Conditions: Diabetic Kidney Disease (DKD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
This phase 2a, double-blind, randomized, placebo-controlled study will assess the efficacy, safety, tolerability, and pharmacokinetics (PK), of repeat doses of CSL346 in subjects with diabetic kidney disease (DKD) and albuminuria receiving standard of care treatment.

Detailed description:

Arms:
arm 1: Administered as a single intravenous (IV) loading dose followed by subcutaneous (SC) infusions arm 2: Administered as a single intravenous (IV) loading dose followed by subcutaneous (SC) infusions arm 3: Administered as a single IV loading dose followed by SC infusions

Interventions: intervention 1: CSL346 intervention 2: Placebo
Intervention descriptions: intervention 1: VEGF-B antagonist monoclonal antibody intervention 2: Normal saline

Protocol document:
Prot_000.pdf: 
 
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. 
 

SAP_001.pdf: 
SAP version: Final 3.0 
 
Page 1 of 59  
Date: 29 Sep 2022 
Confidential 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
Study Title: 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 
Study Number: 
CSL346_2001 
Study Product: 
CSL346 
Development Phase: 
2a 
Sponsor: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Version: 
Final 3.0 
Version Date: 
29Sep2022 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations.  
 
COMMERCIAL IN CONFIDENCE 
This document and the information contained herein are proprietary and confidential. This document 
and the contained information are intended for disclosure to and use by those personnel who are under 
an obligation of confidentiality by a signed agreement with the Sponsor (CSL Behring LLC). This 
document and the contained information may be disclosed and used only to the extent necessary to 
conduct the clinical study. Reproduction or disclosure of this document or its contained information is 
forbidden unless at the express request or with the written consent of CSL Behring LLC. 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 2 of 59  
Date: 29 Sep 2022 
Confidential 
Table of Contents 
Table of Contents ....................................................................................................................... 2 
List of Tables .............................................................................................................................. 5 
List of Figures ............................................................................................................................ 5 
1 
Modification History .......................................................................................................... 6 
2 
List of Abbreviations .......................................................................................................... 9 
3 
Purpose ............................................................................................................................. 12 
4 
Study Design ..................................................................................................................... 12 
4.1 
Objectives and Endpoints ............................................................................................ 14 
4.1.1 
Primary Objective ................................................................................................... 14 
4.1.2 
Secondary Objectives .............................................................................................. 14 
4.1.3 
Exploratory Objectives............................................................................................ 14 
4.1.4 
Exploratory Endpoints ............................................................................................ 15 
4.1.5 
Primary Study Hypotheses ...................................................................................... 17 
4.1.6 
Key Secondary Study Hypotheses .......................................................................... 17 
4.2 
Study Treatments ......................................................................................................... 17 
4.3 
Randomization Procedures and Blinding..................................................................... 18 
4.4 
Determination of the Sample Size ............................................................................... 18 
4.5 
Planned Interim Analyses and Reviews ....................................................................... 19 
4.5.1 
Interim Analysis ...................................................................................................... 19 
4.5.2 
Independent Data Monitoring Committee Review Meetings for Safety Monitoring
 ................................................................................................................................. 19 
5 
Changes from the Protocol Planned Analyses .................................................................. 19 
6 
Study Analysis Sets........................................................................................................... 19 
6.1 
Screened Analysis Set .................................................................................................. 19 
6.2 
Intent-to-Treat Analysis Set ......................................................................................... 19 
6.3 
Safety Analysis Set ...................................................................................................... 20 
6.4 
Per-Protocol Analysis Set ............................................................................................ 20 
6.5 
Pharmacokinetic Analysis Set ...................................................................................... 20 
6.6 
Pharmacodynamic Analysis Set ................................................................................... 20 
7 
General Considerations ..................................................................................................... 20 
7.1 
COVID-19 Impact ....................................................................................................... 21 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 3 of 59  
Date: 29 Sep 2022 
Confidential 
8 
Data Handling Conventions .............................................................................................. 23 
8.1 
Missing Data ................................................................................................................ 23 
8.2 
General Derived Variables ........................................................................................... 23 
8.2.1 
Reference Dates and Study Days ............................................................................ 23 
8.2.2 
Durations ................................................................................................................. 24 
8.2.3 
Baseline Definition.................................................................................................. 24 
8.2.4 
Change from Baseline ............................................................................................. 25 
8.2.5 
Multiple Assessments .............................................................................................. 25 
8.2.6 
Actual Treatment ..................................................................................................... 26 
8.2.7 
Derived Variables .................................................................................................... 26 
8.3 
Stratification and Covariates ........................................................................................ 27 
8.4 
Study Periods Relative to Treatment............................................................................ 27 
9 
Study Population ............................................................................................................... 27 
9.1 
Subject Disposition ...................................................................................................... 27 
9.2 
Protocol Deviations ...................................................................................................... 28 
9.3 
Demographic and Baseline Characteristics> ............................................................... 29 
9.4 
Prior/Concomitant Medications ................................................................................... 30 
10 Efficacy Analyses ............................................................................................................. 31 
10.1 
Analysis of Primary Endpoint(s) ................................................................................. 31 
10.1.1 
Primary Estimand .................................................................................................... 31 
10.1.2 
Primary Efficacy Analysis ....................................................................................... 32 
10.1.3 
Sensitivity Analyses of Primary Endpoint(s) .......................................................... 33 
10.1.4 
Subgroup Analyses of Primary Endpoint(s) ............................................................ 34 
10.2 
Analysis of Key Secondary Endpoint(s) ...................................................................... 34 
10.2.1 
Key Secondary Estimand ........................................................................................ 34 
10.3 
Analysis of Other Secondary Endpoints ...................................................................... 34 
10.4 
Missing Data and Imputation ....................................................................................... 35 
10.5 
Treatment Compliance ................................................................................................. 35 
11 Safety Analyses ................................................................................................................. 36 
11.1 
Extent of Exposure ....................................................................................................... 36 
11.2 
Adverse Events ............................................................................................................ 36 
11.3 
Clinical Laboratory Evaluations .................................................................................. 39 
11.4 
Other Safety Measures ................................................................................................. 41 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 4 of 59  
Date: 29 Sep 2022 
Confidential 
11.4.1 
Immunogenicity ...................................................................................................... 41 
11.4.2 
Vital Signs ............................................................................................................... 42 
11.4.3 
ECG ......................................................................................................................... 42 
12 Pharmacokinetic Analyses ................................................................................................ 43 
12.1 
Drug Concentration Measures ..................................................................................... 44 
12.2 
Deriving and Summarizing Pharmacokinetic Parameters ........................................... 45 
12.3 
Pharmacokinetic Statistical Analyses .......................................................................... 46 
13 Pharmacodynamic and Biomarkers Analyses ................................................................... 46 
13.1 
Biomarker Analyses ..................................................................................................... 46 
14 Pharmacokinetic/Pharmacodynamic Analyses ................................................................. 46 
15 References ......................................................................................................................... 47 
16 Appendices ....................................................................................................................... 48 
16.1 
SAS Code ..................................................................................................................... 48 
16.2 
PK Parameters .............................................................................................................. 50 
16.3 
Standard of Care Therapies .......................................................................................... 51 
16.4 
Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors .............................................. 51 
16.5 
SMQs for COVID-19 associated AEs.......................................................................... 51 
16.6 
COVID-19 Vaccines .................................................................................................... 52 
16.7 
Factors to be Addressed in Per Protocol Analysis Set ................................................. 53 
16.8 
Schedule of Assessments ............................................................................................. 54 
16.9 
Directionality of One-sided Tests ................................................................................ 57 
16.10 Non-SI Units ................................................................................................................ 59 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 5 of 59  
Date: 29 Sep 2022 
Confidential 
List of Tables 
Table 1 
Study Objectives, Endpoints and Summary Measures .................................... 16 
Table 2 
TEAE Assignment in Case of Missing AE Start Date Elements ..................... 37 
Table 3 
 Laboratory Values of Potential Clinical Importance ....................................... 41 
Table 4 
Vital Signs of Potential Clinical Importance ................................................... 42 
Table 5 
ECG Parameters of Potential Clinical Importance .......................................... 43 
 
List of Figures 
Figure 1 
Study Design Overview ................................................................................... 13 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 6 of 59  
Date: 29 Sep 2022 
Confidential 
1 
Modification History 






CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 9 of 59  
Date: 29 Sep 2022 
Confidential 
2 
List of Abbreviations 
Abbreviation 
Term 
ACR 
Albumin to creatinine ratio 
ADaM 
Analysis Data Model 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AKI 
Acute Kidney Injury 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BLQ 
Below level of quantification 
BMI 
Body mass index 
BP 
Blood Pressure 
CI 
Confidence interval 
CDISC 
Clinical Data Interchange Standards Consortium  
CTMS 
Clinical Trail Management System 
CV 
Coefficient of Variation 
DBL 
Database lock 
DBP 
Diastolic blood pressure 
DKD 
Diabetic Kidney Disease 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EGF 
Epidermal growth factor 
EOS 
End of study 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FMV 
First morning void 
HbA1c 
hemoglobin A1c 
HDL 
High density lipoprotein 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 10 of 59  
Date: 29 Sep 2022 
Confidential 
Abbreviation 
Term 
IP 
Investigational product 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous 
KIM-1  
Kidney injury molecule-1 
LDL 
Low density lipoprotein 
LLN 
Lower limit of the normal 
LVEF 
Left ventricular ejection fraction 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model repeated measures 
NC 
Not calculated 
NEFA 
Non-esterified fatty acids 
NGAL 
Neutrophil gelatinase-associated lipocalin 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred term 
QTcB 
Corrected QT interval (Bazett’s formula) 
QTcF 
Corrected QT interval (Fridericia’s formula) 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SBP 
Systolic blood pressure 
SCr 
Serum creatinine 
SDG 
Standardized Drug Grouping 
SEM 
Standard error of the mean 
SGLT2i 
Sodium-glucose cotransporter 2 inhibitor 
SC 
Subcutaneous 
SD 
Standard Deviation 
 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 11 of 59  
Date: 29 Sep 2022 
Confidential 
Abbreviation 
Term 
SDTM 
Study Data Tabulation Model 
SMQ 
Standard MedDRA Query 
SOC 
System organ class 
sTNFR1 
soluble tumor necrosis factor receptor 1 
T2DM 
Type II diabetes mellitus 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Tables, figures, and listings 
ULN 
Upper limit of the normal 
WHO 
World Health Organization 
VEGF-B 
Vascular Endothelial Growth Factor Bd 
VEGF-R1  
soluble VEGF receptor 1 
 
 
 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 12 of 59  
Date: 29 Sep 2022 
Confidential 
3 
Purpose 
This statistical analysis plan (SAP) provides a detailed and complete description of the 
planned final analysis for the study CSL346_2001. Mock table, figure, and listing (TFL) 
shells will be provided in a separate supporting document along with details for the practical 
implementation of the analyses. 
This SAP complies with the International Council for Harmonisation (ICH) E9 ‘Statistical 
Principles for Clinical Trials’ and E9 (R1) ‘Statistical Principles for Clinical Trials: 
Addendum: Estimands and Sensitivity Analysis in Clinical Trials’. It is based upon the 
following study documents: 
• Study Protocol (dated 16 Jan 2020); 
• Study Protocol Amendment 1 (dated 07 May 2020); 
• Study Protocol Amendment 2 (dated 27 May 2021); 
• Protocol Deviation Plan (dated 04 Sep 2020); 
• Case Report Form (CRF), Version 1.0 (dated 28 Aug 2020). 
All decisions regarding the analysis of the study results, as defined in this version of the SAP, 
have been made before database lock (DBL) of the study data. 
Deviations from the analyses in this SAP will be detailed in the clinical study report (CSR). 
4 
Study Design 
This is a prospective, multicenter, randomized, double-blind, placebo-controlled, proof of 
concept study to investigate the efficacy, safety, tolerability, and pharmacokinetics (PK) of 
repeat doses of CSL346 in 100 subjects with diabetic kidney disease (DKD) and albuminuria 
receiving standard of care treatment. The study will be divided into 4 periods: Screening, 
Lead-in, Treatment, and Follow-up, as shown in the following schematic: 


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Figure 1 
Study Design Overview 
 
Screening Period 
The Screening Period begins with the completion of the informed consent process and 
includes up to 6 weeks for determination of subject eligibility. During Screening (Visit 1 and 
Visit 2), the investigator or delegate will assess the subject’s eligibility for the study 
according to Inclusion / Exclusion Criteria. A subcutaneous (SC) test infusion is to be done at 
Visit 2 after other subject eligibility criteria have been confirmed. 
Lead-in Period 
During the Lead-in Period, subjects will have a study visit approximately 1 week before 
randomization (Visit 3, Day –7 ± 4 days). The subject’s eligibility to continue into the 
Treatment Period will be assessed according to Randomization Criteria. 
Treatment Period 
The Treatment Period will include up to 12 weeks of approximately monthly (every 4 weeks) 
administration of investigational product (IP). Using an Interactive Response Technology 
(IRT) system, eligible subjects will be randomized (1:1:2) to receive blinded IP (8 mg/kg 
CSL346, 16 mg/kg CSL346, or placebo). Randomization will be stratified by whether the 
subjects are receiving a concomitant sodium-glucose cotransporter 2 inhibitor (SGLT2i). At 
least half of the population should be receiving an SGLT2i. 
Each subject’s first dose of IP at Visit 4 (Day 1) will be an intravenous (IV) loading dose of 3 
mg/kg CSL346 for subjects randomized to 8 mg/kg CSL346 and 6 mg/kg CSL346 for 
subjects randomized to 16 mg/kg CSL346, or placebo (subjects randomized to placebo). The 
subject’s first SC dose of IP will be administered as 8 mg/kg, 16 mg/kg, or placebo, 
respectively. Subjects will receive 3 subsequent SC infusions at Visit 7 (Week 4), Visit 8 
(Week 8), and Visit 9 (Week 12) for a total of 4 SC doses. 


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Follow-up Period  
The Follow-up Period will continue for 12 weeks after the subject’s last dose of IP to evaluate 
changes in safety, efficacy, PK, and pharmacodynamic (PD) parameters after stopping 
treatment. 
4.1 
Objectives and Endpoints 
4.1.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of CSL346 administered every 
4 weeks for up to 12 weeks (4 doses) in subjects with DKD. 
4.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of CSL346 administered every 4 weeks for up to 
12 weeks (4 doses) in subjects with DKD. 
2. To evaluate the effect of CSL346 on serum creatinine (SCr) concentration and estimated 
glomerular filtration rate (eGFR) in subjects with DKD. 
3. To evaluate the effect of CSL346 on blood pressure (BP) in subjects with DKD. 
4. To evaluate the PK of CSL346 in subjects with DKD. 
5. To evaluate the immunogenicity of CSL346 in subjects with DKD. 
4.1.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
1. To explore the effect of CSL346 on the following potential PD biomarkers: 
• biomarkers of lipid metabolism; 
• biomarkers of glycemic control; 
• novel plasma, serum and urinary biomarkers. 
2. To measure the concentration of CSL346 in the urine and explore its association with 
albuminuria. 
3. To explore the relationship between PD biomarkers and CSL346 PK characteristics. 


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4. To evaluate the frequency of subjects with macroalbuminuria (albumin to creatinine ratio 
(ACR) > 300 mg/g [33.9 mg/mmol]) at Baseline regressing to microalbuminuria (ACR 
> 30 and ≤ 300 mg/g [> 3.39 and ≤ 33.9 mg/mmol]) or normoalbuminuria (ACR ≤ 30 
mg/g [3.39 mg/mmol]), or from microalbuminuria to normoalbuminuria. 
5. To explore possible dose response for the primary and secondary efficacy and safety 
endpoints. 
4.1.4 
Exploratory Endpoints 
The exploratory endpoints for this study are: 
1. Changes from Baseline to each assessment in fasting values for the following PD 
biomarkers: 
• biomarkers of lipid metabolism including but not limited to circulating total 
cholesterol, triglycerides, high density lipoproteins (HDL), low density lipoproteins 
(LDL), glycerol, non-esterified fatty acids (NEFA), and ketones; 
• biomarkers of glycemic control including but not limited to fasting glucose and 
hemoglobin A1c (HbA1c); 
• novel biomarkers, including but not limited to soluble tumor necrosis factor receptor 1 
(sTNFR1), and urinary VEGF-A, soluble VEGF receptor 1 (VEGF-R1), kidney injury 
molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), epidermal 
growth factor (EGF), clusterin, and monocyte chemoattractant protein-1 (MCP-1). 
2. Concentration of CSL346 found in urine at Week 1 (Visit 5) and Week 12 (Visit 9). 
3. Number (percent) of patients who regress from macroalbuminuria to microalbuminuria or 
normoalbuminuria, or from microalbuminuria to normoalbuminuria at Week 16 (Visit 10) 
compared to Baseline. 


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Table 1 
Study Objectives, Endpoints and Summary Measures 
Objectives 
Endpoints 
Summary Measure(s) 
Primary  
Change in log-transformed urinary 
albumin-to-creatinine ratio (ACR) 
from Baseline to Week 16 (Visit 10) 
Geometric mean ratio for CSL346 
(8 mg/kg and 16 mg/kg combined) 
versus placebo (80% confidence 
interval CI), expressed as percent 
change from Baseline 
Key 
Secondary 
Treatment-emergent adverse events 
(TEAEs), including adverse events 
of special interest (AESIs) from the 
time of first dose of IP through End 
of Study (EOS) 
Number and percentage of subjects 
overall, by severity, by relatedness, 
by seriousness, and by action (i.e. 
IP discontinuation) 
 
Observed value and change from 
Baseline in SCr and eGFR through 
EOS 
Mean (standard deviation (SD)) 
Other 
Secondary 
Observed value and change from 
Baseline in systolic and diastolic 
blood pressure (SBP and DBP) 
through EOS 
Mean (SD) 
 
CSL346 serum PK: 
Maximum concentration (Cmax) 
after IV loading dose  
Time to reach Cmax in serum (Tmax) 
after IV loading dose 
Cmax after first SC dose 
Tmax in serum after first SC dose 
Area under the concentration-time 
curve in first dosing interval 
(AUC0-τ) 
Ctrough after each dose 
Mean (SD), coefficient of variation 
(% CV) and geometric mean for all 
parameters except Tmax; Median 
(minimum, maximum) for Tmax 
 
Presence of Anti-Drug Antibody 
(ADA) at Week 4 (Visit 7), Week 8 
(Visit 8), and Week 16 (Visit 10) 
Number and percentage of subjects 
with positive result (with reciprocal 
titer)  
 
 


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Objectives 
Endpoints 
Summary Measure(s) 
Exploratory 
Changes from Baseline to each 
assessment in fasting values for PD 
biomarkers 
Mean (SD) 
 
Concentration of CSL346 found in 
urine at Week 1 (Visit 5) and Week 
12 (Visit 9) 
Mean (SD) 
 
Number (percent) of patients who 
regress from macroalbuminuria to 
microalbuminuria or 
normoalbuminuria, or from 
microalbuminuria to 
normoalbuminuria at Week 16 
(Visit 10) compared to Baseline 
Number and percentage of subjects 
 
4.1.5 
Primary Study Hypotheses 
The primary study hypothesis is that the ACR geometric mean ratio for CSL346 (8 mg/kg 
and 16 mg/kg combined) versus placebo (80% CI) at 16 weeks is less than 1. The test for 
superiority will be conducted at the one-sided, 0.10 alpha level.  
Hypotheses will be tested using a one-sided test at α=0.10: 
H0: GMR >= 1.0 vs. H1: GMR < 1.0 
(i.e. 𝐺𝐺𝐺𝐺𝐺𝐺= 
0.5∗(CSL3468mg
kg + CSL34616mg
kg )
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
), 
where GMR is the geometric mean ratio of the change from baseline in albumin/creatinine 
ratio. 
4.1.6 
Key Secondary Study Hypotheses  
The key secondary hypothesis regarding decreases in serum creatinine, blood pressure (SBP 
and DBP) and eGFR will be conducted in a similar manner as for the primary study 
hypothesis, but using mean instead of geometric mean. 
4.2 
Study Treatments 
CSL346 will be administered at an initial IV loading dose of 3 mg/kg or 6 mg/kg IV in the 
arm, followed by 8 mg/kg or 16 mg/kg SC, respectively, in the abdomen at least 2 hours but 


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no more than 6 hours later. Subsequent SC infusions (8 mg/kg or 16 mg/kg per dose) will be 
administered every 4 weeks for 12 weeks. 
All doses of IP will be administered by IV or SC infusion at the study site. Subjects will be 
considered to have received a complete dose of IP if they receive at least 80% of IP. Subjects 
experiencing a mild local injection site reaction deemed unacceptable by the subject or 
investigator may have administration and / or dose adjustments. 
Eligible subjects will be randomized by means of IRT. The IRT will assign the IP to each 
subject. Randomization will be done centrally. Subjects will be stratified by whether subjects 
are receiving concomitant treatment with an SGLT2i. More details can be found in the 
clinical study protocol. 
4.3 
Randomization Procedures and Blinding 
Eligible subjects will be randomized by means of IRT in a 1:1:2 ratio to CSL346 8mg/kg, 
CSL346 16 mg/kg and placebo, respectively.  Investigational product will be prepared by the 
unblinded site pharmacist (or other dedicated unblinded site personnel) and blinded for 
administration to study subjects. IV loading doses and SC doses of CSL346 and placebo will 
appear identical to site staff and subjects. Randomization will be done centrally. Subjects will 
be stratified by concomitant use of SGLT2is. More details can be found in the clinical study 
protocol referenced above. 
4.4 
Determination of the Sample Size 
The sample size estimation is based on 2 treatment arms because the primary endpoint 
analyses will compare CSL346 (8 mg/kg and 16 mg/kg combined) with placebo. The planned 
sample size is 100 subjects with 50 subjects receiving CSL346 (8 mg/kg, n = 25 and 16 
mg/kg, n = 25) and 50 subjects receiving placebo. Assuming a SD of 0.65 for the change 
from Baseline to Week 16 (Visit 10) in ACR following natural log transformation, a sample 
size of 94 subjects is estimated to provide 85% power to detect a 27% reduction in the 
geometric mean ACR for CSL346 versus placebo, i.e. ln (1 – 0.27) = –0.315 on the natural 
log scale, using a one-sided alpha = 0.10. For this study, statistical significance will be 
achieved with an observed treatment effect of –0.173 on the natural log scale, or 
approximately –16% when expressed as a percent difference in treatments, depending on the 
observed variability. The planned total sample size of 100 subjects accounts for an assumed 
6% drop-out rate. The actual early discontinuation rate will be assessed throughout the study 
and up to 124 subjects may be randomized if necessary, to target 94 completed subjects 
(subjects who received all doses and completed the Week 16 ACR assessment). 


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4.5 
Planned Interim Analyses and Reviews 
4.5.1 
Interim Analysis 
For decision-making and development purposes, an interim analysis of unblinded data will be 
performed after enrollment is complete and all randomized subjects complete the 16-week 
ACR measurement (i.e., 4 weeks after the fourth dose). These results will be summarized in 
an interim, nonregulatory, analytical report. A formal data cutoff and unblinding will occur at 
this milestone. A final statistical analysis of all efficacy and safety data will occur after all 
subjects have completed the full 24 weeks of the study for the clinical study report. 
4.5.2 
Independent Data Monitoring Committee Review Meetings for 
Safety Monitoring 
The roles and responsibilities of the Independent Data Monitoring Committee (IDMC) and 
the safety and efficacy date review schedules are described in the IDMC Charter. In short, the 
IDMC will have appropriate access to unblinded study data to facilitate periodic assessment 
of the efficacy and safety of the IP as well as make recommendations regarding the 
continuation and/or potential modification of the study. A separate IDMC Statistical Analysis 
Plan specifies the analyses and output for the IDMC. 
5 
Changes from the Protocol Planned Analyses 
The following represent changes in this SAP from the protocol: 
• Definition for the Per Protocol Analysis Set has been edited in this SAP and is 
different from the definition provided in the protocol. 
• VEGF-B analyses have been removed as the assay is not available. 
6 
Study Analysis Sets 
6.1 
Screened Analysis Set 
The Screened analysis set consists of all subjects who provided written informed consent. 
6.2 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set comprises all subjects who were randomized. The ITT 
analysis set will be analyzed using the treatment to which the subject was randomized, 
regardless of the treatment actually received. The ITT analysis set will be used in the analysis 
of the primary endpoint. Any subject who receives a treatment randomization number will be 
considered to have been randomized. 


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6.3 
Safety Analysis Set 
The Safety Analysis Set (SAF) comprises all subjects in the ITT Analysis Set who receive at 
least 1 dose of CSL346 or placebo, and will be based on the actual treatment received. In the 
event that a subject receives both CSL346 and placebo, the subject will be included in the 
CSL346 group for this analysis set. Subjects receiving only placebo will be included in the 
placebo group. 
6.4 
Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set is a subset of data from subjects in the ITT Analysis Set. 
Data is excluded for subjects violating specified entry criteria, or for data following 
occurrence of events which may impact ACR. Subjects with data (full or partial) to be 
excluded from the PP Analysis Set will be documented in the data review meeting minutes 
before database lock and before study data unblinding for the interim analysis. Criteria for 
determining the PP Analysis Set are described in Section 16.7. A second data review meeting 
will be held prior to final database lock. 
6.5 
Pharmacokinetic Analysis Set 
The PK Analysis Set comprises all subjects who receive an infusion of CSL346 with at least 
1 quantifiable concentration of CSL346 after administration. The actual treatment will be 
used for subjects in this analysis set. 
6.6 
Pharmacodynamic Analysis Set 
The PD Analysis Set comprises subjects in the SAF for whom analysis results were obtained 
for at least 1 of the exploratory biomarkers of interest. The actual treatment will be used for 
subjects in this analysis set. 
7 
General Considerations 
Datasets submitted to regulatory agencies will be created according to Clinical Data 
Interchange Standards Consortium (CDISC) standards. Submission data will be provided in 
Study Data Tabulation Model (SDTM) format. Analysis data will be provided in Analysis 
Data Model (ADaM) format. 
Statistical Analysis System (SAS) version 9.4 or higher will be used to perform all data 
analyses. 
Continuous variables will be summarized in terms of the number of observations (n), mean, 
SD, median, first quartile, third quartile, minimum and maximum. Other descriptive statistics 
(e.g. standard error [SE], CV%) may be reported when appropriate. For repeated assessments 


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of continuous variables, the change from baseline will also be summarized. Categorical 
variables will be summarized using frequency counts and percentages. Analyses that use 
other descriptive statistics will have the specific descriptive statistics identified with the 
analysis in the applicable SAP section. 
7.1 
COVID-19 Impact 
During the course of this study, the global COVID-19 pandemic may still be pervasive, 
impacting the study in a variety of ways. This section describes how the impact of COVID-19 
will be documented. 
Protocol Deviations 
Protocol deviations due to the COVID-19 pandemic will be collected in the Clinical Trial 
Management System (CTMS) per the study specific Protocol Deviation Plan or another 
method as described in the study specific protocol deviations plan. 
Covance’s CTMS: Pandemic related protocol deviations are identified within CTMS by using 
the term “COVID-19” as the first term within the deviation description. In addition, the sub-
category of ‘Other’ will be chosen and COVID-19 will be written in the description field. 
COVID-19-related protocol deviations will be summarized as sub-categories under existing 
categories of protocol deviations (see Section 9.2). All COVID-19 related protocol deviations 
will appear in the listing of protocol deviations and can be identified based on using the term 
“COVID-19” as the first term in the description. During the Biostatistics Data Review 
Meeting a review will be done to ensure that deviations are being marked accordingly. 
Visit Modality, Missed Visits and Missing Assessments 
Changes to subjects’ visits caused by the COVID-19 pandemic will be captured for each 
subject in electronic data capture (EDC), on the “Visit Status” form. The EDC page is 
customized with the protocol specific visits and includes different options for the primary 
visit modality, as well as whether the missed visit/alternate visit modality is due to COVID-
19. Changes to visit modality may be a protocol deviation, and this data is captured. Since 
assessments (e.g. vital signs, laboratory data) collected at each visit are known, the data 
missing due to COVID-19 can be determined. 
Assessments that were missed or required alternate visit modality (e.g. televisits or home 
health visits) due to COVID-19 will be summarized. In addition the number of subjects with 
missed visits or alternate visit modality, by visit, will be summarized. 
Study Treatment Discontinuation or Study Discontinuation 
Subjects who have either study treatment discontinuation or study discontinuation due to 


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COVID-19 will have the reason captured in the electronic case report form (eCRF). On the 
appropriate eCRF form to record either study medication discontinuation (“End of 
Treatment” form) or study discontinuation (“Conclusion of Subject Participation” form), a 
reason will be selected which includes a field for descriptive text. The reason can be either 
“Withdrawal by Subject”, “Physician Decision” or “Other”. The associated free text field 
entry will include “COVID-19”. When either treatment or the study is discontinued due to 
an AE or death, the specific corresponding AE is collected. Discontinuations due to 
COVID-19 adverse events (AE) will then be identified based on whether the Medical 
Dictionary for Regulatory Activities (MedDRA) code for the AE is included in the COVID-
19 standard MedDRA query (SMQ) (Narrow). 
Cases of study treatment discontinuation or study discontinuation due to COVID-19 will be 
included in the summary of subject disposition. 
Adverse Events 
Adverse events associated with COVID-19, which can include a clinically significant 
laboratory finding like a positive test result for COVID-19, will be reported by investigators 
following reporting requirements as outlined in the protocol. COVID-19 associated AEs are 
identified via MedDRA coding. MedDRA version 24.1 has been updated to include COVID-
19 specific preferred terms (PT). Relevant AEs will be identified for reporting by use of 
COVID-19 SMQ (Narrow). A list of those SMQs will be provided by CSL Behring. All 
COVID-19 associated adverse events will be included in standard AE tables as well as a 
COVID-19 specific AE table. 
A listing showing all COVID-19 associated AEs will be provided. 
COVID-19 Vaccinations 
For COVID-19 vaccine data collection, sites will be instructed to inquire if subject has 
received a COVID-19 vaccination and, if answered in the affirmative, should record each 
dose, exact date of administration, and manufacturer of the vaccine on the concomitant 
medications form. Standardized Drug Grouping (SDG) from WHO Drug Dictionary will be 
utilized to identify COVID-19 vaccines (see Appendix 16.6). Any vaccination related adverse 
events experienced by study subjects will be recorded on the AE/SAE eCRF page. 
The data are planned to be summarized as follows: 
• Summary table by SoC and PT of all AEs occurring within 7 days after COVID-19 
vaccine administration; 
• Listing of all AEs occurring within 7 days after COVID-19 vaccine administration; 


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• Listing of all subjects receiving COVID-19 vaccine. 
Overall Summary of Subjects Impacted by COVID-19 
Counts and percentages of subjects with at least one of the following due to COVID-19 will 
be summarized in an overview table: 
• Subjects with any COVID-19 impact; 
• Protocol Deviations; 
• Missing assessment; 
• Missing Visit; 
• Alternate Visit Modality; 
• Study Treatment Discontinuation; 
• Study Discontinuation; 
• Any TEAEs; 
• Any Serious TEAEs; 
• Receipt of COVID vaccine. 
8 
Data Handling Conventions 
8.1 
Missing Data 
Missing data occurs when any requested data are not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in subject listing 
displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Because of the design and duration of the study, missing data are inevitable. The details of 
handling missing data are presented in the corresponding sections of this SAP for respective 
analyses (e.g. primary and secondary efficacy analyses, safety analyses). 
8.2 
General Derived Variables 
8.2.1 
Reference Dates and Study Days 
Reference dates are used to assign study periods relative to treatment (Section 8.4). 
• The safety reference date is the treatment start date (date of IV loading dose), and will 
be used to calculate study day for safety measures. 
• The efficacy reference date is the randomization date and will be used to calculate 
study day for efficacy measures. 


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• The PK reference date is the date and time of the IV loading dose and will be used to 
calculate study day/time for PK measures. 
The respective study day will be calculated as (date of interest - reference date) + 1 if the date 
of interest occurs on or after the reference date. If the date of interest occurs before the 
reference date, then the study day will be calculated as (date of interest – reference date). 
There will be no study day zero. 
8.2.2 
Durations 
Durations (e.g. the duration of an adverse event [AE]) are calculated in days as: 
• event end date – event start date + 1, if end time or start time not available; 
• event end date and time – event start date and time, if both end time and start time 
available. 
Thus, there will be no duration of 0 if end time or start time are not available. If an AE has 
missing or partially missing start or end date, no duration will be calculated. 
To transform durations into weeks, divide the number of days by 7; to report in months, 
divide the number of days by 30.4375; to report in years, divide the number of days by 
365.25. These algorithms return decimal numbers, and ignore the actual numbers of days in 
the months or years (the calendar days) between start date and stop date. The "year" used in 
these algorithms is 365.25 days long, and the "month" is one twelfth of that year. 
8.2.3 
Baseline Definition 
Baseline is defined as the most recent, non-missing value before the first IP administration 
(including unscheduled visits) for all assessments unless otherwise stated. In case of an 
assessment at the same date as the first IP administration (and only the date for that 
assessment is available) it will be assumed the assessment was done before IP administration. 
For the purposes of the analysis of albumin creatinine ratio, baseline will be defined as the 
geometric mean of the 6 values obtained before treatment (3 values from Visit 3 and 3 values 
immediately before treatment at Visit 4). If fewer than 6 values are available, the geometric 
mean of all the available values will be used for baseline. 
Baseline for blood pressure will be the mean of the three values (or all available if fewer than 
three) collected immediately before the IV loading dose. 
Baseline for serum creatinine will be an average of the two samples collected prior to first IP 
administration (Visit 3 and Visit 4). Baseline eGFR will be calculated based on the baseline 


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serum creatinine. These calculated baseline eGFR values will be used to define eGFR 
categories and covariates in statistical analyses. 
For soluble tumor necrosis factor receptor 1 (sTNFR1), exploratory circulating and urinary 
markers, the baseline value will be an average of the two samples collected prior to first IP 
administration (Visit 3 and Visit 4). [Note: Exploratory circulating biomarkers are defined in 
Section 4.1.4 as biomarkers of lipid metabolism including but not limited to circulating total 
cholesterol, triglycerides, high density lipoproteins (HDL), low density lipoproteins (LDL), 
glycerol, non-esterified fatty acids (NEFA), and ketones.  Urinary markers are defined in 
Section 10.3 as VEGF-A, soluble VEGF receptor 1 (VEGF-R1), kidney injury molecule-1 
(KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), clusterin, monocyte 
chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF).] 
8.2.4 
Change from Baseline 
Change from baseline is calculated as: 
• visit value – baseline value. 
Percentage change from baseline is calculated as: 
• (change from baseline / baseline value) * 100. 
Percent change for geometric mean ACR is calculated as: 
• ((geometric mean ACR at a visit / baseline geometric mean ACR) – 1 ) * 100%. 
If either the baseline or visit value is missing, the change from baseline and percentage 
change from baseline is missing. 
8.2.5 
Multiple Assessments 
All data will be reported according to the nominal visit date for which they were reported 
(that is, no visit windows will be applied during dataset creation and the visit will not be 
re-allocated if the actual visit date deviates from the planned date according to the visit 
schedule in the protocol). In the instance of early discontinuation from the study, data 
collected at discontinuation from study should be slotted to the closest scheduled visit. 
Unscheduled data will not be included in by-visit summaries, but will contribute to values of 
clinical importance and will appear chronologically in listings. Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be included in listings. 
If multiple assessments on different days are reported for the same scheduled assessment, 
then the latest assessment for that scheduled assessment will be analyzed unless as specified 
otherwise below. 


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8.2.6 
Actual Treatment 
The subjects’ actual treatment will be derived from exposure data. If a subject receives a 
study treatment that is different from the planned treatment for the entire time of treatment, 
then actual treatment is the treatment actually received. In the event that a subject receives 
both CSL346 and placebo, the subject will be included in the CSL346 group for this analysis 
set. Subjects receiving only placebo will be included in the placebo group. 
8.2.7 
Derived Variables 
Derivation of Body Mass Index (BMI) 
BMI will be calculated using the following formula: 
BMI (kg/m2) = Weight (kg) / [Height (m)]2 
using the height measured at Screening and the weight measured at Day 1 (if available). If 
weight at Day 1 is not available, the assessment prior to IP administration available closest to 
Day 1 will be employed. 
Derivation of ACR 
For the purposes of the analysis of ACR, baseline will be defined as the geometric mean of 
the 6 values obtained before treatment (3 values from Visit 3 and 3 values immediately before 
treatment at Visit 4). ACR (mg/g) will be derived from first morning void (FMV) urine 
samples. 
On-treatment assessments of ACR will be the geometric mean values from multiple FMV 
collections (3 FMV collections, except Visit 9 where only 2 FMV samples will be collected) 
at each time point. 
The ACR will be provided with the lab data. Only the geometric mean values for analysis 
purpose will be calculated. 
Derivation of eGFR 
eGFR will be derived using the following the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) formula [Levey et al. 2009]: 
eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if 
female] x 1.159 [if black], where Scr is serum creatinine, κ is 0.7 for females 
and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates 
the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. 


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The standardized serum creatinine (SCr) is expressed as mg/dL. The years of age will be for 
all eGFR calculations the years of age collected by eCRF. “Black” will be accounted as race 
of “Black or African American”. 
8.3 
Stratification and Covariates 
Stratification of subjects at enrollment will be based on whether subjects are receiving 
concomitant treatment with an SGLT2i. At least 50% of the subjects enrolled are to be 
receiving an SGLT2i. The analysis will include this stratification term in the model and 
results by these subgroups will be reported. 
8.4 
Study Periods Relative to Treatment 
All data will be assigned to one of the four study time periods defined below.  
Screening is defined as the time from signing of the informed consent form through Visit 2. 
The Lead-in Period is defined as the time Post-Visit 2 (from SC saline test infusion) up to 
subject randomization. 
The Treatment Period is defined as the time from randomization through Visit 9 (12 weeks 
after the first administration of IP). 
Follow-up begins after the last administration of IP at Visit 9 through the EOS visit 12 weeks 
later. 
9 
Study Population 
Unless otherwise stated, all tables and listings in Sections 9.1 – 9.4 will be based on the ITT 
analysis set. 
9.1 
Subject Disposition 
The following summaries will be provided for the Screened Analysis Set by each CSL346 
group (8 mg/kg or 16 mg/kg) as well as combined over CSL346 groups, placebo and total 
population for: 
• Subjects who underwent Screening – only total; 
• Screening failures with reason for failure – only total; 
• Subjects eligible for randomization – only total; 
• Subjects not eligible for randomization and reason for being not eligible– only total; 
• Subjects randomized – by treatment and total; 
• Subjects randomized but not treated – by treatment and total; 
• Subjects treated – by treatment and total; 


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• Subjects treated who completed through the final efficacy assessment at Week 16 – by 
treatment and total; 
• Subjects treated who discontinued from the study before the final efficacy assessment 
at Week 16 with reason – by treatment and total; 
• Subjects treated who completed the study at Week 24 – by treatment and total; 
• Subjects treated who discontinued from the study before Week 24 with reason – by 
treatment and total; 
• Subjects entering and discontinuing each period of the study (screening, lead-in, 
treatment, follow-up); 
• Subjects in each of the analysis sets described in Section 6. 
The disposition summary will be given by study period and in addition stratified by: 
• Subjects in each stratum for SGLT2i (obtained from IRT data); 
• Subjects defined by level of eGFR at baseline (20-45, 45 - <60, 60 - <90, ≥90 
mL/min/1.73m2); 
• Subjects defined by level of ACR by 24 hr. urine at baseline (30 - ≤300, >300 - ≤1000 
and >1000 mg/g). 
Disposition events related to COVID-19 will also be presented by counts and percentages. 
Reasons for study discontinuation will be presented in the order they are displayed in the 
CRF. 
By-subject listing will be provided for disposition status for each subject. This will include: 
• Randomization scheme based on the ITT Analysis Set; 
• Subject disposition with date of screening (in case of re-screening, all screening 
records will be listed), date (and time) of the randomization, date (and time) of first IP 
administration, Week 16 date, Week 24 date, and date of completion/withdrawal; 
• Screening failures with reason; 
• Subjects who discontinued from the study with reason for discontinuation. 
9.2 
Protocol Deviations 
A protocol deviation occurs when an investigator site, or study subject, does not adhere to 
protocol-stipulated requirements. Deviations will be assessed by CSL as they are reported 
and then evaluated periodically during study conduct, based on protocol deviation plan for 
this study developed by CSL Behring. 
Deviations will be categorized as either major or minor. Major protocol deviations for 
subjects in the ITT Analysis Set and Per-Protocol Analysis Set will be summarized for 


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number and percentage of subjects with each protocol deviation, though all major and minor 
deviations will be listed. In addition, a summary of violations of inclusion, exclusion, and 
randomization criteria will be provided for ITT Analysis Set and Per-Protocol Analysis Set. 
The final decision regarding protocol deviations and assignment of subjects to analysis 
population will be made during the blinded data review meeting. 
The following by-subject listings will be provided based on the Screened Analysis Set: 
• All protocol deviations (including inclusion and exclusion criteria violations, and 
violations of randomization criteria); 
• Subject assignment to analysis sets and reasons for exclusion. 
9.3 
Demographic and Baseline Characteristics> 
Descriptive statistics as specified in Section 7 will be provided for continuous variables, 
number and percentage of subjects for categorical variables. 
The following summaries will be provided for the ITT and Per-Protocol Analysis Set: 
• Demographic characteristics (e.g. age, race, ethnicity, sex, baseline height, and 
baseline body weight, and BMI). In addition to summarization as a continuous 
variable, age will also be categorized and summarized by <25, 25 to ≤45, >45 to ≤65, 
>65 years. Country will be summarized by number and percentage of subjects in 
USA, Australia, New Zealand; 
• Disease characteristics including the duration since diagnosis of Type II diabetes 
mellitus (T2DM) to enrollment in the screening period of the study, duration of 
albuminuria to enrollment, ACR (30 - ≤300, >300 - ≤1000 and >1000 mg/g), SGLT2i 
status (obtained from IRT data), eGFR status 20 - <45, 45 - <60, 60 - <90, ≥90 
mL/min/1.73m2), signs and symptoms of diabetes (e.g. diabetic retinopathy, 
autonomic neuropathy, peripheral diabetic neuropathy, diabetic ketoacidosis, diabetic 
foot ulcer, other diabetic neuropathy, other active skin ulcer), family history of 
diabetes (e.g. family history of type 1 diabetes, family history of type 2 diabetes) 
• Medical history (coded using MedDRA – the MedDRA version will be populated in 
the tables output) will be presented by system organ class (SOC) and PT. 
In addition, demographics will be provided stratified by SGLT2i presence, baseline eGFR 
and baseline ACR. 
Corresponding by-subject listings will be provided. The listing for disease characteristics will 
include but is not limited to the year of diagnosis as well as the duration for T2DM. The 


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medical history listing will also provide an indicator of whether the condition was active at 
the time of entry into the screening period. 
9.4 
Prior/Concomitant Medications 
Prior/concomitant medications will be coded using World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) B3. The version will be populated in the table output. 
The reported medication will be classified as ‘Prior’ or ‘Concomitant’ as follows. Note that a 
drug which is administered both before and after the first dose of study medication will fall 
into both ‘Prior’ and ‘Concomitant’ categories. 
• ‘Prior’: if the subject has not taken any IP; or if the medication start date [/time] is 
before IP start date [/time]. Note that this period will include the screening and lead-in 
periods of the study; 
• ‘Concomitant’ if the medication end date is after the IP start date [time]. Note this 
includes the treatment and follow-up periods of the study; 
• If the medication start date or end date are partially or completely missing, the 
medication will be assigned to both ‘Prior’ and ‘Concomitant’ unless there is clear 
evidence that the medication stopped before IP start date (that is, the medication 
should be assigned only to ‘Prior’) or that the medication started after IP start date 
[/time] (that is, the medication should be assigned only to ‘Concomitant’). 
Prior and Concomitant medications will be summarized separately showing the number and 
percentage of subjects taking concomitant medications by Anatomical Therapeutic Chemical 
(ATC) classification level 4 and PT. If the ATC level 4 coding is not available for a PT, the 
next available lower level ATC code will be used. Summaries of Prior and Concomitant 
medications will be based upon either the Safety Analysis Set or the Per Protocol Analysis 
Set. 
Counts of the number of subjects with prior and concomitant therapies will be presented in 
tabular form. Counts of the number of subjects on all therapies considered standard of care 
will be provided separately with special note of changes in dose during concomitant 
treatment, refer to Appendix 16.3 for standard of care therapies. As a change in a standard of 
care therapy the following will be accounted: 
• Any new concomitant therapy; 
• Any change in dose or route or frequency of an existing therapy. 


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A further summary will provide treatments associated with COVID-19. Those medications 
will be identified by CSL Behring and a respective flag will be given in SDTM data sets, 
provided by CSL Behring. 
The following listing will be provided: 
• Prior and concomitant medication.  
10 
Efficacy Analyses 
Data for the primary endpoint, ACR, as well as serum creatinine, eGFR, blood pressure and 
some biomarkers will be collected multiple times after the initiation of treatment, therefore, 
the primary analysis for these outcomes will be a mixed effects model repeated measures 
(MMRM) approach. The change from baseline to Weeks 2, 4, 8, 12, 16, and 24 will be 
included in the model. 
Biomarkers of lipid metabolism, glycemic control and novel biomarkers of kidney function 
will also employ a model similar to the primary endpoint (with the exception of biomarkers 
measured only at the beginning and end of the study). Exploratory biomarkers will be the 
subject of a separate report. 
10.1 
Analysis of Primary Endpoint(s) 
10.1.1 Primary Estimand 
The primary interest is to quantify the treatment effect of CSL346 under the situation where 
SGLT2i may be a possible effect modifier and is included in the model. The estimand for the 
ITT Analysis Set is the average effect of CSL346 on the geometric mean ACR at 16 weeks 
averaged across subjects receiving and not receiving SGLT2i. All data collected through 
Week 24 will be used in the analysis. 
The primary estimand in line with the primary interest of the study is described as follows: 
• Treatment Condition: four SC administrations of CSL346 or placebo over a 12-week 
period (Day 1, Weeks 4, 8 and 12) where the primary comparison is between CSL346 
at Week 16, regardless of dose, and placebo, while subjects have not died. The 
“treatment policy strategy” will be used, i.e. changes in dose, for example from 16 
mg/kg to 8 mg/kg OR the number of subcutaneous injections, or treatment 
discontinuation/non-initiation, or other miscellaneous factors influencing ACR will 
not be taken into account in the primary analysis; 
• Population: the target patient population defined by T2DM and DKD and further 
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• Variable: change from baseline at 16 weeks of log ACR; 
• Population-level summary: difference in treatments, calculated as 100% × (geometric 
mean ratio of the treatment comparison – 1) based on log ACR. 
10.1.2 Primary Efficacy Analysis 
The primary analysis is a mixed effects model, repeated measures (MMRM) analysis of the 
change from baseline through 24 weeks of log ACR, with the primary treatment comparison 
at Week 16 (Visit 10). The model will include treatment (at 3 levels: 8 mg/kg CSL346, 
16 mg/kg CSL346, and placebo), baseline log ACR, the stratification variable related to the 
concomitant use of SGLT2i, visit (as a categorical factor), and interactions between visit and 
each of the other model terms as factors. The primary comparison of interest will be 
calculated using a contrast of 0.5 (8 mg/kg CSL346 + 16 mg/kg CSL346) – Placebo. Please 
see Section 16.1 for the corresponding SAS Code for the MMRM model. Because this is an 
early development study and the first study in subjects with T2DM, the one-sided alpha level 
to be employed for this test is 0.10. Estimated treatment effect of individual CSL346 dose 
levels versus placebo will also be summarized. The treatment comparisons will be expressed 
as a percent difference in treatments, calculated as 100% × (geometric mean ratio of the 
treatment comparison – 1). The covariance matrix structure to be employed in the primary 
analysis will be an unstructured pattern. In the event of model convergence issue, a Toeplitz 
heterogeneous structure will be employed. If the model still fails to converge an 
autoregressive structure ARH(1) will be assumed. 
For the purposes of this analysis, baseline will be defined as the geometric mean of the 6 
values obtained before treatment (3 values from Visit 3 and 3 values immediately before 
treatment at Visit 4). For post-treatment, data for ACR will be collected in triplicate. The 
value to be employed in the analysis of each post-treatment visit will be the geometric mean 
of the three values. In the event of missing data, the value for a visit will be the average of the 
values available. There will be only one primary comparison so there is no consideration of 
adjustment for multiple comparisons. Comparisons of CSL346 dose levels with placebo will 
be considered exploratory. The primary analysis will be performed using the ITT Analysis 
Set. That is, the population for which we are estimating the treatment effect is according to 
the treatment to which subjects were randomized. To facilitate characterization of response, a 
line graph of ACR will be provided by relative week with the standard error of measurement 
(SEM) at each time point by treatment, and by treatment and baseline ACR category. 
A supplemental analysis will consider the effects of COVID-19 on the primary endpoint. For 
subjects with treatment discontinuation due to logistical pandemic-related reasons 
(“Conclusion of Subject Participation” eCRF, reason of “Pandemic Related”), observations 


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greater than 28 days after last on-schedule SC infusion received will be excluded. For 
subjects who received no infusions due to logistical pandemic-related reasons, all data will be 
excluded. For subjects who test positive for COVID-19 infection during the study, 
observations on or after the diagnosis date will be excluded. If both conditions apply, then 
data exclusion will begin at (a) 28 days after the last SC infusion or (b) the diagnosis date, 
whichever is earlier. 
An exploratory analysis of the primary endpoint of ACR will be a categorical analysis of the 
number of subjects showing a gross change in albuminuria status from baseline to Week 16. 
As noted above, this will compare the number of subjects in each treatment group who 
improve from macroalbuminuria at baseline (ACR >300 mg/g [33.9 mg/mmol]) regressing to 
microalbuminuria (ACR >30 and ≤300 mg/g [>3.39 and ≤33.9 mg/mmol]) or 
normoalbuminuria (ACR <= 30 mg/g [3.39 mg/mmol]) OR from microalbuminuria to 
normoalbuminuria at Week 16. For analysis of a step change in albuminuria status (i.e., from 
macroalbuminuria or microalbuminuria to normal albuminuria or microalbuminuria to 
normal albuminuria OR from microalbuminuria to macroalbuminuria) Cochran-Mantel-
Haenszel test stratified for SGLT2i will be employed to compare subjects receiving CSL346 
versus placebo. 
10.1.3 Sensitivity Analyses of Primary Endpoint(s) 
A sensitivity analysis will be conducted with regard to the primary endpoint. The analysis 
will be identical to the one identified above, except that the Per Protocol Analysis Set is used. 
In this analysis, subjects will be assigned to the treatment actually received. In the event of a 
decrease in dose (from 16 mg/kg to 8 mg/kg) the subject will be assigned to the highest dose 
treatment received. This analysis will exclude data following major protocol deviations and 
other factors which may influence the primary outcome. Major protocol deviations will be 
determined without knowledge of treatment assignment (i.e., prior to unblinding). Appendix 
16.7 provides a list of major protocol deviations and other reasons for exclusion from the Per 
Protocol Analysis Set. 
The second (to be conducted for Per Protocol Analysis Set) sensitivity analysis is a tipping 
point analysis that will employ multiple imputation for missing data (missing change from 
baseline in ACR) using multiple regression to provide multiple complete data sets [Buuren 
2018]. The same MMRM model will be used to analyze the imputed complete data sets 
(missing ACR values will be imputed for planned ACR assessments up to the individual 
subjects last performed visit before EOS and EOS visit). If the original analysis indicates a 
significant effect, the tipping point analysis adds a value, delta, to the imputation model to 
assess the sensitivity of the “missing at random” assumption. In this case, the delta is 


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increased (decreased) until statistical significance is lost. A conclusion of the sensitivity 
analysis is based on whether the value of delta at the time significance is lost is interpreted as 
likely given the data observed. 
10.1.4 Subgroup Analyses of Primary Endpoint(s) 
Two a priori subgroup analyses to be considered will be based on the strata defined by the 
presence or absence of concomitant use of a SGLT2i and by eGFR status at baseline (20 - 
<45, 45 - <60, 60 - <90, ≥90 mL/min/1.73m2). Each subgroup will be analyzed in a similar 
manner as the primary analysis as a mixed effects model, repeated measures (MMRM) 
analysis of the change from baseline through 24 weeks of log ACR, with the primary 
treatment comparison at Week 16 (Visit 10). The model will include treatment, baseline log 
ACR, and interactions between visit and each of the other model terms as factors. For 
subgroup analysis by SGLT2i, the factor of SGLT2i is not to be included in the model. 
Scatterplots of ACR and/or change in ACR by eGFR will also be provided. 
10.2 
Analysis of Key Secondary Endpoint(s) 
Blood pressure, serum creatinine and eGFR calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula [Levey et al. 2009], Section 8.2.7, will 
employ a model similar to the primary endpoint. These endpoints will not be log-transformed 
prior to analysis. The analysis for these continuous endpoints is an MMRM analysis of 
change from baseline to each post-baseline measurement. The model will include treatment, 
stratification related to the concomitant use of SGLT2is, visit (as a categorical factor), and 
interactions between visit and each of the other model terms, as well as the corresponding 
baseline measurement as a covariate (refer to Section 16.1 for respective SAS code). 
Hypotheses testing will be identical to that of the primary endpoint. Line graphs of the mean 
response over time will be provided as well as by ACR status. 
All of these analyses will be performed on the ITT Analysis Set. 
10.2.1 Key Secondary Estimand 
The treatment condition and population of the estimand for key secondary endpoints is the 
same as for the primary endpoint. The variable in each case will be the mean change from 
baseline through Week 16 in each parameter. Also, in each case, the population level 
summary will be the arithmetic mean change. 
10.3 
Analysis of Other Secondary Endpoints 
Biomarkers of lipid metabolism, glycemic control and novel biomarkers of kidney function 
as well as weight will also employ a model similar to the primary endpoint except for the 


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concentration of CSL346 in urine. The analysis for continuous endpoints is an MMRM 
analysis of change from baseline to each post-baseline measurement (Weeks 4, 8 and 16). 
The model will include treatment, stratification related to the concomitant use of SGLT2i, 
visit (as a categorical factor), and interactions between visit and each of the other model 
terms, as well as the corresponding baseline measurement as a covariate (refer to Section 
16.1 for respective SAS code). Treatment comparisons of interest will be similar to that of the 
primary endpoint. Lipid parameters will be natural log transformed prior to analysis.  
Urinary biomarkers will be normalized for urine creatinine. These urinary biomarkers include 
urinary VEGF-A, soluble VEGF receptor 1 (VEGF-R1), kidney injury molecule-1 (KIM-1), 
neutrophil gelatinase-associated lipocalin (NGAL), clusterin, and monocyte chemoattractant 
protein-1 (MCP-1) and epidermal growth factor (EGF). Normalization is performed by 
dividing the urinary biomarker by urine creatinine collected at the midstream morning void 
taken the same day as the urinary biomarker. Normalized urinary biomarkers should be 
reported in units of pg/µg. To obtain these units, first convert urinary creatinine from units of 
mg/dL to units of µg/mL by multiplying by 10. Then divide the urinary biomarker (pg/mL) 
by urinary creatinine (µg/mL) to get normalized results with units of pg/µg. 
A repeated measures analysis of covariance model will be employed to analyze the 
concentration of CSL346 in urine, collected at Day 1, Day 8, and Day 85. The repeated 
measures analysis of covariance model will include terms for treatment, baseline as a 
covariate and SGLT2i use. 
All analyses for biomarker will be performed on the PD Analysis Set. Analyses for KIM-1, 
NGAL, EGF and MCP-1 will be performed in addition for the PP Analysis Set. Analyses for 
urine CSL346 concentration will be performed on the ITT Analysis Set. 
10.4 
Missing Data and Imputation 
To avoid missing data with regard to the primary endpoint, ACR, procedures will be in place 
to maximize the ability to collect first morning voids for every subject at every planned visit. 
Likewise, every attempt will be made to retain subjects in the study once they are 
randomized. Therefore, it is anticipated that missing data with regard to the primary endpoint 
will be kept to a minimum.  Imputation is only being considered for the sensitivity analysis 
for the primary endpoint. 
10.5 
Treatment Compliance 
The calculation of overall compliance is based on receiving all four injections of IP. An 
injection of at least 80% of the planned volume will satisfy the criteria of receiving a 


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compliant injection at each of the 4 visits. The following summaries will be provided by 
treatment group: 
• The number of subjects receiving all four doses of IP; 
• The number of subjects receiving at least 80% of the planned infusion volume at each 
visit. 
Compliance will be summarized for the Safety Analysis Set. 
A by-subject listing will be provided including: 
• By injection: the randomized and actual treatment administered, planned and actual 
volume of IP, individual and categorized compliance; 
• Overall (across all injections): cumulative planned and cumulative actual volume of 
IP, individual and categorized compliance, number of injections. 
Calculation of compliance and extent of exposure (as described in Section 11.1) will be based 
on drug accountability data collected by eCRF. 
11 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set as defined in Section 6.3 and on 
the treatment which the subject received. 
11.1 
Extent of Exposure 
Exposure to the IP will be descriptively summarized by treatment group: 
• Number of subjects receiving loading dose; 
• Summary statistics for Loading dose received; 
• Number of subcutaneous infusions administered per visit and overall; 
• Summary statistics for Total dose received [mg/kg] per visit and overall; 
• Summary statistics for Total volume received (ml) per visit and overall. 
Total dose received [mg/kg] will be provided with the study data. The listing of individual 
subject data will include all variables presented in the summary tables. 
11.2 
Adverse Events 
AEs will be coded using the MedDRA dictionary (the MedDRA version will be populated in 
the tables output). AEs will start to be collected upon subject’s signing of the informed 
consent form (ICF). AEs observed during the screening and lead-in periods of the study will 
be summarized separately as no treatment is received during this time. TEAEs, defined as 
AEs starting on or after the date of the first administration of the IP (IV loading dose), 


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through the end of the follow up period will be summarized. All AE tables will summarize 
the number and percentage of subjects with TEAEs for each of the three randomized 
treatment groups, for a combined column for the two CSL346 groups, as well as an overall 
column. All AEs regardless of whether they were treatment-emergent or not will be listed. 
Where AE start dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, except if the partial start dates or the AE end date indicate that the AE started 
before the first administration of the IP (IV loading dose) during the treatment period 
(Section 4). 
Table 2 
TEAE Assignment in Case of Missing AE Start Date Elements 
Missing elements 
of AE start 
Rule 
 
Regardless of any missing information for AE start: 
AE end date / time < IP start date / time 
non-TEAE 
Otherwise (i.e., if AE end date / time ≥ IP start date / time) 
 
- 
all 
 
TEAE 
- 
day and month AE start year ≥ IP start year 
TEAE 
AE start year < IP start year 
non-TEAE 
- 
day 
AE start month / year ≥ IP start month / year 
TEAE 
AE start month / year < IP start month / year 
non-TEAE 
- 
time 
AE start date ≥ IP start date 
TEAE 
AE start date < IP start date 
non-TEAE 
 
If AE start dates or end dates are missing or partially missing for an AE, no duration will be 
calculated. If for a TEAE the relationship to study treatment is missing the worst case will be 
assumed for summarizing analysis (i.e. the relationship to study treatment will be assumed to 
be “Related”). A missing severity for a TEAE will be assumed for summaries as “Severe”. 
For non-TEAEs no imputation will be done in case of missing study treatment relationship or 
severity. No other imputations for missing AE information will be done. 
The AESIs for this study are defined as: 
• Injection site reactions (PTs as identified through a standard MedDRA query, 
provided by CSL Behring); 
• Increase in serum creatinine, defined as a confirmed increase in serum creatinine from 
baseline of >0.3 mg/dL; 


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• Albuminuria, defined as a confirmed increase in urinary ACR of > 2-fold increase 
(doubling) from baseline with additional evidence suggesting Acute Kidney Injury 
(AKI); 
• Increased blood pressure, defined as an observed SBP ≥180 mmHg and/or DBP ≥120 
mmHg or an increase from Baseline in either SBP or DBP ≥20 mmHg and greater 
than 160/105 mmHg; 
• A cardiac event will be defined as any clinically-meaningful change from Baseline in 
cardiac-related parameters, such as electrocardiogram (ECG) intervals, cardiac 
troponin levels [Thygesen et al, 2018], or left ventricular ejection fraction (LVEF), as 
reported in the cardiac AESI-specific eCRF. 
For tabulated summaries injection site reactions, increase in serum creatinine, albuminuria, 
and increased blood pressure and cardiac events will be identified in the eCRF as marked by 
the investigator. 
An overview summary of TEAEs, including number and percentages of subjects as well as 
the number of events, will be provided including the following: 
• Any TEAE; 
• TEAEs related to study treatment; 
• TEAEs leading to discontinuation of study treatment (obtained from AE eCRF); 
• TEAEs leading to study withdrawal (obtained from “End of Treatment” or 
“Conclusion of Subject Participation” eCRF); 
• TEAEs leading to dose interruptions; 
• TEAEs by maximum severity (without number of events or TEAE rate); 
• Treatment-emergent AESIs; 
• Serious TEAEs; 
• Serious TEAEs related to study treatment; 
• Fatal TEAEs. 
The above overall AE table will also be provided for the whole study, for the Treatment 
Period and for the Follow-up Period, and for Follow-up Period separately. In addition, the 
overview table will be stratified by SGLT2i as well as ACR and eGFR status separately at 
baseline. 
The following frequency tables will be generated for TEAEs, including number and 
percentages of subjects and the number of events: 
• TEAEs by SOC and PT; 
• TEAEs by PT; 


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• TEAEs by PT through Week 16; 
• TEAEs by PT from Week 16 through Week 24; 
• TEAEs by PT, stratified by SGLT2i; 
• TEAEs by PT, stratified by baseline eGFR (<60 and eGFR>=60 mL/min/1.73m2); 
• TEAEs by SOC, PT, and maximum severity (without number of events); 
• Related TEAEs by SOC and PT; 
• Related TEAEs by PT; 
• Treatment-emergent AESIs by PT; 
• Serious TEAEs by SOC and PT; 
• Related serious TEAEs by SOC and PT; 
• TEAEs with result in drug discontinuation; 
• TEAEs related to COVID-19 infection. 
AEs will be presented in summaries by decreasing overall frequency (overall frequency as 
the number of subjects with that AE). In case of two AEs having the same overall frequency, 
the AEs will be ordered alphabetically. 
The following by-subject listings will be provided: 
• All AEs; 
• SAEs; 
• AEs leading to study withdrawal or permanent discontinuation of study treatment; 
• AESIs by type of AESI. 
11.3 
Clinical Laboratory Evaluations 
The following hematology and serum biochemistry laboratory tests will be summarized by 
visit and by the three randomized treatment groups, including a combined column for the two 
CSL346 groups. The summaries will be provided for the analysis population as described in 
Section 11. Data for urinalysis will only be listed. 
Hematology: Hemoglobin, hematocrit, erythrocytes (RBC) count (RBC indices of MCV; 
MCH; MCHC; RDW, if available), total and differential leukocyte (WBC) counts 
(neutrophils; neutrophil band forms, lymphocytes; monocytes; eosinophils; basophils), 
reticulocytes, and platelet count. 
Serum Biochemistry: Albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), bilirubin (direct), blood urea nitrogen 
(BUN), calcium, carbon dioxide, chloride, creatinine, creatinine kinase, C reactive protein 
(CRP), glucose, potassium, sodium, protein (total), cholesterol (total), HDL cholesterol, LDL 


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cholesterol, bicarbonate, Lactatdehydrogenase (LDH), gamma-glutamyl-transferase (GGT), 
triglycerides, urate (uric acid), international normalized ratio (INR), prothrombin time, and 
activated partial thromboplastin time (aPTT). 
Urinalysis: Bilirubin, glucose, nitrites, pH, leukocyte esterase, blood, ketones, urobilinogen, 
protein, and specific gravity. 
Standard safety laboratory data from the central lab will be presented in SI units (except as 
presented in Appendix 16.10 and in the order presented as given above. Measured laboratory 
values will be summarized descriptively by scheduled visit. Changes from baseline for 
laboratory parameter will be derived and presented in the same way as measured laboratory 
values. 
Samples for standard urinalysis will be taken at screening and Day 1. 
A laboratory value that is outside the reference range is either high abnormal (value above the 
upper limit of the normal [ULN] reference range) or low abnormal (value below the lower 
limit of the normal [LLN] reference range). An abnormal laboratory value is not necessarily 
of potential clinical interest. For each of the hematology and chemistry lab tests, shift tables 
will be constructed to compare the individual subject baseline value with respect to the 
normal range to their Week 24 (or last observed value for dropouts before Week 24) value 
with respect to the normal range. 
The incidence of potentially clinically significant abnormal values for selected laboratory 
measurements will be summarized by visit during the Treatment Period and Follow-up 
Period. Table 3 gives the ranges of potential clinical concern for selected laboratory 
measurements. 
The denominator in percentage calculation at a scheduled visit will be based on the number 
of subjects with a non-missing value at that particular visit. 
Mean plots +/- SD over time will be provided for lab parameter of hematology and serum 
biochemistry. Hy’s law plots for AST versus bilirubin (total) and ALT versus bilirubin (total) 
will be provided. 
 
 


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Table 3 
 Laboratory Values of Potential Clinical Importance 
 
A by-subject listing of all laboratory values including flag for values out of normal range and 
clinically importance will be provided. Listings will include in general all visits (scheduled 
and unscheduled). 
11.4 
Other Safety Measures 
11.4.1 Immunogenicity 
The number and percentage of subjects with a positive immunogenicity test (presence of 
binding antibodies to CSL346) at any time (Weeks 4, 8, and 16) during treatment and follow-
up period will be summarized by treatment group, including a combined CSL346 treatment 
group. A treatment comparison of combined CSL346 treatment group vs. placebo treatment 
group will be done by using Fisher’s Exact Test. 
A by-subject listing for immunogenicity will be provided. 
Laboratory Parameter 
Potential Clinical Importance Range 
Unit 
ACR (Urine) 
Change from baseline >1.5 
mg/g 
Platelet Count 
<40 or >999 
103/UL 
Hematocrit  
<20 or >60 
% 
Hemoglobin  
<7 or >20 
g/dL 
White Blood Cell Count 
(WBC) 
<3 or >20 
109/L 
Neutrophil Count 
<1.5 
109/L 
Serum Creatinine 
Change from baseline ( >0.3 and <0.7) OR 
Change from baseline ≥0.7 
mg/dL 
Fasting Glucose 
<70 or >250 
mg/dL 
Nonfasting Glucose 
<40 or >450 
mg/dL 
Potassium 
<3 or >5.5 
mEq/L 
Troponin-I 
>ULN 
ng/mL 
Alkaline phosphatase 
>2 x ULN 
U/L 
Total bilirubin 
>2 x ULN 
µmol/L 
ALT/SGPT  
>3 x ULN 
U/L 
AST/SGOT  
>3 x ULN 
U/L 


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11.4.2 Vital Signs 
The vital signs will be summarized by visit and by the three randomized treatment groups and 
a combined CSL346 treatment group. The summaries will be provided for the analysis 
population as described in Section 11. 
The following summaries will be provided for systolic and diastolic blood pressure, heart 
rate, body temperature and body weight: 
• Values of vital signs by scheduled visit, 
• Change from baseline by scheduled visit. 
Vital signs will be assessed as a triplicate measurement. For purpose of analysis the mean 
value of such triplicate parameter assessments will be used. 
Vital sign values of potential clinical importance will be determined by using the criteria 
detailed in Table 4. The number and percentage of subjects with vital signs of potential 
clinical importance will be summarized by visit and at any time for the three randomized 
treatment groups and a combined CSL346 treatment group. 
A by-subject listing of all vital sign data (scheduled and unscheduled visits) will also be 
presented. The listing will include a flag for values of potential clinical importance. 
Table 4 
Vital Signs of Potential Clinical Importance 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Hypertensive AESI –  
Flag for crisis 
(definitions are the same; 
clinical presentation 
defines a crisis) 
SBP ≥180 mmHg and/or DBP ≥120 mmHg OR 
an increase from Baseline in either SBP or DBP ≥20 
mmHg and SBP/DBP greater than 160/105 mmHg 
mmHg 
DBP 
<45 
mmHg 
SBP 
<85 
mmHg 
Heart rate 
<40 or >110 
bpm 
 
11.4.3 ECG 
The ECG parameter (PR interval, QRS duration, QT interval, QTcF, QTcB, heart rate) and 
their changes from baseline will be summarized by visit and by the three randomized 
treatment groups and a combined CSL346 treatment group. The summaries will be provided 
for the analysis population as described in Section 11. 


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ECG assessments will be done as a triplicate measurement. For purpose of analysis the mean 
value of such triplicate parameter assessments will be used. 
For QTcF, PR interval, QRS interval and heart rate, values of potential clinical importance 
will be determined by using the criteria detailed in Table 5. The number and percentage of 
subjects with those values of potential clinical importance will be summarized by visit and at 
any time for the three randomized treatment groups and a combined CSL346 treatment 
group. Subgroup summaries will also be provided by gender. The overall interpretation of 
ECG will be summarized at the same time points and treatment groups. 
Table 5 
ECG Parameters of Potential Clinical Importance 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
QTcF Interval 
>450 OR 
<500 or ≥500 OR 
≥500 OR 
increase from Baseline >60 or increase from Baseline 
between >30 and <60 
msec 
Absolute PR Interval 
<120 or >210 
msec 
Absolute QRS Interval 
<75 or >110 or >120 
msec 
Heart rate 
<50 or ≥120 
bpm 
 
A by-subject listing of all ECG data (scheduled and unscheduled visits) will also be 
presented. The listing will include a flag for values of potential clinical importance. 
12 
Pharmacokinetic Analyses 
The PK analysis will be performed using the PK Analysis Set. 
All non-compartmental analyses are to be performed according to CSL SOP PK-GDL-01 and 
will be performed by CSL Behring Clinical Pharmacology & Pharmacometrics by using 
WinNonlin® version 8.1 or later. Alternatively CSL Behring may contracting a Clinical 
Research Organisation to derive the PK parameter. 
After data base lock, CSL Behring Clinical Pharmacology & Pharmacometrics will produce 
all SDTM domains needed for the PK analysis (serum PK analysis). The PC domain 
containing the CSL346 concentrations, nominal blood sampling times, actual sampling time 
relative to the start of the dosing, and actual dosing and the PP domain containing the PK 
parameters will be provided. Any CSL346 serum concentrations which will have been 
excluded from the derivation of the PK parameters will be flagged in the data. 


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Parexel will produce the TFLs for the CSL346 serum concentrations and the PK parameters 
as specified below. 
Population PK analyses will be performed according to the Modeling and Simulation 
Analysis Plan and reported separately. 
12.1 
Drug Concentration Measures 
The handling and imputation of below limit of quantification (BLQ) values for PK parameter 
derivation is described in (1), (2), (3), and (4). The imputation rules below will be used for 
summary statistics of CSL346 serum concentrations. The summaries will be given by 
planned time point. 
• The sampling time of pre-dose samples relative to start of the dose infusion will be 
treated as zero; 
• Concentration values below BLQ in pre-dose samples and in samples taken before the 
time of the first quantifiable concentration will be treated as zero; 
• Post-dose BLQ concentrations flanked by quantifiable concentrations will be set to 
missing; 
• Post-dose BLQ concentrations after the last quantifiable point will be set to missing 
for summary statistics of serum concentrations; 
• The mean/median value at a time point where one or more samples have BLQ values 
will be reported (in tabular or graphical fashion) even if the mean/median value is 
BLQ of the assay; 
• Zero mean or median values will be included in summary tables. 
The lower limit of quantification for CSL346 in serum is 80 ng/mL and in urine it is 
80  ng/mL. Concentrations that are below BLQ should be reported as “< LLOQ” in listings. 
It should be noted that a high proportion of BLQ values may affect the summary statistics; if 
more than 50% of the values are imputed (i.e. BLQ), then the summary statistics (mean, SD, 
median, quartiles) will not be displayed. 
Summary statistics for concentration-time data will include the percentage of BLQ values 
relative to the total N 
%BLQ = 100 * (number of subjects who have BLQ values / total number of subjects) 
at each time point. 
Descriptive statistics will be provided as outlined in Section 7, and in addition the CV% 
(CV% = 100* standard deviation / mean) and geometric mean. 


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Individual CSL346 serum concentration plots will be plotted versus actual sampling time from 
predose on Day 1 through predose on Day 29. Each plot will have a graph on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear 
plot). 
Plots for mean (± SD) CSL346 serum concentrations (on linear and on log-linear scales) 
versus nominal (planned) time will be provided from predose on Day 1 through predose on 
Day 29. All treatment groups will be overlayed for the mean plot. If more than 50% of the 
individual values are BLQ, the mean and SD will be set to missing in the plots. 
Additionally, a box and whisker plot on nominal sampling time for serum concentrations at 
predose time points on Days 29, 57, 85, as well as concentrations on Days113 and 169 will be 
provided. All treatment groups will be displayed in one plot. 
Serum concentrations excluded from the derivation of the PK parameters will also be excluded 
from the summary statistics and the mean plots. A footnote will indicate if serum 
concentrations have been excluded from the analysis. 
A by-subject listing of CSL346 serum concentrations with the concentrations flagged that 
have been excluded from the derivation of the PK parameters based on the PK Analysis Set 
will support the summaries. 
Urine concentration of CSL346 will be summarized by nominal time point using the same 
summary statistics as for serum concentration and a by-subject listing will be provided. 
12.2 
Deriving and Summarizing Pharmacokinetic Parameters 
For subjects belonging to the PK Analysis Set, the PK parameters provided in Appendix 16.2 
will be determined from the CSL346 serum concentration-time data. 
The PK parameter derivation including imputation of the values BLQ and missing data will be 
conducted in accordance to (1), (2), (3), and (4) which gives guidance on how to derive PK 
parameters in the presence of missing data. 
PK parameters of CSL346 will be summarized with the following statistics being provided. 
Variable 
Statistical Parameters: 
Cmax after IV loading dose, 
Cmax after first SC dose, 
Ctrough after each SC dose, 
AUCday1, AUC0-28d, CL after 
first SC dose 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV% 
Tmax after IV loading dose, 
Tmax after first SC dose, 
n, minimum, median, and maximum 


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The geometric CV% will be calculated as 100* square root of ((anti-log of variance for log 
transformed data) minus 1)) CV%=100*sqrt(exp(ln(SD2))-1). 
All PK parameters will be reported to at least 3 significant digits, but to no more significant 
digits than the precision of the original serum concentration data. 
A by-subject listing of CSL346 PK parameters based on the PK Analysis Set will be provided. 
12.3 
Pharmacokinetic Statistical Analyses 
Dose-adjusted PK parameters of AUCday1, AUC0-28d, Cmax after IV loading dose, and Cmax 
after first SC dose will be natural log transformed and analyzed in an analysis of variance 
model, comparing the 8 mg/kg and 16 mg/kg dose levels. The model will be based on the dose 
level as the only effect. The estimate and 90% CI for the difference of 16 mg/kg – 8 mg/kg 
will be exponentiated to obtain the point estimate and CI for the geometric mean ratio. Dose 
proportionality is supported when the 90% CI includes the 1. 
Graphical displays of CSL346 will include a separate display for each natural log transformed 
PK parameter versus natural log transformed dose to evaluate dose proportionality. 
13 
Pharmacodynamic and Biomarkers Analyses 
Unless otherwise specified, these analyses will be based on the PD Analysis Set. 
13.1 
Biomarker Analyses 
Analysis of biomarker is included in efficacy analysis, please refer to Section 10.3. 
14 
Pharmacokinetic/Pharmacodynamic Analyses 
A correlation plot AUC0-28d versus baseline ACR will be provided. The Spearman correlation 
coefficient, a regression line, and slope and intercept of regression will be added to the plot. 
The same plot will be provided for CL versus baseline ACR and for AUC0-28d versus baseline 
eGFR and for CL versus baseline eGFR. 
A correlation plot of Ctrough on Day 29 versus change from baseline in ACR at Day 29 will be 
provided. The Spearman correlation coefficient, a regression line, and slope and intercept of 
regression will be added to the plot. The same plot will be provided for the assessment at Days 
57, 85, and 113. A similar plot will be provided for CL versus change from baseline in eGFR 
on Day 29. 
A correlation plot of urine CSL346 concentration on Day 8 versus baseline ACR on Day 8 will 
be provided. The Spearman correlation coefficient, a regression line, and slope and intercept 
of regression will be added to the plot. The same plot will be provided for urine CSL346 


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concentration at Day 85 versus ACR at Day 85. A correlation plot of urine CSL346 
concentration at Day 85 versus change from baseline in ACR at Day 85 will also be provided. 
The same series of plots will be provided for urine CSL346 concentration versus baseline 
eGFR and urine CSL346 concentration versus the change in eGFR. 
The correlation of systolic blood pressure, measured at 60min after SC dosing at Visit 4, 
versus AUCday1, starting after IV administration, will be presented. The Spearman correlation 
coefficient, a regression line, and slope and intercept of regression will be added to the plot. 
The same plot will be provided for diastolic blood pressure. 
A correlation plot of systolic blood pressure versus Ctrough at Day 29 will be provided. The 
Spearman correlation coefficient, a regression line, and slope and intercept of regression will 
be added to the plot. The same plot will be provided for the assessments at Days 57, 85, and 
113. A similar series of plots will be provided for diastolic blood pressure versus Ctrough at 
Days 29, 57, 85, and 113. 
A correlation plot of change from baseline in total cholesterol versus Ctrough at Day 29 will be 
provided. The Spearman correlation coefficient, a regression line, and slope and intercept of 
regression will be added to the plot. The same plot will be provided for assessments at Days 
57, 85, and 113. The same series of plots will be provided for all other biomarkers. 
A population PKPD analysis may be used to further assess characterization of PK versus PD 
endpoints. If such an analysis will be done, this work will have a separate analysis plan and 
report. 
15 
References 
(1)  Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth 
Universal Definition of Myocardial Infarction. J Am Coll Cardiol. 2018 Oct 30;72(18):2231-
2264. 
(2) Andrew S. Levey, MD, Lesley A. Stevens, MD, MS, FRCP(C), Christopher H. Schmid, 
PhD, Yaping (Lucy) Zhang, MS, Alejandro F. Castro, III, MPH, Harold I. Feldman, MD, 
MSCE, John W. Kusek, PhD, Paul Eggers, PhD, Frederick Van Lente, PhD, Tom Greene, 
PhD, and Josef Coresh, MD, PhD, MHS, for the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI), A New Equation to Estimate Glomerular Filtration Rate, Ann 
Intern Med. 2009 May 5; 150(9): 604–612. 
(3) van Buuren S, Chapman & Hall, Flexible Imputation of Missing Data, 2 ed., Hoboken 
(2018) 
(4) PK-GDL-01, Guideline on the Conduct of Non-compartmental Pharmacokinetic 
Analyses, CSL Behring. 
 


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16 
Appendices 
16.1 
SAS Code 
SAS code for MMRM analysis 
Ods graphics on; 
Proc mixed data=data_set method=reml plots=residualpanel; 
  Class treatment visit patient sglti_yn; 
  Model chglnacr =treatment visit baseline sglti_yn 
treatment*visit sglti_yn*visit baseline*visit / alpha=0.20 cl 
ddfm=kr covb solution; 
  Repeated visit / type=un subject=patient r rcorr; 
 
* *** Estimate for treatment difference at 2 weeks *** *; 
  Estimate "CSL08 vs. PBO at 2 weeks" treatment 1 0 -1 
treatment*visit 1 0 0 0 0 0     0 0 0 0 0 0    -1 0 0 0 0 0 / CL 
alpha=0.2; 
  ESTIMATE "CSL16 vs. PBO at 2 weeks" treatment 0 1 -1 
treatment*visit 0 0 0 0 0 0     1 0 0 0 0 0   -1 0 0 0 0 0 / CL 
alpha=0.2; 
  ESTIMATE "CSL vs. PBO at 2 weeks" treatment 0.5 0.5 -1 
treatment*visit 0.5 0 0 0 0 0     0.5 0 0 0 0 0    -1 0 0 0 0 0 / CL 
alpha=0.2; 
 
* *** Estimate for treatment difference at 16 weeks *** *; 
  Estimate "CSL08 vs. PBO at 16 weeks" treatment 1 0 -1 
treatment*visit 0 0 0 0 1 0     0 0 0 0 0 0    0 0 0 0 -1 0 / CL 
alpha=0.2; 
  ESTIMATE "CSL16 vs. PBO at 16 weeks" treatment 0 1 -1 
treatment*visit 0 0 0 0 0 0     0 0 0 0 1 0   0 0 0 0 -1 0 / CL 
alpha=0.2; 
  ESTIMATE "CSL vs. PBO at 16 weeks" treatment 0.5 0.5 -1 
treatment*visit 0 0 0 0 0.5 0     0 0 0 0 0.5 0    0 0 0 0 -1 0 / CL 
alpha=0.2; 
 
  Lsmeans treatment treatment*visit / diff cl; 
run; 
Ods graphics off; 
 
Where: 
• chglnacr is the repeated measure of change in log ACR collected at Weeks 2, 4, 8, 12, 
16 and 24; 
• treatment takes on three levels (CSL346 8 mg/kg, CSL346 16 mg/kg and placebo) 


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• sglt2i_yn is the stratification variable associated with the presence or absence of a 
concomitant SGLT2i at entry into the trial; 
• baseline is the baseline log ACR used as a covariate in the model; 
• visit is the time variable; 
 
SAS code for multiple imputation 
Proc mi data=data_set out=data_set_imputed nimpute=10 
seed=xxxx round=0.01; 
   Var treatment visit sglti_yn patient chglnacr; 
   Monotone reg(chglnacr = treatment visit sglti_yn patient); 
run; 
 
Where: 
• chglnacr is the repeated measure of change in log ACR collected at Weeks 2, 4, 8, 12, 
16 and 24; 
• treatment takes on three levels (CSL346 8 mg/kg, CSL346 16 mg/kg and placebo) 
• sglt2i_yn is the stratification variable associated with the presence or absence of a 
concomitant SGLT2i at entry into the trial; 
• visit is the time variable; 
 
 


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16.2 
PK Parameters 
Term 
Definition [unit] 
Calculation method 
AUCday1 
Partial AUC from time point 0 to time 
point 1 day [mass * time *volume-1] 
AUC from the time of dosing to 
subject released from the clinic on 
Day 1, using the linear up/log 
down trapezoidal rule 
AUC0-28d 
Partial AUC from time point 0 to 28 
days [mass * time *volume-1] 
AUC from the time of dosing to a 
specified 28 days, using the linear 
up/log down trapezoidal rule 
Cmax 
The maximum observed in serum 
[mass * volume-1] 
 
Ctrough 
Observed concentration at the end of a 
dosing interval, immediately before the 
next dose administration [mass * 
volume-1] 
 
CL 
The total body clearance of drug after 
IV dose or extravascular dose with 
known bioavailability [volume * time-
1] 
When the extrapolated area 
contributes more than 30% to the 
total AUC0-∞, data will be excluded 
from summary statistics unless 
justification is provided to support 
the validity of AUC0-∞. 
Tmax 
The time to reach maximum (peak) 
drug concentration in measured 
biological fluid [time] 
 
 
 
 






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16.7 
Factors to be Addressed in Per Protocol Analysis Set 
The following define major events which could result in subjects’ data being removed from 
the per protocol analysis set. Subjects’ data may be removed completely or from the time of 
the major event up to the end of subject’s study participation. 
At a specific time point, ACR measurements are to be used in summaries and analysis as long 
as there are at least 2 FMVs for that time point (4 FMVs for baseline) available. 
• Extrinsic factors with the potential to impact ACR during treatment period. For any 
such occurrences, data points at or beyond the date of the occurrence will be excluded 
from analysis. [These data will be provided by CSL.] 
o Protocol deviations: 
 Subjects with substantial change in blood pressure medications or DKD 
medications; 
 Prohibited concomitant medications; 
 Initiation of lipid lowering agent; 
 Change in SGLT2i doses; 
 Change in dose in agents that impact tubular secretion of serum creatinine 
(fibrates). 
 Missed intermittent dose 
o Cardiac AESI with heart failure. 
 
• Study drug [to be derived by Parexel]: 
o For subjects receiving fewer than 4 doses of the investigational product, all data 
on or after the date of the last dose + 4 weeks + 1 day will be excluded. If no dose 
is administered then all data for that subject will be excluded. 
 
• Violation of study entry criteria. In these cases, all data from these subjects will be 
excluded from analysis. [These data will be provided by CSL.] 
o Baseline Glycosylated HbA1c >=12 %; 
o Change in SCr from Visit 1 (<63 Days before Day 1) to Visit 2 (Day -21) > 
0.3  mg/dL (26.5 µmol/L); 
o Uncontrolled hypertension: SBP > 160 mmHg or DBP > 100 mmHg prestudy 
(SBP>150 mmHg at randomization). 
 
 






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Notes to the Schedule of Assessments:  
A: Screening Visit 1 should be performed within 6 weeks before Screening Visit 2. 
B: Randomization criteria will include evaluations of BP, serum creatinine, and troponin. 
C: A serum pregnancy test will be performed at Screening for FCBP; serum or urine pregnancy tests will be performed at all other indicated visits.  
D: A comprehensive physical examination will be performed at Visit 2 (Day –21) and at EOS. An abbreviated physical examination will be performed for all 
other indicated visits. 
E: Vital signs include BP (systolic and diastolic), temperature, and pulse. Blood pressure measurements should be taken in triplicate before all other 
assessments. Vital signs in general will be collected before any blood samples that are collected at the same time point. At Visit 2 (Day –21), BP will be the 
only vital sign collected. Instructions for measuring BP will be provided in the Manual of Operations. At Visit 4 (Day 1), vital sign measurements will be 
taken predose, at 30, 60, and 120 minutes (± 15 minutes) after the first IV dose of IP (before the first SC dose of IP) is administered, then at 30 and 60 
minutes (± 15 minutes) after SC dosing. 
F: Height will be measured at Screening only. 
G: Electrocardiograms must be performed in triplicate before any blood samples that are collected at the same time point. 
H: A local assessment of echocardiogram will be performed during Screening unless an echocardiogram was performed for non-study-related reasons within 
3 months before Screening. 
I: 
At Visit 2 (Day –21), a blood sample will be collected for determination of serum creatinine only. 
J: A timed 24-hour urine sample will be collected to assess eligibility (ACR) at Screening (Baseline), and to measure CSL346 levels in urine at subsequent 
indicated visits. 
K: Subjects will collect urine from their first morning void on 3 consecutive days (2 consecutive days for Visit 9) leading up to and including the morning of 
each indicated visit. 
L: Morning midstream urine samples will be collected to evaluate exploratory biomarkers and will also be stored for future research analyses. 
M: Specific instructions for administration of IP are provided in the IMP Handling Manual. At Visit 4 (Day 1), an initial loading dose of IP will be administered 
by IV, followed at least 2 hours (but no more than 6 hours) later by the subject's normal prescribed dose by SC infusion. Subsequent doses of IP will be 
administered by SC infusion. 
N: Serial blood samples for PK will be collected at Visit 4 (Day 1) predose, at 30 (± 5 minutes), 60 (± 10 minutes), and 120 (± 10 minutes) minutes after the 
first IV dose of IP (before the first SC dose of IP) is administered, then after the final vital signs measurement. Single PK samples will also be collected at all 
subsequent visits (before treatment on SC dosing days). 
On biomarker blood sample collection days, subjects will arrive following a minimum 6-hour fast. Blood biomarker samples will be 
collected to evaluate pharmacodynamic and exploratory biomarkers and will also be stored for future research analyses. 
 
 
 


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16.9 
Directionality of One-sided Tests 
Since treatment comparisons in this study are based on one-sided tests, we need to designate the direction of these tests. Directionality 
and method for calculating one-sided p-value from the two-sided p-value is specified in the table below. 
Parameter Name 
Better (Lower 
or Higher) 
Comment 
One sided p-value calculated as: 
Biomarkers of Lipid 
Metabolism:Total Cholesterol  
Lower 
Compared to PBO 
estimate < 1 p-one sided=p/2 
estimate >= 1 p-one sided=1-p/2 
Biomarkers of Lipid Metabolism: 
Triglycerides –  
Lower  
Decreased triglycerides in the fed 
state, compared to PBO could 
indicate activity, but in fasted 
samples, no change would be 
predicted. 
estimate < 1 p-one sided=p/2 
estimate >= 1 p-one sided=1-p/2 
Biomarkers of Lipid Metabolism: 
HDL –  
Higher 
Compared to PBO 
estimate < 1 p-one sided=1-p/2 
estimate >= 1 p-one sided=p/2 
Biomarkers of Lipid Metabolism: LDL 
–  
Lower 
Compared to PBO 
estimate < 1 p-one sided=p/2 
estimate >= 1 p-one sided=1-p/2 
Biomarkers of Lipid Metabolism: 
(Fasting) Glycerol –  
Higher  
Smaller (or no) increase in fasting 
glycerol, NEFA, ketones compared 
to PBO could indicate activity 
estimate < 1 p-one sided=1-p/2 
estimate >= 1 p-one sided=p/2 
Biomarkers of Lipid Metabolism: 
(Fasting) NEFA –  
Higher  
estimate < 1 p-one sided=1-p/2 
estimate >= 1 p-one sided=p/2 
Biomarkers of Lipid Metabolism: 
(Fasting) Ketones –  
Higher  
estimate < 1 p-one sided=1-p/2 
estimate >= 1 p-one sided=p/2 
Biomarkers of VEGF Family: Urinary 
VEGF-A  
Lower  
Decrease in total VEGF-A compared 
to PBO could indicate activity 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Biomarkers of VEGF Family: Urinary 
Soluble VEGF-R1  
Lower  
Decrease in total VEGF-R1 
compared to PBO could indicate 
activity 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Biomarkers of Tubular Injury: KIM-1  
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 58 of 59 
Date: 29 Sep 2022 
Confidential 
Biomarkers of Tubular Injury: NGAL  
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Biomarkers of Tubular Injury: MCP-1 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Biomarkers of Tubular Injury - EGF 
Higher 
Compared to PBO 
estimate < 0 p-one sided=1-p/2 
estimate >= 0 p-one sided=p/2 
Biomarkers of Tubular Injury: 
Clusterin  
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Circulating Biomarker of 
Inflammation: sTNFR1 
Lower  
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
ACR 
Lower 
Compared to PBO 
estimate < 1 p-one sided=p/2 
estimate >= 1 p-one sided=1-p/2 
eGFR 
Higher 
Compared to PBO 
estimate < 0 p-one sided=1-p/2 
estimate >= 0 p-one sided=p/2 
Serum Creatinine 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Blood pressure 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Weight 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
HbA1C 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 
Fasting glucose 
Lower 
Compared to PBO 
estimate < 0 p-one sided=p/2 
estimate >= 0 p-one sided=1-p/2 


CSL Behring  
Study Number: 
CSL346_2001 
 
Study Product: 
CSL346 
 
SAP version: Final 3.0 
 
Page 59 of 59  
Date: 29 Sep 2022 
Confidential 
16.10 
Non-SI Units 
Certain parameters should be reported in non-SI units (conventional units). These parameters, 
along with the specified units for reporting, are shown in the table below. 
Parameter 
Conventional 
Units 
SI Units 
Conversion Factor 
Albumin-
creatinine ratio 
mg/g 
mg/mmol 
To convert ACR in mg/mmol to mg/g, 
divide by 0.113 
Creatinine 
mg/dL 
µmol/L 
To convert Creatinine in µmol/L to 
mg/dL, divide by 88.4 
HbA1c 
% 
HbFract 
To convert HbA1c in HbFract to %, 
multiply by 100 
Total 
cholesterol 
mg/dL 
mmol/L 
To convert Total cholesterol in mmol/L to 
mg/dL, divide by 0.0259  
HDL 
cholesterol 
mg/dL 
mmol/L 
To convert HDL cholesterol in mmol/L to 
mg/dL, divide by 0.0259  
LDL 
cholesterol 
mg/dL 
mmol/L 
To convert LDL cholesterol in mmol/L to 
mg/dL, divide by 0.0259  
Triglycerides 
mg/dL 
mmol/L 
To convert Triglycerides in mmol/L to 
mg/dL, divide by 0.0113 
 


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CSL346_2001 - Statistical Analysis Plan - v3 - 29Sep2022
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