Conditions: Autism Spectrum Disorder (ASD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 211
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacity and the safety of bumetanide/S95008 in the improvement of Autism Spectrum Disorder core symptoms.

Detailed description:
The present study (CL3-95008-002) was performed in children from 2 to less than 7 years old presenting with ASD. A 6-month double-blind treatment period was performed in which efficacy and safety of bumetanide 0.5mg BID were assessed versus placebo. This double-blind period was followed by a 6-month open label treatment period of bumetanide 0.5mg twice daily in which long term safety was evaluated.

Arms:
arm 1: Participants will receive S95008 for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008. arm 2: Participants will receive placebo for 6 months, 26 weeks, and then they will begin an open-label 6 month treatment period with S95008.

Interventions: intervention 1: BUMETANIDE (S95008) for week 0 - 26 intervention 2: PLACEBO for week 0 - 26 intervention 3: Open-Label BUMETANIDE (S95008) for weeks 26 - 52
Intervention descriptions: intervention 1: Oral solution dosed at 0.5 mg/mL Taken twice daily. intervention 2: Oral solution Taken twice daily. intervention 3: Oral solution dosed at 0.5 mg/mL Taken twice daily.

Protocol document:
Prot_000.pdf: 
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
C O N FI D E N TI A L  
D oc u me nt title 
St u dy  offici al title 
St u dy brief title 
Test dr u g c o de 
I n dic ati o n 
Devel o p me nt p h ase 
Pr ot oc ol c o de 
E u dr a C T N u m ber 
Cli nic al Tri al. g ov N u m ber
A M E N D E D C L I NI C A L S T U D Y PR O T O C O L  
Efficac y  a n d safet y of  b u meta ni de  oral  li q ui d f or m ulati o n i n 
c hil dre n a ge d fr o m  2  t o less t ha n 7 years ol d wit h A utis m 
S pectr u m Dis or der.  
A  6- m o nt h 
r a n d o mise d,  d o u bl e-bli n d,  pl ace b o  c o ntr olle d 
m ul tice ntre p ar allel gr o u p st u dy t o ev al u ate effic acy a n d s afety of 
b u met a ni de 0. 5 m g t wice a d ay f oll o we d by a n o pe n l a bel active 6 -
m o nt h t re at me nt peri o d wit h b u met a ni de ( 0. 5 m g t wice a d ay) a n d 
a 6 wee ks disc o nti n u ati o n peri o d after tre at me nt st o p. 
B u meta ni de  – S 9 5 0 0 8 
A utis m  S pectr u m  Dis or der  
P ha se III 
C L 3 - 9 5 0 0 8- 0 0 2 
2 0 1 7- 0 0 4 4 2 0- 3 0 
N C T 0 3 7 1 5 1 5 3
U ni v ers al  Tri al  N u m b er  
N ot  a p pli c a bl e 
S p o ns or 
I nstit ut  d e  R e c h er c h es Int er n ati o n al es  S er vi er (I. R.I. S.)  
5 0  R u e  C ar n ot 
9 2 2 8 4  S ur es n es  C e d e x  – Fr a n c e  
I nt er n ati o n al 
C o or di n at or 
N ot  a p pli c a bl e 
D at e  of t h e  d o c u m e nt 
2 5  M ar c h  2 0 2 1  
V ersi o n  of t h e  d o c u m e nt  
Fi n al  v ersi o n  
S u bst a nti al  A m e n d m e nt 
i nt e gr at e d 
N o  
Fi n al  v ersi o n  d at e  
C o u n tri es  c o n c er n e d 
1  
1 6/ 0 5/ 2 0 1 8  
A L L  
2  
1 2/ 1 2/ 2 0 1 8  
A L L  
3  
1 2/ 0 8/ 2 0 1 9  
A L L  
4  
1 2/ 0 2/ 2 0 2 0  
F R A  
5  
1 4/ 0 2/ 2 0 2 0  
P O L  
6  
0 3/ 0 8/ 2 0 2 0  
F R A  
7  
1 0/ 0 9/ 2 0 2 0  
P O L  
8  
3 0 / 1 1/ 2 0 2 0 
A L L  
9  
2 5 / 0 3/ 2 0 2 1
C Z E  
Si è g e s o ci al -  5 0, r u e  C ar n ot -  9 2 2 8 4  S ur es n es  c e d e x -  Fr a n c e -  T él   0 1 5 5 7 2 6 0 0 0 -  w w w s er vi er c o m
S   A   R   L   a u  c a pit al  d e  7 8 9 5  e ur os •  3 1 9  4 1 6  7 5 6  R C S  N a nt err e


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 /2 9 6  
 
F O L L O W -U P  O F  V E R SI O N S  
 
 
S u bst a nti al 
a m e n d m e nt 
N o  
Fi n al 
v e rs i o n  d at e 
C o u nt ri es 
c o n c e r n e d  
N at u r e  of  m o difi c ati o ns  
I niti al 
p r ot o c ol  
N A  
2 7/ 0 2/ 2 0 1 8 
A L L     
N ot  A p pli c a bl e 
A m e n d e d 
p r ot o c ol 
1   
1 6/ 0 5/ 2 0 1 8 
A L L    
S e cti o ns  5. 2.  a n d  6. 3.: 
 
-  T y p o  err ors 
 
S e cti o n  8. 2. : 
U p d at e   of   t h e   
P ot assi u m 
s u p pl e m e nt ati o n 
r e c o m m e n d ati o ns   i n   c as e of 
h y p o k al a e mi a  
N A  
0 7 / 0 9/ 2 0 1 8 
F R A  
S e e  a p p e n di x 1 9  
 
N A  
1 7 / 0 9/ 2 0 1 8 
D E U  
S e e  a p p e n di x  2 0  
 
N A  
0 3 /1 0 / 2 0 1 8 
P R T  
S e e  a p p e n di x  2 1  
 
2   
1 2/ 1 2/ 2 0 1 8 
A L L  
•  
St u d y   s u m m ar y   s h e et: 
i n cr e as e   of   t h e   t ot al 
pl a n n e d   
n u m b er   
of 
c o u ntri es  (fr o m  1 0 t o  1 2) 
a n d  s u p pr essi o n  of  s af et y  
m e as ur e m e nts   
[ dr u g 
s cr e e nin g ( uri n e),  β H C G] 
•  
S e cti o n   2:   a d diti o n   of 
i nf or m ati o n   a b o ut   ris ks, 
b e n efits a n d   b ur d e ns   i n 
t h e st u d y 
•  
S e cti o n   
4. 2. 1: 
cl arifi c ati o n  of  st u d y  pl a n 
a n d t h at ‘s af et y f oll o w  u p 
visit’ is ‘f oll o w  u p  visit’  
•  
S e cti o n  4. 2. 2:  
 
a d diti o n  of  a l e g e n d i n 
T a bl e ( 4. 2. 2)  1  a b o ut 
I M P  dis p e ns ati o n at 
W 0 2 6  a n d cl arifi c ati o n 
a b o ut  bl o o d  el e ctr ol yt es 
a n al ysis  
 
c orr e cti o n  of  T a bl e 
( 4. 2. 2) 2: s u p pr essi o n  of 
β H C G  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 /2 9 6  
 
a d diti o n  of  i nstr u cti o ns  o n  h o w 
t o  p erf or m  st u d y  e v al u ati o ns  a n d 
n o n- c o m p uls or y  visits  o n  sit e f or 
t h e  p ati e nt  
 
a d diti o n   of 
t h e    T a bl e 
( 4. 2. 2)   3   a b o ut   t h e 
c o n d u ct   i n   c as e   of 
d efi niti v e  dis c o nti n u ati o n 
of   I M P   d uri n g   t h e 
d o u bl e- bli n d  p eri o d  
•  
S e cti o n  4. 3:  a d diti o n al 
i nf or m ati o n  a b o ut 
a n al ysis t o  mi ni mis e  bi as  
•  
S e cti o n   
4. 4. 1: 
cl arifi c ati o n   o n  t h e    w a y 
of   a d mi nistr ati o n   of  t h e 
or al s ol u ti o n  
•  
S e cti o n   4. 6:   cl arifi c ati o n 
o n    V A B S   II   s c al e   f or 
s o ur c e  d at a 
•  
S e cti o n  5. 2: N o n -
s el e cti o n  crit eri a 
 
m o difi c ati o n   of   crit eri o n 
1 5 
 
m o difi c ati o n  of  t h e  n o n -
s el e cti o n   crit eri o n   2 4  t o 
f urt h er  d es cri b e  st a bilis e d 
e pil e ps y 
 
m o difi c ati o n   of   n o n -
s el e cti o n   crit eri on   2 5 
wit h   
a n   i nf or m ati o n 
a b o ut   
alt er n ati v e 
i nt er v e nti o ns 
 
m o difi c ati o n  of  t h e  n o n -
s el e cti o n   crit eri o n   2 7 
wit h   a   cl arifi c ati o n   f or 
t h e  us e  of l a x ati v es 
•  
S e cti o n  5. 4:  E x cl usi o n 
crit eri a 
 
m o difi c ati o n   
of   
t h e 
e x cl usi o n   crit eri o n   3 4 
(i. e.v al u e  of    Q T  i nt er v al 
a n d   
val u e   
of 
h y p er c al ci uri a)  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 /2 9 6  
 
 
m o difi c ati o n  of  e x cl usi o n 
crit eri a  3 5 ( n e p hr o p at h y) 
•  
S e cti o n  5. 6. 1: 
m o difi c ati o n  of 
wit h dr a w al  crit eri a f or:  
 
O c c urr e n c e  of s ei z ur es  
 
Pr ot ei n uri a/ cr e ati ni n uri a  
 
V al u e  of  h y p er c al ci uri a  
 
V al u e  of  Q T  pr ol o n g ati o n 
 
A d diti o n  of  a bs e n c e  of  2 
co ns e c uti v e   
pl a n n e d 
uri n ar y    
m o nit ori n g 
a n al ysis 
•  
S e cti o n  5. 6. 2. Pr o c e d ur e 
A d diti o n   of   i nf or m ati o n 
o n  wit h dr a w al  visit  
•  
S e cti o n  6. 2:  c orr e cti o n  of 
t w o   err ors   of   I M Ps 
dis p e nsi n g   ( at    W 0 2 6) 
d uri n g  t h e   d o u bl e   bli n d 
p eri o d  a n d t h e  o p e n l a b el 
s af et y  e xt e nsi o n  p eri o d 
•  
S e cti o n  6. 3:  a d diti o n  of 
r e c o m m e n d ati o ns  a b o ut 
t h e  us e  of l a x ati v es  a n d 
us e  of li g ht  g as s e d ati o n 
•  
S e cti o n  7. 2: i nf or m ati o n 
o n  w h o  will  b e 
a ut h ori z e d t o  c o m pl et e 
t h e  V A B S II 
•  
S e cti o n  8. 2:  M et h o ds  a n d 
m e as ur e m e nt ti m es  
 
i nf or m ati o n   o n   tr ai ni n g 
b y   t h e   i n v esti g a t ors   o n 
t h e    C-S S R S -C   a n d   t h e 
P A E R S,   i nf or m ati o n   o n 
E C G   r e a di n g   pr o c ess 
( c e ntr alis e d  a n d l o c all y), 
 
cl arifi c ati o n  o n  bi ol o gi c al 
s af et y  m e as ur e m e nts  
 
cl arifi c ati o n   
o n   
t h e 
r e c o m m e n d ati o n   
t h at 
i n v esti g at ors   
s h o ul d  
e n c o ur a g e  p ati e nts  t o  e at 
f o o ds   
c o nt ai ni n g 
p ot assi u m  as  s o o n  as  t h e 
p ati e nt  is  i n cl u d e d  i n  t h e 
st u d y 
•  
S e cti o n  8. 8:  a d diti o n  of 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 /2 9 6  
 
e x pl a n ati o n  a b o ut  c a us al 
c a us al r el ati o ns hi p  
•  
S e cti o n  8. 9. 2:  a d diti o n  of 
i nf or m ati o n   
a b o ut 
r es p o nsi bilit y   
of   t h e 
i n v esti g at or 
•  
S e cti o n  8. 9. 3:  a d diti o n  of 
i nf or m ati o n  a b o ut  n e w 
s af et y i nf or m ati o n  
•  
S e cti o n  1 2. 4:  cl arifi c ati o n 
of   t h e   s e cti o n   
o n 
S u p er vis or y  c o m mitt e e  
•  
S e cti o ns   1 3. 2   a n d   1 3. 3: 
cl arifi c ati o n   
a b o ut 
ass e nt/ c o ns e nt  
•  
S e cti o n  1 4. 1:  a d diti o n  of 
i nf or m ati o n   
f or   
t h e 
i n v esti g at or  aft er t h e fi n al 
d at a   b as e   l o c k   a b o ut 
p arti ci p a nt   d at a   fr o m 
his/ h er   
c e ntr e   
f or 
ar c hi vi n g i n t h e st u d y fil e 
•  
S e cti o n  1 4. 2:  a d diti o n al 
i nf or m ati o n  a b o ut  d at a 
c oll e ct e d  o n  p a p er f or m 
( V A B SII)  o n  d at a  e ntr y 
a n d  d at a  v ali d ati o n 
•  
S e cti o n   1 4. 3:    Ar c hi vi n g: 
f urt h er  cl arifi c ati o n  a b o ut 
ar c hi vi n g  pr o c ess 
•  
S e cti o n 1 8: 
R E F E R E N C E S:  u p d ati n g 
of r ef er e n c es  
 
N A  
1 2/ 1 2/ 2 0 1 8  
B R A  
S e e  a p p e n di x  2 2  
 
N A  
1 3/ 0 3/ 2 0 1 9  
I R L 
S e e  a p p e n di x  2 3  
 
N A  
2 6 / 0 3/ 2 0 1 9 
B R A  
S e e  a p p e n di x  2 4  
 
N A  
2 7/ 0 3/ 2 0 1 9  
I R L 
S e e  a p p e n di x  2 5  
 
N A  
2 6 / 0 4/ 2 0 1 9 
B R A  
S e e  u p d at e d  a p p e n di x  2 4  
 
N A  
3 0 / 0 7/ 2 0 1 9 
U S A  
S e e  a p p e n di x  2 6  
 
3   
1 2/ 0 8/ 2 0 1 9 
A L L  
•  S e cti o n   5. 4.    E x cl usi o n 
crit eri a:   
u p d ati n g   
of 
crit eri o n   
3 4   
a b o ut 
a b n or m al   
uri n ar y 
c al ci u m/ cr e ati ni n e   r ati o 
( > 0. 8 5 m m ol/ m m ol   
of 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 /2 9 6  
 
cr e ati n uri a)  a n d  c al ci uri a 
(≥ 3 m m ol/l)  
•  S e cti o n 5. 6. 1. Wit h dr a w al 
crit eri a:   
u p d ati n g   
of 
crit eri o n  a b o ut  a b n or m al 
uri n ar y 
c al ci u m/ cr e ati ni n e   r ati o 
( > 0. 8 5 m m ol/ m m ol   
of 
cr e ati n uri a)  a n d  c al ci uri a 
( ≥ 3 m m ol/l)  
 
4  
1 2 / 02 / 2 0 2 0 
F R A  
S e e  a p p e n di x  2 7  
 
5  
1 4/ 0 2/ 2 0 2 0  
P O L  
S e e  a p p e n di x  2 8  
 
6  
0 3/ 0 8 / 2 0 20  
F R A  
S e e  u p d at e d  a p p e n di x  2 7  
 
7  
1 0 / 0 9/ 2 0 20  
P O L  
S e e  u p d at e d  a p p e n di x  2 8  
 
8 
3 0 / 11 / 2 0 2 0 
A L L  
•  St u d y s u m m ar y s h e et: 
u p d at e of St u d y 
c o m pl eti o n  d at e 
•  A d diti o n  of t h e 
si g n at ur e  of t h e  
Bi ost atisti cs  H e a d  
•  S e cti o n 4. 2. 1.   St u d y 
pl a n:   u p d at e   of   t h e 
d efi niti o n  of  t h e     E n d 
of tri al   
•  S e cti o n  4. 2. 2. 
I n v esti g ati o n 
s c h e d ul e:  u p d at e  of 
t h e  T a bl e ( 4. 2. 2) 1  a n d 
a d diti o n  of t h e 
m e nti o n  of C A R S 
Q P C  q u esti o n n air e 
f or t h e  p ar e nts 
q u esti o n n air es ( S R S 2 
a n d  q u alit y  of lif e 
q u esti o n n air es)   a n d 
u p d at e  of t a bl e ( 4. 2. 2) 
2 
•  U p d at e  of t h e s e cti o n 
4. 4. 3.  M a n a g e m e nt  of 
t h e  bli n di n g s yst e ms 
•  U p d at e  of t h e s e cti o n 
5. 6. 1. f or  S p e ci al 
c o n d u ct i n  c as e  of 
g astr oi nt esti n al 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 /2 9 6  
 
s y m pt o ms  a n d  w ei g ht 
l oss 
•  S e cti o n  8. 2.  U p d at e 
of  p art  a b o ut r e n al 
ultr as o u n d 
•  S e cti o n  9. 1. 
M e as ur e m e nt  of  dr u g 
c o n c e ntr ati o n:  wit h 
c an c ell ati o n  of t h e 
s e nt e n c e ‘ T h us, t h e 
e x a ct  P K s a m pli n g 
ti m es  c a n n ot  b e 
s p e cifi e d’ 
•  S e cti o n  1 6. 
O w n ers hi p  of t h e 
r es ults – D at a s h ari n g 
p oli c y  a n d  p u bli c ati o n 
p oli c y:  u p d at e  of t h e 
p ar a gr a p h 
•  S e cti o n  1 7. 1. 3.  Fi n al 
st u d y r e p ort:  a d diti o n 
of  a  pri m ar y  cli ni c al  
r e p ort  aft er t h e  6-
m o nt h  d o u bl e- bli n d 
p eri o d,  a  m ai n  cli ni c al 
r e p ort  aft er t h e  6-
m o nt h  o p e n l a b el 
p eri o d  wit h t h e  6-
w e e k f oll o w- u p 
p eri o d  a n d  a d diti o n  of 
a n  a d d e n d u m t o t h e 
r e p ort f or t h e  o pti o n al 
6- m o nt h  e xt e nsi o n 
p eri o d 
•  A d diti o n  of t h e 
a p p e n di x  2 9: 
I nstr u cti o n t o 
i n v esti g at ors f or 
h a n dli n g  d at a ri g hts 
r e q u ests 
 
9  
2 5/ 0 3/ 2 0 2 1 
C Z E  
S e e  a p p e n di x  3 0  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 /2 9 6  
 
S T U D Y  S U M M A R Y  S H E E T  
N a m e  of t h e s p o ns o r:  
I. R.I. S.  
5 0  R u e  C ar n ot  
9 2 2 8 4  S ur es n es  C e d e x - Fr a n c e  
I n di vi d u al   St u d y    T a bl e 
R ef erri n g  t o   P art  of  t h e 
D ossi er  
( F or  N atio n al  A ut h orit y  Us e  o nl y)  
N a m e  of  Fi nis h e d  P r o d u ct:  
 
V ol u m e:  
 
 
N a m e  of  A cti v e I n g r e di e nt : 
B u m et a ni d e ( S 9 5 0 0 8)  
P a g e : 
 
Titl e  of st u d y:  
Effi c a c y  a n d s af et y  of  b u m et a ni d e  or al li q ui d f or m ul ati o n i n  c hil dr e n  a g e d fr o m 2 t o l ess t h a n 7 y e ars  ol d  wit h 
A utis m  S p e ctr u m  Dis or d er.  
A  6 -m o nt h r a n d o mis e d,  d o u bl e -bli n d,  pl a c e b o  c o ntr oll e d  m ulti c e ntr e  p ar all el  gr o u p st u d y t o  e v al u at e  effi c a c y 
a n d s af et y  of  b u m et a ni d e  0. 5 m g t wi c e  a  d a y f oll o w e d  b y  a n  o p e n l a b el  a cti v e  6 -m o nt h tr e at m e nt  p eri o d  wit h 
b u m et a ni d e ( 0. 5 m g t wi c e  a  d a y)  a n d  a  6  w e e ks  dis c o nti n u ati o n  p eri o d  aft er tr e at m e nt st o p.  
Pr ot o c ol  N o.:  C L 3 -9 5 0 0 8 -0 0 2  
C o o r di n at o r(s) or  I n v esti g at o r: 
N ati o n al  c o or di n at ors  a n d i n v esti 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): 
I nt er n ati o n al  m ulti c e ntr e st u d y 
T ot al  pl a n n e d  n u m b er  of  c e ntr es:  Ar o u n d  5 0  
T ot al  pl a n n e d  n u m b er  of  c o u ntri es:  1 2  
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:  u p t o  6 6  w e e ks  
­ 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 3  2 0 1 8  
­ 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  
i n  t h e  o p e n  l a b el  p eri o d  or  i n  t h e  e xt e nsi o n  p eri o d,    w hi c h e v er 
o c c urs t h e l at est)  : Q 4  2 0 2 2  
St u d y  d e v el o p m e nt  p h as e : III 
O bj e cti v e(s):  
T h e pri m ar y  o bj e cti v e  is  t o  d e m o nstr at e  t h e  s u p eri orit y  of  b u m et a ni d e  ( 0. 5 m g   BI D)  or al  li q ui d  f or m ul ati o n 
c o m p ar e d t o  pl a c e b o i n t h e i m pr o v e m e nt  of  A S D  c or e  s y m pt o ms  usi n g  C A R S -2  aft er  6  m o nt hs  of tr e at m e nt i n 
c hil dr e n  a g e d fr o m 2 t o l ess t h a n 7 y e ars  ol d  pr es e nti n g  wit h  a  c o nfir m e d  A S D  di a g n osis.  
T h e s e c o n d ar y  o bj e cti v es ar e: 
- T o  ass ess t h e  e ff e ct  of  b u m et a ni d e  o n t h e s e c o n d ar y  effi c a c y  e n d p oi nts 
- T o  ass ess t h e s af et y  of  b u m et a ni d e  
- T o  c o nfir m t h e  a c c e pt a bilit y  a n d  p al at a bilit y  of t h e  or al li q ui d f or m ul ati o n  
- T o  d es cri b e t h e  b u m et a ni d e  eff e cts  o n  p ati e nts  q u alit y  of lif e  
- T o i m pr o v e  e xisti n g  p h ar m a c o ki n eti c  m o d el  of  b u m et a ni d e i n t his  p o p ul ati o n  
T h e e x pl or at or y  o bj e cti v e  is to  d es cri b e t h e  B u m et a ni d e  eff e ct  o n  utilit y i n d e x s c or es  
M et h o d ol o g y:  
St u d y  d esi g n:  6 -m o nt h,  r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d,  p ar all el  gr o u ps  f oll o w e d  b y  a n  o p e n  
l a b el  a cti v e  6-m o nt h tr e at m e nt  p eri o d  wit h  b u m et a ni d e.  
N u m b e r  of  p a rti ci p a nts : 
Pl a n n e d:  2 0 0  p ati e nts i n cl u d e d  
T ot al f or  e a c h tr e at m e nt ( a p pr o xi m at el y):  1 0 0 i n  b u m et a ni d e  gr o u p,  1 0 0 i n t h e  pl a c e b o  gr o u p  
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: 
- M al e  a n d  f e m al e  p ati e nts fr o m 2 t o l ess t h a n 7 
- Pri m ar y  di a g n osis  of  A S D  as  p er  D S M -5  crit eri a  
- Crit eri a    m et  f or    A S D   o n    A utis m    Di a g n osti c    O bs er v ati o n   S c h e d ul e -G e n eri c  ( A D O S -2)   a n d    A utis m 
Di a g n osis I nt er vi e w  R e vis e d ( A DI -R)  
- C GI ( Cli ni c al  Gl o b al I m pr essi o n) – S e v erit y  r ati n g  S c or e  ≥  4 
- C hil d h o o d  A utis m  R ati n g  S c al e s e c o n d  e diti o n ( C A R S 2 -S T  or  H F) t ot al r a w s c or e  ≥  3 4  
- S o ci al r es p o nsi v e n ess  S c al e s e c o n d  e diti o n ( S R S -2) t ot al s c or e  ≥  6 6  T -S c or e  
- A bs e n c e  of  di a g n osis  of  Fr a gil e  X  or  R ett  S y n dr o m e  
- A bs e n c e   of   a n y   cli ni c all y  si g nifi c a nt   a b n or m alit y  li k el y  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 
a c c or di n g t o t h e j u d g m e nt  of t h e i n v esti g at or.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  9 /2 9 6  
 
N a m e  of t h e s p o ns o r:  
I. R.I. S.  
5 0  R u e  C ar n ot  
9 2 2 8 4  S ur es n es  C e d e x - Fr a n c e  
I n di vi d u al   St u d y    T a bl e 
R ef erri n g  t o   P art  of  t h e 
D ossi er  
( F or  N atio n al  A ut h orit y  Us e  o nl y)  
N a m e  of  Fi nis h e d  P r o d u ct:  
 
V ol u m e:  
 
 
N a m e  of  A cti v e I n g r e di e nt : 
B u m et a ni d e ( S 9 5 0 0 8)  
P a g e : 
 
T est  d r u g :  
B U M E T A NI D E o r al s ol uti o n  d os e d  at  0. 5  m g/ m L 
- F or  p ati e nts    wit h  a    w ei g ht   <  2 5   k g:  b u m et a ni d e   0. 0 2 m g/ k g  c orr es p o n di n g  t o  0. 0 4 ml / k g  or al  li q ui d 
f or m ul ati o n t a k e n t wi c e  d ail y (i n t h e  m or ni n g  at  w a k e  u p  a n d i n t h e  aft er n o o n  3  h o urs  b ef or e  g oi n g t o  b e d 
at t h e l at est)  
- F or  p ati e nts  wit h  a  w ei g ht  ≥  2 5 k g:  b u m et a ni d e  0. 5 m g  c orr es p o n di n g t o  1 m L  or al li q ui d f or m ul ati o n t a k e n 
t wi c e  d ail y (i n t h e  m or ni n g  at  w a k e  u p  a n d i n t h e  aft er n o o n  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est) 
C o m p a r at o r:  
P L A C E B O  
- F or  p ati e nts  wit h  a  w ei g ht  <  2 5  k g:  0 . 0 4 ml/ k g  or al li q ui d f or m ul ati o n t a k e n t wi c e  d ail y (i n t h e  m or ni n g  at 
w a k e  u p  a n d i n t h e  aft er n o o n  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est)  
- F or  p ati e nts  wit h  a  w ei g ht  ≥  2 5 k g:  1 m L  or al li q ui d f or m ul ati o n t a k e n t wi c e  d ail y (i n t h e  m or ni n g  at  w a k e 
u p  a n d i n  t h e  aft er n o o n  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est) 
D u r ati o n  of t r e at m e nt:  
R u n -i n  p eri o d:  u p t o  4  w e e ks ( wit h o ut I M P) 
St u d y tr e at m e nt  p eri o d ( wit h I M P  a d mi nistr ati o n):  5 2  w e e ks ( +/ - 2 8  d a ys)  
F oll o w  u p  p eri o d:  6  w e e ks  aft er  dis c o nti n u ati o n  of I M P  
C rit e ri a f o r  e v al u ati o n:   
Effi c a c y  m e as ur e m e nts : 
Pri m ar y  effi c a c y  e n d p oi nt:  C A R S 2 t ot al  R a w  s c or e,  e x pr ess e d  m ai nl y i n t er ms  of  c h a n g e  fr o m  b as eli n e t o  6 
m o nt h  
S e c o n d ar y  effi c a c y  e n d p oi nts:  
- 
T h e  c h a n g e i n  e a c h i n di vi d u al  C A R S 2  d o m ai n fr o m  b as eli n e t o  6  m o nt h  
- 
T h e  c h a n g e i n  S R S -2 t ot al r a w s c or e fr o m  b as eli n e t o  6  m o nt h  
- 
C GI -I s c or e  at  6  m o nt h 
- 
T h e  c h a n g e i n  Vi n el a n d  A d a pt ati v e  B e h a vi o ur  S c al e II ( V A B S II) fr o m  b as eli n e t o  6  m o nt h  
S af et y  m e as ur e m e nts : 
- 
A d v ers e  e v e nts,  P e di atri c  A d v ers e  E v e nt  R ati n g  S c al e ( P A E R S)  
- 
C li ni c al   l a b or at or y   e v al u ati o n:   bi o c h e mistr y   i n cl u di n g   el e ctr ol yt es    m o nit ori n g,   h a e m at ol o g y,   , 
c al ci uri a,  cr e ati ni n uri a,  pr ot ei n uri a,  
- 
Vit al si g ns  a n d  cli ni c al  e x a mi n ati o n:  w ei g ht,  h ei g ht,  B o d y  M ass I n d e x,  h e art r at e,  bl o o d  pr ess ur e  
- 
El e ctr o c ar di o gr a m  
- 
R e n al ultr as o u n d  
- 
S ui ci d alit y:  C ol u m bi a -S ui ci d e s e v erit y s c al e  C hil dr e n’s  v ersi o n ( C -S S R S -C)  
Ot h er  m e as ur e m e nts : 
- 
A c c e pt a bilit y  a n d  p al at a bilit y  ass ess m e nts  
- 
P a e di atri c  Q u alit y  of  Lif e I n v e nt or y ( P e ds Q L)  
- 
W H O Q O L -Br ef  q u esti o n n air e  
- 
Utilit y i n d e x s c or e  o n  t h e  E Q - 5 D- 3 L  
P h ar m a c o ki n eti c  m e as ur e m e nts : 
- 
C o n c e ntr ati o ns   of   b u m et a ni d e    will   b e   d et er mi n e d   i n   pl as m a   b y    C e p h a c,   usi n g   a   v ali d at e d 
bi o a n al yti c al    m et h o d   b as e d   o n   a   pr ot ei n   pr e ci pit ati o n   f oll o w e d   b y   r e v ers e   p h as e   li q ui d 
c hr o m at o gr a p h y  wit h t a n d e m  m ass s p e ctr o m etri c d et e cti o n.  Pr o c e d ur es  will  b e  d es cri b e d i n  a s e p ar at e 
bi o a n al yti c al  pr ot o c ol  est a blis h e d  b y t h e  ass a y  c e ntr e.  
 
 
 
 
St atisti c al  m et h o ds:  
Effi c a c y  a n al ysis : 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 2 /2 9 6  
 
T a bl e  of  c o nt e nts  
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  .................................................  2 2 
2.  B A C K G R O U N D I N F O R M A TI O N  .................................................................................  2 2 
3.  S T U D Y  O B J E C TI V E S  A N D  P U R P O S E  ........................................................................  2 6 
3. 1.  Pri m ar y  o bj e cti v e  ............................................................................................................  2 6 
3. 2.  S e c o n d ar y  o bj e cti v es ......................................................................................................  2 6  
3. 3.  E x pl or at or y  o bj e cti v es  ....................................................................................................  2 6 
4.  S T U D Y  D E SI G N  ...............................................................................................................  2 6 
4. 1.  E n d p oi nt(s) ......................................................................................................................  2 6  
4. 2.  E x p eri m e nt al  d esi g n .......................................................................................................  2 7  
4. 2. 1.  St u d y  pl a n .....................................................................................................................  2 7  
4. 2. 2.  I n v esti g ati o n s c h e d ul e ..................................................................................................  2 9 
4. 3.  M e as ur es t o  mi ni mis e  bi as  ..............................................................................................  3 5 
4. 4.  St u d y  pr o d u cts  a n d  bli n di n g s yst e ms ..............................................................................  3 6  
4. 4. 1.  Pr o d u cts  a d mi nist er e d  ..................................................................................................  3 6 
4. 4. 2.  I M P  m a n a g e m e nt.......................................................................................................... 3 8  
4. 4. 3.  M a n a g e m e nt  of  bli n di n g s yst e ms .................................................................................  3 9  
4. 5.  Dis c o nti n u ati o n  of t h e st u d y ...........................................................................................  4 0  
4. 5. 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 ...........................................  4 0  
4. 5. 2.  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 ....................................  4 0  
4. 6.  S o ur c e  d at a ......................................................................................................................  4 0  
5.  S E L E C TI 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  ........................................  4 4 
5. 1.  S el e cti o n  crit eri a  .............................................................................................................  4 4 
5. 1. 1.  D e m o gr a p hi c  c h ar a ct eristi cs  ........................................................................................  4 4 
5. 1. 2.  M e di c al  a n d t h er a p e uti c  crit eri a  ...................................................................................  4 4 
5. 1. 3.  I nf or m e d  c o ns e nt ..........................................................................................................  4 4 
5. 2.  N o n -s el e cti o n  crit eri a ......................................................................................................  4 4 
5. 2. 1.  G e n er al  crit eri a  .............................................................................................................  4 4 
5. 2. 2.  M e di c al  a n d t h er a p e uti c  crit eri a  ...................................................................................  4 5 
5. 3.  I n cl usi o n  crit eri a .............................................................................................................  4 6 
5. 4.  E x cl usi o n  crit eri a  ............................................................................................................  4 7 
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 s el e cti o n/i n cl usi o n  visit ....................................  4 8  
5. 6.  P arti ci p a nt  wit h dr a w al  ....................................................................................................  4 8 
5. 6. 1.  Wit h dr a w al  crit eri a  .......................................................................................................  4 8 
5. 6. 2.  Pr o c e d ur e ......................................................................................................................  4 9  
5. 6. 3.  L ost t o f oll o w - u p ..........................................................................................................  5 0 
6.  T R E A T M E N T  O F  P A R TI CI P A N T S  ..............................................................................  5 0 
6. 1.  I M P  a d mi nist er e d ............................................................................................................  5 0 
6. 2.  I M Ps  dis p e nsi n g ..............................................................................................................  5 1 
6. 3.  Pr e vi o us  a n d  c o n c o mit a nt tr e at m e nts .............................................................................  5 1  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 3 /2 9 6  
 
6. 4.  I M P  c o m pli a n c e ..............................................................................................................  5 2 
6. 5.  Dis c o nti n u ati o n  of t h e I M P .............................................................................................  5 2  
7.  A S S E S S M E N T  O F  E F FI C A C Y  ......................................................................................  5 2 
7. 1.  Effi c a c y  m e as ur e m e nts  ...................................................................................................  5 2 
7. 2.  M et h o ds  a n d  m e as ur e m e nt ti m es  ....................................................................................  5 2 
8.  S A F E T Y  M E A S U R E M E N T S  ..........................................................................................  5 5 
8. 1.  S p e cifi c ati o n  of s af et y  p ar a m et ers  ..................................................................................  5 5 
8. 2.  M et h o ds  a n d  m e as ur e m e nt ti m es  ....................................................................................  5 5 
8. 3.  D ef i niti o n  of  A d v ers e  e v e nt ............................................................................................  6 2 
8. 4.  D efi niti o n  of  S eri o us  a d v ers e  e v e nts  ..............................................................................  6 2 
8. 5.  D efi niti o n  of  O v er d os e ...................................................................................................  6 3  
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  ..............................................................  6 3 
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)  .................................  6 3 
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)  .......  6 4 
8. 9.  R e p orti n g  pr o c e d ur es ......................................................................................................  6 4  
8. 9. 1.  Ti m e fr a m e f or  A E r e p orti n g  ........................................................................................  6 4 
8. 9. 2.  R es p o nsi biliti es  of t h e i n v esti g at or  ..............................................................................  6 5 
8. 9. 2. 1.  
D o c u m e nt ati o n  of t h e  e v e nt .....................................................................................  6 6 
8. 9. 2. 2.  
F oll o w- u p  of  a d v ers e  e v e nts  ....................................................................................  6 6 
8. 9. 2. 3.  
S p e ci al sit u ati o ns ( o v er d os es, i nt a k e  of I M P  b y  a  p ers o n  ar o u n d t h e 
p art i ci p a nt) ...............................................................................................................  6 6 
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  ............................................................................  6 7 
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 ...................................  6 7  
8. 9. 3.  R es p o nsi biliti es  of t h e s p o ns or .....................................................................................  6 8  
8. 1 0.  R es p o nsi biliti es  of  D at a  M o nit ori n g  C o m mitt e e  ............................................................  6 8 
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  E F FI C A C Y 
O R  S A F E T Y  ......................................................................................................................  6 8 
9. 1.  M e as ur e m e nt  of  dr u g  c o n c e ntr ati o n ...............................................................................  6 8  
9. 2.  Q u alit y  of lif e  q u esti o n n air es  ..........................................................................................  6 9 
9. 3.  A c c e pt a bilit y  a n d  p al at a bilit y  q u esti o n n air e ...................................................................  7 0  
1 0.  
S T A TI S TI C S  .................................................................................................................  7 0 
1 0. 1.  D et er mi n ati o n  of s a m pl e si z e  .........................................................................................  7 0 
1 0. 2.  St atisti c al  a n al ysis  ...........................................................................................................  7 0 
1 0. 2. 1.  A n al ysis s ets /  Tr e at m e nt  gr o u ps ..................................................................................  7 1 
1 0. 2. 1. 1.  A n al ysis s ets  ............................................................................................................  7 1 
1 0. 2. 1. 2.  Tr e at m e nt  gr o u ps .....................................................................................................  7 1  
1 0. 2. 2.  St atisti c al  m et h o ds  ........................................................................................................  7 1 
1 0. 2. 2. 1.  G e n er al  c o nsi d er ati o ns  .............................................................................................  7 1 
1 0. 2. 2. 2.  Dis p ositi o n  a n d  b as eli n e  c h ar a ct eristi cs  ..................................................................  7 1 
1 0. 2. 2. 3.  Tr e at m e nts  of  p ati e nts  ..............................................................................................  7 2 
1 0. 2. 2. 4.  Effi c a c y  a n al ysis  ......................................................................................................  7 2 
1 0. 2. 2. 4. 1.  St atisti c al  h y p ot h es es  ............................................................................................  7 2 
1 0. 2. 2. 4. 2.  Pri m ar y  effi c a c y  e n d p oi nt .....................................................................................  7 2  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 4 /2 9 6  
 
1 0. 2. 2. 4. 3.  S e c o n d ar y  effi c a c y  e n d p oi nts ................................................................................  7 3  
1 0. 2. 2. 4. 4.  S u b gr o u p  a n al ys es .................................................................................................  7 3  
1 0. 2. 2. 5.  E x pl or at or y  a n al ysis  ................................................................................................  7 4 
1 0. 2. 2. 6.  S af et y  a n al ysis  .........................................................................................................  7 4 
1 0. 2. 2. 6. 1.  A d v ers e  e v e nts ......................................................................................................  7 4  
1 0. 2. 2. 6. 2.  Cli ni c al l a b or at or y  e v al u ati o n  ...............................................................................  7 4 
1 0. 2. 2. 6. 3.  Vit al si g ns,  cli ni c al  e x a mi n ati o n  a n d  ot h er  o bs er v ati o ns r el at e d t o s af et y  ...........  7 4 
1 0. 2. 2. 6. 3. 1.  Vit al si g ns  a n d  cli ni c al  e x a mi n ati o n  ...................................................................  7 4 
1 0. 2. 2. 6. 3. 2.  El e ctr o c ar di o gr a m  ...............................................................................................  7 5 
1 0. 2. 2. 7.  Pl a n n e d i nt eri m  a n al ysis  ..........................................................................................  7 5 
1 0. 2. 3.  Ot h er  e n d p oi nts  a n al y sis ...............................................................................................  7 5 
1 0. 2. 3. 1.  P h ar m a c o ki n eti cs .....................................................................................................  7 5  
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  ......................................  7 5 
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  ..........................................  7 5 
1 2. 1.  St u d y  m o nit ori n g ............................................................................................................  7 5  
1 2. 1. 1.  B ef or e t h e st u d y ............................................................................................................  7 6  
1 2. 1. 2.  D uri n g t h e st u d y ...........................................................................................................  7 6  
1 2. 2.  C o m p ut eris e d  m e di c al fil e  ..............................................................................................  7 6 
1 2. 3.  A u dit - I ns p e cti o n ...........................................................................................................  7 7 
1 2. 4.  S u p er vis or y  c o m mitt e es  ..................................................................................................  7 8 
1 3.  
E T HI C S  .........................................................................................................................  7 8 
1 3. 1.  I nstit uti o n al  Re 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)  ..................................  7 8 
1 3. 2.  St u d y  c o n d u ct .................................................................................................................  7 8  
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 ................................................................  7 8  
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 0  
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  .......................................................  8 0 
1 4. 1.  St u d y  d at a .......................................................................................................................  8 0  
1 4. 2.  D at a  m a n a g e m e nt  ...........................................................................................................  8 1 
1 4. 3.  Ar c hi vi n g ........................................................................................................................  8 2  
1 5.  
I N S U R A N C E .................................................................................................................  8 2 
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  ................................................................................................  8 3 
1 7.  
A D MI NI S T R A TI V E  C L A U S E S  .................................................................................  8 4 
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 ..................................................................  8 4  
1 7. 1. 1.  P ers o ns t o i nf or m  ..........................................................................................................  8 4 
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 ..............................................  8 4  
1 7. 1. 3.  Fi n al st u d y r e p ort ..........................................................................................................  8 4  
1 7. 2.  C o n c er ni n g t h e s p o ns or ..................................................................................................  8 5  
1 7. 3.  C o n c er ni n g t h e i n v esti g at or  ............................................................................................  8 5 
1 7. 3. 1.  C o nfi d e nti alit y -  Us e  of i nf or m ati o n ............................................................................  8 5  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 5 /2 9 6  
 
1 7. 3. 2.  Or g a nis ati o n  of t h e  c e ntr e ............................................................................................  8 6  
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 .......................................................................  8 6  
1 8.  
R E F E R E N C E S  ..............................................................................................................  8 7 
1 9.  
A P P E N DI C E S  ...............................................................................................................  9 0 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 6 /2 9 6  
 
 
List  of t a bl es  
T a bl e  ( 4. 1)  1 -  E n d p oi nts ..........................................................................................................  2 6 
T a bl e  ( 4. 2. 2)  1 - I n v esti g ati o n s c h e d ul e ...................................................................................  3 0 
T a bl e  ( 4. 2. 2)  2 -  C o n d u ct i n  c as e  of  d efi niti v e  dis c o nti n u ati o n  of I M P  d uri n g t h e  d o u bl e 
bli n d  p eri o d  wit h o ut st u d y  wit h dr a w al .....................................................................................  3 4  
T a bl e  ( 4. 2. 2)  3  –  V ol u m e ( m L)  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 ...............  3 4 
T a bl e  ( 4. 4. 1)  1  –  D es cri pti o n  of t h e I M Ps ................................................................................  3 8 
T a bl e  ( 4. 4. 1)  2  –  D es cri pti o n  of  p a c k a gi n g  of t h e  d o u bl e- bli n d I M P ......................................  3 8 
T a bl e  ( 4. 4. 1)  3  –  D es cri pti o n  of  p a c k a gi n g  of t h e  o p e n I M P ...................................................  3 8 
T a bl e  ( 8. 2)  1 -  F o o ds t h at  h a v e  a  hi g h er  p ot assi u m  c o nt e nts ...................................................  6 1 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 7 /2 9 6  
 
 
List  of fi g u r es  
Fi g ur e ( 4. 2. 1)  1  –  St u d y  pl a n ....................................................................................................  2 9  
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 8 /2 9 6  
 
List  of  a p p e n di c es  
A p p e n di x  1:  C orr el ati o n  b et w e e n  or al s ol uti o n  v ol u m e  a n d  p ati e nt  w ei g ht ............................  9 0  
A p p e n di x  2:  D S M 5 ..................................................................................................................  9 1  
A p p e n di x  3:  C A R S 2- S T  ...........................................................................................................  9 6 
A p p e n di x  4:  C A R S 2- H F  ........................................................................................................  1 0 2 
A p p e n di x  5:  C A R S 2- Q P C  .....................................................................................................  1 1 2 
A p p e n di x  6:  S R S 2  Pr e-s c h o ol  v ersi o n ...................................................................................  1 1 9  
A p p e n di x  7:  S R S 2  S c h o ol  v ersi o n .........................................................................................  1 2 3  
A p p e n di x  8:  C- S S R S - C ..........................................................................................................  1 3 0 
A p p e n di x  9:  P A E R S  Cli ni ci a n f or m ......................................................................................  1 4 0  
A p p e n di x  1 0  :  V A B S II ............................................................................................................  1 4 4 
A p p e n di x  1 1:  C GI ..................................................................................................................  1 7 3  
A p p e n di x  1 2:  A c c e pt a bilit y  a n d  p al at a bilit y  q u esti o n n air e ...................................................  1 7 5  
A p p e n di x  1 3:  P A E R S  Y o ut h f or m .........................................................................................  1 8 2  
A p p e n di x  1 4:  P A E R S  P ar e nts f or m .......................................................................................  1 8 5  
A p p e n di x  1 5:  P e ds Q L ............................................................................................................  1 8 8  
A p p e n di x  1 6:  W H O Q O L- B R E F  ............................................................................................  1 9 3 
A p p e n di x  1 7:  E Q- 5 D- 3 L ........................................................................................................  1 9 8  
A p p e n di x  1 8:  W orl d  M e di c al  Ass o ci ati o n  D e cl ar ati o n  of  H elsi n ki ......................................  2 0 2  
A p p e n di x  1 9:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  F R A ...................................  2 0 8  
A p p e n di x  2 0:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  D E U ..................................  2 0 9  
A p p e n di x  2 1:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  P R T ...................................  2 2 1  
A p p e n di x  2 2:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  B R A ..................................  2 2 3  
A p p e n di x  2 3:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol I R L ....................................  2 2 4  
A p p e n di x  2 4:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  B R A ( u p d at e d) ..................  2 2 5  
A p p e n di x  2 5:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol I R L ....................................  2 2 7  
A p p e n di x  2 6:  L o c al  m o difi c ati o n  of t h e  cli ni c al st u d y  pr ot o c ol  U S A ..................................  2 2 9  
A p p e n di x  2 7: S u bst a nti al  a m e n d m e nt  N o.  4  a n d  N°.  6 t o t h e  cli ni c al st u d y  pr ot o c ol  F R A ...  2 3 5 
A p p e n di x  2 8: S u bst a nti al  a m e n d m e nt  N o.  5  a n d  N°.  7 t o t h e  cli ni c al st u d y  pr ot o c ol  P O L ...  2 5 5 
A p p e n di x  2 9:  M ai n  p eri o ds I nstr u cti o ns t o i n v esti g at or f or  h a n dli n g  d at a ri g hts r e q u ests ...  2 7 5  
A p p e n di x  3 0:  S u bst a nti al  a m e n d m e nt  N o.  9 t o t h e  cli ni c al st u d y  pr ot o c ol  C Z E ..................  2 7 7  
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  1 9 /2 9 6  
 
List  of  a b b r e vi ati o ns 
µ m ol  
: mi cr o m ol e  
A DI -R  
: A utis m  Di a g n ost i c I nt er vi e w - R e vis e d  
A D O S -2  
: A utis m  Di a g n osti c  O bs er v ati o n  S c h e d ul e, s e c o n d  e diti o n  
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 P  
: A L 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 m 
: a nt e  m eri di e m  
A S D  
: A utis m  S p e ctr u m  Dis or d ers  
A S T  
: A S p art at e a mi n o Tr a nsf er as e  
bi d  
: bis i n  di e (t wi c e  a  d a y)  
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)  
C A R S 2  
: C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d  E diti o n  
C A R S 2 -H F  
: C hil d h o o d  A utis m  R ati n g  S c al e, S e c o n d  E diti o n –  Hi g h 
f u n cti o ni n g  cli ni c al t o ol 
C A R S 2 -Q P C  
: C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d  E diti o n –  
Q u esti o n n air e f or  p ar e nts  a n d  c ar e gi v ers  
C A R S 2 -S T  
: C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d  E diti o n –  St a n d ar d 
T o ol  
C GI  
: Cli ni c al  Gl o b al I m pr essi o n  
C GI -I 
: Cli ni c al  Gl o b al I m pr essi o n –  Gl o b al I m pr o v e m e nt  
C GI -S  
: Cli ni c al  Gl o b al I m pr essi o ns  S c al e  
C H M P  
: C o m mitt e e f or  M e di ci n al  Pr o d u cts f or  H u m a n  Us e  
c m 
: C e nti m etr e  
C M P  
: Cli ni c al  M o nit ori n g  Pl a n  
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  O r g a nis ati o n 
C -S S R S -C  
: C ol u m bi a  S ui ci d e  S e v erit y  R ati n g  S c al e  C hil dr e n’s  V ersi o n  
C V  
: C urri c ul u m  Vit a e  
D B P  
: Di ast oli c  Bl o o d  Pr ess ur e  
D M C  
: D at a  M o nit ori n g  C o m mitt e e  
D S M -5  
: Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers –  Fift h 
E diti o n –  T e xt r e visi o n 
D M C  
: D at a  S af et y  M o nit ori n g  B o ar d  
e. g. 
: E x e m pli  gr ati a (f or  e x a m pl e)  
E 2  
: Estr a di ol  
E C G  
: El e ctr o C ar di o Gr a m  
e-C R F  
: El e ctr o ni c  C as e  R e p ort  F or m  
E N T  
: E ar,  N os e  a n d  T hr o at  
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  
g  
: gr a m  
G A B A  
: G a m m a -a mi n o b ut yri c  a ci d  
g a m m a  G T  
: G a m m a -Gl ut a m yltr a nsf er as e  
G C P  
: G o o d  Cli ni c al  Pr a cti c e  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 0 /2 9 6  
 
GI  
: G astr oI nt esti n al  
h  
: h o ur  
H A V  
: H e p atitis  A  Vir us  
H Bs  
: S urf a c e  a nti g e n  of  H e p atitis  B  vir us  
H B V  
: 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 n sit y  Li p o pr ot ei n 
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  
H R T  
: H or m o n e  R e pl a c e m e nt  T h er a p y  
i. e. 
: i d  est (t h at is) 
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 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 P M 
: I nt er n ati on al  Cl assifi c ati o n  of  Pr o c e d ur es i n  M e di ci n e  
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 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  a s  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) 
I Q 
: I nt ell e ct u al  C o effi ci e nt 
I R B 
: I nstit uti o n al  R e vi e w  B o ar d 
I R S 
: I nt er a cti v e  R es p o ns e  S yst e m 
I U 
: I nt er n ati o n al  U nit 
I U D 
: I ntr a Ut eri n e ( c o ntr a c e pti v e)  D e vi c e 
I V 
: I ntr a V e n o us (r o ut e) 
I V R S 
: I nt er a cti v e  V oi c e  R es p o ns e  S yst e m 
I W R S 
: I nt er a cti v e  W e b  R es p o ns e  S yst e m 
K  
: K ali u m  
k g  
: kil o gr a m  
L  
: Litr e  
L D L  
: L o w -D e nsit y  Li p o pr ot ei n  
M C V  
: M e a n  C or p us c ul ar  V ol u m e  
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 g  
: milli gr a m  
mi n  
: mi n ut e  
m L  
: Millilitr e  
m m  
: Milli m etr e  
m m H G  
: Milli m etr e  of  m er c ur y  
M M R M  
: Mi x e d  M o d el f or  R e p e at e d  M e as ur e m e nt  
N A  
: N ot  A p pli c a bl e  
N a  
: N atri u m  
n g  
: n a n o gr a m  
N K C C 1  
: N a +/ K +/ 2 Cl - c otr a ns p ort er  
N S  
: N ot st atisti c all y  Si g nifi c a nt  
O C D  
: O bs essi v e  C o m p ulsi v e  Dis or d er  
P A E R S  
: P a e di atri c  A d v ers e  E v e nt  R ati n g  S c al e  
P D  
: P h ar m a c o D y n a mi cs  
P E D  Q L  
: P a e di atri c  Q u alit y  of  Lif e I n v e nt or y  
PI P  
: P a e di atri c I n v esti g ati o n  Pl a n  
P K  
: P h ar m a c o Ki n eti cs  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 1 /2 9 6  
 
p m  
: p ost  m eri di e m  
p o  
: p er  os ( or all y)  
P T  
: Pr ot hr o m bi n  Ti m e 
Q C  
: Q u alit y  C o ntr ol  
Q T c  
: Q T i nt er v al  c orr e ct e d f or  h e art r at e  
S A E  
: S eri o us  A d v ers e  E v e nt  
S B P  
: S yst oli c  Bl o o d  Pr ess ur e  
S D  
: St a n d ar d  D e vi ati o n  
S E  
: St a n d ar d  Err or  
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 R S 2  
: S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  E diti o n  
S S RI  
: S el e cti v e s er ot o ni n r e u pt a k e i n hi bit or  
S U S A R  
: 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 n  
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 
( S 9 5 0 0 8) 
V  
: Visit  
V A B S II  
: Vi n el a n d  A d a pt at i v e  B e h a vi o ur  S al es,  S e c o n d  E diti o n 
W H O  
: W orl d  H e alt h  Or g a ni z ati o n  
W H O -D D  
: W orl d  H e alt h  Or g a ni z ati o n,  Dr u g  Di cti o n ar y  
y o  
: Y e ar s ol d  
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 2 /2 9 6  
 
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 ors  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  f or  e a c h  c o u ntr y  is  gi v e n  i n  s e p ar at e  d o c u m e nts  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 f or [ n a m e  of t h e  c o u ntr y] ". 
T h e  c o m p ositi o n  a n d  r ol e  of t h e  D at a  M o nit ori n g  C o m mitt e e  ar e  d es cri b e d i n  s e cti o ns  8. 1 0 
a n d  1 2. 4. 
2.  B A C K G R O U N D I N F O R M A TI O N  
A utis m   S p e ctr u m    Dis or d ers ( A S D)  is  a  gr o u p  of  c o m pl e x  n e ur o d e v el o p m e nt al  dis or d ers 
c h ar a ct eri z e d  b y t h e  pr es e n c e  of  m ulti pl e  a n d  p ersist e nt  d efi cits i n  s o ci al  c o m m u ni c ati o n  a n d 
s o ci al   i nt er a cti o n   ass o ci at e d    wit h   r estri ct e d   i nt er ests   a n d   st er e ot y p e d   a n d   r e p etiti v e 
b e h a vi o urs.    A eti ol o g y  of    A S D  is  still  p o orl y  u n d erst o o d,  b ut  t h e  dis e as e  a p p e ars  hi g hl y 
g e n eti c all y  h erit a bl e  wit h i d e ntifi e d  g e n eti c  m ut ati o ns – d es pit e  n ot f ull y  p e n etr a nt - i n  a b o ut 
1 5 %  of t h e  c as es.  N o ns p e cifi c  e n vir o n m e nt al ris ks f a ct ors,  as  p ar e nt al  a g e, f o et al  e x p os u r e t o 
al c o h ol  or  v al pr o at e  a n d  pr e m at ur e  birt h/ l o w  birt h  w ei g ht,  h a v e  als o  b e e n i d e ntifi e d. 
T h e    m ost  fr e q u e nt  c o m or bi diti es  a n d  ass o ci at e d  s y m pt o ms  ar e:  l e ar ni n g  dis a biliti es,  sl e e p 
dist ur b a n c es,   e pil e psi es,   a n xi et y,   d e pr essi o n,   att e nti o n   pr o bl e m,   h y p er a c usis,   irrit a bilit y 
(i n cl u di n g   s y m pt o ms   of   a g gr essi o n   t o w ar d   ot h ers,   d eli b er at e   s elf-i nj uri o us n ess,   t e m p er 
t a ntr u ms,   a n d   q ui c kl y   c h a n gi n g    m o o ds),   c o n d u ct   dis or d er,   a n d    O bs essi v e    C o m p ulsi v e 
Dis or d er  ( O C D).   T h e  pr es e n c e  a n d  t h e  s e v erit y  of  t h es e  s y m pt o ms  ar e v er y  h et er o g e n e o us 
a m o n g  p ati e nts  a n d  d e p e n d  o n t h eir  a g e. 
Us u al   c ar es   i n cl u d e   gl o b al   c ar e,   oft e n   i n   s p e ci ali z e d   i nstit uti o ns,   a n d   ps y c h os o ci al 
i nt er v e nti o ns   as   e d u c ati o n al    m e as ur es,   p ati e nts   a n d   f a mili es   s u p p ort   a n d/ or   s p e cifi c 
ps y c h ot h er a pi es ( m ai nl y  b e h a vi o ur al t h er a pi es).  Ass o ci at e d  s y m pt o ms fr e q u e ntl y l e a d t o  dr u g 
pr es cri pti o n,   h o w e v er   o nl y   s e c o n d -g e n er ati o n   a nti ps y c h oti cs   h a v e   d e m o nstr at e d   cli ni c al 
effi c a c y   i n   b e h a vi o ur al   dis or d ers.   Fr e q u e ntl y   pr es cri b e d   off -l a b el   dr u gs   i n cl u d e 
m et h yl p h e ni d at e  a n d  at o m o x eti n e  f or  att e nti o n  dis or d ers,   m el at o ni n  f or  sl e e p  dis or d ers,  a n d 
s el e cti v e  s er ot o ni n r e u pt a k e i n hi bit ors ( S S RIs) f or  a n xi o-d e pr essi v e  dis or d ers,  h o w e v er t h er e 
is  pr es e ntl y  n o  a p pr o v e d tr e at m e nt t ar g eti n g  c or e s y m pt o ms  of  a utis m. 
R e c e nt  st u di es  ( C ell ot,  2 0 1 4)  ( C o g hl a n,  2 0 1 2) s u g g est t h at  G A B A er gi c  n e ur o ns  a n d  cir c uits 
m a y   b e   alt er e d   i n    A S D.    T h e   c o n v ersi o n   of    G A B A -m e di at e d   n e ur o n al   e x cit ati o n   i nt o 
i n hi biti o n  d uri n g  m at ur ati o n  of  s p e cifi c  n e ur o n al  p o p ul ati o ns  h as  b e e n  r e p ort e d t o  b e  alt er e d 
i n  n e ur o d e v el o p m e nt al  dis e as es  s u c h  as  a utis m.    T his  l a c k  of  “ G A B A  s wit c h ”  is  d u e  t o 
p ersist e nt  hi g h  l e v el  of  e x pr essi o n  of    N a +/ K +/ 2 Cl - c o-tr a ns p ort er  ( N K C C 1) vs    K-Cl  c o -
tr a ns p ort ers  ( K C C 2).   T his  i n  tur n    m a y  l e a d  t o  a b n or m al  c ell    mi gr ati o n  a n d  diff er e nti ati o n, 
i m m at ur e  a n d  i m b al a n c e d  n e ur o n al  n et w or k  d e v el o p m e nt  a n d  t h us  t o  cli ni c all y  di a g n os e d 
d efi cits  o bs er v e d i n t his  p at h ol o g y.  
L e v els  of  i ntr a c ell ul ar  c hl ori d e  d et er mi n e  t h e  l e v els  of  n e ur o n al  i n hi biti o n  a n d  h a v e  b e e n 
s h o w n t o  b e  el e v at e d i n i m m at ur e  n e ur o ns  a n d  b ei n g  pr o gr essi v el y  r e d u c e d  wit hi n  n e ur o n al 
d e v el o p m e nt.  T h es e  o bs er v ati o ns s u g g est t h at  dr u gs r e d u ci n g i ntr a c ell ul ar  c hl ori d e l e v els  m a y 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 3 /2 9 6  
 
b e  h el pf ul i n  n or m alisi n g  c hl ori d e l e v els  a n d t h er e b y  r est or e i n hi bit or y  G A B A er gi c  f u n cti o n 
a n d  n e ur o n al  n et w or k  m at ur ati o n. 
B u m et a ni d e  ( B uri n e x ®)  is  a  s ulf o n a mi d e -d eri v e d  l o o p  di ur eti c  us e d  f or  t h e    m a n a g e m e nt  i n 
a d ult  p ati e nts  of  o e d e m a  ass o ci at e d  wit h  c o n g esti v e  h e art  f ail ur e,  h e p ati c  cirr h osis  a n d  r e n al 
di s e as e i n cl u di n g  n e p hr o p ati c s y n dr o m e. 
A cti n g   c e ntr all y   as   a    N K C C 1  i n hi bit or,   b u m et a ni d e   pr o v o k es  r e d u cti o n   of  i ntr a c ell ul ar 
c hl ori d e, s wit c hi n g t h e  a b err a nt  e x cit at or y  a cti o n  of  G A B A i nt o  a n i n hi bit or y  a cti o n. 
U p t o  n o w, t h e  effi c a c y  a n d  s af et y  of  b u m et a ni d e i n  A S D  c hil dr e n  a n d  a d ol es c e nts  h a v e  b e e n 
st u di e d i n  a  cli ni c al  d e v el o p m e nt  pr o gr a m m e  c o nsisti n g  of  5  cli ni c al  st u di es  ( Pl e as e  r ef er t o 
Cli ni c al I n v esti g at or's  Br o c h ur e l at est  v ersi o n,  o n s e cti o n  5 f or f urt h er  d et ails) . 
T h e first  us e  of  B u m et a ni d e i n  A S D  w as  a  pil ot st u d y  c o n d u ct e d i n  5  c hil dr e n  wit h  A S D  a g e  3 
t o  1 1  y e ars  of  a g e ( L e m o n ni er,  2 0 1 0).    T his  st u d y    w as  f oll o w e d  b y  a  pl a c e b o  c o ntr oll e d 
r a n d o mi z e d  p h as e II  st u d y i n  5 4  A S D  c hil dr e n ( B U M E A  st u d y [ N C T 0 1 0 7 8 7 1 4]:( L e m o n ni er, 
2 0 1 2) .  Of  n ot e  as  w ell,  a n f M RI  st u d y ( a c a d e mi c  st u d y),  c arri e d  o ut i n  o p e n l a b el  c o n diti o ns 
i n  7  y o u n g  a utisti c  p ati e nts  s h o w e d  a n  i m pr o v e m e nt  of  f a ci al  pr o c essi n g  aft er  1    m o nt h  of 
b u m et a ni d e tr e at m e nt ( L e m o n ni er,  2 0 1 2; H a dji k h a ni,  2 0 1 5).  
I n  p ar all el,   N e ur o c hl or e  s p o ns or e d  a  r etr os p e cti v e,  o bs er v ati o n al  st u d y  e v al u ati n g  t h e  l o n g-
t er m  s af et y  of    B u m et a ni d e  i n  c hil dr e n  a n d  a d ol es c e nts    wit h    A utis m   S pe ctr u m    Dis or d ers 
( A S D) tr e at e d  wit h  B u m et a ni d e  o n  a n  off-l a b el  b asis i n t h e  C H R U  of  Br est ( Fr a n c e). 
I n  J u n e  2 0 1 2   N e ur o c hl or e  s u b mitt e d  a  P a e di atri c  I n v esti g ati o n  Pl a n  ( PI P)  f or  t h e  c o n diti o n 
‘ A utisti c  S p e ctru m  Dis or d er’  u n d er  Arti cl e  3 0  of t h e  P a e di atri c  R e g ul ati o n. It  w as  a gr e e d  b y 
E M A  o n  3 0  A pril  2 0 1 3 ( E M E A- 0 0 1 3 0 3- PI P 0 1 -1 2).  
N e ur o c hl or e  c arri e d  o ut t h e  p h as e II b  d os e r a n gi n g  st u d y  ass essi n g t h e  effi c a c y  a n d  s af et y  of 
B u m et a ni d e  0. 5,  1. 0  a n d  2. 0 m g    BI D  d os es  ( or al  li q ui d  f or m ul ati o n)  i n    m al e  a n d  f e m al e 
p ati e nts  a g e d  ≥ 2  t o  ≤ 1 8  y e ars  of  a g e  di a g n os e d    wit h    A S D  a c c or di n g  t o    D S M- I V-T R.   T h e 
m ai n  o bj e cti v e  of t h e  st u d y  w as t o  d et er mi n e t h e  o pti m al  d os e  of  b u m et a ni d e  f or t h e  pi v ot al 
p h as e  III  st u d y.   T h e  pri m ar y  crit eri o n   w as  t h e  C A R S  s c al e.   T hr e e  b u m et a ni d e  or al  s ol uti o n 
d os es,  0. 5 - 1-2 m g  a d mi nist er e d  t wi c e  a  d a y,    w er e  t est e d  o v er  a  3    m o nt h -tr e at m e nt  p eri o d. 
Ei g ht y  ei g ht  p ati e nts    w er e  i n cl u d e d  i n  t h e  st u d y.    Usi n g  a  g e n er al  li n e ar    m o d el  i n cl u di n g 
b as eli n e    C A R S   v al u e  as  c o v ari at e,  t h e   diff er e n c e   b et w e e n   b u m et a ni d e   0. 5    m g    BI D  a n d 
pl a c e b o   w as  st atisti c all y  si g nifi c a nt  i n  t h e  F A S -3. 0 6  ( 9 5 %   CI  =[ -5. 6 3  ; -0. 4 9],  p  =  0. 0 1 5). 
W h e n t h e  C A R S  s c or e  w as  e v al u at e d f or  7 3  o ut  of  8 8  p ati e nts  w h o  h a d  a  C A R S  v al u e  at  D 9 0 
( C A R S  c o m pl et ers  a n al ysis), t h e r es ults  w er e  c o nfir m e d  usi n g t h e g e n er al li n e ar  m o d el f or t h e 
c o m p aris o n  b et w e e n   B u m et a ni d e  0. 5  m g   BI D  a n d  pl a c e b o  wit h  a n  esti m at e d  diff er e n c e  at -
2. 9 3  ( 9 5 %  CI =[ - 5. 5 7;-0. 2 9],  p =  0. 0 2 6).  B u m et a ni d e  als o  pr o d u c e d  si g nifi c a nt i m pr o v e m e nts 
o v er  pl a c e b o  o n  t h e  s e c o n d ar y  effi c a c y  e n d p oi nts  ( S R S  s c al e,   C GI -s c al e). O n  a  q u alit ati v e 
p oi nt  of  vi e w,  cli ni ci a ns  d es cri b e t h at  c hil dr e n  wit h  b u m et a ni d e  ar e  m or e  pr es e nt,  m or e  o p e n 
t o t h e  w orl d,  m or e  att e nti v e,  m or e  p arti ci p ati v e,  m or e  willi n g t o  e x c h a n g e, l ess  h y p er a cti v e, 
l ess  a g gr essi v e,  l ess  a git at e d  a n d  l ess  st er e ot y p e d.    T h e  c hil dr e n  als o  l o o k    m or e  at  t h eir 
i nt erl o c ut or. T h e  s af et y  pr ofil e  of  B u m et a ni d e  w as  d os e -r el at e d.  T h e  b est t ol er a bilit y  pr ofil e 
w as  o bs er v e d    wit h  t h e    B u m et a ni d e  0. 5  m g  t wi c e  a  d a y,    w h er e as  a n  i m p ort a nt  n u m b er  of 
a d v ers e  e v e nts  a n d  st u d y  wit h dr a w als  w er e  o bs er v e d  wit h  B u m et a ni d e  1. 0  a n d  2. 0  m g t wi c e  a 
d a y.  C o nsi d eri n g t h e  0. 5 m g  d os e is  eff e cti v e  a n d  pr es e nt e d  a  b ett er  s af et y  pr ofil e t h a n  1 m g 
a n d  2 m g: t his  d os e  w as r et ai n e d f or t h e  p h as e III.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 4 /2 9 6  
 
T a ki n g i nt o  a c c o u nt t h es e  el e m e nts,  b u m et a ni d e  w as  pr o p os e d  as t h e first  c a n di d at e  all o wi n g 
tr e at m e nt  of  A S D  c or e s y mpt o ms i n  p a e di atri c  p o p ul ati o n. 
O n  t h e   2 4 t h F e br u ar y   2 0 1 7,    N e ur o c hl or e  a n d    L es    L a b or at oir es   S er vi er’  e nt er e d  i nt o  a n 
a gr e e m e nt  f or  d e v el o p m e nt  a n d  c o m m er ci alis ati o n  of t h e  b u m et a nid e  p a e di atri c  f or m ul ati o n 
i n  E ur o p e. ‘ L es  L a b or at oir es  S er vi er’ t a k es  o v er t h e  p h as e III  d e v el o p m e nt  pr o gr a m.  
F oll o wi n g  t h e  c o m pl eti o n  of  t h e  p h as e  II,  a   C o m mitt e e  f or    M e di ci n al  Pr o d u cts  f or   H u m a n 
Us e  ( C H M P)   S ci e ntifi c    A d vi c e  pr o c e d ur e    w as  p erf or m e d  b e gi n ni n g  2 0 1 7  t o  dis c uss  t h e 
b u m et a ni d e  p h as e  III  d e v el o p m e nt  pl a n  i n   A S D  p a e di atri c  p ati e nts.   A  r a n d o mis e d,  pl a c e b o 
c o ntr oll e d  st u d y  d esi g n  wit h  a  6 -m o nt h  d o u bl e -bli n d tr e at m e nt  p eri o d f oll o w e d  b y  a  6 - m o nt h 
o p e n l a b ell e d  e xt e nsi o n  p eri o d  w as  c o nsi d er e d  b y t h e  C H M P  as t h e  m ost  a p pr o pri at e t o  h a v e 
a  c o m pr e h e nsi v e  b u m et a ni d e  effi c a c y  a n d  s af et y  ass ess m e nt.    A    m o difi c ati o n  t o  t h e  a gr e e d 
PI P  h as  b e e n  s u b mitt e d  t o  t h e   P a e di atri c    C o m mitt e e  ( P D C O)  of  t h e    E ur o p e a n    M e di ci n e 
A g e n c y  ( E M A)  a n d  h as  r e c ei v e d  a  p ositi v e  d e cisi o n  ( E ur o p e a n    M e di ci n es   A g e n c y  d e cisi o n  
E M A - 0 0 1 3 0 3-PI P 0 1 - 1 2- M 0 2  d at e d  1 0t h  N o v e m b er  2 0 1 7). 
T h e  pr es e nt  st u d y ( C L 3 - 9 5 0 0 8- 0 0 2)  will  b e  p erf or m e d i n  c hil dr e n fr o m 2 t o l ess t h a n 7 y e ars 
ol d  pr es e nti n g    wit h    A S D.    A  6 -m o nt h  d o u bl e -bli n d  tr e at m e nt  p eri o d    will  b e p erf or m e d  i n 
w hi c h  effi c a c y  a n d  s af et y  of  b u m et a ni d e  0. 5 m g   BI D   will  b e  ass ess e d v ers us  pl a c e b o.   T his 
d o u bl e- bli n d  p eri o d  will  b e f oll o w e d  b y  a  6 -m o nt h  o p e n l a b el tr e at m e nt  p eri o d  of  b u m et a ni d e 
0. 5 m g  BI D i n  w hi c h l o n g t er m  s af et y  will  b e  e v al u at e d  a n d  a  6  w e e ks  dis c o nti n u ati o n  p h as e. 
B u m et a ni d e  d os e  will  b e  a d a pt e d  o n  b o d y- w ei g ht. 
T h e  pr es e nt  p h as e III  b u m et a ni d e  p a e di atri c  st u d y  h as  b e e n  d e v el o p e d  b as e d  o n t h e  E ur o p e a n 
G ui d eli n e  a n d  v ali d at e d  b y  t h e  P a e di atri c    C o m mitt e e  i n  t h e    E ur o p e a n    M e di ci n al    A g e n c y 
( E uro p e a n    M e di ci n es   A g e n c y  d e cisi o n,   E M A - 0 0 1 3 0 3-PI P 0 1 - 1 2-M 0 2  d at e d  1 0t h   N o v e m b er 
2 0 1 7). I n t his  d e v el o p m e nt  pr o gr a m  all  c hil dr e n ( e v e n t h e  pl a c e b o  p ati e nts)  will  h a v e  at l e ast 
6  m o nt h s a cti v e tr e at m e nt  b y  b u m et a ni d e.  
T h e  m ai n  b ur d e n  of t his  st u d y f or t h e  p ati e nt is r el at e d t o t h e  o ut p ati e nt  c e ntr e  visits t o f oll o w 
u p  t h e  s af et y  of  t h e  di ur eti c  eff e cts,    w hi c h  r e q uir es  p h ysi c al  e x a mi n ati o n  [i n cl u di n g  bl o o d 
pr ess ur e  ( S B P,  D B P),  h e art  r at e,  b o d y  w ei g ht,  h ei g ht],  bl o o d  a n d  uri n e t ests,  E C G  a n d  r e n al 
ultr as o u n d,  w hi c h  ar e  of l o w  a n d  k n o w n ris ks,  as  w ell  as  a d v ers e  e v e nt  c oll e cti o n.  A d diti o n al 
b ur d e n  c orr es p o n ds t o  c o g niti v e t est  e v al u ati o ns  w hi c h  ar e  n e c ess ar y f or  b u m et a ni d e  effi c a c y 
ass ess m e nt.  
T h e  S p o ns or  n ot es t h at t h es e  cli ni c al st u di es  will  b e  c arri e d  o ut i n  a  v u l n er a bl e  p o p ul ati o n  a n d 
h as i m pl e m e nt e d s e v er al  m e as ur es i n  or d er t o  mi ni mi z e  a n y  p ot e nti al  b ur d e n:  
- 
I n t h e fr a m e w or k  of t his  P a e di atri c I n v esti g ati o n al  Pl a n  e n d ors e d  b y t h e  E M A,  S er vi er 
h as  c h os e n t h e  us e  of  s c al es  a n d  q u esti o n n air es t o  b e  c o m pl et e d  as  m u c h  as  p ossi bl e 
b y   t h e   p ar e nts /l e g al   r e pr es e nt ati v e/ c ar e gi v er i nst e a d   of   p arti ci p a nts.    T his    will 
si g nifi c a ntl y r e d u c e t h e l e n gt h  of  a  visit  w h er e t h e  pr es e n c e  of t h e  c hil d is  c o m p uls or y. 
- 
B as e d  o n  t h e  f a mil y  e n vir o n m e nt  a n d  f or  or g a ni z ati o n al  r e as o ns,  s af et y e v al u ati o ns 
r e q uir e d f or t h e  m ost ti m e  c o ns u mi n g  visits ( S el e cti o n, i n cl usi o n, visit  W e e k  1 2, visit 
W e e k  2 6,  visit  W e e k  3 8  a n d  Visit  5 2)  c o ul d  b e s plitt e d i n s e v er al  d a ys. 
- 
R e g ar di n g  t h e   m a n a g e m e nt  of  bl o o d  s a m pli n g,  all  t h e  c e ntr es  s el e ct e d  f or  t his  st u d y 
ar e  v er y  f a mili ar  wit h  w or ki n g  wit h  c hil dr e n  wit h  A utis m  S p e ctr u m  Dis or d er  ( A S D) 
a n d  t h eir   f a mili es.   I n  t h e   pr e vi o us   st u di es    wit h   b u m et a ni d e  i n    A S D   p a e di atri c 
p o p ul ati o n,   bl o o d  s a m pli n gs    w er e  f o u n d   q uit e   e asil y    m a n a g e a bl e   b y  e x p eri e n c e d 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 5 /2 9 6  
 
t e a ms,  a n d  fi el d  r et ur ns  r e p ort e d t h at  o nl y t h e  v er y  first  s a m pli n gs  w er e  c h all e n gi n g, 
f urt h er  o n es  b e c o mi n g rit u als.  F or t h es e  n e w  st u di es,  all  eff orts  will  b e  m a d e t o  m a k e 
t h e  bl o o d  s a m pli n gs  as  str ess-fr e e  as  p ossi bl e,  c o or di n at e d  wit h  d ail y  a cti viti es  as  f ar 
as  p ossi bl e  a n d t h e  e x p eri e n c e  of  pr e vi o us tri als  c e nt r es will  b e  s h ar e d  wit h t h e  n e w 
o n es.    T h e  i n v esti g at or  a n d/ or  c e ntr e  st aff    will  dis c uss    wit h  t h e  p ar e nts/ c ar er gi v ers 
w hi c h  str at e gi es  ar e    m ost  li k el y  t o   b e  s u c c essf ul  t a ki n g  i nt o  a c c o u nt   p ositi v e   or 
n e g ati v e  p ast  e x p eri e n c es  of  p arti ci p a nts  wit h  d o ct ors  or  bl o o d  s a m pl e t a ki n g.  T h e  sit e 
will   al w a ys   r ef er   t o   p ar e nts/ L e g al    R e pr es e nt ati v e   ( L R) / c ar e gi v er f or   b e h a vi or 
m a n a g e m e nt,  c o m m u ni c ati o n  a n d  c hil d’s  pr ef er e n c es.  T h e st u d y t e a m  will  ai m t o  h a v e 
t h e  s a m e  e x p eri e n c e d  st aff  i n v ol v e d  f or  e a c h  visit.   T h e  st u d y  n urs e  a n d  i n v esti g at or 
will  e x pl ai n    w h at    will  h a p p e n  b ef or e  st arti n g  t h e  v e n e p u n ct ur e  a n d    will  c h e c k  t h e 
u n d erst a n di n g  w h e n  a p pli c a bl e. It’s  u p t o t h e  cli ni c al t e a m t o  d e ci d e  h o w  m u c h ti m e is 
n e c ess ar y t o  e x pl ai n,  di str a ct  or  c o mf ort t h e  p ati e nt.  T h e i n v esti g at or  c a n r ef er t o t o ols 
us e d i n  n or m al  pr a cti c e  or  a v ail a bl e  at its  sit e  s u c h  as  vis u al  s u p p orts  or  s o ci al  st or y 
b o ar ds  t o  pr e p ar e  a  c hil d  f or  h a vi n g  a  bl o o d  s a m pl e,    wit h  t h e  p ar e nt / L R/ c ar e gi v er 
s u p p ort.    L o c al  a n aest h esi a  cr e a ms  or  v a p o -c o ol a nt  s pr a y  c a n  b e  us e d  t o    mi ni mis e 
dis c o mf ort.  T h e n, t h e  bl o o d  s a m pli n gs  s h o ul d  b e  p erf or m e d  q ui c kl y  a n d  effi ci e ntl y t o 
a v oi d  es c al ati o n  of  p ot e nti al  a n xi et y  or irrit a bilit y.  
- 
All  t h os e    m e as ur es  c o ntri b ut e  t o  t h e  i nst all ati o n  of  a  rit u al    m u c h  a p pr e ci at e d  b y 
p ati e nts  wit h  A S D.  
- 
S p o ns or  hi g hl y  r e c o m m e n d s t h at  t h e  s a m e  p ers o n  i n  c h ar g e  of  st u d y  e v al u ati o ns 
f oll o ws  a  gi v e n  c hil d  d uri n g t h e  st u d y i n  or d er t o  mi ni mi z e  a n y  p ot e nti al  bi as i n  st u d y 
ass ess m e nts  a n d  t o  r e d u c e  t h e  b ur d e n  li n k e d  t o  t h e  p ot e nti al  str ess  s uff er e d  b y  t h e 
c hil d. 
- 
P a e di atri c li q ui d  f or m ul ati o n  h as  b e e n  s p e ci all y  d e v el o p e d  f or t his  p a e di atri c  cli ni c al 
pr o gr a m.  T his f or m ul ati o n  s h o w e d  a  g o o d  a c c e pt a bilit y  a n d  p al at a bilit y  pr ofil e i n t h e  
p h as e II.  
F or t h e  b e n efit  of t h e s t u d y,  b u m et a ni d e  c o ul d  b e t h e first  p h ar m a c ol o gi c al  c a n di d at e  all o wi n g 
t h e tr e at m e nt  of  A S D  c or e  s y m pt o ms i n  p a e di atri c  p o p ul ati o n,  a cti n g  o n  a  k e y  c o m p o n e nt  of 
t h e  dis e as e  p at h o p h ysi ol o g y ( alt er ati o n  of  G A B A er gi c  n e ur o ns  a n d  cir c uits, t h e  c o n v ersi o n  of 
G A B A -m e di at e d  n e ur o n al  e x cit ati o n  i nt o  i n hi biti o n  d uri n g    m at ur ati o n  of  s p e cifi c  n e ur o n al 
p o p ul ati o ns  b ei n g r e p ort e d t o  b e  alt er e d i n  n e ur o d e v el o p m e nt al  dis e as es s u c h  as  a utis m). 
A cti n g   c e ntr all y   as   a    N K C C 1  i n hi bit or,   b u m et a ni d e   pr o v o k es  r e d u cti o n   of  i ntr a c el l ul ar 
c hl ori d e,  s wit c hi n g  t h e  a b err a nt  e x cit at or y  a cti o n  of    G A B A  i nt o  a n  i n hi bit or y  a cti o n,  a n d 
t h er ef or e  m a y r est or e i m p ort a nt  d e v el o p m e nt al  c a p a citi es. 
C o ns e q u e ntl y,  as  t h er e  is  n o  dr u g  tr e at m e nt  f or  c or e  s y m pt o ms  of   A S D,   w e  s et  u p  a  st u d y 
wit h  b u m et a ni d e  i n  y o u n g  d e v el o pi n g  p ati e nts   wit h   A S D  i n  or d er  t o  r e d u c e  t h e   A S D  c or e 
s y m pt o ms  a n d  f u n cti o n al  i m p air m e nt  a n d  t o  i m pr o v e  q u alit y  of  lif e.  St u di es  ar e  n e e d e d  i n 
p a e di atri c  p o p ul ati o n,  c hil d h o o d  b ei n g  a  ti m e    w h e n  br ai n  pl asti cit y  is  at  t h e  gr e at est  a n d 
w h ere  b e h a vi o ur al  a n d  e d u c ati v e i nt er v e nti o ns  c o ul d  h a v e t h e  m ost  b e n efit. 
 
F or t h e ris k f or t h e  p ati e nt, t h e s af et y  pr ofil e  of  b u m et a ni d e is si mil ar t o t h at r e p ort e d f or  ot h er 
l o o p  di ur eti cs.   T h e  t ar g et  or g a n  is  t h e  ki d n e y  a n d  t h e  s af et y  pr ofil e  is  r el at e d  t o t h e  p ot e nt 
di ur eti c  a cti vit y  of t h e  c o m p o u n d.  B as e d  o n t h e  s af et y  e x p eri e n c e  g ai n e d  at t his  st a g e  of  dr u g 
d e v el o p m e nt i n  A S D ( 5  cli ni c al  st u di es  d es cri b e d  a b o v e), t h e  s af et y  pr ofil e  of  b u m et a ni d e i n 
A S D  c hil dr e n  a n d  a d ol es c e nts  s e e ms  c o m p ar a bl e t o t h e  o n e  o bs er v e d i n  a d ult  p ati e nts tr e at e d 
f or  o e d e m a.  D es pit e t h e  p e n etr ati o n  of  b u m et a ni d e i nt o  br ai n,  n o t o xi c  eff e cts  o n t h e  C e ntr al 
N er v o us  S yst e m  h a v e  b e e n  o bs er v e d. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 6 /2 9 6  
 
T h e  e m er g e nt  b u m et a ni d e  s af et y  pr ofil e  o bs er v e d  i n  p a e di atri c  p o p ul ati o n    wit h    A S D    w as 
m ai nl y  r el at e d  t o   b u m et a ni d e   di ur eti c   eff e ct  ( e n ur esis,   p oll a ki uri a,   p ol y uri a,   el e ctr ol yt e 
dist ur b a n c es  a n d  d e h y dr ati o n)  a n d  w as  d os e -r el at e d. It  di d  n ot  diff er fr o m t h at  of  b u m et a ni d e 
t a bl ets.    H y p o k al a e mi a  is   a n  i d e ntifi e d  ris k  a n d  t h er ef or e   bl o o d   p ot assi u m  l ev el    will   b e 
r e g ul arl y    m o nit or e d  d uri n g  t h e  p h as e  III  b u m et a ni d e  p a e di atri c  pr o gr a m  ( bl o o d  p ot assi u m 
s a m pli n g  s c h e d ul e  v ali d at e d   wit h  t h e   E M A).  It  h as  t o  b e  hi g hli g ht e d  t h at  all  h y p o k al a e mi a 
r e p ort e d  d uri n g t h e  p h as e  II  N e ur o Cli n 0 2  d os e-r a n g e  st u d y  w er e  as ym pt o m ati c  ( a n d  wit h o ut 
a n y  c ar di a c i m p a ct),  a n d t h us it is  cr u ci al t o  p erf or m  all  pl a n n e d  s a m pli n gs.  L astl y, t h e  m ost 
f a v o ur a bl e   t ol er a bilit y   pr ofil e    w as   o bs er v e d    wit h   b u m et a ni d e   0. 5    m g   t wi c e   a   d a y 
c orr es p o n di n g t o t h e  d os e t h at  will  b e  gi v e n  d uri n g t h e  2 p h as e III st u di es.  
C o nsi d eri n g t h e t ar g et e d  p o p ul ati o n  of  p ati e nts,  a  D at a  M o nit ori n g  C o m mitt e e ( D M C)  will  b e 
s et  u p  a n d    will  b e  r es p o nsi bl e  f or  p eri o di c  r e vi e w  of  p ati e nt’s  s af et y  d at a  t hr o u g h o ut  t h e 
st u d y.  D et ails  o n t h e r ol e  a n d  or g a nis ati o n  of t h e  D M C will  b e  pr o vi d e d i n  a s e p ar at e  c h art er.  
T h e  st u d y  will  b e  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,  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 nts. 
3.  S T U D Y  O B J E C TI V E S  A N D  P U R P O S E 
3. 1.   P ri m a r y  o bj e cti v e  
T h e  pri m ar y  o bj e cti v e  is  t o  d e m o nstr at e  t h e  s u p eri orit y  of  b u m et a ni d e  ( 0. 5 m g    BI D)  or al 
li q ui d  f or m ul ati o n  c o m p ar e d t o  pl a c e b o  i n  t h e i m pr o v e m e nt  of   A S D  c or e  s y m pt o ms  aft er  6 
m o nt hs  of tr e at m e nt i n  A S D  c hil dr e n  a g e d fr o m  2 t o l ess t h a n 7  y e ars  ol d.  
3. 2.  S e c o n d a r y  o bj e cti v es  
- T o  ass ess t h e  eff e ct  of  b u m et a ni d e  o n t h e  ot h er  effi c a c y  e n d p oi nts  
- T o  ass ess t h e s af et y  of  b u m et a ni d e  
- T o  c o nfir m t h e  a c c e pt a bilit y  a n d  p al at a bilit y  of t h e  or al li q ui d f or m ul ati o n  
- T o  d es cri b e t h e  b u m et a ni d e  eff e cts  o n p ati e nts  q u alit y  of lif e  
- T o i m pr o v e  e xisti n g  p h ar m a c o ki n eti c  m o d el  of  b u m et a ni d e i n t his  p o p ul ati o n. 
3. 3.  E x pl o r at o r y  o bj e cti v es 
T o  d es cri b e t h e  B u m et a ni d e  eff e ct  o n  utilit y i n d e x s c or es  
4.  S T U D Y  D E SI G N  
4. 1.  E n d p oi nt(s)  
T a bl e  (4. 1 )  1 - E n d p oi nts  
 
 
O bj e cti v e s 
E n d p oi nt s 
Pri m ar y  
T o   d e m o nstr at e   t h e   s u p eri orit y   of 
b u m et a ni d e   ( 0. 5 m g    BI D)   or al   li q ui d 
f or m ul ati o n  as  c o m p ar e d t o  pl a c e b o i n t h e 
i m pr o v e m e nt  of  A S D  c or e  s y m pt o ms  aft er 
6    m o nt hs   of  tr e at m e nt  i n   c hil dr e n   a g e d 
fr o m 2 t o l ess th a n  7 y e ars  ol d  wit h  A S D  
 
C hil d h o o d    A utis m    R ati n g   S c al e,   S e c o n d 
E diti o n ( C A R S 2) t ot al r a w s c or e.  
M ai n  e x pr essi o n  will  b e  c h a n g e fr o m  b as eli n e 
t o  6  m o nt h. 
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 7 /2 9 6  
 
 
O bj e cti v e s 
E n d p oi nt s 
S e c o n d ar y  
T o  ass ess  t h e  eff e ct  of  b u m et a ni d e  o n  t h e 
ot h er  effi c a c y  e n d p oi nts  
 
 
 
 
 
 
 
T o  ass ess t h e s af et y  of  b u m et a ni d e  
 
- T h e  c h a n g e  i n  S R S -2  t ot al  r a w  s c or e  fr o m 
b as eli n e t o  6  m o nt h  
- C GI -I s c or e  at  6  m o nt h 
- T h e   c h a n g e  i n    V A B S   II   s u bs c or es   fr o m 
b as eli n e t o  6  m o nt h  
- T h e   c h a n g e   i n   e a c h   i n di vi d u al    C A R S 2 
d o m ai n fr o m  b as eli n e t o  6  m o nt h  
 
- A d v ers e   e v e nts   ( A E),   P a e d i atri c    A d v ers e 
E v e nt  R ati n g  S c al e ( P A E R S)  
- Cli ni c al l a b or at or y  e v al u ati o n  
- Vit al  si g ns  a n d  cli ni c al  e x a mi n ati o n:  w ei g ht 
( k g),  h ei g ht  ( m),    B o d y    M ass  I n d e x  ( B MI) 
( k g/ m²),   s yst oli c   bl o o d   pr ess ur e  ( m m H g), 
st a n di n g,   sitti n g;    Di ast oli c   bl o o d   pr ess ur e 
( m m H g), st a n di n g, sitti n g,  h e art r at e ( b p m) 
- El e ctr o c ar di o gr a m  
- R e n al  ultr as o u n d  
- Ass ess m e nt  of  s ui ci d al i d e ati o n  a n d  s ui ci d al 
b e h a vi o ur   usi n g   t h e    C ol u m bi a   S ui ci d e 
S e v erit y    R ati n g   S c al e    C hil dr e n’s   v ersi o n 
( C-S S R S -C)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E x pl or at or y  
T o   c o nfir m   t h e   a c c e pt a bilit y 
a n d 
p al at a bilit y  of t h e  or al li q ui d f or m ul ati o n  
 
T o   d es cri b e   t h e   b u m et a ni d e   eff e cts   o n 
p ati e nts’  q u alit y  of lif e  
 
 
 
 
 
T o   i m pr o v e   e xisti n g   p h ar m a c o ki n eti c 
m o d el  of  b u m et a ni d e i n t his  p o p ul ati o n  
 
T o   d es cri b e   t h e    B u m et a ni d e   eff e ct   o n 
utilit y i n d e x s c or es  
 
A c c e pt a bilit y  a n d  p al at a bilit y  q u esti o n n air e  
 
 
- P a e di atri c  Q u alit y  of  Lif e I n v e nt or y 
( P e ds Q L)  e x pr ess e d i n t er m  of  c h a n g e fr o m 
b as eli n e t o  m o nt h  6  
- W H O Q O L -Br ef  q u esti o n n air e s u m m ari z e d 
at  e a c h  pl a n n e d  visit f or  e a c h  p eri o d  usi n g 
d es cri pti v e st atisti cs  
 
P K  p oi nt s  at  W 0 1 2  a n d  W 0 2 6 
 
 
Utilit y i n d e x s c or e  o n  t h e  E Q -5 D - 3 L  
 
  
R ef er t o s e cti o ns  6. 1 a n d/ or   7. 1 f or f urt h er  d et ails. 
4. 2.  E x p e ri m e nt al  d esi g n  
4. 2. 1.  St u d y  pl a n   
T his st u d y is  di vi d e d i nt o t h e f oll o wi n g  p eri o ds: 
1.  A r u n -i n  p eri o d  u p t o  4  w e e ks  b et w e e n s el e cti o n ( A S S E)  a n d i n cl usi o n ( w e e k  0)  visits: 
T his   p eri o d  is    wit h o ut  I n v esti g ati o n al    M e di ci n al   Pr o d u ct  (I M P)  tr e at m e nt  t o  e v al u at e 
eli gi bilit y.  St a bl e  ps y c h os o ci al i nt er v e nti o n is  m ai nt ai n e d if  a n y.  
T his   p eri o d   all o ws   i n v esti g at ors   t o   p erf or m    E C G,   r e n al   ultr as o u n d,   l a b or at or y 
e x a mi n ati o ns,  a n d  t o  c o m pl et e,  if  n e e d e d,  t h e    w as h -o ut  p eri o d  of  f or bi d d e n  tr e at m e nts 
b ef or e i n cl usi o n. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 8 /2 9 6  
 
2.  D o u bl e- bli n d tr e at m e nt  p eri o d  of  6  m o nt hs  b et w e e n i n cl usi o n ( w e e k  0)  a n d  m o nt h  6 ( w e e k 
2 6): 
At  i n cl usi o n  p ati e nts    will  b e  r a n d o mis e d  t o  o n e  of  t h e  t w o  p ar all el  gr o u ps:  b u m et a ni d e 
0. 5 m g   BI D  or  pl a c e b o   BI D.   T h e  tr e at m e nt  ( b u m et a ni d e  or  pl a c e b o)    will  b e  assi g n e d  at 
i n cl usi o n  b y  a  b al a n c e d r a n d o mis ati o n (r ati o  1: 1). 
- 
P ati e nts  r a n d o mis e d  i n  t h e  b u m et a ni d e  ar m   will  r e c ei v e  b u m et a ni d e  u p  t o  0. 5 m g 
BI D.  B u m et a ni d e  d os es  will  b e  a d a pt e d  o n  b o d y- w ei g ht: 
o  If  t h eir    w ei g ht  is  <  2 5 k g,  t h e y    will  r e c ei v e  b u m et a ni d e  0. 0 2    m g/ k g    BI D 
( or al  s ol uti o n  0. 5    m g/ m L)  c orr es p o n di n g  t o  a  v ol u m e  of  s ol uti o n  of  0. 0 4 
ml/ k g  BI D fr o m i n cl usi o n t o  m o nt h  6 
o  If  t h eir   w ei g ht  is  ≥  2 5 k g,  t h e y   will  r e c ei v e  b u m et a ni d e  0. 5 m g   BI D  ( 1 m L 
or al s ol uti o n  BI D) fr o m i n cl usi o n t o  m o nt h  6  
- 
P ati e nts r a n d o mis e d i n t h e  pl a c e b o  ar m  will r e c ei v e  pl a c e b o  BI D  
T h e  v ol u m e  of t h e  or al s ol uti o n  will  b e  c al c ul at e d  o n  b o d y- w ei g ht: 
o  If t h eir w ei g ht is  <  2 5 k g, t h e y  will r e c ei v e  pl a c e b o  BI D ( c orr es p o n di n g t o  a 
v ol u m e  of  pl a c e b o s ol uti o n  of  0. 0 4  ml/ k g  BI D) fr o m i n cl usi o n t o  m o nt h  6 
o  If t h eir  w ei g ht is  ≥  2 5 k g, t h e y  will r e c ei v e  pl a c e b o  BI D ( 1 m L  pl a c e b o  BI D 
or al s ol uti o n) fr o m i n cl usi o n t o  m o nt h  6 
St a bl e  ps y c h os o ci al i nt er v e nti o n is  m ai nt ai n e d if  a n y. 
 
3.  O p e n l a b el  a cti v e tr e at m e nt  p eri o d  of  6  m o nt hs  b et w e e n  m o nt h  6 ( w e e k  2 6)  a n d  m o nt h  1 2 
( w e e k  5 2): 
- P ati e nts r a n d o mis e d i n t h e  b u m et a ni d e  ar m  d uri n g t h e  d o u bl e  bli n d  p eri o d  will  c o nti n u e 
t o  b e  tr e at e d  b y  b u m et a ni d e  u p  t o  0. 5 m g    BI D  d uri n g  t h e    w h ol e  o p e n  l a b el  p eri o d. 
B u m et a ni d e  d os es  will  b e  a d a pt e d  o n  a  b o d y- w ei g ht  as i n t h e  d o u bl e  bli n d  p eri o d. 
- P ati e nts  r a n d o mis e d  i n  t h e  pl a c e b o  ar m  d uri n g  t h e  d o u bl e  bli n d  p eri o d    will  r e c ei v e 
b u m et a ni d e  u p  t o  0. 5 m g   BI D  d uri n g  t h e    w h ol e  o p e n  l a b el  p eri o d.   B u m et a ni d e  d os es 
will  b e  a d a pt e d  o n  a  b o d y- w ei g ht  as i n t h e  d o u bl e  bli n d  p eri o d. 
 
4.  A f oll o w- u p  visit ( W e n d),  6  w e e ks  aft er tr e at m e nt  dis c o nti n u ati o n: 
 
T his  p eri o d is  wit h o ut  a n y I M P  a n d it  will  b e  c o m pl et e d  at t h e  e n d  of  t h e  st u d y  or i n  c as e 
of  pr e m at ur e  dis c o nti n u ati o n fr o m t h e st u d y  at  a n y  m o m e nt. 
T h e st u d y  pl a n is s h o w n i n   Fi g ur e ( 4. 2. 1)  1. 
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 d  t o  his/ h er  p ar e nts/l e g al 
r e pr es e nt ati v e, 
­ 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 d e q u at 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.  
T h e f oll o wi n g  v ari ati o n  c a n  b e  a c c e pt e d: 
- 
V ari ati o n   of    m a xi m u m   ±   1   d a y   b et w e e n   visits   is   all o w e d   f or    W 0 0 0 + D a y 1 0, 
W 0 0 0 + D a y 1 7  a n d  W 0 0 4  visits 
- 
V ari ati o n  of  m a xi m u m  ±  2  d a ys  b et w e e n  visits is  all o w e d  f or ,  W 0 0 8,  W 0 1 2,  W 0 1 6, 
W 0 2 0  a n d  W 0 2 6  visits 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  2 9 /2 9 6  
 
- 
V ari ati o n   of    m a xi m u m   ±   1   d a y   b et w e e n   visits   is   all o w e d   f or    W 0 2 6 + D a y 1 0, 
W 0 2 6 + D a y 1 7  a n d  W 0 3 0  visits 
- 
V ari ati o n  of    m a xi m u m  ±  2  d a ys  b et w e e n  visits  is  all o w e d  f or    W 0 3 4,    W 0 3 8,    W 0 4 2, 
W 0 4 6  a n d  W 0 5 2  visits 
Fi g u r e  ( 4. 2. 1)  1  – St u d y  pl a n  
 
 
 
 
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 el e cti o n  visit - 
A S S E).  
A  6 -m o nt h  e xt e nsi o n  p eri o d  i n  o p e n -l a b el  is  pr o p os e d  i n  s o m e  c o u ntri es    w h er e  it  is  n ot 
p ossi bl e  t o  pr o vi d e  t h e  tr e at m e nt  at  t h e  e n d  of  t h e m ai n  p eri o ds  vi a a   N a m e d  P ati e nt   B asis 
( N P B)  a c c ess  or  a  P ost- Ac c ess St u d y  Pr o gr a m.   
T h er ef or e,  t h e 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  f oll o w -u p  visit  of  t h e  l ast 
p arti ci p a nt  (i n cl u di n g  a p h o n e  c o nt a ct)  i n t h e o p e n  l a b el  a cti v e  tr e at m e nt  p eri o d  or  i n  t h e 
e xt e nsi o n  p eri o d  w hi c h e v er  o c c urs t h e l at est ,  or t h e  d at e  of t h e l ast  c o nt a ct  att e m pt if t h e l ast 
p arti ci p a nt is  d e cl ar e d l ost t o f oll o w - u p. 
 
4. 2. 2.  I n v esti g ati o n s c h e d ul e 
T a bl e  ( 4. 2. 2)  1 d es cri b es t h e  m e as ur e m e nt  of  effi c a c y  a n d s af et y  ass ess e d  d uri n g t h e st u d y.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti a l 
  3 0 /2 9 6  
 
T a bl e  (4. 2. 2 )  1 - I n v esti g ati o n s c h e d ul e 
 
 
 
 
 
S el e cti o n  
I n cl usi o n 
D o u bl e -bli n d  2 6  w e e k tr e at m e nt  p eri o d  
 
Visits t o  c o m pl et e i n  c as e  of I M P 
dis c o nti n u ati o n  d uri n g t h e  d o u bl e  bli n d 
p eri o d  B U T  n ot  wit h dr a w al fr o m t h e st u d y  
 A S S E  
W 0 0 0  
W 0 0 0  
  4 8/ 7 2 h 
W 0 0 0  
  D a y  1 0 
W 0 0 0  
  D a y  1 7 
W 0 0 4  
W 0 0 8  
W 0 1 2  
W 0 1 6  
W 0 2 0  
W 0 2 6  
 
W 0 1 2  
W 0 2 6  
I nf or m e d c o ns e nts/ ass e nts  
X ( 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p h y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I Q t est( 2) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
D S M -5  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
A D O S -2 ( 3) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
A DI -R ( 4) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
S el e cti o n /  N o n s el e cti o n  crit eri a  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl usi o n /  N o n-i n cl usi o n  crit eri a 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
A utis m  di a g n osti c  hist o r y 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
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 ( 5) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n c o mit a nt tr e at m e nts ( 5) 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
I R S 
P ati e nt  n u m b er  
R a n d o mis ati o n  
I M P  all o c ati o n 
 
X 
 
 
X 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
I M P dis p e ns ati o n  
Or al s ol uti o n  v ol u m e  a d a pt ati o n t o  p ati e nt  w ei g ht if 
n e e d e d  
 
X  
X 
 
 
 
X  
X  
X  
X 
X  
X  
X ( 6) 
X 
 
 
 
C o m pli a n c e I M P  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
 
 
 
 
( 1)   T o  o bt ai n  at t h e l at est  at  A S S E  b ut  b ef or e  a n y  pr o c e d ur e r el at e d t o t h e st u d y 
( 2)  O nl y t o  b e  p erf or m e d if r etr os p e cti v e  e x a m is  n ot  a v ail a bl e i n t h e  1 2  m o nt hs  pri or t o  A S S E 
( 3)  S h o ul d  n ot  b e  p erf or m e d if  a n  A D O S -2  e v al u ati o n  h as  b e e n  d o n e  wit hi n t h e  1 2  m o nt hs  pri or t o  A S S E  a n d is  d o c u m e nt e d i n t h e sit e  
( 4)  O nl y t o  b e  p erf or m e d if r etr os p e cti v e A DI -R is  n ot  a v ail a bl e  aft er t h e  4  y. o.  of t h e  p ati e nt 
( 5) I n cl u di n g  n o n-p h ar m a c ol o gi c al t h er a pi es ( ps y c h ot h er a p y  s o ci al s kills tr ai ni n g   b e h a vi o ur al i nt er v e nti o ns   et c)  
 ( 6)  First I M P  dis p e ns ati o n  of t h e  o p e n l a b el  2 6  w e e k  a cti v e tr e at m e nt  p eri o d 
 
 
 
 
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti a l 
  3 1 /2 9 6  
 
 
T a bl e  (4. 2. 2 )  1  – I n v esti g ati o n s c h e d ul e ( c o nti n u e d) 
 
 
 
 
 
S el e cti o n  
I n cl usi o n 
D o u bl e -bli n d  2 6  w e e k tr e at m e nt  p eri o d  
 
Visits t o  c o m pl et e i n  c as e  of I M P 
dis c o nti n u ati o n  d uri n g t h e  d o u bl e  bli n d 
p eri o d  B U T  n ot  wit h dr a w al fr o m t h e st u d y  
 
A S S E  
W 0 0 0  
W 0 0 0  
  4 8/ 7 2 h 
W 0 0 0  
  D a y  1 0 
W 0 0 0  
  D a y  1 7 
 
D 0 1 7  
W 0 0 4  
W 0 0 8  
W 0 1 2  
W 0 1 6  
W 0 2 0  
W 0 2 6  
 
W 0 1 2  
W 0 2 6  
Effi c a c y  m e as u r e m e nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C A R S 2 -H F / C A R S 2 -S T/  C A R S 2 -Q P C  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
C GI  
X ( 1) 
X ( 1)  
 
 
X ( 2) 
X ( 2) 
X ( 2) 
X  
X ( 2) 
X ( 2) 
X  
 
X  
X  
S R S -2  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
V A B S II  
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
S af et y  m e as u r e m e nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S ui ci d alit y ( C -S S R S -C)  
 
X  
 
 
 
 
 
X  
 
 
X  
 
 
 
A d v ers e  e v e nts  
P A E R S s c al e   
 
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
L a b or at or y t ests ( bl o o d  a n d  uri n e)  
X  
 
 
 
 
 
 
X  
 
 
X  
 
 
 
Bl o o d  el e ctr ol yt es  m o nit ori n g ( K,  N a)  
( p erf or m e d l o c all y  e x c e pt  at  A S S E) 
X  
 
X  
X  
X  
X  
X (  3) 
X  
X (  3) 
X (  3) 
X  
 
 
 
E C G  
X ( 6) 
 
 
 
 
X ( 5) 
X ( 5) 
X ( 5) 
 
 
X ( 5) 
 
 
 
R e n al  ultr as o u n d  
Sitti n g  a n d st a n di n g  bl o o d  pr ess ur e/ H e art r at e  
X  
X  
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
X ( 5) 
X  
 
 
 
B o d y  W ei g ht  a n d  H ei g ht  
X  
X ( 4) 
 
 
X ( 4) 
X ( 4) 
X ( 4) 
X  
X ( 4) 
X ( 4) 
X  
 
 
 
P h a r m a c o ki n eti cs  ( bl o o d s a m pl es) 
 
 
 
 
 
 
 
X  
 
 
X  
 
 
 
Ot h e r  m e as u r e m e nts  
P e ds Q L  
 
 
 
X  
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
 
W H O Q O L -Br ef   
 
X  
 
 
 
X  
X  
X  
 
 
X  
 
 
 
E Q 5 D -3 L  
 
X  
 
 
 
 
 
X  
 
 
X  
 
 
 
A c c e pt a bilit y  Q u esti o n n air e  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
( 1)  C GI-S  o nl y   
( 2) C GI -I  onl y   
( 3)  Pr e s cri b e d  b as e d  o n t h e  cli ni c al  o pi ni o n  of  n e p hr ol o gist  or i n v esti g at or  
( 4)  O nl y  b o d y  w ei g ht  
( 5) R es ults  of t h e  e x a m s h o ul d  b e  a v ail a bl e  at t his  visit   pr es cri pti o n t o  b e  d o n e  at t h e  pr e vi o us  visit   
( 6)  E C G  Tri pli c at e  o nl y  at  A S S E 
 
 
 
 
 
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti a l 
  3 2 /2 9 6  
 
 
T a bl e  (4. 2. 2 )  1  – I n v esti g ati o n s c h e d ul e ( c o nti n u e d) 
 
 
 
O p e n l a b el  2 6  w e e k  a cti v e tr e at m e nt  p eri o d  
 
F U  
 
 
W D  
Wit h dr a w al  visit t o  b e  u n d er g o n e 
i n  c as e  of I M P  d efi niti v e 
dis c o nti n u ati o n  or i n  c as e  of t ot al 
wit h dr a w al fr o m t h e st u d y 
w h at e v er t h e  p eri o d  
 
W 0 2 6  
  4 8/ 7 2 h 
W 0 2 6  
  D a y  1 0 
W 0 2 6  
  D a y  1 7 
 
( D 1 9 9) 
W 0 3 0  
W 0 3 4  
W 0 3 8  
W 0 4 2  
W 0 4 6  
W 0 5 2  
 
W e n d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n c o mit a nt tr e at m e nts ( 1) 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
X  
I R S 
I M P  all o c ati o n  
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
I M P  d efi niti v e  dis c o nti n u ati o n 
 
 
 
 
 
 
 
 
 
 
 
 
X  
I M P  dis p e ns ati o n 
Or al s ol uti o n  v ol u m e  a d a pt ati o n t o  p ati e nt  w ei g ht  
 
 
 
X  
 
X  
X  
X  
X  
X  
 
 
 
 
 
C o m pli a n c e I M P  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
 
X  
Effi c a c y  m e as u r e m e nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
C A R S 2 -H F / C A R S 2 -S T )/ C A R S 2-Q P C  
 
 
 
 
 
X  
 
 
X  
 
X  
 
X ( 4) ( 7) 
C GI  
 
 
 
 
 
X ( 6) 
 
 
X  
 
X  
 
X ( 7) 
S R S -2  
 
 
 
 
 
X  
 
 
X  
 
 
 
 X ( 4) ( 7) 
V A B S II  
 
 
 
 
 
 
 
 
X  
 
 
 
X ( 4) ( 7) 
S af et y  m e as u r e m e nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
S ui ci d alit y ( C -S S R S -C)  
 
 
 
 
 
X  
 
 
X  
 
 
 
X  
A d v ers e  e v e nts  
P A E R S s c al e   
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
X  
X  
L a b or at or y t ests ( bl o o d  a n d  uri n e)  
 
 
 
 
 
X  
 
 
X  
 
 
 
X  
Bl o o d  e l e ctr ol yt es  m o nit ori n g ( K,  N a)  
( p erf or m e d l o c all y  e x c e pt at W D)  
X  
X  
X  
X  
X ( 2) 
X  
X ( 2) 
X ( 2) 
X  
 
 
 
X  
E C G  
 
 
 
X ( 5) 
X ( 5) 
X (  ) 
 
 
X ( 5) 
 
 
 
X  
R e n al  ultr as o u n d  
Sitti n g  a n d st a n di n g  bl o o d  pr ess ur e/  H e art r at e  
 
 
 
 
 
X  
 
 
 
X  
 
 
X ( 5) 
X  
 
 
 
X  
X  
B o d y  W ei g ht  a n d  H ei g ht  
 
 
X ( 3) 
X ( 3) 
X ( 3) 
X  
X ( 3) 
X ( 3) 
X  
 
 
 
X  
 
Ot h e r  m e as u r e m e nts  
P e ds Q L  
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
 
X ( 4) ( 7) 
W H O Q O L -Br ef   
 
 
 
X  
X  
X  
 
 
X  
 
 
 
X ( 4) ( 7) 
E Q 5 D -3 L   
A c c e pt a bilit y  Q u esti o n n air e  
 
 
 
 
 
X  
 
 
 
X  
 
 
 
 
X ( 4) ( 7) 
X ( 7) 
( 1)  I n cl u di n g  n o n-p h ar m a c ol o gi c al t h er a pi es ( ps y c h ot h er a p y  s o ci al s kills tr ai ni n g   b e h a vi o ur al i nt er v e nti o ns   et c) 
 ( 2)   Pr es c ri b e d  b as e d  o n t h e  cli ni c al  o pi ni o n  of  n e p hr ol o gist  or i n v esti g at or 
( 3)  O nl y  b o d y  w ei g ht 
 
( 4)  O nl y t o  b e  u n d er g o n e  aft er t h e l ast I M P i nt a k e  b y  p ati e nts  dis c o nti n ui n g  pr e m at ur el y fr o m t h e st u d y  aft er  W 0 0 0   D a y 1 0 
( 5)  R es ults  of t h e  e x a m s h o ul d  b e  a v ail a bl e  at t his  visit   pr es cri pti o n t o  b e  d o n e  at t h e  pr e vi o us  visit 
( 6)  C GI-I  o nl y 
 
 ( 7) S h o ul d  n ot  b e  d o n e i n  c as e  of st u d y  dis c o nti n u ati o n f or  c o ns e nt  wit h dr a w al 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 3 /2 9 6  
 
F or f urt h er  pr a cti c al  d et ail s,  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 ns  7,  8 a n d 9.  
F or  or g a nis ati o n al r e as o ns  A S S E,  W 0 0 0,  W 0 1 2,  W 0 2 6,  W 0 3 8  a n d  W 0 5 2  visits  c a n  b e  s plit i n 
s e v er al  d a ys, i n  or d er t o  b e  a bl e t o  c o m pl et e  all t h e st u d y  e v al u ati o ns. 
T h e f oll o wi n g r e c o m m e n d ati o ns s h o ul d  b e f oll o w e d: 
F or  A S S E:  
- E C G,  r e n al  ultr as o u n d  a n d l a b or at or y t ests  c o ul d  b e  p erf or m e d  aft er  A S S E visit d at e 
b ut al w a ys d uri n g t h e r u n i n  p eri o d  a n d r es ults  m ust  b e  a v ail a bl e f or t h e i n cl usi o n  visit 
F or  W 0 0 0,  W 0 1 2,  W 0 2 6, W 0 3 8,  W 0 5 2: 
- C A R S 2  a n d    C GI  st u d y  ass ess m e nts  pl a n n e d  at  t h e  c orr es p o n di n g  visit  s h o ul d  b e 
p erf or m e d  o n t h e s a m e  d a y  
- effi c a c y  e v al u ati o ns  s h o ul d  b e  al w a ys  p erf or m e d  pri or t o  a n y  s af et y  pr o c e d ur e i n  c as e 
b ot h  effi c a c y  e v al u ati o ns  a n d  s af et y  pr o c e d ur es  h a v e  b e e n  pl a n n e d t o  b e  p erf or m e d  o n 
t h e s a m e  d a y,  
- p ar e nts  q u esti o n n air es  ( C A R S    Q P C, S R S 2  a n d  q u alit y  of  lif e  q u esti o n n air es)  a n d 
Vi n el a n d s c al e  c o ul d  b e  c o m pl et e d  o n sit e  wit hi n  3  d a ys  pri or t o t h e  d a y  of t h e  visit, 
- s af et y  e v al u ati o ns  c o ul d  b e  d o n e wit hi n   7 d a ys  pri or t o t h e  visit  d at e.  
F urt h er m or e, t a ki n g i nt o  a c c o u nt l o c al r e g ul ati o n, it is  n ot  c o m p uls or y f or t h e  p ati e nt t o  att e n d 
t h e  visits  W 0 0 0 + 4 8 h/ 7 2 h,  W 0 0 0 + D a y  1 0,  W 0 0 0 + D a y 1 7, W 0 2 6 + 4 8 h/ 7 2 h,  W 0 2 6 + D a y  1 0  a n d 
W 0 2 6 + D a y 1 7  o n sit e. 
I n s u c h  a  c as e t h e f oll o wi n g r e c o m m e n d ati o ns s h o ul d  b e f oll o w e d: 
- 
T h e   pl a n n e d   bl o o d  s a m pli n g  f or   el e ctr ol yt es  ( N a   a n d    K)   at  t h es e   visits    wi ll   b e 
p erf or m e d l o c all y. 
- 
A p h o n e  c o nt a ct    m ust   b e  est a blis h e d   b y  t h e  i n v esti g at or    wit h  t h e   p ati e nt  ( w h e n 
p ossi bl e)  a n d  t h e  p ar e nt(s)/  l e g all y  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  i n 
or d er t o  c oll e ct  a n y  a d v ers e  e v e nt  at t h es e  visits.  
- 
vit al si g ns  will  b e  c oll e ct e d  at  h o m e  b y  a st u d y  n urs e  w h e n r e q uir e d. 
S p e ci al  c o n d u ct  i n  t h e  c as e  of  d efi niti v e  dis c o nti n u ati o n  of  I M P  d uri n g  t h e  d o u bl e  bli n d 
p eri o d: 
1.  P ati e nt  will  c o m pl et e t h e st u d y e v al u ati o ns  pl a n n e d  at  W D  visit.  
2.  If I M P  d efi niti v e  dis c o nti n u ati o n  o c c urs  pri or t o  W 0 1 2: 
a. p ati e nt   will  att e n d    W 0 1 2  visit  (if  t h er e is  at l e ast  2   m o nt hs  b et w e e n    W D  a n d 
W 0 1 2)   a n d    will   b e   i n vit e d   t o   c o m pl et e    C A R S 2,   S R S -2,    C GI   a n d    A E 
ass ess m e nt  at  W 0 1 2    as  pl a n n e d i n t h e i n v esti g ati o n s c h e d ul e (T a bl e  ( 4. 2. 2)  1). 
b.  p ati e nt    will  at t e n d  t h e n    W 0 2 6   visit   a n d    will   b e  i n vit e d  t h e n  t o   c o m pl et e 
C A R S 2,   S R S -2,    C GI  a n d    A E  ass ess m e nt  at    W 0 2 6  visit  as  pl a n n e d  i n  t h e 
i n v esti g ati o n s c h e d ul e (T a bl e  ( 4. 2. 2)  1). 
3.  If I M P  d efi niti v e  dis c o nti n u ati o n  o c c urs  b et w ee n  W 0 1 2  a n d  W 0 2 6:  
a. p ati e nt  will  att e n d  W 0 2 6 (if t h er e is  at l e ast  2  m o nt hs  b et w e e n  W D  a n d  W 0 2 6) 
a n d    will  b e  i n vit e d  t o  c o m pl et e   C A R S 2,  S R S -2,   C GI  a n d    A E  ass ess m e nt  at 
W 0 2 6  as  pl a n n e d i n t h e i n v esti g ati o n s c h e d ul e (T a bl e ( 4. 2. 2)  1) . 
I n  s u c h  a  c as e,  C A R S 2,  S R S-2,  C GI  e v al u ati o ns  a n d  A E  ass ess m e nts  at  W 0 1 2  a n d  W 0 2 6  will 
b e  c o m pl et e d    O N L Y  if  t h e  p ati e nt    w h o  h as  d efi niti v e l y dis c o nti n u e d  t h e  I M P  d uri n g  t h e 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 4 /2 9 6  
 
d o u bl e  bli n d p eri o d,  d o es  n ot r e q uir e  a n i m p ort a nt  m o difi c ati o n  o n  his/ h er  c urr e nt  b a c k gr o u n d 
m e di c al  c ar e (s e e s e cti o n  5. 6. 1. ). 
T h e  c o n d u ct i n t h e  c as e  of  d efi niti v e  dis c o nti n u ati o n  of I M P  d uri n g t h e  d o u bl e  bl i n d  p eri o d is 
s u m m ari z e d i n t h e T a bl e  ( 4. 2. 2)  2. 
T a bl e  (4. 2. 2 )  2 - C o n d u ct i n  c as e  of  d efi niti v e  dis c o nti n u ati o n  of I M P  d u ri n g t h e  d o u bl e  bli n d  p e ri o d  
wit h o ut st u d y  wit h d r a w al  
  
Visit  
( w h e n I M P is 
d efi nit el y 
dis c o nti n u e d)  
W D  
 
(t o  b e  p erf or m e d) 
W 0 1 2  
 
(t o  b e  p erf or m e d) 
W 0 2 6  
 
(t o  b e  p erf or m e d) 
W e n d  
 
(t o  b e  p erf or m e d) 
D 0 1 7  
x  
x  
x  
N A  
W 0 0 4  
x  
x  
x  
N A  
W 0 0 8  
x  
N A  
x  
N A  
W 0 1 2  
x  
N A  
x  
N A  
W 0 1 6  
x  
N A  
x  
N A  
W 0 2 0  
x  
N A  
N A  
X  
W 0 2 6  
x  
N A  
N A  
X  
N A:  N ot  a p pli c a bl e 
 
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 4 m L  
S e e  T a bl e  ( 4. 2. 2)  3 
T a bl e  (4. 2. 2 )  3  – V ol u m e ( m L)  of  bl o o d  c oll e ct e d  p e r  p a rti ci p a nt  d u ri n g t h e st u d y  
 
 
A S S E  
W 0 0 0 
+  4 8/ 7 2 h  
W 0 0 0 
+  D a y  1 0  
W 0 0 0 
+  D a y  1 7  
W 0 0 4 
 
W 0 1 2 
 
W 0 2 6 
 
H a e m at ol o g y  
1  
 
 
 
 
1  
1  
 
Bi o c h e mistr y  
4 
 
 
 
 
2. 5  
2. 5  
 
S er ol o g y  
 
 
 
 
 
 
 
P h ar m a c o ki n eti c  
 
 
 
 
 
1  
1  
 
N a/ K  m o nit ori n g  
1  
1  
1  
1  
1  
1  
1  
 
T O T A L  v ol u m e ( m L)  p e r  visit  
6  
1  
1  
1  
1  
5. 5  
5. 5  
 
 
 
 
 
W 0 2 6 
+  4 8/ 7 2 h  
W 0 2 6 
+  D a y  1 0  
W 0 2 6 
+  D a y  1 7  
W 0 3 0    
W 0 3 8 
 
W 0 5 2 
 
 
 
 
Bi o c h e mistr y  
 
 
 
 
2. 5  
2. 5  
 
 
H a e m at ol o g y  
 
 
 
 
1  
1  
 
 
N a/ K  m o nit ori n g  
1  
1  
1  
1  
1  
1  
 
 
T O T A L  v ol u m e ( m L) p e r  visit  
1  
1  
1  
1  
4. 5  
4. 5  
 
 
 
T O T A L   v ol u m e   ( m L)   p e r 
p a rti ci p a nt  
3 4 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 5 /2 9 6  
 
4. 3.  M e as u r es t o  mi ni mis e  bi as  
T h e f oll o wi n g  m e as ur es  h a v e  b e e n t a k e n t o  a v oi d  bi as es: 
- T his  is  a  r a n d o mis e d,   pl a c e b o -c o ntr oll e d  st u d y  c arri e d   o ut  i n   d o u bl e -bli n d  c o n diti o ns. 
A cti v e tr e at m e nt ( b u m et a ni d e)  a n d  pl a c e b o  or al f or m ul ati o ns  will  h a v e t h e  s a m e  a p p e ar a n c e 
a n d t h e s a m e t ast e.  
- A n I nt er a cti v e  R es p o ns e  S yst e m (I R S)  will  b e  us e d f or t h e tr e at m e nt  all o c ati o n:  b u m et a ni d e 
or  pl a c e b o  will  b e  assi g n e d  at i n cl usi o n ( W 0 0 0)  b y  b al a n c e d (r ati o  1: 1) r a n d o mis ati o n,  wit h 
str atifi c ati o n  o n t h e  c o u ntr y  a n d  o n t h e  p ati e nt  s e x.  T h e  str u ct ur e  r es p o nsi bl e  f or  d esi g ni n g 
a n d  c o nstr u cti n g t h e r a n d o mis ati o n list i n  bli n d  will  b e t h e C e nt er  of  E x c ell e n c e  M et h o d ol o g y 
a n d  V al oris ati o n  of  D at a of I. R.I. S. 
- I n v estig at ors   i n   c h ar g e   of   di a g n osis   s h o ul d   h a v e   a   d e e p   k n o wl e d g e   o n   t h e    A utis m 
Di a g n osti c    O bs er v ati o n   S c h e d ul e,   s e c o n d   e diti o n   ( A D O S -2)   a n d    A utis m    Di a g n osti c 
I nt er vi e w - R e vis e d ( A DI -R)  di a g n osti c t o ols.  
- Tr ai ni n g  s essi o ns  o n ass ess m e nt s c al es  will  b e  or g a ni z e d  for t h e i n v esti g at ors  pri or t o t h eir 
i n v ol v e m e nt  a n d t h eir  p arti ci p ati o n  will  b e  m a n d at or y. 
- I n  or d er t o  m ai nt ai n t h e  d o u bl e-bli n d  c o n diti o ns, t h e  m ai n  effi c a c y  crit eri o n  ( C A R S 2)  will 
b e  ass ess e d  b y  a n  i n d e p e n d e nt  r at er.   T his  r at er    will  n ot  b e  i n v ol v e d    wit h  a n y  as p e ct  of 
m e di c al  m a n a g e m e nt  of t h e  p ati e nt  a n d  will  n ot  h a v e  a c c es s t o  p ati e nt  d at a.  T h e i n d e p e n d e nt 
r at er  will  b e i nstr u ct e d  n ot t o  dis c uss  w h at  a d v ers e  e v e nt (if  a n y) t h e  p ati e nt is  e x p eri e n ci n g 
fr o m his/ h er    m e di c ati o n.  P ri or  t o  b ei n g  e x a mi n e d  b y t h e  i n d e p e n d e nt  r at er,  p ati e nts  a n d 
p ar e nt/l e g al r e pr es e nt ati v e(s)  or  c ar e gi v er ( w h e n  a p pli c a bl e)  will  b e i nstr u ct e d  n ot t o  dis c uss 
w h at   (if   a n y)   a d v ers e   e v e nt 
p ati e nt m a y   b e   e x p eri e n ci n g.    As   f ar   as   p ossi bl e   s a m e 
i n d e p e n d e nt r at er  will  ass ess  C A R S 2 f or  a  gi v e n  p ati e nt  all  al o n g t h e  st u d y (fr o m  W 0 0 0 till 
W 0 5 2  a n d  at l e ast till  W 0 2 6)  a n d,  w h e n  p ossi bl e,  all t h e  p ati e nts f or  a  gi v e n sit e. 
- T h e l a b or at or y  p ar a m et ers  will  b e  p erf or m e d  b y  a  c e ntr al l a b or at or y i n  or d er t o  c e ntr ali z e 
a n d  h ar m o nis e  t h e  d at a,   wit h  t h e  e x c e pti o n  of   N a + / K+  w hi c h  s h o ul d  b e    m o nit or e d al w a ys 
l o c all y w h e n t h e  p ati e nt is  u n d er tr e at m e nt t o  q ui c kl y m a n a g e  P ot assi u m  S u p pl e m e nt ati o n 
w h e n  n e e d e d. 
- I n  a d diti o n  t o  i m m e di at e  l o c al  s af et y r e a di n g f or  s af et y  r e as o ns,  a  c e ntr ali z e d  ass ess m e nt 
will  b e  p erf or m e d f or  e a c h  E C G ( c e ntr al r e a di n g r e p orts f or  E C G  o v err ul e l o c al r e a di n g f or 
i n cl usi o n/ e x cl usi o n/ wit h dr a w al  crit eri a). 
- S a m pl es f or  p h ar m a c o ki n eti c  a n al ysis  will  b e s e nt t o t h e  c e ntr al l a b or at or y  a n d tr a nsf err e d t o 
t h e  ass a y  c e ntr e C e p h a c f or  a n alysis  usi n g  a  v ali d at e d  ass a y    m et h o d.   T h e  ass a y  c e ntr e  i n 
c h ar g e  of  b u m et a ni d e  m e as ur e m e nt  will  b e  pr o vi d e d  wit h t h e tr e at m e nt  c o d es  s o t h at  o nl y 
s a m pl es  fr o m   p ati e nts   b ei n g  tr e at e d    wit h   b u m et a ni d e    will   b e   ass a y e d.    T h e  r es ults   of 
b u m et a ni d e  bl o o d  c o n c e ntr at i o n   will  b e  tr a nsf err e d  fr o m   C e p h a c  t o  t h e  P K  d e p art m e nt  of 
I. R.I. S.  b ef or e t h e  cli ni c al  d at a b as e [ ass o ci at e d t o  st atisti c al  a n al ysis ( A S S E  W 0 2 6  p eri o d)] 
is l o c k e d  a n d  bli n d is  br o k e n.  I n  or d er t o  pr e v e nt  a  bli n d  br e a k,  a d mi nistr ati o n  a n d  s a m pl e 
ti m es   will o nl y  b e  r e c or d e d  o n  t h e  r e q uisiti o n  f or m  a n d  n ot  o n  t h e  el e ctr o ni c   C as e  r e p ort 
F or m  ( e -C R F).   T h e  c e ntr al  l a b or at or y    will  c a pt ur e  d at a  of  t h e  r e q uisiti o n  f or m  a n d    will 
c al c ul at e t h e ti m e  aft er  d os e.  R e al ti m e  aft er  d os e  will  b e tr a nsf err e d t o C e p h a c f or  a nal ys es. 
T h e  P K  d e p art m e nt    will  r e c ei v e  o nl y  r e c o d e d  d at a  (r e c o d e d  p ati e nt  n u m b er).  P K  r es ults 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 6 /2 9 6  
 
fr o m C e p h a c a n d r e q uisiti o n f or m  d at a fr o m t h e  c e ntr al l a b or at or y  will  b e tr a nsf err e d t o t h e 
I. R.I. S.  D at a  M a n a g e m e nt  d e p art m e nt  o nl y  aft er  bli n d is  br o k e n. 
- T h e  m ai n  a n al ysis  of t h e  st u d y  c o n c er ns t h e  d o u bl e  bli n d  p eri o d fr o m  W 0 0 0 t o  W 0 2 6  visit. 
T h e  bli n d  will  b e  br o k e n  as  s o o n  as  all  effi c a c y  a n d  s af et y  d at a  c oll e ct e d  d uri n g t his  p eri o d 
ar e  a v ail a bl e  a n d t h e  m a n d at or y st e ps  d efi n e d i n s e cti o n 1 4. 2   “ D at a  M a n a g e m e nt ”  h a v e  b e e n 
p erf or m e d.   N e v ert h el ess,  alt h o u g h t h e  bli n d  will  b e  br o k e n  c e ntr all y b ef or e t h e  e n d  of t h e 
st u d y,   n eit h er   t h e   i n v esti g at ors,   n or   t h e   r at ers,   n or   t h e   p ati e nts /l e g al 
r e pr es e nt ati v es/ c ar e gi v ers,  n or t h e  p ar e nts,  n or t h e l o c al  pr oj e ct  m a n a g ers,  n or t h e  m o nit ors 
will  b e i nf or m e d  of t h e  st u d y tr e at m e nt t a k e n  d uri n g t h e  d o u bl e -bli n d tr e at m e nt  p eri o d  a n d 
of  t h e  st u d y  r es ults  of t h e  first  p eri o d  b ef or e  t h e  d at a b as e l o c k  f or  t h e  w h ol e  st u d y  p eri o d 
( W 0 0 0- W 0 5 2). 
4. 4.  St u d y  p r o d u cts  a n d  bli n di n g s yst e ms  
4. 4. 1.  P r o d u ct s  a d mi nist e r e d 
I n t h e fr a m e  of t his  pr ot o c ol, I M Ps  ar e  S  9 5 0 0 8 ( at t h e  d os e  of  0. 5  m g/ bi d)  a n d  pl a c e b o. 
T h e  I M P  dis p e ns e d   will  b e  a n  or al  f or m ul ati o n  (s ol uti o n  of  0. 5 m g/ m L  of  b u m et a ni d e  or  a 
pl a c e b o  s ol uti o n  wit h t h e  s a m e  a p p e ar a n c e  a n d t ast e).  T his  s ol uti o n  will  b e  a d mi nist er e d wit h 
a  1  m L  gr a d u at e d  pi p ett e.  
---------------------------------------------------------------------------------------------------------------  
All t h e  p ati e nts  will t a k e  o r all y t h e st u d y t r e at m e nt t wi c e  a  d a y:  
- 
i n t h e  m o r ni n g  at  w a k e u p  
- 
i n t h e  aft e r n o o n,  3  h o u rs  b efo r e  g oi n g t o  b e d  at t h e l at est.  
I n  a n y  c as e  t h e  st u d y  t r e at m e nt    m ust  b e  t a k e n  a r o u n d  1 5    mi n ut es  b ef o r e  a n y  f o o d 
i nt a k e. 
T h e   pi p ett e  c o nt ai ni n g  t h e  o r al  s ol uti o n  s h o ul d   b e  a d mi nist e r e d p r ef e r a bl y  i nt o  t h e 
m o ut h  of t h e  p ati e nt.  
---------------------------------------------------------------------------------------------------------------  
T h e  v ol u m e  of t h e  or al  s ol uti o n  will  b e  a d a pt e d  a c c or di n g t o  a  b o d y -w ei g ht  b asis f or  p ati e nts 
wit h  a  w ei g ht l o w er t h a n  2 5 K g ( S e e   A p p e n di x  1). 
 
A n  a d a pt ati o n  of t h e  o r al  s ol uti o n  v ol u m e  a c c o r di n g t o t h e  w ei g ht  of t h e  p ati e nts  will  b e 
p e rf o r m e d  d u ri n g t h e st u d y at  visits  W 0 1 2,  W 0 2 6  a n d  W 0 3 8. 
E a c h  tr e at m e nt  dis p e ns e d  t hr o u g h o ut  t h e  st u d y    will  b e  si mil ar  s o  t h at  it  is  n ot  p ossi bl e  t o 
diff er e nti at e t h e st u d y tr e at m e nts ( b u m et a ni d e  or  pl a c e b o).  
- F r o m s el e cti o n t o i n cl usi o n :  p ati e nts  will  n ot t a k e I M P. 
- D u ri n g t h e  d o u bl e -bli n d  p e ri o d  of  6  m o nt hs : fr o m  W 0 0 0 (i n cl usi o n) t o  W 0 2 6  visits 
T h e  first  st u d y tr e at m e nt i nt a k e  will  b e  o n t h e  d a y  of t h e i n cl usi o n  visit i n t h e  aft er n o o n,  3 
h o urs  b ef or e  g oi n g t o sl e e p  at  ni g ht  at t h e l at est. 
 P ati e nts  wit h  a  b o d y  w ei g ht  <  2 5  k g: 
P ati e nts  r a n d o mis e d  i n  t h e  b u m et a ni d e  ar m :  fr o m    W 0 0 0  t o    W 0 2 6  visits    will  t a k e 
0. 0 2  m g/ k g  of  b u m et a ni d e t wi c e  a  d a y  i. e.: 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 7 /2 9 6  
 
- 
v ol u m e  of  b u m et a ni d e  or al  s ol uti o n  ( m L)  =  0. 0 4  x  b o d y    w ei g ht  ( k g)  i n  t h e 
m or ni n g  at  w a k e - u p, 
- 
v ol u m e  of  b u m et a ni d e  or al  s ol uti o n  ( m L)  =  0. 0 4  x  b o d y    w ei g ht  ( k g)  i n  t h e 
aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est. 
P ati e nts r a n d o mis e d i n t h e  pl a c e b o  ar m: fr o m  W 0 0 0 t o  W 0 2 6  visits  will t a k e  pl a c e b o 
s ol uti o n t wi c e  a  d a y i. e.: 
- 
t h e  v ol u m e  of  pl a c e b o  or al  s ol uti o n  ( m L)  =  0. 0 4  x  b o d y    w ei g ht  ( k g)  i n  t h e 
m or ni n g  at  w a k e - u p, 
- 
t h e  v ol u m e  of  pl a c e b o  or al  s ol uti o n  ( m L)  =  0. 0 4  x  b o d y    w ei g ht  ( k g)  i n  t h e 
aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est. 
 P ati e nts  wit h  a  w ei g ht ≥  2 5 k g: 
P ati e nts  r a n d o mis e d  i n  t h e  b u m et a ni d e  ar m :  fr o m    W 0 0 0  t o    W 0 2 6  visits    will  t a k e 
0. 5 m g  of  b u m et a ni d e t wi c e  a  d a y i. e .: 
- 
1 ml  of  b u m et a ni d e  or al s ol uti o n i n t h e  m or ni n g at  w a k e- u p, 
- 
1 ml  of  b u m et a ni d e  or al  s ol uti o n i n t h e  aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d 
at t h e l at est . 
P ati e nts r a n d o mis e d i n t h e  pl a c e b o  ar m : fr o m  W 0 0 0 t o  W 0 2 6  visits  will t a k e  pl a c e b o 
s ol uti o n t wi c e  a  d a y i. e.: 
- 
1 ml  of  pl a c e b o  or al s ol uti o n i n t h e  m or ni n g  at  w a k e- u p, 
- 
1 ml  of  pl a c e b o  or al s ol uti o n i n t h e i n t h e  aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d 
at t h e l at est . 
 
- 
D u ri n g t h e  o p e n l a b el t r e at m e nt  p e ri o d  of  6  m o nt hs: fr o m  W 0 2 6 t o  W 0 5 2  visits 
All  p ati e nts  will  b e tr e at e d  b y  b u m et a ni d e. 
 F or  p ati e nts  wit h  a  w ei g ht  <  2 5  k g: 
Fr o m  W 0 2 6 t o  W 0 5 2  visits,  p ati e nts  will t a k e  0. 0 2  m g/ k g  of  b u m et a ni d e t wi c e  a  d a y: 
- 
t h e  v ol u m e  of  b u m et a ni d e  or al  s ol uti o n ( m L)  =  0. 0 4  x  b o d y  w ei g ht ( k g) i n t h e 
m or ni n g  at  w a k e - u p, 
- 
t h e  v ol u m e  of  b u m et a ni d e  or al  s ol uti o n ( m L)  =  0. 0 4  x  b o d y  w ei g ht ( k g) i n t h e 
aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d  at t h e l at est. 
 F or  p ati e nts  wit h  a  w ei g ht ≥  2 5 k g: 
Fr o m  W 0 2 6 t o  W 0 5 2  visits, t h e  p ati e nts  will t a k e  0. 5  m g  of  b u m et a ni d e t wi c e  a  d a y, 
i n t h e  m or ni n g at  w a k e- u p a n d i n t h e i n t h e  aft er n o o n  3  h o urs  b ef or e  g oi n g t o  b e d  at 
t h e l at est  i. e.: 
- 
1 ml  of  b u m et a ni d e  or al s ol u ti o n i n t h e  m or ni n g  at  w a k e- u p, 
- 
1 ml  of  b u m et a ni d e  or al  s ol uti o n  i n t h e  aft er n o o n,  3  h o urs  b ef or e  g oi n g t o  b e d 
at t h e l at est . 
- D u ri n g t h e  F oll o w -u p  p e ri o d, t h e p ati e nts  will  n ot  b e tr e at e d  wit h I M P.  
T a bl e  ( 4. 4. 1)  1pr o vi d es  a  d es cri pti o n  of t h e I M P( s). 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 8 /2 9 6  
 
T a bl e  (4. 4. 1 )  1  – D es c ri pti o n  of t h e I M Ps  
 
 
S 9 5 0 0 8  
Pl a c e b o  
P h ar m a c e uti c al f or m  
Or al s ol uti o n  
Or al s ol uti o n  
U nit  d os a g e  
0. 5  m g/ m L  
1  m L  c orr es p o n ds t o  0. 5  m g  of  b u m et a ni d e  
0 
A p p e ar a n c e,  c ol o ur  
C ol o url ess t o  p al e  y ell o w s ol uti o n 
C ol o url ess t o  p al e  y ell o w s ol uti o n  
C o m p ositi o n  
B u m et a ni d e  0. 5  m g  
S o di u m  m et h yl  p ar a h y dr o x y b e n z o at e  
S o di u m  pr o p yl  p ar a h y dr o x y b e n z o at e  
 
S o di u m  m et h yl  p ar a h y dr o x y b e n z o at e  
S o di u m  pr o p yl  p ar a h y dr o x y b e n z o at e  
 
  
T a bl e  ( 4. 4. 1)  2 a n d T a bl e  ( 4. 4. 1)  3 pr o vi d e  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 Ps. 
T a bl e  (4. 4. 1 )  2  – D es c ri pti o n  of  p a c k a gi n g  of t h e  d o u bl e -bli n d  I M P 
 
N u m b er  of  u nits  of t h e  p h ar m a c e uti c al f or m  p er 
pri m ar y  p a c k a gi n g  
6 0 m L  of  S 9 5 0 0 8  or  pl a c e b o  or al  s ol uti o n i n  a n  a m b er 
gl ass   b ottl e    wit h   p ol y pr o p yl e n e   /   l o w   d e nsit y 
p ol y et h yl e n e  c hil d -r esist a nt  a n d t a m p er-e vi d e nt  c a p 
N u m b er  of  pri m ar y  p a c k a gi n g  p er s e c o n d ar y  p a c k a gi n g  2   b ottl es   of   S 9 5 0 0 8   or   pl a c e b o   p er   b o x    wit h   2 
gr a d u at e d  pi p ett es  of  1 m L  
N u m b er  of  s e c o n d ar y  p a c k a gi n g  p er  p arti ci p a nt  a n d  p er 
tr e at m e nt  p eri o d 
1  b o x  gi v e n  p er  visit  wit h  all o c ati o n  b y t h e I R S  
  
T a bl e  (4. 4. 1 )  3  – D es c ri pti o n  of  p a c k a gi n g  of t h e  o p e n I M P  
 
N u m b er  of  u nits  of t h e  p h ar m a c e uti c al f or m  p er 
pri m ar y  p a c k a gi n g  
6 0 m L  of  S 9 5 0 0 8  or al s ol uti o n i n  a n  a m b er  gl ass  b ottl e 
wit h   p ol y pr o p yl e n e   /   l o w   d e nsit y   p ol y et h yl e n e 
c hil d-r esist a nt  a n d t a m p er-e vi d e nt  c a p 
N u m b er  of  pri m ar y  p a c k a gi n g  p er s e c o n d ar y  p a c k a gi n g  2  b ottl es  of  S 9 5 0 0 8  p er  b o x  wit h  2  gr a d u at e d  pi p ett es 
of  1 m L  
N u m b er  of  s e c o n d ar y  p a c k a gi n g  p er  p arti ci p a nt  a n d  p er 
tr e at m e nt  p eri o d 
1  b o x  gi v e n  p er  visit  wit h  all o c ati o n  b y t h e I R S  
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  e a c h  c o u ntr y i n v ol v e d 
i n t h e  st u d y,  as  w ell  as t h e r e c o m m e n d ati o ns i n  A p p e n di x 1 8  of t h e  E ur o p e a n  G ui d e t o  G o o d 
M a n uf a ct uri n g  Pr a cti c e.  
4. 4. 2.  I M P  m a n a g e m e nt 
I M P   will  b e  s u p pli e d  fr o m  t h e    m a n uf a ct uri n g  sit e / U nit é  d’ A p p ui   Cli ni q u e (l es   L a b or at ori es 
S er vi er  I n d ustri e,  9 0 5  r o ut e  d e   S ar a n,  4 5 2 2 0    GI D Y,   F R A N C E).   F or  s o m e  c o u ntri es,  a n 
i nt er m e di at e st or a g e  c h os e n  b y I. R.I. S  will  b e i n v ol v e d i n s u p pl yi n g t h e  c e ntr es. 
T h e I nt er a cti v e  R es p o ns e  S yst e m (I R S)  will tri g g er t h e first s hi p m e nts  of t h e I M Ps  a n d t h e r e -
s u p pli es. 
T h e  I M P    will  t h e n   b e   s e nt   b y  t h e    Cli ni c al   S u p pl y    U nit  ( C S U)   eit h er   dir e ctl y  t o  t h e 
i n v esti g ati o n al  c e nt ers  or t o i nt er m e di at e  st or a g e  c e nt ers  or t o l o c al  p h ar m a ci es  d ep e n di n g  o n 
t h e  g e o gr a p hi c  ar e as  a n d t h e l o c al r e g ul at or y r e q uir e m e nts. 
T h e I M Ps  will  b e s e nt t o t h e i n v esti g at or ( or t o t h e  p h ar m a cists)  w h o  will  a c k n o wl e d g e t h e r e c ei pt 
b y si g ni n g  a n d r et ur ni n g t h e s hi p pi n g f or m.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  3 9 /2 9 6  
 
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  ex 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 nstituti 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  a c c or di n g t o l o c al  or g a ni z ati o n . 
R e m ai ni n g  tr e at m e nts  ( us e d  a n d   u n us e d  I M Ps)    will  s u bs e q u e ntl y   b e  c oll e ct e d.    A n  I M P 
r e c o v er y a n d d estr u cti o n  f or m  ( R D F)     will  b e c o m pl et e d   b ef or e  s hi p m e nt  of I MP to  t h e 
I nt er m e di at e  st or a g e  sit e  p e n di n g  d estr u cti o n  or  dir e ctl y t o t h e d estr u cti o n  b o d y. D estr u cti o n 
of I M P m a y   b e p ossi bl e ( aft er  dr u g a c c o u nt a bilit y   a n d  s p o ns or a ut h ori z ati o n) 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 e r t he l ast  visit  of t he l ast tr e at e d p ati e nt. 
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,  if  a n y,  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 
i n v esti g at or’s  br o c h ur 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 ovi 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 Ps  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, 
a n d/ or if  a p pli c a bl e t o t h e  I R S.  T h e i n v esti g at or  will  n otif y t h e  m o nit o r  of  all  c o m pl ai nts  s et 
o ut  b y  a  p arti ci p a nt ( c h a n g e  of t ast e,  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 Ps  t o  t h e  s p o ns or  ( b at c h  r e 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 d i 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  i d e ntif y  t h e 
p arti ci p a nts i n  p oss essi o n  of t h e  I M P  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,  a n d   will 
c o nt a ct t h e m i m m e di at el y t o  arr a n g e r et ur n  a n d r e -s u p pl y  of I M P (if r e q uir e d). 
4. 4. 3.  M a n a g e m e nt  of  bli n di n g s yst e ms  
A  c e ntr alis e d I W R S  d e c o di n g s yst e m  will  b e  us e d i n t his st u d y. 
T h e  first  p art  of t h e  st u d y  (fr o m  W 0 0 0 t o  W 0 2 6) is  d o u bl e -bli n d e d i n  w hi c h t h e  p ati e nt, t h e 
i n v esti g at ors,   all   ot h er   sit e   p ers o n n el,   a n d  I. R.I. S.    will   n ot   h a v e   k n o wl e d g e   of   p ati e nt 
tr e at m e nt. 
T h e  bli n d  f or  a n y  st u d y  p arti ci p a nt  s h o ul d  o nl y  b e  br o k e n  b y  t h e  i n v esti g at or  or  a ut h oris e d 
p ers o n if it is  a bs ol ut el y  n e c ess ar y t o  as c ert ai n t h e t y p e  of tr e at m e nt  gi v e n.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 0 /2 9 6  
 
T h e  cir c u mst a n c es  u n d er  w hi c h t h e  c o d e  m a y  b e  br o k e n  ar e  a n y  s eri o us  a d v ers e  e v e nt  a n d/ or 
a n y  s e v er e  m e di c al  c o n diti o n  w h e r e t h e  k n o wl e d g e  of t h e  all o c at e d t r e at m e nt is  n e c ess a r y 
f o r t h e f oll o w  u p  of t h e  p ati e nt. 
All i nf or m ati o n  c o n c er ni n g  a d v ers e  dr u g r e a cti o ns,  dr u g i nt er a cti o ns  a n d t h e  pr o c e d ur e t o  b e 
f oll o w e d i n t h e  e v e nt  of  o v er d os e is  gi v e n i n t h e I n v esti g at or’s  Br o c h ur e f or  b u m et a ni d e  a n d 
t h e  S u m m ar y  of  Pr o d u ct  C h ar a ct eristi cs ( S m PC  B u m et a ni d e, N o v e m b er  2 0 1 7) ( pr o vi d e d  wit h 
t his  pr ot o c ol). 
T h e  pr o c e d ur e t o  b e  f oll o w e d  b y t h e i n v esti g at or  or  a ut h ori z e d  p ers o n is  d et ail e d i n t h e  I R S 
m a n u al. T h e  s yst e m is  a v ail a bl e  2 4  h o urs  a  d a y,  7  d a ys  a  w e e k. If I W R S is  n ot  a v ail a bl e, t h e 
h el p d es k  of t h e I W R S  will  b e  c o nt a ct e d  b y  p h o n e. 
A d diti o n all y,  d e c o di n g  will  b e  p ossi bl e  b y  c alli n g t h e  E m er g e n c y  P h o n e  N u m b er  of I. R.I. S. 
( + 3 3  1  5 5  7 2  6 0  0 0)  7/ 7 d  a n d  2 4/ 2 4 h). 
 
T h e  D M C  m a y  als o  as k f or s p e cifi c  c as es  as f ar  as t h e s af et y  of  p ati e nts is  c o n c er n e d. 
4. 5.  Dis c o nti n u ati o n  of t h e st u d y  
4. 5. 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 alt 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  s u c h  as    D M C  r e c o m m e n d ati o n  or  o c c urr e n c e  of  n e w  s ci e ntifi c 
/ cli ni c al  k n o wl e d g e t h at  m a y j e o p ar dis e t h e  p arti ci p a nts’ s af et y. 
Aft er  h a vi n g  i nf or m e d  t h e  c o or di n at or(s),  t h e  s p o ns or  or  t h e    D at a    M o nit ori n g    C o m mitt e e 
( D M C)   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 oriti es    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  c o or di n at or(s).  T h e I E Cs  a n d  C o m p et e nt  A ut h oriti e s  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   S e cti o n  4. 2. 2 sh 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 he  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    D at a 
M o nit ori n g    C o m mitt e e  ( D M C),  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 oriti es.  
4. 5. 2.  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. 6.  S o u r c e  d at a  
T h e f oll o wi n g  d at a  will  b e  c o nsi d er e d  as s o ur c e  d o c u m e nts: 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 1 /2 9 6  
 
- 
t h e  p ati e nt’s    m e di c al  fil e  [i n cl u di n g    E C G  tr a ci n g,  r e n al  ultr as o u n d  r e p ort,  cli ni c al 
l a b or at or y r e p orts,  a n d  all  ot h er  p ati e nt’s  e x a mi n ati ons r es ults],  
- 
Di a g n osti c   a n d   St atisti c al    M a n u al   of    M e nt al    Dis or d ers – Fift h    E diti o n  ( D S M -5)  
A p p e n di x  2,  
- 
A D O S 2  p a p er  m o d ul es 
- 
A DI - R  p a p er  m o d ul es 
- 
I nt ell e ct u al   C o effi ci e nt  (I Q) t o  d et er mi n e  t h e   C A R S 2  v ersi o n  t o  b e  us e d  f or  a  gi v e n 
p a ti e nt. If  a n I Q t est  h as  b e e n  p erf or m e d  wit hi n t h e  1 2  m o nt hs  pri or t o  s el e cti o n  a n d it 
is  d o c u m e nt e d i n t h e  sit e, it is  n ot  n e c ess ar y t o  r e p e at t his e v al u ati o n  at  A S S E  f or  a 
gi v e n  p ati e nt.  I n  t h e  fr a m e w or k  of  t his  st u d y  n o  s p e cifi c  r e c o m m e n d ati o n  r e g ar di n g  
t h e t y p e  of I Q t est is  gi v e n t o t h e  cli ni ci a n.  W h e n  n e e d e d,  e a c h  sit e  will  ass ess t h e I Q 
of  a  gi v e n  p ati e nt   wit h  t h e  I Q/ d e v el o p m e nt al  q u esti o ns  t ests   w hi c h  t h e y  us e  i n  t h eir 
us u al  m e di c al  pr a cti c e,  
- 
C hil d h o o d    A utis m    R ati n g   S c al e,   S e c o n d    E diti o n –   St a n d ar d T o ol   ( C A R S 2 -S T)  
( A p p e n di x  3)  or  C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d  E diti o n – Hi g h  f u n cti o ni n g 
cli ni c al t o ol ( C A R S 2 -H F)  (A p p e n di x  4 )  a n d  C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d 
E diti o n  –  Q u esti o n n air e f or  p ar e nts  a n d  c ar e gi v ers ( C A R S 2 -Q P C)  (A p p e n di x  5 ), 
- 
S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  E diti o n  ( S R S - 2) Pr e -s c h o ol  V ersi o n ( A p p e n di x 
6)  
- 
S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  E diti o n ( S R S - 2)   S c h o ol  V ersi o n ( A p p e n di x  7) 
- 
C- S S R S -C  ( A p p e n di x  8)  a n d  P A E R S  Cli ni ci a n f or m  ( A p p e n di x  9), 
- 
Vi n el a n d  A d a pt ati v e  B e h a vi o ur  S al es,  S e c o n d  E diti o n ( V A B S II)  ( A p p e n di x  1 0), 
- 
Cli ni c al  Gl o b al I m pr essi o n ( C GI)  (A p p e n di x  1 1 ), 
- 
A c c e pt a bilit y  a n d  p al a t abilit y  q u esti o n n air e  ( A p p e n di x  1 2), 
- 
P A E R S Y o ut h f or m  ( A p p e n di x  1 3)  a n d  P A E R S  P ar e nt f or m  ( A p p e n di x  1 4),  
- 
Q u alit y  of lif e  q u esti o n n air es:  P e ds Q L  q u esti o n n air e  ( A p p e n di x  1 5),  W H O Q O L-Br ef . 
( A p p e n di x 1 6 ),  E Q 5 D- 3 L  ( A p p e n di x  1 7), 
- 
P ati e nt’s  di ar y f or st u d y  m e di c ati o n i nt a k e.  
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. 
T h e  di a g n osti c  crit eri a  of  “ A utis m  S p e ctr u m    Dis o r d er ”  a c c or di n g  t o  t h e    D S M-5  s h o ul d  b e 
dir e ctl y r e c or d e d i n t h e  p a p er  c o p y  b y i n v esti g at or  a n d  s h o ul d  b e  k e pt i n t h e  p ati e nt’s  m e di c al 
fil e,  t h e n  t h e  s c or es    m ust  b e  e nt er e d  i n  t h e  e-C R F a n d    will  b e  c o nsi d er e d  as  s o ur c e  d at a. 
D S M - 5 s p e cifi ers  m ust  b e  d o c u m e nt e d f or  all st u d y s u bj e cts. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 2 /2 9 6  
 
T h e  A D O S - 2 ( L or d,  2 0 1 2) is  a  s e mi-str u ct ur e d,  st a n d ar di z e d  ass ess m e nt  of  c o m m u ni c ati o n, 
s o ci al i nt er a cti o n,  pl a y/i m a gi n ati v e  us e  of  m at eri als  a n d  r estri cti v e  a n d  r e p etiti v e  b e h a vi o urs 
f or i n di vi d u als w h o  h a v e  b e e n r ef err e d  b e c a us e  of  p ossi bl e  a utis m  s p e ctr u m  dis or d ers ( A S D). 
T h e   A D O S -2  is  a  r e visi o n  of  t h e   A D O S,   w hi c h  h a v e  b e e n  r ef err e d  t o  as  t h e  g ol d  st a n d ar d 
o bs er v ati o n al  ass ess m e nt f or  d i a g n osi n g  A S D. 
T h e    A D O S -2   c o nt ai ns  fi v e   ass ess m e nt    m o d ul es.    E a c h    m o d ul e   off ers  st a n d ar d   a cti viti es 
d esi g n e d  t o  eli cit  b e h a vi o urs  t h at  ar e  dir e ctl y  r el e v a nt  t o  t h e  di a g n osis  of   A S D  at  diff er e nt 
d e v el o p m e nt al  l e v els  a n d  c hr o n ol o gi c al  a g es.  I n  t h e  fr a m e w or k   of  t his  st u d y  o nl y  f o ur 
m o d ul es  will  b e  us e d: 
- 
T o d dl er  M o d ul e: f or  us e  wit h t o d dl ers  w h o  ar e  1 2 t o  3 0  m o nt hs  of  a g e  a n d  w h o  d o  n ot 
c o nsist e ntl y  us e  p hr as e s p e e c h  
- 
M o d ul e 1:  f or   us e    wit h   c hil dr e n    w h o   ar e   3 1    m o nt hs   a n d   ol d er   a n d    w h o   d o   n ot 
c o nsist e ntl y  us e  p hr as e s p e e c h  
- 
M o d ul e  2:  f or  us e  wit h  c hil dr e n  of  a n y  a g e  w h o  us e  p hr as e  s p e e c h,  b ut  w h o  ar e  n ot 
v er b all y fl u e nt 
- 
M o d ul e  3: f or  us e  wit h  v er b all y fl u e nt  c hil dr e n  a n d  y o u n g  a d ol es c e nts 
E a c h  A D O S -2  m o d ul e  h as its  o w n  Pr ot o c ol  b o o kl et,  w hi c h  pr o vi d es  or d er  a n d str u ct ur e t o t h e 
a d mi nistr ati o n,  c o di n g  a n d s c ori n g  of t h e  m o d ul e.  
T h e   A D O S -2  is  a  hi g hl y  str u ct ur e d  o bs er v ati o n al  ass ess m e nt  t h at  r e q uir es  s p e cifi c  tr ai ni n g. 
Pr of essi o n als  usi n g t h e  A D O S -2  s h o ul d  h a v e  pri or  e d u c ati o n, tr ai ni n g  a n d  e x p eri e n c e.  W h e n 
usi n g t h e  A D O S -2,  e x a mi n ers  n e e d t o  b e  s uffi ci e ntl y f a mili ar  wit h  t h e  a cti viti es  a n d  c o d es  s o 
t h at t h e y  c a n f o c us t h eir  att e nti o n  o n  o bs er v ati o n  of t h e i n di vi d u al  b ei n g  ass ess e d, r at h er t h a n 
o n  a d mi nistr ati o n  r ul es.    T his  r e q uir es  pr a cti s ce  i n  o bs er v ati o n  a n d  c o di n g,  as    w ell  as  i n 
a d mi nist eri n g t h e  a cti viti es.  
I n  t h e  fr am e w or k  of  t his  st u d y  t h e    A D O S - 2 s h o ul d  b e  c o m pl et e d  b y  a    M e di c al    D o ct or 
( c hil d & a d ol es c e nt  ps y c hi atrist,  n e ur o p a e di atrist) or  b y  a  ps y c h ol o gist f ulfilli n g t h e f oll o wi n g 
r e q uir e m e nts: 
o  e x p eri e n c e d  o n  A S D  a n d  c o- m or bi d  di a g n os es  
o  k n o wl e d g e  o n  c hil d  d e v el o p m e nt  
o  pl a yi n g  a  k e y r ol e  o n t h e  c urr e nt sit e  or g a ni z ati o n  
o  b ei n g i n v ol v e d i n t h e  di a g n osis  of  A S D  p ati e nts  o n  a r e g ul ar  b asis 
o  d e e pl y  k n o wl e d g e  of   A D O S -2  ( h a vi n g  p erf or m e d  a n  offi ci al  tr ai ni n g   will  b e 
pr ef er a bl e)  
o  us e d t o  p erf or m  A D O S- 2 ( or  at l e ast  A D O S - 1)  o n  a r e g ul ar  b asis 
T h e  p a p er    m o d ul es  of    A D O S -2  s h o ul d  b e  k e pt  i n  t h e  p ati e nts’    m e di c al  fil e,  t h e y    will  b e 
c o nsi d er e d  as  s o ur c e  d at a.   S o m e   d at a of  t h e    A D O S -2    will  b e  e nt er e d  i n  t h e  e -C R F.  If 
r etr os p e cti v e   A D O S-2  h as  b e e n  p erf or m e d   wit hi n  t h e  1 2   m o nt hs  pri or  t o s el e cti o n  a n d  it  is 
d o c u m e nt e d i n t h e  sit e, it is  n ot  n e c ess ar y t o r e p e at  A D O S -2  e v al u ati o n  at  A S S E f or  a  gi v e n 
p ati e nt.  
T h e  A DI -R is  a n  e xt e n d e d i nt er vi e w  d esi g n e d t o  eli cit  a  f ull  r a n g e  of i nf or m ati o n  n e e d e d t o 
pr o d u c e  a  di a g n osis  of  a utis m  a n d t o  assist  i n t h e  ass ess m e nt  of r el at e d  dis or d ers  h er e r ef err e d 
t o  as  A S D.  Us e  of t h e  A DI-R i n v ol v es  a n  e x p eri e n c e d  cli ni c al i nt er vi e w er  a n d  a n i nf or m a nt, 
s o m e o n e  w h o is f a mili ar  wit h t h e  c hil d’s  b e h a vi o ur  at t h at  a g e.  A d mi nistr ati o n  of t h e  A DI -R 
r e q uir es   us e   of  its I nt er vi e w   Pr ot o c ol    w hi c h  f o c us es   pri m aril y   o n  t h e  t hr e e   d o m ai ns   of 
f u n cti o ni n g: l a n g u a g e/ c o m m u ni c ati o n;  r e ci pr o c al  s o ci al i nt er a cti o ns  a n d  r estri ct e d,  r e p etiti v e 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 3 /2 9 6  
 
a n d  st er e ot y p e d  b e h a vi o urs  a n d i nt er est.  S c ori n g is t h e n  c o n d u ct e d  usi n g t h e  C o m pr e h e nsi v e 
Al g orit h m  F or m. 
I n  t h e  fr a m e w or k   of  t his   st u d y  t h e    A DI-R   c o ul d   b e   c o m pl et e d   b y   a    M e di c al    D o ct or 
( c hil d & a d ol es c e nt   ps y c hi atrist,   n e ur o p a e di atrist)   or   b y  a   ps y c h ol o gist  f ulfilli n g  t h e s a m e 
r e q uir e m e nts  as f or  A D O S- 2  a n d tr ai n e d i n t h e  us e  of (s e mi-) str u ct ur e d i nt er vi e ws. 
T h e  p a p er    m o d ul es  of    A DI -R  s h o ul d  b e  k e pt  i n  t h e  p ati e nts’    m e di c al  fil e,  t h e y    will  b e 
c o nsi d er e d  as  s o ur c e  d at a.  If  pr e vi o us  A DI -R is  a v ail a bl e  ( d o n e  aft er t h e  4 y o  of t h e  p ati e nt) 
a n d  d o c u m e nt e d i n t h e  c e nt er, it is  n o t  n e c ess ar y t o r e p e at t h e A DI -R e v al u ati o n  at  A S S E f or 
a  gi v e n  p ati e nt. 
T h e  p a p er  c o p y  of  t h e   C A R S 2 -S T  or   C A R S 2 -H F    m ust  b e  c o m pl et e d  b y  i n d e p e n d e nt  r at er 
wit h t h e  a d e q u at e  s c or es  a n d  r ati n g j ustifi c ati o ns.  T h e n  s c or es  will  b e  e nt er e d i n t h e  e -C R F. 
C o m pl et e d  p a p er  c o pi es  will  b e  us e d  as  a  s o ur c e  d o c u m e nt  a n d  s h o ul d  b e  k e pt i n t h e  p ati e nt’s 
m e di c al  fil e.   T h e  p a p er  f or m  of  t h e    C A R S 2 -Q P C    m ust  b e  c o m pl et e d  b y  t h e  p ar e nts/l e g al 
r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e), t h e y  will  b e  k e pt i n t h e  p ati e nts’  m e di c al  fil e 
a n d  will  b e  c o ns i d er e d  as s o ur c e  d at a. 
T h e   p a p er  f or m   of  t h e   S R S - 2 ( pr es c h o ol   or  s c h o ol) m ust   b e  c o m pl et e d   b y   p ar e nt/l e g al 
r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  a n d   will  b e  c o nsi d er e d  as  a  s o ur c e  d o c u m e nt. 
T h e  a ns w ers t o t h e  q u esti o n n air e  wi ll  b e tr a nsf err e d i n t he  e-C R F.  
T h e  p a p er  c o p y  of    C GI    m ust  b e  ass ess e d  b y  i n v esti g at or ,  s h o ul d  b e  k e pt  i n  t h e  p ati e nt’s 
m e di c al fil e  a n d  will  b e  c o nsi d er e d  as s o ur c e  d at a.   Th e n s c or es  will  b e r e c or d e d i n t h e  e -C R F . 
T h e    C -S S R S -C    will  h a v e  t o  b e  c o m pl et e d  b y  i n v esti g at or  o n  p a p er  c o pi es  a n d  t h e n  d at a 
e nt er e d i n t h e  e -C R F.  T h e  p a p er  c o pi es s h o ul d  b e  k e pt i n t h e  p ati e nt’s  m e di c al fil e  a n d  wil l  b e 
c o nsi d er e d  as s o ur c e  d at a.  
T h e  p a p ers  f or ms  of  t h e  P A E R S   will  b e  c o m pl et e d  b y  t h e  p ati e nt  ( w h e n  p ossi bl e)  a n d  t h e 
p ar e nt/l e g al  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  will  b e  c o nsi d er e d  as  s o ur c e  d at a. 
D at a  c oll e ct e d fr o m  P A E R S  Cli ni ci a n  p a p er f or m  b y t h e i n v esti g at or s h o ul d  b e r e p ort e d i n t h e 
e-C R F.   T h e  p a p er  c o p y  s h o ul d  b e  k e pt  i n  t h e  p ati e nt’s    m e di c al  fil e  a n d  b e  c o nsi d er e d  as 
s o ur c e d at a.  
T h e    V A B S  II    will  h a v e  t o  b e  c o m pl et e d  b y  i n v esti g at or  o n  p a p er  c o pi es.  T h e n  t h e  p a p er 
c o pi es    will  b e  s e nt   t o  I. R.I. S. T h e  d u pli c at e  p a p er  c o pi es  s h o ul d  b e  k e pt  i n  t h e  p ati e nt’s 
m e di c al fil e  a n d  will b e  c o nsi d er e d  as s o ur c e  d at a.  
T h e  a c c e pt a bilit y  a n d  p al at a bilit y  q u esti o n n air e    will  h a v e  t o  b e  c o m pl et e d  b y  t h e  p ati e nt 
( w h e n   p ossi bl e)   a n d   t h e   p ar e nts/l e g all y   a ut h ori z e d   r e pr es e nt ati v e   or   c ar e gi v er   ( w h e n 
a p pli c a bl e)  o n  p a p er  c o pi es.   T h e  d at a    will  b e  tr a nsf err e d  i n  t h e  e -C R F.   T h e  p a p er  c o pi es 
s h o ul d  b e  k ept i n t h e  p ati e nt’s  m e di c al fil e  a n d  will  b e  c o nsi d er e d  as s o ur c e  d at a.  
P e ds Q L,  W H O Q O L -Br ef a n d E Q 5 D- 3 L  q u esti o n n air es  will  b e  c o m pl et e d  b y  p ar e nts/l e g all y 
a ut h ori z e d  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  o n  p a p er  c o pi es.   T h e  d at a    will  b e 
tr a nsf erre d  i n  t h e  e -C R F.   T h e  p a p er  c o pi es  s h o ul d  b e  k e pt  i n  t h e  p ati e nt’s    m e di c al  fil e  a n d 
will  b e  c o nsi d er e d  as s o ur c e  d at a.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
 4 4 /2 9 6  
 
5.
S E L E C TI 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.  S el e cti o n  c rit e ri a  
5. 1. 1.  D e m o g r a p hi c  c h a r a ct e risti cs  
1.
M al e  or f e m al e
2.   
A g e d fr o m  2 t o l ess t h a n 7 y e ars  of  a g e
3.
O ut  p ati e nts ( p ati e nts li vi n g i n  a n i nstit uti o n  c a n  b e s el e ct e d)
4.
Li vi n g  wit h t h eir  p ar e nt/l e g al r e pr es e nt ati v e(s)  or  c ar e gi v er ( w h e n  a p pli c a bl e)
T h os e  p ati e nts  w h o  d o  n ot li v e  wit h t h eir  p ar e nt/l e g al r e pr es e nt ati v e(s) (i. e. i nt er n e es
p ati e nts li vi n g i n  a n i nstit uti o n,  p ati e nt li vi n g  wit h  ot h er f a mil y  m e m b er,  et c.)  c a n  b e 
s el e ct e d  i n  t h e  st u d y  if  t h er e is a n  i d e ntifi e d  c ar e gi v er   w h o  c o ul d  a c c o m p a n y  t h e 
p ati e nt  at  e a c h  visit t o t h e  R es e ar c h  C e nt er. I n  s u c h  a  c as e, t h e  c ar e gi v er  will  b e i n 
c h ar g e   t o   c o m pl et e   t h e   pl a n n e d   st u d y   e v al u ati o ns   i nt e n d e d   f or   t h e   p ati e nt 
p ar e nt/l e g al r e pr es e nt ati v e.  
P ati e nt  l e g al  r e pr es e nt ati v e : A n  i n di vi d u al  or  j uri di c al  or  ot h er  b o d y  a ut h oriz e d 
u n d er  a p pli c a bl e l a w t o  c o ns e nt,  o n  b e h alf  of  a  pr os p e cti v e  s u bj e ct, t o t h e  s u bj e ct's 
p arti ci p ati o n i n t h e  cli ni c al tri al.  
P ati e nt  c ar e gi v er : a  p ers o n    w h o  h as  a  d ail y  c o nt a ct  /  a  p ers o n al  c o nt a ct  f or  a 
mi ni m u m  of 5 0 %  of t h e ti m e  p er  w e e k  wit h t h e  p arti ci p a nt  a n d  w h o  k n o ws  hi m/ h er 
f or  at l e ast  o n e  y e ar.  T h e  c ar e gi v er  n e e ds t o  b e t h e s a m e  p ers o n t hr o u g h o ut t h e st u d y 
a n d  n e e ds t o  b e  willi n g t o  att e n d  st u d y  visits,  o v ers e e t h e  p ati e nt’s  c o m pli a n c e  a n d 
r e p ort  o n  p ati e nt’s st at us  as  w ell  as si g n  a n i nf or m e d  c o ns e nt. 
5. 1. 2.  M e di c al  a n d t h e r a p e uti c  c rit e ri a  
5.
Pri m ar y  di a g n osis  of  A utis m  S p e ctr u m  Dis or d er  as p er  D S M -5  crit eri a .
6.
Crit eri a    m et  f or    A S D  o n    A utis m    Di a g n osti c    O bs er v ati o n   S c h e d ul e  ( A D O S-2)  a n d
A utis m  Di a g n osti c I nt er vi e w  R e vis e d ( A DI -R).
-
If  r etr os p e cti v e    A D O S-2  h as  b e e n  ass ess e d    wit hi n  t h e  1 2    m o nt hs  pri or  t o
s el e cti o n  a n d  d o c u m e nt e d i n t h e  c e nt er, it is  n ot  n e c ess ar y t o  r e p e at  A D O S-2
e v al u ati o n  at  A S S E.
-
If  pr e vi o us    A DI-R  is  a v ail a bl e  ( ass ess e d  aft er  t h e  4 y o  of  t h e  p ati e nt)  a n d
d o c u m e nt e d i n t h e  c e nt er, it is  n ot  n e c ess ar y t o  r e p e at t h e  A DI - R e v al u ati o n  at
A S S E.
7.
C GI ( Cli ni c al  Gl o b al I m pr essi o n) -S e v erit y r ati n g s c or e   ≥  4.
8.
A bs e n c e  of  a n y  cli ni c all y  si g nifi c a nt  a b n or m alit y li k el y 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,  b as e d  o n t h e j u d g m e nt  of t h e i n v esti g at or.
5. 1. 3.  I nf o r m e d  co 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 of t h e pr ot o c ol. 
5. 2.  N o n -sel e cti o n   c rit e ri a 
5. 2. 1.  G e n e r al   c rit e ri a 
9.
A bs e n c e  of    writt e n  i nf or m e d  ass e nt  of  t h e  p ati e nt (f or  t h os e  p ati e nts  a bl e  t o  gi v e
ass e nt) .


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 5 /2 9 6  
 
1 0.  
A bs e n c e  of    writt e n  c o ns e nt  of  o n e  or  t h e  t w o  p ar e nts/l e g al  r e pr es e nt ati v e(s)    a n d 
c ar e gi v er ( w h e n  a p pli c a bl e)   a c c or d i n g t o l o c al r e g ul ati o n. 
1 1.  
P ar e nts/l e g al  r e pr es e nt ati v e(s)  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  u n a bl e t o  c o p e  wit h t h e 
st u d y  c o nstr ai nts. 
1 2.  
P ati e nts  n ot  a bl e  t o  f oll o w  t h e  st u d y  ass ess m e nts  d efi n e d  b y  t h e  pr ot o c ol,    wit h  t h e 
e x c e pti o n   of   s elf -r ati n g   q u esti o n n air es    whi c h    will   b e   ass ess e d   b y   p ar e nt/l e g al 
r e pr es e nt ati v e  or  c ar e gi v er( w h e n  a p pli c a bl e)  f or  t h os e  pati e nts  u n a bl e  t o  c o m pl et e 
t h e m. 
1 3.  
P ati e nts  p arti ci p ati n g  i n  a n ot h er  st u d y  at  t h e  s a m e  ti m e  or  h a vi n g  p arti ci p at e d  i n 
a n ot h er  st u d y  wit h  m e di ci n al  pr o d u ct  wit hi n t h e  3  m o nt hs  pri or t o i n cl usi o n  ( p ati e nts 
p arti ci p ati n g t o  d at a  c oll e cti o n r e gist er  c a n  b e s el e ct e d) . 
1 4.  
P ati e nts  h a vi n g  alr e a d y  b e e n tr e at e d  b y  b u m et a ni d e  f or  A S D  wit h o ut  cli ni c al  b e n efit 
a c c or di n g t o i n v esti g at or’s  o pi ni o n. 
1 5.  
( A) P ati e nts  h a vi n g  alr e a d y  b e e n i ncl u d e d i n t h e st u dy. 
1 6.  
P ati e nts   h a vi n g   a   first   d e gr e e   r el ati v e   li vi n g   i n   t h e   s a m e   h o m e   a n d   alr e a d y 
p arti ci p ati n g ( alr e a d y i n cl u d e d) i n t h e st u d y . 
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  
R el at e d t o t h e st u di e d  dis e as e  
1 7.  
K n o w n  m o n o g e ni c s y n dr o m e ( Fr a gil e  X,  R ett  S y n dr o m e, list  n ot  e x h a usti v e) 
R el at e d t o  ot h e r  ps y c hi at ri c  c o n diti o ns  
1 8.  
P ati e nts  h a vi n g  a  hi g h  s ui ci d al ris k  a c c or di n g t o t h e i n v esti g at or j u d g e m e nt  or  h a vi n g 
att e m pt e d  a  s ui ci d e i n t h e  pr e vi o us  3  m o nt hs  b as e d  o n i nf or m ati o n  o bt ai n e d  d uri n g t h e 
i n v esti g at or i nt ervi e w. 
1 9.  
A n y  ot h er  ass o ci at e d  ps y c hi atri c  c o n diti o n li k el y 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  a n d/ or r e q uiri n g t h e  us e  of  a f or bi d d e n  c o n c o mit a nt  ps y c h otr o pi c  m e di c ati o n. 
R el at e d t o  mis c ell a n e o us  c o n diti o ns  
2 0.  
C hr o ni c  h e p ati c  dis e as es  as  a ut oi m m u n e  h e p at itis;  c hr o ni c  h e p atitis  A,  B,  C;  cirr h osis; 
Wils o n’s  dis e as e;  pri m ar y  s cl er osi n g  c h ol a n gitis;  n o n -al c o h oli c  f att y  li v er  dis e as e; 
al p h a 1- a ntitr y psi n  d efi ci e n c y (list  n ot  e x h a usti v e). 
2 1.  
C hr o ni c r e n al  d ysf u n cti o n. 
2 2.  
C hr o ni c  c ar di a c  d ysf u n cti o n. 
2 3.  
K n o w n  h y p ers e nsiti vit y t o s ul p h o n a mi d e, t hi a zi d es  d eri v at e,  b u m et a ni d e  a n d/ or  a n y  of 
t h e  e x ci pi e nts. 
2 4.  
( B) A n y   ot h er  s e v er e,   u n c o ntr oll e d   or  c hr o ni c  c o n diti o n  i n c o m p ati bl e    wit h  st u d y 
tr e at m e nt  or li k el y 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 [e. g.  n e o pl asi c,  n e ur ol o gi c 
(su c h  as   u n c o ntr oll e d  e pil e ps y ; e pil e ps y  is  c o nsi d er e d  as   u n c o ntr oll e d  i n  c as e   of 
e pil e pti c  s ei z ur e  o c c urr e n c e  t h at  r e q uir es  a n y  a nti -e pil e pti c  tr e at m e nt    m o difi c ati o ns 
d uri n g  t h e  s cr e e ni n g  p eri o d,  p ul m o n ar y,    m et a b oli c  a n d  di g esti v e  dis or d ers,  k n o w n 
h y p er uri c e mi a), list  n ot  e x h a usti v e ]. 
R el at e d t o  p r e vi o us  a n d  c o n c o mit a nt t r e at m e nts  
2 5.  
( A) P ati e nt    wit h   u nst a bl e   ps y c h ot h er a p y,   b e h a vi o ur al,   c o g niti v e   or   c o g niti v e -
b e h a vi o ur al t h er a p y.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 6 /2 9 6  
 
“ u nst a bl e ”  m e a ns:  
•  st art e d  or st o p p e d  d uri n g s el e cti o n  p eri o d (i. e. i n t h e  m o nt h  pri or t o i n cl usi o n) 
•  pl a n n e d t o  b e  si g nifi c a ntl y  m o difi e d  d uri n g t h e  d o u bl e  bli n d tr e at m e nt  p eri o d 
(i n t er ms  of t y p e  of t h er a p y  or i n t er ms  of t h er a p y r h yt h m). 
- Pl a n n e d  cl assi c  i nt err u pti o ns  d uri n g  t h e  d o u bl e  bli n d  p eri o d  ( e g  s u m m er 
v a c ati o ns)  ar e  n ot  c o nsi d er e d  as  a n  e x cl usi o n  crit eri o n. 
- P ati e nts   h a vi n g   n o   ps y c h ot h er a p y,   b e h a vi o ur al,   c o g niti v e   or   c o g niti v e -
b e h a vi o ur al t h er a p y  ar e  n ot  c o nsi d er e d  as  a n  e x cl usi o n  crit eri o n  b ut t h es e 
p ati e nts   w o n’t  b e  a bl e  t o  st art  o n e  d uri n g  s el e cti o n  p eri o d  (i n  t h e    m o nt h 
pri or t o i n cl usi o n)  a n d  d uri n g t h e  d o u bl e  bli n d tr e at m e nt  p eri o d. 
Alt er n ati v e  i nt er v e nti o ns  ( h y p er b ari c  o x y g e n,  s e cr eti n,  c h el ati o n,  e x cl usi o n  di ets  n ot 
j ustifi e d  b y  m e di c al r e as o ns)  ar e f or bi d d e n  all  al o n g t h e st u d y. 
 
2 6.  
P ati e nt   r e q uiri n g   c o n c o mit a nt   ps y c h otr o pi c    m e di c ati o n   ( e x c e pti o ns   r e p ort e d ,   Se e 
S e cti o n   6. 3). 
2 7.  
( A) P ati e nts r e q uiri n g  c o ntr ai n di c at e d  m e di c ati o ns ( n o n -e x h a usti v e list):  
- C hr o ni c   a d mi nistr ati o n   of   n o n -st er oi d al   a nti-i nfl a m m at or y   dr u gs: ris k   of    N S AI Ds 
n e p hr ot o xi cit y i n cr e as e d  
- n o n- r e p ol arisi n g   n e ur o m us c ul ar   bl o c ki n g   a g e nts: h y p o k ali e mi a   i n cr e as e s t h e 
s e nsiti vit y t o  n o n-r e p ol arisi n g  n e ur o m us c ul ar  bl o c ki n g  a g e nts 
- Di git alis  gl y c osi d es: Ris k  of  di git alis t o xi cit y  s e c o n d ar y t o h y p o k ali e mi a ( a n d  p ossi bl y 
h y p o m a g n es e mi a)  
- A nti arr h yt h mi cs: Ris k  of  c ar di ot o xi cit y ( Q T  pr ol o n g ati o n, t ors a d es  d e  p oi nt e,  c ar di a c 
arr est) s e c o n d ar y t o h y p o k ali e mi a ( a n d  p ossi bl y  h y p o m a g n es e mi a)  
- A nti h y p ert e nsi v e   a g e nts   ( A n gi ot e nsi n   II   r e c e pt ors   a nt a g o nists,    A n gi ot e nsi n 
C o n v erti n g    E n z y m e   I n hi bit ors)      a n d    m e di ci n al   pr o d u cts   i n d u ci n g   p ost ur al 
h y p ot e nsi o n ( e. g. tri c y cli c  a nti d e pr ess a nts): I n cr e as e d ris k  of  p ost ur al  h y p ot e nsi o n 
- P ot assi u m  d e pl eti n g  a g e nts  s u c h  as  ot h er  di ur eti cs,  l a x ati v es  (r ef er  t o  s e cti o n 6. 3 
Pr e vi o us   a n d   c o n c o mit a nt   tr e at m e nts),   c hr o ni c   hi g h   d os es   of    mi n er al o   a n d 
gl u c o c orti c oi ds,  a m p h ot eri ci n  B: T h e  p ot assi u m  d e pl eti n g  eff e ct  of  b u m et a ni d e  m a y 
b e i n cr e as e d  b y  ot h er  p ot assi u m  d e pl eti n g  a g e nts ( ot h er  di ur eti cs, l a x ati v es …)  
- A mi n o gl y c osi d es: O t ot o xi c   a n d   n e p hr ot o xi c   eff e cts   of   a mi n o gl y c osi d es    m a y   b e 
i n cr e as e d  b y  c o n c o mit a nt  a d mi nistr ati o n  of  b u m et a ni d e 
- Pr o b e n e ci d: D e cr e as e d  b u m et a ni d e  eff e cti v e n ess.   Pr o b e n e ci d  h as  b e e n  d e m o nstr at e d 
t o  pr o d u c e  a  d os e r el at e d i n hi biti o n  of  b u m et a ni d e i n d u c e d  n atri ur esis 
- I o di n at e d  c o ntr ast  pr o d u cts: Ris k  of r e n al i ns uffi ci e n c y  d u e t o d e h y dr ati o n pr o v o k e d  b y 
a  c o n c o mit a nt  a d mi nistr ati o n  of  b u m et a ni d e 
- Lit hi u m: B u m et a ni d e  r e d u c es  lit hi u m  cl e ar a n c e  r es ulti n g  i n   hi g h  s er u m  l e v els   of 
lit hi u m 
- Hi g h  d os es  of  Vit a mi n  D ( >  1 0 0  0 0 0 I U/ 3  m o nt hs) r e c ei v e d  as  a  s u p pl e m e nt:  Ris k  of 
n e p hr o c al ci n osis 
- D es m o pr essi n: I n cr e as e d ris k  of s e v er e  h y p o n atr e mi a 
5. 3.  I n cl usi o n  c rit e ri a 
2 8.  
P ati e nt still f ulfilli n g  all t h e s el e cti o n  crit eri a  
2 9.  
C A R S 2 ( S T  or  H F) -  T ot al r a w s c or e  ≥  3 4 
3 0.  
S R S - 2 [ p ar e nt r e p ort- pr e -s c h o ol  or s c h o ol  a g e  v ersi o n]  ≥   6 6 T-S c or e  
Pr es c h o ol  v ersi o n:  A  T -s c or e  of  6 6  c orr es p o n ds t o  a  T ot al  R a w s c or e  of  8 3 t o  8 4 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 7 /2 9 6  
 
S c h o ol  v ersi o n:  A  T -s c or e  of  6 6  c orr es p o n ds t o  a  T ot al  R a w  s c or e  of 7 3 t o  7 5 f or 
m al e  p ati e nts  a n d  a  T ot al  R a w s c or e  of  6 6 t o  6 8 f or f e m al e  p ati e nts) 
3 1.  
P ati e nt   r es p e cti n g    w as h   o ut   p eri o ds   f or   f or bi d d e n  tr e at m e nts,   c o nsi d eri n g  t h es e 
tr e at m e nts  w er e  n ot  or  p o orl y  eff e cti v e  w h e n  a p pli c a bl e. 
5. 4.  E x cl usi o n  c rit e ri a  
3 2.  
A n y  n o n- s el e cti o n crit eri o n  w hi c h  c o ul d  h a v e  a p p e ar e d  aft er t h e s el e cti o n  visit  
3 3.  
P ati e nts  h a vi n g  alr e a d y  b e e n tr e at e d  b y  b u m et a ni d e f or  A S D ( wit h  cli ni c al  b e n efit)  b ut 
st o p p e d i n l ess t h a n  3  m o nt h  pri or t o i n cl usi o n 
3 4.  
 ( C) A n y  cli ni c all 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 cr e e ni n g  p eri o d  t h at  is 
li k el y t o i nt erf er e  wit h t h e st u d y  c o n d u ct  or  e v al u ati o n:  
- 
p h ysi c al  e x a mi n ati o n,  
- 
r e n al   ultr as o n o gr a p h y   es p e ci all y   u ni q u e   ki d n e y,   r e n al   h y p o pl asi a,   r e n al 
d ys pl asi a,  n e p hr o c al ci n osis,  r e n al  h y p er e c h o g e ni cit y, l oss  of c orti c o m e d ull ary 
diff er e nti ati o n (list  n ot  e x h a usti v e)  
- 
E C G l o n g  Q T i nt er v al ( Q T C F   ≥   4 6 0 ms), 
- 
l a b or at or y t est  es p e ci all y: 
 
h y p o k al a e mi a ( K < 3. 5 m E q/ L), 
 
 Cli ni c all y r el e v a nt  h y p er c al ci uri a.  
I n  c as e  of  a b n or m al  uri n ar y  c al ci u m/ cr e ati ni n e  r ati o  t h at    m a y  b e  t h e 
e x pr essi o n  of  a  cli ni c all y  r el e v a nt  h y p er c al ci uri a,  a  r et est  s h o ul d  b e 
p erf or m e d  as  s o o n  as  p ossi bl e.  B as e d  o n t h es e  r es ults, t h e i n v esti g at or 
s h o ul d  h a v e  a  dis c ussi o n  wit h t h e l o c al  p a e di atri c  n e p hr ol o gist i n  or d er 
t o  ass ess  w h et h er it  c orr es p o n ds t o t h e  pr es e n c e  of  a  cli ni c all y r el e v a nt 
h y p er c al ci uri a  a c c or di n g  t o  t h eir  cli ni c al  j u d g m e nt  ( b as e d  o n  br o a d er 
s o ur c es i n cl u di n g ris k f a ct ors,  m e di c al  hist or y,  cli ni c al  e x a mi n ati o n  a n d 
ot h er  bi ol o gi c al  p ar a m et ers).  
 
p ositi v e f or  h e p atitis  A  or  h e p atitis  B  s er ol o g y  n ot  e x pl ai n e d  b y 
a  v a c ci n ati o n  or  b y  a  p ast  r es ol v e d  i nf e cti o n,  p ositi v e  f or  h e p at itis   C 
s er ol o g y 
 
3 5.  
 ( A) Cli ni c all y  r el e v a nt   n e p hr o p at h y a c c or di n g  t o  i n v esti g at or’s  cli ni c al  j u d g m e nt 
( b as e d  o n  br o a d er  s o ur c es i n cl u di n g ris k f a ct ors,  m e di c al  hist or y,  cli ni c al  e x a mi n ati o n 
a n d  bi ol o gi c al  p ar a m et ers). 
3 6.  
e G F R  ≤  9 0    m L/ mi n/ 1. 7 3 m²  ( esti m at e d  gl o m e r ul ar  filtr ati o n  r at e, S c h w art z  f or m ul a 
2 0 0 9) . 
3 7.  
S e v er e el e ctr ol yt e  i m b al a n c e t h at  is  li k el y  t o  i nt erf er e    wit h t h e  st u d y  c o n d u ct  or 
e v al u ati o n. 
3 8.  
P ati e nt    w h o  h as  a  c urr e nt  s ui ci d e  ris k  a c c or di n g  t o  t h e  i n v esti g at or  ( b as e d  o n  t h e 
i nf or m ati o n   o bt ai n e d   d uri n g  t h e   e v al u ati o n   of  t h e    C-S S R S -C  ( C hil dr e n   v ersi o n) 
B as eli n e/ S cr e e ni n g:  “s ui ci d al i d e ati o n ”  p art, it e m  4  or  5 is  “ y es ” i n  “ 6  m o nt hs ”  p art) . 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 8 /2 9 6  
 
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 s el e cti o n/i n cl usi o n  visit  
T h e f oll o wi n g  a d diti o n a l  ass ess m e nts  will  b e r e c or d e d  at t h e s el e cti o n  visit: 
­ I nf or m ati o n  o n  pr e vi o us  or  c o n c o mit a nt  ps y c h ol o gi c al  t h er a p y  ( d et ails  o n  t h e 
t y p e  of t h er a p y,  n u m b er  of  h o urs  p er  w e e k), if  a n y. 
­ I nf or m ati o n  o n  pr e vi o us  ps y c h otr o pi c tr e at m e nt, if  a n y. 
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 d uri n g  t h e  d o u bl e  bli n d  tr e at m e nt  p eri o d  ( W 0 0 0 - W 0 2 6) 
d o es  n ot  m e a n t h at t h e  p arti ci p a nt  pr e m at ur el y st o ps t h e  p arti ci p ati o n i n t h e st u d y. 
I n t h e  c as e  of  p r e m at u r e  dis c o nti n u ati o n  of  I M P  d u ri n g t h e  d o u bl e  bli n d  p e ri o d  a n d, if 
t h e  p ati e nt d o es  n ot  r e q ui r e  a n  i m p o rt a nt  m o difi c ati o n  o n  his/ h e r  c u r r e nt  b a c k g r o u n d 
m e di c al  c a r e,  h e/s h e  will  b e i n vit e d t o  c o m pl et e C A R S 2,  S R S -2,  C GI e v al u ati o ns a n d  A E  
ass ess m e nt  f o r    W 0 1 2  (if   dis c o nti n u ati o n o c c u rs  p ri o r  t o W 0 1 2)   a n d    W 0 2 6   visit   as 
pl a n n e d i n t h e i n v esti g ati o n s c h e d ul e ( S e cti o n  4. 2. 2 ). 
I m p ort a nt  m o difi c ati o n  of  c urr e nt  m e di c al  c ar e is  d efi n e d  as f oll o ws:  
- 
N e wl y i niti at e d f or m al  b e h a vi o ur al,  c o g niti v e  or  c o g niti v e -b e h a vi o ur al t h er a p y 
- 
I n cr e as e/ d e cr e as e    w e e kl y   pr es cri b e d   h o urs   > 2 5 %   of   b e h a vi o ur al,   c o g niti v e   or 
c o g niti v e- b e h a vi o ur al t h er a p y 
- 
N e wl y i niti at e d  or r e c e ntl y  c h a n g e d  p h ar m a c ot h er a p y:  
o  I ntr o d u cti o n  of  a  ps y c h otr o pi c    m e di c ati o n  ( c o nsi d er e d  as  f or bi d d e n  i n  t h e 
st u d y, s e cti o n 6. 3)  
o  I ntr o d u cti o n  or  d os e i n cr e as e  of  a n  a nti ps y c h oti c 
o  I ntr o d u cti o n  or  d os e i n cr e as e  of  A D H D tr e at m e nt 
T h e f oll o wi n g  crit eri a  will l e a d t o  a  pr e m at ur e  dis c o nti n u ati o n  of I M P:  
- 
S er u m  p ot assi u m l e v els  <  3 m E q/ L   
- 
A n y s ui ci d e  att e m pt,  w h at e v er its s e v erit y  
- 
Hi g h  s ui ci d al ris k,  a c c or di n g t o i n v esti g at or's j u d g m e nt  or  wit h  a  s ui ci d al i d e ati o n  of  4  or 
5  o n  C- S S R S - C 
- 
N e p hr o c al ci n osis  o bs er v e d  at t h e r e n al  ultr as o u n d  
- 
O c c urr e n c e  of s ei z ur e(s)  
o  i n  a  p ati e nt  wit h o ut  a n y  m e di c al  hist or y of s ei z ur e.  
o  or i n  a  p ati e nt  wit h  a  m e di c al  hist or y  of  s ei z ur e if t his r e q uir e  a n y  m o difi c ati o n  of 
t h e  o n- g oi n g  a nti-e pil e pti c tr e at m e nt.  
- 
A n y s y m pt o ms  or si g ns  of  p ot e nti al r e n al f u n cti o n f ail ur e.  
- 
e G F R  ≤  8 0 m L/ mi n/ 1. 7 3 m² ( esti m at e d  gl o m er ul ar filtr ati o n r at e,  S c h w art z f or m ul a  2 0 0 9). 
- 
Cli ni c all y  r el e v a nt  n e p hr o p at h y  a c c or di n g  t o  i n v esti g at or’s  cli ni c al  j u d g m e nt  ( b as e d  o n 
br o a d er   s o ur c es   i n cl u di n g   ris k   f a ct ors,    m e di c al   hist or y ,   cli ni c al   e x a mi n ati o n a n d 
bi ol o gi c al  p ar a m et ers).  
- 
Cli ni c all y r el e v a nt  h y p er c al ci uri a.  
I n  c as e  of  a b n or m al  uri n ar y  c al ci u m/ cr e ati ni n e  r ati o  t h at    m a y  b e  t h e  e x pr essi o n  of  a 
cli ni c all y r el e v a nt  h y p er c al ci uri a,  a r et est s h o ul d b e  p erf or m e d  as  s o o n  as  p ossi bl e.  B as e d 
o n  t h es e  r es ults,  t h e  i n v esti g at or  s h o ul d   h a v e   a   dis c ussi o n    wit h  t h e  l o c al   p a e di atri c 
n e p hr ol o gist  i n  or d er  t o  ass ess    w h et h er  it  c orr es p o n ds  t o  t h e  pr es e n c e  of  a  cli ni c all y 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  4 9 /2 9 6  
 
r el e v a nt  h y p er c al ci uri a  a c c or di n g  t o  t h eir  cli ni c al  j u d g m e nt  ( b as e d  o n  br o a d er  s o ur c es 
i n cl u di n g   ris k f a ct ors,    m e di c al   hist or y,   cli ni c al   e x a mi n ati o n   a n d   ot h er   bi ol o gi c al 
p ar a m et ers).  
A d diti o n al  uri n ar y  r et est(s)  a n d  ot h er  a p pr o pri at e  e x a ms  s h o ul d  b e  p erf or m e d  if  t h e y 
j u d g e t h e m  as r el e v a nt f or t h e  p ati e nt’s s af et y.  
- 
A bs e n c e  of  2  c o ns e c uti v e  pl a n n e d  el e ctr ol yt es  m o nit ori n g  a n al ysis. 
- 
A bs e n c e  of  2  c o ns e c uti v e  pl a n n e d  uri n ar y  m o nit ori n g  a n al ysis. 
- 
O c c urr e n c e   of    Q T   pr ol o n g ati o n  ( Q T C F ≥   4 8 0 ms ),  t ors a d e   d e   p oi nt e   a n d   v e ntri c ul ar 
arr h yt h mi a .  E v e n if  a  1 2-l e a d  E C G r e a di n g  a n d i nt er pr et ati o n  will  b e  c e ntr alis e d,  a l o c al 
ass ess m e nt of E C G  e x a ms is n e c ess ar y  f or  d et e cti o n  of   m e di c al  ur g e n ci es  a n d   m ust  b e 
e n cl os e d  i n  t h e  s o ur c e  d at a.   C e ntr al  r e a di n g  r e p orts  f or   E C G  o v err ul e  l o c al  r e a di n g  f or 
i n cl usi o n/ e x cl usi o n/ wit h dr a w al  crit eri a. 
- 
O c c urr e n c e   of   a   n e w   ps y c hi atri c   or   ot h er    m e di c al   c o n diti o ns  l e a di n g  t o   n e c ess ar y 
a d mi nistr ati o n  of f or bi d d e n  c o n c o mit a nt  m e di c ati o n  or li k el y 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. 
- 
A n y   e v e nt   or   cir c u mst a n c es   r el at e d   or   u nr el at e d   t o   t h e   tr e at m e nt   j ustif yi n g   t h e 
dis c o nti n u ati o n  of tr e at m e nt i n t h e i n v esti g at or’s  o pi ni o n  (i n cl u di n g tr e at m e nt  f ail ur e i. e. 
l a c k  of  effi c a c y). 
- 
M aj or   d e vi ati o n  t o   pr 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,  e. g.  a n y    m e di c al  e v e nt  r e q uiri n g  a d mi nistr ati o n  of  a n 
u n a ut h oris e d  c o n c o mit a nt tr e at m e nt (s e e s e cti o n   6. 3). 
Ot h er  crit eri a  f or  pr e m at ur e  dis c o nti n u ati o n  of  I M P  a n d  f or  pr e m at ur e   wit h dr a w al  fr o m  t h e 
st u d y: 
- 
L ost -t o-f oll o w  u p. 
- 
A n y   n o n- m e di c al   cir c u mst a n c es   l e a di n g   t o   p ati e nt    wit h dr a w al   ( e. g.   ass e nt/ c o ns e nt 
wit h dr a w al) . 
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  t h e  effi c a c y  a n d  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.  
S p e ci al  c o n d u ct i n  c as e  of  g astr oi nt esti n al s y m pt o ms  a n d  w ei g h t l oss 
If t h e  p ati ent  e x p eri e n c es  di g esti v e  s y m pt o ms  ( ≥  3 li q ui d  st o ols  p er  d a y  a n d/ or  ≥  3  v o mits 
p er  d a y) or  di g esti v e  s y m pt o ms    wit h  a    w ei g ht  l oss  gr e at er  t h a n  5 %,  t h e  st u d y  tr e at m e nt 
s h o ul d  b e t e m p or aril y i nt err u pt e d.  S u c h  a n i nt err u pti o n  will l ast  4 8 h/ 7 2 h o urs. 
I n  s u c h  a  cas e  a  m o nit ori n g  of   K +,   N a +   m ust  b e  d o n e l o c all y pri or t o  st u d y  tr e at m e nt  r e -
i ntr o d u cti o n.  F urt h er  el e ctr ol yt es  f oll o w  u p    will  b e l o c all y d o n e  a c c or di n g  t o  t h e  cli ni c al 
o pi ni o n  of t h e  m e di c al  d o ct or. 
If t h es e s y m pt o ms  ar e  p ersist e nt f oll o wi n g  7 2 h o urs, t h e  st u d y tr e at m e nt s h o ul d b e d efi nit el y 
wit h dr a w n. 
5. 6. 2.  P r o c e d u r e  
T h e  i n v esti g at or    m ust   n otif y  t h e  s p o ns or   of  st u d y    wit h dr a w als   b y   e nt eri n g   d at a   of  t h e 
wit h dr a w al  visit i n t h e  e -C R F.  T h e i n v esti g at or  m ust  r e c or d t h e r e as o n  a n d t h e  e x a ct  d at e  of 
t h e  pr e m at ur e  dis co nti n u ati o n fr o m t h e  st u d y i n t h e  e -C R F. If  m or e t h a n  o n e r e as o n is  gi v e n, 
t h e i n v esti g at or  m ust i n di c at e t h e  m ai n r e as o n. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 0 /2 9 6  
 
I n  c as e  of  pr e m at ur e  dis c o nti n u ati o n fr o m t h e st u d y  a  wit h dr a w al  visit  will  b e  d o n e  as s o o n  as 
p ossi bl e  aft er t h e l ast  d os e i nt a k e  a n d  wit hi n  o n e  w e e k  at t h e l at est  
I n  t h e   c as e   of   pr e m at ur e    wit h dr a w al   of  I M P   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  e-C R F 
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/s 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 / tr e at m e nt 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. 
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  a n d  his/ h er  p ar e nts/l e g al r e pr es e nt ati v e(s)  a n d  c ar e gi v er ( w h e n  a p pli c a bl e)  or 
a  p ers o n  ar o u n d t h e m  ( 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 ci 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. 
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 d mi nist e r e d 
D uri n g t h e r u n i n  a n d t h e f oll o w  u p  p eri o ds  p ati e nts  will  n ot r e c ei v e I M P. 
D u ri n g  t h e  t r e at m e nt  p e ri o d  (f r o m  W 0 0 0  t o  W 0 5 2),  t h e  p ati e nt  will  t a k e  o r all y  t wi c e  a 
d a y: 
- i n t h e  m o r ni n g  at  w a k e-u p  
- i n t h e  aft e r n o o n,  3  h o u rs  b ef o r e  g oi ng t o  b e d  at  ni g ht  at t h e l at est  
t h e f oll o wi n g  v ol u m e  of t h e  or al s ol uti o n: 
F or  p ati e nts  wit h  a  w ei g ht  <  2 5 k g: 
- 
T h e  v ol u m e ( m L)  =  0. 0 4  x  b o d y  w ei g ht ( k g) t wi c e  p er  d a y  fr o m i n cl usi o n t o  W 0 5 2 
F or  p ati e nts  wit h  a  w ei g ht   ≥  2 5 k g: 
- 
1  ml t wi c e  p er  d a y fr o m i n cl usi o n t o  W 0 5 2 
T h e st u d y tr e at m e nt s h o ul d  b e t a k e n  at l e ast  1 5  mi n ut es  b ef or e  a n y f o o d i nt a k e. 
T h e  first  st u d y  tr e at m e nt  i nt a k e   will  t a k e  pl a c e  i n  t h e  aft er n o o n  at  t h e  l at est  3  h o urs  b ef or e 
g oi n g t o  b e d  at  ni g ht  of t h e i n cl usi o n  visit  d a y.  
T h e l ast I M P i nt a k e  will t a k e  pl a c e i n t h e  m or ni n g  of t h e  d a y  of t h e s c h e d ul e d  visit. 
T h e  d es cri pti o n  of t h e I M P is  d et ail e d i n  S e cti o n   4. 4. 1. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 1 /2 9 6  
 
6. 2.  I M Ps  dis p e nsi n g 
D o u bl e  bli n d t r e at m e nt  p e ri o d: IM P  b o x  dis p e nsi n g  will  o c c ur  at  W 0 0 0 ( 1  Kit  A),  W 0 0 4 ( 1 
Kit  A),  W 0 0 8 ( 1  Kit  A),  W 0 1 2 ( 1  Kit  A),  W 0 1 6 ( 1  Kit  A),  W 0 2 0 ( 1  Kit  A).  T h e  kit  n u m b er  of 
Kit  A  will st art  b y 2 0 X X X X a n d t h e l a b el  will  b e or a n g e . 
O p e n l a b el s af et y  e xt e nsi o n  p e ri o d:  I M P  b o x  dis p e nsi ng  will  o c c ur  at W 0 2 6    ( 1    Kit    B), 
W 0 3 0 ( 1  Kit  B),  W 0 3 4 ( 1  Kit  B),  W 0 3 8 ( 1  Kit  B),  W 0 4 2 ( 1  Kit  B),  W 0 4 6 ( 1  Kit  B).  T h e  kit 
n u m b er  of  Kit  B  will st art  b y 2 2 X X X X a n d t h e l a b el  will  b e bl u e . 
T h e  Kit  n u m b er(s)  will  b e  gi v e n t o  p ati e nt  a c c or di n g t o  n u m b er(s)  all o c at e d  b y  I R S  ( pl e as e 
s e e  d et ails i n I R S  m a n u al). 
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 Ps  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  
T his  is  a  p a e di atri c  st u d y,  tr e at m e nts  a d mi nistr at e d  t o  t h e  p ati e nts  s h o ul d  b e  i n -l a b el  or 
r e c o m m e n d e d  as  p er l o c al  c ar e  g ui d eli n es. 
F or bi d d e n  a n d  c o ntr ai n di c at e d  m e di c ati o ns 
C o ntr ai n di c at e d   m e di c ati o ns  ( d u e  t o  s af et y  r e as o ns)   w er e  list e d  i n  n o n-s el e cti o n  crit eri a 2 7. 
W h e n  a p pli c a bl e,  c o nsi d eri n g  t h es e  tr e at m e nts    m a y  n ot  b e  or  p o orl y  b e  eff e cti v e  f or  t h e 
p ati e nt, t h e  w as h o ut  p eri o d  b ef or e i n cl usi o n s h o ul d  b e  of 3  w e e ks . 
Ps y c h otr o pi c tr e at m e nts  a n d tr e at m e nts li k el y t o i nt erf er e  wit h t h e C N S f u n cti o n  m a y  b y t h eir 
a cti vit y i nt erf er e  wit h t h e st u d y  e v al u ati o ns, t h es e  ar e f or bi d d e n.  
W h e n  a p pli c a bl e,  c o nsi d eri n g  t h es e  tr e at m e nts    m a y  n ot  b e  or  p o orl y  b e  eff e cti v e  f or  t h e 
p ati e nt, t h e  w as h o ut  p eri o d  b ef or e i n cl usi o n is t h e f oll o wi n g: 
- 
B e n z o di a z e pi n es  wit h  m e di u m  or s h ort  h alf- lif e: 3  w e e ks  
- 
B e n z o di a z e pi n es  wit h l o n g  h alf- lif e: 4  w e e ks  
- 
A nti ps y c h oti cs: 4  w e e ks  
- 
Sti m ul a nts: 3  w e e ks  
E x c e pti o n: M et h yl p h e ni d at e,  At o m o x eti n e,  G u a nf a ci n e  st a biliz e d f or  at l e ast  4  w e e ks  pri or t o t h e 
i n cl usi o n  a n d  n ot  pl a n n e d t o  b e  m o difi e d  or st o p p e d  d uri n g t h e  W 0 0 0-W 0 2 6  p eri o d . 
Tr e at m e nts  wit h s p e ci al  w ar ni n g  a n d  pr e c a uti o n  of  us e  
- 
N S AI Ds  c o ul d  b e  e x c e pti o n all y  a d mi nist er e d  at t h e l o w est  p ossi bl e  d os e  a n d  d uri n g  a 
p eri o d  n ot  e x c e e di n g  2  c o ns e c uti v e  d a ys  f or  t h e  p ati e nts    w h o  d o  n ot  r es p o n d  t o 
p ar a c et a m ol. D uri n g t his  p eri o d t h e st u d y tr e at m e nt s h o ul d  b e t e m p or aril y i nt err u pt e d. 
- 
Vit a mi n  D s u p pl e m e nt ati o n ,  w h e n r e q uir e d, s h o ul d  n ot  e x c e e d  1 0 0  0 0 0 I U/ 3  m o nt hs. 
- 
B e n efit ris k  ass ess m e nt  s h o ul d  b e t a k e n i nt o  a c c o u nt  b ef or e  pr es cri bi n g  a  n e p hr ot o xi c 
a n d/ or  ot ot o xi c  dr u g  c o n c o mit a ntl y t o  b u m et a ni d e.  
- 
L a x ati v es  ar e f or bi d d e n  e x c e pt  os m oti c l a x ati v es  s u c h  as  P ol y et h yl e n e  gl y c ol. D os a g e 
s h o ul d  b e i n  a c c or d a n c e  wit h t h e  S m P c  of t h e  dr u g.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 2 /2 9 6  
 
Aft er  h a vi n g  r ul e d  o ut  a  c o nsti p ati o n  c a us e d  b y  or g a ni c  c o n diti o ns,  e d u c ati o n  s h o ul d 
b e t h e first st e p i n tr e at m e nt ( di et ar y  c h a n g es: i n cr e as e d i nt a k e  of fl ui ds  a n d fi b er …). 
A ut h ori z e d  m e di c ati o ns  
T o  r eli e v e   p ai n   a n d  f e v er   d uri n g  t h e  st u d y   P A R A C E T A M O L  s h o ul d   b e   pr ef err e d  (s e e 
N S AI Ds s p e ci al  w ar ni n g).  
M el at o ni n e is  a ut h oris e d f or sl e e p  ai d.  
 
L i g ht  g as  s e d ati o n  us e d  t o  p erf or m  t h e  r e q uir e d  st u d y  s af et y  e x a ms  is  n ot  c o nsi d er e d  as 
f or bi d d e n  c o n c o mit a nt tr e at m e nt. 
6. 4.  I M P  c o m pli a n c e 
St u d y    m e di c ati o n  t a k e n  b y  e a c h  p arti ci p a nt    m ust  b e  r e c or d e d  t o g et h er    wit h  c orr es p o n di n g 
ti m es i n t h e  p ati e nt’s  di ar y f or st u d y  m e di c ati o n i nt a k e  pr o vi d e d  b y t h e i n v esti g at or. 
T h e  n u m b er  of  or al s ol uti o n f or m ul ati o n  d os es t a k e n  b y t h e  p arti ci p a nt is 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 ( e- crf) 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  e q ui v al e nt  d o c u m e nt. 
If t h e  p arti ci p a nt,  p ar e nts/l e g al r e pr es e nt ati v e(s)  or  c ar e gi v er ( w h e n  a p pli c a bl e)  di d  n ot  bri n g 
b a c k  t h e  p ati e nt’s  di ar y  f or  st u d y    m e di c ati o n  a n d/ or  t h e  li q ui d  b ottl e/s  dis p e ns e d  at  t h e 
pr e vi o us   visit,  t h e  i n v esti g at or    m ust   esti m at e  t h e   n u m b er   of   I M P   d os es  t a k e n   b y  t h e 
p arti ci p a nt   si n c e   t h e   pr e vi o us   visit,   b y   q u esti o ni n g   hi m/ h er   or   his/ h er   p ar e nts/l e g al 
r e pr es e nt ati v e(s)  or  c ar e gi v er ( w h e n  a p pli c a bl e). 
T h e  c o m p li 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  a n d fr o m t h e  q u esti o ni n g 
of t h e  p arti ci p a nt  or  p ar e nts/l e g al r e pr es e nt ati v e(s)  or  c ar e gi v er ( w h e n  a p pli c a bl e).  
6. 5.  Dis c o nti n u ati o n  of t h e I M P  
I n  c as e  of  dis c o nti n u ati o n  of  t h e  I M P  b ef or e    W 5 2,  t h e  p arti ci pa 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.   
S p e cifi c r ul es  m a y  b e f oll o w e d i n s o m e  c o u ntri es  a c c or di n g t o l o c al r e g ul ati o n. 
7.  A S S E S S M E N T  O F  E F FI C A C Y  
7. 1.  Effi c a c y  m e as u r e m e nts   
Effi c a c 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. 2. 2)  1. 
T h e  effi c a c y  ass ess m e nts  ar e t h e f oll o wi n g:  
- C hil d h o o d  A utis m  R ati n gs  S c al e,  S e c o n d  e diti o n ( C A R S 2) 
- Cli ni c al  Gl o b al I m pr essi o n ( C GI)  
- S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  e diti o n ( S R S - 2) 
- Vi n el a n d  A d a pt ati v e  B e h a vi o ur  S al es,  S e c o n d  E diti o n ( V A B S II) 
7. 2.  M et h o ds  a n d  m e as u r e m e nt ti m es  
T h e C hil d h o o d    A utis m    R ati n gs  S c al e,  S e c o n d  e diti o n  ( C A R S 2) ( S c h o pl er,  2 0 1 0) is  t h e 
m ai n  effi c a c y  crit eri o n.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 3 /2 9 6  
 
I n  or d er  t o    m ai nt ai n  t h e  d o u bl e  bli n d  c o n diti o ns,  t h e    C A R S 2  s h o ul d  b e  c o m pl et e d  by  a n 
i n d e p e n d e nt  r at er,  e. g.  a n i n di vi d u al q u alifi e d  t o  p erf or m   C A R S 2  e v al u ati o n w h o  is    m as k e d 
fr o m  a s u bj e ct's  d at a i n  or d er t o  mi ni mi z e  bi as. 
I n t h e fr a m e w or k  of t his st u d y t h e i n d e p e n d e nt r at er  c o ul d  b e: 
- a  m e di c al  d o ct or:  c hil d  &  a d ol es c e nt  ps y c hi atrist  or  n e ur o -p a e di atri ci a n  
-  a  cli ni c al  ps y c h ol o gist /  h e alt h  pr of essi o n al  wit h: 
o  a  d et ail e d  k n o wl e d g e  a n d  e x p eri e n c e  of  A S D  a n d  c hil d  d e v el o p m e nt 
o  w h o  pl a ys  a  k e y r ol e i n t h e  c urr e nt sit e  or g a ni z ati o n  of t h e t e a m 
o  a n d is i n v ol v e d i n t h e  di a g n osis  of  A S D  p ati e nts  o n  a r e g ul ar  b asis 
o  a n d  w h o  h as  a  d et ail e d  k n o wl e d g e  a n d  e x p eri e n c e  of  A D O S- 2 ( c ertifi c ati o n  pr ef er a bl e)  
o  w h o  p erf or ms  A D O S- 2 ( or  at l e ast  A D O S - 1)  o n  a r e g ul ar  b asis 
A    m a n d at or y  tr ai ni n g  f or    C A R S 2    will   b e   p erf or m e d  f or  i n d e p e n d e nt  r at ers   b ef or e  t h eir 
i n v ol v e m e nt i n t h e  st u d y.  O nl y  r at ers  w h o  h a v e  s u c c essf ull y  c o m pl et e d t his tr ai ni n g  will  b e 
i n v ol v e d i n t h e tri al.  T h e  ai m is t o  pr o vi d e  a n  h o m o g e n e o us tr ai ni n g  a n d  c o m m o n r ati n g r ul es 
o n t his t o ol i n  or d er t o  mi ni mi z e  bi as r el at e d t o i n di vi d u al r ati n g  v ari a bilit y.  
T h e  C A R S 2 is  a  1 5 it e m r at e d i nstr u m e nt t h at  will  b e  ass ess e d:  
- At I n cl usi o n  
-  D uri n g t h e  D o u bl e  Bli n d tr e at m e nt  p eri o d  at:  W 0 0 4,  W 0 1 2,  W 0 2 6  visits 
-  D uri n g t h e  O p e n  L a b el tr e at m e nt  p eri o d  at:  W 0 3 8,  W 0 5 2  visits 
- At    W e n d   visit   or at  t h e    wit h dr a w al   visit  i n  c as e   of   pr e m at ur e    wit h dr a w al  aft er   visit 
W 0 0 0 + D a y 1 0 
As f ar  as  p ossi bl e  s a m e i n d e p e n d e nt r at er  will  ass ess  C A R S 2 f or  a  gi v e n  p ati e nt  all  al o n g t h e 
st u d y (fr o m  W 0 0 0 till  W 0 5 2  a n d  at l e ast till  W 0 2 6)  a n d,  w h e n  p ossi bl e,  all t h e  p ati e nts f or  a 
gi v e n sit e. 
T h e  C A R S 2 i n cl u d es t hr e e f or ms: 
- C hil d h o o d    A utis m    R ati n g   S c al e,   S e c o n d    E diti o n -St a n d ar d    V ersi o n   ( C A R S 2 -S T)  
w hi c h  s h o ul d  b e  us e d f or  a ss essi n g  p ati e nts  wit h  o v er all I Qs  ≤  7 9,  w h o  h a v e  n ot a bl y 
i m p air e d  c o m m u ni c ati o n,  or  w h o  ar e  y o u n g er t h a n  6  y e ars  of  a g e r e gar dl ess  of t h eir 
esti m at e d I Q.  
- C hil d h o o d  A utis m  R ati n g  S c al e,  S e c o n d  E diti o n -Hi g h  F u n cti o ni n g  V ersi o n  ( C A R S 2 -
H F)  is  us e d t o  ass ess  pati e nts  wit h  esti m at e d  o v er all  I Qs  ≥  8 0,  w h o  h a v e  r el ati v el y 
g o o d  v er b al s kills  a n d  w h o  ar e  a g e d  6  or  ol d er. 
- Q u esti o n n air e  f or  P ar e nts  or   C ar e gi v ers  ( C A R S 2 -Q P C)  is  a n  u ns c or e d  q u esti o n n air e 
pr o vi d e d  f or  a c q uiri n g i nf or m ati o n  fr o m  p ar e nts/l e g al  r e pr es e nt ati v e(s)  or  c ar e gi v er 
( w h e n   a p pli c a bl e)   f or   s u bs e q u e nt   us e   b y   pr of essi o n als    m a ki n g    C A R S 2-S T   or 
C A R S 2 -H F r ati n gs.  
T h e  c h oi c e  of t h e  C A R S 2 f or m (st a n d ar d  v ersi o n  or  hi g h f u n cti o ni n g  v ersi o n)  a p pli c a bl e f or  a 
gi v e n  p ati e nt  will  b e  b as e d  o n: 
- t h e  a g e  of t h e  p atie nt 
- t h e I Q  of t h e  p ati e nt: If  a I Q  h as  b e e n  p erf or m e d  wit hi n t h e  1 2  m o nt hs  pri or t o s el e cti o n, it is 
n ot  n e c ess ar y  t o r e p e at t h e I Q t est  at  A S S E. 
I n    m a ki n g  r ati n gs,  i n d e p e n d e nt  r at er  s h o ul d  c o m p ar e  t h e  p ati e nt’s  b e h a vi o ur   wit h  t h at  of  a 
t y pi c all y  d e v el o pi n g i n di vi d u al  of t h e  s a m e  a g e.  W h e n  b e h a vi o urs  ar e  o bs er v e d t h at  ar e  n ot 
t y pi c al  f or  a n  i n di vi d u al   of  t h e  s a m e  a g e,  t h e n  t h e   p e c uli arit y,  fr e q u e n c y,  i nt e nsit y  a n d 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 4 /2 9 6  
 
d ur ati o n  of  t h es e  b e h a vi o urs  s h o ul d  b e  c o nsi d er e d.    All  b e h a vi o ur  s h o ul d  b e  r at e d    wit h o ut 
r e co urs e t o  c a us al  e x pl a n ati o n. 
R ati n g  v al u es f or  e a c h  of t h e  1 5  C A R S 2 -S T/ C A R S 2 -H F it e ms r a n g e fr o m  1 t o  4.  G e n er all y,  a 
r ati n g   v al u e   of   1  i n di c at es  t h at   a n  i n di vi d u al   b e h a vi o ur  is    wit hi n   n or m al  li mits  f or   a n 
i n di vi d u al  of  t h at  a g e,    w h er e as  a  v al u e  of  4  i n di cat es  t h at  t h e  i n di vi d u al’s  b e h a vi o ur  is 
s e v er el y  a b n or m al  f or  s o m e o n e  of t h at  a g e.  F or  e a c h it e m, t h e i n d e p e n d e nt  r at er  will  r e c or d 
n ot es  w hi c h j ustif y t h e r ati n gs.  T h e r ati n g  v al u es  ar e s u m m e d t o  pr o d u c e  a  T ot al s c or e. 
T h e Cli ni c al  Gl o b al  I m p r essi o n  S c al e  ( C GI) ( G u y,  1 9 7 6) will  b e  ass ess e d  b y t h e  m e di c al 
d o ct or; 
T h e  C GI s c al e r at es:  
- T h e  s e v erit y  of  ill n ess  ( Cli ni c al    Gl o b al  I m pr essi o ns – S e v erit y  ( C GI -S)):  at   S el e cti o n, 
I n cl usi o n,  W 0 1 2,  W 0 2 6,  W 0 5 2,  W e n d  visits  or  at t h e  wit h dr a w al visit i n  c as e  of  pr e m at ur e 
wit h dr a w al  
- T h e    Gl o b al  I m pr o v e m e nt  ( Cli ni c al    Gl o b al  I m pr essi o n – Gl o b al  I m pr o v e m e nt  ( C GI -I))  i n 
c o m p aris o n  wit h  
•  p ati e nt’s  c o n diti o n  at  i n cl usi o n  f or      W 0 0 0 + D a y  1 7,    W 0 0 4,    W 0 0 8,    W 0 1 2,    W 0 1 6, 
W 0 2 0,    W 0 2 6,    W 0 3 8,    W 0 5 2   or   at   t h e    wit h dr a w al   visit   (i n   c as e   of   pr e m at ur e 
wit h dr a w al  d uri n g t h e  d o u bl e  bli n d  or  wit h dr a w al  d uri n g  o p e n l a b el tr e at m e nt  p eri o d ) 
•  p ati e nt’s  c o n diti o n  at    W 0 2 6  f or    W 0 3 8,    W 0 5 2  or  at  t h e   wit h dr a w al  visit  (i n  c as e  of 
pr e m at ur e  wit h dr a w al  d uri n g t h e  o p e n l a b el tr e at m e nt  p e ri o d) 
•  f or  W e n d  visit:  
o  p ati e nt’s  c o n diti o n  c o m p ar e d t o  W 0 5 2 f or  p ati e nts  c o m pl eti n g t h e st u d y  
o  p ati e nt’s   c o n diti o n   c o m p ar e d   t o    Wit h dr a w al   visit   f or   p ati e nts   h a vi n g 
pr e m at ur el y  wit h dr a w n fr o m t h e st u d y 
T h e S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  E diti o n ( S R S - 2) ( C ost a nti n o,  2 0 1 2) is  a  6 5 it e ms, 
Li k ert  s c al e,  o bj e cti v e  m e as ur e  of  s y m pt o ms  ass o ci at e d  wit h  a utis m.  T h e  S R S -2  g e n er at es  a 
T ot al s c or e t h at s er v es  as  a n i n d e x  of s e v erit y  of s o ci al  d efi cits i n t h e  a utis m s p e ctr u m.  
It  will  b e  c o m pl et e d  b y t h e  p ar e nts/l e g al r e pr es e nt ati v e  or  c ar e gi v er ( w h e n  a p pli c a bl e): 
- At I n cl usi o n  
-  D uri n g t h e  D o u bl e  Bli n d tr e at m e nt  p eri o d  at:  W 0 0 4,  W 0 1 2,  W 0 2 6  visits 
-  D uri n g t h e  O p e n  L a b el tr e at m e nt  p eri o d  at:  W 0 3 8,  W 0 5 2  visits 
- At t h e  wit h dr a w al  vi sit i n  c as e  of  pr e m at ur e  wit h dr a w al  aft er  visit  W 0 0 0 + D a y 1 0 
It  is  hi g hl y  r e c o m m e n d e d  s a m e  p ar e nt/l e g al  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n  a p pli c a bl e) 
c o m pl et es t h e  S R S -2  all  al o n g t h e st u d y.  
I n t h e fr a m e w or k  of t his st u d y t h e f oll o wi n g f or ms  will  b e  c o m pl et ed: 
- 
S R S - 2  Pr es c h o ol f or m ( a g es  2 t o  41/2) 
- 
S R S - 2  S c h o ol f or m ( a g es  4 t o  1 8  y o).  
F or  y o u n g er  c hil dr e n,  s o m e  o v erl a p  i n  f or m  a g e  h as  b e e n  pr o vi d e d  s o  t h at  a n  ol d er  pr e -
s c h o ol er  c a n  b e  r at e d  a n d  s c or e d  o n  eit h er  Pr es c h o ol  or  S c h o ol  a g e  f or ms.   C hil dr e n  i n  t his 
o v erl a p pi n g  p eri o d  ar e  g e n er all y  r at e d  o n t h e  S c h o ol -A g e  F or m,  e x c e pt e d  f or t h os e  c hil dr e n 
wit h l o w er f u n cti o ni n g,  wit h  b e h a vi o ur  m or e si mil ar t o t h at  d es cri b e d  o n t h e  Pr es c h o ol  F or m. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 5 /2 9 6  
 
T h e Vi n el a n d    A d a pt ati v e    B e h a vi o u r  S c al es -S e c o n d    E diti o n  ( V A B S  II) is  d esi g n at e d  t o 
m e as ur e  a d a pt ati v e  b e h a vi o ur.  It  e x pl or es  5  d o m ai ns:   C o m m u ni c ati o n,   D ail y   Li vi n g  S kills, 
S o ci ali z ati o n,  M ot or  S kills  a n d  M al a pt ati v e  B e h a vi o ur. 
It  will  b e  c o m pl et e d  b y  a  M e di c al  D o ct or  or  a  Ps y c h ol o gist/  H e alt h  pr of essi o n al  wit h : 
o  a  d et ail e d  k n o wl e d g e  a n d  e x p eri e n c e  of  A S D  a n d  c hil d  d e v el o p m e nt 
o  w h o  pl a ys  a  k e y r ol e i n t h e  c urr e nt sit e  or g a ni z ati o n  of t h e t e a m 
o is i n v ol v e d i n t h e  di a g n osis  of  A S D  p ati e nts  o n  a r e g ul ar  b asis 
o  a n d  h as  b e e n tr ai n e d  o n  V A B SII  wit h t h e s p o ns or tr ai ni n g 
 
- At I n cl usi o n  
-  D uri n g t h e  D o u bl e  Bli n d tr e at m e nt  p eri o d  at:  W 0 2 6  visit 
-  D uri n g t h e  O p e n  L a b el tr e at m e nt  p eri o d  at:  W 0 5 2  visit 
- At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al  aft er  visit  W 0 0 0 + D a y 1 0  
 
It is  hi g hl y r e c o m m e n d e d t h e s a m e r at er  wit h t h e s a m e p ar e nt/l e g al r e pr es e nt ati v e  or  c ar e gi v er 
( w h e n  a p pli c a bl e)  c o m pl et es t h e  V A B S II  all  al o n g t h e st u d y. 
8.  S A F E T Y  M E A S U R E M E N T S   
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. 2. 2)  1. 
Ass ess m e nt  of  s ui ci d al i d e ati o n  a n d  s ui ci d al  b e h a vi o ur  usi n g t h e  C ol u m bi a  S ui ci d e  S e v erit y 
R ati n g  S c al e  C hil dr e n’s  v ersi o n ( C -S S R S -C)  
- P h ysi c al  e x a mi n ati o n:  bl o o d  pr ess ur e  ( S B P,    D B P),  h e art  r at e,  b o d y    w ei g ht,  h ei g ht, 
B MI,  
- 1 2- l e a d  E C G 
- R e n al  ultr as o u n d 
- L a b or at or y  p ar a m et ers  
- A d v ers e  e v e nts  
- P A E R S  
T h e i n v esti g at or  m a y  als o  c o n d u ct  a n y  ot h er  ass ess m e nts  h e/s h e  d e e ms  n e c ess ar y  d uri n g t h e 
st u d y t o  e ns ur e t h e s af et y  of t h e  p ati e nt. 
8. 2.  M et h o ds  a n d  m e as u r e m e nt ti m es  
T h e C ol u m b i a   S ui ci d e   S e v e rit y  r ati n g   S c al e    C hil d r e n’s  v e rsi o n  ( C-S S R S -C) ( P os n er, 
2 0 0 7)    ( P os n er,  2 0 1 1) ass ess es  s ui ci d al  i d e ati o n  a n d  s ui ci d al  b e h a vi o ur .  I n v esti g at or    will 
c o m pl et e  a n  e- tr ai ni n g  o n t his t o ol  pri or t o t h e st u d y st art. 
T h e  C -S S R S - C i n cl u d es t w o f or ms: 
- B as eli n e/ S cr e e ni n g  v ersi o n:  c o m pl et e d  at  W 0 0 0 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 6 /2 9 6  
 
- Si n c e   L ast   Visit  v ersi o n:  t o  b e  c o m pl et e d  at    W 0 1 2,    W 0 2 6,    W 0 3 8,    W 0 5 2 or  at  t h e 
wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al  
T h e  P a e di a t ri c    A d v e rs e    E v e nt    R ati n g   S c al e  ( P A E R S) ( S h a pir o,  2 0 0 9) is  a n  i n v e nt or y 
r e p ort   d esi g n e d  t o  i d e ntif y   si g ns/s y m pt o ms   e x p eri e n c e d   b y  t h e   p ati e nt   si n c e  t h e   st u d y 
tr e at m e nt  i niti ati o n. I n v esti g at or    will  c o m pl et e  an  e- tr ai ni n g o n  t his  t o ol  pri or  t o  t h e  st u d y 
st art. 
T h e  P A E R S  will  b e  c o m pl et e d:  
o  D uri n g  t h e    D o u bl e    Bli n d   p eri o d  at:    W 0 0 0,    W 0 0 0 + D a y   1 7,    W 0 0 4,    W 0 0 8, 
W 0 1 2,  W 0 1 6,  W 0 2 0,  W 0 2 6  visits  
o  D uri n g t h e  O p e n  L a b el  p eri o d  at:  W 0 2 6 + D a y 1 7,  W 0 3 0,  W 0 3 4,  W 0 3 8,  W 0 4 2, 
W 0 4 6,  W 0 5 2  visits 
o  At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al  
 
P A E R S i n cl u d es t hr e e f or ms: 
- Y o ut h f or m, t o  b e  c o m pl et e d  w h e n  p ossi bl e  b y t h e  p ati e nt, 
- P ar e nt  f or m,  t o  b e  c o m pl et e d  b y  a  p ar e nt/l e g al  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n 
a p pli c a bl e). 
o  As f ar  as  p ossi bl e s a m e p ers o n s h o ul d  c o m pl et e t h e f or m  d uri n g t h e st u d y 
- Cli ni ci a n f or m fill e d  aft er  ass ess m e nt  of  y o ut h f or m  a n d  p ar e nt f or ms 
P h ysi c al  e x a mi n ati o ns  
- D B P,   S B P   a n d   h e art  r at e    m ust   b e   al w a ys   ass ess e d.    A p pr o pri at e   c o n diti o ns   ar e 
ass ess m e nt i n  a  sitti n g  or l yi n g  p ositi o n  aft er  5 -mi n ut e r est  a n d  at  1 m n  aft er  st a n di n g 
p ositi o n ( ort h ost ati c  h y p ot e nsi o n:  k n o w n  eff e ct  of  b u m et a ni d e): 
o  At  S el e cti o n  
o  D uri n g t h e  D o u bl e  Bli n d  p eri o d  at:  W 0 0 0,  W 0 0 2,  W 0 1 2,  W 0 2 6  visits 
o  D uri n g t h e  O p e n  L a b el  p eri o d  at:  W 0 2 8,  W 0 3 8,  W 0 5 2  visits 
o  At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  dis c o nti n u ati o n.  
D B P  a n d  S B P  will  b e  m e as ur e d  wit h t h e  s p e cifi c  d e vi c e  pr o vi d e d  b y t h e  S p o ns or f or 
t h e st u d y. 
- B o d y  w ei g ht  m ust  b e  ass ess e d:  
o  At  S el e cti o n  
o  D uri n g  t h e    D o u bl e    Bli n d   p eri o d   at:    W 0 0 0,    W 0 0 0 + D a y 1 7,    W 0 0 4,    W 0 0 8, 
W 0 1 2,  W 0 1 6,  W 0 2 0,  W 0 2 6  visits  
o  D uri n g t h e  O p e n  L a b el  p eri o d  at:  W 0 2 6 + D a y 1 7 ,  W 0 3 0,    W 0 3 4,    W 0 3 8, W 0 4 2, 
W 0 4 6,  W 0 5 2  visits 
o  At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al.  
- H ei g ht  m ust  b e  ass ess e d:  
o  At  S el e cti o n  
o  D uri n g t h e  D o u bl e  Bli n d  p eri o d  at:  W 0 1 2,  W 0 2 6 visits  
o  D uri n g t h e  O p e n  L a b el  p eri o d  at:  W 0 3 8,  W 0 5 2  visits 
o  At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al  
1 2 -l e a d  E C G 
T h e f oll o wi n g  1 2- l e a d  E C Gs  will  b e  p erf or m e d  d uri n g t h e st u d y: 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 7 /2 9 6  
 
- A  first  1 2 -l e a d   E C G    will  b e  pr es cri b e d  at  t h e  s el e cti o n  visit  a n d  th e  ass ess m e nt  of  t h e 
r e c or di n g    m ust  b e  a v ail a bl e  b ef or e  I n cl usi o n  visit. A n   E C G  i n  tri pli c at e  ( 3   E C G  i n  1 0 
mi n ut es) is  e x p e ct e d.  
- 
D uri n g t h e  D o u bl e  Bli n d tr e at m e nt  p eri o d  4  E C G S  will  b e  p erf or m e d  a n d its  ass ess m e nt 
b y  l o c al  c ar di ol o gist/ q u alifi e d  p ers o n  s h o ul d  b e  a v ail a bl e  at    W 0 0 4,    W 0 0 8,    W 0 1 2  a n d 
W 0 2 6  visits 
- 
D uri n g t h e  O p e n  L a b el tr e at m e nt  p eri o d  4  E C G S  will  b e  p erf or m e d  a n d its  ass ess m e nt  b y 
l o c al  c ar di ol o gist/ q u alifi e d  p ers o n  s h o ul d  b e  a v ail a bl e  at  W 0 3 0,  W 0 3 4,  W 0 3 8  a n d  W 0 5 2 
visits  
- At t h e  wit h dr a w al  visit in  c as e  of  pr e m at ur e  wit h dr a w al  
E C G  d e vi c e   will  b e  t h e  s a m e  f or  all  c e ntr es  a n d   will  b e  s u p pli e d  b y  t h e   C R O  i n  c h ar g e  of 
E C G  c e ntr al  r e a di n g.  T h e  E C G  d e vi c e  s h o ul d  b e  us e d  o nl y  f or t h e  pr es e nt  st u d y  a n d  f or t h e 
sist er  st u d y  ( C L 3- 9 5 0 0 8- 0 0 1).   T h e  r e c or di n g  s h o ul d  b e  d o n e  u n d er  t h e  s u p er visi o n  of  t h e 
i n v esti g at or  or  a  c ar di ol o gist  or  a  s p e ci ali z e d  p ers o n  ass o ci at e d  wit h t h e  c e ntr e.  A n  E C G i n 
tri pli c at e ( 3  E C G i n  1 0  mi n ut es) is  o nl y  e x p e ct e d f or s el e cti o n  visit. 
 
E v e n if t h e  1 2 -l e a d  E C G r e a di n g  a n d i nt er pr et ati on  will  b e  c e ntr alis e d,  a l o c al  ass ess m e nt  of 
E C G  e x a ms is n e c ess ar y  f or  d et e cti o n  of    m e di c al  ur g e n ci es  a n d    m ust  b e  e n cl os e d  i n  t h e 
s o ur c e   d at a.    C e ntr al   r e a di n g   r e p orts   f or    E C G   o v err ul e   l o c al   r e a di n g   f or 
i n cl usi o n/ e x cl usi o n/ wit h dr a w al  crit eri a. 
T h e   E C G  c e nt r al  r e a di n g  c e ntr e   will  b e  i n  c h ar g e  of  t h e  c o di n g  of  t h e  a b n or m aliti es  of  t h e 
E G C  usi n g t h e  c h art iss u e d fr o m  MI N E S O T A  di cti o n ar y. 
F or  e a c h   E C G  ti m e -p oi nt,  t h e  f oll o wi n g  p ar a m et ers   will  b e  ass ess e d:  h e art  r at e  ( b p m),   R R 
i nt er v al  ( ms e c),  P R  i nt er v al  ( ms e c),    Q R S  c o m pl e x  ( ms e c),    Q T  a n d    Q T c F  i nt er v al  ( ms e c) 
( Fri d eri ci a’s  c orr e cti o n f or m ul a i nt er v al), si n us r h yt h m. 
A  q u alit ati v e  ass ess m e nt  of  t h e   E C G  r e c ei v e d   will  als o b e p erf or m e d b y  a  c e ntr al  r e a di n g 
str u ct ur e: I d e ntifi e d  a b n or m aliti es,  o v er all  ass ess m e nt  a n d c o m p aris o n  v ers us  b as eli n e.  
D uri n g  t h e   st u d y,   all  fi n di n gs   o n  l a b or at or y   e x a mi n ati o ns,    E C G   or   vit al   si g ns   h a vi n g 
c o nsi d er e d  as  cli ni c all y  si g nifi c a nt  b y t h e i n v esti g at or  will  b e  f oll o w e d -u p  u ntil t h e  p ati e nt’s 
v al u e r et ur ns t o  n or m al  or is st a bili z e d.  
R e n al  ult r as o u n d  
A r e n al  ultr as o u n d  will  b e  p r es cri b e d: 
- 
A t  t h e  s el e cti o n  visit  a n d  t h e  ass ess m e nt  of  t h e  r e c or di n g    m ust  b e  a v ail a bl e  b ef or e 
I n cl usi o n  visit. 
- 
D uri n g  t h e    D o u bl e  bli n d  tr e at m e nt  p eri o d  it    will  b e  pr es cri b e d  at    W 0 2 0  a n d  t h e 
ass ess m e nt  of t h e r e c or di n g  m ust  b e  a v ail a bl e f or/ d uri n g  at  W 0 2 6  visit 
- 
D uri n g  t h e    O p e n  l a b el  tr e at m e nt   p eri o d  it    will   b e   pr es cri b e d   at    W 0 4 6   a n d  t h e 
ass ess m e nt  of t h e r e c or di n g  m ust  b e  a v ail a bl e f or/ d uri n g  at  W 0 5 2  visit 
- 
At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al.  
 
T h is  e x a m  c o ul d  b e  d o n e  wit hi n  7  d a ys  pri or t o t h e  d a y  of t h e  visit. 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 8 /2 9 6  
 
T his  e x a m  s h o ul d  b e  ass ess e d  b y  a  n e p hr ol o gist  or b y  a  q u alifi e d  s p e ci alist w h o  will tr a ns mit 
t h e r e n al  ass ess m e nt t o  t h e  i n v esti g at or.    As  f ar  as  p ossi bl e t h e s a m e  n e p hr ol o gist/ q u alifi e d 
sp e ci alist  will  ass ess r e n al  ultr as o u n d  e x a ms f or  a  gi v e n  p ati e nt  all  al o n g t h e st u d y.  
Bi ol o gi c al  S af et y  m e as u r e m e nts  
T o  e ns ur e  h o m o g e n eit y  of t h e  r es ults,  all  bi ol o gi c al  ass ess m e nts  ( e x c e pt  N a + / K+  p ar a m et ers 
u n d er tr e at m e nt)  will  b e  c arri e d  o ut  b y t h e  c e ntr al l a b or at or y  c h os e n  b y I. R.I. S.  T h e r ef er e n c e 
v al u es  of  m e as ur e d  p ar a m et ers  will  b e  m e nti o n e d i n  e a c h l a b or at or y r e p ort.  
Bi ol o gi c al r es ults  will  b e  s e nt t o  sit e fr o m  c e ntr al l a b or at or y  vi a  a l a b or at or y r e p ort,  wit h t h e 
e x c e pti o n  f or  N a + / K+  p ar a m et ers  w hi c h  will  b e  ass ess e d l o c all y  ( e x c e pt  at t h e  s el e cti o n  visit 
b ef or e  t h e  first  I M P  i nt a k e  a n d  at  t h e   wit h dr a w al  visit  ( W D)  aft er  t h e  l ast  I M P  i nt a k e.   All 
l a b or at or y  r e p orts  ( c e ntr al  a n d  l o c al)  s h o ul d  b e  ass ess e d  b y  i n v esti g at or  a n d  k e pt  i n  t h e 
p ati e nt‘s  m e di c al fil e. 
T h e  s a m pli n g  pr o c ess  a n d  st or a g e  c o n diti o ns  o n  sit e    will  b e  d es cri b e d  i n  t h e  l a b or at or y 
m a n u al  pr o vi d e d  b y t h e  c e ntr al l a b or at or y. 
T h e l a b or at or y t ests  will  b e  p erf or m e d:  
- 
S el e cti o n  visit (l a b or at or y t ests  will  b e  pr es cri b e d  at) ,  s o t h at t h e r es ults  ar e  a vail a bl e f or 
t h e i n cl usi o n  visit 
- 
D uri n g t h e  d o u bl e  bli n d tr e at m e nt   p eri o d at  W 0 0 0 + 4 8/ 7 2 h  ( o nl y  N a + / K+ ),  W 0 0 0 + D a y 1 0 
( o nl y    N a+ / K+ ),    W 0 0 0 + D a y 1 7  ( o nl y    N a+ / K+ ),    W 0 0 4  ( o nl y    N a+ / K+ ),      W 0 1 2  a n d    W 0 2 6 
visits  
- 
D uri n g  t h e o p e n- l a b el  e xt e nsi o n  p eri o d,  at    W 0 2 6 + 4 8/ 7 2 h  ( o nl y    N a+ / K+ ),    W 0 2 6 + D a y 1 0 
( o nl y    N a+ / K+ ),    W 0 2 6 + D a y 1 7  ( o nl y    N a+ / K+ ),    W 0 3 0  ( o nl y    N a+ / K+ ),        W 0 3 8  a n d    W 0 5 2 
visits  
- 
At t h e  wit h dr a w al  visit i n  c as e  of  pr e m at ur e  wit h dr a w al 
T h e  r es ults  s h o ul d   b e  c h e c k e d  c ar ef ull y   b y  i n v esti g at or   o n c e  r e c ei v e d,  a n d  t h e   p ati e nt / 
p ar e nt/l e g al  r e pr es e nt ati v e(s)  or  c ar e gi v er  ( w h e n  a p pli c a bl e)  s h o ul d  b e  c o nt a ct e d  a g ai n  t o 
i nf or m t h e m  a b o ut r es ults  a n d  a n y  a b n or m alit y t h at  n e c essit at es  a s p e cifi c f oll o w- u p. 
L a b o r at o r y t ests  at  S el e cti o n  visit  
At  s el e cti o n  visit,  bl o o d  a n d  uri n ar y t es t  s a m pli n gs  will  b e  pr es cri b e d.  All t h e r es ults  of t h es e 
e x a mi n ati o ns  m ust  b e  a v ail a bl e f or t h e i n cl usi o n  visit.  
T h e f oll o wi n g  p ar a m et ers  will  b e  a n al ys e d  o n  bl o o d s a m pli n gs:  
- 
Bi o c h e mist r y   p a r a m et e rs :   s o di u m,   p ot assi u m,   c al ci u m,   c hl ori d e,    m a g n esi u m, 
bi c ar b o n at es,  p h os p h or,  ur e a,  uri c  a ci d,  cr e ati ni n e,  cr e ati ni n e  cl e ar a n c e -e G F R  ( S c h w art z 
f or m ul e  2 0 0 9),    A S T,    A L T,  t ot al  bilir u bi n,  fr e e  bilir u bi n,  c o nj u g at e d  bilir u bi n,  ( A L P), 
G a m m a -Gl ut a m yltr a nsf er as e  ( g a m m a  G T), t ot al  c h ol est er ol,  H D L  a n d  L D L  c h ol est er ol, 
tri gly c eri d es,  gl u c os e,  pr ot ei n ( T ot al,  Al b u mi n) 
- 
H a e m at ol o g y  p a r a m et e rs:  h a e m o gl o bi n,  h a e m at o crit,  er yt hr o c yt es,    w hit e  bl o o d  c ells 
c o u nt,  pl at el ets,  M C V. 
- 
S c r e e ni n g f o r  h e p atitis  A,  B  a n d  C  s er ol o gi c  m ar k ers. 
T h e f oll o wi n g  p ar a m et ers  will  b e  a n al ys e d  o n  uri n ar y s a m pli n gs: 
- 
C al ci u ri a,  p r ot ei n u ri a  a n d  c r e ati ni n u ri a  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  5 9 /2 9 6  
 
L a b o r at o r y t ests  d u ri n g t h e st u d y:  
T h e f oll o wi n g  p ar a m et ers  will  b e  a n al ys e d  o n  bl o o d s a m pli n gs:  
- 
Bi o c h e mist r y   p a r a m et e rs :   s o di u m,   p ot assi u m,   c al ci u m,   c hl ori d e,    m a g n esi u m, 
bi c ar b o n at es,   p h os p h or,   ur e a,   ur i c   a ci d,   cr e ati ni n e,   cr e ati ni n e   cl e ar a n c e   ( S c h w art z 
f or m ul e  2 0 0 9),    A S T,    A L T,  t ot al  bilir u bi n,  fr e e  bilir u bi n,  c o nj u g at e d  bilir u bi n,  ( A L P), 
G a m m a -Gl ut a m yltr a nsf er as e  ( g a m m a  G T), t ot al  c h ol est er ol,  H D L  a n d  L D L  c h ol est er ol, 
tri gl y c eri d es,  gl u c os e,  pr ot ei n ( T ot al,  Al b u mi n). 
- 
H a e m at ol o g y  p a r a m et e rs:  h a e m o gl o bi n,  h a e m at o crit,  er yt hr o c yt es,    w hit e  bl o o d  c ells 
c o u nt,  pl at el ets,  M C V. 
T h e f oll o wi n g  p ar a m et ers  will  b e  a n al ys e d  o n  uri n ar y s a m pli n gs: 
- 
C al ci u ri a,  p r ot ei n u ri a  a n d  c r e ati ni n u ri a  
 
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 0 /2 9 6  
 
 
 
B L O O D  A N A L Y SI S  
U RI N E 
A N A L Y S I S  
   
 
Bi o c h e mistr y 
e x cl u di n g   N a/ K  
N a/ K  m o nit ori n g 
vi a l o c al l a b or at or y  
H a e m at ol o g y  
C al ci uri a, 
Cr e ati ni n uri a 
Pr ot ei n uri a  
D o u bl e  bli n d t r e at m e nt  p e ri o d  
W 0 0 0   
+  4 8/ 7 2 h  
 
X 
 
 
W 0 0 0  
+  D a y  1 0  
 
X 
 
 
W 0 0 0  
+  D a y  1 7  
 
X 
 
 
W 0 0 4  
 
X 
 
 
W 0 1 2  
X 
X 
X 
X 
W 0 2 6  
X 
X 
X 
X 
O p e n l a b el t r e at m e nt  p e ri o d  
W 0 2 6   
+  4 8/ 7 2 h  
 
X 
 
 
W 0 2 6  
+  D a y  1 0  
 
X 
 
 
W 0 2 6  
+  D a y  1 7  
 
X 
 
 
W 0 3 0  
 
X 
 
 
W 0 3 8  
X 
X 
X 
X 
W 0 5 2  
X 
X 
X 
X 
A d diti o n al l a b or at or y t ests  c o ul d  b e  p erf or m e d  d uri n g t h e  st u d y if t h e  m e di c al  d o ct or  d e e ms 
t h e m  as  n e c ess ar y. 
 
E L E C T R O L Y T E S  M O NI T O RI N G  
I n t h e fr a m e w or k  of t his  st u d y t h e  m o nit ori n g  of  el e ctr ol yt es  u n d er tr e at m e nt  will  b e  ass ess e d 
l o c all y.   T his   will  all o w  s a vi n g  ti m e  i n  t h e  d eli v er y  of  l a b or at or y  r es ults  a n d  t o    m a n a g e  t h e 
P ot assi u m s u p pl e m e nt ati o n  w h e n  n e e d e d. 
I n v estig at ors  s h o ul d  al w a ys  e n c o ur a g e  p ati e nts t o  e at  f o o ds  c o nt ai ni n g  p ot assi u m  as  s o o n  as 
t h e y  k n o w t h at t h e y  will  b e i n cl u d e d i n t h e st u d y. S e e  T a bl e  ( 8. 2)  1 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 1 /2 9 6  
 
T a bl e  (8. 2 )  1 - F o o ds t h at  h a v e  a  hi g h e r  p ot assi u m  c o nt e nts  
 
F r uit  a n d  n uts  
 
Fr uit i n  p arti c ul ar - b a n a n as,  a pri c ots,  a v o c a d os,  
bl a c k c urr a nts, r h u b ar b, fr es h fr uit j ui c es  
Dri e d fr uits  e g  c urr a nts, r aisi ns,  pr u n es, fi gs,  
s ult a n as,  ar e ri c h s o ur c es  of  p ot assi u m 
All  v ari eti es  of  n ut  e g  al m o n ds,  p e a n uts  a n d  
w al n uts  
P ot at o es  
P ot at o es  ar e  v e r y ri c h s o ur c es  of  p ot assi u m if t h e y  ar e  n ot  b oil e d 
J a c k et  p ot at o es 
Or di n ar y fri e d  c hi ps  
I nst a nt  p ot at o  pr o d u cts  e g  w affl es,  p ot at o  cr o q u ett es 
P ot at o  cris ps  
V e g et a bl es  a n d  p uls es  
 
I n  p arti c ul ar - s pr o uts,  m us hr o o ms,  p ars ni ps, 
s pi n a c h,  b a k e d  b e a ns,  ki d n e y  b e a ns, l e ntils 
C e r e als  
C er e als  w hi c h  ar e  hi g h i n br a n  e g  br a n fl a k es, all  br a n,  m u esli  
Bis c uits,  c a k es  a n d s w e ets 
Fr uit  c a k es, fi g r olls,  m u esli  b ars  
C h o c ol at e, f u d g e, li q u ori c e  
Mil k  a n d  d ai r y  p r o d u cts  
Dri n ki n g  mil k  or  e ati n g  y o g h urts  
  
T h e  first  el e ctr ol yt es    m o nit ori n g  u n d er  tr e at m e nt,  i n  b ot h  d o u bl e  a n d  o p e n  l a b el  p eri o ds, 
s h o ul d  b e  p erf or m e d l o c all y n o l at er t h a n  7 2 h  aft er  W 0 0 0  a n d  W 0 2 6 r es p e cti v el y. 
I n  c as e  of  a n y  a b n o r m alit y,  el e ct r ol yt es  will  b e  m o nit o r e d  u ntil  r et u r n t o  n o r m al  v al u es.  
I n  c as e  of Mil d  H y p o k al a e mi a ( 3 m E q/ L  ≤  K
+ <  3. 5  m E q/ L)  arisi n g  u n d er st u d y tr e at m e nt:  
→ 
F o o ds   c o nt ai ni n g  P ot assi u m    will   b e  r e c o m m e n d e d   s u c h   as  l e af y   gr e e n   v e g et a bl es, 
t o m at o es,  citr us  fr uits,  or a n g es  or  b a n a n as. A n  a d e q u at e  c ar e  s h o ul d  b e  i m pl e m e nt e d  f or 
t h e  h y p o k al a e mi a f oll o w  u p. 
→ P ati e nt  will  b e  s u p pli e d  wit h  or al  p ot assi u m  a c c or di n g t o i n v esti g at or’s  o pi ni o n  w hi c h  c a n 
b e  b as e d  o n  l o c al  g ui d eli n es  or  l o c al    m e di c al  pr a cti c e . T h e  d os e  c o ul d  b e  a d a pt e d  t o 
h y p o k al a e mi a s e v erit y  or  p ati e nts’  w ei g ht. 
T h e f oll o wi n g  P ot assi u m C hl ori d e d os es  ar e r e c or d e d  o nl y f or i n di c ati v e  p ur p os es: 
 < 2 0  k g =  4 0 0  m g/ d a y ( 2 0 0  bi d) 
 2 0- 4 0  k g  =  6 0 0  m g/ d a y ( 3 0 0  bi d) 
 4 0  k g  =  1 2 0 0  m g/ d a y ( 6 0 0  bi d) 
I n  c as e  of M o d e r at e    H y p o k al a e mi a  ( 2. 2 m E q/ L   ≤    K + <  3    m E q/ L)  arisi n g  u n d er  st u d y 
tr e at m e nt: 
→ T h e st u d y tr e at m e nt s h o ul d  b e i m m e di at el y  dis c o nti n u e d.  
→ A n  a d e q u at e  c ar e s h o ul d  b e i m pl e m e nt e d f or t h e  h y p o k al e mi a f oll o w  u p. 
→ C ar di a c  m o nit ori n g   will  b e  p erf or m e d  a n d  l e v el  of  p ot assi u m  s h o ul d  b e    m o nit or e d  u ntil 
r et ur n  wit hi n  n or m al r a n g e 
→ 
P ati e nt   will  b e  s u p pli e d  wit h  or al  p ot assi u m. A c c or di n g  t o  i n v esti g at or’s  o pi ni o n   w hi c h 
c a n  b e  b as e d  o n  l o c al  g ui d eli n es  or  l o c al    m e di c al  pr a cti ce,  t h e  d os e  c o ul d  b e  a d a pt e d  t o 
h y p o k al a e mi a s e v erit y  or  p ati e nts’  w ei g ht. 
T h e f oll o wi n g  P ot assi u m  C hl ori d e d os es  ar e r e c or d e d  o nl y f or  i n di c ati v e  p ur p os es: 
 
 < 2 0  k g =  4 0 0  m g/ d a y ( 2 0 0  bi d) 
 2 0- 4 0  k g  =  6 0 0  m g/ d a y ( 3 0 0  bi d) 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 2 /2 9 6  
 
 4 0  k g  =  1 2 0 0  m g/ d a y ( 6 0 0  bi d) 
I n  c as e  of S e v e r e  H y p o k al a e mi a ( <  2. 2 m E q/ L), arisi n g  u n d er st u d y tr e at m e nt:  
→ T h e st u d y tr e at m e nt s h o ul d  b e i m m e di at el y  dis c o nti n u e d. 
→  T h e  p ati e nt  s h o ul d  b e i m m e di at el y  h os pit ali z e d,  a n  a d e q u at e  c ar e  s h o ul d  b e i m pl e m e nt e d 
f or t h e  h y p o k alae mi a f oll o w  u p ( e g i ntr a v e n o us K Cl a n d/ or  or al  hi g h K d os e  a c c or di n g t o 
t h e  h os pit al  us u al  pr a cti c e).  I n  a n y  c as e t h e l e v el  of  p ot assi u m  s h o ul d  b e  m o nit or e d  u ntil 
r et ur n  wit hi n  n or m al r a n g e. 
P ot assi u m s u p pl e m e nt ati o n  will  n ot  b e  pr o vi d e d  b y t h e  S p o ns or. 
8. 3.  D efi niti o n  of  A d v e rs e  e v e nt   
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  a n d  aft er I M P  dis c o nti n u ati o n)  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 a ti 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   s o ci al   r e as o ns,    A S D   di a g n osis,   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  hist or y  ( e. g. pl a q u e  a n d 
s cr e w r e m o v al f oll o wi n g  a n  ost e os y nt h esis  p erf or m e d  b ef or e t h e st u d y) ,  
 pr o p h yl a cti c  pr o c e d ur es ( e. g.  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. g ast r os c o p y t o 
c o ntr ol t h e  e v ol uti o n  of  a n  a n ci e nt,  pr e vi o usl y- di a g n os e d  hi at al  h er ni a ). 
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 e at h, 
­ is lif e-t hr e at e ni n g( 1), 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 3 /2 9 6  
 
­ 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  existi 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 eat 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.  
( 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    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. 
I n t h e fr a m e w or k  of t his  st u d y  a  d ail y  d os e  a d mi nistr ati o n  gr e at er t h a n  2 m L ( or t h e  m a xi m u m 
d ail y  d os e  r e c o m m e n d e d  i n a p p e n di x  1 f or  t h os e  p ati e nts   wit h  a   w ei g ht  <  2 5 k g)  s h o ul d  b e 
c o nsi d er e d  as  o v er d os e.   
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  
A n  a d v ers e  e v e nt  of  s p e ci al  i nt er est  ( A E O SI)  is  o n e  of  s ci e ntifi c  a n d    m e di c al  i nt er est  or 
c o n c er n r e g ar di n g t h e I M P f or  w hi c h r e c or di n g r ul es,  s p e ci al  d o c u m e nt ati o n  s u c h  as  h os pit al 
r e c or ds  a n d/ or  a dj u di c ati o n  c o m mitt e e  c o ul d  b e  a p pr o pri at e.  It    m a y  b e  a  s eri o us or  n o n -
s eri o us  A E t h at  m a y r e q uir e f urt h er i n v esti g ati o n i n  or d er t o  c h ar a ct eri z e  a n d  u n d erst a n d.  
I n t h e  fr a m e w or k  of t his  st u d y  pr ot o c ol  A E O SI i n cl u d e  a n y  bi ol o gi c al  P ot assi u m  el e ctr ol yt e 
a b n or m alit y  <  3. 5  m E q/ L. 
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 ( as  d efi n e d i n  S e cti o n  8. 4 ), 
­ a n  a d v ers e  e v e nt of s p e ci al i nt er est ( as  d efi n e d i n  S e cti o n  8. 6 ), 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 4 /2 9 6  
 
­ a n  o v er d os e  of t h e I 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  b y  a  p ers o n  ar o u n d t h e  p arti ci p a nt, 
- 
if t h er e  ar e si g ns  or s y m pt o ms, 
- 
if t h er e  ar e  n o si g ns  or sy m pt o ms, i n t h e f oll o wi n g  c as es: 
- if t h e  p ers o n is  a  mi n or s u bj e ct, 
- if t h e i nt a k e  of tr e at m e nt is i nt e nti o n al (i n cl u di n g s ui ci d e  att e m pt). 
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 
i nt e nsit 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  t est  dr u g.   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 I nt e nsit y  s h o ul d  b e  e v al u at e d  a c c or di n g t o t h e f oll o wi n g r ul e: 
­ mil d: si g ns  or s y m pt o ms,  e asil y t ol er at e d, r eli e v e d  wit h s y m pt o m ati c tr e at m e nt,  
­ m o d er at e:   e n o u g h   dis c o mf ort  t o   c a us e  i nt erf er e n c e    wit h   us u al   a cti vit y,   o nl y   p arti all y 
r eli e v e d  wit h s y m pt o m ati c tr e at m e nt, 
­ s e v er e:   i n c a p a cit y   i n   s o m e   r e g ul ar   a cti viti es,   n ot   e asil y   r eli e v e d    wit h   s y m pt o m ati c 
tr e at m e nt. 
T h e  c a us al  r el ati o ns hi p  t o t h e t est  dr u g  or t o t h e  e x p eri m e nt al  pr o c e d ur es  m ust  b e  ass ess e d 
w h e n r e p orti n g t h e  A E i n t h e  A E f or m. C as es ti c k e d  “r el at e d ”  b y t h e i n v esti g 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  t est  dr u g  ( 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  t est   dr u g …),    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  d r u g  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 e r 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 t est  dr u g, f o r  e v e nt  ass o ci at e d  wit h  a n y  p r o c e d u r e/ c o n diti o n 
r e q ui r e d   b y  t h e  st u d y   p r ot o c ol :  pr o c e d ur e  ( bl o o d  s a m pli n g,  r e n al  e c h o gr a p h y,  et c.), 
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 ati n g  t o  t h e  c o n diti o ns  of  t h e 
pr ot o c ol 
­ at  a n y ti m e  aft er t h e first i nt a k e  of t h e t est  d r u g u p t o t h e  p arti ci p a nt’s l ast  st u d y  visit f or 
all  e v e nts,  
­ aft er t h e  p arti ci p a nt’s l ast st u d y  visit:  
 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  f oll o w  u p  st u d y  visit  ( W E N D)  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 (I M P  or  e x p eri m e nt al  pr o c e d ur e). 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 5 /2 9 6  
 
 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 vers e 
e v e nt r el at e d t o t h e r es e ar c h (I M P  or  e x p eri m e nt al  pr o c e d ur e). 
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 
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  
i n t h e  d e di c at e d f or m  of t h e  e-C R F.  
T h es e r ul es  a p pl y  als o t o  p ati e nts  w h o  pr e m at ur el y  st o p t h e t est  dr u g  d uri n g t h e  d o u bl e  bli n d 
p eri o d,  b ut  w h o still  p arti ci p at e i n t h e  st u d y. 
 
All  ot h er  a d v ers e  e v e nts  
 
 
 
 
 
 
 t o  b e 
r e p o rt e d 
as 
M e di c al 
hist o r y  
 
 
 
 
 
 
 
 
A d v e rs e    E v e nts   ass o ci at e d 
wit h:  
- 
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 
- 
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  
- 
A  pr o d u ct  ot h er  t h a n  t h e  t est 
dr u g,   t a k e n   as   a   p art   of 
pr ot o c ol  
 
All   a d v e rs e 
e v e nts 
(i n cl u di n g 
all  E RI N)  
 
All  E RI N  
 
All   
S A E 
r el at e d  t o  t h e 
r es e ar c h 
(I M P, 
e x p eri m e nt al 
pr o c e d ur e) 
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 
 t o  b e 
r e p o rt e d 
as 
A d v e rs e 
E v e nt  
 
 
 
 
 
 
 
 
 
Si g ni n g  of t h e  
c o ns e nt f or m  
1 st 
a d mi nistr ati o n  
of t h e t est  dr u g  
 
P arti ci p a nt's 
l ast st u d y  visit 
 
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 
st u d y  visit 
 
 
 
 
 
 
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, 
­ B as e d  o n  his/ h er  cli ni c al j u d g m e nt, t h e i n v esti g at or  c o ul d  d e ci d e  t o i nt e r r u pt  o r  st o p t h e 
t r e at m e nt  wit h o ut  r es u mi n g it, sh o ul d  a n  a d v e rs e  r e a cti o n  o c c u r . 
­ 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 a ti 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 R B/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. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 6 /2 9 6  
 
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 R B/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 efit -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. 
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 mi ssi 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 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. 
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 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. 
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   ( o v e r d os es,   i nt a k e   of   I 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)  
O v e r d os e  of I 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 otifi e d i m m e di at el y ( E RI N).  
­ 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:  
 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, 
 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), 
 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 ents ” t o  b e r e p ort e d  ot h er wis e),  
 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 c t e d f or  ass a y  of t h e I M P t a k e n. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 7 /2 9 6  
 
I nt a k e  of  I 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 ntT 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 e d i n 
t h e i n v esti gat 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 o w 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 vesti 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 dy  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 R B/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 dv 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: 
 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, 
 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  e-m ail  t h e m  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( 0 1. 5 5. 7 2. 6 0. 0 0  f or  a  c all  fr o m   Fr a n c e,   or  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)  or t h e l o c al  p h o n e  h otli n e ( c o nt a ct  d et ails 
ar e  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  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.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 8 /2 9 6  
 
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 v e 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 ur t h er  c o ns ult ati o ns, 
l a b or at or y  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 n d 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,  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  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 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 u i d eli n es  a n d  l o c al 
r e g ul ati o ns. 
I n  c as e   of  a n y   n e w  s af et y  i nf or m ati o n  (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) , t h e  s p o ns or  will i nf or m  all i n v esti g at ors i n v ol v e d i n  a n y  st u d y  wit h t h e  s a m e  dr u g 
t h at t his  n e w s af et y i nf or m ati o n  h as b e e n  r e p ort e d. 
As  a r es ult,  st u d y  p arti ci p a nts  will  b e i nf or m e d  vi a  his/ h er r es p e cti v e i n v esti g at or  of t his  n e w 
s af et y  i nf or m ati o n  a n d   will  r e c ei v e  a  r e vis e d  i nf or m e d  c o ns e nt  t o  b e  si g 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 ‘’ 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’’. 
T h e  c o n c er n e d    A ut h oriti es    will  b e  n otifi e d  as  s o o n  as  p ossi bl e  b y  t h e  s p o ns or  of  t h e    D at a 
M o nit ori n g    C o m mitt e e  ( D M C)  r e c o m m e n d ati o ns  if  a n y,    w h er e  r el e v a nt  f or  t h e  s af et y  of 
s u bj e cts (i. e.  m o difi c ati o n  or t er mi n ati o n  of t h e st u d y). 
8. 1 0.  R es p o nsi biliti es  of  D at a  M o nit o ri n g  C o m mitt e e  
I n  a c c or d a n c e    wit h  t h e    D M C  c h art er  a n d  t h e  r ul es  f or    D M C  f u n cti o ni n g,  t h e    D M C  is 
r es p o nsi bl e   f or   r e vi e wi n g   t h e   s af et y   d at a   o n   a   r e g ul ar   b asis,   a n d   pr o vi di n g    writt e n 
r e c o m m e n d ati o ns  t o  t h e   S p o ns or   r e g ar di n g  t h e   c o n d u ct   of  t h e   st u d y   ( m o difi c ati o n   or 
t er mi n ati o n). 
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   E F FI C A C Y    O R 
S A F E T Y  
9. 1.  M e as u r e m e nt  of  d r u g  c o n c e nt r ati o n  
T h e  c o n c e ntr ati o ns  of  b u m et a ni d e  will  b e  d et er mi n e d i n  pl as m a  b y  C e p h a c,  usi n g  a  v ali d at e d 
bi o a n al yti c al    m et h o d   b as e d   o n  a   pr ot ei n   pr e ci pit ati o n  f oll o w e d   b y  r e v ers e   p h as e  li q ui d 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  6 9 /2 9 6  
 
c hr o m at o gr a p h y  wit h t a n d e m  m ass  s p e ctr o m etri c  d et e cti o n.  Pr o c e d ur es  will  b e  d es cri b e d i n  a 
s e p ar at e  bi o a n al yti c al  pr ot o c ol  est a blis h e d  b y t h e  ass a y  c e ntr e. 
F or  e a c h  p ati e nt,  2  P K  s a m pl es   will  b e  c oll e ct e d  at    W 0 1 2  a n d    W 0 2 6,  d uri n g  t h e  bi ol o gi c al 
ass ess m e nt.  
All  s a m pl es   will  b e  s hi p p e d  t o t h e  c e ntr al l a b or at or y  a n d t h e n  t h e  first  s a m pl es  ( ali q u ots  1) 
will  b e tr a nsf err e d fr o m t h e  c e ntr al l a b or at or y t o t h e  ass a y  c e ntr e ( C e p h a c) f or  a n al ysis  usi n g 
a  v ali d at e d  ass a y    m et h o d.   T h e  ass a y  c e ntr e  i n  c h ar g e  of  b u m et a ni d e    m e as ur e m e nt    will  b e 
pr o vi d e d    wit h  t h e  tr e at m e nt  c o d es  s o  t h at  o nl y  s a m pl es  fr o m  p ati e nts  b ei n g  tr e at e d    wit h 
b u m et a ni d e  will  b e  ass a y e d  
T h e  s e c o n d  s a m pl es  ( ali q u ots  2)  will  b e  s t or e d  b y t h e  c e ntr al l a b or at or y  u ntil t h e  e n d  of t h e 
st u d y  w h e n t h e y  will  b e  d estr o y e d  u p o n r e q u est fr o m I. R.I. S,  u nl ess  n e e d e d  d uri n g t h e  c o urs e 
of t h e  st u d y. If  n e e d e d, t h e  st u d y  s a m pl es  will  b e  s e nt t o t h e  ass a y  c e nt er  u p o n  s p e ci al r e q u est 
fr o m I. R.I. S. 
At t h e  e n d  of t h e  st u d y,  u p o n  r e q u est  of  I. R.I. S., t h e  ass a y  c e ntr e  will  b e  r es p o nsi bl e  f or t h e 
d estr u cti o n  of t h e s a m pl es r e c ei v e d.  
I n  or d er t o  pr e v e nt  a  bli n d  br e a k,  a d mi nistr ati o n  a n d  s a m pli n g ti m es  will  o nl y  b e r e c or d e d  o n 
t h e  r e q uisiti o n  f or m   a n d   n ot   o n  t h e   el e ctr o ni c    C as e  r e p ort   F or m  ( e-C R F).    T h e   c e ntr al 
l a b or at or y  will  c a pt ur e  d at a  of t h e r e q uisiti o n f or m  a n d  will  c al c ul at e t h e ti m e  aft er  d os e.  R e al 
ti m e  aft er  d os e   will  b e  tr a nsf err e d  t o   C e p h a c  f or  a n al ys es.   T h e  P K  d e p art m e nt   will  r e c ei v e 
o nl y   r e c o d e d   d at a   (r e c o d e d   p ati e nt   n u m b er).    Bi o a n al yti c al   r es ults   fr o m    C e p h a c   a n d 
r e q uisiti o n  f or m  d at a  fr o m  t h e  c e ntr al  l a b or at or y    will  b e  tr a nsf err e d  t o  t h e  I. R.I. S.    D at a 
M a n a g e m e nt  d e p art m e nt  o nl y  aft er  bli n d is  br o k e n.  
9. 2.  Q u alit y  of lif e  q u esti o n n ai r es  
P e ds Q L  ( V ar ni,   1 9 9 9) is   a   bri ef,   st a n d ar di z e d,   g e n eri c   ass ess m e nt   i nstr u m e nt   t h at 
s yst e m ati c all y   ass ess es   p ati e nts'   a n d   p ar e nt/l e g al   r e pr es e nt ati v e   or   c ar e gi v er   ( w h e n 
a p pli c a bl e)  p er c e pti o ns  of  h e alt h  r el at e d  q u alit y  of lif e.  F o ur  d iff er e nt  d o m ai ns  ar e  e x pl or e d: 
p h ysi c al,  e m oti o n al, s o ci al  a n d s c h o ol f u n cti o ni n g. 
I n  t h e  fr a m e w or k  of  t his  st u d y,  P e ds Q o L  pr o x y-r e p ort e d  v ersi o ns  i nt e n d e d  f or  p ar e nt/l e g al 
r e pr es e nt ati v e  or  c ar e gi v er ( w h e n  a p pli c a bl e)  will  b e  c o m pl et e d: 
- 
at I n cl usi o n,  
- 
d uri n g t h e  d o u bl e  bli n d tr e at m e nt  p eri o d:  W 0 0 4,  W 0 1 2  a n d  W 0 2 6  visits 
- 
d uri n g t h e  o p e n l a b el  p eri o d:  W 0 3 0,  W 0 3 8  a n d  W 0 5 2  visits 
- 
i n  c as e  of  pr e m at ur e  wit h dr a w al aft er  visit  W 0 0 0 + D a y 1 0. 
W H O Q O L -B r ef   ( W H O Q O L  Gr o u p,  1 9 9 4) ( W H O Q O L,  1 9 9 8 a) ( W H O Q O L  Gr o u p,  1 9 9 8 b) 
is  a  H e alt h-R el at e d  Q u alit y  of lif e  q u esti o n n air e i nt e n d e d t o   d o c u m e nt t h e  q u alit y  of lif e  of 
p ar e nts/l e g al r e pr es e nt ati v es  or  c ar e gi v ers ( w h e n  a p pli c a b l e)  of  c hil dr e n  wit h  A S D.  Diff er e nt 
d o m ai ns  ar e  e x pl or e d:  p h ysi c al,  ps y c h ol o gi c al,  s o ci al  r el ati o ns hi ps,  e n vir o n m e nt  a n d  g e n er al 
h e alt h. 
T h e    W H O Q O L -Br ef    will  b e  c o m pl et e d  b y  p ar e nt/l e g al  r e pr es e nt ati v e  or  c ar e gi v er  ( w h e n 
a p pli c a bl e): 
- 
at I n cl usi o n, 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 0 /2 9 6  
 
- 
d uri n g t h e  d o u bl e  bli n d tr e at m e nt  p eri o d:  W 0 0 4,  W 0 0 8,  W 0 1 2  a n d  W 0 2 6  visits, 
- 
d uri n g t h e  o p e n l a b el  p eri o d:  W 0 3 0,  W 0 3 4,  W 0 3 8  a n d  W 0 5 2  visits, 
- 
i n  c as e  of  pr e m at ur e  wit h dr a w al aft er  visit  W 0 0 0 + D a y 1 0. 
Q U A LI T Y  O F  LI F E  U TI LI T Y I N S T R U M E N T S  
E Q - 5 D- 3 L  ( K h a n n a,  2 0 1 3) is  a  st a n d ar dis e d    m e as ur e  of  h e alt h  st at us  d e v el o p e d  b y  t h e 
E ur o Q ol    Gr o u p  i n  or d er  t o  pr o vi d e  a  si m pl e,  g e n eri c    m e as ur e  of  h e alt h  f or  cli ni c al  a n d 
e c o n o mi c   a p pr ais al.  It   e x pl or es   diff er e nt   d o m ai ns   s u c h   us    m o bilit y,   a n xi et y/ d e pr es si o n, 
p ai n/ dis c o mf ort, s elf-c ar e  a n d  us u al  a cti viti es.  
I n t h e fr a m e w or k  of t his  st u d y,  E Q- 5 D-3 L will  b e  c o m pl et e d  b y  p ar e nt/l e g al r e pr es e nt ati v e  or 
c ar e gi v er ( w h e n  a p pli c a bl e) t o  c oll e ct t h eir  utilit y:  
- 
at I n cl usi o n, 
- 
d uri n g t h e  d o u bl e  bli n d tr e at m e nt  p eri o d:  W 0 1 2  a n d  W 0 2 6  visits, 
- 
d uri n g t h e  o p e n l a b el  p eri o d:  W 0 3 8  a n d  W 0 5 2  visits, 
- 
i n  c as e  of  pr e m at ur e  wit h dr a w al aft er  visit  W 0 0 0 + D a y 1 0. 
It   is   hi g hl y   r e c o m m e n d e d   s a m e   p a r e nts/l e g al   r e p r es e nt ati v e   o r   c a r e gi v e r   ( w h e n 
a p pli c a bl e)  c o m pl et es t h e  q u esti o n n ai r es  as f a r  as  p ossi bl e  all  al o n g t h e st u d y.  
9. 3.  A c c e pt a bilit y  a n d  p al at a bilit y  q u esti o n n ai r e  
It is  a  q u esti o n n air e  m ai nl y  f or  p ar e nt/l e g al  r e pr es e nt ati v e(s)  or  c ar e gi v er  ( w h e n  a p pli c a bl e) 
r e g ar di n g t h e  e as e  of  us e t o  us e t h e  d osi n g  d e vi c e. It als o i n cl u d es   a  5 -p oi nt  h e d o ni c  s c al e 
( pi ct ori al s c al e  of f a ci al  e x pr essi o ns) f or  p ati e nts. 
It  will  b e  c o m pl et e d  at  W 0 2 6  or i n  c as e  of  pr e m at ur e  wit h dr a w al. 
1 0.  S T A TI S TI C S   
1 0. 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  esti m at e d t o  m e et t h e  pri m ar y  e n d p oi nt  d efi n e d  as t h e  c h a n g e i n  C A R S 
fr o m  b as eli n e t o  6  m o nt hs  usi n g  a t w o-si d e d  St u d e nt’s t est. 
Wit h  a t ot al  of  1 7 0  p ati e nts, st atisti c al si g nifi c a n c e s h o ul d  b e  est a blis h e d  wit h  a  p o w er  of  9 0 % 
a n d  a t y p e- o n e  err or  of  0. 0 5 f or  a n  eff e ct si z e  of  0. 5  b et w e e n  gr o u ps. 
Ass u mi n g  ar o u n d   1 5 %   pr e m at ur el y    wit h dr a w al  r at e,  t h e  t ot al   n u m b er   of   p ati e nts  t o   b e 
i n cl u d e d is  2 0 0. 
Missi n g  d at a    will  b e  i m p ut e d  usi n g  a  r ef er e n c e  b as e d    m ulti pl e  i m p ut ati o n    wit h  a  j u m p -t o-
r ef er e n c e  a p pr o a c h  or  a st a n d ar d  m ulti pl e i m p ut ati o n  d e p e n di n g  o n t h e r e as o ns  of  wit h dr a wal. 
Si m ul ati o ns  w er e  c arri e d  o ut t o  e v al u at e t h e i m p a ct  of t his  pr o c e d ur e  o n  p o w er  u n d er  v ari o us 
s c e n ari os.  T h e  r es ults  o n  1 0 0 0  si m ul ati o ns  h a v e  s h o w n t h at  p o w er  d o es  n ot  dr o p  u n d er  8 0 % 
i n t h e  w orst  c as e s c e n ari o. 
1 0. 2.  St atisti c al  a n al ysis  
St atisti c al  a n al ysis will  b e  p erf or m e d  b y  t h e  I. R.I. S.   C e nt er  of   E x p ertis e    M et h o d ol o g y  a n d 
V al oris ati o n  of  D at a.  
A  St atisti c al  A n al ysis  Pl a n,  a n d  ass o ci at e d t e m pl at es f or  T a bl es,  Listi n gs  a n d  Gr a p hs,  will  b e 
writt e n   a n d   c o m pl et e d   b ef or e   st u d y   u n bli n di n g.    T h es e   s p e cifi c ati o ns    w ill   d et ail   t h e 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 1 /2 9 6  
 
i m pl e m e nt ati o n   of   all   t h e   pl a n n e d   st atisti c al   a n al ys es   i n   a c c or d a n c e    wit h   t h e    m ai n 
c h ar a ct eristi cs st at e d i n t h e  pr ot o c ol.  
T w o  s ets  of  st atisti c al  a n al ysis   will  b e  p erf or m e d:  a  first  a n al ysis  at  t h e  e n d  of  t h e  d o u bl e 
bli n d  tr e at m e nt  p eri o d  a n d  a  s e c o n d  a n al ysis  at  t h e  e n d  of  t h e  o p e n  l a b el  a cti v e  tr e at m e nt 
p eri o d.  T h e  m ai n  a n al ysis  will  b e t h e first  o n e  b as e d  o n t h e  d o u bl e  bli n d tr e at m e nt  p eri o d. 
1 0. 2. 1.  A n al ysis s ets /  T r e at m e nt  g r o u ps  
1 0. 2. 1. 1.  A n al ysis s ets  
R a n d o mis e d  S et ( R S):  
All  p ati e nts t o  w h o m  a t h er a p e uti c  u nit  w as r a n d o ml y  assi g n e d  usi n g I R S  at  W 0.  
 
S af et y  S et ( S S):  
All  p ati e nts  h a vi n g r e c ei v e d  at l e ast  o n e  d os e  of I M P.  
1 0. 2. 1. 2.  T r e at m e nt  g r o u ps  
F or t h e  6- m o nt hs  d o u bl e- bli n d  p eri o d, tr e at m e nt  gr o u ps  will  b e  d efi n e d  as: 
- 
B u m et a ni d e  gr o u p  
- 
Pl a c e b o  gr o u p 
It  will c orr es p o n d t o  all o c at e d tr e at m e nt  b y I R S  e x c e pt f or s af et y  a n al ys es f or  w hi c h tr e at m e nt 
r e c ei v e d  at  W 0  will  b e  c o nsi d er e d. 
F or t h e  o p e n- l a b el  a cti v e tr e at m e nt  p eri o d, tr e at m e nt  gr o u ps  will  b e  d efi n e d  as: 
- 
B u m et a ni d e  gr o u p :  p ati e nts  wit h  B u m et a ni d e  0. 5  m g  B I D r e c ei v e d  at  W 0 
- 
Pl a c e b o  /    B u m et a ni d e  gr o u p:  p ati e nts    wit h  pl a c e b o  r e c ei v e d  at    W 0  a n d  tr e at e d  b y 
B u m et a ni d e  0. 5  m g  BI D i n t h e  o p e n l a b el  p eri o d. 
1 0. 2. 2.  St atisti c al  m et h o ds  
1 0. 2. 2. 1.  G e n e r al  c o nsi d e r ati o ns  
T h e  f oll o wi n g  d es cri pti v e  st atisti cs   will  b e  pr o vi d e d  d e p e n di n g  o n  t h e  n at ur e  of  c o nsi d er e d 
d at a:  
- 
Q u alit ati v e  d at a :  n u m b er  of  o bs er v e d  v al u es,  n u m b er  a n d  p er c e nt a g e  of  p ati e nts  p er 
cl ass. 
- 
Q u a ntit ati v e  d at a :  n u m b er  of  o bs er v e d  v al u es,  m e a n  a n d  st a n d ar d  d e vi ati o n,  m e di a n, 
first  a n d t hir d  q u artil es,  mi ni m u m  a n d  m a xi m u m. 
1 0. 2. 2. 2.  Dis p ositi o n  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  d at a  a n d  ot h er  b as eli n e  c h ar a ct eristi cs    will  b e  s u m m ari z e d  usi n g  d es cri pti v e 
st atisti cs  b y tr e at m e nt  gr o u p, t o  ass ess t h eir  c o m p ara bilit y,  a n d  o v er all i n t h e  R S. 
Dis p ositi o n  of  p ati e nts,  i n cl u di n g  r e as o ns  f o r    wit h dr a w al  a n d  pr ot o c ol  d e vi ati o ns    will  b e 
s u m m ari z e d o v er all  a n d  b y  visit i n t h e  R S. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 2 /2 9 6  
 
1 0. 2. 2. 3.  T r e at m e nts  of  p ati e nts  
E xt e nt  of  e x p os ur e  a n d  tr e at m e nt  c o m pli a n c e,  as    w ell  as  pri or  a n d  c o n c o mit a nt  tr e at m e nts 
will  b e s u m m ari z e d  b y tr e at m e nt  gr o u p i n t h e  S S. 
1 0. 2. 2. 4.  Effi c a c y  a n al ysis 
All  effi c a c y  a n al ys es  will  b e  c arri e d  o ut  o n t h e  R S.  
1 0. 2. 2. 4. 1.  St atisti c al  h y p ot h es es  
T h e  h y p ot h es es t o  b e t est e d  ar e: 
L et μ 0 a n d μ 1 b e t h e  p o p ul ati o n  m e a ns  of t h e  c h a n g e fr o m  b as eli n e i n  C A R S t ot al r a w  s c or e  at 
6    m o nt h  ( pri m ar y  e n d p oi nt)   u n d er   pl a c e b o  a n d B u m et a ni d e ,  r es p e cti v el y.    T h e  st atisti c al 
h y p ot h es es t h at  will  b e t est e d  ar e:  
 
H 0: μ 0 = μ 1( n o  diff er e n c e  b et w e e n  B u m et a ni d e  a n d  pl a c e b o) 
v ers us 
H 1: μ 0 ≠ μ 1( diff er e n c e  b et w e e n  B u m et a ni d e  a n d  pl a c e b o) 
 
T h e  t y p e  I  err or   of  t h e  st atisti c al  t ests    will   b e  s et  at   5 %  ( bil at er al  sit u ati o n),    w hi c h  is 
c o nsist e nt    wit h  t h e   o bj e cti v e   of   d e m o nstr ati n g  t h e  s u p eri orit y   v ers us   pl a c e b o  ( u nil at e r al 
sit u ati o n  at  2. 5 %). 
Si mil ar  h y p ot h es es  will  als o  b e t est e d f or t h e  s e c o n d ar y  effi c a c y  p ar a m et ers. 
1 0. 2. 2. 4. 2.  P ri m a r y  effi c a c y  e n d p oi nt  
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  C A R S t ot al r a w  s c or e,  e x pr ess e d i n t er m  of  c h a n g e fr o m 
b as eli n e t o  6  m o nt h. 
Pri m ar y  a n al ysi s: B u m et a ni d e  will  b e  c o m p ar e d t o  pl a c e b o  usi n g  a  g e n er al li n e ar  m o d el  wit h 
b as eli n e  C A R S  a n d str atifi c ati o n f a ct ors  as  c o v ari at es.  
Missi n g  d at a  h a n dli n g :  C A R S  v al u es  p ost tr e at m e nt  dis c o nti n u ati o n  d u e t o  a d v ers e  e v e nt  or 
l a c k  of  effi c a c y  will  b e i m p ut e d  usi n g  a r ef er e n c e  b as e d  m ulti pl e i m p ut ati o n  wit h  a j u m p-t o-
r ef er e n c e  a p pr o a c h.  T his  a p pr o a c h  ass u m es tr e at m e nt  b e n efit i n  p ati e nts  w h o  dis c o nti n u e t h e 
B u m et a ni d e  ar m  dis a p p e ars  i m m e di at el y  u p o n  dis c o nti n u ati o n.   Tr e at m e nt  eff e ct  esti m ati o n 
will t a k e i nt o  a c c o u nt t h e  sit u ati o ns  w h e n  a  p ati e nt  c a n  n o l o n g er t ol er at e  or  b e n efit fr o m t h e 
tr e at m e nt  ( o c c urr e n c e  of  A E, l a c k  of  effi c a c y).  C A R S  v al u es  p ost tr e at m e nt  dis c o nti n u ati o n 
d u e t o  ot h ers  r e as o ns  will  b e i m p ut e d  usi n g  a   m ulti pl e i m p ut ati o n  a p pr o a c h  ass u mi n g t h e s e 
p ati e nts  c o ul d  h a v e t h e or eti c all y  c o nti n u e d t o  b e tr e at e d  wit h o ut  b ei n g  p ut  at  u n d u e ris k. 
S e nsiti vit y   a n al ysis:  s e nsiti vit y  a n al ys es   d et ail e d  i n  t h e   S A P  t o  ass ess  r o b ust n ess  t o  t h e 
m et h o d  f or  h a n dli n g    missi n g  d at a   will  b e  p erf or m e d  i n cl u di n g  a    mi x e d m o d el  f or  r e p e at e d 
m e as ur e m e nt.  
S u p pl e m e nt ar y  a n al ysis: 
T h e  pri m ar y  a n al ysis  will  b e  r e p e at e d  f or t h e  C A R S t ot al  s c or e  e x pr ess e d i n t er m  of  c h a n g e 
fr o m  b as eli n e t o  3  m o nt h. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 3 /2 9 6  
 
T h e  C A R S t ot al  s c or e  a n d  s u bs c or es  will  b e  s u m m ari z e d  b y tr e at m e nt  gr o u p  at  e a c h  pl a n n e d 
visit  f or  e a c h  p eri o d  ( d o u bl e -bli n d  tr e at m e nt  p eri o d  a n d  o p e n -l a b el  a cti v e  tr e at m e nt  p eri o d) 
usi n g  d es cri pti v e st atisti cs.  
1 0. 2. 2. 4. 3.  S e c o n d a r y  effi c a c y  e n d p oi nts  
S R S t ot al  r a w s c o r e: 
T h e   c h a n g e  i n   S R S  t ot al   s c or e  fr o m   b as eli n e  t o   6    m o nt h    will   b e   c o m p ar e d   b et w e e n  
B u m et a ni d e  gr o u p  a n d  pl a c e b o  gr o u p  usi n g  a  g e n er al  li n e ar    m o d el    wit h  b as eli n e  S R S  a n d 
str atifi c ati o n f a ct ors  as  c o v ari at es. 
F or    missi n g  d at a  h a n dli n g  a n d  s e nsiti vit y  a n al ysis,  t h e  s a m e  a p pr o a c h  as  f or  t h e  pri m ar y 
e n d p oi nt  will  b e  p erf or m e d. 
S u p pl e m e nt ar y  a n al ysis:   
T h e  m ai n  a n al ysis  will  b e r e p e at e d f or t h e  S R S t ot al  s c or e  e x pr ess e d i n t er m  of  c h a n g e fr o m 
b as eli n e t o  3  m o nt h. 
T h e  S R S  t ot al  s c or e  a n d  s u bs c or es   will  b e  s u m m ari z e d  b y  tr e at m e nt  gr o u p  at  e a c h  pl a n n e d 
visit  f or  e a c h  p eri o d  ( d o u bl e -bli n d  tr e at m e n t  p eri o d  a n d  o p e n-l a b el  a cti v e  tr e at m e nt  p eri o d) 
usi n g  d es cri pti v e st atisti cs.  
C GI -I: 
T h e  C GI -I  at  6  m o nt hs  will  b e  a n al y z e d  usi n g a  R o b ust  G e n er al  Li n e ar  M o d el  usi n g  a r a n k -
b as e d  a n al ysis  ( Wil c o x o n  s c or es).    A n al ysis    will  i n cl u d e  t h e  fi x e d,  c at e g ori c al  eff e cts  of 
tr e at m e nt, str atifi c ati o n f a ct ors  a n d  n o i nt er a cti o n. 
Vi n el a n d II:  
T h e  c h a n g e i n  e a c h  Vi n el a n d II  s u bs c or e fr o m  b as eli n e t o  6  m o nt h  will  b e  c o m p ar e d  b et w e e n 
B u m et a ni d e  gr o u p  a n d  pl a c e b o  gr o u p  usi n g  a  g e n er al li n e ar  m o d el  wit h  b as eli n e  s u bs c or e  a n d 
str atifi c ati o n f a ct ors  as  c o v ari at es. 
T h e  Vi n el a n d  II  s u bs c or es  will  b e  s u m m ari z e d  b y tr e at m e nt  gr o u p  at  e a c h  pl a n n e d  visit  f or 
e a c h  p eri o d  ( d o u bl e -bli n d  tr e at m e nt  p eri o d  a n d  o p e n -l a b el  a cti v e  tr e at m e nt  p eri o d)  usi n g 
d es cri pti v e st atisti cs.  
P e ds Q L:  
T h e  P e d s Q L  q u esti o n n air e  will  b e  s u m m ari z e d  b y tr e at m e nt  gr o u p  at  e a c h  pl a n n e d  visit  f or 
e a c h  p eri o d  ( d o u bl e -bli n d  tr e at m e nt  p eri o d  a n d  o p e n -l a b el  a cti v e  tr e at m e nt  p eri o d)  usi n g 
d es cri pti v e st atisti cs.  
W H O Q O L -B r ef:  
T h e    W H O Q O L -Br ef  q u esti o n n air e   will  b e  s u m m ari z e d  b y  tr e at m e nt  gr o u p  at  e a c h  pl a n n e d 
visit  f or  e a c h  p eri o d  ( d o u bl e -bli n d  tr e at m e nt  p eri o d  a n d  o p e n -l a b el  a cti v e  tr e at m e nt  p eri o d) 
usi n g  d es cri pti v e st atisti cs.  
1 0. 2. 2. 4. 4.  S u b g r o u p  a n al ys es  
A d diti o n al  d es cri pti v e  a n al ys es  c o ul d  b e  pr o vi d e d i n s u b p o p ul ati o n  of i nt er est. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 4 /2 9 6  
 
1 0. 2. 2. 5.    E x pl o r at o r y  a n al ysis 
E Q - 5 D-3 L:  
E a c h i n d e x  utilit y  d eri v e d fr o m t h e  E Q - 5 D-3 L  will  b e s u m m ari z e d  b y tr e at m e nt  gr o u p  at  e a c h 
pl a n n e d  visit  f or  e a c h  p eri o d  ( d o u bl e -bli n d tr e at m e nt  p eri o d  a n d  o p e n -l a b el  a cti v e tr e at m e nt 
p eri o d)  usi n g  d es cri pti v e st atisti cs.  
1 0. 2. 2. 6.    S af et y  a n al ysis 
1 0. 2. 2. 6. 1.  A d v e rs e  e v e nts  
D o u bl e- bli n d tr e at m e nt  p eri o d:  
N u m b er  of  e v e nts,  n u m b er  a n d  p er c e nt a g e  of  p ati e nts  r e p orti n g  at l e ast  o n e  e v e nt,  pr es e nt e d 
b y  pri m ar y  s yst e m  or g a n  cl ass,  a n d  pr ef err e d t er m  will  b e  pr o vi d e d f or  s eri o us  a d v ers e  e v e nts 
a n d  e m er g e nt  a d v ers e  e v e nts  u n d er tr e at m e nt  d uri n g t h e  d o u bl e -bli n d tr e at m e nt  p eri o d i n t h e 
S af et y  S et.  
E m er g e nt  a d v ers e  e v e nts  will  b e  d es cri b e d  a c c or di n g t o t h e s eri o us n ess, t h e i nt e nsit y, t h e  
r el ati o ns hi p, t h e  a cti o n t a k e n r e g ar di n g t h e I M P, t h e r e q uir e m e nt  of  a d d e d t h er a p y,  a n d t h e 
o ut c o m e. 
Of  n ot e, t h e s eri o us n ess  a n d t h e r el ati o ns hi p t o t h e I M P  of t h e  a d v ers e  e v e nt  c orr es p o n d t o t h e 
i n v esti g at or  o pi ni o n  or,  i n  c as e  of  e v e nts  u p gr a d e d  b y  t h e  s p o ns or  f or  s eri o us n ess  or  f or 
c a us alit y i n  c as e  of  S A E, t o t h e s p o ns or  o pi ni o n. 
O p e n -l a b el  a cti v e tr e at m e nt  p eri o d: 
T h e  s a m e  a n al ysis    will  b e  p erf or m e d  f or  a d v ers e  e v e nts  o c c urr e d  or    w ors e n e d  d uri n g  t h e 
o p e n- l a b el  a cti v e tr e at m e nt  p eri o d i n t h e  S af et y  S et. 
P ost -tr e at m e nt  p eri o d: 
All  a d v ers e  e v e nts r e p ort e d  aft er t h e l ast s t u d y  dr u g i nt a k e  will  b e list e d. 
1 0. 2. 2. 6. 2.  Cli ni c al l a b o r at o r y  e v al u ati o n  
F or  cli ni c al  l a b or at or y  p ar a m et ers,  t h e  f oll o wi n g  a n al ys es    will  b e  p erf or m e d  b y  tr e at m e nt 
p eri o d ( d o u bl e- bli n d tr e at m e nt  p eri o d  a n d  o p e n- l a b el  a cti v e tr e at m e nt  p eri o d): 
­ N u m b er  a n d  p er c e nt a g e  o f  p ati e nts   wit h  at  l e ast  o n e  hi g h/l o w  e m er g e nt  a b n or m al  v al u e 
u n d er tr e at m e nt,  a c c or di n g t o t h e l a b or at or y r ef er e n c e r a n g es  a n d t o t h e  c ut -offs f or  P C S A 
v al u es.  
­ L a b or at or y   p ar a m et ers   cl assifi e d   ( n u m b er   a n d   p er c e nt a g e   of   p ati e nts  i n   e a c h   cl ass) 
a c c or di n g t o t h es e r ef er e n c e r a n g es  a n d  c ut-offs,  a n d  usi n g  s hift t a bl es fr o m  b as eli n e t o t h e 
w orst ( hi g h  a n d/ or l o w)  v al u es  u n d er tr e at m e nt. 
1 0. 2. 2. 6. 3.  Vit al si g ns,  cli ni c al  e x a mi n ati o n  a n d  ot h e r  o bs e r v ati o ns  r el at e d t o s af et y  
1 0. 2. 2. 6. 3. 1.  Vit al si g ns  a n d  cli ni c al  e x a mi n ati o n  
Vit al  si g ns  a n d  cli ni c al  e x a mi n ati o n    will  b e  d es cri b e d  b y  tr e at m e nt  p eri o d  ( d o u bl e -bli n d 
tr e at m e nt  p eri o d  a n d  o p e n-l a b el  a cti v e tr e at m e nt  p eri o d), i n t er ms  of  v al u e  at  b as eli n e,  v al u e 
at  e a c h  p ost-b as eli n e  visit  u n d er tr e at m e nt;  as  w ell  as i n t er ms  of  c h a n g e fr o m  b as eli n e t o  e a c h 
p ost  b as eli n e  visit  u n d er tr e at m e nt.  


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 5 /2 9 6  
 
1 0. 2. 2. 6. 3. 2.  El e ct r o c a r di o g r a m  
Pr es e n c e  of  cli ni c all y si g nifi c a nt  E C G  a b n or m aliti es ( y es/ n o)  will  b e list e d f or  e a c h i n di vi d u al  
p ati e nts.  
1 0. 2. 2. 7.  Pl a n n e d i nt e ri m  a n al ysis  
N o f or m al  effi c a c y i nt eri m  a n al ysis is  pl a n n e d.  
1 0. 2. 3.  Ot h e r  e n d p oi nts  a n al ysis 
1 0. 2. 3. 1.  P h a r m a c o ki n eti cs  
P h ar m a c o ki n eti c i nt er pr et ati o n  
T o  ass ess  P K  pr ofil es  of  b u m et a ni d e i n  c hil dr e n,  a  p o p ul ati o n  p h ar m a c o ki n eti c  m o d el  will  b e 
b uilt  usi n g t h e s p ars e  c o n c e ntr ati o ns ti m e  d at a  of  b u m et a ni d e  c oll e ct e d i n t h e  p h as e III st u di es 
as  well  as t h e  d at a fr o m  p h as e II b  st u d y.  T h e  p o p ul ati o n  P K  a n al ysis  will  pr o vi d e  p o p ul ati o n 
P K  p ar a m et ers  a n d  t h eir  ass o ci at e d  v ari a bilit y .  I n  t his  a n al ysis,  t h e  p ot e nti al  i nfl u e n c e  of 
c o v ari at es   will  b e  als o  i n v esti g at e d.  I n di vi d u al  s e c o n d ar y  P K  p ar a m et ers (s u c h  as A U C 1 2,ss, 
C mi n )   will  b e  d eri v e d  fr o m  t h e    m o d el  f or  e a c h  p ati e nt.   T h e  p o p ul ati o n  P K  a n al ysis   will  b e 
d et ail e d i n  a s e p ar at e  D at a  A n al ysis  Pl a n.  
E x pl or at or y   ass ess m e nt   of   t h e   r el ati o ns hi p   b et w e e n   e x p os ur e   a n d   p h ar m a c o d y n a mi cs 
( effi c a c y  a n d   p ot e nti ally  s af et y)    will   b e   p erf or m e d  a n d  if  a p pli c a bl e,   p o p ul ati o n   P K/ P D 
m o d els  will  b e  d e v el o p e d  a n d  a  D at a  A n al ysis  Pl a n  will  b e s et  u p. 
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 R B/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 o ri 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 
dist ri b uti o n  of  m o nit ori n g r e p orts. 
­ I n d e p e n d a nt  a u dit  m a y  b e  c o n d u ct e d  b y I RI S t o  e ns ur e  m o nit ori n g  pr a cti c es  ar e  p erf or m e d 
c o nsist e ntl y  a cr oss  all  p arti ci p ati n g sit es  a n d t h a t  m o nit ors  ar e f oll o wi n g t h e  C M P. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 6 /2 9 6  
 
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.  
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 i n  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 es   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 ed   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 ase  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. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 7 /2 9 6  
 
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. 
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: 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
 7 8 /2 9 6  
 
­ gi v e  a c cess 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 ble f or 
t h e  au dit t o  t h e  co m p ut eris e d  m e di c al  files  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  stu d y, if t h e tr a c kin g of t h e  c h a n g es 
m a d e  to  t h e  me di c al fil es  ca n n ot  b e a c c ess e d  i n t h e  co m p ut er.  
1 2. 4.  S u p e r vis o r y   c o mmitt e es  
I n t h e fr a m e of  t his st u d y, a D at a  M o nit ori n g  C o m mitt e e  ( D M C)  will  be s et  up. 
A c c or di n g   t o   t h e   “ G ui d eli n e   o n   d at a    
m o nit ori n g   c o m mitt e es ”  
( G ui d eli n e 
C H M P/ E W P/ 5 8 7 2/ 0 3  C orr.,  2 7  J ul y  2 0 0 5) , t h e  d e cisi o n t o  s et  u p  of  a  D M C  s h o ul d t a ke i nt o 
a c c o u nt  t h e st u d y p o p ul ati o n  as w ell  as t h e st u d y d ur ati o n.  T h e  pr es e nt  st u d y t a k es pl a c e  i n 
p arti ci p a nts  a g e d fr o m 2  t o 7   wit h  A S D.  As  t his v ul n er a bl e  p o p ul ati o n  will  b e  e x p os e d  t o 
st u d y tr e at m e nt f or  u p t o  5 6  w e e ks f oll o w e d  b y  a  6  w e e k  dis c o nti n u ati o n  p eri o d, t h e  s et- u p  of 
a  D M C is j ustifi e d i n  or d er t o  d et e ct  a n y  p ot e nti al  h ar m t o  p ati e nts  as  e arl y  as  p ossi bl e. 
All  al o n g t h e st u d y, i n or d er  t o e ns ur e p ati e nts’  s af et y,  t h e   D M C will  b e  r es p o nsi bl e f or a 
f oll o w u p  of  t h e p ati e nts  b y  a  p eri o di c al  r e vi e w of  s af et y d at a  i n cl u di n g all a d v ers e  e v e nts 
wit h  all  h y p o k al a e mi a.    T h e  D M C  will  tr e at all d at a  as stri ctl y  c o nfi d e nti al a n d will  n ot 
dis cl os e t h e m t o  a n y o n e   els e t h a n  m e m b ers  of t h e  D M C. 
D M C  r e c o m m e n d ati o ns will  b e  f or w ar d e d t o t h e I E C/ C o m p et e nt  A ut h oriti es o nl y if  r el e v a nt 
f or t h e  s af et y  of  p arti ci p a nts.  D et ails  of t h e r ol e  a n d  or g a nis ati o n  of t h e  D M C  ar e  d et ail e d i n  a 
s e p ar at e  D M C  c h art er. 
1 3. E T HI C S
1 3. 1.  I nstit uti o n al  R e vi e w  Bo a r d(s)/I n d e p e n d e nt  Et hi cs   Co 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 ass e nt/ c o ns e nt  f or m" d o c u m e nt,  t h e 
" 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 ( a d a pt, if  a p pli c a bl e), 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 I n v esti g at or’s Br o c h ur e  of 
a d mi nist er e d  I M Ps  will  b e  s u b mitt e d  t o  I E C(s) b y  t h e  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 R B/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   co n d u ct  
T h e st u d y  will b e p e rf or m e d in  a c c or d a n c e  wit h t h e  et hi c al  pri n ci ples st at e d i n t h e  De cl ar ati o n  
of H elsi n ki  1 9 6 4,  as re vis e d i n  F ort al e z a,  2 0 1 3  P arti ci p a nt inf or m ati o n  a n d i nf or m e d co ns e nt 
1 3. 3.  P a rti ci p a n t i nf o r m ati o n  a nd  i nf o r m e d  co ns e nt  
I n a n y c as e, t h e p arti ci p a nt  a n d his/ h er  p ar e nt/l e g a l r e pr es e nt ati v e m us t b e  i nf or m e d t h at 
h e/s h e is entitl e d t o  b e i nf or m e d  a b o ut th e o u t c o m e of th e st u d y  b y t h e in 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  hi m/ h er  is t o c oll e ct writt e n  ass e nt  fr o m e a c h 
p arti ci p a nt  ( as m u c h  as  p ossi bl e),  w h e n   o f a p pr o pri at e  i nt ell e ct u al m at urit y  a n d    writt e n 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  7 9 /2 9 6  
 
c o ns e nt  f or m(s)  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 
a n d  his/ h er  c ar e gi v er ( w h e n  a p pli c a bl 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 Ps.    T h e   p arti ci p a nt,   his/ h er   p ar e nt(s)/l e g al 
r e pr es e nt ati v e  a n d  his/ h er  c ar e gi v er  ( w h e n  a p pli c a bl e)    m ust  b e  i nf or m e d  t h at  t he y  h a v e  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 t h e y  ar e fr e e t o r e c o nsi d er  ass e nt/ c o ns 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  a n d t h e  c ar e gi v er  ( w h e n  a p pli c a bl 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  ass e nt/ c o ns 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  a n d   his/ h er  c ar e gi v er 
( w h e n  a p pli c a bl 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 st 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. 
W h e n   a p pli c a bl e  t w o   ori gi n al   p ati e nt   c ar e gi v er  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  c ar e gi v er  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.    T w o  ori gi n al  p arti ci p a nt  i nf or m ati o n  a n d 
ass 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. 
T h e  p arti ci p a nt,  his/ h er  p ar e nt(s)/l e g al r e pr es e nt ati v e  a n d t h e  c ar e gi v er ( w h e n  a p pli c a bl 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  ass e nt/ c o ns e nt f or m,  si g n e d  b y t h e i n v esti g at or 
a n d  b y t h e 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  p arti ci p a nt  e nt eri n g  i n  a  n e w  a g e  s et  ( 7 -8 y o;  9 -1 1 y o;  1 2 -1 8 y o;  p ati e nt  b e c o mi n g    m aj or) 
m ust  si g n  a  n e w  ass e nt f or m/I C F,  d e p e n di n g  o n  p ati e nt’s l e v el  of  u n d erst a n di n g  a c c or di n g t o 
i n v esti g at or’s j u d g e m e nt,  c orr es p o n di n g t o  his/ h er  n e w  a g e s et. 
I n   c as e   of   a n y   u nf or es e e n   c o n diti o n   t h at   n e c essit at es   eit h er   a n   i nt eri m   or   p er m a n e nt 
r e pl a c e m e nt of  t h e  c ar e gi v er,  t h e   p ers o n  r e pl a ci n g  t h e  c ar e gi v er    m ust  si g n  a n  i nf or m e d 
c o ns e nt. 
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 ms f or t h e  p arti ci p a nt,  his/ h er  p ar e nt(s)/l e g al 
r e pr es e nt ati v e  a n d  his/ h er  c ar e gi v er ( w h e n  a p pli c a bl 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,  i n  t h e   " 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  a n d  i n  t h e  “I nf or m a nt  i nf or m ati o n 
a n d  c o ns e nt f or m ”  att a c h e d t o t h e  pr ot o c ol 
                                                 
* 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 ar e  b e  pr e p ar e d:  o n e f or t h e  p arti 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 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 0 /2 9 6  
 
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 ass e nt/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 R B/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 ass e nt/ 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 R B/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  his/ h er  p ar e nts/l e g al  r e pr es e nt ati v es  a n d 
his/ h er  c ar e g i v er  ( w h e n  a p pli c a bl e)    m ust  c o m pl et e,  d at e  a n d  si g n  t w o  ori gi n als  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 ass e nt/ 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 o n d u ct e d 
t h e  i nf or m e d  c o ns e nt  dis c ussi o n.   H e/s h e   will  r e c ei v e  o n e  si g n e d  ori gi n al  a m e n d m e nt  t o  t h e 
i nf or m ati o n  a n d ass e nt/ c o ns e nt f or m. 
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. 
D at a  e ntr y  at  t h e i n v esti g at or’s  sit e  will  b e  p erf or m e d  b y t h e i n v esti g at or  or  b y t h e  d esi g n at e d 
p ers o n fr o m  his/ h er t e a m  aft er  c o m pl eti o n  of t h e  p arti ci p a nt’s  M e di c al  Fil e.  
U p o n  e ntr y,  d at a    will  b e  tr a ns mitt e d  vi a  t h e  I nt er n et  fr o m  t h e  st u d y  c e ntr e  t o  t h e  st u d y 
d at a b a s e. 
T h e i n v esti g at or  or t h e  d esi g n at e d  p ers o n fr o m  his/ h er t e a m  a gr e es t o  c o m pl et e t h e  e -C R F,  at 
e a c h  p arti ci p a nt  visit,  a n d  all  ot h er  d o c u m e nts  pr o vi d e d  b y  t h e  s p o ns or  ( e. g.  d o c u m e nts 
r el ati n g t o t h e I M P  m a n a g e m e nt …). 
T h e  e C R F  s h o ul d  b e  c o m pl et e d  wit hi n  5  d a ys  aft er t h e  visit  of  p arti ci p a nt  a n d  b ef or e t h e  n e xt 
s c h e d ul e  visit. 
D at a  r e c or d e d  dir e ctl y  o n  e -C R F  a n d  c o nsi d er e d  as  s o ur c e  d at a  (s e e  S e cti o n 4. 6 )    m ust  b e 
c oll e ct e d  i m m e di at el y  i n  t h e  e -C R F.   T h e  ot h er  e -C R F  f or ms    m ust  b e c o m pl et e d  as  s o o n  as 
p ossi bl e f oll o wi n g  e a c h  visit. 
All  c orr e cti o ns  of  d at a  o n t h e  e -C R F  m ust  b e  m a d e  b y t h e i n v esti g at or  or  b y t h e  d esi g n at e d 
p ers o n  fr o m   his/ h er  t e a m   usi n g   el e ctr o ni c   d at a   cl arifi c ati o ns   a c c or di n g  t o  t h e   pr o vi d e d 
i nstr u cti o ns.    All  d at a    m odifi c ati o n    will  b e  r e c or d e d  usi n g  t h e  a u dit  tr ail  f e at ur e  of  I nf or m 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 1 /2 9 6  
 
s oft w ar e,  i n cl u di n g  d at e,  r e as o n  f or    m o difi c ati o n  a n d  i d e ntifi c ati o n  of  t h e  p ers o n    w h o  h as 
m a d e t h e  c h a n g e.  
I n  or d er t o  e ns ur e  c o nfi d e nti alit y  a n d  s e c urit y  of t h e  d at a,  us er n a m es  a n d  p ass wor ds  will  b e 
us e d  t o  r estri ct  s yst e m  a c c ess  t o  a ut h oris e d  p ers o n n el   o nl y,    w h et h er  r esi d e nt    wit hi n  t h e 
i n v esti g at or’s sit es, t h e s p o ns or  or t hir d  p arti es. 
D at a  will  b e  v erifi e d i n  a c c or d a n c e  wit h t h e  m o nit ori n g  str at e g y  d efi n e d  f or t h e  st u d y.  Aft er 
c o m p ari n g   t h es e   d at a   t o   t h e   s o ur c e   d o c u m e nts,   t h e    m o nit or    will   r e q u est   c orr e cti o n   / 
cl arifi c ati o n fr o m t h e i n v esti g at or  usi n g  el e ctr o ni c  d at a  cl arifi c ati o ns t h at  s h o ul d  b e  a ns w er e d 
a n d  cl os e d  as  q ui c kl y  as  p ossi bl e.  
D at a  c a n  b e  fr o z e n  d uri n g  t h e  st u d y  aft er t h eir  v ali d ati o n.  H o w e v er  t h e  i n v esti g at or  h as  t h e 
p ossi bilit y t o  m o dif y  a  d at a if  d e e m e d  vi a  a r e q u est t o t h e s p o ns or. 
Aft er t h e l ast  visit  of t h e  p arti ci p a nt  at t h e  d o u bl e -bli n d  2 4  w e e k tr e at m e nt  p eri o d  a n d  at t h e 
o p e n  l a b el  2 8  a cti v e  tr e at m e nt  p eri o d,  t h e  i n v esti g at or  or  c o -i n v esti g at or    m ust  att est  t h e 
a ut h e nti cit y  of t h e  d at a  c oll e ct e d i n t h e  e- C R F  b y  e nt eri n g  his/ h er  us er  n a m e  a n d  p ass w or d. 
Aft er  t h e  fi n al  d at a  b as e  l o c k,  t h e  i n v esti g at or,  or  a n  a ut h oris e d   m e m b er  of  t h eir  t e a m,   will 
h a v e t o  d o w nl o a d  fr o m t h e   e-C R F  a n  el e ctr o ni c  fil e  c o nt ai ni n g  p arti ci p a nt  d at a  fr o m  his/ h er 
c e ntr e f or  ar c hi vi n g i n t h e st u d y fil e (s e e  S e cti o n  1 4. 3 ). 
1 4. 2.  D at a  m a n a g e m e nt 
D at a  ar e  c oll e ct e d  vi a  a  e C R F  a n d st or e d i n  a s e c ur e d  d at a b as e.  
F or   d at a   c oll e ct e d   o n  t h e   e -C R F, Cli ni c al    D at a    M a n a g e m e nt    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   pr o c essi n g   i n cl u di n g   d at a   v ali d ati o n   p erf or m e d   a c c or di n g   t o   a 
s p e cifi c ati o n    m a n u al  d es cri bi n g  t h e  c h e c ks  t o  b e  c arri e d  o ut.   As  a  r es ult  of  d at a  v ali d ati o n, 
d at a    m a y   r e q uir e   s o m e   c h a n g es.    A n   el e ctr o ni c   d at a   cl arifi c ati o n   f or m   is   s e nt   t o   t h e 
i n v esti g at or  w h o is  r e q uir e d t o  r es p o n d t o t h e  q u er y  a n d  m a k e  a n y  n e c ess ar y  c h a n g es t o t h e 
d at a.  
F or  d at a  c oll e ct e d  o n  p a p er  f or m  ( V A B SII),  t h e Cli ni c al   D at a    M a n a g e m e nt   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  pr o c essi n g i n cl u di n g: 
- 
D at a  e ntr y:  i n d e p e n d e nt,  bli n d,  d o u bl e  d at a  e ntr y    wit h  a  t hir d  p ers o n  r es ol vi n g  a n y 
dis cr e p a n c y b et w e e n first  a n d s e c o n d  e ntr y, 
- 
D at a  v ali d ati o n  p erf or m e d  a c c or di n g t o  a  s p e cifi c ati o n  m a n u al  d es cri bi n g t h e  c h e c ks t o 
b e  c arri e d  o ut.  As  a  r es ult  of  d at a  v ali d ati o n,  d at a  m a y  r e q uir e  s o m e  c h a n g es.  A  d at a 
cl arifi c ati o n   f or m  is   s e nt  t o  t h e  i n v esti g at or   f or   c o nfir m ati o n   or   c orr e cti o n   a n d 
si g n at ur e.  I n  s o m e  c as es,    m e nti o n e d  i n  t h e  s p e cifi c ati o n    m a n u al,  c h a n g es  ( o b vi o us  
err ors)  ar e  n ot  s u bj e ct t o t h e i n v esti g at or’s  a p pr o v al.  A r e c or d  of t h es e  d at a  c h a n g es is 
pr o vi d e d t o t h e i n v esti g at or  w h e n t h e st u d y is  c o m pl et e d. 
F or  d at a  tr a nsf err e d  fr o m   C R Os  ( C e ntr al  l a b or at or y,   E C G,  I R S,  P K),  t h e    D at a    &   Cli ni c al 
L o gisti cs  of  I. R.I. S .  is  r es p o nsi bl e  f or  d at a  tr a nsf er:    C R Os  pr o vi d e  el e ctr o ni c  tr a nsf er  of 
c o m p ut eris e d   d at a   t o   t h e Cli ni c al    D at a    M a n a g e m e nt    D e p art m e nt of   I. R.I. S.    D at a   ar e 
tr a nsf err e d  a c c or di n g t o  a tr a nsf er  pr ot o c ol iss u e d  b y t h e I. R.I. S.  d at a  m a n a g er. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 2 /2 9 6  
 
T h e  M e di c al  D at a  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  r el at e d  t o  a d v ers e  e v e nts  usi n g 
M e d D R A,  
­ m e di c ati o ns  usi n g  W H O -D D.  
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 at i 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 R B/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.  
At t h e  e n d  of t h e  d o u bl e - bli n d  2 6 w e e k tr e at m e nt  p eri o d,  w h e n  d at a  v ali d ati o n is  a c hi e v e d,  a 
bli n d r e vi e w  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 ad e  a v ail a bl e f or  d at a  a n al ysis.  
At t h e  o p e n l a b el  2 6  w e e k a cti v e tr e at m e nt  p eri o d,  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 e w 
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  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 oris e d    m e m b er   of  t h eir  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  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 a ti o n  of t h e  ar c hi vi n g  p eri o d. T h es e  d at a i n cl u d e  all  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.  
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 bilit 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. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 3 /2 9 6  
 
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. 
S er vi er’s 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-
p ort 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 vier’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   C h 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 a ls.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. 
 
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. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 4 /2 9 6  
 
A ut h ors  a n d si g n at or y(i es)  of t h e  p u bli c ati o n(s) s h all  b e  d efi n e d  as  p er t h e  p u bli c ati o n  p oli c y. 
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  sp 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. 
Wit h  t h e  a gr e e m e nt  of  t h e  p arti ci p a nt  a n d  his  p ar e nts/l e g al  r e pr es e nt ati v es,  t h e  i n v esti g at or 
will  i nf or m  t h e  p arti ci p a nt’s  g e n er al  pr a ctiti o n er  a b o ut  his/ h er  p ati e nt’s  p arti ci p ati o n  i n  t h e 
cli ni c al st u d 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(s)  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  wi t 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 R B/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 R B/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 R B/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 i n  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 as f oll o ws:  
- a  pri m ar y  cli ni c al r e p ort  aft er t h e  6 - m o nt h  d o u bl e- bli n d  p eri o d,  
- a  m ai n  cli ni c al r e p ort  aft er t h e  6 - m o nt h  o p e n l a b el  p eri o d  wit h t h e  6- w e e k f oll o w- u p  p eri o d,  
-  a n  a d d e n d u m t o t h e r e p ort f or t h e  o pti o n al  6- m o nt h  e xt e nsi o n  p eri o d i n  o p e n l a b el. 
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( s) 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(s)  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. 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 5 /2 9 6  
 
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 Pa 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,  
­ s u p pl y t h e i n v esti g at or  wit h  S m P C, t h e  o n e  b est s uit e d t o  e ns ur e  p arti ci p a nt s af et y,  a n d  a n y 
p ot e nti al  u p d at e d  v ersi o n  d uri n g t h e st u d y: 
 f or  t h e  t est  dr u g  if    m ar k et e d,  t o  b e  a p p e n d e d  t o  I n v esti g at or’s  br o c h ur e  (s e cti o n  4. 
G ui d a n c e f or t h e i n v esti g at or 
­ 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 i n v esti g at or  or  c o or di n at or(s)  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 hic h is t o  b e  s e nt t o t h e 
I E C(s). 
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 0 8  a n d st u d y  C L 3- 9 5 0 0 8- 0 0 2 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 is 
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. 
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 a t 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 t h eir r e q u est. 
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.  
A  p arti ci p a nt  s cr e e ni n g l o g  a n d  a f ull i d e ntifi c ati o n  a n d  e nr ol m e nt list  of  e a c h  p arti ci p a nt  will 
b e  c o m pl et e d  a n d  k e pt i n  a  s af e  pl a c e  b y t h e i n v esti g at or  w h o  s h o ul d  a gr e e t o  pr o vi d e  a c c ess 
o n sit e  t o t h e  a u dit or  a n d/ or 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.  T h e i nf or m ati o n 
will  b e tr e at e d i n  c o m pli a n c e  wit h  pr of essi o n al s e cr e c y.  
T h e  p arti ci p a nt  s cr e e ni n g  l o g    m ust  b e  c o m pl et e d  fr o m  t h e    m o m e nt  t h e  i n v esti g at or  c h e c ks 
t h at  a  p arti ci p a nt  c o ul d  p ot e nti all y t a k e  p art i n t h e st u d y ( b y  ass ess m e nt  of  p arti ci p a nt  m e di c al 
hist or y  d uri n g  a  visit  or  b y  e x a mi n ati o n  of t h e  m e di c al fil e). 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 6 /2 9 6  
 
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  (i n d e p e n d e nt  r at er,  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,  n e p hr 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 uip m e nt,  a n d t h e r ef er 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 cess  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).   


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 7 /2 9 6  
 
1 8.  R E F E R E N C E S  
   
   
    
 
 
 
 
C ell ot  G,  C er u bi ni  E,  G A B A er gi c  si g n ali n g  as t h er a p e uti c t ar g et  f or  a utis m  s p e ctr u m  dis or d ers,  Fr o nti ers i n 
p e di atri cs – C hil d  a n d  N e ur o d e v el o p m e nt al  Ps y c hi atr y,  2 0 1 4 J ul y,  V ol u m e  2. [ P E 0 1 4 5 6 4 5]  
 
 
 
C o g hl a n  S,  H or d er  J, I n kst er  B,  M e n d e z  M. A n dr ei n a,   M ur p h y  D G,  G A B A  s yst e m  d ysf u n cti o n i n  a utis m  a n d 
r el at e d  dis or d ers:  Fr o m  s y n a ps e  t o  s y m pt o ms,    N e ur os ci e n c e  a n d    Bi o b e h a vi or al    R e vi e ws  3 6  ( 2 0 1 2)  2 0 4 4–
2 0 5 5. [ P E 0 1 4 5 6 4 1]  
 
 
C ost a nti n o, J N ,  Gr u b er  C P, ( 2 0 1 2).  S o ci al  R es p o nsi v e n ess  S c al e,  S e c o n d  E diti o n ( S R S-2) ( M a n u al).  T orr a n c e, 
C A:  W est er,  Ps y c h ol o gi c al  S er vi c es  
 
 
 
G u y    W. - 0 2 8   C GI:   Cli ni c al    Gl o b al  I m pr essi o n.  I n:   E C D E U  ass ess m e nt    m a n u al f or  ps y c h o p h ar m a c ol o g y; 
1 9 7 6,  2 1 7 -2 2 2.  B o o k  c h a pt er. [ P E 0 0 3 5 1 7 7]  
 
 
H a dji k h a ni  N,  Z ür c h er  N R,  R o gi er  O,  R u est  T,  Hi p p ol yt e  L,  B e n -Ari  Y,  L e m o n ni er  E.. I m pr o vi n g  e m oti o n al 
f a c e   p er c e pti o n  i n   a utis m wit h   di ur eti c   b u m et a ni d e:   a   pr o of -of -c o n c e pt   b e h a vi or al   a n d  f u n cti o n al   br ai n 
i m a gi n g  pil ot st u d y.  A utis m.  2 0 1 5  F e b; 1 9( 2): 1 4 9-5 7. [ P E 0 1 4 5 3 0 2]  
 
 
 
 
K h a n n a  R,  J ari w al a  K,  B e ntl e y  J P.  H e alt h  utilit y  ass ess m e nt  usi n g  E Q -5 D  a m o n g  c ar e gi v ers  of  c hil dr e n  wit h 
a utis m.  V al u e  H e alt h.  2 0 1 3 J ul -A u g; 1 6( 5): 7 7 8 -8 8. [ P E 0 1 4 5 6 4 3]  
 
 
L e m o n ni er    E,    D e gr e z    C,   P h el e p    M,    T y zi o    R,  J oss e   F,    Gr a n d g e or g e    M,    H a dji k h a ni    N,  B e n -Ari    Y.    A 
r a n d o mis e d  c o ntr oll e d tri al  of  b u m et a ni d e i n t h e tr e at m e nt  of  a utis m i n  c hil dr e n.  Tr a nsl  Ps y c hi atr y.  2 0 1 2  D e c 
1 1; 2: e 2 0 2. [ P E 0 1 4 5 3 1 2]  
 
 
L e m o n ni er  E,  B e n -Ari  Y.  T h e  di ur eti c  b u m et a ni d e  d e cr e as es  a utisti c  b e h a vi o ur i n fi v e i nf a nts tr e at e d  d uri n g  3 
m o nt hs  wit h  n o si d e  eff e cts.  A ct a  P a e di atr.  2 0 1 0  D e c; 9 9( 1 2): 1 8 8 5 -8. [ P E 0 1 4 5 3 1 3]  
 
 
L or d    C,    R utt er    M,    Di L a v or e  P C,    Risi  S,    G ot h a m    K,    Bis h o p  S L ( 2 0 1 2).    A utis m    Di a g n osti c    O bs er v ati o n al 
S c h e d ul e  M o d ul es  1 -4,  S e c o n d  E diti o n ( M a n u al).  T orr a n c e,  C A  W est er,  Ps y c h ol o gi c al  S er vi c es  
   
   
    
 
M ars h all  W A,  T a n n er  J M.  V ari ati o ns i n  P at er n  of P u b ert al  C h a n g es i n  B o ys.  Ar c h.  Dis.  C hil d h. 1 9 7 0;  4 5: 1 3 -
2 3. [ P E 0 0 7 6 1 4 1]  
   
   
   
 
 
M ars h all  W A,  T a n n er J M.  V ari ati o ns i n  P at er n  of  P u b ert al  C h a n g es i n  Girls.  Ar c h.  Dis.  C hil d h. 1 9 6 9;  4 4: 2 9 1 -
3 0 3. [ P E 0 0 7 6 1 4 0]  
 
 
 
P os n er  K,  Br o w n  G K,  St a nl e y  B,  Br e nt, D A,  Y ers h o v a  K V,  O q u e n d o  M A,  C urri er  G W,  M el vi n  G A,  Gr e e n hill 
L,  S h e n  S,    M a n n  JJ.   T h e    C ol u m bi a -S ui ci d e  S e v erit y  r ati n g  S c al e:  i niti al  v ali dit y  a n d  i nt er n al  c o nsist e n c y 
fi n di n gs  fr o m  t hr e e    m ultisit e  st u di es    wit h  a d ol es c e nts  a n d  a d ults.    A m  J  Ps y c hi atr y  2 0 1 1;  1 6 8:  1 2 6 6-1 2 7 7. 
[ P E 0 1 2 0 1 2 2] 
 
 
P os n er    K,    O q u e n d o    M A,    G o ul d    M,  St a nl e y    B,    D a vi es    M.    C ol u m bi a  Cl assifi c ati o n    Al g orit h m  of  S ui ci d e 
Ass ess m e nt  ( C -C A S A):  cl assifi c ati o n   of  s ui ci d al  e v e nts  i n  t h e   F D A's   p e di atri c  s ui ci d al  ris k  a n al ysis   of 
a nti d e pr ess a nts.  A m J  Ps y c hi atr y  2 0 0 7;  1 6 4( 7): 1 0 3 5 -4 3. [ P E 7 2 7 8 3]  
 
 
S c h o pl er E,   V a n   B o ur g o n di e n    M E,  W ell m a n   GJ,   L o v e  S R  ( 2 0 1 0).   C hil d h o o d  A utis m   R ati n g  S c al e,  S e c o n d 
E diti o n ( M a n u al).  T orr a n c e,  C A  W est er,  Ps y c h ol o gi c al  S er vi c es  
 
 
S h a pir o  M,  Sil v a  S G,  C o m pt o n  S,  C hris m a n  A,  D e V e a u g h -G eiss  J,  Br el a n d -N o bl e  A,  K o n d o  D,  Kir c h n er  J, 
M ar c h  J S.    T h e  c hil d  a n d  a d ol es c e nt  ps y c hi atr y  tri als  n et w or k  ( C A P T N):  i nfr astr u ct ur e  d e v el o p m e nt  a n d 
l ess o ns l e ar n e d.  C hil d  a n d  A d ol es c e nt  Ps y c hi atr y  a n d  M e nt al  H e alt h  2 0 0 9;  3( 1 2):  1-1 3. [ P E 0 0 7 6 1 0 5]  
 
S c h w ar z  GI,  M u ñ o z  A,  S c h n ei d er  M F,  M a k  R H,  K as k el  F,  W ar a d y  B A,  F urt h  SI;  N e w  e q u ati o ns t o  esti m at e 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 8 /2 9 6  
 
G R F i n  c hil dr e n  wit h  C K D. J  A m  S o c  N e p hr ol.  2 0 0 9  M ar.  2 0 ( 3):  6 2 9 -3 7  
 
 
V ar ni J W,  S ei d M,  R o d e  C A.  T h e  P e ds Q L:  m e as ur e m e nt  m o d el f or t h e  p e di atri c  q u alit y  of lif e i n v e nt or y.  M e d 
C ar e.  1 9 9 9  F e b; 3 7( 2): 1 2 6 -3 9. [ P E 0 0 7 0 1 8 4]  
 
   
 
 
T h e    W H O Q O L    Gr o u p.    T h e    D e v el o p m e nt   of  t h e    W H O    Q u alit y   of    Lif e  Ass ess m e nt   I nstr u m e nt   ( T h e 
W H O Q O L) i n  Orl e y  J  a n d  K u y k e n  W  ( e ds).  Q u alit y  of  Lif e  Ass ess m e nt:  I nt er n ati o n al  P ers p e cti v es.  B erli n. 
S pri n g er -V erl a g.  1 9 9 4;  1 -5 7 [ P E 0 1 4 5 6 6 4]  
 
 
T h e    W orl d    H e alt h    Or g a ni z ati o n    Q u alit y   of    Lif e    Ass ess m e nt   ( W H O Q O L):   d e v el o p m e nt   a n d   g e n er al 
ps y c h o m etri c  pr o p erti es.  S o c  S ci  M e d.  1 9 9 8 J u n; 4 6( 1 2): 1 5 6 9 -8 5 ( a) [ P E 0 1 4 5 6 6 2]  
   
 
 
D e v el o p m e nt  of t h e  W orl d  H e alt h  Or g a ni z ati o n  W H O Q O L- B R E F  q u alit y  of lif e  ass ess m e nt.  T h e  W H O Q O L 
Gr o u p.  Ps y c h ol  M e d.  1 9 9 8  M a y; 2 8( 3): 5 5 1 -8 ( b) [ P E 0 1 4 5 6 6 3]  
 


S 9 5 0 0 8  
A m e n d e d  cli ni c al st u d y  pr ot o c ol  n o.  C L 3 -9 5 0 0 8 -0 0 2 - Fi n al  v ersi o n  
 
( c) I. R.I. S. - 2 5  M ar c h  2 0 2 1 - C o nfi d e nti al  
  8 9 /2 9 6  
 
Ot h e r  r e g ul at o r y  r ef e r e n c es:  
I C H  T o pi c  E 6 – G ui d eli n e f or  G o o d  Cli ni c al  Pr a cti c e:  C o ns oli d at e d  g ui d eli n e fi n alis e d (st e p 
4) i n  J u n e  1 9 9 6.  A d o pt e d  b y  C P M P,  J ul y  9 6, iss u e d  as  C P M P/I C H/ 1 3 5/ 9 5/st e p  5,  p ost  st e p 
err at a, J ul y  2 0 0 2.  
I C H   E 6  ( R 2),  I nt e gr at e d    A d d e n d u m  t o    G o o d   Cli ni c al  Pr a cti c e  ( G C P),  St e p  5,    A d o pt e d  b y 
C H M P,  1 5  D e c e m b er  2 0 1 6, iss u e d  as  E M A/ C H M P/I C H/ 1 3 5/ 1 9 9 5 
I C H   T o pi c   E 9 – St atisti c al  Pri n ci pl es f or   Cli ni c al   Tri als:   A d o pt e d  b y   C P M P,    M ar c h  1 9 9 8, 
iss u e d  as  C P M P/I C H/ 3 6 3/ 9 6/st e p  5. 
I C H    E 9  ( R 1) - A d d e n d u m  o n  esti m a n ds  a n d  s e nsiti vit y  a n al ysis  i n  cli ni c al  tri als  t o  t h e 
g ui d eli n e  o n  st atisti c al    pri n ci pl es  f or  cli ni c al  tri als – A d o pt e d  b y    C H M P  f or  r el e as e  f or 
c o ns ult ati o n,  A u g ust  3 1t h  2 0 1 7 
I C H  T o pi c  E 2 A – Cli ni c al  S af et y  D at a  M a n a g e m e nt:  D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d 
R e p orti n g, iss u e d  as  C P M P/I C H/ 3 7 7/ 9 5. 
I C H    T o pi c   E 1 1- Cli ni c al  I n v esti g ati o n  of    M e di ci n al  Pr o d u cts  i n  t h e  p e di atri c  P o p ul ati o n. 
N ot e f or  g ui d a n c e  o n  cli ni c al i n v esti g ati o n  of  m e di ci n al  pr o d u cts i n t h e  p a e di atri c  p o p ul ati o n. 
A d o pt e d   b y    C H M P,   J ul y   2 0 0 0,   iss u e d   as    C H M P/I C H/ 2 7 1 1/ 9 9/st e p 5,   J a n u ar y   2 0 0 1. 
[ P E 0 0 5 9 7 5 6] 
A d d e n d u m   t o   I C H    E 1 1:    Cli ni c al   I n v esti g ati o n   of    m e di ci n al   pr o d u cts   i n   t h e   p e di atri c 
p o p ul ati o n.    A d o pti o n  b y  t h e    R e g ul at or y    M e m b ers  of  t h e  I C H    Ass e m bl y  u n d er  St e p  4.  1 8 
A u g ust  2 0 1 7. [ P E 0 1 4 3 4 1 6] 
D et ail e d  g ui d a n c e  o n  t h e  c oll e cti o n,  v erifi c ati o n  a n d  pr es e nt ati o n  of  a d v ers e  e v e nt/r e a cti o n 
r e p orts  arisi n g  fr o m  cli ni c al  tri als  o n    m e di cin al  pr o d u cts  f or  h u m a n  us e  (‘ C T -3’),  ( 2 0 1 1/ C 
1 7 2/ 0 1) 
G ui d eli n e  o n  Missi n g  D at a i n  C o nfir m at or y  Cli ni c al  Tri als – A d o pt e d  b y  C H M P,  J u n e  2 0 1 0, 
iss u e d  as  E M A/ C P M P/ E W P/ 1 7 7 6/ 9 9  R e v.  1 
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  2 0 0 1  o n t h e  a p pr o xi m ati o n  of t h e l a ws, r e g ul ati o ns  a n d  a d mi nistr ati v e  pr o visi o ns  of 
t h e  M e m b er  St at es  r el ati n g t o t h e i m pl e m e nt ati o n  of  g o o d  cli ni c al  pr a cti c e i n t h e  c o n d u ct  of 
cli ni c al tri als  o n  m e di ci n al  pr o d u cts f or  h u m a n  us e). 
E ur o p e a n  M e di ci n es  A g e n c y  ( E M A).  O pi ni o n  of t h e  P e di atri c  C o m mitt e e  o n t h e  a gr e e m e nt 
of  a  p a e di atri c I n v esti g ati o n  Pl a n. Iss u es  as  E M A E M E A - 0 0 1 3 0 3-PI P 0 1 -1 2 . 
G ui d eli n e  o n  t h e  cli ni c al  d e v el o p m e nt  of    m e di ci n al  pr o d u cts  f or  t h e  tr e at m e nt  of    A utis m 
S p e ctr u m  D is or d er ( A S D).  E A M/ C H M P/ 5 9 8 0 8 2/ 2 0 1 3. 

SAP_001.pdf: 
Document title 
Study title 
Test drug code 
Indication 
Development phase 
Protocol code 
EudraCT Number
ClinicalTrial.gov Number
Universal Trial Number 
Sponsor 
Date of the document 
Version of the document 
STATISTICAL ANALYSIS PLAN (SAP) ATTACHED TO 
CL3-95008-002 STUDY 
Efficacy and safety of Bumetanide oral liquid formulation 
in children aged from 2 to less than 7 years old with Autism 
Spectrum Disorder 
Bumetanide – S95008 
Autism Spectrum Disorder 
Phase III 
CL3-95008-002 
2017-004420-30 
NTC03715153
Not applicable 
Institut de Recherches Internationales Servier (I.R.I.S.) 50 
Rue Carnot 
92284 Suresnes Cedex - France 
21 July 2021 
Version 3.0 
CONFIDENTIAL 




S95008 
CL3-95008-002 - Statistical Analysis Plan - Version 3.0 
 
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Follow up of versions 
Version 
Release date 
(dd/mm/yyyy) 
Key modifications (*) 
Impact 
1.0 
12/11/2018 
Definition of the primary estimand 
added 
3.4.2.1. Primary analysis 
 
 
Additional sensitivity analysis 
3.4.2.2 Sensitivity 
analyses 
 
 
MMRM moved from sensitivity 
analyses to supplementary analyses 
3.4.2.2 Sensitivity 
analyses  
3.4.2.3 Supplementary 
analyses 
 
 
Missing data handling, sensitivity 
analysis and supplementary 
analyses added for CGI-I analysis 
3.4.3.2 CGI-I 
 
 
Main analysis performed on the 
Adaptative Behavior Composite 
score instead of the domain scores 
3.4.3.3 VABS II 
 
 
Supplementary analyses added for 
VABS II analysis 
3.4.3.3 VABS II 
 
 
Subgroup analyses added 
3.4.4 Subgroups analysis 
 
 
Safety analyses on open-label 
period replaced by analyses on 
combined periods (double-blind + 
open-label) for adverse events and 
laboratory parameters  
3.6. Safety analysis 
 
 
Analysis of C-SSRS added 
3.6.2 C-SSRS 
 
 
Additional listings and analyses for 
potassium parameter 
3.6.3 Clinical laboratory 
evaluation 
 
 
Additional ECG analyses 
3.6.4.2 Electrocardiogram 
2.0 
09/12/2019 
Add justifications on the choice of 
the estimand based on comments 
from FDA. 
3.4.2.1. Primary analysis 
3.0 
21/07/2021 
Additional analysis set and periods 
Additional analyses related to 
Covid-19 pandemic. 
Additional analyses related to the 
optional extension part 
Additional CARS2 responders 
analysis. 
 
All sections impacted 
 


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Additional analysis for the VABS II 
domain 
Additional analysis for quality of 
life questionnaires 
Subgroups analysis were deleted 
Details on analysis period for safety 
were added. 
(*) Main changes as compared to the statistical analyses planned in the protocol 
 


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Table of contents 
Signatories .................................................................................................................................. 2 
Follow up of versions ................................................................................................................. 3 
Table of contents ........................................................................................................................ 5 
List of tables ............................................................................................................................... 7 
List of figures ............................................................................................................................. 8 
List of abbreviations ................................................................................................................... 9 
1. INTRODUCTION ............................................................................................................. 11 
1.1. Study objectives .............................................................................................................. 11 
1.2. Study design .................................................................................................................... 12 
1.2.1. Study plan ..................................................................................................................... 12 
1.2.2. Type of randomisation .................................................................................................. 13 
1.3. Determination of sample size ......................................................................................... 13 
2. ANALYSIS SETS / TREATMENT GROUPS ................................................................ 14 
2.1. Analysis sets ................................................................................................................... 14 
2.2. Treatment arms ............................................................................................................... 14 
3. STATISTICAL METHODS ............................................................................................. 15 
3.1. General considerations .................................................................................................... 15 
3.1.1. Descriptive statistics ..................................................................................................... 15 
3.1.2. General definitions ....................................................................................................... 15 
3.2. Disposition and baseline characteristics ......................................................................... 16 
3.2.1. Disposition of patients .................................................................................................. 16 
3.2.2. Protocol deviations ....................................................................................................... 16 
3.2.3. Demographic data and other baseline characteristics ................................................... 16 
3.3. Treatments of patients ..................................................................................................... 17 
3.3.1. Extent of exposure and treatment compliance .............................................................. 17 
3.3.2. Concomitant treatments and therapies .......................................................................... 17 
3.3.3. Acceptability and palatability questionnaires ............................................................... 17 
3.4. Efficacy analysis ............................................................................................................. 17 
3.4.1. Statistical hypotheses.................................................................................................... 17 
3.4.2. Primary efficacy endpoint ............................................................................................ 18 
3.4.2.1. 
Primary analysis ....................................................................................................... 18 
3.4.2.2. 
Sensitivity analyses .................................................................................................. 20 
3.4.2.3. 
Supplementary analyses ........................................................................................... 20 
3.4.3. Secondary efficacy endpoints ....................................................................................... 21 
3.4.3.1. 
Social Responsiveness Scale ................................................................................... 21 
3.4.3.2. 
Clinical Global Impression Scale ............................................................................ 22 
3.4.3.3. 
Vineland Adaptative Behaviour Scale II (VABS II) ............................................... 23 
3.4.3.4. 
Paediatric Quality of Life Inventory ........................................................................ 23 
3.4.3.5. 
Abbreviated World Health Organization Quality of Life - Bref ............................. 24 
3.4.4. Subgroups analysis ....................................................................................................... 25 
3.5. Exploratory analysis ....................................................................................................... 25 
3.5.1. EuroQol – 5-Dimension – Three-level ......................................................................... 25 


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3.6. Safety analysis ................................................................................................................ 26 
3.6.1. Adverse events.............................................................................................................. 27 
3.6.2. Columbia Suicide Severity Rating Scale Children’s version ....................................... 27 
3.6.3. Clinical laboratory evaluation ...................................................................................... 28 
3.6.4. Vital signs, clinical examination and other observations related to safety ................... 29 
3.6.4.1. 
Vital signs and clinical examination ........................................................................ 29 
3.6.4.2. 
Electrocardiogram .................................................................................................... 30 
4. INTERIM ANALYSIS ...................................................................................................... 31 
5. APPENDICES .................................................................................................................... 32 
5.1. Statistical methods details ............................................................................................... 32 
5.1.1. General Linear Model................................................................................................... 32 
5.1.1.1. 
For continuous data .................................................................................................. 32 
5.1.1.2. 
Robust General Linear Model using rank-based analysis ....................................... 33 
5.1.2. Pattern imputation based .............................................................................................. 33 
5.1.3. Mixed-effects model with repeated measurements ...................................................... 37 
5.1.4. Logistic regression........................................................................................................ 37 
5.2. Software .......................................................................................................................... 38 
6. REFERENCES .................................................................................................................. 39 
 
 
 


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List of tables 
Table (3.6) 1 - Definition of periods of emergence for safety events ...................................... 26 
 


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List of figures 
Figure (1.2.1) 1 - Study plan .................................................................................................... 13 
 


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List of abbreviations 
% 
: percentage 
µmol 
: micromole 
AE 
: Adverse Event 
b.i.d. 
: bis in die (twice a day) 
BMI 
: Body Mass Index 
BP 
: Blood Pressure 
b.p.m 
: beats per minute (heart rate unit) 
CARS2 
: Childhood Autism Rating Scale, Second Edition  
CGI 
: Clinical Global Impression Scale 
CGI–I 
: Clinical Global Impression Scale – Global Improvement 
CGI–S 
: Clinical Global Impression Scale – Severity 
CHMP 
: Committee for Medicinal Products for Human Use 
CI 
: Confidence Interval 
cm 
: centimetre 
CPK 
: Creatine PhosphoKinase 
CPMP 
: Committee for Proprietary Medicinal Products 
C–SSRS–C 
: Columbia Suicide Severity Rating Scale Children’s version 
DBP 
: Diastolic Blood Pressure 
DMC 
: Data Monitoring Committee 
e.g. 
: exempla gratia (for example) 
EAE 
: Emergent Adverse Event 
ECG 
: ElectroCardioGram 
e–CRF 
: electronic-Case Report Form 
EMA 
: European Medicines Agency 
EQ–5D–3L 
: EuroQol – 5-Dimension – Three-level 
g 
: gram 
G/L 
: Giga (109) per litre 
GLM 
: General Linear Model 
h 
: hour 
HR 
: Heart Rate 
i.e. 
: id est 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
ICH 
: International Conference on Harmonization 
IME 
: Important Medical Event 
IMP 
: Investigational Medicinal Product 
IRS 
: Interactive Response System 
IS 
: Included Set 
IU 
: International Unit 
IVRS 
: Interactive Voice Response System 
IWRS 
: Interactive Web Response System 
kg 
: kilogram 
L 
: Litre 
LLN 
: Lower Limit of Normal laboratory reference range 
LLS 
: Lower Limit used to define potentially clinically Significant 
abnormal values 
m 
: metre 
Max 
: Maximum 


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MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: milligram 
MI 
: Multiple Imputation 
min 
: minute 
Min 
: Minimum 
mL 
: millilitre 
mm 
: millimetre 
mmHg 
: millimetre of mercury 
mmol 
: millimole 
MMRM 
: Mixed-effects Model for Repeated Measures 
msec 
: millisecond 
NA 
: Not Applicable 
Na+ 
: Sodium 
NAE 
: Number of Adverse Events 
NEAE 
: Number of Emergent Adverse Events 
ng 
: nanogram 
NPD 
: Number of Protocol Deviations 
PCSA 
: Potentially Clinically Significant Abnormal value 
PedsQL 
: Paediatric Quality of Life Inventory 
po 
: per os (orally) 
PPS 
: Per Protocol Set 
PT 
: Preferred Term 
PV 
: PharmacoVigilance 
QTc 
: QT interval corrected for heart rate 
RGLM 
: Robust General Linear Model 
RS 
: Randomised Set 
s 
: second 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SBP 
: Systolic Blood Pressure 
SD 
: Standard Deviation 
SE 
: Standard Error 
SEAE 
: Serious Emergent Adverse Event 
SOC 
: System Organ Class 
SRS–2 
: Social Responsiveness Scale, Second Edition 
SS 
: Safety Set 
T/L 
: Tera (1012) per litre 
TLG 
: Tables, Listings and Graphs 
TU 
: Therapeutic Unit 
ULN 
: Upper Limit of Normal laboratory reference range 
ULS 
: Upper Limit used to define potentially clinically Significant 
abnormal values 
WHO 
: World Health Organization 
WHO–DRL 
: World Health Organization, Drug Reference List 
WHOQOL–BREF 
: Abbreviated World Health Organization Quality of Life 
 
 
 
 


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1. INTRODUCTION 
This Statistical Analysis Plan details the planned analyses to be performed, in accordance with 
the main characteristics of the amended study protocol. The templates for Tables, Listings and 
Graphs (TLG) are described in a separate document. 
The study was divided into three periods: 
­ Double-blind treatment period of 6 months between inclusion (week 0) and month 6 
(week 26). 
­ Open label active treatment period of 6 months between month 6 (week 26) and month 12 
(week 52). 
­ 6-month optional extension period with bumetanide proposed in some countries where it 
was not possible to provide the treatment at the end of the main periods via a Named Patient 
Basis (NPB) access or a Post-Access Study Program. 
This Statistical Analysis Plan detailed the analysis associated to these three periods. The main 
analysis will be the first one based on the double-blind period. The blind will be broken as soon 
as all efficacy and safety data collected during the double-blind are available and all the 
mandatory steps required for study unblinding have been performed. Then, only data of the 
double-blind period will be analysed following the first database-lock (and unblinding), the 
analyses of the other periods (open-label and extension) will be performed at the end of each 
period. 
Nevertheless, although the blind will be broken before the end of the study, neither the 
investigators, nor the raters, nor the patients, nor the parents/legal representatives/caregivers, 
nor the monitors will be informed of the study treatment taken during the double-blind treatment 
period before the database lock at the end of the open-label period. 
Of note, this SAP does not cover the pharmacokinetic data analyses described in the study 
protocol. These analyses are covered in separate analysis plans written by I.R.I.S. Clinical 
Pharmacokinetics. 
According to the EMA “Guidance on the management of clinical trials during the COVID-19 
(coronavirus) pandemic”, a risk assessment was performed by the Sponsor on aggregated and 
blinded data to evaluate the implications on recruitment, loss of patients during the trial, ability 
to record data and ability to interpret the treatment effect. The risk assessment is described in a 
separate document. 
1.1. Study objectives 
The primary objective is to demonstrate the superiority of bumetanide (0.5mg BID) oral liquid 
formulation compared to placebo in the improvement of ASD core symptoms after 6 months of 
treatment in ASD children and adolescents aged from 2 to less than 7 years old. 
The secondary objectives are: 
­ To assess the effect of bumetanide on the other efficacy endpoints. 
­ To assess the safety of bumetanide. 
­ To confirm the acceptability and palatability of the oral liquid formulation. 
­ To describe the bumetanide effects on patients quality of life. 
­ To improve existing pharmacokinetic model of bumetanide in this population. 


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1.2. Study design 
The study CL3-95008-002 is a phase III, international, multicentre, 6-month, randomised, 
double-blind, placebo-controlled study with two parallel groups (bumetanide or placebo) 
followed by an open-label active 6-month treatment period with bumetanide and a 6-week 
discontinuation period after treatment stop. 
1.2.1. 
Study plan 
The study is divided into the following periods: 
­ A run-in period without treatment up to 4 weeks (from ASSE to W0) to allow investigators 
to perform ECG, renal ultrasound, laboratory examinations and to respect the wash-out 
period of any unauthorised treatment before inclusion.  
­ A double-blind period of 6 months (from W000 to W026): at W000, patients are randomised 
(1:1) in double-blind conditions to one of the two treatment groups: bumetanide or placebo. 
­ An open-label period of 6 months (from W026 to W052): 
 Patients randomised in the S95008 arm during the double-blind period will continue to 
be treated by S95008 during the whole open-label period. 
 Patients randomised in the placebo arm during the double-blind period will receive 
bumetanide during the whole open-label period. 
­ A follow-up period of 6 weeks after treatment discontinuation (from W052 to WEND). A 
WEND visit should be planned 6 weeks after Investigational Medicinal Product (IMP) stop 
(W052 or premature withdrawal). 
­ A 6-month optional extension period with Bumetanide is proposed in some countries where 
it is not possible to supply Bumetanide (study formulation) at the end of the follow up period 
via a Named Patient Basis (NPB) access or a Post-Access Study Program. This extension is 
optional and proposed to the patients based on the investigator’s clinical judgement (clinical 
benefit observed during the main study without no major safety concern). 
IMPs are supplied as two oral administrations per day with 1 mL graduated pipette upon waking 
in the morning and in the afternoon, 3 hours before going to bed at the latest.  
The volume of the oral solution will be adapted according to a body-weight basis for patients 
with a weight lower than 25 kg. 
The appearance and taste of the solution are the same for all IMPs throughout the study. The 
first IMP intake takes place on the day of the inclusion visit in the afternoon.  
An adaptation of the oral solution volume according to the weight of the patients will be 
performed during the study at visits W012, W026 and W038. 
The study plan is shown in Figure (1.2.1) 1. 


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Figure (1.2.1) 1 - Study plan 
 
 
 
1.2.2. 
Type of randomisation 
The treatment randomisation and allocation are centralised using an Interactive Response 
System (IRS) procedure. The treatment (bumetanide or placebo) is assigned at inclusion visit 
by a balanced, non-adaptive randomisation with stratification on country and gender. 
1.3. Determination of sample size 
The sample size was estimated to meet the primary endpoint defined as the change in CARS2 
from baseline to 6 months using a two-sided Student’s test.  
With a total of 170 patients, statistical significance should be established with a power of 90% 
and a type-one error of 0.05 for an effect size of 0.5 between groups. 
Assuming around 15% prematurely withdrawal rate, the total number of patients to be included 
is 200. 
Missing data will be imputed using a reference based multiple imputation with a jump-to-
reference approach or a standard multiple imputation depending on the reasons of withdrawal. 
Simulations were carried out to evaluate the impact of this procedure on power under various 
scenarios. The results on 1000 simulations have shown that power does not drop under 80% in 
the worst-case scenario. 
 
 


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2. ANALYSIS SETS / TREATMENT GROUPS 
2.1. Analysis sets 
­ The Randomised Set (RS) is constituted of included and randomised (i.e. for whom a 
therapeutic unit was randomly assigned using IWRS) patients. 
­ The Safety Set (SS) is constituted of all patients having taken at least one dose of IMP. 
­ Randomised Set Open (RSO) patients of the RS having taken at least one dose of 
Bumetanide during the open-label period. 
­ Safety Set Open (SSO): patients of the SS having taken at least one dose of Bumetanide 
during the open-label period. 
­ Randomised Set Combined (RSC): patients of the RS having taken at least one dose of 
Bumetanide during the open-label period and with a delay between end of double-blind 
period and start of open-label period less than 30 days. 
­ Safety Set Combined (SSC): patients of the SS having taken at least one dose of Bumetanide 
during the open-label period and with a delay between end of double-blind period and start 
of open-label period less than 30 days. 
The size of each analysis set, and reasons for exclusion will be described. 
Listings of patients with their membership, or not, to each analysis set and of excluded patients 
with reasons for exclusion will be provided. 
2.2. Treatment arms 
For the 26-week double-blind period, treatment arms will be defined as: 
­ S95008 arm. 
­ Placebo arm. 
For the open-label period, treatment group will be defined as: 
­ Placebo/ S95008 arm: patients assigned to placebo group at W000 and treated by bumetanide 
0.5 mg BID in the open-label period. 
For the combined period (double-blind+open label periods), treatment group will be defined as: 
­ S95008 / S95008 arm: patients assigned to bumetanide 0.5 mg BID group at W000 and 
treated by bumetanide 0.5 mg BID in the open-label period. 
It will correspond to allocated treatment by IRS except for safety analyses for which treatment 
received at W000 will be considered. 
 
 


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3. STATISTICAL METHODS 
3.1. General considerations 
3.1.1. 
Descriptive statistics 
For qualitative data, number of observed values, number and percentage of patients per class 
will be presented. Unless otherwise specified in the TLG, no class "Missing" is considered. 
For quantitative data, number of observed values, mean, standard deviation, median, first and 
third quartiles, minimum and maximum will be presented. 
For events: number of patients having experienced the event (n), number of events that occurred 
and number of patients at risk for the event (N) will be presented as well as the patients-years 
at risk for the event (NPY), the crude incidence rate and the annual incidence rate calculated as 
follows: 
­ NPY = sum of patient’s period duration in years. 
­ Crude incidence rate (i.e. percentage): % = 100 x (n / N). 
­ Annual incidence rate (i.e. exposure-adjusted incidence rate): npy = 100 x (n / NPY). Of 
note that the annual incidence rate is interpreted as the number of patients with events per 
100 patients-years. 
3.1.2. 
General definitions 
Unless specified otherwise in Sections 3.2 to 3.6, the following definitions will be considered: 
 
Three analysis periods will be defined: 
­ Double-blind period. 
­ Open-label period. 
­ Combined period.  
For each, start date, stop date, first and last IMP intake date, baseline and under treatment period 
will be specified. 
 
­ Analysable value will be defined as any non-missing value. 
­ Baseline value will be defined as the last analysable value prior to the first IMP intake of the 
considered analysis period (i.e. before or the same* date as the first IMP intake date). 
Note:  
 In case of patient included and/or randomised but not treated (i.e. patients with treatment 
duration equal to 0): value at baseline (for the double-blind or combined period) is defined 
as the last analysable value prior or equal to date of inclusion visit. 
 * For parameters measured the day of inclusion for the double-blind or combined period 
(resp. the day of W26 or W26B for open-label period) but before the first IMP intake of 
the considered period. 
 
­ Post-baseline value will be defined as any value recorded at a given timepoint after baseline. 
­ Change from baseline will be defined as the arithmetic difference between a post-baseline 
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3.2. Disposition and baseline characteristics 
Disposition of patients and baseline characteristics will be described by randomised treatment 
group, to assess their comparability, and overall. 
3.2.1. 
Disposition of patients 
Disposition of patients, including reasons for study*/treatment withdrawal**, will be 
summarized during the double-blind period, during the open-label period, and during the study 
(excluding extension period) overall as well as during the double-blind period and during the 
open-label period by visit, in the RS. The number and percentage of patients who completed 
the double-blind (resp. open-label) period before (resp. after) the initiation of COVID-19 
Pandemic will be also provided. 
Note:  
­ * Study withdrawal related to COVID-19 pandemic will be also described. 
­ ** Information related to treatment withdrawal will only be described for the double-blind 
period. 
A listing of patients with treatment withdrawal but having completed the double-blind period 
as well as a listing of patients with a delay between the double-blind and open-label periods 
will be provided. 
The number and percentage of patients entering in the extension period will be described in the 
RS. 
In order to assess the drop-out pattern between the treatment groups, the time to premature IMP 
withdrawal in the double-blind period will be described overall and by reason (lack of efficacy 
or AE; other reasons of withdrawal), in the RS using a Kaplan-Meier analysis. Withdrawn and 
completed patients’ characteristics during the double-blind will be described overall, in the RS, 
and their comparability at inclusion visits assessed. 
3.2.2. 
Protocol deviations 
Protocol deviations before or at inclusion, as well as after inclusion, will be described by 
category of important deviations (based on ICH E3 guideline and ICH E3 Q&A) during the 
double-blind period, during the open-label period, and during the study (excluding extension 
period but including the deviations occurring between double-blind and open-label periods 
when there is a delay between them) in the RS. 
The same analysis will be performed for protocol deviations after the initiation of COVID-19 
Pandemic (i.e. after start of COVID-19 impact) (before or at inclusion, as well as after 
inclusion). 
3.2.3. 
Demographic data and other baseline characteristics 
Demographic data and other baseline characteristics such, vital signs, history and diagnosis of 
the disease will be described in the RS. 
Baseline value of efficacy endpoints will also be described in the RS: 
­ CARS2: total raw score, version of the questionnaire used (ST or HF), severity of ASD. 
­ SRS-2 total raw score and core symptoms A and B. 
­ CGI-S score. 
­ Vineland adaptative behaviour scale: VABS II Adaptative Behavior Composite score, 
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The Columbia-suicide severity rating scale children (C-SSRS-C) base during lifetime and 
during the past 6 months will be also described in the RS. 
Moreover all specific (resp. non-specific) previous treatments taken within the 6 months before 
selection will be described in the RS, by ATC code; as well as all medical history other than 
studied disease and surgical or medical procedures history, by primary system organ class and 
preferred term. Previous therapies by ATC code for the disease will also be described in the 
RS. 
3.3. Treatments of patients 
3.3.1. 
Extent of exposure and treatment compliance 
Extent of exposure (follow-up duration (month), treatment duration (month), treatment 
exposure (month)) and treatment compliance (%) will be described in the SS for double-blind 
period, in the SSO for open-label period and in the SSC for the combined period. 
It is of note that treatment duration will also be described in classes: 
­ For double-blind period and open-label period: (<4 weeks, [4 weeks; 12 weeks], 
> 12 weeks). 
­ For combined period: (< 26 weeks, [26 weeks; 38 weeks], and > 38 weeks). 
3.3.2. 
Concomitant treatments and therapies 
All specific (resp. non-specific) concomitant treatments taken at inclusion, during the double-
blind (resp. open-label, combined) period, at the first IMP intake of the open-label period and 
after the last IMP intake of the double-blind (resp. open-label) period will be described in the 
SS (SSO when open-label and SSC when combined), by ATC code. Therapies for autism 
spectrum disorder will also be described at inclusion and during the double-blind period in the 
SS and during the open-label in the SSO and during the combined period in the SSC. The 
number and percentage of patients with at least one therapy of ASD will be described overall 
and by type of therapy at inclusion in the SS. The number and percentage of patients with at 
least one new added therapy / one modification in current therapy / one clinically relevant 
modification in therapy will be described overall and by type of therapy in each period. 
3.3.3. 
Acceptability and palatability questionnaires 
The acceptability and palatability questionnaires will be presented using descriptive statistics 
for the visit at which it has been collected (W026 or before in case of premature withdrawal) in 
the RS by treatment group (S95008 VS placebo) for the double-blind period. 
3.4. Efficacy analysis 
All efficacy analyses will be performed on the randomised set. 
3.4.1. 
Statistical hypotheses 
The hypotheses to be tested are: 
Let μ0 and μ1 be the population means of the change from baseline of the CARS2 at W026 
(primary endpoint) under placebo and bumetanide respectively. The statistical hypotheses that 
will be tested are: 
H0: μ0 = μ1 (no difference between bumetanide and placebo) 
versus 
H1: μ0 ≠ μ1 (difference between bumetanide and placebo) 


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The type I error of the statistical tests will be set at 5% (bilateral situation), which is consistent 
with the objective of demonstrating the superiority versus placebo (unilateral situation at 2.5%). 
Similar hypotheses will also be considered for the secondary efficacy parameters. However, for 
all other analyses than the primary analysis, no p-value will be provided. 
3.4.2. 
Primary efficacy endpoint 
3.4.2.1. 
Primary analysis 
Definition:  
The primary estimand is defined according to the primary objective of the trial, which is to 
evaluate treatment effect: 
­ Taking into account the unfavorable outcome when patients are unable to continue taking 
the study drug due to an adverse event or for lack of efficacy. 
­ Independently of treatment discontinuations for non-medical reasons because those patients 
would have theoretically continued to be treated as planned in clinical practice. 
The attributes of the primary estimand will be defined as following: 
­ Population: children and adolescents aged from 2 to less than 7 years old with Autism 
Spectrum Disorder. 
­ Variable: change in CARS2 total score from baseline to W026. 
­ Summary measure: difference in means. 
­ Intercurrent events: 
 Treatment discontinuation due to lack of efficacy or AE (hypothetical strategy): 
 For S95008 arm, the quantification of the treatment effect cannot ignore the situation 
where a patient can no longer tolerate or benefits from the treatment, from whom a 
continuation of the treatment would not be conceivable. Bumetanide is a treatment 
with a rapid onset and short duration of action. So, the assumption that the treatment 
benefit in patients who discontinue the active arm disappears immediately upon 
discontinuation is clinically meaningful. CARS2 values after this intercurrent event 
will be considered as missing and imputed using a reference based multiple imputation 
(“jump-to-reference” approach).  
 For placebo arm, it will be considered as if patients were stayed under placebo, and 
CARS2 values after the intercurrent event will be considered as missing and imputed 
using a multiple imputation (MAR approach). 
 Treatment discontinuation for other reason (hypothetical strategy): a reasonable 
question is what difference is attributable to treatment if no such events occurred 
namely if patients were stayed under their randomised treatment. CARS2 values after 
the intercurrent events will be considered as missing and imputed in both arms using 
multiple imputations (MAR approach). 
Primary endpoint: the primary efficacy endpoint is defined as the change from baseline to W026 
of the CARS2 total score. 
Primary analysis: bumetanide will be compared to placebo on the primary efficacy endpoint in 
the RS, using a General Linear Model (see Appendix 5.1.1.1) including the fixed, categorical 
effect of treatment, gender and country as well as the continuous fixed covariate of baseline 
value. 
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The assumptions underlying the model, as for instance, the normality and homoscedasticity of 
residuals and detection of outliers, will be checked. 
Missing data handling: 
­ For all study premature withdrawals due to other reasons as well as for study premature 
withdrawals due to lack of efficacy or AE in placebo arm, missing data will be imputed in 
both arms using a multiple imputation based on similar patients in the same treatment arm 
(missing at random assumption).  
­ For study premature withdrawals due to lack of efficacy or AE in S95008 arm, missing data 
will be imputed using a reference based multiple imputation with a jump-to-reference 
approach (missing not at random assumption).  
Missing data as well as data considered as missing for the primary analysis due to the strategy 
used to handle intercurrent event will be imputed in the same way. 
Multiple imputation inference involves 3 consecutive phases. 
1/ Imputation step:  
A total of 100 imputed complete data sets will be generated. 
The imputation step of missing data with a monotone pattern will be separated in several 
sequences: 
­ For all patients with study or drug premature withdrawals due to other reasons as well as for 
patients with study or drug premature withdrawals due to lack of efficacy or AE in placebo 
arm, the regression method (adjusted on the same covariates as the model [1] and considering 
all longitudinal data of planned visits) will be used to impute missing data (i.e. based on 
patient completers under corresponding treatment arm).  
­ For patients with study or drug premature withdrawals due to lack of efficacy or AE in 
S95008 arm, the imputation step will be done sequentially for each time point t separately 
(W4, W12 and W26) based on placebo patients with non missing data at the timepoint t. The 
regression method will be adjusted on the same covariates as model [1] except the treatment 
variable (which is a modified variable in order to consider the placebo data as reference for 
imputation) and considering all longitudinal data of planned visits up to timepoint t. 
It is of note that for missing data with an arbitrary missing pattern, the first imputation step 
might be preceded by one MI approach based on MCMC method using treatment groups, 
baseline and variable of interest at the planned visit. 
2/ Analysis step: 
The same model as [1] (described above) will be applied to each of the 100 imputed datasets. 
3/ Combination step: 
Statistical inferences will be generated by combining results from the 100 analyses using 
Rubin’s formulae. The multiple imputation estimator of the difference between bumetanide and 
placebo is the average of the individual 100 estimators. The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward, 2007).  
 
Statistical elements: Finally, the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment arm means. 
­ Two-sided 95% CI of the estimate. 
­ Two-sided p-value. 


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3.4.2.2. 
Sensitivity analyses 
• Unadjusted analysis: 
The same primary analysis will be performed for the primary endpoint using a General Linear 
Model (ANCOVA) without any covariates. The following model will be considered instead of 
model [1]: 
GENERAL LINEAR MODEL (ANCOVA): change = baseline treatment [2] 
3.4.2.3. 
Supplementary analyses 
• Treatment policy estimand:  
The primary analysis will be repeated for the primary endpoint using all CARS2 values reported 
regardless of occurrence of treatment discontinuation. 
In case of CARS2 values are still missing, the same imputation process as in the primary 
analysis will be performed for these individuals.  
• Hypothetical estimand based on Mixed-effects Model for Repeated Measures 
A Mixed-effects Model for Repeated Measures (MMRM) (see Appendix 5.1.3) using the 
longitudinal data at each planned post-baseline visit of the double-blind period (W004, W012 
and W026) will be performed as if patients had continued their randomised treatment. In this 
analysis, all data occurring after all intercurrent events will be considered as missing. The 
comparison associated with the analysis will be the contrasts between Bumetanide and placebo 
for the change from baseline to W026 of the CARS2 total score. The model will include the 
fixed, categorical effects of country, gender, treatment, visit, treatment by visit interaction, 
country by visit interaction and gender by visit interaction as well as the continuous, fixed 
covariates of baseline and visit-by-baseline interaction:  
 
MMRM: change at each visit = baseline country gender treatment visit treatment*visit 
baseline*visit country*visit gender*visit [4] 
 
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment arm means. 
­ Two-sided 95% CI of the estimate. 
• W012 analysis: 
The primary analysis will be repeated for the CARS2 total score expressed in term of change 
from baseline to W012.  
• CARS2 responders analysis: 
Definition:  
CARS2 responders will be defined as patients having an improvement of at least 4.5 points in 
the CARS2 total raw score as compared to baseline (Jurek et al., 2021). 
 
Main Analysis: 
CARS2 responders at W012 and at W026 will be analysed using a logistic regression model 
with the fixed categorical effect of treatment, country and gender. 
Note: In case of a complete separation of data (zero cell count in a treatment group), only 
descriptive statistics will be provided. In case of quasi-completed separation of data, a logistic 
regression with penalized maximum likelihood will be used (see Appendix 5.1.4). 
 


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Missing data handling: 
The 100 datasets imputed for the primary analysis and supplementary analysis at W012 (based 
on the changes from baseline in CARS2 total scores) will be used to derive, the CARS2 
responders. Analysis step will be based on the logistic regression model described above and 
then the combination step will be applied. 
 
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the odds ratio between treatment groups. 
­ Two-sided 95% CI of the estimate. 
• Descriptive analysis: 
The CARS2 total score and subscores will be summarized using descriptive statistics and 
graphs (expect for subscores): 
­ During the double-blind period: baseline, each planned post-baseline visit (W004, W012 and 
W026) as well as change from baseline to each planned post-baseline visit will be described 
in the RS by treatment groups (S95008 vs placebo). 
­ During the open-label period: OL baseline, each OL planned post-baseline visit (W038 and 
W052) as well as change from OL baseline to each OL planned post-baseline visit will be 
described in the RSO for the Placebo/S95008 arm.  
­ During the combined period: baseline, each planned post-baseline visit as well as change 
from baseline to each planned post-baseline visit will be described in the RSC for the 
S95008/S95008 arm. 
­ At the follow-up visit (WEND), the change from the last post-baseline visit under treatment 
during the open-label period to WEND will be described in the RSO by treatment groups 
(S95008/S95008 vs Placebo/S95008). 
 
The proportions of CARS2 responders will also be summarized at each planned post-baseline 
visit for each period. 
The proportions of CARS2 performed remotely at baseline, W012 and W026 will be described 
in the RS by treatment groups (S95008 vs placebo). 
3.4.3. 
Secondary efficacy endpoints 
3.4.3.1. 
Social Responsiveness Scale 
Definition: The main analytical approach will be defined as the change in SRS-2 total raw score 
from baseline to W026. 
Main Analysis: A General Linear Model with the fixed categorical effect of treatment, country 
and gender as well as the continuous, fixed covariate of baseline will be used for the SRS-2 
change from baseline in the RS. 
GENERAL LINEAR MODEL (ANCOVA): change = baseline country gender treatment 
Missing data handling: For missing data handling, the same approach as for the primary 
endpoint will be performed. Data considered as missing for the analysis due to the strategy used 
to handle intercurrent event will be imputed in the same way. 
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 95% CI of the estimate. 


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Supplementary analyses: 
• W012 analysis: 
The same analysis will be repeated for the SRS total score expressed in term of change from 
baseline to W012.  
 
• Descriptive analysis: 
The same approaches as for the primary endpoint will be performed for the SRS total score. 
3.4.3.2. 
Clinical Global Impression Scale 
Definition:  
­ The main analytical approach will be defined as the CGI-I score at W026. 
­ Responders CGI will be defined as patients with the CGI-I equal to “much improved” or 
“very much improved”. 
Main analysis: A Robust General Linear Model (RGLM) using a rank-based analysis 
(Wilcoxon scores) (see Appendix 5.1.1.2) with the fixed categorical effect of treatment, country 
and gender will be used for the CGI-I score at W026 in the RS.  
RANK-BASED GLM: CGI-I score = country gender treatment 
Missing data handling: for missing data handling, the same approach as for the primary 
endpoint will be performed (see Appendix 5.1.2). 
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment arms medians. 
­ Two-sided 95% CI of the estimate. 
Supplementary analyses:  
• W012 analysis: 
The RGLM will be repeated for the CGI-I at W012.  
 
• CGI responders analysis: 
CGI responders at W012 and W026 will be analysed using a logistic regression model with the 
fixed categorical effect of treatment, country and gender in the RS. 
Note: In case of a complete separation of data (zero cell count in a treatment group), only 
descriptive statistics will be provided. In case of quasi-completed separation of data, a logistic 
regression with penalized maximum likelihood will be used (see Appendix 5.1.4). 
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the odds ratio between treatment groups. 
­ Two-sided 95% CI of the estimate. 
 
• Descriptive analysis: 
The CGI-I, CGI-S and CGI responders will be summarized using descriptive statistics and 
graphs: 
­ During the double-blind period: number and percentage of patient at each planned visit (for 
CGI-I and CGI responders: W000+Day 17, W004, W008, W012, W016, W020 and W026 / 
for CGI-S: W012 and W026) and the value at each planned visit for the CGI-S will be 
described in the RS by treatment groups (S95008 VS placebo). 


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­ During the open-label period: number and percentage of patient at each planned visit (W038 
(only for CGI-I and CGI responders) and W052) and the value at each planned visit for the 
CGI-S will be described in the RSO for the Placebo/S95008 arm. Of note that only CGI-I 
compared to W026 will be considered. 
­ During the combined period: number and percentage of patient at each planned visit and the 
value at each planned visit for the CGI-S will be described in the RSC for the S95008/S95008 
arm. Of note that only CGI-I compared to W000 will be considered. 
Moreover, the CGI-I (compared to W052) will be described at the follow-up visit (WEND) 
during the open-label period in the RSO by treatment groups (S95008/S95008 vs 
Placebo/S95008). 
The number and percentage of patients at each planned visit in the extension period for the 
CGI-I (of note that CGI-I compared to the inclusion in the extension period will be considered) 
will be described in the RS patients included in the extension period. 
3.4.3.3. 
Vineland Adaptative Behaviour Scale II (VABS II) 
Definition: The main analytical approach will be defined as the change in standard score of each 
domain from baseline to W026. 
Main Analysis: A General Linear Model with the fixed categorical effect of treatment, country 
and gender as well as the continuous, fixed covariate of baseline will be used for the change in 
standard score of each domain in the RS.  
GENERAL LINEAR MODEL (ANCOVA): change = baseline country gender treatment 
Missing data handling: for missing data handling, the same approach as for the primary 
endpoint will be performed. Of note that there is only one post-baseline planned visit (W026) 
to consider. 
Statistical elements: The following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment arm means. 
­ Two-sided 95% CI of the estimate. 
Supplementary analysis:  
VABS II standard domains scores, and Adaptative Behavior Composite standard score will be 
summarized using descriptive statistics and graphs: 
­ During the double-blind period: baseline, W026 as well as change from baseline to W026 
will be described in the RS by treatment groups (S95008 vs placebo).  
­ During the open-label period: OL baseline, W052 as well as change from OL baseline to 
W052 will be described in the RSO for the Placebo/S95008 arm. 
­ During the combined period: baseline, each planned post-baseline visit as well as change 
from baseline to each planned post-baseline visit will be described in the RSC for the 
S95008/S95008 arm. 
3.4.3.4. 
Paediatric Quality of Life Inventory 
Definition: the four dimensions (Physical, Emotional, Social and School), the physical* and 
psychosocial health summary scores, and the total score will be calculated.  
*Note: the physical health summary score is in fact the same as the Physical domain score. Only 
the latest will be presented, with a note in the output mentioning that it is the same. 


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The PedsQL questionnaire has been already validated in children with chronic conditions 
(Varni et al., 2003) and pediatric population with psychiatric disorders (Limbers et al., 2011). 
The psychometric properties will be checked separately. 
Analysis: 
A General Linear Model with the fixed categorical effect of treatment, country and gender as 
well as the continuous, fixed covariate of baseline will be used for the change from baseline to 
W026 in the four dimensions, the physical and psychosocial health summary scores and the 
total score in the RS. 
GENERAL LINEAR MODEL (ANCOVA): change = baseline country gender treatment 
Missing data handling:  missing data will be imputed using the multiple imputation approach 
(MI).  
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 95% CI of the estimate. 
Supplementary analysis: 
The four dimensions, the physical and psychosocial health summary scores and the total score 
will be summarized using descriptive statistics and graphs: 
­ During the double-blind period: baseline, each planned post-baseline visit (W004, W012 and 
W026) as well as change from baseline to each planned post-baseline visit will be described 
in the RS by treatment groups (S95008 vs placebo). 
­ During the open-label period: OL baseline, each OL planned post-baseline visit as well as 
change from OL baseline to each OL planned post-baseline visit (W030, W038 and W052) 
will be described in the RSO for the Placebo/S95008 arm. 
­ During the combined period: baseline, each planned post-baseline visit as well as change 
from baseline to each planned post-baseline visit will be described in the RSC for the 
S95008/S95008 arm. 
3.4.3.5. 
Abbreviated World Health Organization Quality of Life - Bref 
Definition: the four domain scores (Physical, Psychological, Social Relations and Environment) 
will be calculated.  
The WHOQOL-Bref questionnaire has been validated in parents of children with autistic 
disorder (Latefa et al., 2014). The psychometric properties will be checked separately. 
Analysis: A General Linear Model with the fixed categorical effect of treatment, country and 
gender as well as the continuous, fixed covariate of baseline will be used for the change from 
baseline to W026 in the four domains scores in the RS. 
GENERAL LINEAR MODEL (ANCOVA): change = baseline country gender treatment 
Missing data handling:  missing data will be imputed using the multiple imputation approach 
(MI).  
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 95% CI of the estimate. 


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Supplementary analysis: 
The four domains scores will be summarized using descriptive statistics and graphs: 
­ During the double-blind period: baseline, each planned post-baseline visit (W004, W008, 
W012 and W026) as well as change from baseline to each planned post-baseline visit will 
be described in the RS by treatment groups (S95008 vs placebo). 
­ During the open-label period: OL baseline, each OL planned post-baseline visit (W030, 
W034, W038 and W052) as well as change from OL planned baseline to each OL 
post-baseline visit will be described in the RSO for the Placebo/S95008 arm. 
­ During the combined period: baseline, each planned post-baseline visit as well as change 
from baseline to each planned post-baseline visit will be described in the RSC for the 
S95008/S95008 arm. 
3.4.4. 
Subgroups analysis 
Not applicable. 
3.5. Exploratory analysis 
3.5.1. 
EuroQol – 5-Dimension – Three-level 
Definition: The EuroQoL-5D-3L questionnaire (EQ-5D) is composed of 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), and a Visual 
Analog Scale (EQ-5D VAS). 
The dimensional 5-level system will be converted into a single index utility score (EQ-5D index 
score).  
Psychometric properties of the EQ-5D-3L Questionnaire were studying in caregivers of autistic 
children (Khanna et al., 2013).  
The psychometric properties will be checked separately. 
Analysis: 
A General Linear Model with the fixed categorical effect of treatment, country and gender as 
well as the continuous, fixed covariate of baseline will be used for the change from baseline to 
W026 in the EQ-5D index score (resp. EQ-5D VAS) in the RS. 
GENERAL LINEAR MODEL: change = baseline country gender treatment 
Missing data handling:  missing data will be imputed using the multiple imputation approach 
(MI).  
Statistical elements: the following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 95% CI of the estimate. 
Supplementary analysis: 
The EQ-5D VAS and the EQ-5D index score will be summarized using descriptive statistics 
and graphs: 
­ During the double-blind period: baseline and change from baseline to each post-baseline 
visit will be described in the RS by treatment groups (S95008 vs placebo). 
­ During the open-label period: OL baseline and change from OL baseline to each OL 
post-baseline visit will be described in the RSO for the Placebo/S95008 arm for patients. 
­ During the combined period: baseline and change from baseline to each post-baseline visit 
will be described in the RSC for the S95008/S95008 arm. 


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3.6. Safety analysis 
All safety analyses will be performed on the taken treatment at W000 as following: 
­ For the double-blind period in the SS by treatment group (S95008 vs placebo). 
­ For the open-label period: in the SSO on the Placebo/S95008 arm. 
­ For the combined period: in the SSC on the S95008/S95008 arm. 
Six periods are of interest to present accurately the safety endpoints. The start and end date of 
these periods are summarized in the following table: 
Table (3.6) 1 - Definition of periods of emergence for safety events 
Period ID 
ANALYSIS PERIOD 
START 
END 
#1 
Emergent during the 
double-blind period 
First intake in double-
blind 
End of double-blind period 
(including W26) 
#2 
Treatment Emergent 
during the double-blind 
period 
First intake in double-
blind 
Min(Last intake in double-
blind + 2 days, First intake 
in open-label) 
#3 
Emergent during the 
open-label period 
First intake in open-
label (W26 not 
included) 
End of open-label period 
(including W52 and 
follow-up) 
#4 
Treatment Emergent 
during the open-label 
period 
First intake in open-
label (W26 not 
included) 
Last intake in open-label + 
2 days (included) 
#5 
Emergent from the 
combined period 
First intake in double-
blind 
End of open-label period 
(including W52 and 
follow-up) 
#6 
Treatment Emergent from 
the combined period 
First intake in double-
blind 
Last intake in open-label + 
2 days (included)  
Listing of main safety data (including adverse events) and start/end date of each period will be 
provided for:  
­ Patients who had a delay superior to 30 days between the double-blind and the open-label 
period will be listed separately. 
 


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3.6.1. 
Adverse events 
Definition:  
­ Emergent Adverse Events (EAE) during the double-blind (resp. open-label, combined) 
period are defined as all adverse events which occur in the period #1 (resp. #3, #5) (as per 
table above), or which started strictly before period #1 (resp. #3, #5) but which worsen (in 
terms of intensity) or become serious according to the investigator opinion during period #1 
(resp. #3, #5). 
­ Treatment Emergent Adverse Events (TEAE) during the double-blind (resp. open-label, 
combined) period are defined as all adverse events which occur in the period #2 (resp. #4, 
#6) (as per table above), or which started strictly before period #2 (resp. #4, #6) but which 
worsen (in terms of intensity) or become serious according to the investigator opinion during 
period #2 (resp. #4, #6). 
­ AE starting during the run-in period are defined as all adverse events which started 
strictly before period #1. 
Analyses: 
Number of events as well as number, percentage and annual incidence rate of patients reporting 
at least one event, presented by primary System Organ Class (SOC), and Preferred Term (PT), 
will be provided for: 
­ Serious EAE and deaths for period #1, #3 and #5. 
­ TEAE, TEAE leading to IMP withdrawal, TEAE requiring new treatment or increase of on-
going treatment, TEAE requiring surgical or medical procedure, TEAE related to IMP, 
serious TEAE, severe TEAE, non-serious TEAE for periods #2, #4 and #6. 
TEAE will be described according to the seriousness, the intensity, the relationship with the 
IMP, the action taken regarding the IMP, the requirement of added therapy and the outcome. 
Moreover, TEAE, TEAE related to IMP and serious TEAE will be presented according to their 
time to onset in weeks calculated from the start of the period #2 (resp. #4 and #6). 
AE starting during the run-in period will be also described by SOC and PT in the SS. 
All adverse events reported after the last Bumetanide intake + 2 days (excluded) will be listed. 
All COVID-19 infection reported during the study will be listed. 
Number of events as well as number, percentage of patients reporting at least one event, 
presented by primary System Organ Class (SOC), and Preferred Term (PT), will be provided 
for all AE and all serious AE occurring after the first intake in the extension part in the patients 
included in the extension period. 
3.6.2. 
Columbia Suicide Severity Rating Scale Children’s version 
Definition:  
The C-SSRS-C data will be mapped to Columbia Classification Algorithm for Suicide 
Assessment (C-CASA) (Guidance for Industry, Suicidality, FDA CDER, September 2010) 
following C-SSRS Scoring and Data Analysis Guide (February 2013) (C-SSRS Guide). The 
following endpoints will be thus considered: 
 
11 preferred C-SSRS categories: 
­ For Suicidal ideation:  
 Wish to be dead (category 1). 
 Non-specific active suicidal thoughts (category 2). 
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 Active suicidal ideation with some intent to act, without specific plan (category 4). 
 Active suicidal ideation with specific plan and intent (category 5). 
­ For Suicidal behaviour:  
 Preparatory acts of behaviour (category 6). 
 Aborted attempt (category 7). 
 Interrupted attempt (category 8). 
 Actual attempt (non-fatal) (category 9). 
 Completed suicide (category 10). 
­ Self-injurious behaviour without suicidal intent (category 11). 
 
Endpoints derived from these C-SSRS categories: 
­ Suicidal ideation or behaviour: at least one “yes” answer present at any assessable visit (i.e. 
categories 1 to 10 analysable) during the considered period to any one of the 1 to 
10 categories. 
­ Suicidal ideation: at least one “yes” answer present at any assessable visit during the 
considered period to any one of the 1 to 5 categories. 
­ Suicidal behaviour: at least one “yes” answer present at any assessable visit during the 
considered period to any one of the 6 to 10 categories. 
­ Suicidal ideation score: maximum suicidal ideation category (1-5 on the CSSRS) among any 
assessable visit of the considered period; 0 if no ideation is present. 
Baseline: 
For suicidal ideation and suicidal behaviour (for items and the four associated derived C-SSRS 
endpoints), baseline will be defined as the value at W000, lifetime. 
Analyses:  
The 11 preferred C-SSRS categories as well as the four associated derived C-SSRS endpoints 
will be described during the double-blind (resp. open-label, combined) treatment period (i.e. 
periods #2, #4 and #6). Moreover, a listing of all patients having at least one post-baseline 
category equal to “yes” will be performed. 
3.6.3. 
Clinical laboratory evaluation  
Definition:  
­ A laboratory value is considered as analysable if non-missing and not flagged in the 
ClinTrial database as "not analysable". 
­ The analyses will be performed on periods #2, #4 and #6. 
­ A value is considered as occurring during the considered period if the sampling date is 
between the start and last date of the considered period. 
­ Baseline for each period is defined in Section 3.1.2. 
­ For each considered period: 
 High emergent abnormal value under treatment according to the laboratory reference 
ranges is defined as value ≤ ULN (Upper Limit of Normal laboratory reference range) or 
missing at the baseline of the considered period and > ULN under treatment. 
 Low emergent abnormal value under treatment according to the laboratory reference 
ranges is defined as value ≥ LLN (Lower Limit of Normal laboratory reference range) or 
missing at baseline of the considered period and < LLN under treatment. 


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 High emergent abnormal value under treatment according to the cut-offs for PCSA values 
is defined as value ≤ ULS (Upper Limit used to define potentially clinically Significant 
abnormal values) or missing at baseline of the considered period and > ULS under 
treatment. 
 Low emergent abnormal value under treatment according to the cut-offs for PCSA values 
is defined as value ≥ LLS (Lower Limit used to define potentially clinically Significant 
abnormal values) or missing at baseline of the considered period and < LLS under 
treatment. 
Analyses: 
For each biochemical, haematological (blood and urine sample) parameter and for electrolytes 
monitoring (Potassium, Sodium), the following analysis will be performed for each period: 
­ Number and percentage of patients with at least one high/low emergent abnormal value 
under treatment, according to the laboratory reference ranges and to the cut-offs for PCSA 
values. 
­ Laboratory parameters classified (number and percentage of patients in each class) according 
to these reference ranges and cut-offs and using shift tables from baseline in the considered 
period to the worst (high and/or low) values under treatment. 
Moreover, listings of patients with out-of-range or PCSA analysable values emergent under 
treatment in each period and of non-analysable values excluded from analyses will be provided. 
Additionally, for potassium parameter, number and percentage of patients with hypokalaemia 
will be described by severity (mild: 3mEq/L ≤ 𝐾𝐾+< 3.5 mEq/L / moderate: 2.2mEq/L ≤ 
𝐾𝐾+< 3 mEq/L / severe: 𝐾𝐾+< 2.2mEq/L) in each period. 
3.6.4. 
Vital signs, clinical examination and other observations related to safety 
3.6.4.1. 
Vital signs and clinical examination 
Definition: 
­ A value is considered as analysable if collected under appropriate circumstances.  
­ The analyses will be performed separately for periods #2, #4 and #6. 
­ A value is considered as occurring during the considered period if the associated visit date 
is between the start and last date of the considered period. 
­ Baseline for each period is defined in Section 3.1.2. 
Analyses 
The following vital signs and clinical examination will be analysed: 
­ Weight (kg). 
­ BMI (kg/m²) (quantitative value and by class). 
­ HR (b.p.m). 
­ SBP (mmHg). 
­ DBP (mmHg). 
Quantitative parameters will be described separately for each period, in terms of value at 
baseline, value at each planned post-baseline visit under treatment as well as in terms of change 
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3.6.4.2. 
Electrocardiogram 
Definition: 
­ ECG parameters will be the following: heart rate (b.p.m), RR interval (msec), PR interval 
(msec), QRS complex (msec), QT and QTcF interval (msec) (Fridericia’s correction formula 
interval). 
­ A value is considered as analysable if non-missing value obtained from an interpretable 
ECG.  
­ An ECG is considered as interpretable if the quality of the trace is "Correct", with "Minor 
problems" or "Missing data". 
­ The analyses will be performed separately for periods #2, #4 and #6. 
­ A value is considered as occurring during the considered period if the assessment date is 
between the start and last date of the considered period. 
­ Baseline for each period is defined in Section 3.1.2.  
Analyses: 
Presence of clinically significant ECG abnormalities will be described as well as sinus rhythm 
at each planned visit under treatment. 
ECG parameters will be described separately for each period, in terms of value at baseline, 
value at each planned post-baseline visit under treatment; as well as, for quantitative endpoints, 
in terms of change from baseline to each planned post baseline visit under treatment.  
Moreover values and changes form baseline of the concerned period of corrected QT interval 
will be described in classes (i.e., ≤ 450, ]450 ; 480[, [480 ; 500] and > 500 msec for values, and 
≤ 30, ]30 ; 60] and > 60 msec for changes). 
 
 


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4. INTERIM ANALYSIS 
Not applicable. 
 
 


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5. APPENDICES 
5.1. Statistical methods details 
5.1.1. 
General Linear Model 
5.1.1.1. 
For continuous data 
A model that will be used for this study is the General Linear Model studying treatment effect 
with baseline gender and country (as fixed effect) as covariates:  
Yijkt = γ Xijkt + ai + bj + dk+εijkt 
Where: 
­ Yijkt is the response from the tth patient, of gender k, in country j, that received treatment i. 
­ Xijkt is the baseline value of the analysed variable for the tth patient, of gender k, in country 
j, that received treatment i. 
­ γ denotes the common slope of the baseline covariate. 
­ ai denotes the intercept of the ith treatment. 
­ bj denotes the fixed effect of country j. 
­ dk denotes the fixed effect of the gender k. 
­ εijkt ~ iid N(0, σε2) denotes the experimental unit error associated with the tth patient of gender 
k, in country j, that received treatment i. 
The model can also be written in matrix notation as: 
Y = Xβ + ε 
Where: 
­ Y is the vector of observations. 
­ X is the design matrix of the fixed effects and baseline factors. 
­ β is the unknown vector of the fixed effects and baseline factors. 
­ ε is the unobserved vector of independent and identically distributed random errors, such as 
,R)
0
N(
~
ε
 where R = 
2
ε
σ In. 
Estimate: 
The estimate βˆ of β is given by: 
C
X
R
X
Var
Y
X
X
X
ˆ
)
ˆ
(
)ˆ
(
with 
)
(
ˆ
1
=
′
=
′
′
=
−
−
−
β
β
 
Confidence interval and p-value: 
The Sum of Squares using a Least-Squares-means contrast is used for computing the Sum of 
Squares under H0: Lβ = 0 (where Lβ denotes a linear estimable combination of the fixed 
effects). 
The 95% confidence interval of βˆ  is given by: 
 
'
ˆ
ˆ
975
.0,
L
C
L
t
L
ν
β ±
 
Where: 
­ νˆ  denotes the approximate degrees of freedom by Kenward Roger. 
­ 
975
0,νˆt
is the 0.975th quantile of the t-distribution with νˆ degrees of freedom. 


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The Least-Squares approach provides estimates of the linear parameters that are unbiased and 
have minimum variance among linear estimators. 
The treatment effect is estimated by the difference of the Least-Squares-means of each studied 
treatment group. 
Validation of hypothesis:  
For the validation of the model used, the following points will be studied: 
a) Normality and homoscedasticity of residuals 
The assumptions of normality and homoscedasticity of residuals will be investigated on the 
chosen final model using some graphs and descriptive statistics. 
b) Detection of outliers 
The detection will be done using graphics. 
5.1.1.2. 
Robust General Linear Model using rank-based analysis 
The rank-based analysis is analogous to the least-squares analysis except that the Euclidean 
distance to minimize is replaced by a different measure of distance that is based on the 
dispersion function of Jaeckel (ref. Rfit: Rank-based Estimation for Linear Models):  
βˆ = Argmin||Y-Xβ||φ 
With ||.||φ the following measure of distance, R being the rank and φ the Wilcoxon score 
function:  
ห|𝑢𝑢|ห𝜑𝜑 = ෍𝜑𝜑ቆ𝑅𝑅(𝑢𝑢𝑖𝑖)
𝑛𝑛+ 1ቇ𝑢𝑢𝑖𝑖
𝑛𝑛
𝑖𝑖=1
  
As such analysis cannot be implemented directly from SAS, the function rfit of the package 
Rfit of R will be used. Of note that only the phase 2 analysis set (see Section 5.1.2) will be 
performed in R. 
5.1.2. 
Pattern imputation based 
We will implement a hybrid approach using control-based pattern imputation and standard 
multiple imputation depending on the treatment group and the reasons of withdrawal. 
 
Standard multiple imputation (Rubin, 1987) replaces each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute. Each value is a Bayesian 
drawn from the conditional distribution of the missing observation given the observed data, 
made in such a way that the set of imputation properly represents the information about the 
missing value that is contained in the observed data for the chosen model. 
 
The multiply imputed data sets are then analysed by using standard procedures for complete 
data and combining the results from these analyses, based on the change from baseline. 
Multiple imputation inference involves 3 consecutive phases (phase 1: imputation step, phase 
2: analysis step and phase 3: combination step). 
 


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1/ PHASE 1: Imputation step 
To guarantee the reproduction of results, the seed will be fixed at 95008. 
This part will be divided in 3 steps summarized hereafter: 
 
Step 1: 
First, data collected post treatment withdrawal (if any) should be considered as missing. All 
intermittent missing data (i.e. with an arbitrary missing pattern) of baseline and variable of 
interest at the planned visits will be first imputed using a MI approach based on MCMC method 
(with single chain) by treatment groups, in case the initial dataset has not a strict monotone 
missing pattern. 
A dataset is said to have a monotone missing pattern if missing values always occur at the end 
of data records; if we note Yi =(Yi,0,Yi,1,…,Yi,t,…Yi,T) the measured variable at each time t from 
baseline (t=0) to the end of the study (t=T) for an individual i, the missing pattern is monotone 
if, for all individuals and all times, if Yi,t is missing, then Yi,t+1 is also missing and if Yi,t is not 
missing, then Yi,t-1 is not missing also.  
A total of 100 imputed partially completed datasets will be generated.  
In case of patients with no data available at baseline and at any post baseline visit, a regression 
method will be used on the 100 imputed partially completed datasets to perform the imputation 
at the baseline visit only, using in this order: baseline covariates (e.g. country, gender), 
treatment in the model. 
This dataset will serve as a basis for Step 2a and Step 2b (DATA_BASIS).  
For the following step, the entry dataset will be sorted by imputation, by treatment and by 
patient. 
Step 2: 
In this sequence, remaining missing data of DATA_BASIS will be imputed. The treatment group 
and the reason for study or drug premature withdrawals have to be considered as the imputation 
rules will be different. For this imputation step, countries with less than 10 patients will be 
gathered to avoid strata with no observed values. 


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a) For all placebo patients and patients in S95008 arm with study or drug premature 
withdrawals due to other reasons: 
To impute those missing data, all data will be considered (regardless of the treatment and of the 
reason of withdrawal) in order to benefit of all data available at each visit. However, at the end, 
only data (imputed or initially complete) from all placebo patients and data from S95008 
patients, completers or with initially missing data due to other reasons will be considered (the 
other being imputed with jump-to-placebo method, as explained in step 2b).  
A regression method will be used to perform the imputation, using in this order: baseline, 
baseline covariates (e.g. country, gender), treatment and variable of interest at the planned visits 
in the model. Of note, for imputing data of visit i, data up to visit i-1 are to be considered for 
the imputation, even if the data of visit i-1 already results of an imputation (this is taken into 
account in PROC MI with the order of the variables put in the VAR statement). This is 
applicable for variable of interest at each planned post-baseline visits. 
Of note, for subgroup analysis, the subgroup should not be added as a covariate in the regression 
model. 
 
b) For patients with study or drug premature withdrawals due to lack of efficacy or 
AE in S95008 arm 
To impute those missing data, an input dataset will be prepared with data from all placebo 
patients (completers or with missing values regardless of the reason), and from S95008 patients, 
with missing data due to AE/lack of efficacy. 
 
The jump-to-placebo approach will be set up for these patients’ imputations, by using the 
%mistep macro from James Roger (https://www.lshtm.ac.uk/research/centres-projects-
groups/missing-data#dia-missing-data , zip file MISTEP20180327). 
A sequence of %mistep will be run, considering as the first model (for the first post-baseline 
visit): baseline baseline covariates (e.g. country, gender), treatment*. The subsequent model 
(for the second post-baseline visit) will include, in addition to variables included in the first 
model, the residuals of this first model (put at the end of the statement). The other subsequent 
models will be implemented in the same way. 
*at each visit the treatment variable is derived such as the missing value in the S95008 will be 
imputed using the placebo arm as reference.  
 
This macro will be used because no SAS procedure are currently available to perform the jump 
to reference approach. 
Step 3: 
Finally we can assemble back all subjects with complete data: all patients from Step2a and 
remaining S95008 patients from Step2b (DATA_COMPLETE). 
 
In case of imputed data at W026 (respectively W012 depending on the analysis) are outside of 
the endpoint ranges, the imputed data will be replaced by the boundary that was overpassed. 
 


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Endpoint 
Min 
Max 
CARS2 total score 
15 
60 
SRS2 total score 
0 
195 
CGI-I 
1 
7 
VABS II Adaptative Behavior 
Composite standard score 
20 
160 
VABS II Communication domain 
standard score 
20 
160 
VABS II Daily Living Skills 
Domain standard score 
20 
160 
VABS II Socialisation Domain 
standard score 
20 
160 
PedsQL total score 
0 
2300 
PedsQl Physical functioning score 
0 
800 
PedsQl 
Emotional 
functioning 
score 
0 
500 
PedsQl Social functioning score 
0 
500 
PedsQl School functioning score 
0 
500 
PedsQL 
Psychosocial 
Health 
Summary score 
0 
1500 
WHOQOL-Bref Physical Domain 
Score 
0 
100 
WHOQOL-Bref 
Psychological 
Domain Score 
0 
100 
WHOQOL-Bref Social Relations 
Domain Score 
0 
100 
WHOQOL-Bref 
Environment 
Domain Score 
0 
100 
EQ-5D-3L index score 
0 
1 
EQ-5D-3L VAS 
0 
100 
2/ PHASE 2: Analysis step 
The planned model will be applied to each of the 100 imputed datasets obtained at the previous 
step (DATA_COMPLETE). For each imputed dataset i (i=1,2…,m), the estimate of the 
difference between groups and the associated standard error will be stored. 
Of note that for CGI-I analysis, before this analysis step, the imputed data will be rounded to 
the nearest unit. Moreover, this analysis step will be done on the change from baseline (whereas 
imputations were done on visit’s value). 
 
3/ PHASE 3: Combination step 
Statistical inferences will be generated by combining results from the 100 analyses using 
Rubin’s formulae. The multiple imputation estimator of the difference between Bumetanide 
and placebo is the average of the individual 100 estimators. The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward, 2007).  
 
 
Mean 
Variance 
Estimate 
Mean(Ôi) 
Variance(Ôi) 
Standard error 
Mean(Ûi) 
Variance(Ûi) 
 


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Let Ôi  and Ûi be the point and variance estimates from the ith imputed data set, i=1,2…,m. 
Then the point estimates for O from multiple imputations is the average of the m complete-data 
estimates: 
∑
=
=
m
i
m
1
i
Ô
1
Ô
 
 
Let Û be the within-imputation variance, which is the average of the m complete-data estimates: 
∑
=
=
m
i
m
1
i
Û
1
Û
 
 
and B be the between-imputation variance: 
∑
=
−
−
=
m
i
m
1
2
i
)
Oˆ
Oˆ
(
1
1
B
 
 
Then the variance estimate associated with Ô is the total variance: 
B
m)
1
(1
 
Û
T
+
+
=
 
5.1.3. 
Mixed-effects model with repeated measurements 
A model that will be used for this study is the mixed-effects model with repeated measurements 
(MMRM). The model will include the fixed, categorical effects of country, gender, treatment, 
visit, treatment by visit interaction, country by visit interaction and gender by visit interaction 
as well as the continuous, fixed covariates of baseline and visit-by-baseline interaction: 
MMRM: change at each visit = baseline country gender treatment visit treatment*visit baseline*visit 
country*visit gender*visit 
The analysis will fit an unstructured (UN) variance-covariance matrix. This model allows 
different variances of the response at each time-point; that is there is no constraint of common 
variance at all times. In case of non-convergence of the algorithm with an unstructured 
variance-covariance matrix, the following structures will be tested in the following order: 
Heterogeneous Toeplitz, Heterogeneous compound symmetry, Toeplitz then Compound 
symmetry. The first (co)variance structure yielding convergence will be used as the primary 
analysis. 
The Kenward-Roger method will be used for the approximation of the denominator degrees of 
freedom. 
Estimate: 
Inference is made at the selected time-point by constructing estimates of the effects at that time: 
these are adjusted treatment effects or ‘LS-means’. The effects are based on the observations at 
that actual time-point, combined with contributions from all the observations at other times, 
mediated by the estimated covariance matrix. 
5.1.4. 
Logistic regression 
To analyse the CARS2 and CGI responders, a logistic regression model with the fixed 
categorical effect of treatment, country and gender will be used. 
 
In case of quasi-completed separation of data with the model mentioned above, the following 
models will be tested sequentially, until no facing the warning anymore: 


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­ A logistic regression model with the fixed categorical effect of treatment, pooled countries 
and gender 
­ A penalized logistic regression model with the fixed categorical effect of treatment, country 
and gender 
­ A penalized logistic regression model with the fixed categorical effect of treatment, pooled 
countries and gender. 
5.2. Software  
Statistical analyses will be performed using SAS®/PC Software version 9.4 and R version 3.1.1 
for the non-parametric approach with adjustment. 
 
 


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6. REFERENCES 
Guideline 
 
Guideline on Missing Data in Confirmatory Clinical Trials – Adopted by CHMP, June 2010, issued as 
EMA/CPMP/EWP/1776/99 Rev. 1. 
 
ICH E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
 
ICH E3 - Structure and Content of Clinical Study Reports – Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5. 
 
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, issued 
as EMA/CHMP/ICH/435606/2012. 
 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
 
ICH E9(R1) - Addendum – Adopted by CPMP, 30 January 2020, issued as EMA/CHMP/ICH/436221/2017. 
Points to consider 
Points to Consider on Adjustment for Baseline Covariates – Adopted by CPMP, May 2003, issued as 
CPMP/EWP/2863/99. 
Points to Consider on Multiplicity Issues in Clinical Trials – Adopted by CPMP, September 2002, issued as 
CPMP/EWP/908/99. 
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