Conditions: Inflammation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 91
Healthy volunteers: no

Brief summary:
This is a multicenter, double-masked, randomized, vehicle-controlled, parallel-comparison study conducted at sites in the United States (US) in subjects undergoing routine unilateral cataract extraction and lens replacement (CELR) surgery via phacoemulsification

Detailed description:
This is a phase 2, multicenter, double-masked, randomized, vehicle-controlled, parallel-comparison study conducted at sites in the US assessing the safety and ocular efficacy of VVN461 for treating post-operative ocular inflammation in subjects who undergo routine unilateral CELR surgery via phacoemulsification without surgical complication. Approximately 90 subjects (30 per group) will be randomized in a 1:1:1 ratio. Subjects will administer 1 eye drop in the study eye four times a day (QID) for 14 days.

Arms:
arm 1: VVN461 Ophthalmic Solution, 1.0% arm 2: VVN461 Ophthalmic Solution, 0.5% arm 3: VVN461 Vehicle

Interventions: intervention 1: VVN461 Ophthalmic Solution 1.0% intervention 2: VVN461 Ophthalmic Solution 0.5% intervention 3: Vehicle
Intervention descriptions: intervention 1: Topical ocular drug intervention 2: Topical ocular drug intervention 3: Topical ocular drug

Protocol document:
Prot_002.pdf: 
NCT06164743  
Clinical Study VVN461-CS201  
Protocol  
13 February 2024 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1  of 5 9  
T itl e Pa g e  
A  p h as e 2, d o u bl e -m as k e d, r a n d o mi z e d, v e hi cl e -c o nt r oll e d st u d y of 
V V N 4 6 1 O p ht h al mi c S ol uti o n i n t r e ati n g p ost -o p e r ati v e o c ul a r 
i nfl a m m ati o n i n s u bj e cts u n d e r g oi n g r o uti n e u nil at e r al c at a r a ct 
s u r g e r y 
Pr ot oc ol N u m ber : 
V V N 4 6 1 -C S -2 0 1  
N ati o n al Cli nic al Tri al N u m ber:  
N C T 0 6 1 6 4 7 4 3  
I n vesti g ati o n al Ne w Dr u g N u m ber:  
1 6 6 9 2 7  
St u d y  P h ase : 
2  
S p o ns or:  
Vi va Visi o n Bi otec h ( H o n g K o n g) L t d. 
U nit 2 0 2 A of t he 2 n d Fl o or of B uil di n g 2 E  
P hase O ne, H o n g K o n g Scie nce Par k  
H o n g K o n g, 0 0 0 0 0 0, C hi na  
Me dic al M o nit or :  
 
 
 
 
 
Versi o n N u m ber:  
4. 0  
Iss ue D ate : 
1 3 Fe br uar y 2 0 2 4  
 
 
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns i nf or mati o n fr o m  Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  a n d is of c o nfi de ntial, tra de secret, 
a n d/ or pr o prietar y nat ure a n d ma y n ot be discl ose d u nless s uc h discl os ure is re q uire d b y fe deral or state la w or 
re g ulati o n. It is l oa ne d t o y o u f or y o ur c o nfi de ntial re vie w o n be half of Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d. o nl y 
a n d is n ot t o be p h ot oc o pie d, discl ose d, or tra ns mitte d t o a n y ot her pers o n or part y wit h o ut t he a d va nce writte n 
a p pr o val of  Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2  of 5 9  
P r ot o c ol S y n o psis  
Title:  
A  p hase 2, d o u ble -mas ke d, ra n d o mize d, ve hicle -c o ntr olle d st u d y of V V N 4 6 1 
O p ht hal mic S ol uti o n i n treati n g p ost -o perati ve oc ular i nfla m mati o n i n s u bj ects 
u n der g oi n g r o uti ne u nilateral cataract s ur ger y  
P h ase:  
2  
Desi g n/ C o n d uct:  
T his is a m ultice nter, d o u ble -mas ke d, ra n d o mize d, ve hicle -c o ntr olle d, parallel -
c o m paris o n st u d y c o n d ucte d at sites i n t he U nite d States ( U S) i n s u bj ects 
u n der g oi n g r o uti ne u nilateral cataract e xtracti o n a n d le ns re place me nt ( C E L R) 
s ur ger y via p hac oe m ulsificati o n 
O bjecti ves:  
P ri m ar y:  
E val uate t he oc ular efficac y of 2 differe nt d oses of V V N 4 6 1 O p ht hal mic 
S ol uti o n i n treati n g p ost -o p erati ve oc ular i nfla m mati o n ass ociate d 
wit h 
cataract s ur ger y c o m pare d wit h t he oc ular efficac y of a matc hi n g V e hicle  
Sec o n d ar y:  
E val uate t he safet y of  V V N 4 6 1  
E n d p oi nts:  
P ri m ar y E n d p oi nt : 
 
P r o p orti o n of s u bj ects wit h a nteri or c ha m ber cell ( A C C) Gra de 0 i n 
the st u d y e ye at Visit 6 ( Da y 1 4)  
Sec o n d ar y E n d p oi nt s: 
 
Pr o p orti o n of s u bj ects wit h A C C Gra de 0  i n t he st u d y e ye at Visit 5 
( Da y 7) 
 
Pr o p orti o n of s u bj ects wit h a nteri or c ha m ber flare ( A C F) Gr a de 0 i n 
t he st u d y e ye at Visit 6 ( Da y 1 4) 
 
Pr o p orti o n of s u bj ects wit h A C F  Gra de 0 i n t he st u d y e ye at Visit 5 
( Da y 7) 
 
P r o p orti o n of s u bj ects re q uiri n g resc ue me dicati o n bef ore Visit 6 
( Da y 1 4) 
E x pl or at or y E n d p o i nts: 
 
M ea n c ha n ge fr o m baseli ne ( C F B) i n A C C Gra de i n t he st u d y e ye at 
eac h visit  
 
Mea n C F B i n A C F Gra de i n t he st u d y e ye at eac h visit  
 
Pr o p orti o n of s u bj ects wit h n o p ost -o perati ve oc ular pai n i n t he st u d y 
e ye at Visit 6 ( Da y 1 4)  
 
Pr o p orti o n of s u bj ects w it h n o p ost-o perati ve oc ular pai n i n t he st u d y 
e ye at Visit 5 ( Da y 7)  
P o p ul ati o n St u die d:  
A p pr o xi matel y 9 0 c o m plete d s u bj ects ( 3 0 per gr o u p)  w h o ha ve u n der g o ne 
ro uti ne u nilateral C E L R s ur ger y via p hac oe m ulsificati o n wit h o ut s ur gical 
c o m plicati o n.  
S u bj ects w h o meet all i ncl usi o n criteria will be eli gi ble f or st u d y  partici pati o n.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3  of 5 9  
I ncl usi o n Criteri a:  
1.  ≥2 1 years of a ge a n d i n g o o d ge neral healt h at Visit 1 ( Scree ni n g)  
2.  Willi n g a n d a ble t o pr o vi de i nf or me d c o nse nt a n d pr o vi de rele va nt 
pri vac y a ut h orizati o n(s)  
3.  Willi n g a n d a ble t o c o m pl y wit h st u d y re q uire me nts a n d visit sc he d ule  
4.  Clear oc ular me dia ( ot her t ha n cataract) i n t he st u d y e ye  
5.  P la n ni n g t o 
u n der g o r o uti ne 
u nilateral 
C E L R 
s ur ger y 
via 
p hac oe m ulsificati o n e xtracti o n a n d i m pla ntati o n of a n i ntra o c ular 
le ns. All o w e d i n t he st u d y e ye at Visit 2 ( Da y of S ur ger y): 
a. 
Li m bal rela xi n g i ncisi o ns (las er -assiste d a n d n o n -laser) 
b.  I ntraca meral i nj ecti o ns 
a n d i ntraca meral 
me dicati o ns, 
e xcl u di n g t h ose i de ntifie d i n E xcl usi o n Criteri o n # 2  
6.  A t Visit 1 ( Scree ni n g), has t he p ote ntial, i n t he o pi ni o n of t he 
I n vesti gat or, for p ost o perati ve best c orrecte d vis ual ac uit y ( B C V A ) 
≤0 . 2 L o garit h m of t he Mi ni m u m A n gle of Res ol uti o n ( L o g M A R) 
(i.e., 2 0/ 3 2 S nelle n or better) i n t he st u d y e ye as assesse d usi n g Earl y 
Treat me nt Di a betic Reti n o pat h y St u d y ( E T D R S)  
7.  A t Visit 1 ( Scree ni n g), has B C V A ≤1. 0 L o g M A R (i.e., 2 0/ 2 0 0 
S nelle n) i n t he n o n -st u d y e ye d ue t o pat h ol o g y ot her t ha n cataract  as 
assesse d usi n g E T D R S  
8.  A ble t o self -a d mi nister e ye dr o ps  
9.  At Visit 3 ( Baseli ne/ Ra n d o mi zati o n; Da y  1), has A C C  Gra de  ≥2 i n 
t he st u d y e ye 
S u bj ects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria will n ot be eli gi ble 
f or st u d y partici pati o n.  
E xcl usi o n Criteri a : 
O p ht h al mic ( Eit her E ye)  
1.  A n y oc ular pai n at Visit 1 ( Scree ni n g)  
2.  Use d wit hi n 1 wee k bef ore Visit 2 ( Da y of S ur ger y), or be pla n ni n g 
t o use d uri n g t he st u d y, cortic oster oi ds, oral or t o pical n o n -ster oi dal 
a nti -i nfla m mat or y dr u gs ( N S AI Ds), or  O mi dria ®  (i.e., p he n yle p hri ne 
a n d ket or olac i nj ecti o n) .  
N o te: L o w-d ose acet ylsalic yli c aci d (i.e., ba b y a s piri n or si milar) is 
all o we d  
3.  M o derate t o se vere li d, c o nj u ncti val, or c or neal fi n di n gs at Visit 1 
( Scree ni n g) 
4.  C or neal a b n or malit y (e. g., str o mal, e pit helial, 
or e n d ot helial 
d ystr o p hies, i ncl u di n g e pit heli al base me nt me m bra ne d ystr o p h y)  
5.  Hist or y of c hr o nic/ rec urre nt i nfla m mat or y e ye disease (e. g., scleritis, 
a n y u veitis, her pes keratitis)  
6.  A n y si g ns of i ntra oc ular i nfla m mati o n (cell/flare) at 
Visit 1 
( Scree ni n g)  
7.  I ntra oc ular press ure (I O P) ≥2 4 m m H g at Visit 1 ( Scree ni n g)  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4  of 5 9  
O p ht h al mic ( St u d y E ye)  
8.  Usi n g  or u n willi n g t o f or g o c o ntact le ns use wit hi n defi ne d wi n d o ws 
bef ore Visit 2 ( Da y of S ur ger y) a n d f or t he d urati o n of t he st u d y  
a. 
P ol y met h yl met hacr ylate c o ntact le nses ( 6 m o nt hs bef ore 
s ur ger y a n d t hr o u g h o ut st u d y) 
b.  Gas per mea ble ri gi d le nses ( 1 m o nt h bef or e s ur ger y a n d 
t hr o u g h o ut st u d y)  
c. 
E xte n de d wear or dail y s oft le nses ( 7 da ys bef ore s ur ger y a n d 
t hr o u g h o ut st u d y)  
9.  K n o w n pat h ol o g y t hat ma y affect vis ual ac uit y, partic ularl y reti nal 
c ha n ges t hat affect visi o n (e. g., 
mac ular de ge nerati o n, c yst oi d 
mac ular e de ma, pr oliferati ve dia betic reti n o pat h y)  
1 0.  Ca ps ule or z o n ular a b n or malities wit h pre -o perati ve cr ystalli ne le ns 
tilt or dece ntrati o n (e. g., Marfa n’s s y n dr o me) or a b n or malities t hat 
ma y affect p ost -o perati ve ce ntrati o n or tilt of t he cr ystalli ne l e ns (e. g.,  
pse u d oe xf oliati o n s y n dr o me)  
1 1.  Hist or y of m o derate t o se vere oc ular tra u ma wit h t he p ossi bilit y of 
pre vi o us z o n ule de hisce nce  
1 2.  O c ular or peri oc ular s ur gical i nter ve nti o ns wit hi n defi ne d wi n d o ws  
bef ore Vi sit 1 ( Scree ni n g) 
a. 
Micr oi n vasi ve gla uc o ma s ur ger y, a n y i n cisi o nal oc ular 
s ur ger y, or i ntraca meral dr u g de p ot t o l o wer I O P (a n y 
hist or y)  
b.  I ntra oc ular s ur ger y ( 6 m o nt hs) 
c. 
Laser s ur ger y, li m bal rela xi n g i ncisi o n pr oce d ure, e yeli d 
s ur ger y ( 3 m o nt hs) 
1 3.  P u pil a b n or malities (e. g., n o n -reacti ve, t o nic p u pils, a b n or mall y 
s hape d p u pils, p u pils t hat d o n ot dilate at least 3. 5 m m u n der 
mes o pic/sc ot o pic c o n diti o ns)  
1 4.  Kerat oc o n us or si g nifica nt irre g ular asti g matis m o n pre -o perati ve 
oc ular t o p o gra p h y  
1 5.  Ha ve a c o n diti o n, or be i n a sit uati o n, t hat ma y p ut t he s u bj ect at 
si g nifica nt risk of c o m ple x s ur ger y a n d s ur gical c o m plicati o ns t hat 
w o ul d lea d t o wit h dra wal fr o m t he st u d y  
O p ht h al mic ( N o n -st u d y E ye) 
1 6.  U n der we nt c ataract s ur ger y < 1 4 da ys bef ore Visit 1 ( Scree ni n g) or, 
d uri n g t he st u d y, will re q uire cataract s ur ger y < 1 da y after Visit 2 
( Da y of S ur ger y) 
Ge ner a l 
1 7.  W it hi n 3 0 da ys bef ore 
Visit 1 ( Scree ni n g), partici pate d in a n 
i n vesti gati o nal dr u g or de vice st u d y, or ha ve use d a n i n vesti gati o nal 
dr u g or de vic e 
1 8.  A ller g y or h y perse nsiti vit y t o t he i n vesti gati o nal pr o d uct (I P) or its 
e xci pie nts  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5  of 5 9  
1 9.  S ig nifica nt s yste mic disease (e. g., u nc o ntr olle d dia betes ; m yast he nia 
gra vis ; he patic, re nal, car di o vasc ular , or e n d ocri ne dis or ders)  
2 0.  U nc o ntr olle d s yste mic disease, defi ne d as, wit hi n 3 0 da ys  bef ore V isit 
1 ( Scree ni n g), a c ha n ge i n disease stat us or me dicati o ns t hat ma y p ut 
t he s u bj ect at i ncrease d ris k or c o nf o u n d i nter pretati o n of st u d y res ults 
2 1.  C ha n ges wit hi n 3 0 da ys  bef ore V isit 1 ( Scree ni n g), or a ntici pate d 
c ha n ges d uri n g t he st u d y, t o t he d osa ge of s yste mic me dicati o n t hat 
c o ul d ha ve a s u bsta ntial effect  o n I O P  
2 2.  K n o w n blee di n g te n de ncies  
2 3.  Ac ute or c hr o nic disease or ill ness t hat w o ul d p ut t he s u bj ect at 
i ncrease d ris k or c o nf o u n d i nter pretati o n of st u d y res ults (e. g., 
a ut oi m m u ne disease, c o n necti ve tiss ue disease, i m m u n o deficie nc y, 
s us pecte d gla uc o ma, gla uco mat o us c ha n ges i n t he f u n d us or vis ual 
fiel d, oc ular i nfla m mati o n, etc.) 
2 4.  R e q uires,  is li kel y t o re q uire, or is u n willi n g t o disc o nti n ue t he use of 
pr o hi bite d me dicati o ns  
2 5.  P re g na nt, n ursi n g, or pla n ni n g a pre g na nc y d uri n g t he st u d y 
2 6.  U n willi n g or u na ble t o us e a n acce pta ble met h o d of c o ntr ace pti o n 
t hr o u g h o ut t he st u d y if a w o ma n of c hil d beari n g p ote ntial ( W O C B P) 
2 7.  U n willi n g or u na ble t o use a n acce pta ble met h o d of c o ntr ace pti o n 
t hr o u g h o ut t he st u d y if a male se x ual part ner of a W O C B P 
I n vesti g ati o n al Pr o d ucts:  
 
V V N 4 6 1, 1. 0 %  
 
V V N 4 6 1, 0. 5 %  
 
Ve hicle  
D osi n g Re gi me n:  
A p pr o xi matel y 9 0 c o m plete d s u bj ects will be ra n d o mize d i n a 1: 1: 1 rati o t o 
V V N 4 6 1, 1. 0 %, V V N 4 6 1, 0. 5 %, or a matc hi n g Ve hicle t hat d oes n ot c o ntai n 
t he acti ve p har mace utical i n gre die nt ( A PI). S u bj ects will a d mi nister 1 e ye dr o p 
i n t he st u d y e ye f o ur ti mes a d a y ( QI D) f or 1 4 da ys. 
Assess me nts/ E v al u ati o ns:  
E ffic ac y: 
 
Oc ular i nfla m mati o n ( Sta n dar dizati o n of 
U veitis 
N o me nclat ure 
[ S U N] Scale) 
 
P ost -o perati ve oc ular pai n ( N u meric P ai n Rati n g Scale [ N P R S])  
S afet y:  
 
A d verse e ve nt ( A E) m o nit ori n g ( oc ular a n d n o n -oc ular)  
 
Cli nicall y rele va nt c ha n ges fr o m baseli ne i n t he f oll o wi n g:  
o  
B C V A  
o  
Slit la m p bi o micr osc o p y  
o  
I O P 
o  
Dilate d o p ht hal m osc o p y  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 6  of 5 9  
D ur ati o n of St u d y:  
S u bj ects will be assesse d at 7 visits o ver a p pr o xi matel y 8 wee k s. 
Visits 
will i ncl u de a scree ni n g visit, t he da y of cat aract s ur ger y, a 
baseli ne/ra n d o mizati o n visit, a n d efficac y a n d safet y e val uati o n visits after 3, 
7, a n d 1 4 da ys of QI D d osi n g wit h I P i n t he st u d y e ye. T he st u d y will c o ncl u de 
wit h a safet y f oll o w -u p v isit a p pr o xi matel y 1 wee k after t he e n d of t he pla n ne d 
d osi n g peri o d.  
St atistic al M et h o ds:  
A  sa m ple size of a p pr o xi matel y 9 0 c o m plete d s u bj ects will be ra n d o mize d i n 
a 1: 1: 1 rati o t o V V N 4 6 1, 1. 0 %, V V N 4 6 1, 0. 5 %, a n d a mat c hi n g Ve hicle t hat 
d oes n ot c o ntai n  t he A PI. Wit h a sa m ple size i n eac h gr o u p of 3 0, t he st u d y 
will ha ve 8 0 % p o wer t o detect a differe nce of 3 5 %, ass u mi n g a res p o nse rate 
of 3 0 % i n t he Ve hicle gr o u p, a n d a t w o -si de d 0. 0 5 si g nifi ca nce le vel f or a 
P ears o n c hi -s q uare test. A dr o p-o ut rate of 1 0 % is ass u me d, res ulti n g i n a t otal 
sa m ple size of a p pr o xi matel y 1 0 2 s u bj ects. 
T he F ull A nal ysis Set ( F A S) will c o nsist of all s u bj ects w h o are ra n d o mize d. 
S u bj ects will be a nal yze d i n t he gr o u p t o w hic h t he y are ra n d o mize d. T his set 
will b e use d f or t he a nal ysis of all efficac y e n d p oi nts as t he pri mar y a nal ysis.  
T he P er Pr ot oc ol ( P P) A nal ysis Set is a s u bset of t he F A S a n d will i ncl u de all 
s u bj ects i n t he F A S w h o c o m plete st u d y-re q uire d treat me nt a n d w h o f oll o w 
t he pr ot oc ol wit h o ut si g nifica nt de viati o ns. T he deter mi nati o n of si g nifica nt 
pr ot oc ol de viati o ns will be ma de bef ore data b ase l oc k a n d u n mas ki n g.  
T he S afet y A nal ysis Set ( S A F) will i ncl u de all s u bj ects w h o recei ve at least 
o ne d ose of I P, as i n dicate d o n t he d osi n g rec or d. S u bj ects will be a nal yze d  i n 
t he gr o u p acc or di n g t o t he treat me nt recei ve d. All safet y varia bles will be 
a nal yze d usi n g t he S A F, a n d o nl y o bser ve d data will be i ncl u de d (i.e., missi n g 
data will re mai n missi n g f or t he safet y a nal ysis).  
Pri m ar y Esti m a n d : T he pri mar y esti ma n d is treat me nt differe nce bet wee n 
V V N 4 6 1 ( 1. 0 % or 0. 5 %) a n d t he Ve hicle i n t he pr o p orti o n of s u bj ects wit h 
A C C  Gra de 0  at Visit 6 ( Da y 1 4) i n t he st u d y e ye usi n g t he F A S.  
T ar g et P o p ul ati o n : S u bj ects u n der g oi n g r o uti ne cataract s ur ger y w h o m eet 
t he st u d y e ntr y criteria. 
E n d p oi nt : Pr o p orti o n of s u bjects wit h A C C Gra de 0  i n t he st u d y e ye at Visit 
6 ( Da y 1 4).  
Tre at me nt 
C o n diti o n(s) : Treat me nt c o n diti o n is base d o n ra n d o mize d 
treat me nt. 
P o p ul ati o n -le vel S u m m ar y: T he differe nce i n pr o p orti o ns i n s u bj ects wit h 
A C C  Gra de 0  i n t he st u d y e ye at Visit 6 ( Da y 1 4) a n d t he c orres p o n di n g  
p -val ue.  
T he pr o p ose d pr oce d ures t o ha n dle missi n g data a n d i nterc urre nt e ve nts are as 
f oll o ws: 
 
Disc o nti n uati o n of st u d y t her a p y wit h c o nti n ue d partici pati o n i n t he 
st u d y wit h o ut recei pt of resc ue t hera p y 
o  
Treat me nt P olic y A p pr oac h –  n o i m p utati o n; use o bser ve d 
data  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 7  of 5 9  
 
Recei pt of resc ue t hera p y (t o pical c ortic oster oi d) i n t he st u d y e ye  
o  
C o m p osite A p pr oac h –  s u bj ects w h o recei ve resc ue t hera p y 
at or bef ore t he assess me nt visit will be ass u me d t o ha ve 
faile d t he pri mar y e n d p oi nt 
 
Missi n g data wit h or wit h o ut wit h dra wal, re gar dless of reas o n  
o  
H y p ot hetical A p pr oac h –  n o i m p utati o n; a nal ysis will be 
base d o n s u bj ects w h o ha ve a n e val ua ble a nteri or c ha m ber  
in t he st u d y e ye at Visit 6 ( Da y 1 4)  
P ears o n’s c hi -s q uare will be use d t o test t he pri mar y e n d p oi nt bet wee n t he 2 
differe nt d oses of V V N 4 6 1 v ers us t he Ve hicle. T he pri mar y a nal ysis will als o 
be perf or me d o n t he P P A nal ysis Set.  
T he sec o n dar y efficac y e n d p oi nts will i ncl u de t he pr o p orti o n of s u bj ects wit h 
A C C  G ra de 0, t he pr o p orti o n of s u bj ects wit h A C F Gra de 0, a n d t he pr o p orti o n 
of s u bj ects re q uiri n g resc ue me dicati o n. T hese e n d p oi nts will be a nal yze d 
re gar dless of t he si g nifica nce of t he pri mar y e n d p oi nt a nal ysis. 
E x pl orat or y e n d p oi nts will be a nal yze d i n a ma n ner si milar t o t he sec o n dar y 
e n d p oi nts. Mea n C F B  i n A C C Gra de a n d A C F Gra de will be a nal yze d usi n g 
mi xe d m o del re peate d meas ur es. T he m o del will i ncl u de treat me nt, visit, a n d 
treat me nt b y visit i nteracti o n as fi xe d effects a n d a c o variate f or baseli ne 
meas ure me nt ( w here a p pr o priate) 
wit h a ra n d o m effect f or site. 
A n 
u nstr uct ure d c o varia nce a m o n g re peate d meas ure me nts will be ass u me d. O nl y 
data fr o m bef ore t he use of resc ue me dicati o n will be i ncl u de d i n t hese 
anal yses. T he pr o p orti o n of s u bj ects wit h n o p ost -o perati ve oc ular pai n i n t he 
st u d y e ye at Visit 5 ( Da y 7) a n d Visit 6 ( Da y 1 4) will als o be a nal yze d.  
Safet y a nal yses will be perf or me d o n all s u bj ects i n t he S A F. T he assess me nt 
of safet y will be base d o n t he s u m mar y of oc ular a n d n o n -oc ular A Es, B C V A, 
a n d o p ht hal mic e xa mi nati o ns  usi n g slit la m p bi o micr os c o p y a n d dilate d 
o p ht hal m osc o p y. S u m maries will be pr o vi de d b y treat me nt gr o u p a n d, f or 
oc ular assess me nts, se paratel y b y e ye.  
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 8  of 5 9  
T a bl e of C o nt e nts  
1  
I ntr o d ucti o n ......................................................................................................................... 1 2  
1. 1  Bac k gr o u n d  ....................................................................................................................... 1 2  
1. 2  St u d y R ati o nale  ................................................................................................................. 1 3  
1. 3  Ris k/ Be nefit Assess me nt  .................................................................................................. 1 3  
1. 3. 1  K n o w n P ote ntial Ris ks  .............................................................................................. 1 3  
1. 3. 2  K n o w n P ote ntial Be nefits  ......................................................................................... 1 3  
1. 3. 3  Assess me nt of Be nefits a n d Ris ks  ............................................................................ 1 4  
2  
St u d y O bjecti ves a n d E n d p oi nts ........................................................................................ 1 5  
3  
St u d y Desi g n  ........................................................................................................................ 1 6  
3. 1  O verall Desi g n of t he St u d y  .............................................................................................. 1 6  
3. 2  Rati o nale f or t he St u d y Desi g n  ......................................................................................... 1 7  
3. 3  D ose J ustificati o n  .............................................................................................................. 1 7  
3. 4  E n d of St u d y Defi niti o n  .................................................................................................... 1 8  
4  
St u d y P o p ul ati o n  ................................................................................................................. 1 9  
4. 1  I n cl usi o n Criteria .............................................................................................................. 1 9  
4. 2  E x cl usi o n Criteria  ............................................................................................................. 1 9  
4. 3  Scree n Fail ures  .................................................................................................................. 2 1  
5  
St u d y Tre at me nt(s) or I nter ve nti o n(s)  .............................................................................. 2 2  
5. 1  I n v esti gati o nal Pr o d ucts .................................................................................................... 2 2  
5. 1. 1  Descri pti o n  ................................................................................................................ 2 2  
5. 1. 2  D osa ge a n d A d mi nistrati o n ....................................................................................... 2 2  
5. 2  Pre parati o n/ St ora ge/ H a n dli n g/ Acc o u nt a bilit y  .................................................................. 2 3  
5. 2. 1  Ac q uisiti o n a n d Acc o u nt a bilit y  ................................................................................ 2 3  
5. 2. 2  Pr o d uct F or m ulati o n, A p peara n ce, Pac ka gi n g, a n d La b eli n g  ................................... 2 3  
5. 2. 3  Pr o d uct St ora ge a n d Sta bilit y .................................................................................... 2 3  
5. 3  Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Mas ki n g  .............................................. 2 4  
5. 4  D osi n g A d h ere n ce a n d D osi n g Diar y  ............................................................................... 2 4  
5. 4. 1  D osi n g A d h ere n ce  ..................................................................................................... 2 4  
5. 4. 2  D osi n g Diar y  ............................................................................................................. 2 4  
5. 5  Pri or a n d C o nc o mita nt T hera p y  ........................................................................................ 2 4  
5. 5. 1  Pr o hi bite d Me dicati o ns a n d Pr oce d ures  .................................................................... 2 5  
5. 5. 2  Resc ue Me dic ati o n  .................................................................................................... 2 6  
6  
St u d y Disc o nti n u ati o n/ S u bject Wit h dr a w al  ..................................................................... 2 7  
6. 1  Disc o nti n uati o n of I n v esti gati o nal Pr o d uct  ...................................................................... 2 7  
6. 2  S u bject Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ....................................................... 2 7  
6. 3  L ost t o F oll o w -U p  ............................................................................................................. 2 7  
7  
St u d y Pr oce d ures  ................................................................................................................ 2 9  
7. 1  Visit Descri pti o ns .............................................................................................................. 2 9  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 9  of 5 9  
7. 1. 1  Visit 1 ( Scree ni n g; Da y -3 0 t o Da y -1)  ..................................................................... 2 9  
7. 1. 2  Visit 2 ( Da y of S ur ger y; Da y 0)  ................................................................................ 2 9  
7. 1. 3  Visit 3 ( Baseli ne/ Ra n d o mizati o n; Da y 1)  ................................................................. 3 0  
7. 1. 4  Visit 4 ( Da y 3 ± 1)  .................................................................................................... 3 0  
7. 1. 5  Visit 5 ( Da y 7 ± 1)  .................................................................................................... 3 1  
7. 1. 6  Visit 6 ( E n d of Treat me nt; Da y 1 4 ± 2)  .................................................................... 3 1  
7. 1. 7  Visit 7 ( E n d of St u d y; Earl y T er mi nati o n; Da y 2 1 ± 2)  ........................................... 3 2  
7. 1. 8  U nsc he d ule d Visits  ................................................................................................... 3 2  
7. 1. 9  Earl y Ter mi nati o n  ..................................................................................................... 3 2  
8  
St u d y Assess me nts  .............................................................................................................. 3 3  
8. 1  Efficac y E val uati o ns  ......................................................................................................... 3 3  
8. 2  Safet y E val uati o ns  ............................................................................................................ 3 3  
8. 2. 1  A d verse E v e nts a n d Seri o us A d verse E v e nts  ........................................................... 3 3  
8. 2. 2  Heart Rate, Bl o o d Press ure, a n d Ot her Safet y E v al uati o ns  ...................................... 3 7  
9  
St atistic al C o nsi der ati o ns  ................................................................................................... 3 8  
9. 1  Statistical H y p ot hesis  ........................................................................................................ 3 8  
9. 2  Sa m ple Siz e Deter mi nati o n ............................................................................................... 3 8  
9. 3  A nal ysis P o p ulati o ns  ......................................................................................................... 3 9  
9. 4  Statistical A nal yses  ........................................................................................................... 3 9  
9. 4. 1  Baseli ne Descri pti ve A nal yses  .................................................................................. 3 9  
9. 4. 2  Efficac y A nal yses  ..................................................................................................... 4 0  
9. 4. 3  Safet y A nal yses  ......................................................................................................... 4 1  
9. 5  I nteri m A nal ysis ................................................................................................................ 4 2  
9. 6  S u b gr o u p A n al ys es  ........................................................................................................... 4 2  
9. 7  E x pl orat or y A nal yses  ........................................................................................................ 4 2  
9. 8  Missi n g, U n use d, or S p uri o us Data  .................................................................................. 4 2  
9. 9  Ta b ulati o n of I n di vi d ual S u bject Data  .............................................................................. 4 2  
1 0  S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  ........................................ 4 3  
1 0. 1  
Re g ulat or y Iss ues, Et hical C o ncer ns, a n d St u d y O versi g ht  .......................................... 4 3  
1 0. 1. 1  
I nf or me d C o nse nt Pr ocess .................................................................................... 4 3  
1 0. 1. 2  
St u d y Disc o nti n uati o n a n d Cl os ure  ...................................................................... 4 4  
1 0. 1. 3  
C o nfi de ntialit y a n d Pri vac y  .................................................................................. 4 4  
1 0. 1. 4  
Ke y R oles a n d St u d y G o ver na nce  ........................................................................ 4 5  
1 0. 1. 5  
Cli nical M o nit ori n g  ............................................................................................... 4 5  
1 0 . 1. 6 
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol  ................................................................ 4 5  
1 0. 1. 7  
Data Ha n dli n g a n d Rec or d Kee pi n g  ..................................................................... 4 6  
1 0. 1. 8  
Pr ot oc ol De viati o ns  ............................................................................................... 4 7  
1 0. 1. 9  
P u blicati o n a n d Data S hari n g P olic y  .................................................................... 4 7  
1 0. 1. 1 0  C o nflict of I nt erest P olic y  ..................................................................................... 4 7  
1 1  Refere nces  ............................................................................................................................ 4 8  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 0  of 5 9  
1 2  A p pe n dices  ........................................................................................................................... 4 9  
1 2. 1  
A p pe n di x 1: Sc he d ule of Pr oce d ures a n d Assess m e nts  ................................................ 5 0  
1 2. 2  
A p pe n di x 2: W o ma n of C hil d beari n g P ote ntial ( W O C B P)  .......................................... 5 1  
1 2. 3  
A p pe n di x 3: Slit La m p Bi o micr osc o p y  ........................................................................ 5 2  
1 2. 4  
A p pe n di x 4: N u meric Pai n Rati n g Scale ( N P R S) ......................................................... 5 4  
1 2. 5  
A p pe n di x 5: Best C orrecte d Vis ual Ac uit y ( B C V A)  .................................................... 5 5  
1 2. 6  
A p pe n di x 6: I ntra oc ul ar Press ure (I O P)  ....................................................................... 5 6  
1 2. 7  
A p pe n di x 7: Dilate d O p ht hal m osc o p y .......................................................................... 5 7  
1 2. 8  
A p pe n di x 8: C o m plia nce State me nt  ............................................................................. 5 8  
1 2. 9  
A p pe n di x 9: I n vesti gat or A gree me nt  ............................................................................ 5 9  
 
List of Ta bl es  
Ta ble 1  Pr o hi bite d Me dicati o ns a n d Pr oce d ures  ........................................................................ 2 6  
Ta ble 2  St u d y A d mi nistrati ve Str uct ure ..................................................................................... 4 5  
Ta ble 3  Slit La m p Tiss ue/ Str uct ure Assess me nts  ...................................................................... 5 2  
Ta ble 4  S U N W or ki n g Gr o u p Gra di n g Scale f or t h e A nteri or C ha m ber ................................... 5 3  
 
L ist of Fi g u res 
Fi g ure 1  Cli nical St u d y Dia gra m ................................................................................................. 1 7  
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 1  of 5 9  
A b b re vi ati o ns a n d D efi niti o n of Te r ms  
A C C  
a nteri or c h a m ber cell  
A C F  
a nteri or c h a m ber flare  
A E  
a d verse e ve nt  
A PI  
acti ve p har m ace utical i n gre die nt  
B C V A  
b est correcte d v is ual ac uit y 
C E L R  
cataract e xtracti o n a n d le ns re place me nt  
C F B  
c ha n ge fr o m baseli ne  
C F R  
C o de of Fe d eral Re g ul ati o ns  
e C R F 
electr o nic case re p ort f or m  
E T D R S  
Earl y Treat me nt Dia betic Reti n o pat h y St u d y  
F A S  
F ull A nal ysis Set  
F D A  
U nite d States 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 L P  
G o o d La b orat or y Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I N D 
I n v esti gati o nal Ne w Dr u g 
I O P 
i ntra oc ular press ure 
I P 
i n vesti gati o nal pr o d u ct 
I R B 
I nstit uti o nal Re vie w B oar d  
J A K 
J a n us ki nase 
J A K-S T A T  
J a n us ki nase-si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n 
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 R e g ul at or y Acti vities  
N P R S  
N u meric Pai n Rati n g Scale  
N S AI D  
n o n -ster oi dal a nti-i nfla m mat or y dr u g 
P P  
Per Pr ot oc ol  
QI D  
q u ater i n die  (f o ur ti mes a da y) 
S A E  
seri o us a d verse e v e nt  
S A F  
Safet y A nal ysis Set  
S A P  
Statistical A nal ysis Pla n  
S U N  
Sta n dar dizati o n of U veitis N o me nclat ure  
T E A E  
treat me nt e mer ge nt a d verse e ve nt  
T Y K 2  
t yr osi ne ki nas e 2  
U S  
U nite d States  
V A  
vis ual ac uit y  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 2  of 5 9  
1  Intr o d ucti o n  
1. 1  
B ac k gr o u n d  
Intr a oc ular i nfla m mati o n is a n a ntici pate d se q uela of i ntra oc ul ar s ur ger y, s uc h as cataract 
e xtracti o n a n d le ns re pla ce me nt ( C E L R) s ur ger y , a n d is ma nifest e d pri nci pall y as c o nj u ncti val 
i njecti o n, c or neal e de m a, ciliar y fl us h, a n d a q ue o us cells a n d fl are. In ge neral, tra u ma t o t he 
i nter nal str uct ures of t h e e ye is acc o m p a nie d b y t he pr o d ucti o n of pr osta gla n di ns a n d ot her 
vas oacti ve m oieties,  t he releas e of pr o-i nfla m mat or y c yt o ki n es, a n i ncreas e i n bl o o d fl o w t o t he 
affecte d area, a n d e xtra vasati o n of pr otei n a n d cell ular bl o o d ele m e nts . U ntreate d i nfla m mati o n 
ma y l ea d t o c o m plicati o ns , s uc h as c yst oi d mac ular e de ma a n d c or neal scarri n g. T h us, ma na gi n g 
a n d treati n g p ost -o perati ve i nfla m mati o n is a n i m p orta nt g o al f oll o wi n g cataract s ur ger y ( Ki m et 
al., 2 0 1 9). 
C urre nt p ost -o perati ve m e dicati o n re gi me ns c o m m o nl y i ncl u de t o pical c ortic oster oi ds. Treat me nt 
wit h c or tic oster oi ds is e m pl o ye d t o re d u ce pai n a n d disc o mf ort, a n d t o facilitate rec o ver y of t he 
bl o o d -a q ue o us barri er. W he n a d mi nistere d at t he ti me of s ur ger y a n d d uri n g t he i m me diate p ost -
o perati ve peri o d, c ortic oster oi ds ca n re verse t he cli nical ma nifest ati o n s of i nfla m mati o n. I n t he 
U nite d States ( U S), t o pi cal c ortic oster oi ds are r o uti nel y prescri be d wit h u p t o f o ur ti mes dail y 
( QI D) d osi n g f or at least 2 wee ks f oll o wi n g cataract s ur ger y (Ki m et al., 2 0 1 9 ). 
T he J a n us ki nase (J A K) p at h wa y pla ys a ke y r ole i n i nfla m mat or y cell re g ul ati o n , cyt o ki ne 
pr o d ucti o n, a n d pr o -i nfl a m mat or y si g nal tra ns d ucti o n. D ysre g ulati o n of t he J A K pat h wa y is 
ass ociate d wit h t he pat h o ge n esis of vari o us i nfla m mat or y a n d a ut oi m m u ne dis or ders. T heref ore, 
J A K i nhi bit ors ha ve t he p ote ntial t o alle viate t he i nfla m mat or y pr ocess. T he J a n us ki nase-si g nal 
tra ns d ucer a n d acti vat or of tra nscri pti o n (J A K-S T A T) pat h wa y is k n o w n t o be i m p orta nt f or 
i nfla m mat or y cell re g ul ati o n, c yt o ki ne pr o d ucti o n, a n d pr o-i nfla m mat or y si gnal tra ns d ucti o n 
(We n et al., 2 0 2 1 ). 
V V N 4 6 1 is a hi g hl y acti ve J A K i n hi bit or wit h p ote nt i n hi biti o n of J A K 1 a n d t yr osi n e ki nase 2 
( T Y K 2), a n d m o d erate i n hi biti o n o n J A K 2. T h us, t his m olec ule is u n d er de vel o p me nt i n b ot h 
C hi na a n d t he  U S f or a nti -i nfla m mat or y acti vit y b y oral ( Q Y 2 0 1), t o pical der mal ( Q Y 2 1 1), a n d 
oc ular ( V V N 4 6 1) r o utes.  Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  ( Vi va Visi o n; S p o ns or) is 
c o n d ucti n g cli nical st u di es i n C hi na o n V V N 4 6 1 O p ht hal mic S ol uti o n f or t he treat me nt of n o n -
i nfecti o us a nteri or u veitis u n der a C hi nese I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n. The 
d osi n g re gi me ns i n t hese st u dies differ fr o m t h ose c urre ntl y i nte n de d f or t he o pe ni n g st u d y f or t he 
U S I N D  a p plicati o n , w hic h is t o pical oc ular treat me nt of p ost-o perati ve i nfla m mati o n a n d pai n 
f oll o wi n g i ntra o c ular s ur ger y. 
V V N 4 6 1 O p ht hal mic S ol uti o n is a preser ve d m ulti d ose pr o d uct, i nte n de d f or t o pical oc ular 
i nstillati o n. As a ne w c he mical e ntit y, the i nte n de d re g ulat or y r o ute is 5 0 5( b)( 1) . 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 3  of 5 9  
See t he I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n.  
1. 2  
S t u d y R ati o n a le 
V V N 4 6 1 is a hi g hl y acti ve J A K i n hi bit or wit h str o n g i n hi biti o n o n J A K 1/ T Y K 2, a n d m o derate 
i n hi biti o n o n J A K 2. T he J A K-S T A T pat h wa y is a gr o u p of si g nali n g p at h wa ys c o m p ose d of 
rece pt ors, J A K pr otei ns, a n d si g nal tr a ns d ucers a n d tra nscri pti o n acti vat ors. Ma n y c yt o ki ne s 
d eli ver si g nals t hr o u g h t he J A K-S T A T pat h w a y. T heref ore, b ei n g cl osel y ass ociate d wit h t he 
h e mat ol o gic al s yste m a n d i m m u ne s yste m, t his si g nali n g pat h wa y pl a ys a n i m p orta nt r ole i n 
i m m u ne-me diate d i nfla m mat i o n (O’ S hea et al., 2 0 1 5 ; Star k & Dar nell, Jr., 2 0 1 2 ; Villari n o et al., 
2 0 1 5 ). 
O c ular i nfla m mati o n is k n o w n a n d e x pecte d t o occ ur after r o uti ne cataract s ur ger y. As a str o n g 
J A K i n hi bit or, it is t he orize d t hat V V N 4 6 1 ma y ha ve t hera p e utic be nefits f or  t he treat me nt of post -
o pera ti ve oc ul ar i nfla m m ati o n i n s u bjects u n der g oi n g r o uti ne cataract s ur ger y. 
1. 3  
R is k/ Be nefit Assess me nt 
T his secti o n pr o vi des hi g h -le vel i nf or mati o n re gar di n g k n o w n p ote ntial ris ks a n d be nefits. M ore 
detaile d i nf or mati o n ca n be f o u n d i n t he  I n vesti gat or’s Br oc h ure. 
1. 3. 1  
K n o w n P ote nti al Ris k s 
T here are k n o w n ris ks a n d c o m plicati o ns of r o uti n e cat aract s ur ger y, i ncl u di n g b ut n ot li mite d t o  
oc ular i nfla m mati o n, o c ular disc o mf ort, br uisi n g a n d s welli n g ar o u n d t h e s ur gical site, c ha n ges i n 
i ntra oc ular press ure (I O P), a n d op p ort u nistic i nfecti o n. I n rare  i nsta nces, lo n ger ter m 
c o m plicati o ns (e. g., p ost eri or ca ps ular o pacifi cati o n , cyst oi d mac ular e de ma ) ma y o cc ur. T h e se 
ris ks are n ot attri b uta ble t o t he i n vesti gati o nal pr o d uct (I P) b ut are i n here nt t o t he disease state 
bei n g  i n vesti gated . 
A  p hase 1 st u d y was c o n d ucte d i n  3 0 h ealt h y a d ult s u bjects t o e val uate t he safet y, t olera bilit y, a n d 
p har mac o ki netics of  V V N 4 6 1  (f or m ulati o n stre n gt hs 1. 0 % , 0. 5 %, a n d 0. 2 5 % ). The p h ase 1 st u d y 
re p orte d a relati vel y l o w i nci de nce of tr eat me nt e mer ge nt a d verse e v e nts ( T E A Es), wit h t he m ost 
c o m m o n a d verse e ve nts ( A Es) bei n g  i ntra oc ular press ure test a b n or mal ( 2/ 30; 6. 7 %), H er pes 
z oster ( 1/ 3 0; 3. 3 %) , a n d c or neal e pit heli u m d efect ( 1/ 3 0; 3. 3 %). I ntr a oc ular press ur e test 
a b n or malities were tra nsie nt, relate d t o I P , a n d res ol ve d wit h o ut i nter ve nti o n. T he i nci de nce of 
Her pes z oster was relate d t o I P  a n d res ol ve d wit h treat me nt.  T he i nci de n ce of c or neal e pit heli u m 
defect  w as n ot relat e d t o I P . 
1. 3. 2  
K n o w n P ote nti al Be nefit s 
T his is t he first st u d y of V V N 4 6 1 i n s u bjects u n d er g oi n g r o uti ne cataract s ur ger y. T h eref ore, t here 
are n o k n o w n o c ular h ealt h be nefits f or t his p o p ulati o n.   


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 4  of 5 9  
P re-cli nical st u dies i n D utc h ra b bits f o u n d t hat V V N 4 6 1 was c o m para ble t o a c ortic oster oi d 
c o m m o nl y use d i n cli nical practice, de x a m et has o ne o p ht hal mic s ol uti o n, 0. 1 %, at c o ntr olli n g  
oc ular i nfla m mati o n, re d uci n g t he e x u dati o n of a nteri or c ha m ber cells ( A C C s), a n d res ol vi n g 
i nfla m mat or y lesi o ns i n n o n-i nfecti o us u veitis. It is t he orize d t hat V V N 4 6 1 ma y ha v e t hera p e utic 
be nefits f or t he  tr eat me nt of p ost-o perati ve o c ular i nfla m mati o n after r o uti n e cataract s ur ger y.  
1. 3. 3  
Assess me nt of Be nefits a n d Ris ks  
It is t he j u d g me nt of Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d. t hat t here is a fa v ora ble be n efit-ris k 
rati o f or t he use of V V N 4 6 1  i n su bjects e x per i e nci n g p ost-o perati ve oc ular i nfla m mati o n aft er 
u n der g oi n g r o uti ne cataract s ur ger y. Pre -cli nical st u dies i n D utc h ra b bits f o u n d t hat V V N 4 6 1 
perf or me d c o m p ara bl y t o de x a met has o ne o p ht hal mic s ol uti o n, 0. 1 %, at c o ntr olli n g o c ular 
i nfla m mati o n, a n d V V N 4 6 1 may h a ve t he a d va nta ge of a v oi di n g si de effects, s uc h as cataract a n d 
i ncreas e d I O P, t hat are ass ociate d wit h l o n g-ter m use of de x a met has o n e o p ht hal mic s ol uti o n, 
0. 1 % . 
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 5  of 5 9  
2  St u d y  O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y O bjecti ve:  
E val uate t he  o c ular efficac y of 2 differe nt 
d oses of V V N 4 6 1 O p ht hal mic S ol uti o n i n 
treati n g p ost-o perati ve oc ular i nfla m mati o n 
ass ociate d 
wit h cataract s ur ger y c o m pare d 
wit h t he oc ular efficac y of a matc hi n g Ve hi cle  
Sec o n d ar y O bjecti ve:  
E val uate t he safet y of V V N 4 6 1  
P ri m ar y E n d p oi nt:  
 Pr o p orti o n of s u bjects wit h A C C Gra de 0 
i n t he st u d y e ye at Visit 6 ( Da y 1 4) 
Sec o n d ar y E n d p oi nts:  
 Pr o p orti o n of s u bjects wit h A C C Gra de 0 
i n t he st u d y e ye at Visit 5 ( Da y 7) 
 Pr o p orti o n 
of 
s u bjects 
wit h 
a nteri or 
c ha m ber flare ( A C F) Gra de 0 i n t he st u d y 
e ye at Visit 6 ( Da y 1 4)  
 Pr o p orti o n of s u bjects wit h A C F Gra de 0 
i n t he st u d y e ye at Visit 5 ( Da y 7) 
 Pr o p orti o n of s u bjects re q uiri n g resc ue 
me dicati o n bef ore Visit 6 ( Da y 1 4)  
E x pl or at or y E n d p oi nts:  
 Mea n c ha n ge fr o m baseli ne ( C F B) i n A C C 
Gra de i n t he st u d y e ye at eac h visit 
 Mea n C F B i n A C F Gra d e i n t he st u d y e ye 
at eac h visit  
 Pr o p orti o n of s u bjects 
wit h n o p ost -
o perati ve oc ular pai n i n t he st u d y e ye at 
Visit 6 ( Da y 1 4)  
 Pr o p orti o n of s u bjects 
wit h n o p ost -
o perati ve oc ular pai n i n t he st u d y e ye at  
Visit 5 ( Da y 7)  
 
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 6  of 5 9  
3  St u d y  Desi g n  
3. 1  
O ver all Desi g n of t he St u d y  
T his is a  p hase 2, 
m ultice nter, d o u ble -mas k e d, ra n d o mize d, ve hicle -c o ntr olle d, parallel -
c o m paris o n st u d y c o n d ucte d at  sites in t he U S assessi n g t he safet y a n d oc ular efficac y of V V N 4 6 1 
f or treati n g p ost-o perati ve oc ular i nfla m mati o n  i n su bjects  w h o u n d er g o r o uti ne u nilateral C E L R 
s ur ger y via p h ac oe m ulsificati o n wit h o ut s ur gical c o m plicati o n. A p pr o xi matel y 9 0 c o m plete d 
s u bjects ( 3 0 per gr o u p) will be ra n d o mize d i n a 1: 1: 1 rati o. S u bjects wil l a d mi nister 1 e ye dr o p i n 
t he st u d y e ye f o ur ti mes a da y ( QI D) f or 1 4 da ys. The I P i n t he st u d y will b e: 
 V V N 4 6 1, 1. 0 %  
 V V N 4 6 1, 0. 5 %  
 Ve hicl e  
T here will be a t otal of 7 visits o ver a p pr o xi matel y 8 wee ks f or eac h s u bject. A  det aile d Sc he d ul e 
o f Pr oce d ures a n d Ass ess me nts i s pr o vi de d i n A p pe n di x 1 : Sc he d ule of Pr oce d ures a n d 
Assess me nt , a n d t he ge n eral fl o w of t h e st u d y is o utli ne d i n Fi g ure 1 .  
V isits will i ncl u de a scree ni n g visit, the d a y of cataract s ur ger y, a b aseli n e/ ra n d o mizati o n visit, 
a n d effic ac y a n d safet y e val uati o n visits after 3, 7, a n d 1 4 da ys of QI D d osi n g wit h I P i n t he st u d y 
e ye. T he st u d y will c o ncl u de wit h a safet y f oll o w -u p visit a p pr o xi matel y 1 wee k after t he e n d of 
t he pla n ne d d osi n g p eri o d. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 7  of 5 9  
Fi g ure 1  
Cli nic al St u d y Di a gr a m  
 
A b bre viati o ns : I P =i n vesti gati o nal pr o d uct; QI D = q u ater i n die  (f o ur ti mes a da y) 
3. 2  
R ati o n ale f or t he St u d y  Desi g n  
P re-cli nical st u dies i n D utc h ra b bits f o u n d t hat V V N 4 6 1 was c o m para ble t o de x a met has o ne 
o p ht hal mic s ol uti o n, 0. 1 %, at c o ntr olli n g oc ular  i nfla m mati o n, re d uci n g t he e x u dati o n of A C C, 
a n d res ol vi n g i nfla m mat or y lesi o ns i n n o n -i nfecti o us u veitis. It is t he orize d t hat V V N 4 6 1 m a y 
ha ve t hera p e utic be nefits f or t he treat me nt of p ost -o perati ve oc ular i nfl a m mati o n after r o uti ne 
cataract s ur ger y. T he us e of Ve hicle as a c o ntr ol is sta n dar d practice i n o p ht hal m ol o g y  res earch.  
See t he I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n.  
3. 3  
D ose J ustific ati o n  
T he I P f or m ulati o n stre n gt hs  (1. 0 % a n d 0. 5 % ) pr o p ose d f or t he st u d y were selecte d bas e d o n t heir 
pre vi o us use i n a p hase 1 st u d y i n healt h y a d ult h u ma n s u bjects a n d are furt her s u p p orte d b y 
e xte nsi ve n o n -cli nical a n d pre -cli nic al testi n g i n a ni mal m o dels.  
See t he I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 8  of 5 9  
3. 4  
E n d of St u d y  Defi niti o n  
A  s u bject is c o nsi dere d t o ha ve c o m plete d t he st u d y if t he s u bject has c o m plete d t he last visit or 
t he last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of Pr oce d ures a n d Assess me nts ( A p pe n di x 1 : 
Sc he d ule of Pr oce d ures a n d Assess me nt ). The e n d of t he st u d y is defi ne d as c o m ple ti o n of t he last 
visit or pr oce d ure s h o w n i n t he sc he d ule i n t he st u d y gl o ball y.  
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 1 9  of 5 9  
4  St u d y  P o p ul ati o n  
T he st u d y p o p ulati o n will c o nsist of s u bjects w h o h a ve u n der g o ne r o uti ne u nilateral C E L R s ur ger y 
via p hac oe m ulsific ati o n wit h o ut s ur gical c o m plicati o n.  
4. 1  
I ncl usi o n Criteri a 
S u bjects 
w h o 
meet 
all i ncl usi o n 
criteria  at 
Visit 
1 ( Scree ni n g) 
a n d/ or 
Visit 
3 
(Bas eli ne/ Ra n d o mizati o n ) will be eli gi ble f or st u d y partici pati o n . 
1.  ≥2 1 years of a ge a n d i n g o o d ge n eral h ealt h at Visit 1 ( Scree ni n g)  
2.  Willi n g a n d a ble t o pr o vi de i nf or me d c o nse nt a n d pr o vi de rel e va nt pri v ac y a ut h orizati o n(s)  
3.  Willi n g a n d a ble t o c o m pl y wit h st u d y re q uire m e nts a n d visit sc he d ule  
4.  Clear oc ular m e dia ( ot her t ha n cataract) i n t he st u d y e ye  
5.  Pla n ni n g t o u n der g o r o uti ne u nilateral C E L R s ur ger y via p h ac oe m ulsificati o n e xtracti o n 
a n d i m pla ntati o n of a n i ntra oc ular l e ns. All o w e d  i n t he st u d y e ye at Visit 2 ( Da y of 
S ur ger y):  
a. Li m bal r ela xi n g i ncisi o ns (laser -assiste d a n d n o n -l aser) 
b.  I ntr aca meral i njecti o ns a n d i ntraca m eral me dicati o ns, e x cl u di n g t h ose i de ntifie d i n 
E x cl usi o n Criteri o n # 2  
6.  At Visit 1 ( Scree ni n g), has t he p ote ntial, i n t he o pi ni o n of t he I n v esti gat or , for p ost o perati ve 
best c orrect e d vis ual ac uit y ( B C V A ) ≤0 . 2 L o garit h m of t he Mi ni m u m A n gle of Res ol uti o n 
( L o g M A R) (i.e., 2 0/ 3 2 S nelle n or b etter) i n t he st u d y e ye as ass esse d usi n g Earl y Treat me nt 
Dia betic Reti n o pat h y St u d y ( E T D R S)  
7.  A t Visit 1 ( Scree ni n g), h as B C V A ≤1. 0 L o g M A R (i.e., 2 0/ 2 0 0 S nelle n) i n t he n o n -st u d y 
e ye d ue t o pat h ol o g y ot h er t ha n cataract as ass esse d usi n g E T D R S  
8.  A ble t o self -a d mi ni ster e ye dr o ps 
9.  At Visit 3 ( Baseli ne/ Ra n d o mizati o n; Da y 1), has A C C Gra de  ≥2 i n t he st u d y e ye  
4. 2  
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g e x cl usi o n criteria will n ot be eli gi ble f or st u d y 
partici pati o n.  
O p ht h al mic  ( Eit her E ye) 
1.  A n y o c ular pai n at Visit 1 ( Scree ni n g)  
2.  Use d wit hi n 1 wee k bef ore Visit 2 ( Da y of S ur ger y), or be pla n ni n g t o use d uri n g t he st u d y, 
c ortic oster oi ds, oral or t o pical n o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds), or 
O mi dria ®  (i.e., p h e n yle p hri ne a n d ket or ol ac i njecti o n).  
N ote : L o w-d os e acet yls alic ylic aci d (i.e., ba b y as piri n or si milar) is all o we d  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 0  of 5 9  
3.  M o derate t o se v ere li d, c o nj u ncti val, or c or neal fi n di n gs at Visit 1 ( Scree ni n g)  
4.  C or neal a b n or malit y (e. g., str o mal, e pit helial, or e n d ot helial d ystr o p hies, i ncl u di n g 
e pit helial  base me nt me m bra ne d ystr o p h y)  
5.  Hist or y of c hr o nic/r ec urre nt i nfla m mat or y e ye dis ease (e. g., scleritis, a n y u veitis, her pes 
keratitis)  
6.  A n y si g ns of i ntra o c ular i nfla m mati o n (cell/flare) at Visit 1 ( Scree ni n g)  
7.  I O P ≥2 4 m m H g at Visit 1 ( Scree ni n g)  
O p ht h al mic ( S t u d y E ye) 
8.  Usi n g or u n willi n g t o f or g o c o ntact le ns use wit hi n defi ne d wi n d o ws bef ore Visit 2 ( Da y 
of S ur ger y) a n d f or t he d urati o n of t he st u d y  
a. P ol y m et h yl met hacr yl ate c o ntact l e nses ( 6 m o nt hs bef ore s ur ger y a n d t hr o u g h o ut 
st u d y) 
b.  Gas per mea ble ri gi d le ns es  ( 1 m o nt h bef ore s ur ger y a n d t hr o u g h o ut st u d y) 
c. E xte n de d wear or d ail y s oft le nses ( 7 da ys b ef ore s ur ger y a n d t hr o u g h o ut st u d y)  
9.  K n o w n pat h ol o g y t hat ma y affect vis ual ac uit y, partic ularl y reti nal c ha n ges t hat affect 
visi o n (e. g., 
mac ular de ge nerati o n, c yst o i d 
mac ular e d e ma, pr oliferati ve dia betic 
reti n o pat h y) 
1 0.  Ca ps ule or z o n ular a b n or malities wit h pre -o p erati ve cr ystalli ne l e ns tilt or dece ntrati o n 
(e. g., Marfa n’s s y n dr o me) or a b n or malities t hat ma y affect p ost-o perati ve ce ntrati o n or tilt 
of t he cr ystalli ne le ns (e. g., pse u d o e xf oliati o n s y n dr o me) 
1 1.  Hist or y of m o derate t o se vere oc ular tra u ma wit h t he p ossi bilit y of pre vi o us z o n ule 
de hisce nce  
1 2.  Oc ular or p eri oc ular s ur gic al i nter ve nti o ns wit hi n defi ne d wi n d o ws bef ore Visit 1 
( Scree ni n g) 
a. Micr oi n vasi ve gl a uc o ma s ur g er y, a n y i ncisi o nal oc ular s ur ger y, or i ntraca meral 
dr u g d e p ot t o l o wer I O P (a n y hist or y)  
b.  I ntr a oc ular s ur ger y ( 6 m o nt hs) 
c. Las er s ur ger y, li m bal rel a xi n g i ncisi o n pr oce d ure, e yeli d s ur ger y ( 3 m o nt hs)  
1 3.  P u pil a b n or malities (e. g., n o n -reacti ve, t o nic p u pils, a b n or mall y s h a pe d p u pils, p u pils t hat 
d o n ot dilate at least 3. 5 m m u n der mes o pic/sc ot o pic c o n diti o ns)  
1 4.  Kerat oc o n us or si g nifica nt irre g ular asti g matis m o n pre -o perati ve oc ul ar t o p o gra p h y  
1 5.  Ha ve a c o n diti o n, or be i n a sit uati o n, t hat ma y p ut t he s u bject at s i g nifica nt ris k of c o m ple x 
s ur ger y a n d s ur gical c o m plicati o ns t hat w o ul d lea d t o wit h dra wal fr o m t he st u d y 
O p ht h al mic ( N o n -st u d y E ye) 
1 6.  U n der we nt cataract s ur ger y  < 1 4 da ys b ef ore Visit 1 ( Scree ni n g) or, d uri n g t he st u d y, will 
re q uire cataract s ur ger y < 1 da y aft er Visit 2 ( Da y of S ur ger y)  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 1  of 5 9  
Ge ner al  
1 7.  Wit hi n 3 0 da ys b ef ore Visit 1 ( Scree ni n g), p artici p ate d i n a n i n vesti gati o nal dr u g or de vice 
st u d y, or ha v e use d a n i n vesti gati o nal dr u g or de vice 
1 8.  Aller g y or h y perse nsiti vit y t o t he I P or its e xci pie nts  
1 9.  Si g nifica nt s yste mic dise ase (e. g., u n c o ntr olle d dia betes; m yast he nia gra vis; he patic, re n al, 
car di o vas c ular, or e n d ocri ne dis or ders)  
2 0.  U nc o ntr olle d s yste mic disease, d efi ne d as, wit hi n 3 0 da ys bef ore Visit 1 ( Scree ni n g), a 
c ha n ge i n dise ase stat us or me dicati o ns t hat m a y p ut t he s u bject at i ncrease d ris k or 
c o nf o u n d i nter pretati o n of st u d y res ults  
2 1.  C ha n ges wit hi n 3 0 da ys bef ore Visit 1 ( Scree ni n g), or a ntici pate d c ha n ges d uri n g t he st u d y, 
t o t he d osa ge of s yste mic me dicati o n t hat c o ul d ha ve a s u bsta ntial effect o n I O P 
2 2.  K n o w n blee di n g te n de n cies  
2 3.  Ac ute or c hr o ni c disease or ill ness t hat w o ul d p ut t he s u bject at i ncreas e d ris k or c o nf o u n d 
i nter pretati o n of st u d y res ults (e. g., a ut oi m m u ne disease, c o n necti ve tiss ue disease, 
i m m u n o deficie nc y, s us p ecte d gla uc o ma, gla uc o mat o us c ha n ges i n t he f u n d us or vis ual 
fiel d, oc ular i nfla m mati o n, etc.) 
2 4.  Re q uires, is li kel y t o re q uire, or is u n willi n g t o disc o nti n ue t he use of pr o hi bite d 
me dicati o ns  
2 5.  Pre g n a nt, n ursi n g, or pla n ni n g a pre g na n c y d uri n g t he st u d y  
2 6.  U n willi n g or u na ble t o use a n acce p ta bl e met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y if 
a w o ma n of c hil d beari n g p ote ntial ( W O C B P ; A p pe n di x 2 : 
W o ma n of C hil d beari n g 
P ote ntial ( W O C B P) ) 
2 7.  U n willi n g or u na ble t o use a n acce pta bl e met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y if 
a male se x ual part ner of a W O C B P  
4. 3  
Scree n F ail ure s 
S cree n fail ures are defi n e d as s u bjects w h o c o ns e nt t o partici pate i n t he st u d y b ut w h o are n ot 
s u bse q ue ntl y ra n d o ml y assi g ne d t o I P a n d ent ere d i n t he st u d y. A  mi ni mal set of scree n fail ure 
i nf or mati o n is re q uir e d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure s u bjects, t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uir e me nts , a n d t o res p o n d t o q ueries 
fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, 
eli gi bilit y criteria, a n d a n y seri o us a d verse e v e nt  ( S A E), or n o n-seri o us A Es.  
P r os pecti ve s u bjects wh o d o n ot meet t he criteria f or st u d y partici pati o n  (scree n fail ure) b eca us e 
of tra nsie nt c o n diti o ns t hat are e x pecte d t o c h a n ge, i ncl u di n g b ut n ot li mite d t o scree n fail ures f or 
hi g h I O P, m a y b e rescree ne d a t I n v esti gat or discreti o n ( ma xi m u m of 1 rescree n p er pr os pecti ve 
s u bject). Rescree n e d s u bjects s h o ul d be assi g ne d a ne w s u bj ect  i de ntificati o n n u m ber , an d t he 
ori gi nal s u bject i de ntificati o n n u m ber s h o ul d be rec or de d as a scree n fail ure. 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 2  of 5 9  
5  St u d y  Tre at me nt (s) or I nter ve nti o n(s) 
5. 1  
I n vesti g ati o n al Pr o d ucts 
T hree ( 3) I Ps will be a d mi nistere d d uri n g t he st u d y: 
 V V N 4 6 1, 1. 0 %  
 V V N 4 6 1, 0. 5 %  
 Ve hicle  
T he matc hi n g V e hicle will be i de ntical t o  t he acti ve d oses of I P, ex ce pt Ve hicle will n ot c o ntai n 
t he acti ve p h ar mace utical i n gre die nt ( A PI). All I P will be a d mi nistere d t o picall y t o t h e st u d y e ye 
as e ye dr o ps. 
5. 1. 1  
Descri pti o n  
B ot h f or m ulati o ns of V V N 4 6 1 a n d t he m atc hi n g Ve hicle are c ol orless t o li g ht yell o w sterile 
s ol uti o ns pac ka ge d i n 5 m L m ulti d ose l o w -de nsit y p ol yet h yle ne e ye dr o p b ottles. T he I P  will be 
pr o vi de d i n i d e ntical pri mar y pac ka gi n g . IP will be s u p plie d t o sites i n cart o ns. Eac h cart o n will 
c o ntai n 1 l o w -de nsit y p ol yet h yle n e e ye dr o p b ottl e. 
5. 1. 2  
D os a ge a n d A d mi nistr ati o n  
S u bjects will be ra n d o mize d t o 1 of 3 p ossi ble gr o u ps i n a 1: 1: 1 rati o. St u d y pers o n nel will pr o vi de 
trai ni n g t o s u bjects o n pr o per e ye dr o p a d mi nistrati o n, p r o per I P st ora ge w he n n ot i n use, a n d 
pr o per use of t he d osi n g diar y . 
A ll s u bjects, irres pecti ve of gr o u p, will a d mi nister 1 e ye dr o p i n t he st u d y e ye QI D f or a peri o d of 
1 4 da ys.  If t h e s u bject misses t heir e ye w hile a d mi nisteri n g a n e ye dr o p, a sec o n d e ye dr o p ma y 
be a d mi nistere d. If t he s u bject misses t heir e ye w hile a d mi nisteri n g a s ec o n d e ye dr o p, a t hir d e ye 
dr o p ma y n ot be a d mi nistere d. T h e misse d d ose s h o ul d be rec or de d i n t he d osi n g diar y.  
If a s u bject f or gets or misses a sc h e d ule d d ose of I P, t he s u bject s h o ul d a d mi nister  t he misse d d ose 
as s o o n as p ossi ble . Th e misse d d ose s h o ul d be rec or de d i n t h e d osi n g diar y. T he  QI D d osi n g 
sc he d ule s h o ul d t he n be res u me d. S u bjects w ill a d mi nister  t heir first d ose of I P a n d ma ke t heir 
first d osi n g diar y e ntr y i n t he c li nic u n der t he s u pervisi o n of st u d y p ers o n nel t o e ns ure pr o per 
d osi n g tec h ni q ue  a n d d osi n g diar y us e.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 3  of 5 9  
5. 2  
Pre p ar ati o n/ St or a ge/ H a n dli n g/ Acc o u nt a bilit y  
5. 2. 1  
Ac q uisiti o n a n d Acc o u nt a bilit y  
IP will be pr o vi de d t o eac h site. O nce t he I P has bee n deli vere d t o t he site, it will be st ore d i n a 
li mite d-access area o nl y accessi ble t o trai ne d st u d y pers o n nel . Use d a n d u n use d I P will be 
mai ntai ne d at t he site f or acc o u nta bilit y b y t he cli nical st u d y m o nit or.  
W he n a ut h orize d b y t h e S p o ns or , a n d after t he cli nical st u d y 
m o nit or has v erifie d dr u g 
acc o u nta bilit y is c o m plete a n d acc urate, use d a n d u n use d I P  eit her will be r et ur ne d t o t he S p o ns or 
or desi g nee , or will be dis p ose d/ destr o ye d b y t h e sites i n acc or da nce wit h t he re q uire me nts of 
a p plica ble l o cal a ut h orities a n d re g ul at or y b o dies t o e ns ure dis p osal of I P d oes n ot e x p ose h u ma n 
bei n gs t o ris ks fr o m t he dr u g.  
5. 2. 2  
Pr o d uct F or m ul ati o n, A p pe ar a nce, P ac k a gi n g, a n d L a beli n g  
IP will be  d eli vere d t o sites i n i de ntical pac ka gi n g a n d l a bele d i n acc or da n ce wit h fe d eral 
re g ulati o ns f or i n vesti gati o nal ne w dr u gs. La bels will i ncl u de ver bati m t he f oll o wi n g state m e nt: 
“ Ca uti o n: N e w Dr u g –  Li mite d b y Fe deral la w t o i n vesti gati o nal us e. ”  
T he f or m ulati o n i ncl u d es p ol yet h yle n e gl yc ol (a c os ol ve nt), h y dr o x y pr o p yl bet a -c ycl o de xtri n (a 
s ol u bilizer), citric aci d (a p H b uffer), s o di u m citrate (a p H b uffer), s o di u m c hl ori de (a t o nicit y 
a ge nt), a n d a preser vati v e, be nzal k o ni u m c hl ori de 0. 0 2 % ( w/ v). Water f or i njecti o n is use d as t he 
fi nal dil ue nt f or t his pr o d uct. T here are n o n o v el e x ci pie nts use d i n t he f or m ulati o n. T he pr o d uct 
is ma n ufact ur e d ase pticall y a n d is i nte n de d t o be use d as a sterile pr o d uct as Ve hi cle ( 0 . 0 % 
V V N 4 6 1), 0. 5 % V V N 4 6 1, a n d 1. 0 % V V N 4 6 1 . 
A d diti o nal details ma y als o be i ncl u de d o n t he la bel, pr o vi de d t hat t hese details d o n ot p ose a ris k 
t o st u d y mas ki n g. T his ma y i n cl u de b ut is n ot li mite d t o t he pr ot oc ol n u m ber, I P v ol u me per 
c o ntai ner, st ora ge re q uire me nts, ma n ufact ur er, a n d l ot n u m ber.  
5. 2. 3  
Pr o d uct St o r a ge a n d St a bilit y  
IP will be st ore d at a m bi e nt r o o m  te m perat ur e ( 1 5° C t o 2 5° C [ 5 9° F t o 7 7° F]) a n d pr otecte d fr o m 
li g ht i n a li mite d-access area accessi ble o nl y t o trai ne d st u d y pers o n nel.  O ne -d a y te m perat ure 
e x c ursi o ns d uri n g ha n dli n g, ware h o usi n g, a n d s hi p pi n g o perati o ns are per mitte d u p t o 4 0 ° C 
(1 0 4° F ), b ase d o n sta bilit y dat a.  
O pe ne d a n d u n o p e ne d  b ottles of I P will be m ai ntai ne d at t h e site f or acc o u nta bilit y b y t he cli nical 
st u d y m o nit or. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 4  of 5 9  
5. 3  
Me as ures t o Mi ni miz e Bi as: R a n d o miz ati o n a n d M as ki n g  
E li gi ble s u bjects will be ra n d o mize d in a 1: 1: 1 rati o i n t he electr o nic data ca pt ure syst e m . The I P 
will be dis pe nse d to s u bjects b y trai ne d st u d y pers o n nel  o nl y . 
T he ra n d o mizati o n sc he d ule will be c o m p uter -ge n erate d i n t he electr o nic data ca pt ur e s yste m , a n d 
all I P will be mas ke d t o t he S p o ns or, st u d y pers o n nel,  a n d st u d y s u bjects t hr o u g h o ut t he st u d y u ntil 
after t h e fi nal d ata base has bee n l oc ke d. A p pr o priate preca uti o ns m ust be ta ke n t o pre ve nt 
u na ut h orize d access t o t he ra n d o mizati o n sc he me. U nless t he s u bject’s safet y re q uir es ot her wise , 
a n d if ti me per mits, t he decisi o n t o u n mas k a treat me nt assi g n me nt is t o be ma de j oi ntl y b y t h e 
I n v esti gat or a n d t he M e dical M o nit or  after c o ns ultati o n wit h t he S p o ns or.  
If u n mas ki n g is re q uir e d d uri n g t he st u d y, t he i nte grit y of t h e st u d y assess m e nts a n d c ollect e d data 
will b e mai ntai ne d b y li miti n g access t o t he u n mas ke d data.  
5. 4  
D osi n g A d here nce a n d D osi n g Di ar y  
5. 4. 1  
D osi n g A d here nce  
S t u d y pers o n n el will pr o vi de trai ni n g t o s u bjects o n pr o per e ye dr o p a d mi nistrati o n , pr o per I P 
st ora ge w h e n n ot i n use, a n d pr o per use of t he d osi n g diar y. S u bjects will als o recei ve writte n 
i nstr ucti o ns. S u bjects will recei ve a n e w s u p pl y of I P, as a p plica ble, as i n dicate d i n A p pe n di x 1 : 
Sc he d ule of Pr oce d ures a n d Assess me nt . St u d y p erso n nel will re vie w s u bject d osi n g a d h ere n ce, 
as rec or de d i n t he d osi n g diar y, at eac h pl a n ne d visit a n d will pr o vi de re mi n ders a n d i nstr ucti o n 
a b o ut t he QI D d osi n g sc h e d ule a n d d osi n g a d here n ce, as nee de d.  
5. 4. 2  
D osi n g Di ar y  
S u bjects will be as ke d t o rec or d t hei r dail y use of I P i n a d osi n g diar y t hat will be c ollecte d a n d 
re vie we d wit h t he m d uri n g eac h pla n ne d visit. S u bjects will recei ve ver bal a n d writte n i nstr ucti o n 
o n t he pr o per us e of t he d osi n g diar y at Visit 3 ( Baseli ne/ Ra n d o mizati o n ), as well as v er bal an d 
writte n i nstr ucti o n o n pr o per e ye dr o p a d mi nistrati o n  a n d pr o per I P st ora ge w he n n ot i n use f or 
d osi n g.  
E m pt y fiel d e ntries i n t he d osi n g diar y will be c o u nte d as misse d d oses, o nce verifie d wit h t he 
s u bject, f or t he p ur p ose of meas uri n g d osi n g a d here nce. St u d y pers o n nel will re vie w s u bj ect 
d osi n g a d here nce, as rec or de d i n t he d osi n g diar y, at eac h pla n ne d visit a n d will pr o vi de re mi n ders 
a n d i nstr ucti o n a b o ut pr o per use of t he d osi n g diar y, as n ee de d.  
5. 5  
Pri o r a n d C o nc o mit a nt T her a p y  
F or t his pr ot oc ol, a prescri pti o n me dicati o n is defi ne d as a m e dicati o n t hat ca n be prescri be d o nl y 
b y a pr o perl y a ut h orize d/lice nse d cli nicia n . M e di cati o ns t o be re p orte d i n t he  electr o nic cas e re p ort 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 5  of 5 9  
f or m (eC R F ) are c o nc o mita nt 
prescri pti o n 
me dicati o ns, 
o ver-t he-c o u nter 
me dicati o ns , 
su p ple me nts , a n d me dicati o ns pr o vi de d at Visit 2 ( Da y of S ur ger y) as part of site’s sta n dar d 
practice d uri n g r o uti ne cataract s ur ger y . (N ote:  C ortic oster oi ds, oral or  t o pical N S AI Ds [e x cl u di n g 
lo w -d ose acet ylsalic ylic aci d ], a n d Omi dri a ®  [i.e., p he n yle p hri ne a n d k et or olac i njecti o n] are 
pr o hi bite d .) 
A ll me dicati o ns t hat t he s u bject has ta ke n wit hi n 3 0 da ys bef ore Visit 1 ( Scree ni n g) a n d t hr o u g h 
Visit 7 ( Da y 2 1; E n d of St u d y) or e xit fr o m t he st u d y will be rec or de d i n t he e C R F a n d t he s u bject’s 
s o urce d o c u me nts. S u bjects will be as ke d f or details a b o ut a n y c h a n ges i n d o c u me nte d me dicati o ns 
at all visits. T h e ge neric n a me of t he dr u g, d ose, r o ute of a d mi nistrati o n, d urati o n of treat me nt 
(i ncl u di n g start a n d st o p dates), fre q ue nc y, i n dicatio n, a n d w het her or n ot t he me dicati o n was ta ke n 
d ue t o a n A E or as resc ue will be rec or de d f or eac h me dicati o n. Pri or a n d c o n c o mita nt me dicati o ns 
will be c o de d usi n g t h e W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y ( W H O Dr u g).  
5. 5. 1  
Pr o hi bite d Me dic ati o ns a n d Pr oce d ures  
M e dicati o ns t hat are n ot e x plicitl y pr o hi bite d b y t he pr ot oc ol ma y b e use d, as n ee de d, t hr o u g h o ut 
t he st u d y a n d rec or de d as c o nc o mita nt me di cati o ns. All me dicati o ns t a ke n b y a s u bject d uri n g t he 
st u d y, w h et her all o we d or pr o hi bite d, s h o ul d b e rec or de d as c o nc o mita nt m e dicati o ns . Ta ble 1  lists 
t he pr o hi bite d me dicati o ns a n d pr oce d ures f or t he p ur p oses of t he st u d y, as well as t h e mi ni m u m 
ti mefra mes f or dis c o nti n uati o n nee de d f or st u d y eli gi bility .  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 6  of 5 9  
T a ble 1  
Pr o hi bite d Me dic ati o ns a n d Pr oce d ures  
M e dic ati o ns a n d Pr o ce d ures N ot Per mitte d  
Ti mefr a me  
O p ht h al mic ( St u d y E ye) 
Micr oi n vasi ve gla uc o ma s ur ger y, a n y i ncisi o nal oc ular 
s ur ger y, or i ntraca meral dr u g de p ot t o l o wer I O P  
A n y hist or y a n d t hr o u g h o ut st u d y  
I ntra o c ular s ur ger y 
6 
m o nt hs 
bef ore s ur ger y a n d t hr o u g h o ut st u d y 
(e xcl u di n g pla n ne d cataract s ur ger y) 
Laser s ur ger y, li m bal rela xi n g i ncisi o n pr oce d ure, e yeli d 
s ur ger y 
N ote: Li m bal rela xi n g i ncisi o ns (laser -assiste d a n d n o n -
laser) are all o we d i n t he st u d y e ye at Visit 2 ( Da y of 
S ur ger y)  
3 m o nt hs bef ore s ur ger y a n d t hr o u g h o ut st u d y  
C o ntact le nses  
T hr o u g h o ut st u d y a n d wit hi n defi ne d wi n d o ws bef ore 
Visit 2 ( Da y of S ur ger y)  
a. 
P ol y met h yl met hacr ylate c o nt act le nses  
b.  Gas p er mea ble ri gi d le nses  
c. 
E xte n de d wear or dail y s oft le nses  
a. 
6 m o nt hs bef ore s ur ger y  
b.  1 m o nt h bef ore s ur ger y  
c. 
7 da ys bef ore s ur ger y  
O p ht h al mic ( N o n-st u d y E ye) 
Cataract s ur ger y  
1 4 da ys bef ore Visit 1 ( Scree ni n g) or will re q uire 
cataract s ur ger y < 1 da y after Visit 2 ( Da y of S ur ger y)  
Ge ner al  
Ot her i n vesti gati o nal dr u g or de vice  
3 0 da ys bef ore Visit 1 ( Scree ni n g) a n d t hr o u g h o ut st u d y  
C ha n ges t o s yste mic 
me dic ati o n t hat c o ul d ha ve a 
s u bsta ntial effect o n I O P 
3 0 da ys bef ore Visit 1 ( Scree ni n g) a n d t hr o u g h o ut st u d y  
C ortic oster oi ds, oral or t o pical N S AI Ds, or O mi dria ®  
(i.e., p he n yle p hri ne a n d ket or olac i nj ecti o n) 
N ote : Lo w -d ose acet ylsalic yli c aci d (i.e., ba b y as piri n 
or si milar) is all o we d  
1 wee k bef ore Visit 2 ( Da y of S ur ger y)  a n d t hr o u g h o ut 
st u d y 
A b bre viati o ns: I O P=i ntra o c ul ar press ure; N S AI D = n o nster oi dal a nti -i nfla m mat or y dr u g 
5. 5. 2  
Resc ue Me dic ati o n  
S u bjects are eli gi ble t o be resc ue d at a n y ti me at t he I n vesti gat or’s dis creti o n a n d place d o n 
a p pr o priate treat me nt or t hera p y. Alt h o u g h t h e use of resc ue me dicati o n is all o wa ble at a n y ti me , 
a d va nce c o ns ultati o n wit h t he Me dical M o nit or is preferre d , if possi ble . If a dela y i n resc u e w o ul d 
place t he s u bject at u n necessar y ris k, t he I n vesti gat or s h o ul d pr ocee d wit h resc ue i m me diatel y .  
T he date  of r esc u e me di cati o n a d mi nistrati o n, as well as t he na me of t he resc ue  me dicati o n a n d 
d osa ge re gi me n, m ust be rec o r de d as c o nc o mita nt me dicati o ns i n t he e C R F, wit h a n ote i n dicati n g 
t hat t he me dicati o n was use d f or resc u e. S u bjects w h o re q uire resc ue will be c o u nte d as treat me nt 
fail ures a n d u n d er g o f oll o w-u p safet y assess me nts a n d pr oce d ures. E ver y atte m pt s h o ul d be ma de 
t o ha ve s u bjects c o nti n ue i n t he st u d y f or safet y e val uati o ns, e ve n if s u bjects disc o nti n ue I P. T he 
nee d f or resc u e me dicati o n itself will n ot be c o nsi dere d a n A E.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 7  of 5 9  
6  St u d y Disc o nti n u ati o n /S u bject  Wit h dr a w al  
6. 1  
Disc o nti n u ati o n of I n vesti g ati o n al Pr o d uct 
A  s u bject ma y b e disc o nti n ue d fr o m I P at a n y ti m e if t he s u bject, t he I n vesti gat or, or t he S p o ns or 
feels t hat it is n ot i n t he s u bject’s best i nterest t o c o nti n ue. S u bjects ma y h a ve I P wit h dra w n b y t he 
I n v esti gat or d ue t o a n A E or d ue t o t he nee d f or resc ue. S u bjects w h o ha v e I P wit h dr a w n d ue t o 
a n A E s h o ul d be f oll o we d f or at least 1 w ee k f or safet y m o nit ori n g, or u ntil t he A E has res ol v e d.  
6. 2  
S u bject  Disc o nti n u ati o n /Wit h dr a w al fr o m t he St u d y  
S u bjects  are free t o wit h dra w fr o m p artici pati o n i n t he st u d y at a n y  ti me u p o n re q uest. A n 
I n v esti gat or ma y disc o nti n ue or wit h dra w a s u bject fr o m t he st u d y f or a n y reas o n, i ncl u di n g b ut 
n ot li mite d t o t he f oll o wi n g:  
 A d verse e ve nt  
 Fail ure t o meet ra n d o mizati o n criteria  
 L ost t o f oll o w -u p  
 I n v esti gat or decisi o n  
 Pre g n a nc y  
 Pr ot oc ol de viati o n  
 Wit h dra wal of c o nse nt   
T he r eas o n f or s u bject disc o nti n uati o n or wit h dra wal fr o m t he st u d y will be rec or de d  i n t he e C R F. 
S u bject s w h o si g n t he i nf or me d c o nse nt f or m a n d are r a n d o mize d b ut  d o n ot recei ve I P ma y b e 
re place d. S u bjects w h o  si g n t h e i nf or me d c o ns e nt f or m, are ra n d o mize d, recei ve at least 1 d ose of 
I P, an d s u bse q u e ntl y wit h dra w or are wit h dra w n /disc o nti n ue d fr o m t he st u d y  m a y n ot b e r e place d.  
6. 3  
L ost t o F oll o w -U p  
A  s u bject will be c o nsi d ere d l ost t o f oll o w -u p if t hey fail t o ret ur n f or a s c he d ule d v isit a n d are 
u na ble t o be c o nta cte d b y st u d y pers o n nel. 
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bject fails t o ret ur n t o a site f or a re q uir e d visit: 
 T he site will atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit . The site will  
c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g n e d visit sc he d ule a n d 
ascert ai n if t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y . 
 B ef ore a s u bject is dee m e d l ost t o f oll o w-u p, t he I n vesti gat or or desi g n ee will ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he s u bject ( w h ere p ossi ble, 3 tele p h o ne calls a n d, if necessar y, 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 8  of 5 9  
a certifie d letter t o t he s u bject’s last k n o w n m aili n g a d dress or l ocal e q ui vale nt met h o ds). 
T hese c o nta ct atte m pts s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or d or st u d y fil e. 
 S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, t he s u bject will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w -u p . 
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 2 9  of 5 9  
7  St u d y  Pr oce d ure s 
W ritte n i nf or me d c o nse nt a n d rele v a nt pri vac y a ut h orizati o n(s) will be o btai ne d fr o m all s u bjects 
bef ore  a n y pr oce d ures relate d t o t he st u d y are perf or me d. T he Sc he d ul e of Pr oce d ures a n d 
Assess me nts  (A p p e n di x 1 : Sc he d ule of Pr oce d ures a n d Assess me nt) lists the pr oce d ures t hat 
s h o ul d occ ur at e ac h st u d y visit.  
7. 1  
V isit Descri pti o ns 
P r oce d ures s h o ul d be perf or me d i n t he or der liste d; pr oce d ures f oll o we d b y a n “ *” ma y occ ur at 
ot her ti mes d uri n g t he visit, if nee de d, t o  acc o m m o date site o perati o ns a n d/ or s u bject b o dil y 
f u ncti o ns, pr o vi de d t he pr oce d ure is c o m plete d bef ore i n-cli nic a d mi nistrati o n of I P. 
7. 1. 1  
Visit 1 ( Scree ni n g ; D a y -3 0 t o D a y -1 )  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 1 ( Scree ni n g; Da y -3 0 t o Da y -1 ): 
 E x plai n t he p ur p ose a n d c o n d uct of t he st u d y t o t h e s u bject, a ns wer su bject q uesti o ns, a n d 
o btai n writte n i nf or me d c o nse nt a n d  pri vac y a ut h orizati o n(s)  
 O btai n i nf or mati o n , i ncl u di n g: de m o gra p hics, c o nc o mita nt me dicati o ns, a n d oc ular a n d 
s yste mic me dical a n d me dicati o n hist or y a n d s ur gical hist or y  
 Heart rate a n d bl o o d pr ess ure  
 S u bject a d mi nistrati o n of test e ye dr op  
 Pai n sc ore trai ni n g  
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
 Dilate d o p ht hal m osc o p y  
 Uri ne pre g n a nc y test ( o nl y f or W O C B P) *  
 A b bre viate d p h ysic al e x a mi nati o n *  
 Deter mi ne st u d y eli gi bilit y base d o n I ncl usi o n/ E x cl usi o n criteria  
7. 1. 2  
Visit 2 ( D a y of S ur ger y; D a y 0)  
A t Visit 2 ( Da y of S ur ger y; 
D a y 0) , s u bjects 
will u n der g o r o uti ne C E L R s ur ger y via 
p hac oe m ulsificati o n e xtracti o n a n d i m pla ntati o n of a n i ntra oc ular le ns. I n vesti gat ors s h o ul d use 
t heir sta n dar d pr o ce d ure f or r o uti ne cataract s ur gery.  
Li m bal rela xi n g i ncisi o ns (laser -assiste d a n d n o n -laser) a n d i ntraca meral i njecti o ns a n d 
me dicati o ns are all o we d d uri n g t he s ur ger y. ( N ote:  C ortic oster oi ds , oral or  t o pical N SAI Ds  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 0  of 5 9  
[e x cl u di n g l o w -d ose acet ylsalic ylic aci d ], a n d O mi dria®  [i.e., p he n yl e p hri ne a n d ket or olac 
i njecti o n] are pr o hi bite d.) 
A ll me dicati o ns gi ve n t o s u bjects as part of t he cataract s ur ger y pr oce d ure, i ncl u di n g b ut n ot 
li mite d t o se dati ves, l ocal a nest hetics, a n d to pical a nti bi otics, s h o ul d be rec or de d i n t he e C R F as 
c o nc o mita nt me dicati o ns . 
A fter t he cataract s ur ger y, s u bjects s h o ul d n ot be pr o vi de d wit h a n y prescri pti o n or o ver-t he-
c o u nter pai n me dicati o n , or me dicati o n s i nte n de d t o mi ni mize oc ular i nfla m mati o n. S u bjects will 
be assesse d f or safet y a n d ra n d o mize d at Visit 3 ( Baseli ne/ Ra n d o mizati o n; Da y 1) . 
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 2 ( Da y of S ur ger y):  
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 Uri ne pre g n a nc y test ( o nl y f or W O C B P) * 
 Cataract s ur ger y  
7. 1. 3  
Visit 3 ( B aseli ne/ R a n d o miz ati o n; D a y 1)  
T he f oll o wi n g pr oce d ures will be perf or me d  at Visit 3 ( Baseli ne/ Ra n d o mizati o n; Da y 1):  
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 Pai n sc ore trai ni n g  
 N u meric Pai n Rati n g Sca le (N P R S ) 
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
o  N ote : T he I O P pr oce d ure re q uires t he a d mi nistrati o n of pr o paracai n e 0. 5 % t o t he 
e ye b ef ore testi n g ; t here s h o ul d al wa ys b e ≥3 0 mi n utes bet wee n t he a d mi nistrati o n  
of t o pical a nest hetic a n d I P.  
 Deter mi ne st u d y eli gi bilit y base d o n I ncl usi o n/ E x cl usi o n criteria  
 Ra n d o mizati o n  
 Dis pe nse I P  
 Pr o vi de i nstr ucti o ns f or I P use, d osi n g a d here n ce, a n d d osi n g diar y e ntries  
 S u per vise d first d ose of I P  
 Sc he d ule  or c o nfir m n e xt visit a n d re mi n d s u bject t o ret ur n wit h d osi n g diar y  
7. 1. 4  
Visit 4 ( D a y 3 ± 1)  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 4 ( Da y 3 ± 1):  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 1  of 5 9  
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 N P R S  
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
 Re vie w d osi n g a d here nce a n d dair y e ntries  
 Sc he d ule or c o nfir m ne xt visit a n d re mi n d s u bject t o ret ur n wit h I P a n d d osi n g diar y 
7. 1. 5  
Visit 5 ( D a y 7 ± 1)  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 5 ( Da y 7 ± 1):  
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 N P R S  
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
 C ollect u n use d I P  
 Re vie w d osi n g a d here nce a n d dair y e ntries  
 Dis pe nse I P  
 Sc he d ule or c o nfir m ne xt visit a n d re mi n d s u bject t o ret ur n wit h I P a n d d osi n g diar y 
7. 1. 6  
Visit 6 ( E n d of Tre at me nt ; D a y 1 4 ± 2)  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 6 ( E n d of Treat me nt; Da y 1 4 ± 2) : 
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 N P R S  
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
 C ollect u n use d I P  
 Re vie w d osi n g a d here nce a n d dair y e ntries  
 Uri ne pre g n a nc y test ( o nl y f or W O C B P) *  
 Sc he d ule or c o nfir m ne xt visit  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 2  of 5 9  
7. 1. 7  
Visit 7 ( E n d of St u d y; E arl y Ter mi n ati o n; D a y 2 1 ± 2)  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 7 ( E n d of St u d y; E arl y Ter mi nati o n; Da y 2 1 
± 2):  
 A E m o nit ori n g  
 C o nc o mita nt me dicati o n  u p date  
 B C V A  
 Slit la m p bi o micr osc o p y  
 I O P 
 Dilate d o p ht hal m osc o p y  
 Uri ne pre g n a nc y test ( o nl y f or W O C B P) *  
 Release s u bject  fr o m st u d y 
7. 1. 8  
U nsc he d ule d Visits  
S afet y pr oce d ures a n d efficac y assess me nts c o n d ucte d at u ns c he d ule d visit s are at t he discreti o n 
of t he I n vesti gat or. I nf or mati o n will be c ollecte d d uri n g u nsc h e d ule d visits a b o ut c ha n ges t o 
c o nc o mita nt me dicati o ns a n d a n y A E s e x perie n ce d si nce t he last visit. 
If a s u bject re p orts t heir s u p pl y of I P t o be l ost, destr o ye d, or u n usa ble d ue t o u nacce pta ble 
te m perat ur e e x c ursi o ns, a ne w s u p pl y of I P ma y b e dis pe nse d t o t he s u bject. 
7. 1. 9  
E arl y Ter mi n ati o n  
In t he e ve nt t hat a s u bject wit h dra ws or is ter mi nate d fr o m t he st u d y  b ef ore t he e n d of t he st u d y, 
ever y atte m pt will be ma de t o ens ure t hat t he s u bject ret ur ns t o t he site as s o o n as p ossi ble a n d 
c o m pletes t he Visit 7 ( E n d of St u d y; Earl y T er mi nati o n) assess me nts bef ore bei n g disc har ge d fr o m 
t he st u d y. A n y u n use d I P s h o ul d be c ollecte d d uri n g a n earl y ter mi nati o n visit.  
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 3  of 5 9  
8  St u d y Assess me nt s 
T he Sc he d ule of Pr oce d ures a n d Assess me nts ( A p pe n di x 1 : Sc he d ule of Pr oce d ures a n d 
Assess me nt ) pr o vi des a list of st u d y assess me nts a n d e v al uati o ns t o be perf or me d a n d t he ti mi n g 
of eac h . 
8. 1  
Effic ac y E v al u ati o ns  
E fficac y ass ess me nts will be c o n d u cte d at t he ti me p oi nts i n dicate d o n t he Sche d ule of Pr oce d ures 
a n d Assess me nts ( A p pe n di x 1 : Sc he d ule of Pr oce d ures a n d Ass ess me nt) a n d as detaile d i n t he 
c orres p o n di n g a p pe n dic es. T he effic ac y assess me nts selecte d f or t he st u d y are c o m m o n t o ols 
wit hi n t he fiel d of o p ht hal m ol o g y a n d are ge nerall y rec o g nize d as relia ble, acc urate, a n d rele va nt  
i n assessi n g t he healt h a n d f u ncti o n of h u ma n e yes. Efficac y assess me nts i n t he st u d y i ncl u de: 
 S lit la m p bi o micr osc o p y (A p pe n di x 3 : Slit La m p Bi o micr osc o p)  
o  O c ular i nfla m mati o n ( Sta n dar dizati o n of U veitis N o me nclat ure [ S U N] Scale)  
 N u meric Pai n Rati n g Scale  (A p pe n di x 4 : N u meric Pai n Rati n g Scale ( N P R S)) 
8. 2  
S afet y E v al u ati o ns  
S afet y ass ess me nts will be perf or me d at t he ti me p oi nts i n dicate d o n t he S c he d ule of Pr oce d ures 
a n d Assess me nts ( A p pe n di x 1 : Sc he d ule of Pr oce d ures a n d Ass ess me nt) a n d as detaile d i n t he 
c orres p o n di n g a p pe n di ces. T he s afet y assess me nts selecte d f or t he st u d y are all c o m m o n t o ols 
wit hi n t he fiel d of o p ht hal m ol o g y a n d are ge nerall y rec o g nize d as relia ble, acc urate, a n d rele va nt 
i n assessi n g t he h ealt h a n d f u ncti o n of h u ma n e yes. Safet y assess me nts i n t he st u d y i ncl u de: 
 A E m o nit ori n g ( oc ul ar a n d n o n -oc ular ) 
 P re g n a nc y test ( uri ne; o nl y f or W O C B P as defi ne d i n A p pe n di x 2 : W o ma n of C hil d beari n g 
P ote ntial ( W O C B P) ) 
 Best correcte d v is ual ac uit y (A p pe n di x 5 : Best C orrect e d Vis ual Ac uit y ( B C V A) 
 Slit la m p bi o micr osc o p y ( A p pe n di x 3 : Slit La m p Bi o micr osc o p) 
 I ntr a oc ular press ure (A p pe n di x 6 : I ntr a oc ular Press ure (I O P)) 
 D ilate d o p ht hal m osc o p y (A p pe n di x 7 : Dilate d O p ht hal m osc o p) 
8. 2. 1  
A d verse E ve nt s an d Seri o us A d verse E ve nt s 
A Es  will be m o nit ore d t hr o u g h o ut t he st u d y. S u bject s will be e nc o ura ge d t o re p ort a n y a d v erse 
fi n di n gs d uri n g t he st u d y, w het her or n ot t he y are relate d t o I P. T hese ca n be c ollecte d eit her i n a n 
u ns olicite d fas hi o n wit h o ut a n y pr o m pti n g or i n res p o nse t o a ge neral q uesti o n s uc h as: “ Ha v e y o u 
n otice d a n yt hi n g differe nt si nce y o u starte d t he st u d y; be ga n t he I P, etc .? ” 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 4  of 5 9  
A ll AEs will be ca pt ure d o n t he a p pr o priate  s o urce d oc u me nts a n d rec or de d i n t he e C R F. 
Inf or mati o n t o be c ollecte d at mi ni m u m i ncl u des e ve nt des cri pti o n, o nset, assess me nt of s e verit y, 
relati o ns hi p t o I P, a n d outc o me . 
T he I n vesti gat or will rec or d all A Es wit h s tart dates occ urri n g a n y ti me aft er i nf or me d c o nse nt is 
o btai ne d u ntil 7 (f or n o nseri o us A Es) or 3 0 da ys (f or  S A Es) a fter t he last da y of st u d y partici pati o n. 
At eac h visit, t he I n vesti gat or will i n q uire a b o ut t he occ urre n ce of A E s/ S A Es si nce t he last visit. 
S A Es will be f oll o we d f or o utc o me i nf or mati o n u ntil res ol uti o n or sta bilizati o n . 
A n y me dical c o n diti o n t hat is prese nt at t he ti me t hat t he s u bject is scree ne d will be c o nsi dere d as 
baseli ne a n d n ot re p ort e d as a n A E. H o we v er, if t he s u bject’s c o n diti o n deteri orat es at a n y ti me 
d uri n g t he st u d y, it will be rec or de d as a n A E . 
8. 2. 1. 1  Defi niti o n s 
A n A E i s a n y u nt o war d me dical occ urre nce i n a s u bject te m p orall y ass ociate d wit h t he use of I P, 
w het her or n ot c o nsi dere d relate d t o t he I P. An A E ca n t heref ore b e a n y u n fa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or 
e x acer bate d) te m p orall y ass ociate d wit h t he use of I P wit h o ut a n y j u dg m e nt o n ca usalit y.  
A n A E is c o nsi dere d “seri o us” if it: 
 Res ults i n d eat h  
 Is a life-t hr eate ni n g A E 
N ote:  A n A E is “life -t hr eate ni n g” if, i n t he vie w of t he I n v esti gat or or S p o ns or, its 
occ urre nce pla ces t h e s u bject at i m me diate ris k of deat h. It d oes n ot i ncl u de a n A E 
t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d death  
 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  
 Res ults i n p ersiste nt or si g nifica nt i nca p acit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns  
 Is a co n ge nital a n o mal y  or birt h defect  
Im p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire h os pitalizati o n 
ma y b e c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize 
t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve n t o n e of t hese o utc o mes . 
8. 2. 1. 2  Cl assific ati o n of A d verse E ve nts  
Se verit y of A d verse E ve nt s 
T he se verit y of a ll A Es will be assesse d b y t he I n vesti gat or a n d gra d e d as f oll o ws:  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 5  of 5 9  
 M il d: R e q uires mi ni mal or n o treat me nt a n d d o es n ot i nterfere wit h t he s u bject’s dail y 
acti vities 
 M o der ate:  R es ults i n a l o w le vel of i nc o n ve nie nce or c o ncer n a n d ma y ca use s o me 
i nterfere nce wit h f u ncti o ni n g 
 S e vere:  Interr u pts a s u bj ect’s us ual d ail y acti vit y a n d ma y re q uire s yst e mic dr u g t hera p y 
or ot her treat me nt. Se vere e ve nts are us uall y p ote ntiall y life -t hreate ni n g or i nca pacitati n g. 
T he ter m “se v ere” d oes n ot necessaril y e q u ate t o “seri o us .”  
Rel ati o ns hi p of A d verse E ve nts  
A ll A Es m ust ha ve t heir relati o ns hi p t o I P assesse d b y t h e I n v esti gat or w h o e x a mi nes a n d e val uates 
t he s u bject b as e d o n t e m p oral relati o ns hi p a n d  t h eir cli nical j u d g me nt. In a cli nical st u d y, t h e I P 
m ust al wa ys b e s us pect.  
T he rel ati o ns hi p of a n A E t o t he I P will be deter mi ne d usi n g t he b el o w cat e g ories. Fi nal 
deter mi nati o n of A E attri b uti o n a n d e x pecte d ness will be d eter mi ne d b y t h e S p o ns or i n 
c o ns ultati o n wit h t he Me dical M o nit or.  
 U nrel ate d:  T he A E is c o m pletel y i n d e pe n de nt of I P a d mi nistrati o n, a n d/ or e vi de nce e xists 
t hat t he e ve nt is defi nitel y relate d t o a n ot her eti ol o g y. T h ere m ust be a n alter nati ve, 
defi niti ve e ti ol o g y d oc u me nte d b y t h e I n vesti gat or. 
 U nli kel y:  A  cli nical e ve nt, i ncl u di n g a n a b n or m al la b orat or y test res ult, w h ose te m p oral 
relati o ns hi p t o I P ad mi nistrati o n ma kes a ca usal relati o ns hi p i m pr o ba ble (e. g., t he e v e nt 
di d n ot occ ur wit hi n a reas o na ble ti m e after a d mi nistrati o n of I P) a n d i n w hi c h ot her dr u gs 
or c he micals or u n derl yi n g diseas e pr o vi des pla usi ble e x pla nati o ns (e. g., t he s u bject’s 
cli nical c o n diti o n, ot her c o nc o mita nt treat me nts).  
 P ossi bl y: S o me e vi de nce t o s u g gest a ca usal relati o ns hi p (e. g. , t he e ve nt occ urre d wit hi n 
a reas o n a ble ti me after a d mi nistrati o n of I P). H o we ver, ot her fact ors ma y ha ve c o ntri b ute d 
t o t he e ve nt (e. g., t he s u bject’s cli nical c o n diti o n, ot her c o nc o mita nt e v e nts). 
 P r o b a bl y: E vi de n ce t o s u g gest a ca us al relati o ns hi p, a n d  t he i nfl ue nce of ot her fact ors is 
u nli kel y. T he cli nical e v e nt, i ncl u di n g a n a b n or m al la b orat or y test res ult, occ urs wit hi n a 
reas o na bl e ti me after a d mi nistrati o n of t he I P, is u nli kel y t o be attri b ute d t o c o nc urre nt 
disease or ot h er dr u gs or c he micals, a n d f oll o ws a cli nicall y reas o na ble res p o nse o n 
wit h dra wal.  
 D efi nitel y:  C lear e vi de n ce t o s u g gest a ca usal rel ati o ns hi p, a n d ot her p ossi ble c o ntri b uti n g 
fact ors ca n be r ule d o ut. T he cli nical e ve nt, i ncl u di n g a n a b n or mal la b orat or y test res ult, 
occ urs i n a pla usi ble ti me relati o ns hi p t o I P a d mi nistrati o n a n d ca n n ot be e x plai ne d b y 
c o nc urre nt dise ase or ot h er dr u gs or c h e micals. T he res p o nse t o wit h dra wal of t h e st u d y 
i nter ve nti o n ( dec h alle n ge) s h o ul d 
be cli nicall y 
pla usi ble. 
T he e v e nt 
m ust 
be 
p har mac ol o gic al l y or p h e n o me n ol o gicall y defi niti ve, wit h use of a satisfact or y rec h alle n ge 
pr oce d ure if necessar y.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 6  of 5 9  
E x pecte d ness  
A n A E or s us pecte d a d verse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he 
I n v esti gat or’s Br oc h ure, pac ka ge i nsert, or de vi ce la beli n g, if it is n ot liste d at t he s pecificit y or 
se verit y t hat has bee n o bser ve d, or if it is n ot co nsiste nt wit h t he ris k i nf or mati o n descri be d i n t he 
pr ot oc ol, as a me n de d. “ U ne x pecte d,” as use d i n t his defi niti o n, als o refers t o A Es or s us pecte d 
a d verse reacti o ns t hat are me nti o ne d i n t he I n vesti gat or’s Br oc h ure, pac ka ge i nsert, or de vice 
la beli n g as o cc urri n g wit h a cl ass of dr u gs  ( or ot her me dical pr o d ucts) or as a ntici pate d fr o m t he 
p har mac ol o gic al pr o perti es or ot her c haract eristics of t he I P, b ut are n ot s pecificall y m e nti o ne d as 
occ urri n g wit h t he p artic ular I P u n d er i n vesti gati o n.  
T he I n v esti gat or a n d c o ntract researc h or ga nizati o n, i n c o nj u ncti o n wit h t h e Me dical M o nit or a n d 
t he S p o ns or, will be res p o nsi ble f or det er mi ni n g w het her a n A E is u ne x pecte d (i.e., if t he nat ure, 
se verit y, or fre q u e nc y of t he e ve nt is n ot c o nsiste nt wit h t he ris k i nf or mati o n pre vi o usl y descri be d 
f or t he I P). 
8. 2. 1. 3  A d verse E ve nt Re p orti n g  Re q uire me nts  
A cc or di n g t o fe deral re g ulati o ns, a n I n vesti gat or m ust i m me diatel y re p ort  t o t he S p o ns or a n y S A E, 
w het her or n ot c o nsi dere d dr u g -relate d, i ncl u di n g t h ose liste d i n t he pr ot oc ol or I n v esti gat or’s 
Br oc h ure  a n d m ust i ncl u de a n assess me nt of w het her t here is a reas o n a ble p ossi bilit y t hat t he dr u g 
ca use d t he e ve nt.  
A cc or di n g t o fe deral  re g ulati o ns, t he S p o ns or m ust n otif y t he U S F o o d a n d Dr u g A d mi nistrati o n 
( F D A) an d all partici pati n g I n vesti gat ors as s o o n as p ossi ble, b ut i n n o case later t ha n 1 5 cale n dar 
da ys after t he S p o ns or det er mi nes t hat a p ote ntial s eri o us ris k arisi n g fr o m a cli nical st u d y q u alifies 
f or re p orti n g. S p o ns or m ust re p ort a n y s us pect e d a d verse reacti o n t hat is b ot h seri o us a n d 
u ne x pecte d. T he S p o ns or m ust re p ort a n A E as a s us pecte d a d verse reacti o n o nl y if 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  ( See 2 1 C o de of Fe deral 
Re g ulati o ns [ C F R ] 3 1 2. 3 2 [c][1 ]). 
F urt her m ore, t he S p o ns or m ust als o n otif y F D A of a n y u ne x pecte d fatal or life -t hreate ni n g 
s us pecte d a d v erse reacti o n as s o o n as p ossi ble b ut i n n o case l ater t ha n 7 cale n dar da ys after t he 
S p o ns or ’s i nitial recei pt of t he i nf or mati o n ( See 2 1 C F R 3 1 2. 3 2[c][2 ]). 
8. 2. 1. 4  Pre g n a nc y  
In di vi d uals w h o are pre g na nt are n ot p er mitte d t o partici pate i n t he st u d y. A ll pre g na n cies are t o 
be re p orte d fr o m t he ti me i nf or me d c o nse nt is si g n e d u ntil t he e n d of t he st u d y ( Visit 7). S u bjects 
w h o re p ort b ec o mi n g pre g n a nt or h a vi n g a se x ual part ner ( W O C B P) w h o has bec o m e pre g n a nt 
will ha ve I P wit h dr a w n , will res u me sta n dar d of care treat me nt f or t heir c o n diti o n, a n d will 
u n der g o safet y f oll o w -u p visits a n d asse ss me nts. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 7  of 5 9  
A n y re p ort of pre g n a nc y fr o m a s u bject m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or or its 
dele gate usi n g t he Pre g n a nc y Re p ort F or m . 
E ver y eff ort s h o ul d be m a de t o gat her i nf or mati o n re gar di n g t he pre g n a nc y o utc o me a n d c o n diti o n 
of t he i nfa nt. It is t he res p o nsi bilit y of t h e I n vesti gat or t o o btai n t his i nf or mati o n wit hi n 
a p pr o xi matel y 3 0 cale n d ar da ys after t he i nitial n otificati o n a n d a p pr o xi matel y 3 0 cale n dar da ys 
after deli ver y, if a p plica ble. 
P re g n a nc y c o m plicati o ns s uc h as s p o nta ne o us a b orti o n/ miscarria ge or c o n ge nital a b n or malit y are 
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 usi n g t he Seri o us A d verse E ve nt F or m. 
Electi ve a b orti o ns are n ot c o nsi dere d a n S A E . 
8. 2. 2  
He art R ate, Bl o o d Press ure, a n d O t her S afet y E v al u ati o ns 
S afet y e v al uati o ns will b e assess e d at t he ti me p oi nts i n dicate d o n t he Sc he d ule of Pr oce d ures a n d 
Assess me nts ( A p pe n di x 1 : Sc he d ule of Pr oce d ures a n d Ass ess me nt). A n a b bre vi ate d p h ysical 
e x a mi nati o n will be c o m plete d at Visit 1 ( Scree ni n g), a n d heart rate a n d bl o o d press ure will be 
c hec k e d . 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 8  of 5 9  
9  St atistic al C o nsi der ati o n s 
A  se parate Statistical A n al ysis Pla n ( S A P) will be pre pare d bef ore t he data base is l oc ke d a n d t he 
st u d y is u n mas ke d a n d will i nc l u de a m ore tec h nical a n d detaile d d escri pti o n of t he statistical 
a nal ys es descri be d i n t his secti o n. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal ys es.  
C o nti n u o us meas ures will be s u m marize d descri pti vel y b y t he mea n, sta n dar d de viati o n, me dia n, 
a n d mi ni m u m  a n d ma xi m u m val ues. Cate g orical meas ures will be s u m marize d b y t h e fre q u e nc y 
a n d perce nta ge of s u bjects.  
9. 1  
St atistic al H y p ot hesi s 
T he pri mar y effic ac y e n d p oi nt is t he pr o p orti o n of s u bjects wit h A C C Gra de 0 i n t he st u d y e ye at 
Visit 6 ( Da y 1 4 ). 
T he N ull H y p ot hesis : At p ost-o perati ve Da y 1 4, t here is n o differe nce i n pr o p orti o n of s u bjects 
wit h A C C Gra de 0 i n t he st u d y e y e bet wee n a n acti ve tr eat me nt gr o u p  (V V N 4 6 1, 1. 0 % , or 
V V N 4 6 1, 0. 5 % ) a n d t he Ve hicle gr o u p . 
A lter n ati ve H y p ot hesis: At p ost -o perati ve Da y 1 4, t here is a differe nce i n pr o p orti o n of s u bjects 
wit h  A C C Gra de 0 i n t he st u d y e y e  bet wee n a n acti ve tr eat me nt gr o u p (V V N 4 6 1, 1. 0 % , or 
V V N 4 6 1, 0. 5 % ) a n d t he Ve hicle gr o u p . 
T he pri mar y h y p ot h esis f or t he st u d y is t h at at least o ne d ose re gi me n of V V N 4 6 1 is s u peri or t o 
Ve hicle wit h res pect t o t he pr o p orti o n of s u bjects wit h  A C C Gra de 0 i n t he st u d y e y e at Visit 6 
( Da y 1 4). 
F or t h e pri mar y e n d p oi nt , a se q ue ntial testi n g pr oce d ure will be e m pl o ye d t o c o ntr ol t h e o verall 
T y pe I err or rat e at t w o-si de d 5% wit h res pect t o m ulti ple c o m paris o ns f or t he f oll o wi n g 
h y p ot hes es: V V N 4 6 1, 1. 0 % , t o Ve hicle ( H1) a n d V V N 4 6 1, 0. 5 %, t o Ve hicle ( H2). T he testi n g 
pr oce d ure will b e d o ne i n a hierarc hical or der as H 1 a n d H 2. If H 1 is not si g nifica nt , t he n H 2 will 
n ot be teste d.  
9. 2  
S a m ple Size D eter mi n ati o n  
A sa m ple siz e of a p pr o xi matel y 9 0 c o m plete d s u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 
V V N 4 6 1, 1. 0 %, V V N 4 6 1, 0. 5 %, a n d a matc hi n g Ve hicle t hat d oes n ot c o ntai n t he A PI. Wit h a 
sa m ple siz e i n eac h gr o u p of 3 0, t he st u d y will h a ve 8 0 % p o wer t o detect a differe nce of 3 5 %, 
ass u mi n g a res p o nse rate of 3 0 % i n t he Ve hicle gr o u p, a n d a t w o -si de d 0. 0 5 si g nifica nce le vel f or 
a Pears o n c hi -s q u are test. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 3 9  of 5 9  
A dr o p -o ut rate of 1 0 % is ass u me d, res ulti n g i n a t otal sa m ple size of a p pr o xi matel y 1 0 2 s u bject s 
(3 4 f or V V N 4 6 1 , 1. 0 %, 3 4 f or V V N 4 6 1, 0. 5 %, a n d 3 4 f or Ve hicl e). 
9. 3  
A n al ysis P o p ul ati o n s 
T he F ull A nal ysis Set ( F A S) will c o nsist of all s u bjects w h o are ra n d o mize d. S u bjects will be 
a nal yze d i n t he gr o u p  t o w hic h t he y are ra n d o mize d. T his set will be use d f or t he a nal ysis of all 
effic ac y e n d p oi nts as t he pri mar y a nal ysis.  
T he Per Pr ot oc ol ( P P) A nal ysis Set is a s u bset of t he F A S a n d will i ncl u de all s u bjects i n t he F A S 
w h o c o m plete st u d y -re q uire d treat me nt a n d 
w h o f oll o w t he pr ot oc ol 
wit h o ut si g nifica nt 
de viati o ns. T he deter mi nati o n of si g nifica nt pr ot o c ol de viati o ns will be ma de bef ore dat a base l o c k 
a n d u n mas ki n g.  
T he Safet y A nal ysis Set ( S A F) will i ncl u de all s u bjects w h o recei v e at least o ne d ose of I P,  as 
i n dicate d o n t he d osi n g rec or d. S u bjects will be a nal yze d i n t he gr o u p acc or di n g t o t he treat me nt 
recei v e d. All safet y vari a bles will be a n al yze d usi n g t he S A F, a n d o nl y o bser ve d d ata will be 
i ncl u de d (i.e., missi n g data will re mai n missi n g f or t he safet y a nal ysis).  
9. 4  
St atistic al A n al yses  
T he statistical a nal yses of t he st u d y will be perf or m e d o n t he dat a t hr o u g h Da y 2 1, after all s u bjects 
ha ve eit her c o m plete d t h e Da y 2 1 visit or disc o nti n ue d earl y fr o m t he st u d y , a n d after t he st u d y 
data base h as bee n cl ea n e d, verifi e d, a n d l oc ke d. It is pla n ne d t hat t he d ata fr o m all sites t hat 
partici pate i n t he st u d y will be c o m bi ne d s o t hat t he tar get sa m ple siz e will be a v aila ble f or 
a nal ysis.  
9. 4. 1  
B aseli ne Descri pti ve A n al yse s 
D e m o gra p hic c h aracteristics , i ncl u di n g a ge (years), se x, race, et h nicit y, a n d ot her b aseli ne 
c haracteristics , will be s u m marize d descri pti vel y b y treat me nt gr o u p a n d o v erall. Me dical hist or y 
(c o de d usi n g the 
M e di cal Dicti o nar y f or Re g ulat or y Acti vities [ Me d D R A]) a n d pri or a n d 
c o nc o mita nt me dicati o ns  (c o de d usi n g W H O Dr u g ) will be s u m marize d b y treat me nt a n d o verall.  
T he n u m bers of s u bjects w h o were e nr olle d a n d c o m plete d eac h visit of t he st u d y will be pr o vi de d, 
as well as t h e reas o ns f or all e nr oll me nt disc o nti n uati o ns, gr o u pe d b y maj or reas o ns ( e. g., l ost t o 
f oll o w-u p). A list of dis c o nti n ue d s u bjects, pr ot o c ol de viati o ns, a n d s u bjects e x cl u de d fr o m t he 
a nal ysis s ets will be pr o vi de d as well . 
E x p os ure t o I P a n d a d h ere nce t o t he d osi n g sc h e d ule will be s u m marize d b y treat me nt a n d o verall.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 0  of 5 9  
9. 4. 2  
Effic ac y A n al yses  
S u m mar y d escri pti ve st atistics will be prese nt e d f or all st u d y visits at w hic h efficac y data are 
c ollecte d. Effi cac y a n al yses will be prese nte d f or t he st u d y e ye a n d will o nl y i ncl u de data  fr o m 
bef ore t he earliest o bs er ve d i nsta nce of resc u e t hera p y. I n ot her w or ds, d at a t hat occ urs after t he 
earliest o bser ve d res c ue t hera p y will be set t o missi n g . 
Efficac y a nal yses will be c o n d ucte d usi n g t he F A S , i n ge neral, a n d se nsiti vit y a nal ys es f or pri mar y 
a n d sec o n dar y e n d p oi nts will be c o n d ucte d usi n g t he P P A nal ysis Set . 
9. 4. 2. 1  Pri m ar y Effic ac y A n al yses  
Pri mar y Esti ma n d : T he pri mar y esti ma n d is tr eat me nt differe nce bet wee n V V N 4 6 1 ( 1. 0 % or 
0. 5 %) a n d t he Ve hicle i n t he pr o p orti o n of s u bjects wit h A C C Gra de 0 at Visit 6 ( Da y 1 4) i n t he 
st u d y e ye usi n g t he F A S. 
Tar ge t P o p ulati o n: S u bjects u n der g oi n g r o uti ne cataract s ur ger y w h o meet t he st u d y e ntr y criteria .  
E n d p oi nt : Pr o p orti o n of s u bjects wit h A C C Gra de 0 i n t he st u d y e ye at Visit 6 ( Da y 1 4) . 
Treat me nt C o n diti o n : Treat me nt c o n diti o n is base d o n ra n d o mize d treat me nt. 
P o p ulati o n -Le v el S u m mar y : T h e differe nce i n pr o p orti o ns i n s u bjects wit h A C C Gra de 0 i n t he 
st u d y e ye at Visit 6 ( Da y 1 4) a n d t he c orres p o n di n g p-v al ue . 
I nterc urre nt E ve nts a n d Strate gies t o A d dress I nterc urre nt E v e nts 
 Disc o nti n uati o n of st u d y t hera p y wit h c o nti n ue d p artici pati o n i n t he st u d y wit h o ut recei pt 
of resc u e t hera p y  
o  Treat me nt P olic y A p pr oac h –  n o i m p utati o n; use o bser ve d dat a  
 Recei pt of res c ue t hera p y (t o pical c ortic oster oi d) i n t he st u d y e ye  
o  C o m p osite A p pr oac h –  s u bjects w h o recei ve resc ue t hera p y at or bef ore t he 
assess me nt visit will be ass u me d t o ha ve faile d t he pri mar y e n d p oi nt  
 Missi n g data wit h or wit h o ut wit h dra wal, re gar dl ess of reas o n  
o  H y p ot hetic al A p pr oac h –  n o i m p utati o n; a nal ysis will be base d o n s u bjects w h o 
ha ve a n e val ua ble  a nteri or c ha m ber i n t he st u d y e ye at Visit 6 ( Da y 1 4)  
Pears o n’s c hi -s q uare will be use d t o test t he pri mar y e n d p oi nt b et wee n t he 2 differe nt d oses of 
V V N 4 6 1 vs t he Ve hi cle. T he pri mar y a n al ysis will als o be perf or me d o n t h e P P A nal ysis Set.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 1  of 5 9  
9. 4. 2. 2  Sec o n d ar y Effi c ac y A n al yses  
T he sec o n dar y efficac y e n d p oi nts will i ncl u de t he pr o p orti o n of s u bjects wit h A C C Gra de 0, t he 
pr o p orti o n of s u bjects wit h A C F Gra de 0, a n d t he pr o p orti o n of s u bjects re q uiri n g resc u e 
me dicati o n. T hes e e n d p oi nts will be a n al yze d re gar dl ess of  t he si g nifi ca nce of t he pri mar y 
e n d p oi nt a nal ysis.  
9. 4. 3  
S afet y A n al yses  
S afet y a n al yses will be perf or me d o n all s u bjects i n t he S A F. T he assess me nt of safet y will be 
base d o n t he s u m mar y of oc ular a n d n o n -o c ular A Es, B C V A, a n d o p ht hal mic e x a mi nati o ns usi n g 
slit la m p bi o micr osc o p y a n d dilate d o p ht hal m osc o p y. S u m maries will be pr o vi de d b y treat me nt 
gr o u p a n d, f or oc ular assess me nts, se paratel y b y e ye.  
9. 4. 3. 1  A d verse E ve nt s 
A Es will be c o de d usi n g Me d D R A  a n d c ate g orize d b y s yste m or ga n class usi n g preferre d ter ms. 
Se parate s u m maries of A Es relate d t o treat me nt (as re p orte d b y t he I n vesti gat or) a n d b y se v erit y 
will be prese nte d. T he n u m ber of deat hs a n d S A Es will als o be prese nte d, a n d e ve nts lea di n g t o 
disc o nti n uati o n fr o m t he st u d y will be liste d a n d t a b ulate d.   
9. 4. 3. 2  Cl i nic al L a b or at or y Tests 
T here will n ot be a n y a nal ysis of c li nical la b orat or y dat a. Uri ne pre g na n c y tests will be c o n d ucte d 
at Visit 1 ( Scree ni n g), Visit 2 ( Da y of S ur ger y; D a y 0), Visit 6 ( Da y 1 4), a n d Visit 7 ( Da y 2 1) f or 
W O C B P . Res ults of uri ne pre g na n cy tests  will be prese nte d i n a listi n g.  
9. 4. 3. 3  Ot her S afet y E v al u ati o ns  
S u m mar y statistics f or o bser ve d a n d C F B  f or B C V A a n d I O P w ill be pres e nte d. A b n or malities i n 
slit la m p bi o micr osc o p y a n d dilate d o p ht hal m osc o p y will be s u m marize d b y fre q ue nc y a n d 
perce nt a ge.  T he fre q ue n c y a n d pr o p orti o n of s u bjects treate d wit h resc u e me dicati o ns will be 
s u m marize d. 
He art R ate a n d Bl o o d Press ure  
H eart rate a n d bl o o d press ure  will be a ssesse d d uri n g scree ni n g. T hes e meas ure me nts will be 
prese nte d i n a listi n g. 
P h ysic al E x a mi n ati o ns  
A n a b bre viate d p h ysical e x a mi nati o n  w ill be c o n d ucte d d uri n g scree ni n g . The res ults will be 
s h o w n i n a listi n g. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 2  of 5 9  
9. 5  
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d f or t he st u d y. 
9. 6  
S u b gr o u p A n al yses  
S u b gr o u p  a nal ys es ma y b e c o n d ucte d base d o n  bas eli ne s u bject c haracteristi cs  o n a p ost h oc basis.  
9. 7  
E x pl or at or y A n al yses  
E x pl orat or y e n d p oi nts will be a nal yze d i n a ma n ner si milar t o t he sec o n dar y e n d p oi nts. Mea n C F B 
i n A C C Gra de a n d A C F Gra de will be a nal yz e d usi n g mi x e d m o del re peate d meas ures. T he m o del 
will i ncl u de treat me nt, visit, a n d treat me nt b y visit i nteracti o n as fi x e d effects a n d a c o variate f or 
baseli ne meas ur e me nt ( w here a p pr o priat e) wit h a ra n d o m effect f or site. A n u nstr uct ure d 
c o varia n ce a m o n g re p eate d meas ur e me nts will be ass u me d. O n l y d ata fr o m bef ore t he use of 
resc ue me dicati o n will be i ncl u de d i n t hese a nal ys es. T he pr o p orti o n of s u bjects wit h n o p ost-
o perati ve oc ular pai n i n t he st u d y e ye at Visit 5 ( Da y 7) a n d Visit 6 ( Da y 1 4) will als o be a nal yze d.  
9. 8  
Missi n g, U n use d, or S p uri o us D at a  
M issi n g data f or c o nti n u o us e n d p oi nts will be c o nsi dere d missi n g at ra n d o m wit h t he a n al ysis 
usi n g mi x e d m o del re peate d meas ures . Ot her wise, o bser ve d dat a will be a n al yze d at eac h visit. 
9. 9  
T a b ul ati o n of I n di vi d u al S u bject D at a  
All data c ollecte d i n t he st u d y will be pres e nte d i n i n di vi d ual s u bject data listi n gs f or all s u bjects.  
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 3  of 5 9  
1 0  S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  
1 0. 1  Re g ul at or y Iss ues, Et hic al C o ncer ns, a n d St u d y O versi g ht  
1 0. 1. 1  
I nf or me d C o nse nt Pr ocess 
1 0. 1. 1. 1  C o nse nt/ Asse nt D oc u me nt s 
C o nse nt f or ms descri bi n g i n detail t he st u d y i nter ve nti o n, st u d y pr oce d ures, a n d ris ks will be gi ve n 
t o t he s u bject, a n d writte n d oc u me ntati o n of i nf or me d c o nse nt a n d pri vac y a ut h orizati o n will be 
re q uire d b ef ore starti n g i nter ve nti o n/a d mi nisteri n g I P. T h e writte n c o ns e nt d oc u me nt will e m b o d y 
t he ele me nts of i nf or me d c o nse nt as descri be d b y t h e I nter n ati o nal C o u ncil f or Har m o nisati o n 
(I C H) a n d will als o c o m pl y wit h l ocal r e g ulati o ns. 
If a p pr o priate a n d re q uir e d b y t he l ocal I nstit uti o nal Re vie w B o ar d (I R B), asse nt fr o m t he s u bject 
will als o be o btai ne d. If a s u bject is u na ble t o si g n t he i nf or me d c o nse nt f or m, a le gal re prese nt ati ve 
ma y si g n f or t he m.  
1 0. 1. 1. 2  C o nse nt Pr oce d ures a n d D oc u me nt ati o n  
Inf or me d c o nse nt is a pr ocess t hat is i nitiate d bef ore a pr os pecti ve s u bject a gr ees t o p artici pate i n  
a cli nical st u d y, a n d t his pr ocess c o nti n ues t hr o u g h o ut s t u d y p artici pati o n. I nf or me d co nse nt f or ms 
will be a p pr o ve d b y t he I R B, a n d t h e s u bject w ill be as ke d t o rea d a n d re vie w t he d o c u me nt. T h e 
I n v esti gat or will e x plai n t he res earc h st u d y t o t h e s u bject a n d a ns wer a n y q u esti o ns t hat ma y arise. 
A ver bal e x pla nati o n will be pr o vi de d i n ter ms s uite d t o t he s u bject’s c o m pre he nsi o n of t he 
p ur p oses, pr o ce d ures, a n d p ote ntial ris ks of t he st u d y a n d of  t h eir ri g hts as a res earc h s u bject. T h e 
su bject  will ha ve t he o p p ort u nit y t o caref ull y re vi e w t he writte n c o nse nt f or m a n d as k q uesti o ns 
bef ore s i g ni n g. T he s u bject sh o ul d ha ve t he o p p ort u nit y t o disc uss t he  st u d y wit h t heir fa mil y or 
s urr o gates or t hi n k a b o ut it bef ore a greei n g t o partici pate  i n t he st u d y. T he s u bject will si g n a n d 
date t he i nf or me d c o ns e nt f or m bef ore an y pr oce d ures are do ne s pecificall y f or t he st u d y.  T h e 
su bject  m ust be i nf or me d t hat part ici pati o n is v ol u ntar y a n d t hat t he y ma y wit h dra w fr o m t he st u d y 
at a n y ti me, wit h o ut prej u dice. A c o p y of t he si g ne d a n d dat e d i nf or m e d c o nse nt f or m will be gi ve n 
t o t he s u bject f or t heir rec or ds. T he i nf or me d c o nse nt pr ocess will be c o n d ucte d a n d d oc u me nte d 
i n t he s o urce d oc u me nt (i ncl u di n g t he date), a n d t he f or m si g ne d a n d date d, bef ore t he s u bject 
u n der g oes a n y st u d y -s p ecific pr oce d ures. T h e ri g hts a n d welfare of t he s u bject will be pr otect e d 
b y e m p hasizi n g t o t he m t hat t he q ualit y of t heir m e dical car e will n ot be a d versel y affecte d if t he y 
decli ne t o partici pat e i n t he st u d y.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 4  of 5 9  
1 0. 1. 2  
St u d y Disc o nti n u ati o n a n d Cl os ur e 
T he  st u d y ma y b e te m p oraril y s us pe n de d or pre mat urel y ter mi nate d if t here is s ufficie nt reas o n a ble 
ca use. Writte n n otificati o n, d oc u me nti n g t he reas o n f or st u d y s us p e nsi o n or ter mi nati o n, will b e 
pr o vi de d b y t h e s us pe n di n g or ter mi nati n g part y t o  s u bjects, I nv esti gat ors, f u n di n g a ge nc y  (if 
a p plica ble), t he S p o ns or , a n d re g ulat or y a ut h orities . If t he st u d y is pre m at urel y ter mi nate d or 
s us pe n de d, t he I n v esti gat or will pr o m ptl y i nf or m s u bjects, t he I R B, a n d t he S p o ns or a n d will 
pr o vi de t he reas o n(s) f or t he ter mi nati o n or s us pe nsi o n. S u bject s will be c o ntacte d, as a p plica ble, 
a n d be i nf or me d of c ha n ges t o visit sc he d ule s. 
Circ u msta nces t hat ma y warra nt ter mi nati o n or s us pe nsi o n ma y i ncl u d e, b ut are n ot li mite d t o:  
 Deter mi nati o n of u ne x pecte d, si g nifi ca nt, or u nacce pta ble ris k t o s u bjects 
 I ns ufficie nt c o m plia n ce wit h pr ot oc ol re q uire me nts  
 Data t hat are n ot s uffici e ntl y c o m plete a n d/ or e val ua ble  
 Deter mi nati o n of f utilit y  
T he s t u d y ma y res u me o nce c o n cer ns a b o ut safet y, pr ot o c ol c o m plia nce, a n d data q ualit y are 
a d dresse d a n d satisf y t he S p o ns or, I R B , a n d/ or F D A . 
1 0. 1. 3  
C o nfi de nti alit y a n d Pri v ac y  
S u bject  c o nfi de ntialit y a n d pri vac y will be strictl y hel d i n tr ust b y t he partici pati n g I n vesti gat ors, 
st u d y pers o n n el, an d t he S p o ns or(s) a n d t heir i nter ve nti o ns. T his c o nfi de ntialit y will be e xte n de d 
t o c o ver cli nical i nf or mati o n relati n g t o s u bjects. T heref ore, t he st u d y pr ot oc ol, d oc u me ntati o n, 
data, a n d all ot her i nf or mati o n ge nerate d will be hel d i n strict c o nfi d e nce. N o i nf or m ati o n 
c o ncer ni n g t he st u d y or t he st u d y d ata w ill be release d t o a n y u n a ut h orize d t hir d part y wit h o ut 
a d va nce d w ritte n a p pr o val of t he S p o ns or.  
A ll researc h acti vities will be c o n d ucte d i n as pri v ate a setti n g as p ossi ble.  
T he St u d y M o nit or, ot her a ut h or iz e d re pres e ntati ves of t he S p o ns or, re prese ntati ves of t h e I R B, 
re g ulat or y a ge n cies, a n d t he p har mace utical c o m pa n y s u p pl yi n g I P will be a ble t o i ns pect all 
d oc u me nts a n d rec or ds re q uire d t o be mai ntai ne d b y t he I n vesti gat or, i ncl u di n g, b ut n ot li mite d t o , 
me dical rec or ds (i.e., offi ce, cli nic, or h os pital) a n d p har mac y rec or ds f or t h e s u bjects i n t he st u d y. 
Sites will per mit access t o s uc h rec or ds.  
T he st u d y s u bject’s c o nta ct i nf or mati o n will be sec urel y st or e d at eac h site f or i nter nal use d uri n g 
t he st ud y. At t he e n d of t he st u d y, all rec or ds will c o nti n ue t o be k e pt i n a sec ure l ocati o n f or as 
l o n g a p eri o d as dictat e d b y t he re vie wi n g I R B, I nstit uti o nal p olicies, or S p o ns or re q uire m e nts.  
S t u d y s u bj ect res earc h d ata, w hic h is f or p ur p oses of statistical a nal ysis a n d scie ntific re p orti n g, 
will be tra ns mitte d t o a n d st ore d i n a n electr o nic data ca pt ur e s yste m. T his will n ot i ncl u de t he 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 5  of 5 9  
s u bject’s c o nt act or i de ntif yi n g i nf or mati o n. Rat her, i n di vi d ual s u bjects a n d t heir res earc h d ata 
will be i de ntifie d b y a  u ni q ue st u d y i de ntificati o n n u m ber. T he st u d y data e ntr y a n d st u d y 
ma na ge me nt s yste ms use d b y sites a n d b y c o ntract researc h or ga nizati o n st u d y p ers o n nel will be 
sec ure d a n d pass w or d pr otecte d.  
1 0. 1. 4  
Ke y R ol es a n d St u d y G o ver n a nce  
T a ble 2  
St u d y A d mi nistr ati ve Str uct ure  
Title/ R ole  
C o nt act I nf or m ati o n  
S p o ns or:  
Vi va Visi o n Bi otec h ( H o n g K o n g) Li mite d  
 
 
 
 
 
C hief Me dic al Officer:  
 
 
 
 
 
Me dic al M o nit or:  
 
 
 
 
 
 
  
C o ntr act Rese a rc h Or g a niz ati o n:  
 
 
 
 
1 0. 1. 5  
Cli nic al M o nit ori n g  
L e xitas P har ma Ser vices, I nc., will c o n d uct t he cli nical m o nit ori n g f or t he st u d y. A cli nical 
m o nit ori n g pla n ma y b e use d a n d will descri be i n detail w h o will c o n d uct t he m o nit ori n g, at w hat 
fre q ue n c y m o nit ori n g will be d o ne, at w hat le vel of detail m o nit ori n g will be perf or me d, a n d t he 
distri b uti o n of m o nit ori n g re p orts.  
1 0. 1. 6  
Q u alit y Ass ur a nce a n d Q u alit y C o ntr ol  
E ac h site will perf or m i nter nal q ualit y ma na ge me nt of st u d y c o n d u ct, data , a n d d oc u me ntati o n a n d 
c o m pleti o n. A n i n di vi d ualize d q ualit y ma na ge m e nt pla n ma y be  de vel o p e d t o descri be a site’s 
q ualit y ma na ge me nt.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 6  of 5 9  
Q ualit y c o ntr ol  p r oce d ures will be i m ple me nte d be gi n ni n g wit h t he dat a e ntr y s yste m, a n d data 
q ualit y c o ntr ol c hec ks t hat will be r u n o n t he data base will be ge n erat e d. A n y missi n g data or d ata 
a n o malies will be c o m m u nicate d t o t he site(s) f or clarificati o n/res ol uti o n.  
F oll o wi n g writte n Sta n dar d O perati n g Pr oce d ures , the m o nit ors will verif y t hat t he cli nical st u d y 
is c o n d ucte d, a n d d ata are ge n erate d , d oc u me nt e d (rec or de d), a n d re p orte d i n c o m plia nce wit h t he 
pr ot oc ol, I C H Go o d Cli nical Practice  (G C P ), a n d a p plica ble re g ulat or y re q uire me nts (e. g., G o o d 
La b orat or y Practice [ G L P ], G o o d Ma n ufact uri n g Practice [G M P ]).  
T he site will pr o vi de direct access t o all st u d y-relat e d sites, s o urce dat a/ d oc u me nts, a n d re p orts f or 
t he p ur p ose of m o nit ori n g a n d a u diti n g b y t h e S p o ns or, a n d i ns pe cti o n b y l ocal a n d re g ulat or y 
a ut h orities.  
1 0. 1. 7  
D at a H a n dli n g a n d Rec or d Kee pi n g  
1 0. 1. 7. 1  D at a C ollecti o n a n d M a n a ge me nt Res p o nsi bilities  
D ata c ollecti o n is t he res p o nsi bilit y of st u d y pers o n nel at t he site u n der t he s u per visi o n of t he site’s 
I n v esti gat or. T he I n v esti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bilit y, 
a n d ti meli ness of t he data re p orte d . 
All s o urce d oc u m e nts s h o ul d be c o m plete d i n a neat, l e gi ble ma n ner t o ens ure acc urate 
i nter pretati o n of dat a. 
C o pies of t he st u d y visit w or ks heets ma y be pr o vi de d f or use as s o urce d oc u me nt w or ks heets f or 
rec or di n g data f or eac h s u bject e nr olle d i n t he st u d y. Data rec or de d i n t h e e C R F d eri v e d fr o m 
s o urce d oc u m e nts s h o ul d be c o nsiste nt wit h t he data rec or de d o n t he s o urce d oc u me nts.  
C li nical data (i ncl u di n g A Es, c o nc o mita nt me dicati o ns, a n d e x pecte d a d v erse reacti o ns data) w ill 
be e ntere d i nt o  a n electr o nic data ca pt ure s y ste m pr o vi de d b y Le xitas P har ma Ser vices, I nc. T he 
electr o nic dat a ca pt ur e s yste m will be c o m plia nt wit h  2 1 C F R Part 1 1. T he data s yste m i ncl u des 
pass w or d pr otecti o n a n d i nter nal q ualit y c h ec ks, s uc h as a ut o matic ra n ge c hec ks, t o i d e ntif y data 
t hat a p pear i nc o nsiste nt, i nc o m plete, or i n acc urate. Cli nical data will be e ntere d directl y fr o m t h e 
s o urce d oc u m e nts. 
1 0. 1. 7. 2  St u d y Rec or ds Rete nti o n  
S t u d y d oc u me nts s h o ul d be ret ai ne d f or a mi ni m u m of 2 years after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns 
i n a n I C H re gi o n or u ntil at least 2 years ha v e 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 st u d y i nter ve nti o n. T hese d o c u me nts s h o ul d be retai n e d f or a l o n ger p eri o d, 
h o we ver, if re q uire d b y l ocal re g ulati o ns. N o rec or ds will be destr o ye d wit h o ut a d va nce w ritte n 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 7  of 5 9  
c o nse nt of t h e S p o ns or, if a p plica bl e. 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 
In v esti gat or w he n t hes e d oc u me nts n o l o n ger nee d t o be  retai ne d.  
1 0. 1. 8  
P r ot oc ol D e vi ati o ns  
A  pr ot oc ol de viati o n is a n y n o n -c o m plia nce wit h t he cli nical st u d y pr ot oc ol, I C H G C P, or Ma n ual 
of Pr oce d ures  re q uir e me nts. The n o n -c o m plia nce ma y be o n t he p art of t he s u bject, t he 
In v esti gat or, or t he st u d y pers o n nel. As a res ult of de viati o ns, c orrecti ve acti o ns are t o be 
de vel o pe d b y t he site a n d i m ple me nte d pr o m ptl y.  
T hese practices are c o nsiste nt wit h I C H G C P:  
 4. 5 C o m plia nce wit h Pr ot oc ol, secti o ns 4. 5. 1, 4. 5. 2, a n d 4. 5. 3  
 5. 1 Q ualit y Ass ura nce a n d Q ualit y C o ntr ol, se cti o n 5. 1. 1  
 5. 2 0 N o n -c o m plia nce, s ecti o ns 5. 2 0. 1, a n d 5. 2 0. 2.  
It is t he I n v esti gat or’s res p o nsi bilit y t o us e c o nti n u o us vi gila nce t o i d e ntif y a n d re p ort pr ot oc ol 
de viati o ns . All pr ot oc ol de viati o ns m ust be a d dresse d i n st u d y s o urce d oc u me nts  a n d re p ort e d t o 
t he S p o ns or a n d t he re vie wi n g I R B per t heir p olici es. The In vesti gat or is res p o nsi ble f or k n o wi n g 
a n d a d heri n g t o t he re vie wi n g I R B ’s re q uire me nts. 
1 0. 1. 9  
P u blic ati o n a n d D at a S h ari n g P olic y  
T he  st u d y will c o m pl y wit h t he C li nical Trials Re gistrati o n a n d Res ults I nf or mati o n S u b missi o n 
r ule. As s uc h, t he st u d y will be re gistere d at Cli nical Trials. g o v, a n d t he res ults fr o m t he st u d y will 
be s u b mitte d t o Cli nical Trials. g o v. I n a d diti o n, e ver y atte m pt will be ma de t o p u blis h res ults i n 
peer -re vie we d j o ur nals. 
T he i nstit uti o ns a n d I n vesti gat ors p artici pati n g i n t h e st u d y s hall h a ve n o ri g ht t o p u blis h or prese nt 
t he res ults of t he st u d y wit h o ut a d va nce writte n c o nse nt fr o m t he S p o ns or. 
1 0. 1. 1 0  C o nflict of I nterest P oli c y  
T he i n de pe n de n ce of t he st u d y fr o m a n y act ual or percei ve d i nfl ue nce, s uc h as b y t he 
p har mace utical i n d ustr y, is critical. T heref ore, a n y act ual c o nflict of i nterest of pers o ns w h o ha ve 
a r ole i n t he desi g n, c o n d uct, a nal ysis, p u blicati o n, or a n y as pect of t he st u d y will be discl ose d a n d 
ma na ge d. F urt h er m ore,  p ers o ns w h o ha v e a percei ve d c o nflict of i nterest will be re q uire d t o ha v e 
s uc h c o nflicts ma na ge d i n a wa y t hat is a p pr o priat e t o t heir partici pati o n i n t he desi g n a n d c o n d uct 
of t he st u d y.  


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 8  of 5 9  
1 1  R efere nces 
J a bs D A, N usse n blatt R B, & R ose n b a u m J T; Sta n dar dizati o n of U veitis N o me nclat ure ( S U N) 
W or ki n g Gr o u p. Sta n dar diz ati o n of u veitis n o me nclat ure f or re p orti n g cli nical data. Res ults of t he 
First I nter n ati o nal W or ks h o p. A meric a n J o ur n al of O p ht h al m ol o gy . 2 0 0 5; 1 4 0( 3): 5 0 9-5 1 6.  
Ki m T, Sall K, H olla n d EJ, Brazzell R K, C o ultas S, & G u pta P K. Safet y a n d efficac y of t wice 
dail y a d mi nistrati o n of K PI -1 2 1 1 % f or oc ular i nfl a m mati o n a n d pai n f oll o wi n g cataract s ur ger y. 
Cli nic al O p ht h al m ol o gy . 2 0 1 9; 1 3: 6 9-8 6.  
O’ S hea JJ, Sc h wartz D M, Villa ri n o A V, Ga di na M, McI n n es I B, & La ure nce A. T he J A K-S T A T 
pat h wa y: I m p act o n h u ma n disease a n d t hera pe utic i nter ve nti o n. A n n u al Revie w of Me dici ne . 
2 0 1 5; 6 6: 3 1 1 -3 2 8.  
Star k G R & Dar nell J E Jr. T he J A K -S T A T pat h w a y at t we nt y. I m m u nity. 2 0 1 2; 3 6( 4): 5 0 3-5 1 4.  
Vil lari n o A V, Ka n n o Y, Fer di na n d J R, & O’ S h ea JJ. Mec ha nis ms of Ja k/ S T A T si g nali n g i n 
i m m u nit y a n d disease. J o ur n al of I m m u n ol o gy . 2 0 1 5; 1 9 4( 1): 2 1-2 7.  
We n J, H u H, C he n M, Ya n g H, Z h a o Y, & Li u Y. R ole of J a n us ki nase (J A K) i n hi bit or i n 
a ut oi m m u ne oc ular i nfl a m mati o n: A s yst e matic re vi e w. 
J o ur n al of I m m u n ol o gy Res e arc h . 
2 0 2 1; 2 0 2 1: 2 3 2 4 4 0 0.  
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 4 9  of 5 9  
1 2  A p pe n di ces 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 0  of 5 9  
1 2. 1  A p pe n di x 1: Sc he d ule of Pr oce d ures a n d Assess me nt s 
St u d y Peri o d  
Scree ni n g  
C at ar act 
S ur ger y  
Tre at me nt Peri o d  
E n d of 
Tre at me nt  
E n d of 
St u d y  
Visit N o.  
1  
2  
3  
4  
5  
6  
7  
St u d y D a y  
D a y -3 0 t o -1  
D a y 0  
D a y 1  
D a y 3 ± 1  
D a y 7 ± 1  
D a y 1 4 ± 2  
D a y 2 1 ± 2  
I nf or me d c o nse nt/ Asse nt 
X  
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n criteria 
X  
 
X 1 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
Me dical/ Oc ular/ S ur gical hist or y  
X  
 
 
 
 
 
 
Heart rate a n d bl o o d press ure  
X  
 
 
 
 
 
 
A b bre viate d p h ysical e xa mi nati o n  
X  
 
 
 
 
 
 
Uri ne pre g na nc y test  
X  
X  
 
 
 
X  
X  
Pri or/ C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
S u bj ect a d mi nistrati o n of test e ye dr o p  
X  
 
 
 
 
 
 
Ra n d o mizati o n  
 
 
X  
 
 
 
 
Dis pe nse I P  
 
 
X  
 
X  
 
 
C ollect u n use d I P  
 
 
 
 
X  
X  
 
I n-cli nic a d mi nistrati o n of I P  
 
 
X  
 
 
 
 
P ai n sc ore trai ni n g  
X  
 
X  
 
 
 
 
N P R S  
 
 
X  
X  
X  
X  
 
D osi n g a d here nce  
 
 
 
X  
X  
X  
 
A E m o nit ori n g  
 
X  
X  
X  
X  
X  
X  
Slit la m p bi o micr osc o p y  
X  
 
X  
X  
X  
X  
X  
B C V A  
X  
 
X  
X  
X  
X  
X  
I O P 
X  
 
X  
X  
X  
X  
X  
Dilate d o p ht hal m osc o p y  
X  
 
 
 
 
 
X  
A b bre viati o ns: 
A C C =a nteri or c ha m ber cell; 
A E =a d verse e ve nt; B C V A = b est correcte d v is ual ac uit y; C E L R =cat aract e xtracti o n a n d le ns re place me nt; 
I O P =i ntra o c ular press ure; I P =i n vesti gati o nal pr o d uct; N P R S = N u meric P ai n Rati n g Scale  
1Incl usi o n a n d e xcl usi o n criteria will be assesse d at Visit 1 ( Scree ni n g) ; s u bj ects w h o meet eli gi bilit y re q uire me nts at Visit 1 ( Scree ni n g) will c o nti n ue t o be eli gi ble 
f or st u d y partici pati o n if t he y prese nt at Visit 3 ( Baseli ne/ Ra n d o mizati o n ) wit h  A C C i nfla m mati o n ≥2 i n t he st u d y e ye  after ha vi n g c o m plete d C E L R s ur ger y  
at Visit 2 ( Da y of S ur ger y) wit h o ut s ur gical c o m plicati o n s. 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 1  of 5 9  
1 2. 2  A p pe n di x 2: W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  
P re g n a nc y or ref us al t o a d here t o c o ntrace pti o n re q uire ments is e x cl usi o nar y . 
Fe male s u bjects a n d fe m ale part ners of male s u bjects are c o nsi dere d of n o n -c hil d beari n g p ote ntial 
if t he y ha v e bee n i n me n o pa use f or at l east 1 year, ha ve h a d a t u bal li gati o n at least 1 year b ef ore 
Visit 1 ( Scree ni n g) , or h a ve ha d a t otal h ysterect o m y. C o ntrace pti o n is n ot re q uire d d uri n g t he 
st u d y f or t h ose of n o n-c hil d beari n g p ot e ntial.  
Se x uall y acti ve fe male s u bjects of c hil d beari n g p ote ntial wit h a part ner ca p a ble of fat heri n g 
c hil dre n m ust be willi n g t o use 1 or m ore of t he f oll o wi n g f or ms of c o ntrace pti o n fr o m t he ti me of 
si g ni n g t he i nf or me d c o nse nt f or m f or t he d urati o n of t he st u d y:  
 H or m o nal c o ntrace pti o n ( oral, i m pla nta ble, i nject a ble, tra ns der mal)  
 Mec ha nic al c o ntrace pti o n (s per mici de i n c o nj u ncti o n wit h a barrier met h o d s uc h  as a 
c o n d o m or dia p hra g m)  
 I ntr a uteri ne d e vice 
 Vasect o miz e d part ner(s) ( 6 m o nt hs mi ni m u m)  
 W he n i n kee pi n g wit h a s u bject’s us ual lifest yl e a n d prefere nces, a bsti ne nce ma y als o be 
re gar de d as a n a de q uate met h o d of birt h c o ntr ol, w here a bsti ne n ce i n t his c o nte xt is defi ne d 
as refrai ni n g fr o m a n y s e x ual acti vities or c o ntact t hat ma y res ult i n creati o n of a z y g ote.  
o  N ote:  If a s u bj ect w h o was a bsti ne nt u n der t his defi niti o n bec o mes se x uall y acti ve 
d uri n g t he st u d y, t he y m ust a gree t o us e acce pt a ble c o ntrace pti o n as defi n e d a b o ve 
f or t he re m ai n der of t h e st u d y. 
Se x uall y acti ve male s u bjects wit h part ners w h o are W O C B P m ust be willi n g t o use 1 or m ore of 
t he a b o ve f or ms of birt h c o ntr ol f or eit her t he ms el ves or t heir part ner, as a p pr o priate, fr o m t he 
ti me of si g nin g t he i nf or me d c o nse nt f or m f or t he d urati o n of t he st u d y.  
 M ale s u bjects w h o u n der we nt a v asect o m y at least 6 m o nt hs bef ore V isit 1 ( Scree ni n g) are 
n ot re q uire d t o use a n y ot her f or ms of c o ntrace pti o n d uri n g t he st u d y. 
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 2  of 5 9  
1 2. 3  A p pe n di x 3: Slit L a m p Bi o micr o s c o py  
T he slit la m p bi o micr osc o p y e x a mi nati o n will b e perf or me d wit h t he slit la m p usi n g a bea m wi dt h 
a n d i nte nsit y t hat pr o vi d es o pti mal e val uati o n of t he a nteri or se g me nt. T he slit la m p bi o micr osc o p y 
e x a mi nati o n d oes n ot re q uire fl u ores cei n d ye, alt h o u g h  fl u orescei n d ye ma y be use d at I n vesti gat or 
discreti o n.  
T he slit la m p bi o micr os c o p y e x a mi nati o n m ust be perf or me d bef ore a n y pr oce d ures t hat w o ul d 
re q uire c o nt act wit h t he e ye a n d bef ore t he a p plicati o n of a n y dilati n g or a n est hetic e ye dr o ps. T he 
I n v estigat or s h o ul d use t heir sta n dar d e x a mi nati o n tec h ni q ue. T his pr oce d ure s h o ul d be perf or me d 
i n t he sa me ma n ner f or all s u bjects. W he n p ossi ble, t he sa me I n v esti gat or s h o ul d c o n d uct all slit 
la m p bi o micr osc o p y e x a mi nati o ns at eac h visit f or a gi v e n s u bject t hr o u g h o ut t he st u d y t o e ns ure 
c o nsiste nt gra di n g.  
T he I n vesti gat or m ust e xa mi ne eac h e ye (ri g ht e ye first, t he n left e ye) a n d rec or d a gra de f or eac h 
tiss ue/str uct ure liste d i n Ta ble 3 . O bser vati o ns s h o ul d be rec or de d i n t he s o urce d oc u me nt a n d 
l o g ge d i n t he a p pr o priat e e C R F. 
A ll s u bjects will u n der g o r o uti ne cataract s ur ger y a n d  i m pla ntati o n of a n i ntra oc ular l e ns; 
theref ore, all s u bjects will c ha n ge fr o m pha kic t o pse u d o p ha kic. T his s h o ul d n ot be c o nsi dere d a n 
A E, as it is a pla n ne d part of t he st u d y desi g n.  
T a ble 3  
Slit L a m p Tiss ue/ Str uct ure Assess me nts  
Tiss ue/ Str uct ure  
Gr a de  
E yeli ds & A d ne x a  
0 = N or mal; n o s welli n g/a b n or malit y of t he e yeli d tiss ue 
1 = A b n or mal  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, Cli nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 
C o nj u ncti v a  
C o nj u ncti v al H y pere mi a  
E de m a ( C he m osis)  
C o nj u ncti v al Disc h ar g e/ E x u d ate  
0 = N o ne  
1 = Mil d  
2 = M o derate  
3 = Se vere  
C or ne a  
C or ne al E de m a  
0 = N o ne  
1 = Mil d  
2 = M o derate  
3 = Se vere  
Iris 
0 = N or mal  
1 = A b n or mal  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, Cli nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 3  of 5 9  
Tiss ue/ Str uct ure  
Gr a de  
P u pil  
0 = N or mal  
1 = A b n or mal  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, Cli nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 
Scler a  
0 = N or mal; wit h o ut a n y re d ness/a b n or malit y  
1 = A b n or mal  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, Cli nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _  
Cr yst alli ne Le ns St at us  
P ha kic  
Pse u d o p ha kic  
A p ha kic  
T he se verit y of o c ular i nfla m mati o n will be assesse d b y t he In vesti gat or usi n g a slit la m p a n d 
gra de d usi n g t he  S U N W or ki n g Gr o u p Gra di n g Scale f or t he A nteri or C ha m ber ( Ta ble 4 ). 
T a ble 4  
S U N W or ki n g Gr o u p Gr a di n g Sc ale f or t he A nteri or C h a m ber  
A nteri or C h a m ber Cells  
 
A nteri or C h a m ber Fl are  
Gr a de  
Cells i n Fiel d 1 
Gr a de  
Descri pti o n  
0  
0  
0  
N o ne  
0. 5 +  
1 – 5  
1 +  
6 – 1 5  
1 +  
Fai nt  
2 +  
1 6 – 2 5  
2 +  
M o derate (iris a n d le ns details clear)  
3 +  
2 6 – 5 0  
3 +  
Mar ke d (iris a n d le ns details haz y)  
4 +  
> 5 0  
4 +  
I nte nse (fi bri n or plastic a q ue o us) 
A b bre viati o ns: S U N = Sta n dar dizati o n of U veitis N o me nclat ure  
1Fiel d size is a 1 m m b y 1 m m slit bea m 
Refere nce: J a bs et al., 2 0 0 5  
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 4  of 5 9  
1 2. 4  A p pe n di x 4: N u meric P ai n R ati n g Sc ale ( N P R S)  
S u bjects will be as ke d at eac h p ost -o p erati ve visit , e x cl u di n g Visit 7 ( Da y 2 1), t o rate t heir oc ular 
pai n i n t he st u d y e ye usi n g a n 1 1 -p oi nt N P R S scale. S u bjects will be pr o vi de d wit h pai n sc ore 
trai ni n g t o hel p har m o nize s u bjecti ve re p orti n g acr oss s u bjects a n d acr oss sites. 
“ 0” will re prese nt n o oc ular pai n. “ 1 0” will re pres e nt t he w o rst oc ular p ai n i ma gi na ble.  
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 5  of 5 9  
1 2. 5  A p pe n di x 5: Best C orrecte d Vis u al Ac uit y ( B C V A ) 
B C V A testi n g s h o ul d prece de a n y e x a mi nati o n re q uiri n g c o ntact wit h t he e ye a n d s h o ul d prece de 
p u pil dilati o n or i nstillati o n of a nest hetic e ye dr o ps. B C V A testi n g will  b e perf or me d f oll o wi n g 
ma nifest refracti o n . S u bjects will be teste d i n t heir ri g ht e ye first, f oll o we d b y t he left e ye.  
B C V A will be e val uate d i n eac h e ye i n di vi d uall y usi n g E T D R S c harts at a dista nce of 4 meters  
a n d sc ore d o n a Lo g M A R scale . BC V A s h o ul d  be e val u ate d c o nsiste ntl y t hr o u g h o ut t he st u d y 
usi n g t he sa me m et h o d, e q ui p me nt, a n d li g hti n g c o n diti o ns at eac h site .  
S u bjects will be i nstr uct e d t o r ea d t he letters o n t he E T D R S c hart fr o m the t o p left -h a n d c or ner 
al o n g eac h r o w, o n e letter at a ti me , t h e n d o w n eac h r o w, o n e at a ti me. T h ere are n o n u m bers o n 
t he c hart, o nl y letters. If a s u bject rea ds a n u m ber, t he e x a mi ner s h o ul d re mi n d t he s u bject t hat the 
c hart c o nt ai ns n o n u m bers , a n d t he e x a mi ner s h o ul d t he n re q u est a letter i nstea d of a n u m ber  fr o m 
t he s u bject. S u bjects s h o ul d be e nc o ura ge d t o g uess if a letter a p pears u n clear. If a s u bject i de ntifies 
a letter as 1 of 2 p ossi ble letters, t he e x a mi ner s h o ul d as k t he s u bject t o pic k 1 letter o nl y.  
S u bjects will be i nstr ucte d t o rea d sl o wl y at a r at e of a b o ut 1 letter  per s ec o n d. If at a n y p oi nt t he 
s u bject rea ds t o o q uic kl y, t he e x a mi ner s h o ul d st o p t he s u bject a n d re mi n d t he s u bject t o rea d 
sl o wl y i n or der t o ac hie v e t he best i de ntificati o n of eac h letter. If a s u bject l oses t heir place me nt 
i n t he c hart, t he e x a mi ner s h o ul d as k t he s u bject t o g o bac k t o t he li ne w here t h e place was l ost. 
T he s u bject s h o ul d n ot pr ocee d t o t he ne xt letter u ntil t he y ha ve gi ve n a defi nite res p o nse. If a 
s u bject c ha n ges a res p o nse bef ore m o vi n g o n t o t he ne xt letter, t he e x a mi ner m ust acce pt t he 
c ha n ge. T h e e x a mi ner s h o ul d circle eac h c orrect letter o n t he V A  w or ks heet a n d dra w a si n gle li ne 
t hr o u g h eac h i nc orrect letter. 
At t he e n d of t he t est, t h e e x a mi ner will c o u nt t h e n u m ber of letters i n c orrectl y i de ntifie d , u p t o 
a n d i ncl u di n g t he last li ne rea d , a n d will rec or d t he res ults o n t he s o urce d oc u me nt. A V A letter 
sc ore will be calc ulate d a n d rec or de d i n t he s o urce d oc u me nts a n d in t he e C R F . 
Eac h letter has a sc ore val ue of 0. 0 2 l o g u nits. Si nce t here are 5 letters pe r li ne, t he t otal sc ore f or 
a li ne o n t he L o g M A R c hart re pres e nts a c ha n ge of 0. 1 l o g u nits. T he f or m ula use d i n calc ulati n g 
t he sc ore is: 
C alc ul ati o n : L o g M A R V A = Baseli ne val ue + ( n X 0. 0 2)  
w here : 
B aseli ne val ue is t he L o g M A R  n u m ber of t he last li ne rea d (at least 1 letter rea d 
c orrectl y i n t his li ne), a n d  
 
“ n” is t he t otal n u m ber of letters misse d , u p t o a n d i ncl u di n g t he last li ne rea d, a n d 
 
“ 0.0 2” is t he val ue f or eac h letter  
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 6  of 5 9  
1 2. 6  A p pe n di x 6: I ntr a oc ul ar Press ure (I O P)  
Int ra oc ular press ur e meas ure me nts ( 1 meas ure m e nt per e ye) sh o ul d be c o n d ucte d after t he slit 
la m p e x a mi nati o n is c o m plete d a n d bef ore p u pil dilati o n. T his met h o d re q uires t he a d mi nistrati o n 
of pr o paracai ne 0. 5 % t o t he e ye bef ore testi n g . T h ere s h o ul d al wa ys be ≥3 0 mi n utes bet wee n t h e 
a d mi nistrati o n  of t o pical a nest hetic a n d I P.  
IO P m eas ur e me nts s h o ul d be perf or me d usi n g a G ol d ma n n a p pla nati o n t o n o meter, ha n d h el d 
c o ntact t o n o meter, o r p n e u mat o n o meter  acc or di n g t o t he I n vesti gat or’s st a n dar d pr oce d ure. T h e 
sa me met h o d of meas uri n g I O P s h o ul d be use d o n t he sa me s u bject at all visits. N o n -c o ntact a n d 
re b o u n d met h o ds of testi n g I O P are n ot per mitte d.  
Meas ure me nts s h o ul d be ta ke n wit h t he s u bject seate d. All press ures s h o ul d be rec or de d i n m m H g, 
a n d meas ur e me nts s h o ul d be rec or de d i n t he e C R F .  
 
 


Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 7  of 5 9  
1 2. 7  A p pe n di x 7: Dil ate d O p ht h al m osc o p y  
A  dilate d f u n d us e x a mi nati o n will be p erf or me d after t he a p plicati o n of dilati n g dr o ps ( 1 % 
tr o pica mi de) a n d u p o n t h e I n vesti gat or c o nfir mi n g wit h a pe n li g ht t hat b ot h e yes are f ull y dilate d 
after w aiti n g 2 0 mi n utes. If t he p u pils are still res p o nsi ve t o li g ht, a n a d diti o nal dr o p will  be a d de d 
t o eac h e ye, a n d t he I n vesti gat or will  wait t o pr ocee d u ntil t he p u pils n o  l o n ger res p o n d t o t he pe n 
li g ht. Si nce dilati n g dr o ps are bei n g a p plie d, t h e f u n d us e x a mi nati o n m ust be perf or me d after 
vis ual ac uit y, I O P, a n d slit la m p e x a mi nati o n.  
T he e val u ati o n will i ncl u de assess me nt of t he vitre o us, reti na, m ac ula, c h or oi d, o ptic n er ve, a n d 
o ptic ner ve c u p -t o-disc rati o. After t he pr oce d ure, t he I n v esti gat or  will d eter mi ne if fi n di n gs are 
wit hi n n or mal li mits or are a b n or mal. O nl y s hifts fr o m N or mal t o A b n or mal , Cli nicall y 
Si g nifica nt , or fr o m A b n or mal , Not Cli nicall y Si g nifica nt , to A b n or m al , Cli nicall y Si g nifica nt, 
w ill be rec or de d as A Es. 
Vitre o us  
N or mal:  A bse nce of a n y o pacit y  
A b n or mal:  Prese nce of o pacit y  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, C li nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 
Reti n a  
N or mal:  A bse nce of acti ve i nfla m mati o n or si g nifica nt str uct ural c ha n ges  
A b n or mal:  Prese nce of acti ve i nfla m mat or y si g ns or si g nific a nt str uct ural c ha n ges  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, C li nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _  
M ac ul a  
N or mal:  A bse nce of acti ve i nfla m mati o n or si g nifica nt str uct ural c ha n ges  
A b n or mal:  Prese nce of acti ve i nfla m mat or y si g ns or si g nific a nt str uct ural c ha n ges  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, C li nicall y Sig nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _  
C h or oi d  
N or mal:  A bse nce of acti ve i nfla m mati o n or si g nifica nt str uct ural c ha n ges  
A b n or mal:  Prese nce of acti ve i nfla m mat or y si g ns or si g nific a nt str uct ural c ha n ges  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal , C li nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 
O ptic Ner ve  
N or mal:  A bse nce of a n y da ma ge  
A b n or mal:  Prese nce of a n y da ma ge  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, C li nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 
C u p -t o-Disc  R ati o  
V ertical O ptic Ner ve C u p -t o-Disc Rati o: _ _. _ _ _ _  
H oriz o ntal O ptic Ner ve C u p -t o-Disc Rati o: _ _. _ _ _ _  
Ot her  
I n dic ate a n y ot her dil ate d f u n d us o p ht h al m osc o p y fi n di n gs:  
N or mal  
A b n or mal  
N ot Cli nicall y Si g nifica nt  
Cli nicall y Si g nifica nt  
If A b n or mal, C li nicall y Si g nifica nt, s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ 




Vi va Visi o n Bi otec h ( H o n g K o n g) Lt d.  
 
Cli nical St u d y Pr ot oc ol: V V N 4 6 1 -C S -2 0 1  
 
 
V V N 4 6 1  O p ht hal mic S ol uti o n  
C O N FI D E N TI A L  
P r ot oc ol, v4 . 0, 1 3 Fe b 2 0 2 4  
 
P a ge 5 9  of 5 9  
1 2. 9  A p pe n di x 9 : I n vesti g at or A gree me nt 
A p h as e 2, d o u bl e -m as k e d, r a n d o mi z e d, v e hi cl e -c o nt r oll e d st u d y of 
V V N 4 6 1 O p ht h al mi c S ol uti o n i n t r e ati n g p ost -o p e r ati v e o c ul a r 
i nfl a m m ati o n i n s u bj e cts u n d e r g oi n g r o uti n e u nil at e r al c at a r a ct 
s u r g e r y 
V e rsi o n N u m b e r : 4 . 0 
Iss u e D at e: 1 3  F e b r u a r y 2 0 2 4  
I ha ve rea d t he cli nical st u d y pr ot oc ol a n d u n derst a n d it. I a gree t o c o n d uct t he st u d y as o utli ne d 
i n t his d oc u me nt a n d i n acc or da n ce wit h G C P, a ll l ocal a n d fe d eral re q uire me nts a n d re g ulati o ns, 
a n d i n c o m plia nce wit h t h ose pre ce pts set f ort h i n t he Declarati o n of Helsi n ki wit h res pect t o t he 
use of h u ma n s u bjects i n cli nical st u dies a n d i n vesti gati o ns.  
T he In vesti gat or  will a ss ure t hat n o de viati o n fr o m, or c ha n ges t o, t he pr ot oc ol will ta ke place 
wit h o ut a d va nce a gree m e nt fr o m t he  S p o ns or a n d d oc u me nte d a p pr o val f r o m t he I R B, ex ce pt 
w here necessar y t o eli mi nate a n i m me diate hazar d(s) t o su bject s. All pers o n nel i n v ol ve d i n t he 
c o n d uct of t he st u d y ha v e c o m plete d H u ma n S u bj ects Pr otecti o n a n d I C H G C P Trai ni n g.  
T he pr ot oc ol, i nf or me d c o nse nt f or m(s), recr uit me nt materials, a n d all s u bject materials will be 
s u b mitte d t o t he I R B i n a d va nce f or re vie w a n d a p pr o val. A p pr o val of b ot h t he pr ot oc ol a n d t h e 
i nf or me d c o nse nt f or m m ust be o btai ne d bef ore a n y s u bject is e nr olle d. A n y a m e n d me nt t o t he 
pr ot oc ol will re q uire re vie w a n d a p pr o val b y t h e I R B bef ore t he c h a n ges are i m ple me nte d t o t he 
st u d y. All c ha n ges t o t he c o nse nt f or m will be a p pr o ve d b y t he I R B ; a deter mi nati o n will be ma de 
re gar di n g w het her a n e w c o nse nt n ee ds t o b e o btai ne d fr o m s u bjects w h o pr o vi de d i nf or me d 
c o nse nt  u si n g a pre vi o usl y a p pr o ve d versi o n of t he c o nse nt f or m.  
F urt her, I a gree t o mai ntai n t he c o nfi de ntialit y of all i nf or mati o n recei ve d or de vel o pe d i n 
c o n necti o n wit h t his pr ot oc ol.  
 
Si g n at ure of I n vesti g at or:  
 
 
 
Na me ( pri nte d)  
Si g nat ure  
Date  
 
 

SAP_003.pdf: 
NCT06164743 
Clinical Study VVN461-CS201  
Statistical Analysis Plan 
19 January 2024 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
Page 1 of 41 
Final Version 1.0_2024-01-19 
 
Statistical Analysis Plan for a phase 2, double-masked, 
randomized, vehicle-controlled study of VVN461 
Ophthalmic Solution in treating post-operative ocular 
inflammation in subjects undergoing routine unilateral 
cataract surgery 
 
 
 
Protocol No: 
VVN461-CS-201 
Protocol Date: 
2023-12-04 
Sponsor:  
VivaVision Biotech (Hong Kong) Ltd. 
Unit 202A of the 2nd Floor of Building 2E  
Phase One, Hong Kong Science Park  
Hong Kong, 000000, China  
 
SAP Version: 
1.0 
SAP Date: 
2024-01-19 (Final) 
Prepared by: 
Lexitas Pharma Services, Inc. 
 
 
 
 
Confidentiality Statement  
This document contains information from VivaVision Biotech (Hong Kong) Ltd. and is of confidential, trade secret, and/or 
proprietary nature and may not be disclosed unless such disclosure is required by federal or state law or regulation. It is loaned to 
you for your confidential review on behalf of VivaVision Biotech (Hong Kong) Ltd. only and is not to be photocopied, disclosed, 
or transmitted to any other person or party without the advance written approval of VivaVision Biotech (Hong Kong) Ltd.  
 
 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
Page 2 of 41 
Final Version 1.0_2024-01-19 
 
 
SIGNATURE PAGE 
 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
Page 3 of 41 
Final Version 1.0_2024-01-19 
 
TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................................ 5 
LIST OF FIGURES ...................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
9.5. 
Efficacy and Safety Variables ............................................................................................ 15 
9.5.1. 
Efficacy and Safety Measurements Assessed and Flow Chart ................................... 15 
9.5.1.1. 
Visit and Procedure Schedule ............................................................................. 16 
9.5.1.2. 
Demographics and Baseline Characteristics ....................................................... 16 
9.5.1.3. 
Efficacy Assessments .......................................................................................... 16 
9.5.1.4. 
Safety Assessments ............................................................................................. 17 
9.5.2. 
Appropriateness of Measurements ............................................................................. 24 
9.5.3. 
Primary Efficacy Variable(s) ...................................................................................... 24 
9.5.4. 
Drug Concentration Measurements ............................................................................ 24 
9.6. 
Data Quality Assurance ..................................................................................................... 24 
9.6.1. 
Training and Education of Investigators and Study Site Personnel ........................... 25 
9.6.2. 
Dosing Diary............................................................................................................... 25 
9.6.3. 
Monitoring of Study Sites........................................................................................... 25 
9.6.4. 
Data Entry and Verification of Database Used for Analysis and Reporting .............. 26 
9.6.5. 
Clinical Study Report ................................................................................................. 26 
9.6.6. 
Inter-Laboratory Standardization Methods ................................................................ 26 
9.7. 
Statistical Methods Planned in the Protocol and Determination of Sample Size .............. 26 
9.7.1. 
Statistical and Analytical Plans .................................................................................. 26 
9.7.1.1. 
Analysis Populations ........................................................................................... 28 
9.7.1.2. 
Analysis of Subject Disposition .......................................................................... 29 
9.7.1.3. 
Analysis of Demographic and Baseline Characteristics ..................................... 30 
9.7.1.4. 
Analysis of Study Medication Compliance and Exposure .................................. 31 
9.7.1.5. 
Analysis of Efficacy ............................................................................................ 31 
9.7.1.6. 
Analysis of Safety ............................................................................................... 34 
9.7.2. 
Determination of Sample Size .................................................................................... 37 
9.8. 
Changes in the Conduct of the Study or Planned Analyses ............................................... 38 


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    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
9.8.1. 
Protocol Amendments ................................................................................................ 38 
9.8.2. 
Changes from Protocol-Specified Analyses ............................................................... 38 
9.8.3. 
SAP Amendments....................................................................................................... 38 
REFERENCES ............................................................................................................................ 39 
Appendix I: Schedule Of Assessments ...................................................................................... 40 
 
 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
LIST OF TABLES 
Table 1 
SUN Working Group Grading Scale for the Anterior Chamber ................................ 17 
Table 2 
Slit Lamp Tissue/Structure Assessments .................................................................... 21 
Table 3 
Schedule of Assessments ............................................................................................ 40 
 
 
 
 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
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Final Version 1.0_2024-01-19 
 
LIST OF FIGURES 
Figure 1: Study Schematic ............................................................................................................ 15 
 
 
 


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    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
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Final Version 1.0_2024-01-19 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ACC 
Anterior Chamber Cell 
ACF 
Anterior Chamber Flare  
AE 
Adverse   Event 
API 
Active Pharmaceutical Ingredient  
ATC 
Anatomical Therapeutic Chemical Classification  
BCVA 
Best Corrected Visual Acuity 
CELR 
Cataract Extraction And Lens Replacement 
CFB 
Change From Baseline 
CRF 
Case Report Form 
Ecrf 
Electronic Case Report Form 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FAS 
Full Analysis Set  
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice  
IOP 
Intraocular Pressure  
IP 
Investigational Product  
MMRM 
Mixed-Effect Repeated Measures  
NPRS 
Numeric Pain Rating Scale  
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
PP 
Per Protocol  
PT 
Preferred Term  
QID 
Four Times A Day  
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set  
SAP 
Statistical Analysis Plan 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
SD 
Standard Deviation 
SOC 
System Organ Class  
SUN 
Standardization Of Uveitis Nomenclature  
TEAE 
Treatment-Emergent Adverse Events  
US 
United States  
WHODRUG 
World Health Organization Drug Dictionary  
WOCBP 
Women Of Childbearing Potential  
 
 
 


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    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
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Final Version 1.0_2024-01-19 
 
PROTOCOL SYNOPSIS 
Title:  
A phase 2, double-masked, randomized, vehicle-controlled study of VVN461 
Ophthalmic Solution in treating post-operative ocular inflammation in 
subjects undergoing routine unilateral cataract surgery  
Phase:  
2  
Design/Conduct:  
This is a multicenter, double-masked, randomized, vehicle-controlled, parallel 
comparison study conducted at sites in the United States (US) in subjects 
undergoing routine unilateral cataract extraction and lens replacement 
(CELR) surgery via phacoemulsification  
Objectives:  
Primary:  
Evaluate the ocular efficacy of 2 different doses of VVN461 Ophthalmic 
Solution in treating post-operative ocular inflammation associated with 
cataract surgery compared with the ocular efficacy of a matching Vehicle  
Secondary:  
Evaluate the safety of VVN461  
Endpoints:  
Primary Endpoint:  
• 
Proportion of subjects with anterior chamber cell (ACC) Grade 0 in 
the study eye at Visit 6 (Day 14)  
Secondary Endpoints:  
• 
Proportion of subjects with ACC Grade 0 in the study eye at Visit 5 
(Day 7)  
• 
Proportion of subjects with anterior chamber flare (ACF) Grade 0 in 
the study eye at Visit 6 (Day 14)  
• 
Proportion of subjects with ACF Grade 0 in the study eye at Visit 5 
(Day 7)  
• 
Proportion of subjects requiring rescue medication before Visit 6 (Day 
14)  
Exploratory Endpoints:  
• 
Mean change from baseline (CFB) in ACC Grade in the study eye at  
each visit   
• 
Mean CFB in ACF Grade in the study eye at each visit   
• 
Proportion of subjects with no post-operative ocular pain in the study 
eye at Visit 6 (Day 14)  
• 
Proportion of subjects with no post-operative ocular pain in the study 
eye at Visit 5 (Day 7)   
Population Studied:  
Approximately 90 completed subjects (30 per group) who have undergone 
routine unilateral CELR surgery via phacoemulsification without surgical 
complication.  
Subjects who meet all inclusion criteria will be eligible for study participation.  
 


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Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
 
Inclusion Criteria:  
1. ≥21 years of age and in good general health at Visit 1 (Screening)  
2. Willing and able to provide informed consent and provide relevant 
privacy authorization(s)  
3. Willing and able to comply with study requirements and visit schedule  
4. Clear ocular media (other than cataract) in the study eye  
5. Planning to undergo routine unilateral CELR surgery via 
phacoemulsification extraction and implantation of an intraocular lens. 
Allowed in the study eye at Visit 2 (Day of Surgery):  
a. 
Limbal relaxing incisions (laser-assisted and non-laser)  
b. Intracameral injections and intracameral medications, 
excluding those identified in Exclusion Criterion #2  
6. At Visit 1 (Screening), has pinhole best corrected visual acuity 
(BCVA) ≤0.2 Logarithm of the Minimum Angle of Resolution 
(LogMAR) (i.e., 20/32 Snellen) in the study eye as assessed using 
Early Treatment Diabetic Retinopathy Study (ETDRS)   
7. At Visit 1 (Screening), has BCVA ≤1.0 LogMAR (i.e., 20/200 Snellen) 
in the non-study eye due to pathology other than cataract as assessed 
using ETDRS  
8. Able to self-administer eye drops  
9. At Visit 3 (Baseline/Randomization; Day 1), has ACC Grade ≥2 in the 
study eye  
Subjects who meet any of the following exclusion criteria will not be eligible 
for study participation.   
Exclusion Criteria:  
Ophthalmic (Either Eye)   
1. Any ocular pain at Visit 1 (Screening)  
2. Used within 1 week before Visit 1 (Screening), or be planning to use 
during the study, corticosteroids, oral or topical non-steroidal 
antiinflammatory drugs (NSAIDs), or Omidria® (i.e., phenylephrine 
and ketorolac injection)  
3. Moderate to severe lid, conjunctival, or corneal findings at Visit 1 
(Screening)  
4. Corneal abnormality (e.g., stromal, epithelial, or endothelial 
dystrophies, including epithelial basement membrane dystrophy)  
5. History of chronic/recurrent inflammatory eye disease (e.g., scleritis, 
any uveitis, herpes keratitis)  
6. Any signs of intraocular inflammation (cell/flare) at Visit 1 
(Screening)   
7. Intraocular pressure (IOP) ≥24 mmHg at Visit 1 (Screening) 


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Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
Ophthalmic (Study Eye)  
8. Using or unwilling to forgo contact lens use within defined windows 
before Visit 2 (Day of Surgery) and for the duration of the study  
a. 
Polymethyl methacrylate contact lenses (6 months before 
surgery and throughout study) 
b. Gas permeable rigid lenses (1 month before surgery and 
throughout study) 
c. 
Extended wear or daily soft lenses (7 days before surgery and 
throughout study) 
9. Known pathology that may affect visual acuity, particularly retinal 
changes that affect vision (e.g., macular degeneration, cystoid macular 
edema, proliferative diabetic retinopathy)  
10. Capsule or zonular abnormalities with pre-operative crystalline lens 
tilt or decentration (e.g., Marfan’s syndrome) or abnormalities that 
may affect post-operative centration or tilt of the crystalline lens (e.g., 
pseudoexfoliation syndrome)  
11. History of moderate to severe ocular trauma with the possibility of 
previous zonule dehiscence  
12. Ocular or periocular surgical interventions within defined windows 
before Visit 1 (Screening)  
a. 
Microinvasive glaucoma surgery, any incisional ocular 
surgery, or intracameral drug depot to lower IOP (any history)  
b. Intraocular surgery (6 months)  
c. 
Laser surgery, limbal relaxing incision procedure, eyelid 
surgery (3 months)  
13. Pupil abnormalities (e.g., non-reactive, tonic pupils, abnormally 
shaped pupils, pupils that do not dilate at least 3.5 mm under 
mesopic/scotopic conditions)  
14. Keratoconus or significant irregular astigmatism on pre-operative 
ocular topography  
15. Have a condition, or be in a situation, that may put the subject at 
significant risk of complex surgery and surgical complications that 
would lead to withdrawal from the study  
Ophthalmic (Non-study Eye)  
16. Underwent cataract surgery <14 days before Visit 1 (Screening) or, 
during the study, will require cataract surgery <1 day after Visit 2 (Day 
of Surgery)  
General  
17. Within 30 days before Visit 1 (Screening), participated in an 
investigational drug or device study, or have used an investigational 
drug or device  
 


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Statistical Analysis Plan 
 
 
 
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Final Version 1.0_2024-01-19 
 
 
18. Allergy or hypersensitivity to the investigational product (IP) or its 
excipients  
19. Significant systemic disease (e.g., uncontrolled diabetes; myasthenia 
gravis; hepatic, renal, cardiovascular, or endocrine disorders) 
20. Uncontrolled systemic disease, defined as, within 30 days before Visit 
1 (Screening), a change in disease status or medications that may put 
the subject at increased risk or confound interpretation of study results 
21. Changes within 30 days before Visit 1 (Screening), or anticipated 
changes during the study, to the dosage of systemic medication that 
could have a substantial effect on IOP  
22. Known bleeding tendencies  
23. Acute or chronic disease or illness that would put the subject at 
increased risk or confound interpretation of study results (e.g., 
autoimmune disease, connective tissue disease, immunodeficiency, 
suspected glaucoma, glaucomatous changes in the fundus or visual 
field, ocular inflammation, etc.)  
24. Requires, is likely to require, or is unwilling to discontinue the use of 
prohibited medications  
25. Pregnant, nursing, or planning a pregnancy during the study  
26. Unwilling or unable to use an acceptable method of contraception 
throughout the study if a woman of childbearing potential (WOCBP)  
27. Unwilling or unable to use an acceptable method of contraception 
throughout the study if a male sexual partner of a WOCBP  
Investigational Products:   
• 
VVN461, 1.0%  
• 
VVN461, 0.5%  
• 
Vehicle   
Dosing Regimen:  
Approximately 90 completed subjects will be randomized in a 1:1:1 ratio to 
VVN461, 1.0%, VVN461, 0.5%, or a matching Vehicle that does not contain 
the active pharmaceutical ingredient (API). Subjects will administer 1 eye 
drop in the study eye four times a day (QID) for 14 days.  
Assessments/Evaluations:  
Efficacy:  
• 
Ocular inflammation (Standardization of Uveitis Nomenclature 
[SUN] Scale)  
• 
Post-operative ocular pain (Numeric Pain Rating Scale [NPRS])  
Safety:  
• 
Adverse event (AE) monitoring (ocular and non-ocular)  
• 
Clinically relevant changes from baseline in the following: 
▪ 
BCVA   
▪ 
Slit lamp biomicroscopy   
▪ 
IOP 
▪ 
Dilated ophthalmoscopy  


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Duration of Study:  
Subjects will be assessed at 7 visits over approximately 8 weeks.  
Visits will include a screening visit, the day of cataract surgery, a 
baseline/randomization visit, and efficacy and safety evaluation visits after 3, 
7, and 14 days of QID dosing with IP in the study eye. The study will 
conclude with a safety follow-up visit approximately 1 week after the end of 
the planned dosing period.  
Statistical Methods:  
A sample size of approximately 90 completed subjects will be randomized in 
a 1:1:1 ratio to VVN461, 1.0%, VVN461, 0.5%, and a matching Vehicle that 
does not contain the API. With a sample size in each group of 30, the study 
will have 80% power to detect a difference of 35%, assuming a response rate 
of 30% in the Vehicle group, and a two-sided 0.05 significance level for a 
Pearson chi-square test. A drop-out rate of 10% is assumed, resulting in a 
total sample size of approximately 102 subjects.  
The Full Analysis Set (FAS) will consist of all subjects who are randomized. 
Subjects will be analyzed in the group to which they are randomized. This set 
will be used for the analysis of all efficacy endpoints as the primary analysis.   
The Per Protocol (PP) Analysis Set is a subset of the FAS and will include all 
subjects in the FAS who complete study-required treatment and who follow 
the protocol without significant deviations. The determination of significant 
protocol deviations will be made before database lock and unmasking.  
The Safety Analysis Set (SAF) will include all subjects who receive at least 
one dose of IP, as indicated on the dosing record. Subjects will be analyzed in 
the group according to the treatment received. All safety variables will be 
analyzed using the SAF, and only observed data will be included (i.e., 
missing data will remain missing for the safety analysis).  
Primary Estimand: The primary estimand is treatment difference between 
VVN461 (1.0% or 0.5%) and the Vehicle in the proportion of subjects with 
ACC Grade 0 at Visit 6 (Day 14) in the study eye using the FAS.  
Target Population: Subjects undergoing routine cataract surgery who meet the 
study entry criteria.  
Endpoint: Proportion of subjects with ACC Grade 0 in the study eye at Visit 6 
(Day 14).  
Treatment Condition(s): Treatment condition is based on randomized 
treatment.  
Population-level Summary: The difference in proportions in subjects with 
ACC Grade 0 in the study eye at Visit 6 (Day 14) and the corresponding  p-
value. 


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The proposed procedures to handle missing data and intercurrent events are as 
follows:  
• 
Discontinuation of study therapy with continued participation in the 
study without receipt of rescue therapy 
o 
Treatment Policy Approach – no imputation; use observed data 
• 
Receipt of rescue therapy (topical corticosteroid) in the study eye  
o 
Composite Approach – subjects who receive rescue therapy at 
or before the assessment visit will be assumed to have failed the 
primary endpoint  
• 
Missing data with or without withdrawal, regardless of reason  
o 
Hypothetical Approach – no imputation; analysis will be based 
on subjects who have an evaluable anterior chamber in the study 
eye at Visit 6 (Day 14)  
Pearson’s chi-square will be used to test the primary endpoint between the 2 
different doses of VVN461 versus the Vehicle. The primary analysis will also 
be performed on the PP Analysis Set.  
The secondary efficacy endpoints will include the proportion of subjects with 
ACC Grade 0, the proportion of subjects with ACF Grade 0, and the 
proportion of subjects requiring rescue medication. These endpoints will be 
analyzed regardless of the significance of the primary endpoint analysis. 
Secondary efficacy comparisons with p-values that claim statistical 
significance should be understood to be “nominal,” as they will not be 
adjusted for multiplicity. 
Exploratory endpoints will be analyzed in a manner similar to the secondary 
endpoints. Mean CFB in ACC Grade and ACF Grade will be analyzed using 
mixed model repeated measures. The model will include treatment, visit, and 
treatment by visit interaction as fixed effects and a covariate for baseline 
measurement (where appropriate) with a random effect for site. An 
unstructured covariance among repeated measurements will be assumed. Only 
data from before the use of rescue medication will be included in these 
analyses. The proportion of subjects with no post-operative ocular pain in the 
study eye at Visit 5 (Day 7) and Visit 6 (Day 14) will also be analyzed. 
Exploratory efficacy comparisons with p-values that claim statistical 
significance should be understood to be “nominal,” as they will not be 
adjusted for multiplicity. 
Safety analyses will be performed on all subjects in the SAF. The assessment 
of safety will be based on the summary of ocular and non-ocular AEs, BCVA, 
and ophthalmic examinations using slit lamp biomicroscopy and dilated 
ophthalmoscopy. Summaries will be provided by treatment group and, for 
ocular assessments, separately by eye.  
 
 
 


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9.5. 
EFFICACY AND SAFETY VARIABLES 
9.5.1. 
Efficacy and Safety Measurements Assessed and Flow Chart 
This is a phase 2, multicenter, double-masked, randomized, vehicle-controlled, parallel-
comparison study conducted at sites in the US assessing the safety and ocular efficacy of 
VVN461 for treating post-operative ocular inflammation in subjects who undergo routine 
unilateral CELR surgery via phacoemulsification without surgical complication. Approximately 
90 completed subjects (30 per group) will be randomized in a 1:1:1 ratio. Subjects will 
administer 1 eye drop in the study eye four times a day (QID) for 14 days. The IP in the study 
will be:  
• 
VVN461, 1.0%  
• 
VVN461, 0.5%  
• 
Vehicle  
There will be a total of 7 visits over approximately 8 weeks for each subject. A detailed Schedule 
of Procedures and Assessments is provided in Appendix 1: Schedule of Procedures and 
Assessment, and the general flow of the study is outlined in Figure 1.   
Visits will include a screening visit, the day of cataract surgery, a baseline/randomization visit, 
and efficacy and safety evaluation visits after 3, 7, and 14 days of QID dosing with IP in the 
study eye. The study will conclude with a safety follow-up visit approximately 1 week after the 
end of the planned dosing period.  
Figure 1: Study Schematic 
  
Abbreviations: IP=investigational product; QID= quater in die (four times a day) 
 


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9.5.1.1. 
Visit and Procedure Schedule 
Reference Appendix I. 
9.5.1.2. 
Demographics and Baseline Characteristics 
9.5.1.2.1. Demographics and Disease Characteristics 
Demographic characteristics including age (years), sex, race, ethnicity, study eye(s), abbrieviated 
physical exam, blood pressure, and heart rate.  
9.5.1.2.2. Medical and Surgical History 
Ocular and non-ocular medical and surgical history will be collected at Visit 1 (Screening). 
9.5.1.2.3. Prior and Concomitant Medications 
All medications that the subject has taken within 30 days before Visit 1 (Screening) and through 
Visit 7 (Day 21; End of Study) or exit from the study will be recorded in the eCRF and the 
subject’s source documents. Subjects will be asked for details about any changes in documented 
medications at all visits. The generic name of the drug, dose, route of administration, duration of 
treatment (including start and stop dates), frequency, indication, and whether or not the 
medication was taken due to an AE or as rescue will be recorded for each medication. Prior and 
concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODrug). Restricted and prohibited prior and concomitant therapy are outlined in the 
protocol.  
Subjects are eligible to be rescued at any time at the Investigator’s discretion and placed on 
appropriate treatment or therapy. Although the use of rescue medication is allowable at any time, 
advance consultation with the Medical Monitor is preferred, if possible. If a delay in rescue 
would place the subject at unnecessary risk, the Investigator should proceed with rescue 
immediately. 
The date of rescue medication administration, as well as the name of the rescue medication and 
dosage regimen, must be recorded as concomitant medications in the eCRF, with a note 
indicating that the medication was used for rescue. Subjects who require rescue will be counted 
as treatment failures and undergo follow-up safety assessments and procedures. Every attempt 
should be made to have subjects continue in the study for safety evaluations, even if subjects 
discontinue IP. The need for rescue medication itself will not be considered an AE. 
9.5.1.3. 
Efficacy Assessments 
Efficacy assessments will be conducted at the timepoints indicated on the Schedule of 
Procedures and Assessments (Appendix 1: Schedule of Procedures and Assessment). The 
efficacy assessments selected for the study are common tools within the field of ophthalmology 
and are generally recognized as reliable, accurate, and relevant in assessing the health and 


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function of human eyes. Efficacy assessments in the study include Anterior Chamber grading 
and the Numeric Pain Rating Scale (NPRS). 
Anterior Chamber: 
The severity of ocular inflammation will be assessed by the Investigator using a slit lamp and 
graded using the SUN Working Group Grading Scale for the Anterior Chamber (Table 1 Jabs et 
al., 2005).  
Table 1 
SUN1 Working Group Grading Scale for the Anterior Chamber   
Anterior Chamber Cells  
  
Anterior Chamber Flare  
Grade  
Cells in Field2  
Grade   
Description   
0  
0  
0  
None  
0.5+  
1–5  
1+  
6–15  
1+  
Faint  
2+  
16–25  
2+  
Moderate (iris and lens details clear)  
3+  
26–50  
3+  
Marked (iris and lens details hazy)  
4+  
>50  
4+  
Intense (fibrin or plastic aqueous)  
1 SUN = Standardization of Uveitis Nomenclature 
2 Field size is a 1 mm by 1 mm slit beam  
Numeric Pain Rating Scale: 
Subjects will be asked at each post-operative visit, excluding Visit 7 (Day 21), to rate their ocular 
pain in the study eye using an 11-point NPRS scale. Subjects will be provided with pain score 
training to help harmonize subjective reporting across subjects and across sites.  
“0” will represent no ocular pain. “10” will represent the worst ocular pain imaginable.   
 
9.5.1.4. 
Safety Assessments 
9.5.1.4.1. Adverse Events 
AEs will be monitored throughout the study. Subjects will be encouraged to report any adverse 
findings during the study, whether or not they are related to IP. These can be collected either in an 
unsolicited fashion without any prompting or in response to a general question such as: “Have you 
noticed anything different since you started the study; began the IP, etc.?”  


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All AEs will be captured on the appropriate source documents and recorded in the eCRF. 
Information to be collected at minimum includes event description, onset, assessment of severity, 
relationship to IP, and outcome.  
The Investigator will record all AEs with start dates occurring any time after informed consent is 
obtained until 7 (for nonserious AEs) or 30 days (for SAEs) after the last day of study participation. 
At each visit, the Investigator will inquire about the occurrence of AEs/SAEs since the last visit. 
SAEs will be followed for outcome information until resolution or stabilization.  
Any medical condition that is present at the time that the subject is screened will be considered as 
baseline and not reported as an AE. However, if the subject’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening AE 
o Note: An AE is “life-threatening” if, in the view of the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE 
that, had it occurred in a more severe form, might have caused death 
 Insubject hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
 A congenital anomaly or birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  
Severity of adverse events are described with the following scale: 
 Mild: requires minimal or no treatment and do not interfere with the subject’s daily 
activities 
 Moderate: results in a low level of inconvenience or concern and may cause some 
interference with functioning 
 Severe: interrupts a subject’s usual daily activity. Severe events are usually potentially life-
threatening or incapacitating. The term “severe” does not necessarily equate to “serious.”  


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Relationship of adverse events to study intervention are classified according to the following scale: 
 Unrelated: The AE is completely independent of IP administration, and/or evidence exists 
that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the Investigator.  
 Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to IP administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of IP) and in which other drugs 
or chemicals or underlying disease provides plausible explanations (e.g., the subject’s 
clinical condition, other concomitant treatments).  
 Possibly: Some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of IP). However, other factors may have contributed 
to the event (e.g., the subject’s clinical condition, other concomitant events).  
 Probably: Evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the IP, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
 Definitely: Clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to IP administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study 
intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary.   
Expectedness  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure, package insert, or device labeling, if it is not listed at the specificity or 
severity that has been observed, or if it is not consistent with the risk information described in the 
protocol, as amended. “Unexpected,” as used in this definition, also refers to AEs or suspected 
adverse reactions that are mentioned in the Investigator’s Brochure, package insert, or device 
labeling as occurring with a class of drugs (or other medical products) or as anticipated from the 
pharmacological properties or other characteristics of the IP, but are not specifically mentioned as 
occurring with the particular IP under investigation.  
The Investigator and contract research organization, in conjunction with the Medical Monitor and 
the Sponsor, will be responsible for determining whether an AE is unexpected (i.e., if the nature, 


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severity, or frequency of the event is not consistent with the risk information previously described 
for the IP). 
9.5.1.4.2. Clinical Laboratory Assessments 
9.5.1.4.2.1. Pregnancy 
Individuals who are pregnant are not permitted to participate in the study. All pregnancies are to 
be reported from the time informed consent is signed until the end of the study (Visit 7). Subjects 
who report becoming pregnant or having a sexual partner (WOCBP) who has become pregnant 
will have IP withdrawn, will resume standard of care treatment for their condition, and will 
undergo safety follow-up visits and assessments.  
Any report of pregnancy from a subject must be reported within 24 hours to the Sponsor or its 
delegate using the Pregnancy Report Form.  
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the Investigator to obtain this information within 
approximately 30 calendar days after the initial notification and approximately 30 calendar days 
after delivery, if applicable.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to the Sponsor using the Serious Adverse Event Form. 
Elective abortions are not considered an SAE. 
9.5.1.4.3. Vital Signs 
Vital signs including seated systolic blood pressure, diastolic blood pressure and heart rate were 
obtained at Visit 1 (Screening). 
9.5.1.4.4. Physical Examination 
An abbreviated physical examination was obtatined at Visit 1 (Screening). Any clinically 
significant findings will be noted.  
9.5.1.4.5. Slit Lamp Biomicroscopy 
The slit lamp biomicroscopy examination will be performed with the slit lamp using a beam 
width and intensity that provides optimal evaluation of the anterior segment. The slit lamp 
biomicroscopy examination does not require fluorescein dye, although fluorescein dye may be 
used at Investigator discretion.  
The slit lamp biomicroscopy examination must be performed before any procedures that would 
require contact with the eye and before the application of any dilating or anesthetic eye drops. 
The Investigator should use their standard examination technique. This procedure should be 
performed in the same manner for all subjects. When possible, the same Investigator should 
conduct all slit lamp biomicroscopy examinations at each visit for a given subject throughout the 
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The Investigator must examine each eye (right eye first, then left eye) and record a grade for 
each tissue/structure listed in Table 2. Observations should be recorded in the source document 
and logged in the appropriate eCRF.  
All subjects will undergo routine cataract surgery and implantation of an intraocular lens; 
therefore, all subjects will change from phakic to pseudophakic. This should not be considered 
an AE, as it is a planned part of the study design.  
Table 2 
Slit Lamp Tissue/Structure Assessments  
Tissue/Structure   
Grade   
Eyelids & Adnexa  
0 
= Normal; no swelling/abnormality of the eyelid tissue  
1 
= Abnormal  
                    Not Clinically Significant   
                    Clinically Significant   
                            If Abnormal, Clinically Significant, specify: ____________  
Conjunctiva  
Conjunctival Hyperemia  
Edema (Chemosis)  
Conjunctival Discharge/Exudate  
0 
= None  
1 
= Mild  
2 
= Moderate  
3 
= Severe  
Cornea  
Corneal Edema  
0 
= None  
1 
= Mild  
2 
= Moderate  
3 
= Severe  
Iris  
0 
= Normal  
1 
= Abnormal  
                    Not Clinically Significant   
                    Clinically Significant   
                            If Abnormal, Clinically Significant, specify: ____________  
Tissue/Structure   
Grade   
Pupil  
0 
= Normal  
1 
= Abnormal  
                    Not Clinically Significant   
                    Clinically Significant   
                            If Abnormal, Clinically Significant, specify: ____________  
Sclera  
0 
= Normal; without any redness/abnormality  
1 
= Abnormal  
                    Not Clinically Significant   
                    Clinically Significant   
                            If Abnormal, Clinically Significant, specify: ____________  
Crystalline Lens Status  
Phakic   
Pseudophakic  
Aphakic  


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9.5.1.4.6. Dilated Ophthalmoscopy (Fundus Exam) 
A dilated fundus examination will be performed after the application of dilating drops (1% 
tropicamide) and upon the Investigator confirming with a pen light that both eyes are fully 
dilated after waiting 20 minutes. If the pupils are still responsive to light, an additional drop will 
be added to each eye, and the Investigator will wait to proceed until the pupils no longer respond 
to the pen light. Since dilating drops are being applied, the fundus examination must be 
performed after visual acuity, IOP, and slit lamp examination.  
The evaluation will include assessment of the vitreous, retina, macula, choroid, optic nerve, and 
optic nerve cup-to-disc ratio. After the procedure, the Investigator will determine if findings are 
within normal limits or are abnormal. Only shifts from Normal to Abnormal, Clinically 
Significant, or from Abnormal, Not Clinically Significant, to Abnormal, Clinically Significant, 
will be recorded as AEs.  
Vitreous  
Normal: Absence of any opacity   
Abnormal: Presence of opacity  
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
Retina  
Normal: Absence of active inflammation or significant structural changes   
Abnormal: Presence of active inflammatory signs or significant structural changes   
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
Macula  
Normal: Absence of active inflammation or significant structural changes   
Abnormal: Presence of active inflammatory signs or significant structural changes   
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
Choroid  
Normal: Absence of active inflammation or significant structural changes   
Abnormal: Presence of active inflammatory signs or significant structural changes   
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
Optic Nerve  
Normal: Absence of any damage   
Abnormal: Presence of any damage  
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
Cup-to-Disc Ratio  
Vertical Optic Nerve Cup-to-Disc Ratio: __. __ __  
Horizontal Optic Nerve Cup-to-Disc Ratio: __. __ __  


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Other  
Indicate any other dilated fundus ophthalmoscopy findings: Normal   
Abnormal  
Not Clinically Significant   
Clinically Significant   
If Abnormal, Clinically Significant, specify: ____________  
 
9.5.1.4.7. Intraocular Pressure 
Intraocular pressure measurements (1 measurement per eye) should be conducted after the slit 
lamp examination is completed and before pupil dilation. This method requires the 
administration of proparacaine 0.5% to the eye before testing. There should always be ≥30 
minutes between the administration of topical anesthetic and IP. 
IOP measurements should be performed using a Goldmann applanation tonometer, handheld 
contact tonometer, or pneumatonometer according to the Investigator’s standard procedure. The 
same method of measuring IOP should be used on the same subject at all visits. Non-contact and 
rebound methods of testing IOP are not permitted.  
Measurements should be taken with the subject seated. All pressures should be recorded in 
mmHg, and measurements should be recorded in the eCRF.   
9.5.1.4.8. Best Corrected Visual Acuity 
BCVA testing should precede any examination requiring contact with the eye and should 
precede pupil dilation or instillation of anesthetic eye drops. BCVA testing will be performed 
following manifest refraction. Subjects will be tested in their right eye first, followed by the left 
eye. Testing of the study eye (pre-surgery) will be completed using a pinhole occluder to 
determine potential visual acuity (VA).  
BCVA will be evaluated in each eye individually using ETDRS charts at a distance of 4 meters 
and scored on a LogMAR scale. BCVA should be evaluated consistently throughout the study 
using the same method, equipment, and lighting conditions at each site.   
Subjects will be instructed to read the letters on the ETDRS chart from the top left-hand corner 
along each row, one letter at a time, then down each row, one at a time. There are no numbers on 
the chart, only letters. If a subject reads a number, the examiner should remind the subject that 
the chart contains no numbers, and the examiner should then request a letter instead of a number 
from the subject. Subjects should be encouraged to guess if a letter appears unclear. If a subject 
identifies a letter as 1 of 2 possible letters, the examiner should ask the subject to pick 1 letter 
only.  
Subjects will be instructed to read slowly at a rate of about 1 letter per second. If at any point the 
subject reads too quickly, the examiner should stop the subject and remind the subject to read 
slowly in order to achieve the best identification of each letter. If a subject loses their placement 


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in the chart, the examiner should ask the subject to go back to the line where the place was lost. 
The subject should not proceed to the next letter until they have given a definite response. If a 
subject changes a response before moving on to the next letter, the examiner must accept the 
change. The examiner should circle each correct letter on the VA worksheet and draw a single 
line through each incorrect letter.  
At the end of the test, the examiner will count the number of letters incorrectly identified, up to 
and including the last line read, and will record the results on the source document. A VA letter 
score will be calculated and recorded in the source documents and in the eCRF.  
Each letter has a score value of 0.02 log units. Since there are 5 letters per line, the total score for 
a line on the LogMAR chart represents a change of 0.1 log units. The formula used in calculating 
the score is:  
Calculation:  LogMAR VA = Baseline value + (n X 0.02)  
where:  Baseline value is the LogMAR number of the last line read (at least 1 letter read correctly 
in this line), and   
  
“n” is the total number of letters missed, up to and including the last line read, and  
  
“0.02” is the value for each letter 
9.5.2. 
Appropriateness of Measurements 
All assessments used in this study are widely used and generally recognized as reliable, accurate, 
and relevant. 
9.5.3. 
Primary Efficacy Variable(s) 
The primary efficacy endpoint is difference in proportions in subjects with ACC Grade 0 in the 
study eye at Visit 6 (Day 14) 
9.5.4. 
Drug Concentration Measurements 
No drug concentration measurements will be made for this study. 
 
9.6. 
DATA QUALITY ASSURANCE 
Each site will perform internal quality management of study conduct, data, and documentation 
and completion. An individualized quality management plan may be developed to describe a 
site’s quality management.   


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Quality control procedures will be implemented beginning with the data entry system, and data 
quality control checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution.   
Following written Standard Operating Procedures, the monitors will verify that the clinical study 
is conducted, and data are generated, documented (recorded), and reported in compliance with 
the protocol, ICH Good Clinical Practice (GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practice [GLP], Good Manufacturing Practice [GMP]).   
The site will provide direct access to all study-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities.   
9.6.1. 
Training and Education of Investigators and Study Site Personnel 
 
Study personnel will provide training to subjects on proper eye drop administration, proper IP 
storage when not in use, and proper use of the dosing diary. Subjects will also receive written 
instructions. Subjects will receive a new supply of IP, as applicable, as indicated in Appendix 1: 
Schedule of Procedures and Assessment. Study personnel will review subject dosing adherence, 
as recorded in the dosing diary, at each planned visit and will provide reminders and instruction 
about the QID dosing schedule and dosing adherence, as needed. 
9.6.2. 
Dosing Diary 
Subjects will be asked to record their daily use of IP in a dosing diary that will be collected and 
reviewed with them during each planned visit. Subjects will receive verbal and written 
instruction on the proper use of the dosing diary at Visit 3 (Baseline/Randomization), as well as 
verbal and written instruction on proper eye drop administration and proper IP storage when not 
in use for dosing.   
Empty field entries in the dosing diary will be counted as missed doses, once verified with the 
subject, for the purpose of measuring dosing adherence. Study personnel will review subject 
dosing adherence, as recorded in the dosing diary, at each planned visit and will provide 
reminders and instruction about proper use of the dosing diary, as needed. 
9.6.3. 
Monitoring of Study Sites 
Lexitas Pharma Services, Inc., will conduct the clinical monitoring for the study. A clinical 
monitoring plan may be used and will describe in detail who will conduct the monitoring, at 
what frequency monitoring will be done, at what level of detail monitoring will be performed, 
and the distribution of monitoring reports. 


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9.6.4. 
Data Entry and Verification of Database Used for Analysis and 
Reporting 
Data collection is the responsibility of study personnel at the site under the supervision of the 
site’s Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Copies of the study visit worksheets may be provided for use as source document worksheets for 
recording data for each subject enrolled in the study. Data recorded in the eCRF derived from 
source documents should be consistent with the data recorded on the source documents.   
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) will 
be entered into an electronic data capture system provided by Lexitas Pharma Services, Inc. The 
electronic data capture system will be compliant with 21 CFR Part 11. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
9.6.5. 
Clinical Study Report 
The final clinical study report will be reviewed and approved by the sponsor and, when 
appropriate, medical, clinical, statistical, and/or regulatory staff from Lexitas. 
9.6.6. 
Inter-Laboratory Standardization Methods 
Not applicable.  
9.7. 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
This section of the analysis plan describes the analyses explicitly mentioned in the protocol as 
well as additional analyses not explicitly mentioned in the protocol but planned prior to 
unmasking.. Section 9.8 describes any changes to analyses that were explicitly mentioned in the 
protocol or statistical analysis plan. 
9.7.1. 
Statistical and Analytical Plans 
General Conventions 
Summary statistics for the data collected during this study will be presented to give a general 
description of the subjects studied. Data from all sites will be combined in the computation of 
these descriptive summaries. Categorical variables will be summarized by the frequency and 
percentage of subjects in each category. Unless otherwise noted, the denominator to determine 


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the percentage of subjects in each category will be based on the number of subjects with 
available data. Continuous variables will be summarized using N, mean, standard deviation (SD), 
median, minimum, and maximum values. 
Number of subjects, minimums, and maximums will be calculated to the same number of 
decimal places as the source data. Means, medians, other quartiles, and confidence limits will be 
calculated to one more decimal place than the source data. Standard deviations will be calculated 
to two more decimal places than the source data. Percentages will be calculated to the nearest 
one decimal place. Zero count cells will be displayed as “0” with percentage of (0%). Unless 
otherwise noted, summaries will be performed by the treatment group and presented in the order 
of High Dose, Low Dose, Vehicle.  
Results that cannot be calculated (such as standard deviation for a single subject or due to small 
sample sizes that lead to convergence issues) will be reported as “--".  
Statistical tests will be presented as two sided p-values rounded to four decimal places; p values 
less than 0.0001 will be presented as '<0.0001' and p values=1 will be presented as '>0.9999' in 
all tables. Unless otherwise indicated, statistical testing will be carried out at the α = 0.05 
significance level. 
Baseline values will be defined as the last measurement prior to dosing of double-masked study 
medication. Ocular measurements will use the most recent measurement for each eye. 
All data collected in this study will be presented in individual subject data listings for all 
subjects. 
Computations for all results will be performed using SAS Version 9.4 (Version 9.4, SAS/STAT 
15.2) computer software package (SAS Institute, Inc., 2013, 2020), unless otherwise specified. 
Strata and Covariates 
For analysis of continuous efficacy endpoints, mixed-effect repeated measures (MMRM) models 
will model the change from baseline of each endpoint as the dependent variable with the baseline 
measurement of the corresponding endpoint as a covariate with treatment, visit, and treatment by 
visit interaction as fixed effects.  
Subgroups 
Subgroup analyses may be conducted based on baseline characteristics on a post hoc basis.  
Multiplicity 
For the primary endpoint, a sequential testing procedure will be employed to control the overall 
Type I error rate at two-sided 5% with respect to multiple comparisons for the following 
hypotheses: VVN461, 1.0%, to Vehicle (H1) and VVN461, 0.5%, to Vehicle (H2). The testing 
procedure will be done in a hierarchical order as H1 and H2. If H1 is not significant, then H2 
will not be tested. The secondary and exploratory efficacy endpoints will be analyzed regardless 


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of the significance of the primary endpoint analysis. Both, between group and within group, 
comparisons with p-values that claim statistical significance should be understood to be 
“nominal,” as they will not be adjusted for multiplicity. 
Missing Data and Outliers 
Missing data for continuous endpoints will be considered missing at random with the analysis 
using mixed model repeated measures. Otherwise, observed data will be analyzed at each visit. 
Visit Windows 
The nominal visits listed in the CRF will be used in the summaries. In general, unscheduled 
visits will not be summarized in tables unless otherwise noted. 
Missing Dates 
Missing dates that occur for prior or concomitant medications or AEs will be queried for a date. If 
no date is obtained, the following imputation rules will apply: 
 For start dates, if the given year (or year-month) is the same as study drug administration, 
the start date will be imputed as study drug administration date; otherwise, missing month-
day (or day) will be imputed as ’01-01’ (or ’01’). 
 For stop dates, missing months will be imputed as ‘12’ and missing days will be imputed 
as the last day of the month. If this creates a date after discontinuation/completion, the date 
of discontinuation/completion will be used. 
Imputed dates will only be used to classify events or medications, such as occurring before or 
after the start of treatment. Imputed dates will only be used in tables. Listings will display the 
available date data. 
Interim Analysis 
Not applicable. 
9.7.1.1. 
Analysis Populations 
9.7.1.1.1. Populations 
The Full Analysis Set (FAS) consists of all subjects who were randomized. Subjects will be 
analyzed in the group to which they were randomized. This set will be used for the analysis of all 
efficacy endpoints as the primary analysis. 
The Per Protocol (PP) Analysis Set is a subset of the FAS and will include all subjects in the 
FAS who completed study-required treatment and who followed the protocol without significant 
deviations. The determination of significant protocol violations will be made prior to locking the 
final database and unmasking. Reasons for exclusion will include but are not limited to: 
 Subjects with poor study-drug compliance 


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 Non-compliance with the protocol 
 Prohibited medication use 
 Assessments performed out of order 
 Visits out of window 
Subjects will be analyzed in the group to which they were treated. 
The Safety Analysis Set will include all subjects who took at least one dose of investigational 
product, as indicated on the dosing record. Subjects will be analyzed in the group according to 
the treatment received. All safety variables will be analyzed using the Safety Analysis Set and 
only observed data will be included (i.e., missing data will remain missing for the safety 
analysis). 
9.7.1.1.2. Analysis Eyes 
The study eye is the eye that meets all inclusion and no exclusion criteria. If both eyes are eligible, 
the Investigator will designate the study eye. The study eye is the surgical eye. Efficacy analyses 
will be performed on the study eye using the FAS. Sensitivity analyses will be performed for 
primary and secondary endpoints using the PP Analysis Set.   
Safety analyses will be presented for the study eye and the non-study eye. 
9.7.1.2. 
Analysis of Subject Disposition 
The number of subjects randomized at each site will be summarized by treatment group and 
overall. 
Subjects’ enrollment and disposition during the study will be summarized by treatment group 
and overall. The reasons for discontinuation will be listed in the order as they appear on the 
eCRF. 
Summary tables will include the following. The percentages will be calculated based on the 
number of randomized subjects.  
 Number of subjects screened 
 Number and percentage of subjects treated  
 Number and percentage of subjects in the Full Analysis Set 
 Number and percentage of subjects in the Per-Protocol Analysis Set 
 Number and percentage of subjects in the Safety Analysis Set 
 Number and percentage of subjects treated who completed the study 
 Number and percentage of subjects treated who discontinued from the study 
 The reasons for study discontinuation 
 Number and percentage of subjects attending each visit 
A table of protocol deviations will be presented using the FAS. 


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A listing of subjects who do not meet all inclusion criteria or meet exclusion criteria will be 
provided. 
9.7.1.3. 
Analysis of Demographic and Baseline Characteristics 
9.7.1.3.1. Demographics and Disease Characteristics 
Demographic characteristics include age (years), age group (<65 years, ≥65 years), sex, race, and 
ethnicity. These characteristics, as well as clinically significant findings during abbreviated 
physical exam, systolic and diastolic blood pressure, and heart rate, will be summarized 
descriptively by treatment group and overall using the FAS, PP, and Safety Analysis Sets. For 
categorical parameters, the percentages will be calculated overall and based on the number of 
subjects in each treatment group based on non-missing observations.  
9.7.1.3.2. Medical and Surgical History 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, Mozzicato, 2009). The frequency and percentage of subjects with any 
medical and/or surgical history was summarized by treatment group using the FAS. System 
organ class (SOC) will be sorted alphabetically and preferred term (PT) within each SOC will be 
sorted by overall descending order of frequency according to the following rules in order: 
1. Descending frequency within High Dose;  
2. Descending frequency within Low Dose; 
3. Descending frequency within Vehicle; 
4. PT in alphabetical order. 
The medical and surgical history will include both the ocular and the general (non-ocular) 
history. Ocular medical history, ocular surgical history, general (non-ocular) medical history and 
general (non-ocular) surgical history will be summarized separately. Ocular and non-ocular 
medical and surgical histories are identified according to which CRF the event is recorded. 
Ocular medical history will be summarized separately for study eye and non-study eye 
9.7.1.3.3. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (B3 WHO Drug Global, Lagerlund et al., 2020) for anatomical therapeutic chemical 
classification (ATC) and preferred drug name.  
The frequency and percentage of subjects with coded medications will be summarized by 
treatment group using the Safety Analysis Set. A subject who used multiple medications was 
counted only once for each ATC and preferred drug name. Therapeutic Subgroup is sorted 
alphabetically, and preferred term is sorted by descending frequency overall within each Level 3 
term according to:  
1. Descending frequency within High Dose; 


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2. Descending frequency within Low Dose; 
3. Descending frequency within Vehicle; 
4. PT in alphabetical order. 
Prior and concomitant medications will be summarized separately. Ocular medications are 
defined as those medications for which an eye has been specified (OD, OS, or OU). Ocular and 
non-ocular medications will be summarized separately. Ocular medications will be summarized 
separately for study eye and non-study eye. 
Prior medications are defined as any medications that started and stopped prior to the date of 
cataract surgery. Concomitant medications are defined as any medications that are ongoing or 
start after the start of cataract surgery, including medications provided at Visit 2 (Day of 
Surgery) as part of the cataract surgery, through the end of study/exit from study visit. 
Medications taken after Visit 7 or withdrawal from the study are not considered concomitant. 
9.7.1.4. 
Analysis of Study Medication Compliance and Exposure 
Treatment adherence and exposure will be assessed by the data from the Study Drug 
Administration and Treatment Adherence eCRFs and will be summarized by treatment group 
using the Safety Analysis Set. 
Treatment adherence was assessed by 5 questions: Did subject return IP at this visit, and if so, 
how many used vitals and how many un-used vials, did subject miss any doses since the last 
visit, and if so, how many doses missed. Descriptive statistics will be presented for these 
measures by visit by treatment group. 
Duration of exposure of double-masked study drug will be calculated as the total number of days 
from the first double-masked dose date to the last double-masked dose date plus 1 (one) 
regardless of temporary dose interruptions.  
 
9.7.1.5. 
Analysis of Efficacy 
Summary descriptive statistics will be presented for all study visits at which efficacy data are 
collected. Efficacy analyses will be presented by the study eye. 
For subjects who discontinue treatment prior to the Visit 7, the data collected on the Early 
Termination eCRFs will not be summarized unless the termination within the visit windows of a 
particular visit.  
All longitudinal models will be fit using the MIXED procedure in SAS. Categorical analyses will 
be conducted using the FREQ procedure. 
Secondary and exporatory endpoints will be analyzed in a similar manner to the primary 
endpoint regardless of the significance of the primary endpoint analysis. All efficacy analyses 
will be conducted using the FAS and PP Analysis Sets. 


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9.7.1.5.1. Primary Efficacy Analysis 
Primary Estimand: The primary estimand is treatment difference between VVN461 (1.0% or 
0.5%) and the Vehicle in the proportion of subjects with ACC Grade 0 at Visit 6 (Day 14) in the 
study eye using the FAS.  
Target Population: Subjects undergoing routine cataract surgery who meet the study entry 
criteria.   
Endpoint: Proportion of subjects with ACC Grade 0 in the study eye at Visit 6 (Day 14).  
Treatment Condition: Treatment condition is based on randomized treatment.  
Population-Level Summary: The difference in proportions in subjects with ACC Grade 0 in the 
study eye at Visit 6 (Day 14) and the corresponding p-value.  
 
Intercurrent Events and Strategies to Address Intercurrent Events  
• 
Discontinuation of study therapy with continued participation in the study without receipt 
of rescue therapy 
o Treatment Policy Approach – no imputation; use observed data  
• 
Receipt of rescue therapy (topical corticosteroid) in the study eye  
o Composite Approach – subjects who receive rescue therapy at or before the 
assessment visit will be assumed to have failed the primary endpoint  
• 
Missing data due to discontinuation due to Lack of Efficacy or Advese Event  
o Composite Approach – subjects who discontinue due to Lack of Efficacy or 
Adverse Event before the assessment visit will be assumed to have failed the 
primary endpoint 
• 
Missing data with or without withdrawal, regardless of reason 
o Hypothetical Approach – no imputation; analysis will be based on subjects who 
have an evaluable anterior chamber in the study eye at Visit 6 (Day 14)  
Pearson’s chi-square will be used to test the primary endpoint between the 2 different doses of 
VVN461 vs the Vehicle. Analyses will be also performed on observed data without failure 
criteria for rescue. These analyses will also be performed on the PP Analysis Set.  
A sensitivity analysis with control-based multiple imputation method will be carried out in the 
following three steps: 
1) Imputation: Missing binary data will be filled in 25 different times to generate 25 
imputed datasets. The following code will be used to impute the 25 datasets with data 
of subjects prior to rescue medications. 


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The control is where treatment = 3. This imputes data for all arms according to the 
control treatment. 
 
2) Analysis: Each of the 25 imputed datasets will be analyzed at Visit 6 using PROC 
FREQ where the propotions of responders in each treatment arm will be calculated: 
 
 
  
 
  
 
  
 
 
 
3) Pooling: The results from the 25 imputed datasets will be combined for estimation 
using PROC MIANALYZE.  
 
Results will include treatment arm proportions: 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
As well the difference between proportions: 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
The sensitivity analyses will only be performed on the primary endpoint at Visit 6. All analyses 
will each be performed with the FAS and Per Protocol Analysis Sets. 
9.7.1.5.2. Secondary Efficacy Analyses 
The secondary efficacy endpoints include the following:  
• 
Proportion of subjects with ACC Grade 0 in the study eye at Visit 5 (Day 7)  
• 
Proportion of subjects with anterior chamber flare (ACF) Grade 0 in the study eye at 
Visit 6 (Day 14)  
• 
Proportion of subjects with ACF Grade 0 in the study eye at Visit 5 (Day 7)  
• 
Proportion of subjects requiring rescue medication before Visit 6 (Day 14) 


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9.7.1.5.3. Exploratory Efficacy Analysis 
Exploratory endpoints will include the proportion of subjects with no postoperative ocular pain 
(NPRS = 0) in the study eye at Visit 5 (Day 7) and at Visit 6 (Day 14).  
Observed mean NPRS prior to rescue mediation will also be analyzed at each given visit. 
The following study eye endpoints will be analyzed at each visit using a mixed model repeated 
measures: 
1) Mean CFB in ACC Grade 
2) Mean CFB in ACF Grade 
3) Mean NPRS 
The model will include treatment, visit, and treatment by visit interaction as fixed effects and a 
covariate for baseline measurement (where appropriate) with a random effect for site. An 
unstructured covariance among repeated measurements will be assumed. If the model fails to 
converge using this covariance structure, spatial power or compound symmetry will be 
implemented in this order until convergence is reached. If convergence is not reached, values 
will be denoted as “--”. Only data from before the use of rescue medication will be included in 
these analyses.  
  
 
 
  
   
  
   
 
  
   
  
   
  
   
  
run;  
9.7.1.6. 
Analysis of Safety 
Safety will be evaluated by AEs, changes from baseline in IOP measurements and Best 
Corrected Visual Acuity (BCVA), as well as, Slit Lamp Biomicroscopy and Dilated 
Ophthalmoscopy Exams. 
The Safety Analysis Set will be used for all safety analyses. All data, including data after rescue 
therapy, will be summarized as observed and no data imputation will be performed. No statistical 
treatment group comparisons will be performed, unless otherwise specified. Analyses will be 
presented by study eye and non-study eye, if applicable. 
For by visit summaries, data collected using Early Termination eCRFs will not be summarized 
unless the termination occurred within the visit windows of a particular visit. 
All visits will be included in listings. 


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9.7.1.6.1. Adverse Events 
AEs are coded using MedDRA. Treatment-emergent adverse events (TEAE) are defined as 
events that start on or after the date of first dose of double-masked study drug up to and 
including the last dose of double-masked study medication. Pretreatment adverse events are 
events that begin prior to the date of double-masked study medication. Ocular AEs are defined as 
those events for which an eye has been specified (OD, OS, or OU).  
Ocular and non-ocular AEs are summarized separately and will each be summarized separately 
for treatment-emergent adverse events. Ocular AEs will be presented by study eye and non-study 
eye.  
In all summaries of AEs, percentages are calculated based on the number of subjects in each 
treatment group of the Safety Analysis Set. 
Overall summaries of AEs by treatment will include:  
 the number of AEs and SAEs reported; 
 the number and percentage of subjects who experienced any AE; 
 the number and percentage of subjects who experienced any serious adverse event (SAE) 
and the reason for seriousness; 
 the number and percentage of subjects with any AE by worst severity and worst 
relationship.  
 the number and percentage of subjects with any TEAEs leading to discontinuation of 
double-masked study drug; 
 the number and percentage of subjects with any TEAEs leading to study termination. 
Summaries of the frequency and percentage of subjects with AEs by SOC and preferred term by 
treatment group will include: 
 All AEs by SOC and preferred term; 
 All AEs by SOC, preferred term, and maximum severity; 
 All AEs by SOC, preferred term, and maximum relationship. 
System organ class (SOC) will be sorted alphabetically, and preferred term (PT) within each 
SOC will be sorted by overall descending order of frequency according to the following rules in 
order: 
1. 
Descending frequency within High Dose;  
2. 
Descending frequency within Low Dose; 
3. 
Descending frequency within Vehicle; 
4. 
Descending frequency within Low Dose; 
Subjects are counted only once for each SOC and PT. In summaries of maximum severity and 
maximum relationship, subjects with multiple occurrences of events will only be counted once at 
the maximum severity/relationship per SOC and PT.  


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Any treatment-emergent AEs that have a missing severity will be presented as severe in the 
summary table but will be presented with a missing severity in the data listing. Any treatment-
emergent AEs that have a missing relationship will be presented as “Related” in the summary 
table but will be presented with a missing relationship in the data listing. 
All AEs are displayed in listings. In addition, separate listings will be provided for:  
 Subjects with any treatment-emergent adverse event leading to study drug 
discontinuation or study termination; 
 Subjects with any serious adverse event (treatment-emergent or otherwise); 
 Subject deaths. 
9.7.1.6.2. Clinical Laboratory Tests 
The results of pregnancy tests for women of childbearing potential will be listed only. 
9.7.1.6.3. Slit Lamp Biomicroscopy 
The frequency and percentage of subjects with observed values of each category as well as the 
categorical shift from baseline at each post-baseline visit will be tabulated at each scheduled visit 
for the study eye and non-study eye. The percentages are calculated based on the number of 
subjects at each visit in each treatment group based on non-missing observations of the Safety 
Analysis Set. The percentages for the shift will be calculated based on the number of subjects 
with both baseline and post-baseline values. 
9.7.1.6.4. Dilated Ophthalmoscopy (Fundus Exam) 
The frequency and percentage of subjects with observed values of each category as well as the 
categorical shift from baseline at each post-baseline visit will be tabulated at each scheduled visit 
for the study eye and non-study eye. The percentages are calculated based on the number of 
subjects at each visit in each treatment group based on non-missing observations of the Safety 
Analysis Set. The percentages for the shift will be calculated based on the number of subjects 
with both baseline and post-baseline values. 
Descriptive summaries of the observed cup-to-disc ratio at each scheduled visit as well as the 
change from baseline at each post-baseline visit will be presented for both eyes. 
9.7.1.6.5. Intraocular Pressure 
Descriptive summaries of the observed values at each scheduled visit as well as the change from 
baseline at each post-baseline visit will be presented for the study eye and non-study eye. 
9.7.1.6.6. Best Corrected Visual Acuity 
Descriptive summaries of the observed values of LogMAR at each scheduled visit as well as the 
change from baseline at each post-baseline visit will be presented for the study eye and non-


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study eye. A categorical analysis of subjects who lose 3 or more lines ETDRS in either eye at 
each visit or final visit will be conducted. 
9.7.2. 
Determination of Sample Size 
A sample size of approximately 90 completed subjects will be randomized in a 1:1:1 ratio to 
VVN461, 1.0%, VVN461, 0.5%, and a matching Vehicle that does not contain the API. With a 
sample size in each group of 30, the study will have 80% power to detect a difference of 35%, 
assuming a response rate of 30% in the Vehicle group, and a two-sided 0.05 significance level 
for a Pearson chi-square test.  
A drop-out rate of 10% is assumed, resulting in a total sample size of approximately 102 subjects 
(34 for VVN461, 1.0%, 34 for VVN461, 0.5%, and 34 for Vehicle). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
9.8.1. 
Protocol Amendments 
Protocol, Amendment 1 (Version 2.0) – 16 November 2023 
1) Add additional occurrences of existing safety procedures scheduled during study conduct. 
2) Additional updates were made for consistency with the changes outlined above or 
changes administrative in nature. 
Protocol, Amendment 2 (Version 3.0) – 04 December 2023 
1) Revise the primary endpoint grading scale. 
2) Additional updates were made for consistency with the changes outlined above or 
changes administrative in nature. 
9.8.2. 
Changes from Protocol-Specified Analyses 
Exploratory Efficacy Analysis: 
1) Observed analysis of NPRS  
2) Mean NPRS analysis using mixed model repeated measures 
9.8.3. 
SAP Amendments 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 


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REFERENCES 
 
1. Jabs DA, Nussenblatt RB, & Rosenbaum JT; Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical 
data. Results of the First International Workshop. American Journal of Ophthalmology. 
2005;140(3):509-516. 
2. Mozzicato P. (2009). MedDRA: An overview of the medical dictionary for regulatory 
activities. Pharmaceutical Medicine 23: 65-75. 
3. Lagerlund O, Strese S, Fladvad M & Lindquist M. (2020). WHODrug: A global, 
validated and updated dictionary for medicinal information. Therapeutic Innovation & 
Regulatory Science 54: 1116–1122. 
4. SAS Institute Inc. What’s New in Base SAS® 9.4 and SAS® Viya®. (2013). SAS 
Institute Inc., Cary, NC, USA.  
5. SAS Institute Inc. (2020). SAS/STAT User’s Guide. SAS Institute Inc., Cary, NC, USA.  
 


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Appendix I: Schedule Of Assessments 
Table 3 
Schedule of Assessments 
Study Period  
Screening  
Cataract 
Surgery   
Treatment Perio d  
End of 
Treatment  
End of Study  
Visit No.  
1  
2  
3  
4  
5  
6  
7  
Study Day  
Day -30 to -1  
Day 0  
Day 1  
Day 3 ± 1  
Day 7 ± 1  
Day 14 ± 2  
Day 21 ± 2  
Informed consent/Assent  
X  
  
  
  
  
  
  
Inclusion/Exclusion criteria  
X  
  
X1  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
Medical/Ocular/Surgical history  
X  
  
  
  
  
  
  
Heart rate and blood pressure   
X  
  
  
  
  
  
  
Abbreviated physical examination  
X  
  
  
  
  
  
  
Urine pregnancy test  
X  
X  
  
  
  
X  
X  
Prior/Concomitant medications  
X  
X  
X  
X  
X  
X  
X  
Subject administration of test eye drop  
X  
  
  
  
  
  
  
Randomization   
  
  
X  
  
  
  
  
Dispense IP  
  
  
X  
  
X  
  
  
Collect unused IP  
  
  
  
  
X  
X  
  
In-clinic administration of IP  
  
  
X  
  
  
  
  
Pain score training   
X  
  
X  
  
  
  
  
NPRS  
  
  
X  
X  
X  
X  
  
Dosing adherence   
  
  
  
X  
X  
X  
  
AE monitoring   
  
X  
X  
X  
X  
X  
X  
Slit lamp biomicroscopy   
X  
  
X  
X  
X  
X  
X  
BCVA  
X  
  
X  
X  
X  
X  
X  
IOP  
X  
  
X 
X  
X  
X  
X  
Dilated ophthalmoscopy  
X  
  
  
  
  
  
X  
                                                          
 


VivaVision Biotech (Hong Kong) Ltd. 
 
    VVN461-CS-201 
Statistical Analysis Plan 
 
 
 
Confidential 
 
Page 41 of 41 
Final Version 1.0_2024-01-19 
 
Abbreviations: ACC=anterior chamber cell; AE=adverse event; BCVA=best corrected visual acuity; CELR=cataract extraction and lens replacement; IOP=intraocular pressure; 
IP=investigational product; NPRS=Numeric Pain Rating Scale  
1 Inclusion and exclusion criteria will be assessed at Visit 1 (Screening); subjects who meet eligibility requirements at Visit 1 (Screening) will continue to be eligible for study 
participation if they present at Visit 3 (Baseline/Randomization) with ACC inflammation ≥2 in the study eye after having completed CELR surgery at Visit 2 (Day of Surgery) 
without surgical complications.