Clinical trial NCT02218489
Conditions: Blepharitis
Keywords: Pain Corticosteroid Meibomian Gland Disease Blepharitis Eyelid Ocular Discomfort
Sponsor: Kala Pharmaceuticals, Inc.
Start date: 2014-07-01; Completion date: 2016-06-01
Enrollment: 206 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to determine the efficacy and safety of KPI-121 ophthalmic suspension compared to vehicle (placebo) in subjects with signs and symptoms of inflammatory meibomian gland disease.

Detailed description:
This is a Phase II, multicenter, double-masked, randomized, vehicle-controlled, parallel-group study designed to evaluate the efficacy and safety of KPI-121 ophthalmic suspension versus vehicle in subjects with signs and symptoms of inflammatory meibomian gland disease. The product will be studied over 28 days, with 1-2 drops instilled in each eye four times daily (QID).

Arms: arm 1: Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease arm 2: KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease
Interventions: intervention 1: KPI-121 intervention 2: Vehicle
Intervention descriptions: intervention 1: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. Subjects randomized to placebo control arm will receive the same bottles containing all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate. intervention 2: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.

Protocol documents:
Prot_SAP_000.pdf: 
N C T 0 2 2 1 8 4 8 9   
 
St u dy I D:  
K PI -1 2 1 -C -0 0 3   
 
St u dy Titl e:  
A P h as e 2, D o u bl e -M ask e d, R a n d o miz e d, V e hicl e -C o ntr oll e d  
St u dy t o Ev al u at e t h e Eff ect of K PI -1 2 1 0. 2 5 % O p ht h al mic  
S us p e nsi o n o n Si g ns a n d Sy m pt o ms of I nfl a m m at ory  
M ei b o mi a n Gl a n d Dis e as e  
 
D at e:  
0 3 N ov 2 0 1 5  




K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
 
K  A  L  A  P  H  A  R   M  A  C  E  U  TI  C  A  L S, I  N  C.   
Cli ni c al  P r ot o c ol   K PI  -1 2 1 -C  -0 0 3   
I n v esti g at o r Si g n at u r e  P a g e  
P r oj e ct:  
K  PI -1 2 1  
 
C o  m p o u n d   N u  m b e r/  N a  m e:          
K PI  -1 2 1   
 
P r ot o c ol   N u  m b e r:  
K PI  -1 2 1 -C  -0 0 3   
 
P r ot o c ol   Titl e:  
A  P h as e  2,   D o u bl e  -M as k e d,   R a n d o  mi z e d,   V e hi cl e  -C o ntr oll e d 
St u d y  t o  E v al u at e t h e  Eff e ct of   K PI -1 2 1  0. 2 5  %   O p ht h al  mi c 
S us p e nsi o n  o n  Si g ns  a n d  S y  m pt o  m s  of I nfl a  m  m at or y 
M ei b o  mi a n   Gl a n d   Dis e as e    
 
S p o ns o r:  
K al a  P h ar  m a c e uti c als  , I n c. 
 
1 0 0   B e a v er  St,  S uit e  2 0 1  
 
W alt h a  m,   M  A  0 2 4 5 3    
 
Iss u e   D at e:  
O  ri gi n al:  1 6 J u n  2 0 1 4  
 
Cl arifi c ati o n  L ett er:    0 3 J ul  2 0 1 4  
 
A  m e n d  m e nt  1:    1 1 J ul  2 0 1 4  
 
A  m e n d  m e nt  2:   0 7   A u g  2 0 1 4   
 
Cl arifi c ati o n  L ett er:   2 8   A u g  2 0 1 4   
 
A  m e n d  m e nt  3:   1 2  S e p  2 0 1 4   
 
A  m e n d  m e nt  4:    1 2  N o v  2 0 1 4   
 
A  m e n d  m e nt  5:    1 0   D e c  2 0 1 4  
 
A  m e n d  m e nt  6:    1 2  J u n  2 0 1 5  
 
A  m e n d  m e nt  7:    1 2   A u g  2 0 1 5  
 
A  m e n d  m e nt  8:    0 3   N o v  2 0 1 5  
 
C o nt a ct f o r  S e ri o us   A d v e rs e   E v e nts  :   
 
 
 
 
     
 
 
 
 
   
 
 
 
 
I n v esti g at o r  N a  m e ( p ri nt e d  o r t y p e d):   
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
I n v esti g at o r 's  Si g n at u r e: 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                 _ _ _ _ _ _ _ _ _ _ _ _ _ _       
 
D at e    
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
S  Y  N  O P SI S   
St u d y  Titl e:         
K PI  -1 2 1 -C  -0 0 3:    A  P h as e  2,   D o u bl e -M as k e d,   R a n d o  mi z e d, 
V e hi cl e  -C o ntr oll e d  St u d y t o  E v al u at e t h e  Eff e ct  of   K PI  -1 2 1  0. 2 5  % 
O p ht h al  mi c  S us p e nsi o n  o n  Si g ns  a n d  S y  m pt o  ms  of I nfl a  m  m at or y 
M ei b o  mi a n   Gl a n d   Dis e as e    
O bj e cti v es:          
T h e  pri  m ar y  o bj e cti v e  of t his st u d y is t o i n v esti g at e t h e s af et y  a n d 
effi c a c y  of   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  c o  m p ar e d t o 
v e hi cl e  i n s u bj e cts   wit h si g ns  a n d s y  m pt o  ms  of i nfl a  m  m at or y 
m ei b o  mi a n  gl a n d  dis e as e (  M  G  D).    
St u d y  P o p ul ati o n:        T h e st u d y  p o p ul ati o n   will  c o nsist  of s u bj e cts   wit h   mil d t o   m o d er at e 
i nfl a  m  m at or y M  G  D  .    
N u  m b er  of 
S u bj e cts:  
U p t o  7 5 0 s u bj e cts   w h o  ar e  di a g n os e d   wit h i nfl a  m  m at or y   M  G  D   will 
b e s cr e e n e d.   Fr o  m t h os e s cr e e n e d,  a p pr o xi  m at el y  2 0 0  s u bj e cts   will 
b e r a n d o  mi z e d t o   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  or v e hi cl e .  
I n v esti g ati o n al 
Pr o d u ct s: 
K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  or v e hi cl e  will  b e s u p pli e d 
as i n v esti g ati o n al  pr o d u ct. 
R o ut e  a n d   D ur ati o n 
of   A d  mi nistr ati o n : 
1 t o  2  dr o ps  of i n v esti g ati o n al  pr o d u ct   will  b e i nstill e d i n  e a c h  e y e 
f o ur ti  m es  p er  d a y (  QI  D) f or  u p t o 3 0  d a ys.  
St u d y   D esi g n:    
 
T his is  a  P h as e  2,   m ulti- c e nt er,  d o u bl e-  m as k e d, r a n d o  mi z e d, 
v e hi cl e -c o ntr oll e d,  p ar all el -gr o u p st u d y  d esi g n e d t o  e v al u at e t h e 
s af et y  a n d  effic a c y  of   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  i n 
s u bj e cts   wit h i nfl a  m  m at or y  M  G  D  .   
 
A p pr o xi  m at el y  7 5 0 s u bj e cts   will  b e s cr e e n e d  a n d  u p t o  2 0 0 s u bj e cts 
will  b e r a n d o  mi z e d  at  u p t o  1 2  c e nt ers l o c at e d i n t h e   U nit e d  St at es 
(  U S).   
 
Aft er  a r u n-i n  p eri o d  of tr e at  m e nt   wit h  v e hi cl e, s u bj e cts   will  b e 
r a n d o  mi z e d t o  1  of  2 st u d y  ar  ms i n  a n  a p pr o xi  m at e  1: 1 r ati o.   T h e 
st u d y  ar  ms  ar e:  1)   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n 
a d  mi nist er e d  as  1 -2  dr o ps i n  e a c h  e y e   QI  D f or  u p t o  3 0  d a ys  or  2) 
v e hi cl e  a d  mi nist er e d  as  1- 2  dr o ps i n  e a c h  e y e   QI  D f or  u p t o  3 0 
d a ys.    
 
F urt h er  m or e, s u bj e cts   will  b e  assi g n e d t o  a st u d y  ar  m  b as e d  o n t h e 
str atifi c ati o n  of: 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     S u bj e ct’s  Visit  1 (  D a y   -1 4)  
 
 
   A  N  D 
•     Visit    1 (  D a y - 1 4) i n v esti g at or-r at e d  p ost eri or li d   m ar gi n 
h y p er e  mi a s c or e        
 
 
T his st u d y   will i n cl u d e  u p t o  6  cli ni c  visits  o v er  6   w e e ks.  At   Visit  1 
S cr e e ni n g ( 1 4  ±  1  d a ys  pri or t o   D a y  1), s u bj e cts   w h o   m e et s cr e e ni n g 
i n cl usi o n/ e x cl usi o n  crit eri a   will  b e gin  a  2 -w e e k r u n  -i n  p eri o d  d uri n g 
w hi c h t h e y   will  b e tr e at e d   wit h  1  -2  dr o ps  of si n gl e -m as k e d  v e hi cl e 
i n  e a c h  e y e   QI  D f or  1 4  ±  1  d a ys.   
 
At   Visit  2   R a n d o  mi z ati o n (  D a y  1), s u bj e cts   w h o  c o nti n u e t o   m e et 
i n cl usi o n/ e x cl usi o n  crit eri a (  wit h t h e  e x c e pti o n  of I n cl usi o n   Crit eri a 
# 4  a n d  # 7 )   will  b e  eli gi bl e f or r a n d o  mi z ati o n t o   K PI-1 2 1  0. 2 5  % 
o p ht h al  mi c  s us p e nsi o n  or v e hi cl e .   
 
F oll o  wi n g r a n d o  mi z ati o n, s u bj e cts  will   r et ur n t o t h e  cli ni c f or 
e v al u ati o n  at  St u d y   Visit  3  (  D a y  8 ±  1  d a y) , Visit   4  (  D a y  1 5 ±  1 
d a y),  Visit   5 (  D a y  2 2  ±  1  d a y)  a n d   Visit  6 (  D a y  2 9  ±  1  d a y).  At 
Visits  3   (  D a y  8 ±  1  d a y)  a n d  5  (D a y  2 2  ±  1  d a y)   e v al u ati o ns   will 
i n cl u d e 
  a n d s u bj e ct-r at e d  ass ess  m e nt  of o c ul ar 
dis c o  mf ort.  A  c  o  m pl et e st u d y  e v al u ati o n   will  b e  c o n d u ct e d  at  St u d y 
Visits   4  a n d  6.  S u bj e cts   will  b e r el e as e d fr o  m t h e st u d y  at t h e  e n d  of 
Visit  6   (  D a y  2 9 ±  1  d a y).  
 
Ass ess  m e nts   will i n cl u d e   
•     I n v esti g at or-r at e d  ass ess  m e nt  of  p ost eri or li d   m ar gi n 
h y p er e  mi a  
•  
 
  
•     I n v esti g at or-r at e d  ass ess  m e nt  of  c o nj u n cti v al  h y p er e  mi a 
•     I n v esti g at or-r at e d  ass ess  m e nt  of t h e c h ar a ct er  of t h e 
m ei b o  mi a n  gl a n ds’  c o nt e nts  
•     I n v esti g at or-r at e d  ass ess  m e nt  of t h e  e x pr essi bilit y  of t h e 
m ei b o  mi a n  gl a n ds 
•     T e ar  fil  m  br e a k u p  ti  m e ( T F  B  U T) 
•     C or n e al fl u or es c ei n st ai ni n g 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•  
 
dis c o  mf ort  ass ess  m e nt 
•     I n-c li ni c su bj e ct -rat e d  a ss ess  m e nt  of o c ul ar  d is c o  mf ort 
•     B est  c orr e ct e d  vis u al  a c uit y (  B  C  V  A) 
•     Slit  la  m p  b i o  mi cr os c o p y 
•     I ntr a o c ul ar  pr ess ur e (I  O P)   m e as ur e  m e nt  
•     Dil at e d   o p ht h al  m os c o p y  
Effi c a c y  E n d p oi nts       P ri  m a r y   Effi c a c y   E n d p oi nts:  
 
C o  m p aris o n  of   m e a n 
  S e v erit y   Ass ess  m e nt  S c or e 
b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e 
v e hi cl e  gr o u p:  
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
4 ) 
 
C o  m p aris o n  of   m e a n   p ost eri or li d   m ar gi n  h y p er e  mi a
 
 
 
  at   Visit  2 b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p: 
•     Visit  4   
 
S e c o n d a r y   Effi c a c y   E n d p oi nts:  
 
C o  m p aris o n  of   m e a n 
  S e v erit y   Ass ess  m e nt  S c or e 
b et  w e e n t h e   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e 
v e hi cl e  gr o u p:  
•     Visit  6 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
6)  
 
C o  m p aris o n  of   m e a n   p ost eri or li d   m ar gi n  h y p er e  mi a 
 
 
 
at   Visit  2  b et  w e e n t h e   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  6 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
 
 
        
 
        
 
 
E x pl o r at o r y   E n d p oi nts:   
 
C o  m p aris o n  of   m e a n i n v esti g at or  -r at e d  ass ess  m e nt  of  c o nj u n cti v al 
h y p er e  mi a  b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n 
gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n   i n v esti g at or-r at e d c h ar a ct er  of t h e   m ei b o  mi a n 
gl a n ds’  c o nt e nts  b et  w e e n t h e   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4 
•     Visit  6   
 
C o  m p aris o n  of   m e a n   i n v esti g at or-r at e d  e x pr essi bilit y  of t h e 
e v al u at e d   m ei b o  mi a n  gl a n ds  b et  w e e n t h e   K PI- 1 2 1  0. 2 5  % 
o p ht h al  mi c  s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4 
•     Visit  6   
 
C o  m p aris o n  of   m e a n  c or n e al fl u or es c ei n st ai ni n g  b et  w e e n t h e   K PI  -
1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p: 
•     Visit  4   
•     Visit  6 
 
C o  m p aris o n  of   m e a n  T F  B  U T  b et  w e e n t h e   K PI- 1 2 1  0. 2 5  % 
o p ht h al  mi c  s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n 
  Fr e q u e n c y   Ass ess  m e nt 
S c or e  b et  w e e n t h e   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  gr o u p 
a n d t h e  v e hi cl e  gr o u p :  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 7  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     Visit   4  ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o Visit 
4 ) 
•     Visit   6 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o  Visit 
6)  
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2) i n  p ost eri or li d 
m ar gi n  h y p er e  mi a 
 f or 
s u bj e cts   wit h  gr e at er t h a n  or  e q u al t o  a  gr a d e  of  1 i n  at l e ast  o n e 
p ost eri or li d   m ar gi n (i. e.,   R  U L,  L  U L,   R L L,  L L L)  at   Visit  2  b et  w e e n  
t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  
gr o u p : 
•     Visit  4  as  c o  m p ar e d t o   Visit  2 
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
 
 
 
 
 
 
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   i n v esti g at or-
r at e d  ass ess  m e nt  of  c o nj u n cti v al  h y p er e  mi a  b et  w e e n t h e   K PI- 1 2 1 
0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d  t h e  v e hi cl e  gr o u p: 
•     Visit  4  as  c o  m p ar e d t o   Visit  2 
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   i n v esti g at or-
r at e d  ass ess  m e nt  of t h e  c h ar a ct er  of t h e   m ei b o  mi a n  gl a n ds’  c o nt e nts 
b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  gr o u p  a n d  t h e 
v e hi cl e  gr o u p : 
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   b et  w e e n  
i n v esti g at or-r at e d  ass ess  m e nt  of t h e  e x pr essi bilit y  of t h e   m ei b o  mi a n 
gl a n ds t h e   K PI- 1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e 
v e hi cl e  gr o u p : 
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 8  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e   (  Visit  2) c or n e al 
fl u or es c ei n st ai ni n g b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p: 
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6  as  c o  m p ar e d t o   Visit  2 
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)  T F  B  U T 
b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  gr o u p  a n d  t h e 
v e hi cl e  gr o u p : 
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n   c h a n g e fr o  m  b as eli n e (  Visit  2)         
 
  S e v erit y Ass ess  m e nt   S c or e  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  % 
o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p: 
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
4  a n d   Visit  2)  
•     Visit  6 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
6  a n d   Visit  2) 
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)         
 
  Fr e q u e n c y Ass ess  m e nt   S c or e  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  % 
o p ht h al  mi c s us p e nsi o n  gr o u p  a n d   wit hi n t h e  v e hi cl e  gr o u p:  
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
4  a n d   Visit  2)  
•     Visit  6 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit 
6  a n d   Visit  2)  
 
C o  m p aris o n  of t h e   m e a n 
  S e v erit y Ass ess  m e nt 
S c or e  b et  w e e n   K PI -1 2 1  0. 0 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d 
t h e  v e hi cl e  gr o u p  
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  d a y  pr  i or t o Visit  4  )  
•     Visit  6 ( b as e d  o n t h e   m e a n s c or e f or t h e  d a y  pri or t o   Visit   6) 
 
C o  m p aris o n  of t h e   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)         
 
  S e v erit y Ass ess  m e nt   S c or e  b et  w e e n   K PI -1 2 1  0. 0 2 5  % 
o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 9  O F 8 5  
0 3  N O  V   2 0 1 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  d a y  pri or t o   Visit  4 
a n d   Visit  2)  
•     Visit  6 ( b as e d  o n t h e   m e a n s c or e f or t h e  d a y  pri or t o   Visit   6 
a n d   Visit  2) 
S af et y  E n d p oi nts  
•     I  O P   m e as ur e  m e nts 
•     Slit -l a  m p   Bi o  mi cr os c o p y  
•     B  C  V  A   
•     O p ht h al  m os c o p y     
•     A d v ers e  E v e nt (  A E)   m o ni  t ori n g 
Eli gi bilit y   Crit eri a:       I n cl usi o n   C rit e ri a:  
 
At   Visit  1  a n d   Visit  2, i n di vi d u als  of  eit h er  g e n d er  or  a n y r a c e   will 
b e  eli gi bl e f or st u d y  p arti ci p ati o n if t h e y:  
 
1.    Pr o vi d e   writt e n i nf or  m e d  c o ns e nt  a n d   H e alt h I ns ur a n c e 
P ort a bilit y  a n d   A c c o u nt a bilit y   A ct  (  HI P  A  A)  a ut h ori z ati o n 
pri or t o  a n y st u d y-r el at e d  pr o c e d ur es. 
2.    Ar e  1 8  y e ars  of  a g e  or  ol d er.     
3.    Ar e   willi n g  a n d  a bl e t o f oll o  w i nstr u cti o ns  a n d  c a n  b e 
pr es e nt f or t h e r e q uir e d st u d y  visits f or t h e  d ur ati o n  of t h e 
st u d y. I n  a d diti o n, t h e y   m ust  d e  m o nstr at e: 
a.    Si n gl e -m as k e d i n v esti g ati o n al  pr o d u ct  us e 
c o  m pli a n c e  of  at l e ast  8 0  %  d uri n g t h e fi n al   w e e k  of 
t h e r u n-i n  p h as e   A  N  D  
b.  
  c o  m pli a n c e  of  at l e ast  8 0  % i n t h e 
fi n al   w e e k  of t h e r u n-i n  p h as e. 
4.    U p o n  e x a  mi n ati o n   at  Visit  1   O  N  L  Y  ,  h a v e A  L  L   5  of t h e 
f oll o  wi n g  crit eri a i n t h e s a  m e or  b ot h  e y es :   
a.  
 
 
 
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 0  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
e.    A n   u n a n est h eti z e d  S c hi r  m e r  s c or e 
 
 
5.    Ar e   w o  m  e n  of  c hil d  b e ari n g  p ot e nti al (   W  O  C  B P) , w h o  ar e   
n ot  pr e g n a nt  or l a ct ati n g  a n d  n ot s e x u all y  a cti v e (i. e., 
a bsti n e nt) f or  1 4  d a ys  pri or t o   Visit  1  a n d  ar e  willi n g t o 
r e  m ai n s o t hr o u g h  3 0  d a ys f oll o  wi n g   Visit  6  or t h e l ast 
a d  mi nistr ati o n  of t h e  i n v esti g ati o n al  pr o d u ct or  u ntil 
c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al  c y cl e f oll o  wi n g 
t h e l ast  a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct, 
w hi c h e v er  p eri o d  of ti  m e is l o n g er.    Alt er n ati v el y,    W  O  C  B P 
w h o  ar e  n ot  a bsti n e nt   m ust  h a v e  b e e n  usi n g  o n e  of t h e 
f oll o  wi n g  a c c e pt a bl e   met h o ds  of  birt h  c o ntr ol f or t h e ti  m es 
s p e cifi e d:  
a.    I ntr a ut eri n e  d e vi c e (I  U  D) i n  pl a c e f or  at l e ast  3 
m o nt hs  pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast 
a d  mi nistr ati o n  of i n v esti g ati o n al  pr o d u ct  or  u ntil 
c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al  c y cl e 
f oll o  win g l ast  a d  mi nistr ati o n  of t h e  i n v esti g ati o n al 
pr o d u ct ,   w hi c h e v er  p eri o d  of ti  m e is l o n g er. 
b.    B arri er   m et h o d ( c o n d o  m  or  di a p hr a g  m)   wit h 
s p er  mi ci d e f or  at l e ast  3   m o nt hs  pri or t o   Visit  1 
t hr o u g h   Visit  6  or l ast  a d  mi nistr ati o n  of t h e 
i n v esti g ati o n al  pr o d u ct or  u ntil  c o  m pl eti o n  of t h e 
s u bj e ct’s first   m e nstr u al  c y cl e f oll o  wi n g l ast 
a d  mi nistr ati o n  of t h e  i n v esti g ati o n al  pr o d u ct, 
w hi c h e v er  p eri o d  of ti  m e is l o n g er. 
c.    St a bl e  h or  m o n al  c o ntr a c e pti v e f or  at l e ast   
3   m o nt hs  pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast 
a d  mi nist r ati o n  of t h e i n v esti g ati o n al  pr o d u ct or  u ntil 
c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al  c y cl e 
f oll o  wi n g  a d  mi nistr ati o n  of t h e i n v esti g ati o n al 
pr o d u ct,   w hi c h e v er  p eri o d  of ti  m e is l o n g er.  
N  O  T  E:   F or   D e p o -Pr o v er a i nj e cti o n  c o ntr a c e pti v es, t h e 
st at e  m e nt r eg ar di n g first   m e nstr u al  c y cl e f oll o  wi n g 
a d  mi nistr ati o n  of t h e  i n v esti g ati o n al  pr o d u ct is  n ot 
a p pli c a bl e,  as f e  m al es r e c ei vi n g t his f or  m  of 
c o ntr a c e pti o n   will  n ot  h a v e   m e ns es.  
d.    I n  a   m o n o g a  m o us r el ati o ns hi p   wit h  a s ur gi c all y 
st erili z e d (i. e.,  v as e ct o  mi z e d)  p art n er f or  at l e ast  6 
m o nt hs  pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 1  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct  or  u ntil 
c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al  c y cl e 
f oll o  wi n g  a d  mi nistr ati o n  of t h e i n v esti g ati o n al 
pr o d u ct,   w hi c h e v er  p eri o d  of ti  m e is l o n g er.  
6.    Ar e   p ost  m e n o p a us al   w o  m e n , w h o  h  a v e  h a d  n o   m e nstr u al 
c y cl e f or  at l e ast  1  y e ar  pri or t o   Visit  1  or  h a v e  u n d er g o n e 
o n e  of t h e f oll o  wi n g st erili z ati o n  pr o c e d ur es  at l e ast  6 
m o nt hs  pri or t o   Visit  1: 
a.    Bil at er al t u b al li g ati o n   
b.    H yst er e ct o  m y 
c.    H yst er e ct o  m y   wit h  u nil at er al  or  bil at er al 
o o p h or e ct o  m y.  
d.    Bil at er al  o o p h or e ct o  m y   
 
E x cl usi o n   C rit e ri a:   
 
I n  or d er f or s u bj e cts t o  b e  eli gi bl e  at   Visit  1  a n d   Visit  2 t h e y   m a y 
n ot:  
 
1.    H a v e  k n o  w n  h y p ers e nsiti vit y  or  c o ntr ai n di c ati o n t o t h e 
i n v esti g ati o n al  pr o d u ct(s)  or t h eir  c o  m p o n e nts. 
2.    H a v e  us e d  a n y  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  3 0  d a ys 
pri or t o  S cr e e ni n g (  Visit  1)  a n d f or t h e  d ur ati o n  of t h e st u d y : 
a.    O c ul ar, i n h al e d,  or i ntr a n as al  c orti c ost er oi ds   
b.    O c ul ar  or  or al  n o n  -st er oi d al  a nti-i nfl a  m  m at or y  dr u gs 
(  N S  AI  Ds) wi  t h t h e  e x c e pti o n  of l o  w  d os e  as piri n (≤  
8 1   m g  p er  d a y ) 
c.    T o pi c al  o c ul ar  a nti bi oti cs 
d.    T o pi c al  o c ul ar  a nti hist a  mi n es  or   m ast  c ell st a bili z ers  
e.    Or al  a nti hist a  mi n es 
f.    T o pi c al  or  n as al  v as o c o nstri ct ors  
3.    H a v e  us e d  a n y  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  6 0  d a ys 
pri or  t o  S cr e e ni n g (  Visit  1) a n d f or t h e  d ur ati o n  of t h e st u d y : 
a.    T o pi c al  c y cl os p ori n e (  R est asis ® ) 
b.    A n y f or  m  of t o pi c al l ot e pr e d n ol  et a b o n at e ( L E)   
4.    H a v e  alt er e d  or al  d osi n g  of t h e f oll o  wi n g   wit hi n  3 0  d a ys 
pri or t o  S cr e e ni n g (  Visit  1)  or  a nti ci p at e  alt er ati o n  of  d osi n g 
d uri n g t h e st u d y: 
a.    T etr a c y cli n e  c o  m p o u n ds ( e. g., t etr a c y cli n e, 
d o x y c y cli n e,  or   mi n o c y cli n e)   


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 2  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
b.    O  m e g a- 3  a n d   O  m e g a- 6 s u p pl e  m e nts 
5.    H a v e  alt er e d  d osi n g  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  6 
m o nt hs  pri or t o  S cr e e ni n g (  Visit  1)  or  a nti ci p at e  alt er ati o n  of 
d osi n g  d uri n g t h e st u d y: 
a.    A nti c h oli n er gi cs   
b.    A nti d e pr ess a nts 
c.    Is otr eti n oi n 
d.    Or al  c orti c ost er oi ds 
e.    S yst e  mi c i  m  m u n os u p pr essi v e  a g e nts  
6.    B e  u n  willi n g t o  a bst ai n fr o  m t h e  us e  of  a n y t o pi c al 
o p ht h al  mi c   m e di c ati o ns  at   Visit  1 ( S cr e e ni n g)  a n d f or t h e 
d ur ati o n  of t h e st u d y, i n c l u di n g: 
a.    E y el as h  gr o  wt h   m e di c ati o ns  
b.    E y e  dr o ps,  g els,  or  artifi ci al t e ars  
7.    B e  u n  willi n g t o  a bst ai n fr o  m t h e  us e   of  t u  m or  n e cr osis f a ct or 
(T  N F )  bl o c ki n g  a g e nts ( e. g.  et a n er c e pt,  a d ali  m u  m a b, 
i nfli xi  m a b)  at   Visit  1 ( S cr e e ni n g)  a n d f or t h e  d ur ati o n  of t h e 
st u d y. 
8.    B e  c urr e ntl y r e c ei vi n g tr e at  m e nt f or  gl a u c o  m a,  h a v e  hist or y 
of  or  c urr e nt  gl a u c o  m a,  or  a n I  O P  o v er  2 1  m  m  H g  at   Visit  1 
( S cr e e ni n g)  or   Visit  2 (  R a n d o  mi z ati o n). 
9.    I niti at e  or  alt er t h e  us e (if  usi n g  u p o n  e ntr y)  of  or al 
c o ntr a c e pti v es,  or  f e  m al e  h or  m o n e r e pl a c e  m e nt 
t h er a p y/s u p pl e  m e nt ati o n   wit hi n  4 8  h o urs  pri or t o   Visit  1  a n d 
f or t h e  d ur ati o n  of t h e st u d y. 
1 0.  B e  u n  willi n g t o  a bst ai n fr o  m   w e ari n g  c o nt a ct l e ns es f or  1 4 
d a ys  pri or t o   Visit  1  a n d t hr o u g h o ut t h e st u d y.  
1 1.  B e   m o n o c ul ar  or  h a v e  a   B  C  V  A,  usi n g  c orr e cti v e l e ns es if 
n e c ess ar y,  of  + 1. 0 l o g  M  A  R  or   w ors e  as  ass ess e d  b y  E arl y 
Tr e at  m e nt   Di a b eti c   R eti n o p at h y  St u d y ( E T  D  R S). 
1 2.  B e   u n  willi n g t o  dis c o nti n u e   w ar  m  c o  m pr ess t h er a p y, li d 
e x pr essi o n,  or li d   m ass a g e  1 4  d a ys  pri or t o   D a y  1  a n d f or t h e 
d ur ati o n  of t h e st u d y.   
1 3.  H a  v e  a  di a g n osis  of:  
a.    O n g oi n g  o c ul ar i nf e cti o n   
b.    M o d er at e t o s e v er e  pi n g u e c ul a  or  pt er y gi a 
c.    St e v e ns -J o h ns o n  S y n dr o  m e  
d.    Si g nifi c a nt  c o nj u n cti v al s c arri n g 
e.    Si g nifi c a nt  a nt eri or  bl e p h aritis  
f.    R os a c e a   wit h  c or n e al i n v ol v e  m e nt. 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
g.    S e v er e/s eri o us  o c ul ar  c o n diti o n t h at i n t h e j u d g  m e nt 
of t h e i n v esti g at or  c o ul d  c o nf o u n d st u d y  ass ess  m e nts 
or li  mit  c o  m pli a n c e.  
h.    S e v er e/s eri o us s yst e  mi c  dis e as e  or  u n c o ntr oll e d 
m e di c al  c o n diti o n t h at i n t h e j u d g  m e nt  of t h e 
i n v esti g at or  c o ul d  c o nf o u n d st u d y  ass ess  m e nts  or 
li  mit  c o  m pli a n c e. 
1 4.  H a v e  c o n c urr e nt  a c ut e  h or d e ol u  m (st y e)  or  c h al a zi o n. 
1 5.  H a v e si g nifi c a nt  a nt eri or  bl e p h aritis, si g nifi c a nt  d a n dr uff,  or 
D e  m o d e x f olli c ul ar u  m   i nf est ati o n. 
1 6.  H a v e   c o  m pl et e  o bstr u cti o n  of  t h e m ei b o  mi a n   gl a n ds  
e v al u at e d  t h at pr es e nt   wit h  n o  e x pr essi bilit y.  
1 7.  H a v e  c o n c urr e nt si g n  s  of   m o d er at e t o s e v er e  c hr o ni c  e y eli d 
m ar gi n i nfl a  m  m ati o n (  m o d er at e t o s e v er e  e y eli d   m ar gi n 
t el a n gi e ct asi a a n d  e y eli d   m ar gi n s c arri n g)  or li d str u ct ur al 
a b n or  m aliti es s u c h  as  e ntr o pi o n,  e ctr o pi o n, tri c hi asis,  or l as h 
l oss. 
1 8.  H a v e  h a d  o c ul ar s ur g er y i n t h e  p  ast  9 0  d a ys  or r e q uir e  o c ul ar 
s ur g er y  d uri n g t h e st u d y.  
1 9.  H a v e  a cti v e  or  h a v e  h a d  a n  o ut br e a k  of  h er p eti c  k er atitis 
wit hi n  1  y e ar  of   Visit  1.   
2 0.  H a v e  us e d  e y e   m a k e- u p ( e. g.,  e y eli n er,   m as c ar a,  e y e 
s h a d o  w,  e y eli d  glitt er,  e y eli d  c o n c e al er  or  b as e),  e y el as h 
c url e rs,  e y eli d  gl u e,  or f als e  e y el as h es  at   Visit  1  or  ar e 
u n  willi n g t o  dis c o nti n u e t h e  us e  of t h es e  pr o d u cts  o n t h e 
d a ys  of st u d y  visits. 
2 1.  H a v e  p er  m a n e nt  e y eli n er.   
2 2.  H a v e  a  d o c u  m e nt e d  hist or y  of  o c ul ar  all er gi es,   w hi c h, i n t h e 
j u d g  m e nt  of t h e i n v esti g at or,  ar e li k el y t o  h a v e  a n  a c ut e 
i n cr e as e i n s e v erit y  d u e t o t h e  e x p e ct e d ti  mi n g  of  e x p os ur e 
t o t h e  all er g e n t o   w hi c h t h e s u bj e ct is s e nsiti v e.   S u bj e cts 
s e nsiti v e t o s e as o n al  all er g e ns t h at  ar e  n ot  e x p e ct e d t o  b e 
pr es e nt  d uri n g t h e st u d y  ar e  p er  mitt e d.  
2 3.  B e   a n  e  m pl o y e e  of t h e sit e t h at is  dir e ctl y i n v ol v e d i n t h e 
m a n a g e  m e nt,  a d  mi nistr ati o n,  or s u p p ort  of t his st u d y  or  b e 
a n i  m  m e di at e f a  mil y   m e  m b er  of t h e s a  m e. 
2 4.  I n t h e  o pi ni o n  of t h e I n v esti g at or  or st u d y  c o or di n at or,  b e 
u n  willi n g  or  u n a bl e t o  c o  m pl y   wit h t h e st u d y  pr ot o c ol  or 
u n a bl e t o s u c c essf ull y i nstill  e y e  dr o ps.  
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
T A  B  L  E   O F C O  N  T  E  N  T S  
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   O F  T E  R  M S  ..............................1 9  
1.     I  N T  R  O  D  U  C TI  O  N ................................................................................................2 1  
1. 1.     D E S  C  RI P TI  O  N   O F IN  V E S TI  G  A TI  O  N  A L P R  O  D  U  C T  ....................................................2 2  
1. 2.     JU S TI FI  C  A TI  O  N  F  O  R R O  U T E   O F A D  MI  NI S T  R  A TI  O  N   A  N  D D O S E S E L E  C TI  O  N  ............2 3  
1. 3.     G  C P  C O  M P LI  A  N  C E  ..............................................................................................2 3  
1. 4.     P O P  U L  A TI  O  N  T  O   B E S T  U  DI E  D  ...............................................................................2 3  
2.     T  RI  A L   O  BJ E  C TI  V E S   A  N  D  P  U  R P  O S E  ..............................................................2 4  
2. 1.     O BJ E  C TI  V E  ..........................................................................................................2 4  
3.     T  RI  A L   D E SI  G  N  ...................................................................................................2 5  
3. 1.     P RI  M  A  R  Y E F FI  C  A  C  Y E N  D P  OI  N T S  .........................................................................2 5  
3. 2.     S E  C  O  N  D  A  R  Y E F FI  C  A  C  Y E N  D P  OI  N T S  ....................................................................2 5  
3. 3.     E X P L  O  R  A T  O  R  Y E F FI  C  A  C  Y E N  D P  OI  N T S  ................................................................2 5  
3. 4.     S A F E T  Y E N  D P  OI  N T S  ............................................................................................3 3  
3. 5.     D E S  C  RI P TI  O  N   O F T RI  A L D E SI  G  N  ..........................................................................3 3  
3. 5. 1.     I n v esti g ati o n al  pr o d u ct ....................................................................................3 5  
3. 5. 2.     M et h o ds t o   Mi ni  mi z e   Bi as   ..............................................................................3 7  
4.     S E L E  C TI  O  N   O F  S  U  BJ E  C T S  ..............................................................................3 8  
4. 1.     S U  BJ E  C T IN  C L  U SI  O  N C RI T E  RI  A  ............................................................................3 8  
4. 2.     S U  BJ E  C T E X  C L  U SI  O  N C RI T E  RI  A  ..........................................................................3 9  
5.     P  R  O  C E  D  U  R E S  ....................................................................................................4 2  
5. 1.     V I SI T D E S  C  RI P TI  O  N S  ...........................................................................................4 2  
5. 1. 1.     Visit  1:   1 4  ±  1   D a ys  Pri or t o   D a y  1   –  S cr e e ni n g  ...........................................4 2  
5. 1. 2.     Visit  2:    D a y  1 (  R a n d o  mi z ati o n)   .....................................................................4 3  
5. 1. 3.     Visit  3:   D a y  8  ±  1  d a y   –  
 ......................................................4 4  
5. 1. 4.     Visit  4:   D a y  1 5  ±  1  d a y   –  St u d y  Visit   .............................................................4 5  
5. 1. 5.     Visit  5:   D a y  2 2  ±  1  d a y   –  
 ....................................................4 5  
5. 1. 6.     Visit  6:   D a y  2 9  ±  1  d a y   –  E n d  of  St u d y   Visit  .................................................4 6  
5. 1. 7.     U ns c h e d ul e d   Visit   ...........................................................................................4 6  
5. 1. 8.     E arl y  T er  mi n ati o n   Visit  ..................................................................................4 7  
5. 2.     R E S  C  U E M E  DI  C  A TI  O  N U S E  ..................................................................................4 7  
5. 3.     S U  BJ E  C T W
I T  H  D  R  A   W  A L   A  N  D/O  R D I S  C  O  N TI  N  U  A TI  O  N ..........................................4 7  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 5  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
5. 4.     C O L L E  C TI  O  N   O F D A T  A  ........................................................................................4 8  
6.     T  R E  A T  M E  N T   O F  S  U  BJ E  C T S  ............................................................................4 9  
6. 1.     IN  V E S TI  G  A TI  O  N  A L P R  O  D  U  C T S  T  O   B E A D  MI  NI S T E  R E  D  ..........................................4 9  
6. 2.     C O  N  C  O  MI T  A  N T M E  DI  C  A TI  O  N S  ............................................................................4 9  
6. 2. 1.     P er  mitt e d   M e di c ati o ns  a n d  T h er a pi es  .............................................................4 9  
6. 2. 2.     M e di c ati o ns   a n d  Pr o c e d ur es   N ot  P er  mitt e d  ....................................................4 9  
6. 3.     IN  V E S TI  G  A TI  O  N  A L  P  R  O  D  U  C T U S E C O  M P LI  A  N  C E  ..................................................5 1  
6. 4.     D R  U  G A C  C  O  U  N T  A  BI LI T  Y  .....................................................................................5 1  
6. 5.     M AI  N T E  N  A  N  C E   O F R A  N  D  O  MI Z  A TI  O  N   A  N  D P R  O  C E  D  U  R E  F  O  R B R E  A  KI  N  G  T  H E 
C O  D E  .........................................................................................................5 1  
7.     A S S E S S  M E  N T   O F  E F FI  C  A  C  Y   ..........................................................................5 3  
8.     A S S E S S  M E  N T   O F  S  A F E T  Y   ...............................................................................5 4  
8. 1.     S A F E T  Y P A  R  A  M E T E  R S  .........................................................................................5 4  
8. 2.     A D  V E  R S E E V E  N T D E FI  NI TI  O  N S  ............................................................................5 4  
8. 3.     P R  O  C E  D  U  R E S  F  O  R A E  R E P  O  R TI  N  G   B  Y  T  H E IN  V E S TI  G  A T  O  R  ..................................5 6  
8. 4.     R E S  C  U E T H E  R  A P  Y  ...............................................................................................5 6  
8. 5.     S E  RI  O  U S A D  V E  R S E E V E  N T R E P  O  R TI  N  G   B  Y  T  H E IN  V E S TI  G  A T  O  R  ...........................5 7  
9.     S T  A TI S TI  C S  ........................................................................................................5 9  
9. 1.     S T  A TI S TI  C  A L M E T  H  O  D S  ......................................................................................5 9  
9. 1. 1.     S u bj e ct   Dis p ositi o n,   D e  m o gr a p hi c  a n d   B a c k gr o u n d   C h ar a ct eristi c s .............5 9  
9. 1. 2.     A n al ysis  of  Effi c a c y   ........................................................................................5 9  
9. 1. 3.     A n al ysis  of  S af et y   ...........................................................................................5 9  
9. 2.     S A  M P L E S I Z E E S TI  M  A TI  O  N  ..................................................................................6 0  
9. 3.     L E  V E L   O F S I  G  NI FI  C  A  N  C E .....................................................................................6 0  
9. 4.     P R  O  C E  D  U  R E  F  O  R A C  C  O  U  N TI  N  G  F  O  R M I S SI  N  G, U N  U S E  D , O  R S P  U  RI  O  U S D A T  A  .....6 0  
9. 5.     P R  O  C E  D  U  R E  F  O  R R E P  O  R TI  N  G D E  VI  A TI  O  N S  F  R  O  M  T  H E S T  A TI S TI  C  A L P L  A  N  ..........6 0  
1 0.     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   .................................6 1  
1 1.     Q  U  A LI T  Y   C  O  N T  R  O L   .......................................................................................6 2  
1 2.     E T  HI  C S ...............................................................................................................6 3  
1 2. 1.     I nstit uti o n al   R e vi e  w   B o ar d ..............................................................................6 3  
1 2. 2.     I nf or  m e d   C o ns e nt   R e q uir e  m e nts .....................................................................6 3  
1 3.     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   ...............................................6 4  
1 3. 1.     D at a   Q u alit y   C o ntr ol  a n d   R e p orti n g   ................................................................6 4  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 6  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 3. 2.     R e c or ds   R et e nti o n   ............................................................................................6 4  
1 4.     P  U  B LI  C  A TI  O  N  P  O LI  C  Y  ..................................................................................6 5  
1 5.     R E F E  R E  N  C E S   ...................................................................................................6 6  
1 6.     A P P E  N  DI  C E S   ....................................................................................................6 7  
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
LI S  T   O F   T  A  B  L  E S   
 
T A  B L E 1:     S U  M  M  A  R  Y   O F E F FI  C  A  C  Y E N  D P  OI  N T S  ..........................................................2 9  
T A  B L E 2:     C O  M P  O SI TI  O  N   O F K PI  -1 2 1  0. 2 5  %  (W /V ) D R  U  G P R  O  D  U  C T  ..........................3 6  
T A  B L E 3:     C O  M P  O SI TI  O  N   O F V E  HI  C L E  .........................................................................3 6  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 8  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
LI S  T   O F  FI  G  U  R  E S   
F I  G  U  R E 1:    S T  U  D  Y S C  H E  M  A TI  C  ....................................................................................3 5  
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 1 9  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
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   O F  T  E  R   M S   
A  R          
A d v ers e   R e a cti o n   
A E          
A d v ers e  E v e nt   
B  C  V  A        
B est   C orr e ct e d   Vis u al   A c uit y   
B L          
B as eli n e   
°C 
D e gr e es   C elsi us   
C  C L  R  U          C or n e a  a n d   C o nt a ct  L e ns   R es e ar c h   U nit   
C  R F        
C as e   R e p ort  F or  m   
C  R  O          
C o ntr a ct   R es e ar c h   Or g a ni z ati o n   
e  C  R F        
El e ctr o ni c   C as e   R e p ort  F or  m  
E E         
Effi c a c y  E v al u a bl e  
E T  D  R S        
E arl y  Tr e at  m e nt  of   Di a b eti c   R eti n o p at h y  St u d y  
°F 
D e gr e es  F a hr e n h eit   
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   
HI P  A  A        
H e alt h I ns ur a n c e  P ort a bilit y  a n d   A c c o u nt a bilit y   A ct   
I  C  H        
I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o ni z ati o n 
I  D        
I d e ntifi c ati o n 
I  O P        
I ntr a o c ul ar  Pr ess ur e 
I  R  B        
I nstit uti o n al   R e vi e  w   B o ar d 
I T T        
I nt e nt-t o-Tr e at  
I  U  D        
I ntr a ut eri n e  d e vi c e 
I   W  R S        
I nt er a cti v e    W e b   R es p o ns e  S yst e  m  
K  C S          
K er at o c o nj u n cti vitis si c c a   
K PI          
K al a  P h ar  m a c e uti c als, I n c.   
L E         
L ot e pr e d n ol  et a b o n at e  
L L L         
L eft  L o  w er  Li d  
L  U L         
L eft   U p p er  Li d  
M  A  R          
Missi n g  at r a n d o  m   
M e d  D  R  A        M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es    
M  G  D          
M ei b o  mi a n   Gl a n d   Dis e as e   
m L           
Millilit er   
m  m          
Milli  m et er   
m  m  H g          
Milli  m et er  of   M er c ur y   
M P P          
M u c us  P e n etr ati n g  P arti cl es    
N  D  A          
N e  w   Dr u g   A p pli c ati o n   
N EI          
N ati o n al  E y e I nstit ut e   
N S  AI  D        
N o nst er oi d al   A nti  -i nfl a  m  m at or y   Dr u g 
P  D F         
P ort a bl e   D o c u  m e nt  F or  m at  
R L L        
Ri g ht  L o  w er  Li d   


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 0  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
R  U L        
Ri g ht   U p p er  Li d   
QI  D        
F o ur  Ti  m es   D ail y  
S  A E         
S eri o us   A d v ers e  E v e nt  
 
 
S  A  R         
S us p e ct e d   A d v ers e   R e a cti o n  
S  O P         
St a n d ar d   O p er ati n g  Pr o c e d ur e  
T F  B  U T        
T e ar  Fil  m  Br e a k  -u p  Ti  m e  
T  N F         
T u  m or   N e cr osis  F a ct or  
U P T           
Uri n e  Pr e g n a n c y  T est   
U S          
U nit e d  St at es  of   A  m eri c a   
W  O  C  B P        
W o  m e n  of   C hil d   B e ari n g  P ot e nti al    
w/ v          
W ei g ht t o   V ol u  m e    


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 1  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1.         
I  N  T  R  O  D  U  C  TI  O  N  
 
M ei b o  mi a n  gl a n d  d ysf u n cti o n    (  M  G  D), t h e   m ost  c o  m  m o n t y p e  of  e v a p or ati v e  dr y  e y e, is  a 
dis or d er i n   w hi c h   m ei b o  mi a n  gl a n ds  eit h er  h y p ers e cr et e  or  ar e  o bstr u ct e d (  D E   W S   R e p ort, 
2 0 0 7).     A c c or di n g t o  G e erli n g 1, M  G  D   is  hi g hl y u n d er  di a g n os e d  a n d  u n d ertr e at e d . T h e r ol e 
of f u n cti o ni n g   m ei b o  mi a n  gl a n ds i n  a c hi e vi n g  a n  o pti  m al  o c ul ar s urf a c e,  a n d t h us  g o o d 
o v er all  visi o n, is  oft e n   mis u n d erst o o d 1.    M a n y  ar e  n ot  a  w ar e  of t h e  q u alit y  of lif e iss u es 
ass o ci at e d   wit h  M  G  D  , i n cl u di n g r e d,  p uff y  e y es  a n d  dis c o  mf ort1.   
 
O v er  7   milli o n  p e o pl e i n t h e   U nit e d  St at es  e x p eri e n c e  dr y  e y e s y  m pt o  ms  of s o  m e s e v erit y, 
s o  m e  of   w hi c h i n cl u d e t h e s u b -t y p e  of M  G  D
2.     Dr y  e y e  dis e as e,  als o  c all e d 
k er at o c o nj u n cti vitis si c c a (  K  C S) , is  c h ar a ct eri z e d  b y s e v er al s y  m pt o  ms  of  o c ul ar  dis c o  mf ort, 
i n cl u di n g  b ut  n ot li  mit e d t o  dr y  e y e s e ns ati o n, f or ei g n  b o d y s e ns atio n, irrit ati o n,  b ur ni n g, 
t e ari n g,  o c ul ar  p ai n,  a n d it c hi n g.    P ati e nts   wit h  dr y  e y e  dis e as e, i n cl u di n g M  G  D  ,   m a y 
e x p eri e n c e si g nifi c a nt  o c ul ar  dis c o  mf ort  a n d r e d u c e d  vis u al f u n cti o n, t h us r es ulti n g i n  a 
d e cr e as e d  q u alit y  of lif e  or   w or k  pr o d u cti vit y 2.  
 
C urr e nt tr e at  m e nt  s f or M  G  D   v ar y   wi d el y,  a n d  c a n i n cl u d e   m ass a g e  a n d li d  e x pr essi o n  as   w ell 
as t etr a c y cli n e  a n d  d o x y c y cli n e , t h o u g h t h es e  ar e  g e n er all y c o nsi d er e d  t o  b e  o nl y   mil dl y 
eff e cti v e 3.    A n ot h er  o pti o n is t o pi c al  c y cl os p ori n e (  R est asis ® ), t h e  o nl y pr es cri pti o n 
m e di c ati o n  c urr e ntl y  a p pr o v e d  b y t h e   F o o d  a n d   Dr u g   A d  mi nistr ati o n  ( F  D  A) f or us e i n 
p ati e nts   wit h  dr y  e y e  dis e as e.     R est asis ®  is i n di c at e d t o i n cr e as e t e ar  pr o d u cti o n i n  p ati e nts 
w h os e t e ar  pr o d u cti o n is  pr es u  m e d t o  b e s u p pr ess e d  d u e t o  o c ul ar i nfl a  m  m ati o n  ass o ci at e d 
wit h   K  C S,  b ut  a si g nifi c a nt  p er c e nt a g e  of  p ati e nts  e x p eri e n c e  a d v ers e r e a cti o ns t o t h e  dr u g, 
i n cl u di n g  o c ul ar irrit ati o n  u p o n i nstill ati o n, sl o  w  o ns et  of r es p o ns e,  a n d li  mit e d  effi c a c y.    
 
I nfl a  m  m ati o n  h as  a  pr o  mi n e nt r ol e i n t h e  d e v el o p  m e nt  a n d  pr olif er ati o n  of  dr y  e y e  dis e as e 4. 
F a ct ors  a d v ers el y  aff e cti n g t e ar fil  m st a bilit y  a n d  os  m ol arit y  c a n i niti at e  a n i nfl a  m  m at or y 
c as c a d e t h at l e a ds t o t h e  d e v el o p  m e nt  of  a s elf -p er p et u ati n g i nfl a  m  m at or y  c y cl e 4. T o pi c al 
c orti c ost er oi ds  ar e  us e d t o tr e at  a n  arr a y  of  o c ul ar  c o n diti o ns t h at  h a v e  a n i nfl a  m  m at or y 
c o  m p o n e nt,  a n d  ar e  g e n er all y i n di c at e d f or tr e at  m e nt  of st er oi d -r es p o nsi v e i nfl a  m  m at or y 
c o n diti o ns  of t h e  c o nj u n cti v a,  c or n e a,  a n d  a nt eri or s e g  m e nt 5. 
 
L ot e pr e d n ol  et a b o n at e ( L E)  is  a n  est er  c orti c ost er oi d t h at is r a pi dl y   m et a b oli z e d t o i n a cti v e 
m et a b olit es,  a n d  h as  b e e n r e p ort e d t o  h a v e f e  w er si d e  eff e cts t h a n tr a diti o n al 
gl u c o c orti c ost er oi ds.    L E   w as  a p pr o v e d  b y  F  D  A i n  1 9 9 8  u n d er   N e  w   Dr u g   A p pli c ati o n 
(  N  D  A)  2 0-5 8 3 ( L ot e  m a x ® ;   B a us c h   &  L o  m b).   L ot e  m a x  h as  g ai n e d   wi d e  a c c e pt a n c e  b y 
o p ht h al  m ol o gists f or  us e i n t h e tr e at  m e nt  of  o c ul ar i nfl a  m  m ati o n.    
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 2  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
K al a  P h ar  m a c e uti c als, I n c.  (  K PI)  h as  d e v el o p e d  a n i  m pr o v e d f or  m ul ati o n  of  L E,  d esi g n at e d 
K PI  -1 2 1,  usi n g  a  pr o pri et ar y t e c h n ol o g y  k n o  w n  as   M u c us  P e n etr ati n g  P arti cl es (  M P P).    M P P 
t e c h n ol o g y  utili z es s u b  mi cr o n  dr u g  p arti cl es f or  m ul at e d t o  e n h a n c e  p e n etr ati o n t hr o u g h t h e 
m u c o us l a y er  of t h e t e ar fil  m.   Pr e cli ni c al st u di es  h a v e s h o  w n i  m pr o v e d  p h ar  m a c o ki n eti cs f or 
K PI  -1 2 1  c o  m p ar e d t o  L ot e  m a x,  wit h  pr ol o n g e d  dr u g  pr es e n c e  o n t h e  o c ul ar s urf a c e  a n d 
i n cr e as e d  dr u g  p e n etr ati o n i nt o  o c ul ar tiss u es.   T his i  m pr o v e d  p h ar  m a c o ki n eti c  pr ofil e  h as t h e 
p ot e nti al t o r e d u c e  d osi n g str e n gt h  of  L E  as  c o  m p ar e d t o  L ot e  m a x.    
 
K al a  P h ar  m a c e uti c als, I n c.   i nt e n ds to  d e v el o p   K PI -1 2 1 f or t h e tr e at  m e nt  of  M  G  D  .    St u d y 
K PI  -1 2 1 -C  -0 0 3  will  e v al u at e t h e s af et y   a n d  effi c a c y  of   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n i n s u bj e cts   wit h  M  G  D  .     A d diti o n al i nf or  m ati o n  a b o ut   K PI-1 2 1, i n cl u di n g 
n o n cli ni c al  p h ar  m a c ol o g y st u d y r es ults,  a n d  p ot e nti al ris ks  a n d  b e n efits t o  h u  m a n s u bj e cts,  is 
f o u n d i n t h e I n v esti g at or’s   Br o c h ur e. 
 
1. 1.         
D E S  C  RI P  TI  O  N   O F IN  V  E S  TI  G  A  TI  O  N  A  L P R  O  D  U  C  T  
 
K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  c o nt ai ns s u b  mi cr o n  p arti cl es  of  L E s us p e n d e d i n  a 
f or  m ul ati o n  c o nsisti n g  of  e x ci pi e nts t h at  h a v e  b e e n  us e d i n  ot h er  F  D  A-a p pr o v e d  o p ht h al  mi c 
pr o d u cts.   K al a   is  d e v el o pi n g t his i  m pr o v e d  L E f or  m ul ati o n f or t h e tr e at  m e nt  of o c ul ar 
i nfl a  m  m at or y  dis e as e i n cl u di n g i nfl a  m  m at or y M  G  D  . 
 
K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  c o nt ai ns  0. 2 5  % (  w/ v)  L E i n  a n  ess e nti all y  is ot o ni c 
f or  m ul ati o n t h at is  b uff er e d t o   m ai nt ai n  p  H  5. 0 –  7. 0.  It is  a st eril e,  a q u e o us s u b  mi cr o n 
s us p e nsi o n  of  L E  a n d  is fill e d i n  a   w hit e, l o  w-d e nsit y  p ol y et h yl e n e  pl asti c  dr o p p er  b ottl e   wit h 
a   w hit e,  c o ntr oll e d -dr o p  p ol y et h yl e n e ti p  a n d  a  p ol y pr o p yl e n e  c a p.  E a c h  b ottl e  c o nt ai ns  5. 5 
m L  n o  mi n al fill  v ol u  m e.   
 
T h e  v e hi cl e  c o ntr ol  h as  t h e s a  m e  c o  m p ositi o n  as   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  
e x c e pt it  d o es  n ot  c o nt ai n  L E.   T h e  v e hi cl e is  ess e nti all y is ot o ni c  a n d is  b uff er e d  t o m ai nt ai n 
p  H  5. 0  –  7. 0.   It is  a st eril e,  a q u e o us s ol uti o n s u p pli e d i n t h e s a  m e   w hit e, l o  w -d e nsit y 
p ol y et h yl e n e  pl asti c  dr o p p er  b ottl e   wit h t h e s a  m e   w hit e , c o ntr oll e d -dr o p  p ol y et h yl e n e ti p  a n d 
w hit e  p ol y pr o p yl e n e  cl os ur e  as   K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n.  
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1. 2.         
J U S  TI FI  C  A  TI  O  N  F  O  R R O  U  T  E   O F A D   M I  NI S  T  R  A  TI  O  N   A  N  D D O S  E S E  L  E  C  TI  O  N  
 
K PI  -1 2 1   will  b e  a d  mi nist er e d  as  a t o pi c al  o p ht h al  mi c s us p e nsi o n.   S u bj e cts  will   s elf-
a d  mi nist er  1 t o  2  dr o ps  of  eit h er   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  or  v e hi cl e  QI  D.   
 
Dir e ct i nstill ati o n is t h e   m ost  effi ci e nt   m et h o d f or  d eli v er y t o t h e  o c ul ar s urf a c e  a n d is  a n 
a c c e pt e d  a n d   wi d el y  us e d   m et h o d f or t o pi c al  a p pli c ati o n t o t h e  e y e.  T his st u d y   will  e x a  mi n e 
s af et y  a n d  effi c a c y  of   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  v ers us  v e hi cl e  d os e d   QI  D f or  2 8 
d a ys i n s u bj e cts   wit h  si g ns  a n d s y  m pt o  ms  of i nfl a  m  m at or y  M  G  D  .  
 
F or  a d diti o n al  d et ails  o n t h e t o xi c ol o g y st u di es  a n d t h e r es p e cti v e s af et y   m ul ti pl es, s e e t h e 
I n v esti g at or’s   Br o c h ur e.  
 
1. 3.         
G  C P  C O   M P  LI  A  N  C  E      
 
T his  cli ni c al tri al   will  b e  c o n d u ct e d i n  c o  m pli a n c e   wit h  t h e  pr ot o c ol, I nt er n ati o n al   C o nf er e n c e 
o n   H ar  m o ni z ati o n (I  C  H)  g ui d eli n es ,   G o o d   Cli ni c al  Pr a cti c es (  G  C P)  g ui d eli n es  a n d  ot h er 
a p pli c a bl e r e g ul at or y r e q uir e  m e nts.  
 
1. 4.         
P O P  U  L  A  TI  O  N   T  O   B  E S T  U  DI  E  D  
 
U p t o   7 5 0  s u bj e cts   wit h   mil d t o   m o d er at e i nfl a  m  m at or y  M  G  D   will  b e s cr e e n e d f or t his st u d y.  
A p pr o xi  m at el y   2 0 0  s u bj e cts   will  b e r a n d o  mi z e d t o  eit h er   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  or v e hi cl e . 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
2.         
T  RI  A  L   O  B J  E  C  TI  V  E S   A  N  D   P  U  R P  O S  E  
2. 1.         
O B J  E  C  TI  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 i n v esti g at e t h e s af et y  a n d  effi c a c y   of   K PI -1 2 1  0. 2 5  % 
o p ht h al  mi c s us p e nsi o n  c o  m p ar e d t o  v e hi cl e  i n s u bj e cts   wit h si g ns  a n d s y  m pt o  ms  of 
i nfl a  m  m at or y M  G  D  .    
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 5  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
3.         
T  RI  A  L   D  E SI  G  N   
3. 1.         
P RI   M  A  R  Y E F FI  C  A  C  Y E N  D P  OI  N  T S  
 
C o  m p aris o n  of   m e a n 
  S e v erit y   Ass ess  m e nt  S c or e  b et  w e e n t h e   K PI-1 2 1 
0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4 ( b as e d  o n t h e   m e a n s c or e f or t h e  3  d a ys  pri or t o   Visit  4  ) 
 
C o  m p aris o n  of   m e a n   p ost eri or li d   m ar gi n  h y p er e  mi a 
 
 
  at   Visit  2 b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
 
 
3. 2.         
S E  C  O  N  D  A  R  Y E F FI  C  A  C  Y E N  D P  OI  N  T S  
 
C o  m p aris o n  of   m e  a n 
  S e v erit y   Ass ess  m e nt  S c or e  b et  w e e n t h e   K PI-1 2 1 
0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  6 
 
 
C o  m p aris o n  of   m e a n   p ost eri or li d   m ar gi n  h y p er e  mi a 
 
 
  at   Visit  2 b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  6   
 
 
 
        
 
        
 
 
3. 3.         
E X P  L  O  R  A  T  O  R  Y E F FI  C  A  C  Y E N  D P  OI  N  T S  
 
C o  m p aris o n  of   m e a n i n v esti g at or  -r at e d  ass ess  m e nt  of  c o nj u n cti v al  h y p er e  mi a  b et  w e e n t h e 
K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n   i n v esti g at or-r at e d  c h ar a ct er  of t h e   m ei b o  mi a n  gl a n ds’  c o nt e nts  b et  w e e n 
t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 6  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n   i n v esti g at or-r at e d  e x pr essi bilit y  of t h e  e v al u at e d   m ei b o  mi a n  gl a n ds 
b et  w e e n t h e  K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n  c or n e al fl u or es c ei n st ai ni n g  b et  w e e n t h e   K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n  T F  B  U T   b et  w e e n t h e   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d 
t h e  v e hi cl e  gr o u p: 
•     Visit  4   
•     Visit  6   
 
C o  m p aris o n  of   m e a n 
  Fr e q u e n c y   Ass ess  m e nt  S c or e  b et  w e e n t h e   K PI-1 2 1 
0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:   
•     Visit   4 
 
•     Visit   6 
 
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2) i n  p ost eri or li d   m ar gi n  h y p er e  mi a     
f or s u bj e cts   wit h  gr eat er t h a n  or  e q u al t o  a  gr a d e  of  1 
i n  at l e ast  o n e  p ost eri or li d   m ar gi n (i. e.,   R  U L,  L  U L,   R L L,  L L L)  at   Visit  2  b et  w e e n t h e   K PI-
1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p : 
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
 
 
 
 
 
 
 
C o  m p aris o n  of   m e  a n  c h a n g e fr o  m  b as eli n e (  Visit  2)  i n v esti g at or-r at e d  ass ess  m e nt  of 
c o nj u n cti v al  h y p er e  mi a  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e 
v e hi cl e  gr o u p:  
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
 
C o  m p aris o n  of   m e a n  c h a n g e   fr o  m  b as eli n e (  Visit  2) i n v esti g at or-r at e d  ass ess  m e nt  of t h e 
c h ar a ct er  of t h e   m ei b o  mi a n  gl a n ds’  c o nt e nts  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   b et  w e e n  i n v esti g at or-r at e d  ass ess  m e nt  of 
t h e  e x pr essi bilit y  of t h e   m ei b o  mi a n  gl a n ds t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p 
a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o  Visit  2   
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   c or n e al fl u or es c ei n st ai ni n g  b et  w e e n  t h e 
K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n  c h a n g e f  r o  m  b as eli n e (  Visit  2) T F  B  U T  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  % 
o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4   as  c o  m p ar e d t o   Visit  2  
•     Visit  6   as  c o  m p ar e d t o   Visit  2  
 
C o  m p aris o n  of   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2)   
  S e v erit y Ass ess  m e nt 
S c or e  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p:  
•     Visit  4 
  
•     Visit  6 
 
 
C o  m p aris o n  of   m e a  n  c h a n g e fr o  m  b as eli n e (  Visit  2)  
  Fr e q u e n c y Ass ess  m e nt 
S c or e  b et  w e e n  t h e   K PI-1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d   wit hi n t h e  v e hi cl e  gr o u p :  
•     Visit  4 
  
•     Visit  6 
  
 
C o  m p aris o n  of t h e   m e a n 
  S e v erit y   Ass ess  m e nt  S c or e  b et  w e e n   K PI-1 2 1 
0. 0 2 5  %  o p ht h al  mi c s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e  gr o u p   
•     Visit  4 
  
•     Visit  6 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 2 8  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
C o  m p aris o n  of t h e   m e a n  c h a n g e fr o  m  b as eli n e (  Visit  2) 
  S e v erit y 
Ass ess  m e nt  S c or e  b et  w e e n   K PI  -1 2 1  0. 0 2 5  %  o p ht h al  mi c  s us p e nsi o n  gr o u p  a n d t h e  v e hi cl e 
gr o u p   
•     Visit  4 
  
•     Visit  6 










K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
3. 4.         
S A F  E  T  Y E N  D P  OI  N  T S  
 
•     I  O P   m e as ur e  m e nts 
•     Slit -l a  m p  bi o  mi cr os c o p y  
•     B  C  V  A   
•     O p ht h al  m os c o p y     
•     A E   m o nit ori n g   
 
3. 5.         
D E S  C  RI P  TI  O  N   O F T RI  A  L D E SI  G  N  
 
T his is  a  P h as e  2 ,   m ulti-c e nt er,  d o u bl e -m as k e d, r a n d o  mi z e d,   v e hi cl e -c o ntr oll e d, 
p ar all el -gr o u p st u d y  d esi g n e d t o  e v al u at e t h e s af et y  a n d  effi c a c y  of   K PI -1 2 1  0. 2 5  % 
o p ht h al  mi c s us p e nsi o n  i n s u bj e cts   wit h i nfl a  m  m at or y M  G  D  .  
 
T his st u d y   will i n cl u d e  u p t o  6  cli ni c  visits, i n cl u di n g  2   w e e ks  of si n gl e -m as k e d  v e hi cl e r u n  -i n 
f oll o  w e d  b y  u p t o 3 0  d a ys  of i n v esti g ati o n al  pr o d u ct  d osi n g (  K PI -1 2 1  0. 2 5  %  o p ht h al  mi c 
s us p e nsi o n  or  v e hi cl e).    
 
U p t o   7 5 0  s u bj e cts  at  u p t o  1 2  c e nt ers l o c at e d i n t h e   U nit e d  St at es (  U S)   will  b e s cr e e n e d  at 
Visit  1 ( S cr e e ni n g).   S u bj e ct   m e eti n g  eli gi bilit y  crit eri a   will  e nt er  a  1 4  -d a y r u n -i n  p eri o d  of 
QI  D  d osi n g   (1 -2  dr o ps  p er  e y e  of si n gl e -m as k e d  v e hi cl e  ).    A p pr o xi  m at el y  2 0 0 s u bj e cts   will 
b e r a n d o  mi z e d t o   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  or  v e hi cl e . 
 
At   Visit  2,   su bj e cts  w h o  c o nti n u e t o   m e et i n cl usi o n/ e x cl usi o n  crit eri a (  wit h t h e  e x c e pti o n  of 
I n cl usi o n   Crit eri a  # 4  a n d  # 7) will  b e r a n d o  mi z e d i n  a n  a p pr o xi  m at e  1: 1 r ati o t o  eit h er  1)   K PI  -
1 2 1  0. 2 5  %  o p ht h al  mi c  s us p e nsi o n  a d  mi nist er e d  as  1 -2  dr o ps i n  e a c h  e y e   QI  D f or  u p t o  4 
w e  e ks  or  2)  v e hi cl e  a d  mi nist er e d  as  1 -2  dr o ps i n  e a c h  e y e   QI  D f or  u p t o  4   w e e ks.      
 
T h e st u d y  e y e   will  b e s el e ct e d  b as e d  o n t h e  q u alifi c ati o n  crit eri a  e nt er e d i nt o t h e I nt er a cti v e 
W e b   R es p o ns e  S yst e  m (I   W  R S) f or str atifi c ati o n  at r a n d o  mi z ati o n   .   T h es e s c or es  ar e  b as e d  o n 
fi n di n gs  at   Visit  1  o nl y. If  b ot h  e y es  q u alif y f or t h e st u d y, t h e st u d y  e y e will  b e  d esi g n at e d   as 
O  D.    R a n d o  mi z ati o n  n u  m b ers   will  b e  assi g n e d t o s u bj e ct  s as t h e y  ar e  e nt er e d i nt o t h e I   W  R S, 
b as e d  o n t h e f oll o  wi n g  2 str atifi c ati o n  crit eri a:   
 
•     S u bj e ct’s  Visit  1 (  D a y   -1 4)  
 s c or e 
 
   A  N  D 
•     Visit  1 (  D a y   -1 4)  i n v esti g at or-r at e d  p ost eri or li d   m ar gi n  h y p er e  mi a s c or e        
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
T h e I   W  R S   will  assi g n   m as k e d st u d y  kit  n u  m b ers ,  a n d  bottl es  of i n v esti g ati o n al  pr o d u ct   will 
b e  dis p e ns e d  at  d esi g n at e d  visits.  T h e  S p o ns or, I n v esti g at ors,  a n d st u d y st aff   will  b e   m as k e d 
d uri n g t h e r a n d o  mi z ati o n  pr o c ess  a n d t hr o u g h o ut  t h e r e  m ai n d er  of t h e st u d y.   
 
S u bj e cts   will r et ur n t o t h e  cli ni c f or  c o  m pl et e st u d y  e v al u ati o n s at   V isits  4  a n d  6 (  D a y  1 5  ±  1 
d a y  a n d   D a y  2 9  ±  1  d a y, r es p e cti v el y).   S u bj e ct s will  als o r et ur n  at   Visits  3  a n d  5 (  D a y  8  ±  1 
d a y  a n d   D a y  2 2  ±  1  d a y, r es p e cti v el y) 
,  e v al u at e 
o c ul ar  dis c o  mf ort , a n d  ass ess  c o n c o  mit a nt  m e di c ati o n  us e  a n d   A E  s.   S u bj e cts   will  dis c o nti n u e 
d osi n g  a n d  b e r el e as e d fr o  m t h e st u d y  at   Visit  6 (  D a y  2 9  ±  1  d a y).  
 
 
 
A s u  m  m ar y  of  e v e nts is  pr o vi d e d i n   A p p e n di x  1  .    Ass ess  m e nts i n t his st u d y   will i n cl u d e: 
•     I n-cli ni c s u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  dis c o  mf ort (A p p e n di x  2  ) 
•  
 s e v erit y  a n d fr e q u e n c y  ass ess  m e nts (A p p e n di x  3  ) 
•     I n v esti g at or-rat e d  a ss ess  m e nt  of p ost eri or  li d m  ar gi n  h y p er e  mi a  (A p p e n di x  4  ) 
•     I n v esti g at or-r at e d  ass ess  m e nt  of t h e c h ar a ct er  of  t h e c o nt e nt  of   m ei b o  mi a n  gl a n ds  
(A p p e n di x  4  ) 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  e x pr essi bilit y  of   m ei b o  mi a n  gl a n ds (A p p e n di x  4  ) 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  c o nj u n cti v al  h y p er e  mi a (A p p e n di x  5  ) 
•     U n a n est h eti z e d  S c hir  m er  T est (  A p p e n di x  6  ) 
•     B  C  V  A   (A p p e n di x  7  ) 
•     Slit  la  m p  b i o  mi cr os c o p y (A p p e n di x  8  ) 
•     C or n e al fl u or es c ei n st ai ni n g (  A p p e n di x  9  ) 
•     I  O P m  e as ur e  m e nt  (A p p e n di x  1 0  ) 
•     Dil at e d  o p ht h al  m os c o p y (  A p p e n di x  1 1  ) 
•  
 
•  
 
•     T F  B  U T  (A p p e n di x  1 4  ) 
 
 
 
 






K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
b e r et ur n e d t o t h e sit e  at   Visit  6 (  D a y  2 9  ±  1  d a y ).   T he  b o x l a b els  a n d t h e  dr o p p er  b ottl e 
l a b els   will  c o nt ai n t h e f oll o  wi n g i nf or  m ati o n: s p o ns or  n a  m e,  pr ot o c ol  n u  m b er, r a n d o  mi z ati o n 
n u  m b er, st or a g e t e  m p er at ur e,  a n d r e q uir e d st at e  m e nt(s)  p er t h e  a p pr o pri at e r e g ul at or y  a g e n c y.  
 
All i n v esti g ati o n al   pr o d u cts  will   b e st or e d i n  a s e c ur e  ar e a   wit h li  mit e d  a c c ess  at  c o ntr oll e d 
r o o  m t e  m p er at ur e ( 1 5-2 5 °C/ 5 9   -7 7 °F).    At   Visits  1  a n d  2,   w h e n s u bj e cts r e c ei v e t h e first  d os e 
i n t h e  cli ni c, t h at  d os e   will  c o u nt  as  1  of t h eir 4  d ail y  d os es.  S u bj e cts   will t h e n s elf -a d  mi nist er 
3  a d diti o n al  d os es  of i n v esti g ati o n al  pr o d u ct  d uri n g t h e r e  m ai n d er  of t h at  d a y t o  c o  m pl et e 
QI  D  d osi n g.    All  visits s h o ul d  b e s c h e d ul e d i n t h e   m or ni n g t o  all o  w s u bj e cts t o r e c ei v e  a f ull 
d a y  of  QI  D  d osi n g.   
 
S u bj e cts   will  b e  as k e d t o i nstill  1  d os e  u p o n  a  w a k e ni n g  a n d t h e n  3 s u bs e q u e nt  d os es 
a p pr o xi  m at el y  4  h o urs  aft er t h eir  pr e vi o us  d os e.   T h e  4  d os es   will  b e  d es cri b e d  as  “  M or ni n g 
D os e, ”  “  Mi d  -M or ni n g   D os e, ”  “  Aft er n o o n   D os e, ”  a n d  “ E v e ni n g   D os e. ”     
 
3. 5. 2.         M et h o ds t o    Mi ni  mi z e   Bi as    
 
T o   mi ni  mi z e  bi as, t h e f oll o  wi n g   m e as u r es   will  b e t a k e n: 
•     I n v esti g ati o n al  pr o d u ct all o c ati o n ( K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  v ers us 
v e hi cl e ) will  b e r a n d o  mi z e d  a n d   m as k e d t o t h e s p o ns or  , s u bj e cts, a n d  s el e ct 
i n v esti g ati v e st aff.   
•     T h e r a n d o  mi z ati o n s c h e d ul e   will  b e  g e n er at e d  b y  t h e r a n d o  mi z ati o n st atisti ci a n (  w h o 
is  n ot  o n t h e  pr oj e ct t e a  m)  or  d esi g n e e  a n d   m ai nt ai n e d i n  a s e c ur e  a n d li  mit e d-a c c ess 
l o c ati o n s e p ar at e fr o  m t h e st u d y I n v esti g at or a n d   m e  m b ers  of t h e  pr oj e ct t e a  m.    


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3 8  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
4.         
S  E  L  E  C  TI  O  N   O F  S  U  B J  E  C  T S  
4. 1.         
S U  B J  E  C  T IN  C  L  U SI  O  N C RI  T  E  RI  A  
 
At   Visit  1  a n d   Visit  2, i n di vi d u als  of  eit h er  g e n d er  or  a n y r a c e   will  b e  eli gi bl e f or st u d y 
p arti ci p ati o n if t h e y:  
1.    Pr o vi d e   writt e n i nf or  m e d  c o ns e nt  a n d  HI P  A  A   a ut h ori z ati o n  pri or t o  a n y st u d y -r el at e d 
pr o c e d ur es.  
2.    Ar e  1 8  y e ars  of  a g e  or  ol d er.     
3.    Ar e   willi n g  a n d   a bl e t o f oll o  w i nstr u cti o ns  a n d  c a n  b e  pr es e nt f or t h e r e q uir e d st u d y 
visits f or t h e  d ur ati o n  of t h e st u d y.  I n  a d diti o n, t h e y   m ust  d e  m o nstr at e:  
a.    Si n gl e -m as k e d i n v esti g ati o n al  pr o d u ct  us e  c o  m pli a n c e  of  at l e ast  8 0  %  d uri n g 
t h e fi n al   w e e k  of t h e r u n-i n  p h as e A  N  D    
b.    Di ar y  c o  m pl eti o n  c o  m pli a n c e  of  at l e ast  8 0  % i n t h e fi n al   w e e k  of t h e r u n  -i n 
p h as e.  
4.    U p o n  e x a  mi n ati o n  at   Visit  1   O  N  L  Y  ,  h a v e A  L  L   5  of t h e f oll o  wi n g  crit eri a i n t h e  s a  m e 
or  b ot h  e y es:    
a.  
 
 
 
 
 
 
 S e v e rit y  Ass ess  m e nt  . 
e.    A n   u n a n est h eti z e d  S c hi r  m e r  s c or e 
 
5.    Ar e   w o  m e n  of  c hil d  b e ari n g  p ot e nti al (   W  O  C  B P)  ,   w h o  ar e  n ot pr e g n a nt  or l a ct ati n g 
a n d  n ot s e x u all y  a cti v e (i. e.,  a bsti n e nt) f or  1 4  d a ys  pri or t o   Visit  1  a n d  ar e  willi n g t o 
r e  m ai n s o t hr o u g h  3 0  d a ys f oll o  wi n g   Visit  6  or t h e l ast  a d  mi nistr ati o n  of t h e 
i n v esti g ati o n al  pr o d u ct  or  u ntil  c o  m pl eti o n  of t h e s u bj e ct’s first m e nstr u al  c y cl e 
f oll o  wi n g t h e l ast  a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct,   w hi c h e v er  p eri o d  of 
ti  m e is l o n g er.    Alt er n ati v el y,    W  O  C  B P   w h o  ar e  n ot  a bsti n e nt   m ust  h a v e  b e e n  usi n g 
o n e  of t h e f oll o  wi n g  a c c e pt a bl e   m et h o ds  of  birt h  c o ntr ol f or t h e ti  m es s p e cifi e d:   
a.    I  U  D i n  pl a c e f or  at l e ast  3   m o nt hs  pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast 
a d  mi nistr ati o n  of i n v esti g ati o n al  pr o d u ct  or  u ntil  c o  m pl eti o n  of t h e s u bj e ct’s 
first   m e nstr u al  c y cl e f oll o  wi n g l ast  a d  mi nistr ati o n  of t h e i n v esti g ati o n al 
pr o d u ct,   w hi c h e v er  p eri o d  of ti  m e is l o n g er.  
b.    B arri er   m et h o d ( c o n d o  m  or  di a p hr a g  m)   wit h s p er  mi ci d e f or  at l e ast  3   m o nt hs 
pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast  a d  mi nistr ati o n  of t h e i n v esti g ati o n al 
pr o d u ct  or  u ntil  c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al  c y cl e f oll o wi n g l ast 
a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct,   w hi c h e v er  p eri o d  of ti  m e is 
l o n g er. 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 3 9  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
c.    St a bl e  h or  m o n al  c o ntr a c e pti v e f or  at l e ast   
3   m o nt hs  pri or t o   Visit  1 t hr o u g h   Visit  6  or l ast  a d  mi nistr ati o n  of t h e 
i n v esti g ati o n al  pr o d u ct  or  u ntil  c o  m pl eti o n  of t h e s u bj e ct’s first   m e nstr u al 
c y cl e f oll o  wi n g  a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct,   w hi c h e v er  p eri o d 
of ti  m e is l o n g er.   
N  O  T  E:   F or   D e p o -Pr o v er a i nj e cti o n  c o ntr a c e pti v es, t h e st at e  m e nt r e g ar di n g 
first   m e nstr u al  c y cl e f oll o  wi n g  a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct is 
n ot  a p pli c a bl e,  as f e  m al es r e c ei vi n g t his f or  m  of  c o ntr a c e pti o n   will  n ot  h a v e 
m e ns es.   
d.    I n  a   m o n o g a  m o us r el ati o ns hi p   wit h  a s ur gi c all y st erili z e d (i. e.,  v as e ct o  mi z e d) 
p art n er f or  at l e ast  6   m o nt hs  pri or t o   Visit  1  t hr o u g h   Visit  6 or l ast 
a d  mi nistr ati o n  of t h e i n v esti g ati o n al  pr o d u ct  or  u ntil  c o  m pl eti o n  of t h e 
s u bj e ct’s first   m e nstr u al  c y cl e f oll o  wi n g  a d  mi nistr ati o n  of t h e i n v esti g ati o n al 
pr o d u ct,   w hi c h e v er  p eri o d  of ti  m e is l o n g er .  
6.    Ar e  p ost  m e n o p a us al   w o  m e n  , w h o   h a v e  h a d  n o   m e nstr u al  c y cl e f or  at l e a st  1  y e ar  pri or 
t o   Visit  1  or h a v e  u n d er g o n e  o n e  of t h e f oll o  wi n g st erili z ati o n  pr o c e d ur es  at l e ast  6 
m o nt hs  pri or t o   Visit  1:   
a.    Bil at er al t u b al li g ati o n   
b.    H yst er e ct o  m y   
c.    H yst er e ct o  m y   wit h  u nil at er al  or  bil at er al  o o p h or e ct o  m y.   
d.    Bil at er al  o o p h or  e ct o  m y  
 
4. 2.         
S U  B J  E  C  T E X  C  L  U SI  O  N C RI  T  E  RI  A  
 
I n  or d er f or s u bj e cts t o  b e  eli gi bl e  at   Visit  1  a n d   Visit  2 t h e y   m a y  n ot: 
 
1.    H a v e  k n o  w n  h y p ers e nsiti vit y  or  c o ntr ai n di c ati o n t o t h e   i n v esti g ati o n al  pr o d u ct(s)  or 
t h eir  c o  m p o n e nts. 
2.    H a v e  us e d  a n y  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  3 0  d a ys  pri or t o  S cr e e ni n g (  Visit 
1)  a n d f or t h e  d ur ati o n  of t h e st u d y : 
a.    O c ul ar, i n h al e d,  or i ntr a n as al  c orti c ost er oi ds   
b.    O c ul ar  or  or al   N S  AI  Ds   wit h t h e  e x c e pti o n  of l o  w  d os e  as piri n (  ≤  8 1   m g  p er 
d a y ) 
c.    T o pi c al  o c ul ar  a nti bi oti cs  
d.    T o pi c al  o c ul ar  a nti hist a  mi n es  or   m ast  c ell st a bili z ers  
e.    Or al  a nti hist a  mi n es   
f.    T o pi c al  or  n as al  v as o c o nstri ct ors  
3.    H a v e  us e d  a n y  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  6 0  d a ys  pri or t o  S cr e e ni n g (  Visit 
1)  a n d f or t h e  d ur ati o n  of t h e st u d y : 
a.    T o pi c al  c y cl os p ori n e (  R est asis ® ) 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 0  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
b.    A n y f or  m  of t o p  i c al L E  
4.    H a v e  alt er e d  or al  d osi n g  of   t h e f oll o  wi n g wit hi n  3 0  d a ys  pri or t o  S cr e e ni n g (  Visit  1)  or 
a nti ci p at e  alt er ati o n  of  d osi n g  d uri n g t h e st u d y : 
a.    T etr a c y cli n e  c o  m p o u n ds ( e. g., t etr a c y cli n e,  d o x y c y cli n e,  or   mi n o c y cli n e)   
b.    O  m e g a  -3  or   O  m e g a -6 s u p pl e  m e nts  
5.    H a v e  alt er e d  d osi n g  of t h e f oll o  wi n g   m e di c ati o ns   wit hi n  6   m o nt hs  pri or t o  S cr e e ni n g 
(  Visit  1)  or  a nti ci p at e  alt er ati o n  of  d osi n g  d uri n g t h e st u d y: 
a.    A nti c h oli n er gi cs   
b.    A nti d e pr ess a nts   
c.    Is otr eti n oi n 
d.    Or al  c orti c ost er oi ds   
e.    S yst e  mi c i  m  m u n os u p pr essi v e  a g e nts  
6.    B e  u n  wi  lli n g t o  a bst ai n fr o  m t h e  us e  of  a n y t o pi c al  o p ht h al  mi c   m e di c ati o ns  at   Visit  1 
( S cr e e ni n g)  a n d f or t h e  d ur ati o n  of t h e st u d y, i n cl u di n g: 
a.    E y el as h  gr o  wt h   m e di c ati o ns  
b.    E y e  dr o ps,  g els,  or  artifi ci al t e ars   
7.    B e  u n  willi n g t o  a bst ai n fr o  m t h e  us e   of  T  N F -bl o c ki n g  a g e nts ( e. g.  et a n er c e pt, 
a d ali  m u  m a b, i nfli xi  m a b)  at   Visit  1 ( S cr e e ni n g)  a n d f or t h e  d ur ati o n  of t h e st u d y.  
8.    B e  c urr e ntl y r e c ei vi n g tr e at  m e nt f or  gl a u c o  m a,  h a v e  hist or y  of  or  c urr e nt  gl a u c o  m a,  or 
a n I  O P  o v er  2 1  m  m  H g  at   Visit  1 ( S cr e e ni n g)  or   Visit  2 (  R a n d o  mi z a ti o n). 
9.    I niti at e  or  alt er t h e  us e (if  usi n g  u p o n  e ntr y)  of  or al  c o ntr a c e pti v es, or  f e  m al e  h or  m o n e 
r e pl a c e  m e nt t h er a p y/s u p pl e  m e nt ati o n   wit hi n  4 8  h o urs  pri or t o   Visit  1  a n d f or t h e 
d ur ati o n  of t h e st u d y.  
1 0.  B e  u n  willi n g t o  a bst ai n fr o  m   w e ari n g  c o nt a ct l e ns es f or   1 4  d a ys  pri or t o   Visit  1  a n d 
t hr o u g h o ut t h e st u d y. 
1 1.  B e   m o n o c ul ar  or  h a v e  a   B  C  V  A,  usi n g  c orr e cti v e l e ns es if  n e c ess ar y,  of  + 1. 0 l o g  M  A  R 
or   w ors e  as  ass ess e d  b y  E T  D  R S . 
1 2.  B e   u n  willi n g t o  dis c o nti n u e   w ar  m  c o  m pr ess t h er a p y, li d  e x pr essi o n,  or li d   m ass a g e  1 4 
d a ys  pri or t o   D a y  1  a n d f or t h e  d ur ati o n  of t h e st u d y.   
1 3.  H a v e  a  di a g n osis  of:   
a.    O n g oi n g  o c ul ar i nf e cti o n   
b.    M o d er at e t o s e v er e  pi n g u e c ul a  or  pt er y gi a    
c.    St e v e ns -J o h ns o n  S y n dr o  m e  
d.    Si g ni fi c a nt  c o nj u n cti v al s c arri n g 
e.    Si g nifi c a nt  a nt eri or  bl e p h aritis  
f.    R os a c e a   wit h  c or n e al i n v ol v e  m e nt.   
g.    S e v er e/s eri o us  o c ul ar  c o n diti o n t h at i n t h e j u d g  m e nt  of t h e i n v esti g at or  c o ul d 
c o nf o u n d st u d y  ass ess  m e nts  or li  mit  c o  m pli a n c e.  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 1  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
h.    S e v er e/s eri o us s yst e  mi c  dis e as e  o r  u n c o ntr oll e d   m e di c al  c o n diti o n t h at i n t h e 
j u d g  m e nt  of t h e i n v esti g at or  c o ul d  c o nf o u n d st u d y  ass ess  m e nts  or li  mit 
c o  m pli a n c e.  
1 4.  H a v e  c o n c urr e nt  a c ut e  h or d e ol u  m (st y e)  or  c h al a zi o n.   
1 5.  H a v e si g nifi c a nt  a nt eri or  bl e p h aritis, si g nifi c a nt  d a n dr uff,  or   D e  m o d e x f ol  li c ul ar u  m 
i nf est ati o n. 
1 6.  H a v e  o bstr u cti o n  of   m ei b o  mi a n  gl a n ds t h at  pr es e nt   wit h  n o  e x pr essi bilit y.   
1 7.  H a v e  c o n c urr e nt si g ns  of   m o d er at e t o s e v er e  c hr o ni c  e y eli d   m ar gi n i nfl a  m  m ati o n 
(  m o d er at e t o s e v er e  e y eli d   m ar gi n t el a n gi e ct asi a  a n d  e y eli d   m ar gi n s c arri n g)  or li d 
str u ct ur al  a b n or  m aliti es s u c h  as  e ntr o pi o n,  e ctr o pi o n, tri c hi asis,  or l as h l oss.  
1 8.  H a v e  h a d  o c ul ar s ur g er y i n t h e  p ast  9 0  d a ys  or r e q uir e  o c ul ar s ur g er y  d uri n g t h e st u d y.   
1 9.  H a v e  a cti v e  or  h a v e  h a d  a n  o ut br e a k  of  h er p eti c  k er atitis   wit hi n  1  y e ar  of   Visit  1.   
2 0.  H a v e  us e d  e y e   m a k e  -u p ( e. g.,  e y eli n er,   m as c ar a,  e y e s h a d o  w,  e y eli d  glitt er,  e y eli d 
c o n c e al er  or  b as e),  e y el as h  c url ers,  e y eli d  gl u e,  or f als e  e y el as h es  at   Visit  1  or  ar e 
u n  willi n g t o  dis c o nti n u e t h e  us e  of t h es e  pr o d u cts  o n t h e  d a ys  of st u d y  visits.  
2 1.  H a v e   p er  m a n e nt  e y eli n er.  
2 2.  H a v e  a  d o c u  m e nt e d  hist or y  of  o c ul ar  all er gi es,   w hi c h, i n t h e j u d g  m e nt  of t h e 
i n v esti g at or,  ar e li k el y t o  h a v e  a n  a c ut e i n cr e as e i n s e v erit y  d u e t o t h e  e x p e ct e d ti  mi n g 
of  e x p os ur e t o t h e  all er g e n t o   w hi c h t h e s u bj e ct is s e nsiti v e.   S u bj e cts s e nsiti v e t o 
s e as o n al  all er g e ns t h at  ar e  n ot  e x p e ct e d t o  b e  pr es e nt  d uri n g t h e st u d y  ar e  p er  mitt e d.  
2 3.  B e   a n  e  m pl o y e e  of t h e sit e t h at is  dir e ctl y i n v ol v e d i n t h e   m a n a g e  m e nt,  a d  mi nistr ati o n, 
or s u p p ort  of t his st u d y  or  b e  a n i  m  m e di at e f a  mil y   m e  m b er  of t h e  s a  m e. 
2 4.  I n t h e  o pi ni o n  of t h e I n v esti g at or  or st u d y  c o or di n at or,  b e  u n  willi n g  or  u n a bl e t o 
c o  m pl y   wit h t h e st u d y  pr ot o c ol  or  u n a bl e t o s u c c essf ull y i nstill  e y e  dr o ps . 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 2  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
5.         
P  R  O  C  E  D  U  R  E S  
 
Writt e n I nf or  m e d   C o ns e nt    a n d   HI P  A  A  a ut h ori z ati o n  will   b e  o bt ai n e d fr o  m  all s u bj e cts  pri or 
t o  a n y st u d y  pr o c e d ur es  b ei n g  p erf or  m e d. 
 
5. 1.         
V I SI  T D E S  C  RI P  TI  O  N  S  
5. 1. 1.         Visit  1:   1 4  ±  1   D a ys  P ri o r t o   D a y  1   –  S c r e e ni n g  
 
Aft er   sit e st aff  o bt ai ns writt e n i nf or  m e d  c o ns e nt  a n d   HI P  A  A  a ut h ori z ati o n  ,  ea c h s u bj e ct   will 
b e  assi g n e d  a  S u bj e ct I d e ntifi c ati o n (I  D)  c o nsisti n g  of  a  3 -di git I n v esti g at or  n u  m b er  pl us  a  3 -
di git  S u bj e ct  n u  m b er.   T h e  S u bj e ct I  D   will  b e  us e d  as t h e  pri  m ar y s u bj e ct i d e ntifi er f or t h e 
d ur ati o n  of t h e st u d y.   T h e f oll o  wi n g   will  b e  p erf or  m e d/ ass ess e d i n  or d er t o  d et er  mi n e i niti al 
eli gi bilit y f or st u d y  p arti ci p ati o n:   
 
•     N o n  -o c ul ar  a n d  o c ul ar   m e di c al  hist or y  
•     C o n c o  mit a nt   m e di c ati o n  us a g e  a n d   m e di c ati o ns t a k e n  d uri n g t h e   6   m o nt hs  pri or t o 
s cr e e ni n g  
•     Uri n e  pr e g n a n c y t est (  U P T) f or    W  O  C  B P   
•     S u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  dis c omf ort    
•  
 
•     I n v esti g at or-r at e d  ass ess  m e nt  of si g ns 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  b ul b ar  c o nj u n cti v al  h y p er e  mi a 
•  
 
•     T F  B  U T  
•     C or n e al fl u or es c ei n st ai ni n g   
•     U n a n est h eti z e d  S c hir  m er  T est  e v al u ati o n   
•     B  C  V  A   
•     Slit -l a  m p  bi o  mi cr os c o p y 
•     I  O P   m e as ur e  m e nt 
•     Dil at e d  o p ht h al  m os c o p y   
•     R e vi e  w  of i n cl usi o n  a n d  e x cl usi o n  crit eri a t o  d et er  mi n e s cr e e ni n g  eli gi bilit y   
•     D osi n g  of r u n  -i n i n v esti g ati o n al  pr o d u ct i n  cli ni c 
•     Dis p e nsi n g  of i n v esti g ati o n al  pr o d u ct   
•  
 
 
T h e  first  d os e  of si n gl e-m as k e d i n v esti g ati o n al  pr o d u ct   will  b e t a k e n i n t h e  cli ni c   u n d er t h e 
s u p er visi o n  of st u d y  p ers o n n el.   Pri or t o  a d  mi nistr ati o n, s u bj e cts   will  b e i nstr u ct e d r e g ar di n g 
pr o p er i nstill ati o n  of i n v esti g ati o n al  pr o d u ct .  Si n c e s u bj e cts   will r e c ei v e  1  d os e  of 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
i n v esti g ati o n al  pr o d u ct i n t h e  cli ni c, t h e y   will s elf-a d  mi nist er  at   m ost  3  a d diti o n al  d os es  o n t h e 
first  d a y.   
 
I nst r u cti o ns t o s u bj e ct:  
 
•     D os e r u n  -i n i n v esti g ati o n al  pr o d u ct  as i nstr u ct e d. 
•  
 
•  
 
•     R et ur n f or   Visit  2 s c  h e d ul e d i n  1 4  ±  1  d a y s. 
 
5. 1. 2.         Visit   2 :  D a y  1   (  R a n d o  mi z ati o n) 
 
T h e r a n d o  mi z ati o n  visit   will  o c c ur  1 4  ±  1  d a y  aft er   Visit  1 ( S cr e e ni n g).  S u bj e cts s h o ul d  d os e 
r u n-i n i n v esti g ati o n al  pr o d u ct i n  b ot h  e y es   QI  D  u ntil t h e   Visit  2:   D a y  1 (  R a n d o  mi z ati o n).  
 
T h e f oll o  wi n g   will  b e  p erf or  m e d/ ass ess e d  at   Visit  2 :  
 
•     Us e  of  a n y  c o n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit   
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•     S u bj e ct -r at e d o c ul ar  dis c o  mf ort  ass ess  m e nt  
•     I n v esti g at or-r at e d  ass ess  m e nt  of si g ns 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  b ul b ar  c o nj u n cti v al  h y p er e  mi a 
•  
 
•     T F  B  U T  
•     C or n e al fl u or es c ei n st ai ni n g   
•     B  C  V  A   
•     Slit -l a  m p  bi o  mi cr os c o p y 
•     I  O P   m e as ur e  m e nt 
•  
 
•     U n us e d r u n  -i n i n v esti g ati o n al  pr o d u ct  c oll e ct e d,  c o u nt e d,  a n d  c o  m pli a n c e  ass ess e d 
  
•     U p o n  v erifi c ati o n  of   s u bj e ct eli gi bilit y  (S e cti o n  4  wit h t h e  e x c e pti o n  of I n cl usi o n 
Crit eri a  # 4  a n d  # 7)  , r a n d o  mi z ati o n  of  a p pr o pri at e s u bj e cts t o r e c ei v e   QI  D  d osi n g 
of  eit h er   K PI -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  or  v e hi cl e.    
•     D osi n g  of r a n d o  mi z e d i n v esti g ati o n al  pr o d u ct   i n  cli ni c 
•     Dis p e nsi n g  of   r a n d o  mi z e d i nv esti g ati o n al  pr o d u ct  
•  
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
T h e first  d os e  of  d o u bl e -m as k e d i n v esti g ati o n al  pr o d u ct   will  b e   t a k e n i n t h e  cli ni c  u n d er t h e 
s u p er visi o n  of  a  d esi g n at e d  d osi n g  c o or di n at or.   T his  d osi n g  c o or di n at or,   w h o is  n ot 
r es p o nsi bl e f or st u d y  ass ess  m e nts,   will  als o  b e r e q uir e d t o  dis p e ns e  a n d r etri e v e 
i n v esti g ati o n al  pr o d u ct t o/fr o  m t h e s u bj e cts.  Pri or t o d osi n g , s u bj e cts   will  b e i nstr u ct e d 
r e g ar di n g  pr o p er   m et h o d f or i nstill ati o n  of t h eir  assi g n e d i n v esti g ati o n al  pr o d u ct i n cl u di n g  b ut 
n ot li  mit e d t o s h a ki n g  t h e b ottl e  pri or t o  e a c h i nstill ati o n.   Si n c e s u bj e cts   will r e c ei v e  1  d os e 
of i n v esti g ati o n al  pr o d u ct i n t h e  cli ni c, t h e y   will s elf -a d  mi nist er  at   m ost  3  a d diti o n al  d os es  of 
i n v esti g ati o n al  pr o d u ct  o n t h e first  d a y. 
 
I nst r u cti o ns t o s u bj e ct:  
 
•     D os e i n v esti g ati o n al  pr o d u ct  as i nstr u ct e d   
•  
 
•  
 
•     R et ur n f or   Visit  3  o n   D a y  8  ±  1  d a y.   
 
5. 1. 3.         Visit   3 : D a y  8   ±  1  d a y  –  Di a r y   C oll e cti o n   
 
T his  visit   will  o c c ur  o n  D a y  8  ±  1  d a y   as  c al c ul at e d fr o  m   Visit  2:   D a y  1,  a n d t h e f oll o  wi n g 
e v al u ati o ns   will  b e  p erf or  m e d:   
 
•     Us e  of  a n y  c o n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit   
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•     S u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  dis c o  mf ort 
•  
 
•     Us e d  a n d  u n us e d  d o u bl e  -m as  k e d i n v esti g ati o n al  pr o d u ct  c o u nt e d  a n d  c o  m pli a n c e 
ass ess e d 
 
•  
 
 
I nst r u cti o ns t o s u bj e ct:  
 
•     D os e i n v esti g ati o n al  pr o d u ct  as i nstr u ct e d.   
•  
 
•  
 
•     R et ur n f  or   Visit  4  o n   D a y  1 5  ±  1  d a y . 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 5  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
5. 1. 4.         Visit   4 : D a y  1 5   ±  1  d a y  –  St u d y   Visit  
 
T his  visit   will  o c c ur  o n   D a y  1 5  ±  1  d a y  as  c al c ul at e d fr o  m   Visit  2:   D a y  1,  a n d t h e f oll o  wi n g 
e v al u ati o ns   will  b e  p erf or  m e d/ ass ess e d:   
 
•     Us e  of  a n y  c o n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit   
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•  
 
•     Us e d  a n d  u n us e d  d o  u bl e -m as k e d i n v esti g ati o n al  pr o d u ct  c oll e ct e d,  c o u nt e d,  a n d 
c o  m pli a n c e  ass ess e d 
  
•     S u bj e ct -r at e d  o c ul ar  dis c o  mf ort  ass ess  m e nt 
•     I n v esti g at or-r at e d  ass ess  m e nt  of si g ns 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  b ul b ar  c o nj u n cti v al  h y p er e  mi a 
•  
 
•     T F  B  U T  
•     C or n e al fl u or es c ei n st ai ni n g   
•     B  C  V  A   
•     Slit -l a  m p  bi o  mi cr os c o p y 
•     I  O P   m e as ur e  m e nt 
•     R e  -s u p pl y  of  d o u bl e-m as k e d i n v esti g ati o n al  pr o d u ct t o l ast  u ntil   Visit  6.     
•  
 
 
I nst r u cti o ns t o s u bj e ct:  
 
•     D os e   i n v esti g ati o n al  pr o d u ct  as i nstr u ct e d. 
•  
 
•  
 
•     R et ur n f  or   Visit  5  o n   D a y  2 2  ±  1  d a y . 
 
5. 1. 5.         Visit   5 : D a y  2 2   ±  1  d a y  –  Di a r y   C oll e cti o n   
 
T his  visit   will  o c c ur  o n   D a y  2 2  ±  1  d a y  as  c al c ul at e d fr o  m   Visit  2:   D a y  1,  a n d t h e f oll o  wi n g 
e v al u ati o ns   will  b e  p erf or  m e d:   
 
•     Us e  of  a n y  c o n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit   
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•     S u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  dis c o  mf ort 
•  
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 6  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     Us e d  a n d  u n us e d  d o u bl e  -m as k e d i n v esti g ati o n al  pr o d u ct  c o u nt e d  a n d  c o  m pli a n c e 
ass ess e d (
 
•  
 
 
I nst r u cti o ns t o s u bj e ct:  
 
•     D os e i n v esti g ati o n al  pr o d u ct  as i nstr u ct e d.   
•  
 
•  
 
•     R et ur n f or   Visit  5  o n   D a y   2 9  ±  1  d a y . 
 
5. 1. 6.         Visit  6:   D a y   2 9  ±  1  d a y  –  E n d  of  St u d y   Visit   
 
T h e  E n d  of  St u d y  visit   will  o c c ur  o n   D a y  2 9  ±  1  d a y  as  c al c ul at e d fr o  m   Visit  2:   D a y  1,  a n d 
t h e f oll o  wi n g   will  b e  p erf or  m e d/ ass ess e d:  
 
•     Us e  of  a n y  c o n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit   
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•     U P T f or    W  O  C  B P   
•  
 
•     Us e d  a n d  u n us e d  d o u  bl e -m as k e d i n v esti g ati o n al  pr o d u ct  c oll e ct e d,  c o u nt e d,  a n d 
c o  m pli a n c e  ass ess e d 
  
•     S u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  dis c o  mf ort 
•     I n v esti g at or-r at e d  ass ess  m e nt  of si g ns 
•     I n v esti g at or-r at e d  ass ess  m e nt  of  b ul b ar  c o nj u n cti v al  h y p er e  mi a 
•  
 
•     T F  B  U T  
•     C or n e al fl u or es c ei n st ai ni n g   
•     B  C  V  A   
•     Slit -l a  m p  bi o  mi cr os c o p y 
•     I  O P   m e as ur e  m e nt 
•     Dil at e d  o p ht h al  m os c o p y   
•  
 
•     R el e as e  of s u bj e ct fr o  m t h e st u d y   
 
5. 1. 7.         U ns c h e d ul e d   Visit   
 
A n y  visits  or  pr o c e d ur es  p erf or  m e d  b e y o n d t h os e s p e cifi e d   wit hi n t h e  pr ot o c ol   m ust  b e 
d o c u  m e nt e d i n t h e   U ns c h e d ul e d   Visit  p a g es  of t h e  e  C  R F.   U ns c h e d ul e d  visits   m a y i n cl u d e  b ut 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
ar e  n ot li  mit e d t o r e p orti n g  a d v ers e  e v e nts (  A Es),  c h a n g es i n  c o n c o  mit a nt   m e di c a ti o ns,  or 
o p ht h al  mi c  ass ess  m e nts  as  d e e  m e d  a p pr o pri at e  b y  a n  a p pr o pri at el y  q u alifi e d  p h ysi ci a n.  If t h e 
s u bj e ct is  dis c o nti n ui n g st u d y  p arti ci p ati o n  at t h e  u ns c h e d ul e d  visit, t h e  e  C  R Fs f or   Visit  6 
s h o ul d  b e  c o  m pl et e d r at h er t h a n t h e  e  C  R Fs f or  a n   U ns c h e d ul e d   Visit.  
 
5. 1. 8.         E a rl y   T e r  mi n ati o n   Visit   
 
I n t h e  e v e nt  of t er  mi n ati o n  pri or t o   Visit  6,  e v er y  att e  m pt   will  b e   m a d e t o  e ns ur e t h at  all   Visit 
6  ass ess  m e nts  ar e  p erf or  m e d.  If t his is  n ot f e asi bl e,  at l e ast t h e f oll o  wi n g s h o ul d  b e 
p erf or  m e d/ ass ess e d:   
 
•     Us e  of  a n y  c o  n c o  mit a nt   m e di c ati o ns si n c e t h e l ast  visit  
•     O c c urr e n c e  of  a n y   A Es si n c e t h e l ast  visit   
•     Us e d  a n d  u n us e d i n v esti g ati o n al  pr o d u ct  c oll e ct e d  a n d  c o  m pli a n c e  ass ess e d          
 
•     S u bj e ct -r at e d  ass ess  m e nt  of  o c ul ar  disc o  mf ort  
•     B  C  V  A   
•     Slit l a  m p  bi o  mi cr os c o p y   
•     I  O P   m e as ur e  m e nt 
 
5. 2.         
R E S  C  U  E M
E  DI  C  A  TI  O  N U S  E  
 
A n y s u bj e cts  n ot r es p o n di n g  a d e q u at el y t o t h e st u d y   m e di c ati o n   m a y  b e r es c u e d  a n d  pl a c e d 
o n  alt er n at e t h er a p y  at t h e I n v esti g at or's  dis cr eti o n  at  a n y ti  m e.  T h e  c h oi c e  of r es c u e 
m e di c ati o n is  at t h e I n v esti g at or's  dis cr eti o n.   A n y s u bj e ct  pl a c e d  o n r es c u e t h  er a p y   will 
dis c o nti n u e  us e  of t h e st u d y   m e di c ati o n  a n d  c o nti n u e st u d y  p arti ci p ati o n t hr o u g h   Visit  6.   
R es c u e d s u bj e cts   will  b e  c o nsi d er e d tr e at  m e nt f ail ur es,  b ut t h e  n e e d f or r es c u e t h er a p y   will 
n ot  b e  c o nsi d er e d  a n   A E.   R es c u e d s u bj e cts  e x p eri e n ci n g  a n   A E  at t h e ti  m e  of r es c u e   will  b e 
f oll o  w e d t hr o u g h st a bili z ati o n  or r es ol uti o n  of t h e   A E  or t h e  e n d  of t h e st u d y (  w hi c h e v er 
c o  m es l ast).    R es c u e d s u bj e cts s h o ul d  n ot  b e   wit h dr a  w n fr o  m t h e st u d y,  b ut r at h er f oll o  w e d t o 
r es ol uti o n  of si g ns  a n d s y  m pt o  ms  or  u ntil t h e I n v esti g at or  h as  d e e  m e d t h e s u bj e ct is st a bl e. 
 
5. 3.         
S U  B J  E  C  T W
I  T  H  D  R  A   W  A  L   A  N  D/O  R D I S  C  O  N  TI  N  U  A  TI  O  N  
 
A n y s u bj e ct   w h o   wis h es t o   dis c o nti n u e  i n v esti g ati o n al  pr o d u ct  us e  or wit h dr a  w   fr o  m 
p arti ci p ati o n i n t h e st u d y f or  a n y r e as o n is  e ntitl e d t o  d o s o   wit h o ut  o bli g a ti o n.   T h e 
I n v esti g at or   m a y  als o dis c o nti n u e  a n y s u bj e ct  fr o  m i n v esti g ati o n al pr o d u ct  us e  or fr o  m st u d y 
p arti ci p ati o n, if  d e e  m e d  n e c ess ar y.   
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 8  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
I n v esti g ati o n al  pr o d u ct  us e   m a y  b e  dis c o nti n u e d  a n d  a n y s u bj e ct   m a y  b e  dis c o nti n u e d fr o  m 
st u d y  p arti ci p ati o n  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  or t h e 
s p o ns or f or  a n y r e as o n i n cl u di n g  b ut  n ot li  mit e d  t o: 
 
1.    O c c urr e n c e  of  a n y   m e di c al  c o n diti o n  or  cir c u  mst a n c e t h at  e x p os es t h e s u bj e ct t o 
s u bst a nti al ris k  a n d/ or  d o es  n ot  all o  w t h e s u bj e ct t o  a d h er e t o t h e r e q uir e  m e nts  of t h e 
pr ot o c ol.  
2.    A n y  S  A E,  cli ni c all y si g nifi c a nt   A E, s e v er e l a b or at or y  a b n or  m alit y, i nt er  c urr e nt 
ill n ess,  or  ot h er   m e di c al  c o n diti o n t h at i n di c at es t o t h e I n v esti g at or t h at  c o nti n u e d 
p arti ci p ati o n is  n ot i n t h e  b est i nt er est  of t h e s u bj e ct.  
3.    S u bj e ct's  d e cisi o n t o   wit h dr a  w.  
4.    A n y   w o  m a n   w h o  b e c o  m es  pr e g n a nt   w hil e  p arti ci p ati n g i n t h e st u d y.  I nf or  m  ati o n  o n 
t h e  pr e g n a n c y  a n d  o ut c o  m e   will  b e r e q u est e d.   
5.    S u bj e ct’s f ail ur e t o  c o  m pl y   wit h  pr ot o c ol r e q uir e  m e nts  or st u d y r el at e d  pr o c e d ur es.  
6.    T er  mi n ati o n  of t h e st u d y  b y t h e  S p o ns or,  F  D  A,  or  ot h er r e g ul at or y  a ut h oriti es.   
 
I n t h e  e v e nt st u d y  dis c o nti n u ati o n  of  a r a n d o  mi z e d s u bj e ct is  n e c ess ar y, t h e I n v esti g at or 
s h o ul d   m a k e  e v er y  att e  m pt t o  h a v e  t h e s u bj e ct  c o  m pl et e   Visit  6  ass ess  m e nts  as  p ossi bl e.  If  a 
n o n -s eri o us   A E is  u nr es ol v e d  at t h e ti  m e  of t h e s u bj e ct’s fi n al st u d y  visit,  a n  eff ort   will  b e 
m a d e t o f oll o  w  u p  u ntil t h e   A E is r es ol v e d  or st a bili z e d, t h e s u bj e ct is l ost t o f oll o  w  -u p,  or 
t h er e is s o  m e  ot h er r es ol uti o n  of t h e  e v e nt.   T h e I n v esti g at or s h o ul d   m a k e  e v er y  att e  m pt t o 
f oll o  w  all s eri o us  a d v ers e  e v e nts ( S  A Es) t o r es ol uti o n.   T h e r e as o n f or  pr e  m at ur e 
dis c o nti n u ati o n s h o ul d  b e  e nt er e d  o nt o t h e   C as e   R e p ort  F or  m (  C  R F)  a n d r e c or d e d i n t h e 
s u bj e ct  c h art. 
 
S u bj e cts   w h o   wit h dr a  w fr o  m t h e st u d y   will  n ot  b e r e pl a c e d.  
 
A d diti o n all y, t h e tri al  or  p arts  of t h e tri al   m a y  b e  dis c o nti n u e d  b y t h e s p o ns or  or  at t h e 
r e c o  m  m e n d ati o n  of t h e I n v esti g at or  aft er  c o ns ult ati o n   wit h   K al a  P h ar  m a c e uti c als, I n c.   T his 
m a y  b e  b as e d  o n  a si g nifi c a nt  n u  m b er  of   A Es  of  a si  mil ar  n at ur e t h at   w arr  a nt s u c h  a cti o n.     
 
5. 4.         
C O  L  L  E  C  TI  O  N   O F D A  T  A  
 
S o ur c e  d o c u  m e nt ati o n f or  d at a  c oll e ct e d i n t his st u d y   will  b e   m ai nt ai n e d  at t h e i n v esti g ati v e 
sit e.  I n  c as es   w h er e  n o s o ur c e   will  b e  us e d   ( e. g., s u bj e ct  di ar y), it   will  b e  n ot e d i n t h e 
I n v esti g at or fil es.   T h e   C  R F   will  b e  el e ctr o ni c ( e  C  R F)  a n d  d at a   will  b e  e nt er e d fr o  m s o ur c e 
d o c u  m e nt ati o n i nt o t h e  e  C  R F .    After st u d y  c o  m pl eti o n,  a n  ar c hi v al  c o p y [ e. g.,  P ort a bl e 
D o c u  m e nt  F or  m at ( P  D F)]  of t h e  e  C  R F  d at a   will  b e r et ai n e d  b y t h e sit e.   
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 4 9  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
6.         
T  R  E  A  T   M  E  N  T   O F   S U  B J  E  C  T S   
6. 1.         
IN  V  E S  TI  G  A  TI  O  N  A  L P R  O  D  U  C  T  S   T  O   B  E A D   M I  NI S  T  E  R  E  D  
 
All s u bj e cts   m e eti n g  eli gi bilit y  crit eri a  at   Visit  1   will r e c ei v  e  2  b ottl es  of si n gl e -m as k e d 
i n v esti g ati o n al  pr o d u ct (v e hi cl e ).   S u bj e cts   w h o  c o nti n u e t o   m e et  eli gi bilit y  crit eri a  at   Visit  2 
will  b e r a n d o  mi z e d t o  eit h er   K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  or  v e hi cl e .    O n e  kit  of 
r a n d o  mi z e d i n v esti g ati o n al  pr o d u ct  c o nt ai ni n g  3  dr o p p er  b ottl es   will  b e  all o c at e d t o  e a c h 
s u bj e ct  at   Visit  2.    At   Visit  2 (  D a y  1/  R a n d o  mi z ati o n), s u bj e cts   will r e c ei v e  2  b ottl es  of 
d o u bl e -m as k e d i n v esti g ati o n al  pr o d u ct (  K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  or  v e hi cl e ).  
At   Visit  4 (  D a y  1 5   ±  1  d a y ), s u bj e cts   will r e c ei v e  1  a d diti o n al  b ottl e  of  d o u bl e-m as k e d 
i n v esti g ati o n al  pr o d u ct fr o  m t h e  kit  all o c at e d.    All  b ottl es   will  b e r et ur n e d t o t h e sit e  at   Visit  6 
(D a y  2 9  ±  1  d a y  ).   T h e i n v esti g ati o n al  pr o d u ct   will  b e st or e d  at t h e sit e i n  a s e c ur e  ar e a   with 
li  mit e d  a c c ess  at  c o ntr oll e d r o o  m t e  m p er at ur e ( 1 5-2 5 °C/ 5 9  -7 7 °F).  
 
S u bj e cts   will  b e  as k e d t o  a d  mi nist er i n v esti g ati o n al  pr o d u ct   QI  D.   Pri or t o  e a c h i nstill ati o n, 
s u bj e ct   will  b e i nstr u ct e d t o s h a k e  t h e b ottl e.   T h e s u bj e cts   will r e c or d t h e ti  m e  of 
a d  mi nis tr ati o n  of  e a c h  d os e  of i n v esti g ati o n al  pr o d u ct  at t h e ti  m e  of i nstill ati o n (A p p e n di x 
1 2 ).    C o  m pli a n c e   wit h i nstill ati o n  of i n v esti g ati o n al  pr o d u ct   will  b e r e vi e  w e d  a n d  ass ess e d  at 
e a c h  cli ni c  visit.  
 
6. 2.         
C O  N  C  O   M I  T  A  N  T M
E  DI  C  A  TI  O  N S  
 
All   m e di c ati o ns t h at t h e s u bj e ct  h as t a k e n  6   m o nt hs  pri or t o   Visit  1  a n d t hr o u g h   Visit  6  or 
dis c o nti n u ati o n fr o  m t h e st u d y   will  b e r e c or d e d i n t h e  e  C  R F  a n d t h e s u bj e ct  c h art.   T h e 
g e n eri c  n a  m e  of t h e  dr u g,  d os e, r o ut e  of  a d  mi nistr ati o n,  d ur ati o n  of tr e at  m e nt ( i n cl u di n g st art 
a n d st o p  d at es), fr e q u e n c y, i n di c ati o n,  a n d   w h et h er  or  n ot t h e   m e di c ati o n   w as t a k e n  d u e t o  a n 
A E   will  b e r e c or d e d f or  e a c h   m e di c ati o n.   
 
6. 2. 1.         P e r  mitt e d    M e di c ati o ns  a n d   T h e r a pi es  
 
M e di c ati o ns   a n d t h er a pi es  n ot s p e cifi c all y  e x cl u d e d i n  S e cti o n  6. 2. 2  m a y  b e t a k e n  as 
n e c ess ar y.  
 
6. 2. 2.         M e di c ati o ns    a n d  P r o c e d u r es  N ot  P e r  mitt e d   
 
T h e f oll o  wi n g  pr o c e d ur es  a n d   m e di c ati o ns  ar e  n ot  all o  w e d f or t h e ti  m e  p eri o ds s p e cifi e d.   
 
Wit hi n  1 4  ±    1  d a ys  pri or t o   Visit  1 ( S cr e e ni n g)  a n d f o r t h e  d ur ati o n  of t h e st u d y: 
•     W ar  m  c o  m pr ess es    
•     Li d   m ar gi n  e x pr essi o n  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 0  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     Li d   m ar gi n   m ass a g e  
 
Fr o  m  Visit  1 ( S cr e e ni n g)  a n d f or t h e  d ur ati o n  of t h e st u d y:   
•     E y el as h  gr o  wt h   m e di c ati o ns  
•     E y e  dr o ps,  g els,  or  artifi ci al t e ars (i n cl u di n g  gl a u c o  m a   m e di c ati o ns)  
•     A n y  ot h er   t o pi c al  o p ht h al  mi c   m e di c ati o n 
•     T  N F -bl o c ki n g  a g e nts ( e. g.  et a n er c e pt,  a d ali  m u  m a b, i nfli xi  m a b)   
 
Wit hi n  4 8  h o urs  pri or t o   Visit  1 ( S cr e e ni n g)  a n d f or t h e  d ur ati o n  of t h e st u d y, i niti at e  or  alt er 
us e  of:  
•     Or al  c o ntr a c e pti v es,  a n d f e  m al e  h or  m o n e r e pl a c e  m e nt t h er  a p y/s u p pl e  m e nt ati o n   
 
Wit hi n  3 0  d a ys  pri or t o  S cr e e ni n g (  Visit  1)  a n d f or t h e  d ur ati o n  of t h e st u d y:    
•     O c ul ar, i n h al e d,  or i ntr a n as al  c orti c ost er oi ds   
•     O c ul ar  or  or al   N S  AI  Ds   wit h t h e  e x c e pti o n  of l o  w  d os e  as piri n (  ≤   8 1   m g  p er  d a y) 
•     T o pi c al  o c ul ar  a nti bi oti cs  
•     T o pi c al  o c ul ar  a nti hist a  mi n es  or   m ast  c ell st a bili z ers  
•     Or al  a nti hist a  mi n es   
•     T o pi c al  or  n as al  v as o c o nstri ct ors  
 
Wit hi n  3 0  pri or t o   Visit  1 ( S cr e e ni n g),  h a v e  alt er e d  or  a nti ci p at e  alt er ati o n  of:    
•     Or al  d osi n g  of t etr a c y cli n e  c o  m p o u n ds ( e. g., t etr a c y cli n e,  d o x y c y cli n e,  or 
mi n o c y cli n e).     
•     O  m e g a  -3  or   O  m e g a -6 s u p pl e  m e nts  
 
Wit hi n  6 0  d a ys  pri or t o  S cr e e ni n g (  Visit  1)  a n d f or t h e  d ur ati o n  of t h e st u d y:    
•     T o pi c al  c y cl os p ori n e (  R est asis ® ) 
•     A n y f or  m  of t o pi c al   L E  
 
W   it hi n  6   m o nt hs  pri or t o  S cr e e ni n g (  Visit  1)  h a v e  alt er e d  o r  a nti ci p at e  alt er ati o n  of  d osi n g 
d uri n g t h e st u d y:  
•     A nti c h oli n er gi cs   
•     A nti d e pr ess a nts   
•     Is otr eti n oi n 
•     Or al  c orti c ost er oi ds   
•     S yst e  mi c i  m  m u n os u p pr essi v e  a g e nts   
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 1  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
6. 3.         
IN  V  E S  TI  G  A  TI  O  N  A  L  P  R  O  D  U  C  T   U S  E  C O   M P  LI  A  N  C  E  
 
C o  m pli a n c e   will  b e  ass ess e d  b y  c o  m p ari n g   i n v esti g ati o n al  pr o d u ct a c c o u nt a bilit y r e c or ds 
wit h t h e  d osi n g i nf or  m ati o n   r e c or d e d  d ail y  b y t h e s u bj e ct.  T h e sit e   will  d o c u  m e nt t his 
c o  m p aris o n  al o n g   wit h  v erifi c ati o n  of t h e  n u  m b ers  of  us e d  a n d  u n us e d  i n v esti g ati o n al  pr o d u ct 
b ottl es.  T h e  n u  m b er  of   miss e d  d os es  as  ass ess e d  at  e a c h  cli ni c  visit  sh o ul d  b e  d o c u  m e nt e d i n 
t h e  e  C  R F.   
 
6. 4.         
D R  U  G A C  C  O  U  N  T  A  BI  LI  T  Y  
 
S p o ns or st u d y   m o nit ors  or  d esi g n e es   will  c o n d u ct  a c c o u nt a bilit y  of  i n v esti g ati o n al  pr o d uct  
(K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n , v e hi cl e ,  or r u n-i n  pr o d u ct).    A c c o u nt a bilit y   will  b e 
as c ert ai n e d  b y  p erf or  mi n g r e c o n cili ati o n  b et  w e e n t h e  a m o u nt  of  dr u g s e nt t o t h e sit e   a n d t h e 
a  m o u nt  u n us e d  at t h e ti  m e  of r e c o n cili ati o n.  
 
Cli ni c al tri al   m at eri als   will  b e s hi p p e d t o t h e i n v esti g ati o n al sit es  u n d er s e al e d  c o n diti o ns.  
S hi p  m e nt r e c or ds   will  b e  v erifi e d  b y  c o  m p ari n g t h e s hi p  m e nt i n v e nt or y s h e et t o t h e  a ct u al 
q u a ntit y  of  dr u g r e c ei v e d  at t h e sit e.    A c c ur at e r e c or ds  of r e c ei pt  a n d  dis p ositi o n  of t h e 
i n v esti g ati o n al  pr o d u ct ( e. g.,  d at es,  q u a ntit y, s u bj e ct  n u  m b er,  d os e  dis p e ns e d, r et ur n e d)   m ust 
b e   m ai nt ai n e d  b y t h e  I n v esti g at or or  his/ h er  d esi g n e e.    
 
I n v esti g ati o n al  pr o d u ct will  b e st or e d   at  c o ntr oll e d  r o o  m t e  m p er at ur e (1 5 -2 5 °C  /5 9 -7 7 °F)  i n  a n 
ar e a li  mit e d  t o c o ntr oll e d  a c c ess.  
 
At t h e  e n d  of t h e st u d y,  all st u d y   m at eri als,   i n cl u di n g  a n y  u n us e d i n v esti g ati o n al  pr o d u cts 
(K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n , v e hi cl e ,  or r u n-i n  pr o d u ct),  as   w ell  as  ori gi n al 
c o nt ai n ers ( e v e n if  e  m pt y),   will  b e r et ur n e d t o  t h e  dr u g-p a c k a gi n g  v e n d or  i n  a c c or d a n c e   wit h 
s p o ns or  or  d esi g n e e’s  S t a n d ar d O  p er ati n g  P r o c e d ur es ( S  O Ps), f oll o  wi n g  a p pr o v al  b y t h e 
S p o ns or.   All r et ur ns  of  i n v esti g ati o n al  pr o d u ct will  b  e  d o c u  m e nt e d.   T h e st u d y   m o nit or  or 
d esi g n e e   will  v erif y  dr u g  a c c o u nt a bilit y.    All  dr u g  a c c o u nti n g  pr o c e d ur es   m ust  b e  c o  m pl et e d 
b ef or e t h e st u d y is  c o nsi d er e d  c o  m pl et e.  
 
6. 5.         
M
AI  N  T  E  N  A  N  C  E   O F R A  N  D  O   M I  Z  A  TI  O  N   A  N  D P R  O  C  E  D  U  R  E  F  O  R B R  E  A  KI  N  G   T  H  E C O  D  E  
 
T h e s p o ns or, t h e  pr o j e ct t e a  ms  at t h e  d esi g n at e d   C o ntr a ct   R es e ar c h   Or g a ni z ati o ns (  C  R  Os), 
a n d i n v esti g ati v e st aff r es p o nsi bl e f or  ass ess  m e nts  of st u d y  e n d p oi nts   will  b e   m as k e d t o 
i n v esti g ati o n al  pr o d u ct  assi g n  m e nts.    A  d osi n g  c o or di n at or,   w h o is  n ot r es p o nsi bl e f or st u d y 
ass es s  m e nts,   will  b e r e q uir e d t o  dis p e ns e  a n d r etri e v e  d o u bl e -m as k e d,   i n v esti g ati o n al  pr o d u ct 
t o t h e s u bj e cts. I n  c as e  of   m e di c al  e  m er g e n c y,  or  o c c urr e n c e  of  a n  S  A E, t h e r a n d o  mi z ati o n 
c o d e   m a y  b e  u n  m as k e d  a n d   m a d e  a v ail a bl e t o t h e I n v esti g at or, s p o ns or,  a n d/ or  ot h er 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 2  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
p ers o n n el i n v ol v e d i n t h e   m o nit ori n g  or  c o n d u ct  of t his st u d y.  I n t h e  a bs e n c e  of   m e di c al 
n e e d, t h e r a n d o  mi z ati o n  c o d e   will  n ot  b e  a v ail a bl e t o t h e  a b o v e i n di vi d u als  u ntil  aft er t h e 
st u d y is  c o  m pl et e d  a n d t h e  d at a b as e is l o c k e d.    
 
I n t h e  e v e nt  of  a m e di c al  n e e d, t h e I n v esti g at or   will tr e at  e a c h s u bj e ct  as  n e e d e d.   Si n c e t h er e 
is  n o s p e cifi c  a nti d ot e t o   K PI-1 2 1, i  m  m e di at e  e  m er g e n c y  u n  m as ki n g is  n ot  n e c ess ar y.  If t h e 
I n v esti g at or f e els it is  n e c ess ar y t o  u n  m as k  a s u bj e ct’s  assi g n  m e nt  aft er  a n  e  m er g e n cy 
sit u ati o n, t h e I n v esti g at or   m a y  c all t h e   m e di c al   m o nit or  a n d  n otif y t h e s p o ns or.   T h e 
i n v esti g ati o n al  pr o d u ct  assi g n  m e nt   will  b e r e v e al e d  o n  a s u bj e ct-b y -s u bj e ct  b asis   wit h t h e 
a p pr o v al  of t h e   m e di c al   m o nit or  a n d s p o ns or, t h us l e a vi n g t h e   m as ki n g  of t h e  r e  m ai ni n g 
s u bj e cts i nt a ct. 
 
A r a n d o  mi z ati o n  c o d e   will  b e  c o  m p ut er  -g e n er at e d   K al a  P h ar  m a c e uti c als, I n c.  or  d esi g n e e.  
R a n d o  mi z ati o n t e a  m   m e  m b ers   will   w or k i n d e p e n d e ntl y  of  ot h er t e a  m   m e  m b ers  at t h e   C  R  O.  
St u d y  p ers o n n el, st u d y s u bj e cts, t h e s p o ns or,  a n d  pr o j e ct t e a  ms  at t h e   C  R  Os i n v ol v e d i n t h e 
st u d y   will  b e   m as k e d t o i n v esti g ati o n al  pr o d u ct  assi g n  m e nts.  
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
7.         
A  S S  E S S   M  E  N  T   O F  E F FI  C  A  C  Y   
 
Effi c a c y  ass ess  m e nts i n cl u d e t h e  f oll o  wi n g: 
•     I n v esti g at or-rat e d  a ss ess  m e nt  of p ost eri or  li d m  ar gi n  h y p er e  mi a  
•  
 
•     I n v esti g at or-rat e d  a ss ess  m e nt  of c o nj u n cti v al  h y p er e  mi a  
•     I n v esti g at or-r at e d  ass ess  m e nt  of t h e  c h ar a ct er  of t h e m ei b o  mi a n  gl a  n d s’ c o nt e nts  
•     I n v esti g at or-r at e d  ass ess  m e nt  of t h e  e x pr essi bilit y  of t h e   m ei b o  mi a n  gl a n ds 
•     T F  B  U T  
•     C or n e al   Fl u or es c ei n  St ai ni n g  
•  
 
•     I n-c li ni c su bj e ct -rat e d  a ss ess  m e nt  of o c ul ar  d is c o  mf ort 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
8.         
A S S  E S S   M  E  N  T   O F  S  A F  E  T  Y   
8. 1.         
S A F  E  T  Y P A  R  A   M  E  T  E  R S  
 
S af et y  p ar a  m et ers i n cl u d e:  
•     Ass ess  m e nt  of   A Es   
•     I  O P   m e as ur e  m e nts 
•     Slit -l a  m p b i o  mi cr os c o p y  
•     B  C  V  A   
•     Dil at e d  o  p ht h al  m os c o p y    
 
8. 2.         
A D  V  E  R S  E E V  E  N  T D E FI  NI  TI  O  N S  
 
A d v e rs e   E v e nt   (  A  E):  A n y  u nt o  w ar d   m e di c al  o c c urr e n c e  ass o ci at e d   wit h t h e  us e  of  a n 
i n v esti g ati o n al  pr o d u ct i n  h u  m a ns, w h et h er  or  n ot  c o nsi d er e d  dr u g r el at e d.    
 
A d v e rs e   R e a cti o n (  A  R)  : a n y  A E   c a us e d  b y  a  dr u g.   A d v ers e r e a cti o ns  ar e  a s u bs et  of  all 
s us p e ct e d  a d v ers e r e a cti o ns   w h er e t h er e is r e as o n t o  c o n cl u d e t h at t h e  dr u g  c a us e d t h e  e v e nt.   
 
S us p e ct e d   A d v e rs e   R e a cti o n ( S  A  R) :  
A n y   A E   f or   w hi c h t h er e is  a r e as o n a bl e  p ossi bilit y t h at t h e  dr u g  c a us e d t h e A E  .  F or t h e 
p ur p os es  of I  N  D s af et y r e p orti n g,  “ r e as o n a bl e  p ossi bilit y”  m e a ns t h er e is  e vi d e n c e t o s u g g est 
a  c a us al r el ati o ns hi p  b et  w e e n t h e  dr u g  a n d t h e  A E  .   A S  A  R  i  m pli es  a l esser  d e gr e e  of  c ert ai nt y 
a b o ut  c a us alit y t h a n  a d v ers e r e a cti o n,   w hi c h   m e a ns  a n y  A E   c a us e d  b y  a  dr u g.   
 
U n e x p e ct e d:    A n   A E  or  S  A  R is  c o nsi d er e d   “ u n e x p e ct e d ”  if it is  n ot list e d i n t h e 
I n v esti g at or’s   Br o c h ur e  or is  n ot list e d  at t h e s p e cifi cit y  or s e v erit y t h at  h as  b e e n  o bs er v e d;  or, 
if  a n I n v esti g at or’s B  r o c h ur e is  n ot r e q uir e d  or  a v ail a bl e, is  n ot  c o nsist e nt   wit h t h e ris k 
i nf or  m ati o n  d es cri b e d i n t h e  g e n er al i n v esti g ati o n al  pl a n  or  els e  w h er e i n t h e  c urr e nt 
a p pli c ati o n.    
 
Lif e  -t h r e at e ni n g: A n   A E   or  S  A  R  is  c o nsi d er e d  “lif e-t hr e at e ni n g ” if, i n t h e  vi e  w  of  eit h er t h e 
I n v esti g at or or s p o ns or, its  o c c urr e n c e  pl a c es t h e  p ati e nt  or s u bj e ct  at i  m  m e di at e ris k  of  d e at h. 
It  d o es  n ot i n cl u d e  a n A E   or s us p e ct e d  a d v ers e r e a cti o n t h at,  h a d it  o c c urr e d i n  a   m or e s e v er e  
f or  m,   mi g ht  h a v e  c a us e d  d e at h.  
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 5  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
A   S  E  RI  O  U S   A  D  V  E  R S  E   E  V  E  N  T ( S  A  E)  is  a n y A E   or s us p e ct e d  a d v ers e r e a cti o n  o c c urri n g 
at  a n y  d os e t h at :  
 
•     R es ults i n  d e at h.   
•     Is lif e-t hr e at e ni n g. 
•     R es ults i n  a  p ersist e nt  or si g nifi c a nt i n c a p a cit y  or s u bst a nti al  disr u pti o n  of   t h e 
a bilit y t o  c o n d u ct  n or  m al lif e f u n cti o ns . 
•     R e q uir es i n p ati e nt  h os pit ali z ati o n.   
•     Pr ol o n gs i n p ati e nt  h os pit ali z ati o n.  
•     Is  a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct. 
•     Is  a si g nifi c a nt   m e di c al  e v e nt (i. e., o n e t h at   m a y j e o p a r di z e t h e s u bj e ct  or   m a y 
r e q uir e i nt er v e nti on t o  pr e v e nt  o n e  or   m or e  of t h e  ot h er  o ut c o  m es list e d  a b o v e ). 
 
A   N  O  N  -S  E  RI  O  U S   A  D  V  E  R S  E   E  V  E  N  T  is  a n y A E   t h at  d o es  n ot   m e et t h e  d efi niti o ns f or 
S  A E s  as  d es cri b e d  a b o v e.   
 
E a c h  A  E   will  b e  cl assifi e d  as   S  E  RI  O  U S  o r   N  O  N -S  E  RI  O  U S  usi n g t h e  d efi niti o ns  pr o vi d e d 
a b o v e.  
 
T h e  S  E  V  E  RI  T  Y  of  e a c h  A E   will  b e  cl assifi e d  as   MI  L  D,    M  O  D  E  R  A  T  E,  o r  S  E  V  E  R  E.      
T h e  I n v esti g at or will r e vi e  w  e a c h  e v e nt  a n d  ass ess its   R  E  L  A  TI  O  N S  HI P   t o us e  of 
i n v esti g ati o n al  pr o d u ct ( u nr el at e d,  u nli k el y,  p ossi bl y,  pr o b a bl y,  d efi nit el y). T h e  A E   will  b e 
ass ess e d  usi n g t h e f oll o  wi n g  d efi niti o ns : 
 
U n r el at e d  :      
•     E v e nt  o c c urri n g  b ef or e  d osi n g.  
•     E v e nt  or i nt er c urr e nt ill n ess  d u e   w h oll y t o f a ct ors  ot h er t h a n  i n v esti g ati o n al 
pr o d u ct  us e . 
 
U nli k el y  :   
•     P o or t e  m p or al r el ati o ns hi p   wit h  i n v esti g ati o n al  pr o d u ct us e . 
•     E v e nt  e asil y  e x pl ai n e d  b y s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors.  
 
P ossi bl e : 
§     R e as o n a bl e t e  m p or al r el ati o ns hi p   wit h   i n v esti g ati o n al  pr o d u ct us e . 
§     E v e nt  c o ul d  b e  e x pl ai n e d  b y s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors.   
 
P r o b a bl e:  
§     R e as o n a bl e t e  m p or al r el ati o ns hi p   wit h   i n v esti g ati o n al  pr o d u ct us e . 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 6  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
§     Li k el y t o  b e  k n o  w n r e a cti o n t o  a g e nt  or  c h e  mi c al  gr o u p,  or  pr e di ct e d  b y  k n o  w n 
p h ar  m a c ol o g y.  
§     E v e nt  c a n n ot  e asil y  b e  e x pl ai n e d  b y s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors.   
 
D efi nit e:      
•     Disti n ct t e  m p or al r el ati o ns hi p   wit h   i n v esti g ati o n al  pr o d u ct us e . 
•     K n o  w n r e a cti o n t o  a g e nt  or  c h e  mi c al  gr o u p,  or  pr e di ct e d  b y  k n o  w n  p h ar  m a c ol o g y.   
•     E v e nt  c a n n ot  b e  e x pl ai n e d  b y s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors.    
 
8. 3.         
P R  O  C  E  D  U  R  E S  F  O  R A  E  R E P  O  R  TI  N  G   B  Y   T  H  E IN  V  E S  TI  G  A  T  O  R  
 
A  E s   will  b e   m o nit or e d t hr o u g h o ut t h e st u d y  a n d   will  b e r e c or d e d  o n t h e   C  R F   wit h t h e  d at e 
a n d ti  m e  of  o ns et,  d at e  a n d ti  m e  of r es ol uti o n,  s e v erit y, s eri o us n ess,  c a us alit y (r el ati o ns hi p t o 
us e  of  i n v esti g ati o n al  pr o d u ct), tr e at  m e nt r e q uir e d, a n d t h e  o ut c o  m e.    
T o  eli cit  A  E s, si  m pl e  q u esti o ns   wit h   mi ni  m al  s u g g esti o ns  or i  m pli c ati o ns  s h o ul d  b e  us e d  as 
t h e i niti al  q u esti o ns  at  all  e v al u ati o n  p oi nts  d uri n g t h e tri al.   F or  e x a  m pl e: 
 
•     H o  w  h a v e  y o u f elt si n c e  y o ur l ast  ass ess  m e nt ?   
•     H a v e  y o u  h a d  a n y  h e alt h  pr o bl e  ms si n c e   y o ur l ast  ass ess  m e nt ?  
 
T h e s e v erit y  of  e a c h  A E   s h o ul d  b e  c at e g ori z e d  as   mil d,   m o d er at e,  or s e v er e.  
 
T h e  c a us alit y  of  us e  of  i n v esti g ati o n al  pr o d u ct i n r el ati o n t o t h e A E   will  b e  ass ess e d  b y t h e 
P ri n ci p al I n v esti g at or aft er  c ar ef ul   m e di c al  c o nsi d er ati o n  a n d  c at e g ori z e d  as  u nr el at e d, 
u nli k el y,  p ossi bl e,  pr o b a bl e,  or  d efi nit e.  
 
If  a n   A E  o c c urs, t h e I n v esti g at or will i nstit ut e s u p p ort  a n d/ or   tr e at as  d e e  m e d  a p pr o pri at e.    
If  a n o n -S  A E  is  u nr es ol v e d  at t h e ti  m e  of t h e l ast  d a y  of t h e st u d y,  a n  eff ort   will  b e   m ad e t o 
f oll o  w  u p  u ntil t h e   A E is r es ol v e d  or st a bili z e d, t h e s u bj e ct is l ost t o f oll o  w-u p,  or t h er e is 
s o  m e  ot h er r es ol uti o n  of t h e  e v e nt.   T h e  I n v esti g at or s h o ul d   m a k e  e v er y  att e  m pt t o f oll o  w 
S  A E s t o r es ol uti o n. 
 
8. 4.         
R E S  C  U  E T H  E  R  A P  Y  
 
A n y s u bj e cts  n ot r es p o n di n g  a d e q u at el y t o t h e st u d y   m e di c ati o n   m a y  b e r es c u e d  a n d  pl a c e d 
o n  alt er n at e t h er a p y  at t h e I n v esti g at or's  dis cr eti o n  at  a n y ti  m e.  T h e  c h oi c e  of r es c u e 
m e di c ati o n is  at t h e I n v esti g at or's  dis cr eti o n.   A n y s u bj e ct  pl a c e d  o n r es c u e t h  er a p y   will 
dis c o nti n u e  us e  of t h e st u d y   m e di c ati o n  a n d  c o nti n u e st u d y  p arti ci p ati o n t hr o u g h   Visit  6.   
R es c u e d s u bj e cts   will  b e  c o nsi d er e d tr e at  m e nt f ail ur es,  b ut t h e  n e e d f or r es c u e t h er a p y   will 
n ot  b e  c o nsi d er e d  a n   A E.   R es c u e d s u bj e cts  e x p eri e n ci n g  a n   A E  at t h e ti  m e  of r es c u e   will  b e 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
f oll o  w e d t hr o u g h st a bili z ati o n  or r es ol uti o n  of t h e   A E  or t h e  e n d  of t h e st u d y (  w hi c h e v er 
c o  m es l ast).  
 
8. 5.         
S E  RI  O  U S A D  V  E  R S  E E V  E  N  T R E P  O  R  TI  N  G   B  Y   T  H  E IN  V  E S  TI  G  A  T  O  R  
 
S e ri o us   A d v e rs e   E v e nt   R e p o rti n g  
It is t h e r es p o nsi bilit y  of t h e I n v esti g at ors  or t h eir  d esi g n e es t o r e p ort  a n y  e v e nt  of t his  n at ur e 
t o t h e s p o ns or or  a  d esi g n e e   wit hi n  2 4  h o urs  of t h e  e v e nt  b ei n g  br o u g ht t o t h e  I n v esti g at ors’ or 
t h eir st affs’ att e nti o n.  It is  als o t h e r es p o nsi bilit y  of t h e  I n v esti g at or t o r e p ort  all  SA Es 
r e p ort e d  at t h eir sit e t o t h eir Instit uti o n al  R  e vi e  w  B  o ar d (I  R  B) ,  as r e q uir e d.  T h e  I n v esti g at or 
s h o ul d   m a k e  e v er y  att e  m pt t o f oll o  w  all  S  A Es t o r es ol uti o n.    
 
T h e f oll o  wi n g i nf or  m ati o n s h o ul d  b e  pr o vi d e d   w h e n  a n  S  A E is r e p ort e d t o   t h e s p o ns or  or 
d esi g n e e : 
1.    Pr ot o c ol   N u  m b er  
1.    Sit e   N u  m b er  
2.    S u bj e ct   N u  m b er  
3.    S u bj e ct   D e  m o gr a p hi c i nf or  m ati o n, i n cl u di n g:  
•     D at e  of   Birt h   
•     S e x  
•     R a c e   
4.    I n v esti g ati o n al  pr o d u ct st art  d at e 
5.    D at e  of l ast  d os e  of   i n v esti g ati o n al  pr o d u ct  
6.    D at e   i n v esti g ati o n al  pr o d u ct r ei niti at e d (if i n v esti g ati o n al  pr o d u ct i nt err u pt e d)  
7.    S  A E i nf or  m ati o n, i n cl u di n g:  
•     S  A E t er  m ( di a g n osis  o nl y; if  k n o  w n  or s eri o us si g ns/s y  m pt o  ms)  
•     D es cri pti o n  of  S  A E/ n arr ati v e   
•     D at e/ti  m e  of  o ns et   
•     S e v erit y  
•     O ut c o  m e   
•     D at e/ti  m e  of r es ol uti o n  or  d e at h (if  d ur ati o n  <  2 4  h o urs)   
•     R el ati o ns hi p t o   i n v esti g ati o n al  pr o d u ct 
•     A cti o n t a k e n   wit h   i n v esti g ati o n al  pr o d u ct 
8.    Crit eri a f or  cl assif yi n g t h e  e v e nt  as s eri o us, i n cl u di n g   w h et h er t h e   S A E  :   
•     R es ult  e d  i n  d e at h. 
•     W as    lif e-t hr e at e ni n g 
•     R e q uir e  d  i n p ati e nt  h os pit ali z ati o n. 
•     Pr ol o n g e d  i n p ati e nt  h os pit ali z ati o n. 
•     R es ult  e d  i n  a  p ersist e nt  or si g nifi c a nt i n c a p a cit y  or s u bst a nti al  disr u pti o n  of t h e 
a bilit y t o  c o n d u ct  n or  m al lif e f u n cti o ns.  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 5 8  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
•     W as    a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct  
•     I  m p ort a nt   m e di c al  e v e nts t h at   m a y  n ot r es ult i n  d e at h, w er e   n ot  lif e-t hr e at e ni n g,  or 
di d  n ot  r e q uir e  h os pit ali z ati o n   m a y  b e  c o nsi d er e d s eri o us   w h e n,  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, t h e y   m a y j e o p ar di z e t h e  p ati e nt  or 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  o ut c o  m es list e d i n 
t his  d efi niti o n.  E x a  m pl es  of s u c h   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.   
9.    C o n c o  mit a nt   m e di c ati o ns   
1 0.  R el e v a nt  hist or y   
1 1.  P ossi bl e  c a us es  of  S  A E  ot h er t h a n  i n v esti g ati o n al  pr o d u ct 
1 2.  C o p y  of   A E   p a g e fr o  m t h e  C  R F   
 
N  O  T  E  : If  a n  S  A E  o c c urs i n  a n y st u d y i n v ol vi n g K PI  -1 2 1  0. 2 5  %  o p ht h al  mi c s us p e nsi o n  t h at 
is  u n e x p e ct e d  a nd is  d et er  mi n e d t o  b e r el at e d  or  p ossi bl y r el at e d t o  i n v esti g ati o n al  pr o d u ct,  all 
sit es   will  b e  n otifi e d  b y t h e s p o ns or a n d  e a c h sit e  s h o ul d r e p ort it t o its I  R  B.   
 




K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 0  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
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,   m ost  c urr e nt  v e  rsi o n)  a n d  c at e g ori z e d  b y 
s yst e  m  or g a n  cl ass  usi n g  pr ef err e d t er  ms.    A Es   will  b e t a b ul at e d  b y st u d y  gr o u p   wit h r es p e ct 
t o t h eir  S e v erit y  a n d r el ati o ns hi p t o t h e i n v esti g ati o n al  pr o d u ct.    O p ht h al  m os c o p y fi n di n gs 
will  b e s u  m  m ari z e d  d es cri pti v el y.  I  O P   m e as ur  e  m e nts,   B  C  V  A  a n d   Bi o  mi cr os c o p y   will  b e 
s u  m  m ari z e d  as s af et y  o ut c o  m es .   
 
9. 2.         
S A   M P  L  E S I  Z  E E S  TI   M  A  TI  O  N  
 
A s a  m pl e si z e  of  7 1 i n  e a c h  gr o u p   will  h a v e  9 0  %  p o  w er t o  d et e ct  a n  eff e ct si z e  of          usi n g  a 
2 -gr o u p  t-t est   wit h  a         2 -si d e d si g nifi c a n c e l e v el . 
 
9. 3.         
L E  V  E  L   O F S I  G  NI FI  C  A  N  C  E 
 
T h e  pri  m ar y  ass ess  m e nt  of t h e  d os e -r es p o ns e will  b e  e v al u at e d  usi n g  a  5  % l e v el  of 
si g nifi c a n c e.  Si n c e  b ot h  c o -pri  m ar y  e n d p oi nts   will  b e r e q uir e d t o  b e si g nifi c a nt  at t h e  0. 0 5 
l e v el, t h er e is  n o  a dj ust  m e nt  n e e d e d f or   m ulti pl e  c o  m p aris o ns. 
 
All  ot h er r e p ort e d   p -v al u es   will  b e  c o nsi d er e d  d es cri pti v e  a n d  h y p ot h esis  g e n er ati n g.  
 
9. 4.         
P R  O  C  E  D  U  R  E  F  O  R A C  C  O  U  N  TI  N  G  F  O  R M
I S SI  N  G, U N  U S  E  D , O  R S P  U  RI  O  U S D A  T  A  
 
A n y   missi n g,  u n us e d,  or s p uri o us  d at a   will  b e  n ot e d i n t h e fi n al  cli ni c al st u d y r e p ort.    M ulti pl e 
i  m p ut ati o ns will  b e  e  m pl o y e d t o  a n al y z e i n c o  m pl et e  d at a s ets  u n d er t h e  ass u  m pti o n t h at 
missi n g  d at a  ar e,  at   w orst,  c h ar a ct eri z e d  as   missi n g  at r a n d o  m (  M  A  R).   T h e r e as o ns f or 
missi n g  d at a   will  b e r e c or d e d  a n d t h e i  m p a ct  of t h es e r e as o ns  a n d  a n y tr e at  m e nt  gr o u p 
i  mb al a n c e  o n t h e  ass u  m pti o n  of   M  A  R   will  b e  e v al u at e d.  I  m p ut ati o n   will  b e  c arri e d  o ut  o nl y 
o n t h e  c o -pri  m ar y  e n d p oi nts  a n d ti  m e  p oi nts.  
 
9. 5.         
P R  O  C  E  D  U  R  E  F  O  R R E P  O  R  TI  N  G D E  VI  A  TI  O  N S  F  R  O   M   T  H  E S T  A  TI S  TI  C  A  L P L  A  N  
 
A n y  d e vi ati o ns fr o  m t h e st atisti c al  a n al ysis  pl a n   will  b e  d es cri b e d  a n d  a j ust  ifi c ati o n  gi v e n i n 
t h e fi n al  cli ni c al st u d y r e p ort. 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 1  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 0.         
D  I  R  E  C  T A  C  C  E S S   T  O   S O  U  R  C  E   D  A  T  A/  D  O  C  U   M  E  N  T S   
 
T h e  I n v esti g at or will  p er  mit tri al  -r el at e d   m o nit ori n g,  a u dits, I  R  B r e vi e  w,  a n d r e g ul at or y 
i ns p e cti o n(s)  b y  pr o vi di n g  dir e ct  a c c ess t o s o urc e  d at a  a n d  d o c u  m e nts (s u c h  as t ests 
p erf or  m e d  as  a r e q uir e  m e nt f or  p arti ci p ati o n i n t h e st u d y  a n d  ot h er   m e di c al r e c or ds r e q uir e d 
t o  c o nfir  m i nf or  m ati o n  c o nt ai n e d i n t h e  c as e r e p ort f or  m s u c h  as   m e di c al  hist or y) t o t h e 
m o nit or.   


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 2  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 1.         
Q  U  A  LI  T  Y   C  O  N  T  R  O  L   
 
T h e  pr o gr ess  of t h e st u d y   will  b e   m o nit or e d  b y  o n -sit e,   writt e n,  e-m ail  , a n d t el e p h o n e 
c o  m  m u ni c ati o ns  b et  w e e n  p ers o n n el  at t h e st u d y  c e nt er  a n d  t h e s p o ns or ( or  d esi g n at e d 
m o nit or).   T h e   I n v esti g at or will  all o  w   K al a  P h ar  m a c e uti c als  , I n c.   m o nit ors  or  d esi g n e e t o 
i ns p e ct  all C  R Fs  ; su bj e ct  r e c or ds (s o ur c e  d o c u  m e nts); si g n e d i nf or  m e d  c o ns e nt f or  ms; HI P  A  A 
a ut h ori z ati o ns;  r e c or ds  of i n v esti g ati o n al  pr o d u ct r e c ei pt, st or a g e,  a n d  dis p ositi o n; a n d 
r e g ul at or y fil es r el at e d t o t h e st u d y. 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 3  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 2.         
E  T  HI  C S   
1 2. 1.         I nstit uti o n al   R e vi e  w   B o a r d  
 
T his  pr ot o c ol  a n d t h e i nf or  m e d  c o ns e nt f or  m   m ust  b e  a p pr o v e d  b y  a n  a p pr o pri at e l y 
c o nstit ut e d  a n d  q u alifi e d  I  R  B  a n d t h e  a p pr o v als   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 
pri or t o t h e st art  of  e nr oll  m e nt i nt o t h e st u d y.    M at eri als  us e d t o r e cr uit  s u bj e cts   will  b e 
a p pr o v e d  b y t h e  a p pr o pri at e I  R  B  a n d t h e  a p pr o v als   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 
pri or t o t h eir  us e. I n  a d diti o n, t h e  I n v esti g at or’s   Br o c h ur e s h o ul d  b e s u b  mitt e d t o t h e I  R  B.  
Writt e n I  R  B  a p pr o v al   m ust  a d e q u at el y i d e ntif y t h e  pr ot o c ol  a   n d i nf or  m e d  c o ns e nt f or  m.  
C o pi es  of  all  a p pr o v e d   m at eri als,  all  c orr es p o n d e n c e   wit h t h e I  R  B,  a n d   writt e n  a p pr o v al fr o  m 
t h e I  R  B   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 at e d   m o nit or). 
 
A n y   m o difi c ati o n  of st u d y  pr o c e d ur es  or  a  m e n d  m e nts t o t h e  pr ot o c  ol   m ust  b e  a p pr o v e d  b y t h e 
I  R  B  pri or t o i  m pl e  m e nt ati o n.  I n t h e  e v e nt t h at  a   m o difi c ati o n  or  a  m e n d  m e nt is  c o nsi d er e d  b y 
t h e I n v esti g at or t o  b e i  m  m e di at el y  n e c ess ar y t o  e ns ur e s u bj e ct s af et y, t h e I n v esti g at or will 
pr o  m ptl y  n otif y  his  or  h er  I  R  B  a n d t h e s p o ns or. 
 
I n v esti g at ors   will r e p ort  all  S  A Es r e p ort e d  at t h eir sit e t o t h eir I  R  B,  as  a p pr o pri at e.    
 
1 2. 2.         I nf o r  m e d   C o ns e nt   R e q ui r e  m e nts  
 
Writt e n i nf or  m e d  c o ns e nt   will  b e  o bt ai n e d fr o  m  e a c h  p arti ci p a nt  pri or t o  a n y st u d y   -r el at e d 
pr o c e d ur es  b ei n g  p erf or  m e d  (pri or t o  or  u p o n   Visit  1 - S cr e e ni n g) .    A  c o p y  of t h e si g n e d  a n d 
d at e d  i nf or  m e d c o ns e nt  d o c u  m e nt   will  b e  gi v e n t o  e a c h s u bj e ct.   T h e  ori gi n al si g n e d  a n d 
d at e d i nf or  m e d  c o ns e nt  d o c u  m e nt   m ust  b e   m ai nt ai n e d i n t h e st u d y fil es  at t h e i n v esti g ati v e 
sit e  a n d  b e  a v ail a bl e f or s p o ns or  or  d esi g n e e r e vi e  w. 
 
E a c h i nf or  m e d  c o ns e nt   will  c o nt ai n  I n v esti g at or c o nt a ct i nf or  m ati o n   wit h  a t el e p h o n e  n u  m b er 
t h e s u bj e ct or t h e  s u bj e ct’s  a ut h ori z e d r e pr es e nt ati v e  c a n  c all  2 4  h o urs  a  d a y if t h e y  h a v e 
m e di c al  c o n c er ns.    


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 4  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 3.         
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   
 
All  pr o c e d ur es f or t h e  h a n dli n g  a n d  a n al ysis  of  d at a   will  b e  c o n d u ct e d  usi n g   G  C P   a n d  will   
m e et   I  C  H  g ui d eli n es  a n d   U S F  D  A  r e g ul ati o ns f or t h e  h a n dli n g  a n d  a n al ysis  of  d at a f or 
cli ni c al tri als.  
 
1 3. 1.         D at a   Q u alit y   C o nt r ol  a n d   R e p o rti n g   
 
Aft er  d at a  h a v e  b e e n  e nt er e d i nt o t h e st u d y  d at a b as e,  a s yst e  m  of  c o  m p ut eri z e d  d at a  v ali d ati o n 
c h e c ks   will  b e i  m pl e  m e nt e d  a n d  a p pli e d t o t h e  d at a b as e.    Q u er y r e p orts  p ert ai ni n g t o  d at a 
o  missi o ns  a n d  dis cr e p a n ci es   will  b e f or  w ar d e d t o t h e  cli ni c al  I n v esti g at or a n d   m o nit or(s) f or 
r es ol uti o n.   T h e st u d y  d at a b as e   will  b e  u p d at e d i n  a c c or d a n c e   wit h t h e r es ol v e d  q u er y r e p orts.  
All  c h a n g es t o t h e st u d y  d at a b as e   will  b e  d o c u  m e nt e d.   
 
1 3. 2.         R e c o r ds   R et e nti o n   
 
T h e st u d y  c e nt er   will r et ai n  all r e c or ds r el at e d t o t h e st u d y i n  a c c or d a n c e   wit h l o c al  a n d I  C  H 
G  C P  g ui d eli n es.   
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 5  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 4.         
P  U  B  LI  C  A  TI  O  N  P O  LI  C  Y   
 
T h e i nstit uti o n  a n d  I n v esti g at ors  p arti cip ati n g i n t his tri al s h all  h a v e  n o ri g ht t o  p u blis h  or 
pr es e nt t h e r es ults  of t his st u d y   wit h o ut t h e  pri or   writt e n  c o ns e nt  of  t h e s p o ns or. 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 6  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 5.         
R  E F  E  R  E  N  C  E S     
 
1.    G e erli n g   G,  T a u b er J,   B a u d o ui n   C,  et  al.  T h e I nt  er n ati o n al    W or ks h o p  o n   M ei b o  mi a n 
Gl a n d   D ysf u n cti o n:   R e p ort  of t h e s u b c o  m  mitt e e  o n   m a n a g e  m e nt  a n d tr e at  m e nt  of 
m ei b o  mi a n  gl a n d  d ysf u n cti o n.   I n v est   O p ht h al  m ol  Vis  S ci.  2 0 1 1; 5 2( 4): 2 0 5 0-2 0 6 4. 
d oi: 1 0. 1 1 6 7/i o vs. 1 0 -6 9 9 7 g.  
 
2.    D E   W S   R e p ort.   T h e  d efi niti o n  a n d  cl assifi c ati o n  of  dr y  e y e  dis e as e .;  2 0 0 7: 7 5-9 2. 
A v ail a bl e  at:  htt p://  w  w  w.s ci e n c e dir e ct. c o  m/s ci e n c e/ arti cl e/ pii/ S 1 5 4 2 0 1 2 4 1 2 7 0 0 8 1 2. 
A c c ess e d   A pril  2 9,  2 0 1 4.   
 
3.    F o ul ks   G  N,   B or c h  m a n   D,   Y a p p ert   M,  S u n g -H y e   K,   M c  K a y J   W.  T o pi c al  a zit hr o  m y ci n 
t h er a p y  of   m ei b o  mi an  gl a n d  d ysf u n cti o n:   Cli ni c al r es p o ns e  a n d li pi d  alt er ati o ns.  C or n e a  . 
2 0 1 0; 2 9( 7): 7 8 1 -7 8 8.  d oi: 1 0. 1 0 9 7/I  C  O. 0 b 0 1 3 e 3 1 8 1 c d a 3 8f.  
 
4.    St e v e ns o n    W,   C h a u h a n  S  K,   D a n a   R.   Dr y  e y e  dis e as e:   A n i  m  m u n e -m e di at e d  o c ul ar 
s urf a c e  dis or d er.  Ar c h   O p ht h al  m ol .  2 0 1 2; 1 3 0( 1): 9 0-1 0 0. 
d oi: 1 0. 1 0 0 1/ ar c h o p ht h al  m ol. 2 0 1 1. 3 6 4.  
 
5.    L a n e  S S,   H oll a n d  EJ.  L ot e pr e d n ol  et a b o n at e  0. 5  %  v ers us  pr e d nis ol o n e  a c et at e  1. 0  % f or 
t h e tr e at  m e nt  of i nfl a  m  m ati o n  aft er  c at ar a ct s ur g er y. J   C at ar a ct  R efr a ct  S ur g . 
2 0 1 3; 3 9( 2): 1 6 8 -1 7 3.  d oi: 1 0. 1 0 1 6/j.j crs. 2 0 1 2. 1 0. 0 3 9.  
 
6.   
 
 
 
7.    Br o n   AJ,  E v a ns   V E,  S  mit h J  A.   Gr a di n g  of   c or n e al  a n d  c o nj u n cti v al st ai ni n g i n t h e  c o nt e xt 
of  ot h er  dr y  e y e t ests.  C or n e a  .  2 0 0 3; 2 2( 7): 6 4 0-6 5 0.  
 
8.    L e  m p   M  A.   R e p ort  of t h e   N ati o n al  E y e I nstit ut e/I n d ustr y   w or ks h o p  o n   Cli ni c al  Tri als i n 
Dr y  E y es.   C L A  O  J   Off  P u bl   C o nt a ct  L e ns  Ass o c   O p ht h al  m ol I n c  .  1 99 5; 2 1( 4): 2 2 1 -2 3 2.  
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L         
 
P A  G  E 6 7  O F 8 5  
0 3  N O  V   2 0 1 5  
C  O  N FI  D  E  N  TI  A  L   
1 6.         
A  P P  E  N  DI  C  E S  
 
 
 






K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 0  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 2 :  S U  B J  E  C  T -R A  T  E  D O C  U  L  A  R D I S  C  O   M F  O  R  T A S S  E S S   M  E  N  T  
S u bj e cts   will  b e  as k e d t o s u bj e cti v el y r at e t h eir  o c ul ar  dis c o  mf ort s e v erit y  a n d fr e q u e n c y  at 
Visits  1  -6.   Sit e  p ers o n n el  will  as k t h e s u  bj e ct t h e f oll o  wi n g  q u esti o n  a n d r e c or d t h eir  a ns  w er 
i n t h e  e  C  R F.   
 
S e v e rit y  of  S y  m pt o  ms  
 
O n  a v er a g e  o v er t h e  p ast  d a y,  h o  w   w o ul d  y o u r at e t h e s e v erit y  of  y o ur  o c ul ar  dis c o  mf ort 
(s u c h  as irrit ati o n,  dr y n ess,  b ur ni n g, fl u ct u ati n g  visi o n  at  n e ar t as ks) ? 
 
0  =     N o n e   
1  =     Mil d   
2  =     M o d er at e   
3  =     S e v er e  
4  =     V er y  S e v er e   
 
F r e q u e n c y  of  S y  m pt o  ms  
 
O n  a v er a g e  o v er t h e  p ast  d a y,  h o  w  oft e n  h a v e  y o u  h a d t his l e v el  of  o c ul ar  dis c o  mf ort (s u c h  as 
irrit ati o n,  dr y n ess,  b ur ni n g, fl u ct u ati n g  visi o n  at  n e ar t as ks) ? 
 
0  =     N e v er   
1  =     S o  m eti  m es  
2  =     Oft e n   
3  =     C o nst a ntl y   
 
 
 
 
  
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 1  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 3 :  
 
 
S u bj e cts   will  b e  as k e d t o s u bj e cti v el y r at e t h eir  o c ul ar  dis c o  mf ort s e v erit y  a n d fr e q u e n c y  at 
Visit  1 f or  eli gi bilit y.  
 
 
 
T h e  l e n gt h  of t h e li n e  b et  w e e n t h e         
 st arti n g  p oi nt  a n d t h e first  p oi nt   w h er e t h e 
s u bj e ct’s   m ar k  cr oss es t h e li n e   will  b e   m e as ur e d  a n d r e c or d e d i n   milli  m et ers.  
 
 S E  V  E  RI  T  Y A S S  E S S   M  E  N  T  
 
Pl e as e  pl a c e  a si n gl e li n e  a cr oss t h e li n e  b el o  w t o i n di c at e  h o  w  s e v er e, 
 
  y o u f e el  y o ur  e y e  dis c o  mf ort (f or  e x a  m pl e, irrit ati o n,  dr y n ess, 
b ur ni n g,  or fl u ct u ati n g  visi o n  d uri n g r e a di n g  or  c o  m p ut er  us e)   w as:  
 
                                                                                                               
 
 
 
          
 F R  E  Q  U  E  N  C  Y A S S  E S S   M  E  N  T  
 
Pl e as e  pl a c e  a si n gl e li n e  a cr oss t h e li n e  b el o  w t o i n di c at e  h o  w  oft e n , 
 
  y o u f e el  y o ur  e y e  dis c o  mf ort (f or e x a  m pl e, irrit ati o n,  dr y n ess, 
b ur ni n g,  or fl u ct u ati n g  visi o n  d uri n g r e a di n g  or  c o  m p ut er  us e )   w as: 
 
           
                                                                                                                
 
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 2  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 4 :  IN  V  E S  TI  G  A  T  O  R -R A  T  E  D A S S  E S S   M  E  N  T   O F S I  G  N S O F M  G  D    
 
E y eli d    M a r gi n   H y p e r e  mi a (l o  w e r  e y eli d):   
0  =     N or  m al        
N or  m al  a g e- a p pr o pri at e r e d n ess  a n d  v as c ul at ur e.   
1  =     Mil d          
Sli g htl y  dil at e d  bl o o d  v ess els;  v ess els  c ol or e d  pi n k,  pr es e nt i n  gr e at er 
t h a n  2 5  %  of t h e l o  w er  e y eli d   m ar gi n 
2  =     M o d er at e        
M or e  a p p ar e nt  dil ati o n  of  bl o o d  v ess els;  v ess els r e d,  pr es e nt i n 
gr e at er t h a n  2 5  %  of t h e l o  w er  e y eli d   m ar gi n.  
3  =     S e v er e        
I n cr e as e d  v as c ul arit y  of t h e  e y eli d   m ar gi n;  n u  m er o us  a n d  o b vi o us 
dil at e d  bl o o d  v ess els,  d e e p r e d i n  c ol or,  pr es e nt i n  gr e at er t h a n  2 5 % 
of t h e l o  w er  e y eli d   m ar gi n. 
4  =     V er y  S e v er e        Cl e arl y i n cr e as e d  v as c ul arit y  of t h e  e y eli d   m ar gi n;  n u  m er o us  dil at e d 
bl o o d  v ess els  d e e p r e d  c ol or,  pr es e nt i n  gr e at er t h a n  7 5  %  of t h e l o  w er 
e y eli d   m ar gi n.  
 
C h a r a ct e r  of    M ei b o  mi a n   Gl a n d   C o nt e nt (  1 0  gl a n ds i n  t h e   mi d dl e  p a rt  of l o  w e r li d) 
0  =     N or  m al          
Cl e ar li q ui d   
1  =     Mil d          
H a z y, t ur bi d li q ui d   
2  =     M o d er at e          T ur bi d li q ui d   wit h  cl u  m ps  
3  =     S e v er e        
S oli d ( p ast e)  
4  =     N o  gl a n ds  e x pr essi bl e   
T h e   m ost s e v e r e fi n di n g i n  a n y  o n e   m ei b o  mi a n  gl a n d s h o ul d  b e  r e c o r d e d f o r   t his 
e v al u ati o n  
 
E x p r essi bilit y  of    M ei b o  mi a n   Gl a n d (  1 0  gl a n ds i n t h e  mi d dl e  p a rt  of l o  w e r li d)   
0  =     N or  m al        
9  –  1 0  gl a n ds  e x pr essi bl e  
1  =     Mil d          
6  –  8  gl a n ds  e x pr essi bl e  
2  =     M o d er at e          3  –  5  gl a n ds  e x pr essi bl e  
3  =     S e v er e        
1  –  2  gl a n ds  e x pr essi bl e  
4  =     N o  gl a n ds  e x pr essi bl e 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 3  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 5 :  IN  V  E S  TI  G  A  T  O  R -R A  T  E  D A S S  E S S   M  E  N  T   O F B U  L  B  A  R C O  N J  U  N  C  TI  V  A  L H Y P  E  R  E   M I  A  
I n v esti g at ors   will r at e  b ul b ar  c o nj u n cti v al  h y p er e  mi a  at   Visits  1,  2,  4,  a n d  6  usi n g t h e   C or n e a 
a n d   C o nt a ct  L e ns   R es e ar c h   U nit  (  C  C L  R  U). 
 
 
 
0  =     N o n e 
1  =     V er y  Sli g ht 
2  =     Sli g ht 
3  =     M o d er at e 
4  =     S e v er e 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 4  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A p p e n di x   6 :    U n a n est h eti z e d  S c hi r  m e r   T est  
 
U n a n est h eti z e d  S c hir  m er  T est   will  b e  c o n d u ct e d  at   Visit  1.     
I d e nti c al  S c hir  m er  T est stri ps   will  b e s u p pli e d t o  e a c h sit e.   
 
U n a n est h eti z e d  S c hi  r  m e r   T est  
•     W hil e still i n t h e  pl asti c s h e at h, f ol d t h e  n ot c h e d  e n d  of t h e  u n a n est h eti z e d 
S c hir  m er  T est  at t h e  a p e x  of  “ v ”.    A d diti o n all y, f ol d  a  p arti al s e c o n d f ol d  at t h e 
h alf  w a y  p oi nt  of t h e stri p s o t h at t h e stri p  d o es  n ot li e  dir e ctl y i n t h e s u bj e ct’s li n e 
of si g ht.  
•     R e  m o v e t h e ri g ht  e y e stri p fr o  m t h e s h e at h.  
•     As k t h e s u bj e ct t o l o o k  u p  a n d  g e ntl y  dr a  w t h e ri g ht l o  w er li d i n  a  d o  w n  w ar d  a n d 
t e  m p or al  dir e cti o n.  
•     Pl a c e t h e r o u n d e d  e n d  of t h e stri p t o  w ar d t h e t e  m p or al  o n e -t hir d  of t h e l o  w er 
e y eli d.  
•     R e p e at t his  pr o c e d ur e i n t h e l eft  e y e.  
•     D ar k e n t h e r o o  m,  b ut  e ns ur e t h at t h e  L ar g e  E   of  t h e  E T  D  R S  c h art is  visi bl e. 
•     I nstr u ct t h e s u bj e ct t o r el a x  a n d l o o k  at t h e  c h art   w hil e  bli n ki n g n or  m all y  or  h a v e 
p ati e nts  g e ntl y  cl os e  e y es.  
•     R e  m o v e s  tri ps  aft er  5   mi n ut es. 
•     Aft er r e  m o vi n g t h e stri ps,   wit h  a s h ar p  p e n cil  dr a  w  a  h ori z o nt al li n e  a cr oss t h e 
l e a di n g  e d g e  of   m oist ur e  a n d  a s e c o n d  h ori z o nt al li n e  a cr oss t h e l o  w est  p oi nt  of 
m oist ur e.  
•     Usi n g  a   r ul er  a n d/ or t h e   milli  m et ers r e c or d e d  o n t h e stri ps,   m e as ur e  a  p oi nt 
h alf  w a y  b et  w e e n t h e  2 li n es  a n d r e c or d t his  as t h e  a  m o u nt  of   w etti n g.  
 
 
 
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 5  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 7 :  E  T  D  R S  B E S  T C O  R  R  E  C  T V I S  U  A  L A C  UI  T  Y  
 
B  C  V  A   will  b e  c o n d u ct e d  at   Visits   1,  2,  4  a n d  6.    
 
Vis u al  a c uit y t esti n g s h o ul d  pr e c e d e  a n y  e x a  mi n ati o n r e q uiri n g  c o nt a ct   wit h t h e  e y e  or 
i nstill ati o n  of st u d y  d y es.   L o g  M  A  R  vis u al  a c uit y   m ust  b e  ass ess e d  usi n g  a n  E T  D  R S  or 
m o difi e d  E T  D  R S  c h art.    Vis u al  a c uit y t esti n g s h o ul d  b e  p erf or  m e d   w  it h  b est  c orr e cti o n  usi n g 
s u bj e ct’s  o  w n  c orr e cti v e l e ns es (s p e ct a cl es  o nl y)  or  pi n h ol e r efr a cti o n.  
 
A n  E T  D  R S  or   m o difi e d  E T  D  R S  c h art   m a y  b e  us e d.  If  a  Li g ht h o us e  c h art is  us e d ( 2 4. 5 ”  b y 
2 5 ”;  eit h er r efl e ct a n c e  or r etr o -ill u  mi n at e d), t h e s u bj e ct   m ust  vi e  w t h e  c h art fr o  m  a  dist a n c e  of 
e x a ctl y  4   m et ers ( 1 3. 1 f e et).  If s  m all er r e pr o d u cti o ns ( 1 8 ”  b y  1 8 ”,  e. g.,  Pr e v e nt   Bli n d n ess)  ar e 
us e d, t h e s u bj e ct  vi e  wi n g  dist a n c e s h o ul d  b e  e x a ctl y  1 0 f e et.    R efl e ct a n c e   w all  c h arts s h o ul d 
b e fr o nt all y ill u  mi n at e d ( 6 0   w att  b ul b  or  a   w ell -lit r o o  m). 
 
T h e s u bj e ct s h o ul d  b e  p ositi o n e d  a c c or di n g t o t h e  el e v ati o n  of t h e  c h art ( eit h er s e at e d  or 
st a n di n g) s o t h at t h e  c h art is  at  a  c o  mf ort a bl e  vi e  wi n g  a n gl e.   T h e ri g ht  e y e s h o ul d  b e t est e d 
first.   T h e s u bj e ct s h o ul d  att e  m pt t o r e a d  ea c h l ett er, li n e -b y -li n e, l eft t o ri g ht,  b e gi n ni n g   wit h 
li n e  1  at t h e t o p  of t h e  c h art.   T h e s u bj e ct s h o ul d  b e t ol d t h at t h e  c h art  h as l ett ers  o nl y,  n o 
n u  m b ers.  If t h e s u bj e ct r e a ds  a  n u  m b er,  h e  or s h e s h o ul d  b e r e  mi n d e d t h at t h e  c h art  c o nt ai ns 
n o  n u  m b ers ,  a n d t h e  e x a  mi n er s h o ul d t h e n r e q u est  a l ett er i nst e a d  of t h e  n u  m b er.   T h e s u bj e ct 
s h o ul d  b e  as k e d t o r e a d sl o  wl y,  a b o ut  1  l ett er  p er s e c o n d, t o  a c hi e v e t h e  b est i d e ntifi c ati o n  of 
e a c h l ett er.    H e/s h e is  n ot t o  pr o c e e d t o t h e  n e xt l ett er  u ntil  h e/s h e  h as  gi v e n  a  d efi nit e 
r es p o ns e.  If t h e s u bj e ct  c h a n g es  a r es p o ns e  b ef or e  h e  h as r e a d  al o u d t h e  n e xt l ett er, t h e n t h e 
c h a n g e   m ust  b e  a c c e pt e d.  
 
M a xi  m u  m  eff ort s h o ul d  b e   m a d e t o i d e ntif y  e a c h l ett er  o n t h e  c h art   ; t h e s u bj e ct s h o ul d  b e 
e n c o ur a g e d  t o  g u ess.     W h e n it b e c o  m es  e vi d e nt t h at  n o f urt h er   m e a ni n gf ul r e a di n gs  c a n  b e 
m a d e, t h e  e x a  mi n er s h o ul d st o p t h e t est.   T h e  n u  m b er  of l ett ers   miss e d  or r e a d i n c orr e ctl y 
s h o ul d  b e  n ot e d. 
 
I n  o r d e r t o  p r o vi d e st a n d a r di z e d  a n d   w ell -c o nt r oll e d  ass ess  m e nts  of  vis u al  a c uit y  d u r i n g 
t h e st u d y,  c o nsist e ntl y  us e t h e s a  m e li g hti n g  c o n diti o ns t h r o u g h o ut t h e st u d y. 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 6  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
C al c ul ati o ns  :  l o g  M  A  R   V  A  =   B as eli n e  v al u e  + ( n   X  0. 0 2) 
w h er e:          
t h e  b as eli n e  v al u e is t h e l o g  M  A  R  n u  m b er  of t h e l ast li n e r e a d ( at l e ast 1  l ett er 
r e a d  c orr e ctl y i n t his li n e), a n d  
“ n ” is t h e t ot al  n u  m b er  of l ett ers   miss e d  u p t o  a n d i n cl u di n g t h e l ast li n e r e a d, 
a n d   
“ 0. 0 2 ” is t h e  v al u e f or  e a c h l ett er  


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 7  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 8 :  S LI  T L A   M P B I  O   M I  C  R  O S  C  O P  Y 
 
T h e  bi o  mi cr os c o p y  e x a  m   wi ll  b e  p erf or  m e d  at   Visits  1,  2,  4  a n d  6.  It s h o ul d  b e  p erf or  m e d 
wit h t h e slit l a  m p  usi n g  a  b e a  m   wi dt h  a n d i nt e nsit y   t h at pr o vi d e  o pti  m al  e v al u ati o n  of  t h e 
a nt eri or s e g  m e nt.  
 
T his  pr o c e d ur e   will  b e t h e  p erf or  m e d i n t h e s a  m e   m a n n er f or  all s u bj e cts  o bs er v e d   at t h e 
I n v esti g at or’s sit e.   
 
L as h es    
             0  =   N or  m al  
             1  =   A b n or  m al  
 
E y eli d   
E d e  m a         
             0  =   N or  m al,  n o s  w elli n g  of t h e li d tiss u e  
             1  =   A b n or  m al  
 
C o nj u n cti v a   
E d e  m a    
              0  =   N or  m al,  n o s  w elli n g  of t h e  c o nj u n cti v a  
              1  =   A b n or  m al  
      P al p e br al   C o nj u n cti v al  Er yt h e  m a  
        
0  =   N or  m al ,  n o r e d n ess  of t h e  c o nj u n cti v a 
        
1  =   A b n or  m al  
 
C o r n e a   
I nfiltr at es 
             0  =   A bs e nt  
             1  =  Pr es e nt  
E n d ot h eli al   C h a n g es  
             0  =   N or  m al,   N o n e  
             1  =   A b n or  m al,  pi g  m e nt,  k er at o pr e ci pit at es,  g utt at a  
      E d e  m a  
             0  =   N or  m al   N o n e, tr a ns p ar e nt  a n d  cl e ar  
             1  =   A b n or  m al  
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 8  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A nt e ri o r   C h a  m b e r   
      C ells   
             0  =   N or  m al,   N o  c ells s e e n  
             1  =   A b n or  m al ( + t o  + + +  c ells)  
      Fl ar e  
             0  =   N or  m al,   N o  T y n d all  eff e ct  
             1  =   A b n or  m al,  T y n d all  b e a  m i n t h e  a nt eri or  c h a  m b er  
 
L e ns  P at h ol o g y       
 0  =   N or  m al;  n o  o p a cit y i n t h e l e ns  
 1  =   A b n or  m al;  e xisti n g  o p a cit y i n t h e l e ns;  a p h a ki c  or  ps e u d o p h a ki c  e y es  or  ot h er   
                  a b n or  m al fi n di n gs.  
 
S cl e r a  
I nj e cti o n 
            0  =   N or  m al,   wit h o ut  a n y r e d n ess   
            1  =   A b n or  m al  
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 7 9  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 9 :  C O  R  N  E  A  L F L  U  O  R  E S  C  EI  N S T  AI  NI  N  G  
 
C or n e al st ai ni n g   will  b e  p erf or  m e d  at   Visit  1,  2,  4,  a n d  6.    C or n e al st ai ni n g  ass ess  m e nt   will  b e 
p erf or  m e d  usi n g   m et h o ds  d e v el o p e d  b y t h e   N ati o n al  E y e I nstit ut es (  N EI)   Dr y  E y e 
W or ks h o p
7, 8. 
 
E v al u ati o n   T e c h ni q u e   
1.    Pl a c e   m a g nifi c ati o n  at  1 6 x   
2.    Us e  a  y ell o  w  b arri er filt er (   Wr att e n  or  Tiff e n  # 1 1  or  # 1 2)    
3.    Pl a c e  5  µ l  of  n o n-pr es er v e d,  2  % fl u or es c ei n i nt o  e y e  usi n g  a  2 -2 0 µl   mi cr o pi p ett e fitt e d 
wit h  a  cl e a n  pi p ett e ti p.   
4.    G e ntl y t o u c h t h e  dr o p  at t h e ti p t o t h e l o  w er  p al p e br al  c o nj u n cti v a  of t h e ri g ht  e  y e.   
5.    I n  or d er t o t h or o u g hl y   mi x t h e fl u or es c ei n   wit h t h e t e ar fil  m,  as k t h e s u bj e ct t o  bli n k 
s e v er al ti  m es  a n d   m o v e  his/ h er  e y e  ar o u n d.   
6.    W ait  2. 5   mi n ut es t o  ass ess  c or n e a    
7.    M e as ur e st ai ni n g  u n d er   C o b alt  bl u e li g ht ( 4 6 5  n  m t o  4 9 0  n  m)    
8.    C o  m p ar e st ai ni n g   wit h st a  n d ar d   wit h s c ori n g i n  e a c h  of  5  ar e as  of t h e  5  c or n e al 
s e cti o ns  as  d es cri b e d  b el o  w:  
 
S c o ri n g s yst e  m  
1.    Gr a d e  e a c h  of  5 s e cti o ns  of  c or n e a (s u p eri or, i nf eri or,  n as al, t e  m p or al,  c e ntr al)   
2.    Pr o vi d e  gr a d es f or  e a c h  of t h e  5 s e cti o ns:  
a.    Gr a d e  b y   N EI s c al e ( d efi niti o n   b el o  w)  as  0,  1 (  mil d),  2 (  m o d er at e),  3 (s e v er e)  
3.    T ot al s c or e is  o bt ai n e d  b y s u  m  mi n g  e a c h  of t h e  5 s e cti o ns  of t h e  c or n e a   
a.    N EI s c or e   will  b e fr o  m  0  -1 5  
4.    D efi niti o ns   
a.    N EI  S c ori n g  S yst e  m ( 0,  1,  2,  3)   
i.   Gr a d e  0   
N o  visi bl e st ai ni n g   wit hi n t h e s e cti o n  of  c or n e a  b ei n g  e  v al u at e d  
ii.   Gr a d e  1       MI L  D   
S  m all  a  m o u nt  of   mi cr o p u n ct at e st ai ni n g   wit hi n t h e s e cti o n  of  c or n e a 
b ei n g  e v al u at e d  
iii.   Gr a d e  2       M  O  D E  R  A T E   
M e di u  m  a  m o u nt  of   mi cr o p u n ct at e st ai ni n g   wit hi n t h e s e cti o n  of  c or n e a 
b ei n g  e v al u at e d  or   mil d  a  m o u nt  of   m a cr o p u n ct at e st ai n  
i v.   Gr a d e  3       S E  V E  R E  
Si g nifi c a nt  a  m o u nt  of   mi c o p u n ct at e   or   m a cr o p u n ct at e st ai ni n g   wit hi n 
t h e s e cti o n  of  c or n e a  b ei n g  e v al u at e d 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 0  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
 
                                           


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 1  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 1 0 :  I  O P M
E  A S  U  R  E   M  E  N  T  
 
I  O P   m e as ur e  m e nts   will  b e  p erf or  m e d  utili zi n g   G ol d  m a n n  a p pl a n ati o n t o n o  m et er y  a c c or di n g 
t o t h e I n v esti g at or’s st a n d ar d  pr o c e d ur e.    All  pr ess ur es will  b e r e c or d e d i n   m  m  H g.  I  O P 
ass ess  m e nts   will  o c c ur  at st u d y   Visits  1,  2,  4,  a n d  6.  
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 2  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 1 1 :  D I  L  A  T  E  D O P  H  T  H  A  L   M  O S  C  O P  Y  
 
Dil at e d  o p ht h al  m os c o p y   will i n cl u d e  ass ess  m e nt  of t h e  o pti c  n er v e  h e a d f or  p all or  a n d 
c u p pi n g ( c u p t o  dis c r ati o),  a n d   will  b e  p erf or  m e d  at   Visit  1  a n d   Visit  6.    Aft er t h e 
o p ht h al  m os c o p y  pr o c e d ur e, t h e I n v esti g at or   will  d et er  mi n e if fi n di n gs  ar e   wit hi n  n or m al 
li  mits  or  ar e  a b n or  m al.   F or  a b n or  m al fi n di n gs  at   Visit  1, t h e I n v esti g at or   will  d et er  mi n e 
w h et h er  or  n ot t h e  a b n or  m alit y   w o ul d  e x cl u d e s u bj e ct fr o  m st u d y  p arti ci p ati o n.     
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 3  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 4  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
        
 
 
 
 
 
 
 
 
 


K PI  -1 2 1 -C  -0 0 3  C LI  NI  C  A  L P R  O  T  O  C  O  L FI  N  A  L          
P A  G  E 8 5  O F 8 5  
0 3  N O  V   2 0 1 5  
 
 
A P P  E  N  DI  X 1 4 :  T E  A  R F I  L   M B R  E  A  K -U P T I   M  E 
 
T his  ass ess  m e nt s h o ul d  b e  p erf or  m e d  b y  b ot h t h e i n v esti g at or  a n d  a n i n di vi d u al t o r e c or d 
ti  m es. 
  
•     P erf or  m t h e  e x a  mi n ati o n   wit h t h e slit l a  m p  at  1 6  X   m a g nifi c ati o n  a n d  c o b alt  bl u e 
ill u  mi n ati o n. 
•     Dr a  w  5   µ L  of  2  % s o di u  m fl u or es c ei n i nt o t h e s u p pli e d  2 -2 0  µl   mi cr o pi p ett e fitt e d   wit h 
a  cl e a n  pi p ett e ti p.  
•     C ar ef ull y  pr ess t h e  pl u n g er  of t h e  pi p ett e,  all o  wi n g  a  dr o p t o f or  m  o n t h e  e n d  of t h e 
ti p. 
•     G e ntl y t o u  c h t h e  dr o p  at t h e ti p t o t h e l o  w er  p al p e br al  c o nj u n cti v a  of t h e ri g ht  e y e.   
•     I n  or d er t o t h or o u g hl y   mi x t h e fl u or es c ei n   wit h t h e t e ar fil  m,  as k t h e s u bj e ct t o  bli n k 
t hr e e f ull ti  m es f or  e v e n  distri b uti o n. 
•     I nstr u ct t h e s u bj e ct t o  h ol d  his  or  h er  e y e  o p e n f or  as l o n g  as  p ossi bl e. 
•     S c a n t h e  c or n e a, f o c usi n g  o n t h e t e ar fil  m  a n d  e pit h eli u  m.   D o  n ot  h ol d t h e li g ht st e a d y 
i n  o n e  p ositi o n.  Usi n g  a st o p  w at c h,   m e as ur e t h e ti  m e i nt er v al  b et  w e e n  a  c o  m pl et e 
bli n k  a n d t h e  a p p e ar a n c e  of t h e first  bl a c k  or  dr y  e y e  ar e a.    
•     P erf or  m t his  ass ess  m e nt t hr e e ti  m es i n t h e ri g ht  e y e, r e c or di n g  e a c h ti  m e i n t h e  c as e 
r e p ort f or  m. 
•     R e p e at t h es e st e ps f or t h e l eft  e y e.