A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants With Presbyopia
Phase: PHASE3
Conditions: Presbyopia
Sponsor: Allergan

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
1 
Titl e  P a g e 
P r ot o c ol   Titl e:    A  P h as e  3,   M ulti c e nt er,   D o u bl e-  M as k e d,   R a n d o  mi z e d,   V e hi cl e-  C o ntr oll e d, 
P ar all el-  Gr o u p  St u d y  E v al u ati n g t h e  S af et y  a n d  Effi c a c y  of   A  G  N- 1 9 0 5 8 4 i n  P arti ci p a nts   wit h 
Pr es b y o pi a 
P r ot o c ol   N u  m b e r:   1 8 8 3- 3 0 2- 0 1 3 
A  m e n d  m e nt   N u  m b e r:    1 
P r o d u ct:    A  G  N- 1 9 0 5 8 4 
B ri ef  P r ot o c ol   Titl e:    P h as e  3  effi c a c y st u d y  of   A  G  N- 1 9 0 5 8 4 i n  p arti ci p a nts   wit h  pr es b y o pi a 
D e v el o p  m e nt  P h as e:   3 
S p o ns o r   N a  m e:    All er g a n, I n c. 
L e g al   R e gist e r e d   A d d r ess:    
2 5 2 5   D u p o nt   Dri v e, Ir vi n e,   C  A  9 2 6 1 2,   U S  A 
I n v esti g ati o n al   N e  w   D r u g   N u  m b e r:  
S e ri o us   A d v e rs e   E v e nt   R e p o rti n g:    
All e r g a n    M e di c al  S af et y  P h ysi ci a n   C o nt a ct I nf o r  m ati o n:  
All e r g a n  Si g n at o r y:     
Vi c e  Pr esi d e nt,   Gl o b al  T h er a p e uti c   Ar e a   H e a d 
O p ht h al  m ol o g y 
All er g a n, I n c. 
R ef er t o t h e fi n al  p a g e  of t his  pr ot o c ol f o  r  el e ctr o ni c si g n at ur e  a n d  d at e  of  a p pr o v al. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
2 
P r ot o c ol   A  m e n d  m e nt  S u  m  m a r y  of   C h a n g es 
D  O  C  U   M  E  N  T   HI S  T  O  R  Y 
D o c u  m e nt
   D at e
 
A  m e n d  m e nt  1 
Pl e as e r ef er t o t h e fi n al  p a g e  of t his  pr ot o c ol f or t h e  d at e 
of  a p pr o v al f or   A  m e n d  m e nt  1 
Ori gi n al  Pr ot o c ol 
0 7   D e c e  m b er  2 0 1 8 
A  m e n d  m e nt  1 
O v er all   R ati o n al e f or t h e   A  m e n d  m e nt: 
All er g a n  d e ci d e d t o  e nr oll  a p pr o xi  m at el y  1 0 0  a  d diti o n al  p arti ci p a nts i nt o  St u d y  1 8 8 3- 3 0 2- 0 1 3 i n 
or d er t o i n cr e as e st atisti c al  p o  w er f or  effi c a c y  e n d p oi nts.  T h e f oll o  wi n g is  a s u  m  m ar y  of  c h a n g es 
a n d  ass o ci at e d r ati o n al es   m a d e  t o t h e  ori gi n al  pr ot o c ol. 
S e cti o n   N o.  a n d 
N a  m e 
D es c ri pti o n  of   C h a n g e 
B ri ef   R ati o n al e 
1. 1.  S y n o psis;  4. 1. 
O v er all   D esi g n; 
9. 2.  S a  m pl e  Si z e 
D et er  mi n ati o n; 
1 0. 5.   A p p e n di x  5: 
St u d y  T a b ul ar 
S u  m  m ar y 
P arti ci p a nt  e nr oll  m e nt   w as i n cr e as e d t o 
a p pr o xi  m at el y  2 0 0  p arti ci p a nts  p er 
st u d y i nt er v e nti o n  gr o u p ( ori gi n all y 
1 5 0  p er  gr o u p) f or  a t ot al  of  4 0 0 
p arti ci p a nts i n t h e st u d y ( ori gi n all y 
3 0 0)  p arti ci p a nts. 
P arti ci p a nt s a  m pl e si z e   w as  ori gi n all y  d eri v e d 
b as e d  o n t h e  v e hi cl e  gr o u p i nt er v e nti o n  eff e ct 
fr o  m  P h as e  2  d at a ( 3. 6  %).   Aft er  a n al ysis  of 
P h as e  3  St u d y  1 8 8 3- 3 0 1- 0 1 3, t h e  v e hi cl e  gr o u p 
i nt er v e nti o n  eff e ct   w as  d et er  mi n e d t o  b e  8. 8  %. 
T h er ef or e,  p arti ci p a nt s a  m pl e si z e   w as i n cr e as e d 
i n  St u d y  1 8 8 3- 3 0 2- 0 1 3 t o i n cr e as e t h e  p o  w er  of 
t h e  h y p ot h esis t esti n g. 
1. 1.  S y n o psis;  4. 1. 
O v er all   D esi g n; 
9. 2.  S a  m pl e  Si z e 
D et er  mi n ati o n 
T h e  1 0  %  dr o p o ut r at e   w as r e  m o v e d 
fr o  m s a  m pl e si z e  d et er  mi n ati o n. 
Dr o p o ut r at e   w as r e  m o v e d  b e c a us e  dr o p o ut 
p arti ci p a nts   will  b e r e g ar d e d  as  a f ail ur e f or t h e 
a n al ys es  p ert ai ni n g t o t h e  pr o p orti o n  of 
p arti ci p a nts  g ai ni n g  3-li n es  or   m or e i n   m es o pi c, 
hi g h  c o ntr ast,  bi n o c ul ar,   D  C  N  V  A. 
6. 3.   M e as ur es t o 
Mi ni  mi z e   Bi as: 
R a n d o  mi z ati o n 
a n d   Bli n di n g 
T h e   m a xi  m u  m  n u  m b er  of  p arti ci p a nts 
t o  b e  e nr oll e d   wit h  br o  w n iris  c ol or  or 
n o n- e  m  m etr o p e st at us   w as i n cr e as e d t o 
1 0 0 ( ori gi n all y  7 5)  a n d  5 0 ( ori gi n all y 
3 5)  p er  ar  m, r es p e cti v el y 
T his  u p d at e   w as   m a d e  b as e d  o n t h e i n cr e as e i n 
p arti ci p a nt s a  m pl e si z e  dis c uss e d i n t his s u  m  m ar y 
of  c h a n g es t a bl e. 
9. 2.  S a  m pl e  Si z e 
D et er  mi n ati o n 
U p d at es t o  v e hi cl e  gr o u p i nt er v e nti o n 
eff e ct ( 3. 6  % t o  8. 8  %),   A  G  N- 1 9 0 5 8 4 
eff e ct ( 1 6  % t o  1 8. 4  %),  a n d  p o  w er 
( 9 0  % t o  8 0  %)   w er e   m a d e.  T h e  eff e cts 
of  e  m  m etr o p es/ n o n- e  m  m etr o p es   w er e 
r e  m o v e d. 
T h es e  c h a n g es   w er e i nf or  m e d  a n d i  m pl e  m e nt e d 
p er  P h as e  3  St u d y  1 8 8 3- 3 0 1- 0 1 3 r es ults. 
9. 4. 1. 3. 
S e c o n d ar y 
A n al ys es 
T h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt 
a n d  all  ot h er s e c o n d ar y  effi c a c y 
e n d p oi nts   w er e   m o difi e d t o  a  o n e-l e v el 
g at e k e e pi n g  pr o c e d ur e ( ori gi n al 
pr ot o c ol  h a d  a t  w o-l e v el  g at e k e e pi n g 
pr o c e d ur e)  
T his  c h a n g e  all o  ws  all  ot h er s e c o n d ar y  effi c a c y 
e n d p oi nts t o  b e  e v al u at e d   wit h o ut  h a vi n g t o first 
t est t h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt ( p er t h e 
ori gi n al  pr ot o c ol). 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
3 
T a bl e  of   C o nt e nts 
Titl e  P a g e ........................................................................................................................................ 1  
P r ot o c ol   A  m e n d  m e nt  S u  m  m a r y  of   C h a n g es ............................................................................... 2  
T a bl e  of   C o nt e nts ........................................................................................................................... 3  
List  of   T a bl es .................................................................................................................................. 6  
List  of  Fi g u r es ............................................................................................................... .................. 6 
1.  
P r ot o c ol  S u  m  m a r y .......................................................................................................... 7  
1. 1.  
S y n o psis ...................................................................................................................... ...... 7 
1. 2.  
S c h e  m a ........................................................................................................................ ...... 9 
1. 3.  
S c h e d ul e  of   A cti viti es ..................................................................................................... 1 0  
2.  
I nt r o d u cti o n .................................................................................................................. . 1 7 
2. 1.  
St u d y   R ati o n al e ............................................................................................................... 1 7  
2. 2.  
B a c k gr o u n d .................................................................................................................... . 1 7 
2. 3.  
B e n efit/  Ris k   Ass ess  m e nt ................................................................................................ 1 8  
3.  
O bj e cti v es  a n d   E n d p oi nts ............................................................................................ 1 9  
4.  
St u d y   D esi g n .................................................................................................................. 2 0  
4. 1.  
O v er all   D esi g n ................................................................................................................  2 0  
4. 1. 1.  
Cli ni c al   H y p ot h es es ........................................................................................................ 2 0  
4. 2.  
S ci e ntifi c   R ati o n al e f or  St u d y   D esi g n ............................................................................ 2 0  
4. 3.  
J ustifi c ati o n f or   D os e ...................................................................................................... 2 0  
4. 4.  
E n d  of  St u d y   D efi niti o n .................................................................................................. 2 0  
5.  
St u d y  P o p ul ati o n ........................................................................................................... 2 1  
5. 1.  
I n cl usi o n   Crit eri a ............................................................................................................ 2 1  
5. 2.  
E x cl usi o n   Crit eri a ........................................................................................................... 2  2  
5. 3.  
Lif est yl e   C o nsi d er ati o ns ................................................................................................. 2 4  
5. 4.  
S cr e e n  F ail ur es ............................................................................................................... . 2 4 
6.  
St u d y I nt e r v e nti o n ........................................................................................................ 2 5  
6. 1.  
St u d y I nt er v e nti o n(s)   A d  mi nist er e d ................................................................................ 2 5  
6. 1. 1.  
St u d y  S u p pli es ................................................................................................................ 2 5  
6. 1. 2.  
I nstr u cti o ns f or   Us e  a n d   A d  mi nistr ati o n ......................................................................... 2 6 
6. 2.  
Pr e p ar ati o n/  H a n dli n g/ St or a g e/  A c c o u nt a bilit y ................................................................ 2 6  
6. 3.  
M e as ur es t o   Mi ni  mi z e   Bi as:   R a   n d o  mi z ati o n  a n d   Bli n di n g ............................................ 2 7  
6. 4.  
St u d y I nt er v e nti o n   C o  m pli a n c e ...................................................................................... 2 8  
6. 5.  
C o n c o  mit a nt  T h er a p y  ..................................................................................................... 2 8 
6. 5. 1.  
Pr o hi bit e d I nt er v e nti o ns  a n d  W as h o ut   B ef or e t h e  St u d y ................................................ 2 8  
6. 5. 2.  
P er  mitt e d I nt er v e nti o ns ................................................................................................... 2 9  
6. 5. 3.  
R es c u e   M e di ci n e ............................................................................................................. 2 9  

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
4 
6. 5. 4.  
Pr o hi bit e d I nt er v e nti o ns   D uri n g t h e  St u d y ..................................................................... 2 9  
6. 6.  
D os e   M o difi c ati o n .......................................................................................................... 2 9  
6. 7.  
I nt er v e nti o n  aft er t he  E n d  of t h e  St u d y ........................................................................... 2 9 
7.  
Dis c o nti n u ati o n  of  St u d y I nt e r v e nti o n  a n d  P a rti ci p a nt 
Dis c o nti n u ati o n/   Wit h d r a  w al........................................................................................ 3 0  
7. 1.  
Dis c o nti n u ati o n  of  St u d y I nt er v e nti o n ............................................................................ 3 0  
7. 2.  
P arti ci p a nt   Dis c o nti n u ati o n/   W it h dr a  w al fr o  m t h e  St u d y ................................................ 3 0 
7. 3.  
L ost t o  F oll o  w   U p ........................................................................................................... 3 1  
8.  
St u d y   Ass ess  m e nts  a n d  P r o c e d u r es............................................................................. 3 2  
8. 1.  
Effi c a c y   Ass ess  m e nts ..................................................................................................... 3 2  
8. 2.  
S af et y   Ass ess  m e nts ......................................................................................................... 3 5  
8. 2. 1.  
Vit al  Si g ns ...................................................................................................................  .... 3 5 
8. 2. 2.  
Pr e g n a n c y  T esti n g ........................................................................................................... 3 5  
8. 2. 3.  
P h ot o pi c  a n d   M es o pi c,   Hi g h   C o ntr a st   C orr e ct e d   Dist a n c e   Vis u al 
A c uit y f or  E a c h  E y e  a n d   Bi n o c ul arl y ............................................................................. 3 6  
8. 2. 4.  
N e ar   C o ntr ast  S e nsiti vit y ................................................................................................ 3 6  
8. 2. 5.  
St u d y I nt er v e nti o n  T ol er a bilit y  a n d   Dr o p   C o  mf ort   Ass ess  m e nts ................................... 3 6  
8. 2. 6.  
T e  m p or al/ S u pr a or bit al   H e a d a c h e   Vis u al   A n al o g  S c al e ................................................. 3 6  
8. 2. 7.  
I ntr a o c ul ar  Pr ess ur e ........................................................................................................ 3 7 
8. 2. 8.  
Slit-l a  m p   Bi o  mi cr os c o p y ................................................................................................ 3 7  
8. 2. 9.  
M a nif est   R efr a cti o n ........................................................................................................ 4 0  
8. 2. 1 0.   Dil at e d  F u n d us c o pi c  E x a  mi n ati o n .................................................................................. 4 0  
8. 2. 1 1.   S ui ci d al   Ris k   M o nit ori n g ................................................................................................ 4 1  
8. 3.  
A d v ers e  E v e nts  a n d  S eri o us   A d v ers e  E v e nts   ................................................................. 4 1 
8. 3. 1.  
Ti  m e  P eri o d  a n d  Fr e q u e n c y f or  C oll e cti n g   A d v ers e  E v e nt  a n d 
S eri o us   A d v ers e  E v e nt I nf or  m ati o n ................................................................................ 4 1  
8. 3. 2.  
M et h o d  of   D et e cti n g   A d v ers e  E v e nts  a n d  S eri o us   A d v ers e 
E v e nts ........................................................................................................................  ...... 4 2 
8. 3. 3.  
F oll o  w- u p  of   A d v ers e  E v e nts  a n d  S eri o us   A d v ers e  E v e nts  ........................................... 4 2 
8. 3. 4.  
R e g ul at or y   R e p orti n g   R e q uir e  m e nts f o  r  S eri o us   A d v ers e  E v e nts .................................. 4 2 
8. 3. 5.  
Pr e g n a n c y ..................................................................................................................... ... 4 3 
8. 3. 6.  
M e di c ati o n  Err ors ........................................................................................................... 4 3  
8. 4.  
Tr e at  m e nt  of   O v er d os e ................................................................................................... 4 3  
8. 5.  
P h ar  m a c o ki n eti cs ............................................................................................................ 4 4  
8. 6.  
P h ar  m a c o d y n a  mi cs ......................................................................................................... 4 4  
8. 7.  
G e n eti cs ......................................................................................................................  .... 4 4 
8. 8.  
Bi o  m ar k ers  a n d   Ot h er   Ass ess  m e nts ............................................................................... 4 4  
8. 8. 1.  
Bi o  m ar k ers ....................................................................................................................  .. 4 4 
8. 8. 2.  
D et er  mi n ati o n  of   D o  mi n a nt  E y e ..................................................................................... 4 4  
8. 9.  
H e alt h  E c o n o  mi cs ........................................................................................................... 4 4  
9.  
St atisti c al   C o nsi d e r ati o ns ............................................................................................. 4 5  
9. 1.  
St atisti c al   H y p ot h es es ..................................................................................................... 4 5  

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
5 
9. 2.  
S a  m pl e  Si z e   D et er  mi n ati o n ............................................................................................ 4 5  
9. 3.  
P o p ul ati o ns f or   A n al ys es ................................................................................................ 4 6  
9. 4.  
St atisti c al   A n al ys es ......................................................................................................... 4 6  
9. 4. 1.  
Effi c a c y   A n al ys es  ........................................................................................................... 4 6 
9. 4. 2.  
S af et y   A n al ys es ............................................................................................................... 4 8  
9. 4. 3.  
Ot h er   A n al ys es ................................................................................................................  4 8  
9. 5.  
I nt eri  m   A n al ys es ............................................................................................................. 4 9  
9. 5. 1.  
D at a   M o nit ori n g   C o  m  mitt e e ........................................................................................... 4 9  
1 0.  
S u p p o rti n g   D o c u  m e nt ati o n  a n d   O p e r ati o n al   C o nsi d e r ati o ns .................................. 5 0  
1 0. 1.  
A p p e n di x  1:   R e g ul at or y,  Et hi c al,  a n d  St u d y   O v ersi g ht 
C o nsi d er ati o ns ................................................................................................................  5 1  
1 0. 1. 1.   R e g ul at or y  a n d  Et hi c al   C o nsi d er ati o ns ........................................................................... 5 1  
1 0. 1. 3.   I nf or  m e d   C o ns e nt  Pr o c ess .............................................................................................. 5 2 
1 0. 1. 4.   D at a  Pr ot e cti o n................................................................................................................  5 2  
1 0. 1. 5.   P osti n g   Cli ni c al  St u d y   D at a ............................................................................................ 5 2  
1 0. 1. 6.   D at a   Q u alit y   Ass ur a n c e .................................................................................................. 5 3  
1 0. 1. 7.   S o ur c e   D o c u  m e nts .......................................................................................................... 5 3  
1 0. 1. 8.   St u d y  a n d  Sit e   Cl os ur e .................................................................................................... 5 3 
1 0. 1. 9.   P u bli c ati o n  P oli c y ........................................................................................................... 5 4  
1 0. 1. 1 0.   C o  m pli a n c e   wit h  Pr ot o c ol............................................................................................... 5 4  
1 0. 2.  
A p p e n di x  2:   A d v ers e  E v e nts:   D efi niti o ns  a n d  Pr o c e d ur es f or 
R e c or di n g,  E v al u ati n g,  F oll o  w- u p,  a n d   R e p orti n g ......................................................... 5 5  
D efi niti o n  of   A E ............................................................................................................................ 5 5  
D efi niti o n  of  S  A E .............................................................................................................  ............. 5 6 
R e c or di n g  a n d  F oll o  w-  U p  of   A Es  a n d/ or  S  A Es ............................................................................ 5 7  
R e p orti n g  of  S  A Es ............................................................................................................. ............ 5 9 
1 0. 3.  
A p p e n di x  3:   A b br e vi ati o ns ............................................................................................. 6 0  
1 0. 4.  
A p p e n di x  4:  St a n d ar d   Dis c o nti n u ati o n   Crit eri a.............................................................. 6 2  
1 0. 5.  
A p p e n di x  5:  St u d y  T a b ul ar  S u  m  m ar y ............................................................................ 6 4  
1 0. 6.  
A p p e n di x  6:   C o ntr a c e pti v e   G ui d a n c e  a n d   C oll e cti o n  of 
Pr e g n a n c y I nf or  m ati o n ................................................................................................... 6 6  
D efi niti o ns: ..................................................................................................................  .................. 6 6 
C o ntr a c e pti o n   G ui d a n c e: ....................................................................................................... ........ 6 6 
Pr e g n a n c y  T esti n g: ............................................................................................................ ............. 6 8 
C oll e cti o n  of  Pr e g n a n c y I nf or  m ati o n: .......................................................................................... . 6 8 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
6 
1 0. 8.  
A p p e n di x  8:  P ati e nt   R e p ort e d   O ut c o  m es   Q u esti o n n air es, 
D es cri pti o ns,  a n d   I nstr u cti o ns......................................................................................... 8 5 
1 0. 8. 2.   N e ar   Visi o n  Pr es b y o pi a  T as k  - b as e d   Q u esti o n n air e ...................................................... 1 0 1 
1 1.  
R ef e r e n c es ....................................................................................................................  1 2 1  
 
List  of  T a bl es 
T a bl e  1- 1  
S c h e d ul e  of   Visits  a n d  Pr o c e d ur es:  S cr e e ni n g t o   Visit  3 ..................................  1 0  
T a bl e  1 – 2  
S c h e d ul e  of   Visits  a n d  Pr o c e d ur es:   Visit  4 t o   Visit  5/ E arl y  E xit ......................  1 4  
T a bl e  8- 1  
Effi c a c y   Ass ess  m e nts ........................................................................................  3 3  
T a bl e  1 0 – 1  
Hi g hl y  Eff e cti v e   C o ntr a c e pti v e   M et h o ds ..........................................................  6 7  
 
List  of  Fi g u r es 
Fi g ur e  1- 1  
St u d y  S c h e  m a ......................................................................................................  9  
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
7 
1.     
P r ot o c ol  S u  m  m a r y 
1. 1.     
S y n o psis 
P r ot o c ol   Titl e:    A  P h as e  3,   M ulti c e nt er,   D o u bl e-  M as k e d,   R a n d o  mi z e d,   V e hi cl e-  C o ntr oll e d, 
P ar all el-  Gr o u p  St u d y  E v al u ati n g t h e  S af et y  a n d  Effi c a c y  of   A  G  N- 1 9 0 5 8 4 i n  P arti ci p a nts   wit h 
Pr es b y o pi a  
P r ot o c ol   N u  m b e r:   1 8 8 3- 3 0 2- 0 1 3 
B ri ef   Titl e:    P h as e  3  effi c a c y st u d y  of   A  G  N- 1 9 0 5 8 4 i n  p arti ci p a nts   wit h  pr es b y o pi a 
St u d y   R ati o n al e:  
I n  pr e vi o us st u di es,   All er g a n  est a blis h e d t h e s af et y  a n d  effi c a c y  of s e v er al ( 0. 5  % t o  1. 5  %) 
c o n c e ntr ati o ns  of   A  G  N- 1 9 0 5 8 4  d os e d  o n c e  d ail y,  b il at er all y  or i n t h e  n o nd o  mi n a nt  e y e,  o v er  a 
p eri o d  of  u p t o  2 8  d a ys i n  p arti ci p a nts   wit h   pr es b y o pi a.  St u d y  1 8 8 3- 3 0 2-0 1 3 is  a   m ulti c e nt er, 
d o u bl e-  m as k e d, r a n d o  mi z e d,  v e hi cl e- c o ntr oll e d,  p a r all el  gr o u p,  P h as e  3 st u d y  e v al u ati n g t h e 
effi c a c y  a n d s af et y  of   A  G  N- 1 9 0 5 8 4 ( 1. 2 5  %  pil o c ar pi n e)  d os e d  o n c e  d ail y,  bil at er all y,  o v er  a 
p eri o d  of  3 0  d a ys i n  p arti ci p a nts   wit h  pr es b y o pi a. 
O bj e cti v es  a n d    M e as u r es: 
T h e  o bj e cti v es  of t his st u d y  ar e t o  e v al u a t e t h e  effi c a c y  a n d s af et y  of   A  G  N- 1 9 0 5 8 4   w h e n 
a d  mi nist er e d  bil at er all y,  o n c e  d ail y f or  3 0  d a ys i n  p arti ci p a nts   wit h  pr es b y o pi a. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 
8 
O bj e cti v es
    M e as u r es
 
T o  e v al u at e t h e  effi c a c y  of   A  G  N- 1 9 0 5 8 4 
w h e n  a d  mi nist er e d  bil at er all y,  o n c e  d ail y f or 
3 0  d a ys i n  p arti ci p a nts   wit h  pr es b y o pi a. 
•     M es o pi c  a n d  p h ot o pi c,  hi g h  c o ntr ast  dist a n c e- c orr e ct e d 
n e ar  vis u al  a c uit y (  D  C  N  V  A)  f or  e a c h  e y e  a n d  bi n o c ul arl y 
•     M es o pi c  a n d  p h ot o pi c,  hi g h  c o ntr ast  dist a n c e- c orr e ct e d 
i nt er  m e di at e  vis u al  a c uit y f or  e a c h  e y e  a n d  bi n o c ul arl y 
•     P ati e nt r e p ort e d  o ut c o  m es  q u esti o n n air es:  
o     M es o pi c  a n d  P h ot o pi c   N e ar   Visi o n  Pr es b y o pi a  T as k-
b as e d   Q u esti o n n air e 
o     Pr es b y o pi a I  m p a ct  a n d   C o pi n g   Q u esti o n n air e 
T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of 
A  G  N- 1 9 0 5 8 4   w h e n  a d  mi nist er e d  bil at er all y, 
o n c e  d ail y f or  3 0  d a ys i n  p arti ci p a nts   wit h 
pr es b y o pi a 
•     A d v ers e  e v e nts 
•     P h ot o pi c  a n d   m es o pi c  hi g h  c o ntr ast  c orr e ct e d  dist a n c e 
vis u al  a c uit y f or  e a c h  e y e  a n d  bi n o c ul arl y 
•     N e ar   C o ntr ast s e nsiti vit y 
•     Vit al si g ns ( bl o o d  pr ess ur e  a n d  h e art r at e) 
•     St u d y  dr u g t ol er a bilit y  a n d  dr o p  c o  mf ort  ass ess  m e nts 
•     T e  m p or al/s u pr a or bit al  h e a d a c h e  vis u al  a n al o g s c al e 
•     I ntr a o c ul ar  pr ess ur e 
•     Slit-l a  m p  bi o  mi cr os c o p y 
•     M a nif est r efr a cti o n 
•     Dil at e d f u n d us c o pi c  e x a  mi n ati o n 
•     Pr e g n a n c y t est f or   w o  m e n  of  c hil d b e ari n g  p ot e nti al 
O v e r all  St u d y   D esi g n: 
T his is  a   m ulti c e nt er,  d o u bl e-  m as k e d, r a n d o  mi z e d  ,  p ar all el- gr o u p,  v e hi cl e- c o ntr oll e d,  P h as e  3 
st u d y i n  p arti ci p a nts   wit h  pr es b y o pi a.  T h e st u d y  p o p ul ati o n   will  c o nsist  of  a d ult   m al e  a n d f e  m al e 
p arti ci p a nts   wit h  o bj e cti v e  a n d s u bj e cti v e  e vi d e n c e  of  pr es b y o pi a. 
N u  m b e r  of  P a rti ci p a nts: 
A p pr o xi  m at el y  2 0 0  p arti ci p a nts  p er  gr o u p   will  b e    e nr oll e d.  P arti ci p a nts   w h o  pr e  m at ur el y 
dis c o nti n u e fr o  m t h e st u d y   will  n ot  b e r e pl a c e d. 
N u  m b e r  of  Sit es: 
T h er e   will  b e  a p pr o xi  m at el y  5 0 sit es i n t h e   U nit e d  St at es. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
A  G  N- 1 9
 
I nt e r v en
P arti ci p a
o n c e  d ai
y e ars  a n
w ors e t h
st u d y  c o
1 4,  a n d 
D at a    M
1. 2.  
T h e st u d
Fi g u r e  1
 
 
0 5 8 4 
n ti o n   G r o u
a nts   will  b e 
ly, i n  e a c h  e
d   >  5 0  y e ars
a n  2 0/ 6 0), i
n sists  of t h e 
3 0. 
o nit o ri n g    C
S c h e  m a
y  s c h e  m a is 
- 1     St u d
p s  a n d  St u dy
ra n d o  mi z e d  i
y e, f or  3 0  d a
),  b as eli n e b
ris  c ol or ( bro
f oll o  wi n g v
o m  mitt e e:   N
a  
pr o vi d e d i n 
y   S c h e  m a 
y    D u r ati o n:
in  a  1: 1 r ati o
a ys.  T his r a n
i n o c ul ar   DC
o w n  a n d  n o  n
v isits:  s cr e e ni
N  o 
Fi g ur e  1- 1 .
9 
 
o  t o r e c ei v e 
n d o  mi z ati o n 
C  N  V  A ( 2  gr
n -b r o  w n),  a nd
in g (  D a ys -
e it h er   A  G  N
will  b e str a
o u ps:  2 0/ 4 0  t
d  e  m  m etr o p
3 0 t o - 1),   D
Pr ot o c
-1 9 0 5 8 4  or  v
tifi e d  b y  a ge
to  2 0/ 6 0 i n c l
es/ n o n- e  m m
a y  1 ( b as eli n
c ol  1 8 8 3- 3 0 2
v e hi cl e  d os e d
e  ( 2  gr o u ps: ≤
l usi v el y,  a nd
m  etr o p es.  T h i
n e),  a n d   D a y
2 - 0 1 3       
d  
≤   5 0 
d  
is 
s  3,  7, 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 
 
1. 3.     
S c h e d ul e  of   A cti viti es 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 
 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 3 
 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 4 
 
T a bl e  1 – 2     S c h e d ul e  of   Visits  a n d  P r o c e  d u r es:   Visit  4 t o   Visit  5/  E a rl y   E xit 

 
 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 5 
 

 
 
 
A p pr o v al  D at e: 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 6 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 7 
 
2.     
I nt r o d u cti o n 
All er g a n is i n v esti g ati n g  pil o c ar pi n e   H  C  l  o p ht h al  mi c s ol uti o n  1. 2 5  % (  A  G  N- 1 9 0 5 8 4)  as  a 
n o ni n v asi v e, r e v ersi bl e,  p h ar  m a c ol o gi c al tr e at  m e nt  f or  pr es b y o pi a,  a  c o n diti o n i n   w hi c h t h e  e y e 
e x hi bits  a  di  mi nis h e d  a bilit y t o f o c u s  o n  n e ar  o bj e cts   wit h i n cr e asi n g  a g e. 
2. 1.     
St u d y   R ati o n al e 
I n  pr e vi o us st u di es,   All er g a n  est a blis h e d t h e s af et y  a n d  effi c a c y  of  v ari o us  c o n c e ntr ati o ns  of 
A  G  N- 1 9 0 5 8 4  d os e d  o n c e  d ail y,  bil at er all y  or i n   t h e  n o n d o  mi n a nt  e y e,  o v er  a  p eri o d  of  u p t o 
2 8  d a ys i n  p arti ci p a nts   wit h   pr es b y o pi a.  St u d y  1 8 8 3- 3 0 2- 0 1 3 is a   m ulti c e nt er,  d o u bl e-  m as k e d, 
r a n d o  mi z e d,  v e hi cl e- c o ntr oll e d,  p ar all el  gr o u p,  P h as e  3 st u d y  e v al u ati n g t h e s af et y,  effi c a c y,  a n d 
t ol er a bilit y  of   A  G  N- 1 9 0 5 8 4  d os e d  o n c e  d ail y,  bil at er all y,  o v er  a  p eri o d  of  3 0  d a ys i n  p arti ci p a nts 
wit h  pr es b y o pi a. 
2. 2.     
B a c k g r o u n d 
T h e i  m p air  m e nt  of  n e ar  visi o n is  c o  m  m o n  a  m o n g  ol d er  a d ults. I n  2 0 0 5,  1. 0 4 4  billi o n  p e o pl e 
gl o b all y   w er e  esti  m at e d t o  h a v e  pr es b y o pi a,  a n d  pr e v al e n c e is  e x p e ct e d t o i n cr e as e t o  1. 7 8 2 
billi o n  b y  2 0 5 0 ( H ol d e n  2 0 0 8  ).   B ot h  n o ns ur gi c al  a n d s ur gi c al   m et h o ds f or t h e  c orr e cti o n  of 
pr es b y o pi a  ar e  a v ail a bl e.  Tr a diti o n al  n o ns ur gi c al  m et h o ds  of r efr a cti v e  c orr e cti o n f or  pr es b y o pi a 
i n cl u d e t h e  us e  of  d e di c at e d r e a di n g s p e ct a cl es,  bif o c al  or  v arif o c al s p e ct a cl es,  a n d   m o n o visi o n 
or   m ultif o c al  c o nt a ct l e ns es.   A  n u  m b er  of s ur gi c al t e c h ni q u es  ar e  als o  us e d f or t h e tr e at  m e nt  of 
pr es b y o pi a,   w hi c h i n cl u d e   m o n o visi o n  P  R  K  or  L  A SI  K,  c o n d u cti v e  k er at o pl ast y, i ntr a o c ul ar 
l e ns es,  a n d  c or n e al i nl a ys.   H o  w e v er, f or  e a c h of t h e  e xisti n g t e c h n ol o gi es   m e nti o n e d  a b o v e, 
vis u al  q u alit y is r e d u c e d  at  1  or   m or e  vi e  wi n g  dist a n c es,  a n d  e a c h  c o  m es   wit h its  o  w n  u ni q u e 
s af et y ris ks  a n d  ass o ci at e d  c o  m pli c ati o ns.  F or  e x a  m pl e,  bif o c als  a n d  pr o gr essi v e l e ns es ( e g, 
r e a di n g  gl ass es,  c o nt a cts)  pr o d u c e  o pti c al  a b err ati o ns  a n d  c a n i n cr e as e t h e ris k  of f alls 
(J o h ns o n  2 0 0 7, L or d  2 0 0 2 ).   M ultifo c al  o pti cs r e d u c e i  m a g e  q u alit y  u nif or  ml y  at  all  vi e  wi n g 
dist a n c es.  F or s ur gi c al t e c h n ol o gi es, s ur gi c al ris ks,  a n d t h e  n e e d f or r e p o siti o ni n g  a n d 
e x pl a nt ati o n,  or r e gr essi o n  of  eff e ct  h a v e li  m it e d t h eir   wi d es pr e a d  a d o pti o n (M os hirf ar  2 0 1 7  , 
R ui z  2 0 0 9  , T o  mit a  2 0 1 5 ).  T h us, t h er e r e  m ai ns  a  n e e d f or  a  n o ni n v asi v e, r e v ersi bl e, 
p h ar  m a c ol o gi c al tr e at  m e nt f or  pr es b y o pi a. 
Pil o c ar pi n e is  a   m us c ari ni c r e c e pt or  a g o nist t h at   mi  mi cs t h e  a cti o ns  of t h e  p ar as y  m p at h eti c 
n e ur otr a ns  mitt er,  a c et yl c h oli n e,  o n s  m o ot h   m us cl e .  T his  c a us es  2  eff e cts t h at  e n h a n c e  n e ar 
visi o n:  1)  c o nstri cti o n  of t h e iris s p hi n ct er   m us c l e, r es ulti n g i n  p u pil  c o nstri cti o n (  mi osis),  a n d 
2)  c o ntr a cti o n  of t h e  cili ar y   m us cl e, r es ulti n g  i n  c e ntr al l e ns st e e p e nin g  a n d l e ns  a c c o  m  m o d ati o n 
(f o c usi n g fr o  m  dist a n c e t o  n e ar) (G ar cí a- L á z ar o  2 0 1 2  ).   R e d u ci n g t h e  p u pil si z e  h as l o n g  b e e n 
r e c o g ni z e d  as  a n  eff e cti v e   w a y t o i n cr e as e t h e us ef ul  d e pt h  of f o c us, i n  p art  b y r e d u ci n g 
p eri p h er al  a b err ati o ns ( T u c k er  1 9 7 5 ). 
Pil o c ar pi n e  o p ht h al  mi c s ol uti o ns  ar e  c urr e ntl y  us e d f or t h e r e d u cti o n  of  el e v at e d I  O P i n  p ati e nts 
wit h  o p e n- a n gl e  gl a u c o  m a  or  o c ul ar  h y p ert e nsi o n  ,   m a n a g e  m e nt  of  a c ut e- a n gl e  cl os ur e  gl a u c o  m a, 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 8 
 
pr e v e nti o n  of  p ost o p er ati v e  el e v at e d I  O P  ass o ci at e d    wit h l as er s ur g er y,  a n d i n d u cti o n  of   mi osis 
(Pil o c ar pi n e   H  Cl  o p ht h al  mi c s ol uti o n  p a c k a g e i ns ert  2 0 1 1 ).   C urr e ntl y, t he  us e  of  pil o c ar pi n e 
o p ht h al  mi c s ol uti o n is li  mit e d  b y t h e  c o  m  m o nl y  e x p eri e n c e d   A E  of t e  m p or al  a n d  p eri or bit al 
h e a d a c h e (i e,  br o  w  a c h e),   w hi c h is  b eli e v e d t o  b e   d u e t o t h e r a pi dit y  of t h e  cili ar y   m us cl e 
c o ntr a cti o n ( Ts ai  2 0 0 9 ).   H o  w e v er,   All er g a n  h as  est a blish e d  a n  a c c e pt a bl e s af et y  pr ofil e  of 
A  G  N- 1 9 0 5 8 4 i n  3  P h as e  2  cli ni c al st u di e  s ( St u di es  1 9 9 2 0 1- 0 0 7,  1 9 9 2 0 1- 0 0 9,  a n d  1 9 9 2 0 1- 0 1 0). 
T his is li k el y  b e c a us e t h e  p os ol o g y  of  pil o c ar pi n e   e v al u at e d f or t h e tr e at  m e nt  of  pr es b y o pi a t o 
d at e is  of l o  w er  c o n c e ntr ati o n ( 0. 5  % t o  1. 5  %)  a n d l ess fr e q u e ntl y  a d  mi nist er e d ( o n c e t o t  wi c e 
d ail y) t h a n f or t h e tr e at  m e nt  of  gl a u c o  m a ( 1. 0  % t o   4. 0  %  a d  mi nist er e d  u p t o  4 ti  m es  d ail y).   As  a 
r es ult,  dis c o nti n u ati o n r at es f or  all  P h as e  2  cli ni c al st u di es   w er e  g e n er all y l o  w  a n d s af et y 
p ar a  m et ers   w er e  n ot  cli ni c all y si g nifi c a n t  b et  w e e n  p arti ci p a nts t h at r e c ei v e d   A  G  N- 1 9 0 5 8 4 
c o  m p ar e d t o  p arti ci p a nts t h at r e c ei v e d  v e hi cl e  or  a  c o  m bi n ati o n t h er a p y.  T h e   m aj orit y  of   A Es 
r e p ort e d i n  a n y tr e at  m e nt  gr o u p   w er e   mil d t o   m o d er at e i n i nt e nsit y.  
Effi c a c y   m e as ur es f or  P h as e  2  cli ni c al st u di es  i n cl u d e d   m es o pi c  u n c orr e ct e d  n e ar  vis u al  a c uit y 
li n e  a n d l ett er i  m pr o v e  m e nt.   Of t h e  v ari o us  c on c e ntr ati o ns  of   A  G  N- 1 9 0 5 8 4  e v al u at e d,  n e ar 
visi o n   w as   m ost i  m pr o v e d  c o  m p ar e d   wit h  v e hi cl e  u n d er   m es o pi c  a n d  p h ot o pi c  c o n diti o ns  at t h e 
1. 0  %  a n d  1. 5  %  pil o c ar pi n e  c o n c e ntr ati o ns, r es p e cti v el y. 
M or e  d et ail e d i nf or  m ati o n r e g ar di n g  cli ni c al s af et y    fi n di n gs,  cli ni c al  effi c a c y fi n di n gs,  c h e  mistr y, 
a n d  p h ar  m a c ol o g y is  pr o vi d e d i n t h e I  B. 
2. 3.     
B e n efit/  Ris k   Ass ess  m e nt 
C urr e ntl y  a v ail a bl e  a p pr o a c h es t o  pr es b y o pi a  c orr e cti o n i n cl u d e  n o ns ur gi c al  o pti o ns (s p e ct a cl es 
or  c o nt a ct l e ns es)  a n d s ur gi c al  o pti o ns ( P  R  K  or  L  A SI  K,  c o n d u cti v e  k er a t o pl ast y, i ntr a o c ul ar 
l e ns es,  or  c or n e al i nl a ys).  E a c h  a p pr o a c h  h as its  o  w n ris k- b e n efit r ati o. B e c a us e t h e ris k- b e n efit 
r ati o   wit h  n o ns ur gi c al  o pti o ns is g e n er all y l o  w er t h a n t h at  of s ur g i c al  pr o c e d ur es,  b ot h  hist ori c al 
a n d  c o nt e  m p or ar y  pr a cti c e  h as  b e e n  t o  att e  m pt  n o ns ur gi c al  or  p h ar  m a c ol o gi c al tr e at  m e nt  b ef or e 
r es orti n g t o   m or e in v asi v e  alt er n ati v es. 
Alt h o u g h t h e  us e  of s p e ct a cl es  a n  d  c o nt a ct l e ns es t o  c orr e ct  pr es b y o pi a is   wi d es pr e a d, t his 
a p pr o a c h  h as li  mit ati o ns.   M ultif o c al s p e ct a cl es i  m p air  d e pt h  p er c e pti o n  a n d  e d g e- c o n tr ast 
s e nsiti vit y  at  criti c al  dist a n c es f or  d e t e cti n g  o bst a cl es i n t h e  e n vir o n  me nt ( L or d  2 0 0 2 ), a n d 
v arif o c al l e ns es  h a v e  a  c orri d or  of  n o n dist ort e d  visi o n.  F or t h es e r e as o ns,  ol d er  p e o pl e  ar e   m or e 
t h a n t  wi c e  as li k el y t o f all   w h e n   w e ari n g   m ultif o c al s p ect a cl es,  a n d   m a n y  p arti ci p a nts  h a v e 
diffi c ult y  a dj usti n g t o  usi n g t h e  m  (J o h ns o n  2 0 0 7 , L or d  2 0 0 2).   As  a r es ult,   All er g a n is  d e v el o pi n g 
a  n o ni n v asi v e, r e v ersi bl e,  p h ar  m a c ol o gi c al tr e at  m e nt f or  pr es b y o pi a. 
M or e  d et ail e d i nf or  m ati o n  a b o ut t h e  k n o  w n  a n d    e x p e ct e d  b e n efits  a n d ris ks  a n d r e as o n a bl y 
e x p e ct e d   A Es  of   A  G  N- 1 9 0 5 8 4   m a y  b e f o u n d i n t h e I  B. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 9 
 
3.     
O bj e cti v es  a n d   E n d p oi nts 
O bj e cti v es
    M e as u r es
 
T o  e v al u at e t h e  effi c a c y  of   A  G  N- 1 9 0 5 8 4 
w h e n  a d  mi nist er e d  bil at er all y,  o n c e  d ail y f or 
3 0  d a ys i n  p arti ci p a nts   wit h  pr es b y o pi a. 
•     M es o pi c  a n d  p h ot o pi c,  hi g h  c o ntr ast   D  C  N  V  A f or  e a c h  e y e 
a n d  bi n o c ul arl y 
•     M es o pi c  a n d  p h ot o pi c,  hi g h  c o ntr ast   D  CI  V  A f or  e a c h  e y e 
a n d  bi n o c ul arl y 
•     P  R  O  q u esti o n n air es:  
o     M es o pi c  a n d  P h ot o pi c   N  V P T  Q 
o     PI  C  Q 
T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of 
A  G  N- 1 9 0 5 8 4   w h e n  a d  mi nist er e d  bil at er all y, 
o n c e  d ail y f or  3 0  d a ys i n  p arti ci p a nts   wit h 
pr es b y o pi a 
•     A Es 
•     P h ot o pi c  a n d   m es o pi c  hi g h  c o ntr ast   C  D  V  A f or  e a c h  e y e 
a n d  bi n o c ul arl y 
•     N e ar   C o ntr ast s e nsiti vit y 
•     Vit al si g ns ( bl o o d  pr ess ur e  a n d  h e art r at e) 
•     St u d y  dr u g t ol er a bilit y  a n d  dr o p  c o  mf ort  ass ess  m e nts 
•     T e  m p or al/s u pr a or bit al  h e a d a c h e   V  A S 
•     I  O P 
•     Slit-l a  m p  bi o  mi cr os c o p y 
•     M a nif est r efr a cti o n 
•     Dil at e d f u n d us c o pi c  e x a  mi n ati o n 
•     Pr e g n a n c y t est f or    W  O  C  B P 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 0 
 
4.     
St u d y   D esi g n 
4. 1.     
O v e r all   D esi g n 
T his is  a   m ulti c e nt er,  d o u bl e-  m as k e d, r a n d o  mi z e d  ,  p ar all el- gr o u p,  v e hi cl e- c o ntr oll e d,  P h as e  3 
st u d y i n  p arti ci p a nts   wit h  pr es b y o pi a.  P arti c i p a nts   will r e c ei v e   A  G  N- 1 9 0 5 8 4  or  v e hi cl e  d os e d 
o n c e  d ail y,  bil at er all y, f or  3 0  d a ys.   A p pr o xi  m a t el y  4 0 0  p arti ci p a nts   wit h  pr es b y o pi a   will  b e 
e nr oll e d  at  a p pr o xi  m at el y  5 0 sit es i n t h e   U nit e d  St at es. 
T his st u d y  c o nsists  of t h e f oll o  wi n g  visits: s cr e e ni n g,   D a y  1 ( b as eli n e),  a n d   D a ys  3,  7,  1 4,  a n d  3 0.  
A st u d y s c h e  m a is l o c at e d i n  S e cti o n   1. 2   a n d t he  S o  A is l o c at e d i n  S e cti o n  1. 3 . 
A p pr o xi  m at el y  2 0 0  p arti ci p a nts  p er  gr o u p   will  b e    e nr oll e d.  P arti ci p a nts   w h o  pr e  m at ur el y 
dis c o nti n u e fr o  m t h e st u d y   will  n ot  b e r e pl a c e d. 
4. 1. 1.     
Cli ni c al   H y p ot h es es 
•     A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  d os e d  bil at er all y,  o n c e  d ail y f or  3 0  d a ys   will 
d e  m o nstr at e  a si g nifi c a nt i  m pr o v e m e nt i n   D  C  N  V A  o v er  v e hi cl e. 
•     A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  d os e d  bil at er all y,  o n c e  d ail y f or  3 0  d a ys   will 
d e  m o nstr at e  a n  a c c e pt a bl e s af et y  a n d t ol er a bilit y  pr ofil e. 
4. 2.     
S ci e ntifi c   R ati o n al e f o r  St u d y   D esi g n 
T h e  c urr e nt  P h as e  3  cli ni c al st u d y is  d esi g n e d t o  e v al u at e t h e  effi c a c y, s af e t y,  a n d t ol er a bilit y  of 
A  G  N- 1 9 0 5 8 4  v ers us  v e hi cl e  o v er  a  3 0- d a y st u d y   i nt er v e nti o n  p eri o d   w h e n  a d  mi nist er e d  o n c e 
d ail y  bil at er all y i n  p ar ti ci p a nts   wit h  pr es b y o pi a. 
All er g a n  P h as e  2  St u di es  1 9 9 2 0 1- 0 0 7  a n d   1 9 9 2 0 1- 0 0 9 s u p p ort t h e  a d  mi nistr ati o n  of 
A  G  N- 1 9 0 5 8 4   m o n ot h er a p y  as  a n  eff e cti v e  a n d  s af e tr e at  m e nt f or  pr es b y o pi a i n  d os es  u p t o  1. 5  %. 
T h e  c urr e nt  P h as e  3 st u d y   will  e v al u at e   A  G  N- 1 9 0 5 8 4   i n  a n  e x p a n d e d  p arti ci p a nt  p o p ul ati o n t o 
est a blis h  effi c a c y  a n d s af et y. 
4. 3.     
J ustifi c ati o n f o r   D os e 
T hr o u g h   m o d eli n g  a n d  e v al u ati o n  of t h e  P h as e  2 r es ults ( St u di es  1 9 9 2 0 1- 0 0 7,  1 9 9 2 0 1- 0 0 9,  a n d 
1 9 9 2 0 1- 0 1 0),   All er g a n  h as  d et er  mi n e d t h e  o pti  m al  d os e  of   A  G  N- 1 9 0 5 8 4 t o  b e  1. 2 5  % f or t h e 
tr e at  m e nt  of  pr es b y o pi a. 
4. 4.     
E n d  of  St u d y   D efi niti o n 
T h e  E  O S is  d efi n e d  as t h e  d at e  of t h e l ast  visit  of t h e l ast  p arti ci p a nt i n t h e st u d y. 
A  p arti ci p a nt is  c o nsi d er e d t o  h a v e  c o  m pl et e d t h  e st u d y if  h e/s h e  h as  c o  m p l et e d  all  p h as es  of t h e 
st u d y i n cl u di n g t h e l ast  visit. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 2 
 
3. 0 1 
M al e  a n d f e  m al e    
4.    
I nf o r  m e d   C o ns e nt 
4. 0 1 
C a p a bl e  of  gi vi n g si g n e d i nf or  m e d  c o ns  e nt,   w hi c h i n cl u d es  c o  m pli a n c e   wit h t h e 
r e q uir e  m e nts  a n d r estri cti o ns list e d i n t h e I  C F  a n d i n t his  pr ot o c ol 
4. 0 2 
Writt e n i nf or  m e d  c o ns e nt fr o  m t h e  p arti ci p a n   t  or  a l e g all y  a ut h ori z e d r e pr es e nt ati v e 
h as  b e e n  o bt ai n e d  pri or t o  a n y st u d y-r el at e d  pr o c e d ur es 
4. 0 3 
Writt e n  d o c u  m e nt ati o n  h as  b e e n  o bt ai n e d i n    a c c or d a n c e   wit h t h e r el e v a nt  c o u ntr y 
a n d l o c al  pri v a c y r e q uir e  m e nts,   w h er e  a p pl i c a bl e ( e g,    Writt e n   A ut h ori z ati o n f or   Us e 
a n d   R el e as e  of   H e alt h  a n d   R es e ar c h  St u d y I nf or  m ati o n f or t h e   U nit e d  St at es) 
5.    
Ot h e r   
5. 0 1 
A bl e,  as  ass ess e d  b y t h e i n v esti g at or,  a n d   willi n g t o f oll o  w st u d y i nstr u cti o ns  a n d 
li k el y t o  c o  m pl et e  all r e q uir e d st u d y  visits 
 
5. 2.     
E x cl usi o n   C rit e ri a 
P arti ci p a nts  ar e  e x cl u d e d fr o  m t h e st u d y if   a n y  of t h e f oll o  wi n g  crit eri a  a p pl y: 
1.   
    M e di c al   
 
C o n diti o ns   
 
1. 0 1 
U n c o ntr oll e d s yst e  mi c  dis e as e   
1. 0 3 
A n y  cli ni c al  c o n diti o n  or  pr e vi o us s ur g er y t h at   mi g ht  aff e ct   t h e  a bs or pti o n,  distri b uti o n, 
bi otr a nsf or  m ati o n,  or  e x cr eti o n  of   A  G  N- 1 9 0 5 8 4.   Hist or y  of  c at ar a ct s ur g er y,  p h a ki c 
i ntr a o c ul ar l e ns s ur g er y,  c or n e al i nl a y s ur g er y, r a di al  k er at ot o  m y,  or  a n y i ntr a o c ul ar 
s ur g er y.   H o  w e v er,  p arti ci p a nts   wit h  hist or y  of  P  R  K  or  L  A SI  K   wit h   C  D  V  A   m e eti n g 
i n cl usi o n  crit eri a   will  b e  all o  w e d t o  e nr oll. 
1. 0 4 
K n o  w n  all er g y  or s e nsiti vit y t o t h e st u d y   i nt er v e nti o n  or its c o  m p o n e nts  or  ot h er 
c h oli n er gi c  a g o nist   m e di c ati o ns 
2.   
  P ri o r/  C o n c o  mit a nt   
 
T h e r a p y   
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 3 
 
2. 0 1 
C o n c urr e nt  us e  of  a n y t o pi c al    o p ht h al  mi c   m e di c ati o ns, i n cl u di n g  artifi ci al t e ars,  ot h er 
t h a n t h e st u d y i nt er v e nti o n d uri n g t h e  c o urs e  of t h e st u d y  
2. 0 2 
C o n c urr e nt  us e  of t e  m p or ar y  or  p er  m a n e nt  p u n c  t al  pl u gs  or  hist or y  of  p u n ct al  c a ut er y i n 
o n e  or  b ot h  e y es 
3.      
P ri o r/  C o n c u r r e nt   Cli ni c al  St u d y   E x p e ri e n c e 
3. 0 1 
C urr e nt  e nr oll  m e nt i n  a n i n v esti g ati o n al  dr u g   or  d e vi c e st u d y  or  p art i ci p ati o n i n s u c h  a 
st u d y   wit hi n  3 0  d a ys  of  e ntr y i nt o t his st u d y 
3. 0 2 
P arti ci p ati o n i n  a  bl o o d  or  pl as  m a  d o n ati o n  pr o gr a  m   wit hi n  3 0  d a ys  pri or t o st u d y 
i nt er v e nti o n  a d  mi nistr ati o n 
4.   
   Di a g n osti c   
 
Ass ess  m e nts   
 
4. 0 2 
S e v er e  dr y  e y e  dis e as e ( d efi n e d  as t ot al  c or n e al st ai ni n g  ≥   gr a d e  3  o n t h e  5- p oi nt   O xf or d 
s c al e  a n d  a n   O S  DI s c or e  of  >  3 3)  at t h e s cr e e ni n g  visit 
4. 0 3 
C or n e al  a b n or  m aliti es (i n cl u di n g  k er at o c  o n us,  c or n e al s c ar,  F u c hs’  e n d ot h eli al 
d ystr o p h y,  g utt at a,  or  e d e  m a) i n  eit h er  e y e t h at  ar e li k el y t o  i nt erf er e   wit h  vis u al  a c uit y 
4. 0 4 
N arr o  w iri d o c or n e al  a n gl es ( S h aff er  gr a d e   ≤   2  or l o  w er  o n  g o ni os c o p y  e x a  mi n ati o n), 
hist or y  of  a n gl e- cl os ur e  gl a u c o  m a,  or  pr e vi o us iri d ot o  m y 
4. 0 5 
Hist or y  of iris tr a u  m a,   A di e  ’s t o ni c  p u pil,  a b n or  m al  p u pil s h a p e i n  eit h er  e y e,  or 
a nis o c ori a  >  1   m  m  b et  w e e n  p u pils  u n d er   m e s o pi c  c o n diti o ns  at t h e s cr e e ni n g  visit 
4. 0 6 
L e ns  o p a cit y i n  eit h er  e y e t h at is  d et er  mi n e d t o  c a us e si g nifi c a nt  dist ur b a n c e  of t h e 
c e ntr al  vis u al  a xis  o n s cr e e ni n g  bi o  mi cr os c o p y 
4. 0 7 
Di a g n osis  of  a n y t y p e  of  gl a u  c o  m a  or  o c ul ar  h y p ert e nsi o n 
4. 0 8 
Bif o c al  or   m ultif o c al s p e ct a cl es  or  c o nt a ct l e  ns es f or  h a bit u al  c orr e cti o n.  P arti ci p a nts 
willi n g t o   w e ar st u d y- pr o vi d e d   m o n of o c al  c orr  e cti o n ( eit h er s p e ct a cl es  or  c o nt a ct l e ns es) 
d uri n g t h e st u d y  c a n  b e  e nr oll e d 
4. 0 9 
A b n or  m al  a n d  cli ni c all y si g nifi c a nt r es ults  a c c o  r di n g t o t h e i n v esti g at or  or  d esi g n e e,  o n 
p h ysi c al/ o p ht h al  mi c  e x a  mi n ati o n  or   m e di c al  hist or y 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 5 
 
6.     
St u d y I nt e r v e nti o n 
St u d y i nt er v e nti o n is  d efi n e d  as  a n y i n v esti g ati o n al i nt e r v e nti o n i nt e n d e d t o  b e  a d  mi nist er e d t o  a 
st u d y  p arti ci p a nt  a c c or di n g t o t h e st u d y  pr ot o c ol. 
6. 1.     
St u d y I nt e r v e nti o n(s)   A d  mi nist e r e d 
St u d y I nt e r v e nti o n   N a  m e  
A  G  N- 1 9 0 5 8 4 
V e hi cl e 
D os a g e  F o r  m ul ati o n 
T o pi c al  e y e  dr o p 
T o pi c al  e y e  dr o p 
I d e ntit y  of  F o r  m ul ati o n 
Pil o c ar pi n e   H  Cl  1. 2 5  %   O p ht h al  mi c 
S ol uti o n 
Pil o c ar pi n e   H  Cl  Pl a c e b o   O p ht h al  mi c 
S ol uti o n 
D r u g  S u bst a n c e 
Pil o c ar pi n e  1. 2 5  % 
N ot  a p pli c a bl e 
R o ut e  of   A d  mi nist r ati o n  
T o pi c al  e y e  dr o p 
T o pi c al  e y e  dr o p 
D osi n g I nst r u cti o ns   
1  dr o p i n  e a c h  e y e  o n c e  d ail y    
1  dr o p i n  e a c h  e y e  o n c e  d ail y 
M a n uf a ct u r e r 
All er g a n  S al es,  L L  C. 
All er g a n  S al es,  L L  C. 
N u  m b e r  a n d   Ti  mi n g  of 
I nt e r v e nti o ns 
1  dr o p  bil at er all y,  o n c e  d ail y    
1  dr o p  bil at er all y,  o n c e  d ail y 
 
As t his is  a  d o u bl e-  m as k e d st u d y,   A  G  N- 1 9 0 5 8 4  a n d   V e hi cl e   will  b e s u p pli e d i n i d e nti c all y 
a p p e ari n g  b ottl es  a n d  c art o ns. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 6 
 
6. 2.     
P r e p a r ati o n/  H a n dli n g/ St o r a g e/  A c c o u nt a bilit y 
T h e i n v esti g at or  or  d esi g n e e   m ust  c o nfir  m  a p pr o pri at e t e  m p er at ur e  c o n diti o ns  h a v e  b e e n 
m ai nt ai n e d  d uri n g tr a nsit f or  all st u d y i nt er v e nti  o n r e c ei v e d  a n d  a n y  dis cr e p a n ci es  ar e r e p ort e d 
a n d r es ol v e d  b ef or e  us e  of t h e st u d y i nt er v e nti o n. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 7 
 
O nl y  p arti ci p a nts  e nr oll e d i n   t h e st u d y   m a y r e c ei v e st u d y i nt er v e nti o n,  a n d  o nl y  a ut h ori z e d sit e 
st aff   m a y s u p pl y  or  a d  mi nist er st u d y i nt er v e nti o n.    All st u d y i nt er v e nti o n   m ust  b e st or e d i n  a 
s e c ur e,  e n vir o n  m e nt all y  c o ntr oll e d,  a n d   m o nit o r e d (  m a n u al  or  a ut o  m at e d)  ar e a i n  a c c or d a n c e 
wit h t h e l a b el e d st or a g e  c o n diti o ns   wit h  a c c ess li  m  it e d t o t h e i n v esti g at or  a n d  a ut h ori z e d sit e 
st aff.   All st u d y i nt er v e nti o n   m ust  b e st or e d  u pri g ht, i n  a r efri g er at or,  a n d  pr ot e ct e d fr o  m fr e e zi n g. 
P arti ci p a nts   will  b e i nstr u ct e d  o n t h e  pr o p er st or a g e  of st u d y i nt er v e nti o n  a n d t o  k e e p it  o ut  of t h e 
r e a c h  of  c hil dr e n  at  all ti  m es. 
6. 3.     
M e as u r es t o    Mi ni  mi z e   Bi as:   R a n d o  mi z ati o n  a n d   Bli n di n g 
All  p arti ci p a nts   will  b e  c e ntr all y  assi g n e d t o   r a n d o  mi z e d st u d y i nt er v e nti o n  usi n g t h e I x  R S. 
R a n d o  mi z ati o n  a n d  kit  assi g n  m e nt   will  b e  c o n d u ct e d  o n   D a y  1 ( b as eli n e).   At   D a y  1,  p arti ci p a nts 
will  b e r a n d o  mi z e d i n  a  1: 1 r a  ti o i nt o  1  of t h e  2 st u d y  gr o u ps.  T his r a n d o  mi z ati o n   will  b e 
str atifi e d  b y  a g e ( 2  gr o u ps:  ≤   5 0  y e ars  a n d  >  5 0  y e ars),  b as elin e  bi n o c ul ar   D  C  N  V  A ( 2  gr o u ps: 
2 0/ 4 0 t o  2 0/ 6 0 i n cl usi v el y,  a n d   w ors e t h a n  2 0/ 6 0), iris  c ol or ( br o  w n  a n d  n o n- br o  w n),  a n d 
e  m  m etr o p es/ n o n- e  m  m etr o p es.   A   m a xi  m u  m  of  5 0  % ( 1 0 0  p er  ar  m)  of t h e  p arti ci p a nts  e nr oll e d 
will  h a v e  br o  w n iris  c ol or,  a n d  a   m a xi  m u  m  of  2 5  % ( 5 0  p er  ar  m)  of t h e  p arti ci p a nts   will  b e  n o n-
e  m  m etr o p es ( a s p h er e  o utsi d e  of - 0. 5 0   D t o  + 0 . 7 5   D  a n d/ or  a  c yli n d er  gr e at er t h a n  0. 7 5   D). 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 8 
 
6. 5.     
C o n c o  mit a nt   T h e r a p y 
T h e  us e  of  a n y  c o n c o  mit a nt   m e di c ati o n,  pr es cri pti  o n  or  o v er-t h e- c o u nt er, is t o  b e r e c or d e d  o n t h e 
p arti ci p a nt’s  e  C  R F  at  e a c h  visit  al o n g   w it h t h e r e as o n t h e   m edi c ati o n is t a k e n. 
Fr o  m s cr e e ni n g t o t h e  E  O S, sit e st aff   will  q u es ti o n  e a c h  p arti ci p a nt s p e cifi c all y  o n t h e  us e  of 
c o n c o  mit a nt   m e di c ati o ns.  Sit e st aff   m ust  n otif y t h e s p o ns or i  m  m e di at el y if  a  p arti ci p a nt 
c o ns u  m es  a n y  c o n c o  mit a nt   m e di c ati o ns  n ot  p er  m itt e d  b y t h e  pr ot o c ol.  P arti ci p a nts   w h o  us e d 
pr o hi bit e d  c o n c o  mit a nt   m e di c ati o ns   m a y  b e  dis c o n ti n u e d fr o  m t h e st u d y  at t h e  dis cr eti o n  of t h e 
i n v esti g at or  or t h e s p o ns or. 
6. 5. 1.     
P r o hi bit e d I nt e r v e nti o ns  a n d    W as h o ut   B ef o r e t h e  St u d y 
Us e  of   m e di c ati o ns t h at   m a y  h a v e  a s u bst a nti al  e  ff e ct  o n  vis u al f u n cti o n  or t h e  o pti c al  pr o p erti es 
of t h e  e y e is  pr o hi bit e d  2   w e e ks  pri or  t o   D a y  1  visit  a n d  d uri n g t h e st u d y: 
•     s yst e  mi c   m e di c ati o ns   wit h  p ot e nti al  o c ul ar si d e  eff e ct s, i n cl u di n g t o pir a  m at e, 
h y dr o x y c hl or o q ui n e,  et h a  m b ut ol,  p h os p h o di est er as e  5 i n hi bit ors (sil d e n afil,  v ar d e n afil, 
t a d al afil),  or t a  m o xif e n  
•     o p ht h al  mi c, s yst e  mi c,  or i ntr a n as al  a nti c h oli n er gi cs  a n d  α - a dr e n er gi c r e c e pt or  a g o nists 
wit h  p ot e nti al  p u pill ar y  or  a c c o  m  m o d ati v e  eff e cts, i n cl u di n g  o x y  m et a z oli n e,  pil o c ar pi n e, 
t etr a h y dr o z oli n e,  p h e n yl e p hri n e,  n a p h a z oli n e,  c ycl o p e nt ol at e,  atr o pi n e,  b et a- bl o c k ers,  or 
a nti hist a  mi n es  
•     s yst e  mi c   m a pr otili n e, tri c y cli c  a nti d e pr e ss a nts,  or   m o n o a  mi n e  o xi d as e i n hi bit ors 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
2 9 
 
6. 5. 2.     
P e r  mitt e d I nt e r v e nti o ns 
A n y   m e di c ati o n  or  v a c ci n e (i n cl u di n g  o v er-t h e- c  o u nt er  or  pr es cri pti o n   m e di ci n es,  vit a  mi ns, 
a n d/ or  h er b al s u p pl e  m e nts) t h at t h e  p arti ci p a nt is r e c ei vi n g  at t h e  ti  m e  of  e nr oll  m e nt  or r e c ei v es 
d uri n g t h e st u d y   m ust  b e  r e c or d e d  al o n g   wit h: 
•     I n di c ati o n 
•     D at es  of  a d  mi nistr ati o n i n cl  u di n g st art  a n d  e n d  d at es 
•     D os a g e i nf or  m ati o n i n cl u di n g  d os e  a n d fr e q u e n c y 
T h er a p y  c o nsi d er e d  n e c ess ar y f or t h e  p arti ci p a nt’  s   w elf ar e   m a y  b e  gi v e n  at t h e  dis cr eti o n  of t h e 
i n v esti g at or. If t h e  p er  missi bilit y  of  a s p e cific   m e di c ati o n/i nt er v e nti o n is i n  q u esti o n,  pl e as e 
c o nt a ct t h e s p o ns or. 
T h e s p o ns or  or  d esi g n e e s h o ul d  b e  c o nt a ct e d if t h er e  ar e  a n y  q u esti o ns r e g ar di n g  c o n c o  mit a nt  or 
pri or t h er a p y. 
T h e  c o n c urr e nt  us e  of  n o n o c ul ar   m e di c ati o ns t h at   d o  n ot  h a v e  a s u bst a nti al  eff e ct  o n t h e  p u pil, 
a c c o  m  m o d ati v e  pr o p erti es,  or r eti n al f u n cti o n  of t h e  e y e   will  b e  p er  mitt e d  d uri n g t h e st u d y if  a 
st a bl e  d osi n g r e gi  m e n is  est a blis h e d.  T h e  d osi n g  r e gi  m e n is  n ot  c o nsi d er e d t o  b e st a bl e if  a 
p arti ci p a nt st arts, st o ps,  or  c h a n g es t h e  d os e/ dr u g  d uri n g t h e st u d y. 
A n y   m e di c ati o n t a k e n  d uri n g t h e st u d y  b et  w e e n t h  e  d at e  of t h e first  d os e  of st u d y i nt er v e nti o n 
a n d t h e  d at e  of t h e  E  O S  visit   will  b e r e c or d e d  i n t h e  e  C  R F  as  a  c o n c o  mit a nt   m e di c ati o n;  a n y 
m e di c ati o n st art e d  aft er t h e  E  O S  visit   will  n ot   b e  c o nsi d er e d  a  c o n c o  mit a nt   m e di c ati o n  a n d 
s h o ul d  n ot  b e  c a pt ur e d i n t h e  e  C  R F. 
6. 5. 3.     
R es c u e    M e di ci n e 
R es c u e   m e di ci n e is  n ot  a p pli c a bl e. 
6. 5. 4.     
P r o hi bit e d I nt e r v e nti o ns   D u ri n g t h e  St u d y 
Us e  of  o c ul ar   m e di c ati o ns  ot h er t h a n st u d y i nt e  r v e nti o n  or   m e di c ati o ns  a d  mi nist er e d t o  c o n d u ct 
st u d y  pr o c e d ur es  ar e  pr o hi bit e d fr o  m  t h e s cr e e ni n g  visit  u ntil st u d y  e xit. 
T h e  d e cisi o n t o  a d  mi nist er  a  pr o hi bit e d   m e di c ati o n/tr e at  m e nt   will  b e   m a d e   wit h t h e s af et y  of t h e 
st u d y  p arti ci p a nt  as t h e  pri  m ar y  c o nsi d er ati o n.    W h e n  p ossi bl e,   All er g a n s h o ul d  b e  n otifi e d  b ef or e 
t h e  pr o hi bit e d   m e di c ati o n/tr e at  m e nt is  a d  mi nist er e d. 
6. 6.     
D os e    M o difi c ati o n 
D os e   m o difi c ati o n is  n ot  a p pli c a bl e. 
6. 7.     
I nt e r v e nti o n  aft e r t h e   E n d  of t h e  St u d y 
N o i nt er v e nti o ns  aft er t h e  e  n d  of t h e st u d y  ar e  pl a n n e d. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 0 
 
7.     
Dis c o nti n u ati o n  of  St u d y I nt e r v e nti o n  a n d  P a rti ci p a nt 
Dis c o nti n u ati o n/   Wit h d r a  w al 
A  pr e  m at ur e  dis c o nti n u ati o n   will  o c c ur if  a  p ar  ti ci p a nt   w h o si g ns t h e I  C F  a n d is  d os e d  c e as es 
p arti ci p ati o n i n t h e st u d y, r e g ar dl ess  of  cir c u  m st a n c es,  b ef or e t h e  c o  m pl eti o n  of t h e  pr ot o c ol-
d efi n e d st u d y  pr o c e d ur es. 
R e as o ns f or  dis c o nti n u ati o n fr o  m t h e st u d y i n  t er v e nti o n  a n d/ or t h e st u d y   m a y i n cl u d e t h e 
f oll o  wi n g: 
•     A E 
•     L a c k  of  effi c a c y 
•     L ost t o f oll o  w- u p 
•     N o n c o  m pli a n c e   wit h st u d y  dr u g 
•     P h ysi ci a n  d e cisi o n 
•     Pr e g n a n c y 
•     Pr ot o c ol  d e vi ati o n 
•     Sit e t er  mi n at e d  b y s p o ns or 
•     St u d y t er  mi n at e d  b y s p o ns or 
•     Wit h dr a  w al  b y s u bj e ct 
•     D e at h  
•     Ot h er 
7. 1.     
Dis c o nti n u ati o n  of  St u d y I  nt e r v e nti o n 
S e e t h e  S o  A ( S e cti o n  1. 3 ) f or  d at a t o  b e  c oll e ct e d at t h e ti  m e  of  e arl y  e xit. 
P arti ci p a nts   w h o  dis c o nti n u e t h e  st u d y i nt er v e nti o n  e arl y   will  b e  e n c o ur a g e d t o st a y i n t h e st u d y 
f or t h e s af et y  ass ess  m e nts  at   D a y  3 0. 
7. 2.     
P a rti ci p a nt   Dis c o nti n u ati o n/   Wit h d r a  w al f r o  m t h e  St u d y 
•     A  p arti ci p a nt   m a y   wit h dr a  w fr o  m t h e st u d y  at   a n y ti  m e  at  his/ h er  o  w n r e q u est  or   m a y  b e 
wit h dr a  w n  at  a n y ti  m e  at t h e  dis cr eti o n  of   t h e i n v esti g at or f or s af et y,  b e h a vi or al, 
c o  m pli a n c e,  or  a d  mi nistr ati v e r e as o ns. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 1 
 
•     If t h e  p arti ci p a nt   wit h dr a  ws  c o ns e nt f or  dis cl os ur e  of f ut ur e i nf or  m ati o n, t h e s p o ns or   m a y 
r et ai n  a n d  c o nti n u e t o  us e  an y  d at a  c oll e ct e d  b ef or e s u c h   a   wit h dr a  w al  of  c o ns e nt. 
•     If  a  p arti ci p a nt   wit h dr a  ws fr o  m t h e st u d y,  h e/s h e   m a y r e q u est  d estr u cti o n  of  a n y s a  m pl es 
t a k e n  a n d  n ot t est e d,  a n d t h e i n v esti g at or   m ust  d o c u  m e nt t his i n t h e sit e st u d y r e c or ds. 
•     S e e t h e  S o  A ( S e cti o n  1. 3 ) f or  d at a t o  b e  c oll e ct e d at t h e ti  m e  of  e arl y  e xit. 
7. 3.     
L ost t o  F oll o  w   U p 
A  p arti ci p a nt   will  b e  c o nsi d er e d l ost t o f oll o  w- u p   if  h e  or s h e r e p e at e dl y f ails t o r et ur n f or 
s c h e d ul e d  visits  a n d is  u n a bl e  t o  b e  c o nt a ct e d  b y t h e st u d y sit e. 
T h e f oll o  wi n g  a cti o ns   m ust  b e t a k e n if  a  p arti ci p a nt f ails t o r et ur n t o t h e  cli ni c f or  a r e q uir e d 
st u d y  visit: 
•     T h e sit e   m ust  att e  m pt t o  c o nt a ct t h e  p arti ci p a nt  a n d r es c h e d ul e t h e   miss e d  visit  as s o o n  as 
p ossi bl e  a n d  c o u ns el t h e  p arti ci p a nt  o n t h e  i  m p ort a n c e  of   m ai nt ai ni n g t h e  assi g n e d  visit 
s c h e d ul e  a n d  as c ert ai n   w h et h er  or  n ot t h e  p arti ci p a nt   wis h es t o  a n d/ or s h o ul d  c o nti n u e i n t h e 
st u d y. 
•     B ef or e  a  p arti ci p a nt is  d e e  m e d l ost t o f oll o  w- u p, t h e i n v esti g at or  or  d esi g n e e   m ust   m a k e 
e v er y  eff ort t o r e g ai n  c o nt a ct  wit h t h e  p arti ci p a nt (  w h er e  p ossi  bl e,  3 t el e p h o n e  c alls  a n d, if 
n e c ess ar y,  a  c ertifi e d l ett er t o  t h e  p arti ci p a nt’s l ast  k n o  w n   m ailin g  a d dr ess  or l o c al  e q ui v al e nt 
m et h o ds).  T h es e  c o nt a ct  att e  m pts   will  b e  d o c u  m  e nt e d i n t h e  p arti ci p a nt’s   m e di c al r e c or d. 
•     S h o ul d t h e  p arti ci p a nt  c o nti n u e t o  b e  u nr e a c h a bl e,  h e/s h e   will  b e  c o nsi d er e d t o  h a v e 
wit h dr a  w n fr o  m t h e st u d y. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 3 
 
T a bl e  8- 1      
Effi c a c y   Ass ess  m e nts 
Ass ess  m e nt
   Ti  mi n g
 
M e as u r e  m e nt
 
Vis u al   A c uit y   
M es o pi c,  hi g h  c o ntr ast 
D  C  N  V  A f or  e a c h  e y e  a n d 
bi n o c ul arl y 
 
•   S cr e e ni n g 
•   D a y s  1,  1 4,  a n d  3 0:  
H o urs  0,  0. 2 5,  0. 5,  1,  3,  6,  8,  a n d  1 0 
•   D a y s  3  a n d  7:  
H o urs  0,  1,  a n d  3 
 
•     Vis u al  a c uit y f or  n e ar ( 4 0- c  m), i nt er  m e di at e 
( 6 6- c  m)  a n d  dist a n c e ( 4-  met er) t ar g ets   will  b e 
m e as ur e d i n   m es o pi c  a n d  p h ot o pi c  c o n diti o ns. 
•     M es o pi c  c o n diti o n is  d efi n e d  as li g hti n g  3. 2 t o 
3. 5  c a n d el as  p er s q u ar e   m et er ( c d/  m 2;  1 0 t o 
1 1 l u x)   m e as ur e d  at t h e t ar g et. 
P h ot o pi c  c o n diti o n is  d efi n e d  as li g hti n g 
≥   8 0  c d/  m2 ( 2 5 1 l u x)   m e as ur e d  at t h e t ar g et. 
P h ot o pi c,  hi g h  c o ntr ast 
D  C  N  V  A f or  e a c h  e y e  a n d 
bi n o c ul arl y 
 
•   S cr e e ni n g 
•   D a y s  1,  1 4,  a n d  3 0:  
H o urs  0,  0. 2 5,  0. 5,  1,  3,  6,  8,  a n d  1 0 
•   D a y s  3  a n d  7:  
H o urs  0,  1,  a n d  3 
 
 
M es o pi c  a n d  p h ot o pi c, 
hi g h  c o ntr ast   D  CI  V  A f or 
e a c h  e y e  a n d  bi n o c ul arl y 
•   S cr e e ni n g 
•   D a y s  1,  1 4,  a n d  3 0:  
H o urs  0,  1,  3,  6,  8,  a n d  1 0 
•   D a y s  3  a n d  7:  
H o urs  0,  1,  a n d  3 
 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 4 
 
Ass ess  m e nt
   Ti  mi n g
 
M e as u r e  m e nt
 
P  R  O   Q u esti o n n ai r es  
M es o pi c  a n d  P h ot o pi c 
N  V P T  Q   
•   D a y  1,   H o ur  0 
•   D a y  1 4,   H o ur  1 
•   D a y  3 0,   H o ur  3 
 
•     C o  m pris e d  of  1 2  q u esti o ns  o n  4 r e a di n g t as ks 
(i e, r e a di n g  a  p ar a gr a ph fr o  m  a  b o o k, r e a di n g 
e x c er pts fr o  m  a n  arti cl e i n  a  n e  ws p a p er, r e a di n g  a 
p orti o n  of  a  n utriti o n l a b el,  a n d r e a di n g  a s e cti o n 
fr o  m  a r est a ur a nt   m e n u) 
•     P arti ci p a nts   will  c o  m pl et e s p e cifi c r e a di n g t as ks 
u n d er   m es o pi c  a n d  p h ot o pi c  c o n diti o ns   wit h o ut 
a n y  n e ar- visi o n  c orr e cti o n  
•     P arti ci p a nts   will t h e n  a n s  w er  3  q u esti o ns f or  e a c h 
t as k, r ati n g t h eir  visi o n-r el at e d r e a di n g  a bilit y  a n d 
s atisf a cti o n   wit h t h eir  visi o n-r el at e d r e a di n g 
a bilit y 
•     T h er e is  n o  e x pli cit r e c all  p eri o d  us e d f or t h e 
N  V P T  Q; t h e i nt e nti o n is f or  p ati e nts t o  c o  m pl et e 
t h e   N  V P T  Q i  m  m e di at el y  aft er  c o  m pl eti n g  e a c h 
t as k. 
•     F or   m or e  d et ails  o n i nst r u cti o ns  a n d  q u esti o ns i n 
N  V P T  Q,  pl e as e s  e e  A p p e n di x    8 
PI  C  Q  
•   D a y  1,   H o ur  0 
•   D a y  3 0,   H o ur  3 
 
•     P arti ci p a nts   will  a ns  w er  2 0  q u esti o ns  a b o ut t h e 
d e gr e e t o   w hi c h t h e y   w er e i  m p a ct e d  b y t h eir 
diffi c ult y s e ei n g  u p  cl os e ( e g, f o u n d  d ail y  n e ar-
visi o n t as ks  diffi c ult,  or  e x p eri e n c e d s elf-
c o ns ci o us n ess);  or  e n g a g e d i n  c o pi n g  b e h a vi ors 
( e g,  c h a n g e d t h e f o nt si z e  o n  el e ctr o ni c s cr e e ns) 
d uri n g t h e  pr e vi o us  7  d a ys 
•     F or   m or e  d et ails  o n i nst r u cti o ns  a n d  q u esti o ns i n 
PI  C  Q,  pl e as e s e e  A p p e n di x  8   

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 5 
 
8. 2.     
S af et y   Ass ess  m e nts 
Pl a n n e d ti  m e p oi nts f or  all s af et y  ass ess  m e nts  ar e  pr o vi d e d i n t h e  S o  A ( S e cti o n  1. 3 ). 
8. 2. 1.     
Vit al  Si g ns 
Vit al si g ns   will  b e  ass ess e d  as f oll o  ws: 
•     Bl o o d  pr ess ur e  a n d  p uls e r at e   will  b e  ass ess e d. 
•     S yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e   w ill  b e   m e as ur e d  usi n g  a n  a p pr o pri at e 
s p h y g  m o  m a n o  m et er  aft er  p arti ci p a nts  h a v e  b e e n   at r est (s e at e d) f or  at l e ast  5   mi n ut es. 
Bl o o d  pr ess ur e   will  b e r e c or d e d i n   m  m   H g. 
•     H e art r at e   will  b e   m e as ur e d i n  b p  m  aft er t h e  p arti ci p a nt  h as  b e e n i n  a r esti n g st at e (s e at e d) 
f or  at l e ast  5   mi n ut es.  P uls e   will  b e  c o u nt e d f or  3 0 s e c o n ds,   m ulti pli e d  b y  2,  a n d r e c or d e d 
i n  b p  m. 
•     Bl o o d  pr ess ur e  a n d  p uls e   m e as ur e  m e nts   will   b e  ass ess e d   wit h  a  c o  m pl et el y  a ut o  m at e d 
d e vi c e.   M a n u al t e c h ni q u es   will  b e  us e d  o nl y if  a n  a ut o  m at e d  d e vi c e is  n ot  a v ail a bl e. 
M a n u al t e c h ni q u es   will  b e  us e d     o nl y  b y  a d e q u at el y tr ai n e d  p ers o n n el;   w h e n e v er  p ossi bl e, 
t h e s a  m e  p ers o n s h o ul d  p erf or  m  all   m a n u al  ass ess  m e nts  as   m u c h  as  p ossi bl e. 
•     P arti ci p a nts s h o ul d r efr ai n fr o  m s  m o ki n g  or  i n g esti n g  c aff ei n e  d uri n g t h e  3 0   mi n ut es 
pr e c e di n g t h e   m e as ur e  m e nt. 
8. 2. 2.     
P r e g n a n c y   T esti n g 
Pr e g n a n c y t est  kits   will  b e  pr o vi d e d  b y t h e i n v esti g at or  a n d   will  b e  a d  mi nist er e d  a c c or di n g t o t h e 
i nstr u cti o ns  pr o vi d e d   wit h t h e t ests.    W  O  C  B P   m ust  h a v e  a  n e g ati v e t est r es ult  b ef or e r e c ei vi n g 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 6 
 
st u d y i nt er v e nti o n.  T his t est   will  als o  b e  p erf or  m e d  at t h e   D a y  3 0  ( E arl y  E xit)  visit,  a n d   m a y  b e 
p erf or  m e d  at  a n y  ot h er  visit,  at t h e i n v esti g at or’s  dis cr eti o n.   At  e a c h   visit, t h e i n v esti g at or s h o ul d 
dis c uss  c o nt r a c e pti v e  us e  c o  m pli a n c e   wit h    W  OC  B P.   A d diti o n al  d et ails  ar e  pr o vi d e d i n 
A p p e n di x  6  . 
8. 2. 3.     
P h ot o pi c  a n d    M es o pi c,   Hi g h   C o nt r ast  C o r r e ct e d   Dist a n c e   Vis u al   A c uit y f o r 
E a c h   E y e  a n d   Bi n o c ul a rl y 
P h ot o pi c  a n d   m es o pi c,  hi g h  c o ntr ast   C  D  V  A, f or  e a c h  e y e  a n d  bi n o c ul arl y,   will  b e  ass ess e d  usi n g 
t h e  pr o vi d e d  vis u al  a c uit y  c h arts f or  dist a n c e  visi o n i n  a r o o  m   wit h   m es o pi c li g hti n g  c o n diti o ns 
( d efi n e d  b y li g hti n g  3. 2 t o  3. 5  c a n d el as [ c d]/  m2 [ 1 0 t o  1 1 l u x]   m e as ur e d  at t h e t ar g et)  a n d 
p h ot o pi c li g hti n g  c o n diti o ns  ( d efi n e d  b y li g hti n g ≥   8 0  c d/  m2 [ 2 5 1 l u x]   m e as ur e d  at t h e t ar g et). 
F or c e d  c h oi c e l ett er  b y-l ett er s c ori n g   will  b e  us e d f or  e a c h t est  a n d t h e t ot al  n u  m b er  of  c orr e ct 
l ett ers  or t h e  hi g h est  v al u e ( n u  m b er)  of t h e  gri d i d e ntifi e d ( as  a p pli c a bl e)   will  b e r e c or d e d. 
F urt h er  d et ails  ar e  o utli n e d i n t h e  Pr o c e d ur e   M a n u al. 
8. 2. 4.     
N e a r   C o nt r ast  S e nsiti vit y 
N e ar  c o ntr ast s e nsiti vit y  ass ess  m e nt   w  ill  b e  c o n d u ct e d  u n d er  p h ot o pi c  c o n diti o ns.   A 
P elli-  R o bs o n  c o ntr ast s e nsiti vit y  c h art   will  b e  us e d .  T h e l o g arit h  mi c  c o ntr ast s e nsiti vit y  v al u e  of 
t h e l ast tri pl et  of   w hi c h  at l e ast  2 l ett ers  ar e  c orr e ctl y r e a d is   m ar k e d  as t h e  c o ntr ast s e nsiti vit y. 
F urt h er  d et ails  ar e  o utli n e d i n t h e  Pr o c e d ur e   M a n u al. 
8. 2. 5.     
St u d y I nt e r v e nti o n   T ol e r a bilit y  a n d   D r o p   C o  mf o rt   Ass ess  m e nts 
T h e  pr es e n c e  a n d s e v erit y  of  o c ul ar s y  m pt o  ms   will  b e  eli cit e d fr o  m t h e  p arti ci p a nt f or  b ot h  e y es 
aft er  d osi n g.  S y  m pt o  ms, i n cl u di n g  bl urr e d  visi o n,  f or ei g n  b o d y s e ns ati o n,  p ai n,  b ur ni n g/sti n gi n g, 
t e ari n g,  a n d it c hi n g,   will  b e  cl assifi e d  usi n g  a  5-p oi nt  gr a di n g s c al e   wit h  0  =  n o n e,  + 0. 5  = tr a c e, 
+ 1  =   mil d,  + 2  =   m o d er at e,  a n d  + 3  = s e v er e.  T h e  d ur ati o n  of s y  m pt o  ms ( <  1   mi n ut e, 
1 t o  5   mi n ut es,  >  5   mi n ut es)   will  b e  c a pt ur e d  o n c e  i  m  m e di at el y  aft er t h e se c o n d  e y e is i nstill e d 
wit h  a  dr o p  of st u d y i nt er v e nti o n.   If  a n y  ot h er  o c ul ar s y  m pt o  ms  ar e  pr es e nt, t h es e   will  als o  b e 
c a pt ur e d. 
P arti ci p a nts   will  b e  as k e d t o r at e t h e  o v er all  c o mf ort  of t h e  e y e  dr o ps  usi n g  a  6- p oi nt s c al e (i e, 
s o ot hi n g,  v er y  c o  mf ort a bl e,  c o  mf ort a bl e,  u n c o  m f ort a bl e,  v er y  u n c o  mf ort a bl e,  a n d i nt ol er a bl e) 
i  m  m e di at el y  aft er t h e s e c o n d  e y e is i nstill e d   wit h  a dr o p  of st u d y i nt er v e nti o n, f or  b ot h  e y es. 
8. 2. 6.     
T e  m p o r al/ S u p r a o r bit al   H e a d a c  h e   Vis u al   A n al o g  S c al e 
P arti ci p a nts   will  b e  as k e d t o r at e t h e  d e gr e e  of  t e  m p or al  a n d s u pr a or bit al  h e a d a c h e  e x p eri e n c e d 
aft er t h e s e c o n d  e y e is i n still e d   wit h  a  dr o p  of st u d y i nt er v e nti o n, f or t h e ri g ht  a n d l eft  e y es 
s e p ar at el y.   H e a d a c h e   will  b e r e p ort e d  o n  a n  u n  m ar k e d  1 0 0-  m  m   wi d e   V  A S, r a n gi n g fr o  m  n o  p ai n 
o n t h e l eft t o   w orst  p ossi bl e  p ai n  o n t h e ri g ht. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 7 
 
8. 2. 7.     
I nt r a o c ul a r  P r ess u r e 
I  O P   m ust  b e   m e as ur e d  aft er t h e  bi o  mi cr os c o pi c e x a  m is  c o  m pl et e d  a n d  pri or t o  p u pil  dil ati o n. 
M e as ur e  m e nts   will  b e t a k e n  usi n g  a   G ol d  m a n n  a p pl   a n ati o n t o n o  m et er  affi x e d t o  a slit-l a  m p   wit h 
t h e  p arti ci p a nt s e at e d.  T h e  p arti ci p a nt  a n d slit-l a  m p s h o ul d  b e  a dj ust e d s o t h at t h e  p arti ci p a nt’s 
h e a d is fir  ml y  p ositi o n e d  o n t h e  c hi n r est  a n d  a g ai nst t h e f or e h e a d r est   wit h o ut l e a ni n g f or  w ar d 
or str ai ni n g.  Ti g ht fitti n g  n e c k  w e ar s h o ul d  b e l o os e n e d.   B ot h  e y es   will  b e t est e d,   wit h t h e ri g ht 
e y e  pr e c e di n g t h e l eft  e y e.  T h e   m e as ur er   will l o o k t hr o u g h t h e  bi n o c ul ar  vi e  w er  of t h e slit l a  m p 
at l o  w  p o  w er.  T h e t e nsi o n  k n o b   will  b e  pr es et  at  a l o  w- pr ess ur e  v al u e ( 4 t o  6   m  m   H g).  T h e 
m e as ur er   will f oll o  w t h e i  m a g e  of t h e fl u or es c ei n st ai n e d s e  mi cir cl es   w hil e sl o  wl y r ot ati n g t h e 
t e nsi o n  k n o b  u ntil t h e i n n er  b or d ers  of t h e fl u or esc ei n ri n gs t o u c h  e a c h  ot h er  at t h e   mi d p oi nt  of 
t h eir  p uls ati o n i n r es p o ns e t o t h e  c ar di a c  c y cl e. W h e n t his i  m a g e is r e a c h e d, t h e   m e as ur er   will 
t a k e  his/ h er fi n g ers  off t h e t e nsi o n  k n o b  a n d r e c or d t h e I  O P r e a di n g  al o n g wit h t h e  d at e  a n d ti  m e 
of  d a y. 
8. 2. 8.     
Slit-l a  m p   Bi o  mi c r os c o p y 
Bi o  mi cr os c o pi c  e x a  mi n ati o ns   will  b e  p erf or  m e d   usi n g  a slit-l a  m p.  T h e  e x a  mi n ati o ns   will i n cl u d e 
e v al u ati o n  of t h e  c o n diti o n  of t h e  e y eli ds,  c o nj u n cti v a,  c or n e a,  a n t eri or  c h a  m b er,  a n d iris/ p u pil. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 8 
 
E y eli d/  E y eli d    M a r gi ns/  L as h es: 
E d e  m a 
    
 
   0     
(  N o n e)     
=      N o  e d e  m a 
+ 0. 5     
( Tr a c e)     
=      L o c ali z e d,  mi ni  m al (tr a c e) s  w elli n g 
+ 1     
(  Mil d)     
=      L o c ali z e d,   mil d s  w elli n g 
+ 2     
(  M o d er at e)     =      Diff us e,   m o d er at e s  w elli n g 
+ 3     
( S e v er e)     
=      Diff us e, s e v er e s  w elli n g 
Er yt h e  m a 
    
 
   0     
(  N o n e)     
=      N o  er yt h e  m a 
+ 0. 5     
( Tr a c e)     
=      L o c ali z e d,   mi ni  m a l (tr a c e) fl us h r e d dis h  c ol or  
+ 1     
(  Mil d)     
=      L o c ali z e d,   mil d, fl us h r e d dis h  c ol or 
+ 2     
(  M o d er at e)     =      Diff us e r e d dis h  c ol or  e n c o  m p assi n g t h e  e ntir e li d   m ar gi n 
+ 3     
( S e v er e)     
=      D e e p  diff us e r e d dis h  c ol or  of li d   m ar gi ns  a n d s u p eri or 
a n d/ or i nf eri or  e y eli d 
C o nj u n cti v a (  B ul b a r): 
H y p er e  mi a     
   0     
(  N o n e)     
=      N o  h y p er e  mi a 
+ 0. 5     
( Tr a c e)     
=      Mi ni  m al (tr a c e) fl us h, r e d dis h  c ol or 
+ 1     
(  Mil d)     
=      Mil d fl us h, r e d dis h  c ol or 
+ 2     
(  M o d er at e)     =      Bri g ht r e d  c ol or 
+ 3     
( S e v er e)     
=      D e e p,  bri g ht  diff us e r e d n ess 
E d e  m a    
 
   0     
(  N o n e)     
=      N o  e d e  m a 
+ 0. 5     
( Tr a c e)     
=      L o c ali z e d,  mi ni  m al (tr a c e) s  w elli n g 
+ 1     
(  Mil d)     
=      L o c ali z e d,   mil d s  w elli n g 
+ 2     
(  M o d er at e)    =      Diff us e,   m o d er at e s  w elli n g 
+ 3     
( S e v er e)     
=      Diff us e, s e v er e s  w elli n g 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
3 9 
 
C o nj u n cti v a ( P al p e b r al): 
H y p er e  mi a     
   0     
(  N o n e)     
=      N o  h y p er e  mi a 
+ 0. 5     
( Tr a c e)     
=      Mi ni  m al (tr a c e) fl us h, r e d dis h  c ol or 
+ 1     
(  Mil d)     
=      Mil d fl us h, r e d dis h  c ol or 
+ 2     
(  M o d er at e)     =      Bri g ht r e d  c ol or 
+ 3     
( S e v er e)     
=      D e e p,  bri g ht  diff us e r e d n ess 
E d e  m a    
 
   0     
(  N o n e)     
=      N o  e d e  m a 
+ 0. 5     
( Tr a c e)     
=      L o c ali z e d,  mi ni  m al (tr a c e) s  w elli n g 
+ 1     
(  Mil d)     
=      L o c ali z e d,   mil d s  w elli n g 
+ 2     
(  M o d er at e)    =      Diff us e,   m o d er at e s  w elli n g 
+ 3     
( S e v er e)     
=      Diff us e, s e v er e s  w elli n g 
C o r n e a: 
E d e  m a    
 
   0     
(  N o n e)     
=      N o  e d e  m a 
+ 0. 5     
( Tr a c e)     
=      L o c ali z e d,   mi ni m al (tr a c e)  e pit h eli al  h a z e 
+ 1     
(  Mil d)     
=      D ull  gl ass  a p p e ar a n c e  of  e pit h eli u  m t h at   m a y i n cl u d e fi n e 
l o c ali z e d   mi cr o c ysti c  c h a n g es 
+ 2     
(  M o d er at e)    =      D ull  gl ass  a p p e ar a n c e  of t h e  e pit h eli u  m   wit h l ar g e 
n u  m b er  of  c ysti c  c h a n g es   wit h  or   wit h o ut str o  m al  e d e  m a 
  + 3     
( S e v er e)     
=      E pit h eli al  b ull a e  an d/ or str o  m al  e d e  m a, l o c ali z e d  or 
diff us e,   wit h  or   wit h o ut str o  m al stri a e 
S u p erfi ci al  P u n ct at e   K er at o p at h y 
  0     
=      
N o s u p erfi ci al  p u n ct at e  k er at o p at h y 
+ 0. 5     =      
Tr a c e 
+ 1     
=      
Mil d 
+ 2     
=      
M o d er at e 
+ 3     
=     
S e v er e 
A nt e ri o r   C h a  m b e r: 
T h e  a nt eri or  c h a  m b er   will  b e  e v al u a t e d f or  p at h ol o g y. If  p at h ol o g y is pr es e nt, it   will  b e  d es cri b e d. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 0 
 
I ris/ P u pil: 
T h e iris/ p u pil   will  b e  e v al u at e d f or  p at h ol o g y.  If  p at h ol o g y is  pr es e nt, it   will  b e  d es cri b e d. 
8. 2. 9.     
M a nif est   R ef r a cti o n 
M a nif est r efr a cti o n ( dist a n c e  a n d  n e ar)   will  b e    p erf or  m e d  a c c or di n g t o st a n d ar d  cli ni c al  pr a cti c e 
i n  b ot h   m es o pi c  a n d  p h ot o pi c  c o n diti o ns. 
If  a  p arti ci p a nt l os es ≥   1 li n e  of   C  D  V  A  or   D  C  N  V  A  c o  m p are d   wit h   H o ur  0  of t h e s a  m e st u d y 
visit  at   H o ur  1  aft er  d osi n g,  a   m a nif est r efr a c ti o n s h o ul d  b e r e p e at e d  u n d er t h e s a  m e li g hti n g 
c o n diti o ns. 
A d diti o n al  d et ails  ar e  o utli n e d i n t h e  Pr o c e d ur e   M a n u al. 
8. 2. 1 0.     Dil at e d  F u n d us c o pi c   E x a  mi n ati o n 
T h e f u n d us  ass ess  m e nts s h o ul d  b e  c o n d u ct e d t h  r o u g h  a  dil at e d  p u pil.  T h e  e x a  mi n ati o ns   will 
i n cl u d e  e v al u ati o n  of t h e l e ns,  vitr e o us, f u n d us,  an d  o pti c  n er v e.  T h e   C/  D r ati o   will  b e  ass ess e d. 
T h e i n v esti g at or s h o ul d  n ot e  if t h e  p u pil  dil at e d  n or  m all y. 
L e ns: 
L e ns   Ass ess  m e nt: 
Us e  bi o  mi cr os c o pi c  e x a  mi n ati o n, i n dir e ct l e ns  es,  dir e ct/i n dir e ct  o p ht h al  m os c o p y,  et c.,  as 
a p pr o pri at e, t o  vis u ali z e. 
L e ns  St at us: 
T h e l e ns   will  b e  e v al u at e d f or  p at h ol o g y. If  p at h ol o g y is  pr es e nt, it   will  b e  d es cri b e d. 
C at ar a ct   Ass ess  m e nt: 
U n d er  dil at e d  e x a  mi n ati o n, t h e  pr es e n c e  a n d s e  v erit y  of  n u cl e ar,  c o rti c al,  a n d  p ost eri or 
s u b c a ps ul ar  c at ar a ct l e ns  o p a citi es   will  b e  e v al u at e d.   At t h e first  dil at e d  e x a  mi n ati o n,  e a c h t y p e 
of  c at ar a ct, if  pr es e nt,   will  b e  gr a d e d  usi n g  t h e s c al e  b el o  w.   At t h e l ast f oll o  w- u p  dil at e d 
e x a  mi n ati o n,  e a c h t y p e  of  c at ar a ct   will  b e  ass ess e d  f or  c h a n g e fr o  m  b as eli n e  a n d if  c h a n g e d, t h e 
c urr e nt s e v erit y   will  b e  gr a d e d  usi n g t h e s c al e  b el o  w: 
  0     
=      N o n e 
+ 1     
=      Mil d 
+ 2     
=      M o d er at e 
+ 3     
=     S e v er e 
Vit r e o us: 
T h e  vitr e o us   will  b e  e v al u at e d f or  p at h ol o g y. If  p a t h ol o g y is  pr es e nt, it   will b e  d es cri b e d. It   will 
b e  n ot e d if t h e  c o n diti o n is  n ot  e v al u a bl e. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 1 
 
F u n d us: 
T h e f u n d us ( p ost eri or  p ol e;  p eri p h er y,   w h e n  d il at e d)   will  b e  e v al u at e d f or  p at h ol o g y. If 
p at h ol o g y is  pr es e nt, it   will  b e  d es cri b e d. It   w ill  b e  n ot e d if t h e  c o n diti o n is  n ot  e v al u a bl e. 
O pti c   N e r v e: 
T h e  o pti c  n er v e   will  b e  e v al u at e d f or  p at h ol o g y. If  p at h ol o g y is  pr es e nt, it   will  b e  d es cri b e d. It 
will  b e  n ot e d if t h e  c o n diti o n is  n ot  e v al u a bl e. 
C/  D   R ati o: 
C/  D r ati o   will  b e r e p ort e d  usi n g  a  0. 0 t o  1. 0 s c al  e. It   will  b e  n ot e d  if t h e  c o n diti o n is  n ot 
e v al u a bl e. 
8. 2. 1 1.     S ui ci d al   Ris k    M o nit o ri n g 
S ui ci d al ris k   m o nit ori n g is  n ot  a p pli c a bl e t o t his  o p ht h al  m ol o g y st u d y. 
8. 3.     
A d v e rs e   E v e nts  a n d  S  e ri o us   A d v e rs e   E v e nts 
T h e  d efi niti o ns  of  a n   A E  or  S  A E  c a n  b e f o u n d i n  A p p e n di x  2  . 
A Es   will  b e r e p ort e d  b y t h e  p arti ci p a nt ( or,   w h  e n  a p pr o pri at e,  b y  a  c ar e gi v er, s urr o g at e,  or t h e 
p arti ci p a nt’s l e g all y  a ut h ori z e d r e pr es e nt ati v e). 
T h e i n v esti g at or  a n d  a n y  q u alifi e d  d esi g n e es  ar e r es p o nsi bl e f or  d et e cti n g,  d o c u  m e nti n g,  a n d 
r e c or di n g  e v e nts t h at   m e et t h e  d efi niti o n  of  a n   A E  or  S  A E  a n d r e  m ai n r es p o nsi bl e f or f oll o  wi n g 
u p   A Es t h at  ar e s eri o us,  c o nsi d er e d r el at e d t o t h e st u d y i nt er v e nti o n  or st u d y  pr o c e d ur es,  or t h at 
c a us e d t h e  p arti ci p a nt t o  dis c o nt i n u e t h e st u d y i nt er v e nti o n (i e, r e p e at tr e at  m e nt)  or st u d y (s e e 
S e cti o n  7 ). 
8. 3. 1.     
Ti  m e  P e ri o d  a n d  F r e q u e n c y f o r   C oll e cti n g   A d v e rs e   E v e nt  a n d  S e ri o us   A d v e rs e 
E v e nt I nf o r  m ati o n 
All  S  A Es fr o  m t h e si g ni n g  of t h e I  C F  u ntil  3 0  d a ys    aft er t he l ast  d os e  of s t u d y i nt er v e nti o n   will 
b e  c oll e ct e d  at t h e ti  m e p oi nts s p e cifi e d i n t h e  S o A ( S e cti o n   1. 3 ),  a n d  as  o bs er v e d  or r e p ort e d 
s p o nt a n e o usl y  b y st u d y  p arti ci p a nts. 
All   A Es fr o  m t h e si g ni n g  of t h e I  C F  u ntil  3 0  d a ys   aft er t h e l ast  d os e  of st u d y i nt er v e n ti o n   will  b e 
c oll e ct e d  at t h e ti  m e p oi nts s p e cifi e d i n t h e  S o  A ( S e cti o n  1. 3 ),  a n d  as  o bs er v e d  or r e p ort e d 
s p o nt a n e o usl y  b y st u d y  p arti ci p a nts. 
M e di c al  o c c urr e n c es t h at  b e gi n  b ef or e t h e st art  of st u d y i nt er v e nti o n,  b ut  aft er  o bt ai ni n g 
i nf or  m e d  c o ns e nt   will  b e r e c or d e d i n t h e   A E s e cti o n  of t h e  e  C  R F. 
All  S  A Es   will  b e r e c or d e d  a n d r e p ort e d t o t h e s p  o ns or  or  d esi g n e e   wit hi n  2 4  h o urs,  as i n di c at e d 
i n A p p e n di x  2  .  T h e i n v esti g at or   will s u b  mit  a n y  u p d at ed  S  A E  d at a t o t h e s p o ns or   wit hi n 
2 4  h o urs  of it  b ei n g  a v ail a bl e. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 2 
 
I n v esti g at ors  ar e  n ot  o bli g at e d t o  a cti v el y s e e k   A E  or  S  A E i nf or  m ati o n  aft er  c o n cl usi o n  of t h e 
st u d y  p arti ci p ati o n.   H o  w e v er, if  t h e i n v esti g at or l e ar ns  of  a n y S  A E, i n cl u di n g  a  d e at h,  at  a n y 
ti  m e  aft er  a  p arti ci p a nt  h as  b e e n  dis c h ar g e d fr o  m t h e st u d y,  a n d  h e/s h e  c o nsi d ers t h e  e v e nt t o  b e 
r e as o n a bl y r el at e d t o t h e st u d y i nt er v e nti o n  or st u d y p arti ci p ati o n, t h e i n v esti g at or   m ust  pr o  m ptl y 
n otif y t h e s p o ns or. 
T h e   m et h o ds  of r e c or di n g,  e v al u ati n g,  a n d  ass ess i n g  c a us alit y  of   A Es  a n d  S  A Es  a n d t h e 
pr o c e d ur es f or  c o  m pl eti n g  a n d tr a ns  mitti n g  S  A E r e p orts  ar e  pr o vi d e d i n  A p p e n di x  2  . 
8. 3. 2.     
M et h o d  of   D et e cti n g   A d v e rs e   E v e nts  a n d  S e ri o us   A d v e rs e   E v e nts 
C ar e   will  b e t a k e n  n ot t o i ntr o d u c e  bi as   w h e n  d et e cti n g   A Es  a n d/ or  S  A Es.   O p e n- e n d e d  a n d 
n o n-l e a di n g  v er b al  q u esti o ni n g  of  t h e  p arti ci p a nt is t h e  pr ef err e d   m et h o d t o i n q uir e  a b o ut 
A E  o c c urr e n c es. 
8. 3. 3.     
F oll o  w- u p  of   A d v e rs e   E v e nts  a n d  S e ri o us   A d v e rs e   E v e nts 
Aft er t h e i niti al   A E/ S  A E r e p ort,   t h e i n v esti g at or is r e q uir e d t o pr o a cti v el y f oll o  w  e a c h  p arti ci p a nt 
at s u bs e q u e nt  visits/ c o nt a cts.   All   A Es/ S  A Es   w ill  b e f oll o  w e d  u ntil r es ol uti o n, st a bili z ati o n, t h e 
e v e nt is  ot h er  wis e  e x pl ai n e d,  or t h e  p arti ci p a n t is l ost t o f oll o  w- u p ( as  d efi n e d i n  S e cti o n 7. 3 ). 
T h e i n v esti g at or is  o bli g at e d t o  p erf or  m  or  arr a n g e  f or t h e  c o n d u ct  of s u p pl e  m e nt al 
m e as ur e  m e nts  a n d/ or  e v al u ati o ns  as   m e di c all y i n di  c at e d  or  as r e q u est e d  b y   All er g a n t o  el u ci d at e 
t h e  n at ur e  a n d/ or  c a us alit y  of t h e   A E  or  S  A E  as f ull y  as  p ossi bl e.  T his   m a y i n cl u d e  a d diti o n al 
l a b or at or y t ests  or i n v esti g atio ns,  hist o p at h ol o gi c al  e x a  mi n ati o ns,  or  c o ns ult ati o n   wit h  ot h er 
h e alt h  c ar e  pr of essi o n als. 
If  a  p arti ci p a nt  di es  d uri n g  p arti ci p ati o n i n t h e stu d y, t h e i n v esti g at or   will   pr o vi d e   All er g a n   wit h 
a  c o p y  of  a n y  p ost  m ort e  m fi n di n gs i n cl u di n g  hist o p at h ol o g y. 
If  a  p arti ci p a nt is  h os pit ali z e d  a n d  dis c h ar g e d, f oll o  w- u p  att e  m pts   m ust  b e   m a d e t o  o bt ai n t h e 
dis c h ar g e s u  m  m ar y fr o  m t h e  h os pit al  a n d, if  o bt ai n e d, it s h o ul d  b e s e nt t o t h e s p o ns or. 
N e  w  or  u p d at e d i nf or  m ati o n   will  b e r e c or d  e d i n t h e  ori gi n all y  c o  m pl et e d  e  C  R F. 
T h e i n v esti g at or   will s u b  mit  a n y  u p d at e d  S  A E  d at a  t o   All er g a n   wit hi n  2 4  h o urs  of r e c ei pt  of t h e 
i nf or  m ati o n. 
8. 3. 4.     
R e g ul at o r y   R e p o rti n g   R e q ui r e  m e nts f o r  S e ri o us   A d v e rs e   E v e nts 
•     Pr o  m pt  n otifi c ati o n  b y t h e i n v esti g at or t o t h e s p o ns or  of  a n  S  A E is  ess e nti al s o t h at l e g al 
o bli g ati o ns  a n d  et hi c al r es p o nsi bil iti es t o  w ar ds t h e s af et y  of  p arti ci p a nts  a n d t h e s af et y  of 
a st u d y i nt er v e nti o n  u n d er  cli ni c al i n v esti g ati o n  ar e   m et.  
•     T h e s p o ns or  h as  a l e g al r es p o nsi bilit y t o  n o tif y  b ot h t h e l o c al r eg ul at or y  a ut h orit y  a n d 
ot h er r e g ul at or y  a g e n ci es  a b o ut t h e s af e t y  of  a st u d y i nt er v e nti o n  u n d er  cli ni c al 
i n v esti g ati o n.  T h e s p o ns or   will  c o  m pl y   wit h  c o u ntr y-s p e cifi c r e g ul at or y r e q uir e  m e nts 
r el ati n g t o s af et y r e p orti n g t o t h e r e g ul at or y  a ut h orit y, I  R  Bs/I E  Cs,  a n d i n v esti g at ors.  

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 3 
 
•     I n v esti g at or s af et y r e p orts   m ust  b e  pr e p ar e d f or s us p e ct e d  u n e x p e ct e d s eri o us  a d v ers e 
r e a cti o ns  a c c or di n g t o l o c al r eg ul at or y r e q uir e  m e nts  a n d s p o ns or  p oli c y  a n d f or  w ar d e d t o 
i n v esti g at ors  as  n e c ess ar y. 
•     A n i n v esti g at or   w h o r e c ei v es  a n i n v esti g at or   s af et y r e p ort  d es cri bi n g  a n  S  A E  or  ot h er 
s p e cifi c s af et y i nf or  m ati o n ( e g, s u  m  m ar y  or  listi n g  of  S  A Es) fr o  m t he s p o ns or   will r e vi e  w 
a n d t h e n fil e it  al o n g   wit h t h e I  B  a n d   will  n ot if y t h e I  R  B/I E  C, if  a p pr o pri at e  a c c or di n g t o 
l o c al r e q uir e  m e nts. 
8. 3. 5.     
P r e g n a n c y 
•     If  a  pr e g n a n c y is  c o nfir  m e d  aft er t h e  p arti ci p a nt  h as r e c ei v e d t h e st u d y i nt er v e nti o n, t h e 
p arti ci p a nt   m a y  c h o os e t o  e xit  t h e st u d y  aft er  a p pr o pri at e s af et y f oll o  w- u p  or t o r e  m ai n i n 
t h e st u d y f or  all s af et y  a n d  effi c a c y f oll o  w- u p  ass ess  m e nts t hr o u g h t h e  E  O S  visit. 
•     D et ails  of  all  pr e g n a n ci es i n f e  m al e  p arti ci p a nts  a n d, if i n di c at e d, f e  m al e  p art n ers  of   m al e 
p arti ci p a nts   will  b e  c oll e ct e d  aft er t h e st art  of st u d y i nt er v e nti o n  a n d t hr o u g h t h e  d ur ati o n 
of t h e  pr e g n a n c y . 
•     If  a  pr e g n a n c y is r e p ort e d, t h e i n v esti g at or s h o ul d i nf or  m   All er g a n   wit hi n  2 4  h o urs  of 
l e ar ni n g  of t h e  pr e g n a n c y  a n d s h o ul d f oll o  w t h e  pr o c e d ur es  o utli ne d i n A p p e n di x  6.   
•     A b n or  m al  pr e g n a n c y  o ut c o  m es ( e g, s p o nt a n e  o us  a b orti o n, f et al  d e at h, still birt h, 
c o n g e nit al  a n o  m ali es,  e ct o pi c  pr e g n a n c y)  or  g e n eti c  a b n or  m aliti es (  w h et h er l e a di n g t o  a n 
el e cti v e  a b orti o n  or  n ot)  ar e  c o nsi d er e d  S  A Es. 
8. 3. 6.     
M e di c ati o n   E r r o rs 
M e di c ati o n  err or r ef ers t o  a n y    u ni nt e n d e d  err or i n t h e  d osi n g  a n d/ or  a d  mi nistr ati o n  of t h e st u d y 
i nt er v e nti o n  as  p er i nstr u cti o ns i n t h e  pr ot o c ol.   M e di c ati o n  err ors  g e n er all y f all i nt o  4  c at e g ori es 
as f oll o  ws: 
•     Wr o n g st u d y  dr u g 
•     Wr o n g  d os e (i n cl u di n g  d osi n g r e gi  m e n, st   r e n gt h, f or  m,  c o n c e ntr ati o n,  a  m o u nt) 
•     Wr o n g r o ut e  of  a d  mi nistr ati o n 
•     Wr o n g  p arti ci p a nt (i e,  n ot  a d  mi nist er   e d t o t h e i nt e n d e d  p arti ci p a nt) 
8. 4.     
T r e at  m e nt  of   O v e r d os e 
Tr e at  m e nt  of  o v er d os e is  n ot  a p pli c a bl e t o t his  o p ht h al  m ol o g y st u d y. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 5 
 
H e alt h  c ar e r es o ur c e  utili z ati o n  o ut c o  m es  ar e   n ot  e v al u at e d i n t his st u d y. 
F or  a d diti o n al  d et ail  o n  P  R  O  ass ess  m e nts,  pl e as e s e e t h e  P  R  O   Ass ess  m e nts   M a n u al . 
9.     
St atisti c al   C o nsi d e r ati o ns 
9. 1.     
St atisti c al   H y p ot h es es 
T h e  n ull  a n d  alt er n ati v e  h y p ot h es es f or  t h e  pri  m ar y  effi c a c y  e n d p oi nt  ar e: 
•     H 0:   A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  a n d  v e hi cl e  d os e d  bil at er all y,  o n c e  d ail y f or  3 0  d a ys 
h a v e t h e s a  m e  eff e ct i n t h e  pr o p orti o n  of  p arti ci p a nts   g ai ni n g  3 li n es  or   m or e i n   m es o pi c, 
hi g h  c o ntr ast,  bi n o c ul ar   D  C N  V A  at   D a y  3 0,   H o ur  3; 
•     H A :   A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  a n d  v e hi cle  d os e d  bil at er all y,  o n c e  d ail y f or  3 0 
d a ys  d o  n ot  h a v e t h e s a  m e  eff e ct i n t h e  pr o p or ti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or   m or e 
i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ular   D  C  N  V A  at   D a y  3 0,   H o ur  3. 
T h e  n ull  a n d  alt er n ati v e  h y p ot h es es f or t h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt  ar e: 
•     H 0:   A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  a n d  v e hi cl e  d os e d  bil at er all y,  o n c e  d ail y f or  3 0  d a ys 
h a v e t h e s a  m e  eff e ct i n t h e  pr o p orti o n  of  p arti ci p a nts   g ai ni n g  3 li n es  or   m or e i n   m es o pi c, 
hi g h  c o ntr ast,  bi n o c ul ar   D  C N  V A  at   D a y  3 0,   H o ur  6; 
•     H A :   A  G  N- 1 9 0 5 8 4  o p ht h al  mi c s ol uti o n  a n d  v e hi cle  d os e d  bil at er all y,  o n c e  d ail y f or  3 0 
d a ys  d o  n ot  h a v e t h e s a  m e  eff e ct i n t h e  pr o p or ti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or   m or e 
i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ular   D  C  N  V A  at   D a y  3 0,   H o ur  6. 
9. 2.     
S a  m pl e  Si z e   D et e r  mi n ati o n 
T h e  pri  m ar y  effi c a c y  e n d p oi nt is  t h e  pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or   m or e i n 
m es o pi c,  hi g h  c o ntr ast,  bi n o c ul  ar   D  C  N  V  A  at   D a y  3 0,   H o ur  3.  T h e  k e y s e c o n d ar y  effi c a c y 
e n d p oi nt is t h e  pr o p orti o n  of  p ar ti ci p a nts  g ai ni n g  3 li n es  or   m or e i n   m es o pi c,  hi g h  c o ntr ast, 
bi n o c ul ar   D  C  N  V  A  at   D a y  3 0,   H o ur  6.  T h e s a  m pl e  si z e  c al c ul ati o n is  b as e d  o n t h e  k e y s e c o n d ar y 
effi c a c y  e n d p oi nt.  T h e  v e hi cl e  gr o u p i nt er v e nti o n  eff e ct   w as  8. 8  %  a n d t h e   A  G  N- 1 9 0 5 8 4  eff e ct 
w as  1 8. 4  % i n t h e first  P h as e  3  St u d y  1 8 8 3- 3 0 1- 0 1 3.   Ass u  mi n g t h e s a  m e  u n d erl yi n g r es p o ns e 
r at es f or  St u d y  1 8 8 3- 3 0 2- 0 1 3,  a p pr o xi  m at el y  2 0 0  p arti ci p a nts   will  b e r eq uir e d i n  e a c h st u d y 
i nt er v e nti o n  gr o u p t o  d et e ct t h e  a b o v e  diff er e n c e   wit h  a  p o  w er  of 8 0  %  or  gr e at er  at t h e  2-si d e d 
5  % si g nifi c a n c e l e v el. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 6 
 
9. 3.     
P o p ul ati o ns f o r   A n al ys es 
T h e  a n al ysis  p o p ul ati o ns   will  c o nsist  of   p arti ci p a nts  as  d efi n e d  b el o  w: 
•     T h e I T T  p o p ul ati o n i n cl u d es  all r a n d o  mi z e d  p ar ti ci p a nts.  P arti ci p a nts   will  b e s u  m  m ari z e d 
a c c or di n g t o t h e r a n d o  mi z e d st u d y i nt er v e nti o n. 
•     T h e s af et y  p o p ul ati o n i n cl u d es  all tr e at e d  p arti ci p a nts   w h o r e c ei v e   ≥   1  a d  mi nistr ati o n  of 
st u d y i nt er v e nti o n.  P arti ci p a nts   will  b e s u  m  m ari z e d  a c c or di n g t o t h e st u d y i nt er v e nti o n 
t h e y  a ct u all y r e c ei v e d. 
9. 4.     
St atisti c al   A n al ys es 
T h e  S  A P   will  b e  d e v el o p e d  a n d fi n ali z e d  b ef or e  d at a b as e l o c k  a n d  u n  m as ki n g  a n d   will  d es cri b e 
t h e  p arti ci p a nt  p o p ul ati o ns t o  b e i n cl u d e d i n t h e  a n al ys es,  a n d  pr o c e d ur es f or  a c c o u nti n g f or 
missi n g,  u n us e d,  a n d s p uri o us  d at a.  T his s e cti o n is    a s u  m  m ar y  of t h e  pl a n n e d st atisti c al  a n al ys es 
of t h e  pri  m ar y  a n d s e c o n d ar y  e n d p oi nts. 
9. 4. 1.     
Effi c a c y   A n al ys es 
T h e  effi c a c y  a n al ys es   will  b e  b as e d  o n t h e I T T  p o p ul ati o n.   B as eli n e f or  effi c a c y is  d efi n e d  as t h e 
l ast  n o n  missi n g  effi c a c y  ass ess  m e nt  b ef or e t h e first  d os e  of st u d y i nt er v e nti o n.   All st atisti c al 
t ests   will  b e  2-si d e d  h y p ot h esis t ests  p erf or  m e d  at t h e  5  % l e v el  of  si g nifi c a n c e f or   m ai n  eff e cts. 
All  c o nfi d e n c e i nt er v als   will  b e  2-si d e d  9 5  %  c o nf  i d e n c e i nt er v als,  u nl ess st at e d  ot h er  wis e.  
9. 4. 1. 1.     A n al ysis   E n d p oi nts 
T h e  pri  m ar y  a n d s e c o n d ar y  effi c a c y  e n d p oi nts  ar e lis  t e d  b el o  w  a n d  a n al ys es   will  b e  d es cri b e d i n 
t h e f oll o  wi n g s e cti o ns.  T h e  a n al ys es f or  ot h er effi c a c y  e n d p oi nts list e d  b el o  w   will  b e  d es cri b e d 
i n t h e  S  A P. 
P ri  m a r y   Effi c a c y   E n d p oi nt: 
•     Pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or  m or e i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar 
D  C  N  V A  at   D a y  3 0,   H o ur  3. 
K e y  S e c o n d a r y   Effi c a c y   E n d p oi nt: 
•     Pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or  m or e i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar 
D  C  N  V A  at   D a y  3 0,   H o ur  6. 
S e c o n d a r y   Effi c a c y   E n d p oi nts: 
1.    Pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3-li n es  or  m or e i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar, 
D  C  N  V A  at   D a y  3 0,   H o ur  8. 
2.    C h a n g e fr o  m  b as eli n e   m es o pi c,  hi g h  c o ntr a  st,  bi n o c ul ar   D  C  N  V A l ett ers  at   D a y  3 0, 
H o ur  0. 5. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 7 
 
3.    Pr o p orti o n  of  p arti ci p a nts  a c hi e vi n g  2 0/ 4 0  or  b ett er i n  p h ot o pi c,  hi g h  c o ntr ast,  bi n o c ul ar, 
D  C  N  V A  at   D a y  3 0,   H o ur  1. 
4.    M es o pi c   N  V P T  Q  P erf or  m a n c e s c or e   m e a n  c h a   n g e fr o  m  b as eli n e  at   D a y  3 0,   H o ur  3. 
5.    C h a n g e fr o  m  b as eli n e  p h ot o pi c,  hi g h  c o ntr ast,  bi n o c ul ar   D  CI  V A l ett ers  at   D a y  3 0,   H o ur  3. 
6.    Pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3-li n es  or  m or e i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar, 
D  C  N  V A  at   D a y  3 0,   H o ur  1 0. 
7.    C h a n g e fr o  m  b as eli n e   m es o pi c,  hi g h  c o ntr a  st,  bi n o c ul ar   D  C  N  V A l ett ers  at   D a y  3 0, 
H o ur  0. 2 5.  
8.    Pr o p orti o n  of  p arti ci p a nts  a c hi e vi n g  2 0/ 4 0  or  b ett er i n  p h ot o pi c,  hi g h  c o ntr ast,  bi n o c ul ar, 
D  C  N  V A  at   D a y  3 0,   H o ur  3. 
9.    M es o pi c   N  V P T  Q  S atisf a cti o n s c or e   m e a n  c h a   n g e fr o  m  b as eli n e  at   D a y  3 0,   H o ur  3. 
1 0.  PI  C  Q   C o pi n g s c or e   m e a n  c h a n g e fr o  m  b as eli n e  at   D a y  3 0,   H o ur  3. 
1 1.  PI  C  Q I  m p a ct s c or e   m e a n  c h a n g e fr o  m  b as eli n e  at   D a y  3 0,   H o ur  3. 
9. 4. 1. 2.     P ri  m a r y   A n al ys es 
T h e  pr o p orti o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or    m or e i n   m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar 
D  C  N  V  A  at   D a y  3 0,   H o ur  3   will  b e  a n al y z e d  usi n g  c h  i-s q u ar e t est.   Missi n g  d at a   will  b e r e g ar d e d 
as  3-li n e  g ai n f ail ur e. 
9. 4. 1. 3.     S e c o n d a r y   A n al ys es 
T h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt is t h e  pr o p orti  o n  of  p arti ci p a nts  g ai ni n g  3 li n es  or   m or e i n 
m es o pi c,  hi g h  c o ntr ast,  bi n o c ul ar     D  C  N  V  A  at   D a y  3 0,   H o ur  6.  
T h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt   will  b e  a n al y z e d    usi n g  a  c hi-s q u ar e t est.   Missi n g  d at a   will 
b e r e g ar d e d  as  3-li n e  g ai n f ail ur e.  
All  a n al ys es f or  ot h er s e c o n d ar y  effi c a c y  e n d p oi nts   will  b e  b as e d  o n  o bs er v e d  d at a  o nl y. 
S e c o n d ar y  e n d p oi nts  1,  3,  6,  a n d  8   will  b e  a n al y z e d  usi n g  a  c hi-s q u ar e t est.  S e c o n d ar y  e n d p oi nts 
2,  4,  5,  a n d  7   will  b e  a n al y z e d  usi n g   M  M  R  M   wit h st u d y i nt er v e nti o n  gr o u p,  visit,  visit  b y st u d y 
i nt er v e nti o n  gr o u p i nt er a cti o n, a g e  gr o u p,  b as eli n e  bi n o c ul ar  D  C  N  V  A s e v erit y, iris  c ol or, 
e  m  m etr o p es/ n o n- e  m  m etr o p es,  b as eli n e  v al u e,  a n d  b as eli n e  v al u e  b y  visit i nt er a cti o n  as fi x e d 
eff e cts.  T h e   wit hi n- p arti ci p a nt  c o rr el ati o n  err or str u ctur e is  u nstr u ct ur e d.  S e c o n d ar y  e n d p oi nts  9, 
1 0,  a n d  1 1   will  b e  a n al y z e d  usi n g  a n al ysis  of  c o v ari a n c e   wit h st u d y i nt er v e nti o n  gr o u p,  a g e 
gr o u p,  b as eli n e  bi n o c ul ar   D  C  N  V  A s e v erit y,  iris  c ol or,  e  m  m etr o p es/ n o n- e  m  m etr o p es,  a n d 
b as eli n e  d o  m ai n s c or e  as fi x e d  eff e cts. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 8 
 
T o  c o ntr ol t h e  o v er all  T y p e  1  err or r at e i n t h e   effi c a c y  a n al ysis,  a  g at e k e e pi n g t esti n g  pr o c e d ur e 
will  b e  us e d.  S e c o n d ar y  effi c a c y  e n d p oi nts   will  b e   t est e d  o nl y if t h e  pri  m ar y  effi c a c y  e n d p oi nt is 
st atisti c all y si g nifi c a nt.   A  pr o p er   m ulti pl e  c o  m p aris o n  pr o c e d ur e   will  b e  pr e-s p e cifi e d i n t h e  S  A P. 
9. 4. 2.     
S af et y   A n al ys es 
T h e s af et y  a n al ysis   will  b e  p erf or  m e d  usi n g t h e s a f et y  p o p ul ati o n  a n d   will  b e f ull y  d efi n e d i n t h e 
S  A P.  T h e s af et y  p ar a  m et ers   will i n cl u d e   A Es,   vit al si g ns ( bl o o d  pr ess ur e  a n d  h e art r at e), 
m es o pi c  a n d  p h ot o pi c,  hi g h  c o nt  r ast,  bi n o c ul ar   C  D  V  A,  n e ar c o ntr ast s e nsiti vit y, st u d y 
i nt er v e nti o n t ol er a bilit y  a n d  dr o p  c o  mf ort  ass ess  m e nts, t e  m p or al/s u pr a or bit al  h e a d a c h e 
ass ess  m e nt  usi n g   V  A S, I  O P, slit-l a  m p  bi o  mi cr os c o p y,   m a nif est r efr a cti o n,  dil at e d f u n d us c o pi c 
e x a  mi n ati o n,  a n d  pr e g n a n c y t est.  F or  e a c h s a f et y  p ar a  m et er, t h e l ast  n o n  missi n g s af et y 
ass ess  m e nt  b ef or e t h e first  d os e  of st u d y i nt e r v e nti o n   will  b e  us e d  as t h e  b as eli n e. 
9. 4. 2. 1.     A d v e rs e   E v e nts 
A n   A E   will  b e  c o nsi d er e d  a  T E  A E if t h e   A E  b e g a n  or   w ors e n e d (i n cr e as e d i n s e v erit y  or  b e c a  m e 
s eri o us)  o n  or  aft er t h e  d at e  of  t h e first  d os e  of st u d y i nt er v e nti o n.   H o  w e v er,  a n   A E t h at  o c c urs 
m or e t h a n  3 0  d a ys  aft er t h e l ast  d os e  of st  u d y i nt er v e nti o n   will  n ot  b e  c o u nt e d  as  a  T E  A E. 
A n   A E   will  b e  c o nsi d er e d  a tr e at  m e nt- e  m er g e nt   S  A E if it is  a  T E  A E t h at  a d diti o n all y   m e ets  a n y 
S  A E  crit eri a. 
T h e  n u  m b er  a n d  p er c e nt a g e  of  p arti ci p a nts r e p orti n g  T E  A Es  d uri n g t h e st u d y   will  b e t a b ul at e d 
b y s yst e  m  or g a n  cl ass  a n d  pr ef err e d t er  m  a n d  b y s y st e  m  or g a n  cl ass,  pr ef err e d t er  m,  a n d s e v erit y. 
If   m or e t h a n  o n e   A E is  c o d e d t o t h e s a  m e  pr ef err e d t er  m f or t h e s a  m e  p arti ci p a nt, t h e  p arti ci p a nt 
will  b e  c o u nt e d  o nl y  o n c e f or t h at  pr ef err e d t er  m  usi n g t h e   m ost s e v er e  a n d   m ost r el at e d 
o c c urr e n c e f or t h e s u  m  m ari z ati o ns  b y s e v erit y  a n d  b y r el ati o ns hi p t o st u d y i nt er v e nti o n. 
S u  m  m ar y t a bl es   will  b e  pr o vi d e d f o r  p arti ci p a nts   wit h  S  A Es  a n d  p arti ci p a nts   wit h   A Es l e a di n g t o 
dis c o nti n u ati o n if  5  or   m or e  p arti ci p a nts r e p ort e d  s u c h  e v e nts.  Listi n gs  of  all   A Es,  S  A Es,  a n d 
A Es l e a di n g t o  dis c o nti n u ati o n  b y  p a  rti ci p a nt   will  b e  pr es e nt e d. 
9. 4. 2. 2.     Ot h e r  S af et y   A n al ys es 
All  ot h er s af et y  v ari a bl es   will  b e  a n al y z e d   wit h   d es cri pti v e st atisti cs.   D e t ail e d   m et h o ds f or t h e 
a n al ysis  of  ot h er s af et y  v ari a bl e s   will  b e  d es cri b e d i n t h e  S  A P. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
4 9 
 
A d diti o n al  P  R  O  e x pl or at or y  a n al ys es   will  b e  d es cri b e  d i n  a s e p ar at e  S  A P t o  b e fi n ali z e d  pri or t o 
d at a b as e l o c k. 
9. 5.     
I nt e ri  m   A n al ys es 
N o i nt eri  m  a n al ysis is  pl a n n e d. 
9. 5. 1.     
D at a    M o nit o ri n g   C o  m  mitt e e 
N ot  a p pli c a bl e. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
5 0 
 
1 0.     
S u p p o rti n g   D o c u  m e nt ati o n  a n d   O p e r ati o n al   C o nsi d e r ati o ns 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
5 1 
 
1 0. 1.     
A p p e n di x  1:   R e g ul at o r y,   Et hi c al,  a n d  St u d y   O v e rsi g ht 
C o nsi d e r ati o ns 
1 0. 1. 1.     R e g ul at o r y  a n d   Et hi c al   C o nsi d e r ati o ns 
•     T his st u d y   will  b e  c o n d u ct e d i n  a c c or d a n c e   w  it h t h e  pr ot o c ol  a n d   wit h t h e f oll o  wi n g: 
o    C o ns e ns us  et hi c al  pri n ci pl es  d eri v e d fr o  m   i nt er n ati o n al  g ui d eli n es i n cl u di n g t h e 
D e cl ar ati o n  of   H elsi n ki  a n d   C o u n cil f or I nt er n ati o n al   Or g a ni  z ati o ns  of   M e di c al  S ci e n c es 
I nt er n ati o n al  Et hi c al   G ui d eli n es 
o    A p pli c a bl e I  C  H/I nt er n ati o n al   Or g a ni z a  ti o n f or  St a n d ar di z ati o n   G  C P  g ui d eli n es 
o    A p pli c a bl e l a  ws  a n d r e g ul ati o ns 
•     T h e  pr ot o c ol,  pr ot o c ol  a  m e n d  m e nts, I  C F,  I  B,  a n d  ot h er r el e v a nt  d o c u  m e nts ( e g, 
a d v ertis e  m e nts)   m ust  b e s u b  mitt e d t o  a n I  R  B/I E  C  b y t h e i n v esti g at or  a n d r e vi e  w e d  a n d 
a p pr o v e d  b y t h e I  R  B/I E  C  b ef or e t h e st u d y is i niti at e d. 
•     A n y  a  m e n d  m e nts t o t h e  pr ot o c ol   will r e q uir  e I  R  B/I E  C  a p pr o v al  b ef or e i  m pl e  m e nt ati o n  of 
c h a n g es   m a d e t o t h e st u d y  d esi g n,  e x c e pt f or  c h a n g es  n e c ess ar y t o  e li  mi n at e  a n i  m  m e di at e 
h a z ar d t o st u d y  p arti ci p a nts.  
•     T h e i n v esti g at or   will  b e r e s p o nsi bl e f or t h e f oll o  wi n g: 
o    Pr o vi di n g   writt e n s u  m  m ari es  of t h e st at us  of  t h e st u d y t o t h e I  R  B/I E  C  a n n u all y  or   m or e 
fr e q u e ntl y i n  a c c or d a n c e   wit h t h e r e q uir e  m e nts,  p oli ci es,  a n d  pr o c e d ur es  est a blis h e d  b y 
t h e I  R  B/I E  C 
o    N otif yi n g t h e I  R  B/I E  C  of  S  A Es  or  ot h er si g n  ifi c a nt s af et y fi n di n gs  as r e q uir e d  b y 
I  R  B/I E  C  pr o c e d ur es 
o    Pr o vi di n g  o v ersi g ht  of t h e  o v er all  c o n d u ct  of  t h e st u d y  at t h e sit e  a n d  a d h er e n c e t o 
r e q uir e  m e nts  of  a p pli c a bl e l o c al r e g ul ati o ns, f or  e x a  m pl e  2 1   C F  R, I  C  H  g ui d eli n es, t h e 
I  R  B/I E  C,  a n d  E ur o p e a n r e g ul ati o n  5 3 6/ 2 0 1 4 f or  cli ni c al st u di es (if  a p pli c a bl e) 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
5 2 
 
1 0. 1. 3.     I nf o r  m e d   C o ns e nt  P r o c ess 
•     T h e i n v esti g at or  or  his/ h er r e pr es e nt ati v e  will  e x pl ai n t h e  n at ur e    of t h e st u d y t o t h e 
p arti ci p a nt  or  his/ h er l e g all y  a ut h ori z e d r e pr es e nt ati v e  a n d  a ns  w er  all  q u esti o ns r e g ar di n g t h e 
st u d y.  
•     P arti ci p a nts   m ust  b e i nf or  m e d t h at t h eir  p art i ci p ati o n is  v ol u nt ar y.  P arti ci p a nts   will  b e 
r e q uir e d t o si g n  a st at e  m e nt  of i nf or  m e d  c o ns e nt t h at   m e ets t h e r e q uir e  m e nts  of  2 1   C F  R  5 0, 
l o c al r e g ul ati o ns, I  C  H  g ui d eli n es,   H e alt h I ns ur a n c e  P ort a bilit y  a n d   A c c o u nt a bilit y   A ct 
r e q uir e  m e nts,   w h er e  a p pli c a bl e,  an d t h e I  R  B/I E  C  or st u d y  c e nt er.  
•     T h e   m e di c al r e c or d   m ust i n cl u d e  a st at e  m e nt  t h at   writt e n i nf or  m e d  c o ns e nt   w as  o bt ai n e d 
b ef or e t h e  p arti ci p a nt   w as  e nr oll e d i n t h e st u d y  a n d t h e  d at e t h e   writt e n  c o ns e nt   w as  o bt ai n e d. 
T h e  a ut h ori z e d  p ers o n  o bt ai n i n g t h e i nf or  m e d  c o ns e nt   m ust  als o si g n t h e I  C F. 
•     P arti ci p a nts   m ust  b e r e- c o ns e nt e d t o t h e   m ost   c urr e nt  v ersi o n  of t he I  C F(s)  d uri n g t h eir 
p arti ci p ati o n i n t h e st u d y.  
•     A  c o p y  of t h e I  C F(s)   m ust  b e  pr o vi d e d t o   t h e  p arti ci p a nt  or t h e p arti ci p a nt’s l e g all y 
a ut h ori z e d r e pr es e nt ati v e. 
1 0. 1. 4.     D at a  P r ot e cti o n 
•     P arti ci p a nts   will  b e  assi g n e d  a  u ni q u e i d e ntifi er .   A n y  p arti ci p a nt r e c or ds  or  d at as ets t h at  ar e 
tr a nsf err e d t o t h e s p o ns or   will  c o nt ai n t h e i d e ntifi er  o nl y;  p arti ci p a nt  n a  m es  or  a n y 
i nf or  m ati o n   w hi c h   w o ul d   m a k e t h e  p arti ci p a nt i d e ntifi a bl e   will  n ot  b e tr a nsf err e d.  
•     T h e  p arti ci p a nt   m ust  b e i nf or  m e d t h at  his/ h er  p ers o n al st u d y-r el at e d  d at a   will  b e  us e d  b y t h e 
s p o ns or i n  a c c or d a n c e   wit h l o c al  d at a  pr ot e cti o n l a  ws.  T h e l e v el  of  dis c l os ur e   m ust  als o  b e 
e x pl ai n e d t o t h e  p arti ci p a nt.  
•     T h e  p arti ci p a nt   m ust  b e i nf or  m e d t h at  his/ h er   m e di c al r e c or ds   m a y  b e  e x a  mi n e d  b y   Cli ni c al 
Q u alit y   Ass ur a n c e  a u dit ors  or  ot h er  a ut h or  i z e d  p ers o n n el  a p p oi nt e d  b y t h e s p o ns or,  b y 
a p pr o pri at e I  R  B/I E  C   m e  m b ers,  a n d  b y i n s p e ct ors fr o  m r e g ul at or y  a ut h oriti es. 
1 0. 1. 5.     P osti n g   Cli ni c al  St u d y   D at a 
•     St u d y  d at a  a n d i nf or  m ati o n   m a y  b e  p u blis h e d i n   n o n pr o  m oti o n al,  p e er-r e vi e  w e d  p u bli c ati o ns 
eit h er  b y  or  o n  b e h alf  of t h e s p o ns or.  
•     Cli ni c al st u d y r e p orts, s af et y  u p d at es,  a n d  a  n n u al r e p orts   will  b e  pr o vi d e d t o r e g ul at or y 
a ut h oriti es  as r e q uir e d. 
•     C o  m p a n y-s p o ns or e d st u d y i nf or  m ati o n  a n d t a b ul  ar st u d y r es ults   will  b e  p ost e d  o n t h e   U nit e d 
St at es   N ati o n al I nstit ut es  of   H e alt h's   w e bsit e   w  w  w.  Cli ni c al Tri als . g o v  a n d  ot h er  p u bli cl y 
a c c essi bl e sit es 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
5 3 
 
1 0. 1. 6.     D at a   Q u alit y   Ass u r a n c e 
•     All  p arti ci p a nt  d at a r el ati n g t o t h e st u d y   will  b e r e c or d e d  o n  pri nt e d  or  el e ctr o ni c   C  R Fs 
u nl ess tr a ns  mitt e d t o t h e s p o ns or  or  d esi g n e e  el e ctr o ni c all y ( e g, l a b or at or y  d at a).  T h e 
i n v esti g at or is r es p o nsi bl e f or  v erif yi n g t hat  d at a  e ntri es  ar e  a c c ur at e  a n d  c orr e ct  b y 
p h ysi c all y  or  el e ctr o ni c all y si g ni n g t h e   C  R F.  
•     T h e i n v esti g at or   m ust   m ai nt ai n  a c c ur at e  d o c u  m e nt ati o n (s o ur c e  d at a) t h at s u p p orts t h e 
i nf or  m ati o n  e nt er e d i n t h e   C  R F.  
•     T h e i n v esti g at or   m ust  p er  mit st u d y-r el at e d  m o nit ori n g,  a u dits, I  R  B/I E  C r e vi e  w,  a n d 
r e g ul at or y  a g e n c y i ns p e cti o ns  a n d  pr o vi d e dir e ct  a c c ess t o s o ur c e  d at a  d o c u  m e nts.  
•     T h e s p o ns or  or  d esi g n e e is r es p o nsi bl e f or t h e  d at a   m a n a g e  m e nt  of t his st u d y i n cl u di n g 
q u alit y  c h e c ki n g  of t h e  d at a.  
•     St u d y   m o nit ors   will  p erf or  m  o n g oi n g s o ur c e  d at a  v erifi c ati o n t o  c o nfir  m t h at  d at a  e nt er e d 
i nt o t h e   C  R F  b y  a ut h ori z e d sit e  p ers o n n el  ar e  a cc ur at e,  c o  m pl et e,  a n d  v erifi a bl e fr o  m s o ur c e 
d o c u  m e nts; t h at t h e s af et y  a n d ri g hts  of  p arti ci p a nts  ar e  b ei n g  pr ot e ct e d;  a n d t h at t h e st u d y is 
b ei n g  c o n d u ct e d i n  a c c or d a n c e   wit h t h e  c urr e n tl y  a p pr o v e d  pr ot o c ol  a n d  a n y  ot h er st u d y 
a gr e e  m e nts, I  C  H   G  C P,  a n d  all  a p p li c a bl e r e g ul at or y r e q uir e  m e nts.  
•     R e c or ds  a n d  d o c u  m e nts, i n cl u di n g si g n e d I  C Fs,  p e  rt ai ni n g t o t h e  c o n d u ct of t his st u d y   m ust 
b e r et ai n e d  b y t h e i n v esti g at or  as st at e d i n t h e  cli ni c al tri al  a gr e e  m e nt.   N o r e c or ds   m a y  b e 
d estr o y e d  d uri n g t h e r et e nti o n  p eri o d   wit h o ut t h e   writt e n  a p pr o v al  of t h e s p o ns or.   N o r e c or ds 
m a y  b e tr a nsf err e d t o  a n ot h er l o c ati o n  or  p art  y   wit h o ut   writt e n  n otifi c ati o n t o t h e s p o ns or.  
1 0. 1. 7.     S o u r c e   D o c u  m e nts 
•     S o ur c e  d o c u  m e nts  pr o vi d e  e vi d e n c e f or t h e  e xist e n c e  of t h e  p arti ci p a nt  a n d s u bst a nti at e t h e 
i nt e grit y  of t h e  d at a  c oll e ct e d.  S o ur c e  d o c u  m e nts  ar e fil e d  at t h e i n v esti g at or’s sit e. 
•     D at a r e p ort e d  o n t h e   C  R F  or  e nt er e d i n t h e  e  C  R F t h at  ar e tr a ns cri b e d fr o  m s o ur c e  d o c u  m e nts 
m ust  b e  c o nsist e nt   wit h t h e s o ur c e  d o c u  m e nts   or t h e  dis cr e p a n ci es   m ust  b e  e x pl ai n e d.  T h e 
i n v esti g at or   m a y  n e e d t o r e q u est  pr e vi o us   m e dic al r e c or ds  or tr a nsf er  r e c or ds,  d e p e n di n g  o n 
t h e st u d y. 
•     D efi niti o n  of   w h at  c o nstit ut es s o ur c e  d at a  c a n    b e f o u n d i n  S e cti o n  4. 0  of I  C  H  E 6,   G  C P: 
C o ns oli d at e d   G ui d a n c e  a n d r e c or ds   m ust  b e  attr  i b ut a bl e, l e gi bl e,  c o nte  m p or a n e o us,  ori gi n al, 
a n d  a c c ur at e. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
5 4 
 
1 0. 1. 9.     P u bli c ati o n  P oli c y 
•     All er g a n  as   t h e s p o ns or  h as  pr o pri et ar y i nt er est i n t his st u d y.   A ut h ors hi p  a n d   m a n us cri pt 
c o  m p ositi o n   will r efl e ct j oi nt  c o o p er ati o n  b et  w e e n   m ulti pl e i n v esti g at ors  a n d sit es  a n d 
All er g a n  p ers o n n el.   A ut h ors hi p   will  b e  est a blis  h e d  pri or t o t h e   writi n g  of t h e   m a n us cri pt.   As 
t his st u d y i n v ol v es   m ulti pl e  c e nt ers,  n o i n di vi d ual  p u bli c ati o ns   will  b e  all o  w e d  pri or t o 
c o  m pl eti o n  of t h e fi n al r e p ort  of t h e   m ulti c e n t er st u d y  e x c e pt  as  a gr e e d   wit h   All er g a n. 
•     T h e s p o ns or   will  c o  m pl y   wit h t h e r e q uir e  m e nts f or  p u bli c ati o n  of st u d y r es ults. I n 
a c c or d a n c e   wit h st a n d ar d  e dit ori al  a n d  et hi c a l  pr a cti c e, t h e s p o ns or   will  g e n er all y s u p p ort 
p u bli c ati o n  of   m ulti c e nt er st u di es  o nl y i n t h eir  e ntir et y  a n d  n ot  as i n di vi d u al sit e  d at a. 
•     A ut h ors hi p   will  b e  d et er  mi n e d  b y   m ut u al  a gr e  e  m e nt  a n d i n li n e   wit h I nt er n ati o n al   C o  m  mitt e e 
of   M e di c al J o ur n al  E dit ors  a ut h ors hi p r e q uir e  m e nts. 
1 0. 1. 1 0.     C o  m pli a n c e   wit h  P r ot o c ol 
T h e i n v esti g at or is r es p o nsi bl e f or  c o  m pli a n c e   wi  t h t h e  pr ot o c ol  at t h e i n v esti g ati o n al sit e.   A 
r e pr es e nt ati v e  of t h e s p o ns or   will   m a k e fr e q u ent  c o nt a ct   wit h t h e i n v esti g at or  a n d  his/ h er 
r es e ar c h st aff  a n d   will  c o n d u ct r e g ul ar   m o nit ori n g visits  at t h e sit e t o r e vi e  w  p arti ci p a nt  a n d 
st u d y i nt er v e nti o n  a c c o u nt a bilit y r e c or ds f or  c o  m pli a n c e   wit h t h e  pr ot o c ol.  Pr ot o c ol  d e vi ati o ns 
will  b e  dis c uss e d   wit h t h e i n v esti g at or  u p o n i d e ntifi c ati o n.  T h e  us e  of t h e  d at a  c oll e ct e d f or t h e 
p arti ci p a nt   will  b e  dis c uss e d t o  d et er  mi n e if t h e  d at a  ar e t o  b e i n cl u d e d i n t h e  a n al ysis.  T h e 
i n v esti g at or   will  e nt er  d at a t h at   m a y  b e  e x clu d e d fr o  m  a n al ysis  as  d efi n e d  b y t h e  pr ot o c ol 
d e vi ati o n s p e cifi c ati o ns.  Si g nifi c a nt  pr ot o c ol  d e vi ati o ns   will   b e r e p ort e d t o t h e I  R  B/I E  C 
a c c or di n g t o t h e I  R  B/I E  C’s r e p orti n g r e q uir e  m e nts. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 0 
1 0. 3.     
A p p e n di x  3:   A b b r e vi ati o ns 
A b b r e vi ati o n/  T e r  m   
   D efi niti o n   
 
A E 
a d v ers e  e v e nt 
A E SI 
a d v ers e  e v e nt  of s p e ci al i nt er est 
b p  m 
b e ats  p er   mi n ut e 
C/  D 
c u p t o  dis c 
C  DI S  C 
Cli ni c al   D at a I nt er c h a n g e  St a n d ar ds   C o ns orti u  m 
C  D  V  A 
c orr e ct e d  dist a n c e  vis u al  a c uit y 
C F  R 
C o d e  of  F e d er al   R e g ul ati o ns 
C  R F 
c as e r e p ort f or  m 
D  CI  V  A 
dist a n c e- c orr e ct e d i n t er  m e di at e  vis u al  a c uit y 
D  C  N  V  A 
dist a n c e- c orr e ct e d  n e ar  vis u al  a c uit y 
D E T 
dr y  e y e t est 
e  C  R F 
el e ctr o ni c  c as e r e p ort f or  m 
E  O S 
e n d  of t h e st u d y 
F  D  A 
F o o d  a n d   Dr u g   A d  mi nistr ati o n 
F S  H 
f olli cl e-sti  m ul ati n g  h or  m o n e 
G  C P 
G o o d   Cli ni c al  Pr a cti c e 
H  R T 
h or  m o n al r e pl a c e  m e nt t h er a p y 
I  B 
I n v esti g at or's   Br o c h ur e 
I  C F 
i nf or  m e d  c o ns e nt f or  m 
I  C  H 
I nt er n ati o n al   C o u n cil f or   H ar  m o ni z ati o n 
I  D 
i d e ntifi c ati o n 
I E  C 
i n d e p e n d e nt  et hi cs  c o  m  mitt e e 
I  O P 
i ntr a o c ul ar  pr ess ur e 
I  R  B 
i nstit uti o n al r e vi e  w  b o ar d 
I T T 
i nt e nt-t o-tr e at 
I x  R S 
i nt er a cti v e  el e ctr o ni c r es p o ns e s yst e  m 
L  A SI  K 
l as er- assist e d i n sit u  k er at o  mil e usis  
M  M  R  M 
mi x e d   m o d el r e p e at e d   m e as ur e 
N  CI 
N ati o n al   C a n c er I nstit ut e 
N EI   V F  Q- 2 5 
N ati o n al  E y e I nstit ut e   Vis u al  F u n cti o n   Q u esti o n n air e  2 5 
N  V P T  Q 
N e ar   Visi o n  Pr es b y o pi a    T as k- b as e d   Q u esti o n n air e  
O  D 
ri g ht  e y e 
O S 
l eft  e y e 
O S  DI 
O c ul ar  S urf a c e   Dis e as e I n d e x 
PI  C  Q 
Pr es b y o pi a I  m p a ct  a n d   C o pi n g   Q u esti o n n air e  

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 1 
A b b r e vi ati o n/  T e r  m   
   D efi niti o n   
 
P  R  K 
p h ot or efr a cti v e  k er at e ct o  m y  
P  R  O 
p ati e nt r e p ort e d  o ut c o  m es 
S  A E 
s eri o us  a d v ers e  e v e nt 
S  A P 
st atisti c al  a n al ysis  pl a n 
S o  A 
s c h e d ul e  of  a cti viti es 
T E  A E 
tr e at  m e nt- e  m er g e nt  a d v ers e  e v e nt 
V  A S 
vis u al  a n al o g s c al e 
W  O  C  B P 
w o  m e n  of  c hil d b e ari n g  p ot e nti al 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 2 
1 0. 4.     
A p p e n di x  4:  St a n d a r d   Dis c o nti n u ati o n   C rit e ri a 
C  DI S  C  S u b  missi o n   V al u e 
C  DI S  C   D efi niti o n 
A E 
A n y  u nt o  w ar d   m e di c al  o c c u  rr e n c e i n  a  p ati e nt  or 
cli ni c al i n v esti g ati o n  s u bj e ct  a d  mi nist er e d  a 
p h ar  m a c e uti c al  pr o d u ct  a n d   w hi c h  d o es  n ot 
n e c ess aril y  h a v e  a  c a us al r el ati o ns hi p   wit h t his 
tr e at  m e nt.   A n   A E  c a n t h er ef or e  b e  a n y  u ni nt e n d e d 
si g n (i n cl u di n g  a n  a b n or  m al l a b or at or y fi n di n g), 
s y  m pt o  m,  or  dis e as e t e  m p or all y  ass o ci at e d   wit h t h e 
us e  of  a   m e di ci n al (i n v esti g ati o n al)  pr o d u ct, 
w h et h er  or  n ot r el at e d t o t h e   m e di ci n al 
(i n v esti g ati o n al)  pr o d u ct.  F or f urt h er i nf or  m ati o n, 
s e e t h e I  C  H   G ui d eli n e f or   Cli ni c al  S af et y   D at a 
M a n a g e  m e nt:   D efi niti o ns  a n d  St a n d ar ds f or 
E x p e dit e d   R e p orti n g (  m o difi e d fr o  m I  C  H  E 2  A) 
S y n o n y  ms: si d e  eff e ct,  a d v ers e  e x p eri e n c e.  S e e 
als o  S  A E, s eri o us  a d v ers e  e x p eri e n c e. (  C  DI S  C 
gl oss ar y) 
C o  m pl et e d 
T o  p oss ess  e v er y  n e c ess ar y  or  n or  m al  p art  or 
c o  m p o n e nt  or st e p;  h a vi n g  c o  m e  or  b e e n  br o u g ht t o 
a  c o n cl usi o n (  N  CI) 
D e at h 
T h e  a bs e n c e  of lif e  or  st at e  of  b ei n g  d e a d (  N  CI) 
L a c k  of  effi c a c y 
T h e l a c k  of  e x p e ct e d  or  d esir e d  eff e ct r el at e d t o  a 
t h er a p y (  N  CI) 
L ost t o f oll o  w- u p 
T h e l oss  or l a c k  of  c o n ti n u ati o n  of  a s u bj e ct t o 
f oll o  w- u p 
N o n- c o  m pli a n c e   wit h st u d y  dr u g 
A n i n di c ati o n t h at  a s u bj e ct  h as  n ot  a gr e e d   wit h  or 
f oll o  w e d t h e i nstr u cti o ns r el at e d t o t h e st u d y 
m e di c ati o n (  N  CI) 
Ot h er 
Diff er e nt t h a n t h e  o n e(s)  pr e vi o usl y s p e cifi e d  or 
m e nti o n e d (  N  CI) 
P h ysi ci a n  d e cisi o n 
A  p ositi o n,  o pi ni o n  or j u d g  m e nt r e a c h e d  aft er 
c o nsi d er ati o n  b y  a  p h ysi ci a n   wit h r ef er e n c e t o 
s u bj e ct (  N  CI) 
Pr e g n a n c y 
Pr e g n a n c y is t h e st at e  or  c o n diti o n  of  h a vi n g  a 
d e v el o pi n g  e  m br y o  or f et us i n t h e  b o d y ( ut er us), 
aft er  u ni o n  of  a n  o v u  m  a n d s p er  m at o z o o n,  d uri n g 
t h e  p eri o d fr o  m  c o n c e pti o n t o  birt h. (  N  CI) 
Pr o gr essi v e  dis e as e 
A  dis e as e  pr o c ess t h at is   i n cr e asi n g i n  e xt e nt  or 
s e v erit y (  N  CI) 
Pr ot o c ol  d e vi ati o n 
A n  e v e nt  or  d e cisi o n t h at st a n ds i n  c o ntr ast t o t h e 
g ui d eli n es s et  o ut  b y t h e  pr ot o c ol (  N  CI) 
S cr e e n f ail ur e 
T h e  p ot e nti al s u bj e ct   w h o  d o es  n ot   m e et  o n e  or 
m or e  crit eri a r e q uir e d f or  p arti ci p ati o n i n  a tri al 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 3 
C  DI S  C  S u b  missi o n   V al u e 
C  DI S  C   D efi niti o n 
Sit e t er  mi n at e d  b y s p o ns or 
A n i n di c ati o n t h at  a  cli ni c al st u d y   w as st o p p e d  at  a 
p arti c ul ar sit e  b y its s p o ns or (  N  CI) 
St u d y t er  mi n at e d  b y s p o ns or 
A n i n di c ati o n t h at  a  cli ni c al st u d y   w as st o p p e d  b y 
its s p o ns or (  N  CI) 
Wit h dr a  w al  b y s u bj e ct 
A n i n di c ati o n t h at  a st u d y  p arti ci p a nt  h as r e  m o v e d 
its elf fr o  m t h e st u d y (  N  CI) 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 4 
1 0. 5.     
A p p e n di x  5:  St u d y   T a b ul a r  S u  m  m a r y 
P a r a  m et e r   G r o u p 
P a r a  m et e r 
V al u e 
Tri al i nf or  m ati o n      
Tri al  Titl e 
A  P h as e  3,   M ulti c e nt er,   D o u bl e-  M as k e d, 
R a n d o  mi z e d,   V e hi cl e-  C o ntr oll e d,  P ar all el-
Gr o u p  St u d y  E v al u ati n g t h e  S af et y  a n d 
Effi c a c y  of   A  G  N- 1 9 0 5 8 4  i n  P arti ci p a nts 
wit h  Pr es b y o pi a 
 
Cli ni c al  St u d y  S p o ns or 
All er g a n, I n c. 
 
Tri al  P h as e   Cl assifi c ati o n 
P h as e  3  Tri al 
 
Tri al I n di c ati o n 
Pr es b y o pi a 
 
Tri al I n di c ati o n  T y p e 
Tr e at  m e nt 
 
Tri al  T y p e 
Effi c a c y 
S af et y 
 
Tri al  L e n gt h 
3 0  d a ys  pl us  u p t o  3 0- d a y s cr e e ni n g  p eri o d 
 
Pl a n n e d   C o u ntr y  of I n v esti g ati o n al  Sit es      
U nit e d  St at es 
 
Pl a n n e d   N u  m b er  of  P arti ci p a nts 
4 0 0 
 
F  D  A-  R e g ul at e d   D e vi c e  St u d y 
N o 
 
F  D  A-  R e g ul at e d   Dr u g  St u d y 
Y es 
 
P e di atri c  St u d y 
N o 
P arti ci p a nt 
i nf or  m ati o n 
Di a g n osis   Gr o u p 
Pr es b y o pi a 
 
H e alt h y  P arti ci p a nt I n di c at or 
N o 
 
Pl a n n e d   Mi ni  m u  m   A g e  of  P arti ci p a nts     
4 0 
 
Pl a n n e d   M a xi  m u  m   A g e  of  P arti ci p a nts     
5 5 
 
S e x  of  P arti ci p a nts 
M al e  or f e  m al e 
 
St a bl e   Dis e as e   Mi ni  m u  m   D ur ati o n 
N ot s p e cifi e d 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 5 
P a r a  m et e r   G r o u p 
P a r a  m et e r 
V al u e 
Tr e at  m e nts     
I n v esti g ati o n al  T h er a p y  or  Tr e at  m e nt 
A  G  N- 1 9 0 5 8 4 ( Pil o c ar pi n e   H  Cl  1. 2 5  % 
O p ht h al  mi c  S ol uti o n) 
 
I nt er v e nti o n  T y p e 
Dr u g 
 
P h ar  m a c ol o gi c al   Cl ass  of I n v est.  T h er a p y      
C h oli n er gi c  a g o nist 
 
D os e  p er   A d  mi nistr ati o n 
1  bil at er all y 
 
D os e   U nits 
Dr o p 
 
D osi n g  Fr e q u e n c y 
O n c e  d ail y 
 
R o ut e  of   A d  mi nistr ati o n 
T o pi c al  e y e  dr o p 
 
C urr e nt  T h er a p y  or  Tr e at  m e nt 
N o 
 
A d d e d  o n t o  E xisti n g  Tr e at  m e nts 
N o 
 
C o ntr ol  T y p e 
V e hi cl e 
 
C o  m p ar ati v e  Tr e at  m e nt   N a  m e 
A  G  N- 1 9 0 5 8 4   V e hi cl e 
Tri al  d esi g n     
St u d y  T y p e 
I nt er v e nti o n al 
 
I nt er v e nti o n   M o d el 
P ar all el 
 
Pl a n n e d   N u  m b er  of   Ar  ms 
2 
 
Tri al is   R a n d o  mi z e d 
Y es 
 
R a n d o  mi z ati o n   Q u oti e nt 
1: 1 
 
Tri al   Bli n di n g  S c h e  m a 
D o u bl e-  m as k e d 
 
Str atifi c ati o n  F a ct ors 
A g e ( 2  gr o u ps:   ≤   5 0  y e ars  a n d  >  5 0  y e ars); 
b as eli n e  bi n o c ul ar   D  C  N  V  A ( 2  gr o u ps: 
2 0/ 4 0 t o  2 0/ 6 0 i n cl usi v el y,  a n d   w ors e t h a n 
2 0/ 6 0); iris  c ol or ( br o  w n  a n d  n o n- br o  w n), 
a n d  e  m  m etr o p es/ n o n- e  m  m etr o p es 
 
A d a pti v e   D esi g n 
N o 
 
St u d y  St o p   R ul es 
N o n e 
 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 6 
1 0. 6.     
A p p e n di x  6:   C o nt r a c e pti v e   G ui d a n  c e  a n d   C oll e cti o n  of  P r e g n a n c y 
I nf o r  m ati o n 
D efi niti o ns: 
W  O  C  B P 
A   w o  m a n is  c o nsi d er e d f ertil e f oll o  wi n g   m e n a  r c h e  a n d  u ntil  b e c o  mi n g  p ost  m e n o p a us al  u nl ess 
p er  m a n e ntl y st eril e (s e e  b el o  w). 
W o  m e n i n t h e f oll o  wi n g  c at e g o ri es  a r e  n ot  c o nsi d e r e d    W  O  C  B P:    
1.    Pr e  m e n ar c h al 
2.    Pr e  m e n o p a us al f e  m al e   wit h  1  of t h e f oll o  wi n g: 
•     D o c u  m e nt e d  h yst er e ct o  m y 
•     D o c u  m e nt e d  bil at er al s al pi n g e ct o  m y 
•     D o c u  m e nt e d  bil at er al  o o p h or e ct o  m y 
N ot e:   D o c u  m e nt ati o n  c a n  c o  m e fr o  m t h e sit e    p ers o n n el’s: r e vi e  w of t h e  p arti ci p a nt’s 
m e di c al r e c or ds,   m e di c al  e x a  mi n ati o n,  or   m e di c al  hist or y i nt er vi e  w. 
3.    P ost  m e n o p a us al f e  m al e 
•     A  p ost  m e n o p a us al st at e is  d efi n e d  as  n o   m e ns  es f or  1 2   m o nt hs   wit h o ut  a n  alt er n ati v e 
m e di c al  c a us e.   A  hi g h  F S  H l e v el i n t h e  p ost  m e n o p a us al r a n g e   m a y  b e  us e d t o  c o nfir  m  a 
p ost  m e n o p a us al st at e i n   w o  m e n  n ot  usi n g  h or  m o n al  c o ntr a c e pti o n  or   H  R T.   H o  w e v er, i n 
t h e  a bs e n c e  of  1 2   m o nt hs  of  a  m e n orr h e a,  a si n gl e  F S  H   m e as ur e  m e nt is i ns uffi ci e nt.  
•     F e  m al es  o n   H  R T  a n d   w h os e   m e n o p a us al st at us is  i n  d o u bt   will  b e r e q uir e d t o  us e  o n e  of 
t h e  n o n estr o g e n  h or  m o n al  hi g hl y  eff e cti v e  c o ntr a c e pti o n   m et h o ds if t h e y   wis h t o 
c o nti n u e t h eir   H  R T  d uri n g t h e st u d y.   Ot h er  wis e, t h e y   m ust  dis c o nti n u e   H  R T t o  all o  w 
c o nfir  m ati o n  of  p ost  m e n o p a us al st at us  b ef or e st u d y  e nr oll  m e nt. 
C o nt r a c e pti o n   G ui d a n c e: 
F e  m al e  P arti ci p a nts 
F e  m al e  p arti ci p a nts  of  c hil d b e ari n g  p ot e nti al  ar e  eli gi bl e t o  p arti ci p at e if t h e y  a gr e e t o  us e  a 
hi g hl y  eff e cti v e   m et h o d  of  c o ntr a c e pti o n  c o ns ist e ntl y  a n d  c orr e ctl y  as  d es cri b e d i n T a bl e  1 0 – 1 . 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 7 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 8 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
6 9 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 0 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 1 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 2 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 3 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 4 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 5 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 6 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 7 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 8 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
7 9 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
8 0 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
8 1 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
8 2 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
8 3 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
8 4 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
A  G  N- 1 9
 
0 5 8 4 
8 7 
Pr ot o c ol  1 8 8 3- 3 0 2 - 0 1 3       

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 1 
1 0. 8. 2.     N e a r   Visi o n  P r es b y o pi a   T as k- b as e d   Q u esti o n n ai r e 
N e a r   Visi o n  P r es b y o pi a   T as k  - b as e d   Q u esti o n n ai r e (  N  V P  T  Q) 
I nst r u cti o ns:  T his  q u esti o n n air e i n cl u d es  1 2  q u esti o ns  o n  f o ur r e a di n g t as ks t h at  y o u  ar e  a b o ut 
t o  c o  m pl et e.  
 
Y o u   will  b e  as k e d t o r e a d t e xt fr o  m t h e f oll o  wi n g  e x a  m pl es: 
•     P ar a gr a p h fr o  m  a  b o o k 
•     N e  ws p a p er  arti cl e 
•     M e n u 
•     N utriti o n l a b el 
 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 2 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 3 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 4 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 5 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 6 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 7 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 8 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 0 9 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 0 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 1 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 2 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 3 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 4 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 5 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 6 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 7 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 8 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 1 9 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 2 0 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
 
 
Pr ot o c ol  1 8 8 3- 3 0 2- 0 1 3       
A  G  N- 1 9 0 5 8 4 
1 2 1 
1 1.     
R ef e r e n c es 
G ar cí a- L á z ar o  S,  F err er-  Bl as c o  T,   R a d h a kris h n a n     H,   C er vi n o   A,   C h ar  m a n    W  N,   M o nt es-  Mi c o   R. 
Vis u al f u n cti o n t hr o u g h  4  c o nt a ct l e ns- b as e d  pi n h  ol e s yst e  ms f or  pr es b y o pi a. J   C at ar a ct   R efr a ct 
S ur g.  2 0 1 2; 3 8( 5): 8 5 8- 8 6 5. 
H ol d e n   B  A,  Fri c k e  T  R,   H o  S  M,    W o n g   R,  S c hl e n  t h er   G,   Cr o nj é  S,  et  al.   Gl o b al  visi o n 
i  m p air  m e nt  d u e t o  u n c orr e ct e d  pr es by o pi a.   Ar c h   O p ht h al  m ol.  2 0 0 8; 1 2 6: 1 7 3 1- 1 7 3 9. 
J o h ns o n  L,   B u c kl e y J  G,  S c all y   AJ,  Elli ott   D  B.   M u ltif o c al s p e ct a cl es i n cr e as e  v ari a bilit y i n t o e 
cl e ar a n c e  a n d ris k  of  tri p pi n g i n t h e  el d erl y. I n v est   Op ht h al  m ol   Vis  S ci.  2 0 0 7; 4 8: 1 4 6 6- 1 4 7 1. 
L or d  S  R,   D a y h e  w J,   H o  wl a n d   A.   M ultif o c al  gl ass e  s i  m p air  e d g e- c o ntr ast s e nsiti vit y  a n d  d e pt h 
p er c e pti o n  a n d i n cr e as e t h e ris k  of f alls i n  ol d er  p e o pl e. J   A  m   G eri atr  S o c.  2 0 0 2; 5 0: 1 7 6 0- 1 7 6 6. 
M os hirf ar   M,   D es a ut els J  D,    W all a c e   R T,   K o e n    N,   H o o p es  P  C.   C o  m p aris o n  of  F  D  A s af et y  a n d 
effi c a c y  d at a f or   K  A  M  R  A  a n d   R ai n dr o p  c or n e al i nl a ys. I nt J   O p ht h al  m ol. 
2 0 1 7; 1 0( 9): 1 4 4 6- 1 4 5 1. 
Pil o c ar pi n e  h y dr o c hl ori d e  o p ht h al  mi c s ol uti o n  1  % ,  2  %,  a n d  4  %.  P a c k a g e I ns ert.  F ort    W ort h, 
T  X:   Al c o n  L a b or at ori es, I n c.  2 0 1 1. 
R ui z  L  A,   C e p e d a  L  M,  F u e nt es   V  C. I ntr astr o  m al  c orr e cti o n  of  pr es b y o pi a  usi n g  a f e  mt os e c o n d 
l as er s yst e  m. J   R efr a ct  S ur g.  2 0 0 9; 2 5( 1 0): 8 4 7- 8 5 4. 
T o  mit a   M.   A d v a n c es i n I  m pl a nt ati o n   O v er t h e  Y e ars.   C h a n g es i n t e c h ni q u e  h a v e  a  dir e ct 
c orr el ati o n   wit h  d e cr e as es i n  a  c or n e al i nl a y’s r e  m o v al r at e.   C at ar a ct   R efr a ct  S ur g  T o d a y. 
2 0 1 5;J u n e: 6 7- 6 8. 
Ts ai J  C,  F or b es   M.   M e di c al   M a n a g e  m e nt  of    Gl a u c o  m a.  3r d  e d.    W est Isli p,   N e  w   Y or k: 
Pr of essi o n al   C o  m  m u ni c ati o ns, I n c.; 2 0 0 9. 
T u c k er J,   C h ar  m a n    W  N.  T h e  d e pt h- of-f o c us  of  t h e  h u  m a n  e y e f or  S n ell e n l ett ers.   A  m J   O pt o  m 
P h ysi ol   O pt.  1 9 7 5; 5 2( 1): 3 – 2 1. 

 
 
A p pr o v al D at e : 
 
 
0 6- M ar- 2 0 2 0
A L L  E  R   G   A  N
A L L  E  R   G   A  N
 
 
 
 
 
 
 
 
 
 
D at e (  D  D/  M  M  M/  Y  Y  Y  Y)/ Ti  m e (  P T)  
Si g n e d  b y:  
J u stifi c ati o n  
  
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
1 8 8 3- 3 0 2- 0 1 3   Pr ot o c ol   A  m e n d  m e nt  1
0 6-  M ar- 2 0 2 0  0 9: 3 2   G  M T- 0 8 0
Cli ni c al   D e v el o p  m e nt   A p pr o v al