The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or Ocular Hypertension
Phase: PHASE3
Conditions: Glaucoma, Open-Angle, Ocular Hypertension
Sponsor: Allergan

 
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 : 
 
 
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Aller ga n C o nfi de nti al  
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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 : 
 
 
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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 
 
 
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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 : 
 
 
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Aller ga n C o nfi de nti al  
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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 
 
 

 
 
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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 
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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  

 
 
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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
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S u m mar y o f
s ...................
ffi cac y Meas
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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 
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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
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at me nt Gr o u
n g ................ .
o sa ge A dj ust
/Treat me nts .
o ns/ Treat m e
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i o n ..............
q ue ............. .
ent O bser vat
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sure ............. .
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s, E q ui p men
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ami nati o n.... .
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m istr y ...........
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C ollecti o n . .
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P ri mar y a n d 
able ............. .
ria ble ..........
n al ysis .........
y ses .............
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u ps/ Ra n d o m
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tme nts ........ .
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ti o n ..............
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A p pr o v al D at e : 
 
 
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g a n C o nfi de nti a
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7. 3. 4  
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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 ..................
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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 
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n al St u d y E n t
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n al yses ........ .
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I nstr uc
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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  
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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  ...................
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v e nt ............ .
d verse E ve nt
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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
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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 ............
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ri o us A d vers
S t u d y Me dic
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m e d C o nse n
u lati o ns .......
or I E C Re g u
d  Cli nical Pr
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se E ve nt ......
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n t Re g ulati on
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u lati o ns .......
ractice .........
rds; Electr o n
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F R Part 5 0) 
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m e nt 2 
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a nd  
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ns 
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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