Clinical trial NCT04956666
Conditions: Acute Lymphoblastic Leukemia
Keywords: Acute Lymphoblastic Leukemia Phase II Oncology / Haematology Continued treatment Pegaspargase Lyophilized pegaspargase Roll-over study / extension study
Sponsor: Institut de Recherches Internationales Servier
Start date: 2021-06-15; Completion date: 2023-01-23
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to provide treatment with lyophilized S95014 in pediatric patients with ALL who completed the CL2-95014-002 study during the induction phase and who are clinically benefitting from S95014 without major toxicity.

Detailed description:

Arms: arm 1: Lyophilized S95014 reconstituted was provided 5 mL of extractable volume with the concentration of 750 U/mL.

The vial of lyophilized powder (3.750 U/vial) was reconstituted with 5.2 mL of Sterile Water For Injection to obtain a 750 U/mL solution for single use.
Interventions: intervention 1: Lyophilized S95014
Intervention descriptions: intervention 1: Each patient was administrated, over 1 to 2 hours, every 2 weeks Lyophilized S95014 intravenously at the dose of 1000, 2000 or 2500U/m2, as per investigator's judgement.

In total, 9 infusions of lyophilized S95014 were administrated (at week 7, 9, 11, 15, 17, 19, 23, 25 and 27).Patients received other backbone chemotherapy agents as per ALL-MB 2015.

Protocol documents:
Prot_000.pdf: 
 
 
 
Study Protocol  
A Multicentre, Roll-over Study to Provide Continued Treatment With Lyophilized Pegaspargase (S95014) 
in Pediatric Patients With Acute Lymphoblastic Leukemia (ALL) 
NCT04956666 
Document Date: December 2, 2020 




S 9 5 0 1 4  
Cli ni c al  st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3   – Fi n al  v ersi o n  
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     SY N O P SI S  
N a m e  of t h e s p o ns o r:  
I. R.I. S. 
N a m e  of  Fi nis h e d  P r o d u ct:  
L y o p hili z e d  p e g as p ar g a s e  
N a m e  of  A cti v e I n g r e di e nt : 
P e g as p ar g as e   
S 9 5 0 1 4  
O n c as p ar ®  
Titl e  of  st u d y:    A    m ulti c e ntr e,  r oll-o v er   st u d y  t o  pr o vi d e  c o nti n u e d  tr e at m e nt    wit h  l y o p hili z e d  p e g as p ar g as e 
( S 9 5 0 1 4) i n  P e di atri c  P ati e nts  wit h  A c ut e  L y m p h o bl asti c  L e u k e mi a ( A L L) 
 
St u d y  B ri ef  Titl e : R oll -o v er  st u d y  of  L y o p hili z e d  p e g a s p ar g as e ( S 9 5 0 1 4) f or m ul ati o ns i n  A L L  
 
St u d y  P u bli c  Titl e : A  r oll-o v er  st u d y  t o  pr o vi d e c o nti n u e d  tr e at m e nt  wit h l y o p hili z e d  p e g as p ar g a s e ( S 9 5 0 1 4) i n 
P e di atri c  P ati e nts  wit h  A c ut e  L y m p h o bl asti c  L e u k e mi a ( A L L)  
 
Pr ot o c ol  N o.:  C L 2 -9 5 0 1 4 -0 0 3  
C o o r di n at o r, I n v esti g at o rs   
N ati o n al  c o or di n at or  a n d i n v e sti g at ors: list e d i n  a s e p ar at e  d o c u m e nt  
St u d y  c e nt r e (s): 
6 -1 0  c e ntr es i n  R ussi a  
St u d y  p e ri o d:  
­  St u d y  d ur ati o n f or t h e  p arti ci p a nt:  a p pr o xi m at el y  7  m o nt hs  
­  St u d y  i niti ati o n  d at e  ( pl a n n e d  d at e  of  first  visit  first  p arti ci p a nt ): 
Q 2  2 0 2 1  
­  St u d y  c o m pl eti o n  d at e ( pl a n n e d  d at e  of l ast  visit l ast  p arti ci p a nt ): 
Q 3  2 0 2 2  
St u d y  d e v el o p m e nt  p h as e : II 
O bj e cti v e(s):   
T h e  pri m ar y  o bj e cti v e  of  t his  st u d y  is  t o  pr o vi d e  tr e at m e nt    wit h  l y o p hili z e d  S 9 5 0 1 4  i n  p e di atri c  p ati e nts    wit h 
A L L  w h o  c o m pl et e d  t h e  C L 2-9 5 0 1 4 -0 0 2 st u d y  d uri n g t h e i n d u cti o n  p h a s e . 
S e c o n d ar y  o bj e cti v e is t o  ass e ss t h e s af et y  pr ofil e  of l y o p hili z e d  S 9 5 0 1 4  d uri n g t h e  c o ns oli d ati o n  p h as e.  
M et h o d ol o g y:   
T his  is   a    m ulti c e ntr e ,  n o n -r a n d o mi z e d   r oll-o v er   st u d y   of  l y o p hili z e d   P e g as p ar g as e   ( O n c as p ar ®,   S 9 5 0 1 4) 
f or m ul ati o n i n t h e tr e at m e nt  of  p e di atri c  p ati e nts  wit h  A L L.  This  st u d y is  d esi g n e d t o  pr o vi d e  c o nti n u e d  a c c ess t o 
S 9 5 0 1 4   d uri n g  t h e  c o ns oli d ati o n   p h as e  i n   p ati e nts  w h o  c o m pl et e d   t h e    C L 2-9 5 0 1 4 -0 0 2  st u d y  a n d    w h o  ar e 
cli ni c all y  b e n efitti n g fr o m  S 9 5 0 1 4  wit h o ut  m aj or t o xi cit y .  
 
Writt e n  i nf or m e d  c o ns e nt  a n d  ass e nt  ( w h e n  a p pr o pri at e)    will  b e  o bt ai n e d  fr o m  e a c h  p ati e nt  a n d/ or  his/ h er 
p ar e nt(s)/l e g al r e pr es e nt ati v e  d uri n g t h e i n cl usi o n  visit,  c orr es p o n di n g t o t h e  wit h dr a w al  visit  of t h e i niti al  C L 2 -
9 5 0 1 4 -0 0 2  st u d y.   S af et y   ass ess m e nt  i n cl u di n g  l a b or at or y  t ests,    E C G,   c ar di a c  i m a gi n g   a n d   pr e g n a n c y  t est 
p erf or m e d  d uri n g t h e  wit h dr a w al  visit  of t h e i niti al  C L 2 -9 5 0 1 4 -0 0 2  st u d y  c a n  b e  u s e d t o  ass ess t h e i n cl usi o n i n 
t his r oll-o v er st u d y.  
 
T h e st u d y  d ur ati o n  will  b e  a p pr o xi m at el y  7  m o nt hs, i n cl u di n g t h e tr e at m e nt  p eri o d  c o nsisti n g  of t h e  c o ns oli d ati o n 
p h as e  ( a p pr o xi m at el y   6    m o nt hs)  a n d  t h e  f oll o w -u p   p eri o d  ( 3 0   d a ys  aft er  t h e  l a st   S 9 5 0 1 4  i nf usi o n).    Aft er 
c o m pl eti n g  t h e  c o ns oli d ati o n  p h as e,  p ati e nt    will  b e  dis c o nti n u e d  fr o m  t h e  st u d y  a n d    will  b e  tr e at e d  as  p er 
i n v e sti g at or’s j u d g m e nt. 
L y o p hili z e d  S 9 5 0 1 4  will  b e  a d mi nist er e d I V,  o v er  1 t o  2  h o urs,  e v er y t w o  w e e ks  d uri n g t h e  c o ns oli d ati o n  p h as e 
at t h e  d os e  of  1 0 0 0,  2 0 0 0  or  2 5 0 0  U/ m²,  as  p er i n v esti g at or’s j u d g m e nt.  P ati e nts  will  b e  a d mi nist er e d  9 i nf usi o ns 
of l y o p hili z e d  S 9 5 0 1 4,  at  w e e k  7,  9,  1 1,  1 5,  1 7,  1 9,  2 3,  2 5  a n d  2 7 ( 3  p h as es  S 1,  S 2  a n d  S 3).  P ati e nts  will r e c ei v e 
ot h er  b a c k b o n e  c h e m ot h er a p y  a g e nts  as  p er  A L L -M B  2 0 1 5  pr ot o c ol.  
 
S e c o n d ar y  o bj e cti v e  of  t his  r oll -o v er  st u d y  is  t o  ass ess  t h e  s af et y  pr ofil e  of  l y o p hili z e d  S 9 5 0 1 4  d uri n g  t h e 
c o ns oli d ati o n  p h as e . All  a d v ers e  e v e nts  r e g ar dl ess  of  gr a d e  or  c a us alit y  a n d  s e v erit y  will  b e  c oll e ct e d  aft er  t h e 


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Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
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N a m e  of t h e s p o ns o r:  
I. R.I. S.
N a m e  of  Fi nis h e d  P r o d u ct:  
L y o p hili z e d  p e g as p ar g a s e  
N a m e  of  A cti v e I n g r e di e nt : 
P e g as p ar g as e   
S 9 5 0 1 4  
O n c as p ar ®  
i nf or m e d  c o ns e nt is  si g n e d  a n d  d uri n g t h e  e ntir e tr e at m e nt  p eri o d. 
N u m b e r  of  i n cl u d e d p a rti ci p a nts : 
Pl a n n e d:  A p pr o xi m at el y  8 8   
Di a g n osis  a n d  m ai n  c rit e ri a  f o r i n cl usi o n: 
I n cl usi o n crit eri a  
- 
P ati e nt  w h o  c o m pl et e d  t h e  C L 2-9 5 0 1 4 -0 0 2 st u d y
- 
P ati e nt  c urr e ntl y r e c ei vi n g  cli ni c al  b e n efit fr o m  pr e vi o us tr e at m e nt  wit h  S 9 5 0 1 4  as  p er i n v e sti g at or’s
j u d g m e nt
-
Si g n e d i nf or m e d  c o ns e nt  a n d  ass e nt,  w h e n  a p pr o pri at e
- 
Hi g hl y  eff e cti v e  c o ntr a c e pti o n  m et h o d
N o n -i n cl usi o n crit eri a:  
- 
U nli k el y t o  c o o p er at e i n t h e st u d y
- 
Pr e g n a nt  a n d l a ct ati n g  w o m e n
- 
P arti ci p a nt  alr e a d y  e nr oll e d  i n t h e st u d y (i nf or m e d  c o ns e nt si g n e d)
- 
Pri or s ur g er y  or  b o n e  m arr o w tr a ns pl a nt r el at e d t o t h e st u di e d  dis e as e
- 
Hist or y  of  s e nsiti vit y t o  p ol y et h yl e n e  gl y c ol ( P E G)  or  P E G -b as e d  dr u gs
- 
Ps y c hi atri c ill n e ss/s o ci al sit u ati o n t h at  w o ul d li mit  c o m pli a n c e  wit h st u d y r e q uir e m e nts
- 
Gr o u p  “ E ”  a n d  “ T -H R ”  p ati e nts  a c c or di n g t o  A L L -M B  2 0 1 5  pr ot o c ol  cl assifi c ati o n
- 
M aj or  s af et y  iss u e  d u e  t o  pr e vi o us  S 9 5 0 1 4  a d mi nistr ati o n  ( e. g.  n o n  r e c o v er y  of  s af et y  p ar a m et er s,
s eri o us  h y p ers e nsiti vit y, s eri o us  p a n cr e atitis, s eri o us  h a e m orr h a g e, s eri o us t hr o m b o e m b oli c  e v e nt)
-
Si g nifi c a nt  l a b or at or y  a b n or m alit y   or   u n c o ntr oll e d  i nt er c urr e nt  ill n ess  ( e. g.  lif e -t hr e at e ni n g  a c ut e
t u m or   l ysis   s y n dr o m e,   s y m pt o m ati c   c o n g esti v e   h e art   f ail ur e,   c ar di a c   arr h yt h mi a,   s e v er e   or
u n c o ntr oll e d  a cti v e  a c ut e  i nf e cti o n)  li k el y  t o  j e o p ar di z e  t h e  p ati e nts’  s af et y  or  t o  i nt erf er e   wit h  t h e
c o n d u ct  of t h e st u d y, i n t h e i n v esti g at or’s  o pi ni o n
Te st d r u g : 
L y o p hilize d S 9 5 0 1 4 rec o nstit ute d will  pro v i de 5 m L  of extracta ble  vol u me  wit h  the  co nc e ntrati o n  of 7 5 0 U/ m L.  
T he  vial of ly o p hilize d p o w der  (3. 7 5 0 U/ v ial) is rec o nstit uted wit h  5.2 m L  of S W FI  t o o btai n a 7 5 0 U/ m L  
s ol uti o n f or si n gle use. 
L y o p hilize d S 9 5 0 1 4 will be a d mi nistere d I V e ver y t w o wee ks at t he d ose of 1 0 0 0, 2 0 0 0 or 2 5 0 0 U/ m², as 
per  i n vesti gat or’s j u d g me nt. Patie nts  will  recei ve ot her  bac k b o ne  c he m ot hera p y  a ge nts as per  A L L -
M B  2 0 1 5 pr ot oc ol . 
C o m p a r at o r:  N o n e  
D u r ati o n  of t r e at m e n t:  
A cti v e tr e at m e nt  p eri o d:  6  m o nt hs  
F oll o w -u p  p eri o d:  3 0  d a ys  
Crit e ri a f o r  e v al u ati o n:  
S af et y  m e as ur e m e nt:  
Saf et y  a ss ess m e nts  will  b e  p erf or m e d  a n d r e p ort e d t hr o u g h o ut t h e  st u d y.  T his  will i n cl u d e:  
­  a d v ers e  e v e nts ( A E s), tr e at m e nt  e m er g e nt  a d v er s e  e v e nts ( T E A Es),  a d v ers e  e v e nts  of  s p e ci al i nt er est ( A E SI)
ass ess m e nts  
­  p h ysi c al  e x a mi n ati o ns,  p erf or m a n c e  st at us
­  l a b or at or y  ass e ss m e nts i n cl u di n g h a e m at ol o g y ,  bl o o d  bi o c h e mistr y,  uri n al ysis a n d  c o a g ul ati o n  p ar a m et ers
­  vit al si g ns  m e as ur e m e nts
­  pr e g n a n c y t est f or  w o m e n  of  c hil d b e ari n g  p ot e nti al


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Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
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N a m e  of t h e s p o ns o r:  
I. R.I. S. 
N a m e  of  Fi nis h e d  P r o d u ct:  
L y o p hili z e d  p e g as p ar g a s e  
N a m e  of  A cti v e I n g r e di e nt : 
P e g as p ar g as e   
S 9 5 0 1 4  
O n c as p ar ®  
­  R e c or di n g  of  a n y  c h a n g e  or  a d diti o n  of  a  n e w  c o n c o mit a nt tr e at m e nt  
 
A d v ers e  e v e nts  will  b e  c oll e ct e d r e g ar dl ess  of  gr a d e  or st u d y  dr u g r el ati o ns hi p  a n d  will  b e  gr a d e d  a c c or di n g t o 
c urr e nt  N CI  C T C A E  crit eri a  5. 0 . 
 
S af et y  a n al ysis:  d es cri pti v e  s u m m ari e s  of  d e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs  wit h  a  d es cri pti o n  of  p ati e nt 
dis p ositi o n  a n d listi n g  of  m e di c al  hist or y  will  b e  pr o vi d e d.  T h e  n u m b er  a n d  p er c e nt a g e  of  p ati e nts  wit h  a d v ers e 
e v e nts  will  b e t a b ul at e d  b y  s yst e m  or g a n  cl ass  a n d  pr ef err e d t er m.  
D at a  M o nit o ri n g  C o m mitt e e:  N ot  a p pli c a bl e   
 
 






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Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
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T a bl e  of  c o nt e nts  
T a bl e  of  c o nt e nts  ........................................................................................................................  7 
1.  A D MI NI S T R A TI V E  S T R U C T U R E  O F  T H E  S T U D Y  .................................................  1 6 
2.  B A C K G R O U N D I N F O R M A TI O N  .................................................................................  1 6 
2. 1.  O v er vi e w  of  dis e as e  e pi d e mi ol o g y  a n d  c urr e nt tr e at m e nt  .............................................  1 6 
2. 2.  S 9 5 0 1 4 ............................................................................................................................  1 6  
2. 2. 1.  M e c h a nis m  of  a cti o n  of  S 9 5 0 1 4 ..................................................................................  1 6  
2. 2. 2.  P e g yl at e d  as p ar a gi n as e  d e v el o p m e nt  a n d st at us  ..........................................................  1 7 
2. 2. 3.  D e v el o p m e nt  of  a l y o p hili z e d  S 9 5 0 1 4 f or m ul ati o n .....................................................  1 7  
2. 2. 4.  St u d y r ati o n al e  a n d  d esi g n  ...........................................................................................  1 8 
3.  S T U D Y  O B J E C TI V E S  A N D  E N D P OI N T S  ...................................................................  1 8 
4.  S T U D Y  D E SI G N  ...............................................................................................................  1 8 
4. 1.  I n v esti g ati o n al  pl a n......................................................................................................... 1 8  
4. 1. 1.  St u d y  pl a n .....................................................................................................................  1 8  
4. 1. 2.  I n v esti g ati o n s c h e d ul e ..................................................................................................  2 0 
4. 2.  M e as ur es t o  mi ni mis e  bi as  .............................................................................................  2 2 
4. 3.  St u d y  pr o d u cts  a n d  bl i n di n g s yst e ms .............................................................................  2 2 
4. 3. 1.  Pr o d u cts  a d mi nist er e d ..................................................................................................  2 2  
4. 3. 2.  I M P  m a n a g e m e nt .........................................................................................................  2 3 
4. 3. 3.  M a n a g e m e nt  of  bli n di n g s yst e ms  .................................................................................  2 4 
4. 4.  Dis c o nti n u ati o n  of t h e st u d y  or t e m p or ar y  h alt ..............................................................  2 4  
4. 4. 1.  Pr e m at ur e  dis c o nti n u ati o n  of t h e st u d y  or t e m p or ar y  h alt ...........................................  2 4  
4. 4. 2.  Pr e m at ur e  dis c o nti n u ati o n  of t h e st u d y i n  a n i n v esti g at or sit e ( e arl y sit e  cl os ur e)  ......  2 4 
4. 4. 3.  Dis c o nti n u ati o n  of t h e st u d y i n t h e  e v e nt  of  o bj e cti v e r e a c h e d ...................................  2 5  
4. 5.  S o ur c e  d at a  .....................................................................................................................  2 5 
5.  I N C L U SI O N  A N D  WI T H D R A W A L  O F  P A R TI CI P A N T S  ........................................  2 5 
5. 1.  I n cl usi o n  crit eri a .............................................................................................................  2 5 
5. 2.  N o n -i n cl usi o n  crit eri a .....................................................................................................  2 5 
5. 2. 1.  G e n er al  crit eri a  .............................................................................................................  2 5 
5. 2. 2.  M e di c al  a n d t h er a p e uti c  crit eri a  ...................................................................................  2 6 
5. 3.  D efi niti o n  of  w o m e n  of  c hil d b e ari n g  p ot e nti al  a n d  c o ntr a c e pti o n  m et h o ds ..................  2 6  
5. 4.  R et est  m a n a g e m e nt  b ef or e t h e i n cl usi o n  ........................................................................  2 6 
5. 5.  A d diti o n al i nf or m ati o n r e c or d e d  at t h e i n cl usi o n  visit ...................................................  2 6  
5. 6.  P arti ci p a nt  wit h dr a w al  ....................................................................................................  2 7 
5. 6. 1.  Wit h dr a w al  crit eri a  .......................................................................................................  2 7 
5. 6. 2.  Pr o c e d ur e ......................................................................................................................  2 7  
5. 6. 3.  L ost t o f oll o w- u p ..........................................................................................................  2 7  
6.  T R E A T M E N T  O F  P A R TI CI P A N T S  ..............................................................................  2 8 


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6. 1.  I M P  a n d  NI M Ps  a d mi nist er e d ........................................................................................  2 8 
6. 1. 1.  I M P ...............................................................................................................................  2 8 
6. 1. 2.  NI M Ps  ..........................................................................................................................  2 8 
6. 2.  I M P  dis p e nsi n g ...............................................................................................................  2 8 
6. 3.  Pr e vi o us  a n d  c o n c o mit a nt tr e at m e nts .............................................................................  2 9  
6. 4.  I M P  c o m pli a n c e ..............................................................................................................  3 0 
6. 5.  Dis c o nti n u ati o n  of t h e I M P ............................................................................................  3 0  
7.  A S S E S S M E N T  O F  E F FI C A C Y  ......................................................................................  3 0 
8.  A S S E S S M E N T  O F  S A F E T Y  ...........................................................................................  3 0 
8. 1.  S p e cifi c ati o n  of s af et y  p ar a m et ers  ..................................................................................  3 0 
8. 2.  M et h o ds  a n d  m e as ur e m e nt ti m es  ...................................................................................  3 0 
8. 3.  D efi niti o n  of  A d v ers e  e v e nts ..........................................................................................  3 3  
8. 4.  D efi niti o n  of  S eri o us  a d v ers e  e v e nts ..............................................................................  3 3  
8. 5.  D efi niti o n  of  O v er d os e ...................................................................................................  3 4  
8. 6.  D efi niti o n  of  A d v ers e  e v e nt  of s p e ci al i nt er est  ..............................................................  3 4 
8. 7.  D efi niti o n  of  E v e nts r e q uiri n g  a n i m m e di at e  n otifi c ati o n ( E RI N)  .................................  3 4 
8. 8.  Cl assifi c ati o n  of  a n  a d v ers e  e v e nt (s eri o us n ess, s e v erit y,  c a us alit y,  e x p e ct e d n ess) ......  3 4  
8. 9.  R e p orti n g  pr o c e d ur es ......................................................................................................  3 5  
8. 9. 1.  Ti m e fr a m e f or  A E r e p orti n g  .......................................................................................  3 5 
8. 9. 2.  R es p o nsi biliti es  of t h e i n v esti g at or  ..............................................................................  3 6 
8. 9. 2. 1.  
D o c u m e nt ati o n  of t h e  e v e nt .....................................................................................  3 7  
8. 9. 2. 2.  
F oll o w- u p  of  a d v ers e  e v e nts ....................................................................................  3 7  
8. 9. 2. 3.  
S p e ci al sit u ati o ns ( pr e g n a n c y,  o v er d os es, i nt a k e  of I M P/ NI M P  a  p ers o n  ar o u n d t h e 
p arti ci p a nt)  ...............................................................................................................  3 7 
8. 9. 2. 4.  
R e c or di n g   M et h o ds i n t h e  e-C R F  ............................................................................  3 8 
8. 9. 2. 5.  
Pr o c e d ur e f or  a n  e v e nt r e q uiri n g  a n i m m e di at e  n otifi c ati o n ...................................  3 8  
8. 9. 3.  R es p o nsi biliti es  of t h e s p o ns or .....................................................................................  3 9  
8. 1 0.  M a n a g e m e nt  of t o xi citi es  ...............................................................................................  3 9 
9.  O T H E R  A S S E S S M E N T S  N O T  S P E CI FI C A L L Y  R E L A T E D  T O  S A F E T Y  ............  4 0 
9. 1.  Ass ess m e nts r el at e d t o i n cl usi o n  crit eri a.  .......................................................................  4 0 
9. 2.  M e as ur e m e nt  of  pl as m a  as p ar a gi n as e  a cti vit y  ...............................................................  4 0 
9. 3.  Ass ess m e nt  of i m m u n o g e ni cit y ......................................................................................  4 1  
9. 4.  Ass ess m e nt  of  bi o m ar k ers ..............................................................................................  4 1  
1 0.  
S T A TI S TI C S  .................................................................................................................  4 1 
1 0. 1.  P o p ul ati o n .......................................................................................................................  4 1  
1 0. 1. 1.  D et er mi n ati o n  of s a m pl e si z e  .......................................................................................  4 1 
1 0. 1. 2.  A n al ysis s u bs et  .............................................................................................................  4 1 
1 0. 2.  St atisti c al  a n al ysis ........................................................................................................... 4 1  
1 0. 2. 1.  S af et y  A n al ysis  .............................................................................................................  4 1 
1 0. 2. 1. 1.  A d v ers e  E v e nts  ........................................................................................................  4 1 
1 0. 2. 1. 2.  Ot h er  S af et y  E v al u ati o ns  .........................................................................................  4 2 
1 0. 2. 2.  P o p ul ati o n  A n al ysis......................................................................................................  4 2  


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  9 /5 4  
 
1 0. 2. 2. 1.  S u bj e ct  Dis p ositi o n  ..................................................................................................  4 2 
1 0. 2. 2. 2.  D e m o gr a p hi c  a n d  B as eli n e  C h ar a ct eristi cs  .............................................................  4 2 
1 0. 2. 2. 3.  C o n c o mit a nt  M e di c ati o n  .........................................................................................  4 2 
1 0. 3.  H a n dli n g  of  Missi n g,  U n us e d,  a n d  S p uri o us  D at a .........................................................  4 2  
1 0. 4.  Pl a n n e d I nt eri m  A n al ysis................................................................................................  4 3  
1 0. 5.  Pr o c e d ur es f or  R e p orti n g  C h a n g es t o t h e  Pl a n n e d  A n al ysis ..........................................  4 3  
1 1.  
DI R E C T  A C C E S S  T O  S O U R C E  D A T A /  D O C U M E N T S  ......................................  4 3 
1 2.  
Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E ..........................................  4 3 
1 2. 1.  St u d y  m o nit ori n g ............................................................................................................  4 3  
1 2. 1. 1.  B ef or e t h e st u d y  ...........................................................................................................  4 3 
1 2. 1. 2.  D uri n g t h e st u d y ...........................................................................................................  4 4  
1 2. 2.  C o m p ut eris e d  m e di c al fil e  ..............................................................................................  4 4 
1 2. 3.  A u dit -  I ns p e cti o n ...........................................................................................................  4 5 
1 3.  
E T HI C S  .........................................................................................................................  4 6 
1 3. 1.  I nstit uti o n al  R e vi e w  B o ar d(s)/I n d e p e n d e nt  Et hi cs  C o m mitt e e(s) ..................................  4 6 
1 3. 2.  St u d y  c o n d u ct  .................................................................................................................  4 6 
1 3. 3.  P arti ci p a nt i nf or m ati o n  a n d i nf or m e d  c o ns e nt ...............................................................  4 6  
1 3. 4.  M o difi c ati o n  of t h e i nf or m ati o n  a n d  c o ns e nt f or m ........................................................  4 7  
1 4.  
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  ......................................................  4 7 
1 4. 1.  St u d y  d at a  .......................................................................................................................  4 7 
1 4. 2.  D at a  m a n a g e m e nt  ...........................................................................................................  4 8 
1 4. 3.  Ar c hi vi n g ........................................................................................................................  4 9  
1 5.  
I N S U R A N C E  ................................................................................................................  4 9 
1 6.  
O W N E R S HI P  O F  T H E  R E S U L T S  –  D A T A  S H A RI N G  P O LI C Y  A N D 
P U B LI C A TI O N  P O LI C Y  ................................................................................................  5 0 
1 7.  
A D MI NI S T R A TI V E  C L A U S E S  .................................................................................  5 1 
1 7. 1.  C o n c er ni n g t h e s p o ns or  a n d t h e i n v esti g at or ..................................................................  5 1  
1 7. 1. 1.  P ers o ns t o i nf or m .........................................................................................................  5 1  
1 7. 1. 2.  S u bst a nti al  pr ot o c ol  a m e n d m e nt  a n d  a m e n d e d  pr ot o c ol..............................................  5 1  
1 7. 1. 3.  Fi n al st u d y r e p ort .........................................................................................................  5 1  
1 7. 2.  C o n c er ni n g t h e s p o ns or ..................................................................................................  5 2  
1 7. 3.  C o n c er ni n g t h e i n v esti g at or ............................................................................................  5 2  
1 7. 3. 1.  C o nfi d e nti alit y  - Us e  of i nf or m ati o n  ............................................................................  5 2 
1 7. 3. 2.  Or g a nis ati o n  of t h e  c e ntr e ............................................................................................  5 3  
1 7. 3. 3.  D o c u m e nt ati o n s u p pli e d t o t h e s p o ns or .......................................................................  5 3  
1 8.  
R E F E R E N C E S  .............................................................................................................  5 3 
1 9.  
A P P E N DI C E S  ...............................................................................................................  5 4 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
 1 0 /5 4  
List  of t a bl es  
T a bl e  ( 4. 1. 2)  1 - I n v esti g atio n s c h e d ul e ...............................................................................................  2 1  
T a bl e ( 4. 3. 1)  1  –  D es cri pti o n  of t h e I M P .............................................................................................  2 2  
T a bl e  ( 4. 3. 1)  2  –  D es cri pti o n  of  S 9 5 0 1 4  p a c k a gi n g ............................................................................  2 2 
T a bl e  ( 8. 2)  1 - L o c al  Cli ni c al l a b or at or y  p ar a m et ers  c oll e cti o n  pl a n  ..................................................  3 2 
T a bl e  ( 8. 1 0)  1 -  Crit eri a f or  S 9 5 0 1 4 i nt err u pti o n  or  dis c o nti n u ati o n ...................................................  4 0 


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 1 /5 4  
 
List  of fi g u r es  
Fi g ur e  ( 4. 1. 1)  1  –  St u d y  pl a n ...............................................................................................................  1 9 
 
 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
 1 2 /5 4  
List  of  a p p e n di c es  
A p pe n di x 1: A L L- M B 2 0 1 5 pr ot oc ol .................................................................................................. 5 5  
A p pe n di x 2: Patie nt  perf or ma nce stat us  .............................................................................................1 9 6  
A p pe n di x 3: Trial C o n d uct D uri n g Nati o nal or I nter nati o nal P u blic Healt h E mer ge nc y ..................1 9 7  
A p pe n di x 4: W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki .....................................................1 9 8  
A p pe n di x 5: I nstr ucti o ns t o i n vesti gat or f or ha n dli n g data ri g hts re q uests ........................................2 0 4  


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 3 /5 4  
 
List  of  a b b r e vi ati o ns 
A D L  
:  A cti viti es  of  D ail y  Li vi n g  
A E  
:  A d v ers e  E v e nt  
A E O SI  
:  A d v ers e  E v e nt  Of  S p e ci al I nt er est  
A L L  
:  A c ut e  L y m p h o bl asti c  L e u k e mi a  
A L P  
:  Al k ali n e  P h os p h at as e  
A L T  
:  A L a ni n e  a mi n o Tr a nsf er as e  
A N O V A  
:  A n al ysis  of  V ari a n c e  
A P T T  
:  A cti v at e d  P arti al  T hr o m b o pl asti n  Ti m e  
A S T  
:  A S p art at e  a mi n o Tr a nsf er as e  
A U C  
:  Ar e a  U n d er t h e  C ur v e  
B F M  
:  B erli n -Fr a n kf urt -M u nst er  
B MI  
:  B o d y  M ass I n d e x  
B P  
:  Bl o o d  Pr ess ur e  
b p m  
:  b e ats  p er  mi n ut e ( h e art r at e  u nit)  
B S A  
:  B o d y  S urf a c e  Ar e a  
B U N  
:  Bl o o d  Ur e a  Nitr o g e n  
C BI  
:  C e ntr al  B usi n ess I nt elli g e n c e  
C H M P  
:  C o m mitt e e f or  M e di c al  Pr o d u cts f or  H u m a n  Us e  
CI  
:  C o nfi d e n c e I nt er v al  
c m  
:  C e nti m etr e  
C m a x  
:  m a xi m u m  C o n c e ntr ati o n  
C M P  
:  Cli ni c al  M o nit ori n g  Pl a n  
CI S O  
:  C hi ef I nf or m ati o n  S e c urit y  Offi c er  
C O G  
:  C hil dr e n’s  O n c ol o g y  Gr o u p  
C o V  
:  C o effi ci e nt  of  V ari ati o n  
C R A  
:  Cli ni c al  R es e ar c h  Ass o ci at e  
C R F  
:  C as e  R e p ort  F or m  
C R O  
:  C o ntr a ct  R es e ar c h  Or g a nis ati o n  
C S R  
:  Cli ni c al  St u d y  R e p ort  
C T C A E  
:  C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts  
C V  
:  C urri c ul u m  Vit a e  
D A P  
:  D at a  A n al ysis  Pl a n  
D P O  
:   D at a  Pr ot e cti o n  Offi c er  
E C G  
:  El e ctr o C ar di o Gr a m  
E C O G  
:  E ast er  C o o p er ati v e  O n c ol o g y  Gr o u p  
e C R F  
:  El e ctr o ni c  C as e  R e p ort  F or m  
E E A  
:  E ur o p e a n  E c o n o mi c  Ar e a  
e. g.  
:  E x e m pli  gr ati a (f or  e x a m pl e)  
E LI S A  
:  E n z y m e -Li n k e d I m m u n os or b e nt  Ass a ys  
E M A  
:  E ur o p e a n  M e di ci n es  A g e n c y  
E RI N  
:  E v e nt  R e q uiri n g I m m e di at e  N otifi c ati o n  
E U  
:  E ur o p e a n  U ni o n  
F A S  
:  F ull  A n al ysis  S et  
F D P  
:  Fi bri n  D e gr a d ati o n  Pr o d u ct  
g  
:  gr a m  


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 4 /5 4  
 
G/ L  
:  Gi g a ( 1 0 9) p er litr e  
G C P  
:  G o o d  Cli ni c al  Pr a cti c e  
G G T  
:  G a m m a -Gl ut a m yl  Tr a nsf er as e ( G a m m a -Gl ut a m yl 
Tr a ns p e pti d as e)  
G M R  
:  G e o m etri c  M e a n  R ati o  
h  
:  h o ur  
H Bs  
:  S urf a c e  a nti g e n  of  H e p atitis  B  vir us  
H C V  
:  H e p atitis  C  vir us  
H D L  
:  Hi g h -D e nsit y  Li p o pr ot ei n  
H E V  
:  H e p atitis  E  vir us  
HI V  
:  H u m a n I m m u n o d efi ci e n c y  Vir us  
H R  
:  H e art  R at e  
I. R.I. S. 
:  I nstit ut  d e  R e c h er c h es I nt er n ati o n al es  S er vi er 
I C F 
:  I nf or m e d  C o ns e nt  F or m 
I C H 
:  I nt er n ati o n al  C o nf er e n c e  o n  H ar m o nis ati o n 
I C T R 
:  I nt er n ati o n al  C e ntr e f or T h er a p e uti c  R es e ar c h  
i. e. 
:  i d  est (t h at is) 
I E C 
:  I n d e p e n d e nt  Et hi cs  C o m mitt e e 
I M P 
:  I n v esti g ati o n al  M e di ci n al  Pr o d u ct:  a  p h ar m a c e uti c al f or m  of  a n 
a cti v e i n gr e di e nt  or  pl a c e b o  b ei n g t est e d  or  us e d  as  a r ef er e n c e 
i n  a  cli ni c al tri al (t est  dr u g /  pl a c e b o / r ef er e n c e  pr o d u ct) 
I N R 
:  I nt er n ati o n al  N or m ali z e d  R ati o 
I U 
:  I nt er n ati o n al  U nit 
I V 
:  I ntr a V e n o us (r o ut e) 
k g  
:  kil o gr a m  
L  
:  Litr e  
L D H  
:  L a ct at e  D e H y dr o g e n as e  
L D L  
:  L o w -D e nsit y  Li p o pr ot ei n  
L V E F  
:  L eft  V e ntri c ul ar  Ej e cti o n  Fr a cti o n  
M A H  
:  M ar k eti n g  A ut h ori z ati o n  H ol d er  
M e d D R A  
:  M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
M RI  
:  M a g n eti c  R es o n a n c e I m a gi n g  
M U G A  s c a n   
:  M ulti -G at e d  A c q uisiti o n s c a n  
N C C N  
:  N ati o n al  C o m pr e h e nsi v e  C a n c er  N et w or k  
N C A  
:  N o n -C o m p art m e nt al  A n al ysis  
N CI  
:  N ati o n al  C a n c er I nstit ut e  
N G O  
:  N o n -G o v er n m e nt al  Or g a ni z ati o n  
NI M P  
:  N o n -I n v esti g ati o n al  M e di ci n al  Pr o d u ct ( b a c k b o n e r e gi m e n  us e d 
i n t h e fr a m e  of  A L L-M B  2 0 1 5  pr ot o c ol)  
µ m ol  
:  mi cr o m ol e  
m g  
:  milli gr a m  
mi n  
:  mi n ut e  
m L  
:  m illilit er 
N A  
:  N ot  A p pli c a bl e  
P A A  
:  Pl as m a  As p ar a gi n as e  A cti vit y  
P C R  
:  P ol y m er as e  C h ai n  R e a cti o n  
P E G  
:  P ol y Et h yl e n e  Gl y c ol  
P D  
:  P h ar m a c o D y n a mi cs  


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 5 /5 4  
 
P K  
:  P h ar m a c o Ki n eti cs  
P K A S  
:  P h ar m a c o ki n eti c  A n al ysis  S et  
P S  
:  P erf or m a n c e  St at us  
P T  
:  Pr ot hr o m bi n  Ti m e  
R B C  
:  R e d  Bl o o d  C ells  
R N A  
:  Ri b o n u cl ei c  A ci d  
S A E  
:  S eri o us  A d v ers e  E v e nt  
S A P  
:  St atisti c al  A n al ysis  Pl a n  
S A S  
:  S af et y  A n al ysis  S et  
S D  
:  St a n d ar d  D e vi ati o n  
s e c 
:  s e c o n d  
S m P C  
:  S u m m ar y  of  Pr o d u ct  C h ar a ct eristi cs  
S W FI  
:  St eril e  W at er f or I nj e cti o n  
t ½ z 
:  t er mi n al  h alf-lif e 
t est  dr u g 
:  Dr u g s u bst a n c e i n  a  gi v e n  d os a g e f or m, t est e d i n  a  cli ni c al tri al. 
In t his st u d y, it  c orr es p o n ds t o  S 9 5 0 1 4  pr o d u ct   
t m a x 
:  ti m e  c orr es p o n di n g t o  C m a x 
T S H  
:  T h yr oi d  Sti m ul ati n g  H or m o n  
U S  
:  U nit e d  St at es  
V  
:  Visit  
W B C  
:  W hit e  Bl o o d  C ells  
W H O -Dr u g   
:  W orl d  H e alt h  Or g a ni z ati o n  Dr u g  Di cti o n ar y  
W O C B P  
:  W o m a n  of  C hil d  B e ari n g  P ot e nti al  
 
 


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 6 /5 4  
 
1.   A D MI NI S T R A TI V E  S T R U C T U R E  O F  T H E  S T U D Y  
N o n  s p o ns or  p arti es,  s p o ns or (s) p arti es  a n d  C R O  r es p o nsi bl e  f or l o c al  m a n a g e m e nt  of t h e  st u d y  ar e 
d es cri b e d i n  a s e p ar at e  d o c u m e nt  e ntitl e d  A d mi nistr ati v e  p art  of  cli ni c al st u d y  pr ot o c ol.  
T h e list  of i n v esti g at ors  is  d es cri b e d i n  a s e p ar at e  d o c u m e nt  att a c h e d t o t h e  pr ot o c ol  a n d  e ntitl e d  " List 
of i n v esti g at ors ".  
2.   B A C K G R O U N D I N F O R M A TI O N  
2. 1.   O v e r vi e w  of  dis e as e  e pi d e mi ol o g y  a n d  c u r r e nt t r e at m e nt  
L e u k e mi a  is  t h e    m ost   c o m m o n   p e di atri c    m ali g n a n c y.    A c ut e  l y m p h o bl asti c  l e u k e mi a  ( A L L)  is 
t y pi c all y  c h ar a ct eri z e d  b y t h e  pr olif er ati o n  of l ar g e  n u m b er  of i m m at ur e l y m p h oi d  c ells i n t h e  b o n e 
m arr o w,  p eri p h er al  bl o o d  a n d  ot h er  or g a ns.  A L L is t h e  m ost  c o m m o n t y p e ( 4 6. 6 %)  of  a c ut e l e u k e mi a 
i n  c hil d h o o d  a n d t h e  m ost  c o m m o nl y  di a g n os e d  c a n c er i n  c hil dr e n  ( 2 5 %) (Es p ar z a,  2 0 0 5;  N o o n e  et 
al,  2 0 1 8 ). A p pr o xi m at el y  1 0 0 0  c hil dr e n  ar e  n e wl y  di a g n os e d  wit h  A L L  e a c h  y e ar i n  R ussi a  (K a pri n, 
2 0 1 9 ).  
T h e tr e at m e nt  of  A L L i n cl u d es l o n g -t er m  us e  of  m ulti a g e nt  c h e m ot h er a p y (N ati o n al  C o m pr e h e nsi v e 
C a n c er    N et w or k   cli ni c al  pr a cti c e  g ui d eli n es ),  of    w hi c h  as p ar a gi n as e  is  a  c or n erst o n e  c o m p o n e nt 
(H o el z er  D  et  al,  2 0 1 6 , Ass eli n  B  et  al,  1 9 9 9 ).  As p ar a gi n e is  a  n o n ess e nti al  a mi n o  a ci d  f or  n or m al 
c ell  gr o wt h  b ut is  c o nsi d er e d  ess e nti al f or l e u k a e mi c  c ells  as t h es e  c ells  ar e  d e p e n d e nt  o n  e x o g e n o us 
s o ur c es   of   as p ar a gi n e  f or  s ur vi v al.    As p ar a gi n as e  s el e cti v el y   kills  l e u k a e mi c   c ells   b y   d e pl eti n g 
as p ar a gi n e l e v els.  (Ass eli n  B  et  al,  1 9 9 9 ).  N ati v e Es c h eri c hi a  c oli - d eri v e d  L-as p ar a gi n as e ( E.  c oli   L-
as p ar a gi n as e) is  o n e  of t h e  as p ar a gi n as e  pr e p ar ati o ns t h at  h a v e  b e e n  us e d  f or t h e tr e at m e nt  of  A L L 
si n c e  1 9 7 0s;  h o w e v er, its  us e is  ass o ci at e d  wit h  hi g h i m m u n o g e ni cit y,  w hi c h  c a n  b e  m a nif est e d  b y 
t h e  o c c urr e n c e  of  h y p ers e nsiti vit y r e a cti o ns  (Sil v er m a n  L B  et  al,  2 0 1 0 )  a n d/ or t h e  n e utr ali z ati o n  of 
as p ar a gi n as e  a cti vit y  wit h o ut  a n y  si g ns  of  h y p ers e nsiti vit y  (i. e.  sil e nt i n a cti v ati o n)  (T o n g  W H  et  al, 
2 0 1 4 ).  M or e o v er,  E.  c oli  L-as p ar a gi n as e  m ust  b e  a d mi nist er e d fr e q u e ntl y (i. e. t hr e e ti m es  w e e kl y),  as 
t h e  dr u g  h as  a  v er y s h ort  eli mi n ati o n  h alf-lif e (Ass eli n  B  et  al,  1 9 9 9 ). 
C o ns e q u e nt  t o  t h es e  li mit ati o ns,   p e g yl at e d   f or m ul ati o ns   of  E.   c oli     L-as p ar a gi n as e   h a v e   b e e n 
d e v el o p e d, i n cl u di n g  p e g as p ar g as e ( O n c as p ar ®) [ wit h  a s u c ci ni mi d yl s u c ci n at e li n k er]. 
T h e  w orl d wi d e  st a n d ar d tr e at m e nts f or  p e di atri c  A L L i n cl u d e t h e tr e at m e nt  pr ot o c ols  est a blis h e d  b y 
t h e   C hil dr e n’s   O n c ol o g y   Gr o u p  ( C O G)  a n d  t h e   B erli n- Fr a n kf urt-M u nst er  ( B F M)  gr o u p.  I n   R ussi a, 
a p pr o xi m at el y   9 0%  of  n e wl y -di a g n os e d  p e di atri c  p ati e nts  wit h  A L L  ar e tr e at e d i n  c o m pli a n c e  wit h 
t h e  A L L- M B  2 0 1 5  pr ot o c ol (s e e A p p e n di x 1 ). 
2. 2.   S 9 5 0 1 4 
D et ail e d i nf or m ati o n  o n t h e  n o n cli ni c al  a n d  cli ni c al  e x p eri e n c e  wit h  S 9 5 0 1 4  is  pr o vi d e d i n t h e l at est 
v ersi o n  of t h e  I n v esti g at or’s  Br o c h ur e. 
2. 2. 1.   M e c h a nis m  of  a cti o n  of  S 9 5 0 1 4 
T h e  m e c h a nis m  of  a cti o n  of  L -as p ar a gi n as e is t h e  e n z y m ati c  cl e a v a g e  of t h e  a mi n o  a ci d  as p ar a gi n e 
i nt o  as p arti c  a ci d  a n d  a m m o ni a,  wit h  s u bs e q u e nt  d e pl eti o n  of  as p ar a gi n e i n t h e  bl o o d  pl as m a.  Si n c e 
l y m p h o bl asti c  t u m or  c ells,  u nli k e  h e alt h y  c ells,  a p p e ar  t o  b e  u n a bl e  t o  s y nt h eti z e  as p ar a gi n e,  t h e 
as p ar a gi n e  d e pl eti o n  r es ults i n i n hi biti o n  of  c ell  pr ot ei n  s y nt h esis  a n d t h er ef or e i n t h eir  d estr u cti o n. 


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 7 /5 4  
 
H e n c e,    w h e n  pl as m a  l e v els  of   L -as p ar a gi n e  d e cr e as e,  i ntr a c ell ul ar  l e v els  of   L -as p ar a gi n e  b e c o m e 
m ar k e dl y  l o w,   pr ot ei n  s y nt h esis  is  i n hi bit e d,   a n d  l e u k e mi c   c ells   u n d er g o   a p o pt osis.    U nl ess   a n 
e xtr a c ell ul ar  s u p pl y  of  L -as p ar a gi n e is  a v ail a bl e,  L -as p ar a gi n as e is  a  s p e cifi c  c h e m ot h er a p e uti c  a g e nt 
f or l e u k e mi c  c ells  w hil e  pr es er vi n g  n o n-l e u k e mi a  c ells.  T h e  g o al  of  as p ar a gi n as e t h er a p y is  s ust ai n e d 
s yst e mi c  d e pl eti o n  of  as p ar a gi n e.   
2. 2. 2.   
P e g yl at e d  as p a r a gi n as e  d e v el o p m e n t  a n d st at us 
O n c as p ar ®   ( p e g as p ar g as e;   S 9 5 0 1 4)  is   a   v ari ati o n   of  t h e   e n z y m e    L-as p ar a gi n as e    m o difi e d   b y 
c o v al e ntl y  b o n di n g  u nits  of    m o n o m et h o x y  p ol y et h yl e n e  gl y c ol  ( P E G)  t o  t h e  e n z y m e,  f or mi n g  t h e 
a cti v e  p h ar m a c e uti c al i n gr e di e nt  P E G - L-as p ar a gi n as e.   
I n   t h e  U nit e d   S t at es   ( U S),   S 9 5 0 1 4   r e c ei v e d   a p pr o v al   i n   1 9 9 4   f or   s e c o n d-li n e   us e   i n   a c ut e 
l y m p h o bl asti c  l e u k a e mi a  ( A L L)   f oll o wi n g   t h e   d e v el o p m e nt   of   h y p ers e nsiti vit y   t o   n ati v e    L-
as p ar a gi n as e.  I n  2 0 0 6, t h e  U S  a ut h ori z ati o n  of  S 9 5 0 1 4  w as  e x p a n d e d t o i n cl u d e  first -lin e tr e at m e nt 
of  A L L.  
P e g as p ar g as e is  n o w  v er y  w ell  est a blis h e d i n  cli ni c al  pr a cti c e i n t h e first -li n e tr e at m e nt  of  A L L  a n d is 
li c e ns e d  i n    m a n y  c o u ntri es  (H e o    Y A  et  al,  2 0 1 9 ).  It  h as  b e e n  d et er mi n e d  b y  t h e    W orl d    H e alt h 
Or g a ni z ati o n  ( W H O)  a n  ess e nti al    m e di c ati o n  n e e d e d  t o    m e et  t h e  n e e ds  of  a  h e alt h  s yst e m  a n d  is 
i n cl u d e d i n t h e  List  of  Ess e nti al  M e di ci n es ( W H O  2 0 1 9). 
T h e  s af et y  pr ofil e  of  p e g as p ar g as e  h as  als o  b e e n    w ell  c h ar a ct eri z e d  o v er  t h es e  l ast  2 5  y e ars  of 
c o nsist e nt   us e  i n    A L L  tr e at m e nt   pr ot o c ols.    T h e    m ost   c o m m o n  ( > 5 %)   gr a d e   ≥ 3    A Es  i n cl u d e d 
h e p at ot o xi cit y   ( el e v at e d   tr a ns a mi n as es,   i n cr e as e d   bilir u bi n   a n d   h y p o al b u mi n e mi a),   f e bril e 
n e utr o p e ni a,   h y p ertri gl y c eri d e mi a,   h y p er gl y c e mi a,   p a n cr e atitis,   c o a g ul o p at h y,   e m b oli c   a n d  
t hr o m b oti c  e v e nts,  a n d  h y p ers e nsiti vit y.  F or  f urt h er  d et ails,  pl e as e  r ef er  t o  t h e  l ast  v ersi o n  of  t h e 
I n v esti g at or’s  Br o c h ur e. 
S o  f ar,  S 9 5 0 1 4  is  n ot  a p pr o v e d  y et  i n    R ussi a  a n d  t h e  pr o d u ct  is  o nl y  a v ail a bl e  t hr o u g h  a  n o n -
g o v er n m e nt al  or g a ni z ati o n  ( N G O)  s p e ci al  r e q u est.  T h us,  p ati e nts tr e at e d i n  A L L -M B  2 0 1 5  pr ot o c ol 
ar e  a d mi nist er e d  S 9 5 0 1 4  d uri n g t h e i n d u cti o n  p h as e ( o n e  d os e)  a n d  n ati v e  L -as p ar a gi n as e  d uri n g t h e 
c o ns oli d ati o n  p h as e.   O n c e  a p pr o v e d,  S 9 5 0 1 4  is  e x p e ct e d  t o  pl a y  a n  i m p ort a nt  r ol e  i n   R ussi a  as  a 
first-li n e tr e at m e nt f or  A L L. 
2. 2. 3.   
D e v el o p m e nt  of  a l y o p hili z e d  S 9 5 0 1 4 f o r m ul ati o n 
Diff er e nt   f or m ul ati o ns   c o nt ai ni n g   diff er e nt   q u a ntit ati v e   a n d   q u alit ati v e   c o m p ositi o ns   of 
cr y o pr ot e ct a nts   w er e  i n v esti g at e d  t o  i d e ntif y  t h e  b est  p r o d u ct  c o m p ositi o n  t h at  c o ul d   wit hst a n d  t h e 
l y o p hili z ati o n  pr o c ess  a n d  g u ar a nt e e  t h e  pr o d u cti o n  of  hi g h-q u alit y  dr u g  pr o d u ct    wit h  i m pr o v e d 
st a bilit y.   T h e  l y o p hili z e d  S 9 5 0 1 4  p o w d er  f or  I nj e cti o n  is  pr o vi d e d  i n  a  si n gl e -us e  vi al   w hi c h  aft er 
r e c o nstit ut e d    will   c o nt ai n   3, 7 5 0    U/ 5 m L   of   a cti v e   P E G yl at e d    L-as p ar a gi n as e  [ 7 5 0    U/ m L   aft er 
r e c o nstit uti o n  wit h  5. 2  m L  of  st eril e  w at er f or i nj e cti o n ( S W FI)],  w hi c h is  e q ui v al e nt t o t h e  str e n gt h 
of  li q ui d  S 9 5 0 1 4.   T h e  l y o p hili z e d  S 9 5 0 1 4  f or m ul ati o n  h as  a  l o n g er  s h elf -lif e  as  c o m p ar e d  t o  t h e 
li q ui d f or m ul ati o n ( 3 6  m o nt hs  vs  8  m o nt hs). 
A   c o m p ar ati v e,   si n gl e -d os e   a n d   4 -w e e k   r e p e at   d os e,   p h ar m a c o ki n eti c   a n d   p h ar m a c o d y n a mi c 
pr e cli ni c al  st u d y  of  I V  a d mi nist er e d  li q ui d  a n d  l y o p hili z e d  S 9 5 0 1 4  f or m ul ati o ns   w as  p erf or m e d  i n 
d o gs. I n t his  st u d y, l y o p hili z e d  S 9 5 0 1 4  h as  b e e n  d e m o nstr at e d t o  b e  e q ui v al e nt t o t h e  ori gi n al li q ui d 
S 9 5 0 1 4.  


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 8 /5 4  
 
S 9 5 0 1 4 li q ui d  f or m ul ati o n  h a d  b e e n  a ut h ori z e d  b y  c e ntr ali z e d  r e vi e w  pr o c e d ur es i n  2 8  c o u ntri es i n 
t h e    Eur o p e a n    U ni o n  ( E U)   a n d  3  c o u ntri es  i n  t h e    E ur o p e a n    E c o n o mi c    Ar e a  ( E E A)  i n  first  li n e 
tr e at m e nt   of    A L L   i n   2 0 1 6.    T h e   l y o p hili z e d   f or m ul ati o n   of   S 9 5 0 1 4   d e m o nstr at e d 
p h ar m a c o ki n eti c/ p h ar m a c o d y n a mi c  c o m p ar a bilit y t hr o u g h  c o m pr e h e nsi v e  a n al yti c al  a n d  n o n -cli ni c al 
c o m p ar a bilit y  ass ess m e nt  r e c o m m e n d e d  b y  t h e    C o m mitt e e  f or    M e di c al  Pr o d u cts  f or    H u m a n    Us e 
( C H M P)   of   t h e    E ur o p e a n    M e di ci n es    A g e n c y   ( E M A).    C o ns e q u e ntl y,   t h e   us e   of  l y o p hili z e d 
f or m ul ati o n  w as  a p pr o v e d f or  S 9 5 0 1 4  b y  c e ntr ali z e d r e vi e w  pr o c e d ur e i n  2 8  c o u ntri es i n t h e  E U  a n d 
3  c o u ntri es i n t h e  E E A i n  2 0 1 7. 
2. 2. 4.   St u d y  r ati o n al e  a n d  d esi g n  
A   p h as e  II,   p ar all el,   o p e n -l a b el   st u d y,   n a m e d    C L 2- 9 5 0 1 4-0 0 2,    w as   s et - u p  t o   d e m o nstr at e  t h e 
p h ar m a c o ki n eti c   c o m p ar a bilit y   of   b ot h  li q ui d   a n d  l y o p hili z e d  S 9 5 0 1 4  f or m ul ati o ns  i n   n e wl y-
di a g n os e d  p a e di atri c   A L L  p ati e nts.  
T h e  pr es e nt    C L 2 - 9 5 0 1 4- 0 0 3  st u d y  is  d esi g n e d  t o  pr o vi d e  c o nti n u e d   a c c ess  t o  S 9 5 0 1 4  d uri n g  t h e 
c o ns oli d ati o n  p h as e  i n  p ati e nts    w h o  c o m pl et e d   t h e    C L 2- 9 5 0 1 4-0 0 2  st u d y  a n d    w h o  ar e  cli ni c all y 
b e n efitti n g fr o m  S 9 5 0 1 4  wit h o ut  m aj or t o xi cit y .  
P ati e nts  will  b e  a d mi nist er e d l y o p hili z e d  S 9 5 0 1 4  d uri n g t h e  c o ns oli d ati o n  p h as e  at t h e  d os e  of  1 0 0 0, 
2 0 0 0   or  2 5 0 0    U/ m² ,  as   p er  i n v esti g at or’s  j u d g m e nt .    B a c k b o ne   c h e m ot h er a p y  r e gi m e n    will   b e 
a d mi nist er e d  as  p er  A L L - M B  2 0 1 5  pr ot o c ol. 
T h e  st u d y  will  b e  c o n d u ct e d i n  c o m pli a n c e  wit h t h e  pr ot o c ol,  G C P, t h e  et hi c al  pri n ci pl es t h at  h a v e 
t h eir  ori gi n i n t h e  D e cl ar ati o n  of  H elsi n ki a n d t h e  a p pli c a bl e r e g ul at or y r e q uir e m e n ts. 
3.   S T U D Y  O B J E C TI V E S  A N D  E N D P OI N T S  
T h e  m ai n  o bj e cti v e  of  t his  r oll -o v er  st u d y  is  t o  pr o vi d e  c o nti n u e d   a c c ess  t o  S 9 5 0 1 4  d uri n g  t h e 
c o ns oli d ati o n  p h as e  i n  p ati e nts    w h o  c o m pl et e d   t h e    C L 2- 9 5 0 1 4-0 0 2  st u d y  a n d    w h o  ar e  cli ni c all y 
b e n efitti n g fr o m  S 9 5 0 1 4  wit h o ut  m aj or t o xi cit y .  
S e c o n d ar y  o bj e cti v e  of t his r oll- o v er st u d y is t o  ass ess t h e s af et y  pr ofil e  of l y o p hili z e d  S 9 5 0 1 4  d uri n g 
t h e  c o ns oli d ati o n  p h as e.  All  a d v ers e  e v e nts  r e g ar dl ess  of  gr a d e  or  c a us alit y  a n d  s e v erit y  will  b e 
c oll e ct e d  aft er t h e i nf or m e d  c o ns e nt is si g n e d  a n d  d uri n g t h e  e ntir e tr e at m e nt  p eri o d (s e e  s e cti o n 8 ). 
4.   S T U D Y  D E SI G N  
4. 1.   I n v esti g ati o n al  pl a n 
4. 1. 1.   St u d y  pl a n  
T h e  pr es e nt  C L 2 - 9 5 0 1 4- 0 0 3  st u d y  is  a    m ulti c e ntre,  n o n- r a n d o mi z e d  r oll- o v er  st u d y  of  l y o p hili z e d 
P e g as p ar g as e ( O n c as p ar ®,  S 9 5 0 1 4) f or m ul ati o n  i n t h e tr e at m e nt  of  p e di atri c  p ati e nts  wit h  A L L w h o 
c o m pl et e d  t h e  C L 2- 9 5 0 1 4- 0 0 2 st u d y  d uri n g t h e i n d u cti o n  p h as e.  
 


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  1 9 /5 4  
 
Writt e n  i nf or m e d  c o ns e nt  a n d  ass e nt  ( w h e n  a p pr o pri at e)   will  b e  o bt ai n e d  fr o m  e a c h  p ati e nt  a n d/ or 
his/ h er  p ar e nt (s)/l e g al r e pr es e nt ati v e d uri n g t h e i n cl usi o n  visit,  c orr es p o n di n g t o t h e  wit h dr a w al  visit 
of t h e i niti al  C L 2 - 9 5 0 1 4- 0 0 2 st u d y.  
L y o p hili z e d  S 9 5 0 1 4  will  b e  a d mi nist er e d  e v er y t w o  w e e ks  d uri n g t h e  c o ns oli d ati o n  p h as e  at t h e  d os e 
of  1 0 0 0,  2 0 0 0  or  2 5 0 0  U/ m²,  as  p er i n v esti g at or’s j u d g m e nt.  P ati e nts  will  b e  a d mi nist er e d  9 i nf usi o ns 
of l y o p hili z e d  S 9 5 0 1 4,  at  w e e k  7,  9,  1 1,  1 5,  1 7,  1 9,  2 3,  2 5  a n d  2 7 ( 3  p h as es  S 1,  S 2  a n d  S 3).  P ati e nts 
will r e c ei v e  ot h er  b a c k b o n e  c h e m ot h er a p y  a g e nts  as  p er  A L L - M B  2 0 1 5  pr ot o c ol. 
T h e  st u d y  d ur ati o n  will  b e  a p pr o xi m at el y  7  m o nt hs, i n cl u di n g t h e tr e at m e nt  p eri o d  c o nsisti n g  of  t h e 
c o ns oli d ati o n  p h as e  a n d t h e f oll o w- u p  p eri o d . Aft er  c o m pl eti n g  t h e  c o ns oli d ati o n  p h as e,  p ati e nt  will 
b e  dis c o nti n u e d fr o m t h e st u d y  a n d  will  b e tr e at e d  as  p er i n v esti g at or’s j u d g m e nt . 
F or  m or e  d et ails  a b o ut t h e st atisti c al  a n al ys es  pl e as e r ef er t o t h e  se cti o n  1 0 . 
T h e st u d y  pl a n is s h o w n i n  Fi g ur e  ( 4. 1. 1)  1. 
Fi g u r e  (4. 1. 1 )  1  – St u d y  pl a n   
 
 
T h e st u d y  will  b e  di vi d e d i nt o t h e f oll o wi n g  p eri o ds f or  e a c h  p arti ci p a nt: 
­   I n cl usi o n  visit:  t o  o bt ai n  i nf orm e d  c o ns e nt   a n d  c h e c k  t h e  i n cl usi o n/ n o n-i n cl usi o n  crit eri a . T h e 
i n cl usi o n visit  of  C L 2 - 9 5 0 1 4-0 0 3  st u d y  will  c orr es p o n d t o t h e  wit h dr a w al  visit  of t h e i niti al  C L 2 -
9 5 0 1 4- 0 0 2 st u d y.  
­   T r e at m e nt  p e ri o d:  As  p er   A L L -M B  2 0 1 5  pr ot o c ol,  tr e at m e nt  p eri o d   will  st art  at   D a y  1  of  t h e 
c o ns oli d ati o n  p h as e.  P ati e nt s  will  b e  o n tr e at m e nt  u ntil t h e  e n d  of t h e  c o ns oli d ati o n  p h as e,  u nl ess 
t h e y  m e et  a  dis c o nti n u ati o n  crit eri o n  as  d es cri b e d i n s e cti o n 5. 6. 1 .  
­   Wit h d r a w al  visit:  u p  t o  3 0  d a ys  aft er  t h e  l ast  d os e  of  S 9 5 0 1 4  d uri n g  t h e  c o ns oli d ati o n  p h as e. 
P ati e nt    will   c o nti n u e   r e c ei vi n g   b a c k b o n e   c h e m ot h er a p e uti c   r e gi m e n   as   p er    A L L -M B   2 0 1 5 
pr ot o c ol,  a c c or di n g t o  p h ysi ci a n’s  j u d g m e nt. 
­   F oll o w- u p  visit :  a  c o nt a ct  or  t el e p h o n e  c all    will  b e  d o n e  a p pr o xi m at el y  3 0  d a ys  aft er  t h e  l ast 
S 9 5 0 1 4  i nf usi o n,  e x c e pt  i n  c as e  of  c o ns e nt    wit h dr a w al.  F oll o w -u p  of  a d v ers e  e v e nts  a n d  t h e 
p ati e nt’s s ur vi v al  will  b e r e c or d e d.  
T h e st u d y st art is  d efi n e d  as t h e  d at e  of t h e first  visit  of t h e first  p arti ci p a nt.   


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 0 /5 4  
 
E n d  of  Tri al is  d efi n e d  as t h e  d at e  of t h e l ast  visit  of t h e l ast  p arti ci p a nt  (f oll o w- u p  visit). 
I n  c as e  of  n o n-i n cl usi o n  of  a  p arti ci p a nt, it is t h e i n v esti g at or’s r es p o nsi bilit y t o  e ns ur e, i n  a c c or d a n c e 
wit h t h e l o c al st a n d ar ds  of  c ar e  a n d  m e di c al  pr a cti c es t h at:   
­   T h e r e as o n  of  n o n-i n cl usi o n is  e x pl ai n e d t o t h e  p arti ci p a nt, 
­   A n y  e v e nt  ass o ci at e d  wit h  a n y  pr o c e d ur e/ c o n diti o n  r e q uir e d  b y t h e  st u d y  pr ot o c ol  ( e. g.  a n  e v e nt 
o c c urri n g f oll o wi n g t h e  dis c o nti n u ati o n  of  a f or bi d d e n tr e at m e nt) is  c oll e ct e d, 
­   A n  a d e q u at e  alt er n ati v e  m e di c al  c ar e is  pr o p os e d t o t h e  p arti ci p a nt.  
A   n o n -i n cl usi o n   visit  is   n ot    m a n d at oril y   c arri e d   o ut,   pr o vi d e d  t h es e  r e q uir e m e nts  ar e    m et  a n d 
d o c u m e nt e d i n t h e  m e di c al fil e  of t h e  p arti ci p a nt.  
4. 1. 2.   I n v esti g ati o n s c h e d ul e 
T a bl e ( 4. 1. 2)  1  d es cri b es t h e  m e as ur e m e nt  of s af et y  ass ess e d  d uri n g t h e st u d y . 
 
 


S 9 5 0 1 4      
   
   
   
   
  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -9 5 0 1 4 -0 0 3  –  Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 1 /5 4  
 
T a bl e  (4. 1. 2 )  1 - I n v esti g ati o n s c h e d ul e  
 
   
      
   
   
 
 
 
I n cl usi o n 
visit  
C o ns oli d ati o n  p h as e  
Wit h d r a w al 
visit  
F oll o w -
u p  visit  
S 1  
S 2  
S 3  
W 7   
W 9   W 1 1   W 1 5   W 1 7   W 1 9   W 2 3   W 2 5   W 2 7  
I nf or m e d  c o ns e nt 
X   
  
  
  
  
  
  
  
  
  
 
 
I n cl usi o n   /   n o n-i n cl usi o n 
crit eri a   
X   
  
  
  
  
  
  
  
  
  
 
 
R el e v a nt  m e di c al / s ur gi c al 
hist or y  
X   
  
  
  
  
  
  
  
  
  
 
 
Pr e vi o us tr e at m e nts  
X   
  
  
  
  
  
  
  
  
  
 
 
C o n c o mit a nt tr e at m e nts   
X  
X  
X   
 
Pr e g n a n c y t est (s er u m)  1  
X   
  
  
  
X   
  
  
X   
  
  
X   
 
H ei g ht/ W ei g ht/ B S A   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X    
 
 
S 9 5 0 1 4  a d mi nistr ati o n  
(s e cti o n  6. 1) 
 
X   
X   
X   
X   
X   
X   
X   
X   
X    
 
 
Vit al si g ns  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
P h ysi c al   e x a mi n ati o n   / 
E C O G   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
E C G 1 
X   
  
  
  
  
  
  
  
  
  
X   
 
C ar di a c i m a gi n g 1 
X   
  
  
  
  
  
  
  
  
  
X   
 
A d v er s e  e v e nts   
X  
X  
X   
X  
Pl as m a  As p ar a gi n as e 
A cti vit y  ass ess m e nt  
(s e cti o n  9. 2) 
 
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
 
 
La b or at or y t ests 1 
  Bl o o d  h a e m at ol o g y   
X   
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X   
 
  Bl o o d  bi o c h e mistr y   
X   
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X   
 
  Bl o o d  c o a g ul ati o n  
X   
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X   
 
  Uri n ar y  bi o c h e mistr y   
X   
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X 
pr e-
d os e  
X   
 
  H e p atitis s er ol o g y  
X   
  
  
  
  
  
  
  
  
  
X   
 
1 R es ults  of  pr e g n a n c y t est,  c ar di a c i m a gi n g,  E C G  a n d l a b or at or y t ests  p erf or m e d i n t h e fr a m e  of  pr e vi o us  C L 2 -9 5 0 1 4 -0 0 2 st u d y 
wit h dr a w al  visit  c a n  b e  us e d t o  ass ess  p ati e nt’s i n cl usi o n i n  or d er t o  a v oi d  u n n e c ess ar y  e x a m  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 2 /5 4  
 
  
F or  f urt h er  pr a cti c al  d et ails,  m et h o ds  of  m e as ur e m e nt  ar e  pr o vi d e d i n s e cti o n 8 . 
T h e  m a xi m u m t ot al  v ol u m e  of  bl o o d  c oll e ct e d  p er  p arti ci p a nt  d uri n g t h e st u d y  will  b e   3 1 0 m L 
d uri n g  t h e   c o ns oli d ati o n   p h as e .  All  t h es e   s a m pl es   ar e   alr e a d y   p art   of  t h e   us u al   s af et y 
ass ess m e nt  p erf or m e d i n t h e fr a m e  of  A L L - M B  2 0 1 5  pr ot o c ol.  
4. 2.   M e as u r es t o  mi ni mis e  bi as  
T his  st u d y  is  a n  o p e n -l a b el  st u d y,  a n d  all  s u bj e cts    will  r e c ei v e  S 9 5 0 1 4  l y o p hili z at e  as  t h e 
I M P.    T h e   d os e   f or   e a c h   p ati e nt    will   b e   d et er mi n e d   as   p er   i n v esti g at or’s   j u d g m e nt. 
R a n d o mi z ati o n  a n d  bli n di n g  will  n ot  b e  us e d.  
4. 3.   St u d y  p r o d u cts  a n d  bli n di n g s yst e ms  
4. 3. 1.   P r o d u cts  a d mi nist e r e d  
S 9 5 0 1 4  l y o p hili z at e (t est  dr u g) is t h e I M P  a n d it  will  b e  m a n uf a ct ur e d  u n d er t h e r es p o nsi bilit y 
of  L es  L a b or at oir es  S er vi er I n d ustri e ( Gi d y,  Fr a n c e). 
C urr e ntl y,  S 9 5 0 1 4 is  n ot  a ut h ori z e d i n  R ussi a  i n  a n y  of its f or m ul ati o ns. 
T a bl e  ( 4. 3. 1)  1 pr o vi d es  a  d es cri pti o n  of t h e I M P. 
T a bl e  (4. 3. 1 )  1  – D es c ri pti o n  of t h e I M P  
 
 
S 9 5 0 1 4  
L y o p hili z at e  
P h a r m a c e uti c al f o r m   
P o w d er f or s ol uti o n f or i nf usi o n  
U nit  d os a g e  
3 7 5 0  U / 5  ml  vi al  
 
A p p e a r a n c e,  c ol o u r   
L y o p hili z e d  dr u g  pr o d u ct:  W hit e t o  off  w hit e  c a k e   
R e c o nstit ut e d  dr u g  pr o d u ct:  C ol o url ess s ol uti o n  
 
C o m p ositi o n   ( C o m p o n e nt/ 
A m o u nt  p e r  m L/  F u n cti o n)  
E a c h  vi al  c o nt ai ns  4 0 5 0    U  S 9 5 0 1 4  a cti v e  i n gr e di e nt,  s u cr os e  as  l y o pr ot e ct a nt, 
s o di u m  p h os p h at e  m o n o b asi c  a n d  di b asi c  as  b uff eri n g  a g e nts,  s o di u m  c hl ori d e f or 
t o ni cit y,  s o di u m  h y dr o xi d e  a n d  h y dr o c hl ori c  a ci d f or  P H  a dj ust m e nt. 
Aft er r e c o nstit uti o n  wit h  5. 2  ml  S W FI t h e  vi al  c o nt ai ns  7 5 0  U /  ml  or  3 7 5 0 /  5 ml 
S 9 5 0 1 4  a cti v e i n gr e di e nt  
 
  
T a bl e ( 4. 3. 1)  2  pr o vi d es  a  d es cri pti o n  of t h e  p a c k a gi n g  of t h e I M P.  
T a bl e  (4. 3. 1 )  2  – D es c ri pti o n  of  S 9 5 0 1 4  p a c k a gi n g  
   
N u m b e r   of   u nits   of  t h e   p h a r m a c e uti c al  f o r m   p e r 
p ri m a r y  p a c k a gi n g  
4 0 5 0  U  of  S 9 5 0 1 4  p o w d er f or s ol uti o n f or i nf usi o n i n 
a n i n di vi d u al  cl e ar  gl ass  vi al  
N u m b e r   of   p ri m a r y   p a c k a gi n g   p e r   s e c o n d a r y 
p a c k a gi n g  
1  vi al  of  S 9 5 0 1 4  l y o p hili z at e p er  b o x  
N u m b e r  of s e c o n d a r y  p a c k a gi n g  p e r  p ati e nt  a n d  p e r 
t r e at m e nt  p e ri o d 
T h e  n u m b er  of  vi als  p er  p ati e nt    will  d e p e n d  o n  t h e 
p ati e nt’s  B S A  a n d t h e  d os e  all o c at e d  
T h e l a b elli n g  of  p a c k a g es  c o m pli es  wit h t h e  r e g ul at or y r e q uir e m e nts  of t h e  c o u ntr y i n v ol v e d 
i n t h e st u d y. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 3 /5 4  
 
B a c k b o n e t h er a p y  dr u gs  will  b e  a d mi nist er e d  as  p er  A L L  M B  2 0 1 5  pr ot o c ol  (s e e  A p p e n di x 
1 ).   T h e y    will  b e  r e g ar d e d  as   NI M Ps  a n d    will  n ot  b e  pr o vi d e d  b y  t h e  S p o ns or.  F or  f urt h er 
i nf or m ati o n  a b o ut t h e  NI M Ps,  pl e as e r ef er t o s e cti o n 6. 1. 2 . 
4. 3. 2.   I M P  m a n a g e m e nt  
I M P r e c ei pt,  dis p e nsi n g  a c c or di n g t o t h e  e x p eri m e nt al  d esi g n  of t h e  st u d y (f or t h e  d es cri pti o n 
of   dis p e nsi n g    m et h o ds,   r ef er   t o  s e cti o n  6. 2 ),   a c c o u nt a bilit y   a n d   c oll e cti o n   ar e   t h e 
r es p o nsi bilit y  of t h e i n v esti g at or  a n d/ or  p h ar m a cist  of t h e  m e di c al i nstit uti o n. 
S p e cifi c  h a n dli n g  c o n diti o ns  a n d  cl e a ni n g  pr o c e d ur es    will  b e  d es cri b e d  i n   t h e   P h ar m a c y 
M a n u al.  
St a bilit y  a n d st or a g e  
T h e  I M P  s h o ul d  b e  st or e d i n  a  s e c ur e  ar e a  wit h r estri ct e d  a c c ess.  S p e cifi c  st or a g e  c o n diti o ns  
ar e  m e nti o n e d  o n I M P l a b elli n g  a n d  ar e  d et ail e d i n  t h e I n v esti g at or’s  Br o c h ur e. 
T h e  i n v esti g at or/ p h ar m a cist  is  r es p o nsi bl e  f or  t h e  I M P  t e m p er at ur e    m o nit ori n g  o n  a  d ail y 
b asis   usi n g   F O N T -CI R T -F O R M -3 1 1   “ T h er a p e uti c    U nit  t e m p er at ur e  l o g   s h e et  -  c e ntr e ” 
(r e c or di n g  Mi n- M a x t e m p er at ur e  e v er y  w or ki n g  d a y)  or  a n  e q ui v al e nt  d o c u m e nt.  
I n  c as e of t e m p er at ur e  d e vi ati o n, t h e i n v esti g at or/ p h ar m a cist s h o ul d i m m e di at el y:  
­   pl a c e t h e m i n  q u ar a nti n e,   
­   al ert  t h e    m o nit or  or  t h e  l o c al  pr oj e ct    m a n a g er  if  t h e    m o nit or  is  a bs e nt,  f or w ar d  hi m  all 
n e e d e d i nf or m ati o n  a n d i m pl e m e nt t h e i nstr u cti o ns  r e c ei v e d. 
F urt h er m or e, t h e i n v esti g at or/ p h ar m a cist  m ust  p ut i n  pl a c e  a n  a d e q u at e  c orr e cti v e/ pr e v e nti v e 
a cti o n  o n c e t h e first t e m p er at ur e  d e vi ati o n  o c c urs i n  or d er t o  a v oi d r e c urr e n c e . 
I M P  m a n a g e m e nt  will  b e  v erifi e d  o n  a r e g ul ar  b asis  b y t h e st u d y  m o nit or. 
T h e i n v esti g at or  a n d/ or t h e  p h ar m a cist  of t h e  m e di c al  i nstit uti o n  a n d/ or  a  d esi g n at e d  p ers o n 
fr o m t h eir  st u d y t e a m  m ust  c o m pl et e i n  r e al ti m e  all t h e  d o c u m e nts  pr o vi d e d  b y t h e  s p o ns or 
c o n c er ni n g  I M P  m a n a g e m e nt  (t h er a p e uti c  u nit tr a c ki n g  f or m  or  a n  e q ui v al e nt  d o c u m e nt …). 
T h er a p e uti c  u nit tr a c ki n g f or m,  or  a n  e q ui v al e nt  d o c u m e nt, is t h e s o ur c e  d o c u m e nt t o f ulfil. 
T h e  i n v esti g at or  a n d/ or  t h e  p h ar m a cist  of  t h e    m e di c al  i nstit uti o n  s h o ul d  o nl y  us e  t h e  I M P 
pr o vi d e d f or t h e  p arti ci p a nts i n v ol v e d i n t h e st u d y. 
All  d ef e cts  or  d et eri or ati o n  of I M P  or t h eir  p a c k a gi n g  ar e t o  b e r e p ort e d t o t h e  st u d y  m o nit or. 
T h e   i n v esti g at or    will   n otif y   t h e    m o nit or   of   all   c o m pl ai nts   s et   o ut   b y   a   p arti ci p a nt 
( a p p e ar a n c e …). 
I n t h e  e v e nt  of  a nti ci p at e d r et ur n  of I M P t o t h e s p o ns or ( b at c h re c all), t h e s p o ns or  will  pr e p ar e 
a n i nf or m ati o n l ett er i nt e n d e d f or t h e i n v esti g at or  a n d/ or  p h ar m a cist  of t h e  m e di c al i nstit uti o n. 
T his l ett er  will  b e s e nt  b y t h e  p ers o n l o c all y r es p o nsi bl e f or t h e st u d y t o  e a c h st u d y  c e ntr e.  O n 
r e c ei pt  of t h e l ett er, t h e i n v esti g at or  a n d/ or t h e  p h ar m a cist  will v erif y t h e  pr es e n c e  of t h e I M P 
o n  sit e   at  t h e    m o m e nt  t h e  i n ci d e nt   b e c o m es   k n o w n,   b y   usi n g,   a m o n g   ot h er  t o ols,  t h e 
t h er a p e uti c  u nit tr a c ki n g f or m,  or  a n  e q ui v al e nt  d o c u m e nt. 
 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 4 /5 4  
 
D estr u cti o n  
D estr u cti o n  of t h e  I M P is t h e  r es p o nsi bilit y  of t h e  s p o ns or  a n d/ or t h e i n v esti g at or  a n d/ or t h e 
p h ar m a cist  of t h e  m e di c al i nstit uti o n.  
Us e d  r e m ai ni n g  tr e at m e nts   will  b e  l o c all y  d estr o y e d  a n d  u n us e d  I M P    will  s u bs e q u e ntl y  b e 
c oll e ct e d  a n d  st or e d  a c c or di n g  t o  t h e  l o c al   pr o c e d ur es   a n d  r e q uir e m e nts,   b y  t h e   p ers o n 
r es p o nsi bl e f or t h e I M P  m a n a g e m e nt. 
A  c ertifi c at e d  d estr u cti o n f or  u n us e d I M P  will  b e  p erf or m e d  a c c or di n g t o  st a n d ar d  m o d aliti es 
f or  t h at  cl ass   of   pr o d u ct  a n d  t h e  att est ati o n    m ust   b e  s e nt  t o  t h e  s p o ns or.    T h e   pr a cti c al 
pr o c e d ur es  f or  d estr u cti o n  of  u n us e d  I M P  will  b e  d efi n e d  b y t h e  s p o ns or  a n d  a d a pt e d t o t h e 
c e ntr e.  A n I M P  c oll e cti o n  a n d  d estr u cti o n f or m  will  b e  c o m pl et e d  b ef or e t h e s hi p m e nt  of I M P 
t o  d estr u cti o n.    D estr u cti o n  of  I M P    m a y  b e  p ossi bl e    w h e n  t h e  pr o d u ct  h as  b e e n  us e d,  h as 
e x pir e d  or  aft er  at l e ast t h e l ast  visit  of t h e l ast tr e at e d  p arti ci p a nt.  
4. 3. 3.   M a n a g e m e nt  of  bli n di n g s yst e ms  
N ot  a p pli c a bl e 
4. 4.   Dis c o nti n u ati o n  of t h e st u d y   o r t e m p o r a r y  h alt 
4. 4. 1.   P r e m at u r e  dis c o nti n u ati o n  of t h e st u d y   o r t e m p o r a r y  h alt 
T his  st u d y    m a y   b e  t e m p or aril y   h a lt e d   or   pr e m at ur el y   dis c o nti n u e d  at   a n y  ti m e  f or  a n y 
s uffi ci e nt r e as o n a bl e  c a us e.  
Aft er   h a vi n g  i nf or m e d  t h e  n ati o n al  c o or di n at or,  t h e   s p o ns or   or  t h e  I n d e p e n d e nt    Et hi cs 
C o m mitt e e  (I E C)  or  t h e   C o m p et e nt   A ut h orit y  m a y  t er mi n at e  t h e  st u d y  b ef or e  its  s c h e d ul e d 
t er m.    T w o  c o pi es   of  t h e    writt e n  c o nfir m ati o n    will   b e   d at e d  a n d  si g n e d   b y  t h e  n ati o n al  
c o or di n at or.    T h e   I E Cs   a n d    C o m p et e nt    A ut h orit y  will   b e   i nf or m e d   a c c or di n g   t o   l o c al 
r e g ul ati o ns. 
If t h e  st u d y is  pr e m at ur el y  dis c o nti n u e d, t h e  o n-g oi n g  p arti ci p a nts  s h o ul d  b e  s e e n  as  s o o n  as 
p ossi bl e  a n d t h e s a m e  ass ess m e nts  as  d es cri b e d i n  se cti o n  5. 6  s h o ul d  b e  p erf or m e d.  
U n d er  s o m e  cir c u mst a n c es, t h e i n v esti g at or  m a y  b e i nf or m e d  of  a d diti o n al  pr o c e d ur es t o  b e 
f oll o w e d  i n  or d er  t o  e ns ur e  t h at  a d e q u at e  c o nsi d er ati o n  is  gi v e n  t o  t h e  pr ot e cti o n  of  t h e 
p arti ci p a nt ’s i nt er ests.  
I n  c as e  of  st u d y  s us p e nsi o n  (t e m p or ar y  h alt),  t h e  st u d y    m a y  r es u m e  o n c e  c o n c er ns  a b o ut 
s af et y,   pr ot o c ol   c o m pli a n c e,   d at a   q u alit y   ar e   a d dr ess e d   a n d   s atisf y   t h e   S p o ns or,   t h e 
I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E C)  a n d  C o m p et e nt  A ut h orit y. 
4. 4. 2.   P r e m at u r e  dis c o nti n u ati o n  of t h e st u d y i n  a n i n v esti g at o r sit e ( e a rl y sit e  cl os u r e)  
T h e  s p o ns or  r es er v es t h e  ri g ht t o  cl os e  a  st u d y  sit e  at  a n y ti m e  f or  a n y  s uffi ci e nt  r e as o n a bl e 
c a us e  at t h e s ol e  dis cr eti o n  of t h e s p o ns or.  
T h e i n v esti g at or  m a y  als o i niti at e  st u d y -sit e  cl os ur e  at  a n y ti m e,  pr o vi d e d t h er e is r e as o n a bl e 
c a us e  a n d s uffi ci e nt  n oti c e is  gi v e n i n  a d v a n c e  of t h e i nt e n d e d t er mi n ati o n. 
R e as o ns f or t h e  e arl y  cl os ur e  of  a st u d y sit e  b y t h e s p o ns or  or i n v esti g at or  m a y i n cl u d e  b ut  ar e 
n ot li mit e d t o:  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 5 /5 4  
 
­   F ail ur e  of t h e i n v esti g at or t o  c o m pl y  wit h t h e  pr ot o c ol, t h e r e q uir e m e nts  of t h e I E C  or l o c al 
C o m p et e nt  A ut h oriti es, t h e s p o ns or's  pr o c e d ur es,  or  G C P  g ui d eli n es 
­   I n a d e q u at e r e cr uit m e nt  of  p arti ci p a nts  b y t h e i n v esti g at or 
­   Dis c o n ti n u ati o n  of f urt h er st u d y i nt er v e nti o n  d e v el o p m e nt 
T h e I E C(s)  a n d  C o m p et e nt  A ut h oriti es  will  b e i nf or m e d  a c c or di n g t o l o c al r e g ul ati o ns. 
4. 4. 3.   Dis c o nti n u ati o n  of t h e st u d y i n t h e  e v e nt  of  o bj e cti v e  r e a c h e d  
N ot  a p pli c a bl e 
4. 5.   S o u r c e  d at a   
P ati e nt’s  m e di c al fil e ( e. g .  E C G r e p ort,  cli ni c al l a b or at or y  e x a mi n ati o n’s r e p orts  a n d  all  ot h er 
p ati e nts’  e x a mi n ati o n r es ults)   will  b e  c o nsi d er e d  as s o ur c e  d o c u m e nts. 
S o ur c e  d at a  a n d  s o ur c e  d o c u m e nts  of  t h e  c e ntr e  s h o ul d  b e  cl e arl y  i d e ntifi e d  i n  a  s p e cifi c, 
d et ail e d  a n d si g n e d  d o c u m e nt  b ef or e t h e  b e gi n ni n g  of t h e st u d y. 
5.   I N C L U SI O N A N D  WI T H D R A W A L  O F  P A R TI CI P A N T S  
5. 1.   I n cl usi o n c rit e ri a 
1.   P ati e nt  w h o  c o m pl et e d  t h e  C L 2- 9 5 0 1 4- 0 0 2 st u d y 
2.   P ati e nt  c urr e ntl y r e c ei vi n g  cli ni c al  b e n efit fr o m  pr e vi o us tr e at m e nt  wit h  S 9 5 0 1 4  as  p er 
i n v esti g at or’s j u d g m e nt 
3.   I nf or m e d  c o ns e nt  o bt ai n e d  as  d es cri b e d i n s e cti o n  1 3. 3  of t h e  pr ot o c ol 
4.   W o m e n  of  c hil d b e ari n g  p ot e nti al  ( W O C B P)    m ust  us e  a  hi g hl y  eff e cti v e   m et h o d  of 
birt h  c o ntr ol  ( b ot h  d es cri b e d i n  s e cti o n  5. 3 ) d uri n g  st u d y tr e at m e nt  a n d  f or  6  m o nt hs 
aft er  t h e  l ast  d os e  of  I M P . I n  c as e  of  us e  of  or al  c o ntr a c e pti o n   w o m e n  s h o ul d  h a v e 
b e e n  st a bl e  o n  t h e  s a m e  c o ntr a c e pti v e  dr u g  (i. e.  s a m e  a cti v e  pri n ci pl e)  f or  at  l e ast  1 
m o nt h  pri or t o t h e first I M P  a d mi nistr ati o n. I n  c as e  of  us e  of  h or m o n al  c o ntr a c e pti o n, 
W O C B P  a n d  m al e  p arti ci p a nts  wit h  W O C B P  p art n ers  s h o ul d  us e  a  s e c o n d  m et h o d  of 
c o ntr a c e pti o n,  als o  c all e d  b arri er    m et h o d,  s u c h  as    m al e  or  f e m al e  c o n d o ms,  c a p, 
di a p hr a g m  or  s p o n g e    wit h  s p er mi ci d e.    H o w e v er,  si n c e  t h er e  is  a  p ot e nti al  f or  a n 
i n dir e ct  i nt er a cti o n  b et w e e n  S 9 5 0 1 4  a n d  or al  c o ntr a c e pti v es,  t h e  c o n c o mit a nt  us e  of 
S 9 5 0 1 4   a n d   or al   c o ntr a c e pti v es  is   n ot  r e c o m m e n d e d.    A    m et h o d   ot h er  t h a n   or al 
c o ntr a c e pti v es s h o ul d  b e  us e d i n  W O C B P. 
5.   M al e  p arti ci p a nts  wit h  W O C B P  p art n ers  m ust  us e  a  c o n d o m  d uri n g t h e st u d y  a n d  u ntil 
at  l e ast  6    m o nt hs  aft er  t h e  l ast  d os e  of  I M P.   I n  a d diti o n,  c o ntr a c e pti o n  s h o ul d  b e 
c o nsi d er e d  f or  t h eir  f e m al e   p art n ers.   C o ntr a c e pti v e    m e as ur es   d o   n ot  a p pl y  if  t h e 
p arti ci p a nt is  st eril e,  v as e ct o mi z e d  or  s e x u all y  a bsti n e nt.  S p er m  d o n ati o n  will  n ot  b e 
all o w e d  d uri n g t h e st u d y  a n d f or  6  m o nt hs  aft er t h e l ast  d os e  of I M P . 
5. 2.   N o n -i n cl usi o n c rit e ri a 
5. 2. 1.   G e n e r al  c rit e ri a  
6.   U nli k el y t o  c o o p er at e i n t h e st u d y 
7.   Pr e g n a nt  a n d l a ct ati n g  w o m e n   
8.   P arti ci p a nt  alr e a d y i n cl u d e d i n t h e st u d y (i nf or m e d  c o ns e nt si g n e d) 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 6 /5 4  
 
5. 2. 2.   M e di c al  a n d t h e r a p e uti c  c rit e ri a  
9.   Si g nifi c a nt   l a b or at or y   a b n or m alit y   or   u n c o ntr oll e d   i nt er c urr e nt   ill n ess   ( e. g.   lif e -
t hr e at e ni n g  a c ut e t u m or l ysis  s y n dr o m e,  s y m pt o m ati c  c o n g esti v e  h e art f ail ur e,  c ar di a c 
arr h yt h mi a,  s e v er e  or  u n c o ntr oll e d  a cti v e  a c ut e  i nf e cti o n)  li k el y  t o  j e o p ar di z e  t h e 
p at i e nts’  s af et y  or  t o  i nt erf er e    wit h  t h e  c o n d u ct  of  t h e  st u d y,  i n  t h e  i n v esti g at or’s 
o pi ni o n 
1 0.  Hist or y  of s e nsiti vit y t o  p ol y et h yl e n e  gl y c ol ( P E G)  or  P E G -b as e d  dr u gs  
1 1.  Ps y c hi atri c   ill n ess/s o ci al   sit u ati o n   t h at    w o ul d   li mit   c o m pli a n c e    wit h   st u d y 
r e q uir e m e nts 
1 2.  Gr o u p  “ E ”  a n d  “ T -H R ”  p ati e nts  a c c or di n g t o  A L L - M B  2 0 1 5  pr ot o c ol cl assifi c ati o n  
1 3.  M aj or  s af et y iss u e  d u e t o  pr e vi o us  S 9 5 0 1 4  a d mi nistr ati o n ( e. g.  n o n r e c o v er y  of  s af et y 
p ar a m et ers,  s eri o us  h y p ers e nsiti vit y ,  s eri o us  p a n cr e atitis,  s eri o us  h a e m orr h a g e,  s eri o us 
t hr o m b oe m b oli c  e v e nt )  
5. 3.   D efi niti o n  of  w o m e n  of  c hil d b e a ri n g  p ot e nti al  a n d  c o nt r a c e pti o n  m et h o ds  
W o m e n  of  c hil d b e a ri n g  P ot e nti al 
A  w o m a n is  c o nsi d er e d  of  c hil d b e ari n g  p ot e nti al  ( W O C B P), i. e.  f ertil e,  f oll o wi n g  m e n ar c h e 
a n d   u ntil   b e c o mi n g   p ost -m e n o p a us al   u nl ess   p er m a n e ntl y   st eril e.   P er m a n e nt   st erili z ati o n 
m et h o ds   i n cl u d e   h yst er e ct o m y,   bil at er al   s al pi n g e ct o m y   a n d   bil at er al   o o p h or e ct o m y.    A 
p ost m e n o p a us al  st at e is  d efi n e d  as  n o  m e ns es  f or  1 2  m o nt hs  wit h o ut  a n  alt er n ati v e  m e di c al 
c a us e.  
 
C o nt r a c e pti o n  m et h o ds  
 
D efi niti o n  of  hi g hl y  eff e cti v e  c o nt r a c e pti o n  m et h o ds f o r t h e st u d y:   
Hi g hl y  eff e cti v e  m et h o ds  of  birt h  c o ntr ol r ef er t o t h os e  w hi c h r es ult i n  a l o w f ail ur e r at e (i. e. 
l ess  t h a n  1 %  p er  y e ar),    w h e n  us e d  c o nsist e ntl y  a n d  c orr e ctl y,  s u c h  as  c o m bi n e d  h or m o n al 
c o ntr a c e pti o n   ass o ci at e d    wit h   i n hi biti o n   of   o v ul ati o n   ( or al,   i ntr a v a gi n al,   tr a ns d er m al), 
pr o g est o g e n- o nl y  h or m o n al  c o ntr a c e pti o n  w h e n  ass o ci at e d  wit h i n hi biti o n  of  o v ul ati o n ( or al  , 
i nj e ct a bl e,  i m pl a nt a bl e),  s o m e  i ntr a  ut eri n e  d e vi c es  (I U Ds),  i ntr a ut eri n e  h or m o n e- r el e asi n g 
s yst e m (I U S), tr u e s e x u al  a bsti n e n c e ( w h e n t his is i n li n e  wit h t h e  pr ef err e d  a n d  us u al lif est yl e 
of t h e  p arti ci p a nt),  bil at er al t u b al  o c cl usi o n,  m al e st erili z ati o n ( v as e ct o m y).   
5. 4.   R et est  m a n a g e m e nt  b ef o r e t h e i n cl usi o n  
A  p ati e nt  w h o  h as  a  l a b or at or y  r es ult(s) t h at  d o es  n ot  s atisf y t h e  e ntr a n c e  crit eri a  m a y  h a v e 
t h e  t est  (s)  r e p e at e d  o n c e  pr o vi di n g  t h at  t h e  i n v esti g at or  j u d g es  it  r el e v a nt  a c c or di n g  t o  t h e 
p ati e nt  /  p arti ci p a nt  pr e vi o us  r es ults,  or    m e di c al  hist or y  a n d  if  s/ h e  c o nsi d ers  l a b or a t or y 
a b n or m aliti es  ar e  li k el y  t o  b e  tr a nsi e nt.    R es ults  of  t h e  t est(s)  r e p e at e d  s h o ul d  b e  o bt ai n e d 
b ef or e  t h e  i n cl usi o n.  I n  t his  c as e  t h e  p ati e nt/ p arti ci p a nt   will  n ot  b e  r e q uir e d  t o  si g n  a n ot h er 
i nf or m e d  c o ns e nt,  a n d t h e  ori gi n al  p ati e nt /  p arti ci p a nt I D  n um b er  assi g n e d  b y t h e i n v esti g at or 
will  b e  us e d. 
In   a n y   c as e,  t h e  l ast   r es ult   a v ail a bl e   f or   e a c h   p ar a m et er    m ust   b e   c o nsi d er e d   f or  t h e 
p ati e nt/ p arti ci p a nt i n cl usi o n.  
5. 5.   A d diti o n al i nf o r m ati o n  r e c o r d e d  at t h e i n cl usi o n  visit  
N ot  a p pli c a bl e 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 7 /5 4  
 
5. 6.   P a rti ci p a nt  wit h d r a w al  
5. 6. 1.   Wit h d r a w al  c rit e ri a  
Pr e m at ur e  dis c o nti n u ati o n  of  I M P  c orr es p o n ds  t o  p arti ci p a nt  pr e m at ur el y  dis c o nti n u ati o n  of 
t h e st u d y.  
I nf or m ati o n t o  b e  c oll e ct e d  d uri n g t h e l ast  visit  of t h es e  p arti ci p a nts is  gi v e n i n  s e cti o n  5. 6. 2 . 
T h es e  f oll o w -u p    m o d aliti es  ar e   us e d  t o  e ns ur e  s af et y  e v al u ati o n   of  all   p arti ci p a nts    w h o 
r e c ei v e d t h e I M P. 
T h e r e as o ns f or  pr e m at ur e  dis c o nti n u ati o n  of I M P  ar e: 
­   A d v e rs e  e v e nts  a c c or di n g t o t h e j u d g e m e nt  of t h e i n v esti g at or  or  a c c or di n g t o t h e  crit eri a  
d efi n e d i n  se cti o n  8. 1 0  
­   Pr e g n a n c y  (s e cti o n 8. 9. 2. 3 ) 
­   M aj o r   d e vi ati o n  t o   p r ot o c ol   if  it  i nt erf er es    wit h  t h e  st u d y   e v al u ati o ns   a n d/ or  if  it 
j e o p ar dis es  p arti ci p a nt’s s af et y 
­   P r o g r essi v e   dis e as e   d o c u m e nt e d    wit h   a p pr o pri at e    m et h o d   of   e v al u ati o n   a c c or di n g  t o 
dis e as e  c h ar a ct eristi cs  
­   N o n -m e di c al  r e as o n  ( e. g.  c o ns e nt  wit h dr a w al,  p arti ci p a nt’s r e m o v al)  
­   Ot h e r,  p h ysi ci a n  d e cisi o n  
5. 6. 2.   P r o c e d u r e  
U p o n  dis c o nti n u ati o n  of tr e at m e nt t h e i n v esti g at or  m ust: 
­   N otif y t h e  Cli ni c al  R es e ar c h  Ass o ci at e ( C R A) i m m e di at el y  
­   I n di c at e t h e  m ai n r e as o n, if t h er e  ar e s e v er al r e as o ns 
­   R e c or d t his i nf or m ati o n i n t h e  e C R F 
I n t h e  c as e  of  pr e m at ur e  wit h dr a w al  fr o m t h e  st u d y  d u e t o  a n  a d v ers e  e v e nt  ( e v e nt  r e q uiri n g 
i m m e di at e   n otifi c ati o n   or   n ot),  t h e  i n v esti g at or    m ust    m a k e   e v er y   eff ort  t o   c oll e ct  t h e 
i nf or m ati o n  r el ati n g  t o  t h e   o ut c o m e   of  t h e   e v e nt.  If   n e c ess ar y,  t h e  i nf or m ati o n    will   b e 
c oll e ct e d   aft er w ar ds  (s e e  s e cti o n  8. 9 ).    T his  i nf or m ati o n  is  r e c or d e d  i n  t h at   p art   of  t h e 
el e ctr o ni c  c as e  r e p ort  f or m  w hi c h  c o n c er ns  a d v ers e  e v e nts.  If t h e i n v esti g at or  c a n n ot  c oll e ct 
t h e i nf or m ati o n fr o m  a  visit,  h e  m ust  c oll e ct it fr o m t h e  d o ct or  e ns uri n g t h e f oll o w-u p  of t h e 
p arti ci p a nt.  
If  t h e  st u d y  is  st o p p e d  /  I M P  is  dis c o nti n u e d  as  a  r es ult  of  a n  e v e nt  r e q uiri n g  i m m e di at e 
n otifi c ati o n, t h e  pr o c e d ur e  d es cri b e d i n  s e cti o n 8. 9. 2. 5  is t o  b e i m pl e m e nt e d. 
T h e  dis p ositi o ns t o  b e t a k e n  aft er t h e I M P  dis c o nti n u ati o n  ar e  d es cri b e d i n  s e cti o n 6. 5 . 
All  s a m pl es    will  b e  d estr o y e d  aft er    m a n d at or y  ass ess m e nt  is  c o m pl et e d  a n d  at  t h e  l at est 
b ef or e t h e fi n al  v ersi o n  of t h e  cli ni c al r e p ort. 
5. 6. 3.   L ost t o f oll o w- u p  
W h e n  t h e  i n v esti g at or  h as  n o  n e ws  of  t h e  p arti ci p a nt,  h e/s h e    m ust    m a k e  e v er y  eff ort  t o 
c o nt a ct   hi m/ h er   or   a   p ers o n   ar o u n d   hi m/ h er   ( p h o n e   c alls,   l ett ers   i n cl u di n g   r e gist er e d 
o n es … et c.),  t o   est a blis h  t h e  r e as o n  f or  t h e   dis c o nti n u ati o n   of  I M P   a n d  t o   s u g g est  t h e 
p arti c i p a nt  c o m es t o  a n  e n d- of-st u d y  visit.  If  all t h es e  att e m pts t o  c o nt a ct t h e  p arti ci p a nt f ail, 
t h e i n v esti g at or  c a n t h e n  d e cl ar e t h e  p arti ci p a nt  “l ost t o  f oll o w-u p ”.  T h e i n v esti g at or  s h o ul d 
d o c u m e nt  all t h es e  att e m pts i n t h e  c orr es p o n di n g  m e di c al fil e.  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
 2 8 /5 4  
 
6. 
T R E A T M E N T  O F P A R TI CI P A N T S
6. 1.  I M P a n d NI M Ps  a d mi nistere d  
6. 1. 1.  
I M P 
S 9 5 0 1 4 l y o p hi lizate is c onsi dere d  as the st u d y  I M P. 
S 9 5 0 1 4  d osa ge is calc ulate d acc or di n g to  b od y  surf ace area ( B S A). T he  BS A  will be 
calc ulate d by  the  i n vesti gat or bas e d  o n th e he i g ht a n d wei g ht meas ure d o n the da y of S 9 5 0 1 4 
i nf usi o n (all B S A calc ulati o ns are ro u n de d t o 2 deci mal pl aces). Hei g ht an d wei g ht m eas ure d 
wit hi n 3 da ys be f ore the date of S 9 5 0 1 4 i nf usi o n will be acce pta ble. 
B S A (m²) = √ ( Hei g ht [c m] x Wei g ht [k g]/ 3 6 0 0)  
St u d y  sites are re q uire d to  use o nl y  cali brate d a nd  certifie d scales t hr o u g h o ut t he st u d y. 
L y o p hilize d S 9 5 0 1 4 will be a d mi nistere d I V, o ver 1 t o 2 h o urs, e ver y t w o wee ks  d uri n g t he 
c o ns oli dati o n p hase at t he d ose of 1 0 0 0, 2 0 0 0 or 2 5 0 0 U/ m², as per i n vesti gat or’s j u d g me nt . 
Patie nts will be a d mi nistere d  9 i nf usi o ns of l y o p hilize d S 9 5 0 1 4, at wee k 7, 9, 1 1, 1 5, 1 7, 1 9, 
2 3, 2 5 a n d 2 7 ( 3 p hases S 1, S 2 a n d S 3). Patie nts will recei ve ot her b ac k b o ne c he m ot hera p y 
a ge nts as per A L L - M B 2 0 1 5 pr ot oc ol. 
6. 1. 2.  
NI M Ps 
Bac k b o ne  t hera p y dr u gs use d d uri n g t he w h ole treat me nt peri o d will be a d mi nistere d as per 
A L L M B 2 0 1 5 pr ot oc ol (see A p pe n di x 1 ). T he y will be re gar de d as NI M Ps a n d will n ot be 
pr o vi de d b y t he S p o ns or. 
Bac k b o ne t hera pies use d d uri n g t he c o ns oli dati o n p hase are, as f oll o ws: 
­ De xa met has o ne 
­ Met h otre xate  
­ 6- M P  ( 6- merca pt o p uri ne)
­ Vi ncristi ne
­ Da u n or u bici n
­ I dar u bici n
­ Met h otre xate/c ytara bi ne/ pre d nis ol o ne i ntrat hecal
­ B ortez o mi b
­ I mati ni b
­ Dasati ni b
F or f urt her details a b o ut NI M Ps, please refer t o res pecti ve S m P C. 
6. 2.  I M P dis pe nsi n g 
Patie nts will recei ve l y o p hilize d S 9 5 0 1 4 e ver y  tw o  w ee ks d uri n g t he c o ns oli dati o n p hase at 
t he d ose of 1 0 0 0, 2 0 0 0 or 2 5 0 0 U / m², as per i n vesti gat or’s j u d g me nt. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  2 9 /5 4  
 
At t h e  wit h dr a w al  visit  of t h e  st u d y, t h e i n v esti g at or  will  pr o p os e  a tr e at m e nt  a d a pt e d  t o t h e 
n at ur e  of t h e  cli ni c al  st at e  of t h e  p ati e nt  a n d  a c c or di n g t o  his/ h er t h er a p e uti c  gr o u p  a s  d efi n e d 
i n  A L L- M B  2 0 1 5  pr ot o c ol ( m ai nt e n a n c e  p h as e). 
I M P    will  b e  dis p e ns e d  b y  t h e  p h ar m a cist/r es p o nsi bl e  of  t h e  h e alt h c ar e  est a blis h m e nt  u p o n 
pr es cri pti o n  of t h e i n v esti g at or  o nl y. 
T h e  i n v esti g at or    m a y  o nl y  us e  t h e  I M P  pr o vi d e d  f or  t h e  p ati e nts  i n v ol v e d  i n  t h e  st u d y  a n d 
tr e at e d  u n d er  his/ h er r es p o nsi bilit y  or t h at  of  a  d esi g n at e d  c o-i n v esti g at or. 
F or  e a c h  p ati e nt, t h e I M P  will  o nl y  b e  dis p e ns e d  d uri n g t h e st u d y. 
F urt h er  i nstr u cti o ns  f or  t h e  pr e p ar ati o n  a n d  dis p e ns ati o n  of   S 9 5 0 1 4   ar e  d es cri b e d  i n  t h e 
P h ar m a c y  M a n u al.  
All  d os a g es  of  S 9 5 0 1 4  pr es cri b e d t o t h e  p ati e nt  a n d  all  d os e  c h a n g es  d uri n g t h e st u d y  m ust  b e 
r e c or d e d i n t h e  e C R F. 
T h e  d et a c h a bl e  p orti o n  of t h e l a b el  o n t h e  I M P  b o x  m ust  b e  st u c k  b y t h e i n v esti g at or  o n  a n 
I M P  l a b el  c oll e cti o n  f or m  or  o n  t h e  pr es cri pti o n  f or m    w h er e  t h e  I M P  ar e  dis p e ns e d  b y  a 
p h ar m a cist.  
6. 3.   P r e vi o us  a n d  c o n c o mit a nt t r e at m e nts  
If  a  p ati e nt r e c ei v es  a n y  dr u g  ot h er t h a n  S 9 5 0 1 4  a n d  b a c k b o n e t h er a pi es  us e d i n t h e fr a m e  of 
A L L -M B  2 0 1 5  d uri n g t h e  p eri o d fr o m t h e  d a y  of i nf or m e d  c o ns e nt t o  t h e  wit h dr a w al  d a y, t h e 
f oll o wi n g i nf or m ati o n  will  b e  e nt er e d i n  e C R F: 
-  N a m e  of  dr u g  or t h er a p y  
-  St art  d at e  a n d  e n d  d at e  of tr e at m e nt  
-  R o ut e  of  a d mi nistr ati o n  
-  I n di c ati o n 
 
T h e f oll o wi n g tr e at m e nts  ar e t o  b e  us e d  wit h  c a uti o n  d uri n g t h e  w h ol e  tr e at m e nt  p eri o d: 
­   Li v e  v a c ci n es  
­   C o u m ari n/ w arf ari n  a n d  h e p ari n,  di p yri d a m ol e,  a c et yls ali c yli c  a ci d  or  n o n -st er oi d al  a nti-
i nfl a m m at or y  m e di ci n es ( e. g. i b u pr of e n,  n a pr o x e n). 
­   Pr e d nis o n e ,   m et h otr e x at e, vi n cristi n e ,  c yt ar a bi n e (s e e   A L L-M B  2 0 1 5  pr ot o c ol  f or  f urt h er 
d et ails)  
F or f urt h er i nf or m ati o n  a b o ut t h e  dr u g -dr u g i nt er a cti o ns,  pl e as e r ef er t o t h e  l ast  v ersi o n of t h e 
I n v esti g at or’s  Br o c h ur e. 
T h e  p ati e nt  a n d  his/ h er  p ar e nt(s)/l e g al r e pr es e nt ati v e  m ust  b e t ol d t o  n otif y t h e  i n v esti g ati o n al 
sit e  a b o ut  a n y  n e w    m e di c ati o ns  h e/s h e  t a k es  aft er  h a vi n g  si g n e d  t h e  I C F  of  t h e  st u d y.    All 
m e di c ati o ns  ( ot h er  t h a n  st u d y  dr u gs)  a n d  si g nifi c a nt  n o n -dr u g  t h er a pi es  (i n cl u di n g  bl o o d 
tr a nsf usi o n)  a d mi nist er e d  d uri n g t h e st u d y  m ust  b e list e d  o n t h e  e C R F. 
F or  a  gi v e n  p ati e nt ,  pr e vi o us  tr e at m e nts  a n d  c o n c o mit a nt  tr e at m e nts  alr e a d y  r e p ort e d  i n  t h e 
i niti al  C L 2- 9 5 0 1 4-0 0 2  st u d y  a n d  n ot  o n g oi n g  at t h e ti m e  of i n cl usi o n,  will  n ot  b e r e p ort e d i n 
t h e  e C R F. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 0 /5 4  
 
6. 4.   I M P  c o m pli a n c e  
T h e  n u m b er  of i nj e ct a bl e  vi als  dis p e ns e d  ar e t o  b e  c o u nt e d  b y t h e i n v esti g at or  or  a  d esi g n at e d 
p ers o n fr o m  his/ h er t e a m  a n d r e c or d e d i n t h e  el e ctr o ni c  c as e r e p ort f or m  a n d t h er a p e uti c  u nit 
tr a c ki n g f or m,  or  a n  e q ui v al e nt  d o c u m e nt. 
T h e  c o m pli a n c e  will  b e  ass ess e d fr o m t h e  m et h o d  d es cri b e d  a b o v e. 
6. 5.   D is c o nti n u ati o n  of t h e I M P 
Aft er  t h e  dis c o nti n u ati o n  of  t h e  I M P,  t h e  p arti ci p a nts’  tr e at m e nt  is  l eft   t o  t h e  p h ysi ci a n’s 
dis cr eti o n ,  a c c or di n g t o l o c al r e g ul ati o n  a n d  pr a cti c e.  
7.   A S S E S S M E N T  O F  E F FI C A C Y  
 
N ot  a p pli c a bl e 
8.   A S S E S S M E N T  O F  S A F E T Y  
All  a d v ers e  e v e nts  a n d  ot h er  sit u ati o ns  r el e v a nt  t o  t h e  s af et y  of  t h e  p arti ci p a nts    m ust  b e 
f oll o w e d  u p  a n d  f ull y  a n d  pr e cis el y  d o c u m e nt e d i n  or d er  t o  e ns ur e t h at t h e  s p o ns or  h as t h e 
n e c ess ar y i nf or m ati o n t o  c o nti n u o usl y  ass ess t h e  b e n efit- ris k  b al a n c e  of t h e  cli ni c al tri al. 
8. 1.   S p e cifi c ati o n  of s af et y  p a r a m et e rs  
S af et y  m e as ur e m e nts  p erf or m e d  d uri n g t h e st u d y  ar e i n di c at e d i n  T a bl e  ( 4. 1. 2)  1 . 
S af et y  ass ess m e nt  of l y o p hili z e d  S 9 5 0 1 4  will i n cl u d e: 
­   a d v ers e  e v e nts ( A Es)  ass ess m e nts  
­   p h ysi c al  e x a mi n ati o ns,  p erf or m a n c e st at us  E C O G (s e e  A p p e n di x  2 ) 
­   l a b or at or y   ass ess m e nts   i n cl u di n g  h a e m at ol o g y,   bl o o d   bi o c h e mistr y,   c o a g ul ati o n 
p ar a m et ers,  uri n al ysis,  h e p atitis  s er ol o g y  
­   vit al si g ns  m e as ur e m e nts  
 
A d v ers e  e v e nts  will  b e  c oll e ct e d  r e g ar dl ess  of  gr a d e  or  I M P r el ati o ns hi p  a n d  will  b e  gr a d e d 
a c c or di n g t o  c urr e nt  N ati o n al  C a n c er  Instit ut e ( N CI)  C T C A E  crit eri a  5. 0  
 
A n y si g nifi c a nt  a b n or m alit y  d et e ct e d  d uri n g s af et y  ass ess m e nts fr o m t h e  p ati e nt I C F si g n at ur e  
u ntil t h e  wit h dr a w al  visit  m ust  b e r e p ort e d  o n t h e  a d e q u at e  e C R F  p a g e  b y t h e i n v esti g at or  at 
e a c h  visit ( A E,  m e di c al  hist or y  or si g n  & s y m pt o ms).  
8. 2.   M et h o ds  a n d  m e as u r e m e nt ti m es  
R el e v a nt    m e di c al  hist o r y   will  b e  r e p ort e d  t o  i d e ntif y  a n y    m e di c al  c o n diti o n    w hi c h  c o ul d 
pr e cl u d e  p ati e nt’s i n cl usi o n: 
­   I niti al  di a g n osis 
­   Pr e vi o us  c h e m ot h er a pi es,  b o n e  m arr o w tr a ns pl a nts,  s ur g eri es, r a di ot h er a pi es r el at e d t o t h e 
st u di e d  dis e as e 
­   C o n c o mit a nt si g ns  a n d s y m pt o ms r el at e d t o t h e st u di e d  dis e as e 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 1 /5 4  
 
­   C o n c o mit a nt  a n d  pr e vi o us tr e at m e nts 
 
Cli ni c al  e x a mi n ati o n  a n d  vit al si g ns  m e as u r e m e nts 
­   S er u m  pr e g n a n c y t est  will  o nl y  b e  p erf or m e d f or  W O C B P  (s e e se cti o n   5) 
­   C o m pl et e  cli ni c al  e x a mi n ati o n ,  h ei g ht  a n d  w ei g ht  m e as ur e m e nt  a n d  E C O G  P S  ass ess m e nt 
will  b e  p erf or m e d  
­   Vit al  si g ns    m e as ur e m e nts  i n cl u d e  bl o o d  pr ess ur e  ( B P),  h e art  r at e  ( H R)  a n d  t e m p er at ur e. 
B P  a n d  H R  will  b e  m e as ur e d  b y  a n  a ut o m ati c  d e vi c e i n s u pi n e  p ositi o n  aft er  5  mi n r est.  
 
Vit al  si g ns  a n d  p erf or m a n c e  st at us  m e as ur e m e nts  will  b e  p erf or m e d  at i n cl usi o n ,  b ef or e  e a c h 
S 9 5 0 1 4 i nf usi o n  a n d  d uri n g t h e  wit h dr a w al  visit. 
 
L a b o r at o r y t ests 
All  l a b or at or y  t ests   p erf or m e d   d uri n g  t h e  st u d y   p eri o d    will   b e  ass a y e d  i n  a n  i d e ntifi e d 
l a b or at or y  at  h os pit al. I nt er-visits l a b or at or y t ests  c o ul d  b e  ass a y e d  b y l o c al l a b or at ori es. I n  all 
c as es, t h e f ull  v ali d at e d  s et  of  n or m al r a n g es  v al u es  will  b e  c oll e ct e d,  as  w ell  as  a n y  u p d at e i n 
t h es e  v al u es  d uri n g t h e st u d y  a n d  m ust  b e  d o c u m e nt e d i n t h e  c orr es p o n di n g  e C R F p a g es.  
All  s a m pl es    will  b e  d estr o y e d  aft er    m a n d at or y  ass ess m e nt  is  c o m pl et e d  a n d  at  t h e  l at est 
b ef or e t h e fi n al  v ersi o n  of t h e  cli ni c al  r e p ort. 
T h e l a b or at or y  p ar a m et ers  c oll e cti o n  pl a n is  d es cri b e d i n  T a bl e ( 8. 2)  1 .  
B l o o d   h a e m at ol o g y,   bl o o d   bi o c h e mistr y,   bl o o d  c o a g ul ati o n  a n d   uri n ar y   a n al ysis    will   b e 
p erf or m e d  at i n cl usi o n ,  b ef or e  e a c h  S 9 5 0 1 4 i nf usi o n  a n d  d urin g t h e  wit h dr a w al  visit.  
H e p atitis s er ol o g y  will  b e  p erf or m e d  at i n cl usi o n   a n d  d uri n g t h e  wit h dr a w al  visit. 
Pr e g n a n c y t est  will  b e  p erf or m e d  at i n cl usi o n ,  b ef or e  e a c h  p h as e  of t h e  c o ns oli d ati o n (i. e.  S 1, 
S 2  a n d  S 3)  a n d  d uri n g t h e  wit h dr a w al  visit. 
R es ults  of  pr e g n a n c y t est  a n d l a b or at or y  t ests p erf or m e d i n t h e fr a m e  of  pr e vi o us  C L 2 - 9 5 0 1 4-
0 0 2  st u d y    wit h dr a w al   visit   c a n   b e   us e d  t o   ass ess   p ati e nt’s  i n cl usi o n  i n   or d er  t o   a v oi d 
u n n e c ess ar y  e x a m . 
 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 2 /5 4  
 
T a bl e  (8. 2 )  1 - L o c al  Cli ni c al l a b o r at o r y  p a r a m et e r s  c oll e cti o n  pl a n  
T est  C at e g o r y   
T est  N a m e  
H a e m at ol o g y  
Ha e m at o crit,  H a e m o gl o bi n,  R e d  bl o o d  c ells  ( R B C), W hit e  bl o o d  c ells ( W B C ),  Pl at el ets, 
Diff er e nti al  ( B as o p hils,    E osi n o p hils,    L y m p h o c yt es,    M o n o c yt es, N e utr o p hils,    Bl asts  i n 
a bs ol ut e  v al u e  a n d i n  %)  
Bi o c h e mistr y  
Al b u mi n,    Al k ali n e  P h os p h at a s e  ( A L P),    A L T,    A S T,  A m m o ni a,  Bi c ar b o n at es,  G a m m a -
gl ut a m yl -tr a nsf er as e   ( G G T),    L a ct at e   d e h y dr o g e n a s e   ( L D H),    C al ci u m,   P h os p h or us, 
S o di u m,   P ot assi u m,    Cr e ati ni n e,    T ot al    Bil ir u bi n,    T ot al    C h ol est er ol,    L D L,    H D L, 
Tri gl y c eri d es,  B U N  or  Ur e a,  Uri c  A ci d  
A m yl as e,  Li p as e,  Gl u c os e   
Uri n ar y  a n al ysis   
M a cr os c o pi c  P a n el ( Di psti c k) ( Bl o o d,  Gl u c os e,  K et o n es,  Pr ot ei n)  
If  t h e   di psti c k  t e st  is  at  l e a st   2 +   o n   o n e   or    m or e p ar a m et er(s),   q u a ntit ati v e   uri n ar y 
bi o c h e mistr y t e sts  will  b e  p erf or m e d  o n t h e  a b n or m al  p ar a m et er(s)  
Bl o o d  c o a g ul ati o n  
Pr ot hr o m bi n ti m e  - I nt er n ati o n al  N or m ali z e d  R ati o (I N R), fi bri n o g e n,  pr ot ei n  S  a cti vit y, 
a ntit hr o m bi n  a cti vit y , a cti v at e d  P arti al  T hr o m b o pl asti n  Ti m e  ( a P T T),  D-di m er,  F D P   
H e p atitis  s er ol o g y  
H bs A g,   H bs A b,   H b c A b,  if   H bs A g  or   H b c A b  p ositi v e  c h e c k  vir al  l o a d  ( H B V -D N A)  at 
b as eli n e,  H C V  R N A -P C R,  H E V  R N A -P C R  
Pr e g n a n c y  T est  
P r e g n a n c y   t esti n g   is    m a n d at or y   at   i n cl usi o n  (s er u m),   b ef or e   e a c h  p h a s e  of   t h e 
c o ns oli d ati o n (i. e.  S 1,  S 2,  S 3)  a n d  at  wit h dr a w al  visit  (s er u m) f or  W O C B P 
All s a m pli n gs f or  bi o c h e mistr y s h o ul d  b e t a k e n i n f asti n g  c o n diti o ns. 
A b n or m al   l a b or at or y   v al u es   or   t est/ e x a ms   r es ults   (i. e.  bl o o d   pr ess ur e  r e c or di n g)    will 
c o nstit ut e  a n  A E if t h e y  ar e:  
­   ass o ci at e d  wit h si g ns  a n d s y m pt o ms,  or 
­   d e e m e d  cli ni c all y si g nifi c a nt i n t h e i n v esti g at or’s  o pi ni o n,  or 
­   if t h e y r e q uir e  c ur ati v e t h er a pi es,  or 
­   ass o ci at e d  wit h  d el a y  of st u d y  m e di c ati o n,  or  
­   ass o ci at e d  wit h st u d y  dis c o nti n u ati o n 
 
T ri pli c at e  El e ct r o c a r di o g r a ms  ( E C G)  will  b e  ass ess e d  at  i n cl usi o n  a n d  at  t h e   wit h dr a w al 
visit.  
 
L V E F  ass ess m e nt  will  b e  p erf or m e d t hr o u g h  e c h o c ar di o gr a p h y  or  M U G A  s c a n  at i n cl usi o n  
a n d  at  t h e wit h dr a w al  visit .  
 
R es ults  of   L V E F  ass ess m e nt  a n d   E C G  p erf or m e d  i n  t h e  fr a m e  of  pr e vi o us   C L 2 - 9 5 0 1 4- 0 0 2 
st u d y  wit h dr a w al  visit  c a n  b e  us e d t o  ass ess  p ati e nt’s i n cl usi o n i n  or d er t o  a v oi d  u n n e c ess ar y 
e x a m 
P ost- wit h dr a w al f oll o w -u p:  Aft er t h e  wit h dr a w al  visit,  a  c o nt a ct  or t el e p h o n e  c all  will  b e  d o n e 
a p pr o xi m at el y  3 0  d a ys  aft er t h e l ast  S 9 5 0 1 4 i nf usi o n,  e x c e pt i n  c as e  of  c o ns e nt  wit h dr a w al.   
T h e f oll o wi n g i nf or m ati o n  will  b e  c oll e ct e d:   
­   f oll o w- u p  a d v ers e  e v e nts  
­   t h e first  n e w  a nti c a n c er tr e at m e nt  aft er  wit h dr a w al  a n d its st arti n g  d at e. 
 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 3 /5 4  
 
8. 3.   D efi nit i o n  of A d v e rs e  e v e nts  
A n  a d v ers e  e v e nt is  d efi n e d  as  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a s u bj e ct  p arti ci p ati n g i n  a 
cli ni c al  st u d y,  w h et h er  or  n ot t h er e is  a  c a us al r el ati o ns hi p  wit h t h e I M P  a n d/ or  e x p eri m e nt al 
pr o c e d ur es,  o c c urri n g  or  d et e ct e d  fr o m  t h e  d at e  t h e  p arti ci p a nt  si g ns  t h e  i nf or m ati o n  a n d 
c o ns e nt  f or m,  irr es p e cti v e  of  t h e  p eri o d  of  t h e  st u d y  ( p eri o ds   wit h o ut  a d mi nistr ati o n  of  t h e 
I M P ( e. g. r u n-i n  p eri o d)  ar e  als o  c o n c er n e d). 
A n  a d v ers e  e v e nt  c a n t h er ef or e  b e:  
­   a n y  u nf a v o ur a bl e  a n d  u ni nt e n d e d  si g n   (i n cl u di n g  a n  a b n or m al  fi n di n g  fr o m  a n  a d diti o n al 
e x a mi n ati o n  s u c h  as l a b t ests,  X-r a ys,  E C G,  …) w hi c h is  d e e m e d  cli ni c all y r el e v a nt  b y t h e 
i n v esti g at or,  
­   a n y s y m pt o m  or  dis e as e,  
­   a n y    w ors e ni n g  d uri n g  t h e  st u d y  of  a  s y m pt o m  or  a  dis e as e  alr e a d y  pr es e nt    w h e n  t h e 
p arti ci p a nt  e nt er e d t h e  st u d y (i n cr e as e i n fr e q u e n c y  a n d/ or i nt e nsit y), i n cl u di n g t h e  st u di e d 
p at h ol o g y, 
a n d  d et e ct e d  d uri n g  a  st u d y  visit  or  at  a n  a d diti o n al  e x a mi n ati o n  or  o c c urr e d  si n c e  t h e 
pr e vi o us   st u d y   visit   (i n cl u di n g   r el e v a nt   e v e nt  r e p ort e d  i n   p arti ci p a nt’s   di ar y   or   s af et y 
e v al u ati o n s c al e).  
Of  n ot e: 
A n y  h os pit alis ati o n  f o r   a d mi nist r ati o n   of   a nti -t u m o r al  t r e at m e nt   a n d/ o r   ass o ci at e d 
p r ot o c ol  ( d u ri n g  o r  aft e r  t h e  st u d y)  o r  ot h e r  c a r e    m e as u r es  f o r  c a n c e r  ( e. g.  o v e r ni g ht 
h os pit al  st a y  t o  r e c ei v e  a  bl o o d  o r  pl at el ets  t r a nsf usi o n),  f o r  s o ci al  r e as o ns,  e d u c ati o n al 
p u r p os e  ( e. g. l e ar ni n g  of  di a b et es  m a n a g e m e nt  b y t h e  p arti ci p a nt)  or r o uti n e  c h e c k-u p  s h o ul d 
n ot  b e  c o nsi d er e d  as  a n  a d v ers e  e v e nt  a n d s h o ul d  n ot  b e r e p ort e d i n t h e  e -C R F . T h e f oll o wi n g 
pr o c e d ur es,  w h et h er  pl a n n e d  b ef or e t h e  st u d y  or  n ot,  w h et h er l e a di n g t o  a  h os pit alis ati o n  or 
n ot,  s h o ul d  n ot  b e  r e p o rt e d  i n t h e  e-C R F  a n d  k e pt i n t h e s o u r c e  d at a ( o r  p ati e nt fil e) :  
   t h er a p e uti c   pr o c e d ur es   r el at e d   t o   a   n o n-a g gr a v at e d    m e di c al   h ist or y   ( e. g.   c at ar a ct 
e xtr a cti o n  n ot  d u e  t o  a n  a g gr a v ati o n  of  t h e  c at ar a ct  d uri n g  t h e  st u d y,  h a e m o di al ysis 
s essi o ns r el at e d t o  a r e n al i ns uffi ci e n c y  n ot  a g gr a v at e d  d uri n g t h e st u d y), 
   pr o p h yl a cti c  pr o c e d ur es ( e. g. st erilis ati o n,  wis d o m t e et h r e m o v al),  
   c o mf ort  pr o c e d ur es ( e. g.  c os m eti c s ur g er y),  
   c o ntr ol  pr o c e d ur es  of  a  pr e -e xisti n g  c o n diti o n  wit h o ut  a g gr a v ati o n ( e. g.  c ol o n os c o p y t o 
c o ntr ol t h e r e missi o n  of  c ol o n  c a n c er). 
8. 4.   D efi niti o n  of  S e ri o us  a d v e rs e  e v e nts  
A n y  a d v ers e  e v e nt t h at  at,  a n y  d os e:  
­   r es ults i n  d eat h,  
­   is lif e-t hr e at e ni n g( 1), 
­   r e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n, 
­   is  m e di c all y si g nifi c a nt( 2), 
­   r es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y( 3), 
­   is  a  c o n g e nit al  a n o m al y/ birt h  d ef e ct( 4). 
( 1) Lif e -t hr e at e ni n g i n t his  c o nt e xt r ef ers t o  a n  e v e nt i n  w hi c h t h e  p arti ci p a nt  w as  at ris k  of  d e at h  at t h e 
ti m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n  e v e nt  w hi c h  h y p ot h eti c all y  mi g ht  h a v e  c a us e d  d e at h if it  w er e 
m or e s e v er e.   


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 4 /5 4  
 
( 2) A n y  e v e nt t h at  mi g ht  n ot  b e i m m e di at el y  lif e -t hr e at e ni n g  or  r es ult i n  d e at h  or  h os pit alis ati o n,  b ut 
mi g ht j e o p ar dis e t h e  p arti ci p a nt  or   mi g ht  r e q uir e i nt er v e nti o n  t o  pr e v e nt  o n e  of  t h es e  o ut c o m es  (f or 
e x a m pl e:  o e d e m a  or  all er gi c  br o n c h os p as m t h at r e q uir e d i nt e nsi v e tr e at m e nt  at  h o m e,  bl o o d  d ys cr asi a, 
c o n v ulsi o ns t h at  d o  n ot  r es ult i n  h os pit alis ati o n,  or  d e v el o p m e nt  of  dr u g  d e p e n d e n c e  or  dr u g  a b us e). 
T h e  i n v esti g at or  s h o ul d  e x er cis e  his/ h er  s ci e ntifi c  a n d    m e di c al  j u d g e m e nt  t o  d e ci d e   w h et h er  or  n ot 
s u c h  a n  e v e nt r e q uir es  e x p e dit e d r e p orti n g t o s p o ns or. 
( 3)  Dis a bilit y/i n c a p a cit y  i n  t his  c o nt e xt  r ef ers  t o  a n y  e v e nt  t h at  s eri o usl y  disr u pts  t h e  a bilit y  of  t h e 
p arti ci p a nt t o l e a d  a  n or m al lif e, i n  ot h er  w or ds l e a ds t o  a  p ersist e nt  or  p er m a n e nt  si g nifi c a nt  c h a n g e, 
d et eri or ati o n, i nj ur y  or  p ert ur b ati o n  of t h e  p arti ci p a nt's  b o d y  f u n cti o ns  or  str u ct ur e,  p h ysi c al  a cti vit y 
a n d/ or  q u alit y  of lif e. 
( 4) C o n g e nit al  a n o m al y  or  birt h  d ef e ct r ef ers t o t h e  e x p os ur e t o t h e I M P  b ef or e  c o n c e pti o n (i n  m e n  or 
w o m e n)  or  d uri n g  pr e g n a n c y t h at r es ult e d i n  a n  a d v ers e  o ut c o m e  i n t h e  c hil d. 
8. 5.   D efi niti o n  of  O v e r d os e  
T his r ef ers t o  a n y i nt a k e  of  a  q u a ntit y  of I M P  or  a  pr o d u ct  ot h er t h a n t h e I M P t a k e n  as  p art  of 
t h e  pr ot o c ol ( NI M P)  w hi c h is  a b o v e t h e  m a xi m u m  d os e r e c o m m e n d e d i n t h e  st u d y  pr ot o c ol, 
i n d e p e n d e ntl y  of t h e  o c c urr e n c e  of  a n y  a d v ers e  e v e nt. 
T h e  q u a ntit y s h o ul d  b e  c o nsi d er e d  p er  a d mi nistr ati o n  or  c u m ul ati v el y r e g ar di n g t h e  m a xi m u m 
d os e r e c o m m e n d e d i n t h e st u d y  pr ot o c ol  or i n  A L L- M B  2 0 1 5  pr ot o c ol f or  NI M P.  
8. 6.   D efi niti o n  of  A d v e rs e  e v e nt  of s p e ci al i nt e r est  
N ot  a p pli c a bl e 
8. 7.   D efi niti o n  of  E v e nts  r e q ui ri n g  a n i m m e di at e  n otifi c ati o n ( E RI N)  
A n  e v e nt  m ust  b e  n otifi e d i m m e di at el y  (i. e. wit h o ut  d el a y  a n d  wit hi n  2 4  h o urs  at t h e l at est ) 
t o t h e s p o ns or if it is: 
­   a s eri o us  a d v ers e  e v e nt,  
­   a n  o v er d os e  of t h e I M P/ NI M P  e v e n if  as y m pt o m ati c,   
­   a n y i nt a k e  of t h e I M P / NI M P  b y  a  p ers o n  ar o u n d t h e  p arti ci p a nt, 
­   a  pr e g n a n c y.  
8. 8.   Cl assifi c ati o n  of  a n  a d v e rs e  e v e nt (s e ri o us n ess, s e v e rit y,  c a us alit y,  e x p e ct e d n ess)  
It is i m p ort a nt t h at t h e i n v esti g at or  gi v es  his/ h er  o w n  o pi ni o n  r e g ar di n g t h e  s e ri o us n ess, t h e 
s e v e rit y of t h e  e v e nt  as  w ell  as t h e  c a us e -eff e ct  r el ati o ns hi p  b et w e e n  a n  a d v ers e  e v e nt  a n d 
t h e r es e ar c h (I M P  or st u d y  pr ot o c ol).  T his  e v al u ati o n  m ust  b e  ass ess e d  b y t h e i n v esti g at or  a n d 
r e p ort e d  i n  t h e   A E  f or m.  I n  a d diti o n,  t h e  s p o ns or   will  b e  r es p o nsi bl e  f or  t h e  e v al u ati o n  t h e 
e x p e ct e d n ess  of t h e  e v e nt ( S e e  S e cti o n  8. 9. 3 ). 
T h e   S e ri o us n ess   s h o ul d  b e  e v al u at e d  a c c or di n g  t o  i nt er n ati o n al  g ui d a n c es  (s e e  d efi niti o n 
S e cti o n   8. 4 ,  i n  a c c or d a n c e    wit h  I C H    T o pi c    E 2 A  a n d    DI R E C TI V E  2 0 0 1/ 2 0/ E C    O F    T H E 
E U R O P E A N  P A R LI A M E N T  A N D  O F  T H E  C O U N CI L  of  4  A pril) . 
T h e  s e v e rit y  of  all  A Es  will  b e  gr a d e d  a c c or di n g t o t h e  N ati o n al  C a n c er  I nstit ut e  C o m m o n 
T o xi cit y  Crit eri a f or  A d v ers e  E v e nt ( N CI - C T C A E)  o n  a fi v e- p oi nt s c al e ( Gr a d e  1 t o  5): 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 5 /5 4  
 
­   Gr a d e  1:  Mil d;  as y m pt o m ati c  or  mil d  s y m pt o ms;  cli ni c al  or  di a g n osti c  o bs er v ati o ns  o nl y; 
i nt erv e nti o n  n ot i n di c at e d. 
­   Gr a d e  2:    M o d er at e;    mi ni m al,  l o c al  or  n o n -i n v asi v e  i nt er v e nti o n  i n di c at e d;  li miti n g  a g e-
a p pr o pri at e i nstr u m e nt al  A D L 1. 
­   Gr a d e   3:   S e v er e   or    m e di c all y   si g nifi c a nt   b ut   n ot   i m m e di at el y   lif e -t hr e at e ni n g; 
h os pit ali z ati o n  or  pr ol o n g ati o n  of  h os pit ali z ati o n  i n di c at e d;  dis a bli n g;  li miti n g  s elf -c ar e 
A D L 2. 
­   Gr a d e  4:  Lif e -t hr e at e ni n g  c o ns e q u e n c es;  ur g e nt i nt er v e nti o n i n di c at e d. 
­   Gr a d e  5:  D e at h r el at e d t o  A E.  
T h e  c a us e -eff e ct  r el ati o ns hi p   
T h e  i n v esti g at or  h as  t o  ass ess  i n  t h e    A E  f or m  if  t h e    A E  is  r el at e d  or  n ot  t o  t h e  r es e ar c h, 
m e a ni n g:   
­   a d v ers e  e v e nt r el at e d t o I M P  
­   a d v ers e  e v e nt r el at e d t o st u d y  pr ot o c ol i. e. r el at e d t o:  
o   a  pr o c e d ur e s c h e d ul e d i n t h e st u d y  pr ot o c ol (i. e.  e x er cis e t est,  M RI,  et c.),  or   
o   a  c h a n g e  or  wit h dr a w al  of  pr e vi o us /  c o n c o mit a nt tr e at m e nt r el at e d t o t h e  c o n diti o ns  of 
t h e  pr ot o c ol  or 
o   a  pr o d u ct  ot h er t h a n t h e I M P, t a k e n  as  p art  of t h e  pr ot o c ol ( NI M P  or  ot h er); 
M or e o v er,  t h e  i n v esti g at or  h as  t o  ass ess  if  t h e    A E  is  r el at e d  t o  dis e as e  pr o gr essi o n.   C as es 
ti c k e d  “r el at e d ”  b y t h e i n v estig at or  or j u d g e d  b y t h e  s p o ns or  as  h a vi n g  a r e as o n a bl e  s us p e ct e d 
c a us al r el ati o ns hi p t o t h e  I M P ( A E li n k e d t o t h e  m e c h a nis m  of  a cti o n  of t h e  I M P …),  will  b e 
c o nsi d er e d  as  s us p e ct e d  A d v ers e  Dr u g  R e a cti o n. I n  g e n er al, if  a r el ati o ns hi p  b et w e e n  A E  a n d 
I M P  is  at  l e ast  r e as o n a bl y  p ossi bl e  (i. e.  t h e  r el ati o ns hi p  c a n n ot  b e  r ul e d  o ut)  it  is  t o  b e 
c o nsi d er e d  as  “r el at e d ”.  
8. 9.   R e p o rti n g  p r o c e d u r es  
8. 9. 1.   Ti m e f r a m e f o r  A E  r e p o rti n g  
A n y  e v e nt  m e eti n g t h e  a b o v e  m e nti o n e d  d efi niti o ns (s e e  s e cti o ns  8. 3  t o 8. 7 )  m ust  b e r e p ort e d 
t o t h e s p o ns or  o n  a n a d v ers e  e v e nt f or m  if it  o c c urr e d: 
­   b ef or e t h e first i nt a k e  of t h e I M P f or  e v e nts r el at e d t o t h e r es e ar c h  
­   at  a n y ti m e  aft er t h e  a d mi nistr ati o n  of I M P,  u p t o t h e  p arti ci p a nt’s  wit h dr a w al  visit f or  all 
e v e nts,  
­   u p t o  3 0  c al e n d ar  d a ys  aft er t h e  p arti ci p a nt's  l ast i nt a k e  of I M P f or  all  E RI N, r e g ar dl ess  of 
t h e s u p p os e d r ol e  of t h e r es e ar c h. 
­   irr es p e cti v e  of t h e ti m e  of  o ns et  aft er t h e  e n d  of t h e  st u d y i n  c as e  of  s eri o us  a d v ers e  e v e nt 
r el at e d t o t h e r es e ar c h. 
Of   n ot e,   e v e nts   o c c urri n g   b et w e e n  t h e  si g n at ur e   of  t h e  i nf or m e d   c o ns e nt   a n d  t h e  first 
a d mi nistr ati o n  of t h e t est  dr u g f or  w hi c h t h e i n v esti g at or  d o es  n ot  c o nsi d er  a n  ass o ci ati o n  wit h 
                                                 
1 I nstr u m e nt al   A cti viti es  of   D ail y   Li vi n g  ( A D L)  r ef er  t o  pr e p ari n g    m e als,  s h o p pi n g  f or  gr o c eri es  or 
cl ot h es,  usi n g t h e t el e p h o n e,  m a n a gi n g  m o n e y,  et c.  
2 S elf -c ar e    A D L  r ef er  t o  b at hi n g,   dr essi n g  a n d   u n dr essi n g,  f e e di n g  s elf,   usi n g  t h e  t oil et,  t a ki n g 
m e di c ati o ns,  a n d  n ot  b e dri d d e n ”.  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 6 /5 4  
 
a n y  pr o c e d ur e/ c o n diti o n  r e q uir e d  b y t h e  st u d y  pr ot o c ol  m ust  b e  r e p ort e d  as  m e di c al  hist o r y  
or  as si g ns  a n d s y m pt o ms r el at e d t o t h e st u di e d  dis e as e i n t h e  d e di c at e d f or m  of t h e  C R F . 
F or  a  gi v e n  p ati e nt ,  m e di c al  hist ori es  a n d  a d v ers e  e v e nts  alr e a d y  r e p ort e d i n t h e i niti al  C L 2-
9 5 0 1 4- 0 0 2 st u d y  will  n ot  b e r e p ort e d i n t h e  e C R F ,  e x c e pt i n  c as e  of  w ors e ni n g. 
 
8. 9. 2.   R es p o nsi biliti es  of t h e i n v esti g at o r 
F or  a n y  a d v ers e  e v e nt  a n d s p e ci al sit u ati o n  m e nti o n e d  a b o v e t h e i n v esti g at or  m ust: 
­   N ot e i n t h e  p a rti ci p a nt's  m e di c al fil e  t h e  d at e  o n  w hi c h  h e/s h e l e ar n e d  of t h e  e v e nt ( at  a 
f oll o w-u p  visit  or  a  t el e p h o n e  c o nt a ct   wit h  t h e  p arti ci p a nt  or  a  t hir d  p ers o n,    …)  a n d  a n y 
ot h er r el e v a nt i nf or m ati o n  w hi c h  h e/s h e  h as l e ar n e d  of t h e  e v e nt, 
­   Ass ess  t h e  e v e nt i n t er ms  of s eri o us n ess, i nt e nsit y  a n d  c a us alit y, 
­   R e p o rt t h e  e v e nt t o t h e s p o ns o r   usi n g t h e  A E f or m (i n  c as e  of  E RI N, t h e r e p orti n g s h o ul d 
b e  d o n e i m m e di at el y),  
­   D o c u m e nt  t h e  e v e nt  wit h  a d diti o n al  us ef ul i nf or m ati o n,  
­   E ns ur e t h e  f oll o w-u p   of t h e  e v e nt,  
­   F ulfil  his/ h e r  r e g ul at o r y  o bli g ati o ns  t o t h e  C o m p et e nt  A ut h oriti es  a n d/ or t o t h e  I E C, i n 
a c c or d a n c e  wit h l o c al r e g ul ati o ns.  
M or e o v er,  t h e  i n v esti g at or    m ust  r e p ort  t o  t h e  s p o ns or   a n d/ or  t o  t h e  I E C   a n d/ or  t o  t h e 
C o m p et e nt    A ut h oriti es  i n  a c c or d a n c e    wit h  t h e  l o c al  r e g ul ati o n,  a n y  n e w  i nf o r m ati o n t h at 
mi g ht  m at e ri all y i nfl u e n c e t h e  b e n ef it-ri s k  a s s e s s m e nt  of t h e t e st  d r u g  o r t h at  w o ul d  b e 
s uffi ci e nt t o  c o n si d e r  c h a n g e s i n t h e t e st  d r u g  a d mi ni st r ati o n  o r i n t h e  o v e r all  c o n d u ct  of 
t h e  cli ni c al i n v e sti g ati o n. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 7 /5 4  
 
8. 9. 2. 1.   D o c u m e nt ati o n  of t h e  e v e nt 
T h e  i n v esti g at or    m ust  e ns ur e  t h at  all  e v e nts  ar e    w ell  d o c u m e nt e d.  I n  p arti c ul ar  f or   E RI N, 
h e/s h e  s h o ul d  pr o vi d e t h e  s p o ns or,  as t h e y  b e c o m e  a v ail a bl e,  wit h  a n o n y mi z e d  c o pi es  of t h e 
d o c u m e nts   w hi c h  pr o vi d e  a d diti o n al  us ef ul  i nf or m ati o n,  s u c h  as  h os pit al  a d missi o n  r e p orts, 
r e p orts  of  f urt h er  c o ns ult ati o ns,  l a b or at or y  t est  r e p orts,  r e p orts  of  ot h er  e x a mi n ati o ns  ai di n g 
di a g n osis ( w h er e  p ossi bl e, t h e r es ults fr o m  pr e -t est  dr u g  ass ess m e nts  s h o ul d  b e  a p p e n d e d f or 
c o m p aris o n    wit h  t h e  r es ults  o bt ai n e d  u n d er  t est  dr u g),  or  t h e  a ut o ps y  r e p ort,  if  a ut o ps y  is 
p erf or m e d.  
8. 9. 2. 2.   F oll o w- u p  of  a d v e rs e  e v e nts  
T h e i n v esti g at or  m ust  e ns ur e t h at  f oll o w -u p  of t h e  p arti ci p a nt is  a p pr o pri at e t o t h e  n at ur e  of 
t h e  e v e nt,  a n d t h at it  c o nti n u es  u ntil r es ol uti o n if  d e e m e d  n e c ess ar y. 
A n y   c h a n g e  i n  t er ms   of   di a g n osis,  i nt e nsit y,  s eri o us n ess,    m e as ur es  t a k e n,   c a us alit y   or 
o ut c o m e  r e g ar di n g  a n  a d v ers e  e v e nt  alr e a d y  r e p ort e d  m ust  b e  writt e n  u p i n  a  n e w  c o m pl et e 
e v al u ati o n  of  t h e  e v e nt  d o c u m e nt e d  o n  a n  “ A d v ers e  e v e nt ”  p a g e  pr e vi o usl y  cr e at e d  f or  t h e 
e v e n t. 
If t h e  a d v ers e  e v e nt  h as  n ot r es ol v e d  at t h e  p arti ci p a nt's fi n al  visit i n t h e  st u d y, t h e  p arti ci p a nt 
m ust  b e f oll o w e d  u p  s uit a bl y  a n d  a n y i nf or m ati o n  o n t h e  o ut c o m e  of t h e  e v e nt  will  b e  n ot e d 
o n  a n  «  A d v ers e  E v e nt  »  p a g e  pr e vi o usl y  cr e at e d f or t h e  e v e nt 
If t h e f oll o w-u p  of t h e  p arti ci p a nt is  n ot  d o n e  b y t h e i n v esti g at or  hi m/ h ers elf ( h os pit alis ati o n, 
f oll o w e d  b y  a  s p e ci alist  or t h e  p arti ci p a nt's  g e n er al  pr a ctiti o n er,  …), t h e i n v esti g at or  will  d o 
e v er yt hi n g t o  est a blis h/ m ai nt ai n  c o nt a ct  wit h t h e  p ers o n/ d e p art m e nt i n  c h ar g e  of f oll o w- u p  of 
t h e  p arti ci p a nt. 
8. 9. 2. 3.   S p e ci al   sit u ati o ns   ( p r e g n a n c y,   o v e r d os es,   i nt a k e   of   I M P / NI M P  a   p e rs o n 
a r o u n d t h e  p a rti ci p a nt)  
P r e g n a n c y  
If  a f e m al e  p arti ci p a nt i n t h e st u d y  b e c o m es  pr e g n a nt, t h e i n v esti g at or  m ust: 
­   st o p i m m e di at el y t h e t est  dr u g (if t h e  pr e g n a n c y is  a  n o n-i n cl usi o n  crit eri o n),  
­   r e p ort it  o n  a n  «  A d v ers e  E v e nt  »  p a g e  as  w ell  as  o n t h e s p e cifi c  p a p er  pr e g n a n c y f or m ( 1st 
p a g e) t o  b e  n otifi e d i m m e di at el y ( E RI N), 
­   c o ntri b ut e  t o  t h e  f oll o w -u p  of  t his  pr e g n a n c y  a n d  pr o vi d e  t h e  s p o ns or    wit h  i nf or m ati o n 
c o n c er ni n g  t his  f oll o w -u p  ( n ot a bl y  usi n g  t h e  2 n d  p a g e  of  t h e  s p e cifi c  p a p er  pr e g n a n c y 
f or m). 
­   If  t h e   p art n er   of  a   p arti ci p a nt   b e c o m es   pr e g n a nt   d uri n g  t h e  c o urs e   of  t h e  st u d y,  t h e 
pr e g n a n c y  s h o ul d  n ot  b e  r e p ort e d  i n  t h e  e -C R F.    T h e  i n v esti g at or  s h o ul d  i m m e di at el y 
c o nt a ct  t h e  s p o ns or  ( c o nt a ct  d et ails  pr o vi d e d  i n  t h e  i n v esti g at or’s  st u d y  fil e)    w h o    will 
i nf or m  hi m/ h er  a b o ut t h e  pr o c e d ur e t o  b e f oll o w e d. 
O v e r d os e  of I M P  o r  NI M P  
­   I n  c as e  of  o v er d os e,  t h e  i n v esti g at or  s h o ul d  r e p ort  it  o n  a n  “ A d v ers e   E v e nt ”  p a g e  t o  b e 
n ot ifi e d i m m e di at el y ( E RI N).  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 8 /5 4  
 
­   O v er d os e  s h o ul d  b e  f oll o w e d -u p t o  e ns ur e t h at t h e i nf or m ati o n is  as  c o m pl et e  as  p ossi bl e 
wit h r e g ar ds t o:  
o   d os e  d et ails  ( n u m b er  of  u nits,  d ur ati o n …)  a n d,  if   m ulti pl e  o v er d os e,  d et ails  r e g ar di n g 
ot h er  m e di ci n al  pr o d u cts  or s u bst a n c e,  
o   c o nt e xt  of  o c c urr e n c e, i. e. i nt e nti o n al (s ui ci d e  att e m pt,  ot h er r e as o n)  or  a c ci d e nt al ( err or 
i n  pr es cri pti o n,  a d mi nistr ati o n,  dis p e nsi n g,  d os a g e),  
o   r el at e d si g ns  a n d s y m pt o ms ( “ N o r el at e d  a d v ers e  e v e nts ” t o  b e r e p ort e d  ot h er wis e),  
o   o ut c o m e. 
­   I ns of ar  as p ossi bl e,  a  bl o o d s a m pl e s h o ul d  b e  c oll e ct e d f or  ass a y  of t h e I M P t a k e n.  
I nt a k e  of I M P/ NI M P b y  a  p e rs o n  a r o u n d t h e  p a rti ci p a nt  
T his  e v e nt  s h o ul d  n ot  b e r e p ort e d i n t h e  e -C R F.  T h e i n v esti g at or  s h o ul d i m m e di at el y  c o nt a ct 
t h e  s p o ns or ( c o nt a ct  d et ails  pr o vi d ed i n t h e i n v esti g at or’s  st u d y fil e)  w h o  will i nf or m  hi m/ h er 
a b o ut t h e  pr o c e d ur e t o  b e f oll o w e d. 
8. 9. 2. 4.   R e c o r di n g  M et h o ds i n t h e   e-C R F   
A d v ers e  e v e nts  m ust  b e  d o c u m e nt e d  o n t h e  «  A d v ers e  E v e nt  »  p a g e  of t h e  e- C R F.   
I n  c as e  of  c hr o ni c  dis e as e: 
­   if t h e  dis e as e is  k n ow n  w h e n t h e  p arti ci p a nt  e nt ers i n t h e  st u d y,  o nl y  w ors e ni n g (i n cr e as e d 
fr e q u e n c y  a n d/ or i nt e nsit y  of t h e  e pis o d es/ att a c ks)  will  b e  d o c u m e nt e d  as  a n  a d v ers e  e v e nt,  
­   if  t h e  dis e as e  is  d et e ct e d  d uri n g  t h e  st u d y  a n d  if  r e p e at e d  e pis o d es  e n a bl e  di a g n osis  of  a 
c hr o ni c  dis e as e,  t h e  e pis o d es    will  b e  gr o u p e d  o n  t h e  « A d v ers e   E v e nt »  p a g e  pr e vi o usl y 
cr e at e d f or t h e  e v e nt  w hi c h  will  cl e arl y  d es cri b e t h e  di a g n osis.  
8. 9. 2. 5.   P r o c e d u r e f o r  a n  e v e nt  r e q ui ri n g  a n i m m e di at e  n otifi c ati o n   
I n  c as e  of  a n  e v e nt r e q uiri n g  a n i m m e di at e  n otifi c ati o n, t h e i n v esti g at or  m ust: 
­   I m m e di at el y aft er  b ei n g  i nf or m e d  of  t his  e v e nt,  fill  i n t h e p a rti ci p a nt's  m e di c al  fil e  as 
w ell  as  t h e  «   A d v e rs e   E v e nt  »  p a g e  of  t h e  e -C R F  a c c or di n g  t o  t h e  g e n er al  i nstr u cti o ns 
a v ail a bl e  i n  t h e  e -C R F,    wit h o ut    w aiti n g  f or  t h e  r es ults  of  t h e  cli ni c al  o ut c o m e  or  of 
a d diti o n al  i n v esti g ati o ns.    W h e n  d at a    will  b e  s u b mitt e d  i nt o   I nf or m,  a n  e-m ail    will  b e 
i m m e di at el y  a n d  a ut o m ati c all y s e nt t o t h e s p o ns or. 
­   Pr o vi d e t h e  s p o ns or ( p ers o n  d esi g n at e d i n t h e  c o nt a ct  d et ails  pr o vi d e d i n t h e i n v esti g at or’s 
st u d y  fil e),  as  t h e y  b e c o m e  a v ail a bl e,    wit h  a n o n y mi z e d  c o pi es  of  t h e  d o c u m e nts    w hi c h 
pr o vi d e  a d diti o n al  us ef ul i nf or m ati o n, 
­   F ulfil  his/ h er  r e g ul at or y  o bli g ati o ns  t o  t h e    C o m p et e nt    A ut h oriti es  a n d/ or  t o  t h e  I E C,  i n 
a c c or d a n c e  wit h  l o c al r e g ul ati o ns. 
If  a n  a d v ers e  e v e nt i niti all y  n o n-s eri o us  w ors e ns  a n d  b e c o m es  s eri o us  ( E RI N), t his  m ust  b e 
r e p ort e d i m m e di at el y  o n  a n  " A d v ers e  e v e nt "  p a g e  of t h e  e-C R F.  
I n  c as e  t h e  e-C R F  is  u n a v ail a bl e    w h e n  t h e  i n v esti g at or    w as  i nf or m e d  of  t h e   E RI N,  h e/ s h e 
s h o ul d: 
­   I m m e di at el y fill i n  a  p a p er  " A d v ers e  e v e nt "  p a g e: 
o   F or s eri o us  e v e nt  o n  a  p a p er  " A d v ers e  e v e nt  – I niti al i nf or m ati o n "  p a g e,  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  3 9 /5 4  
 
o   F or  e v e nt  i niti all y  n o n -s eri o us  o n  a  p a p er  " A d v ers e  e v e nt  –  I niti al  i nf or m ati o n "  p a g e, 
a n d  t h e    w ors e ni n g  l e a di n g  t o  s eri o us n ess  o n  a  p a p er  " A d v ers e  e v e nt  –    A d diti o n al 
i nf or m ati o n "  p a g e,  
­   I m m e di at el y  s e n d  t h e m  b y  f a x  or  b y  e -m ail   t o  t h e  p ers o n(s)  d esi g n at e d  i n  t h e  c o nt a ct 
d et ails  pr o vi d e d  i n  t h e  i n v esti g at or’s  st u d y  fil e  or  o utsi d e    w or ki n g  h o urs,  t h e  2 4 - h o ur 
p h o n e  li n e   (i nt er n ati o n al   pr efi x  f oll o w e d   b y   3 3. 1. 5 5. 7 2. 6 0. 0 0  f or  a  c all  fr o m   o utsi d e 
Fr a n c e,  a n d/ or  t h e  2 4- h o ur  p h o n e li n e  of t h e I C T R i n  R ussi a  8  4 9 5  9 3 7 0 7 0 0,  e xt.  2),  
­   As  s o o n  as t h e  e -C R F  b e c o m es  a v ail a bl e, t h e i n v esti g at or  s h o ul d  e nt er t h es e  d at a i n t h e  « 
A d v ers e  E v e nt  »  p a g e  of t h e  e- C R F.  
8. 9. 3.   R es p o nsi biliti es  of t h e s p o ns o r  
I n   a c c or d a n c e    wit h  i nt er n ati o n al   g ui d a n c es,  t h e   ass ess m e nt   of  t h e   s eri o us n ess   a n d  t h e 
c a us alit y  of  a d v ers e  e v e nts  ar e  us u all y  m a d e  b y t h e i n v esti g at or  b ut f alls  als o  u n d er  s p o ns or’s 
d uti es,  w h o is r es p o nsi bl e f or  e ns uri n g t h at  all s us p e ct e d  u n e x p e ct e d s eri o us  a d v ers e r e a cti o ns 
ar e r e p ort e d t o  C o m p et e nt  A ut h oriti es  a n d  Et hi cs  C o m mitt e es.   
T h e  s p o ns or  will  r e vi e w t h e  s eri o us n ess  of t h e  a d v ers e  e v e nts  a n d t h e  c a us alit y  of  ( at l e ast) 
t h e  s eri o us  a d v ers e  e ve nts,  w h et h er  r e p ort e d  b y t h e i n v esti g at or  or  u p gr a d e d  b y t h e  s p o ns or. 
T h e  c a us alit y  a n d  t h e  s eri o us n ess    m a y  b e  u p gr a d e d  ( b ut  n e v er  d o w n gr a d e d).    A n o n y mi z e d 
c o pi es  of  d o c u m e nts  pr o vi di n g  us ef ul  i nf or m ati o n  s u c h  as  r e p orts  of  f urt h er  c o ns ult ati o ns, 
l a b or at ory  t ests  r e p orts,  r e p orts  of  ot h er  e x a mi n ati o n  ai di n g  di a g n osis   m a y  b e  as k e d  f or  t h e 
e v e nt  ass ess m e nt.  If  t h e  ass ess m e nts  of  t h e  i n v esti g at or  a n d  t h e  s p o ns or  ar e  diff er e nt,  b ot h 
will  b e r e p ort e d i n t h e  cli ni c al st u d y r e p ort.  
I n   a d diti o n,  t h e  s p o ns or  is  r es p o nsi bl e  f or   d et er mi ni n g    w h et h er   a n    A E  is  e x p e ct e d   o r 
u n e x p e ct e d .  A n  A E  will  b e  c o nsi d er e d  u n e x p e ct e d if t h e  n at ur e,  s e v erit y,  or fr e q u e n c y  of t h e 
e v e nt is  n ot  c o nsist e nt  wit h t h e ris k i nf or m ati o n  pr e vi o usl y  d es cri b e d f or t h e I M P. 
I n d e p e nd e ntl y   of   t h e   r e g ul at or y   o bli g ati o ns   of   t h e   i n v esti g at or,   a n d   a c c or di n g   t o   t h e 
r e q uir e m e nts  st at e d  i n  I C H    G o o d    Cli ni c al   Pr a cti c e   g ui d eli n es  a n d  l o c al  r e g ul ati o ns,  t h e 
s p o ns or   m ust  r e p ort  t h e  p h ar m a c o vi gil a n c e  d at a  a n d  a n y  n e w  s af et y  fi n di n g  li k el y  t o  aff e c t 
t h e   b e n efit  /ris k   b al a n c e   of  t h e   pr o d u ct  t o  t h e   a p pr o pri at e    A ut h oriti es   a n d  t o   all  t h e 
i n v esti g at ors i n v ol v e d.  A n y  n e w  s af et y fi n di n g li k el y t o  aff e ct t h e  b e n efit /ris k  b al a n c e  of t h e 
pr o d u ct    will  b e  als o  n otifi e d  t o  t h e  tri al  s u bj e cts  i n v ol v e d  -  t hr o u g h  t h e  i n v esti g at ors  -  as 
m e nti o n e d i n  1 3. 4  " M o difi c ati o n  of t h e i nf or m ati o n  a n d  c o ns e nt f or m " 
8. 1 0.  M a n a g e m e nt  of t o xi citi es 
A n  A E f or  w hi c h  a  c a us al r el ati o ns hi p t o  S 9 5 0 1 4 is  e vi d e ntl y r ul e d  o ut  will  n ot  b e  c o nsi d er e d 
t o xi cit y.   For   p ati e nts    w h o   d o   n ot  t ol er at e  t h e   pr ot o c ol -s p e cifi e d   d osi n g   s c h e d ul e,   d os e 
i nt err u pti o ns  a n d/ or r e d u cti o ns  ar e  eit h er r e c o m m e n d e d  or  m a n d at e d  d uri n g t h e  c o ns oli d ati o n 
p h as e. 
T h e  r es ults  of l a b or at or y t ests  s h o ul d  b e  a v ail a bl e  b ef or e t h e  S 9 5 0 1 4  a d mi nistr ati o n i n  or d er 
t o  c o m pl y  wit h  m a n ag e m e nt  of t o xi citi es if  a p pli c a bl e.  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 0 /5 4  
 
F or  e a c h  p ati e nt,  o n c e  a  d os e r e d u cti o n  h as  o c c urr e d, t h e  d os e  m a y  n ot  b e r e -es c al at e d  d uri n g 
t h e tr e at m e nt  p eri o d  u nl ess t h er e is  d o c u m e nt e d  a gr e e m e nt  wit h t h e  S p o ns or. 
T a bl e  (8. 1 0 )  1 - C rit e ri a f o r  S 9 5 0 1 4 i nt e r r u pti o n  o r  dis c o nti n u ati o n   
 
T o xi cit y  
A cti o n t o  b e t a k e n  
H y p e rs e nsiti vit y  
 
Gr a d e  1  h y p ers e nsiti vit y  
S y m pt o m ati c tr e at m e nt  
I nf usi o n r at e s h o ul d  b e r e d u c e d  b y  5 0 % 
Gr a d e  2  h y p ers e nsiti vit y  
S 9 5 0 1 4 i nf usi o n i nt err u pti o n  
S y m pt o m ati c tr e at m e nt  
U p o n  r e c o v er y,  i nf usi o n  c a n  b e  r es u m e d    wit h  a n  i nf usi o n  r at e 
re d u c e d  b y  5 0 % 
Gr a d e  3 -4  h y p ers e nsiti vit y  
S 9 5 0 1 4  dis c o nti n u ati o n  
S y m pt o m ati c tr e at m e nt  
S wit c h  t o    Er wi n as e  s h o ul d  b e  c o nsi d er e d  as  p er  i n v e sti g at or’s 
j u d g m e nt 
P a n c r e atitis  
 
Gr a d e  2  p a n cr e atitis  
S 9 5 0 1 4 i nt err u pti o n  u ntil r e c o v er y  
Cli ni c al  p a n cr e atitis  ( Gr a d e  3-4)  
S 9 5 0 1 4  dis c o nti n u ati o n *  
H e p at ot o xi cit y  
 
Gr a d e  3  A L T  a n d/ or  A S T i n cr e as e   
S 9 5 0 1 4  i nt err u pti o n, c a n  b e r es u m e d  if r es ol v e d ≤  Gr a d e  2  
Gr a d e  4  A L T  a n d/ or  A S T i n cr e as e    
If  n ot r e c o v er e d  wit hi n  2  w e e ks: S 9 5 0 1 4  dis c o nti n u ati o n  
If r es ol v e d ( ≤  Gr a d e  2)  wit hi n  2  w e e ks:  S 9 5 0 1 4  c a n  b e r es u m e d 
Gr a d e  3  t ot al bilir u bi n i n cr e as e  
S 9 5 0 1 4  i nt err u pti o n, c a n  b e r es u m e d  if r es ol v e d ≤  Gr a d e  2  
Gr a d e  4  t ot al bilir u bi n i n cr e as e  
S 9 5 0 1 4  dis c o nti n u ati o n *  
H a e m o r r h a g e   
 
≥  Gr a d e  2  h a e m orr h a g e  
S 9 5 0 1 4 i nt err u pti o n  u ntil r es ol v es t o  Gr a d e  1  
Gr a d e  4  h a e m orr h a g e  
S 9 5 0 1 4  dis c o nti n u ati o n  
T h r o m b osis  
 
Gr a d e  3  t hr o m b oti c  e v e nt 
S 9 5 0 1 4 i nt err u pti o n  u ntil r e c o v er y  
Gr a d e  4  or s eri o us  t hr o m b oti c  e v e nt  
S 9 5 0 1 4  dis c o nti n u ati o n  
 
*i n  c as e  of  hi g h -ris k  of r el a ps e,  S 9 5 0 1 4  mi g ht  b e r ei ntr o d u c e d  at  a l o w er  d os e  as  p er i n v esti g at or’s j u d g m e nt  
Pr o p h yl a cti c tr e at m e nt f or  h y p ers e nsiti vit y s h o ul d  b e  a d mi nist er e d  as  p er l o c al  pr a cti c e.   
F or f urt h er  d et ails  a b o ut t h e  m a n a g e m e nt  of  S 9 5 0 1 4 t o xi citi es ,  pl e as e r ef er t o A L L - M B 2 0 1 5 
pr ot o c ol ( A p p e n di x  1 )  a n d I n v esti g at or’s  Br o c h ur e. 
9.   O T H E R  A S S E S S M E N T S  N O T  S P E CI FI C A L L Y  R E L A T E D  T O  S A F E T Y  
9. 1.   Ass ess m e nts  r el at e d t o i n cl usi o n  c rit e ri a.  
N ot  a p pli c a bl e 
9. 2.   M e as u r e m e nt  of  pl as m a  as p a r a gi n as e  a cti vit y 
Pl as m a    As p ar a gi n as e    A cti vit y    will   b e   ass ess e d   b ef or e  n e xt   S 9 5 0 1 4  i nf usi o n   d uri n g  t h e 
c o ns oli d ati o n  p h as e ,  as  p er l o c al  pr a cti c e.  P A A  will  b e  d et er mi n e d  usi n g  a  c o u pl e d  e n z y m ati c 
a cti vit y  ass a y  v ali d at e d  a c c or di n g  t o  c urr e nt  r e g ul at or y  g ui d eli n es.  If  as p ar a gi n as e  a cti vit y 
v al u es  f ail  t o  r e a c h  t ar g et  l e v els,  a  s wit c h  t o  a  diff er e nt  as p ar a gi n as e  pr e p ar ati o n  c o ul d  b e 
c o nsi d er e d. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 1 /5 4  
 
9. 3.   Ass ess m e nt  of i m m u n o g e ni cit y  
I n  p ati e nts    w h o    w er e  f o u n d  t o  b e  p ositi v e  f or  a nti-dr u g  a nti b o di es  ( A D A)  i n  t h e  pr e vi o us 
C L 2 - 9 5 0 1 4-0 0 2  st u d y,  s a m pl es  will  b e  c oll e ct e d f or  A D A  m o nit ori n g  b ef or e  e a c h  S 1,  S 2  a n d 
S 3  p h as e  a n d  at t h e  wit h dr a w al/ e n d - of-st u d y  visit. 
9. 4.   Ass ess m e nt  of  bi o m a r k e rs  
N ot  a p pli c a bl e 
1 0.   S T A TI S TI C S  
 
T h e  s af et y  a n al ysis  m et h o ds  ar e  s p e cifi e d  b el o w.  U nl ess  ot h er wis e  s p e cifi e d,  c at e g ori c al  d at a 
will   b e   s u m m ari z e d   usi n g   fr e q u e n ci es   a n d   p er c e nt a g es,   a n d   c o nti n u o us   d at a    will   b e 
s u m m ari z e d   usi n g   d es cri pti v e  st atisti cs.    T h e   d es cri pti v e  st atisti cs    will   b e  t h e   n u m b er   of 
s u bj e cts,  m e a n, st a n d ar d  d e vi ati o n,  mi ni m u m,  m e di a n,  a n d  m a xi m u m.   
1 0. 1.  P o p ul ati o n 
1 0. 1. 1.   D et e r mi n ati o n  of s a m pl e si z e 
T h e  s a m pl e  si z e  w as  ori gi n all y  d et er mi n e d t o  pr o vi d e  s uffi ci e nt  st atisti c al  p o w er t o  est a blis h 
t h e  P K  c o m p ar a bilit y  b et w e e n t h e li q ui d  a n d l y o p hili z e d f or m ul ati o ns i n t h e  C L 2- 9 5 0 1 4- 0 0 2 
st u d y.  Aft er  c o m pl eti n g t h e  C L 2 - 9 5 0 1 4-0 0 2  st u d y,  p ati e nts  w h o  a gr e e t o  p arti ci p at e  a n d  m e et 
t h e  eli gi bilit y  r e q uir e m e nts  will  b e i n cl ud e d  i n t his  st u d y.  N o f urt h er  c o nsi d er ati o n is  us e d t o 
d et er mi n e t h e s a m pl e si z e  of t his st u d y.  
1 0. 1. 2.   A n al ysis s u bs et  
S af et y  A n al ysis  S et  
T h e  s af et y  a n al ysis  s et  ( S A S) is  d efi n e d  as t h e  s et  of  all  s u bj e cts  w h o  h a v e  r e c ei v e d  at l e ast 
o n e  d os e  of  S 9 5 0 1 4  i n t h e  stu d y.  T h e  s af et y  e n d p oi nts  will  b e  a n al ys e d i n t h e  s af et y  a n al ysis 
s et. U nl ess  ot h er wis e  st at e d, t h e  s af et y  a n al ysis  will  b e  c o n d u ct e d i n t h e  o v er all  S A S  a n d  b y 
d os e  gr o u ps if  a p pli c a bl e. 
1 0. 2.  St atisti c al  a n al ysis 
1 0. 2. 1.   
S af et y  A n al ysis 
1 0. 2. 1. 1.   
A d v e rs e  E v e nts  
A d v ers e  e v e nts  ( A E)    will   b e  ass ess e d  a c c or di n g  t o  t h e    N ati o n al    C a n c er  I nstit ut e  ( N CI) 
C o m m o n  T er mi n ol o g y  Crit eri a  A d v ers e  E v e nts ( C T C A E)  v 5. 0.  L a b or at or y  a b n or m aliti es  will 
b e  cl assifi e d i nt o  C o m m o n  T er mi n ol o g y  Crit eri a ( C T C)  gr a d e  a c c or di n g t o  C T C A E  v 5. 0  a n d 
will  b e r e p or t e d  as  a d v ers e  e v e nts.  
 
A d v ers e   e v e nts    will   b e   s u m m ari z e d  i n   hi er ar c hi c al  t a bl es,   pr es e nti n g  t h e   n u m b er   a n d 
p er c e nt a g e  of  p ati e nts  h a vi n g  at  l e ast  o n e   A E,  a n d  h a vi n g  at  l e ast  o n e   A E  i n  e a c h  pri m ar y 
s yst e m  or g a n  cl ass  a n d  f or  e a c h  pr ef err e d  t er m  usi n g    M e d D R A  c o di n g ,  o v er all  a n d  at  e a c h 
d os e l e v el .  A Es  will  b e  s ort e d  b y  d es c e n di n g  fr e q u e n c y,  a n d  al p h a b eti c all y  w h er e  fr e q u e n c y 
is ti e d.  S u c h s u m m ari es  will  b e  pr o d u c e d f or  all  A Es, s eri o us  a d v ers e  e v e nts ( S A Es),  gr a d es  3 
or  4  A Es,  A Es l e a di n g t o st u d y tr e at m e nt  dis c o nti n u ati o n,  a n d  A Es l e a di n g t o  d os e- a dj ust m e nt 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 2 /5 4  
 
or i nt err u pti o n  of  a n y  of t h e  dr u gs  of t h e tr e at m e nt.  All  of t h es e  s u m m ari es  will  b e  b y  s yst e m 
or g a n  cl ass,  pr ef err e d t er m  a n d, i n  s o m e  c as e s,  m a xi m u m  gr a d e.  M ost  of t h e  s u m m ari es  will 
b e  pr o d u c e d t wi c e,  o n c e f or  all  e v e nts r e g ar dl ess  of  st u d y tr e at m e nt r el ati o ns hi p,  a n d  o n c e f or 
e v e nts s us p e ct e d t o  b e st u d y tr e at m e nt r el at e d.  All  d e at hs  will  b e list e d  a n d s u m m ari z e d.  
All  a d v ers e  e v e nts  will  b e list e d,  a n d  a n y  ot h er i nf or m ati o n  c oll e ct e d ( e. g.,  st art/ e n d  d at es  a n d 
d ur ati o n  of  a d v ers e  e v e nt,  s e v erit y   or  r el at e d n ess  t o  st u d y    m e di c ati o n)    will  b e  list e d  as 
a p pr o pri at e.  
 
A Es  of  s p e ci al i nt er est  will  b e  s u m m ari z e d  s e p ar at el y.  All  s u c h  e v e nts  will  b e i d e ntifi e d  pri or 
t o  d at a b as e l o c k.  
1 0. 2. 1. 2.   
Ot h e r  S af et y  E v al u ati o ns 
D es cri pti v e  st atisti cs  of l a b or at or y  p ar a m et ers  a n d  c o nti n u o us  v ari a bl es  of  vit al  si g ns  will  b e 
c al c ul at e d f or  e a c h  ti m e  p oi nt.  S hift t a bl es f or  q u alit ati v e  uri n al ysis r es ults  at  e a c h ti m e  p oi nt 
aft er  t h e  st art  of  a d mi nistr ati o n   will  b e  cr e at e d.  H ei g ht,   w ei g ht,  b o d y  s urf a c e  ar e a  ( B S A)  a n d 
b o d y  m ass i n d e x ( B MI)  will  b e s u m m ari z e d  o v er  visit .   
 
S hift  t a bl es    will   b e   pr o vi d e d  f or  l a b or at or y   p ar a m et ers  t o   c o m p ar e   a  s u bj e ct’s   b as eli n e 
l a b or at or y  e v al u ati o n  r el ati v e t o t h e  w orst  v al u e  d uri n g t h e tr e at m e nt  p eri o d  usi n g  C o m m o n 
T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts ( C T C A E)  gr a d es. I n  a d diti o n, t h e  n or m al l a b or at or y 
r a n g es  will b e  us e d t o  e v al u at e  w h et h er  a  p arti c ul ar l a b or at or y t est  v al u e  w as  n or m al, l o w,  or 
hi g h f or  e a c h  visit  v al u e r el ati v e t o  w h et h er  or  n ot t h e  b as eli n e  v al u e  w as  n or m al, l o w,  or  hi g h 
(i n cl u di n g  c at e g or y  “ hi g h  a n d l o w ”).  S u bj e cts  wit h  a b n or m al l a b or at or y  v al u es  will  b e list e d 
a n d  v al u es  o utsi d e t h e  n or m al r a n g es  will  b e fl a g g e d. 
1 0. 2. 2.   
P o p ul ati o n  A n al ysis 
1 0. 2. 2. 1.   
S u bj e ct  Dis p ositi o n  
S u bj e ct   dis p ositi o n    will   b e  t a b ul at e d  f or   all   s u bj e cts   b y   s u m m ari zi n g  t h e   n u m b er   a n d 
p er c e nt a g e  of  s u bj e cts  w h o  ar e i n cl u d e d i n  t h e  s af et y a n al ys is  s et,  c o m pl et e d  st u d y tr e at m e nt, 
dis c o nti n u e d fr o m t h e st u d y tr e at m e nt  a n d  b y t h e  pri m ar y r e as o n f or  dis c o nti n u ati o n. 
A  listi n g    will  pr es e nt  d at es  of  st u d y  tr e at m e nt  dis c o nti n u ati o n  a n d  t h e  pri m ar y  r e as o n,  if 
a p pli c a bl e f or  e a c h s u bj e ct.  
1 0. 2. 2. 2.   D e m o g r a p hi c  a n d  B as eli n e  C h a r a ct e risti cs  
D e m o gr a p hi c  a n d  b as eli n e  m e as ur e m e nts  will  b e  s u m m ari z e d f or t h e  s af et y  a n al ysis  s et  usi n g 
st a n d ar d  d es cri pti v e  s u m m ari es  or  c at e g ori c al  s u m m ari es,  as  a p pr o pri at e.  I n  a d diti o n  t o  t h e 
s u m m ar y  t a bl es,  a  listi n g   will  b e  pr o vi d e d  f or  a ll  d e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs 
d at a. I n  a d diti o n, listi n g  of  m e di c al  hist or y  will  b e  pr o vi d e d. 
F or t his  p ur p os e,  d at a  of t h e  C L 2- 9 5 0 1 4- 0 0 2 st u d y  m a y  b e  us e d. 
1 0. 2. 2. 3.   C o n c o mit a nt  M e di c ati o n 
C o n c o mit a nt  m e di c ati o n f or  e a c h s u bj e ct  will  b e list e d.  
1 0. 3.   H a n dli n g  of  Missi n g,  U n us e d,  a n d  S p u ri o us  D at a   
A d v e rs e  e v e nts ( A Es)  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 3 /5 4  
 
­   H a n dli n g  of  u n k n o w n  c a us alit y  ass ess m e nt: 
o   If  a  s u bj e ct e x p eri e n c e  a n  A E  wit h  a  missi n g  c a us alit y  ass ess m e nt, t h e  r el ati o ns hi p  of 
t h e  A E  will  b e  c o u nt e d  as  “r el at e d ”. 
­   H a n dli n g  of  u n k n o w n s e v erit y  gr a d es:  
o   If  a  s u bj e ct  e x p eri e n c es  m or e t h a n  o n e  A E  c at e g ori z e d  u n d er t h e  s a m e  pr ef err e d t er m, 
o n e  of t h e m is  c at e g ori z e d  as  “s e v er e ”  a n d  o n e  of  t h e m is  c at e g ori z e d  as  “ u n k n o w n ”, 
t h e s e v erit y  of t his  A E s h o ul d  b e  c o u nt e d  as  “s e v er e ”. 
o   If  a  s u bj e ct  e x p eri e n c es  m or e t h a n  o n e  A E  c at e g ori z e d  u n d er t h e  s a m e  pr ef err e d t er m, 
o n e  of t h e m is  c at e g ori z e d  as  “ mil d ”  or  “ m o d er at e ”  a n d  o n e  of t h e m is  c at e g ori z e d  as 
“ u n k n o w n ”, t h e s e v erit y  of t his  A E s h o ul d  b e  c o u nt e d  as  “ u n k n o w n ”.  A  c ol u m n  “ U N K ” 
s h o ul d  b e i ns ert e d  f or t h os e  A Es  at t h e  e n d  of  t h e t a bl e  ( b ef or e t h e  “ T ot al ”  c ol u m n if 
a p pli c a bl e).  
1 0. 4.   Pl a n n e d I nt e ri m  A n al ysis  
N ot  a p pli c a bl e 
1 0. 5.   P r o c e d u r es f o r  R e p o rti n g  C h a n g es t o t h e  Pl a n n e d  A n al ysis    
D et ails  of  pl a n n e d  a n al ys es  will  b e  s p e cifi e d i n t h e  St atisti c al  A n al ysis  Pl a n ( S A P).  C h a n g es 
t o t h e  pl a n n e d  a n al ysis  will  b e  d o c u m e nt e d i n  S A P  a m e n d m e nts.  T h e  S A P  will  b e  fi n ali z e d 
pri or t o t h e  d at a b as e l o c k. 
1 1.   DI R E C T  A C C E S S  T O  S O U R C E  D A T A /  D O C U M E N T S  
T h e   i n v esti g at or    will   all o w   t h e    m o nit ors,   t h e   p ers o ns   r es p o nsi bl e   f or   t h e   a u dit,   t h e 
r e pr es e nt ati v es  of t h e  I E C,  a n d  of t h e  C o m p et e nt  A ut h oriti es t o  h a v e  dir e ct  a c c ess t o  s o ur c e 
d at a /  d o c u m e nts. 
1 2.   Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E  
1 2. 1.  St u d y  m o nit o ri n g  
Cli ni c al  sit e    m o nit ori n g  is  c o n d u ct e d  t o  e ns ur e  t h at  t h e  ri g hts  a n d    w ell -b ei n g  of  h u m a n  
s u bj e cts  ar e  pr ot e ct e d, t h at t h e  r e p ort e d tri al  d at a  ar e  a c c ur at e,  c o m pl et e,  a n d  v erifi a bl e,  a n d 
t h at   t h e   c o n d u ct   of   t h e   tri al   is   i n   c o m pli a n c e    wit h   t h e   c urr e ntl y   a p pr o v e d 
pr ot o c ol/ a m e n d m e nt(s),  wit h  G C P,  a n d  wit h  a p pli c a bl e r e g ul at or y r e q uir e m e nt(s).  
­   M o nit ori n g f or t his st u d y  will  b e  p erf or m e d  b y t h e str u ct ur e  m e nti o n e d i n  S e cti o n  1.  
­   D et ails  of  cli ni c al  sit e   m o nit ori n g  ar e  d o c u m e nt e d  i n  a   Cli ni c al    M o nit ori n g  Pl a n  ( C M P). 
T h e    C M P   d es cri b es  i n   d et ail    w h o    will   c o n d u ct  t h e    m o nit ori n g,   at    w h at   fr e q u e n c y 
m o nit ori n g    will  b e  d o n e,  at    w h at  l e v el  of  d et ail    m o nit ori n g    will  b e  p erf or m e d,  a n d  t h e 
distri b uti o n  of  m o nit ori n g r e p orts.  
 
M a n a g e m e nt  of  t h e  tri al  i n  t h e  e v e nt  of   N ati o n al  or  I nt er n ati o n al  P u bli c   H e alt h   E m er g e n c y 
s u c h  as  C o vi d- 1 9  p a n d e mi c is  d es cri b e d i n  A p p e n di x  3 . 
1 2. 1. 1.   B ef o r e t h e st u d y  
T h e i n v esti g at or  will  all o w t h e  m o nit or t o  visit t h e  sit e  a n d f a ciliti es  w h er e t h e  st u d y  will t a k e 
pl a c e i n  or d er t o  e ns ur e  c o m pli a n c e  wit h t h e  pr ot o c ol r e q uir e m e nts. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 4 /5 4  
 
Tr ai ni n g  s essi o ns  m a y  b e  or g a nis e d  f or t h e i n v esti g at ors  a n d/ or i nstr u cti o n  m a n u als  m a y  b e 
gi v e n t o t h e i n v esti g at ors. 
1 2. 1. 2.   D u ri n g t h e st u d y  
T h e i n v esti g at or  will  all o w t h e  m o nit or t o:  
­   r e vi e w  of t h e st u d y sit e’s  pr o c ess es  a n d  pr o c e d ur es, 
­   v erif y   a p pr o pri at e   cli ni c al  i n v esti g at or  s u p er visi o n   of  st u d y  sit e  st aff   a n d  t hir d-p art y  
v e n d ors, 
­   i ns p e ct t h e sit e, t h e f a ciliti es  a n d t h e  m at eri al  us e d f or t h e st u d y, 
­   m e et  all  m e m b ers  of  his/ h er t e a m i n v ol v e d i n t h e st u d y,  
­   c o ns ult t h e  d o c u m e nts r el e v a nt t o t h e st u d y, 
­   h a v e  a c c ess  t o  t h e  el e ctr o ni c  c as e  r e p ort  f or ms  (i. e.  a c c ess  t o  a n  a n al o gi c  p h o n e  li n e  or 
his/ h er  c o m p ut er), 
­   c h e c k t h at t h e  el e ctr o ni c  c as e r e p ort f or ms h a v e  b e e n fill e d  o ut  c orr e ctl y,  
­   dir e ctl y  a c c ess  s o ur c e  d o c u m e nts  f or  c o m p aris o n  of  d at a  t h er ei n    wit h  t h e  d at a  i n  t h e 
el e ctr o ni c  c as e r e p ort f or ms,  
­   v erif y  t h at  t h e  st u d y  is  c arri e d  o ut  i n  c o m pli a n c e   wit h  t h e  pr ot o c ol  a n d  l o c al  r e g ul at or y 
r e q uir e m e nts. 
T h e  st u d y    m o nit ori n g   will  b e  c arri e d  o ut  at  r e g ul ar  i nt er v als,  d e p e n di n g  o n  t h e  r e cr uit m e nt 
r at e  a n d /  or t h e i n v esti g ati o n s c h e d ul e,  a n d  arr a n g e d  b et w e e n t h e i n v esti g at or  a n d  m o nit or. 
All i nf or m ati o n  d e alt  wit h  d uri n g t h es e  visits  will  b e tr e at e d  as stri ctl y  c o nfi d e nti al.  
1 2. 2.  C o m p ut e ris e d  m e di c al fil e  
If  c o m p ut eris e d  m e di c al fil es  ar e  us e d,  a n d if t h e  c o m p ut er  s yst e m  all o ws,  n o  c h a n g e  m a d e i n 
t h e  m e di c al fil es  b y t h e i n v esti g at or  s h o ul d  o bs c ur e t h e  ori gi n al i nf or m ati o n.  T h e r e c or d  m ust 
cl e arl y  i n di c at e  t h at  a  c h a n g e   w as   m a d e  a n d  cl e arl y  pr o vi d e  a   m e a ns  t o  l o c at e  a n d  r e a d  t h e 
pri or i nf or m ati o n (i. e.  a u dit tr ail).  T h e i n v esti g at or  will s a v e  d at a  at r e g ul ar i nt er v als.  
T h e  i n v esti g at or    m ust   g u ar a nt e e  t h e  i nt e grit y   of  t h e  st u d y   d at a  i n  t h e    m e di c al  fil e s   b y 
i m pl e m e nti n g   s e c urit y    m e as ur es  t o   pr e v e nt   u n a ut h oris e d   a c c ess  t o  t h e   d at a   a n d  t o  t h e 
c o m p ut er s yst e m.  
If  t h e   c o m p ut eris e d    m e di c al  fil es   ar e   c o nsi d er e d   as   n ot   v ali d at e d   b y  t h e   s p o ns or,  t h e 
i n v esti g at or  u n d ert a k es: 
­   at  t h e  st art  of  t h e  st u d y,  t o  pri nt  t h e    m e di c al  fil es  of  all  p arti ci p a nts  all o wi n g  a  r eli a bl e 
v erifi c ati o n  of t h e st u d y  crit eri a ( e. g.  m e di c al  hist or y/ pr e vi o us tr e at m e nts/  c h ar a ct eristi cs  of 
t h e st u di e d  dis e as e  d o c u m e nt e d  wit hi n t h e  p eri o d  of ti m e  d efi n e d  b y t h e st u d y  pr ot o c ol), 
­   d uri n g t h e st u d y, t o  pri nt i n r e al ti m e  e a c h  d at a  e ntr y  a n d  e a c h  d at a  c h a n g e.  
T h e i n v esti g at or  will  p ers o n all y  si g n,  d at e  a n d  gi v e  t h e  n u m b er  of  p a g es  o n t h e  first  or l ast 
p a g e  of  e a c h  pri nt -o ut.  At  e a c h  visit  b y t h e  m o nit or, t h e i n v esti g at or  will  pr o vi d e  all t h e  pri nt-
o uts  of t h e  m e di c al fil es  of t h e  p arti ci p a nts.  T h e  m o nit or  will  p ers o n all y si g n  a n d  d at e t h e first 
( or l ast)  p a g e t h e n i niti al  all  p a g es i n  e a c h  p a p er  pri nt- o ut. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 5 /5 4  
 
If  t h e  c o m p ut er  s yst e m  all o ws  t h e  tr a c ki n g  of  t h e  c h a n g es    m a d e  t o  t h e    m e di c al  fil es,  t h e 
i n v esti g at or  will  s u p pl y t h e  m o nit or,  at  e a c h  visit,  wit h  a  pri nt-o ut  of t h e  m e di c al fil es  of t h e 
p arti ci p a nts  a n d t h e r e c or ds  of t h e  c h a n g es  m a d e.  E a c h  pri nt -o ut  will  b e  p ers o n all y  d at e d  a n d 
si g n e d,  b y t h e i n v esti g at or  a n d t h e  m o nit or  o n t h e first  p a g e.  T h e  n u m b er  of  p a g es  will  als o  b e 
i n di c at e d  b y t h e i n v esti g at or  a n d t h e  m o nit or  o n t h e first  p a g e. 
If t h e  c o m p ut eris e d  m e di c al fil es  ar e  c o nsi d er e d  as  v ali d at e d  b y t h e  s p o ns or, t h e i n v esti g at or 
u n d ert a k es t o  gi v e  a c c ess t o t h e  m o nit or t o t h e  c o m p ut eris e d  m e di c al fil es  of  all  p arti ci p a nts. 
If  t h e    m o nit or  c a n n ot  a c c ess  t o  t h e  tr a c ki n g  of  t h e  c h a n g es    m a d e  t o  t h e    m e di c al  fil es,  t h e 
i n v esti g at or    will  s u p pl y  t h e    m o nit or,  at  e a c h  visit,    wit h  a  pri nt-o ut  of  t h e  r e c or ds  of  t h e 
c h a n g es  m a d e t o t h e  m e di c al fil es  of t h e  p arti ci p a nts.  E a c h  pri nt -o ut  will  b e  p ers o n all y  d at e d 
a n d  si g n e d,  b y t h e i n v esti g at or  a n d t h e  m o nit or  o n t h e  first  p a g e.  T h e  n u m b er  of  p a g es  will 
als o  b e i n di c at e d  b y t h e i n v esti g at or  a n d t h e  m o nit or  o n t h e first  p a g e. 
T h e i n v esti g at or  u n d ert a k es t o  k e e p: 
­   all    m e di c al  fil e  pri nt -o uts  si g n e d  a n d  d at e d  b y  hi m/ h er  a n d  b y  t h e    m o nit or    w h e n  t h e 
c o m p ut er s yst e m is  c o nsi d er e d  as  n ot  v ali d at e d  b y t h e s p o ns or,  
­   if  t h e  c o m p ut er  s yst e m  us e d  all o ws  c h a n g es  t o  b e    m a d e,  t h e  pri nt-o uts  of  t h e  a u dit  tr ail 
w h e n  t h e  c o m p ut er  s yst e m  is  c o nsi d er e d  as  n ot  v ali d at e d  b y  t h e  s p o ns or  or    w h e n  t h e 
m o nit or  c a n n ot  a c c ess t o t h e  a u dit tr ail i n t h e  c o m p ut er s yst e m,  
­   all  ori gi n al  s o ur c e -d o c u m e nts ( ori gi n als  of  s p e cifi c  e x a mi n ati o ns, i nf or m e d  c o ns e nt f or ms, 
t h er a p e uti c  u nit tr a c ki n g f or m...). 
1 2. 3.  A u dit  - I ns p e cti o n 
T h e i n v esti g at or s h o ul d  b e i nf or m e d t h at  a n  a u dit  m a y  b e  c arri e d  o ut  d uri n g  or  aft er t h e  e n d  of 
t h e st u d y. 
T h e  i n v esti g at or  s h o ul d  b e  i nf or m e d  t h at  t h e   C o m p et e nt   A ut h oriti es    m a y  als o  c arr y  o ut  a n 
i ns p e cti o n i n t h e  f a ciliti es  of t h e  s p o ns or  a n d/ or t h e  st u d y  c e ntr e(s).  T h e  s p o ns or  will i nf or m 
t h e   i n v esti g at ors   c o n c er n e d   i m m e di at el y   u p o n   n otifi c ati o n   of   a   p e n di n g   st u d y   c e ntr es 
i ns p e cti o n.  Li k e wis e, t h e i n v esti g at or  will i nf or m t h e s p o ns or  of  a n y  p e n di n g i ns p e cti o n. 
T h e  i n v esti g at or    m ust  all o w  t h e  r e pr es e nt ati v es  of  t h e    C o m p et e nt    A ut h oriti es  a n d  p ers o ns 
r es p o nsi bl e f or t h e  a u dit:  
­   t o i ns p e ct t h e sit e, f a ciliti es  a n d  m at eri al  us e d f or t h e st u d y, 
­   t o  m e et  all  m e m b ers  of  his/ h er t e a m i n v ol v e d i n t h e st u d y, 
­   t o  h a v e  dir e ct  a c c ess t o st u d y  d at a  a n d s o ur c e  d o c u m e nts, 
­   t o  c o ns ult  all  of t h e  d o c u m e nts r el e v a nt t o t h e st u d y. 
If t h e  c o m p ut eris e d  m e di c al fil e is  c o nsi d er e d  as  n ot  v ali d at e d, t h e i n v esti g at or  u n d ert a k es t o 
pr o vi d e  all  t h e  s o ur c e -d o c u m e nts  a n d  t h e  pri nt -o uts  of  t h e    m e di c al  fil es  of  t h e  p arti ci p a nts 
a n d, if t h e  c o m p ut er s yst e m  us e d  all o ws, t h e r e c or d  of t h e  c h a n g es  m a d e  d uri n g t h e st u d y. 
If t h e  c o m p ut eris e d  m e di c al fil e is  c o nsi d er e d  as  v ali d at e d, t h e i n v esti g at or  u n d ert a k es t o: 
­   gi v e  a c c ess t o t h e r e pr es e nt ati v es  of t h e  C o m p et e nt  A ut h oriti es  a n d  p ers o ns r es p o nsi bl e f or 
t h e  a u dit t o t h e  c o m p ut eris e d  m e di c al fil es  of  all  p arti ci p a nts, 
­   pr o vi d e t h e  pri nt -o uts  of t h e  c h a n g es  m a d e  d uri n g t h e  st u d y, if t h e tr a c ki n g  of t h e  c h a n g es 
m a d e t o t h e  m e di c al fil es  c a n n ot  b e  a c c ess e d i n t h e  c o m p ut er.  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  4 6 /5 4  
 
1 3.   E T HI C S  
1 3. 1.  I nstit uti o n al  R e vi e w  B o a r d(s)/I n d e p e n d e nt  Et hi cs  C o m mitt e e(s) 
T h e  st u d y  pr ot o c ol,  t h e  " P arti ci p a nt  i nf or m ati o n  a n d  c o ns e nt / ass e nt  f or m "  d o c u m e nt,  t h e 
"P ar e nt(s)/ L e g al   r e pr es e nt ati v e   i nf or m ati o n   a n d   c o ns e nt   f or m "   d o c u m e nt,   t h e   list   of 
i n v esti g at ors  d o c u m e nt,  t h e  i ns ur a n c e  d o c u m e nts,  t h e  S m P C  or  I n v esti g at or’s    Br o c h ur e  of 
a d mi nist er e d  I M P  a n d   NI M Ps  will  b e  s u b mitt e d t o  ( a n)  I E C(s)  b y  t h e  i n v esti g at or(s)  or  t h e 
n ati o n al  c o or di n at or(s)  or t h e s p o ns or i n  a c c or d a n c e  wit h l o c al r e g ul ati o ns. 
T h e  st u d y  will  n ot  st art i n  a  c e ntr e  b ef or e  writt e n  a p pr o v al  b y  c orr es p o n di n g I E C(s)  h as  b e e n 
o bt ai n e d, t h e l o c al r e g ul at or y r e q uir e m e nts  h a v e  b e e n  c o m pli e d  wit h,  a n d t h e  si g n at ur e  of  t h e 
cli ni c al st u d y  pr ot o c ol  of  e a c h  c o ntr a ct u al  p art y i n v ol v e d  h as  b e e n  o bt ai n e d. 
1 3. 2.  St u d y  c o n d u ct  
T h e st u d y  will  b e  p erf or m e d i n  a c c or d a n c e  wit h t h e  et hi c al  pri n ci pl es st at e d i n t h e  D e cl ar ati o n 
of  H elsi n ki  1 9 6 4,  as  r e vis e d i n  A p p e n di x  4  wit h t h e  G C P  a n d  wit h t h e  a p pli c a bl e  r e g ul at or y 
r e q uir e m e nts. 
1 3. 3.  P a rti ci p a nt i nf o r m ati o n  a n d i nf o r m e d  c o ns e nt  
I n  a n y  c as e,  t h e  p arti ci p a nt  ( a n d/ or  his/ h er  l e g al  r e pr es e nt ati v e,    w h e n  r e q uir e d)    m ust  b e 
i nf or m e d  t h at   h e/s h e  is  e ntitl e d  t o   b e  i nf or m e d  a b o ut  t h e   o ut c o m e   of  t h e  st u d y   b y  t h e 
i n v esti g at or. 
T h e i n v esti g at or  or  a  p ers o n  d esi g n at e d  b y  h i m/ h er is t o  c oll e ct  writt e n c o ns e nt/ as s e nt  fr o m 
e a c h  p arti ci p a nt,   w h e n  of  a p pr o pri at e  i nt ell e ct u al    m at urit y  a n d  writt e n  c o ns e nt  fr o m  his/ h er 
p ar e nt(s)  ( a c c or di n g  t o  l o c al  r e g ul ati o ns)/l e g al  r e pr es e nt ati v e  b ef or e  his/ h er  p arti ci p ati o n  i n 
t h e st u d y. 
Pri or t o t his,  e a c h  p arti ci p a nt i n t h e  pr es e n c e  of  his/ h er  p ar e nt(s)/l e g al  r e pr es e nt ati v e  s h o ul d 
b e  i nf or m e d  b y  t h e  i n v esti g at or  or  his/ h er  d el e g at e  t o  t h e  f ull est  e xt e nt  p ossi bl e  a b o ut  t h e 
st u d y i n l a n g u a g e  a n d t er ms  h e/s h e is  a bl e t o  u n d erst a n d.  T h e i n v esti g at or  s h o ul d  als o i nf or m 
t h e  p ar e nt(s)/l e g al  r e pr es e nt ati v e  of t h e  o bj e cti v es,  b e n efits,  ris ks  a n d  r e q uir e m e nts i m p os e d 
b y t h e  st u d y,  as  w ell  as t h e  n at ur e  of I M P   an d  NI M Ps .  T h e  p arti ci p a nt  m ust  b e i nf or m e d t h at 
h e/s h e  h as t h e  p ossi bilit y  n ot t o  p arti ci p at e i n t h e  st u d y  a n d t h at  h e/s h e i s  fr e e t o  r e c o nsi d er 
his/ h er  as s e nt  at  a n y ti m e. 
T h e  p ar e nt(s)/l e g al r e pr es e nt ati v e  of t h e  p arti ci p a nt  a n d t h e  p arti ci p a nt *  will  b e  pr o vi d e d  wit h 
a n i nf or m ati o n  a n d  c o ns e nt / ass e nt f or m i n  cl e ar,  si m pl e l a n g u a g e.  T h e  p arti ci p a nt  a n d  his/ h er 
p ar e nt(s)/l e g al r e pr es e nt ati v e  m ust  b e  all o w e d  a m pl e ti m e t o i n q uir e  a b o ut  d et ails  of t h e  st u d y 
a n d t o  d e ci d e  w h et h er  or  n ot t o  p arti ci p at e i n t h e s t u d y. 
T w o  ori gi n al  l e g al  r e pr es e nt ati v e  i nf or m ati o n  a n d  c o ns e nt  f or ms    m ust  b e  c o m pl et e d,  c o -
si g n e d  a n d  d at e d  p ers o n all y  b y  p arti ci p a nt’s  p ar e nt(s)/l e g al  r e pr es e nt ati v e  a n d  b y t h e  p ers o n 
r es p o nsi bl e f or  c oll e cti n g t h e i nf or m e d  c o ns e nt. 
                                                 
*  D e p e n di n g  o n t h e  a g e  of t h e  mi n or, t w o  diff er e nt  writt e n i nf or m ati o n  a n d  c o ns e nt f or ms  m a y  b e  pr e p ar e d:  o n e f or t h e  p a rti ci p a nt  a n d  o n e 
f or  his/ h er  p ar e nt(s)/l e g al r e pr es e nt ati v e 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
 4 7 /5 4  
 
T w o  ori gi n al s  p arti ci p a nt i nf or m ati o n  a n d  c o ns e nt/ as s e nt f or ms  m ust  b e  c o m pl et e d,  c o -si g n e d 
a n d  d at e d  p ers o n all y  b y t h e  p arti ci p a nt if  c a p a bl e  a n d  b y t h e  p ers o n r es p o nsi bl e f or  c oll e cti n g 
t h e i nf or m e d  c o ns e nt/ass e nt.  
If  t h e  p ar e nt(s)/l e g al  r e pr es e nt ati v e  ar e(is)  u n a bl e  t o  r e a d,  a n  i m p arti al    wit n ess  s h o ul d  b e 
pr es e nt  d uri n g t h e  e ntir e i nf or m e d  c o ns e nt  dis c ussi o n.  T h e  p ar e nt(s)/l e g al r e pr es e nt ati v e  m ust 
gi v e  c o ns e nt  or all y,  a n d  if  c a p a bl e  of  d oi n g  s o,  c o m pl et e,  si g n  a n d   p ers o n all y  d at e  t h e 
i nf or m ati o n  a n d  c o ns e nt  f or m.    T h e    wit n ess    m ust  t h e n  c o m pl et e,  si g n  a n d  d at e  t h e  f or m 
t o g et h er  wit h t h e  p ers o n r es p o nsi bl e f or  c oll e cti n g t h e i nf or m e d  c o ns e nt. 
T h e  p arti ci p a nt's  p ar e nt(s)/l e g al  r e pr es e nt ati v e  will  b e  gi v e n  o n e  si g n e d  ori gi n al i nf or m ati o n 
a n d  c o ns e nt f or m,  a n d  o n e  ori gi n al i nf or m ati o n  a n d  ass e nt f or m.  T h e  s e c o n d  ori gi n als  will  b e 
k e pt  b y t h e i n v esti g at or  
A   c o p y   of   t h e   i nf or m ati o n   a n d   ass e nt/ c o ns e nt   f or m   f or   t h e   p arti ci p a nt   a n d   his/ h er 
p ar e nt(s)/l e g al   r e pr es e nt ati v e  i n  t h e  l a n g u a g e(s)   of  t h e   c o u ntr y  is   or   ar e   gi v e n  i n  t h e 
" P arti ci p a nt   i nf or m ati o n   a n d   c o ns e nt   f or m "   d o c u m e nt   a n d   i n   t h e   " P ar e nt(s)/ L e g al 
r e pr es e nt ati v e i nf or m ati o n  a n d  c o ns e nt f or m "  d o c u m e nt  att a c h e d t o t h e  pr ot o c ol 
1 3. 4.  M o difi c ati o n  of t h e i nf o r m ati o n  a n d  c o ns e nt f o r m  
A n y  c h a n g e t o t h e i nf or m ati o n  a n d  c o ns e nt f or m  c o nstit ut es  a n  a m e n d m e nt t o t his  d o c u m e nt 
a n d    m ust   b e  s u b mitt e d  f or   a p pr o v al  t o  t h e   I E C(s),   a n d  if   a p pli c a bl e  t o  t h e    C o m p et e nt 
A ut h oriti es.  
A  c o p y  of  t h e  n e w  v ersi o n  of  t h e  i nf or m ati o n  a n d  c o ns e nt  f or m  i n  t h e  l a n g u a g e(s)  of  t h e 
c o u ntr y  will  b e  gi v e n i n t h e  a m e n d m e nt t o t h e  “ P arti ci p a nt I nf or m ati o n  a n d  c o ns e nt f or m ”. 
S u c h  a m e n d m e nts    m a y  o nl y  b e  i m pl e m e nt e d  aft er    writt e n  a p pr o v al  of  t h e  I E C  h as  b e e n 
o bt ai n e d  a n d  c o m pli a n c e    wit h  t h e  l o c al  r e g ul at or y  r e q uir e m e nts,    wit h  t h e  e x c e pti o n  of  a n 
a m e n d m e nt r e q uir e d t o  eli mi n at e  a n i m m e di at e ris k t o t h e st u d y  p arti ci p a nts.  
E a c h  p arti ci p a nt  aff e ct e d  b y t h e  a m e n d m e nt  a n d/ or  his/ h er  p ar e nt(s)/l e g al r e pr es e nt ati v e  m ust 
c o m pl et e,  d at e  a n d  c o -si g n  o n e,  or t w o if  r e q uir e d  b y l o c al  r e g ul ati o n,  ori gi n al(s)  of t h e  n e w 
v ersi o n  of  t h e  i nf or m ati o n  a n d  c o ns e nt  f or m  t o g et h er    wit h  t h e  p ers o n    w h o  c oll e ct e d  t h e 
i nf or m e d  c o ns e nt  ( a n d  a n i n d e p e n d e nt  wit n ess, if  a p pli c a bl e).  H e/ S h e/ T h e y  will  r e c ei v e  o n e 
si g n e d  c o p y ( or  ori gi n al, if r e q uir e d  b y l o c al r e g ul ati o n)  of t h e  a m e n d m e nt t o t h e i nf or m ati o n 
a n d  c o ns e nt f or m(s).  T h e si g n e d  ori gi n al(s)  will  b e  k e pt  b y t h e i n v esti g at or 
1 4. 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 4. 1.  St u d y  d at a  
A  2 1  C R F  P art  1 1 - c o m pli a nt el e ctr o ni c  d at a  c a pt ur e  s yst e m is  g oi n g t o  b e  us e d f or t his  st u d y. 
A n  el e ctr o ni c  c as e r e p ort f or m ( e -C R F)  is  d esi g n e d t o r e c or d t h e  d at a r e q uir e d  b y t h e  pr ot o c ol 
a n d  c oll e ct e d  b y t h e i n v esti g at or.  
T h e  e -C R F  will  b e  pr o d u c e d  b y I. R.I. S. i n  c o m pli a n c e  wit h its s p e cifi c ati o ns.  T h e i n v esti g at or 
or  a  d esi g n at e d  p ers o n  fr o m  his/ h er  t e a m    will  b e  tr ai n e d  f or  t h e  us e  of  t h e  e -C R F  b y  t h e 
s p o ns or. 


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D ata entr y  at t he i n vesti gat or’s site will be  pe rf or me d by  t he i n vesti gat or or  by  t he desi g nate d 
pers o n  fr o m his/ her tea m after c o m pleti o n  of t he partici pa nt’s  Me dic al File. 
U p o n  entr y,  data will b e tra ns mitte d  via t he I nter net fr o m t he st u d y ce ntre t o t he st u d y 
dat a base. 
T he i n vesti gat or or t he d esig nat e d pers o n fro m hi s/ her team a gr ees to c o m plet e t he e-C R F , at 
eac h p artici pant vi sit, a n d all othe r d ocu me nt s pro vi de d b y t he s p o ns or ( e. g. d o c u me nts 
relati n g to  th e I M P ma na ge me nt…). 
Data rec or de d  directl y o n  e- C RF  a nd  c onsi dere d  as so urce dat a (see secti o n 4.5 ) m ust be 
c ollecte d i m mediatel y  i n t he e-C R F.  T h e othe r e-C R F f or m s m us t be c o m plete d as so o n as 
p ossi bl e foll o wi n g e ach vi sit. 
All c orrecti o ns of data o n t he e -C R F  m ust be ma de b y t he i n vesti gat or or b y t he desi g nat e d 
pers o n fr o m his/ her tea m usi n g electr o ni c data clarificati o ns acc or di n g t o t he pr o vi de d 
i nstr ucti o ns. All data m o dificati o n will be rec or de d usi n g t he a u dit trail feat ure of I nf or m 
soft ware, i ncl u di n g date, reaso n f or m o dificati o n a n d i de ntificati o n of t he pers o n w h o has 
ma de t he c h a n ge.  
I n or d er to e ns ur e co nfi de nt ialit y a n d sec urit y of t he da ta, user na mes an d pa ssw or ds w ill be 
use d t o restric t syste m access to a ut h orise d pers o n ne l o nly, w he the r resi dent w it hi n t he 
i n vesti gat or’s sites, the s p o ns or or t hir d parties. 
Data  will be v erifie d i n acc or d a nce  wit h t he m onit ori n g  strateg y  defi n e d  for  t he st u d y. After 
c o m pari ng t hes e d ata t o t he s o urc e d ocu me nt s, the 
m o nit or w ill re q uest correcti o n / 
clarificati o n fr o m t he i n v esti gator us i n g electr o nic data clarificatio ns t ha t sh o ul d be ans we re d 
a n d cl ose d as q uic kl y as p ossi ble. 
Da ta ca n be f r oze n d uri ng t he s t u dy a ft er thei r va li dati o n. H o we ver, the i n vesti gat or ha s the 
p ossi bilit y  t o m o dif y a data if dee me d n ecess ar y  vi a a re q u est to t he s p o ns or . 
A fter t he last visit of the  pa rtici pa nt, t he i n vesti gat or or co -i n vesti gat or m ust attest t he 
a ut he nticit y  of t he data c ollecte d i n t he e-C R F  by  e nteri n g hi s/ her user na m e an d pas sw or d. 
Af ter t he data b ase l oc k, t he i n vesti gat or or a n a ut h orize d me m ber of his/ her tea m will  have t o 
d o w nl oa d fr o m t he e -C R F  a n electr o nic file c o ntai ni n g p artici pa nt d ata of his/ her ce ntre f or 
arc hi vi n g it i n t he st u d y file (s ee secti o n 1 4. 3).  
1 4. 2.  D at a m a n a ge me nt 
Data ar e c ollecte d via a C R F  a n d st ore d in  a sec ure d data b ase. 
F or d ata c ollecte d o n t he e -C R F,  t he Cli nical Dat a Ma na ge me nt of I. R .I. S. is resp o nsi ble f or 
data pr o cessi n g i ncl u di n g d ata v ali dati o n perf or me d acc or di n g t o a s p ecificati o n m a n ual 
descri bi n g t he c h ec ks to be carrie d o ut. As a res ult of data vali dati o n, data ma y re q uire s o me 
c ha n ges. A n el ectr o ni c data cl ari ficati o n f or m is se nt t o t he i n vesti gat or w h o is re q uire d t o 
res p o n d t o t he q uer y a n d ma ke a n y ne cessar y c ha n ges t o t he d ata.  
F or data tra nsferre d fr o m  ce ntral la b or at or y, t he Cli nical Data Ma na ge me nt of I. R.I. S. is 
res p o nsi ble f or data tra nsfer. 
Ce ntralise d l a b orat or y pr o vi d e(s) electr o ni c tra nsfer of 
c o m p uterise d data t o t he Cli nical Data Ma na ge me nt of I. R.I. S. Data are tra nsferre d acc or di n g 
t o a tra nsfer pr ot oc ol iss ue d b y t h e I. R.I. S. da ta ma na ger. 


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T h e  M e di c al  R e vi e w   D e p art m e nt  of I. R.I. S. is r es p o nsi bl e f or  d at a  c o di n g i n cl u di n g: 
­   m e di c al / s ur gi c al  hist or y,  a d v ers e  e v e nts  a n d  pr o c e d ur es  usi n g  M e d D R A, 
­   m e di c ati o ns  usi n g  W orl d  H e alt h  Or g a ni z ati o n,  Dr u g  Di cti o n ar y ( W H O- Dr u g).  
T h e  c o di n g  pr o c ess is  d es cri b e d i n  a s p e cifi c ati o n  m a n u al. 
T h e  i n v esti g at or  as c ert ai ns  h e/s h e   will  a p pl y  d u e  dili g e n c e  t o  a v oi d  pr ot o c ol  d e vi ati o ns. 
U n d er  n o  cir c u mst a n c es  s h o ul d  t h e  i n v esti g at or  c o nt a ct  t h e  s p o ns or  or  its  r e pr es e nt ati v es 
m o nit ori n g t h e  st u d y, if  a n y, t o r e q u est  a p pr o v al  of  a  pr ot o c ol  d e vi ati o n,  as  n o  d e vi ati o ns  ar e 
p er mitt e d.  If  t h e  i n v esti g at or  f e els  a  pr ot o c ol  d e vi ati o n    w o ul d  i m pr o v e  t h e  c o n d u ct  of  t h e 
st u d y t his  m ust  b e  c o nsi d er e d  a  pr ot o c ol  a m e n d m e nt,  a n d  u nl ess s u c h  a n  a m e n d m e nt is  a gr e e d 
u p o n  b y  t h e  s p o ns or  a n d  a p pr o v e d  b y  t h e  I E C  it  c a n n ot  b e  i m pl e m e nt e d.    All  i m p ort a nt 
pr ot o c ol  d e vi ati o ns  will  b e r e c or d e d  a n d r e p ort e d i n t h e  cli ni c al st u d y r e p ort. 
W h e n  d at a  v ali d ati o n is  a c hi e v e d,  a  r e vi ew  of t h e  d at a is  p erf or m e d  a c c or di n g t o t h e  s p o ns or 
st a n d ar d  o p er ati n g  pr o c e d ur e.    W h e n  t h e  d at a b as e  h as  b e e n  d e cl ar e d  t o  b e  c o m pl et e  a n d 
a c c ur at e, it  will  b e l o c k e d  a n d t h e  I M P  c o d es  will  b e  u n bli n d e d  a n d  m a d e  a v ail a bl e  f or  d at a 
a n al ysis.  
1 4. 3.  A r c hi vi n g  
T h e i n v esti g at or  will  k e e p  all i nf or m ati o n  r el e v a nt t o t h e  st u d y  f or  at l e ast  2 5  y e ars  aft er t h e 
e n d  of t h e st u d y,  or  m or e if s p e cifi e d  b y t h e l o c al r e g ul ati o n.  
At  t h e  e n d  of  t h e  st u d y,  t h e  i n v esti g at or  or  a n  a ut h ori z e d    m e m b er  of  his/ h er  t e a m   will 
d o w nl o a d  a n  el e ctr o ni c  c o p y  of  e a c h  p arti ci p a nt’s  d at a fr o m t h e  e -C R F  a n d s h o ul d  k e e p it i n  a 
r eli a bl e,  s e c ur e  a n d  d ur a bl e l o c ati o n. T h e fil e i n cl u d es  al l  d at a  a n d  c o m m e nts r e p ort e d i n t h e 
e- C R F , t h e  hist or y  of  all  q u eri es  a n d si g n at ur es  a n d t h e f ull  a u dit tr ail r e p orts.  
T h e  fil e  m ust i n cl u d e  a p pr o pri at e  r estri cti o ns  ( p ass w or d  pr ot e cti o n)  a n d  a d e q u at e  pr ot e cti o n 
fr o m l oss,  p h ysi c al  d a m a g e  or  d et eri or ati o n f or t h e  d ur ati o n  of t h e  ar c hi vi n g  p eri o d. 
1 5.   I N S U R A N C E  
I. R.I. S.,  or  a n y  p ar e nt  c o m p a n y  of   S E R VI E R    G R O U P  i n  c h ar g e  of  t h e    m a n a g e m e nt  of 
cli ni c al   tri als,   is   i ns ur e d   u n d er   t h e   li a bilit y   i ns ur a n c e   pr o gr a m   s u bs cri b e d   b y    L E S 
L A B O R A T OI R E S  S E R VI E R t o  c o v er its li a bi lit y  as  s p o ns or  of  cli ni c al tri als  o n  a  w orl d wi d e 
b asis.  
W h er e  a n  i n d e m nifi c ati o n  s yst e m  a n d/ or  a    m a n d at or y  p oli c y  ar e  i n  pl a c e,  I. R.I. S.  or  a n y 
p ar e nt  c o m p a n y  of  S E R VI E R   G R O U P   will  b e  i ns ur e d  u n d er  a  l o c al  a n d  s p e cifi c  p oli c y  i n 
stri ct  a c c or d a n c e  wit h  a n y a p pli c a bl e l a w.   
All  r el e v a nt  i ns ur a n c e  d o c u m e nt ati o n  ar e  i n cl u d e d  i n  t h e  fil e  s u b mitt e d  t o  a n y  a ut h oriti es’ 
a p pr o v al  of  w hi c h is r e q uir e d. 


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1 6.   O W N E R S HI P  O F  T H E  R E S U L T S  –  D A T A  S H A RI N G  P O LI C Y  A N D 
P U B LI C A TI O N  P O LI C Y  
I. R.I. S.,  a cti n g  as t h e  st u d y  s p o ns or,  ass u m es f ull r es p o nsi biliti es r el ati n g t o t his f u n cti o n  a n d 
r et ai ns  e x cl usi v e  pr o p ert y ri g hts  o v er t h e r es ults  of t h e st u d y,  w hi c h it  m a y  us e  as it  d e e ms fit.  
I. R.I. S.  will  e ns ur e t h at t h e  k e y  d esi g n  el e m e nts  of t his  pr ot o c ol  will  b e  p ost e d i n  a  p u bli cl y 
a c c essi bl e   d at a b as e   s u c h   as   cli ni c altri als. g o v.   I n   a d diti o n,   u p o n   st u d y   c o m pl eti o n   a n d 
fi n ali z ati o n   of  t h e   st u d y   r e p ort,  t h e   r es ults   of  t his   st u d y    will   b e   eit h er   s u b mitt e d   f or 
p u bli c ati o n  a n d/ or  p ost e d i n  a  p u bli cl y  a c c essi bl e  d at a b as e  of  cli ni c al st u d y r es ults .  
A n y  pr oj e ct  of  p u bli c ati o n  a n d/ or  c o m m u ni c ati o n  r el ati v e t o t h e  st u d y  a n d/ or  r el ati v e t o t h e 
o bt ai n e d  r es ults  d uri n g t h e  st u d y  or  aft er t h e  st u d y  e n d  s h all  b e  s u b mitt e d t o t h e  s p o ns or i n 
a c c or d a n c e    wit h  t h e  g ui d eli n es  s et  f ort h  i n  t h e  a p pli c a bl e  p u bli c ati o n  p oli c y  or  fi n a n ci al 
a gr e e m e nt.   
T h e  i n v esti g at or,    w h o  s u b mitt e d  t h e  pr oj e ct,  s h all  t a k e  t h e  s p o ns or's  c o m m e nts  i nt o  d u e 
c o nsi d er ati o n. 
As  t h e  st u d y  is  a    m ulti c e ntr e  o n e,  t h e  first  p u bli c ati o n    m ust  b e  p erf or m e d  o nl y    wit h  d at a 
c oll e ct e d   fr o m   s e v er al   c e ntr es   a n d   a n al ys e d   u n d er   t h e   r es p o nsi bilit y   of   I. R.I. S.    T h e 
i n v esti g at or  c o m mits  hi ms elf  n ot t o  p u blis hi n g  or  c o m m u ni c ati n g  d at a  c oll e ct e d i n  o nl y  o n e 
c e ntr e  or  p art  of t h e  c e ntr es  b ef or e t h e  p u bli c ati o n  of t h e  c o m pl et e r es ults  of t h e  st u d y,  u nl ess 
pri or  writt e n  a gr e e m e nt fr o m t h e  ot h er i n v esti g at ors  a n d I. R.I. S.  h as  b e e n  pr o vi d e d. 
 
D at a   S h ari n g   P oli c y   is   a v ail a bl e   at   htt ps:// cli ni c altri als.s er vi er. c o m/ d at a -r e q u est- port al/ . 
R es e ar c h ers  c a n  as k  f or  a  st u d y  pr ot o c ol,  p ati e nt -l e v el  a n d/ or  st u d y-l e v el  cli ni c al  tri al  d at a 
i n cl u di n g  cli ni c al st u d y r e p orts ( C S Rs). 
T h e y  c a n  as k f or  all i nt er v e nti o n al  cli ni c al st u di es:  
­   s u b mitt e d  f or  n e w    m e di ci n es  a n d  n e w  i n di c ati o ns  a p pr o v e d  aft er  1  J a n u ar y  2 0 1 4  i n  t h e 
E ur o p e a n  E c o n o mi c  Ar e a ( E E A)  or t h e  U nit e d  St at es ( U S). 
­   W h er e  S er vi er  or  a n  affili at e  ar e t h e  M ar k eti n g  A ut h ori z ati o n  H ol d ers ( M A H).  T h e  d at e  of 
t h e first  M ar k eti n g  A ut h ori z ati o n  of t h e  n e w  m e di ci n e ( or t h e  n e w i n di c ati o n) i n  o n e of t h e 
E E A  M e m b er  St at es  will  b e  c o nsi d er e d  wit hi n t his s c o p e. 
I n  a d diti o n,  S er vi er’s  d at a s h ari n g  p oli c y i n cl u d es  all i nt er v e nti o n al  cli ni c al st u di es i n 
p ati e nts:  
­   s p o ns or e d  b y  S er vi er, 
­   wit h  a first  p ati e nt  e nr oll e d  as  of  1 J a n u ar y  2 0 0 4  o n w ar ds, 
f or  N e w  Ch e mi c al  E ntit y  or  N e w  Bi ol o gi c al  E ntit y  ( n e w  p h ar m a c e uti c al  f or m  e x cl u d e d)  f or  
w hi c h  d e v el o p m e nt  h as  b e e n t er mi n at e d  b ef or e  a n y  M ar k eti n g  a ut h ori z ati o n ( M A)   a p pr o v al 
 
T h e  d at as ets  g e n er at e d  a n d/ or  a n al ys e d  d uri n g t h e  c urr e nt st u d y  will  b e  a v ail a bl e  u p o n r e q u est 
fr o m w w w. cli ni c altri als.s er vi er. c o m   aft er t h e  M ar k eti n g  A ut h oris ati o n  h as  b e e n  gr a nt e d. 
 
S u m m ar y  r es ults  a n d  a  l a y  s u m m ar y    will  b e  p u blis h e d  o n  w w w. cli ni c altri als.s er vi er. c o m  
wit hi n  6  m o nt hs  aft er t h e  e n d  of t h e st u d y.  


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1 7.   A D MI NI S T R A TI V E  C L A U S E S  
1 7. 1.  C o n c e r ni n g t h e s p o ns o r  a n d t h e i n v esti g at o r  
1 7. 1. 1.   P e rs o ns t o i nf o r m 
I n  a c c or d a n c e    wit h  l o c al  r e g ul ati o ns,  t h e  i n v esti g at or  a n d/ or  t h e  s p o ns or    will  i nf or m,  t h e 
Dir e ct or  of t h e  m e di c al i nstit uti o n, t h e  p h ar m a cist i n v ol v e d i n t h e  st u d y  a n d t h e  Dir e ct or  of 
t h e  a n al ysis l a b or at or y. 
1 7. 1. 2.   S u bst a nti al  p r ot o c ol  a m e n d m e nt  a n d  a m e n d e d  p r ot o c ol  
If  t h e  pr ot o c ol    m ust  b e  alt er e d  aft er  it  h as  b e e n  si g n e d,  t h e    m o difi c ati o n  or  s u bst a nti al 
a m e n d m e nt  m ust  b e  dis c uss e d  a n d  a p pr o v e d  b y  t h e  c o or di n at or  a n d t h e s p o ns or. 
T h e  s u bst a nti al  pr ot o c ol  a m e n d m e nt  m ust  b e  dr aft e d i n  a c c or d a n c e  wit h t h e  s p o ns or  st a n d ar d 
o p er ati n g   pr o c e d ur e   a n d   a n   a m e n d e d   pr ot o c ol    m ust   b e   si g n e d   b y   b ot h   p arti es.    B ot h 
d o c u m e nts  m ust  b e  k e pt  wit h t h e i niti al  pr ot o c ol. 
All  s u bst a nti al   a m e n d m e nts   a n d   c orr es p o n di n g   a m e n d e d   pr ot o c ols    m ust   b e  s e nt   b y  t h e 
i n v esti g at or(s)  or  t h e  c o or di n at or(s)  or  t h e  s p o ns or,  i n  a c c or d a n c e   wit h  l o c al  r e g ul ati o ns,  t o 
t h e  I E C t h at  e x a mi n e d t h e i niti al  pr ot o c ol.  T h e y  c a n  o nl y  b e i m pl e m e nt e d  aft er  a  f a v o ur a bl e 
o pi ni o n  of t h e I E C  h as  b e e n  o bt ai n e d, l o c al r e g ul at or y r e q uir e m e nts  h a v e  b e e n  c o m pli e d  wit h, 
a n d  t h e  a m e n d e d  pr ot o c ol  h as  b e e n  si g n e d,    wit h  t h e  e x c e pti o n  of  a    m e as ur e  r e q uir e d  t o 
eli mi n at e  a n i m m e di at e ris k t o t h e st u d y  p arti ci p a nts.  
W h e n  t h e  s u b missi o n  is  p erf or m e d  b y  t h e  i n v esti g at or  or  t h e  c o or di n at or,  t h e  l att er    m ust 
tr a ns mit  a  c o p y  of I E C’s  n e w  writt e n  o pi ni o n t o t h e s p o ns or, i m m e di at el y  u p o n r e c ei pt. 
F urt h er m or e,  t h e  s u bst a nti al  a m e n d m e nt  a n d  a m e n d e d  pr ot o c ol  ar e  t o  b e  s u b mitt e d  t o  t h e 
C o m p et e nt  A ut h oriti es i n  a c c or d a n c e  wit h l o c al r e g ul ati o ns.  
1 7. 1. 3.   Fi n al st u d y  r e p o rt  
T h e  st u d y  r e p ort  will  b e  dr aft e d  b y  M e di c al  Writi n g  D e p art m e nt  in  c o m pli a n c e  wit h  I. R.I. S. 
st a n d ar d  o p er ati n g  pr o c e d ur e. 
T o  e ns ur e  a  c o m pr e h e nsi v e  d at a  a n al ysis,  d at a  c oll e ct e d  i n  t h e  i niti al   C L 2 - 9 5 0 1 4-0 0 2  st u d y 
c o ul d  b e  us e d i n t h e  C L 2- 9 5 0 1 4- 0 0 3  Cli ni c al  St u d y  R e p ort ( C S R). 
T h e  s p o ns or’s  r e pr es e nt ati v e  a n d  t h e  c o or di n at or  m ust    m ut u all y  a gr e e  o n  t h e  fi n al  v ersi o n. 
O n e  c o p y  of t h e fi n al r e p ort  m ust  b e  d at e d  a n d  si g n e d  b y  t h e  c o or di n at or a n d t h e  Dir e ct or  of 
t h e C e nt er f or  T h er a p e uti c I n n o v ati o n. 
T h e  cli ni c al  st u d y  r e p ort,  t h e  s u m m ar y  of  t h e  r es ults  of  t h e  cli ni c al  tri al  t o g et h er    wit h  a 
s u m m ar y  t h at  is  u n d erst a n d a bl e  t o  a  l a y p ers o n   will  b e  s u b mitt e d   w h er e  a p pli c a bl e   wit hi n  6 
m o nt hs  aft er t h e  e n d  of t h e  cli ni c al tri al  w orl d wi d e.  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  5 2 /5 4  
 
1 7. 2.  C o n c e r ni n g t h e s p o ns o r  
T h e s p o ns or  u n d ert a k es t o: 
­   s u p pl y t h e i n v esti g at or   wit h  a d e q u at e  a n d  s uffi ci e nt i nf or m ati o n  c o n c er ni n g t h e  I M P  a n d 
t h e  NI M Ps a d mi nist er e d  d uri n g t h e st u d y t o  e n a bl e  hi m/ h er t o  c arr y  o ut t h e st u d y, 
­   s u p pl y t h e i n v esti g at or  wit h i n v esti g at or’s  br o c h ur e if t h e t est  dr u g is  n ot  m ar k et e d,  
­   o bt ai n   a n y   a ut h oris ati o n   t o   p erf or m   t h e   st u d y   a n d/ or   i m p ort   li c e n c e   f or   t h e   I M P  
a d mi nist er e d t h at  m a y  b e r e q uir e d  b y t h e l o c al  a ut h oriti es  b ef or e t h e  b e gi n ni n g  of t h e st u d y 
­   pr o vi d e  t h e   c o or di n at or   a n n u all y,   or    wit h   a n ot h er   fr e q u e n c y   d efi n e d   b y   t h e   l o c al 
r e g ul ati o ns,  wit h  a  d o c u m e nt  d es cri bi n g st u d y  pr o gr ess  w hi c h is t o  b e s e nt t o t h e I E C(s). 
­   t a k e  all t h e  n e c ess ar y  pr e c a uti o ns t o  m ai nt ai n t h e  s af et y  of t h e  pr o c ess e d  d at a, i n  p arti c ul ar 
t h eir  c o nfi d e nti alit y,  t h eir  i nt e grit y  a n d  t h eir  a v ail a bilit y,  b y  ass essi n g  ris ks  i d e ntifi e d 
c o n c er ni n g  p ers o n al  d at a  pr ot e cti o n.   T h e  f oll o wi n g    m e as ur es   will  b e  i m pl e m e nt e d  ( n o n -
e x h a usti v e):    
o   M a n a g e m e nt  of  a ut h oris ati o n t o  a c c ess t o  p ers o n al  d at a ( e- C R F)  
o   I d e ntifi c ati o n  a n d  a ut h e nti c ati o n  m e as ur es  b ef or e  a c c essi n g  p ers o n al  d at a ( e-C R F)  
o   Tr a c e a bilit y  m e as ur es f or t h e  a c c e ss t o  a n d  m o difi c ati o n  of  p ers o n al  d at a ( e- C R F)  
o   S e c ur e d  d at a tr a nsf er  
o   Ti m e li mit f or st ori n g  p ers o n al  d at a  
­   h a n dl e  a n y  s e c urit y  br e a c h  b y i m pl e m e nti n g  a n i nt er n al  c o m mitt e e (i n cl u di n g  CI S O,  D P O, 
c o m m u ni c ati o n   d e p art m e nt …)  i n   or d er  t o   q u alif y  t h e   s e c urit y  i n ci d e nt   (I nf or m ati o n 
s yst e ms,  n at ur e  a n d  n u m b er  of  p ers o n al  d at a  i m p a ct e d),  t o  d efi n e  a n  a cti o n  pl a n  f or 
c orr e cti v e  a cti o ns  a n d t o  n otif y t o r el e v a nt  p ers o n ( a ut h orit y  a n d/ or if  n e e d e d i n di vi d u als). 
1 7. 3.  C o n c e r ni n g t h e i n v esti g at o r 
1 7. 3. 1.   C o nfi d e nti alit y  -  Us e  of i nf o r m ati o n 
All  d o c u m e nts  a n d  i nf or m ati o n  gi v e n  t o  t h e  i n v esti g at or  b y  t h e  s p o ns or    wit h  r es p e ct  t o  
S 9 5 0 1 4  a n d st u d y  C L 2 - 9 5 0 1 4- 0 0 3 ar e stri ctl y  c o nfi d e nti al.  
T h e i n v esti g at or  e x pr essl y  a gr e es t h at  d at a  o n  his/ h er  pr of essi o n al  a n d  cli ni c al  e x p eri e n c e i s 
c oll e ct e d  b y  t h e  s p o ns or  o n  p a p er  a n d  c o m p ut er  a n d   st or e d  f or  its  s ol e  us e  r el ati n g  t o  its 
a cti viti es  as t h e s p o ns or  of  cli ni c al tri als, i n  a c c or d a n c e  wit h  G C P.   
H e/s h e  h as  a ri g ht t o  a c c ess,  m o dif y,  a n d  d el et e  his/ h er  o w n  p ers o n al  d at a  b y  a p pl yi n g t o t h e 
s p o ns or. 
I n  c as e  p ati e nt  w a nts t o  e x er cis e  his/ h er ri g hts r e g ar di n g  p ers o n al  d at a  pr ot e cti o n,  h e/s h e  will 
c o nt a ct  t h e  i n v esti g at or.    T h e  i n v esti g at or    will  f or w ar d  t h e  r e q u est  t o  t h e   s p o ns or   (s e e 
A p p e n di x  5 ).  
T h e i n v esti g at or  a gr e es t h at  h e/s h e  a n d t h e  m e m b ers  of  his/ h er t e a m  will  us e t h e i nf or m ati o n 
o nl y i n t h e fr a m e w or k  of t his  st u d y, f or  c arr yi n g  o ut t h e  pr ot o c ol.  T his  a gr e e m e nt is  bi n di n g 
as  l o n g  as  t h e  c o nfi d e nti al  i nf or m ati o n  h as  n ot  b e e n  dis cl os e d  t o  t h e  p u bli c  b y  t h e  s p o ns or. 
T h e  cli ni c al  st u d y  pr ot o c ol  gi v e n  t o  t h e  i n v esti g at or    m a y  b e  us e d  b y  hi m/ h er  or  his/ h er 
c oll e a g u es t o  o bt ai n t h e i nf or m e d  c o ns e nt  of  st u d y  p arti ci p a nts.  T h e  cli ni c al  st u d y  pr ot o c ol  as 
w ell  as  a n y i nf or m ati o n  e xtr a ct e d  fr o m it  m ust  n ot  b e  dis cl os e d t o  ot h er  p arti es  wit h o ut t h e 
writt e n  a ut h oris ati o n  of t h e s p o ns or. 
T h e  i n v esti g at or    m ust  n ot  dis cl os e  a n y  i nf or m ati o n    wit h o ut  t h e  pri or    writt e n  c o ns e nt  fr o m 
I. R.I. S.,  e x c e pt t o t h e r e pr es e nt ati v es  of t h e  C o m p et e nt  A ut h oriti es,  a n d  o nl y  at th eir r e q u est. 


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
  5 3 /5 4  
 
I n  t h e  l att er  c as e,  t h e  i n v esti g at or  c o m mits  hi ms elf/ h ers elf  t o  i nf or mi n g  I. R.I. S.  pri or  t o 
dis cl os ur e  of i nf or m ati o n t o t h es e  a ut h oriti es. 
1 7. 3. 2.   O r g a nis ati o n  of t h e  c e nt r e  
E v er y  p ers o n  t o    w h o m  t h e  i n v esti g at or  d el e g at es  u n d er  his/ h er  r es p o nsi bilit y  a  p art  of  t h e 
f oll o w-u p  of t h e  st u d y  ( c o -i n v esti g at or,  n urs e …)  a n d  a n y  ot h er  p ers o n i n v ol v e d i n t h e  st u d y 
f or  t his   c e ntr e  ( c ar di ol o gist,   p h ar m a cist …)    m ust  fi g ur e  i n  t h e   " Or g a nis ati o n   of   c e ntr e " 
d o c u m e nt. 
T his  d o c u m e nt s h o ul d  b e fill e d i n  at t h e  b e gi n ni n g  of t h e st u d y  a n d  u p d at e d  at  a n y  c h a n g e  of  a 
p ers o n i n v ol v e d i n t h e st u d y i n t h e  c e ntr e. 
1 7. 3. 3.   D o c u m e nt ati o n s u p pli e d t o t h e s p o ns o r  
T h e i n v esti g at or  u n d ert a k es  b ef or e t h e st u d y  b e gi ns: 
­   t o  pr o vi d e  his/ h er  d at e d  a n d  si g n e d  E n glis h  C urri c ul u m  Vit a e ( C V) ( m a xi m u m  2 p a g es)  or 
t o  c o m pl et e i n  E n glis h t h e  C V f or m  pr o vi d e d  b y t h e  s p o ns or  a n d t o  s e n d it t o t h e  s p o ns or, 
t o g et h er  wit h t h at  of  his/ h er  c o-i n v esti g at or(s), 
­   t o   pr o vi d e   a   d et ail e d   d es cri pti o n   of   t h e    m et h o ds,   t e c h ni q u es,   a n d   i n v esti g ati o n al 
e q ui p m e nt,  a n d t h e r ef e r e n c e  v al u es f or t h e  p ar a m et ers  m e as ur e d, 
­   t o   pr o vi d e   a n y   ot h er   d o c u m e nt   r e q uir e d   b y   l o c al   r e g ul ati o n   ( e. g.   F o o d    &    Dr u g 
A d mi nistr ati o n  1 5 7 2 f or m), 
­   t o  s e n d,  a  c o p y  of t h e  I E C’s  o pi ni o n  wit h  d et ails  of its  c o m p ositi o n  a n d t h e  q u alifi c ati o ns 
of its  c o nstit u e nt  m e m b ers.  
T h e  C Vs  of  ot h er  m e m b ers  of t h e t e a m i n v ol v e d i n t h e  st u d y  (if  p ossi bl e i n  E n glis h)  will  b e 
c oll e ct e d  d uri n g  t h e  c o urs e  of  t h e  st u d y  ( at  l e ast,    m e m b ers  i n v ol v e d  i n  t h e  p arti ci p a nts’ 
m e di c al f oll o w - u p/st u d y-r el at e d  d e cisi o n  pr o c ess  a n d  p ers o ns i n v ol v e d i n t h e  m e as ur e m e nt  of 
m ai n  ass ess m e nt  crit eri a).  
1 8.   R E F E R E N C E S  
A n gi olill o  A L,  S c h or e  RJ,  D e vi d as  M,  B or o wit z  MJ,  C arr oll  AJ,  G  asti er -F ost er  J M,  et  al.  P h ar m a c o ki n eti c  a n d 
p h ar m a c o d y n a mi c  pr o p erti es  of  c al as p ar g as e  p e g ol  Es c h eri c hi a  c oli  L -a s p ar a gi n a s e  i n t h e tr e at m e nt  of  p ati e nts 
wit h  a c ut e  l y m p h o bl asti c l e u k e mi a:   R es ults  fr o m  C hil dr e n´s   O n c ol o g y  Gr o u p  St u d y   A A L L 0 7 P 4.  J  Cli n  O n c ol 
2 0 1 4;  3 2:  3 8 7 4 -8 2 [ P E 0 1 5 0 5 5 0]  
Ass eli n  B L.  T h e t hr e e  as p ar a gi n a s es:  C o m p ar ati v e  p h ar m a c ol o g y  a n d  o pti m al  us e i n  c hil d h o o d l e u k e mi a.   A d v 
E x p  M e d  Bi ol  1 9 9 9 a;  4 5 7:  6 2 1 -6 2 9. [ P E 0 1 5 0 5 5 3]  
Es p ar z a   S D,   S a k a m ot o    K M.    T o pi cs   i n   p e di atri c   l e u k e mi a — a c ut e   l y m p h o bl asti c   l e u k e mi a.    M e d G e n M e d 
2 0 0 5; 7: 2 3  [P E 0 1 5 9 1 8 1]  
H e o   Y A   et   al.   P e g a s p ar g as e:    A    R e vi e w  i n    A c ut e    L y m p h o bl asti c    L e u k a e mi a.  Dr u gs  ( 2 0 1 9)   7 9: 7 6 7 – 7 7 7 
[ P E 0 1 5 3 5 2 5] 
H o el z er  D,  B ass a n  R,  D o m br et  H,  et  al.  A c ut e l y m p h o bl asti c l e u k a e mi a i n  a d ult  p ati e nts:  E S M O  cli ni c al  pr a cti c e 
g ui d eli n e s f or  di a g n osis,  tr e at m e nt  a n d f oll o w-u p.  A n n  O n c ol.  2 0 1 6; 2 7( S u p pl  5): v 6 9 – 8 2. [ P E 0 1 2 8 9 1 9]  
K a pri n,  V.  St ari ns k y,  G.  P etr o v a  “ M ali g n a nt  n e o pl as ms i n  R ussi a i n  2 0 1 8 ( m or bi dit y  a n d  m ort alit y) ”,  p u blis h e d 
i n  M os c o w,  2 0 1 9 
M as etti    R;  P essi o n.    A  First -li n e  tr e at m e nt  of  a c ut e  l y m p ho bl asti c  l e u k e mi a    wit h  p e g as p ar a gi n as e.    Bi ol o gi cs. 
2 0 0 9;  3: 3 5 9 -3 6 8. [ P E 0 1 5 1 6 9 5]  


S 9 5 0 1 4  
Cli ni c al st u d y  pr ot o c ol  n ° C L 2 -0 5 0 1 4 -0 0 3  - Fi n al  v ersi o n  
( c) I. R.I. S. - 2  D e c e m b er  2 0 2 0  - C o nfi d e nti al  
 5 4 /5 4  
 
N ati onal  Co m pre he nsi ve Ca nc er  Net w or k (N C C N).  Ac ute  L y m p h o blas tic L e u ke mia. 20 2 0  [P E 0 1 5 9 1 8 0]  
N o o ne A M;  Ho wla der  N ; Kra pc h o M; Miller D; Brest A; Yu  M et al. 20 1 8.  SE E R  Ca ncer S tatistics R e vie w, 
1 9 7 5 -2 0 1 5 - Secti o n  29 : C hil d h o o d Ca ncer by  t he IC C C  [ P E 0 1 5 3 3 0 6] 
Sil v er ma n L B,  Gel ber R D,  Dalt o n  VK,  e t al. Im pr o ve d  outc o me  f or chil dre n  wit h  ac ute ly m p h o blastic  
le u kae mia: res ults of Da na -Far ber  C o n s orti um  Pr ot oc ol 9 1-0 1.  Bl o o d. 2 0 0 1; 9 7 : 1 2 1 1-1 2 1 8 [ P E 0 1 5 0 5 7 2]  
T o n g 
W H, P ieters R, Kas pers GJ, et al. A pr os pecti ve st u d y o n dr u g m o nit ori n g of P E Gas para gi nase a n d 
Er wi nia as para gi nase a n d as para gi n a se a nti b o dies i n pe diatric ac ute l y m p h o blastic le u ke mia. 
Bl o o d. 
2 0 1 4; 1 2 3( 1 3): 2 0 2 6 – 3 3. [ P E 0 1 5 1 9 2 3]  
Va n d er S l uis I M et al. Co ns e ns us  e xpert  rec o m me n dati o ns  for  ide ntificati o n  a nd  ma na ge me nt  of aspara gi nase  
h y perse nsiti vit y  a n d  sile nt i na cti vati o n. Hae mat o l o gica. 2 0 16;  1 0 1( 3): 2 7 9-2 8 5.  [P E 0 1 5 5 8 3 8]  
Vr o o m a n L M et al. Effica c y a n d t o xicit y of pe gas par gase a n d calas par gase pe g ol i n c hil d h o o d ac ute 
ly m p h o blastic le u ke mia/l y m p h o ma: Res ults of D F CI 1 1 -0 0 1.  J o ur n al of Cli nic al O nc ol o gy  3 7, n o.  1 5 _s u p pl 
( Ma y 2 0, 2 0 1 9) 1 0 0 0 6 -1 0 0 0 6 [ P E 0 1 5 3 9 8 9]  
Ot h er re g ul at or y  refere nces: 
I C H T o pic  E 6 – G ui deli ne  for  Go o d  Cli nical Practice: C o ns oli date d g ui deli ne  fi nalise d (ste p 4) i n Ju ne  19 9 6.  
A d o pte d b y  C P M P,  Jul y  9 6, iss ue d as C P M P /I C H/ 1 3 5/ 9 5/ste p 5, post  ste p errata, J ul y 2 0 0 2. 
I CH  T o pic  E 9 – Statistical  Pri nci ples  f or Cli nica l T rials: A d o pte d b y  C P M P,  Marc h  1 9 9 8,  iss ued as  
C P M P/I C H/ 3 6 3/ 9 6/ste p 5.  
I C H To pi c E 2 A  – C li nical Safet y Data  Ma na ge me nt: De fi niti o ns an d  Sta n dar ds for  Ex pe dite d  Re p orti n g, iss ue d 
as C P M P /I C H/ 3 7 7/ 9 5. 
Detaile d  gui da nce o n  the c ollecti o n,  verificati o n  an d  prese ntati o n of a dverse e ve nt/reacti o n  re p orts  arisi n g fr o m 
cli nical trials o n  me dici nal  pr o d ucts  f or hu ma n  use (‘ C T-3’),  (2 0 1 1/ C  1 7 2/ 0 1)  
DI R E C T I V E 2 0 0 1/ 2 0/ E C O F T H E E U R O P E A N P A R LI A M E N T A N D O F T H E C O U N CI L of 4 A pril 2 0 0 1 o n 
t he a p pr o xi mati o n of t he la ws, re g ulati o ns a n d a d mi nistrati ve pr ov isi o ns of t he Me m ber States relati n g t o t he 
i m ple me ntati o n of g o o d cli nic al practice 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). 
Re g ulati o n  (E U)  N o 5 3 6/ 2 0 1 4  of the  Eur o pea n  P arlia me nt an d of  the  C o u n cil of 1 6  A pr il 2 0 1 4  o n  cli nical trials 
o n  me dici nal  pro d ucts  for  h u ma n u se. 
Cli nical  In vesti gat or's  Br oc h ure - O N C A S P A R ®  (pe gas p ar g ase) (P E G - L-as para gi nase,  EZ -0 0 2,  SH P  6 7 4)  - 
Versi o n  n° 5 o f 2 1  Oct o ber  2 0 2 0  [N P 4 0 7 9 0 ]  
1 9. A P P E N DI C E S
A p pe n di x 1: A L L - M B 2 0 1 5 pr ot oc ol 
A p pe n di x 2: Patie nt  pe rf or ma nce stat us 
A p pe n di x 3: Trial C o n d uct D uri n g Nati o nal or I nter nati o nal P u blic Healt h E mer ge nc y 
A p pe n di x 4: W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki 
A p pe n di x 5: I nstr ucti o ns t o i n vesti gat or f or ha n dli n g data ri g hts re q uests 

SAP_001.pdf: 
 
 
 
StaƟsƟcal Analysis Plan  
A MulƟcentre, Roll-over Study to Provide ConƟnued Treatment With Lyophilized Pegaspargase (S95014) 
in Pediatric PaƟents With Acute LymphoblasƟc Leukemia (ALL) 
NCT04956666 
Document Date: February 2, 2023