Clinical trial NCT03857542
Conditions: Presbyopia
Sponsor: Allergan
Start date: 2019-03-01; Completion date: 2020-09-10
Enrollment: 427 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical study will evaluate pilocarpine hydrogen chloride (HCl) ophthalmic solution (AGN-190584) in an expanded participant population to establish efficacy, safety, and tolerability versus the vehicle-control when administered, over a 30-day study intervention period, once daily bilaterally in participants with presbyopia.

Detailed description:

Arms: arm 1: Participants received one drop of vehicle in each eye, once daily, for up to 30 days. arm 2: Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Interventions: intervention 1: Pilocarpine HCl Ophthalmic Solution intervention 2: Vehicle
Intervention descriptions: intervention 1: Pilocarpine HCl ophthalmic solution 1.25%, one drop in each eye, once daily, for up to 30 days. intervention 2: Vehicle, one drop in each eye, once daily, for up to 30 days.

Protocol documents:
Prot_000.pdf: 
 
 
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

SAP_001.pdf: 
   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 1 of 44
Title Page
Protocol Title: A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled,
Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants with 
Presbyopia
Protocol Number: 1883-302-013
Compound Number: AGN-190584
Short Title: Phase 3 efficacy study of AGN-190584 in participants with presbyopia
Sponsor Name: Allergan, Inc.
Legal Registered Address: 2525 Dupont Drive, Irvine, CA 92612, USA
Enter 
Registry 
Name
Phase 3 efficacy study of AGN-190584 in participants with presbyopia
Approval Date: August 20, 2020


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 2 of 44
Table of Contents
Title Page .........................................................................................................................................1
Table of Contents.............................................................................................................................2
List of Tables ...................................................................................................................................3
List of Figures..................................................................................................................................3
SAP Version History........................................................................................................................4
1.
Introduction.......................................................................................................................5
1.1.
Study Design.....................................................................................................................7
2.
Statistical Hypotheses.....................................................................................................16
3.
Sample Size Determination ............................................................................................17
4.
Populations for Analysis.................................................................................................18
5.
Statistical Analyses.........................................................................................................19
5.1.
General Considerations...................................................................................................19
5.2.
Participant Disposition....................................................................................................20
5.3.
Primary Endpoint(s) Analysis.........................................................................................20
5.3.1.
Definition of Endpoint(s)................................................................................................20
5.3.2.
Main Analytical Approach..............................................................................................20
5.3.3.
Sensitivity Analysis ........................................................................................................20
5.4.
Secondary Endpoint(s) Analysis.....................................................................................20
5.4.1.
Key Secondary Analysis.................................................................................................20
5.4.2.
Other Secondary Analyses..............................................................................................21
5.4.3.
Multiplicity Adjustment..................................................................................................22
5.6.
Safety Analyses...............................................................................................................25
5.6.1.
Extent of Exposure..........................................................................................................25
5.6.2.
Adverse Events ...............................................................................................................25
5.6.3.
Vital Signs.......................................................................................................................26
5.6.4.
Mesopic, High Contrast, Binocular CDVA....................................................................26
5.6.5.
Photopic, High Contrast, Binocular CDVA....................................................................26
5.6.6.
Study Intervention Tolerability and Drop Comfort Assessments...................................26
5.6.7.
Temporal/Supraorbital Headache Visual Analog Scale .................................................26
5.6.8.
Intraocular Pressure ........................................................................................................27
5.6.9.
Slit Lamp Biomicroscopy ...............................................................................................27
5.6.10.
Near Contrast Sensitivity................................................................................................27
5.7.1.
Health Outcomes Analyses.............................................................................................27
5.7.2.
Subgroup Analyses for Efficacy Parameters ..................................................................27
5.8.
Interim Analyses.............................................................................................................28
5.8.1.
Data Monitoring Committee...........................................................................................28


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 3 of 44
6.
Supporting Documentation.............................................................................................29
6.1.
Appendix 1 List of Abbreviations ..................................................................................30
6.2.
Appendix 2: Changes to Protocol-Planned Analyses .....................................................32
6.3.
Appendix 3: Supporting Study Information ...................................................................33
6.3.1.
Demographics .................................................................................................................33
6.3.2.
Baseline Characteristics..................................................................................................33
6.3.3.
Protocol Deviations.........................................................................................................33
6.3.4.
Medical History ..............................................................................................................33
6.3.5.
Ophthalmic Medical History...........................................................................................33
6.3.6.
Prior/Concomitant medications ......................................................................................33
6.4.
Appendix 4: PRO Scoring Algorithm.............................................................................35
6.4.1.
NVPTQ Performance Domain Score..............................................................................35
6.4.2.
NVPTQ Satisfaction Domain Score ...............................................................................36
6.4.3.
PICQ Coping Score.........................................................................................................37
6.4.4.
PICQ Impact Score .........................................................................................................38
6.5.
Data handling convention...............................................................................................39
6.5.1.
Visit Time Windows.......................................................................................................39
6.5.2.
Missing Date of the Last Dose of Study Intervention.....................................................40
6.5.3.
Missing Severity Assessment for Adverse Events..........................................................40
6.5.4.
Missing Causal Relationship to Study Drug for Adverse Events...................................40
6.5.5.
Missing Date Information for Adverse Events ...............................................................40
6.5.6.
Missing Date Information for Prior or Concomitant Medications..................................42
6.5.6.1.
Incomplete Start Date.........................................................................................42
6.5.6.2.
Incomplete Stop Date.........................................................................................43
7.
References.......................................................................................................................44
List of Tables
Table 1-1
Schedule of Visits and Procedures: Screening to Visit 3.................................... 8
Table 1-2
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit...................... 13
Table 5-1
Hypotheses and Corresponding Efficacy Parameters ....................................... 23
List of Figures
Figure 1-1
Study Schema...................................................................................................... 7
Figure 5-1
Graphical Testing Procedure ......................................................................... 24


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 4 of 44
SAP Version History
This Statistical Analysis Plan (SAP) for study 1883-302-013 is based on the protocol dated
March 06, 2020.
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 5 of 44
1.
Introduction
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in the final protocol 
amendment 1 of study 1883-302-013 (dated 06 March 2020). Specifications of tables, figures, 
and data listings are contained in a separate document. The SAP for health economics data will 
be prepared separately.


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 6 of 44
Objectives and Endpoints
The objectives of this study are to evaluate the efficacy and safety of AGN-190584 when 
administered bilaterally, once daily for 30 days in participants with presbyopia. Details of the 
study objectives and corresponding endpoints are described in the table below:
Objectives
Endpoints
To evaluate the efficacy of AGN-190584 
when administered bilaterally, once daily 
for 30 days in participants with presbyopia.

Mesopic and photopic, high contrast DCNVA for each eye 
and binocularly

Mesopic and photopic, high contrast DCIVA for each eye and 
binocularly

PRO questionnaires: 
o
Mesopic and Photopic NVPTQ
o
PICQ
To evaluate the safety and tolerability of 
AGN-190584 when administered 
bilaterally, once daily for 30 days in 
participants with presbyopia

AEs

Photopic and mesopic high contrast CDVA for each eye and 
binocularly

Near Contrast sensitivity

Vital signs (blood pressure and heart rate)

Study drug tolerability and drop comfort assessments

Temporal/supraorbital headache VAS

IOP

Slit-lamp biomicroscopy

Manifest refraction

Dilated funduscopic examination


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 7 of 44
1.1.
Study Design
Study 1883-302-013 is a multicenter, double-masked, randomized, vehicle-controlled, parallel 
group, phase 3 study evaluating the efficacy and safety of AGN-190584 (1.25% pilocarpine) 
dosed once daily, bilaterally, over a period of 30 days in participants with presbyopia. The study 
population will consist of adult male and female participants with objective and subjective 
evidence of presbyopia. Approximately 200 participants per group will be randomized.
Participants will be randomized in a 1:1 ratio to receive either AGN-190584 or vehicle dosed 
once daily, in each eye, for 30 days. This randomization will be stratified by age (2 groups: 
≤50 years and > 50 years), baseline binocular DCNVA (2 groups: 20/40 to 20/60 inclusively, and 
worse than 20/60), iris color (brown and non-brown), and emmetropes/non-emmetropes. This 
study consists of the following visits: screening (Days -30 to -1), Day 1 (baseline), and Days 3, 
7, 14, and 30.
Study interventions, either AGN-190584 or vehicle will be administered as topical eye drop once 
daily. Following the study schema (Figure 1-1), study intervention will be administered by 
designated site personnel on visit days and at home by the participant in-between office visits, 
ideally prior to starting their day. On the day before office visits, the study intervention must be 
administered no less than 16 hours before the scheduled visit time.
Figure 1-1
Study Schema
The schedule of activities for Study 1883-302-013 is presented in Table 1-1 and Table 1-2.


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 8 of 44
Table 1-1
Schedule of Visits and Procedures: Screening to Visit 3


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 9 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 10 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 11 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 12 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 13 of 44
Table 1-2
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 14 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 15 of 44


   Statistical Analysis Plan    1883-302-013
AGN-190584
Page 16 of 44
2.
Statistical Hypotheses
For the primary efficacy analysis, the null hypothesis is that there is no difference between AGN-
190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days in the 
proportion of participants gaining 3 lines or more from baseline in mesopic, high contrast, 
binocular DCNVA without losing more than 5-letters of mesopic, high contrast, binocular 
CDVA with the same refractive correction at Day 30, Hour 3. The alternative hypothesis is that
there is a difference between AGN-190584 ophthalmic solution and vehicle.
For the key secondary efficacy analysis, the null hypothesis is that there is no difference between
AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days in the 
proportion of participants gaining 3 lines or more from baseline in mesopic, high contrast, 
binocular DCNVA at Day 30, Hour 6. The alternative hypothesis is that there is a difference 
between AGN-190584 ophthalmic solution and vehicle.
The hypotheses will be tested using chi-square tests at a significance level of 5%.


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3.
Sample Size Determination
The primary efficacy parameter is the proportion of participants gaining 3 lines or more from 
baseline in mesopic, high contrast, binocular DCNVA without losing more than 5-letters of 
mesopic, high contrast, binocular CDVA with the same refractive correction at Day 30, Hour 3.
The key secondary efficacy parameter is the proportion of participants gaining 3 lines or more
from baseline in mesopic, high contrast, binocular DCNVA at Day 30, Hour 6. The sample size 
calculation is based on the key secondary efficacy parameter.
The vehicle group intervention effect and AGN-190584 effect are assumed to be 8.8% and 
18.4%, respectively, as observed in the Phase 3 study 1883-301-013. Two hundred (200) 
participants will be required in each study intervention group to detect the above difference with 
a power of 80% or greater at the 2-sided 5% significance level. 


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4.
Populations for Analysis
Two analysis populations were defined for this study as follows:

The intent-to-treat (ITT) population will consist of all randomized participants.  The 
analysis using the ITT population will be based on the study intervention assigned.

The safety population will consist of all participants who received at least 1 
administration of study intervention.  The analysis using the safety population will be 
based on the actual study intervention received.


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5.
Statistical Analyses
5.1.
General Considerations

Efficacy endpoints will be analyzed using the ITT population, and the safety endpoints 
will be analyzed using the safety population.

The baseline for efficacy and safety will be the last non-missing assessment prior to the 
first administration of study intervention. For participants who were randomized but not 
treated, the baseline value will be the assessment collected on or prior to the 
randomization date, whichever is later.

The change from baseline values will be computed as the postbaseline value minus the 
baseline value.

Continuous variables will be summarized by number of participants with observed values 
(n), mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), minimum 
(min), and maximum (max).

Categorical variables will be summarized by number of participants with observed values
or events (n), frequency count (n1) and percentage of participants with observed values or 
events.

All statistical hypothesis tests will be performed at the 2-sided 5% significance level, 
unless stated otherwise. All confidence intervals will be at least 2-sided 95% confidence 
intervals.

In general, statistical analyses will be performed using SAS version 9.4 or higher. 
MedDRA version 22.1 or higher will be used to code adverse events, biomicroscopy, and 
medical history. WHODRUG Enhanced B2 will be used to code medications.
To control the overall Type 1 error rate in the efficacy analysis, a gatekeeping testing strategy
will be used. All secondary efficacy endpoints will be tested only if the primary efficacy 
endpoint is statistically significant and the testing procedures are described in the graphical 
procedure in Figure 5-1.
For primary and key secondary analyses, participants with missing data will be regarded as non-
responders. Analyses for other secondary efficacy endpoints will be based on observed data only.
Per confirmation of the site, DCNVA measurements were not conducted correctly for
participants at investigator site 051 at screening visit and baseline visit (Day 1 Hour 0). In error, 
the participants were corrected for near vision rather than distance vision when these 


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measurements were taken. Therefore, it is decided to exclude all participants from this site from 
efficacy analyses. These participants will be included in all safety analyses.
5.2.
Participant Disposition
The number of participants screened for the study will be provided. 
Summary of study disposition post randomization will be provided by study intervention group 
as randomized for the following:

Number of participants randomized; this frequency count will be used as the denominator 
to calculate the percentages described below

Number and percentage of participants treated 

Number and percentage of participants who completed the study

Number and percentage of participants who discontinued the study

Reasons for discontinuation from the study 
5.3.
Primary Endpoint(s) Analysis
5.3.1.
Definition of Endpoint(s)
The primary efficacy parameter will be the proportion of participants gaining 3 lines or more 
from baseline in mesopic, high contrast, binocular DCNVA without losing more than 5-letters of 
mesopic, high contrast, binocular CDVA with the same refractive correction at Day 30, Hour 3.
5.3.2.
Main Analytical Approach
The primary efficacy parameter will be analyzed using a chi-square test with 2-sided 95% 
confidence interval based on the normal approximation based on pooled variance without 
continuity correction.  
5.3.3.
Sensitivity Analysis
As a sensitivity analysis, a 2-sided 95% confidence interval using Wilson-Newcombe method
will be presented.
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Key Secondary Analysis
The key secondary efficacy endpoint will be the proportion of participants gaining 3 lines or 
more from baseline in mesopic, high contrast, binocular DCNVA at Day 30, Hour 6. The key 
secondary efficacy parameter will be analyzed in the same way as the primary efficacy 
parameter.


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5.4.2.
Other Secondary Analyses
Other secondary efficacy endpoints include:
1. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 8.
2. Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.5.
3. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 1.
4. Change from baseline in Mesopic NVPTQ Performance score at Day 30, Hour 3.
5. Change from baseline in photopic, high contrast, binocular DCIVA letters at Day 30, Hour 
3.
6. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 10.
7. Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.25. 
8. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 3.
9. Change from baseline in Mesopic NVPTQ Satisfaction score at Day 30, Hour 3.
10. Change from baseline in PICQ Coping score at Day 30, Hour 3.
11. Change from baseline in PICQ Impact score at Day 30, Hour 3.
All secondary endpoints related to proportion of participant gaining 3 lines or more or achieving 
20/40 better (endpoints 1, 3, 6 and 8) will be analyzed with the same analysis method as the 
primary efficacy parameter.
Timepoints are defined as scheduled measurement times made for each visit. Change from 
baseline in mesopic, high contrast, binocular DCNVA letters (endpoints 2 and 7) will be 
analyzed using mixed-effects model with repeated measures (MMRM) by timepoint that 
includes treatment, visit, treatment by visit interaction, age group, baseline DCNVA severity,
iris color, and emmetropes/non-emmetropes as factors as well as baseline DCNVA value, and 
baseline DCNVA value by visit interaction as covariates under the assumption of missing at 
random (MAR). An unstructured covariance matrix will be used as the covariance structure for 


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repeated measurements.  A sensitivity analysis will be implemented with the missing data 
imputed with the average outcome of the vehicle arm under the assumption of missing not at 
random (MNAR). Change from baseline in photopic, high contrast, binocular DCIVA letters
(endpoints 4) will be analyzed with the similar way as change from baseline in mesopic, high 
contrast, binocular DCNVA letters. Baseline DCIVA will be included as the covariate instead of 
baseline DCNVA.
NVPTQ and PICQ scoring algorithms are provided in Appendix 4.  Change from baseline in the 
mesopic NVPTQ Performance score, Mesopic NVPTQ Satisfaction score, PICQ Coping score,
and PICQ Impact score (endpoints 4, 9, 10 and 11) will be analyzed using an analysis of 
covariance (ANCOVA) model that includes treatment, age group, baseline DCNVA severity, iris 
color, emmetropes/non-emmetropes as factors as well as baseline PRO score as covariate. Also, 
the cumulative distribution function (CDF) curves will be presented for each of the change from 
baseline PRO domain scores. The CDF curves (one per domain score for a total of four) 
represent the cumulative proportion of patients with any particular level of CFB in PRO domain 
scores at Day 30 Hour 3, by treatment arm. Curves will be produced with a vertical line drawn at 
the responder threshold.
5.4.3.
Multiplicity Adjustment
The graphical procedure displayed in Figure 5-1 will be employed to control the overall 
familywise error rate at α=0.05 for the following hypotheses testing. Let 1ry, 2ry, H1, H2, H3, 
H4, H5, H6, H7, H8, H9, H10, and H11 represent the treatment effect comparisons of AGN-
190584 with vehicle. Details of the hypotheses and corresponding efficacy parameters are 
described in Table 5-1.


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Table 5-1
Hypotheses and Corresponding Efficacy Parameters
Hypothesis
Efficacy Parameter
1yr
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA 
without losing more than 5-letters of mesopic, high contrast, binocular CDVA with the same 
refractive correction at Day 30, Hour 3
2ry
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 6
H1
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 8
H2
Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, Hour 0.5
H3
Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, DCNVA 
at Day 30, Hour 1
H4
Change from baseline in photopic, high contrast, binocular DCIVA letters at Day 30, Hour 3
H5
Change from baseline in Mesopic NVPTQ Performance score at Day 30, Hour 3
H6
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 10
H7
Change from baseline mesopic, high contrast, binocular DCNVA letters at Day 30, Hour 0.25
H8
Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, DCNVA 
at Day 30, Hour 3
H9
Change from baseline in Mesopic NVPTQ Satisfaction score at Day 30, Hour 3
H10
Change from baseline in PICQ Coping score at Day 30, Hour 3
H11
Change from baseline in PICQ Impact score at Day 30, Hour 3


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Figure 5-1
Graphical Testing Procedure
Specifically, 2ry, H2, H3, H4 and H5 will be tested at a=0.01 separately. If  2ry, H2, H3, H4 or H5 is rejected,  H7, H8 or H9 will 
then be tested. If H9 is rejected, H10 and H11 will then be tested. H1 and H6 will be tested only if all other endpoints are 
significant.


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5.6.
Safety Analyses
The safety analyses will be performed using the safety population. The safety parameters will 
include AEs, vital signs (blood pressure and heart rate), mesopic and photopic, high contrast, 
CDVA, for each eye and binocularly, study intervention tolerability and drop comfort 
assessments, temporal/supraorbital headache assessment using VAS, IOP, slit-lamp 
biomicroscopy and near contrast sensitivity. For each safety parameter, the last non-missing 
safety assessment before the first dose of study intervention will be used as the baseline for all 
analyses of that safety parameter. 
5.6.1.
Extent of Exposure
The exposure to study intervention, calculated as (last study intervention date - first study 
intervention date + 1), will be summarized using descriptive statistics by treatment for the safety 
population.
5.6.2.
Adverse Events
An AE will be considered a treatment emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) after the first administration of study 
intervention. However, an AE that occurs more than 30 days after the last administration of study 
intervention will not be counted as a TEAE.
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by descending percentage in any group, by SOC and PT, and further categorized by 
severity and causal relationship to the study intervention. If more than 1 AE is coded to the same 
PT for the same participant, the participant will be counted only once for that PT using the 
greatest severity and strictest causality for the summarization by severity and causal relationship.
The incidence of common (≥5% of participants in any treatment group) TEAEs will be 
summarized by SOC, PT, and treatment group.
The total number of TEAEs by severity will be summarized by treatment group. The total 
number of TEAEs as well as headache of special interest by causal relationship to the study 
intervention will be summarized by treatment group. The number and percentage of participants 
reporting study intervention related TEAEs will be tabulated by SOC and PT.
An ocular AE is defined as the location of AE occurring in the eye. Ocular and nonocular 
headache of special interest will be summarized.


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A TESAE is defined as an SAE that is also a TEAE. The number and percentage of participants 
who have TESAEs will be summarized by PT and treatment group. In addition, the incidence of 
on-therapy SAEs that lead to death will be summarized separately by PT for each treatment 
group.
Summary tables will be provided for TEAEs leading to discontinuation and TESAEs. Listings of 
all TEAEs, SAEs, and AEs leading to discontinuation by participant will be presented.
5.6.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressure, and pulse rate) and 
changes from baseline values at each assessment timepoint will be presented by treatment group.
5.6.4.
Mesopic, High Contrast, Binocular CDVA
Change from baseline in number of letters in binocular mesopic, high contrast, CDVA will be 
summarized descriptively for each assessment timepoint by treatment group.
5.6.5.
Photopic, High Contrast, Binocular CDVA
Change from baseline in number of letters in binocular photopic, high contrast, CDVA will be 
summarized descriptively for each assessment timepoint by treatment group.
5.6.6.
Study Intervention Tolerability and Drop Comfort Assessments
Ocular tolerability assessment will be performed at each visit. Symptoms of blurred vision, 
foreign body sensation, pain, burning/stinging, tearing, and itching will be assessed using a 
5-point scale (0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 = severe) for the severity and 
a 3-point scale (<1 min, 1 to 5 min, and >5 min) for the duration. Drop comfort will be assessed 
using a 6-point scale (soothing, very comfortable, comfortable, uncomfortable, very 
uncomfortable, and intolerable). For the severity, duration, and drop comfort, the number and 
percentage of participants in each category will be tabulated for each time point by treatment 
group.
5.6.7.
Temporal/Supraorbital Headache Visual Analog Scale
Temporal and supraorbital headache will be separately assessed for each eye using a VAS at 
each visit. The reported values and the changes from baseline will be summarized using 
descriptive statistics for each time point for each eye by treatment group.


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5.6.8.
Intraocular Pressure
IOP is measured for each eye using the Goldmann applanation tonometer at each visit.
Tabulations will be based on the worst change (greater increase from baseline) between 2 eyes 
assessed at each visit. Descriptive statistics for IOP and changes from baseline at each 
assessment timepoint will be presented by treatment group. 
5.6.9.
Slit Lamp Biomicroscopy
Biomicroscopy will be performed in each eye at each visit, by slit lamp examination, without 
pupil dilation, including but not limited to lids/lashes, conjunctiva, cornea, and anterior chamber. 
Observations for the examination will be graded on a 5-point scale (0=none, 0.5=trace, 1=mild, 
2=moderate, 3=severe) except for the anterior chamber (in cells: 0=0 cells, +0.5=1-5 cells, +1=6-
15 cells, +2=16-25 cells, +3=26-50 cells, and +4=>50 cells; in flare: 0=none, +1=faint, 
+2=moderate, +3= marked and +4=intense).
The number and percentage of participants with clinically significant biomicroscopy findings 
will be tabulated by finding category, assessment timepoint and treatment group. A clinically 
significant finding is defined as more than one severity grade increase (worsening) from baseline
in one or both eyes. If a pathology is recorded at a follow-up visit but not at baseline, the 
baseline will be imputed with the same pathology, with a grade of zero (none).
5.6.10.
Near Contrast Sensitivity
Near contrast sensitivity assessment is conducted under photopic conditions. A Pelli-Robson 
contrast sensitivity chart is used. The logarithmic contrast sensitivity value of the last triplet of 
which at least 2 letters are correct read is marked as contrast sensitivity.  Descriptive statistics for 
near contrast sensitivity and changes from baseline at each assessment timepoint will be 
presented by treatment group. 


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5.8.
Interim Analyses 
No interim analysis is planned for this study.
5.8.1.
Data Monitoring Committee
Data monitoring committee is not required for this study.


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6.
Supporting Documentation


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6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ANCOVA
analysis of covariance
bpm
beats per minute
CDF
cumulative distribution function
CDVA
corrected distance visual acuity
DCIVA
distance-corrected intermediate visual acuity
DCNVA
distance-corrected near visual acuity
eCRF
electronic case report form
ID
identification
IOP
intraocular pressure
ITT
intent-to-treat
IxRS
interactive electronic response system
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mm Hg
millimeters of mercury
MMRM
mixed model repeated measure
MNAR
missing not at random
NEI VFQ-25
National Eye Institute Visual Function Questionnaire 25
NVPTQ
Near Vision Presbyopia Task-based Questionnaire 
OD
right eye
OS
left eye
OSDI
Ocular Surface Disease Index
PCS
potentially clinically significant
PICQ
Presbyopia Impact and Coping Questionnaire 
PRO
patient reported outcomes


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PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
VAS
visual analog scale
WHO DDE
World Health Organization Drug Dictionary Enhanced 
WOCBP
women of childbearing potential


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6.2.
Appendix 2: Changes to Protocol-Planned Analyses
The primary efficacy endpoint will be the proportion of participants gaining 3 lines or more from 
baseline in mesopic, high contrast, binocular DCNVA without losing more than 5-letters of 
mesopic, high contrast, binocular CDVA with the same refractive correction at Day 30, Hour 3.


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6.3.
Appendix 3: Supporting Study Information
6.3.1.
Demographics
Demographic parameters (age; age groups of ≤ 50 years and > 50 years; sex; race; ethnicity) will 
be summarized descriptively by treatment group for the ITT populations.
6.3.2.
Baseline Characteristics
Baseline binocular DCNVA (2 groups: 20/40 to 20/60 inclusively, and worse than 20/60), iris 
color (brown and non-brown), and emmetropes/non-emmetropes will be summarized 
descriptively with frequency and percentage by treatment group for the ITT population.
6.3.3.
Protocol Deviations
Unique participants reporting significant protocol deviations will be summarized in total and by 
treatment group for all randomized participants.
6.3.4.
Medical History
Medical and surgical history will be summarized by treatment group for the Safety Population. 
Medical history includes prior medical history (prior to Day 1, first dose date) and still ongoing.
6.3.5.
Ophthalmic Medical History
Ophthalmic medical and surgical history will be summarized by treatment group for the Safety 
Population. Ophthalmic medical history includes prior medical history (prior to Day 1, first dose 
date) and still ongoing.
6.3.6.
Prior/Concomitant medications 
Prior medication is defined as any medications taken prior to the start of study intervention. 
Concomitant medication is defined as any medication taken on or after the start of study 
intervention regardless of the start date of the medication.
The number and percentage of participants with prior and concomitant medication use will be 
summarized by treatment group and Anatomical Therapeutic Chemical code for the safety 
population. If a participant took a specific medication multiple times or took multiple 
medications within the same therapeutic class, the participant will be counted only once for the 
coded drug name or therapeutic class. Formulations (including salts, esters, etc.) containing the 
same active ingredient will be pooled under the coded drug name of the base compound. 
Medications containing multiple active ingredients of different coded drug names will be 


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reviewed during the course of the study and may be pooled under a single coded drug name 
for analyses. No statistical comparisons will be performed.


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6.4.
Appendix 4: PRO Scoring Algorithm 
6.4.1.
NVPTQ Performance Domain Score
To account for the impact of squinting on performance, the responses to the pair of performance 
and squinting items on each task is combined into a new testlet variable informed by a series of 
item response theory models. For performance and squinting, this new testlet variable is created 
by combining all possible response categories according to Table 1.
Table 1
Testlet variable values based on combining performance item responses and 
squinting item responses
                                                 
Squinting
Performance
Yes, but I still 
could not read 
any of the text 
(2)
Yes, and squinting 
helped me read some 
or all of the text (1)
No, I did 
not squint 
(0)
I could not read any of the text due 
to problems seeing up close (0)
0
0
0
Poor (1)
0
1
Fair (2)
1
2
Good (3)
2
3
Very Good (4)
3
4
Excellent (5)
4
5
Note. The values in parentheses are the raw values corresponding to the item response. These are 
the variable values in the ADaM datasets. 
If the response to either the performance or squinting item within a task is missing, then the 
corresponding testlet is assigned a missing value. Because the four tasks are highly related, there 
is no limit on the number of missing testlet scores to be able to calculate the performance domain 
score. The performance domain score is calculated as the average of the non-missing testlet 
values as follows:
NVPTQ Performance Score = (Book testlet + Newspaper testlet + Menu testlet + Nutrition Label 
testlet) / (# testlets with non-missing responses)


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The NVPTQ Performance Score ranges from 0 to 5, with 0 corresponding to poorest 
performance and 5 corresponding to best performance. Thus, higher scores correspond to better 
outcomes  This algorithm puts the performance score on the original performance item response 
metric, which also ranges from 0 to 5, so the performance item responses can be referenced when 
interpreting the score. Individual-level score changes of 0.75 points or greater can be considered 
clinically meaningful; i.e., an individual whose NVPTQ Performance Score increases by at least 
0.75 points from baseline can be considered a responder.
6.4.2.
NVPTQ Satisfaction Domain Score
To account for the impact of squinting on satisfaction, the responses to the pair of satisfaction 
and squinting items on each task is combined into a new testlet variable informed by a series of 
item response theory models. For satisfaction and squinting, this new testlet variable is created 
by combining all possible response categories according to Table 2.
Table 2
Testlet variable values based on combining satisfaction item responses and 
squinting item responses
                                                 
Squinting
Satisfaction
Yes, but I still 
could not read 
any of the text 
(2)
Yes, and squinting 
helped me read some 
or all of the text (1)
No, I did 
not squint 
(0)
Very dissatisfied (0)
0
0
0
Dissatisfied (1)
0
1
Neither satisfied nor dissatisfied (2)
1
2
Satisfied (3)
2
3
Very satisfied (4)
3
4
Note. The values in parentheses are the raw values corresponding to the item response. These are 
the variable values in the ADaM datasets. 
If the response to either the satisfaction or squinting item within a task is missing, then the 
corresponding testlet is assigned a missing value. Because the four tasks are highly related, there 
is no limit on the number of missing testlet scores to be able to calculate the satisfaction domain 
score. The satisfaction domain score is calculated as the average of the non-missing testlet values 
as follows:


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NVPTQ Satisfaction Score = (Book testlet + Newspaper testlet + Menu testlet + Nutrition Label 
testlet) / (# testlets with non-missing responses)
The NVPTQ Satisfaction Score ranges from 0 to 4, with 0 corresponding to greatest 
dissatisfaction and 4 corresponding to greatest satisfaction . Thus, higher scores correspond to 
better outcomes. This algorithm puts the satisfaction score on the original satisfaction item 
response metric, which also ranges from 0 to 4, so the satisfaction item responses can be 
referenced when interpreting the score. Individual-level score changes of 1.00 points or greater 
can be considered clinically meaningful; i.e., an individual whose NVPTQ Satisfaction Score 
increases by at least 1.00 points from baseline can be considered a responder.
6.4.3.
PICQ Coping Score
The coping domain consists of the following 8 items: 

Item 1: Normal-sized text 

Item 2: Small-sized text 

Item 3: Information on a computer 

Item 4: Information on a cell phone 

Item 5: Increase font size 

Item 6: Use glasses to read close 

Item 12: Hold reading materials farther out or closer 

Item 13: Squint to read 
Each of these items includes response categories ranging from 0, corresponding to “Never”, to 4, 
corresponding to “All of the time.” Items 3, 4, 5, and 6 include additional response categories, 
labeled with values of 9 or 10, to indicate that the question is not applicable because the 
participant did not use the object being evaluated (e.g., “I did not use a computer over the past 7 
days”) or because the participant did not have the opportunity to change his behavior (e.g., “I 
permanently increased the font size on my computer, tablet, or cell phone prior to the past 7 
days”). Responses in these “not applicable” categories labeled 9 or 10 are assigned missing 
values. 
Because of the similarity of the content of certain item pairs, two new testlet variables are 
created prior to scoring. The testlet variable for Item 1 and Item 2 is calculated by computing the 
mean of the non-missing responses to the two items. The testlet variable for Item 3 and Item 4 is 
calculated by computing the mean of the non-missing responses to the two items. If either item 
in the testlet pair has a missing value, the testlet value is assigned the value of the non-missing 
item. If both items in the testlet pair have missing values, then the testlet is assigned a missing 
value.


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Items 1&2 Testlet = (Item 1 + Item 2)/ # non-missing responses to Item 1 and Item 2
Items 3&4 Testlet = (Item 3 + Item 4) /# non-missing responses to Item 3 and Item 4 
After the testlet variables have been created, the coping domain score is calculated as the mean 
of the non-missing values to the coping testlets and single coping items. Because the coping 
items are well-related and internally consistent, and because missing data are expected for some 
items due to the “not applicable” response categories, there is no limit on the number of missing 
item responses to be able to calculate the coping domain score. 
PICQ Coping Score = (Item 1&2 Testlet + Item 3&4 Testlet + Item 5 + Item 6 + Item 12 + Item 
13) /# non-missing responses to the 6 components of the coping score 
The PICQ Coping Score ranges from 0 to 4, with 0 corresponding to least amount of coping and 
4 corresponding to the greatest amount of coping. Thus, higher scores correspond to poorer 
outcomes. This algorithm puts the coping score on the original item response metric, which also 
ranges from 0 to 4, so the coping item responses can be referenced when interpreting the score. 
Individual-level score changes of 1.00 points or greater can be considered clinically meaningful; 
i.e., an individual whose PICQ Coping Score decreases by at least 1.00 points from baseline can 
be considered a responder. 
6.4.4.
PICQ Impact Score
The impacts domain consists of the following 6 items: 

Item 9: Rely on others 

Item 15: Rest eyes 

Item 16: Feel older 

Item 17: Feel self-conscious 

Item 19: Take longer to complete a task 

Item 20: Inconvenient 
The first five impacts items include response categories ranging from 0, corresponding to 
“Never”, to 4, corresponding to “All of the time.” Item 20 uses response categories ranging from 
0, corresponding to “Not at all”, to 4, corresponding to “Extremely.” Item 9 includes an 
additional response category, labeled with a value of 9, to indicate that the question is not 
applicable because the subject did not have the opportunity to experience the impact (i.e., “Never 
because I used or did something to help”). Responses in this “not applicable” category are 
assigned missing values. 
Because of the similarity of the content of Item 16 and Item 17, a new testlet variable is created 
prior to scoring by computing the mean of the non-missing responses to the two items. If either 


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item in the testlet pair has a missing value, the testlet is assigned the value of the non-missing 
item. If both items in the testlet pair have missing values, then the testlet is assigned a missing 
value. 
Items 16&17 Testlet = (Item 16 + Item 17) /# non-missing responses to Item 16 and Item 17 
After the testlet variable has been created, the impacts domain score is calculated as the mean of 
the non-missing values to the impacts testlet and single impacts items. Because the impacts items 
are well-related and internally consistent, and because missing data are expected for some items 
due to the “not applicable” response categories, there is no limit on the number of missing item 
responses to be able to calculate the impacts domain score. 
PICQ Impacts Score = (Item 9 + Item 15 + Items 16&17 Testlet + Item 19 + Item 20) /# non-
missing responses to the 5 components of the impacts score 
The PICQ Impacts Score ranges from 0 to 4, with 0 corresponding to least amount of impacts 
and 4 corresponding to the greatest amount of impacts. Thus, higher scores correspond to poorer 
outcomes. This algorithm puts the impacts score on the original item response metric, which also 
ranges from 0 to 4, so the impacts item responses can be referenced when interpreting the score. 
Individual-level score changes of 1.00 points or greater can be considered clinically meaningful; 
i.e., an individual whose PICQ Impacts Score decreases by at least 1.00 points from baseline can 
be considered a responder.
6.5.
Data handling convention
6.5.1.
Visit Time Windows
For ITT and safety by-visit analyses, all follow-up visits or the exit visit, participants will be 
reassigned with the visit number based on the number of days from the first dose date according 
to the following windows corresponding to relevant analysis.
Analysis Phase
Analysis Visit 
(Derived)
Study Visit (eCRF)
Statistical Analyses Window
Pretreatment
Baseline
Day 1 (Visit 1)
Treatment Day ≤ 1, 
pre-dose/randomization
Treatment
Day 1
Day 1 (Visit 1)
Treatment Day 1, 
post dose/randomization
Day 3
Day 3 (Visit 2)
Treatment Day [2, 4]
Day 7
Day 7 (Visit 3)
Treatment Day [5, 10]


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Analysis Phase
Analysis Visit 
(Derived)
Study Visit (eCRF)
Statistical Analyses Window
Day 14
Day 14 (Visit 4)
Treatment Day [11, 21]
Day 30
Day 30 (Visit 5)
Treatment Day [22, 45]
If multiple assessments were taken within an analysis window, the assessment obtained on the 
day closest to the target day will be used; in the case of a tie, the assessment obtained on the later 
day will be used in the analysis.
6.5.2.
Missing Date of the Last Dose of Study Intervention
When the date of the last dose of study intervention is missing for a participant in the safety 
population, all efforts should be made to obtain the date from the investigator. If the data is still 
missing after all efforts have been made, the last available dosing record date will be used as the 
last dose date.
6.5.3.
Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If the severity of a TEAE is missing, the maximum 
severity will be assigned to the event for the summarization by severity. The value will be 
displayed as missing in the data listing.
6.5.4.
Missing Causal Relationship to Study Drug for Adverse Events
If the relationship to the study intervention is missing for a TEAE, the event will be considered 
related to the study intervention for the summarization. The value will be displayed as missing in 
the data listing.
6.5.5.
Missing Date Information for Adverse Events
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., partly missing):
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields.


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
If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields.

If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day.

If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date 
is after the month of the date of the first dose of study intervention, the first day of the 
month will be assigned to the missing day.
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date:

If the stop date is after the date of the first dose of study intervention, the date of the first 
dose of study intervention will be assigned to the missing start date.

If the stop date is before the date of the first dose of study intervention, the stop date will 
be assigned to the missing start date.


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6.5.6.
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including rescue medications, incomplete (i.e., partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
6.5.6.1.
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields.

If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields.

If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day.

If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date 
is after the month of the date of the first dose of study intervention, the first day of the 
month will be assigned to the missing day.


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6.5.6.2.
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study intervention is missing, 
impute it as descripted in Section 6.5.3. If the imputed stop date is before the start date (imputed 
or non-imputed start date), the imputed stop date will be equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
intervention, the month and day of the last dose of study intervention will be assigned to 
the missing fields.

If the year of the incomplete stop date is before the year of the last dose of study 
intervention, December 31 will be assigned to the missing fields.

If the year of the incomplete stop date is after the year of the last dose of study 
intervention, January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of study intervention, the day of the last dose of study intervention will be 
assigned to the missing day.

If either the year of the incomplete stop date is before the year of the date of the last dose 
of study intervention or if both years are the same but the month of the incomplete stop 
date is before the month of the date of the last dose of study intervention, the last day of 
the month will be assigned to the missing day.

If either the year of the incomplete stop date is after the year of the date of the last dose of 
study intervention or if both years are the same but the month of the incomplete stop date 
is after the month of the date of the last dose of study intervention, the first day of the 
month will be assigned to the missing day.


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7.
References
Not Applicable.


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21-Aug-2020
16:48:35
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