 
a n d t he o bjecti ves of t he st u d y, t he detaile d researc h pr ot oc ol a n d t he ris ks a n d c o nstrai nts of t he researc h. 
Bef ore bei n g i ncl u de d i n t he st u d y, eac h partici pa nt m ust gi ve his/ her writte n c o nse nt. T he te xt of t he 
c o nse nt is t o be si g ne d a n d date d a n d i nitialle d o n eac h pa ge b y t he s u bj ect a n d date d a n d si g ne d b y t he 
I n vesti gat or. 
 

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1 2. 2.  E t hics C o m mittee a n d C o m pete nt A ut h orities 
T he st u d y will be carrie d o ut i n c o nf or mit y wit h t he pri nci ples of t he Declarati o n of Helsi n ki as m o difie d 
i n F ortaleza ( 2 0 1 3), a n d Nati o nal Re g ulati o n.  
T his st u d y will be u n derta ke n after a p p r o val b y t he Et hics C o m mittee a n d  of the C o m pete nt  A ut h orit ies. 
 
1 2. 3.  P r ot oc ol a me n d me nts  
Neit her t he I n vesti gat or n or t he S p o ns or ca n m o dif y t he pr ot oc ol wit h o ut a gree me nt fr o m t he ot her part y. 
A n y pr ot oc ol m o dificati o ns m ust be t he t o pic/ matter of a n a me n d me nt w hic h will be date d a n d si g ne d b y 
t he t w o parties a n d m ust be i ncl u de d as a n a d de n d u m t o t he pr ot oc ol. 
De pe n di n g o n t he i m p orta nce of t he c ha n ges t o t he st u d y c o n diti o ns, t he a me n d me nt ma y be se nt t o t he 
Et hics C o m mittee a n d/ or Healt h C o m pete nt A ut h orities eit her f or a p pr o val or f or i nf or mati o n.  
 
A s u bsta ntial pr ot oc ol a me n d me nt m ust be s u b mitte d t o t he A N S M, i n or der t o n otif y t he res ults of S A D 
part of t he st u d y. 
1 2. 4.  P r ot oc ol de vi ati o ns 
N o de viati o ns are s yste maticall y t olerate d. 
A n y pr ot oc ol de viati o ns 
will be n otifie d t o t he 
M o nit or/ S p o ns or o n a n o n g oi n g basis, a n d n o later t ha n t he date of t he bli n d re vie w, a n d will gi ve rise t o 
a disc ussi o n t o defi ne t heir stat us ( mi n or –  maj or). 
 
1 3.  D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
1 3. 1.  Arc hi v al 
All d oc u me nts relat e d t o t he st u d y m ust be ke pt b y t he I n vesti gat or i n a p pr o priate files. T he arc hi ves of 
t he s u bj ects, ori gi nal i nf or me d c o nse nt f or ms, s o urce d oc u me nts, case re p ort f or ms, i n ve nt or y of st u d y 
pr o d ucts, c orres p o n de nce wit h t he S p o ns or a n d Et hics c o m mittee relat e d t o t he st u d y, m ust be file d. 
T he I n vesti gat or a ut h orises direct access t o t he s o urce d oc u me nts f or m o nit ori n g, a u dits a n d i ns pecti o ns. 
T he I n vesti gat or kee ps a list i de ntif yi n g t he s u bject na mes ( wit h a d dresses a n d/ or me dical file n u m bers), 
t heir res pecti ve c o de n u m ber a n d t he dates of e ntr y i nt o t he st u d y a n d e n d of st u d y, i n or der t o be a ble t o 
verif y t he c o nc or da nce bet wee n t he data c o ntai ne d i n t he case re p ort f or ms a n d t h ose i n t he s o urce 
d oc u me nts . 
 
T hese d oc u me nts m ust be ke pt o n t he I n vesti gat or site u ntil at least fiftee n years. E ve n at t he e n d of t his 
peri o d, n o destr ucti o n ca n be ac hie ve d u nless a ut h orize d i n writi n g b y a d ul y ma n date d S p o ns or’s 
re prese ntati ve.  
If t he I n vesti gat or/I nstit uti o n is n o l o n ger a ble t o be res p o nsi ble f or esse ntial d oc u me nts t he S p o ns or m ust 
be n otifie d i n writi n g of t his c ha n ge a n d i nf or me d as t o w h o m t he res p o nsi bilit y has bee n tra nsferre d. 
 
1 3. 2.  C o nfi de nti alit y 
All i nf or mati o n o btai ne d d uri n g t he st u d y (e xce pt t he i nf or me d c o nse nt f or m data) will be i n p ut o nt o 
c o m p uter b y E U R O FI N S O P TI M E D, s u bc o ntracte d b y t he S p o ns or i n c o nf or mit y wit h t he “ I nf or mati o n 
T ec h n ol o g y a n d Li bert y La w” ( Article 4 0 of 6 Ja n uar y 1 9 7 8) w hic h res pects t he E ur o pea n Directi ve 
9 5/ 4 6/ C E. 
 
1 3. 3.  O w ners hi p of res ults  
T he S p o ns or is t he s ole o w ner of t h e data a n d researc h res ults. He reser ves t he ri g ht t o use t he m i n a n y 
f or m w hats oe ver, t o s u b mit t he m t o t he Healt h A ut h orities of a n y c o u ntr y. 

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S h o ul d t he st u d y ge nerate res ults li kel y t o be pate nte d, t he n o nl y t he S p o ns or will be a ut h orise d t o de p ose 
s uc h a pate nt, i n his na me a n d at his c osts. 
 
1 4.  F I N A N CI N G A N D I N S U R A N C E 
T he S p o ns or certifies t hat it has ta ke n o ut a lia bilit y i ns ura nce p olic y w hic h c o vers t he c urre nt researc h i n 
acc or da nce wit h l ocal la ws a n d re q uire me nts.  
A n i ns ura nce certificate will be pr o vi de d t o t he I n vesti gat or i n c o u ntries re q uiri n g t his d oc u me nt. 
 
1 5.  P U B LI C A TI O N 
All i nf or mati o n iss ui n g fr o m t he st u d y will be c o nsi dere d t o be c o nfi de ntial, a n d m ust n ot be di v ul ge d 
wit h o ut t he S p o ns or’s pri or a gree me nt.  
T he st u d y res ults ma y be p u blis he d or prese nte d b y t he I n vesti gat or or a nal ysis e x perts, i n c olla b orati o n 
wit h t he S p o ns or, wit h t he s p o ns or’s writte n per missi o n. T he S p o ns or ma y use t he st u d y res ults f or a n y 
p u blicati o n or c o m m u nicati o n, wit h t he writte n a gree me nt of t he I n vesti gat or or t h e a nal ysis e x perts if 
t he y are cite d. 
 
 
 
 
1 6.  LI S T O F A P P E N DI C E S 
 
A P P E N DI X I : D E C L A R A TI O N O F H E L SI N KI 
 

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A P P E N DI X I  
D E C L A R A TI O N O F H E L SI N KI  
 

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