A Phase 2A, Open-Label Study Evaluating the Safety and Different Injection Techniques of CCH for the Treatment of Edematous Fibrosclerotic Panniculopathy (EFP)
Phase: PHASE2
Conditions: Edematous Skin
Sponsor: Endo Pharmaceuticals



E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  2 
 
 
 
2.    
S  U  M  M  A  R  Y   O F   C  H  A  N  G  E S  
Pr ot o c ol  a  m e n d  m e nt(s)  a n d  a  m e n d e d i nf or  m e d  c o ns e nt f or  m(s)  ( as  n e c ess ar y)  h a v e b e e n 
r e vi e  w e d  a n d  a p pr o v e d  b y t h e  g o v er ni n g I  R  Bs  b ef or e i  m pl e  m e nt ati o n  of t h e  a  m e n d  m e nt  at  e a c h 
st u d y  c e nt er.  
A  m e n d  m e nt  1   w as i n c or p or at e d i nt o t h e  pr ot o c ol  o n  2 9   A u g ust  2 0 1 8.  T h e  pri  m ar y r e as o n f or t his 
a  m e n d  m e nt is t o  r e  m o v e   M  RIs  a n d t o  c orr e ct  err ors in,  a n d  u p d at e, t h e  ori gi n al  pr ot o c ol.  T h e 
m aj or  c h a n g es t o t h e  pr ot o c ol  ar e  o utli n e d  b el o  w.   R e visi o ns i n st yl e,   mi n or  c orr e cti o ns   (s u c h  as 
s p elli n g  err ors,  et c),  a n d  ot h er   mi n or  c h a n g es t h at  d o  n ot i  m p a ct  c o nt e nt   m a y  als o  h a v e  b e e n 
m a d e.   
S e cti o n  
O ri gi n al   T e xt   
R e vis e d   T e xt  /  R e as o n f o r   C h a n g e 
Gl o b all y  a n d 
8. 1. 2  C oll a g e n as e 
Cl ostri di u  m 
Hist ol yti c u  m    
St u d y  dr u g   w as  ori gi n all y r ef err e d t o 
as  E  N 3 8 3 5 .  This  h as  b e e n  c orr e ct e d  t o 
C  C  H t hr o u g h o ut t h e  pr ot o c ol.   
E  N 3 8 3 5 r ef ers t o t h e  a p pr o v e d 
f or  m ul ati o n  of t h e st u d y  dr u g.  T h e 
f or  m ul ati o n  us e d f or  E F P st u di es  h as 
b e e n   m o difi e d  a n d is r ef err e d t o  as 
C  C  H.   S e cti o n   8. 1. 2 w as  u p d at e d t o 
e x pl ai n t his  c h a n g e.  
Titl e  P a g e     
N  A   
T h e   N  C T  n u  m b er  h as  b e e n  a d d e d 
3  S p o ns or   C o nt a ct 
I nf or  m ati o n  
T  B  D  
  a n d  c o nt a ct 
i nf or  m ati o n  a d d e d 
4  S y n o psis 
Esti  m at e d  d at e first s u bj e ct  e nr oll e d: 
A u g ust  2 0 1 8 
Esti  m at e d  d at e first s u bj e ct  e nr oll e d:  
S e pt e  m b er  2 0 1 8 
4  S y n o psis   
5  S c h e d ul e  of  E v e nts  
7  List  of 
A b br e vi ati o  ns  
9. 3  O bj e cti v es   
1 0. 4  Dis c ussi o n  of 
St u d y   D esi g n  
1 1. 2  E x cl usi o n  
Crit eri a   
1 2. 5  S el e cti n g  a n d 
M ar ki n g   Di  m pl es   
1 3. 1  3- D 
P h ot o gr a p h y 
1 3. 2  M  RI   
1 7. 5  Effi c a c y 
A n al ysis   
All  s u bj e cts  e nr oll e d i n t h e st u d y   w er e 
t o  h a v e   M  RIs  at S cr e e ni n g,   D a y  4,  
D a y    8,   D a y  1 5,   D a y  2 2,   D a y  4 3,  a n d 
D a y  7 1.  
M  RIs   will   n o l o n g er  b e  p erf or  m e d i n 
t his st u d y  a n d  all   m e nti o n  of   M  RIs  h as 
b e e n  d el et e d.  E x cl usi o n   Crit eri a  # 3  “Is 
u n a bl e t o  u n d er g o   M  RI ”  a n d 
S e cti o n   1 3. 2 “  M  RI ”  h a v e  b e e n  d el et e d 
i n t h eir  e ntir et y.  E v al u ati o n  of s e pt a e 
m or p h ol o g y  a n d t h e  us ef ul n ess  of   M  RI 
i n  e v al u ati n g  o ut c o  m es  of tr e at  m e nt 
f or  E F P  h a v e  b e e n r e  m o v e d fr o  m t h e 
o bj e cti v es  a n d  e n d p oi nts. 
1 0. 3. 4  Tr e at  m e nt I  V 
D e e p  a n d  S h all o  w 
I nj e cti o ns,  5 
Ali q u ots   
N e e dl e  p ositi o ns   C  a n d  E   w er e 
i n c orr e ct i n Fi g ur e   4 . 
Fi g ur e   4 w as  c orr e ct e d s o t h e  P ositi o n   
C is  b et  w e e n  p ositi o ns   A  a n d   B  a n d 
P ositi o n  E is  b et  w e e n  p ositi o ns   A  a n d 
D t o   m at c h t h e  a c c o  m p a n yi n g t e xt. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 
 
 
 
S e cti o n  
O ri gi n al   T e xt   
R e vis e d   T e xt  /  R e as o n f o r   C h a n g e 
1 2. 5  S el e cti n g  a n d 
M ar ki n g   Di  m pl es   
N o n e   
T h e f oll o  wi n g t e xt   w as  a d d e d t o  cl arif y 
t he  s el e cti o n  of tr e at  m e nt  ar e a: 
If  all  4  q u a dr a nts ( b ot h  b utt o c ks  a n d 
b ot h t hi g hs)   m e et  e ntr y  crit eri a f or  a 
si n gl e s u bj e ct, t h e t hi g hs   will  b e 
tr e at e d.   N o s u bj e ct   will  h a v e tr e at  m e nt 
i n  all  4  q u a dr a nts ( b ot h  b utt o c ks  a n d 
b ot h t hi g hs)  d uri n g t his st u d y. 
1 3. 1  3- D 
P h ot o gr a p h y 
F or  3 -  D  p h ot o gr a p hi c i  m a g es t a k e n  o n 
D a ys  4,  8,  1 5,  2 2,  4 3,  a n d  7 1,  a  c e ntr al 
ass ess or  bli n d e d t o t h e tr e at  m e nt  ar  m 
a n d st u d y  visit  d a y   will  c o  m pl et e  a  5 -
p oi nt  Li k ert s c al e t o  g a u g e t h e l e v el  of 
a est h eti c i  m pr o v e  m e nt  a c hi e v e d (fr o  m 
b as eli n e) i n  e a c h tr e at  m e nt  ar e a.  T h e 
ass ess or   will  als o  e v al u at e  c h a n g e 
fr o  m  b as eli n e i n t h e  v ol u  m e  of t h e 
s el e ct e d  di  m pl es i n  e a c h tr e at  m e nt 
ar e a.  
A  c e ntr al  ass ess or   will  n ot  e v al u at e 
di  m pl e  v ol u  m e. 
1 4. 5  R e p orti n g 
A d v ers e  E v e nts  a n d 
S eri o us   A d v ers e 
E v e nts  
1 4. 6  S p e ci al 
R e p orti n g  Sit u ati o ns 
T h e titl e  of t h e  E n d o  S  A E r e p orti n g 
f or  m  h as  b e e n  u p d at e d (f or  m all y 
Cli ni c al  Tri al   R e p ort  F or  m f or  S  A Es) 
f or  us e i n   m ulti pl e  e v e nt r e p orti n g 
sit u ati o ns. 
T h e  u p d at e d  n a  m e  of t h e  E n d o  e v e nt 
r e p orti n g f or  m is:  S eri o us   A d v ers e 
E v e nt ( S  A E)/  R e p ort a bl e  E v e nt  F or  m . 
1 7. 5  Effi c a c y 
Ass ess  m e nts   
•    C h a n g e fr o  m  b as eli n e i n t h e  bli n d e d 
ass ess or’s  Li k ert  S c al e s c or e  of 
a est h eti c  a p p e ar a n c e i n  e a c h 
tr e at  m e nt  ar e a ( b utt o c ks  or t hi g hs) 
at   D a ys  4,  8,  1 5,  2 2,  4 3,  a n d  7 1  b y 
e a c h tr e at  m e nt  ar  m.   
•    C h a n g e fr o  m  b as eli n e i n t h e  bli n d e d 
ass ess or’s  e v al u ati o n  of  di  m pl e 
d e pt h  a n d  v ol u  m e i n  e a c h tr e at  m e nt 
ar e a ( b utt o c ks  or t hi g hs)   D a ys  4,  8, 
1 5,  2 2,  4 3,  a n d  7 1  b y tr e at  m e nt  ar  m.  
Eff i c a c y  e n d p oi nts   will  n ot  b e 
e v al u at e d  o n   D a ys  4,  8,  a n d  1 5,  a n d t h e 
bli n d e d  ass ess or   will  n ot  e v al u at e 
di  m pl e  d e pt h  a n d  v ol u  m e. 
1 7. 5  Effi c a c y 
Ass ess  m e nts   
T h e  c e ntr al  ass ess or  Li k ert  S c al e s c or e 
of  a est h eti c  a p p e ar a n c e i  m pr o v e  m e nt 
fr o  m  b as eli n e i n t h e  3-  D  p h ot o gr a p hi c 
i  m a g e  a n d  c h a n g e fr o  m  b as eli n e i n 
di  m pl e  v ol u  m e  a n d  d e pt h ( b y   M  RI  a n d 
H e xs el   C S S)  … 
Di  m pl e  d e pt h  a n d  v ol u  m e   will  n ot  b e 
m e as ur e d  b y   M  RI   a n d   H e xs el   C S S.  
2 4. 6  S u bj e ct 
C o nfi d e nti alit y   
All s u bj e ct r e c or ds s u b  mitt e d t o  E n d o 
or its  d esi g n e e   will  b e i d e ntifi e d  o nl y 
b y  i niti als  a n d  c o d e  n u  m ber.  
E n d o   will  n ot  us e i niti als  as  s u bj e ct 
i d e ntifi ers. 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 
 
 
 
4.    
S  Y  N  O P SI S  
N a  m e  of  S p o ns o r/  C o  m p a n y:   E n d o  P h ar  m a c e uti c als I n c.  
N a  m e  of I n v esti g ati o n al  P r o d u ct:   C  C  H   
N a  m e  of   A cti v e I n g r e di e nt  :   C oll a g e n as e  cl ostri di u  m  hist ol yti c u  m 
Titl e  of  St u d y:     A  P h as e  2 a,   O p e n- L a b el  St u d y  E v al u ati n g t h e  S af et y  a n d   Diff er e nt I nj e cti o n  T e c h ni q u es 
of  C  C  H   f or t h e  Tr e at  m e nt  of  E d e  m at o us  Fi br os cl er oti c  P a n ni c ul o p at h y 
L e a d  P ri n ci p al I n v esti g at o r:   
 
St u d y  p e ri o d:   
Esti  m at e d  d at e first s u bj e ct  e nr oll e d:  S e pt e  m b er  2 0 1 8 
Esti  m at e d  d at e l ast  s u bj e ct  c o  m pl et e d: J a n u ar y  2 0 1 9  
P h as e  of  d e v el o p  m e nt:   
2 a 
O bj e cti v es:    
P ri  m a r y:  
T h e  pri  m ar y  o bj e cti v e  of t his st u d y is t o  ass ess t h e tr e at  m e nt  eff e cts  of   C  C  H     w h e n  a d  mi nist er e d  b y 
diff er e nt i nj e cti o n t e c h ni q u es i n s u bj e cts   wit h  e d e  m at o us fi br os cl er oti c  p a n ni c ul o p at h y ( E F P). 
S e c o n d a r y:  
T h e s e c o n d ar y  o bj e cti v e  of t his st u d y is t o  ass ess t h e s af et y  of   C  C  H   w h e n  a d  mi nist er e d  usi n g  diff er e nt 
i nj e cti o n t e c h ni q u es i n s u bj e cts   wit h  E F P. 
E x pl o r at o r y:   
T h e  e x pl or at or y  o bj e cti v es  of t his st u d y i n cl u d e:  
•    T o  ass ess t h e i  m  m u n o g e ni cit y  of  C  C  H   i n t h e tr e at  m e nt  of  E F P. 
•    T o  ass ess t h e  us ef ul n ess  of  3 -  D  p h ot o gr a p h y i n  e v al u ati n g  o ut c o  m es  of tr e at  m e nt f or  E F P. 
St u d y   D esi g n:   
T his is  a  P h as e  2 a,  o p e n -l a b el,   m ulti c e nt er,  e x pl or at or y st u d y t o  e v al u at e t h e s af et y  a n d  eff e cti v e n ess  of 
diff er e nt i nj e cti o n t e c h ni q u es  of  C  C  H   f or t h e tr e at  m e nt  of  a d ult   w o  m e n   wit h   mil d,   m o d er at e  or s e v er e 
E F P ( as  ass ess e d  b y t h e i n v esti g at or  usi n g t h e  C  li ni ci a n   R e p ort e d  P h ot o n u  m eri c   C ell ulit e  S e v erit y  S c al e 
[C  R  -P  C S S ]). 
A p pr o xi  m at el y  6 0 s u bj e cts   will  b e  e nr oll e d,  3 0   wit h  2  eli gi bl e  b utt o c ks (t o  b e  d os e d i n t h e  b utt o c ks)  a n d 
3 0   wit h  2  eli gi bl e t hi g hs (t o  b e  d os e d i n t h e t hi g hs).   N o s u bj e cts   will  b e tr e at e d  f or  E F P i n  b ot h t h e 
b utt o c ks  a n d t h e t hi g hs.  T h e  3 0 s u bj e cts i n  e a c h tr e at  m e nt r e gi o n ( b utt o c ks  or t hi g hs)   will  b e  assi g n e d t o 
1  of  5 i nj e cti o n t e c h ni q u e tr e at  m e nt  ar  ms.  
S u bj e cts   will  p arti ci p at e i n t h e st u d y f or  a p pr o xi  m at el y  9 2  d a ys.  F oll o  wi n g  a s cr e e ni n g  p eri o d  of  u p t o 
2 1  d a ys, s u bj e cts   will  p arti ci p at e i n  u p t o  3 tr e at  m e nt  visits s e p ar at e d  b y  2 1  d a ys (  D a ys  1,  2 2,  a n d  4 3). 
F oll o  wi n g t h e first  d os e  of st u d y  dr u g, s u bj e cts   will r et ur n f or  ass ess  m e nts  o n   D a ys  4,  8,  1 5,  2 2,  4 3 
a n d  7 1. 
N u  m b e r  of s u bj e cts (  pl a n n e d):    Ap pr o xi  m at el y  6 0  
St u d y  c e nt e r s: A p pr o xi  m at el y  5 sit es i n t h e   U nit e d  St at es   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  6 
 
 
 
N a  m e  of  S p o ns o r/  C o  m p a n y:   E n d o  P h ar  m a c e uti c als I n c.  
N a  m e  of I n v esti g ati o n al  P r o d u ct:   C  C  H   
N a  m e  of   A cti v e I n g r e di e nt  :   C oll a g e n as e  cl ostri di u  m  hist ol yti c u  m 
Di a g n osis  a n d i n cl usi o n/ e x cl usi o n  c rit e ri a:   
H e alt h y,  n o n pr e g n a nt,  n o nl a ct ati n g f e  m al e s u bj e cts  at l e ast  1 8  y e ars  of  a g e   wit h  e vi d e n c e  of  c ell ulit e   i n 
2  bil at er al tr e at  m e nt  ar e as ( d efi n e d  as ri g ht  a n d l eft  b utt o c ks   O  R ri g ht  a n d l eft  p ost er ol at er al t hi g hs)  will 
b e  e nr oll e d i n t his st u d y.   
S u bj e cts   will  b e  e x cl u d e d fr o  m t h e st u d y if t h e y  h a v e  a  c o a g ul ati o n  dis o r d er, r e q uir e  a nti c o a g ul a nt  or 
a nti pl at el e t   m e di c ati o n,  h a v e  e vi d e n c e  or  hist or y  of   m ali g n a n c y ( ot h er t h a n  e x cis e d  b as al-c ell 
c ar ci n o  m a) i n t h e  pr e vi o us  5  y e ars,  h a v e  a  hist or y  of  k el oi d al s c arri n g  or  a b n or  m al   w o u n d  h e ali n g,  or 
h a v e  a t att o o l o c at e d   wit hi n  2  c  m  of t h e sit e  of i nj e cti o n.  S u bj e cts   w ill  als o  b e  e x cl u d e d t h e y  h a v e  a 
hist or y  of l o  w er  e xtr e  mit y t hr o  m b osis  or  p ost-t hr o  m b osis s y n dr o  m e,  a  v as c ul ar  dis or d er ( e g,  v ari c os e 
v ei ns, t el a n gi e ct asi a), i nfl a  m  m ati o n  or  a cti v e i nf e cti o n, s e v er e s ki n l a xit y, fl a c ci dit y,  a n d/ or s a g gi n g,  or 
a n y  a cti v e  c ut a n e o us  alt er ati o n i n cl u di n g r as h,  e c z e  m a,  ps ori asis,  or s ki n  c a n c er i n t h e  ar e as t o  b e 
tr e at e d. 
S u bj e cts   w h o  h a v e  h a d  a n y  of t h e f oll o  wi n g i n t h e  ar e a t o  b e tr e at e d: li p os u cti o n, i nj e cti o ns ( e g, 
m es ot h er a p y), r a di ofr e q u e n c y  d e vi c e tr e at  m e nts, l as er tr e at  m  e nt, s ur g er y (i n cl u di n g s u b cisi o n  a n d/ or 
p o  w er e d s u b cisi o n),  or  a n y i n v esti g ati o n al tr e at  m e nt f or  E F P/ c ell ulit e i n t h e  pr e vi o us  1 2   m o nt hs; 
E n d er  m ol o gi e ®  or  si  mil ar tr e at  m e nts i n t h e  pr e vi o us  6  m o nt hs;   m ass a g e t h er a p y i n t h e  pr e vi o us 
3  m o nt hs;  or  cr e a  ms ( e g  ,   C ell u v er a™,  Tri L asti n® ) t o  pr e v e nt  or   miti g at e  E F P   wit hi n t h e  2   w e e ks  pri or t o 
t h e st art  of st u d y  dr u g  a d  mi nistr ati o n   will  als o  b e  e x cl u d e d fr o  m t h e st u d y. 
I n v esti g ati o n al  p r o d u ct,  d os a g e  a n d   m o d e  of  a d  mi nist r ati o n:   
T h er e  ar e  5 tr e at  m e nt  ar  ms  p er  r e gi o n ( b utt o c ks  or t hi g h) i n t his st u d y   wit h  e a c h  ar  m r e pr es e nti n g  a 
diff er e nt i nj e cti o n t e c h ni q u e  as f oll o  ws: 
•    Tr e at  m e nt I:  S h all o  w I nj e cti o n,  3  ali q u ots. 
•    Tr e at  m e nt II:  S h all o  w i nj e cti o n,  1  ali q u ot.  
•    Tr e at  m e nt III:   D e e p i nj e cti o n,  1  ali q u ot. 
•    Tr e at  m e nt I  V:  D e e p  a n d s h all o  w i nj e cti o ns,  5  ali q u ots.   
•    Tr e at  m e nt   V:  S h all o  w i nj e cti o n,  4  ali q u ots.  
I nj e cti o n t e c h ni q u es  diff er fr o  m  e a c h  ot h er i n,  at l e ast  b ut  n ot li  mit e d t o,  c o n c e ntr ati o n  of t h e C  C  H   
i nj e ct at e,  a n gl e  of i nj e cti o n,  d e pt h  of i nj e cti o n,  v ol u  m e  of i nj e cti o n,  a n d st u d y  dr u g  a d  mi nistr ati o n  at 
i nj e cti o n sit e.  
A cr oss  all tr e at  m e nt  ar  ms, st u d y  dr u g   will  b e  a d  mi nist er e d s u b c ut a n e o usl y   w hil e t h e s u bj e ct is i n  a 
pr o n e  p ositi o n.  E a c h s u bj e ct   will r e c ei v e  2 4 i nj e cti o ns f or  a t ot al  d os e  of  1. 6 8   m g ( 0. 8 4   m g  p er tr e at  m e nt 
r e gi o n)  at  e a c h tr e at  m e nt  visit.  T h e  c u  m ul ati v e C  C  H    d os e   will  b e  5. 0 4   m g f or  e a c h s u bj e ct t h at 
c o  m pl et es t h e  3 tr e at  m e nt  visits.  
D u r ati o n  of st u d y:   
S u bj e cts   w h o  c o  m pl et e t h e st u d y   will  p arti ci p at e f or  u p t o  9 2  d a ys i n cl u di n g  a  2 1  d a y  s cr e e ni n g  p eri o d,  a 
4 3  d a y  a cti v e tr e at  m e nt  p eri o d,  a n d  a  2 8  d a y f oll o  w- u p  p eri o d.  
R ef e r e n c e t h e r a p y,  d os a g e  a n d   m o d e  of  a d  mi nist r ati o n:   N ot  a p pli c a bl e   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  7 
 
 
 
N a  m e  of  S p o ns o r/  C o  m p a n y:   E n d o  P h ar  m a c e uti c als I n c.  
N a  m e  of I n v esti g ati o n al  P r o d u ct:   C  C  H   
N a  m e  of   A cti v e I n g r e di e nt  :   C oll a g e n as e  cl ostri di u  m  hist ol yti c u  m 
C rit e ri a f o r   e v al u ati o n: 
Effi c a c y  : Li k ert  S c al e s c or e  of  a est h eti c  a p p e ar a n c e,   H e xs el   C S S (  B)  d e pr essi  o n  d e pt h s c al e ,  a n d  di  m pl e 
d e pt h  a n d  v ol u  m e.  
S af et y :   A d v ers e  e v e nts,  vit al si g ns,  a n d cli ni c al l a b or at or y t ests . 
St atisti c al  m  et h o ds:  
S a  m pl e si z e  c o nsi d e r ati o n:   
N o s a  m pl e si z e  esti  m ati o n   w as  d o n e f or t his st u d y.   
A n al ysis  p o p ul ati o ns:  
S af et y  P o p ul ati o n:  T h e  S af et y  P o p ul ati o n   will i n cl u d e  all s u bj e cts   w h o r e c ei v e  at l e ast  1  i nj e cti o n of 
st u d y  dr u g.   All s af et y  a n al ys es   will  b e  b as e d  o n t his  p o p ul ati o n. 
E v al u a bl e  P o p ul ati o ns:  T h e  E v al u a bl e  P o p ul ati o n   will i n cl u d e  all s u bj e cts i n t h e  S af et y  P o p ul ati o n   w h o 
h a v e  c o  m pl et e d s cr e e ni n g  pr o c e d ur es  a n d  at l e ast  1  p ost  b as eli n e  ass ess  m e nt  of t h e  Li k ert  S c al e s c or e  of 
a est h eti c  a p p e ar a n c e i  m pr o v e  m e nt . All  effi c a c y  a n al ysis   will  b e  b as e d  o n t his  p o p ul ati o n  . 
A n al ys es:  
T h e  c e ntr al  ass ess or  Li k ert  S c al e s c or e  of  a est h eti c  a p p e ar a n c e i  m pr o v e  m e nt fr o  m  b as eli n e i n t h e  3  -D 
p h ot o gr a p hi c i  m a g e ,  ch a n g e fr o  m  b as eli n e i n t h e   H e xs el   C S S (  B)  d e pr essi o n  d e pt h s c al e ,  a n d c h a n g e 
fr o  m  b as eli n e i n  di  m pl e  v ol u  m e  a n d  d e pt h will  b e s u  m  m ari z e d  b y tr e at  m e nt  ar  m  a n d st u d y  visit  usi n g 
a p pr o pri at e  d es cri pti v e st atisti cs. I n  a d diti o n,  a li n e ar   mi x e d   m o d el   will  b e  utili z e d t o fit  c h a n g e fr o  m 
b as eli n e  of  e a c h  e n d p oi nt   wit h tr e at  m e nt  ar  m,  c ell ulit e  di  m pl es,  a n d st u d y  visit  as fi x e d  eff e cts, s u bj e ct 
as r a n d o  m  eff e ct,  a n d  ass ess  m e nts  a cr oss st u d y  visits  as r e p e at e d   m e as ur e.  T h e fi x e d  eff e ct  esti  m at es 
a n d t h e  c orr es p o n di n g  9 5  %  c o nfi d e n c e i nt er v als   will  b e  pr es e nt e d f or  e a c h  e n d p oi nt. 
A Es   will  b e s u  m  m ari z e d  b y  pr o p orti o n  of s u bj e cts  e x p eri e n ci n g  e a c h  e v e nt  a n d  b y tr e at  m e nt  ar  m. 
D es cri pti v e st atisti cs   will  b e  pr es e nt e d f or  a ct u al  a n d  c h a n g e fr o  m  b as eli n e  at  e a c h st u d y  visit f or  vit al 
si g ns  a n d cli ni c al  l a b or at or y t est r es ults  b y tr e at  m e nt  ar  m.  
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  8 
 
 
 
5.    
S  C  H  E  D  U  L  E   O F   E  V  E  N  T S  
P r o c e d u r es  
S c r e e ni n g   
(  D a y-2 1 t o   D a y  -1)  
D a y  1   
D a y  4   
( ±  1  d a y) 
D a y  8   
( ±  1  d a y) 
D a y  1 5   
( ±  2  d a ys) 
D a y  2 2   
( ±  2  d a ys) 
D a y  4 3   
( ±  2  d a ys) 
E n d  of  St u d y/   
E a rl y   T e r  mi n ati o n   
 D a y  7 1 ( ±  3  d a ys)   
U ns c h e d ul e d 
Cli ni c   Visit a 
I nf or  m e d  c o ns e ntb  
X    
 
 
 
 
 
 
 
 
I n cl usi o n/ e x cl usi o n  crit eri a 
r e vi e  w 
X     
X c  
 
 
 
 
 
 
 
D e  m o gr a p hi c  d at a   
X    
 
 
 
 
 
 
 
 
3- D  P h ot o gr a p h y   
X     
X d, e  
X     
X     
X     
X d, e  
X d, e  
X 
 
M e di c al/s ur gi c al/ E F P  hist or y 
(i n cl u di n g  pr e vi o us tr e at  m e nt) 
X    
 
 
 
 
 
 
 
 
Pri or/ c o n c o  mit a nt 
m e di c ati o ns/ pr o c e d ur es   
X     
X e  
X     
X     
X     
X     
X     
X     
X 
P h ysi c al  E x a  mi n ati o n  
X    
 
 
 
 
 
     
X     
X 
H ei g ht   
X    
 
 
 
 
 
 
 
 
W ei g ht   
X     
X e  
 
 
 
 
     
X     
X 
Fit z p atri c k s ki n t y p e  
X    
 
 
 
 
 
 
 
 
Vit al si g ns   
X     
X f 
 
 
 
X f 
X f 
X     
X 
1 2 -l e a d  E  C  G 
X    
 
 
 
 
 
 
 
 
Cli n c al   L a b or at or y  T ests  
X    
 
 
 
 
 
     
X     
X 
A nti  -A  U  X  -I/ a nti-A  U  X  -II 
a nti b o d y l e v el s a  m pl e  
     
Xe  
 
 
 
 
     
X 
 
S er u  m  pr e g n a n c y t e st  
X    
 
 
 
 
 
 
 
 
Uri n e  pr e g n a n c y t est   
     
Xe  
 
 
 
X e  
X e  
X     
X 
Assi g n  m e nt  of tr e at  m e nt  ar e a 
( b utt o c ks  or t hi g hs) 
X    
 
 
 
 
 
 
 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  9 
 
 
 
P r o c e d u r es  
S c r e e ni n g   
(  D a y-2 1 t o   D a y  -1)  
D a y  1   
D a y  4   
( ±  1  d a y) 
D a y  8   
( ±  1  d a y) 
D a y  1 5   
( ±  2  d a ys) 
D a y  2 2   
( ±  2  d a ys) 
D a y  4 3   
( ±  2  d a ys) 
E n d  of  St u d y/   
E a rl y   T e r  mi n ati o n   
 D a y  7 1 ( ±  3  d a ys)   
U ns c h e d ul e d 
Cli ni c   Visit a 
S el e cti o n  of  2  di  m pl e s   wit hi n 
e a c h tr e at  m e nt  ar e a f or 
v ol u  m etri c  ass ess  m e nt  
X     
X e  
 
 
 
 
 
 
 
C  R  -P  C S S  
X  
 
 
 
 
 
 
 
 
H e xs el   D e pr essi o n   D e pt h  S c al e       
X    
 
 
 
 
X     
X     
X 
 
Assi g n  Tr e at  m e nt   Ar  m ( d osi n g 
i nj e cti o n t e c h ni q u e) 
     
Xe  
 
 
 
 
 
 
 
M ar k t h e  di  m pl e i nj e cti o n sit e s      
     
Xe  
 
 
 
X e  
X e  
 
 
St u d y  dr u g  a d  mi nistr ati o n  
     
X 
 
 
 
X     
X    
 
 
I nj e cti o n sit e r e a cti o ns/l o c al 
t ol er a bilit y i n t h e tr e at e d  ar e as 
     
X     
X     
X     
X     
X     
X     
X     
X 
All  ot h er  a d v ers e  e v e nts  
X 
aD uri n g  u ns c h e d ul e d  visits t h e i n v e sti g at or  or  d esi g n e e   m a y  p erf or  m  a n y st u d y  pr o c e d ur e t h at t h e y  d e e  m  cli ni c all y  n e c ess ar y ( e  g,  vit al si g ns,  cli ni c al l a b or at or y 
t ests,  pr e g n a n c y t est,  et c). 
bP erf or  m e d  pri or t o  a n y  st u d y -r e q uir e d  ass ess  m e nts. 
cS h o ul d  b e r e ass ess e d  a n d  v erifi e d  pri or t o st u d y  dr u g  a d  mi nistr ati o n.  
dC o  m pl et e  b ef or e  a n d  aft er   m ar ki n g i nj e cti o n sit es.   
eC o  m pl et e  pri or t o st u d y  dr u g  a d  mi nistr ati o n.   
fVit al si g ns   will  b e  c oll e ct e d  u p t o  4  h o urs  pri or t o,  a n d  at  1 5  a n d  3 0   mi n ut es  aft er st u d y  dr u g  a d  mi nistr ati o n  o n   D a ys  1,  2 2,  a n d  4 3.   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 0 
 
 
 
6.    
T  A  B  L  E   O F   C  O  N  T  E  N  T S,   LI S  T   O F   T  A  B  L  E S,   A  N  D   LI S  T   O F 
FI  G  U  R  E S  
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
1.  
TI T L E  P  A  G E  ................................................................................................................ 1 
2.  
S  U  M  M  A  R  Y   O F   C  H  A  N  G E S  ........................................................................................ 2 
3.  
S P  O  N S  O  R   C  O  N T  A  C T I  N F  O R  M  A TI  O  N   ................................................................... 4 
4.  
S  Y  N  O P SI S  ................................................................................................................... 5 
5.  
S  C  H E  D  U L E   O F  E  V E  N T S  ........................................................................................... 8 
6.  
T  A  B L E  O F   C  O  N T E  N T S,  LI S T   O F   T  A  B L E S,   A  N  D  LI S T   O F  FI  G  U  R E S  ............... 1 0 
7.  
LI S T   O F   A  B  B  R E  VI  A TI  O  N S..................................................................................... 1 5  
8.  
I  N T  R  O  D  U  C TI  O  N ...................................................................................................... 1 6 
8. 1.  
B a c k gr o  u n d ................................................................................................................. 1 6  
8. 1. 1.  
E d e  m at o us  Fi br os cl er oti c  P a n ni c ul o p at h y ................................................................. 1 6  
8. 1. 2.  
C oll a g e n as e   Cl ostri di u  m   Hist ol yti c u  m   ....................................................................... 1 7 
8. 2.  
S u  m  m ar y  of   N o n cli ni c al  St u di es  ................................................................................ 1 8 
8. 3.  
S u  m  m ar y  of   K n o  w n   Ris ks  a n d   B e n efits ..................................................................... 1 8  
8. 4.  
R ati o n al e   ..................................................................................................................... 1 9 
9.  
O  BJ E  C TI  V E S   ............................................................................................................. 1 9 
9. 1.  
Pri  m ar y   O bj e cti v e  ....................................................................................................... 1 9 
9. 2.  
S e c o n d ar y   O bj e cti v e  ................................................................................................... 1 9 
9. 3.  
E x pl or at or y   O bj e cti v es ............................................................................................... 1 9  
1 0.  
I  N  V E S TI  G  A TI  O  N  A L  P L  A  N ..................................................................................... 2 0 
1 0. 1.  
St u d y   D esi g n  ............................................................................................................... 2 0 
1 0. 2.  
S el e cti o n  of   D os es ...................................................................................................... 2 0  
1 0. 3.  
St u d y   Dr u g   A d  mi nistr ati o n ......................................................................................... 2 0 
1 0. 3. 1.  
Tr e at  m e nt I:  S h all o  w I nj e cti o n,  3   Ali q u ots ................................................................ 2 2  
1 0. 3. 2.  
Tr e at  m e nt II:  S h all o  w I nj e cti o n,  1   Ali q u ot ................................................................. 2 3  
1 0. 3. 3.  
Tr e at  m e nt III:   D e e p I nj e cti o n,  1   Ali q u ot .................................................................... 2 4  
1 0. 3. 4.  
Tr e at  m e nt I  V:   D e e p  a n d  S h all o  w I nj e cti o ns,  5   Ali q u ots ............................................ 2 5  
1 0. 3. 5.  
Tr e at  m e nt   V:  S h all o  w I nj e cti o ns,  4   Ali q u ots  ............................................................. 2 6 
1 0. 3. 6.  
C ar e  Pr o c e d ur es   Aft er I nj e cti o n   ................................................................................. 2 7 
1 0. 4.  
Dis c ussi o n  of  St u d y   D esi g n, I n cl u di n g t h e   C h oi c e  of   C o ntr ol   Gr o u ps ...................... 2 7  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 1 
 
 
 
1 1.  
S E L E  C TI  O  N   A  N  D   WI T  H  D  R  A  W  A L   O F  S  U  BJ E  C T S  .............................................. 2 8 
1 1. 1.  
S u bj e ct I n cl usi o n   Crit eri a  ........................................................................................... 2 8 
1 1. 2.  
S u bj e ct  E x cl usi o n   Crit eri a  .......................................................................................... 2 8 
1 1. 3.  
S u bj e ct   Dis c o nti n u ati o n   Crit eri a  ................................................................................. 3 0 
1 1. 3. 1.  
R e pl a c e  m e nt  Pr o c e d ur es   ............................................................................................. 3 0 
1 2.  
T  R E  A T  M E  N T   O F  S  U  BJ E  C T S .................................................................................. 3 1  
1 2. 1.  
St u d y   Visits  ................................................................................................................. 3 1 
1 2. 1. 1.  
S u bj e ct  S cr e e ni n g  ....................................................................................................... 3 1 
1 2. 1. 2.  
S cr e e ni n g   Ass ess  m e nts  ............................................................................................... 3 1 
1 2. 1. 3.  
D e  m o gr a p hi c   D at a   ...................................................................................................... 3 1 
1 2. 1. 4.  
M e di c al/ S ur gi c al/ E F P   Hist or y   .................................................................................... 3 1 
1 2. 2.  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns  a n d  Pr o c e d ur es .................................................. 3 1  
1 2. 2. 1.  
Pr o hi bit e d   M e di c ati o ns  a n d  Pr o c e d ur es ..................................................................... 3 2  
1 2. 3.  
Tr e at  m e nt   C o  m pli a n c e  ................................................................................................ 3 2 
1 2. 4.  
Bli n di n g  a n d   R a n d o  mi z ati o n ...................................................................................... 3 2  
1 2. 5.  
S el e cti n g  a n d   M ar ki n g   Di  m pl es  ................................................................................. 3 2 
1 2. 6.  
C  R  -P  C S S  .................................................................................................................... 3 3 
1 3.  
A S S E S S  M E  N T   O F  E F FI  C  A  C  Y   ................................................................................ 3 3 
1 3. 1.  
3-  D  P h ot o gr a p h y ......................................................................................................... 3 3  
1 3. 2.  
H e xs el   D e pr essi o n   D e pt h  S c al e   .................................................................................. 3 3 
1 4.  
A S S E S S  M E  N T   O F  S  A F E T  Y   ..................................................................................... 3 4 
1 4. 1.  
D efi niti o ns   .................................................................................................................. 3 4 
1 4. 1. 1.  
A d v ers e  E v e nts   ........................................................................................................... 3 4 
1 4. 1. 2.  
S eri o us   A d v ers e  E v e nts .............................................................................................. 3 4  
1 4. 2.  
M o nit ori n g   A d v ers e  E v e nts ........................................................................................ 3 5  
1 4. 3.  
R el ati o ns hi p t o  St u d y   Dr u g ........................................................................................ 3 5  
1 4. 4.  
I nt e nsit y   Ass ess  m e nt .................................................................................................. 3 6 
1 4. 5.  
R e p orti n g   A d v ers e  E v e nts  a n d  S eri o us   A d v ers e  E v e nts ............................................ 3 6  
1 4. 5. 1.  
R e p orti n g   A d v ers e  E v e nts .......................................................................................... 3 6  
1 4. 5. 2.  
R e p orti n g  S eri o us   A d v ers e  E v e nts ............................................................................. 3 6  
1 4. 5. 2. 1.  
F oll o  w-  U p  Pr o c e d ur es f or  S eri o us   A d v ers e  E v e nts ................................................... 3 7  
1 4. 6.  
S p e ci al   R e p orti n g  Sit u ati o ns  ....................................................................................... 3 7 
1 4. 6. 1.  
A d v ers e  E v e nts  of  S p e ci al I nt er est   ............................................................................. 3 7 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 2 
 
 
 
1 4. 6. 2.  
O v er d os e/  Mis us e/  A b us e ............................................................................................. 3 7  
1 4. 6. 2. 1.  
O v er d os e ..................................................................................................................... 3 7  
1 4. 6. 2. 2.  
Mis us e/  A b us e   ............................................................................................................. 3 8 
1 4. 6. 3.  
Pr e g n a n c y  ................................................................................................................... 3 8 
1 4. 6. 4.  
A Es/ S  A Es  E x p eri e n c e d  b y   N o ns u bj e cts  E x p os e d t o  St u d y   M e di c ati o n .................... 3 8  
1 4. 7.  
Cli ni c al  L a b or at or y  T ests   ........................................................................................... 3 8 
1 4. 8.  
A nti  -A  U  X  -I  a n d   A nti-A  U  X  -II   A nti b o di es ................................................................. 4 0 
1 4. 9.  
Vit al  Si g ns   .................................................................................................................. 4 0 
1 4. 1 0.  
El e ctr o c ar di o gr a  m  ....................................................................................................... 4 0 
1 4. 1 1.  
P h ysi c al  E x a  mi n ati o n  ................................................................................................. 4 0 
1 4. 1 2.  
Fit z p atri c k  S c al e  ......................................................................................................... 4 0 
1 4. 1 3.  
Ot h er  S af et y   Ass ess  m e nts   ........................................................................................... 4 1 
1 5.  
A S S E S S  M E  N T   O F  P  H  A  R  M  A  C  O  KI  N E TI  C S   ........................................................... 4 1 
1 6.  
A S S E S S  M E  N T   O F  P  H  A  R  M  A  C  O  D  Y  N  A  MI  C S   ........................................................ 4 1 
1 7.  
S T  A TI S TI  C  A L   C  O  N SI  D E  R  A TI  O  N S   A  N  D   M E T  H  O  D S  ......................................... 4 1 
1 7. 1.  
D et er  mi n ati o n  of  S a  m pl e  Si z e   .................................................................................... 4 1 
1 7. 2.  
A n al ysis  P o p ul ati o ns .................................................................................................. 4 1  
1 7. 2. 1.  
S af et y  P o p ul ati o n ........................................................................................................ 4 1  
1 7. 2. 2.  
E v al u a bl e  P o p ul ati o n .................................................................................................. 4 1  
1 7. 3.  
S u bj e ct   Dis p ositi o n  ..................................................................................................... 4 1 
1 7. 4.  
D e  m o gr a p hi cs  a n d   Ot h er   B as eli n e   C h ar a ct eristi cs   ..................................................... 4 2 
1 7. 5.  
Effi c a c y   A n al ys es  ....................................................................................................... 4 2 
1 7. 6.  
S af et y   A n al ys es  .......................................................................................................... 4 2 
1 7. 6. 1.  
Pri or,   C o n c o  mit a nt,  a n d  F oll o  w- u p   M e di c ati o n ......................................................... 4 3  
1 7. 6. 2.  
St u d y   Dr u g  E x p os ur e .................................................................................................. 4 3  
1 7. 6. 3.  
M e as ur e  m e nt  of  Tr e at  m e nt   C o  m pli a n c e   .................................................................... 4 3 
1 7. 6. 4.  
A d v ers e  E v e nts   ........................................................................................................... 4 3 
1 7. 6. 5.  
Vit al  Si g ns   .................................................................................................................. 4 4 
1 7. 6. 6.  
Cli ni c al  L a b or at or y  P ar a  m et ers   .................................................................................. 4 4 
1 7. 6. 7.  
P h ysi c al  E x a  mi n ati o n  ................................................................................................. 4 4 
1 7. 6. 8.  
A nti  -A  U  X  -I  a n d   A nti-A  U  X  -II   A nti b o di es ................................................................. 4 4 
1 7. 6. 9.  
Ot h er  S af et y   M e as ur e  m e nts   ........................................................................................ 4 4 
1 7. 7.  
P h ar  m a c o ki n eti c   A n al ys es  .......................................................................................... 4 4 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 3 
 
 
 
1 7. 8.  
P h ar  m a c o d y n a  mi c   A n al ys es  ....................................................................................... 4 4 
1 7. 9.  
Ot h er   D at a ( e g,   H e alt h  E c o n o  mi cs/  Q  O L,  P h ar  m a c o g e n eti c,  et c)   .............................. 4 4 
1 7. 1 0.  
I nt eri  m   A n al ysis .......................................................................................................... 4 5 
1 7. 1 1.  
St atisti c al  S oft  w ar e  ..................................................................................................... 4 5 
1 8.  
S T  U  D  Y   D  R  U  G   M  A T E  RI  A L S  A  N  D   M  A  N  A  G E  M E  N T   ........................................... 4 5 
1 8. 1.  
St u d y   Dr u g I d e ntit y  .................................................................................................... 4 5 
1 8. 2.  
St u d y   Dr u g  P a c k a gi n g  a n d  L a b eli n g  .......................................................................... 4 5 
1 8. 3.  
St u d y   Dr u g  St or a g e  ..................................................................................................... 4 5 
1 8. 4.  
St u d y   Dr u g  Pr e p ar ati o n  .............................................................................................. 4 5 
1 8. 5.  
St u d y   Dr u g   A c c o u nt a bilit y ......................................................................................... 4 6  
1 8. 5. 1.  
St u d y   Dr u g   H a n dli n g  a n d   Dis p os al ............................................................................ 4 6  
1 9.  
DI R E  C T   A  C  C E S S  T  O  S  O  U  R  C E   D  A T  A/  D  O  C  U  M E  N T S  ......................................... 4 6 
1 9. 1.  
S o ur c e   D o c u  m e nts ...................................................................................................... 4 6  
1 9. 2.  
St u d y   M o nit ori n g ........................................................................................................ 4 6  
1 9. 3.  
A u dits  a n d I ns p e cti o ns ................................................................................................ 4 6  
1 9. 4.  
I nstit uti o n al   R e vi e  w   B o ar d (I  R  B) ............................................................................... 4 6 
1 9. 5.  
D at a   R e c or di n g  a n d   D o c u  m e nt ati o n ........................................................................... 4 7  
2 0.  
Q  U  A LI T  Y   C  O  N T  R  O L   A  N  D   Q  U  A LI T  Y   A S S  U  R  A  N  C E   ......................................... 4 7 
2 1.  
E T  HI C S  ...................................................................................................................... 4 7 
2 1. 1.  
Et hi cs   R e vi e w ............................................................................................................. 4 7  
2 1. 2.  
Et hi c al   C o n d u ct  of t h e  St u d y ...................................................................................... 4 8  
2 1. 3.  
S u bj e ct I nf or  m ati o n  a n d   C o ns e nt  ............................................................................... 4 8 
2 2.  
D  A T  A   H  A  N  D LI  N  G   A  N  D   R E  C  O  R  D  K E E PI  N  G   ....................................................... 4 9 
2 2. 1.  
D at a   C oll e cti o n   ........................................................................................................... 4 9 
2 2. 2.  
St u d y   D o c u  m e nt ati o n  ................................................................................................. 4 9 
2 3.  
R E P  O  R TI  N  G   A  N  D  P  U  B LI  C  A TI  O  N   ......................................................................... 4 9 
2 4.  
I  N  V E S TI  G  A T  O  R   O  B LI  G  A TI  O  N S ........................................................................... 5 0 
2 4. 1.  
R e g ul at or y   D o c u  m e nts   ............................................................................................... 5 0 
2 4. 2.  
D el e g ati o n  of   R es p o nsi biliti es  a n d   A d e q u at e   R es o ur c es ........................................... 5 0  
2 4. 3.  
M e di c al   C ar e  of  St u d y  S u bj e cts   ................................................................................. 5 1 
2 4. 4.  
Us e  of I n v esti g ati o n al   M at eri als   ................................................................................. 5 1 
2 4. 5.  
R et e nti o n  of   R e c or ds .................................................................................................. 5 1  
2 4. 6.  
S u bj e ct   C o nfi d e nti alit y  ............................................................................................... 5 2 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 4 
 
 
 
2 5.  
T E  R  MI  N  A TI  O  N   O F  S T  U  D  Y  .................................................................................... 5 2 
2 6.  
I  N  V E S TI  G  A T  O  R’ S  S T  A T E  M E  N T ........................................................................... 5 3 
2 7.  
R E F E  R E  N  C E S   ........................................................................................................... 5 4 
A P P E  N  DI  X   A.  C L  I  NI CI  A  N   R E P  O  R T E  D  P  H  O T  O  N  U  M E  RI  C  S E  V E  RI T  Y  SC  A L E 
F  O  R   C E L L  U LI T E (  C  R -P  C S S)  F  O  R  T  H E   B  U T T  O  C K ............................................. 5 5  
A P P E  N  DI  X   B.  C LI  NI CI  A  N   R E P  O  R T E  D  P  H  O T  O  N  U  M E  RI  C  S E  V E  RI T  Y  S  C  A L E 
F  O  R   C E L L  U LI T E (  C  R -P  C S S)  F  O  R  T  H E  T  HI  G  H  ................................................... 5 6 
A P P E  N  DI  X   C.  H E  X S E L   C E L L  U LI T E  S E  V  E  RI T  Y  S  C  A L E (  C S S) (  B )   D E P T  H   O F 
D E P  R E S SI  O  N S   .......................................................................................................... 5 7 
 
LI S  T   O F   T  A  B  L  E S   
T a bl e   1: 
V ol u  m e  a n d   C o n c e ntr ati o n  of   C  C  H I nj e cti o ns  b y  Tr e at  m e nt   Ar  m ............................ 2 1  
T a bl e   2: 
Cli ni c al  L a b or at or y  T ests   ........................................................................................... 3 9 
T a bl e   3: 
Fit z p atri c k  S c al e  ......................................................................................................... 4 1 
 
LI S  T   O F  FI  G  U  R  E S   
Fi g ur e   1: 
Tr e at  m e nt I:  S h all o  w I nj e cti o n,  3   Ali q u ots ................................................................ 2 2  
Fi g ur e   2: 
Tr e at  m e nt II,  S h all o  w I nj e cti o n,  1   Ali q u ot ................................................................. 2 3  
Fi g ur e   3: 
Tr e at  m e nt III:   D e e p I nj e cti o n,  1   Ali q u ot .................................................................... 2 4  
Fi g ur e   4: 
Tr e at  m e nt I  V:   D e e p  a n d  S h all o  w I nj e cti o ns,  5   Ali q u ots ............................................ 2 5  
Fi g ur e   5: 
Tr e at  m e nt   V:  S h all o  w I nj e cti o ns,  4   Ali q u ots  ............................................................. 2 6 
 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 5 
 
 
 
7.    
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S 
T h e f oll o  wi n g  a b br e vi ati o ns  ar e  us e d i n t his st u d y  pr ot o c ol. 
A b b r e vi ati o n    o r S p e ci al  T e r  m       
E x pl a n ati o n 
3-  D 
3- di  m e nsi o n al 
A E   
A d v ers e  e v e nt   
C F  R   
C o d e  of  F e d er al   R e g ul ati o ns   
C  R  -P  C S S  
Cli ni ci a n   R e p ort e d  P h ot o n u  m eri c   C ell ulit e  S e v erit y  S c al e   
C T  A   
Cli ni c al  Tri al   A ut h ori z ati o n   
D  H  H S   
D e p art  m e nt  of   H e alt h  a n d   H u  m a n  S er vi c es   
E  C  G   
El e ctr o c ar di o gr a  m  
e  C  R F  
El e ctr o ni c   C as e   R e p ort  F or  m  
E  D  C  
El e ctr o ni c  d at a  c a pt ur e  
E F P  
E d e  m at o us fi br os cl er oti c  p a n ni c ul o p at h y 
F  D  A  
F o o d  a n d   Dr u g   A d  mi nistr ati o n 
G  C P   
G o o d   Cli ni c al  Pr a cti c e   
G  AI S  -I 
I n v esti g at or   Gl o b al   A est h eti c I  m pr o v e  m e nt  S c al e  
G  AI S  - S 
S u bj e ct   Gl o b al   A est h eti c I  m pr o v e  m e nt  S c al e 
I  B 
I n v esti g at or   Br o c h ur e 
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 
I E  C 
I n d e p e n d e nt  Et hi cs   C o  m  mitt e e 
I  N  D 
I n v esti g ati o n al   N e  w   Dr u g 
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 
M  A  A   
M ar k eti n g   A ut h ori z ati o n   A p pli c ati o n 
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
N  D  A   
N e  w   Dr u g   A p pli c ati o n   
P  R -P  C S S  
P ati e nt   R e p ort e d  P h ot o n u  m eri c   C ell ulit e  S e v erit y  S c al e   
S  A E  
S eri o us  a d v ers e  e v e nt  
T E  A E  
Tr e at  m e nt -e  m er g e nt  a d v ers e  e v e nt  
W  H  O   
W orl d   H e alt h   Or g a ni z ati o n 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 6 
 
 
 
8.    
I  N  T  R  O  D  U  C  TI  O  N 
8. 1.    
B a c k g r o u n d   
8. 1. 1.    
E d e  m at o us  Fi b r os cl e r oti c  P a n ni c ul o p at h y   
E d e  m at o us fi br os cl er oti c  p a n ni c ul o p at h y ( E F P),  c o  m  m o nl y  k n o  w n  as  c ell ulit e  h as  b e e n  d efi n e d 
as  a l o c al   m et a b oli c  dis or d er  of s u b c ut a n e o us tiss u es t h at r es ults i n  a  c o nt o ur  a b n or  m alit y  of t h e 
s ki n (K h a n  et  al,  2 0 1 0 a  ).  T h e  c o n diti o n   m a nif ests  as  di  m pl e d s ki n,  p arti c ul arl y i n t h e  gl ut e al-
f e  m or al r e gi o n (H e xs el  et  al,  2 0 1 0  ; R a  wli n gs,  2 0 0 6  ).  E F P is  c a us e d  b y  h er ni ati o n  of 
s u b c ut a n e o us f at l o b ul es t hr o u g h t h e  d er  m o h y p o d er  m al j u n cti o n  a n d/ or s h ort e ni n g  of t h e 
c oll a g e n s e pt a t h at  cr oss t h e  h y p o d er  m al l a y er  a n d  c o n n e ct t h e  d er  mis t o t h e  u n d erl yi n g f as ci a. 
T his  cr e at es  a n  u n e v e n s urf a c e   wit h  di  m pli n g ( H e xs el  et  al,  2 0 1 0  ; K h a n  et  al,  2 0 1 0 a  ).  E F P is  a 
m e di c al  c o n diti o n r es ulti n g i n  a  p ot e nti all y  c os  m eti c all y  u n a c c e pt a bl e  alt er ati o n  of t h e s  ki n,  a n d 
aff e cts  a n  esti  m at e d  8 5  % t o  9 8  %  of  p ost p u b ert al   w o  m e n ( K h a n  et  al,  2 0 1 0 a  ; R a  wli n gs,  2 0 0 6  ).  
T h e  p at h o p h ysi ol o g y  of  E F P is  n ot  c o  m pl et el y  u n d erst o o d,  b ut t h er e  ar e  3   m ai n t h e ori es:  e d e  m a 
r es ulti n g fr o  m  e x c essi v e  h y dr o p hili a  of t h e i nt er c ell ul ar   m atri x,  alt er ati o n  of t h e r e gi o n al 
mi cr o cir c ul ati o n,  a n d  diff er e nt  a n at o  mi c al  c o nf or  m ati o n  of  c oll a g e n o us s u b c ut a n e o us tiss u es i n 
w o  m e n  v e  rs us   m e n (T err a n o v a  et  al,  2 0 0 6 ). 
It is  k n o  w n t h at  E F P is  diff er e nt fr o  m  g e n er ali z e d  o b esit y. I n  g e n er ali z e d  o b esit y,  a di p o c yt es 
u n d er g o  h y p ertr o p h y  a n d  h y p er pl asi a t h at  ar e  n ot li  mit e d t o t h e  p el vis, t hi g hs,  a n d  a b d o  m e n 
(K h a n  et  al  ,  2 0 1 0 a). I n  ar e as  of  E F P,  a di p o c yt es  h a v e  p h ysi ol o gi c  a n d  bi o c h e  mi c al  pr o p erti es 
t h at  diff er fr o  m  a di p os e tiss u e l o c at e d  els e  w h er e.  L ar g e,   m et a b oli c all y-st a bl e  a di p o c yt es 
c h ar a ct eri z e  E F P - pr o n e  ar e as; t h us, t h e r es p o nsi v e n ess t o  c at e c h ol a  mi n e-i n d u c e d li p ol ysis is l ess 
i n  E F P tiss u es  c o  m p ar e d t o  vis c er al f at,   w hi c h  h as t h e  gr e at est r es p o nsi v e n ess (K h a n  et  al, 
2 0 1 0 a ).  
S u b c ut a n e o us f at l o b es  ar e s e p ar at e d fr o  m  o n e  a n ot h er  b y t hi n,  us u all y ri gi d str a n d s  of 
c oll a g e n o us  c o n n e cti v e tiss u es,   w hi c h  cr oss t h e f att y l a y ers  a n d  c o n n e ct t h e  d er  mis t o t h e 
u n d erl yi n g f as ci a.  T h es e s e pt a st a bili z e t h e s u b c utis  a n d  di vi d e t h e f at. I n  E F P, s h ort e ni n g  of t h e 
c oll a g e n s e pt a  d u e t o fi br osis  pr o v o k es r etr a cti o n  at t h e i ns erti o n  p oi nts  of t h e tr a b e c ul a e, 
c a usi n g t h e  d e pr essi o ns t h at  c h ar a ct eri z e  E F P ( H e xs el  et  al,  2 0 1 0  ).  T h er e  ar e  a  hi g h er  p er c e nt a g e 
of t hi n n er,  p er p e n di c ul ar  h y p o d er  m al s e pt a i n   w o  m e n   wit h  E F P t h a n i n   m e n ( K h a n  et  al,  2 0 1 0 a  ). 
W ei g ht  g ai n   m a k es  E F P   m or e  n oti c e a bl e,  b ut it   m a y  b e  pr es e nt  e v e n i n t hi n s u bj e cts.   G e n eti cs 
m a y  als o  pl a y  a r ol e si n c e  E F P t e n ds t o r u n i n f a  mili es.   
T h er e  ar e t h er a pi es t h at  h a v e  b e e n  utili z e d i n  a n  att e  m pt t o tr e at  c ell ulit  e;  h o  w e v er, t h er e  ar e  n o 
a p pr o v e d  p h ar  m a c ol o gi c tr e at  m e nts.   D es pit e   m ulti pl e t h er a p e uti c   m o d aliti es, t h er e is littl e 
s ci e ntifi c  e vi d e n c e t h at  a n y  of t h es e tr e at  m e nts  ar e  b e n efi ci al. I n f a ct,   m u c h  of t h e  e vi d e n c e is 
a n e c d ot al, s u bj e cti v e,  or  b as e d  o nl y  o n  p ati e nt s elf -ass ess  m e nt  (A vr a  m,  2 0 0 4  ).  S o  m e  of t h e 
hist ori c al tr e at  m e nts f or  E F P  h a v e i n cl u d e d   w ei g ht l oss ( K h a n  et  al,  2 0 1 0 b  ), t o pi c al  a g e nts 
(  A vr a  m,  2 0 0 4),   m ass a g e (C ollis  et  al,  1 9 9 9  ), li p os u cti o n (A vr a  m,  2 0 0 4  ; K h a n  et  al,  2 0 1 0 b  ), 
m es ot h er a p y   (K h a n  et  al,  2 0 1 0 b  ), r a di ofr e q u e n c y (K h a n  et  al,  2 0 1 0 b  ), s u b cisi o n  a n d  p o  w er e d 
s u b cisi o n (H e xs el  a n d   M a z z u c o,  2 0 0 0  ),  a n d l as er t h er a pi es (B o y c e  et  al,  2 0 0 5  ; Di  B er n ar d o,   
2 0 1 1 ); s o  m e  of t h es e tr e at  m e nts   m a y  p os e  a n i n cr e as e d ris k f or  a d v ers e  eff e cts (A vr a  m,  2 0 0 4  ).  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 7 
 
 
 
T h er e r e  m ai ns  a n  u n  m et   m e di c al  n e e d f or s af e  a n d  eff e cti v e t h er a pi es t o i  m pr o v e t h e  a est h eti c 
o ut c o  m e i n   w o  m e n   wit h  c ell ulit e.  T o  eff e cti v el y tr e at  c ell ulit e,  a t h er a p e uti c  a p pr o a c h   m a y 
r e q uir e  disr u pti o n  of t h e  d er  m al s e pt a,   w hi c h  ar e  c o  m p os e d  of  c oll a g e n  a n d  c a us e t h e s ki n 
di  m pli n g t h at is  b ot h ers o  m e t o   m a n y   w o  m e n. 
8. 1. 2.    
C oll a g e n as  e   Cl ost ri di u  m   Hist ol yti c u  m   
E  N 3 8 3 5 is  c urr e ntl y  a p pr o v e d ( br a n d  n a  m e   XI  A F L E  X ® ) f or:  1) t h e tr e at  m e nt  of  a d ults   wit h 
D u p u ytr e n’s  c o ntr a ct ur e   wit h  a  p al p a bl e  c or d  a n d,  2) f or t h e tr e at  m e nt  of  a d ult   m e n   wit h 
P e yr o ni e’s  dis e as e   wit h  a  p al p a bl e  pl a q u e  a n d  c ur v a t ur e  d ef or  mit y  of  at l e ast  3 0°  at t h e st art  of 
t h er a p y.  
E  N 3 8 3 5 is  a  p ar e nt er al l y o p hili z e d  pr o d u ct  c o  m pris e d  of  2  c oll a g e n as es, is ol at e d  a n d  p urifi e d 
fr o  m t h e f er  m e nt ati o n  of Cl ostri di u  m  hist ol yti c u  m,   i n  a n  a p pr o xi  m at e  1: 1   m ass r ati o, 
C oll a g e n as e   I (  A  U  X-I,   Cl ostri di al  cl ass I  c oll a g e n as e)  a n d   C oll a g e n as e II (  A  U  X-II;   Cl ostri di al 
cl ass II  c oll a g e n as e).   C oll a g e n as e   A  U  X -I is  a si n gl e  p ol y p e pti d e  c h ai n  c o nt ai ni n g  a p pr o xi  m at el y 
1, 0 0 0  a  mi n o  a ci ds  of  k n o  w n s e q u e n c e  a n d   wit h  a   m ol e c ul ar   w ei g ht  of  1 1 4  k  D a.   C oll a g e n a s e 
A  U  X  -II is  als o  a p pr o xi  m at el y  1, 0 0 0  a  mi n o  a ci ds l o n g  a n d  h as  a   m ol e c ul ar   w ei g ht  of  1 1 3  k  D a.  
T h es e  2   c oll a g e n as es  ar e  n ot i  m  m u n ol o gi c all y  cr oss-r e a cti v e  a n d  h a v e  diff er e nt s p e cifi citi es, 
s u c h t h at t o g et h er t h e y  b e c o  m e s y n er gisti c,  pr o vi di n g  a  v er y  br o a d  h y dr ol y zi n g r e a cti vit y t o  w ar d 
c oll a g e n.   B e c a us e t h es e  c oll a g e n as es  ar e  pr ot ei n as es t h at  c a n  h y dr ol y z e t h e tri pl e -h eli c al r e gi o n 
of  c oll a g e n  u n d er  p h ysi ol o gi c al  c o n diti o ns,  E  N 3 8 3 5  h as t h e  p ot e nti al t o  b e  eff e cti v e i n l ysi n g 
s u b d er  m al  c oll a g e n, s u c h  as t h os e  o bs er v e d i n t h e  d er  m al s e pt a,   w hi c h  ar e t h e  u n d erl yi n g  c a us e 
of t h e s ki n  di  m pli n g i n   w o  m e n   wit h  E F P.  
E n d o  P h ar  m a c e uti c als I n c. ( E n d o) l e ar n e d t h at  a   m u c h  diff er e nt  c o n c e ntr ati o n  of t h e  a p pr o v e d 
E  N 3 8 3 5 f or  m ul ati o n   w as  n e e d e d t o  eff e cti v el y t ar g et t h e  c oll  a g e n as e str u ct ur al   m atri x ( e g, 
d er  m al s e pt a)  at t h e sit e  of i nj e cti o n. I n  a d diti o n t o t his, t h e  o b vi o us  p h ysi ol o gi c al  a n d 
p at h ol o gi c al  diff er e n c es i n t h e tr e at  m e nt  ar e as f or  E F P ( c o  m p ar e d t o  a p pr o v e d i n di c ati o ns), 
m a n d at e d t h e  n e e d t o  d e v el o p  a  n e  w f or  m ul ati o n  of  E  N 3 8 3 5 t o tr e at t his  c o n diti o n.  T h e  dil u e nt 
t o o  h a d t o  b e  o pti  mi z e d s o t h at t h e  n e  w f or  m ul ati o n  c a n  b e  dil ut e d   m or e,  y et  off er  gr e at er 
st a bilit y   wit h  p ot e nti all y l ess i nj e cti o n sit e  a d v ers e  e v e nts  (  A E).  T h us,  E n d o  d e v el o p e d  a  n e  w 
f or  m ul ati o n  of  E  N 3 8 3 5 f or t h e tr e at  m e nt  of  E F P,  a n d t his  n e  w f or  m ul ati o n is  h er e aft er r ef err e d 
t o  as   C  C  H. 
A r e c e nt  P h as e  2 b, 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 ( E  N 3 8 3 5- 2 0 1)  of 
3 7 5  w o  m e n r a n d o  mi z e d t o tr e at  m e nt  of  o n e tr e at  m e nt  ar e a ( q u a dr a nt) ( q u a dr a nt   w as  d  efi n e d i n 
st u d y  E  N 3 8 3 5- 2 0 1  as  a l eft  b utt o c k,  a ri g ht  b utt o c k,  a l eft  p ost er ol at er al t hi g h  or  a ri g ht 
p ost er ol at er al t hi g h)  of  c ell ulit e   wit h   C  C  H  0. 8 4   m g  or  pl a c e b o i n  a  1: 1 r ati o  ass ess e d t h e 
eff e cti v e n ess  a n d s af et y  of   C  C  H.  Effi c a c y i n t his st u d y   w as  e v a l u at e d  b as e d  o n  c ell ulit e 
ass ess  m e nts  usi n g   Cli ni ci a n   R e p ort e d  P h ot o n u  m eri c   C ell ulit e  S e v erit y  S c al e (  C  R -P  C S S),  P ati e nt 
R e p ort e d  P h ot o n u  m eri c   C ell ulit e  S e v erit y  S c al e ( P  R  -P  C S S), I n v esti g at or   Gl o b al   A est h eti c 
I  m pr o v e  m e nt  S c al e (  G  AI S-I),  S u bj e ct   Gl o b al   A est heti c I  m pr o v e  m e nt  S c al e (  G  AI S - S),  a n d 
S u bj e ct  S atisf a cti o n   wit h   C ell ulit e  Tr e at  m e nt.  
R es ults fr o  m t h e  E  N 3 8 3 5- 2 0 1 st u d y  d e  m o nstr at e d t h at tr e at  m e nt ( 3  visits  a p pr o xi  m at el y  2 1  d a ys 
a p art) i  m pr o v e d t h e  c ell ulit e s e v erit y  of t h e tr e at  m e nt  ar e a  as  ass ess e d  b y t h e  pri  m ar y  e n d p oi nt  of 
2-l e v el  c o  m p osit e r es p o n d er  a n al ys es, t h e  pr o p orti o n  of r es p o n d ers  b as e d  o n  a n i  m pr o v e  m e nt  of 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 8 
 
 
 
≥  2 l e v els i n t h e  a p p e ar a n c e  of  c ell ulit e i n  b ot h t h e  p ati e nt  P  R -P  C S S  a n d t h e  cli ni ci a n   C  R -P  C S S 
of  b utt o c ks  a n d t hi g hs   w as st atisti c all y si g nifi c a ntl y  gr e at er i n s u bj e cts   w h o r e c ei v e d  E  N 3 8 3 5 
0. 8 4   m g ( 1 0. 6  %;  p  <  0. 0 0 1)  c o  m p ar e d t o s u bj e cts   w h o r e c ei v e d  pl a c e b o ( 1. 6  %);  1- l e v el ( or 
gr e at er) r es p o n d ers i n t h e  P  R- P  C S S  of   C  C  H -tr e at e d s u bj e cts ( 7 2. 3  %)   w as si g nifi c a ntl y  gr e at er 
t h a n  1-l e v el r es p o n d ers i n t h e  pl a c e b o  gr o u p ( 5 1. 6  %) (p  <  0. 0 0 1); st atisti c all y si g nifi c a nt ( p  ≤ 
0. 0 0 1) i  m pr o v e  m e nt i n t h e  a p p e ar a n c e  of  c ell ulit e  b as e d  o n t h e s u bj e ct  S-  G  AI S   w er e  o bs er v e d i n 
C  C  H  0. 8 4-  m g  gr o u p ( 7 3. 1  %)  c o  m p ar e d t o t h e  pl a c e b o  gr o u p ( 4 4. 0  %);  a n d  6 2. 9  %  of s u bj e cts i n 
t h e   C  C  H  0. 8 4   m g  gr o u p   w er e s atisfi e d  or  v er y s atisfi e d   wit h t h e r es ults  of t h eir  c ell ulit e 
tr e at  m e nt  c o  m p ar e d   wit h  o nl y  3 5. 9  %  of s u bj e cts i n t h e  pl a c e b o  gr o u p (p  <  0. 0 0 1).   
T h e st u d y  als o  d e  m o nstr at e d   C  C  H t o  b e   w ell t ol er at e d   wit h  n o s eri o us  a d v ers e  e v e  nts ( S  A Es) 
r el at e d t o   C  C  H.  S af et y r es ults fr o  m  a t ot al  of  4 st u di es ( 1  pil ot,  2  P h as e  1,  a n d  2  P h as e  2 st u di es) 
i n   w hi c h  4 3 5  a d ult f e  m al es r e c ei v e d s u b c ut a n e o us i nj e cti o ns  of   C  C  H i n di c at e t h at t h e   m aj orit y  of 
tr e at  m e nt-e  m er g e nt  a d v ers e  e v e nts ( T E  A Es)  ar e t r a nsi e nt,  n o ns eri o us,   mil d  or   m o d er at e i n 
i nt e nsit y,  a n d r el at e d t o t h e l o c al  a d  mi nistr ati o n  of   C  C  H.  T h e i  m  m u n o g e ni cit y  pr ofil e  aft er  3 
tr e at  m e nts  of   C  C  H i n di c at e t h at  gr e at er t h a n  9 0  %  of   C  C  H-tr e at e d s u bj e cts   w er e s er o p ositi v e f or 
A  U  X  -I  a n d/ or   A  U  X-II  a nti bo di es; t his  pr ofil e  of   C  C  H is si  mil ar t o t h at  o bs er v e d i n t h e 
D u p u ytr e n’s  c o ntr a ct ur e  a n d  P e yr o ni e’s  dis e as e  pr o gr a  ms. 
N o  n e  w s af et y si g n als  h a v e  b e e n s e e n i n  o n g oi n g  P h as e  3 st u di es  of   C  C  H t h at  h a v e tr e at e d   m or e 
t h a n  4 0 0 s u bj e cts   wit h  E F P  of t h e  b utt o c ks   wit h  1. 6 8   m g  of   C  C  H ( 0. 8 4   m g  p er  b utt o c k). 
A  P h as e  1,  o p e n l a b el s af et y  a n d  p h ar  m a c o ki n eti c st u d y  of  a si n gl e  d os e  of   C  C  H  0. 8 4   m g i n  1 1 
f e  m al e s u bj e cts   wit h  E F P s h o  w e d t h at t h er e   w er e  n o  q u a ntifi a bl e l e v els  of   A  U  X-I  or   A  U  X-II  at 
a n y ti  m e  p oi nt  aft er s u b c ut a n e o us i nj e cti o n  of  0. 8 4   m g  of st u d y  dr u g i nt o  o n e  q u a dr a nt.   A s e c o n d 
P h as e  1,  o p e n-l a b el s af et y  a n d  p h ar  m a c o ki n eti c st u d y  of  a si n gl e  d os e  of   C  C  H  0. 8 4   m g  p er 
tr e at  m e nt  ar e a i n t  w o tr e at  m e nt  ar e as ( b utt o c k- b utt o c k, t hi g h-t hi g h,  or  b utt o c k-t hi g h) 
c o n c urr e ntl y (t ot al  d os e  of  1. 6 8   m g) s h o  w e d t h at t h er e   w er e  n o  q u a ntifi a bl e l e v els  of   A  U  X- I  or 
A  U  X  -II  at  a n y ti  m e  p oi nt  p ost- d os e  attri b ut a bl e t o t h e i nj e cti o n  of   C  C  H  1. 6 8   m g. 
T h e r es ults fr o  m t h es e st u di es s u g g est t h at s u b c ut a n e o us i nj e cti o ns  of   C  C  H i n t h e  ar e a  of 
c ell ulit e   m a y  b e  a   w ell -t ol er at e d  a n d  eff e cti v e   m e di c al tr e at  m e nt f or  a d ults   wit h  E F P. 
8. 2.    
S u  m  m a r y  of   N o n cli ni c al  St u di es  
N o n cli ni c al st u di es  n e c ess ar y t o s u p p ort  cli ni c al st u di es  h a v e  b e e n  p erf or  m e d  a n d  ar e 
s u  m  m ari z e d i n t h e I n v esti g at or   Br o c h ur e (I  B)  (E n d o,  2 0 1 7 ).   N o n cli ni c al st u di es i n t h e f oll o  wi n g 
ar e as   w er e  p erf or  m e d: t o xi c ol o g y, r e pr ot o xi cit y,  g e n ot o xi cit y,  a n d  h y p ers e nsiti vit y.  
8. 3.    
S u  m  m a r y  of   K n o  w n   Ris ks  a n d   B e n efits  
A s u  m  m ar y  of s af et y ris ks is  pr o  vi d e d i n t h e I  B ( E n d o,  2 0 1 7 ).  T h e f oll o  wi n g   A Es  h a v e  b e e n 
c o  m  m o nl y  o bs er v e d: l o c al i nj e cti o n sit e r e a cti o ns (i n cl u di n g i nj e cti o n sit e  br uisi n g, i nj e cti o n sit e 
s  w elli n g,  a n d i nj e cti o n sit e  p ai n) f or t h e  v ari o us  a p pr o v e d i n di c ati o ns  as   w ell  as t h os e  b ei n g 
i n v esti g at e d.  
I n t h e  P h as e  2 b st u d y  of C  C  H   i n   w o  m e n   wit h  E F P, t h e f oll o  wi n g tr e at  m e nt r el at e d   A Es   w er e 
r e p ort e d  ≥  2  %  of  1 8 9 C  C  H  -tr e at e d f e  m al e s u bj e cts: i nj e cti o n sit e  br uisi n g ( 7 5. 1  %), i nj e cti o n site 
p ai n ( 5 9. 3  %), i nj e cti o n sit e  n o d ul e ( 1 4. 3  %), i nj e cti o n sit e  pr urit us ( 1 1. 1  %), i nj e cti o n sit e 
s  w elli n g ( 7. 4  %), i nj e cti o n sit e i n d ur ati o n ( 5. 8  %), i nj e cti o n sit e   m ass ( 5. 3  %), i nj e cti o n sit e 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  1 9 
 
 
 
dis c ol or ati o n ( 3. 2  %),  a n d i nj e cti o n sit e  er yt h e  m a ( 2. 1  %).  T h es e  e v e nts  ar e si  mil ar t o  e v e nts 
r e p ort e d i n t h e  cli ni c al tri als  of  E  N 3 8 3 5 f or t h e  a p pr o v e d i n di c ati o ns.  
P ost  m ar k eti n g s af et y  d at a  ar e  c o nsist e nt   wit h s af et y  d at a r e p ort e d i n  cli ni c al tri als.   A Es r e p ort e d 
t o  d at e i n  o n g oi n g  P h as e  3 tri als  of C  C  H   f or t h e tr e at  m e nt  of  E F P  of t h e  b utt o c ks  h a v e  n ot 
i n di c at e d  a n y  n e  w s af et y si g n als. 
8. 4.    
R ati o n al e   
T h e r es ults fr o  m t h e  P h as e  2 b  E F P st u d y ( E  N 3 8 3 5- 2 0 1) f urt h er s u g g est e d t h at   C  C  H    0. 8 4 m g  p er 
tr e at  m e nt  ar e a ( q u a dr a nt) is  a n  eff e cti v e tr e at  m e nt  of  E F P  b as e d  o n i  m pr o v e  m e nt i n t h e s e v erit y 
of  c ell ulit e  as  d et er  mi n e d  b y t h e I n v esti g at or  a n d t h e s u bj e ct.  T h er e   w er e  n o s af et y  c o n c er ns 
f oll o  wi n g  0. 8 4   m g  p er tr e at  m e nt  ar e a i n t h e tr e at  m e nt  of  E F P.  S af et y fi n di n gs fr o  m t h e  P h as e  2 b 
E F P  a n d  o n g oi n g  P h as e  3 st u di es  ar e si  mil ar t o t h at  o bs er v e d i n  pr e vi o us  cli ni c al st u di es   wit h 
C  C  H   i n t h e tr e at  m e nt  of  E F P  a n d   XI  A F L E  X i n t h e tr e at  m e nt  of   D u p u ytr e n’s  c o ntr a ct ur e  a n d 
P e yr o ni e’s  dis e as e, i n t h at t h e   m aj orit y  of   A Es  o c c urr e d  at t h e sit e  of i nj e cti o n  a n d r es ol v e d 
b ef or e t h e  n e xt s c h e d ul e d tr e at  m e n t.  T h e i  m  m u n o g e ni cit y  pr ofil e  of C  C  H   i n t h e  P h as e  2 b  E F P 
st u d y is si  mil ar i n  pr e vi o us st u di es  a n d  pr o gr a  ms. 
I n p ut fr o  m  p u blis h e d lit er at ur e,  as   w ell  as i n p ut fr o  m  a est h eti c   m e di ci n e s p e ci alists, i n di c at e d  a 
d esir e t o i n v esti g at e   m ulti pl e i nj e cti o n/ d osi n g t e c h ni q u es  of  C  C  H   f or  E F P tr e at  m e nt  a n d t o 
e x a  mi n e t h e r ol e  3 - di  m e nsi o n al ( 3-D) i  m a gi n g  p ar a di g  ms  c a n  pl a y i n  vis u ali zi n g t h e tr e at  m e nt 
eff e ct  of  C  C  H    o n  E F P. 
T his  cli ni c al st u d y  pr ot o c ol   will  e x pl or e t h es e  diff er e nt tr e at  m e nt  a n d  o ut c o  m e  ass ess  m e nt 
p ar a di g  m   p ossi biliti es.  L e ar ni n gs fr o  m t his st u d y  c o ul d  assist  b ot h t h e s p o ns or  a n d t h e  a est h eti c 
m e di ci n e  c o  m  m u nit y i n  d esi g ni n g f ut ur e  cli ni c al st u di es.   
9.    
O  B J  E  C  TI  V  E S 
9. 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  ass ess t h e tr e at  m e nt  eff e cts  of   C  C  H     w h e n  a d  mi nist er e d 
b y  diff er e nt i nj e cti o n t e c h ni q u es i n s u bj e cts   wit h  E F P. 
9. 2.    
S e c o n d a r y   O bj e cti v e  
T h e s e c o n d ar y  o bj e cti v e  of t his st u d y is t o  ass ess t h e s af et y  of  C  C  H     w h e n  a d  mi nist er e d  usi n g 
diff er e nt i nj e cti o n t e c h ni q u es i n s u bj e cts   wit h  E F P. 
9. 3.    
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 i n cl u d e: 
•    T o  ass ess t h e i  m  m u n o g e ni cit y  of  C  C  H   i n t h e tr e at  m e nt  of  E F P. 
•    T o  ass ess t h e  us ef ul n ess  of  3 -  D  p h ot o gr a p h y i n  e v al u ati n g  o ut c o  m es  of tr e at  m e nt f or 
E F P.  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h a r  m a c e uti c als I n c. 
P a g e  2 0 
 
 
 
1 0.    
I  N  V  E S  TI  G  A  TI  O  N  A  L  P  L  A  N  
1 0. 1.    
St u d y   D esi g n  
T his is  a  P h as e  2 a,  o p e n-l a b el,   m ulti c e nt er,  e x pl or at or y st u d y t o  e v al u at e t h e s af et y  a n d 
eff e cti v e n ess  of  diff er e nt i nj e cti o n t e c h ni q u es  of  C  C  H   f or t h e tr e at  m e nt  of  a d ult   w o  m e n   wit h 
mil d,   m o d er at e  or s e v er e  E F P ( as  ass ess e d  b y t h e i n v esti g at or  usi n g t h e   C  R  -P  C S S).  
A p pr o xi  m at el y  6 0 s u bj e cts   will  b e  e nr oll e d,  3 0   wit h  2  eli gi bl e  b utt o c ks (t o  b e  d os e d i n t h e 
b utt o c ks)  a n d  3 0   wit h  2  eli gi bl e t hi g hs (t o  b e  d os e d i n t h e t hi g hs)  at  a p pr o xi  m at el y  5 sit es i n t h e 
U nit e d  St at es.   N o s u bj e cts   will  b e tr e at e d f or  E F P i n  b ot h t h e  b utt o c ks  a n d t h e t hi g hs.  T h e  3 0 
s u bj e cts i n  e a c h tr e at  m e nt r e gi o n ( b utt o c ks  or t hi g hs)   will  b e  assi g n e d t o  1  of  5 i nj e cti o n 
t e c h ni q u e tr e at  m e nt  ar  ms  o n   D a y  1. 
S u bj e cts   will  p arti ci p at e i n t h e st u d y f or  a p pr o xi  m at el y  9 2  d a ys.  F oll o  wi n g  a s cr e e ni n g  p eri o d  of 
u p t o  2 1  d a ys, s u bj e cts   will  p arti ci p at e i n  u p t o  3 tr e at  m e nt  visits s e p ar at e d  b y  2 1  d a ys (  D a ys  1, 
2 2,  a n d  4 3).  F oll o  wi n g t h e first  d os e  of st u d y  dr u g, s u bj e cts   will r et ur n f or  ass ess  m e nts  o n   D a ys 
4,  8,  1 5,  2 2,  4 3  a n d  7 1. 
T h e  c o  m pl et e s c h e d ul e  of  e v e nts is  pr o v i d e d i n  S e cti o n  5. 
1 0. 2.    
S el e cti o n  of   D os es  
T h e  d os a g e  of  C  C  H    c h os e n f or t his st u d y is  b as e d  o n t h e  e x p eri e n c e fr o  m s e v er al  e arli er st u di es 
as   w ell  as  o n g o i n g  P h as e  3  cli ni c al st u di es.  T h e  d os e  of  1. 6 8   m g ( 0. 8 4   m g  p er r e gi o n)  h as  b e e n 
s h o  w n t o  b e s af e  a n d   w ell- t ol er at e d. 
1 0. 3.    
St u d y   D r u g   A d  mi nist r ati o n  
T h er e  ar e  5 tr e at  m e nt  ar  ms  p er r e gi o n ( b utt o c ks  or t hi g h) i n t his st u d y   wit h  e a c h  ar  m 
r e pr es e nti n g  a  diff er e nt i nj e cti o n t e c h ni q u e  as f oll o  ws: 
•    Tr e at  m e nt I:  S h all o  w I nj e cti o n,  3  ali q u ots. 
•    Tr e at  m e nt II:  S h all o  w i nj e cti o n,  1  ali q u ot.  
•    Tr e at  m e nt III:   D e e p i nj e cti o n,  1  ali q u ot. 
•    Tr e at  m e nt I  V:   D e e p  a n d s h all o  w i nj e cti o ns,  5  ali q u ots. 
•    Tr e at  m e nt   V:  S h all o  w i nj e cti o n,  4  ali q u ots. 
I nj e cti o n t e c h ni q u es  diff er fr o  m  e a c h  ot h er i n,  at l e ast  b ut  n ot li  mit e d t o,  c o n c e ntr ati o n  of t h e 
C  C  H   i nj e ct at e,  a n gl e  of i nj e cti o n,  d e pt h  of i nj e cti o n,  v ol u  m e  of i nj e cti o n  a n d st u d y  dr u g 
a d  mi nistr ati o n  at i nj e cti o n sit e.   
A cr oss  all tr e at  m e nt  ar  ms, st u d y  dr u g   will  b e  a d  mi nist er e d s u b c ut a n e o usl y   w hil e t h e s u bj e ct is i n 
a  pr o n e  p ositi o n.  E a c h s u bj e ct   will r e c ei v e  2 4 i nj e cti o ns f or  a t ot al  d os e  of  1. 6 8   m g ( 0. 8 4   m g  p er 
tr e at  m e nt r e gi o n)  at  e a c h tr e at  m e nt  visit.  T h e  c u  m ul ati v e C  C  H    d os e   will  b e  5. 0 4   m g f or  e a c h 
s u bj e ct t h at  c o  m pl et es t h e  3 tr e at  m e nt  visits.   
T h e i nj e cti o n  v ol u  m e  a n d  c o n c e ntr ati o n f or  e a c h tr e at  m e nt  ar  m  ar e  o utli n e d   i n T a bl e   1.

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  2 1 
 
 
 
T a bl e  1:   
V ol u  m e  a n d   C o n c e nt r ati o n  of   C  C  H   I nj e cti o ns  b y   T r e at  m e nt   A r  m  
T r e at  m e nt   
N u  m b e r  of 
s u bj e cts/ a r e a 
D os e/   
i nj e cti o n 
V ol u  m e/i nj e cti o n   
D r u g 
c o n c e nt r ati o n/i nj e cti o n  
T ot al  v ol u  m e/t r e at  m e nt 
visit  
T r e at  m e nt I:  S h all o  w 
I nj e cti o n,  3  ali q u ots 
6 ( b utt o c ks)  
6 (t hi g hs)  
0. 0 7   m g 
  
0. 3   m L 
( gi v e n  as  3- 0. 1   m L 
ali q u ots) 
0. 2 3   m g/  m L 
7. 2   m L 
( 1 2 i nj e cti o ns/ tr e at  m e nt 
ar e a  x  2 tr e at  m e nt  ar e as  x 
0. 3   m L) 
T r e at  m e nt II:  S h all o  w 
i nj e cti o n,  1  ali q u ot 
6 ( b utt o c ks)  
6 (t hi g hs)  
0. 0 7   m g 
  
0. 3   m L 
( gi v e n  as  1-  0. 3   m L  ali q u ot) 
0. 2 3   m g/  m L 
7. 2   m L 
( 1 2 i nj e cti o ns/ tr e at  m e nt 
ar e a  x  2 tr e at  m e nt  ar e as  x 
0. 3   m L) 
T r e at  m e nt III:   D e e p 
i nj e cti o n,  1  ali q u ot 
6 ( b utt o c ks)  
6 (t hi g hs)  
0. 0 7   m g 
  
0. 3   m L 
( gi v e n  as  1-  0. 3   m L  ali q u ot) 
0. 2 3   m g/  m L 
7. 2   m L 
( 1 2 i nj e cti o ns/ tr e at  m e nt 
ar e a  x  2 tr e at  m e nt  ar e as  x 
0. 3   m L) 
T r e at  m e nt I  V:   D e e p  a n d 
s h all o  w i nj e cti o ns, 
5  ali q u ots 
6 ( b utt o c ks)  
6 (t hi g hs)  
0. 0 7   m g 
  
1. 5   m L 
( gi v e n  as  5-  0. 3 m L 
ali q u ots) 
  
0. 0 4 7   m g/  m L  
3 6   m L 
( 1 2 i nj e cti o ns/ tr e at  m e nt 
ar e a  x  2 tr e at  m e nt  ar e as  x 
1. 5   m L) 
T r e at  m e nt   V:  S h all o  w 
i nj e cti o n,  4  ali q u ots 
6 ( b utt o c ks)  
6 (t hi g hs)  
0. 0 7   m g 
  
1. 2   m L 
( gi v e n  as  4- 0. 3   m L 
ali q u ots) 
0. 0 6 0   m g/  m L 
2 8. 8   m L 
( 1 2 i nj e cti o ns/ tr e at  m e nt 
ar e a  x  2 tr e at  m e nt  ar e as  x 
1. 2   m L) 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  2 7 
 
 
 
•    M ai nt ai n t h e  3 0°  a n gl e  of t h e  n e e dl e t o t h e s ki n s urf a c e, r e p ositi o n t h e  n e e dl e t o 
a p pr o xi  m at el y  6 0° fr o  m  P ositi o n   A  a n d t o  w ar ds t h e s u bj e ct’s s h o ul d er ( P ositi o n   B), 
a n d i nj e ct  0. 3   m L  of st u d y  dr u g  b y  g e ntl y  p us hi n g t h e s yri n g e  pl u n g er. 
•    M ai nt ai n t h e  3 0°  a n gl e  of t h e  n e e dl e t o t h e s ki n s urf a c e, r e p ositi o n t h e  n e e dl e t o 
a p pr o xi  m at el y  6 0° fr o  m  P ositi o n   B  a n d t o  w ar ds s u bj e cts  ot h er s h o ul d er ( P ositi o n   C) 
a n d i nj e ct  0. 3   m L  of st u d y  dr u g  b y  g e ntl y  p us hi n g t h e s yri n g e  pl u n g er. 
•    M ai nt ai n t h e  3 0°  a n gl e  of t h e  n e e dl e t o t h e s ki n s urf a c e, r e p ositi o n t h e  n e e dl e 
o p p osit e t o  p ositi o n   A  a n d t o  w ar ds  ot h er si d e  of t h e s u bj e ct ( P ositi o n   D)  a n d i nj e ct 
0. 3   m L  of st u d y  dr u g  b y  g e ntl y  p us hi n g t h e s yri n g e  pl u n g er. 
•    A  3   m L s yri n g e   wit h  1. 2   m L  of st u d y  dr u g   will  b e s uffi ci e nt f or  o n e i nj e cti o n sit e.  
•    Us e t  w el v e ( 1 2)  3   m L s yri n g es (  wit h  1. 2   m L st u d y  dr u g i n  e a c h) i n  e a c h tr e at  m e nt 
ar e a ( e a c h  b utt o c k  or  e a c h t hi g h) t o  a d  mi nist er  a t ot al  of  1 2 i nj e cti o ns  of  1. 2   m L  e a c h 
(t ot al  of  1 4. 4   m L,  4  ali q u ots  of  0. 3   m L  e a c h)  at  1 2 i nj e cti o n sit es. 
•    Dis c ar d t h e  us e d  n e e dl e s a n d s yri n g es.   
•    A t ot al  of  2 4 i nj e cti o ns   will  b e  a d  mi nist er e d  a cr oss  2 tr e at  m e nt  ar e as.   
1 0. 3. 6.    
C a r e  P r o c e d u r es   Aft e r I nj e cti o n   
N  O T E:   C  C  H   is  a f or ei g n  pr ot ei n  a n d I n v esti g at ors s h o ul d  b e  pr e p ar e d t o  a d dr ess  a n d   m a n a g e  a n 
all er gi c r e a cti o n s h o ul d it  o c c ur.   At t h e ti  m e  of  e a c h i nj e cti o n,  a  1: 1, 0 0 0 s ol uti o n  of  e pi n e p hri n e 
f or i nj e cti o n,  5 0-  m g  di p h e n h y dr a  mi n e i nj e cti o n  or  a s uit a bl e  e q ui v al e nt,  a n d  o x y g e n   m ust  b e 
a v ail a bl e   wit h t h e I n v esti g at or  a n d sit e st aff   m ust  b e f a  mili ar   wit h t h eir  us e.  T o  e v al u at e t h e 
s u bj e ct f or  p ossi bl e i  m  m e di at e i  m  m u n ol o gi c al   A Es, t h e s u bj e ct   will r e  m ai n i n  dir e ct  o bs er v ati o n 
of   m e di c al  p ers o n n el   w h o  ar e s kill e d i n t h e   m a n a g e  m e nt  of  a n  all er gi c r e a cti o n f or  3 0   mi n ut es 
aft er r e c ei vi n g t h e i nj e cti o ns  of st u d y  dr u g  a n d  u ntil t h e s u bj e ct  e x hi bits  n o si g n  of  a n 
i  m  m u n ol o gi c al  or  ot h er  cli ni c all y si g nifi c a nt s yst e  mi c  or l o c al   A E.  T h e s u bj e ct’s  vit al si g ns 
s h o ul d  b e st a bl e  b ef or e t h e s u bj e ct  c a n l e a v e  dir e ct  o bs er v ati o n.  
T h e I n v esti g at or  or  q u alifi e d  d esi g n e e   will t h e n  a p pl y  a st eril e  dr essi n g t o t h e i nj e cti o n  ar e as 
wit h  h y p o all er g e ni c t a p e.  T h e s u bj e ct   will  b e i nstr u ct e d t o r e  m o v e t h e  dr essi n g i n t h e  e v e ni n g. 
1 0. 4.    
Dis c ussi o n  of  St u d y   D esi g n, I n cl u di n g t h e   C h oi c e  of   C o nt r ol   G r o u ps   
T his is  a n  e x pl or at or y st u d y t o  ass ess t h e s af et y  a n d tr e at  m e nt  eff e ct  of  diff er e nt i nj e cti o n 
t e c h ni q u es  of C  C  H   f or t h e tr e at  m e nt  of  E F P.  T h e st u d y   will  als o  e x pl or e t h e  us e  of  3-D 
p h ot o gr a p h y i n  ass essi n g  o ut c o  m es i n  E F P.   N o  c o ntr ol  gr o u ps   will  b e  e  m pl o y e d. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  2 8 
 
 
 
1 1.    
S  E  L  E  C  TI  O  N   A  N  D   WI  T  H  D  R A  W  A  L   O F  S  U  B J  E  C  T S   
1 1. 1.    
S u bj e ct I n cl usi o n   C rit e ri a  
N o s u bj e ct   will  b e  assi g n e d t o tr e at  m e nt  u ntil  all  eli gi bilit y  crit eri a  h a v e  b e e n s atisfi e d.  T o 
q u alif y f or t h e st u d y  a s u bj e ct   m ust:  
1.    B e  a bl e   t o  pr o vi d e  v ol u nt ar y   writt e n i nf or  m e d  c o ns e nt  pri or t o t h e i niti ati o n  of  a n y st u d y-
s p e cifi c  pr o c e d ur es  p er t h e  p oli c y  of t h e  g o v er ni n g 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). 
2.    B e f e  m al e  a n d  at l e ast  1 8  y e ars  of  a g e  at t h e ti  m e   of  c o ns e nt. 
3.    H a v e  e vi d e n c e  of  c ell ulit e i n  2  bil at er al tr e at  m e nt  ar e as ( d efi n e d  as ri g ht  a n d l eft  b utt o c ks 
O  R ri g ht  a n d l eft  p ost er ol at er al t hi g hs)  as  ass ess e d  b y t h e I n v esti g at or  at t h e  S cr e e ni n g 
visit,  a n d f ulfills t h e f oll o  wi n g r e q uir e  m e nts:  
a.    h as  a s c or e  of  2 (  mil d),  3 (  m o d er at e)  or  4 (s e v er e)  as r e p ort e d  b y t h e I n v esti g at or 
(  C  R-P  C S S) i n  2 tr e at  m e nt  ar e as (t  w o t hi g hs  or t  w o  b utt o c ks)  at t h e  S cr e e ni n g   Visit.  
b.    h as  at l e ast  2  di  m pl es fr o  m  e a c h tr e at  m e nt  ar e a t h at:  
−    ar e is ol at e d  a n d s e p ar at e d  b y  at l e ast  5  c  m fr o  m  a n y  ot h er  di  m pl es. 
−    s c or e  2  or  3  o n t h e   H e xs el  d e pr essi o n s c al e.  
−    h a v e  di  m pl e   wi dt h: l e n gt h r ati o  ≥  0. 5.  
4.    B e   willi n g t o  a p pl y s u ns cr e e n t o t h e  d osi n g  ar e as  b ef or e  e a c h  e x p os ur e t o t h e s u n   w hil e 
p arti ci p ati n g i n t h e st u d y (i e, s cr e e ni n g t hr o u g h  e n d  of st u d y ). 
5.    B e j u d g e d t o  b e i n  g o o d  h e alt h,  b as e d  u p o n t h e r es ults  of  a   m e di c al  hist or y,  p h ysi c al 
e x a  mi n ati o n,  a n d l a b or at or y  pr ofil e  at s cr e e ni n g. 
6.    H a v e  a  n e g ati v e s er u  m  pr e g n a n c y t est  at t h e  S cr e e ni n g   Visit  a n d  n e g ati v e  uri n e 
pr e g n a n c y  at   D a y  1 ( b ef or e i nj e cti o n  of st u d y  dr u g),  b e  usi n g  a n  eff e cti v e  c o ntr a c e pti o n 
m et h o d ( e g,  a bsti n e n c e, i ntr a ut eri n e  d e vi c e,  h or  m o n al [ estr o g e n/ pr o g esti n] 
c o ntr a c e pti v es,  or  d o u bl e  b arri er  c o ntr ol) f or  at l e ast  1   m e nstr u al  c y cl e  pri or t o st u d y 
e nr oll  m e nt  a n d t hr o u g h   D a y  7 1 ;  or  b e   m e n o p a us al  d efi n e d  as  at l e ast  1 2   m o nt hs  of 
a  m e n orr h e a i n t h e  a bs e n c e  of  ot h er  bi ol o gi c al  or  p h ysi ol o gi c al  c a us es ( as  d et er  mi n e d  b y 
t h e I n v esti g at or),  or  b e  p ostm e n o p a us al f or  at l e ast  1  y e ar,  or  b e s ur gi c all y st eril e 
( h yst er e ct o  m y,  bil at er al  o o p h or e ct o  m y,  bil at er al t u b al li g ati o n). 
7.    B e   willi n g  a n d  a bl e t o  c o  m pl y   wit h  all  pr ot o c ol r e q uir e d st u d y  visits  a n d  ass ess  m e nts.   
1 1. 2.    
S u bj e ct   E x cl usi o n   C rit e ri a  
A s u bj e ct   w h o   m e et  s a n y  of t h e f oll o  wi n g  crit eri a   will  b e  e x cl u d e d fr o  m t h e st u d y:  
1.    Is  pr e g n a nt  or is i nt e n di n g t o  b e c o  m e  pr e g n a nt  d uri n g t h e st u d y.  
2.    Is  pr es e ntl y  n ursi n g/ br e astf e e di n g  or  pr o vi di n g  br e ast   mil k. 
3.    H as  a n y  of t h e f oll o  wi n g s yst e  mi c  c o n diti o ns: 
a.    C o a g ul ati o n  dis or d er. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  2 9 
 
 
 
b.    E vi d e n c e  or  hist or y  of   m ali g n a n c y ( ot h er t h a n  e x cis e d  b as al- c ell  c ar ci n o  m a)  u nl ess 
t h er e  h as  b e e n  n o r e c urr e n c e i n  at l e ast  5  y e ars. 
c.    Hist or y  of  k el oi d al s c arri n g  or  a b n or  m al   w o u n d  h e ali n g. 
d.    C o n c urr e nt  dis e as es  or  c o n diti o ns t h at   mi g ht i nt erf er e   wit h t h e  c o n d u ct  of t h e st u d y, 
c o nf o u n d t h e i nt er pr et ati o n  of t h e st u d y r es ults,  or  e n d a n g er t h e s u bj e ct’ s w ell  - b ei n g. 
A n y  q u esti o ns  a b o ut  c o n c urr e nt  dis e as es s h o ul d  b e  dis c uss e d   wit h t h e   M e di c al 
M o nit or. 
e.    E vi d e n c e  of  cli ni c all y si g nifi c a nt  a b n or  m aliti es  o n  p h ysi c al  e x a  mi n ati o n,  vit al si g ns, 
el e ctr o c ar di o gr a  m ( E  C  G),  or  cli ni c al l a b or at or y  v al u es.  
4.    H as  a n y  of t h e   f oll o  wi n g l o c al  c o n diti o ns i n t h e  ar e as t o  b e tr e at e d: 
a.    Hist or y  of l o  w er  e xtr e  mit y t hr o  m b osis  or  p ost-t hr o  m b osis s y n dr o  m e. 
b.    V as c ul ar  dis or d er ( e g,  v ari c os e  v ei ns, t el a n gi e ct asi a).   
c.    I nfl a  m  m ati o n  or  a cti v e i nf e cti o n. 
d.    S e v er e s ki n l a xit y, fl a c ci dit y,  a n d/ or s a g gi n g.  
e.    A cti v e  c ut a n e o us  alt er ati o n i n cl u di n g r as h,  e c z e  m a,  ps ori asis,  or s ki n  c a n c er. 
5.    H as  a t att o o l o c at e d   wit hi n  2  c  m  of t h e sit e  of i nj e cti o n.   
6.    R e q uir es  a nti c o a g ul a nt  or  a nti pl at el et   m e di c ati o n  d uri n g t h e st u d y  or  h as r e c ei v e d 
a nti c o a g ul a nt  or  a nti pl at el et   m e di c ati o n ( e x c e pt f or  ≤  1 5 0   m g  as piri n  d ail y)   wit hi n  7  d a ys 
b ef or e i nj e cti o n  of st u d y  dr u g. 
7.    H as  us e d  a n y  of t h e f oll o  wi n g f or t h e tr e at  m e nt  of  E F P  o n t h e  ar e a t o  b e tr e at e d   wit hi n 
t h e ti  m eli n es i d e ntifi e d  b el o  w  or i nt e n ds t o  us e  a n y  of t h e f oll o  wi n g  at  a n y ti  m e  d uri n g 
t h e  c o urs e  of t h e st u d y: 
a.    Li p os u cti o n   wit hi n t h e tr e at  m e nt  ar e as  d uri n g t h e  1 2-  m o nt h  p eri o d  b ef or e i nj e cti o n  of 
st u d y  dr u g. 
b.    I nj e cti o ns ( e g,   m es ot h er a p y); r a di ofr e q u e n c y  d e vi c e tr e at  m e nts; l as er tr e at  m e nt;  or 
s ur g er y (i n cl u di n g s u b cisi o n  a n d/ or  p o  w er e d s u b cisi o n)   wit hi n t h e tr e at  m e nt  ar e as 
d uri n g t h e  1 2-  m o nt h  p eri o d  b ef or e i nj e cti o n  of st u d y  dr u g. 
c.    A n y i n v esti g ati o n al tr e at  m e nt f or  E F P/ c ell ulit e  o n tr e at  m e nt  ar e as  d uri n g t h e 
1 2-  m o nt h  p eri o d  b ef or e t h e i nj e cti o n  of st u d y  dr u g. 
d.    E n d er  m ol o gi e ®  or si  mil ar tr e at  m e nts   wit hi n t h e tr e at  m e nt  ar e as  d uri n g t h e  6 -  m o nt h 
p eri o d  b ef or e i nj e cti o n  of st u d y  dr u g. 
e.    M ass a g e t h er a p y   wit hi n t h e tr e at  m e nt  ar e as  d uri n g t h e  3  -  m o nt h  p eri o d  b ef or e 
i nj e cti o n  of st u d y  dr u g. 
f.   Cr e a  ms ( e g,   C ell u v er a ™,  Tri L asti n® ) t o  pr e v e nt  or   miti g at e  E F P   wit hi n t h e tr e at  m e nt 
ar e as  d uri n g t h e  2 -  w e e k  p eri o d  b ef or e i nj e cti o n  of st u d y  dr u g. 
8.    H as r e c ei v e d  a n i n v esti g ati o n al  dr u g  or tr e at  m e nt   wit hi n  3 0  d a ys  b ef or e i nj e cti o n  of st u d y 
dr u g. 
9.    H as  a  k n o  w n s yst e  mi c  all er g y t o  c oll a g e n as e  or  a n y  ot h er  e x ci pi e nt   of st u d y  dr u g. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 0 
 
 
 
1 0.  H as  a  hist or y  of  dr u g  or  al c o h ol  a b us e. 
1 1.  I nt e n ds t o i niti at e  a n i nt e nsi v e s p ort  or  e x er cis e  pr o gr a  m  d uri n g t h e st u d y. 
1 2.  I nt e n ds t o i niti at e  a   w ei g ht r e d u cti o n  pr o gr a  m  d uri n g t h e st u d y. 
1 3.  I nt e n ds t o  us e t a n ni n g s pr a y  or t a n ni n g  b o ot hs  d uri n g t h e st u d y. 
1 4.  H as  pr e vi o usl y r e c ei v e d  a n y  c oll a g e n as e tr e at  m e nts ( e g,  S a nt yl ®   oi nt  m e nt  a n d/ or 
XI  A F L E  X/  XI  A P E  X ® ). 
1 5.  W as  a s u bj e ct i n  a  pr e vi o us  c ell ulit e  cli ni c al tri al  of   C  C  H  :   A  U  X-C  C  - 8 3 0,   A  U  X-C  C  - 8 3 1, 
E  N 3 8 3 5- 1 0 2,  E  N 3 8 3 5- 1 0 4,  E  N 3 8 3 5- 2 0 1,  E  N 3 8 3 5- 2 0 2,  E  N 3 8 3 5- 2 0 5,  E  N 3 8 3 5- 3 0 2,  or 
E  N 3 8 3 5- 3 0 3. 
1 6.  H as  a n y    ot h er  c o n diti o n(s) t h at, i n t h e I n v esti g at or’s  o pi ni o n,   mi g ht i n di c at e t h e s u bj e ct is 
u ns uit a bl e f or t h e st u d y. 
1 1. 3.    
S u bj e ct   Dis c o nti n u ati o n   C rit e ri a  
A  pr e  m at ur e  dis c o nti n u ati o n   will  o c c ur   w h e n  a s u bj e ct   w h o si g n e d i nf or  m e d  c o ns e nt  c  e as es 
tr e at  m e nt  a n d/ or  p arti ci p ati o n i n t h e st u d y, r e g ar dl ess  of  cir c u  mst a n c es,  pri or t o t h e  c o  m pl eti o n 
of t h e  pr ot o c ol.  S u bj e cts  c a n  b e  pr e  m at ur el y  dis c o nti n u e d fr o  m t h e st u d y f or  a n y  of t h e f oll o  wi n g 
r e as o ns: 
•    A n  a d v ers e  e v e nt.   
•    A  pr ot o c ol  vi ol ati o n   (r e as o n   m ust  b e s p e cifi e d, f or  e x a  m pl e: l a c k  of  c o  m pli a n c e   wit h 
pr ot o c ol r e q uir e d st u d y  visits/ ass ess  m e nts,  us e  of  a  pr o hi bit e d  c o n c o  mit a nt 
m e di c ati o n,  et c).   
•    Wit h dr a  w al  b y s u bj e ct (r e as o n   m ust  b e s p e cifi e d). 
•    T h e s u bj e ct   w as  “ l ost t o f oll o  w- u p ”. 
•    Ot h er r e as o  ns (r e as o n   m ust  b e s p e cifi e d, f or  e x a  m pl e: t h e s u bj e ct   m o v e d,  pr e g n a n c y, 
i n v esti g at or  d e cisi o n,  S p o ns or  d e cisi o n t o t er  mi n at e tri al,  et c). 
S u bj e cts   w h o  dis c o nti n u e,  or  ar e   wit h dr a  w n fr o  m st u d y  tr e at  m e nt f or  a n y r e as o n,   will  b e 
e n c o ur a g e d t o  c o  m pl et e t h e r e  m ai ni n g st u d y  visits  a n d  ass ess  m e nts  a n d  pr o vi d e  a n y  a d diti o n al 
f oll o  w- u p i nf or  m ati o n  as r e q uir e d  b y t h e st u d y,  u nl ess t h e s u bj e ct s p e cifi c all y i n di c at es t h at t h e y 
will  n ot  p arti ci p at e i n  a n y f urt h er  e v al u ati o ns.  T h e  d at e  a s u bj e ct  dis c o nti n u es fr o  m t h e tr e at  m e nt 
a n d/ or st u d y  a n d t h e r e as o n f or  dis c o nti n u ati o n   will  b e r e c or d e d i n t h e s o ur c e  d o c u  m e nt ati o n  a n d 
El e ctr o ni c   C as e   R e p ort  F or  m ( e  C  R F).  
1 1. 3. 1.    
R e pl a c e  m e nt  P r o c e d u r es   
S u bj e cts   w h o  dis c o nti n u e fr o  m tr e at  m e nt  a n d/ or   w h o  dis c o nti n u e fr o  m  t h e st u d y   will  n ot  b e 
r epl a c e d.  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 1 
 
 
 
1 2.    
T  R  E  A  T  M  E  N  T   O F  S  U  B J  E  C  T  S 
1 2. 1.    
St u d y   Visits  
T h e  S c h e d ul e  of  E v e nts t o  b e  p erf or  m e d  at  e a c h st u d y  visit is s h o  w n i n  S e cti o n    5. Pr o vi d e d 
b el o  w  ar e f urt h er  d et ails   w h er e  a d diti o n al i nstr u cti o n  a b o ut t h e  ass ess  m e nts t h at   will  b e 
p erf or  m e d is  d e e  m e d t o  b e  n e e d e d.  
1 2. 1. 1.    
S u bj e ct  S c r e e ni n g   
I n v esti g at ors   will  b e  e xp e ct e d t o   m ai nt ai n  a  S cr e e ni n g  L o g  of  all  p ot e nti al st u d y s u bj e cts.  T his 
l o g   will i n cl u d e li  mit e d i nf or  mati o n  a b o ut t h e  p ot e nti al s u bj e ct  a n d t h e  d at e  a n d  o ut c o  m e  of t h e 
s cr e e ni n g  pr o c ess ( e g,  e nr oll e d i nt o t h e st u d y, r e as o n f or i n eli gi bilit y,  or r ef us e d t o  p arti ci p at e). 
I n v esti g at ors   will  pr o vi d e i nf or  m ati o n  a b o ut t h e st u d y t o s u bj e cts   w h o  a p p e ar t o   m e et t he  crit eri a 
f or  p arti ci p ati o n i n t h e st u d y.  
1 2. 1. 2.    
S c r e e ni n g   Ass ess  m e nts  
Aft er  o bt ai ni n g i nf or  m e d  c o ns e nt, t h e f ull  ass ess  m e nt  of  eli gi bilit y   will  b e  c o n d u ct e d  a n d  pri or t o 
st u d y  e ntr y, s cr e e ni n g  ass ess  m e nts   will  b e  p erf or  m e d  a c c or di n g t o t h e s c h e d ul e  of  e v e nts i n 
S e cti o n  5.   
1 2. 1. 3.    
D e  m o g r a p hi c   D at a 
T h e f oll o  wi n g  d e  m o gr a p hi c i nf or  m ati o n   will  b e r e q uir e d f or st u d y  e ntr y:  
•    D at e  of  birt h. 
•    G e n d er.   
•    R a c e  a n d  et h ni cit y.   
1 2. 1. 4.    
M e  di c al/ S u r gi c al/  E F P   Hist o r y  
D uri n g t h e s cr e e ni n g  p eri o d, t h e I n v esti g at or  or  q u alifi e d  d esi g n e e   will  o bt ai n  a   m e di c al  a n d 
s ur gi c al  hist or y fr o  m  e a c h s u bj e ct t h at i n cl u d es r el e v a nt  di a g n os es  a n d/ or  pr o c e d ur es/t h er a pi es 
wit h  o ns et/r es ol uti o ns  d at es.   M e di c al  h  ist ori es s h o ul d  als o i n cl u d e  hist or y  of  E F P (st art  d at e, 
f a  mil y  hist or y,  a n d  pri or tr e at  m e nt),  a n d  hist or y  of t o b a c c o  a n d  al c o h ol  us e ( n e v er,  c urr e nt, 
f or  m er). 
1 2. 2.    
P ri o r  a n d   C o n c o  mit a nt   M e di c ati o ns  a n d  P r o c e d u r es   
All  pri or   m e di c ati o ns t a k e n   wit hi n  9 0  d a ys  b ef or e   D a y  1   will  b e r e c or d e d.   All   m e di c ati o ns 
(i n cl u di n g  o v er-t h e- c o u nt er   m e di c ati o ns) t a k e n  b y t h e s u bj e ct  o n   D a y  1 t hr o u g h t h e  e n d  of t h e 
st u d y   m ust  b e r e c or d e d. I n  a d diti o n,  all  pri or tr e at  m e nts (  m e di c ati o ns  o r  pr o c e d ur es) f or  E F P 
m ust  b e r e c or d e d.  
A d diti o n all y,  a n y  di a g n osti c, t h er a p e uti c  or s ur gi c al  pr o c e d ur es  p erf or  m e d  d uri n g t h e st u d y 
p eri o d s h o ul d  b e r e c or d e d i n cl u di n g t h e  d at e, i n di c ati o n f or,  a n d  d es cri pti o n  of t h e  pr o c e d ur e. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 2 
 
 
 
1 2. 2. 1.    
P r o hi bit e d   M e di c ati o ns  a n d  P r o c e d u r es  
T h e f oll o  wi n g   m e di c ati o ns  a n d  pr o c e d ur es  ar e  pr o hi bit e d f or s u bj e cts  d uri n g t h e st u d y:  
•    A nti c o a g ul a nts (  w arf ari n,  h e p ari n,  dir e ct t hr o  m bi n i n hi bit ors,  F a ct or   X i n hi bit ors)  a n d 
a nti pl at el et  a g e nts ( as piri n  >   1 5 0   m g/ d a y  a n d  P 2  Y 1 2 i n hi bit ors, s u c h  as  cl o pi d o gr el), 
w hi c h  c a n  c a us e  a d diti o n al  br uisi n g.   H o  w e v er, t h e  us e  of  as piri n  at  a  d os e l e v el  of 
≤   1 5 0   m g  p er  d a y   will  b e  p er  mitt e d  d uri n g st u d y. 
•    Li p os u cti o n   wit hi n t h e tr e at  m e nt  ar e as.  
•    I nj e cti o ns ( e g,   m es ot h er a p y); r a di ofr e q u e n c y  d e vi c e tr e at  m e nts; l as er tr e at  m e nt;  or 
s ur g er y (i n cl u di n g s u b cisi o n  a n d/ or  p o  w er e d s u b cisi o n)  i n t h e tr e at  m e nt  ar e as. 
•    A n y i n v esti g ati o n al tr e at  m e nt f or  E F P/ c ell ulit e  o n tr e at  m e nt  ar e as  or  a n y  ot h er 
i n v esti g ati o n al  dr u g  or tr e at  m e nt.  
•    E n d er  m ol o gi e  or si  mil ar tr e at  m e nts   wit hi n t h e tr e at  m e nt  ar e as.  
•    M ass a g e t h er a p y   wit hi n t h e tr e at  m e nt  ar e as  d uri n g t h e  3  -  m o nt h  p eri o d  b ef or e 
i nj e cti o n  of st u d y  dr u g. 
•    Cr e a  ms ( e g,   C ell u v er  a ,  Tri L asti n)   wit hi n t h e tr e at  m e nt  ar e as. 
1 2. 3.    
T r e at  m e nt   C o  m pli a n c e   
S u bj e cts   will r e c ei v e st u d y  dr u g  a d  mi nist er e d  b y t h e  I n v esti g at or  at t h e I n v esti g at or’s sit e. 
A c ci d e nt al  or i nt e nti o n al  o v er d os es s h o ul d  b e r e p ort e d t o t h e  S p o ns or/ d esi g n e e  pr o  m ptl y. 
1 2. 4.    
Bli n di n g  a n d   R a n d o  mi z ati o n   
T his st u d y   will  b e  c o n d u ct e d  as  a n  o p e n- l a b el i n v esti g ati o n;  n o  bli n di n g  of  assi g n e d tr e at  m e nt 
wil  l  o c c ur.  S u bj e cts   will  b e s e q u e nti all y  assi g n e d t o  Tre at  m e nt   A r  ms   A t o  E  at   D a y  1. 
1 2. 5.    
S el e cti n g  a n d   M a r ki n g   Di  m pl es  
If  all  4  q u a dr a nts ( b ot h  b utt o c ks  a n d  b ot h t hi g hs)   m e et  e ntr y  crit eri a f or  a si n gl e s u bj e ct, t h e 
t hi g hs   will  b e tr e at e d.   N o s u bj e ct   will  h a v e tr e at  m e nt i n  all  4  q u a dr a nts ( b ot h  b utt o c ks  a n d  b ot h 
t hi g hs)  d uri n g t his st u d y. 
S el e cti o n  of  di  m pl es t o  b e tr e at e d i n t h e tr e at  m e nt  ar e as ( b ot h  b utt o c ks  or  b ot h t hi g hs) is  at t h e 
dis cr eti o n  of t h e i n v esti g at or.   Di  m pl es   m ust  b e   w ell  d efi n e d,  e vi d e nt   w h e n t h e s u bj e ct is st a n di n g 
i n  a  c o nsist e nt, st a n d ar di z e d r el a x e d  p os e (  wit h o ut t h e  us e  of  a n y   m a ni p ul ati o n s u c h  as s ki n 
pi n c hi n g  or   m us cl e  c o ntr a cti o n),  a n d s uit a bl e f or tr e at  m e nt.  E a c h s u bj e ct   will r e c ei v e  3 tr e at  m e nt 
visits  of st u d y  dr u g  u nl ess t h e tr e at  m e nt  ar e a is  di  m pl e -fr e e  at   D a y  2 2  a n d/ or   D a y  4 3.   A  di  m pl e-
fr e e  b utt o c k  or t hi g h  at   D a y 1 is  pr e cl u d e d  b y t h e  eli gi bilit y  crit eri a.   A  di  m pl e-fr e e  b utt o c k or 
t hi g h  at   D a y  2 2  a n d/ or   D a y  4 3  d o es  n ot  pr e cl u d e tr e at  m e nt  of t h e  c o ntr al at er al  b utt o c k  or t hi g h 
u nl ess it is  als o  di  m pl e -fr e e.  
D et ail e d i nstr u cti o ns f or t h e   m ar ki n g  a n d   i  m a gi n g  of  di  m pl es   will  b e  pr o vi d e d i n t h e  3-D 
P h ot o gr a p h y   M a n u al. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 3 
 
 
 
1 2. 6.    
C  R  -P  C S S  
T h e   C  R -P  C S S  -   B utt o c k (A p p e n di x   A  )  a n d t h e   C  R-P  C S S  -  T hi g h (A p p e n di x   B  )   will  b e  us e d t o 
ass ess t h e s e v erit y  of  c ell ulit e  of  b ot h tr e at  m e nt  ar e as  at  S cr e e ni n g ( e a c h  b utt o c k  or  e a c h t hi g h 
i n d e p e n d e ntl y).  T h e s c al e is  a  5-l e v el  p h ot o n u  m eri c s c al e  d e v el o p e d s p e cifi c all y f or  cli ni ci a ns 
a n d  us e d  b y t h e I n v esti g at or t o  ass ess t h e s e v erit y  of t h e s u bj e ct’ s  c ell ulit e i n  e a c h  b utt o c k  or 
t hi g h  b y li v e  ass ess  m e nts.  T h e r ati n gs r a n g e fr o  m  0 (  N o n e) t o  4 ( S e v er e)   wit h l a b els  a n d 
d es cri pt ors t o  ai d t h e I n v esti g at or i n t h e  ass ess  m e nts.  T his  ass ess  m e nt s h o ul d  b e   m a d e   w hil e t h e 
s u bj e ct is i n t h e st a n di n g  p ositi o n   wit h r el a x e d  gl ut e us   m us cl es . 
I n v esti g at ors   will  b e tr ai n e d  a n d  q u alifi e d  o n t h e  us e  of t h e   C  R-P  C S S  pri or t o  ass essi n g  a n y 
s u bj e cts. 
1 3.    
A S S  E S S  M  E  N  T   O F   E F FI  C  A  C  Y   
1 3. 1.    
3- D  P h ot o g r a p h y   
Alt h o u g h  3-  D  p h ot o gr a p hs  ar e  n ot  dir e ct  effi c a c y   m e as ur e  m e nts,  3  -  D  p h ot o gr a p h y   will  b e 
utili z e d i n t h e  ass ess  m e nt  of tr e at  m e nt  eff e ct.  T h e I n v esti g at or  or  q u alifi e d  d esi g n e e   will 
p h ot o gr a p h  e a c h tr e at  m e nt  ar e a ( e a c h  b utt o c k  or  e a c h  t hi g h)  usi n g  a  S p o ns or-s u p pli e d 
st a n d ar di z e d  3-  D  c a  m er a i n  a st a n d ar di z e d   m a n n er.  T h e s u bj e ct   will  b e st a n di n g f or  e a c h 
p h ot o gr a p h y s essi o n  a n d   will  b e   w e ari n g  a st a n d ar di z e d  p h ot o gr a p hi c  g ar  m e nt  as  d es cri b e d i n 
t h e  3-  D  P h ot o gr a p h y   M a n u al.  T h e I n v esti g at or  or  q u alifi e d  d esi g n e e   will  p h ot o gr a p h  e a c h  of t h e 
2 tr e at  m e nt  ar e as ( 2   b utt o c ks  or  2 t hi g hs)   w hil e t h e s u bj e ct is st a n di n g i n  a  c o nsist e nt, 
st a n d ar di z e d r el a x e d  p os e.  
O n  e a c h tr e at  m e nt  d a y (  D a y    1,   D a y  2 2,  a n d   D a y  4 3),  3-  D  p h ot o gr a p hs   will  b e t a k e n  b ef or e  a n d 
aft er   m ar ki n g  di  m pl es  a n d i nj e cti o n sit es.   At s cr e e ni n g  a n d  all  ot h er st u d y  visit  d a ys,  a si n gl e s et 
of  p h ot o gr a p hs   will  b e t a k e n.  3-  D  p h ot o gr a p hs   will  b e t a k e n  pri or t o  pri or t o st u d y  dr u g  d osi n g. 
F or  3 -  D  p h ot o gr a p hi c i  m a g es t a k e n  o n   D a ys  4,  8,  1 5,  2 2,  4 3,  a n d  7 1,  a  c e ntr al  ass ess or  bli n d e d t o 
t h e tr e at  m e nt  ar  m  a n d st u d y  visit  d a y   will  c o  m pl et e  a  5-p oi nt  Li k ert s c al e t o  g a u g e t h e l e v e l  of 
a est h eti c i  m pr o v e  m e nt  a c hi e v e d (fr o  m  b as eli n e) i n  e a c h tr e at  m e nt  ar e a.   
All  d e  -i d e ntifi e d  p h ot o gr a p hs fr o  m t his st u d y  ar e t h e  pr o p ert y  of  E n d o  a n d   m a y  b e  utili z e d f or 
cli ni c al  d e v el o p  m e nt, s ci e ntifi c  c o  m  m u ni c ati o n,   m ar k eti n g, r e g ul at or y  p ur p os es,  a n d/ or l e g al 
a p pli c ati o ns  as r e q uir e d/ d esir e d  b y  E n d o. 
1 3. 2.    
H e xs el   D e p r essi o n   D e pt h  S c al e   
T h e   H e xs el   C ell ulit e  S e v erit y  S c al e (  H e xs el   C S S) is  a  p h ot o n u  m eri c s c al e t h at l o o ks  at  5  k e y 
m or p h ol o gi c f e at ur es  of  c ell ulit e: (  A)  n u  m b er  of  e vi d e nt  d e pr essi o ns, (  B)  d e pt h  of  d e pr essi o ns, 
(  C)   m or p h ol o gi c al  a p p e ar a n c e  of s ki n s urf a c e  alt er ati o ns, (  D) l a xit y, fl a c ci dit y  or s a g gi n g  of 
s ki n,  a n d ( E)  c urr e nt  cl assifi c ati o n s c al e  b as e d  o n   m e di c al lit er at ur e  (H e xs el  et  al,  2 0 0  9;  
N ür n b er g er  a n d   M üll er,  1 9 7 8  ). E a c h  of t h es e f e at ur es is  e v al u at e d  o n  a  4 -p oi nt s c al e fr o  m  a l o  w 
of  0 t o  a  hi g h  of  3.  F or t his st u d y,  o nl y (  B)  d e pt h  of  d e pr essi o ns   will  b e  ass ess e d. 
T h e  I n v esti g at or  or  q u alifi e d  d esi g n e e   will i n d e p e n d e ntl y  us e t h e   H e xs el   C S S (  B)  d e pt h  of 
d e pr essi o ns i n  ass ess t h e s e v erit y  of  E F P i n  e a c h  b utt o c k  or  e a c h t hi g h ( s e e A p p e n di x   C  ).  T his 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 4 
 
 
 
ass ess  m e nt s h o ul d  b e   m a d e   w hil e t h e s u bj e ct is i n t h e st a n di n g  p ositi o n   wit h r el a x e d  gl ut e us 
m us cl es.   
1 4.    
A S S  E S S  M  E  N  T   O F  S  A F  E  T  Y   
1 4. 1.    
D efi niti o ns   
1 4. 1. 1.    
A d v e rs e   E v e nts   
A n   A E   is  a n y  u nf a v or a bl e  or  u ni nt e n d e d  c h a n g e i n  b o d y str u ct ur e (si g ns),  b o d y f u n cti o n 
(s y  m pt o  ms), l a b or at or y r es ult ( e g,  c h e  mistr y,  E  C  G,   X-r a y,  et c),  or   w ors e ni n g  of  a  pr e-e xisti n g 
c o n diti o n  ass o ci at e d t e  m p or all y   wit h t h e  us e  of t h e st u d y   m e di c ati o n   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 st u d y   m e di c ati o n.   A d v ers e  e v e nts   will  b e  c a pt ur e d  o n c e  a s u bj e ct  h as si g n e d t h e 
i nf or  m e d  c o ns e nt.   A Es i n cl u d e: 
•    C h a n g es i n t h e  g e n er al  c o n diti o n  of t h e s u bj e ct 
•    S u bj e cti v e s y  m pt o  ms  off er e d  b y  or  eli cit e d fr o  m t h e s u bj e ct 
•    O bj e ct  i v e si g ns  o bs er v e d  b y t h e I n v esti g at or  or  ot h er st u d y  p ers o n n el 
•    All  c o n c urr e nt  dis e as es t h at  o c c ur  aft er t h e st art  of t h e st u d y, i n cl u di n g  a n y  c h a n g e i n 
s e v erit y  or fr e q u e n c y  of  pr e- e xisti n g  dis e as e  
•    All  cli ni c all y r el e v a nt l a b or at or y  a b n or  m aliti es  or  p h ysi  c al fi n di n gs t h at  o c c ur  d uri n g 
t h e st u d y 
A tr e at  m e nt  -e  m er g e nt   A E ( T E  A E) is  a n y  c o n diti o n t h at   w as  n ot  pr es e nt  pri or t o tr e at  m e nt   wit h 
st u d y   m e di c ati o n  b ut  a p p e ar e d f oll o  wi n g tr e at  m e nt,   w as  pr es e nt  at tr e at  m e nt i niti ati o n  b ut 
w ors e n e d  d uri n g tr e at  m e nt,  or   w as  pr es e nt  at tr e at  m e nt i niti ati o n  b ut r es ol v e d  a n d t h e n 
r e a p p e ar e d   w hil e t h e i n di vi d u al   w as  o n tr e at  m e nt (r e g ar dl ess  of t h e i nt e nsit y  of t h e   A E   w h e n t h e 
tr e at  m e nt   w as i niti at e d). 
All   A Es, i n cl u di n g  b ot h  o bs er v e d  or  v ol u nt e er e d  pr o bl e  ms,  c o  m pl ai nts, si g ns   or s y  m pt o  ms   m ust 
b e r e c or d e d  o n t h e   A E  p a g e  of t h e  e  C  R F, r e g ar dl ess  of   w h et h er  ass o ci at e d   wit h t h e  us e  of st u d y 
m e di c ati o n.  T his   w o ul d i n cl u d e   A Es r es ulti n g fr o  m  c o n c urr e nt ill n ess, r e a cti o ns t o  c o n c urr e nt 
m e di c ati o n  us e,  or  pr o gr essi o n  of  dis e as e st at es ( e x cl u di n g t h e  dis e as e  u n d er st u d y).   A  c o n diti o n 
pr es e nt  at  b as eli n e t h at   w ors e ns  aft er i niti ati o n  of st u d y tr e at  m e nt   will  b e  c a pt ur e d  as  a n   A E; t h e 
o ns et  d at e   will  b e t h e  d at e t h e  e v e nt   w ors e n e d.  T h e   A E s h o ul d  b e r e c or d e d i n st a n d ar d   m e di c al 
t er  mi n ol o g y   w he n  p ossi bl e. 
1 4. 1. 2.    
S e ri o us   A d v e rs e   E v e nts  
A s eri o us  a d v ers e  e v e nt ( S  A E) is  d efi n e d  as  a n   A E t h at:   
•    R es ults i n  d e at h   
•    Is i  m  m e di at el y lif e-t hr e at e ni n g (t h er e is  a n i  m  m e di at e ris k  of  d e at h fr o  m t h e   A E  as it 
o c c urr e d; t his  d o es  n ot i n cl u d e  a n   A E t h at  h a d it  o c c urr e d i n  a   m or e s eri o us f or  m   m a y 
h a v e  c a us e d  d e at h) 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 5 
 
 
 
•    R es ults i n  or  pr ol o n gs  a n i n p ati e nt  h os pit ali z ati o n (  N ot e:  a  h os pit ali z ati o n f or  el e cti v e 
or  pr e - pl a n n e d s ur g er y,  pr o c e d ur e,  or  dr u g t h er a p y  d o es  n ot  c o nstit ut e  a n  S  A E)  
•    R es ults i n  p er  m a n e nt  or s u bst a nti al  dis a bilit y ( p er  m a n e nt  or s u bst a nti al  disr u pti o n  of 
o n e’ s  a bilit y t o  c o n d u ct  n or  m al lif e f u n cti o ns)   
•    Is  a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct (i n  offs pri n g  of  a s u bj e ct  usi n g t h e st u d y 
m e di c ati o n r e g ar dl ess  of ti  m e t o  di a g n osis)   
•    Is  c o nsi d er e d  a n i  m p ort a nt   m e di c al e v e nt  
I  m p ort a nt   m e di c al  e v e nts  ar e  d efi n e d  as  e v e nts t h at,  b as e d  u p o n  a p pr o pri at e   m e di c al j u d g  m e nt, 
m a y j e o p ar di z e t h e s u bj e ct  a n d   m a y 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  o n e  of t h e 
ot h er s eri o us  o ut c o  m es.  E x a  m pl es  of i  m p ort a nt   m e di c al  e v e nts i n cl u d e  all er gi c  br o n c h os p as  m 
r e q uiri n g i nt e nsi v e tr e at  m e nt i n  a n  e  m er g e n c y r o o  m  or  at  h o  m e,  bl o o d  d ys cr asi as  or  c o n v ulsi o ns 
t h at  d o  n ot r es ult i n i n p ati e nt  h os pit ali z ati o n,  or t h e  d e v el o p  m e nt  of  dr u g  d e p e n d e n c y  or  dr u g 
a b us e.  
1 4. 2.    
M o nit o ri n g   A d v e rs e   E v e nts   
At  e a c h st u d y  visit, s u bj e cts   will  b e  q u eri e d r e g ar di n g  a n y   A Es t h at  h a v e  o c c urr e d si n c e t h e l ast 
st u d y  visit.  S u bj e cts   will  b e  as k e d t o  v ol u nt e er i nf or  m ati o n  c o n c er ni n g   A Es   wit h  a  n o n- l e a di n g 
q u esti o n s u c h  as,  “  H o  w  d o  y o u f e el ? ”  St u d y  c e nt er   p ers o n n el   will t h e n r e c or d  all  p erti n e nt 
i nf or  m ati o n i n t h e s o ur c e  d o c u  m e nts  a n d t h e  e  C  R F.  T h e st u d y  dr u g  c o  m pli a n c e r e c or d s h o ul d 
als o  b e r e vi e  w e d t o  d et e ct  p ot e nti al  o v er d os es (i nt e nti o n al/ u ni nt e nti o n al). 
1 4. 3.    
R el ati o ns hi p t o  St u d y   D r u g   
T h e  d e gr e e  of  “ r el at e d n ess”  of t h e   A E t o t h e st u d y   m e di c ati o n   m ust  b e  d es cri b e d  usi n g t h e 
f oll o  wi n g s c al e:  
•    N ot  r el at e d   i n di c at es t h at t h e   A E is  d efi nit el y  n ot r el at e d t o t h e st u d y   m e di c ati o n. 
•    U nli k el y  r el at e d   i n di c at es t h at t h er e  ar e  ot h er,   m or e li k el y  c a us es  a n d st u d y 
m e di c ati o n is  n ot s  us p e ct e d  as  a  c a us e.  
•    P ossi bl y  r el at e d  i n di c at es t h at  a  dir e ct  c a us e  a n d  eff e ct r el ati o ns hi p  b et  w e e n st u d y 
m e di c ati o n  a n d t h e   A E  h as  n ot  b e e n  d e  m o nstr at e d,  b ut t h er e is  e vi d e n c e t o s u g g est 
t h er e is  a r e as o n a bl e  p ossi bilit y t h at t h e  e v e nt   w as  c a us e d  b y t h e st u d y   m e di c ati o n. 
•    P r o b a bl y  r el at e d  i n di c at es t h at t h er e is  e vi d e n c e s u g g esti n g  a  dir e ct  c a us e  a n d  eff e ct 
r el ati o ns hi p  b et  w e e n t h e   A E  a n d t h e st u d y   m e di c ati o n. 
It is t h e  S p o ns or’s  p oli c y t o  c o nsi d er  “Pr o b a bl y r el at e d ”  a n d  “ P ossi bl y r el at e d ”  c a us alit y 
ass ess  m e nts  as  p ositi v e  c a us alit y.  “ N ot r el at e d  ”  a n d  “ U nli k el y r el at e d  ”  c a us alit y  ass ess  m e nts  ar e 
c o nsi d er e d  as  n e g ati v e  c a us alit y.  
Ass ess  m e nts   will  b e r e c or d e d  o n t h e  e  C  R F  a n d   m ust i n di c at e  cl e arl y t h e r el ati o ns hi p  b ei n g 
ass ess e d.  F or  e x a  m pl e,  a n   A E t h at  a p p e ars  d uri n g  a  pl a c e b o r u n-i n  p h as e   w o ul d  b e  ass ess e d   wit h 
r es p e ct t o t h e  pl a c e b o tr e at  m e nt r e c ei v e d  a n d/ or st u d y  pr o c e d ur es  c o n d u ct e d  d uri n g t his  p h as e. If 
t h e   A E  c o nti n u e d i nt o  a n  a cti v e tr e at  m e nt  p h as e, t h e r el ati o ns hi p   w o ul d  b e  ass ess e d f or t h e  a cti v e 
tr e at  m e nt  p h as e  o nl y if t h e   A E   w ors e n e d. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 6 
 
 
 
1 4. 4.    
I nt e nsit y   Ass ess  m e nt  
T h e i nt e nsit y ( or s e v erit y)  of   A Es is  c h ar a ct eri z e d  as   mil d,   m o d er at e,  or s e v er e:   
•    Mil d     A Es  ar e  us u all y tr a nsi e nt, r e q uiri n g  n o s p e ci al tr e at  m e nt,  a n d  d o  n ot i nt erf er e 
wit h t h e s u bj e  ct ’s  d ail y  a cti viti es. 
•    M o d e r at e     A Es i ntr o d u c e  a l o  w l e v el  of i n c o n v e ni e n c e  or  c o n c er n t o t h e s u bj e ct  a n d 
m a y i nt erf er e   wit h  d ail y  a cti viti es,  b ut  ar e  us u all y  a  m eli or at e d  b y si  m pl e t h er a p e uti c 
m e as ur es.   
•    S e v e r e    A Es i nt err u pt  a s u bj e ct’s  us u al  d ail y  a cti vit y  a n d t y pi c all y r e q uir e s yst e  mi c 
dr u g t h er a p y  or  ot h er tr e at  m e nt. 
1 4. 5.    
R e p o rti n g   A d v e rs e   E v e nts  a n d  S e ri o us   A d v e rs e   E v e nts   
1 4. 5. 1.    
R e p o rti n g   A d v e rs e   E v e nts   
T hr o u g h o ut t h e st u d y,   A Es   will  b e  d o c u  m e nt e d  o n t h e s o ur c e  d o c u  m e nt  a n d  o n t h e  a p pr o pri at e 
p a g e  of t h e  e  C  R F   w h et h er  or  n ot  c o nsi d er e d tr e at  m e nt-r el at e d.  T his i n cl u d es  a n y  n e  w si g ns, 
s y  m pt o  ms, i nj ur y  or ill n ess, i n cl u di n g i n cr e as e d s e v erit y  of  pr e vi o usl y  e xisti n g si g ns, s y  m pt o  ms, 
i nj ur y,  or ill n ess.   C o n diti o ns  e xisti n g  pri or t o s cr e e ni n g   will  b e r e c or d e d  as  p art  of t h e s u bj e ct ’s 
m e di c al  hist or y.  T h e I n v esti g at or is r es p o nsi bl e f or  ass essi n g t h e r el ati o ns hi p  of   A Es t o t h e st u d y 
m e di c ati o n; r el ati o ns hi p   will  b e  cl assifi e d  as  n ot r el at e d,  u nli k el y r el at e d,  p ossi bl y r el at e d,  or 
pr o b a bl y r el at e d.   
All   A Es   will  b e  c oll e ct e d  b y   t h e I n v esti g at or fr o  m t h e ti  m e  of si g ni n g t h e i nf or  m e d  c o ns e nt 
t hr o u g h  2 8  d a ys  aft er t h e l ast  d os e  of st u d y   m e di c ati o n; t his i n cl u d es  a n y   A Es t h at  ar e  o n g oi n g  at 
t h e ti  m e  of  c o  m pl eti o n/t er  mi n ati o n  of t h e st u d y.   All  o n g oi n g   A Es   m ust  b e f oll o  w e d  u ntil 
r es ol uti o n  or f or  2 8  d a ys  aft er t h e s u bj e ct’s l ast st u d y  visit,   w hi c h e v er  c o  m es first.  
1 4. 5. 2.    
R e p o rti n g  S e ri o us   A d v e rs e   E v e nts   
A n y  S  A E, i n cl u di n g  d e at h r es ulti n g fr o  m  a n y  c a us e,   w hi c h  o c c urs t o  a n y s u bj e ct  p arti ci p ati n g i n 
t his st u d y,   m ust  b e r e p ort e d  vi a  e  m ail  or f a x  b y t h e I n v esti g at or  usi n g t h e  E n d o  S eri o us   A d v ers e 
E v e nt ( S  A E)/  R e p ort a bl e  E v e nt  F or  m   wit hi n  2 4  h o urs  of first  b e c o  mi n g  a  w ar e  of t h e  S  A E.  S  A Es 
will  b e  c oll e ct e d  b y t h e I n v esti g at or fr o  m t h e ti  m e  of si g ni n g t h e i nf or  m e d  c o ns e nt t hr o u g h  2 8 
d a ys  aft er t h e l ast  d os e  of st u d y   m e di c ati o n.  S  A Es t h at  o c c ur   wit hi n  2 8  d a ys, f oll o  wi n g  c ess ati o n 
of t h e st u d y tr e at  m e nt,  or   wit hi n  2 8  d a ys, f oll o  wi n g  pr e  m at ur e  dis c o nti n u ati o n fr o  m t h e st u d y f or 
a n y r e as o n,   m ust  als o  b e r e p ort e d   wit hi n t h e s a  m e ti  m efr a  m e.   A n y  S  A E t h at is f elt  b y t h e 
I n v esti g at or t o  b e r el at e d t o t h e st u d y   m e di c ati o n   m ust  b e r e p ort e d r e g ar dl ess  of t h e  a  m o u nt  of 
ti  m e si n c e t h e l ast  d os e r e c ei v e d.  F oll o  w- u p i nf or  m ati o n  c oll e ct e d f or  a n y i niti al r e p ort  of  a n 
S  A E   m ust  als o  b e r e p ort e d t o t h e  S p o ns or   wit hi n  2 4  h o urs  of r e c ei pt  b y t h e I n v esti g at or.  
All  S  A Es   will  b e f oll o  w e d  u ntil r es ol uti o n, st a bili z ati o n  of  c o n diti o n,  or  u ntil f oll o  w- u p is  n o 
l o n g er  p ossi bl e. 
I n t h e  e v e nt  dis c ussi o n is  n e c ess a r y  r e g a r di n g t r e at  m e nt  of  a s u bj e ct,  c all t h e   M e di c al 
M o nit o r (s e e  c o nt a ct i nf o r  m ati o n i n   S e cti o n  3 ). 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 7 
 
 
 
All  S  A  Es s h o ul d  b e s e nt  vi a t h e  e  m ail  a d d r ess,  o r f a x e d t o t h e f a x  n u  m b e r,  p r o vi d e d i n 
S e cti o n  3 . 
T h e  S p o ns or   will  d et er  mi n e   w h et h er t h e  S  A E   m ust  b e r e p ort e d   wit hi n  7  or  1 5  d a ys t o r e g ul at or y 
a ut h oriti es i n  c o  m pli a n c e   wit h l o c al  a n d r e gi o n al l a  w. If s o, t h e  S p o ns or ( or t h e  S p o ns or’ s 
r e pr es e nt ati v e)   will r e p ort t h e  e v e nt t o t h e  a p pr o pri at e r e g ul at or y  a ut h oriti es.  T h e I n v esti g at or 
will r e p ort  S  A Es t o t h e I  R  B  p er t h eir I R  B  p oli c y.   
1 4. 5. 2. 1.    F oll o  w- U p  P r o c e d u r es f o r  S e ri o us   A d v e rs e   E v e nts   
T o  f ull y  u n d erst a n d t h e  n at ur e  of  a n y  S  A E,  o bt ai ni n g f oll o  w-u p i nf or  m ati o n is i  m p ort a nt. 
W h e n e v er  p ossi bl e, r el e v a nt   m e di c al r e c or ds s u c h  as  dis c h ar g e s u  m  m ari es,   m e di c al 
c o ns ult ati o ns,  a n d t h e li k e s h o ul d  b e  o bt ai n e d. I n t h e  e v e nt  of  d e at h, r e g ar dl ess  of  c a u s e,  all 
att e  m pts s h o ul d  b e   m a d e t o  o bt ai n t h e  d e at h  c ertifi c at e  a n d  a n y  a ut o ps y r e p ort.  T h es e r e c or ds 
s h o ul d  b e r e vi e  w e d i n  d et ail,  a n d t h e I n v esti g at or s h o ul d  c o  m  m e nt  o n  a n y  e v e nt, l a b 
a b n or  m alit y,  or  a n y  ot h er fi n di n g,  n oti n g   w h et h er it s h o ul d  b e  c o nsi d er e d  a s eri o us  or  n o n-
s eri o us   A E,  or   w h et h er it s h o ul d  b e  c o nsi d er e d  as  p art  of t h e s u bj e ct’s  hist or y. I n  a d diti o n,  all 
e v e nts  or  ot h er fi n di n gs  d et er  mi n e d t o  b e  S  A Es s h o ul d  b e i d e ntifi e d  o n t h e f oll o  w- u p  S  A E f or  m 
a n d t h e I n v esti g at or s h o ul d  c o nsi d er   w h et h er t h e  e v e nt is r el at e d  or  n ot r el at e d t o st u d y  dr u g.   All 
e v e nts  d et er  mi n e d t o  b e  n o ns eri o us s h o ul d  b e r e p ort e d  o n t h e  e  C  R F. 
1 4. 6.    
S p e ci al   R e p o rti n g  Sit u ati o ns  
1 4. 6. 1.    
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 s u c h  as  br uisi n g,  e c c h y  m osis,  h e  m at o  m as,  a n d  c o nt usi o ns t h at  o c c ur r e  m ot e t o 
t h e sit e  of  dr u g  a d  mi nistr ati o n,  or a n y   h y p ers e nsiti vit y r e a cti o ns, i n cl u di n g  a n a p h yl a xis,   will  b e 
r e c or d e d  a n d  e v al u at e d f or s eri o us n ess  a n d s e v erit y. 
I n  a d diti o n, l o c al   A Es  ass o ci at e d   wit h t h e i nj e cti o n sit e, i n cl u di n g  br uisi n g,  p ai n,  n o d ul es/  m ass, 
ul c er ati o n,  er yt h e  m a,  pr urit us, s  w elli n g,  a n d/ or i n d ur ati o n,   will  b e r e c or d e d  a n d  e v al u at e d f or 
s eri o us n ess  a n d s e v erit y. 
1 4. 6. 2.    
O v e r d os e/  Mis us e/  A b us e   
1 4. 6. 2. 1.    O v e r d os e   
St u d y  dr u g  o v er d os e is  a n y  a c ci d e nt al  or i nt e nti o n al  us e  of st u d y  dr u g i n  a n  a  m o u nt  hi g h er t h a n 
t h e  d os e i n di c at e d  b y t h e  pr ot o c ol f or t h at s u bj e ct.  St u d y  dr u g  c o  m pli a n c e s h o ul d  b e r e vi e  w e d t o 
d et e ct  p ot e nti al i nst a n c es  of  o v er d os e (i nt e nti o n al  or  a c ci d e nt al).  
A n y st u d y  dr u g  o v er d os e  d uri n g t h e st u d y   will  b e r e c or d e d.  
A n  o v er d os e is  n ot   a n   A E  p er  s e,  h o  w e v er  all   A Es  ass o ci at e d   wit h  a n  o v er d os e s h o ul d  b ot h  b e 
e nt er e d  o n t h e   A d v ers e  E v e nt  e  C  R F  a n d r e p ort e d  usi n g t h e  pr o c e d ur es  d et ail e d  pr e vi o usl y,  e v e n 
if t h e  e v e nts  d o  n ot   m e et s eri o us n ess  crit eri a. If t h e   A E  ass o ci at e d   wit h  a n  o v er d os e  d o es  n ot 
m e et s eri o us n ess  crit eri a, it   m ust still  b e r e p ort e d  usi n g t h e  E n d o   S eri o us   A d v ers e  E v e nt ( S  A E)/ 
R e p ort a bl e  E v e nt  F or  m  a n d i n  a n  e x p e dit e d   m a n n er,  b ut s h o ul d  b e  n ot e d  as  n o ns eri o us  o n t h e 
f or  m  a n d t h e   A d v ers e  E v e nt  e  C  R F.  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 8 
 
 
 
1 4. 6. 2. 2.    Mis us e/  A b us e   
N ot  a p pli c a bl e. 
1 4. 6. 3.    
P r e g n a n c y  
A n y  u n c o  m pli c at e d  pr e g n a n c y t h at  o c c urs i n  a s u bj e ct  d uri n g t his  cli ni c al st u d y   will  b e   r e p o rt e d 
f o r t r a c ki n g  p u r p os es  o nl y.   All s u bj e ct  pr e g n a n ci es t h at  ar e i d e ntifi e d  d uri n g  or  aft er t his st u d y, 
w h er e t h e  esti  m at e d  d at e  of  c o n c e pti o n is  d et er  mi n e d t o  h a v e  o c c urr e d  d uri n g st u d y  dr u g t h er a p y 
or   wit hi n  2 8  d a ys  of t h e l ast  d os e  of st u d y  dr u g  n e e d t o  b e r e p ort e d, f oll o  w e d t o  c o n cl usi o n,  a n d 
t h e  o ut c o  m e r e p ort e d,  e v e n if t h e s u bj e ct is  dis c o nti n u e d fr o  m t h e st u d y.  T h e i n v esti g at or s h o ul d 
r e p ort  all pr e g n a n ci es   wit hi n  2 4  h o urs  usi n g t h e I niti al  Pr e g n a n c y   R e p ort  F or  m,  a n d  a n y 
pr e g n a n c y- ass o ci at e d  S  A E  usi n g t h e  S eri o us   A d v ers e  E v e nt ( S  A E)/  R e p ort a bl e  E v e nt  F or  m, 
a c c or di n g t o t h e  us u al ti  m eli n es  a n d  dir e cti o ns f or  S  A E r e p orti n g.   M o nit ori n g  of t h e  pr e g n a n c y 
s h o ul d  c o nti n u e  u ntil  c o n cl usi o n  of t h e  pr e g n a n c y  a n d  1  or   m or e  F oll o  w- u p  Pr e g n a n c y   R e p ort 
F or  m(s)  d et aili n g  pr o gr ess,  a n d  a  T  w o   M o nt h  F oll o  w- u p  Pr e g n a n c y   R e p ort  F or  m  d et aili n g t h e 
o ut c o  m e, s h o ul d  b e s u b  mitt e d. 
Pr e g n a n c y its elf is  n ot r e g ar d e d  as  a n   A E  u nl ess t h er e is s us pi ci o n t h at t h e i n v esti g ati o n al 
pr o d u ct  u n d er st u d y   m a y  h a v e i nt erf er e d   wit h t h e  eff e cti v e n ess  of  a  c o ntr a c e pti v e   m e di c ati o n. 
Li k e  wis e,  el e cti v e  a b orti o ns   wit h o ut  c o  m pli c ati o ns  ar e  n ot  c o nsi d er e d   A Es.   A n y  S  A Es 
ass o ci at e d   wit h  pr e g n a n c y ( e g,  c o n g e nit al  a b n or  m aliti es/ birt h  d ef e cts/s p o nt a n e o us   mis c arri a g es 
or  a n y  ot h er s eri o us  e v e nts)   m ust  a d diti o n all y  b e r e p ort e d  as s u c h  usi n g t h e  S eri o us   A d v ers e 
E v e nt ( S  A E) /  R e p ort a bl e  E v e nt  F or  m.  S p o nt a n e o us   mis c arri a g es s h o ul d  als o  b e r e p ort e d  a n d 
h a n dl e d  as  S  A Es.   
S u bj e cts s h o ul d  b e i nstr u ct e d t o i  m  m e di at el y  n otif y t h e i n v esti g at or  of  a n y  pr e g n a n ci es.   A 
s u bj e ct   w h o  b e c o  m es  pr e g n a nt   m ust  b e i  m  m e di at el y   wit h dr a  w n fr o  m t h e st u d y.   Att e  m pts t o 
o bt ai n t h e  pr e g n a n c y f oll o  w- u p  a n d  pr e g n a n c y  o ut c o  m e i nf or  m ati o n  d et ail e d  a b o v e  ar e 
n e c ess ar y,  e v e n if  a s u bj e ct  dis c o nti n u es tr e at  m e nt  b e c a us e  of  pr e g n a n c y  
1 4. 6. 4.    
A  Es/ S  A  Es   E x p e ri e n c e d  b y   N o ns u bj e cts     E x p os e d t o  St u d y   M e di c ati o n 
N o n  s u bj e cts  ar e  p ers o ns   w h o  ar e  n ot  e nr oll e d i n t h e st u d y  b ut  h a v e  b e e n  e x p os e d t o st u d y 
m e di c ati o n, i n  cl u di n g i nst a n c es  of  di v ersi o n  of st u d y   m e di c ati o n.   All s u c h   A Es/ S  A Es  o c c urri n g 
i n  n o ns u bj e cts fr o  m s u c h  e x p os ur e   will  b e r e p ort e d t o t h e  E n d o  P  V  R  M   D e p art  m e nt (  w h e n t h e 
n o ns u bj e ct  a gr e es)  o n t h e  S eri o us   A d v ers e  E v e nt ( S  A E)/  R e p ort a bl e  E v e nt  F or  m  r e g ar dl ess of 
w h et h er t h e  e v e nt is s eri o us  or  n ot. I nstr u cti o ns f or  c o  m pl eti n g t h e f or  m f or  e v e nts  e x p eri e n c e d 
b y  n o n s u bj e cts   will  b e pr o vi d e d.  S  A Es  o c c urri n g i n  n o ns u bj e cts  e x p os e d t o st u d y   m e di c ati o n 
will  b e  pr o c ess e d   wit hi n t h e s a  m e  S  A E r e p orti n g ti  m eli n es  as  d es c  ri b e d i n  S e cti o n  1 4. 5. 2, 
R e p orti n g  S eri o us   A d v ers e  E v e nts.   A d diti o n all y, t h e  dr u g  a c c o u nt a bilit y s o ur c e  d o c u  m e nt ati o n 
at t h e  c e nt er  s h o ul d r efl e ct t his  o c c urr e n c e.  
1 4. 7.    
Cli ni c al   L a b o r at o r y   T ests   
Cli ni c al l a b or at or y t ests   will  b e  c o n d u ct e d  a c c or di n g t o t h e  S c h e d ul e  of  E v e nts ( S e cti o n    5). 
Cli ni c al l a b or at or y t ests   will  b e  p erf or  m e d  b y  a  d esi g n at e d  c e ntr al l a b or  at or y.  E a c h sit e   will  b e 
pr o vi d e d   wit h i nstr u cti o ns  o n s p e ci  m e n  c oll e cti o n,  pr e p ar ati o n,  p a c k a gi n g  a n d tr a ns p ort.   R ef er t o 
t h e  c e ntr al l a b or at or y   m a n u al f or f urt h er i nf or  m ati o n r e g ar di n g s a  m pl e  c oll e cti o n,  h a n dli n g,  a n d 
l a b eli n g.  T h e r es ults  of t h e t ests   will  b e r et ur n e d t o t h e i n v esti g ati o n al sit es.  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  3 9 
 
 
 
Cli ni c al l a b or at or y t est  d at a   will  b e r e vi e  w e d  b y t h e i n v esti g at or,  or  d esi g n e e,  a n d  a d diti o n al 
cli ni c al l a b or at or y t ests   m a y  b e  or d er e d  at  his/ h er  dis cr eti o n ( e g, if t h e r es ults  of  a n y  cli ni c al 
l a b or at or y t est f alls  o utsi d e t h e r ef er e n c e r a n g e  or  cli ni c al s y  m pt o  ms  n e c essit at e  a d diti o n al 
t esti n g t o  e ns ur e s af et y).   A n y  a d diti o n al t esti n g   will  b e  p erf or  m e d  b y t h e  d esi g n at e d  c e ntr al 
l a b or at or y,  u nl ess  us e  of  a l o c al l a b or at or y is  n e c ess ar y t o  pr ot e ct t h e s af et y  of t h e s u bj e ct. 
T h e  cli ni c al  l a b or at or y  p ar a  m et ers t h at   will  b e   m e as ur e d i n t his st u d y  ar e list e d i n T a bl e   2. 
T a bl e  2:     
Cli ni c al   L a b o r at o r y   T ests 
H e  m at ol o g y 
Bi o c h e  mist r y   
U ri n al ysis   
H e  m o gl o bi n 
Gl u c os e 
Gl u c os e 
H e  m at o crit   
S o di u  m 
Pr ot ei n  
R e d  bl o o d  c ell 
P ot assi u  m 
S p e cifi c  gr a vit y  
W hit e  bl o o d  c ell (  W  B  C)     
C al ci u  m   
p  H 
Pl at el ets  
C hl ori d e 
K et o n es   
W  B  C   Diff er e nti al   
C  O 2 
Bilir u bi n   
 
I n or g a ni c  p h os p h at e 
Ur o bili n o g e n 
 
Bl o o d  ur e a  nitr o g e n  
Nitrit e   
 
Cr e ati ni n e   
Bl o o d * 
 
Cr e ati ni n e  cl e ar a n c e    
L e u k o c yt es *  
 
As p art at e tr a ns a  mi n as e (  A S T)      
 
 
Al a ni n e tr a ns a  mi n as e (  A L T)      
 
 
G a  m  m a  -gl ut a  m yl tr a nsf er as e 
(  G  G T) 
 
 
T ot al  bilir u bi n ( T  B L) ( dir e ct 
bilir u bi n r efl e x if  el e v at e d)  
 
 
Al b u  mi n 
 
 
Al k ali n e  p h os p h at as e (  A L P)      
 
 
Uri c  a ci d   
 
*  Mi cr os c o pi c  e x a  mi n ati o n   will  b e  p erf or  m e d if  bl o o d  or l e u k o c yt e s  ar e  d et e ct e d  b y  di psti c k.   
F or   w o  m e n  of  c hil d b e ari n g  p ot e nti al,  a s er u  m  pr e g n a n c y t est   will  b e  p erf or  m e d  at t h e  S cr e e ni n g 
Visit  a n d  uri n e  pr e g n a n c y t ests   will  b e  p erf or  m e d  as  o utli n e d i n t h e  S c h e d ul e  of  E v e nts.  F e  m al e 
s u bj e cts  of  c hil d b e ari n g  p ot e nti al   m ust  h a v e  a  n e g ati v e  pr e g n a n c y t est  at t h e  S cr e e ni n g  a n d 
D a y    1 Visits t o  b e  e nr oll e d i n t h e st u d y  ,  a n d  pri or t o  a n y  ot h er d osi n g   wit h st u d y   m e di c ati o n . If 
n e c ess ar y,  a d diti o n al  uri n e  pr e g n a n c y t ests  c a n  b e  p erf or  m e d  at  a n y ti  m e  d uri n g 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.   Uri n e  pr e g n a n c y t est  kits   will  b e s u p pli e d  b y t h e  S p o ns or. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 0 
 
 
 
1 4. 8.    
A nti  -A  U  X  -I  a n d   A nti-A  U  X  -II   A nti b o dies  
S er u  m s a  m pl es   will  b e  c oll e ct e d  b ef or e i nj e cti o n  o n   D a y 1  a n d  at t h e   D a y  7 1  visit  a n d   will  b e 
t est e d f or  bi n di n g  a nti-A  U  X  -I  a n d  a nti-A  U  X  -II  a nti b o d y  a n d  a nti-A  U  X  -I  a n d  a nti-A  U  X  -II 
n e utr ali zi n g  a nti b o di es.  
T h e s er u  m s a  m pl es  o bt ai n e d   will  b e  pr o c ess e d, st or e d  a n d t h e n s hi p p e d  o n  dr y i c e t o t h e 
d esi g n at e d  c e ntr al  cli ni c al l a b or at or y  a c c or di n g t o t h e i nstr u cti o ns i n t h e l a b or at or y   m a n u al. 
1 4. 9.    
Vit al  Si g ns   
Vit al si g n   m e as ur e  m e nts   will  b e  d o c u  m e nt e d  as  d es cri b e d i n t h e  S c h e d ul e  of  E v e nts.  T h es e 
p ar a  m et ers i n cl u d e  p uls e r at e, r es pir at or y r at e, s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e,  a n d  b o d y 
t e  m p er at ur e.  P uls e  a n d  bl o o d  pr ess ur e r e a di n gs   will  b e t a k e n  aft er t h e s u bj e ct  h as  b e e n sitti n g f or 
5   mi n ut es.  
T h e i n v esti g at or   will r e vi e  w  all  vit al si g n  v al u es f or  cli ni c al si g nifi c a n c e.   A n y  vit al si g n  v al u e 
m e eti n g t h e i n v esti g at or  ’s  crit eri a f or  cli ni c al si g nifi c a n c e   will  b e r e c or d e d  as  a n   A E  or  S  A E  as 
a p pr o pri at e. 
1 4. 1 0.    El e ct r o c a r di o g r a  m   
A  1 2  -l e a d E  C  G  r e c or di n g   will  b e  c o n d u ct e d  at t h e  S cr e e ni n g   Visit.  T h e s u bj e ct s h o ul d  b e i n  a 
s upi n e  p ositi o n f or  at l e ast  5   mi n ut es  b ef or e t h e r e c or di n g is  c o n d u ct e d.  L e a d  p ositi o n   will  b e 
t h at  of  a st a n d ar d  1 2-l e a d  E  C  G;  n o  a d diti o n al  or s p e ci al l e a d  pl a c e  m e nts   will  b e  n e c ess ar y.  
A  q u alifi e d  p h ysi ci a n   will i nt er pr et, si g n,  a n d  d at e t h e  E  C  Gs.  E  C  G fi n di n gs   will  b e  d o c u  m e nt e d 
as  n or  m al;  a b n or  m al,  cli ni c all y si g nifi c a nt;  or  a b n or  m al,  n ot  cli ni c all y si g nifi c a nt.  T h e 
I n v esti g at or  or  q u alifi e d  d esi g n e e   m ust si g n  a n d  d at e t h e  E  C  G, t h er e b y  a c k n o  wl e d gi n g r e vi e  w  of 
E  C  G r es ults.  E  C  G  ass ess  m e nts   m ust  b e  “ wit hi n  n or  m al li  mits  ”  or i nt er pr et e d  as  “ a b n or  m al,  n ot 
cli ni c all y si g nifi c a nt ” f or t h e s u bj e ct t o  b e i n cl u d e d i n t h e st u d y. 
A n y  E  C  G r es ult   m e eti n g t h e I n v esti g at or  ’s  or  S p o ns or’s  crit eri a f or  cli ni c al si g nifi c a n c e   will  b e 
r e c or d e d  as  a n   A E  or  S  A E  as  a p pr o pri at e.  
1 4. 1 1.    P h ysi c al   E x a  mi n ati o n  
All  p h ysi c al  e x a  mi n ati o ns   will  b e  p erf or  m e d  b y  a  p h ysi ci a n  or  h e alt h  pr of essi o n al list e d  o n t h e 
F or  m  F  D  A  1 5 7 2  a n d li c e ns e d t o  p erf or  m  p h ysi c al  e x a  mi n ati o ns.   H ei g ht  a n d  b o d y   w ei g ht   will  b e 
m e as ur e d  a n d r e c or d e d  at t h e ti  m es  o utli n e d i n t h e  S c h e d ul e  of  E v e nts. 
T h e I n v esti g at or   will r e vi e  w  all  p h ysi c al  e x a  m fi n di n gs f or  cli ni c al si g nifi c a n c e.   A n y  p h ysi c al 
e x a  m fi n di n g   m e eti n g t h e I n v esti g at or ’s  or  S p o ns or’s  crit eri a f or  cli ni c al si g nifi c a n c e   will  b e 
r e c or d e d  as  a n   A E  or  S  A E  as  a p pr o pri at e. 
1 4. 1 2.    Fit z p at ri c k  S c al e  
At s cr e e ni n g, t h e I n v esti g at or   will  als o  ass ess t h e s u bj e ct  ’s s ki n t y p e  usi n g t h e  Fit z p atri c k s c al e 
(T a bl e   3).   O nl y t h e  Fit z p atri c k  S c al e s h o  w n  b el o  w   m a y  b e  us e d  d uri n g t h e st u d y. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 1 
 
 
 
T a bl e  3:   
Fit z p at ri c k  S c al e  
I    
P al e   w hit e s ki n,  bl u e/ h a z el  e y es,  bl o n d/r e d  h air   
Al  w a ys  b ur ns,  d o es  n ot t a n   
II 
F air s ki n,  bl u e  e y es  
B ur ns  e asil y, t a ns  p o orl y  
III 
D ar k er   w hit e s ki n  
T a ns  aft er i niti al  b ur n  
I  V 
Li g ht  br o  w n s ki n  
B ur ns   mi ni  m all y, t a ns  e asil y  
V  
Br o  w n s ki n  
R ar el y  b ur ns, t a ns  d ar kl y  e asil y  
VI  
D ar k  br o  w n  or  bl a c k s ki n  
N e v er    b ur ns,  al  w a ys t a ns  d ar kl y 
1 4. 1 3.    Ot h e r  S af et y   Ass ess  m e nts   
N ot  a p pli c a bl e.   
1 5.    
A S S  E S S  M  E  N  T   O F  P  H  A  R  M  A  C  O  KI  N  E  TI  C S 
N ot  a p pli c a bl e.   
1 6.    
A S S  E S S  M  E  N  T   O F  P  H  A  R  M  A  C  O  D  Y  N  A  MI  C S   
N ot  a p pli c a bl e.   
1 7.    
S  T  A  TI S  TI  C  A  L   C  O  N SI  D  E  R  A  TI  O  N S   A  N  D   M  E  T  H  O  D S  
1 7. 1.    
D et e r  mi n ati o n  of  S a  m pl e  Si z e   
N o s a  m pl e si z e  esti  m ati o n     w as  d o n e f or t his st u d y. 
1 7. 2.    
A n al ysis  P o p ul ati o ns   
T  w o  p o p ul ati o ns  ar e  c o nsi d er e d i n t h e st atisti c al  a n al ysis  of t h e st u d y. 
1 7. 2. 1.    
S af et y  P o p ul ati o n 
T h e  S af et y  P o p ul ati o n   will i n cl u d e  all s u bj e cts   w h o r e c ei v e  at l e ast  1  i nj e cti o n  of st u d y  dr u g.   All 
s af et y  a n al ys es   wil l  b e  b as e d  o n t his  p o p ul ati o n. 
1 7. 2. 2.    
E v al u a bl e  P o p ul ati o n 
T h e  E v al u a bl e  P o p ul ati o n   will i n cl u d e  all s u bj e cts i n t h e  S af et y  P o p ul ati o n   w h o  h a v e  c o  m pl et e d 
s cr e e ni n g  pr o c e d ur es  a n d  at l e ast  1  p ost  b as eli n e  ass ess  m e nt   of t h e Li k ert  S c al e s c or e  of  a est h eti c 
a p p e ar a n c e i  m pr o v e  m e nt.   All  effi c a c y  a n al ysis   will  b e  b as e d  o n t his  p o p ul ati o n. 
1 7. 3.    
S u bj e ct   Dis p ositi o n  
T h e  n u  m b er  of s u bj e cts i n cl u d e d i n  e a c h st u d y  p o p ul ati o n   will  b e s u  m  m ari z e d  b y tr e at  m e nt  ar  m. 
S u bj e cts  e x cl u d e d fr o  m t h e  S af et y  a n d  E v al u a bl e  P o p ul ati o ns  will  b e list e d  b y tr e at  m e nt  ar  m.   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 2 
 
 
 
T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts  c o  m pl et e d  a n d  pr e  m at ur el y  dis c o nti n u e d  d uri n g t h e st u d y 
will  b e  pr es e nt e d f or  e a c h tr e at  m e nt  ar  m.   R e as o ns f or  pr e  m at ur e  dis c o nti n u ati o n fr o  m t h e 
tr e at  m e nt  p eri o d  as r e c or d e d  o n t h e t er  mi n ati o n  p a ge  of t h e  e  C  R F   will  b e s u  m  m ari z e d ( n u  m b er 
a n d  p er c e nt a g e)  b y tr e at  m e nt  ar  m f or  all s u bj e cts.   
T h e  p er c e nt a g e  of  pr e  m at ur e  dis c o nti n u ati o ns  d u e t o   A Es   will  b e t a b ul at e d  a n d  c o  m p ar e d 
b et  w e e n tr e at  m e nt  ar  ms.  
1 7. 4.    
D e  m o g r a p hi cs  a n d   Ot h e r   B as eli n e   C h a r a ct e risti cs   
D e  m o  gr a p hi c  a n d  ot h er  b as eli n e  c h ar a ct eristi cs (i n cl u di n g  g e n d er,  a g e, r a c e,  h ei g ht,   w ei g ht, 
m e di c al  a n d  E F P  hist or y)   will  b e s u  m  m ari z e d  b y tr e at  m e nt  ar  m,  usi n g  d es cri pti v e st atisti cs.  T h e 
d es cri pti v e s u  m  m ari es   will i n cl u d e fr e q u e n c y t a bl es f or  all  c at e g ori c al  r es p o ns e  v ari a bl es  a n d 
n u  m b er,   m e a n, st a n d ar d  d e vi ati o n,   mi ni  m u  m,  a n d   m a xi  m u  m f or  all  c o nti n u o us  v ari a bl es. 
1 7. 5.    
Effi c a c y   A n al ys es   
T h e  effi c a c y  e n d p oi nts f or t his st u d y   will i n cl u d e:  
•    C h a n g e fr o  m  b as eli n e i n t h e  bli n d e d  ass ess or’  s  Li k ert  S c al e s c or e  of  a est h eti c 
a p p e ar a n c e i n  e a c h tr e at  m e nt  ar e a ( b utt o c ks  or t hi g hs)  at   D a ys  2 2,  4 3,  a n d  7 1  b y  e a c h 
tr e at  m e nt  ar  m. 
•    C h a n g e fr o  m  b as eli n e i n  di  m pl e  d e pt h  a n d  v ol u  m e i n  e a c h tr e at  m e nt  ar e a ( b utt o c ks  or 
t hi g hs)   D a ys  2 2,  4 3,  a n d  7 1  b y tr e at  m e nt  ar  m.  
•    C h a n g e fr o  m  b as eli n e i n t h e   H e xs el   C S S (  B)  d e pr essi o n  d e pt h s c al e  at   D a  ys  2 2,  4 3, 
a n d  7 1  b y tr e at  m e nt  ar  m. 
T h e  c e ntr al  ass ess or  Li k ert  S c al e s c or e  of  a est h eti c  a p p e ar a n c e i  m pr o v e  m e nt fr o  m  b as eli n e i n t h e 
3-  D  p h ot o gr a p hi c i  m a g e,  c h a n g e fr o  m  b as eli n e i n t h e   H e xs el   C S S (  B)  d e pr essi o n  d e pt h s c al e, 
a n d   c h a n g e fr o  m  b as eli n e i n  di  m pl e  v ol u  m e  a n d  d e pt h   will  b e s u  m  m ari z e d  b y tr e at  m e nt  ar  m  a n d 
st u d y  visit  usi n g  a p pr o pri at e  d es cri pti v e st atisti cs. I n  a d diti o n,  a li n e ar   mi x e d   m o d el   will  b e 
utili z e d t o fit  c h a n g e fr o  m  b as eli n e  of  e a c h  e n d p oi nt   wit h tr e at  m e nt  ar  m,  c ell ulit e  di  m pl es,  a n d 
st u d y  visit  as fi x e d  eff e cts, s u bj e ct  as r a n d o  m  eff e ct,  a n d  ass ess  m e nts  a cr oss st u d y  visits  as 
r e p e at e d   m e as ur e.  T h e fi x e d  eff e ct  esti  m at es  a n d t h e  c orr es p o n di n g  9 5  %  c o nfi d e n c e i nt er v als 
will  b e  pr es e nt e  d f or  e a c h  e n d p oi nt. 
1 7. 6.    
S af et y   A n al ys es  
T h e s af et y  p ar a  m et ers f or t his st u d y   will i n cl u d e:   
•    A Es.   
•    Vit al si g ns.    
•    Cli ni c al l  a b or at or y  p ar a  m et ers.   
A Es   will  b e s u  m  m ari z e d  b y  pr o p orti o n  of s u bj e cts  e x p eri e n ci n g  e a c h  e v e nt  a n d  b y tr e at  m e nt 
ar  m.   D es cri pti v e st atisti cs   will  b e  pr es e nt e d f or  a ct u al  a n d  c h a n g e fr o  m  b as eli n e  at  e a c h st u d y 
visit f or  vit al si g ns  a n d  cli ni c al  l a b or at or y t est r es ults  b y tr e at  m e nt  ar  m.  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 3 
 
 
 
T h e  p ar a  m et ers f or i  m  m u n o g e ni cit y  of  C  C  H   i n t his st u d y i n cl u d e:  
•    A nti  -A  U  X  -I/ a nti-A  U  X  -II  a nti b o d y l e v els. 
•    N e utr ali zi n g  a nti b o di es t o   A  U  X-  I  a n d   A  U  X-II. 
1 7. 6. 1.    
P ri o r,   C o n c o  mit a nt,  a n d  F oll o  w- u p   M e di c ati o n  
T h e   W orl d   H e alt h   Or g a ni z ati o n (  W  H  O)   Dr u g   Di cti o n ar y   will  b e  us e d t o  cl assif y  pri or  a n d 
c o n c o  mit a nt   m e di c ati o ns  b y t h er a p e uti c  cl ass.  Pri or   m e di c ati o n   will  b e  d efi n e d  as  a n y 
m e di c ati o n t a k e n  pri or t o t h e first  d os e  of st u d y  dr u g.   C o n c o  mit a nt   m e di c ati o n is  d efi n e d  as  a n y 
m e di c ati o n t a k e n  b et  w e e n t h e  d at e  of fi  rst  d os e  of st u d y  dr u g  a n d t h e  d at e  of l ast  d os e  of st u d y 
dr u g.   A n y   m e di c ati o ns st art e d  aft er t h e l ast  d os e  of st u d y  dr u g   will  b e  c o nsi d er e d  as f oll o  w- u p 
m e di c ati o ns.   
Pri or,  c o n c o  mit a nt  a n d f oll o  w- u p   m e di c ati o n  us e   will  b e s u  m  m ari z e d  d es cri pti v el y  b y t h e 
n u  m b er  a n d  p er c e nt a g e  of s u bj e cts i n f or  e a c h  pr ef err e d t er  m ( g e n eri c  n a  m e fr o  m   W  H  O 
di cti o n ar y)  b y tr e at  m e nt  ar  m.   M ulti pl e  us e  of t h e s a  m e   m e di c ati o n  b y  a s u bj e ct   will  b e  c o u nt e d 
o nl y  o n c e.  
1 7. 6. 2.    
St u d y   D r u g   E x p os u r e  
T h e f oll o  wi n g i nf or  m ati o n r e g ar di n g tr e at  m e nt  will  b e s u  m  m ari z e d  p er  e a c h tr e at  m e nt  ar e a ( e a c h 
b utt o c k  or  e a c h t hi g h)  b y tr e at  m e nt  ar  m: 
•    T ot al  n u  m b er  of tr e at  m e nt  visits.  
•    N u  m b er  of s u bj e cts   w h o  h a d tr e at  m e nt s essi o n  d o n e  or tr e at  m e nt s essi o n  n ot  d o n e  at 
e a c h tr e at  m e nt  visit.  
•    F or s u bj e cts   w h o  h a d t h e tr e at  m e nt s essi o n  d o n e, t h e  n u  m b er  of s u bj e cts   w h o  g ot  all 
r e q uir e d i nj e cti o ns  p er  pr ot o c ol  at t h e tr e at  m e nt  visit  or   w h o r e c ei v e d l ess t h a n t h e 
r e q uir e d i nj e cti o ns  p er  pr ot o c ol.  
•    N u  m b er  of i nj e cti o ns  gi v e n  at  e a c h tr e at  m e nt  visit.   
•    N u  m b er  of  di  m pl es tr e at e d   at  e a c h tr e at  m e nt  visit.  
•    A v er a g e  n u  m b er  of i nj e cti o ns  p er  di  m pl e  at  e a c h tr e at  m e nt  visit.  
S u bj e cts   w h o  di d  n ot r e c ei v e  all  3 tr e at  m e nt  visits  a n d   w h o  di d  n ot r e c ei v e t h e r e q uir e d i nj e cti o ns 
p er  pr ot o c ol  at  a tr e at  m e nt  visit   will  b e list e d.   
1 7. 6. 3.    
M e as u r e  m e nt  of   T r e at  m e nt   C o  m pli a n c e   
N ot  a p pli c a bl e  as st u d y  dr u g is  a d  mi nist er e d  at t h e   c e nt er  b y t h e i n v esti g at or.  
1 7. 6. 4.    
A d v e rs e   E v e nts   
T h e   M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es (  M e d  D  R  A)   will  b e  us e d t o  c o d e   A Es.   
A n   A E ( cl assifi e d  b y  pr ef err e d t er  m) t h at st art e d  o n  or   aft er t h e  d at e  of t h e first  d os e  of t h e st u d y 
dr u g   will  b e  c o nsi d er e d  a  T E  A E if it   w as  n ot  pr es e nt  pri or t o t h e first  d os e  of st u d y  dr u g,  or   w as 
pr es e nt  pri or t o t h e first  d os e  of st u d y  dr u g  b ut i n cr e as e d i n i nt e nsit y  d uri n g t h e tr e at  m e nt  p eri o d. 
If   m or e t h a n  1   A E is r e p ort e d  pri or t o t h e first  d os e  of st u d y  dr u g  a n d  c o d e d t o t h e s a  m e 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 4 
 
 
 
pr ef err e d t er  m, t h e n t h e   A E   wit h t h e  gr e at est i nt e nsit y   will  b e  us e d  as t h e  b e n c h  m ar k f or 
c o  m p aris o n t o t h e   A Es  o c c urri n g  d uri n g t h e tr e at  m e nt  p eri o d   w hi c h   w er e  als o  c o d e d t o  t h at 
pr ef err e d t er  m.   A n y   A E  pr es e nt  pri or t o t h e first  d os e  of st u d y  dr u g t h at i n cr e as es i n i nt e nsit y 
d uri n g t h e tr e at  m e nt  p eri o d   will  b e r e -e nt er e d   wit h  a  n e  w st art  d at e  of t h e  d at e  of i n cr e as e d 
i nt e nsit y. 
D es cri pti v e st atisti cs (t h e  n u  m b er  a n d  p er c e nt a g e) f or s u bj e cts r e p orti n g  T E  A Es i n  e a c h 
tr e at  m e nt  ar  m   will  b e t a b ul at e d  b y s yst e  m  or g a n  cl ass  a n d  pr ef err e d t er  m;  b y s yst e  m  or g a n  cl ass, 
pr ef err e d t er  m,  a n d s e v erit y;  a n d  b y s yst e  m  or g a n  cl ass,  pr ef err e d t er  m,  a n d r el ati o ns hi p t o st u d y 
dr u g. If   m or e t h a n  1  A E is  c o d e d t o t h e s a  m e  pr ef err e d t er  m f or t h e s a  m e s u bj e ct, t h e s u bj e ct   will 
b e  c o u nt e d  o nl y  o n c e f or t h at  pr ef err e d t er  m  usi n g t h e   m ost s e v er e  a n d   m ost r el at e d  o c c urr e n c e 
f or t h e s u  m  m ari z ati o n  b y s e v erit y  a n d  b y r el ati o ns hi p t o t h e st u d y  dr u g. 
Listi n gs  will  b e  pr es e nt e d f or s u bj e cts   wit h  S  A Es, s u bj e cts   wit h   A Es l e a di n g t o  dis c o nti n u ati o n 
of st u d y  or st u d y  dr u g,  a n d s u bj e cts   w h o  di e (if  a n y). 
1 7. 6. 5.    
Vit al  Si g ns   
D es cri pti v e st atisti cs f or  vit al si g ns  a n d t h eir  c h a n g es fr o  m  b as eli n e  at  e a c h st u d y  visit  a n d  at t h e 
e n d  of st u d y   will  b e  pr es e nt e d  b y tr e at  m e nt  ar  m.  
1 7. 6. 6.    
Cli ni c al   L a b o r at o r y  P a r a  m et e rs   
D es cri pti v e st atisti cs f or  cli ni c al l a b or at or y  v al u es i n I nt er n ati o n al  S yst e  m  of   U nits  a n d  c h a n g es 
fr o  m  b as eli n e  at  e a c h  ass ess  m e nt ti  m e  p oi nt   will  b e  pr es e nt e d  b y tr e at  m e nt  ar  m f or  e a c h  cli ni c al 
l a b or at or y  p ar a  m et er. 
1 7. 6. 7.    
P h ysi c al   E x a  mi n ati o n 
B o d y   w ei g ht  a n d  c h a n g e fr o  m  b as eli n e   will  b e  pr es e nt e d  b y tr e at  m e nt  ar  m.    
1 7. 6. 8.    
A nti  -A  U  X  -I  a n d   A nti-A  U  X  -II   A nti b o di es 
A nti  -A  U  X  -I  a n d  a nti-A  U  X  -II  a nti b o d y l e v els  a n d  a s u bs et  of s u bj e ct   A nti-A  U  X  -I a n d  a nti-
A  U  X  -II  n e utr ali zi n g  a nti b o di es   will  b e s u  m  m ari z e d  usi n g  a p pr o pri at e  d es cri pti v e st atisti cs. 
1 7. 6. 9.    
Ot h e r  S af et y   M e as u r e  m e nts   
N ot  a p pli c a bl e.   
1 7. 7.    
P h a r  m a c o ki n eti c   A n al ys es  
N ot  a p pli c a bl e.   
1 7. 8.    
P h a r  m a c o d y n a  mi c   A n al ys es  
N ot  a p pli c a bl e.   
1 7. 9.    
Ot h e r   D at a ( e g,   H e alt h   E c o n o  mi c  s/  Q  O  L,  P h a r  m a c o g e n eti c,  et c)  
N ot  a p pli c a bl e.   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 5 
 
 
 
1 7. 1 0.    I nt e ri  m   A n al ysis 
N o i nt eri  m  a n al ysis is  pl a n n e d f or t his st u d y. 
1 7. 1 1.    St atisti c al  S oft  w a r e  
St atisti c al  a n al ys es   will  b e  p erf or  m e d  usi n g   V ersi o n  9. 3  ( or  hi g h er)  of  S  A S®  ( S  A S I nstit ut e, 
C ar y,   N  C).   
1 8.    
S  T  U  D  Y   D  R  U  G   M  A  T  E  RI  A  L S    AN  D   M  A  N  A  G  E  M  E  N  T   
1 8. 1.    
St u d y   D r u g I d e ntit y  
C  C  H   is   m a n uf a ct ur e d  a n d s u p pli e d  b y  E n d o. 
C  C  H   is  a st eril e l y o p hili z e d  p o  w d er  c o nsisti n g  of  0. 9 2   m g  of  c oll a g e n as e  cl ostri di u  m 
hist ol yti c u  m,  1 8. 9   m g s u cr os e,  1. 1   m g  Tris,  3 7. 7   m g   m a n nit ol,  a n d  h y dr o c hl ori c  a ci d  qs t o 
p  H  8. 5. 
C  C  H   st eril e  dil u e nt f or r e c o nstit uti o n is  0. 6  % s o di u  m  c hl ori d e  a n d  0. 0 3  %  c al ci u  m  c hl ori d e 
d e h y dr at e i n   w at er f or i nj e cti o n.  
1 8. 2.    
St u d y   D r u g  P a c k a gi n g  a n d   L a b eli n g  
E a c h  vi al  of st u d y  dr u g  a n d  dil u e nt   will   mi ni  m all y  b e l a b el e d   wit h  c o nt e nts,  S p o ns or 
i d e ntifi c ati o n, st or a g e,  a d  mi nistr ati o n/ us e,  a n d  a p pr o pri at e  c a uti o ns st at e  m e nts.  St u d y  dr u g  vi als 
a n d  dil u e nt  vi als   will  b e  p a c k a g e d  1 0  vi als  p er  c art o n.  
1 8. 3.    
St u d y   D r u g  St o r a g e  
All st u d y  dr u g   will  b e  pr o vi d e d  b y  E n d o.  St u d y  dr u g   m ust  b e st or e d i n  a n  a p pr o pri at e, s e c ur e 
ar e a.  St u d y  dr u g   m ust  b e  k e pt i n  a t e  m p er at ur e -m o nit or e d r efri g er at or ( 2°  C  - 8°  C)   wit h l o c k e d 
a c c ess  u ntil  us e d  or r et ur n e d t o  E n d o.  
1 8. 4.    
St u d y   D r u g  P r e p a r ati o n  
R ef e  r t o t h e   R e c o nstit uti o n I nstr u cti o ns f or  d et ail e d  pr e p ar ati o n i nstr u cti o ns t o  b e  us e d f or  e a c h 
ar  m.   
F or  e a c h  d os e s essi o n t h e 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)   will  assi g n t h e  a p pr o pri at e 
n u  m b er  of  dr u g  a n d  dil u e nt  vi als r e q uir e d  b as e d  o n t h e  ar  m  b ei n g  d os e d.  
Us e d  dr u g/ dil u e nt  vi als s h o ul d  b e st or e d i n  a s e c ur e l o c ati o n  u ntil r e c o n cil e d  a n d r et ur n e d  b y t h e 
m o nit or.   Dis p os e  of  us e d  n e e dl es  a n d s yri n g es  p er l o c al r e g ul ati o ns.  
T h e r e c o nstit ut e d st u d y  dr u g s ol uti o n s h o ul d  b e  a d  mi nist er e d  as s o o n  as  p ossi bl e  aft er 
r e c o nstit uti o n.  T h e st u d y  dr u g s ol uti o n  c a n  b e  k e pt  at r o o  m t e  m p er at ur e f or  u p t o  4  h o urs 
f oll o  wi n g t h e st art  of t h e r e c o nstit uti o n  pr o c ess. If   m or e ti  m e is  n e e d e d  pri or t o i nj e cti o n, 
r efri g er at e t h e r e c o nstit ut e d  dr u g  vi al/s yri n g e f or  u p t o  2 4  h o urs.   R e  m o v e  dr u g/ pr e p ar e d s yri n g es 
fr o  m t h e r efri g er at or  a n d  all o  w it t o st a n d  at r o o  m t e  m p er at ur e f or  1 5   mi n ut es  pri or t o i nj e cti o n 
of st u d y  dr u g. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 6 
 
 
 
1 8. 5.    
St u d y   D r u g   A c c o u nt a bilit y  
A  dr u g i n v e nt or y f or  m   m ust  b e  k e pt  c urr e nt  b y t h e   c e nt er  st aff  d esi g n at e d t o  b e r es p o nsi bl e f or 
r e c o nstit uti o n  a n d   m ust  b e   m a d e  a v ail a bl e t o t h e  cli ni c al   m o nit or,  E n d o  e  m pl o y e es, I  R  B/I E  C, 
a n d r e g ul at or y  a g e n ci es f or r o uti n e i ns p e cti o n  a n d  a c c o u nt a bilit y  d uri n g   m o nit ori n g  visits.   W h e n 
i nstr u ct e d  b y  E n d o, t h e I n v esti g at or  a gr e es t o r et ur n  all  ori gi n al  us e d  or  u n us e d st u d y  dr u g  vi als 
t o  E n d o’s r et ur n  v e n d or. 
1 8. 5. 1.    
St u d y   D r u g   H a n dli n g  a n d   Dis p os al  
T h e I n v esti g at or  a gr e es  n ot t o s u p pl y st u d y  dr u g t o  a n y  p ers o n  e x c e pt t o t h os e s u bj e cts  e nr oll e d 
i n 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 r e c or di n g t h e r e c ei pt  a n d  us e  of  all  dr u gs 
s u p pli e d  a n d f or  e ns uri n g t h e s u p er visi o n  of t h e st or a g e  a n d  all o c ati o n  of t h es e s u p pli es.   All  us e d 
a n d  u n us e d st u d y  dr u g   will  b e r et ur n e d,  a n d  u nit  c o u nts   will  b e  p erf or  m e d   w h e n e v er   m e di c ati o n 
is r et ur n e d.  T h e c e nt er    m ust  a c c o u nt f or  all st u d y  dr u g r e c ei v e d  a n d its  us e.   At t h e  e n d  of t h e 
st u d y,  all  us e d  a n d  u n us e d  dr u g   will  b e r et ur n e d t o  E n d o’s r et ur n  v e n d or. 
1 9.    
DI  R  E  C  T   A  C  C  E S S   T  O  S  O  U  R  C  E   D  A  T  A/  D  O  C  U  M  E  N  T S   
1 9. 1.    
S o u r c e   D o c u  m e nts  
S o ur c e  d o c u  m e nts i n cl u d e  b ut  ar e  n ot li  mit e d t o  ori gi n al  d o c u  m e nts,  d at a  a n d r e c or ds s u c h  as 
h os pit al/   m e di c al r e c or ds (i n cl u di n g  el e ctr o ni c  h e alt h r e c or ds),  cli ni c  c h arts, l a b r es ults, s u bj e ct 
di ari es,  d at a r e c or d e d i n  a ut o  m at e d i nstr u  m e nts,   mi cr ofil  m  or   m a g n eti c   m e di a,  a n d  p h ar  m a c y 
r e c or ds,  et c.  T his st u d y  all o  ws f or  dir e ct  d at a  e ntr y  of   C  R-P  C S S  o nl y.  
1 9. 2.    
St u d y   M o nit o ri n g  
A r e pr es e nt ati v e  of  E n d o   will   m e et   wit h t h e I n v esti g at or  a n d  his/ h er st aff  pri or t o t h e  e ntr a n  c e  of 
t h e first s u bj e ct t o r e vi e  w st u d y  pr o c e d ur es  a n d   m et h o ds  of r e c or di n g fi n di n gs i n t h e  e  C  R F.  
Aft er  e nr oll  m e nt  of t h e first s u bj e ct,  a n  E n d o r e pr es e nt ati v e   will  b e  assi g n e d t o  p eri o di c all y 
m o nit or  e a c h I n v esti g at or   c e nt er  f or st u d y  pr o gr ess  a n d t o  v erif y t h at st a n d ar ds  of   G o o d   Cli ni c al 
Pr a cti c e (  G  C P)   w er e f oll o  w e d.  T h e I n v esti g at or is  e x p e ct e d t o  pr e p ar e f or t h e   m o nit or  visit, 
e ns uri n g t h at  all s o ur c e  d o c u  m e nts,  c o  m pl et e d  e  C  R Fs, si g n e d  c o ns e nt f or  ms  a n d  ot h er st u d y 
r el at e d  d o c u  m e nts  ar e r e a dil y  a v ail a bl e f or r e vi e  w. 
1 9. 3.    
A u dits  a n d I ns p e cti o ns   
T h e I n v esti g at or s h all  p er  mit  a u dits  a n d i ns p e cti o ns  b y t h e  S p o ns or, its r e pr es e nt ati v es  a n d 
m e  m b ers  of r e g ul at or y  a g e n ci es.  T h e i n v esti g at or s h o ul d i  m  m e di at el y  n otif y t h e  S p o ns or  of  a n 
u p c o  mi n g  F  D  A  or  ot h er r e g ul at or y  a g e n c y i ns p e cti o n. 
1 9. 4.    
I nstit uti o n al   R e vi e  w   B o a r d (I  R  B)  
T h e I n v esti g at or s h all  p er  mit   m e  m b ers  of t h e I  R  B/I E  C t o  h a v e  dir e ct  a c c ess t o s o ur c e 
d o c u  m e nts. 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 7 
 
 
 
1 9. 5.    
D at a   R e c o r di n g  a n d   D o c u  m e nt ati o n   
All  d at a r e c or di n gs  a n d s o ur c e  d o c u  m e nt ati o n (i n cl u di n g  el e ctr o ni c  h e alt h   r e c or ds)   m ust  b e   m a d e 
a v ail a bl e t o t h e  S p o ns or ( or  d esi g n e e),  F  D  A  a n d  a n y  ot h er r e g ul at or y  a g e n ci es t h at r e q u est 
a c c ess t o st u d y r e c or ds, i n cl u di n g s o ur c e  d o c u  m e nts, f or 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 
f e d er al  a n d l o c al r e g ul ati o ns. 
2 0.    
Q  U  A  LI  T  Y   C  O  N  T  R  O  L   A  N  D   Q  U  A  LI  T  Y   A S S  U  R  A  N  C  E 
St e ps t o  ass ur e t h e  a c c ur a c y  a n d r eli a bilit y  of  d at a i n cl u d e t h e s el e cti o n  of  q u alifi e d  pri n ci p al 
i n v esti g at ors  a n d  a p pr o pri at e st u d y  c e nt ers, r e vi e  w  of  pr ot o c ol  pr o c e d ur es   wit h t h e  pri n ci p al 
i n v esti g at ors  a n d  ass o ci at e d  p ers o n n el  pri or t o st art  of t h e st u d y,  a n d  p eri o di c   m o nit ori n g  visits 
c o n d u ct e d  b y t h e  S p o ns or  or  S p o ns or r e pr es e nt ati v e.  Si g nifi c a nt  a n d/ or r e p e at e d  n o n- c o  m pli a n c e 
will  b e i n v esti g at e d  a n d r e  m e di al  a cti o n i nstit ut e d   w h e n  a p pr o pri at e.  F ail ur e t o  c o  m pl y   wit h 
r e  m e di al  acti o ns   m a y r es ult i n i n v esti g at or  c e nt er  t er  mi n ati o n  a n d r e g ul at or y  a ut h orit y 
n otifi c ati o n.  
T h e  S p o ns or  or its  d esi g n e e   will  utili z e  q u alifi e d   m o nit ors t o r e vi e  w  a n d  e v al u at e  a cti viti es 
c o n d u ct e d  at I n v esti g at or  C e nt er  s. 
T h e  d at a   will  b e  e nt er e d i nt o t h e  cli ni c al st u d y  d at a b as e  a n d  v erifi e d f or  a c c ur a c y, f oll o  wi n g 
pr o c e d ur es  d efi n e d  b y t h e  S p o ns or ( or  d esi g n e e).   D at a   will  b e  pr o c ess e d  a n d  a n al y z e d f oll o  wi n g 
pr o c e d ur es  d efi n e d  b y t h e  S p o ns or ( or  d esi g n e e). 
T h e st u d y   will  b e   m o nit or e d  a n d/ or  a u dit e d  at i nt er v als t o  e ns ur e t h at t h e  cli ni c al st u d y is 
c o n d u ct e d  a n d  d at a  ar e  g e n er at e d,  d o c u  m e nt e d (r e c or d e d),  a n d r e p ort e d i n  c o  m pli a n c e   wit h t h e 
St u d y  Pr ot o c ol; I nt er n ati o n al   C o u n cil f or   H ar  m o nis ati o n (I C  H),  E 6  c o ns oli d at e d  g ui d eli n es;  a n d 
ot h er  a p pli c a bl e r e g ul ati o ns.  T h e  e xt e nt,  n at ur e,  a n d fr e q u e n c y  of   m o nit ori n g  a n d/ or  a u dits   will 
b e  b as e d  o n s u c h  c o nsi d er ati o ns  as t h e st u d y  o bj e cti v es  a n d/ or  e n d p oi nts, t h e  p ur p os e  of t h e 
st u d y, st u d y  d esi g n  c o  m pl e xit y,  a n d  e nr oll  m e nt r at e.   At t h e  c o n cl usi o n  of  a  pr o gr a  m,  a 
c o  m pl i a n c e st at e  m e nt   will  b e  g e n er at e d  b y t h e  S p o ns or ( or  d esi g n e e) listi n g  all  a u dit  a cti viti es 
p erf or  m e d  d uri n g t h e  cli ni c al st u d y. 
2 1.    
E  T  HI  C S 
2 1. 1.    
Et hi cs   R e vi e  w   
A p pr o v al  b y t h e I  R  B/I E  C  pri or t o t h e st art  of t h e st u d y   will  b e t h e r es p o nsi bilit y  of t h e 
I n v esti g at or.   A  c o p y  of  a p pr o v al  d o c u  m e nt ati o n   will  b e s u p pli e d t o  E n d o  al o n g   wit h  a r ost er  of 
I  R  B   m e  m b ers t h at  d e  m o nstr at es  a p pr o pri at e  c o  m p ositi o n ( a   D e p art  m e nt  of   H e alt h  a n d   H u  m a n 
S er vi c es [  D  H  H S]   Ass ur a n c e   N u  m b er   will s atisf y t his r e q uir e  m e nt).   
T h e st u d y  pr ot o c ol, t h e i nf or  m e d  c o ns e nt f or  m,  a d v ertis e  m e nts,   m at eri als  b ei n g  pr o vi d e d t o 
s u bj e cts  a n d  a  m e n d  m e nts (if  a n y)   will  b e  a p pr o v e d t o I R  B/I E  Cs  at  e a c h st u d y  c e nt er i n 
c o nf or  m a n c e   wit h I  C  H  E 6, t h e   C o d e  of  F e d er al   R e g ul ati o ns (  C F  R),  Titl e  2 1,  P art  5 6  a n d  a n y 
ot h er  a p pli c a bl e l o c al l a  ws.  T h e I n v esti g at or is r es p o nsi bl e f or s u p pl yi n g t h e I R  B/I E  C   wit h  a 
c o p y  of t h e  c urr e nt I  B,  P a c k a g e I ns ert,  or  S P  C  as   w ell  as  a n y  u p d at es iss u e d  d uri n g t h e st u d y. 
D uri n g t h e  c o urs e  of t h e st u d y, t h e I n v esti g at or   will  pr o vi d e ti  m el y  a n d  a c c ur at e r e p orts t o t h e 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 8 
 
 
 
I  R  B/I E  C  o n t h e  pr o gr ess  of t h e st u d y,  at i nt er v als  n ot  e x c e e di n g  1  y e ar ( or  as  a p pr o pri at e),  a n d 
will  n otif y t h e I  R  B/I E  C  of  S  A Es  or  ot h er si g nifi c a nt s af et y fi n di n gs,  p er t h e  p oli c y  of t h e 
I  R  B/I E  C.   At t h e  c o n cl usi o n  of t h e st u d y, t h e I n v esti g at or   will s u b  mit  a fi n al r e p ort  or  cl os e  o ut 
r e p ort t o t h e I  R  B/I E  C  a n d  pr o vi d e  a  c o p y t o  E n d o 
A n y  a  m e n d  m e nt t o t his  pr ot o c ol   will  b e  pr o vi d e d t o t h e I n v esti g at or i n   writi n g  b y  E n d o.   N o 
pr ot o c ol  a  m e n d  m e nt   m a y  b e i  m pl e  m e nt e d (  wit h t h e  e x c e pti o ns  n ot e d  b el o  w)  b ef or e it  h as  b e e n 
a p pr o v e d  b y t h e I R  B  a n d t h e si g n at ur e  p a g e, si g n e d  b y t h e I n v esti g at or,  h as  b e e n r e c ei v e d  b y 
E n d o   W h er e t h e  pr ot o c ol is  a  m e n d e d t o  eli  mi n at e  or r e d u c e t h e ris k t o t h e s u bj e ct, t h e 
a  m e n d  m e nt   m a y  b e i  m pl e  m e nt e d  b ef or e I  R  B r e vi e  w  a n d  a p pr o v al.   H o  w e v er, t h e I  R  B   m ust  b e 
i nf or  m e d i n   writi n g  of s u c h  a n  a  m e n d  m e nt  a n d  a p pr o v al  o bt ai n e d   wit hi n r e as o n a bl e ti  m e li  mits. 
D e vi ati n g fr o  m t h e  pr ot o c ol is  p er  mitt e d  o nl y if  a bs ol ut el y  n e c ess ar y f or t h e s af et y  or  cli ni c al 
m a n a g e  m e nt  of t h e s u bj e ct,  a n d   m ust  b e i  m  m e di at el y r e p ort e d t o  E n d o.  
T h e I n v esti g at or   will  b e r es p o nsi bl e f or s u p pl yi n g  u p d at e d s af et y  a n d/ or st u d y i nf or  m ati o n t o 
st u d y s u bj e cts  as it  b e c o  m es  a v ail a bl e.   
2 1. 2.    
Et hi c al   C o n d u ct  of t h e  St u d y   
T his  cli ni c al st u d y is  d esi g n e d t o  c o  m pl y   wit h t h e I  C H   G ui d a n c e  o n   G e n er al   C o nsi d er ati o ns f or 
Cli ni c al  Tri als ( 6 2  F  R  6 6 1 1,   D e c e  m b er  1 7,  1 9 9 7),   N o n cli ni c al  S af et y  St u di es f or t h e   C o n d u ct  of 
H u  m a n   Cli ni c al  Tri als f or  P h ar  m a c e uti c als ( 6 2  F  R  6 2 9 2 2,   N o v e  m b er  2 5,  1 9 9 7),   G o o d   Cli ni c al 
Pr a cti c e:   C o ns oli d at e d   G ui d a n c e ( 6 2  F  R  2 5 6 9 2,   M a y  9,  1 9 9 7)  a n d  2 1   C F  R  p arts  5 0,  5 4,  5 6  a n d 
3 1 2. 
T h e st u d y   will  b e  c o n d u ct e d i n f ull  c o  m pli a n c e   wit h I C  H  E 6(  R 2), t h e  F  D  A  g ui d eli n es f or   G  C P 
a n d i n  a c c or d a n c e   wit h t h e  et hi c al  pri n ci pl es t h at  h a v e t h eir  ori gi ns i n t h e   D e cl ar ati o n  of   H elsi n k i 
d efi n e d i n  2 1   C F  R,  3 1 2. 1 2 0. 
2 1. 3.    
S u bj e ct I nf o r  m ati o n  a n d   C o ns e nt  
S u bj e cts,  aft er  h a vi n g t h e st u d y  e x pl ai n e d t o t h e  m  a n d  a n  o p p ort u nit y t o  h a v e t h eir  q u esti o ns 
a ns  w er e d s uffi ci e ntl y,   will  gi v e  v ol u nt ar y  a n d   writt e n i nf or  m e d  c o ns e nt (i n  c o  m pli a n c e   wit h 
I  C  H  E 6,  4. 8  a n d  2 1   C F  R  P arts  5 0  a n d  3 1 2)  b ef or e  p arti ci p ati n g i n  a n y st u d y-r el at e d  pr o c e d ur es. 
T h e  c o ns e nt s h all  b e   writt e n i n  a l a n g u a g e  u n d erst a n d a bl e t o t h e s u bj e ct.  S u bj e cts  u n a bl e t o 
r e a d (illit er at e) s h all  h a v e t h e  c o ns e nt  pr o c ess  p erf or  m e d i n t h e  pr es e n c e  of  a n i n d e p e n d e nt 
wit n ess   w h o s h all  als o si g n t h e  c o ns e nt.  E a c h s u bj e ct   will r e a d,  ass e nt  u n d erst a n di n g,  a n d si g n  a n 
i nstr u  m e nt  of i nf or  m e d  c o ns e nt  aft er  h a vi n g  h a d  a n  o p p ort u nit y t o  dis c uss t h e st u d y  a n d  c o ns e nt 
d o c u  m e nts   wit h t h e I n v esti g at or  b ef or e si g ni n g,  a n d   will  b e   m a d e  a  w ar e t h at  h e/s h e   m a y 
wit h dr a  w fr o  m t h e st u d y  at  a n y ti  m e.    
I n  a d diti o n t o  o bt ai ni n g i nf or  m e d  c o ns e nt, t h e I n v esti g at or is r es p o nsi bl e f or  o bt ai ni n g  a n y 
a d diti o n al  d o c u  m e nt ati o n t o  d e  m o nstr at e  c o  m pli a n c e   wit h l o c al  pri v a c y l a  ws  a p pli c a bl e t o 
a cti viti es  p erf or  m e d.   
T h e  c o ns e nt  pr o c ess s h all  b e r e c or d e d i n s o ur c e  d o c u  m e nts.  Si g n e d  c o pi es  of t h e i nf or  m e d 
c o ns e nt  a n d/ or  ass e nt   will  b e  gi v e n t o t h e  S u bj e ct  a n d  ori gi n als   will  b e  pl a c e d i n t h e I n v esti g at or 
st u d y fil es.   

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  4 9 
 
 
 
A  u ni q u e  S u bj e ct i d e nti  fi c ati o n  n u  m b er   will  b e  assi g n e d  at t h e ti  m e t h at t h e  S u bj e ct si g ns t h e 
i nf or  m e d  c o ns e nt f or  m. 
2 2.    
D  A  T  A   H  A  N  D  LI  N  G   A  N  D   R  E  C  O  R  D  K  E  E PI  N  G   
2 2. 1.    
D at a   C oll e cti o n   
D at a  c oll e cti o n   will i n v ol v e t h e  us e  of  a n  el e ctr o ni c  d at a  c a pt ur e ( E  D  C) s yst e  m t o   w hi c h  o nl y 
a ut h ori z e d  p ers o n n el   will  h a v e  a c c ess.  T h e s yst e  m   will  b e s e c ur e d t o  pr e v e nt  u n a ut h ori z e d 
a c c ess t o t h e  d at a  or t h e s yst e  m.  T his   will i n cl u d e t h e r e q uir e  m e nt f or  a  us er I  D  a n d  p ass  w or d t o 
e nt er  or  c h a n g e  d at a.  T h e l e v el  of  a c c ess t o t h e  E  D  C s yst e  m   will  b e  d e p e n d e nt  o n t h e  p e rs o n’s 
r ol e i n t h e st u d y. 
St u d y  d at a   will  b e  c oll e ct e d fr o  m s o ur c e  d o c u  m e nts  a n d  e nt er e d i nt o  a n  e  C  R F   wit hi n t h e  E  D  C 
s yst e  m.  T h e I n v esti g at or   will  b e r es p o nsi bl e f or  e ns uri n g t h e  e  C  R Fs  ar e  c o  m pl et e d i n  a ti  m el y 
m a n n er r el ati v e t o t h e s u bj e ct  ’s  visit. I n  a dditi o n t o  p eri o di c   m o nit ori n g  o c c urri n g   wit hi n t h e 
s yst e  m  b y  a  S p o ns or   m o nit or,  pr o gr a  m  m ati c  e dit  c h e c ks   will  b e  us e d t o r e vi e  w  E  D  C  d at a f or 
c o  m pl et e n ess, l o gi c,  a n d  a d h er e n c e t o t h e st u d y  pr ot o c ol.   As  a r es ult  of t his   m o nit ori n g  a n d t h es e 
c h e c ks,  q u eri es  m a y  b e iss u e d  el e ctr o ni c all y t o t h e  cli ni c al st u d y   c e nt ers  a n d  cl os e d 
el e ctr o ni c all y  b y t h e   m o nit or,  d at a   m a n a g e  m e nt st aff  or  a ut h ori z e d st aff  at t h e st u d y  c e nt er . 
A d diti o n all y, t h e I n v esti g at or   will r e vi e  w  e  C  R Fs,  e ns ur e  all   missi n g  or  c orr e ct e d  d at a is  pr  o vi d e d 
a n d   will si g n t h e  e  C  R F  p a g es   wit h  a n  el e ctr o ni c si g n at ur e.  
A n  el e ctr o ni c  a u dit tr ail   will  b e   m ai nt ai n e d i n t h e  E  D  C s yst e  m t o tr a c k  all  c h a n g es   m a d e t o  d at a 
e nt er e d i n t h e  e  C  R F.   D at a   will  b e r etri e v a bl e i n s u c h  a f as hi o n t h at  all i nf or  m ati o n r e g ar di n g 
e a c h i n di vi d u al s u bj e ct is  attri b ut a bl e t o t h at s u bj e ct.   U nl ess  ot h er  wis e i n di c at e d,  all  d at a 
c a pt ur e d i n t h e  e  C  R F   m ust first  b e  c a pt ur e d i n s o ur c e  d o c u  m e nts.   D at a t h at  c a n  b e  dir e ctl y 
r e c or d e d i n t h e  e  C  R F   will  b e  cl e arl y i d e ntifi e d i n t h e s e cti o n(s)  of t h e  pr ot o c ol t h at  d es cri b es t h e 
ass ess  m e nt(s).  
I n  a d diti o n,  a n y  c o nt a ct   wit h t h e s u bj e ct  vi a t el e p h o n e  or  ot h er   m e a ns t h at  pr o vi d e si g nifi c a nt 
cli ni c al i nf or  m ati o n   m ust  b e  d o c u  m e nt e d i n s o ur c e  d o c u  m e nts  as  d es cri b e d  a b o v e.  
2 2. 2.    
St u d y   D o c u  m e nt ati o n  
U p o n st u d y  c o  m pl eti o n, t h e  c o  m pl et e  e  C  R F, i n  p ort a bl e  d o c u  m e nt f or  m at ( P  D F),   will  b e  cr e at e d 
fr o  m t h e  E  D  C s yst e  m.  St u d y c e nt er s   will  b e  pr o vi d e d   wit h t h e  P  D F  of t h e  e  C  R F f or t h eir 
s u bj e cts.  
2 3.    
R  E P  O  R  TI  N  G   A  N  D  P  U  B  LI  C  A  TI  O  N 
All  d at a  g e n er at e d i n t his st u d y  ar e t h e  pr o p ert y   of  E n d o   A n i nt e gr at e d  cli ni c al  a n d st atisti c al 
r e p ort   will  b e  pr e p ar e d  at t h e  c o  m pl eti o n  of t h e st u d y. 
P u bli c ati o n  of t h e r es ults  b y t h e I n v esti g at or   will  b e s u bj e ct t o   m ut u al  a gr e e  m e nt  b et  w e e n t h e 
I n v esti g at or  a n d  E n d o 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 0 
 
 
 
2 4.    
I  N  V  E S  TI  G  A  T  O  R   O  B  LI  G  A  TI  O  N S 
2 4. 1.    
R e g ul at o r y   D o c u  m e nts   
T h e I n v esti g at or is r es p o nsi bl e f or  cr e ati n g  a n d/ or   m ai nt ai ni n g  all st u d y  d o c u  m e nt ati o n r e q uir e d 
b y  2 1  C F  R  5 0,  5 4,  5 6  a n d  3 1 2, I C  H,  E 6  S e cti o n  8,  as   w ell  as  a n y  ot h er  d o c u  m e nt ati o n  d efi n e d i n 
t h e  pr ot o c ol  or t h e I n v esti g at or   A gr e e  m e nt.  T h e I n v estig at or   m ust   m ai nt ai n t h e  d o c u  m e nt ati o n 
r el ati n g t o t his st u d y  a n d  p er  mit  E n d o  or  a   m e  m b er  of  a r e g ul at or y  a g e n c y  a c c ess t o s u c h r e c or ds. 
T h e I n v esti g at or   m ust  pr o vi d e t h e f oll o  wi n g  k e y  d o c u  m e nts t o  E n d o  pri or t o t h e st art  of t h e 
st u d y:  
•    A  c o  m pl et e d  a n d si g n e d  F or  m  F  D  A 1 5 7 2. If  d uri n g t h e  c o urs e  of t h e st u d y  a n y 
i nf or  m ati o n r e p ort e d  o n t h e  F or  m  F  D  A  1 5 7 2  c h a n g es,  a r e vis e d  F or  m  F  D  A 1 5 7 2   m ust 
b e  c o  m pl et e d  a n d r et ur n e d t o  E n d o f or s u b  missi o n t o t h e  F  D  A.  F or st u di es  e x e c ut e d 
o utsi d e t h e   U nit e d  St at es,  d o c u  m e nt ati o n r e q uir e d  b y t h e  g o v er ni n g r e g ul at or y 
a ut h orit y   m a y  b e s u bstit ut e d f or t h e  F or  m  F  D  A  1 5 7 2. 
•    A f ull y  e x e c ut e d  c o ntr a ct.   
•    T h e I n v esti g at or ’s  St at e  m e nt  p a g e i n t his  pr ot o c ol si g n e d  a n d  d at e d  b y t h e 
I n v esti g at or  a n d  a n y s u bs e q u e nt  a  m e n d  m e nt si g n at ur e  p a g es. 
•    T h e I  B  a c k n o  wl e d g  m e nt  of r e c ei pt  p a g e.  
•    C urri c ul a  vit a e f or t h e  Pri n ci p al I n v esti g at or  a n d  all  S u b  -I n v esti g at ors list e d  o n  F or  m 
F  D  A  1 5 7 2, i n cl u di n g  a  c o p y  of  e a c h  p h ysi ci a n’ s li c e ns e (if  a p pli c a bl e).  
•    A  c o p y  of t h e  ori gi n al I  R  B/I E  C  a p pr o v al f or  c o n d u cti n g t h e st u d  y. If t h e st u d y is 
o n g oi n g, r e n e  w als   m ust  b e s u b  mitt e d  at  y e arl y i nt er v als  or s h ort er i nt er v als  d efi n e d 
b y t h e I  R  B/I E  C.   All s u bs e q u e nt   m o difi c ati o ns   m ust  b e s u b  mitt e d  a n d  a p pr o v e d  b y t h e 
I  R  B. 
•    A  c o p y  of t h e I  R  B/I E  C- a p pr o v e d i nf or  m e d  c o ns e nt f or  m. 
•    A list  of   I R  B/I E  C   m e  m b ers  or   D  H  H S   Ass ur a n c e   N u  m b er. 
•    L a b or at or y  c ertifi c ati o ns  a n d  n or  m al r a n g es (if l o c al l a bs  ar e r e q uir e d  b y t h e 
pr ot o c ol). 
•    A fi n a n ci al  dis cl os ur e  a gr e e  m e nt  c o  m pl et e d  a n d si g n e d  b y t h e I n v esti g at or  a n d  all 
S u b-I n v esti g at ors list e d  o n  F or  m  F  D  A  1 5 7 2. I n v esti g at or  c e nt er  st aff t h at s u b  mitt e d 
a n i niti al fi n a n ci al  dis cl os ur e  ar e  als o r es p o nsi bl e f or i nf or  mi n g  E n d o  of  a n y  c h a n g es 
t o t h eir i niti al fi n a n ci al  dis cl os ur e f or  m  1  y e ar  aft er t h e  c o  m pl eti o n  of t h e st u d y. 
A  c o  m pl et e list  of r e q uir e d r e g ul at or y  d o c u  m e nts   will  b e s u p pli e d  b y  E n d o  or its r e pr es e nt ati v e. 
2 4. 2.    
D el e g ati o n  of   R es p o nsi biliti es  a n d   A d e q u at e   R es o u r c es   
T h e I n v esti g at or s h o ul d  h a v e  a d e q u at e ti  m e t o  c o n d u ct t h e st u d y  pr o p erl y  a n d s h o ul d  h a v e  a n 
a d e q u at e  n u  m b er  of  q u alifi e d st aff t o  assist   wit h t h e  c o n d u ct  of t h e st u d y.  T h e I n v esti g at or s h all 
d el e g at e t as ks  o nl y t o i n di vi d u als  q u alifi e d  b y  e d u c ati o n, tr ai ni n g  a n d  e x p eri e n c e t o  p e rf or  m t h e 
d el e g at e d t as ks.  T h e I n v esti g at or s h all  h a v e  dir e ct  o v ersi g ht  of  all  d el e g at e d  a cti viti es  a n d s h all 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 1 
 
 
 
d o c u  m e nt  d el e g ati o n  of r es p o nsi biliti es.  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  all  d el e g at e d 
st aff  h a v e  b e e n  pr o p erl y tr ai n e d  o n t h e  pr ot o c ol  a n d t h eir  assi g n e d st u d y r es p o nsi biliti es.  
2 4. 3.    
M e di c al   C a r e  of  St u d y  S u bj e cts   
T h e I n v esti g at or  a n d/ or  a  q u alifi e d s u b-i n v esti g at or s h all  b e r es p o nsi bl e f or t h e s u bj e cts’   m e di c al 
c ar e.   A n y  u nr el at e d   m e di c al  c o n diti o n  dis c o v er e d  d uri n g t h e  c o urs e  of t h e st u d y s h o ul d  b e 
c o  m  m u ni c at e d t o t h e s u bj e ct s o t h at t h e y   m a y s e e k  a p pr o pri at e   m e di c al  c ar e.  T h e I n v esti g at or 
will r e p ort  all   A Es  as r e q uir e d  b y t h e  pr ot o c ol.  T h e I n v esti g at or   will i nf or  m st u d y s u bj e cts  of 
n e  w i nf or  m ati o n r e g ar di n g t h e st u d y  dr u g  as it  b e c o  m es  a v ail a bl e.  
2 4. 4.    
Us e  of I n v esti g ati o n al   M at e ri als   
T h e I n v esti g at or   will  a c k n o  wl e d g e t h at t h e st u d y  dr u g s u p pli es  ar e i n v esti g ati o n al  a n d  as s u c h 
m ust  b e  us e d stri ctl y i n  a c c or d a n c e   wit h t h e  pr ot o c ol  a n d  o nl y  u n d er t h e s u p er visi o n  of t h e 
Pri n ci p al I n v esti g at or  or  S u b-I n v esti g at ors list e d  o n  F or  m  F  D  A 1 5 7 2 ( or  ot h er r e g ul at or y 
d o c u  m e nt,  d e p e n di n g  o n r e gi o n).  St u d y  dr u g   m ust  b e st or e d i n  a s af e  a n d s e c ur e l o c ati o n.   At 
st u d y i niti ati o n,  a r e pr es e nt ati v e fr o  m  E n d o   will i n v e nt or y t h e st u d y  dr u g  at t h e  c e nt er .  T h e 
I n v esti gat or   m ust   m ai nt ai n  a d e q u at e r e c or ds  d o c u  m e nti n g t h e r e c ei pt  a n d  dis p ositi o n  of  all st u d y 
s u p pli es.  E n d o  or its r e pr es e nt ati v e   will s u p pl y f or  ms t o  d o c u  m e nt t ot al i n v e nt or y  as   w ell  as 
s u bj e ct s p e cifi c  a c c o u nt a bilit y.  T h e I n v esti g at or is r es p o nsi bl e f or   m o nit ori n g s u bj e ct’s  us e  of t h e 
st u d y  dr u g t o  e ns ur e  c o  m pli a n c e   wit h t h e  pr ot o c ol.   All st u d y s u p pli es s h all  b e r et ur n e d t o  E n d o 
or its  d esi g n e e (t his   will i n cl u d e  e  m pt y  vi als).  
2 4. 5.    
R et e nti o n  of   R e c o r ds   
F e d er al  a n d l o c al r e g ul ati o ns r e q uir e t h at t h e I n v esti g at or r e t ai n  a  c o p y  of  all r e g ul at or y 
d o c u  m e nts  a n d r e c or ds t h at s u p p ort t h e  d at a f or t his st u d y ( e g, i nf or  m e d  c o ns e nts, l a b or at or y 
r e p orts, s o ur c e  d o c u  m e nts, st u d y  dr u g  dis p e nsi n g r e c or ds) f or   w hi c h e v er  of t h e f oll o  wi n g is t h e 
l o n g est  p eri o d  of ti  m e: 
•    A  p eri o d  of  2  y e ars f oll o  wi n g t h e fi n al  d at e  of  a p pr o v al  b y t h e  F  D  A  or  ot h er 
r e g ul at or y  a g e n c y  of t h e st u d y  dr u g f or t h e  p ur p os es t h at   w er e t h e s u bj e ct  of t h e 
i n v esti g ati o n;  or 
•    A  p eri o d  of  5  y e ars f oll o  wi n g t h e  d at e  o n   w hi c h t h e r es ults  of t h e i n v esti g ati o n   w er e 
s u b  mitt e d t o t h e  F  D  A  or  ot h er r e g ul at or y  a g e n c y i n s u p p ort  of,  or  as  p art  of,  a n 
a p pli c ati o n f or  a r es e ar c h  or   m ar k eti n g  p er  mit f or t h e st u d y  dr u g f or t h e  p ur p os es t h at 
w er e t h e s u bj e ct  of t h e i n v esti g ati o n   
E n d o   will  n otif y I n v esti g at ors  o n c e  o n e  of t h e  a b o v e  2  ti  m e fr a  m es  h as  b e e n s atisfi e d. 
If t h e i n v esti g ati o n  d o es  n ot r es ult i n t h e s u b  missi o n  of t h e  d at a i n s u p p ort  of,  or  as  p art  of,  a n 
a p pli c ati o n f or  a r es e ar c h  or   m ar k eti n g  p er  mit, r e c or ds   m ust  b e r et ai n e d f or  a  p eri o d  of  2  y e ars 
f oll o  wi n g  n otifi c ati o n  b y  E n d o t h at t h e  e ntir e  cli ni c al i n v esti g ati o n ( n ot   m er el y t h e I n v esti g at or’s 
p orti o n) is  c o  m pl et e d, t er  mi n at e d,  or  dis c o nti n u e d  or  2  y e ars f oll o  wi n g   wit h dr a  w al  of t h e 
I n v esti g ati o n al   N e  w   Dr u g A p  pli c ati o n (I  N  D)/  Cli ni c al  Tri al   A ut h ori z ati o n (  C T  A)  or r e q u est f o r 
m ar k eti n g  a p pr o v al (  N e  w   Dr u g   A p pli c ati o n [  N  D  A]/  M ar k eti n g   A ut h ori z ati o n   A p pli c ati o n 
[  M  A  A]).  

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 2 
 
 
 
If t h e I n v esti g at or r etir es, r el o c at es,  or f or  ot h er r e as o ns   wit h dr a  ws fr o  m t h e r es p o nsi bilit y  of 
k e e pi n g t h e st u d y r e c or ds,  c ust o d y   m ust  b e tr a nsf err e d t o  a  p ers o n   w h o   will  a c c e pt t h e 
r es p o nsi bilit y.  E n d o   m ust  b e  n otifi e d i n   writi n g  of t h e  n a  m e  a n d  a d dr ess  of t h e  n e  w  c ust o di a n. 
St u d y r e c or ds s h o ul d  n ot  b e  d estr o y e d   wit h o ut  c o ns ult ati o n   wit h  E n d o. 
2 4. 6.    
S u bj e ct   C o nfi d e nti alit y  
All s u bj e ct r e c or ds s u b  mitt e d t o  E n d o  or its  d esi g n e e   will  b e i d e ntifi e d  o nl y  b y  c o d e  n u  m b er. 
S u bj e cts ’  n a  m es  ar e  n ot t o  b e tr a ns  mitt e d t o  E n d o.  T h e I n v esti g at or   will  k e e p  a   M ast er  S u bj e ct 
List  o n   w hi c h t h e i d e ntifi c ati o n  n u  m b er  a n d t h e f ull  n a  m e,  a d dr ess,  a n d t el e p h o n e  n u  m b er  of 
e a c h s u bj e ct  ar e li st e d. It is t h e I n v esti g at ors ’ r es p o nsi bilit y t o i nf or  m st u d y s u bj e cts t h at 
r e pr es e nt ati v es  of t h e  S p o ns or,  F  D  A,  or  ot h er r e g ul at or y  a g e n ci es   m a y r e vi e  w  all r e c or ds t h at 
s u p p ort t h eir  p arti ci p ati o n i n t h e st u d y.  T h e I n v esti g at or   will  a d h er e t o  all  pri v a c y  l a  ws t o   w hi c h 
h e/s h e is s u bj e ct.  
2 5.    
T  E  R  MI  N  A  TI  O  N   O F  S  T  U  D  Y   
T h e  S p o ns or  h as t h e ri g ht t o s us p e n d  or t er  mi n at e t h e st u d y  at  a n y ti  m e.  T h e st u d y   m a y  b e 
s us p e n d e d  or t er  mi n at e d f or  a n y r e as o n. 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 3 
 
 
 
2 6.    
I  N  V  E S  TI  G  A  T  O  R’ S  S  T  A  T  E  M  E  N  T  
I  a gr e e t o  c o n d u ct t h e st u d y i n  a c c or d a n c e   wit h t h e  pr ot o c ol,  a n d   wit h  all  a p pli c a bl e  g o v er n  m e nt 
r e g ul ati o ns  a n d   G o o d   Cli ni c al  Pr a cti c e  g ui d a n c e. 
 
 
    _ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ 
I n v esti g at or’s  Si g n at ur e  
D at e   
 
 
 
T y p e d / Pri nt e d N a  m e  of I n v esti g at or   
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 4 
 
 
 
2 7.    
R  E F  E  R  E  N  C  E S   
A vr a  m   M  M.   C ell ulit e:  a r e vi e  w  of its  p h ysi ol o g y  a n d t  r e at  m e nt. J   C os  m et  L as er  T h er . 
2 0 0 4; 6( 4): 1 8 1- 5. 
B o y c e  S,  P a b b y   A,   C h u c h alt k ar e n  P,   Br a z zi ni   B,   G ol d  m a n   M P.   Cli ni c al  e v al u ati o n  of  a  d e vi c e 
f or t h e tr e at  m e nt  of  c ell ulit e:  Tri a cti v e. A  m  J   C os  m et  S ur g .  2 0 0 5; 2 2: 2 3 3- 7. 
C  ollis   N,  Elli ot  L  A,  S h ar p e   C,  S h ar p e   D T.   C ell ulit e tr e at  m e nt:  a   m yt h  or r e alit y:  a  pr os p e cti v e 
r a n d o  mi z e d,  c o ntr oll e d tri al  of t  w o t h er a pi es,  E n d er  m ol o gi e  a n d  a  mi n o p h ylli n e  cr e a  m. Pl ast 
R e c o nstr  S ur g .  1 9 9 9; 1 0 4( 4): 1 1 1 0- 4. 
Di  B er n ar d o   B E.  Tr e at  m e nt  of  c ell uli  t e  usi n g  a  1 4 4 0- n  m  p uls e d l as er   wit h  o n e-y e ar f oll o  w - u p. 
A est h et  S ur g  J .  2 0 1 1; 3 1( 3): 3 2 8- 4 1. 
E n d o  P h ar  m a c e uti c als I n c.   C oll a g e n as e  cl ostri di u  m  hist ol yti c u  m f or I nj e cti o n 
(  A  A 4 5 0 0/ E  N 3 8 3 5),   V ersi o n  8. 0. I n v esti g ati o n al   Br o c h ur e. J ul y  2 0 1 7. 
H e xs el   D,  d e   Oli v eir  a   D al’ F or n o  T,   M a z z u c o   R.   D efi niti o n,  cli ni c al  as p e cts,  cl assifi c ati o ns,  a n d 
di a g n osti c t e c h ni q u es. I n:   G ol d  m a n   M P,   H e xs el   D,  e ds.  C ell ulit e:  P at h o p h ysi ol o g y  a n d 
Tr e at  m e nt .  2 n d  e d.   N e  w   Y or k,   N  Y: I nf or  m a   H e alt h c ar e;  2 0 1 0: 1 3  2 1. 
H e xs el   D  M,   D al’ F or n o  T,   H e xs e  l   C L.   A  v ali d at e d  p h ot o n u  m eri c  c ell ulit e s e v erit y s c al e. J  E ur 
A c a d   D er  m at ol  V e n er e ol .  2 0 0 9; 2 3( 5): 5 2 3- 5 2 8. 
H e xs el   D  M,   M a z z u c o   R.  S u b cisi o n:   A tr e at  m e nt f or  c ell ulit e.   I nt  J   D er  m at ol. 
2 0 0 0; 3 9( 7): 5 3 9- 4 4. 
K h a n   M  H,   Vi ct or  F,   R a o   B,  S a di c k   N S.  Tr e at  m e nt  of  c ell  ulit e:  P art I.  P at h o p h ysi ol o g y.  J  A  m 
A c a d   D er  m at ol .  2 0 1 0 a; 6 2( 3): 3 6 1- 7 0. 
K h a n   M  H,   Vi ct or  F,   R a o   B,  S a di c k   N S.  Tr e at  m e nt  of  c ell ulit e:  P art II.   A d v a n c es  a n d 
c o ntr o v ersi es.  J  A  m  A c a d   D er  m at ol .  2 0 1 0 b; 6 2( 3): 3 7 3- 8 4. 
N ür n b er g er  F,   M üll er   G.  S o-  c all e d  c ell ulit e:  a n i n v e nt e d  dis e as e.  J   D er  m at ol  S ur g   O n c ol . 
1 9 7 8; 4( 3): 2 2 1- 2 2 9. 
R a  wli n gs   A  V.   C ell ulit e  a n d its tr e at  m e nt. I  nt  J   C os  m eti c  S ci .  2 0 0 6; 2 8( 3): 1 7 5- 9 0. 
T err a n o v a  F,   B er ar d es c a  E,   M ai b a c h   H.   C ell ulit e:  n at ur e  a n d  a eti o p at h o g e n esis.   I nt  J   C os  m eti c 
S ci .  2 0 0 6; 2 8( 3): 1 5 7- 6 7. 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 5 
 
 
 
A P P  E  N  DI  X   A.     C  LI  NI  CI  A  N   R  E P  O  R  T  E  D  P  H  O  T  O  N  U  M  E  RI  C  S  E  V  E  RI  T  Y   
S  C  A  L  E  F  O  R   C  E  L  L  U  LI  T  E  (  C  R-P  C S S)  F  O  R   T  H  E 
B  U  T  T  O  C  K 
 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 6 
 
 
 
A P P  E  N  DI  X     B.   C  LI  NI  CI  A  N   R  E P  O  R  T  E  D  P  H  O  T  O  N  U  M  E  RI  C  S  E  V  E  RI  T  Y   
S  C  A  L  E  F  O  R   C  E  L  L  U  LI  T  E  (  C  R-P  C S S)  F  O  R   T  H  E   T  HI  G  H  
 
 
 

E  N 3 8 3 5- 2 0 9  Pr ot o c ol   A  m e n d  m e nt  1 
2 9   A u g ust  2 0 1 8 
E n d o  P h ar  m a c e uti c als I n c.  
P a g e  5 7 
 
 
 
A P P  E  N  DI  X   C.     H  E  X S  E  L   C  E  L  L  U  LI  T  E  S  E  V  E  RI  T  Y   S  C  A  L  E (  C S S) (  B) 
D  E P  T  H   O F   D  E P  R  E S SI  O  N S   
 
 
 
D e pt h  of  d e pr essi o ns     
0  =  n o  d e pr essi o ns  
1  = s u p erfi ci al  d e pr essi o ns  
2  =   m e di u  m  d e pt h  d e pr essi o ns  
3  =  d e e p  d e pr essi o ns