Conditions: no Condition
Keywords: Healthy volunteers
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
Primary objective:

•To evaluate the tolerability and safety of ascending single doses of DF2755A in healthy adult male and female volunteers.

Secondary Objectives:

* To determine the pharmacokinetics parameters of DF2755A
* To establish a dose concentration-response relationship over a wide range of doses in order to select a narrower range of dose and dosing regimen to be subsequently studied in patients after single administration
* To evaluate the effect of ascending single doses on the pharmacodynamics parameters
* To compare metabolites pathway in Human with the one observed in animals

Please note that the study has been closed after Part A (single ascending doses), so all the objectives were revised accordingly.

Detailed description:
The study was a phase I, single center, double-blind, placebo controlled, randomized, ascending single doses study in healthy male and female volunteers.

The design consisted of a double blind comparison of the test compound versus placebo in which the dose is increased in successive treatment periods.

The escalating dose had the aim of achieving enough safety information on an interval of doses possibly encompassing both the effective dose and the maximum tolerated dose (defined as the highest dose devoid of any clinical signs/symptoms). Practically, of the two Parts planned - part A and Part B - only the Part A took place.

The Part A consisted of single doses of 50 mg oad, 150 mg oad, 450 mg oad or 700 mg oad of DF2755A tested in healthy male and female volunteers who were hospitalized approximately for 4 days (D-1 morning to D4 morning).

The planned Part B should have consisted of repeated doses of 100 mg bid, 200 mg bid or 300 mg bid of DF2755A) but it was not performed. Hence, the study was terminated at the end of Part A and, consequently, both the methodology and the endpoints were revised accordingly.

Arms:
arm 1: Placebo was administered once a day (oad) as matching oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. arm 2: The experimental drug was administered once a day (oad) as one oral capsule of 50 mg.

The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. arm 3: The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. arm 4: The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. arm 5: The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions.

Interventions: intervention 1: DF2755A intervention 2: Placebo
Intervention descriptions: intervention 1: DF2755A was planned to be administered in two different parts:

Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad).

Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) but not performed (repeated oral administration from Day 1 to Day 14). intervention 2: Single oral dose administration on D1

Protocol document:
Prot_000.pdf: 
 
 
 
 
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  
 










)
l o g(
)
2 5
.1
l o g(
1;
)
l o g(
)8
.0
l o g(
1
;
r
r
H
L
 
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  
 
Pr ot oc ol versi o n 6 . 0–  2 7/ M A R/ 2 0 1 8 
 
7 4  / 8 5  
 
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. 
 


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 5  / 8 5  
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. 


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 6  / 8 5  
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 
 


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 7  / 8 5  
 
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  
 


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  / 8 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 
 
7 9  / 8 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 
 
8 0  / 8 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 
 
8 1  / 8 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 
 
8 2  / 8 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 
 
8 3  / 8 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 
 
8 4  / 8 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 
 
8 5  / 8 5  
 
 
 

SAP_001.pdf: 
1.
Statistical Analysis Plan – Version 1.0 – April 05, 2019
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Temp-DMS-829 A 18/07/16 
STATISTICAL ANALYSIS PLAN
Protocol N° BPS0115 / OP099516.DOM – Part A 
Version 1.0 - Date: April 05, 2019 
An Ascending Dose Tolerability Study and Pharmacokinetic 
Assessment in Healthy Male and Female Volunteers after Single & 
Multiple Oral Administration of DF2755A 
SPONSOR 
DOMPÉ FARMACEUTICI S.P.A 
Via Santa Lucia 6  
20122 Milano 
ITALY 
AUTHOR 
Patrick BRUNET-LECOMTE 
EUROFINS OPTIMED Clinical Research 
1, rue des Essarts 
38610 Gières 
FRANCE
« This document is the property of the Sponsor and may not – in full or in part – be passed on, reproduced, 
published or used by authorities or other applicants for approval or registration purposes without the express 
permission of the Sponsor. » 
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Temp-DMS-829 A 18/07/16 
SIGNATURES 
Protocol N°: BPS0115 / OP099516.DOM 
Title: An Ascending Dose Tolerability Study and Pharmacokinetic Assessment in 
Healthy Male and Female Volunteers after Single & Multiple Oral Administration 
of DF2755A 
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TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................... 6 
STUDY DESIGN ......................................................................................................................... 6 
OBJECTIVES OF THE STUDY ...................................................................................................... 7 
CRITERIA FOR EVALUATION ..................................................................................................... 7 
STUDY SCHEDULE .................................................................................................................... 8 
2 
DEFINITION OF POPULATIONS AND STUDY TREATMENTS ........................................ 11 
2.1 
RANDOMIZATION ......................................................................................................... 11 
2.2 
JUSTIFICATION FOR NUMBER OF SUBJECTS ................................................................... 11 
2.3 
SCREENING, INCLUSION AND RANDOMIZATION NUMBERS ............................................ 11 
2.4 
ANALYSIS POPULATIONS .............................................................................................. 12 
2.5 
STUDY TREATMENT ...................................................................................................... 12 
3 
STATISTICAL ELEMENTS ....................................................................................................... 13 
3.1 
STATISTICAL METHODS ................................................................................................ 13 
3.2 
DESCRIPTIVE STATISTICS ............................................................................................. 13 
3.3 
STATISTICAL TESTS ...................................................................................................... 13 
4 
STATISTICAL ANALYSES ....................................................................................................... 17 
4.1 
SAMPLE SIZE OF ANALYSED SETS ................................................................................. 17 
4.2 
DEMOGRAPHIC CHARACTERISTICS ............................................................................... 17 
4.3 
PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSES ....................................... 20 
4.4 
SAFETY: ADVERSE EVENTS .......................................................................................... 22 
4.5 
SAFETY: LABORATORY CRITERIA ................................................................................. 24 
4.6 
SAFETY: VITAL SIGNS .................................................................................................. 27 
4.7 
SAFETY: PHYSICAL EXAMINATION ............................................................................... 29 
4.8 
SAFETY: ECG .............................................................................................................. 30 
4.9 
CONDUCT OF THE STUDY .............................................................................................. 31 
5 
INDIVIDUAL DATA ..................................................................................................................... 32 
6 
APPENDIX: Normal ranges for clinical criteria ................................................................. 39 
DOCUMENTATION HISTORY 
Version 
Effective date 
Reason for change 
Draft 1.1 
February 6, 2018 
Document creation by Eurofins Optimed 
Draft 1.2 
May 30, 2018 
Integration of Pharmacokineticc analysis by PhinC development 
Draft 2 
October 24, 2018 
Document sent to sponsor for reading 
Draft 3 
April 04, 2019 
Integration of sponsor comments 
Version 1.0 
April 05, 2019 
Final version 
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LIST OF ABBREVIATIONS 
General terms 
a.m.
Ante meridian 
EOS
End Of Study Visit 
ICH
International Conference on Harmonization 
IMP
Investigational Medicinal Product 
MAD
Multiple administration dose 
MedDRA
Medical Dictionary for Regulatory Activities 
NTEAE
Non-Treatment Emergent Adverse Event 
SAD
Single administration dose 
Safety & medical 
AE 
Adverse Event 
BP 
Blood pressure   
bpm 
beats per minute   
BW
Body Weight 
ECG 
Electrocardiogram   
HR 
Heart Rate   
IV 
Intravenous 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure   
TEAE 
Treatment Emergent Adverse Event 
Biologics 
ALT 
Alanine Leucine Transferase 
AST 
Alanine serine transferase   
CHC 
Chronic viral hepatitis C 
CPK 
Creatine phosphokinase 
GGT 
Gamma Glutamy1 Transferase   
HBs 
Hepatitis B surface antigen   
HCV 
Hepatitis C virus   
HIV 
Human Immunodeficiency Virus 
HIV1 
Human Immunodeficiency Virus type 1   
HIV2 
Human Immunodeficiency Virus type 2   
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
PNM 
Polimorphonuclear leukocytes 
ROS 
Reactive Oxygen Spieces 
WBC 
White Blood Cells   
Bioanalysis 
ALQ 
LOQ 
Above limit of quantification 
Limit of quantification 
ULOQ 
Upper limit of quantification 
Pharmacokinetics 
Ae,ur 
Amount excreted in urine 
Ae,f 
Amount excreted in feces 
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AUC 
Area under the plasma concentration-time curve 
AUC0-t 
Area under the plasma concentration-time curve from 
time zero to the final time point 
AUC0- 
Area under the plasma concentration-time curve from 
time zero to infinity 
AUC0-24 
Area under the plasma concentration-time curve from 
time zero to 24 hours post-dosing 
CL/F 
Apparent clearance  
CLR 
Renal clearance 
Cmax 
Maximum plasma concentration 
fe,ur 
Percentage of the dose excreted in the urine  
fe,f 
Percentage of the dose excreted in the feces  
PK 
Pharmacokinetic(s) 
t1/2 
Terminal half-life 
tlast 
Time of last measurable concentration 
tmax 
Time of maximum plasma concentration 
Vz/F 
Apparent volume of distribution 
z
Terminal phase rate constant 
Statistics 
CI 
Confidence Interval 
GM 
Geometric mean 
Min 
Minimum 
Max 
Maximum 
N 
Number 
PDS 
Pharmacodynamic set 
PKS 
Pharmacokinetic set 
RS 
Randomized set 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean  
SS 
Safety set 
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1 
INTRODUCTION 
In accordance with the main characteristics of the protocol, the Statistical Analysis Plan 
(SAP) details that the scheduled analyses are to be performed in order to evaluate the 
tolerability and safety of ascending single and repeated doses of  DF2755A in healthy adult 
male and female volunteers. 
Study design 
The study is a phase I, single center, double-blind, placebo controlled, randomized, 
ascending single and repeated doses study in healthy male and female volunteers. 
The design consists of a double blind comparison of the test compound versus placebo in 
which the dose is increased in successive treatment periods.  
The Multiple Ascending Dose (MAD) will be initiated only after the authorization, from ANSM 
of a substantial amendment that will be presented in order to notify the results of Single 
Ascending Dose (SAD) part of the study. Besides in order to decide to move forward from 
SAD to MAD, the pharmacokinetic data for all doses administered during SAD will be 
evaluated (i.e. plasma: quantitative determination of DF2755A bound and unbound; 
qualitative and preliminary quantitative determination of known metabolites; urine and 
faeces: qualitative and quantitative determination of parent compound and qualitative and 
preliminary quantitative investigation of known metabolites). 
Dose will be escalated in order to achieve enough safety information on an interval of doses 
possibly encompassing both the effective dose and the maximum tolerated dose (defined as 
the highest dose devoid of any clinical signs/symptoms).  
Part A: Single doses of 50 mg oad, 150 mg oad, 450 mg oad or 700 mg oad of DF2755A are 
planned to be tested in healthy male and female volunteers. 
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Objectives of the study 
Primary objectives 

To evaluate the tolerability and safety of ascending single and repeated doses of
DF2755A in healthy adult male and female volunteers.
Secondary objectives 

To determine the pharmacokinetics parameters of DF2755A.

To establish a dose concentration-response relationship over a wide range of doses
in order to select a narrower range of dose and dosing regimen to be subsequently
studied in patients after single and multiple administration.

To evaluate the effect of ascending single and repeated doses on the
pharmacodynamics parameters.

To compare metabolites pathway in Human with the one observed in animals.
Criteria for evaluation 
Primary evaluation criteria: 
AE, vital signs, 12-lead ECG, physical examination, laboratory exams. 
Secondary evaluation criteria: 
Pharmacokinetics: measurement of pharmacokinetics parameters: Cmax, tmax, λz, t1/2, AUC0-t, 
AUC0-∞, Vz/F, CL/F, Ae,ur, Ae,f, fe,f, fe,ur, CLR, parent:metabolite(s) ratio. 
Pharmacodynamics: measurement of leukocyte markers: CD11b, CD18 and reactive oxygen 
species (ROS). 
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Study schedule 
Table 1: STUDY FLOW CHART – PART A: from cohort 1 to cohort 4 
Visit/Period
Screening
Inclusion
End of study visit
Day
D-21 to D-2
D-1
D1
D2
D3
D4
Informed consent
X
Inclusion/Exclusion criteria1
X
X
Previous Medical / Surgical History
X
Prior/concomitant medications
X
X
X
X
X
X
Physical/Medical examinations
X
X
X
Body weight, height
X
X
X
Haematology
X
X
X
X
Hemostasis
X
X
X
X
Biochemistry
X
X
X
X
Urinalysis
X
X
X
X
Serology
X
Urine test for drug abuse
X
X
Alcohol breath test
X
X
Admission
X
Discharge
X
Randomization
X
Study Drug / Placebo Administration2
X
Vital signs : Blood pressure / Heart rate 
/ Oral body temperature
X
X
X
X
X
12-lead ECG recording3
X
X
X
X
X
X
Blood sample for Pharmacokinetics
X
X
X
X
Blood sample for Pharmacodynamic5
X
X
X6
X6
Urine collection
X
X
X
X
X
Faeces collection
X
X
X
X
X
AE collection4
Treatment period
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1Confirmation of the Inclusion/exclusion criteria prior to randomization number assignment;   
2Dose: Cohort 1, 2; 3 & 4;    Single dose in the morning; All subjects will be in fasting conditions from the evening before (at least 10 h, overnight); 
3Safety ECG;  
4All AEs will be reported 
5 Starting only from the second ascending dose; 
6 T48h or T72h: time will be determined after results of the first dose administered. 
When ECG, vital signs and PK are required at the same time, this specific order will be followed: vital signs first, then ECG and blood sample for PK at the end. 
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Table 2: DETAILED FLOW CHART – PART A
1 T48h or T72h: time will be determined after results of the first dose administered
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2 
 DEFINITION OF POPULATIONS AND STUDY TREATMENTS 
2.1 
Randomization 
The randomization list was prepared to permit that one of the two first subjects treated per 
each cohort, received a placebo. 
The treatments were allocated at D1 for both parts. 
2.2 
Justification for number of subjects 
No formal sample size calculation was made. The subjects treated with test product and the 
subjects treated with placebo are considered sufficient to detect drug effects and determine 
pharmacokinetic parameters before escalating to the next dose level. 
SAD cohorts: Thirty -two (32) healthy volunteers (HV) + 4 reserve subjects (total 36) will be 
enrolled to have 4 groups. Three groups of eight (8) male subjects and one group of 4 M +4 
F. 
MAD cohorts: MAD cohorts: Thirty -six (36) healthy volunteers (HV) + 4 reserve subjects 
(total 40) will be enrolled to have 3 groups. Two groups of twelve (12) male subjects and 
group of 6M+6 F. 
2.3 
Screening, inclusion and randomization numbers 
The screening number was S and 3 digits, for example: S003. It was a chronological number. 
The screening number was used throughout the screening period, until subjects are 
randomized. 
The inclusion number was composed of 7 digits, 3 for the number of centre (001) and 4 for 
the inclusion number: from 1001 to 1032 for part A. It will be a chronological number. 
The randomization number was the same as the inclusion number and the treatment number. 
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2.4 
Analysis populations 
The Randomized set (RS) will be defined as all randomized subjects. 
The Safety set (SS) will be defined as all included subjects having taken at least one dose of 
study drug. 
The pharmacokinetic set (PKS) will be defined as all the included subjects who have taken at 
least one dose of study drug without major protocol deviations affecting pharmacokinetics 
and with available data.  
The pharmacodynamic set (PDS) will be defined as all the included subjects who have taken 
at least one dose of study drug without major protocol deviations affecting 
pharmacodynamics and with available data. 
2.5 
Study treatment 
Name of the compound: 
DF2755A 
Pharmaceutical form:      
Capsules of 50 mg, and 200 mg 
Dose per administration: 
 Part A: 50 mg oad, 150 mg oad, 450 mg oad or 700 mg oad
Timing for administration: 
 Part A: Single oral dose administration on D1 according to the 
randomization. The administration will take place at around 8:00 
a.m with 200 ml of tap water, in sitting position, in fasting
conditions.
Name of the compound: 
Placebo 
Pharmaceutical form:      
Matching capsule 
Dose per administration: 
 NA 
Timing for administration: 
 Part A: Single oral dose administration on D1 according to the 
randomization. The administration will take place at around 8:00 
a.m with 200 ml of tap water, in sitting position, in fasting
conditions.
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3 
STATISTICAL ELEMENTS 
The statistical analysis performed by EUROFINS OPTIMED pertains to description at 
baseline, conduct of the study and safety analysis with statistical software SAS (version 9.4). 
The pharmacokinetic statistical analysis will be performed by PhinC Development. 
The Correlation analysis between pharmacokinetic and pharmacodynamic parameters will be 
performed by EUROFINS OPTIMED. 
Interim analysis: For each part of the study, an interim PK analysis on DF2577Y (the acid 
form of DF2755A) and its metabolites (if any) will be performed after completion of each dose 
level. This analysis will be done on anonymized data provided by the bioanalytical center to 
prevent any violation of the double blind condition of the study. 
Final PK analysis will be performed using final validated bioanalytical data and actual PK 
blood sampling times. 
For safety parameters (laboratory safety parameters, vital signs, ECG), in case of repeat 
assessments, the last assessment prior to the administration of the study treatment and the 
first assessment after the administration will be used for descriptive statistics. All 
assessments, including the repeat assessment will be included in the data listings and will be 
flagged accordingly. 
3.1 
Statistical methods 
The methodology presented in this statistical analysis plan takes into account methods 
planned in the protocol. 
3.2 
Descriptive statistics 
At least the following descriptive statistics will be reported: 

Continuous variables: Number of observations (N), mean, standard deviation (SD),
standard error of the mean (SEM) minimum (Min), median and maximum (Max).

Categorical variables: Frequency (n) and percentage (%).
3.3 
Statistical tests 
Safety analysis 
The safety analysis will be descriptive. 
Pharmacokinetic analysis 
In the first time, pharmacokinetic analysis will be performed for the single ascending dose 
part (part A). 
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
Descriptive statistics for drug concentrations:
For descriptive statistics, individual bound and unbound plasma concentrations of DF
2577Y and its related metabolites will be presented by dose level and nominal time
points, when applicable.
Descriptive statistics for the plasma concentrations will be presented as number of
available data (N), mean, standard deviation (SD) and will be calculated if at least 2/3
of the plasma values per time-point are above LOQ. For descriptive statistics
calculations, concentrations below LOQ will be set to zero (0) if they are reported
before the first quantifiable sample or considered as missing data if they are reported
after the first quantifiable data.
Individual measured plasma concentration vs. actual time curve will be produced in
graphic for each compound (parent and metabolites), for each subject, for each dose
level on both linear/linear and log/linear scales where applicable. Similarly, mean
plasma concentration vs. time curves will also be produced for each dose level.

Derivation of PK parameters and descriptive statistics for PK parameters:
For the calculation of the PK parameters from plasma concentrations of DF2755Y
and its metabolites (if any) using NCA approach the following rules will be applied:

All the plasma concentrations validated by the bioanalytical laboratory and
provided to the pharmacokineticist will be used for the PK analysis.

The actual blood sampling time points related to the preceding administration
will be used.

At time points in the lag-time between time zero and the first concentration
equal or above the limit of quantification (LOQ), concentrations below LOQ
will be set to zero (0). Concentrations below LOQ between 2 concentrations
equal or above LOQ will be considered as missing data. Trailing
concentrations below LOQ will not be used in calculations.

For plasma concentration above the upper limit of quantification (ULOQ) and
reported as above the limit of quantification (ALQ) in the final plasma
concentration tables, ALQ will be replaced by the first measurement for the
PK analysis.

Not reported concentration (NR) will be excluded from the PK analysis.

Pre-dose concentration is less than or equal to 5% of Cmax value in a PK
profile, the subject's data can be included in all PK measurements and
calculations without any adjustments. If the pre-dose value is greater than 5%
of Cmax, the subject will be dropped from all statistical evaluations (applicable
only at the predose on day 1).
The urinary PK parameters will be calculated from the urine concentrations, the 
volume of urine collected in each collection interval sample and the start and stop 
time of each interval. 
The fecal PK parameters will be calculated from the fecal concentrations, the weight 
of feces collected in each collection interval sample and the start and stop time of 
each interval. 
The following PK parameters of DF 2577Y bound and unbound (or related 
metabolites) will be derived from for each subject: 
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
Cmax The observed maximum plasma concentration of DF 2577Y (or
metabolites) measured in a subject after dosing identified by inspection of
the plasma drug concentration versus (vs.) time data.

tmax The time at which Cmax was apparent, identified by inspection of the
plasma drug concentration vs. time data.

λz The terminal plasma elimination rate-constant will be estimated from
log-linear regression analysis of the terminal phase of the plasma
concentration vs. time profile. For the slope of the terminal elimination
phase to be accepted as reliable, the following criteria will be imposed:
o
a coefficient r² ≥ 0.90,
o
a minimum of 3 data points, including the last measured data point
and excluding Cmax, are available for the regression.
If these 2 criteria could not be met, the slope of the terminal elimination 
phase will be considered as not calculable and all the parameters 
derived from this value (AUC0-, t1/2, …) will be reported as not
calculable (NC).  

t1/2 will be calculated according to the following equation: t1/2 = ln(2)/ λz.

AUC0-24 The area under the concentration vs. time curve from time zero
(pre-dose) to 24 h post-dose will be calculated using a linear trapezoidal
method.

AUC0-t The area under the concentration vs. time curve from time zero
(pre-dose) to the time of last quantifiable concentration will be calculated
using a linear trapezoidal method.

AUC0- The area under the serum drug concentration vs. time curve from
time zero to infinity: [AUC0-∞ = AUC0-t + (Ct/λz), where Ct = the observed
concentration of drug for the last sample on the PK profile in which drug
was detected, and λz as defined above. The percentage of extrapolation of
AUC0- should normally not exceed 20% to consider the value as reliable.

fu Fraction of unbound in plasma defined as the ration of the unbound
concentration over the total concentration

CL/F The apparent oral clearance will be estimated, for the parent drug
only, using the formula:
CL/F = Dose / AUC0-

Vz/F The apparent volume of distribution will be calculated for the parent
drug only, based on the terminal elimination phase, as follows
Vd/F=CL/F / λz 

Parent to metabolite ratios will be calculated for Cmax and AUC0-∞ as the
ratio of the metabolite (Cmax or AUC0-∞) over the parent drug (Cmax or AUC0-∞).

Ae,ur(t1-t2) Amount of DF 2577Y (or metabolites) excreted in urine over a
fraction of time t1 to time t2 from :
Ae = DF 2577Y (or metabolites) concentration × Urinary volume of the 
fraction 

Ae,ur(0-72) the cumulative amount excreted in urine from 0 to 72 h as the sum 
of all the amount excreted over each period of time 

fe,ur (t1-t2) Percentage of the dose excreted in the urine for DF2577Y only, 
between time t1 and time t2 as (Ae,ur(t1-t2)/dose)x100 

fe,ur (0-72) Total percentage of the dose excreted in the urine for DF 2577Y 
only, between 0 and 72 h as (Ae,ur(0-72)/dose)x100 

CLR Renal clearance determined as the ratio Ae0-72/AUC0-72 with t = 24 h
post-dose and tlast

Ae,f(t1-t2) Amount of DF 2577Y (or metabolites) excreted in feces over a
fraction of time t1 to time t2 from :
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Ae = DF 2577Y (or metabolites) concentration × feces weight 

Ae,f(0-72) the cumulative amount excreted in feces from 0 to 72 h as the sum 
of all the amount excreted over each period of time 

fe,f (t1-t2) Percentage of the dose excreted in the feces for DF 2577Y only, 
between time t1 and time t2 as (Ae,f(t1-t2)/dose)x100 

fe,f (0-72) Total percentage of the dose excreted in the feces for DF 2577Y 
only, between 0 and 72 h as (Ae,f(0-72)/dose)x100 
Individual derived PK parameters will be presented by dose level for each compound 
(parent and/or metabolites). Descriptive statistics of the PK parameters will be 
presented as N, mean, SD, standard error (SE), coefficient of variation (CV%), 
median, minimum (Min), maximum (Max) values, and geometric mean (GM). 
Derivation of PK parameters will be carried out using WinNonlin® Professional 
software (Version Phoenix 6.4 – Pharsight Corporation – Moutain View, California – 
USA) using the methodology described above. 

Dose proportionality assessment:
For DF 2577Y bound and unbound and related metabolites, the hypothesis that Cmax,
AUC0-∞ are dose proportional will be formally tested using a power model approach.
AUC and Cmax values, for all dose levels, will be analyzed for dose proportionality
using analysis of variance techniques.
Data will be fitted to the following model:
log(AUC or Cmax) =  + [β x log(Dose)]
This is usually referred to as a power model because after exponentiation:
AUC0-∞ or Cmax =  x Doseβ
Prior to the analysis, the assumption of a linear relationship between the log AUC0-∞
(Cmax) and log-dose will be tested using analysis of variance by partitioning the sums
of squares for treatments into those for linearity and departures from linearity. If the
departures from linearity are significant then the hypothesis of dose proportionality is
rejected and the power model analysis will not be performed.
In case, AUC0-∞ could not be considered as reliable in a majority of subjects (e.g. too
large percentage of extrapolation, poor quality of ke determination), dose
proportionality assessment will be performed on AUC0-t values.
The estimate obtained for β is a measure of dose proportionality. The estimate of β
together with its 90% confidence interval (CI) (βl, βu) will be presented to quantify the
degree of non-proportionality.
The dose proportionality will be confirmed if the 90% CI of β (βl, βu) is contained
completely within the following critical region:
where r, defined as the dose ratio, is equal to h/l, h being the highest dose and l the 
lowest dose. 
Assessment of the dose proportionality will be performed on the complete dose 
range. In case of departures from linearity or of negative conclusion of dose 
proportionality on the complete dose, further investigation using the same 
methodology might be done on a restrained dose range. 
For each day of PK assessment, the individual AUC and Cmax values will be 
presented graphically by dose level. The mean AUC and Cmax values along with the 
SD will also be displayed graphically by dose level. 
The statistical package SAS® v.9.4 will be used to perform all statistical analyses. 
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4 
STATISTICAL ANALYSES 
4.1 
Sample size of analysed sets 
The objective of analysis presented below is to describe analysis populations. 
Criteria 
Number of subjects in the Randomized Set (RS) 
Number of subjects in the Safety Set (SS) 
Reasons of exclusion from SS 
Number of subjects in the pharmacokinetic set (PKS) 
Reasons of exclusion from the PKS 
Number of subjects in the pharmacodynamics set (PDS) 
Reasons of exclusion from PDS 
Statistical method 
Descriptive statistics by dose group and overall. 
Title of table 
Sample size of analysed sets by dose group and overall. 
4.2 
Demographic characteristics 
The objective of analysis presented below is to describe the demographic and baseline 
characteristics. 
Demography 
Criteria 
Age (years) 
Gender (Male/Female) 
 If Female, is she infertile or in post-menopause 
 for at least 2 years? (yes/no) 
Weight (kg) 
Height (cm) 
BMI (kg/m²) 
Populations 
RS and PKS/PDS/SS Sets (in case different from the RS). 
Statistical method 
Descriptive statistics. 
Title of table 
Demographic characteristics by dose group and overall. 
Medical and surgical history 
Criteria 
System Organ Class (SOC), MedDRA dictionary 
Preferred Term (PT), MedDRA dictionary 
Information 
All history events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. 
Populations 
RS. 
Statistical method 
Descriptive statistics as subject count by SOC and PT. 
Listing of medical history events by dose group and subject. 
Title of table 
Number and percentage of medical and surgical history events 
by SOC and PT by dose group and overall. 
Listing of medical and surgical history by dose group and 
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subject. 
Previous medications 
Criteria 
ATC term, Who Drug dictionary 
preferred name term, Who Drug dictionary 
Populations 
RS. 
Statistical method 
Descriptive statistics. 
A listing will be performed by subject. 
Title of table 
Number and percentage of previous medications by ATC term 
and preferred name term by dose group and overall. 
Listing of previous medications by dose group and subject. 
Physical examination at screening and D-1 
Criteria 
For each examination: assessment (normal/abnormal) and 
clinically significant (yes/no) 
At screening 
Skin and mucous 
Ear/nose/throat 
Pulmonary 
Cardiac 
Gastro-intestinal 
Neurological 
At D-1 
Overall examination 
Information 
Result and clinically significant will be summarised in one 3-
class criterion (normal/abnormal NCS/abnormal CS). 
Populations 
RS. 
Statistical method 
Descriptive statistics. 
If relevant, listing of abnormal findings by subject. 
Title of table 
Physical examination at screening and D-1 by dose group and 
overall. 
If relevant, Listing of abnormal findings by dose group and 
subject. 
Urine drug screen 
Criteria 
Results (negative/positive/not done) 
information 
Urine drug screen criteria are assessed at screening and at D-1. 
Results concern: 
Cannabinoids, 
amphetamines, cocaine, 
benzodiazepines, opiates and cotinine. 
Populations 
RS. 
Statistical method 
Descriptive statistics. 
Title of table 
Urine drug screen at screening and at D-1 by dose group and 
overall. 
Alcohol breath test 
Criterion 
Result (negative/positive) 
Information 
Alcohol breath test performed at screening and at D-1. 
Populations 
RS. 
Statistical method 
Descriptive statistics. 
Title of table 
Alcohol breath test at screening and at D-1 by dose group and 
overall. 
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Serology 
Criteria 
HIV1 and 2 antibodies (negative/positive/not done) 
HCV antibodies (negative/positive/not done) 
HBs antigen (negative/positive/not done) 
Information 
Serology criteria are assessed at screening. 
Populations 
RS. 
Statistical method 
Descriptive statistics. 
Title of table 
Serology at screening by dose group and overall. 
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4.3 
Pharmacokinetics and pharmacodynamics analyses 
Criteria 
Cmax (ng/mL);  
tmax (h);  
λZ;  
t1/2(h):;  
AUC0-24 (h×ng/mL);  
AUC0-t (h×ng/mL);  
AUC0-∞ (h×ng/mL);  
fu  
VZ/F (DF2577Y only);  
CL/F (DF2577Y only);  
Ae,ur ; fe,ur 
Ae,f ; fe,f 
CLR;  
Parent:metabolite(s) ratio for Cmax and AUCs. 
Information 
Interim analyses will be performed after completion of each 
dose level, using anonymized data provided by the 
bioanalytical center 
Final PK analysis will be performed using validated 
bioanalytical data and actual PK blood sampling times of the 
part A of the study 
Population 
PKS 
Statistical method 
Descriptive statistics of concentrations and PK parameters 
Dose proportionality analysis using power model (section 
3.3) 
Title of tables 
List of concentrations 
Descriptive statistics of concentrations 
List of PK parameters 
Descriptive statistics of PK parameters 
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Pharmacodynamic analysis: correlation between Cmax and pharmacodynamics criteria 
Criteria 
Pharmacokinetic criterion 
DF2577Y  Cmax (ng/mL) 
Pharmacodynamic criteria 
Leukocyte markers: CD11b, CD18 
Information 
DF2577Y concentration assessed at D1 (pre-dose, T30min, 
T1h, T2h, T3h, T4h, T5h, T6h, T7h, T8h, T9h, T10h, T11, 
T12h, T16h), D2 (T24h, T36h, T40h), D3 (T48h, T60h) and 
D4 (T72h). 
Leukocytes markers not assessed for first cohort. 
Leukocytes markers assessed at D1 (Tcmax, Tcmax+3h, 
T12h), D2 (T24h), D3 (T48h) or D4 (T72h) (time determined 
after the results of the first dose administered). 
Population 
PKS 
Statistical method 
Time matched: D1 (Tcmax, Tcmax+3h, T12h), D2 (T24h), 
D3 (T48h) or D4 (T72h). 
The relationship between values of pharmacodynamic 
parameters time matched with DF2577Y (bound and 
unbound) plasma concentrations will be first evaluated by 
visual inspection of graphs relating pharmacodynamic 
parameters with DF2577Y (bound and unbound) plasma 
concentrations.  
In case of reliable relationships, basic models, such as 
Emax model, will be first developed. Then, the selected 
models will be optimized by testing covariate such as BMI, 
age, etc.  
Further model development might be done depending on 
the results of each modelling. 
Title of tables 
Cmax concentration vs CD11b for each time matched. 
Cmax concentration vs CD18 for each time matched. 
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4.4 
Safety: Adverse events 
The objective of analysis presented below is to evaluate the safety of study drugs through 
adverse events reported during the study. 
Criteria 
AE number 
Description 
SOC term MedDRA) 
PT term MedDRA) 
Start date and time 
Time since last study drug administration 
End date and time 
AE Duration 
Severity (mild/moderate/severe) 
Serious (yes/no) 
Expected (yes/no) 
Congenital anomaly or birth defect (yes/no) 
Significant disability (yes/no) 
Death (yes/no) 
Life threatening (yes/no) 
Other medically important event (yes/no) 
Hospitalization (yes/no) and if yes, date of hospitalization 
Relationship to study treatment (none / unlikely /possible / 
probable / highly probable / not assessable) 
Outcome (recovered-resolved / recovering-resolving / 
recovered-resolved with sequelae / not recovered-not 
resolved / fatal /unknown) 
Action taken with study product (dose increased / dose not 
changed / dose reduced / dose interrupted / drug withdrawn 
/ not applicable / unknown) 
Other actions (yes/no) and if yes specify 
Concomitant medication recorded (yes/no) 
Information 
AEs will be coded according to the Medical Dictionary for 
Regulatory Activity (MedDRA). They will be classified into 
pre-defined standard categories according to chronological 
criteria: 
-
Treatment emergent AEs (TEAE): AEs that occurs for
the first time or if present before worsened during an
exposure to drug(s).
-
Non-treatment emergent AEs (NTEAE): AEs that
occurs before the study drug administration.
An AE occurring during the run-out will be related to the last 
day of treatment administration received. 
AEs will be individually listed per dose group, subject 
number, presenting: assigned dose group, verbatim, Primary 
System Organ Class (SOC), Lowest Level Term (LLT), 
Preferred Term (PT), emergence (yes or no) date and time of 
onset, date and time of last study drug administration before 
AE, duration, time from onset since last study drug 
administration, intensity and seriousness, relationship to 
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study drug, the required action taken and outcome. 
The non-treatment emergent AEs will be summarised by 
SOC and PT for the safety set. 
The treatment emergent AEs will be summarised by SOC, 
PT and dose group for the safety set. It will consist in the 
evaluation of the number of AEs and the number of subjects 
reporting these AEs.
Population 
SS. 
Statistical method 
For each part: 
The TEAEs will be summarized by dose group and overall. 
The analysis will include the evaluation of the number of 
adverse events, the number of subjects reporting these 
adverse events and the % of subjects within the dose group. 
In case of few adverse events (≤ 5), only a listing will be 
prepared by dose group and subject. 
TEAEs will be individually listed per dose group, subject, 
emergence, day, SOC, LLT, PT, date and time of onset and 
offset, time since last product administration, duration, 
intensity and seriousness, relationship to study product, 
action taken and outcome. 
NTEAEs will be summarised by dose group and subject. 
Serious adverse events (SAEs) will be summarised by dose 
group and subject. 
Title of tables 
For each part: 
Treatment emergent AEs - SS - By dose group.  
Listing of treatment emergent AEs - SS - By dose group, 
subject, SOC, LLT and PT. 
NTAEs - By dose group. 
Listing of NTAEs by dose group, subject, SOC, LLT and PT. 
- SS.
SAEs - By dose group. 
Listing of SAEs by dose group, subject, SOC, LLT and PT - 
SS. 
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4.5 
Safety: Laboratory criteria 
The objective of analysis presented below is to evaluate the safety laboratory variables. 
Biochemistry, hematology and hemostasis criteria 
Criteria 
Biochemistry 
Creatinine (µmol/L) 
Glucose (mmol/L) 
Total protein (g/L) 
Urea (mmol/L) 
Albumin (g/L) 
Globulin (albumin/globulin ratio) 
Total cholesterol (mmol/L) 
Triglycerides (mmol/L) 
Sodium (mmol/L) 
Potassium (mmol/L) 
Chloride (mmol/L) 
Calcium (mmol/L) 
Uric acid (IU/L) 
AST (IU/L) 
ALT (IU/L) 
GGT (IU/L) 
Alkaline phosphatase (IU/L) 
CPK (IU/L) 
Total bilirubin (µmol/L) 
Conjugated bilirubin (µmol/L) 
LDH (IUl/L) 
LDL (mmol/L) 
HDL (mmol/L) 
Phosphore (mmol/L) 
Hematology 
Hemoglobin (g/L) 
Hematocrit (no unit) 
Red blood cells (Tera/L) 
White blood cells (Giga/L) 
Neutrophils (Giga/L) 
Eosinophils (Giga/L) 
Basophils (Giga/L) 
Lymphocytes (Giga/L) 
Monocytes (Giga/L) 
Platelets (Giga/L) 
Reticulocytes (Giga/L) 
MCV (fL) 
MCH (fmol) 
MCHC (mmol/L) 
Hemostasis 
aPTT subject (s) 
aPTT ratio 
Prothrombin time (s) 
Prothrombin level 
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Information 
Part A: criteria assessed at screening, D-1, D2 and at end of 
study visit (D4.). 
Part A, baseline: last assessed value at D-1. 
Emergent value is defined as any normal value at pre-dose 
assessment (baseline value) according to laboratory range 
becoming abnormal at post-dose assessment or lower 
(upper) abnormal baseline value becoming upper (lower) 
abnormal at post-dose assessment. 
Laboratory ranges are reported in database. 
Population 
SS. 
Statistical method 
For each criterion 
Values, position according to laboratory range and clinical 
assessment will be described at screening, baseline, each 
scheduled assessment during treatment phase and at end of 
study visit overall. 
Change between the values from baseline to each scheduled 
assessment during treatment phase and end of study visit 
will be described by dose group and overall. 
Listing of emergent values according to laboratory range 
from Baseline to each scheduled assessment during 
treatment phase and end of study visit by dose group and 
subject. 
Title of tables 
For each criterion 
Name of criterion (unit): 
Values, position according to laboratory range and clinical 
assessment at screening, baseline, during treatment phase 
and at end of study visit. 
Change between the values from baseline to during 
treatment phase and to end of study visit.  
Listing of emergent values from baseline to during treatment 
phase and to end of study visit by dose group and subject. 
Urinalysis and microscopic criteria 
Criteria 
Urine appearance (clear/slightly cloudy/cloudy/opaque) 
Urine color (pale yellow/dark yellow/brown/red) 
For 
each 
criterion, 
result 
and 
clinical 
assessment 
(normal/abnormal NCS/abnormal CS) 
Urinalysis 
pH 
Ketone bodies (negative/positive) 
Protein (negative/positive) 
Glucose (negative/positive) 
Blood (negative/positive) 
Leucocytes (negative/positive) 
Nitrite (negative/positive) 
Urobilinogen bodies (negative/positive) 
Bilirubin bodies (negative/positive) 
Nitrite (negative/positive) 
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Specific density 
Microscopic analysis 
Red blood cells 
Crystallography 
Flat cells 
Round cells 
Cylinders 
Mucus 
Bacteria 
Information 
Part A: criteria assessed at screening, D-1, D2 and at end of 
study visit (D4). 
Part A: baseline: last assessed value at D-1. 
Emergent value is defined as any normal value at pre-dose 
assessment (baseline value) according to laboratory range 
becoming abnormal at post-dose assessment or lower 
(upper) abnormal baseline value becoming upper (lower) 
abnormal at post-dose assessment. 
Laboratory ranges are reported in database. 
Population 
SS. 
Statistical method 
pH and specific density: same method as for biology criteria. 
For each qualitative criterion 
Result will be described at screening, baseline, each 
scheduled assessment during treatment phase and at end of 
study visit. 
Listing of emergent values from baseline to each scheduled 
assessment during treatment phase and to end of study visit 
by dose group and subject. 
Microscopic criteria 
Listing of microscopic criteria by subject and visit. 
Title of table 
pH and specific density: same tables as for biology criteria. 
For each qualitative criterion: 
Name of criterion: 
Result at screening, baseline, during treatment phase and at 
end of study visit by dose group and overall. 
Listing of emergent values from baseline to during treatment 
phase and to end of study visit by dose group and subject. 
Microscopic criteria 
Listing of microscopic criteria by dose group, subject and 
visit. 
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4.6 
Safety: Vital signs 
The objective of analysis presented below is to evaluate the safety of study drugs through 
vital signs criteria. 
Blood pressure, heart rate and oral body temperature 
Criteria 
Supine systolic blood pressure (mmHg) 
Supine diastolic blood pressure (mmHg) 
Supine heart rate (bpm) 
Standing systolic blood pressure (mmHg) 
Standing diastolic blood pressure (mmHg) 
Standing heart rate (bpm) 
Oral temperature (°C) 
Result (normal/abnormal) 
Clinically significant (yes/no) 
Abnormal Finding/Relevant comments 
Orthostatic hypotension (yes/no) 
Information 
Criteria assessed at screening, D-1, D1 (pre-dose, T1h, 
T3h, T5h, T8h, T12h), D2 (T24h) and at end of study visit 
(D4) 
Part A:, baseline: last assessed value at D1 pre-dose. 
Emergent value is defined as any normal value at pre-dose 
assessment (baseline value) according to normal range 
becoming abnormal at post-dose assessment or lower 
(upper) abnormal baseline value becoming upper (lower) 
abnormal at post-dose assessment. 
Normal ranges values are reported in appendix. 
Result and clinically significant will be summarised in one 3-
class criterion (normal/abnormal NCS/abnormal CS). 
Systolic orthostatic hypotension: when (supine-standing) 
SBP ≥20 mmHg.
Diastolic orthostatic hypotension: when (supine-standing) 
DBP ≥20 mmHg.
Population 
SS. 
Statistical method 
For each criterion 
Values, position according to normal ranges values will be 
described at screening, D-1, baseline, each scheduled 
assessment during treatment phase and at end of study visit 
overall. 
Change between the values from baseline to each scheduled 
assessment during treatment phase and end of study visit 
will be described by dose group and overall. 
Listing of emergent values according to normal ranges 
values from baseline to each scheduled assessment during 
treatment phase and end of study visit by dose group and 
subject. 
Orthostatic hypotension reported will be listed by dose group, 
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subject and day(time)-point. 
Title of tables 
For each criterion 
Name of criterion (unit): 
Values, position according to normal ranges values at 
screening, D-1, baseline, during treatment phase and at end 
of study visit and change from baseline.  
Listing of emergent values from baseline to end of study visit 
by dose group and subject. 
Vitals: Result and clinical significance at each day(time) point 
assessment from screening to end of study. 
Orthostatic hypotension: Listing by dose group, subject and 
daytime-point. 
Weight 
Criteria 
Weight (kg) 
Information 
Criteria assessed at D-1 and at end of study visit (D4) 
Baseline: last assessed value at D-1. 
Population 
SS 
Statistical method 
Value at baseline and at end of study visit and change from 
baseline by dose group and overall. 
Title of tables 
Weight (kg): Value at baseline and at end of study visit and 
change from  baseline by dose group and overall. 
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4.7 
Safety: Physical examination 
The objective of analysis presented below is to evaluate the safety of study drugs through 
physical examination. 
Physical examination 
Criteria 
Result (normal/abnormal)  
Clinically significant (yes/no) 
Abnormal findings 
Population 
SS. 
Information 
Physical examination is assessed at end of study visit (D4). 
Statistical method 
Physical examination: listing of abnormal findings by 
subject. 
Title of table 
Physical examination: Listing of abnormal findings at end of 
study visit – By dose group and subject. 
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4.8 
Safety: ECG 
The objective of analysis presented below is to evaluate the safety of study drugs through 
ECG criteria. 
Criterion 
Heart rate (bpm) 
PR (ms) 
QRS (ms) 
QT (ms) 
QTc Fridericia (ms) 
Result (normal/abnormal) 
Comment 
Clinically significant (yes/no) 
Information 
Part A: criteria assessed at screening, D-1, D1 (pre-dose, 
T1h, T2h, T3h, T4, T6h, T8h, T12h), D2 (T24h), D3 (T48h) 
and at end of study visit (D4). 
Baseline: last assessed value at D1 pre-dose. 
Emergent value is defined as any normal value at pre-dose 
assessment (baseline value) according to normal range 
becoming abnormal at post-dose assessment or lower 
(upper) abnormal baseline value becoming upper (lower) 
abnormal at post-dose assessment. 
Normal ranges values are reported in appendix. 
Result and clinically significant will be summarised in one 3-
class criterion (normal/abnormal NCS/abnormal CS). 
Population 
SS. 
Statistical method 
For each criterion 
Values, position according to normal ranges values will be 
described at screening, D-1, baseline, each scheduled 
assessment during treatment phase and at end of study visit 
overall. 
Change between the values from baseline to each scheduled 
assessment during treatment phase and end of study visit 
will be described by dose group and overall. 
Listing of emergent values according to normal ranges 
values from Baseline to each scheduled assessment during 
treatment phase and end of study visit by dose group and 
subject. 
Title of tables 
For each criterion 
Name of criterion (unit): 
Values, position according to normal ranges values at 
screening, D-1, baseline, during treatment phase and at end 
of study visit and change from baseline.  
Listing of emergent values from baseline to end of study visit 
by dose group and subject. 
ECG: Result and clinical significance at each day(time) point 
assessment from screening to end of study. 
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4.9 
Conduct of the study 
The objective of analysis presented below is to describe the parameters of the conduct of 
study. 
Duration of the study 
Criterion 
Duration of the study (days) 
Definition 
End of the study date – screening date + 1 
Populations 
RS and PKS/PDS/SS Sets (in case different from the RS). 
Statistical method 
Descriptive statistics - By dose group and overall 
Title of table 
Duration of the study (days) – By dose group and overall. 
Study normally completed 
Criteria 
Subject successfully completed the study (yes/no) 
If no: 
 Reason for the withdrawal (lost to follow-up/adverse 
clinical 
 experience/adverse laboratory experience/deviation 
 from protocol/consent withdrawal/other) 
Information 
If necessary, reason of withdrawal will be listed by dose group 
and subject. 
Population 
RS. 
Statistical method 
Descriptive statistics by dose group and overall 
Title of table 
Subject who successfully completed the study – By dose group 
and overall. 
Concomitant medications 
Criteria 
ATC term, Who Drug dictionary 
preferred name term, Who Drug dictionary 
Population 
RS. 
Statistical method 
The concomitant treatments started after the first treatment 
administration will be summarized by ATC term and preferred 
name term and by dose group and overall.  
The analysis consists in the evaluation of the number of 
concomitant treatments, in the number of subjects reporting 
these concomitant treatments and the % of subjects within the 
dose group. 
Concomitant treatments started after the first treatment 
administration will be listed by dose group and subject. 
If relevant, concomitant treatments started before the first 
treatment administration will be listed by dose group and 
subject. 
Title of table 
Concomitant treatments started after the first treatment 
administration by ATC term and preferred name term – By dose 
group and overall. 
Listing of concomitant treatments started after the first treatment 
administration by dose group and subject. 
Listing of concomitant treatments started before the first 
treatment administration by dose group and subject. 
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5 
INDIVIDUAL DATA 
Individual data listings, included unscheduled evaluations, will be presented by dose group, 
subject, visit and time, if relevant, for following criteria: 

Discontinued subjects
Completion/discontinuation date 
Status (completed / adverse event / lost to follow-up / withdrawal by subject / physician 
decision / death / protocol violation / study terminated by sponsor /other) and if other, specify 

Eligibility of subject
Are all the inclusion criteria answered Yes (yes/no) and if no: number of criteria and 
comment 
Are all the exclusion criteria answered No (yes/no) and if no: number of criteria and comment 
Is the subject eligible to participate in the study? (yes/no) 
Date of confirmation of eligibility 

Visit dates
Date of visit 
Date of randomization 

Analysed populations
Subject in Randomized Set (yes/no)  
Subject in Safety Set (yes/no) 
Subject in Pharmacokinetic Set (yes/no)  
Subject in Pharmacodynamic Set (yes/no) 

Informed consent and demography
Date of consent 
Date of birth  
Age (years),  
Gender (Male/Female) 
If Female, is she infertile or in post-menopause for at least 2 years? (yes/no) 
Weight (kg)  
Height (cm) 
BMI (kg/m²) 

General medical and surgical history
Medical/surgical history (yes/no) and if yes: 
Start date, nature  
MedDRA codes  
Ongoing (yes/no) 
Start date 
End date 

Previous medication
Medication number 
Medication  
Dose  
Unit 
Route 
Indication  
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Frequency  
Start date 
End date 
ATC term (Who-drug dictionary) 
Preferred name term (Who-drug dictionary) 

Physical examination at screening
For each examination: assessment (normal/abnormal), clinically significant (yes/no) and 
abnormal findings 
At screening 
Skin and mucous 
Ear/nose/throat 
Pulmonary 
Cardiac 
Gastro-intestinal 
Neurological 
At D-1 
Overall examination 

Serology
Sample number for: 
HIV1 and 2 antibodies (negative/positive/not done) 
HCV antibody (negative/positive/not done) 
HBs antigen (negative/positive/not done) 

Urine drug screen
Sample number 
Date and time 
Result (negative/positive/not done) 

Alcohol breath test
Date and time of test 
Result (negative/positive/not done) 

Concomitant medications
Medication number  
Medication  
Dose  
Unit 
Route 
Indication  
Frequency  
Start date 
End date 
On-going (yes/no) 
ATC term (Who-drug dictionary) 
Preferred name term (Who-drug dictionary) 

Study drug administration
Date and time of drug administration 
Administered dose (mg) 
Administration performed according to the protocol (yes/no) and if no, comment 

Pharmacokinetics blood sampling
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Scheduled time 
Actual date/time 
Sample collected (yes/no) 
Before meal (yes/no/unknown) 
Fasting state (yes/no/unknown) 

Pharmacokinetic concentration and criteria
Sample number 
Concentration 
Comment (Sample not received/analytical problem (yes/no) 
Cmax (ng/mL);  
tmax (h);  
λZ;  
t1/2(h):;  
AUC0-24 (h×ng/mL);  
AUC0-t (h×ng/mL);  
AUC0-∞ (h×ng/mL);  
fu  
VZ/F (DF2577Y only);  
CL/F (DF2577Y only);  
Ae,ur ; fe,ur 
Ae,f ; fe,f 
CLR;  
Parent:metabolite(s) ratio for Cmax and AUCs. 

Pharmacodynamic blood sampling
Scheduled time 
Actual date/time 
Sample collected (yes/no) 
Fasting state (yes/no/unknown) 

Pharmacodynamic criteria
CXCL1 (Gro alfa) 
CXCL2 (Gro beta) (Biorad) 
CXCL5 (ENA-78) 
CXCL6 (GCP-2) 
CXCL8 (IL-8) 

Urine sample
Sample collected (yes/no) 
Time interval 
Start date and time 
End date and time 
Urine volume collected (mL) 
Comment 

Faeces sample
Sample collected (yes/no) 
Time interval 
Start date and time 
End date and time 
Faeces weight (mg) 
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Comment 

Adverse events
AE number 
Description 
SOC term MedDRA) 
PT term MedDRA) 
LLT term MedDRA) 
HLT term MedDRA) 
HLGT term MedDRA) 
Start date and time 
Time since last study drug administration 
End date and time 
AE Duration 
Severity (mild/moderate/severe) 
Serious (yes/no) 
Expected (yes/no) 
Congenital anomaly or birth defect (yes/no) 
Significant disability (yes/no) 
Death (yes/no) 
Life threatening (yes/no) 
Other medically important event (yes/no) 
Hospitalization (yes/no) and if yes, date of hospitalization 
Relationship to study treatment (none / unlikely /possible / probable / highly probable / not 
assessable) 
Outcome (recovered-resolved / recovering-resolving / recovered-resolved with sequelae / not 
recovered-not resolved / fatal /unknown) 
Action taken with study product (dose increased / dose not changed / dose reduced / dose 
interrupted / drug withdrawn / not applicable / unknown) 
Other actions (yes/no) and if yes specify 
Concomitant medication recorded (yes/no) 

Biochemistry
Date and time of assessment 
Fasting state (yes/no/unknown) 
Value, laboratory range and clinical at each assessment, change and emergent value 
(yes/no) according to laboratory ranges from baseline for: 
Creatinine (µmol/L) 
Glucose (mmol/L) 
Total protein (g/L) 
Urea (mmol/L) 
Albumin (g/L) 
Globulin (albumin/globulin ratio) 
Total cholesterol (mmol/L) 
Triglycerides (mmol/L) 
Sodium (mmol/L) 
Potassium (mmol/L) 
Chloride (mmol/L) 
Calcium (mmol/L) 
Uric acid (IU/L) 
AST (IU/L) 
ALT (IU/L) 
GGT (IU/L) 
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Alkaline phosphatase (IU/L) 
CPK (IU/L) 
Total bilirubin (µmol/L) 
Conjugated bilirubin (µmol/L) 
LDH (IUl/L) 
LDL (mmol/L) 
HDL (mmol/L) 
Phosphore (mmol/L) 
Comments  

Hematology
Date and time of assessment 
Value, laboratory range and clinical at each assessment, change and emergent value 
(yes/no) according to laboratory ranges from baseline for:  
Hemoglobin (g/L) 
Hematocrit (no unit) 
Red blood cells (Tera/L) 
White blood cells (Giga/L) 
Neutrophils (Giga/L) 
Eosinophils (Giga/L) 
Basophils (Giga/L) 
Lymphocytes (Giga/L) 
Monocytes (Giga/L) 
Platelets (Giga/L) 
Reticulocytes (Giga/L) 
MCV (fL) 
MCH (fmol) 
MCHC (mmol/L) 
Comments 

Hemostasis
aPTT subject (s) 
aPTT ratio 
Prothrombin time (s) 
Prothrombin level 
Comments  

Urinalysis
Date and time of assessment 
Urine appearance (clear/slightly cloudy/cloudy/opaque) 
Urine color (pale yellow/dark yellow/brown/red) 
Result, laboratory range (if relevant) and clinical at each assessment and emergent value 
(yes/no) according to laboratory ranges from baseline (or baseline values for qualitative 
criteria) for: 
Urinalysis 
pH 
Ketone bodies (negative/positive) 
Protein (negative/positive) 
Glucose (negative/positive) 
Blood (negative/positive) 
Leucocytes (negative/positive) 
Nitrite (negative/positive) 
Urobilinogen bodies (negative/positive) 
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Bilirubin bodies (negative/positive) 
Nitrite (negative/positive) 
Specific density 
Microscopic analysis 
Red blood cells 
Crystallography  
Flat cells 
Round cells 
Cylinders 
Mucus 
Bacteria  

Vitals
Scheduled time 
Position (supine/standing)  
Actual time position 
Actual time measurement 
Supine systolic blood pressure value (mmHg)  
Supine diastolic blood pressure value (mmHg) 
Supine heart rate value (bpm)  
Oral temperature (°C) 
Weight (kg) 
Result (normal/abnormal) 
Clinically significant (yes/no) 
Comment  

Physical examination at end of study visit
Results (normal/abnormal) and if relevant 
Clinically significant (yes/no) 
Abnormal physical finding 
ECG
Scheduled time 
Time performed 
Heart rate (bpm)  
PR (ms) 
QRS (ms) 
QT (ms) 
QTc Fridericia (ms) 
Result (normal/abnormal) 
Clinically significant (yes/no) 
Comment 
Duration of study
Duration of study (days) 
Study restrictions
Did the subject respect the study restrictions throughout the course of the study? (yes/no) 
and if no, specify 
Study comments
Comments 
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6 
APPENDIX: Normal ranges for clinical criteria 
Criterion 
Unit 
Normal ranges 
Vital signs 
Oral body 
temperature 
°C 
[36.3 – 37.5[ 
Supine SBP 
mmHg 
[90 – 140] for ≤ 45
years 
[90 – 150] for > 45 
years 
Supine DBP 
mmHg 
[50 – 90] 
Supine HR 
bpm 
[40 – 100] 
Electrocardiogram 
PR 
ms 
[120 – 210[ 
QRS 
ms 
[0 – 120[ 
QTc Fridericia 
ms 
[0 – 430] for male and 
[0 – 450] for female  
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Temp-DMS-832 - B 07/08/2017 
16.1.10 Documentation of inter-laboratory standardisation methods and quality 
assurance procedures 
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Temp-DMS-832 - B 07/08/2017 
16.1.11 Publications based on the study 
Not applicable. 
16.1.12 Important publications referenced in the report 
Not applicable. 
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