Randomized, Parallel Arm, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis in Healthy Subjects
Phase: PHASE3
Conditions: Mydriasis, Dilation
Sponsor: Ocuphire Pharma, Inc.

 
 
 
C O N FI D E N TI A L  
 
Cli nic al St u d y P h ase 3  P r ot oc ol  
O PI -N Y X R M -3 0 1  
MI R A -2  
 
R a n d o mize d,  P ar allel  Ar m , D o u ble -M as ke d,  Pl ace b o -C o ntr olle d  St u dy  o f the  
S afety  a n d  Effic acy  o f Ny x ol  (0. 7 5 %  P he nt ol a mi ne  O p ht h al mic  S ol uti o n)  to  
Reverse  P h ar m ac ol o gic ally -I n d uce d My dri asis  in  He alt hy  S u bjects  
 
 
Oc u p hire P har m a, I nc.  
3 7 0 0 0 Gra n d Ri ver A ve n ue, S uite 1 2 0  
Far mi n gt o n Hills , MI 4 8 3 3 5  
 
 
 
 
 
Versi o n:  
0 2  
Ori gi n al:  
A u g ust  2 0 , 2 02 0  
A me n d me nt  1 : 
 
Fe br u ar y 5, 2 0 2 1  
 
 
C O N FI D E N TI A L  
T his d oc u me nt c o ntai ns Oc u p hire P har m a, I nc.  ( Oc u p hire) i nf or mati o n t hat is c o nfi de ntial, a 
tra de secret a n d/ or pr o pri eta y i n nat ure. It is l oa ne d t o y o u f or y o ur c o nfi d e ntial use o n be half of 
Oc u p hire a n d is n ot t o be p h ot oc o pie d, discl ose d or tra ns mitte d t o a n y ot her pers o n or part y w h o 
is n ot c o vere d b y a C o nfi de ntial Discl os ure A gree me nt wit h Oc u p hire. As t he Pri nci pal 
I n v esti gat or y o u are res p o nsi ble f or t he safe kee pi n g a n d ret ur n of t his d oc u me nt t o Oc u p hire 
u p o n re q uest. Y o u will b e se nt u p date d i nf or m ati o n a n d/ or a me n d me nts as t he y bec o me 
a vaila ble.
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2  
0 2 /0 5 /2 1  
 
S U M M A R Y O F C H A N G E S  F O R A M E N D M E N T 1  
B ol d  u n derli ne d  te xt s h o ws a d diti o ns;  stri ket hr o u g h te xt s h o ws deleti o ns.  F or  c ha n ges t hat affect  
m ulti ple  secti o ns of  t he pr ot oc ol,  t he c ha n ge  is liste d o nce  at t he first i nsta nce bel o w,  a n d eac h 
s u bse q ue nt pr ot oc ol  secti o n i nc or p orati n g t hat c ha n ge  is als o liste d at t hat p oi nt.  A d mi nistrati ve  a n d 
mi n or  e diti n g  c ha n ges n ot  affect i n g t he c o nte nt  or  c o n d uct  of  t he pr ot oc ol  ha ve  bee n  ma de;  t hese are  
n ot  liste d. N o ne  of  t he c ha n ges ma de  affect  t he ris ks t o t he s u bjects i n t his st u d y. 
Secti o n : L oc ati o n  
Descri pti o n  of  C h a n ge  
R ati o n ale  f or 
C h a n ge  
S y n o psis:  Desi g n,  
p. 1 1  
A  ra n d o mize d, parallel  ar m,  d o u ble -mas ke d,  place b o -c o ntr olle d  
P hase  3  st u d y i n at least 1 6 8  ra n d o mize d s u bjects ( 1 6 0 c o m plete d  
e v al u a ble  f or effic ac y ), e val uati n g  t he safet y a n d  efficac y  of  
N y x ol  i n s u bjects wit h  p har mac ol o gicall y -i n d uce d m y driasis.  
Gl o bal c ha n ge t o 
clarif y  t hat 
e val ua ble s u bjects , 
w hic h are defi ne d 
wit hi n t he pr ot oc o l, 
will be use d f or 
efficac y a n al ysis 
S y n o psis:  Desi g n,  
p. 1 1  
T hat  is, a p pr o xi matel y  6 0 %  of  t he ra n d
mize d s u bjects will  
recei ve o ne  dr o p  of  2. 5 %  p he n yle p hri ne  1  o ur  bef ore  treat me nt 
( 9 6 c o m plete d  e v al u a ble  s u bjects), a p pr o xi ma el y  2 0 %  will  
recei ve o ne  dr o p  of  1 %  tr o pica mi de 1  h o r  bef ore  treat me nt ( 3 2 
c o m plete d  e v al u a ble  s u bjects), a n d  a p pr o xi matel y  2 0 %  will  
recei ve Pare m y d  1  h o ur  bef ore  treat me nt ( 3 2 c o m plete d  e v al u a ble  
s u bjects). 
S y n o psis:  Patie nt  
P o p ula ti o n, p. 1 2  
1 6 8 ra n d o mize d ( 1 6 0 c o m plete d  e al u a ble ) healt h y s u bjects. 
S y n o psis:  Visit  
Sc he d ule,  p. 1 4  
Ra n d o mizati o n  will  be  stratifie d 3: 1: 1  b y  m y driatic  a ge nt  ( 2. 5 % 
p he n yle p hri ne,  1 %  tr o pica i de, a n d  Pare m y d),  wit h  
ra n d o mizati o n i nt o ea h  m y driatic  a ge nt ca p pe d at a p pr o xi matel y  
9 6 : 3 2: 3 2 c o m plete d  e v al u a ble  s u bjects. 
S y n o psis:  Esti mate d  
T otal  Sa m ple  Size,  
p. 1 4  
A p pr o xi matel y  1 6 8  ra n d o mize d healt h y  s u bjects, wit h  
a p pr o xi matel y  1 6 0  c o m plete d  e v al u a ble  s u bjects. 
S y n o psis:  Sa m ple  
Size  J ustificati o n, 
p. 1 4  
9. 1  Sa m ple  Size,  p. 4 1  
A  sa m ple si e of  1 6 0  c o m plete d  e v al u a ble  s u bjects ( 8 0 per  
tr
t me nt gr o u p)  is nee de d  f or t he st u d y. T he  pri mar y  efficac y  
e n d p oi nt  will  be  met  if s u bjects s h o w a p ositi ve  effect  f or N y x ol  
( α =  0. 0 5  si g nifica nce, t w o-taile d). O ne  h u n dre d  a n d  si xt y 
c o m pl te d  e v al u a ble  s u bjects will  pr o vi de  
 
 bet wee n  t he N y x ol  a n d  place b o  ar ms i n 
perce nta ge  of  s u bjects ret ur ni n g t o ≤ 0. 2  m m  baseli ne  p u pil  
dia meter  at 9 0  mi n utes.  
S y n o psis:  D urati o n  of  
S u bject  Partici pati o n  
a n d  St u d y,  p. 1 7  
T he  e x ec uti o n  of  t he e ntire  st u d y (first s u bject scree n t hr o u g h last 
ra n d o mize d s u bject c o m plete d e v al u a ble ) is e x pecte d  t o be  
a p pr o xi matel y  3  t o 6  m o nt hs.  
4. 1 0  E val ua ble  
s u bjects, p. 3 0  
4. 1 0  E v al u a ble  s u bjects 
S u bjects  are  e v al u a ble  f or effic ac y  if t he y recei ve d  o ne  or  t w o 
dr o ps  of  st u d y tre at m e nt a n d  h a d  a  p u pil  di a m eter  
m e as ure m e nt  at  t he 9 0 -mi n ute  ti m e p oi nt  at  Visit  1 . 
A p pe n di x  2,  p. 4 9  
R A N D O MI Z A TI O N  S C H E M A  F O R  E V A L A U B L E  
S U B J E C T S  B Y  I N V E S TI G A TI O N A L T R E A T M E N T,  
M Y D RI A TI C  A G E N T,  A N D  I RI S C O L O R  
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3  
0 2 /0 5 /2 1  
 
S y n o psis:  Sec o n dar y  
Efficac y  E n d p oi nts,  
p. 1 5  
4. 1  Pri mar y  a n d  
sec o n dar y e n d p oi nts,  
p. 2 4  
7. 2  Assessi n g,  
rec or di n g, a n d  
a n al yzi n g  of  efficac y  
para meters,  p. 3 4  
S u bject  will  be  all o we d  t o accli mate  t o t hese li g hti n g c o n diti o ns  
( wit h t he e y es o pe n  n or mall y  f or a mi ni m u m  
) pri or  t o 
t he p u pil  dia meter,  B C D V A  a n d  D C N V A  (safet y meas ures) , a n d  
acc o m m o dati o n  meas ure me nts  at all sc he d ule d ti me p oi nts. S u bject  
will  sit i n t he e xa m  c hair  faci n g t he ill u mi nate d c hart d uri n g  t he 
accli mati o n  peri o d  a n d f or all assess me nts
 
 a n d  t he 
sc h e d ule d re mai ni n g  safet y assess me nts  (e. g. 
 
, a d verse  e ve nts,  s u bject q uesti o n naire,  etc.). 
T o clarif y t hat 
r o o m li g hts 
s h o ul d be o n 
d uri n g 
acc o m m o dati o n 
meas ure me nts  
9. 2  A nal ysis  
P o p ulati o ns,  p. 4 1  
Per  Pr ot oc ol  P o p ulati o n  ( P P):  T he  per  pr ot oc ol  ( P P) p o p ulati o n  
i ncl u ded s all s u bjects i n t he F A S mI T T  
 
, ha d  all sc he d ule d p u pil  dia meter  
meas ure me nts  d uri n g  Visit  1,  h a d  a n  i ncre ase of  >  0. 2  m m  i n P D  
i n t he st u d y e ye at  Ti m e  0  mi n utes  c o m p are d  t o B aseli ne  ( Ti m e 
– 1  h o ur),  a n d  ha d  n o  maj or  pr ot oc ol  d vi ati o ns.  T he  P P  p o p ulati o n  
will  be  use d  f or t he pri mar y  e n d p oi nt a na ysis a n d  t o a nal yze  
selecte d sec o n d ar y efficac y  e n d p oi nts. 
T o clarif y t he P P 
p o p ulati o n as 
ha vi n g a n i ncrease 
of > 0. 2 m m i n 
P D i n t he st u d y 
e ye at Ti me 0 
mi n utes c o m pare d 
t o Baseli ne  
S y n o psis  Sec o n dar y  
Efficac y  E n d p oi nts,  
p. 1 5  
4. 1  Pri mar y  a n d  
sec o n dar y e n d p oi nts,  
p. 2 3  
Sec o n dar y  efficac y  e n d p oi nts  (f or t he st u d y e ye; a n d  f or t he n o n -
st u d y e y e; a n d  f or t he best  of  eit her  e ye) will  i ncl u de: 
Gl o bal c h a n ge per 
F D A fee d bac k t o 
defi ne a n d use t he 
mI T T p o p ulati o n 
as well as 
i m p utati o n 
met h o ds f or 
missi n g data f or 
pri mar y efficac y 
a nal ysis.  
 
T o har m o nize t he 
pr ot oc ol wit h t he 
fi nal versi o n of 
t he Statistical 
A nal ysis P la n 
( V 1. 0) 
 
 
S y n o psis:  Sec o n dar y  
Efficac y  E n d p oi nts,  
p. 1 6  
4. 1. 1  Pri mar y  a n d  
sec o n dar y e n d p oi nts , 
p. 2 4  
7. 1  S pecificati o n  of  
t he efficac y  
para meters,  p. 3 3  
All  of  t he efficac y e n d p oi nts  will  be  a nal yze d  b y  F ull  A nal ysis  Set  
( F A S) a n d  Per  Pr ot oc ol  ( P P).T he  M o difie d  I nte nt-t o-Tre at  
( mI T T) will  be  use d  f r t he pri m ar y  e n d p oi nt  a n al ysis  a n d  t o 
a n al yze  selecte d sec n d ar y effic ac y  e n d p oi nts.  T he  Per  Pr ot oc ol  
( P P) p o p ul ati o n  will  be  use d  t o a n al yze  selecte d sec o n d ar y 
effic ac y  e n d p oi nts  S o m e  All of  t he efficac y  e n d p oi nts  will  be  
a n al yze d  o verall,  b y  m y driatic  a ge nt,  a n d  b y  li g ht/ dar k iri des. 
9  S T A TI S TI C S,  p. 4 1  
A det aile d prese nt ati o n of t he st atistic al a p pr o ac h is o utli ne d i n 
t he St atistic al A n al ysis Pl a n. 
9. 2  A nal ysis  
P o p ulati o ns,  p. 4 1  
F ull  A nal ysis  Set  M o difie d  I nte nt t o Tre at  (F A S mI T T ): T he  
F A S mI T T  will  i ncl u de all ra n d o mize d s u bjects w h o  recei ve d o ne  
or  t w o dr o ps  of  st u d y treat me nt a n d  t he n ha d  at least o ne  sc he d ule d 
p u pil  dia meter  meas ure me nt  d uri n g  Visit  1.  T he  F A S mI T T  will  be  
use d  f or t he pri m ar y  e n d p oi nt  a n al ysis  a n d  t o a nal yze  selecte d 
sec o n d ar y  efficac y  e n d p oi nts. 
9. 3. 2  De m o gra p hics  
a n d  baseli ne  
c h aracteristics,  p. 4 2  
De m o gra p hic  a n d  Baseli ne  c haracteristics  s uc h as a ge,  race a n d  
se x, will  be  s u m marize d b y  treat me nt gr o u p  usi n g  t he F A S mI T T , 
P P , S P,  a n d  t he A R P.   
9. 3. 4  Me dical  hist or y  
a n d  
pri or/c o nc o mita nt  
me dicati o ns,  p. 4 2  
Me dical  hist or y  will  be  c o de d  usi n g  t he latest versi o n  of  Me dical  
Dicti o nar y  f or Re g ulat or y  Acti vities  ( Me d D R A) a n d  will  be  
s u m marize d b y  treat me nt gr o u p  usi n g  t he F A S S P .  
Pri or  me dicati o ns  ( me dicati o ns wit h  a n  e n d  date  pri or  t o t he date  of  
ra n d o mizati o n) a n d  c o nc o mita nt  me dicati o ns  ( me dicati o ns wit h  a 
start or  e n d  date  after  t he date  of  ra n d o mizati o n) will  be  c o de d  
usi n g  W H O Dr u g  a n d  will  b ot h  be  s u m marize d b y  treat me nt gr o u p  
usi n g  t he F A S S P . 
9. 3. 5  A nal ysis  of  
efficac y , p. 4 2  
Efficac y  will  be  assesse d  usi n g  t he F A S mI T T  a n d  P P  wit h  s u bjects 
i ncl u de d i n t he treat me nt ar m  i n w hic h  t he y were  ra n d o mize d. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4  
0 2 /0 5 /2 1  
 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 2  
F or t he a nal ysis of t he pri mar y efficac y e n d p oi nt , o bser ve d case 
data will be use d ( n o i m p utati o n will be perf or me d f or missi n g 
data) f or t he pri mar y a nal ysis  i m p ut ati o n will be perf or m e d f or 
missi n g d at a as descri be d i n t he S t atistic al A n al ysis P l a n. 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 2  
If warra nte d, co nfir mat or y a nal yses usi n g t he A R P wit h i m p utati o n 
f or missi n g data will als o be perf or me d f or t he sec o n dar y efficac y 
e n d p oi nts.  
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 3  
T he  a n al ysis will  be  perf or me d  usi n g  t he F A S mI T T  a n d  P P,  wit h  
s u bjects i ncl u de d i n t heir ra n d o mize d treat me nt re gar dless of  t he 
treat me nt t he y act uall y recei ve d. 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 3  
Eac h  A N C O V A  will  be  perf or me d  usi n g  t he F A S mI T T  a n d  P P  
wit h  s u bjects i ncl u de d i n t heir ra n d o mize d treat me nt re gar dless of  
t he treat me nt t he y act uall y  recei ve d. 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 3  
F or t hese e n d p oi nts, t he F A S mI T T  a n d P P will be use d wit h 
s u bjects i ncl u de d i n t heir ra n d o mize d treat me nt re gar dless of t he 
treat me nt t he y act uall y recei ve d. 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 3  
A c o m p aris o n of t he st u d y a n d n o n -st u d y e ye f or e ac h s u bject 
will be c o m plete d f or t he pri m ar y effic a y e n d p oi nt, as well as 
b y m y dri atic a ge nt.  
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 3  
Ot her s u b gr o u ps, s uc h as a ge, se x, a n d ra e  ma y be a nal yze d as 
well. If t here is s ufficie nt sa m ple, a nal ysis of safet y a n dselecte d 
efficac y e n d p oi nts will be c o m p lete d f or t he s u b gr o u p of pe diatric 
s u bjects. 
9. 3. 5  A nal ysis  of  
efficac y,  p. 4 4  
O bser ve d  val ues  a n d  c ha n ge  fr o m baseli ne  (-1  h o ur)  i n c o nj u ncti val  
h y pere mia  at eac h  ti me p oi nt ( 0 mi n,  3 0  mi n utes,  6 0  mi n utes,  9 0  
mi n utes,  2  h o urs,  3,  h o urs,  4  h o urs,  6  h o urs,  a n d  2 4  h o urs),  will  be  
s u m marize d f or t he st u d y ye , a n d  t he n o n -st u d y e ye, a n d t he best  
of  eit her  e ye. Treat me nts  will  be  c o m pare d  usi n g  t he sa me 
A N C O V A  m o del  pr p ose d  f or t he c o nti n u o us  sec o n dar y efficac y  
e n d p oi nts.  
 
 
Vis ual  ac uit y  ass ss me nts  ( B C D V A a n d  D C N V A)  will  als o  be  
s u m marize d t eac h  time p oi nt  ( 0 mi n utes,  9 0  mi n utes,  6  h o urs,  a n d  
2 4  h urs)  usi n g  letters, a n d  l o g M A R u nits , a n d  t he n u m ber  of  li nes 
rea d. Letters  will  be  rec or de d, a n d  later c o n verte d t o l o g M A R a n d  
n u m ber  of  li nes rea d b y  pr o gra m mi n g  f or s uc h a nal yses.  O ne  letter 
is e q ui ale nt  t o 0. 0 2  l o g M A R. As  a  refere nce , fi ve letters is 
re prese nte d b y  1  li ne. Treat me nts  will  be  c o m pare d  usi n g  t he sa me 
A N C O V A  m o del  pr o p ose d  f or t he c o nti n u o us  sec o n dar y efficac y  
e n d p oi nts.  
 
 
. 
F or  I O P, Baseli ne  is defi ne d  as t he scree ni n g val ue.  O bser ve d  
val ues  a n d  c h a n ge  fr o m baseli ne  i n I O P at 6  h o urs  will  be  
s u m marize d f or t he st u d y e ye, a n d  t he n o n -st u d y e ye, a n d t he best  
of  eit her  e ye. 
9. 4  Pr o ce d ure  f or 
acc o u nti n g f or 
missi n g,  u n use d,  or  
s p uri o us data , p. 4 4  
F or  t he s u m marizati o n a n d  a nal ysis of  t he pri m ar y  efficac y data  
e n d p oi nt , t he f oc us will  be  o n  o bser ve d  case data  o nl y.  N o  
i m p utati o n will  be  perf or me d  f or missi n g  data.  As  a p pr o priate,  
c o nfir mat or y  efficac y  a nal yses  will  be  perf or me d  usi n g  i m p utati o n 
f or missi n g  data;  details  of  t he i m p utati o n, if perf or me d,  will  be  
i ncl u de d i n t he st u d y Statistical  A nal ysis  Pla n  i m p ut ati o n will  be  
perf or m e d  f or missi n g  d at a  as  descri be d  i n t he St atistic al  
A n al ysis  Pl a n . F or  t he s u m marizati o n a n d  a n al ysis  of  sec o n d ar y 
effic ac y  e n d p oi nts  a n d  safet y data,  o bser ve d  case data  o nl y  will  be  
use d.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
6  
0 2 /0 5 /2 1  
 
 
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 R M -3 0 1  
MI R A -2  
 
R a n d o mize d,  P ar allel  Ar m,  D o u ble -M as ke d , Pl ace b o -C o ntr olle d  St u dy  o f the   
S afety  a n d  Effic acy  o f N y x ol  ( 0. 7 5 % P he nt ol a mi ne  O p ht h al mic  S ol uti o n)  to   
Reverse  P h ar m ac ol o gic ally -I n d uce d My dri asis  in  He alt hy  S u bjects  
 
Versi o n:  
 
 
0 2  
 
 
Ori gi n al:  
 
 
A u g ust  2 0 , 2 02 0  
A me n d me nt 1:  
 
Fe br u ar y 5, 2 0 2 1  
 
I n v esti gat or A gree me nt: 
I, t he u n d ersi g ne d, h a ve re vie we d t his pr ot oc ol a n d I a gree t o c o n d uct t his pr ot oc ol i n acc or da nce 
wit h G o o d C li nical Practice, t he et hical pri nci ples set f ort h i n t he Decl arati o n of Helsi n ki a n d 
wit h t he U. S. C o de  of Fe deral Re g ulati o ns g o ver ni n g t he pr otecti o n of h u m a n s u bjects 
(2 1  C F R  5 0), I nstit uti o nal Re vie w B o r ds ( 2 1 C F R 5 6) a n d t he o bli gati o ns of cli nical 
i n vesti gat ors (2 1  C F R 3 1 2).  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Pr i nte d Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
7  
0 2 /0 5 /2 1  
 
P R O C E D U R E S I N C A S E O F E M E R G E N C Y  
 
E M E R G E N C Y C O N T A C T I N F O R M A TI O N  
R ole i n St u d y  
N a me  
C o nt act I nf or m ati o n  
Cli nical St u d y Lea der  
 
  
 
 
E mail: 
 
Me dical M o nit or  
 
 
 
 
E mail: 
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
8  
0 2 /0 5 /2 1  
 
A B B R E VI A TI O N S  A N D  T E R M S  
A b brevi ati o n  
F ull ter m  
A E  
A d verse E v e nt  
A N C O V A  
A nal ysis of C o varia nce  
A R P  
All Ra n d o mize d  P o p ulati o n  
B C D V A  
Best C orrecte d Dista n ce Vis ual Ac uit y  
B P  
Bl o o d Press ure  
° C 
De gree Ce nti gra de  
C C L R U  
C or nea a n d C o ntact L e ns Researc h U nit  
C F R  
C o de of Fe d eral Re g ulati o ns  
C H F  
C o n gesti ve Heart Fail ure  
CI  
C o nfi de nce I nter val  
C R O  
Cli nical Researc h Or ga ni zati o n  
C S R  
Cli nical St u d y Re p ort  
° F 
De gree Fa hre n h eit  
D B  
Data base  
D C N V A  
Dista nce C orrecte d Near Vis ual Ac uit y  
e C R F 
Electr o nic Case Re p ort F or m  
E T D R S  
Earl y Treat me nt  Dia betic Reti n o pat h y St u d y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
H R  
Heart Rate  
I B 
I n v esti gat ors’ Br oc h ure 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I N D 
I n v esti gati o nal Ne w Dr u g A p plicati o n  
I O P 
I ntr ao c ular Press ur e  
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-T o -Treat  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
9  
0 2 /0 5 /2 1  
 
I U D 
I ntr a-Uteri ne De vice  
L D P E  
L o w -De nsit y P ol yet h yle ne  
L S M  
Least S q uares M ea n  
M a x 
Ma xi m u m  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
mI T T  
M o difie d I nte nt -t o-Treat  
N y x ol  
0. 7 5 % P he nt ola mi ne O p ht hal mic S ol uti o n or 1 % P he nt ola mi ne Mes ylate 
O p ht hal mic S ol uti o n  ( N y x ol ®) 
O D  
Oc ul us De xter  
O R  
O d ds Rati o  
O S  
Oc ul us Si nister  
O T C  
O ver T he C o u nter  
O U  
Oc ul us Uter q ue ( b ot h e y es)  
Pare m y d ®  
1 % H y dr o x ya m p het a mi ne H y dr o br o mi de/ 0. 2 5 % T r o pica mi de 
P D  
P u pil Dia meter  
R A F  
R o yal Air F orc
 
S A E  
Seri o us A d verse E v e nt  
S E  
Sta n dar d Err or  
S O C  
S yste m Or ga n Class  
S P  
Safet y P o p ulati o n  
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
U S  
U nite d States  
U S P  
U nite d States P har mac o p eia  
V A  
Vis ual Ac uit y  
 
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 0  
0 2 /0 5 /2 1  
 
1.  S T U D Y  S U M M A R Y  
St u d y N u m ber  
O PI -N Y X R M -3 0 1  
Cli nic al P h ase  
P hase  3  
T y pe of St u d y  
Ra n d o mize d, parallel ar m, d o u ble -mas ke d, place b o -c o ntr olle d 
st u d y of t he safet y a n d efficac y of N y x ol ( 0. 7 5 % P he nt ola mi ne 
O p ht hal mic S ol uti o n) t o re verse p har m ac ol o gicall y -i n d uce d 
m y driasis i n healt h y s u bjects.  
N a me of I n vesti g ati o n al 
Pr o d uct  
N y x ol ® E ye D r o ps –  0. 7 5 % P he nt ola mi ne O p ht hal mic S ol uti o n  
D ur ati o n of St u d y  
2 da ys, i ncl u di n g scree ni n g /treat me nt a n d f oll o w-u p . 
R ati o n ale  
N y x ol is a o nce -d ail y preser vati ve -free e ye dr o p f or m ulati o n of 
p he nt ola mi ne, w hic h is a n o n -selecti ve al p ha-1 a n d al p ha-2 
a dre ner gic a nt a g o nist t hat acts o n t he a dre ner gic rece pt ors a n d 
i n hi bits c o ntracti n of t he s m o ot h m uscle. P he nt ola mi ne 
i n hi bits c o ntracti o n of t he iris dilat or m uscle, res ulti n g i n a 
s maller p pil size. 
P har mac ol o gicall y -i n d uce d m y driasis is ac hieve d eit her b y 
sti m ulati n g t he iris dilat or m uscle wit h t he use of direct or i n direct 
al p ha 1 a g nists (e. g. p h e n yle p hri ne , h y dr o x y a m p heta mi ne ), or b y 
bl oc ki n g t he iris s p hi ncter m uscle wit h t he use of m uscari nic 
a nta g o nists  or c ycl o ple gi c dr u gs  (e. g., tr o pi ca mi de), or 
c o m bi nati o n  (e. g., Pare m y d ® , w hic h is 1 %  h y dr o x ya m p heta mi ne 
h y dr o br o mi de  a n d 0. 2 5 %  tr o pica mi de).  
N y x ol,  eit her b y  directl y  a nta g o nizi n g  t he al p ha -1  rece pt or or  b y  
i n directl y a nta g o nizi n g  t he p u pil  dilati o n  effect of  m uscari nic  
bl oc ki n g,  ca n e x p e dite t he re versal of  m y driasis  pri or  t o nat ural  
re versal. 
I n a re v ersal of  m y driasis  p hase  2  cli nical  st u d y ( MI R A-1) , N y x ol  
all o we d p u pil  dilati o n  of  m ore  s u bjects t o ret ur n t o baseli ne  faster, 
it was  ge nerall y  well -t olerate d i n t he e y e ( m ost c o m m o n  c o m plai nt  
was  mil d  t o m o derate  c o nj u ncti val  h y pere mia)  a n d t here were  n o  
cli nicall y mea ni n gf ul  s yste mic effects  as meas ure d  b y  heart  rate 
( H R) a n d bl o o d  pre ss ure ( B P). 
St u d y O bjecti ves  
T he o bjecti ves of t his st u d y are:  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 1  
0 2 /0 5 /2 1  
 
•  T o e val uate t he effi cac y of N y x ol t o e x pe dite t he re versal 
of p har mac ol o gic all y-i n d uce d m y driasis  acr oss m ulti ple 
m y driatic a ge nts  wit h a n e m p hasis o n p he n yle p hri ne  
•  T o e val uate t he effi cac y of N y x ol t o ret ur n s u bjects t o 
baseli ne acc o m m o dati o n after w orse ni n g (wit h c y cl o ple gi c 
a ge nts  tr o pica mi de a n d Pare m y d ) 
•  T o e val uate t he s afet y of N y x ol  
•  T o e val uate a n y a d diti o nal be nefits of t he re versal of 
p har mac ol o gic all y-i n d uced  m y driasis  
T he S p o ns or i nte n ds t o use t his first P hase 3 re gistrati o n st u d y t o 
e val uate N y x ol  f or t he i n dicati o n “t he treat me nt of 
p har mac ol o gicall y -i n d uce d m y driasis pr o d uce d b y a dre ner gic 
( p he n yle p hri ne) or paras y m pat h ol ytic (tr o pica mi de) a ge nts, or a 
co m bi nati o n t here of.”  
Desi g n  
A ra n d o mize d, p arallel ar m, d o u ble -mas ke d, place b o -c o ntr olle d 
P hase 3 st u d y i n at least 1 6 8  ra n d o mize d s u bjects ( 1 6 0 e val ua ble 
f or efficacy ), e v al uati n g t he safet y a n d efficac y of N y x ol i n 
s u bjects wit h p har mac ol o gicall y-i n d uce d m y driasis. 
F oll o wi n g t he s uccessf ul c o m pleti o n of scree ni n g , eac h s u bject 
will be stratifie d b y e ye c ol or a n d t he n si m ulta ne o usl y  be  
ra n d o mized  to  m y driatic a ge nt (u n mas ke d ) a n d tr eat me nt 
(mas ke d )  
Treat me nt ra n d o mizati o n will be 1: 1 , N y x ol or place b o ( ve hi cle). 
S tratificati o n b y iris c ol or will be 1: 1, li g ht or dar k iri des, as s h o w n 
i n A p pe n di x  1 . 
T he m y driatic a ge nt ra n d o mizati o n will be 3: 1: 1  ( 2. 5 % 
p he n yle p hri ne, 1 % tr o pi ca mi de, a n d Pare m y d ). T h at is, 
a p pr o xi matel y 6 0 % of t h e ra n d o mize d s u bj ects will recei ve o ne 
dr o p of 2. 5 % p he n yl e p hri ne 1 h o ur bef ore treat me nt ( 9 6 e val ua ble 
s u bjects), a p pr o xi matel y 2 0 % will recei v e o ne dr o p of 1 % 
tr o pica mi de 1 h o ur bef ore treat me nt ( 3 2 e val ua ble  s u bjects), a n d 
a p pr o xi matel y 2 0 % will recei v e Pare m y d 1 h o ur bef ore tr eat me nt 
( 3 2 e val ua ble s u bj ects). 
A ra n d o mizati o n sc h e ma b y i n vesti gati o nal treat me nt, m y driatic 
a ge nt, a n d iris c ol or  is s h o w n i n A p pe n di x 2 . 
T R E A T M E N T  ( N Y X O L O R P L A C E B O) 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) . A D U L T S U BJ E C T S 
(≥ 1 8 Y E A R S  O L D) WI L L H A V E T W O D R O P S O F  
T R E A T M E N T  A D MI NI S T E R E D FI V E MI N U T E S A P A R T I N 
T H E S T U D Y E Y E ( O D) A N D O N E D R O P O F T R E A T M E N T  
A D MI NI S T E R E D I N T H E N O N -S T U D Y E Y E ( O S) O N E H O U R 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 2  
0 2 /0 5 /2 1  
 
A F T E R M Y D RI A TI C D R U G I N S TI L L A TI O N.  P E DI A T RI C 
S U BJ E C T S ( < 1 8 Y E A R S O L D) WI L L H A V E O N E  D R O P O F 
T R E A T M E N T  A D MI NI S T E R E D I N E A C H E Y E  O N E H O U R 
A F T E R M Y D RI A TI C D R U G I N S TI L L A TI O N.  
 
T he st u d y a n d n o n -st u d y e ye will 
b ot h be e val uate d at all assess me nts.  
P atie nt P o p ul at i o n  
1 6 8 ra n d o mize d ( 1 6 0 e val ua ble) healt h y s u bjects.  
I ncl usi o n Criteri a 
1.  Males or fe m ales ≥ 1 2  years of a g e.  
2.  Ot her wise healt h y a n d well c o ntr olle d s u bjects.  
3.  A bilit y t o c o m pl y wit h all pr ot oc ol -ma n date d pr o ce d ures 
i n de pe n de ntl y a n d t o tte n d all sc he d ule d offi ce visits.  
4.  A d ults  ( ≥ 1 8 years f a ge) w illi n g t o gi ve writte n i nf or me d 
c o nse nt t o partici pate i n t his st u d y.  C hil dre n a ge d 1 2 -1 7 
years t o pr o vi de i g ne d asse nt f or m, as well as a s e parat e 
pare ntal/ Le g al G uar di a n c o nse nt.  
E xcl usi o n Criteri a  
O p ht h al mic  (i n eit her e ye):  
1.  
Cli nicall y  si g nifica nt oc ular  disease  as dee me d  b y  t he 
I n v esti gat or (e. g., cat aract,  gla uc o ma,  c or neal  e de ma,  
u veitis,  se vere kerat o c o nj u ncti vitis  sicca) t hat mi g ht  
i nterfere wit h  t he st u d y. 
2  
U n willi n g  or  u na ble  t o disc o nti n ue  use  of  c o ntact  le nses at  
scree ni n g u ntil  st u d y c o m pleti o n.  
3  
U n willi n g  or  u na ble  t o s us pe n d use  of  t o pical me dicati o n  at 
scree ni n g u ntil  st u d y c o m pleti o n. 
4.  
Oc ular  tr a u ma, oc ular  s ur ger y or  n o n -refracti ve laser 
treat me nt wit h i n t he 6  m o nt hs  pri or  t o scree ni n g. 
5.  
Use  of  a n y t o pical prescri pti o n  or  o ver -t h e-c o u nt er ( O T C) 
o p ht hal mic  me dicati o ns  of  a n y ki n d  wit hi n  7  da ys  of  
scree ni n g, wit h  t he e x ce pti o n  of  a) li d scr u bs wit h  O T C  
pr o d ucts  (e. g., O C u S O F T ®  li d scr u b, Steri Li d ® , ba b y  
s ha m p o o, etc.) or  b)  O T C  l u bricati n g dr o ps  f or dr y  e ye  
(preser ve d  a n d u n preser ve d  artifici al  tears), w hi c h  ma y  
ha ve  bee n  use d  pri or  t o, b ut  n ot  at scree ni n g u ntil  st u d y 
c o m pleti o n . 
6.  
Rece nt  or  c urre nt  e vi de nce  of  o c ular  i nfecti o n or  
i nfla m mati o n i n eit her e ye (s uc h as c urre nt  e vi d e nce of  
cli nicall y  si g nifica nt ble p haritis,  c o nj u ncti vitis,  or  a hist or y  
of  her pes  si m ple x or  h er pes  z oster keratitis  at Scree ni n g  i n 
eit her e ye).  
7.  
Hist or y  of  dia betic  reti n o pat h y or  dia betic  mac ular  e de ma. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 3  
0 2 /0 5 /2 1  
 
8.  
Cl ose d  or  ver y  n arr o w  a n gles t hat i n t he I n vesti gat or’s 
o pi ni o n  are p ote ntiall y  o ccl u da ble  if t he s u bject’s p u pil  is 
dilate d.  
9.  
Hist or y  of  a n y tr a u matic (s ur gical or  n o ns ur gi cal)  or  n o n -
tra u matic c o n diti o n  affecti n g  t he p u pil  or  iris (e. g., 
irre g ularl y s ha pe d p u pil,  ne ur o ge nic  p u pil  dis or der,  iris 
atr o p h y, iri d ot o m y, iri dect o m y, etc.). 
1 0.  K n o w n  aller g y or  c o ntr ai n dicati o n  t o a n y  c o m p o ne nt  of  t h e 
m y driatic  a ge nts  or  t he v e hicle  f or m ulati o n. 
1 1.  Hist or y  of  ca uterizati o n  of  t he p u n ct u m  or  p u n ctal  pl u g  
(silic o ne or  c olla ge n) i nserti o n or  re m o val. 
 
 
 
S yste mic:  
1.  
K n o w n  h y perse nsiti vit y  or  c o ntr ai n dicati o n  t o α - a n d/ or β  
a dre n oce pt or  a nta g o nists  (e. g., c hr o ni c o bstr ucti ve  
p ul m o nar y  disease  or  br o nc hial  ast h ma;  a b n or m all y  l o w 
bl o o d  press ure  ( B P) or  heart  rate ( H R); sec o n d- or  t hir d-
de gree  h eart  bl oc ka ge  or  C o n gesti ve  Heart  Fail ure  ( C H F); 
se vere di a betes).  
2.  
Cli nicall y  s g nifica nt s yste mic disease  (e. g., u nc o ntr olle d  
dia bete
 m yast he nia  gra vis,  ca ncer, he patic,  re nal, 
e n d ocri ne  or  car di o vasc ul ar dis or ders)  t hat mi g ht  i nterfere 
wit h  t he st u d y. 
3  
I nitiati o n of  treat me nt wit h  or  a n y c ha n ges  t o t he c urre nt  
d osa ge,  dr u g  or  re gi me n of  a n y s yste mic a dre ner gic or  
c h oli ner gic dr u gs  wit hi n  7  da ys  pri or  t o scree ni n g, or  
d uri n g  t he st u d y (see A p pe n di x  3 ). 
4.  
Partici pati o n  i n a n y i n vesti gati o nal st u d y wit hi n  3 0  da ys  
pri or  t o scree ni n g. 
5.  
Fe males  of  c hil d beari n g  p ote ntial  w h o  are pre g na nt,  
n ursi n g,  pla n ni n g  a pre g na nc y,  or  n ot  usi n g  a m e dicall y  
acce pta ble f or m of  birt h  c o ntrol.  Acce pta bl e  met h o ds  
i ncl u de t he use  of  at least o ne  of  t he f oll o wi n g: i ntra uteri ne 
de vice  (I U D), h or m o nal  ( oral, i njecti o n, pat c h,  i m pla nt, 
ri n g), barrier  wit h  s per mici de (c o n d o m, dia p hra g m),  or  
a bsti ne nce.  A  fe male is c o nsi dere d  t o b e  of  c hil d beari n g  
p ote ntial  
u nless  
s he 
is 
pre -me nstr ual,  
1  
year  
p ost me n o pa usal , or  3  m o nt hs  p ost -s ur gical sterilizati o n. 
All  fe males of  c hil d beari n g  p ote ntial  i ncl u di n g t h ose wit h  
p ost -t u bal li gati o n m ust  ha ve  a ne gati ve  uri ne  pre g na nc y  
test res ult at Visit  1/ Scree ni n g  a n d m ust  i nte n d t o n ot  
bec o me  pre g na nt  d uri n g  t he st u d y. 
6.  
Resti n g  H R  o utsi de  t he n or mal  ra n ge ( 5 0-1 1 0  b eats  per  
mi n ute)  at t he Scree ni n g  Visit.  H R  ma y  be  re peate d o nl y  
o nce  if o utsi de  t he n or mal  ra n ge f oll o wi n g at least a 5 -
mi n ute  rest peri o d  in  t he sitti n g p ositi o n.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 4  
0 2 /0 5 /2 1  
 
7.  
H y perte nsi o n  wit h  resti n g diast olic  B P  >  1 0 5  m m H g  or  
s yst olic B P  >  1 6 0  m m H g  at t he Scree ni n g  Visit.  B P  ma y  
be  re p eate d o nl y  o nce  if o utsi de  t he s pecifie d ra n ge 
f oll o wi n g at least a 5 -mi n ute  rest peri o d  i n t he sitti n g 
p ositi o n.  
Visit Sc he d ule  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
N u m ber of 
I n vesti g ati o n al Sites 
A p pr o xi matel y  1 2  sites 
Esti m ate d T ot al S a m ple 
Size  
A p pr o xi matel y 1 6 8  ra n d o mize d healt h y s u bjects, wit h 
a p pr o xi matel y 1 6 0 e val u a ble s u bjects. 
S a m ple Size J ustific ati o n  A  sa m ple size of  1 6 0  e val ua ble s u bjects ( 8 0 per  tr eat me nt gr o u p)  is 
nee de d  f or t he st u d y. T he  pri mar y  efficac y  e n d p oi nt  will  be  met  if 
s u bjects s h o w a p ositi ve  effect  f or N y x ol  ( α =  0. 0 5  si g nifica nce, 
t w o-taile d). O ne  h u n dre d  a n d six t y e val ua ble s u bj ects will  pr o vi de  
at least 
 
 
 
.  
All  s u bjects will  be
 
 
 F urt her m ore,  s u bjects will  be  ra n d o mize d at a 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A
o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 5  
0 2 /0 5 /2 1  
 
rati o of  3: 1: 1  t o o ne  of  t hree m y driatic  a ge nts  (2. 5 %  p he n yle p hri ne,  
1 %  tr o pica mi de, a n d Pare m y d ).  
It is ass u me d  t hat t here will  be  a 5 %  dr o p -o ut  d uri n g  Visit  1 . T o  
acc o u nt  f or t his dr o p -o ut,  a t otal of  1 6 8  s u bjects will  be  
ra n d o mize d i nt o t he st u d y. 
Pri m ar y Effic ac y 
E n d p oi nt  
Perce nta ge  of  s u bjects’ st u d y e yes ret ur ni n g t o ≤ 0. 2  m m  fr o m 
baseli ne  p u pil  dia meter  at 9 0  mi n utes.  
Sec o n d ar y Effic ac y 
E n d p oi nts  
Sec o n dar y efficac y e n d p oi nts (f or t he st u d y e ye  a n d t he n o n-st u d y 
e ye) will i ncl u de: 
•  Perce nta ge of s u bjects ret ur ni n g t o ≤ 0. 2 m m  fr o m baseli ne 
p u pil di a meter  at eac h  re mai ni n g ti me p oi nt (3 0 mi n utes , 
6 0 mi n utes , 2 h o urs, 3 h o urs, 4 h o urs, 6 h o urs , 2 4 h o urs) 
•  C ha n ge (i n m m) fr o m m a x p u pil di a m eter  ( 0 mi n utes) at 
eac h ti me p oi nt ( 3 0 mi n utes , 6 0 mi n utes , 9 0 mi n utes , 2 
h o urs, 3 h o urs  4 h o urs, 6 h o urs , 2 4 h o urs) 
•  Perce nt a g e of s u bjects wit h u nc ha n ge d acc o m m o d ati o n  
fr o m bas eli ne (-1 h o ur) at t he f oll o wi n g ti me p oi nts (0 mi n, 
6 0 mi n utes , 9 0 mi n utes , 2 h o urs, 3 h o urs, 4 h o urs , 6 h o urs )  
•  Ti me  ( h o urs) t o ret ur n t o ≤ 0. 2  m m  fr o m baseli ne  p u pil  
di
meter  (ti me s a vi n gs a n al ysis )  
 
Meas ure me nts:  
 P u pil dia meter will be meas ure d wit h a Ne ur O ptics VI P -
3 0 0  p u pill o meter ( m m).  
 Acc o m m o dati o n will be meas ure d b y t he 
 
 
 
 
 
 
T he p h ot o pic li g hti n g c o n diti o ns i n t he r o o m will be defi ne d as 
 
 
 
 
 
 
 
 
 
 s h o ul d be 
 f or acc o m m o d ati o n meas ure me nts a n d t he re mai ni n g 
safet y assess me nts (e. g. c o nj u ncti val h y pere mia, a d verse e v e nts , 
s u bject q uesti o n naire, et c.). T he s u bject will be i n t he sa me r o o m 
f or all assess m e nts, a n d ever y eff ort will be ma de t o ha ve t he sa me 
pers o n perf or m t he meas ure me nts at all ti me p oi nts. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 6  
0 2 /0 5 /2 1  
 
S o me  of t he efficac y e n d p oi nts will be a nal yze d o verall, b y 
m y driatic a ge nt, a n d b y li g ht/ dar k iri des at all ti me p oi nts . Eac h 
m y driatic a ge nt will be a nal yze d i n di vi d uall y, a n d a n a d diti o nal 
a nal ysis c o m bi ni n g 1 % tr o pica mi de a n d t he Pare m y d s u bjects i nt o 
a “tr o pica mi de” gr o u p will be perf or me d.  E x pl orat or y a nal yses 
ma y  be perf or me d t o c o m pare 
 
t. 
T he M o difie d I nte nt -t o-Treat ( mI T T ) will be use d f or t he pri mar y 
e n d p oi nt a nal ysis a n d t o a nal yze s electe d s ec o n dar y efficac y 
e n d p oi nts . T he Per Pr ot oc ol (P P ) p o p ulati o n will be use d t o 
a nal yze s electe d s ec o n dar y efficac y e n d p oi nts.  
S afet y E n d p oi nts  
T he pri mar y safet y meas ures are c o nj u ncti v al h y pere mi a, 
s u bjecti ve oc ul ar t oler a bilit y, a n d a d verse e ve nts  ( A Es).  
A nal ysis f or c o nj u ncti val h y pere mia  i ncl u des cha n ge fr o m baseli ne 
(-1 h o ur) i n t he c o nj u ncti val h y pere mia gra di n g  scale ( C C L R U 
i ma ges) at each ti me p oi nt ( 0 mi n, 3 0 mi n utes , 6 0 mi n utes , 9 0 
mi n utes , 2 h o urs, 3, h o urs, 4 h o urs, 6 h o urs , 2 4 h o urs), f or st u d y 
e ye a n d n o n -st u d y e ye. A n y i ncreas e of t w o u nits i n c o nj u ncti val 
h y pere mia bet w ee n c o ns ec uti ve ti me p oi nts is c o nsi dere d a n A E.  
Ot her safet y meas ures i ncl u de i m pair me nt  i n V A (B C D V A a n d 
D C N V A )  i ntr a oc ul ar press ure (I O P), a n d s yste mic s afet y as 
me as ure d b y H R a n d B P . Uri ne pre g na nc y tests f or fe mal es of 
c hil d bear n g p ote ntial will be perf or me d at scree ni n g . 
S u bject  Q uesti o n n aire  val ues will be s u m marize d b y treat me nt 
gr o u p a n d ti me p oi nt ( -1 h o ur, 0 mi n utes, 6 0 mi n utes, 9 0 mi n utes, 3 
h o urs, 6 h o urs, a n d 2 4 h o urs) . 
Mea s ure me nts: 
•  C o nj u ncti val h y pere mia  will be assesse d vis uall y wit h  a 
gra di n g scale  ( 0-3)  usi n g i ma ges fr o m t he C C L R U  
•  S u bjecti ve oc ular t olera bilit y meas ure d o n a 4 -p oi nt scale 
( 0-3)  
•  B C D V A Dista nce will b e meas ure d bi n oc ularl y i n 
p h ot o pic c o n diti o ns b y Sta n dar d E T D R S ill u mi nate d c hart 
( o n wall or sta n d) at 4 meters  (letters rec or de d, lat er 
c o n verte d t o l o g M A R a n d n u m ber of li nes )  
•  D C N V A Rea di n g/ Near will be meas ure d bi n oc ul arl y i n 
p h ot o pic c o n diti o ns b y Near Vis ual A c uit y C hart i n t he 
Precisi o n Visi o n S mall 9 1 4 Ill u mi nat or Ca bi net (li g ht b o x) 
at 1 6 i nc hes ( ~4 0  c m) (letters rec or de d, later c o n v erte d t o 
l o g M A R a n d n u m ber of li nes) 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 7  
0 2 /0 5 /2 1  
 
•  I O P is meas ure d wit h t he T o n o-Pe n  
•  S u bject  Q uesti o n naire  will be a  brief  s y m pt o m s ur ve y 
(A p pe n di x 4 ) 
St u d y Me dic ati o ns, D ose 
a n d M o de of 
A d mi nistr ati o n  
N y x ol ® E ye Dr o ps  (P he nt ola mi ne O p ht hal mic S ol uti o n) : 
T w o  dr o p s ( d ose d 
 a part) of  N y x ol  i n t he st u d y e ye ( O D) 
( 1-h o ur  p ost  m y driatic  dr u g  i nstillati o n) a n d o ne  dr o p  of  N y x ol  i n 
t he n o n -st u d y e ye ( O S). N ote:  Pe diatric  s u bjects will  recei ve o nl y  
o ne  dr o p  i n eac h e ye.  
 
Place b o  (N y x ol  ve hicl e):  
T w o  dr o p s ( d ose d 
 a part) of  P lace b o i n t he st u d y e ye 
( O D) ( 1-h o ur  p ost  m y dri atic  dr u g  i nstillati o n) a n d o ne  dr o p  of  
P lace b o i n t he n o n -st u d y e ye ( O S). N ot e:  Pe diatric  s u bjects will  
recei v e o nl y  o ne  dr o p  i n eac h e ye.  
D ur ati o n of S u bject 
P artici p ati o n  
a n d St u d y  
T he t otal le n gt h of s u bject partici pati o n is 
 
 
 
 
 
 
T he e xec uti o n of t he e ntire st u d y (first s u bject scree n t hr o u g h last 
ra n d o mize d s u bject e val u a ble) is e x pecte d t o be a p pr o xi matel y 3 t o 
6 m o nt hs.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 8  
0 2 /0 5 /2 1  
 
T A B L E O F C O N T E N T S  
S U M M A R Y  O F  C H A N G E S  F O R  A M E N D M E N T  1  ........................................................................................ 2  
S P O N S O R  SI G N A T U R E  &  C O N T A C T S  .......................................................................................................... 5  
I N V E S TI G A T O R’ S A G R E E M E N T  ................................................................................................................... 6  
A B B R E VI A TI O N S  A N D  T E R M S  ....................................................................................................................... 8  
1.  
S T U D Y  S U M M A R Y  .................................................................................................................................. 1 0  
2.  
I N T R O D U C TI O N...................................................................................................................................... 2 0  
2. 1.  
I n vesti g ati o n al pr o d ucts  ................................................................................................................... 2 0  
2. 2.  
Fi n di n gs  fr o m n o ncli nic al  a n d  cli nic al st u dies ............................................................................... 2 0  
2. 3.  
Desi g n  j ustific ati o n ........................................................................................................................... 2 1  
2. 4.  
R o ute  of  a d mi nistr ati o n,  d os a ge  re gi m e n,  a n d  tre at m e nt peri o d  ................................................. 2 2  
2. 5.  
C o m pli a nce  ....................................................................................................................................... 2 3  
2. 6.  
St u d y  p o p ul ati o n ............................................................................................................................... 2 3  
3.  
O B J E C TI V E S  A N D  P U R P O S E  .......................................... ................................................................. 2 3  
4.  
S T U D Y  D E SI G N  ................................................................. ......... .......................................................... 2 3  
4. 1.  
Pri m ar y  a n d  sec o n d ar y e n d p oi nts  ..................... 
...
............................................................. 2 3  
4. 2.  
Descri pti o n  a n d  sc he d ule of  visits  a n d  pr oce d ures  .... ................................................................... 2 5  
4. 3.  
Me as ures  t a k e n t o mi ni mize/ a v oi d  bi as  ...... .... 
.................................................................... 2 7  
4. 4.  
St u d y  m e dic ati o ns  ..................................... ....... .............................................................................. 2 7  
4. 4. 1.  Pac k a gi n g  a n d  la beli n g ....................................... ............................................................................ 2 7  
4. 4. 2.  St ora g e  of  st u d y me dicati o n  a n d  dis pe nsi n g  ..................................................................................... 2 8  
4. 4. 3.  St u d y  me dicati o n  a d mi nistrati o n  ........ .......... ................................................................................... 2 8  
4. 4. 4.  St u d y  me dicati o n  acc o u nta bilit y  .. . ........ ....................................................................................... 2 8  
4. 4. 4. 1.  Recei pt  a n d dis p ositi o n  of  st u d y me dicati o n  .............................................................................. 2 8  
4. 4. 4. 2.  Ret ur n  of  st u d y me dicati o n  .. .... ............................................................................................. 2 8  
4. 5.  
E x pecte d  d ur ati o n  of  s u bje
 p artici p ati o n  .................................................................................... 2 8  
4. 6.  
R a n d o miz ati o n  a n d  pr oce d ure  f or bre a ki n g  t he c o de ................................................................... 2 8  
4. 7.  
C ollecti o n  of  d at a  ....... ......... ........ ................................................................................................ 2 9  
4. 8.  
C o m plete d  s u bject ......... ... ........................................................................................................... 2 9  
4. 9.  
N o n -c o m pleti n g  s u bject...... .. ....................................................................................................... 2 9  
4. 9. 1.  St u d y  me dicati o n  disc o n n uati o n  ...................................................................................................... 2 9  
4. 9. 2.  Reas o ns  f or wit h dra wal  fr o m st u d y ................................................................................................... 3 0  
4. 9. 3.  E ntire  st u d y ter mi nate d ...................................................................................................................... 3 0  
4. 9. 4.  Acti o ns  after  disc o nti n uati o n  ............................................................................................................. 3 0  
4. 1 0.  
E v al u a ble  s u bjects ............................................................................................................................ 3 0  
4. 1 1.  
C o m plete d  st u d y ............................................................................................................................... 3 0  
4. 1 2.  
Pr o ce d ure  after  t he c o m pleti o n  of  t he st u d y .................................................................................. 3 0  
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 bject  i ncl usi o n criteri a  ................................................................................................................. 3 0  
5. 2  
S u bject  e x cl usi o n  criteri a  ................................................................................................................. 3 1  
6.  
T R E A T M E N T  O F  S U B J E C T S  ................................................................................................................ 3 2  
6. 1.  
Tre at m e nt  a d here nce  ....................................................................................................................... 3 2  
6. 2.  
C o nc o mit a nt  m e dic ati o ns  ................................................................................................................ 3 2  
7.  
A S S E S S M E N T  O F  E F FI C A C Y  ............................................................................................................... 3 3  
7. 1.  
S pecific ati o n  of  t he effic acy  p ar a m eters  ......................................................................................... 3 3  
7. 2.  
Assessi n g,  rec o r di n g,  a n d  a n al yzi n g  of  effic ac y  p ar a m eters  ......................................................... 3 3  
7. 2. 1.  Scree ni n g/ Da y  1  ................................................................................................................................. 3 4  
7. 2. 2.  Treat me nt  Visit  1/ Da y  1  ..................................................................................................................... 3 4  
7. 2. 3.  F oll o w -U p  Visit  / Da y  2  ..................................................................................................................... 3 5  
7. 2. 4.  U nsc h e d ule d  Visits  ............................................................................................................................ 3 5  
7. 2. 5.  Visit  variati o n ..................................................................................................................................... 3 6  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
1 9  
0 2 /0 5 /2 1  
 
8.  
A S S E S S M E N T  O F  S A F E T Y  .................................................................................................................... 3 6  
8. 1.  
S pecific ati o n  of  s afet y p ar a m eters  .................................................................................................. 3 6  
8. 2.  
Assessi n g,  rec o r di n g,  a n d  a n al yzi n g  s afet y p ar a m eters  ................................................................ 3 6  
8. 3.  
A d verse  e v e nts a n d  seri o us a d verse  e ve nts .................................................................................... 3 7  
8. 3. 1.  A d verse  e v e nt defi niti o ns  ................................................................................................................... 3 7  
8. 3. 2.  F oll o w -u p  of  s u bjects after  a d verse  e ve nts ........................................................................................ 4 1  
9.  
S T A TI S TI C S  .............................................................................................................................................. 4 1  
9. 1.  
S a m ple  Size  ....................................................................................................................................... 4 1  
9. 2.  
A n al ysis  P o p ul ati o ns  ........................................................................................................................ 4 1  
9. 3.  
St atistic al  Met h o ds  ........................................................................................................................... 4 2  
9. 3. 1.  Ge n eral  c o nsi derati o ns ....................................................................................................................... 4 2  
9. 3. 2.  De m o gra p hic  a n d  baseli ne  c haracteristics  ......................................................................................... 4 2  
9. 3. 3.  S u bject  dis p ositi o n  ............................................................................................................................. 4 2  
9. 3. 4.  Me dical  hist or y  a n d  pri or/c o nc o mita nt  me dicati o ns  .......................................................................... 4 2  
9. 3. 5.  A nal ysis  of  efficac y ........................................................................................................................... 4 2  
9. 3. 6.  A nal ysis  of  safet y ............................................................................................................................... 4 3  
9. 4.  
Pr o ce d ure  f or acc o u nti n g  f or missi n g,  u n use d,  or  s p uri o us d at a  ................................................. 4 4  
9. 5.  
Pr o ce d ure  f or re p orti n g  de vi ati o ns  fr o m t he st atistic al pl a n  ........................................................ 4 4  
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  ............................................................ 4 4  
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  ... ................................................................... 4 5  
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  .............................................................. 4 5  
1 2. 1.  
G C P  c o m pli a nce  ........................................... 
............................................................................. 4 5  
1 2. 2.  
I nstit uti o n al Re vie w  B o ar d  (I R B) ..... 
...................................................................................... 4 5  
1 2. 3.  
Pr ot oc ol  De vi ati o ns/ Vi ol ati o ns  ........ ......... ................................................................................... 4 5  
1 2. 4.  
I nf o r m e d c o nse nt  a n d  asse nt  re q uire m e nts  ................................................................................... 4 6  
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  .................................................................................... 4 6  
1 3. 1.  
D at a  e ntr y ............................. ....... .................................................................................................. 4 6  
1 3. 2.  
D at a  q u alit y  c o ntr ol  a n d  re p rti n g  ................................................................................................. 4 6  
1 3. 3.  
Arc hi vi n g  of  d at a  ......... 
..... ................................................................................................... 4 7  
1 3. 4.  
Rec or ds  rete nti o n  ...... ......... ........ ................................................................................................. 4 7  
1 3. 5.  
A m e n d m e nts  t o t he pr ot oc ol  ............................................................................................................ 4 7  
A P P E N DI X  1:  I RI S C O L O R  C H
R T  ... .......................................................................................................... 4 8  
A P P E N DI X  2:  R A N D O MI Z A TI O N  S C H E M A  F O R  E V A L U A B L E  S U B J E C T S  B Y  I N V E S TI G A TI O N A L 
T R E A T M E N T,  M Y D RI A TI C  A G E N T,  A N D  I RI S C O L O R  ......................................................................... 4 9  
A P P E N DI X  3:  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 0  
A P P E N DI X  4:  S U B J E C T  Q U E S TI O N N AI R E  ................................................................................................ 5 1  
A P P E N DI X  5:  C O N J U N C TI V A L  H Y P E R E MI A  G R A DI N G  S C A L E  U SI N G  I M A G E S F R O M  C C L R U 5 2  
A P P E N DI X  6:  VI S U A L  A C UI T Y  C H A R T S  .................................................................................................... 5 3  
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 0  
0 2 /0 5 /2 1  
 
2.   I N T R O D U C TI O N 
2. 1.  I nvesti g ati o n al pr o d ucts  
T he test pr o d uct is N y x ol ®  E ye Dr o ps –  0. 7 5 % P h e nt ola mi ne O p ht hal mic S ol uti o n ( N y x ol), a 
n o n -selecti ve al p ha-1 a n d al p ha -2 a dre ner gic a nta g o nist. N ote t hat t he c o nce ntrati o n of 0. 7 5 % 
refers t o p he nt ola mi ne free base, a n d is t he sa me a n d use d i n place of 1 % p he nt ola mi ne mes ylate 
dr u g s u bsta nce, w hi c h w as h o w N y x ol ha d bee n d escri be d i n  all pri or st u di es. Place b o c o ntr ol is 
N y x ol ve hicle al o ne.  
2. 2.  Fi n di n gs  fr o m n o ncli nic al  a n d  cli nic al st u dies 
Detaile d fi n di n gs fr o m n o ncli nical a n d cli nical st u dies a n d p ote ntial ris k are pr o vi de d i n t he 
I n v esti gat ors’ Br oc h ure (I B) (2 0 2 0 ).  
N y x ol has bee n assesse d i n se ve n i n vesti gat or -i nitiate d a n d s p o ns or e d P hase 1 a n d P hase 2 
cli nical trials. Acr oss all trials, 1 6 8 of 2 3 2 a d ult pat ie nts were e x p ose d t o at least o ne d ose of 
p he nt ola mi ne mes ylate o p ht hal mic s ol uti o n . 
I n pri or cli nical trials, N y x ol  has de m o nstrate d a c o nsiste nt a bilit y t o decrease p u pil b y 
a p pr o xi matel y 2 0 % ( ~ 1 –  1. 5 m m) i n b ot h mes o pic a n d p h ot o pic c o n diti o ns . Ke y p upil dia meter 
data are s u m marize d b el o w ( Ta ble 1 ). 
T a ble  1 :  Effic ac y of 1 % N y x ol i n Re d uci n g P u pil Di a meter i n Mes o pic C o n diti o ns i n P h ase 
2 Tri als  
 
St u d y  
Gr o u p  
Mes o pic C o n diti o ns  
Pre -Tre at me nt 
( B aseli ne) P u pil 
Di a meter  
P ost -
Tre at me nt 
P u pil 
Di a meter  
C h a n ge ( %)  
p -v al ue 
c o m p are d 
t o b aseli ne 
p -v al ue 
c o m p are d 
t o pl ace b o 
N Y X -S N V 1 
Place b o ( N = 1 6)  
6. 6 m m  
6. 4 m m  
-0. 2 m m ( -3 %)  
p = 0. 0 8  
p < 0. 0 0 0 1  
 
1. 0 % N y x ol ( N = 3 2)  
6. 5 m m  
5. 2 m m  
-1. 3 m m ( -2 0 %)  
p < 0. 0 0 0 1  
N Y X -0 1a 2 2 
Place b o ( N = 3 8)  
6. 2 5 m m  
6. 3 1 m m  
0. 0 7 m m ( + 1 %)  
p = 0. 6  
p < 0. 0 0 0 1  
1. 0 % N y x ol ( N = 4 0)  
6. 1 7 m m  
5. 3 1 m m  
-0. 8 6 m m ( -1 4 %)  
p < 0. 0 0 0 1  
N Y X G -2 0 1  
Place b o ( N = 2 0)  
4. 5 7 m m  
4. 5 2 m m  
-0. 0 5 m m ( -1 %)  
p = 0. 6 1 7 8  
p < 0. 0 0 0 1  
1. 0 % N y x ol ( N = 1 9)  
4. 6 9 m m  
3. 7 0 m m  
-1. 0 0 m m ( -2 1 %)  
p < 0. 0 0 0 1  
N y x ol was o bser v e d t o be well -t olerate d at si n gle d oses u p t o a n d i ncl u di n g 1. 0 % dail y i n eac h 
e ye. T his i ncl u des 5 9 patie nts w h o recei ve d m ulti ple d oses of u p t o 1 % N y x ol f or at least 1 4 
da ys. Safet y of t he patie nts i n t hese trials was e val uate d b y A E m o n it ori n g, p h ysical 
e xa mi nati o ns, a n d vital si g n assess me nts. Acr oss all trials, n o healt h y v ol u nteers or patie nts 
re p orte d a treat me nt-e mer ge nt S A E. N o deat hs o cc urre d i n a n y of t he trials. N o cli nicall y 
mea ni n gf ul c ha n g es were o bser ve d i n p h ysical e xa mi nat i o ns or vital si g ns, i ncl u di n g bl o o d 
press ure a n d heart rate. A Es re p orte d were mil d t o m o derate i n i nte nsit y wit h t he m ost c o m m o n 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 1  
0 2 /0 5 /2 1  
 
bei n g tra nsie nt c o nj u ncti val h y pere mia a n d oc ular irritati o n; h o we ver, N y x ol d osi n g at or near 
be dti me was o bser v e d t o miti ga te or mi ni mize t hese si de effects d uri n g t he da yti me. 
P h ase 2  Revers al of P h ar m ac ol o gic ally I n d uce d My dri asis St u d y ( MI R A-1) : 
I n O PI -N Y X R M -2 0 1  ( MI R A-1) , 3 2  ot her wise healt h y s u bjects ra n d o mize d at Visit 1 i n a 1: 1 
rati o t o recei ve 1 dr o p O U of 1 % N y x ol  ( 1 % P he nt ola mi ne Mes ylate O p ht hal mic S ol uti o n)  or 1 
dr o p of place b o ( ve hicl e) at Visit 1 a n d 1 dr o p of t he alter nati ve st u d y me di cati o n at Visit 2. O ne 
h o ur bef ore a d mi nistrati o n of st u d y me dicati o n, s u bjects recei ve d 1 dr o p O U of a m y driatic 
a ge nt (2. 5 % p h e n yle p hri ne  or  1 %  tr o pica mi de). E ac h s u bject r ecei ve d t he s a me m y driatic a g e nt 
t hr o u g h o ut t he st u d y. P u pil dia meter was me as ure d 3 0 mi n utes, 1, 2, 4, a n d 6 h o urs after d osi n g 
at Visit  1 a n d 2 a n d c o m pare d t o t he bas eli ne.  
I n t his st u d y, N y x ol de m o nstrate d a statisticall y si g nifica nt re d u cti o n i n P D  fr o m ma xi m u m 
ti me p oi nt c o m pare d t o place b o  at 1 h o ur, 2 h o urs, 4 h o urs, a n d 6 h o urs.  T hese statisticall y 
si g nifica nt a n d cli nical m ea ni n gf ul (t y picall y great er t ha n 1 m m re d u cti o n) P D re d ucti o ns were 
o bser ve d at eac h  ti me p oi nt, i ncl u di n g w he n stratifie d b y b ot h par s y m pat h etic (tr o pica mi de) a n d 
a dre ner gic ( p he n yle p hri n e) a ge nts.  
A d diti o nall y, N y x ol was effecti ve at ret ur ni n g a st atisticall y si g nifica nt perce nt of s u bjects’ e yes 
t o baseli ne P D c o m pare d wit h place b o treat me nt at e ver y ti me p oi nt wit h  esti ma ble res ults, 
re gar dl ess of w het h er t he P D t hres h ol d use d was ≤ 0. 5 m m a b o ve baseli ne ( 2-h o ur ti me p oi nt) or 
t he m ore stri n ge nt, ≤ 0 m m a b o ve baseli ne ( 4 -h o ur a n d 6 -h o ur  ti me p oi nts). T he re d u cti o n i n ti me 
nee de d t o a c hie ve re vers al of m y driasis i n eit her e ye w s statisticall y  si g nifica nt wit h N y x ol 
treat me nt c o m pare d wit h place b o treat me nt, re g ar dless of t he t hres h ol d e xa mi ne d or t h e 
m y driatic a ge nt use d. I n t his st u d y, N y x ol le d t o a n a vera g e ti me -sa vi n gs of 2. 2 h o urs t o ret ur n 
P D t o ≤ 0 m m a b o ve baseli ne. A d diti o nall y, 4 0 % of s u bjects gi ve n  p he n yle p hri ne a n d 3 0 % of 
s u bjects gi ve n tr o pica mi de ac hie v e d a ti me sa vi n gs of m ore t ha n 4 h o urs wit h N y x ol , base d o n a 
p ost -h oc a nal ysis . 
I n a p ost-h oc a nal ysis of t he pla n ne d P h se 3 pri m ar y e n d p oi nt (t he  p erce nt of s u bjects t hat 
ret ur ne d t o wit hi n ≤ 0. 2 m m of baseli ne p u pil dia meter), a statisticall y si g nifica nt perce nta ge of 
s u bjects i n t he N y x ol  gr o u p  c o m pare d t o place b o after b ei n g dilate d  wit h eit her p he n yle p hri ne or 
tr o pica mi de ret ur n e d t o b aseli ne at 2 h o urs (2 9 %  vs 1 3 %, res pecti vel y; p  = . 0 3 ). T his differe nce 
wi de ne d ( 6 8 % f or N y x ol  a n d 2 3 % f or pl ace b o) at 4 h o urs ( p  < . 0 0 0 1).   
I n t his st u d y, there were n o se vere a d vers e e v e nts, wit h o nl y mil d t o m o derate c o nj u ncti val 
h y pere mia t hat res ol ve d i n m ost patie nts b y 6 h o urs.  
2. 3.  Desi g n  j ustific ati o n 
P u p il size is u n der t he c o ntr ol of t w o o p p osi n g sets of m uscles –  t he circ ul ar c o nstrict or m uscles 
c o ntr olle d b y t he c h oli ner gic ner v o us s yste m  a n d t he ra dial dilat or m uscles, c o ntr olle d b y t he 
a dre ner gic ner v o us s yste m. 3, 4 T he ra dial dilat or m uscles c o ntai n pre d o mi na ntl y α -1 a dre n er gic 
rece pt ors t hat ca n b e i n hi bite d b y α -1 a nta g o nists 5; t heref ore it is p ossi ble t o i n hi bit dilati o n of 
t he p u pil t hr o u g h bl oc ka de of t he ra dial dilat or m uscles.  
P har mac ol o gicall y i n d uc e d m y driasis is ac hie ve d eit her b y sti m ulati n g t he iris dilat or m uscle 
wit h t he use of direct or i n direct al p ha -1  a g o nists ( e. g., p he n yle p hri ne , h y dr o x ya m p heta mi ne ), b y 
bl oc ki n g t he iris s p hi ncter m uscle wit h t he use of m uscari nic a n ta g o nists or c ycl o ple gic dr u gs  
(e. g., tr o pica mi de), or c o m bi nati o n (e. g., Pare m y d ® , w hic h is 1 % h y dr o x ya m p heta mi ne 
h y dr o br o mi de  a n d 0. 2 5 %  tr o pica mi de). A t y pical  i n d uce d m y driasis dilates t he p u pil t o 6 -8 m m, 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 2  
0 2 /0 5 /2 1  
 
a size s uita ble f or o p ht hal mic e xa mi nati o n of t he reti na a n d ot her str u ct ures of t he i nteri or of t he 
e ye.  
S uc h p har mac ol o gicall y i n d uce d m y driasis ca n l ast fr o m a fe w h o urs (t y picall y 6 h o urs) t o da ys, 
de pe n di n g o n t he pi g me ntati o n of t he iris, t he a ge of  t he s u bject, a n d ot her u n k n o w n-t o-date 
fact ors. T h e si de effects of s uc h dilati o n are s e nsiti vit y t o li g ht a n d bl urre d visi o n. Als o, ma n y 
dilati n g a ge nts  ca use c ycl o ple gia  (l oss of acc o m m o dati o n), t he te m p orar y paral ysis of t he m uscle 
w hic h all o ws t he e ye  t o f oc us o n near o bj ects. Accelerati n g m y driatic re v ersal after a n e y e e x a m 
ma y be  be neficial f or m a n y s u bjects. 
P he nt ola mi ne is a n o n -selecti ve al p ha-1 a n d al p ha -2 a dre n er gic a nta g o nist acti n g o n  a dre n er gic 
rece pt ors a n d is k n o w n t o i n hi bit c o ntracti o n of t he iris dilat or m uscle, res ulti n g i n a s maller 
p u pil size. T o c o u nteract t he dilat or y effects of m y driatic a ge nt , N y x ol is pr o p ose d t o be i nstille d 
i n t he e yes p ost  e ye e xa m all o wi n g a ra pi d re v ersal  of m y driasis , t here b y mi ni mizi n g t he si de 
effects a n d disc o mf ort p ost e xa m.  
Alt h o u g h acc o m m o dati o n will be st u die d acr oss v ari o us m y driatic a ge nts, a decreas e i n t he 
a m plit u de of acc o m m o dati o n wit h m y driasis w o ul d o nl y be e x pect e d wit h t he use of m y driatic 
a ge nts t hat i ncl u de tr o pic a mi de. Tr o pica mi de is a m uscari nic a nta g o nist t hat elicits c ycl o ple gia, 
or paral ysis of t he ciliar y m uscle of t he e y e, res ulti n g i n a l oss of acc o m m o dati o n. P he n yle p hri ne 
is a s y m pat hetic a g o nist t hat s h o ws m y driatic effect t hr o u g h direct acti o n o n s y m pat hetic ner ve 
rece pt ors l ocate d o n t he p u pillar y dilat or m uscle of t he iris, a n d as s uc h w o ul d n ot be e x pecte d t o 
ha ve materi al c ha n g es i n acc o m m o dati o n.  
I n a pre vi o us P hase 2  re v ersal of p har mac ol o gicall y i n d uce d m y driasis cli nical st u d y  ( MI RA -1) , 
N y x ol was effecti ve at i n d uci n g re versal of m y dri asis  wit h b ot h a dre ner gi c  ( p he n yle p hri ne) a n d 
paras y m pat hetic (tr o pica mi de) m y driatic a ge nts  as descri be d a b o ve. T he pl ace b o o utc o m es i n 
t his st u d y de m o nstrate d  t hat t he nat ural r e versal of m y driasis ta kes l o n ger wit h tr o pica mi de t ha n 
wit h  p he n yle p hri ne. Des pite t his differe nce  N y x ol was  a ble t o re v erse m y driasis faster i n t he 
vast maj orit y of e yes r e g ar dless of t he m y driatic a ge nt use d , b ut faster f or p he n yle p hri ne as 
e x pecte d gi v e n t he p ha r mac ol o g y of N y x ol   
Al p ha -1 a dre ner gi c a nta g o nists ha ve bee n s h o w n t o be safe a n d effecti ve f or t he p har mac ol o gical 
re vers al of m y driasis. I n 1 9 9 0, t he F D A a p pr o ve d Da pi praz ol e H y dr o c hl ori de O p ht hal mic 
S ol uti o n 0. 5 % ( Re v -E yes) f or t his i n dicati o n, h o we ver , t he pr o d uct was wit h dra w n a n d 
disc o nti n ue d b y t he ma n ufact ur er f or reas o ns n ot relate d t o safet y or efficac y. Ma n y pe o ple w h o 
u n der g o p u pil dilati o n f or a n a n n ual o p ht hal mic e xa mi nati o n or ot her o p ht hal mic pr oce d ure 
re q uiri n g p u pil dilati o n c o nti n ue t o re q uest a n o pti o n f or ra pi d r e versal of t he m y driasis.  
2. 4.  R o ute  of  a d mi nistr ati o n,  d os a ge  re gi me n, a n d  tre at me nt peri o d  
As t he i nte n de d r o ute of a d mi nistrati o n f or N y x ol  is t o pical oc ular, t his is t he r o ute t o be use d i n 
t his st u d y.  
T he d ose f or o n e dr o p of N y x ol selecte d f or t his st u d y, 0. 7 5 %, was bas e d u p o n : 1) precli nical 
safet y st u dies, 2) t he res ults of t he pre vi o us o p ht hal mic cli nical st u dies descri be d a b o ve  a n d i n 
t he I B, a n d 3) cli nical st u dies c o n d ucte d wit h var yi n g d oses of dr u gs i n t he sa me class .6  
S U BJ E C T S ≥ 1 8 Y E A R S O L D WI L L R E C EI V E T W O D R O P S ( D O S E D 5  MI N U T E S  
A P A R T)  O F T R E A T M E N T ( N Y X O L O R P L A C E B O) I N T H EI R S T U D Y E Y E A N D O N E 
D R O P O F T R E A T M E N T I N T H EI R N O N -S T U D Y E Y E. S U BJ E C T < 1 8 Y E A R S O L D WI L L 
R E C EI V E O N E D R O P O F T R E A T M E N T I N T H EI R S T U D Y E Y E A N D O N E D R O P O F 
T R E A T M E N T I N T H EI R N O N -S T U D Y E Y E . 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 3  
0 2 /0 5 /2 1  
 
N ote t hat 0. 7 5 % P he nt ola mi ne O p ht hal mic S ol uti o n, w hic h e x presses t he p he nt ola mi ne mes ylate 
c o nce ntr ati o n i n free b as e, is t he ne w n o me ncl at ure bei n g use d i n place of 1 % P he nt ola mi ne 
Mes ylate O p ht hal mic S ol uti o n , w hic h was h o w N y x ol ha d bee n des cri be d i n pri or st u dies, 
i ncl u di n g MI R A-1 . 
2. 5.  C o m pli a nce  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol a n d i n acc or da nce wit h G o o d 
Cli nical Practice, t he et hi cal pri nci ples set f ort h i n t he Declarati o n of Helsi n ki a n d wit h t he U. S. 
C o de of Fe d eral Re g ulati o ns.  
2. 6.  St u dy  p o p ul ati o n  
A sa m ple size of a p pr o xi matel y 1 6 8 healt h y s u bjects ≥ 1 2  years of a ge will be ra n d o mize d i n a 
1: 1 rati o t o o ne of t w o mas ke d treat me nt ar ms ( N y x ol or Place b o), wit h t h e e x pectati o n t hat 
a p pr o xi matel y 1 6 0  s u bjects will c o m plete t he st u d y . Ra n d o mizati o n will be stratifie d 1: 1 b y 
li g ht/ dar k c ol or iri des a n d f urt her ra n d o mize d 3: 1: 1 t o u n mas ke d m y driatic a ge nt  (2. 5 % 
p he n yle p hri ne , 1 % tr o pi ca mi de, a n d Pare m y d ). T h e s u bjects will be recr uite d fr o m 
a p pr o xi matel y 1 2 i n vesti gati o nal sites.  
3.  O B J E C TI V E S  A N D  P U R P O S E  
T he MI R A -2 st u d y is a r a n d o mize d, parallel ar m, d o u ble -mas ke d, place b o -c o ntr olle d st u d y of 
t he safet y a n d effi cac y of N y x ol ( 0. 7 5% P he nt ola mi ne O p ht hal mic S ol uti o n) t o re verse 
p har mac ol o gicall y -i n d uc e d m y driasis i n healt h y s u bjects. 
T he o bjecti ves of t his st u d y are:  
•  T o e val uate t he effi cac y of N y x ol t o e x pe dite t he re versal of p har m ac ol o gi c all y-i n d uce d 
m y driasis  acr oss m ulti ple m y driatic a g nts wit h a n e m p hasis o n p he n yle p hri ne  
•  T o e val uate t he effi cac y of N y x ol o ret ur n s u bjects t o baseli ne acc o m m o d ati o n after 
w orse n i n g ( wit h c y cl o ple gic a ge nts tr o pica mi de a n d Pare m y d) 
•  T o e val uate t he s afet y of N y x ol  
•  T o e val uate a n y a d diti o nal be nefits of t he re versal of p har mac ol o gicall y -i n d uce d m y driasis 
T he S p o ns or i nte n ds t o use t his first P hase 3 re gistrati o n st u d y t o e val uate N y x ol f or t he 
i n dicati o n “t he treat me nt of p har mac ol o gicall y-i n d uce d m y driasis pr o d uce d b y a dre ner gic 
( p he n yle p hri ne) or paras y m pat h ol ytic (tr o pica mi de) a ge nts, or a c o m bi nati o n t here of.” 
4.  S T U D Y  D E SI G N  
4. 1.  Pri m ary  a n d  sec o n d ary e n d p oi nts 
Effic ac y:  
T he pri mar y eff ic ac y e n d p oi nt is t he perce nta ge of s u bjects’ st u d y e yes ret ur ni n g t o ≤ 0. 2 m m 
baseli ne p u pil dia meter at 9 0 mi n utes.  
T he  st u d y e ye is defi n e d  as t he ri g ht e ye ( O D). T h e  n o n -st u d y e ye is defi ne d  as t he left e y e ( O S). 
T he  st u d y a n d n o n -st u d y e ye will  b ot h  be  e val u ate d  at all assess me nts.  Sec o n dar y efficac y 
e n d p oi nts (f or t he st u d y e ye  a n d f or t h e n o n -st u d y e ye) will i ncl u de: 
•  Perce nt of s u bje cts ret ur ni n g t o ≤ 0. 2 m m  fr o m baseli ne p u pil di a m eter  at eac h 
re mai ni n g ti me p oi nt (3 0 mi n utes , 6 0 mi n utes , 2 h o urs, 3 h o urs, 4 h o urs, 6 h o urs, 2 4 
h o urs)  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 4  
0 2 /0 5 /2 1  
 
•  C ha n ge (i n m m) fr o m ma x p u pil di a meter  ( 0 mi n utes) at eac h ti me p oi nt ( 3 0 mi n utes , 6 0 
mi n utes , 9 0 mi n utes , 2 h o urs, 3 h o urs, 4 h o urs, 6 h o urs, 2 4 h o urs) 
•  Perce nt a g e of s u bjects wit h u nc ha n ge d acc o m m o d ati o n  fr o m baseli ne (-1 h o ur) at eac h 
ti me p oi nt ( 0 mi n, 6 0 mi n utes , 9 0 mi n utes , 2 h o urs, 3 h o urs, 4 h o urs , 6 h o urs)  
•  Ti me  (h o urs ) t o ret ur n t o ≤ 0. 2  m m  fr o m baseli ne  p u pil  dia meter  (ti me s a vi n gs a n al ysis )  
Meas ure me nts:  
•  P u pil  dia meter  will  be  meas ure d  wit h  a Ne ur O ptics  VI P -3 0 0  p u pill o meter  ( m m). 
•  Acc o m m o dati o n  will  be  meas ure d  b y  t he R A F  Near  P oi nt  R ule  (meas ure d  i n ce nti meters 
a n d t he n c o n v erte d  t o Di o pters ). U nc h a n ge d  acc o m m o dati o n  fr o m Baseli ne  (-1  h o ur)  is 
defi ne d  as a c ha n g e fr o m baseli ne  val ue  ≥ -1,  as m eas ure d  i n di o pters.  
 
 
 
 
 pri or t o t he p u pil dia meter, 
B C D V A  a n d D C N V A  (s afet y meas ures) at all sc h e d ule d ti me p oi nts. S u bject will sit i n t he e xa m 
c hair faci n g t he ill u mi nate d c hart d uri n g t he accli mati o n peri o d a n d f or all assess me nts.  
 
 f or acc o m m o dati o n meas ure me nts a n d  t he re mai ni n g safet y 
assess me nts (e. g. c o nj u n cti val h y pere mia, a d verse e ve nts, brief s u bject q u esti o n naire, etc.). T he 
s u bject will be i n t he sa me r o o m f or all ass ess me nts, a n d e ver y eff ort will be ma de t o ha ve t he 
sa me pers o n p erf or m t he meas ure me nts at all ti me p oi nts. 
S o me  of t he effic ac y e n d p oi nts will be a nal yze d o verall, b y m y driatic a g e nt, a n d b y li g ht/ dar k 
iri des at all ti me p oi nts. Eac h m y driatic a g e nt will be a nal yze d i n di vi d uall y, a n d a n a d diti o nal 
a nal ysis c o m bi ni n g 1 % tr o pica mi de a n d t he Pare m y d s u bjects i nt o a “tr o pica mi de” gr o u p will be 
perf or me d. E x pl orat or y a nal yses ma y  be perf or me d t o c o m pare efficac y e n d p oi nts bet wee n t he 
st u d y e ye a n d n o n-st u d y e ye wit hi n t he sa me s u bj ect. 
S afet y:  
T he pri mar y safet y meas ures are c o nj u ncti val h y p ere mia, s u bjecti ve oc ular t olera bilit y , a n d A Es. 
O t her safet y meas ur es i ncl u de i m pair me nt i n V A (B C D V A  a n d D C N V A ), i ntra oc ular press ure 
(I O P), s u bject q uesti o n naire, a n d s yste mic safet y as meas ure d b y H R a n d B P. Uri ne pre g na n c y 
tests f or fe males of c hil d beari n g p ote ntial will be perf or me d at scree ni n g pri or t o d osi n g of st u d y 
me dicati o n . 
Meas ure me nts:  
•  C o nj u ncti val h y pere mia  will be assesse d vis uall y wit h a 4-p oi nt c o nj u ncti val h y pere mia 
gra di n g scale ( 0 -3) wit h C C L R U i ma ges ( A p pe n di x 5 )  
•  S u bjecti ve oc ular t olera bilit y meas ure d o n a 4 -p oi nt scale  ( 0-3)  
•  B C D V A Dista nce will b e meas ur e d bi n oc ularl y i n p h ot o pic c o n diti o ns b y Sta n dar d 
E T D R S ill u mi nate d c hart ( o n wall or sta n d) at  
 (letters rec or de d, lat er c o n verte d 
t o l o g M A R a n d n u m ber of li nes) 
•  D C N V A Rea di n g/ Near will be meas ure d bi n oc ul arl y i n p h ot o pic c o n diti o ns b y Near 
Vis ual Ac uit y C hart i n t he 
 at 
 (letters rec or de d, later c o n vert e d t o l o g M A R a n d n u m ber of li nes) 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 5  
0 2 /0 5 /2 1  
 
•  I O P is meas ure d wit h t he T o n o-Pe n  
•  S u bject Q uesti o n naire will be a brief s y m pt o m s ur ve y  
4. 2.  Descri pti o n  a n d  sc he d ule of  visits  a n d  pr oce d ures  
A sa m ple size of a p pr o xi matel y 1 6 8  healt h y s u bjects ≥1 2  years of a ge will be ra n d o mize d i n a 
1: 1 rati o t o o ne of t w o treat me nt ar ms ( N y x ol or  Pl ace b o) , wit h t he e x pectati o n t hat 
a p pr o xi matel y 1 6 0  s u bjects will c o m plete t he st u d y. 
 
 a n d 3 : 1: 1 b y m y driatic a ge nt (2. 5 %  p h e n yle p hri ne , 1 % tr o pica mi de, 
a n d Pare m y d ). S u bjects will recei ve t heir m y driatic a ge nt 1 h o ur bef ore treat me nt.  St u d y 
pr oce d ures are s h o w n i n detail i n  Ta ble 2 . 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 7  
0 2 /0 5 /2 1  
 
4. 3.  Me as ures  t a ke n t o mi ni mize/ av oi d  bi as  
T his is a place b o -c o ntr olle d, d o u ble -mas ke d,  1: 1 r a n d o mize d, 2 -ar m P hase 3  st u d y.  
 
4. 4.  St u dy  me dic ati o ns  
St u d y Me dic ati o n I de ntific ati o n 
Est a blis he d n a me  
P he nt ola mi ne mes ylate –  pare nt p he nt ola mi ne  
C A S re gistr y n u m ber  
6 5 -2 8 -1  –  pare nt 5 0 -6 0 -2  
C he mic al cl ass  
A n al p ha-a dre n er gic a nt a g o nist,  it is a me m ber 
of t he f oll o wi n g classes: i mi daz oles, of 
p he n ols, is a tertiar y a mi n o c o m p o u n d a n d a 
s u bstit ute d a nili ne. 
C he mic al n a me  
3 -[ N-( 4, 5-di h y dr o -1 H -i mi daz ol-2 -yl met h yl) -4 -
met h yla nili n o] p he n ol ; met ha nes ulf o nic aci d 
M olec ul ar f or m ul a  
C 1 8H 2 3N 3O 4S –  pare nt C 1 7H 1 9N 3O  
M olec ul ar wei g ht  
3 7 7. 1 4 0 –  pare nt 2 8 1 .3 5 2  
Dr u g n a me/f or m ul ati o n  
N y x ol / a q ue o us is ot o nic s ol uti o n  
C o nce ntr ati o n acti v e  
1 % –  pare nt 0. 7 5 %  
M a n uf act urer dr u g s u bst a nce  
M a n uf act urer dr u g pr o d uct, pl ace b o  Bi oc o nce pt La b orat ories I n c.  
S t or a ge re q uire me nts 
 
 
  
St ore d i n a sec ure d l ocati o n (l oc ke d) wit h n o 
access f or u na ut h orize d p ers o n nel.  
 
F or m ul ati o n  
N y x ol  (0. 7 5 %  P he nt ola mi ne O p ht hal mic S o l uti o n) is a clear, c ol orless t o sli g htl y br o w n,  
sterile, n o n-pres er ve d, is ot o nic, b uffere d a q ue o us s ol uti o n c o ntai ni n g 1 % p he nt ola mi ne 
mes ylate (  e q ui val e nt t o 0. 7 5 %  p he nt ola mi ne free base ), ma n nit ol a n d s o di u m acetate. 
Place b o f or N y x ol  is a clear, c ol orless, sterile, n o n -preser ve d, is ot o nic, b uffere d a q u e o us 
s ol uti o n c o ntai ni n g ma n nit ol a n d s o di u m acetate. T he p H of t he st u d y me dicati o ns ma y be 
a dj uste d wit h  
 ( U S P) a n d/or  
l ( U S P) t o  
.   
4. 4. 1.  P ac k a gi n g  a n d  l a beli n g 
T he i n vesti gati o nal pr o d ucts, acti ve a n d place b o, are b ot h pac ka ge d i n 1-ml L D P E dr o p per 
b ottles c o ntai ni n g 0. 6 ml s ol uti o n f or si n gle -d ose use. Eac h b ottle  is wra p pe d wit h a n 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 8  
0 2 /0 5 /2 1  
 
al u mi n u m f oil o ver wra p i m per mea ble t o wat er a n d o x y ge n,  a n d will be la bele d wit h a n 
i n vesti gati o nal la bel s h o wi n g t he st u d y pr ot oc ol n u m ber a n d ot her rele va nt i nf or mati o n, 
i ncl u di n g a state me nt “ Ca uti o n –  Ne w Dr u g –  Li mite d b y Fe deral ( U S) La w t o 
I n v esti gati o nal Use ”.  
4. 4. 2.  St or a ge  of  st u d y me dic ati o n  a n d  dis pe nsi n g  
Pri or t o dis pe nsi n g , all i n vesti gati o nal material m ust be st ore d i n a sec ure l o cati o n wit h 
strictl y li mite d access d oc u me nte d b y si g nat ure of a ut h orize d pers o ns w h o ma y dis pe nse 
i n vesti gati o nal materials. 
 
 St u d y 
me dicati o n m ust  n ot be fr oze n a n d m ust be pr otecte d  fr o m li g ht. All i n vesti gati o nal st u d y 
me dicati o n m ust be st ore d i n a sec ure facilit y, wit h access li mi te d t o t he I n vesti gat or a n d 
a ut h orize d staff.  
4. 4. 3.  St u d y  m e dic ati o n  a d mi nistr ati o n  
St u d y me dicati o n  will be a d mi nistere d b y t he I n vesti gat or or desi g nee  at t he site o n 
Treat me nt Visit 1 .  
4. 4. 4.  St u d y  me dic ati o n  acc o u nt a bilit y  
4. 4. 4. 1.  Recei pt  a n d  dis p ositi o n  of  st u dy me dic ati o n  
T he I n vesti gat or or d esi g nee ( e. g., st u d y c o or di nat or or p har macist) will mai ntai n a f ull 
acc o u nta bilit y rec or d f or t he st u d y me dicati o n a n d will be res p o nsi ble f or rec or di n g t he 
recei pt, dis pe nsi n g, a n d ret ur n of all s u p plies of t h e st u d y me dic ati o n usi n g t he i n ve nt ories 
s u p plie d b y Oc u p hire . T h e I n vesti gat or or d esi g ne e will acc o u nt f or all st u d y me dicati o n. 
T he m o nit or will re vie w dis pe nsi n g a n d st u d y me dicati o n acc o u nta bilit y rec or ds d uri n g 
site visits a n d at t he c o m pleti o n of t h  st u d y a n d note a n y discre p a ncies.   
4. 4. 4. 2.  Ret ur n  of  st u dy me dic ati o n  
W he n t he st u d y is c o m pl te d or is t r mi nate d b y Oc u p hire, all st u d y material i ncl u di n g 
use d a n d u n use d st u d y m e dicati o n b ottles will be ret ur ne d t o Oc u p hir e ( or its desi g nee) or 
destr o ye d u n der t he direct i o n of sa me. All st u d y me dicati o n acc o u nti n g pr o ce d ures m ust 
be c o m plete d bef ore t h e st u d y is c o nsi dere d c o m plete d . A fi nal st u d y me di cati o n 
dis p ositi o n will be c o m plete d b y t he st u d y c o or di n at or.  
4. 5.  E x pecte d  d ur ati o n  of  s u bject p artici p ati o n  
T he t otal le n gt h of s u bject partici pati o n is 
, as s u m marize d b el o w: 
•  
 
 
 
 
 
T he  e x ec uti o n  of  t h e e ntire st u d y (first s u bj ect s cree ne d t hr o u g h last ra n d o mize d s u bject 
c o m plete d) is e x pecte d  t o be  a p pr o xi matel y  3  t o 6  m o nt h s. 
4. 6.  R a n d o miz ati o n  a n d  pr oce d ure  f or bre a ki n g  t he c o de 
A  ra n d o mizati o n c o d e f or all ocati n g  s u bjects t o tr eat me nt will  be  pre p are d  b y  a mas ke d  
bi ostatisticia n  n ot  c o n necte d wit h  t he st u d y. S u bjects  will  be  ra n d o mize d b y  m y driatic  
a ge nt ( u n mas ke d) a n d str atifie d b y  li g ht or  dar k  iri des. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
2 9  
0 2 /0 5 /2 1  
 
At  t he i nitiati o n of  st u d y relate d pr oce d ures,  e v er y  p ote ntial  s u bject is assi g ne d  a 
S cree ni n g  n u m ber  i n n u merical  or der.  O nce  a s u bject is q ualifie d  f or t he st u d y, t he s u bject 
is assi g ne d  a r a n d o miz ati o n n u m ber  i n t he or der  pr o vi de d  b y  t he bi ostatisticia n.  
T he  st u d y me dicati o ns  will  be  mas ke d  t o b ot h  I n v esti gat or a n d st u d y s u bjects, as well  as 
Oc u p hire . O nl y  i n case of  me dical  e mer ge nc y  or  o cc urre nce  of  S A E s will  t he 
ra n d o mizati o n c o de b e  u n mas ke d  b y  t he Me dical  M o nit or  a n d ma de  a v aila ble t o t he 
I n v esti gat or, Oc u p hir e,  a n d/ or ot her  pers o n nel  i n v ol ve d i n t he m o nit ori n g  or  c o n d uct  of  
t his st u d y. 
4. 7.  C ollecti o n  of  d at a  
St u d y s pecific data t hat h as bee n o utli ne d i n t he pr ot oc ol will be e ntere d i nt o t he cli nical 
data base b y i n di vi d ual(s) desi g nate d b y t he I n v esti gat or. Data is verifie d el ectr o nicall y 
usi n g a series of o nli ne pr o gra m me d e dit c h ec ks t hat ha ve bee n create d b y t he Cli nical 
Data Ma na g er a n d pr o gra m me d b y t h e Cli nical Data Pr o gra m mer or Desi g nee. Dat a 
discre pa n cies will be br o u g ht t o t he atte nti o n of t he cli nic l tea m a n d i n v esti gate d b y t he 
st u d y m o nit or a n d site staff. St u d y m o nit ors  will re vie w a n d v erif y all dat a c ollecte d i n t he 
electr o nic Cas e Re p ort F o r m (eC R F ) a gai nst  a n y a p plica ble  s o urce d oc u m e ntati o n d uri n g 
re m ote re vi e w or sc h e d ul e d m o nit ori n g visits. T he st u d y m o nit or will w or k cl osel y wit h 
t he site staff t o a d dress a n y discre pa n cies w hic h ha ve bee n f o u n d s o t hat pr o per res ol uti o ns 
ca n be ma d e a n d  d o c u me nte d i n t he cli nical data b ase. A n a u dit trail wit hi n t he s yste m will 
trac k all c h a n ges ma de t o t he data. 
4. 8.  C o m plete d  s u bject 
A c o m plete d s u bject is d efi ne d as o n e w h o c o m pl etes all pla n ne d d osi n g a n d pr oce d ures 
t hr o u g h t he e n d of Visit 2 .   
4. 9.  N o n -c o m pleti n g  s u bject 
A n o n -c o m pleti n g s u bject is defi ne d as o ne w h o e xits t he st u d y b y t heir o w n v oliti o n or at 
t he discreti o n of t he I n v esti gat or a n d/ or t he Me dical M o nit or  pri or t o c o m pleti n g all of t he 
st u d y pr oce d ures re q uir e d i n t his pr ot oc ol. A n y su bject  ma y deci de t o v ol u ntaril y 
wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice.  
4. 9. 1.  St u d y  me dic ati o n  disc o nti n u ati o n  
T he st u d y me dicati o n ma y be disc o nti n ue d f or t he f oll o wi n g reas o ns:  
•  A d verse E ve nts: A E s i n cl u de cli nicall y si g nifica nt la b orat or y a b n or m alities a n d 
i nterc urre nt diseases r e p orte d b y t he s u bject or o bs er ve d b y t he In vesti gat or wit h 
d oc u me ntati o n o n t he eC R F  
•  De at h:  If a s u bject dies, t he A E  t hat ca us e d t he deat h s h o ul d be d oc u me nte d o n t he 
eC R F a n d be  n ote d as seri o us a n d fatal . 
•  Dis all o we d c o nc urre nt me dic ati o n: A n y me dicati o n n ot all o we d b y t he pr ot oc ol 
w o ul d be a pr ot oc ol vi olati o n . 
•  L ac k of effic a c y:  A s u bject ma y elect t o disc o nti n ue partici pati o n i n t he st u d y f or 
a percei ve d lac k of efficac y . 
•  I n vesti g at or decisi o n:  A s u bject ma y be disc o nti n ue d f or reas o ns ot her t h a n t h ose 
b ullete d pre vi o usl y if t he In v esti gat or t hi n ks it is n ot i n t he best i nterest of t he 
s u bject t o c o nti n ue. 
•  Ot her:  If t h ere is a n y ot h er  reas o n f or s u bject disc o nti n uati o n  t his s h o ul d be  n ote d  
o n  t he eC R F . 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 0  
0 2 /0 5 /2 1  
 
T he  reas o n f or pre mat ure  st u d y me dicati o n  disc o nti n uati o n  s h o ul d be  e ntere d o nt o  t he 
a p pr o priate eC R F.   
4. 9. 2.  Re as o ns  f or w it h dr a w al fr o m st u d y 
•  S u bject  wit h dra ws c o nse nt . 
•  S u bject  is l ost t o f oll o w-u p . 
•  S u bject  wit h dra ws f or ot her reas o n . 
4. 9. 3.  E ntire  st u d y ter mi n ate d 
T he e ntire st u d y ma y be t er mi nate d b y I n v esti gat ors or Oc u p hir e . Pr o m pt, writte n n otice of 
reas o na bl e ca us e t o t he ot her part y (Oc u p hire  or I n ves ti gat ors, res pecti vel y) is re q uire d. 
Pr o m pt n otice t o t he I R B a n d t o re g ulat or y a ut h orities is als o re q uire d.  
4. 9. 4.  Acti o ns  after  disc o nti n u ati o n  
All s u bjects w h o disc o nti n ue st u d y me dicati o n d ue t o a re p ort of a n A E m ust  be f oll o we d -
u p a n d pr o vi de d a p pr o pri ate me dical care u ntil t heir si g ns a n d s y m pt o ms ha ve re mitte d or 
sta bilize d or u ntil me dical assess me nts  ha ve ret ur n e d t o acce pta ble or pre -st u d y li mits. 
F or a n y s u bject w h o c h o oses t o wit h dra w c o nse nt or w h o is n o n -c o m plia nt, e ver y p o ssi ble 
eff ort s h o ul d be ma d e b y t he I n v esti gat or t o ass ur e t h e 6 h o ur meas ure me nts are assess e d 
pri or t o disc o nti n uati o n , i n a d diti o n t o a f oll o w-u p  tele p h o ne call t hat i ncl u des assess me nts 
f or A E s, c o n c o mita nt me dicati o ns a n d s u bject e v al u ate d c o nj u ncti val h y pere mia .  
4. 1 0.  Ev al u a ble  su bjects  
S u bject s are e v al ua bl e f or effic ac y if t h e y  recei ve d o ne or t w o dr o ps of st u d y treat me nt 
a n d ha d a p u pil dia meter meas ure me nt at t he 9 0 -mi n ute ti me p oi nt at Visit 1.   
4. 1 1.  C o m plete d  st u dy 
T he  st u d y is c o m plete d  w he n  all ra n d o mize d s u bjects ha ve  c o m plet e d  t he st u d y, all eC R Fs  
ha ve  bee n  c o m plete d,  a n d all eC R F  data  e nt ere d  i nt o t he data base.  Fi nal  D B  l oc k will  
occ ur  after t he l ast ra n do mize d  s u bject c o m pletes  last visit , all data  has  bee n  e ntere d a n d 
all q ueries  res ol v e d.  
4. 1 2.  Pr oce d ure  after  t he c o m pleti o n  of  t he st u dy 
W he n t he st u d y is c o m plete d, t he C R O will pr o vi de Oc u p hire a n d t he I n v esti gat or w it h a 
brief (i.e., o n e t o t hree p a ges) re p ort , c o ntai ni n g a descri pti o n of t he st u d y, t he n u m ber of 
s u bjects e nr olle d, t he n u m ber of s u bjects c o m plet e d  t he n u m ber of s u bjects w h o dr o p pe d 
o ut a n d w h y, effi cac y fi n di n gs a n d A E s. 
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  
5. 1  
S u bject  i ncl usi o n criteri a 
1.  Males  or  fe m ales ≥ 1 2  years  of  a g e. 
2.  Ot her wise  healt h y  a n d w ell  c o ntr olle d  s u bjects.  
3.  A bilit y  t o c o m pl y wit h  all pr ot oc ol -ma n date d  pr oce d ures  i n de pe n de ntl y a n d t o 
atte n d all sc he d ule d offic e  visits .  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 1  
0 2 /0 5 /2 1  
 
4.  A d ults  (≥ 1 8  years  of  a ge) willi n g  t o gi ve  writte n  i nf or me d c o nse nt  t o partici pate  i n 
t his st u d y. C hil dre n  a ge d 1 2 -1 7  years  t o pr o vi de  si g ne d asse nt  f or m, as well  as a 
se parat e pare ntal/ Le gal  G uar dia n  c o ns e nt.  
5. 2  
S u bject  excl usi o n  criteri a 
E xcl u de d fr o m t he st u d y will be i n di vi d uals wit h t he f oll o wi n g c haracter istics: 
O p ht h al mic  (i n eit her e ye):  
1.  
Cli nicall y si g nifica nt oc ular disease as dee m e d b y t he I n vesti gat or (e. g., cat aract, 
gla uc o ma, c or neal e de ma, u veitis, se vere k erat oc o nj u ncti vitis sicca) t hat mi g ht 
i nterfere wit h t he st u d y. 
2.  
U n willi n g or u na ble t o disc o nti n ue use of c o nt act l e nses at scree ni n g u ntil st u d y 
c o m pleti o n.  
3.  
U n willi n g or u na ble t o s us pe n d use of t o pical me di cati o n at scree ni n g u ntil st u d y 
c o m pleti o n.  
4.  
Oc ular tr a u ma, oc ular s ur ger y or n o n -refracti ve l as er treat me nt wit hi n t he 6 
m o nt hs pri or t o scree ni n g.  
5.  
Use of a n y t o pical prescri pti o n or o ver -t he-c o u nter ( O T C) o p ht hal mic 
me dicati o ns of a n y ki n d wit hi n 7 da ys of scree ni n g, wit h t he e xce pti o n of a) li d 
scr u bs wit h O T C pr o d ucts (e. g., O C u S O F T ®  li d scr u b, Steri Li d® , ba b y s ha m p o o, 
etc.) or b) O T C l u bricati n g dr o ps f or dr y e ye ( preser ve d a n d u n preser ve d 
artificial tears), w hic h m a y ha ve b ee n use d pri or t o, b ut n ot at scree ni n g u ntil 
st u d y c o m pleti o n. 
6.  
Rece nt or c urre nt e vi de n ce of oc ular i nf ecti o n or i nfla m mati o n i n eit her e y e (s uc h 
as c urre nt e vi de n ce of cli nicall y si g nifica nt ble p haritis, c o nj u ncti vitis, or a hist or y 
of her pes si m ple x or her pes z oster k eratitis at Scree ni n g i n eit her e y e).  
7.  
Hist or y of dia betic reti n o pat h y or dia betic mac ular e de ma.  
8.  
Cl ose d or ver y narr o w a n gles t hat i n t he I n v esti gat o r’s o pi ni o n are p ote ntiall y 
occl u da ble if t h e s u bject’s p u pil is dilate d.  
9.  
Hist or y of a n y tra u m atic (s ur gical or n o ns ur gical) or n o n -tr a u matic c o n diti o n 
affecti n g t he p u pil or iris (e. g., irre g ularl y s h a pe d p u pil, ne ur o ge nic p u pil dis or der, 
iris atr o p h y, iri d ot o m y, iri dect o m y, etc.).  
1 0.  K n o w n aller g y or c o ntr ai n dicati o n t o a n y c o m p o n e nt of t he m y driatic a ge nts or t he 
ve hicle f or m ulati o n.  
1 1.  
Hist or y of ca uterizati o n of t he p u nct u m or p u nctal pl u g (silic o ne or c olla ge n) 
i nserti o n or re m o val. 
S yste mic:  
1.  
K n o w n  h y perse nsiti vit y  or  c o ntrai n dicati o n  t o α - a n d/ or β  a dre n oce pt or  
a nta g o nists  (e. g., c hr o ni c  o bstr ucti ve  p ul m o nar y  disease  or  br o nc hial  ast h m a;  
a b n or mall y  l o w bl o o d  press ure  ( B P) or  h eart  rate ( H R); sec o n d- or  t hir d-de gree  
heart  bl oc k a ge  or  C o n gesti ve  Heart  Fail ure  ( C H F); se vere di a betes).  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 2  
0 2 /0 5 /2 1  
 
2.  
Cli nicall y  si g nifica nt s yste mic disease  (e. g., u nc o ntr olle d  dia betes,  m yast he nia  
gra vis,  ca n cer, h e patic,  re nal, e n d ocri n e or  car di o v asc ular  dis or d ers)  t hat mi g ht  
i nterfere wit h  t he st u d y. 
3.  
I nitiati o n of  tr eat me nt wit h  or  an y  c ha n g es  t o t he c urre nt  d osa g e,  dr u g  or  
re gi me n of  a n y s yste mic a dre n er gic or  c h oli ner gic  dr u gs  wit hi n  7  da ys  pri or  t o 
scree ni n g, or  d uri n g  t he st u d y (see A p pe n di x  3 ). 
4.  
Partici pati o n  i n a n y i n vesti gati o nal st u d y wit hi n  3 0  da ys  pri or  t o scree ni n g. 
5.  
Fe males  of  c hil d beari n g  p ote ntial  w h o  are pre g na nt,  n ursi n g,  pla n ni n g  a 
pre g na n c y,  or  n ot  usi n g  a me dicall y  acce pta ble f or m of  birt h  c o ntr ol. 
Acce pt a ble  met h o ds  i ncl u de t he use  of  at least o n e  of  t he f oll o wi n g: 
i ntra uteri ne de vi ce  (I U D), h or m o nal  ( oral, i njecti o n, patc h,  i m pla nt, ri n g), 
barrier  wit h  s per mici de (c o n d o m, dia p hra g m),  or  a bsti ne nce.  A  fe male is 
c o nsi dere d  t o be  of  c hil d beari n g  p ote ntial  u nless  s he is pre -me nstr ual,  1  year  
p ost me n o pa usal  or  3  m o nt hs  p ost -s ur gical sterilizati o n. All  fe males of  
c hil d beari n g  p ote ntial  i ncl u di n g t h ose wit h  p ost -t u bal li gati o n m ust  ha ve  a 
ne gati ve  uri ne  pre g na n c y  test res ult at Visit  1/ Scree ni n g  a n d m ust  i nte n d t o n ot  
bec o me  pre g na nt  d uri n g  t he st u d y. 
6.  
Resti n g  H R  o utsi de  t he n or mal  ra n ge ( 5 0-1 1 0  beats  per  mi n ute)  at t he 
Scree ni n g  Visit.  H R  ma y  be  re p eate d o nl y  o nce  if o utsi de  t he n or mal  ra n g e 
f oll o wi n g at least a 5 -mi n ute  rest peri o d  i n t he sitti n g p ositi o n.  
7.  
H y perte nsi o n  wit h  resti n g diast olic  B P  >  1 0 5  m m H g  or  s yst olic B P  >  1 6 0  
m m H g  at t he Scree ni n g  Visit.  B P  ma y  be  re peate d o nl y  o nce  if o utsi de  t he 
s pecifie d ra n ge f oll o wi n g at least a 5 -mi n ute  rest peri o d  i n t he sitti n g p ositi o n.  
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 matel y 1 6 8 healt h y s u bj cts ≥ 1 2  years of a ge will be ra n d o mize d i n a 1: 1 rati o t o 
o ne o f t w o treat me nt ar ms ( N y x ol or Place b o), wit h t he e x pect ati o n t hat a p pr o xi matel y 
1 6 0  s u bjects will c o m plete t he st u d y. Ra n d o mizati o n will be stratifie d 1: 1 b y li g ht/ dar k 
c ol or iri des a n d f urt her ra n d o mize d 3: 1: 1 t o m y driatic a ge nt ( 2. 5 % p he n yle p hri ne, 1 % 
tr o pica mi de, a n d Pare m y d) . S u bjects will recei ve t heir m y driatic a ge nt 1 h o ur bef ore 
treat me nt o n  Treat me nt Visit 1 o n Da y 1. T here will be n o treat me nt a d mi nistere d o n 
F oll o w -U p Visit / Da y 2.  
6. 1.  Tre at me nt  a d here nce  
All s u bjects will be treate d b y t he I n vesti gat or or d esi g nee at t he st u d y cli ni c o n Visit 1 .  
6. 2.  C o nc o mit a nt  me dic ati o ns  
As n ote d i n t he e xcl usi o n criteria ( Secti o n 5. 2 ), u s e of a n y t o pical prescri pti o n or o ver-t he-
c o u nter ( O T C) o p ht hal mic me dicati o ns of a n y ki n d wit hi n 7 da ys of scree ni n g are 
pr o hi bite d , wit h t he e xce pti o n of a) li d scr u bs wit h O T C pr o d ucts (e. g., O C u S O F T ® li d 
scr u b, Steri Li d ®, ba b y s ha m p o o, etc.) or b) O T C l u bricati n g dr o ps f or dr y e ye ( preser ve d 
a n d u n preser ve d artificial tears), w hic h m a y ha ve bee n use d pri or t o, b ut n ot at scree ni n g 
u ntil st u d y c o m pleti o n.  A lar ge n u m ber of dr u gs, b ot h prescri pti o n a n d o ver -t he-c o u nter 
( O T C), c o ntai n acti ve i n gre die nts t hat ca n affect P D. T his w o ul d i ncl u de ma n y e ye dr ops, 
s uc h as Visi ne, t hat w o ul d be use d t o re d u ce re d ness, m ost c o u g h or c ol d pr e parati o ns, 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 3  
0 2 /0 5 /2 1  
 
a nti hista mi nes a n d br o nc h o dilat ors, m ost n ose -dr o ps, m ost bl o o d -press ure me dicati o ns, 
ma n y dr u gs use d f or mi grai nes, a n d ma n y ot h er pr o d ucts .  
A d diti o nall y, initiati o n of treat me nt wit h or a n y c ha n ges t o t he c urre nt d os a ge, dr u g or 
re gi me n of a n y s yste mic a dre ner gic or c h oli ner gic dr u gs (see A p pe n di x 3 ) wit hi n 7 da ys 
pri or t o scree ni n g, or d uri n g t he st u d y , is pr o hibite d . H o we ver , a s u bject ca n be treate d 
wit h a s yste mic a dre n o ce pt or a nta g o nist , f or e x a m ple, as l o n g as t he partic ular a ge nt a n d 
its d ose a n d re gi me n ha d bee n c o nsiste nt f or t h e 7 da ys pri or t o Scree ni n g, a n d t here was 
n o reas o n t o belie v e t hat alterati o n w o ul d be necessar y at s o me p oi nt later d uri n g t he 
st u d y. 
If t here is a ny q uesti o n a b o ut w het her a me dic ati o n is acce pt a ble, t he Me dic al M o nit or 
s h o ul d be c o ns ulte d bef ore pr ocee di n g 
Use of all me dicati o ns s h o ul d be d oc u me nte d o n t he a p pr o pri ate eC R F. I n v esti gat ors are 
e nc o ura g e d t o c o ntact t he Me dical M o nit or f or a n y q uesti o ns re gar di n g all o we d 
me dicati o ns. J u d g me nt of c o nti n ue d st u d y partici pati o n  b y t he s u bject, a n d i ncl usi o n of 
t his s u bject’s s u bse q ue nt visits i n t he safet y a n d efficac y a nal ysis will be ma de b y 
Oc u p hire.  
All me dicati o ns w hic h t he s u bject has ta k e n wit hi n 3 0 da ys  pri or t o t he Scree ni n g Visit 
a n d d uri n g t he st u d y will be rec or de d i n t he eC R F. T he na me of t h e dr u g, d ose, r o ute of 
a d mi nistrati o n, d urati o n of treat me nt a n d i n dicati o n  will be rec or de d f or eac h me dicati o n. 
F or c o m bi nati o n pr o d u cts (e. g., C o ntac ® , C os o pt® ), t he bra n d n a me is re q uire d. F or 
n o n -c o m bi nati o n pr o d ucts, t he ge neric n a m  is desire d. T he use of r o uti ne o p ht hal mic 
dia g n ostic p har mace utical a ge nts (e. g., fl u orescei n a n d l ocal a nest hetic) will be all o we d, 
a n d s h o ul d be d oc u me nte d. A n y c ha n ge i n d osi n g para meters s h o ul d als o be rec or de d i n 
t he eC R F.  
7.  A S S E S S M E N T  O F  E F FI C A C Y  
7. 1.  S pecific ati o n  of  t he effic acy p ar a meters  
T he pri mar y effic ac y e n d p oi nt is t he p erce nta ge of s u bjects’ st u d y e yes wit h t w o dr o ps of 
treat me nt ret ur ni n g t o ≤ 0. 2 m m baseli ne p u pil dia meter at 9 0 mi n utes. 
T he st u d y e ye is defi n e d as t he ri g ht e ye ( O D). T h e n o n -st u d y e ye is defi ne d as t he left e y e 
( O S). T he st u d y a n d n o n-st u d y e ye will b ot h be e v al uate d at all assess m e nts. N ote t hat 
s u bjects ≥ 1 8 years ol d will recei ve t w o dr o ps ( d ose d
) of tr eat me nt i n t heir 
st u d y e ye a n d o ne dr o p of treat me nt i n t heir n o n-st u d y e ye. S u bjects < 1 8 years ol d will 
recei v e o ne dr o p of treat me nt i n t heir st u d y e ye a n d o ne dr o p of treat me nt i n t heir n o n-
st u d y e ye. Sec o n dar y efficac y e n d p oi nts ca n be f o u n d i n Secti o n 4. 1 .  
T he M o difie d I nte nt -t o-Treat ( mI T T ) will be use d f or t he pri mar y e n d p oi nt a nal ysis a n d t o 
a nal yze s electe d s ec o n dar y effic ac y e n d p oi nts . T he Per Pr ot oc ol (P P ) p o p ulati o n will be 
use d t o a nal yze s electe d sec o n dar y effi cac y e n d p oi nts.  S o me  of  t he efficac y  e n d p oi nts  will  
be  a nal yz e d  o verall,  b y  m y driatic  a ge nt, a n d b y  li g ht/dar k  iri des.  
7. 2.  Assessi n g,  rec or di n g, a n d  a n alyzi n g  of  effic acy p ar a meters  
P u pil dia meter will be meas ure d at Treat me nt Visit 1  a n d F oll o w -U p  Visit 2 . 
Acc o m m o dati o n will be meas ure d at Treat me nt Visit 1.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 4  
0 2 /0 5 /2 1  
 
•  P u pil dia meter will be meas ure d wit h t he 
 ( m m) 
•  Acc o m m o dati o n will be meas ure d b y t he 
 
 U nc h a n ge d acc o m m o dati o n fr o m 
Baseli ne ( -1 h o ur) is defi ne d as a c h a n ge fr o m bas eli ne val ue ≥ -1, as meas ure d i n 
di o pters.  
T he p h ot o pic li g hti n g c o n diti o ns i n t he r o o m will be defi ne d as 
 
 
 
. S u bject will sit i n t he e xa m c hair at a dista n ce of  
 fr o m t he 
dista nce E T D R S 
 f or all ass ess me nts. S u bject will be all o we d t o 
accli mate t o t hese li g hti n g c o n diti o ns (
  
 t he p u pil dia meter, B C D V A 
a n d D C N V A  (s afet y meas ures) at all sc h e d ule d ti me p oi nts. 
 
 f or acc o m m o dati o n meas ure m e nts a n d  t he re mai ni n g safet y assess me nts (e. g. 
c o nj u ncti val h y pere mia, a d verse e ve nts, s u bject q uesti o n naire, etc.). T he s u bject will be i n 
t he sa me r o o m f or all ass ess me nts, a n d e ver y eff ort will be ma de t o ha ve t h e same pers o n 
perf or m t he meas ure m e nts at all ti me p oi nts.  
7. 2. 1.  Scree ni n g / D a y 1  
I n di vi d uals w h o are p ote ntial s u bjects are i de ntifi e d b y t he st u d y ce nter t o sc he d ule t he 
S cree ni n g V isit. The  Scree ni n g V isit s h o ul d occ ur t he sa me  da y as Treat me nt Visit 1, 
w here t he d os e of st u d y treat me nt is gi ve n.  
O nce s u bjects arri ve at t he st u d y ce nter, a me m ber of t he st u d y ce nter st aff will i nter vie w 
t he i n di vi d ual as t o t heir q ualificati o ns f or partici pati o n i n t he st u d y, a n d if t he s u bject 
wis hes t o c o nti n ue, t he I nf or me d C o se nt f or m is si g ne d, a n d a Scree ni n g n u m ber is 
assi g ne d . C hil dre n a ge d 1 2 -1 7 years t o pr o vi d e asse nt. Scree ni n g i ncl u des a n e x pla nati o n 
of t he st u d y, a me dical a n d o p ht hal mi  hist or y, de m o gra p hics, a re vie w of 
pri or/c o nc o mita nt me dicati o ns  a uri ne pre g n a nc y test (f or fe m ales of c hil d beari n g 
p ote ntial ), a n d H R / B P  T he sec o n d ste p i n scree ni n g i ncl u des pr oc e d ures s uc h as I O P 
assess me nt a n d an  o p ht h al mic e xa mi nati o n  t hat i ncl u des bi o micr osc o p y a n d direct or 
i n direct o p ht hal m osc o p y  wit h o ut dilati o n .  
I n v esti gat ors are ca uti o n e d t o a p pr o priat el y n ote all o bser vati o ns of c o nj u n cti val 
h y pere mia (als o calle d c o nj u ncti val er yt he ma) o n t he bi o micr osc o p y eC R F at scree ni n g.  
7. 2. 2.  Tre at me nt  Visit  1/ D a y  1  
Treat me nt Visit 1 s h o ul d be t he sa me da y as Scree ni n g. O nce t he s u bject h as c o m plete d 
t he Scree ni n g ass ess me nts part of t he visit a n d it is c o nfir me d t hat he/s he m eets all of t he 
i ncl usi o n criteria b ut n o n e of t he e x cl usi o n criteria, t he visit will t he n tra nsiti o n t o t he 
Treat me nt Visit 1 assess me nts. As part of t he Treat me nt Visit 1 , t he s u bject:   
• 
 
 
• 
 
 
 
 
 
  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 5  
0 2 /0 5 /2 1  
 
• 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
. A d ult  
s u bjects (≥ 1 8  years  ol d)  will  ha ve  t w o dr o ps  ( d ose d 5  mi n utes  a part) of  treat me nt 
a d mi nistere d  i n t he St u d y  E ye  ( O D) a n d o n  dr o p  of  treat me nt a d mi nistere d  i n t he N o n -
St u d y  E ye  ( O S) o ne  h o ur  after m y driatic  dr u g  i nstillati o n. Pe diatric  s u bjects (< 1 8  years  
ol d ) will  ha ve  o ne  dr o p  o f treat me nt a d mi nistere d  i n eac h e y e o ne  h o ur  after m y driatic  
dr u g  i nstillati o n. 
 
7. 2. 3.  F oll o w -U p  Visit  / D a y  2   
O n Da y  2 , t he s u bject will ret ur n t o t he cli nic f or  a F oll o w -U p  Visit .  
As part of t he F oll o w-U p Visit , t he s u bject: 
• Will  be  ass esse d  at 2 4  h o urs  +  6  h o urs  rel ati ve t o st u d y treat me nt a d mi nistrati o n  d uri n g  
Treat me nt  Visit  1  f or t h e f oll o wi n g: c o nc o mita nt  me dicati o ns,  H R/ B R,  p u pil  dia meter , 
B C D V A , D C N V A , c o nj u ncti val  h y pere mia , A Es , a n d s u bject q uesti o n nair e . 
7. 2. 4.  U nsc he d ule d  Visits  
A n U nsc he d ule d V isit ma y be a n y visit t o t he I n v esti gat or ot her t ha n t he s pecific visits 
re q ueste d i n t he pr ot o c ol as p ossi bl y re q uire d f or t he s u bject’s o p ht hal mic c o n diti o n. T he 
I n v esti gat or will perf or m all pr oce d ures necessar y t o e val uate t he st u d y partici pa nt at t hese 
visits a n d rec or d a n y A Es  i n t he eC R F . 
As n ote d  i n Secti o n 4. 9. 4 , e ver y p ossi ble eff ort s h o ul d be ma de b y In vesti g at ors t o ass ure 
t hat s u bjects w h o disc o nti n ue earl y fr o m t he st u d y ha ve a tel e p h o ne f oll o w-u p t hat 
i ncl u des assess me nts of A Es , c o nc o mita nt me dicati o ns a n d s u bject-e v al uate d c o nj u ncti val 
h y pere mia . 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 6  
0 2 /0 5 /2 1  
 
7. 2. 5.  Visit  v ari ati o n  
Visits o n Da y 2  ma y occ ur bet wee n 2 4 t o 3 0 h o urs after t he b aseli ne ( 0 mi n ute ) ti me p oi nt 
o n Treat me nt D a y 1 . 
8.  A S S E S S M E N T  O F  S A F E T Y  
8. 1.  S pecific ati o n  of  s afety p ar a meters  
T he assess me nt of s afet y a n d t olera bilit y is t he sec o n dar y o bjecti ve of t his st u d y. T he 
assess me nt of safet y will be e val uat e d b y:  
•  C o nj u ncti val h y pere mia  meas ure d wit h C C L R U i ma ges usi n g a 4 -p oi nt scale  ( 0-3)  
–  A p pe n di x 5 . 
o  N o ne ( 0) = N or mal A p pears w hite wit h a s mall n u m ber of c o n ju ncti val 
bl o o d vessel  easil y o bser ve d  
o  Mil d ( + 1) = Pr o mi ne nt , pi n kis h-re d c ol or of b ot h t he b ul bar a n d p al pe bral 
c o nj u ncti va  
o  M o derate ( + 2) = Bri g ht, scarlet r e d c ol or of t h e b ul bar a n d pal pe bral 
c o nj u ncti va  
o  Se vere ( + 3) = Beef y re d wit h petec hiae, d ar k re d b ul bar a n d pal pe bral 
c o nj u ncti va wit h e vi de nce of s u bc o nj u ncti val he m orr ha ge   
•  S u bjecti ve oc ular t olera bilit y  meas ure d  o n a 4 -p oi nt scale  
o  0 –  N o disc o mf ort  
o  1 –  Mil d disc o mf ort  
o  2 –  M o derate disc o mf ort  
o  3 –  Se vere disc o mf ort  
•  B C D V A Dista nce will be meas ure d bi n oc ularl y i n p h ot o pic c o n diti o ns b y Sta n dar d 
E T D R S  
 at 
 –  A p pe n di x  6  
•  D C N V A Rea di n g/ Near will be meas ure d bi n oc ul arl y i n p h ot o pic c o n diti o ns b y Near 
Vis ual Ac uit y C hart i n t he 
 
 –  A p pe n di x  6  
•  I O P is meas ure d wit h t he T o n o-Pe n  
•  H R  a n d B P  (As per t he site’s n or mal e q ui p me nt a n d pr oce d ure s) 
•  A Es  
•  Brief S u bject  Q uesti o n naire  –  A p pe n di x 4  
8. 2.  Assessi n g,  rec or di n g, a n d  a n alyzi n g  s afety p ar a meters  
T he ti mi n g f or rec or di n g safet y para meters ma y be f o u n d i n Secti o n 4. 2 , Ta ble 2 : 
Scree ni n g a n d M y driatic/ Treat me nt Sc he d ul e . 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 7  
0 2 /0 5 /2 1  
 
8. 3.  A dverse  eve nts  a n d  seri o us  a dverse  eve nts  
All A Es a n d S A Es t hat occ ur f oll o wi n g c o ns e nt a n d u ntil t he fi nal st u d y visit s h o ul d be 
c ollecte d a n d rec or de d o n t he A E or S A E e C R F p a ge . O nl y treat me nt-e mer ge nt a d verse 
e ve nts/a d vers e reacti o ns ( T E A Es) will be s u m marize d (see Secti o n 9. 3. 5 ). 
All A Es /a d verse reacti o ns occ urri n g d uri n g t he st u d y (i.e. o nce t he s u bj ect has si g ne d t he 
i nf or me d c o nse nt/asse nt) m ust be d oc u me nte d, re gar dless of t he ass u m pti o n of ca usal 
relati o ns hi p, o n t he res pecti ve eC R F. All  treat me nt-e mer ge nt  A Es / a d verse reacti o ns m ust 
be d oc u me nte d fr o m t he ti me t he s u bject recei ves t he st u d y me dicati o n u ntil t he s u bject’s 
partici pati o n i n t he st u d y has bee n c o m plet e d. If a s u bject has o n g oi n g A Es /a d verse 
reacti o ns at t he ti me of st u d y c o m pleti o n  or disc o nti n uati o n fr o m t he st u d y , t he o n g oi n g 
A Es /a d verse reacti o ns m ust  be f oll o we d -u p a n d pr o vi de d a p pr o priate me di cal care u ntil 
t he si g ns a n d s y m pt o ms ha ve re mitte d or sta bilize d or u ntil me dical assess me nts  ha ve 
ret ur ne d t o a cce pta ble or pre-st u d y li mits. 
D oc u me ntati o n of A Es /a d verse reacti o ns i ncl u des start date a n d e n d date, s e verit y, 
relati o ns hi p t o st u d y me dicati o ns, acti o n(s) ta ke n, seri o us ness a n d o utc o me.  
8. 3. 1.  A d verse  e v e nt defi niti o ns  
T he f oll o wi n g defi niti o ns of ter ms a p pl y t o t his secti o n:  
A dverse eve nt . A n A E is a n y u nt o war d me dical occ urre n ce ass ociate d wit h t he use of a 
st u d y me dicati o n i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. A n A E ca n t heref ore 
be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a b n or mal la b orat or y fi n di n gs), 
s y m pt o m, or disease te m p oraril y ass oci t e d wit h t he use of t he st u d y me dicati o n, w het her 
or n ot relate d t o t he st u d y me dicati o n. St u d y me dicati o n i ncl u de s t he i n vesti gati o nal dr u g 
u n der e val u ati o n a n d t he c o m parat or pr o d uct or v e hicle place b o t hat is gi ve n or 
a d mi nistere d d uri n g a n y p hase of t he st u d y.  
Me dical c o n diti o ns/ diseases prese nt bef ore st arti n g t he i n vesti gati o nal treat me nt are o nl y 
c o nsi dere d A E s if t he y w o se n after starti n g t he i n vesti gati o nal treat me nt. A b n or mal test 
res ults c o nstit ute A Es o nl y if t he y i n d uce cli nical si g ns or s y m pt o ms, are c o nsi dere d 
cli nicall y si g nifica nt, or re q uire t hera p y. 
T he occ urre n ce of A Es s h o ul d be s o u g ht b y o pe n -e nde d q uesti o ni n g of t he s u bject at eac h 
visit d uri n g t he st u d y. At eac h cli nic assess me nt /visit, st u d y pers o n nel s h o ul d as k t he 
f oll o wi n g q uesti o n: “ Ha v e y o u ha d a n y pr o ble ms si nce y o ur last assess me nt /visit ?”. A Es 
als o ma y be dete cte d w h e n t he y are v ol u nte ere d b y t he s u bject d uri n g or bet wee n visits or 
t hr o u g h st u d y assess me nts. 
Life -t hre ate ni n g a dverse eve nt or life-t hre ate ni n g s us pecte d a dverse r e acti o n. A n A E  or 
s us pecte d a d v erse reacti o n is c o nsi dere d “life-t hreate ni n g” if, i n t he vie w of eit her t he 
In v esti gat or or O c u p hire , its occ urre n ce places t he s u bject or s u bject at i m me diate ris k of 
deat h. It d oes n ot i ncl u de a n A E  or s us pecte d a d v erse reacti o n t hat, h a d it o cc urre d i n a 
m ore se vere f or m, mi g ht ha ve ca use d deat h.  
Seri o us a dverse eve nt or seri o us s us pecte d a dverse re acti o n . A n A E  or s us pecte d a d v erse 
reacti o n is c o nsi dere d ‘‘seri o us’’ if, i n t he vie w of eit her t he In v esti gat or or Oc u p hire,  it 
res ults i n a n y of t he f oll o wi n g o utc o mes:  
•  Deat h  
•  L ife t hreat e ni n g a d vers e e ve nt  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 8  
0 2 /0 5 /2 1  
 
•  In p atie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n  
•  P ersiste nt  or  si g nifica nt i nca pacit y or  s u bsta ntial disr u pti o n  of  t he a bilit y t o c o n d uct  
n or mal  life f u ncti o ns  
•  C o n g e nital  a n o mal y/ birt h  defect   
•  Ot her  me dicall y  i m p orta nt seri o us e ve nt  
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hr eate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt or s u bj ect a n d ma y re q uire m e dical or s ur gical 
inter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  
Treat me nt o n a n o ut p atie nt e mer ge nc y b asis t hat d oes n ot res ult i n h os pital a d missi o n, or a 
h os pitalizati o n t hat is electi ve or is a pre pl a n ne d tr eat me nt f or a pre -e xisti n g c o n diti o n  t hat 
is u nrelate d t o t he me dicati o n u n der st u d y a n d has n ot w orse ne d si nce t he start of t he 
st u d y, is n ot c o nsi dere d a n S A E. 
S us pecte d a dverse re a cti o n  mea ns a n y A E  f or w hic h t here is a reas o n a ble p ossi bilit y t hat 
t he dr u g ca us e d t he A E . F or t he p ur p os es of I N D safet y re p orti n g, “reas o n a ble p ossi bilit y” 
mea ns t here is e vi d e nce t o s u g gest a ca us al relati o ns hi p bet wee n t he dr u g a n d t he A E . 
S us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y a b o ut ca usalit y t ha n 
a d verse reacti o n, w hic h mea ns a n y A E  ca use d b y a dr u g.  
U ne x pecte d a d verse eve nt or u ne x pecte d s us pecte d a dverse r e acti o n . A n A E  or s us pecte d 
a d verse reacti o n is c o nsi dere d  “u n e x pecte d ” if i  is n ot liste d i n t he In vesti gat or s’ B r oc h ure 
or is n ot liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d; or, if a n In v esti gat or s’ 
B r oc h ure is n ot re q uir e d or a vaila ble  is n ot c o nsiste nt wit h t he ris k i nf or mati o n descri be d 
i n t he ge neral i n vesti gati o nal pla n or else w h ere i n t he c urre nt a p plicati o n, as a me n de d. 
“ U ne x pecte d,” as use d i n t his defi niti o n, als o refers t o A Es  or s us pecte d a d verse reacti o ns 
t hat are me nti o ne d i n t he In v esti gat or s’ B r oc h ure as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p h ar mac ol o gical pr o perties of t he dr u g b ut are n ot s pecificall y 
me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.  
T he st u d y me dicati o n rel ati o ns hi p f or eac h A E /a d verse reacti o n s h o ul d be deter mi ne d b y 
t he I n v esti gat or usi n g t hese e x pla nati o ns: 
•  N ot rel at e d  
•  U nli kel y rel ate d  
•  P ossi bl y rel ate d  
•  Pr o b a bl y rel ate d  
•  Defi nitel y rel at e d  
•  U n k n o w n  
U nless t he relati o ns hi p is c o nsi dere d t o be “ N ot relate d” or “ U nli kel y relate d” a n d t here is 
a n y vali d reas o n, e ve n if u n deter mi ne d , f or s us p ecti n g a p ossi ble ca use-a n d -effect 
relati o ns hi p bet wee n t h e st u d y me dicati o n a n d t he occ urre nce of t he A E, t h e n t he A E 
s h o ul d be c o nsi dere d “ rel ate d”.  
If t he rel ati o ns hi p bet wee n t he A E/ S A E a n d t he i n vesti gati o nal pr o d uct is deter mi ne d b y 
Oc u p hire  t o be a n yt hi n g ot her t ha n “N ot relate d” or “ U nli kel y rel ate d” t he e ve nt will be 
c o nsi dere d t o be relate d t o t he i n vesti gati o nal pr o d uct f or t he p ur p os es of e x pe dite d 
re g ulat or y re p orti n g. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
3 9  
0 2 /0 5 /2 1  
 
Severity  of a n A E  is defi ne d as a q ualitati ve assess me nt of t he le vel of disc o mf ort of a n 
A E  as is deter mi ne d b y t he I n vesti gat or or re p ort e d t o hi m/ her b y t he s u bject. T he 
assess me nt of se verit y is ma de irres p ecti ve of st u d y me dicati o n relati o ns hi p or seri o us ness 
of t he e ve nt a n d s h o ul d b e e val uat e d acc or di n g t o t he f oll o wi n g scale:  
•  1 = Mil d: prese nt, b ut n ot distressi n g, a n d n o disr u pti o n of n or mal dail y acti vit y  
•  2 = M o derat e: disc o mf ort s ufficie nt t o re d uce or affect n or m al dail y acti vit y  
•  3 = Se vere: i nca pacitati n g, wit h  i na bilit y t o w or k or perf or m n or mal dail y acti vit y 
A  c ha n ge i n s e verit y f or a re p ort e d A E  will  re q uir e an  e n d d ate  f or t h e pre vi o us  se verit y 
a n d a ne w  start a n d e n d d ate  f or t he n e w  se v erit y. F or  e x a m ple,  a c h a n ge i n se verit y ma y  
g o  fr o m mil d  t o se vere or  fr o m se vere t o m o derat e.  I n eit her case t he start or  e n d 
ti mes/dates  s h o ul d be  rec or de d.  
T he  ter m “se v ere”  is use d  t o descri be  t he i nte nsit y of  a n e ve nt/reacti o n;  t he e ve nt/reacti o n  
itself ma y  be  of  relati vel y mi n or  me dical  si g nifica nce (s uc h as a s e vere hea dac h e) . T his  is 
n ot  t he sa me as a “ Seri o us”  A d vers e  E ve nt,  w hic h  is base d  o n  a s u bject/e v e nt o utc o me  or  
acti o n criteria us u all y  ass ociate d  wit h  e ve nts  t hat p ose  a t hreat t o t he s u bject’s life or  vital  
f u ncti o ns. “ Seri o us ness ” ( N O T se v erit y) ser ves as a g ui de  fo r d efi ni n g  re g ul at or y re p orti n g 
o bli gati o ns.  
Acti o n  ta ke n i n res p o nse t o a n A E  is c o de d as:  
•  D ose  i ncrease d: A n  i n di cati o n t hat a me dicati o n  sc he d ule was  m o difie d  b y  a d diti o n; 
eit her b y  c ha n gi n g  t he fre q ue nc y, str e n gt h or  a m o u nt.  
•  D ose  n ot  c ha n g e d:  A n  i n dicati o n t hat a me dicati o n  sc he d ule was  m ai ntai ne d.  
•  D os e re d u ce d: A n  i n dicati o n t hat a me dicati o n  sc he d ule was  m o difie d  b y  s u btracti o n, 
eit her b y  c ha n gi n g  t he fre q ue nc y, str e n gt h or  a m o u nt.  
•  D ose  i nterr u pt e d: A
 i n di cati o n t hat a me dicati o n  s c he d ule was  m o difie d  b y  te m p oraril y 
ter mi nati n g a prescri be d  re gi me n o f me dicati o n.  
•  Dr u g  wit h dra w n:  A n  i n dicati o n t hat a me dicati o n  sc he d ule was  m o difie d  t hr o u g h 
ter mi nati o n of  a pres cri b e d  re gi me n of  m e dicati o n.  
•  N ot  a p plica ble:  Det er mi nati o n  of  a val ue  is n ot  rel e va nt i n t he c urre nt  c o nte xt  
•  U n k n o w n:  N ot  k n o w n,  n ot  o bser ve d,  n ot  rec or de d, or  ref use d 
A d diti o nal Ot her Acti o n Ta ke n:  
•  C o nc o mita nt  Me dicati o n  
•  H os pitalizati o n  
O utc o me  of  a n A E  is c o d e d as: 
•  Fatal : T he  ter mi nati o n of  life as a res ult of  a n a d v erse e v e nt.  
•  N ot  rec o v ere d/ n ot res ol v e d: O ne  of  t he p ossi ble  res ults of  a n a d v erse e ve nt o utc o me  
t hat i n dicates t hat t he e ve nt has  n ot  i m pr o ve d or  rec u perat e d. 
•  Rec o vere d/res ol ve d : O ne  of  t he p ossi ble  res ults of  a n a d verse e v e nt o utc o me  t hat 
i n dicates t hat t he e ve nt h as  i m pr o ve d or  rec u perat e d. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 0  
0 2 /0 5 /2 1  
 
•  Rec o vere d/ Res ol ve d  wit h  se q uelae: O n e of  t h e p ossi ble  res ults of  a n a d verse e v e nt 
o utc o me  w here  t he s u bject rec u p erate d b ut  retai ne d pat h ol o gical  c o n diti o ns  res ulti n g 
fr o m t he pri or  diseas e  or  i nj ur y. 
•  Rec o veri n g/res ol vi n g:  O ne  of  t he p ossi ble  res ults of  a n a d verse e ve nt o utc o me  t hat 
i n dicates t hat t he e ve nt is i m pr o vi n g 
•  U n k n o w n:  N ot  k n o w n,  n ot  o bser ve d,  n ot  rec or de d, or  ref use d 
I n pre vi o us cli nical st u di es of N y x ol  t he m ost fre q ue ntl y re p orte d A E  was c o nj u ncti val 
h y pere mia.  
I n t he prese nt st u d y, a n y i ncre ase of t w o u nits i n c o nj u ncti v al h y pere mi a bet wee n 
c o nsec uti ve ti me p oi nts is c o nsi dere d a n A E.  
In vesti g at ors are c a uti o ne d t o use t he a p pr o pri ate ver b ati m ter m o n t he A E  f or m t o 
descri be t his o bser v ati o n:  
•  Re d ness rel ate d t o i nstill ati o n t h at is tr a nsie nt (i.
 is n o l o n ger prese nt 2 
h o urs after i nstill ati o n) = “c o nj u ncti v al er yt h
m a u p o n i nstill ati o n ”  
•  Re d ness t h at is N O T tr a nsie nt (i.e., is prese nt 2 h o urs after i nstill ati o n) = 
“c o nj u ncti v al h y pere mi a ”  
E x pe dite d  re p orti n g  of  Seri o us  a n d  U ne x pecte d  A d verse  E ve nts : A ll S A Es  (relat e d a n d 
u nrelate d)  will  be  rec or de d f oll o wi n g s u bject si g nat ure of  t he i nf or me d c o nse nt /asse nt a n d 
u ntil  t he F oll o w -U p  Visit  (Da y  2 ). A n y  S A Es  “s us pecte d” t o b e  relat e d t o t he st u d y 
me dicati o n  a n d disc o vere d  b y  t he I n vesti gat or at a n y ti me after  t he st u d y s h o ul d be  
re p orte d. 
A n y  S A E  t hat occ urs  m ust  be  re p orte d t o t he C R O  wit hi n  2 4  h o urs  of  its occ urre nce  or  
wit hi n  2 4  h o urs  of  lear ni n g of  its occ urre nce.  Rec urre nt  e pis o des,  c o m plicati o ns,  or  
pr o gressi o n  of  t he i nitial S A E  m ust  be  re p orte d t o t he C R O  as f oll o w-u p  t o t he ori gi nal  
e pis o de wit hi n  2 4  h o urs  of  t h  I n vesti gat or recei vi n g t he i nf or mati o n. I nf or mati o n a b o ut 
all S A Es  will  be  c ollecte d  a n d rec or de d o n  t he S A E  f or m. All  perti ne nt  me dical  rec or ds 
a n d i nf or mati o n c ollecte d  d uri n g  t he treat me nt a n d f oll o w-u p  of  t he s u bject s h o ul d be  
mai ntai ne d  at t he site wit h  a c o p y e maile d t o
 T he  
I n v esti gat or m ust  assess t he S A E  relati o ns hi p a n d c o m plete t he S A E  f or m. T he  C R O  ma y  
re q uest a d diti o nal  i nf or m ati o n. F oll o w -u p  i nf or mati o n (e. g., disc har ge  s u m mar y) will  be  
retai ne d i n t he s u bject’s c hart a n d a c o p y will  be  e maile d t o 
 I n a d diti o n,  all S A Es  s h o ul d be  rec or de d o n  t he A E  eC R F  
pa ge  wit h  t he seri o us q uesti o n  mar ke d  “ Yes ”.  
It is t he In v esti gat or’s  res p o nsi bilit y t o n otif y  t he a p pr o vi n g  I R B of  a n y S A Es  o n  a ti mel y 
basis  as i nstr ucte d b y  Oc u p hire  f oll o wi n g Oc u p hir e ’s deter mi nati o n  of  ca us alit y.  All  
s u bjects w h o  e x perie nce  a n S A E  s h o ul d be  f oll o w e d cli nicall y a n d u n der g o  t he a p pr o priat e 
d ia g n ostic e val uati o ns  u ntil  sta bilizati o n or  res ol uti o n of  t he e ve nt. Oc u p hire  will  re p ort all 
S A Es  t o t he U S  F o o d  a n d Dr u g  A d mi nistrati o n  ( F D A) o n  t h e a p pr o priate  sc he d ule 
de pe n di n g  if t he e v e nt  is dr u g  relate d or  n ot  dr u g  relate d, e x p ecte d, u ne x pecte d  ( bas e d o n  
t he a vaila ble i nf or m ati o n i n t he I n v esti gat ors’ Br oc h ure).  
A n y  deat h  occ urri n g  d uri n g  t he st u d y a n d f oll o w-u p  peri o d  m ust  be  re p ort e d as a n S A E.  
F or  a n y d eat h  occ urri n g  t hr o u g h t he e n d of  t he st u d y, re gar dl ess of  t he de gree  of  
relati o ns hi p t o st u d y me dicati o n , t he S A E  res ulti n g i n t he deat h  m ust  be  re p orte d t o the  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 1  
0 2 /0 5 /2 1  
 
C R O . A  deat h  occ urri n g  after c o m pleti o n  of  t he st u d y i ncl u di n g t he Safet y  F oll o w -u p  
Visit s, t hat is n ot  reas o na bl y ass ociate d wit h  st u d y me dicati o n  a d mi nistrati o n,  d oes  n ot  
re q uire c o m plet i o n of  t he S A E  f or m. 
8. 3. 2.  F oll o w -u p  of  s u bjects after  a d verse  e v e nts  
If a n A E /a d v erse reacti o n occ urs, t he I n vesti gat or will i nstit ute s u p p ort a n d/ or treat me nt as 
dee me d a p pr o priate. All  S A Es  o n g oi n g  at t he ti me of t he last visit, or disc o nti n uati o n fr o m 
t he st u d y, will be f oll o we d u p  u ntil t he A E /a d verse reacti o n is res ol v e d or sta bilize d, t he 
s u bject is l ost t o f oll o w-u p, or t here is ot her res ol uti o n t o t he e ve nt.  
9.  S T A TI S TI C S  
A detaile d pres e ntati o n of t he statistical a p pr oac h  is o utli ne d i n t he Statistical A nal ysis 
Pla n.  
9. 1.  S a m ple  S ize 
A  sa m ple size of  1 6 0  e val ua ble s u bjects ( 8 0 per  tr eat me nt gr o u p)  is nee de d  f or t he st u d y.  
T he pri mar y effic ac y e n d p oi nt will be met if s u bjects  s h o w a p ositi ve effect f or N y x ol ( α = 
0. 0 5  si g nifica nce, t w o-taile d). O ne h u n dre d a n d si xt y  e val ua ble s u bjects will pr o vi de at 
least 
 
 
 
 T he 
ass u m pti o ns f or t his p o wer calc ulati o n are esti mat e d fr o m t he MI R A -1 P hase 2 res ults a n d 
a dj uste d f or t he 3: 1: 1 m y driatic a ge nt gr o u ps.  
All  s u bjects will  be  ra n d o mize d i nt o t he st u d y i n a 1: 1  rati o t o o ne  of  t he t w o treat me nt 
ar ms ( N y x ol or  pla ce b o) , wit h  a 1: 1  stratificati o n b y  li g ht/ dar k iri des. F urt her m ore,  
su bjects  will  be  ra n d o mi ze d i nt o t he st u d y at a rati o of  3: 1: 1  t o o ne  of  t he t hree m y driatic  
a ge nts,  2. 5 %  p he n yle p hri ne,  1 %  tr o pica mi de, a n d Pare m y d.  T heref ore,  if 9 6  s u bjects are 
ra n d o mize d t o 2. 5 %  p h e n yle p hri n
 t he n 3 2  s u bjects will  be  assi g ne d  t o 1 %  tr o pica mi de 
a n d 3 2  s u bjects t o Pare m y d  res ulti n g i n 1 6 0  t otal s u bjects.  
It is ass u me d t hat t here will be a 5 % dr o p-o ut bef ore t he 9 0 mi n ute efficac y assess me nt. 
T o acc o u nt f or t his dr o p -o ut, a t otal of 1 6 8 s u bjects will be ra n d o mize d i nt o t he st u d y.  
9. 2.  A n alysis  P o p ul ati o ns  
M o difie d I nte nt -t o-Tre at  (mI T T ): T he mI T T  will  i ncl u de all ra n d o mize d s u bjects w h o 
recei v e d o ne or t w o dr o ps of st u d y treat me nt a n d t he n ha d at least o ne sc he d ule d p u pil 
dia meter meas ure me nt d uri n g  Visit 1. T h e mI T T  will be use d f or t he pri m ar y e n d p oi nt 
a nal ysis a n d t o a nal yz e s electe d sec o n dar y efficac y e n d p oi nts.  
Per Pr ot oc ol P o p ul ati o n ( P P):   T he p er pr ot oc ol ( P P) p o p ulati o n i ncl u de s all s u bjects i n 
t he mI T T w h o ha d  t w o dr o ps of st u d y treat me nt i n t heir St u d y E ye, ha d all sc he d ule d p u pil 
dia meter meas ure me nts d uri n g Vi sit 1, ha d a n i ncrease of > 0. 2 m m i n  P D i n t he st u d y e ye 
at Ti me 0 mi n utes  c o m pare d t o Baseli ne ( Ti me – 1 h o u r), a n d ha d n o m aj or pr ot oc ol 
de viati o ns. T he P P p o p ulati o n will be use d t o a nal yze selecte d sec o n dar y efficac y 
e n d p oi nts .  
All R a n d o mize d P o p ul ati o n ( A R P ):  T h e A R P  will i ncl u de all ra n d o mize d s u bjects. T his 
p o p ulati o n is als o k n o w n as t he i nte nt -t o-treat (I T T) p o p ulati o n . T he A R P  will be use d i n 
c o nfir mat or y effic ac y a n al yses . 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr
d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 2  
0 2 /0 5 /2 1  
 
S afet y P o p ul ati o n  ( S P): T he S P  will i ncl u de all ra n d o mize d s u bjects w h o ha ve recei ve d 
at least o ne dr o p  of st u d y treat me nt. T he S P  will  be use d t o s u m marize s afet y varia bles.  
9. 3.  St atistic al  Met h o ds   
9. 3. 1.  Ge ner al  co nsi der ati o ns  
All c o nti n u o us varia bles will  be s u m marize d b y tr eat me nt a n d ti me p oi nt (as a p plica ble) 
usi n g descri pti ve statistics ( n, mea n, me dia n, sta n d ar d de viati o n, mi ni m u m, a n d 
ma xi m u m). All cate g oric al varia bles will  be s u m marize d b y tr eat me nt a n d ti me p oi nt (as 
a p plica ble) usi n g fre q ue n c y c o u n ts a n d perce nt a ges.  
All st u d y data will be liste d b y treat me nt, s u bject a n d ti me p oi nt (as a p plica ble).  
All statistical tests will be perf or me d usi n g a  si g nifica nce le vel of 5 % (t w o-taile d). T he p -
val ues f or t he a nal ysis of sec o n dar y effi cac y e n d p oi nts wil l be c o nsi dere d descri pti ve. 
9. 3. 2.  De m o gr a p hic  a n d  b aseli ne  ch ar acteristi cs  
De m o gra p hic a n d B aseli ne c haracteristics s uc h as a ge, race n d se x, will b e s u m marize d 
b y treat me nt gr o u p usi n g t he mI T T , P P, S P , a n d t he A RP  T h ese data will als o be pr o vi de d 
i n b y-s u bject listi n gs. 
9. 3. 3.  S u bject  d is p ositi o n 
S u bject  dis p ositi o n, i ncl u di n g ra n d o mizati o n, a n d c o m pleti o n  a n d wit h dra wal fr o m t he 
st u d y will be s u m marize d usi n g t he A R P . T hese data will als o be pr o vi de d i n b y -s u bject 
listi n gs. 
9. 3. 4.  Me dic al  h ist or y a n d  p ri or/co c o mit a nt  m e dic ati o ns  
Me dical hist or y will be c o de d usi n g t he latest versi o n of Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A)  a n d will be s u m marize d b y tr eat me nt gr o u p usi n g t he 
S P .  
Pri or me dicati o ns ( me dic ati o s wit h a n e n d date pri or t o t he date of ra n d o mizati o n) a n d 
c o nc o mita nt me dicati o ns ( me dicati o ns wit h a start or e n d date after t h e date of 
ra n d o mizati o n) will be c o de d usi n g W H O Dr u g a n d will b ot h be s u m marize d b y treat me nt 
gr o u p usi n g t he S P . 
Me dical hist or y  a n d pri or a n d c o nc o mita nt me dicati o ns wil l als o be pr o vi de d i n b y -s u bject 
listi n gs.  
9. 3. 5.  A n al ysis  of  effic ac y 
Efficac y will be assesse d usi n g t he mI T T  a n d P P wit h s u bjects i ncl u de d i n t he treat me nt 
ar m i n w hic h t he y were ra n d o mize d . F or  t he a n al ysis of t he pri mar y efficac y e n d p oi nt, 
i m p utati o n will be perf or me d f or missi n g data as descri be d i n t he S tatistical A nal ysis P la n. 
If t he a n al ysis usi n g t he P P s h o ws a p ositi ve effect f or N y x ol at t he 0. 0 5 le vel of 
si g nifica nce, t he pri mar y e n d p oi nt will be c o nsi dere d met. C o nfir mat or y a n al yses ma y  be 
perf or me d usi n g t he A R P , wit h i m p utati o n perf or me d f or missi n g data. F or t he a nal ysis of 
t he sec o n dar y efficac y e n d p oi nts, o nl y o bser ve d case data will be use d.  
F or all efficac y e n d p oi nts, B aseli ne is defi ne d  as -1  h o ur  pri or t o treat me nt o n Visit 1 . Ma x 
ti me p oi nt is defi ne d as ti me 0 mi n utes, d uri n g w hic h ma xi m u m p u pil dia meter is e x pecte d.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 3  
0 2 /0 5 /2 1  
 
All efficac y data will be s u m marize d b y treat me nt gr o u p, st u d y da y a n d ti me p oi nt ( -1  h o ur  
[ baseli ne], 0 mi n utes, 3 0 mi n utes, 6 0 mi n utes , 9 0 mi n utes , 2 h o ur s, 3 h o urs,  4 h o ur s, 6 
h o ur s, a n d 2 4 h o urs ), as a p pr o priate. 
T he pri mar y effic ac y e n d p oi nt is t he p erce nta ge of s u bjects  ret ur ni n g t o ≤ 0. 2 m m baseli ne 
p u pil dia meter at 9 0 mi n utes  p ost -treat me nt i n t he st u d y e ye. T he pri mar y efficac y 
e n d p oi nt will be a nal yze d usi n g a l o gistic re gressi o n m o del wit h treat me nt, m y driatic 
a ge nt, a n d li g ht/ dar k iri d es as fact ors a n d t he baseli ne  p u pil dia meter as a c o variate. T h e 
perce nt a ge of s u bjects i n eac h tr eat me nt gr o u p meeti n g t he criteria, t he o d ds rati o ( O R) 
wit h 9 5 % c o nfi de nce i nter val  (CI ) a n d p-v al ue will be pr o vi de d.  T he a n al ysis  will be 
perf or me d usi n g t he mI T T a n d P P , wit h s u bjects i ncl u de d i n t heir ra n d o mi ze d treat me nt 
re gar dl ess of t he treat me nt t he y act uall y recei ve d.  
Sec o n dar y  effic ac y  e n d p oi nts  are i n dicate d i n Secti o n 4. 1 .  
E ac h of t he c o nti n u o us sec o n dar y effi cac y e n d p oi nts  wi ll be a nal yze d usi n g a nal ysis of 
c o varia n ce ( A N C O V A)  wit h c ha n ge fr o m baseli n e as t he de p e n de nt varia ble, treat me nt , 
m y driatic a ge nt , a n d li g ht/ dar k iri des as fact ors , a n d t he res pecti ve baseli n e (-1 h o ur) val ue 
i ncl u de d as t he c o v ariate. N ote t hat m ost  sec o n dar y efficac y e n d p oi nts are i n relati o n t o 
baseli ne ( -1 h o ur), w h ereas s o me p u pil dia meter e n d p oi nt s are i n relati o n t o ma x ( 0 
mi n ute). Eac h A N C O V A will be perf or me d us i n g t he mI T T  a n d P P wit h s u bjects i ncl u de d 
i n t heir ra n d o mize d tr eat me nt re gar dl ess of t he trea me nt t he y act uall y r ecei ve d. T he 
o ut p ut fr o m eac h A N C O V A will i ncl u de t he L S M a n d S E f or b ot h treat me nt gr o u ps, al o n g 
wit h t he place b o -c orrecte d L S M, its 9 5 % CI a n d ass ociate d p -val ue.  
A c o m paris o n of t he st u d y a n d n o n -st u d y e ye f or eac h s u bject will be c o m pl ete d f or t he 
pri mar y efficac y e n d p oi nt, as well as b y m y driatic a ge nt.  
F or eac h of t h e sec o n d ar y e n d p oi nts  r late d t o perce nt of s u bjects a c hie vi n g certai n 
criteria, t he a nal ysis will be perf or me d usi n g a l o gistic re gressi o n m o del wit h treat me nt, 
m y driatic a ge nt , li g ht/ dar k iri des, a n d t he res p ecti ve baseli ne  as a c o v ariate . F or eac h 
a nal ysis, t he perce nta ge of s bjects i n eac h treat m e nt gr o u p meeti n g t he criteria, t he O R  
wit h 9 5 % CI a n d p -val ue will be pr o vi de d. F or t h ese e n d p oi nts, t he mI T T a n d P P  will be 
use d wit h s u bjects i ncl u de d i n t heir ra n d o mize d tr eat me nt re g ar d less of t he treat me nt t he y 
act uall y recei ve d.  
I n a d diti o n, eac h s ec o n dar y effic ac y e n d p oi nt will be a nal yze d b y li g ht/ dar k iri des a n d b y 
m y driatic a ge nt usi n g t he sa me m o del i n dicate d a b o ve  b ut wit h o ut iri des or m y driatic 
a ge nt as a fact or , as a p pr o priate. Eac h m y driatic a ge nt will be a nal yze d i n di vi d uall y, a n d 
a n a d diti o nal a nal ysis c o m bi ni n g 1 % tr o pica mi de a n d t he Pare m y d s u bjects i nt o a 
“tr o pica mi de” gr o u p will be perf or me d.  Ot her s u b gr o u ps, s uc h as a g e, se x, a n d race, ma y 
be a nal yz e d as w ell . If t h ere is s uffici e nt sa m ple, a nal ysis  of selecte d  efficac y  e n d p oi nts 
will be c o m plete d f or t he s u b gr o u p of  pe diatric s u bjects.   
9. 3. 6.  A n al ysis  of  safet y  
N o statistical a nal ysis of safet y data will be perf or me d i n t his st u d y. Safet y will be 
assesse d usi n g t he S P wit h s u bjects i ncl u de d i n t he treat me nt gr o u p t he y act uall y recei v e d, 
re gar dl ess of t heir ra n d o mize d treat me nt. O bs er ve d case d ata will be use d; n o i m p utati o n 
will be perf or me d f or missi n g safet y data.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 4  
0 2 /0 5 /2 1  
 
F or H R a n d B P, Baseli ne is defi ne d as t he scree ni n g val ue. H R a n d B P val ues  a n d c ha n g e 
fr o m B aseli ne i n t he val u es will be s u m marize d b y treat me nt gr o u p a n d ti m e p oi nt 
(scree ni n g, 6 h o urs, a n d 2 4  h o u rs).  
O bser ve d v al ues a n d c ha n ge fr o m baseli ne ( -1 h o ur) i n c o nj u ncti val h y pere mia at eac h 
ti me p oi nt ( 0 mi n, 3 0 mi n utes , 6 0 mi n utes , 9 0 mi n utes , 2 h o urs, 3, h o urs, 4 h o urs, 6 h o urs, 
a n d 2 4 h o urs), will be s u m marize d f or t h e st u d y e ye  a n d t he n o n-st u d y e y e. Treat me nts 
will be c o m pare d usi n g t he sa me A N C O V A m o del pr o p ose d f or t h e c o nti n u o us sec o n dar y 
effic ac y e n d p oi nts . C o nj u ncti val h y pere mia will als o be s u m marize d cate g ori call y. 
Vis ual ac uit y assess me nts ( B C D V A  a n d D C N V A ) will als o be s u m marize d at eac h 
ti me p oi nt (0 mi n utes, 9 0 mi n utes , 6 h o urs, a n d 2 4 h o urs), usi n g letters a n d l o g M A R u nits. 
Letters will be rec or de d, a n d later c o n v erte d t o l o g M AR  b y pr o gra m m i n g f or s uc h 
a nal yses. O ne l etter is e q ui vale nt t o 0. 0 2 l o g M A R. As a refere nce f i ve letters is 
re pres e nte d b y 1  li ne. Treat me nts will be c o m pare d usi n g t he sa me A N C O V A m o del 
pr o p ose d f or t he c o nti n u o us sec o n dar y effi cac y e n d p oi nts.  D C N V A will als o be a nal yze d 
b y m y driatic a ge nt usi n g a m o del t hat d oes n ot i ncl u de  t he m y driatic a ge nt as a fact or.  
F or I O P, Baseli ne is d efi n e d as t he scree ni n g val u e  O bser ve d val ues a n d c ha n ge fr o m 
baseli ne i n I O P at 6 h o urs will be s u m marize d f or t he st u d y e ye  a n d t he n o n-st u d y e ye. 
Oc ular t olera bilit y val ues will be s u m marize d b y treat me nt gr o u p at ti me p oi nt 0 m i n utes.  
S u bject  Q uesti o n naire val ues will be s u m marize d b y treat me nt gr o u p ( o verall a n d b y 
m y driatic a ge nt ) a n d ti me p oi nt  (-1 h o ur, 0 mi n utes, 6 0 mi n utes , 9 0 mi n utes , 3 h o urs, 6 
h o urs, a n d 2 4 h o urs) . 
Ver bati m descri pti o ns of A Es will be c o de d usi n g  Me d D R A.  O nl y t reat me nt-e mer ge nt 
A Es  (T E A Es;  t h ose t hat occ ur after t he first d ose of st u d y me dicati o n or i ncre asi n g i n 
severity after i niti ati o n of st u dy me dic ati o n) will be s u m marize d . T E A Es a n d seri o us A Es 
( S A Es) will be s u m mariz e d b y treat me nt gr o u p, b y s yste m or ga n class ( S O C), se verit y, 
a n d relati o ns hi p t o st u d y me dicati o n. Deat hs, wit h dra wal fr o m st u d y me dicati o n d ue t o 
A Es, a n d wit h dra w al fr o m t he st u d y d ue t o A Es will eac h b y s u m marize d b y treat me nt 
g r o u p. N ote t hat i n Me d D R A, oc ular e v e nts are c o de d t o t he S O C of “s pecial se nses” . 
T h us , usi n g S O C i n t he s u m maries will pr o vi de a se parati o n of o c ular a n d n o n -oc ular A Es . 
All safet y data will be pr o vi de d i n b y -s u bject listi n gs. Safet y listi n gs f or pe diatric s u bjects 
ma y be  pr o vi de d.  
9. 4.  Pr oce d ure  f or acc o u nti n g  f or missi n g,  u n use d,  or  s p uri o us d at a  
F or t he s u m mariz ati o n a n d a nal ysis of t he pri mar y efficac y e n d p oi nt , i m p utati o n will be 
perf or me d f or missi n g data as descri b e d i n t he Statistical A nal ysis Pla n . F or t he 
s u m marizati o n a n d a n al ysis of sec o n dar y effi cac y e n dp oi nts a n d safet y dat a, o bser ve d case 
data o nl y will be use d . 
9. 5.  Pr oce d ure  f or re p orti n g devi ati o ns  fr o m t he st atistic al pl a n  
A n y de viati o ns fr o m t he S tatistical A nal ysis P la n will be descri be d a n d a j ustificati o n 
gi ve n i n t he fi nal Cli nical St u d y Re p ort ( C S R).  
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 he I n vesti ga t or will per mit st u d y-relate d m o nit ori n g visits, a u dits, I R B re vie w, a n d 
re g ulat or y i ns pecti o n(s) b y pr o vi di n g direct access t o s o urce data a n d d oc u me nts. 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 5  
0 2 /0 5 /2 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  
T he pr o gress of t he st u d y will be m o nit ore d b y o n -site, writte n, a n d tele p h o ne 
c o m m u nicati o ns bet wee n pers o n nel at t he I n v esti gat or’s site a n d t he Me di cal M o nit or . 
S h o ul d t he C O VI D -1 9 p a n de mic restri ct m o nit ors fr o m tra veli n g t o a site, re m ote re vie w 
will be c o n d ucte d t o t he e xte nt p ossi ble, w hile still e ns uri n g t he st u d y is m o nit ore d 
a p pr o priatel y p er a p plica ble re g ulati o ns a n d g ui deli nes . T he I n vesti gat or will all o w 
Oc u p hire, t he St u d y M o nit or, a n d t he Me dical M o nit or t o i ns pect all eC R Fs, s u bject 
rec or ds (s o urce d oc u me nts), si g ne d c o nse nt /asse nt f or ms, rec or ds of st u d y me dicati o n 
recei pt, st ora g e, pre parati o n, a n d dis p ositi o n, a n d re g ulat or y files relate d t o t his st u d y.  
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 nce  
T he pr o p ose d st u d y is s u bject t o all a p plica ble g o ver n me ntal r ules a n d re g ulati o ns 
c o ncer ni n g t he c o n d uct of cli nical trials o n h u ma n s u bjects. T his i ncl u des, b ut is n ot 
necessaril y li mite d t o , t he a p pr o val of I nstit uti o nal Re vie w B oar ds, t he Helsi n ki 
Decl arati o n, U. S. F D A L a w, I C H G C P g ui deli nes, o btai ni n g pr os pecti ve i nf or me d 
c o nse nt, m o nit ori n g of t he c o n d uct of t he st u d y a n d t he c o m plete ness of t he eC R Fs  b y 
Oc u p hire or its desi g nee(s), a n d a p pr o priate rec or d rete nti o n b y t he I n vesti gat or.  
1 2. 2.  I nstit uti o n al Revie w  B o ar d  (I R B) 
T his pr ot oc ol, materials use d t o recr uit s u bjects, a n d materials use d t o d oc u me nt 
c o nse nt /asse nt m ust be a p pr o ve d b y t he I R B pri or t o i nitiati o n of t he st u d y. Writte n I R B 
a p pr o val m ust a de q u atel y i de ntif y t he pr ot oc ol a n d i nf or me d c o nse nt /asse nt. I n a d diti o n t o 
a p pr o vi n g t he pr ot oc ol, t he I R B m ust als o a p pr o ve t he S u bject  I nf or m ati o n a n d 
C o nse nt /Asse nt /Pare ntal C o nse nt  F or m, as well as a n y a d vertisi n g t o ols t hat will be use d 
f or t he st u d y. C o pies of all a p pr o v d m teri als, all c orres p o n d e nce wit h t he I R B a n d 
writte n a p pr o val fr o m t he I R B m ust be ma de a vaila ble t o Oc u p hire, pri or  t o t he start of 
s u bject e nr oll me nt i nt o t he st u d y.  
1 2. 3.  Pr ot oc ol  Devi ati o ns/ Vi ol ati o ns  
T he I n vesti gat or s h o ul d n ot de viate fr o m t he re q uire me nts of t his pr ot oc ol wit h o ut pri or 
writte n a p pr o val of t h e Me dical M o nit or or S p o ns or e xce pt i n t he e ve nt of a me dical 
e mer ge n c y.  
A re p orta bl e  pr ot oc ol de viati o n is defi ne d as n o na d here nce t o t he pr ot oc ol t hat i n v ol ves 
i ncl usi o n/e xcl usi o n criteria, affects s u bject safet y, ri g hts or welfare, or has t he p ote ntial t o 
affect t he i nte grit y of t he data. E xa m ples of maj or pr ot oc ol de viati o ns  i ncl u de stu d y 
e nr oll me nt  b y i neli gi ble s u bject , loss of ke y data s uc h as e q ui p me nt  malf u n cti o n  (e. g., 
p u pill o meter), a n d/ or use  of a pr o hi bite d me dicati o n d uri n g t he st u d y .  
All pr ot oc ol de viati o ns will be re p orte d b y e nt eri n g t he e ve nt i n t he a p pr o priate e C R F 
pa ge. Pr ot oc ol de viati o ns s h o ul d be re p orte d t o t he I R B i n acc or da n ce wit h I R B -s pecific 
g ui deli nes. If t here is a n y q uesti o n as t o w het her t he de viati o n is re p orta bl e, Oc u p hire or 
desi g nee a n d t he I R B s h o ul d be c o ntacte d.  
All c ha n ges t o t he pr ot oc ol will b e ma de b y t he S p o ns or or desi g nee as a n a p pr o ve d 
a me n d me nt t o t he pr ot oc ol, s u b mitte d t o t he F D A, a n d a p pr o ve d b y t he I R B pri or t o 
i m ple me ntati o n.  
C ha n ges i m ple me nte d wit h o ut pri or a p pr o val will be c o nsi dere d Pr ot oc ol Vi olati o ns.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 6  
0 2 /0 5 /2 1  
 
1 2. 4.   I nf or me d c o nse nt  a n d  ass e nt re q uire me nts 
Writte n i nf or me d c o ns e nt will be o btai ne d fr o m eac h a d ult s u bject. A si g n e d asse nt f or m 
will be o btai ne d f or all mi n ors a ges 1 2 -1 7, as well as a se parate pare nt al/ Le gal G uar dia n 
c o nse nt. A c o p y of t h e si g ne d a n d date d c o nse nt /asse nt d oc u me nt will be gi ve n t o eac h 
s u bject or pare nt g uar dia n . T he ori gi nal si g ne d a n d date d i nf or me d c o nse nt/asse nt 
d oc u me nt m ust be mai ntai ne d i n t he st u d y files at t he I n v esti gat or’s site.   
T he In vesti gat or is r es p o nsi ble f or e ns uri n g t hat n o s u bject is s u bject to a n y st u d y -relate d 
e xa mi nati o n or acti vit y b ef ore t h at s u bject has gi v e n i nf or me d c o ns e nt /asse nt. T he s u bject 
m ust gi ve writte n c o nse nt /asse nt after t he recei pt of detaile d i nf or mati o n. T he ver bal 
e x pla nati o n will c o ver all t he ele me nts s pecifi e d i n t he w ritte n i nf or mati o n pr o vi de d f or 
t he s u bject. 
It s h o ul d be e m p hasize d t hat t he s u bject is at li bert y t o wit h dra w c o nse nt/asse nt t o 
partici pate at a n y ti me, wit h o ut pe nalt y or l oss of be nefits t o w hic h t he s u bject is ot her wise 
e ntitle d. S u bject s w h o ref use t o gi ve, or wit h dra w, writte n i nf or me d c o ns e nt/asse nt ma y 
n ot be i ncl u de d or c o nti n ue d i n t his st u d y, b ut t his will n ot i m pact o n t heir s u bse q ue nt 
care.  
T he In vesti gat or will i nf or m t he s u bject of t he ai ms, met h o ds, a ntici pate d be nefits a n d 
p ote ntial hazar ds of t he st u d y, i ncl u di n g a n y disc o mf ort it ma y e ntail.  T he s u bject m ust be 
gi ve n e ver y o p p ort u nit y t o clarif y a n y p oi nts he/ s h e d oes n ot u n dersta n d a n d if necessar y, 
as k f or m ore i nf or mati o n. At t he e n d of t he i nte vi e w, t he s u bject ma y be gi ve n ti me t o 
reflect if t his is re q uire d, or if t he s u bject re q uests m ore ti me. S u bject s a n d/ or le gal 
g uar dia n will be re q uire d t o si g n a n d  dat  t he i nf or me d c o nse nt f or m.  
A c o p y of t he si g ne d a n d date d c o nse nt /asse nt d o c u me nt will be gi ve n t o eac h s u bject. T he 
ori gi nal si g ne d a n d date d i nf or me d c o nse nt /asse nt d oc u me nt m ust be mai ntai ne d i n t he 
st u d y files at t he I n vesti gat or’s site. Si g ne d i nf or m e d c o nse nt/asse nt m ust b e o b tai ne d pri or 
t o t he c o n d ucta nce of a n y st u d y pr oce d ures. 
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 oce d ures f or t he h a n dli n g a n d a nal ysis of data will be c o n d ucte d usi n g g o o d 
c o m p uti n g practices me eti n g I C H a n d U. S. F D A g ui d eli nes f or t he ha n dli n g a n d a nal ysis 
of data f or cli nical trials.  
1 3. 1.   D at a  entry  
St u d y s pecific data t hat h as bee n o utli ne d i n t he pr ot oc ol will be e ntere d i nt o t he cli nical 
data base b y i n di vi d ual(s) desi g nate d b y t he I n v esti gat or.  
1 3. 2.  D at a  q u ality  c o ntr ol  a n d  re p orti n g 
Data is verifie d electr o nicall y usi n g a series of pr o gra m me d e dit c hec ks t h at ha ve bee n 
creat e d b y t he Cli nical D ata Ma na g er a n d pr o gra m me d b y t he Cli nical Data Pr o gra m mer 
or Desi g nee. Data discre pa ncies will be br o u g ht t o t he atte nti o n of t he cli nical tea m a n d 
i n vesti gate d b y t he C R A a n d site staff. C R As will re vie w a n d v erif y all data c ollecte d i n 
t he eC R F a gai nst s o urce d oc u me ntati o n d uri n g sc he d ule d m o nit ori n g visits. T he C R A will 
w or k cl osel y wit h t he site staff t o a d dress a n y dis cre pa n cies w hic h ha ve b ee n f o u n d s o t hat 
pr o per res ol uti o ns ca n be ma de a n d d oc u m e nte d i n t he cli nical data bas e. A n a u dit trail 
wit hi n t he s yste m will trac k all c ha n g es ma de t o t h e data.  
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 7  
0 2 /0 5 /2 1  
 
1 3. 3.   Arc hivi n g  of  d at a  
Arc hi ve d versi o ns of t he data base will be s a ve d b y  Oc u p hire c o nsiste nt wit h I C H G o o d 
Cli nical Practices ( G C P) G ui deli nes, c o m pl yi n g wit h w hic he ver of t h e re q uire me nts is 
l o n ger. Oc u p hir e will n otif y t he In vesti gat or w h e n d oc u me nts s h o ul d be ret ur ne d.  
1 3. 4.   Rec or ds  rete nti o n 
T he I n vesti gat or’s site a n d cli nical la b orat or y will retai n all rec or ds relate d t o t he st u d y i n 
c o m plia nce wit h I C H G C P  G ui deli nes.  
1 3. 5.   A me n d me nts  t o t he pr ot oc ol  
M o dificati o ns of t he si g ne d pr ot oc ol are o nl y p ossi ble b y a p pr o ve d pr ot o c ol a me n d me nts 
a n d wit h t he a gree me nt of all res p o nsi ble pers o ns. T he pr oce d ure f or a p pr o val of a 
pr ot oc ol a me n d me nt is i de ntical t o t hat f or a p pr o val of t he pr ot oc ol. T he I R B m ust be 
i nf or me d of all pr ot oc ol a me n d me nts a n d s h o ul d be as ke d f or its o pi ni o n as t o w het her a 
f ull re-e v al uati o n of t he et hical as pects of t he st u d y is ne essar y b y t h e c o m mittee. T his 
s h o ul d be f ull y d oc u me nte d. 
T he In vesti gat or m ust n ot i m ple me nt a n y de viati o n fr o m or c ha n ge t o t he pr ot oc ol, wit h o ut 
disc ussi o n wit h, a n d a gree me nt b y Oc u p hire a n d pri or re vie w a n d d oc u me nte d 
a p pr o val/fa v ora ble o pi ni o n of t he a me n d me nt fr o m t he rele va nt et hics c o m mittee, e xce pt 
w here it is necessar y t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects, or w here t he 
c ha n ge(s) i n v ol ves o nl y l o gistical or a d mi nistrati ve as pects o f t h e st u d y (e. g., c ha n ge i n 
m o nit or, c ha n ge of tel e p h o ne n u m ber ). 
Pr ot oc ol a me n d me nts will be s u b mitte d t o t he a p pr o priate a ut h orit y(ies) as re q uire d b y t he 
a p plica ble re g ulat or y re q uire me nt(s).  
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 8  
0 2 /0 5 /2 1  
 
A P P E N DI X  1 : I RI S C O L O R  C H A R T  
 
St u d y e nr ollme nt i ncl u des b ot h li g ht a n d dar k -c ol ore d e yes . E x a m ples  of li g ht iri des ( 
 
) a n d dar k  iri des (
 f or t he p ur p oses of t his st u d y are det aile d i n t he 
c hart bel o w .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
p
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
4 9  
0 2 /0 5 /2 1  
 
A P P E N DI X  2 : R A N D O MI Z A TI O N  S C H E M A  F O R  E V A L U A B L E  S U B J E C T S  B Y  
I N V E S TI G A TI O N A L T R E A T M E N T,  M Y D RI A TI C  A G E N T , A N D  I RI S C O L O R   
 
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
5 0  
0 2 /0 5 /2 1  
 
A P P E N DI X  3 : 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  
T he f oll o wi n g dr u gs are e xa m ples of dr u gs w hic h ca n n ot be use d wit hi n 7  da ys pri or t o Scree ni n g, or 
d uri n g t he st u d y u nless  t he dr u g, d ose a n d re gi me n has bee n c o nsiste nt f or t he 7  da ys pri or t o 
Scree ni n g. T his list is n ot i ncl usive of all dr u gs i n t hese cl asses. If t here is a ny d o u bt, ple ase 
c o ns ult wit h t he Me dic al M o nit or. 
Al p h a -1 -a g o nists  
Met h yl 
n ore pi ne p hri ne  
Na p haz oli ne  
O x y metaz oli ne  
Tetra h y dr oz oli ne  
P he n yle p hri ne  
X yl o metaz oli ne  
 
Al p h a -2 -a g o nists  
Bri m o ni di ne  
Cl o ni di ne  
G ua nfaci ne  
G ua na be n z  
G ua n o xa be n z  
G ua net hi di ne  
X ylazi ne  
Tiza ni di ne  
Met h yl d o pa  
N o n -selective al p h a-
a nt a g o nists  
P he n o x y be nza mi ne  
T olaz oli ne  
La betal ol  
Car ve dil ol  
 
Al p h a -1 -a nt a g o nists   
Alf uz osi n  
Praz osi n  
D o xaz osi n  
Ta ms ul osi n  
Teraz osi n  
 
Al p h a -2 -a nt a g o nists  
Ati pa mez ole  
I d az o xa n 
Y o hi m bi ne   
 
 
Acetylc h oli ne 
rece pt or a g o nists  
Pil ocar pi ne  ( M3 
rece pt ors) 
 
Acetylc h oli ne 
rece pt or 
a nt a g o nists  
Sc o p ola mi ne  
Dic ycl o veri ne  
T olter o di ne  
O x y b ut y ni n  
I pratr o pi u m 
Ma m ba T o xi n 
( M T7) 
Pire nze pi ne  
Tele nze pi n e  
 
A ntiverti g o  
meclizi ne  
Sc o p ola mi ne  
G astr oi ntesti n al  
atr o pi ne  
bella d o n na  
 
P ar ki ns o nis m  
a ma nta di ne  
be nztr o pi ne  
bi peri de n  
tri he x y p he ni d yl 
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o ve d
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
5 2  
0 2 /0 5 /2 1  
 
A P P E N DI X  5 : C O N J U N C TI V A L  H Y P E R E MI A  G R A DI N G  S C A L E  U SI N G  I M A G E S 
F R O M  C C L R U  
 
 
 
 
O PI- N Y X R M- 3 0 1 _ Pr ot oc ol A m d 1 _ 0 5 Fe b 2 0 2 1 | V V- T M F- 1 3 1 2 8 | 1. 0
A p pr o
D o w nl oa de d b y Es meral da Car d osa o n 1/ 3 1/ 2 0 2 2

Oc u p hire  P har ma,  I nc. 
 
 
 
 
   Cli nical  Pr ot oc ol  
O PI -N Y X R M -3 0 1  
 
 
 
 
 
  MI R A -2  
C O N FI D E N TI A L  
5 4  
0 2 /0 5 /2 1  
 
Bi bli o gr a p h y  
1.  Mc D o nal d, M. P he nt ola mi ne Mes ylate Treat me nt of Se vere Ni g ht Visi o n C o m plai nts,.  
2.  H olla da y, J., Me yer, A. & Pitlic k, B. P he nt ola mi ne Mes ylate O p ht hal mic S ol uti o n 1 % O nce 
Dail y Re d uces P u pil Dia meter a n d I m pr o v es Ni g ht Visi o n Dist ur ba nces.  
3.  Stei n ha uer, S. R., Sie gle, G. J., C o n dra y, R. & Pless, M. S y m pat hetic a n d paras y m pat hetic 
i n ner vati o n of p u pillar y dilati o n d uri n g s ustai ne d pr ocessi n g. I nter n ati o n al j o ur n al of 
psyc h o p hysi ol o gy : offici al j o ur n al of t he I nter n ati o n al Or g a niz ati o n of Psyc h o p hysi ol o gy  5 2 , 
7 7 – 8 6 ( 2 0 0 4).  
4.  Y os hit o mi, T., It o, Y. & I n o mat a, H. A dre ner gic e xcitat or y a n d c h oli ner gic i n hi bit or y 
i n ner vati o ns i n t he h u ma n iris dilat or. Ex peri me nt al eye res e arc h  4 0 , 4 5 3– 9 ( 1 9 8 5).  
5.  Y u, Y. & K oss, M. C. al p ha( 1 A) -a dre n oce pt ors me diate s y m pat heticall y e v o ke d p u pillar y 
dilati o n i n rats. T he J o ur n al of p h ar m ac ol o gy a n d ex peri me nt al t her a p e utics  3 0 0 , 5 2 1– 5 
( 2 0 0 2). 
6.  H o ga n, T. S., Mc Da niel, D. D  Bartlett, J. D., Hart, K. K. & Pa g giari n o, D. A. D ose -Res p o nse 
St u d y of Da pi praz ole H Cl i n t he Re versal of M y driasis I n d u ce d b y 2. 5 % P h e n yle p hri ne. 
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