Conditions: Glaucoma, Open-Angle Ocular Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 594
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of bimatoprost SR in participants with open-angle glaucoma or ocular hypertension. The study includes a 12-month treatment period with an 8-month extended follow-up.

Detailed description:

Arms:
arm 1: Study Eye: bimatoprost sustained release (SR) 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months. arm 2: Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months. arm 3: Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

Interventions: intervention 1: Bimatoprost SR intervention 2: Active Comparator: Timolol 0.5% intervention 3: Sham: Applicator Without Needle intervention 4: Timolol Vehicle (placebo)
Intervention descriptions: intervention 1: Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32. intervention 2: Timolol 0.5% administered once in the morning and once in the evening for up to 20 months. intervention 3: Sham administered on Day 1, Week 16, and Week 32. intervention 4: Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

Protocol document:
Prot_001.pdf: 
 
N C T 0 2 2 4 7 8 0 4  
 
St u d y I D: 1 9 2 0 2 4 -0 9 1  
 
Titl e: Effic acy a n d S af et y of Bi m at o pr ost S ust ai n e d -R el e as e ( S R) i n P ati e nts Wit h O p e n -a n gl e Gl a uc o m a 
or Oc ul ar Hy p ert e nsi o n  
 
Pr ot oc ol  A m e n d m e nt 2  D at e: 1 6 -M ar -2 0 1 7  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Title Pa ge 
A L L E R G A N – C O N FI D E N TI A L 
T he f oll o wi n g c o ntai ns c o nfi de ntial, pr o prietar y i nf or mati o n  
w hic h is t he pr o pert y of Aller ga n 
 
T he Effic ac y a n d S afet y of Bi m at o pr ost S R i n P atie nts Wit h O pe n- a n gle Gl a uc o m a or 
Oc ul ar H y perte nsi o n 
 
Pr ot oc ol N u m b er:   
1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
E u dra C T N u m b er: 
2 0 1 4- 0 0 3 0 3 7- 2 6  
P hase: 
3 
Na me of I n vesti gati o nal Pr o d uct:  
Bi mat o pr ost S R 
S p o ns or: 
Aller ga n ( N ort h A merica) 
2 5 2 5 D u p o nt Dri ve 
Ir vi ne, Calif or nia U S A 
9 2 6 1 2 
+ 1- 7 1 4- 2 4 6- 4 5 0 0 
+ 1- 8 0 0- 3 4 7- 4 5 0 0 
 
Aller ga n Lt d. 
1st Fl o or, Marl o w 
I nter nati o nal, 
T he Par k wa y, Marl o w 
B uc ki n g ha ms hire 
S L 7 1 Y L U nite d Ki n g d o m 
Tel: + 4 4 ( 0) 1 6 2 8 4 9 4 4 4 4 
Fa x: + 4 4 ( 0) 1 6 2 8 4 9 4 4 4 9  
E mer ge nc y Tele p h o ne N u m b ers:  
Refe r t o t he St u d y C o ntacts Pa ge. 
  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Aller ga n Si g nat or y: 
Refer t o t he fi nal pa ge of t his pr ot oc ol f or electr o nic si g nat ure 
a n d date of a p pr o val. 
 
T he f oll o wi n g i nf or mati o n ca n be f o u n d o n F D A F or m 1 5 7 2 a n d/ or st u d y c o ntacts pa ge: na me a n d 
c o ntact i nf or mati o n of Aller ga n st u d y pers o n nel a n d e mer ge nc y tele p h o ne n u m bers; na me, a d dress, 
a n d state me nt of q ualificati o ns of eac h i n vesti gat or; na me of eac h s u bi n vesti gat or w or ki n g u n der t he 
s u per visi o n of t he i n vesti gat or; na me a n d a d dress of t he researc h facilities t o be use d; na me a n d 
a d dress of eac h re vie wi n g i nstit uti o nal re vie w  b oar d (I R B); U S 2 1 C F R 3 1 2. 2 3 secti o n 6(iii) b. 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
I N V E S TI G A T O R SI G N A T U R E P A G E 
I N V E S TI G A T O R: 
 
 
 
 
I a gree t o: 
•  I m ple me nt a n d c o n d uct t his st u d y dili ge ntl y an d i n strict c o m plia nce wit h t he pr ot oc ol, 
g o o d cli nical practices a n d all a p plica ble la ws a n d re g ulati o ns 
•  Mai ntai n all i nf or mati o n s u p plie d b y Aller ga n i n c o nfi de nce, a n d w he n t his i nf or mati o n 
is s u b mitte d t o a n i nstit uti o nal re vie w b oar d (I R B), i n de pe n de nt et hics c o m mittee (I E C) 
or a n ot her gr o u p, it will be s u b mitte d wit h a de si g nati o n t hat t he material is c o nfi de ntial 
•  E ns ure t hat all pers o ns assisti n g wit h t he trial are a de q uatel y i nf or me d a b o ut t he pr ot oc ol, 
t he i n vesti gati o nal pr o d uct(s), a n d t heir trial- relate d d uties a n d f u ncti o ns. 
I ha ve rea d t his pr ot oc ol i n its e ntiret y a n d I a gree t o all as pects. 
 
 
 
 
 
I n vesti gat or Pri nte d Na me  
  
Si g nat ure 
  
Date 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Ta ble of C o nte nts 
Ta ble of C o nte nts ............................................................................................................. ......... 4 
List of Ta bles ................................................................................................................ ............. 8 
List of Fi g ures ............................................................................................................... ............ 9 
Pr ot oc ol S u m mar y .............................................................................................................. .... 1 0 
1.   Bac k gr o u n d a n d Cli nical Rati o nale ................................................................................. 2 4  
1. 1  
Gla uc o ma O ver vie w............................................................................................... 2 4  
1. 2  
Bi mat o pr ost ( L U MI G A N ® ) ................................................................................... 2 5 
1. 3  
Bi mat o pr ost S R ...................................................................................................... 2 6  
1. 3. 1   N o ncli nical St u dies wit h  Bi mat o pr ost S R .................................................. 2 6 
1. 3. 2   Ot her Bi o de gra da ble Oc ular I m pla nts ....................................................... 2 8  
1. 3. 3   Cli nical St u d y wit h Bi mat o pr ost S R .......................................................... 2 8  
1. 4  
St u d y Rati o nale ...................................................................................................... 2 8  
2.   St u d y O bjecti ves a n d Cli nical H y p ot heses ...................................................................... 2 9  
2. 1  
St u d y O bjecti ves .................................................................................................... 2 9  
2. 2  
Cli nical H y p ot heses ............................................................................................... 2 9  
3.   St u d y Desi g n .................................................................................................................. .. 2 9 
4.   St u d y P o p ulati o n a n d E ntr y Criteria ................................................................................ 3 1  
4. 1  
N u m ber of Patie nts ................................................................................................. 3 1  
4. 2  
St u d y P o p ulati o n C haracteristics ........................................................................... 3 1  
4. 2. 1   Patie nts Wit h Sic kle Cell Trait or Disease ................................................. 3 1  
4. 3  
I ncl usi o n Criteria .................................................................................................... 3 1 
4. 4  
E xcl usi o n Criteria................................................................................................... 3 3  
4. 5  
Per missi ble a n d Pr o hi bite d Me dicati o ns/ Treat me nts ............................................. 3 7  
4. 5. 1   Per missi ble Me dicati o ns/ Treat me nts ......................................................... 3 7  
4. 5. 2   Pr o hi bite d Me dicati o ns/ Treat me nts ........................................................... 3 8  
4. 5. 3   Defi niti o n of Fe males of ( N o n-) C hil d beari n g P ote ntial a n d/ or Acce pta ble 
C o ntrace pti ve Met h o ds .............................................................................. 4 0  
5.   St u d y Treat me nts ............................................................................................................. 4 1  
5. 1  
St u d y Treat me nts a n d F or m ulati o ns ....................................................................... 4 1  
5. 2  
C o ntr ol Treat me nts ................................................................................................. 4 1  
5. 3  
Met h o ds f or Mas ki n g ............................................................................................. 4 1  
5. 4  
Treat me nt All ocati o n Rati o a n d Stratificati o n........................................................ 4 3  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
5
5
5
5
5
5
6.   R
6
6
6
6
6
7.   S
7
7
7
g a n C o nfi de nti a
5 . 5 
Met h o
5 . 6 
Treat m
5. 6. 1  
5 . 7 
St ora g
5 . 8 
Pre pa r
5 . 9 
Treat m
5. 9. 1  
5. 9. 2  
5. 9. 3  
5. 9. 4  
5 . 1 0  Retre a
R es p o nse M
6 . 1 
Effica c
6. 1. 1  
6 . 2 
Safet y 
6 . 4 
E xa mi
6. 4. 1  
6. 4. 2  
6. 4. 3  
6 . 5 
Ot her S
6 . 6 
S u m m
S tatistical Pr
7 . 1 
A nal y s
7 . 2 
C ollec
7. 2. 1  
7. 2. 2  
7 . 3 
H y p ot h
7. 3. 1  
a l 
d  f or Assi gn
m e nt Re gi me
Treat me nt R
e of St u d y M
rati o n of St u d
m e nt A d mi ni
Patie nt Pre p
St u d y Trea t
A d mi nistr a
I m me diate 
at me nt .........
eas ures a n d 
cy Meas ure s
Pri mar y E f
Meas ures ..
nati o n Pr oc e
Me dical H i
 
M
6. 4. 1. 1
 
P
6. 4. 1. 2
 
V
6. 4. 1. 3
Pre g na nc y 
La b orat or y
 
H
6. 4. 3. 1
 
S
6. 4. 3. 2
 
U
6. 4. 3. 3
S t u d y S u p pl
m ar y of Met h o
roce d ures ....
sis P o p ulatio
ti o n a n d Der
Pri mar y E f
Sec o n dar y 
h esis a n d M
Pri mar y E f
n me nt t o Tre
en a n d D osi n
R e gi me n/ Do
M e dicati o ns/
d y Me dicati o
strati o n .......
p arati o n ..... .
tme nt L oca t
ati o n Tec h niq
P osttreat m e
....................
S u m mar y o f
s ...................
ffi cac y Meas
....................
ed ures, Test s
ist or y, P h ysi
M e dical Hist
P h ysical E x a
V ital Si g ns ...
Testi n g ...... .
y  Pr oce d ures
H e mat ol o g y .
S er u m C hem
U ri nal ysis ....
lies ...............
o ds of Data 
....................
o ns .............. .
ri vati o n of P
ffi cac y Varia
Efficac y Va r
et h o ds of An
ffi cac y A naly
5 
at me nt Gr o u
n g ................ .
o sa ge A dj ust
/Treat me nts .
o ns/ Treat m e
....................
....................
i o n ..............
q ue ............. .
ent O bser vat
....................
f Data C olle
....................
sure ............. .
....................
s, E q ui p men
ical E xa mi na
tor y ............ .
ami nati o n.... .
....................
....................
...................
....................
m istr y ...........
....................
....................
C ollecti o n . .
....................
....................
P ri mar y a n d 
able ............. .
ria ble ..........
n al ysis .........
y ses .............
Pr
u ps/ Ra n d o m
....................
tme nts ........ .
....................
ents ............. .
....................
....................
....................
....................
ti o n ..............
....................
ecti o n Met h o
....................
....................
....................
n t, a n d Tec hn
ati o n, a n d Vi
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
Sec o n dar y E
....................
....................
....................
....................
rot oc ol 1 9 2 0 2 4
G D D- T A
m izati o n ........
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
o ds .............. .
....................
....................
....................
n i q ues ..........
ital Si g ns.....
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
E fficac y Ass
....................
....................
....................
....................
4 - 0 9 1 A me n dm
A - T- 0 0 4 v 2 0 1 3
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
ess me nts .... .
....................
....................
....................
....................
m e nt 2 
. 9 
.... 4 3 
.... 4 4 
.... 4 4 
.... 4 5 
.... 4 6 
.... 4 6 
.... 4 6 
.... 4 6 
.... 4 7 
.... 4 7 
.... 4 8 
.... 4 8 
.... 4 8 
.... 4 8 
.... 4 9 
.... 5 2 
.... 5 2 
.... 5 2 
.... 5 3 
.... 5 3 
.... 5 3 
.... 5 3 
.... 5 4 
.... 5 4 
.... 5 4 
.... 5 4 
.... 5 5 
.... 5 5 
.... 5 6 
.... 5 6 
.... 5 7 
.... 5 7 
.... 5 7 
.... 5 7 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
7
7
7
7
8.   S
8
8
8
g a n C o nfi de nti a
7. 3. 2  
7. 3. 4  
7 . 4 
S u b gr o
7 . 5 
I nterim
7 . 6 
A nal y s
7 . 7 
Sa m pl e
S t u d y Visit S
8 . 1 
Patie n t
8. 1. 1  
8. 1. 2  
8 . 2 
Was h o
8 . 3 
Pr oce d
a l 
Sec o n dar y 
Safet y A n a
o u p A nal yse
m  A nal yses..
ses f or U S F
e Size Calcu
S c he d ule a nd
t E ntr y Pr oc
O ver vie w o
I nf or me d C
o ut I nter vals 
d ures f or Fi n
Efficac y A n
al yses ...........
s ..................
....................
D A ............ .
u lati o n .........
d  Pr oce d ures
ed u res .........
o f E ntr y Pr o
C o nse nt a n d 
....................
n al St u d y E n t
6 
n al yses ........ .
....................
....................
....................
....................
....................
s ..................
....................
ce d ures ...... .
Patie nt Pri v
....................
tr y ...............
Pr
....................
....................
....................
....................
....................
....................
....................
....................
....................
v ac y ............. .
....................
....................
rot oc ol 1 9 2 0 2 4
G D D- T A
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
4 - 0 9 1 A me n dm
A - T- 0 0 4 v 2 0 1 3
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
m e nt 2 
. 9 
.... 5 8 
.... 5 9 
.... 5 9 
.... 5 9 
.... 6 0 
.... 6 1 
.... 6 1 
.... 6 2 
.... 6 2 
.... 6 2 
.... 6 2 
.... 6 3 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
8
8
8
8
8
8
9.   A
9
9
9
9
1 0.   A
1
1
1
1
g a n C o nfi de nti a
8 . 5 
I nstr uc
8 . 6 
U nsc h e
8 . 7 
C o m p l
8 . 8 
Earl y D
8 . 9 
Wit h d r
8 . 1 0  St u d y T
A d verse E v e
9 . 1 
Defi ni t
9. 1. 1  
9. 1. 2  
9. 1. 3  
9. 1. 4  
9 . 2 
Pr oce d
9 . 3 
Pr oce d
9 . 4 
Pr oce d
A d mi nistrat i
1 0. 1   Pr otec t
1 0. 1. 1  
1 0. 1. 2  
1 0. 1. 3  
1 0. 1. 4  
1 0. 2   C ha n g
1 0. 3   Patie n t
1 0. 3. 1  
1 0. 4   D oc u m
a l 
cti o ns f or t he
ed ule d Visit
lia nce wit h P
D isc o nti n uat
ra wal Criter i
T er mi nati on
ents .............
ti o ns ...........
A d verse E v
Seri o us A d
Se verit y ...
Relati o ns h i
d ures f or Re p
d ures f or Re p
d ures f or U n m
ive Ite ms ....
ti o n of H um
C o m plia nc
Rele va nt C
C o m plia nc
C o m plia nc
C o m plia nc
( U S 2 1 C FR
es t o t he Pr o
t C o nfi de ntia
Patie nt Pri v
m e ntati o n ....
e Patie nts .....
s ..................
P r ot oc ol .......
ti o n of Patie
ia .................
n  ...................
....................
....................
v e nt ............ .
d verse E ve nt
....................
ip t o St u d y D
p orti n g A d v e
p orti n g a Se r
m as ki n g of S
....................
m a n S u bjects .
e wit h I nf or m
C o u ntr y Re g u
e Wit h I R B 
e Wit h G o o d
e Wit h Elect
R  Part 1 1) ...
o t oc ol ..........
alit y ............
v ac y ............
....................
7 
....................
....................
....................
nts ............. .
....................
....................
....................
....................
....................
...................
....................
D r u g or St ud
erse E ve nts .
ri o us A d vers
S t u d y Me dic
....................
....................
m e d C o nse n
u lati o ns .......
or I E C Re g u
d  Cli nical Pr
tr o nic Rec or
....................
....................
....................
....................
....................
Pr
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
d y Pr oce d ur e
....................
se E ve nt ......
cati o n ..........
....................
....................
n t Re g ulati on
....................
u lati o ns .......
ractice .........
rds; Electr o n
....................
....................
....................
....................
....................
rot oc ol 1 9 2 0 2 4
G D D- T A
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
e ..................
....................
....................
....................
....................
....................
n s ( U S 2 1 C
....................
....................
....................
n ic Si g nat ure
....................
....................
....................
....................
....................
4 - 0 9 1 A me n dm
A - T- 0 0 4 v 2 0 1 3
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
....................
F R Part 5 0) 
....................
....................
....................
es Re g ulati o
....................
....................
....................
....................
....................
m e nt 2 
. 9 
.... 8 2 
.... 8 3 
.... 8 3 
.... 8 3 
.... 8 4 
.... 8 5 
.... 8 5 
.... 8 5 
.... 8 5 
.... 8 6 
.... 8 6 
.... 8 6 
.... 8 7 
.... 8 7 
.... 8 8 
.... 8 8 
.... 8 9 
a nd  
.... 8 9 
.... 8 9 
.... 8 9 
ns 
.... 8 9 
.... 8 9 
.... 9 0 
.... 9 0 
.... 9 0 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 0. 4. 1   S o urce D oc u me nts ..................................................................................... 9 0  
1 0. 4. 2   Case Re p ort F or m C o m pleti o n................................................................... 9 1  
1 0. 4. 3   St u d y S u m mar y .......................................................................................... 9 2  
1 0. 4. 4   Rete nti o n of D oc u me ntati o n ...................................................................... 9 2  
1 0. 5   La beli n g, Pac ka gi n g, a n d Ret ur n or Dis p osal of St u d y Me dicati o ns/ Treat me nts .. 9 2  
1 0. 5. 1   La beli n g/ Pac ka gi n g .................................................................................... 9 2  
1 0. 5. 2   Cli nical S u p pl y I n ve nt or y .......................................................................... 9 3  
1 0. 5. 3   Ret ur n or Dis p osal of St u d y Me dica ti o ns/ Treat me nts a n d/ or S u p plies ..... 9 3 
1 0. 6   M o nit ori n g b y t he S p o ns or .................................................................................... 9 3  
1 0. 7   Ha n dli n g of Bi ol o gical S peci me ns......................................................................... 9 4  
1 0. 8   P u blicati o ns ............................................................................................................ 9 4  
1 0. 9   C o or di nati n g I n vesti gat or ...................................................................................... 9 4  
1 0. 1 0  Vi de o Rec or di n g a n d G o ni osc o pic P h ot o gra p h y ................................................... 9 4  
1 1.   Refere nces .................................................................................................................... .... 9 5 
1 2.   Attac h me nts ................................................................................................................... .. 9 8 
1 2. 1   Pac ka ge I nsert ........................................................................................................ 9 8  
1 2. 2   Gl ossar y of A b bre viati o ns ...................................................................................... 9 9  
1 2. 3   Pr ot oc ol A me n d me nt S u m mar y ........................................................................... 1 0 1  
1 2. 3. 1   A me n d me nt 1 ........................................................................................... 1 0 1  
1 2. 3. 2   A me n d me nt 2 ........................................................................................... 1 1 3  
 
List of Ta bles 
Ta ble 1  
Treat me nt Gr o u ps ........................................................................................... 1 0  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Ta ble 7  
Treat me nt Gr o u ps ........................................................................................... 3 0  
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Pr ot oc ol S u m m ar y 
 
St u d y C o m p o u n d:  Bi mat o pr ost s ustai ne d-release ( S R) bi o de gra da ble i m pla nts c o ntai ni n g preser vati ve-free 
A G N- 1 9 2 0 2 4 ( bi mat o pr ost)  
P h ase: 3 
St u d y O bjecti ves:   
T o e val uate t he i ntra oc ular press ure (I O P)-l o weri n g efficac y a n d safet y of 2 d ose stre n gt hs of Bi mat o pr ost S R 
i n patie nts wit h o pe n-a n gle gla uc o ma ( O A G) or oc ular h y perte nsi o n ( O H T) after i nitial a n d re peate d 
a d mi nistrati o ns  
Cli nic al H y p ot heses:   
At least 1 d ose stre n gt h ( 1 0 µ g or 1 5 µ g) of Bi mat o pr ost S R will ha ve a n I O P-l o weri n g effect t hat is n o ni nferi or 
t o t hat of t o picall y a d mi nistere d ti mol ol maleate 0. 5 % ( hereafter referre d t o as ti m ol ol) e ye dr o ps i n patie nts 
wit h O A G or O H T f oll o wi n g si n gle a n d re peat a d mi nistrati o n. 
Bi mat o pr ost S R a d mi nistere d i ntraca merall y i n d ose stre n gt hs of 1 0 µ g or 1 5 µ g will ha ve a n acce pta ble safet y 
pr ofile i n patie nts wit h O A G or O H T f oll o wi n g si n gle a n d re peat a d mi nistrati o n. 
St u d y Desi g n 
Str uct ure : P hase 3, m ultice nter, ra n d o mize d, mas ke d, parallel- gr o u p c o m paris o n ( 2 d ose stre n gt hs of 
Bi mat o pr ost S R vers us acti ve c o ntr ol), re peat a d mi nistrati o n 
D ur ati o n : A p pr o xi matel y 2 2 m o nt hs, c o nsisti n g of scree ni n g of u p t o 2 8 da ys bef ore was h o ut, was h o ut peri o d 
of u p t o 4 2 da ys bef ore i nitial a d mi nistrati o n of st u d y me dicati o n, 5 2- wee k treat me nt peri o d, pl us 8 m o nt hs 
e xte n de d f oll o w- u p  
St u dy Tre at me nt Gr o u ps : Bi mat o pr ost S R d ose gr o u ps: 1 0 µ g a n d 1 5 µ g 
C o ntr ol : Ti m ol ol e ye dr o ps pl us S ha m nee dleless pr oce d ure (t hat i n v ol ves t o uc hi n g t he e ye at t he area of 
i nserti o n wit h a nee dleless a p plicat or). 
D os a ge/ D ose Re gi me n : Patie nts will recei ve 1 of 2 d ose stre n gt hs of Bi mat o pr ost S R or C o ntr ol treat me nt i n t he 
st u d y e ye o n Da y 1 ( wit h re peat a d mi nistrati o n of t he same d ose stre n gt h or S ha m at W ee k 1 6 a n d Wee k 3 2). 
Bi mat o pr ost S R-treate d patie nts will recei ve i ntraca meral a d mi nistrati o n of Bi mat o pr ost S R i n t he st u d y e ye 
usi n g a prefille d a p plicat or. Ti m ol ol ve hicle e ye dr o ps will be use d t wice dail y ( BI D; i n t he m or ni n g a n d 
e ve ni n g) t o mas k t he treat me nt of patie nts recei vi n g Bi mat o pr ost S R i n t he st u d y e ye. T he fell o w e ye will 
recei ve a S ha m nee dleless pr oce d ure ( hereafter calle d S ha m a d mi nistrati o n or S ha m a d mi nistrati o n pr oce d ure) 
pl us t o pical ti m ol ol e y e dr o ps, BI D. C o ntr ol gr o u p patie nts will recei ve a S ha m a d mi nistra ti o n pl us ti mol ol i n 
b ot h e yes. 
All patie nts will be mas ke d t o t heir treat me nt gr o u p. Treat me nt gr o u ps are s h o w n i n Ta ble 1. 
T a ble 1 
Tre at me nt Gr o u ps 
Treat me nt 
St u d y E ye Treat m e nt 
Fell o w E ye Treat me nt 
Bi mat o pr ost S R 1 0 µ g  
D ose stre n gt h: 1 0 µ g 
E ye dr o ps: Ve hicle BI D 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps: Ti m ol ol BI D 
Bi mat o pr ost S R 1 5 µ g 
D ose stre n gt h: 1 5 µ g 
E ye dr o ps: Ve hicle BI D 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps: Ti m ol ol BI D 
C o ntr ol 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps: Ti m ol ol BI D 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps: Ti m ol ol BI D 
BI D = t wice dail y 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
T he patie nts will be gi n self-a d mi nistrati o n of t he st u d y- pr o vi de d e ye dr o ps ( ve hicle or ti m ol ol) i n b ot h e yes, 
starti n g wit h t he e ve ni n g d ose o n t he first a d mi nistrati o n ( Bi mat o pr ost S R or S ha m a d mi nistrati o n) da y visit. 
Patie nts will c o nti n ue self-a d mi nistrati o n of t he st u d y- p r o vi de d e ye dr o ps i n t he m or ni n g ( 0 8: 0 0 ± 1 h o ur) a n d 
i n t he e ve ni n g ( 2 0: 0 0  ± 1 h o ur) a p pr o xi matel y 1 2 h o urs a part t hr o u g h o ut t he st u d y, wit h t he e xce pti o n of t he 
m or ni n g of a s u bse q ue nt visit, o n w hic h t he m or ni n g e ye dr o p a d mi nistrati o n will be perf or me d at t he st u d y 
site. 
R a n d o miz ati o n/ Str atific ati o n : Ra n d o mizati o n t o treat me nt gr o u ps will use a 1: 1: 1 rati o ( Bi mat o pr ost S R 
1 0 µ g: Bi mat o pr ost S R 1 5 µ g: C o ntr ol). Ra n d o mizati o n will be stratifie d b y baseli ne st u d y e ye H o ur 0 I O P 
( ≤ 2 5 m m H g or > 2 5 m m H g). 
Visit Sc he d ule: Patie nts w h o c o m plete t he e ntire st u d y wit h o ut r ecei vi n g n o nst u d y I O P-l o weri n g me dicati o n i n 
b ot h e yes will ha ve a mi ni m u m of 2 5 visits a n d 6 p h o ne calls. 
 
 
  
 
 
o  
o  
 
o  
 
 
 
Patie nts w h o ha ve n ot recei ve d n o nst u d y  I O P-l o weri n g me dicati o n ( pr o hi bite d pri or t o Wee k 5 2) i n b ot h e yes 
will recei ve a re peat a d mi nistrati o n of  Bi mat o pr ost S R ( or S ha m a d mi nistrati o n i n C o ntr ol gr o u p st u d y e yes a n d 
all fell o w e yes) at t he W ee k 1 6 a n d W ee k 3 2 visits as i n dicate d. A d mi nistrati o n s h o ul d n ot occ ur if t he 
i n vesti gat or belie ves t hat t here are a n y safet y c o ncerns. Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o weri n g 
me dicati o n  i n b ot h e yes will be f oll o we d f or at least 1 2 m o nt hs f oll o wi n g t he last a d mi nistrati o n of 
Bi mat o pr ost S R or S ha m, at w hic h ti me t he y ma y e xit earl y at t he i n vesti gat or’s discreti o n. 
St u d y P o p ul ati o n C h ar acteristics 
N u m ber of P atie nts : A p pr o xi matel y 6 0 0 patie nts will be e nr olle d i n t he st u d y. 
C o n diti o n/ Dise ase : Patie nts wit h O A G ( pri mar y O A G, pse u d oe xf oliati ve gla uc o ma, or pi g me ntar y gla uc o ma) 
or O H T w h o re q uire I O P-l o weri n g me dicati o ns i n b ot h  e yes. T he e ye t hat meets t he e ntr y criteria will be 
selecte d as t he st u d y e ye. If b ot h e yes meet t he e ntr y criteria, t he e ye wit h t he hi g her I O P at baseli ne H o ur 0 will 
be selecte d as t he st u d y e ye. If b ot h e yes ha ve t he sa me I O P at H o ur 0, t he n t he ri g ht e ye will be desi g nate d as 
t he st u d y e ye. 
Key I ncl usi o n Criteri a :  
•  
•  
Dia g n osis of eit her O A G (ie, pr i mar y, pse u d oe xf oliati o n, or pi g me ntar y gla uc o ma) or O H T i n eac h 
e ye a n d b ot h e yes re q uire I O P-l o weri n g treat me nt ( N ote: dia g n osis d oes n ot ha ve t o be t he sa me i n 
b ot h e yes) 
•  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
•  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Key Excl usi o n Criteri a : 
•  
T he f oll o wi n g s ur g ical hist or y: 
a. 
Hist or y or e vi de nce of c o m plicate d cataract s ur ger y i n t he st u d y e ye: e g, s ur ger y res ulti n g i n 
c o m plicate d le ns place me nt (s uc h as a nteri or c h a m ber i ntra oc ular le ns i m pla nt [I O L], s ulc us 
I O L, a p ha kia, etc) or i ntra o perati ve c o m plicati o ns (s uc h as a p osteri or ca ps ular tear [ wit h or 
wit h o ut vitre o us l oss], s u bsta ntial iris tra u ma, etc) 
N ote: hist or y of u nc o m plicate d catar act s ur ger y is n ot a n e xcl usi o n. 
b.  Hist or y of p ha kic I O L i nserti o n f or refr acti ve err or c orrecti o n i n t he st u d y e ye 
•  
 
 
 
Res p o nse Me as ures 
Effic acy : I ntra oc ular press ure meas ure d b y G ol d ma n n a p pla nati o n t o n o metr y   
S afety : A d verse e ve nts; 
 
 
Ge ner al St atistic al Met h o ds a n d T y pes of A n al yses:    
T he i nte nt-t o-treat p o p ulati o n (I T T) is defi ne d as all ra n d o mize d patie nts a n d will be use d f or de m o gra p hic a n d  
efficac y a nal yses. T he per pr ot oc ol ( P P) p o p ulati o n will c o nsist of t he s u bset of t he I T T p o p ulati o n wit h n o 
pr ot oc ol de viat i o ns affecti n g t he pri mar y efficac y a nal ysis a n d will be use d t o c o nfir m t he pri mar y efficac y 
a nal ysis. A list of patie nts e xcl u de d fr o m t he P P p o p ulati o n will be fi nalize d pri or t o data base l oc k. T he safet y 
p o p ulati o n is defi ne d as all patie nts w h o recei ve d st u d y dr u g treat me nt a n d will be use d f or safet y a nal yses.  
A nal yses i n t he I T T p o p ulati o n will be base d o n t he treat me nt t o w hic h a patie nt was ra n d o mize d, a n d a nal yses 
i n b ot h t he P P a n d safet y p o p ulati o ns will be base d o n t he act ual treat me nt a patie nt recei ve d. 
C o nti n u o us varia bles will be s u m marize d b y descri pti ve statistics i ncl u di n g sa m ple size, mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma xi m u m. Cate g ori cal varia bles will be s u m marize d b y fre q ue nc y a n d 
perce nta ge. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
T he pri mar y efficac y varia ble is st u d y e ye ti me- matc he d I O P c ha n ge fr o m baseli ne. Mea n I O P c ha n ge fr o m 
baseli ne will be c o m pare d bet wee n eac h Bi mat o pr ost S R  d ose stre n gt h a n d ti m ol ol f or eac h h o ur ( H o urs 0 
a n d 2) usi n g t he I T T p o p ulati o n. T he c o m paris o ns at Wee k 1 2 will be c o nsi dere d t he pri mar y a nal ysis. 
I ntra oc ular press ure c ha n ge fr o m baseli ne will be a nal yze d usi n g a mi xe d-effects m o del re peate d meas ures 
( M M R M) a p pr oac h. T he m o del will i ncl u de I O P ti me- matc he d c ha n ge fr o m baseli ne as t he res p o nse varia ble 
a n d treat me nt, ti me p oi nt ( H o urs 0 a n d 2 at eac h visit of Wee ks 2, 6, a n d 1 2), treat me nt- b y-ti me p oi nt i nteracti o n, 
a n d baseli ne I O P stratificati o n as fi xe d effects. U nstr u ct ure d c o varia nce matri x will be use d f or re peate d 
meas ures o n t he sa me patie nt; if t he m o del wit h u nstr u ct ure d c o varia nce matri x fails t o c o n ver ge, m ulti ple 
i m p utati o n ( MI) will be i m ple me nte d bef ore M M R M. 
Wit hi n t he fra me w or k of t his m o del, t he mea n differe nce bet wee n eac h Bi mat o pr os t S R d ose stre n gt h a n d 
ti m ol ol ( Bi mat o pr ost S R mi n us ti m ol ol) a n d t he c orres p o n di n g 2-si de d 9 5 % c o nfi de nce i nter val will be 
pr o vi de d f or eac h h o ur ( H o urs 0 a n d 2) at eac h visit. T he f or mal n o ni nf eri orit y test will be perf or me d at 
Wee k 1 2 f or eac h Bi mat o pr ost S R d ose stre n gt h vers us ti m ol ol usi n g a n o ni nferi orit y mar gi n of 1. 5 m m H g. A 
gate kee pi n g pr oce d ure will be use d t o c o ntr ol t he o verall t y pe I err or rate at t he 0. 0 5 le vel f or eac h h o ur at 
Wee k 1 2, testi n g Bi mat o pr ost S R 1 5 µ g a gai nst ti m ol ol first a n d f oll o we d b y t he c o m paris o n bet wee n 
Bi mat o pr ost S R 1 0 µ g a n d ti m ol ol. T he test of Bi mat o pr ost S R 1 0 µ g vers us ti m ol ol f or a gi ve n h o ur at 
Wee k 1 2 is vali d o nl y if t he n o ni nferi orit y of Bi mat o pr ost S R 1 5 µ g t o ti m ol ol is de m o nstrate d f or t he sa me 
ti me p oi nt. Bi mat o pr ost S R 1 5 µ g ( or 1 0 µ g) will be declare d n o ni nferi or t o ti m ol ol if t he u p per li mit of t he 9 5 % 
c o nfi de nce i nter val is ≤ 1. 5 m m H g f or b ot h H o urs 0 a n d 2 at W ee k 1 2.   
F or t he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( U S F D A), t he pri mar y efficac y varia ble will be t he st u d y 
e ye I O P. T he pri mar y a nal ysis will be base d o n W ee ks 2,  6, a n d 1 2 usi n g t he I T T p o p ulati o n. S pecificall y, t he 
f oll o wi n g a nal ysis will be perf or me d: I O P will be a nal yze d usi n g a n M M R M a p pr oac h base d o n t he sa me 
m o del as descri be d f or t he pri mar y efficac y a nal ysis of ti me- matc he d I O P c ha n ge fr o m baseli ne. Wit hi n t he 
fra me w or k of t his m o del, t he mea n differe nce bet wee n eac h Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol gr o u p 
a n d t he c orres p o n di n g 9 5 % c o nfi de nce i nter val will be pr o vi de d f or eac h h o ur ( H o u rs 0 a n d 2) a n d eac h visit 
( W ee ks 2, 6, a n d 1 2). A gate kee pi n g pr oce d ure will be use d t o c o ntr ol t he o verall t y pe I err or rate at t he 
0. 0 5 le vel f or eac h ti me p oi nt, testi n g Bi mat o pr ost S R 1 5 µ g a gai nst ti m ol ol first a n d f oll o we d b y t he 
c o m paris o n bet wee n Bi mat o pr ost S R 1 0 µ g a n d ti m ol ol. T he test f or Bi mat o pr ost S R 1 0 µ g vers us ti m ol ol f or a 
gi ve n h o ur at a visit is vali d o nl y if t he n o ni nferi orit y of Bi mat o pr ost S R 1 5 µ g t o ti m ol ol has bee n 
de m o nstrate d f or t he gi ve n ti me p oi nt. Eac h Bi mat o pr ost S R d ose stre n gt h t hat s h o ws n o ni nferi orit y t o ti m ol ol at 
all 6 ti me p oi nts wit h a 1. 5 m m H g mar gi n (ie, t he u p per li mit of t he 9 5 % c o nfi de nce i nter val is ≤ 1. 5 m m H g) 
will be declare d cli nicall y n o ni nferi or t o ti m ol ol if t he u p per li mit of t he 9 5 % c o nfi de nce i nter val is 
≤ 1. 0 m m H g f or 3 or m ore ti me p oi nts.   
A d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) a n d will be 
s u m marize d f or all e ve nts re gar dless of ca usalit y an d f or treat me nt-relate d a d verse e ve nts. Oc ular a d verse 
e ve nts a n d safet y varia bles will be ta b ulate d b y st u d y e ye a n d fell o w e ye wit hi n eac h treat me nt d ose stre n gt h or 
gr o u p, a n d n o n oc ular safet y varia bles will be s u m marize d b y patie nt. 
Sa m ple Size Calc ulati o n: T he sa m ple size calc ulati o n is base d o n t he pri mar y efficac y  a nal ysis of t he I O P f or 
U S F D A re vie w beca use t he sa m ple size base d o n t he pri m ar y efficac y a nal ysis f or ot her re gi o ns is e x pecte d t o 
be s maller. Base d o n si m ulati o ns, a sa m ple size of 5 4 0 patie nts ( 1 8 0 per gr o u p) will pr o vi de a p pr o xi matel y 9 5 % 
a n d 8 1 % p o wer t o s h o w n o ni nferi orit y ( NI) of Bi mat o pr ost S R 1 5 µ g a n d Bi mat o pr ost S R 1 0 µ g, res pecti vel y, 
t o ti m ol ol at all 6 sc he d ule d ti me p oi nts base d o n a n NI mar gi n of 1. 5 m m H g a n d at 3 or m ore ti me p oi nts base d 
o n a n NI mar gi n of 1. 0 m m H g. Ass u mi n g a pre mat ure disc o nti n uati o n rate of 1 0 % wit hi n 1 2 wee ks ( bef ore t he 
pri mar y data base l oc k), a p pr o xi matel y 6 0 0 patie nts ( 2 0 0  per gr o u p) are t o be e nr olle d i nt o t his st u d y. 
 
 


 
 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
 
A p pr o v al  D at e: 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1.  
B ac k gr o u n d a n d Cli nic al R ati o n ale  
1. 1  
Gl a uc o m a O ver vie w 
Gla uc o ma is a fa mil y of diseases c o m m o nl y c haracterize d b y pr o gressi ve o ptic ne ur o pat h y 
wit h ass ociate d vis ual fiel d de fects a n d is t he lea di n g ca use of irre versi ble bli n d ness i n t he 
w orl d.  Gla uc o ma is classifie d b y Bec ker- S ha ffer i nt o 3 br oa d t y pes:  de vel o p me ntal, 
a n gle-cl os ure, a n d o pe n-a n gle gla uc o ma ( O A G) ( Sta m per et al, 2 0 0 9 ).  O pe n-a n gle gla uc o ma 
is f urt her cate g orize d i nt o pri mar y O A G ( P O A G, s o meti mes als o referre d t o as c hr o nic O A G) 
a n d sec o n dar y O A G ( w hic h i ncl u des pi g me nta r y a n d pse u d oe xf oliati o n gla uc o ma), t he 
f or mer bei n g t he pre d o mi na nt f or m of O A G.  Pri mar y O A G is c haracterize d as a m ulti-
fact orial o ptic ne ur o pat h y wit h a c haracteristic ac q uire d atr o p h y of t he o ptic ner ve a n d l oss of 
ga n gli o n cells a n d t heir a x o ns, de vel o pi n g i n t h e prese nce of o pe n a nteri or c ha m ber ( A C) 
a n gles, a n d ma nifesti n g c haracteri stic vis ual fiel d a b n or malities (A merica n Aca de m y 
of O p ht hal m ol o g y, 2 0 1 0a ).  It is esti mate d t hat 2. 2 5 millio n pe o ple i n t he U nite d States ( U S) 
o ver t he a ge of 4 0 years ha ve P O A G, half of w h o m are u na ware of t heir disease des pite 
de m o nstra ble vis ual fiel d l oss ( Q ui gle y, 1 9 9 6 ).  Gl o ball y, o ver 6 0 milli o n pe o ple are 
esti mate d t o be affecte d b y gla uc o ma (t he ma j orit y of w h o m ha ve o pe n a n gle gla uc o ma) a n d 
t hese n u m bers are e x pecte d t o i ncrease o ver ti me (Q ui gle y a n d Br o ma n, 2 0 0 6; 
Var ma et al, 2 0 1 1; C o o k a n d F oster, 2 0 1 2 ). 
Alt h o u g h ma n y ris k fact ors ha ve bee n ass ociat e d wit h O A G, ele vate d i ntra oc ular press ure 
(I O P) re mai ns t he m ost pr o mi ne nt fact or an d t he o nl y fact or e xisti n g t hat o p ht hal mic 
i nter ve nti o n ca n relia bl y affect (Sta m per et al, 2 0 0 9 ).  A n u m ber of c o ntr olle d trials ha ve 
de m o nstrate d t hat l o weri n g I O P will sl o w or dela y t he a p peara nce or pr o gressi o n of 
gla uc o mat o us da ma ge.  Lar ge, ra n d o mize d cli nic al trials s uc h as t he Oc ular H y perte nsi o n 
Treat me nt St u d y ( O H T S) ( Kass et al, 2 0 0 2 ) a n d t he Earl y Ma nifest Gla uc o ma Trial ( E M G T) 
(Heijl et al, 2 0 0 2 ) a d dresse d t he val ue of earl y detecti o n a n d l o weri n g of ele vate d I O P i n 
oc ular h y perte nsi o n ( O H T) or P O A G.  T he effect s a n d para meters of vari o us i nter ve nti o ns i n 
e yes wit h esta blis he d gla uc o mat o us da ma ge were a d dresse d b y t he C olla b orati ve I nitial 
Gla uc o ma Treat me nt St u d y ( CI G T S) ( Lic hter et al, 2 0 0 1 ) a n d t he A d va nce d Gla uc o ma 
I nter ve nti o n St u d y ( A GI S) (A GI S, 2 0 0 0 ).  T he c urre ntl y a vaila ble a p pr oac hes t o l o weri n g 
I O P i ncl u de p har mac ol o gical t hera p y, laser tra bec ul o plast y, i ncisi o nal s ur ger y, a n d 
c ycl o destr ucti ve pr oce d ures.  Eac h of t hese a p pr oac hes has its o w n ris k- be nefit rati o.  
Beca use t he ris k- be nefit rati o w it h dr u g t hera p y a p pears t o be l o wer t ha n t hat of s ur gical 
pr oce d ures, b ot h hist orical a n d c o nte m p orar y practice has bee n t o atte m pt p har mac ol o gical 
treat me nt bef ore res orti n g t o ot her m ore i n vasi ve alter nati ves. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Patie nt n o na d here nce t o t o pical t hera p y is o ne of t he maj or c halle n ges t o pre ve nti n g visi o n 
l oss d ue t o gla uc o ma, as c o nsiste nt I O P re d uctio n is ass ociate d wit h re d uce d ris ks of t he 
de vel o p me nt a n d pr o gressi o n of o ptic ner ve da ma ge ( Frie d ma n, 2 0 0 9; Tsai, 2 0 0 9 ).  I n 
patie nts t hat are n o na d here nt t o me dical t hera p y, g ui deli nes ar e pr o vi de d t o cli nicia ns f or 
assisti n g patie nts wit h bei n g a d here nt ( B u de nz, 2 0 0 9 ).  Ne vert heless, fre q ue ntl y, patie nts 
wit h O A G or O H T n ot ta ki n g t heir me dicati o ns w ill re q uire i ncisi o nal s ur ger y t o c o ntr ol t he 
I O P.  S o me of t he disa d va nta ges of perf or min g i ncisi o nal s ur ger y i n cl u de t he si g nifica nt 
si g ht-t hreate ni n g c o m plicati o ns t hat ca n occ ur wit h s ur ger y, s uc h as t he gl o be perf orati o n, 
s u prac h or oi dal he m orr ha ge, h y p ot o n y mac ul o pat hy, c or neal dec o m pe nsa ti o n, a n d cataract 
f or mati o n or pr o gressi o n t hat ma y occ ur wit h filteri n g s ur ger y (M osae d et al, 2 0 0 9 ).  Gi ve n 
t he ris ks ass ociate d wit h i ncisi o nal s ur ger y, s ustai ne d-release f or m ulati o ns of oc ular 
a nti h y perte nsi ve dr u gs are i n de ve l o p me nt as a n alter nati ve t o s ur ger y f or t he ma na ge me nt of 
ele vate d I O P ( K ni g ht a n d La wre nce, 2 0 1 4 ). 
1. 2  
Bi m at o pr ost ( L U MI G A N ® ) 
Bi mat o pr ost is a me m ber of a series of u ni q ue pr osta n oi d c o m p o u n ds t hat are p ote nt a n d 
efficaci o us oc ular a nti h y perte nsi ve a ge nts ( Wo o d war d et al, 1 9 9 4, 2 0 0 1, a n d 2 0 0 4).  
Bi mat o pr ost a p pears t o mi mic t he acti v it y of bi ol o gicall y acti ve pr osta mi des 
( St u d y BI O- 9 9- 3 0 8; Matias et al, 2 0 0 4 ).  C he micall y, pr osta mi des differ fr o m pr osta gla n di n 
a nal o gs b y bei n g ne utral beca use t he y lac k car b o x ylic aci ds (Kra uss a n d Wo o d war d, 2 0 0 4 ).  
Pr osta mi des ca n be bi os y nt heticall y deri ve d fr o m a na n da mi de, a n e n d o ge n o us me m bra ne 
li pi d (K oza k et al, 2 0 0 2; We ber et al, 2 0 0 4; W o o d war d et al, 2 0 0 1; Yu et al, 1 9 9 7 ).  T he 
pr osta mi de pat h wa y lea ds t o t he bi os y nt hesis of n o vel li pi d a mi des t hat l o wer I O P. 
T he I O P-l o weri n g efficac y of L U MI G A N ( bi mat o pr ost o p ht hal mic s ol uti o n) 0. 0 3 % is well 
esta blis he d.  I n p hase 3 st u dies i n patie n ts wit h P O A G or O H T, L U MI G A N a d mi nistere d 
o nce dail y as m o n ot hera p y was s u peri or t o ti m ol ol at all ti me p oi nts ( Hi g gi n b ot ha m et al, 
2 0 0 2 ).  T his was f urt her s u bsta ntiate d i n t he e xte nsi o n st u dies w hic h f oll o we d patie nts i n a 
mas ke d ma n ner f or u p t o 4 years ( C o he n et al, 2 0 0 4; Willia ms et al, 2 0 0 8 ; 
St u d y 1 9 2 0 2 4- 0 1 4).  I n cli nical st u dies of patie nts wit h O A G or O H T wit h a mea n baseli ne 
I O P of 2 6 m m H g, t he I O P-l o weri n g effect of L U MI G A N o nce dail y i n t he e ve ni n g was 7 t o 
8 m m H g ( C o he n et al, 2 0 0 4; L U MI G A N ®  Pac ka ge I nsert, 2 0 1 2; Willia ms et al, 2 0 0 8). 
L U MI G A N was a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) i n 2 0 0 1.  
Worl d wi de, L U MI G A N 0. 0 3 % is c urre ntl y lice nse d a n d mar kete d i n m ore t ha n 8 0 c o u ntries 
a n d L U MI G A N 0. 0 1 % is lice nse d a n d mar kete d i n m ore t ha n 4 0 c o u ntries.  Preser vati ve-free 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
2 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
bi mat o pr ost o p ht hal mic s ol uti o n 0. 0 3 % has bee n a p pr o ve d si nce N o ve m ber 2 0 1 2 f or 
l o weri n g I O P, a n d is c urre ntl y mar kete d i n 1 0 c o u ntries. 
1. 3  
Bi m at o pr ost S R 
A s ustai ne d-release f or m ulati o n of bi mat o pr ost was de vel o pe d at Aller ga n, I nc. t o e val uate 
oc ular a nti h y perte nsi ve t hera pies t hat d o n ot re q uire patie nt self-a d mi nistrati o n.  Bi mat o pr ost 
S R refers t o t he bi o de gra da ble, s ustai ne d-re lease, preser vati ve-free bi mat o pr ost i m pla nt 
w hic h is prel oa de d i n a n a p plicat or f or a d mi nistrati o n; t o get her t he y c o m prise t he 
Bi mat o pr ost S ustai ne d Release pr o d uct (a n d will he ncef ort h be referre d t o as 
Bi mat o pr ost S R).  T he Bi mat o pr ost S R i m pla nt is i njecte d i nt o t he A C via t he c or neal li m b us 
usi n g t he prefille d a p plicat or.  T he bi o de gra da ble p ol y mer matri x gra d uall y de gra des t o 
car b o n di o xi de a n d water s o t hat t here is n o nee d  t o re m o ve t he Bi mat o pr ost S R i m pla nt o nce 
t he dr u g has bee n release d.  T he Bi mat o pr ost S R i m pla nt use d i n t his st u d y c o ntai ns t otal 
preser vati ve-free bi mat o pr ost l oa ds of 1 0 µ g or 1 5 µ g, t o pr o vi de a vera ge dail y release (as 
deter mi ne d b y i n vitr o st u dies) of a p pr o xi matel y 1 1 0 n g or 1 7 0 n g, res pecti vel y, o ver a n 
a p pr o xi mate 3- m o nt h d urati o n i n t h e A C.  I n c o ntrast, a t y pical 3 5 µ L dr o p of L U MI G A N 
0. 0 3 % c o ntai ns a p pr o xi matel y 1 0 µ g of bi mat o pr ost.  T h us, wit h  t o pical t hera p y, a patie nt 
w o ul d ha ve dr u g e x p os ure t o t he oc ular s urface t otali n g a p pr o xi matel y 9 0 0 µ g o ver 
3 m o nt hs.  S u bsta ntiall y re d uci n g t he t otal dail y dr u g e x p os ure t o t he e ye a n d deli veri n g t he 
dr u g directl y t o t he a q ue o us h u m or ma y re d uce t he a d verse effects t hat occ ur wit h t o pical 
t hera p y.  T he Bi mat o pr ost S R i m pla nt is e x pecte d t o release dr u g o ver a p pr o xi matel y 3 t o 
4 m o nt hs, a n d > 7 5 % p ol y mer matri x de gra d ati o n is e x pecte d wit hi n a p pr o xi matel y 
1 2 m o nt hs.  Alt h o u g h t he bi o de gra dati o n pr ocess of t he Bi mat o pr ost S R i m pla nt e xcee ds t he 
dr u g release d urati o n, e x perie nce fr o m precli nical st u dies, t he p hase 1/ 2 cli nical st u d y 
1 9 2 0 2 4- 0 4 1 D, a n d a p pr o ve d i ntra vitreal i m pla nts c o m p ose d of si milar bi o de gra da ble 
p ol y mers pr o vi de s u p p ort f or t he a ntici pate d safet y i n a p hase 3 cli nical trial wit h re peate d 
a d mi nistrati o n. 
1. 3. 1  
N o ncli nic al St u dies wit h Bi m at o pr ost S R 
P har mac ol o g y, t o xic ol o g y, a n d p har mac o ki netic st u dies wit h m ulti ple d ose stre n gt hs, i m pla nt 
sizes a n d f or m ulati o ns
of Bi mat o pr ost S R were d o ne i n 
2 s pecies ( Bea gle d o g, C y n o m ol g us m o n ke ys) wit h a ra n ge of a nteri or c ha m ber a n gle sizes 
i n or der t o s u p p ort t he cli nical pr o gra m.  T hese st u dies b uil d o n t he alrea d y c o nsi dera ble 
a m o u nt of n o ncli nical a n d cli nical i nf or mati o n a vaila ble f or t o pical bi mat o pr ost (see 
I n vesti gat or’s Br oc h ure f or a d diti o nal details). 
sizes a n d f or m ulati o ns
of Bi mat o pr ost S R were d o ne i n 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
2 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
N o ncli nical st u dies wit h p har mac ol o g y e n d p oi nts (
s h o we d d ose-relate d re d ucti o ns i n I O P i n n or m ote nsi ve 
C y n o m ol g us m o n ke ys a n d Bea gle d o gs, as well as i n laser-i n d uce d oc ular h y perte nsi ve 
C y n o m ol g us m o n ke ys f oll o wi n g si n gle d oses.  To xic ol o g y st u dies, of at least 6 t o 1 2 m o nt hs 
d urati o n a n d i ncl u di n g si n gle a n d re peat Bi mat o pr ost S R a d mi nistrati o n, were c o n d ucte d i n 
C y n o m ol g us m o n ke ys a n d Bea gle d o gs (
 Si n gle a n d re peat oc ular t o xicit y st u dies 
wit h 
Bi mat o pr ost S R i n d o gs wit h var yi n g A C a n gle sizes de m o nstrate d 
acce pta ble safet y a n d oc ular t olera bilit y wit h si n gle d oses ≤ 2 0 µ g 
a n d wit h re peat d oses of ≤ 1 5 µ g 
F urt her m ore, n o a d verse dr u g- or i m pla nt-relate d oc ular fi n di n gs ha ve bee n 
see n f oll o wi n g t hree i ntraca meral i njecti o ns of u p t o 2 0 µ g (t w o 1 0 µ g i m pla nts) Bi mat o pr ost 
S R i n t he 1 8- m o nt h re peat d ose G o o d La b orat or y Practice ( G L P) st u d y i n d o gs 
P har mac o ki netic st u dies (
i n Bea gle d o gs de m o nstrate d t hat 
s yste mic e x p os ure of bi mat o pr ost a n d bi mat o pr ost aci d was bel o w t he li mit of q ua ntitati o n 
( B L Q) wit h d oses ≤ 6 0 µ g.  A q ue o us h u m or c o nce ntrati o ns ge nerall y pea ke d b y 1 0 wee ks 
p ost d ose f or d oses ≤ 3 0 µ g 
 t he n decli ne d t o l o w le vels 
s u g gesti ve of near-c o m plete dr u g release fr o m t he de vice at 3 m o nt hs f or d oses ≤ 2 0 µ g.  B y 
1 4 wee ks f oll o wi n g a 2 0 µ g 
d ose, oc ular tiss ues sa m ples were c ollecte d f or 
a nal ysis, w hic h de m o nstrate d t hat dr u g a n d meta b olite c o nce ntrati o ns were B L Q i n a q ue o us 
h u m or, vitre o us h u m or, r eti na, a n d t he re m na nt i m pla nts, b ut detecte d i n c or nea, c h or oi d, a n d 
iris-ciliar y b o d y.  A p har mac o ki netic st u d y 
was c o n d ucte d i n Bea gle d o gs 
c o m pari n g t he oc ular distri b uti o n of t o pical bi mat o pr ost 0. 0 3 % s ol uti o n or a si n gle 
Bi mat o pr ost S R i m pla nt ( 1 5 µ g).  F oll o wi n g t o pical a d mi nistrati o n, 
bi mat o pr ost a n d bi mat o pr ost aci d distri b ute d i nt o t he iris-ciliar y b o d y as well as ot her ( off 
tar get) tiss ues wit h c o nce ntrati o ns i n t he b ulbar c o nj u ncti va, e yeli d mar gi n, a n d peri or bital 
fat si g nifica ntl y hi g her t ha n t h ose o bser ve d i n t he iris-ciliar y b o d y. I n c o ntrast, f oll o wi n g 
a d mi nistrati o n of a si n gle 
Bi mat o pr ost S R i m pla nt at 1 5 µ g, bi mat o pr ost a n d 
bi mat o pr ost aci d c o nce ntrati o ns were eit her bel o w t he li mit of q ua ntitati o n ( B L Q) or near t he 
detecti o n li mit i n b ul bar c o nj u ncti va, e yeli d ma r gi n, a n d peri or bital fat w hile t he hi g hest 
bi mat o pr ost a n d bi mat o pr ost aci d c o nce ntrati o ns were o bser ve d i n t he tar get tiss ue, t he iris 
ciliar y b o d y. Reti nal c o nce ntrati o ns were B L Q f oll o wi n g b ot h t o pical a n d Bi mat o pr ost S R 
a d mi nistrati o n. 
n d p oi nts 
s h o we d d ose-relate
gs 
g 
a n d wit h re peat d oses of 
g 
F urt her m ore, n o a d verse dr u g- or 
P har mac o ki netic st u dies (
i n Bea gle d o gs de m o nstrate d t hat 
ac o ki netic st u d y 
was c o n d ucte d i n Bea gle d o gs 
wit h 
Bi mat o pr ost S R i n d o gs w
g 
 t he n decli ne d t o l o w le vels 
1 4 wee ks f oll o wi n g a 2 0 µ g 
d ose, 
Bi mat o pr ost S R i m pla nt ( 1 5 
a d mi nistrati o n of a si n gle 
Bi mat
  Si n gle a n d re peat oc


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1. 3. 2  
Ot her Bi o de gr a d a ble Oc ul ar I m pl a nts 
A n u m ber of s ustai ne d-release dr u g deli ver y i m pla nts usi n g t he Aller ga n bi o de gra da ble 
p ol ylactic aci d ( P L A ) a n d/ or p ol ylactic-c o- gl yc olic aci d ( P L G A) N O V A D U R®  dr u g deli ver y 
s yste m  prece de d t he de vel o p me nt of t he Bi mat o pr ost S R  i m pla nt.  T he e xte nsi ve cli nical 
e x perie nce wit h pre vi o us i ntra oc ular i m pla nts de m o nstrates t he safet y a n d t olera bilit y of a n 
i ntra oc ular bi o de gra da ble i m pla nt a d mi nistere d i nt o t he e ye via a n a p plicat or s yste m.  F or 
e xa m ple, late p hase cli nical trials of s ustai ne d-release i m pla nts ha ve bee n c o m plete d f or t he 
O Z U R D E X ®  de xa met has o ne i ntra vitreal i m pla nt usi n g t he N O V A D U R dr u g deli ver y s yste m 
f or i ntra oc ular i njecti o ns.  Beca use Bi mat o pr ost S R is si milar t o O Z U R D E X i n a n u m ber of 
as pects a n d uses t he N O V A D U R dr u g deli ver y s y ste m f or i ntra oc ular i njecti o ns, t hese data 
ma y be s u p p orti ve of t he safet y a n d t ole ra bilit y of Bi mat o pr ost S R i n h u ma ns. 
1. 3. 3  
Cli nic al St u d y wit h Bi m at o pr ost S R 
St u d y 1 9 2 0 2 4- 0 4 1 D was a P hase 1/ 2, paire d-e ye  c o m paris o n e val uati n g t he safet y a n d 
efficac y of 4 d ose stre n gt hs of Bi mat o pr ost S R ( 6 µ g, 1 0 µ g, 1 5 µ g, or 2 0 µ g [ 2 × 1 0 µ g 
i m pla nts]), as si n gle or re peat a d mi nistrati o n i n o ne e ye (st u d y e ye), vers us t he use of t o pical 
L U MI G A N ®  0. 0 3 % i n t he fell o w e ye ( n o nst u d y e ye).  T he o bjecti ve of t his st u d y was t o 
e val uate t he safet y a n d I O P-l o weri n g efficac y  of Bi mat o pr ost S R i n patie nts wit h O A G. 
A t otal of 1 0 9 patie nts recei ve d a si n gle a d mi nistrati o n a n d 2 4 patie nts recei ve d a re peat 
a d mi nistrati o n of Bi mat o pr ost S R.  A tre n d i n d ose-res p o nse was o bser ve d acr oss t he 4 d ose 
stre n gt hs t hat were teste d.  Data s u g gest t hat t he i m pla nt ma y pr o vi de t o pical pr osta gla n di n 
a nal o g-li ke efficac y u p t o 3 t o 4 m o nt hs p ost-i m pl a ntati o n i n t he maj orit y of patie nts.  Data 
f oll o wi n g t he sec o n d a d mi nistrati o n i n t he re d ose d patie nts s h o we d si milar I O P l o weri n g t o 
t hat o bser ve d f oll o wi n g t he first a dmi nistrati o n of Bi mat o pr ost S R.  
Bi mat o pr ost S R s h o we d a n acce pta ble safet y pr ofile  wit h si n gle a n d re peat a d mi nistrati o ns i n 
St u d y 1 9 2 0 2 4- 0 4 1 D.  M ost a d verse e ve nts were oc ular, mil d or m o derate i n se verit y, 
occ urre d wit hi n t he first 2 da ys after Bi mat o pr ost S R a d mi nistrati o n, a n d were c o nsi dere d 
relate d t o t he st u d y dr u g a d mi nistrati o n pr oce d ure.  T here were n o re p orts of seri o us st u d y 
dr u g-relate d a d verse e ve nts, a n d n o ne w sa fet y c o ncer ns were o bser ve d after t he sec o n d 
treat me nt.  Please refer t o t he I n vesti gat or’s Br oc h ure f or details o n re p orte d safet y fi n di n gs. 
1. 4  
St u d y R ati o n ale 
I n t he 1 9 2 0 2 4- 0 4 1 D P hase 1/ 2 cli nical st u d y, res ults s u g gest t hat Bi mat o pr ost S R pr o vi des 
I O P-l o weri n g efficac y si milar t o t o pical pr ostagla n di n a nal o gs i n t he d ose stre n gt hs pr o p ose d 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
2 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
f or t his P hase 3 i n vesti gati o n.  A d diti o nall y, t he safet y pr ofile of Bi mat o pr ost S R at d ose 
stre n gt hs of 2 0 µ g ( 2 × 1 0 µ g) or less i n t he P hase 1/ 2 st u d y was acce pta ble, a n d s u p p orts 
a d diti o nal cli nical st u d y i n ma n.  St u d y 1 9 2 0 2 4- 0 9 1 is a ra n d o mize d, patie nt a n d efficac y 
e val uat or- mas ke d, parallel- gr o u p c o m paris o n t o e v al uate t he safet y a n d I O P-l o weri n g effects 
of re peate d a d mi nistrati o ns of 1 0 µ g or 1 5 µ g Bi mat o pr ost S R i n patie nts wit h O A G or O H T 
a n d o pe n iri d oc or neal a n gles i nferi orl y i n t he st u d y e ye b y cli nical g o ni osc o p y. 
T he 2 d ose stre n gt hs of Bi mat o pr ost S R will be c o m pare d vers us a c o ntr ol gr o u p treate d wit h 
t he acti ve c o m parat or, t o picall y a p plie d ti m ol ol 0. 5 %.  Ti m ol ol is a well-esta blis he d 
treat me nt f or I O P l o weri n g i n gla uc o ma a n d O HT, a n d has bee n use d as a c o m parat or i n 
ot her I O P-l o weri n g st u dies ( Wei nre b a n d Ka uf ma n, 2 0 0 9 ). 
2.  
St u d y O bjecti ves a n d Cli nic al H y p ot heses  
2. 1  
St u d y O bjecti ves 
•  To e val uate t he I O P-l o weri n g efficac y a n d sa fet y of 2 d ose stre n gt hs of Bi mat o pr ost 
S R i n patie nts wit h O A G or O H T aft er i nitial a n d re peate d a d mi nistrati o ns 
2. 2  
Cli nic al H y p ot heses 
•  At least 1 d ose stre n gt h ( 1 0 µ g or 1 5 µ g) of Bi mat o pr ost S R will ha ve a n 
I O P-l o weri n g effect t hat is n o ni nferi or t o t hat of t o picall y a d mi nistere d ti m ol ol 
maleate 0. 5 % ( hereafter referre d t o as ti m ol ol) e ye dr o ps i n patie nts wit h O A G or 
O H T f oll o wi n g si n gle a n d re peat a d mi nistrati o ns. 
•  Bi mat o pr ost S R a d mi nistere d i ntraca merall y i n d ose stre n gt hs of 1 0 µ g or 1 5 µ g will 
ha ve a n acce pta ble safet y pr ofile i n pa tie nts wit h O A G or O H T, f oll o wi n g si n gle a n d 
re peat a d mi nistrati o ns. 
3.  
St u d y Desi g n 
T his st u d y is a m ultice nter, d ose-ra n gi n g, ra n d o mize d, parallel- gr o u p, patie nt a n d 
efficac y-e val uat or mas ke d 5 2- wee k e val uati o n ( 5 2- wee k treat me nt peri o d wit h 8 m o nt hs 
e xte n de d f oll o w- u p) of t he safet y a n d efficac y of Bi mat o pr ost S R c o m pare d t o ti m ol ol t wice 
dail y ( BI D) i n patie nts wit h O A G or O H T.  T h e patie nts a n d t he e val uat ors of t he pri mar y 
e n d p oi nt (I O P) will be mas ke d t o t he treat me nt recei ve d.  T he site c o or di nat or a n d desi g nate d 
staff will n ot be mas ke d t o w het her t he patie nt recei ve d 1 of t he t w o d ose stre n gt hs of 
Bi mat o pr ost S R or t he S ha m a d mi nistrati o n, b ut will be mas ke d t o t he s pecific d ose stre n gt h 
t hat t he patie nt recei ves.  Ve hicle e ye dr o ps will be use d BI D t o mas k t he treat me nt of 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
patie nts recei vi n g Bi mat o pr ost S R i n t he st u d y e ye.  T he fell o w e ye will recei ve a S ha m 
a d mi nistrati o n pl us t o pical ti m ol ol e ye dr o ps BI D.  C o ntr ol gr o u p patie nts will recei ve a 
S ha m a d mi nistrati o n pl us ti m ol ol i n b ot h e yes  (see Ta ble 7).  T he st u d y will be c o n d ucte d at 
a p pr o xi matel y 1 6 0 sites gl o ball y. 
T w o Bi mat o pr ost S R d ose stre n gt hs ( 1 0 µ g or 1 5 µ g) will be teste d i n t his st u d y.  Patie nts 
will recei ve a sc he d ule d sec o n d a d mi nistrati o n of  Bi mat o pr ost S R at 1 6 wee ks f oll o wi n g t he 
first a d mi nistrati o n a n d a t hir d sc he d ule d a dmi nistrati o n at 1 6 wee ks f oll o wi n g t he sec o n d 
a d mi nistrati o n (ie, 3 2 wee ks after t he i nitial a d mi nistrati o n).  C o ntr ol gr o u p patie nts will 
recei ve S ha m a d mi nistrati o ns at all a d mi nistrati o n visits. 
T a ble 7 
Tre at me nt Gr o u ps 
Treat me nt 
St u d y E ye Treat m e nt 
Fell o w E ye Treat me nt 
Bi mat o pr ost S R 1 0 µ g 
D ose stre n gt h: 1 0 µ g 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps:  Ve hicle BI D 
E ye dr o ps:  Ti m ol ol BI D 
Bi mat o pr ost S R 1 5 µ g 
D ose stre n gt h: 1 5 µ g 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps:  Ve hicle BI D 
E ye dr o ps:  Ti m ol ol BI D 
C o ntr ol 
S ha m a d mi nistrati o n pr oce d ure 
S ha m a d mi nistrati o n pr oce d ure 
E ye dr o ps:  Ti m ol ol BI D 
E ye dr o ps:  Ti m ol ol  BI D 
BI D = t wice dail y 
 
Patie nts will be gi n self-a d mi nistrati o n of t he st u d y- pr o vi de d e ye dr o ps i n b ot h e yes starti n g 
wit h t he e ve ni n g d ose o n t he first a d mi nistrati o n ( Da y 1) visit (at w hic h t he y will recei ve 
Bi mat o pr ost S R a d mi nistrati o n or S ha m a d mi nistrati o n).  Patie nts will c o nti n ue 
self-a d mi nistrati o n of st u d y- pr o vi de d e ye dr o ps i n t he m or ni n g (at 0 8: 0 0 ± 1 h o ur) a n d i n t he 
e ve ni n g (at 2 0: 0 0 ± 1 h o ur), w hic h is a p pr o xi matel y 1 2 h o urs a part.  Patie nts will be 
i nstr ucte d n ot t o a d mi nister t heir dr o ps o n t he m or ni n g of a st u d y visit.  Dr o ps will be 
a d mi nistere d i m me diatel y after t he H o ur 0 I O P meas ure me nt. 
T he d urati o n of t he st u d y f or eac h patie nt is a p pr o xi matel y 2 2 m o nt hs (scree ni n g d urati o n of 
u p t o 2 8 da ys bef ore was h o ut, pl us was h o ut of u p t o 4 2 da ys bef ore t he first a d mi nistrati o n, 
pl us t he 5 2- wee k treat me nt peri o d, pl us 8 m o nt hs e xte n de d f oll o w- u p).  Patie nts will be 
f oll o we d f or at least 1 2 m o nt hs after t heir last Bi mat o pr ost S R ( or S ha m) a d mi nistrati o n, a n d 
ma y e xit earl y at or after t he t welft h m o nt h f o ll o wi n g t he last a d mi nistrati o n if t here are n o 
safet y c o ncer ns i n t he o pi ni o n of t he i n vesti gat or. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
4.  
St u d y P o p ul ati o n a n d E ntr y Criteri a 
4. 1  
N u m ber of P atie nts  
E nr oll me nt of a p pr o xi matel y 6 0 0 patie nts i n t otal at a p pr o xi matel y 1 6 0 sites, wit h 
a p pr o xi matel y 2 0 0 patie nts per gr o u p, is pla n ne d t o e ns ure 1 8 0 c o m plete d patie nts per gr o u p, 
ass u mi n g a pre mat ure disc o nti n uati o n rate of 1 0 %. 
4. 2  
St u d y P o p ul ati o n C h ar acteristics 
T he st u d y p o p ulati o n c o nsists of patie nts wit h O A G or O H T a n d a n o pe n iri d oc or neal a n gle 
i nferi orl y b y cli nical g o ni osco p y i n t he st u d y e ye, a n d O A G or O H T i n t he fell o w e ye, w here 
b ot h e yes re q uire I O P-l o weri n g me dicati o n.  T he e ye t hat meets t he e ntr y criteria 
( Secti o ns 4. 3 a n d 4. 4) will be selecte d as t he st u d y e ye.  If b ot h e yes meet t he e ntr y criteria, 
t he e ye wit h t he hi g her I O P at Baseli ne H o ur 0 will be selecte d as t he st u d y e ye.  If b ot h e yes 
ha ve t he sa me I O P, t he n t he ri g ht e ye will be desi g nate d as t he st u d y e ye. 
A n gle q ualificati o n will be i n de pe n de n tl y c o nfir me d as bei n g q ualifie d b y 
2 o p ht hal m ol o gists, a n d e n d ot helial cell de ns it y q ualificati o n f or st u d y e ntr y will be 
deter mi ne d b y t he Rea di n g Ce nter base d o n s pec ular micr osc o p y assess me nt (see Pr ot oc ol 
Pr oce d ure Ma n ual f or details). 
4. 2. 1  
P atie nts Wit h Sic kle Cell Tr ait or Dise ase 
Patie nts wit h sic kle cell trait or disease ( or ot her he m o gl o bi n o pat hies) ma y be e nr olle d at t he 
discreti o n of t he i n vesti gat or base d o n a n i n di vi d ual ris k- be nefit assess me nt. Beca use of a 
sli g htl y hi g her ris k of I O P ele vati o n a n d i ntra oc ular c o m plicati o ns i n t he setti n g of a 
micr o h y p he ma, patie nts wit h t hese dis or ders ma y u n der g o o pti o nal a d diti o nal bi o micr osc o p y 
a n d I O P meas ure me nts after i njecti o n/ S ha m i n jecti o n at t he i n vesti gat or’s discreti o n (see 
Secti o n 8. 4).  A d diti o nal i nf or mati o n a b o ut t he Bi mat o pr ost S R e x perie nce i n patie nts wit h 
sic kle trait is pr o vi de d i n t he I n vesti gat or’s Br oc h ure. 
4. 3  
I ncl usi o n Criteri a 
T he f oll o wi n g are re q uire me nts f or e ntr y i nt o t he st u d y: 
1.  Male or fe male, ≥ 1 8 years of a ge 
2.  Writte n i nf or me d c o nse nt has bee n o btai ne d 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
3.  Writte n d oc u me ntati o n has bee n o btai ne d i n acc or da nce wit h t he rele va nt c o u ntr y a n d 
l ocal pri vac y re q uire me nts, w here a p plica ble (e g, Writte n A ut h orizati o n f or Use a n d 
Release of Healt h a n d Researc h St u d y I nf or m ati o n [ U S sites] a n d writte n Data Pr otecti o n 
c o nse nt [ E U sites]) 
4.  
  
 
 
   
5.  Patie nt has t he a bilit y t o u n de rsta n d a n d willi n g ness t o f oll ow st u d y i nstr ucti o ns a n d is 
li kel y t o c o m plete all re q uire d visits a n d pr oce d ures 
6.  
 
7.  Dia g n osis of eit her O A G (ie, pri mar y, pse u d oe xf oliati o n, or pi g me ntar y gla uc o ma) or 
O H T i n eac h e ye a n d b ot h e yes re q uire I O P-l o weri n g treat me nt ( N ote:  dia g n osis d oes 
n ot ha ve t o be t he sa me i n b ot h e yes) 
8.  
  
9.  
  
1 0.  
 
 
 
  
1 1.  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 2.  
 
 
  
 
  
1 3.  
 
 
1 4.  
 
4. 4  
E xcl usi o n Criteri a 
T he f oll o wi n g are criteria f or e xcl usi o n fr o m partici pati n g i n t he st u d y: 
N o n- oc ular Criteria f or E xcl usi o n 
1.  U nc o ntr olle d s yste mic disease 
2.  Fe male patie nts w h o are pre g na nt, n ursi n g, or pla n ni n g a pre g na nc y, or w h o are of 
c hil d beari n g p ote ntial a n d n ot usi n g a relia b le mea ns of c o ntrace pti o n d uri n g t he st u d y 
(see Secti o n 4. 5. 3) 
3.  
 
4.  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
•  
 
5.  A n y c o n diti o n w hic h w o ul d precl u de t he pa tie nt’s a bilit y t o c o m pl y wit h st u d y 
re q uire me nts, i ncl u di n g c o m pleti o n of t he st u d y 
6.  Patie nts w h o ha ve a c o n diti o n or are i n a sit u ati o n w hic h, i n t he i n vesti gat or’s o pi ni o n, 
ma y p ut t he patie nt at si g nifica nt ris k, ma y c o nf o u n d t he st u d y res ults, or ma y i nterfere 
si g nifica ntl y wit h t he patie nt’s partici pati o n i n t he st u d y 
7.  
8.  
 
 
9.  Pre vi o us e nr oll me nt i n a n ot her Al ler ga n Bi mat o pr ost S R st u d y   
1 0.   
Oc ular Criteria f or E xcl usi o n 
1 1.  
1 2.  
 
 
1 3.  T he f oll o wi n g s ur gical hist or y: 
a. Hist or y or e vi de nce of c o m plicate d cataract  s ur ger y i n t he st u d y e ye: e g, s ur ger y 
res ulti n g i n c o m plicate d le ns place me nt (s uch as a nteri or c ha m ber i ntra oc ular le ns 
i m pla nt [I O L], s ulc us I O L, a p ha kia, etc) or i ntra o perati ve c o m plicati o ns (s uc h as 
a p osteri or ca ps ular tear [ w it h or wit h o ut vitre o us l oss], s u bsta ntial iris tra u ma, 
etc). N ote: hist or y of u nc o m plicate d cataract s ur ger y is n ot a n e xcl usi o n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
b.  
1 4.  I ntra oc ular s ur ger y (i ncl u di n g cataract s ur ger y) a n d/ or a n y oc ular lase r s ur ger y wit hi n t he 
6 m o nt hs pri or t o tre at me nt ( Da y 1) i n t he st u d y e ye  
1 5.  
 
 
1 6.  
 
  
1 7.  
 
 
 
 
 
1 8.  
 
 
 
 
1 9.  
 
 
2 0.  
2 1.  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
b.  
 
2 2.  
 
2 3.  
 
 
 
 
 
 
 
2 4.  
2 5.  A ntici pate d nee d f or a n y i ncisi o nal or laser oc ular s ur ger y i n eit her e ye wit hi n t he first 
5 2 wee ks of t he st u d y d urati o n 
2 6.  
 
 
2 7.  
 
2 8.  A n y hist or y of tra bec ulect o m y or ot her t y pes of gla uc o ma s ur ger y, i ncl u di n g a gla uc o ma 
set o n or a q ue o us b y pass ste nts, i n eit her e ye 
2 9.  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
3 0.  
 
 
3 1.  
 
 
 
3 2.  
3 3.  
 
 
3 4.  
 
4. 5  
Per missi ble a n d Pr o hi bite d Me dic ati o ns/ Tre at me nts 
4. 5. 1  
Per missi ble Me dic ati o ns/ Tre at me nts 
T he fell o w e yes of patie nts ra n d o mize d t o t he Bi mat o pr ost S R or C o ntr ol gr o u ps will recei ve 
ti m ol ol BI D f or I O P l o weri n g. 
I nter mitte nt use of artificial tear pr o d ucts is all o we d if t he y are n ot ta ke n ≤ 1 5 mi n utes bef ore 
a n y st u d y pr oce d ure or ≤ 1 5 mi n utes bef ore or after t o pical a d mi nistrati o n of st u d y 
me dicati o n.  I nter mitte nt use of oc ular dec o n gesta nts or a nti hista mi nes is all o we d if n ot ta ke n 
wit hi n 2 da ys pri or t o a sc he d ule d visit a n d/ or ≤ 1 5 mi n utes bef ore or after t o pical 
a d mi nistrati o n of st u d y me dicati o n.  Use of artif icial tear pr o d ucts an d oc ular dec o n gesta nts 
or a nti hista mi nes ma y be restarte d 3 da ys af ter a n y Bi mat o pr ost S R ( or S ha m) a d mi nistrati o n 
pr oce d ure. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Use of p ost o perati ve t o pical oc ular a nti b i otics, c orticoster oi ds, a n d n o n-ster oi dal 
a nti-i nfla m mat or y dr u gs ( N S AI Ds) fr o m t he A d mi nistrati o n Da y ( o n Da y 1, Wee k 1 6, a n d 
Wee k 3 2) t o Da y 7 f oll o wi n g a d mi nistrati o n is all o we d. 
S yste mic beta- bl oc ker c o ntai ni n g me dicati o ns  are per mitte d, pr o vi de d t hat t he d ose/ d osi n g 
re gi me n has re mai ne d sta ble f or at least 2 m o nt hs pri or t o Scree ni n g, a n d is n ot a ntici pate d t o 
c ha n ge d uri n g t he d urati o n of t he st u d y. 
Re q uire d s ur gical pr oce d ures ma y be perf or me d i n t he fell o w e ye o nl y after c o m pleti o n of 
Wee k 5 2. 
I n a d diti o n, t hera p y c o nsi dere d necessar y f or t he patie nt’s welfare ma y be gi ve n at t he 
discreti o n of t he i n vesti gat or .  If c o nc urre nt me dicati o ns ma y ha ve a n effect o n st u d y 
o utc o mes, t hese me dicati o ns s h o ul d be a d mi ni stere d i n d osa ges t hat re mai n c o nsta nt 
t hr o u g h o ut t he e ntire d urati o n of t he st u d y.  If t he per missi bilit y of a s pecific 
me dicati o n/treat me nt is i n q uesti o n, please c o ntact Aller ga n. 
T he use of s yste mic N S AI Ds is als o per mitte d. 
I n t he u nli kel y e ve nt t hat t he Bi mat o pr ost S R i m pla nt re q uires re m o val f or si g nifica nt safet y 
reas o ns, t his ma y be perf or me d at t he discreti o n of t he i n vesti gat or f oll o wi n g a disc ussi o n 
wit h t he me dical safet y p h ysicia n at Aller ga n (s ee Pr ot oc ol Pr oce d ure Ma n ual f or details).   
N ote t hat i n t he e ve nt t hat t he i n vesti gat or perf or ms a n u na ntici pate d i ncisi o nal s ur gical 
pr oce d ure o n t he st u d y e ye d uri n g w hic h oc ular fl ui d is t o be re m o ve d, oc ular fl ui d/i m pla nt 
sa m ples ma y be c ollecte d f or a nal ysis (see Pr otoc ol Pr oce d ure Ma n ual f o r f urt her details) at 
t he i n vesti gat or’s discreti o n.   
4. 5. 2  
Pr o hi bite d Me dic ati o ns/ Tre at me nts 
T he decisi o n t o a d mi nister a pr o hi bite d me dicat i o n a n d/ or treat me nt is d o ne wit h t he safet y 
of t he st u d y partici pa nt as t he pri mar y c o nsi derati o n.  W he n p ossi ble, Aller ga n s h o ul d be 
n otifie d bef ore t he pr o hi bite d me dicati o n/treat me nt is a d mi nistere d. 
D uri n g t he st u d y, patie nts s h o ul d n ot partici pat e i n ot her i n vesti ga ti o nal dr u g or de vice 
st u dies. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
3 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
N o nst u d y I O P-l o weri n g Me dicati o ns 
Use of a n y t o pical o p ht hal mic me dicati o n c o ntai ni n g a n oc ular a nti h y perte nsi ve, ot her t ha n 
use of st u d y me dicati o n (ti m ol ol) i n  C o ntr ol gr o u p or fell o w e yes, is pr o hi bite d as c o nc urre nt 
t hera p y i n eit her e ye, u nless necessar y f or t he safet y of t he patie nt d ue t o i na de q uate c o ntr ol 
of I O P as deter mi ne d b y t he i n vesti gat or.  I na de q uate c o ntr ol of I O P s h o ul d be c o nfir me d at a 
s u bse q ue nt visit (sc he d ule d or u nsc he d ule d visit).  Pri or t o Wee k 5 2, t he i n vesti gat or will be 
e x pecte d t o attest t o t he nee d f or a d diti o nal n o nst u d y I O P- l o weri n g me dicati o n f or safet y 
reas o ns.  After t he Wee k 5 2 visit, n o nstu d y t o pical I O P-l o weri n g me dicati o ns will be 
per mitte d if i n t he i n vesti gat or’s  cli nical j u d g me nt t he I O P is n ot a de q uatel y c o ntr olle d at t w o 
c o nsec uti ve visits.  I nitiati o n of me di cati o n i n o ne e ye s h o ul d n ot a ut o maticall y lea d t o 
i nitiati o n of me dicati o n i n t he ot her e ye.  Eac h e ye s h o ul d be e val uate d o n  a n i n di vi d ual basis 
w he n deter mi ni n g t he nee d f or a d diti o nal n o nst u d y I O P-l o weri n g me dicati o ns.  If n o nst u d y 
I O P-l o weri n g me dicati o n is i nitiate d pri or t o Wee k 5 2, t he i n vesti gat or will be e x pecte d t o 
attest t o t he nee d f or a d diti o nal n o nst u d y I O P-l o weri n g me dicati o n f or safet y reas o ns f or 
eac h e ye i n di vi d uall y.  
C o ntact Le nses 
Use of s oft c o ntact le nses wit hi n 3 da ys a n d us e of ri gi d gas per mea ble or har d c o ntact le nses 
wit hi n 1 wee k pri or t o a sc he d ul e d st u d y visit or A d mi nistrati o n Da y, or use of c o ntact le nses 
of a n y ki n d wit hi n 1 wee k f oll o wi n g a n y Bi mat o pr ost S R ( or S ha m) a d mi nistrati o n i n eit her 
e ye is pr o hi bite d.  
C o ntact le nses s h o ul d be re m o ve d pri or t o i nstilli n g a n y st u d y- pr o vi de d e ye dr o ps a n d 
patie nts s h o ul d wait at least 1 5 mi n utes bef ore p utti n g c o ntact le nses bac k i n t he e yes after 
i nstilli n g t o pical dr o ps. 
Ot her Me dicati o ns 
T he f oll o wi n g me dicati o ns ( or classes of me di cati o ns) a n d treat me nt pr oce d ures are n ot 
per mitte d as c o nc urre nt t hera p y d uri n g t h e st u d y t hr o u g h 1 2 m o nt hs after t he last 
Bi mat o pr ost S R or S ha m a d mi nistrati o n u nless t he patie nt has alrea d y bee n treate d wit h 
n o nst u d y I O P-l o weri n g me dicati o n i n b ot h e yes: 
•  S u bc o nj u ncti val, s u b- Te n o n’s, i ntra vitreal, or ot her o p ht hal mic i njecti o ns of a n y 
me dicati o ns i n eit her e ye  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
•  S ur gical pr oce d ures t hat are n ot relate d t o Bi mat o pr ost S R ( or s ha m) a d mi nistrati o n 
pr oce d ures i n t he st u d y e ye (s ur gical pr oce d ures are all o we d i n t he fell o w e ye after 
Wee k 5 2 as descri be d i n Secti o n 4. 5. 1) 
•  Use of a n y t o pical o p ht hal mic me dicati o ns  (e xce pt as descri be d a b o ve a n d i n 
Secti o n 4. 5. 1) i n eit her e ye. 
•  Use of a n y o p ht hal mic (i ncl u di n g t o pical, i n tra vitreal, s u b- Te n o n’s, s u bc o nj u ncti val) 
c ortic oster oi ds i n eit her e ye fr o m 2 m o nt hs pri or t o t he baseli ne visit t hr o u g h 
1 2 m o nt hs after t he last a d mi nistrati o n, e x ce pt f or use of p ost o perati ve t o pical oc ular 
c oritc oster oi ds after a d mi nistrati o n as descri be d i n Secti o n 4. 5. 1. 
•  Oral, i ntra m usc ular, or i ntra ve n o us c ort ic oster oi ds fr o m 2 m ont hs pri or t o t he 
baseli ne visit t hr o u g h t he t welft h m o nt h after t he last i njecti o n. 
•  Use of L A TI S S E ®  ( bi mat o pr ost f or h y p otric h osis) d uri n g t he st u d y peri o d i n eit her 
e ye  
•  S yste mic use of car b o nic a n h y dr ase i n hi bit ors (e g, Dia m o x ® )   
•  A n y i nitiati o n of or alterati o ns i n s yst e mic re gi me n of beta- bl oc ker c o ntai ni n g 
me dicati o ns fr o m 2 m o nt hs pri or t o Scree ni n g t hr o u g h t he fi nal st u d y visit 
4. 5. 3  
Defi niti o n of Fe m ales of ( N o n -) C hil d be ari n g P ote nti al a n d/ or 
Acce pt a ble C o ntr ace pti ve Met h o ds 
F or p ur p oses of t his st u d y, w o me n will be c o nsi dere d of c hil d beari n g p ote ntial u nless t he y 
are nat urall y p ost me n o pa usal or  per ma ne ntl y sterilize d (ie, h ysterect o m y).  Nat ural 
me n o pa use is defi ne d as t he per ma ne nt ce ssati o n of me nstr ual peri o ds, deter mi ne d 
retr os pecti vel y after a w o ma n has e x perie nce d 1 2 m o nt hs of  a me n orr hea wit h o ut a n y ot her 
o b vi o us pat h ol o gical or p h ysi ol o gical ca use.  F o r w o me n of c hil d beari n g p ote ntial w h o ma y 
partici pate i n t he st u d y, t he f oll o wi n g met h o ds of c o ntrace pti o n, if pr o perl y use d, are 
ge nerall y c o nsi dere d relia ble:  h or m o nal c o ntrace pti ves (ie, or al, patc h, i njecti o n, i m pla nt), 
male c o n d o m wit h i ntra va gi nal s per mici de, dia p hra g m or cer vical ca p wit h s per mici de, 
va gi nal c o ntrace pti ve ri n g, i ntra ute ri ne de vice, s ur gical sterilizati o n ( bilateral t u bal li gati o n, 
bilateral sal pi n gect o m y), vasect o mize d part ner, or tr ue se x ual a bsti ne nce ( w he n t his is i n li ne 
wit h t he preferre d a n d us ual lifest yle of t he s u bject). 
T he i n vesti gat or a n d eac h patie nt  will deter mi ne t he a p pr o priate met h o d of c o ntrace pti o n f or 
t he patie nt d uri n g t he partici pati o n i n t he st u d y. 
If a fe male bec o mes pre g na nt d uri n g t he st u d y, t he i n vesti gat or will n otif y t he s p o ns or 
i m me diatel y after t he pre g na nc y is c o nfir me d a n d t he patie nt will be e xite d fr o m t he st u d y 
after a p pr o priate safet y f oll o w- u p.  T he i n ve sti gat or will ( 1) n otif y t he patie nt’s p h ysicia n 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
t hat t he patie nt was bei n g treate d wit h a n in vesti gati o nal dr u g ( u n mas k t he st u d y treat me nt as 
nee de d f or pre g na nc y m o nit ori n g), a n d ( 2) f o ll o w t he pr o gress of t he pre g na nc y.  T he 
i n vesti gat or m ust d oc u me nt t he o utc o me of t he pre g na nc y a n d pr o vi de a c o p y of t he 
d oc u me ntati o n t o Aller ga n. 
5.  
St u d y Tre at me nts  
5. 1  
St u d y Tre at me nts a n d F or m ul ati o ns 
T he cli nical f or m ulati o ns of Bi mat o pr ost S R c o ntai n preser vati ve-free bi mat o pr ost dis perse d 
i n a bi o de gra da ble p ol y mer matri x (i ncl udi n g P L A a n d P L G A).  T hese bi o de gra da ble 
i m pla nts are prel oa de d i n t he a p plicat or.  T he f or m ulati o ns use d i n t his st u d y are Bi mat o pr ost 
S R 1 0 µ g 
a n d Bi mat o pr ost 1 5 µ g 
 
5. 2  
C o ntr ol Tre at me nts  
F or S ha m a d mi nistrati o n, a nee dleless a p plicat or is pr o vi de d. 
T he f oll o wi n g t o pical e ye dr o ps are als o use d as c o ntr ols: 
•  Ti m ol ol 0. 5 % o p ht hal mic s ol uti o n (
) c o ntai ns ti m ol ol 
maleate 0. 6 8 % (re prese nti n g 0. 5 % ti m ol ol fr ee base), be nzal k o ni u m c hl ori de 0. 0 1 %, 
di basic s o di u m p h os p hate he pta h y drate, m o n o basic s o di u m p h os p hate, s o di u m 
h y dr o xi de a n d/ or h y dr oc hl oric aci d t o a dj ust p H, a n d p urifie d water 
•  Ti m ol ol ve hicle (
), is i de ntical i n a p peara nce t o t he 
ti m ol ol 0. 5 % o p ht hal mic s ol uti o n a n d c o ntai ns all i n gre die nts of t he a b o ve e xcl u di n g 
ti m ol ol maleate 
5. 3  
Met h o ds f or M as ki n g 
Patie nts i n t he C o ntr ol gr o u p will recei ve ti m ol o l e ye dr o ps BI D pl us S ha m a d mi nistrati o n i n 
b ot h e yes.  Ve hicle e ye dr o ps will be use d BI D t o mas k t he treat me nt of patie nts recei vi n g 
Bi mat o pr ost S R i n t he st u d y e ye.  Treat me nt f o r fell o w e yes of patie nts assi g ne d t o 1 of t he 
2 Bi mat o pr ost S R d ose gr o u ps will be a S ha m a d mi nistrati o n pr oce d ure + ti m ol ol e ye dr o ps 
BI D . 
T he site c o or di nat or a n d desi g nate d staff will n ot  be mas ke d t o w het her t he patie nt recei ve d 
1 of t he 2 d ose stre n gt hs of Bi mat o pr ost S R or  t he S ha m a d mi nistrati o n pr oce d ure, b ut will 
be mas ke d t o t he s pecific i m pla nt d ose stre n gt h.  T he patie nt a n d t he re mai ni n g staff will be 
mas ke d t o t he patie nt’s treat me nt assi g n me nt.  Efficac y I O P meas ure me nts will be mas ke d b y 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
usi n g a 2- pers o n rea di n g met h o d as descri be d i n Secti o n 6. 1. 1 (f or o pti o nal p ost o perati ve 
I O P meas ure me nts f or patie nts wit h sic kle cell disease or trait [ or ot her he m o gl o bi n o pat hies], 
see Secti o n 8. 4). 
T he site staff w h o perf or m I O P rea di n gs will be  mas ke d re gar di n g t he st u d y e ye ( w hic h e ye 
recei ve d Bi mat o pr ost S R or t he S ha m a d mi nistrati o n pr oce d ure), Bi mat o pr ost S R d ose 
stre n gt h, a n d t he st u d y treat me nts t hat are deli vere d i n b ottles.  Site pers o n nel a n d patie nts 
will be i nstr ucte d a n d re mi n de d t hr o u g h o ut t he st u d y n ot t o disc uss st u d y me dicati o n 
assi g n me nts t o e ns ure mai nte na nce of t he mas ki n g. 
Desi g nate d site pers o n nel will be res p o nsi ble f or recei vi n g, dis pe nsi n g, a n d c ollecti n g st u d y 
me dicati o n a n d perf or mi n g dr u g acc o u nta bilit y, as well as verificati o n of patie nt d osi n g 
c o m plia nce; sites are e nc o ura ge d t o assi g n a n u n mas ke d staff me m ber (e g, site c o or di nat or) 
t o t his tas k t o a v oi d u n mas ki n g a d diti o nal pers o n nel.  Base d o n t he ra n d o mizati o n sc he d ule, 
t hese desi g nate d pers o n nel will dis pe nse t he st u dy me dicati o n t o t he patie nt.  All b ottles will 
c o ntai n si milar mas ke d la bels f or t he st u d y, i de ntif yi n g t he e ye of a d mi nistrati o n b y “ Ri g ht” 
a n d “ Left”. 
I n t he e ve nt t hat t he patie nt re q uires t o pical c ortic oster oi ds or a nti-i nfla m mat or y dr o ps i n 
o nl y o ne e ye d uri n g t he 7 da ys after t he a d mi ni strati o n pr oce d ure, i n or der t o mai ntai n 
mas ki n g t he i n vesti gat or will be i nstr ucte d t o dis pe nse t he re q uire d me dicati o n wit h o ut 
discl osi n g w hic h e ye is t he st u d y e ye, or t he e ti ol o g y of t he si g ns/s y m pto ms t hat re q uire t he 
me dicati o n. 
T he i n vesti gat or is str o n gl y e nc o ura ge d n ot t o use pr o hi bite d me dicati o ns as o utli ne d i n 
Secti o n 4. 5. 2.  I n or der t o mai ntai n mas k i n g i n t he e ve nt t hat n o nst u d y I O P-l o weri n g 
me dicati o ns ( pr o hi bite d pri or t o Wee k 5 2 u nless re q uire d f or a safet y reas o n a n d atteste d t o 
b y t he i n vesti gat or) are a d mi nistere d, if a pa tie nt is starte d o n a n o nst u d y I O P-l o weri n g 
me dicati o n i n o nl y o ne e ye, t he patie nt will c o nt i n ue t o use t he st u d y- pr o vi de d e ye dr o ps i n 
t hat e ye as directe d.  T he n o nst u d y I O P-l o weri n g me dicati o n will be prescri be d b y t he 
i n vesti gat or acc or di n g t o l ocal sta n dar d of care practices a n d use d i n a d diti o n t o t he 
st u d y- pr o vi de d e ye dr o ps i n t hat e ye.  T he e ye n ot recei vi n g a n o nst u d y I O P-l o weri n g 
me dicati o n will c o nti n ue t o recei ve t he st u d y- pr o vi de d e ye dr o ps as directe d.  If t he e ye 
recei vi n g t he n o nst u d y I O P-l o weri n g me dicati o n is a Bi mat o pr ost S R st u d y e ye, t he e ye will 
recei ve S ha m a d mi nistrati o n o n t he a d mi nistratio n da y(s).  If t he e ye recei vi n g t he n o nst u d y 
I O P-l o weri n g me dicati o n is a C o ntr ol gr o u p st u d y e ye or a fell o w e ye, t he e ye will c o nti n ue 
t o recei ve S ha m a d mi nistrati o n o n t he a d mi nistrati o n da y(s).  If b ot h e yes are recei vi n g 
n o nst u d y I O P-l o weri n g me dicati o ns, t he patie n t will disc o nti n ue use of t he Aller ga n 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
st u d y- pr o vi de d e ye dr o ps  a n d will n ot recei ve a d diti o nal Bi mat o pr ost S R or S ha m 
a d mi nistrati o n (see Secti o n 5. 6. 1).  H o we ver, as descri be d i n Secti o n 8. 8,  t he patie nt will still 
re mai n i n t he st u d y a n d be f oll o we d f or 1 2 mo nt hs f oll o wi n g t heir last a d mi nistrati o n of 
Bi mat o pr ost S R or S ha m. 
5. 4  
Tre at me nt All oc ati o n R ati o a n d Str atific ati o n 
Ra n d o mizati o n t o treat me nt gr o u ps will use a 1: 1: 1 rati o.  Patie nts will be ra n d o mize d t o 
recei ve Bi mat o pr ost S R (eit her 1 0 µ g or 1 5 µ g) pl us ve hicle e ye dr o ps, or a S ha m 
a d mi nistrati o n pr oce d ure pl us ti m ol ol e ye dr o ps, i n t he st u d y e ye.  Ra n d o mizati o n will be 
stratifie d b y Baseli ne stu d y e ye H o ur 0 I O P ( ≤ 2 5 m m H g or > 2 5 m m H g). 
5. 5  
Met h o d f or Assi g n me nt t o Tre at me nt Gr o u ps/ R a n d o miz ati o n 
Pri or t o i nitiati o n of a n y st u d y pr oce d ures, ea c h patie nt w h o pr o vi des i nf or me d c o nse nt will 
be assi g ne d a s u bject n u m ber t h at will ser ve as t he patie nt’s i de ntificati o n n u m ber o n all 
st u d y d oc u me nts. 
Eli gi ble patie nts will be ra n d o ml y assi g ne d t o 1 of 3 treat me nt gr o u ps i n a 1: 1: 1 rati o t o 
recei ve st u d y Bi mat o pr ost S R 1 0 µ g, Bi mat o pr ost S R 1 5 µ g, or ti m ol ol.  T he ra n d o mizati o n 
will be stratifie d b y Baseli ne H o ur 0 I O P ( baseli ne st u d y e ye I O P ≤ 2 5 m m H g or 
> 2 5 m m H g). 
F or deter mi nati o n of stratificati o n gr o u p assi g n me nt f or eac h patie nt, sites will be re q uire d t o 
e nter baseli ne I O P at H o ur 0  data i nt o electr o nic data ca pt ure ( E D C).  Electr o nic data ca pt ure 
will assi g n a stratificati o n c o de ass ociate d wit h o ne of t he stratificati o n gr o u ps f or t he 
Baseli ne H o ur 0 I O P. 
At t he ti me of ra n d o mizati o n ( C ycle 1 Da y 1 A d mi nistrati o n Da y) a n a ut o mate d I nteracti ve 
Voice/ We b Res p o nse S yste m (I V/ W R S) will be use d t o ma na ge t he ra n d o mizati o n a n d 
treat me nt assi g n me nt base d o n a ra n d o mizati o n sche me pre pare d b y Aller ga n Bi ostatistics.  
T he site will e nter t he stratificati o n gr o u p assi g n me nt c o de ( o btai ne d fr o m t he E D C) i nt o 
I V/ W R S at t he ti me of ra n d o mizati o n.  A ra n d o mi zati o n n u m ber will be assi g ne d t o a patie nt 
acc or di n g t o t he or der of e nr oll me nt wit hi n ea c h I O P strat u m ( baseli n e st u d y e ye H o ur 0 I O P 
≤ 2 5 m m H g or > 2 5 m m H g) acr oss t he st u d y.  T hat is, I V/ W R S will assi g n t he ne xt 
a vaila ble ra n d o mizati o n n u m ber t o t he patie nt at t he ti me w he n t he i n vesti gat or re q uests 
ra n d o mizati o n.  St u d y me dicati o n will be la bele d wit h me dicati o n kit n u m bers.  T he I V/ W R S 
s yste m will pr o vi de t he site wit h t he s pecific me dicati o n kit n u m ber(s) f or eac h ra n d o mize d 
patie nt at t he ti me of ra n d o mizati o n.  Sites wi ll dis pe nse st u d y me dicati o n acc or di n g t o t he 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
I V/ W R S i nstr ucti o ns.  Sites will als o call t he I V R S or l o g o nt o t he I W R S at s u bse q ue nt visits 
t o o btai n a st u d y me dicati o n kit n u m ber f or dis pe nsi n g st u d y me dicati o n.  Sites will recei ve 
t he I V/ W R S c o nfir mati o n n otificati o ns f or eac h tra nsacti o n.  All n otificati o ns are t o be 
mai ntai ne d wit h t he st u d y s o urce d oc u me nts. 
5. 6  
Tre at me nt Re gi me n a n d D osi n g 
T he treat me nt gr o u ps are s h o w n i n Ta ble 7.  Patie nts ra n d o mize d t o 1 of t he Bi mat o pr ost S R 
d ose gr o u ps will recei ve a n i ntraca meral a d mi nist rati o n of Bi mat o pr ost S R i n t he st u d y e ye 
o n Da y 1, Wee k 1 6, a n d Wee k 3 2, i n a d diti o n t o usi n g t o pical ve hicle e ye dr o ps ( 1 dr o p 
BI D).  T he y will recei ve ti m ol ol e ye dr o ps ( 1 dr o p BI D) pl us S ha m a d mi nistrati o n i n t he 
fell o w e ye.  Patie nts ra n d o mize d t o t he C o ntr ol gr o u p will recei ve a S ha m a d mi nistrati o n i n 
b ot h e yes o n Da y 1, Wee k 1 6, a n d Wee k 3 2, i n a d diti o n t o ti m ol ol e ye dr o ps ( 1 dr o p BI D) i n 
b ot h e yes. 
After t he A d mi nistrati o n Da y 1 visit ( Bi mat o pr os t S R or S ha m a d mi nistrati o n pr oce d ure), t he 
patie nts s h o ul d start a d mi nistrati o n of t he st u d y- pr o vi de d e ye dr o ps i n b ot h e yes, starti n g 
wit h t he e ve ni n g d ose.  Patie nts s h o ul d c o nti n ue a d mi nisteri n g st u d y- pr o vi de d e ye dr o ps i n 
t he m or ni n g (at 0 8: 0 0 ± 1 h o ur) a n d i n t he e ve ni n g ( 2 0: 0 0 ± 1 h o ur), a p pr o xi matel y 1 2 h o urs 
a part.  Patie nts will be i nstr ucte d n ot t o a d mi nister t he st u d y- pr o vi de d e ye dr o ps o n t he 
m or ni n g of st u d y visits (e xce pt a d mi nistrati o n vi sits), a n d t o bri n g t heir st u d y me dicati o ns t o 
t heir visit f or i nstillati o n i m mediatel y after t he H o ur 0 I O P meas ure me nts.  If t he patie nt 
arri ves ha vi n g ta ke n t he m or ni n g d ose of st u d y- pr o vi de d e ye dr o ps, t he site  s h o ul d atte m pt t o 
resc he d ule wit hi n t he visit win d o w.  E xce pti o n is ma de f or t h e Da y 2 st u d y visit after a n y 
i njecti o n.  As t his visit is pri maril y f or safet y p ur p oses, patie nts s h o ul d u n der g o t he visit 
re gar dless of w het her t he y di d or di d n ot use t he st u d y me dicati o n t h at m or ni n g.  Site 
pers o n nel a n d patie nts will be re mi n de d t o ta ke  a p pr o priate ca uti o n d uri n g a d mi nistrati o n of 
st u d y me dicati o ns d uri n g t he visit t o e ns ure mai nte na nce of mas ki n g. 
5. 6. 1  
Tre at me nt Re gi me n/ D os a ge A dj ust me nts  
Patie nts w h o ha ve recei ve d n o nst u d y t o pical I O P-l o weri n g me dicati o n ( pr o hi bite d bef ore 
Wee k 5 2 u nless re q uire d f or safet y reas o ns d ue t o i na de q uate I O P c o ntr ol a n d atteste d t o b y 
t he i n vesti gat or) i n a Bi mat o pr ost S R st u d y e ye will recei ve S ha m a d mi nistrati o n i n t hat e ye 
o n t he Bi mat o pr ost S R re peat a d mi nistrati o n da y(s).  Patie nts w h o ha ve recei ve d n o nst u d y 
t o pical I O P-l o weri n g me dicati o n i n a fell o w e ye or a C o ntr ol Gr o u p st u d y e ye will c o nti n ue 
t o recei ve S ha m a d mi nistrati o n i n t hat e ye o n t he a d mi nistrati o n da y(s). 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o we ri n g me dicati o n i n b ot h e yes will n ot u n der g o 
Bi mat o pr ost S R a d mi nistrati o n or S h a m a d mi nistrati o n i n eit her e ye. 
Patie nts w h o use n o nst u d y I O P-l o weri n g me dica ti o n ( pr o hi bite d bef ore Wee k 5 2 u nless 
re q uire d f or safet y reas o ns d ue t o i na de q uate I OP c o ntr ol a n d atteste d t o b y t he i n vesti gat or) 
i n o nl y o ne e ye will be f oll o we d f or t he d urati o n of t he st u d y.  If use d i n b ot h e yes, patie nts 
will be f oll o we d at mi ni m u m f or 1 2 m o nt hs afte r t he last a d mi nistrati o n of Bi mat o pr ost S R 
or S ha m.  Patie nts usi n g n o nst u d y I O P-l o weri n g me dicati o ns i n b ot h e yes pri or t o t he 
Wee k 1 6 or Wee k 3 2 A d mi nistrati o n Da y will n ot  atte n d t he a d mi nistrati o n visit(s), n or will 
t he y atte n d t he Da y 2, Da ys 4 a n d 8 ( p h o ne call), or 2- wee k visits (ie, Wee ks 2, 1 8, a n d 3 4) 
f oll o wi n g a n a d mi nistrati o n.  T he y w o ul d c o nti n ue t he sc he d ule at Wee k 2 2 or Wee k 3 8, as 
a p pr o priate f or t he a d mi nistrati o n c ycle. 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o we ri n g me dicati o n i n b ot h e yes bef ore t he ti me 
of t he M o nt h 1 4 visit are n ot re q u ire d t o atte n d t he M o nt h 1 4 or 1 8 visits u nless t he visit is 
1 2 m o nt hs after t heir last i njecti o n or S ha m, at w hic h ti me t he patie nt ma y e xit earl y a n d 
s h o ul d c o m plete all M o nt h 2 0/ E xit visit e xa mi nati o ns.  Patie nts w h o ha ve recei ve d n o nst u d y 
I O P-l o weri n g me dicati o n i n b ot h e yes b y t he ti me of t he M o nt h 1 6 visit are n ot re q uire d t o 
atte n d t he M o nt h 1 8 visit, u nless t h at visit is 1 2 m o nt hs after t hei r last i njecti o n or S ha m, at 
w hic h ti me t he patie nt ma y e xit earl y a n d s h o ul d c o m plete all M o nt h 2 0/ E xit visit 
e xa mi nati o ns. 
F or patie nts w h o ha ve n ot recei ve d n o nst u d y I O P-l o weri n g me dicati o ns b y t he ti me of st u d y 
disc o nti n uati o n or c o m pleti o n, p ostst u d y e val ua ti o ns re gar di n g t he nee d f or I O P-l o weri n g 
me dicati o ns s h o ul d be c o n d ucte d acc or di n g t o t he treati n g p h ysicia n’s cli nical o pi ni o n. 
5. 7  
St or a ge of St u d y Me dic ati o ns/ Tre at me nts 
T he st u d y me dicati o n m ust be st ore d i n a sec u re area a n d a d mi nistere d o nl y t o patie nts 
e ntere d i nt o t he cli nical st u d y, at n o c ost t o  t he patie nt, i n acc or da nce wit h t he c o n diti o ns 
s pecifie d i n t his pr ot oc ol.  O nl y assi g ne d st u d y pers o n nel, a ut h orize d b y t he i n vesti gat or, 
ma y ha ve access t o st u d y me dicati o n.  Bi mat o pr ost S R a n d S ha m nee dleless a p plicat or m ust 
be st ore d  i n t he ori gi nal seal e d f oil p o uc h.  I n vesti gati o nal me dici nal pr o d uct m ust be st ore d 
as descri be d i n t he I n vesti gat or ’s Br oc h ure.  Sites m ust re p ort a n y te m perat ure e xc ursi o ns as 
descri be d i n t he Pr ot oc ol Pr oce d ure Ma n ual or c o ntact Aller ga n or its desi g nee f or f urt her 
i nstr ucti o ns. 
F or f urt her details o n st ora ge, i ncl u di n g re q ui re me nts f or st u d y- pr o vi de d  e ye dr o ps, please 
refer t o t he Pr ot oc ol Pr oce d ure Ma n ual a n d/ or c o ntact Aller ga n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
5. 8  
Pre p ar ati o n of St u d y Me dic ati o ns/ Tre at me nts  
Bi mat o pr ost S R is l oa de d i nt o t he si n gle use a p plicat or d uri n g ma n ufact uri n g a n d is pr o vi de d 
wit hi n t he a p plicat or as a sterile, fi nis he d pr o d uct.  St u d y site pers o n nel s h o ul d n otif y 
Aller ga n or its desi g nee i m me di atel y t o a d vise of a n y sit ua ti o n i n w hic h t he st u d y me dicati o n 
is defecti ve. 
5. 9  
Tre at me nt A d mi nistr ati o n  
St u d y me dicati o n m ust o nl y be a d mi nistere d t o pa tie nts w h o meet t he eli gi bilit y criteria i n 
acc or da nce wit h t he c o n diti o ns s pecifie d i n t his  pr ot oc ol.  Me dicati o n will be la bele d wit h 
eit her a si n gle pa nel la bel or  b o o klet la bel.  Rec or ds of use of me dicati o n kit n u m bers f or 
eac h patie nt will be mai ntai ne d b y t he site a n d rec or de d i n t he electr o nic case re p ort f or m 
(e C R F) as a p pr o priate. 
5. 9. 1  
P atie nt Pre p ar ati o n 
A d mi nistrati o n Da y assess me nts (i ncl u di n g vital si g ns a n d q uer y f or c o nc o mita nt 
me dicati o ns a n d a d verse e ve nts) s h o ul d be c o m ple te d as o utli ne d i n Secti o n 8. 4.  At least 
3 a d mi nistrati o ns of a br oa d s pectr u m t o pical  o p ht hal mic a nti bi otic dr o p a n d t o pical 
a nest hetic dr o p s h o ul d be a d mi nistere d t o eac h  e ye a p pr o xi matel y e ver y 5 mi n utes be gi n ni n g 
a p pr o xi matel y 1 5 mi n utes pri or t o t he pr oce d ure.  Wit h t he patie nt i n a s u pi ne p ositi o n, t he 
e ye a n d c o nj u ncti val f or nices s h o ul d be irri gate d wit h 5 % o p ht hal mic p o vi d o ne-i o di ne 
s ol uti o n a n d t he li ds a n d s urro u n di n g or bital area s h o ul d be pre p pe d a n d dra pe d acc or di n g t o 
t he sta n dar d pr ot oc ol detaile d i n t he Pr ot oc ol Pr oce d ure Ma n ual.  
5. 9. 2  
St u d y Tre at me nt L oc ati o n 
At t he discreti o n of t he i n vesti gat or, Bi ma t o pr ost S R ( or S ha m) a d mi nistrati o n ma y be 
perf or me d at a n A m b ulat or y S ur gical Ce nter ( A S C; free sta n di n g or h os pital base d) or i n t he 
office setti n g (e g, i n a pr oce d ure r o o m wit h a n o perati n g micr osc o pe).  As a sta n dar d A S C 
tec h ni q ue a n i ntra ve n o us cat heter ma y be place d a n d i ntra ve n o us se dati ves ma y be use d at 
t he discreti o n of t he i n vesti gat or a n d/ or a nest hesi ol o gist.  T he A m b ulat or y S ur gical Ce nter 
ma y ha ve sta n dar d o perati n g pr oce d ures t hat re q uire a n electr ocar di o gra m a n d/ or a c hest 
ra di o gra p h perf or me d pri or t o t he pr oce d ure.  A se parate sta n dar d c o nse nt t o ha ve t he 
pr oce d ure at a n A m b ulat or y S ur gical Ce nter  ma y be re q uire d per t he sta n dar d o perati n g 
pr oce d ures at t he facilit y. 
Sterile tec h ni q ue will be practice d at all ti mes. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
5. 9. 3  
A d mi nistr ati o n Tec h ni q ue 
I ntraca meral a d mi nistrati o n of Bi mat o pr ost S R m ust be perf or me d b y a n o p ht hal m ol o gist 
w h o has ha d a de q uate trai ni n g a n d has bee n a p pr o ve d b y Aller ga n t o perf or m t he pr oce d ure.  
T he pri nci pal i n vesti gat or at a site ma y desi g na te a s u bi n vesti gat or t o perf or m t he pr oce d ure, 
s u bject t o Aller ga n a p pr o val a n d trai ni n g.  T he st u d y me dicati o n kit s h o ul d be rea dil y 
a vaila ble d uri n g t he pr oce d ure. 
T he pr oce d ure is descri be d i n detail i n t he Pr ot oc ol Pr oce d ure Ma n ual.  I n brief, f oll o wi n g 
t he sterile pre parati o n a n d sterile fiel d set u p, a n a p pr o priatel y size d sterile li d s pec ul u m 
s h o ul d be place d bet wee n t he e yeli ds of t he patie nt.  T he e ntra nce site f or t he a p plicat or 
nee dle is j ust a nteri or t o t he i nserti o n of t he c o nj u ncti va t hr o u g h t he clear c or nea i n t he 
s u peri or or te m p oral q ua dra nt.  T he traject or y of t he nee dle s h o ul d be parallel t o t he iris 
pla ne.  T he e ye is sta bilize d b y eit her c o u nt er tracti o n wit h a sterile t o ot he d f orce ps or 
c o u nter press ure wit h a c ott o n ti p pe d a p plicat or as t he nee dle is  a d va nce d t hr o u g h t he c or nea.  
T he act uat or b utt o n is de presse d u ntil a n a u di ble a n d/ or pal pa ble cl ic k is hear d.  T he 
Bi mat o pr ost S R i m pla nt s h o ul d be visi ble e xiti n g t he nee dle be vel i nt o t he a q ue o us h u m or.  
T he nee dle is t he n i m me diatel y re m o ve d fr o m t he a nteri or c ha m ber, a n d t he w o u n d is 
c hec ke d f or a q ue o us lea ka ge.  F oll o wi n g re m o val of t he li d s pec ul u m a n d sterile dra pe, 
a d diti o nal dr o ps of br oa d s pectr u m a nti bi otics s h o ul d be a p plie d. 
T he pr oce d ure f or t he sec o n d a n d t hir d a d mi nistrati o ns of Bi mat o pr ost S R is t he sa me. 
T he pr oce d ure f or all S ha m a d mi nistrati o ns is  t he sa me; h o we ver, t he S ha m a p plicat or will 
n ot ha ve a nee dle a n d t h us will n ot e nter t he a nte ri or c ha m ber ( b ut s h o ul d t o uc h t he e ye at t he 
area of rec o m me n de d i nserti o n). 
5. 9. 4  
I m me di ate P osttre at me nt O bser v ati o n 
F oll o wi n g st u d y treat me nt a d mi nistrati o n, t he patie nt  is all o we d t o sit u pri g ht a n d is ke pt f or 
a mi ni m u m of 1 h o ur of o bser vati o n.  T he s ur ge o n will e xa mi ne eac h of t he patie nt’s e yes t o 
e ns ure t hat t he a nteri or c ha m ber is f or m e d pri or t o t he patie nt bei n g release d. 
T he patie nt will be s u p plie d a b ottle of t o pical o p ht hal mic a nti bi otic dr o ps a n d i nstr ucti o ns t o 
use t he m f or t he ne xt 3 da ys (i ncl u di n g t he da y of t he a d mi nistrati o n) i n b ot h e yes a n d t o 
f oll o w u p as per pr ot oc ol. 
Pri or t o lea vi n g t he site, patie nts s h o ul d be i nst r ucte d t o c o ntact t he stu d y site i m me di atel y if 
t he y e x perie nce a n y a d verse e ve nts after treat ment.  If t he patie nt re p orts ha vi n g e x perie nce d 
a d verse e ve nts, t hese s h o ul d be re c or de d o n t he a p pr o priate e C R F. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
T he sa me p osttreat me nt o bser vati o n re q ui re me nts a p pl y after t he sec o n d a n d t hir d 
a d mi nistrati o ns of Bi mat o pr ost S R or S ha m a d mi nistrati o n. 
N ote:  Patie nts wit h sic kle cell disease or  trait ( or ot her he m o glo bi n o pat hies) ma y u n der g o 
o pti o nal bi o micr osc o p y a n d I O P e xa mi nati o n i n b ot h e yes 4 h o urs after eac h Bi mat o pr ost S R 
a d mi nistrati o n ( or S ha m a d mi nistrati o n).  T his o pti o nal I O P e xa mi nati o n is f or p ost o perati ve 
p ur p oses o nl y, a n d as s uc h d oes n ot re q uire a mas ke d, 2- pers o n rea di n g met h o d.  T he I O P 
s h o ul d be ta ke n o nl y o nce t o a v oi d e xcessi ve p osta d mi nistrati o n ( or S ha m a d mi nistrati o n) 
ma ni p ulati o n of t he e ye, a n d s h o ul d be ta ke n b y t he i n vesti gat or ( or ot her u n mas ke d, 
q ualifie d pers o n nel).  T his p osta d mi nistrati o n ( o r S ha m a d mi nistrati o n) e xa mi nati o n ma y be 
perf or me d usi n g a G ol d ma n n a p pla nati o n t o n o me ter or a ha n d- hel d t o n o meter.  ( See t he 
St u d y Pr oce d ure Ma n ual f or details.) 
5. 1 0  
Retre at me nt  
A d mi nistrati o n of Bi mat o pr ost S R will occ ur at fi xe d i nter vals of 1 6 wee ks, u p t o a t otal of 
3 a d mi nistrati o ns.  Patie nts will be rea d mi nist ere d t he Bi mat o pr ost S R d ose stre n gt h t o w hic h 
t he y were ra n d o mize d u nless i n t he i n vesti gat or’s o pi ni o n it w o ul d n ot be i n t he best i nterest 
of t he patie nt t o rea d mi nister Bi mat o pr ost S R  base d o n pre vi o us a d verse e ve nts or safet y 
c o ncer ns.  Patie nts w h o ha ve bee n treate d wit h n o nst u d y I O P-l o weri n g me dicati o n i n o nl y 
o ne e ye will still atte n d a d mi nistrati o n visits; if  t he treate d e ye is t he Bi mat o pr ost S R st u d y 
e ye, t he patie nt will recei ve a S ha m a d mi nistra ti o n i n t hat e ye.  C o ntr ol gr o u p st u d y e yes a n d 
fell o w e yes t hat ha ve bee n treate d wit h n o nstu d y I O P-l o weri n g me dicati o ns will c o nti n ue t o 
recei ve S ha m a d mi nistrati o ns.  Patie nts w h o ha ve bee n treate d wit h n o nst u d y I O P-l o weri n g 
me dicati o n i n b ot h e yes will n ot atte n d t he A d mi nistrati o n Da y visits, n or will t he y atte n d t he 
Da y 2, Da ys 4 a n d 8 ( p h o ne call), or t he 2- wee k  visits (ie, Wee ks 2, 1 8, a n d 3 4) f oll o wi n g a n 
a d mi nistrati o n. 
6.  
Res p o nse Me as ures a n d S u m m ar y  of D at a C ollecti o n Met h o ds 
Detaile d i nf or mati o n o n e q ui p me nt a n d met h o d ol o g y t o be use d is pr o vi de d i n t he Pr ot oc ol 
Pr oce d ure Ma n ual. 
6. 1  
Effic ac y Me as ures 
6. 1. 1  
Pri m ar y Effic ac y Me as ure 
T he pri mar y efficac y meas ure, I O P, will be meas ure d usi n g a G ol d ma n n a p pla nati o n 
t o n o meter.  E xa mi ners mas ke d t o t he treat me nt assi g n me nt s h o ul d perf or m all efficac y I O P 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
4 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
meas ure me nts at a p pr o xi matel y t he sa me ti me  of da y f or a gi ve n patie nt t hr o u g h o ut t he st u d y 
w he ne ver p ossi ble. 
A 2- pers o n rea di n g met h o d will be use d f or a ll efficac y I O P meas ure me nts, w herei n 1 pers o n 
a dj usts t he dial i n a mas ke d fas hi o n a n d a s ec o n d pers o n rea ds a n d rec or ds t he val ue.  T he 
ri g ht e ye is t o be meas ure d first a n d t he left e ye meas ure d sec o n d.  T w o c o nsec uti ve 
meas ure me nts will be ta ke n of eac h e ye.  If t he first 2 meas ure me nts differ b y > 1 m m H g, a 
t hir d meas ure me nt will be ta ke n.  If t he first 2 meas ure me nts differ b y 1 m m H g or less, t he 
I O P f or t he gi ve n e ye will be t he a vera ge of t he 2 rea di n gs.  If t he differe nce bet wee n t he first 
2 meas ure me nts is > 1 m m H g, t he I O P f or t he gi ve n e ye will be t he me dia n of t he 
3 rea di n gs. 
All H o ur 0 I O P e xa mi nati o ns s h o ul d be sc he d ule d at 0 8: 0 0 ± 1 h o ur.  As sc he d uli n g per mits, 
t he patie nt s h o ul d ha ve a p pr o xi matel y t he same H o ur 0 ti me of da y t hr o u g h o ut t he st u d y.  
H o ur 2 I O P e xa mi nati o ns s h o ul d occ ur 2 h o urs after t he H o ur 0 I O P e xa m.  T he acce pta ble 
wi n d o w f or t he H o ur 2 I O P e xa mi nati o n is ± 3 0 mi n utes. 
6. 2  
S afet y Me as ures 
T he f oll o wi n g will be c ollecte d a n d rec or de d o n t he a p pr o priate e C R F pa ge(s):  
A d verse E ve nts:  All a d verse e ve nts, fr o m t he m o me nt t he patie nt si g ns t he i nf or me d 
c o nse nt f or m, will be m o nit ore d a n d rec or de d i n  t he patie nt’s s o urce d oc u me nts.  All e ve nts 
will be re p orte d t o Aller ga n o n a n a d verse e v e nt e C R F, i ncl u di n g seri o us ness, se verit y, acti o n 
ta ke n a n d relati o ns hi p t o st u d y dr u g.  If a d verse e ve nts occ ur, t he first c o ncer n will be t he 
safet y of t he st u d y patie nt. 
Wei g ht a n d Hei g ht:  Wei g ht will be meas ure d i n p o u n ds (l b) or kil o gra ms ( k g) usi n g a 
scale.  Hei g ht will be meas ure d i n i nc hes (i n) or ce nti meters (c m).  Hei g ht a n d wei g ht will be 
meas ure d at scree ni n g as part of t he de m o gra p hic data; hist orical patie nt i nf or mati o n a n d/ or 
patie nt re p orts s h o ul d n ot be use d f or eit her meas ure me nt.  
Vit al si g ns:  S yst olic a n d diast olic bl o o d press ure a n d p ulse rate will be meas ure d after 
patie nts ha ve bee n at rest (seate d) f or at least 5 mi n utes.  B o d y te m perat ure will be meas ure d 
orall y ( or wit h a n i nfrare d f ore hea d t her m o meter) a n d rec or de d as ° F or ° C. 
He m at ol o g y, bl o o d c he mistr y, a n d uri n al ysis:  Bl o o d a n d uri ne sa m ples will be c ollecte d 
f or bl o o d c he mistr y a n d he mat ol o g y pa nels a n d uri nal ysis.   


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Pre g n a nc y:  Fe males of c hil d beari n g p ote ntial will ha ve pre g na nc y tests perf or me d.  
Pre g na nc y test kits will be pr o vi de d b y 
 or a desi g nate d 
re gi o nal la b orat or y a n d will be a d mi nistere d acc or di n g t o t he i nstr ucti o ns pr o vi de d wit h t he 
tests. 
 
 
 
 
 
 
 
 
 
 
  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
6. 4  
St u d y
t he st
patie n
t o geth
6. 4. 1
6. 4. 1
A st a
past o
pr oc e
t h ose
t o t he
g a n C o nfi de nti a
E x
y  e val uati o ns
tu d y w he ne v
n t, t he n a n a
h er a n d dis c
1  
M
 
M
1 . 1
n dar d me di c
o r c urre ntl y 
ed ures s h o ul
e st o p pe d wit
e scree ni n g v
a l 
x a mi n ati o
s s h o uld  b e p
v er p ossi ble. 
atte m pt s h o ul
uss fi n di n g s
M e dic al Hi
M e dic al His
cal hist or y ( i
has) will be 
d ha ve a n a s
thi n 6 0 da y s
v isit will be r
n Pr oce d u
p erf or me d b
 If it is n ot p
ld be ma de t
s) f or at least
st ory, P hy
st ory   
incl u di n g al l
ca pt ure d i n
ss ociate d me
 pri or t o t he 
rec or de d.  I n
5 2 
u res, Test s
b y t he sa me i
p ossi ble t o u
to ha ve i n ve s
t 1 visit. 
y sic al E x am
 rele va nt c on
t he patie nt s
edical hist or y
scree ni n g v
n  a d diti o n, a
P
s, E q ui p me
in vesti gat or /
u se t he sa me
sti gat ors o ve
m i n ati o n, 
n diti o ns t ha t
so urce d oc u m
y  e ntr y.  C ur
v isit a n d pr oc
all pre vi o us m
P r ot oc ol 1 9 2 02
G D D- T A
e nt, a n d T
/s u bi n vesti ga
e i n di vi d ual t
erla p (e xa mi
a n d Vit al
t t he patie nt 
m e nts.  All s
rre nt me dica
ce d ures wit h
m e dicati o ns 
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
T ec h ni q ues
at or t hr o u gh
to f oll o w t h e
ine t he patie n
l Sig ns  
has ha d i n t h
sur gical 
ati o ns as wel
h i n 9 0 da ys p
ta ke n f or OA
m e nt 2 
. 9 
s  
h o ut 
e 
n t 
h e 
l as 
p ri or 
A G 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
or O H
d oc u m
6. 4. 1
T he p
t he fo
heart /
l y m p
o nl y. 
6. 4. 1
T he b
a n y in
•  
•  
•  
6. 4. 2
Uri n e
pre g n
di pst i
testin
6. 4. 3
A ce n
a n y r
b l o od
g a n C o nfi de nti a
H T f or at le a
m e nt pa ge. 
 
P h
1 . 2
p atie nt will b
o ll o wi n g s ys
/car di o vasc u
hatic; a n d s k
 
V i
1 . 3
b el o w vital s
n vasi ve pr o c
P ulse rat e
f or a mi ni
3 0 sec o n d
Bl o o d pr e
mi ni m u m
b e meas ur
b l o o d pre
Te m perat u
( or wit h a
2  
P r
e will be c oll
n a nc y test).  
ic k met h o d a
n g if re q uire d
3  
L
n tral la b orato
re peat la b ora
d  c he mistry, 
a l 
ast 3 m o nt hs 
h y sic al Ex
b e e xa mi ned
ste ms:  ge ner
u lar; l u n gs; a
k i n.  T he pat
it al Sig ns 
si g ns will be
ce d ures. 
e ( beats per m
im u m of 5 m
d s (a n d m ulti
ess ure ( m m H
m  of 5 mi n ute
re d wit h a s p
ss ure measu
u re (° C/° F): 
an i nfrare d f o
reg n a nc y  
lecte d fr o m 
T he uri ne t e
at all s pecifi
d  b y t he l oca
a b or at or y
o r y (
 w
at or y tests.  B
he mat ol o g y
pri or t o st u d
x a mi n ati o n
d  b y q ualified
ral a p pearan
ab d o me n; n e
tie nt’s hei g ht
 meas ure d a
m i n ute [ b pm
m i n utes pri or
iplie d b y 2 t
H g):  t he pa t
es pri or t o m
p h y g m o ma n
u ri n g de vice)
 patie nts s ho
o re hea d t her
Testi n g  
fe males of c
est f or pre g n
e d ti me p oi n t
al i nstit uti o n
y  Pr oce d ur
w ill a nal yze 
B l o o d a n d ur
y, a n d uri naly
5 3 
d y e ntr y wil l
n  
d  me dical pe
n ce; hea d, e y
eur ol o gic; e x
t a n d wei g ht
at all patie nt 
m ]):  t he patie
r t o meas urem
o o btai n b p m
tie nt s h o ul d 
m eas ure me nt .
n o mete r ( man
). 
o ul d be seat e
rm o meter). 
chil d beari n g 
anc y will b e
ts.  Ser u m te
. 
res 
bl o o d a n d u
ri ne sa m ples
y sis. 
P
l be rec or ded
ers o n nel f or 
y es, ears, n o s
x tre mities; ba
t will be reco
visits a n d s h
ent s h o ul d b e
m e nt.  P uls e
m ). 
be resti n g i n
.  S yst olic/ di
n ual s p h y g m
e d a n d t he b
p ote ntial f o
e perf or me d 
esti n g ma y b
u ri ne s pecim
s will be o bta
P r ot oc ol 1 9 2 02
G D D- T A
d  o n t he a pp
a n y p h ysic a
se, a n d t hr oa
ac k; m usc ul
o r de d at t he 
h o ul d be rec o
e resti n g i n a
e rate is t hen
n  a seate d po
iast olic bl o o
m o ma n o met e
b o d y te m per a
r pre g na nc y
at t he site u t
b e perf or med
 
m e ns f or t his 
ai ne d f or t he
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
p r o priate s ou
al a b n or malit
at; 
os keletal; 
Scree ni n g v
o r de d pri or t
a seate d p osi
n  c o u nte d o ve
o siti o n f or a 
d press ure w
er or a ut o ma
at ure ta ke n o
y  testi n g ( urin
tilizi n g t he 
d  i nstea d of u
, 
 
st u d y; i ncl u
e a nal ysis of 
m e nt 2 
. 9 
u rce 
ty of 
v isit 
to 
iti o n 
er 
w ill 
ate d 
o rall y 
n e 
u ri ne 
di n g 
f


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
Refe r
c ollec
La b o
Alle r
la b or
e ve nt
E val u
l ocal 
6. 4. 3
He m a
( H bA
c o nce
c o u nt
b a n ds
6. 4. 3
Ser u m
as pa r
direc t
t otal 
6. 4. 3
Uri n e
estera
( W BC
6. 5  
T he f
•  
•  
•  
g a n C o nfi de nti a
r t o t he Ce nt
cti o n a n d s h
rat or y test re
rga n or its d e
rat or y res ults
ts s h o ul d be 
u ati o n a n d m
site practice
 
H
3 . 1
at ol o g y will 
A 1c), mea n c
entrati o n ( M
t, R B C m orp
s, l y m p h ocy
 
S e
3 . 2
m  c he mistry
rtate tra nsam
t bilir u bi n, g
b ilir u bi n, t ot
 
U r
3 . 3
e will be a na
ase, nitrite, p
C s, R B Cs, c
O t
foll o wi n g w i
All s u p pl i
c he mistr y
S hi p pi n g 
G o ni osc o
a l 
tral La b orato
ip me nt pr oc
es ults will be
esi g nee.  T he
s f or a n y a dv
reflecte d on
m a na ge me nt 
e. 
e m at ol o g y
be meas ure d
cor p usc ular h
M C H C), mea n
p h ol o g y, t ot a
y tes, m o n ocy
er u m C hem
 will i ncl u de
m i nase ( A S T)
g l uc ose, i n di
tal c h olester
ri n aly sis  
al yze d f or cla
p H, pr otei n, 
asts, bacteri
ther St u d y
ill be pr o vi d
ies nee de d f o
y, a n d he mato
materials f o
p y i ma gi n g 
o r y Ma n ual f
e d ures. 
e f or war de d 
e i n vesti gato
v erse e ve nts .
n  a n a d verse 
of a b n or ma l
y   
d  a n d i ncl ud
h e m o gl o bi n 
n  c or p usc ula
al w hite bl oo
y tes, bas o p hi
m istry   
e al b u mi n, al
), bicar b o nat
rect bilir u bin
rol, t otal pr o t
arit y, c ol or, b
s pecific grav
a, crystals, a
y  S u p plies
e d b y Allerg
o r ce ntral lab
o l o g y), uri ne
o r s hi p me nt o
e q ui p me nt (
5 4 
for f urt her d e
fr o m t he ce
o r or q ualifie
.  La b orat ory
e ve nt e C R F
l la b orat or y 
d es he mat oc r
( M C H), mea
ar v ol u me (M
o d cell ( W B C
ils, a n d e osin
lkali ne p h os
te, calci u m, 
n , ma g nesi u
tei n, urea ni t
b ilir u bi n, blo
v it y, ur o bilin
an d e pit heli a
s 
g a n or desi gn
b orat or y b lo
e pre g na nc y 
o f la b orat ory
(selecte d site
P
etails re gard
ntral la b ora t
ed site pers o n
y  test res ults
F  pa ge. 
res ults s h ou
rit, he m o gl ob
a n c or p usc u
M C V), plate l
C ) c o u nt a nd
n o p hils).   
sp hatase, ala n
c hl ori de, cr e
u m, p h os p h o r
tr o ge n, a n d u
o o d, gl uc os e
n o ge n, a n d m
al cells). 
n ate d s u p pli e
o o d a n d uri n e
y  test kits, an
y  sa m ples t o 
es o nl y)  
P r ot oc ol 1 9 2 02
G D D- T A
d i n g ce ntral l
tor y t o t he s t
n nel m ust r e
s t hat re prese
u l d be c o n d uc
bi n, gl ycate d
u lar he m o glo
lets, re d bl oo
d  differe ntial
n i ne tra nsam
eati ni ne, cre
ro us, p otass i
u ric aci d. 
e, ket o nes, le
m icr osc o pic 
ers: 
e sa m pli n g (
n d oc ular fl u i
ce ntral la b o
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
la b orat or y 
tu d y site a n d
evie w all 
ent a d verse 
cte d acc or di
d  he m o gl o bi
o bi n 
o d cell ( R B C
l ( ne utr o p hil
m i nase ( A LT
ati ne ki nase
iu m, s o di u m
eu k oc yte 
se di me nt 
(uri nal ysis, b
id c ollecti o n
o rat or y  
m e nt 2 
. 9 
d  t o 
in g t o 
in, 
C ) 
ls, 
T ), 
, 
m , 
b l o o d 
n  kits 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
•  As nee de d:  A S- O C T, S pec ular Micr osc o pe, c o ntact ( ultras o u n d) pac h y metr y 
e q ui p me nt, li g ht meter, ca mera a n d relate d s u p plies f or iris c ol or p h ot o gra p h y 
•  A ncillar y a d mi nistrati o n pr oce d ure s u p plie s a n d p ost o perati ve t o pical o p ht hal mic 
a nti bi otics ma y be s u p plie d 
Sites t hat are n ot a ble t o recei ve s u p plies fr o m  Aller ga n d ue t o c o u ntr y re g ulati o ns will nee d 
t o pr o vi de t heir o w n s u p plies. 
Aller ga n will n ot be pr o vi di n g a n y n o nst u d y I O P-l o weri n g me dicati o ns. 
6. 6  
S u m m ar y of Met h o ds of D at a C ollecti o n 
T his st u d y will use e C R Fs usi n g re m ote electr o nic data ca pt ure t hr o u g h a q ualifie d t hir d 
part y ve n d or.  T he data will be e ntere d o n t he e C R Fs i n a ti mel y ma n ner o n a n o n g oi n g basis.  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat  data are pr o perl y rec or de d o n eac h patie nt’s 
e C R Fs a n d relate d d oc u me nts.  A n i n vesti gat or w h o has si g ne d t he pr ot oc ol si g nat ure pa ge 
s h o ul d pers o nall y si g n f or t he case re p ort f or ms (as i n dicate d i n t he e C R Fs) t o e ns ure t hat t he 
o bser vati o ns a n d fi n di n gs are rec or de d o n t he e C R Fs c orrectl y a n d c o m pl etel y.  A certifie d 
electr o nic c o p y of t he e C R F i ncl u di n g data c o rrecti o ns will be pr o vi de d t o t he site f or 
arc hi vi n g at t he e n d of t he st u d y. 
A ce ntral la b orat or y (
will be use d f or a nal ysis of bl o o d c he mistr y a n d he mat ol o g y, uri nal ysis, a n d 
oc ular fl ui d sa m ple a nal ysis (if oc ular fl ui d is o btai ne d).  La b orat or y data will be tra nsferre d 
t o Aller ga n o n a peri o dic basis t hr o u g h o ut t he st u d y. 
7.  
St atistic al Pr oce d ures 
T hree data base l oc ks are pla n ne d.  T he first da ta base l oc k will ta ke place after all patie nts 
ha ve c o m plete d or pre mat urel y disc o nti n ue d bef ore t he Wee k 1 2 visit.  Si milarl y, t he 
data base will be l oc ke d after all patie nts ha ve c o m plete d or pre mat ur el y disc o nti n ue d bef ore 
Wee k 5 2 a n d M o nt h 2 0/ E xit.  A nal yses will be pe rf or me d aft er eac h l oc k.  Pri or t o t he first 
data base l oc k a detaile d a nal ysis pla n will be fi nalize d.  To mai ntai n t he i nte grit y of t he 
o n g oi n g st u d y, Aller ga n st u d y pers o n nel w h o ar e directl y i n v ol ve d i n data ha n dli n g a n d 
s u p p orti n g t he trial (s uc h as t he cli nical st u d y tea m) will re mai n mas ke d t o treat me nt 
assi g n me nt of i n di vi d ual patie nts d uri n g t he st u d y. To a v oi d p ote ntial data u n mas ki n g 
bet wee n l oc ks a n d t o pr otect trial i nte grit y,  st u d y statistical pers o n nel w h o ha ve bee n 
u n mas ke d after eac h l oc k will n o l o n ger be i n v ol ve d directl y i n a n y o n g oi n g mas ke d st u d y 
c o n d uct. A n ot her statisticia n, w h o is still ma s ke d t o st u d y treat me nt, will ass u me t hese 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
res p o nsi bilities u ntil t he ne xt l oc k. U n mas ke d data ha n dli n g a n d a p pr o priate data a n d res ults 
access will be s pecifie d pri or t o eac h l oc k.   
Efficac y a nal yses s pecific f or t he U S F D A ( Di visi o n of Tra ns pla nt a n d O p ht hal m ol o g y 
Pr o d ucts) re vie w are desc ri be d i n Secti o n 7. 6. 
T he details of all a nal yses will be pr o vi de d i n t he a nal ysis pla n. 
7. 1  
A n al ysis P o p ul ati o ns 
T he i nte nt-t o-treat p o p ulati o n (I T T) is defi ne d as  all ra n d o mize d patie nts a n d will be use d f or 
de m o gra p hic a n d efficac y a nal yses.  T he per pr ot oc ol ( P P) p o p ulati o n will c o nsist of t he 
s u bset of t he I T T p o p ulati o n wit h n o pr ot oc ol de viati o ns affecti n g t he pri mar y efficac y 
a nal ysis a n d will be use d t o c o nfir m t he pri mar y efficac y a nal ysis.  A list of patie nts e xcl u de d 
fr o m t he P P p o p ulati o n will be fi nalize d pri or t o data base l oc k.  T he safet y p o p ulati o n is 
defi ne d as all patie nts w h o recei ve d st u d y dr u g treat me nt a n d will be use d f or safet y 
a nal yses.  A nal yses i n t he I T T p o p ulati o n will be base d o n t he treat me nt t o w hic h a patie nt 
was ra n d o mize d, a n d a nal yses i n b ot h P P a n d safet y p o p ulati o ns will be base d o n t he act ual 
treat me nt a patie nt recei ve d. 
7. 2  
C ollecti o n a n d Deri v ati o n of Pr i m ar y a n d Sec o n d ar y Effic ac y 
Assess me nts 
T he pri mar y efficac y meas ure me nt is I O P, w hic h will be meas ure d i n eac h e ye usi n g t he 
G ol d ma n n a p pla nati o n t o n o meter.  T w o c o nsec uti ve meas ure me nts will be ta ke n f or eac h 
e ye.  If t hese 2 meas ure me nts differ b y > 1 m m H g t he n a t hir d meas ure me nt will be 
perf or me d.  If t he first 2 meas ure me nts differ b y 1 m m H g or less, or a t hir d meas ure me nt is 
re q uire d b ut o nl y 2 meas ure me nts are o btai ne d, t he n t he I O P val ue f or a gi ve n e ye is t he 
a vera ge of t he 2 meas ure me nts.  If 3 meas ure me n ts are re q uire d (ie, t he first 2 meas ure me nts 
differ b y > 1 m m H g) a n d o btai ne d, t he n t he I O P val ue f or t he gi ve n e ye is t he me dia n of t he 
3 meas ure me nts.  If, f or a n y reas o n, o nl y a si n gle meas ure me nt is o btai ne d, t he n t his 
meas ure me nt will be use d as t he I O P val ue. 
To a v oi d c o nf o u n di n g of efficac y data, I O P meas ur e me nts o btai ne d after i nitiati n g t he use of 
n o nst u d y I O P-l o weri n g me dicati o n i n a n e ye will  be e xcl u de d fr o m t he calc ulati o n of t he 
s u m mar y statistics a n d t he statistical a nal yses f or t hat e ye b ut ra w val ues will be prese nte d i n 
t he listi n gs. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
7. 2. 1  
Pri m ar y Effic ac y Vari a ble 
T he pri mar y efficac y varia ble is t he st u d y e ye ti me- matc he d I O P c ha n ge fr o m baseli ne 
(f oll o w- u p mi n us ti me- matc he d baseli ne) at eac h h o ur e val uate d ( H o urs 0 a n d 2). 
7. 2. 2  
Sec o n d ar y Effic ac y Vari a ble 
T he sec o n dar y efficac y varia ble is ti me- matc he d I O P. 
7. 3  
H y p ot hesis a n d Met h o ds of A n al ysis 
I n ge neral, c o nti n u o us varia bles will be s u m mari ze d b y descri pti ve statistics i ncl u di n g 
sa m ple size, mea n, sta n dar d de viati o n, media n, mi ni m u m, a n d ma xi m u m.  Cate g orical 
varia bles will be s u m marize d b y fre q ue nc y a n d perce nta ge. 
7. 3. 1  
Pri m ar y Effic ac y A n al yses 
T he pri mar y efficac y varia ble is t he st u d y e ye ti me- matc he d I O P c ha n ge fr o m baseli ne.  
Mea n I O P c ha n ge will be c o m pare d bet wee n eac h Bi mat o pr ost S R d ose stre n gt h a n d t he 
ti m ol ol gr o u p f or eac h h o ur ( H o urs 0 a n d 2) usi n g t he I T T p o p ulati o n.  T he c o m paris o ns at 
Wee k 1 2 will be c o nsi dere d t he pri mar y a nal ysis. 
T he n ull a n d alter nati ve h y p ot heses f or t he c o m paris o n bet wee n a gi ve n Bi mat o pr ost S R 
d ose stre n gt h a n d ti m ol ol at eac h h o ur of Wee k 1 2 are: 
•  N ull h y p ot hesis:  t he differe nce i n mea n I O P c ha n ge fr o m baseli ne bet wee n t he gi ve n 
Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol  ( Bi mat o pr ost S R mi n us ti m ol ol) is 
> 1. 5 m m H g. 
•  Alter nati ve h y p ot hesis:  t he differe nce ( B i mat o pr ost S R mi n us ti m ol ol) i n mea n I O P 
c ha n ge fr o m baseli ne bet wee n t he gi ve n Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol is 
≤ 1. 5 m m H g. 
I ntra oc ular press ure c ha n ge fr o m baseli ne will be a nal yze d usi n g a mi xe d-effects m o del 
re peate d meas ures ( M M R M) a p pr oac h.  T he m o del will i ncl u de I O P ti me- matc he d c ha n ge 
fr o m baseli ne as t he res p o nse varia ble a n d treatme nt, ti me p oi nt ( H o urs 0 a n d 2 at eac h visit 
of Wee ks 2, 6, a n d 1 2), treat me nt- b y-ti me p oi nt i n teracti o n, a n d baseli ne I O P stratificati o n as 
fi xe d effects. U nstr uct ure d c o varia nce matri x will be use d f or re peate d meas ures o n t he sa me 
patie nt; if t he m o del wit h u nstr uct ure d c o va ria nce matri x fails t o c o n ver ge, m ulti ple 
i m p utati o n ( MI) will be i m ple me nte d bef ore M M R M.  T he details of t he m o del 
s pecificati o ns will be pr o vi de d i n t he a nal ysis pla n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Wit hi n t he fra me w or k of t his m o del, t he mea n differe nce bet wee n eac h Bi mat o pr ost S R d ose 
stre n gt h a n d ti m ol ol ( Bi mat o pr ost S R mi n us ti m ol ol) a n d t he c orres p o n di n g 2-si de d 9 5 % 
c o nfi de nce i nter val will be pr o vi de d f or eac h h o ur ( H o urs 0 a n d 2) at eac h visit.  T he f or mal 
n o ni nferi orit y test will be perf or me d at Wee k 1 2 f or eac h Bi mat o pr ost S R d ose stre n gt h 
vers us ti m ol ol usi n g a n o ni nferi orit y mar gi n of  1. 5 m m H g.  A gate kee pi n g pr oce d ure will be 
use d t o c o ntr ol t he o verall t y pe I err or rate at  t he 0. 0 5 le vel f or eac h h o ur at Wee k 1 2, testi n g 
Bi mat o pr ost S R 1 5 µ g a gai nst ti m ol ol first a n d f oll o we d b y t he c o m paris o n bet wee n 
Bi mat o pr ost S R 1 0 µ g a n d ti m ol ol.  T he test of Bi mat o pr ost S R 1 0 µ g vers us ti m ol ol f or a 
gi ve n h o ur at Wee k 1 2 is vali d o nl y if t he n o ni nferi orit y of Bi mat o pr ost S R 1 5 µ g t o ti m ol ol 
is de m o nstrate d f or t he sa me ti me p oi nt.  Bi mat o pr ost S R 1 5 µ g ( or 1 0 µ g) will be declare d 
n o ni nferi or t o ti m ol ol if t he u p per li mit of t he 9 5 % c o nfi de n ce i nter val is ≤ 1. 5 m m H g f or 
b ot h H o urs 0 a n d 2 at Wee k 1 2.   
Se nsiti vit y a nal yses of ha n dli n g missi n g data wi ll be perf or me d usi n g m ulti ple i m p utati o n. 
7. 3. 2  
Sec o n d ar y Effic ac y A n al yses  
Sec o n dar y efficac y a nal yses c o m pari n g eac h Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol t o 
test t he n o- differe nce n ull h y p ot hesis will be perfor me d at sc he d ule d visits ( Wee ks 2, 6, a n d 
1 2) a n d h o urs f or ( 1) I O P a n d ( 2) ti me- matc he d I O P c ha n ge fr o m baseli ne. 
T he a nal ysis of ti me- mat c he d I O P c ha n ge fr o m baseli ne utilizes t he i de ntical m o del as t hat 
descri be d f or t he pri mar y a nal ysis i n Secti o n 7. 3. 1 wit h t he sa me 2-si de d 9 5 % c o nfi de nce 
i nter vals c o nstr ucte d at eac h h o ur a n d eac h visit f or t he mea n differe nce bet wee n eac h 
Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol ( Bi m at o pr ost S R mi n us ti m ol ol).  A n u p per 9 5 % 
c o nfi de nce li mit of t he mea n differe nce t hat is  less t ha n zer o c orresp o n ds t o a si g nifica nt 
differe nce i n fa v or of t he gi ve n Bi mat o pr ost S R d ose stre n gt h f or t he gi ve n ti me p oi nt. 
Eac h Bi mat o pr ost S R d ose stre n gt h t hat de m o nstrates t he f oll o wi n g at all sc he d ule d 
ti me p oi nts wit hi n t he 1 2- wee k peri o d (at H o urs 0 a n d 2 at Wee ks 2, 6, a n d 1 2) will be 
c o nsi dere d s u peri or t o ti m ol ol: 
•  T he u p per 9 5 % c o nfi de nce li mit of t he mea n differe nce is less t ha n zer o (ie, a 
si g nifica nt differe nce i n fa v or of t he gi ve n Bi mat o pr ost S R d ose stre n gt h) 
T he a nal ysis of I O P will be si milarl y perf or me d as descri be d a b o ve wit h I O P re placi n g ti me-
matc he d I O P c ha n ge fr o m baseli ne i n t he a nal ysis m o del. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
5 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 
7. 3. 4  
S afet y A n al yses 
T he Me dical Dicti o nar y f or Re g ulat or y Acti vitie s ( Me d D R A) n o me nclat ure will be use d t o 
c o de a d verse e ve nts.  A d verse e ve nts will be c o de d fr o m t he ver bati m te xt i nt o preferre d ter m 
a n d s yste m or ga n class ( S O C).  T he n u m ber  a n d perce nt of patie nts re p orti n g treat me nt 
e mer ge nt a d verse e ve nts will be ta b ulate d base d o n t he pri mar y S O C a n d preferre d ter ms.  
S u m mar y ta bles will be ge nerate d f or all a d vers e e ve nts re gar dless of ca usalit y as well as 
treat me nt-relate d a d verse e ve nts f or t he e ntire st u d y a n d b y treat me nt c ycle. 
Ot her safet y varia bles i ncl u de vital si g ns ( bl o o d press ure, p ulse  rate, a n d te m perat ure) a n d 
pre g na nc y test res ults.  
 
 
  
7. 4  
S u b gr o u p A n al yses 
S u b gr o u p a nal yses f or t he pri mar y varia ble will be perf or me d  
7. 5  
I nteri m A n al yses 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y.  Eac h data base l oc k will c orres p o n d t o a 
milest o ne a n d statistical a nal ysis w he n all ra n d o mize d patie nts ha ve eit her c o m plete d or 
e xite d fr o m t he tar gete d visit. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
6 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
7. 6  
A n al yses f or U S F D A  
Pri m ary Effic acy A n alyses 
F or t he U S F D A re vie w, t he pri mar y efficac y varia ble will be t he st u d y e ye I O P.  T he 
pri mar y a nal ysis will be base d o n Wee ks 2, 6, a n d 1 2 usi n g t he I T T p o p ulati o n.  Mea n I O P 
will be c o m pare d bet wee n eac h Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol f or eac h h o ur 
( H o urs 0 a n d 2) at Wee ks 2, 6, a n d 1 2. 
T he n ull a n d alter nati ve h y p ot heses f or t he c o m paris o n bet wee n a gi ve n Bi mat o pr ost S R 
d ose stre n gt h a n d ti m ol ol f or eac h h o ur at eac h visit are: 
•  T he n ull h y p ot hesis is t hat t he differe nce i n  mea n I O P bet wee n t he gi ve n Bi mat o pr ost 
S R d ose stre n gt h a n d ti m ol ol ( Bi mat o pr ost S R mi n us ti m ol ol) is > 1. 5 m m H g. 
•  T he alter nati ve h y p ot hesis is t hat t he diff ere nce ( Bi mat o pr ost S R mi n us ti m ol ol) i n 
mea n I O P bet wee n t he gi ve n Bi mat o pr os t S R d ose stre n gt h a n d ti m ol ol is 
≤ 1. 5 m m H g. 
I O P will be a nal yze d usi n g a n M M R M a p pr oac h base d o n t he sa me m o del as descri be d i n 
Secti o n 7. 3. 1.  Wit hi n t he fra me w or k of t his m o del, t he mea n differe nce bet wee n eac h 
Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol a n d t he c orres p o n di n g 2-si de d 9 5 % c o nfi de nce 
i nter val will be pr o vi de d f or eac h h o ur ( H o urs 0 an d 2) a n d eac h visit ( Wee ks 2, 6, a n d 1 2).  
A gate kee pi n g pr oce d ure will be use d t o c o ntr ol t he o verall t y pe I err or rate at t he 0. 0 5 le vel 
at eac h ti me p oi nt, testi n g Bi mat o pr ost S R 1 5 µ g a gai nst ti m ol ol first a n d f oll o we d b y t he 
c o m paris o n bet wee n Bi mat o pr ost S R 1 0 µ g a n d ti m ol ol.  T he test f or Bi mat o pr ost S R 1 0 µ g 
vers us ti m ol ol f or a gi ve n h o ur at a visit is vali d  o nl y if t he n o ni nferi orit y of Bi mat o pr ost S R 
1 5 µ g t o ti m ol ol has bee n de m o nstrate d f or t he gi ve n ti me p oi nt. 
Eac h Bi mat o pr ost S R d ose stre n gt h t hat s h o ws n o ni nferi orit y t o ti m ol ol at all 6 ti me p oi nts 
wit h a 1. 5 m m H g mar gi n (ie, t he u p per li mit of t he 9 5 % c o nfi de nce i nter val is ≤ 1. 5 m m H g) 
will be declare d cli nicall y n o ni nferi or t o ti m ol ol if t he u p per li mit of t he 9 5 % c o nfi de nce 
i nter val is ≤ 1. 0 m m H g f or 3 or m ore ti me p oi nts. 
Se nsiti vit y a nal yses of ha n dli n g missi n g data wi ll be perf or me d usi n g m ulti ple i m p utati o n. 
Sec o n d ary Effic acy A n alyses 
F or eac h Bi mat o pr ost S R d ose stre n gt h w hic h de m o nstrates efficac y (cli nical n o ni nferi orit y) 
as descri be d i n t he pri mar y efficac y a nal yses, sec o n dar y efficac y a nal yses c o m pari n g t he 
Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol t o test t he n o- differe nce n ull h y p ot hesis will be 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
6 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
perf or me d at sc he d ule d visits ( Wee ks 2, 6,  a n d 1 2) a n d h o urs f or I O P.  A gate kee pi n g 
pr oce d ure will be use d t o c o ntr ol t he o verall t y pe I err or rate at t he 0. 0 5 le vel wit hi n eac h 
d ose stre n gt h; t he s pecific se q ue nce of t he te sts will be pr o vi de d i n t he a nal ysis pla n. 
7. 7  
S a m ple Size C alc ul ati o n 
T he sa m ple size calc ulati o n is base d o n t he pri m ar y efficac y a nal ysis of t he I O P f or U S F D A 
re vie w si nce t he sa m ple size base d o n t he pri mar y efficac y a nal ysis f or ot her re gi o ns is 
e x pecte d t o be s maller. 
T he sa m ple size is esti mate d base d o n a 2-si de d t-test wit h α  = 0. 0 5 at eac h ti me p oi nt a n d t he 
ass u m pti o n t hat t he mea n I O P differe nce bet wee n Bi mat o pr ost S R 1 0 µ g a n d ti m ol ol 
is - 0. 2 5 m m H g (ie, Bi mat o pr ost S R 1 0 µ g is 0. 2 5 m m H g better i n I O P-l o weri n g t ha n 
ti m ol ol) at Wee ks 2 a n d 6 a n d 0 m m H g at Wee k 1 2, wit h a c o m m o n sta n dar d de viati o n of 
4. 0 m m H g a n d a c o m m o n wit hi n-s u bject c orrela ti o n of 0. 6.  It is als o ass u me d t hat t he 
efficac y (I O P-l o weri n g effect) of Bi mat o pr ost S R 1 5 µ g is better t ha n t hat of Bi mat o pr ost S R 
1 0 µ g b y 0. 2 5 m m H g at eac h ti me p oi nt ( H o urs 0 a n d 2).  T hese ass u m pti o ns are base d o n 
t he data o btai ne d fr o m t he o n g oi n g cli nical st u d y 1 9 2 0 2 4- 0 4 1 D.  Base d o n si m ulati o ns, a 
sa m ple size of 5 4 0 patie nts ( 1 8 0 per gr o u p) will pr o vi de a p pr o xi matel y 9 5 % a n d 8 1 % p o wer 
t o s h o w n o ni nferi orit y ( NI) of Bi mat o pr ost S R 1 5 µ g a n d Bi mat o pr ost S R 1 0 µ g, 
res pecti vel y, t o ti m ol ol at all 6 sc he d ule d ti mep oi nts base d o n a n NI mar gi n of 1. 5 m m H g 
a n d at 3 or m ore ti me p oi nts base d o n a n NI  mar gi n of 1. 0 m m H g.  Ass u mi n g a pre mat ure 
disc o nti n uati o n rate of 1 0 % wit hi n 1 2 wee ks ( b ef ore pri mar y data base l oc k), a p pr o xi matel y 
6 0 0 patie nts ( 2 0 0 per gr o u p) are t o be e nr olle d i nt o t his st u d y. 
8.  
St u d y Visit Sc he d ule a n d Pr oce d ures 
Patie nts w h o c o m plete t he e ntire st u d y wit h o ut recei vi n g n o nst u d y I O P-l o weri n g me dicati o n 
will ha ve a mi ni m u m of 2 5 visits a n d 6 p h o ne ca lls.  
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
6 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 
 
8. 1  
P atie nt E ntr y Pr oce d ures  
8. 1. 1  
O ver vie w of E ntr y Pr oce d ures 
Pr os pecti ve patie nts as defi ne d b y t he criteria i n Secti o ns 4. 3 a n d 4. 4 (i ncl usi o n/e xcl usi o n 
criteria) will be c o nsi dere d f or e ntr y i nt o t his st u d y.   
8. 1. 2  
I nf or me d C o nse nt a n d P atie nt Pri v ac y 
T he st u d y will be disc usse d wit h t he patie nt a n d a patie nt wis hi n g t o partici pate m ust gi ve 
i nf or me d c o nse nt pri or t o a n y st u d y-relate d pr oced ures or c ha n ge i n treat me nt.  T he patie nt 
m ust als o gi ve a ut h orizati o n ( U S o nl y), data  pr otecti o n c o nse nt ( E ur o pe o nl y), a n d ot her 
writte n d oc u me ntati o n i n acc or da nce wit h t h e rele va nt c o u ntr y a n d l ocal pri vac y 
re q uire me nts ( w here a p plica ble) pri or t o a n y st u dy-relate d pr oce d ures or c ha n ge i n treat me nt. 
Eac h patie nt w h o pr o vi des i nf or me d c o nse nt wi ll be assi g ne d a s u bject n u m ber t hat will be 
use d o n patie nt d oc u me ntati o n t hr o u g h o ut t he st u d y. 
8. 2  
Was h o ut I nter v als 
All patie nts m ust pr o vi de i nf or me d c o nse nt pri or t o be gi n ni n g a n y dr u g was h o ut f or t he 
p ur p oses of i ncl usi o n i n t his st u d y.  Patie nt s c urre ntl y bei n g treate d wit h I O P-l o weri n g 
me dicati o n(s) i n eit her e ye will be gi n was h o ut of t hese me dicati o n(s) f oll o wi n g c o m pleti o n 
of t he scree ni n g pr oce d ures.  T he Scree ni n g a n d Was h o ut peri o ds ma y n ot be c o nc urre nt.  
T he Was h o ut peri o d will be u p t o 4 2 da ys  de pe n di n g o n t he mi ni m u m was h o ut peri o d 
sc he d ule bel o w. 
If patie nts ca n n ot disc o nti n ue t heir prescri be d t hera p y f or u p t o 6 wee ks t o meet t he was h o ut 
peri o d f or st u d y e ntr y, t he i n vesti gat or ma y s witc h t he patie nt’s me dicati o n t o o ne t hat 
re q uires a s h orter was h o ut i nter val d uri n g t he was h o ut of t he ori gi nal me dicati o n ( Ta ble 8).  
N o net heless, t he i n vesti gat or s h o ul d a d he re t o t he mi ni m u m was h o ut peri o d f or all 
I O P-l o weri n g me dicati o ns as i n dicate d i n Ta ble 8. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
6 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
If, after i nitial was h o ut, t he I O P d oes n ot meet e ntr y criteria a n d t he i n vesti gat or belie ves t his 
is d ue t o i na de q uate was h o ut, if ti me re mai ns i n t he Was h o ut peri o d, he/s he ma y perf or m 
a d diti o nal was h o ut, as l o n g as t he t otal Was h o ut peri o d d oes n ot e xcee d 4 2 da ys. 
F or patie nts u n der g oi n g a was h o ut, i nteri m safet y e val uati o n(s) of I O P at s o me ti me d uri n g 
t he was h o ut peri o d ma y be perf or me d at t he discreti o n of t he i n vesti gat or. 
N ote:  Me dicati o ns s h o ul d o nl y be disc o nti n ue d ( was he d o ut) if t he i n vesti gat or feels t hat it 
is safe a n d a p pr o priate, a n d if t he patie nt is willi n g t o disc o nti n ue t he me dicati o n f or t he 
d urati o n of t he st u d y.  If t he me dicati o n ca n n ot be disc o nti n ue d, t he n t he patie nt will n ot be 
eli gi ble f or st u d y e ntr y. 
8. 3  
Pr oce d ures f or Fi n al St u d y E ntr y 
T he res ults fr o m t he scree ni n g oc ular a n d p h ysical e xa mi nati o ns, a n d la b orat or y tests 
( he mat ol o g y/ bl o o d c he mistr y/ uri nal ysis) m ust be e val uate d a n d deter mi ne d t o be acce pta ble 
t o t he i n vesti gat or pri or t o t he patie nt’s e ntr y i nt o t he st u d y.  If re peat la b orat or y tests are 
d o ne, t he res ults m ust be re vie we d pri or t o st u d y treat me nt i nitiati o n o n Da y 1.  Rea di n g 
Ce nter q ualificati o n of e n d ot helial cell de nsit y m ust be c o nfir me d b y t he Baseli ne visit.  
After c o nfir mati o n of eli gi bilit y o n Da y 1, I V/ W R S is c o ntacte d f or ra n d o mizati o n.  
H o we ver, t his c o ntact f or ra n d o mizati o n ma y ta ke place at t he e n d of t he Baseli ne visit if 
nee de d.  See Secti o n 5. 5 f or t he met h o d f or assi g n me nt t o treat me nt gr o u ps/ra n d o mizati o n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
6 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
A patie nt is c o nsi dere d t o ha ve e nr olle d i n t he st u d y at t he ti me of t he first st u d y treat me nt 
a d mi nistrati o n ( or S ha m). 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
6 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
6 6 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
6 7 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
6 8 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
6 9 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 0 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 1 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 2 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 3 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 4 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 5 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 6 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 7 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 8 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
7 9 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
8 0 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller g
 
 
 
g a n C o nfi de nti a l 
8 1 
P r ot oc ol 1 9 2 02
G D D- T A
2 4- 0 9 1 A me n d m
A - T- 0 0 4 v 2 0 1 3
m e nt 2 
. 9 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
8. 5  
I nstr ucti o ns f or t he P atie nts 
Patie nts s h o ul d be i nstr ucte d t o strictl y f oll o w t he st u d y visit sc he d ule a n d t o re p ort all 
c ha n ges i n t heir c o n diti o n t o t he i n vesti gati ve site. 
I nstr ucti o n s h o ul d be gi ve n t o t he patie nt t o mai ntai n a sta ble d ose of a n y c o nc o mita nt 
me dicati o n use d c hr o nicall y, or a n y ne w me di cati o ns i nitiate d d uri n g t he st u d y w he ne ver 
p ossi ble.  Patie nts s h o ul d be i nstr ucte d t o c o m m u nicate a n y c ha n ges t o t heir me dicati o n at 
t heir ne xt st u d y visit.  Patie nts s h o ul d als o be re mi n de d t o c o ntact t he st u d y site if t he y are 
e x perie nci n g a n y diffic ulties d uri n g t heir st u d y partici pati o n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Patie nts s h o ul d kee p t he st u d y me dicati o n b ottles  i n t he ori gi nal kit t hat was pr o vi de d a n d 
ret ur n t he b ottles t o t he desi g nate d ( u n mas ke d) site staff.  Patie nts s h o ul d be i nstr ucte d t hat 
b ottles of pr o vi de d me dicati o ns s h o ul d o nl y be use d f or 2 8 da ys eac h. 
Patie nts will be i nstr ucte d n ot t o a d mi nister  t he st u d y- pr o vi de d e ye dr o ps t he m or ni n g of 
st u d y visits (e xce pt A d mi nistrati o n Da y visits) a n d t o bri n g t heir st u d y me dicati o ns t o t heir 
visit f or i nstillati o n i m me diat el y after t he H o ur 0 I O P meas ure me nts.  Site pers o n nel a n d 
patie nts will be re mi n de d t o ta ke a p pr o pr iate ca uti o n d uri n g a d mi nistrati o n of st u d y 
me dicati o ns d uri n g t he visit t o e ns ure mai nte na nce of mas ki n g.  Patie nts s h o ul d i nstill t heir 
m or ni n g d ose of st u d y- pr o vi de d e ye dr o ps o n t h e da y of t he A d mi nistrati o n Da y visits. 
Patie nts s h o ul d be i nstr ucte d t o re m o ve t heir c o ntact le nses bef ore i nstillati o n of a n y t o pical 
o p ht hal mic me dicati o n, a n d t o kee p c o ntact le nses  o ut f or at least 1 5 min utes after i nstillati o n 
of e ye dr o ps. 
8. 6  
U nsc he d ule d Visits 
A d diti o nal e xa mi nati o ns ma y be perf or me d as necessar y t o e ns ure t he safet y a n d well bei n g 
of patie nts d uri n g t he st u d y peri o d.  U nsc he d ul e d visit e C R Fs s h o ul d be c o m plete d f or eac h 
u nsc he d ule d visit.  A n assess me nt of a n y a d verse e ve nt s h o u l d be c o m plete d. 
8. 7  
C o m pli a nce wit h Pr ot oc ol 
Patie nts m ust be a ble t o a d here t o t he st u d y vi sit sc he d ule; a p pr o priate i ncl usi o n, e xcl usi o n, 
a n d treat me nt criteria; per mitte d a n d pr o hi bite d me dicati o n criteria; a n d testi n g para meters as 
descri be d i n t he pr ot oc ol.  At eac h st u d y visit, patie nts will be as ke d if t he y ha ve use d t heir 
st u d y- pr o vi de d e ye dr o ps as i nstr ucte d a n d w het her t he y ha ve use d a n y c o nc o mita nt 
me dicati o ns/t hera pies or ha d a n y c o nc urre nt pr oce d ures si nce t he pre vi o us visit. 
Patie nts s h o ul d be sc he d ule d f or st u d y visits as cl osel y t o t he da y s pecifie d i n t he visit 
sc he d ule as p ossi ble. 
8. 8  
E arl y Disc o nti n u ati o n of P atie nts 
Patie nts ma y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me. 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o weri n g me dicati o n i n o nl y o ne e ye will be 
f oll o we d f or t he d urati o n of t he st u d y t hr o u g h t he M o nt h 2 0 visit. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o we ri n g me dicati o n i n b ot h e yes, or w h o d o n ot 
c o m plete a n A d mi nistrati o n Da y visit, ma y di sc o nti n ue t he st u d y 1 2 mo nt hs after t he last 
Bi mat o pr ost S R or S ha m a d mi nistrati o n at w hic h ti me t he y s h o ul d c o m plete t he 
M o nt h 2 0/ E xit visit pr oce d ures. 
N otificati o n of earl y patie nt disc o nti n uati o n fr o m t he st u d y a n d t he reas o n f or disc o nti n uati o n 
will be ma de t o t he s p o ns or a n d will be clearl y d oc u me nte d o n t he a p pr o priate e C R F. 
W he n patie nts e xit bef ore M o nt h 2 0, t he site  s h o ul d c o m plete all pr oce d ures f or t he 
M o nt h 2 0/ E xit visit at t he patie nt’s last visit. 
8. 9  
Wit h dr a w al Criteri a 
After t he first a d mi nistrati o n ( or S ha m), fail ure  t o u n der g o a n A d mi nistrati o n Da y visit d oes 
n ot i n dicate t otal wit h dra wal fr o m t he st u d y .  Patie nts w h o ha ve recei ve d n o nst u d y 
I O P-l o weri n g me dicati o n i n o nl y o ne e ye will c onti n ue t hr o u g h t he d urati o n of t he st u d y.  
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o weri n g me dicati o n i n b ot h e yes, or patie nts w h o 
d o n ot u n der g o C ycle 2 or 3 ( or b ot h) A d mi ni strati o n Visits, will still be f oll o we d f or 
1 2 m o nt hs after t he last Bi mat o pr ost S R or S h a m a d mi nistrati o n f or safet y reas o ns.  T hese 
patie nts are eli gi ble f or Earl y Di sc o nti n uati o n ( Earl y E xit) as descri be d i n Secti o n 8. 8, a b o ve.  
T he i n vesti gat or s h o ul d c o nsi d er wit h dra wi n g a patie nt fr o m t he st u d y earl y if a n y of t he 
f oll o wi n g criteria are met: 
•  Patie nt de vel o ps ( or has a n e xacer bati o n of) a me dical c o n diti o n t hat, i n t he o pi ni o n 
of t he i n vesti gat or, c o m pr o mises t he patie nt’s a bilit y t o par tici pate i n t he st u d y 
•  Patie nt de vel o ps ( or has a n e xacer bati o n of) a me dical c o n diti o n t hat, i n t he o pi ni o n 
of t he i n vesti gat or, c o m pr o mises t he patie nt’s a bilit y t o par tici pate i n t he st u d y 
•  Patie nt is u n willi n g or u na ble t o c o nti n ue t o c o m pl y wit h st u d y pr oce d ures 
•  Patie nt is u n willi n g or u na ble t o c o nti n ue i n t he st u d y 
If a patie nt de vel o ps ( or has a n e xacer bati o n of) a me dical c o n diti o n t h at, i n t he o pi ni o n of 
t he i n vesti gat or, w o ul d p ut t he patie nt at a n u nacce pta ble me dical ris k b y c o nti n ui n g st u d y 
partici pati o n, t he patie nt will be wit h dra w n fr o m t he st u d y. 
W he ne ver p ossi ble, t he decisi o n t o wit h dra w  a patie nt fr o m t he st u d y or st u d y treat me nt 
s h o ul d be disc usse d wit h Aller ga n. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
8. 1 0  
St u d y Ter mi n ati o n 
T he st u d y ma y be st o p pe d at his/ he r st u d y site at a n y ti me b y t he site i n vesti gat or.  Aller ga n 
ma y st o p t he st u d y (a n d/ or t he st u d y site) f or a n y reas o n wit h a p pr o priate n otificati o n. 
9.  
A d verse E ve nts  
A d verse e ve nts occ urri n g d uri n g t he st u d y will be rec or de d o n a n a d verse e ve nt e C R F.  If 
a d verse e ve nts occ ur, t he first c o ncer n w ill be t he safet y of t he st u d y partici pa nts. 
9. 1  
Defi niti o ns 
9. 1. 1  
A d verse E ve nt 
A n a d verse e ve nt is a n y u nt o war d me dical occ urr e nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he 
me dici nal (i n vesti gati o nal) pr o d uct.  I n a d diti o n, d uri n g t he scree ni n g peri o d, a d verse e ve nts 
will be assesse d re gar dless of t he a d mi nistrati o n of a p har mace utical pr o d uct. 
N ote:  A d verse e ve nts m ust be c ollecte d o nce i n f or me d c o nse nt has bee n o btai ne d, re gar dless 
of w het her or n ot t he patie nt ha s bee n a d mi nistere d st u d y dr u g. 
Pr o gressi o n of treat me nt i n dicati o n i ncl u di n g ne w or w orse ni n g of  a ntici pate d cli nical si g ns 
or s y m pt o ms, w hic h are c ollecte d as cli nical efficac y varia bles a n d assesse d as u ne q ui v ocall y 
ass ociate d wit h t he disease pr o gressi o n a n d / o r lac k of efficac y, s h o ul d N O T be re p orte d as 
a d verse e ve nts u nless t he disease pr o gressi o n is greater t ha n a ntic i pate d i n t he nat ural c o urse 
of t he disease. 
A d verse e ve nts will be assesse d, d oc u me nte d, a n d rec or de d i n t he C R F t hr o u g h o ut t he st u d y 
(ie, after i nf or me d c o nse nt has bee n o btai ne d).  At eac h visit, t he i n vesti gat or will be gi n b y 
q uer yi n g f or a d verse e ve nts b y as ki n g eac h pati e nt a ge neral, n o n directe d q uesti o n s uc h as 
“ H o w ha ve y o u bee n feeli n g si nce t he last visit?”  Directe d q uesti o ni n g a n d e xa mi nati o n will 
t he n be d o ne as a p pr o priate.  All re p orte d a d verse e ve nts will be d oc u me nte d o n t he 
a p pr o priate case re p ort f or m. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
9. 1. 2  
Seri o us A d verse E ve nt 
A seri o us a d verse e ve nt is a n y a d verse e ve nt oc c urri n g at a n y d ose t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes:  deat h, a life-t hreate ni n g a d verse e ve nt, i n patie nt h os pitalizati o n or 
pr ol o n gati o n of e xisti n g h os pitalizat i o n, a persiste nt or si g nifica nt disa bilit y/i nca pacit y, or a 
c o n ge nital a n o mal y/ birt h defect.  I m p orta nt me di cal e ve nts t hat ma y n ot res ult i n deat h, be 
life-t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d a seri o us a d verse e ve nt w he n, 
base d u p o n a p pr o priate me dical j u d g me nt, t he y  ma y je o par dize t he patie nt or s u bject a n d 
ma y re q uire me dical or s ur gical i nter ve nti o n t o  pre ve nt o ne of t he o utc o mes liste d i n t his 
defi niti o n.  ( See Secti o n 9. 3 f or pr oce d ur es f or re p orti n g a seri o us a d verse e ve nt.) 
Aller ga n c o nsi ders all ca ncer a d verse e ve nts as seri o us a d verse e ve nts.  I n a d diti o n, Aller ga n 
c o nsi ders a n y a b orti o n (s p o nta ne o us or n o ns p o nta ne o us) as a seri o us a d verse e ve nt. 
Pre pla n ne d s ur geries or pr oce d ures f or pre- e xisti n g, k n o w n me dical c o n diti o ns f or w hic h a 
patie nt re q uires h os pitaliza ti o n is n ot re p orta ble as a seri o us a d verse e ve nt. 
A n y pre pla n ne d s ur ger y or pr oce d ure s h o ul d be clearl y d oc u me nte d i n t he site s o urce 
d oc u me nts b y t he me dicall y q ualifie d i n vesti gat or at t he ti me of t he patie nt’s e ntr y i nt o t he 
st u d y.  If it has n ot bee n d oc u me nte d at t he ti me of t he patie nt’s e ntr y i nt o t he st u d y, t he n it 
s h o ul d be d oc u me nte d as a seri o us a dverse e ve nt a n d re p orte d t o Aller ga n. 
9. 1. 3  
Se verit y 
A cli nical deter mi nati o n will be ma de of t he i nte nsit y of a n a d verse e ve nt.  T he se verit y 
assess me nt f or a cli nical a d verse e ve nt m ust be  c o m plete d usi n g t he f oll o wi n g defi niti o ns as 
g ui deli nes: 
Mil d 
A ware ness of si g n or s y m pt o m, b ut easil y t olerate d. 
M o derate  
Disc o mf ort e n o u g h t o ca use i nterfere nce wit h us ual acti vit y. 
Se vere  
I nca pacitati n g wit h i na bilit y t o w or k or d o us ual acti vit y. 
N ot a p plica ble  
I n s o me cases, a n a d vers e e ve nt ma y be a n ‘all or n ot hi n g’ fi n di n g 
w hic h ca n n ot be gra de d. 
 
9. 1. 4  
Rel ati o ns hi p t o St u d y Dr u g or St u d y Pr oce d ure 
A deter mi nati o n will be ma de of t he relati o ns hi p (if a n y) bet wee n a n a d verse e ve nt a n d t he 
st u d y dr u g or st u d y pr oce d ure, as a p plica ble.  A ca usal relati o ns hi p is prese nt if a 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
deter mi nati o n is ma de t hat t here is a reas o na bl e p ossi bilit y t hat t he a d verse e ve nt ma y ha ve 
bee n ca use d b y t he dr u g or st u d y pr oce d ure. 
If a n a d verse e ve nt is dee me d relate d t o stu d y treat me nt, t he i n vesti gat or will be as ke d t o 
f urt her deli neate w het her t he a d verse e ve nt was relate d t o t he a d mi nistrati o n pr oce d ure 
( vers us t he st u d y me dicati o n). 
N ote:  A st u d y pr oce d ure occ urri n g d uri n g t h e Scree ni n g/ Baseli ne peri o d ca n i ncl u de a 
was h o ut of me dicati o n or i ntr o d ucti o n of a r u n-i n me dicati o n or st u d y re q uire d dia g n ostic 
pr oce d ure. 
9. 2  
Pr oce d ures f or Re p orti n g A d verse E ve nts 
A n y a d verse e ve nt m ust be rec or de d o n t he a p pr o priate case re p ort f or m. 
All a d verse e ve nts t hat are dr u g- relate d a n d u ne x pecte d ( n ot liste d as treat me nt-relate d i n t he 
c urre nt I n vesti gat or's Br oc h ure) m ust be re p orte d t o t he g o ver ni n g I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee (I R B/I E C) as re q uire d b y t he I R B/I E C, l ocal 
re g ulati o ns, a n d t he g o ver ni n g healt h a ut h orities.  A n y a d ve rse e ve nt t hat is mar ke d 
“ o n g oi n g” at t he e xit visit m ust be f oll o we d u p as a p pr o priate. 
9. 3  
Pr oce d ures f or Re p orti n g a Seri o us A d verse E ve nt 
A n y seri o us a d verse e ve nt occ urri n g d uri n g t he st u d y peri o d ( be gi n ni n g wit h i nf or me d 
c o nse nt) a n d f or at least 4 m o nt hs  after t he last d ose of st u d y dr u g m ust be i m me diatel y 
re p orte d b ut n o later t ha n 2 4 h o urs after lear ni n g of a seri o us a d ve rse e ve nt.  Seri o us a d verse 
e ve nts m ust be re p orte d t o Aller ga n ( or A ge n t of Aller ga n) as listed o n t he Aller ga n St u d y 
C o ntacts Pa ge a n d rec or de d o n t he seri o us a d verse e ve nt f or m.  All patie nts wit h a seri o us 
a d verse e ve nt m ust be f oll o we d u p a n d t he o utc o mes re p orte d.  T he i n vesti gat or m ust s u p pl y 
t he s p o ns or a n d t he I R B/I E C wit h a n y a d diti o nal re q ueste d i nf or mati o n (e g, a ut o ps y re p orts 
a n d disc har ge s u m maries). 
I n t he e ve nt of a seri o us a d verse e ve nt, t he i n vesti gat or m ust: 
1.  N otif y Aller ga n i m me di atel y b y fa x or e m ail usi n g t he seri o us a d verse e ve nt f or m 
(c o ntact details ca n be f o u n d o n pa ge 1 of t he seri o us a d verse e ve nt f or m); p h o ne 
n u m bers a n d rele va nt Aller ga n pers o n nel c o ntacts  are als o o n t he fr o nt pa ge of pr ot oc ol. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
2.  O btai n a n d mai ntai n i n his/ her files all pe rti ne nt me dical rec or ds, i nf or mati o n, a n d 
me dical j u d g me nts fr o m c ollea g ues w h o assist e d i n t he treat me nt a n d f oll o w- u p of t he 
patie nt. 
3.  Pr o vi de Aller ga n wit h a c o m plete, writte n descri pti o n of t he a d verse e ve nt(s) o n t he 
seri o us a d verse e ve nt f or m descri bi n g t he e ve nt c hr o n ol o gicall y, i ncl u di n g a n y treat me nt 
gi ve n (e g, me dicati o ns a d mi nistere d, pr oce d ur es perf or me d) f or t he a d verse e ve nt(s).  
S u m marize rele va nt cli nical i nf or mati o n a b o u t t he e ve nt:  si g ns, s y m pt o ms, dia g n osis, 
cli nical c o urse a n d rele va nt cli nical la b orat or y tests, etc.   I ncl u de a n y a d diti o nal or 
alter nati ve e x pla nati o n(s) f or t he ca usalit y w hic h i ncl u des a state me nt as t o w het her t he 
e ve nt was or was n ot relate d t o t h e use of t he i n vesti gati o nal dr u g. 
4.  Pr o m ptl y i nf or m t he g o ver ni n g I R B/I E C of t h e seri o us a d verse e ve n t as re q uire d b y t he 
I R B/I E C, l ocal re g ulati o ns, a n d t he g o ver ni n g healt h  a ut h orities. 
9. 4  
Pr oce d ures f or U n m as ki n g of St u d y Me dic ati o n 
W he n necessar y f or t he safet y a n d pr o per trea t me nt of t he patie nt, t he i n vesti gat or ca n 
u n mas k t he patie nt’s treat me nt assi g n me nt t o deter mi ne w hic h treat me nt has bee n assi g ne d 
a n d i nstit ute a p pr o priate f oll o w- u p care.  W h e n p ossi ble, t he s p o ns or ( Aller ga n Me dical 
Safet y P h ysicia n) s h o ul d be n otifie d pri or t o  u n mas ki n g st u d y me dicati o n.  T he i n vesti gat or 
s h o ul d i nf or m t he s p o ns or ( Aller ga n Me dical Safet y P h ysicia n) of t he u n mas ki n g if t here is 
n o n otificati o n pri or t o t he u n mas ki n g. 
T he treat me nt assi g n me nt f or t he patie nt ca n be deter mi ne d b y desi g nate d site pers o n nel 
calli n g i nt o t he I V R S or I W R S s yste m via pass w or d pr otecte d access.  T he reas o n f or 
brea ki n g t he c o de m ust be rec or de d i n t he patie nt’s s o urce d oc u me nts. 
1 0.  
A d mi nistr ati ve Ite ms 
T his pr ot oc ol is t o be c o n d ucte d i n acc or d a nce wit h t he a p plica ble  G o o d Cli nical Practice 
( G C P) re g ulati o ns a n d g ui deli nes, e g, t he I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
G ui deli ne o n G C P. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
8 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 0. 1  
Pr otecti o n of H u m a n S u bjects 
1 0. 1. 1  
C o m pli a nce wit h I nf or me d C o nse nt Re g ul ati o ns ( U S 2 1 C F R 
P art 5 0) a n d Rele v a nt C o u ntr y Re g ul ati o ns 
Writte n i nf or me d c o nse nt is t o be o btai ne d fr o m eac h patie nt pri or t o a n y st u d y-relate d 
acti vities or pr oce d ures i n t he st u d y, a n d/ or fr o m t he patie nt's le gall y a ut h orize d 
re prese ntati ve.  If t he patie nt is u n der t he legal a ge of c o nse nt, t he c o nse nt f or m m ust be 
si g ne d b y t he le gall y a ut h orize d re prese ntati ve i n acc or da nce wit h t he rele va nt c o u ntr y a n d 
l ocal re g ulat or y re q uire me nts. 
T here are s pecial sit uati o ns i n w hic h oral i nf or me d c o nse nt ma y be ta ke n.  A p pr o val t o utilize 
oral c o nse nt pr oce d ures a n d i n str ucti o ns o n h o w t o pr o perl y o btai n oral i nf or me d c o nse nt 
m ust be o btai ne d fr o m Aller ga n pers o n nel. 
1 0. 1. 2  
C o m pli a nce Wit h I R B or I E C Re g ul ati o ns 
T his st u d y is t o be c o n d ucte d i n acc or da nce wit h I R B re g ulati o ns ( U S 2 1 C F R Part 5 6. 1 0 3) 
or a p plica ble I E C re g ulati o ns.  T he i n ves ti gat or m ust o btai n ap pr o val fr o m a pr o perl y 
c o nstit ute d I R B/I E C pri or t o i nit iati n g t he st u d y a n d rea p pr o val or re vie w at least a n n uall y.  
Aller ga n is t o be n otifie d i m me diatel y if t he re s p o nsi ble I R B/I E C has bee n dis q ualifie d or if 
pr ocee di n gs lea di n g t o dis q ualificati o n ha ve be g u n.  C o pies of all I R B/I E C c orres p o n de nce 
wit h t he i n vesti gat or s h o ul d be pr o vi de d t o Aller ga n. 
1 0. 1. 3  
C o m pli a nce Wit h G o o d Cli nic al Pr actice 
T his pr ot oc ol is t o be c o n d ucte d i n acc or d a nce wit h t he a p plica ble G C P re g ulati o ns a n d 
g ui deli nes. 
1 0. 1. 4  
C o m pli a nce Wit h Electr o nic Rec o r ds; Electr o nic Si g n at ures 
Re g ul ati o ns ( U S 2 1 C F R P art 11) 
T his st u d y is t o be c o n d ucte d i n c o m plia nce wit h t he re g ulati o ns o n electr o nic rec or ds a n d 
electr o nic si g nat ure. 
1 0. 2  
C h a n ges t o t he Pr ot oc ol 
T he i n vesti gat or m ust n ot i m ple me nt a n y de via ti o n fr o m or c ha n ges of t he pr ot oc ol wit h o ut 
a p pr o val b y Aller ga n a n d pri or re vie w a n d d oc u me nte d a p pr o val/fa v ora ble o pi ni o n fr o m t he 
I R B/I E C of a pr ot oc ol a me n d me nt, e xce pt w here necessar y t o eli mi nate i m me diate hazar ds 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
t o st u d y patie nts, or w he n t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects of t he 
st u d y (e g, c ha n ge i n m o nit ors, c ha n ge of tele p h o ne n u m bers). 
1 0. 3  
P atie nt C o nfi de nti alit y 
A re p ort of t he res ults of t his st u d y ma y be p u blis he d or se nt t o t he a p pr o priate healt h 
a ut h orities i n a n y c o u ntr y i n w hic h t he st u d y dr u g ma y ulti matel y be mar kete d, b ut t he 
patie nt’s na me will n ot be discl ose d i n t h ese d oc u me nts.  T he patie nt's na me ma y be 
discl ose d t o t he S p o ns or of t he st u d y, Aller ga n , or t he g o ver ni n g healt h a ut h orities or t he 
F D A if t he y i ns pect t he st u d y rec or ds.  A p pr o priate preca uti o ns will be ta ke n t o mai ntai n 
c o nfi de ntialit y of me dical rec or ds a n d pers o nal i nf or mati o n. 
1 0. 3. 1  
P atie nt Pri v ac y 
Writte n a ut h orizati o n ( U S sites o nl y), data pr otecti o n c o nse nt ( E ur o pea n sites o nl y), a n d 
ot her d oc u me ntati o n i n acc or da nce wit h t he rele va nt c o u ntr y a n d l ocal pri vac y re q uire me nts 
( w here a p plica ble) is t o be o btai ne d fr o m eac h patie nt pri or t o e nr oll me nt i nt o t he st u d y, 
a n d/ or fr o m t he patie nt's le gall y a ut h orize d re prese ntati ve i n acc or da nce wit h t he a p plica ble 
pri vac y re q uire me nts (e g, t he Healt h I ns ura nce P ort a bilit y a n d Acc o u nta bilit y Act Sta n dar ds 
f or Pri vac y of I n di vi d uall y I de ntifia ble Healt h I nf or mati o n (“ HI P A A”), E ur o pea n U ni o n Data 
Pr otecti o n Directi ve 9 5/ 4 6/ E C [“ E U Directi ve”]). 
I n acc or da nce wit h HI P A A re q uire me nts, a d diti o nal p ur p oses of t his st u d y ma y i ncl u de 
p u blis hi n g of a n o n y m o us patie nt data fr o m t he st u d y. 
1 0. 4  
D oc u me nt ati o n 
1 0. 4. 1  
S o urce D oc u me nts 
S o urce d oc u me nts ma y i ncl u de a patie nt's me dical rec or ds, h os pital c harts, cli nic c harts, t he 
i n vesti gat or's patie nt st u d y files, as well as t he res ults of dia g n ostic tests s uc h as X-ra ys, 
la b orat or y tests, a n d electr ocardi o gra ms.  T he i n vesti gat or's c o p y of t he case re p ort f or ms 
ser ves as part of t he i n vesti gat or's rec or d of a patie nt's st u d y-relate d data. 
T he f oll o wi n g i nf or mati o n s h o ul d be e ntere d i nt o t he patie nt's me dical rec or d: 
•  Patie nt’s na me 
•  Patie nt’s c o ntact i nf or mati o n 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
•  T he date t hat t he patie nt e ntere d t he st u d y, patie nt n u m ber, a n d me dicati o n kit 
n u m bers 
•  T he st u d y title a n d/ or t he pr ot oc ol n u m ber  of t he st u d y a n d t he na me of Aller ga n 
•  A state me nt t hat i nf or me d c o nse nt was o btai ne d (i ncl u di n g t he date).  A state me nt t hat 
writte n a ut h orizati o n ( U S sites o nl y), data pr otecti o n c o nse nt ( E U sites o nl y), or ot her 
c o u ntr y a n d l ocal patie nt pri vac y re q uir e d d oc u me ntati o n f or t his st u d y has bee n 
o btai ne d (i ncl u di n g t he date). 
•  Dates of all patie nt st u d y visits 
•  All c o nc urre nt me dicati o ns  ( List all prescri pti o n a n d n o n prescri pti o n me dicati o ns 
bei n g ta ke n at t he ti me of e nr oll me nt.  At eac h  s u bse q ue nt visit, c ha n ges t o t he list of 
me dicati o ns a n d a n y c o nc urre nt pr oce d ures s h o ul d be rec or de d.) 
•  Occ urre nce a n d stat us of a n y a d verse e ve nts  (i ncl u di n g a n y pr oced ure-relate d a d verse 
e ve nts d ue t o c o m plicati o ns) 
•  T he date t he patie nt e xite d t he st u d y, a n d a n otati o n as t o w het her t he patie nt 
c o m plete d t he st u d y or reas o n f or disc o nti n uati o n 
•  T he res ults of la b orat or y tests perf or me d b y t he site (e g, bl o o d c he mistr y a n d 
he mat ol o g y, uri nal ysis, a n d pre g na nc y tests) 
•  D oc u me ntati o n of t he patie nt's me dical hist or y 
•  Vital si g ns, p h ysical e xa mi nati o n fi n di n gs 
•  I O P a n d o p ht hal mic e xa mi nati o n fi n di n gs 
•  Dates of Bi mat o pr ost S R or S ha m a d mi nistrati o n pr oce d ure 
•  D oc u me ntati o n of w het her a n y pr oce d ur e i ncl u di n g st u d y treat me nt a d mi nistrati o n 
was perf or me d acc or di n g t o t he pr ot oc ol, n oti n g a n y de viati o ns (if a p plica ble) 
•  Bi n oc ular c ol or p h ot o gra p hs, vis ual fiel d pri nt- o uts, tr eat me nt vi de o (if ta ke n), 
A S- O C T a n d mac ular O C T pri nt- o uts 
1 0. 4. 2  
C ase Re p ort F or m C o m pleti o n 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat  data are pr o perl y rec or de d o n eac h patie nt's 
case re p ort f or ms a n d relate d d oc u me nts.  A n i n vesti gat or w h o has si g ne d t he pr ot oc ol 
si g nat ure pa ge s h o ul d pers o nall y si g n f or t he case re p ort f or ms (as i n dicate d i n t he case 
re p ort f or ms) t o e ns ure t hat t he o bser vati o ns a n d fi n di n gs are rec or de d o n t he case re p ort 
f or ms c orrectl y a n d c o m pletel y.  T he case re p ort f or ms are t o be s u b mitte d t o Aller ga n i n a 
ti mel y ma n ner at t he c o m pleti o n of t he st u d y, or as ot her wise s pecifie d b y Aller ga n a n d will 
be mai ntai ne d i n a ce ntral data re p osit or y. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 0. 4. 3  
St u d y S u m m ar y 
A n i n vesti gat or's s u m mar y will be pr o vi de d t o Aller ga n wit hi n a s h ort ti me after t he 
c o m pleti o n of t he st u d y, or as desi g nate d b y Alle r ga n.  A s u m mar y is als o t o be pr o vi de d t o 
t he res p o nsi ble I R B/I E C. 
1 0. 4. 4  
Rete nti o n of D oc u me nt ati o n 
All st u d y relate d c orres p o n de nce, patie nt r ec or ds, c o nse nt f or ms, patie nt pri vac y 
d oc u me ntati o n, rec or ds of t he distri b uti o n a n d us e of all i n vesti gati o nal pr o d ucts, a n d c o pies 
of case re p ort f or ms s h o ul d be mai ntai ne d o n file. 
F or c o u ntries falli n g wit hi n t he sc o pe of t he I C H g ui deli nes, t he s p o ns or-s pecific esse ntial 
d oc u me nts s h o ul d be retai ne d u ntil at least 2 years after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at leas t 2 years ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t h e i n vesti gati o nal pr o d uct.  T hese d oc u me nts 
s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y t he ap plica ble re g ulat or y 
re q uire me nt(s) or if nee de d b y t he s p o ns or. 
I n a d diti o n, f or c o u ntries n ot falli n g wit hi n t he sc o pe of t he I C H g ui deli nes, l ocal re g ulat or y 
re q uire me nts s h o ul d be f oll o we d re gar di n g t he rete nti o n of cli nical st u d y d oc u me ntati o n. 
Aller ga n re q uires t hat it be n otifie d i n writi n g if t he i n vesti gat or wis hes t o reli n q uis h 
o w ners hi p of t he data s o t hat m ut uall y a gree d- u p o n arra n ge me nts ca n be ma de f or tra nsfer of 
o w ners hi p t o a s uita bl y q ua lifie d, res p o nsi ble pers o n. 
1 0. 5  
L a beli n g, P ac k a gi n g, a n d Ret ur n or Dis p os al of St u d y 
Me dic ati o ns/ Tre at me nts 
1 0. 5. 1  
L a beli n g/ P ac k a gi n g 
Pac ka ge d a n d la bele d st u d y me dicati o n will be s u p plie d b y Aller ga n. 
T he asse m ble d Bi mat o pr ost S R ( or S ha m a p plicat or) is i n di vi d uall y pac ka ge d i nt o a 
la mi nate d f oil p o uc h wit h desicca nt a n d seale d.  T he e ntire f oil p o uc h pac ka ge is ter mi nall y 
sterilize d.  Eac h p o uc h will be place d i nt o its o w n cart o n.  T he me dicati o n will be i de ntifie d 
as a n i n vesti gati o nal pr o d uct.  T he st u d y n u m ber a n d me dicati o n kit n u m ber will be 
i de ntifie d o n t he me dicati o n la bels. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
T he st u d y- pr o vi de d e ye dr o ps (ti m ol ol or ti m o l ol ve hicle) will be i de ntifie d as a n 
i n vesti gati o nal pr o d uct a n d pr o vi de d i n i de nticall y a p peari n g b ottles pac ke d i n cart o ns.  Eac h 
cart o n will c o ntai n 2 i de nticall y a p peari n g b ottles, eac h of w hic h will be la bele d f or t he left 
or ri g ht e ye.  T he st u d y n u m ber a n d me dicati o n kit n u m ber will be i de ntifie d o n t he 
me dicati o n la bels a n d cart o ns. 
T he st u d y me dicati o n c o nte nts are desc ri be d i n Secti o ns 5. 1 a n d 5. 2. 
Desi g nate d site pers o n nel will be res p o nsi ble f or recei vi n g, dis pe nsi n g, a n d c ollecti n g st u d y 
me dicati o ns t hat are deli vere d i n b o ttles a n d perf or mi n g dr u g acc o u nta bilit y. 
1 0. 5. 2  
Cli nic al S u p pl y I n ve nt or y 
T he i n vesti gat or m ust kee p a n acc urate acc o u n ti n g of t he n u m ber of i n vesti gati o nal u nits 
recei ve d fr o m Aller ga n, dis pe nse d t o t he patie nts, t he n u m ber of u nits ret ur ne d t o t he 
i n vesti gat or b y t he patie nt, a n d t he n u m ber of u nits ret ur ne d t o Aller ga n d uri n g a n d at t he 
c o m pleti o n of t he st u d y.  A detaile d i n ve nt or y m ust be c o m plete d f or t he st u d y me dicati o n.  
T he st u d y me dicati o n m ust be dis pe nse d o nl y b y a n a p pr o priatel y q ualifie d pers o n t o patie nts 
i n t he st u d y.  T he me dicati o n is t o be use d i n acc or da nce wit h t he pr ot oc ol b y patie nts w h o 
are u n der t he direct s u per vis i o n of a n i n vesti gat or. 
1 0. 5. 3  
Ret ur n or Dis p os al of St u d y Me dic ati o ns/ Tre at me nts a n d/ or 
S u p plies 
All cli nical st u d y me dicati o ns/treat me nts a n d/ or  s u p plies will be ret ur ne d t o Aller ga n or 
Aller ga n desi g nee f or destr ucti o n.  Use d a p pl icat ors will be dis p ose d of i m me diatel y i n a 
s har ps c o ntai ner. 
A n y malf u ncti o ni n g a p plicat ors s h o ul d be ret ur ne d t o Aller ga n or desi g nee.  Writte n 
i nstr ucti o ns pr o vi de d b y Aller ga n s h o ul d be f oll o we d w he n ret ur ni n g a malf u ncti o ni n g 
a p plicat or t o Aller ga n or its re prese ntati ve. 
1 0. 6  
M o nit ori n g b y t he S p o ns or 
A re prese ntati ve of t he s p o ns or will m o nit or t he st u d y o n a peri o dic basis.  T he deter mi nati o n 
of t he e xte nt a n d nat ure of m o nit ori n g will be base d o n c o nsi derati o ns s uc h as t he o bjecti ve, 
p ur p ose, desi g n, c o m ple xit y, bli n di n g, size, a n d e n d p oi nts of t he st u d y. 
A ut h orize d re prese ntati ves of Aller ga n or re g ulat or y a ut h orit y re prese ntati ves will c o n d uct 
o n-site visits t o re vie w, a u dit a n d c o p y st u d y- relate d d oc u me nts.  T hese re prese ntati ves will 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
meet wit h t he i n vesti gat or(s) a n d a p pr o priate staff at m ut ua ll y c o n ve nie nt ti mes t o disc uss 
st u d y-relate d data a n d q uesti o ns. 
1 0. 7  
H a n dli n g of Bi ol o gic al S peci me ns  
La b orat or y s peci me ns f or bl o o d c he mistr y pa nel, he mat ol o g y i ncl u di n g c o m plete bl o o d 
c o u nt wit h differe ntial, a n d uri nal ysis will be  se nt t o a ce ntralize d cli nical la b orat or y 
(
) wit h certificati o n fr o m a rec o g nize d accre ditati o n a ge nc y (e g, C olle ge of A merica n 
Pat h ol o g y [ C A P] or Cli nical La b orat or y I m pr o ve me nt A me n d me nts [ C LI A] certificati o n) t o 
be assa ye d usi n g vali date d met h o ds.  All bl o o d a n d uri ne sa m ples will be st ore d at t he 
ce ntralize d cli nical la b orat or y f oll o wi n g testi n g, a n d will be discar de d after a ti me peri o d 
i n dicate d b y Aller ga n.  Aller ga n s hall ha ve f ull o w ners hi p ri g hts t o a n y bi ol o gical 
s peci me ns/sa m ples deri ve d fr o m t he st u d y. 
See t he 
La b orat or y Ma n ual a n d t he Pr ot oc ol Pr oce d ure Ma n ual f or pr oce d ural 
details. 
1 0. 8  
P u blic ati o ns 
Aller ga n, as t he s p o ns or, has pr o prietar y i ntere st i n t his st u d y.  A ut h ors hi p a n d ma n uscri pt 
c o m p ositi o n will reflect j oi nt c o o perati o n bet w ee n m ulti ple i n vesti gat ors a n d sites a n d 
Aller ga n pers o n nel.  A ut h ors hi p will be esta blis he d pri or t o t he writi n g of t he ma n uscri pt.  As 
t his st u d y i n v ol ves m ulti ple ce nters, n o i n di vi d ual p u blicati o ns will be all o we d pri or t o 
c o m pleti o n of t he fi nal re p ort of t he m ultice n ter st u d y e xce pt as a gree d wit h Aller ga n. 
1 0. 9  
C o or di n ati n g I n vesti g at or 
A si g nat or y C o or di nati n g I n vesti gat or will be de si g nate d pri or t o t he writi n g of t he Cli nical 
St u d y Re p ort. 
1 0. 1 0  
Vi de o Rec or di n g a n d G o ni osc o pic P h ot o gr a p h y 
I n c o nse nti n g patie nts, t he pr oce d ure of a dmi nisteri n g t he Bi mat o pr ost S R a n d/ or S ha m 
A d mi nistrati o n ma y be vi de o rec or de d.  T he vi de o rec or di n g will be ma de of t he e ye as 
vie we d t hr o u g h a n o perati n g micr osc o pe.  T he vi de o rec or di n gs ma y be use d t o re vie w t he 
st u d y pr oce d ure a n d/ or f or ge neral researc h, e d ucati o n, or i nf or mati o nal p ur p oses. 
I n c o nse nti n g patie nts, g o ni o p h ot o gra p hic i ma ges of t he i nferi or iri d oc or neal a n gle ma y be 
o btai ne d. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
T he patie nt’s decisi o n a b o ut w het her t o all o w vi de o rec or di n g or g o ni osc o pic p h ot o gra p h y 
will n ot affect t heir eli gi bilit y f or partici pati o n i n t he st u d y. 
1 1.  
Refere nces 
A GI S I n vesti gat ors. T he A d va nce d Gla uc o ma I nter ve nti o n St u d y ( A GI S): 7. T he relati o ns hi p 
bet wee n c o ntr ol of i ntra oc ular press ure a n d vi s ual fiel d deteri orati o n. A m J O p ht hal m ol. 
2 0 0 0; 1 3 0: 4 2 9- 4 4 0. 
A merica n Aca de m y of O p ht hal m ol o g y Gla u c o ma Pa nel. Prefe rre d Practice Patter n®  
G ui deli nes. Pri mar y o pe n-a n gle gla uc o ma. Sa n Fra ncisc o, C A: A merica n Aca de m y of 
O p ht hal m ol o g y; 2 0 1 0a. 2 7 p. 
B u de nz D L. A cli nicia n's g ui de t o t he asse ss me nt a n d ma na ge me nt of n o na d here nce i n 
gla uc o ma. O p ht hal m ol o g y. 2 0 0 9; 1 1 6: S 4 3- S 4 7. 
C o he n J S, Gr oss R L, C heet ha m J K, Va n De n b ur g h A M, Ber nstei n P, W hitc u p S M. T w o- year 
d o u ble- mas ke d c o m paris o n of bi mat o pr ost wit h ti m o l ol i n patie nts wit h gla uc o ma or oc ular 
h y perte nsi o n. S ur v O p ht hal m ol. 2 0 0 4; 4 9 ( S u p pl 1): S 4 5- S 5 2. 
C o o k C, F oster P. E pi de mi ol o g y of gla uc o ma:  W hat’s ne w?  Ca n J O p ht hal m ol. 
2 0 1 2; 4 7: 2 2 3- 2 2 6. 
Frie d ma n D S. I ntr o d ucti o n: ne w i nsi g hts o n e n ha nci n g a d here nce t o t o pical gla uc o ma 
me dicati o ns. O p ht hal m ol o g y. 2 0 0 9; 1 1 6: S 2 9. 
Heijl A, Les ke M C, Be n gtss o n B, H y ma n L,  Be n gtss o n B, H ussei n M. Re d ucti o n of 
i ntra oc ular press ure a n d gla uc o ma pr o gressi o n: res ults fr o m t he Earl y Ma nifest Gla uc o ma 
Trial. Arc h O p ht hal m ol. 2 0 0 2; 1 2 0: 1 2 6 8- 1 2 7 9. 
Hi g gi n b ot ha m EJ, Sc h u ma n J S, G ol d ber g I, Gr oss R L, Va n De n b ur g h A M, C he n K, et al. 
O ne- year, ra n d o mize d st u d y c o m pari n g bi mat o pr ost a n d ti m ol ol i n gla uc o ma a n d oc ular 
h y perte nsi o n. Arc h O p ht hal m ol. 2 0 0 2; 1 2 0: 1 2 8 6- 1 2 9 3. 
Kass M A, He uer D K, Hi g gi n b ot ha m EJ, J o h ns o n C A, Ke lt ner J L, Miller J P, et al. T he Oc ular 
H y perte nsi o n Treat me nt St u d y: a ra n d o mize d tria l deter mi nes t hat t o pical oc ular h y p ote nsi ve 
me dicati o n dela ys or pre ve nts t he o nset of pri mar y o pe n-a n gle gla uc o ma. Arc h O p ht hal m ol. 
2 0 0 2; 1 2 0: 7 0 1- 7 1 3. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
K ni g ht O’ RJ, La wre nce S D. S ustai ne d dr u g de li ver y i n gla uc o ma. C urre nt O pi ni o n i n 
O p ht hal m ol o g y 2 0 1 4; 2 5( 2): 1 1 2- 1 1 7. 
K oza k K R, Cre ws B C, M orr o w J D, Wa n g L- H, Ma  Y H, Wei na n der R, et al. Meta b olis m of 
t he e n d oca n na bi n oi ds, 2-arac hi d o n yl gl ycer ol a n d a na n da mi de, i nt o pr osta gla n di n, 
t hr o m b o xa ne, a n d pr ostac ycli n gl ycer ol esters a n d et ha n ola m i des. J Bi ol C he m. 
2 0 0 2; 2 7 7: 4 4 8 7 7- 4 4 8 8 5. 
Kra uss A H, Wo o d war d D F. U p date o n t he mec ha nis m of acti o n of bi mat o pr ost: a re vie w a n d 
disc ussi o n of ne w e vi de nce. S ur v O p ht hal m ol. 2 0 0 4; 4 9( S u p pl 1): S 5- 1 1. 
Lic hter P R, M usc h D C, Gilles pie B W, G uire K E, Ja nz N K, Wre n P A, et al. I nteri m cli nical 
o utc o mes i n t he C olla b orati ve I n itial Gla uc o ma Treat me nt St u d y c o m pari n g i nitial treat me nt 
ra n d o mize d t o me dicati o ns or s ur ger y. O p ht hal m ol o g y. 2 0 0 1; 1 0 8: 1 9 4 3- 1 9 5 3. 
L U MI G A N ®  [ Pac ka ge I nsert]. Ir vi ne, C A: Aller ga n, I nc. 2 0 1 2. 
Matias I, C he n J, De Petr ocellis L, Bis o g n o T,  Li gresti A, Fezza F, et al. Pr osta gla n di n 
et ha n ola mi des ( pr osta mi des): i n vitr o p har mac ol o g y a n d meta b olis m. J P har mac ol E x p T her. 
2 0 0 4; 3 0 9: 7 4 5- 7 5 7. 
M osae d S, D usti n L, Mi nc kler D S. C o m p arati ve o utc o mes bet wee n ne wer a n d ol der 
s ur geries f or gla uc o ma. Tra ns A m O p ht hal m ol S oc. 2 0 0 9; 1 0 7: 1 2 7- 3 3. 
Q ui gle y H A. N u m ber of pe o ple wit h gla uc o ma w orl d wi de. Br J O p ht hal m ol. 
1 9 9 6; 8 0: 3 8 9- 3 9 3. 
Q ui gle y H A, Br o ma n A T. T he n u m ber of pe o pl e wit h gla uc o ma w orl d wi de i n 2 0 1 0 a n d 2 0 2 0. 
Br J O p ht hal m ol. 2 0 0 6; 9 0: 2 6 2- 2 6 7. D oi: 1 0. 1 1 3 6/ bj o. 2 0 0 5. 0 8 1 2 2 4. D o w nl oa de d fr o m 
bj o. b m.c o m, A pril 9, 2 0 1 4. 
Sta m per R L, Lie ber ma n M F, Dra ke M V, e ds. I ntr o d ucti o n a n d Classificati o n of t he 
Gla uc o mas. I n: Sta m per R L, Lie ber ma n M F, Dra ke M V, e dit ors. Bec ker- S haffer's Dia g n osis 
a n d T hera p y of t he Gla uc o mas, 8t h e d. A mster da m, Net herla n ds: M os b y Else vier; 2 0 0 9; C ha p 
1: 1- 7. 
Tsai J C. A c o m pre he nsi ve pers pecti ve o n patie nt a d here nce t o t o pical gla uc o ma t hera p y. 
O p ht hal m ol o g y. 2 0 0 9; 1 1 6: S 3 0- S 3 6. 
Var ma R, Lee P P, G ol d ber g I, K ota k S. A n asse ss me nt of t he healt h a n d ec o n o mic b ur de ns of 
gla uc o ma. A m J O p ht hal m ol. 2 0 1 1; 1 5 2: 5 1 5- 5 2 2. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
We ber A, Ni J, Li n g K H, Ac hea m p o n g A, Ta n g- Li u D D, B ur k R, et al. F or mati o n of 
pr osta mi des fr o m a na n da mi de i n F A A H k n oc k o ut mice a nal yze d b y H P L C wit h ta n de m 
mass s pectr o metr y. J Li pi d Res. 2 0 0 4; 4 5: 7 5 7- 7 6 3. 
Wei nre b R N, Ka uf ma n P L. T he Gla uc o ma Researc h C o m m u nit y a n d F D A l o o k t o t he f ut ure:  
a re p ort fr o m t he N EI/ F D A C D E R Gla uc o ma Cli nical Trial Desi g n a n d E n d p oi nts 
S y m p osi u m. I n v O p ht hal o m ol & Vis Sci. 2 0 0 9; 5 0( 4): 1 4 9 7- 1 5 0 5. 
Willia ms R D, C o he n J S, Gr oss R L, Li u C C, Sa f ya n E, Bat o osi n g h A L. L o n g-ter m efficac y 
a n d safet y of bi mat o pr ost f or i ntra oc ular press ure l o weri n g i n gla uc o ma a n d oc ular 
h y perte nsi o n: year 4. Br J O p ht hal m ol. 2 0 0 8; 9 2: 1 3 8 7- 1 3 9 2. 
Wo o d war d D F, C ha n M F, B ur ke J A, C he n g- Be n nett A, C he n G, Fair bair n C E, et al. St u dies 
o n t he oc ular h y p ote nsi ve effects of pr osta gl a n di n F 2 al p ha ester pr o dr u gs a n d rece pt or 
selecti ve pr osta gla n di n a nal o gs. J Oc ul P har mac ol. 1 9 9 4; 1 0: 1 7 7- 1 9 3. 
Wo o d war d D F, Kra uss A H, C he n J, Lai R K, S pa da C S, B ur k R M. T he p har mac ol o g y of 
bi mat o pr ost ( L u mi ga n). S ur v O p ht hal m ol. 2 0 0 1; 4 5( S u p pl 4): S 3 3 7- S 3 4 5. 
Wo o d war d D F, P hel ps R L, Kra uss A H, We ber A, S h ort B, C he n J, et al. Bi mat o pr ost: A n o vel 
a nti gla uc o ma a ge nt. Car di o vasc Dr u g Re v. 2 0 0 4; 2 2: 1 0 3- 1 2 0. 
Yu M, I ves D, Ra mes ha C S. S y nt hesis of pr osta gla n di n E 2 et ha n ola mi de fr o m a na n da mi de 
b y c ycl o o x y ge nase- 2. J Bi ol C he m. 1 9 9 7; 2 7 2: 2 1 1 8 1- 2 1 1 8 6. 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 2.  
Att ac h me nts 
1 2. 1  
P ac k a ge I nsert 
T he a p pr o priate pac ka ge i nsert or S u m mar y of Pr o d uct C haracteristics will be s u p plie d t o 
i n vesti gat ors i n c o u ntries w here ti m ol ol (st u d y- pr o vi de d e ye dr o ps) is mar kete d. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
9 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 2. 2  
Gl oss ar y of A b bre vi ati o ns 
Ter m/ A b bre vi ati o n
 Defi niti o n
 
A B M D 
A nteri or Base me nt Me m bra ne Disease 
A C 
A nteri or c ha m ber 
A R M D 
A ge-relate d Mac ular De ge nerati o n 
A S C 
A m b ulat or y S ur gical Ce nter 
A S- O C T 
A nteri or se g me nt o p tical c o here nce t o m o gra p h y 
B C V A 
Best-c orrecte d vis ual ac uit y 
BI D 
T wice dail y 
B L Q 
Bel o w t he li mit of q ua ntitati o n 
C R F 
Case re p ort f or m 
D M E K 
Desce met’s Me m bra ne E n d ot helial Kerat o plast y 
D S E K 
Desce met’s Stri p pi n g E n d ot helial Kerat o plast y 
e C R F 
Electr o nic case re p ort f or m 
E D C 
Electr o nic data ca pt ure 
E U 
E ur o pea n U ni o n 
F D A 
F o o d a n d Dr u g A d mi nistrati o n 
G C P 
G o o d Cli nic al Practices 
G L P 
G o o d La b orat or y Practice 
HI P A A 
Healt h I ns ura nce P orta b ilit y a n d Acc o u nta bilit y Act 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I O L 
I ntra oc ular le ns i m pla nt 
I O P 
I ntra oc ular press ure 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-t o-treat 
I V/ W R S 
I nteracti ve v oice/ we b res p o nse s yste m 
Me d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M M R M 
Mi xe d-effects m o del re peate d meas ures 
NI 
N o ni nferi orit y 
N S AI D 
N o n-ster oi dal a nti-i nfla m mat or y dr u g 
O A G 
O pe n-a n gle gla uc o ma 
O C T 
O ptical c o here nce t o m o gra p h y 
O H T 
Oc ular h y perte nsi o n 
O U 
B ot h e yes 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Ter m/ A b bre vi ati o n
 Defi niti o n
 
P A S 
Peri p heral a nteri or s y nec hiae 
P L A 
P ol ylactic aci d 
P L G A 
P ol ylactic- c o- gl yc olic aci d 
P O A G 
Pri mar y o pe n-a n gle gla uc o ma 
P P 
Per pr ot oc ol 
R B C 
Re d bl o o d cell 
S C/ T 
Patie nts wit h sic kle cell disease or trait or ot her 
he m o gl o bi n o pat hies 
S O C 
S yste m Or ga n Class ( Me d D R A) 
S R 
S ustai ne d release 
U S 
U nite d States 
W B C 
W hite bl o o d cell 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 2. 3  
Pr ot oc ol A me n d me nt S u m m ar y 
1 2. 3. 1  
A me n d me nt 1 
Title:  T he Efficac y a n d Safet y of Bi mat o pr ost S R i n Patie nts Wit h O pe n-a n gle Gla uc o ma or 
Oc ular H y perte nsi o n 
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 1 
Date of A me n d me nt:  A u g ust 2 0 1 5 
A me n d me nt S u m m ar y 
T his s u m mar y i ncl u des c ha n ges ma de t o Pr ot oc ol 1 9 2 0 2 4- 0 9 1 (a p pr o ve d Se pte m ber 2 0 1 4).  
T his pr ot oc ol was a me n de d t o clarif y s o me s ecti o ns a n d t o m o dif y t he i ncl usi o n/e xcl usi o n 
criteria. 
F oll o wi n g is a s u m mar y of c o nte nt- orie nte d c ha n ges t hat were ma de t o eac h secti o n of t he 
pr ot oc ol, a n d a brief rati o nale f or t hese c ha n ge s.  Mi n or e dit orial an d d oc u me nt f or matti n g 
re visi o ns ha ve n ot bee n s u m marize d. 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Title 
Pa ge 
U p date d Aller ga n Me dical Safet y P h ysicia n a n d Aller ga n 
Si g nat or y i nf or mati o n. 
 
Pr ot oc ol 
S u m mar y 
U p date d a n d re or dere d t he f oll o wi n g ke y i ncl usi o n criteria 
as f oll o ws: 
•  
Dia g n osis of eit her O A G (ie, pri mar y O A G, 
pse u d oe xf oliati o n gla uc o ma, or pi g me ntar y gla uc o ma) 
or O H T i n eac h e ye, a n d b ot h e yes re q uire 
I O P-l o weri n g treat me nt ( N ote:  dia g n osis d oes n ot ha ve 
t o be t he sa me i n b ot h e yes) 
•  
 
 
 
 
 
 
 
 
 
•  
 
 
  
 
 
Re vise d ke y e ntr y criteria base d o n 
t he u p date d i ncl usi o n a n d e xcl usi o n 
criteria i n t he b o d y of t he pr ot oc ol. 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
  
 
 
 
 
 
Secti o n 
1. 3. 3 
T he o bjecti ve of t his sta ge of t he st u d y is t o e val uate t he 
safet y a n d i ntra oc ular press ure (I O P)-l o weri n g efficac y of 
Bi mat o pr ost S R i n patie nts wit h O A G. 
As of Marc h 2 0 1 5 A pril, 2 0 1 4, a t otal of 8 7 1 0 9 patie nts ha d 
recei ve d a si n gle a d mi nistrati o n; a n d of t h ose as of J u ne 
2 0 1 5, 1 2 2 4 ha d recei ve d a re peat a d mi nistrati o n of 
Bi mat o pr ost S R.  Base d o n a re vie w of t he efficac y data as 
of Marc h 2 0 1 5,  a tre n d i n d ose-res p o nse has bee n o bser ve d 
acr oss t he 4 d ose stre n gt hs t hat were teste d.  A vaila ble data 
s u g gest t hat t he i m pla nt ma y pr o vi de t o pical pr osta gla n di n 
a nal o g-li ke efficac y u p t o 3 t o  4 m o nt hs p ost-i m pla ntati o n 
i n t he maj orit y of patie nts.   fr o m t he 1 0 µ g a n d 1 5 µ g 
si n gle a d mi nistrati o ns s h o w c o m para ble I O P press ure 
l o weri n g bet wee n t he st u d y e ye a n d t he n o nst u d y e ye 
d uri n g t he first 1 2 t o 1 6 wee ks after d osi n g.  Of t he 6 7 
patie nts acr oss all d ose gr o u ps w h o ha d reac he d t he W ee k 
1 6 visit, 6 2 ( 9 2. 5 %) ha d n ot re q uire d t he use of a d diti o nal 
i ntra oc ular press ure-l o weri n g t o pical me dicati o n b y t hat 
visit.  A t otal of 1 2 patie nts ha d recei ve d a re peat 
a d mi nistrati o n of Bi mat o pr ost S R ( 2 at 6 µ g, 5 at 1 0 µ g, a n d 
5 at 1 5 µ g), pr o vi di n g u p t o 2 0 wee ks of data f oll o wi n g t he 
sec o n d a d mi nistrati o n.  T he ti mi n g of t he sec o n d 
a d mi nistrati o n ra n ge d fr o m 2 0 wee ks after t he first d ose i n 
t he 6 µ g gr o u p, 1 4 t o 3 3 wee ks ( 1 4, 1 6, 1 9, 2 4, a n d 3 3 
wee ks) i n t he 1 0 µ g gr o u p, a n d 1 7 t o 3 7 wee ks ( 1 7, 1 9, 1 9, 
2 6, a n d 3 7 wee ks) i n t he 1 5 µ g gr o u p.  Data f or u p t o 1 6 
wee ks of f oll o w u p afterf oll o wi n g t he sec o n d 
a d mi nistrati o n i n t he re d ose d patie nts s h o we d si milar I O P 
l o weri n g t o t hat o bser ve d f oll o wi n g t he first a d mi nistrati o n 
of Bi mat o pr ost S R. 
As of A pril Marc h, 2 0 1 4 2 0 1 5, Bi mat o pr ost S R has s h o w n 
a n acce pta ble safet y pr ofile  wit h si n gle a n d re peat 
U p date d t he s u m mar y of data fr o m 
St u d y 1 9 2 0 2 4- 0 4 1 D wit h m ore 
c urre nt res ults. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
a d mi nistrati o ns i n o n g oi n g st u d y 1 9 2 0 2 4- 0 4 1 D.  T he m ost 
fre q ue ntl y re p orte d a d verse e ve nts ( > 1 0 % of patie nts) f or 
t he st u d y e ye ha ve bee n c o nj u ncti val h y perae mia, 
c o nj u ncti val hae m orr ha ge, e ye pai n, f orei g n b o d y se nsati o n, 
a n d lacri mati o n i ncrease d.  M ost of t hese a d verse e ve nts 
were oc ular, mil d i n se verit y, occ urre d wit hi n t he first 
8 da ys after Bi mat o pr ost S R a d mi nistrati o n, a n d were 
c o nsi dere d relate d t o t he st u d y dr u g a d mi nistrati o n 
pr oce d ure.  T here ha ve bee n n o re p orts of seri o us st u d y 
dr u g-relate d a d verse e ve nts, a n d n o ne w safet y c o ncer ns 
ha ve bee n o bser ve d after t he sec o n d treat me nt.  Please refer 
t o t he I n vesti gat or’s Br oc h ure f or details o n re p orte d safet y 
fi n di n gs. 
Secti o n 
4. 3 
U p date d t he f oll o wi n g i ncl usi o n criteria: 
 
 
7.  Dia g n osis of eit her O A G (ie, pri mar y pse u d oe xf oliati o n, 
or pi g me ntar y gla uc o ma) or O H T  i n eac h e ye a n d b ot h e yes 
re q uire I O P-l o weri n g treat me nt.  ( N ote:  dia g n osis d oes n ot 
ha ve t o be t he sa me i n b ot h e yes) 
U p date d i ncl usi o n criteria 4, 7, a n d 
8 f or better clarit y.   
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
 
 
Secti o n 
4. 4 
U p date d t he f oll o wi n g e xcl usi o n criteri o n: 
 
  
 
 
  
 
  
U p date d t he f oll o wi n g i ncl usi o n criteria: 
 
 
  
 
  
 
 
 
  


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
 
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
A d de d t he f oll o wi n g e xcl usi o n criteri o n: 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
  
 
Secti o n 
4. 5. 1 
Re vise d t he f oll o wi n g:  I nter mitte nt use of oc ular 
dec o n gesta nts or a nti hista mi nes is all o we d if n ot ta ke n 
wit hi n 2 wee ks da ys pri or t o a sc he d ule d visit a n d/ or ≤ 1 5 
mi n utes bef ore or after t o pi cal a d mi nistrati o n of st u d y 
me dicati o n. 
A d de d t he f oll o wi n g: Re q uire d s ur gical pr oce d ures ma y be 
perf or me d i n t he fell o w e ye o nl y after c o m pleti o n of W ee k 
5 2. 
U p date d as f oll o ws: N ote t hat i n t he e ve nt t hat t he 
i n vesti gat or perf or ms a n u na ntici pate d i ncisi o nal s ur gical 
pr oce d ure o n t he st u d y e ye d uri n g w hic h oc ular fl ui d is t o 
be re m o ve d, oc ular fl ui d/i m pla nt sa m ples ma y be c ollecte d 
f or a nal ysis (see Pr ot oc ol Pr oce d ure Ma n ual f or f urt her 
details).) at t he i n vesti gat or’s discreti o n. 
Decrease d t o 2 da ys i n or der t o 
re d uce li mitati o ns o n patie nts i n a 
2- year st u d y. 
 
Beca use t his is n ot a paire d e ye 
c o m paris o n, t he fell o w e ye ma y 
ha ve re q uire d s ur ger y after t he 
treat me nt peri o d has bee n 
c o m plete d.   
 
Re vise d  t he descri pti o n of oc ular 
fl ui d c ollecti o n f or clarit y. 
Secti o n 
4. 5. 2 
N o nst u d y I O P-l o weri n g Me dicati o ns 
Use of a n y t o pical o p ht hal mic me dicati o n c o ntai ni n g a n 
oc ular a nti h y perte nsi ve, ot her t ha n use of st u d y me dicati o n 
(ti m ol ol) i n C o ntr ol gr o u p or fell o w e yes, is pr o hi bite d as 
c o nc urre nt t hera p y i n eit her e ye d uri n g t he st u d y t hr o u g h 
Wee k 5 2, u nless necessar y f or t he safet y of t he patie nt d ue 
t o i na de q uate c o ntr ol of I O P as deter mi ne d b y t he 
i n vesti gat or.  N o nst u d yI na de q uate c o ntr ol of I O P s h o ul d be 
c o nfir me d at a s u bse q ue nt visi t (sc he d ule d or u nsc he d ule d 
visit).  Pri or t o Wee k 5 2 t he i n vesti gat or will be e x pecte d t o 
attest t o t he nee d f or a d diti o nal n o nst u d y I O P -l o weri n g 
me dicati o n f or safet y reas o ns.  After t he W ee k 5 2 visit, 
n o nst u d y t o pical I O P-l o weri n g me dicati o ns will be 
per mitte d after t he Wee k 5 2 visit, if i n t he i n vesti gat or’s 
cli nical j u d g me nt t he I O P is n ot a de q uatel y c o ntr olle d at 
t w o c o nsec uti ve visits at least 1 wee k a part.  I nitiati o n of 
me dicati o n i n o ne e ye s h o ul d n ot a ut o maticall y lea d t o 
i nitiati o n of me dicati o n i n t he ot her e ye.  Eac h e ye s h o ul d 
be e val uate d o n a n i n di vi d ual basis w he n deter mi ni n g t he 
nee d f or a d diti o nal n o n-st u d y I O P-l o weri n g me dicati o ns.  If 
n o nst u d y I O P l o weri n g me dicati o n is i nitiate d pri or t o 
Wee k 5 2, t he i n vesti gat or will be e x pecte d t o attest t o t he 
nee d f or a d diti o nal n o n-st u d y I O P- l o weri n g me dicati o n f or 
safet y reas o ns f or eac h e ye i n di vi d uall y.  
C o ntact Le nses 
Use of s oft c o ntact le nses wit hi n 3 da ys a n d use of ri gi d gas 
per mea ble or har d c o ntact le nses wit hi n 1 wee k pri or t o a 
sc he d ule d st u d y visit or A d mi nistrati o n Da y, or use of 
c o ntact le nses of a n y ki n d wit hi n 1 wee k f oll o wi n g a n y 
Bi mat o pr ost S R ( or S ha m) a d mi nistrati o n i n eit her e ye is 
pr o hi bite d. 
C o ntact le nses s h o ul d be re m o ve d pri or t o i nstilli n g a n y 
st u d y- pr o vi de d e ye dr o ps a n d patie nts s h o ul d wait at least 
1 5 mi n utes bef ore p utti n g c o ntact le nses bac k i n t he e yes 
U p date d te xt f or clarit y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U p date d te xt f or clarit y a n d t o 
re d uce li mitati o ns f or patie nts w h o 
use c o ntact le nses.   
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
after i nstilli n g t o pical dr o ps. 
Ot her Me dicati o ns 
•  
S ur gical pr oce d ures t hat are n ot relate d t o Bi mat o pr ost 
S R ( or s ha m) a d mi nistrati o n pr oce d ures i n eit her e ye 
t he st u d y e ye.  ( S ur gical proce d ures are all o we d i n t he 
fell o w e ye after Wee k 5 2 as descri be d i n Secti o n 4. 5. 1) 
•  
Use of a n y n o nst u d y t o pical o p ht hal mic me dicati o ns 
(e xce pt as descri be d a b o ve a n d i n Secti o n 4. 5. 1) i n 
eit her e ye 
•  
Use of s oft c o ntact le nses wit hi n 1 wee k a n d use of 
ri gi d gase per mea ble or har d c o ntact le nses wit hi n 2 
wee ks pri or t o a sc he d ule d st u d y visit, or use of c o ntact 
le nses of a n y ki n d wit hi n 2 wee ks f oll o wi n g a n y 
Bi matr o pr ost S R ( or S ha m) a d mi nistrati o n i n eit her e ye  
Secti o n 
4. 5. 3 
F or w o me n of c hil d beari n g p ote ntial w h o ma y partici pate i n 
t he st u d y, t he f oll o wi n g met h o ds of c o ntrace pti o n, if 
pr o perl y use d, are ge nerall y c o nsi dere d relia ble:  h or m o nal 
c o ntrace pti ves (ie, oral, patc h,  i njecti o n, i m pla nt), male 
c o n d o m wit h i ntra va gi nal s per mici de, dia p hra g m or 
cer vical ca p wit h s per mici de, va gi nal c o ntrace pti ve ri n g, 
i ntra uteri ne de vice, s ur gical sterilizati o n ( bilateral t u bal 
li gati o n, bilateral sal pi n gect o m y), vasect o mize d part ner, or 
tr ue se x ual a bsti ne nce, w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifes t yle of t he s u bject. 
 
T he i n vesti gat or will ( 1) n otif y t he patie nt’s p h ysicia n t hat 
t he patie nt was bei n g treate d wit h a n i n vesti gati o nal dr u g 
( Bi mat o pr ost S R u n mas k t he stu d y treat me nt as nee de d f or 
pre g na nc y m o nit ori n g), a n d ( 2) f oll o w t he pr o gress of t he 
pre g na nc y. 
U p date d te xt f or clarit y. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 0 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Secti o n 
5. 3 
T he i n vesti gat or is str o n g l y e nc o ura ge d n ot t o use 
pr o hi bite d me dicati o ns as o utli ne d i n Secti o n 4. 5. 2.  I n 
or der t o mai ntai n mas ki n g i n t he e ve nt t hat n o nst u d y I O P-
l o weri n g me dicati o ns ( pr o hi bite d pri or t o Wee k 5 2 u nless 
re q uire d f or a safet y reas o n a n d atteste d t o b y t he 
i n vesti gat or) are a d mi nistere d, if a patie nt is starte d o n a 
n o nst u d y I O P-l o weri n g me dicati o n i n o nl y o ne e ye, t he 
patie nt will c o nti n ue t o use t he st u d y- pr o vi de d e ye dr o ps i n 
t hat e ye as directe d.  T he n o nst u d y I O P-l o weri n g 
me dicati o n will be prescri be d b y t he i n vesti gat or acc or di n g 
t o l ocal sta n dar d of care practices. a n d use d i n a d diti o n t o 
t he st u d y- pr o vi de d e ye dr o ps i n t hat e ye.  T he e ye n ot 
recei vi n g a n o nstu d y I O P-l o weri n g me dicati o n will 
c o nti n ue t o recei ve t he st u d y- pr o vi de d e ye dr o ps as 
directe d.  If t he e ye recei vi n g  t he n o nst u d y I O P-l o weri n g 
me dicati o n is a Bi mat o pr ost S R st u d y e ye, t he e ye will 
recei ve S ha m a d mi nistrati o n o n t he a d mi nistrati o n da y(s).  
If t he e ye recei vi n g t he n o nst u d y I O P-l o weri n g me dicati o n 
is a C o ntr ol gr o u p st u d y e ye or a fell o w e ye, t he e ye will 
c o nti n ue t o recei ve S ha m a d mi nistrati o n o n t he 
a d mi nistrati o n da y(s).  If b ot h e yes are recei vi n g n o nst u d y 
I O P-l o weri n g me dicati o ns, t he patie nt will disc o nti n ue use 
of t he Aller ga n st u d y- pr o vi de d e ye dr o ps  a n d will n ot 
recei ve a d diti o nal Bi mat o pr ost S R or S ha m a d mi nistrati o n 
(see Secti o n 5. 6. 1).).  H o we ver, as descri be d i n Secti o n 8. 8, 
t he patie nt will still re mai n i n t he st u d y a n d be f oll o we d f or 
1 2 m o nt hs f oll o wi n g t heir last a d mi nistrati o n of 
Bi mat o pr ost S R or S ha m. 
U p date d te xt f or clarit y. 
Secti o n 
5. 6 
If t he patie nt arri ves ha vi n g ta ke n t he m or ni n g d ose of 
st u d y- pr o vi de d e ye dr o ps, t he site s h o ul d atte m pt t o 
resc he d ule wit hi n t he visit wi n d o w.  E xce pti o n is ma de f or 
t he Da y 2 st u d y visit after a n y i njecti o n.  As t his visit is 
pri maril y f or safet y p ur p oses, patie nts s h o ul d u n der g o t he 
visit re gar dless of w het her t he y di d or di d n ot use t he st u d y 
me dicati o n t hat m or ni n g.) 
U p date d te xt f or clarit y. 
Secti o n 
5. 6. 1 
Patie nts w h o ha ve recei ve d n o ns t u d y t o pical I OP- l o weri n g 
me dicati o n ( pr o hi bite d bef ore W ee k 5 2 u nless re q uire d f or 
safet y reas o ns d ue t o i na de q uate I O P c o ntr ol a n d atteste d t o 
b y t he i n vesti gat or) i n a Bi mat o pr ost S R st u d y e ye will 
recei ve S ha m a d mi nistrati o n i n t hat e ye o n t he Bi mat o pr ost 
S R re peat a d mi nistrati o n da y(s). 
 
Patie nts w h o use n o nst u d y I O P-l o weri n g me dicati o n 
( pr o hi bite d bef ore W ee k 5 2 u nless re q uire d f or safet y 
reas o ns d ue t o i na de q uate I O P c o ntr ol a n d atteste d t o b y t he 
i n vesti gat or) i n o nl y o ne e ye will be f oll o we d f or t he 
d urati o n of t he st u d y. 
 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o weri n g 
me dicati o n i n b ot h e yes bef ore t he ti me of t he M o nt h 1 4 
visit are n ot re q uire d t o atte n d t he M o nt h 1 4 or 1 8 visits 
u nless t he visit is 1 2 m o nt hs after t heir last i njecti o n or 
U p date d te xt f or clarit y.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M o nt hs 1 4 a n d 1 8  visits will be 
o pti o nal f or patie nts alrea d y treate d 
wit h n o nst u d y I O P-l o weri n g 
me dicati o n i n b ot h e yes. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
S ha m, at w hic h ti me t he patie nt ma y e xit earl y a n d s h o ul d 
c o m plete all M o nt h 2 0/ E xit visit e xa mi nati o ns.  Patie nts 
w h o ha ve recei ve d n o nst u d y I O P-l o weri n g me dicati o n i n 
b ot h e yes b y t he ti me of t he M o nt h 1 6 visit are n ot re q uire d 
t o atte n d t he M o nt h 1 8 visit, u nless t hat visit is 1 2 m o nt hs 
after t heir last i njecti o n or S ha m, at w hic h ti me t he patie nt 
ma y e xit earl y a n d s h o ul d c o m plete all M o nt h 2 0/ E xit visit 
e xa mi nati o ns. 
Secti o n 
5. 9. 1 
Wit h t he patie nt i n a s u pi ne p ositi o n, t he e ye a n d 
c o nj u ncti val f or nices s h o ul d be irri gate d wit h at least 1 0 m L 
of 5 % o p ht hal mic p o vi d o ne-i o di ne s ol uti o n a n d t he li ds a n d 
s urr o u n di n g or bital area s h o ul d be pre p pe d a n d dra pe d 
acc or di n g t o t he sta n dar d pr ot oc ol detaile d i n t he Pr ot oc ol 
Pr oce d ure Ma n ual. 
Re vise d te xt t o be c o nsiste nt wit h 
t he Pr oce d ure Ma n ual. 
Secti o n 
5. 1 0 
Patie nts w h o ha ve bee n treate d wit h n o nst u d y I O P-l o weri n g 
me dicati o n ( pr o hi bite d bef ore W ee k 5 2) i n o nl y o ne e ye 
will still atte n d a d mi nistrati o n visits; if t he treate d e ye is t he 
Bi mat o pr ost S R st u d y e ye, t h e patie nt will recei ve a S ha m 
a d mi nistrati o n i n t hat e ye.   
U p date d te xt f or clarit y. 
Secti o n 
6. 2 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
Secti o n 
6. 3 
 
Secti o n 
8. 3 
Secti o n 
8. 4 
  
 
 
Secti o ns 
8. 4. 1, 
8. 4. 3. 4, 
8. 4. 3. 6, 
8. 4. 3. 1 1, 
8. 4. 3. 1 3, 
8. 4. 3. 1 8, 
8. 4. 3. 2 1, 
8. 4. 3. 2 2, 
8. 4. 4. 2, 
a n d 
8. 4. 4. 4 
Secti o n 
8. 4. 3. 1 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Secti o ns 
8. 4. 4. 1 
a n d 
8. 4. 4. 3 
  
Secti o n 
8. 4. 4. 2 
Secti o n 
8. 5 
Patie nts s h o ul d be i nstr ucte d t o re m o ve t heir c o ntact le nses 
bef ore i nstillati o n of a n y st u d y- pr o vi de d t o pical o p ht hal mic 
me dicati o n, a n d t o kee p c o ntact le nses o ut f or at least 
1 5 mi n utes after i nstillati o n of e ye dr o ps. 
A d de d i nf or mati o n i ncl u de d i n t he 
patie nt dr o ps i nstr ucti o n ha n d o ut f or 
c o nsiste nc y. 
Secti o n 
8. 8 
Patie nts w h o ha ve recei ve d n o nst u d y I O P-l o weri n g 
me dicati o n i n b ot h e yes, or w h o d o n ot c o m plete a n 
A d mi nistrati o n Da y visit, ma y disc o nti n ue t he st u d y 1 2 
m o nt hs after t he last Bi mat o pr ost S R or S ha m 
a d mi nistrati o n. at w hic h ti me t he y s h o ul d c o m plete t he 
M o nt h 2 0/ E xit visit pr oce d ures. 
U p date d te xt f or clarit y. 
Secti o n 
8. 9 
After t he first a d mi nistrati o n ( or S ha m), fail ure t o u n der g o 
a n A d mi nistrati o n visit d oes n ot i n dicate t otal wit h dra wal 
fr o m t he st u d y.  Patie nts w h o ha ve recei ve d n o nst u d y 
I O P-l o weri n g me dicati o n i n o nl y o ne e ye will be f oll o we d 
f or t he d urati o n of t he st u d y.  Patie nts w h o ha ve recei ve d 
n o nst u d y I O P-l o weri n g me dicati o n i n b ot h e yes, or patie nts 
w h o d o n ot u n der g o C ycle 2 or 3 ( or b ot h) a d mi nistrati o ns 
( or S ha m a d mi nistrati o ns), will still be f oll o we d f or 1 2 
m o nt hs after t he last Bi mat o pr ost S R or S ha m 
a d mi nistrati o n f or safet y reas o ns.  T hese patie nts are 
eli gi ble f or Earl y Disc o nti n uati o n ( Earl y E xit) as descri be d 
i n Secti o n 8. 8, a b o ve. 
• Patie nt de vel o ps ( or has a n e xacer bati o n of) a me dical 
c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d 
p utc o m pr o mises t he patie nt at a n u nacce pta ble me dical ris k 
b y c o nti n ui n g patie nt’s a bilit y t o partici pate i n t he st u d y 
partici pati o n 
If a patie nt de vel o ps ( or has a n e xacer bati o n of) a me dical 
c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d p ut 
t he patie nt at a n u nacce pta ble me dical ris k b y c o nti n ui n g 
st u d y partici pati o n, t he patie nt will be wit h dra w n fr o m t he 
st u d y. 
U p date d te xt f or clarit y, as i n t his 
st u d y desi g n, patie nts are f oll o we d 
f or 1 2 m o nt hs after t heir last 
i njecti o n ( or S ha m) f or safet y 
p ur p oses, a n d cessati o n of i njecti o n 
d oes n ot c o nstit ute st u d y 
wit h dra wal. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
1 2. 3. 2  
A me n d me nt 2 
Title: T he Efficac y a n d Safet y of Bi mat o pr ost S R i n Patie nts Wit h O pe n- a n gle Gla uc o ma or 
Oc ular H y perte nsi o n 
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
Date of A me n d me nt: Marc h 2 0 1 7 
A me n d me nt S u m m ar y 
T his s u m mar y i ncl u des c ha n ges ma de t o Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 1 (a p pr o ve d 
A u g ust 2 0 1 5). T his pr ot oc ol was a me n de d t o c h a n ge t he scree ni n g re q uire me nt f or a n gle 
eli gi bilit y c o nfir mati o n i n t he st u d y e ye, m o dif y/clarif y t he i ncl usi o n/e xcl usi o n criteria, 
clarif y t he statistical a nal yses, a n d c ha n ge a d di ti o nal pr oce d ures f or patie nts wit h sic kle cell 
disease fr o m re q uire d t o o pti o nal. 
F oll o wi n g is a s u m mar y of c o nte nt- orie nte d c ha n ges t hat were ma de t o eac h secti o n of t he 
pr ot oc ol, a n d a brief rati o nale f or t hese c ha n ges. Mi n or e dit orial a n d d oc u me nt f or matti n g 
re visi o ns ha ve n ot bee n s u m marize d. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Pr ot oc ol 
S u m mar y 
Re m o ve d te xt fr o m t he visit sc he d ule secti o n referri n g t o 
rea di n g ce nter c o nfir mati o n of iri d oc or neal a n gle: 
•  
Scree ni n g ( u p t o 2 8 da ys); W as h o ut peri o d of u p t o 
4 2 da ys f or b ot h e yes ( w hic h ma y be gi n o nce scree ni n g 
pr oce d ures ha ve bee n c o m plete d a n d t he site has 
o btai ne d c o nfir mati o n of a nteri or se g me nt o ptical 
c o here nce t o m o gra p h y [ A S- O C T] iri d oc or neal a n gle 
q ualificati o n fr o m t he Rea di n g Ce nter); Baseli ne 
( Da ys - 3 t o - 1 u p t o 3 da ys) 
U p date d t he f oll o wi n g ke y i ncl usi o n criteria: 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  
U p date d t he f oll o wi n g ke y e xcl usi o n criteri o n: 
•  
T he f oll o wi n g s ur g ical hist or y: 
a.  
Hist or y or e vi de nce of c o m plicate d cataract 
s ur ger y i n t he st u d y e ye: e g, s ur ger y res ulti n g i n 
c o m plicate d le ns place me nt (s uc h as a nteri or 
c ha m ber i ntra oc ular le ns i m pla nt (I O L); p ha kic 
I O L; s ulc us I O L; a p ha kia, etc) or i ntra o perati ve 
c o m plicati o ns (e g s uc h as a p osteri or ca ps ular tear 
[ wit h or wit h o ut vitre o us l oss], s u bsta ntial iris 
tra u ma, etc) 
N ote: hist or y of u nc o m plicate d cataract s ur ger y is 
n ot a n e xcl usi o n. 
 
U p date d t he statistical a nal yses as f oll o ws: 
•  
I ntra oc ular press ure c ha n ge fr o m baseli ne will be 
a nal yze d usi n g a mi xe d-effects m o del re peate d 
U p date d t o reflect c ha n ges i n t he 
b o d y of t he pr ot oc ol. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 5 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
meas ures ( M M R M) a p pr oac h. T he m o del will i ncl u de 
t he fi xe d effects of treat me nt; I O P ti me- matc he d 
c ha n ge fr o m baseli ne I O P stra tificati o n; visit ( as t he 
res p o nse varia ble a n d treat me nt, ti me p oi nt ( H o urs 0 
a n d 2 at eac h visit of Wee ks 2, 6, a n d 1 2),; h o ur; t he 
t w o- wa y i nteracti o n bet wee n treat me nt a n d eac h of 
h o ur a n d visit; a n d t he t hree- wa y treat me nt- b y-
ti me p oi nt i nteracti o n bet wee n treat me nt, h o ur, a n d visit 
a n d baseli ne I O P stratificati o n as fi xe d effects. 
U nstr uct ure d c o varia nce matri x will be use d f or 
re peate d meas ures o n t he sa me patie nt; if t he m o del 
wit h u nstr uct ure d c o varia nce matri x fails t o c o n ver ge, 
m ulti ple i m p utati o n ( MI) will be i m ple me nte d bef ore 
M M R M. 
•  
F or t he U nite d States F o o d a n d Dr u g A d mi nistrati o n 
( U S F D A), t he pri mar y efficac y varia ble will be t he 
st u d y e ye ti me- matc he d I O P.  T he pri mar y a nal ysis 
will be base d o n Wee ks 2, 6, a n d 1 2 usi n g t he I T T 
p o p ulati o n.  S pecificall y, t he f oll o wi n g a nal ysis will be 
perf or me d:  ti me- matc he d I O P will be a nal yze d usi n g 
a n M M R M a p pr oac h base d o n t he sa me m o del as 
descri be d f or t he pri mar y efficac y a nal ysis of ti me-
matc he d I O P c ha n ge fr o m baseli ne.   
•  
Sa m ple Size Calc ulati o n:  T he sa m ple size calc ulati o n 
is base d o n t he pri mar y efficac y a nal ysis of t he 
ti me- matc he d I O P f or U S F D A re vie w beca use t he 
sa m ple size base d o n t he pri mar y efficac y a nal ysis f or 
ot her re gi o ns is e x pecte d t o be s maller. 
Ta ble 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
1 1 6 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
 
Ta bles 2-
5 
Secti o n 
1. 3. 1 
N o ncli nical st u dies wit h p har mac ol o g y e n d p oi nts ( Re p orts 
s h o we d d ose-relate d re d ucti o ns i n I O P i n n or m ote nsi ve 
C y n o m ol g us m o n ke ys a n d Bea gle d o gs, as well as i n laser-
i n d uce d oc ular h y perte nsi ve C y n o m ol g us m o n ke ys 
f oll o wi n g si n gle d oses.  T o xic ol og y st u dies, of at least 6 t o 
1 2 m o nt hs d urati o n a n d i ncl u di n g si n gle a n d re peat 
Bi mat o pr ost S R a d mi nistrati o n, were c o n d ucte d i n 
C y n o m ol g us m o n ke ys a n d Bea gle d o gs (
 Si n gle a n d re peat oc ular t o xicit y st u dies wit h 
Bi mat o pr ost S R i n d o gs wit h var yi n g A C 
a n gle sizes de m o nstrate d acc e pta ble safet y a n d oc ular 
t olera bilit y wit h si n gle d oses ≤ 2 0 µ g 
a n d wit h re peat d oses of 
≤ 1 5 µ g 
 F urt her m ore, n o 
a d verse dr u g- or i m pla nt-relate d oc ular fi n di n gs ha ve bee n 
see n f oll o wi n g t hree i ntraca meral i njecti o ns of u p t o 2 0 µg 
(t w o 1 0 µ g i m pla nts) Bi mat o pr ost S R ( 9 m o nt h ti me p oi nt 
i ncl u di n g hist o pat h ol o g y) i n t he o n g oi n g 1 8- m o nt h re peat 
d ose G o o d La b orat or y Practice ( G L P) st u d y i n d o gs ( Re p ort 
1). 
P har mac o ki netic st u dies (
i n 
Bea gle d o gs de m o nstrate d t h at s yste mic e x p os ure of 
bi mat o pr ost a n d bi mat o pr ost aci d was bel o w t he li mit of 
q ua ntitati o n ( B L Q) wit h d oses ≤ 6 0 µ g.  A q ue o us h u m or 
c o nce ntrati o ns ge nerall y pea ke d b y 1 0 wee ks p ost d ose f or 
d oses ≤ 3 0 µ g (
t he n 
decli ne d t o l o w le vels s u g gesti ve of near-c o m plete dr u g 
release fr o m t he de vice at 3 m o nt hs f or d oses ≤ 2 0 µ g.  B y 
1 4 wee ks f oll o wi n g a 2 0 µ g 
 d ose, oc ular 
tiss ues sa m ples were c ollecte d f or a nal ysis, w hic h 
de m o nstrate d t hat dr u g a n d meta b olite c o nce ntrati o ns were 
B L Q i n a q ue o us h u m or, vitre o us h u m or, reti na, a n d t he 
re m na nt i m pla nts, b ut detecte d i n c or nea, c h or oi d, a n d iris-
ciliar y b o d y. A p har mac o ki netic st u d y ( P K 1 4 0 2 5- P K) was 
c o n d ucte d i n Bea gle d o gs c o m p ari n g t he oc ular distri b uti o n 
of t o pical bi mat o pr ost 0. 0 3 % s ol uti o n or a si n gle 
Bi mat o pr ost S R i m pla nt ( 1 5 µ g).  F oll o wi n g 
t o pical a d mi nistrati o n, bi mat o pr ost a n d bi mat o pr ost aci d 
distri b ute d i nt o t he iris-ciliar y b o d y as well as ot her ( off 
U p date d i nf or mati o n fr o m 
c o m plete d st u dies 
 Si n gle a n d re peat oc ular t o xicit y st u dies wit h 
Bi mat o pr ost S R i n d o gs wit h var yi n g A C 
c o nce ntrati o ns ge nerall y pea ke d b y 1 0 wee ks p ost d ose f or 
g (
t he n 
1 4 wee ks f oll o wi n g a 2 0 µ g 
 d ose, oc ular 
of t o pical bi mat o pr ost 0. 0 3 % s ol uti o n or a si n gle 
Bi mat o pr ost S R i m pla nt ( 1 5 
Bi mat o pr ost S R a d mi nistrati o n, were c o n d ucte d i n 
C y n o m ol g us m o n ke ys a n d Bea gle d o gs (
C y n o m ol g us m o n ke ys a n d Bea gle d o gs (
 Si n gle a n d re peat oc ular t o xicit y st u dies wit h 
 Si n gle a n d re peat oc ular t o xicit y st u dies wit h 
e pta ble safet y a n d oc ular 
g 
t olera bilit y wit h si n gle d oses 
a n d wit h re peat d oses of 
a n d wit h re peat d oses of 
g 
 F urt her m ore, n o 
a n d wit h re peat d oses of 
P har mac o ki netic st u dies (
i n 
d ose G o o d La b orat or y Practice 
1). 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
1 1 7 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
tar get) tiss ues wit h c o nce ntrati o ns i n t he b ul bar c o nj u ncti va, 
e yeli d mar gi n, a n d peri or bital fat si g nifica ntl y hi g her t ha n 
t h ose o bser ve d i n t he iris-ciliar y b o d y. I n c o ntrast, 
f oll o wi n g a d mi nistrati o n of a si n gle 
Bi mat o pr ost S R i m pla nt at 1 5 µ g, bi mat o pr ost a n d 
bi mat o pr ost aci d c o nce ntrati o ns were eit her bel o w t he li mit 
of q ua ntitati o n ( B L Q) or near t he detecti o n li mit i n b ul bar 
c o nj u ncti va, e yeli d mar gi n, a n d peri or bital fat w hile t he 
hi g hest bi mat o pr ost a n d bi mat o pr ost aci d c o nce ntrati o ns 
were o bser ve d i n t he tar get tiss ue, t he iris ciliar y b o d y. 
Reti nal c o nce ntrati o ns were B L Q f oll o wi n g b ot h t o pical 
a n d Bi mat o pr ost S R a d mi nistrati o n. 
Secti o n 
1. 3. 3 
St u d y 1 9 2 0 2 4- 0 4 1 D is a n o n g oi n g was a P hase 1/ 2, paire d-
e ye c o m paris o n e val uati n g t he safet y a n d efficac y of 4 d ose 
stre n gt hs of Bi mat o pr ost S R ( 6 µ g, 1 0 µ g, 1 5 µ g, or 2 0 µ g 
[ 2 × 1 0 µ g i m pla nts]), as si n gle or re peat a d mi nistrati o n i n 
o ne e ye (st u d y e ye), vers us t he use of t o pical L U MI G A N ®  
0. 0 3 % i n t he fell o w e ye ( n o nst u d y e ye).  T he o bjecti ve of 
t his st u d y is was t o e val uate t he safet y a n d I O P-l o weri n g 
efficac y of Bi mat o pr ost S R i n patie nts wit h O A G. 
As of Marc h 2 0 1 5, a t otal of 1 0 9 patie nts ha d recei ve d a 
si n gle a d mi nistrati o n; a n d as of J u ne 2 0 1 5, 2 4 patie nts ha d 
recei ve d a re peat a d mi nistrati o n of Bi mat o pr ost S R.  Base d 
o n a re vie w of t he efficac y data as of Marc h 2 0 1 5, a A tre n d 
i n d ose res p o nse has bee n was o bser ve d acr oss t he 4 d ose 
stre n gt hs t hat were teste d.  A vaila ble d Data s u g gest t hat t he 
i m pla nt ma y pr o vi de t o pical pr osta gla n di n a nal o g-li ke 
efficac y u p t o 3 t o 4 m o nt hs p ost-i m pla ntati o n i n t he 
maj orit y of patie nts.  Data f oll o wi n g t he sec o n d 
a d mi nistrati o n i n t he re d ose d patie nts s h o we d si milar I O P 
l o weri n g t o t hat o bser ve d f oll o wi n g t he first a d mi nistrati o n 
of Bi mat o pr ost S R.  
As of Marc h 2 0 1 5, Bi mat o pr ost S R has s h o w n s h o we d a n 
acce pta ble safet y pr ofile wit h si n gle a n d re peat 
a d mi nistrati o ns i n o n g oi n g s St u d y 1 9 2 0 2 4- 0 4 1 D.  M ost 
a d verse e ve nts were oc ular, mil d or m o derate i n se verit y, 
occ urre d wit hi n t he first 8 2 da ys after Bi mat o pr ost S R 
a d mi nistrati o n, a n d were c o nsi dere d relate d t o t he st u d y 
dr u g a d mi nistr ati o n pr oce d ure.  T here has s h o w n were n o 
re p orts of seri o us st u d y dr u g-relate d a d verse e ve nts, a n d n o 
ne w safet y c o ncer ns has s h o w n were o bser ve d after t he 
sec o n d treat me nt.  Please refer t o t he I n vesti gat or’s 
Br oc h ure f or details o n re p orte d safet y fi n di n gs. 
U p date d i nf or mati o n fr o m rece ntl y 
c o m plete d st u d y 
Secti o n 3 
T he st u d y will be c o n d ucte d at a p pr o xi matel y 1 6 5 0 sites 
gl o ball y. 
Re vise d t o reflect act ual n u m ber of 
sites 
Secti o n 
4. 1 
E nr oll me nt of a p pr o xi matel y 6 0 0 patie nts i n t otal at 
a p pr o xi matel y 1 5 0 1 6 0 sites, wit h a p pr o xi matel y 
2 0 0 patie nts per gr o u p, is pla n ne d t o e ns ure 1 8 0 c o m plete d 
patie nts per gr o u p, ass u mi n g a pre mat ure disc o nti n uati o n 
rate of 1 0 %. 
Re vise d t o reflect act ual n u m ber of 
sites 
Secti o n 
4. 2 
T he st u d y p o p ulati o n c o nsists of patie nts wit h O A G or 
O H T a n d a n o pe n iri d oc or neal a n gle i nferi orl y b y cli nical 
Re vise d f or c o nsiste nc y wit h 
u p date d i ncl usi o n criteria 
t h ose o bser ve d i n t he iris-ciliar y b o d y. I n c o ntrast, 
f oll o wi n g a d mi nistrati o n of a si n gle 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 8 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
g o ni osc o p y i n t he st u d y e y e, a n d O A G or O H T i n t he 
fell o w e ye, w here b ot h e yes re q uire I O P-l o weri n g 
me dicati o n.  T he e ye t hat meets t he e ntr y criteria 
( Secti o ns 4. 3 a n d 4. 4) will be selecte d as t he st u d y e ye.  If 
b ot h e yes meet t he e ntr y crite ria (i ncl u di n g iri d oc or neal 
a n gles t hat ha ve bee n c o nfir me d as q ualifie d b y t he Rea di n g 
Ce nter a nteri or se g me nt o pti cal c o here nce t o m o gra p h y [ A S-
O C T assess me nt]), t he e ye wit h  t he hi g her I O P at Baseli ne 
H o ur 0 will be selecte d as t he st u d y e ye.  If b ot h e yes ha ve 
t he sa me I O P, t he n t he ri g ht e ye will be desi g nate d as t he 
st u d y e ye. 
A n gle q ualificati o n will be i n de pe n de ntl y c o nfir me d as 
bei n g q ualifie d b y 2 o p ht hal m ol o gists, a n d e n d ot helial cell 
de nsit y q ualificati o n f or st u d y e ntr y will be deter mi ne d b y 
t he Rea di n g Ce nter base d o n A S- O C T a n d s pec ular 
micr osc o p y assess me nt res pecti vel y (see Pr ot oc ol 
Pr oce d ure Ma n ual f or details). 
Secti o n 
4. 2. 1 
4. 2. 1  
Patie nts Wit h Sic kle Cell Trait or Disease 
At scree ni n g all patie nts will be teste d f or sic kle cell trait or 
disease.  Patie nts wit h sic kle cell trait or disease ( or ot her 
he m o gl o bi n o pat hies) ma y be e nr olle d at t he discreti o n of 
t he i n vesti gat or base d o n a n i n di vi d ual ris k- be nefit 
assess me nt.  Beca use of a s li g htl y hi g her ris k of I O P 
ele vati o n a n d i ntra oc ular c o m plicati o ns i n t he setti n g of a 
micr o h y p he ma, patie nts wit h t hese dis or ders m ust ma y 
u n der g o o pti o nal a d diti o nal safet y m o nit ori n g 
( bi o micr osc o p y a n d I O P meas ure me nts) after 
i njecti o n/ S ha m i njecti o n at t he i n vesti gat or’s discreti o n (as 
o utli ne d i n see Secti o n 8. 4).  A d diti o nal i nf or mati o n a b o ut 
t he Bi mat o pr ost S R e x perie nce i n patie nts wit h sic kle trait 
is pr o vi de d i n t he I n vesti gat or’s Br oc h ure. 
Base d o n t he o n g oi n g safet y 
m o nit ori n g of t he 1 9 2 0 2 4- 0 9 1 a n d 
1 9 2 0 2 4- 0 9 2 st u dies, n o i ncrease d 
ris k of h y p he ma or micr o h y p he ma 
wit h sic kle cell traits or sic kle cell 
disease is c o nfir me d. T here are 
4 0 0 + patie nts ha d at least o ne 
Bi mat o pr ost S R i njecti o n i n t he 
2 st u dies (esti mate d base d o n 1: 1: 1 
rati o), t here is o nl y o ne re p ort of 
micr o h y p he ma i n a N O N-sic kle cell 
patie nt. N o a nteri or c ha m ber safet y 
c o ncer ns re p orte d i n t he 1 4 sic kle 
cell or traits patie nts. 
Secti o n 
4. 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 1 9 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
Secti o n 
4. 4 
9. Pre vi o us e nr oll me nt i n a n ot her Aller ga n Bi mat o pr ost S R 
St u d y 1 9 2 0 2 4- 0 4 1 D 
1 3. T he f oll o wi n g s ur gical hist or y: 
a. Hist or y or e vi de nce of c o m p licate d cataract s ur ger y i n t he 
st u d y e ye: e g, s ur ger y res ulti n g i n c o m plicate d le ns 
place me nt (s uc h as a nteri or c ha m ber i ntra oc ular le ns 
i m pla nt ([I O L]);, p ha kic I O L;, s ulc us I O L;, a p ha kia;, etc) or 
i ntra o perati ve c o m plicati o ns (e g, s uc h as a p osteri or 
ca ps ular tear [ wit h or wit h o ut vitre o us l oss], iris tra u ma, 
etc). N ote: hist or y of u nc o m pli cate d cataract s ur ger y is n ot 
a n e xcl usi o n. 
 
 
 
 
Re vise d beca use m ulti ple st u dies 
are o n g oi n g. 
 
 
Re vise d f or clarit y 
 
 
 
 
 
 
 
 
 
 
Secti o n 
5. 3 
T he site c o or di nat or a n d desi g nate d staff will n ot be mas ke d 
t o w het her t he patie nt recei ve d 1 of t he 2 d ose stre n gt hs of 
Bi mat o pr ost S R or t he S ha m a d mi nistrati o n pr oce d ure, b ut 
will be mas ke d t o t he s pecific i m pla nt d ose stre n gt h.  T he 
patie nt a n d t he re mai ni n g staff will be mas ke d t o t he 
patie nt’s treat me nt assi g n me nt.  Efficac y I O P 
meas ure me nts will be mas ke d b y usi n g a 2- pers o n rea di n g 
met h o d as descri be d i n Secti o n 6. 1. 1 (f or o pti o nal 
p ost o perati ve I O P meas ure me nts f or patie nts wit h sic kle 
cell disease or trait [ or ot her he m o gl o bi n o pat hies], see 
Secti o n 8. 4). 
Base d o n t he o n g oi n g safet y 
m o nit ori n g of t he 1 9 2 0 2 4- 0 9 1 a n d 
1 9 2 0 2 4- 0 9 2 st u dies, n o i ncrease d 
ris k of h y p he ma or micr o h y p he ma 
wit h sic kle cell traits or sic kle cell 
disease is c o nfir me d. T here are 
4 0 0 + patie nts ha d at least o ne 
Bi mat o pr ost S R i njecti o n i n t he 
2 st u dies (esti mate d base d o n 1: 1: 1 
rati o), t here is o nl y o ne re p ort of 
micr o h y p he ma i n a N O N-sic kle cell 
patie nt. N o a nteri or c ha m ber safet y 
c o ncer ns re p orte d i n t he 1 4 sic kle 
cell or traits patie nts. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 0 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Secti o n 
5. 7 
I n vesti gati o nal me dici nal pr o d uct m ust be st ore d as 
descri be d i n t he I n vesti gat or’s Br oc h ure.I n vesti gati o nal 
me dici nal pr o d uct m ust be st ore d at a r o o m te m perat ure 
re prese nti n g a us ual a n d c usto mar y w or ki n g e n vir o n me nt, 
as descri be d i n t he Pr ot oc ol Pr oce d ure Ma n ual.  
Wit h t he pr o d uct bei n g u n der 
de vel o p me nt, t he c urre nt details o n 
t he st ora ge c o n diti o ns will be 
reflecte d i n t he I n vesti gat or’s 
Br oc h ure. 
Secti o n 
5. 9. 4 
N ote:  Patie nts wit h sic kle cell disease or trait ( or ot her 
he m o gl o bi n o pat hies) will be e x pecte d t o ma y u n der g o 
o pti o nal bi o micr osc o p y a n d I O P e xa mi nati o n i n b ot h e yes 
4 h o urs after eac h Bi mat o pr ost S R a d mi nistrati o n ( or S ha m 
a d mi nistrati o n).  T his o pti o nal I O P e xa mi nati o n is f or 
p ost o perati ve p ur p oses o nl y, a n d as s uc h d oes n ot re q uire a 
mas ke d, 2- pers o n rea di n g met h o d.  T he I O P s h o ul d be 
ta ke n o nl y o nce t o a v oi d e xcessi ve p osta d mi nistrati o n ( or 
S ha m a d mi nistrati o n) ma ni p ula ti o n of t he e ye, a n d s h o ul d 
be ta ke n b y t he i n vesti gat or ( or ot her u n mas ke d, q ualifie d 
pers o n nel).  T his p osta d mi nistrati o n ( or S ha m 
a d mi nistrati o n) e xa mi nati o n ma y be perf or me d usi n g a 
G ol d ma n n a p pla nati o n t o n o meter or a ha n d- hel d t o n o meter.  
( See t he St u d y Pr oce d ure Ma n ual f or details.) 
Base d o n t he o n g oi n g safet y 
m o nit ori n g of t he 1 9 2 0 2 4- 0 9 1 a n d 
1 9 2 0 2 4- 0 9 2 st u dies, n o i ncrease d 
ris k of h y p he ma or micr o h y p he ma 
wit h sic kle cell traits or sic kle cell 
disease is c o nfir me d. T here are 
4 0 0 + patie nts ha d at least o ne 
Bi mat o pr ost S R i njecti o n i n t he 
2 st u dies (esti mate d base d o n 1: 1: 1 
rati o), t here is o nl y o ne re p ort of 
micr o h y p he ma i n a N O N-sic kle cell 
patie nt. N o a nteri or c ha m ber safet y 
c o ncer ns re p orte d i n t he 1 4 sic kle 
cell or traits patie nts. 
Secti o n 
6. 2 
He mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis:  Bl o o d a n d 
uri ne sa m ples will be c ollecte d f or bl o o d c he mistr y a n d 
he mat ol o g y pa nels (i ncl u di n g sic kle cell testi n g b y l ocal 
la b orat ories) a n d uri nal ysis. 
 
 
 
 
 
 
 
 
 
 
 
Base d o n t he o n g oi n g safet y 
m o nit ori n g of t he 1 9 2 0 2 4- 0 9 1 a n d 
1 9 2 0 2 4- 0 9 2 st u dies, n o i ncrease d 
ris k of h y p he ma or micr o h y p he ma 
wit h sic kle cell traits or sic kle cell 
disease is c o nfir me d. T here are 
4 0 0 + patie nts ha d at least o ne 
Bi mat o pr ost S R i njecti o n i n t he 
2 st u dies (esti mate d base d o n 1: 1: 1 
rati o), t here is o nl y o ne re p ort of 
micr o h y p he ma i n a N O N-sic kle cell 
patie nt. N o a nteri or c ha m ber safet y 
c o ncer ns re p orte d i n t he 1 4 sic kle 
cell or traits patie nts. 
 
 
 
 
 
 
 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 1 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
 
 
 
 
 
 
 
 
 
Secti o n 
6. 4. 3. 1 
T he bl o o d tests perf or me d at t he scree ni n g visit will i ncl u de 
testi n g f or sic kle cell disease or trait b y a site-selecte d a n d 
q ualifie d l ocal la b orat or y, as o utli ne d i n t he Pr ot oc ol 
Pr oce d ure Ma n ual. 
Base d o n t he o n g oi n g safet y 
m o nit ori n g of t he 1 9 2 0 2 4- 0 9 1 a n d 
1 9 2 0 2 4- 0 9 2 st u dies, n o i ncrease d 
ris k of h y p he ma or micr o h y p he ma 
wit h sic kle cell traits or sic kle cell 
disease is c o nfir me d. T here are 
4 0 0 + patie nts ha d at least o ne 
Bi mat o pr ost S R i njecti o n i n t he 
2 st u dies (esti mate d base d o n 1: 1: 1 
rati o), t here is o nl y o ne re p ort of 
micr o h y p he ma i n a N O N-sic kle cell 
patie nt. N o a nteri or c ha m ber safet y 
c o ncer ns re p orte d i n t he 1 4 sic kle 
cell or traits patie nts. 
Secti o n 7 
T hree data base l oc ks are pla n ne d.  T he first data base l oc k 
will ta ke place after all patie nts ha ve c o m plete d or 
pre mat urel y disc o nti n ue d bef ore t he Wee k 1 2 visit.  
Si milarl y, t he data base will be l oc ke d after all patie nts ha ve 
c o m plete d or pre mat urel y disc o nti n ue d bef ore Wee k 5 2 a n d 
M o nt h 2 0/ E xit.  A nal yses will be perf or me d after eac h l oc k.  
Pri or t o t he first data base l oc k a detaile d a nal ysis pla n will 
be fi nalize d.  T o mai ntai n t he i nte grit y of t he o n g oi n g st u d y, 
Aller ga n st u d y pers o n nel w h o are directl y i n v ol ve d i n data 
ha n dli n g a n d s u p p orti n g t he trial (s uc h as t he cli nical st u d y 
tea m) will re mai n mas ke d t o treat me nt assi g n me nt of 
i n di vi d ual patie nts u ntil d uri n g t he st u d y c o m pleti o n. T o 
a v oi d p ote ntial data u n mas ki n g bet wee n l oc ks a n d t o 
pr otect trial i nte grit y, st u d y statistical pers o n nel w h o ha ve 
U p date d te xt f or clarit y. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 2 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
bee n u n mas ke d after eac h l oc k will n o l o n ger be i n v ol ve d 
directl y i n a n y o n g oi n g mas ke d st u d y c o n d uct. A n ot her 
statisticia n, w h o is still mas ke d t o st u d y treat me nt, will 
ass u me t hese res p o nsi bilities u ntil t he ne xt l oc k. U n mas ke d 
data ha n dli n g a n d a p pr o priat e data a n d res ults access will 
be s pecifie d pri or t o eac h l oc k. 
Secti o n 
7. 2 
T o a v oi d c o nf o u n di n g of efficac y data, I O P meas ure me nts 
o btai ne d after i nitiati n g t he use of n o nst u d y I O P-l o weri n g 
me dicati o n i n a n e ye will be treate d as missi n g f or t hat e ye 
e xcl u de d fr o m t he calc ulati o n of t he s u m mar y statistics a n d 
t he statistical a nal yses f or t hat e ye b ut ra w val ues will be 
prese nte d i n t he listi n gs. 
U p date d te xt f or clarit y. 
Secti o n 
7. 3. 1 
I ntra oc ular press ure c ha n ge fr o m baseli ne will be a nal yze d 
usi n g a mi xe d-effects m o del re peate d meas ures ( M M R M) 
a p pr oac h.  T he m o del will i ncl u de t he fi xe d effects of 
treat me nt; I O P ti me- matc he d c ha n ge fr o m baseli ne I O P 
stratificati o n; visit (as t he res p o nse varia ble a n d treat me nt, 
ti me p oi nt ( H o urs 0 a n d 2 at eac h visit of Wee ks 2, 6, a n d 
1 2); h o ur; t he t w o- wa y, treat me nt- b y-ti me p oi nt i nteracti o n, 
bet wee n treat me nt a n d eac h of h o ur a n d visit; a n d t he t hree-
wa y i nteracti o n bet wee n treat me nt, h o ur, a n d visit baseli ne 
I O P stratificati o n as fi xe d effects. U nstr uct ure d c o varia nce 
matri x will be use d f or re peate d meas ures o n t he sa me 
patie nt; if t he m o del wit h u nstr uct ure d c o varia nce matri x 
fails t o c o n ver ge, m ulti ple i m p utati o n ( MI) will be 
i m ple me nte d bef ore M M R M.  T he details of t he m o del 
s pecificati o ns will be pr o vi de d i n t he a nal ysis pla n. 
U p date d te xt f or clarit y. 
Secti o n 
7. 3. 2 
Sec o n dar y efficac y a nal yses c o m pari n g eac h Bi mat o pr ost 
S R d ose stre n gt h a n d ti m ol ol t o test t he n o- differe nce n ull 
h y p ot hesis will be perf or me d at sc he d ule d visits ( W ee ks 2, 
6, a n d 1 2) a n d h o urs f or ( 1) ti me- matc he d I O P a n d ( 2) ti me-
matc he d I O P c ha n ge fr o m baseli ne. 
T he a nal ysis of ti me- matc he d I O P will be si milarl y 
perf or me d as descri be d a b o ve wit h ti me matc he d I O P 
re placi n g ti me- matc he d I O P c ha n ge fr o m baseli ne i n t he 
a nal ysis m o del. 
U p date d te xt f or clarit y. 
Secti o n 
7. 6 
F or t he U S F D A re vie w, t he pri mar y efficac y varia ble will 
be t he st u d y e ye ti me- matc he d I O P. 
F or eac h Bi mat o pr ost S R d ose stre n gt h w hic h de m o nstrates 
efficac y (cli nical n o ni nferi orit y) as descri be d i n t he pri mar y 
efficac y a nal yses, sec o n dar y efficac y a nal yses c o m pari n g 
t he Bi mat o pr ost S R d ose stre n gt h a n d ti m ol ol t o test t he n o-
differe nce n ull h y p ot hesis will be perf or me d at sc he d ule d 
visits ( Wee ks 2, 6, a n d 1 2) a n d h o urs f or ti me- matc he d I O P. 
U p date d te xt f or clarit y. 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 3 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
Secti o n 
7. 7 
T he sa m ple size calc ulati o n is base d o n t he pri mar y efficac y 
a nal ysis of t he ti me- matc he d I O P f or U S F D A re vie w si nce 
t he sa m ple size base d o n t he pri mar y efficac y a nal ysis f or 
ot her re gi o ns is e x pecte d t o be s maller. 
U p date d te xt f or clarit y. 
Secti o n 
8. 2 
 
 
 
 
 
 
Secti o n 
8. 3 
 
 
Secti o n 
8. 4 
  
 
  
Secti o n 
8. 4. 1 
 
 
 
 
Secti o ns 
8. 4. 3. 1, 
8. 4. 3. 8, 
8. 4. 3. 1 5 
 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
Aller ga n C o nfi de nti al  
Pr ot oc ol 1 9 2 0 2 4- 0 9 1 A me n d me nt 2 
 
 
1 2 4 
G D D- T A- T- 0 0 4 v 2 0 1 3. 9 
 
Secti o n
 Re visi o n
  
R ati o n ale
 
 
Secti o ns 
8. 4. 3. 7, 
8. 4. 3. 1 4, 
8. 4. 3. 2 2 
 
 
 


 
 
A p pr o v al D at e : 
 
 
1 6- M ar- 2 0 1 7
A L L E R G A N
A L L E R G A N
 
 
 
 
 
 
 
 
 
 
D at e ( D D/ M M M/ Y Y Y Y)/ Ti m e ( P T)  
Si g n e d b y:  
J u stifi c ati o n  
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Pr ot o c ol 1 9 2 0 2 4- 0 9 1 A m e n d m e nt 2

SAP_000.pdf: 
 
NCT02247804 
 
Study ID: 192024-091 
 
Title: Efficacy and Safety of Bimatoprost Sustained-Release (SR) in Patients With Open-angle Glaucoma 
or Ocular Hypertension 
 
Statistical Analysis Plan Amendment 3 Date: 19‐Apr‐2018 


Allergan PLC 
 
Page 1 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
1.0 
TITLE PAGE 
 
 
192024-091 
THE EFFICACY AND SAFETY OF BIMATOPROST SR IN PATIENTS WITH 
OPEN-ANGLE GLAUCOMA OR OCULAR HYPERTENSION 
STATISTICAL ANALYSIS PLAN Amendment 3 - Clinical Study Report 
Final: 19APR2018 
Confidentiality Statement 
This document is the property of Allergan, Plc., and may not⎯in full or part⎯be passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, Plc. 
 
 


Allergan PLC 
 
Page 2 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
TABLE OF CONTENTS .................................................................................................................. 2 
2.1 
List of Tables ...................................................................................................................... 3 
3.0 
LIST OF ABBREVIATIONS ........................................................................................................... 4 
4.0 
INTRODUCTION ............................................................................................................................ 6 
5.0 
OBJECTIVES ................................................................................................................................. 17 
6.0 
PATIENT POPULATIONS ............................................................................................................ 18 
6.1 
Intent-to-Treat Population ................................................................................................. 18 
6.2 
Safety Population .............................................................................................................. 18 
6.3 
Per-Protocol Population .................................................................................................... 18 
6.4 
Data Collected but not Analyzed ...................................................................................... 18 
7.0 
PATIENT DISPOSITION .............................................................................................................. 19 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................ 20 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................ 22 
9.1 
Extent of Exposure ........................................................................................................... 22 
10.0 
EFFICACY ANALYSES ............................................................................................................... 23 
10.1 
Primary Efficacy Parameter(s) .......................................................................................... 23 
10.1.1 
Primary Efficacy Analysis .................................................................................. 23 
10.2 
Secondary Efficacy Parameter(s) ...................................................................................... 26 
10.2.1 
Secondary Efficacy Analysis #1 ......................................................................... 26 
10.2.2 
Secondary Efficacy Analysis #2 ......................................................................... 27 
10.3 
Efficacy Analyses for US FDA......................................................................................... 27 
10.3.1 
Primary Efficacy Analysis for US FDA ............................................................. 27 
10.3.2 
Secondary Efficacy Analysis for US FDA ......................................................... 28 
 
 
11.0 
SAFETY ANALYSES .................................................................................................................... 31 
11.1 
Adverse Events ................................................................................................................. 31 
11.2 
Vital Signs ........................................................................................................................ 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 3 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
11.3.13  Pregnancy Test ................................................................................................... 39 
11.4 
Subgroup Analyses for Safety Variables .......................................................................... 39 
12.0 
HEALTH OUTCOMES ANALYSES ............................................................................................ 40 
13.0 
INTERIM ANALYSIS ................................................................................................................... 41 
14.0 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 42 
15.0 
STATISTICAL SOFTWARE ......................................................................................................... 43 
16.0 
DATA HANDLING CONVENTIONS .......................................................................................... 44 
16.1 
Visit Time Windows ......................................................................................................... 44 
16.2 
Derived Variables ............................................................................................................. 46 
16.3 
Repeated or Unscheduled Assessments of Safety Parameters .......................................... 46 
16.4 
Missing Severity Assessment for Adverse Events ............................................................ 46 
16.5 
Missing Causal Relationship to Study Treatment for Adverse Events ............................. 47 
16.6 
Missing Date Information for Adverse Events ................................................................. 47 
16.7 
Missing Date Information for Prior or Concomitant Medications .................................... 48 
16.7.1 
Incomplete Start Date ......................................................................................... 48 
16.7.2 
Incomplete Stop Date ......................................................................................... 49 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................................... 51 
18.0 
REFERENCES ............................................................................................................................... 52 
19.0 
AMENDMENTS ............................................................................................................................ 53 
19.1 
Amendment 1 ................................................................................................................... 53 
19.2 
Amendment 2 ................................................................................................................... 58 
19.3 
Amendment 3 ................................................................................................................... 62 
 
2.1 
LIST OF TABLES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 4 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AS-OCT 
anterior segment optical coherence tomography 
BCVA 
best corrected visual acuity 
BID 
twice daily dosing 
CCT 
central corneal thickness 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
ITT 
intent to treat 
IOP  
intraocular pressure  
LOCF 
last observation carried forward 
MCMC 
Markov chain Monte Carlo 
MD 
mean deviation 
MI 
multiple imputation 
MMRM 
mixed-effects model for repeated measures 
OAG 
open-angle glaucoma  
OHT 
ocular hypertension  
OCT 
optical coherence tomography 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SITA 
Swedish Interactive Thresholding Algorithm 
SOC 
system organ class 


Allergan PLC 
 
Page 5 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
SR 
sustained release 
TEAE 
treatment-emergent adverse event 
US 
United States 
 


Allergan PLC 
 
Page 6 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
4.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data for Study 192024-091. 
Specifications of tables, figures, and data listings are contained in a separate document. 
Study 192024-091 is a Phase 3, multicenter, randomized, masked, parallel-group 
comparison, active-controlled, repeat administration study in patients at least 18 years of 
age who have been diagnosed with open-angle glaucoma (OAG) or ocular hypertension 
(OHT). 
The length of the study will be approximately 22 months for each patient, consisting of 
screening of up to 28 days before washout, washout period of up to 42 days before initial 
administration of study medication, 52-week treatment period, plus 8 months extended 
follow-up. Signed informed consent from the patient or the patient’s legally authorized 
representative will be obtained before any study-related procedures are begun. All 
patients who provide informed consent will be assigned a subject number. Patients 
meeting all inclusion and no exclusion criteria will be randomized in a 1:1:1 ratio to 
receive 1 of 2 dose strengths of Bimatoprost SR treatment (Bimatoprost 10 µg or 15 µg 
plus vehicle twice daily [BID] eye drops) or control treatment (Sham administration 
procedure plus timolol BID eye drops) in the study eye on Day 1. The randomization will 
be further stratified by baseline study eye Hour 0 IOP (≤ 25 mm Hg or > 25 mm Hg). 
Patients who have not received non-study IOP-lowering medication in both eyes will 
receive a repeat administration of Bimatoprost sustained release (SR) or control treatment 
in the study eye at the Week 16 and Week 32 visits. 
All patients will be masked to their treatment group. Treatment groups are shown as 
follows: 
Treatment 
Study Eye Treatment 
Fellow Eye Treatment 
Bimatoprost SR 10 µg  
Dose strength: 10 µg 
Eye drops: Vehicle BID 
Sham administration procedure 
Eye drops: Timolol BID 
Bimatoprost SR 15 µg 
Dose strength: 15 µg 
Eye drops: Vehicle BID 
Sham administration procedure 
Eye drops: Timolol BID 
Control 
Sham administration procedure 
Eye drops: Timolol BID 
Sham administration procedure 
Eye drops: Timolol BID 
BID = twice daily 
 


Allergan PLC 
 
Page 7 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Three database locks are planned. The first database lock will take place after all patients 
have completed or prematurely discontinued before the Week 12 visit (defined as 
Week 12 Lock). Similarly, the database will be locked after all patients have completed 
or prematurely discontinued before Week 52 (defined as Week 52 Lock) and 
Month 20/Exit (defined as Final Lock). To avoid potential data unmasking between locks 
and to protect trial integrity, study personnel who have been unmasked after each lock 
will no longer be involved directly in any ongoing study conduct. Another statistician, 
who is still masked to study treatment, will assume these responsibilities until the next 
lock. Unmasked data handling and appropriate data and results access will be specified 
prior to each lock. 
 
 


Allergan PLC 
 
Page 8 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 9 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 10 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 11 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 12 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 13 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 14 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 15 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 16 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 17 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
5.0 
OBJECTIVES 
The objective of this study is to evaluate the intraocular pressure (IOP)-lowering efficacy 
and safety of 2 dose strengths of Bimatoprost SR in patients with OAG or OHT after 
initial and repeated administrations. 
The clinical hypotheses are: 
• At least 1 dose strength (10 µg or 15 µg) of Bimatoprost SR will have an 
IOP-lowering effect that is noninferior to that of topically administered timolol 0.5% 
(hereafter referred to as timolol) eye drops in patients with OAG or OHT following 
single and repeat administrations. 
• Bimatoprost SR administered intracamerally in dose strengths of 10 µg or 15 µg will 
have an acceptable safety profile in patients with OAG or OHT following single and 
repeat administrations. 


Allergan PLC 
 
Page 18 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
6.0 
PATIENT POPULATIONS 
6.1 
INTENT-TO-TREAT POPULATION 
The intent-to-treat (ITT) population will consist of all randomized patients. 
6.2 
SAFETY POPULATION 
The safety population will consist of all patients who received at least 1 dose of study 
treatment. 
6.3 
PER-PROTOCOL POPULATION 
The per-protocol (PP) population will consist of the subset of patients in the ITT 
population who had the primary efficacy variable measured. IOP measures deemed being 
influenced by other medications would be excluded from PP analysis. The PP population 
will be used to confirm the primary efficacy analyses. A separate document to define 
further criteria and details of data to be excluded from the PP analyses will be finalized 
prior to the Week 12 database lock. 
 
6.4 
DATA COLLECTED BUT NOT ANALYZED 
Clinical lab test data and general (non-ophthalmic) physical examination will only be 
collected at screening and will not be analyzed. 
Any other data collected, but not analyzed, will be described in the clinical study report. 


Allergan PLC 
 
Page 19 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
7.0 
PATIENT DISPOSITION 
The number and percentage of patients in the 3 study populations (ITT, Safety, and PP) 
will be summarized by treatment group; the number of patients screened will be 
summarized overall only. 
The number and percentage of patients who complete and the number and percentage of 
patients who prematurely discontinue will be presented for each treatment group and 
pooled across treatment groups for the ITT population by Cycle and for the entire study. 
The study completers will be defined as the patients who received at least 1 injection and 
complete the extended safety follow up visits. The completers for each cycle will be 
defined as the patients who received injection in the relevant cycle and completed the 
cycle by either receiving the following injection or completing the extended safety follow 
up visits. The reasons for premature discontinuation from each administration cycle and 
the entire study will be summarized (number and percentage) by treatment group for the 
ITT population. For patients who prematurely discontinue due to adverse events (AEs), 
the reason will be further classified into ocular AE and nonocular AE. All patients who 
prematurely discontinue during the study will be listed by discontinuation reason for the 
ITT population. 


Allergan PLC 
 
Page 20 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Continuous variables will be summarized by number of patients and mean, standard 
deviation (SD), median, minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of patients. 
Demographics 
Demographic parameters including age, age group, race, race group, and sex; and 
baseline characteristics including weight (kg), and height (cm) will be summarized 
descriptively by treatment group for the ITT population. Patient’s age (years) will be 
classified into categories of less than 45 years, between 45 years and 65 years, inclusive, 
and greater than 65 years. In addition, race will be further grouped as white versus 
nonwhite. 
Other disease characteristics (for study eye only), including iris color, diagnosis of either 
OAG (primary OAG, pseudoexfoliation glaucoma, pigmentary glaucoma) or OHT, 
baseline Hour 0 IOP (≤ 25 mm Hg or > 25 mmHg), iridocorneal angle size, and central 
endothelial cell density, will be summarized descriptively by treatment group for the ITT 
population. Study eye iris color will be summarized by color for each of the following 
categories: monochromic, heterochromic peripupillary, and heterochromic diffuse. 
Medical History and Ophthalmic History 
Findings in patients’ medical histories, and ophthalmic histories, will be coded using the 
Medical Dictionary for Regulatory Activities. The number and percentage of patients 
with abnormalities in medical histories (ophthalmic excluded) in each system organ class 
(SOC) and preferred term will be summarized by treatment group for the safety 
population.  
Abnormalities in ophthalmic history in each system organ class and preferred term will 
be separately summarized as frequency count and percent by treatment group for study 
eye and pooled for fellow eye in the safety population. 
Surgical and Ophthalmic surgical history will be presented in listings. 
Prior and Concomitant Medications/Procedures 
Prior medication is defined as any medication taken before the date of the first dose of 
study treatment. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of study treatment. If any medication is taken before the date of 
the first dose of study treatment and continues after initiation of study treatment, it will be 
considered as both a prior and concomitant medication. 


Allergan PLC 
 
Page 21 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Prior and concomitant medications will be separately summarized using the safety 
population for each treatment group as the number and percentage of patients under each 
indication preferred term (MedDRA) and unique base preferred name from the World 
Health Organization Drug Dictionary Enhanced (WHODDE). 
Concurrent procedures will be provided in the listings. 
Non-study IOP Lowering Medications/Procedures 
A non-study IOP-lowering medication is defined as a medication for which the 
investigator specifically marked “Yes” to the question “Is this medication used as a non-
study IOP-lowering medication?” on the concomitant medication electronic case report 
from (eCRF). A non-study IOP-lowering procedure is defined as a procedure for which 
the investigator specifically marked “Yes” to the question “Was this an IOP-lowering 
procedure?” on the concurrent procedure eCRF.  
Other medications or procedures that could potentially reduce IOP but are not marked in 
the eCRF as non-study IOP-lowering medications/procedures will be listed in the 
separate document used to identify data excluded from the PP analysis.             
Washout Ocular Medication 
Similarly, washout ocular medications will be tabulated by treatment group for the study 
eye and pooled for the fellow eye. 


Allergan PLC 
 
Page 22 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
EXTENT OF EXPOSURE 
Throughout the study, each patient will receive up to 3 administrations of Bimatoprost 
SR or Sham injection in each eye with a fixed interval of 16 weeks. The number and 
percentage of patients receiving Bimatoprost SR or Sham treatment in the study eye 
during the study will be tabulated by the number of treatment administrations for each 
treatment group. 
Each patient’s study duration will be calculated as the number of days between the exit 
date and Day 1 Administration Day, inclusively (date of the exit - Day 1 Administration 
date + 1). Patients’ study duration will be summarized using descriptive statistics for each 
treatment group. 


Allergan PLC 
 
Page 23 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
10.0 
EFFICACY ANALYSES 
The primary efficacy variable for country/regions other than US will be time-matched 
IOP change from baseline in the study eye. The primary efficacy variable for the United 
States (US) Food and Drug Administration (FDA) (Division of Transplant and 
Ophthalmology Products) is IOP in the study eye (Section 10.3.1). 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance. All confidence intervals will be 2-sided 95% confidence intervals, unless 
stated otherwise. 
10.1 
PRIMARY EFFICACY PARAMETER(S) 
The primary efficacy measurement is IOP. IOP of each eye will be measured using the 
Goldmann applanation tonometer at Hours 0 (08:00 ± 1 hour) and 2 (2 hours after Hour 0 
[± 30 minutes]) of each visit other than administration days. For each IOP assessment, 
two consecutive measurements will be taken for each eye. If these 2 measurements differ 
by > 1 mm Hg, a third measurement will be performed for the given eye. The IOP value 
for a given eye will be the median of all measurements. 
Intraocular pressure values at Hours 0 and 2 of Baseline visit will be considered as the 
time-matched baseline values for the corresponding timepoints of follow-up visits (eg, 
study eye IOP time-matched change from baseline at Hour 0 of Week 12 will be 
calculated as: study eye IOP at Hour 0 of Week 12 – study eye IOP at Hour 0 of 
Baseline). 
To avoid confounding of efficacy data, IOP values obtained after initiating the use of 
non-study IOP-lowering medication or procedure in an eye will be excluded from the 
calculation of the summary statistics and the statistical analyses for that eye but raw 
values will be presented in the listings.  
10.1.1 
Primary Efficacy Analysis 
The primary efficacy variable is the study eye time-matched IOP change from baseline at 
each hour evaluated (Hours 0 and 2). Mean IOP change from baseline will be compared 
between each Bimatoprost SR dose strength and the timolol group for each evaluation 
hour using the ITT population. The comparisons at Week 12 will be considered the 
primary analysis. 
The null and alternative hypotheses for the comparison between a given Bimatoprost SR 
dose strength and timolol at each evaluation hour of Week 12 are: 


Allergan PLC 
 
Page 24 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
• Null hypothesis: the difference in mean IOP change from baseline between the given 
Bimatoprost SR dose strength and timolol (Bimatoprost SR minus timolol) is 
> 1.5 mm Hg. 
• Alternative hypothesis: the difference (Bimatoprost SR minus timolol) in mean IOP 
change from baseline between the given Bimatoprost SR dose strength and timolol is 
≤ 1.5 mm Hg. 
Intraocular pressure change from baseline will be analyzed using a mixed-effects model 
with repeated measures (MMRM). The model will include IOP time-matched change 
from baseline as the response variable and treatment, timepoint (Hours 0 and 2 at each 
visit of Weeks 2, 6, and 12), treatment-by-timepoint interaction and baseline IOP 
stratification as fixed factors, as well as time-matched baseline IOP (either Hour 0 or 
Hour 2 according to the response variable) as a covariate and timepoint-by-baseline time-
matched IOP interaction. Unstructured covariance matrix will be used for repeated 
measures on the same patient; if the model with unstructured covariance matrix fails to 
converge, multiple imputation (MI) will be implemented before MMRM. 
Mis-stratified subjects, if any, will be analyzed based on the stratum to which the subjects 
should have been randomized. 
Within the framework of this model, the mean difference between each Bimatoprost SR 
dose strength and timolol (Bimatoprost SR minus timolol) and the corresponding 2-sided 
95% confidence interval will be provided for each hour (Hours 0 and 2) at each visit. The 
formal noninferiority test will be performed at each evaluation hour of Week 12 for each 
Bimatoprost SR dose strength versus timolol using a noninferiority margin of 1.5 mm 
Hg. 
 
 
 
  
 
 
  
  
 
  
  
  
  
  
 
 
 
 
 
 
 


Allergan PLC 
 
Page 25 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
  
 
  
 
  
 
  
 
A gatekeeping procedure will be used to control the overall type I error rate at the 0.05 
level for each hour at Week 12, testing Bimatoprost SR 15 µg against timolol first and 
followed by the comparison between Bimatoprost SR 10 µg and timolol. The test of 
Bimatoprost SR 10 µg versus timolol is valid only if the noninferiority of Bimatoprost 
SR 15 µg to timolol is demonstrated. Bimatoprost SR 15 µg (or 10 µg) will be declared 
noninferior to timolol if the upper limit of the 95% confidence interval is ≤ 1.5 mm Hg 
for both Hours 0 and 2 at Week 12. 
The following sensitivity analyses will be performed for the primary efficacy variable.  
1. PP population analysis – The analysis outlined for primary efficacy analysis will 
be repeated on the PP population. 
2. Time-matched last observation carried forward (LOCF) analysis – Missing value 
will be imputed by time-matched LOCF method. At each visit/hour, treatment 
difference and its 95% confidence interval will be based on least square means by 
using an Analysis of Covariance (ANCOVA) model with IOP time-matched 
change from baseline as the response variable, treatment as a factor, and time-
matched baseline IOP (either Hour 0 or Hour 2 according to the response variable) 
as a covariate. 
3. Multiple imputation implementation before performing ANCOVA analysis – Step 
1: Intermittent missing values at each hour of Week 2, 6, and 12 will first be 
imputed by treatment group using Markov chain Monte Carlo (MCMC) method 
(defined as the MCMC step) with seed=79214203 resulting in data with a 
monotone pattern. Step 2: Multiple imputation by treatment group using linear 
regression with factors of demographics and baseline characteristics including but 
not limited to race group, sex, and lens status; and age, baseline IOP values at both 
Hour 0 and Hour 2 as covariates (defined as the regression step) will be applied to 
the data obtained from the MCMC step. The seed for the second multiple 
imputation step=63128917. Step 2 will immediately follow step 1 and the entire 
procedure will be repeated 25 times to provide reliable statistical inference (JW 
Graham, 2007). 
 


Allergan PLC 
 
Page 26 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
  
 
  
  
  
      
 
  
 
  
 
 
  
 
 
  
  
  
 
   
  
  
                       
 
  
  
                       
  
                       
 
  
 
                       
  
                       
 
  
  
                       
 
                       
 
  
  
                       
 
     
 
  
   
                      
 
                       
 
  
 
   
 
10.2 
SECONDARY EFFICACY PARAMETER(S) 
The secondary efficacy variable is the study eye IOP at each hour evaluated. 
10.2.1 
Secondary Efficacy Analysis #1 
The 2-sided 95% confidence interval for the mean difference in study eye time-matched 
IOP change from baseline between each Bimatoprost SR dose strength and timolol 
(Bimatoprost SR minus timolol) derived in the primary analysis will be used for 
secondary analysis of superiority comparison. If the upper 95% confidence limit is less 
than zero, the difference will be considered significant and in favor of the given 
Bimatoprost SR dose strength for the given timepoint. 


Allergan PLC 
 
Page 27 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Bimatoprost SR 15 µg (or 10 µg) will be considered superior to timolol if it demonstrates 
significant difference in favor of Bimatoprost SR 15 µg (or 10 µg) at each of the 6 
timepoints within the 12-week period (Hours 0 and 2 at Weeks 2, 6, and 12). 
10.2.2 
Secondary Efficacy Analysis #2 
Similarly, the superiority test of study eye IOP at each hour of a visit will be performed 
using the same MMRM model as described above in Section 10.1.1 with the response 
variable of study eye IOP.  
Bimatoprost SR 15 µg (or 10 µg) will be considered superior to timolol if it demonstrates 
significant difference in favor of Bimatoprost SR 15 µg (or 10 µg) at each of the 6 
timepoints within the 12-week period (Hours 0 and 2 at Weeks 2, 6, and 12). 
10.3 
EFFICACY ANALYSES FOR US FDA 
10.3.1 
Primary Efficacy Analysis for US FDA 
For US FDA review, the primary efficacy variable will be the study eye IOP. The 
primary analysis will be based on Weeks 2, 6, and 12 using the ITT population. Mean 
IOP will be compared between each Bimatoprost SR dose strength and timolol for each 
hour (Hours 0 and 2) at Weeks 2, 6, and 12. Intraocular pressure measurements obtained 
after initiating the use of non-study IOP-lowering medication in an eye will be treated as 
missing for that eye. 
The null and alternative hypotheses for the comparison between a given Bimatoprost SR 
dose strength and timolol for each hour at each visit are: 
• The null hypothesis is that the difference in mean IOP between the given Bimatoprost 
SR dose strength and timolol (Bimatoprost SR minus timolol) is > 1.5 mm Hg. 
• The alternative hypothesis is that the difference (Bimatoprost SR minus timolol) in 
mean IOP between the given Bimatoprost SR dose strength and timolol is 
≤ 1.5 mm Hg. 
Intraocular pressure will be analyzed using an MMRM approach based on the same 
MMRM model as described above with IOP as the response variable. The mean 
difference between each Bimatoprost SR dose strength and timolol and the corresponding 
2-sided 95% confidence interval will be provided for each hour (Hours 0 and 2) and each 
visit (Weeks 2, 6, and 12). 
A gatekeeping procedure will be used to control the overall type I error rate at the 
0.05 level. Bimatoprost SR 15 µg will be tested against timolol first at each timepoint 
(Hours 0 and 2 at Weeks 2, 6, and 12) and then followed by the comparison between 


Allergan PLC 
 
Page 28 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Bimatoprost SR 10 µg and timolol. The test for Bimatoprost SR 10 µg versus timolol for 
a given hour at a visit is valid only if the noninferiority of Bimatoprost SR 15 µg to 
timolol has been demonstrated for the given timepoint. 
Bimatoprost SR 15 µg (or 10 µg) will be declared noninferior to timolol if the upper limit 
of the 95% confidence interval is ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 
2 at Weeks 2, 6, 12). Each Bimatoprost SR dose strength that shows noninferiority to 
timolol will be declared clinically noninferior to timolol if the upper limit of the 95% 
confidence interval is ≤ 1.0 mm Hg for 3 or more timepoints. 
Analysis will be repeated on PP population as a sensitivity analysis. The same analysis 
will also be repeated with missing values imputed by time-matched LOCF and multiple 
imputation as sensitivity analysis (similar to Section 10.1.1). 
10.3.2 
Secondary Efficacy Analysis for US FDA 
For each Bimatoprost SR dose strength which demonstrates efficacy (clinical 
noninferiority) as described in the primary efficacy analyses for US FDA, the secondary 
efficacy analysis is to test the superiority of the Bimatoprost SR dose strength versus 
timolol.  
For the superiority test of study eye IOP at each hour of a visit, the null hypothesis is that 
there is no difference between a given Bimatoprost SR dose strength and timolol. The 
alternative hypothesis is that there is a difference. The null hypothesis will be tested using 
the same MMRM model as described for the primary efficacy analysis for US FDA. A 
2-sided 95% confidence interval for the mean difference in study eye IOP between each 
Bimatoprost SR dose strength and timolol (Bimatoprost SR minus timolol) will be 
provided. If the upper 95% confidence limit is less than zero, the difference will be 
considered significant and in favor of the given Bimatoprost SR dose strength for the 
given timepoint. 
The following gatekeeping procedure will be applied to control the overall type I error 
rate at the 0.05 level for the US FDA primary and secondary hypotheses sequentially. 
1. Bimatoprost SR 15 µg is noninferior to timolol at all six time points using a non-
inferiority margin of 1.5 mmHg. 
2. Bimatoprost SR 10 µg is noninferior to timolol at all six time points using a non-
inferiority margin of 1.5 mmHg. 
3. Bimatoprost SR 15 µg is superior to timolol at all 6 timepoints. 
4. Bimatoprost SR 10 µg is superior to timolol at all 6 timepoints. 


Allergan PLC 
 
Page 29 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
The above hypotheses will be tested in a sequential order. If at any step a test fails, the 
test procedure will stop and no further hypotheses will be tested. Following the above 
testing sequence, if Bimatoprost SR 10 µg demonstrates noninferiority to timolol at all 
six time points using a non-inferiority margin of 1.5 mm Hg, Bimatoprost SR 15 µg will 
be tested for superiority and considered statistically superior to timolol, if it shows 
statistically significant difference in favor of Bimatoprost SR 15 µg at all 6 time points 
(Hours 0 and 2 at Weeks 2, 6, and 12). A similar criterion for claiming superiority of 
Bimatoprost SR 10 µg over timolol will be employed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 30 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Allergan PLC 
 
Page 31 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
11.0 
SAFETY ANALYSES 
The safety analysis will be performed using the safety population. The safety parameters 
will include the following nonocular safety parameters: nonocular AEs, clinical 
laboratory values, vital signs, and pregnancy; 
 
 
 
 
 
Unless otherwise stated, the last nonmissing safety assessment 
before the first dose of study treatment will be used as the baseline for all analyses of that 
safety parameter. Continuous variables will be summarized by number of patients and 
mean, SD, median, the 1st quartile and the 3rd quartile, minimum, and maximum values. 
Categorical variables will be summarized by number and percentage of patients. 
 
 
  
For all safety by-cycle summary analyses, in order to compare cycles of similar duration, 
the data included in each cycle will be, 
• Cycle 1 (16 weeks): data from the 1st injection to the 2nd injection date -1 or upper 
bound of week 15 visit window (section 16.1) if a patient didn’t receive the 2nd 
injection; 
• Cycle 2 (16 weeks): data from the 2nd injection to the 3rd injection date -1 or upper 
bound of week 31 visit window (section 16.1) if a patient didn’t receive the 3rd 
injection; 
• Cycle 3 (20 weeks): data from the 3rd injection to upper bound of week 52  visit 
window (section 16.1); 
• Extended safety follow up: data after week 52 for patients with 3 injections and 
extended follow up.   
11.1 
ADVERSE EVENTS 
Adverse events will be coded by SOC and preferred term using the Medical Dictionary 
for Regulatory Activities. 


Allergan PLC 
 
Page 32 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
For a given AE and patient, if more than 1 severity grade is reported, the worst severity 
grade (the greater of the onset and maximum severity recorded on the electronic case 
report from [eCRF]), will be used for analysis. 
Adverse events will be classified into ocular AEs and nonocular AEs. An ocular AE will 
be determined as indicated on the AE form of eCRF, and thus are not limited to AEs with 
primary SOCs of eyes. The treatment-related ocular AEs will be further broken down by 
either related to injection procedure or related to study drug as indicated on eCRF. Ocular 
AEs will be tabulated by treatment group for the study eye and pooled for the fellow eye, 
and nonocular AEs will be summarized by treatment group for patient. Analysis by cycle 
of treatment will also be performed. 
Treatment-Emergent Adverse Events 
An AE will be considered a treatment-emergent adverse event (TEAE) for the study 
treatment period if the AE meets 1 of the following criteria: 
• The onset date is on or after the first study treatment date. 
• The onset date is before the first study treatment date and either: 
○ The severity of the event worsened on or after the first treatment date.  
○ The event became serious on or after the first study treatment date. 
An AE will be considered as a TEAE for a treatment cycle if the AE meets 1 of the 
following criteria: 
• The onset date is on or after the treatment administration of the cycle but prior to the 
next cycle administration.  
• The onset date is before the treatment administration of the cycle and either: 
○ The severity of the event worsened on or after the treatment administration of the 
cycle. 
○ The event became serious on or after the treatment administration of the cycle.  
Overall summary of TEAEs will be provided on a per-patient basis for categories of all 
TEAEs, treatment-related TEAEs, injection procedure-related TEAEs, study drug-related 
TEAEs, serious TEAEs (STEAEs), deaths, and TEAEs leading to study discontinuation. 
Each category (except deaths) will be further classified into ocular and nonocular 
subcategories. 


Allergan PLC 
 
Page 33 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
The number and percentage of patients reporting TEAEs will be provided on a per-
patient basis by 1) SOC and preferred term; 2) SOC, preferred term and severity in 
descending order of frequency for each treatment group.  
The number and percentage of patients reporting nonocular TEAEs in each treatment 
group will be tabulated by SOC and preferred term. Also the number and percentage of 
patients reporting treatment-related (including study drug related or injection procedure 
related) nonocular TEAEs in each treatment group will be tabulated by SOC and 
preferred term.  
Similar analyses will be done for ocular TEAEs including 1) by PT and severity; 2) 
treatment-related TEAEs by PT for each treatment group by study eye and fellow eye. In 
addition, similar analyses will be performed for ocular TEAEs by treatment cycle. 
Within each treatment cycle, ocular TEAEs identified (onset or worsened) within 2 days 
of administration and identified more than 2 days of administration of each cycle will be 
summarized by each treatment group for study eye and pooled for fellow eye. 
Serious TEAEs 
Nonocular and ocular STEAEs will be summarized by preferred term and treatment 
group, respectively.  
TEAEs Leading to Study Discontinuation 
Nonocular TEAEs and ocular TEAEs leading to premature discontinuation of the study 
will be summarized by preferred term and treatment, respectively. 
Similarly, ocular TEAEs leading to premature discontinuation will also be tabulated by 
treatment group by treatment cycle.  
Ocular TEAEs Leading to Study Drug Discontinuation or Regimen Change 
Ocular TEAEs leading to study drug discontinuation will be summarized by preferred 
term and treatment for the entire study period and also for each cycle. Ocular TEAEs 
leading to study drug discontinuation or regimen change are defined as the ocular TEAEs 
with action regarding study drug reported as “Discontinued” or “Regimen Changed” on 
the eCRF AE form.  
Ocular TEAEs Leading to Implant Removal  
Ocular TEAEs leading to implant removal will be summarized by preferred term and 
treatment for the entire study period and also for each cycle.  


Allergan PLC 
 
Page 34 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
TEAEs of Special Interest 
Corneal TEAEs and Anterior chamber inflammation TEAEs of interest will be 
summarized by preferred term and treatment group, respectively. Similar analyses will be 
done by treatment cycle. The full list of corneal AEs and Anterior chamber inflammation 
AEs of interest will be provided prior to each database lock.  
Additional subcategory of TEAEs may be analyzed separately, such as for ocular TEAE 
associated with use of a prostaglandin analog (PGA), etc. 
11.2 
VITAL SIGNS 
Descriptive statistics for vital signs (systolic and diastolic blood pressures [mm Hg], 
pulse rate [bpm], and temperature [Celsius]) at baseline and changes from baseline values 
at each scheduled follow-up visit will be presented by treatment group.  
11.3 
OTHER SAFETY PARAMETERS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 35 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 36 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 37 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 38 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 


Allergan PLC 
 
Page 39 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
11.3.13 
Pregnancy Test 
Positive pregnancy test results of females of childbearing potential will be presented in a 
data listing. 
11.4 
SUBGROUP ANALYSES FOR SAFETY VARIABLES 
Subgroup analyses for safety variables are not planned, but may be performed. 


Allergan PLC 
 
Page 40 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
12.0 
HEALTH OUTCOMES ANALYSES 
Not applicable. 


Allergan PLC 
 
Page 41 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
13.0 
INTERIM ANALYSIS 
No interim analysis is planned for this study. Each database lock will correspond to a 
milestone and statistical analysis will be provided when all randomized patients have 
either completed or exited from the targeted visit (Weeks 12, Week 52, and 
Month 20/Exit). 


Allergan PLC 
 
Page 42 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
14.0 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation is based on the primary efficacy analysis of the time-matched 
IOP for US FDA review because the sample size based on the primary efficacy analysis 
for other regions is expected to be smaller. 
The sample size is estimated based on a 2-sided t-test with α = 0.05 at each timepoint and 
the assumption that the mean IOP difference between Bimatoprost SR 10 µg and timolol 
is -0.25 mm Hg (ie, Bimatoprost SR 10 µg is 0.25 mm Hg better in IOP-lowering than 
timolol) at Weeks 2 and 6 and 0 mm Hg at Week 12, with a common SD of 4.0 mm Hg 
and a common within-subject correlation of 0.6. It is also assumed that the efficacy 
(IOP-lowering effect) of Bimatoprost SR 15 µg is better than that of Bimatoprost SR 
10 µg by 0.25 mm Hg at each timepoint (Hours 0 and 2). These assumptions are based on 
the data obtained from the ongoing clinical study 192024-041D. Based on simulations, a 
sample size of 540 patients (180 per group) will provide approximately 95% and 81% 
power to show noninferiority of Bimatoprost SR 15 µg and Bimatoprost SR 10 µg, 
respectively, to timolol at all 6 scheduled timepoints based on a noninferiority margin of 
1.5 mm Hg and at 3 or more timepoints based on an noninferiority margin of 1.0 mm Hg. 
Assuming a premature discontinuation rate of 10% within 12 weeks (before primary 
database lock), approximately 600 patients (200 per group) are to be enrolled into this 
study. 


Allergan PLC 
Page 43 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
15.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed 
 


Allergan PLC 
 
Page 44 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
16.0 
DATA HANDLING CONVENTIONS 
16.1 
VISIT TIME WINDOWS 
For all analyses, all follow-up visits or the exit visit will be reassigned with the visit 
number based on the study days 
 


Allergan PLC 
 
Page 45 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 


Allergan PLC 
 
Page 46 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
 
 
 
 
 
  
  
16.2 
DERIVED VARIABLES 
No Applicable. 
16.3 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a patient has repeated assessments before the start of the first treatment, unless 
otherwise stated, the results from the final nonmissing assessment made prior to the start 
of the study treatment will be used as baseline. If end-of-study assessments are repeated 
or if unscheduled visits occur, the last nonmissing postbaseline assessment will be used 
as the end-of-study assessment for generating summary statistics. However, all 
postbaseline assessments will be used for safety evaluation, and all assessments will be 
presented in the data listings. 
16.4 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started before the date of the first dose of study 
treatment, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of study treatment, an intensity of severe will 
be assigned. The imputed values for severity assessment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 


Allergan PLC 
 
Page 47 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
16.5 
MISSING CAUSAL RELATIONSHIP TO STUDY TREATMENT 
FOR ADVERSE EVENTS 
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
16.6 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (ie, partly missing). 
Missing Month and Day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
treatment , the month and day of the first dose of study treatment will be assigned to 
the missing fields. 
• If the year of the incomplete start date is before the year of the first dose of study 
treatment, December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the first dose of study 
treatment, January 1 will be assigned to the missing fields. 
Missing Month Only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure. 
Missing Day Only 
• If the month and year of the incomplete start date are the same as the month and year 
of the first dose of study treatment, the day of the first dose of study treatment will be 
assigned to the missing day. 
• If either the year of the incomplete start date is before the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of study treatment, the last 
day of the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of study treatment, the first 
day of the month will be assigned to the missing day. 


Allergan PLC 
 
Page 48 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date: 
• If the stop date is after the date of the first dose of study treatment, the date of the first 
dose of study treatment will be assigned to the missing start date. 
• If the stop date is before the date of the first dose of study treatment, the stop date will 
be assigned to the missing start date. 
16.7 
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS 
For prior or concomitant medications, including washout and IOP-lowering medications, 
incomplete (ie, partly missing) start dates and/or stop dates will be imputed. When the 
start date and the stop date are both incomplete for a patient, the start date will be 
imputed first. 
16.7.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date unless the start date > 1 year is 
marked. If the stop date is complete (or imputed) and the imputed start date is after the 
stop date, the start date will be imputed using the stop date. If in the cases that the start 
date > 1 year is marked, the same month and day of the first dose of study treatment and 
the previous year of the first dose of study treatment will be assigned to the missing 
fields. 
Missing Month and Day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to 
the missing fields. 
• If the year of the incomplete start date is before the year of the first dose of study 
treatment, December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the first dose of study 
treatment, January 1 will be assigned to the missing fields. 


Allergan PLC 
 
Page 49 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Missing Month Only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure. 
Missing Day Only 
• If the month and year of the incomplete start date are the same as the month and year 
of the first dose of study treatment, the day of the first dose of study treatment will be 
assigned to the missing day. 
• If either the year of the incomplete start date is before the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of study treatment, the last 
day of the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of study treatment, the first 
day of the month will be assigned to the missing day. 
16.7.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date unless the stop date is marked as 
ongoing. If the imputed stop date is before the start date (imputed or nonimputed start 
date), the imputed stop date will be equal to the start date. If the stop date is marked as 
ongoing, the study exit date will be assigned to the missing fields. If the study exit date is 
not available, the last visit date will be used for imputation.  
Missing Month and Day 
• If the year of the incomplete stop date is the same as the year of the study exit date, 
the month and day of the study exit date will be assigned to the missing fields. 
• If the year of the incomplete stop date is before the year of the study exit date, 
December 31 will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the study exit date, January 
1 will be assigned to the missing fields. 
Missing Month Only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure. 


Allergan PLC 
 
Page 50 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
Missing Day Only 
• If the month and year of the incomplete stop date are the same as the month and year 
of the  study exit date, the day of the study exit date will be assigned to the missing 
day. 
• If either the year of the incomplete stop date is before the year of the study exit date 
or if both years are the same but the month of the incomplete stop date is before the 
month of the study exit date, the last day of the month will be assigned to the missing 
day. 
• If either the year of the incomplete stop date is after the year of the study exit date or 
if both years are the same but the month of the incomplete stop date is after the month 
of the study exit date, the first day of the month will be assigned to the missing day. 


Allergan PLC 
 
Page 51 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Two additional terms the time-matched baseline IOP (either Hour 0 or Hour 2 according 
to the response variable) and timepoint-by-baseline Hour 0 IOP interaction were added to 
the primary efficacy analysis model, but were not presented in protocol amendment 2, 
dated 16MAR2017.  


Allergan PLC 
 
Page 52 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
18.0 
REFERENCES 
Graham JW, Olchowski AE, Gilreath TD. How many imputations are really needed? 
Some practical clarifications of multiple imputation theory. Prev Sci 2007 Sep; 
8(3):206-13. 


Allergan PLC 
 
Page 53 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
19.0 
AMENDMENTS 
19.1 
AMENDMENT 1 
1. Updated visit schedule tables 4-1 to 4-5 per protocol amd 2. 
2. In section 6.3, per-protocol definition is updated to “The per-protocol (PP) population 
will consist of the subset of patients in the ITT population who 1) had the primary 
efficacy variable measured; 2) did not have any significant protocol deviations 
affecting the primary efficacy analyses which include but are not limited to the 
following: 
• violation of key inclusion/exclusion criteria 
• wrong or multiple randomization 
 
with no protocol deviations affecting the primary efficacy analyses andIOP measures 
deemed being influenced by other medications would be excluded from PP analysis, 
regardless whether the medication constitutes as a protocol deviation. The PP 
population will be used to confirm the primary efficacay analyses. A separate 
document to define the key inclusion/exclusion criteria and details of list of patients 
whose data will be excluded from the PP population analyses will be finalized prior to 
the Week 12 database lock.”. 
3. In section 7.0, updated “The number and percentage of patients in the 3 study 
populations (ITT, Safety, and PP) will be summarized by treatment group and study 
center; the number of patients screened will be summarized overall only by the study 
center. ”.  
4. In section 7.0, deleted “Patients screened but not randomized along with the 
associated reasons for failure to randomize will be tabulated overall for the all 
screened patients.”.  
5. In section 7.0,  added the study and cycle completer definition “The study completers 
will be defined as the patients who received at least 1 injection and complete the 
extended safety follow up visits. The completers for each cycle will be defined as the 
patients who received injection in the relevant cycle and completed the cycle by 
either receiving the following injection or completing the extended safety follow up 
visits.”. 
6. In section 10.1, added “The non-study IOP-lowering medication is defined as the 
medication being specifically marked as “Yes” to the question “Is this Medication 
used as a non-study IOP-lowering Medication?” on concomitant medication 
electronic case report from (eCRF).”. 


Allergan PLC 
 
Page 54 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
7. In section 10.1.1, updated the primary efficacy analysis model, “The model will 
include IOP time-matched change from baseline as the response variable and 
treatment, timepoint (Hours 0 and 2 at each visit of Weeks 2, 6, and 12), treatment-
by-timepoint interaction and baseline IOP stratification as fixed effects factors, as 
well as time-matched baseline IOP (either Hour 0 or Hour 2 according to the response 
variable) as a covariate and timepoint-by-baseline Hour 0 IOP interaction.”. 
8. In section 10.1.1, added “Mis-stratified subjects, if any, will be analyzed based on the 
stratum to which the subjects should have been randomized.”  
9. In section 10.1.1, updated psedudo 
 code for primary efficacy analysis.  
10. In section 10.1.1, sensitivity analyses on primary efficacy variable were updated “At 
each visit/hour, treatment difference and its 95% confindence interval will be based 
on least square means by using an Analysis of Covariance (ANCOVA) model with 
IOP time-matched change from baseline as the response variable, treatment as a 
factor, and time-matched baseline IOP (either at Hour 0 and baseline IOP at or Hour 2 
according to the response variable) as a covariates. ”. 
11. In section 10.1.1, sensitivity analyses on primary efficacy variable using MI were 
updated “Step 2: Multiple imputation by treatment group using linear regression with 
factors of demographics and baseline characteristics including but not limited to race 
group, sex, and lens status; and age, IOP baseline IOP values at both Hour 0 and Hour 
2 as a covariates (defined as the regression step) will be applied to the data obtained 
from the MCMC step.”. 
12. In section 10.1.1, updated psedudo 
 code for MI.  
13. In section 10.2.1, deleted “For the superiority test of study eye time-matched IOP 
change from baseline at each hour of a visit, the null hypothesis is that there is no 
difference between a given Bimatoprost SR dose strength and timolol. The alternative 
hypothesis is that there is a difference. The null hypothesis will be tested using the 
same MMRM model as described for the primary efficacy analysis in Section 10.1.”. 
14. In section 10.2.1, updated “The A 2-sided 95% confidence interval for the mean 
difference in study eye time-matched IOP change from baseline between each 
Bimatoprost SR dose strength and timolol (Bimatoprost SR minus timolol) will be 
provided derived in the primary analysis will be used for secondary analysis of 
superiority comparison.”. 
15. In section 10.3.2, deleted “The comparison will be made between each Bimatoprost 
SR dose strength and timolol for study eye IOP at each timepoint (Hours 0 and 2 at 
Weeks 2, 6, and 12) using the ITT population.”. 


Allergan PLC 
 
Page 55 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
16. In section 10.3.2, superiority claiming criterion for secondary efficacy analysis for US 
FDA is updated “Bimatoprost SR 15 µg will be tested for superiority and considered 
statistically superior to timolol, if it shows statistically significant difference in favor 
of Bimatoprost SR 15 µg at 3 or more all 6 time points and numerically better at the 
remaning time points of all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, and 
12).”. 
17. 
 
 
 
 
18. 
 
 
 
19. In section 11.0, definition of cycle and safety follow up is added “For all cycle 
summary analyses, in order to compare cycles of similar duration, the data included 
in each cycle will be,  
• Cycle 1 (16 weeks): data from the 1st injection to the 2nd injection date -1 or upper 
bound of week 15 visit window (section 16.1) if a patient didn’t receive the 2nd 
injection; 
• Cycle 2 (16 weeks): data from the 2nd injection to the 3rd injection date -1 or upper 
bound of week 31 visit window (section 16.1) if a patient didn’t receive the 3rd 
injection 
• Cycle 3 (20 weeks): data from the 3rd injection to upper bound of week 52  visit 
window (section 16.1); 
• Safety follow up: data after week 52 for patients with 3 injections and safety 
follow up.”.  
20. In section 11.1, the overall summary of AEs was updated to “Overall summary of 
AEs will be provided on a per-patient basis for categories of all TEAEs, treatment-
related TEAEs, injection procedure-related TEAEs, study drug-related TEAEs, 
serious adverse events TEAEs (STEAEs), deaths, and AEs leading to study 
discontinuation.” 


Allergan PLC 
 
Page 56 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
21. In section 11.1, TEAE summary table was updated to “the number and percentage of 
patients reporting TEAEs will be provided on a per-patient basis by 1) SOC and 
preferred term; 2) SOC, preferred term and severity in descending order of frequency 
for each treatment group.”. 
22. In section 11.1, non-ocular TEAEs summary was updated to “The number and 
percentage of patients reporting nonocular TEAEs in each treatment group will be 
tabulated by 1) descending percentage in any group; 2) by SOC, and preferred term 
and severity; and 3). Also the number and percentage of patients reporting treatment-
related by causal relationship to the study treatment (including study drug related or 
injection procedure related) nonocular TEAEs in each treatment group will be 
tabulated by SOC and preferred term. 
23. In section 11.1, deleted “If more than 1 nonocular AE is coded to the same preferred 
term for the same patient, the patient will be counted only once for that preferred term 
using the greatest severity and strictest causality for the summarization by severity 
and causal relationship.”. 
24. In section 11.1, ocular TEAEs summary was updated to “Similar analyses will be 
done for ocular TEAEs including 1) by PT and severity; 2) treatment-related TEAEs 
by PT for each treatment group by study eye and fellow eye. Additionally, ocular 
TEAEs in each treatment group will also be tabulated by 1) by causal relationship to 
the study drug; 2) by causal relationship to injection procedure. ”. 
25. In section 11.1, serious TEAEs summary was updated to “Nonocular and ocular 
STEAEs will be summarized by preferred term and treatment group, respectively.”. 
26. 
 
 
27. 
 
 
 
 
 
 


Allergan PLC 
 
Page 57 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
28. 
 
 
 
 
29. 
 
 
 
30. 
 
 
 
31. 
 
 
32. Deleted section 16.4 MISSING DATE OF THE LAST DOSE OF STUDY 
TREATMENT, and all following sections were re-numbered. “When the date of the 
last dose of study treatment is missing for a patient in the safety population, all efforts 
should be made to obtain the date from the investigator. If after all efforts are made it 
is still missing, the last available dosing record date will be used as the last dose 
date.”. 
33. In section 17.0, updated changes in this amendment to analyses specified in protocol, 
“There are no major changes to the analyses specified in protocol amendment 1, dated 
11AUG2015.Two additional terms the time-matched baseline IOP (either Hour 0 or 
Hour 2 according to the response variable) and timepoint-by-baseline Hour 0 IOP 
interaction were added to the primary efficacy analysis model, but were not presented 
in protocol amendment 2, dated 16MAR2017.”. 


Allergan PLC 
 
Page 58 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
19.2 
AMENDMENT 2 
1. In section 6.3, updated “The per-protocol (PP) population will consist of the subset of 
patients in the ITT population who 1)had the primary efficacy variable measured. ; 2) 
did not have any significant protocol deviations affecting the primary efficacy 
analyses which include but are not limited to the following:  
• violation of key inclusion/exclusion criteria 
• wrong or multiple randomization 
IOP measures deemed being influenced by other medications would be excluded 
from PP analysis, regarless whether the medication constitute as a protocol deviation. 
The PP population will be used to confirm the primary efficacy analyses. A separate 
document to define the key inclusion/exclusion further criteria and details of patients 
whose data will to be excluded from the PP analyses will be finalized prior to the 
Week 12 database lock.” 
2. In section 6.4, updated “Clinical lab test data and general (non-ophthalmic) physical 
examination will only be collected at screening and will not be analyzed.” 
3. In section 8.0, updated “Prior and concomitant medications will be separately 
summarized using the safety population for each treatment group as the number and 
percentage of patients under each indication preferred term (MedDRA) and unique 
base preferred name from the World Health Organization Drug Dictionary Enhanced 
(WHODDE).” 
4. In section 8.0, added “A non-study IOP-lowering medication is defined as a 
medication for which the investigator specifically marked “Yes” to the question “Is 
this medication used as a non-study IOP-lowering medication?” on the concomitant 
medication electronic case report from (eCRF). A non-study IOP-lowering procedure 
is defined as a procedure for which the investigator specifically marked “Yes” to the 
question “Was this an IOP-lowering procedure?” on the concurrent procedure eCRF. 
Other medications or procedures that could potentially reduce IOP but are not marked 
in the eCRF as non-study IOP-lowering medications/procedures will be listed in the 
separate document used to identify data excluded from the PP analysis.” 
5. In section 10.1, updated “To avoid confounding of efficacy data, IOP values obtained 
after initiating the use of non-study IOP-lowering medication or procedure in an eye 
will be excluded from the calculation of the summary statistics and the statistical 
analyses for that eye, but raw values will be presented in the listings.” 
6. In section 10.1, moved “The non-study IOP-lowering procedure is defined as the 
procedure being specifically marked as “Yes” to the question “Was this an IOP-
lowering procedure?” on concurrent procedure eCRF.” to section 8.0  


Allergan PLC 
 
Page 59 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
7. In section 10.1.1, updated the primary efficacy analysis model, “The model will 
include IOP time-matched change from baseline as the response variable and 
treatment, timepoint (Hours 0 and 2 at each visit of Weeks 2, 6, and 12), treatment-
by-timepoint interaction and baseline IOP stratification as fixed factors, as well as 
time-matched baseline IOP (either Hour 0 or Hour 2 according to the response 
variable) as a covariate and timepoint-by-baseline Hour 0 time-matched IOP 
interaction.” 
8. In section 10.1.1, updated pseudo 
 code for primary efficacy analysis. 
9. 
 
 
10. 
 
 
 
 
 
 
 
 
11. 
 
 
 
 
12. 
 
 
 
 
 
 
 
 
 
 


Allergan PLC 
 
Page 60 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
 
 
 
 
13. 
 
 
 
14. In section 11.0, updated “Continuous variables will be summarized by number of 
patients and mean, SD, median, the 1st quartile and the 3rd quartile, minimum, and 
maximum values.”  
15. In section 11.0, updated “Extended safety follow up: data after week 52 for patients 
with 3 injections and safety extended follow up.” 
16. In section 11.1, deleted “If more than 1 ocular AE is coded to the same preferred term 
for the same patient eye, the patient eye will be counted only once for that preferred 
term using the greatest severity and strictest causality for the summarization by 
severity and causal relationship.” 
17. In section 11.1, added “Ocular AEs leading to study drug discontinuation will be 
summarized by preferred term and treatment for the entire study period and also for 
each cycle. Ocular AEs leading to study drug discontinuation are defined as the 
ocular AEs with action regarding study drug reported as “Discontinued” or “Regimen 
Changed” on the eCRF AE form.” 
18. Delete IOP section (originally section 11.3.4), all subsequent section numbers were 
updated. 
19. 
 
 
 
 
 
 


Allergan PLC 
 
Page 61 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
20. 
 
 
21. 
 
 
22. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


Allergan PLC 
 
Page 62 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
19.3 
AMENDMENT 3 
1. 
 
 
 
2. In section 11.1, updated “Overall summary of TEAEs will be provided on a per-
patient basis for categories of all TEAEs, treatment-related TEAEs, injection 
procedure-related TEAEs, study drug-related TEAEs, serious TEAEs (STEAEs), 
deaths, and TEAEs leading to study discontinuation.”. 
3. In section 11.1, updated “Nonocular TEAEs and ocular TEAEs leading to premature 
discontinuation of the study will be summarized by preferred term and treatment, 
respectively. Similarly, ocular TEAEs leading to premature discontinuation will also 
be tabulated by treatment group by treatment cycle. ” 
4. In section 11. 1, updated “Ocular TEAEs leading to study drug discontinuation will 
be summarized by preferred term and treatment for the entire study period and also 
for each cycle. Ocular TEAEs leading to study drug discontinuation or regimen 
change are defined as the ocular TEAEs with action regarding study drug reported as 
“Discontinued” or “Regimen Changed” on the eCRF AE form.”  
5. In section 11.1, updated “Ocular TEAEs leading to implant removal will be 
summarized by preferred term and treatment for the entire study period and also for 
each cycle.” 
6. In section 11.1, updated “Corneal TEAEs and Anterior chamber inflammation TEAEs 
will be summarized by preferred term and treatment group, respectively. Similar 
analyses will be done by treatment cycle. The full list of corneal AEs and Anterior 
chamber inflammation AEs will be provided prior to each database lock. Additional 
subcategory of TEAEs may be analyzed separately, such as for ocular TEAE 
associated with use of a prostaglandin analog (PGA), etc.” 
7. In section 16.7.2, deleted “If the date of the last dose of study treatment is missing, 
impute it as described in Section 16.4.”, updated “If the stop day date is marked as 
ongoing, the study exit date will be assigned to the missing fields.”, and added “If the 
study exit date is not available, the last visit date will be used for imputation.”. 
8. In section 16.7.2, updated the following, 
“Missing Month and Day 
• If the year of the incomplete stop date is the same as the year of the last dose of 
study treatment study exit date, the month and day of the last dose of study 
treatment study exit date will be assigned to the missing fields. 


Allergan PLC 
 
Page 63 
Bimatoprost SR 
192024-091 Statistical Analysis Plan Amendment 3(Final) 
19APR2018 
• If the year of the incomplete stop date is before the year of the last dose of study 
treatment study exit date, December 31 will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the last dose of study 
treatment study exit date, January 1 will be assigned to the missing fields. 
Missing Day Only 
• If the month and year of the incomplete stop date are the same as the month and 
year of the last dose of study treatment study exit date, the day of the last dose of 
study treatment study exit date will be assigned to the missing day. 
• If either the year of the incomplete stop date is before the year of the date of the 
last dose of study treatment study exit date or if both years are the same but the 
month of the incomplete stop date is before the month of the date of the last dose 
of study treatment study exit date, the last day of the month will be assigned to the 
missing day. 
 
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
 
            
 
           
 
            
 
         
 
     
 
   
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
BIM SR study 192024-091 Statistical Analysis Plan Text_Amd 3