Conditions: Edematous Skin
Keywords: Edematous Fibrosclerotic Panniculopathy Cellulite Collagenase Clostridium Histolyticum
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The study will evaluate the safety and effectiveness of different injection techniques of Collagenase Clostridium Histolyticum (CCH) for the treatment of adult women with mild, moderate or severe Edematous Fibrosclerotic Panniculopathy (commonly known as Cellulite).

Detailed description:

Arms:
arm 1: In Treatment I, CCH will be injected subcutaneously while the participant lies in a prone position. Each injection will consist of a single skin injection of study drug administered as three 0.1 milliliters (mL) aliquots (for a total injection volume of 0.3 mL).

During each treatment visit, 8 syringes (4 syringes per treatment area) will be prepared for dosing. Each syringe will contain 0.9 mL of CCH (3 injections in each syringe). Dose per participant per treatment visit = up to 1.68 milligrams (mg) of CCH (0.84 mg in each treatment area). arm 2: In Treatment II, CCH will be injected subcutaneously while the participant is in a prone position. Each injection will consist of a single skin injection of study drug administered as a single shallow injection of a 0.3 mL aliquot.

During each treatment visit, 8 syringes (4 syringes per treatment area) will be prepared for dosing. Each syringe will contain 0.9 mL of CCH (3 injections in each syringe). Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area). arm 3: In Treatment III, CCH will be injected subcutaneously while the participant is in a prone position. Each injection will consist of a single skin injection of study drug administered as a single deep injection of a 0.3 mL study drug aliquot.

During each treatment visit, 8 syringes (4 syringes per treatment area) will be prepared for dosing. Each syringe will contain 0.9 mL of CCH (3 injections in each syringe). Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area). arm 4: In Treatment IV, CCH will be injected subcutaneously while the participant lies in a prone position. Each injection will consist of a single skin injection of study drug administered as five 0.3 mL (for a total injection volume of 1.5 mL).

During each treatment visit, 24 syringes (12 syringes per treatment area) will be prepared for dosing. Each syringe will contain 1.5 mL of CCH (5 aliquots of 0.3 mL, for each injection, in each syringe). Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area). arm 5: In Treatment V, CCH will be injected subcutaneously while the participant lies in a prone position. Each injection will receive a single skin injection of study drug administered as four 0.3 mL aliquots (for a total injection volume of 1.2 mL).

During each treatment visit, 24 syringes (12 syringes per treatment area) will be prepared for dosing. Each syringe will contain 1.2 mL of CCH (4 aliquots of 0.3 mL each). Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area).

Interventions: intervention 1: collagenase clostridium histolyticum (CCH)
Intervention descriptions: intervention 1: Endo Pharmaceuticals Inc. (Endo) is developing collagenase clostridium histolyticum (CCH) for the treatment of EFP. Because CCH is a proteinase that can hydrolyze the triple-helical region of collagen under physiological conditions, CCH has the potential to be effective in lysing sub-dermal collagen, such as those observed in the dermal septa, which are the underlying cause of the skin dimpling in women with Edematous Fibrosclerotic Panniculopathy (EFP). CCH targets the collagenase structural matrix (for example, dermal septa) at the site of injection and does not require systemic exposure to be effective.

Protocol document:
Prot_000.pdf: 


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  
 

SAP_001.pdf: 
Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
1 1- Fe b- 2 0 1 9
E n d o P har m ace ut icals I nc.
Pa ge 1
 
S A P M O D U L E 1 – D E T AI L E D S T A TI S TI C A L M E T H O D O L O G Y
St u d y E N 3 8 3 5 -2 0 9
A P H A S E 2 A, O P E N -L A B E L S T U D Y E V A L U A TI N G T H E S A F E T Y A N D 
DI F F E R E N T I N J E C TI O N T E C H NI Q U E S O F C O L L A G E N A S E 
C L O S T RI DI U M HI S T O L Y T I C U M F O R T H E T R E A T M E N T O F
E D E M A T O U S FI B R O S C L E R O TI C P A N NI C U L O P A T H Y
Fe br u ar y 1 1 , 2 0 19
E n d o P h ar m ace utic als I nc. 
1 4 0 0 At w ater Dri ve 
M al ver n, P A 1 9 3 5 5 
U S A


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
1 1- Fe b- 2 0 1 9
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T A B L E O F C O N T E N T S
1.  
I N T R O D U C TI O N....................................................................................................8
2.  
S T U D Y O BJ E C TI V E S .............................................................................................8
2. 1.  
Pri mar y O bject i ve.....................................................................................................8
2. 2.  
Sec o n dar y  O bjecti ve................................................................................................. 8
2. 3.  
E x pl or at or y  O bjecti ves .............................................................................................8
3.  
S T U D Y D E SI G N A N D M E A S U R E S ......................................................................8
3. 1.  
St u d y  Desi g n............................................................................................................8
3. 2.  
I ncl usi on Cri t eria ....................................................................................................1 2
3. 3.  
E xcl usi o n Cri t eria ...................................................................................................1 2
3. 4.  
Treat me nt Re gi o n a n d Area ....................................................................................1 4
3. 5.  
S el ect i on of Di m ples a n d I nject i on Si tes D uri n g Treat me nt Visits ..........................1 4
3. 5. 1.  
S el ect i n g a n d Mar ki n g t he Di m ples ........................................................................1 4
3. 6.  
St u d y  Dr u g A d mi nistrati o n.....................................................................................1 4
3. 6. 1.  
Deter mi nat i on of Sa m ple Size .................................................................................1 7
3. 6. 2.   
B li n di n g a n d Ra n d omizat i on ...................................................................................1 7
3. 7.  
Cli nicia n Re p orte d P h ot o n u meric Cell ulite Se verit y Scale ( C R -P C S S) ...................1 7
3. 8.  
3- D P h ot o gra p h y ....................................................................................................1 8
3. 9.  
Di m ple A nal ysis .....................................................................................................1 8
3. 1 0.  
Br ui se A nal ysis.......................................................................................................1 9
3. 1 1.  
He xsel De pressi o n De pt h Scale ..............................................................................1 9
3. 1 2.  
Me dical a n d S ur gical Hist or y ..................................................................................1 9
3. 1 3.  
E de m at o us Fi br oscler otic Pa n nic ul o pat h y Disease ( E F P) Hist or y........................... 2 0
3. 1 4.  
S u bsta nce Use ........................................................................................................2 0
3. 1 5.  
Pri or/ C o nc o mi ta nt Me dic atio ns a n d Pr oce d ures ......................................................2 0
3. 1 6.  
Pr o hi bite d Me dicati o ns ...........................................................................................2 0
3. 1 7.  
A d verse E ve nts .......................................................................................................2 1
3. 1 7. 1.  
A d verse E ve nts ( A E) ..............................................................................................2 1
3. 1 7. 2.  
S eri o us A d verse E ve nts ( S A Es) ..............................................................................2 1
3. 1 7. 3.  
A d verse E ve nts of S pecial I nterest ..........................................................................2 1
3. 1 8.  
Cli nical Safet y  La b orat or y Tests.............................................................................2 1
3. 1 9.  
Pre g na nc y Test .......................................................................................................2 2


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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3. 2 0.  
Vi t al Sig ns ..............................................................................................................2 2
3. 2 1.  
1 2- Lea d Electr ocar di o gra m ( E C G) .........................................................................2 2
3. 2 2.  
P h ysical E xa mi nat i on .............................................................................................2 3
3. 2 3.  
I mm u n o ge nicit y ......................................................................................................2 3
4.  
S T U D Y P A R A M E T E R S ........................................................................................2 3
4. 1.  
S u bject Dis p osit i on ................................................................................................. 2 3
4. 2.  
Pr ot oc ol  De viati ons ................................................................................................2 4
4. 3.  
Pri or C o nc o mi ta nt a n d F ollo w -u p Me di c atio ns....................................................... 2 4
4. 4.  
Pri or E F P Treat m e nt ...............................................................................................2 4
4. 5.  
Efficac y Para meters ................................................................................................2 5
4. 5. 1.  
I mpr o ve m e nt i n Aest het ic A p peara nce usi n g 3 -D P h ot o gra p hic I ma ge ...................2 5
4. 5. 2.  
C ha n ge i n Di m ple A nal ysis Para meters usi n g 3 -D P h ot o gra p hic I ma ge ..................2 5
4. 5. 3.  
C ha n ge fr o m Baseli ne i n Di m ple De pt h De pressi o n b y He xsel C S S ( B) .................2 5
4. 6.  
S af et y Para m eters ...................................................................................................2 5
4. 6. 1.  
A d verse E ve nts .......................................................................................................2 5
4. 6. 1. 1.  
Treat me nt E mer ge nt A d verse E ve nts ( T E A Es) .......................................................2 6
4. 6. 1. 2.  
I nte nsity of  Ad verse E ve nts ....................................................................................2 6
4. 6. 1. 3.  
Relati o ns hi p t o St u d y  Dr u g.....................................................................................2 6
4. 6. 2.  
Vi t al Sig ns a n d Cli nical La b orat ories ......................................................................2 6
4. 6. 2. 1.  
P ote nti all y Cli nicall y I mp orta nt La b orat or y  Val ues ................................................2 6
4. 6. 2. 2.  
P ote nti all y Cli nicall y I mp orta nt Vi t al Si g n Values ..................................................2 7
4. 6. 3.  
Br ui se A nal ysis usi n g L * A * B * C o or di nates ...........................................................2 7
4. 7.  
Ot her Safet y Para m eters .........................................................................................2 8
4. 7. 1.  
I mm u n o g e nicit y......................................................................................................2 8
5.  
A N A L Y SI S P O P U L A TI O N S .................................................................................2 8
6.   
S T A TI S TI C A L M E T H O D S ...................................................................................2 8
6. 1.  
Ge neral Met h o d o l og y .............................................................................................2 8
6. 2.  
A d j ustme nt s for C o vari ates .....................................................................................2 9
6. 3.  
Deri ve d Varia bles ...................................................................................................2 9
6. 4.  
Ha n dli n g of Mis si n g Data .......................................................................................3 1
6. 4. 1.  
I mp utati o n of  Partial Dates.....................................................................................3 1
6. 4. 1. 1.  
T E A E Stat us f or C o m pletel y U n k n o w n Start Date ..................................................3 1
6. 4. 1. 2.  
C o nc o mita nt Stat us of Me dicati o n f or C o m p letel y U n k n o w n Start Date .................3 1


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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6. 4. 1. 3.  
Missi n g E F P O nset Date .........................................................................................3 2
6. 5.  
I nteri m A nal yses.....................................................................................................3 2
7.  
S T A TI S TI C A L A N A L Y S E S ..................................................................................3 2
7. 1.  
S u bject Dis p osi tio n ................................................................................................. 3 2
7. 2.  
Pr ot oc ol  De viati on ..................................................................................................3 2
7. 3.  
De m o gra p hics a n d Baseli ne C haracterist ics............................................................3 2
7. 4.  
Me dical a n d S ur gical Hist or y ..................................................................................3 3
7. 5.  
E F P Hi st or y............................................................................................................ 3 3
7. 6.  
C o nc o mita nt Me dicati o ns a n d Pr oce d ures ...............................................................3 3
7. 7.  
Efficac y A nal yses ...................................................................................................3 4
7. 7. 1.  
I mpr o ve m e nt in Aest het ic A p peara nce usi n g 3 -D P h ot o gra p hic I ma ges ..................3 4
7. 7. 1. 1.  
A nal ysis of Treat me nt Re gi o n a n d Area ..................................................................3 4
7. 7. 2.  
C ha n ge i n Di m ple A nal ysis Para meters usi n g 3 -D P h ot o gra p hic I ma ge ..................3 4
7. 7. 3.  
C ha n ge fr o m Baseli ne i n Di m ple De pt h De pressi o n b y He xsel C S S ( B) .................3 4
7. 8.  
S af et y A nal yses ......................................................................................................3 4
7. 8. 1.  
St u d y  Dr u g E x p os ure..............................................................................................3 5
7. 8. 2.  
A d verse E ve nts .......................................................................................................3 5
7. 8. 3.  
Cli nical La b ora t or y................................................................................................. 3 7
7. 8. 4.  
Vi t al Sig ns.............................................................................................................. 3 7
7. 8. 5.   
1 2- Lea d E C G ..........................................................................................................3 7
7. 8. 6.  
P h ysical E xa mi nat i on .............................................................................................3 7
7. 8. 7.  
Br ui se A nal ysis usi n g L * A * B * C o or di nates ...........................................................3 7
7. 9.  
Ot her Safet y Para m eters .........................................................................................3 8
7. 9. 1.  
I mm u n o ge nicit y ......................................................................................................3 8
8.  
C H A N G E F R O M P R O T O C O L ..............................................................................3 8
9.  
R E VI SI O N HI S T O R Y ...........................................................................................3 9
1 0.  
R E F E R E N C E S .......................................................................................................3 9
1 1.  
T A B L E S, LI S TI N G S, A N D G R A P H S H E L L S ......................................................3 9


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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LI S T O F T A B L E S
Ta ble 1:  
Sc he d ule of E ve nts ................................................................................................. 1 0
Ta ble 2:  
V ol u me a n d C o nce ntrati o n of  I njecti ons ................................................................. 1 6
Ta ble 3:  
C R -P C S S B utt oc k Scale .........................................................................................1 7
Ta ble 4:  
C R -P C S S T hi g h Scale ............................................................................................1 7
Ta ble 5:  
Li kert Scal e of Le vel of Aest hetic I m pr o ve me nt.....................................................1 8
Ta ble 6:  
He xsel C S S ( B) De pt h of De pressi o ns ....................................................................1 9
Ta ble 7:  
Cli nical Safet y  La b orat or y Para meters ....................................................................2 2
Ta ble 8:  
Fi tz patric k Scale .....................................................................................................2 3
Ta ble 9:  
P ote nti all y Cli nicall y I mp orta nt La b orat or y  Criteria ...............................................2 7
Ta ble 1 0: 
P ote nti all y Cli nicall y I mp orta nt Vi t al Si g n Crit eria .................................................2 7
Ta ble 1 1: 
A nal ysis P o p ulat i ons ..............................................................................................2 8
Ta ble 1 2: 
Deri ve d Varia bles a n d Defi nit i on ............................................................................3 0
Ta ble 1 3: 
C ha n ges fr o m Pr ot oc ol ...........................................................................................3 8
Ta ble 1 4: 
Re visi o n Hist or y .....................................................................................................3 9


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S
A b bre vi ati o n  
Defi niti o n
A E
A d verse e ve nt
A OI
Ar ea of I nterest
A T C
A nat o mical t hera pe utic c he mical
A U X -I
Cl ostri dial class I c olla ge nase
A U X -II
Cl ostri dial class II c olla ge nase
B MI
B o d y ma ss i n de x
b p m
Beats per mi n ute
b r p m
Breat hs per mi n ute
C C H
C olla ge nase cl ostri di u m hist ol ytic u m
CI
C o nfi de nce int er val
c m
Ce nti meter
C R -P C S S  
Cli nicia n -R e p orte d P h ot o n u meric Cell ulite Se verit y Scale
C S S
Cell ulite Se verit y Scale
D M P
Data Ma na ge me nt Pla n
3 - D
T hree di me nsi o nal
E C G
Electr ocar di o gra m
E D C
Electr o nic data ca pt ure
E O S
E n d of st u d y
e C R F
Electr o nic case re p ort f or m
e Cr Cl
Creati ni ne cleara nce (esti mate d)
E F P
E de mat o us fi br oscler otic pa n nic ul o pat h y
He xsel C S S  
He xsel C e ll ulite Se verit y Scale
I A T
I ma ge A nal ysis Tec h nicia n
I E C
I n de pe n de nt Et hics C o m mittee
I R B
I nstit uti o nal Re vie w B oar d
k g
Kil o gra m
m
Meter
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
m g
Milli gra m
m L
Milliliter
N
N u m b e r of s u bjects
O T C
O ver t he c o u nter
P CI
P ote ntiall y cli nicall y i m p orta nt
P T
Preferre d ter m


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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A b bre vi ati o n  
Defi niti o n
S A E
Seri o us a d verse e ve nt
S A P
Statistical a nal ysis pla n
S Cr
Ser u m creati ni ne
S D
Sta n dar d de viati o n
S O C
S yste m or ga n class
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
U L N
U p per li mit of n or ma l
U S
U nite d States
W H O
W orl d Healt h Or ga nizati o n


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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1.  
I N T R O D U C TI O N
T his Statist ical A nal ysis Pl a n ( S A P) descri bes t he pla n ne d a nal yses t o e val uate t he safet y a n d 
effect i ve ness of differe nt i nject i on tec h ni q ues of  colla ge nase c l ostridi u m h ist ol ytic u m (C C H ) i n 
a d ult w o me n wit h mil d, mo derate or se vere ede m at o us fi br oscler otic p a n nic ulo pat h y
( E F P)/cell ulite.
T he ge neral i nf or mat i on a b o ut t he st u d y  is detaile d i n t he E N 3 8 3 5 -2 0 9 pr ot oc ol a me n d me nt 1 , 
date d A u g ust 2 9, 2 0 1 8 .(1 )
2.  
S T U D Y O B J E C TI V E S
2. 1.  
Pri m ar y O bjecti ve
T he pri mar y  o bjecti ve of t his st u d y is t o assess t he treat me nt effects of C C H w he n a d mi nistere d 
b y differe nt i njecti on tec h ni q ues i n s u bjects wit h E F P .
2. 2.  
Sec o n d ar y O bjecti ve
T he sec o n dar y  o bjecti ve of t his st u d y is t o assess t he safety of  C C H w he n a d mi nistere d usi n g
differe nt i nject i on tec h ni q ues i n s u bjects wit h E F P.
2. 3.  
E x pl or at or y O bjecti ves
T he e x pl orat or y  o bject i ves i ncl u de:

T o assess t he i m m u n o ge nicit y of C C H i n t he treat me nt of E F P

T o assess t he usef ul ness of 3 -D p h ot o gra p h y  in e val uat i ng o utc o m es of treat me nt for 
E F P
3.  
S T U D Y D E SI G N A N D M E A S U R E S
3. 1.  
St u d y Desi g n
T his is a P hase 2a, o pe n -label, m ul tice nter, e x pl orat or y st u d y t o e val uate t he safety a n d
effect i ve ness of differe nt i njecti on tec h ni q ues o f C C H f or t he treat me nt of a d ult w o me n with
E F P. T hi s st u d y will be perf or me d at a p pr o xi matel y 5 sites i n t he U nite d States ( U S).
S u bjects ha vi n g t he e vi de nce of cell ulite i n 2 b utt oc ks or 2 t hig hs (treat me nt area) at t he 
Scree ni n g V isit will be e nr o lle d if t he y satisf y t he criteria bel o w :

Ha ve a C R-P C S S sc ore of 2 ( mil d), 3 ( m o derate) or 4 (se vere) as re p orte d b y  t he 
I n vesti gat or i n 2 treat me nt areas (t w o t hi g hs or t w o b utt ocks) 

Ha ve at least 2 di m ples fr o m eac h treat me nt area t hat:

are is o late d a n d se parate d b y at least 5 c m fr o m a n y ot her di mples


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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
sc ore 2 or 3 o n t he He xsel de pressi o n scale

ha ve d i m ple wi dt h: le n gt h rati o ≥ 0. 5
If b ot h b utt oc ks a n d b ot h t hi g hs meet e ntr y  crit eria for a si n gle s u bject, t he n t he t hi g hs will be 
treate d. N o s u bject will be treate d f or E F P i n b ot h t he b utt oc ks a n d t he t hi g hs d uri n g t his st u d y.
T he st u d y  will e nr oll a p pr o xi matel y 6 0 s u bjects; 3 0 s u bjects wi t h 2 eli gi ble b utt oc ks (t o be d ose d 
i n t he b utt oc ks) a n d 3 0 s u bjects wi t h 2 eli gi ble t hig hs (t o be d ose d i n t he t hi g hs). T he 3 0 s u bjects 
i n eac h treat me nt re gio n ( b utt oc ks or t hi g hs) will be assi g ne d se q ue ntiall y t o 1 of 5 i njecti on 
tec h ni q ue treat me nt ar ms o n Da y 1 (ie, 6 s u bjects per re gi o n per treat me nt ar m) . N o c o ntr ol 
gr o u ps will be e m pl o ye d. S u bjects w h o disc o nti n ue fr o m t he st u d y will not be re pl ace d.
S u bjects w h o c o m plete t he st u d y  will partici pate f or a p pr o xi matel y 9 2 da ys i ncl u di n g a 2 1 -da y  
of  scree ni n g perio d, a 4 3 -da y tr e at me nt perio d a n d a 2 8-da y  fol l ow- u p peri o d. S u bjects will 
recei ve t he st u d y inject i ons o n Da y s 1, 2 2 , a n d 4 3. A d dit i onal sc he d ule d assess me nts will be 
perf or m e d o n Da ys 4, 8, 1 5 , a n d 7 1.
Ta ble 1 b elo w descri bes t he sc he d ule of e ve nts a n d assess me nts perf or me d d uri n g scree ni n g, 
treat me nt visits, a n d assess me nt visits.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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E n d o P har m ace ut icals I nc.
Pa ge 1 0
T a ble 1:  
Sc he d ule of E ve nts
Pr oce d ure
Scree 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 arl y 
Ter mi n ati o n/
D a y 7 1
( ± 3 d a ys)
U nsc he d ule d
Cli nic Visit a
I nf or me d c o nse ntb
X
I ncl usi o n/e xcl usi o n criteria re vie w
X
X c
De m o gra p hic data
X
3 -D P h ot o gra p h y
X
X d,e
X    
X    
X    
X d,e
X d,e
X
Me dical/s ur gical/ E F P hist or y (i ncl u di n g 
pre vi o us treat me nt)
X
Pri or/c o nc o mita nt me dicati o ns/ pr oce d ures
X
X e
X    
X    
X    
X
X
X
X
P h ysical E xa mi nati o n
X
X
X
Hei g ht
X
Wei g ht
X
X e
X
X
Fitz patric k s ki n t y pe
X
Vital si g ns
X
X f
X f
X f
X
X
1 2- lea d E C G
X
Safet y La b orat or y Tests
X
X
X
A nti -A U X - 1/a nti-A U X -II a nti b o d y le vel 
sa m ple
X e
X
Ser u m pre g na nc y test
X
Uri ne pre g na nc y test
X e
X e
X e
X
X
Assi g n me nt of treat me nt area ( b utt oc ks or 
t hi g hs)
X
Selecti o n of 2 di m ples wit hi n eac h treat me nt 
area f or v ol u metric assess me nt
X e
C R -P C S S
X
He xsel De pressi o n De pt h Scale
X
X
X
X
Assi g n Treat me nt Ar m ( d osi n g i njecti o n 
tec h ni q ue)
X e
Mar k t he di m ple i njecti o n sites
X e
X e
X e


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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Pa ge 1 1
T a ble 1:  
Sc he d ule of E ve nts ( C o nti n ue d)
Pr oce d ure
Scree 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 arl y 
Ter mi n ati o n/
D a y 7 1
( ± 3 d a ys)
U nsc he d ule d
Cli nic Visit a
St u d y  dr u g a d mi nistrati o n
X
X
X
I njecti o n site reacti o ns/l ocal t olera bilit y i n t he 
treate d areas
X    
X    
X    
X    
X
X
X
X
All ot her a d verse e ve nts
-------------------------------------------------X ------------------------------------------------------------------
a D uri n g u nsc he d ule d visits t he i n vesti gat or or desi g nee ma y perf or m a n y st u d y pr oce d ure t hat t he y dee m cli nicall y necessar y (e g, vital si g ns, cli nical la b orat or y 
assess me nts, pre g na nc y t est, etc).
b Perf or me d pri or t o a n y st u d y -re q uire d assess me nts.
c S h o ul d be reassesse d a n d verifie d pri or t o st u d y dr u g a d mi nistrati o n.
d C o m plete bef ore a n d after mar ki n g i njecti o n sites.
e C o m plete pri or t o st u d y dr u g a d mi nistrati o n.
f Vital si g ns will b e c ollecte 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 utes after st u d y dr u g a d mi nistrati o n o n Da ys 1, 2 2, a n d 4 3.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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3. 2.  
I ncl usi o n Criteri a
N o s u bj ect will be assi g ne d t o treat me nt u ntil all eli gi bilit y cri t eria ha ve bee n sat isfie d. T o
q ualif y  for t he st u d y  a s u bject must:
1.
Be a ble t o pr o vi de v o l unt ar y writte n i nf or me d c o nse nt prior t o t he i nit iati on of a n y  st u d y 
s pecific pr oce d ures per t he p olic y of t he g o ver nin g I nsti t utio nal Re vie w B oar d (I R B)/
I n de pe n de nt Et hics C o m mittee (I E C).
2.
Be fe male a n d at least 1 8 years of a ge at t he ti me of c o nse nt.
3.
Ha ve e vi de nce of cell ulite i n 2 bilateral treat me nt areas ( defi ne d as ri g ht a n d left b utt oc ks 
O R ri g ht a n d left p oster ol ateral t hig hs) as assess e d b y t he I n vesti gat or at t he Scree ni n g 
visit, a n d f ulfil ls t he f oll owi n g re q ui re me nts:
a.
has a sc ore of 2 ( mil d), 3 ( m o derate) or 4 (se vere) as re p orte d b y  t he I n vestigat or 
( C R-P C S S) i n 2 treat me nt areas (t w o t hi g hs or t w o b utt oc ks) at t he Scree ni n g Visit.
b.
has at l east 2 di m ples fr o m eac h treat me nt area t hat:

are is o late d a n d se parate d b y at least 5 c m fr o m a n y ot her di mples

sc ore 2 or 3 o n t he He xsel de pressi o n scale

ha ve d i m ple wi dt h: le n gt h rati o ≥ 0. 5
4.
Be willi n g t o a p pl y s u nscree n t o t he d osi n g areas bef ore eac h e x p os ure t o t he s u n w hile
parti ci pat i n g i n t he st u d y (ie, scree ni n g t hr o u g h e n d of st u d y).
5.
Be j u d ge d t o be i n g o o d healt h, base d u p o n t he res ults of a me dical hist or y , p h ysical
e xa mi nat i on, a n d la b orat or y  pr ofile at scree ni n g.
6.
Ha ve a ne gat i ve ser u m pre g na nc y test at t he Scree ni n g Visit a n d ne gati ve uri ne
pre g na nc y at Da y  1 ( bef ore i njecti o n of st u d y dr u g), be usi n g a n effecti ve c o ntrace pti o n
met h o d (e g , a bst i ne nce, i ntra uteri ne de vice, h or m o nal [estr o ge n/ pr o gesti n]
c o ntrace pti ves, or d o u ble barrier c o ntr ol) f or at least 1 me nstr ual c ycle pri or t o st u d y
e nr o llme nt a n d t hr o u g h Da y  7 1; or be me n o pa usal defi ne d as at least 1 2 mo nt hs of
a me n orr hea i n t he a bse nce of ot her bi o l ogi cal or p h ysi o l ogical ca uses (as deter mi ne d b y
t he I n vest i gat or), or be p ost-me n o pa usal f or at least 1 y ear, or be s ur gicall y sterile
( h ysterect o m y, bilateral o o p h orect o m y, bilateral t u bal li gati o n).
7.
Be willi n g a n d a ble t o c o m pl y wit h all pr ot oc ol re q uire d st u d y  visits a n d assess me nts.
3. 3.  
E xcl usi o n Cri teri a
A s u bject will be e xcl u de d fr o m st u d y partici pat i on if s he:
1.
Is pre g na nt or is i nte n di n g t o bec o me pre g na nt d uri n g t he st u d y.
2.
Is prese ntl y n ursi n g/ breastfee di n g or pr o vi di n g breast mil k.
3.
Has a n y o f t he f o ll owi n g s yste mic c o n dit i ons:
a.
C oa g ulati o n dis or der.
b.
E vi de nce or hi st or y of mali g na nc y ( ot her t ha n e xcise d basal-cell carci n o ma) u nless 
t here has bee n n o rec urre nce i n at least 5 years.


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c.
Hi st or y of k eloi dal  scarri n g or a b n or mal w o u n d heali n g.
d.
C o nc urre nt diseases or c o n dit i ons t hat mi g ht i nterfere wi t h t he c o n d uct of t he st u d y, 
c o nf o u n d t he i nter pretati o n of t he st u d y res ults, or e n da n ger t he s u bject’s well-bei n g. 
A n y q uest i ons a b o ut c o nc urre nt diseases s h o ul d be disc usse d wit h t he Me dical 
M o ni t or.
e.
E vi de nce of cli nicall y  sig nifica nt a b n or malit ies o n ph ysical e xa mi nat i on, vital si g ns, 
electr ocar dio gr a m  ( E C G), or cli nical la b orat or y val ues.
4.
Has a n y o f t he f o ll owi n g l o c al  c o n ditio n s i n t he areas t o be treate d:
a.
Hi st or y of lo wer e xtre mi t y t hr o m b osis or p ost-t hr o m b osis s y n dr o me.
b.
Vasc ular dis or der (e g , varic ose vei ns, tela n giectasia).
c.
I nfla m mati on or acti ve i nfect i on.
d.
Se vere s ki n la xit y, flacci dit y,  a n d/ or sa g gi n g.
e.
Act i ve c uta ne o us alterati o n i ncl u di n g ras h, ecze ma, ps oriasis, or s ki n ca ncer.
5.
Has a tatt o o l ocate d wit hi n 2 c m o f t he sit e of injecti o n.
6.
Re q ui res a ntic oa g ula nt or a nti platelet me dicat i on d uri n g t he st u d y  or has recei ve d 
a nt ic oa g ula nt or a ntipl at elet me dicat i on (e xce pt f or ≤1 5 0 m g as piri n dail y) wit hi n 7 da ys 
bef ore i nject i on of st u d y  dr u g.
7.
Has use d a n y  of t he f oll owi n g f or t he treat m e nt of E F P o n t he area t o be treate d wit hi n 
t he ti meli nes i de nt ifie d bel o w or i nte n ds t o use a n y of  t he fol l owi n g at a n y  ti me d uri n g 
t he c o urse of t he st u d y:
a.
Li p os uct i on wi t hi n t he treat me nt areas d uri n g t he 1 2 -m o nt h peri o d bef ore i nject i on of 
st u d y dr u g.
b.
I njectio ns (e g , mes ot hera p y); ra diof re q ue nc y de vice treat me nts; laser treat me nt; or 
s ur ger y (i ncl u di n g s u bcisi on a n d/ or p o were d s u bcisi o n) wit hi n t he treat me nt areas 
d uri n g t he 1 2 -m o nt h peri o d bef ore i nject i on of st u d y  dr u g.
c.
A n y i n vest i gati onal treat me nt f or E F P/ cell ulit e o n treat me nt areas d uri n g t he 
1 2- m o nt h peri o d bef ore t he i nject i on of st u d y  dr u g.
d.
E n der m ol o gi e ® or si milar treat me nts wit hi n t he treat me nt areas d uri n g t he 6 -m o nt h 
peri o d bef ore i njecti o n of st u d y  dr u g.
e.
Massa ge t hera p y  wit hi n t he treat me nt areas d uri n g t he 3 -m o nt h peri o d bef ore 
i njecti on of st u d y  dr u g.
f.
Crea ms (e g , Cell u vera™, Tri Lasti n® ) t o pre ve nt or miti gate E F P wit hi n t he treat me nt 
areas d uri n g t he 2 -wee k peri o d bef ore i nject i on of st u d y dr u g.
8.
Has recei ve d a n i n vest i gati onal dr u g or treat me nt w ithi n 3 0 da ys bef ore i nject i on of  st u d y 
dr u g.
9.
Has a k n o w n s yste mic aller g y  t o c olla ge nase or a n y ot her e xci pie nt of st u d y dr u g.
1 0. Has a hist or y  of dr u g or alc o h o l a b use.
1 1. I nt e n ds t o i nit iate a n i nte nsi ve s p ort or e xercise pr o gra m d uri n g t he st u d y.
1 2. I nte n ds t o i nitiate a wei g ht re d ucti o n pr o gra m d uri n g t he st u d y.
1 3. I nte n ds t o use ta n ni n g s pra y or ta n ni n g b o ot hs d uri n g t he st u d y.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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Pa ge 1 4
1 4. Has pre vi o usl y recei ve d a n y  c olla ge nase treat me nts (e g, Sa nt yl® oi nt me nt  a n d/ or 
XI A F L E X/ XI A P E X ® ).
1 5. Was a s u bject i n a pre vi o us cell ulite c li nical trial 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. A n y ot her c o n dit i on(s) t hat, i n t he I n vest i gat or’s o pi ni on, mi g ht i n dicate t he s u bject is 
u ns uita ble f or t he st u d y .
3. 4.  
Tre at me nt Re gi o n a n d Are a
Treat me nt re gi o n is defi ne d as b utt oc ks O R p oster ol ateral t hig hs. A s u bject will ha ve t w o 
treat me nt areas defi ne d as b ot h b utt oc ks ( left a n d ri g ht b utt oc ks) O R b ot h t hig hs (left a n d ri g ht 
p oster ol ateral t hig hs).
3. 5.  
Selecti o n of Di m pl es a n d I njecti o n Sites D uri n g Tre at me nt Visits
3. 5. 1.  
Selecti n g a n d M ar ki n g t he Di m ples
T he i n vest i gat or will select di m ples i n t he treat me nt areas (left a n d ri g ht b utt oc ks O R left a n d 
rig ht p oster ol ateral t hig hs ) t hat are well defi ne d, e vi de nt w he n t he s u bject is sta n di n g i n a 
c o nsiste nt rela xe d p ose ( wit h o ut t he use of a n y ma ni p ulat i on s uc h as s ki n pi nc hi n g or m uscle 
c o ntractio n), a n d s uita ble f or treat me nt . If b ot h b utt oc ks a n d b ot h t hi g hs meet e ntr y  crit eria for a 
si n gle s u bject, t he n t he t hi g hs will be treate d. N o s u bject will be treate d f or E F P i n b ot h t he 
b utt oc ks a n d t he t hi g hs d uri n g t his st u d y .
T he I n vesti gat or will i de ntif y at least t w o ( 2) di m ples per treat me nt area w hic h s h o uld be s pace d 
o ut b y  at least 5 c m fr om ot her di m ples a n d sc ore 2 or 3 o n t he He xsel de pressi o n scale ( see 
Ta ble 6 f or Q uesti o n B o n He xsel sc ore).
3. 6.  
St u d y Dr u g A d mi nistr ati o n
Eac h s u bject will recei ve 2 4 i nject i ons f or a t otal of 1. 6 8 m g ( 0. 8 4 m g per treat me nt area ) at eac h 
treat me nt visit. T he c u mulat i ve C C H d ose will be 5. 0 4 m g f or eac h s u bject w h o c o m p letes t he 3 
treat me nt visits.
Eac h s u bject will recei ve st u d y  dr u g o n Da y  1, Da y  2 2 a n d Da y 4 3 (treat me nt visits) u nless t he 
treat me nt area is di m ple-free at Treat me nt Visit 2 ( Da y 2 2) a n d/ or Treat me nt Visit 3 ( Da y 4 3). 
A di m ple -free b utt oc k or t hi g h at Treat me nt Visit 1 ( Da y1) is precl u de d b y  t he eli gi bilit y crit eria. 
A di m ple -free b utt oc k or t hi g h at Treat me nt Visit 2 ( Da y 2 2) a n d/ or Treat me nt Visit 3 ( Da y 4 3) 
d oes n ot precl u de treat me nt of t he c o ntralateral b utt oc k or t hi gh u nless it i s als o di m ple-free.
T he st u d y  dr u g, C C H , will be a d mi nistere d usi n g 1 of  5 i nject i on t ec h ni q ues. Eac h of t he 
i njecti on tec h ni q ues are referre d t o as a treat me nt ar m (I - V). S u bjects will be se q ue nt ially 
assi g ne d t o a treat me nt ar m at Da y 1. I nject i on tec h ni q ues differ fr o m eac h ot her i n, 
c o nce ntrati o n of t he C C H i njectate, a n gle of i njectio n, de pt h of i nject i on, v ol u me o f i njecti on 
a n d st u d y dr u g a d mi nistrati o n at i njecti o n site.
At  e ver y tr e at me nt visit, irres pecti ve of t he treat me nt ar m (i njecti on tec h ni q ue) assi g ne d, all 
eli gi ble s u bjects will recei ve t he sa me a m o u nt of st u d y  dr u g (C C H , 0. 8 4 m g) i njecte d i n eac h 


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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Pa ge 1 5
assi g ne d treat me nt area. All eli gi ble s u bjects wit h di m ples (i n eac h b utt oc k or t hi g h) t hat re q uire 
treat me nt t o i mpr o ve t he aest het ic a p peara nce will recei ve f ull treat me nt c o urse wit h C C H
i njecti ons. Acr oss all treat me nt ar ms, s t u d y dr u g will be a d mi nistere d s u bc uta ne o usl y w hile 
s u bject is i n a pr o ne p ositi o n. 
T he i nject i on v o l ume a n d c o nce ntrati o n f or eac h treat me nt ar m are o utli ne d i n Ta ble 2 bel o w.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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T a ble 2:  
V ol u me a n d C o nce ntr ati o n of I njecti o ns
Tre at me nt
N u m ber of 
S u bjects/ Are a
D ose/
I njecti o n
V ol u me/I njecti o n
Dr u g 
C o nce ntr ati o n/
I njecti o n
T ot al V ol u me/
Tre at me nt Visit
Treat me nt I: S hall o w i njecti o n, 3 ali q u ots
6 ( b utt oc ks)
6 (t hi g hs)
0. 0 7 m g  
0. 3 m L ( gi ve 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 njecti o ns/ treat me nt 
area x 2 treat me nt areas x 0. 3 m L)
Treat me nt II: S hall o w i njecti o n, 1 ali q u ot
6 ( b utt oc ks)
6 (t hi g hs)
0. 0 7 m g  
0. 3 m L ( gi ve 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 njecti o ns/ treat me nt 
area x 2 treat me nt areas x 0. 3 m L)
Treat me nt III: Dee p i njecti o n, 1 ali q u ot
6 ( b utt oc ks)
6 (t hi g hs)
0. 0 7 m g  
0. 3 m L( gi ve 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 njecti o ns/ treat me nt 
area x 2 treat me nt areas x 0. 3 m L)
Treat me nt I V: Dee p a n d s hall o w i njecti o ns, 5 ali q u ots  
6 ( b utt oc ks )
6 (t hi g hs)
0. 0 7 m g  
1. 5 m L ( gi ve n as 5 - 0. 3 ali q u ots)  
0. 0 4 7 m g/ m L  
3 6 m L ( 1 2 i njecti o ns/ treat me nt 
area x 2 treat me nt areas x 1. 5 m L)
Treat me nt V: S hall o w i njecti o n, 4 ali q u ots
6 ( b utt oc ks)
6 (t hi g hs)
0. 0 7 m g  
1. 2 m L ( gi ve 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 njecti o ns/ treat me nt 
area x 2 treat me nt areas x 1. 2 m L)


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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3. 6. 1.  
Deter mi n ati o n of S a m ple Size 
A sa m ple size o f 6 0 s u bjects ( 3 0 wit h t w o eli gi ble b utt oc ks a n d 3 0 wit h t w o eli gi ble t hi g hs) was 
c h ose n e m piricall y base d o n t he pra g m at ic criteria a n d p u blis he d data of pre vi o us st u dies.
3. 6. 2.  
Bli n di n g a n d R a n d o miz ati o n
T his is a n o pe n -la bel st u d y. S u bjects will be se q ue nt iall y assi g ne d to a treat me nt ar m at Da y 1 .
3. 7.  
Cli nici a n Re p orte d P h ot o n u meric Cell ulite Se verit y Sc ale 
( C R-P C S S)
T he C R -P C S S - B utt oc k ( Ta ble 3 ) a n d t he C R-P C S S - T hi g h ( Ta ble 4 ) will be use d t o assess t he 
se verity of  cell ulit e of bot h treat m e nt areas res pecti vel y at Scree ni n g (eac h b utt oc k or eac h t hi g h
i n de pe n de ntl y). 
T hese rati n gs will be mar ke d o n t he s o urce d oc u me ntati o n a n d t he n e ntere d i nt o t he Electr o nic 
Data Ca pt ure ( E D C) s y st e m. 
T he scale is a 5 -level p h ot o n u meric scale de vel o pe d s pecificall y f or cli nicia ns a n d use d b y t he 
I n vesti gat or t o assess t he se verity of  t he s u bject’s cell ulite i n eac h b utt oc k or t hig h b y  li ve 
assess me nts. 
T he rati n gs ra n ge fr o m 0 ( N o ne) t o 4 ( Se vere) wit h la bels a n d descri pt ors t o ai d t he I n vest i gat or 
i n t he assess me nts. T his assessme nt s h o ul d be m a de w hile t he s u bject is i n t he sta n di n g p osit i on 
wi t h r ela xe d gl ute us muscles. See c hart bel o w f or details .
T a ble 3:  
C R -P C S S B utt oc k Sc ale
R ati n g  
Le vel of Se verit y  
Descri pti o n
0  
N o ne
N o di m ples or e vi de nt cell ulite
1  
Al m ost N o ne  
Fe w di m ples t hat are m ostl y s u perficial i n de pt h
2  
Mil d
Se veral di m ples of w hic h m ost are s hall o w i n de pt h
3  
M o derate
Ma n y  di m ples of w hic h m ost are m o derate i n de pt h
4  
Se vere
A l ot of di m ples wit h s o me of m ore se vere de pt h
T a ble 4 :  
C R -P C S S T hi g h Sc ale
R ati n g  
Le vel of Se verit y  
Descri pti o n
0  
N o ne
N o de pressi o ns or raise d areas
1  
Al m ost N o ne  
A fe w de pressi o ns or u n d ulati o ns t hat are m ostl y s u perficial i n de pt h
2  
Mil d
Se veral u n d ulati o ns t hat are s hall o w i n de pt h wit h areas of sli g ht pr ot u bera nces
3  
M o derate
Ma n y  u n d ulati o ns wit h alter nati n g areas of pr ot u bera nces a n d de pressi o ns, of 
w h ic h m ost are m o derate i n de pt h
4  
Se vere
A l ot of u n d ulati o ns wit h alter nati n g areas of pr ot u bera nces a n d de pressi o ns, s o me 
of m ore se vere de pt h.
T he i n vest i gat or will g o t hr o u g h a trai ni n g pr ocess a n d will nee d t o pass a q ualif yi n g e xercise
pri or t o usi n g t he C R -P C S S .


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3. 8.  
3- D P h ot o gr a p h y
T he 3 -D p h ot o gra p hs are n o t direct efficac y meas ure me nts; h o we ver , 3- D p h ot o gra p h y  will b e
utilize d i n t he assess me nt of treat me nt effect. T he i n vesti gat or or q ualifie d desi g nee will 
p h ot o gra p h eac h treat me nt area ( b ot h b utt oc ks a n d b ot h t hig hs) pri or t o i nject i ons usi n g a 
S p o ns or -s u p plie d sta n dar dize d di gital ca mera i n a sta n dar dize d ma n ner as per 3-D p h ot o gra p h y  
ma n ual , at t he f o ll owi n g ti me p oi nts:

Bef ore a n d after mar ki n g di m ples a n d i nject i on sites o n treat me nt Da y s 1, 2 2, a n d 4 3 

Si n gle set of p h ot o gra p hs will be ta ke n at scree ni n g a n d all ot her visits
T he 3- D p h ot o gra p h s ta ke n at Da y s 4, 8, 1 5, 2 2, 4 3 , a n d 7 1 [ E n d of St u d y ( E O S)/ Earl y 
ter mi nati o n) will be assesse d b y a ce ntral assess or bli n de d t o t he treat me nt ar m a n d st u d y  visit 
da y . T he ce ntral assess or will c o m p lete a 5-p oi nt Li kert S cale t o ga u ge t he le vel o f aest het ic 
i m pr o ve me nt ac hie ve d (fr om b aseli ne) i n eac h treat me nt area (ie, sc ori n g fr om w orse t o ver y  
m uc h i m pr o ve d, f or aest hetic i m pr o ve me nt). 
T he labels a n d descri pt i ons ass ociate d wit h eac h le vel of aest hetic i m pr o ve me nt ac hie ve d of  
Li k ert S cale are s h o w n i n Ta ble 5 bel o w:
T a ble 5:  
Li kert Sc ale of L e vel of A est hetic Im pr o ve me nt
R ati n g  
Descri pti o n
- 1  
W orse ( T he treate d area a p peara nce is w orse t ha n bef ore treat me nt)
0  
N o c ha n ge ( T he treate d area a p peara nce is esse ntiall y t he sa me as bef ore treat me nt)
1  
I m pr o ve d ( O b vi o us i m pr o ve me nt i n t he treate d area a p peara nce fr o m bef ore treat me nt, b ut a d diti o nal 
treat me nt is i n dicate d)
2  
M uc h I m pr o ve d ( Mar ke d i m pr o ve me nt i n t he treate d area a p peara nce fr o m b ef ore treat me nt, b ut n ot 
c o m pletel y o pti mal)
3  
Ver y  m uc h i m pr o ve d ( O pti mal c os metic res ult fr o m treat me nt of t he treate d di m ples)
3. 9.  
Di m ple A n al ysis
T he I m a ge A nal ysis Tec h nicia n (I A T) will use t he Da y  1-P ost m ar ki n g i ma ge as a refere nce t o 
deter mi ne t he l ocati o n of t he tar get di m ple o n t he Da y 1-Pre m ar ki n g i ma ge.
A traci n g will be ma de ar o u n d t he b or der of c o nca vit y of  t he di m ple o n t he Da y 1-Pre m ar ki n g. 
T he di m ple traci n g will be tra ns p ose d o n t o t he Da y 2 2- Pre Mar ki n g, Da y  4 3-Pre m ar k i n g, a n d 
Da y  7 1/E T i ma ges.
T his traci n g will be use d t o meas ure t he:

Ma x le n gt h, t he lar gest strai g ht li ne dista nce acr oss t he di m ple 

Ma x w i dth, t he lar gest strai g ht li ne dista nce per pe n dic ular t o t he ma x le n gt h 
meas ure me nt 

S urface area of t he di m ple

V ol u me bet wee n t he base of t he di m ple a n d t he i nter p olate d s urface 


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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3. 1 0.  
Br uise A n al ysis
T he I A T will trace t he b r uise o n t he Da y 4 i ma ge i n a d ditio n t o a n area of n or mal s ki n. T he 
br uise traci n g a n d n or mal t iss ue traci n g will be trans p ose d o nt o t he Da y  1-Pre Mar ki n g, Da y 8 ,
a n d Da y 1 5 i ma ges.
A pair of n u merical val ues of t he mea n la b c o l or ( n u m ber) val ue of br uise d area a n d n or mal s ki n 
c olor val ue will  be c ollecte d fr o m t he 3- D p h ot o gra p hs at eac h i ma gi n g e val uati o n visit f or 
br uisi n g.
Br ui se a nal ysis will c o nsist of t w o L * A * B* c ol or meas ure me nts. L * A * B * c ol or val ues will  be 
meas ure d wit hi n t he br uise d tiss ue a n d n or mal tiss ue a rea of i nterest ( AOI ).
3. 1 1.  
He xsel De pressi o n De pt h Sc ale
T he He xsel Cell ulite Se verit y Scale ( He xsel  C S S) is a p h ot o n u m eric scale t hat lo o ks at 5 ke y
m o r p h olo gi c feat ures of cell ulite (2 ,3 ):

A - n u m ber of e vi de nt de pressi o ns

B - de pt h of de pressi o ns

C - m o r p h ol o gical a ppeara n ce of s ki n s urface alterati o ns

D - laxit y,  flacci dity or sa g gi n g of s ki n, a n d 

E - c urre nt classificat i on scale base d o n me dical lit erat ure 
Eac h of t hese feat ures is e val uate d o n a 4 -p oi nt scale fr o m a lo w of  0 t o a hig h of  3. F or t his 
st u d y, o nl y “B - de pt h of de pressi o ns” will be assesse d.
T he i n vest i gat or or q ualifie d desi g nee will use t he He xsel C S S ( B) de pt h of de pressi o ns t o assess 
t he se verit y of  E F P i n eac h b utt oc k or eac h t hi g h. The assess me nt will be ma de w hile t he s u bject 
is i n t he sta n di n g p ositi on wi t h rela xe d glute us m u scles at t he f o ll owi n g visi ts:

Scree ni n g visit 

Da y s 2 2, 4 3 , a n d 7 1( E O S / Earl y ter mi nati on)
T he labels a n d descri pt i ons ass ociate d wit h eac h le vel of de pt h of de pressi o n of He xs el C S S ( B) 
are s h o w n i n Ta ble 6 bel o w .
T a ble 6:  
He xsel C S S ( B) De pt h of De pressi o ns
R ati n g  
Descri pti o n
0  
N o de pressi o ns
1  
S u perficial de pressi o ns
2  
Me di u m de pt h de pressi o ns
3  
Dee p de pressi o ns
3. 1 2.  
Me dic al a n d S ur gic al
Hist or y
A me dical a n d s ur gical hist or y  of t he s u bject will be ta ke n d uri n g t he scree ni n g peri o d. Me dical 
hist or y  will i ncl u de rele va nt dia g n oses a n d/ or pr oce d ures/t hera pies wit h o nset/res ol uti ons dates. 


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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If o nset date is u n k n o w n, t he n c o n diti on w het her i t occ urre d wi t hi n 5 years or more t ha n 5 years 
will be rec or de d o n t he e C R F.
3. 1 3.  
E de m at o us Fi br oscler otic P a n nic ul o p at h y Dise ase (E F P ) Hist or y
E F P di sease hist or y will be o btai ne d fr o m t he s u bject d uri n g t he scree ni n g peri o d . T he E F P
di sease hist or y will incl u d e t he f o ll owi n g:

Fa mil y  hist or y of cell ulite (a ns were d as yes, n o, or u n k n o w n)

O nset date of E F P s y m pt o ms

Pre vi o us treat me nts use d f or E F P
3. 1 4.  
S u bst a nce Use
Hi st or y of t o bacc o a n d alc o h ol use will be ta ke n d uri n g t he scree ni n g peri o d a n d f o ll owi n g 
i nf or mat i on will be rec or de d:

T y pe of s u bsta nce ( Alc o h o l/ T o bacc o)

Hi st or y of usa ge ( Ne ver/ C urre ntl y/F or mer)

N u m ber of years t he pr o d uct was use d (f or c urre nt or f or mer users)

St o p date of usi n g t he pr o d uct (f or f or mer users)
3. 1 5.  
Pri or/ C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures
A n y me dicat i ons (i ncl u di n g O T C me dicat i on) ta ke n d uri n g t he st u d y  or wit hi n 9 0 da ys pri or t o 
Da y  1 will be rec or de d. 
A n y dia g n ostic, t hera pe utic, or s ur gical pr oce d ure perf or me d bef or e t he st u d y or d uri n g t he 
st u d y, i ncl u di n g t he treat me nt of E F P will be rec or de d.
3. 1 6.  
Pr o hi bite d Me dic ati o ns
T he f o ll owi n g m e dicat i ons a n d pr oce d ures are pr o hi bite d f or s u b jects d uri n g t he st u d y:

A nt ic oa g ula nts ( warfari n, he pari n, direct t hr o m bi n i n hi bit ors, Fact or X i n hi bit ors) a n d
a nt i platelet a ge nts (as pirin > 1 5 0 m g/ da y  a n d P 2 Y 1 2 i n hi bit ors, s uc h as cl o pi d o grel),
w hic h ca n ca use a d dit i onal br uisi n g. H o we ver, t he use of as piri n at a d ose le vel o f
≤1 5 0 m g per da y  will be per mitte d d uri n g st u d y.

Li p os uct i on wi t hi n t he treat me nt areas.

I njecti ons (e g, mes ot hera p y ); ra diof re q ue nc y de vice treat me nts; laser treat me nt; or
s ur ger y (i ncl u di n g s u bcisi on a n d/ or p o were d s u bcisi o n).

A n y i n vest i gati onal treat me nt f or E F P/cell ulit e o n treat me nt areas or a n y ot her
i n vesti gatio nal dr u g or treat m e nt.

E n der m ol o gi e or si milar treat me nts wit hi n t he treat me nt areas.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
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
Massa ge t hera p y  wit hi n t he treat me nt areas d uri n g t he 3-m o nt h peri o d bef ore
i njecti on of st u d y  dr u g.

Crea ms (e g, Cell u vera, Tri Lasti n) wit hi n t he treat me nt areas .
3. 1 7.  
A d vers e E ve nts
All A d verse E ve nts ( A E) occ urri n g after si g ni n g t he i nf or me d c o nse nt a n d t hr o u g h 2 8 da ys after 
last d ose are t o be rec or de d o n t he A E pa ges of t he eC R F. C o n dit i ons e xist i n g pri or t o scree ni n g 
will be rec or de d as part of s u bject’s me dical hist or y .
3. 1 7. 1.  
A d verse E ve nts ( A E)
A n A E i s a n y u nfa v ora ble or u ni nte n de d c ha n ge i n b o d y  str uct ure (sig ns), b o d y f u ncti on 
(s y m pt o ms), la b orat or y res ult (e g, c he mistr y, E C G, X-r a y, et c.), or w orse ni n g of a pre -e xist i n g 
c o n ditio n ass ociate d te m p orall y  wit h t he use of t he st u d y me dicatio n w het her or n ot c o nsi dere d 
r elate d t o t he st u d y me dicatio n. T his w o ul d i ncl u de A Es res ult i n g fr om c o nc urre nt ill ness, 
reactio ns t o c o nc urre nt m e dicat i on use, or pr o gressi o n of disease states (e xcl u di n g t he disease 
u n der st u d y ). A c o n ditio n p rese nt at baseli ne t hat w orse ns after i nitiati on of st u d y  treat me nt will 
be ca pt ure d as a n A E; t he o nset date will be t he date t he e ve nt w orse ne d. 
3. 1 7. 2.  
Seri o us A d verse E ve nts ( S A Es)
S eri o us a d verse e ve nt are t h ose A Es t hat meet a n y of t he f oll owi n g cri t eria:

R es ults i n deat h 

Life -t hreate ni n g e ve nt 

Res ults i n or pr ol o n gs a n i n pat ient  h os pitalizati on 

Res ults i n per ma ne nt or s u bsta ntial disa bilit y

Is a c o n ge nital a n oma l y or birt h defect 

A n y i m p orta nt me dical e ve nt t hat ma y je o par dize t he s u bject or m a y re q uire me dical 
i nter ve nt i on t o pre ve nt o ne of t he o utc o mes liste d a b o ve
3. 1 7. 3.  
A d verse E ve nts of S peci al I nterest
A Es s uc h as br uisi n g, ecc h y m o sis, he mat o mas, a n d c o nt usi o ns t hat occ ur re m ote t o t he site of 
dr u g a d mi nistrati o n, or a n y h y perse nsit i vity react i o ns, i ncl u di n g a na p h yla xis, will be rec or de d as 
a n A E of s pecial i nterest a n d re p orte d as a n A E or S A E as a p pr o priate.
I n a d diti on, l o c al  AEs ass ociate d wit h t he i nject i on si te, i ncl u di n g br uisi n g, pai n, n o d ules/ mass,
ul cerat i on, er yt he ma, pr urit us, s welli n g, a n d/ or i n d urati o n, will be rec or de d.
3. 1 8.  
Cli nic al S afet y L a b or at or y Tests
Bl o o d a n d uri ne sa m ples will be c ollecte d f or testi n g t he f oll o wi n g cli nical la b orat or y  para meters 
d uri n g t he scree ni n g peri o d a n d at E O S.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
1 1- Fe b- 2 0 1 9
E n d o P har m ace ut icals I nc.
Pa ge 2 2
T a ble 7:  
Cli nic al S afet y L a b or at or y P ar a meters
He m at ol o g y
Bi oc he mistr y
Uri n al ysis
He m o gl o bi n
He mat ocrit
Re d bl o o d cell
W hite bl o o d cell ( W B C)
Platelets
W B C Differe ntial
Gl uc ose
S o di u m
P otassi u m
Calci u m
C hl ori de
Car b o n di o xi de ( C O 2)
I n or ga nic p h os p hate
Bl o o d urea nitr o ge n ( B U N)
Creati ni ne
Creati ni ne cleara nce
As partate tra nsa mi nase ( A S T)
Ala ni ne tra nsa mi nase ( A L T)
Ga m ma -gl uta m yl tra nsferase ( G G T)
T otal bilir u bi n ( T B L) ( direct bilir u bi n refle x if ele vate d)
Al b u mi n
Al kali n e p h os p hatase ( A L P)
Ur ic aci d
Gl uc ose
Pr otei n
S pecific gra vit y
p H
Ket o nes
Bilir u bi n
Ur o bili n o ge n
Nitrite
Bl o o d *
Le u k oc ytes *
* Micr osc o pic e xa mi nati o n will be perf or me d if bl o o d or le u k oc ytes are detecte d b y di pstic k.
A n y cli nicall y  sig nifica nt l a b orat or y a b n or malit y o bser ve d, will be c o nsi dere d as a n A E or S A E 
as a p pr o priat e.
3. 1 9.  
Pre g n a nc y Test
Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve ne gat i ve pre g na nc y test at Scree ni n g a n d 
Da y  1 t o be e nr olle d i n t he st u d y. Fe male s u bjects of  c hil d beari n g p ote ntial will u n der g o a 
ser u m pre g na nc y at t he Scree ni n g Visit a n d u rine pre g na nc y tests at  Da ys 1, 2 2, a n d 4 3 pri or t o 
st u d y dr u g a d mi nistratio n a n d at Da y 7 1 ( E O S). A d di tio nal  uri ne pre g na nc y tests will be 
perf or m e d at t he discreti on of t he I n vest i gat or w he n re q uire d.
3. 2 0.  
Vit al Si g ns
V ital si g ns meas ure me nts will be ta ke n at Scree ni n g, Da y 1, 2 2, 4 3, a n d at t he E O S visit. O n 
treat me nt visits (Da ys 1, 2 2, a n d 4 3 ), vital si g ns will be assesse d at 4 h o urs pri or t o, a n d at 1 5 
a n d 3 0 mi n utes after st u d y dr u g a d ministrati o n.
Vi t al si g ns meas ure me nts i ncl u de: s yst olic a n d diast olic bl o o d press ure, res pirat or y rate, p ulse 
rate, b o d y t e mperat ure, hei g ht, a n d b o d y  weig ht. 
Hei g ht a n d b o d y  wei g ht meas ure me nts will be ta ke n at Scree ni n g. B o d y wei g ht will als o be 
meas ure d at Da y 1 a n d at E O S visit.
A n y a b n or malit y i n vital si g n o bser ve d, will be c o nsi dere d as a n A E or S A E as a p pr o priate .
3. 2 1.  
1 2- Le a d Electr oc ar di o gr a m ( E C G)
A 1 2- Lea d E C G will be rec or de d d uri n g t he scree ni n g peri o d w hile t he s u bject is i n s u pi ne 
p osi tio n f or at least 5 mi n utes bef ore t he rec or di n g is c o n d ucte d.


Stati stical A nal ysis Pla n ( S A P) M o d ule 1 – St u d y  E N 3 8 3 5- 2 0 9
1 1- Fe b- 2 0 1 9
E n d o P har m ace ut icals I nc.
Pa ge 2 3
E C Gs will be assesse d b y  t he I n vesti gat or a n d gra de d as: 

N or m al 

A b n or m al, n ot cli nicall y si g nifica nt 

A b n or m al, cli nicall y si g nifica nt 
A n y a b n or malit y i n E C G o bser ve d, will be c o nsi dere d as a n A E or S A E as a p pr o priate .
3. 2 2.  
P h ysic al E x a mi n ati o n
A c o m p lete p h ysical e xa mi nati on ( b y b o d y  s yste m) o n eac h s u bject will be perf or me d at 
scree ni n g. T hi s e val uati on will i ncl u de a n e xa mi nati o n of hea d, e y es, ears, n ose a n d t hr oat, s ki n, 
nec k, c hest , heart , l un gs , breast s, l y m p h n o des, a b d o me n, bac k, e xtre mit ies, m u sc ulos kele t al
s yste m, a n d ce ntral ner v o us s yste m. P h ysical e xa mi nat i on fi n di n gs will be rec or de d as n or mal,
a b n or mal or n ot d o ne as n ot sta n dar d of care .
A n y a b n or malit y i n p h ysical  e xa mi nati on o bser ve d , will be c o nsi dere d as a n A E or S A E as 
a p pr o priate.
T he s u bject’s s ki n ty pe will  be assesse d at scree ni n g usi n g t he Fitz patric k scale s h o w n bel o w .
T a ble 8:  
Fitz p atric k Sc ale
I
Pale w hite s ki n, bl ue/ hazel e yes, bl o n d/re d hair
Al wa y s b ur ns, d oes n ot ta n
II
Fair s ki n, bl ue e yes
B ur ns easil y, ta ns p o orl y
III
Dar ker w hite s ki n
Ta ns after i nitial b ur n
I V
Li g ht b r ow n  s ki n
B ur ns mi ni mall y, ta ns easil y
V
Br o w n s ki n
Rarel y  b ur ns, ta ns dar kl y easil y
VI
Dar k b r ow n  or blac k s ki n
Ne ver b ur ns, al wa ys ta ns dar kl y
3. 2 3.  
I m m u n o ge nicit y
I mm u n o ge nicit y varia bles i ncl u de a nti -A U X -I/a nti-A U X -II bi n di n g (ie, a nti- dr u g) a n d
ne utralizi n g a nt i b o d y res ults. Ser u m  sa m ples will be c ollecte d at Da y 1 ( bef ore i nject i on) a n d at 
t he Da y 7 1 ( E O S) visit f or t he deter mi nat i on of ser u m  a nti-A U X -I a n d a nt i-A U X -II a nti b o d y 
le vels a n d ne utralizi n g a nti b o dies t o A U X-I a n d A U X-II. A s u bset ( base d o n e ver y  ot her sa mple 
fr om t he Da y 7 1 u p per a n d lo wer q uartiles of all p osit i ve bi n di n g a nt i b o d y titers) of s u bject 
sa m ples will be teste d f or ne utralizi n g a nti b o dies fr o m t he Da y 1 a n d Da y 7 1 visits; a d dit i onal 
sa m ples will be retai ne d.
4.  
S T U D Y P A R A M E T E R S
4. 1.  
S u bject Dis p ositi o n
S u bjects will be c o nsi dere d as c o m plet i n g t he st u d y if t he y c om p lete a ll t he sc he d ule d treat me nt 
a n d t he Da y 7 1/ E O S visit. A pre mat ure disc o nt i n uati o n will occ ur if s u bjects di sc o nti n ue 
treat me nt a n d/ or partici pat i on i n t he st u d y. S u bjects w h o disc o n tin ue earl y f or a n y reas o n, will be 


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e nc o ura ge d t o ha ve all Da y 7 1/ E O S pr oce d ures a n d assess me nt s c o mplete d at a n earl y 
ter mi nati o n visit. 
T he reas o n f or earl y disc o nt i n uati on will be rec or de d i n e C R F f or t he s u bjects w h o d o n ot 
c o mplete t he st u d y . T he reas o n of scree n fail ure will als o be rec or de d i n e C R F f or s u bjects w h o 
are n ot e nr olle d a n d are co nsi dere d scree n fail ures .
4. 2.  
Pr ot oc ol De vi ati o ns
P r ot oc ol de viat i ons will be i de nt ifie d a n d d oc u me nte d pri or t o data base l oc k. Pr ot oc ol de viat i ons 
will be deri ve d fr o m t he e C R F data a n d will be o btai ne d fr o m t he cli nical m o nit ori n g re p orts. All 
de viat i ons fr om t hese t w o s o urces will be rec o ncile d a n d d u plicate de viat i ons will be re m o ve d. 
W he n a de viat i on is b ot h f o u n d i n t he data base a n d i n cli nical m o nit ori n g re p orts, i n m ost cases 
t he te xt of t he de viat i on fr o m t he data base will be retai ne d. T he e xce pti on t o t his r ule will occ ur 
if t he de viati on fr o m t he m o nit ori n g re p ort pr o vi des i m p orta nt i nf or mati on n ot f o u n d i n t he 
data base. I n t hat case, t he i nf or mati o n will be rec o ncile d i n t he data base.
P ossi ble pr ot oc ol  de viat i ons i ncl u de, b ut are n ot restricte d t o t he f o ll owi n g de viat i on t y pes: 

I neli gi ble s u bject/st u d y e ntr y crit eria n ot satisfie d 

I nf or me d c o nse nt n ot c o m plete d c orrectl y 

N o n -c o mplia nce of st u d y  treat me nt

Pr o hi bite d me dicat i ons/ pr oce d ure 

Vi sit/ pr oce d ure missi n g or o ut of wi n d o w
T he E n d o st u d y tea m will a p pr o ve all fi nal pr ot oc ol de viati o n assi g n me nts a n d classif y t he m as 
eit her major or mi n or d uri n g a pr ot oc ol  de viati on re vie w meet i n g hel d pri or t o t he data base l oc k. 
4. 3.  
Pri or C o nc o mit a nt a n d F oll o w -u p Me dic ati o ns
All me dicati o ns will be c o de d usi n g W orl d Healt h Or ga nizat i on ( W H O) Dr u g Dict i onar y  -
Gl o bal B 3 f or m at 2 0 1 8, b y act i ve i n gre die nt a n d W H O a nat o mical t hera pe utic c he mical ( A T C) 
classificat i on of i n gre die nts.
A pri or m e dicatio n is defi ne d as a n y me dicat i on ta ke n prior t o t he first i nject i on of  t he st u d y 
dr u g.
A c o nc o mit a nt me dicatio n is a n y  me dicatio n ta ke n bet wee n t he date of first i njecti on of t he st u d y  
dr u g a n d t he date of last i nject i on of st u d y  dr u g or t he me dicat i on is re p orte d as o n g oi n g. A n y 
me dicat i ons starte d after t he last i njecti o n of  t he st u d y dr u g will be c o nsi dere d as f oll ow- u p 
me dicat i ons.
4. 4.  
Pri or E F P Tre at me nt
Pri or E F P treat m e nt will be o btai ne d fr o m t he prior/c o nc o mi t a nt me dicat i on a n d / or
pri or/c o nc o mita nt pr oce d ure pa ges of t he e C R F. If o n eit her of t hese pa ges a me dicat i on or 
pr oce d ure is re p orte d wit h t he i n dicat i on ‘ E F P/cell ulite’ wit h a st art date pri or t o t he first 
i njecti on of  st u d y dr u g, t he n t he me dicati o n or pr oce d ure will be c o nsi dere d a pri or E F P 
treat me nt. 


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All me dicati o ns will be classifie d as E F P Dr u g. All pr oce d ures will be classifie d i nt o o ne of t he 
f oll owi n g gr o u ps:

Li p os uct i on

Laser

Massa ge

Ra di of re q ue nc y

Mes ot hera p y

Crea m

Ot her
T he cl assificat i on will be re vie we d a n d a p pr o ve d b y t he st u d y me dical m o nit or. A n y E F P 
treat me nt use d after t he Da y 1 visit will be n ote d a n d re p orte d as a pr ot oc ol vi o lati on.
4. 5.  
Effic ac y P ar a meters
4. 5. 1.  
I m pr o ve me nt i n Aest hetic A p pe ar a nce usi n g 3 -D P h ot o gr a p hic I m a ge
I mpr o ve m e nt fr om baseli ne i n aest het ic a p peara nce of t he treat me nt area will be assesse d b y a 
bli n de d ce ntral assess or usi n g a 5- p oi nt Li k ert Scale i n eac h treat me nt area (ie, fr om w orse t o 
ver y  muc h i m pr o ve d , for aest heti c i m pr o ve me nt) at Da y  2 2, 4 3 a n d 7 1 . T he efficac y will be 
e val uate d at Da y 2 2, 4 3 a n d 7 1. 
4. 5. 2.  
C h a n ge i n Di m ple A n al ysis P ar a meters usi n g 3 -D P h ot o gr a p hic I m a ge
Di m ple a nal ysis para meter s, ma x le n gt h, ma x widt h, s urface area a n d v o l ume bet wee n t he 
di m ple base a n d i nter p olate d s urface , will be assesse d b y I A T i n eac h treat me nt area at Da y  1, 
Da y  2 2, 4 3, a n d 7 1/ E T. T he c ha n ge i n t hese para meters fr o m Da y 1 will be e val uate d at Da y 2 2, 
4 3, a n d 7 1/ E T.
4. 5. 3.  
C h a n ge fr o m B aseli ne i n Di m ple De pt h De pressi o n b y He xsel C S S ( B)
Di m ple de pt h de pressi o n will be assesse d b y I n vesti gat or at  t he Scree ni n g visit , Da y  2 2, 4 3, a n d 
7 1 usi n g He xsel C S S ( B) de pt h of de pressi o ns scale a n d gra de d as; N o de pressi o ns ( 0), 
S u perficial de pressi o ns ( 1), Me diu m de pt h de pressi o ns ( 2) a n d Dee p de pressi ons ( 3). 
T he c ha n ge fr o m baseli ne at eac h p ost baseli ne visits will be a nal yze d a n d s u m marize d f or 
He xsel C S S ( B) de pt h of de pressi o ns scale sc ore of eac h treat me nt area.
4. 6.  
S afet y P ar a meters
4. 6. 1.  
A d verse E ve nts
A d verse E ve nt ver bat i m ter ms as re p orte d b y t he i n vestig at or of  a d verse e ve nt will be ma p pe d t o 
S y st e m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T) usi n g t he Me dical Dict i onar y  for 
Re g ulat or y  Act i vities ( Me d D R A) dicti o n ar y . T he versi o n t o be use d will be defi ne d i n Data 
Ma na ge me nt Pla n
( D M P).


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4. 6. 1. 1.  
Tre at me nt E mer ge nt A d vers e E ve nts ( T E A Es)
T E A Es are defi ne d as a n y A Es t hat occ ur or w orse n (i ncrease i n se verit y)  o n t he sa me da y or 
after t he first i njecti on o n Da y  1.
T he f o ll owi n g r ul es will a p pl y i n cases w here t he start date of a n A E is k n o w n: 

If t he A E o nset date is pri or t o first i njecti on o n Da y 1, t he n t he A E will n ot be 
c o nsi dere d a T E A E. 

If t he A E o nset date or date of A E w orse ni n g is e q ual t o or later t ha n first i njecti on o n 
Da y  1, t he n t he A E will be c o nsi dere d a T E A E. 
Refer t o secti o n 6. 4. 1. 1 t o ide nt if y T E A E stat us w he n start date of a n A E is u n k n o w n.
4. 6. 1. 2.  
I nte nsit y of A d verse E ve nts
I nte nsity ( or se verit y) of AEs will be gra de d as “ Mil d”, “ M o derate” or “ Se vere”. F or A Es wit h 
missi n g se verit y,  t he most se vere assess me nt will be i m p ute d f or a nal yses, f oll o wi n g w orst case 
pri nci ple.
4. 6. 1. 3.  
Rel ati o ns hi p t o St u d y Dr u g
Ca usal relat i ons hi p of A E wit h st u d y  dr u g will be classifie d b y t he I n vesti gat or a n d will be 
re p orte d as f oll ows:

N ot relate d

U nli kel y  relate d

P ossi bl y relate d

Pr o ba bl y  relate d
Relate d a d verse e ve nts are A Es wit h t he relati o ns hi p descri be d b y t he i n vest i gat or as “ pr o ba bl y 
r elate d” or “ p ossi bl y relate d”. “ N ot relate d” or “ U nli kel y relate d” ca usalit y assess me nts are 
c o nsi dere d as ne gati ve ca usalit y.
A n y missi n g relati o ns hi p of a n A E t o st u d y dr u g will  be c o nsi dere d as r elate d t o st u d y dr u g for 
t he a nal yses, f oll o wi n g w orst case pri nci ple. 
4. 6. 2.  
Vit al Si g ns a n d Cli nic al L a b or at orie s
4. 6. 2. 1.  
P ote nti all y Cli nic all y I m p ort a nt L a b or at or y V al ues
P ote nti all y Cli nicall y I mp orta nt ( P CI) l a b orat or y v alues are prese nte d i n Ta ble 9 bel o w .






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All st atistical tests of  efficac y para meters will be t w o -si de d with a si g nifica nce le vel o f = 0 . 0 5, 
u nless s pecifie d ot her wise. Statistical tests will be s u p p orte d b y prese nti n g esti mates a n d 9 5 % 
c o nfi de nce i nter vals ( CI) f or t he res pecti ve treat me nt effects. T hese esti mates a n d CI w ill be base d 
o n t he li near re gressi o n m o del. 
C o nti n u o us data will be s u m mariz e d usi n g descri pti ve statist ics. Discrete data will be 
s u m marize d usi n g fre q ue nc y c o u nts a n d perce nta ges . The de n o mi nat or will be base d o n t he 
n u m ber of s u bjects i n t he a p pr o priate p o p ulat i on. 
F or t he p ur p ose of dis pla y, t he s u m mar y  res ults will be r o u n de d as f oll o ws: 

Mi n i m u m a n d ma xi m u m : sa me n u m ber of deci mal places as t he ra w data. 

Mea n a n d Me dia n: o ne m ore deci mal place t ha n t he ra w data. 

S D: T w o m o re deci mal places t ha n t he ra w data. 

Perce nta ges will be dis pla ye d wit h o ne deci mal place preci sio n . A zer o c o u nt will be 
left bla n k.

T he sta n dar d f or m of a perce nt a ge c ha n ge varia ble is 0 deci mal place.
F or cate g orical varia bles wit h missi n g val ues, a cate g or y  d oc u me nti n g t he fre q ue nc y of missi n g 
val ues will be dis pla ye d i n t he s u m mar y ta bles. 
S u m mar y  ta bles, s u bject listi n gs, gra p hs a n d a n y s u p p orti ve S A S o ut p ut will i ncl u de f oot n otes
t hat will i n dicate:

D ate of data e xtracti o n

D ate a n d ti me o f o ut p ut ge nerati o n

S A S pr o gra m  na me, i ncl u di n g t he pat h, t hat ge nerate d t he o ut p ut
W he n calc ulati n g perce nta ges, t he de n o mi nat or will be base d o n t he n u m ber of s u bjects wit h n o n -
missi n g val ues. I f the de n o mi nat or is e x pecte d t o c ha n ge o ver ti me, t he n t he de n o mi nat or use d t o 
calc ulate t he perce nta ge will be base d o n t he n u m ber of s u bjects wit h n o n -missi n g val ues at eac h 
visit. A n y s u bject re m o ve d fr o m a n a nal ysis will be n ote d at t he b ott o m of t he ta ble alo n g wi t h 
t he reas o n t he s u bject was re m o ve d. 
E m pt y s u m mar y ta bles will be prese nte d wit h a n ote stati n g t hat “ N o S u bjects Met Criteria.”
S u bject list i n gs of all data fr om t he e C R Fs as well as a n y deri ve d varia bles will be prese nte d.
6. 2.  
A dj ust me nts f o r C o v ari ates
N ot a p plica ble.
6. 3.  
Deri ve d V ari a bles
Ta ble 1 2 defi nes t he deri ve d varia bles f or st u d y para meters.


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T a ble 1 2:    
Deri ve d V ari a bles a n d Defi niti o n
V ari a ble
Defi niti o n
A ge Gr o u p
< 3 5 y ears
3 5 – < 4 5 years
4 5 – < 6 5 years
≥6 5 y ears
Hei g ht (c m)
If hei g ht is rec or de d i n i nc hes, t he n hei g ht is e q ual t o t he rec or de d val ue 
m ulti plie d b y 2. 5 4 a n d t he n r o u n de d t o 1 deci mal place .
Wei g ht ( k g)
If wei g ht is rec or de d i n p o u n ds, t he n wei g ht is e q ual t o t he rec or de d value 
m ulti plie d b y 0. 4 5 4 a n d t he n r o u n de d t o 1 deci mal place .
B o d y Mass I n de x ( B MI)
B MI will be c o m p ute d usi n g hei g ht a n d b o d y wei g ht meas ure d at scree ni n g 
as, B MI ( k g/ m 2) = Wei g ht ( k g) / Hei g ht ( m)2
B MI Gr o u p
U n der wei g ht ( < 1 8. 5 k g/ m 2)
N or mal Wei g ht ( 1 8. 5 – < 2 5. 0 k g/ m 2)
O ver wei g ht ( 2 5. 0 – < 3 0. 0 k g/ m 2)
O bese ( ≥3 0. 0 k g/ m 2)
Relati ve Da y
T he da y  of first i njecti o n of st u d y dr u g will be c o nsi dere d as relati ve da y 1
St u d y Da y (f or assess me nt o n or 
after Da y 1)
St u d y Da y will be c o m p ute d as, Date of Assess me nt – Date of Da y 1 + 1
St u d y Da y (f or assess me nt bef ore 
Da y  1)
St u d y Da y will be c o m p ute d as, Date of Assess me nt – Date of Da y 1
Baseli ne
Baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt/assess me nt pri or 
t o t he first d ose of st u d y dr u g. F or vital si g ns, t he baseli ne will be t he Da y 
1 pre -d ose val ues. F or cli nical la b orat ories t his c o ul d be t he scree ni n g 
val ue, or it c o ul d be a n u nsc he d ule d la b, if t he u nsc he d ule d la b is t he 
cl osest val ue prece di n g t he first i njecti o n.
C ha n ge f r om Baseli ne
C ha n ge f r om baseli ne will be deri ve d as, p ost -baseli ne visit/ti me p oi nt 
val ue – t he baseli ne val ue.
Last Date i n St u d y
 T he date of Da y 7 1 if t he s u bject c o m pletes t he st u d y
 T he date of earl y ter mi nati o n visit if t he s u bject is ter mi nate d earl y 
fr o m st u d y at a n o n- sc he d ule d visit
 T he date of t he latest sc he d ule d visit if t he s u bject is ter mi nate d earl y 
fr o m st u d y at a sc he d ule d visit or l ost t o f oll o w- u p.
A ge at E F P S y m pt o m O nset
Date of E F P s y m pt o ms re p orte d – Date of Birt h/ 3 6 5. 2 5. See secti o n 6. 4. 1. 3
f or ha n dli n g of partial or u n k n o w n E F P s y m pt o m o nset dates.
Ti me S i nce L ast E F P T reat me nt  
Date of m ost rece nt E F P treat me nt – Date of i nf or me d c o nse nt)/ 3 6 5. 2 5. See 
secti o n 6. 4. 1. 3 f or ha n dli n g of partial or u n k n o w n E F P treat me nt dates.
Baseli ne C R -P C S S Sc ore
I n vesti gat or baseli ne C R-P C S S sc ores f or eac h treat me nt area will be base d 
o n t he i n vesti gat or’s C R -P C S S e val uati o n d o ne at t he Scree ni n g visit.
Baseli ne f or He xsel De pressi o n 
De pt h Scale
T he i n vesti gat or assess me nt perf or me d at Scree ni n g f or eac h treat me nt area 
will be c o nsi dere d as Baseli ne.
D urati o n of E x p os ure at E ac h V isit   
Date/ Ti me of Last I njecti o n – Date/ Ti me of First I njecti o n 
D urati o n of A E
A E e n d date – A E start date + 1
A E O nset Da y
A E start date - Date of first i njecti o n + 1


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6. 4.  
H a n dli n g of Missi n g D at a
S u bjects w h o disc o nt i n ue t he st u d y prior t o or after t he i nit iati on of t he st u d y  dr u g will n ot be 
re place d a n d a vaila ble data f or t hese s u bjects u ntil t he p oi nt of disc o nti n uat i on will  be 
s u m marize d. 
T he missi n g baseli ne assess me nt will n ot be i m p ute d.
F or cate g orical varia bles wit h missi n g val ues, a cate g or y  d oc u me nti n g t he fre q ue nc y of missi n g 
val ues will be dis pla ye d i n t he s u m mar y ta bles.
S u bjects w h o disc o n tin ue earl y will be e nc o ura ge d t o ha ve all D a y 7 1 pr oce d ures a n d 
assess me nts c o m plete d at a n earl y ter mi nati on visit. 
T here will be n o i m p utati o n of missi n g val ues f or safety data, h o we ver missi n g relat i ons hi p 
bet wee n A E a n d st u d y  dr u g will be c o nsi dere d as relate d t o st u d y dr u g f oll owi n g w orst case 
pri nci ple. Missi n g se verit y of  a n A E will be s u m marize d as a se vere A E.
I mm u n o ge nici t y sa mples wi t h a p ositive titer val ue will u n der g o a l o g tra nsf or mat i on f or 
a nal yses. Sa m ples wit h titer le vel less t ha n 1 will be assi g ne d or i m p ute d as a l o g tra nsf or me d 
titer of zer o ( 0) f or a nal yses.
6. 4. 1.  
I m p ut ati o n of P arti al D ates
6. 4. 1. 1.  
T E A E S t at us f or Co m pletel y U n k n o w n St art D ate
T he f o ll owi n g r ul es will a p pl y i n cases w here start date of a n A E is c o m pletel y u n k n o w n: 

If t he A E o nset date is u n k n o w n a n d t he e n d date is after first i njecti on o n Da y  1 or 
o n g oi n g, t he n t he A E will be c o nsi dere d a T E A E. 

If t he A E o nset date is u n k n o w n a n d t he e n d date is bef ore first i nject i on o n Da y  1, 
t he n t he A E will n ot be c o nsi dere d a T E A E. 

If b ot h t he start a n d e n d dates are u n k n o w n ( or e n d date is o n g oi n g), t he n t he A E will 
be c o nsi dere d a T E A E, f o ll owi n g t he w orst -case pri nci ple. 
If t he A E o nset date is partl y prese nt a n d mo nt h/ year is pri or t o t he first i nject i on date t he n t he 
A E will n ot be c o nsi dere d a T E A E.
6. 4. 1. 2.  
C o nc o mit a nt St at us of Me dic ati o n f or C o m pletel y U n k n o w n St art D ate
T he f o ll owi n g r ul es will a p pl y i n cases w here start date of c o nc o mita nt me dicati on is c om p letel y 
u n k n o w n: 

If t he me dicati o n o nset date is u n k n o w n a n d t he e n d date is after first i njecti on o n 
Da y  1 b ut bef ore t he last i nject i on date or me d icati o n is o n g oi n g, t he n t he me dicati o n 
will be c o nsi dere d as c o nc o mita nt. 

If t he me dicati o n o nset date is u n k n o w n a n d t he e n d date is bef ore first i njecti on o n 
Da y  1, t he n t he me dicat i on will n ot be c o nsi dere d as c o nc o mita nt. 


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
If b ot h t he start a n d e n d dates are u n k n o w n , t he n t he me dicati on will be c o nsi dere d as 
c o nc o mita nt . T his a p pr oac h is c o nsi dere d t o be t he m ost c o nser vati ve f oll owi n g t he 
w orst -case pri nci ple. 
If t he me dicati o n o nset date is partl y prese nt a n d m o nt h/ year is prior t o t he first i nject i on date, 
the n t he me dicat i on will  not be c o nsi dere d as c o nc o mita nt.
6. 4. 1. 3.  
Missi n g E F P O nset D ate
Missi n g E F P o nset da ys will be i m p ute d wit h t he first da y  of t he mo nt h a n d missi n g o nset m o nt h 
will be i m p ute d wit h Ja n uar y. If t he E F P o nset date is i n dicate d as c o m pletel y u n k n o w n b ut 
starti n g less t ha n 5 years a g o, t he E F P o nset date will be i m p ute d as t he i nf or me d c o nse nt date 
mi n us 5 y ears. If t he E F P o nset date is i n dicate d as c o m pletel y u n k n o w n b ut starti n g m ore t ha n 
5 years a g o, t he E F P o nset date will n ot be i m p ute d. M issi n g E F P me dicati o n/treat me nt e n d da ys 
will be i m p ute d wit h t he last da y  of t he mo nt h a n d missi n g e n d m o nt hs will be i m p ute d wit h 
Dece m ber, e xce pt if t he e n d year is e q ual t o t he date of i nject i on ye ar a n d t he n t he E F P 
me dicat i on/treat m e nt e n d date will be i m p ute d wit h t he first i njecti on date.
6. 5.  
I nteri m A n al yses
N o i nt eri m a nal ysis is pla n ne d i n t his st u d y. 
7.  
S T A TI S TI C A L A N A L Y S E S
7. 1.  
S u bject Dis p ositi o n
T he n u m ber of s u bjects i ncl u de d i n eac h st u d y  p o p ulat i on will be s u m marize d b y treat me nt ar m
a n d b y tr e at me nt re gi o n (ie, B utt oc k s, Thi g h s, a n d O verall). S u bje cts e xcl u de d fr o m t he safet y or 
e val ua ble p o p ul at i ons will be liste d.
T he n u m ber a n d perce nta ges of  s u bjects scree ne d, c o m plete d, a n d disc o nti n ue d d uri n g t he st u d y
a n d st ud y treat me nt , as well as t he reas o n f or disc o nti n uati on fr o m st u d y a n d reas o n f or
di sc o nti n uati on of st u d y dr u g will be s u m marize d b y treat me nt ar m . 
A listi n g of dis p osi tio n data will be pr o vi de d. Scree n fail ure reas o n s will als o be prese nte d .
7. 2.  
Pr ot oc ol De vi ati o n
Pr ot oc ol  de viati on will n ot be s u m marize d. A list i n g of all pr ot oc ol de viati ons will be prese nte d. 
7. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics
De m o gra p hics a n d baseli ne c haracterist ics will be s u m marize d b y treat me nt ar m a n d b y 
treat me nt re gio n ( ie, B utt oc k s, Thi g h s, a n d O verall) usi n g t he S af et y P o p ulati o n. A ge, hei g ht (at 
scree ni n g), b o d y wei g ht (at scree ni n g) a n d b o d y mass i n de x ( B MI) i n k g/ m 2 will be s u m marize d 
as c o nti n u o us varia bles usi n g descri pt i ve statistics. 
Ge n der, race a n d et h nicit y will  be s u m marize d as cate g orical varia bles usi n g fre q ue nc y c o u nts 
a n d perce nta ges . 
Refer t o Ta ble 1 2 f or descript i ons of a ge cate g ori es a n d B MI gr o u ps.


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T he f ol l owi n g baseli ne c haracterist ics will be s u m marize d usi n g fre q ue nc y c o u nts a n d 
perce nta ges:

C R -P C S S c ell ulite se verit y rati n gs at scree ni n g ( Mea n a n d S D will als o be pr o vi de d)

He xsel C S S ( B) de pressi o n de pt h scale sc ores at scree ni n g ( Mea n a n d S D will als o be 
pr o vi de d)

S ki n cate g or y  base d o n Fitz patric k scale assess me nt

Re p ort of t o bacc o a n d alc o h ol use 

Alc o h o l use ( Ne ver, C urre nt , a n d F or mer)

T o bacc o use ( Ne ver, C urre nt , a n d F or mer)
All de m o gra p hic a n d baseli ne c haracte ristics will be prese nte d i n s u bject listi n gs.
7. 4.  
Me dic al a n d S ur gic al Hist or y
Me dical hist or y  will be c o de d usi n g Me d D R A dicti o n ar y. T he versio n  t o be use d will be defi ne d 
i n D M P . Me di c al a n d s ur gical histor y  data will n ot be s u m marize d; h o we ver , a s u bject listi n g 
will be pr o vi de d.
7. 5.  
E F P Hist or y
E F P hist or y  will be s u m marize d b y treat me nt ar m a n d b y treat me nt re gio n ( ie, B utt oc k s, Thi g h s, 
a n d O verall) usi n g c o u nts a n d perce nta ges w hic h will i ncl u de: 

Fa mil y  hist or y of cell ulite ( Yes/ N o)

A ge ( years) at E F P s y m p t o m o nset (s u m marize d descri pti vel y)

Pri or treat m e nts for E F P i ncl u di n g li p os ucti o n, laser, massa ge, ra di ofre q ue nc y , dr u g, 
mes ot hera p y , crea m, ot her, or n o ne. S u bjects ca n re p ort m ore t ha n 1 pri or E F P 
treat me nt.

N u m ber of pri or E F P treat me nts ( 0, 1, 2, or ≥3)

Ti me ( years) si nce m ost rece nt E F P treat me nt (s u m marize d descri pt i vel y)
Refer t o Ta ble 1 2 f or c o mp utati o n of  “a ge at E F P o nset” a n d “ti me si nce last E F P treat me nt .” 
E F P hist or y  will be liste d.
7. 6.    
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures
T he pri or, c o nc o mita nt a n d f o ll ow- u p me d icatio n will  be s u m marize d b y treat me nt ar m a n d b y 
treat me nt re gio n ( ie, B utt oc k s, Thi g h s, a n d O verall) usi n g fre q ue nc y c o u nts a n d perce nta ges b y 
acti ve i n gre die nt wit hi n eac h A T C, wit h A T C a n d acti ve i n gre die nts or dere d al p ha bet icall y. 
M ul tiple use of  t he sa me me dicati on b y a s u bject will be c o u nte d o nl y  o nce.
A s u bject listi n g of me d icatio ns i n dicati n g pr i or, c o nc o mita nt a n d f o ll ow- u p me d icati ons a n d 
pr oce d ures will be pr o vi d e d. Si milarl y  a se parate listi n g of me dicat i ons a n d pr oce d ures f or E F P/
Cell ulite will als o be prese nte d .


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7. 7.  
Effic ac y A n al yses
Efficac y para meters will be s u m marize d a n d a nalyz e d f or eac h treat me nt area b y treat me nt ar m 
usi n g t he E val ua ble P o p ulati o n.
7. 7. 1.  
I m pr o ve me nt i n Aest hetic A p pe ar a nce usi n g 3-D P h ot o gr a p hic I m a ge s
7. 7. 1. 1.  
A n al ysis of Tre at me nt Re gi o n a n d Are a
T he Li kert Scale sc ore of i m pr o ve me nt i n aest het ic a p peara nce fr om baseli ne will be a nal yze d 
usi n g a li near mi xe d m o del wit h treat me nt ar m, st u d y  visit, i nteractio n of  treat me nt ar m a n d 
st u d y visit as fi xe d effects. T he fi xe d effect esti mates a n d 9 5 % CIs f or i nteracti o n effect of 
treat me nt ar m a n d st u d y visit will be prese nte d. T his m o del will be fitte d usi n g t he res p o nse f or 
eac h treat me nt area ( ie, left b utt oc k, ri g ht b utt oc k, left t hi g h, a n d ri g ht t hi g h) a n d f or t he a vera ge 
of  left a n d rig ht of  treat me nt area ( ie, a vera ge of left b utt oc k a n d ri g ht b utt oc k; a vera ge of left 
t hig h a n d ri g ht t hi g h).
T he Li kert Scale rati n g of i m pr o ve me nt i n aest het ic a p peara nce fr om baseli ne will als o be 
s u m marize d usi n g c o u nt a n d perce nta ge b y treat me nt ar m a n d st u d y visit/ da y ( Da y 2 2, 4 3, a n d 
7 1) f or eac h treat me nt area a n d wit h mea n a n d S D.
A listi n g of Li kert Scale sc ores will be pr o vi de d.
7. 7. 2.  
C h a n ge i n Di m ple A n al ysis P ar a meters usi n g 3 -D P h ot o gr a p hic I m a ge
T he o bser ve d a n d c ha n ge fr o m Da y  1 pre- mar ki n g i ma ge i n di m ple a nal ysis para meters, ma x 
le n gt h, ma x wi dt h, s urface area , a n d v o l ume bet wee n t he di m ple base a n d i nter p olate d s urface ,
will be s u m marize d at Da y  2 2, 43, a n d 7 1/ E T b y treat me nt area a n d treat me nt ar m usi n g 
descri pt i ve statistics. 
I n a d diti on, t he v ol u me a n d de pt h data will be a nal yze d usi n g t he li near mi xe d effect m o del 
descri be d i n Secti o n 7. 7. 1. 1.
A listi n g of di m ple a nal ysis para meters will be pr o vi de d.
7. 7. 3.  
C h a n ge fr o m B aseli ne i n Di m ple De pt h De pressi o n b y He xsel C S S ( B)
T he c ha n ge fr o m baseli ne i n t he He xs el C S S ( B) de pressi o n de pt h scale f or eac h treat me nt area
at Da ys 2 2, 4 3 , a n d 7 1 will be a nal yze d a n d s u m marize d as descri be d i n Sect i on 7. 7. 1. 1 .
I n a d diti on, a s hift ta ble of He xsel  C S S ( B) de pressio n de pt h e val uat i on at b aseli ne a n d p ost 
baseli ne st u d y  visit/ da y will be prese nte d usi n g c o u nts a n d perce nta ges.
A listi n g of He xsel C S S ( B) val ues will be pr o vi de d.
7. 8.  
S afet y A n al yses
S af et y data will be s u m marize d b y treat me nt ar m a n d b y treat me nt re gio n ( ie, B utt oc k s, Thi g h s, 
a n d O verall) usi n g t he Safet y P o p u lati on.


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7. 8. 1.  
St u d y Dr u g E x p os ure
T he n u m ber of i nject i ons of st u d y  dr u g gi ve n o n Da ys 1 , 2 2, a n d 4 3, will be s u m marize d per 
treat me nt area a n d b y tr e at me nt ar m usi n g c o u nts a n d perce nta ges as:

S u bjects w h o recei ve d 1 2 i njecti ons per treat me nt area

S u bjects w h o recei ve d less t ha n 1 2 i njecti ons per treat me nt area al o n g wit h reas o n
T he f ol l owi n g will be s u m mar ize d at eac h treat me nt visit b y treat me nt area a n d treat me nt ar m 
usi n g descri pt i ve statistics:

N u m ber of i njecti o ns gi ve n

N u m ber of di m ples treate d

A vera ge n u m ber of i nject i ons per di m ple

D ura tio n of  e x p os ure (refer t o Ta ble 1 2 f or c o mp utati o n of  e x p os ure d uratio n)
T he n u m ber of s u bjects treate d at eac h tr eat me nt visit will be s u m marize d usi n g fre q ue nc y c o u nt 
a n d perce nta ge b y tr e at me nt area a n d treat me nt ar m.
A s u bject list i n g of o verall e x p os ure, a n d i njecti on stat us will be pr o vi de d al o n g wi t h t he reas o ns 
f or recei vi n g less t ha n 1 2 i njecti ons per treat m e nt  area.
7. 8. 2.  
A d verse E ve nts
All A E s u m mar y  ta bles will incl u de o nl y  T E A Es, u nless ot her wise s pecifie d. 
A E s will be s u m marize d b y S O C a n d P T. A s u bject will o nl y  be c o u nte d o nce per S O C a n d P T.
F or A Es b y  se verit y gra de ( mil d, mo derate, se vere), if a s u bject h as mul tiple e ve nts occ urri n g i n 
t he sa me S O C or sa me P T, t he n t he e ve nt wit h t he ma xi m u m i nte nsity (ie, se vere) will be 
c o u nte d. 
F or A Es b y  r el atio ns hi p t o st u d y  dr u g, if a s u bject has m ulti ple e ve nts occ urri n g i n t he sa me 
S O C or sa me P T, t he e ve nt wit h t he hi g hest ass ociati o n ( ie, r elate d) t o st u d y dr u g will be 
s u m marize d. 
A E s will be prese nte d i n decreasi n g or der of t he i nci de nces at S O C le vel a n d wit hi n eac h S O C, 
i n decreasi n g or der of t he i nci de nces at t he P T le vel.
A n o verall s u m mar y o f A E a n d A E rel ate d t o st u d y dr u g will be prese nte d a n d will i ncl u de: 

T otal  n u m ber of T E A Es re p orte d

T otal  n u m ber of T E A Es re p orte d b y se verit y

T otal  n u m ber of A Es of s pecial i nterest

S u bjects wit h a n y T E A E 

S u bjects wit h a n y s pecial i nterest A E

S u bjects wit h a n y seri o us T E A E 

S u bjects wit h a n y se vere T E A E 


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
S u bjects wit h n o se vere T E A Es, b ut at least o ne m o derate T E A E

S u bjects wit h n o se vere T E A Es, b ut at least o ne mil d T E A E

S u bjects wit h a n y T E A Es lea di n g t o dr u g i nterr u pti o n/ wit h dra w n 

S u bjects wi t h a n y T E A Es lea di n g t o st u d y disc o nti n uati on 

S u bjects wit h a n y T E A Es res ult i n g i n deat h 
T he f o ll owi n g s u m mar y ta bles will be prese nte d b y  S O C a n d P T: 

All T E A Es 

T E A Es b y  se verit y

T E A Es b y  r el atio ns hi p t o st u d y  dr u g

All n o n- st u d y dr u g relate d T E A Es

All st u d y dr u g relate d T E A Es

St u d y  dr u g relate d T E A Es b y se verit y

S eri o us T E A Es

S eri o us st u d y  dr u g relate d T E A Es

D urati o n of  st u d y dr u g relate d T E A Es ( < 1 4 da ys, 1 4 – 2 1 da y s a n d > 2 1 da ys)

T E A Es l ea di n g t o dr u g i nterr u pti o n/ wit h dra w n

St u d y  dr u g relate d T E A E s lea di n g t o dr u g i nterr u pti o n/ with dra w n

T E A Es l ea di n g t o st u d y disc o nti n uati on

St u d y  dr u g relate d T E A E lea di n g t o st u d y disc o nti n uati on

T E A Es res ult i n g i n deat h

St u d y  dr u g relate d T E A Es res ulti n g i n deat h

A Es of special  int erest
S eri o us a n d m ost c o m m o n  n on- s erio us T E A E b y  or der of fre q ue nc y ( M ost fre q ue nt, 2 n d m o st 
fre q ue nt, a n d 3 r d m o st fre q ue nt) will be s u m marize d b y P T. M ost c o m mo n  n o n-serio us A Es are 
a n y preferre d ter m t hat at least 5 % of t he s u bjects re p orte d at least o nce.
T he f o ll owi n g listi n gs will be prese nte d b y  s u bject: 

All A Es

S eri o us A Es 

A Es res ult i n g i n dr u g i nterr u pti o n/ wit h dra w n

A Es res ult i n g i n st u d y disc o nti n uati on

A Es res ult i n g i n deat hs 

A Es of s pecial i nterest




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7. 9.  
Ot her S afet y P ar a meters
7. 9. 1.  
I m m u n o ge nicit y
T he i m m u n o ge nicit y a nal ysis o f bi n di n g a n d ne utralizi n g a nt i-A U X -I a n d a nti-A U X -II
a nt i b o dies will s u m marize t he n u m ber of s u bjects wit h a n i m m u n o ge nicity sa m ple, t he 
perce nta ges of s u bjects wit h a p ositi ve sa m ple, a n d t he a vera ge titer le vel of t he p ositi ve sa m ples 
at Da y 1 a n d E O S alo n g wi t h s u m mar y statistics if a nti b o d y assa ys are c on d ucte d . T he titer 
le vels will be l o garit h micall y tra nsf or me d pri or t o bei n g s u m marize d.
T he n u m ber a n d perce nta ge of assa ye d ser u m sa m ples t hat will detect t he prese nce or a bse nce of
ne utralizi n g a nt i b o dies ( p ositi ve/ ne gati ve) t o A U X-I a n d A U X-II will be s u m marize d b y 
a nt i dr u g a nt i b o d y q uartiles usi n g fre q ue nc y  c o u nt a n d perce nta ge at Da y 1 a n d E O S .
A listi n g of i m m u n o ge nicity res ults b y s u bject will be pr o vi de d.
8.  
C H A N G E F R O M P R O T O C O L
T his S A P is pre pare d base d o n t he ori gi nal  st u d y pr ot oc ol date d J u ne 2 7, 2 0 1 8 a n d t he a me n de d 
pr ot oc ol  date d A u g ust 2 9, 2 0 1 8 . There are n o pla n ne d c ha n ges eit her i n t he c o n d uct of t he st u d y 
or pl a n ne d a nal ysis at t he ti me of pre pari n g t his S A P. 
Ta ble 1 3 lists a n y si g nifica nt c ha n ges i n t he S A P fr o m w hat is pr o p ose d i n t he pr ot oc ol.
T a ble 1 3:  
C h a n ges fr o m Pr ot oc ol
Te xt i n Pr ot oc ol
C h a n ge i n S A P
J ustific ati o n
a li near mi xe d m o del will be
utilize d t o fit c ha n ge fr o m baseli ne 
of eac h e n d p oi nt wit h treat me nt 
ar m, cell ulite di m ples, a n d st u d y 
visit as fi xe d effects, s u bject as 
ra n d o m effect, a n d assess me nts 
acr oss st u d y visits as re peate d 
meas ure. T he fi xe d effect esti mates 
a n d t he c orres p o n di n g 9 5 % 
c o nfi de nce i nter vals will be 
prese nte d f or eac h e n d p oi nt.
T he Li kert Scale sc ore of 
i m pr o ve me nt i n aest hetic 
a p peara nce fr o m baseli ne will be 
a nal yze d usi n g a li near mi xe d m o del 
wit h treat me nt ar m, st u d y visit, 
i nteracti o n of treat me nt ar m a n d 
st u d y visit as fi xe d effects. T he 
fi xe d effect esti mates a n d 9 5 % CIs 
f or i nteracti o n effect of treat ment 
ar m a n d st u d y visit will be 
prese nte d. T his m o del will be fitte d 
usi n g t he res p o nse f or eac h 
treat me nt area (ie, left b utt oc k, ri g ht 
b utt oc k, left t hi g h, a n d ri g ht t hi g h) 
a n d f or t he a vera ge of left a n d ri g ht 
of treat me nt area ( ie, a vera ge of left 
b utt o c k a n d ri g ht b utt oc k; a vera ge 
of left t hi g h a n d ri g ht t hi g h). 
Clarif y  t he sa me m o del will fit t o 
t he res p o nse f or eac h treat me nt area. 
Re m o ve t he c o variate of cell ulite 
di m ples fr o m t he m o del as t he
n u m ber of di m ples treate d is n ot 
pla y  a n r ole 


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9.  
R E VI SI O N HI S T O R Y
N o n -e dit orial c ha n ges ma de t o a n y of t he mo d ul es of t his S A P are rec or de d i n Ta ble 1 4.
T a ble 1 4:  
Re visi o n Hist or y
Versi o n  
D ate
Re visi o n A ut h or
C o m me nts
1. 0  
2 3 -Oct - 2 0 1 8  
E n d o P har mace uticals I nc.  
P u blis he d v ersi on
2. 0  
1 1 -Fe b - 2 0 1 9
U p date d f o r i ma ge a nal ysis
1 0.  
R E F E R E N C E S
1.
Cl i nical St u d y Pr ot oc ol: A P hase 2a, O pe n -La bel  St u d y E val uati n g t he Safety a n d 
Differe nt I njecti o ns Tec h ni q ues of C C H f or t he Treat me nt of E de mat o us Fi br oscler otic 
Pa n nic ul o pat h y, A me n d me nt 1: 2 9 A u g ust 2 0 1 8 .
2.
He xsel D M, Dal ’F or n o T, He xsel C L. A vali date d p h ot o n u meric cell ulite se verit y scale. 
J E ur Ac a d Der m at ol Ve nere ol . 2 0 0 9; 2 3 ( 5): 5 2 3- 8.
3.
N ür n ber ger F, M üller G. S o -calle d cell ulite: a n i n ve nte d disease. J Der m at ol S ur g O nc ol . 
1 9 7 8; 4( 3): 2 2 1 - 2 2 9.
1 1.  
T A B L E S, LI S TI N G S, A N D G R A P H S H E L L S
T he l a yo uts of  t he s u m mar y ta bles, s u bject listi n gs, a n d gra p hs are prese nte d i n S A P M o d ule 2.
T hese la y o uts i nc or p orate all t he a p pr o priate ta ble titles, ta ble n u m bers, a n d f o ot n otes.