Clinical trial NCT03960866
Conditions: Open Angle Glaucoma Ocular Hypertension
Keywords: Open Angle Glaucoma Ocular Hypertension
Sponsor: Ocuphire Pharma, Inc.
Start date: 2019-05-28; Completion date: 2019-09-11
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are:

* To evaluate the efficacy of Phentolamine Mesylate to lower intra-ocular pressure (IOP) in the treatment of Open-Angle Glaucoma (OAG) and Ocular Hypertension (OHT).
* To evaluate the ocular and systemic safety of Phentolamine Mesylate compared to its vehicle.
* To evaluate additional efficacy of Phentolamine Mesylate to improve visual performance.

Detailed description:
Placebo-controlled double-masked, multiple dose Phase 2 study in 40 patients with IOP ≥ 22 and ≤30 mmHg, evaluating ocular and systemic safety and efficacy following administration of Phentolamine mesylate 1.0% QD at 8PM to 10PM in both eyes for 14 days.

Arms: arm 1: 1 drop in each eye daily (QD) at or before bedtime (8pm to 10pm) for 14 days arm 2: 1 drop in each eye daily (QD) at or before bedtime (8pm to 10pm) for 14 days
Interventions: intervention 1: Phentolamine Mesylate Ophthalmic Solution 1% intervention 2: Phentolamine Mesylate Ophthalmic Solution Vehicle (Placebo)
Intervention descriptions: intervention 1: Topical Sterile Ophthalmic Solution intervention 2: Topical Sterile Ophthalmic Solution

Protocol documents:
Prot_002.pdf: 
O c u p hir e  P h ar m a,  I n c. 
1      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
 
 
 
C O N FI D E N TI A L  
 
Cli ni c al  St u d y   Ph as e   2  Pr ot o c ol  
O PI -N Y X G - 2 0 1 
O RI O N- 1 
 
R a n d o miz e d,  Pl a c e b o -C o ntr oll e d,  D o u bl e -M as k e d  St u d y  of  t h e S af et y  a n d  
Effi c a c y  of  P h e nt ol a mi n e  M es yl at e  O p ht h al mi c  S ol uti o n  i n S u bj e ct s wit h  O p e n  
A n gl e  Gl a u c o m a  or  O c ul ar  H y p ert e nsi o n  
 
O c u p hir e  P h ar m a,  I n c. 
 
 
 
 
 
 
 
 
 
V e rsi o n:  
0 2 
O ri gi n al:  
M a r c h   1 4,  2 0 1 9 
A m e n d m e nt   1: 
A p ril   8,  2 0 1 9 
 
 
C O N FI D E N TI A L  
T his   d o c u m e nt  c o nt ai ns  O c u p hir e P h ar m a,  I n c. ( O c u p hir e) i nf or m ati o n t h at is  c o nfi d e nti al,  a 
tr a d e s e cr et  a n d/ or  pr o pri etar y  i n n at ur e.   It is l o a n e d t o y o u  f or  y o ur c o nfi d e nti al   us e  o n b e h alf  
of  O c u p hir e  a n d  is  n ot t o  b e  p h ot o c o pi e d,  dis cl os e d  or tr a ns mitt e d t o a n y   ot h er  p ers o n or  p art y  
w h o  is  n ot c o v er e d  b y   a  C o nfi d e nti al  Dis cl os ur e A gr e e m e nt  wit h   O c u p hir e.  As  t h e Pri n ci p al  
I n v esti g at or y o u  ar e  r es p o nsi bl e f or t h e s af e k e e pi n g a n d  r et ur n of  t his  d o c u m e nt t o  O c u p hir e 
u p o n  r e q u est.  Y o u  will  b e  s e nt  u p d at e d i nf or m ati o n  a n d/ or a m e n d m e nts  as  t h e y b e c o m e  
a v ail a bl e.




O c u p hir e  P h ar m a,  I n c. 
3      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
I N V E S TI G A T O R’ S  A G R E E M E N T  
 
O PI -N Y X G - 2 0 1 
O RI O N - 1 
R a n d o miz e d,  Pl a c e b o - C o ntr oll e d,  D o u bl e-M as k e d  St u d y   of t h e S af et y   a n d Effi c a c y   of 
P h e nt ol a mi n e  M es yl at e   O p ht h al mi c S ol uti o n  i n S u bj e ct s wit h  O p e n  A n gl e   Gl a u c o m a  or 
O c ul ar  H y p ert e nsi o n  
 
V e rsi o n:  
0 2 
O ri gi n al:  
M a r c h   1 4,  2 0 1 9 
A m e n d m e nt   1: 
A p ril   8,  2 0 1 9 
 
I n v esti g at or A gr e e m e nt:  
I, t h e  u n d ersi g n e d, h a v e  r e vi e w e d t his  pr ot o c ol a n d  I a gr e e  t o  c o n d u ct t his  pr ot o c ol i n a c c or d a n c e  
wit h   G o o d  Cli ni c al Pr a cti c e,  t h e et hi c al  pri n ci pl es  s et f ort h i n t h e D e cl ar ati o n   of  H elsi n ki a n d  
wit h  t h e U. S.   C o d e  of F e d er al   R e g ul ati o ns  g o v er ni n g t h e  pr ot e cti o n  of  h u m a n s u bj e cts 
( 2 1 C F R   5 0), I nstit uti o n al R e vi e w   B o ar ds ( 2 1 C F R   5 6) a n d  t h e  o bli g ati o ns  of cli ni c al  
i n v esti g at ors ( 2 1 C F R   3 1 2). 
 
Si g n at ur e:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D at e :  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Pri nt e d  N a m e:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 




O c u p hir e  P h ar m a,  I n c. 
5      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
A B B R E VI A TI O N S  A N D  T E R M S  
 
 
A b br e vi ati o n   
F ull  t er m 
A E  
A d v ers e  E v e nt  
A M  
A nt e  M eri di a n  –  i n t h e m or ni n g  
A N C O V A   
A n al ysis  of  C o v ari a n c e  
A R  
All  R a n d o mi z e d  
B C D V A   
B est  C orr e ct e d  Dist a n c e  Vis u al  A c uit y   
B P  
Bl o o d  Pr ess ur e  
°C  
D e gr e e  C e nti gr a d e  
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 F R  
C o d e  of  F e d er al  R e g ul ati o ns  
C H F  
C o n g esti v e  H e art  F ail ur e  
CI  
C o nfi d e n c e  I nt er v al 
C R F  
C as e  R e p ort  F or m  
C S  
C o ntr a st S e nsiti vit y  
C S R  
Cli ni c al  St u d y  R e p ort  
D C N V A   
Dist a n c e  C orr e ct e d  N e ar  Vis u al  A c uit y  
E T D R S   
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  
°F  
D e gr e e  F a hr e n h eit  
F A S  
F ull  A n al ysis  S et  
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  
H Cl  
H y dr o c hl ori c  A ci d  
H R  
H e art  R at e  
I B 
I n v esti g at ors’ Br o c h ur e  
I C F 
I nf or m e d C o ns e nt  F or m  


O c u p hir e  P h ar m a,  I n c. 
6      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
I C H 
I nt er n ati o n al C o u n cil  f or H ar m o ni sati o n  
I N D 
I n v esti g ati o n al N e w  Dr u g  a p pli 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 -T r e at 
L A SI K   
L as er -A ssist e d i n sit u K er at o mil e usis  
L D P E  
L o w  D e nsit y  P ol y et h yl e n e  
L S M  
L e ast  S q u ar es  M e a n  
l o g M A R   
l o g arit h m of  t h e M i ni m u m A n gl e  of  R es ol uti o n  
m m H g  
milli m et ers  of  m er c ur y  
M e d D R A   
M e di c al  Di cti o n ar y  f or R e g ul at or y  A cti viti es  
N a O H  
S o di u m  h y dr o xi d e  
N y x ol  
P h e nt ol a mi n e  M es yl at e  O p ht h al mi c  S ol uti o n  1  %  ( N y x ol ®) 
O A G  
O p e n  A n gl e  Gl a u c o m a  
O D  
Ri g ht  e y e  
O H T  
O c ul ar  H y p ert e nsi o n  
O R  
O d ds  R ati o  
O S  
L eft  e y e  
O T C  
O v er -T h e -C o u nt er  
O U  
B ot h  e y es  
P A S  
P eri p h er al  A nt eri or  S y n e c hi a e  
p H  
M e as ur e  of  a ci dit y/ al k ali nit y  
P M  
P ost  M eri di a n  
P O A G  
Pri m ar y  O p e n  A n gl e  Gl a u c o m a  
P P  
P er  Pr ot o c ol  
P R K  
P h ot or efr a cti v e  K er at e ct o m y  
R x  
Pr es cri pti o n  


O c u p hir e  P h ar m a,  I n c. 
7      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
Q D  
O n c e  d ail y  
S A E  
S eri o us  A d v ers e  E v e nt  
S E  
St a n d ar d  Err or  
S O C  
S yst e m  Or g a n  Cl ass  
S O P  
St a n d ar d  O p er ati n g  Pr o c e d ur e  
S P  
S af et y  P o p ul ati o n  
T E A E  
Tr e at m e nt  E m er g e nt  A d v ers e  E v e nt  
T M  
Tr a b e c ul ar  M es h w or k  
U S  
U nit e d  St at es  
U S P  
U nit e d  St at es  P h ar m a c o p ei a  
V A  
Vis u al  A c uit y  
 
 
 
 
 
 
 


O c u p hir e  P h ar m a,  I n c. 
8      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
1.   S T U D Y  S U M M A R Y  
St u d y  N u m b e r   
O PI -N Y X G - 2 0 1 
Cli ni c al  P h as e   
P h as e   2 
T y p e  of  S t u d y  
1 4  D a y  S af et y  a n d   Effi c a c y 
N a m e   of I n v esti g ati o n al 
P r o d u ct  
N y x ol  E y e   Dr o ps - 1 %   P h e nt ol a mi n e M es yl at e  o p ht h al mi c  
s ol uti o n ( N y x ol ) 
D u r ati o n  of  S t u d y   
U p  t o  7- 8 w e e ks,  i n cl u di n g s cr e e ni n g,  w as h o ut, tr e at m e nt a n d  
f oll o w- u p.  Tr e at m e nt   p eri o d is  1 4 d a ys.  
R ati o n al e  
P h e nt ol a mi n e  m es yl at e , t h e a cti v e  dr u g  i n  Ny x ol , is  a  n o n-
s el e cti v e  al p h a- 1  &  al p h a- 2-a dr e n er gi c   a nt a g o nist a cti n g   o n t h e 
a dr e n er gi c   n er v o us s yst e m a n d  i n hi bits c o ntr a cti o n   of t h e s m o ot h 
m us cl e.    S o m e  al p h a- 1-a dr e n er gi c   a nt a g o nists h a v e  b e e n  s h o w n t o 
l o w er i ntr a o c ul ar  pr ess ur e (I O P)  vi a t h e u v e os cl er al   p at h w a y a n d  
a q u e o us  h u m or  pr o d u cti o n.   T h e  m aj or   c o n v e nti o n al  o utfl o w 
p at h w a y i n cl u d es t h e  tr a b e c ul ar m es h w or k  ( T M), w hi c h  h as  
s m o ot h-m us cl e -li k e pr o p erti es  a n d  al p h a - 2-a dr e n er gi c  r e c e pt ors. 
N y x ol  c a n  p ot e nti all y  aff e ct  t his  p at h w a y t hr o u g h s m o ot h m us cl e  
r el a x ati o n  of t h e T M,   a d di n g  a c o m pl e m e nt ar y  m e c h a nis m  f or I O P 
l o w eri n g.  
Pr e vi o us  P h as e   2 cli ni c al  tri als s h o w e d t h at N y x ol  si g nifi c a ntl y 
r e d u c es I O P i n  n or m ot e nsi v e s u bj e cts aft er   a si n gl e tr e at m e nt. 
St u d y  O bj e cti v es   
T h e  o bj e cti v es   of t his st u d y ar e:  
•   T o  e v al u at e  t h e effi c a c y   of N y x ol  t o l o w er I O P i n O p e n  
A n gl e  Gl a u c o m a  ( O A G) a n d  O c ul ar   H y p ert e nsi o n ( O H T). 
•   T o  e v al u at e  t h e o c ul ar  a n d  s yst e mi c s af et y  of  Ny x ol  
c o m p ar e d  t o its v e hi cl e.  
•   T o  e v al u at e   a d diti o n al effi c a c y  of   Ny x ol  t o i m pr o v e  vis u al 
p erf or m a n c e . 
D esi g n  
Pl a c e b o - c o ntr oll e d,  d o u bl e-m as k e d,  m ulti pl e   d os e, P h as e   2 st u d y 
i n a p pr o xi m at el y   4 0 r a n d o mi z e d s u bj e cts wit h  el e v at e d  I O P, 
e v al u ati n g  s af et y a n d  effi c a c y  f oll o wi n g a d mi nistr ati o n   of  Ny x ol  
Q D  at   8 P M t o  1 0 P M i n b ot h  e y es  f or  1 4 d a ys.  


O c u p hir e  P h ar m a,  I n c. 
9      
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
P ati e nt   P o p ul ati o n   
4 0  s u bj e cts e x p eri e n ci n g  O A G   or O H T.   
I n cl usi o n C rit e ri a   
S u bj e ct s m a y   q u alif y i n eit h er  e y e.   T h e  e y e  wit h  t h e hi g h er  I O P at  
t h e Q u alifi c ati o n  Visit  at  8 A M  is d esi g n at e d  as  t h e st u d y e y e  f or 
t h e pri m ar y   e n d p oi nt effi c a c y  a n al ysis.   I n t h e c as e  w h er e   b ot h 
e y es   h a v e t h e s a m e I O P, t h e st u d y e y e  will   b e t h e RI G H T  e y e.  S e e  
S e cti o n   9 f or m or e  i nf or m ati o n  o n st atisti c al a n al ysis.   A L L  
T R E A T M E N T S  WI L L  B E  A D MI NI S T E R E D  T O  B O T H  E Y E S  
( O U).  
1.   1 8  y e ars   of a g e   or gr e at er . 
2.   Di a g n osis  of  O A G  or  O H T.    Th e   di a g n osis of  O H T   m ust b e  
i n B O T H  e y es.   F or  O A G  it c a n  b e  i n eit h er  e y e   a n d O H T  i n 
t h e f ell o w e y e.   A  r e p ort e d  hist or y of  u ntr e at e d  O H T  wit h  
I O P ≥ 2 2 m m H g  a n d  ≤   3 0m m H g  is pr ef err e d . 
3.   U ntr e at e d    or  tr e at e d  O A G/ O H T   wit h    2   or  f e w er   o c ul ar 
h y p ot e nsi v e  m e di c ati o ns.  
4.   U ntr e at e d    ( p ost- w as h o ut)  m e a n   I O P  ≥    2 2m m H g   a n d  
≤ 3 0 m m H g  i n t h e st u d y e y e  at  t h e Q u alifi c ati o n   Visit ( 8A M ). 
5.   C orr e ct e d   vis u al a c uit y  i n e a c h  e y e   + 1. 0 l o g M A R  or b ett er  
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 ) i n 
e a c h  e y e   ( e q ui v al e nt t o  2 0/ 2 0 0  or b ett er)  at   t h e S cr e e ni n g  
Visit  a n d  Q u alifi c ati o n  Visit . 
6.   Ot h er wis e  h e alt h y  a n d  w ell - c o ntr oll e d s u bj e cts. 
7.   A bl e  a n d  willi n g  t o gi v e  si g n e d  i nf or m e d  c o ns e nt  a n d f oll o w 
st u d y i nstr u cti o ns. 
8.   A bl e  t o s elf-a d mi nist er   st u d y m e di c ati o n   or t o  h a v e  st u d y 
m e di c ati o n  a d mi nist er e d  b y  a c ar e gi v er  t hr o u g h o ut t h e st u d y 
p eri o d. 
 
 
 


O c u p hir e  P h ar m a,  I n c. 
1 0       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
E x cl usi o n  C rit e ri a   
O p ht h al mi c : 
1.   Cl os e d   or v er y  n arr o w  a n gl es  ( Gr a d e  0- 1, S h aff er)   or 
a n gl es  t h at t h e i n v esti g at or j u d g es as   o c cl u d a bl e  a n d/ or 
wit h  e vi d e n c e   of p eri p h er al  a nt eri or  s y n e c hi a e ( P A S) ≥  
1 8 0  d e gr e es  b y   g o ni os c o p y wit hi n   6  m o nt hs  pri or t o 
S cr e e ni n g  Visit  i n eit h er  e y e.   
2.   Gl a u c o m a:   ps e u d o-e xf oli ati o n   or  pi g m e nt  dis p ersi o n 
c o m p o n e nt,  hist or y  of  a n gl e   cl os ur e  or n arr o w  a n gl es.  
N ot e:   Pr e vi o us l as er  p eri p h er al iri d ot o m y is N O T  all o w e d.  
3.   K n o w n  h y p ers e nsiti vit y  t o a n y  α -a dr e n o c e pt or   a nt a g o nists. 
4.   Pr e vi o us  l as er  a n d/ or  n o n-l as er gl a u c o m a  s ur g er y  or 
pr o c e d ur e  i n eit h er  e y e . 
5.   R efr a cti v e   s ur g er y  i n  eit h er   e y e   (i. e.  r a di al  k er at ot o m y,  
P R K,  L A SI K,  c or n e al  cr oss  li n ki n g). 
6.   O c ul ar  tr a u m a i n eit h er  e y e  wit hi n   t h e  6    m o nt hs  pri or t o 
S cr e e ni n g,    or  o c ul ar    s ur g er y   or   n o n-refr a cti v e   l as er 
tr e at m e nt wit hi n  t h e  3  m o nt hs  pri or t o  Scr e e ni n g . 
7.   R e c e nt    or  c urr e nt   e vi d e n c e    of  o c ul ar   i nf e cti o n   or 
i nfl a m m ati o n i n eit h er  e y e.    C urr e nt e vi d e n c e  of  cli ni c all y  
si g nifi c a nt bl e p h aritis,  c o nj u n cti vitis,   or  a  hist or y  of h er p es  
si m pl e x   or  h er p es z ost er  k er atitis  at   Scr e e ni n g  i n eit h er  e y e . 
8.   O c ul ar  m e di c ati o n  i n eit h er  e y e   of a n y   ki n d wit hi n   3 0 d a ys  
of  S cr e e ni n g,  wit h  t h e e x c e pti o n   of a)   o c ul ar  h y p ot e nsi v e 
m e di c ati o ns  ( w hi c h   m ust  b e w as h e d   o ut a c c or di n g  t o  t h e 
pr o vi d e d  s c h e d ul e),  b)  li d  s cr u bs ( w hi c h c a n   b e us e d   pri or 
t o   Scr e e ni n g   b ut  c a n n ot  b e  us e d   aft er    Scr e e ni n g)   or  c)  
l u bri c ati n g  dr o ps f or  dr y e y e   ( pr es er v ati v e -fr e e artifi ci al  
t e ars), w hi c h  c a n  b e  us e d  t hr o u g h o ut t h e st u d y. 
9.   Cli ni c all y  si g nifi c a nt o c ul ar  dis e as e  i n eit h er  e y e  as  d e e m e d  
b y   t h e  i n v esti g at or  (i. e.,  c or n e al   e d e m a,    u v eitis,  s e v er e 
k er at o c o nj u n cti vitis  si c c a)  t h at  mi g ht   i nt erf er e  wit h   t h e 
st u d y,   i n cl u di n g  gl a u c o m at o us   d a m a g e   s o  s e v er e  t h at 
w as h o ut  of  o c ul ar   h y p ot e nsi v e m e di c ati o ns  f or  1  m o nt h is 
n ot j u d g e d  s af e (i. e., c u p -t o- dis c r ati o  >  0. 8, s e v er e  vis u al 
fi el d d ef e ct) . 
1 0.  Hist or y   of di a b eti c  r eti n o p at h y. 


O c u p hir e  P h ar m a,  I n c. 
1 1       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
1 1.  C o nt a ct  l e ns w e ar  wit hi n  3  d a ys  pri or  t o a n d  f or t h e d ur ati o n  
of t h e st u d y. 
1 2.  C e ntr al   c or n e al    t hi c k n ess  i n  eit h er   e y e    > 6 0 0  μ m   at  
S cr e e ni n g . 
1 3.  A n y    a b n or m alit y  i n  eit h er   e y e    pr e v e nti n g  r eli a bl e 
a p pl a n ati o n t o n o m etr y  ( e.g.  c e ntr al  c or n e al  s c arri n g). 
S yst e mi c:  
1.   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 α -  a n d/ or  β -
a dr e n o c e pt or   a nt a g o nists  
(i. e.   c hr o ni c   o bstr u cti v e 
p ul m o n ar y  dis e as e   or   br o n c hi al  ast h m a;   a b n or m all y   l o w 
bl o o d  pr ess ur e   or  h e art  r at e; s e c o n d  or  t hir d d e gr e e  h e art  
bl o c k  or  C H F;  s e v er e di a b et es) . 
2.   Cli ni c all y   si g nifi c a nt  s yst e mi c  dis e as e   (i. e.,   u n c o ntr oll e d 
di a b et es,   m y ast h e ni a   gr a vis,   c a n c er,   h e p ati c,   r e n al, 
e n d o cri n e  or  c ar di o v as c ul ar  dis or d ers)  t h at mi g ht  i nt erf er e 
wit h  t h e st u d y. 
3.   P arti ci p ati o n   i n  a n y   i n v esti g ati o n al  st u d y  wit hi n   3 0  d a ys  
pri or  t o  Scr e e ni n g . 
4.   Us e   of  a n y   t o pi c al  or  s yst e mi c  a dr e n er gi c   or   c h oli n er gi c 
dr u gs  u p  t o  3 0 d a ys  pri or  t o S cr e e ni n g ,  or  d uri n g t h e  st u d y 
u nl ess t h e  dr u g,   d os e a n d  r e gi m e n h as  b e e n  c o nsist e nt  f or 
t h e  3 0 d a ys   pri or t o S cr e e ni n g . 
5.   C h a n g es  i n s yst e mi c m e di c ati o n  t h at  c o ul d  h a v e a n  eff e ct   o n 
I O P wit hi n   3 0 d a ys   pri or t o  Scr e e ni n g   or a nti ci p at e d   d uri n g 
t h e st u d y. 
6.   W o m e n   of c hil d b e ari n g  p ot e nti al  w h o  ar e   pr e g n a nt,  n ursi n g, 
pl a n ni n g  a  pr e g n a n c y,  or  n ot  usi n g  a  m e di c all y  a c c e pt a bl e  
f or m  of birt h   c o ntr ol.  A n   a d ult w o m a n  is c o nsi d er e d  t o b e  
of  
c hil d b e ari n g    p ot e nti al   u nl ess   s h e  is   1  y e ar  
p ost m e n o p a us al  or  3  m o nt hs  p ost- s ur gi c al st erili z ati o n.  All  
f e m al es of   c hil d b e ari n g p ot e nti al   m ust  h a v e  a  n e g ati v e  uri n e 
pr e g n a n c y  t est  r es ult  at   t h e   Scr e e ni n g   a n d     Qu alifi c ati o n  
e x a mi n ati o n s  a n d     m ust  i nt e n d  t o   n ot  b e c o m e    pr e g n a nt 
d uri n g t h e  st u d y.  
7.   R esti n g  h e art  r at e ( H R)  o utsi d e  t h e  n or m al  r a n g e ( 50- 1 1 0  
b e ats  p er  mi n ut e)  at  t h e S cr e e ni n g   or Q u alifi c ati o n  Visit . H R  
m a y   b e   r e p e at e d  o n c e   o nl y  if  o utsi d e  t h e  n or m al  r a n g e 


O c u p hir e  P h ar m a,  I n c. 
1 2       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
f oll o wi ng   at   l e ast  a   5   mi n ut e   r est  p eri o d   i n  t h e  sitti n g 
p ositi o n. 
8.   H y p ert e nsi o n  wit h  r esti n g di ast oli c   bl o o d  pr ess ur e  ( B P)  > 
1 0 5  m m H g   or s yst oli c B P   >  1 6 0 m m H g  at  t h e S cr e e ni n g   or 
Q u alifi c ati o n  Visit . B P  m a y   b e r e p e at e d o nl y  o n c e  if  o utsi d e 
t h e s p e cifi e d  r a n g e f oll o wi n g at  l e ast  a  5 mi n ut e  r est  p eri o d 
i n t h e sitti n g  p ositi o n.  






O c u p hir e  P h ar m a,  I n c. 
1 5       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
S e c o n d a r y  Effi c a c y  
E n d p oi nts  
S e c o n d ar y  effi c a c y   e n d p oi nts will   b e a n al y z e d  b y  st u d y e y e , 
f ell o w e y e  a n d  all  e y es  ( u nl ess  ot h er wis e i n di c at e d) a n d  will  
i n cl u de:  
•   C h a n g e  fr o m B as eli n e  t o D a y   1 5 i n m e a n   di ur n al I O P i n 
t h e f ell o w e y e  a n d  all  e y es.  
•   C h a n g e  fr o m B as eli n e  t o D a y   8 i n m e a n   di ur n al I O P. 
•   M e a n  I O P at  e a c h   p ost-tr e at m e nt ti m e p oi nt ( 8A M ,  1 0A M  
a n d   4P M ;  o n D a y   8 a n d  D a y   1 5).   
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  t o D a y   8 a n d  
D a y   1 5 i n I O P at  e a c h  ti m e p oi nt ( 8A M ,  1 0A M ,  4P M ), a n d  
D a y   1 6 at  8 A M . 
•   P er c e nt a g e   of s u bj e cts  a c hi e vi n g r e d u cti o ns  fr o m  Bas eli n e  
t o D a y   8 a n d  D a y   1 5 i n I O P at  8 A M   of gr e at er  t h a n  or 
e q u al  t o  1 0 %,  1 5 %,  2 0 %,  2 5 % a n d   3 0 %. 
•   P er c e nt a g e  of  s u bj e cts  a c hi e vi n g D a y   8, D a y   1 5  a n d D a y  
1 6  I O P l e v els at  8 A M   of l ess t h a n  or e q u al  t o  1 6m m H g,  
1 8 m m H g,  2 0 m m H g  a n d   2 2 m m H g.  
•   C h a n g e  a n d   per c e nt  c h a n g e  fr o m  Bas eli n e  D a y   8, D a y   1 5, 
a n d  D a y   1 6 i n I O P at   8 A M. 
•   C h a n g e  a n d  p er c e nt  c h a n g e  t o D a y s  8,  1 5, a n d   1 6 i n  p u pil 
di a m et er  at  8 A M . 
•   P er c e nt a g e   of s u bj e cts  a c hi e vi n g r e d u cti o ns  fr o m  Bas eli n e  
t o D a y   8, D a y   1 5 a n d  D a y   1 6 i n  p u pil di a m et er  at  8 A M   of 
gr e at er  t h a n  or e q u al  t o  1 0 %,  1 5 %,  2 0 %,  2 5 %, a n d   3 0 %. 
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  t o D a y   8, D a y  
1 5,  a n d  D a y   1 6 i n b est  c orr e ct e d  dist a n c e   vis u al a c uit y  
( B C D V A) ( ET D R S  hi g h  c o ntr ast ) ( p h ot o pi c a n d   m es o pi c) 
at  8 A M . 
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  t o D a y   8, D a y  
1 5,  a n d  D a y   1 6 i n  dist a n c e c orr e ct e d  n e ar  vis u al  a c uit y  
(D C N V A)  ( E TD R S  hi g h  c o ntr ast ) ( p h ot o pi c a n d   m es o pi c) 
at  8 A M .  
•   P er c e nt a g e   of s u bj e cts  a c hi e vi n g i m pr o v e m e nts  fr o m 
B as eli n e  t o D a y   8, D a y   1 5, a n d  D a y   1 6 i n B C D V A  a n d  
D C N V A  ( p h ot o pi c a n d  m es o pi c)   of gr e at er  t h a n  or e q u al  t o 
1  li n e,  2 li n es a n d   3 li n es. 
All  S e c o n d ar y   E n d p oi nts r el at e d t o I O P will   b e a n al y z e d  
a d diti o n all y  i n t h os e s u b p o p ul ati o ns wit h  B as eli n e  I O P  of 
< 2 5 m m H g  a n d  ≥ 2 5 m m H g.  


O c u p hir e  P h ar m a,  I n c. 
1 6       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
F or  e a c h  s u bj e ct at  e a c h  ti m e p oi nt ( 8 A M,  1 0 A M, 4 P M),  t h e I O P 
v al u e  is t h e a v er a g e  I O P (fr o m t h e  2 m e as ur e m e nts  t a k e n at  t h at 
ti m e p oi nt) i n t h e st u d y e y e  or  i n t h e f ell o w e y e.   T h e  li g hti n g 
c o n diti o ns  will   b e  k e pt s a m e fr o m visit  t o visit.   E v er y  eff ort  
s h o ul d  b e m a d e  t o  h a v e t h e s a m e cli ni ci a n  p erf or m  t h e I O P 
m e as ur e m e nts  at  all  ti m e p oi nts a n d  at  all  visits.  
P ri m a r y  S af et y  
E n d p oi nts  
T h e  pri m ar y  s af et y m e as ur es  ar e   o bj e cti v e  bi o mi cr os c o pi c a n d  
o p ht h al m os c o pi c  e x a mi n ati o n , s u bj e cti v e o c ul ar  t ol er a bilit y, a n d  
A Es.   Ot h er  s af et y m e as ur es  ar e  s yst e mi c s af et y as  m e as ur e d  b y  
h e art  r at e a n d   bl o o d pr ess ur e.   Uri n e  pr e g n a n c y  t ests f or f e m al es of  
c hil d b e ari n g   p ot e nti al will   b e  c o n d u ct e d.  Pl e as e  s e e T a bl e   1 f or 
d et ails   o n m e as ur e m e nts  e x p e ct e d  at  e a c h   visit. 
St u d y   Me di c ati o ns,  
D os e   a n d M o d e   of 
A d mi nist r ati o n  
N y x ol  E y e   Dr o ps: 
O n e  dr o p  of  N y x ol  i n e a c h  e y e  d ail y  at  8 P M  t o 1 0 P M  f or 1 4  d a ys  
fr o m D a y   1 t hr o u g h D a y  1 4  f or s u bj e cts r a n d o mi z e d t o a cti v e  
tr e at m e nt. 
Pl a c e b o  ( Ny x ol  v e hi cl e):  
O n e  dr o p  of  pl a c e b o  i n e a c h  e y e  d ail y  at  8 P M  t o 1 0 P M  f or  1 4 d a ys  
fr o m D a y   1 t hr o u g h D a y  1 4  f or s u bj e cts r a n d o mi z e d t o pl a c e b o.    
D u r ati o n  of  S u bj e ct  
P a rti ci p ati o n  
a n d  S t u d y 
T h e  t ot al l e n gt h of  s u bj e ct p arti ci p ati o n  is a p pr o xi m at el y   7- 8 
w e e ks  wit h  si x cli ni c  visits  a n d   o n e t el e p h o n e c all  f oll o w  u p 
s u m m ari z e d  b el o w: 
•   S cr e e ni n g  Visit  ( 1 d a y) . 
•   W as h o ut  Visit/ p eri o d  ( as n e c ess ar y)  ( 4- 5 w e e ks  wit h  s af et y 
c h e c k  visit  at   2 w e e ks ). 
•   Q u alifi c ati o n/ B as eli n e  Visit  ( 1 d a y) . 
•   Tr e at m e nt -st u d y  Visit D a y   8 ( 1 w e e k) . 
•   Tr e at m e nt -st u d y  Visit D a y   1 5 ( 1 w e e k) . 
•   F oll o w- u p  cli ni c  Visit   o n D a y   1 6 ( 1 d a y) . 
•   F oll o w- u p t el e p h o n e  c all  at  D a y   2 2 ( 1 w e e k) .  
T h e  e x e c uti o n   of t h e e ntir e  st u d y (first s u bj e ct s cr e e n t hr o u g h l ast 
r a n d o mi z e d s u bj e ct c o m pl et e d ) is e x p e ct e d  t o  b e a p pr o xi m at el y   6 
m o nt hs.  


O c u p hir e  P h ar m a,  I n c. 
1 7       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
T A B L E  O F  C O N T E N T S  
S P O N S O R  SI G N A T U R E   & C O N T A C T S  .......................................................................... 2  
I N V E S TI G A T O R’ S A G R E E M E N T ................................................................................. 3  
A B B R E VI A TI O N S  A N D  T E R M S  ................................................................................... 5  
1.  
S T U D Y  S U M M A R Y  ............................................................................................ 8  
2.  
I N T R O D U C TI O N  ............................................................................................. 1 9  
2. 1.  
I n v esti g ati o n al  p r o d u cts  ............................................................................... 1 9  
2. 2.  
Fi n di n gs  f r o m n o n cli ni c al  a n d  cli ni c al  st u di es  ...................................................... 1 9  
2. 3.  
R o ut e  of  a d mi nist r ati o n,  d os a g e  r e gi m e n,  a n d  t r e at m e nt p e ri o d  ................................. 2 1  
2. 4.  
C o m pli a n c e  .............................................................................................. 2 1  
2. 5.  
St u d y  P o p ul ati o n  ........................................................................................ 2 1  
3.  
O B J E C TI V E S  A N D  P U R P O S E  ............................................................................. 2 2  
4.  
S T U D Y  D E SI G N  .............................................................................................. 2 3  
4. 1.  
P ri m a r y  a n d  s e c o n d a r y  e n d p oi nts  .................................................................... 2 3  
4. 2.  
D es c ri pti o n  a n d  s c h e d ul e of  visits  a n d  p r o c e d u r e s .................................................. 2 4  
4. 3.  
M e as u r es  t a k e n t o mi ni mi z e/ a v oi d  bi as  .............................................................. 2 6  
4. 4.  
St u d y  m e di c ati o ns  ...................................................................................... 2 6  
4. 4. 1.  P a c k a gi n g  a n d  l a b eli n g ..................................................................................................................... 2 6  
4. 4. 2.  St or a g e  of  st u d y m e di c ati o n  .............................................................................................................. 2 6  
4. 4. 3.  St u d y  m e di c ati o n  a c c o u nt a bil it y ....................................................................................................... 2 6  
4. 4. 3. 1.  R e c ei pt  a n d  dis p ositi o n  of  st u d y m e di c ati o n  ............................................................................. 2 6  
4. 4. 3. 2.  R et ur n  of  st u d y m e di c ati o n  ....................................................................................................... 2 7  
4. 5.  
E x p e ct e d  d u r ati o n  of  s u bj e ct p a rti ci p ati o n  .......................................................... 2 7  
4. 6.  
R a n d o mi z ati 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  .............................................. 2 7  
4. 7.  
C oll e cti o n  of  d at a  ....................................................................................... 2 7  
4. 8.  
C o m pl et e d  s u bj e ct ...................................................................................... 2 7  
4. 9.  
N o n -c o m pl eti n g  s u bj e ct  ................................................................................ 2 8  
4. 9. 1.  St u d y  m e di c ati o n  dis c o nti n u ati o n  ..................................................................................................... 2 8  
4. 9. 2.  R e as o ns  f or Wit h dr a w al  fr o m St u d y  ................................................................................................. 2 8  
4. 9. 3.  E ntir e  st u d y t er mi n at e d ..................................................................................................................... 2 8  
4. 9. 4.  A cti o ns  aft er  dis c o nti n u ati o n  ............................................................................................................ 2 8  
4. 1 0.  
C o m pl et e d  st u d y ........................................................................................ 2 9  
4. 1 1.  
P r o c e d u r e  aft e r  t h e c o m pl eti o n  of  t h e st u d y ......................................................... 2 9  
5.  
S U B J E C T  I N C L U SI O N A N D  E X C L U SI O N  C RI T E RI A  ............................................... 3 0  
5. 1.  
S u bj e ct  i n cl usi o n c rit e ri a  .............................................................................. 3 0  
5. 2  
S u bj e ct  e x cl usi o n  c rit e ri a  .............................................................................. 3 0  
6.  
T R E A T M E N T  O F  S U B J E C T S  .............................................................................. 3 3  
6. 1.  
T r e at m e nt  a d h e r e n c e  ................................................................................... 3 3  
6. 2.  
C o n c o mit a nt  m e di c ati o ns  .............................................................................. 3 3  
7.  
A S S E S S M E N T  O F  E F FI C A C Y  ............................................................................. 3 5  
7. 1.  
S p e cifi c ati o n  of  t h e effi c a c y  p a r a m et e rs  ............................................................. 3 5  
7. 2.  
Ass essi n g,  r e c o r di n g , a n d  a n al y zi n g  of  effi c a c y  p a r a m et e rs  ....................................... 3 5  
7. 2. 1.  S cr e e ni n g  .......................................................................................................................................... 3 6  
7. 2. 2.  W as h o ut  P eri o d  ................................................................................................................................. 3 7  
7. 2. 3.  Q u alifi c ati o n  Visit/ B as eli n e  ( D a y 1)  ................................................................................................. 3 7  
7. 2. 4.  St u d y  D a y   8  ±  1 D a y  ......................................................................................................................... 3 8  
7. 2. 5.  St u d y  D a y  1 5   ±  1 D a y  ....................................................................................................................... 3 9  
7. 2. 6.  F oll o w -u p  Visit  ( D a y 1 6)  .................................................................................................................. 4 0  
7. 2. 7.  F oll o w -u p  p h o n e  c all  ( D a y 2 2)  ......................................................................................................... 4 0  


O c u p hir e  P h ar m a,  I n c. 
1 8       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
7. 2. 8.  U ns c h e d ul e d  Visits  ........................................................................................................................... 4 1  
7. 2. 9.  Visit  v ari ati o n  .................................................................................................................................... 4 1  
8.  
A S S E S S M E N T  O F  S A F E T Y  ................................................................................ 4 2  
8. 1.  
S p e cifi c ati o n  of  s af et y  p a r a m et e r s  .................................................................... 4 2  
8. 2.  
Ass essi n g,  r e c o r di n g,  a n d  a n al y zi n g  s af et y  p a r a m et e rs  ............................................ 4 2  
8. 3.  
A d v e rs e  e v e nts  .......................................................................................... 4 2  
8. 3. 1.  A d v ers e  e v e nt  d efi niti o ns  .................................................................................................................. 4 3  
8. 3. 2.  F oll o w -u p  of  s u bj e cts aft er  a d v ers e  e v e nts  ....................................................................................... 4 6  
9.  
S T A TI S TI C S  .................................................................................................. 4 7  
9. 1.  
S a m pl e  Si z e  .............................................................................................. 4 7  
9. 2.  
A n al ysis  P o p ul ati o ns  ................................................................................... 4 7  
9. 3.  
St atisti c al  M et h o ds  ..................................................................................... 4 7  
9. 3. 1.  G e n er al  C o nsi d er ati o ns  ..................................................................................................................... 4 7  
9. 3. 2.  D e m o gr a p hi c  a n d  B as eli n e  C h ar a ct eristi c s  ....................................................................................... 4 7  
9. 3. 3.  S u bj e ct  Dis p osit i o n ........................................................................................................................... 4 7  
9. 3. 4.  M e di c al  Hist or y  a n d  Pri or/ C o n c o mit a nt  M e di c ati o ns  ....................................................................... 4 8  
9. 3. 5.  A n al ysis  of  Effi c a c y  .......................................................................................................................... 4 8  
9. 3. 5.  A n al ysis  of  S af et y  ............................................................................................................................. 4 9  
9. 4.  
P r o c e d u r e  f o r a c c o u nti n g  f o r missi n g,  u n us e d,  o r  s p u ri o us d at a  ................................. 4 9  
9. 5.  
P r o c e d u r e  f o r r e p o rti n g  d e vi ati o ns  f r o m t h e st atisti c al pl a n  ...................................... 5 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  A N D  D O C U M E N T S  ......................................... 5 1  
1 1.  
Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E  ................................................. 5 2  
1 2.  
E T HI C A L  C O N SI D E R A TI O N S  A N D  G C P  C O M P LI A N C E  ........................................... 5 3  
1 2. 1.  
G C P  c o m pli a n c e  ........................................................................................ 5 3  
1 2. 2.  
I nstit uti o n al R e vi e w  B o a r d  (I R B) ..................................................................... 5 3  
1 2. 3.  
P r ot o c ol  D e vi ati o ns/ Vi ol ati o ns  ........................................................................ 5 3  
1 2. 4.  
I nf o r m e d c o ns e nt  r e q ui r e m e nts  ....................................................................... 5 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  .......................................................... 5 5  
1 3. 1.  
D at a  E nt r y  ............................................................................................... 5 5  
1 3. 2.  
D at a  q u alit y  c o nt r ol  a n d  r e p o rti n g  ................................................................... 5 5  
1 3. 3.  
A r c hi vi n g  of  d at a  ....................................................................................... 5 5  
1 3. 4.  
R e c o r ds  r et e nti o n  ....................................................................................... 5 5  
1 3. 5.  
A m e n d m e nts  t o t h e p r ot o c ol  .......................................................................... 5 5  
A P P E N DI X  1:  A D R E N E R GI C  A N D  C H O LI N E R GI C  D R U G S  .............................................. 5 6  
BI B LI O G R A P H Y  .................................................................................................... 5 8  
 
 




O c u p hir e  P h ar m a,  I n c. 
2 0       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
P r es cri bi n g I nf or m ati o n i n I B) a n d  l o c al i nj e ct a bl e a d mi nistr ati o n   of Or a V ers e  ( N o v al ar, S a n  
Di e g o,  C alif or ni a;  s e e Or a V ers e  Pr es cri bi n g  I nf or m ati o n i n I B). 
D esi g n  j ustifi c ati o n 
T h e  t w o pri m ar y  m e c h a nis ms  t o l o w er I O P i n cl u d e d e cr e asi n g  t h e  a m o u nt  of  a q u e o us  h u m or 
pr o d u cti o n  i n t h e e y e  a n d  i n cr e asi n g t h e  o utfl o w of   a q u e o us  h u m or fr o m t h e e y e 3.   P h e nt ol a mi n e 
is  a  n o n-s el e cti v e  al p h a-a dr e n er gi c   a nt a g o nist a cti n g   o n t h e a dr e n er gi c   n er v o us s yst e m a n d  
i n hi bits c o ntr a cti o n   of t h e s m o ot h m us cl e.   F or  e x a m pl e,   p h e nt ol a mi n e m es yl at e  i n hi bits 
c o ntr a cti o n   of t h e iris  dil at or m us cl e,  r es ulti n g i n  a s m all er  p u pil si z e. 
Al p h a- a dr e n er gi c  a nt a g o nists,  i n cl u di n g  p h e nt ol a mi n e,  h a v e b e e n   pr e vi o usl y s h o w n t o l o w er I O P 
vi a t h e  a q u e o us  h u m or  pr o d u cti o n  a n d  u v e os cl er al   p at h w a y r es p e cti v el y.   T h e m aj or  
c o n v e nti o n al  o utfl o w  p at h w a y t h o u g h  i n cl u d es t h e tr a b e c ul ar m es h w or k  ( T M),  a tiss u e wit h  
c o ntr a ctil e  pr o p erti es  a n d  α - 2-a dr e n er gi c  r e c e pt ors.  It is w ell  a c c e pt e d  t h at r el a xi n g  of t h e T M  is 
t h e o pti m al  I O P l o w eri n g s ol uti o n.   T h us, t h e  n o n-s el e cti v e α -a nt a g o nist  N y x ol  is li k el y t o r el a x 
t h e T M  a n d  l o w er I O P  vi a t his m aj or   o utfl o w  p at h w a y. 
Tr e at m e nt   of gl a u c o m a  f o c us es  o n  o n e  of t h e m aj or  ris k f a ct ors: i ntr a o c ul ar  pr ess ur e (I O P), t h e 
pr ess ur e  of  t h e  a q u e o us  h u m or i n t h e a nt eri or  c h a m b er   of t h e e y e.   I O P is  a b al a n c e  b et w e e n  
pr o d u cti o n  (i nfl o w) a n d   o utfl o w  of  a q u e o us  h u m or i nt o a n d   o ut  of t h e a nt eri or  c h a m b er.  
A q u e o us  h u m or  is  pr o d u c e d b y  t h e cili ar y   b o d y.   A dr e n er gi c  a g o nists, s u c h as   e pi n e p hri n e 
g e n er all y  d e cr e as e   pr o d u cti o n  of  a q u e o us  h u m or3.  P ar a d o xi c all y,   pr a z osi n a n d   p h e nt ol a mi n e, 
b ot h  a dr e n er gi c   a nt a g o nists, als o  d e cr e as e   pr o d u cti o n  of  a q u e o us  h u m or a n d  l o w er I O P4. 
T h e   c o n v e nti o n al  o utflo w   p at h w a y f or t h e a q u e o us   h u m or i n cl u d es -  b ut is  n ot li mit e d t o - t h e 
tr a b e c ul ar  m es h w or k.   T h e T M  h as  s m o ot h-m us cl e – li k e  pr o p erti es a n d  is a cti v el y  i n v ol v e d i n 
a q u e o us  h u m or  d y n a mi cs  t hr o u g h c o ntr a ctil e  m e c h a nis ms.    S m o ot h-m us cl e – r el a xi n g s u bst a n c es 
ar e   k n o w n t o i n cr e as e  o utfl o w r at es a n d  r e d u c e I O P  wit h o ut aff e cti n g  t h e cili ar y  m us cl e,  
cir c u m v e nti n g  si d e eff e cts  s u c h as   a c c o m m o d ati v e c h a n g es   or mi osis 5.   Pr a z osi n, a n  
al p h a- 1- a nt a g o nist,  h as  b e e n  s h o w n t o e n h a n c e  u v e os cl er al   o utfl o w i n r a b bits6.  N y x ol  c a n  
p ot e nti all y  r e d u c e I O P  b y i n cr e asi n g  a q u e o us  h u m or  o utfl o w  vi a t his  p at h w a y as  w ell.   
Pr e vi o us  cli ni c al  st u di es  of N y x ol   c o n d u ct e d i n n or m al  h e alt h y  s u bj e cts  or s u bj e cts wit h  s e v er e 
ni g ht  visi o n  c o m pl ai nts   h a v e s h o w n t h at si n gl e d os es  a n d  tr e at m e nts f or  u p t o  3 0 d a ys  h a v e  
r es ult e d i n st atisti c all y si g nifi c a nt r e d u cti o ns i n I O P i n  n or m ot e nsi v e s u bj e cts, wit h   n o si g nifi c a nt 
l oc al   or s yst e mi c  a d v ers e eff e cts 2. 
Fr o m   a cli ni ci a n’s  p ers p e cti v e,  t h e c urr e ntl y  a v ail a bl e  tr e at m e nts f or gl a u c o m a   h a v e diff er e nt  
li mit ati o ns a n d  ris ks t h at  m ust  b e c o nsi d er e d  w h e n  t ail ori n g t h e c h oi c e   of tr e at m e nt t o a n  
i n di vi d u al s u bj e ct’s n e e ds  a n d  pr ef er e n c es.    S o m e t h er a p e uti c cl ass es  h a v e   k n o w n s yst e mi c 
a d v ers e  eff e cts,  f or e x a m pl e,  b et a -a dr e n er gi c   a nt a g o nists ( wit h c ar di o v as c ul ar  a n d  r es pir at or y 
eff e cts  s u c h as  br a d y c ar di a,  d ys p n e a,  a n d  w h e e zi n g) 7 a n d  al p h a - a g o nists ( wit h c e ntr al   n er v o us 
s yst e m eff e cts  s u c h as   dr y  m o ut h, fati g u e,  s e d ati o n, a n d   di z zi n ess)8.  O c ul ar  si d e eff e cts  ar e  
c o m m o n  wit h  t o pi c al  a g e nts a n d  t h e a c c e pt a bilit y   of diff er e nt  si d e eff e cts  c a n  v ar y  b y  p ati e nt.  
Wit h  r es p e ct t o effi c a c y,  t he  B alti m or e  E y e   S ur v e y  of  5 3 0 8 s u bj e cts f o u n d t h at  7 8 %  of  1 0, 4 4 4 
e y es  wit h  pri m ar y  O A G  ( P O A G) h a d  s cr e e ni n g I O P  of  <  2 5 m m H g 9, i n di c ati n g t h e i m p ort a n c e 
of  a c hi e vi n g  effi c a c y  at  t h es e l o w er I O P l e v els.   A r e gi m e n t h at e n c o ur a g es  c o m pli a n c e  is als o  
a n  i m p ort a nt  c o nsi d er ati o n.  Cli ni ci a ns  a n d  p ati e nts   w o ul d b e n efit  fr o m  h a vi n g a n   a d diti o n al 
t h er a p e uti c  o pti o n f or i n di vi d u ali zi n g gl a u c o m a  tr e at m e nt. 


O c u p hir e  P h ar m a,  I n c. 
2 1       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
2. 3.   R o ut e  of  a d mi nistr ati o n,   d os a g e r e gi m e n,  a n d tr e at m e nt  p eri o d 
As  t h e i nt e n d e d r o ut e  of a d mi nistr ati o n  f or N y x ol  is t o pi c al o c ul ar,  t his is t h e r o ut e t o  b e us e d  i n 
t his st u d y.   
T h e   d os e s el e ct e d f or t his st u d y, 1 %,  w as  s el e ct e d b as e d   u p o n pr e cli ni c al  s af et y st u di es a n d  t h e 
r es ults  of t h e  pr e vi o us o p ht h al mi c  cli ni c al  st u di es d es cri b e d   a b o v e. 
T h e  tr e at m e nt  p eri o d,  1 4 d a ys,  is s el e ct e d  o n t h e b asis   of pr e cli ni c al  s af et y st u di es d es cri b e d  i n 
t h e I B i n  a d diti o n t o o pti m al  effi c a c y  s h o w n b y   ot h er dr u gs 1 0.  
2. 4.   C o m pli a n c e    
T his  st u d y will   b e c o n d u ct e d  i n c o m pli a n c e  wit h  t h e  pr ot o c ol a n d  i n a c c or d a n c e  wit h   G o o d 
Cli ni c al  Pr a cti c e,  t h e et hi c al   pri n ci pl es s et f ort h i n t h e D e cl ar ati o n   of  H elsi n ki a n d  wit h  t h e U. S.  
C o d e  of  F e d er al   R e g ul ati o ns. 
2. 5.   St u d y   P o p ul ati o n 
A s a m pl e si z e  of  a p pr o xi m at el y  4 0  s u bj e cts  at l e ast  1 8 y e ars  of  a g e  a n d  wit h  O A G  or  O H T , will 
b e  r a n d o mi z e d  i n   a   1: 1  r ati o  t o  t h e   N y x ol   1 %   a n d   pl a c e b o   gr o u ps,   wit h  t h e   e x p e ct ati o n  t h at  
a p pr o xi m at el y  3 6  s u bj e ct s  will  c o m pl et e t h e st u d y.   
 
  
 


O c u p hir e  P h ar m a,  I n c. 
2 2       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
3.   O B J E C TI V E S  A N D  P U R P O S E  
T h e  o bj e cti v es   of t his st u d y ar e:  
•   T o  e v al u at e  t h e effi c a c y   of N y x ol  t o l o w er I O P i n O A G  a n d  O H T.  
•   T o  e v al u at e  t h e o c ul ar  a n d  s yst e mi c s af et y  of  Ny x ol  c o m p ar e d  t o its v e hi cl e . 
•   T o  e v al u at e   a d diti o n al effi c a c y  of  N y x ol  t o i m pr o v e  vis u al p erf or m a n c e . 
 


O c u p hir e  P h ar m a,  I n c. 
2 3       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
4.   S T U D Y  D E SI G N  
4. 1.   Pri m ar y   a n d s e c o n d ar y  e n d p oi nts 
Effi c a c y:  
T h e  pri m ar y  effi c a c y   e n d p oi nt is t h e  c h a n g e fr o m  Bas eli n e  t o D a y   1 5 i n m e a n   di ur n al I O P i n t h e 
st u d y e y e .  M e a n   di ur n al I O P is t h e m e a n   of t h e I O P m e as ur e m e nts  at  all  t hr e e ti m e p oi nts ( 8 A M, 
1 0 A M,  4 P M).   
A L L  T R E A T M E N T S  WI L L  B E  A D MI NI S T E R E D  T O  B O T H  E Y E S  A N D  I O P WI L L  B E  
M E A S U R E D  I N B O T H  E Y E S.  
T h e  e y e  wit h  t h e  hi g h er I O P at  t h e Q u alifi c ati o n  Visit  at  8 A M  is d esi g n at e d  as  t h e st u d y e y e.   I n 
t h e c as e  w h er e   b ot h e y es   h a v e t h e s a m e I O P, t h e st u d y e y e  will   b e t h e RI G H T  e y e.   B as eli n e  I OP 
e v al u ati o ns  will  o c c ur  b ef or e   d osi n g  o n D a y   1.  Tr e at m e nt -st u d y I O P e v al u ati o ns  will  o c c ur   o n 
D a ys   8  ±  1 D a y  a n d  D a y   1 5  ±  1 D a y .   F oll o w- u p I O P  e v al u ati o ns will  o c c ur  at   8A M   ±  1 5 
mi n ut es   o n D a y   1 6. 
I O P m e as ur e m e nts  at  t h e B as eli n e   Visit a n d   b ot h Tr e at m e nt -st u d y  Visits will   b e  d o n e at  8 A M,  
1 0 A M  a n d   4 P M.  All  I O P m e as ur e m e nts   h a v e  a  wi n d o w  of  ±  1 5 mi n ut es  wit h  at  l e ast  2  h o urs 
b et w e e n  t h e 8 A M  a n d  1 0 A M  ass ess m e nts.  I O P will   b e m e as ur e d  t wi c e i n  b ot h e y es   at all  ti m e 
p oi nts.   T h e  m e a n  I O P at  e a c h  ti m e p oi nt ( 8 A M, 1 0 A M,   4 P M) is t h e a v er a g e   of t h e  2 I O P 
m e as ur e m e nts  at  t h at ti m e p oi nt.  If t h e diff er e n c e  i n t h e t w o I O P m e as ur e m e nts  is  >  5 m m H g,   a 
t hir d m e as ur e m e nt  will  b e   o bt ai n e d, a n d  t h e t hr e e v al u es  a v er a g e d.  
S e c o n d ar y  effi c a c y   e n d poi nts  will   b e a n al y z e d  b y  st u d y e y e , f ell o w e y e  a n d  all  e y es  ( u nl ess 
ot h er wis e  i n di c at e d) a n d  will  i n cl u de:  
•   C h a n g e  fr o m B as eli n e  t o D a y   1 5 i n m e a n   di ur n al I O P i n t h e f ell o w e y e  a n d  all  e y es.  
•   C h a n g e  fr o m B as eli n e  t o D a y   8 i n m e a n   di urn al  I O P. 
•   M e a n  I O P at  e a c h   p ost-tr e at m e nt ti m e p oi nt ( 8 A M,  1 0 A M a n d   4 P M;  o n D a y   8 a n d  D a y  
1 5).   
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m B as eli n e  t o D a y   8 a n d  D a y   1 5 i n I O P at  e a c h  ti m e p oi nt 
( 8 A M,  1 0 A M, 4 P M),  a n d  D a y   1 6 at  8 A M.  
•   P er c e nt a g e   of s u bj e cts  a c hi e vi n g r e d u cti o ns  fr o m B as eli n e  t o D a y   8 a n d  D a y   1 5 i n I O P at  
8 A M   of gr e at er  t h a n or   e q u al t o  1 0 %,  1 5 %,  2 0 %,  2 5 % a n d   3 0 %. 
•   P er c e nt a g e  of  s u bj e cts  a c hi e vi n g D a y   8, D a y   1 5  a n d D a y   1 6 I O P l e v els at  8 A M   of l ess 
t h a n  or e q u al  t o  1 6m m H g,   1 8 m m H g,  2 0 m m H g  a n d  22 m m H g .  
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  D a y   8, D a y   1 5, a n d  D a y   1 6 i n I O P at  8 A M.  
•   C h a n g e  a n d  p er c e nt  c h a n g e  t o D a ys   8,  1 5, a n d   1 6 i n  p u pil di a m et er  at  8 A M.  
•   P er c e nt a g e   of s u bj e cts  ac hi e vi n g r e d u cti o ns  fr o m B as eli n e  t o D a y   8, D a y  1 5  a n d  D a y   1 6 
i n  p u pil di a m et er  at  8 A M,   of gr e at er  t h a n  or e q u al  t o  1 0 %,  1 5 %,  2 0 %,  2 5 %, a n d   3 0 %. 
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  t o D a y   8, D a y   1 5, a n d  D a y   1 6 i n b est  c orr e ct e d  
dist a n c e   vis u al a c uit y  ( B C D V A) ( ET D R S   hi g h c o ntr ast ) ( p h ot o pi c a n d   m es o pi c) at  8 A M . 


O c u p hir e  P h ar m a,  I n c. 
2 4       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
•   C h a n g e  a n d  p er c e nt  c h a n g e  fr o m  Bas eli n e  t o D a y   8, D a y   1 5, a n d  D a y   1 6 i n dist a n c e  
c orr e ct e d  n e ar   vis u al a c uit y  ( D C N V A) ( E TD R S  hi g h  c o ntr ast ) ( p h ot o pi c  a n d  m es o pi c) at  
8 A M .  
•   P er c e nt a g e   of s u bj e cts  a c hi e vi n g i m pr o v e m e nts  fr o m  Bas eli n e  t o D a y   8, D a y   1 5, a n d  D a y  
1 6  i n B C D V A  a n d  D C N V A  ( p h ot o pi c a n d  m es o pi c)   of gr e at er  t h a n  or e q u al  t o  1 li n e,  2 
li n es a n d   3 li n es. 
All  S e c o n d ar y   E n d p oi nts r el at e d t o I O P will   b e a n al y z e d   a d diti o n all y i n t h os e s u b p o p ul ati o ns 
wit h  B as eli n e  I O P of  < 2 5 m m H g  a n d  ≥ 2 5 m m H g.  
T h e  li g hti n g  c o n diti o ns will   b e  k e pt t h e s a m e fr o m visit  t o visit.   E v er y  eff ort  s h o ul d  b e m a d e  t o 
h a v e t h e  s a m e cli ni ci a n  p erf or m  t h e I O P m e as ur e m e nts  at  all  ti m e p oi nts a n d  at  all  visits.  
S af et y: 
T h e  pri m ar y  s af et y m e as ur es  ar e   obj e cti v e   bi o mi cr os c o pi c a n d   o p ht h al m os c o pi c e x a mi n ati o n,  
s u bj e cti v e o c ul ar  t ol er a bilit y, a n d  a d v ers e  e v e nts  (A Es ).  Ot h er  s af et y m e as ur es  ar e  s yst e mi c 
s af et y as  m e as ur e d  b y  h e art  r at e a n d   bl o o d pr ess ur e.   Uri n e   pr e g n a n c y t ests f or f e m al es  of 
c hil d b e ari n g   p ot e nti al will   b e  c o n d u ct e d.  
4. 2.   D es cri pti o n   a n d s c h e d ul e  of visits   a n d  pr o c e d ur es 
A p pr o xi m at el y  4 0 s u bj e cts  wit h  eit h er  O A G   or O H T  will   b e r a n d o mi z e d, f or  a t ar g et  of  3 6 
c o m pl et e d  s u bj e cts.  S u bj e ct s will   b e r a n d o mi z e d i n  a  1: 1 r ati o t o r e c ei v e  1  % N y x ol   or pl a c e b o  
o n c e  d ail y  f or  1 4 d a ys   b e gi n ni n g at   8 P M t o  1 0 P M  o n D a y   1 a n d   c o nti n ui n g t hr o u g h D a y   1 4.  
Effi c a c y  e v al u ati o ns  (I O P) will  t a k e pl a c e  at  t h e B as eli n e  a n d  t h e Tr e at m e nt -st u d y  Visit d a ys  
(D a y   8  ±  1 D a y  a n d  D a y   1 5  ±  1 D a y ) at   8A M ,  1 0A M , a n d   4P M .  All  I O P m e as ur e m e nts  h a v e   a 
wi n d o w  of  ±  1 5  mi n ut es  wit h  at  l e ast  2  h o urs b et w e e n  t h e 8 A M  a n d   1 0 A M ass ess m e nts.  T h er e  
will   b e  F oll o w- u p  Visits  o n D a y   1 6 at  8 A M   ±  1 5 mi n ut es  a n d  b y   p h o n e  o n D a y  2 2  ( 7  d a ys aft er  
t h e l ast Tr e at m e nt -st u d y  Visit). 
St u d y  pr o c e d ur es  ar e  s h o w n i n d et ail  i n T a bl e   1: 
 
 
 


O c u p hir e  P h ar m a,  I n c. 
2 5       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
T a bl e  1:  S c r e e ni n g,   W as h o ut, Q u alifi c ati o n , T r e at m e nt -st u d y,  a n d  F oll o w-U p s Visits  a n d  P r o c e d u r es  
  
S cr e e ni n g  
W as h o ut
† †  
( as  n e c ess ar y) 
Q u alifi c ati o n/ B a s eli n e *   
Tr e at m e nt  
Tr e at m e nt  
F oll o w -
u p  
T C 
F oll o w -
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*If  t h e s u bj e ct m e ets  all  t h e i n cl usi o n crit eri a  a n d  n o n e  of  t h e e x cl usi o n  crit eri a,  i n cl u di n g all  t hr e e I O P m e as ur e m e nts,  t his  Qu alifi c ati o n   Visit b e c o m es  t h e  Bas eli n e   Visit.  A  s u bj e ct n u m b er  is assi g n e d  aft er  
t h e s u bj e ct is q u alifi e d . 
* * N e w  t est ( V F 2 4 - 2 or  3 0 - 2 ar e  a c c e pt a bl e)  is r e q uir e d t o e v al u at e  s cr e e ni n g crit eri a  if t h e i nf or m ati o n is n ot  a v ail a bl e  fr o m  a pr e vi o us  t est wit hi n  t h e l ast si x m o nt h s. 
* * * C o nt a ct  or  N o n -C o nt a ct  P a c h y m etr y  c a n  b e  p erf or m e d  pr o vi di n g  th e  s a m e t y p e of  p a c h y m et er  is us e d  t hr o u g h o ut t h e st u d y f or all  s u bj e cts at  a n  i n di vi d u al sit e. 
†I O P  m e as ur e m e nts  h a v e  a  wi n d o w  of  ±  1 5  mi n ut es  wit h  at l e ast  2  h o urs  b et w e e n t h e  8 A M  a n d 1 0 A M  ass ess m e nts . 
† †S u bj e cts  n ot  pr e vi o usl y  tr e at e d wit h  a n y  gl a u c o m a  dr u gs  will  n ot  r e q uir e  a w as h o ut  p eri o d  a n d  m a y  r et ur n t h e f oll o wi n g d a y  or  u p  t o 3 5  d a ys  l at er f or t h eir Q u alifi c ati o n/ B as eli n e  Visit.


O c u p hir e  P h ar m a,  I n c. 
2 6       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
4. 3.   M e as ur es  t a k e n t o mi ni miz e/ a v oi d   bi as 
T his  is  a  d o u bl e m as k e d,  pl a c e b o   c o ntr oll e d st u d y wit h   1: 1 r a n d o mi z ati o n.   
4. 4.   St u d y   m e di c ati o ns 
N y x ol  ( 1 %) is  a st eril e,  n o n- pr es er v e d, is ot o ni c, b uff er e d   a q u e o us s ol uti o n  c o nt ai ni n g 
p h e nt ol a mi n e  m es yl at e  ( 1. 0 %),  m a n nit ol a n d  s o di u m a c et at e.   Pl a c e b o  is N y x ol  v e hi cl e,  
c o nsisti n g  of  n o n- pr es er v e d,  is ot o ni c, b uff er e d   a q u e o us s ol uti o n  c o nt ai ni n g  m a n nit ol a n d  
s o di u m a c et at e.   T h e  st u d y m e di c ati o ns  m a y  b e  a dj ust e d  wit h  N a O H  ( U S P)  or H Cl  ( U S P) 
t o  p H  4. 8.  T h e   pr o d u ct is p a c k a g e d  i n  a  o n e ml  L D P E   dr o p p er b ottl e   c o nt ai ni n g  0. 6 ml  f or 
si n gl e  d os e us e.  
4. 4. 1.  P a c k a gi n g  a n d  l a b eli n g 
N y x ol  ( 1 %) a n d  v e hi cl e  will   b e s u p pli e d as   a cl e ar,  c ol orl ess  t o sli g htl y  br o w n, 
n o n- pr es er v e d   a q u e o us s ol uti o ns i n  o n e ml   dr o p p er b ottl es   c o nt ai ni n g  0. 6 ml.   E a c h  b ottl e  
will   b e l a b el e d wit h  i n v esti g ati o n al l a b els wit h  t h e st u d y  n u m b er, s u bj e ct i niti als a n d   ot h er 
r el e v a nt i nf or m ati o n, i n cl u di n g  a st at e m e nt “ C a uti o n   – N e w  Dr u g   – Li mit e d  b y  F e d er al  
( U S) L a w  t o I n v esti g ati o n al Us e ”.    
4. 4. 2.  St o r a g e  of  st u d y  m e di c ati o n 
Pri or  t o  dis p e nsi n g t o t h e s u bj e ct, all  i n v esti g ati o n al m at eri al   m ust  b e st or e d i n  a s e c ur e 
l o c ati o n wit h  stri ctl y li mit e d a c c ess   d o c u m e nt e d b y  si g n at ur e  of  a ut h ori z e d  p ers o ns w h o  
m a y   dis p e ns e i n v esti g ati o n al m at eri als.   T h e   pr o d u cts s h o ul d  b e st or e d r efri g er at e d ( 2° C  t o 
8° C,  3 6° F  t o  4 6° F)  u ntil t h e  d a y b ef or e   us e  or  u ntil  pr o vi d e d t o t h e s u bj e ct.   St u d y 
m e di c ati o n   m ust  n ot  b e fr o z e n a n d   m ust  b e pr ot e ct e d  fr o m li g ht.  T h e  s u bj e ct s h o ul d  b e 
i nstr u ct e d t h at t h e  pr o d u ct m a y   b e k e pt  at  r o o m t e m p er at ur e o n c e   dis p e ns e d ( u p t o  2 5° C, 
7 7° F).   
4. 4. 3.  St u d y  m e di c ati o n  a c c o u nt a bilit y  
4. 4. 3. 1.  R e c ei pt   a n d  dis p ositi o n  of st u d y  m e di c ati o n 
T h e  I n v esti g at or  or d esi g n e e  (e. g. , st u d y  c o or di n at or  or p h ar m a cist)  will  m ai nt ai n   a f ull 
a c c o u nt a bilit y  r e c or d f or t h e st u d y m e di c ati o n  a n d  will   b e r es p o nsi bl e f or r e c or di n g t h e 
r e c ei pt,  dis p e nsi n g, a n d  r et ur n  of all  s u p pli es  of t h e st u d y dr u g   usi n g t h e i n v e nt ori es 
s u p pli e d b y  t h e  S p o ns or.  E a c h  s u bj e ct will  r e c ei v e s uffi ci e nt st u d y m e di c ati o n  f or t h e 
d ur ati o n  of t h e  tri al.   A  St u d y M e di c ati o n  B o x  will   b e  dis p e ns e d at  B as eli n e  Visit  ( D a y  1). 
As  d es cri b e d  i n S e cti o n   7. 2. 3, t h e s u bj e ct will  e m pt y  a n y  r e m ai ni n g  c o nt e nts fr o m t h e 
u nit- d os e  dr o p p er  b ottl e  f oll o wi n g e a c h  i nstill ati o n a n d  will  r et ur n i n  b a g gi es i n t h e 
ori gi n al  b o x es  A L L  o p e n e d  b ottl es  as  w ell  as  a n y   u n o p e n e d st u d y m e di c ati o n  at  
Tr e at m e nt -st u d y Visits  ( D a y  8  ±  1 D a y  a n d  D a y   1 5  ±  1 D a y ).  At  t h e D a y   8 Visit , t h e  b o x 
will   b e r e- dis p e ns e d t o t h e s u bj e ct f oll o wi n g st u d y  dr u g a c c o u nt a bilit y  a n d  r e m o v al  of 
o p e n e d st u d y  m e di c ati o n  m at eri als.    St u d y m e di c ati o n  a c c o u nt a bilit y  will  a g ai n  b e  
c o n d u ct e d  at  t h e D a y   1 5 Visit ,  b ut t h e b o x  will  n ot   b e r e- dis p e ns e d.  T h e  I n v esti g at or or  
d esi g n e e  will   a c c o u nt f or all  r e c ei v e d a n d  r et ur n e d st u d y m e di c ati o n.   T h e   m o nit or will  
r e vi e w  dis p e nsi n g a n d  st u d y m e di c ati o n   a c c o u nt a bilit y r e c or ds  d uri n g sit e visits  a n d  at  t h e 
c o m pl eti o n   of t h e st u d y  a n d  n ot e a n y  dis cr e p a n ci es.   All  i n v esti g ati o n al st u d y m e di c ati o n  
m ust  b e  st or e d i n  a s e c ur e f a cilit y, wit h  a c c ess  li mit e d t o t h e I n v esti g at or a n d   a ut h ori z e d 
st aff.  


O c u p hir e  P h ar m a,  I n c. 
2 7       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
4. 4. 3. 2.  R et ur n   of st u d y  m e di c ati o n 
W h e n  t h e st u d y is c o m pl et e d   or is t er mi n at e d b y   O c u p hir e, all  st u d y m at eri al  i n cl u di n g 
us e d  a n d   u n us e d st u d y m e di c ati o n  b ottl es  will   b e r et ur n e d t o  O c u p hir e ( or its d esi g n e e)   or 
d estr o y e d   u n d er t h e dir e cti o n   of s a m e.  All  st u d y m e di c ati o n  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 d.    A fi n al st u d y m e di c ati o n  
dis p ositi o n  will   b e c o m pl et e d  b y  t h e st u d y  c o or di n at or. 
4. 5.   E x p e ct e d   d ur ati o n  of s u bj e ct  p arti ci p ati o n 
T h e  t ot al l e n gt h  of s u bj e ct p arti ci p ati o n  is a p pr o xi m at el y   7- 8 w e e ks  wit h  si x cli ni c  visits  a n d  
o n e t el e p h o n e  c all  s u m m ari z e d  b el o w: 
•   S cr e e ni n g  Visit  ( 1 d a y) . 
•   W as h o ut  Visit/ p eri o d  ( as n e c ess ar y)  ( 4- 5 w e e ks  wit h  s af et y c h e c k  visit  at   2 w e e ks ). 
•   Q u alifi c ati o n/ B as eli n e  Visit  ( 1 d a y) . 
•   Tr e at m e nt -st u d y Visit  D a y   8 ( 1 w e e k) . 
•   Tr e at m e nt -st u d y Visit  D a y   1 5 ( 1 w e e k) . 
•   F oll o w- u p  cli ni c  Visit   o n D a y   1 6 ( 1 d a y) . 
•   F oll o w- u p t el e p h o n e  c all   o n D a y   2 2 ( 1 w e e k) . 
T h e   e x e c uti o n   of  t h e  e ntir e   st u d y  (first  s u bj e ct  s cr e e n   t hr o u g h  l ast  r a n d o mi z e d  s u bj e ct 
c o m pl et e d)  is e x p e ct e d  t o  b e a p pr o xi m at el y   6  m o nt hs. 
4. 6.   R a n d o miz ati o n  a n d  pr o c e d ur e  f or  br e a kin g  t h e  c o d e 
A r a n d o mi z ati o n  c o d e  f or all o c ati n g  t h e st u d y tr e at m e nts will   b e pr e p ar e d  b y   a m as k e d  
bi ost atisti ci a n   n ot c o n n e ct e d  wit h  t h e st u d y.  
At  t h e i niti ati o n  of st u d y r el at e d pr o c e d ur es,  e v er y   p ot e nti al s u bj e ct is assi g n e d   a 
S cr e e ni n g  n u m b er  i n n u m eri c al  or d er.   O n c e   a s u bj e ct is q u alifi e d  f or t h e st u d y 
(Q u alifi c ati o n/ B as eli n e   Visit) t h e s u bj e ct is assi g n e d   a r a n d o miz ati o n n u m b er  i n t h e  or d er 
pr o vi d e d  b y  t h e bi ost atisti ci a n.  
T h e  st u d y m e di c ati o ns  will   b e m as k e d  t o  b ot h I n v esti g at or a n d  st u d y s u bj e cts, as  w ell  as  
O c u p hir e.   Tr e at m e nt  assi g n m e nts  will   b e m as k e d  t o t h e I n v esti g at or, O c u p hir e,  a n d  t h e 
s u bj e cts.  O nl y  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 s eri o us  a d v ers e e v e nts  
( S A E) will  t h e r a n d o mi z ati o n  c o d e  b e u n m as k e d  b y  t h e st u d y p h ar m a cist   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,  O c u p hir e,  a n d/ or  ot h er  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.  
4. 7.   C oll e cti o n   of  d at a 
T h e  s o ur c e d o c u m e nt ati o n  f or all  d at a  c oll e ct e d  i n t h e st u d y will  m ai nt ai n e d  b y  t h e 
i n v esti g at or i n t h e s u bj e ct fil es at  t h e st u d y sit e.   All  ori gi n al d at a  c oll e ct e d   d uri n g t his tri al 
is t o  b e r e c or d e d  o n  p a p er c as e  r e p ort f or ms ( C R Fs) a n d  t h e n el e ctr o ni c a ll y e nt er e d  i nt o 
t h e d at a b as e  f oll o wi n g st u d y c o m pl eti o n . T h e  p a p er  C R F  is c o nsi d er e d  t o  b e t h e s o ur c e 
d o c u m e nt ati o n  f or t his st u d y.   
4. 8.   C o m pl et e d  s ubj e ct  
A  c o m pl et e d  s u bj e ct is d efi n e d  as   o n e w h o  c o m pl et es  all   pl a n n e d  d osi n g  a n d  pr o c e d ur es 
t hr o u g h D a y   2 2. 


O c u p hir e  P h ar m a,  I n c. 
2 8       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
4. 9.   N o n- c o m pl eti n g  s u bj e ct 
A  n o n- c o m pl eti n g  s u bj e ct is d efi n e d  as   o n e w h o  e xits  t h e st u d y b y  t h eir  o w n v oliti o n   or at  
t h e dis cr eti o n   of t h e I n v esti g at or  a n d/ or t h e M e di c al   M o nit or  pri or t o c o m pl eti n g  all   of t h e 
st u d y  pr o c e d ur es r e q uir e d  i n t his  pr ot o c ol.  A n y  su bj e ct  m a y  d e ci d e  t o  v ol u nt aril y 
wit h dr a w  fr o m t h e st u d y at  a n y  ti m e  wit h o ut pr ej u di c e.    
4. 9. 1.  St u d y  m e di c ati o n  dis c o nti n u ati o n  
T h e  st u d y m e di c ati o n  m a y   b e  dis c o nti n u e d f or t h e f oll o wi n g r e as o ns: 
•   A d v e rs e  E v e nts:  A d v ers e  e v e nts  i n cl u di n g cli ni c all y  si g nifi c a nt l a b or at or y 
a b n or m aliti es  a n d  i nt er c urr e nt dis e as es  r e p ort e d b y  t h e s u bj e ct  or o bs er v e d  b y  t h e 
i n v esti g at or wit h   d o c u m e nt ati o n  o n t h e c as e  r e p ort f or m (C R F ). 
•   D e at h:  If  a s u bj e ct di es,  t h e a d v ers e  e v e nt  t h at c a us e d  t h e d e at h  s h o ul d  b e 
d o c u m e nt e d  o n t h e  C R F  a n d   b e  n ot e d as  s eri o us  a n d f at al. 
•   Dis all o w e d  c o n c u r r e nt  m e di c ati o n:  A n y  m e di c ati o n   n ot all o w e d  b y  t h e  pr ot o c ol 
w o ul d  b e  a  pr ot o c ol  vi ol ati o n.  
•   L a c k   of effi c a c y:   A s u bj e ct m a y  el e ct  t o  dis c o nti n u e p arti ci p ati o n  i n t h e st u d y f or  a 
p er c ei v e d  l a c k of  effi c a c y.   
•   I n v esti g at o r d e cisi o n:  A  s u bj e ct m a y  b e   dis c o nti n u e d f or r e as o ns  ot h er t h a n t h os e 
b ull et e d   pr e vi o usl y if t h e i n v esti g at or t hi n ks it is  n ot i n t h e b est  i nt er est  of t h e 
s u bj e ct t o  c o nti n u e. 
•   Ot h e r:  If t her e  is a n y  ot h er  r e as o n f or s u bj e ct  dis c o nti n u ati o n t his s h o ul d b e   n ot e d 
o n t h e  C R F.  
T h e  r e as o n f or pr e m at ur e  st u d y m e di c ati o n   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 
a p pr o pri at e  C R F.   I n t h e e v e nt  t h at  dis c o nti n u ati o n  of st u d y m e di c ati o n   o c c urs aft er   a 
c o m pl et e d  si n gl e  d os e, t h e I n v esti g at or will  m a k e  e v er y  att e m pt  t o c o m pl et e  all  s u bs e q u e nt 
s af et y ass ess m e nts  at  D a y   1 5 a n d  D a y   2 2.   
4. 9. 2.  R e as o ns f o r  Wit h d r a w al  f r o m St u d y  
•   S u bj e ct  wit h dr a ws   c o ns e nt. 
•   S u bj e ct  is  n o n- c o m pli a nt, e. g . miss e d  t hr e e  or  m or e d ail y   us e  of m e di c ati o n . 
•   S u bj e ct  is l ost t o f oll o w- u p. 
•   S u bj e ct  wit h dr a ws  f or  ot h er r e as o n. 
4. 9. 3.  E nti r e  st u d y t e r mi n at e d 
T h e  e ntir e  st u d y m a y   b e t er mi n at e d b y  I n v esti g at ors  or t h e  S p o ns or.   Pr o m pt,  writt e n  
n oti c e  of r e as o n a bl e  c a us e  t o t h e  ot h er p art y  ( S p o ns or  or I n v esti g at ors, r es p e cti v el y) is 
r e q uir e d.   Pr o m pt  n oti c e t o t h e I R B a n d  t o r e g ul at or y a ut h oriti es  is als o  r e q uir e d. 
4. 9. 4.  A cti o ns  aft e r  dis c o nti n u ati o n  
All  s u bj e cts w h o   dis c o nti n u e st u d y m e di c ati o n   d u e t o  a r e p ort  of a n  A E  m ust   b e f oll o w e d-
u p  a n d   pr o vi d e d  a p pr o pri at e m e di c al  c ar e   u ntil t h eir si g ns a n d  s y m pt o ms  h a v e r e mitt e d  or 
st a bili z e d  or  u ntil  a b n or m al l a b or at or y fi n di n gs h a v e  r et ur n e d t o a c c e pt a bl e   or pr e -st u d y 
li mits. 


O c u p hir e  P h ar m a,  I n c. 
2 9       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
F or  a n y  s u bj e ct w h o  c h o os es  t o  wit h dr a w  c o ns e nt  or w h o  is  n o n-c o m pli a nt,  e v er y   p ossi bl e 
eff ort  s h o ul d  b e m a d e  b y  t h e I n v esti g at or t o ass ur e  t h er e is  a fi n al visit  t h at i n cl u d es all  
e x a mi n ati o ns  list e d f or t h e  F oll o w- u p  Visit. 
4. 1 0.  C o m pl et e d  st u d y 
T h e  st u d y is c o m pl et e d  w h e n  all  r a n d o mi z e d s u bj e cts  h a v e c o m pl et e d  t h e st u d y, all  C R Fs  
h a v e  b e e n  c o m pl et e d,  a n d  all  C R F  d at a  e nt er e d  i nt o t h e d at a b as e.   Fi n al  D B  l o c k will  
o c c ur  aft er  t h e l ast r a n do mi z e d  s u bj e ct c o m pl et es,  all  d at a  h as  b e e n  e nt er e d  a n d  all  q u eri es  
r es ol v e d.   
4. 1 1.  Pr o c e d ur e  aft er  t h e c o m pl eti o n  of  t h e st u d y 
W h e n  t h e st u d y is c o m pl et e d,   O c ul os will   pr o vi d e  O c u p hir e a n d  t h e I R B wit h   a bri ef  (i. e., 
o n e  t o t hr e e  p a g es) r e p ort,  c o nt ai ni n g  a  d es cri pti o n  of t h e st u d y, t h e  n u m b er  of s u bj e cts 
e nr oll e d, t h e  n u m b er  of  s u bj e cts c o m pl et e d  t h e  n u m b er  of s u bje ct s w h o   dr o p p e d  o ut a n d  
w h y,  effi c a c y  fi n di n gs a n d  a d v ers e  e v e nts.  
 


O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
5.   S U B J E C T  I N C L U SI O N A N D  E X C L U SI O N  C RI T E RI A  
S u bj e ct s m a y   q u alif y i n eit h er  e y e.   T h e  e y e  wit h  t h e hi g h er  I O P at  t h e 
Q u alifi c ati o n/ B as eli n e  Visit  at  8 A M  is d esi g n at e d  as  t h e st u d y e y e .  I n t h e c as e  w h er e   b ot h 
e y es   h a v e t h e s a m e I O P, t h e st u d y e y e  will   b e t h e RI G H T  e y e.   S e e  S e cti o n   9 f or m or e  
i nf or m ati o n  o n st atisti c al a n al ysis.   A L L  T R E A T M E N T S  WI L L  B E  A D MI NI S T E R E D 
T O  B O T H  E Y E S  ( O U).  
5. 1.   S u bj e ct  i n cl usi o n crit eri a  
1.   1 8  y e ars   of a g e   or gr e at er.  
2.   Di a g n osis  of  O A G   or O H T.    Th e   di a g n osis  of O H T   m ust  b e i n B O T H  e y es.   F or  
O A G   it  c a n   b e  i n  eit h er   e y e   a n d   O H T   i n  t h e  f ell o w  e y e.     A  r e p ort e d  hist or y  of 
u ntr e at e d  O H T  wit h  I O P ≥   2 2 mm H g  a n d  ≤   3 0m m H g  is pr ef err e d . 
3.   U ntr e at e d  or  tr e at e d O A G/ O H T  wit h   2  or f e w er o c ul ar   h y p ot e nsi v e  m e di c ati o ns. 
4.   U ntr e at e d  ( p ost- w as h o ut) m e a n  I O P ≥  2 2 m m H g   a n d ≤   3 0m m H g  i n t h e st u d y e y e  at  
t h e Q u alifi c ati o n   Visit ( 8 A M). 
5.   C orr e ct e d   vis u al  a c uit y   i n  e a c h   e y e   + 1. 0  l o g M A R  or  b ett er   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) i n e a c h  e y e  ( e q ui v al e nt t o  2 0/ 2 0 0  or b ett er).  
6.   Ot h er wis e  h e alt h y  a n d  w ell   c o ntr oll e d s u bj e cts. 
7.   A bl e  a n d  willi n g  t o gi v e  si g n e d i nf or m e d  c o ns e nt a n d  f oll o w st u d y i nstr u cti o ns. 
8.   A bl e  t o s elf-a d mi nist er   st u d y m e di c ati o n   or t o  h a v e  st u d y m e di c ati o n  a d mi nist er e d  
b y   a c ar e gi v er  t hr o u g h o ut t h e st u d y  p eri o d. 
5. 2  
S u bj e ct   e x cl usi o n crit eri a  
E x cl u d e d  fr o m t h e st u d y will   b e i n di vi d u als wit h  t h e f oll o wi n g c h ar a ct eristi cs  i n eit h er  
e y e:  
O p ht h al mi c:    
1.   Cl os e d   or v er y  n arr o w  a n gl es  ( Gr a d e  0- 1, S h aff er 1)  or a n gl es  t h at t h e i n v esti g at or 
j u d g es as  o c cl u d a bl e   a n d/ or wit h  e vi d e n c e  of  p eri p h er al   a nt eri or s y n e c hi a e  ( P A S) ≥  
1 8 0  d e gr e es  b y   g o ni os c o p y wit hi n   6  m o nt hs  pri or t o S cr e e ni n g  Visit  i n eit h er  e y e.   
2.   Gl a u c o m a:   ps e u d o-e xf oli ati o n   or  pi g m e nt  dis p ersi o n  c o m p o n e nt,  hist or y  of a n gl e  
cl os ur e,   or n arr o w  a n gl es.   N ot e:   Pr e vi o us l as er  p eri p h er al iri d ot o m y is N O T  
all o w e d.  
3.   K n o w n  h y p ers e nsiti vit y  t o a n y  α -a dr e n o c e pt or   a nt a g o nists. 
4.   Pr e vi o us  l as er  a n d/ or  n o n-l as er gl a u c o m a  s ur g er y  or  pr o c e d ur e i n eit h er  e y e . 
5.   R efr a cti v e  s ur g er y i n eit h er  e y e  (i. e. r a di al  k er at ot o m y, P R K,  L A SI K,  c or n e al  cr oss  
li n ki n g). 
6.   O c ul ar  tr a u m a i n eit h er  e y e  wit hi n  t h e  6  m o nt hs  pri or t o  Scr e e ni n g,   or  o c ul ar s ur g er y 
or  n o n- r efr a cti v e l as er tr e at m e nt wit hi n  t h e  3  m o nt hs  pri or t o  Scr e e ni n g . 
7.   R e c e nt   or c urr e nt   e vi d e n c e  of o c ul ar  i nf e cti o n  or i nfl a m m ati o n i n eit h er  e y e.   C urr e nt  
e vi d e n c e  of  cli ni c all y   si g nifi c a nt bl e p h aritis,  c o nj u n cti vitis,   or  a  hist or y of  h er p es  
si m pl e x   or h er p es  z ost er  k er atitis  at   Scr e e ni n g  i n eit h er  e y e . 


O c u p hir e  P h ar m a,  I n c. 
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8.   O c ul ar  m e di c ati o n  i n eit h er  e y e   of a n y   ki n d wit hi n  3 0  d a ys   of  Scr e e ni n g,  wit h  t h e 
e x c e pti o n    of  a)    o c ul ar   h y p ot e nsi v e  m e di c ati o ns   ( w hi c h    m ust   b e  w as h e d    o ut 
a c c or di n g   t o  t h e  pr o vi d e d  s c h e d ul e),  b)  li d  s cr u bs  ( w hi c h  c a n   b e  us e d   pri or  t o 
S cr e e ni n g   b ut  c a n n ot  b e us e d  aft er   Scr e e ni n g )  or  c)  l u bri c ati n g  dr o ps  for   dr y e y e  
( pr es er v ati v e-fr e e artifi ci al  t e ars), w hi c h  m a y   b e us e d  t hr o u g h o ut t h e st u d y. 
9.   Cli ni c all y  si g nifi c a nt  o c ul ar  dis e as e  i n eit h er  e y e  as  d e e m e d  b y  t h e i n v esti g at or (i. e., 
c or n e al  e d e m a,  u v eitis,  s e v er e k er at o c o nj u n cti vitis  si c c a) t h at mi g ht  i nt erf er e wit h  
t h e  st u d y,  i n cl u di n g   gl a u c o m at o us   d a m a g e  s o  s e v er e  t h at    w as h o ut  of   o c ul ar  
h y p ot e nsi v e  m e di c ati o ns  f or  1  m o nt h is  n ot j u d g e d s af e (i. e., c u p -t o- dis c r ati o  >  0. 8, 
s e v er e  vis u al fi el d d ef e ct) . 
1 0.  Hist or y   of di a b eti c  r eti n o p at h y. 
1 1.  C o nt a ct  l e ns w e ar  wit hi n   3 d a ys  pri or  t o a n d  f or t h e  d ur ati o n  of t h e st u d y. 
1 2.  C e ntr al  c or n e al  t hi c k n ess i n eit h er   > 6 0 0 μ m  at   Scr e e ni n g . 
1 3.  A n y  a b n or m alit y  i n eit h er  e y e   pr e v e nti n g r eli a bl e a p pl a n ati o n t o n o m etr y ( e. g. c e ntr al  
c or n e al  s c arri n g). 
S yst e mi c:  
1.   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 α -  a n d/ or β - a dr e n o c e pt or a nt a g o nists  
(i. e.  c hr o ni c  o bstr u cti v e  p ul m o n ar y  dis e as e   or  br o n c hi al ast h m a;   a b n or m all y  l o w 
bl o o d  pr ess ur e   or  h e art   r at e;  s e c o n d  or  t hir d  d e gr e e   h e art   bl o c k  or  C H F;   s e v er e 
di a b et es) . 
2.   Cli ni c all y   si g nifi c a nt  s yst e mi c  dis e as e   (i. e.,   u n c o ntr oll e d  di a b et es,   m y ast h e ni a  
gr a vis,   c a n c er,   h e p ati c,   r e n al,  e n d o cri n e  or  c ar di o v as c ul ar   dis or d ers)  t h at  mi g ht  
i nt erf er e wit h  t h e st u d y. 
3.   P arti ci p ati o n  i n a n y  i n v esti g ati o n al st u d y wit hi n   3 0 d a ys  pri or  t o  Scr e e ni n g . 
4.   Us e   of a n y  t o pi c al  or s yst e mi c a dr e n er gi c   or c h oli n er gi c  dr u gs   u p t o  3 0 d a ys   pri or t o 
S cr e e ni n g ,  or  d uri n g t h e st u d y  u nl ess t h e dr u g,   d os e a n d  r e gi m e n h as  b e e n   c o nsist e nt 
f or t h e  3 0 d a ys  pri or  t o S cr e e ni n g.  
5.   C h a n g es  i n s yst e mi c m e di c ati o n  t h at c o ul d  h a v e  a n  eff e ct   o n I O P wit hi n   3 0 d a ys  
pri or  t o  Scr e e ni n g   or a nti ci p at e d   d uri n g t h e st u d y. 
6.   W o m e n   of c hil d b e ari n g   p ot e nti al w h o  ar e   pr e g n a nt,  n ursi n g,  pl a n ni n g  a pr e g n a n c y,  
or  n ot  usi n g  a  m e di c all y   a c c e pt a bl e   f or m  of  birt h   c o ntr ol.  A n   a d ult  w o m a n   is 
c o nsi d er e d  t o  b e  of c hil d b e ari n g   p ot e nti al  u nl ess  s h e is  1 y e ar   p ost m e n o p a us al  or  3 
m o nt hs  p ost- s ur gi c al st erili z ati o n.  All  f e m al es  of c hil d b e ari n g   p ot e nti al  m ust  h a v e 
a  n e g ati v e  uri n e  pr e g n a n c y  t est r es ult at  t h e  Scr e e ni n g  e x a mi n ati o n  a n d  m ust  i nt e n d 
t o  n ot  be c o m e   pr e g n a nt  d uri n g t h e st u d y.  
7.   R esti n g  h e art  r at e ( H R)  o utsi d e t h e  n or m al  r a n g e ( 50- 1 1 0  b e ats  p er  mi n ut e  at  t h e 
S cr e e ni n g   or  Q u alifi c ati o n   Visit.   H R   m a y   b e  r e p e at e d  o n c e   o nl y  if  o utsi d e  t h e 
s p e cifi e d r a n g e f oll o wi n g at  l e ast  a  5 mi n ut e  r est p eri o d  i n t h e sitti n g  p ositi o n. 
  
8.   H y p ert e nsi o n  wit h  r esti n g di ast oli c   bl o o d  pr ess ur e ( B P)  >  1 0 5 m m H g   or s yst oli c B P  
>  1 6 0  m m H g  at  t h e  S cr e e ni n g  or Q u alifi c ati o n  Visit.  B P  m a y   b e r e p e at e d o n c e   o nl y 


O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
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if  o utsi d e t h e s p e cifi e d r a n g e f oll o wi n g at  l e ast  a  5 mi n ut e  r est  p eri o d i n t h e sitti n g 
p ositi o n.  
 


O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
6.   T R E A T M E N T  O F  S U B J E C T S 
A p pr o xi m at el y  4 0 s u bj e cts  wit h  eit h er  O A G   or O H T  will   b e  e nr oll e d, wit h   a t ar g et 
c o m pl eti o n   of  3 6 s u bj e ct s.  P at e nts  will   b e r a n d o mi z e d i n  a  1: 1 r ati o t o r e c ei v e  1  %  Ny x ol  
or  pl a c e b o  o n c e  d ail y  f or  1 4 d a ys   b e gi n ni n g at   8 P M t o  1 0 P M  o n D a y   1 (B as eli n e  Visit ) 
a n d   c o nti n ui n g t hr o u g h D a y   1 4.  I O P e v al u ati o ns  will  t a k e pl a c e  at  8 A M,   1 0 A M, a n d   4 P M 
o n  D a y   8  ±  1 D a y  a n d   o n D a y   1 5  ±  1 D a y , a n d  at  8 A M   o n D a y   1 6.  All  I O P m e as ur e m e nts  
h a v e  a  wi n d o w  of   ±  1 5 mi n ut es  wit h  at  l e ast  2  h o urs b et w e e n  t h e 8 A M  a n d   1 0 A M 
ass ess m e nts.  T h er e  will   b e  a  F oll o w- u p  p h o n e t el e p h o n e c all   7 d a ys  aft er  t h e l ast 
Tr e at m e nt -st u d y  Visit ( D a y  2 2). 
6. 1.   Tr e at m e nt  a d h er e n c e  
All  s u bj e cts will   b e i nstr u ct e d  o n t h e i m p ort a n c e  of f oll o wi n g t h e o n c e - a-d a y   d osi n g 
r e gi m e n.   B e gi n ni n g t h e  d a y of  t h e B as eli n e  Visit  ( D a y  1) s u bj e cts will  i nstill  o n e  dr o p  of 
st u d y m e di c ati o n  i n e a c h  e y e  at   8 P M t o  1 0 P M a n d  r e p e at t his  pr o c e d ur e  1 3 ti m es f or  a 
t ot al  of  1 4  d os es.  S u bj e ct s ar e  t o bri n g   u n us e d  b ottl es i nt o t h e st u d y sit e  o n t h e D a y   8 Visit  
a n d  t h e D a y   1 5 Visit .   Tr e at m e nt  a d h er e n c e will   b e m e as ur e d  b y   c o u nti n g t h e  dr o p p er 
b ottl es  at  t h e st art  of t h e st u d y, a n d  t h os e r e m ai ni n g at  e a c h  st u d y visit.    
6. 2.   C o n c o mit a nt  m e di c ati o ns 
As   n ot e d i n t h e e x cl usi o n  crit eri a  (S e cti o n   5. 2), t h e f oll o wi n g ar e   pr o hi bit e d: 
•   Us e   of  o c ul ar m e di c ati o n  wit hi n   3 0 d a ys   of t h e S cr e e ni n g  Visit ,  or a nti ci p at e d   us e 
d uri n g t h e  st u d y, wit h  t h e e x c e pti o n   of l u bri c ati n g  dr o ps f or  dr y e y e  (pr es er v ati v e -fr e e 
artifi ci al  t e ars), w hi c h  m a y  b e  us e d  t hr o u g h o ut t h e st u d y.  
•   Us e   of a n y  t o pi c al  or s yst e mi c a dr e n er gi c  or   c h oli n er gi c dr u gs   u p t o  3 0 d a ys   pri or t o 
S cr e e ni n g ,  or  d uri n g t h e st u d y  u nl ess t h e dr u g,   d os e a n d  r e gi m e n h as  b e e n   c o nsist e nt 
f or t h e  3 0 d a ys  pri or  t o S cr e e ni n g  (A p p e n di x  1 ).   A l ar g e  n u m b er  of dr u gs,   b ot h 
pr es cri pti o n  a n d   o v er-t h e- c o u nt er, c o nt ai n  a cti v e  i n gr e di e nts t h at c a n  aff e ct  i ntr a o c ul ar 
p r ess ur e.  T his   w o ul d i n cl u d e m a n y  e y e   dr o ps, s u c h as  Visi n e,  t h at  w o ul d  b e us e d  t o 
r e d u c e r e d n ess,  m ost  c o u g h  or c ol d  pr e p ar ati o ns,  a nti hist a mi n es  a n d   br o n c h o dil at ors, 
m ost  n os e- dr o ps,  m ost  bl o o d- pr ess ur e  m e di c ati o ns,  m a n y  dr u gs  us e d  f or mi gr ai n es,  
a n d  m a n y  ot h er  pr o d u cts.   If t h er e is  a n y  q u esti o n  a b o ut w h et h er   a m e di c ati o n  is 
a c c e pt a bl e,  O c u p hir e   or t h e M e di c al   M o nit or s h o ul d  b e c o ns ult e d   b ef or e  pr o c e e di n g. 
•   C h a n g es  i n s yst e mi c m e di c ati o n  t h at  c o ul d  h a v e a n  eff e ct   o n o c ul ar   a ut o n o mi c t o n e  3 0 
d a ys  pri or  t o S cr e e ni n g  or  a nti ci p at e d   d uri n g t h e st u d y.  
I nt er mitt e nt  us e  of  o v er-t h e- c o u nt er ( O T C) pr es er v ati v e -fr e e artifi ci al  t e ar l u bri c a nt 
pr o d u cts  is a c c e pt a bl e.   H o w e v er,   n o  ot h er o c ul ar  m e di c ati o ns  ( O T C  or  pr es cri pti o n) ar e  
all o w e d  wit hi n   3 0 d a ys  of  t h e S cr e e ni n g  Visit,   or  d uri n g t h e st u d y.  
T o pi c al   or s yst e mi c t h er a p y wit h   a g e nts t h at  c o ul d  h a v e a n  eff e ct   o n I O P is t o  b e 
c o nsist e nt  i n  d os e, r e gi m e n a n d   a g e nt wit hi n  t h e  3 0 d a ys  pri or  t o  Scr e e ni n g  a n d  t hr o u g h o ut 
t h e st u d y.  F or  e x a m pl e,   a s u bj e ct c a n  b e  tr e at e d wit h   a s yst e mi c  a dr e n o c e pt or  a nt a g o nist 
as  l o n g as  t h e p arti c ul ar  a g e nt  a n d  its  d os e a n d  r e gi m e n h a d  b e e n   c o nsist e nt f or t h e t hirt y 
3 0  d a ys  pri or  t o  Scr e e ni n g,  a n d  t h er e w as   n o r e as o n t o b eli e v e  t h at alt er ati o n   w o ul d  b e 
n e c ess ar y  at  s o m e  p oi nt l at er  d uri n g t h e st u d y.  
Us e   of all  m e di c ati o ns  s h o ul d  b e  d o c u m e nt e d  o n t h e  a p pr o pri at e C R F.   I n v esti g at ors ar e  
e n c o ur a g e d  t o c o nt a ct   O c u p hir e  or t h e M e di c al   M o nit or f or a n y   q u esti o ns r e g ar di n g 


O c u p hir e  P h ar m a,  I n c. 
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all o w e d  m e di c ati o ns.   J u d g m e nt  of  c o nti n u e d st u d y p arti ci p ati o n  b y  t h e s u bj e ct, a n d  
i n cl usi o n  of t his s u bj e ct’s s u bs e q u e nt visits  i n t h e s af et y a n d  effi c a c y  a n al ysis  will   b e m a d e  
b y   O c u p hir e. 
All  m e di c ati o ns  w hi c h  t h e s u bj e ct h as  t a k e n wit hi n   3 0 d a ys  pri or  t o t h e S cr e e ni n g  Visit  
a n d   d uri n g t h e st u d y will   b e r e c or d e d i n t h e C R F.   T h e  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 a n d  i n di c ati o n will   b e r e c or d e d f or e a c h  m e di c ati o n.   
F or   c o m bi n ati o n  pr o d u cts ( e. g.,  C o nt a c ®), t h e br a n d  n a m e  is r e q uir e d.  F or  
n o n- c o m bi n ati o n  pr o d u cts, t h e  g e n eri c  n a m e  is d esir e d.   T h e   us e of  r o uti n e  o p ht h al mi c 
di a g n osti c  p h ar m a c e uti c al  a g e nts  ( e. g., fl u or es c ei n a n d  l o c al a n est h eti c ) will   b e all o w e d,  
a n d  i n di vi d u al  d o c u m e nt ati o n  n ot r e q uir e d.  A n y  c h a n g e  i n  d osi n g p ar a m et ers  s h o ul d als o  
b e  r e c or d e d i n t h e C R F.  
 






O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
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C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
Vis u al  fi el d t ests  of  2 4- 2  or  3 0- 2 ar e  a c c e pt a bl e.   
7. 2. 2.  W as h o ut  P e ri o d  
Aft er  S cr e e ni n g,  st u d y p arti ci p a nts  will   b e r e q uir e d t o r efr ai n fr o m a d mi nistr ati o n   of a n y  
gl a u c o m a   dru gs  f or at  l e ast  2 8 d a ys  a n d   n o m or e  t h a n  3 5 d a ys   pri or t o t h e 
Q u alifi c ati o n/ B as eli n e  Visit .  T h e   w as h o ut s u bj e cts will   b e  br o u g ht b a c k  i n a p pr o xi m at el y  
tw o  w e e ks  aft er  t h e  S cr e e ni n g Visit  f or  a n I O P s af et y c h e c k .  I n t h e j u d g em e nt   of t h e 
i n v esti g at or, if t h er e is a n y  ris k t o t h e e y e (s) of  t h e s u bj e ct,  or if t h e m e a n  I O P i n eit h er  e y e  
is > 3 0 m m H g,  t h e n a n   a p pr o pri at e r es c u e or   pri or m e di c ati o n  will   b e a d mi nist er e d,  a n d  t h e 
s u bj e ct will   b e  c o nsi d er e d  a s cr e e n f ail ur e.  A d v ers e e v e nts  o c c urri n g   d uri n g t h e  w as h o ut 
p eri o d  a n d   a r e vi e w of  c o n c o mit a nt  m e di c ati o ns  will  als o   b e ass ess e d  at  t his visit.   
U n m e di c at e d  s u bj e cts  w h o m e et  t h e i n cl usi o n/ e x cl usi o n crit eri a  aft er  s cr e e ni n g  d o  n ot 
h a v e  a  w as h o ut  p eri o d.  T h es e  s u bj e cts m a y  r et ur n t h e f oll o wi n g  d a y or   u p t o  3 5 d a ys  l at er 
f or t h eir Q u alifi c ati o n/ B as eli n e  Visit.  
7. 2. 3.  Q u alifi c ati o n  Visi t/ B as eli n e ( D a y  1) 
At  t h e Q u alifi c ati o n/ B as eli n e   Visit, t h e s u bj e ct will   b e as k e d   h o w  d o  his/ h er e y es  f e el, a n d  
if t h er e h a v e  b e e n  a n y  c h a n g es  i n t h eir m e di c al   c o n diti o n,  or  c o n c o mit a nt m e di c ati o ns  
si n c e t h eir l ast visit.   A n y  a d v ers e  c h a n g es  i n t h e  c o n diti o n  of t h e s u bj e ct at  t his visit  ar e  
r e c or d e d i n t h e M e di c al/ O p ht h al mi c  Hist or y  C R F.  
At  t h e Q u alifi c ati o n/ B as eli n e  Visit : 
• F e m al es  of   c hil d b e ari n g  p ot e nti al will  t a k e  a  uri n e  pr e g n a n c y t est at  8 A M . 
• R e vi e w   of c o n c o mit a nt  m e di c ati o ns  at  8 A M . 
• I O P m e as ur e m e nts   usi n g  a 
 at   t h e B as eli n e  visit  a n d  
b ot h  Tr e at m e nt -st u d y visits  will   b e  d o n e at  8 A M,  1 0 A M  a n d   4 P M.  All  I O P m e as ur e m e nts  
h a v e  a    wi n d o w  of  ±  1 5  mi n ut es   wit h   at   l e ast  2  h o urs  b et w e e n   t h e  8 A M  a n d   1 0 A M 
ass ess m e nts.  I O P will   b e m e as ur e d  t wi c e i n  b ot h e y es  at  e a c h  ti m e p oi nt.   T h e m e a n   v al u e 
at  e a c h  ti m e p oi nt f or t h e st u d y e y e  will   b e us e d  i n effi c a c y  ass ess m e nts.   If t h e diff er e n c e  
i n t h e t w o I O P m e as ur e m e nts  is > 5  m m H g,   a t hir d m e as ur e m e nt  will   b e  o bt ai n e d, a n d  t h e 
t hr e e v al u es  a v er a g e d.  
• P u pil  di a m et er ,  usi n g  a 
, n e ar   vis u al a c uit y   usi n g  a st a n d ar d 
c h art  h el d  at   1 4 i n c h es a n d  dist a n c e   vis u al a c uit y  wit h  E T D R S  ar e  m e as ur e d  at  8 A M.  
• R esti n g  H R  a n d  B P  ar e  m e as ur e d  at   8A M  a n d   4 P M.  Bl o o d  pr ess ur e,  usi n g t h e s a m e ar m,  
s a m e c uff  si z e  a p pr o pri at e f or ar m  cir c u mf er e n c e  t hr o u g h o ut t h e st u d y, a n d  h e art  r at e 
s h o ul d  b e m e as ur e d  aft er  at  l e ast  3 mi n ut es  r est i n t h e sitti n g  p ositi o n. If H R   or B P  ar e  
o utsi d e t h e  n or m al  r a n g e (s e e  E x cl usi o n Crit eri a   – S yst e mi c  # 7  a n d   # 8), t h e y m a y  b e  
r e p e at e d  o nl y o n c e  f oll o wi n g at  l e ast  a  5 mi n ut e  r est  p eri o d i n t h e sitti n g p ositi o n . 
• E y e  r e d n ess ( c o nj u n cti v al h y p er e mi a)   vis u all y c h e c k e d  at  8 A M,   1 0 A M a n d   4 P M  usi n g 
 
• A d v ers e  e v e nts  will   b e r e vi e w e d at  e a c h  ti m e p oi nt. 
T o   c o nti n u e i n t h e st u d y, t h e s u bj e ct  m ust  h a v e  a m e a n  I O P ≥   2 2 m m H g  at   8A M  a n d  ≥   1 9 
m m H g  at   1 0A M  a n d   4P M  i n t h e st u d y e y e  aft e r  t h e  w as h o ut p e ri o d  (if r e q uir e d) at  t h e 
Q u alifi c ati o n   Visit (8 A M ). 


O c u p hir e  P h ar m a,  I n c. 
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S u bj e ct s m a y   q u alif y i n eit h er  e y e.   T h e  e y e  wit h  t h e hi g h er  I O P at  t h e Q u alifi c ati o n  Visit  
at  8 A M  is d esi g n at e d  as  t h e st u d y e y e  f or t h e effi c a c y   e n d p oi nts.  I n t h e c as e  w h er e   b ot h 
e y es   h a v e t h e s a m e I O P, t h e st u d y e y e  will   b e t h e RI G H T  e y e.   S e e  S e cti o n   9 f or  mor e  
i nf or m ati o n  o n st atisti c al a n al ysis.   A L L  T R E A T M E N T S  WI L L  B E  A D MI NI S T E R E D  
T O  B O T H  E Y E S  ( O. U.).  
If t h e s u bj e ct m e ets  all   of t h e i n cl usi o n crit eri a  a n d   n o n e  of t h e e x cl usi o n  crit eri a,  i n cl u di n g 
all  t hr e e ti m e p oi nt I O P m e as ur e m e nts,  t his q u alifi c ati o n  visit  b e c o m es  t h e B as eli n e   Visit,  a 
s u bj e ct  n u m b er is assi g n e d,  a n d   h e/s h e is r a n d o mi z e d i nt o t h e st u d y.  
Sit e   p ers o n n el will  d e m o nstr at e  t h e  pr o p er i nstill ati o n t e c h ni q u e t o t h e s u bj e ct at  t h e 
Q u alifi c ati o n/ B as eli n e   Visit ( D a y 1)  a n d  t h e s u bj e ct will  s elf-a d mi nist er   a  d os e  of artifi ci al  
t e ars at  t h e st u d y sit e, i nstilli n g  1  dr o p i n e a c h  e y e  fr o m t h e  u nit- d os e b ottl e  ( N ot e: if  a 
dr o p  is  n ot i nstill e d i nt o t h e e y e,  t h e s u bj e ct s h o ul d w ait  a p pr o xi m at el y   1 0- 1 5 s e c o n ds a n d  
a d mi nist er   a s e c o n d dr o p).    T h e s u bj e ct s h o ul d  b e i n  a s e at e d  p ositi o n a n d  s h o ul d tilt  his  or 
h er  h e a d  b a c k w ar d  f or a d mi nistr ati o n   of t h e st u d y m e di c ati o n.   T h e  b ottl e  of  st u d y 
m e di c ati o n  s h o ul d  b e h el d  at  a n  al m ost  v erti c al  p ositi o n   a b o v e t h e e y e  w hil e  t h e l o w er 
e y eli d  is  p ull e d  d o w n  g e ntl y, a n d   1  dr o p is pl a c e d  i nt o t h e  c o nj u n cti v al c ul - d e-s a c.  T h e  ti p 
of t h e  b ottl e  s h o ul d  n ot t o u c h t h e e y e.   Aft er   a dr o p  is i nstill e d i n e a c h  e y e,  t h e s u bj e ct 
s h o ul d k e e p  t h e e y es  g e ntl y  cl os e d  f or a p pr o xi m at el y   3 0 s e c o n ds.  Aft er  s u c c essf ul 
i nstill ati o n  of t h e  dr o p i n e a c h  e y e,  t h e s u bj e ct s h o ul d c ar ef ull y  e m pt y  a n y  r e m ai ni n g 
c o nt e nts  as  dir e ct e d.  
T h e  s u bj e ct is gi v e n  t h eir st u d y m e di c ati o n   dr o p p er b ottl es , a n d  wit h  i nstr u cti o ns w h e n  t o 
a d mi nist er  t h e e y e   dr o p ( 8P M t o 1 0 P M ), a n d  w h e n  t o r et ur n t o t h e cli ni c.   
E a c h  s u bs e q u e nt e v e ni n g   of  d osi n g, t h e s u bj e ct will  a d mi nist er   o n e  dr o p t o e a c h  e y e  fr o m 
a  si n gl e n e w   u nit- d os e b ottl e  a n d  cl os e  t h e e y es  g e ntl y  f or  3 0 s e c o n ds, t h e n e m pt y  t h e 
r e m ai ni n g  c o nt e nts a n d  st or e t h e  o p e n e d  b ottl e i n t h e  b a g gi e  pr o vi d e d a n d  pl a c e  it i n t h e 
m e di c ati o n   b o x f or r et ur n t o t h e st u d y sit e at  t h e D a y   8 Visit .  E a c h  s u bs e q u e nt e v e ni n g   of 
d osi n g  ( a p pr o xi m at el y 2 4   h o urs b et w e e n   d os es), t h e s u bj e ct will  f oll o w t h e s a m e 
pr o c e d ur es.   At  t h e D a y   8 visit  t h e m e di c ati o n   b o x, c o m pl et e  wit h   o p e n e d b ottl es  a n d  a n y  
u n o p e n e d st u d y  m e di c ati o n  will   b e r et ur n e d t o t h e st u d y sit e w h er e  t h e  b a g gi es  of o p e n e d  
m e di c ati o n  will   b e r e m o v e d, a n d  t h e st u d y m e di c ati o n   b o x will   b e r e- dis p e ns e d wit h  t h e 
u n o p e n e d  m e di c ati o n.    D uri n g t h e s e c o n d w e e k   of tr e at m e nt, s u bj e cts will   c o nti n u e t o 
a d mi nist er   o n e  dr o p  of st u d y m e di c ati o n  t o e a c h  e y e  e v er y   ni g ht  usi n g  a n e w  b ottl e  f or 
e a c h   d os e, t h e n e m pt yi n g  t h e r e m ai ni n g  c o nt e nts of  t h at b ottl e  a n d  st ori n g t h e  o p e n e d 
b ottl es  i n t h e b a g gi es  a n d  pl a ci n g  t h e m b a c k  i n t h e  b o x t o r et ur n t o t h e st u d y sit e at  t h e 
D a y   1 5 Visit .  T h e  D a y  1 5  visit  will   b e t h e l ast d a y   of st u d y tr e at m e nt;  n o f urt h er st u d y 
m e di c ati o n  will   b e  dis p e ns e d at  t his visit.  
T h e  s u bj e ct s h o ul d  b e i nstr u ct e d t o c o nt a ct  t h e i n v esti g at or s h o ul d a d v ers e  e v e nts   of 
c o n c er n  o c c ur  (e. g.,  s h ort n ess  of  br e at h, f ai nti n g, et c. ).  If t h e e v e nt  is lif e-t hr e at e ni n g, t h e n 
t h e s u bj e ct s h o ul d g o  t o t h e e m er g e n c y  r o o m. 
7. 2. 4.  St u d y  D a y   8  ±  1 D a y  
O n   St u d y D a y   8, t h e s u bj e ct s h o ul d  bri n g t h eir  us e d  dr o p p er b ottl es  wit h  a n y   u n us e d 
m e di c ati o ns  wit h  t h e m f or  p ur p os es  of dr u g  a c c o u nt a bilit y.  At  t h e e n d   of t h e  St u d y D a y   8 
Visit  t h e st u d y m e di c ati o n   b o x will   b e r e- dis p e ns e d wit h  t h e  u n o p e n e d m e di c ati o n . 


O c u p hir e  P h ar m a,  I n c. 
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T h e  s u bj e cts will   b e as k e d  if t h e y h a d  a n y   pr o bl e ms wit h  t h eir e y es  fr o m t h e l ast visit , a n d  
if t h er e h a v e  b e e n  a n y  c h a n g es  i n t h eir m e di c al   c o n diti o n,  or  c o n c o mit a nt m e di c ati o ns  
si n c e t h eir l ast visit.   A n y  c h a n g es  i n t h e c o n diti o n   of t h e s u bj e ct  ar e r e c or d e d  as  a n 
a d v ers e  e v e nt.  
I n  a d diti o n,  o n  St u d y D a y   8: 
• R e vi e w   of c o n c o mit a nt  m e di c ati o ns  at  8 A M.  
• I O P m e as ur e m e nts  will  b e   d o n e at  8 A M,   1 0 A M  a n d  4 P M.  All  I O P m e as ur e m e nts   h a v e  a 
wi n d o w  of  ±  1 5  mi n ut es  wit h  at  l e ast  2  h o urs b et w e e n  t h e 8 A M  a n d   1 0 A M ass ess m e nts.  
I O P will   b e m e as ur e d  t wi c e i n  b ot h e y es  at  e a c h  ti m e p oi nt.   T h e  m e a n   v al u e at  e a c h  
ti m e p oi nt f or t h e  st u d y e y e  will   b e us e d  i n effi c a c y  ass ess m e nts.   If t h e diff er e n c e  i n t h e 
t w o I O P m e as ur e m e nts  is  > 5 m m H g,   a t hir d m e as ur e m e nt  will   b e  o bt ai n e d, a n d  t h e t hr e e 
v al u es  a v er a g e d.  
• P u pil  di a m et er , n e ar  a n d  dist a n c e   vis u al a c uit y , r esti n g h e art  r at e a n d   bl o o d pr ess ur e  ar e  
m e as ur e d  at   8A M .  Bl o o d pr ess ur e,   usi n g t h e s a m e ar m,  s a m e c uff  si z e  a p pr o pri at e f or 
ar m  cir c u mf er e n c e  t hr o u g h o ut t h e st u d y, a n d  h e art  r at e s h o ul d  b e m e as ur e d  aft er  at  l e ast 
3  mi n ut es  r est i n t h e sitti n g  p ositi o n. If H R   or B P  ar e   o utsi d e t h e  n or m al r a n g e (s e e 
E x cl usi o n  Crit eri a   – S yst e mi c   # 7 a n d   # 8), t h e y m a y   b e r e p e at e d  o nl y  o n c e f oll o wi n g at  
l e ast  a  5 mi n ut e  r est  p eri o d i n t h e sitti n g  p ositi o n. 
• E y e  r e d n ess ( c onj u n cti v al  h y p er e mi a)   vis u all y c h e c k e d  at  e a c h  ti m e p oi nt  usi n g    
s c al e. 
• A d v ers e  E v e nts  will   b e r e vi e w e d at  e a c h  ti m e p oi nt. 
7. 2. 5.  St u d y  D a y   1 5  ±  1 D a y  
O n   St u d y D a y   1 5, t h e s u bj e ct s h o ul d  bri n g t h eir us e d   dr o p p er b ottl es  a n d  a n y   u n us e d 
m e di c ati o ns  wit h  t h e m f or  p ur p os es  of dr u g  a c c o u nt a bilit y.  
T h e  s u bj e cts will   b e as k e d  if t h e y h a d  a n y   pr o bl e ms wit h  t h eir e y es  fr o m t h e l ast visit , a n d  
if t h er e h a v e  b e e n  a n y  c h a n g es  i n t h eir m e di c al   c o n diti o n,  or  c o n c o mit a nt m e di c ati o ns  
si n c e t h eir l ast visit.   A n y  c h a n g es  i n t h e c o n diti o n   of t h e s u bj e ct  ar e r e c or d e d  as  a n 
a d v ers e  e v e nt.  
I n  a d diti o n,  o n  St u d y D a y   1 5: 
• R e vi e w   of c o n c o mit a nt  m e di c ati o ns  a n d   a uri n e   pr e g n a n c y t est at  8 A M.  
• I O P m e as ur e m e nts  will  b e   d o n e at  8 A M,   1 0 A M  a n d  4 P M.  All  I O P m e as ur e m e nts   h a v e  a 
wi n d o w  of  ±  1 5  mi n ut es  wit h  at  l e ast  2  h o urs b et w e e n  t h e 8 A M  a n d   1 0 A M ass ess m e nts . 
I O P will   b e m e as ur e d  t wi c e i n  b ot h e y es  at  e a c h  ti m e p oi nt.   T h e  m e a n   v al u e at  e a c h  
ti m e p oi nt f or t h e  st u d y e y e  will   b e us e d  i n effi c a c y  ass ess m e nts.   If t h e diff er e n c e  i n t h e 
t w o I O P m e as ur e m e nts  is > 5  m m H g,   a t hir d m e as ur e m e nt  will   b e  o bt ai n e d, a n d  t h e t hr e e 
v al u es  a v er a g e d.  
• P u pil  di a m et er,  n e ar  a n d  d ist a n c e  vis u al a c uit y,  r esti n g h e art  r at e a n d   bl o o d pr ess ur e  ar e  
m e as ur e d  at  8 A M.   Bl o o d pr ess ur e,   usi n g t h e s a m e ar m,  s a m e c uff  si z e  a p pr o pri at e f or 
ar m  cir c u mf er e n c e  t hr o u g h o ut t h e st u d y, a n d  h e art  r at e s h o ul d  b e m e as ur e d  aft er   at l e ast 
3  mi n ut es  r est i n t h e sitti n g  p ositi o n. If H R   or B P  ar e   o utsi d e t h e  n or m al r a n g e (s e e 


O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
E x cl usi o n  Crit eri a   – S yst e mi c   # 7 a n d   # 8), t h e y m a y   b e r e p e at e d  o nl y  o n c e f oll o wi n g at  
l e ast  a  5 mi n ut e  r est  p eri o d i n t h e sitti n g  p ositi o n. 
• E y e  r e d n ess ( c o nj u n cti v al h y p er e mi a)   vis u all y c h e c k e d  at  e a c h  ti m e p oi n 
 
 
• A d v ers e  E v e nts  will   b e r e vi e w e d at  e a c h  ti m e p oi nt. 
• D ist a n c e a n d  n e ar   vis u al a c uit y,   p u pil di a m et er , a n d   a c o m pl et e   o p ht h al mi c e x a mi n ati o n,  
i n cl u di n g  bi o mi cr os c o p y will  als o   b e p erf or m e d  at   4 P M .   
S u bj e cts  c o m pl eti n g  t h eir D a y   1 5 Visit  s h o ul d  b e i nstr u ct e d n ot  t o r es u m e t h eir  ori gi n al 
gl a u c o m a  m e di c ati o n(s)   u ntil aft er  c o m pl eti o n   of t h e D a y   2 2  F oll o w- u p  p h o n e c all.  
7. 2. 6.  F oll o w- u p  Visit  ( D a y  1 6) 
T h e  s u bj e cts will   b e as k e d  if t h e y h a d  a n y   pr o bl e ms wit h  t h eir e y es  fr o m t h e l ast visit , a n d  
if t h er e h a v e  b e e n  a n y  c h a n g es  i n t h eir m e di c al   c o n diti o n,  or  c o n c o mit a nt m e di c ati o ns  
si n c e t h eir l ast visit .  A n y  c h a n g es  i n t h e c o n diti o n   of t h e s u bj e ct  ar e r e c or d e d  as  a n 
a d v ers e  e v e nt.  
I n  a d diti o n,  o n  St u d y D a y   1 6: 
• R e vi e w   of c o n c o mit a nt  m e di c ati o ns  at  8 A M.  
• I O P is m e as ur e d  t wi c e i n t h e st u d y e y e  at   8A M   ±  1 5 mi n ut es  a n d  t h e t w o v al u es  ar e  
a v er a g e d.   If t h e diff er e n c e  i n t h e t w o I O P m e as ur e m e nts  is > 5  m m  H g ,  a t hir d 
m e as ur e m e nt  is  o bt ai n e d, a n d  t h e t hr e e v al u es  ar e  a v er a g e d.  
• P u pil  di a m et er,  n e ar  a n d  dist a n c e   vis u al a c uit y,  r esti n g h e art  r at e a n d   bl o o d pr ess ur e  ar e  
m e as ur e d  at  8 A M.   Bl o o d pr ess ur e,   usi n g t h e s a m e ar m,  s a m e c uff  si z e  a p pr o pri at e f or 
ar m  cir c u mf er e n c e  t hr o u g h o ut t h e st u d y, a n d  h e art  r at e s h o ul d  b e m e as ur e d  aft er  at  l e ast 
3  mi n ut es  r est i n t h e sitti n g  p ositi o n. If H R   or B P  ar e   o utsi d e t h e  n or m al r a n g e (s e e 
E x cl usi o n  Crit eri a   – S yst e mi c   # 7 a n d   # 8), t h e y m a y   b e r e p e at e d  o nl y  o n c e f oll o wi n g at  
l e ast  a  5 mi n ut e  r est  p eri o d i n t h e sitti n g  p ositi o n. 
• E y e  r e d n ess ( c o nj u n cti v al h y p er e mi a)   vis u all y c h e c k e d  at  e a c h  ti m e p oi nt  usi n g  
 
 
• A d v ers e  E v e nts  will   b e r e vi e w e d at  8 A M.  
S u bj e cts  c o m pl eti n g  t h eir D a y   1 6 Visit  s h o ul d  b e r e mi n d e d n ot  t o r es u m e t h eir  ori gi n al 
gl a u c o m a  m e di c ati o n(s)   u ntil aft er  c o m pl eti o n   of t h e D a y   2 2  F oll o w- u p  p h o n e c all.  
7. 2. 7.  F oll o w- u p  p h o n e  c all  ( D a y  2 2) 
O n e  w e e k  aft er  t h eir l ast  d os e, s u bj e cts will   b e c all e d  a n d  as k e d  if t h e y h a d  a n y   pr o bl e ms 
wit h  t h eir e y es  fr o m t h e l ast visit  i n cl u di n g w h et h er  t h eir e y es  ar e  r e d, a n d  if t h er e h a v e  
b e e n  a n y  c h a n g es  i n t h eir m e di c al   c o n diti o n,  or c o n c o mit a nt  m e di c ati o ns  si n c e t h eir l ast 
visit .  A n y  c h a n g es  i n t h e  c o n diti o n  of t h e s u bj e ct  ar e r e c or d e d  as  a n  a d v ers e e v e nt.  
If  a n a d v ers e  e v e nt/r e a cti o n  is  u nr es ol v e d at  t h e ti m e  of t h e l ast visit   or if  a s u bj e ct r e p orts 
a  w ors e ni n g  of s y m pt o ms,  e v er y  eff ort  s h o ul d  b e m a d e  t o f oll o w  u p  u ntil t h e a d v ers e  
e v e nt/ a d v ers e  r e a cti o n 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 
ot h er r es ol uti o n  t o t h e e v e nt.  


O c u p hir e  P h ar m a,  I n c. 
4 1       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
All  s u bj e cts s h o ul d  b e a d vis e d  t o r es u m e t h eir  gl a u c o m a m e di c ati o ns  d uri n g  t his f oll o w-
u p   p h o n e c all.  
7. 2. 8.  U ns c h e d ul e d  Visits  
A n   U ns c h e d ul e d  Visit m a y  b e  a n y  visit  t o t h e I n v esti g at or ot h er  t h a n t h e s p e cifi c visits  
r e q u est e d i n t h e  pr ot o c ol as   p ossi bl y r e q uir e d f or t h e s u bj e ct’s  o p ht h al mi c  c o n diti o n.  T h e  
I n v esti g at or will  p erf or m  all   pr o c e d ur es n e c ess ar y  t o e v al u at e  t h e st u d y  p arti ci p a nt at  t h es e 
visits  a n d  r e c or d a n y  a d v ers e  e v e nts  i n t h e C R F . 
As   n ot e d i n S e cti o n   4. 9, e v er y   p ossi bl e eff ort  s h o ul d  b e m a d e  b y  i n v esti g at ors t o ass ur e  
t h at s u bj e cts w h o   dis c o nti n u e e arl y  fr o m t h e st u d y  h a v e  a fi n al visit  t h at i n cl u d es all  
e x a mi n ati o ns  list e d f or t h e  F oll o w- u p  Visit. 
7. 2. 9.  Visit   v a ri ati o n 
Visits   o n D a y   8 a n d   1 5 m a y  b e   1  d a y e arl y   or l at e.  If t h e visit  is l at e, t h e s u bj e ct s h o ul d  b e 
a d vis e d  t o t a k e a n   a d diti o n al  d os e fr o m  o n e of  t h e  2 s p ar e  dr o p p er b ottl e s  pr o vi d e d i n t h e 
st u d y m e di c ati o n   b o x t h e  ni g ht b ef or e  t h e visit.    T h e s u bj e ct s h o ul d t h e n  e m pt y t h e 
r e m ai ni n g  c o nt e nts a n d  st or e t h e  o p e n e d b ottl e  i n t h e  b a g gi e  pr o vi d e d a n d  pl a c e  it i n t h e 
m e di c ati o n   b o x f or r et ur n t o t h e st u d y sit e at  t h eir n e xt  visit .  If t h e D a y   1 5  Visit o c c urs  
o n e  d a y  e arl y   or l at e, t h e D a y   1 6  Visit a n d  t h e D a y   2 2 t el e p h o n e c all  s h o ul d  b e a dj ust e d  
a c c or di n gl y.   
 
 




O c u p hir e  P h ar m a,  I n c. 
4 3       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
D o c u m e nt ati o n  of  a d v ers e   e v e nts/ a d v ers e r e a cti o ns i n cl u d es st art d at e  a n d  st o p d at e,  
s e v erit y, a cti o n(s)  t a k e n, s eri o us n ess a n d   o ut c o m e.   
8. 3. 1.  A d v e rs e  e v e nt  d efi niti o ns  
T h e  f oll o wi n g d efi niti o ns   of t er ms  a p pl y t o t his s e cti o n: 
A d v ers e  e v e nt  m e a ns  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 dr u g  
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.  
Lif e -t hr e at e ni n g a d v er s e e v e nt   or lif e-t hr e at e ni n g s us p e ct e d a d v ers e  r e a cti o n.  A n  
a d v ers e  e v e nt   or s us p e ct e d a d v ers e  r e a cti o n 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 s u bj e ct  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 d v ers e  e v e nt   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.  
S eri o us  a d v ers e  e v e nt   or s eri o us s us p e ct e d a d v ers e  r e a cti o n.  A n   a d v ers e e v e nt   or 
s us p e ct e d a d v ers e  r e a cti on  is c o nsi d er e d  ‘‘s eri o us’’ 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,  it r es ults i n a n y   of t h e f oll o wi n g o ut c o m es:   
•   D e at h . 
•   A  lif e-t hr e at e ni n g  a d v ers e e v e nt . 
•   In p ati e nt  h os pit ali z ati o n   or  pr ol o n g ati o n  of e xisti n g  h os pit ali z ati o n . 
•   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. 
•   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,   b e lif e-t hr e at e ni n g, or  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 s u bj e ct  or s u bj e ct 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.  
S us p e ct e d  a d v ers e  r e a cti o n m e a ns  a n y  a d v ers e  e v e nt  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 d v ers e  e v e nt.   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 d v ers e   e v e nt.  S us p e ct e d  a d v ers e  r e a cti o n i m pli es  a 
l ess er 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 d v ers e  
e v e nt  c a us e d  b y   a dr u g.   
U n e x p e ct e d  a d v ers e  e v e nt   or u n e x p e ct e d  s us p e ct e d a d v ers e  r e a cti o n. A n  a d v ers e  e v e nt   or 
s us p e ct e d a d v ers e  r e a cti o n 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 
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  br 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,  as  a m e n d e d.   “ U n e x p e ct e d, ”  as  us e d  i n t his  d efi niti o n, als o  r ef ers t o a d v ers e  
e v e nts   or s us p e ct e d  a d v ers e r e a cti o ns t h at ar e  m e nti o n e d  i n t h e i n v esti g ator  br o c h ur e  as  
o c c urri n g  wit h   a cl ass   of  dr u gs or  as  a nti ci p at e d  fr o m t h e p h ar m a c ol o gi c al   pr o p erti es  of t h e 
dr u g  b ut  ar e   n ot s p e cifi c all y  m e nti o n e d as  o c c urri n g  wit h  t h e p arti c ul ar  dr u g   u n d er 
i n v esti g ati o n. 
A n y  m e di c al   c o n diti o n pr es e nt   pri or t o a d mi nistr ati o n   of t h e m as k e d  st u d y m e di c ati o n  
w hi c h  r e m ai ns u n c h a n g e d   or i m pr o v e d s h o ul d N O T   b e r e c or d e d as  a n  a d v ers e  e v e nt  at  
s u bs e q u e nt visits.  


O c u p hir e  P h ar m a,  I n c. 
4 4       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
As   n ot e d i n S e cti o n   7. 2. 1, a n y  c h a n g e  i n t h eir  Bas eli n e  h e alt h  st at us t h at is  n ot c o nsi d er e d  
t o  b e a n   a d v ers e e v e nt  s h o ul d  b e r e c or d e d  o n t h e M e di c al  Hist or y  p a g e  of  t h e C R F  ( e. g., 
t h e s u bj e ct h as  b e e n   di a g n os e d wit h  c a n c er).    
T h e  st u d y m e di c ati o n  r el ati o ns hi p f or e a c h   a d v ers e e v e nt/ a d v ers e  r e a cti o n s h o ul d  b e 
d et er mi n e d  b y  t h e I n v esti g at or  usi n g t h es e  e x pl a n ati o ns: 
•   N ot  R el at e d:   T h e  e v e nt  is cl e arl y  r el at e d t o  ot h er f a ct ors s u c h as  s u bj e ct’s cli ni c al  
c o n diti o n,  t h er a p e uti c i nt er v e nti o ns,  c o n c o mit a nt dis e as e   or t h er a p y a d mi nist er e d  t o 
t h e s u bj e ct a n d   d o es  n ot f oll o w  a  k n o w n r es p o ns e p att er n  t o t h e  pr o d u ct. 
•   P ossi bl y  R el at e d:   T h e   e v e nt f oll o ws  a r e as o n a bl e, t e m p or al s e q u e n c e fr o m t h e ti m e 
of st u d y  m e di c ati o n  a d mi nistr ati o n   a n d/ or f oll o ws  a  k n o w n r es p o ns e p att er n  t o t h e 
st u d y m e di c ati o n   b ut c o ul d   h a v e b e e n   pr o d u c e d b y   ot h er f a ct ors s u c h as  t h e s u bj e ct’s 
cli ni c al  st at e, t h er a p e uti c i nt er v e nti o ns  or  c o n c o mit a nt t h er a p y a d mi nist er e d  t o t h e 
s u bj e ct. 
•   R el at e d:   T h e  e v e nt  f oll o ws  a r e as o n a bl e, t e m p or al s e q u e n c e fr o m t h e ti m e  of st u d y 
m e di c ati o n  a d mi nistr ati o n   a n d/ or f oll o ws  a  k n o w n r es p o ns e p att er n  t o t h e st u d y 
m e di c ati o n  a n d   c a n n ot  b e r e as o n a bl y e x pl ai n e d   b y  ot h er f a ct ors s u c h as  s u bj e ct’s 
cli ni c al  st at e, t h er a p e uti c i nt er v e nti o ns  or  c o n c o mit a nt t h er a p y a d mi nist er e d  t o t h e 
s u bj e ct, a n d  eit h er  o c c urs  i m m e di at el y f oll o wi n g st u d y m e di c ati o n  a d mi nistr ati o n,   or 
i m pr o v es  o n st o p pi n g t h e st u d y m e di c ati o n,   or r e a p p e ars  o n r e p e at  e x p os ur e,  or t h er e is 
a  p ositi v e  r e a cti o n at  t h e a p pli c ati o n  sit e. 
I nt e nsit y (s e v erit y)  of a n  a d v ers e  e v e nt  is d efi n e d  as   a q u alit ati v e  ass ess m e nt   of t h e l e v el 
of  dis c o mf ort  of  a n  a d v ers e  e v e nt  as  is d et er mi n e d  b y  t h e I n v esti g at or  or r e p ort e d t o 
hi m/ h er  b y  t h e s u bj e ct.  T h e  ass ess m e nt   of i nt e nsit y is m a d e  irr es p e cti v e of  st u d y 
m e di c ati o n  r el ati o ns hi p  or s eri o us n ess  of t h e e v e nt  a n d  s h o ul d  b e e v al u at e d  a c c or di n g  t o 
t h e f oll o wi n g s c al e:  
•   1  =  Mil d:   pr es e nt,   b ut  n ot  distr essi n g, a n d   n o  disr u pti o n  of  n or m al d ail y  a cti vit y . 
•   2  =  M o d er at e:    dis c o mf ort s uffi ci e nt t o r e d u c e  or aff e ct   n or m al d ail y  a cti vit y . 
•   3  =  S e v er e:  i n c a p a cit ati n g, wit h  i n a bilit y t o w or k   or p erf or m   n or m al d ail y  a cti vit y . 
A  c h a n g e  i n s e v erit y f or  a r e p ort e d A E  will  r e q uir e  a st o p d at e  f or t h e  pr e vi o us s e v erit y 
a n d   a n e w  st art a n d  st o p d at e  f or t h e n e w  s e v erit y.   F or  e x a m pl e,   a c h a n g e  i n s e v erit y m a y  
g o  fr o m mil d  t o s e v er e  or fr o m s e v er e t o m o d er at e.   I n eit h er  c as e  t h e st art  or st o p d at es  
s h o ul d  b e r e c or d e d.  
A cti o n  t a k e n i n r es p o ns e t o a n  a d v ers e  e v e nt  is c o d e d  as:  
•   1 = N o n e . 
•   2 = St u d y  m e di c ati o n  i nt err u pt e d. 
•   3 = St u d y  m e di c ati o n   dis c o nti n u e d. 
•   4 = N o n -dr u g  t h er a p y. 
•   5 = N e w  O T C   or R x   dr u g a d d e d . 
•   6 = H os pit ali z e d  ( <  2 4  h o urs). 
•   7 = H os pit ali z e d  (≥   2 4  h o urs). 


O c u p hir e  P h ar m a,  I n c. 
4 5       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
O ut c o m e  of  a n  a d v ers e   e v e nt is c o d e d  as : 
•   1 = R e c o v er e d   wit h o ut s e q u el a e. 
•   2 = St a bl e  a n d   o n g oi n g. 
•   3 = O n g oi n g . 
•   4 = D e at h . 
•   5 = U n k n o w n/  L ost  t o f oll o w- u p. 
T h e  t er m “s e v er e ”  is  us e d t o d es cri b e  t h e i nt e nsit y (s e v erit y, s e e  a b o v e)  of a n  
e v e n t/r e a cti o n; t h e e v e nt/r e a cti o n  its elf m a y  b e   of r el ati v el y  mi n or m e di c al  si g nifi c a n c e 
(s u c h as  s e v er e h e a d a c h e).   T his  is  n ot t h e s a m e as   a “ S eri o us ”  A d v ers e   E v e nt, w hi c h  is 
b as e d   o n s u bj e ct/ e v e nt  o ut c o m e  or a cti o n  crit eri a   us u all y ass o ci at e d  wit h   e v e nts th at   p os e  a 
t hr e at t o t h e s u bj e ct’s lif e  or vit al  f u n cti o ns.  “ S eri o us ” n ess  ( N O T s e v erit y) s er v es as   a 
g ui d e  f or  d efi ni n g r e g ul at or y r e p orti n g  o bli g ati o ns. 
I n  pr e vi o us cli ni c al  st u di es  of N y x ol  t h e  m ost fr e q u e ntl y r e p ort e d a d v ers e   e v e nt w as  
c o nj u n cti v al  h y p er e mi a.   I n t h e p r es e nt  st u d y, i n v esti g at o rs  a r e  c a uti o n e d t o us e  t h e 
a p p r o p ri at e  v e r b ati m  t e r m  o n t h e a d v e rs e  e v e nt  f o r m t o d es c ri b e  t his  o bs e r v ati o n:  
•   R e d n ess  r el at e d  t o i nstill ati o n t h at is t r a nsi e nt (i. e., is n o  l o n g e r p r es e nt   2 h o u rs  
aft e r  i nstill ati o n)  =  “ c o nj u n cti v al e r yt h e m a  u p o n  i nstill ati o n ”. 
•   R e d n ess  t h at is N O T  t r a nsi e nt (i. e., is p r es e nt   2 h o u rs  aft e r  i nstill ati o n)  = 
“ c o nj u n cti v al  h y p e r e mi a ” . 
I n v esti g at ors ar e  als o  c a uti o n e d  t o  a p pro pri at el y   n ot e all   o bs er v ati o ns  of  c o nj u n cti v al 
h y p er e mi a  ( als o c all e d   c o nj u n cti v al er yt h e m a)   o n t h e  bi o mi cr os c o p y C R F . 
E x p e dit e d  r e p o rti n g   of S e ri o us   a n d U n e x p e ct e d  A d v e rs e  E v e nts : All  tr e at m e nt 
e m er g e nt  S A Es  (r el at e d a n d  u nr el at e d)  will   b e r e c or d e d fr o m t h e first a d mi nistr ati o n   of 
st u d y m e di c ati o n,  B as eli n e  Visit  ( D a y  1),  u ntil t h e fi n al st u d y visit,  f oll o wi n g t h e e n d  of  
tr e at m e nt  e x p os ur e.  A n y  S A Es  “s us p e ct e d ”  t o b e  r el at e d t o t h e i n v esti g ati o n al  pr o d u ct a n d  
dis c o v er e d  b y  t h e I n v esti g at or at  a n y  ti m e aft er  t h e st u d y s h o ul d  b e r e p ort e d. 
A n y  S A E  t h at o c c urs   m ust  b e r e p ort e d t o  O c ul os wit hi n   2 4  h o urs  of its  o c c urr e n c e  or wit hi n  
2 4  h o urs  of  l e ar ni n g  of its o c c urr e n c e.   R e c urr e nt   e pis o d es, c o m pli c ati o ns,   or  pr o gr essi o n  of 
t h e i niti al S A E  m ust   b e r e p ort e d t o  O c ul os as   f oll o w- u p t o t h e  ori gi n al  e pis o d e wit hi n  2 4  
h o urs  of  t h e  I n v esti g at or  r e c ei vi n g  t h e  i nf or m ati o n.  I nf or m ati o n  a b o ut  all  S A Es  will   b e 
c oll e ct e d  a n d  r e c or d e d o n  t h e S A E  f or m.  All   p erti n e nt m e di c al  r e c or ds  a n d i nf or m ati o n 
c oll e ct e d   d uri n g t h e tr e at m e nt a n d  f oll o w- u p  of t h e s u bj e ct s h o ul d  b e m ai nt ai n e d  at  t h e sit e 
wit h   a c o p y  e m ail e d  t o O G 2 0 1  S af et y @ O c ul os cr. c o m .   T h e  I n v esti g at or  m ust ass ess  t h e 
S A E  r el ati o ns hi p a n d  c o m pl et e  t h e S A E  f or m.   O c ul os m a y  r e q u est  a d diti o n al i nf or m ati o n. 
F oll o w- u p  i nf or m ati o n (e. g. ,  dis c h ar g e s u m m ar y) will   b e r et ai n e d i n t h e s u bj e ct’s c h art  a n d  
a  c o p y  will   b e e m ail e d  t o O G 2 0 1  S af et y @ O c ul os cr. c o m .  I n  a d diti o n, all  S A Es   s h o ul d  b e 
r e c or d e d  o n t h e A d v ers e   E v e nt C R F  p a g e  wit h  t h e s eri o us  q u esti o n m ar k e d  “ Y es ”.  
It is t h e i n v esti g at or’s r es p o nsi bilit y t o  n otif y t h e  a p pr o vi n g I R B  of a n y  S A Es   o n  a ti m el y 
b asis  as  i nstr u ct e d b y  t h e  S p o ns or f oll o wi n g t h e  S p o ns or’s d et er mi n ati o n  of  c a us alit y.   All  
s u bj e cts w h o  e x p eri e n c e  a n  S A E  s h o ul d  b e f oll o w e d cli ni c all y  a n d   u n d er g o t h e  a p pr o pri at e 
di a g n osti c  e v al u ati o ns  u ntil  st a bili z ati o n  or r es ol uti o n  of t h e e v e nt.   T h e   S p o ns or/ O c ul os 
will  r e p ort all  S A Es  t o t h e U S   F o o d a n d  Dr u g  A d mi nistr ati o n  ( F D A)  o n t h e  a p pr o pri at e 


O c u p hir e  P h ar m a,  I n c. 
4 6       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
s c h e d ul e  d e p e n di n g  if t h e e v e nt  is dr u g  r el at e d  or  n ot  dr u g r el at e d, e x p e ct e d,  u n e x p e ct e d  
( b as e d  o n t h e a v ail a bl e  i nf or m ati o n i n t h e I n v esti g at or’s  Br o c h ur e). 
A n y  d e at h  o c c urri n g   d uri n g t h e st u d y a n d  f oll o w  u p  p eri o d  m ust  b e r e p ort e d as  a n  S A E.  
F or  a n y  d e at h  o c c urri n g  t hr o u g h t h e e n d   of t h e st u d y, r e g ar dl ess  of t h e  d e gr e e  of 
r el ati o ns hi p t o st u d y dr u g,  t h e S A E  r es ulti n g i n t h e d e at h   m ust  b e r e p ort e d t o  O c ul os.   A 
d e at h  o c c urri n g  aft er  c o m pl eti o n   of t h e st u d y i n cl u di n g t h e S af et y   F oll o w- u p Visit s, t h at is 
n ot  r e as o n a bl y ass o ci at e d  wit h  st u d y dr u g  a d mi nistr ati o n,   d o es  n ot r e q uir e c o m pl eti o n   of 
t h e S A E  f or m. 
8. 3. 2.  F oll o w- u p   of s u bj e cts aft e r  a d v e rs e  e v e nts  
If a n  a d v ers e  e v e nt/ a d v ers e  r e a cti o n 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 m e nt as  d e e m e d  a p pr o pri at e.   If  a  n o n-s eri o us a d v ers e  e v e nt/ a d v ers e  r e a cti o n is 
u nr es ol v e d  at  t h e ti m e  of t h e l ast 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 d v ers e  
e v e nt/ a d v ers e  r e a cti o n is r es ol v e d  or st a bili z e d, t h e s u bj ect  is l ost t o f oll o w- u p,  or t h er e is 
ot h er r es ol uti o n  t o t h e e v e nt.   
 
 








O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
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C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
d et ai ls  of t h e i m p ut ati o n will   b e i n cl u d e d i n t h e st u d y St atisti c al  A n al ysis  Pl a n.   F or  t h e 
s u m m ari z ati o n  of s af et y d at a,  o bs er v e d  c as e  d at a   o nl y will   b e us e d . 
9. 5.   Pr o c e d ur e  f or r e p orti n g  d e vi ati o ns fr o m t h e st atisti c al  pl a n 
A n y   d e vi ati o ns fr o m t h e st atisti c al pl a n  will   b e d es cri b e d  a n d   a j ustifi 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  ( C S R).   
 
 


O c u p hir e  P h ar m a,  I n c. 
5 1       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
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0 4/ 0 8 / 1 9
 
 
 
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  A N D  D O C U M E N T S  
T h e  I n v esti g at or will  p er mit  st u d y-r el at e d  m o nit ori n g visits,   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 ur c e d at a  a n d   d o c u m e nts. 


O c u p hir e  P h ar m a,  I n c. 
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Cli ni c al  Pr ot o c ol  
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1 1.    Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E  
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,  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 I n v esti g at or’s sit e a n d  t h e M e di c al   M o nit or.  
T h e  I n v esti g at or will  all o w   O c u p hir e, t h e  St u d y  M o nit or, a n d  t h e M e di c al   M o nit or t o 
i ns p e ct all  C R Fs,  s u 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  c o ns e nt f or ms, r e c or ds of  
st u d y m e di c ati o n  r e c ei pt, st or a g e, pr e p ar ati o n,  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 his st u d y.  
 


O c u p hir e  P h ar m a,  I n c. 
5 3       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
1 2.    E T HI C A L  C O N SI D E R A TI O N S  A N D  G C P  C O M P LI A N C E   
1 2. 1.  G C P  c o m pli a n c e  
T h e   pr o p os e d st u d y is s u bj e ct t o all  a p pli c a bl e  g o v er n m e nt al  r ul es a n d  r e g ul ati o ns 
c o n c er ni n g  t h e  c o n d u ct of  cli ni c al  tri als  o n  h u m a n s u bj e cts.  T his  i n cl u d es,  b ut is  n ot 
n e c ess aril y  li mit e d t o, t h e  a p pr o v al of  I nstit uti o n al R e vi e w   B o ar ds, t h e  H elsi n ki 
D e cl ar ati o n,  U. S.  F D A  L a w,  I C H G C P  g ui d eli n es,   o bt ai ni n g  pr os p e cti v e i nf or m e d 
c o ns e nt,  m o nit ori n g  of  t h e  c o n d u ct  of t h e st u d y a n d  t h e c o m pl et e n ess   of t h e C R Fs  b y  
O c u p hir e  or  its d esi g n e e(s),  a n d   a p pr o pri at e r e c or d r et e nti o n b y  t h e I n v esti g at or.   
1 2. 2.  I nstit uti o n al R e vi e w  B o ar d  (I R B) 
T his   pr ot o c ol, m at eri als  us e d  t o r e cr uit s u bj e cts,  a n d m at eri als  us e d  t o  d o c u m e nt  c o ns e nt 
m ust  b e  a p pr o v e d  b y  t h e I R B  pri or t o i niti ati o n  of t h e st u d y.  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.   I n  a d diti o n t o  a p pr o vi n g t h e 
pr ot o c ol, t h e  I R B  m ust als o   a p pr o v e t h e S u bj e ct  I nf or m ati o n a n d   C o ns e nt F or m,  as  w ell  as  
a n y  a d v ertisi n g  t o ols t h at will   b e us e d  f or t h e st u d y.  Writt e n   a p pr o v al als o   m ust i n di c at e 
w h et h er   a p pr o v al w as  gr a nt e d  b as e d   o n f ull c o m mitt e e  r e vi e w  or e x p e dit e d  r e vi e w.  
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  O c u p hir e, pri or  t o t h e st art  of s u bj e ct  e nr oll m e nt 
i nt o t h e st u d y.  
1 2. 3.  Pr ot o c ol  D e vi ati o ns/ Vi ol ati o ns  
If t h e I n v esti g at or d esir es  t o  m o dif y t h e  pr o c e d ur es  a n d/ or d esi g n   of t h e st u d y,  h e or  s h e 
m ust  c o nt a ct  a n d   o bt ai n t h e  c o ns e nt a n d   a p pr o v al  of  O c u p hir e a n d  t h e I R B, r eg ar di n g  t h e 
pr o p os e d  c h a n g es,   pri or t o t h eir i m pl e m e nt ati o n.  C h a n g es  i m pl e m e nt e d aft er   o bt ai ni n g 
t his  a p pr o v al will   b e c o nsi d er e d   Pr ot o c ol D e vi ati o ns.   C h a n g es  i m pl e m e nt e d  wit h o ut  pri or 
a p pr o v al  will   b e  c o nsi d er e d  Pr ot o c ol Vi ol ati o ns.  
1 2. 4.   I nf or m e d c o ns e nt  r eq uir 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  s u bj e ct.   A c o p y   of t h e si g n e d  a n d  
d at 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 nv esti g at or’s  sit e. 
T h e  i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at n o  s u bj e ct is s u bj e ct t o a n y  st u d y-r el at e d 
e x a mi n ati o n   or a cti vit y  b ef or e  t h at s u bj e ct h as  gi v e n  i nf or m e d  c o ns e nt.  T h e  s u bj e ct  m ust 
gi v e  writt e n   c o ns e nt aft er  t h e r e c ei pt  of d et ail e d  i nf or m ati o n.  T h e   v er b al e x pl a n ati o n  will  
c o v er  all  t h e el e m e nts  s p e cifi e d i n t h e writt e n  i nf or m ati o n  pr o vi d e d f or t h e s u bj e ct. 
It s h o ul d  b e e m p h asi z e d  t h at t h e s u bj e ct is at  li b ert y t o  wit h dr a w  c o nse nt  t o p arti ci p at e  at  
a n y  ti m e,  wit h o ut p e n alt y   or l oss  of b e n efits  t o w hi c h  t h e s u bj e ct is  ot h er wis e e ntitl e d.  
S u bj e ct s w h o  r ef us e t o gi v e,   or wit h dr a w,  writt e n  i nf or m e d  c o ns e nt m a y   n ot  b e i n cl u d e d  or 
c o nti n u e d  i n t his st u d y,  b ut t his will   n ot i m p a ct  o n th eir  s u bs e q u e nt c ar e.   
T h e  i n v esti g at or will  i nf or m t h e s u bj e ct  of t h e ai ms,   m et h o ds, a nti ci p at e d  b e n efits  a n d  
p ot e nti al  h a z ar ds   of t h e st u d y, i n cl u di n g a n y  dis c o mf ort  it m a y  e nt ail.   T h e  s u bj e ct  m ust  b e 
gi v e n  e v er y   o p p ort u nit y t o cl arif y  a n y   p oi nts h e/s h e   d o es  n ot  u n d erst a n d a n d  if n e c ess ar y,  
as k  f or m or e  i nf or m ati o n.  At  t h e e n d   of t h e i nt er vi e w, t h e s u bj e ct m a y   b e  gi v e n ti m e t o 
r efl e ct if t his is r e q uir e d,  or if t h e s u bj e ct r e q u ests m or e  ti m e.  S u bj e ct s  a n d/ or l e g al 
g u ar di a n  will   b e r e q uir e d t o si g n a n d  d at e  t h e i nf or m e d  c o ns e nt f or m.  


O c u p hir e  P h ar m a,  I n c. 
5 4       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
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0 4/ 0 8 / 1 9
 
 
 
A  c o p y   of t h e si g n e d a n d  d at 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 at or’s sit e.  Si g n e d  i nf or m e d  c o nse nt   m ust  b e  o bt ai n e d  pri or t o t h e 
c o n d u ct a n c e  of  a n y  st u d y  pr o c e d ur es. 
 


O c u p hir e  P h ar m a,  I n c. 
5 5       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
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 o o d 
c o m p uti n g  pr a cti c es  m e eti n g  I C H a n d  U. S.   F o o d a n d  Dr u g  A d mi nistr ati o n  ( F D A) 
g ui d eli n es  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  E ntr y  
All st u d y  d at a  will  b e  e nt er e d i nt o  a  p a p er  C R F.  C R Fs  ar e  c o nsi d er e d t o  b e t h e s o ur c e 
d o c u m e nts f or t his st u d y.  D at a  will  b e  e nt er e d fr o m t h e  C R F i nt o t h e st u d y  d at a b as e.  
1 3. 2.  D at a  q u alit y   c o ntr ol  a n d r e p orti 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   O c u p hir e 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. 3.   Ar c hi vi n g   of  d at a 
Ar c hi v e d  v ers i o ns  of t h e d at a b as e  will   b e s a v e d b y   O c u p hir e  c o nsist e nt wit h  I C H  G o o d 
Cli ni c al  Pr a cti c es   G ui d eli n es,  c o m pl yi n g wit h  w hi c h e v er  of  t h e r e q uir e m e nts is l o n g er. 
O c u p hir e  will   n otif y t h e i n v esti g at or w h e n   d o c u m e nts s h o ul d  b e r et ur n e d. 
1 3. 4.   R e c or ds  r et e nti o n 
T h e  I n v esti g at or’s sit e a n d  cli ni c al  l a b or at or y 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 
c o m pli a n c e  wit h  I C H G o o d  Cli ni c al  Pr a cti c es   G ui d eli n es. 
1 3. 5.   A m e n d m e nts  t o t h e  pr ot o c ol 
M o difi c ati o ns  of t h e  si g n e d  pr ot o c ol ar e   o nl y  p ossi bl e b y   a p pr o v e d  pr ot o c ol a m e n d m e nts  
a n d  wit h  t h e a gr e e m e nt  of  all  r es p o nsi bl e  p ers o ns.  T h e   pr o c e d ur e f or a p pr o v al   of  a 
pr ot o c ol  a m e n d m e nt  is i d e nti c al t o t h at f or a p pr o v al   of t h e  pr ot o c ol.  T h e  I R B  m ust  b e 
i nf or m e d  of all   pr ot o c ol a m e n d m e nts  a n d  s h o ul d  b e as k e d  f or its  o pi ni o n as  t o w h et h er   a 
f ull r e-e v al u ati o n   of t h e et hi c al  as p e cts   of t h e st u d y is n e c ess ar y  b y  t h e c o m mitt e e.   T his  
s h o ul d  b e f ull y  d o c u m e nt e d. 
T h e  i n v esti g at or  m ust  n ot i m pl e m e nt a n y  d e vi ati o n  fr o m  or c h a n g e  t o t h e  pr ot o c ol,  wit h o ut 
dis c ussi o n  wit h,  a n d   agr e e m e nt  b y   O c u p hir e a n d  pri or  r e vi e w a n d  d o c u m e nt e d  
a p pr o v al/f a v or a bl e  o pi ni o n  of t h e  a m e n d m e nt  fr o m t h e r el e v a nt et hi cs  c o m mitt e e,  e x c e pt  
w h er e  it is n e c ess ar y  t o eli mi n at e  a n  i m m e di at e h a z ar d  t o st u d y s u bj e cts,  or w h er e  t h e 
c h a n g e(s)  i n v ol v es  o nl y l o gisti c al  or a d mi nistr ati v e  as p e cts   of t h e st u d y [e. g.,  c h a n g e  i n 
m o nit or(s),  c h a n g e  of  t el e p h o n e  n u m b er(s)]. 
Pr ot o c ol  a m e n d m e nts  will   b e s u b mitt e d t o t h e  a p pr o pri at e  a ut h orit y(i es) as  r e q uir e d b y  t h e 
a p pli c a bl e  r e g ul at or y r e q uir e m e nt(s). 
 
 
 




O c u p hir e  P h ar m a,  I n c. 
5 7       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 


O c u p hir e  P h ar m a,  I n c. 
5 8       
  
Cli ni c al  Pr ot o c ol  
O PI -N Y X G -2 0 1  A m e n d m e nt   1 
C O N FI D E N TI A L  
 
0 4/ 0 8 / 1 9
 
 
 
Bi bli o g r a p h y 
1.    
M c D o n al d,  M.  P h e nt ol a mi n e  M es ul at e  Tr e at m e nt   of S e v er e   Ni g ht Visi o n   C o m pl ai nts, 
A A O   A bstr a cts. ( 2 0 1 0). 
2.    
H oll a d a y, J.,  M e y er,  A.   & Pittli c k,  B.  P h e nt ol a mi n e M es yl at e  O p ht h al mi c  S ol uti o n  1 % 
O n c e  D ail y  R e d u c es  P u pil  Di a m et er   a n d I m pr o v es  Ni g ht Visi o n  Dist ur b a n c es,  A A O  
A bstr a cts . ( 2 0 1 8). 
3.  
G o el,  M.   A q u e o us H u m or  D y n a mi cs:   A  R e vi e w ~! 2 0 1 0- 0 3- 0 3 ~! 2 0 1 0- 0 6- 1 7 ~! 2 0 1 0- 0 9-
0 2 ~!  O p e n   O p ht h al m ol. J.  4,   5 2 – 5 9 ( 2 0 1 0). 
4.  
Ki el,  J. W.   & R eits a m er,  H.  A.  P ar a d o xi c al  Eff e ct   of  P h e nt ol a mi n e  o n  A q u e o us Fl o w  i n 
T h e   R a b bit. J.  O c ul.   P h ar m a c ol. T h er.  2 3,   2 1 – 2 6 ( 2 0 0 7). 
5.    
Wi e d er h olt,  M.,  T hi e m e,  H.   & St u m pff,  F.  T h e  r e g ul ati o n  of tr a b e c ul ar  m es h w or k a n d  
cili ar y  m us cl e  c o ntr a ctilit y.  Pr o g.  R eti n.  E y e  R es.  1 9,   2 7 1 – 9 5 ( 2 0 0 0). 
6.  
W a n g,  J. et   al. Diff er e nt  eff e cts   of t o pi c al  pr a z osi n a n d   pil o c ar pi n e  o n u v e os cl er al   o utfl o w 
i n r a b bit e y es.  Y a n  k e  x u e   b a o  = E y e  S ci.  1 9,   1 9 1 – 4 ( 2 0 0 3). 
7.    
A nt o n elli- I n c al zi, R.   &  P e d o n e, C.  R es pir at or y  eff e cts   of b et a -a dr e n er gi c  r e c e pt or 
bl o c k ers.  C urr.  M e d.  C h e m.  1 4,   1 1 2 1 – 8 ( 2 0 0 7). 
8.  
Gi o v a n nitti,  J. A.,   T h o ms, S.  M.   & Cr a wf or d,  J. J.  Al p h a- 2 A dr e n er gi c  R e c e pt or   A g o nists: 
A  R e vi e w   of  C urr e nt Cli ni c al   A p pli c ati o ns. A n est h.  Pr o g.  6 2,   3 1 – 3 8 ( 2 0 1 5). 
9.  
S o m m er,  A.  et   al. R el ati o ns hi p  b et w e e n  i ntr a o c ul ar pr ess ur e  a n d  pri m ar y  o p e n  a n gl e  
gl a u c o m a  a m o n g  w hit e   a n d bl a c k  A m eri c a ns.  T h e  B alti m or e  E y e  S ur v e y.  Ar c h.  
O p ht h al m ol. ( C hi c a g o,  Ill.   1 9 6 0) 1 0 9,   1 0 9 0 – 5 ( 1 9 9 1). 
1 0.  
L e wis,  R.  A.  et   al. Fi x e d - d os e  c o m bi n ati o n  of A R - 1 3 3 2 4 a n d  l at a n o pr ost:  A  d o u bl e-
m as k e d,   2 8-d a y,  r a n d o mis e d, c o ntr oll e d  st u d y i n p ati e nts  wit h   o p e n-a n gl e   gl a u c o m a  or 
o c ul ar   h y p ert e nsi o n. Br.  J.   O p ht h al m ol. 1 0 0,   3 3 9 – 3 4 4 ( 2 0 1 6). 
1 1.   S h er w o o d,  M.  B.  et   al. T wi c e -D ail y   0. 2 %  Bri m o ni di n e – 0. 5 % Ti m ol ol  Fi x e d - C o m bi n ati o n 
T h er a p y   vs  M o n ot h er a p y Wit h  Ti m ol ol   or  Bri m o ni di n e i n P ati e nts  Wit h  Gl a u c o m a   or 
O c ul ar   H y p ert e nsi o n. Ar c h.   O p ht h al m ol. 1 2 4,   1 2 3 0 ( 2 0 0 6). 
  
 
                                    

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