Clinical trial NCT05815758
Conditions: Allergic Conjunctivitis
Sponsor: Bausch & Lomb Incorporated
Start date: 2023-04-20; Completion date: 2023-09-18
Enrollment: 512 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the safety and tolerability of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution versus its vehicle in healthy adult subjects and in pediatric subjects.

Detailed description:
The study will consist of 4-5 study visits to compare the safety and tolerability of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution versus its vehicle in healthy adult subjects and in pediatric subjects with a history or family history of atopic disease (including allergic conjunctivitis).

To characterize the plasma pharmacokinetics (PK) of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution following a single dose and 22-day twice daily (BID) topical ocular dosing in a subset of healthy adult subjects.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo) intervention 2: Vehicle of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% ophthalmic solution
Intervention descriptions: intervention 1: Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo) intervention 2: Vehicle of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% ophthalmic solution

Protocol documents:
Prot_000.pdf: 
Bri m o ni di ne Tartrate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 % O p ht hal mic S ol uti o n  
Ba usc h & L o m b I nc or p orate d  
Cli nical Trial Pr ot oc ol: 9 1 3  
0 7 J ul  2 0 2 3 
Cli nic al Tri al Pr ot oc ol: 9 1 3/ 2 2 -1 0 0 -0 0 0 6  
Pr ot oc ol Title:  
A M ulti -Ce nter, D o u ble -Mas ke d, Ra n d o mize d, Ve hicle -
C o ntr olle d, Parallel - Gr o u p St u d y E val uati n g t he Safet y a n d 
P har mac o ki netics of Bri m o ni di ne Tartrate 
0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 % C o m bi nati o n 
O p ht hal mic S ol uti o n, Use d T w o Ti mes Dail y i n Healt h y 
A d ult S u bjects a n d i n Pe diatric S u bjects wit h a Hist or y or 
Fa mil y Hist or y of At o pic Disease (i ncl u di n g Aller gic 
C o nj u ncti vitis)  
Pr ot oc ol N u m ber:  
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
St u d y P h ase:  
3  
I n vesti g ati o n al 
Pr o d uct N a me:  
Bri m o ni di ne Tartrate 0. 0 2 5 % / Ket otife n F u marate 0. 0 3 5% 
C o m bi nati o n O p ht hal mic S ol uti o n 
I N D N u m ber: 
1 5 3 0 3 5  
I n dic ati o n: 
Aller gic C o nj u ncti vitis  
I n vesti g at ors: 
M ulti -Ce nter  
S p o ns or:  
Ba usc h & L o m b  I nc or p orate d 
4 0 0 S o merset C or p orate B o ule var d 
Bri d ge water, NJ 0 8 8 0 7 
C o ntr act Rese arc h 
Or g a niz ati o n:  
Ora, I nc.  
3 0 0 Bric kst o ne S q uare, T hir d Fl o or 
A n d o ver, M A 0 1 8 1 0 
I R B/I E C: 
Al p ha I R B  
1 0 0 1 A ve ni da Pic o, S uite C, # 4 9 7 
Sa n Cle me nte, C A 9 2 6 7 3 
Ori gi n al Pr ot oc ol:  
Date: 1 3 Fe b 2 0 2 3  
A me n d me nt 1:  
Date:  0 7 J ul 2 0 2 3 
C o nfi de nti alit y St ate me nt  
T his pr ot oc ol c o ntai ns c o nfi de ntial, pr o prietar y i nf or mati o n of Ora, I nc. a n d/ or  Ba usc h & 
L o m b I nc or p orate d. F urt her disse mi nati o n, distri b uti o n or c o p yi n g of t his pr ot oc ol or its 
c o nte nts is strictl y pr o hi bite d.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 2 of 7 1  
S P O N S O R P E R S O N N E L  
S p o ns or:  
Ba usc h & L o m b I nc or p orate d  
4 0 0 S o merset C or p orate B o ule var d  
Bri d ge water, NJ 0 8 8 0 7  
S p o ns or Re prese nt ati ve : 
O R A P E R S O N N E L  
De p art me nt Vice Presi de nt:  
Pr oject M a n a ger:  
M E DI C A L M O NI T O R  
Me dic al M o nit or:  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 3 of 7 1  
S Y N O P SI S  
Pr ot oc ol Title:  
A M ulti -Ce nter, D o u ble -Mas ke d, Ra n d o mize d, 
Ve hicle -C o ntr olle d, Parallel -Gr o u p St u d y E val uati n g 
t he Safet y a n d P har mac o ki netics of Bri m o ni di ne 
Tartrate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 % 
C o m bi nati o n O p ht hal mic S ol uti o n, Use d T w o Ti mes 
Dail y i n Healt h y A d ult S u bjects a n d i n Pe diatric 
S u bjects wit h a Hist or y or Fa mil y Hist or y of At o pic 
Disease (i ncl u di n g Aller gic C o nj u ncti vitis)  
Pr ot oc ol N u m ber:  
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
I n vesti g ati o n al Pr o d uct: 
Bri m o ni di ne Tartrate 0. 0 2 5 % / Ket otife n F u marate 
0. 0 3 5 % C o m bi nati o n O p ht hal mic S ol uti o n  
St u d y P h ase:  
3 
Pri m ar y O bjecti ve(s):  
T o c o m pare t he safet y a n d t olera bilit y of bri m o ni di ne 
tartrate 0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % c o m bi natio n 
o p ht hal mic s ol uti o n vers us its ve hicle i n healt h y a d ult 
s u bjects a n d i n pe diatric s u bjects wit h a hist or y or 
fa mil y hist or y of at o pic disease (i ncl u di n g aller gic 
c o nj u ncti vitis).  
Sec o n d ar y O bjecti ve(s):  
T o c haracterize t he plas ma p har mac o ki netics ( P K) of 
bri m o ni di ne tartrate 0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % 
c o m bi nati o n o p ht hal mic s ol uti o n f oll o wi n g a si n gle 
d ose a n d 2 2 -da y BI D t o pical oc ular d osi n g i n a s u bset 
of healt h y a d ult s u bjects.  
O ver all St u d y Desi g n:  
Str uct ure:  
T he st u d y will c o nsist of 4- 5 1 st u d y visits: a Scree ni n g 
Visit ma y be c o n d ucte d t o verif y s u bjects are eli gi ble t o 
partici pate a n d, f oll o wi n g ra n d o mizati o n  at Da y 1, a 
Treat me nt Peri o d of 6 wee ks  t o e val uate t he safet y of 
bri m o ni di ne tartrate/ ket otife n f u marate  c o m bi nati o n  
dr u g pr o d uct c o m pare d t o its ve hicle.  
Scree ni n g Peri o d:  At t he Scree ni n g or  Visit 1  (Da y 1 ) 
(if Scree ni n g a n d Visit 1 are d o ne o n t he sa me da y) , 
s u bjects will si g n t he i nf or me d c o nse nt f or m (I C F) a n d 
ha ve t heir me dical/ me dicati o n hist or y c ollecte d . 
1 Scree ni n g Visit a n d Visit 1 ma y be c o n d ucte d o n t he sa me da y . 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 4 of 7 1  
Treat me nt Peri o d:  Treat me nt will be gi n at Visit 1  after 
s u bjects are ra n d o mize d 2 : 1 t o recei ve eit her 
bri m o ni di ne tartrate 0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 %  
co m bi nati o n o p ht hal mic s ol uti o n or ve hicle o p ht hal mic 
s ol uti o n bilaterall y. At t his visit, s u bjects will 
i nstill/recei ve a n i n-office d ose of t he treat me nt t he y 
were ra n d o mize d t o recei ve. A s u bset of 2 5 healt h y 
a d ult s u bjects will u n der g o P K bl o o d dra wspre- (I P) 
i nstillati o n a n d o ut t o 4 h o urs p ost - I P i nstillati o n. 
Q ualifie d s u bjects will be dis pe nse d t he assi g ne d I P a n d 
a diar y f or at -h o me d osi n g. Visits 2 a n d 3 are safet y 
f oll o w-u p visits , a n d s u bjects will recei ve o ne  d ose i n 
t he office. F or t he P K s u bset , bl o o d dra ws  will als o be  
perf or me d at Visit 3 f oll o wi n g t he  i n- office d ose . 
S u bjects will i nstill/recei ve a fi nal d ose of st u d y 
me dicati o n at -h o me t he e ve ni n g pri or t o Visit 4. 
D ur ati o n:  
T his trial c o nsists of 4- 5 office visits o ver a peri o d of 
a p pr o xi matel y 6- 1 0 wee ks . 
C o ntr ols:  
Ve hicle of b ri m o ni di ne tartrate 0. 0 2 5 %/ k et otife n 
f u marate 0. 0 3 5 % o p ht hal mic s ol uti o n  
D os a ge  I nstill ati o n: 
At Visit 1 , a trai ne d st u d y tec h nicia n will o bser ve t he 
s u bject, s u bject’s careg i ver, or s u bject’s pare nt/le gal 
g uar dia n (if a p plica ble f or s u bjects less t ha n 1 8 years of 
a ge) i nstill 1 dr o p of t he assi g ne d I P i nt o eac h e ye. T he 
s u bjects e nr olle d t o t he P K s u bset will recei ve  1 dr o p of 
t he assi g ne d I P i nt o eac h e ye fr o m a trai ne d tec h nicia n. 
At -h o me d osi n g will be gi n  f oll o wi n g Visit 1. 
At Visit  2 a n d 3 , a trai ne d st u d y tec h nicia n will i nstill 1 
dr o p of t he assi g ne d I P i nt o eac h e ye i n- office. 
At h o me, su bjects, s u bject’s care gi ver or s u bject’s 
pare nt/le gal g uar dia n (if a p plica ble, f or s u bjects less 
t ha n 1 8 years of a ge), will i nstill at-h o me d osi n g i n eac h 
e ye BI D 7. 5 h o urs  a part f or u p t o 6 c o nsec uti ve wee ks 
( u ntil t he e ve ni n g pri or t o Visit 4). 
S u m m ar y of Visit Sc he d ule:  
Scree ni n g Peri o d ( D a y -2 8 t o D a y 1) 1: Scree ni n g  
Tre at me nt Peri o d:  
Visit 1 ( D a y 1, B aseli ne):  Baseli ne Assess me nts, 
E nr oll me nt/ Ra n d o mizati o n , a n d I n -office I nstillati o n  
Visit 2 ( D a y 8 ± 2):  F oll o w -u p    
Visit 3 ( D a y 2 2 ± 3):  F oll o w -u p   
Visit 4 ( D a y 4 3 + 3):  Treat me nt Disc o nti n uati o n & E xit 
Visi t 
1 Scree ni n g Visit a n d Visit 1 ma y be c o n d ucte d o n t he sa me da y  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 5 of 7 1  
Me as ures T a ke n t o Re d uce Bi as:  
Ra n d o mizati o n will be use d t o a v oi d bias i n t he 
assi g n me nt of s u bjects t o I P, t o i ncrease t he li keli h o o d 
t hat k n o w n a n d u n k n o w n s u bject attri b utes (e. g., 
de m o gra p hics a n d baseli ne c haracteristics) are e ve nl y 
bala nce d acr oss treat me nt gr o u ps, a n d t o e n ha nce t he 
vali dit y of statistical c o m paris o ns acr oss treat me nt 
gr o u ps. Fi nall y, mas ke d treat me nt will be use d t o 
re d uce p ote ntial of bias d uri n g data c ollecti o n a n d 
e val uati o n of cli nical e n d p oi nts.  
St u d y P o p ul ati o n C h ar acteristics:  
N u m ber of S u bjects:  
A p pr o xi matel y 6 0 0 s u bjects will be scree ne d i n or der t o 
e nr oll a p pr o xi matel y 5 0 1 s u bjects fr o m a p pr o xi matel y 
6 sites i n t he U nite d States. Of t he s u bject t otal, 
a p pr o xi matel y 1 0 0 pe diatric s u bjects are a ntic i pate d t o 
be e nr olle d i nt o t his st u d y.  
T he a ge classificati o n f or t he pe diatric p o p ulati o n will 
be a p pr o xi matel y 5 0 s u bjects i n eac h of t he f oll o wi n g 
gr o u ps:  
• 5- 1 2 years ol d
• 1 3 -1 7 years ol d
S u bjects will n ot be stratifie d b y a ge gr o u p w he n 
assi g ne d t o I P. 
A s u bset of u p t o 2 5 healt h y a d ult s u bjects ( ~1 6  
s u bjects f or t he I P a n d ~ 9 s u bjects f or t he ve hicle) will 
u n der g o P K bl o o d dra ws t o assess t he s yste mic 
e x p os ure of bri m o ni di ne a n d ket otife n . 
C o n diti o n/ Dise ase:  
Aller gic C o nj u ncti vitis 
I ncl usi o n Criteri a: 
S u bjects m ust : 
1.
be at least 5 years of a ge at Scree ni n g Visit  or Visit
1 (if Scree ni n g a n d Visit 1 are d o ne o n t he sa me
da y), of  eit her se x a n d a n y race (a g o ver n me nt
iss ue d I D a n d/ or birt h certificate will be verifie d at
t he ti me I C F is si g ne d);
2.
pr o vi de writte n i nf or me d c o nse nt a n d si g n t he
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
(HI P A A ) f or m. S u bjects w h o are at least 7 years of
a ge a n d less t ha n 1 8 years of a ge will nee d t o si g n
a n asse nt f or m. I n a d diti o n, all s u bjects bel o w t he
a ge of 1 8 years will be re q uire d t o ha ve b ot h
pare nt s or le gal g uar dia n si g n t he i nf or me d c o nse nt;
3.
be willi n g a n d a ble t o f oll o w all i nstr ucti o ns a n d
atte n d all st u d y visits (a n d be acc o m pa nie d b y a
pare nt/le gal g uar dia n if t he s u bject is u n der t he a ge
of 1 8);
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 of 7 1  
 
4.  be a ble t o self -a d mi nister e ye dr o ps satisfact oril y or 
ha ve a care gi ver or pare nt/le gal g uar dia n (if 
a p plica ble, f or s u bjects less t ha n 1 8 years of a ge) at 
h o me 1 r o uti nel y a vaila ble f or t his p ur p ose; 
5.  f or s u bjects less t ha n 1 8 years of a ge, ha ve eit her a 
hist or y or fa mil y hist or y of at o pic disease ( s uc h as 
at o pic der matitis, ast h ma, aller gic 
c o nj u ncti vitis/r hi nitis, a n d at o pic 
kerat oc o nj u ncti vitis  ( A K C)); 
6.  (if fe male a n d of c hil d beari n g p ote ntial) a gree t o 
ha ve uri ne pre g na nc y testi n g perf or me d at Visit 1 
( m ust be ne gati ve) a n d at e xit visit2; m ust n ot be 
lactati n g; a n d m ust a gree t o use at least 1 me dicall y 
acce pta ble f or m of birt h c o ntr ol t hr o u g h o ut t he 
st u d y d urati o n a n d f or at least 1 4 da ys pri or t o Visit 
1 a n d 1 m o nt h after disc o nti n ui n g  I P. Acce pta ble 
f or ms of birt h c o ntr ol are tr ue 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), s per mici de wit h barrier, oral 
c o ntrace pti ve, i njecta ble or i m pla nta ble met h o d of 
c o ntrace pti o n, tra ns der mal c o ntrace pti ve, 
intra uteri ne de vice, or s ur gical sterilizati o n of male 
part ner at least 3 m o nt hs pri or t o t he first d ose of 
i n vesti gati o nal dr u g ( Visit 1). N ote: W o me n 
c o nsi dere d ca pa ble of bec o mi n g pre g na nt i ncl u de 
all fe males w h o ha ve e x perie nce d me narc he a n d 
ha ve n ot e x perie nce d me n o pa use (as defi ne d b y 
a me n orr hea f or greater t ha n 1 2 c o nsec uti ve m o nt hs) 
or ha ve n ot u n der g o ne s uccessf ul s ur gical 
sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, 
or bilateral o o p h orect o m y ); 
7.  (if male a n d wit h fe male p art ner of c hil d beari n g 
p ote ntial) m ust use at least 1 me dicall y acce pta ble 
f or m of birt h c o ntr ol. N ote: Acce pta ble f or ms of 
birt h c o ntr ol are tr ue 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)  
or vasect o m y at least 3 m o nt hs pri or t o recei vi n g I P 
( Visit 1). Wit h o ut a vasect o m y, m ust use c o n d o ms 
wit h s per mici dal f oa m/ gel/fil m/crea m/s u p p osit or y 
t hr o u g h o ut t he st u d y d urati o n, f or at least 1 4 da ys 
pri or t o a n d 1 m o nt h after disc o nti n ui n g I P; 
8.  ha ve oc ular healt h wit hi n n or mal li mits, i ncl u di n g a 
calc ulate d ( V A)  of 0. 3 l o g M A R or better i n eac h 
e ye as meas ure d usi n g a n Earl y Treat me nt Dia betic 
Reti n o pat h y St u d y ( E T D R S ) c hart. F or s u bjects 
u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble 
t o use t he E T D R S c hart, a best atte m pt at V A  will 
be ma de usi n g t he L E A s y m b ols or Vis ual 
Be ha vi or. F or s u bjects  utilizi n g L E A s y m b ols , 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 7 of 7 1  
 
S nelle n e q ui vale nt u nits of 2 0/ 6 3 or better i n b ot h 
e yes will be re q uire d . S u bjects utilizi n g Vis ual 
Be ha vi or m ust ha ve a passi n g  sc ore; 
9.  (f or selecte d healt h y a d ult s u bjects a greei n g t o 
u n der g o P K bl o o d dra ws) ha ve a b o d y mass i n de x 
( B MI) ≥1 8 a n d ≤3 4 l bs/i n2 a n d a mi ni m u m b o d y 
wei g ht of 9 9 l bs;  
1 0.  (f or selecte d healt h y a d ult s u bjects a greei n g t o 
u n der g o P K bl o o d dra ws) ha ve s uita ble ve n o us 
access f or bl o o d sa m pli n g.  
E xcl usi o n Criteri a:  
S u bjects ma y n ot :  
 
1.  ha ve k n o w n c o ntrai n dicati o ns or se nsiti vities t o t he 
use of a n y of t he I P me dicati o n or c o m p o ne nts;  
2.  ha ve ha d oc ular s ur gical i nter ve nti o n wit hi n 3 
m o nt hs pri or t o Visit 1 or d uri n g t he st u d y a n d/ or a 
hist or y of refracti ve s ur ger y wit hi n t he past 6 
m o nt hs;  
3.  ha ve a k n o w n hist or y of reti nal detac h me nt, 
dia betic reti n o pat h y, or acti ve reti nal disease;  
4.  ha ve t he prese nce of a n acti ve oc ular i nfecti o n 
( bacterial, viral or f u n gal) or positi ve hist or y of a n 
oc ular her petic i nfecti o n at a n y visit;  
5.  use a n y of t he f oll o wi n g disall o we d me dicati o ns 
d uri n g t he peri o d i n dicate d pri or t o Visit 1 a n d 
d uri n g t he st u d y ; 
5 da ys  
•  
artificial tear pr o d ucts, e ye w hite ners (e. g., 
vas oc o nstrict ors), oc ular  dec o n gesta nts, oc ular 
c ortic oster oi ds, oc ular a nti hista mi nes, a n d a n y 
ot her t o pical o p ht hal mic a ge nts;  
1 4 da ys  
•  
 a n y s yste mic me dicati o ns w hic h t he 
i n vesti gat or feels ma y c o nf o u n d st u d y data or 
i nterfere wit h s u bject’s st u d y partici pati o n; 
6.  h a ve used c o ntact le nses wit hi n  2 4 h o urs pri or t o 
eac h visit ( Visit 1, 2, 3, a n d 4);  
7.  ha ve pri or ( wit hi n 7 da ys of be gi n ni n g I P) or 
curre ntl y acti ve si g nifica nt ill ness t hat c o ul d 
c o m pr o mise partici pati o n, i n t he o pi ni o n of t he 
i n vesti gat or; 
 
1 If a care gi ver or pare nt/le gal g uar dia n will a d mi nister e ye dr o ps, t he n he/s he m ust be prese nt at Visit 1 t o a d mi nister e ye dr o ps i n-
office. 
2 F or i de ntifie d pre me narc hal fe males at Visit 1, t heir me narc hal stat us will be q uerie d at eac h s u bse q ue nt visit.  If a s u bject is n o 
l o n ger pre me narc h al at a n y of her s u bse q ue nt visits, t hat s u bject m ust a gree t o ha ve a uri ne pre g na nc y test perf or me d at t hat visit. 
S u bse q ue ntl y t hese s u bjects will f oll o w all t he re q uire me nts of fe male s u bjects of c hil d beari n g p ote ntial re gar di n g pre g na nc y tests a n d 
birt h c o ntr ol.   
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 8 of 7 1  
 
8.  ha ve pri or ( wit hi n 3 0 da ys of be gi n ni n g I P) or 
a ntici pate d c o nc urre nt use of a n I P or de vice d uri n g 
t he st u d y peri o d; 
9.  h a ve bee n ra n d o mize d i n st u d y 9 0 9 or 9 1 0 
c o n d ucte d b y Ba usc h & L o m b;  
1 0.  be  a n e m pl o yee or fa mil y me m ber of e m pl o yee at 
t he i n vesti gati ve site; 
1 1.  ha ve a n oc ular or s yste mic c o n diti o n or is i n a 
sit uati o n t hat t he i n vesti gat or feels ma y p ut t he 
s u bject 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 
s u bject’s st u d y partici pati o n; 
1 2.  ha ve pla n ne d s ur ger y ( oc ular or s yste mic) d uri n g 
t he trial peri o d or wit hi n 3 0 da ys after; 
1 3.  ha ve b o d y wei g ht bel o w t he 5 t h perce ntile f or t heir 
a ge (s u bj ects 1 2 years of a ge or y o u n ger o nl y) (see 
A p pe n di x 2 ); 
1 4.  be a fe male w h o is c urre ntl y pre g na nt, is pla n ni n g a 
pre g na nc y, or lactati n g;  
1 5.  ha ve a n a b n or mal bl o o d press ure ( defi ne d as ≤ 9 0 
or ≥ 1 6 0 (s yst olic) meas ure d i n m m H g or ≤ 6 0 or ≥ 
1 0 0 ( diast olic) meas ure d i n m m H g). F or pe diatric 
s u bjects, a b n or mal bl o o d press ure is defi ne d as ≥ 
1 4 0 (s yst olic) meas ure d i n m m H g or ≥ 9 0 
( diast olic) meas ure d i n m m H g; 
1 6.  ha ve a n i ntra oc ular press ure (I O P) t hat is less t ha n 
5 m m H g or greater t ha n 2 2 m m H g or ha ve a n or mal 
I O P wit h a pri or dia g n osis/ hist or y of gla uc o ma at 
Visit 1;  
1 7.  ha ve s y m pt o ms ass ociate d wit h C O VI D -1 9 or ha ve 
bee n i n c o ntact wit h s o me o ne dia g n ose d wit h 
C O VI D -1 9 wit hi n 1 4 da ys of t he Scree ni n g Visit  or 
Visit 1 (if Scree ni n g a n d Visit 1 are d o ne o n t he 
sa me da y); 
1 8.  (f or selecte d healt h y a d ult s u bjects a greei n g t o 
u n der g o P K bl o o d dra ws) ha ve e xcessi ve 
c o ns u m pti o n of caffei ne - or xa nt hi ne -c o ntai ni n g 
be vera ges ( m ore t ha n 4 c u ps or ser vi n gs per da y) 
wit hi n 4 8 h o urs pri or t o d osi n g at Visit 1 or f or t he 
d urati o n of t he st u d y  (see A p pe n di x 6 ); 
1 9.  (f or selecte d healt h y a d ult s u bjects a greei n g t o 
u n der g o P K bl o o d dra ws) ha ve a hist or y of t o bacc o, 
nic oti ne, or nic oti ne -c o ntai ni n g pr o d uct use wit hi n 
1 2 m o nt hs pri or t o Visit 1;  
2 0.  (f or selecte d healt h y a d ult s u bjects a greei n g t o 
u n der g o P K bl o o d dra ws) ha ve a hist or y or c urre nt 
e vi de nce of dr u g or alc o h ol a b use wit hi n 1 2 m o nt hs 
pri or t o Visit 1;  
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 1 0  of 7 1  
t he first I P d ose i nstillati o n at Visit 1 is defi ne d as t he baseli ne e xa mi nati o n. T he pre -
i nstillati o n e xa mi nati o n f or Visit 2 a n d Visit 3 is defi ne d as pre-i nstillati o n e xa mi nati o n at 
t h ose visits. 
C ha n ges (fr o m t he Visit 1 pre -i nstillati o n Baseline o bser vati o n t o all o bser vati o ns at later 
st u d y visits a n d fr o m pre-i nstillati o n t o 1 5 mi n utes ( + 3 mi n utes) p ost I P i nstillati o n at eac h 
Visits 1 -3) i n bi o micr osc o p y fi n di n gs will be prese nte d at eac h visit b y treat me nt gr o u p. 
Si milarl y, c ha n ges fr o m Baseli ne at Visit 4 i n i ntra oc ular press ure a n d dilate d f u n d osc o p y 
fi n di n gs will be prese nte d b y treat me nt gr o u p. I n a d diti o n, c ha n ges at eac h visit (fr o m t he 
Visit 1 Baseli ne val ue) i n V A  will be prese nte d b y treat me nt gr o u p. I O P a n d Vis ual ac uit y 
c ha n ges fr o m baseli ne will als o be prese nte d usi n g cate g orical s u m maries.  
A s u m mar y of p h ysical e xa mi nati o n res ults a n d a s u m mar y of vital si g ns will be prese nte d at 
eac h a p plica ble visit b y treat me nt gr o u p.  
Dr o p c o mf ort will be s u m marize d usi n g descri pti ve statistics.  
T he q ua ntitati ve varia bles will be s u m marize d usi n g descri pti ve statistics (e. g., n u m ber of 
o bser vati o ns ( n), mea n, sta n dar d de viati o n ( S D), mi ni m u m, me dia n, a n d ma xi m u m). T he 
q ualitati ve varia bles will be s u m marize d usi n g c o u nts a n d perce nta ges.  
T he n u m ber of s u bjects re p orti n g a n y treat me nt e mer ge nt a d verse e ve nt ( T E A E) d uri n g t he 
st u d y will be prese nte d. T he n u m ber of s u bjects f or eac h A E cate g or y ( oc ular a n d n o n -oc ular) 
will be ta b ulate d b y Me dical Dicti o nar y f or Re g ulat or y Acti vities  (Me d D R A ) S yste m Or ga n 
Class, preferre d ter m wit hi n eac h s yste m or ga n class, f or eac h treat me nt gr o u p. T he n u m b er 
of s u bjects re p orti n g seri o us A Es ( S A Es) a n d A E s relate d t o I P will als o be ta b ulate d. I n 
a d diti o n, AE s will als o be s u m marize d b y se verit y. Treat me nt e mer ge nt oc ular AE s will als o 
be s u m marize d at t he e ye le vel f or all treate d e yes.  
S u b gr o u p a nal yses will be perf or me d b y a ge gr o u ps: 5 - 1 2 years ol d, 1 3- 1 7 years ol d, 1 8 -6 4 
years ol d, a n d f or a ges greater t ha n 6 4 years. S u b gr o u p a nal yses will be perf or me d o n t he 
f oll o wi n g e n d p oi nts: AE s, I O P, V A , bi o micr osc o p y, dilate d f u n d osc o p y, a n d t olera bilit y. 
P har mac o ki netics  
Statistical anal ysis  plas ma c o nce ntrati o n s will be base d o n t he P K p o p ulati o n, w hic h will 
i ncl u de all s u bjects wit h at least o ne bl o o d sa m ple dra w n p ost -d ose i n t he s u bset of s u bjects 
f or P K bl o o d dra ws.  P har mac o ki netic para meter a nal yses will be perf or me d usi n g sta n dar d 
n o n -c o m part me ntal a nal ysis, data per mitti n g. W he n p ossi ble, plas ma c o nce ntrati o ns b y 
sc he d ule d ti me p oi nt a n d P K para meters b y da y will be s u m marize d usi n g descri pti ve 
statistics: n, mea n, me dia n, S D, mi ni m u m, ma xi m u m, a n d perce nt c oefficie nt of variati o n ( % 
C V). 
S u m m ar y of K n o w n a n d P ote nti al Ris ks a n d Be nefits t o H u m a n S u bjects  
Refer t o I n vesti gat or’s Br oc h ure (I B) . 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 1  of 7 1  
 
T A B L E O F C O N T E N T S  
 
T A B L E O F C O N T E N T S  .................................................................................................. 1 1 
LI S T O F A B B R E VI A TI O N S  ........................................................................................... 1 4 
1  I N T R O D U C TI O N ...................................................................................................... 1 6 
2  S T U D Y O BJ E C TI V E S  ............................................................................................... 1 7 
3  C LI NI C A L H Y P O T H E S E S  ....................................................................................... 1 7 
4  O V E R A L L S T U D Y D E SI G N  .................................................................................... 1 7 
5  S T U D Y P O P U L A TI O N  ............................................................................................. 1 8 
5. 1  
N U M B E R O F S U BJ E C T S (A P P R O XI M A T E )....................................................................................... 1 8  
5. 2  
S T U D Y P O P U L A TI O N C H A R A C T E RI S TI C S ...................................................................................... 1 8  
5. 3  
IN C L U SI O N C RI T E RI A  ................................................................................................................... 1 8  
5. 4  
E X C L U SI O N C RI T E RI A .................................................................................................................. 1 9  
5. 5  
W
I T H D R A W A L C RI T E RI A (I F A P P LI C A B L E) ................................................................................... 2 1  
6  S T U D Y P A R A M E T E R S  ............................................................................................ 2 1 
6. 1  
S A F E T Y M E A S U R E S  ..................................................................................................................... 2 1  
6. 2  
T O L E R A BI LI T Y M E A S U R E S  .......................................................................................................... 2 1  
6. 3  
P H A R M A C O KI N E TI C M E A S U R E S  .................................................................................................. 2 1  
7  S T U D Y M A T E RI A L S  ............................................................................................... 2 2 
7. 1  
S T U D Y T R E A T M E N T (S ) ................................................................................................................ 2 2  
7. 1. 1  
St u d y Treat me nt(s)/ F or m ulati o n(s)  ........................................................................................ 2 2  
7. 1. 2  
I nstr ucti o ns f or Use a n d A d mi nistrati o n ................................................................................. 2 2  
7. 2  
O T H E R S T U D Y S U P P LI E S  ............................................................................................................. 2 3  
8  S T U D Y M E T H O D S A N D P R O C E D U R E S  .............................................................. 2 3 
8. 1  
S U BJ E C T E N T R Y P R O C E D U R E S  .................................................................................................... 2 3  
8. 1. 1  
O ver vie w  ................................................................................................................................. 2 3  
8. 1. 2  
I nf or me d C o nse nt .................................................................................................................... 2 3  
8. 1. 3  
Was h o ut I nter vals  ................................................................................................................... 2 3  
8. 1. 4  
Pr oce d ures f or Fi nal St u d y E ntr y  ............................................................................................ 2 4  
8. 1. 5  
Met h o ds f or Assi g n me nt t o Treat me nt Gr o u ps:  ...................................................................... 2 4  
8. 2  
C O N C U R R E N T T H E R A PI E S ............................................................................................................ 2 4  
8. 2. 1  
Pr o hi bite d Me dicati o ns/ Treat me nts  ........................................................................................ 2 4  
8. 2. 2  
C o ntact Le ns Use  .................................................................................................................... 2 5  
8. 2. 3  
S pecial Diet or Acti vities  ........................................................................................................ 2 5  
8. 3  
E X A MI N A TI O N P R O C E D U R E S  ....................................................................................................... 2 5  
8. 3. 1  
Pr oce d ures t o be Perf or me d at Eac h St u d y Visit wit h Re gar d t o St u d y O bjecti ve(s)  ............. 2 5  
8. 4  
S C H E D U L E O F V I SI T S, M E A S U R E M E N T S A N D D O SI N G  ................................................................. 3 1  
8. 4. 1  
Sc he d ule d Visits  ...................................................................................................................... 3 1  
8. 4. 2  
U nsc he d ule d Visits  ................................................................................................................. 3 1  
8. 4. 3  
E xit Pr oce d ures  ....................................................................................................................... 3 2  
8. 5  
C O M P LI A N C E WI T H P R O T O C O L  .................................................................................................... 3 2  
8. 6  
S U BJ E C T D I S P O SI TI O N ................................................................................................................. 3 3  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 2  of 7 1  
 
8. 6. 1  
C o m plete d S u bjects ................................................................................................................. 3 3  
8. 6. 2  
Disc o nti n ue d S u bjects  ............................................................................................................. 3 3  
8. 7  
L O S T T O F O L L O W -U P  ................................................................................................................... 3 3  
8. 8  
S T U D Y T E R MI N A TI O N  .................................................................................................................. 3 3  
8. 9  
S T U D Y D U R A TI O N  ....................................................................................................................... 3 3  
8. 1 0  
M O NI T O RI N G  A N D Q U A LI T Y A S S U R A N C E  ................................................................................... 3 4  
9  A D V E R S E E V E N T S  .................................................................................................. 3 4 
9. 1  
D E FI NI TI O N O F A D V E R S E E V E N T ( A E) ........................................................................................ 3 4  
9. 1. 1  
Assess me nt of Se verit y of A d verse E ve nts  ............................................................................. 3 5  
9. 1. 2  
Assess me nt of Ca usalit y of A d verse E ve nts  ........................................................................... 3 5  
9. 2  
S E RI O U S A D V E R S E E V E N T S  ......................................................................................................... 3 5  
9. 2. 1  
E x pe dite d Seri o us A d verse E ve nts  ......................................................................................... 3 8  
9. 2. 2  
Pre g na nc y  ................................................................................................................................ 3 8  
9. 3  
G E N E R A L G UI D E LI N E S F O R R E P O R TI N G A D V E R S E E V E N T S  ......................................................... 3 9  
9. 4  
P R O C E D U R E S F O R U N M A S KI N G (I F A P P LI C A B L E) ......................................................................... 4 1  
1 0  S T A TI S TI C A L H Y P O T H E S E S A N D M E T H O D S O F A N A L Y S E S  ....................... 4 1 
1 0. 1  
S T U D Y P O P U L A TI O N S  .................................................................................................................. 4 1  
1 0. 2  
U NI T O F A N A L Y SI S  ...................................................................................................................... 4 1  
1 0. 3  
P RI M A R Y S T A TI S TI C A L H Y P O T H E SI S  ........................................................................................... 4 1  
1 0. 4  
S A M P L E S I Z E ............................................................................................................................... 4 1  
1 0. 5  
D E M O G R A P HI C A N D B A S E LI N E C H A R A C T E RI S TI C S  ..................................................................... 4 2  
1 0. 6  
S A F E T Y A N A L Y SI S  ...................................................................................................................... 4 2  
1 0. 7  
A D V E R S E E V E N T S  ....................................................................................................................... 4 3  
1 0. 8  
D O SI N G C O M P LI A N C E A N D E X T E N T O F E X P O S U R E  ...................................................................... 4 3  
1 0. 9  
T O L E R A BI LI T Y A N A L Y SI S  ........................................................................................................... 4 3  
1 0. 1 0  
P H A R M A C O KI N E TI C S A N A L Y SI S  .................................................................................................. 4 4  
1 1  C O M P LI A N C E WI T H G O O D C LI NI C A L P R A C TI C E S, E T HI C A L 
C O N SI D E R A TI O N S, A N D A D MI NI S T R A TI V E I S S U E S  ...................................... 4 4 
1 1. 1  
P R O T E C TI O N O F H U M A N S U BJ E C T S  ............................................................................................. 4 4  
1 1. 1. 1  S u bject I nf or me d C o nse nt  ....................................................................................................... 4 4  
1 1. 1. 2  I nstit uti o nal Re vie w B oar d (I R B) A p pr o val ........................................................................... 4 5  
1 1. 2  
E T HI C A L C O N D U C T O F T H E S T U D Y  .............................................................................................. 4 5  
1 1. 3  
S U BJ E C T C O N FI D E N TI A LI T Y  ........................................................................................................ 4 5  
1 1. 4  
D O C U M E N T A TI O N  ....................................................................................................................... 4 5  
1 1. 4. 1  Rete nti o n of D oc u me ntati o n  ................................................................................................... 4 5  
1 1. 5  
L A B E LI N G , P A C K A GI N G , S T O R A G E , A C C O U N T A BI LI T Y ,  A N D R E T U R N  O R  D I S P O S A L  O F  
IN V E S TI G A TI O N A L P R O D U C T  ....................................................................................................... 4 6  
1 1. 5. 1  La beli n g/ Pac ka gi n g  ................................................................................................................. 4 6  
1 1. 5. 2  St ora ge of I n vesti gati o nal Pr o d uct  .......................................................................................... 4 6  
1 1. 5. 3  Acc o u nta bilit y of I n vesti gati o nal Pr o d uct  ............................................................................... 4 6  
1 1. 5. 4  Ret ur n or Dis p osal of I n vesti gati o nal Pr o d uct  ........................................................................ 4 6  
1 1. 6  
R E C O R DI N G O F D A T A O N S O U R C E D O C U M E N T S A N D C A S E R E P O R T S F O R M S ( C R FS ) ................. 4 6  
1 1. 7  
H A N D LI N G O F B I O L O GI C A L S P E CI M E N S  ...................................................................................... 4 6  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 3  of 7 1  
 
1 1. 8  
P U B LI C A TI O N S  ............................................................................................................................. 4 7  
1 2  R E F E R E N C E S  ........................................................................................................... 4 8 
 
1 3  A P P E N DI C E S  ............................................................................................................ 4 9 
A P P E N DI X 1: S C H E D U L E O F VI SI T S A N D M E A S U R E M E N T S  .............................. 4 9 
A P P E N DI X 2: E X A MI N A TI O N P R O C E D U R E S, T E S T S, E Q UI P M E N T, A N D 
T E C H NI Q U E S  ........................................................................................................... 5 1 
A P P E N DI X 3: S U BJ E C T D O SI N G DI A RI E S  ................................................................ 5 9 
A P P E N DI X 4: T A B L E O F FI F T H ( 5 T H) P E R C E N TI L E B O D Y W EI G H T S B Y A G E  6 5 
A P P E N DI X 5: P R O T O C O L A M E N D M E N T S  ............................................................... 6 6 
A P P E N DI X 6: X A N T HI N E -C O N T AI NI N G B E V E R A G E S A N D P R O D U C T S  .......... 6 7 
A P P E N DI X 7: B L O O D C O L L E C TI O N, H A N D LI N G, A N D S HI P M E N T F O R 
P H A R M A C O KI N E TI C A N A L Y SI S  ......................................................................... 6 8 
A P P E N DI X 8: S P O N S O R A P P R O V A L S  ....................................................................... 6 9 
A P P E N DI X 9: O R A A P P R O V A L S  ................................................................................. 7 0 
A P P E N DI X 1 0: I N V E S TI G A T O R’ S SI G N A T U R E  ....................................................... 7 1 
 
 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 4  of 7 1  
 
LI S T O F A B B R E VI A TI O N S  
A C  
aller gic c o nj u ncti vitis 
A K C  
at o pic kerat oc o nj u ncti vitis  
A E  
a d verse e ve nt  
B A K  
be nzal k o ni u m c hl ori de  
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  
B MI  
b o d y mass i n de x  
C F R  
C o de of Fe deral Re g ulati o ns  
C V  
c oefficie nt of variati o n  
D H H S  
De part me nt of Healt h a n d H u ma n Ser vices  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E R C  
et hical re vie w c o m mittee  
E T D R S  
Earl y Treat me nt Dia betic Reti n o pat h y St u d y  
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 nical Practice  
G P C  
gia nt pa pillar y c o nj u ncti vitis  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
I B 
I n vesti gat or’s br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
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 P 
Intra oc ular press ure  
I P 
i n vesti gati o nal pr o d uct 
I R B 
i nstit uti o nal re vie w b oar d 
I S A A C 
I nter nati o nal St u d y of Ast h ma a n d Aller gies i n C hil d h o o d 
l o g M A R 
l o garit h m of t he mi ni m u m a n gle of res ol uti o n 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N C S  
n ot cli nicall y si g nifica nt 
N H A N E SIII  
T hir d Nati o nal Healt h a n d N utriti o n E xa mi nati o n S ur ve y  
O D  
ri g ht e ye 
O S  
left e ye 
P A C  
pere n nial aller gic c o nj u ncti vitis  
P HI  
pr otecte d healt h i nf or mati o n  
P K  
p har mac o ki netics  
R T S M  
Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt  
S A C  
seas o nal aller gic c o nj u ncti vitis 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 5  of 7 1  
 
S D  
sta n dar d de viati o n 
T E A E  
treat me nt e mer ge nt a d verse e ve nt 
V A  
vis ual ac uit y  
V K C  
ver nal kerat oc o nj u ncti vitis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 6  of 7 1  
 
1  
I N T R O D U C TI O N 
Aller g y is descri be d as t he fift h lea di n g gr o u p of c hr o nic diseases, affecti n g 5 0 milli o n 
A merica ns. T he T hir d Nati o nal Healt h a n d N utriti o n E xa mi nati o n S ur ve y ( N H A N E SIII) 
rece ntl y re veale d t hat 4 0 % of t his A merica n test p o p ulati o n re p orte d havi n g e pis o des of 
oc ular aller g y  (Si n g h, 2 0 1 0 ). I n a rece nt re vie w of st u dies o n t he i nci de nce of aller gic 
c o nj u ncti vitis ( A C) ( R osari o, 2 0 1 1 ), a pre vi o us st u d y  (Biel or y, 2 0 0 0 ) was u p date d t hat 
pr o vi de d data o n c hil dre n a n d a d olesce nts w h o partici pate d i n t he I nter nati o nal St u d y of 
Ast h ma a n d Aller gies i n C hil d h o o d ( I S A A C) fr o m as ma n y as 5 7 c o u ntries. T his o n g oi n g 
eff ort re veale d a n i ncrease d pre vale nce fr o m 1 6. 5 % i n 1 9 8 5 t o 2 9. 6 % i n 2 0 0 0 ( Steeri n g 
C o m mittee, 1 9 9 8; Bj or kste n, 2 0 0 8 ). Ot her re p orts ra n ge d fr o m 4 1. 4 % f or pers o ns ha vi n g 
at least o ne e pis o de i n 1 2 m o nt hs, t o 2 0. 7 % f or t h ose ha vi n g 4 or m ore e pis o des 
(Hessel mar, 2 0 0 1 ). 
Oc ular aller g y ra n ges i n se verit y fr o m mil d f or ms, w hic h still i nterfere si g nifica ntl y wit h 
q ualit y of life, t o se vere cases c hara cterize d b y p ote ntial i m pair me nt of vis ual f u ncti o n. 
T he ter m oc ular aller g y refers t o a c ollecti o n of h y perse nsiti vit y dis or ders t hat affect t he 
li d, c o nj u ncti va a n d/ or c or nea. Vari o us cli nical f or ms are i ncl u de d i n t he classificati o n of 
oc ular aller g y: s eas o nal aller gic c o nj u ncti vitis  ( S A C) a n d pere n nial aller gic c o nj u ncti vitis 
( P A C), ver nal kerat oc o nj u ncti vitis ( V K C), at o pic kerat oc o nj u ncti vitis ( A K C), gia nt 
pa pillar y c o nj u ncti vitis ( G P C) a n d c o ntact or dr u g-i n d uce d der m o- c o nj u ncti vitis. 
S A C a n d P A C are t he m ost c o m m o n aller gic diseases, acc o u nti n g f or al m ost 9 0 % of 
oc ular aller gic ma nifestati o ns. Seas o nal fl u x is us ual w he n o ne or m ulti ple p olle n 
se nsitizati o ns are i n v ol ve d, h o we ver, i n a mil d cli mate A C mi g ht n ot disa p pear 
c o m pletel y i n t he c ol der seas o ns, a n d is pere n nial w he n ca use d b y se nsitizati o n t o 
u bi q uit o us a nti ge ns s uc h as mites a n d a ni mal da n der. T hese c o m m o n oc ular aller gic 
diseases ca n be t he m ost diffic ult of t he aller gic e ye diseases t o dia g n ose beca use n o 
t y pical or e xcl usi ve si g ns a n d s y mpt o ms ca n be defi ne d. T he c hr o nic f or ms, V K C, A K C 
a n d G P C, are relati vel y rare b ut cli nicall y well c haracterize d. Eac h of t hese diseases has 
s pecific cli nical feat ures i n ter ms of dia g n osis, p har mac ol o gical a n d n o n- p har mac ol o gical 
ma na ge me nt ( A bels o n, J ul y 2 0 0 3 ). 
C urre nt t hera pies use d f or t he treat me nt of A C i ncl u de a nti hista mi nes, mast cell 
sta bilizers, a n d d ual-acti o n t hera pies. W hile ma n y of t hese t hera pies are effecti ve i n 
pr o vi di n g te m p orar y relief, t here re mai ns a n u n met nee d s pecificall y f or patie nts affecte d 
b y m ore c hr o nic f or ms of oc ular aller g y. 
T he p ur p ose of t his st u d y is t o e val uate t he safet y of Bri m o ni di ne Tartrate 0. 0 2 5 %/ 
Ket otife n F u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n  c o m pare d t o its ve hicle  i n 
a p o p ulati o n of healt h y a d ult s u bjects a n d i n pe diatric s u bjects wit h a hist or y or fa mil y 
hist or y of at o pic disease (i ncl u di n g aller gic c o nj u ncti vitis ). Ala wa y®  (ket otife n f u marate, 
0. 0 3 5 % ) is a sec o n d ge nerati o n hista mi ne H 1 a nta g o nist a n d is c urre ntl y a p pr o ve d f or t he 
te m p orar y relief of itc h y e yes d ue t o ra g wee d, p olle n, grass, a ni mal hair a n d da n der 
(A bels o n, Ma y 2 0 0 3; Ala wa y ®  Ket otife n F u marate O p ht hal mic S ol uti o n, 0. 0 3 5 % La bel 
a p pr o ve d A pril 2 0 2 1 ). L u mif y®  (bri m o ni di ne tartrate, 0. 0 2 5 % ) is a selecti ve al p ha 2-A R 
a g o nist t hat acts as a t o pical vas oc o nstrict or f or relief of oc ular re d ness.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 7  of 7 1  
 
W he n use d as directe d, L u mif y
®  di d n ot de m o nstrate tac h y p h yla xis a n d virt uall y n o 
re b o u n d re d ness was o bser ve d (Ac ker ma n, 2 0 1 9; L u mif y ®  Bri m o ni di ne Tar trate 
O p ht hal mic S ol uti o n, 0. 0 2 5 % . La bel a p pr o ve d Se pte m ber 2 0 2 0 ). B y c o m bi ni n g t he 
a nti hista mi ne ket otife n f u marate wit h t he vas oc o nstrict or bri m o ni di ne tartrate, t he 
c o m bi nati o n is i nte n de d t o utilize t he u ni q ue attri b utes of eac h acti ve a ge nt t o re d uce  
oc ular itc hi n g a n d re d ness f or u p 8 h o urs , w hile mai ntai ni n g a safe pr ofile. I n a d diti o n, 
p har mac o ki netics ( P K ) data will be c ollecte d i n a s u bset of healt h y a d ult s u bjects i n t he 
st u d y t o assess t he s yste mic e x p os ure of bri m o ni di ne a n d ket otife n f oll o wi n g a si n gle 
d ose a n d 2 2- da y BI D t o pical oc ular d osi n g. 
2  
S T U D Y O B J E C TI V E S  
T he pri mar y o bjecti ve is t o c o m pare t he safet y a n d t olera bilit y of bri m o ni di ne tartrate 
0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n vers us its ve hicle i n 
healt h y a d ult s u bjects a n d i n pe diatric s u bjects wit h a hist or y or fa mil y hist or y of at o pic 
disease (i ncl u di n g aller gic c o nj u ncti vitis).  
T he sec o n dar y o bjecti ve is t o c haracterize t he plas ma P K of bri m o ni di ne tartrate 
0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n f oll o wi n g a si n gle 
d ose a n d 2 2- da y BI D t o pical oc ular d osi n g i n a s u bset of healt h y a d ult s u bjects.  
3  
C LI NI C A L H Y P O T H E S E S  
It is h y p ot hesize d t hat t he c o m bi nati o n pr o d uct will be safe a n d t olera ble c o m pare d t o t he 
ve hicle i n a p o p ulati o n of healt h y a d ult s u bjects a n d pe diatric s u bjects wit h a hist or y or 
fa mil y hist or y of at o pic disease (i ncl u di n g aller gic c o nj u ncti vitis). 
4  
O V E R A L L S T U D Y D E SI G N  
T his is a m ulti -ce nter, d o u ble- mas ke d, ra n d o mize d, ve hicle-c o ntr olle d, parallel- gr o u p, 
safety st u d y. A p pr o xi matel y 6 0 0 s u bjects will be scree ne d i n or der t o e nr oll 
a p pr o xi matel y 5 0 1 s u bjects fr o m a p pr o xi matel y 6 sites. Of t he s u bject t otal, 
a p pr o xi matel y 1 0 0 pe diatric s u bjects are a ntici pate d t o be e nr olle d i nt o t his st u d y. 
T he a ge classificati o n  f or t he pe diatric p o p ulati o n will be a p pr o xi matel y 5 0 s u bjects i n 
eac h of t he f oll o wi n g gr o u ps: 
•  5- 1 2 years ol d 
•  1 3- 1 7 years ol d  
S u bjects will n ot be stratifie d b y a ge gr o u p w he n assi g ne d t o I P. 
A s u bset of u p t o 2 5 healt h y a d ult s u bjects ( ~ 1 6 s u bjects f or t he I P a n d ~ 9 s u bjects f or t he 
ve hicle) will u n der g o P K bl o o d dra ws t o assess t he s yste mic e x p os ure of bri m o ni di ne a n d 
ket otife n. 
S u bjects, s u bject’s care gi ver, or s u bject’s pare nt/le gal g uar dia n (if a p plica ble, f or s u bjects 
less t ha n 1 8 years of a ge), will i nstill 1 dr o p of t he assi g ne d i n vesti gati o nal dr u g i n eac h 
e ye B I D 7. 5 h o urs a part f or u p t o 6 c o nsec uti ve wee ks. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 1 8  of 7 1  
 
S u bjects will  ha ve visits o n Da y 8 ( ± 2), Da y  2 2 ( ± 3), a n d Da y 4 3 ( + 3) f or safet y 
e val uati o ns. 
5  
S T U D Y P O P U L A TI O N  
5. 1  
N u m ber of S u bjects ( a p pr o xi m ate)  
A p pr o xi matel y 6 0 0 s u bjects will be scree ne d i n or der t o e nr oll a p pr o xi matel y 5 0 1 
s u bjects. 
5. 2  
St u d y P o p ul ati o n C h ar acteristics  
H ealt h y a d ult s u bjects ( >1 8 years of a ge) w h o d o n ot ha ve a n y c o n diti o ns, i n t he 
i n vesti gat or’s o pi ni o n, t hat ma y p ut t he s u bject at i ncrease d ris k, c o nf o u n d st u d y data, or 
i nterfere si g nifica ntl y wit h t he s u bject’s st u d y partici pati o n. 
A N D  
Pe diatric s u bjec ts ( 5-1 7 years of a ge) wit h a hist or y or fa mil y hist or y of at o pic disease 
(i ncl u di n g aller gic c o nj u ncti vitis). 
5. 3  
I ncl usi o n Criteri a 
S u bjects m ust :  
 
1.  be at least 5 years of a ge at Scree ni n g Visit or Visit 1 (if Scree ni n g a n d Visit 1 are 
d o ne o n t he sa me da y), of eit her se x a n d a n y race (a g o ver n me nt iss ue d I D a n d/ or 
birt h certificate will be verifie d at t he ti me I C F is si g ne d);  
2.  pr o vi de writte n i nf or me d c o nse nt a n d si g n t he Healt h I ns ura nce P orta bilit y  a n d 
Acc o u nta bilit y Act ( HI P A A ) f or m. S u bjects w h o are at least 7 years of a ge a n d 
less t ha n 1 8 years of a ge will nee d t o si g n a n asse nt f or m. I n a d diti o n, all s u bjects 
bel o w t he a ge of 1 8 years will be re q uire d t o ha ve b ot h pare nt s or le gal g uar dia n 
si g n t he i nf or me d c o nse nt; 
3.  be willi n g a n d a ble t o f oll o w all i nstr ucti o ns a n d atte n d all st u d y visits (a n d be 
acc o m pa nie d b y a pare nt/le gal g uar dia n if t he s u bject is u n der t he a ge of 1 8); 
4.  be a ble t o self -a d mi nister e ye dr o ps satisfact oril y or ha ve a care gi ver or 
pare nt/le gal g uar dia n (if a p plica ble, f or s u bjects less t ha n 1 8 years of a ge) at 
h o me 1 r o uti nel y a vaila ble f or t his p ur p ose. 
5.  f or s u bjects less t ha n 1 8 years of a ge, ha ve eit her a hist or y or fa mil y hist or y of 
at o pic disease ( s uc h as, ast h ma, at o pic kera t oc o nj u ncti vitis, aller gic 
c o nj u ncti vitis/r hi nitis, a n d at o pic der matitis  ( A K C)); 
6.  (if fe male a n d of c hil d beari n g p ote ntial) a gree t o ha ve uri ne pre g na nc y testi n g 
perf or me d at Visit 1 ( m ust be ne gati ve) a n d at e xit visit 2; m ust n ot be lactati n g; 
 
1 If a care gi ver or pare nt/le gal g uar dia n will a d mi nister e ye dr o ps, t he n he/s he m ust be prese nt at Visit 1 t o 
a d mi nister e ye dr o ps i n -office.  
2 F or i de ntifie d pre me narc hal fe males at Visit 1, t heir me narc hal stat us will be q uerie d at eac h s u bse q ue nt 
visit.  If a s u bject is n o l o n ger pre me narc hal at a n y of her s u bse q ue nt visits, t hat s u bject m ust a gree t o ha ve 
a uri ne pre g na nc y test perf or me d at t hat visit. S u bse q ue ntl y t hese s u bjects will f oll o w all t he re q uire me nts 
of fe male s u bjects of c hil d beari n g p ote ntial re gar di n g pre g na nc y tests a n d birt h c o ntr ol.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 1 9  of 7 1  
a n d m ust a gree t o use at least 1 me dicall y acce pta ble f or m of birt h c o ntr ol 
t hr o u g h o ut t he st u d y d urati o n a n d f or at least 1 4 da ys pri or t o a n d 1 m o nt h after 
disc o nti n ui n g I P. Acce pta ble f or ms of birt h c o ntr ol are tr ue 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), s per mici de wit h 
barrier, oral c o ntrace pti ve, i njecta ble or i m pla nta ble met h o d of c o ntrace pti o n, 
tra ns der mal c o ntrace pti ve, i ntra uteri ne de vice, or s ur gical sterilizati o n of male 
p art ner at least 3 m o nt hs pri or t o t he first d ose of i n vesti gati o nal dr u g ( Visit 1). 
N ote: W o me n  c o nsi dere d ca pa ble of bec o mi n g pre g na nt i ncl u de all fe males w h o 
ha ve e x perie nce d me narc he a n d ha ve n ot e x perie nce d me n o pa use (as defi ne d b y 
a me n orr hea f or great er t ha n 1 2 c o nsec uti ve m o nt hs) or ha ve n ot u n der g o ne 
s uccessf ul s ur gical sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral 
o o p h orect o m y); 
7.
(if male a n d wit h fe male part ner of c hil d beari n g p ote ntial) m ust use at least 1
me dicall y acce pta ble  f or m of birt h c o ntr ol. N ote: Acce pta ble f or ms of birt h
c o ntr ol are tr ue 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) or vasect o m y at least 3 m o nt hs pri or t o recei vi n g I P ( Visit
1). Wit h o ut a vasect o m y, m ust use c o n d o ms wit h s per mici dal
f oa m/ gel/fil m/crea m/s u p p osit or y t hr o u g h o ut t he st u d y d urati o n, f or at least 1 4
da ys pri or t o a n d 1 m o nt h after disc o nti n ui n g I P;
8. ha ve oc ular healt h wit hi n n or mal li mits, i ncl u di n g a calc ulate d vis ual ac uit y ( V A)
of 0. 3 l o g M A R or better i n eac h e ye as meas ure d usi n g a n Earl y Treat me nt
Dia betic Reti n o pat h y St u d y ( E T D R S ) c hart.  F or s u bjects u n der 1 0 years ol d w h o
are de vel o p me ntall y u na ble t o use t he E T D R S c hart, a best atte m pt at V A  will be
ma de usi n g t he L E A s y m b ols or Vis ual Be ha vi or. F or  s u bjects utilizi n g L E A
s y m b ols, S nelle n e q ui vale nt u nits of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d .
S u bjects utilizi n g Vis ual Be ha vi or m us t ha ve a passi n g sc ore;
9.
(f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve a
b o d y mass i n de x ( B MI) ≥1 8 a n d ≤3 4 l bs/i n2 a n d a mi ni m u m b o d y wei g ht of 9 9 l bs;
1 0. (f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve
s uita ble ve n o us access f or bl o o d sa m pli n g.
5. 4  
E xcl usi o n Criteri a  
S u bjects ma y n ot:  
1. ha ve k n o w n c o ntrai n dicati o ns or se nsiti vities t o t he use of a n y of t he I P
me dicati o n or c o m p o ne nts;
2. ha ve ha d oc ular s ur gical i nter ve nti o n wit hi n 3 m o nt hs pri or t o Visit 1 or d uri n g
t he st u d y a n d/ or a hist or y of refracti ve s ur ger y wit hi n t he past 6 m o nt hs;
3. ha ve a k n o w n hist or y of reti nal detac h me nt, dia betic reti n o pat h y, or acti ve reti nal
disease;
4.
ha ve t he prese nce of a n acti ve oc ular i nfecti o n ( bacterial, viral or f u n gal) or
p ositi ve hist or y of a n oc ular her petic i nfecti o n at a n y visit;
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 2 0  of 7 1  
5. use a n y of t he f oll o wi n g disall o we d me dicati o ns d uri n g t he peri o d i n dicate d pri or
t o Visit 1 a n d d uri n g t he st u d y:
5 da ys
•
artificial tear pr o d ucts, e ye w hite ners (e. g., vas oc o nstrict o rs), oc ular
dec o n gesta nts, oc ular c ortic oster oi ds, oc ular a nti hista mi nes, a n d a n y ot her
t o pical o p ht hal mic a ge nts;
1 4 da ys 
•
a n y s yste mic me dicati o ns w hic h t he i n vesti gat or feels ma y c o nf o u n d st u d y
data or i nterfere wit h s u bject’s st u d y partici pati o n .
6.
Ha ve u sed c o ntact le nses wit hi n  2 4 h o urs pri or t o eac h visit ( Visit  1, 2, 3, a n d 4);
7. ha ve pri or ( wit hi n 7 da ys of be gi n ni n g I P) or c urre ntl y acti ve si g nifica nt ill ness
t hat c o ul d c o m pr o mise partici pati o n, i n t he o pi ni o n of t he i n vesti gat or;
8. ha ve pri or ( wit hi n 3 0 da ys of be gi n ni n g I P) or a ntici pate d c o nc urre nt use of a n I P
or de vice d uri n g t he st u d y peri o d;
9. ha ve bee n ra n d o mize d i n st u d y 9 0 9 or 9 1 0 c o n d ucte d b y Ba usc h & L o m b;
1 0. be a n e m pl o yee or fa mil y me m ber of e m pl o yee at t he i n vesti gati ve site ;
1 1. ha ve a n oc ular or s yste mic c o n diti o n or is i n a sit uati o n t hat t he i n vesti gat or feels
ma y p ut t he s u bject 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 s u bject’s st u d y partici pati o n;
1 2. ha ve pla n ne d s ur ger y ( oc ular or s yste mic) d uri n g t he trial peri o d or wit hi n 3 0
da ys after;
1 3. ha ve b o d y wei g ht bel o w t he 5 t h perce ntile f or t heir a ge (s u bjects 1 2 years of a ge
or y o u n ger o nl y) (see A p pe n di x 4 );
1 4. be a fe male w h o is c urre ntl y pre g na nt, is pla n ni n g a pre g na nc y, or lacta ti n g;
1 5. ha ve a n a b n or mal bl o o d press ure ( defi ne d as ≤ 9 0 or ≥ 1 6 0 (s yst olic) meas ure d i n
m m H g or ≤ 6 0 or ≥ 1 0 0 ( diast olic) meas ure d i n m m H g). F or pe diatric s u bjects,
a b n or mal bl o o d press ure is defi ne d as ≥ 1 4 0 (s yst olic) meas ure d i n m m H g or ≥ 9 0
( diast olic) meas ure d i n m m H g;
1 6. ha ve a n i ntra oc ular press ure (I O P) t hat is less t ha n 5 m m H g or greater t ha n 2 2
m m H g or ha ve a n or mal I O P wit h a pri or dia g n osis/ hist or y of gla uc o ma at Visit
1;
1 7. ha ve s y m pt o ms ass ociate d wit h C O VI D - 1 9 or ha ve bee n i n c o ntact wit h s o me o ne
dia g n ose d wit h C O VI D- 1 9 wit hi n 1 4 da ys of t he Scree ni n g Visit or Visit 1 (if
Scree ni n g a n d Visit 1 are d o ne o n t he sa me da y);
1 8. (f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve
e xcessi ve c o ns u m pti o n of caffei ne - or xa nt hi ne-c o ntai ni n g be vera ges ( m ore t ha n
4 c u ps or ser vi n gs per da y) wit hi n 4 8 h o urs pri or t o d osi n g at Visit 1 or f or t he
d urati o n of t he st u d y (see A p pe n di x 6 )
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 2 1  of 7 1  
1 9. (f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve a
hist or y of t o bacc o, nic oti ne, or nic oti ne-c o ntai ni n g pr o d uct use wit hi n 1 2 m o nt hs
pri or t o Visit 1;
2 0. (f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve a
hist or y or c urre nt e vi de nce of dr u g or alc o h ol a b use wit hi n 1 2 m o nt hs pri or t o
Visit 1;
2 1. (f or selecte d healt h y a d ult s u bjects a greei n g t o u n der g o P K bl o o d dra ws) ha ve
bl o o d d o nati o n or e q ui vale nt bl o o d l oss of > 4 5 0 m L wit hi n 6 0 da ys pri or t o Visit
1.
5. 5  
Wit h dr a w al Criteri a (if a p plic a ble)  
S u bjects 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.  
A d diti o nall y, s u bjects ma y be disc o nti n ue d f or safet y reas o ns as deter mi ne d b y t he 
i n vesti gat or (see Secti o n 8. 6. 2 ). 
6  
S T U D Y P A R A M E T E R S  
6. 1  
S afet y Me as ures  
•
A Es; re p orte d, elicite d a n d o bser ve d
•
Uri ne Pre g na nc y Test
•
Best - C orrecte d Vis ual Ac uit y ( B C V A) usi n g a n E T D R S c hart
•
Slit La m p Bi o micr osc o p y
•
I ntra oc ular Press ure (s h o ul d be perf or me d o n s u bjects ≥ 1 0 years ol d)
•
P h ysical E xa mi nati o n
•
Vital Si g ns (resti n g bl o o d press ure a n d p ulse)
•
Dilate d F u n d us E xa mi nati o n
6. 2  
T oler a bilit y  Me as ures  
Dr o p c o mf ort assess me nt ( 0 -1 0 scale) assesse d b y s u bjects ≥ 1 0 years of a ge i m me diatel y 
u p o n i nstillati o n, at 3 0 sec o n ds, a n d at 1 mi n ute p ost-i nstillati o n at Visits 1, 2, a n d 3. 
6. 3  
P h ar m ac o ki netic Me as ures  
Bl o o d sa m ples will be c ollecte d fr o m t he P K p o p ulati o n at pre - d ose, 0. 2 5 ( ± 3 mi n), 0. 5 
( ± 5 mi n), 1 ( ± 1 0 mi n), 2 ( ± 1 0 mi n), a n d 4 ( ± 2 0 mi n) h o urs f oll o wi n g t he first t o pical 
oc ular i nstillati o n of bri m o ni di ne tartrate 0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % c o m bi nati o n 
o p ht hal mic s ol uti o n or ve hicle o n Da y 1 a n d als o o n Da y 2 2 t o meas ure t he plas ma 
c o nce ntrati o ns of bri m o ni di ne a n d ket otife n. Details o n c ollecti o n, pre parati o n, a n d 
s hi p pi n g of bl o o d sa m ples are pr o vi de d i n t he La b orat or y Ma n ual.  All sa m ples fr o m 
b ot h acti ve a n d place b o gr o u ps will be a nal yze d. U p o n re q uest f or data i ns pecti o n, t he 
bi oa nal ytical la b ma y be u n bli n de d.  If t he data all o ws, t he f oll o wi n g P K para meters will 
be esti mate d: C ma x , Cmi n , Tma x , A U C0- t, A U C 0- 4 h, a n d acc u m ulati o n rati o ( RC ma x  a n d RA U C ). 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 2 2  of 7 1  
Para meter  
Defi niti o n  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C mi n  
Mi ni m u m o bser ve d plas ma c o nce ntrati o n  
T ma x  
Ti me of ma xi m u m o bser ve d plas ma c o nce ntrati o n  
A U C 0-t 
Area u n der t he plas ma dr u g c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he last 
q ua ntifia ble dr u g c o nce ntrati o n  
A U C 0 -4 h 
Area u n der t he plas ma dr u g c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t hr o u g h 4 h 
R C ma x  
Acc u m ulati o n rati o of C ma x at stea d y -state t o Cma x  after t he first d ose  
R A U C  
Acc u m ulati o n rati o of A U C 0- t at stea d y -state t o A U C0- t after t he first d ose  
7  
S T U D Y M A T E RI A L S  
7. 1  
St u d y Tre at me nt(s)  
7. 1. 1  St u d y Treat me nt(s)/ F or m ulati o n(s)  
•
B ri m o ni di ne tartrate 0. 0 2 5 % / ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic
s ol uti o n ( n = 3 3 4)
•
Ve hicle o p ht hal mic s ol uti o n ( n = 1 6 7 )
7. 1. 2  I nstr ucti o ns f or Use a n d A d mi nistrati o n 
At Visit 1, a trai ne d st u d y tec h nicia n will o bser ve t he s u bject, s u bject’s care gi ver, or 
s u bject’s pare nt/le gal g uar dia n (if a p plica ble, f or s u bjects less t ha n 1 8 years of a ge) i nstill 
i n vesti gati o nal dr u g i nt o eac h e ye acc or di n g t o t he directi o ns f or use. T he s u bjects 
e nr olle d t o t he P K s u bset will recei ve 1 dr o p of t he assi g ne d I P i nt o eac h e ye fr o m a 
trai ne d tec h nicia n. At h o me d osi n g will be gi n t he m or ni n g f oll o wi n g Visit 1. 
At h o me, s u bjects, s u bject’s care gi ver, or s u bject’s pare nt/le gal g uar dia n (if a p plica ble, 
f or s u bjects less t ha n 1 8 years of a ge), will i nstill 1 dr o p of t he assi g ne d in vesti gati o nal 
dr u g i n eac h e ye B I D 7. 5 h o urs a part f or u p t o 6 c o nsec uti ve wee ks ( u ntil t he e ve ni n g 
pri or t o Visit 4) . S u bjects m ust re m o ve  c o ntact le nses  bef ore i nstillati o n of i n vesti gati o nal 
dr u g a n d wait at least 1 0 mi n utes bef ore rei nsert i n g c o ntact le nses . 
At Visits  2 a n d 3, a trai ne d st u d y tec h nicia n will i nstill i n vesti gati o nal d r u g i n-office 7. 5 
h o urs fr o m t he pre vi o us or f oll o wi n g at- h o me d ose.  
T he fi nal d ose of i n vesti gati o nal dr u g will be t he d ose a d mi nistere d at-h o me t he e ve ni n g 
pri or t o Visit 4 . 
S u bjects will be dis pe nse d t w o st u d y kits , eac h c o ntai ni n g 2 b ottles of assi g ne d I P. Kit 1 
will be dis pe nse d at Visit 1. T he s u bject wil l bri n g Kit 1 t o Visit 2 f or i n-office 
i nstallati o n a n d kit 1 will be ret ur ne d t o t he s u bject f or c o nti n ue d use u ntil Visit 3. Kit 1 
will be c ollecte d at Visit 3. Kit 2 will be dis pe nse d at Visit 3 a n d c ollecte d at Visit 4 . 
All b ottles of acti ve a n d ve hicle treat me nt will be i de ntical i n a p peara nce a n d will be 
pac ka ge d i n i de ntical c o ntai ners. T he i n vesti gati o nal dr u g kits a n d eac h b ottle will ha ve a 
la bel beari n g i nf or mati o n meeti n g a p plica ble re g ulat or y re q uire me nts. I n vesti gati o nal 
dr u g b ottles will c o me wit h directi o ns f or use a n d ot her a p pr o priate i nf or mati o n o n eac h 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 3  of 7 1  
 
part. I n vesti gati o nal d r u g will be pac ka ge d a n d la bele d base d o n t he ra n d o mizati o n list 
ge nerate d pri or t o t he start of t he st u d y. I n vesti gati o nal pr o d uct m ust be st ore d a t r o o m 
te m perat ure at 1 5- 2 5° C ( 5 9- 7 7° F). 
7. 2  
Ot her St u d y S u p plies  
•  Pre g na nc y tests ( Clarit y H C G , R A C Me dical B oca Rat o n, F L)  
•  T he oc ular a nest hetic a ge nt (fl u orescei n s o di u m a n d be n o xi nate h y dr oc hl ori de 
o p ht hal mic s ol uti o n U S P) a n d dilati n g dr o ps use d f or t he I O P a n d dilate d 
F u n d osc o p y 
•  S u p plies nee de d f or vital si g ns a n d p h ysical e xa mi nati o n will be pr o vi de d b y Ora, 
I nc. 
•  Bl o o d dr a w s u p plies (f or site partici pati n g i n p har mac o ki netic bl o o d dra ws) will 
be s u p plie d b y Bi o A gil yti x , t he P K La b ve n d or. 
8  
S T U D Y M E T H O D S A N D P R O C E D U R E S  
8. 1  
S u bject E ntr y Pr oce d ures  
8. 1. 1  O ver vie w 
S u bjects as defi ne d b y t he criteria i n secti o ns 5. 2, 5. 3, a n d 5. 4  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 
Pri or t o a s u bject’s partici pati o n i n t he trial ( i.e., c ha n ges i n a s u bject’s me dical treat me nt 
a n d/ or st u d y relate d pr oce d ures), t he st u d y will be disc usse d wit h eac h s u bject a n d/ or 
s u bject’s pare nts/le gal g uar dia n, a n d s u bjects wis hi n g t o partici pate m ust gi ve writte n 
i nf or me d c o nse nt (a n d/ or asse nt) usi n g a n i nf or me d c o nse nt f or m. T he i nf or me d c o nse nt 
f or m m ust be t he m ost rece nt versi o n t hat has recei ve d a p pr o val/fa v ora ble re vie w b y a 
pr o perl y c o nstit ute d 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). Fail ure t o o btai n a si g ne d I C F re n ders t he s u bject i neli gi ble f or t he st u d y. 
I n t he e ve nt t hat a s u bject has a me dical c o n diti o n, me dicati o n was h o ut, or needs t o s pea k 
wit h t he I n vesti gat or , s u bject s h o ul d be sc he d ule d f or a Scree ni n g Visit, at w hic h ti me t he 
s u bject will be gi ve n a n i nf or me d c o nse nt f or m. 
8. 1. 3  Was h o ut I nter vals  
Me dicati o ns 
S u bjects will a d here t o t he f oll o wi n g me dicati o n was h o ut i nter vals d uri n g t he peri o d 
i n dicate d pri or t o Visit 1  a n d will refrai n fr o m usi n g t hese me dicati o ns d uri n g t he st u d y:  
5 da ys 
•  artificial tear pr o d ucts, e ye w hite ners (e. g., vas oc o nstrict ors), oc ular 
dec o n gesta nts, oc ular c ortic oster oi ds, oc ular a nti hista mi nes,  a n d a n y ot her t o pical 
o p ht hal mic a ge nts;  
1 4 da ys 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 4  of 7 1  
 
•  a n y s yste mic me dicati o ns w hic h t he i n vesti gat or feels ma y c o nf o u n d st u d y data or 
i nterfere wit h s u bject’s st u d y partici pati o n. 
C o ntact Le nses  
C o ntact le ns use is  all o we d f or t he d urati o n of t he st u d y , b ut su bjects are re q uire d t o 
disc o nti n ue c o ntact le ns use f or a peri o d  of at least 2 4 h o urs pri or t o eac h Visit ( Visits 1 
t hr o u g h 4). A d diti o nall y, s u bjects m ust re m o ve c o ntact le nses bef ore i nstillati o n  of st u d y 
dr u g at h o me a n d wait at least 1 0 mi n utes bef ore rei nserti n g c o ntact le nses . 
8. 1. 4  Pr oce d ures f or Fi nal  St u d y E ntr y 
S u bjects m ust meet all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria i n or der 
t o be e nr olle d i n t he st u d y. 
8. 1. 5  Met h o ds f or Assi g n me nt t o Treat me nt Gr o u ps: 
All s u bjects scree ne d f or t he st u d y w h o si g n a n I C F will be assi g ne d a s u bject n u m ber 
t hat will be e ntere d i n t he Scree ni n g a n d E nr oll me nt L o g. T he s u bject n u m ber will 
c o nsist of t he t hree ( 3) di git site n u m ber, f oll o we d b y t he t hree ( 3) di git u ni q ue s u bject 
i de ntifier, starti n g wit h 0 0 1. 
O nce a s u bject meets all q ualificati o n crit eria at Visit 1, he/s he will be ra n d o mize d t o 
bri m o ni di ne tartrate 0. 0 2 5 % / ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n 
or Ve hicle  i n a 2 : 1 rati o. Eac h s u bject w h o is ra n d o mize d will be assi g ne d a u ni q ue 
Ra n d o mizati o n  n u m ber i n t he Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt ( R T S M ). 
Ra n d o mizati o n n u m bers will be assi g ne d i n a se q ue ntial or der starti n g at t he l o west 
n u m ber a vaila ble. N o n u m bers will be s ki p pe d or o mitte d. Ra n d o mizati o n n u m bers will 
be 5 di gits a n d will be create d i n t he R T S M . Ra n d o mizati o n will be use d t o a v oi d bias i n 
t he assi g n me nt of s u bjects t o treat me nt, t o i ncrease t he li keli h o o d t hat k n o w n a n d 
u n k n o w n s u bject attri b utes (e. g., de m o gra p hics a n d baseli ne c haracteristics) are e ve nl y 
bala nce d acr oss t he  R T S M  treat me nt gr o u ps, a n d t o e n ha nce t he vali dit y of statistical 
c o m paris o ns acr oss treat me nt gr o u ps. Mas ke d treat me nt will be use d t o re d uce p ote ntial 
bias d uri n g data c ollecti o n a n d e val uati o n of cli nical e n d p oi nts. 
8. 2  
C o nc urre nt T her a pies  
T he use of a n y c o nc urre nt me dicati o n, prescri pti o n or o ver- t he-c o u nter, is t o be rec or de d 
o n t he s u bject’s s o urce d oc u me nt a n d c orres p o n di n g electr o nic case re p ort f or m ( eC R F) 
al o n g wit h t he reas o n t he me dicati o n was ta ke n.  
C o nc urre nt e nr oll me nt i n a n ot her i n vesti gati o nal dr u g or me dical de vice st u d y is n ot 
per mitte d.  
8. 2. 1  Pr o hi bite d Me dicati o ns/ Treat me nts  
Refer t o Secti o n 8. 1. 3  f or a c o m plete list of was h o ut peri o ds f or t he f oll o wi n g pr o hi bite d 
me dicati o ns a n d treat me nts:  
•  artificial tears 
•  e ye w hite ners ( e. g., vas oc o nstrict ors) 
•  oc ular dec o n gesta nts  
•  oc ular c ortic oster oi ds  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 2 5  of 7 1  
•
oc ular a nti hista mi nes
•
a n y ot her t o pical o p ht hal mic a ge nts
8. 2. 2  C o ntact Le ns Use  
C o ntact le ns use is all o we d f or t he d urati o n of t he st u d y, b ut s u bjects are re q uire d t o 
disc o nti n ue c o ntact le ns use f or a peri o d of at least 2 4 h o urs pri or t o eac h Visit ( Visits 1 
t hr o u g h 4). A d diti o nall y, s u bjects m ust re m o ve c o ntact le nses bef ore i nstillati o n of st u d y 
dr u g at h o me a n d wait at least 1 0 mi n utes bef ore rei nserti n g c o ntact le nses.  
8. 2. 3  S pecial Diet or Acti vities  
N ot A p plica ble. 
8. 3  
E x a mi n ati o n Pr oce d ures  
8. 3. 1  Pr oce d ures t o be Perf or me d at Eac h St u d y Visit wit h Re gar d t o St u d y 
O bjecti ve(s)  
8. 3. 1. 1  Scree ni n g Visit  ( D a y - 2 8 t o D a y 1)1: Scree ni n g/ I nf or me d C o nse nt 
•
I nf or me d C o nse nt/ HI P A A: Pri or t o a n y c ha n ges i n a s u bject’s me dical treat me nt
a n d/ or st u d y visit pr oce d ures, t he st u d y will be disc usse d wit h eac h s u bject a n d / or
s u bject’s pare nt/le gal g uar dia n. S u bjects wis hi n g t o partici pate m ust gi ve writte n
i nf or me d c o nse nt a n d si g n a HI P A A f or m.
Pri or t o ra n d o mizati o n at Visit 1, if it is deter mi ne d t he s u bject di d n ot i n fact
meet certai n criteria, t he s u bject ma y be br o u g ht bac k at a later date t o re-atte m pt
t he scree ni n g pr ocess o nce t he pr o per was h o ut or ti mefra mes ha ve bee n ac hie ve d.
S u bjects w h o re -atte m pt t he scree ni n g pr ocess wit hi n t he pr ot oc ol wi n d o w will
n ot be gi ve n a ne w s u bject n u m ber. S u bjects w h o re-atte m pt scree ni n g after
was h o ut has bee n met b ut it falls o utsi de of t he pr ot oc ol wi n d o w will be gi ve n a
ne w s u bject n u m ber.
•
De m o gra p hic data a n d me dical/ me dicati o n/ oc ular a n d n o n- oc ular hist or y: C ollect
a n d rec or d all de m o gra p hic data, me dical hist or y,  a n y me dicati o ns, a n d a n y
u n derl yi n g c o n diti o n(s). C urre nt u n derl yi n g c o n diti o ns, i ncl u di n g t h ose t hat be ga n
wit hi n t he last 3 0 da ys, w hic h ma y ha ve bee n res ol ve d bef ore scree ni n g m ust be
rec or de d. Rec or d a n y me dicati o ns t he s u bject is ta ki n g, as well as th ose t he
s u bject ma y ha ve ta ke n b ut disc o nti n ue d wit hi n 6 0  da ys pri or t o Visit 1.
•
Re vie w of I ncl usi o n/ E xcl usi o n Criteria: A re vie w of pr ot oc ol i ncl usi o n a n d
e xcl usi o n criteria will be c o nfir me d f or eac h s u bject.
•
A d verse E ve nt Q uer y
•
Sc he d ule Visit 1: Q ualif yi n g s u bjects will be sc he d ule d t o ret ur n t o t he office  f or
Visit 1. 
1 Scree ni n g Visit a n d Visit 1 ma y be c o n d ucte d o n t he sa me da y . 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 6  of 7 1  
 
8. 3. 1. 2  VI SI T 1 ( D a y 1 ): B aseli ne Assess me nts, E nr oll me nt/ R a n d o miz ati o n , a n d 
I n-Office I nstill ati o n 1  
•  U p date of Me dical/ Oc ular  & N o n -Oc ular  Hist or y/ Me dicati o n Hist or y  
•  A d verse E ve nt Q uer y  
•  Uri ne Pre g na nc y Test (f or fe males of c hil d beari n g p ote ntial) : Fe males of 
c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test t o c o nti n ue i n t he 
st u d y a n d m ust a gree t o use a n acce pta ble  met h o d of c o ntrace pti o n t hr ou g h o ut 
partici pati o n i n t he st u d y. F or pre me narc hal s u bject s, t he pre me narc hal stat us will 
be c ollecte d.  
•  Vital Si g ns:  Resti n g bl o o d press ure a n d p ulse will be c ollecte d t o e xcl u de s u bjects 
t hat ha ve a n a b n or mal bl o o d press ure. F or a d ult s u bjects, t his is d efi ne d as ≤ 9 0 or 
≥ 1 6 0 (s yst olic) meas ure d i n m m H g or ≤ 6 0 or ≥ 1 0 0 ( diast olic) meas ure d i n 
m m H g. F or pe diatric s u bjects, a b n or mal bl o o d press ure is defi ne d as ≥ 1 4 0 
(s yst olic) meas ure d i n m m H g or ≥ 9 0 ( diast olic) meas ure d i n m m H g. 
•  P h ysical E xa m : Ge neral healt h, hea d, e yes, ears, n ose, t hr oat ( H E E N T), a n d ot her 
c o m me nts . 
•  B o d y Wei g ht: F or s u bjects ≤ 1 2 years of a ge, t he i n vesti gat or will c o m pare t he 
s u bject’s b o d y wei g ht t o t he ta ble i n A p pe n di x 4  t o deter mi ne if t he s u bject’s 
b o d y wei g ht falls a b o ve t he 5 t h perce ntile b o d y wei g ht f or t heir a ge gr o u p. If n ot, 
t he s u bject will n ot be e nr olle d. F or selecte d s u bjects a greei n g t o u n der g o P K 
bl o o d dra ws, t he b o d y mass i n de x ( B MI) m ust be ≥1 8 a n d ≤3 4 l bs/i n2 a n d a 
mi ni m u m b o d y wei g ht of 9 9 l bs. 
•  B C V A  Utili zi n g a n E T D R S C hart: S u bjects m ust ha ve a sc ore of 0. 3 l o g M A R or 
better i n eac h e ye i n or der t o q ualif y. T his i nitial V A  will be dee me d t he Baseli ne 
V A . T he use of c orrecti o n will be d oc u me nte d. If a s u bject uses c orrecti o n at t his 
V A  t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  
assess me nts. F or s u bjects u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble t o 
use t he E T D R S c hart, a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols 
or Vis ual Be ha vi or. F or s u bjects utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits 
of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d. S u bjects utilizi n g Vis ual Be ha vi or 
m ust ha ve a passi n g sc ore. A cli nicall y si g nifica nt V A  decrease ( defi ne d as a n 
increase of 0. 2 2 or greater i n l o g M A R sc ore) fr o m Visit 1 will be c o nsi dere d a n 
a d verse e ve nt . Please refer t o A p pe n di x 2  f or details. 
•  Slit La m p Bi o micr osc o p y  ( Pre-I nstillati o n): A slit la m p e xa mi nati o n will be 
perf or me d i n b ot h e yes t o e xcl u de s u bjects wit h disall o we d oc ular c o n diti o ns. 
Fi n di n gs of a b n or malit y w hic h are n ot e xcl usi o nar y s h o ul d be rec or de d as 
Me dical Hist or y , as a p plica ble. 
 
1 If Scree ni n g a n d Visit 1 are c o n d ucte d o n t he sa me da y, I nf or me d C o nse nt/ HI P A A, De m o gra p hic data 
a n d m e dical/ me dicati o n/ oc ular a n d n o n-oc ular hist or y will be c ollecte d at t he start of t he c o m bi ne d visit.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 7  of 7 1  
 
•  I ntra oc ular Press ure ( 1 0 years of a ge or ol der): A n I O P meas ure me nt will be 
perf or me d t o e xcl u de s u bjects wit h I O P less t ha n 5 m m H g or greater t ha n 2 2 
m m H g.  
•  Dilate d F u n d osc o p y: A dilate d f u n d us e xa mi nati o n will be perf or me d b y t he 
I n vesti gat or t o e val uate t he prese nce or a bse nce of cli nicall y si g nifica nt f u n d us 
a b n or malities a n d vitre o us pat h ol o g y. Fi n di n gs s h o ul d be rec or de d as Me dical 
Hist or y, as a p plica ble.  
•  Re vie w  of A p plica ble I ncl usi o n/ E xcl usi o n Criteria : The i n vesti gat or will verif y 
staff me m ber’s re vie w of i ncl usi o n/e xcl usi o n criteria. 
•  E nr oll me nt / Ra n d o mizati o n: Q ualif yi n g s u bjects will be assi g ne d a ra n d o mizati o n 
n u m ber a n d ra n d o mize d t o recei ve  eit her bri m o ni di ne tartrate  0. 0 3 5 %/ ket otife n 
f u marate 0. 0 3 5 % c o m bi nati o n  o p ht hal mic s ol uti o n or ve hicle. 
•  I n-Office I n vesti gati o nal Dr u g I nstillati o n: T he R T S M will assi g n a n 
i n vesti gati o nal dr u g kit n u m ber t o t he s u bject. A trai ne d st u d y tec h nicia n will 
o bser ve t he s u bject, s u bject’s care gi ver, or s u bject’s pare nt/le gal g uar dia n (if 
a p plica ble f or s u bject’s less t ha n 1 8 years of a ge) i nst ill in vesti gati o nal dr u g 
acc or di n g t o t he directi o ns f or use. T he i n vesti gati o nal dr u g kit n u m ber a n d t he 
ti me of i nstillati o n will be rec or de d. T he s u bjects e nr olle d t o t he P K st u d y will 
recei ve 1 dr o p of t he assi g ne d I P i nt o eac h e ye fr o m a trai ne d tec h nicia n. 
•  Dr o p C o mf ort Assess me nt: S u bjects > 1 0 years ol d will assess d r o p c o mf ort 
i m me diatel y u p o n i nstillati o n, at 3 0 sec o n ds, a n d at 1-mi n ute  p ost-i nstillati o n 
 
 
•  P K Bl o o d Dra ws (f or a s u bset of 2 5 healt h y a d ult s u bjects): Ta ke n pre- I P 
i nstillati o n ( wit hi n 1 h o ur pri or t o d osi n g), a n d at 0. 2 5 ( ± 3 mi n) h o ur, 0. 5 ( ± 5 
mi n)  h o ur, 1 ( ± 1 0 mi n)  h o urs, 2 ( ± 1 0 mi n)  h o urs, a n d 4 ( ± 2 0 mi n)  h o urs after 
i n vesti gati o nal dr u g i nstillati o n. 
•  Slit La m p Bi o micr osc o p y  ( P ost-I nstillati o n): A slit -la m p e xa m will be perf or me d 
a p pr o xi matel y 1 5 mi n utes ( + 3 mi n utes) after in vesti gati o nal dr u g i nstillati o n. F or 
t he s u bset of healt h y a d ult s u bjects u n der g oi n g P K bl o o d dra ws, t his slit-la m p 
e xa m will be c o n d ucte d after t he 0. 2 5 h o ur dra w a n d pri or t o t he 0. 5 h o ur dra w. 
•  Dis pe nse In vesti gati o nal Dr u g a n d D osi n g Diar y Dis pe nsati o n: E nr olle d s u bjects 
( or s u bject’s care gi ver or pare nt/le gal g uar dia n, if a p plica ble) will be i nstr ucte d t o 
i nstill 1 dr o p of i n vesti gati o nal dr u g i n eac h e ye, 2 ti mes dail y  7. 5 h o urs a part f or 
u p t o 6 wee ks be gi n ni n g t he ne xt m or ni n g. S u bjects will be i nstr ucte d o n h o w t o 
c o m plete a n d rec or d t he d osi n g ti me i n t heir  dail y diar y . For pe diatric s u bjects, 
s u bject’s care gi ver or s u bject’s pare nt/le gal g uar dia n ca n pr o vi de res p o nse t o 
q uesti o ns , if a p plica ble. 
S u bjects, s u bjects’ care gi ver or pare nt/le gal g uar dia n (if a p plica ble f or s u bjects 
less t ha n 1 8 years of a ge) will be i nstr ucte d N O T t o d ose wit hi n 7. 5 h o urs t he da y 
of t heir ne xt sc he d ule d st u d y visit ( Visit 2). T he y will als o be i nstr ucte d t o bri n g 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 8  of 7 1  
 
b ot h i n vesti gati o nal dr u g a n d t he dail y diar y t o t he ne xt visit ( Visit 2) f or a 
c o m plia nce c hec k.  
•  
A d verse E ve nt Q uer y  
•  
Sc he d ule Visit 2: S u bjects will be as ke d t o ret ur n t o t he office f or Visit 2.  
8. 3. 1. 3  VI SI T 2 ( D a y 8 ± 2 ): F oll o w- u p  
•  U p date of Me dical/ Me dicati o n Hist or y : C ha n ges t o me dical hist or y fr o m baseli ne 
s h o ul d be rec or de d as A Es. 
•  A d verse E ve nt Q uer y  
•  I n vesti gati o nal Dr u g a n d D osi n g Diar y Re vie w a n d C ollecti o n: I n vesti gati o nal 
dr u g will be c ollecte d f or re - dis pe nse at t he e n d of t he visit. D osi n g diar y will be 
c ollecte d a n d re vie we d f or c o m plia nce a n d t o a d dress a n y q ueries . 
•  Uri ne Pre g na nc y Test : T his will be gi ve n t o fe males w h o were pre me narc hal at 
t he pre vi o us visit ( Visit 1) a n d beca me me narc hal t hereafter.  
•  B C V A  Utilizi n g a n E T D R S C hart : If a s u bject use d c orrecti o n at t he baseli ne V A  
t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  
assess me nts. F or s u bjects u n der 1 0 years ol d w h o are de ve l o p me ntall y u na ble t o 
use t he E T D R S c hart, a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols 
or Vis ual Be ha vi or. F or s u bjects utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits 
of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d. S u bjects utilizi n g Vis ual Be ha vi or 
m ust ha ve a passi n g sc ore. A cli nicall y si g nifica nt V A  decrease ( defi ne d as a n 
i ncrease of 0. 2 2 or greater i n l o g M A R sc ore) fr o m Visit 1 will be c o nsi dere d a n 
a d verse e ve nt.  Please refer t o A p pe n di x 2  f or details. 
•  Slit La m p Bi o micr osc o p y ( Pre-I nstillati o n) 
•  I n-Office I n vesti gati o nal Dr u g I nstillati o n: T he s u bject is i nstr ucte d t o ret ur n wit h 
dis pe nse d kit fr o m Visit 1. A trai ne d st u d y tec h nicia n will i nstill i n vesti gati o nal 
dr u g at least 7. 5 h o urs fr o m pre vi o us at- h o me d ose, a n d acc or di n g t o t he 
directi o ns f or use. T he i n vesti gati o nal dr u g kit n u m ber a n d t he ti me of i nstillati o n 
will be rec or de d.  
•   Dr o p C o mf ort Assess me nt: S u bjects > 1 0 years ol d will assess d r o p c o mf ort 
i m me diatel y u p o n i nstillati o n, at 3 0 sec o n ds, a n d at 1-mi n ute p ost -i nstillati o n 
 
 
•  Slit La m p Bi o micr osc o p y  ( P ost-I nstillati o n): A slit -la m p e xa m will be perf or me d 
a p pr o xi matel y 1 5 mi n utes ( + 3 mi n utes) after i n vesti gati o nal dr u g i nstillati o n. 
•  Dis pe nse I n vesti gati o nal Dr u g a n d D osi n g Diar y Dis pe nsati o n: S u bjects, s u bject’s 
care gi ver or pare nt/le gal g uar dia n (if a p plica ble f or s u bjects less t ha n 1 8 years of 
a ge) will be re-dis pe nse d t he sa me kit fr o m Visit 1 a n d i nstr ucte d t o c o nti n ue t heir 
at- h o me d osi n g 7. 5 h o urs f oll o wi n g t heir i n- office d ose, if t he y ha ve n’t c o m plete d 
2 d oses t hat da y alrea d y . S u bjects will c o nti n ue t o i nstill 1 dr o p of i n vesti gati o nal 
dr u g i n eac h e ye, 2 ti mes dail y 7. 5 h o urs a part. S u bjects will c o nti n ue t o c o m plete 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 2 9  of 7 1  
 
t heir dail y diar y as i nstr ucte d . F or pe diatric s u bjects, s u bject’s care gi ver or 
s u bject’s pare nt/le gal g uar dia n ca n pr o vi de res p o nse t o q uesti o ns, if a p plica ble. 
S u bjects ( or s u bjects’ care gi ver or pare nt/le gal g uar dia n ) will be i nstr ucte d N O T 
t o d ose wit hi n 7. 5 h o urs t he da y of t heir ne xt sc he d ule d st u d y visit ( Visit 3). T he y 
will als o be i nstr ucte d t o bri n g b ot h i n vesti gati o nal dr u g a n d t he dail y diar y t o t he 
ne xt visit ( Visit 3 ) f or a c o m plia nce c hec k. 
•  A d verse E ve nt Q ue r y 
•  Sc he d ule f or Visit 3:  S u bjects will be as ke d t o ret ur n t o t he office f or Visit 3  
8. 3. 1. 4  VI SI T 3 ( D a y 2 2 ± 3 ): F oll o w- u p  
•  U p date of Me dical/ Me dicati o n Hist or y : C ha n ges t o me dical hist or y fr o m baseli ne 
s h o ul d be rec or de d as A Es. 
•  A d verse E ve nt Q uer y 
•  I n vesti gati o nal Dr u g a n d D osi n g Diar y Re vie w a n d C ollecti o n: I n vesti gati o nal 
Dr u g  a n d D osi n g diar y will be c ollecte d a n d re vie we d f or c o m plia nce a n d t o 
a d dress a n y q ueries . 
•  Uri ne Pre g na nc y Test : T his will be gi ve n t o fe males w h o were pre me narc hal at 
t he pre vi o us visit ( Visit 2) a n d beca me me narc hal t hereafter.  
•  B C V A  Utilizi n g a n E T D R S C hart: If a s u bject use d c orrecti o n at t he baseli ne V A  
t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  
assess me nts. F or s u bjects u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble t o 
use t he E T D R S c hart, a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols 
or Vis ual Be ha vi or. F or s u bje cts utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits 
of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d. S u bjects utilizi n g Vis ual Be ha vi or 
m ust ha ve a passi n g sc ore. A cli nicall y si g nifica nt V A  decrease ( defi ne d as a n 
i ncrease of 0. 2 2 or greater i n l o g M A R score) fr o m Visit 1 will be c o nsi dere d a n 
a d verse e ve nt.  Please refer t o A p pe n di x 2  f or details. 
•  Slit La m p Bi o micr osc o p y  ( Pre-I nstillati o n) 
•  
I n-Office I n vesti gati o nal Dr u g I nstillati o n: T he R T S M will assi g n a n 
i n vesti gati o nal dr u g kit n u m ber t o t he s u bject. A trai ne d st u d y tec h nicia n will 
i nstill in vesti gati o nal d r u g at least 7. 5 h o urs fr o m pre vi o us at-h o me d ose, a n d 
acc or di n g t o t he directi o ns f or use. T he i n vesti gati o nal dr u g kit n u m ber a n d t he 
ti me of i nstillati o n will be rec or de d. 
•  Dr o p C o mf ort Assess me nt: S u bjects > 1 0 years ol d will assess d r o p c o mf ort 
i m me diatel y u p o n i nstillati o n, at 3 0 sec o n ds, a n d at 1-mi n ute  p ost-i nstillati o n 
 
 
•   P K Bl o o d Dra ws (f or t he sa me s u bset of 2 5 healt h y a d ult s u bjects):  Ta ke n pre-I P 
i nstillati o n ( wit hi n 1 h o ur pri or t o d osi n g), a n d at 0. 2 5 ( ± 3 mi n) h o ur, 0. 5 ( ± 5 
mi n)  h o ur, 1 ( ± 1 0 mi n)  h o urs, 2 ( ± 1 0 mi n)  h o urs, a n d 4 ( ± 2 0 mi n)  h o urs after 
i n vesti gati o nal dr u g i nstillati o n. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 0  of 7 1  
 
•  Slit La m p Bi o micr osc o p y ( P ost -I nstillati o n): A slit -la m p e xa m will be perf or me d 
a p pr o xi matel y 1 5 mi n utes ( + 3 mi n utes) after i n vesti gati o nal dr u g i nstillati o n. F or 
t he s u bset of healt h y a d ult s u bjects u n der g oi n g P K bl o o d dra ws, t his slit-la m p 
e xa m will be c o n d ucte d after t he 0. 2 5 h o ur dra w a n d pri or t o t he 0. 5 h o ur dra w. 
•  Dis pe nse  I n vesti gati o nal Dr u g a n d D osi n g Diar y Dis pe nsati o n: S u bjects, s u bject’s 
care gi ver or pare nt/le gal g uar dia n (if a p plica ble f or s u bjects less t ha n 1 8 years of 
a ge) will be i nstr ucte d t o c o nti n ue t heir at -h o me d osi n g 7. 5 h o urs f oll o wi n g t heir 
i n- office d ose, if t he y ha ve n’t c o m plete d 2 d oses t hat da y alrea d y. 
S u bjects will c o nti n ue t o i nstill 1 dr o p of in vesti gati o nal dr u g i n eac h e ye, 2 ti mes 
dail y 7. 5 h o urs a part. S u bjects ( or s u bjects’ care gi ver or pare nt/le gal g uar dia n) 
will be i nstr ucte d N O T t o d ose o n t he da y of t heir ne xt sc he d ule d st u d y visit 
( Visit 4). T he last d ose f or t his st u d y will be i nstille d at - h o me t he da y pri or t o t he 
ne xt visit ( Visit 4). T he y will als o be i nstr ucte d t o bri n g b ot h i n vesti gati o nal dr u g 
a n d t he dail y diar y t o t he ne xt visit ( Visit 4 ) f or a c o m plia nce c hec k. 
•  A d verse E ve nt Q uer y 
•  Sc he d ule f or Visit 4: S u bjects will be as ke d t o ret ur n t o t he office f or Visit 4 
8. 3. 1. 5  VI SI T 4 ( D a y 4 3 + 3): Tre at me nt Disc o nti n u ati o n  a n d  E xit Visit  
•  U p date of Me dical/ Me dicati o n Hist or y : C ha n ges t o me dical hist or y fr o m baseli ne 
s h o ul d be rec or de d as A Es. 
•  A d verse E ve nt Q uer y  
•  I n vesti gati o nal Dr u g a n d D osi n g Diar y Re vie w a n d C ollecti o n: I n vesti gati o nal 
Dr u g  a n d D osi n g diar y will be c ollecte d a n d re vie we d f or c o m plia nce a n d t o 
a d dress a n y q ueries  
•  Uri ne Pre g na nc y Test : T his will be gi ve n t o all fe males of c hil d beari n g p ote ntial  
•  Vital Si g ns:  Resti n g bl o o d press ure a n d p ulse 
•  P h ysical E xa m : Ge neral healt h, hea d, e yes, ears, n ose, t hr oat, a n d ot her c o m me nts 
•  B C V A  Utilizi n g a n E T D R S C hart : If a s u bject use d c orrecti o n at t he baseli ne V A  
t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  
assess me nts. F or s u bjects u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble t o 
use t he E T D R S c hart, a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols 
or Vis ual Be ha vi or. F or s u bjects utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits 
of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d. S u bjects utilizi n g Vis ual Be ha vi or 
m ust ha v e a passi n g sc ore. A cli nicall y si g nifica nt V A  decrease ( defi ne d as a n 
i ncrease of 0. 2 2 or greater i n l o g M A R sc ore) fr o m Visit 1 will be c o nsi dere d a n 
a d verse e ve nt.  Please refer t o A p pe n di x 2  f or details. 
•  Slit La m p Bi o micr osc o p y  
•  I ntra oc ular Press ure (s h o ul d be perf or me d o n s u bjects 1 0 years of a ge or ol der) 
•  Dilate d F u n d osc o p y 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 3 1  of 7 1  
•
A d verse E ve nt Q uer y
•
St u d y E xit: S u bjects will be e xite d fr o m t he st u d y.
A d verse E ve nts  ( AE s) ( b ot h elicite d a n d o bser ve d) will be m o nit ore d t hr o u g h o ut t he 
st u d y. All A Es ( b ot h elicite d a n d o bser ve d) will be pr o m ptl y re vie we d b y t he i n vesti gat or 
f or acc urac y a n d c o m plete ness. All A Es will be d oc u me nte d o n t he a p pr o priate e C R F . 
If a fe male has a p ositi ve pre g na nc y test d uri n g t he st u d y, t he n t he i n vesti gat or will n otif y 
Ora i m me diatel y. T he i n vesti gat or s hall re q uest fr o m t he s u bject a n d/ or t he s u bject’s 
p h ysicia n c o pies of all relate d me dical re p orts d uri n g t he pre g na nc y a n d s hall d oc u me nt 
t he o utc o me of t he pre g na nc y. T he i n vesti gat or will retai n t hese re p orts t o get her wit h t he 
s u bject’s s o urce d oc u me nts a n d will pr o vi de a c o p y of all d oc u me ntati o n t o Ora. 
8. 4  
Sc he d ule of Visits, Me as ure me nts a n d D osi n g  
8. 4. 1  Sc he d ule d Visits  
Refer t o A p pe n di x 1 f or a sc he d ule of visits a n d meas ure me nts.  
If a ra n d o mize d s u bject d oes n ot atte n d t heir sc he d ule d visit, t he e C R F pa ges f or t he 
misse d visit will be s ki p pe d. All eff orts s h o ul d be ma de t o sc he d ule  t he su bject f or a n 
E xit Visit t o c o m plete E xit Pr oce d ures . 
If a s u bject is disc o nti n ue d at a sc he d ule d st u d y visit, t he re mai ni n g assess me nts s h o ul d 
be ca pt ure d o n t he U nsc he d ule d Visit/ Earl y E xit Visit pa ges of t he S o urce D oc u me nt a n d 
c orres p o n di n g e C R F. 
8. 4. 2  U nsc he d ule d Visits 
F or U nsc he d ule d Visits, t he reas o n f or t he visit s h o ul d be clearl y d oc u me nte d o n t he 
a p pr o priate e C R F, i ncl u di n g fi n di n gs fr o m all e val uati o ns t hat are c o m plete d.  
T hese visits ma y be perf or me d t o e ns ure s u bject safet y. All i nf or mati o n gat here d at 
u nsc he d ule d visits s h o ul d be rec or de d o n t he U nsc he d ule d V isit/ Earl y E xit Visit pa ges 
of t he S o urce D oc u me nt a n d c orres p o n di n g e C R F. 
E val uati o ns t hat ma y be c o n d ucte d at a n U nsc he d ule d Visit (as a p pr o priate, de pe n di n g o n 
t he reas o n f or t he visit), i ncl u de b ut are n ot li mite d t o : 
•
U p date of Me dical/ Me dicati o n Hist or y
•
Assess me nt of A d verse E ve nts
•
B C V A  Utilizi n g a n E T D R S c hart : If a s u bject used c orrecti o n at t h e baseli ne V A  t he n
t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  assess me nts.  F or
s u bjects u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble t o use t he E T D R S c hart,
a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols or Vis ual Be ha vi or. F or
s u bjects utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits of 2 0/ 6 3 or better i n b ot h
e yes will be re q uire d . S u bjects utilizi n g Vis ual Be ha vi or m ust ha ve a passi n g sc ore.
•
Uri ne Pre g na nc y Test (f or fe males of c hil d beari n g p ote ntial)
•
Slit La m p Bi o micr osc o p y
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 2  of 7 1  
 
•  Vital Si g ns (resti n g bl o o d press ure a n d p ulse) 
•  P h ysical E xa mi nati o n  
•  Intra oc ular Press ure (s h o ul d be perf or me d o n s u bjects > 1 0 years ol d) 
•  Dilate d F u n d osc o p y 
8. 4. 3  E xit Pr oce d ures  
F or e xit or earl y ter mi nati o n o n s u bjects t hat are e nr olle d, t he reas o n f or e xiti n g  s h o ul d be 
clearl y d oc u me nte d o n t he a p pr o priate e C R F, i ncl u di n g fi n di n gs fr o m all e val uati o ns t hat 
are c o m plete d.  
E xit pr oce d ures s h o ul d be perf or me d t o e ns ure s u bject safet y. All i nf or mati o n gat here d at 
t he fi nal visit s h o ul d be rec or de d o n t he U nsc he d ule d Visit pa ges of t he S o urce 
D oc u me nt a n d c orres p o n di n g e C R F. 
E val uati o ns t hat ma y be c o n d ucte d a s part of st u d y E xit  (as a p pr o priate, de pe n di n g o n t he 
reas o n f or t he visit), i ncl u de b ut are n ot li mite d t o: 
•  U p date of Me dical/ Me dicati o n Hist or y  
•  Assess me nt of A d verse E ve nts  
•  B C V A  Utilizi n g a n E T D R S c hart: If a s u bject use d c orr ecti o n at t he baseli ne V A  
t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt V A  
assess me nts. F or s u bjects u n der 1 0 years ol d w h o are de vel o p me ntall y u na ble t o 
use t he E T D R S c hart, a best atte m pt at V A  will be ma de usi n g t he L E A s y m b ols 
or Vis ual Be ha vi or. F or s u bjects utilizi n g L E A s y m b ols, S nelle n e q ui vale nt u nits 
of 2 0/ 6 3 or better i n b ot h e yes will be re q uire d. S u bjects utilizi n g Vis ual Be ha vi or 
m ust ha ve a passi n g sc ore.  
•  Uri ne Pre g na nc y Test (f or fe males of c hil d beari n g p ote ntial)  
•  Slit L a m p Bi o micr osc o p y 
•  Vital Si g ns (resti n g bl o o d press ure a n d p ulse) 
•  P h ysical E xa mi nati o n  
•  I ntra oc ular Press ure (s h o ul d be perf or me d o n s u bjects > 1 0 years ol d) 
•  Dilate d F u n d osc o p y 
T he e xit visit nee d n ot be a se parate visit. If a s u bject dis q ualifies d uri n g a sc he d ule d 
visit, t he a b o ve e val uati o ns s h o ul d be rec or de d o n t he U nsc he d ule d Visit of t he S o urce 
D oc u me nt a n d c orres p o n di n g e C R F. 
8. 5  
C o m pli a nce wit h Pr ot oc ol  
S u bjects w h o are i na p pr o priatel y e nr olle d ma y be disc o nti n ue d fr o m t he st u d y. T he 
reas o n f or s uc h disc o nti n uati o n will be rec or de d as “ pr ot oc ol vi olati o n” i n t he s o urce 
d oc u me nt a n d o n t he a p pr o priate pa ge i n t he e C R F. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 3  of 7 1  
 
Site staff will re vie w c o nc o mita nt me dicati o n use at eac h visit. A n y ne w me dicati o n ( or) 
c ha n ges i n e xisti n g c o nc o mita nt me dicati o n use will be  rec or de d i n t he s o urce d oc u me nt 
a n d o n t he C o nc o mita nt me dicati o n e C R F. 
8. 6  
S u bject Dis p ositi o n  
8. 6. 1  C o m plete d S u bjects  
A c o m plete d s u bject is o ne w h o has n ot bee n disc o nti n ue d fr o m t he st u d y. 
8. 6. 2  Disc o nti n ue d S u bjects 
S u bjects ma y be disc o nti n ue d pri or t o t heir c o m pleti o n of t he st u d y d ue t o: 
•  
s u bject re q uest/ wit h dra wal 
•  
A Es 
•  
pr ot oc ol vi olati o ns 
•  
a d mi nistrati ve reas o ns ( e. g., i na bilit y t o c o nti n ue, l ost t o f oll o w u p) 
•  
I n vesti gat or decisi o n 
•  
s p o ns or ter mi nati o n of st u d y 
•  
ot her 
Pri or t o disc o nti n ui n g a s u bject, e ver y eff ort s h o ul d be ma de t o c o ntact t he s u bject, 
sc he d ule a fi nal st u d y visit, a n d o btai n as m uc h f oll o w- u p data as p ossi ble, a n d t o retrie ve 
all st u d y materials. W he ne ver p ossi ble, disc o nti n ue d s u bjects s h o ul d be f oll o we d t hr o u g h 
t he last sc he d ule d st u d y visit. S u bject wit h dra wals will be d oc u me nte d clearl y o n t he 
s o urce d oc u me nt a n d a p plica ble e C R F. 
N ote: I n a d diti o n, a n y s u bject ma y be disc o nti n ue d f or a n y s o u n d me dical reas o n. 
N otificati o n of a s u bject disc o nti n uati o n a n d t he reas o n f or disc o nti n uati o n will be ma de 
t o Ora a n d/ or s p o ns or a n d will be clearl y d oc u me nte d o n t he eC R F.  
8. 7  
L ost t o F oll o w- u p  
S u bjects w h o d o n ot ret ur n f or t heir sc he d ule d visits as defi ne d b y t he visit wi n d o w a n d 
ca n n ot be c o ntacte d , ma y be c o nsi dere d l ost t o f oll o w- u p. Atte m pts t o c o ntact t he 
s u bjects s h o ul d i ncl u de at least 2 p h o ne calls, e mails a n d/ or te xt messa ges a n d a certifie d 
letter. All f oll o w- u p atte m pts will be d oc u me nte d a n d ke pt wit h t he s u bject’s s o urce 
d oc u me ntati o n, a n d t he a p plica ble e C R Fs will be c o m plete d. F or s u bjects t hat are l ost t o 
f oll o w-u p, t he date of earl y ter mi nati o n will be t he date of t he last atte n de d cli nic visit 
a n d t he date of last d ose will be t he date of t he last i n -office i nstillati o n. 
8. 8  
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 a n y ti me b y t he i n vesti gat or, t he s p o ns or, a n d/ or Ora wit h 
a p pr o priate n otificati o n.  
8. 9  
St u d y  D ur ati o n  
T his trial c o nsists of 4- 5 office visits o ver a peri o d of a p pr o xi matel y 6 t o 1 0 wee ks. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 4  of 7 1  
 
8. 1 0  
M o nit ori n g a n d Q u alit y Ass ur a nce  
D uri n g t he c o urse of t he st u d y a n Ora  m o nit or, or desi g nee, will ma ke r o uti ne site visits 
t o re vie w pr ot oc ol c o m plia nce, assess I P acc o u nta bilit y, a n d e ns ure t he st u d y is bei n g 
c o n d ucte d acc or di n g t o t he perti ne nt re g ulat or y re q uire me nts. T he re vie w of t he s u bjects’ 
me dical rec or ds will be perf or me d i n a ma n ner t hat a de q uatel y mai ntai ns s u bject 
c o nfi de ntialit y. F urt her details of t he  st u d y m o nit ori n g will be o utli ne d i n a m o nit ori n g 
pla n. 
Re g ulat or y a ut h orities of d o mestic a n d f orei g n a ge ncies, Ora  q ualit y ass ura nce a n d /or its 
desi g nees ma y carr y o ut o n -site i ns pecti o ns a n d/ or a u dits w hic h ma y i ncl u de s o urce data 
c hec ks. T heref ore , di rect access t o t he ori gi nal s o urce data will be re q uire d f or 
i ns pecti o ns a n d/ or a u dits. All i ns pecti o ns a n d a u dits will be carrie d o ut gi vi n g 
c o nsi derati o n t o data pr otecti o n as well as s u bject c o nfi de ntialit y t o t he e xte nt t hat l ocal, 
state, a n d fe deral la ws a p pl y. 
9  
A D V E R S E E V E N T S  
9. 1  
Defi niti o n of A d verse E ve nt ( A E)  
A n a d verse e ve nt is a n y u nt o war d me dical occ urre nce i n a s u bject partici pati n g i n a 
cli nical st u d y, w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he st u d y 
pr o d uct/ pr oce d ure. T heref ore, a n a d verse e ve nt i ncl u des: 
•  A n y u nfa v ora ble a n d/ or 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 o nset, t hat occ urs at a n y ti me bet wee n t he si g ni n g 
of t he I C F a n d st u d y e xit, wit h o ut a n y j u d ge me nt a b o ut ca usalit y (i.e., w het her or 
n ot it is c o nsi dere d t o be relate d t o t he st u d y pr o d uct) 
•  E xacer bati o n, w orse ni n g, or pr o gressi o n of a pre-e xisti n g ill ness, i ncl u di n g a n 
i ncrease i n se verit y, fre q ue nc y, a n d/ or d urati o n of a pre-e xisti n g e pis o dic e ve nt  or 
c o n diti o n 
•  E ve nts occ urri n g fr o m dr u g o ver d ose (acci de ntal or i nte nti o nal), dr u g a b use or 
mis use, dr u g h y perse nsiti vit y, dr u g e xtra vasati o n, dr u g i nteracti o ns, dr u g 
de pe n de nc y, e ve nts occ urri n g fr o m dr u g wit h dra wal a n d me dicati o n err ors 
•  A c o n diti o n dete cte d or dia g n ose d after st u d y pr o d uct a d mi nistrati o n e ve n t h o u g h 
it ma y ha ve bee n prese nt pri or t o t he start of t he st u d y 
A treat me nt -e mer ge nt a d verse e ve nt ( T E A E) is defi ne d as a n A E wit h a start date o n or 
after t he first d ose of st u d y dr u g, or t hat w orse ne d f oll o wi n g a d mi nistrati o n of st u d y dr u g. 
A n A E d oes n ot i ncl u de t he f oll o wi n g: 
•  Me dical or s ur gical pr oce d ures (e. g., s ur ger y, e n d osc o p y, t o ot h e xtracti o n, 
tra nsf usi o n) as e ve nt ter ms; t he c o n diti o n t hat le d t o t he pr oce d ure is t he A E if it 
meets t he de fi niti o n of a n A E. 
•   Sit uati o ns w here a n u nt o war d me dical occ urre nce has n ot occ urre d (e. g., 
h os pitalizati o n f or c os metic electi ve s ur ger y; a n d s ocial a n d/ or c o n ve nie nce 
a d missi o ns). 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 5  of 7 1  
 
S y m pt o ms ass ociate d wit h disease, w hic h are c o nsiste nt wit h t he s u bject’s us ual cli nical 
c o urse; u nless t he s u bject e x perie nces w orse ni n g of t heir s y m pt o m(s) or t he s y m pt o m(s) 
meet t he criteria f or a n S A E.  
9. 1. 1  Assess me nt of Se verit y  of A d verse E ve nts  
T he se verit y of a n A E will be gra de d as f oll o ws:  
Mil d  
A ware ness of a si g n or s y m pt o m b ut is easil y t olerate d, re q uires n o 
treat me nt, a n d d oes n ot i nterfere wit h s u bject’s dail y acti vities 
M o derate  
L o w le vel of c o ncer n t o t he s u bject a n d ma y i nterfere wit h dail y acti vities 
b ut ca n be relie ve d b y si m ple t hera pe utic care  
Se vere  
I nterr u pts t he s u bject’s dail y acti vit y a n d re q uires s yste mic t hera p y or ot her 
treat me nt 
9. 1. 2  Assess me nt of Ca usalit y of A d verse E ve nts  
T he relati o ns hi p of a n A E t o t he st u d y pr o d uct will be assesse d usi n g t he f oll o wi n g 
g ui deli nes, base d u p o n a vaila ble i nf or mati o n: 
Relate d  
T here is at least a reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o t he 
st u d y dr u g. Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest 
a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E.  
N ot Relate d  
T here is little or n o reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o t he 
st u d y dr u g. T his assess me nt i m plies t hat t he A E/ S A E has little or n o 
te m p oral relati o ns hi p t o t he st u d y dr u g a n d/ or a m ore li kel y or certai n 
alter nati ve eti ol o g y e xists.  
Rati o nale M U S T be pr o vi de d f or a n y “ n ot relate d” assess me nt a n d is rec o m me n de d f or 
“relate d” assess me nts.  
9. 2  
Seri o us A d verse E ve nts  
A n A E is c o nsi dere d “seri o us” if it meets at least o ne of t he f oll o wi n g criteria.  T he 
e ve nt: 
•  Res ults i n deat h  
•  Is life t hreate ni n g ( places t he s u bject at im me diate ris k of deat h)  
N O T E: T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt 
i n w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer 
t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere.  
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
N O T E: T he ter m “ h os pitalizati o n” refers t o a d missi o n t o a h os pital as a n i n -
patie nt  f or m ore t ha n 2 4 h o urs. T heref ore, a n a d verse e ve nt w o ul d meet t he S A E 
criteri o n of “re q uires h os pitalizati o n” o nl y if t he e ve nt necessitate d a d missi o n t o a 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 6  of 7 1  
 
healt h care facilit y f or l o n ger t ha n 2 4 h o urs. Electi ve h os pitalizati o n f or a n 
i nter ve nti o n t hat was alrea d y pla n ne d bef ore i ncl usi o n of t he s u bject i n t he st u d y, 
h os pitaliz ati o n s olel y f or t he p ur p ose of dia g n ostic tests (e ve n if relate d t o a n A E), 
h os pital a d missi o n f or s ocial circ u msta nces, a n d a d missi o n t o a da y -care facilit y 
ma y n ot c o nstit ute s ufficie nt gr o u n ds t o be c o nsi dere d a n S A E. 
Cases i n w hic h s u bjects are retai n e d i n t he e mer ge nc y r o o m f or m ore t ha n 2 4 
h o urs b ut n ot a d mitte d f or me dical care s h o ul d be e val uate d i n di vi d uall y, beca use 
t he criteri o n “ ot her wise me dicall y si g nifica nt” ma y a p pl y (see bel o w). 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
N O T E: T he ter m “ disa bilit y” mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y 
t o c o n d uct n or mal life f u ncti o ns. T his defi niti o n is n ot i nte n de d t o i ncl u de 
e x perie nces of relati vel y mi n or me dical si g nifica nce (e. g., u nc o m plicate d 
he a dac he, i nfl ue nza, or s prai ne d a n kle) t hat ma y tra nsie ntl y i nterfere wit h or 
pre ve nt e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
•  Is a c o n ge nital a n o mal y/ birt h defect 
•  Is c o nsi dere d ot her wise me dicall y si g nifica nt, as deter mi ne d by t he PI or 
me dicall y q ualifie d s u b -i n vesti gat or 
N O T E: T he ter m “ me dicall y si g nifica nt” refers t o i m p orta nt me dical e ve nts t hat 
ma y n ot i m me diatel y be life t hreate ni n g or res ult i n deat h or h os pitalizati o n, b ut, 
base d u p o n a p pr o priate me dical j u d g me nt, t he y je o par dize t he s u bject or 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 ot her o utc o mes liste d i n t he 
defi niti o n of a n S A E.  
E xa m ples of s uc h me dicall y si g nifica nt e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias, 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of 
dr u g de pe n de nc y or dr u g a b use. 
S p o nta ne o us a b orti o n, electi ve a b orti o n a n d ect o pic pre g na nc y will be c o nsi dere d S A Es 
a n d m ust be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of a ware ness of t he e ve nt. 
S u bjects will be wit h dra w n fr o m t he st u d y if a n S A E is i de ntifie d a n d t h o u g ht t o be 
relate d t o t he st u d y dr u g. 
T he i n vesti gat or is res p o nsi ble f or t he re p orti n g of all S A Es.  
Wit hi n 2 4 h o urs f oll o wi n g t he i n vesti gat or’s k n o wle d ge of a n S A E, t he i n vesti gat or 
m ust:  
•  Re p ort t he S A E t o t he s p o ns or/ desi g nee. 
All S A Es occ urri n g bet wee n scree ni n g a n d 3 0 da ys after t he last a d mi nistere d 
d ose of st u d y dr u g (i ncl usi ve) m ust be re p orte d t o t he s p o ns or/ desi g nee, 
i n de pe n de nt of t he circ u msta nce or s us pecte d ca use, a n d re gar dless of t he 
relati o ns hi p t o t he st u d y dr u g or pr ot oc ol, wit hi n 2 4 h o urs fr o m t he ti me t he e ve nt 
was re p orte d t o t he i n vesti gat or. F or e ve nts occ urri n g be y o n d t he 3 0- da y peri o d 
after t he l ast a p plicati o n of st u d y dr u g, or f or a n y ti mefra me greater t ha n 3 0 da ys 
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 3 8  of 7 1  
After  t he e n d of st u d y visit, t he i n vesti gat or d oes n ot nee d t o acti vel y m o nit or s u bjects f or 
ne w S A Es. H o we ver, if t he i n vesti gat or bec o mes a ware of a ne w or pre vi o usl y 
u nre p orte d seri o us a d verse e ve nt wit hi n 3 0 da ys after t he last i n vesti gati o nal dr u g 
i nstillati o n, t he e ve nt s h o ul d be re p orte d t o t he s p o ns or/ desi g nee wit hi n 2 4 h o urs of 
lear ni n g of t he e ve nt. If t he i n vesti gat or bec o mes a ware of a ne w or pre vi o usl y 
u nre p orte d S A E after 3 0 da ys fr o m t he last i n vesti gati o nal dr u g i nstillati o n, o nl y S A Es 
c o nsi dere d relate d t o t he st u d y dr u g s h o ul d be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of 
t he i n vesti gat or’s k n o wle d ge of t he e ve nt. Seri o us a d verse e ve nts re p orte d o utsi de of t he 
pr ot oc ol- re q uire d re p orti n g peri o d will be ca pt ure d wit hi n t he safet y data base as clinical 
trial S A E Re p ort F or m cases f or t he p ur p oses of e x pe dite d re p orti n g. 
9. 2. 1  E x pe dite d Seri o us A d verse E ve nts 
A n y s us pecte d u ne x pecte d seri o us a d verse e ve nt c o nsi dere d relate d t o t he st u d y dr u g ma y 
warra nt e x pe dite d re p orti n g. I n a d diti o n, a n y u ne x pecte d S A E relate d t o a s u bject’s 
partici pati o n i n t he st u d y ( or relate d t o t he c o n d uct of t he st u d y), re gar dless of w het her or 
n ot t he st u d y dr u g was a d mi nistere d, will be e val uate d b y Gl o bal P har mac o vi gila nce a n d 
Ris k Ma na ge me nt t o deter mi ne if e x pe dite d re p orti n g  is re q uire d. F or e xa m ple, a n 
u ne x pecte d, se vere S A E t hat c o ul d be ass ociate d wit h t he st u d y pr oce d ures a n d c o ul d 
m o dif y t he st u d y c o n d uct re q uires e x pe dite d re p orti n g.  
Eac h e x pe dite d safet y re p ort will r o uti nel y i ncl u de a brief c o ver me m ora n d u m, t he 
c o m plete d Me d Watc h F or m F o o d a n d Dr u g A d mi nistrati o n ( F D A ) 3 5 0 0 A, a cli nical 
a nal ysis of t he e ve nt wit h a n y si milar e ve nts t hat ha ve occ urre d wit h t he pr o d uct, a n d a n y 
a d diti o nal perti ne nt i nf or mati o n rec o m me n de d b y t he st u d y me dical m o nit or. O nce t he 
re p ort is c o m pile d, t he st u d y ce nter’s i n vesti gat or m ust s u b mit t he e x pe dite d safet y re p ort 
t o t he l ocal I R B/I E C wit hi n t he re q uire d re p orti n g ti mefra me. F oll o w- u p re p orts s h o ul d 
be s u b mitte d w he n re q ueste d or w he n perti ne nt i nf or mati o n bec o mes a vaila ble. T he 
pri nc i pal i n vesti gat or m ust retai n a c o m plete c o p y of eac h e x pe dite d safet y re p ort as it 
was s u b mitte d t o t he I R B/I E C. It is i m p orta nt t hat t he pri nci pal i n vesti gat or re vie w t hese 
e x pe dite d re p orts, as t he y c o ntai n safet y i nf or mati o n t hat ma y be rele va nt t o eac h of t he 
partici pati n g s u bjects.  
9. 2. 2  Pre g na nc y 
A ll fe male s u bjects of c hil d beari n g p ote ntial a n d male s u bjects wit h fe male part ners of 
c hil d beari n g p ote ntial m ust use at least 1 me dicall y acce pta ble f or m  of birt h c o ntr ol 
t hr o u g h o ut t he st u d y d urati o n, f or at least 1 4 da ys pri or t o ( Visit 1) a n d 1 m o nt h after 
disc o nti n ui n g t he I P, i n a ma n ner s uc h t hat ris k of c o ntrace pti ve fail ure is mi ni mize d. 
A bsti ne nce is all o we d as a birt h c o ntr ol met h o d. Bef ore e nr olli n g a fe male s u bject of 
c hil d beari n g p ote ntial or a male s u bject wit h a fe male part ner of c hil d beari n g p ote ntial, 
t he i n vesti gator m ust re vie w t he f oll o wi n g i nf or mati o n a b o ut st u d y partici pati o n: 
•
I nf or me d c o nse nt re q uire me nt
•
C o ntrace pti ves i n c urre nt use
B y si g ni n g t he i nf or me d c o nse nt f or m, t he i n vesti gat or or desi g nee asserts t hat he/s he has 
disc usse d t his i nf or mati o n wit h t he s u bject a n d pr o vi de d a p pr o priate c o u nseli n g. 
F oll o wi n g t he re vie w of t his i nf or mati o n, t he s u bject m ust si g n t he i nf or me d c o nse nt 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 3 9  of 7 1  
 
f or m t o e nr oll i n t he st u d y. D uri n g t he st u d y, all s u bjects s h o ul d be i nstr ucte d t o c o ntact 
t he i n vesti gat or i m me diatel y if t he y s us pect t hat t he y or t heir part ners mi g ht be pre g na nt 
(e. g., misse d or late me nstr ual peri o d). 
If a s u bject or i n vesti gat or s us pects t hat t he s u bject ma y be pre g na nt pri or t o 
ra n d o mizati o n, t he st u d y dr u g m ust be wit h hel d u ntil t he res ults of la b orat or y pre g na nc y 
testi n g are a vaila ble. If pre g na nc y is c o nfir me d, t he s u bject is c o nsi dere d t o be a scree n 
fail ure, m ust n ot c o nti n ue i n t he st u d y, a n d m ust n ot recei ve st u d y dr u g. If pre g na nc y is 
s us pecte d w hile t he s u bject is recei vi n g st u d y treat me nt, t he stu d y dr u g m ust i m me diatel y 
be wit h hel d u ntil t he res ult of pre g na nc y testi n g is k n o w n. If pre g na nc y is c o nfir me d, t he 
st u d y dr u g will be per ma ne ntl y disc o nti n ue d, a n d t he s u bject a n d ne o nate will be 
f oll o we d u ntil 3 0 da ys after t he pre g na nc y c o mes t o ter m. A Pre g na nc y Re p ort f or m will 
be s u b mitte d t o t he s p o ns or, b ot h w he n pre g na nc y is c o nfir me d, a n d 3 0 da ys after t he 
deli ver y date. I nf or mati o n pr o vi de d o n t he Pre g na nc y Re p ort F or m m ust i ncl u de t he 
o utc o me of t he pre g na nc y a n d a n y c o m plicati o ns occ urri n g d uri n g t he pre g na nc y or t he 
deli ver y. 
If a s u bject is wit h dra w n fr o m t he st u d y a n d is f o u n d t o be pre g na nt wit hi n 3 0 da ys of 
wit h dra wal, t he s u bject a n d ne o nate will be f oll o we d u ntil 3 0 da ys after t he pre g na nc y 
c o mes t o ter m.  
All c o nfir me d pre g na ncies m ust b e i m me diatel y re p orte d t o t he s p o ns or/ desi g nee a n d 
me dical m o nit or o n a Pre g na nc y Re p ort f or m wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness of t he pre g na nc y. If a pre g na nc y is ass ociate d wit h a n S A E, a n S A E re p ort 
f or m s h o ul d als o be s u b mitte d t o t he s p o ns or/ desi g nee a n d me dical m o nit or wit hi n 2 4 
h o urs of t he i n vesti gat or’s a ware ness. A b n or mal pre g na nc y o utc o mes (e. g., s p o nta ne o us 
a b orti o n, fetal deat h, still birt h, c o n ge nital a n o malies, ect o pic pre g na nc y) are c o nsi dere d 
S A Es.  
C o m plete d S A E Re p ort F or ms a n d c o m plete d Pre g na nc y Re p ort F or ms s h o ul d be 
tra ns mitte d t o t he s p o ns or/ desi g nee a n d t he me dical m o nit or usi n g t he c o ntact 
i nf or mati o n pr o vi de d i n Secti o n 9. 2  a b o ve. 
If/ w he n t he i n vesti gat or bec o mes a ware of a n y ne w i nf or mati o n re gar di n g a pre g na nc y, 
t he s p o ns or/ desi g nee a n d me dical m o nit or s h o ul d be n otifie d of t hese u p dates as s o o n as 
t he ne w i nf or mati o n bec o mes a vaila ble. U p dates s h o ul d be d oc u me nte d o n a Pre g na nc y 
Re p ort F or m a n d se nt b y fa x or e mail usi n g t he c o ntact i nf or mati o n pr o vi de d a b o ve. T he 
re port s h o ul d be mar ke d as a f oll o w- u p re p ort” a n d s h o ul d i ncl u de t he u p date d stat us of 
t he pre g na nc y. T he ori gi nal Pre g na nc y Re p ort F or m is n ot t o be altere d. 
9. 3  
Ge ner al G ui deli nes f or Re p orti n g A d verse E ve nts  
It is t he res p o nsi bilit y of t he i n vesti gat or t o d ocu me nt all A Es t hat occ ur d uri n g t he 
c o urse of t he st u d y. T hr o u g h o ut t he st u d y, eff orts will be ma de b y t he i n vesti gat or t o 
re mai n alert t o p ossi ble AEs. T he peri o d of o bser vati o n f or c ollecti o n of A E s e xte n ds 
fr o m t he ti me t he s u bject gi ves i nf or me d c o nse nt u ntil t he last st u d y visit or 
disc o nti n uati o n fr o m t he st u d y. T he first c o ncer n will al wa ys be t he safet y of t he s u bject, 
a n d a p pr o priate me dical i nter ve nti o n will be ma de. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 0  of 7 1  
 
T he A Es s h o ul d be d oc u me nt e d as a si n gle me dical dia g n osis. W he n t his is n ot p oss i ble, 
t he A E s h o ul d be d oc u me nte d i n ter ms of si g ns a n d/ or s y m pt o ms o bser ve d b y t he 
i n vesti gat or or re p orte d b y t he s u bject at eac h st u d y visit. Eac h A E w hic h a p pears t o be 
i n de pe n de nt of a n y pri or e ve nt will be re p orte d se paratel y. 
All A Es occ urri n g after t he s u bject si g ns t he i nf or me d c o nse nt t hr o u g h t he last st u d y visit 
m ust be re p orte d, re gar dless of w het her or n ot t he A E s are c o nsi dere d dr u g-relate d. All 
A Es, w het her i n res p o nse t o a q uer y, o bser ve d b y t he st u d y site pers o n nel, or re p orte d 
s p o nta ne o usl y b y t he s u bject, will be rec or de d. A n y A Es dee me d relate d t o treat me nt 
re p orte d or o bser ve d at t he fi nal st u d y/treat me nt visit will be f oll o we d u ntil sta bilizati o n 
or res ol uti o n ( or u p t o 3 0 da ys after fi nal st u d y visit).  
At eac h visit d uri n g t he st u d y, t he s u bject will be assesse d f or t he occ urre nce of ne w a n d 
o n g oi n g A Es. T olera bilit y si g ns a n d s y m pt o ms t hat res ult i n t he s u bject’s re q uiri n g a 
c o nc o mita nt t hera p y, i nterr u pti o n of treat me nt, or disc o nti n uati o n fr o m t he st u d y will be 
re p orte d as a n A E. T he f oll o wi n g data will be c ollecte d o n all A Es a n d rec or de d o n t he 
a p pr o priate e C R F:  
•  E ve nt na me ( dia g n osis preferre d, if u n k n o w n, rec or d t he si g ns/s y m pt o ms) 
•  O nset date a n d e n d date 
•  Ma xi m u m i nte nsit y (se verit y)  
•  Seri o us ness 
•  Acti o n ta ke n re gar di n g st u d y dr u g 
•  C o rrecti ve treat me nt/t hera p y, if gi ve n 
•  O utc o me 
•  Res ol uti o n 
T he i n vesti gat or will als o pr o vi de a n assess me nt of t he ca usal relati o ns hi p t o t he st u d y 
dr u g (f or pre -treat me nt AE s, ca usalit y is “ n ot relate d”). Rati o nale M U S T be pr o vi de d f or 
a n y “ n ot relate d” assess me nt a n d is rec o m me n de d f or “relate d” assess me nts.  
All A E s m ust be re p orte d re gar dless of w het her t he AE s are c o nsi dere d dr u g-relate d. 
I n or der t o e ns ure t he safet y of t he s u bjects, t he i n vesti gat or s h o ul d ta ke a p pr o priate 
meas ures t o f oll o w all s u bjects  wit h a d verse e ve nts u ntil cli nical rec o ver y is c o m plete, 
pr o gressi o n has bee n sta bilize d, t he s u bject is l ost t o f oll o w- u p, or u ntil deat h. T his ma y 
res ult i n t he nee d f or o bser vati o ns t o c o nti n ue be y o n d t he last pla n ne d pr ot oc ol s pecifie d 
visit, a n d a d di ti o nal i n vesti gati o ns ma y be re q ueste d b y t he m o nit ori n g tea m. 
If a s u bject re q uires f urt her f oll o w- u p of o n g oi n g A Es u p o n disc o nti n uati o n or 
c o m pleti o n of t he st u d y, t he I n vesti gat or s h o ul d sc he d ule p ost- st u d y f oll o w-u p visits, as 
necessar y.  
La b orat or y res ults, vital si g ns, or electr ocar di o gra m (E C G ) a b n or malities are t o be 
rec or de d as A Es ( or S A Es, if a p plica ble) o nl y if at least o ne of t he f oll o wi n g a p pl y : 
•  t he res ult is cli nicall y si g nifica nt 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 1  of 7 1  
 
•  t he s u bject is s y m pt o matic 
•  t he s u bject re q uires eit her c orrecti ve treat me nt or c o ns ultati o n 
•  t he la b res ult, vital si g n, or E C G a b n or malit y lea ds t o st u d y dr u g disc o nti n uati o n 
or d ose m o dificati o n 
•  t he e ve nt f ulfills a criteri o n f or a n S A E  
I n a d diti o n, t he i n vesti gat or’s assess me nt of ca usalit y will be rec or de d. 
Vital si g n a b n or malities are t o be rec or de d as A Es ( or S A Es, if a p plica ble) o nl y if t he y 
are cli nicall y si g nifica nt (f or e xa m ple: are s y m pt o matic, re q uiri n g c orrecti ve treat me nt, 
lea di n g t o disc o nti n uati o n or f ulfilli n g a seri o us ness criteri o n). 
Site staff will pr o vi de s u bjects wit h t he mai n office n u m ber pl us a 2 4 -h o ur n u m ber t o 
re p ort a n y a d verse e ve nts or safet y c o ncer ns. T his i nf or mati o n will be liste d o n t he 
I nf or me d C o nse nt F or m a n d a c o p y will be pr o vi de d t o t he s u bject at t heir Scre e ni n g 
Visit  or Visit 1 (if Scree ni n g a n d Visit 1 are d o ne o n t he sa me da y). 
9. 4  
Pr oce d ures f or U n m as ki n g (if a p plic a ble)  
W he n me dicall y necessar y, t he i n vesti gat or ma y nee d t o deter mi ne w hat treat me nt has 
bee n assi g ne d t o a s u bject. W he n p ossi ble (i.e. , i n n o n-e mer ge nt sit uati o ns), Ora a n d/ or 
t he s p o ns or s h o ul d be n otifie d bef ore u n mas ki n g I P. 
1 0  S T A TI S TI C A L H Y P O T H E S E S A N D M E T H O D S O F A N A L Y S E S  
1 0. 1  
St u d y P o p ul ati o ns   
Safet y P o p ulati o n: T he safet y p o p ulati o n i ncl u des all s u bjects w h o ha ve recei ve d at least 
o ne d ose of st u d y me dicati o n . All safet y a n d t olera bilit y para meters will be a nal yze d 
usi n g t he safet y p o p ulati o n a n d usi n g t he treat me nt t hat s u bjects act uall y recei ve d.  
P har mac o ki neti c (P K ) P o p ulati o n: T he P K p o p ulati o n i ncl u des all e nr olle d s u bject s w h o 
pr o vi de at least o ne bl o o d sa m ple dra w n p ost- d ose. 
1 0. 2  
U nit of A n al ysis   
F or t olera bilit y a n d n o n- oc ular safet y a nal yses, t he u nit of a nal ysis will be t he s u bject (i n 
t he case of assess me nts t hat are rec or de d f or eac h e ye, t he a vera ge of t he e yes will be 
use d). F or t he oc ular safet y a nal yses, t he u nit of a nal ysis will be eac h e ye.  
1 0. 3  
Pri m ar y St atistic al H y p ot hesis  
Statistical h y p ot heses will n ot be teste d i n t his safet y st u d y.  
1 0. 4  
S a m ple Size   
5 0 1 s u bjects will be ra n d o mize d yiel di n g a p pr o xi matel y 3 3 4 s u bjects ra n d o mize d t o 
bri m o ni di ne tartrate 0. 0 2 5 %/ ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n 
a n d 1 6 7 s u bjects ra n d o mize d t o ve hicle. T hree- h u n dre d t hirt y -f o ur acti vel y treate d 
s u bjects yiel d at least 9 5 % pr o ba bilit y of detecti n g A Es t hat occ ur at a rate of 1 % or 
greater.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 2  of 7 1  
 
Of t he s u bject t otal, a p pr o xi matel y 1 0 0 pe diatric s u bjects are a ntici pate d t o be e nr olle d 
i nt o t his st u d y. 
1 0. 5  
De m o gr a p hic a n d B aseli ne  C h ar acteristics  
S u bject de m o gra p hics: ge n der, race, et h nicit y, a n d iris c ol or will be prese nte d usi n g 
discrete s u m mar y statistics. A ge will als o be prese nte d usi n g c o nti n u o us s u m mar y 
statistics. 
1 0. 6  
S afet y A n al ysis  
T he f oll o wi n g safet y varia bles will be rec or de d. All safet y a nal yses will be re peate d o n 
t he a ge s u b gr o u ps - 5- 1 2 years ol d, 1 3- 1 7 years ol d, 1 8- 6 4 years ol d, a n d f or a ges greater 
t ha n 6 4 years. 
•  A d verse E ve nts ( A Es; re p orte d, elicite d a n d o bser ve d) 
•  Uri ne Pre g na nc y Test  
•  Best - C orrecte d Vis ual Ac uit y usi n g a n E T D R S c hart 
•  Slit  La m p Bi o micr osc o p y  
•  I ntra oc ular Press ure (s h o ul d be perf or me d o n s u bjects ≥ 1 0 years ol d) 
•  P h ysical E xa mi nati o n  
•  Vital Si g ns (resti n g bl o o d press ure a n d p ulse) 
•  Dilate d F u n d us E xa mi nati o n  
All safet y para meters will be a nal yze d o n t he Safet y P o p ulati o n. T he r es ults of V A , slit 
la m p bi o micr osc o p y, I O P, vital si g ns will be prese nte d b y treat me nt a n d visit wit h 
n u merical s u m maries. C ha n ge fr o m baseli ne will als o be prese nte d i n t he sa me ma n ner.  
A slit -la m p bi o micr osc o p y e xa mi nati o n of t he c or nea, c o nj u ncti va, a nteri or c ha m ber, iris, 
le ns, a n d li d will be perf or me d at eac h visit. T he res ults will be gra de d as n or mal, 
a b n or mal n ot cli nicall y si g nifica nt ( N C S), or a b n or mal cli nicall y si g nifica nt ( C S).  
T he o bser ve d a n d c ha n ge fr o m baseli ne V A  will be s u m marize d f or ea c h e ye (st u d y e ye 
a n d n o n- st u d y e ye) usi n g c o nti n u o us descri pti ve statistics b y visit f or eac h treat me nt 
gr o u p a n d f or all acti vel y treate d s u bjects. 
T he res ults will be s u m marize d usi n g c o u nts a n d perce nta ges f or eac h treat me nt gr o u p 
a n d f or all acti vel y treate d s u bjects at eac h visit f or eac h e ye. Perce nta ges will be base d 
o n t he n u m ber of s u bjects i n eac h treat me nt gr o u p wit h res p o nses. S hift ta bles f or t he slit-
la m p bi o micr osc o p y para meters will als o be pr o vi de d c o m pari n g eac h f oll o w- u p visit t o 
baseli ne.  
Dilate d F u n d us E xa mi nati o n res ults will be s u m marize d usi n g c o u nts a n d perce nta ges f or 
eac h treat me nt gr o u p a n d f or all acti vel y treate d s u bjects at eac h visit f or eac h e ye. 
Perce nta ges will be base d o n t he n u m ber of s u bjects i n eac h treat me nt gr o u p wit h 
res p o nses. S hift ta bles f or t he dilate d  f u n d osc o p y para meters will als o be pr o vi de d 
c o m pari n g eac h f oll o w- u p visit t o baseli ne . 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 3  of 7 1  
 
P h ysical e xa mi nati o n  res ults, gra de d as n or mal or a b n or mal, will be s u m marize d b y 
treat me nt gr o u p a n d f or all acti vel y treate d s u bjects usi n g c o u nts a n d perce nta ges at eac h 
visit (i ncl u di n g a s u m mar y of baseli ne val ues). C ha n ge fr o m baseli ne will als o be 
s u m marize d t o eac h p ost- baseli ne visit usi n g c o u nts a n d perce nta ges. 
Vital si g ns will be s u m marize d wit h c o nti n u o us descri pti ve statistics at eac h da y 
(i ncl u di n g a s u m mar y of baseli ne val ues) a n d ti me p oi nt b y treat me nt gr o u p a n d f or all 
acti vel y treate d s u bjects. C ha n ge fr o m baseli ne will als o be s u m marize d t o eac h p ost -
baseli ne visit. A d diti o nall y, f or eac h meas ure, a w orst- case l o w a n d w orst -case hi g h p ost-
baseli ne val ue a n d c ha n ge fr o m baseli ne val ue will be prese nte d.  
Hei g ht, wei g ht, a n d B MI will be s u m marize d f or a s u bset of s u bjects usi n g  c o nti n u o us 
descri pti ve statistics at eac h da y (i ncl u di n g a s u m mar y of baseli ne val ues) a n d ti me p oi nt 
b y treat me nt gr o u p a n d f or all acti vel y treate d s u bjects. C ha n ge fr o m baseli ne will als o be 
s u m marize d t o eac h p ost- baseli ne visit. A d diti o nall y, f or eac h meas ure, a w orst-case l o w 
a n d w orst-case hi g h p ost- baseli ne val ue a n d c ha n ge fr o m baseli ne val ue will be 
prese nte d.  
1 0. 7  
A d verse E ve nts  
A d verse e ve nts ( A Es) 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 ) dicti o nar y. Fre q ue ncies a n d perce nta ges of T E A Es will be 
s u m marize d at t he s u bject le vel b y s yste m or ga n class a n d preferre d ter m f or all T E A Es, 
treat me nt relate d T E A Es, seri o us T E A Es, a n d T E A Es ca usi n g pre mat ure treat me nt 
disc o nti n uati o n b y treat me nt gr o u p. A n A E is treat me nt e mer ge nt if it occ urs or w orse ns 
after t he first d ose of st u d y me dicati o n. Si milar s u m maries will be prese nte d f or all 
T E A Es b y ma xi mal se verit y. Se parate s u m maries will be perf or me d f or oc ular a n d n o n -
oc ular A Es.  
1 0. 8  
D osi n g C o m pli a nce a n d E xte nt of E x p os ure   
A s u bject w h o has ta ke n at least 8 0 % b ut n ot greater t ha n 1 2 0 % of t he sc he d ule d d oses  
will be c o nsi dere d as st u d y dr u g c o m plia nt. C o m plia nce f or all treate d s u bjects will be 
s u m marize d wit h descri pti ve statistics b y treat me nt gr o u p. C o u nts a n d perce nta ges of 
c o m plia nt s u bjects ( 8 0 % - 1 2 0 %), n o n -c o m plia nt s u bjects ( < 8 0 %), a n d o ver c o m plia nt 
s u bjects ( > 1 2 0 %) will be s u m marize d. E xte nt of e x p os ure, defi ne d as n um ber of da ys 
eac h s u bject was o n t he st u d y dr u g will be s u m marize d wit h descri pti ve statistics.  
S u b gr o u p a nal yses b y a ge gr o u p ( 5 years – 1 2 years), ( 1 3 years – 1 7 years), ( 1 8 years – 
3 9 years), ( 4 0 years – 6 4 years), a n d ( 6 5 years a n d u p) will be perf or me d as a p pr o priate 
o n necessar y safet y para meters, i ncl u di n g s u m maries of I O P, V A , slit la m p 
bi o mi cr osc o pe, a n d Dilate d f u n d osc o p y. 
1 0. 9  
T oler a bilit y A n al ysis  
Bri m o ni di ne tartrate 0. 0 2 5 % / ket otife n f u marate 0. 0 3 5 % c o m bi nati o n o p ht hal mic s ol uti o n 
will be c o m pare d t o ve hicle f or t he t olera bilit y para meter of dr o p c o mf ort usi n g 2 -sa m ple 
t-tests f or eac h assess me nt ti me p oi nt. S u b gr o u p a nal yses b y a ge gr o u p ( 5 years – 1 2 
years), ( 1 3 years – 1 7 years), ( 1 8 years – 3 9 years), ( 4 0 years – 6 4 years), a n d ( 6 5 years 
a n d u p) will be perf or me d.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 4  of 7 1  
 
1 0. 1 0  P h ar m ac o ki neti cs A n al ysis 
Plas ma c o nce ntrati o ns of bri m o ni di ne a n d ket otife n b y sc he d ule d ti me p oi nt will be 
s u m marize d usi n g descri pti ve statistics: n, mea n, me dia n, sta n dar d de viati o n ( S D), 
mi ni m u m, ma xi m u m, a n d perce nt c oefficie nt of variati o n ( % C V).  
W here data all o w, t he P K para meters  ( Cma x , Cmi n , Tma x , A U C0-t, A U C0- 4 h, RC ma x , a n d 
R A U C ) f or bri m o ni di ne a n d ket otife n will be o btai ne d usi n g sta n dar d n o n- c o m part me ntal 
met h o ds. P K para meters will be s u m marize d usi n g descri pti ve statistics b y da y: n, mea n, 
me dia n, S D, mi ni m u m, ma xi m u m, a n d  % C V . 
C o nce ntrati o n val ues re p orte d as bel o w t he li mit of q ua ntitati o n ( B L Q) bef ore t he first 
q ua ntifia ble c o nce ntrati o n or after t he last q ua ntifia ble c o nce ntrati o n will be set t o zer o 
f or c o nce ntrati o n descri pti ve statistics a n d P K a nal yses. If a c o nce ntrati o n t hat is B L Q is 
i m be d de d bet wee n 2 meas ura ble c o nce ntrati o ns, t he B L Q val ue will be set t o missi n g.  
Fi g ures will be create d t o dis pla y mea n a n d i n di vi d ual s u bject c o nce ntrati o n- ti me c ur ves 
i n plas ma. 
A d diti o nal P K a nal yses ma y be perf or me d at t he S p o ns or’s discreti o n d uri n g or at t he 
c o ncl usi o n of t he st u d y. 
1 1  C O M P LI A N C E WI T H G O O D C LI NI C A L P R A C TI C E S, E T HI C A L 
C O N SI D E R A TI O N S, A N D A D MI NI S T R A TI V E I S S U E S  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, c urre nt G o o d Cli nical 
Practices ( G C Ps), i ncl u di n 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 nes, a n d i n ge neral, c o nsiste nt wit h t he Declarati o n of Helsi n ki. I n a d diti o n, all 
a p plica ble l ocal, state, a n d fe deral re q uire me nts rele va nt t o t he use of I P i n t he c o u ntries 
i n v ol ve d will be a d here d t o. 
1 1. 1  
Pr otecti o n of H u m a n S u b jects 
1 1. 1. 1  S u bject I nf or me d C o nse nt  
I nf or me d c o nse nt/asse nt m ust ta ke place bef ore a n y st u d y s pecific pr oce d ures are 
i nitiate d. Si g ne d a n d date d writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h s u bject 
a n d/ or fr o m t he s u bject’s pare nt or le gal g uar dia n pri or  t o e nr oll me nt i nt o t he st u d y. If t he 
s u bject is u n der t he le gal 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 a le gal 
g uar dia n or as re q uire d b y state a n d/ or l ocal la ws a n d re g ulati o ns. 
All i nf or me d c o nse nt/asse nt f or ms m ust be a p pr o ve d f or use b y t h e s p o ns or a n d recei ve 
a p pr o val/fa v ora ble o pi ni o n fr o m a n I R B/I E C pri or t o t heir use. If t he c o nse nt f or m 
re q uires re visi o n (e. g., d ue t o a pr ot oc ol a me n d me nt or si g nifica nt ne w safet y 
i nf or mati o n), it is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t he a me n de d i nf or me d 
c o nse nt is re vie we d a n d a p pr o ve d b y Ora pri or t o s u b missi o n t o t he g o ver ni n g I R B/I E C 
a n d t hat it is rea d, si g n e d a n d date d b y all s u bjects s u bse q ue ntl y e nr olle d i n t he st u d y as 
well as t h ose c urre ntl y e nr olle d i n t he st u d y. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 4 5  of 7 1  
1 1. 1. 2  I nstit uti o nal Re vie w B oar d (I R B) A p pr o val 
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 o de of 
Fe deral Re g ulati o ns (C F R ) Part 5 6. 1 0 3). T he i n vesti gat or m ust o btai n a p pr o priate I R B 
a p pr o val bef ore i nitiati n g t he st u d y a n d re- a p pr o val at least a n n uall y.  
O nl y a n I R B/ I E C a p pr o ve d versi o n of t he i nf or me d c o nse nt f or m will be use d. 
1 1. 2  Et hic al C o n d uct of t he St u d y  
T his st u d y w ill be c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples t hat ori gi nate d 
wit h t he Declarati o n of Helsi n ki.  
1 1. 3  S u bject C o nfi de nti alit y  
All pers o nal st u d y s u bject data c ollecte d a n d pr ocesse d f or t he p ur p oses of t his st u d y 
s h o ul d be mai ntai ne d b y t he i n vesti gat or a n d his/ her staff wit h a de q uate preca uti o ns as t o 
e ns ure t hat t he c o nfi de ntialit y of t he data  is i n acc or da nce wit h l ocal, state, a n d fe deral 
la ws a n d re g ulati o ns. 
M o nit ors, a u dit ors a n d ot her a ut h orize d re prese ntati ves of Ora, t he s p o ns or, t he I R B/I E C 
a p pr o vi n g t his st u d y, t he F D A, t he De part me nt of Healt h a n d H u ma n Ser vices  (D H H S ), 
ot her d o mestic g o ver n me nt a ge ncies, a n d ot her f orei g n re g ulat or y a ge ncies will be 
gr a nte d direct access t o t he s u bject’s ori gi nal me dical a n d st u d y rec or ds f or verificati o n 
of t he data a n d/ or cli nical trial pr oce d ures. Access t o t his i nf or mati o n will be per mitte d t o 
t he af ore me nti o ne d i n di vi d uals t o t he e xte nt per mitte d b y la w. 
A re p ort o f 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 I P ma y ulti matel y be mar kete d, b ut t he s u bject’s 
i de ntit y will n ot be discl ose d i n t hese d oc u me nts. 
1 1. 4  D oc u me nt ati o n  
S o urce d oc u me nts ma y i n cl u de a s u bject’s me dical rec or ds, h os pital c harts, cli nic c harts, 
t he i n vesti gat or’s st u d y s u bject 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 E CGs . T he i n vesti gat or’s c o p y of t he C R Fs ser ves as t he 
i n vesti gat or’s rec or d of a s u bject’s st u d y-relate d data. 
1 1. 4. 1  Rete nti o n of D oc u me ntati o n 
All st u d y relate d c orres p o n de nce, s u bject  rec or ds, c o nse nt f or ms, rec or d of t he 
distri b uti o n a n d use of all I P, a n d c o pies of C R Fs  s h o ul d be mai ntai ne d o n file f or at least 
t w o 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 u ntil at 
least t w o 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 he I P. T hese d oc u me nts will be retai ne d f or a l o n ger peri o d if re q uire d b y t he a p plica ble 
re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he s p o ns or. It is t he res p o nsi bilit y of 
t he s p o ns or t o i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger 
nee d t o be retai ne d.  
If t he res p o nsi ble i n vesti gat or retires, rel ocates, or f or ot her reas o ns wit h dra ws fr o m t he 
res p o nsi bilit y of kee pi n g st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a pers o n w h o will 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 6  of 7 1  
 
acce pt t he res p o nsi bilit y. T he s p o ns or m ust be n otifie d i n writi n g of t he na me a n d a d dress 
of t he ne w c ust o dia n. 
1 1. 5  L a beli n g, P ac k a gi n g, St or a ge, Acc o u nt a bilit y, a n d Ret ur n or Dis p os al 
of I n vesti g ati o n al Pr o d uct  
1 1. 5. 1  La beli n g/ Pac ka gi n g 
T he i n vesti gati o nal materials will be pac ka ge d a n d la bele d i n a ma n ner c o nsiste nt wit h 
t he st u d y desi g n. T he y will be la belle d acc or di n g t o t he l ocal re g ulat or y re q uire me nts. 
S u bjects will be dis pe nse d t w o kits c o ntai ni n g 2 b ottles of assi g ne d I P eac h. Kit 1 will be 
dis pe nse d at Visit 1. T he s u bject will bri n g Kit 1 t o Visit 2 f or i n -office i nstallati o n a n d 
kit 1 will be  ret ur ne d t o t he s u bject f or c o nti n ue d use u ntil Visit 3. Kit 1 will be c ollecte d 
at Visit 3. Kit 2 will be dis pe nse d at Visit 3 a n d c ollecte d at Visit 4 . 
1 1. 5. 2  St ora ge of I n vesti gati o nal Pr o d uct 
T he I P m ust be st ore d i n a sec ure area accessi ble o nl y t o t he i n vesti gat or a n d his/ her 
desi g nees. T he I P will be a d mi nistere d o nl y t o s u bjects e ntere d i nt o t he cli nical st u d y, i n 
acc or da nce wit h t he c o n dit i o ns s pecifie d i n t his pr ot oc ol. 
I P m ust be st ore d at r o o m te m perat ure at 1 5- 2 5° C ( 5 9- 7 7° F). 
1 1. 5. 3  Acc o u nta bilit y of I n vesti gati o nal Pr o d uct 
T he I P is t o o nl y be prescri be d b y t he pri nci pal i n vesti gat or or his/ her na me d s u b-
i n vesti gat or(s) a n d is t o o nl y be use d i n acc or da nce wit h t his pr ot oc ol. T he I P m ust o nl y 
be distri b ute d t o s u bjects pr o perl y q ualifie d u n der t his pr ot oc ol t o recei ve I P. 
T he i n vesti gat or m ust kee p a n acc urate acc o u nti n g of t he I P recei ve d fr o m t he s p o ns or o n 
t he Pr o d uct Acc o u nta bilit y L o g. 
1 1. 5. 4  Ret ur n or Dis p osal of I n vesti gati o nal Pr o d uct 
All I P  will be ret ur ne d t o t he s p o ns or at t he e n d of t he st u d y. 
1 1. 6  Rec or di n g of D at a o n S o urce D oc u me nts a n d C ase Re p orts F or ms 
( C R Fs) 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat st u d y da ta is c o m pletel y a n d acc uratel y 
rec or de d o n eac h s u bject’s C R F , s o urce d oc u me nt, a n d all st u d y-relate d material. All 
st u d y data s h o ul d als o be attri b uta ble, le gi ble, c o nte m p ora ne o us, a n d ori gi nal. Rec or de d 
dat u m s h o ul d o nl y be c orrecte d i n a ma n ner t hat d oes n ot o bliterate, destr o y, or re n der 
ille gi ble t he pre vi o us e ntr y (e. g., b y dra wi n g a si n gle li ne t hr o u g h t he i nc orrect e ntr y a n d 
writi n g t he re visi o n ne xt t o t he c orrecte d data). A n i n di vi d ual w h o has c orrecte d a data 
e ntr y s h o ul d ma ke clear w h o ma de t he c orrecti o n a n d w he n, b y a d di n g t o t he c orrecti o n 
his/ her i nitials as well as t he date of t he c orrecti o n.  
1 1. 7  H a n dli n g of Bi ol o gic al S peci me ns  
See A p pe n di x 7  ‘ Bl o o d C ollecti o n, Ha n dli n g, a n d S hi p me nt f or P har mac o ki netic 
A nal ysis f or details.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 4 7  of 7 1  
 
1 1. 8  P u blic ati o ns  
A ut h ors hi p a n d ma n uscri pt c o m p ositi o n will reflect c o o perati o n a m o n g all parties 
i n v ol ve d i n t he st u d y. A ut h ors hi p will be esta blis he d bef ore writi n g t he ma n uscri pt. Ora 
a n d t he s p o ns or will ha ve t he fi nal decisi o n re gar di n g t he ma n uscri pt a n d  p u blicati o n. 
 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 4 8  of 7 1  
1 2  R E F E R E N C E S  
1.
A bels o n M B, C ha pi n MJ, S mit h L. Oc ular Aller gic Disease: Mec ha nis ms, Disease
S u b -t y pes, Treat me nt. T he Oc ular S urface , J ul y 2 0 0 3; 1( 3): 3 8- 6 0.
2.
A bels o n M B, C ha pi n MJ, Ka pi k B M, S ha ms N B. Efficac y of ket otife n f u marate
0. 0 2 5 % o p ht hal mic s ol uti o n c o m pare d wit h place b o i n t he c o nj u ncti val aller ge n
c halle n ge m o del. Arc h O p ht hal m ol. Ma y 2 0 0 3; 1 2 1( 5): 6 2 6- 6 3 0.
3.
Ac ker ma n S L, T or kil dse n G L, Mc La uri n E, Vittit o w J L. L o w -d ose bri m o ni di ne f or
relief of oc ular re d ness: i nte grate d a nal ysis of f o ur cli nical trials. Cli n E x p O pt o m.
2 0 1 9; 1 0 2( 2): 1 3 1- 1 3 9.
4.
Ala wa y, Ket otife n F u marate O p ht hal mic S ol uti o n, 0. 0 3 5 %. La bel a p pr o ve d A pril
2 0 2 1
5.
Biel or y L. Aller gic a n d i m m u n ol o gic dis or ders of t he e ye. Part II: oc ular aller g y. J
Aller g y Cli n I m m u n ol 2 0 0 0; 1 0 6: 1 0 1 9 – 1 0 3 2.
6.
Bj or kste n B, Cla yt o n T, Ell w o o d P, Ste wart A, Strac ha n D a n d t he I S A A C P hase III
S t u d y Gr o u p. W orl d wi de ti me tre n ds f or s y m pt o ms of r hi nitis a n d c o nj u ncti vitis:
P hase III  of t he I nter nati o nal St u d y of Ast h ma a n d Aller gies i n C hil d h o o d.
W orl d wi de ti me tre n ds f or s y m pt o ms of r hi nitis a n d c o nj u ncti vitis: p hase III of t he
I nter nati o nal St u d y of Ast h ma a n d Aller gies i n C hil d h o o d. Pe diatr Aller g y I m m u n ol
2 0 0 8; 1 9: 1 1 0- 1 2 4.
7.
Hessel mar B, A ber g B, Eri kss o n B, A ber g N. Aller gic r hi n oc o nj u ncti vitis, ecze ma,
a n d se nsitizati o n i n t w o areas wit h differi n g cli mates. Pe diatr Aller g y I m m u n ol
2 0 0 1; 1 2: 2 0 8 – 2 1 5.
8.
L u mif y, Bri m o ni di ne Tartrate O p ht hal mic S ol uti o n, 0. 0 2 5 %. La bel a p pr o ve d
Se pte m ber 2 0 2 0
9.
R osari o N , Biel or y L . E pi de mi ol o g y of aller gic c o nj u ncti vitis. C urr O pi n Aller g y
Cli n I m m u n ol 2 0 1 1 Oct; 1 1( 5): 4 7 1- 6.
1 0. Si n g h K , A xelr o d S , Biel or y L . T he e pi de mi ol o g y of oc ular a n d nasal aller g y i n t he
U nite d States, 1 9 8 8- 1 9 9 4. J Aller g y Cli n I m m u n ol 2 0 1 0 Oct; 1 2 6( 4): 7 7 8- 7 8 3.e 6.
1 1. Steeri n g C o m mittee ( N o a ut h ors liste d). W orl d wi de variati o n i n pre vale nce of
s y m pt o ms of ast h ma, aller gic r hi n oc o nj u ncti vitis, a n d at o pic ecze ma: I S A A C. T he
I nter nati o nal St u d y of Ast h ma a n d Aller gies i n C hil d h o o d (I S A A C) Steeri n g
C o m mittee. La ncet 1 9 9 8; 3 5 1: 1 2 2 5 – 1 2 3 2.
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 0  of 7 1  
 
3. T he I n vesti gat or will refer t o A p pe n di x 4  f or s u bjects < 1 2 years of a ge o nl y.  
4. P h ysical E xa mi nati o n i ncl u des ge neral healt h, hea d, e yes, ears, n ose, t hr oat ( H E E N T), a n d a n y ot her c o m me nts.  
5. If a s u bject use d c orrecti o n at t he baseli ne visit t he n t he y s h o ul d use t he sa me c orrecti o n t hr o u g h o ut all s u bse q ue nt 
V A  assess me nts . F or s u bjects u n der 1 0 years of a ge w h o are de vel o p me ntall y u na ble t o use E T D R S c hart, a best 
atte m pt at o btai ni n g V A  will be ma de b y usi n g a L E A s y m b ols V A  c hart ( meas ure d as S nelle n e q ui vale nt u nits).  If 
s u bject re q uires Vis ual Be ha vi or, t he y m ust ha ve a passi n g sc ore. 
6. E val uate d pri or t o a n d 1 5 mi n utes ( + 3 mi n utes) p ost I P i nstillati o n at Visits 1-3, a n d o nce at Visit 4.  
7. A g e > 1 0 years ol d.  
8. S u bjects a n d/ or s u bject’s pare nt/le gal g uar dia n will i nstill I P at Visit 1 a n d will be o bser ve d b y a trai ne d st u d y 
tec h nicia n. T he s u bjects e nr olle d t o t he P K st u d y will recei ve 1 dr o p of t he assi g ne d I P i nt o eac h e ye fr o m a trai ne d 
tec h nicia n. 
9. S u bjects ≥ 1 0 years ol d will assess c o mf ort i m me diatel y u p o n i nstillati o n, at 3 0 sec o n ds, a n d at 1 -mi n ute p ost -
i nstillati o n usi n g a 
 f or eac h e ye.  S u bjects < 1 0 years ol d will n ot assess dr o p c o mf ort. 
1 0. (f or s u bjects a greei n g t o u n der g o P K bl o o d dra ws) Pre -d ose ( wit hi n 1 h o ur pri or t o d osi n g) a n d at 0. 2 5 ( ± 3 mi n)  
h o ur , 0. 5 ( ± 5 mi n) h o ur, 1 ( ± 1 0 mi n) h o ur, 2 ( ± 1 0 mi n) h o urs, a n d 4 ( ± 2 0 mi n) h o urs after t he first st u d y dr u g 
a d mi nistrati o n i n t he m or ni n g o n Da y 1 a n d o n Da y 2 2.  
1 1. A ne w kit is dis pe nse d at Visit 1 a n d Visit 3. At Visit 2, t he kit t hat was dis pe nse d at Visit 1 is re -dis pe nse d f or 
d osi n g u n til Visit 3. 
1 2. A ne w d osi n g diar y will be distri b ute d at Visits 1, 2, a n d 3.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 1  of 7 1  
 
A P P E N DI X 2: E X A MI N A TI O N P R O C E D U R E S, T E S T S, E Q UI P M E N T, A N D 
T E C H NI Q U E S  
Vis u al Ac uit y Pr oce d ures ( E T D R S C h art)  
L o g M A R  vis ual  ac uit y  ( V A)  m ust  be  assesse d  usi n g  a n  Earl y  Treat me nt  Dia betic  
Reti n o pat h y  St u d y  ( E T D R S)  c hart.  T he  pr oce d ure  use d  will  be  c o nsiste nt  wit h  t he  
rec o m me n dati o ns pr o vi de d f or usi n g t he E T D R S e ye c hart. V A s h o ul d be e val uate d at t he 
be gi n ni n g of eac h visit i n t he st u d y ( i.e., pri or t o slit-la m p e xa mi nati o n). V A testi n g s h o ul d 
be d o ne wit h m ost rece nt c orrecti o n. 
E q ui p me nt 
T he V A c hart t o be use d is t he E T D R S c hart. If s maller re pr o d ucti o n ( 1 8"  b y 1 8", e. g., 
fr o m Pre ve nt Bli n d ness) wall c harts are use d, t he s u bject vie wi n g dista nce s h o ul d be 
e xactl y  1 0  feet  ( or  as  s pecifie d  b y t he  ma n ufact urer).  I n  A L L  cases,  f or  p ur p oses  of 
sta n dar dizi n g t he testi n g c o n diti o ns d uri n g t he st u d y, all sites m ust use eit her Series 2 0 0 0 
C hart 1 or C hart 2 or  c hart ' R', a n d t he ri g ht e ye s h o ul d be teste d first. T he c hart s h o ul d 
re mai n t he sa me f or all visits at t he site. F or reflecta nce ( wall) c ha rts, t he c hart s h o ul d be 
place d fr o ntall y a n d well- ill u mi nate d. 
Meas ure me nt Tec h ni q ue  
T he c hart s h o ul d be at a c o mf orta ble vie wi n g a n gle. T he ri g ht e ye s h o ul d be teste d first. 
T he s u bject s h o ul d atte m pt t o rea d eac h letter, li ne - b y-li ne, left t o ri g ht, be gi n ni n g wit h 
li ne 1 at t he t o p of t he c hart. T he s u bject s h o ul d be t ol d t hat t he c hart has letters o nl y, n o 
n u m bers. If t he s u bject rea ds a n u m ber, he or s he s h o ul d be re mi n de d t hat t he c hart c o ntai ns 
n o n u m bers, a n d t he e xa mi ner s h o ul d t he n re q uest a letter i n lie u of t he n u m ber. T he s u bject 
s h o ul d be as ke d t o rea d sl o wl y, s o as t o ac hie ve t he best i de ntificati o n of eac h letter. He/s he 
is n ot t o pr ocee d t o t he ne xt letter u ntil he/s he has gi ve n a defi nite res p o nse. 
If t he s u bject c ha n ges a res p o nse (e. g., t hat was a " C" n ot a n " O") bef ore he has rea d al o u d 
t he ne xt letter, t he n t he c ha n ge m ust be acce pte d. If t he s u bject c ha n ges a res p o nse ha vi n g 
rea d t he ne xt letter, t he n t he c ha n ge is n ot t o be acce pte d. T he e xa mi ner s h o ul d ne ver p oi nt 
t o t he c hart or to s pecific letters o n t he c hart d uri n g t he test. 
A ma xi m u m eff ort s h o ul d be ma de t o i de ntif y eac h letter o n t he c hart. W he n t he s u bject 
sa ys he or s he ca n n ot rea d a letter, he or s he s h o ul d be e nc o ura ge d t o g uess. If t he s u bject 
i de ntifies a letter as 1 of 2 letters, he or s he s h o ul d be as ke d t o c h o ose 1 letter a n d, if 
necessar y, t o g uess. W he n it bec o mes e vi de nt t hat n o f urt her mea ni n gf ul rea di n gs ca n be 
ma de, des pite e nc o ura ge me nt t o rea d or g uess, t he e xa mi ner s h o ul d st o p t he test f or t hat 
e ye. H o we ver, all letters o n t he last li ne s h o ul d be atte m pte d as letter diffic ulties var y a n d 
t he last ma y be t he o nl y o ne rea d c orrectl y. T he n u m ber of letters misse d or rea d i nc orrectl y 
s h o ul d be n ote d. 
L o g M A R Vis ual Ac uit y Calc ulati o ns  
T he last li ne i n w hic h a lette r is rea d c orrectl y will be ta ke n as t he base l o g M A R rea di n g. 
T o t his val ue will be a d de d t he n u m ber " N x 0. 0 2" w here ' N' re prese nts t he t otal n u m ber 
of letters misse d u p t o a n d i ncl u de d i n t he last li ne rea d. T his t otal s u m re prese nts t he 
l o g M A R V A f or t hat e ye. 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 2  of 7 1  
 
F or e xa m ple: S u bject c orrectl y rea ds 4 of 5 letters o n t he 0. 2  li ne, a n d 2 of 5 letters o n t he 
0. 1 li ne. 
Base l o g M A R  
= 0. 1  
N (t otal n u m ber of letters i nc orrect o n li ne 0. 2 as well as 0. 1)  
= 4  
N x T ( T = 0. 0 2)  
= 0. 0 8  
Base l o g M A R + ( N x T)  
= 0. 1 + 0. 0 8  
l o g M A R V A 
= 0. 1 8  
Re peat t he pr oce d ure f or t he left e ye.  
I n or der t o pr o vi de sta n dar dize d a n d well-c o ntr olle d assess me nts of V A d uri n g t he st u d y, 
all V A assess me nts at a si n gle site m ust be c o nsiste ntl y d o ne usi n g t he sa me li g hti n g 
c o n diti o ns a n d sa m e c orrecti o n if p ossi ble d uri n g t he e ntire st u d y. If t he sa me c orrecti o n 
ca n n ot be use d ( i.e., a s u bject f or gets his glasses), t he reas o n f or t he c ha n ge i n c orrecti o n 
s h o ul d be d oc u me nte d. 
L E A S y m b ols Vis u al Ac uit y (f or s u bjects u n der t he a ge of 1 0 if nece ss ar y): 
Vis ual ac uit y testi n g is t o be perf or me d i n t he sa me ma n ner at eac h visit. T he L E A s y m b ols 
vis ual ac uit y c hart s h o ul d be use d f or s u bjects u n der t he a ge of 1 0 w he n necessar y. 
Mar k a s p ot o n t he fl o or (e. g. wit h ta pe) t hat is 1 0 feet ( 3 meters) fr o m t he b ott o m of t he 
wall wit h t he e ye c hart. T he test dista nce a n d ill u mi nati o n f or t he c hart m ust be ke pt 
c o nsta nt t hr o u g h o ut t he st u d y. 
First  esta blis h  a  met h o d  of  c o m m u nicati o n  s uc h  as  na mi n g  (si g ni n g)  or  p oi nti n g  
( matc hi n g). Deci de wit h t he c hil d w hic h na mes will be use d t o i de ntif y t he s y m b ols. 
Briefl y p oi nt t o t he first s y m b ol i n eac h li ne i n desce n di n g or der w he n testi n g bi n oc ularl y. 
D o n ot lea ve t he p oi nter cl ose t o t he s y m b ol beca use it ma kes fi xati o n easier, es peciall y i n 
case of a m bl y o pia, laz y e ye. If t he c hil d see ms t o ha ve diffic ulties i n k n o wi n g w hic h li ne 
t o l o o k at, c o ver t he li ne a b o ve t he li ne t o be rea d wit h a w hite car d lea vi n g a little of t he 
u p per li ne visi ble. 
M o ve d o w n u ntil t he c hil d hesitates or misi de ntifies a s y m b ol.  
M o ve bac k u p o ne li ne a n d as k t he c hil d t o i de ntif y all t he s y m b ols o n t hat li ne. 
If t he c hil d i de ntifies all s y m b ols c orrectl y g o t o t he ne xt li ne wit h s maller s y m b ols a n d 
as k t he c hil d t o i de ntif y all t he s y m b ols o n t hat li ne.  
If t he c hil d s ki ps a s y m b ol as k t he c hil d t o tr y a gai n w hile briefl y p oi nti n g t o t hat s y m b ol. 
A c hil d wit h a n a m bl y o pic e ye ma y t y picall y s ki p s y m b ols wit hi n a li ne of s y m b ols. 
 Vis ual ac uit y is rec or de d as t he last li ne o n w hic h at least 3 of t he 5 s y m b ols are 
i de ntifie d c orrectl y. 
W he n teste d 3 meters ( 1 0 feet), t he vis ual ac uit y val ue is f o u n d i n t he mar gi n a djace nt t o 
t hat li ne. S u bjects utilizi n g L E A s y m b ols m ust ha ve S nelle n e q ui vale nt u nits of 2 0/ 6 3 t o 
q ualif y. 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 5 3  of 7 1  
After o btai ni n g g o o d res p o nses wit h bi n oc ular testi n g, pr oc ee d b y testi n g eac h e ye 
se paratel y. 
W he n testi n g m o n oc ularl y, use t he first s y m b ol of eac h li ne or e ver y sec o n d li ne f or o ne 
e ye a n d t he last s y m b ol of eac h li ne f or t he ot her e ye t o deter mi ne o n w hic h li ne t o start 
testi n g. 
A ge -a p pr o priate vis ual ac uit y t est will be perf or me d. F or s u bjects u n der t he a ge of 1 0, 
w he n L E A S y m b ols ca n n ot be assesse d, t he cli nicia n ma y use a n alter nati ve met h o d t o 
e val uate vis ual ac uit y. Vis ual Be ha vi or (fi x a n d f oll o w, wi nce a n d n o wi nce) will be use d 
i n c hil dre n u na ble t o be teste d wit h t he S nelle n c hart. E ver y eff ort s h o ul d be ma de t o o btai n 
a V A meas ure me nt i n c hil dre n. T he sa me V A testi n g met h o d is t o be e m pl o ye d f or all 
st u d y visits f or eac h s u bject. Vis ual Be ha vi or is gra de d as a pass/fail test.  
Pre g n a nc y Testi n g  
Fe male s u bjects of c hil d beari n g p ote ntial will ha ve a uri ne pre g na nc y test rea d at t he site. 
Pre g na nc y tests ( Clarit y H C G uri ne test stri ps, R A C Me dical B oca Rat o n, F L) will be use d.  
Dil ate d F u n d osc o p y  
Dilate d f u n d us e xa ms will be perf or me d usi n g i n direct o p ht hal m osc o p y at Visit 1 ( Da y 1) 
a n d Visit 4 ( Da y 4 3 + 3). T he i n vesti gat or will ma ke o bser vati o ns of t he vitre o us, reti na, 
mac ula, c h or oi d a n d o ptic ner ve. 
O bser vati o ns will be gra de d as N or mal or A b n or mal. A b n or mal fi n di n gs t hat are cli nicall y 
si g nifica nt (as deter mi ne d b y t he i n vesti gat or t hat ma y i nterfere wit h st u d y para meters or 
ot her wise c o nf o u n d t he data) a n d t h ose t hat are n ot cli nicall y si g nifica nt will be d escri be d. 
A n i n direct F u n d osc o p y e xa mi nati o n s h o ul d be perf or me d if reti nal disease is detecte d. 
•
Vi tre o us: E xa mi nati o n s h o ul d e m p hasize t he vis ual a xis.
•
Reti na, Mac ula, C h or oi d:  I ncl u de a n o bser vati o n of t he reti na a n d its bl o o d vessels.
E yes (s u bject) s h o ul d be e xcl u de d fr o m t he st u d y if acti ve i nfla m mati o n is prese nt.
•
O ptic Ner ve:  Si g nifica nt da ma ge or c u p pi n g t o t he o ptic ner ve s h o ul d be n ote d.
It is rec o m me n de d t hat tr o pica mi de 1 % o p ht hal mic s ol uti o n be use d t o dilate s u bjects. T he 
use  of  c ycl o pe nt olate  1 %  o p ht hal mic  s ol uti o n  is  rec o m me n de d  as  sec o n dar y  dilati n g  
me dic ati o n, s h o ul d t he nee d arise.  
I ntr a oc ul ar Press ure 
A p pla nati o n  t o n o metr y,  G ol d ma n n  t o n o meter  re q uire d.  D o  N O T  use  n o n -c o ntact 
t o n o metr y.  It  is  rec o m me n de d  t hat  Fl uress®  (fl u orescei n  s o di u m  a n d  be n o xi nate  
h y dr oc hl ori de o p ht hal mic s ol uti o n U S P ) be use d as t he a nest hetic. It is rec o m me n de d t hat 
s u bjects s h o ul d wait a mi ni m u m of 1 0 mi n utes after i nstillati o n of Fl uress ®  bef ore i nstilli n g 
i n vesti gati o nal dr u g. 
I O P s h o ul d al ways be meas ure d/rec or de d bef ore p u pil dilati o n . 
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 7  of 7 1  
 
Vit al Si g ns  
Eac h s u bject will ha ve vital si g ns assess me nts (resti n g bl o o d press ure a n d p ulse) c o n d ucte d 
at Visits 1  a n d 4 (if e nr olle d). Vital si g ns are t o be c o n d ucte d b y q ualifie d staff me m ber 
w h o ma y be a n y of t he f oll o wi n g: a B oar d -certifie d I n vesti gat or or s u b -I n vesti gat or, N urse 
Practi tio ner , Re gistere d N urse, or P h ysicia n’s Assista nt . 
•  P ulse  ( b p m) 
P ulse will be meas ure d wit h t he s u bjects w h o ha ve bee n i n a resti n g state (seate d) 
f or at least 5 mi n utes. P ulse will be c o u nte d f or 3 0 sec o n ds a n d m ulti plie d b y 2, a n d 
rec or de d i n beats per mi n ute. 
It is rec o m me n de d t hat pe diatric s u bject’s p ulse  s h o ul d n ot be: 
•  < 6 0 (l o wer t ha n 6 0) b p m or > 1 3 0 ( hi g her t ha n 1 3 0) if s u bject is bet wee n 
t he a ges of 5 a n d 1 1 
•  < 5 0 (l o wer t ha n 5 0) b p m or > 1 2 0 ( hi g her t ha n 1 2 0) if s u bject is bet wee n t he 
a ges of 1 2 a n d 1 7  
•  S yst oli c/ Di ast olic Bl o o d Press ure ( m m H g)  
S yst olic a n d diast olic bl o o d press ure s h o ul d be meas ure d i n t he sa me ar m eac h ti me 
usi n g a s p h y g m o ma n o meter wit h t he s u bjects w h o ha ve bee n i n a resti n g  state 
(seate d u pri g ht) at least 5 mi n utes. Bl o o d press ure will be rec or de d i n m m H g. 
B o d y Wei g ht 
B o d y wei g h t will be meas ure d f or s u bjects ≤ 1 2 years of a ge a n d P K s u bjects o n  Visit 1. 
B o d y wei g h t is t o be meas ure d b y q ualifie d staff me m ber w h o ma y be a n y of t he f oll o wi n g: 
a B oar d-certifie d I n vesti gat or or s u b -I n vesti gat or, N urse Practiti o ner, Re gistere d N urse, or 
P h ysicia n’s Assista nt.  
P h ysic al E x a mi n ati o n  
Eac h s u bject will ha ve a p h ysical e xa mi nati o n c o n d ucte d at Visit 1 a n d Visit 4 (if e nr olle d).  
A p h ysical  e xa mi nati o n  ma y  be  c o n d ucte d  b y  a  B oar d -certifie d  I n vesti gat or  or  s u b -
I n vesti gat or, N urse Practitio ner or P h ysicia n’s Assista nt . T he p h ysical e xa mi nati o n will 
als o i ncl u de a n assess me nt of t he f oll o wi n g:  
•  Ge neral healt h  
•  Hea d, E yes, Ears, N ose, T hr o at ( H E E N T)  
•  C o m me nts  
S u bject - Re p orte d Dr o p C o mf ort: 
S u bjects t hat are at least 1 0 years of a ge will assess dr o p c o mf ort  f or eac h e ye i m me diatel y 
u p o n i nstillati o n, a n d at 3 0 sec o n ds, a n d at 1 mi n ute  f oll o wi n g i n-office d osi n g  usi n g t he 
 
 Scale: 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 8  of 7 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Or a pr o priet ar y sc ales – N ot f or distri b uti o n wit h o ut per missi o n  
 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 5 9  of 7 1  
 
A P P E N DI X 3 : S U B J E C T D O SI N G DI A RI E S  
S a m ple D osi n g Di ar y I nstr ucti o ns: 
Visits 1 -2 a n d 2 - 3 D osi n g Di ar y 
 
S u bject I niti als: _ _ _ _ _ _ _ _   
S u bject N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
D O SI N G  I N S T R U C TI O N S 
•  Please d ose O N E  ( 1) dr o p i n eac h e ye wit h t he st u d y dr o ps T W O  ( 2) ti mes a 
da y 7. 5 h o urs a part, starti n g t he m or ni n g after y o ur Visit 1 a p p oi nt me nt. Bel o w 
is a n e xa m ple of a d osi n g sc he d ule: 
o  D ose 1 ( 8: 0 0 A M) 
o  D ose 2 a p pr o xi matel y 8 h o urs after D ose 1 ( 4 : 0 0 P M) 
 
* * D O N O T  d ose a n y e arlier t h a n 7. 5 h o urs after  y o ur pre vi o us d ose * * 
 
•  Circle  Y E S  if d ose was t a ke n or c hec k N O  if d ose was n ot ta ke n 
•  Be s ure t o rec or d w hat ti me y o u t o o k y o ur d ose i n y o ur diar y 
•  Please c o m plete d osi n g u p t o y o ur ne xt sc he d ule d visit, D O N O T  d ose wit hi n 7 . 5 h o urs 
of y o ur ne xt a p p oi nt me nt. 
 
Pri nci pal I n vesti gat or Na me:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2 4- hr p h o ne n u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Visit _ _ _ _ A p p oi nt me nt:  
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Ti me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 0  of 7 1  
 
A P P E N DI X 3 ( C o nti n ue d)  
S u bject I niti als: _ _ _ _ _ _ _ _   
S u bject N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
G E N E R A L I N S T R U C TI O N S  
•  Use a bl ac k pe n  t o fill o ut y o ur diar y.  D O N O T  use w hite- o ut or pe ncil. 
•  E nter t he date f or eac h da y, i n t he f oll o wi n g f or mat: D D/ M M M/ Y Y Y Y.  
F or e x a m ple, J a n u ar y 1 0t h, 2 0 2 3 w o ul d be writte n as 1 0/ J A N/ 2 0 2 3.  
•  If y o u ma ke a n err or, dra w a SI N G L E LI N E  t hr o u g h t he err or, a n d t he n D A T E 
a n d I NI TI A L bel o w t he li ne. T he n e nter t he c orrect val ue or sc ore. 
 
•  Y o u s h o ul d kee p y o ur i n vesti gati o nal dr u g b ottles at r o o m te m perat ure ( 1 5- 2 5° 
[ 5 9-7 7° F]). K ee p t he b ottles o ut of s u nli g ht, a n d do n ot freeze or refri gerate t he 
i n vesti gati o nal dr u g. Please kee p t he b ottle ti g htl y cl ose d w he n n ot i n use. Kee p 
a wa y fr o m c hil dre n.  
•  Was h y o ur ha n ds t h or o u g hl y bef ore usi n g t he st u d y dr o ps. 
•  T o pre ve nt c o nta mi nati o n of t he b ottle a n d s ol uti o n, d o n ot t o uc h t he ti p of t he b ottle 
t o y o ur e ye, e yeli ds, s urr o u n di n g areas or ot her s urfaces. 
•  L o o k u p a n d ge ntl y p ull d o w n t he l o wer e ye li d wit h o ne ha n d. Wit h y o ur ot her ha n d,  
h ol d t he b ottle u psi de d o w n o ver eac h tar get e ye, a n d sl o wl y s q ueeze 1 dr o p o nt o t he 
l o wer s urface of eac h e ye. Ge ntl y cl ose y o ur e ye a n d all o w t he dr o p t o be a bs or be d.  
D O N O T  s q ueeze y o ur e yeli ds s h ut. 
•  If y o u wear c o ntact le nses, y o u m ust re m o ve t he m bef ore i nstillati o n of st u d y dru g a n d 
wait at least 1 0 mi n utes bef ore rei nserti n g c o ntact le nses.  
•  F or  pe diatric  s u bjects,  s u bject’s care gi ver or  s u bject’s  pare nt/le gal  g uar dia n  ca n 
pr o vi de res p o nse t o q uesti o ns , if a p plica ble. 
•  Y o u M U S T  bri n g bac k y o ur c o m plete d diar y a n d i n vesti gati o nal dr u g wit h y o u t o y o ur 
ne xt visit.  
 
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 2  of 7 1  
 
A P P E N DI X 3 ( C o nti n ue d)  
 
S a m ple D osi n g Di ar y I nstr ucti o ns:  
Visits 3 - 4 D osi n g Di ar y 
 
S u bject I niti als: _ _ _ _ _ _ _ _   
S u bject N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
D O SI N G  I N S T R U C TI O N S 
•  Please c o nti n ue t o d ose O N E  ( 1) dr o p i n eac h e ye wit h t he st u d y dr o ps T W O  
( 2) ti mes a da y 7. 5 h o urs a part. Bel o w is a n e xa m ple of a d osi n g sc he d ule:  
o  D ose 1 ( 8: 0 0 A M) 
o  D ose 2 a p pr o xi matel y 8 h o urs after D ose 1 ( 4 : 0 0 P M) 
 
* * D O N O T  d ose a n y e arlier t h a n 7. 5 h o urs fr o m y o ur pre vi o us d ose * * 
 
•  Circle  Y E S  if d ose was ta ke n or c hec k N O  if d ose was n ot ta ke n 
•  Be s ure t o rec or d w hat ti me y o u t o o k y o ur d ose i n y o ur diar y 
•  Please c o m plete d osi n g u p t o y o ur ne xt sc he d ule d visit, D O N O T  d ose t he da y of y o ur 
ne xt a p p oi nt me nt ( Visit 4). 
 
Pri nci pal I n vesti gat or Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2 4- hr p h o ne n u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Visit 4 A p p oi nt me nt:  
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Ti me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 3  of 7 1  
 
A P P E N DI X 3 ( C o nti n ue d)  
S u bject I niti als: _ _ _ _ _ _ _ _   
S u bject N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
G E N E R A L I N S T R U C TI O N S  
•  Use a bl ac k pe n  t o fill o ut y o ur diar y.  D O N O T  use w hite- o ut or pe ncil. 
•  E nter t he date f or eac h da y, i n t he f oll o wi n g f or mat: D D/ M M M/ Y Y Y Y. 
F or e x a m ple, J a n u ar y 1 0t h, 2 0 2 3 w o ul d be writte n as 1 0/ J A N/ 2 0 2 3.  
•  If y o u ma ke a n err or, dra w a SI N G L E LI N E  t hr o u g h t he err or, a n d t he n D A T E 
a n d I NI TI A L bel o w t he li ne.  T he n e nter t he c orrect val ue or sc ore. 
 
•  Y o u s h o ul d kee p y o ur i n vesti gati o nal dr u g b ottles at r o o m te m perat ure ( 1 5- 2 5° 
[ 5 9-7 7° F]). K ee p t he b ottles o ut of s u nli g ht, a n d do n ot freeze or refri gerate t he 
i n vesti gati o nal dr u g. Please kee p t he b ottle ti g htl y cl ose d w he n n ot i n use.  Kee p 
a wa y fr o m c hil dre n.  
•  Was h y o ur ha n ds t h or o u g hl y bef ore usi n g t he st u d y dr o ps. 
•  T o pre ve nt c o nta mi nati o n of t he b ottle a n d s ol uti o n, d o n ot t o uc h t he ti p of t he b ottle 
t o y o ur e ye, e yeli ds, s urr o u n di n g areas or ot her s urfaces. 
•  L o o k u p a n d ge ntl y p ull d o w n t he l o wer e ye li d wit h o ne ha n d. Wit h y o ur ot her ha n d,  
h ol d t he b ottle u psi de d o w n o ver eac h tar get e ye, a n d sl o wl y s q ueeze 1 dr o p o nt o t he 
l o wer s urface of eac h e ye. Ge ntl y cl ose y o ur e ye a n d all o w t he dr o p t o be a bs or be d.  
D O N O T  s q ueeze y o ur e yeli ds s h ut. 
•  If y o u wear c o ntact le nses, y o u m ust re m o ve t he m bef ore i nstillati o n of st u d y dr u g a n d 
wait at least 1 0 mi n utes bef ore rei nserti n g c o ntact le nses  
•  F or  pe diatric  s u bjects,  s u bject’s care gi ver or  s u bject’s  pare nt/le gal  g uar dia n  ca n 
pr o vi de res p o nse t o q uesti o ns , if a p plica ble. 
•  Y o u M U S T  bri n g bac k y o ur c o m plete d diar y a n d i n vesti gati o nal dr u g wit h y o u t o y o ur 
ne xt visit ( Visit 4). 
 
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 5  of 7 1  
 
A P P E N DI X 4: T A B L E O F FI F T H ( 5 T H) P E R C E N TI L E B O D Y W EI G H T S B Y 
A G E  
 
A ge i n  
ye ars  
Se x  
5 T H  Perce ntile  
B o d y Wei g ht  
 
 
K g  
L b  
5  
B o ys  
1 5. 2 3  
3 3. 5 8  
 
Girls  
1 4. 7 1  
3 2. 4 3  
6  
B o ys  
1 6. 9 3  
3 7. 3 2  
 
Girls  
1 6. 4 4  
3 6. 2 4  
7  
B o ys  
1 8. 7 4  
4 1. 3 1  
 
Girls  
1 8. 2 3  
4 0. 1 9  
8  
B o ys  
2 0. 6 6  
4 5. 5 5  
 
Girls  
2 0. 1 5  
4 4. 4 2  
9  
B o ys  
2 2. 7 1  
5 0. 0 7  
 
Girls  
2 2. 3 2  
4 9. 2 1  
1 0  
B o ys  
2 4. 9 3  
5 4. 9 6  
 
Girls  
2 4. 8 7  
5 4. 8 3  
1 1  
B o ys  
2 7. 5 0  
6 0. 6 3  
 
Girls  
2 7. 8 4  
6 1. 3 8  
1 2  
B o ys  
3 0. 5 5  
6 7. 3 5  
 
Girls  
3 1. 1 5  
6 8. 6 7  
 
htt p:// w w w.c dc. g o v/ gr o wt hc harts/ ht ml _c harts/ wta ge. ht m  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n , Nati o nal Ce nte r f or Healt h Statistics A u g ust 2 4, 2 0 0 1  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 6 6  of 7 1  
A P P E N DI X 5 : P R O T O C O L A M E N D M E N T S 
Secti o n  
P a ge  
Descri pti o n of C h a n ge  
R ati o n ale  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
C o n fi de ntial 
A me n d me nt 1  
 Pa ge 6 7  of 7 1  
A P P E N DI X 6: X A N T HI N E -C O N T AI NI N G B E V E R A G E S A N D P R O D U C T S  
C offee:  
All  met h o ds  of  pre parati o n:  dri p,  perc olate,  es press o,  etc.,  i nsta nt  or  
gr o u n d, re g ular or decaffei nate d. C o m merciall y pre pare d c offees (e. g., 
Café Vie n na, Café Fra ncais, etc.)  
Te a:  
All f or ms: re g ular, gree n, blac k, ora n ge, pe k oe, o ol o n g. All met h o ds of 
pre parati o n: stee pe d, bre we d, s u n tea, ice d tea, i nsta nt or bre we d, l o ose or 
ba g ge d teas, decaffei nate d teas.  
S oft Dri n ks:  
All dar k s o das a n d s o me li g hter s o das - re g ular, diet, a n d s u gar free: 
• C o ke/ Pe psi
• R C C ola
• Ora n ge/ Slice
• Mr. Pi b b
• Ta b
• M o u ntai n De w
• Dr. Pe p per
• C h o c olate S o da
• R o ot Beer
Mil k:  
Mil k pr o d ucts c o ntai ni n g c h oc olate (c h oc olate s ha kes, malts, ice -crea m, 
a n d c oc oa)  
B ottle d W ater:   
A q ua J oe  
B a ke d G o o ds:  
C h oc olate  ba ke d  g o o ds,  s uc h  as  De vil’s  F o o d  ca kes,  c h oc olate  c hi p  
c o o kies, Ore o or sa n d wic h t y pe c o o kies, c h oc olate c ustar ds, fr osti n gs, 
ici n gs, etc. 
S n ac ks or Tre ats:  
A n y c h oc olate c o ntai ni n g desserts ( m o usse, p u d di n gs, y o g urts, m oc ha 
pr o d ucts, etc.) or ca n dies c o vere d wit h or c o ntai ni n g c h oc olate.  
N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 6 8  of 7 1  
 
A P P E N DI X 7 : B L O O D C O L L E C TI O N, H A N D LI N G, A N D S HI P M E N T F O R 
P H A R M A C O KI N E TI C A N A L Y SI S   
See se parate La b Ma n ual f or P K bl o o d c ollecti o n, ha n dli n g, a n d s hi p me nt details. 
  
 
N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


N C T 0 5 8 1 5 7 5 8


Bri m o ni di ne Tartr ate 0. 0 2 5 %/ Ket otife n F u marate 0. 0 3 5 %  O p ht hal mic S ol uti o n  
 
Ba usc h & L o m b  I nc or p orate d 
Cli nical Trial Pr ot oc ol: 9 1 3 
0 7 J ul  2 0 2 3 
 
C o nfi de ntial  
A me n d me nt 1                                                                                                                                Pa ge 7 1  of 7 1  
 
A P P E N DI X 1 0 : I N V E S TI G A T O R’ S SI G N A T U R E 
 
Pr ot oc ol Title:  
A M ulti -Ce nter, D o u ble -Mas ke d, Ra n d o mize d, Ve hicle -
C o ntr olle d, Parallel - Gr o u p St u d y E val uati n g t he Safet y a n d 
P har mac o ki netics of Bri m o ni di ne Tartrate 0. 0 2 5 %/ Ket otife n 
F u marate 0. 0 3 5 % C o m bi nati o n O p ht hal mic S ol uti o n, Use d 
T w o Ti mes Dail y i n Healt h y A d ult S u bjects a n d i n Pe diatric 
S u bjects wit h a Hi st or y or Fa mil y Hist or y of At o pic Disease 
(i ncl u di n g Aller gic C o nj u ncti vitis) 
Pr ot oc ol N u m ber:  
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
Fi n al D ate:  
0 7 J ul  2 0 2 3  
I a gree t o i m ple me nt a n d c o n d uct t he st u d y dili ge ntl y a n 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. I a gree t o mai ntai n 
all i nf or mati o n s u p plie d b y Ora a n d t he s p o ns or 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), Et hical Re vie w C o m mittee ( E R C) or 
a n ot her gr o u p, it will be s u b mitte d wit h a desi g nati o n t hat t he material is c o nfi de ntial.  
I ha ve rea d t his pr ot oc ol i n its e ntiret y, i ncl u di n g t he a b o ve state me nt, a n d I a gree t o all 
as pects. 
Si g ne d:  
 
 
Date:    
 
<e nter na me a n d cre de ntials >  
<e nter title >  
<e nter affiliati o n >  
<e nter a d dress >  S pecif y a d dress a n d p h o ne n u m ber f or eac h st u d y l ocati o n. 
<e nter p h o ne n u m ber > 
N C T 0 5 8 1 5 7 5 8

SAP_001.pdf: 
N  C T  0 5 8 1 5 7  5 8  
F O R  M. 1 5 2. 0 6  
S T  A TI  S TI  C  A L   A  N  A L  Y  SI  S   P L  A  N    
A     M ulti  -C e nt er,     D o u bl e  -M a s k e d,     R a n d o  mi z e d,     V e hi cl e  -C o ntr oll e d, 
P ar all el  -Gr o u p    St u d y    E v al u ati n g  t h e    S af et y   a n d    P h ar  m a c o ki n eti c s   of  
Bri  m o ni di n e  T artr at e  0. 0 2 5  %/  K et otif e n  F u  m ar at e   0. 0 3 5  %   C o  m bi n ati o n 
O p ht h al  mi c   S ol uti o n,   U s e d  T  w o  Ti  m e s   D ail y i n   H e alt h y   A d ult   S u bj e ct s 
a n d  i n    P e di atri c    S u bj e ct s    wit h   a    Hi st or y   or   F a  mil y    Hi st or y   of    At o pi c  
Di s e a s e (i n cl u di n g   All er gi c   C o nj u n cti viti s)   
 
 
 
S p o n s or:      
   
B a u s c h   &  L o  m b I n c or p or at e d   
    
    
   
4 0 0   S o  m er s et   C or p or at e   B o ul e v ar d  
Bri d g e  w at er,   N J  0 8 8 0 7   
 
 
Pr ot o c ol   N u  m b er:     
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
 
 
A ut h or:       
 
 
    
    
 
 
St ati sti c s   &   D at a   C or p or ati o n   
 
D at e:          
   
2 9  S  E  P 2 0 2 3  
V er si o n:      
   
1. 0  
 


N  C T  0 5 8 1 5 7  5 8  
 
 
P a g e  2  of  2 9  
A   M ulti  -C e nt er,   D o u bl e  -M a s k e d,   R a n d o  mi z e d,   V e hi cl e  -C o ntr oll e d,   P ar all el  -Gr o u p   St u d y   E v al u ati n g 
t h e    S af et y   a n d    P h ar  m a c o ki n eti c s   of    Bri  m o ni di n e   T art r at e   0. 0 2 5  %/  K et otif e n   F u  m ar at e   0. 0 3 5  %  
C o  m bi n ati o n   O p ht h al  mi c   S ol uti o n,   U s e d  T  w o  Ti  m e s   D ail y i n   H e alt h y   A d ult   S u bj e ct s  a n d i n   P e di at ri c 
S u bj e ct s   wit h  a   Hi st o r y  or  F a  mil y   Hi st or y   of   At o pi c   Di s e a s e (i n cl u di n g   All er gi c   C o nj u n cti viti s)   
Pr ot o c ol   N u  m b er:     
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
 
S  A  P   V er si o n:        
1. 0  
S  A  P   D at e:      
   
2 9  S  E  P 2 0 2 3  
 
St ati sti c al   A n al y si s   Pl a n   A p pr o v al   
 
 
 
Pr e p ar e d  b y:       
    
 
   
    
    
 
 
    
 
 
    
 
 
 
 
 
 
R e vi e  w e d  b y:      
 
    
 
    
   
   
 
 
    
 
 
    
 
 
 
 
 
 
A p pr o v e d  b y:      
 
    
 
    
    
    
    
  
 
 
    
 
 
 
 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
 
 
P a g e  3  of  2 9  
 
A   M ulti  -C e nt er,   D o u bl e  -M a s k e d,   R a n d o  mi z e d,   V e hi cl e  -C o ntr oll e d,   P ar all el  -Gr o u p   St u d y   E v al u ati n g 
t h e    S af et y   a n d    P h ar  m a c o ki n eti c s   of    Bri  m o ni di n e   T art r at e   0. 0 2 5  %/  K et otif e n   F u  m ar at e   0. 0 3 5  %  
C o  m bi n ati o n   O p ht h al  mi c   S ol uti o n,   U s e d  T  w o  Ti  m e s   D ail y i n   H e alt h y   A d ult   S u bj e ct s  a n d i n   P e di at ri c 
S u bj e ct s   wit h  a   Hi  st o r y  or  F a  mil y   Hi st or y  of   At o pi c   Di s e a s e (i n cl u di n g   All er gi c   C o nj u n cti viti s)   
Pr ot o c ol   N u  m b er:     
9 1 3/ 2 2 -1 0 0 -0 0 0 6  
 
S  A  P   V er si o n:        
1. 0  
S  A  P   D at e:      
   
2 9  S  E  P 2 0 2 3  
 
 
 
R e vi e  w e d  b y:      
    
 
    
   
   
 
 
    
 
 
    
 
 
 
 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   4  of  2 9  
T a bl e  of   C o nt e nt s  
T a bl e  of   C o nt e nt s  ................................................................................................................................. 4 
Li st  of   A b br e vi ati o n s  ............................................................................................................................. 6 
1.  
I ntr o d u cti o n ............................................................................................................................ 8 
2.  
St u d y   O bj e cti v e s   .................................................................................................................... 8 
2. 1  
St u d y   V ari a bl e s   ................................................................................................................ 8 
2. 2  
S af et y   V ari a bl e s   ............................................................................................................... 8 
2. 3  
T ol er a bilit y   V ari a bl e s  ........................................................................................................ 8 
2. 4  
P h ar  m a c o ki n eti c   V ari a bl e s   ............................................................................................... 9 
3.  
St u d y   D e si g n  a n d   Pr o c e d ur e s   ............................................................................................... 9 
3. 1  
G e n er al   St u d y   D e si g n   ...................................................................................................... 9 
3. 2  
S c h e d ul e  of   Vi sit s  a n d   A s s e s s  m e nt s   ............................................................................... 9 
3. 3  
St u d y  Tr e at  m e nt s   ........................................................................................................... 1 1  
4.  
S a  m pl e   Si z e   ........................................................................................................................ 1 1  
5.  
D at a   Pr e p ar ati o n   ................................................................................................................. 1 2  
5. 1  
I n p ut   D at a ....................................................................................................................... 1 2  
5. 2  
O ut p ut   D at a   .................................................................................................................... 1 2  
6.  
A n al y si s   P o p ul ati o n s   ........................................................................................................... 1 2  
6. 1  
S af et y   .............................................................................................................................. 1 2  
6. 2  
P h ar  m a c o ki n eti c   ............................................................................................................. 1 2  
7.  
G e n er al   St ati sti c al   C o n si d er ati o n s   ...................................................................................... 1 3  
7. 1  
U nit  of   A n al y si s   ............................................................................................................... 1 3  
7. 2  
Mi s si n g  or I n c o n cl u si v e   D at a   H a n dli n g   .......................................................................... 1 3  
7. 3  
D efi niti o n  of   B a s eli n e   ...................................................................................................... 1 4  
7. 4  
D at a   A n al y si s   C o n v e nti o n s   ............................................................................................. 1 4  
7. 5  
A dj u st  m e nt s f or   M ulti pli cit y   ............................................................................................. 1 4  
8.  
Di s p o siti o n  of   S u bj e ct s   ........................................................................................................ 1 4  
9.  
D e  m o gr a p hi c  a n d   B a s eli n e   Di s e a s e   C h ar a ct eri sti c s   .......................................................... 1 5  
9. 1  
D e  m o gr a p hi c   V ari a bl e s   .................................................................................................. 1 5  
9. 2  
B a s eli n e   Di s e a s e   C h ar a ct eri sti c s   ................................................................................... 1 6  
1 0.  
M e di c al   Hi st or y  a n d   C o n c o  mit a nt   M e di c ati o n s   ................................................................... 1 6  
1 0. 1  
M e di c al   Hi st or y   ............................................................................................................... 1 6  
1 0. 2  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o n s   ............................................................................... 1 6  
1 1.  
D o si n g   C o  m pli a n c e  a n d  Tr e at  m e nt   E x p o s ur e   .................................................................... 1 7  
1 1. 1  
D o si n g   C o  m pli a n c e   ........................................................................................................ 1 7  
1 1. 2  
Tr e at  m e nt   E x p o s ur e  ....................................................................................................... 1 8  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   5  of  2 9  
1 2.  
P h ar  m a c o ki n eti c   A n al y s e s   .................................................................................................. 1 8  
1 3.  
S af et y   A n al y s e s   ................................................................................................................... 1 9  
1 3. 1  
A d v er s e   E v e nt s   .............................................................................................................. 1 9  
1 3. 2  
B e st  -C orr e ct e d   Vi s u al   A c uit y   .......................................................................................... 2 1  
1 3. 3  
Slit  -L a  m p   Bi o  mi cr o s c o p y  ................................................................................................ 2 1  
1 3. 4  
I ntr a o c ul ar   Pr e s s ur e ....................................................................................................... 2 2  
1 3. 5  
Dil at e d   F u n d o s c o p y   E x a  mi n ati o n  ................................................................................... 2 3  
1 3. 6  
P h y si c al   E x a  mi n ati o n   ..................................................................................................... 2 3  
1 3. 7  
Vit al   Si g n s   ....................................................................................................................... 2 3  
1 3. 8  
Dr o p   C o  mf ort   A s s e s s  m e nt   ............................................................................................. 2 3  
1 3. 9  
Pr e g n a n c y  T e st   .............................................................................................................. 2 4  
1 4.  
I nt eri  m   A n al y s e s .................................................................................................................. 2 4  
1 5.  
C h a n g e s fr o  m   Pr ot o c ol  -St at e d   A n al y s e s   ............................................................................ 2 4  
1 6.  
R ef er e n c e s   .......................................................................................................................... 2 4  
1 7.  
R e vi si o n   Hi st or y   ................................................................................................................... 2 4  
1 8.  
T a bl e s  .................................................................................................................................. 2 4  
1 9.  
Li sti n g s  ................................................................................................................................ 2 7  
2 0.  
Fi g ur e s  ................................................................................................................................. 2 8  
 
 
 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   6  of  2 9  
Li st  of   A b br e vi ati o n s  
A b br e vi ati o n   
D efi niti o n   
A  D a  M   
A n al y si s   D at a   M o d el   
A  E   
A d v er s e   E v e nt   
A T  C   
A n at o  mi c al  T h er a p e uti c   C h e  mi c al   
A  U  C 0-t  
Ar e a  u n d er t h e   Pl a s  m a   Dr u g   C o n c e ntr ati o n  -Ti  m e   C ur v e fr o  m  Ti  m e  0 t o t h e 
l a st q u a ntifi a bl e   Dr u g   C o n c e ntr ati o n  
A  U  C 0- 4 h  
Ar e a  u n d er t h e   Pl a s  m a   Dr u g   C o n c e ntr ati o n  -Ti  m e   C ur v e fr o  m  Ti  m e  0 
t hr o u g h  4  h 
B  C  V  A   
B e st  -C orr e ct e d   Vi s u al   A c uit y   
BI  D   
Bi s i n  di e   (T wi c e   D  ail y)  
B L  Q   
B el o  w t h e  Li  mit  of   Q u a ntit ati o n   
C o  m b o   
Bri  m o ni di n e  T artr at e  0. 0 2 5  %/  K et otif e n  F u  m ar at e  0. 0 3 5  %   C o  m bi n ati o n 
O p ht h al  mi c   S ol uti o n   
CI   
C o nfi d e n c e I nt er v al   
C m a x  
M a xi  m u  m   O b s er v e d   Pl a s  m a   C o n c e ntr ati o n   
C mi n  
Mi ni  m u  m   O b s er v e d   Pl a s  m a   C o n c e ntr ati o n   
C  S   
Cli ni c all y   Si g nifi c a nt   
C  V   
C o effi ci e nt  of   V ari ati o n   
e  C  R F  
El e ctr o ni c   C a s e   R e p ort  F or  m   
E  D  C   
El e ctr o ni c   D at a   C a pt ur e   
E T  D  R  S   
E arl y  Tr e at  m e nt  of   Di a b eti c   R eti n o p at h y   St u d y   
I  C F 
I nf or  m e d   C o n s e nt  F or  m 
I  C  H 
I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o ni s ati o n 
I  O  P 
I ntr a o c ul ar   Pr e s s ur e 
l o gM  A  R   
L o g arit h  m  of t h e   Mi ni  m u  m   A n gl e  of  R e s ol uti o n   
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti e s   
N  C  S   
N ot   C  li ni c all y S  i g nifi c a nt 
P  D F   
P ort a bl e   D o c u  m e nt  F or  m at   
P  K   
P h ar  m a c o ki n eti c( s)   
P T   
Pr ef err e d  T er  m   
R T F   
Ri c h  T e xt  F or  m at   
R A  U  C  
A c c u  m ul ati o n   R ati o  of   A  U  C 0-t  at   St e a d y -St at e t o   A  U  C 0-t  aft er t h e  Fir st   D o s e  
R C  m a x  
A c c u  m ul ati o n   R ati o  of   C m a x  at   St e a d y -St at e t o   C m a x  aft er t h e  Fir st   D o s e  
R T  S  M   
R a n d o  mi z ati o n  a n d  Tri al   S u p pl y   M a n a g e  m e nt   
S  A  E   
S eri o u s   A d v er s e   E v e nt   
S  A  P   
St ati sti c al   A n al y si s   Pl a n   
S  D   
St a n d ar d   D e vi ati o n   
S  D  C   
St ati sti c s   &   D at a   C or p or ati o n   
S  D T  M   
St u d y   D at a  T a b ul ati o n   M o d el   
S  E  M   
St a n d ar d   Err or  of t h e   M e a n   
S  O  C   
S y st e  m   Or g a n   Cl a s s   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   7  of  2 9  
A b br e vi ati o n   
D efi niti o n   
T  E  A  E  
Tr e at  m e nt -E  m er g e nt   A d v er s e   E v e nt   
T m a x  
Ti  m e  of   M a xi  m u  m   O b s er v e d   Pl a s  m a   C o n c e ntr ati o n   
W  H  O  D  r u g 
W orl d   H e alt h   Or g a ni z ati o n   Dr u g   Di cti o n ar y   
 
 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   8  of  2 9  
1.    I ntr o d u cti o n 
T h e  p ur p o s e  of t hi s  st ati sti c al  a n al y si s  pl a n (  S  A  P) i s t o  d e s cri b e  i n  d et ail t h e  pl a n n e d  a n al y s e s  a n d r e p orti n g 
f or   pr ot o c ol   9 1 3/ 2 2-1 0 0 -0 0 0 6 ,    A  m e n d  m e nt  1. 0   d at e d   0 7 J  U L 2 0 2 3 .   Th e   st ati sti c al   a n al y si s    m et h o d s  
pr e s e nt e d i n t hi s  d o c u  m e nt   will  s u p er s e d e t h e  st ati sti c al  a n al y si s   m et h o d s  d e s cri b e d i n t h e  cli ni c al  pr ot o c ol.  
If  a d diti o n al  a n al y s e s  ar e r e q uir e d t o  s u p pl e  m e nt t h e  pl a n n e d  a n al y s e s  d e s cri b e d i n t hi s   S  A  P, t h e y   m a y  b e 
c o  m pl et e d  a n d   will  b e i d e ntifi e d i n t h e  cli ni c al  st u d y r e p ort.  
T hi s    S  A  P  i s   b ei n g    writt e n    wit h   d u e   c o n si d er ati o n   of  t h e  r e c o  m  m e n d ati o n s   o utli n e d  i n  t h e    m o st  r e c e nt  
I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o nis ati o n (I  C  H)   E 9   G ui d eli n e  e ntitl e d   G ui d a n c e f or I n d u str y:   St ati sti c al 
Pri n ci pl e s f or   Cli ni c al  Tri al s   a n d t h e   m o st r e c e nt I  C  H   E 3   G ui d eli n e  e ntitl e d   G ui d a n c e f or I n d u str y:   Str u ct ur e 
a n d   C o nt e nt  of   Cli ni c al   St u d y   R e p ort s.  
2.    St u d y   O bj e cti v e s   
T h e   pri  m ar y   o bj e cti v e  i s  t o   c o  m p ar e  t h e   s af et y   a n d  t ol er a bilit y   of   bri  m o ni di n e  t artr at e   0. 0 2 5  %/ k et otif e n  
f u  m ar at e 0. 0 3 5  %  c o  m bi n ati o n  o p ht h al  mi c  s ol uti o n  (C o  m b o  ) v er s u s it s  v e hi cl e i n  h e alt h y  a d ult  s u bj e ct s  a n d 
i n  p e di atri c  s u bj e ct s   wit h  a  hi st or y  or f a  mil y  hi st or y  of  at o pi c  di s e a s e (i n cl u di n g  all er gi c  c o nj u n cti viti s).  
T h e  s e c o n d ar y  o bj e cti v e i s t o  c h ar a ct eri z e t h e  pl a s  m a   P  K  of   C o  m b o   f oll o  wi n g  a  si n gl e  d o s e  a n d  2 2-d a y 
t  wi c e  d ail y (  BI  D) t o pi c al  o c ul ar  d o si n g i n  a  s u b s et  of  h e alt h y  a d ult  s u bj e ct s. 
2. 1    
St u d y   V ari a bl e s   
T h er e  ar e  n o  effi c a c y  v ari a bl e s  or  e n d p oi nt s i n t hi s   P h a s e  3  s af et y  st u d y .  
2. 2    
S af et y   V ari a bl e s   
T h e  v ari a bl e s  t o  a s s e s s  s af et y ar e t h e f oll o  wi n g:   
•    A d v er s e  e v e nt s (  A  E s; r e p ort e d,  eli cit e d,  a n d  o b s er v e d)   
•    Uri n e   Pr e g n a n c y  T e st   
•    B e st  -C orr e ct e d   Vi s u al   A c uit y   (  B  C  V  A)  u si n g  a n   E arl y  Tr e at  m e nt  of   Di a b eti c   R eti n o p at h y   St u d y 
(  E T  D  R  S)  c h art 
•    Slit  L a  m p   Bi o  mi cr o s c o p y   
•    I ntr a o c ul ar   Pr e s s ur e (I  O  P; t o  b e  p erf or  m e d  o n  s u bj e ct s  ≥  1 0  y e ar s  a g e) 
•    P h y si c al   E x a  mi n ati o n   
•    Vit al   Si g n s   
•    Dil at e d  F u n d u s   E x a  mi n ati o n  .  
2. 3    
T ol er a bilit y   V ari a bl e s  
T ol er a bilit y  m e a s ur e s   will  b e  a s s e s s e d  b y  dr o p  c o  mf ort  a s s e s s  m e nt  .  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e   9  of  2 9  
2. 4    
P h ar  m a c o ki n eti c   V ari a bl e s   
T h e  v ari a bl e s  f or   P  K  a n al y si s   will  b e  bl o o d  s a  m pl e s  c oll e ct e d fr o  m t h e   P  K  p o p ul ati o n  at  pr e-d o s e,  0. 2 5 ( ± 3 
mi n),  0. 5 ( ± 5   mi n),  1 ( ± 1 0   mi n),  2 ( ± 1 0   mi n),  a n d  4 ( ± 2 0   mi n)  h o ur s f oll o  wi n g t h e fir st t o pi c al  o c ul ar   i n still ati o n 
of   C o  m b o  or  v e hi cl e  o n   D a y  1  a n d  al s o  o n   D a y  2 2 t o   m e a s ur e t h e  pl a s  m a  c o n c e ntr ati o n s  of  bri  m o ni di n e 
a n d  k et otif e n.   
If  t h e   d at a   all o  w,  th e   f oll o  wi n g    P  K   p ar a  m et er s    will   b e   e sti  m at e d:    Cm a x ,    Cmi n ,   Tm a x ,    A  U  C0-t ,    A  U  C0- 4 h ,   a n d 
a c c u  m ul ati o n r ati o (  R C  m a x  a n d   R A  U  C ). 
3.    St u d y   D e si g n  a n d   Pr o c e d ur e s   
3. 1    
G e n er al   St u d y   D e si g n   
T hi s  i s   a    m ulti -c e nt er,   d o u bl e -m a s k e d,  r a n d o  mi z e d,   v e hi cl e  -c o ntr oll e d,   p ar all el -gr o u p,   s af et y   st u d y.  
A p pr o xi  m at el y    6 0 0    s u bj e ct s     will    b e    s cr e e n e d   i n    or d er   t o    e nr oll    a p pr o xi  m at el y     5 0 1    s u bj e ct s   fr o  m   
a p pr o xi  m at el y   6   sit e s.    Of  t h e   s u bj e ct  t ot al,   a p pr o xi  m at el y   1 0 0   p e di atri c   s u bj e ct s   ar e   a nti ci p at e d  t o   b e  
e nr oll e d i nt o t hi s  st u d y.  
T h e  a g e  cl a s sifi c ati o n f or t h e  p e di atri c  p o p ul ati o n   will  b e  a p pr o xi  m at el y  5 0  s u bj e ct s i n   e a c h  of t h e f oll o  wi n g 
gr o u p s:   
•     5-1 2  y e ar s  ol d  
•    1 3 -1 7  y e ar s  ol d  
S u bj e ct s   will  n ot  b e  str atifi e d  b y  a g e  gr o u p   w h e n  a s si g n e d t o i n v e sti g ati o n al  pr o d u ct.    
A  s u b s et  of  u p t o  2 5  h e alt h y  a d ult  s u bj e ct s ( ~ 1 6  s u bj e ct s f or t h e i n v e sti g ati o n al  pr o d u ct  a n d  ~ 9  s u bj e ct s f or 
t h e  v e hi cl e)   will  u n d er g o   P  K  bl o o d  dr a  w s t o  a s s e s s t h e  s y st e  mi c  e x p o s ur e  of  bri  m o ni di n e  a n d  k et otif e n. 
T h e  s u bj e ct, t h e  s u bj e ct’ s  c ar e gi v er,  or t h e  s u bj e ct’ s  p ar e nt/l e g al  g u ar di a n (if  a p pli c a bl e, f or  s u bj e ct s l e s s 
t h a n  1 8  y e ar s  of  a g e)   will i n still  1  dr o p  of t h e  a s si g n e d i n v e sti g ati o n al  dr u g i n  e a c h  e y e   BI  D a p pr o xi  m at el y 
7. 5  h o ur s  a p art f or  u p t o  6  c o n s e c uti v e   w e e k s.  
S u bj e ct s   will  h a v e  vi sit s  o n   D a y  1 (  Vi sit  1),   D a y  8 (  Vi sit  2),   D a y  2 2 (  Vi sit  3)   a n d  D a y  4 3 (  Vi sit  4) f or  s af et y 
e v al u ati o n s  
3. 2    
S c h e d ul e  of   Vi sit s  a n d   A s s e s s  m e nt s   
T h e  s c h e d ul e  of  vi sit s  a n d  a s s e s s  m e nt s i s  pr o vi d e d i n  T a bl e  1.   
 
 




Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 1   of  2 9  
V  A   will  b e   m a d e  b y  u si n g  a  L  E  A  s y  m b ol s  V  A  c h art (  m e a s ur e d  a s  S n ell e n  e q ui v al e nt  u nit s). If   s u bj e ct r e q uir e s   Vi s u al   B e h a vi or, t h e y 
m u st  h a v e  a  p a s si n g  s c or e.   
6.   E v al u at e d  pri or t o  a n d  1 5   mi n ut e s ( +  3   mi n ut e s)  p o st I  P i n still ati o n  at  Vi sit s  1  -3,  a n d  o n c e  at   Vi sit  4.  
7.   A g e  >  1 0  y e ar s  ol d.   
8.   S u bj e ct s   a n d/ or   s u bj e ct’ s   p ar e nt/l e g al   g u ar di a n    will  i n still  I  P   at    Vi sit   1   a n d    will   b e   o b s er v e d   b y   a  tr ai n e d   st u d y  t e c h ni ci a n  .   T h e  
s u bj e ct s  e nr oll e d t o t h e   P  K  st u d y   will r e c ei v e  1  dr o p  of t h e  a s si g n e d I  P i nt o  e a c h  e y e fr o  m  a tr ai n e d t e c h ni ci a n.  
9.   S u bj e ct s  ≥  1 0  y e ar s  ol d   will  a s s e s s  c o  mf ort i  m  m e di at el y  u p o n i n still ati o n,  at  3 0  s e c o n d s,  a n d  at  1  -mi n ut e  p o st  -i n still ati o n  u si n g  a 
 f or  e a c h  e y e.  S u bj e ct s  <  1 0  y e ar s  ol d   will  n ot  a s s e s s  dr o p  c o  mf ort. 
1 0.  ( For  s u bj e ct s  a gr e ei n g t o  u n d er g o  P  K  bl o o d  dr a  w s)   Pr e -d o s e (  wit hi n  1  h o ur  pri or t o  d o si n g)  a n d  at  0. 2 5 ( ± 3   mi n)  h o ur,  0. 5 ( ± 5   mi n) 
h o ur,  1 ( ± 1 0   mi n)  h o ur,  2 ( ± 1 0   mi n)  h o ur s,  a n d  4 ( ± 2 0   mi n)  h o ur s  aft er t h e fir st  st u d y  dr u g  a d  mi ni str ati o n i n t h e   m or ni n g  o n   D a y  1 
a n d  o n   D a y  2 2.  
1 1.  A  n e  w  kit i s  di s p e n s e d  at   Vi sit  1  a n d   Vi sit  3.   At  Vi sit  2, t h e  kit t h at   w a s  di s p e n s e d  at   Vi sit  1 i s r e  -di s p e n s e d f or  d o si n g  u ntil   Vi sit  3.  
1 2.  A  n e  w  d o si n g  di ar y   will  b e  di stri b ut e d  at  Vi sit s  1,  2,  a n d  3.   
3. 3    
St u d y  Tr e at  m e nt s   
T h e tr e at  m e nt s f or t hi s  st u d y  ar e:  
•    Bri  m o ni di n e t artr at e  0. 0 2 5  % /  k et otif e n f u  m ar at e  0. 0 3 5  %  c o  m bi n ati o n  o p ht h al  mi c  s ol uti o n (  C o  m b o) 
( n = 3 3 4) 
•    V e hi cl e  o p ht h al  mi c  s ol uti o n ( n = 1 6 7)   
All  s u bj e ct s  s cr e e n e d f or t h e  st u d y   w h o  si g n  a n i nf or  m e d  c o n s e nt f or  m (  I  C F)  will  b e  a s si g n e d  a  s u bj e ct 
n u  m b er t h at   will  b e  e nt er e d i n t h e   S cr e e ni n g  a n d   E nr oll  m e nt  L o g.  T h e  s u bj e ct  n u  m b er   will  c o n si st  of t h e 
t hr e e-( 3)-di git  sit e  n u  m b er, f oll o  w e d  b y t h e t hr e e -( 3)-di git  u ni q u e  s u bj e ct i d e ntifi er,  st arti n g   wit h  0 0 1.  
O n c e  a  s u bj e ct   m e et s  all  q u alifi c ati o n  crit eri a  at   Vi sit  1,   th e y  will  b e r a n d o  mi z e d t o   C o  m b o   or  v e hi cl e i n  a 
2: 1  r ati o.    E a c h   s u bj e ct    w h o  i s  r a n d o  mi z e d    will   b e   a s si g n e d   a   u ni q u e   ra n d o  mi z ati o n   n u  m b er  i n  t h e  
R a n d o  mi z ati o n  a n d  Tri al   S u p pl y   M a n a g e  m e nt (  R T  S  M)   s y st e  m .   R a n d o  mi z ati o n  n u  m b er s   will  b e  a s si g n e d 
i n   a   s e q u e nti al   or d er   st arti n g   at  t h e  l o  w e st   n u  m b er   a v ail a bl e.    N o   n u  m b er s    will   b e   s ki p p e d   or   o  mitt e d.  
R a n d o  mi z ati o n  n u  m b er s   will  b e  5  di git s  a n d   will  b e  cr e at e d i n t h e   R T  S  M   s y st e  m .   R a n d o  mi z ati o n   will  b e 
u s e d t o  a v oi d  bi a s i n t h e  a s si g n  m e nt  of  s u bj e ct s t o tr e at  m e nt, t o i n cr e a s e t h e li k eli h o o d t h at  k n o  w n  a n d 
u n k n o  w n  s u bj e ct  attri b ut e s ( e. g.,  d e  m o gr a p hi c s  a n d  b a s eli n e  c h ar a ct eri sti c s)  ar e  e v e nl y  b al a n c e d  a cr o s s 
t h e    R T  S  M  tr e at  m e nt   gr o u p s,   a n d  t o   e n h a n c e  t h e   v ali dit y   of   st ati sti c al   c o  m p ari s o n s  b et  w e e n   tr e at  m e nt 
gr o u p s.   M a s k e d tr e at  m e nt   will  b e  u s e d t o r e d u c e  p ot e nti al  bi a s  d uri n g  d at a  c oll e cti o n  a n d  e v al u ati o n  of 
cli ni c al  e n d p oi nt s.  
4.    S a  m pl e   Si z e   
A t ot al  of   5 0 1  s u bj e ct s   will  b e r a n d o  mi z e d  yi el di n g  a p pr o xi  m at el y  3 3 4  s u bj e ct s r a n d o  mi z e d t o  C o  m b o   a n d 
1 6 7  s u bj e ct s r a n d o  mi z e d t o  v e hi cl e.  T hr e e -h u n dr e d t hirt y -f o ur ( 3 3 4) a cti v el y tr e at e d  s u bj e ct s  yi el d  at l e a st 
9 5  %  pr o b a bilit y  of  d et e cti n g   A  E s t h at  o c c ur  at  a r at e  of  1  %  or  gr e at er.  
Of t h e  s u bj e ct t ot al,  a p pr o xi  m at el y  1 0 0  p e di atri c  s u bj e ct s  ar e  a nti ci p at e d t o  b e  e nr oll e d i nt o t hi s  st u d y.   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 2   of  2 9  
5.    D at a   Pr e p ar ati o n   
5. 1    
I n p ut   D at a 
St u d y  d at a   will  pri  m aril y  b e r e c or d e d  o n t h e  el e ctr o ni c   C a s e   R e p ort  F or  m s (  e  C  R F s ) s u p pli e d  b y  St ati sti c s 
&    D at a    C or p or ati o n  (  S  D  C  )  u si n g  i  M e d  N et T  M     El e ctr o ni c  D  at a   C  a pt ur e   (  E  D  C)   s y st e  m.  I n   a d diti o n,  t h e  
f oll o  wi n g   st u d y   d at a    w hi c h  ar e   n ot   c a pt ur e d   dir e ctl y    wit hi n  t h e   s y st e  m   b ut   ar e   o bt ai n e d  fr o  m   e xt er n al  
v e n d or s    will   al s o   b e  i n cl u d e d  f or   a n al y si s.   T h e s e   d at a   s o ur c e s   ar e   d e s cri b e d  i n   d et ail  i n   d at a  tr a n sf er  
a gr e e  m e nt s  d e v el o p e d  b et  w e e n  d at a   m a n a g e  m e nt  a n d t h e r e s p e cti v e  e xt er n al l a b or at or y:  
•    P  K  c o n c e ntr ati o n  d at a   
W h e n  all  pr er e q ui sit e s f or  d at a b a s e l o c k  h a v e  b e e n   m et, i n cl u di n g  a v ail a bilit y  of  all   m a s k e d  c o n c e ntr ati o n 
d at a, t h e  d at a b a s e   will  b e l o c k e d.  F oll o  wi n g  d at a b a s e l o c k,  a p pr o v al   will  b e  o bt ai n e d fr o  m t h e   S p o n s or t o 
u n  m a s k t h e  st u d y.   A n y  c h a n g e s t o t h e  d at a b a s e  aft er  d at a  h a v e  b e e n l o c k e d  c a n  o nl y  b e   m a d e   wit h t h e 
a p pr o v al  of t h e   S p o n s or i n  c o n s ult ati o n   wit h   S  D  C.   
Fi n al  a n al y si s   will  b e  c arri e d  o ut  aft er t h e f oll o  wi n g  h a v e  o c c urr e d:   
•    D at a b a s e l o c k  h a s  o c c urr e d, i n cl u di n g r e c ei pt  of  all fi n al  v er si o n s  of  e xt er n al  v e n d or  d at a,   wit h 
writt e n  a ut h ori z ati o n  pr o vi d e d  b y  a p pr o pri at e   S  D  C  a n d   S p o n s or  p er s o n n el   
•    A n al y si s  p o p ul ati o n s  h a v e  b e e n  d et er  mi n e d   
•    R a n d o  mi z e d tr e at  m e nt  c o d e s  h a v e  b e e n  u n  m a s k e d   
5. 2    
O ut p ut   D at a   
D at a fr o  m   E  D  C  a n d  e xt er n al  d at a   will  b e tr a n sf err e d t o   Bi o st ati sti c s  a n d i n c or p or at e d i nt o  st a n d ar d f or  m at s 
f oll o  wi n g t h e   St u d y   D at a  T a b ul ati o n   M o d el (  S  D T  M).   D at a   will t h e n  b e   m a p p e d t o  a n al y si s d at a s et s  u si n g 
t h e   A n al y si s   D at a   M o d el (  A  D a  M).   B ot h   S  D T  M- a n d   A  D a  M -f or  m att e d  d at a   will  b e  u s e d t o  cr e at e t h e  s u bj e ct 
li sti n g s,   w hil e  all t a bl e s  a n d fi g ur e s   will  b e  b a s e d  o n t h e   A  D a  M-f or  m att e d  d at a. 
T h e    S  D T  M   a n d    A  D a  M   v er si o n s,  i  m pl e  m e nt ati o n   g ui d e   v er si o n s,    a n d   Pi n n a cl e   2 1   v er si o n    will   b e  
d o c u  m e nt e d i n t h e r e s p e cti v e r e vi e  w er’ s  g ui d e s i n t h e fi n al   C  DI  S  C  p a c k a g e.  
6.    A n al y si s   P o p ul ati o n s   
6. 1    
S af et y   
T h e   S  af et y  p o p ul ati o n i n cl u d e s  all  s u bj e ct s   w h o  h a v e r e c ei v e d  at l e a st  o n e  d o s e  of  st u d y  dr u g .   All  s af et y 
a n d  t ol er a bilit y   p ar a  m et er s    will   b e   a n al y z e d   u si n g  t h e   S  af et y   p o p ul ati o n   a n d   u si n g  t h e  tr e at  m e nt  t h at  
s u bj e ct s  a ct u all y r e c ei v e d.  
6. 2    
P h ar  m a c o ki n eti c   
T h e   P  K  p o p ul ati o n i n cl u d e s  all  e nr oll e d  s u bj e ct s   w h o  pr o vi d e  at l e a st  o n e  bl o o d  s a  m pl e  dr a  w n  p o st -d o s e.   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 3   of  2 9  
7.    G e n er al   St ati sti c al   C o n si d er ati o n s   
7. 1    
U nit  of   A n al y si s   
F or t ol er a bilit y  a n d  n o n -o c ul ar  s af et y  a n al y s e s, t h e  u nit  of  a n al y si s   will  b e t h e  s u bj e ct.  F or  dr o p  c o  mf ort  
a s s e s s  m e nt s t h at  ar e r e c or d e d f or  e a c h  e y e, t h e  a v er a g e  of t h e  e y e s   will  b e  u s e d.   
7. 2    
Mi s si n g  o r I n c o n cl u si v e   D at a   H a n dli n g   
I n  g e n er al, t h er e   will  b e  n o i  m p ut ati o n  of   mi s si n g  d at a  ot h er t h a n f or  p arti al  or   mi s si n g  d at e s w h er e  c o  m pl et e 
d at e s  ar e r e q uir e d t o fl a g  d at a  a s tr e at  m e nt -e  m er g e nt  or  c o n c o  mit a nt   wit h tr e at  m e nt . P arti al/  mi s si n g  st art 
a n d  e n d  d at e s f or   A  E s  a n d  c o n c o  mit a nt   m e di c ati o n s   will  b e i  m p ut e d  a s f oll o  w s:  
P arti al/  mi s si n g  st art  d at e:    
•    D at e s   wit h   mi s si n g  d a y  o nl y   will  b e i  m p ut e d  a s t h e  1 st  of t h e   m o nt h  u nl e s s   t h e m o nt h  a n d  y e ar  ar e 
s a  m e  a s  t h e m o nt h  a n d  y e ar  of fir st  d o s e  of  st u d y   m e di c ati o n  , i n   w hi c h  c a s e   mi s si n g  d a y   will  b e 
i  m p ut e d  a s t h e fir st  d o s e  d a y of  st u d y   m e di c ati o n .  
•    D at e s   wit h  b ot h  d a y  a n d   m o nt h   mi s si n g   will  b e i  m p ut e d  a s  1  J a n  u nl e s s   t h e y e ar i s  s a  m e  a s  t h e 
y e ar  of fir st  d o s e  of  st u d y   m e di c ati o n , i n   w hi c h  c a s e   mi s si n g  d a y  a n d   m o nt h   will  b e i  m p ut e d  a s t h e 
fir st  d o s e  d a y  a n d   m on t h of  st u d y   m e di c ati o n . 
•    C o  m pl et el y   mi s si n g  d at e s   will  b e i  m p ut e d  a s   t h e fir st  d o s e  d at e of  st u d y   m e di c ati o n  u nl e s s t h e  e n d 
d at e   i s  o n  or  b ef or e t h e fir st  d o s e  d at e  of  st u d y   m e di c ati o n, i n   w hi c h  c a s e   mi s si n g  d at e   will  b e 
i  m p ut e d  a s  1  J a n  of t h e  s a  m e  y e ar  a s t h e  e n d  d at e. 
P arti al/  mi s si n g  e n d  d at e:    
•    D at e s   wit h   mi s si n g  d a y  o nl y   will  b e i  m p ut e d  a s t h e l a st  d a y  of t h e   m o nt h  u nl e s s t h e   m o nt h  a n d  y e ar 
ar e t h e  s a  m e  a s t h e   m o nt h  a n d  y e ar  of t h e l a st  d o s e  of  st u d y   m e di c ati o n, i n   w hi c h  c a s e   mi s si n g 
d a y   will  b e i  m p ut e d  a s t h e l a st  d o s e  d a y  of  st u d y   m e di c ati o n.   
•    D at e s   wit h  b ot h  d a y  a n d   m o nt h   mi s si n g   will  b e i  m p ut e d  a s  3 1   D e c  u nl e s s t h e  y e ar i s  s a  m e  a s t h e 
y e ar  of t h e l a st  d o s e  of  st u d y   m e di c ati o n, i n   w hi c h  c a s e   mi s si n g  d a y  a n d   m o nt h   will  b e i  m p ut e d  a s 
t h e l a st  d o s e  d a y  a n d   m o nt h  of  st u d y   m e di c ati o n.  
•    If  t h e   o n g oi n g  fl a g  i s    mi s si n g   or  “  Y e s”  t h e n  t h e   d at e    will   n ot   b e  i  m p ut e d   u nl e s s   d e at h   d at e  i s  
a v ail a bl e, i n   w hi c h  c a s e t h e   mi s si n g  d at e   will  b e i  m p ut e d  a s t h e  d e at h  d at e. If  o n g oi n g i s “  N o” t h e n 
t h e   mi s si n g  e n d  d at e   will  b e i  m p ut e d  a s t h e l a st  d o s e  d at e. 
•    If t h e i  m p ut e d  d at e i s  aft er t h e  d at e  of  d e at h, t h e n t h e  e n d  d at e   will  b e  s et  e q u al t o t h e  d at e  of 
d e at h.   
T h e  ori gi n al  d at e s   will  b e  di s pl a y e d i n  d at a li sti n g s  a n d t h e i  m p ut e d  d at e s   will  b e  u s e d i n  d eri v ati o n s  o nl y 
( st u d y  d a y, tr e at  m e nt-e  m er g e n c e  st at u s , et c).  
V al u e s  of  0   will  b e  c o n si d er e d   mi s si n g   w h e n  c al c ul ati n g t h e  g e o  m etri c   m e a n s  .  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 4   of  2 9  
7. 3    
D efi niti o n  of   B a s eli n e   
B a s eli n e  i s   d efi n e d   a s  t h e  l a st    m e a s ur e  m e nt   pri or  t o  t h e  fir st   d o s e   of   st u d y    m e di c ati o n.    C h a n g e  fr o  m  
b a s eli n e   will  b e  c al c ul at e d  a s , F oll o  w -u p   Vi sit  –  B a s eli n e   Vi sit.   
7. 4    
D at a   A n al y si s   C o n v e nti o n s   
All  d at a  a n al y si s   will  b e  p erf or  m e d  b y   S  D  C.   St ati sti c al  pr o gr a  m  mi n g  a n d  a n al y s e s   will  b e  p erf or  m e d  u si n g 
S  A  S ®     Ver si o n   9. 4   or   hi g h er.   O ut p ut    will   b e   pr o vi d e d  i n    ri c h te xt   for  m at  ( R T F  )  f or  t a bl e s   a n d  p ort a bl e 
d o c u  m e nt  for  m at ( P  D F  ) f or t a bl e s, li sti n g s,  a n d fi g ur e s u si n g l a n d s c a p e  ori e nt ati o n .  
S u  m  m ari e s  f or   c o nti n u o u s   a n d   or di n al   v ari a bl e s    will    i n cl u d e  t h e  n u  m b er   of   o b s er v ati o n s  ( n),   arit h  m eti c  
m e a n,  st a n d ar d  d e vi ati o n (  S  D),   m e di a n,   mi ni  m u  m  , a n d   m a xi  m u  m.  A d diti o n all y,  2 5 t h a n d  7 5 t h p er c e ntil e s, 
g e o  m etri c  m e a n,  a n d   C  V  %   will  b e  pr o vi d e d f or   P  K  c o n c e ntr ati o n s  a n d  p ar a  m et er s.   Mi ni  m a  a n d   m a xi  m a 
will  b e r e p ort e d   wit h t h e  s a  m e  pr e ci si o n  a s t h e r a  w  v al u e s;   m e a n s  a n d   m e di a n s   will  b e  pr e s e nt e d t o  o n e 
a d diti o n al   d e ci  m al   pl a c e  t h a n  r e p ort e d  i n  t h e  r a  w   v al u e s.    St a n d ar d   d e vi ati o n s    will   b e   pr e s e nt e d  t o  t  w o  
a d diti o n al   d e ci  m al   pl a c e s  t h a n  r e p ort e d  i n  t h e  r a  w   v al u e s.    All   s u  m  m ar y   st ati sti c s ,  e x c e pt   n  f or    P  K  
c o n c e ntr ati o n s  a n d  p ar a  m et er s , will  b e  pr e s e nt e d   wit h t h e  s a  m e  n u  m b er  of  si g nifi c a nt  di git s  a s r a  w   P  K 
c o n c e ntr ati o n s ( 3  si g nifi c a nt fi g ur e s).   S u  m  m ari e s f or  di s cr et e  v ari a bl e s   will  i n cl u d e c o u nt s  a n d  p er c e nt a g e s.  
All  p er c e nt a g e s   will  b e r o u n d e d t o  o n e  d e ci  m al  pl a c e (i  . e.,   X  X.  X  %). Diff er e n c e s  b et  w e e n  a cti v e tr e at  m e nt 
gr o u p  a n d  v e hi cl e  will  b e  c al c ul at e d  a s  ,   Acti v e  mi n u s   V e hi cl e.   
All  st ati sti c al t e st s   will  b e t  w o  -si d e d   wit h  a  si g nifi c a n c e l e v el  of  0. 0 5 ( α  =  0. 0 5)  u nl e s s  ot h er  wi s e  s p e cifi e d. 
C o nfi d e n c e i nt er v al s (  CI  s ) f or  diff er e n c e s  b et  w e e n tr e at  m e nt  gr o u p s   will  b e t  w o-si d e d  at  9 5  %  c o nfi d e n c e. 
All  p  -v al u e s   will  b e r o u n d e d t o  4  d e ci  m al  pl a c e s;  p -v al u e s l e s s t h a n  0. 0 0 0 1   will  b e  pr e s e nt e d  a s “ < 0. 0 0 0 1”; 
p- v al u e s  gr e at er t h a n  0. 9 9 9 9   will  b e  pr e s e nt e d  a s “ > 0. 9 9 9 9.”  
U nl e s s  ot h er  wi s e  s p e cifi e d,  s u  m  m ari e s   will  b e  pr e s e nt e d  b y tr e at  m e nt  gr o u p  a n d,   w h er e  a p pr o pri at e,   vi sit.  
Li sti n g s   will  b e  b a s e d  o n  all r a n d o  mi z e d  s u bj e ct s  u nl e s s  ot h er  wi s e  s p e cifi e d  a n d  s ort e d  b y  s u bj e ct  n u  m b er, 
r a n d o  mi z e d tr e at  m e nt,  vi sit/ti  m e  p oi nt,  a n d  p ar a  m et er  a s  a p pli c a bl e. 
V  i sit s i n t h e  o ut p ut s will   b e  l a b ell e d  a s   D a y  1 (  Vi sit  1),   D a y  8 (  Vi sit  2),   D a y  2 2 (  Vi sit  3),   D a y  4 3 (  Vi sit  4). 
7. 5    
A dj u st  m e nt s f or   M ulti pli cit y   
T h er e  ar e  n o f or  m al  h y p ot h e s e s f or t hi s  st u d y, t h er ef or e  a dj u st  m e nt s f or   m ulti pli cit y  d o  n ot  n e e d t o  b e t a k e n 
i nt o  c o n si d er ati o n. 
8.      Di s p o siti o n   of   S u bj e ct s  
S u bj e ct  di s p o siti o n   will  b e  pr e s e nt e d i n t er  m s  of t h e  n u  m b er s  a n d  p er c e nt a g e s  of  s u bj e ct s   w h o  ar e i n cl u d e d 
i n  e a c h  p o p ul ati o n,   w h o  c o  m pl et e d t h e  st u d y,  a n d   w h o  di s c o nti n u e d fr o  m t h e  st u d y.   S u bj e ct s   w h o  ar e  n ot 
di s c o nti n u e d  fr o  m  t h e   st u d y    will   b e   c o n si d er e d   st u d y   c o  m pl et er s.    Di s p o siti o n    will   b e   s u  m  m ari z e d   b y  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 5   of  2 9  
tr e at  m e nt  gr o u p a n d  o v er all f or   all s u bj e ct s.  T h e  n u  m b er  of  s u bj e ct s  e nr oll e d,  s cr e e n  fail e d,  a n d r a n d o  mi z e d 
will  b e  pr e s e nt e d.   
T h e  n u  m b er  a n d  p er c e nt a g e  of  s u bj e ct s  pr e  m at ur el y  di s c o nti n u e d fr o  m t h e  st u d y  a n d t h e r e a s o n s f or  st u d y    
di s c o nti n u ati o n   will  b e  s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or  all  s u bj e ct s.  T h e r e a s o n s f or  st u d y 
di s c o nti n u ati o n  will  b e  b a s e d  o n t h e t ot al  n u  m b er  of  di s c o nti n u ati o n s f or t h at tr e at  m e nt  gr o u p   a n d  o v er all  
f or  all  s u bj e ct s,  a n d t h e r e a s o n s t h at   will  b e  s u  m  m ari z e d i n cl u d e:   A  E, l o st t o f oll o  w-u p,  st u d y t er  mi n at e d  b y 
s p o n s or,  p h y si ci a n  d e ci si o n,   wit h dr a  w al  b y  s u bj e ct,  pr ot o c ol  vi ol ati o n,  a n d  ot h er.  T h e  s u bj e ct  di s p o siti o n 
s u  m  m ar y   will  al s o i n cl u d e t h e  n u  m b er  a n d  p er c e nt a g e  of  s u bj e ct s   wit h  a n y  pr ot o c ol  d e vi ati o n s,  a n y   mi n or 
d e vi ati o n s,  or  a n y   m aj or  d e vi ati o n s  b y tr e at  m e nt  gr o u p  a n d  o v er all f or  all  s u bj e ct s.   A  s u bj e ct li sti n g   will  b e 
pr o vi d e d t h at i n cl u d e s t h e i nf or  m e d  c o n s e nt/ a s s e nt  or r e c o n s e nt  d at e (if  a p pli c a bl e), if t h e  s u bj e ct i s  p art  of 
t h e   P  K  s a  m pl e  s u b gr o u p, t h e d at e  of  st u d y  c o  m pl eti o n  or  di s c o nti n u ati o n,  a n d r e a s o n f or  pr e  m at ur e  st u d y 
di s c o nti n u ati o n.   
T h e  n u  m b er  a n d  p er c e nt a g e  of  s u bj e ct s   wit h   a n y  m aj or  pr ot o c ol  d e vi ati o n s (  m aj or  st at u s  d e ci d e d  b y t h e 
st u d y t e a  m  at t h e  c o n cl u si o n  of t h e  st u d y  pri or t o  d at a b a s e l o c k  a n d  u n  m a s ki n g)   will  b e  s u  m  m ari z e d  b y 
tr e at  m e nt   gr o u p   a n d   o v er all  f or   all   s u bj e ct s.   T h e   pr ot o c ol   d e vi ati o n  c at e g ori e s  ( c o d e s)   t h at    will   b e  
s u  m  m ari z e d  i n cl u d e:  i nf or  m e d   c o n s e nt,  i n cl u si o n/ e x cl u si o n   a n d  r a n d o  mi z ati o n,   t e st   arti cl e/ st u d y   dr u g  
i n still ati o n a n d  a s si g n  m e nt  at  sit e, i  m pr o p er  pr ot o c ol  pr o c e d ur e s  at  sit e (  mi s s e d, r e p e at e d,  n ot  p er  pr ot o c ol), 
sit e’ s f ail ur e t o r e p ort   S  A  E/  A  E,  vi sit  o ut  of   wi n d o  w (  mi s s e d,  e arl y, l at e),  s u bj e ct’ s  n o n -c o  m pli a n c e  wit h t e st 
arti cl e,  s u bj e ct’ s  u s e  of  pr o hi bit e d  c o n c o  mit a nt   m e di c ati o n,  s u bj e ct’ s f ail ur e t o f oll o  w i n str u cti o n s,  a n d  ot h er. 
A  s u bj e ct li sti n g   will  b e  pr o vi d e d t h at i n cl u d e s  t h e  d at e  of t h e  d e vi ati o n,   t h e  vi sit  at   w hi c h t h e  d e vi ati o n 
o c c urr e d,   t h e   d e vi ati o n   c o d e,   d e vi ati o n  d e s cri pti o n,   a cti o n  t a k e n,    w h et h er  t h e   d e vi ati o n    w a s    C  O  VI  D -1 9 
r el at e d, a n d t h e  cl a s sifi c ati o n  of   w h et h er t h e  d e vi ati o n   w a s j u d g e d t o  b e   m aj or  or   mi n or.  
Li sti n g s   will  al s o  b e  pr o vi d e d f or r a n d o  mi z ati o n  s c h e d ul e  a n d i n cl u si o n/ e x cl u si o n  crit eri a.  
9.    D e  m o gr a p hi c  a n d   B a s eli n e   Di s e a s e   C h ar a ct eri sti c s   
9. 1    
D e  m o gr a p hi c   V ari a bl e s   
T h e   d e  m o gr a p hi c   v ari a bl e s   c oll e ct e d  i n  t hi s   st u d y  i n cl u d e   a g e,   s e x,   c hil d b e ari n g   p ot e nti al,    r a c e,  a n d 
et h ni cit y.   S u bj e ct s   w h o r e c or d   m or e t h a n  o n e r a c e   will  b e  gr o u p e d i nt o  a  si n gl e  c at e g or y  d e n ot e d  a s   M ulti pl e  
i n  t h e   s u  m  m ar y  t a bl e   a n d    will  b e   pr e s e nt e d   a s   c oll e ct e d  i n  t h e   b y -s u bj e ct  li sti n g .  Iri s   c ol or    will   al s o   b e  
c oll e ct e d  b y  e y e.  D e  m o gr a p hi c  v ari a bl e s   will  b e  s u  m  m ari z e d f or t h e   S af et y   a n d   P  K  p o p ul ati o n s.  
A g e ( y e ar s)   will  b e  s u  m  m ari z e d  b y tr e at  m e nt  gr o u p   a n d  o v er all f or  all  s u bj e ct s  u si n g  c o nti n u o u s  d e s cri pti v e 
st ati sti c s.   
T h e  n u  m b er  a n d  p er c e nt a g e  of  s u bj e ct s   will  b e  pr e s e nt e d   b y tr e at  m e nt  gr o u p  a n d  o v er all f or  all  s u bj e ct s, 
f or  a g e  c at e g ori e s ( 5-1 2  ,1 3 -1 7,  1 8 -6 4,  a n d  > 6 4  y e ar s ), iri s  c ol or  of ri g ht  e y e  a n d l eft  e y e, s e x,  c hil d b e ari n g 
p ot e nti al f or f e  m al e  s u bj e ct s, r a c e,  a n d  et h ni cit y.  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 6   of  2 9  
A  s u bj e ct li sti n g t h at i n cl u d e s  all  d e  m o gr a p hi c  v ari a bl e s   will  b e  pr o vi d e d.   
9. 2    
B a s eli n e   Di s e a s e   C h ar a ct eri sti c s   
At t h e  s cr e e ni n g  vi sit,  s u bj e ct s   will  si g n t h e i nf or  m e d  c o n s e nt f or  m  , a n d  s cr e e ni n g  vi sit  e v al u ati o n s   will  b e 
p erf or  m e d .   T h e   s cr e e ni n g   vi sit   e v al u ati o n s    will   b e  s u  m  m ari z e d   al o n g    wit h   p o st -tr e at  m e nt   vi sit s  i n  t h eir  
r e s p e cti v e  s e cti o n s. 
1 0.   M e di c al   Hi st or y  a n d   C o n c o  mit a nt   M e di c ati o n s   
Li sti n g s  of   m e di c al  hi st or y  a n d  c o n c o  mit a nt   m e di c ati o n s  will  b e  g e n er at e d  s e p ar at el y,  a s   w ell  a s  s e p ar at el y 
f or  o c ul ar  a n d  n o n-o c ul ar  d at a  f or   m e di c al  hi st or y. 
1 0. 1    
M e di c al   Hi st or y   
M e di c al  hi st or y   will  b e  c o d e d  u si n g   M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti e s (  M e d  D  R  A)   V er si o n  2 6. 0  . 
N o n  -o c ul ar    m e di c al   hi st or y    will   b e   s u  m  m ari z e d   u si n g   di s cr et e   s u  m  m ar y   st ati sti c s   a n d   pr e s e nt e d   b y  
tr e at  m e nt  gr o u p  at t h e  s u bj e ct l e v el  b y   S y st e  m   Or g a n   Cl a s s (  S  O  C)  a n d   Pr ef err e d  T er  m (  P T)  u si n g t h e 
S af et y   p o p ul ati o n.    O c ul ar    m e di c al   hi st or y    will   b e   si  mil arl y   s u  m  m ari z e d   at  t h e   s u bj e ct  l e v el.  If   a   s u bj e ct  
r e p ort s t h e  s a  m e   P T   m ulti pl e ti  m e s   wit hi n t h e  s a  m e   S  O  C, t h at   P T   will  o nl y  b e r e p ort e d  o n c e   wit hi n t h at 
S  O  C.   A s   wit h t h e   P T, if  a  s u bj e ct r e p ort s   m ulti pl e  c o n diti o n s   wit hi n t h e  s a  m e   S  O  C, t h at   S  O  C   will  o nl y  b e 
r ep ort e d  o n c e. I n t h e  s u  m  m ari e s,   S  O  C s  a n d   P T s   wit hi n  a n   S  O  C   will  b e li st e d i n  al p h a b eti c al  or d er.  
1 0. 2    
Pri o r  a n d   C o n c o  mit a nt   M e di c ati o n s   
Pri or   a n d    C o n c o  mit a nt    m e di c ati o n s    will   b e   c o d e d    u si n g   W orl d    H e alt h    Or g a ni z ati o n    Dr u g    Di cti o n ar y  
(W  H  O  Dr u g  ) Gl o b al   B 3,   M ar c h  2 0 2 3  a n d   s u  m  m ari z e d t o t h e t h er a p e uti c  dr u g  cl a s s (  A n at o  mi c al  T h er a p e uti c 
C h e  mi c al [  A T  C]  4  cl a s sifi c ati o n)  a n d  pr ef err e d  n a  m e. If t h e   A T  C  4  cl a s sifi c ati o n i s  n ot  pr o vi d e d, t h e n t h e 
n e xt  hi g h e st  cl a s sifi c ati o n t h at i s  pr o vi d e d i n t h e  c o di n g  di cti o n ar y   will  b e  u s e d.   
Pri or    m e di c ati o n s   ar e  d efi n e d  a s  t h o s e   m e di c ati o n s  li st e d  a s   h a vi n g  b e e n t a k e n   u p t o  3 0  d a y s   pri or  t o   
i niti ati o n   of  st u d y   dr u g   a d  mi ni str ati o n   a n d   e n d e d   b ef or e  t h e  i niti ati o n   of   st u d y   dr u g   a d  mi ni str ati o n.  
C o n c o  mit a nt   m e di c ati o n s  ar e  d efi n e d  a s t h o s e   m e di c ati o n s li st e d  a s  h a vi n g  b e e n t a k e n   (1)  pri or t o  i niti ati o n 
of  st u d y  dr u g  a d  mi ni str ati o n  a n d  c o nti n ui n g f or  a n y  p eri o d  of ti  m e f oll o  wi n g t h e fir st  a d  mi ni str ati o n  of  st u d y 
dr u g  or  (2)  at  a n y ti  m e f oll o  wi n g t h e fir st  a d  mi ni str ati o n  of  st u d y  dr u g.  
Pri or  a n d  c  o n c o  mit a nt   m e di c ati o n s   will  b e  s u  m  m ari z e d  u si n g t h e   S af et y  p o p ul ati o n.   M e di c ati o n s   will  b e 
t a b ul at e d f or  e a c h tr e at  m e nt  gr o u p  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s.   S u bj e ct s   m a y  h a v e   m or e t h a n  o n e 
m e di c ati o n  p er  A T  C t e xt.  At  e a c h l e v el  of  s u bj e ct  s u  m  m ari z ati o n,  a  s u bj e ct   will  b e  c o u nt e d  o n c e if   th e y 
r e p ort  o n e  or   m or e   m e di c ati o n s.   P er c e nt a g e s   will  b e  b a s e d  o n t h e  n u  m b er  of  s u bj e ct s i n  e a c h tr e at  m e nt 
gr o u p.   I n  t h e   s u  m  m ari e s,   A T  C   cl a s s e s   a n d   pr ef err e d   n a  m e s    wit hi n   a n   A T  C   cl a s s    will   b e  li st e d  i n   a n  
al p h a b eti c al  or d er.  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 7   of  2 9  
1 1.   D o si n g   C o  m pli a n c e  a n d  T r e at  m e nt   E x p o s u r e   
S u bj e ct li sti n g s  of  st u d y  dr u g i n still ati o n f or   s u bj e ct  d o si n g  di ar y  e ntri e s,  st u d y  dr u g  a s si g n  m e nt,  a n d  st u d y 
dr u g i n still ati o n f or i n -offi c e  vi sit s  will  b e  pr o d u c e d.   
1 1. 1    
D o si n g   C o  m pli a n c e   
S u bj e ct s   will  b e   d o s e d i n  offi c e  d uri n g   D a y  1 (  Vi sit  1),   D a y  8 (  Vi sit  2),  a n d   D a y  2 2 (  Vi sit  3) .  T h e y   will  al s o 
b e   pr o vi d e d    wit h   a   d o si n g   di ar y  t o   d o c u  m e nt   B  I  D   d o si n g  aft er   D a y   1  (  Vi sit   1  ).  D o si n g   c o  m pli a n c e  (  %  
c o  m pli a n c e)   will  b e  a s s e s s e d  b y  c al c ul ati n g t h e  n u  m b er  of  a ct u al  d o s e s r e c ei v e d  a n d  c o  m p ari n g t h at t o t h e 
n u  m b er  of  e x p e ct e d  d o s e s  a s f oll o  w s:  
C o  m pli a n c e (  %)  =   
N u  m b er  of   A ct u al   D o s e s   R e c ei v e d  x  1 0 0  %   
N u  m b er  of   E x p e ct e d   D o s e s   
T h e  n u  m b er  of  a ct u al  d o s e s r e c ei v e d   will  b e  c al c ul at e d   b y  c o u nti n g t h e  n u  m b er  of  d o s e d r e c or d s i n t h e  
s u bj e ct  di ar y  a n d t h e i n -offi c e i n still ati o n  C  R F  p a g e s  . Fr o  m  D a y  1 (  Vi sit  1  ) t o D a y  4 3 (  Vi sit  4  ),  s u bj e ct s  ar e 
e x p e ct e d t o  b e  d o s e d  2 ti  m e s  d a y, i n cl u di n g i n -offi c e  d o s e s.   H o  w e v er,  o n   D a y  1 ( Vi sit  1  ), t h e y  g et  o nl y  1 
d o s e  o n  sit e  a n d  ar e i n str u ct e d t o t a k e  n o f urt h er  d o s e s  at  h o  m e.  T h e  at -h o  m e  d o si n g  st art s  o n t h e  d a y 
aft er  D a y  1 (  Vi sit  1  ). T h e fi n al  d o s e  of  st u d y  dr u g   will  b e t h e  d o s e  a d  mi ni st er e d  at  h o  m e  t h e  e v e ni n g pri or 
t o D a y  4 3 (  Vi sit  4  ).  
T h e  e x p e ct e d  n u  m b er  of  d o s e s   will  b e  c al c ul at e d  a s:    
F or  s u bj e ct s   w h o  c o  m pl et e   D a y  4 3 (  Vi sit  4  ): 
[  2 x  { (  D at e D a y  4 3 (  Vi sit  4)   -1) –  D at e  of   Fir st   D o s e}  ] +  1  
F or  s u bj e ct s   w h o  di s c o nti n u e  b ef or e   D a y  4 3 (  Vi sit  4  ): 
[  2 x (  D at e  of  St u d y  L a st   D o s e fr o  m t h e   D o si n g   Di ar y  or I n  -offi c e  I n still ati o n P a g e   - D at e   of  Fir st   D o s e )] +  1  
S u bj e ct s t h at  di s c o nti n u e   wit h o ut  c o  m pl eti n g   D a y  4 3 (  Vi sit  4  ) will  b e  e x p e ct e d t o t a k e  2  d o s e s  o n t h eir l a st 
d o s e  d at e.   E xt e nt  of   e x p o s ur e,  d efi n e d  a s   n u  m b er   of  d a y s   e a c h  s u bj e ct   w a s   o n t h e   st u d y   dr u g   will  b e  
s u  m  m ari z e d    wit h   d e s cri pti v e   st ati sti c s.    N u  m b er   of   d a y s   e a c h   s u bj e ct    w a s   o n  t h e   st u d y   dr u g   will   b e  
c al c ul at e d  u si n g  s u bj e ct  di ar y  a n d t h e i n -offi c e i n still ati o n s.  
A  c at e g ori c al  d o si n g  c o  m pli a n c e  v ari a bl e   will  al s o  b e  d eri v e d  a s  n o n  -c o  m pli a nt ( < 8 0 %),  c o  m pli a nt ( ≥ 8 0  % 
a n d  ≤ 1 2 0  %),  a n d  o v er  c o  m pli a nt ( > 1 2 0 %).   
D o si n g  c o  m pli a n c e (  %)   will  b e  s u  m  m ari z e d   wit h   c o nti n u o u s  d e s cri pti v e  st ati sti c s f or  e a c h tr e at  m e nt  gr o u p  
u si n g t h e   S af et y  p o p ul ati o n.  T h e  c o  m pli a n c e  c at e g or i e s d efi n e d  a b o v e   will  b e  s u  m  m ari z e d   wit h  di s cr et e 
s u  m  m ar y  st ati sti c s.   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 8   of  2 9  
1 1. 2    
Tr e at  m e nt   E x p o s ur e  
E xt e nt  of tr e at  m e nt  e x p o s ur e f or  c o  m pl et e d  or  di s c o nti n u e d  s u bj e ct s   will  b e  c al c ul at e d i n  d a y s  u si n g t h e 
f oll o  wi n g: 
F or  s u bj e ct s t h at  c o  m pl et e   D a y  4 3 (  Vi sit  4  ):  
E xt e nt  of   E x p o s ur e ( d a y s)  = (  D at e  of   Vi sit  4    – D at e  of  Fir st   D o s e)    
F or  s u bj e ct s  w h o   d o   n ot  c o  m pl et e   D a y  4 3 (Vi sit  4  ): 
E xt e nt  of   E x p o s ur e ( d a y s)  = (  D at e  of  L a st   D o s e    – D at e  of  Fir st   D o s e)  +  1   
E xt e nt  of tr e at  m e nt  e x p o s ur e f or  e a c h  s u bj e ct  e x p o s e d t o  st u d y  dr u g   will  b e  s u  m  m ari z e d   wit h  c o nti n u o u s 
d e s cri pti v e  st ati sti c s f or  e a c h tr e at  m e nt  gr o u p  u si n g t h e  S  af et y  p o p ul ati o n . 
1 2.   P h ar  m a c o ki n eti c   A n al y s e s   
Bl o o d  s a  m pl e s   will  b e  c oll e ct e d fr o  m  a  s u b s et  of  u p t o  2 5  h e alt h y  a d ult  s u bj e ct s   at  pr e -d o s e,  0. 2 5 ( ± 3   mi n), 
0. 5 ( ± 5   mi n),  1 ( ± 1 0   mi n),  2 ( ± 1 0   mi n),  a n d  4 ( ± 2 0   mi n)  h o ur s f oll o  wi n g t h e fir st t o pi c al  o c ul ar i n still ati o n  of 
bri  m o ni di n e t artr at e  0. 0 2 5  %/ k et otif e n f u  m ar at e  0. 0 3 5  %  c o  m bi n ati o n  o p ht h al  mi c  s ol uti o n  or  v e hi cl e  o n   D a y 
1  a n d  al s o  o n   D a y  2 2 t o   m e a s ur e t h e  pl a s  m a  c o n c e ntr ati o n s  of  bri  m o ni di n e  a n d  k et otif e n.  
P  K  a n al y s e s   will  b e  pri  m aril y  p erf or  m e d  o n t h e   P  K  p o p ul ati o n   wit h  o b s er v e d  d at a  o nl y.  T h e   P  K  e n d p oi nt s   
will  b e  s u  m  m ari z e d  u si n g  d e s cri pti v e  st ati sti c s.  T h e   P  K  e n d p oi nt s  ar e    m a xi  m u  m  o b s er v e d  pl a s  m a  dr u g 
c o n c e ntr ati o n  (  Cm a x ), mi ni  m u  m  o b s er v e d  pl a s  m a  c o n c e ntr ati o n   (  Cmi n ), ti  m e of   m a xi  m u  m  o b s er v e d  pl a s  m a 
c o n c e ntr ati o n   ( Tm a x ),   ar e a   u n d er  t h e   pl a s  m a   dr u g   c o n c e ntr ati o n-ti  m e  c ur v e  fr o  m  ti  m e   0  t o  t h e  l a st  
q u a ntifi a bl e   dr u g   c o n c e ntr ati o n   (A  U  C 0-t ),  ar e a   u n d er  t h e   pl a s  m a   dr u g   c o n c e ntr ati o n -ti  m e  c ur v e  fr o  m   0 
t hr o u g h 4  h o ur s,  (A  U  C 0- 4 ). A c c u  m ul ati o n r ati o  of   C m a x  at  st e a d y -st at e t o   C m a x  aft er t h e fir st  d o s e (  R C  M a x ) a n d 
a c c u  m ul ati o n  r ati o   of   A  U  C 0-t   at   st e a d y -st at e  t o   A  U  C 0-t   aft er  t h e  fir st   d o s e  (  R A  U  C )  will   b e   d et er  mi n e d   b y  
c o  m p ari s o n   of    D a y   1  t o    D a y   2 2.    A d diti o n all y,  t h e   st u d y   dr u g   c o n c e ntr ati o n s    will   b e   s u  m  m ari z e d   u si n g  
c o nti n u o u s  d e s cri pti v e  st ati sti c s  b y  n o  mi n al ti  m e.   
T h e    P  K   p ar a  m et er s   d e s cri b e d   a b o v e  f or   pl a s  m a   c o n c e ntr ati o n s   of   bri  m o ni di n e   a n d   k et otif e n    will   b e  
c o  m p ut e d fr o  m t h e i n di vi d u al  pl a s  m a  st u d y  dr u g  c o n c e ntr ati o n s  b y  a p pl yi n g  a  n o n -c o  m p art  m e nt al  a p pr o a c h 
u si n g   P h o e ni x   Wi n  N o nli n ®  6. 2. 1.  A ct u al  s a  m pli n g ti  m e s   will  b e  u s e d f or t h e  c al c ul ati o n  of   P  K  p ar a  m et er s.   
C o n c e ntr ati o n   v al u e s  r e p ort e d   a s   b el o  w  t h e  li  mit   of   q u a ntit ati o n  (  B L  Q)   b ef or e  t h e  fir st   q u a ntifi a bl e  
c o n c e ntr ati o n  or  aft er t h e l a st  q u a ntifi a bl e  c o n c e ntr ati o n   will  b e  s et t o  z er o f or  c o n c e ntr ati o n  d e s cri pti v e 
st ati sti c s. If  a  c o n c e ntr ati o n t h at i s   B L  Q i s i  m b e d d e d  b et  w e e n  2   m e a s ur a bl e  c o n c e ntr ati o n s, t h e   B L  Q  v al u e 
will  b e  s et t o   mi s si n g.    
V al u e s  of  0   will  b e  c o n si d er e d   mi s si n g   w h e n  c al c ul ati n g t h e  g e o  m etri c   m e a n s.   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  1 9   of  2 9  
If t h e  d at a  all o  w,   me a n  pl a s  m a -c o n c e ntr ati o n  v er s u s ti  m e fi g ur e s   will  b e  pr e s e nt e d f or  e a c h  a n al yt e  o n  a 
li n e ar  s c al e,   wit h  a n d   wit h o ut   S  D  err or  b ar s,  a n d  o n  a  s e  mi-l o g arit h  mi c  s c al e   wit h o ut   S  D  err or  b ar s.   Pl a s  m a 
c o n c e ntr ati o n  v er s u s ti  m e fi g ur e s f or t h e i n di vi d u al  s u bj e ct s   will  b e  pr e s e nt e d  o n  s e  mi -l o g  a n d li n e ar  s c al e s. 
1 3.   S af et y   A n al y s e s   
All  s af et y   a n al y s e s    will  b e  c o n d u ct e d  u si n g  t h e    S af et y    p o p ul ati o n.  All   s af et y   a n al y s e s   d e s cri b e d  i n t hi s  
s e cti o n  will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s  :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s,  a n d  > 6 4 
y e ar s.  
1 3. 1    
A d v er s e   E v e nt s   
A n  a d v er s e  e v e nt i s  a n y  u nt o  w ar d   m e di c al  o c c urr e n c e i n  a  s u bj e ct  p arti ci p ati n g i n  a  cli ni c al   st u d y,   w hi c h 
d o e s  n ot  n e c e s s aril y  h a v e  a  c a u s al r el ati o n s hi p   wit h t h e  st u d y  pr o d u ct/ pr o c e d ur e.  T h er ef or e,  a n  a d v er s e 
e v e nt i n cl u d e s:   
•    A n y  u nf a v or a bl e  a n d/ or  u ni nt e n d e d  si g n (i n cl u di n g  a n  a b n or  m al l a b or at or y   fi n di n g),  s y  m pt o  m,  or 
di s e a s e  o n s et, t h at  o c c ur s  at  a n y ti  m e  b et  w e e n t h e  si g ni n g  of  t h e I  C F  a n d  st u d y  e xit,   wit h o ut  a n y 
j u d g e  m e nt  a b o ut  c a u s alit y (i. e.,   w h et h er  or  n ot it i s  c o n si d er e d t o  b e r el at e d t o t h e  st u d y  pr o d u ct) 
•    E x a c er b ati o n,   w or s e ni n g,  or  pr o gr e s si o n  of  a  pr e  -e xi sti n g ill n e s s, i n cl u di n g  a n  i n cr e a s e i n 
s e v erit y, fr e q u e n c y,  a n d/ or  d ur ati o n  of  a  pr e -e xi sti n g  e pi s o di c  e v e nt  or  c o n diti o n  
•    E v e nt s  o c c urri n g fr o  m  dr u g  o v er d o s e ( a c ci d e nt al  or i nt e nti o n al),  dr u g  a b u s e  or   mi s u s e,  dr u g 
h y p er s e n siti vit y,  dr u g  e xtr a v a s ati o n,  dr u g i nt er a cti o n s,  dr u g  d e p e n d e n c y,  e v e nt s  o c c urri n g fr o  m 
dr u g   wit h dr a  w al  a n d   m e di c ati o n  err or s  
•    A  c o n diti o n  d et e ct e d  or  di a g n o s e d  aft er  st u d y  pr o d u ct  a d  mi ni str ati o n  e v e n t h o u g h   it   m a y  h a v e 
b e e n  pr e s e nt  pri or t o t h e  st art  of t h e  st u d y  
T h e   A  E r e p orti n g  p eri o d  e n d s  u p o n  st u d y  e xit.   St u d y  dr u g i n cl u d e s t h e i n v e sti g ati o n al  dr u g  u n d er  e v al u ati o n 
a n d  v e hi cl e  gi v e n  d uri n g t h e  st u d y.   All   A  E s   will  b e  c o d e d  u si n g t h e   M e d  D  R  A  v er si o n  2 6. 0 .  
Tr e at  m e nt -e  m er g e nt  a d v er s e  e v e nt s ( T  E  A  E)  ar e  d efi n e d  a s  a n   A  E   wit h  a  st art  d at e  o n  or  aft er t h e fir st  d o s e 
of  st u d y  dr u g,  or t h at   w or s e n e d f oll o  wi n g  a d  mi ni str ati o n  of  st u d y  dr u g . A d v er s e  e v e nt s r e c or d e d i n t h e  e  C  R F 
w hi c h  b e g a n  pri or t o tr e at  m e nt   will  n ot  b e i n cl u d e d i n t h e  s u  m  m ar y t a bl e s  b ut   will  b e i n cl u d e d i n t h e   A  E 
d at a li sti n g s.  
S e v erit y  of  a n   A  E i s  d efi n e d  a s  a  q u alit ati v e  a s s e s s  m e nt  of t h e  d e gr e e  of i nt e n sit y  of  a n   A  E  a s  d et er  mi n e d 
b y t h e I n v e sti g at or  or r e p ort e d t o  hi  m/ h er  b y t h e  s u bj e ct.  T h e  a s s e s s  m e nt  of  s e v erit y i s   m a d e irr e s p e cti v e 
of r el ati o n s hi p t o  st u d y  dr u g  or  s eri o u s n e s s  of t h e  e v e nt  a n d  s h o ul d  b e  e v al u at e d  a c c or di n g t o t h e f oll o  wi n g 
s c al e:  
•    Mil d:   A  w ar e n e s s  of  a  si g n  or  s y  m pt o  m  b ut i s  e a sil y t ol er at e d, r e q uir e s  n o tr e at  m e nt,  a n d  d o e s  n ot 
i nt erf er e   wit h  s u bj e ct’ s  d ail y  a cti viti e s 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  2 0   of  2 9  
•    M o d er at e:   L o  w l e v el  of  c o n c er n t o t h e  s u bj e ct  a n d   m a y i nt erf er e   wit h  d ail y  a cti viti e s  b ut  c a n  b e 
r eli e v e d  b y  si  m pl e t h er a p e uti c  c ar e. 
•    S e v er e  : I nt err u pt s t h e  s u bj e ct’ s  d ail y  a cti vit y  a n d r e q uir e s  s y st e  mi c t h er a p y  or  ot h er tr e at  m e nt 
T h e  r el ati o n s hi p   of   e a c h    A  E  t o  t h e   st u d y   dr u g   s h o ul d   b e   d et er  mi n e d   b y  t h e  I n v e sti g at or   u si n g  t h e s e  
e x pl a n ati o n s:  
•    R el at e d  : T h er e i s  at l e a st  a r e a s o n a bl e  p o s si bilit y t h at t h e   A  E/  S  A  E i s r el at e d t o t h e  st u d y  dr u g. 
R e a s o n a bl e  p o s si bilit y   m e a n s t h at t h er e i s  e vi d e n c e t o  s u g g e st  a  c a u s al r el ati o n s hi p  b et  w e e n t h e 
dr u g  a n d t h e   A  E.  
•    N ot   R el at e d  : T h er e i s littl e  or  n o r e a s o n a bl e  p o s si bilit y t h at t h e   A  E/  S  A  E i s r el at e d t o t h e  st u d y 
dr u g.  T hi s  a s s e s s  m e nt i  m pli e s t h at t h e   A  E/  S  A  E  h a s littl e  or  n o t e  m p or al r el ati o n s hi p t o t h e  st u d y 
dr u g  a n d/ or  a   m or e li k el y  or  c ert ai n  alt er n ati v e  eti ol o g y  e xi st s.  
A n  o v er all  s u  m  m ar y   will  b e  pr e s e nt e d t h at i n cl u d e s t h e  n u  m b er  of  e v e nt s  a n d t h e  n u  m b er  a n d  p er c e nt a g e 
of  s u bj e ct s   w h o   e x p eri e n c e d   at  l e a st   o n e   T  E  A  E   b y  tr e at  m e nt   gr o u p  .  T hi s   s u  m  m ar y    will   al s o  i n cl u d e  
br e a k d o  w n s  of  T  E  A  E s f urt h er  c at e g ori z e d  a s  o c ul ar  a n d  n o n -o c ul ar  T  E  A  E s,  tr e at  m e nt-e  m er g e nt  s eri o u s 
a d v er s e  e v e nt s ( T  E -S  A  E  s ), tr e at  m e nt-r el at e d  T  E  A  E s, tr e at  m e nt-r el at e d  T  E-S  A  E s,   T  E  A  E s l e a di n g t o  e arl y 
tr e at  m e nt  di s c o nti n u ati o n,  T  E  A  E s l e a di n g t o  d e at h,  a n d  T  E  A  E s  b y   m a xi  m u  m  s e v erit y. 
A d diti o n al   s u  m  m ari e s   of   T  E  A  E s    will   b e   pr o vi d e d   s h o  wi n g  t h e   n u  m b er   a n d   p er c e nt a g e   of    s u bj e ct s   w h o 
e x p eri e n c e d  at l e a st  o n e  T  E  A  E  b y  tr e at  m e nt  gr o u p.    O c ul ar   a n d  n o n -o c ul ar   T  E  A  E s    will  b e  s u  m  m ari z e d  
s e p ar at el y  b y tr e at  m e nt  gr o u p  at t h e  s u bj e ct l e v el  b y   S  O  C  a n d   P T.  If  a s u bj e ct  r e p ort s t h e  s a  m e   P T   m ulti pl e 
ti  m e s   wit hi n t h e  s a  m e   S  O  C, t h at   P T   will  o nl y  b e r e p ort e d  o n c e   wit hi n t h at   S  O  C.   A s   wit h t h e   P T, if  a s u bj e ct  
r e p ort s   m ulti pl e  c o n diti o n s   wit hi n t h e  s a  m e   S  O  C, t h at   S  O  C   will  o nl y  b e r e p ort e d  o n c e.  I n t h e  s u  m  m ar y, 
S  O  C  s  a n d   P T s   wit hi n  a   S  O  C  will   b e  or d er e d  i n d e s c e n di n g fr e q u e n c y  of   C o  m b o  s u bj e ct s .  
S e p ar at e  s u  m  m ari e s   will  b e  pr o vi d e d f or t h e f oll o  wi n g  c at e g ori e s  of   A  E s:    
•    O c ul ar  T  E  A  E s    
•    N o n  -o c ul ar  T  E  A  E s   
•    Tr e at  m e nt -r el at e d  o c ul ar  T  E  A  E s 
•    Tr e at  m e nt -r el at e d  n o n-o c ul ar  T  E  A  E s  
•    O c ul ar  T  E  -  SA  E s   
•    N o n  -o c ul ar  T  E -S  A  E s   
•    O c ul ar  T  E  A  E s  b y   M a xi  m u  m   S e v erit y   
•    N o n  -O c ul ar  T  E  A  E s  b y   M a xi  m u  m   S e v erit y   
T o  c o u nt t h e  n u  m b er  of  s u bj e ct s   wit h  a n y  T  E  A  E s, if  a  s u bj e ct  h a s   m ulti pl e  T  E  A  E s  c o d e d t o t h e  s a  m e   P T 
wit hi n t h e  s a  m e   S  O  C, t h e  s u bj e ct   will  b e  c o u nt e d  o n c e  u n d er t h e   m a xi  m u  m  s e v erit y.   


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  2 1   of  2 9  
All   A  E s   will  b e  pr e s e nt e d i n  a  s u bj e ct li sti n g.  T h e   A  E s   l e a di n g t o st u d y  dr u g  di s c o nti n u ati o n  will  b e li st e d 
s e p ar at el y.  I n  a d diti o n,  all   S  A  E s   will  b e  pr e s e nt e d i n  a  s e p ar at e li sti n g. 
All   A  E  s u  m  m ari e s   will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s  :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s, 
a n d  > 6 4  y e ar s.  
1 3. 2    
B e st  -C orr e ct e d   Vi s u al   A c uit y    
T h e l o g arit h  m  of t h e   mi ni  m u  m  a n gl e  of r e s ol uti o n (l o g  M  A  R)   B  C  V  A   i s  a s s e s s e d  at  e a c h  vi sit  u si n g  a n   E T  D  R  S 
c h art.   S u bj e ct s  s h o ul d  u s e t h eir   m o st r e c e nt  c orr e cti o n t o  att ai n t h eir   B  C  V  A.  
T h e   o b s er v e d   a n d   c h a n g e  fr o  m   b a s eli n e    B  C  V  A   will   b e   s u  m  m ari z e d  f or   e a c h   e y e   u si n g   c o nti n u o u s  
d e s cri pti v e  st ati sti c s  b y  vi sit f or  e a c h tr e at  m e nt  gr o u p.   A  s u bj e ct li sti n g  of  B  C  V  A   will  al s o  b e  pr o d u c e d.   T hi s 
a n al y si s   will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s,  a n d  > 6 4 
y e ar s.  
1 3. 3    
Slit  -L a  m p   Bi o  mi cr o s c o p y  
A  slit  -l a  m p  bi o  mi cr o s c o p y  e x a  mi n ati o n  of t h e li d  a n d li d   m ar gi n ( er yt h e  m a,  s  w elli n g),  c o nj u n cti v a ( p al p e br al 
a n d    b ul b ar   [ er yt h e  m a/ h y p er e  mi a,    c h e  m o si s]),    c or n e a    ( e d e  m a,    er o si o n,    e n d ot h eli al    c o n diti o n,   l e n s   
p at h ol o g y) , a n d  a nt eri or  c h a  m b er  ( c ell s, fl ar e)   will  b e  p erf or  m e d  at  e a c h  vi sit.  T h e r e s ult s   will  b e  gr a d e d o n 
t h e  s c al e  pr e s e nt e d i n  T a bl e  2. 
 
 


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  2 2   of  2 9  
T a bl e  2.  Gr a di n g   S c al e f or   Slit  L a  m p   Bi o  mi cr o s c o p y   
R e gi o n   
S u b c at e g or y     
S c al e   
Li d  a n d  Li d   M ar gi n    
Er yt h e  m a   
0 (  N o n e;  0),  0. 5 ( + 0. 5),  1 (  Mil d;  + 1),  1. 5 ( + 1. 5),  2 
(  M o d er at e;  + 2),  2. 5 ( + 2. 5)  3 (  S e v er e;  + 3),  3. 5 
( + 3. 5)  4 (  V er y   S e v er e;  + 4) 
 
S  w elli n g   
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
C o nj u n cti v a 
(  P al p e br al  a n d 
B ul b ar)   
Er yt h e  m a/  H y p er e  mi a     0 (  N o n e;  0),  0. 5 ( + 0. 5),  1 (  Mil d;  + 1),  1. 5 ( + 1. 5),  2 
(  M o d er at e;  + 2),  2. 5 ( + 2. 5)  3 (  S e v er e;  + 3),  3. 5 
( + 3. 5)  4 (  V er y   S e v er e;  + 4) 
 
C h e  m o si s   
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
C or n e a   
E d e  m a   
0  (  N o n e;  0),  0. 5 (  Mil d;  + 0. 5),  1 (  M o d er at e;  + 1),  2 
(  S e v er e;  + 2),  3 (  V er y   S e v er e;  + 3) 
 
Er o si o n   
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3) 
 
E n d ot h eli al 
C o n diti o n   
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
 
L e n s   P at h ol o g y    
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
A nt eri or   C h a  m b er     
C ell s   
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
 
Fl ar e  
0 (  N o n e;  0),  1 (  Mil d;  + 1),  2 (  M o d er at e;  + 2),  3 
(  S e v er e;  + 3),  4 (  V er y   S e v er e;  + 4) 
T h e r e s ult s   will  b e  s u  m  m ari z e d  u si n g  b ot h  c o nti n u o u s  d e s cri pti v e  st ati sti c s  a n d  c o u nt s  a n d  p er c e nt a g e s f or 
e a c h tr e at  m e nt  at  e a c h  vi sit f or  e a c h  e y e.  F or t h e  s u  m  m ar y   wit h  c o u nt s,  p er c e nt a g e s   will  b e  b a s e d  o n t h e 
n u  m b er  of t h e r e s p e cti v e  e y e s   wit h  n o n -mi s si n g  a s s e s s  m e nt  at  b a s eli n e  a n d  at t h e r e s p e cti v e  p o st  -b a s eli n e 
vi sit f or t h e  p o p ul ati o n  b ei n g  a n al y z e d.  S hift t a bl e s f or t h e  slit  -l a  m p  bi o  mi cr o s c o p y  p ar a  m et er s   will  al s o  b e 
pr o vi d e d   c o  m p ari n g   e a c h  f oll o  w -u p   vi sit  t o   b a s eli n e.    A   s u bj e ct  li sti n g   of  t h e   slit -la  m p   bi o  mi cr o s c o p y  
p ar a  m et er s   will  al s o  b e  pr o d u c e d.  
T hi s  a n al y si s   will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s  :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s,  a n d 
> 6 4  y e ar s.  
1 3. 4    
I ntr a o c ul ar   Pr e s s ur e 
S u bj e ct s’ I  O  P   will  b e  a s s e s s e d  b y  n o n  -c o nt a ct t o n o  m etr y i n  e a c h  e y e  at   D a y  1 (  Vi sit  1)  a n d   D a y  4 3 ( Vi sit 
4) .   R e s ult s   will  b e t a k e n fr o  m  a  si n gl e   m e a s ur e  m e nt  a n d r e c or d e d i n   m  m  H g. 
T h e I  O  P  v al u e s  a n d  c h a n g e s fr o  m  b a s eli n e f or  e a c h  e y e   will  b e  s u  m  m ari z e d  u si n g  c o nti n u o u s  d e s cri pti v e 
st ati sti c s  b y  vi sit  a n d  e y e f or  e a c h tr e at  m e nt  gr o u p.   A  s u bj e ct li sti n g  of I  O  P   will  al s o  b e  pr o d u c e d.  


Pr ot o c ol   9 1 3/ 2 2 -1 0 0 -0 0 0 6  S  A  P,   V er si o n   1. 0  
2 9  S  E  P 2 0 2 3  
C o nfi d e nti al   &   Pr o pri et ar y   
P a g e  2 3   of  2 9  
T hi s  a n al y si s   will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s  :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s,  a n d 
> 6 4  y e ar s.  
1 3. 5      
Dil at e d  F u n d o s c o p y E x a  mi n ati o n   
A  dil at e d f u n d o s c o p y  e x a  mi n ati o n  of t h e  vitr e o u s, r eti n a,   m a c ul a,  c h or oi d  , a n d  o pti c  n er v e   will  b e  p erf or  m e d 
at  D a y   1   (  Vi sit   1)   a n d    D a y   4 3  (  Vi sit  4).   T h e  r e s ult s    will  b e  gr a d e d  a s    N or  m al,    A b n or  m al (  N ot    Cli ni c all y  
Si g nifi c a nt [  N  C  S  ]),  or   A b n or  m al (  Cli ni c all y   Si g nifi c a nt [C  S  ]).  
T h e r e s ult s   will  b e  s u  m  m ari z e d  u si n g  c o u nt s  a n d  p er c e nt a g e s f or  e a c h tr e at  m e nt  gr o u p  at  e a c h  vi sit f or 
e a c h  e y e.  P er c e nt a g e s   will  b e  b a s e d  o n t h e  n u  m b er  of t h e r e s p e cti v e  e y e s   wit h  n o n  -mi s si n g  a s s e s s  m e nt 
at  b a s eli n e  a n d  at t h e r e s p e cti v e  p o st -b a s eli n e  vi sit f or t h e  p o p ul ati o n  b ei n g  a n al y z e d.   A  s  hift t a bl e f or t h e 
dil at e d f u n d o s c o p y  p ar a  m et er s   will  al s o  b e  pr o vi d e d  c o  m p ari n g  t h e f oll o  w-u p  vi sit t o  b a s eli n e.   A  s u bj e ct 
li sti n g  of t h e  dil at e d f u n d o s c o p y  p ar a  m et er s   will  al s o  b e  pr o d u c e d. 
T hi s  a n al y si s   will  b e r e p e at e d  o n t h e f oll o  wi n g  a g e  s u b gr o u p s  :  5-1 2  y e ar s,  1 3 -1 7  y e ar s,  1 8 -6 4  y e ar s,  a n d 
> 6 4  y e ar s.  
1 3. 6    
P h y si c al   E x a  mi n ati o n   
T h e  p h y si c al  e x a  mi n ati o n r e s ult s,  gr a d e d  a s  n or  m al  or  a b n or  m al,   will  b e  s u  m  m ari z e d  b y tr e at  m e nt  gr o u p 
a n d  f or  all a cti v el y tr e at e d  s u bj e ct s  u si n g  c o u nt s  a n d  p er c e nt a g e s  at  D a y  1 (  Vi sit  1  ) a n d  D a y  4 3 (  Vi sit  4  ). 
S hift t a bl e f or t h e   p h y si c al  e x a  mi n ati o n  p ar a  m et er s  H e a d,   E y e,   E ar,   N o s e,  T hr o at  a n d   G e n er al   H e alt h   will 
al s o  b e  pr o vi d e d  c o  m p ari n g  t h e f oll o  w-u p  vi sit t o  b a s eli n e.   A  s u bj e ct li sti n g  of t h e  p h y si c al  e x a  mi n ati o n 
r e s ult s   will  al s o  b e  pr o d u c e d. 
1 3. 7    
Vit al   Si g n s   
Vit al  si g n s, i n cl u di n g  bl o o d  pr e s s ur e ( s y st oli c  a n d  di a st oli c),  p ul s e,  h ei g ht,   w ei g ht,  a n d  b o d y   m a s s i n d e x  , 
will  b e  s u  m  m ari z e d   wit h  c o nti n u o u s  d e s cri pti v e  st ati sti c s  at   D a y  1 (  Vi sit  1  ) a n d  D a y  4 3 (  Vi sit  4  ) b y tr e at  m e nt 
gr o u p  a n d   f or  all a cti v el y tr e at e d  s u bj e ct s . C h a n g e fr o  m  b a s eli n e   will  al s o  b e  s u  m  m ari z e d t o  e a c h  p o st  -
b a s eli n e  vi sit.   
A  s u bj e ct li sti n g  of t h e  vit al  si g n s r e s ult s   will  al s o  b e  pr o d u c e d.   
1 3. 8    
Dr o p   C o  mf ort   A s s e s s  m e nt   
At  D a y  1 (  Vi sit  1  ), D a y  8 (  Vi sit    2),  a n d D a y  2 2 (  Vi sit   3) ,  dr o p  c o  mf ort   will  b e  a s s e s s e d,  o n  a    
   w h er e 
,  u p o n i n still ati o n,  at  3 0  s e c o n d s  p o st i n still ati o n,  a n d  1 
mi n ut e  p o st i n still ati o n f or  b ot h  e y e s.   Dr o p  c o  mf ort  a s s e s s  m e nt  s c or e s   will  b e   a v er a g e d  o v er  b ot h  e y e s  a n d 
s u  m  m ari z e d   wit h  c o nti n u o u s  d e s cri pti v e  st ati sti c s  at  e a c h  vi sit  b y tr e at  m e nt  gr o u p.  T h e   m e a n  diff er e n c e, 
t  w o-si d e d   9 5  %    CI ,  a n d   p -v al u e  fr o  m   a  t  w o -s a  m pl e  t -t e st   c o  m p ari n g    C o  m b o   a n d    V e hi cl e    will   al s o   b e  
pr o d u c e d.   
A  s u bj e ct li sti n g  of   d r o p  c o  mf ort  a s s e s s  m e nt r e s ult s   will  al s o  b e  pr o d u c e d.