Clinical trial NCT04944290
Conditions: Glaucoma, Open-Angle Ocular Hypertension
Sponsor: Padagis LLC
Start date: 2021-05-28; Completion date: 2022-06-21
Enrollment: 447 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the efficacy and safety of Perrigo's product to an FDA approved product in the treatment of Primary Open Angle Glaucoma or Ocular Hypertension in Both Eyes.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Brinzolamide/brimonidine ophthalmic suspension intervention 2: Simbrinza 0.2%/1% Ophthalmic Suspension
Intervention descriptions: intervention 1: Test product intervention 2: Reference product

Protocol documents:
Prot_000.pdf: 
A  M ulti -C e nt er,  D o u bl e -M as k e d,  R a n d o miz e d,  T w o -Ar m,  P ar all el -Gr o u p,  S af et y  a n d  Effi c a c y 
St u d y  t o C o m p ar e   P erri g o P h ar m a c e uti c als  I nt er n ati o n al D A C  Bri nz ol a mi d e  a n d  Bri m o ni di n e 
T artr at e  O p ht h al mi c  S us p e nsi o n  1 % / 0. 2 % t o  N o v artis  P h ar m a c e uti c als  Si m bri nz a ® 
( bri nz ol a mi d e / bri m o ni di n e t artr at e  1 % / 0. 2 %  o p ht h al mi c s us p e nsi o n) i n t h e  Tr e at m e nt  of 
C hr o ni c  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 i n  b ot h  E y es  
 
 
Pr ot o c ol  N o.:  P R G -N Y -2 0 -0 0 2   
 
N C T 0 4 9 4 4 2 9 0  
 
Pr ot o c ol  D at e:   M a y  2 7,  2 0 2 1  


 
 
A  M ulti -C e nt er,  D o u bl e -M as k e d,  R a n d o miz e d,  T w o -Ar m,  P ar all el -Gr o u p,  S af et y  a n d  Effi c a c y 
St u d y t o  C o m p ar e  P erri g o  P h ar m a c e uti c al s I nt er n ati o n al  D A C  Bri nz ol a mi d e  a n d  Bri m o ni di n e 
T artr at e  O p ht h al mi c  S u s p e n si o n  1 % / 0. 2 % t o  N o v arti s  P h ar m a c e uti c al s  Si m bri nz a ® 
( bri nz ol a mi d e / bri m o ni di n e t artr at e  1 % / 0. 2 %  o p ht h al mi c  s u s p e n si o n) i n t h e  Tr e at m e nt  of 
C hr o ni c  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 n si o n i n  b ot h  E y es  
 
 
Pr ot o c ol  N o.:  P R G -N Y -2 0 -0 0 2  
  
 
 
 
 
 
 
 
 
 
 
C o nfi d e nti al  
 
 
T h e  c o nfi d e nti al i nf or m ati o n  pr o vi d e d i n t his  d o c u m e nt i s f or  u s e  b y  p arti es  dir e ctl y i n v ol v e d 
i n t hi s i n v esti g ati o n.   B y  a c c e pti n g t hi s  d o c u m e nt,  y o u  a gr e e t h at t h e i nf or m ati o n  c o nt ai n e d 
h er ei n  will  n ot  b e  di s cl os e d t o  a n y  p er s o n  n ot  dir e ctl y i n v ol v e d i n t his i n v esti g ati o n  wit h o ut 
writt e n  a ut h oriz ati o n fr o m  P erri g o  P h ar m a c e uti c al s I nt er n ati o n al  D A C  
 
 
 
 
 
 
 
 






P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4  of  6 6  
 
C o nt e nt s  
1  
B A C K G R O U N D  ............................................................................................................................................. 1 0  
2  
S T U D Y  O BJ E C TI V E S  ...................................................................................................................................... 1 1  
2. 1  
E n d p oi nt  ..................................................................................................................................................... 1 1  
2. 2  
S af et y  ......................................................................................................................................................... 1 1  
3  
S T U D Y  D E SI G N  ............................................................................................................................................. 1 1  
3. 1  
T y p e/ D esi g n  of  St u d y  ................................................................................................................................. 1 1  
3. 1. 1  
S cr e e ni n g  a n d  R u n -I n  P h as e .................................................................................................................. 1 2  
3. 1. 2  
R a n d o miz ati o n  a n d  D o u bl e -M as k e d  Tr e at m e nt  P h as e  ......................................................................... 1 2  
3. 2  
St u d y  P o p ul ati o n  ........................................................................................................................................ 1 2  
4  
S E L E C TI O N  A N D  WI T H D R A W A L  O F  S T U D Y  S U BJ E C T S  ................................................................................... 1 2  
4. 1  
I n cl usi o n  Crit eri a......................................................................................................................................... 1 2  
4. 2  
E x cl usi o n  Crit eri a  ........................................................................................................................................ 1 4  
4. 3  
Pr o hi bit e d  M e di c ati o ns  .............................................................................................................................. 1 7  
4. 4  
Pr e c a uti o ns  ................................................................................................................................................. 1 9  
5  
P R O C E D U R E S  ............................................................................................................................................... 2 1  
5. 1  
S u bj e ct  S cr e e ni n g, I nf or m e d  C o ns e nt  a n d  E nr oll m e nt  ............................................................................... 2 1  
5. 1. 1  
Assi g n m e nt  of  S u bj e ct  N u m b er  ............................................................................................................. 2 1  
5. 2  
D e m o gr a p hi cs/ M e di c al  Hist or y  .................................................................................................................. 2 1  
5. 3  
O c ul ar  Hist or y  ............................................................................................................................................. 2 1  
5. 4  
C o n c o mit a nt  M e di c ati o ns  .......................................................................................................................... 2 2  
5. 5  
Vit al  Si g ns  ................................................................................................................................................... 2 2  
5. 6  
Uri n e  Pr e g n a n c y  T est  ................................................................................................................................. 2 2  
5. 7  
E xt er n al  E y e  E x a m  ...................................................................................................................................... 2 2  
5. 7. 1  
Iris  Col or  ................................................................................................................................................. 2 3  
5. 8  
I ntr a o c ul ar  Pr ess ur e (I O P)  M e as ur e m e nt ................................................................................................... 2 3  
5. 8. 1  
Visit  1/ S cr e e ni n g I O P  M e as ur e m e nts  .................................................................................................... 2 4  
5. 8. 2  
Visit  2/ B as eli n e/ D a y  0  ............................................................................................................................ 2 4  
5. 8. 3  
Visit  3/ W e e k  2/ D a y  1 4 ( ±  4  d a ys)  a n d  Visit  4/ W e e k  6/ D a y  4 2 ( ±  4  d a ys) I O P  M e as ur e m e nts  .............. 2 4  
 
 
 
 
 
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5  of  6 6  
 
 
 
5. 1 5  
St u d y  M e di c ati o n  M as ki n g  ......................................................................................................................... 2 7  
5. 1 5. 1  
T hir d -P art y  Dis p e ns er  ........................................................................................................................ 2 7  
5. 1 5. 2  
St u d y  M e di c ati o n  Us e,  S u bj e ct I nstr u cti o ns  a n d  Di ar y  ..................................................................... 2 9  
5. 1 5. 3  
Visit  2/ B as eli n e/ D a y  0  St u d y  M e di c ati o n  &  Di ar y  Dis p e nsi n g  ........................................................... 3 0  
5. 1 5. 4  
Visit  3/ W e e k  2 / D a y  1 4 ( ±  4  d a ys)  a n d  Visit  4/ W e e k  6/ D a y  4 2  St u d y  M e di c ati o n  a n d  Di ar y 
Dis p e nsi n g  &  A c c o u nt a bilit y  ............................................................................................................................... 3 1  
5. 1 5. 5  
U ns c h e d ul e d  Visit  .............................................................................................................................. 3 2  
5. 1 6  
Visit  S p e cifi c  Pr o c e d ur es  ............................................................................................................................. 3 2  
5. 1 6. 1  
Visit  1/ S cr e e ni n g  ................................................................................................................................ 3 2  
5. 1 6. 2  
V isit  2/ B as eli n e/ D a y  0 ....................................................................................................................... 3 3  
5. 1 6. 3  
Visit  3/ W e e k  2/ D a y  1 4 ( ±  4  d a ys)  ...................................................................................................... 3 4  
5. 1 6. 4  
Visit  4/ W e e k  6/ D a y  4 2 ( ±  4  d a ys)  E n d  of  St u d y  or  E arl y  T er mi n ati o n  Visit  ....................................... 3 5  
5. 1 6. 5  
U ns c h e d ul e d  Visit  .............................................................................................................................. 3 5  
5. 1 7  
S u m m ar y  of  Ass ess m e nts  ........................................................................................................................... 3 6  
5. 1 8  
S cr e e n  F ail ur es  ........................................................................................................................................... 3 9  
5. 1 9  
Pr ot o c ol  D e vi ati o ns/ Vi ol ati o ns  ................................................................................................................... 3 9  
5. 2 0  
S u bj e ct/ Tr e at m e nt  C o m pli a n c e  .................................................................................................................. 3 9  
5. 2 1  
Dis c o nti n u ati o n/ Wit h dr a w al  of  St u d y  S u bj e cts  ......................................................................................... 4 0  
6  
M A T E RI A L S  A N D  S U P P LI E S  .......................................................................................................................... 4 1  
6. 1  
St u d y  M e di c ati o n  ....................................................................................................................................... 4 1  
6. 2  
M e di c ati o n  M a n a g e m e nt  .......................................................................................................................... 4 1  
6. 2. 1  
L a b eli n g,  P a c k a gi n g  a n d  Distri b uti o n  ..................................................................................................... 4 1  
6. 2. 2  
R et e nti o n  S a m pl es  ................................................................................................................................. 4 2  
6. 2. 3  
St or a g e  a n d  T est  Arti cl e  A c c o u nt a bilit y  ................................................................................................. 4 3  
6. 2. 4  
R a n d o miz ati o n  ....................................................................................................................................... 4 3  
6. 2. 5  
Pr o c e d ur e f or  Br e a ki n g t h e  Bli n d ........................................................................................................... 4 3  
7  
A D V E R S E  R E A C TI O N S ................................................................................................................................... 4 4  
7. 1  
D e p art ur e fr o m t h e  Pr ot o c ol f or I n di vi d u al  S u bj e cts  .................................................................................. 4 4  
7. 2  
D efi niti o n s .................................................................................................................................................. 4 5  
7. 3  
Eli citi n g  a n d  R e p orti n g  of  A d v ers e  E v e nts  .................................................................................................. 4 6  
7. 3. 1  
E x p e dit e d  R e p orti n g  R es p o nsi biliti es  of t h e  St u d y  C e nt er  .................................................................... 4 7  
7. 3. 2  
S u b mitti n g  a n  E x p e dit e d  S af et y  R e p ort t o t h e I R B  ................................................................................ 4 7  
7. 4  
S A E  &  A Es  R e q uiri n g  Dis c o nti n u ati o n  of  St u d y  Dr u g, i n cl u di n g  Pr e g n a n ci es  ............................................. 4 8  
7. 4. 1  
Pr e g n a n c y  .............................................................................................................................................. 4 9  
7. 5  
P ost  St u d y  A d v ers e  E v e nts .......................................................................................................................... 5 0  
7. 5. 1  
N o n -s eri o us  A d v ers e  E v e nts  .................................................................................................................. 5 0  
7. 5. 2  
S eri o us  A d v ers e  E v e nts  .......................................................................................................................... 5 0  
8  
St atisti c al  A n al ysis  ....................................................................................................................................... 5 0  


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6  of  6 6  
 
8. 1  
St atisti c al  A n al ysis  Pl a n  .............................................................................................................................. 5 0  
8. 1. 1  
A n al ysis  P o p ul ati o ns  .............................................................................................................................. 5 1  
8. 1. 2  
Pl a n n e d  A n al ysis  .................................................................................................................................... 5 1  
8. 1. 3  
S a m pl e  Siz e  C o nsi d er ati o ns  ................................................................................................................... 5 1  
8. 1. 4  
Effi c a c y  M e as ur es  a n d  A n al ysis  ............................................................................................................. 5 2  
8. 1. 5  
S af et y  a n d  A d v ers e  E v e nts  A n al ysis  ....................................................................................................... 5 3  
8. 2  
C o m p ar a bilit y  of  S u bj e cts  at  B as eli n e  ........................................................................................................ 5 3  
9  
C O N S E N T / A S S E N T  C O N SI D E R A TI O N S  A N D  P R O C E D U R E S  ............................................................................ 5 3  
9. 1  
S u bj e ct  C o nfi d e nti alit y  ............................................................................................................................... 5 4  
1 0  
C O N D U C T  O F  S T U D Y  .................................................................................................................................... 5 5  
1 0. 1  
C o m pl eti o n  of  St u d y  ................................................................................................................................... 5 5  
1 0. 2  
Pr o t o c ol  A m e n d m e nts ................................................................................................................................ 5 5  
1 0. 3  
C O VI D -1 9  Ris k  Miti g ati o n  ........................................................................................................................... 5 5  
1 0. 4  
Alt er n ati v e  pr ot o c ol  ass ess m e nts  d uri n g t h e  C O VI D -1 9  P a n d e mi c  o nl y  .................................................... 5 6  
1 0. 4. 1  
S u bj e ct  Dis p ositi o n  d u e t o  C O VI D -1 9 I nf e cti o n  ................................................................................. 5 6  
1 0. 4. 2  
R e g ul at or y  a n d  St u d y  O v ersi g ht  C o nsi d er ati o ns  ............................................................................... 5 6  
1 0. 4. 3  
D o c u m e nt ati o n  of  Pr ot o c ol  D e vi ati o ns  r el at e d t o  C O VI D-1 9  ............................................................ 5 6  
1 1  
R E C O R D S  M A N A G E M E N T  ............................................................................................................................ 5 6  
1 1. 1  
D at a  C oll e cti o n  ........................................................................................................................................... 5 6  
1 1. 2  
S o ur c e  D o c u m e nts  ...................................................................................................................................... 5 8  
1 1. 3  
Fil e  M a n a g e m e nt  at t h e  St u d y  Sit e  ............................................................................................................ 5 8  
1 1. 4  
R e c or ds  R et e nti o n  at t h e  St u d y  Sit e  ........................................................................................................... 5 8  
1 2  
Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E  ........................................................................................... 5 8  
1 2. 1  
M o nit ori n g  ................................................................................................................................................. 5 8  
1 2. 2  
A u diti n g  ...................................................................................................................................................... 5 8  
1 3  
E T HI C S  A N D  R E S P O N SI BI LI T Y  ....................................................................................................................... 5 9  
1 4  
U S E  O F I N F O R M A TI O N  A N D  P U B LI C A TI O N  .................................................................................................. 5 9  
1 5  
I N V E S TI G A T O R  A G R E E M E N T ....................................................................................................................... 6 0  
1 6  
A P P E N DI C E S  ................................................................................................................................................ 6 1  
1 6. 1  
A p p e n di x  A:  St u d y  P ers o n n el  C o nt a cts  ....................................................................................................... 6 1  
1 6. 2  
A p p e n di x  B:  I nstr u cti o ns f or t h e  S u bj e ct  ................................................................................................... 6 2  
1 7  
R ef er e n c e s  .................................................................................................................................................. 6 6  
 




P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  8  of  6 6  
 
T h e  i ntr a o c ul ar  pr ess ur e (I O P)/  G ol d m a nn  A p pl a n ati o n  T o n o m etr y ( G A T)    
  will  b e  p erf or m e d  a n d 
r e c or d e d  at  Visit  2/ B as eli n e  a n d  all s u bs e q u e nt  visits. 
E n d p oi nts:  
T h e  pri m ar y  effi c a c y  e n d p oi nt  will  b e t h e  m e a n  c h a n g e fr o m  B as eli n e i n 
i ntr a o c ul ar  pr ess ur e (I O P)  of  b ot h  e y es  at  all f o ur ti m e  p oi nts ( e. g.,  at 
a p pr o xi m at el y  8: 0 0  a m ( h o ur  0,  b ef or e t h e  m or ni n g  dr o p)  a n d  1 0: 0 0  a m 
( h o ur  2)  at  Visit  3/W e e k  2/ D a y  1 4  (± 4  d a ys)  a n d  Visit  4 /W e e k  6 / D a y  4 2  (± 4 
d a ys)   
S af et y:  
T h e i n ci d e n c e  of  all  a d v ers e  e v e nts r e p ort e d  d uri n g t h e st u d y  will  b e 
s u m m ariz e d  b y tr e at m e nt  gr o u p.   E q ui v al e n c e  of t h e t est  a n d r ef er e n c e  wit h 
r e g ar d t o s af et y  will  b e  e v al u at e d  b y  c o m p ari n g t h e  n at ur e, s e v erit y  a n d 
fr e q u e n c y  of t h eir  a d v ers e  e v e nt  pr ofil es.   


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  9  of  6 6  
 
A B B R E VI A TI O N S  
 
A E  
A d v ers e  E v e nt  
 
 
C AI  
C ar b o ni c  A n h y dr o us I n hi bit or  
CI  
C o nfi d e n c e I nt er v al  
C R A  
Cli ni c al  R es e ar c h  Ass o ci at e  
C O A G  
C hr o ni c  O p e n  A n gl e  Gl a u c o m a  
C R O  
C o ntr a ct  R es e ar c h  Or g a niz ati o n   
e C R F  
El e ctr o ni c  C as e  R e p ort  F or m  
E D C  
El e ctr o ni c  D at a  C a pt ur e  
 
 
F D A  
U S  F o o d  a n d  Dr u g  A d mi nistr ati o n  
 
 
G C P   
G o o d  Cli ni c al  Pr a cti c es  
hr  
H o ur  
I C H 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o niz ati o n 
I O P 
I ntr a o c ul ar  Pr ess ur e 
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I T T 
I nt e nt- t o-tr e at ( p o p ul ati o n) 
I U 
I nt er n ati o n al  U nit 
I U D 
I ntr a-Ut eri n e  D e vi c e  
L o g M ar  
L o g arit h m  of t h e  Mi ni m u m  A n gl e  of  R es ol uti o n  
L S  
L e ast s q u ar es  
M R  
M a nif est r efr a cti o n  
M e d D R A  
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
M in  
Mi n ut es  
N S AI D  
N o n -St er oi d al  A nti -I nfl a m m at or y  Dr u g  
O H  
O c ul ar  H y p ert e nsi o n  
O T C  
O v er t h e  c o u nt er  
PI  
Pri n ci p al I n v esti g at or  
P P  
P er -pr ot o c ol  ( p o p ul ati o n) 
R L D  
R ef er e n c e  List e d  Dr u g  
R x  
Pr es cri pti o n  
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   
SI T A  
S w e dis h I nt er a cti v e  T esti n g  Al g orit h m  
S u b -I  
S u b -I n v esti g at or 
U P T  
Uri n e  Pr e g n a n c y  T est   
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  1 0  of  6 6  
 
1   B A C K G R O U N D  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  1 1  of  6 6  
 
 
2   S T U D Y  O BJ E C TI V E S  
T h e   o bj e cti v es   of  t his  st u d y   ar e  t o   c o m p ar e  t h e   effi c a c y   a n d  s af et y   pr ofil es   of   P erri g o  
P h ar m a c e uti c als  I nt er n ati o n al   D A C   Bri nz ol a mi d e   a n d   Bri m o ni di n e   T artr at e   O p ht h al mi c  
S us p e nsi o n  1 %/ 0. 2 % t o  N o v artis  P h ar m a c e uti c als  Si m bri nz a ® ( bri nz ol a mi d e/ bri m o ni di n e t artr at e 
1 %/ 0. 2 %   o p ht h al mi c  s us p e nsi o n),  i n   or d er  t o   pr o v e   bi o e q ui v al e n c e   b et w e e n  t h e m  i n  t h e  
tr e at m e nt  of  c hr o ni c  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 i n  b ot h  e y es. 
 
2. 1   E n d p oi nt  
 
T h e  pri m ar y  effi c a c y  e n d p oi nt  will  b e t h e  m e a n  c h a n g e fr o m  B as eli n e i n i ntr a o c ul ar  pr ess ur e (I O P) 
of  b ot h  e y es  at  all f o ur ti m e  p oi nts ( e. g.,  at  a p pr o xi m at el y  8: 0 0  a m ( h o ur  0,  b ef or e t h e  m or ni n g 
dr o p)  a n d  1 0: 0 0  a m ( h o ur  2)  at  Visit  3 /W e e k  2/ D a y  1 4  (± 4  d a ys)  a n d  Visit  4 /W e e k  6/ D a y  4 2  (± 4 
d a ys).  
 
2. 2    S af et y  
S af et y  of t h e t est  a n d r ef er e n c e  pr o d u cts  will  b e  c o m p ar e d  b y  e v al u ati n g t h e  n at ur e, s e v erit y  a n d 
fr e q u e n c y  of t h eir  a d v ers e  e v e nt  pr ofil es.   All  a d v ers e  e v e nts t h at  o c c ur  d uri n g t h e st ud y  will  b e 
r e c or d e d  w h et h er  or  n ot t h e y  ar e  c o nsi d er e d t o  b e r el at e d t o t h e  st u d y  m e di c ati o n.  D es cri pti o ns 
of r e a cti o ns  or  c o m pl ai nts  will i n cl u d e t h e  a p pr o xi m at e  d at e  of  o ns et, t h e  d at e t h e  a d v ers e  e v e nt 
e n d e d, t h e s e v erit y  of t h e  a d v ers e  e v e nt,  a n d t h e  o ut c o m e.   C o m p aris o ns  b et w e e n t h e tr e at m e nt 
gr o u ps  will  b e  m a d e  b y t a b ul ati n g t h e fr e q u e n c y  of s u bj e cts  wit h  o n e  or  m or e  a d v ers e  e v e nts 
( cl assifi e d i nt o  M e d D R A t er ms)  d uri n g t h e st u d y.  P e ars o n’s  C hi-S q u ar e t est  or  Fis h er’s  E x a ct t est, 
w hi c h e v er is  m ost  a p pr o pri at e,  will  b e  us e d t o  c o m p ar e t h e  pr o p orti o n  of s u bj e cts i n  e a c h 
tr e at m e nt  gr o u p  wit h  a n y  a d v ers e  e v e nt.   T h e  a d v ers e  e v e nts r e p ort e d  b y  at l e ast fi v e  p er c e nt 
of t h e s u bj e cts i n  a n y tr e at m e nt  gr o u p  will  b e s u m m ariz e d  d es cri pti v el y.  
 
3   S T U D Y  D E SI G N  
 
3. 1   T y p e / D esi g n  of  St u d y  
 
S u bj e cts  i n  t his   m ulti -c e nt er,   d o u bl e -m as k e d,  r a n d o miz e d,   p ar all el -gr o u p  st u d y   w h o   m e et  
eli gi bilit y  crit eri a  at  Visit  2 / B as eli n e ( D a y  0 ),  will  b e  assi g n e d 
 t o t est  pr o d u ct  or 
r ef er e n c e  pr o d u ct, r es p e cti v el y.  O n e  dr o p  of t h e  assi g n e d st u d y  m e di c ati o n  will  b e  a p pli e d i n 
b ot h  e y es t hr e e ( 3) ti m es  d ail y  at  a p pr o xi m at el y  8: 0 0  a m,  4: 0 0  p m,  a n d  1 0: 0 0  p m f or  6  w e e ks ( 4 2 
d a ys).  
 
M al es   a n d  f e m al es,   at  l e ast   1 8   y e ars   of   a g e   wit h   c hr o ni c   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 i n  b ot h  e y es  will  b e  eli gi bl e f or  e nr oll m e nt.  Visits t o t h e st u d y sit e  ar e s c h e d ul e d  at 
Visit  1 / S cr e e ni n g,  Visit  2/ B as eli n e ( D a y  0 ),  Visit  3/ W e e k  2/ D a y  1 4 ( ± 4  d a ys)  a n d  Visit  4/  W e e k 
6/ D a y  4 2 ( ± 4  d a ys).   
 
T h e st u d y  c o nsists  of  a r u n -i n  p h as e  a n d  a si x-w e e k t r e at m e nt ( 4 2  ± 4  d a ys)  d ur ati o n. 








P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  1 5  of  6 6  
 
1.   S u bj e cts   w h o   ar e   pr e g n a nt,   br e astf e e di n g   or   pl a n ni n g   a   pr e g n a n c y   wit hi n  t h e  st u d y  
p arti ci p ati o n  p eri o d.  
2.   S u bj e cts  w h o  ar e f e m al es,  of  c hil d b e ari n g  p ot e nti al  w h o  d o  n ot  a gr e e t o  utiliz e  a n  a d e q u at e 
f or m  of  c o ntr a c e pti o n.  
3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  1 6  of  6 6  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 








P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  2 0  of  6 6  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
     
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  2 1  of  6 6  
 
 
 
 
 
. 
 
 
5   P R O C E D U R E S  
 
5. 1   S u bj e ct  S cr e e ni n g,  I nf or m e d  C o n s e nt  a n d  E nr oll m e nt 
T h e st u d y  p ers o n n el  will r e vi e w t h e I R B  a p pr o v e d i nf or m e d  c o ns e nt f or m  a n d  ass e nt f or m  (if 
a p pli c a bl e) ,  wit h  e a c h s u bj e ct  a n d  gi v e t h e s u bj e ct  a n  o p p ort u nit y t o  h a v e  all  q u esti o ns  a ns w er e d 
b ef or e  pr o c e e di n g.   T h e I R B  a p pr o v e d i nf or m e d  c o ns e nt/ ass e nt f or m  m ust  b e si g n e d  b y  e a c h 
s u bj e ct  b ef or e t h e s u bj e ct is  e nr oll e d i nt o t h e st u d y.   A  c o p y  of t h e si g n e d  c o ns e nt/ ass e nt  will  b e 
gi v e n  t o   e v er y   p arti ci p a nt  ( or  l e g all y   a ut h oriz e d  r e pr es e nt ati v e)   a n d  t h e   ori gi n al   will   b e  
m ai nt ai n e d  wit h t h e  p arti ci p a nt’s r e c or ds.  
 
 
.  
S u bj e cts t h at r e q uir e  a  w as h -o ut  of  m or e t h a n  3 0  d a ys fr o m t h eir i niti al i nf or m e d  c o ns e nt/ ass e nt 
si g ni n g  m ust  b e r e -c o ns e nt e d  b ef or e  a n y f urt h er st u d y  pr o c e d ur es  c a n  b e gi n.  
 
5. 1. 1   A ssi g n m e nt  of  S u bj e ct  N u m b er  
 
 
 
 
 
 
  
 
5. 2   D e m o gr a p hi cs / M e di c al  Hi st or y  
A  d e m o gr a p hi c  pr ofil e  a n d  c o m pl et e  m e di c al  hist or y  will  b e r e c or d e d  pri or t o st arti n g st u d y 
m e di c ati o n .   T h e  m e di c al  hist or y  will i n cl u d e  a  c o m pl et e r e vi e w  of  all  c urr e nt  dis e as es  a n d t h eir 
r es p e cti v e tr e at m e nts. 
 
5. 3   O c ul a r  Hi st or y 
A  c o m pl et e  o c ul ar  a n d s ur gi c al  hist or y  will  b e r e c or d e d  pri or t o st arti n g st u d y  m e di c ati o n.  T h e 
o c ul ar  hist or y  will i n cl u d e  a  c o m pl et e r e vi e w  of  all  pri or  a n d  c urr e nt  o c ul ar  dis e as es  a n d t h eir 
r es p e cti v e tr e at m e nts. 
 
















P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  2 9  of  6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  3 3  of  6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
















P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4 1  of  6 6  
 
f oll o w-u p.  
 
6   M A T E RI A L S  A N D  S U P P LI E S  
 
6. 1   St u d y  M e di c ati o n  
T h e st u d y  m e di c ati o n s u p pli e d  b y  P erri g o  will  c o nsist  of:  
 
T est  Pr o d u ct :  Br i nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  O p ht h al mi c  S us p e nsi o n  1 %/ 0. 2 %, 
P erri g o  P h ar m a c e uti c als I nt er n ati o n al  D A C, 
  
 
R ef er e n c e  Pr o d u ct :   Si m bri nz a ® ( bri nz ol a mi d e/ bri m o ni di n e t artr at e  1 %/ 0. 2 %  o p ht h al mi c 
s us p e nsi o n),  m a n uf a ct ur e d  b y  N o v artis  P h ar m a c e uti c als.  
 
6. 2   M e di c ati o n  M a n a g e m e nt  
 
6. 2. 1   L a b eli n g,  P a c k a gi n g  a n d  Di stri b uti o n  
 
 
 
  
 
All st u d y  m e di c ati o ns  will  b e s u p pli e d t o t h e s u bj e cts i n  1 0 ml  pl asti c  b ottl es.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4 4  of  6 6  
 
7   A D V E R S E  R E A C TI O N S  
T h e  p ot e nti al  a d v ers e r e a cti o ns  of  g e n eri c  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  O p ht h al mi c 
S us p e nsi o n   1 %/ 0. 2 %,   ar e   a nti ci p at e d  t o   b e   si mil ar  t o  t h os e   o bs er v e d  i n   Si m bri nz a ®  
( bri nz ol a mi d e/ bri m o ni di n e t artr at e  1 %/ 0. 2 %)  o p ht h al mi c s us p e nsi o n), 
 
T h e f oll o wi n g  a d v ers e r e a cti o ns  o c c urr e d i n  3 %  t o  5 %  of  p ati e nts tr e at e d  wit h  Si m bri nz a ® i n cl u d e 
bl urr e d  visi o n,  e y e irrit ati o n,  d ys g e usi a ( b a d t ast e ),  dr y  m o ut h,  a n d  e y e  all er g y  m a y  o c c ur.  
 
Ot h er  a d v er s e r e a cti o n s r e p ort e d  wit h i n di vi d u al  a cti v e i n gr e di e nt s  of  S im bri nz a ®  O p ht h al mi c 
S u s p e n si o n  
T h e  m ost fr e q u e ntl y r e p ort e d  a d v ers e r e a cti o ns  o c c urri n g  i n  1 % t o  5 % of  p ati e nts tr e at e d  wit h 
Bri nz ol a mi d e  o p ht h al mi c  s us p e nsi o n  1 % i n  cli ni c al st u di es  w er e  bl e p h aritis,  d er m atitis,  dr y,  e y e, 
f or ei g n   b o d y  s e ns ati o n,   h e a d a c h e,   h y p er e mi a,   o c ul ar   dis c h ar g e,   oc ul ar   dis c o mf ort,   o c ul ar  
k er atitis,  o c ul ar  p ai n,  o c ul ar  pr urit us  a n d r hi nitis.  T h e f oll o wi n g  a d v ers e r e a cti o ns  w er e r e p ort e d 
i n  1 %  of  p ati e nts tr e at e d  wit h  Bri nz ol a mi d e  o p ht h al mi c s us p e nsi o n  1 %:  all er gi c r e a cti o ns,  c h est 
p ai n,  c o nj u n cti vitis,  di arr h e a,  di pl o pi a,  dizzi n ess,  dr y  m o ut h,  d ys p n e a,  d ys p e psi a,  e y e f ati g u e, 
h y p ert o ni a,  k er at o c o nj u n cti vitis,  k er at o p at h y,  ki d n e y  p ai n, li d  m ar gi n  cr usti n g  or sti c k y s e ns ati o n, 
n a us e a,  p h ar y n gitis, t e ari n g  a n d  urti c ari a.  
 
T h e  m ost fr e q u e ntl y r e p ort e d  a d v ers e r e a cti o ns  o c c urri n g  i n  1 0 % t o  3 0%  of  p ati e nts tr e at e d  wit h 
Bri m o ni di n e  T artr at e  0. 2 %  o p ht h al mi c  s us p e nsi o n i n  cli ni c al st u di es  w er e  or al  dr y n ess,  o c ul ar 
h y p er e mi a,  b ur ni n g  a n d sti n gi n g,  h e a d a c h e,  bl urri n g, f or ei g n  b o d y s e ns ati o n, f ati g u e/ dr o wsi n ess, 
c o nj u n cti v al  f olli cl es,   o c ul ar   all er gi c  r e a cti o ns   a n d   o c ul ar   pr urit us.   T h e  f oll o wi n g   a d v ers e  
r e a cti o ns   w er e  r e p ort e d  i n  3 %  t o   9 %   of   p ati e nts  tr e at e d   wit h   Bri m o ni di n e   T artr at e   0. 2 %  
o p ht h al mi c  s us p e nsi o n:   c or n e al  st ai ni n g/ er osi o n,   p h ot o p h o bi a,   e y eli d   er yt h e m a,   o c ul ar  
a c h e/ p a i n,   o c ul ar   dr y n ess,  t e ari n g,   u p p er  r es pir at or y  s y m pt o ms,   e y eli d   e d e m a,  c o nj u n cti v al 
e d e m a,  dizzi n ess,  bl e p h aritis,  o c ul ar irrit ati o n,  g astr oi nt esti n al s y m pt o ms ,  ast h e ni a, c o nj u n cti v al 
bl a n c hi n g,  a b n or m al  visi o n  a n d  m us c ul ar  p ai n.  T h e f oll o wi n g  a d v ers e r e a c ti o ns  w er e r e p ort e d i n 
≤  3 %  of  p ati e nts tr e at e d  wit h  Bri m o ni di n e  T artr at e  0. 2 %  o p ht h al mi c s us p e nsi o n: li d  cr usti n g, 
c o nj u n cti v al   h e m orr h a g e   a b n or m al  t ast e,  i ns o m ni a,   c o nj u n cti v al   dis c h ar g e,   d e pr essi o n,  
h y p ert e nsi o n,  a n xi et y,  p al pit ati o ns/ arr h yt h mi as,  n as al  dr y n ess  a n d s y n c o p e.  
 
T h er e is  n o  p ost  m ar k eti n g  e x p eri e n c e  wit h  Si m bri nz a ®  o p ht h al mi c s us p e nsi o n.  T h e f oll o wi n g 
a d v ers e  r e a cti o ns   h a v e   b e e n  i d e ntifi e d   d uri n g   p ost -a p pr o v al   us e   of   bri m o ni di n e  t artr at e  
o p ht h al mi c s ol uti o ns i n  cli ni c al  pr a cti c e,  a si mil ar  dr u g  c o nt ai ni n g  bri m o ni di n e t artr at e  as  a n 
a cti v e  i n gr e di e nt   ar e   br a d y c ar di a,   h y p ers e nsiti vit y,  iritis,   k er at o c o nj u n cti vitis  si c c a,   mi osis,  
n a us e a,  s ki n  r e a cti o ns  (i n cl u di n g   er yt h e m a,   e y eli d   pr urit us,  r as h,   a n d   v as o dil ati o n)   a n d  
t a c h y c ar di a.  p ai n  of s ki n,  pr urit us, s w elli n g f a c e,  c o nj u n cti vitis, s ki n  dis c ol or ati o n, r as h,  e cz e m a, 
t hr o at ti g ht n ess  a n d  all er gi c  c o nt a ct  d er m atitis. 
 
7. 1   D e p art ur e fr o m t h e  Pr ot o c ol f or I n di vi d u al  S u bj e ct s  
W h e n  a n  e m er g e n c y  o c c urs r e q uiri n g  a  d e p art ur e fr o m t h e  pr ot o c ol f or  a s u bj e ct,  d e p art ur e  will 
b e  o nl y f or t h at s u bj e ct.  I n s u c h  cir c u mst a n c es, t h e i n v esti g at or  or  ot h er  p h ysi ci a n i n  att e n d a n c e 
will  c o nt a ct t h e  M e di c al  M o nit or  or  P erri g o  b y t el e p h o n e  a n d f oll o w  u p  wit h  a  writt e n  d es cri pti o n 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4 5  of  6 6  
 
as s o o n  as  p ossi bl e.   T h e  o v ers e ei n g I R B s h o ul d  als o  b e  n otifi e d i n  a c c or d a n c e  wit h t h e I R B’s 
g ui d eli n es.  
 
7. 2   D efi niti o n s 
A n  a d v ers e  e v e nt ( A E) is  d efi n e d  as  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a s u bj e ct  a d mi nist er e d 
a  m e di ci n 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 t o  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 d v ers e   e v e nt   c a n  t h er ef or e   b e   a n y   u nf a v or a bl e   a n d   u ni nt e n d e d  si g n  (f or  
e x a m pl e,  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  pr o d u ct,  w h et h er  or  n ot  c o nsi d er e d r el at e d t o t his  m e di ci n al  pr o d u ct.  
 
A  s eri o us  a d v ers e  e v e nt ( S A E)  is  a n  a d v ers e  e v e nt t h at r es ults i n  a n y  of t h e f oll o wi n g  o ut c o m es: 
•   D e at h  
•   Lif e- t hr e at e ni n g   e v e nt  ( e. g.,  t h e  s u bj e ct   w as,  i n  t h e   o pi ni o n   of  t h e  i n v esti g at or,   at  
i m m e di at e ris k  of  d e at h fr o m t h e  e v e nt  as it  o c c urr e d.  It  d o es  n ot i n cl u d e  a n  e v e nt t h at, 
h a d it  o c c urr e d i n  a  m or e s e v er e f or m,  mi g ht  h a v e  c a us e d  d e at h)  
•   R e q uir es i n -s u bj e ct  h os pit aliz ati o n  or  pr ol o n gs  h os pit aliz ati o n  
•   A  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y  or s u bst a nti al  disr u pti o n  of t h e  a bilit y t o 
c o n d u ct  n or m al lif e f u n cti o ns  
•   C o n g e nit al  a n o m al y/ birt h  d ef e ct  
•   Ot h er  a d v ers e  e v e nts t h at  m a y  b e  c o nsi d er e d s eri o us  b as e d  u p o n  a p pr o pri at e  m e di c al 
j u d g m e nt,  m a y j e op ar diz e t h e s u bj e ct  a n d  m a y r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o 
pr e v e nt  o n e  of t h e  o ut c o m es list e d  a b o v e.  
 
I m m e di at el y   R e p ort a bl e   A d v ers e   E v e nts  (I R A E):  A n y  s eri o us   A E   or   a n y   A E  t h at   n e c essit at es  
dis c o nti n u ati o n  of st u d y  m e di c ati o n, i n cl u di n g  pr e g n a n c y.  
 
U n e x p e ct e d  A d v ers e  E v e nt :   A n u n e x p e ct e d  e v e nt  is  a n y  a d v ers e  dr u g  e x p eri e n c e, t h e s p e cifi cit y 
or s e v erit y  of  w hi c h is  n ot  c o nsist e nt  wit h t h e  c urr e nt  a p pr o v e d  pr o d u ct l a b eli n g ( p a c k a g e i ns ert) 
f or t h e st u d y  m e di c ati o n, t h e I n v esti g at or’s  Br o c h ur e,  or  as  d es cri b e d i n t h e  cli ni c al  pr ot o c ol  a n d 
c o ns e nt  m at eri als.     
 
I nt e nsit y  of  A d v ers e  E v e nts:   T h e  m a xi m u m i nt e nsit y  of  a n  A E  d uri n g  a  d a y s h o ul d  b e r e c or d e d 
o n t h e  C R F. If t h e i nt e nsit y  of  a n  A E  c h a n g es  o v er  a  n u m b er  of  d a ys, t h e n s e p ar at e  e ntri es s h o ul d 
b e  m a d e  h a vi n g  disti n ct  o ns et  d at es f or t h e  c h a n g e s i n s e v erit y. 
 
Mil d  - A Es  ar e  us u all y tr a nsi e nt, r e q uiri n g  n o s p e ci al tr e at m e nt,  a n d  d o  n ot i nt erf er e  wit h 
s u bj e ct’s  d ail y  a cti viti es. 
 
M o d er at e  - A Es t y pi c all y i ntr o d u c e  a l o w l e v el  of i n c o n v e ni e n c e  or  c o n c er n t o t h e s u bj e ct 
a n d  m a y i nt erf er e  wit h  d ail y  a cti viti es,  b ut  ar e  us u all y  a m eli or at e d  b y si m pl e t h er a p e uti c 
m e as ur es.  
 
S e v er e  - A Es i nt err u pt  a s u bj e ct’s  us u al  d ail y  a cti vit y  a n d tr a diti o n all y r e q uir e s yst e mi c  dr u g 
t h er a p y  or  ot h er tr e at m e nt. 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4 6  of  6 6  
 
C a us al  R el ati o ns hi p t o  St u d y  M e di c ati o n:  T h e f oll o wi n g  crit eri a s h o ul d  b e  us e d i n  ass essi n g t h e 
a p p ar e nt  c a us al r el ati o ns hi p  of  a n  A E t o st u d y  m e di c ati o n.   
 
D efi nit el y  - T h e  A E:  
•  f oll o ws  a r e as o n a bl e t e m p or al s e q u e n c e fr o m st u d y  m e di c ati o n  a d mi nistr ati o n 
•  a b at es  u p o n  dis c o nti n u ati o n  of t h e st u d y  m e di c ati o n ( d e c h all e n g e)  
•  is  c o nfir m e d  b y r e a p p e ar a n c e  of t h e r e a cti o n  o n r e p e at  e x p os ur e 
 
Pr o b a bl y  - T h e  A E:  
•  f oll o ws  a r e as o n a bl e t e m p or al s e q u e n c e fr o m st u d y  m e di c ati o n  a d mi nistr ati o n 
•  a b at es  u p o n  dis c o nti n u ati o n  of t h e st u d y  m e di c ati o n ( d e c h all e n g e)  
•  c a n n ot  b e r e as o n a b l y  e x pl ai n e d  b y t h e  k n o w n  c h ar a ct eristi cs  of t h e s u bj e ct’s st at e. 
 
P ossi bl e  - T h e  A E:  
•  f oll o ws  a r e as o n a bl e t e m p or al s e q u e n c e fr o m st u d y  m e di c ati o n  a d mi nistr ati o n 
•  b ut t h at  c o ul d r e a dil y  b e  pr o d u c e d  b y  a  n u m b er  of  ot h er f a ct ors . 
 
U nli k el y  - T h e  A E:  
•   f oll o ws  a r e as o n a bl e t e m p or al s e q u e n c e fr o m st u d y  m e di c ati o n  a d mi nistr ati o n. 
•   c o ul d  h a v e  b e e n  pr o d u c e d  b y  eit h er t h e s u bj e ct’s  cli ni c al st at e  or  b y st u d y  m e di c ati o n 
a d mi nistr ati o n.  
 
N ot r el at e d  - T h e  A E:  
•   d o es   n ot   h a v e   a  r e as o n a bl e  t e m p or al   ass o ci ati o n   wit h  t h e   a d mi nistr ati o n   of  st u d y  
m e di c ati o n   
•   h as s o m e  ot h er  o b vi o us  e x pl a n ati o n f or t h e  e v e nt.  
 
7. 3   Eli citi n g  a n d  R e p orti n g  of  A d v er s e  E v e nt s  
T h e i n v esti g at or  will  p eri o di c all y  ass ess s u bj e cts f or t h e  o c c urr e n c e  of  a d v ers e  e v e nts.   
 
 
 
ll  a d v ers e  e v e nts ( as  d efi n e d 
i n  S e cti o n  7. 2),  eit h er  o bs er v e d  b y t h e I n v esti g at or  or  o n e  of  his/ h er  m e di c al  c oll a b or at ors,  or 
r e p ort e d  b y t h e  p arti ci p a nt s p o nt a n e o usl y,  or i n r es p o ns e t o  dir e ct  q u esti o ni n g,  will  b e r e p ort e d 
a n d  d o c u m e nt e d i n t h e s o ur c e  d o c u m e nt  a n d t h e st u d y r e p orti n g f or ms.  W h e n r e p orti n g  a n 
a d v ers e  e v e nt, t h e I n v esti g at or  m ust  assi g n  a s e v erit y  gr a d e t o  e a c h  e v e nt  a n d  d e cl ar e  a n  o pi ni o n 
o n t h e r el at e d n ess  of t h e  e v e nt t o t h e st u d y  m e di c ati o n  or  pr o c e d ur e.   S eri o us  or  u n e x p e ct e d 
a d v ers e  e v e nts  m ust  b e r e p ort e d t o   
  wit hi n  2 4  h o urs  of  w h e n t h e I n v esti g at or first l e ar ns 
of t h e  o c c urr e n c e  of t h e  e v e nt.   
 
A d v ers e  e v e nts  will  b e  d o c u m e nt e d i n t h e s o ur c e  d o c u m e nt  a n d r e c or d e d i n  a ti m el y 
m a n n er  o n t h e  e C R Fs.   A d v ers e  e v e nts ( e. g.,  w ors e ni n g  of  c hr o ni c  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  d efi n e  as I O P  ≥  3 6  m m  H g i n  eit h er  e y e) t h at  ar e i d e ntifi e d  at t h e  
l ast  ass ess m e nt  visit ( or t h e  e arl y t er mi n ati o n  visit)  m ust  b e r e c or d e d  o n t h e  A E  e C R F  wit h 
t h e st at us  of t h e  A E  n ot e d.  






P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  4 9  of  6 6  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
7. 4. 1   Pr e g n a n c y  
At t h e ti m e  a  Pri n ci p al I n v esti g at or  or sit e  p ers o n n el  b e c o m es  a w ar e t h at  a st u d y  p arti ci p a nt 
b e c a m e  pr e g n a nt f oll o wi n g  st u d y  p arti ci p ati o n, t h e  Pri n ci p al I n v esti g at or  or  d esi g n e e  will 
r e p ort th e  pr e g n a n c y i m m e di at el y  b y  p h o n e  a n d/ or  b y f a xi n g  a  c o m pl et e d  Pr e g n a n c y  R e p ort t o 
S y m bi o  wit hi n  o n e  w or ki n g  d a y  of  b ei n g  n otifi e d  of t h e  pr e g n a n c y r e p ort.  
 
T h e r e p ort  will i n cl u d e t h e f oll o wi n g  el e m e nts:  
•   P arti ci p a nt ( m ot h er’s)  c o d e d st u d y i d e ntifi er;  
•   D at e  of  p arti ci p a nt’s l ast  m e nstr u al  p eri o d;  
•   T ot al  a c c u m ul at e d  d os e  of st u d y tr e at m e nt  a d mi nist er e d t o  d at e;  
•   D at e  of st u d y  m e di c ati o n  a d mi nistr ati o n.  
 
T h e i n v esti g at or  will f oll o w t h e s u bj e ct  u ntil  c o m pl eti o n  of t h e  pr e g n a n c y  a n d  m ust  ass ess t h e 
o ut c o m e i n t h e s h ort est  p ossi bl e ti m e  b ut  n ot  m or e t h a n  3 0  d a ys  wit hi n  c o m pl eti o n  of t h e 
pr e g n a n c y.  
 
U p o n  d eli v er y,  mis c arri a g e  or  a b orti o n, t h e  Pri n ci p al I n v esti g at or  or  d esi g n e e  m ust f or w ar d  a 
f oll o w-u p  Pr e g n a n c y  R e p ort  wit h  a n y r el e v a nt i nf or m ati o n  o n t h e  pr es e nt  c o n diti o n  of t h e f et us 
, i n cl u di n g: 
•   M ot h er’s  c o d e d st u d y i d e ntifi er(s);  
•   G est ati o n al  a g e  at  d eli v er y,  mis c arri a g e  or  a b orti o n;  
•   Birt h  w ei g ht,  g e n d er, l e n gt h  a n d  h e a d  cir c u mf er e n c e,  if  a v ail a bl e; 
•   A p g ar s c or es r e c or d e d  aft er  birt h, if  a v ail a bl e;  
•   A n y  a b n or m aliti es.  
 
If t h e  o ut c o m e  of t h e  pr e g n a n c y m e et s t h e  crit eri a f or i m m e di at e  cl assifi c ati o n  of  a n  S A E  ( e. g., 
s p o nt a n e o us  or t h er a p e uti c  a b orti o n [ a n y  c o n g e nit al  a n o m al y  d et e ct e d i n  a n  a b ort e d f et us is t o 
b e  d o c u m e nt e d], still birt h,  n e o n at al  d e at h,  or  c o n g e nit al  a n o m al y), t h e i n v esti g at or  will r e p ort 
t h e  e v e nt  b y  p h o n e  a n d  b y f a xi n g  a  c o m pl et e d  S A E r e p ort f or m t o  S y m bi o wit hi n  o n e  w or ki n g 
d a y  of  b ei n g  n otifi e d  of t h e  pr e g n a n c y r e p ort.  


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 0  of  6 6  
 
 
If t h e tri al is  c o m pl et e d  b ef or e t h e  o ut c o m e  of t h e  pr e g n a n c y is  k n o w n,  S y m bi o  will  ass u m e t h e 
r es p o nsi bilit y f or f oll o wi n g  u p  o n t h e  pr e g n a n c y.   S y m bi o  will  c o nt a ct t h e I n v esti g at or  or  St u d y 
c o or di n at or  o n  or  ar o u n d t h e  p ot e nti al  e x p e ct e d  d at e  of  d eli v er y  t o f oll o w-u p  o n t h e  o ut c o m e  of 
pr e g n a n c y  a n d  will  als o  c h e c k  o n t h e st at us  of t h e i nf a nt  8  w e e ks  p ost -d eli v er y.   U p o n  a w ar e n ess 
of t h e  pr e g n a n c y  o ut c o m e  a n d  k n o w n st at us  of t h e i nf a nt f oll o wi n g  8  w e e ks  of  d eli v er y, t h e 
i n v esti g at or  will  c o m pl et e t h e  a p plic a bl e  pr e g n a n c y r e p ort f or ms 
  wit hi n  1  d a y 
of  b ei n g  n otifi e d.  
 
 
7. 5   P ost  St u d y  A d v er s e  E v e nt s  
 
7. 5. 1   N o n -s eri o u s  A d v er s e  E v e nt s  
A d v ers e  e v e nts t h at  ar e i d e ntifi e d  at t h e l ast  ass ess m e nt  visit ( or t h e  e arl y t er mi n ati o n  visit)  m ust 
b e r e c or d e d  o n t h e  A E  e C R F  wit h t h e st at us  of t h e  A E  n ot e d.   T h es e  a d v ers e  e v e nts  m ust  b e 
f oll o w e d  b y t h e i n v esti g at or  u ntil t h e  e v e nts  ar e r es ol v e d,  e v e nts  d et er mi n e d t o  b e  c hr o ni c  or 
t h e s u bj e ct is l ost t o f oll o w-u p.   R es ol uti o n  m e a ns t h e s u bj e ct  h as r et ur n e d t o t h e  b as eli n e st at e 
of  h e alt h,  or t h e i n v esti g at or  d o es  n ot  e x p e ct  a n y f urt h er i m pr o v e m e nt  or  w ors e ni n g  of t h e 
a d v ers e  e v e nt.  
 
7. 5. 2   S eri o u s  A d v er s e  E v e nt s  
S eri o us  a d v ers e  e v e nts t h at  ar e i d e ntifi e d  o n t h e l ast  ass ess m e nt  visit ( or t h e  e arl y t er mi n ati o n 
visit)  m ust  b e  r e c or d e d  o n t h e  A E  e C R F  p a g e  a n d r e p ort e d t o  P erri g o  a c c or di n g t o t h e  pr o c e d ur es 
o utli n e d  a b o v e.  S u bj e cts  wit h  u nr es ol v e d  pr e vi o usl y r e p ort e d s eri o us  a d v ers e  e v e nts,  or  a n y  n e w 
s eri o us   a d v ers e   e v e nts  i d e ntifi e d   o n  t h e  l ast   ass ess m e nt   visit,  s h o ul d   b e  f oll o w e d   b y  t h e  
i n v esti g at or  u ntil t h e  e v e nts  ar e r es ol v e d,  or t h e s u bj e ct is l ost t o f oll o w-u p.   R es ol uti o n  m e a ns 
t h e s u bj e ct  h as r et ur n e d t o t h e  b as eli n e st at e  of  h e alt h,  or t h e i n v esti g at or  d o es  n ot  e x p e ct  a n y 
f urt h er i m pr o v e m e nt  or  w ors e ni n g  of t h e  a d v ers e  e v e nt.   T h e i n v esti g at or s h o ul d  c o nti n u e t o 
r e p ort   a n y  si g nifi c a nt  f oll o w-u p  i nf or m ati o n  t o   P erri g o   u p  t o  t h e   p oi nt  t h at  t h e   e v e nt   h as  
r es ol v e d.   A n y s eri o us  a d v ers e  e v e nt r e p ort e d b y t h e s u bj e ct t o t h e i n v esti g at or  t h at  o c c urs  aft er 
t h e l ast  ass ess m e nt a n d  ar e  d et er mi n e d  b y t h e i n v esti g at or t o  b e r e as o n a bl y  ass o ci at e d  wit h t h e 
us e  of t h e st u d y  dr u g, s h o ul d  b e r e p ort e d t o  P erri g o.  
 
8   St atisti c al  A n al ysis  
T h e s e cti o ns t h at f oll o w  hi g hli g ht s a m pl e siz e  d et er mi n ati o n  a n d t h e  pl a n n e d  a n al ys es f or t his 
st u d y.   A st atisti c al  a n al ysis  pl a n ( S A P)  will  b e  pr e p ar e d s e p ar at el y fr o m t his  pr ot o c ol  w hi c h  gi v es 
d es cri pti o ns   of  t h e  st atisti c al   m et h o ds,   m o d els,   h y p ot h es es   a n d  s u bj e ct   p o p ul ati o ns  t o   b e  
a n al yz e d.   T h e  S A P  will  b e  c o m pl et e d  a n d  a p pr o v e d  b ef or e l o c ki n g t h e  d at a b as e  a n d  u n bli n di n g 
t h e  st u d y  a n d  will  s er v e  as  a  c o m p a ni o n t o t h e  pr ot o c ol  a n d t h e d e f a ct o  d o c u m e nt ati o n  of t h e 
pr o p os e d st atisti c al  e v al u ati o n.   T h e  S A P  will  b e  c o m pl et e d  a n d fi n aliz e d  pri or t o  br e a ki n g t h e 
bli n d.  
 
8. 1   St ati sti c al  A n al ysi s  Pl a n  
 






P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 3  of  6 6  
 
 
 
 
 
 
 
 
 
  
8. 1. 5   S af et y   a n d  A d v er s e  E v e nt s  A n al ysi s 
T h e fr e q u e n c y  a n d  p er c e nt  of s u bj e cts  wit h  a d v ers e  e v e nts  will  b e s u m m ariz e d  b y  M e d D R A 
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 e v erit y  a n d r el ati o ns hi p t o st u d y  dr u g f or  all 
tr e at m e nt  gr o u ps. 
 
  c o m p ar a bl e  s af et y   of  t h e   T est   a n d   R ef er e n c e  
tr e at m e nts  will  b e  e v al u at e d  b y st atisti c al  c o m p aris o n  of t h e  pr o p orti o n  of s u bj e cts  w h o r e p ort e d 
a n y  a d v ers e  e v e nts.   S af et y  c o m p aris o ns  will  b e  p erf or m e d  o nl y f or t h e s af et y i nt e nt -t o-tr e at 
p o p ul ati o n.  
 
8. 2   C o m p ar a bilit y  of  S u bj e cts  at  B as eli n e  
D es cri pti v e st atisti cs  will  b e  pr es e nt e d,  b y tr e at m e nt  gr o u p, f or s u bj e ct  b as eli n e  c h ar a ct eristi cs. 
T h e si g nifi c a n c e  of  a n y  o b vi o us tr e at m e nt  gr o u p  diff er e n c es  will  b e  dis c uss e d i n t h e  C S R . 
 
9   C O N S E N T / A S S E N T  C O N SI D E R A TI O N S  A N D  P R O C E D U R E S  
It  will  b e  m a d e  cl e ar t o t h e s u bj e ct t h at, f or t h e  p ur p os es  of t h e st u d y, t h e y  ar e  c o ns e nti n g  o nl y 
f or  o p ht h al mi c  a p pli c ati o n  of t est  or r ef er e n c e  pr o d u ct.  I n v esti g at ors  m a y  dis c uss t h e  a v ail a bilit y 
of  t h e  st u d y   a n d  t h e   p ossi bilit y  f or   e ntr y   wit h   a   p ot e nti al  s u bj e ct   wit h o ut  first   o bt ai ni n g  
c o ns e nt/ ass e nt.  H o w e v er, i nf or m e d  c o ns e nt/ ass e nt  m ust  b e  o bt ai n e d  a n d  d o c u m e nt e d  pri or t o 
i niti ati o n  of  a n y  pr o c e d ur es t h at  ar e  p erf or m e d s ol el y f or t h e  p ur p os e  of  d et er mi ni n g  eli gi bilit y 
f or r es e ar c h, i n cl u di n g  wit h dr a w al fr o m  c urr e nt  m e di c ati o n(s).   W h e n t his is  d o n e i n  a nti ci p ati o n 
of,  or i n  pr e p ar ati o n f or, t h e r es e ar c h, it is  c o nsi d er e d t o  b e  p art  of t h e r es e ar c h.  
 
T h e st u d y  m ust  b e  a p pr o v e d i n  writi n g  b y  a n  a p pr o pri at e I R B  as  d efi n e d  b y  F D A r e g ul ati o ns.   A 
c o p y  of t h e  L ett er  of  A p pr o v al fr o m t h e I R B,  w hi c h  als o  c o nt ai ns s p e cifi c i d e ntifi c ati o n  of t h e 
d o c u m e nts  a p pr o v e d,  m ust  b e  r e c ei v e d  b y  P erri g o,  pri or t o st u d y  c o m m e n c e m e nt. 
 
P eri o di c st at us r e p orts  m ust  b e s u b mitt e d t o t h e I R B  at l e ast  a n n u all y  as r e q uir e d  b y t h e sit e’s 
I R B,  as  w ell  as  n otifi c ati o n  of  c o m pl eti o n  of t h e st u d y  a n d  a fi n al r e p ort  wit hi n t hr e e  m o nt hs  of 
st u d y  c o m pl eti o n  or t er mi n ati o n.   A  c o p y  of  all r e p orts s u b mitt e d t o t h e I R B  m ust  b e s e nt t o 
P erri g o.  
 
T h e i n v esti g at or(s)  h as  b ot h  et hi c al  a n d l e g al r es p o nsi bilit y t o  e ns ur e t h at  e a c h s u bj e ct  b ei n g 
c o nsi d er e d f or i n cl usi o n i n t his st u d y is  gi v e n  a f ull  e x pl a n ati o n  of t h e  pr ot o c ol.   T his s h all  b e 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 4  of  6 6  
 
d o c u m e nt e d  o n  a  writt e n i nf or m e d  c o ns e nt/ ass e nt f or m,  w hi c h s h all  b e  a p pr o v e d  b y t h e s a m e 
I nstit uti o n al   R e vi e w   B o ar d  (I R B)  r es p o nsi bl e  f or   a p pr o v al   of  t his   pr ot o c ol.   E a c h  i nf or m e d  
c o ns e nt/ ass e nt f or m s h all i n cl u d e t h e  el e m e nts r e q uir e d  b y  F D A r e g ul ati o ns i n  2 1  C F R  P art  5 0.  
T h e i n v esti g at or  a gr e es t o  o bt ai n  a p pr o v al fr o m  P erri g o  of  a n y  writt e n i nf or m e d  c o ns e nt/ ass e nt 
f or m  us e d i n t h e st u d y,  pr ef er a bl y  pri or t o s u b missi o n t o t h e I R B. 
 
O n c e t h e  a p pr o pri at e  ess e nti al i nf or m ati o n  h as  b e e n  pr o vi d e d t o t h e s u bj e ct  a n d f ull y  e x pl ai n e d 
b y t h e i n v esti g at ors ( or  a  q u alifi e d  d esi g n e e)  a n d it is f elt t h at t h e s u bj e ct  u n d erst a n ds t h e 
i m pli c ati o ns  of  p arti ci p ati n g  a n d  h a d t h e  o p p ort u nit y t o  h a v e  all  q u esti o ns  a ns w er e d, t h e I R B-
a p pr o v e d   wri tt e n  i nf or m e d   c o ns e nt/ ass e nt  f or m  s h all   b e  si g n e d   b y  t h e  s u bj e ct  ( or  t h eir  
p ar e nt/l e g all y  a ut h oriz e d r e pr es e nt ati v e)  a n d t h e  p ers o n  o bt ai ni n g  c o ns e nt/ ass e nt (i n v esti g at or 
or  d esi g n e e).   T h e s u bj e ct s h all  b e  gi v e n  a  c o p y  of t h e si g n e d i nf or m e d  c o ns e nt/ ass e n t f or m  a n d 
t h e i n v esti g at or s h all  k e e p t h e  ori gi n al  o n fil e. 
 
If t h e s u bj e ct f ails t o  m e et t h e i n cl usi o n/ e x cl usi o n  crit eri a  at t h e  c o n cl usi o n  of t h e s cr e e ni n g 
p h as e, t h e s u bj e ct  will  b e  wit h dr a w n fr o m st u d y  p arti ci p ati o n.  I n t h e  e v e nt, t h at t h e s u bj e ct is  
r e-s cr e e n e d f or st u d y  p arti ci p ati o n, t hirt y  d a ys ( 3 0)  or  m or e  b e y o n d t h e i niti al s cr e e ni n g,  a  n e w 
i nf or m e d  c o ns e nt/ ass e nt f or m  m ust  b e si g n e d. 
 
9. 1   S u bj e ct  C o nfi d e nti alit y  
All  p arti ci p a nts  ar e  c o n c er n e d f or t h e i n di vi d u al s u bj e ct’s  pri v a c y  a n d,  t h er ef or e,  all s u bj e ct  d at a 
will   b e  i d e ntifi e d   o nl y   b y   a  s u bj e ct  i d e ntifi c ati o n   n u m b er   a n d  s u bj e ct  i niti als.   H o w e v er,  i n  
c o m pli a n c e  wit h f e d er al  g ui d eli n es r e g ar di n g t h e  m o nit ori n g  of  cli ni c al st u di es  a n d i n f ulfill m e nt 
of  his/ h er  o bli g ati o ns t o  P erri g o, i t is r e q uir e d t h at t h e i n v esti g at or  p er mit t h e st u d y  m o nit or,  a n y 
P erri g o   a ut h oriz e d  r e pr es e nt ati v e,   a n d/ or   F D A  r e pr es e nt ati v e  t o  r e vi e w  t h at   p orti o n   of  t h e  
s u bj e ct’s  m e di c al r e c or d t h at is  dir e ctl y r el at e d t o t h e st u d y.   T his s h all i n cl u d e  all st u d y r el e v a nt 
d o c u m e nt ati o n  i n cl u di n g  s u bj e ct   m e di c al   hist ori es  t o   v erif y   eli gi bilit y,  l a b or at or y  t est  r es ult  
r e p orts  t o   v erif y  tr a ns cri pti o n   a c c ur a c y,   a d missi o n/ dis c h ar g e  s u m m ari es  f or   h os pit al  st a ys  
o c c urri n g  w hil e t h e s u bj e ct is  e nr oll e d i n t h e st u d y  a n d  a ut o ps y  r e p orts f or  d e at hs  o c c urri n g 
d uri n g t h e st u d y.  
 
As  p art  of t h e r e q uir e d  c o nt e nt  of i nf or m e d  c o ns e nt, t h e s u bj e ct  m ust  b e i nf or m e d t h at  his/ h er 
m e di c al  c h art  m a y  b e r e vi e w e d  b y  P erri g o  or t h eir  a ut h oriz e d r e pr es e nt ati v e,  or  a r e pr es e nt ati v e 
of t h e  F D A.   S h o ul d  a c c ess t o t h e  m e di c al r e c or d r e q uir e  a s e p ar at e  w ai v er  or  a ut h oriz ati o n, it is 
t h e i n v esti g at or’s r es p o nsi bilit y t o  o bt ai n s u c h  p er missi o n fr o m t h e s u bj e ct i n  writi n g  b ef or e t h e 
s u bj e ct is  e nt er e d i nt o t h e st u d y.  
 
T o   pr es er v e  t h e  s u bj e ct's   c o nfi d e nti al it y,  t h e   d at a   c oll e ct e d   will   b e   a v ail a bl e   o nl y  t o  t h e  
i n v esti g at ors  of t h e st u d y, t h eir s u p p ort st aff,  P erri g o  or t h eir  a ut h oriz e d r e pr es e nt ati v e  a n d 
p ossi bl y t h e  F D A.  
 
All r e p orts  a n d  c o m m u ni c ati o ns r el ati n g t o t h e s u bj e ct i n t h e st u d y  will i d e ntif y  e a c h s u bj e ct  o nl y 
b y t h e s u bj e ct’s i niti als  a n d  b y t h e s u bj e ct  n u m b er.  T h e i n v esti g at or  a gr e es t o f ur nis h  P erri g o  wit h 
c o m pl et e s u bj e ct i d e ntifi c ati o n, if  n e c ess ar y  o n  a  c o nfi d e nti al f oll o w -u p f or m,  w hi c h  will  b e  us e d 
f or t h e  p ur p os e  of  a l o n g-t er m f oll o w-u p, i f  n e e d e d.   T his  will  b e tr e at e d  wit h stri ct  a d h er e n c e t o 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 5  of  6 6  
 
pr of essi o n al st a n d ar ds  of  c o nfi d e nti alit y  a n d  will  b e fil e d  at  P erri g o  u n d er  a d e q u at e s e c urit y  a n d 
r estri ct e d  a c c essi bilit y. 
 
1 0   C O N D U C T  O F  S T U D Y  
T h e i n v esti g ati o n al sit e is t o  m ai nt ai n  c o m pl et e  d o c u m e n t ati o n  of  all  e v e nts  a n d t h e ti m es  at 
w hi c h t h e y  o c c ur.  
 
1 0. 1   C o m pl eti o n  of  St u d y  
T h e i n v esti g ati o n al sit e  will  c o m pl et e t h e st u d y  a n d  c o m pl et e  all  d o c u m e nt ati o n r e q uir e d, i n 
s atisf a ct or y  c o m pli a n c e  wit h t h e  pr ot o c ol,  wit hi n  3. 5  m o nt hs  of  e nr oll m e nt  of t h e l ast  s u bj e ct 
a n d  e xt e n di n g  b e y o n d  as  n e e d e d t o  c o m pl et e  n e c ess ar y  d at a  q u eri es.  
 
It is  a gr e e d t h at, f or r e as o n a bl e  c a us e,  eit h er t h e i n v esti g at or  or  P erri g o  m a y t er mi n at e t his st u d y 
b ef or e  c o m pl eti o n   pr o vi d e d  writt e n  n oti c e is s u b mitt e d  at   a r e as o n a bl e ti m e i n  a d v a n c e  of 
i nt e n d e d t er mi n ati o n.   A n y  e xt e nsi o n  of t his st u d y  m ust  b e  m ut u all y  a gr e e d  u p o n i n  writi n g  b y 
b ot h t h e i n v esti g at or  a n d  P erri g o.  
 
1 0. 2   Pr ot o c ol  A m e n d m e nt s  
T h e I n v esti g at or  will  n ot  m a k e  a n y  c h a n g es t o t his  pr ot o c ol  wit h o ut  pri or  writt e n  c o ns e nt fr o m  
P erri g o  a n d s u bs e q u e nt  a p pr o v al  b y t h e I R B.   A n y  p er m a n e nt  c h a n g e t o t h e  pr ot o c ol,  w h et h er it 
is  a n  o v er all  c h a n g e  or  a  c h a n g e f or s p e cifi c st u d y  c e nt er(s),  m ust  b e  h a n dl e d  as  a  pr ot o c ol 
a m e n d m e nt.  A n y  a m e n d m e nt t o t h e  pr ot o c ol t h at  a p p e ars i n di c at e d  as t h e st u d y  pr o gr ess es  will 
b e f ull y  dis c uss e d  b et w e e n  S y m bi o  L L C  a n d  P erri g o. If  a gr e e m e nt is r e a c h e d r e g ar di n g t h e  n e e d 
f or  a n  a m e n d m e nt, t h e  a m e n d m e nt  will  b e  writt e n  b y  P erri g o.  T h e  writt e n  a m e n d m e nt  m ust  b e 
s u b mitt e d t o t h e  c h air m a n  of t h e I R B i d e ntifi e d  wit h t his r es p o nsi bilit y.   E x c e pt f or ‘ a d mi nistr ati v e 
a m e n d m e nts’,  i n v esti g at ors   m ust   a w ait  I R B   a p pr o v al   of   pr ot o c ol   a m e n d m e nts   b ef or e  
i m pl e m e nti n g t h e  c h a n g e(s).  A d mi nistr ati v e  a m e n d m e nts  ar e  d efi n e d t o  h a v e  n o  eff e ct  o n t h e 
s af et y  of t h e r es e ar c h s u bj e cts, s c o p e  of t h e i n v esti g ati o n,  or  q u alit y  of t h e tri al.   H o w e v er,  a 
pr ot o c ol  c h a n g e i nt e n d e d t o  eli mi n at e  a n  a p p ar e nt i m m e di at e  h az ar d t o s u bj e cts s h o ul d  b e 
i m pl e m e nt e d i m m e di at el y,  a n d t h e I R B  n otifi e d  wit hi n fi v e  d a ys.   P erri g o  will s u b mit  pr ot o c ol 
a m e n d m e nts t o t h e  F D A  or  ot h er r e g ul at or y  a g e n ci es.  
 
W h e n, i n t h e j u d g m e nt  of t h e r e vi e wi n g I R B, t h e i n v esti g at ors  a n d/ or  P erri g o, t h e  a m e n d m e nt t o 
t h e   pr ot o c ol  s u bst a nti all y   alt ers  t h e  st u d y   d esi g n   a n d/ or i n cr e as es  t h e  p ot e nti al  ris k t o  t h e 
s u bj e ct, t h e  c urr e ntl y  a p pr o v e d  writt e n i nf or m e d  c o ns e nt f or m  will r e q uir e si mil ar  m o difi c ati o n.  
I n s u c h  c as es, r e p e at i nf or m e d  c o ns e nt  will  b e  o bt ai n e d fr o m s u bj e cts  e nr oll e d i n t h e st u d y 
b ef or e  e x p e cti n g  c o nti n u e d  p arti ci p ati o n.  
 
1 0. 3   C O VI D -1 9  Ri s k  Miti g ati o n  
T h e st u d y  c e nt er  will  us e ris k  miti g ati o n t o  pr e v e nt  C O VI D -1 9 s pr e a d.  Pr o c ess es  a n d  pr o c e d ur es 
i m pl e m e nt e d  will  b e i n  a c c or d a n c e  wit h  g ui d eli n es  a n d r e c o m m e n d ati o ns iss u e d  b y  W orl d  H e alt h 
Or g a niz ati o n ( W H O),  C e nt ers f or  Dis e as e  C o ntr ol ( C D C), l o c al, f e d er al  a n d I n v esti g at or  g ui d eli n es. 
S u c h  g ui d eli n es s h all i n cl u d e  pr e -s cr e e ni n g  pr o c e d ur es i n cl u di n g  q u esti o n n air es  p ert ai ni n g t o 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 6  of  6 6  
 
s y m pt o ms  of  a n d  e x p os ur e t o  C O VI D -1 9,  e n c o ur a g e m e nt  of  h a n d  w as hi n g  a n d s a nitizi n g, st aff 
us e   of   p ers o n al   pr ot e cti v e   e q ui p m e nt  ( P P E),  s u bj e cts ’   a n d  st aff   us e   of   m as ks,   cl e a ni n g   a n d  
disi nf e cti n g  pr o c e d ur es  of  e q ui p m e nt  a n d f ur nit ur e,  a n d s o ci al  dist a n ci n g i n t h e st u d y  u nit.   
 
1 0. 4   Alt er n ati v e  pr ot o c ol  ass ess m e nt s  d uri n g t h e  C O VI D -1 9  P a n d e mi c  o nl y  
T o  miti g at e  a n y ris ks t h at  m a y  o c c ur  d u e t o t h e  C O VI D -1 9  p a n d e mi c t h at  mi g ht i m p a ct t h e 
c o n d u ct  of t h e tri al, t h e f oll o wi n g  m a y  b e  c o nsi d er e d if  a sit e is  n ot  a bl e t o  p arti ci p at e  at f ull 
c a p a cit y  or  o n -sit e s u bj e ct  p arti ci p ati o n is  c o m pr o mis e d  d u e t o l o c al r e g ul ati o ns  c a us e d  b y 
C O VI D -1 9 r estri cti o ns ( e. g.,  t e m p or ar y sit e  cl os ur es, s u bj e cts  u n a bl e t o  c o m pl et e  o n-sit e  visit):   
•   Sit es  m a y  b e  pl a c e d  o n  a t e m p or ar y  e nr oll m e nt  h ol d.   
•   R e m ot e  m o nit ori n g  visits  m a y  b e  c o n d u ct e d.  
 
 
1 0. 4. 1   S u bj e ct  Di s p ositi o n  d u e t o  C O VI D -1 9 I nf e cti o n  
If  a s u bj e ct is  c o nfir m e d t o  h a v e t est e d  p ositi v e f or  C O VI D-1 9, t h e i n v esti g at or  will  b e i nstr u ct e d 
t o r ec or d  t h e  e v e nt  as  a n  A E  or  S A E.  T h e  s u bj e cts s h o ul d f urt h er  b e i m m e di at el y  dis c o nti n u e d 
fr o m st u d y  m e di c ati o n  a n d st u d y  p arti ci p ati o n  a n d i nstr u ct e d t o  q u ar a nti n e.  
 
1 0. 4. 2   R e g ul at or y  a n d  St u d y  O v er si g ht  C o n si d er ati o n s  
R e m ot e  m o nit ori n g  m a y  b e s u bstit ut e d f or  p h ysi c al  visits t o t h e sit e(s) i n t h e  e v e nt t h at t h e  C R A 
or  Sit e s ar e  n ot  a bl e t o  c o n d u ct  a n  o n -sit e  visit  d u e t o sit e  cl os ur e, l o c al  or f e d er al  g ui d eli n es,  or 
s af et y  g ui d eli n es i n r el ati o n  t o  C O VI D-1 9.    
 
1 0. 4. 3   D o c u m e nt ati o n  of  Pr ot o c ol  D e vi ati o n s r el at e d t o  C O VI D -1 9   
All  pr ot o c ol  vi ol ati o ns  a n d  pr ot o c ol  d e vi ati o ns ( P V/ P D) t h at  o c c ur  as  a r es ult  of t h e  C O VI D -1 9 
p a n d e mi c s h o ul d  b e  d o c u m e nt e d i n t h e s o ur c e  d o c u m e nts  as  P V/ P Ds s p e cifi c all y  o c c urri n g  d u e 
t o t h e  C O VI D-1 9  p a n d e mi c.  As  m u c h  as  p ossi bl e,  d et ail e d r e as o ns f or t h e  P V/ P D ( e. g.,  s u bj e ct is 
ill, sit e  cl os e d, s u bj e ct  u n a bl e t o tr a v el t o sit e) s h o ul d  b e i n cl u d e d i n t h e s o ur c e  d o c u m e nts, 
i n cl u di n g  a n y  pr o c e d ur es/ a cti viti es  n ot  u n d ert a k e n  or  visits  miss e d  as  a r es ult  of   C O VI D-1 9.   All 
pr ot o c ol  d e vi ati o ns  a n d  A Es i m p a ct e d  b y  C O VI D -1 9  will  b e  d o c u m e nt e d i n t h e  C O VI D -1 9  e C R F 
f or m. 
 
1 1   R E C O R D S  M A N A G E M E N T  
 
1 1. 1   D at a  C oll e cti o n  
 
D at a b as e s et -u p  will  b e  p erf or m e d   
 i n  c oll a b or ati o n  wit h t h e  El e ctr o ni c  D at a  C a pt ur e 
( E D C)  v e n d or,  usi n g  a n  a p pr o pri at e f ull y  v ali d at e d,  2 1  C F R  P art  1 1  c o m pli a nt  E D C s yst e m.  e C R Fs 
will  b e  pr o vi d e d t o  e a c h sit e  vi a  a s e c ur e d  w e b li n k.  All  a p pli c a bl e st u d y  d at a  c oll e ct e d  o n  e a c h 
s u bj e ct  will  b e r e c or d e d  b y  a p pr o v e d sit e  p ers o n n el i nt o t h e  e C R F.  O nl y  a ut h oriz e d sit e  p ers o n n el 
will  b e  a bl e t o  e nt er/ m o dif y/ c orr e ct  d at a t o t h e  e C R F.  
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 7  of  6 6  
 
A p pr o v e d st aff  at  S y m bi o  will  v erif y  all  d at a  e nt er e d i nt o  e C R Fs f or  c o m pl et e n ess  a n d  a c c ur a c y 
wit h r ef er e n c e t o t h e s o ur c e  d o c u m e nts  a n d r e c or ds  a n d  will iss u e  m a n u al  d at a  q u eri es t o  c orr e ct 
missi n g  d at a  or  dis cr e p a n ci es f o u n d  a g ai nst t h e s o ur c e  wit hi n t h e  E D C s yst e m.  
 
D at a  v ali d ati o n  will  c o nsist  of  a ut o m at e d  a n d  m a n u al  e dit  c h e c ks t h at  ar e  cr e at e d  dir e ctl y i nt o 
E D C.  A ut o m at e d  e dit  c h e c ks  will  b e  e x e c ut e d  o n  all  d at a  p oi nts  d efi n e d  a n d  d o c u m e nt e d  b y t h e 
st u d y t e a m  a n d  d at a  m a n a g e m e nt.  St u d y  m etri cs  will  b e r e p ort e d fr o m t h e  E D C s yst e m.  
 
Aft er  all  d at a  h a v e  b e e n  v erifi e d  b y  a p pr o v e d st aff  at  S y m bi o,  a n I n v esti g at or  or  S u b -I n v esti g at or 
(list e d  o n  F or m  F D A  1 5 7 2) is r e q uir e d t o r e vi e w  a n d  a p pr o v e  all  e C R Fs  pri or t o  d at a b as e l o c k a n d 
br e a ki n g  of t h e  bli n d.   
 
Aft er  d at a b as e l o c k,  e a c h sit e  will  b e  pr o vi d e d  wit h  a  p ass w or d  pr ot e ct e d  U S B t h at  will i n cl u d e 
t h e  e C R F  d at a fr o m t h eir sit e f or l o c al  ar c hi v al  p ur p os es. 
 
Q u alit y  ass ur a n c e  v erifi c ati o n  vi a  a  1 0 %  d at a b as e  a u dit  of  e C R F  d at a  w ill  b e  c o n d u ct e d  b ef or e 
t h e tr e at m e nt  assi g n m e nt  c o d e is  br o k e n. 
 
D uri n g  e a c h s u bj e ct’s  visit t o t h e  cli ni c,  a  d esi g n e e  p arti ci p ati n g i n t h e st u d y  will r e c or d  pr o gr ess 
n ot es t o  d o c u m e nt  all si g nifi c a nt  o bs er v ati o ns.   At  a  mi ni m u m, t h es e  n ot es  will  c o nt ai n:  
 
a)   D o c u m e nt ati o n  of t h e i nf or m e d  c o ns e nt  pr o c ess;  
b)   T h e  d at e  of t h e  visit  a n d t h e  c orr es p o n di n g  Visit  or  W e e k i n t h e st u d y s c h e d ul e;  
c)   G e n er al s u bj e ct st at us r e m ar ks, i n cl u di n g  a n y si g nifi c a nt  m e di c al fi n di n gs.   T h e s e v erit y, 
fr e q u e n c y,   a n d   d ur ati o n   of   a n y  a d v ers e   e v e nts  a n d  t h e  i n v esti g at or's   ass ess m e nt   of 
r el ati o ns hi p t o st u d y  m e di c ati o n  m ust  als o  b e r e c or d e d. 
d)   A n y  c h a n g es i n  c o n c o mit a nt  m e di c ati o ns  or  d os a g es;  
e)   A  g e n er al r ef er e n c e t o t h e  pr o c e d ur es  c o m pl et e d;  a n d  
f)  T h e si g n at ur e ( or i niti als)  a n d  d at e  of  all  cli ni ci a ns  w h o  m a d e  a n  e ntr y i n t h e  pr o gr ess 
n ot es.  
 
I n  a d diti o n,  a n y  c o nt a ct  wit h t h e s u bj e ct  vi a t el e p h o n e  or  ot h er  m e a ns t h at  pr o vi d es si g nifi c a nt 
cli ni c al i nf or m ati o n  will  als o  b e  d o c u m e nt e d i n t h e  pr o gr ess  n ot es  as  d es cri b e d  a b o v e.  
 
A n y  c h a n g es t o i nf or m ati o n i n t h e st u d y  pr o gr ess  n ot es  a n d  ot h er s o ur c e  d o c u m e nts,  will  b e 
e nt er e d  i n   bl a c k   or   bl u e  i n k ,  i niti al e d  a n d  d at e d  b y  t h e   a ut h oriz e d   p ers o n   m a ki n g  t h e  
c orr e cti o n/ a d diti o n.   C h a n g es  will  b e  m a d e  b y stri ki n g  a si n gl e li n e t hr o u g h  err o n e o us  d at a,  a n d 
cl e arl y  e nt eri n g t h e  c orr e ct  d at a.  ( e. g.,  wr o n g  d at a  ri g ht  d at a).   E ntri es  m a y  n ot  b e  er as e d  or 
m as k e d  wit h  w hit e -o ut fl ui d.  If t h e r e as o n f or t h e  c h a n g e is  n ot  a p p ar e nt,  a  bri ef  e x pl a n ati o n f or 
t h e  c h a n g e  will  b e  writt e n  a dj a c e nt t o t h e  c h a n g e  b y t h e  cli ni ci a n. 
 
F or  tr a ns missi o n  t o   P erri g o,  i nf or m ati o n  fr o m  t h e  st u d y   pr o gr ess   n ot es   a n d   ot h er  s o ur c e  
d o c u m e nts  will  b e  pr o m ptl y  e nt er e d i nt o t h e  d at a b as e.   T h e  d at a b as e  als o  c o nt ai ns  a  c o m pl et e 
a u dit tr ail t o  c a pt ur e  all r e g ul at or y  c o m p o n e nts  of  d at a  c orr e cti o ns ( e. g. i niti al  e ntr y,  n e w  v al u e, 
i niti als  a n d  d at e  of t h e  c h a n g e). 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 8  of  6 6  
 
1 1. 2   S o ur c e  D o c u m e nt s  
S o ur c e  d o c u m e nts  ar e  d efi n e d  as t h e r es ults  of  ori gi n al  o bs er v ati o ns  a n d  a cti viti es  of  a  cli ni c al 
i n v esti g ati o n.     S o ur c e   d o c u m e nts   will  i n cl u d e,   b ut   ar e   n ot  li mit e d  t o,  pr o gr ess   n ot es   a n d  
s cr e e ni n g  l o gs.     All  s o ur c e   d o c u m e nts   p ert ai ni n g  t o  t his  st u d y   will   b e   m ai nt ai n e d   b y  t h e  
i n v esti g at ors   a n d   m a d e   a v ail a bl e  f or  i ns p e cti o n   b y   a ut h oriz e d   p ers o ns.     T h e   ori gi n al  si g n e d  
i nf or m e d  c o ns e nt/ ass e nt f or m f or  e a c h  p arti ci p ati n g  s u bj e ct s h all  b e fil e d  wit h r e c or ds  k e pt  b y 
t h e i n v esti g at ors  a n d  a  c o p y  gi v e n t o t h e s u bj e ct. 
 
1 1. 3   Fil e  M a n a g e m e nt  at t h e  St u d y  Sit e  
It is t h e r es p o nsi bilit y  of t h e i n v esti g at or t o  e ns ur e t h at t h e st u d y  c e nt er fil e is  m ai nt ai n e d i n 
a c c or d a n c e  wit h  S e cti o n  8  of t h e I nt er n ati o n al  C o nf er e n c e  o n  H ar m o niz ati o n (I C H)  G ui d eli n e f or 
G o o d  Cli ni c al  Pr a cti c es ( G C P).  
 
1 1. 4   R e c or d s  R et e nti o n  at t h e  St u d y  Sit e  
F D A r e g ul ati o ns  2 1  C F R § 3 1 2. 5 7 r e q uir e  all i n v esti g at ors  p arti ci p ati n g i n  cli ni c al  dr u g st u di es t o 
m ai nt ai n  d et ail e d  cli ni c a l  d at a f or  o n e  of t h e f oll o wi n g  p eri o ds: 
 
a)   A  p eri o d  of  at l e ast t w o  y e ars f oll o wi n g t h e  d at e  o n  w hi c h  a  N e w  Dr u g  A p pli c ati o n is 
a p pr o v e d  b y t h e  F D A;  
b)   A  p eri o d  of t w o  y e ars  aft er  P erri g o  n otifi es t h e i n v esti g at or t h at  n o f urt h er  a p pli c ati o n is 
t o  b e fil e d  wit h t h e  F D A. 
 
T h e i n v esti g at or  m ust  n ot  dis p os e  of  a n y r e c or ds r el e v a nt t o t his st u d y  wit h o ut  eit h er ( 1) 
writt e n  p er missi o n fr o m  P erri g o  or ( 2)  pr o vi di n g  a n  o p p ort u nit y f or  P erri g o t o  c oll e ct s u c h 
r e c or ds.   T h e i n v esti g at or s h all t a k e r es p o nsi bilit y f or  m ai nt ai ni n g  a d e q u at e  a n d  a c c ur at e 
el e ctr o ni c  or  h ar d  c o p y s o ur c e  d o c u m e nts  of  all  o bs er v ati o ns  a n d  d at a  g e n er at e d  d uri n g t his 
st u d y.   S u c h  d o c u m e nt ati o n is s u bj e ct t o i ns p e cti o n  b y  P erri g o  a n d  R e g ul at or y  a ut h oriti es s u c h 
as t h e  F o o d  &  Dr u g  A d mi nistr ati o n.  
1 2   Q U A LI T Y  C O N T R O L  A N D  Q U A LI T Y  A S S U R A N C E  
 
1 2. 1   M o nit ori n g  
P erri g o  h as  et hi c al, l e g al  a n d s ci e ntifi c  o bli g ati o ns t o  c ar ef ull y f oll o w t his st u d y i n  a  d et ail e d  a n d 
or d erl y  m a n n er i n  a c c or d a n c e  wit h  est a blis h e d r es e ar c h  pri n ci pl es  a n d  F D A r e g ul ati o ns.   All 
m e di c al r e c or ds (s o ur c e  d o c u m e nts)  of t h e s u bj e cts  p arti ci p ati n g i n t his st u d y  m ust  b e  pr es e nt e d 
f or r e vi e w  a n d  v erifi c ati o n  of  e C R Fs. 
 
1 2. 2   A u diti n g  
P erri g o ( or r e pr es e nt ati v e)  m a y  c o n d u ct  a u dits  at t h e st u d y  c e nt er(s).   A u dits  will i n cl u d e,  b ut  ar e 
n ot  b e li mit e d t o,  dr u g s u p pl y,  pr es e n c e  of r e q uir e d  d o c u m e nts, t h e i nf or m e d  c o ns e nt  pr o c ess, 
a n d  c o m p aris o n  of  el e ctr o ni c  c as e r e p ort f or ms  wit h s o ur c e  d o c u m e nts.   T h e i n v esti g at or  a gr e es 
t o  p arti ci p at e  wit h  a u dits  c o n d u ct e d  at  a r e as o n a bl e ti m e i n  a r e as o n a bl e  m a n n er. 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  5 9  of  6 6  
 
R e g ul at or y  a ut h oriti es  w orl d wi d e  m a y  als o  a u dit t h e i n v esti g at or  d uri n g  or  aft er t h e st u d y.  T h e 
i n v esti g at or  s h o ul d   c o nt a ct   P erri g o  i m m e di at el y  if   n otifi e d   of  s u c h   a n   a u dit   a n d   m ust  f ull y  
c o o p er at e  wit h t h e  a u dits  c o n d u ct e d  at  a r e as o n a bl e ti m e i n  a r e as o n a bl e  m a n n er.  
 
1 3   E T HI C S  A N D  R E S P O N SI BI LI T Y  
T his st u d y  m ust  b e  c o n d u ct e d i n  c o m pli a n c e  wit h t h e  pr ot o c ol, t h e  U nit e d  St at es  F o o d  a n d  Dr u g 
A d mi nistr ati o n ( F D A) r e g ul ati o ns,  a n y  ot h er  c o u ntri es r e g ul ati o ns,  a n d I C H  G C P  G ui d eli n es.  
 
1 4   U S E  O F I N F O R M A TI O N  A N D  P U B LI C A TI O N  
All i nf or m ati o n  s u p pli e d  b y  P erri g o i n  c o n n e cti o n  wit h t his st u d y  a n d  n ot  pr e vi o usl y  p u blis h e d, is 
c o nsi d er e d   c o nfi d e nti al  i nf or m ati o n.     T his  i nf or m ati o n  i n cl u d es,   b ut  is   n ot  li mit e d  t o,   d at a,  
m at eri als ( e. g., t h e  cli ni c al  pr ot o c ol,  e C R Fs),  e q ui p m e nt,  e x p eri e n c e ( w h et h er  of  a  s ci e ntifi c, 
t e c h ni c al,  e n gi n e eri n g,  o p er ati o n al,  or  c o m m er ci al  n at ur e),  d esi g ns, s p e cifi c ati o ns,  k n o w -h o w, 
pr o d u ct   us es,   pr o c ess es,  f or m ul a e,   c osts,  fi n a n ci al   d at a,   m ar k eti n g   pl a ns   a n d   dir e ct  s elli n g  
s yst e ms,   c ust o m er  lists   a n d  t e c h ni c al   a n d   c o m m er ci al  i nf or m ati o n  r el ati n g  t o   c ust o m ers   or  
b usi n ess  pr oj e cti o ns  us e d  b y  P erri g o i n its  b usi n ess.  A n y  d at a, i n v e nti o ns,  or  dis c o v eri es  c oll e ct e d 
or  d e v el o p e d,  as  a r es ult  of t his st u d y is  c o nsi d er e d  c o nfi d e nti al.  T his  c o nfi d e nti al i nf or m ati o n 
s h all r e m ai n t h e  s ol e  pr o p ert y  of  P erri g o, s h all  n ot  b e  dis cl os e d t o  a n y  u n a ut h oriz e d  p ers o n  or 
us e d i n  a n y  u n a ut h oriz e d  m a n n er  wit h o ut  writt e n  c o ns e nt  of  P erri g o,  a n d s h all  n ot  b e  us e d 
e x c e pt i n t h e  p erf or m a n c e  of t h e st u d y.   As s u c h,  c o nfi d e nti al st u d y -r el at e d i nf or m ati on s h o ul d 
n ot  b e i n cl u d e d  o n t h e  c urri c ul u m  vit a e  of  a n y  p arti ci p ati n g i n v esti g at or  or st u d y st aff.  
 
T h e i nf or m ati o n  d e v el o p e d  d uri n g t h e  c o urs e  of t his  cli ni c al st u d y is  als o  c o nsi d er e d  c o nfi d e nti al 
a n d  will  b e  us e d  b y  P erri g o i n  c o n n e cti o n  wit h t h e  d e v el o p m e nt  of t h e  dr u g.   T h e i nf or m ati o n 
m a y  b e  dis cl os e d  as  d e e m e d  n e c ess ar y  b y  P erri g o t o  all o w t h e  us e  of t h e i nf or m ati o n  d eri v e d 
fr o m t his  cli ni c al st u d y, t h e i n v esti g at or is  o bli g e d t o  pr o vi d e  P erri g o  wit h  c o m pl et e t est r es ults 
a n d  all  d at a  d e v el o p e d i n t h e st u d y.  T h e i nf or m ati o n  o bt ai n e d  d uri n g t his st u d y  m a y  b e  m a d e 
a v ail a bl e t o  ot h er i n v esti g at ors  w h o  ar e  c o n d u cti n g si mil ar st u di es.  
 
T h e i n v esti g at or s h all  n ot  m a k e  a n y  p u bli c ati o n r el at e d t o t his st u d y  wit h o ut t h e  e x pr ess  writt e n 
p er missi o n  of  P erri g o. 
 
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 0  of  6 6  
 
1 5   I N V E S TI G A T O R  A G R E E M E N T 
 
P R O T O C O L  N U M B E R:   P R G -N Y -2 0 -0 0 2  
 
P R O T O C O L  TI T L E:    
 
 
A  M ulti -C e nt er,  D o u bl e -M as k e d,  R a n d o miz e d,  A cti v e -C o ntr oll e d,  P ar all el -
Gr o u p,  S af et y  a n d  Effi c a c y  St u d y t o  C o m p ar e  P erri g o  P h ar m a c e uti c als 
I nt er n ati o n al  D A C  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  O p ht h al mi c 
S us p e nsi o n  1 %/ 0. 2 % t o  N o v artis  P h ar m a c e uti c als  Si m bri nz a ® 
( bri nz ol a mi d e / bri m o ni di n e t artr at e  1 %/ 0. 2 %  o p ht h al mi c s us p e nsi o n) i n 
t h e  Tr e at m e nt  of  C hr o ni c  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 
i n  b ot h  E y es 
 
I   h a v e   c ar ef ull y  r e a d  t h e  f or e g oi n g   pr ot o c ol   a n d   a gr e e  t h at  it   c o nt ai ns   all  t h e   n e c ess ar y  
i nf or m ati o n f or  c o n d u cti n g t his st u d y s af el y.  I  will  c o n d u ct t his st u d y i n stri ct  a c c or d a n c e  wit h 
t his  pr ot o c ol, I C H  G ui d eli n es f or  G oo d  Cli ni c al  Pr a cti c es, t h e  C o d e  of  F e d er al  R e g ul ati o ns, t h e 
H e alt h  I ns ur a n c e   P ort a bilit y   a n d   A c c o u nt a bilit y   A ct  ( HI P A A)   a n d   a n y  l o c al  r e g ul at or y  
r e q uir e m e nts  a n d  will  att e m pt t o  c o m pl et e t h e st u d y  wit hi n t h e ti m e  d esi g n at e d.  I  will  pr o vi d e 
a c c ess t o  c o pi e s  of t h e  pr ot o c ol  a n d  all  ot h er i nf or m ati o n r el ati n g t o  pr e -cli ni c al  a n d  pri or  cli ni c al 
e x p eri e n c e s u b mitt e d  b y  P erri g o t o  all  p ers o n n el r es p o nsi bl e t o  m e  w h o  p arti ci p at e i n t h e st u d y.  
I  will  dis c uss t his i nf or m ati o n  wit h t h e m t o  ass ur e t h at t h e y  ar e  a d e qu at el y i nf or m e d r e g ar di n g 
t h e   dr u g   a n d   c o n d u ct   of  t h e  st u d y.    I   a gr e e  t o   k e e p  r e c or ds   o n   all  s u bj e ct  i nf or m ati o n  i n  
a c c or d a n c e  wit h  F D A r e g ul ati o ns.  
 
 
 
 
   
 
 
  
   Pri n ci p al I n v esti g at or’s  Pri nt e d  N a m e  
 
 
 
 
   
 
 
  
   Pri n ci p al I n v esti g at or’s  Si g n at ur e  
 
 
 
   
 
 
  
   D at e  




P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 2  of  6 6  
 
1 6. 2   A p p e n di x  B:  I n str u cti o ns f or t h e  S u bj e ct  
 
C h e c k  Visit  Dis p e ns e d:   
  Visit  2 :           
   Visit  3:     
  U ns c h e d ul e d  visit:   
   D at e:  _ _ _ _ _ _ _ _  
 
S U BJ E C T I NI TI A L S:  _ _ _ _ _ _ _ _ _ _ _    S U BJ E C T  N U M B E R:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
SI T E  N U M B E R:  _ _ _ _ _ _ _ _  
 
1.   
Y o ur  d o ct or  h as  gi v e n  y o u t h e st u d y  m e di c ati o n, f or  y o ur  us e i n t h e st u d y.   St or e t h e  st u d y 
m e di c ati o n  at t e m p er at ur e  2 oC- 2 5 oC ( 3 6 oF- 7 7 oF) i n  a s e c ur e d  ar e a  a n d  b ottl es  m ust  b e  k e pt i n 
a n   u pri g ht  p ositi o n  a n d ti g htl y  cl os e d .  K e e p  t his   a n d   all   m e di c ati o ns  o ut   of  t h e r e a c h   of 
c hil dr e n.   K e e p t h e st u d y  m e di c ati o n  b ottl e ti g htl y  cl os e d,  pr ot e ct it fr o m li g ht  a n d  h e at.  F or 
o p ht h al mi c  us e  o nl y.  N ot f or  or al, t o pi c al,  or i ntr a n as al  us e.   
 
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
  
 
 
 
    


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 3  of  6 6  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 4  of  6 6  
 
 
 
 


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 5  of  6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
Y o u  ar e s c h e d ul e d t o r et ur n  at:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Visit  3,  St u d y  W e e k  2)   
( Ti m e)     
   
  
( D at e) 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Visit  4,  St u d y  W e e k  6)   
( Ti m e)     
   
  
( D at e)  
 
A L L  A P P OI N T M E N T S  A R E I M P O R T A N T! I F  Y O U  N E E D  T O  R E -S C H E D U L E  Y O U R  A P P OI N T M E N T, 
P L E A S E  C A L L  Y O U R  S T U D Y  D O C T O R’ S  O F FI C E I M M E DI A T E L Y.  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
N a m e  a n d  T el e p h o n e  N u m b er  of  St u d y  C o or di n at or/ St u d y  Sit e  


P R G -N Y -2 0 -0 0 2  Bri nz ol a mi d e  a n d  Bri m o ni di n e  T artr at e  1 %/ 0. 2 %  O p ht h al mi c  S us p e nsi o n  
                                                                                                                P a g e  6 6  of  6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
A Multi-Center, Double-Masked, Randomized, Two-Arm, Parallel-Group, Safety and Efficacy 
Study to Compare Perrigo Pharmaceuticals International DAC Brinzolamide and Brimonidine 
Tartrate Ophthalmic Suspension 1%/0.2% to Novartis Pharmaceuticals Simbrinza® 
(brinzolamide/brimonidine tartrate 1%/0.2% ophthalmic suspension) in the Treatment of 
Chronic Open Angle Glaucoma or Ocular Hypertension in both Eyes 
 
 
Protocol No.: PRG-NY-20-002  
 
NCT04944290 
 
Protocol Date: May 27, 2021 




Perrigo New York                                                                                                                         Protocol: PRG-NY-20-002 
 
 
 
       
 
1  
CONFIDENTIAL 
Table of Contents 
1 
Purpose of Statistical Analysis Plan ........................................................................................................ 4 
2 
Study Objectives ....................................................................................................................................... 4 
3 
Study Design and Sample Size ................................................................................................................ 4 
3.1 
Study Design ..................................................................................................................................................... 4 
3.2 
Sample Size ....................................................................................................................................................... 5 
4 
Analysis Populations ................................................................................................................................ 5 
5 
Planned Analyses ...................................................................................................................................... 6 
5.1 
Methodological Considerations ........................................................................................................................ 6 
5.2 
Handling of Dropouts or Missing Data ............................................................................................................. 7 
5.3 
Demographics and Baseline Characteristics ..................................................................................................... 7 
5.4 
Subject Disposition ........................................................................................................................................... 7 
5.5 
Protocol Deviations/Violations ......................................................................................................................... 7 
5.6 
Study Drug Exposure and Compliance ............................................................................................................. 8 
5.7 
Efficacy Analyses ............................................................................................................................................. 8 
5.7.1 
Primary Endpoint ................................................................................................................................. 8 
5.7.2 
Comparison to Historic Data .............................................................................................................. 10 
5.8 
Safety Variables and Analyses ........................................................................................................................ 10 
6 
Appendices .............................................................................................................................................. 11 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant Medications ...................... 11 
6.2 
Summary of Assessments ............................................................................................................................... 12 
7 
Tables and Listings ................................................................................................................................. 15 
Table 14.1.1 - Subject Disposition .......................................................................................................................... 17 
Table 14.1.2 - Subject Population (General) ........................................................................................................... 18 
Table 14.1.3 - Subject Enrollment by Study Site .................................................................................................... 19 
Table 14.1.4.1 - Demographic Characteristics  Intent-to-Treat Population ............................................................. 20 
Table 14.1.4.2 - Demographic Characteristics  Per-Protocol Population ................................................................ 21 
Table 14.1.5.1- Baseline Vital Signs  Intent-to-Treat Population ........................................................................... 22 
Table 14.1.5.2- Baseline Vital Signs  Per-Protocol Population ............................................................................... 23 
Table 14.1.6.1- Intraocular Pressure (IOP) Measurement at Baseline  Intent-to-Treat Population ......................... 24 
Table 14.1.6.2- Intraocular Pressure (IOP) Measurement at Baseline  Per-Protocol Population ............................ 25 
Table 14.1.6.3- Study Eye Baseline Mean IOP: Comparison with Historical Data* Intent-to-Treat Population .... 26 
Table 14.1.7 – Days of Exposure and Medication Compliance Rate  Intent-to-Treat Population .......................... 27 
Table 14.2.1.1- Primary Efficacy Analysis: Mean Change from Baseline in IOP of Both Eyes  Per-Protocol 
Population ............................................................................................................................................................ 29 
Table 14.2.1.2- Study Eye Mean IOP and Mean Change from Baseline IOP at /Week 2 and Week 6: A 
Comparison with Historical Data* Intent-to-Treat Population ............................................................................ 30 
Table 14.3.2.1 - Overall Summary of Treatment Emergent Adverse Events (TEAEs)  Intent-to-Treat Population 31 
Table 14.3.2.2- Summary of Treatment-Emergent Adverse Events (TEAEs) by MedDRA System Organ Class 
and Preferred Term  Intent-to-Treat Population .................................................................................................. 32 




Perrigo New York                                                                                                                         Protocol: PRG-NY-20-002 
 
 
 
       
 
3  
CONFIDENTIAL 
List of Abbreviations  
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
 
 
BE 
Bioequivalence 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel Test 
IOP 
Intraocular Pressure 
ITT 
Intent- to-treat (population) 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
OH 
Ocular Hypertension 
PD 
Protocol Deviation 
PP 
Per-Protocol (population) 
PV 
Protocol Violation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
















Perrigo New York                                                                                                                         Protocol: PRG-NY-20-002 
 
 
 
       
 
11  
CONFIDENTIAL 
between Test and Reference treatments with regard to severity and frequency of their adverse 
events will be statistically evaluated using Chi-Square or Fisher’s exact test to compare the 
proportions of subjects of the two treatment groups who report any TEAE. 
Treatment-Emergent Serious Adverse Events (TESAEs) will be discussed within the clinical 
study report. TEAEs, TESAEs and TEAEs that led to study treatment interrupted temporarily or 
study treatment discontinued permanently will be presented in data listings. 
All information pertaining to adverse events will be listed by subject, detailing verbatim term 
given by the investigator, preferred term, system organ class, start date, stop date, severity, 
outcome, action taken and formula relatedness. Separate listings will be created for Serious 
TEAEs and TEAEs leading to study formula discontinuation. 
Concomitant Medications and Vital Signs 
Concomitant medications will be coded using the WHO Drug Dictionary, version March 2021, 
and will be presented in data listings. All vital signs data will be displayed in listings.  
6 
Appendices 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant 
Medications 
Adverse Events 
Handling of partial dates is only considered for the start date. An adverse event with a partial start 
date is considered treatment emergent if: 
- 
only the day is missing and the start month/year is the same or after the month/year of 
the first dose 
- 
the day and month are missing and the start year is the same or greater than the year of 
the first dose date 
- 
the start date is completely missing 
Concomitant Medications 
Handling of partial dates is only considered for the stop date. A medication with a partial stop 
date is considered concomitant if: 
- 
only the day is missing and the stop month/year is the same or after the month/year of 
the first dose 
- 
the day and month are missing and the stop year is the same or greater than the year of 
the first dose date 
- 
the stop date is completely missing or the medication is ongoing