A Phase 2a, Double-blind, Randomized, Placebo-controlled, Proof of Concept Study of Vascular Endothelial Growth Factor (VEGF)-B Blockade With the Monoclonal Antibody CSL346 in Subjects With Diabetic Kidney Disease
Phase: PHASE2
Conditions: Diabetic Kidney Disease (DKD)
Sponsor: CSL Behring

 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
Eff e cti v e  D at e:  We e k  c o m m e n ci n g  2 5 -J u n e-2 0 1 8  
 
  
C LI NI C A L  S T U D Y  P R O T O C O L  
 
A  P h as e  2 a,  D o u bl e -bli n d,  R a n d o mi z e d,  Pl a c e b o -c o ntr oll e d,  Pr o of  of  C o n c e pt  St u d y  of 
Vas c ul ar  E n d ot h eli al  Gr o wt h  F a ct or ( V E G F) - B  Bl o c k a d e  wit h t h e  M o n o cl o n al  A nti b o d y 
C S L 3 4 6 i n  S u bj e cts  wit h  Di a b eti c  Ki d n e y  Dis e as e  
St u d y  N u m b e r:   
C S L 3 4 6 _ 2 0 0 1  
St u d y  P r o d u ct:   
C S L 3 4 6 
D e v el o p m e nt  P h as e:   
2 a 
S h o rt  Titl e:  
V E G F -B  Bl o c k a d e  wit h t h e  M o n o cl o n al  A nti b o d y  C S L 3 4 6 i n 
S u bj e cts  wit h  Di a b eti c  Ki d n e y  Dis e as e  
S p o ns o r:  
C S L  B e hri n g  L L C 
1 0 2 0  First  A v e n u e  
Ki n g  of  Pr ussi a,  P e n ns yl v a ni a  1 9 4 0 6 
U nit e d  St at es  of  A m eri c a  
P r ot o c ol  Ve rsi o n:   
A m e n d m e nt  2 
I N D  N u m b e r:   
1 4 5 3 5 2 
P r ot o c ol  D at e:  
2 7  M a y   2 0 2 1  
C o m pli a n c e:   
T his st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h st a n d ar ds  of 
G o o d  Cli ni c al  Pr a cti c e ( as  d efi n e d  b y t h e I nt er n ati o n al  C o u n cil 
f or  H ar m o nis ati o n),  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  all  a p pli c a bl e  n ati o n al  a n d l o c al 
r e g ul ati o ns.  
 
C o m m e r ci al i n  C o nfi d e n c e .  T his  d o c u m e nt  a n d t h e i nf or m ati o n  c o nt ai n e d  h er ei n  ar e  pr o pri et ar y  a n d 
c o nfi d e nti al.  T his  d o c u m e nt  a n d t h e  c o nt ai n e d i nf or m ati o n  ar e i nt e n d e d f or  dis cl os ur e t o  a n d  us e  b y t h os e 
p ers o n n el  w h o  ar e  u n d er  a n  o bli g ati o n  of  c o nfi d e nti alit y  b y  a si g n e d  a gr e e m e n t  wit h  S p o ns or ( “ C S L B e hri n g ” ). 
T his  d o c u m e nt  a n d t h e  c o nt ai n e d i nf or m ati o n  m a y  b e  dis cl os e d  a n d  us e d  o nl y t o t h e  e xt e nt  n e c ess ar y t o  c o n d u ct 
t h e  cli ni c al st u d y.  R e pr o d u cti o n  or  dis cl os ur e  of t his  d o c u m e nt  or its  c o nt ai n e d i nf or m ati o n is f or bi d d e n  u nl ess 
a t t h e  e x pr ess r e q u est  or  wit h t h e  writt e n  c o ns e nt  of C S L  B e hri n g  L L C . 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
LI S T  O F  P E R S O N N E L  A N D  O R G A NI Z A TI O N S  R E S P O N SI B L E  F O R  C O N D U C T 
O F  T H E  S T U D Y  
A list  of  p ers o n n el  a n d  or g a ni z ati o ns r es p o nsi bl e f or t h e  c o n d u ct  of t h e st u d y  will  b e s u p pli e d 
t o st u d y sit es  as  p art  of t h e I n v esti g at or’s  St u d y  Fil e.  T his list  will  b e  u p d at e d  b y  CS L 
B e hri n g ( or  d el e g at e)  a n d  pr o vi d e d t o t h e st u d y sit es  as  n e e d e d. 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
R E VI SI O N  HI S T O R Y  
D at e  
V e rsi o n   
S u m m a r y  of  C h a n g es  
1 6 J a n u ar y  2 0 2 0   
Ori gi n al   
N ot  a p pli c a bl e  
0 7  M a y  2 0 2 0  
A m e n d m e nt  1 
•   A d d e d  a  hi g h er  d os e  of  C S L 3 4 6 i n  C S L 3 4 6 
tr e at m e nt  ar m  a n d u p d at e d  d os e r ati o n al e 
•   U p d at e d r a n d o mi z ati o n s c h e m e   
•   U p d at e d st atisti c al  a n al ys es  of  pri m ar y  a n d 
s e c o n d ar y  e n d p oi nts  a n d  a d d e d f urt h er 
e x pl or at or y  a n al ys es 
•   I n cr e as e d  d os e  v ol u m es  a n d i nf usi o n 
d ur ati o ns 
•   A d d e d  d os e l e v el st o p pi n g  crit eri a 
•   A d d e d i nj e cti o n sit e r e a cti o n  as  a n  a d v ers e 
e v e nt  of s p e ci al i nt er est   
•   Pr o vi d e d  g ui d a n c e f or  a d mi nistr ati o n  a n d 
d os e  a dj ust m e nts f or  mil d i nj e cti o n sit e 
r e a cti o ns 
•   U p d at e d s a m pl e si z e  esti m ati o n  a n d  a d d e d 
all o w a n c e f or  a n i n cr e as e i n s a m pl e si z e  of 
u p t o  1 2 4 s u bj e cts if t h er e is  a  hi g h er t h a n 
e x p e ct e d  dr o p - o ut r at e 
•   A d d e d  a n d r e vis e d f urt h er  e x pl or at or y 
p h ar m a c o d y n a mi c  bi o m ar k ers 
•   A d d e d i m m u n os u p pr ess a nts  as  a  pr o hi bit e d 
c o n c o mit a nt t h er a p y 
•   R e vis e d lif est yl e r estri cti o ns ( d es cri b e d 
c o ntr a c e pti v e  b arri er  m et h o d  a n d  a dj ust e d 
al c o h ol li mits)  
•   M a d e  e dit ori al r e visi o ns,  w h er e  a p pli c a bl e   
2 7  M a y   2 0 2 1  
A m e n d m e nt  2 
•   A d d e d  p ot e nti al i n cl usi o n  of s u bj e cts  wit h  
esti m at e d  gl o m er ul ar filtr ati o n r at e  b et w e e n 
>  2 0  a n d  <  4 5  m L/ mi n/ 1. 7 3 m 2 s u bj e ct t o 
e n d ors e m e nt  b y t h e I n d e p e n d e nt  D at a 
M o nit ori n g  C o m mitt e e  
•   C h a n g e d t h e  a d v ers e  e v e nts  of s p e ci al 
i nt er est crit eri a f or i n cr e as es i n  al b u mi n -t o-
cr e ati ni n e r ati o  
•   A d d e d  s e nsiti vit y  a n al ysis e m pl o yi n g 
m ulti pl e i m p ut ati o n f or  missi n g  d at a  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   A d d e d s e nsiti vit y  a n al ysis t o r efl e ct t h e 
i m p a ct  of n o v el  c or o n a vir us  2 0 1 9 
•   A d d e d  cl arifi c ati o n f or  us e  of 
a nti h y p ert e nsi v es 
•   A d d e d  S cr e e n e d  A n al ysis  S et  
•   A d d e d  I nt eri m A n al ysis f or  d e cisi o n   m a ki n g 
•   A d d e d  cl arifi c ati o n f or  w o m e n  of 
c hil d b e ari n g  p ot e nti al  or  m al es  wit h  p art n ers 
of  c hil d b e ari n g  p ot e nti al 
•   M a d e  e dit ori al r e visi o ns,  w h er e  a p pli c a bl e 
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Cli ni c al  St u d y  P r ot o c ol  S y n o psis  
Titl e  
A  P h as e  2 a,  D o u bl e- bli n d,  R a n d o mi z e d,  Pl a c e b o- c o ntr oll e d,  Pr o of  of 
C o n c e pt  St u d y  of  Vas c ul ar  E n d ot h eli al  Gr o wt h  F a ct or ( V E G F) -B 
Bl o c k a d e  wit h t h e  M o n o cl o n al  A nti b o d y  C S L 3 4 6 i n  S u bj e cts  wit h 
Di a b eti c  Ki d n e y  Dis e as e  
St u d y  N u m b e r   
C S L 3 4 6 _ 2 0 0 1  
S p o ns o r  
C S L  B e hri n g  L L C  
D e v el o p m e nt 
P h as e  
2 a  
St u d y  P r o d u ct  
C S L 3 4 6 ( v as c ul ar  e n d ot h eli al  gr o wt h f a ct or [ V E G F ]-B  a nt a g o nist 
m A b) 
I n di c ati o n  
Di a b eti c  ki d n e y  dis e as e ( D K D)  
St u d y  S u m m a r y 
a n d  O v e r vi e w  
T his is  a  pr os p e cti v e,  m ulti c e nt er, 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,  pr o of  of  c o n c e pt st u d y t o i n v esti g at e t h e  effi c a c y, 
s af et y, t ol er a bilit y,  a n d  p h ar m a c o ki n eti cs ( P K)  of r e p e at  d os es  of 
C S L 3 4 6 i n  1 0 0 s u bj e cts  wit h  D K D  a n d  al b u mi n uri a r e c ei vi n g 
st a n d ar d  of  c ar e tr e at m e nt.  T h e st u d y  will  b e  di vi d e d i nt o  4  p eri o ds: 
S cr e e ni n g,  L e a d -i n,  Tr e at m e nt,  a n d  F oll o w- u p,  as s h o w n i n t h e 
f oll o wi n g s c h e m ati c: 
 
 
S cr e e ni n g  P eri o d 
T h e  S cr e e ni n g  P eri o d  b e gi ns  wit h t h e  c o m pl eti o n  of t h e i nf or m e d 
c o ns e nt  pr o c ess  a n d i n cl u d es  u p t o  6  w e e ks f or  d et er mi n ati o n  of 
s u bj e ct  eli gi bilit y.  D uri n g  S cr e e ni n g ( Visit  1  a n d  Visit  2), t h e 
I n v esti g at or  or  d el e g at e  will  ass ess t h e s u bje ct’s  eli gi bilit y f or t h e 
st u d y  a c c or di n g t o I n cl usi o n /  E x cl usi o n  Crit eri a.  A s u b c ut a n e o us 
( S C) t est i nf usi o n is t o  b e  d o n e  at  Visit  2  aft er  ot h er s u bj e ct 
eli gi bilit y  crit eri a  h a v e  b e e n  c o nfir m e d.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
 
L e a d -i n  P eri o d 
D uri n g t h e  L e a d- i n  P eri o d, s u bj e cts  will  ha v e  a st u d y  visit 
a p pr o xi m at el y  1  w e e k  b ef or e r a n d o mi z ati o n ( Visit  3,  
D a y   – 7  ±  4  d a ys).  T h e s u bj e ct’s  eli gi bilit y t o  c o nti n u e i nt o t h e 
Tr e at m e nt  P eri o d  will  b e  ass ess e d  a c c or di n g t o  R a n d o mi z ati o n 
Crit eri a.  
 
Tr e at m e nt  P eri o d  
T h e  Tr e at m e nt  P eri o d  will i n cl u d e  1 2  w e e ks  of  a p pr o xi m at el y 
m o nt hl y ( e v er y  4  w e e ks)  a d mi nistr ati o n  of i n v esti g ati o n al  pr o d u ct 
(I P).  Usi n g  a n i nt er a cti v e r es p o ns e t e c h n ol o g y s yst e m,  eli gi bl e 
s u bj e cts  will  b e r a n d o mi z e d ( 1: 1: 2) t o r e c ei v e  bli n d e d I P ( 8  m g/ k g 
C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or  pl a c e b o).  
 
E a c h s u bj e ct’s first  d os e  of I P  at  Visit  4 ( D a y  1)  will  b e  a n 
i ntr a v e n o us (I V) l o a di n g  d os e  of  3  m g/ k g  C S L 3 4 6 (s u bj e cts 
r a n d o mi z e d t o  8  m g/ k g  C S L 3 4 6),  6  m g/ k g  C S L 3 4 6 (s u bj e cts 
r a n d o mi z e d t o  1 6  m g/ k g  C S L 3 4 6),  or  pl a c e b o (s u bj e cts r a n d o mi z e d 
t o  pl a c e b o).  All I V l o a di n g  d os es  will  b e i n  a t ot al  v ol u m e  of  1 0  m L 
a n d  will  b e i nf us e d  o v er t h e  c o urs e  of  a p pr o xi m at el y  2 0  mi n ut es. 
T h e s u bj e ct  will t h e n  b e  m o nit or e d f or  a p pr o xi m at el y  2  h o urs,  d uri n g 
w hi c h  a d v ers e  e v e nts ( A Es)  a n d  vit al si g ns  will  b e r e c or d e d 
p eri o di c all y  as  d es cri b e d i n t h e  S c h e d ul e  of  Ass ess m e nts. If  n o 
cli ni c all y r el e v a nt  A Es  ar e  o bs er v e d  d uri n g t his ti m e, t h e s u bj e ct’s 
first  S C  d os e  of I P  will  b e  a d mi nist er e d  as  a n  8  m g/ k g,  1 6  m g/ k g,  or 
pl a c e b o  2 0  m L  S C i nf usi o n  o v er t h e  c o urs e  of  a p pr o xi m a t el y 
4 0  mi n ut es.  
 
S u bj e cts  will r e c ei v e  3 s u bs e q u e nt  S C i nf usi o ns  at  Visit  7 ( We e k  4), 
Visit  8 ( We e k  8),  a n d  Visit  9 ( We e k  1 2) f or  a t ot al  of  4  S C  d os es. 
  
G ui d a n c e is  pr o vi d e d f or  a d v ers e  e v e nts  of s p e ci al i nt er est  (A E SIs ): 
i nj e cti o n sit e r e a cti o ns; i n cr e as e i n s er u m  cr e ati ni n e ( S Cr), 
al b u mi n uri a,  or  bl o o d  pr ess ur e ( B P);  a n d  c ar di a c -r el at e d  A Es. 
 
D os e  a n d /  or  a d mi nistr ati o n  a dj ust m e nts  ar e  p er mitt e d f or  mil d 
i nj e cti o n sit e r e a cti o ns t h at  ar e  d e e m e d  u n a c c e pt a bl e  a n d  w o ul d 
ot h er wis e l e a d t o  dis c o nti n u ati o n  of t h e I P.  
 
R el e v a nt  u n bli n d e d  d at a fr o m  all s u bj e cts  p arti ci p ati n g i n t h e st u d y 
will  b e r e vi e w e d  b y t h e  I n d e p e n d e nt  D at a  M o nit ori n g  C o m mitt e e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
(I D M C) d uri n g r e g ul arl y -s c h e d ul e d s af et y  a n d  P K r e vi e ws,  as 
d et ail e d i n t h e I D M C  C h art er.  
 
F oll o w- u p  P eri o d 
T h e  F oll o w- u p  P eri o d  will  c o nti n u e f or  1 2  w e e ks  aft er t h e s u bj e ct’s 
l ast  d os e  of I P t o  e v al u at e  c h a n g es i n s af et y,  effi c a c y,  P K,  a n d 
p h ar m a c o d y n a mi c ( P D)  p ar a m et ers  aft er st o p pi n g tr e at m e nt.  
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  of t his st u d y is t o  e v al u at e t h e  effi c a c y  of 
C S L 3 4 6  a d mi nist er e d  e v er y  4  w e e ks f or  1 2  w e e ks ( 4  d os es) i n 
s u bj e cts  wit h  D K D.  
P ri m a r y  E n d p oi nt   C h a n g e i n l o g-tr a nsf or m e d  uri n ar y  al b u mi n -t o-cr e ati ni n e r ati o  
( A C R) fr o m  B as eli n e t o  We e k  1 6 ( Visit  1 0) 
S e c o n d a r y 
O bj e cti v es  
T h e s e c o n d ar y  o bj e cti v es  of  t his st u d y  ar e as f oll o ws : 
1.   T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  C S L 3 4 6  a d mi nist er e d 
e v er y  4   w e e ks f or  u p t o  1 2  w e e ks ( 4  d os es) i n s u bj e cts  wit h  D K D 
2.   T o  e v al u at e t h e  eff e ct  of  C S L 3 4 6  o n  S Cr  c o n c e ntr ati o n  a n d 
e G F R i n s u bj e cts  wit h  D K D  
3.   T o  e v al u at e t h e  eff e ct  of  C S L 3 4 6  o n  B P i n s u bj e cts  wit h  D K D 
4.   T o  e v al u at e t h e  P K  of  C S L 3 4 6 i n s u bj e cts  wit h  D K D 
5.   T o  e v al u at e t h e i m m u n o g e ni cit y  of  C S L 3 4 6 i n s u bj e cts  wit h 
D K D  
S e c o n d a r y 
E n d p oi nts  
T h e s e c o n d ar y  e n d p oi nts  of t his st u d y  ar e  as f oll o ws : 
1.   Tr e at m e nt - e m er g e nt  a d v ers e  e v e nts, i n cl u di n g  A E SIs, fr o m t h e 
ti m e  of first  d os e  of I P t hr o u g h  E n d  of  St u d y ( E O S) 
2.   O bs er v e d  v al u e  a n d  c h a n g e fr o m  B as eli n e  i n  S Cr  a n d  e G F R 
t hr o u g h  E O S 
3.   O bs er v e d  v al u e  a n d  c h a n g e fr o m  B as eli n e  i n s yst oli c  a n d 
di ast oli c  B P t hr o u g h  E O S  
4.   C S L 3 4 6 s er u m  P K:  m a xi m u m  c o n c e ntr ati o n ( C m a x )  aft er I V 
l o a di n g  d os e, ti m e t o r e a c h  Cm a x  i n s er u m ( Tm a x )  aft er I V l o a di n g 
d os e,  C m a x  aft er first  S C  d os e,  T m a x  aft er first  S C  d os e,  ar e a  u n d er 
t h e  c o n c e ntr ati o n-ti m e  c ur v e i n first  d osi n g i nt er v al ( A U C0-τ), 
a n d tr o u g h  c o n c e ntr ati o n ( C tr o u g h) aft er  e a c h  d os e  
5.   Pr es e n c e  of  a nti - dr u g  a nti b o di es  at  We e k  4 ( Visit 7),  We e k  8 
( Visit  8),  a n d  We e k  1 6 ( Visit  1 0) 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
E x pl o r at o r y 
O bj e cti v es  
T h e  e x pl or at or y  o bj e cti v es  of t his st u d y  ar e  as f oll o ws : 
1.   T o  e x pl or e t h e  eff e ct  of  C S L 3 4 6  o n t h e f oll o wi n g  p ot e nti al  P D 
bi o m ar k ers:  
•   B i o m ar k ers  of li pi d  m et a b olis m 
•   Bi o m ar k ers  of  gl y c e mi c  c o ntr ol  
•   N o v el  pl as m a, s er u m,  a n d  uri n ar y  bi o m ar k ers  
2.   T o  m e as ur e t h e  c o n c e ntr ati o n  of  C S L 3 4 6 i n t h e  uri n e  a n d  e x pl or e 
its  ass o ci ati o n  wit h  al bu mi n uri a 
3.   T o  e x pl or e t h e r el ati o ns hi p  b et w e e n  P D  bi o m ar k ers  a n d  C S L 3 4 6 
P K  c h ar a ct eristi cs  
4.   T o  e v al u at e t h e fr e q u e n c y  of s u bj e cts  wit h  m a cr o al b u mi n uri a 
( A C R >  3 0 0  m g/ g [ >  3 3. 9  m g/ m m ol])  at  B as eli n e  r e gr essi n g t o 
mi cr o al b u mi n uri a ( A C R  ≥  3 0  a n d  ≤  3 0 0  m g/ g [ ≥  3. 3 9  a n d 
≤  3 3. 9  m g/ m m ol])  or  n or m o al b u mi n uri a ( A C R  <  3 0  m g/ g 
[ <  3. 3 9 m g/ m m ol]),  or fr o m  mi cr o al b u mi n uri a t o 
n or m o al b u mi n uri a 
5.   T o  e x pl or e  p ossi bl e  d os e r es p o ns e f or t h e  pri m ar y  a n d s e c o n d ar y 
effi c a c y  a n d s af et y  e n d p oi nts 
E x pl o r at o r y 
E n d p oi nts  
T h e  e x pl or at or y  e n d p oi nts f or t his st u d y  ar e  as f oll o ws: 
1.   C h a n g es fr o m  B as eli n e t o  e a c h  ass ess m e nt i n f asti n g  v al u es f or 
t h e f oll o wi n g  P D  bi o m ar k ers:  
•   B i o m ar k ers  of li pi d  m et a b olis m i n cl u di n g, b ut  n ot li mit e d t o , 
cir c ul ati n g t ot al  c h ol est er ol, tri gl y c eri d es,  hi g h  d e nsit y 
li p o pr ot ei ns, l o w  d e nsit y li p o pr ot ei ns,  gl y c er ol,  n o n-est erifi e d 
f att y  a ci ds,  a n d  k et o n es  
•   Bi o m ar k ers  of  gl y c e mi c  c o ntr ol i n cl u di n g,  b ut  n ot li mit e d t o , 
f asti n g  gl u c os e  a n d  h e m o gl o bi n  A 1 c ( H b A 1 c)  
•   N o v el  bi o m ar k ers i n cl u di n g,  b ut  n ot li mit e d t o , s er u m-fr e e 
V E G F - B  a n d s ol u bl e t u m or  n e cr osis f a ct or r e c e pt or- 1  a n d 
uri n ar y  V E G F - A, s ol u bl e  V E G F r e c e pt or  1( V E G F- R 1), 
ki d n e y i nj ur y  m ol e c ul e - 1,  n e utr o p hil  g el ati n as e- ass o ci at e d 
li p o c ali n,  cl ust eri n,  a n d  m o n o c yt e  c h e m o attr a ct a nt  pr ot ei n- 1 
( M C P- 1) 
2.   C o n c e ntr ati o n  of  C S L 3 4 6 f o u n d i n  uri n e  at  We e k  1 ( Visit  5)  a n d 
We e k  1 2 ( Visit  9) 
3.   N u m b er ( p er c e nt)  of  s u bj e cts  w h o r e gr ess fr o m 
m a cr o al b u mi n uri a t o  mi cr o al b u mi n uri a  or  n or m o al b u mi n uri a,  or 
fr o m  mi cr o al b u mi n uri a t o  n or m o al b u mi n uri a  at  We e k  1 6 
( Visit  1 0) c o m p ar e d t o  B as eli n e  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
St u d y  D u r ati o n   
T h e  d ur ati o n  of t h e st u d y f or  a n i n di vi d u al s u bj e ct is  e x p e ct e d t o  b e 
u p t o  a p pr o xi m at el y  3 4  w e e ks.  T his  esti m at e is  b as e d  o n  t h e 
f oll o wi n g: 
•   A n  u p t o  6- w e e k  S cr e e ni n g  P eri o d  
•   A n  u p t o  4- w e e k  L e a d -i n  P eri o d 
•   A  1 2 -w e e k  Tr e a t m e nt  P eri o d 
•   A  1 2 - w e e k  F oll o w- u p  P eri o d 
 
T h e  o v er all st u d y  d ur ati o n (i e, first s u bj e ct’s  S cr e e ni n g  Visit t o l ast 
s u bj e ct’s  E O S  Visit)  will  b e  a p pr o xi m at el y  2 2  m o nt hs. 
N u m b e r  of 
S u bj e cts  
T h e st u d y  will r a n d o mi z e  a t ar g et  of  1 0 0 s u bj e cts:  
•   2 5 s u bj e cts r a n d o mi z e d t o t h e  8  m g/ k g  C S L 3 4 6  gr o u p 
•   2 5 s u bj e cts r a n d o mi z e d t o t h e  1 6  m g/ k g  C S L 3 4 6  gr o u p 
•   5 0 s u bj e cts r a n d o mi z e d t o t h e  pl a c e b o  gr o u p 
 
A s u bj e ct is  c o nsi d er e d  e nr oll e d i n t h e st u d y  o n c e t h e y  h a v e si g n e d 
t h e i nf or m e d  c o ns e nt f or m.  A s u bj e ct is  c o nsi d er e d  eli gi bl e f or 
r a n d o mi z ati o n i nt o t h e st u d y  w h e n  all i n cl usi o n  crit eri a  h a v e  b e e n 
m et,  n o n e  of t h e  e x cl usi o n  crit eri a  h a v e  b e e n  m et,  a n d t h e 
r a n d o mi z ati o n  crit eri a  h a v e  b e e n  m et.  
 
T h e  a ct u al  e arl y  dis c o nti n u ati o n r at e  will  b e  ass ess e d t hr o u g h o ut t h e 
st u d y  a n d  u p t o  1 2 4 s u bj e cts  m a y  b e r a n d o mi z e d, if  n e c ess ar y, t o 
t ar g et  9 4  c o m pl et e d s u bj e cts (s u bj e cts  w h o r e c ei v e d  all  d os es  a n d 
c o m pl et e d t h e  We e k  1 6  A C R  ass ess m e nt).  
St u d y  P o p ul ati o n 
a n d  M ai n  C rit e ri a 
f o r  Eli gi bilit y 
 
I n cl usi o n 
T h e st u d y  will  e nr oll  m al e  a n d f e m al e s u bj e cts  ≥  2 5  y e ars  of  a g e 
wit h  a  di a g n osis  of t y p e  2  di a b et es  m ellit us.  S u bj e cts  m ust  h a v e  a 
uri n ar y  A C R  ≥  1 5 0  m g/ g ( 1 6. 9 5  m g/ m m ol) fr o m  a  2 4- h o ur ti m e d 
uri n e  c oll e cti o n.  T h e i niti al st u d y  p o p ul ati o n  m ust  h a v e  e G F R 
≥  6 0  m L/ mi n/ 1. 7 3 m 2  a n d  gl y c os yl at e d  H b A 1 c  <  1 2 %.  
 
Aft er  a n I D M C  r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first  1 8 
s u bj e cts  wit h  e G F R ≥  6 0  m L/ mi n/ 1. 7 3 m 2, i n cl usi o n  of s u bj e cts  wit h 
e G F R  ≥   4 5 m L/ mi n/ 1. 7 3 m 2 (i n cl u di n g  c hr o ni c  ki d n e y  dis e as e 
st a g e  3 A)  will  b e  p er mitt e d if  a p pr o v e d  b y t h e I D M C.  S u bs e q u e ntl y, 
aft er  a n I D M C  r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first 3 6 
s u bj e cts ( at l e ast  8 s u bj e cts  wit h  e G F R  ≥  4 5 t o  <  6 0  m L/ mi n/ 1. 7 3 m 2) 
f oll o w e d f or  at l e ast  4 w e e ks, i n cl usi o n  of s u bj e cts  wit h  e G F R  >  2 0 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
t o  <  4 5  m L/ mi n/ 1. 7 3 m2 will  b e  p er mitt e d if  a p pr o v e d  b y t h e I D M C.  
If i n cl usi o n  of s u bj e cts  wit h  e G F R  b el o w  6 0  m L/ mi n/ 1. 7 3 m2 is 
e n d ors e d  b y t h e I D M C, t h e f oll o wi n g t ar g et s a m pl e si z e(s)  will  b e 
est a blis h e d f or s u bj e cts  wit h  e G F R i n t h e s p e cifi e d r a n g e: 
•   At  l e ast  3 6 s u bj e cts  wit h  e G F R  <  6 0  m L/ mi n/ 1. 7 3 m2 
•   At l e ast  1 8 s u bj e cts  wit h  e G F R  <  4 5  m L/ mi n/ 1. 7 3 m 2 
T o  a c hi e v e t h es e  t ar g et e d  mi ni m u ms,  a r estri cti o n  m a y  b e i m p os e d 
o n t h e  e nr oll m e nt  of s u bj e cts  wit h  e G F R  ≥   6 0  m L/ mi n/ 1. 7 3 m2 
a n d  /  or  ≥  4 5  m L/ mi n/ 1. 7 3 m2. 
 
S u bj e cts  m ust  h a v e  b e e n t a ki n g st a bl e  d os es  of  a n 
a n gi ot e nsi n- c o n v erti n g  e n z y m e i n hi bit or  or  a n gi ot e nsi n II r e c e pt or 
bl o c k er  t h er a p y f or  at l e ast  8  w e e ks  b ef or e  S cr e e ni n g. S u bj e cts 
t a ki n g  a nti h y p ert e nsi v e  m e di c ati o n(s)  m ust h a v e  b e e n  t a ki n g st a bl e 
d os es f or  at l e ast  8  w e e ks  b ef or e  S cr e e ni n g.  E v er y  eff ort  will  b e 
m a d e t o  e ns ur e t h at  at l e ast  5 0 %  of r a n d o mi z e d s u bj e cts  ar e 
r e c ei vi n g  c o n c o mit a nt tr e at m e nt  wit h  a s o di u m- gl u c os e  c otr a ns p ort er 
2  i n hi bit or ( d os e st a bl e f or  at l e ast  4 w e e ks  b ef or e  S cr e e ni n g).  
 
E x cl usi o n  
S u bj e cts  m ust  n ot  h a v e  a  c urr e nt  di a g n osis  of t y p e  1  di a b et es 
m ellit us,  hist or y  of  a c ut e  ki d n e y i nj ur y  or  c hr o ni c  di al ysis/r e n al 
tr a ns pl a nt, a nti ci p at e d r e n al tr a ns pl a nt ,  u n c o ntr oll e d  h y p ert e nsi o n  or 
C l ass III / I V  h e art f ail ur e, l eft v e ntri c ul ar  ej e cti o n fr a cti o n  <   5 0 %  b y 
e c h o c ar di o gr a m, tr o p o ni n-I  >  t h e  u p p er r ef er e n c e li mit,  b-t y p e 
n atri ur eti c  p e pti d e ( B N P)  >   2 0 0  p g/ m L,  or  al a ni n e tr a ns a mi n as e  >  2 x 
t h e  u p p er li mit  of  n or m al. 
St u d y  P r o d u ct 
D os e,  D osi n g 
R e gi m e n , a n d 
A d mi nist r ati o n   
C S L 3 4 6 is s u p pli e d  as  a st eril e s ol uti o n f or I V  a n d  S C i nf usi o n  at  a 
c o n c e ntr ati o n  of  1 0 0  m g/ m L. 
 
All  C S L 3 4 6  d os es  will  b e  c al c ul at e d  b as e d  o n  w ei g ht  a n d 
n or m ali z e d t o  a st a n d ar d  v ol u m e  wit h st eril e  n or m al  s ali n e.  C S L 3 4 6 
will  b e  a d mi nist er e d  at  a n i niti al l o a di n g  d os e  of  3   m g/ k g  or  6  m g/ k g 
I V i n t h e  ar m, f oll o w e d  b y  8  m g/ k g  or  1 6  m g/ k g  S C, r es p e cti v el y, i n 
t h e  a b d o m e n  at l e ast  2  h o urs  b ut  n o  m or e t h a n  6  h o urs l at er. 
S u bs e q u e nt  S C i nf usi o ns ( 8  m g/ k g  or  1 6  m g/ k g  p er  d os e)  will  b e 
a d mi nist er e d  e v er y  4  w e e ks f or  1 2  w e e ks. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
C o m p a r at o r 
P r o d u ct,  D os e, 
D osi n g  R e gi m e n, 
a n d 
A d mi nist r ati o n  
Pl a c e b o  c o nsists  of  n or m al s ali n e f or I V  a n d  S C i nf usi o n.  D osi n g 
a d mi nistr ati o n, r e gi m e n,  a n d  v ol u m e  will  b e  m at c h e d t o  C S L 3 4 6. 
Effi c a c y 
Ass ess m e nts  
T h e  effi c a c y  of  C S L 3 4 6  will  b e  ass ess e d  b as e d  o n  c h a n g es i n  A C R 
ass o ci at e d  wit h  C S L 3 4 6 tr e at m e nt.  T o  mi ni mi z e i ntr as u bj e ct 
v ari a bilit y,  b as eli n e  v al u es f or t h es e  p ar a m et ers  will  b e  b as e d  o n t h e 
g e o m etri c  m e a n  v al u es fr o m  3 fir st  m or ni n g  v oi d ( F M V)  uri n e 
c oll e cti o ns  o n  2 s e p ar at e  o c c asi o ns (i e,  6 t ot al  F M V s a m pl es)  b ef or e 
t h e first  d os e  of I P.  O n-tr e at m e nt  ass ess m e nts  of  A C R  will  b e t h e 
g e o m etri c  m e a n  v al u es fr o m  m ulti pl e  F M V  c oll e cti o ns  at  e a c h ti m e 
p oi nt.  O nl y  2  F M V s a m pl es  wi ll  b e  c oll e ct e d  at  Visit  9  b e c a us e  a 
ti m e d  2 4-h o ur s a m pl e  will  als o  b e  c oll e ct e d  at t his  Visit.  T h e 
F oll o w- u p  ass ess m e nt  of  A C R  p erf or m e d f or t h e  pri m ar y  a n al ysis 
4  w e e ks  aft er t h e l ast  d os e  of I P ( Visit  1 0)  will  b e  b as e d  o n t h e 
g e o m etri c  m e a n  of  3  F M V s a m pl es.  F or t h e  E O S  Visit, t h e 
ass ess m e nt  of  A C R  will  als o  b e  b as e d  o n t h e  g e o m etri c  m e a n  of 
3  F M V s a m pl es.  
S af et y 
Ass ess m e nts  
T h e s af et y  a n d t ol er a bilit y  of  C S L 3 4 6  will  b e  b as e d  o n  t h e 
f oll o wi n g:  
•   A Es (i n cl u di n g  A E SIs)  
•   Vit al si g ns  
•   P h ysi c al  e x a mi n ati o ns 
•   1 2- l e a d  el e ctr o c ar di o gr a ms 
•   Cli ni c al l a b or at or y  ass ess m e nts ( uri n al ysis,  h e m at ol o g y, 
bi o c h e mistr y, tr o p o ni n-I,  B N P,  S Cr,  a n d  e G F R) 
P h a r m a c o ki n eti cs   S eri al  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of  C S L 3 4 6  c o n c e ntr ati o n 
will  b e  c oll e ct e d  at  Visit  4  ( D a y  1).  Si n gl e  P K s a m pl es  will  als o  b e 
c oll e ct e d  at  all s u bs e q u e nt  visits ( b ef or e tr e at m e nt  o n  S C  d osi n g 
d a ys).  
E x pl o r at o r y 
Ass ess m e nts  
Bi o m ar k ers  of  Li pi d  M et a b olis m 
F asti n g  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of s er u m  gl y c er ol, 
n o n- est erifi e d f att y  a ci ds ,  a n d  k et o n es  will  b e  c oll e ct e d  at  Visit  3 
( D a y -7),  Visit  4 ( D a y  1),  Visit  7 ( We e k  4),  Visit  8 ( We e k   8),  a n d 
Visit  1 0 ( We e k  1 6).  F asti n g  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of 
t ot al  c h ol est er ol, tri gl y c eri d es, hi g h  d e nsit y li p o pr ot ei n,  a n d l o w 
d e nsit y li p o pr ot ei n  l e v els  will  als o  b e  c oll e ct e d  at  Visit  3 ( D a y - 7), 
Visit  4 ( D a y  1),  Visit  7 ( We e k  4),  Visit  8 ( We e k  8),  a n d  Visit  1 0 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
( We e k  1 6)  as  p art  of t h e st a n d ar d  bi o c h e mistr y  p a n el. 
 
Bi o m ar k ers  of  Gl y c e mi c  C o ntr ol  
Bl o o d s a m pl es f or t h e  d et er mi n ati o n  of  H b A 1 c l e v els  will  b e 
c oll e ct e d  at  S cr e e ni n g ( Visit  1),  Visit  4 ( D a y  1),  Visit  1 0 ( We e k  1 6) 
a n d  E O S.  Bl o o d s a m pl es f or t h e  d et er mi n ati o n  of f asti n g  gl u c os e 
l e v els  will  b e  c oll e ct e d  at  Visit  3 ( D a y - 7),  Visit  4 ( D a y  1),  Visit  7 
( We e k  4),  Visit  8 ( We e k  8),  a n d  Visit  1 0 ( We e k 1 6)  as  p art  of t h e 
st a n d ar d  bi o c h e mistr y  p a n el. 
 
N o v el  Pl as m a,  S er u m,  a n d  Uri n ar y  Bi o m ar k ers 
F asti n g  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of s er u m fr e e  V E G F- B 
a n d s ol u bl e t u m or  n e cr osis f a ct or r e c e pt or- 1  l e v els  will  b e  c oll e ct e d 
at  Visit  3 ( D a y  -7),  Visit  4 ( D a y  1),  Visit   7 ( We e k  4),  Visit  8 
( We e k  8),  a n d  Visit  1 0 ( We e k  1 6).  
Uri n e s a m pl es f or t h e  d et er mi n ati o n  of  V E G F- A, s ol u bl e  V E G F - R 1, 
ki d n e y i nj ur y  m ol e c ul e- 1,  n e utr o p hil  g el ati n as e- ass o ci at e d li p o c ali n, 
cl ust eri n,  a n d  m o n o c yt e  c h e m o attr a ct a nt  pr ot ei n- 1  will  b e  c oll e ct e d 
at  Visit  3 ( D a y  - 7),  Visit  4 ( D a y  1),  Visit  7 ( We e k  4),  Visit  8 
( We e k  8),  a n d  Visit  1 0 ( We e k  1 6). 
 
C S L 3 4 6 i n  Uri n e ( P K) 
Ti m e d  2 4- h o ur  uri n e s a m pl es f or t h e  d et er mi n ati o n  of  C S L 3 4 6 
c o n c e ntr ati o n  will  b e  c oll e ct e d  at  S cr e e ni n g ( Visit  1,  B as eli n e), 
Visit   5 ( We e k  1),  a n d  Visit  9 ( We e k  1 2). 
 
A C R  
As  a n  e x pl or at or y  ass ess m e nt, t h e  d at a  g e n er at e d f or t h e  pri m ar y 
a n al ysis  will  als o  b e  us e d t o  e v al u at e  c h a n g es i n  cli ni c al 
c h ar a ct eri z ati o n  of  al b u mi n uri a:  n or m o al b u mi n uri a, 
mi cr o al b u mi n uri a,  or  m a cr o al b u mi n uri a.  
 
T o  d o t his,  e a c h s u bj e ct’s l e v el  of  uri n ar y  A C R ( a v er a g e  of  a v ail a bl e 
F M V s a m pl es  at  e a c h ti m e  p oi nt)  will  b e  c at e g ori z e d  at  B as eli n e  a n d 
at  Visit  1 0 ( We e k  1 6)  as:  
•   M a cr o al b u mi n uri a ( A C R   >  3 0 0  m g/ g [ >  3 3. 9  m g/ m m ol])  
•   Mi cr o al b u mi n uri a ( A C R  ≥  3 0  a n d  ≤  3 0 0  m g/ g [ ≥  3. 3 9  a n d 
≤  3 3. 9  m g/ m m ol]),  or   
•   N or m o al b u mi n uri a ( A C R  <  3 0  m g/ g [ <  3. 3 9  m g/ m m ol]) 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Tr a nsiti o ns  b et w e e n t h es e  c at e g ori es  will  b e  d es cri b e d.  
St atisti c al 
A n al ys es 
 
 
 
 
 
 
 
 
S a m pl e  Siz e 
T h e  pl a n n e d s a m pl e si z e is  1 0 0 s u bj e cts  wit h  5 0 s u bj e cts r e c ei vi n g 
C S L 3 4 6 ( 8  m g/ k g,  n  =  2 5  a n d  1 6  m g/ k g,  n  =  2 5)  a n d  5 0 s u bj e cts 
r e c ei vi n g  pl a c e b o.  Ass u mi n g  a n S D  of  0. 6 5 f or t h e  c h a n g e fr o m 
B as eli n e  t o  We e k  1 6 ( Visit  1 0) i n  A C R f oll o wi n g  n at ur al l o g 
tr a nsf or m ati o n,  a s a m pl e si z e  of  9 4 s u bj e cts is  esti m at e d t o  pr o vi d e 
8 5 %  p o w er t o  d et e ct  a  2 7 % r e d u cti o n i n t h e  g e o m etri c  m e a n  A C R 
f or  C S L 3 4 6  v ers us  pl a c e b o, i e, l n ( 1 t o  0. 2 7)  = - 0. 3 1 5  o n t h e  n at ur al 
l o g s c al e,  usi n g  a  o n e-si d e d  al p h a  =  0. 1 0.  T h e t ot al s a m pl e si z e 
a c c o u nts f or  a n  ass u m e d  6 %  dr o p- o ut r at e.  T h e  a ct u al  e arl y 
dis c o nti n u ati o n r at e  will  b e  ass ess e d t hr o u g h o ut t h e st u d y  a n d  u p t o 
1 2 4 s u bj e cts  m a y  b e r a n d o mi z e d, if  n e c ess ar y, t o t ar g et  9 4  c o m pl et e d 
s u bj e cts (s u bj e cts  w h o r e c ei v e d  all  d os es  a n d  c o m pl et e d t h e  We e k  1 6 
A C R  ass ess m e nt).  
 
Pri m ar y  E n d p oi nt  A n al ysis  
T h e  pri m ar y  a n al ysis is  a  mi x e d  eff e cts  m o d el, r e p e at e d  m e as ur es 
( M M R M)  a n al ysis  of t h e  c h a n g e fr o m B as eli n e  t hr o u g h  2 4  w e e ks  of 
l o g  A C R,  wit h t h e  pri m ar y tr e at m e nt  c o m p aris o n  at  We e k  1 6 
( Visit  1 0).  T h e  pri m ar y  c o m p aris o n  of i nt er est is  a  c o ntr ast  of 
0. 5  ( 8  m g/ k g  C S L 3 4 6  +  1 6  m g/ k g  C S L 3 4 6)  – Pl a c e b o.  
 
F or  d e cisi o n- m a ki n g  a n d  d e v el o p m e nt  p ur p os es,  a n i nt eri m  a n al ysis 
of  u n bli n d e d  d at a  will  b e  p erf or m e d  aft er  e nr oll m e nt is  c o m pl et e  a n d 
all r a n d o mi z e d s u bj e cts  c o m pl et e t h e  1 6- w e e k  A C R  m e as ur e m e nt 
(i e,  4  w e e ks  aft er t h e f ourt h  d os e).  T h es e r es ults  will  b e s u m m ari z e d 
i n  a n i nt eri m,  n o nr e g ul at or y,  a n al yti c al r e p ort.  A fi n al st atisti c al 
a n al ysis  of  all  effi c a c y  a n d s af et y  d at a  will  o c c ur  aft er  all s u bj e cts 
h a v e  c o m pl et e d t h e f ull  2 4  w e e ks  of t h e st u d y f or t h e  cli ni c al st u d y 
r ep ort. 
 
S e c o n d ar y  E n d p oi nt  A n al ys es  
Tr e at m e nt - e m er g e nt  A Es,  d efi n e d  as  A Es  o c c urri n g  at  or  aft er t h e 
st art  of st u d y tr e at m e nt,  will  b e s u m m ari z e d f or  e a c h  C S L 3 4 6  d os e 
l e v el ( 8  m g/ k g  a n d  1 6  m g/ k g)  a n d  pl a c e b o.  A n  o v er vi e w s u m m ar y  of 
A Es, i n cl u di n g t h e  n u m b er  of s u bj e cts  wit h  a n y  A E;  A Es r el at e d t o 
st u d y tr e at m e nt;  A Es l e a di n g t o  dis c o nti n u ati o n  of st u d y tr e at m e nt; 
s eri o us  a d v ers e  e v e nts;  a n d  d e at hs  will  b e  pr o d u c e d.  
 
Tr e at m e nt -e m er g e nt  A Es  will  b e s u m m ari z e d  b y  pr ef err e d t er m  a n d 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
s yst e m  or g a n  cl ass  as  w ell  a s s e v erit y.  A E SIs  will  als o  b e 
s u m m ari z e d s e p ar at el y.  
 
T h e  a n al ysis  of  S Cr,  e G F R,  a n d  B P  will  e m pl o y  a  m o d el si mil ar t o 
t h e  pri m ar y  e n d p oi nt.  T h e  a n al ysis f or t h es e  c o nti n u o us  e n d p oi nts is 
a n  M M R M  a n al ysis  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 
m e as ur e m e nt.  
 
S er u m  c o n c e ntr ati o n  of  C S L 3 4 6  will  b e list e d  b y i n di vi d u al s u bj e ct 
a n d  will  b e s u m m ari z e d  b y  d os e l e v el  a n d  n o mi n al ti m e  p oi nt  usi n g 
d es cri pti v e st atisti cs (i e,  n,  arit h m eti c  m e a n,  S D ,  c o effi ci e nt  of 
v ari ati o n  [ C V %],  m e di a n,  g e o m etri c  m e a n,  g e o m etri c C V % , 
mi ni m u m,  a n d  m a xi m u m). I n di vi d u al s u bj e ct  C S L 3 4 6 s er u m 
c o n c e ntr ati o n  v ers us ti m e  will  b e  pl ott e d  o n li n e ar  a n d 
s e mi-l o g arit h mi c s c al es.  T h e  Ctr o u g h  of  C S L 3 4 6  will  als o  b e 
s u m m ari z e d  vis u all y,  b y  d os e l e v el. 
 
T h e  n u m b er  of s u bj e cts  wit h  a  p ositi v e  i m m u n o g e ni cit y t est  at  a n y 
ti m e  p ost-tr e at m e nt  will  b e  c o u nt e d  a n d  c o m p ar e d  b et w e e n 
tr e at m e nts  wit h  Fis h er’s  E x a ct  Test.  T h e  c o m p aris o n  will  b e  of 
C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g  p o ol e d)  v ers us  pl a c e b o. 
 
E x pl or at or y  E n d p oi nt  A n al ys es  
E x pl or at or y  e n d p oi nts  wi ll  e m pl o y  a  m o d el si mil ar t o t h e  pri m ar y 
e n d p oi nt  a n d  c o nti n u o us s e c o n d ar y  e n d p oi nts.  T h e  a n al ysis f or t h es e 
c o nti n u o us  e n d p oi nts is  a n  M M R M  a n al ysis  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  m e as ur e m e nt.  E x pl or at or y  uri n ar y  bi o m ar k ers 
will  b e  n or m ali z e d t o  cr e ati ni n e l e v el f or  a n al ysis  a n d r e p orti n g.  T h e 
n u m b er  of s u bj e cts  w h o r e gr ess fr o m  m a cr o al b u mi n uri a t o 
mi cr o al b u mi n uri a  or  n or m o al b u mi n uri a,  or fr o m  mi cr o al b u mi n uri a 
t o  n or m o al b u mi n uri a  at  We e k  1 6  will  b e  c o u nt e d  a n d  c o m p ar e d 
b et w e e n tr e at m e nts  usi n g  Fis h er’s  E x a ct  Test.  T h e  c o m p aris o n  will 
b e  of  C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g  p o ol e d)  v ers us  pl a c e b o. 
D at a fr o m t h e  e x pl or at or y  bi o m ar k ers  will  b e s u m m ari z e d 
d es cri pti v el y  b y tr e at m e nt  a n d  visit f or t h e  P D  A n al ysis  S et.  
P h ar m a c o ki n eti c  a n d  P D  e n d p oi nts  will  b e  e x pl or e d  gr a p hi c all y t o 
e v al u at e  p ot e nti al r el ati o ns hi ps.  
 

C S L  B e hri n g 
L L C  
 
St u d y  N u m b e r:    C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6  
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
G:   El e ctr o c ar di o gr a ms  m ust  b e  p erf or m e d i n tri pli c at e  b ef or e  a n y  bl o o d s a m pl es t h at  ar e  c oll e ct e d  at t h e s a m e ti m e  p oi nt.  
H:   A l o c al  ass ess m e nt  of  e c h o c ar di o gr a m  will  b e  p erf or m e d  d uri n g  S cr e e ni n g  u nl ess  a n  e c h o c ar di o gr a m  w as  p erf or m e d f or  n o n -st u d y-r el at e d r e as o ns  wit hi n 
3  m o nt hs  b ef or e  S cr e e ni n g.  
I:  At  Visit  2 ( D a y  – 2 1),  a  bl o o d s a m pl e  will  b e  c oll e ct e d f or  d et er mi n ati o n  of s er u m  cr e ati ni n e  o nl y.  
J:   A ti m e d  2 4 -h o ur  uri n e s a m pl e  will  b e  c oll e ct e d t o  ass ess  eli gi bilit y ( A C R)  at  S cr e e ni n g ( B as eli n e),  a n d t o  m e as ur e  C S L 3 4 6 l e v els i n  uri n e  at s u bs e q u e nt 
i n di c at e d  visits. 
K:   S u bj e cts  will  c oll e ct  uri n e fr o m t h eir first  m or ni n g  v oi d  o n  3  c o ns e c uti v e  d a ys ( 2  c o ns e c uti v e  d a ys f or  Visit  9) l e a di n g  u p t o  a n d i n cl u di n g t h e  m or ni n g  of 
e a c h i n di c at e d  visi t. 
L:   M or ni n g  mi dstr e a m  uri n e s a m pl es  will  b e  c oll e ct e d  t o  e v al u at e  e x pl or at or y  bi o m ar k ers a n d  will  als o  b e st or e d f or f ut ur e r es e ar c h  a n al ys es.  
M:   S p e cifi c i nstr u cti o ns f or  a d mi nistr ati o n  of I P  ar e  pr o vi d e d i n t h e I M P  H a n dli n g  M a n u al.  At  Visit  4 ( D a y  1),  a n i niti al l o a di n g  d os e  of I P  will  b e  a d mi nist er e d 
b y I V, f oll o w e d  at l e ast  2  h o urs ( b ut  n o  m or e t h a n  6  h o urs) l at er  b y t h e s u bj e ct's  n or m al  pr es cri b e d  d os e  b y  S C i nf usi o n.  S u bs e q u e nt  d os es  of I P  will  b e 
a d mi nist er e d  b y  S C i nf usi o n.  
N:   S eri al  bl o o d s a m pl es f or  P K  will  b e  c oll e ct e d  at  Visit  4 ( D a y  1)  pr e d os e,  at  3 0 ( ±  5  mi n ut es),  6 0 ( ±  1 0  mi n ut es),  a n d  1 2 0 ( ±  1 0  mi n ut es)  mi n ut es  aft er t h e  
first I V  d os e  of I P ( b ef or e t h e first  S C  d os e  of I P) is  a d mi nist er e d, t h e n  aft er t h e fi n al  vit al si g ns  m e as ur e m e nt.  Si n gl e  P K  s a m pl es  will  als o  b e  c oll e ct e d  at  all 
s u bs e q u e nt  visits ( b ef or e tr e at m e nt  o n  S C  d osi n g  d a ys).  
O:   O n  bi o m ar k er  bl o o d s a m pl e  c oll e cti o n  d a ys, s u bj e cts  will  arri v e f oll o wi n g  a  mi ni m u m  6 -h o ur f ast.  Bl o o d  bi o m ar k er s a m pl es  will  b e  c oll e ct e d t o  e v al u at e 
p h ar m a c o d y n a mi c  a n d  e x pl or at or y  bi o m ar k ers  a n d  will  als o  b e st or e d f or f ut ur e r es e ar c h  a n al ys es.

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
T a bl e  of  C o nt e nts  
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis  .............................................................................................. 5 
S c h e d ul e  of  Ass ess m e nts  ......................................................................................................... 1 5 
Ta bl e  of  C o nt e nts ..................................................................................................................... 1 8  
List  of  A b br e vi ati o ns  ............................................................................................................... 2 4 
1  
I ntr o d u cti o n .......................................................................................................... 2 7 
1. 1  
B a c k gr o u n d ...................................................................................................... 2 7  
1. 2  
I nf or m ati o n  o n  C S L 3 4 6 ................................................................................... 2 8 
1. 2. 1  
O v er vi e w  ...................................................................................................... 2 8 
1. 2. 2  
N o n cli ni c al  E v al u ati o n  ................................................................................. 2 8 
1. 2. 3  
Cli ni c al  E x p eri e n c e  ...................................................................................... 2 8 
1. 3  
St u d y  O v er vi e w ................................................................................................ 2 9  
1. 4  
P ot e nti al  Ris ks  a n d  B e n efits  ............................................................................. 2 9 
2  
St u d y  O bj e cti v es  a n d  E n d p oi nts ........................................................................... 3 1  
2. 1  
Pri m ar y  O bj e cti v e  a n d  E n d p oi nt ...................................................................... 3 1  
2. 1. 1  
Pri m ar y  O bj e cti v e  ......................................................................................... 3 1 
2. 1. 2  
Pri m ar y  E n d p oi nt ......................................................................................... 3 1  
2. 2  
S e c o n d ar y  O bj e cti v es  a n d  E n d p oi nts ............................................................... 3 1  
2. 2. 1  
S e c o n d ar y  O bj e cti v es  ................................................................................... 3 1 
2. 2. 2  
S e c o n d ar y  E n d p oi nts .................................................................................... 3 2  
2. 3  
E x pl or at or y  O bj e cti v es  a n d  E n d p oi nts ............................................................. 3 2  
2. 3. 1  
E x pl or at or y  O bj e cti v es ................................................................................. 3 2  
2. 3. 2  
E x pl or at or y  E n d p oi nts .................................................................................. 3 3  
3  
St u d y  D esi g n  a n d  O v ersi g ht ................................................................................. 3 4  
3. 1  
O v er all  D esi g n  .................................................................................................. 3 4 
3. 1. 1  
S cr e e ni n g  P eri o d  ........................................................................................... 3 5 
3. 1. 2  
L e a d -i n  P eri o d .............................................................................................. 3 6 
3. 1. 3  
Tr e at m e nt  P eri o d  .......................................................................................... 3 6 
3. 1. 4  
F oll o w- u p  P eri o d .......................................................................................... 3 7  
3. 2  
D o s e  a n d  D osi n g  R e gi m e n ............................................................................... 3 7 
3. 3  
S ci e ntifi c  R ati o n al e  .......................................................................................... 3 7 
3. 3. 1  
St u d y  D esi g n  R ati o n al e ................................................................................ 3 7  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3. 3. 2  
D os e  R ati o n al e  ............................................................................................. 3 9 
3. 4  
Pl a n n e d  St u d y  D ur ati o n ................................................................................... 4 2  
3. 5  
Pl a n n e d  N u m b er  of  S u bj e cts ............................................................................ 4 2  
3. 6  
St u d y  O v ersi g ht ................................................................................................ 4 3  
3. 6. 1  
I n d e p e n d e nt  D at a  M o nit ori n g  C o m mitt e e(s) ............................................... 4 3 
3. 6. 2  
St e e ri n g  C o m mitt e e ...................................................................................... 4 4 
3. 7  
St o p pi n g  Crit eri a .............................................................................................. 4 4  
3. 7. 1  
St u d y  St o p pi n g  Crit eri a  ................................................................................ 4 4 
3. 7. 2  
D os e  L e v el  St o p pi n g  Crit eri a ....................................................................... 4 5  
4  
S el e cti o n  a n d  Wit h dr a w al  of  S u bj e cts .................................................................. 4 5  
4. 1  
Eli gi bilit y  Crit eri a  ............................................................................................ 4 5 
4. 1. 1  
I n cl usi o n  Crit eri a .......................................................................................... 4 6 
4. 1. 2  
E x cl usi o n  Crit eri a  ......................................................................................... 4 7 
4. 1. 3  
R a n d o mi z ati o n  Crit eri a  ................................................................................ 4 9 
4. 2  
S cr e e n  F ail ur es  a n d  R e -scr e e ni n g  .................................................................... 5 0 
4. 3  
Dis c o nti n u ati o n  of  St u d y  Tr e at m e nt  a n d /  or  S u bj e ct  Wit h dr a w al ................... 5 0  
4. 3. 1  
R e as o ns f or  Dis c o nti n u ati o n  of  St u d y  Tr e at m e nt  a n d /  or  S u bj e ct 
Wit h dr a w al  ................................................................................................... 5 0 
4. 3. 2  
Pr o c e d ur es f or  H a n dli n g  Wit h dr a w als .......................................................... 5 1 
4. 3. 3  
S u bj e cts  L ost t o  F oll o w- u p ........................................................................... 5 1  
4. 3. 4  
R e pl a c e m e nt  P oli c y  ...................................................................................... 5 1 
5  
St u d y I nt er v e nti o ns ............................................................................................... 5 2  
5. 1  
I n v esti g ati o n al  Pr o d u ct ..................................................................................... 5 2 
5. 1. 1  
C S L 3 4 6 ......................................................................................................... 5 2  
5. 1. 2  
Pl a c e b o  ......................................................................................................... 5 2 
5. 1. 3  
D osi n g  a n d  A d mi nistr ati o n  of  C S L 3 4 6  or  Pl a c e b o ...................................... 5 3  
5. 1. 4  
P a c k a gi n g,  L a b eli n g,  S u p pl y  a n d  St or a g e .................................................... 5 4  
5. 2  
A c c o u nt a bilit y  a n d  D estr u cti o n ........................................................................ 5 4  
5. 3  
Ot h er I nt er v e nti o ns ........................................................................................... 5 5  
5. 3. 1  
C o n c o mit a nt  St u d y- r el at e d  T h er a pi es .......................................................... 5 5 
5. 4  
A c c ess t o I n v esti g ati o n al  Pr o d u ct  Aft er t h e  E n d  of  St u d y ............................... 5 5  
6  
All o c ati o n t o  Tr e at m e nt  ........................................................................................ 5 6 
6. 1  
S u bj e ct  Assi g n m e nt  .......................................................................................... 5 6 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
6. 2  
R a n d o mi z ati o n  Pr o c e d ur es ............................................................................... 5 6  
6. 3  
Bli n di n g  Pr o c e d ur es ......................................................................................... 5 7  
6. 3. 1  
Bli n di n g  M et h o d ........................................................................................... 5 7  
6. 3. 2  
Br e a ki n g t h e  Bli n d f or  a n  E m er g e n c y .......................................................... 5 7  
6. 3. 3  
Pl a n n e d  U n bli n di n g  Pr o c e d ur es ................................................................... 5 8  
6. 3. 4  
A d - h o c  S af et y  U n bli n di n g ............................................................................ 5 8 
7  
C o ntr ai n di c ati o ns,  P er mitt e d  T h er a pi es  a n d  Pr o hi bit e d  T h er a pi es ...................... 5 9  
7. 1  
C o ntr ai n di c ati o ns  a n d  Pr e c a uti o ns t o  F urt h er  D osi n g ...................................... 5 9  
7. 2  
P er mitt e d  T h er a pi es  .......................................................................................... 5 9 
7. 3  
Pr o hi bit e d  T h er a pi es ......................................................................................... 6 0  
7. 4  
Lif est yl e  R estri cti o ns  ........................................................................................ 6 0 
8  
St u d y  Pr o c e d ur es  a n d  Visit  S c h e d ul e ................................................................... 6 1  
8. 1  
Cli ni c al  Pr o c e d ur es  .......................................................................................... 6 1 
8. 1. 1  
D e m o gr a p hi cs  a n d  S af et y  Ass ess m e nts  ....................................................... 6 2 
8. 1. 2  
P h ar m a c o ki n eti c,  a n d  P h ar m a c o d y n a mi c  a n d  E x pl or at or y  Bi o m ar k er 
Ass ess m e nts  .................................................................................................. 6 4 
8. 1. 3  
Effi c a c y  Ass ess m e nts  ................................................................................... 6 5 
8. 2  
Ot h er  Ass ess m e nts  ............................................................................................ 6 6 
8. 2. 1  
S u b c ut a n e o us  Test I nf usi o n  .......................................................................... 6 6 
8. 2. 2  
E x pl or at or y  Al b u mi n -t o-Cr e ati ni n e  R ati o  .................................................... 6 6 
8. 3  
S a m pl e  C oll e cti o n  ............................................................................................ 6 6 
8. 3. 1  
Bl o o d  S a m pl es .............................................................................................. 6 6  
8. 3. 2  
Uri n e  S a m pl es  .............................................................................................. 6 7 
8. 4  
R et e nti o n  of  S a m pl es f or  F ut ur e  R es e ar c h  ....................................................... 6 8 
8. 5  
C o n c o mit a nt  T h er a pi es ..................................................................................... 6 8  
8. 6  
Visit  S c h e d ul e  ................................................................................................... 6 8 
8. 6. 1  
Ass ess m e nt  Ti m e  Wi n d o ws  .......................................................................... 6 8 
8. 6. 2  
S cr e e ni n g  ...................................................................................................... 6 9 
8. 6. 3  
L e a d -i n ( Visit  3,  D a y  –7)  .............................................................................. 7 1 
8. 6. 4  
Tr e at m e nt  ...................................................................................................... 7 1 
8. 6. 5  
F oll o w- u p ..................................................................................................... 7 7  
9  
A d v ers e  E v e n ts ..................................................................................................... 7 9 
9. 1  
D efi niti o ns  ........................................................................................................ 7 9 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
9. 1. 1  
A d v ers e  E v e nt  .............................................................................................. 7 9 
9. 1. 2  
S eri o us  A d v ers e  E v e nt  .................................................................................. 8 0 
9. 1. 3  
A d v ers e  E v e nts  of  S p e ci al I nt er est  ............................................................... 8 1 
9. 2  
S e v erit y  of  A d v ers e  E v e nts .............................................................................. 9 1  
9. 3  
C a us alit y  of  A d v ers e  E v e nts ............................................................................ 9 1  
9. 4  
O bs er v ati o n  P eri o d f or  A d v ers e  E v e nts ........................................................... 9 1  
9. 5  
F oll o w- u p  of  A d v ers e  E v e nts  ........................................................................... 9 2 
9. 6  
A d v ers e  E v e nt  R e p orti n g ................................................................................. 9 2  
9. 6. 1  
A d v ers e  E v e nts  ............................................................................................. 9 2 
9. 6. 2  
A d v ers e  E v e nts  of  S p e ci al I nt er est  ............................................................... 9 2 
9. 6. 3  
S eri o us  A d v ers e  E v e nts  ................................................................................ 9 2 
9. 6. 4  
Ot h er  Si g nifi c a nt  E v e nts .............................................................................. 9 4  
9. 6. 5  
O v er d os e ....................................................................................................... 9 4  
9. 6. 6  
Pr e g n a n c y  a n d  Br e astf e e di n g  ....................................................................... 9 4 
9. 7  
I nstit uti o n al  R e vi e w  B o ar d / I n d e p e n d e nt  Et hi cs  C o m mitt e e  R e p orti n g 
R e q uir e m e nts  .................................................................................................... 9 5 
1 0  
St atisti cs  ................................................................................................................ 9 5 
1 0. 1  
S a m pl e  Si z e  Esti m ati o n  .................................................................................... 9 5 
1 0. 2  
D es cri pti o n  of  St u d y  A n al ysis  S ets .................................................................. 9 5  
1 0. 2. 1  
S cr e e n e d  A n al ysis  S et  .................................................................................. 9 5 
1 0. 2. 2  
I nt e nt-t o-Tr e at  A n al y sis  S et .......................................................................... 9 6 
1 0. 2. 3  
S af et y  A n al ysis  S et  ....................................................................................... 9 6 
1 0. 2. 4  
P er -pr ot o c ol  A n al ysis  S et  ............................................................................. 9 6 
1 0. 2. 5  
P h ar m a c o ki n eti c  A n al ysis  S et  ...................................................................... 9 6 
1 0. 2. 6  
P h ar m a c o d y n a mi c  A n al ysis  S et  ................................................................... 9 6 
1 0. 3  
St atisti c al  A n al ys es  a n d  M et h o ds  ..................................................................... 9 6 
1 0. 3. 1  
S u bj e ct  Dis p ositi o n  a n d  C h ar a ct eristi cs  ....................................................... 9 7 
1 0. 3. 2  
Effi c a c y  A n al ys es  ......................................................................................... 9 8 
1 0. 3. 3  
S af et y  A n al ys es  ............................................................................................ 9 9 
1 0. 3. 4  
P h ar m a c o ki n eti c  A n al ys es  ............................................................................ 9 9 
1 0. 3. 5  
P h ar m a c o d y n a mi c  A n al ys es  ....................................................................... 1 0 0 
1 0. 3. 6  
P h ar m a c o ki n eti c /  P h ar m a c o d y n a mi c  R el ati o ns hi ps  ................................. 1 0 1 
1 0. 3. 7  
Ot h er  A n al ys es  ........................................................................................... 1 0 1 
1 1  
Q u alit y  Ass ur a n c e  ............................................................................................... 1 0 1 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 2  
R e g ul at or y  a n d  Et hi cs  C o nsi d er ati o ns ................................................................ 1 0 2  
1 2. 1  
R e g ul at or y  C o nsi d er ati o ns ............................................................................. 1 0 2  
1 2. 2  
I nstit uti o n al  R e vi e w  B o ar d / I n d e p e n d e nt  Et hi cs  C o m mitt e e ........................ 1 0 2 
1 2. 3  
S u bj e ct I nf or m ati o n  a n d I nf or m e d  C o ns e nt ................................................... 1 0 2  
1 2. 4  
S u bj e ct  C o nfi d e nti alit y  ................................................................................... 1 0 3 
1 2. 5  
I n d e m nit y  a n d  C o m p e ns ati o n ......................................................................... 1 0 3 
1 3  
A d mi nistr ati v e  C o nsi d er ati o ns  ........................................................................... 1 0 4 
1 3. 1  
Cli ni c al  Tri al  R es e ar c h  A gr e e m e nt  ................................................................ 1 0 4 
1 3. 2  
Cli ni c al  St u d y  R e gistr ati o n  a n d  R es ults  Dis cl os ur e ....................................... 1 0 4  
1 3. 3  
I m pl e m e nt ati o n  of t h e  Cli ni c al  St u d y  Pr ot o c ol  a n d  A m e n d m e nt(s) .............. 1 0 4 
1 3. 4  
Pr ot o c ol  D e vi ati o ns ........................................................................................ 1 0 5  
1 3. 5  
D o c u m e nt ati o n  a n d  R e c or d  K e e pi n g ............................................................. 1 0 5  
1 3. 5. 1  
D at a  C oll e cti o n ........................................................................................... 1 0 5  
1 3. 5. 2  
D at a  Q u alit y  Ass ur a n c e  .............................................................................. 1 0 5 
1 3. 5. 3  
R e c or d  R et e nti o n  ........................................................................................ 1 0 6 
1 3. 6  
St u d y  a n d  Sit e  Cl os ur e ................................................................................... 1 0 6  
1 3. 7  
Cli ni c al  St u d y  R e p ort ..................................................................................... 1 0 6  
1 3. 8  
Us e  of  D at a  a n d  P u bli c ati o ns ......................................................................... 1 0 7  
1 4  
R ef er e n c es  .......................................................................................................... 1 0 8 
1 5  
A p p e n di c es .........................................................................................................  1 1 1  
A p p e n di x  1  
Si g n at ur es ....................................................................................................... 1 1 2  
A p p e n di x  2  
H e p atitis  B  Testi n g  ......................................................................................... 1 1 4  
 
List  of  Ta bl es  
Ta bl e  1  
Ris ks  a n d  Ris k  Miti g ati o n ................................................................................ 3 0  
Ta bl e  2  
Pr e di ct e d  P h ar m a c o ki n eti c  P ar a m et ers  a n d  S af et y  M ar gi ns  ........................... 4 2 
Ta bl e  3  
C S L 3 4 6  C h ar a ct eristi cs  ................................................................................... 5 2 
Ta bl e  4  
Pl a c e b o  C h ar a ct eri sti cs  .................................................................................... 5 2 
Ta bl e  5  
I n v esti g ati o n al  Pr o d u ct  D osi n g ........................................................................ 5 3 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Ta bl e  6  
St u d y  Pr o c e d ur es:  D e m o gr a p hi cs  a n d  S af et y  Ass ess m e nts ............................. 6 2  
Ta bl e  7  
Cli ni c al  Pr o c e d ur es:  P h ar m a c o ki n eti c  Ass ess m e nts  ........................................ 6 4 
Ta bl e  8  
Cli ni c al  Pr o c e d ur es:  P h ar m a c o d y n a mi c  a n d  E x pl or at or y  Bi o m ar k er 
Ass ess m e nts  ..................................................................................................... 6 5 
Ta bl e  9  
O v er vi e w  of  Uri n e  C oll e cti o ns ........................................................................ 6 7  
Ta bl e  1 0  
Ti m e  Wi n d o ws f or  Visits  a n d  Ass ess m e nts  ..................................................... 6 9 
Ta bl e  1 1  
St e p wis e  D osi n g  M o difi c ati o n  of I n v esti g ati o n al  Pr o d u ct  A d mi nistr ati o n f or 
U n a c c e pt a bl e  Mil d I nj e cti o n  Sit e  R e a cti o ns  .................................................... 8 3 
Ta bl e  1 2  
I n cr e as es i n  S er u m  Cr e ati ni n e ......................................................................... 8 5 
Ta bl e  1 3  
St o p pi n g  Crit eri a f or  C ar di a c  Tr o p o ni n- I  L e v els ............................................. 9 0 
Ta bl e   1 4 
I nt er pr et ati o n  of  H e p atitis  B  S er ol o gi c  Test  R es ults...................................... 1 1 4  
 
List  of  Fi g u r es  
Fi g ur e  1  
O v er all  St u d y  D esi g n ....................................................................................... 3 4  
Fi g ur e  2  
Pr e di ct e d  C S L 3 4 6  C o n c e ntr ati o ns  F oll o wi n g  M o nt hl y  S C  D osi n g  wit h I V 
L o a di n g  D os e ................................................................................................... 4 1  
Fi g ur e  3  
Fl o w c h art f or  St e p wis e  M o difi c ati o n  of I n v esti g ati o n al  Pr o d u ct 
A d mi nistr ati o n  D u e t o  U n a c c e pt a bl e  Mil d I nj e cti o n  Sit e  R e a cti o ns  ............... 8 3 
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
List  of  A b b r e vi ati o ns  
A b b r e vi ati o n  
Te r m  
A C Ei  
A n gi ot e nsi n -c o n v erti n g  e n z y m e i n hi bit or  
A C R  
Al b u mi n -t o-cr e ati ni n e r ati o  
A E  
A d v ers e  e v e nt  
A E SI  
A d v ers e  e v e nts  of s p e ci al i nt er est  
A KI  
A c ut e  ki d n e y i nj ur y 
a nti -H B c  
a nti b o d y t o  h e p atitis  B  c or e  a nti g e n 
a nti -H Bs  
a nti b o d y t o  h e p atitis  B s urf a c e  a nti g e n 
A R B  
A n gi ot e nsi n II r e c e pt or  bl o c k er  
A U C  
Ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e 
A U C 0‑ 2 8 d _ss 
A U C  b et w e e n  d os es  at st e a d y st at e  w h er e  d osi n g i nt er v al ( τ)  =  2 8 
d a ys ( 4  w e e ks) 
A U C 0-τ 
Ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e i n  a  d osi n g i nt er v al 
A U C 0- ∞ 
A U C fr o m ti m e  0 t o i nfi nit y  
B P  
Bl o o d  pr ess ur e  
B N P  
B- t y p e  n atri ur eti c  p e pti d e 
CI  
C o nfi d e n c e i nt er v al  
C K D  
C hr o ni c  ki d n e y  dis e as e 
C K D -E PI  
C hr o ni c  Ki d n e y  Dis e as e  E pi d e mi ol o g y  C oll a b or ati o n 
C m a x  
M a xi m u m  c o n c e ntr ati o n  
C O VI D - 1 9 
N o v el  c or o n a vir us  2 0 1 9 
C S L  
C S L  B e hri n g  L L C  
c T nI  
C ar di a c  tr o p o ni n-I 
C T R A  
Cli ni c al  Tri al  R es e ar c h  A gr e e m e nt  
C tr o u g h 
Tr o u g h  c o n c e ntr ati o n 
C tr o u g h _ss 
Tr o u g h  c o n c e ntr ati o ns  at st e a d y st at e 
C V  
C o effi ci e nt  of  v ari ati o n ( %)  
D B P  
Di ast oli c  bl o o d  pr ess ur e 
D K D  
Di a b eti c  ki d n e y  dis e as e  
E C 5 0 
H alf  m a xi m al  eff e cti v e  c o n c e ntr ati o n  
E C G  
El e ctr o c ar di o gr a m  
E C H O  
E c h o c ar di o gr a m 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
A b b r e vi ati o n  
Te r m  
e C R F  
El e ctr o ni c  c as e r e p ort f or m  
e G F R  
Esti m at e d  gl o m er ul ar filtr ati o n r at e  
E O S  
E n d  of st u d y 
F C B P  
F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
F M V  
First  m or ni n g  v oi d 
G C P  
G o o d  Cli ni c al  Pr a cti c e  
H b A 1 c  
H e m o gl o bi n  A 1 c  
H Bs A g  
h e p atitis  B s urf a c e  a nti g e n  
H B V  
H e p atitis  B  vir us  
H D L  
Hi g h  d e nsit y li p o pr ot ei ns  
H F D  
Hi g h -f at  di et ( m o us e  m o d el) 
I C F 
I nf or m e d  c o ns e nt f or m 
I C H 
I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n  of  Te c h ni c al 
R e q uir e m e nts f or  P h ar m a c e uti c als f or  H u m a n  Us e  
I D M C 
I n d e p e n d e nt  D at a  M o nit ori n g  C o m mitt e e 
I E C 
I n d e p e n d e nt  Et hi cs  C o m mitt e e 
I g G 
I m m u n o gl o b uli n  G 
I M P 
I n v esti g ati o n al  M e di ci n al  Pr o d u ct ( H a n di n g M a n u al)  
I P 
I n v esti g ati o n al  pr o d u ct 
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I R T 
I nt er a cti v e r es p o ns e t e c h n ol o g y 
I T T 
I nt e nti o n-t o-Tr e at  
I V 
I ntr a v e n o us 
L V E F  
L eft  v e ntri c ul ar  ej e cti o n fr a cti o n  
M M R M  
Mi x e d  eff e cts  m o d el, r e p e at e d  m e as ur es  
N E F A  
N o n -est erifi e d f att y  a ci ds  
P D  
P h ar m a c o d y n a mi c 
P K  
P h ar m a c o ki n eti c  
R A S  
R e ni n  a n gi ot e nsi n s yst e m  
S A E  
S eri o us  a d v ers e  e v e nt  
S A P  
St atisti c al  a n al ysis  pl a n  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
A b b r e vi ati o n  
Te r m  
S B P  
S yst oli c  bl o o d  pr ess ur e  
S C  
S u b c ut a n e o us 
S Cr  
S er u m  cr e ati ni n e  
S D  
St a n d ar d  d e vi ati o n 
S G L T 2  
S o di u m -gl u c os e  c otr a ns p ort er  2  
S O C  
St a n d ar d  of  c ar e 
T 2 D M  
T y p e  2  di a b et es  m ellit us  
T m a x  
Ti m e t o r e a c h  m a xi m u m  c o n c e ntr ati o n i n s er u m  
U L N  
U p p er li mit  of  n or m al  
U R L  
U p p er r ef er e n c e li mit  
V E G F  
Vas c ul ar  e n d ot h eli al  gr o wt h f a ct or  
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1   
Int r o d u cti o n  
1. 1   B a c k g r o u n d  
Di a b eti c  ki d n e y  dis e as e ( D K D) is t h e  m ost  c o m m o n  c a us e  of  e n d st a g e r e n al  dis e as e  a n d its 
pr e v al e n c e  c o nti n u es t o  gr o w  w orl d wi d e [ G B D  2 0 1 8 ].  Di a b eti c  ki d n e y  dis e as e is first  d et e ct e d 
b y t h e  a b n or m al l oss  of s m all  a m o u nts  of  al b u mi n i nt o t h e  uri n e ( mi cr o al b u mi n uri a).  As  D K D 
pr o gr ess es  wit h i n cr e asi n gl y l ar g er l oss es  of  uri n ar y  al b u mi n, r e n al f u n cti o n  d e cli n es l e a di n g t o 
c hr o ni c  ki d n e y  dis e as e ( C K D)  a n d t h e  e v e nt u al i niti ati o n  of r e n al r e pl a c e m e nt t h er a p y.  T h e 
st a n d ar d  of  c ar e ( S O C) t o sl o w t h e  d e cli n e i n r e n al f u n cti o n i n  p ati e nts  wit h  D K D  h as 
c o nsist e d  of  gl y c e mi c  c o ntr ol,  us e  of r e ni n  a n gi ot e nsi n s yst e m ( R A S) i n hi bit ors,  a n d 
m a n a g e m e nt  of  h y p ert e nsi o n  a n d  h y p erli pi d e mi a [ K D O QI,  2 0 0 7  a n d  2 0 1 2 ].  T h e  S O C is 
e x p e ct e d t o  e v ol v e  o v er t h e  n e xt f e w  y e ars t o i n cl u d e t h e  us e  of s o di u m- gl u c os e  c otr a ns p ort er 
2 ( S G L T 2) i n hi bit ors [ P er k o vi c  et  al,  2 0 1 9 ; S ar afi dis  et  al,  2 0 1 9 ; G ar b er  et  al,  2 0 1 9 ]. 
N e v ert h el ess, tr e at m e nt  wit h  b ot h  R A S  a n d  S G L T 2 i n hi bit ors  d o es  n ot  arr est  or r e v ers e t h e 
pr o gr essi o n  of  D K D [ K h a n  a n d  Q u a g gi n,  2 0 1 5 ; P er k o vi c  et  al,  2 0 1 9 ].  W orl d wi d e,  o v er 
3 0 0, 0 0 0  p ati e nts   wit h  D K D  pr o gr ess t o  e n d st a g e  ki d n e y  dis e as e r e q uiri n g  di al ysis  or r e n al 
tr a ns pl a nt  e a c h  y e ar.  T h us,  a d diti o n al tr e at m e nt  o pti o ns  ar e  n e e d e d t o  pr es er v e r e n al f u n cti o n. 
Vas c ul ar  e n d ot h eli al  gr o wt h f a ct or ( V E G F) - B  pri m aril y r e g ul at es f att y  a ci d tr a ns p ort  a cr oss t h e 
e n d ot h eli u m [ H a g b er g  et  al,  2 0 1 0 ],  w h er e as  ot h er  m e m b ers  of t h e  V E G F f a mil y sti m ul at e  d e 
n o v o  gr o wt h  of  bl o o d  v ess els (i e,  a n gi o g e n esis;  V E G F -A  a n d  pl a c e nt al  gr o wt h f a ct or, t o  a 
l ess er  e xt e nt)  or l y m p h ati c  v ess els (i e, l y m p h a n gi o g e n esis;  V E G F- C  a n d -D). I n  D K D, 
V E G F - B  e x pr essi o n i n t h e  di a b eti c  ki d n e y ( m uri n e  a n d  h u m a n) is  el e v at e d  a n d  ass o ci at e d  wit h 
i n cr e as e d li pi d  d e p ositi o n i n  gl o m er ul ar  p o d o c yt es  as fr e e f att y  a ci ds  ar e s h u nt e d fr o m  a di p os e 
tiss u e ( m uri n e) [F al k e v all  et  al,  2 0 1 7 ].  T h e  D K D  p h e n ot y p e is  o bs er v e d i n  p o d o c yt e-s p e cifi c 
V E G F -B  o v er e x pr essi n g  mi c e [ F al k e v all  et  a l,  2 0 1 7].  R e d u ci n g  V E G F-B  a cti vit y i n  m o us e 
m o d els  of t y p e  1  di a b et es  m ellit us (str e pt o z ot o ci n -i n d u c e d  di a b et es)  a n d t y p e  2  di a b et es 
m ellit us ( T 2 D M,  d b /d b ,  or  hi g h-f at  di et [ H F D]-i n d u c e d)-D K D  wit h  a n  a nti -V E G F - B  a nti b o d y 
r es ults i n i m pr o v e m e nt  of  hist ol o gi c al  e vi d e n c e  of  gl o m er ul ar i nj ur y  a n d r e d u c es  al b u mi n uri a 
[F al k e v all  et  al,  2 0 1 7 ].  T h e  b e n efi ci al  eff e cts  of  bl o c ki n g  V E G F- B  a cti vit y  h a v e  b e e n 
attri b ut e d t o t h e  pr e v e nti o n  of t o xi c li pi d  a c c u m ul ati o n i n t h e  ki d n e y.  A  m ol e c ul e  t h at 
a nt a g o ni z es  V E G F - B  a cti vit y  h as t h e  p ot e nti al t o sl o w t h e r at e  of l oss  of r e n al f u n cti o n  vi a 
p at h w a ys  ot h er t h a n t h os e i m p a ct e d  b y  eit h er  R A S  or  S G L T 2 i n hi biti o n. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1. 2   I nf o r m ati o n  o n  C S L 3 4 6  
1. 2. 1   
O v e r vi e w  
C S L 3 4 6 is  a  n o v el  h u m a ni z e d  m o n o cl o n al  a nti b o d y (i m m u n o gl o b uli n  G  4)  d eri v e d fr o m t h e 
m uri n e  v ari a nt  a nti- V E G F - B  a nti b o d y  k n o w n  as  2 H 1 0.  C S L 3 4 6  bi n ds  wit h  hi g h  affi nit y t o 
V E G F -B,  w hi c h is  e x p e ct e d t o r es ult i n i m pr o v e m e nt  of  D K D  wit h  mi ni m al  off -t ar g et  eff e cts.  
A  d et ail e d  d es cri pti o n  of t h e  c h e mistr y,   p h ar m a c ol o g y,  effi c a c y,  a n d s af et y  of  C S L 3 4 6 is 
pr o vi d e d i n t h e I n v esti g at or’s  Br o c h ur e. 
1. 2. 2   
N o n cli ni c al  E v al u ati o n  
I n  C S L 3 4 6 r e p e at- d os e t o xi cit y st u di es  of  u p t o  a  6- m o nt h  d ur ati o n, t h er e  w er e  n o  a d v ers e 
e v e nts ( A Es) , i n cl u di n g i nj e cti o n sit e r e a cti o ns,  o bs er v e d  u p t o t h e  hi g h est  d os e t est e d, 
1 0 0  m g/ k g,  a d mi nist er e d  b y i ntr a v e n o us (I V)  or  b y s u b c ut a n e o us ( S C) i nj e cti o n.  T h es e  d at a 
ar e s u p p orti v e  of  a d mi nist eri n g r e p e at  d os es  u p t o  1 6  m g/ k g  S C t o s u bj e cts i n  cli ni c al st u di es. 
A  d et ail e d  d es cri pt i o n  of t h e  n o n cli ni c al  d at a  a v ail a bl e f or  C S L 3 4 6 is  pr o vi d e d i n t h e 
I n v esti g at or’s  Br o c h ur e  a n d  A d d e n d u m. 
1. 2. 3   
Cli ni c al  E x p e ri e n c e  
T h e first i n - h u m a n  cli ni c al st u d y,  C S L 3 4 6 _ 1 0 0 1,  a  p h as e  1, 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 si n gl e  as c e n di n g  d os e st u d y t o  e v al u at e t h e s af et y, t ol er a bilit y,  a n d 
p h ar m a c o ki n eti cs ( P K )  of  C S L 3 4 6 i n  h e alt h y  C a u c asi a n  a n d J a p a n es e  a d ult s u bj e cts  w as 
c o m pl et e d i n  M a y  2 0 1 9.  O v er all,  n o  A Es   of  c o n c er n  o c c urr e d f oll o wi n g  a d mi nistr ati o n  of 
si n gl e  d os es  of  C S L 3 4 6  b y  a n I V i nf usi o n ( u p t o  2 0  m g/ k g)  or  S C i nj e cti o n ( u p t o  1 0  m g/ k g) t o 
6 0  h e alt h y  v ol u nt e ers, t h us  d e m o nstr ati n g s af et y  a n d t ol er a bilit y  u p t o t h e  m a xi m u m  e x p os ur es 
a c hi e v e d.  T h e  P K  pr ofil e s u g g ests  d os e  pr o p orti o n alit y  a n d,  as  e x p e ct e d, is si mil ar i n 
C a u c asi a n  a n d J a p a n es e s u bj e cts.  T h e  bi o a v ail a bilit y  aft er  S C  a d mi nistr ati o n is  esti m at e d t o  b e 
6 1 % i n  h e alt h y  v ol u nt e ers.  T his st u d y is s u p p orti v e  of  c o nti n u e d  d e v el o p m e nt  of  C S L 3 4 6, 
i n cl u di n g  a d mi nistr ati o n  of r e p e at  d os es  of  u p t o  1 6  m g/ k g  S C t o s u bj e cts  wit h  D K D. 
A  d et ail e d  d es cri pti o n  of t h e s af et y  a n d  P K  pr ofil e  of  C S L 3 4 6 i n  h e alt h y  a d ult s u bj e cts is 
pr o vi d e d i n t h e I n v esti g at or’s  Br o c h ur e. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  2 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1. 3   St u d y  O v e r vi e w  
T his is  a  pr os p e cti v e,  m ulti c e nt er, 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,  pr o of  of 
c o n c e pt st u d y t o i n v esti g at e t h e  effi c a c y, s af et y, t ol er a bilit y,  a n d  P K  of r e p e at  d os es  of  C S L 3 4 6 
i n s u bj e cts  wit h  D K D  a n d  al b u mi n uri a r e c ei vi n g  S O C tr e at m e nt.  A p pr o xi m at el y  1 0 0 s u bj e cts 
will  b e r a n d o mi z e d ( 1: 1: 2) t o r e c ei v e  8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or  pl a c e b o  a n d 
p arti ci p at e f or  u p t o  3 4  w e e ks.  S e cti o n  3. 1   pr o vi d es  a  d et ail e d  o v er vi e w  of t h e st u d y.  
1. 4   P ot e nti al  Ris ks  a n d  B e n efits   
B e n efits:  S u bj e cts i n  cli ni c al st u di es  g e n er all y  c a n n ot  e x p e ct t o r e c ei v e  dir e ct  b e n efit fr o m 
tr e at m e nts  d uri n g  p arti ci p ati o n,  as  cli ni c al st u di es  ar e  d esi g n e d t o  pr o vi d e i nf or m ati o n  a b o ut 
s af et y  a n d  effi c a c y  of  a  n e w i n v esti g ati o n al  pr o d u ct (I P).  H o w e v er,  b e n efits  m a y i n cl u d e  t h e 
f oll o wi n g: 
1.   O p p ort u nit y t o  c o ntri b ut e t o t h e  u n d erst a n di n g  of  p ot e nti al  n e w tr e at m e nt f or  D K D 
2.   P ot e nti al i m pr o v e m e nts i n  cli ni c all y i m p ort a nt  m ar k ers  ass o ci at e d  wit h  D K D  
3.   Cl os e  m e di c al  e v al u ati o n  a n d st u d y- r el at e d  m e di c ati o n  a n d  pr o c e d ur es 
Ris ks:   Ris ks i d e ntifi e d t o  d at e i n  n o n cli ni c al  a n d  cli ni c al i n v esti g ati o ns  of  C S L 3 4 6  ar e 
n o ns eri o us i nj e cti o n sit e r e a cti o ns  wit h  S C  d osi n g. I n t h e  n o n cli ni c al t o xi c ol o g y st u di es  wit h 
u p t o  6  m o nt hs  of  d osi n g  a d mi nist er e d I V  or  b y  S C i nj e cti o n,  n o  d os e- li miti n g t o xi cit y  w as 
s e e n  u p t o t h e  hi g h est  d os e t est e d.  T h er e  w er e  n o  d os e- li miti n g t o xi citi es i n t h e si n gl e 
as c e n di n g  d os e st u d y i n  h e alt h y  v ol u nt e ers,  a n d t h e  m ost  c o m m o n  A Es r e p ort e d  a cr oss t h e 
3 st u d y  p arts  w er e  u p p er r es pir at or y i nf e cti o n ( P art  A  a n d  P ar t  B),  h e a d a c h e ( P art  A  a n d 
P art   C),  a n d i nj e cti o n sit e  p ai n ( P art  C).  
A d mi nistr ati o n  of t h er a p e uti c  pr ot ei ns, i n cl u di n g  m o n o cl o n al  a nti b o di es s u c h  as  C S L 3 4 6, is 
ass o ci at e d  wit h t h e ris k  of  h y p ers e nsiti vit y  a n d  a n a p h yl a cti c r e a cti o ns, s o m e  of  w hi c h  c a n  b e 
s eri o us  a n d lif e-t hr e at e ni n g.  A p pr o pri at e  pr e c a uti o ns  will  b e t a k e n  d uri n g  C S L 3 4 6 
a d mi nistr ati o n,  wit h  vi gil a nt  m o nit ori n g f or  p ot e nti al  a n a p h yl a cti c r e a cti o ns  a n d tr e at m e nt 
a c c or di n g t o  S O C.  T h e i niti al  a d mi nistr ati o ns  of  C S L 3 4 6  will  b e  p erf or m e d  u n d er  m e di c al 
s u p er visi o n,  a n d s u bj e cts  will  b e  a d vis e d t o s e e k  m e di c al  att e nti o n if  d el a y e d r e a cti o ns  o c c ur 
aft er  dis c h ar g e fr o m t h e sit e.  
A d diti o n al s af et y  m o nit ori n g  a n d /  or ris k  miti g ati o n i m pl e m e nt e d f or t his st u d y  will i n cl u d e 
a nti dr u g  a nti b o d y  d e v el o p m e nt,  w ei g ht  g ai n,  a n d  c o n g e nit al  dis or d ers.  

C S L  B e hri n g  L L C  
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
St u d y  P r o d u ct:   C S L 3 4 6   
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
P a g e  3 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
D ue t o t he p ote ntial f or V E G F- B a nta g o nis m t o m o d ulate V E G F- A t o ne, a d verse effects o n 
re nal a n d car di ac para meters k n o w n t o occ ur i n patie nts wit h metastatic ca n cer treate d wit h 
a nti-V E G F -A a ge nts w ere als o c o nsi dere d.  
S u bj ects  will have e n ha n ce d  safet y m o nit ori n g o ver the 4 wee ks foll o wi n g t heir first ex p os ure 
t o bli n de d I P an d bef ore a d mi nistrati o n of the sec o n d S C d os e at W ee k 4 ( V isit 7) . T his 
i ncl u des fre q u e nt bl o o d press ure ( B P) m o nit ori n g at V isit 4 ( Da y 1) an d st u d y visits at W ee k 1 
(V isit 5) an d W ee k 2 (V isit 6) . 
A n o ver vie w of i de ntifie d a n d p ote ntial ris ks a n d pla n ne d ris k miti gati o n i n t his p hase 2a 
st u d y is pr o vi de d i n  T a ble 1.  
T a bl e  1 
Ris k s  a n d  Ris k  Miti g ati o n  
Ris k  
P ot e nti al/  
I d e ntifi e d  
S o u r c e  
Ris k  Miti g ati o n  
I nj e cti o n sit e 
r e a cti o ns 
I d e ntifi e d 
C S L 3 4 6 _ 1 0 0 1  d at a  o n 
fil e 
•
Ass ess m e nt  at st u d y  visits
•
G ui d a n c e f or  m a n a gi n g l o c al
i nt ol er a n c e
H y p ers e nsiti vit y / 
a n a p h yl a xis  a n d 
i nf usi o n r e a cti o ns; 
a nti b o d y f or m ati o n  
P ot e nti al   
Cl ass  eff e ct  of 
h u m a ni z e d  pr ot ei ns  
•
St a n d ar d  m e as ur es
•
M e as ur e m e nt  of  b as eli n e,  mi d -,  a n d
e n d  of st u d y  a nti -C S L 3 4 6  a nti b o d y
W ei g ht  g ai n   
P ot e nti al   
K n o c k -o ut  m o us e  m o d el 
[H a g b er g  et  al,  2 0 1 0 ] 
•
M o nit or  at st u d y  visits
C o n g e nit al  dis or d ers   
P ot e nti al  
K n o c k -o ut  m o us e  m o d el 
[B ell o m o  et  al,  2 0 0 0 ] 
Pr e cli ni c al st u d y i n  q u ails 
[T o m a n e k  et  al,  2 0 0 6 ] 
• 
I n cl usi o n /  e x cl usi o n  crit eri a
• 
C o ntr a c e pti o n r e q uir e m e nts
• 
Pr e g n a n c y t esti n g
• 
N o n cli ni c al st u di es i n l at er  p h as es
R e n al:  a c ut e 
r e v ersi bl e  eff e ct  o n 
G F R  a n d  / or  c hr o ni c 
ki d n e y i nj ur y   
P ot e nti al   
T h e or eti c al ris k  d u e t o 
V E G F -A  m o d ul ati o n 
[K a m ar z ari a n  et  al,  2 0 1 8 ; 
I z z e di n e et  al,  2 0 1 0 ] 
• 
I n cl usi o n /  e x cl usi o n  crit eri a
• 
St a g e d  a p pr o a c h f or  e nr oll m e nt  of
s u bj e cts  wit h  m o d er at e r e n al
i m p air m e nt
• 
Fr e q u e nt  m o nit ori n g i n first  4  w e e ks  of
tr e at m e nt
• 
M e as ur e  S Cr  a n d  e v al u at e  al b u mi n uri a
at  e a c h  visit
• 
G ui d a n c e f or  m a n a gi n g i n cr e as es i n
S Cr  a n d  al b u mi n uri a

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Ris k  
P ot e nti al/  
I d e ntifi e d  
S o u r c e  
Ris k  Miti g ati o n  
C ar di a c:  m y o c ar di al 
d ysf u n cti o n  wit h 
c hr o ni c  d osi n g   
P ot e nti al   
K n o c k -o ut  m o us e  m o d el 
[B ell o m o  et  al,  2 0 0 0 ] 
Str e pt o z ot o ci n  m o d el 
[L al  et  al,  2 0 1 7 ] 
T h e or eti c al ris k  d u e t o 
V E G F -A  m o d ul ati o n 
[T o u y z  et  al,  2 0 1 8 ] 
•  
E x cl usi o n  crit eri a, i n cl u di n g  b as eli n e 
ass ess m e nt  of  L V E F  b y  E C H O  
•  
Tr e at m e nt  wit h  S O C  
•  
B as eli n e  a n d  p eri o di c  E C G,  B N P,  a n d 
tr o p o ni n l e v els 
•  
G ui d a n c e f or  m a n a gi n g i n cr e as es i n 
tr o p o ni n l e v els 
I n cr e as e d  B P  
P ot e nti al   
T h e or eti c al ris k  d u e t o 
V E G F -A  m o d ul ati o n 
[T o u y z  et  al,  2 0 1 8 ] 
•  
E x cl usi o n  crit eri a  
•  
B P  m e as ur e m e nt  
•  
G ui d a n c e f or  m a n a gi n g i n cr e as es i n 
B P  
B P  =  bl o o d  pr ess ur e;  B N P  =  b -t y p e  n atri ur eti c  p e pti d e;  E C G  =  el e ctr o c ar di o gr a m;  E C H O  =  e c h o c ar di o gr a m; 
G F R  =  gl o m er ul ar filtr ati o n r at e;  L V E F  = l eft  v e ntri c ul ar  ej e cti o n fr a cti o n;  S Cr  = s er u m  cr e ati ni n e; 
S O C   = st a n d ar d  of  c ar e;  V E G F  =  v as c ul ar  e n d ot h eli al  gr o wt h f a ct or. 
 
2   
St u d y  O bj e cti v es  a n d  E n d p oi nts  
2. 1   P ri m a r y  O bj e cti v e  a n d  E n d p oi nt  
2. 1. 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  of t his st u d y is t o  e v al u at e t h e  effi c a c y  of  C S L 3 4 6  a d mi nist er e d  e v er y 
4  w e e ks f or  1 2   w e e ks ( 4  d os es) i n s u bj e cts  wit h  D K D. 
2. 1. 2   
P ri m a r y  E n d p oi nt   
2. 2   S e c o n d a r y  O bj e cti v es  a n d  E n d p oi nts  
2. 2. 1   
S e c o n d a r y  O bj e cti v es   
T h e s e c o n d ar y  o b j e cti v es  of t his st u d y  ar e as f oll o ws : 
1.   T o  e v al u at e t h e s af et y  a n d  t ol er a bilit y  of  C S L 3 4 6  a d mi nist er e d  e v er y  4  w e e ks f or  u p t o 
1 2  w e e ks ( 4  d os es) i n s u bj e cts  wit h  D K D 
2.   T o  e v al u at e t h e  eff e ct  of  C S L 3 4 6  o n s er u m  cr e ati ni n e ( S Cr)  c o n c e ntr ati o n  a n d  esti m at e d 
gl o m er ul ar filtr ati o n r at e ( e G F R) i n s u bj e cts  wit h  D K D  
E n d p oi nt  
S u m m a r y  M e as u r e  
C h a n g e i n l o g -tr a nsf or m e d  uri n ar y 
al b u mi n -t o-cr e ati ni n e r ati o ( A C R) fr o m 
B as eli n e t o  W e e k  1 6 ( Visit  1 0)  
G e o m etri c  m e a n r ati o  f or  C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g 
c o m bi n e d)  v ers us  pl a c e b o  ( 9 5 %  CI),  e x pr ess e d  as  p er c e nt 
c h a n g e fr o m  B as eli n e  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3.   T o  e v al u at e t h e  eff e ct  of  C S L 3 4 6  o n  B P i n s u bj e cts  wit h  D K D 
4.   T o  e v al u at e t h e  P K  of  C S L 3 4 6 i n s u bj e cts  wit h  D K D 
5.   T o  e v al u at e  t h e i m m u n o g e ni cit y  of  C S L 3 4 6 i n s u bj e cts  wit h  D K D 
2. 2. 2   
S e c o n d a r y  E n d p oi nts  
S e c o n d a r y 
O bj e cti v e   
E n d p oi nt  
S u m m a r y  M e as u r e  
1 
Tr e at m e nt -e m er g e nt  a d v ers e  e v e nts, i n cl u di n g 
a d v ers e  e v e nts  of s p e ci al i nt er est ( A E SIs) fr o m 
t h e ti m e  of first  d os e of t h e I P  t hr o u g h  E n d  of 
St u d y ( E O S)  
N u m b er  a n d  p er c e nt a g e  of s u bj e cts 
o v er all,  b y s e v erit y,  b y r el at e d n ess,  b y 
s eri o us n ess,  a n d  b y  a cti o n (i e, I P 
dis c o nti n u ati o n)  
2 
O bs er v e d  v al u e  a n d  c h a n g e fr o m  B as eli n e  i n 
S Cr  a n d  e G F R t hr o u g h  E O S  
M e a n ( S D)  
3 
O bs er v e d  v al u e  a n d  c h a n g e fr o m  B as eli n e  i n 
s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e ( S B P  a n d 
D B P) t hr o u g h  E O S  
M e a n ( S D)  
4 
 
C S L 3 4 6 s er u m  P K:  
•   M a xi m u m  c o n c e ntr ati o n ( C m a x )  aft er I V 
l o a di n g  d os e  
•   Ti m e t o r e a c h  C m a x  i n s er u m ( Tm a x )  aft er 
I V l o a di n g  d os e 
•   C m a x  aft er first  S C  d os e  
•   T m a x  i n s er u m  aft er first  S C  d os e 
•   Ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e 
i n first  d osi n g i nt er v al ( A U C0- τ) 
•   T r o u g h  c o n c e ntr ati o n ( Ctr o u g h) aft er  e a c h 
d os e  
M e a n ( S D),  c o effi ci e nt  of  v ari ati o n 
( % C V)  a n d  g e o m etri c  m e a n f or  all 
p ar a m et ers  e x c e pt  T m a x ;  M e di a n 
( mi ni m u m,  m a xi m u m) f or  Tm a x  
 
5 
Pr es e n c e  of  a nti -dr u g  a nti b o d y  at  W e e k  4 
( Visit 7),  W e e k  8 ( Visit  8),  a n d  W e e k  1 6 
( Visit 1 0)  
N u m b e r  a n d  p er c e nta g e  of s u bj e cts 
wit h  p ositi v e r es ult ( wit h r e ci pr o c al 
tit er)  
 
2. 3   E x pl o r at o r y  O bj e cti v es  a n d  E n d p oi nts  
2. 3. 1   
E x pl o r at o r y  O bj e cti v es  
T h e  e x pl or at or y  o bj e cti v es  of t his st u d y  ar e: 
1.   T o  e x pl or e t h e  eff e ct  of  C S L 3 4 6  o n t h e f oll o wi n g  p ot e nti al  p h ar m a c o d y n a mi c ( P D) 
bi o m ar k ers:  
•   B i o m ar k ers  of li pi d  m et a b olis m 
•   Bi o m ar k ers  of  gl y c e mi c  c o ntr ol  
•   N o v el  pl as m a, s er u m,  a n d  uri n ar y  bi o m ar k ers  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
2.   T o  m e as ur e t h e  c o n c e ntr ati o n  of  C S L 3 4 6 i n t h e  uri n e  a n d  e x pl or e its  ass o ci ati o n  wit h 
al b u mi n uri a 
3.   T o  e x pl or e t h e r el ati o ns hi p  b et w e e n  P D  bi o m ar k ers  a n d  C S L 3 4 6  P K  c h ar a ct eristi cs 
4.   T o  e v al u at e t h e fr e q u e n c y  of s u bj e cts  wit h  m a cr o al b u mi n uri a ( A C R  >  3 0 0  m g/ g 
[ >  3 3. 9 m g/ m m ol])  at  B as eli n e  r e gr essi n g t o  mi cr o al b u mi n uri a ( A C R  ≥  3 0  a n d  ≤  3 0 0  m g/ g 
[ ≥  3. 3 9  a n d  ≤  3 3. 9  m g/ m m ol])  or  n or m o al b u mi n uri a ( A C R  <  3 0  m g/ g [ <  3. 3 9  m g/ m m ol]), 
or fr o m  mi cr o al b u mi n uri a t o  n or m o al b u mi n uri a 
5.   T o  e x pl or e  p ossi bl e  d os e r es p o ns e f or t h e  pri m ar y  a n d s e c o n d ar y  effi c a c y  a n d s af et y 
e n d p oi nts 
2. 3. 2   
E x pl o r at o r y  E n d p oi nts  
T h e  e x pl or at or y  e n d p oi nts f or t his st u d y  ar e  as f oll o ws: 
1.   C h a n g es fr o m  B as eli n e  t o  e a c h  ass ess m e nt i n f asti n g  v al u es f or t h e f oll o wi n g  P D 
bi o m ar k ers:  
•   B i o m ar k ers  of li pi d  m et a b olis m i n cl u di n g, b ut  n ot li mit e d t o , cir c ul ati n g t ot al 
c h ol est er ol, tri gl y c eri d es,  hi g h  d e nsit y li p o pr ot ei ns, l o w  d e nsit y li p o pr ot ei ns,  gl y c er ol, 
n o n- est erifi e d f att y  a ci ds,  a n d  k et o n es   
•   Bi o m ar k ers  of  gl y c e mi c  c o ntr ol i n cl u di n g,  b ut  n ot li mit e d t o , f asti n g  gl u c os e  a n d 
h e m o gl o bi n  A 1 c ( H b A 1 c)   
•   N o v el  bi o m ar k ers i n cl u di n g,  b ut  n ot li mit e d t o , s er u m-fr e e  V E G F- B  a n d s ol u bl e t u m or 
n e cr osis f a ct or r e c e pt or  1 (s T N F R 1),  a n d  uri n ar y  V E G F- A, s ol u bl e  V E G F r e c e pt or  1 
( V E G F- R 1),  ki d n e y i nj ur y  m ol e c ul e- 1,  n e utr o p hil  g el ati n as e-ass o ci at e d li p o c ali n, 
cl ust eri n,  a n d  m o n o c yt e  c h e m o attr a ct a nt  pr ot ei n- 1 
2.   C o n c e ntr ati o n  of  C S L 3 4 6 f o u n d i n  uri n e  at  We e k  1 ( Visit  5)  a n d  We e k  1 2 ( Visit  9) 
3.   N u m b er ( p er c e nt a g e )  of s u bj e cts w h o r e gr ess fr o m  m a cr o al b u mi n uri a t o  mi cr o al b u mi n uri a 
or  n or m o al b u mi n uri a,  or fr o m  mi cr o al b u mi n uri a t o  n or m o al b u mi n uri a  at  We e k  1 6 
( Visit  1 0)  c o m p ar e d t o  B as eli n e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3   
St u d y  D esi g n  a n d  O v e rsi g ht  
3. 1   O v e r all  D esi g n  
T his is  a  pr os p e cti v e,  m ulti c e nt er, 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,  pr o of- of-
c o n c e pt st u d y t o i n v esti g at e t h e  effi c a c y, s af et y, t ol er a bilit y,  a n d  P K  of r e p e at  d os es  of  C S L 3 4 6 
i n s u bj e cts  wit h  D K D  a n d  al b u mi n uri a r e c ei vi n g  S O C tr e at m e nt.  T h e st u d y  will  b e  di vi d e d i nt o 
4  p eri o ds:  S cr e e ni n g,  L e a d -i n,  Tr e at m e nt,  a n d  F oll o w- u p (Fi g ur e  1 ). 
Fi g u r e  1    
O v e r all  St u d y  D esi g n 
 
 
A C R  =  al b u mi n -t o-cr e ati ni n e r ati o; I V  = i ntr a v e n o us;  S C  = s u b c ut a n e o us.  
 
A p pr o xi m at el y  1 0 0 s u bj e cts  will  b e r a n d o mi z e d ( 1: 1: 2) t o r e c ei v e  bli n d e d I P 
( 8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or  pl a c e b o) f or  1 2  w e e ks.  T h e i niti al st u d y  p o p ul ati o n 
will i n cl u d e s u bj e cts  wit h  T 2 D M - D K D  a n d  pr es er v e d r e n al f u n cti o n 
( e G F R  ≥  6 0 m L/ mi n/ 1. 7 3 m 2); t h e first  1 8 s u bj e cts r a n d o mi z e d  will  b e f oll o w e d f or  at le ast 
4  w e e ks  aft er t h eir first  d os e  of I P ( Visit  4,  D a y  1),  at  w hi c h  p oi nt  a n I n d e p e n d e nt  D at a 
M o nit ori n g  C o m mitt e e (I D M C)  will r e vi e w t h eir s af et y  a n d  P K  d at a.  F oll o wi n g t his r e vi e w, 
i n cl usi o n  of s u bj e cts  wit h  e G F R  ≥  4 5 m L/ mi n/ 1. 7 3 m 2 (i n cl u di n g  C K D st a g e 3 A)  will  b e 
p er mitt e d if  a p pr o v e d  b y t h e I D M C.  
S u bs e q u e ntl y,  aft er  a n I D M C r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first  3 6  s u bj e cts ( at l e ast  8 
s u bj e cts  wit h  e G F R  ≥  4 5 t o  <  6 0  m L/ mi n/ 1. 7 3 m 2) f oll o w e d f or  at l e ast  4  w e e ks, i n cl usi o n  of 
s u bj e cts  wit h e G F R  >  2 0 t o  <  4 5  m L/ mi n/ 1. 7 3 m 2  will  b e  p er mitt e d if  a p pr o v e d  b y t h e I D M C. 
If i n cl usi o n  of s u bj e cts  wit h  e G F R  b el o w  6 0  m L/ mi n/ 1. 7 3 m2 is  e n d ors e d  b y t h e I D M C, t h e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
f oll o wi n g t ar g et e d s a m pl e si z e(s) will  b e  est a blis h e d  f or s u bj e cts  wit h  e G F R i n t h e s p e cifi e d 
r a n g e: 
•   At l e ast  3 6 s u bj e cts  wit h  e G F R  <   6 0  m L/ mi n/ 1. 7 3 m2 
•   At l e ast  1 8 s u bj e cts  wit h  e G F R  <   4 5  m L/ mi n/ 1. 7 3 m2  
T o  a c hi e v e t h es e  t ar g et e d  mi ni m u ms,  a r estri cti o n  m a y  b e i m p os e d  o n t h e  e nr oll m e nt  of 
s u bj e cts  wit h  e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2 a n d  /  or  ≥  4 5  m L/ mi n/ 1. 7 3 m2.  
T his st a g e d  a p pr o a c h t o i n cl u di n g s u bj e cts  wit h i n cr e asi n g  d e gr e es  of r e n al i m p air m e nt 
(i e, e G F R   ≥  4 5  a n d e G F R  >  2 0  m L/ mi n/ 1. 7 3 m 2) is  d esi g n e d t o  miti g at e ris k t o s u bj e cts  w hil e 
e n a bli n g  pr eli mi n ar y  ass ess m e nt  of s af et y  a n d  effi c a c y i n t h e st u d y  p o p ul ati o n t h at 
i n cr e asi n gl y r efl e cts t h e t ar g et  p o p ul ati o n f or p h as e   3. 
S u bj e cts r e c ei vi n g  C S L 3 4 6  will  b e  a d mi nist er e d  a n i niti al l o a di n g  d os e  of  3  m g/ k g  or  6  m g/ k g 
I V, f oll o w e d  b y  8  m g/ k g  or  1 6  m g/ k g  S C, r es p e cti v el y,  at l e ast  2  h o urs  b ut  n o  m or e t h a n 
6  h o urs l at er.  S u bs e q u e nt  S C i nf usi o ns ( 8  m g/ k g  or  1 6  m g/ k g  p er  d os e)  will  b e  a d mi nist er e d 
e v er y  4   w e e ks f or  1 2  w e e ks.  S u bj e cts r e c ei vi n g  pl a c e b o  will  b e  a d mi nist er e d  n or m al s ali n e 
usi n g  a  m at c h e d r e gi m e n  a n d  v ol u m e.  T h e  pri m ar y  e n d p oi nt ( A C R)  wi ll  b e  ass ess e d  4  w e e ks 
aft er t h e l ast  d os e  of I P.  
St u d y  pr o c e d ur es  will  b e  c o n d u ct e d  as  d es cri b e d i n t h e  S c h e d ul e  of  Ass ess m e nts . 
3. 1. 1   
S c r e e ni n g  P e ri o d  
T h e  S cr e e ni n g  P eri o d  b e gi ns  wit h t h e  c o m pl eti o n  of t h e i nf or m e d  c o ns e nt  pr o c ess  a n d i n cl u d es 
u p t o  6  w e e ks f or  d et er mi n ati o n  of s u bj e ct  eli gi bilit y.  D uri n g  S cr e e ni n g ( Visit  1  a n d  Visit  2), 
t h e I n v esti g at or  or  d el e g at e  will  ass ess t h e s u bj e ct’s  eli gi bilit y f or t h e st u d y  a c c or di n g t o 
I n cl usi o n  a n d E x cl usi o n  Crit eri a ( S e c ti o n 4. 1. 1  a n d  S e cti o n  4. 1. 2 , r es p e cti v el y).  Visit  2  m ust 
o c c ur  wit hi n  6  w e e ks  aft er  Visit  1.  A n  S C t est i nf usi o n is t o  b e  d o n e  at  Visit  2  aft er s u bj e ct 
eli gi bilit y  h as  b e e n  c o nfir m e d (i e,  ass ess m e nt  of  r es ults fr o m  Visit  1  a n d  ass ess m e nt of  r es ults 
a v ail a bl e  at t h e ti m e  of  Visit  2) (s e e  S e cti o n  8. 2. 1 ). 
S cr e e ni n g  ass ess m e nts  n ot s atisf yi n g i n cl usi o n  crit eri a  c a n  b e r e p e at e d  wit hi n t h e  6 -w e e k 
S cr e e ni n g  P eri o d (si g ni n g  of i nf or m e d  c o ns e nt f or m [ I C F] t o  Visit  2) if t h e I n v esti g at or h as 
r e as o n t o  b eli e v e t h e f ail e d  crit eri a( o n)  m a y  h a v e  c h a n g e d  o n r e p e at  ass ess m e nt.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   If t h e  eli gi bilit y  crit eri a( o n) is  m et  o n t h e r e p e at  ass ess m e nt, t h e s u bj e ct  m a y  pr o c e e d t o t h e 
L e a d -i n  P eri o d 
•   If t h e  eli gi bilit y  crit eri a( o n) is  N O T  m et  o n t h e r e p e at  ass ess m e nt, t h e s u bj e ct  will  b e 
c o nsi d er e d  a s cr e e n f ail ur e ( S e cti o n  4. 2 )  
R e -s cr e e ni n g  of t h e s u bj e ct is  p er mitt e d  o n c e  aft er  a  mi ni m u m  2 - m o nt h i nt er v al  b et w e e n t h e 
i niti al  S cr e e ni n g  Visit  a n d r e-s cr e e ni n g (si g ni n g i nf or m e d  c o ns e nt  d o c u m e nt[s] f or t h e 
r e-s cr e e ni n g  p eri o d).  D uri n g r e-s cr e e ni n g, t h e s u bj e ct  m ust  h a v e  all s cr e e ni n g  pr o c e d ur es  a n d 
ass ess m e nts r e p e at e d t o  d e m o nstr at e  eli gi bilit y f or t h e st u d y.  
3. 1. 2   
L e a d- i n  P e ri o d 
D uri n g t h e  L e a d-i n  P eri o d, s u bj e cts  will  h a v e  a st u d y  visit  a p pr o xi m at el y  1  w e e k  b ef or e 
r a n d o mi z ati o n ( Visit  3,  D a y  – 7  ±  4  d a ys).  T h e s u bj e ct’s  eli gi bilit y t o  c o nti n u e i nt o t h e 
Tr e at m e nt  P eri o d  will  b e  ass ess e d  a c c or di n g t o  R a n d o mi z ati o n  Crit eri a ( S e cti o n  4. 1. 3 ). 
Ass ess m e nts  n ot s atisf yi n g t h e  R a n d o mi z ati o n  Crit eri a  c a n  b e r e ass ess e d  d uri n g t h e  L e a d -i n 
P eri o d if t h e I n v esti g at or  h as r e as o n t o  b eli e v e t h e f ail e d  crit eri a( o n)  m a y  h a v e  c h a n g e d  o n 
r e p e at  ass ess m e nt. If  all  R a n d o mi z ati o n  Crit eri a  ar e s atisfi e d, t h e s u bj e ct  will  b e  eli gi bl e f or 
r a n d o mi z ati o n i n t h e  Tr e at m e nt  P eri o d ( Visit  4,  D a y  1). 
3. 1. 3   
Tr e at m e nt  P e ri o d  
T h e  Tr e at m e nt  P eri o d  will i n cl u d e  1 2  w e e ks  of  a p pr o xi m at el y  m o nt hl y ( e v er y  4  w e e ks) 
a d mi nistr ati o n  of I P.  Usi n g  a n i nt er a cti v e r es p o ns e t e c h n ol o g y (I R T) s yst e m,  eli gi bl e s u bj e cts 
will  b e r a n d o mi z e d ( 1: 1: 2) t o r e c ei v e  bli n d e d I P ( 8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or 
pl a c e b o).  
E a c h s u bj e ct’s first  d os e  of I P  at  Visit  4 ( D a y  1)  will  b e  a n I V l o a di n g  d os e  of  3  m g / k g  C S L 3 4 6 
(s u bj e cts r a n d o mi z e d t o  8  m g/ k g  C S L 3 4 6),  6  m g/ k g  C S L 3 4 6 (s u bj e cts r a n d o mi z e d t o 
1 6  m g/ k g  C S L 3 4 6),  or  pl a c e b o (s u bj e cts r a n d o mi z e d t o  pl a c e b o).  All I V l o a di n g  d os es  will  b e 
i n  a t ot al  v ol u m e  of  1 0  m L  a n d i nf us e d  o v er t h e  c o urs e  of  a p pr o xi m at el y  2 0 mi n ut es.  T h e 
s u bj e ct  will t h e n  b e  m o nit or e d f or  a p pr o xi m at el y  2  h o urs,  d uri n g  w hi c h  A Es  a n d  vit al si g ns 
will  b e r e c or d e d  p eri o di c all y  as  d es cri b e d i n t h e  S c h e d ul e  of  Ass ess m e nts   a n d S e cti o n  8. 1. 1 . If 
n o  cli ni c all y r el e v a nt  A Es  ar e  o bs er v e d  d uri n g t his ti m e, t h e s u bj e ct’s first  S C  d os e  of I P  will 
b e  a d mi nist er e d  as  a n  8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or  pl a c e b o  2 0  m L  S C i nf usi o n 
o v er t h e  c o urs e  of  a p pr o xi m at el y  4 0  mi n ut es.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
S u bj e cts  will r e c ei v e  3 s u bs e q u e nt  S C i nf usi o ns  at  Visit  7 ( We e k  4),  Visit  8 ( We e k  8),  a n d 
Visit   9 ( We e k  1 2) f or  a t ot al  of  4  S C  d os es.  
3. 1. 4   
F oll o w -u p  P e ri o d  
T h e  F oll o w- u p  P eri o d  will  c o nti n u e f or  1 2  w e e ks  aft er t h e s u bj e ct’s l ast  d os e  of I P t o  e v al u at e 
c h a n g es i n s af et y,  effi c a c y,  P K,  a n d  P D  p ar a m et ers  aft er st o p pi n g tr e at m e nt.  
R el e v a nt  u n bli n d e d  d at a fr o m  all s u bj e cts  p arti ci p ati n g i n t h e st u d y  will  b e r e vi e w e d  b y t h e 
I D M C d uri n g r e g ul arl y- s c h e d ul e d s af et y r e vi e ws,  as  d et ail e d i n t h e I D M C  C h art er.  
3. 2   D os e  a n d  D osi n g  R e gi m e n  
At  Visit  4 ( D a y  1),  C S L 3 4 6  will  b e  a d mi nist er e d  at  a n i niti al l o a di n g  d os e  of  3  m g/ k g  or 
6  m g/ k g I V, f oll o w e d  b y  8  m g/ k g  or  1 6  m g/ k g  S C, r es p e cti v el y,  at l e ast  2  h o urs  b ut  n o  m or e 
t h a n  6  h o urs l at er.  S u bs e q u e nt  S C i nf usi o ns ( 8  m g/ k g  or  1 6  m g/ k g  p er  d os e)  will  b e 
a d mi nist er e d  e v er y  4  w e e ks f or  1 2  w e e ks. 
S u bj e cts  e x p eri e n ci n g  a  mil d i nj e cti o n sit e r e a cti o n  d e e m e d  u n a c c e pt a bl e   b y t h e s u bj e ct  or 
I n v esti g at or m a y  h a v e  a d mi nistr ati o n  a n d /  or  d os e  a dj ust m e nts (s e e  S e cti o n  5. 1. 3. 1 ).  
T h e I D M C  will  e v al u at e t h e  n e e d f or  d os e  d e - es c al ati o n  d uri n g  pl a n n e d r e vi e ws  of  e m er gi n g 
d at a (s e e  S e cti o n  3. 6. 1 )  a n d  m a y  dis c o nti n u e t h e  1 6  m g/ k g  C S L 3 4 6  d os e l e v el  as  p er 
pr e d efi n e d  d os e l e v el st o p pi n g  crit eri a ( S e cti o n  3. 7. 2 ). 
Pl a c e b o  c o nsists  of  n or m al s ali n e f or I V  a n d  S C i nf usi o n.  D osi n g  a d mi nistr ati o n, r e gi m e n,  a n d 
v ol u m e  will  b e  m at c h e d t o  C S L 3 4 6. 
3. 3   S ci e ntifi c  R ati o n al e  
3. 3. 1   
St u d y  D esi g n  R ati o n al e  
T his is  a  p h as e  2 a, 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 st u d y  usi n g  a st a n d ar d 
p ar all el - gr o u p st u d y  d esi g n.  T h e i niti al  p o p ul ati o n  will i n cl u d e s u bj e cts  wit h  D K D  d u e t o 
T 2 D M  a n d  pr es er v e d r e n al f u n cti o n ( e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2)  wit h  a l o w er ris k  of r e n al 
a n d  c ar di o v as c ul ar  dis e as e  [N e u e n  et  al,  2 0 1 8 ]. I n cl usi o n  of s u bj e cts  wit h  e G F R  ≥  4 5  a n d 
<  6 0  m L/ mi n/ 1. 7 3 m 2 ( C K D st a g e  3 A)  will  b e  p er mitt e d if  a p pr o v e d  b y t h e st u d y’s I D M C  aft er 
r e vi e wi n g s af et y  a n d  P K  d at a  fr o m t h e first  1 8 s u bj e cts.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  3 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
S u bs e q u e ntl y,  aft er  a n I D M C r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first  3 6 s u bj e cts ( at l e ast  8 
wit h  e G F R  ≥  4 5 t o  <  6 0  m L/ mi n/ 1. 7 3 m 2) f oll o w e d f or  at l e ast  4  w e e ks, i n cl usi o n  of s u bj e cts 
wit h  e G F R  >  2 0 t o  <  4 5  m L/ mi n/ 1. 7 3 m 2  will  b e  p er mitt e d if  a p pr o v e d  b y t h e I D M C.  
If i n cl usi o n  of s u bj e cts  wit h  e G F R  b el o w  6 0  m L/ mi n/ 1. 7 3 m2 is  e n d ors e d  b y t h e I D M C, t h e 
f oll o wi n g t ar g et s a m pl e si z e(s)  will  b e  est a blis h e d f or s u bj e cts  wit h  e G F R i n t h e s p e cifi e d 
r a n g e: 
•   At l e ast  3 6 s u bj e cts  wit h  e G F R  <  6 0  m L/ mi n/ 1. 7 3 m 2 
•   At l e ast  1 8 s u bj e cts  wit h  e G F R  <  4 5  m L/ mi n/ 1. 7 3 m 2 
T o  a c hi e v e t h es e  t ar g et e d  mi ni m u ms,  a r estri cti o n  m a y  b e i m p os e d  o n t h e  e nr oll m e nt  of 
s u bj e cts  wit h  e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2 a n d  /  or  ≥  4 5  m L/ mi n/ 1. 7 3 m2. 
T his st a g e d  a p pr o a c h t o i n cl u di n g s u bj e cts  wit h i n cr e asi n g  d e gr e es  of r e n al i m p air m e nt (i e, 
e G F R  ≥   4 5  a n d e G F R  >  2 0  m L/ mi n/ 1. 7 3 m 2) is d esi g n e d t o  miti g at e ris k t o s u bj e cts  w hil e 
e n a bli n g  pr eli mi n ar y  ass ess m e nt  of s af et y  a n d  effi c a c y i n t h e  st u d y  p o p ul ati o n t h at 
i n cr e asi n gl y r efl e cts t h e t ar g et  p o p ul ati o n f or p h as e   3.  
T w o  d os es  of  C S L 3 4 6  will  b e  ass ess e d t o i n cr e as e t h e li k eli h o o d  of s h o wi n g  a tr e at m e nt  eff e ct, 
ass essi n g t ol er a bilit y  a n d t o  g e n er at e  a d diti o n al  P K /  P D  d at a f or  d os e s el e cti o n i n s u bs e q u e nt 
tri als.  Crit eri a f or  d os e  d e-es c al ati o n  ar e i n  pl a c e.  
Uri n ar y  A C R is  a n  est a blis h e d r e n al s urr o g at e  bi o m ar k er i n t his  p ati e nt  p o p ul ati o n  a n d  h as 
t h er ef or e  b e e n s el e ct e d t o  e v al u at e  effi c a c y f or t h e  pri m ar y  o bj e cti v e [C or es h  et  al,  2 0 1 9 ; 
H e ers pi n k  et  al,  2 0 1 9 ].  T o  mi ni mi z e  v ari a bilit y  a n d  o pti mi z e t h e  a bilit y t o i nt er pr et t h e r es ults, 
m e di c ati o ns  us e d f or  gl y c e mi c  c o ntr ol  a n d t h e tr e at m e nt  of  D K D ( e g,  R A S i n hi bit ors  a n d 
S G L T 2 i n hi bit ors)  m ust  b e st a bl e  b ef or e st u d y  e nr oll m e nt. I n  a d diti o n,  m ulti pl e,  c o ns e c uti v e 
first  m or ni n g  v oi d ( F M V)  uri n e  c oll e cti o ns  at  e a c h ti m e  p oi nt  will  b e  us e d f or  A C R  a n al ysis 
[Kr ö p eli n  et  al,  2 0 1 5 ].  T h es e s a m pl es  will  b e  c oll e ct e d  at  B as eli n e,  p eri o di c all y  d uri n g t h e 
Tr e at m e nt  P eri o d  a n d  at t h e  e n d  of t h e  Tr e at m e nt  P eri o d,  a n d  d uri n g t h e  F oll o w- u p  P eri o d. 
B as e d  o n r es ults fr o m st u di es  c o n d u ct e d i n st a n d ar d  a ni m al  D K D  m o d els,  1 2  w e e ks  of  d osi n g 
is hi g hl y li k el y t o  d e m o nstr at e  A C R  a cti vit y i n  a  cli ni c al st u d y.  T h e  1 2 - w e e k  d ur ati o n  of t h e 
F oll o w- u p  P eri o d  w as  d et er mi n e d  b as e d  o n t h e  e xt e n d e d  h alf-lif e  of  C S L 3 4 6  a n d  e n a bl es 
c h ar a ct eri z ati o n  of t h e tr e at m e nt  eff e ct  w hil e  e x p os ur e  d e cli n es.  

C S L  B e hri n g  L L C  
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
St u d y  P r o d u ct:   C S L 3 4 6   
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
P a g e  3 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3. 3. 2  
D ose  R ati o n ale 
D oses w ere selecte d bas e d o n t he ex pect e d effect of C S L 3 4 6 i n s u bj ects  wit h  D K D. I n t he 
a bse nce o f safet y or to xicit y fi n di n gs an d P D da ta fr o m S t u d y C S L 3 4 6 _ 1 0 0 1, bri d gi n g of P K 
fr o m he alt h y v ol u nteers to s u bj ects  wit h D K D w as ba se d o n p o p ulati o n P K m o delli n g of da ta 
i n healt h y v ol u nteers al o n g wit h P K / P D da ta fr o m m o use m o dels of T 2 D M- D K D ( H F D a n d 
d b /d b ). Pr o p ose d d oses an d re gi me n were selecte d to assess p ha r mac ol o gical acti vit y (e g, 
c ha n ges in al b u mi n uria) in s u bj ects  wit h  T2 D M -D K D.  Phar mac o ki n etic dat a fr o m  d b /d b  mice 
treate d wit h a p h ar mac ol o gicall y acti ve d os e o f 2 H 1 0, t he m uri ne ve rsio n of C S L 3 4 6, was us e d 
to i de ntif y a thres h ol d tar get co nce ntrati o n of C S L 3 4 6 pre dicte d t o pr o vi de p har mac ol o gical 
acti vit y i n s u bj ects wit h  D K D. 
T he P K pr ofile in healt h y su bjects enr olle d i n St u d y C S L 3 4 6 _ 1 0 0 1, a d mi nistere d si n gle d os es 
of C S L 3 4 6 u p t o 2 0 m g/ k g b y I V inf usi o n or u p t o 1 0 m g/ k g b y S C injecti o n, was d os e 
pr o p orti o nal. N o nli near mi xe d effects m o delli n g of these da ta in h ealt h y v ol u nteers w as us e d 
t o esta blis h t he h u m a n p o p ulati o n P K m o del . W ei g ht w as eval uate d f or its infl ue nce o n t he P K 
of C S L 3 4 6, wit h n o si g nifica nt effects fo u n d i n t he he alt h y p o p ulati o n. As preli mi nar y data 
i n di cate t hat PK  e x p osur es  bet wee n healt h y mice a n d d b /d b  mice of t he sa me strai n 
ad mi nister ed 2 H 1 0 are w it hi n 2-f ol d, d ose adj ust me nts for di ffere nt le v els of re nal fu n cti o n 
were d eter mi ne d n ot to b e re q uired. T his w ill be furt her ev al uate d b y i ncl u di n g s u bject da ta 
fr o m this st u dy.  
S electi o n of the lo w d os e w as ba se d o n t he e x pecte d cli nical effect of C S L 3 4 6 o n al b u mi n uria 
i n t he abse nce o f an y safet y c o ncer ns in healt h y s u bjects or n o nc li nical to xicit y fi n di n gs. 
Res ults fr o m an H F D m o use m o del of D K D sh o we d t hat twice w ee kl y d osi n g of b ot h 1 m g/ k g 
a n d 1 0 m g/ k g 2 H 1 0 pre v e nte d t he increase o f al b u mi n uria o ve r 2 0 wee ks. Res ults fr o m 
a n other st u dy, usi n g t he d b /d b  m o del of D K D, als o s h o we d t hat twice w ee kl y d osi n g of 
1 0 m g/ k g 2 H 1 0 a meli orate d al b u mi n uria o ve r 1 0 wee ks . T h e d os e fo r p ha s e 2a w as p re dicte d 
fr o m the P K / P D da ta us i n g 1 0 m g/ k g, as thi s d ose ha d the gr eatest  a nd  mo st re plica ble effect 
o n al b u mi n uria in D K D m o use m o dels. Ser u m C tr o u g h of 2 H 1 0 at stea d y state (a p pr o xi matel y 
4 da ys after th e last w ee k of 1 1 wee ks of twice wee kl y d osi n g) in d b /d b  mo del  mice treat e d 
wit h a 1 0 m g/ k g d ose of 2 H 1 0 t wice w ee kl y a vera ge d 1 8 0 μ g/ m L.  
Differe nces i n p ote nc y bet wee n t he m o use 2 H 1 0 a nti b o d y a n d C S L 3 4 6 were calc ulate d usi n g 
data fr o m  a cell- base d assa y of V E G F - R1  acti vit y [M o ul d et al, 2 0 0 5]. T he  h alf maxi mal 
i n hi bit or y c o ncentrati o ns of 2 H 1 0 i n t he pr es e nce of m o use V E G F- B (2 0 n M) an d of C S L 3 4 6 
i n t he pr ese nce of h u m a n V E G F- B (1. 2 5 n M) w ere 3 n M an d 0. 1 8 n M, res pecti vel y. T he rati o 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
of t h es e  v al u es ( 1 6. 7)  w as  us e d t o  c orr e ct f or t h e  o bs er v e d  eff e cti v e  c o n c e ntr ati o n  of  2 H 1 0 i n 
mi c e  a n d  pr e di ct  a t ar g et  C tr o u g h  of  C S L 3 4 6 i n  h u m a ns.  Wit h t h e  1 6. 7  a dj ust m e nt f or  p ot e n c y,  a 
t ar g et  C S L 3 4 6  Ctr o u g h of  1 1  μ g/ m L  w as  c al c ul at e d. I n  a  dir e ct  bi n di n g  e n z y m e-li n k e d 
i m m u n os or b e nt  ass a y, t h e  h alf  ma xi m al  eff e cti v e  c o n c e ntr ati o n  ( E C5 0) of  2 H 1 0  o n  1  μ g/ m L 
m o us e  V E G F - B  w as  3. 2 1  n M  a n d t h e E C 5 0  of  C S L 3 4 6  o n  1  μg/ m L  h u m a n  V E G F -B  w as 
0. 2 5 7  n M.  W h e n  usi n g t h e r ati o  of t h es e  v al u es ( 1 2. 5) t o  c orr e ct f or t h e  c o n c e ntr ati o n i n  mi c e, 
a t ar g et  C tr o u g h  of  1 4. 4  μ g/m L  w as  c al c ul at e d.  S el e cti o n  of t h e  d os es  w as  b as e d  o n t h e 
1 4. 4  μ g/ m L t ar g et  C tr o u g h,  as t h e  dir e ct  bi n di n g  ass a y  pr o vi d es  a  m or e  a c c ur at e  m e as ur e. 
C o nsi d eri n g t h e  pr ol o n g e d  h alf-lif e ( a p pr o xi m at el y  3 0  d a ys),  u p t o  5  m o nt hs  of  m o nt hl y 
a d mi nistr ati o n  w o ul d   b e r e q uir e d t o r e a c h st e a d y st at e  wit h  S C  a d mi nistr ati o n.  T h er ef or e,  a 
si n gl e l o a di n g  d os e  will  b e  a d mi nist er e d  b y I V i nf usi o n  o n  D a y  1 ( Visit  4), f oll o w e d  b y  a n  S C 
i nf usi o n  o n  D a y  1 ( Visit  4) t o r e a c h  a p pr o xi m at e st e a d y st at e  C S L 3 4 6  c o n c e ntr ati o ns  e arli er i n 
t h e  Tr e at m e nt  P eri o d.  T o  m ai nt ai n t ar g et s er u m  c o n c e ntr ati o ns, I P  will  b e  a d mi nist er e d  b y  S C 
i nf usi o n  e v er y  4  w e e ks t h er e aft er.  
F or t h e l o w  d os e,  a l o a di n g  d os e  of  3  m g/ k g I V, f oll o w e d  b y  a d mi nistr ati o n  of  8  m g/ k g  S C  o n 
D a y  1 ( Visit  4)  a n d  e v er y  4  w e e ks t h er e aft er,  w as s el e ct e d.  Tr o u g h  c o n c e ntr ati o ns  at st e a d y 
st at e ( Ctr o u g h _ss) ar e  pr e di ct e d t o  e x c e e d  1 4. 4  μ g/ m L i n  9 9. 9 %  of s u bj e cts tr e at e d  wit h  8  m g/ k g 
t hr o u g h  We e k  1 6 ( Visit  1 0) (Fi g ur e  2 ).  Pr e di ct e d  m e di a n ( 9 5 %  CI) ar e a  u n d er t h e 
c o n c e ntr ati o n -ti m e  c ur v e (A U C )0- 2 8 d _ss ( A U C  b et w e e n  d os es  at st e a d y st at e  w h er e  d osi n g 
i nt er v al [τ]  =  2 8  d a ys [ 4  w e e ks]) f oll o wi n g r e p e at  d osi n g  of  8  m g/ k g  S C is  1 3 3 6 ( 9 7 0 t o  1 9 2 1) 
μ g• d a y/ m L.  T his  e x p os ur e is  a p pr o xi m at el y  4. 4- ( 6. 0- t o  3. 0-) f ol d l o w er t h a n t h e  m e a n 
A U C 0- ∞ ( A U C fr o m ti m e  0 t o i nfi nit y) e x p os ur e  aft er  1 2  w e e ks  of f oll o w  u p i n  h e alt h y 
v ol u nt e ers  a d mi nist er e d  a si n gl e  2 0  m g/ k g  d os e ( 5 8 3 9  μ g• d a y/ m L) i n  St u d y  C S L 3 4 6 _ 1 0 0 1 
(Ta bl e  2 ). 
S el e cti o n  of t h e  hi g h  d os e  w as  b as e d  o n t h e  u n c ert ai nti es  of tr a nsl ati o n  of  m o us e  dis e as e 
m o d els t o  h u m a ns  a n d t h e l a c k  of  q u a ntit ati v e  d at a  o n  V E G F- B l e v els i n  h u m a n tiss u es  or  a 
v ali d at e d  P D  m ar k er. I n cl u di n g  a  2-f ol d  hi g h er  d os e  all o ws f or  hi g h er l o c al  e x p os ur e i n t h e 
ki d n e y  a n d t h us,  a n i n cr e as e d li k eli h o o d t o  o bs er v e  effi c a c y i n t his  pr o of  of  c o n c e pt st u d y i n 
c as e  a cti vit y is  dri v e n  b y l o c al tiss u e  c o n c e ntr ati o ns  of  V E G F- B  a n d  C S L 3 4 6 r at h er t h a n 
s yst e mi c  e x p os ur e.  A d diti o n all y, t h e  d os e-r es p o ns e r el ati o ns hi p  a cr oss t h es e  2  d os e l e v els  will 
h el p i nf or m  d os e s el e cti o n f or  a  p h as e  2 b  d os e-fi n di n g st u d y. 
F or t his  hi g h  d os e,  a l o a di n g  d os e  of  6  m g/ k g I V  will  b e f oll o w e d  b y  1 6  m g/ k g  S C  o n  D a y  1 
( Visit  4)  a n d  e v er y  4  w e e ks t h er e aft er.  F oll o wi n g r e p e at  d osi n g  at t h e  hi g h  d os e  of  1 6  m g/ k g, 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
m e di a n ( 9 5 %  CI)  A U C 0- 2 8 d _ss is pr e di ct e d t o  b e  2 7 7 0 ( 1 9 3 1 t o  3 8 1 5)  μ g• d a y/ m L.  T his  e x p os ur e 
is  a p pr o xi m at el y  2. 1 ( 3. 0 t o  1. 5) f ol d l o w er t h a n t h e  m e a n  A U C0- ∞  e x p os ur e  aft er  1 2  w e e ks  of 
f oll o w  u p i n  h e alt h y  v ol u nt e ers  a d mi nist er e d  a si n gl e  2 0  m g/ k g  d os e ( 5 8 3 9  μ g• d a y/ m L) i n 
St u d y  C S L 3 4 6 _ 1 0 0 1 ( Ta bl e  2 ). T h e  tr o u g h  c o n c e ntr ati o ns  at st e a d y st at e ( Ctr o u g h _ss) i n s u bj e cts 
tr e at e d  wit h  1 6  m g/ k g  C S L 3 4 6 is  pr e di ct e d t o  e x c e e d  1 4. 4  μg/ m L i n  all (i e,  1 0 0 %) s u bj e cts  at 
We e k  1 6 ( Visit  1 0)  a n d i n  5 9 %  of s u bj e cts  at  We e k  2 4 ( Visit  1 1)  (Fi g ur e  2 ). 
Fi g u r e  2 
P r e di ct e d  C S L 3 4 6  C o n c e nt r ati o ns  F oll o wi n g  M o nt hl y  S C  D osi n g 
wit h I V  L o a di n g  D os e 
 
C m a x  =  m a xi m u m  c o n c e ntr ati o n;  FI H  = first i n  h u m a n;  I V  = i ntr a v e n o us;  q 4 w  =  o n c e  e v er y  4  w e e ks; 
S C   = s u b c ut a n e o us. 
S oli d li n es s h o w t h e  m e di a n  of  1 0 0 0 si m ul ati o ns; s h a d e d r e gi o ns s h o w t h e  9 5 %  Pr e di cti o n I nt er v al  of 
1 0 0 0  si m ul ati o ns;  bl a c k  d as h e d li n e s h o ws  1 4. 4  μ g/ m L t ar g et tr o u g h  c o n c e ntr ati o n;  gr e y  d as h e d li n e s h o ws 
m e a n  C m a x  f oll o wi n g I V  a d mi nistr ati o n  of  a si n gl e  d os e  of  C S L 3 4 6  2 0  m g/ k g t o  h e alt h y  v ol u nt e ers. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
T a b l e 2 
P r e di ct e d  P h a r m a c o ki n eti c  P a r a m et e rs  a n d  S af et y  M a r gi ns  
D os e  G r o u p  
P r e di ct e d  C m a x  
( μg/ m L)  
C m a x  S af et y 
M a r gi n  o v e r 
Si n gl e  2 0  m g/ k g 
a 
P r e di ct e d   
A U C 0- 2 8 d _ss b 
( μg• d a y/ m L)  
A U C  S af et y 
M a r gi n  o v e r 
Si n gl e  2 0  m g/ k g 
a 
8  m g/ k g  S C  wit h  3  m g/ k g 
I V l o a di n g  d os e 
7 4  
6. 3  
1 3 3 6  
4. 4  
1 6  m g/ k g  S C  wit h 
6  m g/ k g I V l o a di n g  d os e  
1 4 9  
3. 2  
2 7 2 0  
2. 1  
A U C  =  ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e;  Cm a x  =  m a xi m u m  o bs er v e d  c o n c e ntr ati o n; I V  = i ntr a v e n o us; 
S C  = s u b c ut a n e o us.  
a 
I n  St u d y  C S L 3 4 6 _ 1 0 0 1,  Cm a x  =  4 7 2  μ g/ m L  a n d  A U C 0- ∞ =  A U C fr o m ti m e  0 t o i nfi nit y,  5 8 3 9  μ g• d a y/ m L  aft er 
a si n gl e  2 0  m g/ k g  d os e.  
b 
A U C 0- 2 8 d _ ss =  A U C  b et w e e n  d os es  at st e a d y st at e  w h er e  d osi n g i nt er v al ( τ)  =  2 8  d a ys ( 4  w e e ks).  
 
I n  g e n er al,  gi v e n t h e  a bs e n c e  of s af et y fi n di n gs  a n d  P D  bi o m ar k er  d at a fr o m 
St u d y  C S L 3 4 6 _ 1 0 0 1 i n  h e alt h y  v ol u nt e ers,  al o n g  wit h t h e  a bs e n c e  of t o xi c ol o gi c al fi n di n gs, 
s el e cti o n  of  d os es  b as e d  o n  P K /  P D  d at a  a v ail a bl e fr o m  m uri n e  dis e as e  m o d els is t h e  m ost 
a p pr o pri at e.  T h e s el e ct e d  d os es  of  8  m g/ k g  a n d  1 6  m g/ k g  S C  gi v e n  e v er y  4  w e e ks  ar e 
pr e di ct e d t o  m ai nt ai n s u bj e cts  at  e x p os ur es  a d e q u at e t o  o bs er v e  a cti vit y  a n d i n  a r a n g e t h at  h as 
b e e n s h o w n t o  b e s af e i n  pr e vi o us  h u m a n  a n d  n o n cli ni c al  e x p eri e n c e. 
3. 4   Pl a n n e d  St u d y  D u r ati o n  
T h e  d ur ati o n  of t h e st u d y f or  a n i n di vi d u al s u bj e ct is  e x p e ct e d t o  b e  u p t o  a p pr o xi m at el y 
3 4  w e e ks.  T his  esti m at e is  b as e d  o n  t h e f oll o wi n g: 
•   A n  u p t o  6- w e e k  S cr e e ni n g  P eri o d  
•   A n  u p t o  4- w e e k  L e a d -i n P eri o d  
•   A  1 2 -w e e k  Tr e at m e nt  P eri o d  
•   A  1 2 - w e e k  F oll o w- u p  P eri o d 
T h e  o v er all st u d y  d ur ati o n (i e, first s u bj e ct’s  S cr e e ni n g  Visit t o l ast s u bj e ct’s  E O S  Visit)  will  b e 
a p pr o xi m at el y  2 2  m o nt hs.  
3. 5   Pl a n n e d  N u m b e r  of  S u bj e cts  
T h e st u d y  will r a n d o mi z e  a t ar g et  of  1 0 0 s u bj e cts: 
•   2 5 s u bj e cts r a n d o mi z e d t o t h e  8  m g/ k g  C S L 3 4 6  gr o u p 
•   2 5 s u bj e cts r a n d o mi z e d t o t h e  1 6  m g/ k g  C S L 3 4 6  gr o u p 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   5 0 s u bj e cts r a n d o mi z e d t o t h e  pl a c e b o  gr o u p 
A s u bj e ct is  c o nsi d er e d  e nr oll e d i n t h e st u d y  o n c e t h e y  h a v e si g n e d t h e I C F.  A s u bj e ct is 
c o nsi d er e d  eli gi bl e f or r a n d o mi z ati o n i nt o t h e st u d y  w h e n  all i n cl usi o n  crit eri a  h a v e  b e e n  m et, 
n o n e  of t h e  e x cl usi o n  crit eri a  h a v e  b e e n  m et,  a n d t h e r a n d o mi z ati o n  crit eri a  h a v e  b e e n  m et 
(S e cti o n  4. 1 ).  
T h e  a ct u al  e arl y  dis c o nti n u ati o n r at e  will  b e  ass ess e d t hr o u g h o ut t h e st u d y  a n d  u p t o 
1 2 4 s u bj e cts  m a y  b e r a n d o mi z e d, if  n e c ess ar y, t o t ar g et  9 4  c o m pl et e d s u bj e cts (s u bj e cts  w h o 
r e c ei v e d  all  d os es  a n d  c o m pl et e d t h e  We e k  1 6  A C R  ass ess m e nt). 
3. 6   St u d y  O v e rsi g ht  
3. 6. 1   
I n d e p e n d e nt  D at a M o nit o ri n g  C o m mitt e e(s)   
T his st u d y  will  us e  a n I D M C.  Voti n g  m e m b ers  of t h e I D M C  will  n ot  b e  e m pl o y e es  of  C S L 
B e hri n g  ( C S L) a n d  will  n ot  h a v e  a fi n a n ci al i nt er est i n t h e s u c c essf ul  d e v el o p m e nt  of  C S L 3 4 6. 
T h e I D M C  will i n cl u d e  3  p h ysi ci a ns  wit h  e x p ertis e i n  tr e at m e nt  of r e n al ( 2)  a n d  c ar di a c ( 1) 
dis e as e  w h o  ar e  e x p eri e n c e d i n t h e  c o n d u ct  a n d  o v ersi g ht  of  cli ni c al tri als i n t his s p a c e,  a n d  a 
st atisti ci a n  wit h si mil ar r el e v a nt  e x p ertis e.  T h e I D M C  will  h a v e  a p pr o pri at e  a c c ess t o 
u n bli n d e d st u d y  d at a t o f a cilit a t e  p eri o di c  ass ess m e nt  of t h e s af et y  of t h e I P.  T h e y  will s er v e  as 
a n  a d vis or y  b o d y  a n d  will  m a k e r e c o m m e n d ati o ns t o t h e  St e eri n g  C o m mitt e e ( S e cti o n  3. 6. 2 ) 
a n d  S p o ns or’s  St u d y  Te a m r e g ar di n g  c o nti n u ati o n,  m o difi c ati o n,  or  dis c o nti n u ati o n  of t h e 
o n g oi n g st u d y.  
A p pr o pri at e  b a c k gr o u n d i nf or m ati o n  a n d  o n g oi n g  c o ns ult ati o n,  as  w ell  as t e c h ni c al  a n d 
l o gisti c al s u p p ort,  will  b e  pr o vi d e d  b y  C S L.  T h e I D M C  will  h a v e t h e  a bilit y t o r e q u est 
a d diti o n al  e xt er n al i n p ut  as  n e e d e d. 
A d diti o n al s u p p ort  will  b e  pr o vi d e d  b y t h e  S p o ns or’s st u d y  L e a d  P h ysi ci a n,  M e di c al  M o nit or, 
Dr u g  S af et y  P h ysi ci a n,  St atisti ci a n,  O p er ati o ns  L e a d,  Cli ni c al  S ci e ntist,  a n d  ot h ers,  as  n e e d e d, 
w h o  will  n ot  h a v e  a c c ess t o  u n bli n d e d st u d y  d at a.  U n bli n d e d  d at a  a n d  pr o gr a m mi n g s u p p ort 
will  b e  pr o vi d e d  b y  a p pr o pri at e i n di vi d u als  n ot i n v ol v e d i n t h e  c o n d u ct  of t h e st u d y  a n d  pl a c e d 
u n d er stri ct  c o nfi d e nti alit y.  
S p e cifi c  d et ails, i n cl u di n g t h e s c o p e,  c o m p ositi o n,  o p er ati n g  pr o c e d ur es,  a n d  m e eti n g 
fr e q u e n c y,  will  b e  d o c u m e nt e d i n t h e I D M C  C h art er  a n d r atifi e d  b y t h e I D M C  b ef or e st u d y 
i niti ati o n. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3. 6. 2   
St e e ri n g  C o m mitt e e  
T h e  St e eri n g  C o m mitt e e,  c o nsisti n g  of s el e ct e d  c oll a b or ati n g  I n v esti g at ors,  will  o nl y  h a v e 
a c c ess t o  bli n d e d st u d y  d at a  a n d  will  b e r es p o nsi bl e f or t h e f oll o wi n g  a cti viti es: 
1.   Pr o vi di n g  g ui d a n c e t o t h e  S p o ns or  wit h r es p e ct t o st u d y  d esi g n, sit e s el e cti o n  a n d fi n al  d at a 
a n al ysis,  a n d  p u bli c ati o n  
2.   Pr o vi di n g  o v ersi g ht  of st u d y  c o n d u ct i n cl u di n g,  b ut  n ot li mit e d t o , t h e f oll o wi n g: 
•   M o nit ori n g  a d h er e n c e t o  pr ot o c ol  –  c o m pli a n c e, r et e nti o n,  a n d  pr ot o c ol  vi ol ati o ns 
•   I n d e p e n d e nt  bli n d e d  ass ess m e nt  of  A E SIs (S e cti o n  9. 6. 2 );  g ui d a n c e  o n  m a n a g e m e nt  of 
A E SIs,  a n d  a d mi nistr ati o n  or  dis c o nti n u ati o n  of I P i n  c o ns ult ati o n  wit h t h e  S p o ns or 
M e di c al  M o nit or  a n d t h e I n v esti g at or 
St e eri n g  C o m mitt e e  o p er ati o n  d et ails ( e g, s c o p e,  c o m p ositi o n,  o p er ati n g  pr o c e d ur e s, a n d  
m e eti n g fr e q u e n c y)  will  b e  d o c u m e nt e d i n t h e  St e eri n g  C o m mitt e e  C h art er  a n d r atifi e d  b y t h e 
St e eri n g  C o m mitt e e  b ef or e st u d y i niti ati o n.  
3. 7   St o p pi n g  C rit e ri a  
3. 7. 1   
St u d y  St o p pi n g  C rit e ri a  
T h e  o n g oi n g  m o nit ori n g  of  all tr e at m e nt- e m er g e nt  A Es i n cl u di n g  s eri o us  a d v ers e  e v e nts 
( S A Es)  a n d  A E SIs  as  d efi n e d i n t h e  pr ot o c ol is  p erf or m e d  b y t h e I D M C.  T h e I D M C 
( u n bli n d e d)  will  us e t h e f oll o wi n g st o p pi n g  crit eri a t o  g ui d e r e c o m m e n d ati o ns t o  c o nti n u e, 
m o dif y,  or  dis c o nti n u e t h e st u d y: 
1.   O n e  or  m or e s u bj e cts  w h o r e c ei v e  C S L 3 4 6  d e v el o p  a tr e at m e nt -e m er g e nt  S A E  attri b ut e d t o 
C S L 3 4 6 t h at is lif e -t hr e at e ni n g  or r es ults i n  d e at h 
2.   T w o  or  m or e s u bj e cts ( at l e ast  o n e  of  w hi c h is r a n d o mi z e d t o t h e  8  m g/ k g  d os e l e v el) 
e x p eri e n c e  a n y tr e at m e nt - e m er g e nt  A E SI r e q uiri n g  p er m a n e nt  dis c o nti n u ati o n  of st u d y 
tr e at m e nt ( “s e v er e ”) t h at  ar e  attri b ut e d t o  C S L 3 4 6 i n cl u di n g:  
•   A n y tr e at m e nt - e m er g e nt  A E SI r e q uiri n g  p er m a n e nt  dis c o nti n u ati o n  of st u d y tr e at m e nt 
( “s e v er e ”), i n cl u di n g i n cr e as es i n  S Cr,  A C R,  or  B P,  attri b ut a bl e t o  C S L 3 4 6,  O R  
•   E vi d e n c e  of  c ar di a c t o xi cit y ( S A E  or  m e eti n g tr o p o ni n- I st o p pi n g  crit eri a; s e e S e cti o n 
9. 1. 3. 5 )  O R 
•   A s e v er e i nj e cti o n sit e r e a cti o n  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
3.   O n e  or  m or e  s u bj e cts  e x p eri e n c e  a tr e at m e nt -e m er g e nt  S A E  of  a c ut e  h e p ati c i nj ur y t h at is 
attri b ut e d t o  C S L 3 4 6  a n d  m e ets t h e  d efi niti o n  of  H y’s l a w: 
•   El e v ati o n i n  al a ni n e tr a ns a mi n as e  >  3 x t h e  u p p er li mit  of  n or m al ( U L N)  a n d  
•   A  c o n c o mit a nt  el e v ati o n i n t ot al  bilir u bi n  >   2 x  U L N  a n d 
•   A bs e n c e  of  ot h er  c a us es s u c h  as  vir al  h e p atitis,  bil e  d u ct  dis e as e,  al c o h ol  a b us e, 
is c h e mi a,  pr e e xisti n g li v er  dis e as e,  or  a n ot h er  dr u g  c a p a bl e  of  c a usi n g t h e  o bs er v e d 
i nj ur y 
4.   T w o  or  m or e s u bj e cts  e x p eri e n c e  a tr e at m e nt - e m er g e nt  S A E  of  dr u g  h y p ers e nsiti vit y 
r e a cti o n 
Crit eri a f or st o p pi n g I P  d osi n g r el at e d t o  A E SIs  ar e  d es cri b e d i n  S e cti o n  9. 1. 3 . 
3. 7. 2   
D os e  L e v el  St o p pi n g  C rit e ri a  
T h e I D M C ( u n bli n d e d)  m a y r e c o m m e n d  dis c o nti n ui n g t h e  1 6  m g/ k g  C S L 3 4 6  d os e l e v el if  2  or 
m or e s u bj e cts   a d mi nist er e d  1 6  m g/ k g  C S L 3 4 6 h a v e  a n y tr e at m e nt -e m er g e nt  A E SI r e q uiri n g 
p er m a n e nt  dis c o nti n u ati o n  of st u d y tr e at m e nt ( “s e v er e ”), t h at  ar e  attri b ut e d t o  C S L 3 4 6 
i n cl u di n g t h e f oll o wi n g: 
1.    I n cr e as es i n  S Cr,  A C R,  or  B P 
2.   E vi d e n c e  of  c ar di a c t o xi cit y ( S A E  or  m e eti n g tr o p o ni n- I st o p pi n g  crit eri a; s e e 
S e cti o n  9. 1. 3. 5 )  
3.   A  s e v er e i nj e cti o n sit e r e a cti o n  
If r a n d o mi z ati o n t o t h e  1 6  m g/ k g  C S L 3 4 6  d os e l e v el is  dis c o nti n u e d, r a n d o mi z ati o n  of s u bj e cts 
will  b e li mit e d t o t h e  8  m g/ k g  C S L 3 4 6  d os e l e v el  or  pl a c e b o.  T h e I D M C  will  pr o vi d e  g ui d a n c e 
f or  o n g oi n g s u bj e cts i n t h e  1 6  m g/ k g  C S L 3 4 6 tr e at m e nt  ar m.  
4   
S el e cti o n  a n d  Wit h d r a w al  of  S u bj e cts  
4. 1   Eli gi bilit y  C rit e ri a  
T h e st u d y  p o p ul ati o n  will  b e s el e ct e d  b as e d  o n i n cl usi o n  a n d  e x cl usi o n  crit eri a  d es cri b e d 
b el o w.  E a c h s u bj e ct s h o ul d  m e et  all  of t h e i n cl usi o n  crit eri a  a n d  n o n e  of t h e  e x cl usi o n  crit eri a 
f or t his st u d y.  S u bj e ct  eli gi bilit y s h o ul d  b e r e vi e w e d  a n d  d o c u m e nt e d  b y  a n  a p pr o pri at el y 
m e di c all y  q u alifi e d  m e m b er  of t h e  I n v esti g at or’s st u d y t e a m  b ef or e s u bj e cts  ar e i n cl u d e d i n t h e 
st u d y. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
4. 1. 1   
I n cl usi o n  C rit e ri a 
T o  b e  e nr oll e d i nt o t h e  st u d y, s u bj e cts  m ust  m e et  all  of t h e f oll o wi n g i n cl usi o n  crit eri a:  
1.   C a p a bl e  of  pr o vi di n g  writt e n i nf or m e d  c o ns e nt  a n d  willi n g  a n d  a bl e t o  a d h er e t o  all 
pr ot o c ol r e q uir e m e nts.  
2.   M al e  a n d f e m al e s u bj e cts  ≥  2 5  y e ars  of  a g e  at t h e ti m e  of si g ni n g t h e I C F. 
3.   C urr e n t  di a g n osis  of  T 2 D M. 
4.   Uri n ar y  A C R  ≥  1 5 0  m g/ g ( 1 6. 9 5  m g/ m m ol) fr o m  a  2 4- h o ur ti m e d  uri n e  c oll e cti o n.  
5.   R e n al f u n cti o n:  e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2  b as e d  o n  c e ntr al l a b or at or y  ass ess m e nt  usi n g 
t h e  C hr o ni c  Ki d n e y  Dis e as e  E pi d e mi ol o g y  C oll a b or ati o n ( C K D-E PI) f or m ul a . 
•   Wit h  a p pr o v al  of t h e I D M C, f oll o wi n g r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first 
1 8 s u bj e cts  wit h  pr es er v e d r e n al f u n cti o n, s u bj e cts  wit h  e G F R  ≥  4 5  m L/ mi n/ 1. 7 3 m 2 c a n 
b e  e nr oll e d . 
•   S u bs e q u e ntl y,  aft er  a n I D M C r e vi e w  of s af et y  a n d  P K  d at a fr o m t h e first  3 6  s u bj e cts 
( at l e ast  8  wit h  e G F R  ≥  4 5 t o  <  6 0  m L/ mi n/ 1. 7 3 m2) f oll o w e d f or  at l e ast  4 w e e ks, 
i n cl usi o n  of s u bj e cts  wit h  e G F R  >  2 0 t o  <  4 5  m L/ mi n/ 1. 7 3 m2 will  b e  p er mitt e d if 
a p pr o v e d  b y t h e I D M C.  
If i n cl usi o n  of s u bj e cts  wit h  e G F R  b el o w  6 0  m L/ mi n/ 1. 7 3 m2 is  e nd ors e d  b y t h e 
I D M C, t h e f oll o wi n g t ar g et s a m pl e si z e(s)  will  b e  est a blis h e d f or s u bj e cts  wit h  e G F R 
i n t h e s p e cifi e d r a n g e: 
o   At l e ast  3 6 s u bj e cts  wit h  e G F R  <  6 0  m L/ mi n/ 1. 7 3 m 2 
o   At l e ast  1 8 s u bj e cts  wit h  e G F R  <  4 5  m L/ mi n/ 1. 7 3 m 2  
T o  a c hi e v e t h es e  t ar g et e d  mi ni m ums,  a r estri cti o n  m a y  b e i m p os e d  o n t h e  e nr oll m e nt 
of s u bj e cts  wit h  e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2 a n d  /  or  ≥  4 5  m L/ mi n/ 1. 7 3 m2.  
6.   Gl y c os yl at e d  H b A 1 c  <  1 2 %.  
7.   S u bj e cts  m ust  h a v e  b e e n t a ki n g st a bl e  d os es  of  a n gi ot e nsi n- c o n v erti n g  e n z y m e i n hi bit or 
( A C Ei)  or  a n gi ot e nsi n II r e c e pt or  bl o c k er ( A R B) t h er a p y f or  at l e ast  8  w e e ks  b ef or e 
S cr e e ni n g.  S u bj e cts  wit h  d o c u m e nt e d i nt ol er a n c e t o tr e at m e nt  wit h  A C Ei  a n d  A R B  c a n  b e 
e nr oll e d.  
•   S u bj e cts t a ki n g  a nti h y p ert e nsi v e  m e di c ati o n(s)  m ust  h a v e  b e e n t a ki n g st a bl e  d os es f or 
at l e ast  8  w e e ks  b ef or e  S cr e e ni n g  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
8.   If t h e s u bj e ct t a k es  S G L T 2 i n hi bit ors,  d os e  m ust  b e st a bl e f or  at l e ast  4  w e e ks  b ef or e 
S cr e e ni n g.  
•   E v er y  eff ort  will  b e  m a d e t o  e ns ur e t h at  at l e ast  5 0 %  of  r a n d o mi z e d s u bj e cts  ar e 
r e c ei vi n g  c o n c o mit a nt tr e at m e nt  wit h  a n  S G L T 2 i n hi bit or 
9.   F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al ( F C B P)  a n d  m al e s u bj e cts  wit h  a f e m al e  p art n er 
of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  a   hi g hl y  eff e cti v e f or m  of  birt h  c o ntr ol i n 
a d diti o n t o  a  b arri er  m et h o d  of  c o ntr a c e pti o n (i e,  m al e  or f e m al e  c o n d o m  wit h  or  wit h o ut 
s p er mi ci d e  a n d  wit h o ut f at-  or  oil- c o nt ai ni n g l u bri c a nts) st arti n g  at  S cr e e ni n g  a n d t hr o u g h 
9 0  d a ys  aft er l ast I P  a d mi nistr ati o n  u nl ess: 
•   M al e s u bj e ct  h as  u n d er g o n e  ef f e cti v e s ur gi c al st erili z ati o n  at l e ast  3  m o nt hs  b ef or e 
e nt eri n g t h e st u d y 
•   T h e f e m al e s e x u al  p art n er(s)  of  m al e s u bj e ct  h as  u n d er g o n e  eff e cti v e s ur gi c al 
st erili z ati o n  at l e ast  3  m o nt hs  b ef or e t h e s u bj e ct  e nt ers t h e st u d y  or is ( ar e)  p ost -
m e n o p a us al 
A c c e pt a bl e  hi g hl y  eff e cti v e f or ms  of  c o ntr a c e pti o n  a n d t h e  d efi niti o n  of  F C B P  ar e  d es cri b e d i n 
S e cti o n  7. 4 . 
1 0.  I n v esti g at or  b eli e v es t h at t h e s u bj e ct  u n d erst a n ds t h e  n at ur e, s c o p e  a n d  p ossi bl e 
c o ns e q u e n c es  of t h e st u d y.  
4. 1. 2   
E x cl usi o n  C rit e ri a  
S u bj e cts  m ust  n ot  b e  e nr oll e d i nt o t h e st u d y if t h e y  m e et  a n y  of t h e f oll o wi n g  e x cl usi o n 
crit eri a:  
1.   C urr e nt  di a g n osis  of  t y p e  1  di a b et es  m ellit us. 
2.   K n o w n  m e di c al  hist or y  or  cli ni c al  e vi d e n c e s u g g esti n g  n o n- di a b eti c r e n al  dis e as e , e x c e pt 
f or  c o n c o mit a nt  h y p ert e nsi v e  n e p hr os cl er osis  or  a si n gl e  ki d n e y. 
3.   Hist or y  of  a c ut e  ki d n e y i nj ur y ( A KI)  wit hi n  1  y e ar  b ef or e  S cr e e ni n g  a n d  c h a n g e i n  S Cr 
fr o m  Visit  1 t o  Visit  2 ( D a y  – 2 1)  >  0. 3  m g/ d L ( 2 6. 5  µ m ol/ L)  b y  c e ntr al l a b or at or y 
ass ess m e nt.  
4.   Hist or y  of  c hr o ni c  di al ysis  or r e n al tr a ns pl a nt;  a cti v e  o n  a  ki d n e y tr a ns pl a nt  w aiti n g list 
( a w aiti n g tr a ns pl a nt)  wit h  a li vi n g  d o n or i d e ntifi e d,  or  a nti ci p at e d tr a ns pl a nt  wit hi n 
6  m o nt hs f oll o wi n g r a n d o mi z ati o n i n t h e st u d y. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
5.   R e q uir e m e nt f or  c o n c o mit a nt tr e at m e nt  wit h  a n y  pr o hi bit e d  c o n c o mit a nt  m e di c ati o n,  as 
i n di c at e d i n S e cti o n  7. 3 . 
6.   U n c o ntr oll e d  h y p ert e nsi o n  d efi n e d  as:  S B P  >  1 6 0  m m H g  or  D B P  >  1 0 0  m m H g.  S e e  als o 
R a n d o mi z ati o n  Crit eri a ( S e cti o n  4. 1. 3 ). 
7.   N e w  Yor k  H e art  Ass o ci ati o n  h e art f ail ur e  Cl ass III  or I V  wit hi n  1  y e ar  b ef or e  S cr e e ni n g. 
8.   M y o c ar di al i nf ar cti o n,  u nst a bl e  a n gi n a, r e v as c ul ari z ati o n  pr o c e d ur e ( e g, st e nt  or  b y p ass 
gr aft s ur g er y),  c er e br o v as c ul ar  a c ci d e nt , tr a nsi e nt is c h e mi c  att a c k,  or  n e w  cli ni c all y 
i m p ort a nt  el e ctr o c ar di o gr a m ( E C G) fi n di n gs  wit hi n  6  m o nt hs  b ef or e  S cr e e ni n g,  or  a 
r e v as c ul ari z ati o n  pr o c e d ur e is  pl a n n e d  d uri n g t h e st u d y. 
9.   L eft  v e ntri c ul ar  ej e cti o n fr a cti o n ( L V E F)  <  5 0 %  b y  e c h o c ar di o gr a m ( E C H O).   
A n  E C H O  p erf or m e d f or  n o n-st u d y-r el at e d r e as o ns  wit hi n  3  m o nt hs  b ef or e  S cr e e ni n g  c a n 
b e  us e d t o s atisf y t his  crit eri o n. 
1 0.  Tr o p o ni n- I l e v els  >  u p p er r ef er e n c e li mit ( U R L).  S e e  als o  R a n d o mi z ati o n  Crit eri a 
(S e cti o n  4. 1. 3 ). 
1 1.  B-t y p e  n atri ur eti c  p e pti d e ( B N P)  >  2 0 0  p g/ m L. 
1 2.  Al a ni n e tr a ns a mi n as e  >  2 x t h e  U L N.  
1 3.  S u bj e ct is  u n a bl e t o t ol er at e  S C t est i nf usi o n.  
1 4.  Pr e g n a nt,  br e astf e e di n g,  or  n ot  willi n g t o  c e as e  br e astf e e di n g. 
1 5.  Hist or y  of  c a n c er  wit hi n  5  y e ars  b ef or e  S cr e e ni n g,  wit h t h e f oll o wi n g  e x c e pti o ns: 
•   B as al  c ell  c ar ci n o m a  of t h e s ki n  
•   S q u a m o us  c ell  c ar ci n o m a  of t h e s ki n 
•   C ar ci n o m a i n -sit u  of t h e  c er vi x 
•   C ar ci n o m a i n -sit u  of t h e  br e ast 
•   I n ci d e nt al  hist ol o gi c fi n di n g  of  pr ost at e  c a n c er ( St a g e  T 1 a  or  T 1 b  usi n g  T N M  cli ni c al 
st a gi n g) 
1 6.  P ositi v e  vir al t est r es ult f or  h e p atitis  B  vir us ( H B V) ( A p p e n di x  2 ),  h e p atitis  C  vir us,  or 
h u m a n i m m u n o d efi ci e n c y  vir us - 1 / - 2  at  S cr e e ni n g. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  4 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 7.  A n y  cli ni c all y si g nifi c a nt  a b n or m aliti es i n  cli ni c al  c h e mistr y,  h e m at ol o g y (i n cl u di n g 
c o a g ul ati o n)  or  uri n al ysis r es ults t h at  w o ul d  m a k e t h e s u bj e ct  u ns uit a bl e t o  p arti ci p at e i n 
t h e  pr o c e d ur es  or i nt er v e nti o n  of t h e st u d y,  as j u d g e d  b y t h e I n v esti g at or. 
1 8.  P a rti ci p at e d i n  a n ot h er i nt er v e nti o n al  cli ni c al st u d y  wit hi n  1 2  w e e ks  b ef or e  S cr e e ni n g. 
1 9.  Pr e vi o usl y r a n d o mi z e d i n t h e  c urr e nt st u d y. 
2 0.  K n o w n  or s us p e ct e d  h y p ers e nsiti vit y t o  C S L 3 4 6  or t o  a n y  of its  e x ci pi e nts. 
2 1.  A n y  ot h er  c o n diti o n t h at r e n d ers t h e s u bj e ct  u n willi n g,  u n a bl e,  or  u nli k el y t o  c o m pl y  wit h 
t h e r e q uir e m e nts  of t h e st u d y,  as j u d g e d  b y t h e I n v esti g at or. 
2 2.  I n v ol v e d i n t h e  pl a n ni n g  a n d /  or  c o n d u ct  of t h e st u d y ( a p pli es t o  C S L st aff, st aff  at t h e 
st u d y sit e,  a n d t hir d- p art y  v e n d ors). 
4. 1. 3   
R a n d o mi z ati o n  C rit e ri a  
T o   b e r a n d o mi z e d i nt o t h e st u d y, s u bj e cts  m ust  m e et t h e f oll o wi n g  R a n d o mi z ati o n  Crit eri a  at 
Visit  3 ( D a y  – 7)  a n d  Visit  4 ( D a y  1): 
1.   S B P  ≤   1 5 0  m m H g  a n d  D B P  ≤  1 0 0  m m H g  at  Visit  3 ( D a y  – 7)  a n d  Visit  4 ( D a y  1). If t h e 
s u bj e ct’s  B P  at  Visit  3 ( D a y  – 7)  or  Visit  4 ( D a y  1)  d o es  n ot s atisf y t his  crit eri o n, 
r a n d o mi z ati o n / tr e at m e nt s h o ul d  b e  d el a y e d  a n d  F M V  uri n e s a m pl es  dis c ar d e d.  T h e 
I n v esti g at or s h o ul d  e ns ur e t h e s u bj e ct is  c o m pli a nt  wit h  c o n c o mit a nt  a nti h y p ert e nsi v e 
m e di c ati o ns  a n d  c a n r e p e at t his  B P  e v al u ati o n  wit h i n  3 t o  1 0  d a ys  of t h e f ail e d  crit eri o n. 
T h e s u bj e ct  will  b e i nstr u ct e d t o  c oll e ct  3  a d diti o n al  F M V  uri n e s a m pl es.   
•   If  a s u bj e ct s atisfi es t h e  B P  crit eri o n  at t h e r es c h e d ul e d  visit, t h e s u bj e ct  c a n  b e 
r a n d o mi z e d.  
•   If  a s u bj e ct f ails t o s atisf y t h e  B P  crit eri o n  at t h e r es c h e d ul e d  visit, t h e s u bj e ct  will  b e 
c o nsi d er e d  a  L e a d -i n f ail ur e ( dis c o nti n u e d fr o m st u d y)  a n d  will  n ot  b e r e-s cr e e n e d   
•   If  a s u bj e ct f ails t o s atisf y t h e  B P  crit eri o n  at  a n y  2  visits (i n cl u di n g  Visit  3,  Visit  4,  a n d 
t h e r es c h e d ul e d  visit), th e s u bj e ct  will  als o  b e  c o nsi d er e d  a  L e a d -i n f ail ur e 
( dis c o nti n u e d fr o m st u d y)  a n d  will  n ot  b e r e-s cr e e n e d 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
2.   C h a n g e i n  S Cr fr o m  Visit  2 ( D a y  – 2 1) t o  Visit  3 ( D a y  – 7)  ≤  0. 3  m g/ d L ( 2 6. 5  µ m ol/ L)  b y 
c e ntr al l a b  ass ess m e nt.  S u bj e cts  w h o  d o  n ot s atisf y t his  crit er i o n  m a y  h a v e  1 r e p e at  S Cr t est 
p erf or m e d  at  a n  u ns c h e d ul e d  visit  wit hi n  1  w e e k  aft er  Visit  3 ( D a y  – 7); f or t h es e s u bj e cts, 
t h e r a n d o mi z ati o n  crit eri o n  will  b e  e v al u at e d  b as e d  o n  c h a n g e i n  S Cr fr o m  Visit  3 ( D a y  –7) 
t o t h e  u ns c h e d ul e d  visit ( ≤  0. 3  m g/ d L  c h a n g e  b y  c e ntr al l a b  ass ess m e nt).  S u bj e cts  w h o 
q u alif y  m ust r et ur n f or r a n d o mi z ati o n ( Visit  4 /  D a y  1)  wit hi n  1  w e e k  aft er t h e  u ns c h e d ul e d 
visit.  S u bj e cts  w h o  d o  n ot  q u alif y  will  b e  c o nsi d er e d  a  L e a d-i n f ail ur e ( dis c o nti n u e d fr o m 
t h e st u d y)  a n d  will  n ot  b e r e-s cr e e n e d.  
3.     Tr o p o ni n-I l e v els  ≤  U R L  at  Visit  3 ( D a y  –7).  
4. 2   S c r e e n  F ail u r es  a n d  R e -s c r e e ni n g 
S cr e e n f ail ur es  ar e  d efi n e d  as i n di vi d u als  w h o  c o ns e nt t o  p arti ci p at e i n t h e st u d y  b ut  w h o  d o 
n ot  m e et t h e  eli gi bilit y  crit eri a f or  p arti ci p ati o n i n t h e st u d y (s e e  S e cti o n  4. 1 ). A  mi ni m al s et  of 
i nf or m ati o n i n cl u di n g  d e m o gr a p h y,  eli gi bilit y  crit eri a, s cr e e n f ail ur e  d et ails,  a n d  a n y  S A E 
s h o ul d  b e r e c or d e d  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) f or  all i n di vi d u als  c o nsi d er e d 
s cr e e n f ail ur es.  
R e -s cr ee ni n g  of s cr e e n f ail ur e s u bj e cts is  p er mitt e d  o n c e  aft er  a  mi ni m u m  2 - m o nt h i nt er v al 
b et w e e n s cr e e n f ail ur e  a n d r e -s cr e e ni n g (si g ni n g i nf or m e d  c o ns e nt  d o c u m e nt[s] f or t h e 
r e-s cr e e ni n g  p eri o d).  D uri n g r e-s cr e e ni n g, t h e s u bj e ct  m ust  h a v e  all s cr e e ni n g  pr o c e d ur es  a n d 
ass ess m e nts r e p e at e d t o  d e m o nstr at e  eli gi bilit y f or t h e st u d y.  All  d at a, i n cl u di n g  c o n c o mit a nt 
m e di c ati o ns,  m e di c al  hist or y,  a n d  A E  d at a  m ust  b e  u p d at e d f or  d o c u m e nt ati o n  of r e-s cr e e ni n g. 
4. 3   Dis c o nti n u ati o n  of  St u d y  Tr e at m e nt  a n d /  o r  S u bj e ct  Wit h d r a w al  
4. 3. 1   
R e as o ns f o r  Dis c o nti n u ati o n  of  St u d y  Tr e at m e nt  a n d /  o r  S u bj e ct 
Wit h d r a w al  
S u bj e cts  m a y  dis c o nti n u e I P  or  wit h dr a w fr o m t h e st u d y  at  a n y ti m e  at t h eir  o w n r e q u est,  or  at 
t h e  dis cr eti o n  of t h e I n v esti g at or  or  C S L f or s af et y,  b e h a vi or al,  or  a d mi nistr ati v e r e as o ns 
( e g,  b e c a us e  of  a n  A E,  pr ot o c ol  d e vi ati o n, l oss t o f oll o w- u p, s u bj e ct  n o n c o m pli a n c e, st u d y 
t er mi n ati o n).  
I n  a c c or d a n c e  wit h t h e I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n  of  Te c h ni c al  R e q uir e m e nts f or 
P h ar m a c e uti c als f or  H u m a n  Us e (I C H)  pri n ci pl es  o f  G o o d  Cli ni c al  Pr a cti c e ( G C P), t h e 
I n v esti g at or  al w a ys  h as t h e  o pti o n t o  a d vis e  a s u bj e ct t o  wit h dr a w fr o m t h e st u d y if t h e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
s u bj e ct's s af et y  or  w ell b ei n g is  c o m pr o mis e d  b y  his  or  h er f urt h er  p arti ci p ati o n i n t h e st u d y. 
C o n c er n f or t h e i nt er ests  of t h e s u bj e ct  m ust  al w a ys  pr e v ail  o v er t h e i nt er ests  of t h e st u d y.  
T h e  I n v esti g at or s h o ul d  c o ns ult  wit h t h e  M e di c al  M o nit or  b ef or e  wit h dr a wi n g s u bj e cts  or 
dis c o nti n ui n g I P, t h e n r e c or d t h e r e as o n  a n d  d at e  of s u bj e ct  wit h dr a w al  or  dis c o nti n u ati o n  of I P 
i n t h e e C R F  a n d i n t h e s u bj e ct's  m e di c al r e c or ds.  
R ef er t o   S e cti o n 4. 3. 2  for  d et ails  o n  h a n dli n g s u bj e ct  wit h dr a w als. 
4. 3. 2   
P r o c e d u r es f o r  H a n dli n g  Wit h d r a w als  
If a s u bj e ct is  wit h dr a w n fr o m t h e st u d y,  att e m pts  will  b e  m a d e t o  c o m pl et e  a n d  d o c u m e nt 
F oll o w- u p  Visits ( Visit  1 0  a n d  E O S). If t h e s u bj e ct is  u n willi n g  or  u n a bl e t o r et ur n f or 
F oll o w- u p  V isits, t h e sit e s h o ul d  att e m pt t o  c oll e ct  A E i nf or m ati o n  b y t el e p h o n e at  4  a n d 
1 2  w e e ks  aft er t h e l ast  d os e  of I P.  
If t h e s u bj e ct is  wit h dr a w n fr o m t h e st u d y  aft er r e c ei vi n g I P,  e v er y  eff ort  will  b e  m a d e t o 
e ns ur e t h at t h e r el e v a nt s af et y  ass ess m e nts  ar e  c o m pl et e d.  T h e s u bj e ct  m a y  als o  b e  as k e d  b y 
t h e I n v esti g at or t o  c o m pl et e  ot h er st u d y  ass ess m e nts.  
If t h e s u bj e ct  wit h dr a ws fr o m t h e st u d y  a n d  als o  wit h dr a ws  c o ns e nt f or  dis cl os ur e  of f ut ur e 
i nf or m ati o n,  C S L  m a y r et ai n  a n d  c o nti n u e t o  us e  a n y  d at a  c oll e ct e d  b ef or e s u c h  wit h dr a w al  of 
c o ns e nt. 
4. 3. 3   
S u bj e cts  L ost t o  F oll o w -u p  
If  a s ubj e ct r e p e at e dl y f ails t o r et ur n f or s c h e d ul e d  visits, t h e sit e  m ust  m a k e  3  att e m pts t o 
c o nt a ct t h e s u bj e ct  a n d  c o u ns el t h e s u bj e ct  o n t h e i m p ort a n c e  of  m ai nt ai ni n g t h e  assi g n e d  visit 
s c h e d ul e  a n d  as c ert ai n  w h et h er  or  n ot t h e s u bj e ct  wis h es t o  a n d /  or s h o ul d  c o nti n u e i n t h e 
st u d y.  All  att e m pts t o  c o nt a ct t h e s u bj e ct s h o ul d  b e  d o c u m e nt e d i n t h e s u bj e ct’s  m e di c al r e c or d. 
A s u bj e ct  will  b e  c o nsi d er e d l ost t o f oll o w- u p if  h e  or s h e r e p e at e dl y f ails t o r et ur n f or 
s c h e d ul e d  visits  a n d is  u n a bl e t o  b e  c o nt a ct e d  b y t h e st u d y sit e.  S u bj e cts l ost t o f oll o w- u p  will 
b e  c o nsi d er e d t o  h a v e  wit h dr a w n fr o m t h e st u d y. 
4. 3. 4   
R e pl a c e m e nt  P oli c y  
S u bj e cts  wit h dr a w n fr o m t h e st u d y  aft er r a n d o mi z ati o n  will  n ot  b e r e pl a c e d  o n  a n i n di vi d u al 
s u bj e ct l e v el.  H o w e v er, t h e  a ct u al  e arl y  dis c o n ti n u ati o n r at e  will  b e  ass ess e d t hr o u g h o ut t h e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
st u d y  a n d  u p t o  1 2 4 s u bj e cts  m a y  b e r a n d o mi z e d, if  n e c ess ar y, t o t ar g et  9 4  c o m pl et e d s u bj e cts 
(s u bj e cts  w h o r e c ei v e d  all  d os es  a n d  c o m pl et e d t h e  We e k  1 6  A C R  ass ess m e nt). 
5   
St u d y I nt e r v e nti o ns  
5. 1   I n v esti g ati o n al  P r o d u ct  
5. 1. 1   
C S L 3 4 6   
C S L 3 4 6  will  b e  m a n uf a ct ur e d  b y  C S L  Li mit e d,  A ustr ali a i n  a c c or d a n c e  wit h I C H  G o o d 
M a n uf a ct uri n g  Pr a cti c e  g ui d eli n es  a n d l o c al r e g ul at or y r e q uir e m e nts.  
C S L 3 4 6 is  a st eril e s ol uti o n f or I V  a n d  S C i nf usi o n  at  a  c o n c e ntr ati o n  of  1 0 0  m g/ m L i n 
si n gl e-us e,  T y p e I,  2 -m L  gl ass  vi als. It  a p p e ars  as  a n  o p al es c e nt t o  cl e ar,  y ell o w t o  c ol orl ess 
li q ui d  wit h  n o  visi bl e  p arti cl es. 
All  d os es  will  b e  n or m ali z e d t o  a st a n d ar d  v ol u m e  wit h  n or m al s ali n e t o  m ai nt ai n  bli n di n g.  
T a bl e  3 
C S L 3 4 6  C h a r a ct e risti cs  
S u bst a n c e  N a m e   
C S L 3 4 6  
A cti v e  S u bst a n c e   
A nti -V E G F -B  h u m a ni z e d I g G  m o n o cl o n al  a nti b o d y  
Tr a d e  N a m e  
N ot  a p pli c a bl e  
St o r a g e  
+ 2 t o  + 8˚ C  
D os a g e  F o r m  
st eril e s ol uti o n f or i nj e cti o n  c o nt ai ni n g  1 0 0  m g/ m L  of  C S L 3 4 6  i n  a  2  m L  vi al 
I g G  = i m m u n o gl o b uli n  G;  V E G F  =  v as c ul ar  e n d ot h eli al  gr o wt h f a ct or. 
5. 1. 2   
Pl a c e b o  
T h e  pl a c e b o  c o m p ar at or is st eril e  n or m al s ali n e t h at is  c o m m er ci all y  a v ail a bl e  a n d  will  b e 
s u p pli e d  b y t h e st u d y sit e. 
T a bl e  4 
Pl a c e b o  C h a r a ct e risti cs  
S u bst a n c e  N a m e  
N ot  a p pli c a bl e  
S u bst a n c e  
N or m al s ali n e ( 0. 9 % s o di u m  c hl ori d e)  
Tr a d e  N a m e  
N ot  a p pli c a bl e   
St o r a g e  
P er  m a n uf a ct ur er’s i nstr u cti o ns  
D os a g e  F o r m  
St eril e s ol uti o n f or i nj e cti o n  
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
5. 1. 3   
D osi n g  a n d  A d mi nist r ati o n  of  C S L 3 4 6  o r  Pl a c e b o  
T h e  I n v esti g at or ( or  d el e g at e)  will  a d mi nist er I P  at t h e st u d y sit e  o nl y t o s u bj e cts i n cl u d e d i n 
t his st u d y f oll o wi n g t h e  pr o c e d ur es s et  o ut i n t his st u d y  pr ot o c ol. I nf or m ati o n  o n t h e  d osi n g 
c h ar a ct eristi cs  of I P is  pr o vi d e d i n  Ta bl e  5 . 
T a bl e  5 
I n v esti g ati o n al  P r o d u ct  D osi n g 
A d mi nist r ati o n 
P a r a m et e r  
C S L 3 4 6  
Pl a c e b o  
D os e  
3  m g/ k g I V  a n d  8  m g/ k g  S C  O R  
6  m g/ k g I V  a n d  1 6  m g/ k g  S C  
N ot  a p pli c a bl e  
 
D os e  R e gi m e n  
I niti al l o a di n g  d os e  of  C S L 3 4 6 
a d mi nist er e d I V, f oll o w e d  b y  S C i nf usi o n  
at l e ast  2  h o urs  b ut  n o  m or e t h a n  6  h o urs 
l at er, t h e n  e v er y  4 w e e ks, f or  a t ot al  of 
4  S C  d os es  
M at c h e d t o  C S L 3 4 6  
M o d e  of  A d mi nist r ati o n   
I V;  S C 
M at c h e d t o  C S L 3 4 6  
A n at o mi c al  L o c ati o n  
I V  a c c ess i n t h e  ar m  a n d  S C i nf usi o n i n t h e 
a b d o m e n  
M at c h e d t o  C S L 3 4 6  
T o t al Inf usi o n  V ol u m e  
All  d os es  will  b e  n or m ali z e d t o  a st a n d ar d 
v ol u m e ( 1 0  m L f or I V  a n d  2 0  m L f or  S C) 
wit h  n or m al s ali n e t o  m ai nt ai n  bli n di n g 
( c al c ul at e d  b as e d  o n  w ei g ht) 
M at c h e d t o  C S L 3 4 6  
I nf usi o n  D u r ati o n a 
≥  2 0  mi n ut es f or I V  
≥  4 0  mi n ut es f or  S C   a 
M at c h e d t o  C S L 3 4 6  
I P  = in v esti g ati o n al  p r o d u ct; I V  = i ntr a v e n o us;  S C  = s u b c ut a n e o us. 
a 
I nf usi o n  d ur ati o n  c a n  b e  a dj ust e d f or t h e s e c o n d  a n d s u bs e q u e nt  S C i nf usi o ns  at t h e  dis cr eti o n  of t h e 
I n v esti g at or as  d es cri b e d i n t h e I M P  H a n dli n g  M a n u al.   
 
Bli n d e d I P  will  b e  pr e p ar e d  a n d  p h ysi c all y  bli n d e d  b y t h e  u n bli n d e d  p h ar m a cist  at t h e sit e,  a n d 
wi ll  b e  d eli v er e d t o  bli n d e d st u d y st aff f or  a d mi nistr ati o n t o t h e s u bj e ct (S e cti o n  6. 3. 1 ). 
D et ail e d i nf or m ati o n  o n t h e  pr e p ar ati o n  a n d  a d mi nistr ati o n  o f I P is  pr o vi d e d i n t h e 
I n v esti g ati o n al  M e di ci n al  Pr o d u ct (I M P)  H a n dli n g  M a n u al.  
5. 1. 3. 1   
A d mi nist r ati o n  a n d  D os e  A dj ust m e nt  
S u bj e cts  e x p eri e n ci n g  a  mil d i nj e cti o n sit e r e a cti o n  d e e m e d  u n a c c e pt a bl e  b y t h e s u bj e ct  or 
I n v esti g at or  m a y  h a v e  a d mi nistr ati o n  a n d /  or  d os e  a dj ust m e nts (s e e  S e cti o n  9. 1. 3. 1 ).  
D et ail e d i nf or m ati o n  o n t h e  pr e p ar ati o n  a n d  a d mi nistr ati o n  of I P  wit h  a dj ust e d  v ol u m es  a n d 
d os es is  pr o vi d e d i n t h e I M P  H a n dli n g  M a n u al.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
5. 1. 3. 2   
Tr e at m e nt  C o m pli a n c e  
All  d os es  of I P  will  b e  a d mi nist er e d  b y I V  or  S C i nf usi o n  at t h e st u d y sit e.  S u bj e cts  will  b e 
c o nsi d er e d t o  h a v e r e c ei v e d  a  c o m pl et e  d os e  of I P if t h e y r e c ei v e  at l e ast  8 0 %  of I P.  
5. 1. 3. 3   
O v e r d os e  
O v er d os e is  d efi n e d  as t h e i nf usi o n  or i n g esti o n  of  a n y  d os e (si n gl e  or  c u m ul ati v e)  of I P t h at is 
≥  1 0 %  o v er t h e r e c o m m e n d e d  d os e.  T h e  eff e cts  of  a n y  p ot e nti al  o v er d os e  wit h  C S L 3 4 6  h a v e 
n ot  b e e n st u di e d. 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  c o nt a ct t h e  M e di c al  M o nit or, t h e 
s u bj e ct s h o ul d  b e  cl os el y  m o nit or e d,  a n d s u p p orti v e tr e at m e nt s h o ul d  b e  a d mi nist er e d,  as 
n e e d e d.  
S e e  S e cti o n  9. 6. 5  f or  o v er d os e r e p orti n g r e q uir e m e nts. 
5. 1. 4   
P a c k a gi n g,  L a b eli n g,  S u p pl y  a n d  St o r a g e  
5. 1. 4. 1   
P a c k a gi n g  a n d  L a b eli n g  
C S L 3 4 6  will  b e  p a c k a g e d  a n d l a b el e d  b y  C S L  or  d el e g at e  a c c or di n g t o  c urr e nt I C H  G o o d 
M a n uf a ct uri n g  Pr a cti c e  a n d  G C P  g ui d eli n es  a n d  n ati o n al l e g al r e q uir e m e nts.  S p e cifi c  d et ails 
r e g ar di n g  p a c k a gi n g  of  C S L 3 4 6  ar e  pr o vi d e d i n t h e I M P  H a n dli n g  M a n u al. 
5. 1. 4. 2   
S u p pl y  a n d  St o r a g e  
C S L 3 4 6  will  b e s u p pli e d t o t h e st u d y sit es  b y  C S L  or  d el e g at e.  Pl a c e b o is  c o m m er ci all y 
a v ail a bl e  n or m al s ali n e  a n d  will  b e s u p pli e d  b y t h e st u d y sit e. 
At t h e st u d y sit e,  C S L 3 4 6  m ust  b e st or e d  u n d er t e m p er at ur e- c o ntr oll e d  a n d  m o nit or e d 
c o n diti o ns fr o m  + 2 t o  + 8˚ C i n  a s e c ur e st or a g e  ar e a  as s p e cifi e d i n t h e I M P  H a n dli n g  M a n u al. 
5. 2   A c c o u nt a bilit y  a n d  D est r u cti o n  
T h e I P  m ust  b e  us e d  o nl y  as  dir e ct e d i n t h e  cli ni c al st u d y  pr ot o c ol. 
T h e  u n bli n d e d  p h ar m a cist  or  d el e g at e  will  c o nfir m r e c ei pt  of  all s hi p m e nts  of  C S L 3 4 6 i n t h e 
I R T s yst e m. 
All s u p pli es  of  C S L 3 4 6  m ust  b e  a c c o u nt e d f or t hr o u g h o ut t h e st u d y i n t h e I R T s yst e m. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
R e c or ds f or t h e  d eli v er y  of  C S L 3 4 6 t o t h e st u d y sit e, t h e i n v e nt or y  at t h e st u d y sit e, t h e  us e  b y 
e a c h s u bj e ct,  a n d t h e  d estr u cti o n  or r et ur n  of  C S L 3 4 6 t o  C S L /  d esi g n e e  m ust  b e  m ai nt ai n e d  b y 
t h e  u n bli n d e d  p h ar m a cist  or  d el e g at e  usi n g t h e I R T s yst e m. 
T h e  I n v esti g at or  d el e g at e ( e g,  u n bli n d e d  p h ar m a cist)  m ust  pr o vi d e r e as o ns f or  a n y 
dis cr e p a n ci es i n r e c or ds  of  dr u g  a c c o u nt a bilit y. 
A n y  u n us e d  vi als  of  C S L 3 4 6  m ust  n ot  b e  d estr o y e d  u ntil t h e  dr u g  a c c o u nt a bilit y 
d o c u m e nt ati o n  h as  b e e n  c h e c k e d  b y t h e  u n bli n d e d st u d y  m o nit or,  a n d  a n y  n e c ess ar y 
p er missi o n f or  d estr u cti o n  h as  b e e n  gi v e n  b y  C S L.  A n y  d estr u cti o n  of  C S L 3 4 6  m ust  b e 
d o c u m e nt e d  a n d  c ertifi c ati o n  pr o vi d e d t o  C S L. 
All  dr u g  a c c o u nt a bilit y r e c or ds  m ust  b e st or e d i n t h e sit e fil e  a n d  m ust  b e r e a dil y  a v ail a bl e f or 
i ns p e cti o n  b y t h e st u d y  m o nit or  a n d /  or  a u dit or,  a n d  o p e n t o r e g ul at or y i ns p e cti o n  at  a n y ti m e. 
F urt h er  d et ails r e g ar di n g  a c c o u nt a bilit y  a n d  d estr u cti o n  of  C S L 3 4 6  ar e  pr o vi d e d i n t h e sit e 
I M P  H a n dli n g  M a n u al. 
5. 3   Ot h e r I nt e r v e nti o ns  
5. 3. 1   
C o n c o mit a nt  St u d y -r el at e d  T h e r a pi es  
R e q uir e d  c o n c o mit a nt  m e di c ati o ns  ar e  d es cri b e d i n t h e I n cl usi o n  Crit eri a ( S e cti o n  4. 1. 1 ). 
M e di c ati o n /  T h e r a p y  
D os e   
P e r mitt e d  P e ri o d  of  Us e  
St a bl e  A C Ei  or  A R B t h er a p y is r e q uir e d  u nl ess  a 
s u bj e ct is i nt ol er a nt  or t h er a p y is  c o ntr ai n di c at e d  a n d 
r e as o ns  ar e  d o c u m e nt e d 
R e gi m e n s h o ul d  b e 
c o nsi d er e d 
a p pr o pri at e i n t h e 
j u d g m e nt  of t h e 
I n v esti g at or 
R e gi m e n s h o ul d  b e st a bl e f or 
at l e ast  8  w e e ks  b ef or e 
S cr e e ni n g ( 4  w e e ks f or 
S G L T 2 i n hi bit ors)  a n d 
r e m ai n  u n c h a n g e d 
t hr o u g h o ut t h e s u bj e ct’s 
p arti ci p ati o n i n t h e st u d y  
St a bl e  a nti h y p erli pi d e mi a  a n d  h y p ert e nsi o n r e gi m e ns a 
Ot h er st a n d ar d  of  c ar e  b a c k gr o u n d  m e di c ati o ns, 
i n cl u di n g  S G L T 2 i n hi bit ors 
St a bl e  a nti di a b et es t h er a p y  
E a c h s u bj e ct’s  T 2 D M s h o ul d 
b e  m a n a g e d  a c c or di n g t o 
st a n d ar d l o c al  g ui d eli n es 
t hr o u g h o ut t h eir p arti ci p ati o n 
i n t h e st u d y 
a  
F or s u bj e cts  b ei n g tr e at e d f or  d ysli pi d e mi a  or  h y p ert e nsi o n.  
5. 4   A c c ess t o I n v esti g ati o n al  P r o d u ct  Aft e r t h e  E n d  of  St u d y  
S u bj e cts  will  n ot  b e  pr o vi d e d  wit h I P  b y  C S L  aft er  c o m pl eti o n  or  dis c o nti n u ati o n fr o m t h e 
st u d y. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
6   
All o c ati o n  t o  Tr e at m e nt 
6. 1   S u bj e ct  Assi g n m e nt  
Aft er  pr o vi di n g  writt e n i nf or m e d  c o ns e nt, t h e s u bj e ct  will  b e iss u e d  a st u d y-l e v el  u ni q u e 
s u bj e ct i d e ntifi c ati o n  n u m b er  b y t h e I R T s yst e m.  T h e s u bj e ct i d e ntifi c ati o n  n u m b er  will  b e 
us e d t o i d e ntif y t h e s u bj e ct f or t h e  d ur ati o n  of t h e st u d y.  S u bj e ct i d e ntifi c ati o n  n u m b ers  will 
n ot  b e r e assi g n e d  or r e us e d. 
6. 2   R a n d o mi z ati o n  P r o c e d u r es  
A r a n d o mi z ati o n s c h e m e  will  b e  us e d t o  e ns ur e  u n bi as e d tr e at m e nt  assi g n m e nt.  A p pr o xi m at el y 
1 0 0 s u bj e cts  will  b e r a n d o mi z e d t o r e c ei v e  8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  or  pl a c e b o i n 
a  1: 1: 2 r ati o  vi a t h e I R T s yst e m. If  d os e l e v el st o p pi n g  crit eri a  ar e tri g g er e d (s e e  S e cti o n  3. 7. 2 ), 
r a n d o mi z ati o n  of s u bj e cts  will  b e li mit e d t o t h e  8  m g/ k g  C S L 3 4 6  d os e l e v el  or  pl a c e b o.  T h e 
r a n d o mi z ati o n  will  b e str atifi e d  b y  S G L T 2 i n hi bit or  us e.  
Usi n g I R T, li mits  will  b e i m p os e d t o  e ns ur e t h at  at l e ast  5 0 %  of t h e s u bj e cts  e nr oll e d i n t h e 
st u d y  will  b e r e c ei vi n g  c o n c o mit a nt tr e at m e nt  wit h  a n  S G L T 2 i n hi bit or. If  e nr oll m e nt  of 
s u bj e cts  n ot r e c ei vi n g  S G L T 2 i n hi bit ors r e a c h es  5 0 % (i e,  5 0 s u bj e cts), f urt h er  e nr oll m e nt i n t h e 
st u d y  m a y  b e r estri ct e d t o  all o w  o nl y s u bj e cts r e c ei vi n g  a n  S G L T 2 i n hi bit or. 
If i n cl usi o n  of s u bj e cts  wit h  e G F R  b el o w  6 0  m L/ mi n/ 1. 7 3 m2 is  e n d ors e d  b y t h e I D M C, t ar g et 
s a m pl e si z e(s)  will  b e  est a blis h e d f or s u bj e cts  wit h  e G F R  <  6 0  m L/ mi n/ 1. 7 3 m 2 a n d  / or  e G F R 
<  4 5  m L/ mi n/ 1. 7 3 m 2. 
T o  a c hi e v e t h es e t ar g et e d  mi ni m u ms, r estri cti o ns  m a y  b e i m p os e d  o n t h e  e nr oll m e nt  of 
s u bj e cts  wit h e G F R  ≥  6 0  m L/ mi n/ 1. 7 3 m 2 a n d  /  or  ≥  4 5  m L/ mi n/ 1. 7 3 m2.  
A n y r estri cti o n  o n  e nr oll m e nt  of s u bj e cts  b as e d  o n  e G F R  will   b e  c o m m u ni c at e d  dir e ctl y t o t h e 
sit es. 
T o  e ns ur e t h e st u d y  bli n d is  m ai nt ai n e d, t h e I R T  e xt er n al s er vi c e  pr o vi d er  will  pr e p ar e t h e 
st u d y r a n d o mi z ati o n  c o d e  a c c or di n g t o t h e  a p pr o v e d r a n d o mi z ati o n s p e cifi c ati o ns .  T h e I R T 
e xt er n al s er vi c e  pr o vi d er  will  k e e p t h e r a n d o mi z ati o n  c o d e  o n fil e. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
6. 3   Bli n di n g  P r o c e d u r es  
6. 3. 1   
Bli n di n g  M et h o d  
U n bli n d e d st u d y sit e  p ers o n n el  d el e g at e d  b y t h e I n v esti g at or ( e g, t h e  u n b li n d e d  p h ar m a cist) 
will  pr e p ar e  a n d  bli n d t h e I P ( C S L 3 4 6  or  pl a c e b o) i n s yri n g es f or  a d mi nistr ati o n t o t h e 
s u bj e cts.  
T h e  u n bli n d e d st u d y sit e  p ers o n n el  will  pr o vi d e t h e  a p pr o pri at el y  bli n d e d I P,  as  assi g n e d  b y 
I R T, t o t h e  bli n d e d st u d y sit e  p ers o n n el r e a d y f or i nf usi o n.  T h e  c ol or  of t h e li q ui d i n t h e 
s yri n g e  will  b e  o bs c ur e d  b y  a p pl yi n g  a tr a nsl u c e nt  y ell o w l a b el t o t h e  o utsi d e  of t h e s yri n g e 
t h at r e n d ers  diff er e n c es i n t h e  c ol or  of t h e  c o nt e nts i n disti n g uis h a bl e.  T h e  bli n d e d s yri n g e(s) 
will t h e n  b e  d eli v e r e d t o st u d y st aff f or  a d mi nistr ati o n t o t h e s u bj e ct.  T h e  bli n d e d I n v esti g at or 
( or  bli n d e d  d el e g at e)  will  a d mi nist er t h e I P.  
St u d y sit e st aff  w h o  will  b e  c o n d u cti n g s af et y  ass ess m e nts, i n cl u di n g t h e I n v esti g at or ,  will  b e 
bli n d e d t o tr e at m e nt  all o c ati o n (i e,  w h et h er t h e s u bj e ct r e c ei v es  C S L 3 4 6  or  pl a c e b o)  a n d t o  kit 
n u m b er  assi g n m e nt.  S u bj e cts  a n d  S p o ns or st aff  will  als o  b e  bli n d e d t o tr e at m e nt  all o c ati o n 
( d o u bl e- bli n d)  a n d  kit  n u m b er  assi g n m e nt,  e x c e pt  as st at e d  b el o w.  
A st u d y-i n d e p e n d e nt  bi o a n al yst,  p h ar m a c o ki n eti cist, st atisti ci a n,  a n d  pr o gr a m mi n g s u p p ort 
r es p o nsi bl e f or t h e s a m pl e  a n al ysis,  P K  e v al u ati o n,  a n d I D M C  o p er ati o ns  will  b e  u n bli n d e d  as 
w ell  as  a r e pr es e nt ati v e fr o m  Cli ni c al  Tri als  S u p pl y  a n d fr o m I R T.  A d diti o n all y,  u n bli n d e d 
m o nit ors  m a y  b e  assi g n e d t o sit es.  D esi g n at e d  u n bli n d e d  p ers o n n el  a gr e e  n ot t o  dis cl os e t h e 
c o nt e nts  of t h e r a n d o mi z ati o n s c h e d ul e, t h e  c o nt e nts  of t h e  kit list,  or  a n y s u bj e ct  kit  n u m b er 
assi g n m e nt.  T h e  P K  a n d s af et y-r el at e d  d at a  pr o vi d e d t o t h e I D M C  d uri n g t h e  c o urs e  of t h e 
st u d y  will  b e  u n bli n d e d.  All i n di vi d u als  wit h  a c c ess t o  u n bli n d e d  d at a  will  b e i n d e p e n d e nt fr o m 
t h e st u d y t e a m,  a n d  will  b e  pl a c e d  u n d er stri ct  c o nfi d e nti alit y t o  pr ot e ct t h e i nt e grit y  of t h e 
st u d y. 
6. 3. 2   
B r e a ki n g t h e  Bli n d f o r  a n  E m e r g e n c y  
T h e r a n d o mi z ati o n  c o d e f or i n di vi d u al s u bj e cts  m a y  b e  u n bli n d e d t o  a sit e  d uri n g t h e st u d y i n 
e m er g e n c y sit u ati o ns f or r e as o ns  of s u bj e ct s af et y, if  k n o wi n g tr e at m e nt  assi g n m e nt  will 
c h a n g e s u bj e ct  m a n a g e m e nt. I n  c as e  of  a n  e m er g e n c y sit u ati o n f or t h e r e as o n  of s u bj e ct s af e t y, 
t h e I n v esti g at or s h o ul d  us e t h e I R T t o i d e ntif y t h e tr e at m e nt  all o c ati o n f or  a s u bj e ct.  W h e n e v er 
p ossi bl e, t h e I n v esti g at or s h o ul d  c o ns ult  wit h t h e  M e di c al  M o nit or  b ef or e  u n bli n di n g t h e 
tr e at m e nt  assi g n m e nt.  T h e r e as o n f or  u n bli n di n g  m ust  b e f ull y  d o c u m e nt e d  a n d t h e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
I n v esti g at or m ust  c o nt a ct t h e  M e di c al  M o nit or  as s o o n  as  p ossi bl e f oll o wi n g  a n y  e m er g e n c y 
u n bli n di n g. 
6. 3. 3   
Pl a n n e d  U n bli n di n g  P r o c e d u r es  
F or  d e cisi o n- m a ki n g  a n d  d e v el o p m e nt  p ur p os es,  a n i nt eri m  a n al ysis  of  u n bli n d e d  d at a  will  b e 
p erf or m e d  aft er  e nr oll m e nt is  c o m pl et e  a n d  all r a n d o mi z e d s u bj e cts  c o m pl et e t h e  1 6 -w e e k 
A C R  m e as ur e m e nt (i e,  4  w e e ks  aft er t h e f o urt h  d os e) .  T h e r a n d o mi z ati o n  c o d e  will  b e 
u n bli n d e d  o n c e  all  effi c a c y  d at a t hr o u g h  1 6  w e e ks  h a v e  b e e n  e nt er e d i nt o t h e st u d y  d at a b as e 
f or  e a c h s u bj e ct  a n d t h es e  d at a  h a v e  b e e n l o c k e d.  T h e r a n d o mi z ati o n  c o d e  will  b e  pr o vi d e d t o 
t h e st atisti c al  v e n d or  gr o u p  o n c e  writt e n  a ut h ori z ati o n  of t his  d at a b as e l o c k  h as  b e e n r e c ei v e d. 
T h es e r es ults  will  b e s u m m ari z e d i n  a n i nt eri m,  n o nr e g ul at or y,  a n al yti c al r e p ort.  A fi n al 
st atisti c al  a n al ysis  of  all  effi c a c y  a n d s af et y  d at a  will  o c c ur  aft er  all s u bj e cts  h a v e  c o m pl et e d 
t h e f ull  2 4  w e e ks  of t h e st u d y f or t h e  cli ni c al st u d y r e p ort. 
C S L’s  Cli ni c al  S af et y  P h ar m a c o vi gil a n c e  p ers o n n el  m a y  u n bli n d t h e r a n d o mi z ati o n  c o d e t o 
f a cilit at e  ass ess m e nt  of 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  e x p eri e n c e d  b y  a n y 
s u bj e ct f or  e x p e dit e d r e p orti n g t o r e g ul at or y  a ut h oriti es. 
6. 3. 4   
A d -h o c  S af et y  U n bli n di n g  
C S L ’s  Gl o b al  Cli ni c al  S af et y  a n d  P h ar m a c o vi gil a n c e  p ers o nn el  m a y,  o n  a n  a d - h o c  b asis, 
u n bli n d t h e r a n d o mi z ati o n  c o d e  dir e ctl y i n t h e I R T  at  a n y ti m e  d uri n g t h e st u d y  b e c a us e  of  a 
s af et y  c o n c er n.  T h e  p ur p os e  of t h e  u n bli n d e d  d at a r e vi e w is t o  d et er mi n e if t h er e is  a ris k t o 
s u bj e ct s af et y t h at  w o ul d r e q uir e f urt h er  a cti o n  eit h er f or t h e i n di vi d u al  m a n a g e m e nt  of  a 
s u bj e ct  or f or t h e  o n g oi n g  c o n d u ct  of t h e st u d y.  T h e  n e e d t o  u n bli n d  a s u bj e ct  or  gr o u p  of 
s u bj e cts  m a y  n ot  n e c ess aril y  aris e  b e c a us e  of  a n  S A E.  T h e  n e e d t o  u n bli n d  o n  a n  a d- h o c  b asis 
will  b e  d et er mi n e d  b y  C S L’s  Gl o b al  Cli ni c al  S af et y  a n d  P h ar m a c o vi gil a n c e s e ni or l e a d ers hi p. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  5 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
7   
C o nt r ai n di c ati o ns,  P e r mitt e d  T h e r a pi es  a n d  P r o hi bit e d  T h e r a pi es  
7. 1   C o nt r ai n di c ati o ns  a n d  P r e c a uti o ns t o  F u rt h e r  D osi n g  
N o s p e cifi c  c o ntr ai n di c ati o ns  h a v e  b e e n  est a blis h e d f or  C S L 3 4 6.  T h e  a d mi nistr ati o n  of 
C S L 3 4 6 t o  a n y s u bj e ct  n ot  m e eti n g t h e  eli gi bilit y  crit eri a f or t his st u d y,  or t o  a n y o n e  n ot 
e nr oll e d i n t his st u d y, is  pr o hi bit e d. 
7. 2   P e r mitt e d  T h e r a pi es  
P er mitt e d t h er a pi es i n cl u d e  a n y t h er a p y r e q uir e d t o tr e at  a  c o n diti o n  of t h e  s u bj e ct t h at is  n ot 
pr o hi bit e d  b y  pr ot o c ol.  
I n  a d diti o n, r e q uir e d  c o n c o mit a nt  m e di c ati o ns  ar e  d es cri b e d i n t h e I n cl usi o n  Crit eri a 
(S e cti o n  4. 1. 1 )  a n d i n S e cti o n  5. 3. 1 . 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
7. 3   P r o hi bit e d  T h e r a pi es  
T h e f oll o wi n g t h er a pi es  ar e  N O T  P E R MI T T E D  d uri n g t h e st u d y: 
M e di c ati o n /  T h e r a p y  
D os e   
P r o hi bit e d  P e ri o d  of  Us e   
N ot es  
Mi n er al o c orti c oi d r e c e pt or  a nt a g o nists, 
c o m bi n ati o n tr e at m e nt  wit h  R A S 
i n hi bit ors  a n d  A R B,  or  dir e ct r e ni n 
i n hi bit orsa 
N A  
Wit hi n  8  w e e ks  b ef or e 
S cr e e ni n g t hr o u g h  E O S  
N A  
Tri m et h o pri m,  
Ci m eti di n e,  
C e p h al os p ori ns,  
Pr o b e n e ci d,  
A mi n o gl y c osi d es,  
K et o c o n a z ol e,  
Cl ofi br at e,  
Dr o n e d ar o n e,  a n d  
R a n ol a zi n e.   
 
Wit hi n  4  w e e ks  b ef or e 
S cr e e ni n g t hr o u g h  E O S  
N A  
F e n ofi br at e  or  n o nst er oi d al  a nti -
i nfl a m m at or y  a g e nts  n ot t a k e n  as  p art  of 
a st a bl e r e gi m e n a 
 
Wit hi n  8  w e e ks  b ef or e 
S cr e e ni n g t hr o u g h  E O S  
N A  
I m m u n os u p pr essi v e  m e di c ati o ns, s u c h 
as  c y cl os p ori n e,  m y c o p h e n ol at e  m of etil, 
t u m or  n e cr osis f a ct or-al p h a i n hi bit ors, 
j a n us  ki n as e i n hi bit ors,  or i nt e gri n 
r e c e pt or  a nt a g o nists  
 
Wit hi n  8  w e e ks  b ef or e 
S cr e e ni n g t hr o u g h  E O S  
S yst e mi c  c orti c ost er oi ds 
ar e  o nl y  p er mitt e d  at l o w 
d os es f or s h ort -t er m 
tr e at m e nt  of  a c ut e 
c o n diti o ns, s u c h  as  a n 
all er gi c r e a cti o n  or  g o ut  
Ot h er i n v esti g ati o n al  a g e nts a 
N/ A  
Wit hi n  1 2  w e e ks  b ef or e 
S cr e e ni n g t hr o u g h  E O S  
T his is  n ot  a p pli c a bl e if t h e 
s u bj e ct is  k n o w n t o  h a v e 
r e c ei v e d  a  pl a c e b o  as  p art 
of  a n ot h er  cli ni c al tri al  
a 
If  a d mi nistr ati o n  of  a n y  pr o hi bit e d t h er a p y  b e c o m es  n e c ess ar y  d uri n g t h e st u d y f or  m e di c al r e as o ns, t h e 
s u bj e ct  m a y  b e  wit h dr a w n fr o m f urt h er st u d y tr e at m e nt  a n d  pr o c e e d t o  F oll o w -u p ( S e cti o n  4. 3. 2 ). 
7. 4   Lif est yl e  R est ri cti o ns   
F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  a n d  m al e s u bj e cts  wit h  a f e m al e  p art n er  of 
c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  a   hi g hl y  eff e cti v e f or m  of  birt h  c o ntr ol i n  a d diti o n t o  a 
b arri er  m et h o d  of  c o ntr a c e pti o n (i e,  m al e  or f e m al e  c o n d o m  wit h  or  wit h o ut s p er mi ci d e  a n d 
wit h o ut f at-  or  oil- c o nt ai ni n g l u bri c a nts) st arti n g  at  S cr e e ni n g  a n d t hr o u g h  9 0  d a ys  aft er l ast I P 
a d mi nistr ati o n.  
C hil d b e ari n g  p ot e nti al is  ass u m e d i n  all f e m al e s u bj e cts  e x c e pt  f or t h e f oll o wi n g: 
•   F e m al e s u bj e cts  a g e d  >  6 0  y e ars  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   F e m al e s u bj e cts  a g e d  4 5 t o  6 0  y e ars (i n cl usi v e)  wit h  a m e n orr h e a f or  ≥  1  y e ar 
•   F e m al e s u bj e cts  w h o  ar e s ur gi c all y st eril e f or  at l e ast  3  m o nt hs  b ef or e  pr o vi di n g i nf or m e d 
c o ns e nt 
Hi g hl y  eff e cti v e  m et h o ds  of  c o ntr a c e pti o n  ar e  as f oll o ws: 
•   A bsti n e n c e,  w h er e  a bsti n e n c e i s t h e  pr ef err e d  a n d  us u al lif est yl e  of t h e s u bj e ct, i n cl u di n g 
r efr ai ni n g fr o m  h et er os e x u al i nt er c o urs e  d uri n g t h e  e ntir e  p eri o d  of ris k  ass o ci at e d  wit h t h e 
I P.  P eri o di c  a bsti n e n c e ( c al e n d ar, s y m pt ot h er m al,  a n d  p ost o v ul ati o n  m et h o ds),  wit h dr a w al 
( c oit us i nt err u pt us), s p er mi ci d es  o nl y,  a n d l a ct ati o n al  a m e n orr h o e a  m et h o ds ar e  n ot 
a c c e pt a bl e  d efi niti o ns  of  a bsti n e n c e 
•   H or m o n al  m et h o ds  ass o ci at e d  wit h i n hi biti o n  of  o v ul ati o n.  A c c e pt a bl e  h or m o n al  m et h o ds 
i n cl u d e  or al  c o ntr a c e pti v es,  c o ntr a c e pti v e  m e di c ati o n  p at c h, c o ntr a c e pti v e  m e di c ati o n 
i nj e cti o n,  estr o g e n /  pr o g esti n  v a gi n al ri n g,  or  c o ntr a c e pti v e  m e di c ati o n i m pl a nt 
•   Us e  of i ntr a ut eri n e  d e vi c e ( pl a c e d  m or e t h a n  3  m o nt hs  b ef or e  pr o vi di n g i nf or m e d  c o ns e nt) 
•   Bil at er al t u b al  o c cl usi o n ( 3  m o nt hs  b ef or e  pr o vi di n g i nf or m e d  c o ns e nt) 
•   Vas e ct o m y ( 3  m o nt hs  b ef or e  pr o vi di n g i nf or m e d  c o ns e nt) 
A d diti o n al lif est yl e r estri cti o ns  d uri n g t h e st u d y i n cl u d e t h e f oll o wi n g: 
1.   F asti n g f or  at l e ast  6  h o urs  b ef or e  arri v al f or  Visit  3 ( D a y  –  7),  Visit  4 ( D a y  1),  Visit  7 
( We e k  4),  Visit  8 ( We e k  8),  a n d  Visit  1 0 ( We e k  1 6).  
2.   R estri ct  al c o h ol i nt a k e t o  ≤  7 st a n d ar d  dri n ks  p er  w e e k  a n d  a v oi d  >  2 st a n d ar d  dri n ks  o n 
a n y si n gl e  o c c asi o n.  
3.   S u bj e cts s h o ul d r efr ai n fr o m str e n u o us  p h ysi c al  a cti vit y,  w hi c h is  n ot  wit hi n t h e s u bj e ct’s 
n or m al  d ail y r o uti n e, fr o m  5  d a ys  b ef or e  Visit  3 ( D a y  – 7)  u ntil  aft er t h e  E O S  Visit.  
4.   A bst ai n fr o m  bl o o d  or  pl as m a  d o n ati o n  u ntil  3  m o nt hs  aft er t h e  E O S  Visit. 
5.   M al e s u bj e cts  o nl y:  a bst ai n fr o m s p er m  d o n ati o n fr o m t h e first  a d mi nistr ati o n  of I P  u ntil 
9 0  d a ys  aft er  t h e l ast I P  a d mi nistr ati o n. 
8   
St u d y  P r o c e d u r es  a n d  Visit  S c h e d ul e  
8. 1   Cli ni c al  P r o c e d u r es  
T h e ti mi n g  a n d fr e q u e n c y  of t h e  cli ni c al  pr o c e d ur es  d es cri b e d i n t h e f oll o wi n g s e cti o ns  ar e 
d et ail e d i n t h e  S c h e d ul e  of  Ass ess m e nts . All  pr o c e d ur es s h o ul d  b e  p erf or m e d  b ef or e I P 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
a d mi nistr ati o n  o n  d osi n g  d a ys  u nl ess  ot h er wis e  n ot e d.  M or e fr e q u e nt  ass ess m e nts  m a y  b e 
p erf or m e d, if  cli ni c all y i n di c at e d,  at t h e  dis cr eti o n  of t h e I n v esti g at or.  
8. 1. 1   
D e m o g r a p hi cs  a n d  S af et y  Ass ess m e nts  
S u bj e ct  d e m o gr a p hi cs  a n d s af et y  ass ess m e nts t o  b e  c o n d u ct e d  d uri n g t his st u d y  ar e  pr o vi d e d i n 
Ta bl e  6 . Cli ni c al l a b or at or y  ass ess m e nts  ar e t o  b e  p erf or m e d  at ti m e  p oi nts  as  d et ail e d i n t h e 
S c h e d ul e  of  Ass ess m e nts . T h e ti m e  wi n d o ws f or  e a c h t y p e  of  ass es s m e nt  ar e  d et ail e d i n 
S e cti o n  8. 6. 1 . 
T a bl e  6  
St u d y  P r o c e d u r es:  D e m o g r a p hi cs  a n d  S af et y  Ass ess m e nts   
Ass ess m e nt   
D es c ri pti o n  
D e m o gr a p hi cs  
•   Y e ar  of  birt h /  a g e  
•   S e x  
•   R a c e  
•   Et h ni cit y ( w h er e  p er mitt e d)  
M e di c al  Hist or y  
•   R el e v a nt  m e di c al  hist or y  wit hi n  1 2  m o nt hs  b ef or e  S cr e e ni n g  
•   Di a g n osis  a n d  dis e as e st at us  
•   C o n c o mit a nt  a n d  pri or  m e di c ati o ns  
•   C o ntr a c e pti o n  m et h o d (if r el e v a nt)  
Pr e g n a n c y  T est  
•   S er u m  a n d /  or  uri n e t ests  f or  b et a-h C G  
Vir ol o g y  
•   HI V  
•   H B V 
(A p p e n di x  2 ) 
•   H C V  
P h ysi c al 
E x a mi n ati o n (f ull 
or  a b br e vi at e d)  
•   As  p er t h e sit e’s st a n d ar d  pr o c e d ur e  
1 2 -l e a d  E C G 
(tri pli c at e) 
•   H e art  R at e  
•   P R I nt er v al   
•   Q R S  D ur ati o n  
•   Q T I nt er v al  
•   Q T c B I nt er v al   •   Q T c F  I nt er v al 
•   I n v esti g at or’s  o v er all i nt er pr et ati o n  
E c h o c ar di o gr a m  
•   T o  ass ess  L V E F;  A ss e ss e d l o c all y  as  p art  of s u bj e ct’s  eli gi bilit y  e v al u ati o n  d uri n g 
S cr e e ni n g.  A n  E C H O  p erf or m e d f or  n o n -st u d y-r el at e d r e as o ns  wit hi n  3  m o nt hs  b ef or e 
S cr e e ni n g  c a n  b e  us e d.  
Tr o p o ni n -Ia  
•   F or  e v al u ati o n  of  p ot e nti al  c ar di a c t o xi cit y   
B N P  
•   T o  ass ess si g n als  of  p ot e nti al  c ar di a c t o xi cit y  
A d v ers e  E v e nts  
•   E v al u ati o n  of  all  a d v ers e  e v e nts ( e g,  c a us alit y / r el at e d n ess, s e v erit y, s eri o us n ess)  
•   A d v ers e  e v e nts  of s p e ci al  i nt er est (S e cti o n  9. 1. 3 ) 
Vit al  S i g ns 
•   Bl o o d  pr ess ur e (s yst oli c  a n d  di ast oli c)   
•   B o d y t e m p er at ur e  
•   P uls e  r at e 
 
H ei g ht  a n d  W ei g ht  
•   H ei g ht  at  S cr e e ni n g  o nl y  
 
Uri n al ysis 
( S cr e e ni n g  a n d 
Visit  4 /  D a y  1 
o nl y)  
•   Bilir u bi n  
•   S p e cifi c  gr a vit y  
•   Gl u c os e  
•   Bl o o d  
•   Nitrit es  
•   K et o n es  
•   p H  
•   Ur o bili n o g e n  
•   L e u k o c yt e  est er as e  
•   Pr ot ei n  
H e m at ol o g y  
•   L e u k o c yt es ( W B C  c o u nt)  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Ass ess m e nt   
D es c ri pti o n  
•   H e m o gl o bi n  
•   H e m at o crit  
 
•   Er yt hr o c yt es ( R B C  c o u nt)  
•   R e d  bl o o d  c ell i n di c es:  M C V , M C H , M C H C , R D W  
•   Pl at el ets   
•   Diff er e nti al ( p er c e nt a g e  a n d  a bs ol ut e):  n e utr o p hils , n e utr o p hil  b a n d f or ms , 
l y m p h o c yt es, m o n o c yt es , e osi n o p hils , b as o p hils  
•   R eti c ul o c yt es  
C o a g ul ati o n  
•   I N R 
•   P T  
•   a P T T  
Bi o c h e mistr y  
•   S o di u m  
•   A S T  
•   P ot assi u m  
•   L D H  
•   C hl ori d e  
•   G G T  
•   Bi c ar b o n at e  
•   Bilir u bi n  –  t ot al 
•   C ar b o n  di o xi d e  –  t ot al 
•   Dir e ct  bilir u bi n  
•   C al ci u m  
•   C R P  
•   Ur e a  nitr o g e n /  B U N  
•   C h ol est er ol  –  t ot al 
•   Cr e ati ni n e  
•   Tri gl y c eri d es  
 
•   Gl u c os e  
•   H D L  C h ol est er ol  
•   Pr ot ei n  –  t ot al 
•   L D L  C h ol est er ol  
•   Al b u mi n  
•   Ur at e ( uri c  a ci d)  
•   Al k ali n e  p h os p h at as e  
•   Cr e ati ni n e  ki n as e  
 
•   A L T  
 
e G F R  
•   Gl o m er ul ar filtr ati o n r at e,  esti m at e d  usi n g t h e  C K D -E PI  e q u ati o n.  
I m m u n o g e ni cit yb 
•   A n al ysis f or t h e  pr es e n c e  of  bi n di n g  a nti b o di es t o  C S L 3 4 6  
A L T  =  al a ni n e  a mi n otr a nsf er as e;  a P T T  =  a cti v at e d  p arti al t hr o m b o pl asti n ti m e;  A S T  =  as p art at e  a mi n otr a nsf er as e; 
b et a -h C G  =  b et a -h u m a n  c h ori o ni c  g o n a d otr o pi n;  B N P  =  b -t y p e  n atri ur eti c  p e pti d e;  B U N  =  bl o o d  ur e a 
nitr o g e n;  C K D -E PI  =  C hr o ni c  Ki d n e y  Dis e as e  E pi d e mi ol o g y  C oll a b or ati o n;  C R P   =  C r e a cti v e  pr ot ei n; 
E C G   = el e ctr o c ar di o gr a m ; E C H O  =  e c h o c ar di o gr a m;  G G T   = g a m m a -gl ut a m yl tr a nsf er as e;  H B V   = h e p atitis 
B  vir us;  h C G   = h u m a n  c h ori o ni c  g o n a d otr o pi n;  H C V   = h e p atitis  C  vir u s;  H D L =  hi g h  d e nsit y li p o pr ot ei n; 
I N R  = I nt er n ati o n al  N or m ali z e d  R ati o;  L D H  = l a ct at e  d e h y dr o g e n as e;  L D L  = l o w  d e nsit y li p o pr ot ei n;  L V E F 
= l eft  v e ntri c ul ar  ej e cti o n fr a cti o n;  M C H  =  m e a n  c or p us c ul ar  h e m o gl o bi n;  M C H C   = m e a n  c or p us c ul ar 
h a e m o gl o bi n  c o n c e ntr ati o n ;  M C V  =  m e a n  c or p us c ul ar  v ol u m e;  P T  = pr ot hr o m bi n ti m e;  Q Tc B   = B a z ett’s 
c orr e cti o n f or m ul a;  Q Tc F   = Fri d eri ci a's  c orr e cti o n f or m ul a ;  R B C  = r e d  bl o o d  c ell;  R D W  =  er yt hr o c yt e 
distri b uti o n  wi dt h;  W B C   = w hit e  bl o o d  c ell . 
a  
A  c o n v e nti o n al ( n ot  hi g h -s e nsiti vit y) tr o p o ni n -I  ass a y s p e cifi c f or t h e  c ardi a c is of or m  of tr o p o ni n -I  will  b e 
p erf or m e d  b y t h e  c e ntr al l a b or at or y.  
b  
I m m u n o g e ni cit y  will  b e  ass ess e d  vi a  a ti er e d  a p pr o a c h  usi n g s cr e e ni n g, s p e cifi cit y,  a n d titr ati o n  ass a ys.  
 
L a b o r at o r y  P a r a m et e rs  
D et ails r el at e d t o t h e  c oll e cti o n,  pr e p ar ati o n,  a n d tr a nsf er  of  bl o o d  a n d  uri n e s a m pl es f or 
l a b or at or y  ass ess m e nts  will  b e  pr o vi d e d i n t h e l a b or at or y  m a n u al.  Tests r es ulti n g i n  a b n or m al 
c e ntr al l a b or at or y  v al u es  d uri n g t h e st u d y  p eri o d t h at  h a v e  b e e n  cl assifi e d  b y t h e I n v esti g at or 
as  cli ni c all y si g nifi c a nt s h o ul d  b e r e p e at e d  b y t h e  c e ntr al l a b or at or y  as s o o n  as  p ossi bl e  aft er 
r e c ei vi n g t h e l a b or at or y r e p ort t o r ul e  o ut l a b or at or y  err or.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
R ef er t o  S e cti o n  9. 6. 2  f or  ass ess m e nt  of  ot h er  a b n or m al l a b or at or y  v al u es. 
Vit al  Si g ns   
Vit al si g ns i n cl u d e  B P (s yst oli c  a n d  di ast oli c),  b o d y t e m p er at ur e,  a n d  p uls e  r at e. Bl o o d 
pr ess ur e  m e as ur e m e nts s h o ul d  b e t a k e n i n t ri pli c at e  b ef or e  all  ot h er  ass ess m e nts.  Vit al si g ns i n 
g e n er al  will  b e  c oll e ct e d  b ef or e  a n y  bl o o d s a m pl es t h at  ar e  c oll e ct e d  at t h e s a m e ti m e  p oi nt.  At 
Visit  2 ( D a y   – 2 1),  B P  will  b e t h e  o nl y  vit al si g n  c oll e ct e d. 
S u bj e cts  m ust  b e s e at e d f or  at l e ast  5  mi n u t es  b ef or e  vit al si g n  m e as ur e m e nts  ar e t a k e n. 
I nstr u cti o ns f or  m e as uri n g  B P  will  b e  pr o vi d e d i n t h e  M a n u al  of  O p er ati o ns.  At  Visit  4 ( D a y  1), 
m e as ur e m e nts  will  b e t a k e n  pr e d os e,  3 0,  6 0,  a n d  1 2 0  mi n ut es  aft er t h e first I V  d os e  of I P  b ut 
b ef or e t h e first  S C  d os e  of I P is  a d mi nist er e d, t h e n  3 0  a n d  6 0  mi n ut es  aft er  S C  d osi n g. 
A d diti o n al  m e as ur e m e nts  will  b e t a k e n  at  Visit  2,  at  Visit  5 ( D a y  8,  a p pr o xi m at e  T m a x ),  at 
Visit   6,  b ef or e  e a c h s u bs e q u e nt  S C I P  a d mi nistr ati o n ( at  Visits  7,  8,  a n d  9),  a n d  d uri n g 
F oll o w- u p ( at  Visit  1 0  a n d  E O S).  A n al ysis  will  b e  b as e d  o n t h e  m e a n  of  3  m e as ur e m e nts  at 
e a c h ti m e p oi nt . 
8. 1. 2   
P h a r m a c o ki n eti c , a n d  P h a r m a c o d y n a mi c  a n d  E x pl o r at o r y 
Bi o m a r k e r  Ass ess m e nts  
P h ar m a c o ki n eti c  ass ess m e nts t o  b e  c o n d u ct e d  d uri n g t h e st u d y  ar e  pr o vi d e d i n  Ta bl e  7 . 
P h ar m a c o d y n a mi c  a n d  e x pl or at or y  bi o m ar k er  ass ess m e nts t o  b e  c o n d u ct e d  d uri n g t h e st u d y 
ar e  pr o vi d e d i n  Ta bl e  8 .  P h ar m a c o ki n eti c ti m e  p oi nts (r el ati v e t o I V  d os e)  a n d  wi n d o ws  ar e 
pr o vi d e d i n  Ta bl e  1 0 .  T h e ti m e  wi n d o ws f or  e a c h t y p e  of  ass ess m e nt  ar e  d et ail e d i n 
S e cti o n  8. 6. 1 . 
T a bl e  7 
Cli ni c al  P r o c e d u r es:  P h a r m a c o ki n eti c  Ass ess m e nts  
P r o c e d u r e  
D es c ri pti o n  
C S L 3 4 6 ( P K  B l o o d S a m pli n g)  
S eri al  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of  C S L 3 4 6  c o n c e ntr ati o n  will 
b e  c oll e ct e d  at  Visit  4 ( D a y  1).  Si n gl e  P K s a m pl es  will  als o  b e  c oll e ct e d 
at  all s u bs e q u e nt  visits ( b ef or e tr e at m e nt  o n  S C  d osi n g  d a ys).  
C S L 3 4 6 ( Ti m e d  2 4 -h o ur  U ri n e) 
Uri n e s a m pl es f or t h e  d et er mi n ati o n  of  C S L 3 4 6  c o n c e ntr ati o n  will  b e 
c oll e ct e d  at  S cr e e ni n g ( Visit  1,  B as eli n e),  Visit  5 ( W e e k  1),  a n d  Visit  9 
( W e e k 1 2).  
P K  =  p h ar m a c o ki n eti c;  S C  = s u b c ut a n e o us . 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
T a bl e  8 
Cli ni c al  P r o c e d u r es:  P h a r m a c o d y n a mi c  a n d  E x pl o r at o r y 
Bi o m a r k e r  Ass ess m e nts  
P r o c e d u r e  
D es c ri pti o n  
Cir c ul ati n g  B i o m ar k ers  of L i pi d 
M et a b olis m   
F asti n g  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of s er u m  gl y c er ol,  N E F A, 
a n d  k et o n es  will  b e  c oll e ct e d  at  Visit  3 ( D a y  – 7),  Visit  4 ( D a y  1),  Visit  7 
( W e e k  4),  Visit  8 ( W e e k  8),  a n d  Visit 1 0 ( W e e k  1 6).  F asti n g  bl o o d 
s a m pl es f or t h e  d et er mi n ati o n  of t ot al  c h ol est er ol, tri gl y c eri d es,  H D L,  a n d  
L D L l e v els  will  b e  c oll e ct e d  at  Visit  3 ( D a y  – 7),  Visit  4 ( D a y  1),  Visit  7 
( W e e k  4),  Visit  8 ( W e e k  8),  a n d  Visit  1 0 ( W e e k  1 6)  as  p art  of t h e 
st a n d ar d  bi o c h e mistr y  p a n el. 
Cir c ul ati n g  B i o m ar k ers  of 
G l y c e mi c C o ntr ol   
Bl o o d s a m pl es f or t h e  d et er mi n ati o n  of  H b A 1 c l e v els  will  b e  c oll e ct e d  at 
S cr e e ni n g ( Visit  1),  Visit  4 ( D a y  1),  Visit  1 0 ( W e e k  1 6) , a n d  E O S.  Bl o o d 
s a m pl es f or t h e  d et er mi n ati o n  of f asti n g  gl u c os e l e v els  will  b e  c oll e ct e d  at 
Visit  3 ( D a y  – 7),  Visit  4 ( D a y  1),  Visit  7 ( W e e k  4),  Vi sit  8 ( W e e k  8),  a n d 
Visit  1 0 ( W e e k  1 6)  as  p art  of t h e st a n d ar d  bi o c h e mistr y  p a n el.  
Ot h er  N o v el  C ir c ul ati n g 
B i o m ar k ers 
F asti n g  bl o o d s a m pl es f or t h e  d et er mi n ati o n  of s er u m fr e e  V E G F -B 
l e v elsa a n d s T N F R 1  will  b e  c oll e ct e d  at  Visit  3 ( D a y  – 7),  Visit  4 ( D a y  1 ), 
Visit  7 ( W e e k  4),  Visit  8 ( W e e k  8),  a n d  Visit  1 0 ( W e e k  1 6).   
N o v el  U ri n e B i o m ar k ers 
Uri n e s a m pl es f or t h e  d et er mi n ati o n  of  V E G F -A, s ol u bl e  V E G F -R 1 a, 
KI M -1,  N G A L,  cl ust eri n,  a n d  M C P -1  will  b e  c oll e ct e d  at  Visit  3   
( D a y  –7),  Visit  4 ( D a y  1),  Visit  7 ( W e e k  4),  Visit  8 ( W e e k  8),  a n d 
Visit  1 0 ( W e e k  1 6).   
E O S  =  E n d  of  St u d y;  H b A 1 c  =  H e m o gl o bi n  A 1 c ; H D L  =  hi g h -d e nsit y li p o pr ot ei ns;  KI M -1  =  ki d n e y  i nj ur y 
m ol e c ul e -1;  L D L  = l o w -d e nsit y li p o pr ot ei ns;  M C P -1  =  m o n o c yt e  c h e m o attr a ct a nt  pr ot ei n -1;  N G A L  = 
n e utr o p hil  g el ati n as e -ass o ci at e d li p o c ali n;  N E F A  =  n o n -est erifi e d f att y  a ci ds; s T N F R 1  = s ol u bl e t u m or 
n e cr osis f a ct or r e c e pt or  1;  V E G F   = v as c ul ar  e n d ot h el i al  gr o wt h f a ct or. 
a  
D e p e n d e nt  o n  a v ail a bilit y  of t h e  ass a ys.  
8. 1. 3   
Effi c a c y  Ass ess m e nts   
T h e  effi c a c y  of  C S L 3 4 6  will  b e  ass ess e d  b as e d  o n  c h a n g es i n  A C R  ass o ci at e d  wit h  C S L 3 4 6 
tr e at m e nt.  T o  mi ni mi z e i ntr as u bj e ct  v ari a bilit y,  b as eli n e  v al u es f or t h es e  p ar a m et ers will  b e 
b as e d  o n t h e  g e o m etri c  m e a n  v al u es fr o m  3  F M V  uri n e  c oll e cti o ns  o n  2  s e p ar at e  o c c asi o ns 
(i e,  6 t ot al  F M V s a m pl es)  b ef or e t h e first  d os e  of I P.  F M V  uri n e s a m pl es f or t h e  d et er mi n ati o n 
of  A C R  will  b e  c oll e ct e d  as i n di c at e d i n t h e  S c h e d ul e  of  Ass ess m e nts .  O n-tr e at m e nt 
ass ess m e nts  of  A C R  will  b e t h e  g e o m etri c  m e a n  v al u es fr o m  m ulti pl e  F M V  c oll e cti o ns  at  e a c h 
ti m e  p oi nt.  O nl y  2  F M V s a m pl es  will  b e  c oll e ct e d  at  Visit  9  b e c a us e  a ti m e d  2 4- h o ur s a m pl e 
will  als o  b e  c oll e ct e d  at t his  Visit.  T h e  F oll o w - u p  ass ess m e nt  of  A C R  p erf or m e d f or t h e 
pri m ar y  a n al ysis  4  w e e ks  aft er t h e l ast  d os e  of I P ( Visit  1 0)  will  b e  b as e d  o n t h e  g e o m etri c 
m e a n  of  3   F M V s a m pl es.  F or t h e  E O S  Visit, t h e  ass ess m e nt  of  A C R  will  als o  b e  b as e d  o n t h e 
g e o m etri c  m e a n  of  3  F M V s a m pl es.   

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
8. 2   Ot h e r  Ass ess m e nts  
8. 2. 1   
S u b c ut a n e o us  Test I nf usi o n  
T o  e ns ur e t h at s u bj e cts  ar e f ull y i nf or m e d  a b o ut t h e r e q uir e m e nts  of t h e st u d y  b ef or e 
e nr oll m e nt,  a  2 0  m L  S C t est i nf usi o n  of  n or m al s ali n e  will  b e  a d mi nist er e d  at  Visit  2.  T hi s t est 
will  b e  p erf or m e d  aft er  c o nfir m ati o n t h at  ass ess m e nt r es ults fr o m  Visit  1  a n d  ass ess m e nt 
r es ults  a v ail a bl e  at t h e ti m e  of  Visit  2 (i e,  e x cl u di n g t h e  Visit  2  S Cr  v al u e) f ulfill 
i n cl usi o n / e x cl usi o n  crit eri a r e q uir e m e nts.  T h e s u bj e ct  a n d  I n v esti g at or ( or  d el e g at e)  will  h a v e 
t h e  o p p ort u nit y t o  e v al u at e t h e t ol er a bilit y  of  a  2 0  m L  S C i nf usi o n t o  d et er mi n e if t h e s u bj e ct 
will  b e  a bl e t o t ol er at e  S C i nf usi o ns  e v er y  4  w e e ks  o v er  a  1 2- w e e k  p eri o d ( 4  S C  d os es). 
8. 2. 2   
E x pl o r at o r y  Al b u mi n -t o-C r e ati ni n e  R ati o  
As  a n  e x pl or at or y  ass ess m e nt, t h e  d at a  g e n er at e d f or t h e  pri m ar y  a n al ysis ( S e cti o n  8. 1. 3 )  will 
als o  b e  us e d t o  e v al u at e  c h a n g es i n  cli ni c al  c h ar a ct eri z ati o n  of  al b u mi n uri a:  n or m o al b u mi n uri a, 
mi cr o al b u mi n uri a,  or  m a cr o al b u mi n uri a.  
T o  d o t his,  e a c h s u bj e ct’s l e v el  of  uri n ar y  A C R  will  b e  c at e g ori z e d  at  B as eli n e  a n d  at  Visit  1 0 
( We e k  1 6)  as f oll o ws: 
•   m a cr o al b u mi n uri a ( A C R  >  3 0 0  m g/ g [ >  3 3. 9  m g/ m m ol])  
•   mi cr o al b u mi n uri a ( A C R  ≥  3 0  a n d  ≤  3 0 0  m g/ g [ ≥  3. 3 9  a n d  ≤  3 3. 9  m g/ m m ol]),  or  
•   n or m o al b u mi n uri a ( A C R  <  3 0  m g/ g [ <  3. 3 9  m g/ m m ol]) 
Tr a nsiti o ns  b et w e e n t h es e  c at e g ori es  will  b e  d es cri b e d  i n t h e st u d y  a n al ys es. 
8. 3   S a m pl e  C oll e cti o n  
8. 3. 1   
Bl o o d  S a m pl es  
D uri n g t h e st u d y,  bl o o d  will  b e t a k e n fr o m  e a c h s u bj e ct f or  vir al t esti n g, l a b or at or y s af et y 
ass ess m e nts,  P K  /  P D  e v al u ati o ns,  a n d f ut ur e r es e ar c h.  
R e p e at  or  u ns c h e d ul e d  bl o o d s a m pl es  m a y  b e t a k e n f or s af et y r e as o ns  or f or t e c h ni c al iss u es 
wit h t h e s a m pl es.  
R ef er t o t h e l a b or at or y  m a n u al f or  d et ails  a b o ut t h e  v ol u m e,  c oll e cti o n, st or a g e,  h a n dli n g,  a n d 
pr o c essi n g  of  bl o o d s a m pl es. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
8. 3. 2   
U ri n e  S a m pl es  
Ti m e d  2 4- h o ur  uri n e s a m pl es  ar e  c oll e ct e d f or  d et er mi n ati o n  of  A C R  d uri n g  S cr e e ni n g  a n d f or 
d et e cti o n  of  C S L 3 4 6 i n  uri n e  at  ot h er i n di c at e d ti m e  p oi nts.  T h e s u bj e ct s h o ul d  c oll e ct  all  uri n e 
o v er  a  2 4- h o ur  p eri o d  a n d r e c or d st art  a n d st o p ti m e  of t h e  c oll e cti o n  p eri o d. 
F M V  uri n e s a m pl es  ar e  c oll e ct e d f or  d et er mi n ati o n  of  A C R  aft er  S cr e e ni n g.  T h e s u bj e ct ’s 
c o m pl et e  F M V s h o ul d  b e  c oll e ct e d  o n  3  c o ns e c uti v e  m or ni n gs,  wit h t h e t hir d  c oll e cti o n  o n t h e 
m or ni n g  of t h e i n di c at e d  visit.  F or  We e k  1 2,  a  F M V s a m pl e s h o ul d  b e  c oll e ct e d  o n 
2  c o ns e c uti v e  m or ni n gs, f oll o w e d  b y  a  2 4- h o ur ti m e d s a m pl e,  as i n di c at e d  i n Ta bl e  9 . 
S a m pl e  c oll e cti o n  c o nt ai n ers s h o ul d  b e  k e pt r efri g er at e d  b y t h e s u bj e ct  u ntil  br o u g ht t o t h e 
st u d y sit e. 
Mi dstr e a m  uri n e s a m pl es f or  P D  a n al ys es  will  b e  c o ll e ct e d  d uri n g r e g ul arl y s c h e d ul e d st u d y 
visits  as i n di c at e d i n t h e  S c h e d ul e  of  Ass ess m e nts   a n d i n Ta bl e  9 . 
T a bl e  9 
O v e r vi e w  of  U ri n e  C oll e cti o ns  
Visit  
U ri n e  S a m pl es  R e q ui r e d   
C oll e cti o n  D a y(s)  
S c r e e ni n g ( Visit  1)  
Ti m e d  2 4 -h o ur  c oll e cti o n   
Wit hi n  1  w e e k  of  Visit  1  
S c r e e ni n g ( Visit  2)  
N o n e  
-- 
We e k  – 1 ( D a y  – 7 /  Visit  3)   
F M V  x 3  
Mi dstr e a m  
D a y  – 9 ,  D a y – 8 ,  D a y – 7 
D a y  – 7  d uri n g  visit  
D a y  1  ( Visit  4) 
F M V  x 3  
Mi dstr e a m  
D a y  – 2,  D a y  – 1,  D a y  1  
D a y  1  d uri n g  visit  
D a y  8 ( Visit  5)  
Ti m e d  2 4 -h o ur  c oll e cti o n  
M or ni n g  of  D a y  7 t hr o u g h 
m or ni n g  of  D a y  8  
We e k  2 ( D a y  1 5 /  Visit  6)   
F M V  x 3  
D a y  1 3,  D a y  1 4,  D a y  1 5  
We e k  4 ( D a y  2 9 /  Visit  7)   
F M V  x 3  
Mi d -str e a m 
D a y  2 7,  D a y  2 8,  D a y  2 9  
D a y  2 9  d uri n g  visit  
We e k  8 ( D a y  5 7 /  Visit  8)   
F M V  x 3  
Mi dstr e a m  
D a y  5 5,  D a y  5 6,  D a y  5 7  
D a y  5 7  d uri n g  visit  
We e k  1 2 ( D a y  8 5 /  Visit  9)   
F M V  x 2  
Ti m e d  2 4 -h o ur  c oll e cti o n  
 
D a y  8 3,  D a y  8 4  
M or ni n g  of  D a y  8 4 t hr o u g h 
m or ni n g  of  D a y  8 5  
We e k  1 6 ( D a y  1 1 3 /  Visit  1 0)   
F M V  x 3  
Mi dstr e a m  
D a y  1 1 1,  D a y  1 1 2,  D a y  1 1 3  
D a y  1 1 3;  d uri n g  visit  
We e k  2 4 ( D a y  1 6 9 /  E O S)   
F M V  x 3  
D a y  1 6 7,  D a y  1 6 8,  D a y  1 6 9  
E O S  =  E n d  of  St u d y;  F M V  = first  m or ni n g  v oi d.  
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
8. 4   R et e nti o n  of  S a m pl es  f o r  F ut u r e  R es e a r c h 
Pl as m a, s er u m,  a n d  uri n e s a m pl es  will  b e r et ai n e d f or f ut ur e r es e ar c h  p ur p os es  as i n di c at e d i n 
t h e S c h e d ul e  of  Ass ess m e nts .  T h es e s a m pl es  m a y  b e  us e d t o  e n a bl e  d e v el o p m e nt  a n d 
m e as ur e m e nt  of  a d d iti o n al  e x pl or at or y  bi o m ar k ers i n t h e f ut ur e.  S a m pl es f or f ut ur e r es e ar c h 
will  b e st or e d  at  –  8 0° C  b y  C S L  a n d r et ai n e d f or  u p t o  1 0  y e ars.  T h es e  ass ess m e nts  will  n ot  b e 
c a pt ur e d i n t h e  cli ni c al  d at a b as e,  a n d  will  b e  a n al y z e d  a n d r e p ort e d s e p ar at el y.  F ut ur e  
bi o m ar k er  a n al ys es  m a y i n cl u d e,  b ut is  n ot li mit e d t o, tr a ns cri pt o m e  pr ofil e i n  p eri p h er al  w h ol e 
bl o o d. 
R ef er t o t h e l a b or at or y  m a n u al f or f urt h er  d et ails  a b o ut t h e  c oll e cti o n, s hi p m e nt, st or a g e,  a n d 
d estr u cti o n  of s a m pl es f or f ut ur e r es e ar c h. 
8. 5   C o n c o mit a nt  T h e r a pi es  
All  dr u g t h er a pi es  a d mi nist er e d t o  a s u bj e ct  u p t o  1 2  w e e ks  b ef or e si g ni n g t h e I C F  m ust  b e 
d o c u m e nt e d i n t h e  e C R F.  All  dr u gs  a n d /  or  pr o c e d ur es  c urr e ntl y  b ei n g  a d mi nist er e d t o  a 
s u bj e ct  at t h e ti m e  of si g ni n g t h e I C F,  a n d  w hi c h  c o nti n u e t o  b e t a k e n i n  a d diti o n t o  C S L 3 4 6 
d uri n g t h e st u d y,  ar e r e g ar d e d  as  c o n c o mit a nt t h er a pi es  a n d  m ust  b e  d o c u m e nt e d i n t h e  e C R F. 
R ef er t o  S e cti o n  7. 2   a n d S e cti o n  7. 3 , r es p e cti v el y, f or p er mitt e d  a n d  pr o hi bit e d  c o n c o mit a nt 
t h er a pi es. 
8. 6   Visit  S c h e d ul e  
8. 6. 1   
Ass ess m e nt  Ti m e  Wi n d o ws  
Ti m e  wi n d o ws f or  all  visits  a n d  ass ess m e nts  ar e  d et ail e d i n  Ta bl e  1 0 . 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  6 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
T a bl e  1 0 
Ti m e  Wi n d o ws f o r  Visits  a n d  Ass ess m e nts  
Visit /  P r o c e d u r e  
Ti m e  Wi n d o w ( R el ati v e t o  S c h e d ul e d  V isit / P r o c e d u r e)  
Visit  1 ( U p t o  – 6  w e e ks;  S cr e e ni n g)    
N ot  a p pli c a bl e  
Visit  2 ( D a y  – 2 1;  S cr e e ni n g)  
±  7  d a ys  
Visit  3 ( D a y  – 7;  L e a d -i n) 
±  4  d a ys  
Visit  4 ( D a y  1)  
N ot  a p pli c a bl e  
Visit  4  Vit al si g ns  
±  1 5  mi n ut es  
Visits  5,  6,  a n d  7 ( W e e ks  1,  2,  a n d  4)   
±  3  d a ys  
Visits  8  a n d  9 ( W e e ks  8  a n d  1 2)  
±  5  d a ys  
Visit  1 0 ( W e e k  1 6;  F oll o w -u p)  
±  7  d a ys  
E O S ( W e e k  2 4;  F oll o w -u p)  
±  7  d a ys  
P K  B l o o d S a m pli n g  T i m e P oi nts  
S eri al  bl o o d s a m pl es f or  P K  will  b e  c oll e ct e d  at  Visit  4 ( D a y  1) 
pr e d os e,  at  3 0 ( ±  5  mi n ut es),  6 0 ( ±  1 0  mi n ut es),  a n d 
1 2 0  ( ± 1 0  mi n ut es)  mi n ut es  aft er t h e first I V  d os e  of I P ( b ef or e 
t h e first  S C  d os e  of I P) is  a d mi nist er e d, t h e n  aft er t h e fi n al  vit al 
si g ns  m e as ur e m e nt.  Si n gl e  P K s a m pl es  will  als o  b e  c oll e ct e d  at 
all s u bs e q u e nt  visits ( b ef or e tr e at m e nt  o n  S C  d osi n g  d a ys).  
E O S  =  E n d  of  St u d y;  I P  = i n v esti g ati o n al  pr o d u ct; I V  = i ntr a v e n o us; P K  =  p h ar m a c o ki n eti c;  S C  = s u b c ut a n e o us.  
 
8. 6. 2   
S c r e e ni n g   
8. 6. 2. 1   
S c r e e ni n g  Visit  1 ( Visit  1,  ≤  6 3  d a ys  b ef o r e  D a y  1)  
All s u bj e cts  m ust  pr o vi d e  writt e n i nf or m e d  c o ns e nt  b ef or e  a n y st u d y- s p e cifi c  ass ess m e nts  or 
pr o c e d ur es  ar e  p erf or m e d.  Writt e n i nf or m e d  c o ns e nt is  n ot r e q uir e d f or  ass ess m e nts  or 
pr o c e d ur es  p erf or m e d  a c c or di n g t o  S O C ( e g, f or  di a g n osis  or tr e at m e nt); r es ults fr o m s u c h 
ass ess m e nts  m a y  b e  us e d i n t h e  d et er mi n ati o n  of st u d y  eli gi bilit y.  
T h e f oll o wi n g  pr o c e d ur es  will  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  S cr e e ni n g  Visit  1: 
•   O bt ai n  writt e n i nf or m e d  c o ns e nt  a n d r e gist er  t h e s u bj e ct  vi a t h e I R T 
•   C o nfir m  a n d  d o c u m e nt t h at t h e s u bj e ct  c o nf or ms  wit h i n cl usi o n /  e x cl usi o n  crit eri a 
•   O bt ai n  d e m o gr a p hi c i nf or m ati o n 
•   O bt ai n  m e di c al  hist or y   
•   P erf or m s er u m  pr e g n a n c y t est ( F C B P  o nl y) 
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  h ei g ht   a n d  w ei g ht 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C o nfir m  L V E F  b as e d  o n l o c al  E C H O.  A n  E C H O  p erf or m e d f or  n o nst u d y- r el at e d r e as o ns 
wit hi n  3  m o nt hs  b ef or e  S cr e e ni n g  c a n  b e  us e d. 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   Vir al s er ol o g y 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g  
o   Tr o p o ni n-I  a n d  B N P 
o   C o a g ul ati o n 
•   C oll e ct  uri n e s a m pl e f or st a n d ar d  uri n al ysis 
•   C oll e ct s u bj e ct’s ti m e d  2 4 - h o ur  uri n e s a m pl e (l e a di n g  u p t o t h e  m or ni n g  of  S cr e e ni n g) 
•   C oll e ct i nf or m ati o n  o n  A Es si n c e si g ni n g t h e I C F 
•   C oll e ct i nf or m ati o n  o n  pri or ( wit hi n t h e  pr e vi o us  3 0  d a ys) /  c o n c o mit a nt t h er a pi es 
T h e  pr o c e d ur es f or  h a n dli n g  S cr e e n  F ail ur es  ar e  d es cri b e d i n  S e cti o n  4. 2 . 
8. 6. 2. 2   
S c r e e ni n g  Visit  2 ( Visit  2,  D a y  – 2 1)  
S cr e e ni n g  Visit  2 s h o ul d  b e  p erf or m e d  wit hi n  6  w e e ks  aft er  S cr e e ni n g  Visit  1.  T h e f oll o wi n g 
pr o c e d ur es  will  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  S cr e e ni n g  Visit  2: 
•   C o nfir m  a n d  d o c u m e nt t h at t h e s u bj e ct  c o nf or ms  wit h i n cl usi o n /  e x cl usi o n  crit eri a 
•   P erf or m  c o m pl et e  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  B P (tri pli c at e)  
•   C oll e ct  bl o o d s a m pl e f or  S Cr  o nl y 
•   C oll e ct i nf or m ati o n  o n  A Es  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
•   P erf or m  S C  n or m al s ali n e t est i nf usi o n  
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit  a n d t o 
arri v e  aft er  a  mi ni m u m  6 - h o ur f ast 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
8. 6. 3   
L e a d- i n ( Visit  3,  D a y – 7)  
T h e f oll o wi n g  pr o c e d ur es  will  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at t h e  s e c o n d  L e a d-i n  Visit 
( Visit 3):  
•   C o nfir m  a n d  d o c u m e nt t h at t h e s u bj e ct  c o nf or ms  wit h r a n d o mi z ati o n  crit eri a f or  B P,  S Cr, 
a n d tr o p o ni n 
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pl i c at e) 
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   Bi o m ar k er  a n al ysis  
•   C oll e ct  uri n e  s a m pl es f or t h e f oll o wi n g: 
o   F M V (f or  D a ys  – 9,  – 8 ,  a n d – 7) 
o   M or ni n g  mi dstr e a m 
•   C oll e ct i nf or m ati o n  o n  A Es  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit  a n d t o 
arri v e  aft er  a  mi ni m u m  6 - h o ur f ast 
8. 6. 4   
Tr e at m e nt  
8. 6. 4. 1   
Tr e at m e nt  Visit  4 ( D a y  1)  
8. 6. 4. 1. 1   
B ef o r e  A d mi nist r ati o n  of I P   
S u bj e cts  w h o  c o m pl et e  all  S cr e e ni n g  ass ess m e nts  a n d  w h o s atisf y t h e r a n d o mi z ati o n  crit eri a 
will  b e  e nr oll e d i nt o t h e st u d y  a n d r a n d o mi z e d.  Aft er r a n d o mi z ati o n, t h e f oll o wi n g  pr o c e d ur es 
ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  4  b ef or e  a d mi nistr ati o n  of I P: 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   C o nfir m  a n d  d o c u m e nt t h at t h e s u bj e ct  c o nf or ms  wit h r a n d o mi z ati o n  crit eri o n f or  B P 
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w e i g ht 
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   H b A 1 c  
o   I m m u n o g e ni cit y 
o   Bi o m ar k er  a n al ysis  
•   C oll e ct  bl o o d s a m pl e f or  P K  b ef or e  d osi n g 
•   C oll e ct  uri n e  s a m pl es f or t h e foll o wi n g: 
o   F M V (f or  D a ys  – 2,  – 1,  a n d  1) 
o   M or ni n g  mi dstr e a m 
o   St a n d ar d  uri n al ysis 
•   C oll e ct i nf or m ati o n  o n  A Es 
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
8. 6. 4. 1. 2   
A d mi nist r ati o n  of I P  a n d  Aft e r  
T h e f oll o wi n g  a d diti o n al  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  4  as r el at e d 
t o  a d mi nistr ati o n  of I P: 
•   R a n d o mi z ati o n  a n d I R T I P  assi g n m e nt 
•   A d mi nist er I V l o a di n g  d os e  of I P 
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  at  3 0,  6 0,  a n d  1 2 0  mi n ut es  aft er I V  d os e 
•   At l e ast  2  h o urs ( b ut  n o  m or e t h a n  6  h o urs)  aft er I V  d os e,  a d mi nist er t h e first  S C  d os e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  at  3 0  a n d  6 0  mi n ut es  aft er  S C  d os e 
•   C oll e ct s eri al  P K  bl o o d s a m pl es  a c c or di n g t o  Ta bl e  1 0  
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   R e mi n d s u bj e ct t o  c oll e ct  a  2 4 - h o ur ti m e d  uri n e s a m pl e  b e gi n ni n g  o n t h e  m or ni n g  of  D a y  7 
a n d  c o nti n ui n g  u ntil t h e  m or ni n g  of  D a y  8 
8. 6. 4. 2   
Tr e at m e nt  Visit  5 ( We e k  1,  D a y  8)  
T h e  f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  5: 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e  
•   C oll e ct s u bj e ct’s ti m e d  2 4 - h o ur  uri n e s a m pl e (f or  D a y  7 t o  D a y  8) 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt  t h er a pi es 
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit 
8. 6. 4. 3   
Tr e at m e nt  Visit  6 ( We e k  2,  D a y  1 5)  
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  6: 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al  si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P  
•   C oll e ct  P K  bl o o d s a m pl e  
•   C oll e ct  uri n e  s a m pl es f or  F M V (f or  D a ys  1 3,  1 4,  a n d  1 5) 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit  a n d t o 
arri v e  aft er  a  mi ni m u m  6 - h o ur f ast 
8. 6. 4. 4   
Tr e at m e nt  Vi sit  7 ( We e k  4,  D a y  2 9) 
8. 6. 4. 4. 1   
B ef o r e  A d mi nist r ati o n  of I P   
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  7  b ef or e  a d mi nistr ati o n 
of I P:  
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   I m m u n o g e ni cit y 
o   Bi o m ar k er  a n al ysis  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e 
•   C oll e ct  uri n e  s a m pl es f or t h e f oll o wi n g: 
o   F M V (f or  D a ys  2 7,  2 8,  a n d  2 9) 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
o   M or ni n g  mi dstr e a m 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
8. 6. 4. 4. 2   
A d mi nist r ati o n  of I P  a n d  Aft e r  
T h e f oll o wi n g  a d diti o n al  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  7  as r el at e d 
t o  a d mi nistr ati o n  of I P: 
•   I R T I P  assi g n m e nt 
•   A d mi nist er t h e s e c o n d  S C  d os e  of I P 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit  a n d t o 
arri v e  aft er  a  mi ni m u m  6 - h o ur f ast 
8. 6. 4. 5   
Tr e at m e nt  Visit  8 ( We e k  8,  D a y  5 7)  
8. 6. 4. 5. 1   
B ef o r e  A d mi nist r ati o n  of I P   
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Vis it  8  b ef or e  a d mi nistr ati o n 
of I P:  
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   I m m u n o g e ni cit y 
o   Bi o m ar k er  a n al ysis  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   C oll e ct  uri n e  s a m pl es f or t h e f oll o wi n g: 
o   F M V (f or  D a ys  5 5,  5 6,  a n d  5 7) 
o   M or ni n g  mi dstr e a m 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
8. 6. 4. 5. 2   
A d mi nist r ati o n  of I P  a n d  Aft e r  
T h e f oll o wi n g  a d diti o n al  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  8  as r el at e d 
t o  a d mi nistr ati o n  of I P: 
•   I R T I P  assi g n m e nt 
•   A d mi nist er t h e t hir d  S C  d os e  of I P 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   R e mi n d s u bj e ct t o  c oll e ct  F M V s a m pl es  o n  D a y  8 3  a n d  D a y  8 4, t o  c oll e ct  a  2 4- h o ur  uri n e 
s a m pl e  b e gi n ni n g  o n t h e  m or ni n g  of  D a y  8 4  a n d  c o nti n ui n g  u ntil t h e  m or ni n g  of  D a y  8 5 
8. 6. 4. 6   
Tr e at m e nt  Visit  9 ( We e k  1 2,  D a y  8 5)  
8. 6. 4. 6. 1   
B ef o r e  A d mi nist r ati o n  of I P   
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  9  b ef or e  a d mi nistr ati o n 
of I P:  
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   Bi o m ar k er  a n al ysis  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e 
•   C oll e ct  uri n e  s a m pl es f or t h e f oll o wi n g: 
o   F M V (f or  D a ys  8 3  a n d  8 4) 
o   Ti m e d  2 4- h o ur  uri n e  s a m pl e (f or  D a y  8 4 t o  8 5) 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al t ol er a bilit y  ass ess m e nt  
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
8. 6. 4. 6. 2   
A d mi nist r ati o n  of  t h e I P a n d  Aft e r  
T h e f oll o wi n g  a d diti o n al  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  9  as r el at e d 
t o  a d mi nistr ati o n of t h e I P : 
•   I R T I P  assi g n m e nt 
•   A d mi nist er t h e f o urt h  S C  d os e  of t h e I P  
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al  t ol er a bilit y  ass ess m e nt 
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit  a n d t o 
arri v e  aft er  a  mi ni m u m  6 - h o ur f ast 
8. 6. 5   
F oll o w -u p   
8. 6. 5. 1   
F oll o w -u p  Visit  1 0 ( We e k  1 6,  D a y  1 1 3)  
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  Visit  1 0:  
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  a b br e vi at e d  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t esti n g  
o   Tr o p o ni n-I  a n d  B N P 
o   H b A 1 c  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
o   I m m u n o g e ni cit y 
o   Bi o m ar k er  a n al ysis  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e  
•   C oll e ct  uri n e  s a m pl es f or t h e f oll o wi n g: 
o   F M V (f or  D a ys  1 1 1,  1 1 2,  a n d  1 1 3) 
o   M or ni n g  mi dstr e a m 
•   C oll e ct i nf or m ati o n  o n  A Es, i n cl u di n g l o c al  t ol er a bilit y  ass ess m e nt 
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 
•   R e mi n d s u bj e ct t o  c oll e ct  F M V  uri n e  s a m pl es f or  3  d a ys l e a di n g  u p t o t h e  n e xt  visit 
8. 6. 5. 2   
E n d  of  St u d y ( We e k  2 4,  D a y  1 6 9)  
T h e f oll o wi n g  pr o c e d ur es  ar e t o  b e  c o n d u ct e d  a n d  d o c u m e nt e d  at  E O S: 
•   P erf or m s er u m  or  uri n e  pr e g n a n c y t est ( F C B P  o nl y) 
•   P erf or m  c o m pl et e  p h ysi c al  e x a mi n ati o n  
•   M e as ur e  vit al si g ns ( B P i n tri pli c at e)  
•   M e as ur e  w ei g ht  
•   P erf or m  1 2 -l e a d  E C G (tri pli c at e) 
•   C oll e ct  bl o o d s a m pl es f or t h e f oll o wi n g: 
o   St a n d ar d  h e m at ol o g y  a n d  bi o c h e mistr y t es ti n g 
o   Tr o p o ni n-I  a n d  B N P 
o   H b A 1 c  
•   C oll e ct tr o u g h  P K  bl o o d s a m pl e 
•   C oll e ct  uri n e  s a m pl es f or  F M V (f or  D a ys  1 6 7,  1 6 8,  a n d  1 6 9) 
•   C oll e ct i nf or m ati o n  o n  A Es 
•   C oll e ct i nf or m ati o n  o n  c o n c o mit a nt t h er a pi es 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  7 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
9   
A d v e rs e  E v e nts  
9. 1   D efi niti o ns  
9. 1. 1   
A d v e rs e  E v e nt  
As  p er t h e 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),  a n  A E is  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  p ati e nt  or  cli ni c al 
i n v esti g ati o n s u bj e ct  a d mi nist er e d  a  p h ar m a c e uti c al  pr o d u ct,  a n d  w hi c h  d o es  n ot  n e c ess aril y 
h a v e  a  c a u s al r el ati o ns hi p  wit h t his tr e at m e nt.  A n  A E  c a n, t h er ef or e,  b e  a n y  u nf a v or 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,  cli ni c all y si g nifi c a nt l a b or at or y fi n di n g), s y m pt o m,  or 
dis e as e t e m p or all y  ass o ci at e d  wit h t h e  us e  of  a  m e di ci n al (i n v esti g ati o n al)  p r o d u ct,  w h et h er  or 
n ot  c o nsi d er e d r el at e d t o t h e  m e di ci n al (i n v esti g ati o n al)  pr o d u ct.  
T h e  p eri o d  of  o bs er v ati o n f or  A Es  e xt e n ds fr o m t h e ti m e t h e s u bj e ct  gi v es i nf or m e d  c o ns e nt 
u ntil t h e  e n d  of st u d y (s e e  S e cti o n  9. 4  f or f urt h er  d et ails). 
A d v ers e  e v e nts  m a y i n cl u d e t h e f oll o wi n g: 
•   E x a c er b ati o n (i e,  a n i n cr e as e i n t h e fr e q u e n c y  or s e v erit y)  of  a  pr e - e xisti n g  c o n diti o n. 
Ill n ess  pr es e nt  b ef or e st u d y  e ntr y s h o ul d  b e r e c or d e d i n t h e  m e di c al  hist or y s e cti o n  of t h e 
e C R F  a n d  o nl y  b e r e p ort e d  as  a n  A E if t h er e is  a n i n cr e as e i n t h e fr e q u e n c y   or s e v erit y  of 
t h e  c o n diti o n  d uri n g t h e st u d y  
•   A  cli ni c al  e v e nt  o c c urri n g  aft er  c o ns e nt  b ut  b ef or e I P  a d mi nistr ati o n 
•   I nt er c urr e nt ill n ess es  wit h  a n  o ns et  aft er  a d mi nistr ati o n  of I P 
A d v ers e  e v e nts  d o  n ot i n cl u d e: 
•   E v e nts i d e ntifi e d  at  S cr e e ni n g  t h at  m e et  e xcl usi o n  crit eri a  
•   M e di c al  or s ur gi c al  pr o c e d ur es (t h e  c o n diti o n t h at l e a ds t o t h e  pr o c e d ur e is t h e  A E) 
•   Sit u ati o ns  w h er e  a n  u nt o w ar d  m e di c al  o c c urr e n c e  h as  n ot t a k e n  pl a c e.  F or  e x a m pl e: 
o   Pl a n n e d  h os pit ali z ati o ns  d u e t o  pr e e xisti n g  c o n diti o ns,  w hi c h  h a v e  n ot  w ors e n e d 
o   H os pit ali z ati o ns t h at  o c c ur f or  pr o c e d ur es  n ot  d u e t o  a n  A E ( e g,  c os m eti c s ur g er y) 
o   H os pit ali z ati o ns f or  a  di a g n osti c  pr o c e d ur e  w h er e t h e  h os pit al st a y is l ess t h a n  2 4  h o urs 
i n  d ur ati o n  or f or  n or m al  m a n a g e m e nt  pr o c e d ur es ( e g,  c h e m ot h er a p y) 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
o   O v e r d os e  of I P  or  a n y  c o n c o mit a nt t h er a p y t h at  d o es  n ot r es ult i n  a n y  a d v ers e si g ns  or 
s y m pt o ms 
F or l a b or at or y s af et y  p ar a m et ers,  a n y i nst a n c es  of  a bs ol ut e  v al u es  b ei n g  o utsi d e t h e r ef er e n c e 
r a n g e  or  c h a n g es  at  a n y  visit  aft er st u d y st art t h at  ar e  c o nsi d er e d b y t h e I n v esti g at or  as 
cli ni c all y si g nifi c a nt  m ust  b e r e c or d e d i n t h e  e C R F  as  A Es. I n  a d diti o n,  at t h e I n v esti g at or ’s 
dis cr eti o n,  a n y  c h a n g es  or tr e n ds  o v er ti m e i n l a b or at or y  p ar a m et ers  c a n  b e r e c or d e d i n t h e 
e C R F  as  A Es if s u c h  c h a n g es  or tr e n ds  ar e  c o ns i d er e d t o  b e  cli ni c all y r el e v a nt,  e v e n if t h e 
a bs ol ut e  v al u es  ar e  wit hi n t h e r ef er e n c e r a n g e.  
L a b or at or y fi n di n gs  d o  n ot  n e e d t o  b e r e p ort e d  as  A Es i n t h e f oll o wi n g  c as es: 
•   L a b or at or y  p ar a m et ers  alr e a d y  b e y o n d t h e r ef er e n c e r a n g e  at s cr e e ni n g,  u nl ess  a f urt h er 
i n cr e as e / d e cr e as e  c a n  b e  c o nsi d er e d  a n  e x a c er b ati o n  of  a  pr e e xisti n g  c o n diti o n  
•   A b n or m al l a b or at or y  p ar a m et ers  c a us e d  b y  m e c h a ni c al  or  p h ysi c al i nfl u e n c es  o n t h e  bl o o d 
s a m pl e ( e g, i n  vitr o  h e m ol ysis)  a n d fl a g g e d  as s u c h  b y t h e l a b or at or y i n t h e l a b or at or y 
r e p ort 
•   A b n or m al  p ar a m et ers t h at  ar e  o b vi o usl y  bi ol o gi c all y i m pl a usi bl e ( e g,  v al u es t h at  ar e 
i n c o m p ati bl e  wit h lif e  or  o utsi d e t h e  m e as uri n g r a n g e) 
•   A n  a b n or m al l a b or at or y  v al u e t h at  c a n n ot  b e  c o nfir m e d  aft er r e p e at  a n al ysis,  pr ef er a bl y i n 
t h e s a m e l a b or at or y (i e, t h e  pr e vi o us r es ult  c o ul d  b e  m ar k e d  as  n ot  v ali d  a n d s h o ul d  n ot 
n e c ess aril y  b e r e p ort e d  as  a n  A E)   
9. 1. 2   
S e ri o us  A d v e rs e  E v e nt  
A n  S A E 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 t h at  at  a n y  d os e:  
•   R es ults i n  d e at h   –  T h e  e v e nt  m ust  b e t h e  c a us e  of  d eat h f or t h e  S A E t o  m e et t his s eri o us 
crit eri o n  
•   Is lif e-t h r e at e ni n g  – T h e t er m  “lif e -t hr e at e ni n g ” r ef ers t o  a n  e v e nt i n  w hi c h t h e s u bj e ct 
w as  at ris k  of  d e at h  at t h e ti m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n  e v e nt t h at  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  h a d  b e e n  m or e s e v er e 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
•   R e q ui r es i n - p ati e nt  h os pit ali z ati o n  o r  p r ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n  – C S L 
c o nsi d ers  “ h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n ” f or  at l e ast  2 4  h o urs 
as t h e  d efi ni n g  crit eri o n f or  a n  S A E.  H os pit al  a d missi o ns f or  pl a n n e d s ur g er y  or f or  n or m al 
dis e as e  m a n a g e m e nt  pr o c e d ur es ( e g,  c h e m ot h er a p y)  ar e  n ot  c o nsi d er e d  as  d efi ni n g  crit eri a 
f or  S A Es 
•   R es ults i n  p e rsist e nt  o r si g nifi c a nt  dis a bilit y  o r i n c a p a cit y  
•   Is  a  c o n g e nit al  a n o m al y  o r  bi rt h  d ef e ct  
•   Is  m e di c ally si g nifi c a nt   – A  m e di c all y si g nifi c a nt  e v e nt is  d efi n e d  as  a n  e v e nt t h at  d o es 
n ot  n e c ess aril y  m e et  a n y  of t h e  S A E  crit eri a,  b ut  w hi c h is j u d g e d  b y  a  p h ysi ci a n t o 
p ot e nti all y j e o p ar di z e t h e s u bj e ct  or r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt  1  o f 
t h e  a b o v e  o ut c o m es list e d  as  a n  S A E  crit eri o n 
A d v ers e  e v e nts t h at  d o  n ot f all i nt o t h e  a b o v e  c at e g ori es  ar e  d efi n e d  as  n o ns eri o us  A Es. 
9. 1. 3   
A d v e rs e  E v e nts  of  S p e ci al I nt e r est  
A d v ers e  e v e nts  of s p e ci al i nt er est  ar e i nj e cti o n sit e r e a cti o ns ( S e cti o n  9. 1. 3. 1 ), i n cr e as e i n 
s er u m  cr e ati ni n e (S e cti o n  9. 1. 3. 2 ),  al b u mi n uri a (S e cti o n  9. 1. 3. 3 ),  or  b as eli n e  bl o o d  pr ess ur es 
(S e cti o n  9. 1. 3. 4 ), a n d  c ar di a c  A Es ( S e cti o n  9. 1. 3. 5 ).  
T h e s af et y  m o nit ori n g  pl a n  a n d  g ui d a n c e f or  ass essi n g  a n d  m a n a gi n g  A E SIs  w er e  d e v el o p e d 
b as e d  o n t h e  a v ail a bl e  n o n cli ni c al  a n d  cli ni c al  d at a  wit h  C S L 3 4 6,  a n d t h e  e x p e ct e d  b as eli n e 
r e n al f u n cti o n i n t h e st u d y  p o p ul ati o n.  
G ui d a n c e f or  ass essi n g  a n d  m a n a gi n g r e n al  a n d  c ar di a c ris k  w er e  d e v el o p e d t o  all o w f or 
c ar ef ul  o bs er v ati o n  of s u bj e cts  e nr oll e d i n t h e st u d y f or  i n cr e as es i n  S Cr, i n cr e as es i n 
al b u mi n uri a, i n cr e as es i n  B P,  a n d  c h a n g es i n  c ar di a c  p ar a m et ers.  
W h e n  a n  A E s atisfi es t h e  crit eri a f or  a n  A E SI  d et ail e d  b el o w, t h e  I n v esti g at or will  ass ess t h e 
A E SI’s  p ot e nti al r el ati o ns hi p t o t h e I P.  T h e  A E/ S A E/ A E SI   eC R F  is t o  b e  c o m pl et e d,  pr o vi di n g 
a d diti o n al  d et ail  a b o ut t h e  A E SI . If t h e I n v esti g at or ass ess es t h e  A E SI  as  n ot  r el at e d t o 
tr e at m e nt  wit h t h e I P,  ot h er  k n o w n  or s us p e ct e d  c a us es  of t h e  A ESI  s h o ul d  b e r e c or d e d ( e g, 
n o n c o m pli a n c e  wit h  S O C  m e di c ati o ns).  
All  e v e nts  will  b e r e vi e w e d  wit h t h e I D M C  d uri n g r e g ul arl y s c h e d ul e d s af et y r e vi e w  m e eti n gs. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
T h e  I n v esti g at or  m ust r e p ort  a n y  A E SI  usi n g t h e A E/ S A E/ A E SI  e C R F.  R e p orti n g r e q uir e m e nts 
f or  A E SIs  ar e  d et ail e d i n S e cti o n  9. 6. 2 . 
9. 1. 3. 1   
I nj e cti o n  Sit e  R e a cti o ns  
I nj e cti o n sit e r e a cti o ns  ar e  a n i d e ntifi e d ris k  wit h t h e  S C  a d mi nistr ati o n  of  C S L 3 4 6.  
T o  cl os el y  m o nit or t h es e  e v e nts,  all i nj e cti o n sit e r e a cti o ns s h o ul d  b e  c o ns i d er e d  A E SIs  a n d t h e 
A E/ S A E/ A E SI  e C R F  m ust  b e  c o m pl et e d.   
F or  mil d i nj e cti o n sit e r e a cti o ns ( d efi n e d  b el o w) t h at  ar e  d e e m e d  u n a c c e pt a bl e  b y t h e s u bj e ct 
or I n v esti g at or,  a n d  w o ul d  ot h er wis e l e a d t o  dis c o nti n u ati o n  of t h e I P, st e p wis e  m o difi c ati o n  of 
t h e  v ol u m e  a n d /  or  d os e  a d mi nist er e d s h o ul d  b e  att e m pt e d,  as  d es cri b e d i n Fi g ur e  3  a n d  Ta bl e  
1 1 . 
A  mil d  i nj e cti o n sit e r e a cti o n is  d efi n e d  as f oll o ws: 
Te n d er n ess  at  a sit e  of  a d mi nistr ati o n,  wit h  or  wit h o ut  ass o ci at e d s y m pt o ms ( e g,  w ar mt h, 
er yt h e m a, it c hi n g).  Mil d t o  m o d er at e  p ai n  at  a sit e  of  a d mi nistr ati o n t h at res ol v es  wit hi n 
4 8  h o urs. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Fi g u r e  3    
Fl o w c h a rt f o r  St e p wis e  M o difi c ati o n  of I n v esti g ati o n al  P r o d u ct  
A d mi nist r ati o n  D u e t o  U n a c c e pt a bl e  Mil d I nj e cti o n  Sit e  R e a cti o ns 
 
I P  = i n v esti g ati o n al  pr o d u ct; I S R  = i nj e cti o n sit e r e a cti o n;  S C  = s u b c ut a n e o us. 
N ot e:  A n  u n a c c e pt a bl e  mil d I S R is  a n y  e v e nt t h at  m e ets  t h e  d efi niti o n  pr o vi d e d t h at, i n t h e  a bs e n c e  of  alt er n ati v e 
d osi n g  pr o visi o ns,  w o ul d r es ult i n t h e s u bj e ct’s  dis c o nti n u ati o n fr o m f urt h er I P  a d mi nistr ati o n.  
 
T a bl e  1 1  
St e p wis e  D osi n g  M o difi c ati o n  of I n v esti g ati o n al  P r o d u ct  
A d mi nist r ati o n f o r  U n a c c e pt a bl e  Mil d I nj e cti o n  Sit e  R e a cti o ns  
 
R a n d o mi z e d  T r e at m e nt  A r m  
8  m g/ k g  
A r m  
1 6  m g/ k g  
A r m  
Pl a c e b o  
A r m  
St a rti n g  D os e   
 
 
 
  D os e  L e v el  
  S C I n f usi o n V ol u m e  
8  m g/ k g  
2 0  m L  
1 6  m g/ k g  
2 0  m L  
Pl a c e b o  
2 0  m L  
St e p  1 ( ≥  S e c o n d  S C  D os e)  
 
 
 
  D os e  L e v el  
  S C I n f usi o n V ol u m e  
8  m g/ k g  
2  ×  1 0  m L  
1 6  m g/ k g  
2  ×  1 0  m L  
Pl a c e b o  
2  ×  1 0  m L  
St e p  2 ( ≥  T hi r d  S C  D os e)  
 
 
 
  D os e  L e v el  
  S C I n f usi o n V ol u m e   
8  m g/ k g  
2  ×  5  m L  
8  m g/ k g  
2  ×  5  m L  
Pl a c e b o  
2  ×  5  m L  
St e p  3  
Dis c o nti n u e f urt h er  d osi n g  
S C  = s u b c ut a n e o us.  
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
S u bj e cts  ar e r a n d o mi z e d i nt o  1  of  3 tr e at m e nt  ar ms:  C S L 3 4 6  8  m g/ k g tr e at m e nt  ar m,  C S L 3 4 6 
1 6  m g/ k g tr e at m e nt  ar m,  or  pl a c e b o tr e at m e nt  ar m.  At t h e st arti n g  d os e, s u bj e cts r a n d o mi z e d t o 
t h e  1 6  m g/ k g tr e at m e nt  ar m r e c ei v e  a  m or e  c o n c e ntr at e d  d os e t h a n s u bj e cts i n t h e  8  m g/ k g 
tr e at m e nt  ar m b e c a us e  b ot h  d os es  ar e  a d mi nist er e d i n t h e s a m e t ot al  v ol u m e ( 2 0  m L).  T h e 
i nf usi o n  v ol u m e (Fi g ur e  3 ),  d os e  a n d /  or t h e  c o n c e ntr ati o n (Ta bl e  1 1 )  of I P  m a y  b e  a dj ust e d if 
t h er e  ar e  mil d i nj e cti o n sit e r e a cti o ns. If  a s u bj e ct  h as  mil d i nj e cti o n sit e r e a cti o ns  at t h e 
st arti n g  d os e t h at  ar e  d e e m e d  u n a c c e pt a bl e  b y t h e s u bj e ct  or I n v esti g at or,  a n d  w o ul d  ot h er wis e 
l e a d t o  dis c o nti n u ati o n  of t h e I P,  pr o c e e d t o  St e p  1.  
I n  St e p  1, t h e  d os e,  w hi c h is t h e s a m e  as t h e  d os e l e v el  a n d  c o n c e ntr ati o n  of t h e st arti n g  d os e, 
is  a d mi nist er e d  as  2 i nf usi o ns  of  1 0  m L i nst e a d  of  a si n gl e i nf usi o n  of  2 0  m L.  T his  a dj ust m e nt 
will  h el p  d et er mi n e if r e d u ci n g t h e  v ol u m e i nf us e d  at  a  gi v e n si t e r e d u c es t h e  o c c urr e n c e  of 
i nj e cti o n sit e r e a cti o ns. If,  aft er  St e p  1, t h e s u bj e ct  c o nti n u es t o  h a v e  mil d i nj e cti o n sit e 
r e a cti o ns t h at  ar e  d e e m e d  u n a c c e pt a bl e  b y t h e s u bj e ct  or I n v esti g at or,  a n d  w o ul d  ot h er wis e 
l e a d t o  dis c o nti n u ati o n  of t h e I P,  c o nt a ct t h e  St u d y  M e di c al  M o nit or t o  dis c uss  a n d  d o c u m e nt 
t h e  a p pr o pri at e  a cti o n t o  b e t a k e n f or t h at s u bj e ct. If t h e  M e di c al  M o nit or  a p pr o v es,  pr o c e e d t o 
St e p  2.  
St e p  2  is  as f oll o ws: 
•   S u bj e cts r a n d o mi z e d t o t h e  8  m g/ k g tr e at m e nt  ar m  ar e t o  b e  a d mi nist er e d  8  m g/ k g  C S L 3 4 6 
i n t w o  5  m L  S C i nf usi o ns,  h al vi n g t h e t ot al i nf usi o n  v ol u m e  a n d t h er e b y  d o u bli n g t h e 
c o n c e ntr ati o n  of  C S L 3 4 6  a d mi nist er e d i n t h e  pr e vi o us s t e p  
•   S u bj e cts r a n d o mi z e d t o t h e  1 6  m g/ k g tr e at m e nt  ar m  ar e t o  b e  a d mi nist er e d 
8  m g/ k g  C S L 3 4 6 i n t w o  5  m L  S C i nf usi o ns,  h al vi n g t h e  d os e l e v el  a n d t ot al i nf usi o n 
v ol u m e  a n d t h er e b y  m ai nt ai ni n g t h e s a m e  c o n c e ntr ati o n  of  C S L 3 4 6  a d mi nist er e d i n t h e 
pr e vi o us s t e p 
T h es e  a dj ust m e nts  will  h el p  d et er mi n e if r e d u ci n g t h e t ot al  d os e i nf us e d  at  a  gi v e n sit e r e d u c es 
t h e  o c c urr e n c e  of i nj e cti o n sit e r e a cti o ns.  
If,  aft er  St e p  2, t h e s u bj e ct  c o nti n u es t o  h a v e  mil d i nj e cti o n sit e r e a cti o ns t h at  ar e  d e e m e d 
u n a c c e pt a bl e  b y t h e s u bj e ct  or I n v esti g at or,  a n d  w o ul d  ot h er wis e l e a d t o  dis c o nti n u ati o n  of t h e 
I P,  c o nt a ct t h e  St u d y  M e di c al  M o nit or t o  dis c uss  a n d  d o c u m e nt t h e  a p pr o pri at e  a cti o n t o  b e 
t a k e n f or t h at s u bj e ct. If t h e  M e di c al  M o nit or  a p pr o v es, t h e n  m o v e t o  St e p  3  a n d  dis c o nti n u e 
f urt h er  d osi n g  wit h I P.  E v er y  eff ort s h o ul d  b e  m a d e t o  c o nti n u e t h e s u bj e ct’s  p arti ci p ati o n i n 
F oll o w- u p  Visits  e v e n if t h e I P is  dis c o nti n u e d. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
F or  a n y i nj e cti o n sit e r e a cti o n t h at  e x c e e ds t h e  d efi niti o n  of  mil d,  eit h er i n  d ur ati o n  or s e v erit y 
of s y m pt o ms, t h e  St u d y  M e di c al  M o nit or  m ust  b e  c o nt a ct e d t o  dis c uss  a n d  d o c u m e nt t h e 
r ati o n al e f or  c o nti n ui n g  a d mi nistr ati o n  of t h e I P  at  a  d e cr e as e d t ot al  S C i nf usi o n  v ol u m e  a n d / 
or  d os e,  or  dis c o nti n ui n g f urt h er  d osi n g. 
9. 1. 3. 2   
S e r u m  C r e ati ni n e  
T h e  crit eri a f or i n cr e as es i n  S Cr  d u e t o  A KI  ar e  b as e d  o n  a  d efi niti o n  of  A KI t h at i n c or p or at es 
a bs ol ut e  c h a n g es i n  S Cr  o v er  a  2 4- t o  4 8- h o ur  p eri o d ( Wai k ar  a n d  B o n v e ntr e,  2 0 0 9 ).  T h e 
p er c e nt  c h a n g es i n  S Cr  aft er s e v er e  A KI  ar e  hi g hl y  d e p e n d e nt  o n  b as eli n e  ki d n e y f u n cti o n. I n 
c o ntr ast, t h e  a bs ol ut e i n cr e as es i n  S Cr  ar e  n e arl y i d e nti c al  a cr oss t h e s p e ctr u m  of  b as eli n e 
ki d n e y f u n cti o n.  C o ns er v ati v e  crit eri a  w er e i d e ntifi e d t o tri g g er  a  c o m pr e h e nsi v e  e v al u ati o n 
t h at  b al a n c es t h e s af et y  of s u bj e cts  e nr oll ed i n t h e st u d y  wit h s m all  c h a n g es i n  S Cr  e x p e ct e d 
d u e t o i ntr as u bj e ct  v ari a bilit y.   
A n  S Cr  A E SI is  d efi n e d  as  a  c o nfir m e d i n cr e as e fr o m  B as eli n e  of  at l e ast  0. 3  m g/ d L.  All  c as es 
m e eti n g t h e  crit eri a s h o w n  i n Ta bl e  1 2   will  b e s p e cifi c ally r e vi e w e d  wit h t h e I D M C  d uri n g 
r e g ul arl y s c h e d ul e d s af et y r e vi e w  m e eti n gs. 
T a bl e  1 2 
I n c r e as es i n  S e r u m  C r e ati ni n e  
S e r u m  C r e ati ni n e  –  I n c r e as e 
f r o m  B as eli n e (C o nfi r m e d)  
I n v esti g at o r  Ass e ss m e nt  
A cti o n  
≥  0. 3 t o  <  0. 7  m g/ d L   
( ≥  2 6. 5 t o  <  6 1. 9  µ m ol/ L) 
E x p e ct e d  c h a n g es  d u e t o I P -r el at e d 
a cti vit y  
C o nti n u e I P  wit h i n cr e as e d 
m o nit ori n g   
≥  0. 7  m g/ d L  
( ≥  6 1. 9  µ m ol/ L) 
R e v ersi bl e  e pis o d e  of  A KI 
u nr el at e d t o I P  
Wit h h ol d I P  u ntil s er u m  cr e ati ni n e 
r et ur ns t o  b as eli n e 
I P r el at e d 
P er m a n e ntl y  dis c o nti n u e I P  
A KI  =  a c ut e  ki d n e y i nj ur y; I P  = i n v esti g ati o n al  pr o d u ct . 
 
If  a s u bj e ct  h as  a n i n cr e as e i n  S Cr t h at  m e ets  crit eri a  o utli n e d i n Ta bl e  1 2  at  a n y  visit  w hil e 
r e c ei vi n g I P, t h e I n v esti g at or  will  c o m pl et e  a n  e C R F r e vi e wi n g  p ossi bl e  c a us es  of  A KI  n ot 
r el at e d t o I P s u c h  as  v ol u m e  d e pl eti o n,  uri n ar y tr a ct i nf e cti o n,  a n d  e x p os ur e t o  a  n e p hr ot o xi c 
a g e nt.  A n y i d e ntifi e d  p ossi bl e r e v ersi bl e  c a us es  of  A KI  n ot r el at e d t o I P  will  b e  a d dr ess e d 
pr o m ptl y  a c c or di n g t o l o c al st a n d ar ds  of  c ar e.  A s e c o n d  m e as ur e m e nt  will  b e  o bt ai n e d  as s o o n 
as  p ossi bl e  wit hi n  a  m a xi m u m  of  1  w e e k. If t h e s p e cifi e d i n cr e as e is  c o nfir m e d, t h e 
I n v esti g at or will  o bt ai n  a t hir d  S Cr  v al u e  wit hi n  1  w e e k  a n d  u p d at e t h e  e C R F.  
T h e  I n v esti g at or will  c o nt a ct t h e  M e di c al  M o nit or  w h o  will  assist  wit h  e v al u ati o n  a n d 
d et er mi n ati o n  of  a p pr o pri at e  a cti o n t o  b e t a k e n.  T his  c o ns ult ati o n  will  h el p  dis c er n si g ns  of 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
p ossi bl e  A KI  n ot r el at e d t o I P fr o m  h e m o d y n a mi c all y  m e di at e d  eff e cts  o n  S Cr /  e G F R 
p ot e nti all y  ass o ci at e d  wit h  I P-r el at e d  a cti vit y, r e v ersi bl e  c a us es  of  A KI  n ot r el at e d t o I P  or 
fr om r e n al i ntri nsi c i nj ur y r el at e d t o I P.  
T h e tr e n di n g  c h a n g es i n  S Cr  o v er  m ulti pl e ti m e  p oi nts  will  b e  e v al u at e d i n t h e  c o nt e xt  of 
c h a n g es i n  al b u mi n uri a,  B P,  a n d  ot h er  cli ni c al  p ar a m et ers  o v er t h at  p eri o d,  a n d 
r e c o m m e n d ati o ns  will  b e  pr o vi d e d t o t h e I n v esti g at or.  T his  m a y i n cl u d e  g ui d a n c e f or 
h ei g ht e n e d  m o nit ori n g  of r e n al  p ar a m et ers,  cli ni c al  m a n e u v ers t o r e v ers e r e v ersi bl e  c a us es  of 
A KI  n ot r el at e d t o I P ( e g, tr e at  a cti v e  uri n ar y tr a ct i nf e cti o n), t e m p or ar y i nt err u pti o n  of I P,  or 
p er m a n e nt  dis c o nti n u ati o n fr o m I P.  T h e  M e di c al  M o nit or  will  b e  a v ail a bl e  2 4  h o urs  a  d a y  a n d 
m ust  b e  c o ns ult e d  b y t h e I n v esti g at or; s u bs e q u e ntl y, t h e I n v esti g at or  will  m a k e t h e  d e cisi o n t o 
eit h er  a d mi nist er t h e  n e xt  m o nt hl y  d os e  of I P  or  p er m a n e ntl y  dis c o nti n u e  a s u bj e ct fr o m 
tr e at m e nt.  N ot e t h at  e v er y  eff ort  will  b e  m a d e t o  c o nti n u e t h e s u bj e ct’s  p arti ci p ati o n i n 
F oll o w- u p  V isits  e v e n if I P  a d mi nistr ati o n is st o p p e d.  
9. 1. 3. 3   
Al b u mi n u ri a  
T h e  crit eri a f or i n cr e as es i n  al b u mi n uri a  w er e  d eri v e d fr o m  a n  a n al ysis  of  bi ol o gi c al  v ari a bilit y  
i n  al b u mi n uri a l e v els i n s u bj e cts wit h  C K D  (Wai k ar  et  al,  2 0 1 8 ).  Wit hi n s u bj e ct  C V is 
a p pr o xi m at el y  3 0 % f or  F M V  uri n ar y  A C R  a n d is  c o m p ar a bl e  a cr oss t h e r a n g e  of  b as eli n e 
v al u es.  T h e  hi g h i ntr as u bj e ct  v ari a bilit y  m a k es it  diffi c ult t o  disti n g uis h r a n d o m  v ari a bilit y 
fr o m  a n  a d v ers e  eff e ct.  
A n  al b u mi n uri a  A E SI ,  b as e d  o n t h e  g e o m etri c  m e a n  of  A C R  v al u es fr o m  u p t o 3  F M V s a m pl es 
c oll e ct e d  at t h at  o n -tr e at m e nt ti m e  p oi nt, is  a  c o nfir m e d ≥  2-f ol d  i n cr e as e ( d o u bli n g) fr o m 
B as eli n e  w it h  a d diti o n al  e vi d e n c e s u g g esti n g A KI .  A d diti o n al  e vi d e n c e s u g g esti n g A KI  
i n cl u d es  o bs er v ati o ns s u c h  as  a c ut e  c h a n g es i n B P   or s er u m  cr e ati ni n e  a n d  ar e  d es cri b e d i n t h e 
st u d y’s  M a n u al  of  O p er ati o ns. 
T h e f oll o wi n g s e q u e n c e is  r e c o m m e n d e d f or  e v al u ati o n  a n d f oll o w- u p: 
•   I niti al fl a g r e c ei v e d fr o m  c e ntr al l a b or at or y f or  A C R  v al u e  ≥  2 x  bas eli n e  v al u e:  
o   Sit e  or d ers  uri n al ysis t o  b e  p erf or m e d l o c all y  a n d  uri n e  c ult ur e if i n di c at e d 
o   O bt ai ns  3  a d diti o n al  F M V  uri n e s a m pl es f or  c o nfir m ati o n  of i n cr e as e d  A C R  v al u e 
b y  c e n tr al l a b or at or y 
•   If  c o nfir m e d (s e c o n d  A C R fl a g r e c ei v e d fr o m  c e ntr al l a b or at or y): 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
o   P erf or ms  n o v el  c or o n a vir us  2 0 1 9 ( C O VI D- 1 9)  p ol y m er as e  c h ai n r e a cti o n  t est, if 
i n di c at e d 
o   R e p e ats  h e m at ol o g y ( w hit e  bl o o d  c ells  a n d  diff er e nti al,  pl at el et  c o u nt)  a n d  bl o o d 
c h e mistr y (i n cl u di n g  bl o o d  ur e a  nitr o g e n  a n al ysis  at  c e ntr al l a b or at or y  
o   O bt ai ns  vit al si g ns, i n cl u di n g  b o d y  w ei g ht  a n d tri pli c at e  m e as ur e m e nts  of  B P  
o   Q u esti o ns s u bj e ct  a b o ut  a d h er e n c e t o,  or  c h a n g es i n,  c o n c o mit a nt  m e di c ati o ns,  a n d 
ot h er  p ot e nti al  c h a n g es t o t h e s u bj e ct’s r o uti n e ( e g,  at y pi c al  di et  or  e x er cis e) 
•   If  a d diti o n al  e vi d e n c e s u g g esti n g A KI  is i d e ntifi e d, t h e  d efi niti o n  of  a n  al b u mi n uri a  A E SI 
is  m et. 
o   C o m pl et es t h e  A E/ S A E/ A E SI  e C R F  t o i n di c at e  a n  A E SI  h as  o cc urr e d  
o   U p d at es t h e  A E/ S A E/ A E SI  e C R F   wit h  a n y  n e w i nf or m ati o n ( e g,  c h a n g es i n,  or 
miss e d  d os es  of  c o n c o mit a nt  m e di c ati o ns,  A Es ) 
T h e  I n v esti g at or will  c o nt a ct t h e  M e di c al  M o nit or  w h o  will  assist  wit h  e v al u ati o n  a n d 
d et er mi n ati o n  of  a p pr o pri at e  a cti o n t o  b e t a k e n.  T his  m a y i n cl u d e  g ui d a n c e f or  h ei g ht e n e d 
m o nit ori n g  of r e n al  p ar a m et ers,  cli ni c al  m a n e u v ers t o r e v ers e r e v ersi bl e  c a us es  n ot r el at e d t o 
I P, t e m p or ar y i nt err u pti o n  of I P,  or  p er m a n e nt  dis c o nti n u ati o n fr o m st u d y tr e at m e nt.  T h e 
M e di c al  M o nit or  will  b e  a v ail a bl e  2 4  h o urs  a  d a y  a n d  m ust  b e  c o nt a ct e d f or  c o ns ult ati o n 
b ef or e t h e  I n v esti g at or  d e cisi o n t o  eit h er  a d mi nist er t h e  n e xt  m o nt hl y  d os e  of I P or 
p er m a n e ntl y  dis c o nti n u e  a s u bj e ct fr o m tr e at m e nt.  N ot e t h at  e v er y  eff ort  will  b e  m a d e t o 
c o nti n u e t h e s u bj e c t’s  p arti ci p ati o n i n  F oll o w- u p  Visits  e v e n if I P is st o p p e d.  
All  c as es  m e eti n g t h es e  crit eri a  will  b e s p e cifi c all y r e vi e w e d  wit h t h e I D M C  d uri n g r e g ul arl y 
s c h e d ul e d s af et y r e vi e w  m e eti n gs.  
9. 1. 3. 4   
Bl o o d  P r ess u r e  
A n  A E SI r el at e d t o  B P is  d efi n e d  as  a n  o bs er v e d  S B P  ≥  1 8 0  m m H g  a n d /  or  D B P  ≥  1 2 0  m m H g 
or  a n i n cr e as e fr o m  B as eli n e i n  eit h er  S B P  or  D B P  ≥  2 0  m m H g  a n d  gr e at er t h a n 
1 6 0 /  1 0 5  m m H g. I n s u bj e cts  pr es e nti n g  wit h  a  S B P  ≥  1 8 0  m m H g  or  a  D B P  ≥  1 2 0  m m H g, t h e 
I n v esti g at or  will  ass ess t h e s u bj e ct f or  e vi d e n c e  of  a  h y p ert e nsi v e  e m er g e n c y, tr e at  pr o m ptl y 
a c c or di n g t o t h e  S O C,  a n d if t h e s u bj e ct is  c o nfir m e d t o  h a v e  a  h y p ert e nsi v e  e m er g e n c y, 
c o m pl et e  a n  S A E f or m.  E vi d e n c e  of  e n d  or g a n  d a m a g e i n cl u d es  h y p ert e nsi v e  e n c e p h al o p at h y, 
r eti n al  h e m orr h a g es,  p a pill e d e m a,  or  a c ut e  a n d s u b a c ut e  ki d n e y i nj ur y.  T h e I n v esti g at or s h o ul d 
n ot  a d mi nist er t h e I P  a n d  m ust  c o nt a ct t h e  M e di c al  M o nit or f or  c o ns ult ati o n  as s o o n  as 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
p ossi bl e  a n d  wit hi n  1  b usi n ess  d a y.  Aft er  c o ns ult ati o n  wit h  M e di c al  M o nit or,  t h e I P  m a y  b e 
p er m a n e ntl y  dis c o nti n u e d  or t h e I P  m a y  b e r es u m e d  wit h i n cr e as e d  m o nit ori n g  of  B P  wit h 
u ns c h e d ul e d  visits  as  di ct at e d  b y  S O C.  N ot e t h at  e v er y  eff ort  will  b e  m a d e t o  c o nti n u e t h e 
s u bj e ct’s  p arti ci p ati o n i n  all st u d y  visits  e v e n if t h e I P is st o p p e d.  
If  a s u bj e ct  h as  a n  o bs er v e d  S B P  ≥  1 8 0  m m H g  a n d /  or  D B P  ≥  1 2 0  m m H g  or  a n i n cr e as e fr o m 
B as eli n e i n  eit h er  S B P  or  D B P  ≥  2 0  m m H g  a n d  >  1 6 0 /  1 0 5  m m H g,  a n d t h e s u bj e ct  h as 
mi ni m al  or  n o s y m pt o ms  a n d t h e i n cr e as e  c o nfir m e d  at l e ast  3 0  mi n ut es l at er, t h e I n v esti g at or 
s h o ul d i nt er v e n e  a c c or di n g t o  S O C  as f oll o ws: 
•   If  a  c a us e f or t h e ris e i n  B P  u nr el at e d t o I P  a d mi nistr ati o n is  n ot i d e ntifi e d, t h e I P  m a y  n ot 
b e  a d mi nist er e d  a n d t h e  I n v esti g at or m ust  c o nt a ct t h e  M e di c al  M o nit or f or  c o ns ult ati o n  as 
s o o n  as  p ossi bl e  a n d  wit hi n  1  b usi n ess  d a y.  Aft er  c o ns ult ati o n  wit h t h e  M e di c al  M o nit or, 
t h e I P  m a y  b e  p er m a n e ntl y  dis c o nti n u e d  or t h e I P  m a y  b e r es u m e d  wit h i n cr e as e d 
m o nit ori n g  of  B P  wit h  u ns c h e d ul e d  visits  as  di ct at e d  b y  S O C.  N ot e t h at  e v er y  eff ort  will  b e 
m a d e t o  c o nti n u e t h e s u bj e ct’s  p arti ci p ati o n i n  all st u d y  visits  e v e n if t h e I P is st o p p e d.  
•   If  a  c a us e f or t h e ris e i n  B P  u nr el at e d t o I P  a d mi nistr ati o n is i d e ntifi e d ( e g,  m e di c ati o n 
n o n c o m pli a n c e  or  ot h er  e xt e n u ati n g  cir c u mst a n c es), t h e  c a us e s h o ul d  b e  a d dr ess e d  a n d t h e 
I P  m a y t h e n  b e  a d mi nist er e d.  T h e I n v esti g at or s h o ul d  c o m pl et e  a n  e C R F r e vi e wi n g 
p ossi bl e  c a us es  of  el e v at e d  B P  n ot r el at e d t o I P.  T h e s u bj e ct s h o ul d  h a v e  u ns c h e d ul e d  visits 
wit h i n cr e as e d  m o nit ori n g  of  B P  as  di ct at e d  b y  S O C. If t h e  S B P  d o es  n ot r et ur n t o 
<  1 8 0  m m H g  or t h e  D B P  d o es  n ot r et ur n t o  <  1 2 0  m m H g,  t h e I n v esti g at or m ust  c o nt a ct t h e 
M e di c al  M o nit or f or  c o ns ult ati o n  b ef or e t h e I n v esti g at or  m a k es  a  d e cisi o n t o  eit h er 
a d mi nist er t h e  n e xt  m o nt hl y  d os e  of I P  or  dis c o nti n u e  a s u bj e ct fr o m tr e at m e nt. 
A d mi nistr ati o n  of I P  m a y  c o nti n u e  wit h i n cr e as e d  m o nit ori n g  of  B P  as  di ct at e d  b y  S O C. 
N ot e t h at  e v er y  eff ort  will  b e  m a d e t o  c o nti n u e t h e s u bj e ct’s  p arti ci p ati o n i n  all st u d y  visits 
e v e n if  I P is st o p p e d.  
All  c as es  will  b e s p e cifi c all y r e vi e w e d  wit h t h e I D M C  d uri n g r e g ul arl y s c h e d ul e d s af et y 
r e vi e w  m e eti n gs.  
T h e i n di c at e d i n cr e as es i n  B P  will  b e  m e as ur e d  a c c or di n g t o t h e  pr ot o c ol- s p e cifi e d  pr o c e d ur e. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  8 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
9. 1. 3. 5   
Ass ess m e nt  a n d  M a n a g e m e nt  of  C a r di a c  A d v e rs e  E v e nts  
A  c ar di a c  A E SI  will  b e  d efi n e d  as  a n y  cli ni c all y   m e a ni n gf ul  c h a n g e fr o m  Bas eli n e i n 
c ar di a c -r el at e d  p ar a m et ers, s u c h  as  E C G i nt er v als,  c ar di a c tr o p o ni n l e v els [T h y g es e n  et  al , 
2 0 1 8 ],  or  L V E F. 
If  at  a n y  p oi nt  a s u bj e ct  h as si g ns  a n d s y m pt o ms  c o nsist e nt  wit h  c ar di a c is c h e mi a,  c o n g esti v e 
h e art f ail ur e,  or  ot h er  u nst a bl e  c ar di a c  e v e nt  wit h  or  wit h o ut  el e v at e d tr o p o ni n  or  B N P l e v els, 
t h e s u bj e ct s h o ul d i m m e di at el y  b e r ef err e d t o t he  e m er g e n c y  d e p art m e nt f or  ur g e nt  c ar di a c 
e v al u ati o n. If  a  c ar di a c  e v e nt  c a n n ot  b e r ul e d  o ut, t h e s u bj e ct s h o ul d  p er m a n e ntl y  dis c o nti n u e 
a d mi nistr ati o n  of I P  a n d  e nt er t h e  F oll o w- u p  P eri o d  of t h e st u d y.  T h e I n v esti g at or ,  or  d el e g at e 
s h o ul d  n otif y t h e  S p o ns or  M e di c al  M o nit or  of t h e  d e cisi o n t o  dis c o nti n u e I P  a n d  c o m pl et e t h e 
A E/ S A E/ A E SI   e C R F t o  pr o vi d e  d et ails r el at e d t o t h e  e v e nt. 
C ar di a c tr o p o ni n-I ( c T nI)  will  b e  m e as ur e d  at t h e  c e ntr al l a b or at or y  d uri n g  S cr e e ni n g  a n d 
t hr o u g h o ut t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y.  S u bj e cts  wit h  c T nI  a b o v e t h e  U R L f or t h e 
ass a y ( d efi n e d  as  e x c e e di n g t h e  9 9 t h  p er c e ntil e  of  a  n or m al r ef er e n c e  p o p ul ati o n)  d uri n g 
S cr e e ni n g  or  L e a d -i n  will  b e  e x cl u d e d fr o m t h e st u d y.  
I n t h e  a bs e n c e  of si g ns  a n d s y m pt o ms  of  a n  u nst a bl e  c ar di a c  e v e nt, if  a n y  c T nI  v al u e r e p ort e d 
b y t h e  c e ntr al l a b or at or y  d uri n g  Tr e at m e nt  or  F oll o w- u p  e x c e e ds t h e  U R L, t h e f oll o wi n g 
g ui d a n c e  will  b e f oll o w e d: 
•   R e p e at  m e as ur e m e nt  of  c T nI  wit hi n  4 8  h o urs t o  c o nfir m 
•   H ol d  n e xt  d os e  of I P  u ntil t h e f oll o wi n g st e ps  ar e  c o m pl et e d  
•   T h e s u bj e ct  will  b e r ef err e d t o t h e l o c al  c ar di ol o gist f or  c ar di a c  e v al u ati o n  wit hi n  1  w e e k, 
a d h eri n g t o l o c al st a n d ar ds  of  c ar e,  as i n di c at e d.  E v er y  eff ort s h o ul d  b e  m a d e t o s e e k 
e v al u ati o n  b y t h e s a m e  c ar di ol o gist  us e d t o  ass ess  L V E F f or  S cr e e ni n g.  As  p ossi bl e, t h e 
s a m e  m et h o d ol o g y s h o ul d  b e  us e d f or  all st u d y- r el at e d  c ar di a c  ass ess m e nts 
o   If t h e l o c al  c ar di ol o gist fi n ds  e vi d e n c e  of  m y o c ar di al  d a m a g e  or  u nst a bl e  c ar di a c  e v e nt, 
s u c h  as  n e w  w all  m oti o n  a b n or m alit y ( W M A)  or  d e cr e as e d  L V E F t o  <  5 0 %  o n 
m y o c ar di al i m a gi n g ( E c h o, r a di o n u cli d e i m a gi n g,  or  c ar di a c  m a g n eti c r es o n a n c e 
i m a gi n g s c a n),  n e w  a b n or m al  d el a y e d  e n h a n c e m e nt  o n  c ar di a c m a g n eti c r es o n a n c e 
i m a gi n g,  or  n e w  Q- w a v es  or is c h e mi c  c h a n g es  o n  E C G,  c o nt a ct t h e  St u d y M e di c al 
M o nit or  t o  d et er mi n e if I P  c a n  b e  a d mi nist er e d, if  a d diti o n al f oll o w- u p is  n e e d e d,  or if 
I P s h o ul d  b e  p er m a n e ntl y  dis c o nti n u e d 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
o   If t h e l o c al  c ar di ol o gist fi n ds  n o  e vi d e n c e  of  m y o c ar di al  d a m a g e  or  u nst a bl e  c ar di a c 
e v e nt, I P  a d mi nistr ati o n  m a y r es u m e 
W h e n e v er  a  c ar di a c -r el at e d A E  is r e p ort e d, t h e sit e  m ust  c o m pl et e t h e A E/ S A E/ A E SI  e C R F t o 
pr o vi d e  d et ails r el at e d t o t h e  e v e nt. 
If  a l o c al  ass ess m e nt  of  c ar di a c tr o p o ni n is  o bt ai n e d  as  p art  of  cli ni c al  pr a cti c e  b y t h e sit e  a n d 
t h e  v al u e is  a b o v e t h e  U R L f or t h e l o c al  ass a y, t h e sit e  will  p erf or m  a  cli ni c al  ass ess m e nt  b as e d 
o n st a n d ar d  cli ni c al  pr a cti c e.  T h e sit e  will  als o  o bt ai n  a  c e ntr al  c T nI. If t h e  c T nI is  el e v at e d, t h e 
a b o v e  pr ot o c ol- m a n d at e d  g ui d a n c e  will  b e f oll o w e d. 
If  a n y f urt h er  c T nI  v al u e  o bt ai n e d is  a b o v e t h e  U R L, t h e  S p o nsor  M e di c al  M o nit or   m ust  b e 
c o nt a ct e d t o  dis c uss  n e xt st e ps. 
T a bl e  1 3 
St o p pi n g  C rit e ri a f o r  C a r di a c  Tr o p o ni n- I  L e v els 
O bs e r v ati o n  
Cli ni c al  C a r e  
A cti o n  
As y m pt o m ati c:   
c T nI  In cr e as e t o  >  U R L  
( 9 9 % C o effi ci e nt  of 
V ari ati o n)  
R ef er t o l o c al  c ar di ol o gist f or 
e v al u ati o n  wit hi n  1  w e e k. 
I m pl e m e nt l o c al st a n d ar d  of  c ar e  as 
i n di c at e d.  
H ol d  n e xt  d os e  u ntil  c ar di a c 
e v al u ati o n  a n d  c o ns ult ati o n  wit h 
St u d y  M e di c al  M o nit or  ar e  c o m pl et e  
If  e vi d e n c e  of  m y o c ar di al  d a m a g e  or 
u nst a bl e  c ar di a c  e v e nt a c o nt a ct 
St u d y  M e di c al  M o nit or t o  d et er mi n e 
n e xt st e ps  wit h r es p e ct t o I P 
a d mi nistr ati o n.  
If  n o  e vi d e n c e  of  m y o c ar di al  d a m a g e: 
c o nti n u e I P  
C o m pl et e  e C R F f or  c ar di a c  A E SI  
S y m pt o m ati c  
R ef er t o  e m er g e n c y  d e p art m e nt f or 
ur g e nt  c ar di a c  e v al u ati o n.  
If  c o nfir m e d  or s us p e ct e d  c ar di a c 
e v e nt a,  n otif y  S p o ns or  M e di c al 
M o nit or  a n d  p er m a n e ntl y  dis c o nti n u e 
I P;  b e gi n  F oll o w-u p  P eri o d;  c o m pl et e 
e C R F f or  c ar di a c  A E SI.  
A E SI  =  a d v ers e  e v e nts  of s p e ci al i nt er est;  c T nI  =  c ar di a c tr o p o ni n -I;  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; I P   = i n v esti g ati o n al  pr o d u ct;  L V E F  = l eft  v e ntri c ul ar  ej e cti o n fr a cti o n;  M RI  =  m a g n eti c 
r es o n a n c e i m a gi n g;  U R L  =  u p p er r ef er e n c e li mit;  W M A  = w all  m oti o n  a b n or m alit y . 
a  
e g,  n e w  W M A  a n d /  or  L V E F  <  5 0 %  o n  m y o c ar di al i m a gi n g ( e c h o c ar di o gr a m, r a di o n u cli d e i m a gi n g,  or 
M RI),  n e w  a b n or m al  d el a y e d  e n h a n c e m e nt  o n  c ar di a c  M RI,  or  n e w  Q -w a v es  or is c h e mi c  c h a n g es  o n  E C G.  
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
9. 2   S e v e rit y  of  A d v e rs e  E v e nts  
T h e s e v erit y  of  e a c h  A E,  S A E,  a n d  A E SI is t o  b e  ass ess e d  b y t h e  I nv esti g at or  as f oll o ws: 
S e v e rit y   
D efi niti o n  
Mil d  
A t y p e  of  A E t h at is  us u all y tr a nsi e nt  a n d  m a y r e q uir e  o nl y  mi ni m al tr e at m e nt  or t h er a p e uti c 
i nt er v e nti o n.  T h e  e v e nt  d o es  n ot  g e n er all y i nt erf er e  wit h  us u al  a cti viti es  of  d ail y li vi n g. 
M o d er at e  
A t y p e  of  A E t h at is  us u all y  all e vi at e d  wit h  a d diti o n al s p e cifi c t h er a p e uti c i nt er v e nti o n.  T h e 
e v e nt i nt erf er es  wit h  us u al  a cti viti es  of  d ail y li vi n g,  c a usi n g  dis c o mf ort  b ut  p os es  n o 
si g nifi c a nt  or  p er m a n e nt ris k  of  h ar m t o t h e s u bj e ct.  
S e v er e  
A t y p e  of  A E t h at i nt err u pts  us u al  a cti viti es  of  d ail y li vi n g,  or si g nifi c a ntl y  aff e cts  cli ni c al 
st at us,  or  m a y r e q uir e i nt e nsi v e t h er a p e uti c i nt er v e nti o n.  
A E  =  a d v ers e  e v e nt.  
S o ur c e:  Cli ni c al  D at a I nt er c h a n g e  St a n d ar ds  C o ns orti u m ( C DI S C)  St u d y  D at a  Ta b ul ati o n  M o d el ( S D T M) 
S e v erit y I nt e nsit y  S c al e f or  A d v ers e  E v e nt  Ter mi n ol o g y.  
9. 3   C a us alit y  of  A d v e rs e  E v e nts  
T h e  c a us al r el ati o ns hi p  of  a n  A E t o I P  m ust  al w a ys  b e  ass ess e d  b y t h e I n v esti g at or .  All  A Es 
will  b e  cl assifi e d  as  eit h er  r el at e d  or  n ot  r el at e d  t o I P. If a  c a us alit y  ass ess m e nt is  n ot 
pr o vi d e d  f or  a n  A E (i n cl u di n g  a n  S A E), t h at  A E  will  b e  c o nsi d er e d r el at e d t o  I P. 
T h e  d e gr e e  of  c ert ai nt y  wit h  w hi c h  a n  A E is  attri b ut e d t o I P  or  a n  alt er n ati v e  c a us e ( e g,  n at ur al 
hist or y  of t h e  u n d erl yi n g  dis e as e,  c o n c o mit a nt t h er a p y)  will  b e  d et er mi n e d  b y  h o w  w ell t h e 
e v e nt  c a n  b e  u n d erst o o d i n t er ms  of: 
•   K n o w n  p h ar m a c ol o g y  of  C S L 3 4 6 
•   Cli ni c all y  a n d /  or  p at h o p h ysi ol o gi c all y  pl a usi bl e  c o nt e xt 
•   R e a cti o n  of  a si mil ar  n at ur e  pr e vi o usl y  o bs er v e d  wit h si mil ar  pr o d u cts,  or r e p ort e d i n t h e 
lit er at ur e f or si mil ar  pr o d u cts  as  b ei n g  pr o d u ct r el at e d ( e g,  h e a d a c h e, f a ci al fl us hi n g, 
p all or) 
•   Pl a usi bilit y s u p p ort e d  b y t h e t e m p or al r el ati o ns hi p ( e g, t h e  e v e nt  b ei n g r el at e d  b y ti m e t o 
a d mi nistr ati o n  or t er mi n ati o n  of tr e at m e nt  wit h  C S L 3 4 6,  dr u g  wit h dr a w al  or r e pr o d u c e d  o n 
r e c h all e n g e) 
9. 4   O bs e r v ati o n  P e ri o d f o r  A d v e rs e  E v e nts  
T h e  o bs er v ati o n  p eri o d f or  A E ( a n d  S A E  or  A E SI) r e p orti n g f or  a n i n di vi d u al s u bj e ct  will st art 
at t h e ti m e  of  gi vi n g  writt e n i nf or m e d  c o ns e nt f or  p arti ci p ati o n i n t h e  c urr e nt st u d y  a n d fi nis h 
at  t h e i n di vi d u al s u bj e ct’s  E O S  Visit. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
If t h e I n v esti g at or b e c o m es  a w ar e  of  a n  S A E t h at  h as st art e d  aft er t h e  o bs er v ati o n  p eri o d  h as 
fi nis h e d,  a n d t h er e is  at l e ast  a  p ossi bl e  c a us al r el ati o ns hi p t o  C S L 3 4 6, t h e  e v e nt  m ust  b e 
r e p ort e d t o  C S L (s e e S e cti o n  9. 6. 3 ). 
9. 5   F oll o w -u p  of  A d v e rs e  E v e nts  
E v er y  eff ort s h o ul d  b e  m a d e t o f oll o w  A Es  u ntil r es ol uti o n  or st a bili z ati o n.  O n g oi n g, 
n o ns eri o us  A Es t h at  h a v e  n ot  r es ol v e d  or st a bili z e d  will  b e f oll o w e d  u ntil t h e s u bj e ct  c o m pl et es 
t h e st u d y.  S eri o us  a d v ers e  e v e nts  will  b e f oll o w e d  u ntil t h e  A E r es ol v es, st a bili z es,  or t h e 
s u bj e ct is l ost t o f oll o w- u p. 
9. 6   A d v e rs e  E v e nt  R e p o rti n g  
9. 6. 1   
A d v e rs e  E v e nts  
At  e a c h  cli ni c al  e v al u ati o n, t h e I n v esti g at or  ( or  d el e g at e)  will  d et er mi n e  w h et h er  a n y  A Es  h a v e 
o c c urr e d.  All  A Es  ar e t o  b e r e c or d e d i n t h e  e C R F. If  k n o w n, t h e  m e di c al  di a g n osis  of  a n  A E 
s h o ul d  b e r e c or d e d i n  pr ef er e n c e t o t h e listi n g  of i n di vi d u al si g ns, l a b or at or y fi n di n gs,  a n d /  or 
s y m pt o ms.  T h e I n v esti g at or  m ust f oll o w  u p  o n t h e  c o urs e  of  a n  A E  u ntil r es ol uti o n  or 
st a bili z ati o n. If  a n  A E is  o n g oi n g  aft er t h e  E O S  Visit, t h e  A E  will  c o nti n u e t o  b e f oll o w e d  u p 
u ntil r es ol uti o n, st a bili z ati o n,  or t h e s u bj e ct is l ost t o f oll o w - u p. 
If,  d uri n g t h e st u d y  p eri o d,  a s u bj e ct  pr es e nts  wit h  a  pr e e xisti n g  c o n diti o n t h at  w as  n ot  n ot e d  at 
t h e ti m e  of st u d y  e ntr y, t h e  c o n diti o n s h o ul d  b e r etr os p e cti v el y r e c or d e d i n t h e  M e di c al  Hist or y 
e C R F.  
9. 6. 2   
A d v e rs e  E v e nts  of  S p e ci al I nt e r est  
A d v ers e  e v e nts  of s p e ci al i nt er est s h o ul d  b e r e p ort e d f oll o wi n g  e x p e dit e d r e p orti n g  pr o c e d ur es, 
as  d es cri b e d f or  S A Es  ( S e cti o n 9. 6. 3 ).  All  A E SIs (i n cl u di n g  n o n-s eri o us a n d s eri o us) t h at  o c c ur 
d uri n g t h e  c o urs e  of t h e st u d y,  w h et h er  or  n ot  c a us all y r el at e d t o I P,  m ust  b e  e nt er e d i nt o t h e 
A E/ S A E/ A E SI   e C R F i m m e di at el y ( wit hi n  2 4  h o urs  of t h e I n v esti g at or b e c o mi n g  a w ar e  of t h e 
e v e nt)  a n d r e p ort e d t o  C S L.  A n  ass ess m e nt  of  c a us alit y t o t h e I P  m ust  b e i n cl u d e d. 
9. 6. 3   
S e ri o us  A d v e rs e  E v e nts  
T his st u d y  will  c o m pl y  wit h  all  a p pli c a bl e r e g ul at or y r e q uir e m e nts  a n d  a d h er e t o t h e f ull 
r e q uir e m e nts  of 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). 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
F or  S A Es  o c c urri n g  d uri n g t h e st u d y, t h e I n v esti g at or  or  d el e g at e  will  e nt er  all r el e v a nt 
i nf or m ati o n i n t h e  e C R F. 
All  S A Es t h at  o c c u r  d u ri n g t h e  c o u rs e  of t h e st u d y,  w h et h e r  o r  n ot  c a us all y  r el at e d t o I P, 
m ust  b e  e nt e r e d i nt o t h e  e C R F i m m e di at el y  ( wit hi n  2 4  h o u rs  of t h e I n v esti g at o r 
b e c o mi n g  a w a r e  of t h e  e v e nt).  A n  ass ess m e nt  of  c a us alit y t o t h e I P  m ust  b e i n cl u d e d.  
A d v ers e  e v e nts  o c c urri n g i n t h e  p eri o d  b et w e e n t h e ti m e t h e s u bj e ct  g a v e  writt e n i nf or m e d 
c o ns e nt  a n d t h e first  e x p os ur e t o I P,  a n d t h at  m e et  1  or  m or e  of t h e s eri o us n ess  crit eri a,  m ust  b e 
e nt er e d i nt o t h e  e C R F i n t h e s a m e  m a n n er  as  ot h er  S A Es  a n d  will  b e i n cl u d e d i n t h e  cli ni c al 
st u d y  d at a b as e.  
A n y  S A E t h at  o c c urs  aft er t h e  E O S  visit t h at is  c o nsi d er e d t o  b e  c a us all y r el at e d t o I P  m ust  b e 
r e p o rt e d i m m e di at el y (i e,  wit hi n  2 4  h o u rs  of t h e  I n v esti g at o r  b e c o mi n g  a w a r e  of t h e 
e v e nt) t o  C S L.  S u c h  e v e nts  ar e  n ot  e nt er e d i nt o t h e  e C R F. 
T h e  mi ni m u m r e p orti n g r e q uir e m e nts f or r e p orti n g  of  S A Es i n cl u d e t h e f oll o wi n g: 
•   S u bj e ct i d e ntifi c ati o n  n u m b er 
•   S us p e ct e d  m e di ci n al  pr o d u ct  a n d /  or  pr o c e d ur e 
•   E v e nt t er m  
•   R e p orti n g s o ur c e i d e ntifi c ati o n 
If t h e  mi ni m u m r e q uir e m e nts f or r e p orti n g  ar e f ulfill e d, t h e I n v esti g at or s h o ul d  n ot  w ait t o 
r e c ei v e  a d diti o n al i nf or m ati o n t o f ull y  d o c u m e nt t h e  e v e nt.  
I n  a d diti o n, t h e I n v esti g at or  m ust  d o t h e f oll o wi n g: 
•   R e p ort  all  S A Es t o t h e r el e v a nt I nstit uti o n al  R e vi e w  B o ar d (I R B) / I n d e p e n d e nt  Et hi cs 
C o m mitt e e (I E C)  wit hi n t h e ti m efr a m e s p e cifi e d  b y t h e I R B / I E C  
•   If t h e s u bj e ct is  a n  a cti v e  p arti ci p a nt i n t h e st u d y: 
o   E nt er  f oll o w- u p i nf or m ati o n i n t h e  e C R F  u ntil t h e  S A E  h as r es ol v e d,  or, i n t h e  c as e  of 
p er m a n e nt i m p air m e nt,  u ntil st a bili z e d  
o   E ns ur e t h at t h e  c a us alit y  ass ess m e nt f or  all  S A Es is  e nt er e d i n t h e  e C R F  
•   If t h e s u bj e ct is  n o l o n g er  p arti ci p ati n g i n t h e st u d y, r e p ort t h e f oll o w- u p i nf or m ati o n t o 
C S L  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
I n  c as es  of  d e at h, t h e I n v esti g at or s h o ul d s u p pl y  C S L  a n d t h e I R B / I E C ( as  a p pli c a bl e)  wit h 
a n y  a d diti o n al i nf or m ati o n  as it  b e c o m es  a v ail a bl e ( e g,  a ut o ps y r e p orts  a n d  d et ail e d  m e di c al 
r e p orts). 
9. 6. 4   
Ot h e r  Si g nifi c a nt  E v e nts  
N o t  a p pli c a bl e. 
9. 6. 5   
O v e r d os e  
A n y  o v er d os e t h at  o c c urs i n  ass o ci ati o n  wit h  a n  a d v ers e si g n  or s y m pt o m  m ust  b e  e nt er e d i nt o 
t h e  e C R F  as  a n  A E; if t h e  A E  m e ets  a n y s eri o us n ess  crit eri a, t h e  e v e nt  m ust  b e r e p ort e d  as  a n 
S A E (s e e  S e cti o n  9. 6. 3 ).  A n y  o v er d os e t h at  d o es  n ot r es ult i n  a n y  a d v ers e si g ns  or s y m pt o ms 
s h o ul d  n ot  b e  c o nsi d er e d  a n  A E (s e e  S e cti o n  9. 1. 1 ). 
D et ails (i e,  v ol u m e, l o c ati o n  of i nf usi o ns, i nf usi o n r at e)  of  o v er d os e  of  C S L 3 4 6 ( d efi n e d i n 
S e cti o n  5. 1. 3. 3 )  m ust  b e r e c or d e d i n t h e st u d y tr e at m e nt  a d mi nistr ati o n  e C R F.  D et ails  of 
o v er d os e  of  a n y  c o n c o mit a nt t h er a p y  m ust  b e r e c or d e d i n t h e  C o n c o mit a nt  M e di c ati o n  e C R F. 
9. 6. 6   
P r e g n a n c y  a n d  B r e astf e e di n g   
A f e m al e s u bj e ct  or f e m al e  p art n er  of  a  m al e s u bj e ct  w h o  b e c o m es  pr e g n a nt  w hil e  p arti ci p ati n g 
i n t h e st u d y,  or  u p t o  a n d i n cl u di n g  3  m o nt hs  aft er t h e l ast  d os e of t h e I P,  m ust  n otif y t h e 
I n v esti g at or i m m e di at el y.  
If  a f e m al e s u bj e ct  b e c o m es  pr e g n a nt or i n iti at es  br e astf e e di n g, s h e  m ust  dis c o nti n u e tr e at m e nt 
wit h t h e I P i m m e di at el y,  h er  p arti ci p ati o n  will  b e  dis c o nti n u e d,  a n d t h e  pr o c e d ur e f or 
dis c o nti n u ati o n  of  a s u bj e ct  will  b e f oll o w e d,  as  d es cri b e d i n  S e cti o n  4. 3 . 
C S L  m ust  b e  n otifi e d  wit hi n  5  d a ys  of t h e I n v esti g at or  b e c o mi n g  a w ar e  of t h e  pr e g n a n c y ( b y 
e ntr y  of  a p pr o pri at e  d at a i nt o t h e  e C R F).  C S L  m ust  als o  b e  n otifi e d  wit hi n  5  d a ys  of t h e 
I n v esti g at or  b e c o mi n g  a w ar e  of  a n y  pr e g n a n c y  o c c urri n g  at  a n y ti m e  u p t o  3  m o nt hs  aft er  e a c h 
s u bj e ct’s fi n al st u d y  visit. 
W h e n e v er  p ossi bl e,  a  pr e g n a n c y i n  a f e m al e s u bj e ct  or f e m al e  p art n er  of  a  m al e s u bj e ct 
e x p os e d t o  C S L 3 4 6 s h o ul d  b e f oll o w e d t o t er m s o  as t o  as s ess  a n y  p ot e nti al  o c c urr e n c e  of 
c o n g e nit al  a n o m ali es  or  birt h  d ef e cts.  A n y f oll o w- u p i nf or m ati o n, i n cl u di n g  pr e m at ur e 
t er mi n ati o n  a n d t h e st at us  of t h e  m ot h er  a n d  c hil d  aft er  d eli v er y, s h o ul d  b e r e p ort e d  b y t h e 
I n v esti g at or t o  C S L  usi n g  a  Pr e g n a n c y  R e p orti n g /  O ut c o m e  F or m. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
All  a b n or m al  pr e g n a n ci es  a n d  n e o n at al  o ut c o m es ( e g, s p o nt a n e o us  a b orti o n, still birt h,  n e o n at al 
d e at h , or  c o n g e nit al  a n o m al y)  will  m e et t h e  crit eri a f or  S A E  cl assifi c ati o n.  T h e  I n v esti g at or 
s h o ul d f oll o w t h e  pr o c e d ur e f or r e p orti n g t h es e  e v e nts  as  S A Es ( S e cti o n  9. 6. 3 ). 
9. 7   I nstit uti o n al  R e vi e w  B o a r d / I n d e p e n d e nt  Et hi cs  C o m mitt e e 
R e p o rti n g  R e q ui r e m e nts  
T h e ti m e fr a m e  wit hi n  w hi c h  a n I R B / I E C  m ust  b e  n otifi e d  of  d e at hs  a n d I P- r el at e d 
u n e x p e ct e d  S A Es is sti p ul at e d  b y  e a c h I R B / I E C.  It is t h e I n v esti g at or’s r es p o nsi bilit y t o 
c o m pl y  wit h t h e r e q uir e m e nts f or I R B / I E C  n otifi c ati o n.  C S L  will  pr o vi d e I n v esti g at or s  wit h 
all  d et ails  of  all  S A Es r e p ort e d t o  h e alt h  a ut h oriti es.  
1 0   St atisti cs  
1 0. 1   S a m pl e  Si z e  Esti m ati o n  
T h e s a m pl e si z e  esti m ati o n is  b as e d  o n  2 tr e at m e nt  ar ms  b e c a us e t h e  pri m a r y  e n d p oi nt  a n al ys es 
will  c o m p ar e  C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g  c o m bi n e d)  wit h  pl a c e b o.  T h e  pl a n n e d s a m pl e 
si z e is  1 0 0 s u bj e cts  wit h  5 0 s u bj e cts r e c ei vi n g  C S L 3 4 6 ( 8  m g/ k g,  n  =  2 5  a n d  1 6  m g/ k g,  n  =  2 5) 
a n d  5 0 s u bj e cts r e c ei vi n g  pl a c e b o.  Ass u mi n g  a n  S D  of  0. 6 5 f or t h e  c h a n g e fr o m  B as eli n e t o 
We e k  1 6 ( Visit  1 0) i n  A C R f oll o wi n g  n at ur al l o g tr a nsf or m ati o n,  a s a m pl e si z e  of  9 4 s u bj e cts is 
esti m at e d t o  pr o vi d e  8 5 %  p o w er t o  d et e ct  a  2 7 % r e d u cti o n i n t h e  g e o m etri c  m e a n  A C R f or 
C S L 3 4 6  v ers us  pl a c e b o, i e, l n  ( 1 –  0. 2 7 )  = – 0. 3 1 5  o n t h e  n at ur al l o g s c al e,  usi n g  a  1-si d e d 
al p h a  =  0. 1 0.  F or t his st u d y, st atisti c al si g nifi c a n c e  will  b e  a c hi e v e d  wit h  a n  o bs er v e d tr e at m e nt 
eff e ct  of  – 0. 1 7 3  o n t h e  n at ur al l o g s c al e,  or  a p pr o xi m at el y  – 1 6 %  w h e n  e x pr ess e d  as  a  p er c e nt 
diff er e n c e  i n tr e at m e nts,  d e p e n di n g  o n t h e  o bs er v e d  v ari a bilit y.  T h e t ot al s a m pl e si z e  a c c o u nts 
f or  a n  ass u m e d  6 %  dr o p-o ut r at e.  T h e  a ct u al  e arl y  dis c o nti n u ati o n r at e  will  b e  ass ess e d 
t hr o u g h o ut t h e st u d y  a n d  u p t o  1 2 4 s u bj e cts  m a y  b e r a n d o mi z e d if  n e c ess ar y, t o t ar get 
9 4  c o m pl et e d s u bj e cts (s u bj e cts  w h o r e c ei v e d  all  d os es  a n d  c o m pl et e d t h e  We e k  1 6  A C R 
ass ess m e nt).  
1 0. 2   D es c ri pti o n  of  St u d y  A n al ysis  S ets  
1 0. 2. 1   S c r e e n e d  A n al ysis  S et  
T h e  S cr e e n e d  A n al ysis  S et  c o m pris es  of  all s u bj e cts  w h o  pr o vi d e d  writt e n i nf or m e d  c o ns e nt. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 0. 2. 2   I nt e nt-t o-Tr e at  A n al ysis  S et  
T h e I nt e nt- t o-Tr e at (I T T)  A n al ysis  S et  c o m pris es  all s u bj e cts  w h o  w er e r a n d o mi z e d.  T h e I T T 
a n al ysis s et  will  b e  a n al y z e d  usi n g t h e tr e at m e nt t o  w hi c h t h e s u bj e ct  w as r a n d o mi z e d, 
r e g ar dl ess  of t h e tr e at m e nt  a ct u all y r e c ei v e d.  T he I T T  a n al ysis s et  will  b e  us e d i n t h e  a n al ysis 
of t h e  pri m ar y  e n d p oi nt. 
A n y s u bj e ct  w h o r e c ei v es  a tr e at m e nt r a n d o mi z ati o n  n u m b er  will  b e  c o nsi d er e d t o  h a v e  b e e n 
r a n d o mi z e d. 
1 0. 2. 3   S af et y  A n al ysis  S et  
T h e  S af et y  A n al ysis  S et  c o m pris es  all s u bj e cts i n t h e I T T  A n a l ysis  S et  w h o r e c ei v e  at l e ast 
1  d os e  of  C S L 3 4 6  or  pl a c e b o,  a n d  will  b e  b as e d  o n t h e  a ct u al tr e at m e nt r e c ei v e d. 
1 0. 2. 4   P e r -p r ot o c ol  A n al ysis  S et  
T h e  P er -Pr ot o c ol ( P P)  A n al ysis  S et  c o m pris es  all s u bj e cts i n t h e I T T  A n al ysis  S et  w h o  c o m pl y 
wit h t h e  pr ot o c ol  a n d  c o m pl et e tr e at m e nt.  Pr ot o c ol  d e vi ati o ns  a n d tr e at m e nt  dis c o nti n u ati o ns 
t h at  will r es ult i n  e x cl usi o n fr o m t h e  P P  A n al ysis  S et  will  b e  d o c u m e nt e d i n t h e  d at a r e vi e w 
m e eti n g  mi n ut es  b ef or e  d at a b as e l o c k  a n d  b ef or e st u d y  d at a  u n bli n di n g.  Pr ot o c ol  d e vi ati o ns 
a n d  tr e at m e nt  dis c o nti n u ati o ns  m a y l e a d t o t h e  e x cl usi o n  of t h e s u bj e ct’s  c o m pl et e s et  of  d at a 
or  a  p orti o n  of t h e s u bj e ct’s  d at a ( e g,  e x cl u di n g  effi c a c y  d at a  c oll e ct e d  aft er  wit h dr a w al  of I P). 
1 0. 2. 5   P h a r m a c o ki n eti c  A n al ysis  S et  
T h e  P K  A n al ysis  S et  c o m pris es  all s u b j e cts  w h o r e c ei v e  a n i nf usi o n  of  C S L 3 4 6  wit h  at l e ast 
1  q u a ntifi a bl e  c o n c e ntr ati o n  of  C S L 3 4 6  aft er  a d mi nistr ati o n. 
1 0. 2. 6   P h a r m a c o d y n a mi c  A n al ysis  S et  
T h e  P D  A n al ysis  S et  c o m pris es s u bj e cts i n t h e  S af et y  A n al ysis  S et f or  w h o m  a n al ysis r es ults 
w er e  o bt ai n e d f or  at  l e ast  1  of t h e  e x pl or at or y  bi o m ar k ers  of i nt er est. 
1 0. 3   St atisti c al  A n al ys es  a n d  M et h o ds  
All  a n al ys es  will  b e  c o n d u ct e d  usi n g  S A S  Versi o n  9. 3  or  hi g h er. I n  g e n er al,  c o nti n u o us 
v ari a bl es  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs ( n u m b er  of  o bs er v ati o ns,  m e a n,  S D , 
9 5 %  CI,  m e di a n,  mi ni m u m  a n d  m a xi m u m).  F or r e p e at e d  m e as ur es,  a bs ol ut e  a n d  c h a n g e fr o m 
b as eli n e  v al u es  will  b e s u m m ari z e d.  F or  p ar a m et ers  w hi c h  ar e  k n o w n t o  h a v e  n o n n or m al 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
distri b uti o ns,  n at ur al l o g tr a nsf or m ati o n  m a y  b e  p erf or m e d  b ef or e st atisti c al  a n al ysis. 
C at e g ori c al  v ari a bl es  will  b e  d es cri b e d  usi n g  p er c e nt a g es  a n d fr e q u e n ci es . 
F or r a n d o mi z ati o n, s u bj e cts  will  b e str atifi e d  a c c or di n g t o  w h et h er  or  n ot t h eir  b a c k gr o u n d 
tr e at m e nt i n cl u d es  a n  S G L T 2 i n hi bit or.  E v er y  eff ort  will  b e  m a d e t o  e ns ur e t h at  at l e ast  5 0 %  of 
r a n d o mi z e d s u bj e cts  ar e  c urr e ntl y t a ki n g  a n  S G L T 2 i n hi bit or. 
A  c o m pl et e  d es cri pti o n  of t h e st atisti c al  a n al ys es  a n d  m et h o ds  will  b e  a v ail a bl e i n  a st atisti c al 
a n al ysis  pl a n ( S A P),  w hi c h  will  b e fi n ali z e d  b ef or e t h e  d at a b as e is l o c k e d.  
1 0. 3. 1   S u bj e ct  Dis p ositi o n  a n d  C h a r a ct e risti cs  
1 0. 3. 1. 1   S u bj e ct  Dis p ositi o n  
S u m m ar y t a bl es  b y tr e at m e nt   gr o u p ( 8  m g/ k g  C S L 3 4 6,  1 6  m g/ k g  C S L 3 4 6,  C S L 3 4 6  c o m bi n e d, 
a n d  pl a c e b o)  a n d t ot al  p o p ul ati o n  will  pr es e nt t h e f oll o wi n g: 
•   T h e  n u m b er  of s u bj e cts  e nr oll e d i nt o t h e st u d y (i e, si g n e d t h e I C F) 
•   T h e  n u m b er  of s u bj e cts r a n d o mi z e d  a n d  w h o  w er e  wit h dr a w n  d u e t o f ail ur e t o  m e et t h e 
R a n d o mi z ati o n  Crit eri a  
•   T h e  n u m b er  of s u bj e cts  w h o r e c ei v e d I P 
•   T h e  n u m b er  of s u bj e cts  w h o  pr e m at ur el y  dis c o nti n u e d I P 
•   T h e  n u m b er  of s u bj e cts  w h o  w er e  wit h dr a w n fr o m t h e st u d y 
•   T h e  n u m b er  of s u bj e cts  w h o  c o m pl et e d t h e st u d y 
Si mil ar t a bl es  will   als o  b e  pr o vi d e d f or  e a c h str at a (i e, t h e  us e  of  c o n c o mit a nt  S G L T 2 
i n hi bit ors). 
R e as o ns f or  dis c o nti n ui n g t h e I P  a n d  wit h dr a wi n g  a s u bj e ct fr o m t h e st u d y  will  b e list e d  b y 
s u bj e ct. 
1 0. 3. 1. 2   S u bj e ct  C h a r a ct e risti cs  
At  mi ni m u m, s u bj e ct  c h ar a ct eristi cs  will  b e  pr es e nt e d i n s u m m ar y t a bl es.  C o nti n u o us  d at a  will 
b e s u m m ari z e d  b y  d es cri pti v e st atisti cs  a n d  c at e g ori c al  d at a  will  b e s u m m ari z e d  b y fr e q u e n c y 
distri b uti o ns.  A g e  will  b e  d es cri b e d  as  b ot h  a  c o nti n u o us  a n d  a  dis cr et e  v ari a bl e.  S u p p orti v e 
d at a  will  b e list e d   b y s u bj e ct. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 0. 3. 2   Effi c a c y  A n al ys es  
Pri m ar y  E n d p oi nt 
T h e  pri m ar y  a n al ysis is  a  mi x e d  eff e cts  m o d el, r e p e at e d  m e as ur es ( M M R M)  a n al ysis  of t h e 
c h a n g e fr o m  B as eli n e  t hr o u g h  2 4  w e e ks  of l o g  A C R,  wit h t h e  pri m ar y tr e at m e nt  c o m p aris o n  at 
We e k  1 6 ( Visit  1 0).  T h e  m o d el  will i n cl u d e tr e at m e nt ( at  3 l e v els:  8  m g/ k g  C S L 3 4 6, 
1 6  m g/ k g  C S L 3 4 6,  a n d  pl a c e b o),  B as eli n e  l o g  A C R, t h e str atifi c ati o n  v ari a bl e r el at e d t o t h e 
c o n c o mit a nt  us e  of  S G L T 2 i n hi bit ors,  visit ( as  a  c at e g ori c al f a ct or),  a n d i nt er a cti o ns  b et w e e n 
visit  a n d  e a c h  of t h e  ot h er  m o d el t er ms  as f a ct ors.  T h e  pri m ar y  c o m p aris o n  of i nt er est is  a 
c o ntr ast  of  0. 5 ( 8  m g/ k g  C S L 3 4 6  +  1 6  m g/ k g  C S L 3 4 6)  –  Pl a c e b o.  Esti m at e d tr e at m e nt  eff e ct 
of i n di vi d u al  C S L 3 4 6  d os e l e v els  v ers us  pl a c e b o  will  als o  b e s u m m ari z e d.  T h e tr e at m e nt 
c o m p aris o ns  will  b e  e x pr ess e d  as  a  p er c e nt  diff er e n c e i n tr e at m e nts,  c al c ul at e d  as 
1 0 0 %  ×  ( g e o m etri c  m e a n r ati o  of t h e tr e at m e nt  c o m p aris o n –  1).  F or t h e  p ur p os es  of t his 
a n al ysis,  B as eli n e  will  b e  d efi n e d  as t h e  g e o m etri c  m e a n  of t h e  6  v al u es  o bt ai n e d  b ef or e 
tr e at m e nt ( 3  v al u es fr o m  Visit  3  a n d  3 v al u es i m m e di at el y  b ef or e tr e at m e nt  at  Visit  4).  T h e 
pr o c e d ur e f or  d et er mi ni n g t h e  c o v ari a n c e  m o d el f or l o g  A C R r esi d u als  will  b e  d efi n e d i n t h e 
S A P.  T h er e  will  b e  o nl y  1  pri m ar y  c o m p aris o n s o t h er e is  n o  c o nsi d er ati o n  of  a dj ust m e nt f or 
m ulti pl e  c o m p aris o ns.  C o m p aris o ns  of  C S L 3 4 6  d os e l e v els  wit h  pl a c e b o  will  b e  c o nsi d er e d 
e x pl or at or y.  T h e  pri m ar y  a n al ysis  will  b e  p erf or m e d  usi n g t h e I T T  A n al ysis  S et. 
T w o s e nsiti vit y  a n al ys es  will  b e  c o nsi d er e d f or t h e  pri m ar y  e n d p oi nt.  T h e first s u c h  a n al ysis 
c o nsi d ers t h e  eff e cts  of  C O VI D - 1 9  o n t h e  pri m ar y  e n d p oi nt. F or s u bj e cts  wit h tr e at m e nt 
dis c o nti n u ati o n / i nt err u pti o n  d u e t o  l o gisti c al  p a n d e mi c-r el at e d r e as o ns,  o bs er v ati o ns  gr e at er 
t h a n  2 8  d a ys  aft er l ast  o n-s c h e d ul e  S C i nf usi on r e c ei v e d  will  b e  e x cl u d e d .  F or s u bj e cts  w h o 
r e c ei v e d  n o i nf usi o ns  d u e t o l o gisti c al  p a n d e mi c-r el at e d r e as o ns,  all  d at a  will  b e  e x cl u d e d.  F or 
s u bj e cts  w h o  c o ntr a ct  C O VI D- 1 9 i nf e cti o n  d uri n g t h e st u d y,  o bs er v ati o ns  o n  or  aft er t h e 
i nf e cti o n  d at e  will  b e  e xcl u d e d. If  b ot h  c o n diti o ns  a p pl y, t h e n  d at a  e x cl usi o n  will  b e gi n  at 
( a)  2 8  d a ys  aft er t h e l ast  S C i nf usi o n  or ( b) t h e i nf e cti o n  d at e, w hi c h e v er is  e arli er . T h e s e c o n d 
s e nsiti vit y a n al ysis  is  a ti p pi n g  p oi nt  a n al ysis t h at will  e m pl o y  m ulti pl e i m p ut ati o n f or  missi n g 
d at a  usi n g  m ulti pl e r e gr essi o n t o  pr o vi d e  m ulti pl e  c o m pl et e  d at a s ets.  T h e s a m e  M M R M  m o d el 
will  b e  us e d t o  a n al y z e t h e  c o m pl et e  d at a s et.  
F or  d e cisi o n- m a ki n g  a n d  d e v el o p m e nt  p ur p os es,  a n i nt eri m  a n al ysis  of  u n bli n d e d  d at a  will  b e 
p er f or m e d  aft er  e nr oll m e nt is  c o m pl et e  a n d  all r a n d o mi z e d s u bj e cts  c o m pl et e t h e  1 6-w e e k 
A C R  m e as ur e m e nt (i e,  4  w e e ks  aft er t h e f o urt h  d os e).  T h es e r es ults  will  b e s u m m ari z e d i n  a n 
i nt eri m,  n o nr e g ul at or y,  a n al yti c al r e p ort.  A f or m al  d at a  c ut off  a n d  u n bli n di n g will  o c c ur  at t his 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  9 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
mil est o n e,  as  d es cri b e d i n  S e cti o n  6. 3. 3 .  A fi n al st atisti c al  a n al ysis  of  all  effi c a c y  a n d s af et y 
d at a  will  o c c ur  aft er  all s u bj e cts  h a v e  c o m pl et e d t h e f ull  2 4  w e e ks  of t h e st u d y f or t h e  cli ni c al 
st u d y r e p ort. 
1 0. 3. 3   S af et y  A n al ys es  
S e c o n d ar y  E n d p oi nts 
Tr e at m e nt - e m er g e nt  A Es,  d efi n e d  as  A Es  o c c urri n g  at  or  aft er t h e st art  of st u d y tr e at m e nt,  will 
b e s u m m ari z e d f or  e a c h  C S L 3 4 6  d os e l e v el ( 8  m g/ k g  a n d  1 6  m g/ k g)  a n d  pl a c e b o.  A n  o v er vi e w 
s u m m ar y  of  A Es, i n cl u di n g t h e  n u m b er  of s u bj e cts  wit h  a n y  A E;  A Es r el at e d t o st u d y 
tr e at m e nt;  A Es l e a di n g t o  dis c o nti n u ati o n  of st u d y tr e at m e nt;  S A Es;  a n d  d e at hs  will  b e 
pr o d u c e d.  Tr e at m e nt -e m er g e nt  A Es  will  b e s u m m ari z e d  b y  pr ef err e d t er m  a n d s yst e m  or g a n 
cl ass  as  w ell  as s e v erit y.  T h es e  a n al ys es  will  b e  p erf or m e d  o n t h e  S af et y  A n al ysis  S et.  A d v ers e 
e v e nts  of s p e ci al i nt er est ( A E SIs)  will  als o  b e s u m m ari z e d s e p ar at el y.  
T h e  a n al ysis  of  S Cr,  e G F R,  a n d  B P  will  e m pl o y  a  m o d el si mil ar t o t h e  pri m ar y  e n d p oi nt.  T h e 
a n al ysis f or t h es e  c o nti n u o us  e n d p oi nts is  a n  M M R M  a n al ysis  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  m e as ur e m e nt.  Si mil ar t o t h e  d efi niti o n i n  S e cti o n  1 0. 3. 2 ,  b as eli n e f or t h es e 
p ar a m et ers  will  b e t h e  a v er a g e  of t h e  v al u es  o bt ai n e d  at  Visit  3  a n d  Visit  4  b ef or e tr e at m e nt. 
T h e  m o d el  will i n cl u d e tr e at m e nt, str atifi c ati o n r el at e d t o t h e  c o n c o mit a nt  us e  of  S G L T 2 
i n hi bit ors,  visit ( as  a  c at e g ori c al f a ct or), i nt er acti o ns  b et w e e n  visit  a n d  e a c h  of t h e  ot h er  m o d el 
t er ms,  as  w ell  as t h e  c orr es p o n di n g  b as eli n e  m e as ur e m e nt  as  a  c o v ari at e.  As  wit h t h e  pri m ar y 
e n d p oi nt  a n al ysis, t h e  pri m ar y  c o m p aris o n  will  b e  of  C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g 
c o m bi n e d)  v ers us  pl a c e b o.  E x pl or at or y  c o m p aris o ns  of  C S L 3 4 6  d os e l e v els  wit h  pl a c e b o  will 
als o  b e  d o n e.  T h es e  a n al ys es  will  b e  p erf or m e d  o n t h e  S af et y  A n al ysis  S et.  
1 0. 3. 4   P h a r m a c o ki n eti c  A n al ys es  
S e c o n d ar y  E n d p oi nts 
S er u m  c o n c e ntr ati o ns  of  C S L 3 4 6  will  b e list e d  b y i n di vi d u al s u bj e ct  a n d  will  b e s u m m ari z e d 
b y  d os e l e v el  a n d  n o mi n al ti m e  p oi nt  usi n g  d es cri pti v e st atisti cs (i e,  n,  arit h m eti c  m e a n,  S D, 
C V %,  m e di a n,  g e o m etri c  m e a n,  g e o m etri c  C V %,  mi ni m u m,  a n d  m a xi m u m). I n di vi d u al s u bj e ct 
C S L 3 4 6 s er u m  c o n c e ntr ati o n  v ers us ti m e  will  b e  pl ott e d  o n li n e ar  a n d s e mil o g arit h mi c s c al es. 
T h e  C tr o u g h  of  C S L 3 4 6  will  als o  b e s u m m ari z e d  vis u all y,  b y  d os e l e v el. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
P K  p ar a m et ers  will  b e  d eri v e d  usi n g  n o n c o m p art m e nt al  a n al ys es,  a n d  will i n cl u d e  t h e 
f oll o wi n g: 
•   C m a x   aft er I V l o a di n g  d os e  
•   T m a x   aft er I V l o a di n g  d os e 
•   C m a x  aft er first  S C  d os e  
•   T m a x  aft er first  S C  d os e  
•   A U C 0-τ 
•   C tr o u g h aft er  e a c h  d os e  
T h e f oll o wi n g  d es cri pti v e st atisti cs  will  b e  pr es e nt e d,  b y  d os e l e v el, f or  all  P K  p ar a m et ers, 
e x c e pt f or  T m a x ,  n,  arit h m eti c  m e a n,  S D,  C V %,  m e di a n,  g e o m etri c  m e a n,  g e o m etri c  C V %, 
mi ni m u m,  a n d  m a xi m u m.  T h e  n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m  will  b e s u m m ari z e d f or 
T m a x .  A d diti o n al i nf or m ati o n  o n t h e  a n al ys es  of  P K  p ar a m et ers  will  b e  pr o vi d e d i n t h e  S A P. 
T h es e  a n al ys es  will  b e  p erf or m e d  o n t h e  P K  A n al ysis  S et.  
D os e - a dj ust e d  P K  e x p os ur e  p ar a m et ers  will  b e  n at ur al l o g tr a nsf or m e d  a n d  a n al y z e d i n  a n 
a n al ysis  of  v ari a n c e  m o d el,  c o m p ari n g t h e  1 6  m g/ k g  a n d  8  m g/ k g  d os e l e v els.  T h e  esti m at e 
a n d  9 0 %  CI f or t h e  diff er e n c e  of  1 6  m g/ k g  –  8  m g/ k g  will  b e  e x p o n e nti at e d t o  o bt ai n t h e  p oi nt 
esti m at e  a n d  CI f or t h e  g e o m etri c  m e a n r ati o.   T h e  p oi nt  esti m at e  a n d  CI  will  b e  us e d t o  ass ess 
d os e  pr o p orti o n alit y. 
E x pl or at or y  E n d p oi nt 
Uri n e  c o n c e ntr ati o n  of  C S L 3 4 6  will  b e list e d  b y i n di vi d u al s u bj e ct  a n d  will  b e s u m m ari z e d  b y 
n o mi n al ti m e  p oi nt  usi n g  d es cri pti v e  st atisti cs. T his  a n al ysis  will  b e  p erf or m e d  o n t h e  P K 
A n al ysis  S et.  
1 0. 3. 5   P h a r m a c o d y n a mi c  A n al ys es  
E x pl or at or y  E n d p oi nt 
D at a fr o m t h e  e x pl or at or y  bi o m ar k ers  will  b e s u m m ari z e d  d es cri pti v el y  b y tr e at m e nt  a n d  visit 
f or t h e  P D  A n al ysis  S et. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 0. 3. 6   P h a r m a c o ki n eti c /  P h a r m a c o d y n a mi c  R el ati o ns hi ps  
E x pl or at or y  E n d p oi nt 
P h ar m a c o ki n eti c  a n d  P D  e n d p oi nts  will  b e  e x pl or e d  gr a p hi c all y t o  e v al u at e  p ot e nti al 
r el ati o ns hi ps.  T h es e  a n al ys es  will  b e  p erf or m e d  o n t h e  P D  A n al ysis  S et.  P o p ul ati o n  P K  a n d 
P K  /  P D  m o d elli n g  m a y  b e  us e d t o f urt h er  ass ess ti m e-d e p e n d e nt  c h ar a ct eri z ati o n  of  P K  v ers us 
P D  e n d p oi nts, t o  b e r e p ort e d s e p ar at el y. 
1 0. 3. 7   Ot h e r  A n al ys es  
S e c o n d ar y  E n d p oi nt 
T h e  n u m b er  of s u bj e cts  wit h  a  p ositi v e i m m u n o g e ni cit y t est  at  a n y ti m e  p osttr e at m e nt  will  b e 
c o u nt e d  a n d  c o m p ar e d  b et w e e n tr e at m e nts  wit h  Fis h er’s  E x a ct  Test.  T h e  c o m p aris o n  will  b e  of 
C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g  p o ol e d)  v ers us  pl a c e b o.  T his  a n al ysis  will  b e  p erf or m e d  o n 
t h e  S af et y  A n al ysis  S et. 
E x pl or at or y  E n d p oi nts 
E x pl or at or y  e n d p oi nts  will  e m pl o y  a  m o d el si mil ar t o t h e  pri m ar y  e n d p oi nt.  T h e  a n al ysis f or 
t h es e  c o nti n u o us  e n d p oi nts is  a n  M M R M  a n al ysis  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  m e as ur e m e nt.  T h e  m o d el  will i n cl u d e tr e at m e nt, str atifi c ati o n r el at e d t o t h e 
c o n c o mit a nt  us e  of  S G L T 2 i n hi bit ors,  visit ( as  a  c at e g ori c al f a ct or),  a n d i nt er a cti o ns  b et w e e n 
visit  a n d  e a c h  of t h e  ot h er  m o d el t er ms,  as  w ell  as t h e  c orr es p o n di n g  b as eli n e  m e as ur e m e nt  as 
a  c o v ari at e.  E x pl or at or y  uri n ar y  bi o m ar k ers  will  b e  n or m ali z e d t o  cr e ati ni n e l e v el f or  a n al ysis 
a n d  r e p orti n g.  Tr e at m e nt  c o m p aris o ns  of i nt er est  will  b e si mil ar t o t h at  of t h e  pri m ar y 
e n d p oi nt.  T h es e  a n al ys es  will  b e  p erf or m e d  o n t h e  P D  A n al ysis  S et.  
T h e  n u m b er  of s u bj e cts  w h o r e gr ess fr o m  m a cr o al b u mi n uri a t o  mi cr o al b u mi n uri a  or 
n or m o al b u mi n uri a,  or fr o m  mi cr o al b u mi n uri a t o  n or m o al b u mi n uri a  at  We e k  1 6  will  b e 
c o u nt e d  a n d  c o m p ar e d  b et w e e n tr e at m e nts  usi n g  Fis h er’s  E x a ct  Test.  T h e  c o m p aris o n  will  b e 
of  C S L 3 4 6 ( 8  m g/ k g  a n d  1 6  m g/ k g  p o ol e d)  v ers us  pl a c e b o.  
1 1   Q u alit y  Ass u r a n c e  
T h e st u d y  m a y  b e s u bj e ct t o  a n  a u dit  b y  C S L,  a n  a ut h ori z e d r e pr es e nt ati v e(s)  of  C S L  a n d /  or 
i ns p e cti o ns  b y  a n  a ut h ori z e d  h e alt h  a ut h orit y ( e g,  U S  F o o d  a n d  Dr u g  A d mi nistr ati o n).  H e alt h 
a ut h oriti es  m a y r e q u est  a c c ess t o  all st u d y  d o c u m e nt ati o n, i n cl u di n g s o ur c e  d o c u m e nts f or 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 2  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
i ns p e cti o n  a n d  c o p yi n g, i n  k e e pi n g  wit h l o c al r e g ul ati o ns.  C S L  will  n otif y t h e I n v esti g at or of 
a n y  u p c o mi n g  a u dit / i ns p e cti o n. 
I n t h e  e v e nt  of  a n  a u dit,  all  p erti n e nt st u d y-r el at e d  d o c u m e nt ati o n  m ust  b e  m a d e  a v ail a bl e t o 
t h e  a u dit or(s). If  a n  a u dit  or i ns p e cti o n  o c c urs, t h e  I n v esti g at or at  e a c h st u d y sit e  will  p er mit 
t h e  a u dit or / i ns p e ct or  dir e ct  a c c ess t o  all r el e v a nt  d o c u m e nts  a n d  all o c at e t h eir ti m e  as  w ell  as 
t h e ti m e  of r el e v a nt st aff t o  dis c uss t h e fi n di n gs  a n d  a n y r el e v a nt iss u es. 
1 2   R e g ul at o r y  a n d  Et hi cs  C o nsi d e r ati o ns  
1 2. 1   R e g ul at o r y  C o nsi d e r ati o ns  
C S L  or its  a g e nts  will s u b mit t h e  a p pr o pri at e  d o c u m e nts t o t h e l o c al r e g ul at or y  a g e n ci es  a n d 
will  a w ait  a p pr o v al  b ef or e st u d y st art. 
T his st u d y  will  b e  c o n d u ct e d  u n d er  a n  U S  F o o d  a n d  Dr u g  A d mi nistr ati o n I n v esti g ati o n al  N e w 
Dr u g  a p pli c ati o n,  T h er a p e uti c  G o o ds  A d mi nistr ati o n  Cli ni c al  Tri al  N otifi c ati o n,  a n d t h e  H e alt h 
R es e ar c h  C o u n cil  of  N e w  Z e al a n d  a n d  d o c u m e nt e d i n  a c c or d a n c e  wit h t h e  a p pli c a bl e 
r e g ul at or y  g ui d eli n es  a n d r e q uir e m e nts. 
T h e  pr o c e d ur es s et  o ut i n t his  cli ni c al st u d y  pr ot o c ol  ar e  d esi g n e d t o  e ns ur e t h at  C S L  a n d t h e 
I n v esti g at or  a bi d e  b y t h e  pri n ci pl es  of t h e  c urr e nt I C H  G C P  g ui d eli n e  o n t h e  c o n d u ct, 
e v al u ati o n  a n d  d o c u m e nt ati o n  of t his st u d y,  as  d es cri b e d i n I C H  T o pi c  E 6 ( G ui d eli n e f or  G C P). 
T h e st u d y  will  als o  b e  c arri e d  o ut  a c c or di n g t o  all  a p pli c a bl e i nt er n ati o n al  a n d  n ati o n al 
r e g ul at or y r e q uir e m e nts. 
1 2. 2   I nstit uti o n al  R e vi e w  B o a r d / I n d e p e n d e nt  Et hi cs  C o m mitt e e  
T h e  I n v esti g at or  m ust s u b mit t h e  cli ni c al st u d y  pr ot o c ol  a n d I C Fs f or r e vi e w  b y  a n  a ut h ori z e d 
a n d  pr o p erl y  c o nstit ut e d ( a c c or di n g t o l o c al  g ui d eli n es) I R B / I E C.  Writt e n  a p pr o v al  m ust  b e 
r e c ei v e d fr o m t h e I R B / I E C  b ef or e  c o m m e n c e m e nt  of t h e st u d y. 
1 2. 3   S u bj e ct I nf o r m ati o n  a n d I nf o r m e d  C o ns e nt  
I nf or m e d  c o ns e nt  of s u bj e cts  a c c or di n g t o t h e st a n d ar ds  of  G C P  a n d t h e pri n ci pl es i n t h e 
D e cl ar ati o n  of  H elsi n ki  m ust  b e i m pl e m e nt e d i n t his  cli ni c al st u d y  b ef or e  pr ot o c ol- s p e cifi e d 
pr o c e d ur es  ar e  c arri e d  o ut. I nf or m ati o n s h o ul d  b e  gi v e n i n  b ot h  or al  a n d  writt e n f or m  a n d 
s h o ul d  b e  d e e m e d  a p pr o pri at e  b y t h e I R B / I E C.  S u bj e ct s, t h eir r el ati v es ( or if  n e c ess ar y, 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
l e g all y  a c c e pt a bl e r e pr es e nt ati v es)  m ust  b e  gi v e n  a m pl e  o p p ort u nit y t o i n q uir e  a b o ut  d et ails  of 
t h e st u d y. 
T h e s u bj e ct ( or if  n e c ess ar y, l e g all y  a c c e pt a bl e r e pr es e nt ati v es)  m ust  b e  pr o vi d e d  wit h  a  c o p y 
of t h e si g n e d I C F. 
S h o ul d t h er e  b e  a n y  a m e n d m e nts t o t h e  cli ni c al st u d y  pr ot o c ol t h at  w o ul d  dir e ctl y  aff e ct t h e 
s u bj e ct’s  p arti ci p ati o n i n t h e st u d y ( e g,  a  c h a n g e i n  a n y  pr o c e d ur e), t h e I C F  m ust  b e  a m e n d e d 
t o i n c or p or at e t his  m o difi c ati o n.  S u bj e cts  m ust  b e i nf or m e d  of t h e  c h a n g e  a n d t h e y  m ust si g n 
t h e  a m e n d e d I C F i n di c ati n g t h at t h e y r e c o ns e nt t o  p arti ci p at e i n t h e st u d y. 
1 2. 4   S u bj e ct  C o nfi d e nti alit y  
All s u bj e ct  n a m es  a n d  c o nt a ct  d et ails  will  b e  k e pt  c o nfi d e nti al.  S u bj e cts  will  b e i d e ntifi e d 
t hr o u g h o ut  d o c u m e nt ati o n  a n d  e v al u ati o n  b y t h e  n u m b er  all ott e d t o t h e m  d uri n g t h e st u d y. 
E a c h s u bj e ct  will  b e t ol d t h at  all st u d y fi n di n gs  will  b e  h a n dl e d i n t h e stri ct est  c o nfi d e n c e. 
T h e  I n v esti g at or  at t h e st u d y sit e  will  b e r es p o nsi bl e f or r et ai ni n g s uffi ci e nt i nf or m ati o n  a b o ut 
e a c h s u bj e ct ( e g,  n a m e,  a d dr ess,  p h o n e  n u m b er,  a n d i d e ntit y i n t h e st u d y) s o t h at r e g ul at or y 
a g e n ci es  or  C S L  m a y  a c c ess t his i nf or m ati o n s h o ul d t h e  n e e d  aris e.  T h es e r e c or ds s h o ul d  b e 
r et ai n e d i n  a  c o nfi d e nti al  m a n n er  as l o n g  as l e g all y  m a n d at e d  a c c or di n g t o l o c al r e q uir e m e nts. 
S u bj e ct  m e di c al r e c or ds  p ert ai ni n g t o t h e st u d y  m a y  b e i ns p e ct e d /  a u dit e d  at  a n y ti m e  b y  C S L 
e m pl o y e es  or t h eir  d ul y  a ut h ori z e d r e pr es e nt ati v es,  a  h e alt h  a ut h orit y,  or t h e I R B  / I E C.  All 
r e c or ds  a c c ess e d  will  b e stri ctl y  c o nfi d e nti al. C o ns e nt t o  p arti ci p at e i n t h e st u d y i n cl u d es 
c o ns e nt t o t h es e i ns p e cti o ns /  a u dits. 
1 2. 5   I n d e m nit y  a n d  C o m p e ns ati o n  
C S L  h as t a k e n  o ut i ns ur a n c e t o  c o v er its  o bli g ati o ns  u n d er  b ot h t h e I n d e m nit y  a n d t h e 
C o m p e ns ati o n  g ui d eli n es f or i nj ur y t o s u bj e cts i n v ol v e d i n t h e st u d y. 
Ot h er  d et ails r e g ar di n g  c o m p e ns ati o n  a n d t h e  o bli g ati o ns  of t h e I n v esti g at or  /  C S L  ar e 
pr o vi d e d i n t h e  Cli ni c al  Tri al  R es e ar c h  A gr e e m e nt ( C T R A) f or t h e st u d y (s e e  S e cti o n  1 3. 1 ). 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 3   A d mi nist r ati v e  C o nsi d e r ati o ns  
1 3. 1   Cli ni c al  Tri al  R es e a r c h  A g r e e m e nt  
T his st u d y  will  b e  c o n d u ct e d  u n d er  a  C T R A  b et w e e n  C S L ( “ S p o ns or ”)  a n d t h e i nstit uti o n(s) 
r e pr es e nti n g t h e i n v esti g ati o n al st u d y sit e(s) ( “ A ut h orit y ”).  Fi n a n ci al s u p p ort t o t h e 
i n v esti g ati o n al sit e(s)  will  b e  d et ail e d i n t h e  C T R A.  T h e  C T R A  m ust  b e si g n e d  b ef or e t h e 
c o m m e n c e m e nt  of t h e st u d y  a n d  will  cl e arl y  d eli n e at e t h e r es p o nsi biliti es  a n d  o bli g ati o ns  of 
t h e I n v esti g at or  a n d  C S L,  a n d  will f or m t h e  c o ntr a ct u al  b asis  u n d er  w hi c h t h e  cli ni c al st u d y 
will  b e  c o n d u ct e d.  C T R A s  m a y  b e  e x e c ut e d  b y  el e ctr o ni c si g n at ur e ( c urr e nt  pr o vi d er 
D o c u Si g n) i n  c o m pli a n c e  wit h  2 1  C F R  P art  1 1  a n d si m pl e  or  a d v a n c e d  el e ctr o ni c si g n at ur e 
a c c or di n g t o  E U  R e g ul ati o n  N o  9 1 0/ 2 0 1 4 -  eI D A S.  
1 3. 2   Cli ni c al  St u d y  R e gist r ati o n  a n d  R es ults  Dis cl os u r e   
C S L  will  pr o vi d e t h e r el e v a nt  cli ni c al st u d y  pr ot o c ol i nf or m ati o n i n  p u bli c  d at a b as e(s)  b ef or e 
or  at  c o m m e n c e m e nt  of t h e st u d y.  C S L  m a y  als o  pr o vi d e st u d y i nf or m ati o n f or i n cl usi o n i n 
n ati o n al r e gistri es  a c c or di n g t o l o c al r e g ul at or y r e q uir e m e nts. 
R es ults  of t his st u d y  will  b e  dis cl os e d  a c c or di n g t o t h e r el e v a nt r e g ul at or y r e q uir e m e nts.  All 
p u bli c ati o ns i n  p e er- r e vi e w e d  m e di c al j o ur n als r es ulti n g fr o m t his st u d y  will  b e list e d i n t h e 
ori gi n al  cli ni c al st u d y  pr ot o c ol r e gistr ati o n r e c or d. 
1 3. 3   I m pl e m e nt ati o n  of t h e  Cli ni c al  St u d y  P r ot o c ol  a n d  A m e n d m e nt(s)  
Wit h t h e  e x c e pti o n  of  m e di c al  e m er g e n ci es,  n o  c h a n g es  or  d e vi ati o ns i n t h e  c o n d u ct  of t h e 
si g n e d  cli ni c al st u d y  pr ot o c ol  will  b e  p er mitt e d  wit h o ut  d o c u m e nt e d  a p pr o v al  of t h e  C S L 
M e di c al  M o nit or  or  d esi g n e e  a n d t h e I R B / I E C. I n t h e  e v e nt  of  a  m e di c al  e m er g e n c y, t h e 
I n v esti g at or at t h e st u d y sit e  will i nstit ut e  a n y  m e di c al  pr o c e d ur es  d e e m e d  a p pr o pri at e. 
H o w e v er,  all s u c h  pr o c e d ur es  m ust  b e  pr o m ptl y r e p ort e d t o t h e  C S L  M e di c al  M o nit or  a n d t h e 
I R B / I E C.  
M o difi c ati o ns t o t h e  cli ni c al st u d y  pr ot o c ol t h at  m a y  aff e ct s u bj e ct s af et y  or t h e  w a y t h e st u d y 
is t o  b e  c o n d u ct e d  will  b e  d o c u m e nt e d i n  a  pr ot o c ol  a m e n d m e nt,  w hi c h  m ust  b e  a p pr o v e d  b y 
t h e I R B / I E C.  
A d mi nistr ati v e  c h a n g es t o t h e  cli ni c al st u d y  pr ot o c ol,  d efi n e d  as  mi n or  c orr e cti o ns  a n d /  or 
cl arifi c ati o ns t h at  h a v e  n o  eff e ct  o n t h e  w a y t h e st u d y is t o  b e  c o n d u ct e d,  will  n ot r e q uir e 
I R B / I E C  a p pr o v al,  b ut  will  b e s u b mitt e d t o t h e I RB / I E C f or t h eir i nf or m ati o n.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 5  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 3. 4   P r ot o c ol  D e vi ati o ns  
All i nst a n c es  w h er e t h e r e q uir e m e nts  of t h e  cli ni c al st u d y  pr ot o c ol  w er e  n ot  c o m pli e d  wit h  will 
b e tr a c k e d.  C orr es p o n di n g s u bj e cts  m a y  b e  wit h dr a w n fr o m t h e st u d y  at t h e  dis cr eti o n  of t h e 
I n v esti g at or a n d  /  or  C S L.  Cli ni c al st u d y  pr ot o c ol  d e vi ati o ns  aris e  w h e n  eit h er s u bj e cts  w h o 
h a v e  b e e n  e nt er e d i n t h e st u d y  a n d /  or t h e st u d y sit es  d e vi at e fr o m t h e I R B / I E C- a p pr o v e d 
st u d y  pr ot o c ol.  
If  a  m aj or  pr ot o c ol  d e vi ati o n (i e,  a  d e vi ati o n t h at  c o ul d  h a v e  a si g nifi c a nt  eff e ct  o n t h e s u bj e ct’s 
s af et y, ri g hts,  or  w elf ar e  a n d /  or  o n t h e i nt e grit y  of t h e st u d y  d at a)  o c c urs, t h e I n v esti g at or 
m ust  n otif y  C S L  a n d t h e  a p pr o pri at e I R B / I E C  as s o o n  as  p ossi bl e  or  as  p er l o c al 
r e q uir e m e nts.  
1 3. 5   D o c u m e nt ati o n  a n d  R e c o r d  K e e pi n g   
1 3. 5. 1   D at a  C oll e cti o n  
T h e  I n v esti g at or ( or  d el e g at e)  will  m ai nt ai n i n di vi d u al r e c or ds f or  e a c h s u bj e ct.  T h es e r e c or ds 
s h o ul d i n cl u d e  d at es  w h e n  a s u bj e ct  visit e d t h e st u d y sit e, r e c or ds  of  vit al si g ns,  m e di c al 
hist or y,  p h ysi c al  e x a mi n ati o ns,  a d mi nistr ati o n  of I P  or  c o n c o mit a nt t h er a p y,  a n y  A Es 
e x p eri e n c e d,  a n d  ot h er  n ot es  as  a p pr o pri at e.  T h es e r e c or ds ( el e ctr o ni c  or  p a p er)  c o nstit ut e 
s o ur c e  d at a.   
El e ctr o ni c  c as e r e p ort f or m  e ntri es  will  b e  c o nsi d er e d s o ur c e  d at a if t h e  e C R F is t h e sit e  of t h e 
ori gi n al r e c or di n gs (i e, t h er e is  n o  ot h er  writt e n  or  el e ctr o ni c r e c or d  of t h e  d at a).  
A n  e C R F  will  b e  pr o vi d e d  b y  C S L ( or  d el e g at e) f or  e a c h s u bj e ct  e nr oll e d i nt o t h e st u d y.  T h e 
I n v esti g at or is r es p o nsi bl e f or  e ns uri n g  a c c ur at e  a n d  pr o p er  c o m pl eti o n  of t h e  e C R F i n  a ti m el y 
m a n n er s o t h at it  al w a ys r efl e cts t h e l at est  o bs er v ati o ns  o n t h e s u bj e cts  e nr oll e d i n t h e st u d y. 
All  e ntri es  o n t h e  e C R F  m ust  b e  b a c k e d  u p  b y s o ur c e  d at a  u nl ess t h e  e C R F is  c o nsi d er e d 
s o ur c e  d at a.  All s o ur c e  d at a  will  b e  k e pt  a c c or di n g t o  all  a p pli c a bl e  r e g ul at or y r e q uir e m e nts. 
S o ur c e  d at a  m ust  b e  c o m pl et e d l e gi bl y f or  e a c h s u bj e ct  e nr oll e d i nt o t h e st u d y  a n d si g n e d  b y 
t h e I n v esti g at or ( or  d el e g at e). 
1 3. 5. 2   D at a  Q u alit y  Ass u r a n c e  
D at a  g e n er at e d t hr o u g h o ut t h e st u d y  will  b e  m o nit or e d  a n d t h e  e C R Fs  c h e c k e d  a g ai nst  t h e 
s u bj e ct r e c or ds f or  c o m pl et e n ess  a n d  a c c ur a c y.  T h e  I n v esti g at or  m ust  pr o vi d 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.  C S L’s st u d y  m o nit or  will  p erf or m t his f u n cti o n.  

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 6  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Aft er  c o m pl eti o n  of  e C R F  p a g es  a n d  e ntr y  of t h e  d at a i nt o  a  d at a b as e, t h e  d at a  will  b e  c h e c k e d 
el e ctr o ni c all y f or  c o nsist e n c y  a n d  pl a usi bilit y.  Q u eri es  will  b e  g e n er at e d f or  q u esti o n a bl e  d at a 
a n d  cl arifi c ati o n s o u g ht fr o m t h e I n v esti g at or.  T h es e  d at a  q u eri es  m ust  b e r es ol v e d i n  a ti m el y 
m a n n er  b y t h e I n v esti g at or  ( or  d el e g at e). 
1 3. 5. 3   R e c o r d  R et e nti o n  
T h e  I n v esti g at or  m ust f oll o w t h e  pri n ci pl es f or r e c or d r et e nti o n  o utli n e d i n t h e C T R A .  A n 
I n v esti g at or st u d y fil e  pr e p ar e d  b y  C S L ( or  d el e g at e),  c o nt ai ni n g  all  a p pli c a bl e  d o c u m e nts f or 
us e  at t h e st u d y sit e,  will  b e  m a d e  a v ail a bl e t o t h e  I n v esti g at or  b ef or e t h e st art  of t h e st u d y.  All 
st u d y  d o c u m e nt ati o n  a n d  m at eri als  m ai nt ai n e d i n t h e I n v esti g at or st u d y f il e  m ust  b e  k e pt i n 
c o nf or m a n c e  wit h  a p pli c a bl e  n ati o n al l a ws  a n d r e g ul ati o ns.  
All st u d y  d o c u m e nt ati o n  a n d  m at eri als  m ai nt ai n e d i n t h e  I n v esti g at or st u d y fil e  at t h e st u d y sit e 
m ust  b e  a v ail a bl e f or i ns p e cti o n  b y  C S L’s st u d y  m o nit or ( or  d el e g at e) t o  d et er mi n e t h at  all 
r e q uir e d  d o c u m e nt ati o n is  pr es e nt  a n d  c orr e ct.  
T h e st u d y  m a y  b e  a u dit e d  or i ns p e ct e d  b y  q u alifi e d  d el e g at es fr o m  C S L  or  a  c o m p et e nt  h e alt h 
a ut h orit y. 
Aft er  c o m pl eti o n  of t h e st u d y, t h e I n v esti g at or is r es p o nsi bl e f or  ar c hi vi n g t h e I n v esti g at or ’s 
st u d y fil e, t h e s u bj e ct’s r e c or ds  a n d t h e s o ur c e  d at a  a c c or di n g t o  a p pli c a bl e r e g ul at or y 
r e q uir e m e nts.  
1 3. 6   St u d y  a n d  Sit e  Cl os u r e  
C S L r es er v es t h e ri g ht t o  pr e m at ur el y  dis c o nti n u e  or s us p e n d t h e st u d y  eit h er  at  a  p arti c ul ar 
sit e  or  at  all st u d y sit es  at  a n y ti m e  a n d f or  a n y r e as o n. If s u c h  a cti o n is t a k e n, t h e  C S L  St u d y 
M o nit or ( or  d el e g at e)  will  dis c uss t his  wit h t h e I n v esti g at or  at  e a c h st u d y sit e  at t h at ti m e  a n d 
n otif y t h e I n v esti g at ors i n  writi n g. If t h e st u d y is s us p e n d e d  or t er mi n at e d f or s af et y r e as o ns, 
all  I n v esti g at ors  a n d t h e r el e v a nt r e g ul at or y  a g e n ci es  will  b e i m m e di at el y  n otifi e d  of t h e  a cti o n 
as  w ell  as t h e r e as o n f or t h e s us p e nsi o n / t er mi n ati o n.  T h e I n v esti g at or  at  e a c h st u d y sit e  will 
a d vis e t h eir I R B  / I E C  o v ers e ei n g t h e st u d y  of t h e s us p e nsi o n / t er mi n ati o n. 
1 3. 7   Cli ni c al  St u d y  R e p o rt  
A  cli ni c al st u d y r e p ort  will  b e  writt e n  aft er t h e  c o m pl eti o n  of t h e st u d y.  C S L  or its  a g e nt  will 
writ e t h e r e p ort i n  c o ns ult ati o n  wit h t h e  I n v esti g at or  or, if  a p pli c a bl e,  a  n o mi n at e d  c o or di n ati n g 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 7  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
I n v esti g at or ( or  d el e g at e).  C S L r e q uir es t h at t h e  c o or di n ati n g I n v esti g at or will si g n t h e  cli ni c al 
st u d y r e p ort.  
Pr o gr ess r e p orts  m a y  b e  pr o vi d e d t o t h e r el e v a nt r e g ul at or y  b o di es i n  a c c or d a n c e  wit h t h eir 
r e q uir e m e nts. 
1 3. 8   Us e  of  D at a  a n d  P u bli c ati o ns  
T h e ri g hts  a n d  o bli g ati o ns  of I n v esti g at ors  a n d  C S L  c o n c er ni n g  a n y f or m al  pr es e nt ati o n  or 
p u bli c ati o n  of  d at a  c oll e ct e d  as  a  dir e ct  or i n dir e ct r es ult  of t his st u d y  will  b e  a d dr ess e d 
s p e cifi c all y i n t h e  C T R A f or t h e st u d y. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 8  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 4   R ef e r e n c es  
B ell o m o  D,  H e a dri c k J P,  Sili ns  G U,  P at ers o n  C A,  T h o m as  P S,  G artsi d e  M,  et  al.  Mi c e 
l a c ki n g t h e  v as c ul ar  e n d ot h eli al  gr o wt h f a ct or-B  g e n e ( Ve gf b)  h a v e s m all er  h e arts, 
d ysf u n cti o n al  c or o n ar y  v as c ul at ur e,  a n d i m p air e d r e c o v er y fr o m  c ar di a c is c h e mi a.  Cir c  R es. 
2 0 0 0  F e b  4; 8 6( 2): E 2 9- E 3 5. 
C or es h J,  H e ers pi n k  HJ L,  S a n g  Y,  M ats us hit a  K,  Ar nl o v J,  Ast or  B C,  et  al.  C h a n g e i n 
al b u mi n uri a  a n d s u bs e q u e nt ris k  of  e n d-st a g e  ki d n e y  dis e as e:  a n i n di vi d u al  p arti ci p a nt- l e v el 
c o ns orti u m  m et a - a n al ysis  of  o bs er v ati o n al st u di es.  L a n c et  Di a b et es  E n d o cri n ol.  2 0 1 9 F e b  7; 
7( 2):  1 1 5 - 2 7. 
F al k e v all  A,  M e hl e m  A,  P al o m b o I,  H ell er  S a hl gr e n  B,  E b ar asi  L,  H e  L,  et  al.  R e d u ci n g 
V E G F - B si g n ali n g  a m eli or at es r e n al li p ot o xi cit y  a n d  pr ot e cts  a g ai nst  di a b eti c  ki d n e y  dis e as e. 
C ell  M et a b.  2 0 1 7  M ar  7; 2 5( 3): 7 1 3- 2 6. 
G ar b er  AJ,  A br a h a ms o n  MJ,  B ar zil a y JI,  Bl o n d e  L,  Bl o o m g ar d e n  Z T,  B us h  M A,  et  al. 
C o ns e ns us  St at e m e nt  b y t h e  A m eri c a n  Ass o ci ati o n  of  Cli ni c al  E n d o cri n ol o gists  a n d 
A m eri c a n  C oll e g e  of  E n d o cri n ol o g y  o n t h e  C o m pr e h e nsi v e  T y p e  2  Di a b et es  M a n a g e m e nt 
Al g orit h m  -  2 0 1 9  E x e c uti v e  S u m m ar y.  E n d o cr  Pr a ct.  2 0 1 9 J a n; 2 5( 1): 6 9- 1 0 0. 
Gl o b al  B ur d e n  of  Dis e as e ( G B D)  2 0 1 7  Dis e as e  a n d I nj ur y I n ci d e n c e  a n d  Pr e v al e n c e 
C oll a b or at ors.  Gl o b al, r e gi o n al,  a n d  n ati o n al i n ci d e n c e,  pr e v al e n c e,  a n d  y e ars li v e d  wit h 
dis a bilit y f or  3 5 4  dis e as es  a n d i nj uri es f or  1 9 5  c o u ntri es  a n d t errit ori es,  1 9 9 0- 2 0 1 7:  a 
s yst e m ati c  a n al ysis f or t h e  Gl o b al  B ur d e n  of  Dis e as e  St u d y  2 0 1 7.  L a n c et.  2 0 1 8  N o v 
1 0; 3 9 2( 1 0 1 5 9): 1 7 8 9- 8 5 8. 
H a g b er g  C E,  F al k e v all  A,  Wa n g  X,  L arss o n  E,  H u us k o J,  Nilss o n I,  et  al.  Vas c ul ar 
e n d ot h eli al  gr o wt h f a ct or  B  c o ntr ols  e n d ot h eli al f att y  a ci d  u pt a k e.  N at ur e.  2 0 1 0  A pr 
8; 4 6 4( 7 2 9 0): 9 1 7- 2 1. 
H e ers pi n k  HJ L,  Gr e e n e  T,  Ti g hi o u art  H,  G a ns e v o ort  R T,  C or es h J,  Si m o n  A L,  et  al.  C h a n g e 
i n  al b u mi n uri a  as  a s urr o g at e  e n d p oi nt f or  pr o gr essi o n  of  ki d n e y  dis e as e:  a  m et a- a n al ysis  of 
tr e at m e nt  eff e cts i n r a n d o mis e d  cli ni c al tri als.  L a n c et  Di a b et es  E n d o cri n ol. 2 0 1 9 
F e b; 7( 2): 1 2 8- 3 9. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 0 9  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
I z z e di n e  H,  M ass ar d  C,  S p a n o J P,  G ol d w ass er  F,  K h a y at  D,  S ori a J C.  V E G F si g n ali n g 
i n hi biti o n-i n d u c e d  pr ot ei n uri a:  m e c h a nis ms, si g nifi c a n c e  a n d  m a n a g e m e nt.  E ur J  C a n c er. 
2 0 1 0 J a n; 4 6( 2): 4 3 9- 4 8. 
K a m ar z ari a n  A,  A u  A,  Yu n g  M,  Z a ki  Kir oll os  E,  P ol e  C, J af ari  G,  et  al.  T o xi c r e n al  eff e cts 
fr o m i ntr a vitr e al  b e v a ci z u m a b f or  pr olif er ati v e  di a b eti c r eti n o p at h y i n t h e  p ati e nts  wit h 
c hr o ni c  di a b eti c  ki d n e y  dis e as e.  A m eri c a n  S o ci et y  of  N e p hr ol o g y  S a n  Di e g o,  C A.  2 0 1 8. 
K h a n  S S,  Q u a g gi n  S E.  T h er a pi es  o n t h e  H ori z o n f or  Di a b eti c  Ki d n e y  Dis e as e.  C urr  Di a b 
R e p.  2 0 1 5  D e c; 1 5( 1 2): 1 1 1. 
Ki d n e y  Dis e as e  O ut c o m es  Q u alit y I niti ati v e ( K D O QI).  K D O QI  Cli ni c al  Pr a cti c e  G ui d eli n es 
a n d  Cli ni c al  Pr a cti c e  R e c o m m e n d ati o ns f or  Di a b et es  a n d  C hr o ni c  Ki d n e y  Dis e as e.  A m J 
Ki d n e y  Dis.  2 0 0 7  F e b; 4 9( 2  S u p pl  2): S 1 3- S 1 5 4. 
Ki d n e y  Dis e as e  O ut c o m es  Q u alit y I niti ati v e ( K D O QI).  K D O QI  Cli ni c al  Pr a cti c e  G ui d eli n e 
f or  Di a b et es  a n d  C K D.  A m J  Ki d n e y  Dis.  2 0 1 2  N o v; 6 0( 5): 8 5 0- 8 6. 
Kr ö p eli n  T F,  d e  Z e e u w  D,  A n dr ess  D L,  Bijls m a  MJ,  P erss o n  F,  P ar vi n g  H H,  et  al.  N u m b er 
a n d fr e q u e n c y  of  al b u mi n uri a  m e as ur e m e nts i n  cli ni c al tri als i n  di a b eti c  n e p hr o p at h y.  Cli n J 
A m  S o c  N e p hr ol.  2 0 1 5  M ar  6; 1 0( 3): 4 1 0- 1 6. 
L al  N,  C hi u  A P,  Wa n g  F,  Z h a n g  D, Ji a J,  Wa n  A,  et  al.  L oss  of  V E G F B  a n d its si g n ali n g i n 
t h e  di a b eti c  h e art is  ass o ci at e d  wit h i n cr e as e d  c ell  d e at h si g n ali n g.  A m J  P h ysi ol  H e art  Cir c 
P h ysi ol.  2 0 1 7 J u n  1; 3 1 2( 6): H 1 1 6 3- H 1 1 7 5. 
M o ul d  A,  Gr e c o  S A,  C a hill  M M,  T o n ks I D,  B ell o m o  D,  P att ers o n  C,  et  al.  Tr a ns g e ni c 
o v er e x pr essi o n  of  v as c ul ar  e n d ot h eli al  gr o wt h f a ct or- B is of or ms  b y  e n d ot h eli al  c ells 
p ot e nti at es  p ost n at al  v ess el  gr o wt h i n  vi v o  a n d i n  vitr o.  Cir c  R es.  2 0 0 5  S e p  1 6; 9 7( 6): e 6 0- e 7 0. 
N e u e n  B L,  O h k u m a  T,  N e al  B,  M att h e ws  D R,  d e  Z e e u w  D,  M a h aff e y  K W,  et  al. 
C ar di o v as c ul ar  a n d r e n al  o ut c o m es  wit h  c a n a glifl o zi n  a c c or di n g t o  b as eli n e  ki d n e y f u n cti o n. 
Cir c ul ati o n.  2 0 1 8  O ct  9; 1 3 8( 1 5): 1 5 3 7- 5 0. 
P er k o vi c  V, J ar di n e  MJ,  N e al  B,  B o m p oi nt  S,  H e ers pi n k  HJ L,  C h ar yt a n  D M,  et  al. 
C a n a glifl o zi n  a n d r e n al  o ut c o m es i n t y p e  2  di a b et es  a n d  n e p hr o p at h y.  N  E n gl J  M e d.  2 0 1 9 
J u n  1 3; 3 8 0( 2 4): 2 2 9 5- 3 0 6. 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 1 0  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
S ar afi dis  P,  F err o  CJ,  M or al es  E,  Orti z  A,  M al ys z k o J,  H ojs  R,  et  al.  S G L T - 2 i n hi bit ors  a n d 
G L P - 1 r e c e pt or  a g o nists f or  n e p hr o pr ot e cti o n  a n d  c ar di o pr ot e cti o n i n  p ati e nts  wit h  di a b et es 
m ellit us  a n d  c hr o ni c  ki d n e y  dis e as e.  A  c o ns e ns us st at e m e nt  b y t h e  E U R E C A- m  a n d t h e 
DI A B E SI T Y  w or ki n g  gr o u ps  of t h e  E R A- E D T A.   N e p hr ol  Di al  Tr a ns pl a nt.  2 0 1 9  F e b 
1; 3 4( 2): 2 0 8- 3 0. 
T h y g es e n  K,  Al p ert J S, J aff e  A S,  C h ait m a n  B R,  B a x JJ,  M orr o w  D A,  et  al.  F o urt h  U ni v ers al 
D efi niti o n  of  M y o c ar di al I nf ar cti o n. J  A m  C oll  C ar di ol.  2 0 1 8  O ct  3 0; 7 2( 1 8): 2 2 3 1- 6 4. 
T o m a n e k  RJ, Is hii  Y,  H olifi el d J S,  Sj o gr e n  C L,  H a ns e n  H K,  Mi k a w a  T.  V E G F f a mil y 
m e m b ers r e g ul at e  m y o c ar di al t u b ul o g e n esis  a n d  c or o n ar y  art er y f or m ati o n i n t h e  e m br y o. 
Cir c  R es.  2 0 0 6  A pr  1 4; 9 8( 7): 9 4 7- 5 3.  
T o u y z  R M,  H err m a n n  S M S,  H err m a n n J.  Vas c ul ar t o xi citi es  wit h  V E G F i n hi bit or t h er a pi es-
f o c us  o n  h y p ert e nsi o n  a n d  art eri al t hr o m b oti c  e v e nts. J  A m  S o c  H y p ert e ns.  2 0 1 8 
J u n; 1 2( 6): 4 0 9- 2 5. 
Wai k ar  S S,  B o n v e ntr e J V.  Cr e ati ni n e  ki n eti cs  a n d t h e  d efi niti o n  of  a c ut e  ki d n e y i nj ur y. J  A m 
S o c  N e p hr ol.  2 0 0 9  M ar; 2 0( 3): 6 7 2- 7 9. 
Wai k ar  S S,  R e b h ol z  C M,  Z h e n g  Z,  H ur wit z  S,  Hs u  C Y,  F el d m a n  HI,  et  al.  Bi ol o gi c al 
v ari a bilit y  of  esti m at e d  G F R  a n d  a l b u mi n uri a i n  C K D.  A m J  Ki d n e y  Dis.  2 0 1 8 
O ct; 7 2( 4): 5 3 8- 4 6.  
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 1 1  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
1 5   A p p e n di c es  
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 1 3  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
Si g n at u r e  of  P ri n ci p al I n v esti g at o r  
 
St u d y  Titl e:   
A  P h as e  2 a,  D o u bl e -bli n d,  R a n d o mi z e d,  Pl a c e b o -c o ntr oll e d,  Pr o of  of 
C o n c e pt  St u d y  of  Vas c ul ar  E n d ot h eli al  Gr o wt h  F a ct or  ( V E G F)-B 
Bl o c k a d e  wit h t h e  M o n o cl o n al  A nti b o d y  C S L 3 4 6 i n  S u bj e cts  Wit h 
Di a b eti c  Ki d n e y  Dis e as e  
P r ot o c ol  N u m b e r:   
C S L 3 4 6 _ 2 0 0 1  A m e n d m e nt  2    
Sit e  N u m b er   
 
I  h a v e r e a d t h e  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2 titl e d  “ A  P h as e  2 a,  D o u bl e- bli n d, 
R a n d o mi z e d,  Pl a c e b o - c o ntr oll e d,  Pr o of  of  C o n c e pt  St u d y  of  V E G F- B  Bl o c k a d e  wit h t h e 
M o n o cl o n al  A nti b o d y  C S L 3 4 6 i n  S u bj e cts  wit h  Di a b eti c  Ki d n e y  Dis e as e ”. 
B y si g ni n g t his  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2, I  a gr e e t o  c o n d u ct t h e  cli ni c al st u d y, 
aft er  a p pr o v al  b y  a n I nstit uti o n al  R e vi e w  B o ar d  or I n d e p e n d e nt  Et hi cs  C o m mitt e e ( as 
a p pr o pri at e), i n  a c c or d a n c e  wit h t h e  Cli ni c al  St u d y  Pr ot o c ol, t h e st a n d ar ds  of  G o o d  Cli ni c al 
Pr a cti c e ( as  d efi n e d  b y t h e I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n)  a n d  a p pli c a bl e 
r e g ul at or y r e q uir e m e nts. 
C h a n g es t o t h e  Cli ni c al  St u d y  Pr ot o c ol  will  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 is 
r e c ei v e d fr o m  C S L  B e hri n g  L L C ( C S L)  a n d t h e I nstit uti o n al  R e vi e w  B o ar d  or I n d e p e n d e nt 
Et hi cs  C o m mitt e e ( as  a p pr o pri at e)  wit h t h e  e x c e pti o n  of  m e di c al  e m er g e n ci es.  
I  will  e ns ur e t h at st u d y st aff f ull y  u n d erst a n d  a n d f oll o w t h e  Cli ni c al  St u d y  Pr ot o c ol. 
 
 
 
( Si g n at ur e) 
 
 
D at e ( D D  M M M  Y Y Y Y)  
( Pri nt e d  n a m e) 
 
 
 
( Titl e) 
 
 

C S L  B e hri n g  L L C  
 
St u d y  N u m b e r:   C S L 3 4 6 _ 2 0 0 1  
 
St u d y  P r o d u ct:   C S L 3 4 6   
 
Pr ot o c ol  v ersi o n:  A m e n d m e nt  2  
 
P a g e  1 1 4  of  1 1 4  
D at e:  2 7  M a y  2 0 2 1  
C o nfi d e nti al  
C S -S O P -0 4 -T 0 2  Versi o n  2. 0  
 
 
Eff e cti v e  D at e:  2 5 -J u n e-2 0 1 8  
A p p e n di x  2   H e p atitis  B  Testi n g  
S u bj e cts  m ust  u n d er g o s cr e e ni n g f or  h e p atitis  B  vir us  ( H B V).  At  a  mi ni m u m, t his i n cl u d es 
t esti n g f or  h e p atitis  B s urf a c e  a nti g e n ( H Bs A g),  a nti b o d y t o  H Bs A g ( a nti- H Bs),  a n d  a nti b o d y 
t o  h e p atitis  B  c or e  a nti g e n t ot al ( a nti-H B c t ot al).  
I nt er pr et ati o n  of  h e p atitis  B s er ol o gi c t est r es ults is  d es cri b e d i n Ta bl e   1 4.  Su bj e cts  ar e 
eli gi bl e f or i n cl usi o n i n t h e st u d y if t h e y t est: 
•   N e g ati v e f or  H Bs A g,  a nti- H B c t ot al,  a n d  a nti- H B s . 
•   N e g ati v e f or  H Bs A g  a n d  a nti - H B c t ot al,  b ut  p ositi v e f or  a nti-H Bs . 
•   N e g ati v e f or  H Bs A g,  b ut  p ositi v e f or  a nti- H B c t ot al  a n d  a nti -H Bs . 
S u bj e cts  ar e i n eli gi bl e f or i n cl usi o n i n t h e st u d y if t h e y t est  p ositi v e f or  H Bs A g, r e g ar dl ess  of 
t h e r es ults  of t h e  ot h er t ests.  
S u bj e cts  w h o t es t  p ositi v e f or  a nti- H B c t ot al  a n d  n e g ati v e f or  H Bs A g  a n d  a nti-H Bs  m ust 
u n d er g o f urt h er t esti n g f or t h e  pr es e n c e  of  H B V  D N A:  
•   If t h e s u bj e ct is  n e g ati v e f or  H B V  D N A, t h e s u bj e ct is  eli gi bl e f or i n cl usi o n i n t h e st u d y.  
•   If t h e s u bj e ct is  p ositi v e f or  H B V  D N A  or t h e  H B V  D N A t est is  n ot  p erf or m e d, t h e 
s u bj e ct is i n eli gi bl e f or i n cl usi o n i n t h e st u d y.  
S u bj e cts  w h o  ar e i n eli gi bl e f or i n cl usi o n i n t h e st u d y  b e c a us e  of  H B V t est r es ults s h o ul d 
c o ns ult  a  p h ysi ci a n  wit h  e x p ertis e i n  H B V.  
T a bl e   1 4 
I nt e r p r et ati o n  of  H e p atitis  B  S e r ol o gi c  Test  R es ults  
Eli gi bilit y  
H Bs A g  
a nti -H Bs  
a nti -H B c t ot al  
I n cl u d e  
−  
−  
−  
I n cl u d e  
−  
+  
−  
I n cl u d e  
−  
+  
+  
E x cl u d e  
+  
+  or  −  
+  or  −  
T est f o r  H B V  D N A a 
−  
−  
+  
+  =  p ositi v e;  −  =  n e g ati v e;  a nti -H B c  =  a nti b o d y t o  h e p atitis  B  c or e  a nti g e n;  a nti -H Bs   = a nti b o d y t o  H Bs A g; 
H Bs A g  =  h e p atitis  B s urf a c e  a nti g e n;  H B V  =  h e p atitis  B  vir us  
a S u bj e cts  p ositi v e f or  H B V  D N A  ar e i n eli gi bl e  a n d s u bj e cts  n e g ati v e f or  H B V  D N A  ar e  eli gi bl e f or i n cl usi o n 
i n t h e st u d y.