Clinical Evaluation Following Use of SYSTANE® BALANCE in Subjects With Lipid-Deficient Dry Eye
Phase: NA
Conditions: Dry Eye
Sponsor: Alcon Research

Pa ge 1 of 5 0
a N o v arti s c o m p a n y
S h ort Ti tle
Cli nic al o utc o mes F o ll o wi n g T re at me nt wit h S Y S T A N E ® B A L A N C E
L o n g T itle
Cli nic al E v al u ati o n F oll o wi n g U se of S Y S T A N E ® B A L A N C E i n S u bjects 
wit h L i pi d-Deficie nt Dr y E ye
Pr ot oc ol N u m ber:
St u d y  P hase:
S p o ns or Na me a n d 
A d dress:
Test Pr o d uct:
I n dicati o n St u die d:
I n vesti gat or A gree me nt:
E X B 1 0 7 - P0 0 1 / N C T 0 2 7 7 6 6 7 0
P hase 4
Alc o n Researc h  Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 7 6 1 3 4- 2 0 9 9
S Y S T A N E ® B A L A N C E L u brica nt E y e Dr o ps
Dr y  E ye
I ha ve rea d t he cli nical st u d y descri be d herei n, rec o g nize its 
c o nfi de ntialit y, a n d a gree t o c o n d uct t he descri be d st u d y i n 
c o m plia nce wit h G o o d Cli nical Practices ( G C P), t he et hical 
pri nci ples c o ntai ne d wit hi n t he Declarati o n of Helsi n ki, t his 
pr ot oc ol, a n d all a p plica ble  re g ulat or y re q uire me nts. 
A d diti o nall y , I will c o m pl y wit h all pr oce d ures f or data 
rec or di n g a n d re p orti n g, will per mit m o nit ori n g, a u diti n g, a n d 
i ns pecti o n of m y researc h ce nter, a n d will retai n all rec or ds u ntil 
n otifie d b y  t he S p o ns or.
Pri nci pal I n vesti gat or:
Si g nat ure
Date
Na me:
A d dress:
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7

Pa ge 2 of 5 0
1 
S Y N O P SI S
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
Test
Pr o d uct:
S Y S T A N E ® B A L A N C E 
L u brica nt E y e Dr o ps, FI D 
1 1 4 6 5 7
St u d y P h ase:
1 
2
3 
4
N/ A
Acti ve I n gre die nt:
Pr o p y le ne g l yc ol ( P G), 0. 6 %
Pr ot oc ol Title:
Cli nical e val uati o n f oll o wi n g use of S Y S T A N E ® B A L A N C E i n 
s u bjects wit h li pi d-deficie nt dr y  e ye
I n vesti g at or(s)/ N o. of 
Sites:
M ultice nter , a p pr o xi matel y 1 0 sites
Ce nter L oc ati o n(s)/ 
U nite d S tates a n d Asia Pacific re gi o n 
N o. of S u bjects
A p pr o xi matel y  2 4 2 s u bjects scree ne d, 2 2 0 s u bjects ra n d o mize d, 2 0 0 
s u bjects e val ua ble
D ur ati o n of Tre at me nt: 7- 1 4 da y  Sali ne r u n-i n peri o d, f oll o we d by a 3 5 da y  acti ve treat me nt 
peri o d
St u d y P o p ul ati o n:
A d ult s u bjects ( ≥1 8 y ears) wit h dr y e ye s y m pt o ms
O bjecti ves :
Pri m ar y O bjecti ve

T o de m o nstrate t hat S Y S T A N E B A L A N C E is n o ni nfer i or t o 
R E F R E S H O P TI V E ® A d va nce d usi n g tear fil m brea k -u p ti me 
( T F B U T) after 3 5 da ys of 4 ti mes dail y ( QI D) d osi n g i n 
s u bjects wit h li pi d-deficie nt dr y  e ye.
Sec o n d ar y O bjecti ves

T o de m o nstrate t hat S Y S T A N E B A L A N C E is s u peri or t o 
R E F R E S H O P TI V E A d va nce d usi n g T F B U T after 3 5 da y s of 
QI D d osi n g i n s u bjects wit h li pi d-deficie nt dr y  e ye. 

T o e val uate c ha n ges i n li pi d la y er t hic k ness ( L L T ) A U C 1 2 0
f oll o wi n g t he use of S Y S T A N E B A L A N C E vers us R E F R E S H 
O P TI V E A d va nce d after 3 5 da ys of QI D d osi n g i n s u bjects
wit h li pi d -deficie nt dr y  e ye.

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T o e val uate c ha n ges i n Gl o bal Oc ular Disc o mf ort usi n g a
vis ual a nal o g scale ( V A S) f oll o wi n g use of S Y S T A N E 
B A L A N C E vers us R E F R E S H O P TI V E A d va nce d after 3 5 
da y s of QI D d osi n g i n s u bjects wit h li pi d- deficie nt dr y  e ye.

Pa ge 3 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
Met h o d ol o g y:
T his is a m ultice nter , pr os pecti ve, d o u ble -mas ke d, ra n d o mize d, 
parallel -gr o u p st u d y assessi n g t he efficac y a n d safet y of S Y S T A N E 
B A L A N C E i n s u bjects wit h li pi d-deficie nt d r y e ye. T he st u d y  
i n v ol ves a Sali ne r u n-i n peri o d (ra n gi n g fr o m 7 t o 1 4 da y s pri or t o t he 
Baseli ne V isit/ Visit 1) f oll o we d b y a 3 5 -da y  treat me nt peri o d. S u bjects 
will be ra n d o mize d 1: 1 i nt o 1 of 2 treat me nt ar ms p ost r u n- i n peri o d.
Tre at me nts:
R u n -in Pr o d uct:
Preser vati ve -free S ali ne
R o ute of A d mi nistr ati o n:
To pical oc ular
D ur ati o n of Tre at me nt:
7- 1 4 da y s
D os a ge:
1 dr o p QI D i n eac h e y e
Test Pr o d uct:
S Y S T A N E B A L A N C E L u brica nt E y e 
Dr o ps
R o ute of A d mi nistr ati o n:
To pical oc ular
D ur ati o n of Tre at me nt:
3 5 da y s
D os a ge:
1 dr o p QI D i n eac h e y e
C o ntr ol Pr o d uct :
R E F R E S H O P TI V E A d va nce d L u brica nt 
E y e Dr o ps
R o ute of A d mi nistr ati o n:
To pical oc ular
D ur ati o n of Tre at me nt:
3 5 da y s
D os a ge:
1 dr o p QI D i n eac h e y e
S u bject Selecti o n: 
I ncl usi o n Criteri a:
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
1.
M ust be willi n g a n d a ble t o atte n d all st u d y  visits
2.
M ust be 1 8 y ears of a ge or ol der at t he ti me of i nf or me d 

Pa ge 4 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
c o nse nt [ patie nts i n Si n ga p ore m ust be 2 1 ye ars of a ge or ol der 
an d patie nts i n Ta i wa n m ust be 2 0 ye ars of a ge or ol der d ue t o 
l ocal re g ulati o ns].
3.
M ust ha ve b ot h of t he f oll o wi n g i n at least o ne e y e at t he 
Scree ni n g V isit a n d Visit 1 ( Da y 0):

T he s u m of 3 meas ures of T F B U T ≤ 1 5 sec o n ds, a n d

U na nest hetize d Sc hir mer I  test of ≥ 3 m m t o ≤ 1 2 m m
4.
M ust ha ve best -c orrecte d vis ual ac uit y ( B C VA) of 5 5 letters or 
better i n eac h e y e as assesse d usi n g a n earl y treat me nt dia betic 
reti n o pat h y st u d y ( E T D R S) or T u m bli n g E c hart
5.
M ust be will i n g t o ta ke t he st u d y pr o d ucts as directe d f or t he 
e ntire st u d y
E xcl usi o n Criteri a:
1.
Use of a n y t o pical oc ular me dicati o n preser ve d wit h 
be nz al k o ni u m c hl ori de ( B A K) or ot her pr o d ucts k n o w n t o be 
t o xic t o t he tear fil m li pi d la yer wit hi n 3 m o nt hs pri or t o t he 
Scree ni n g V isit
2.
Li d h y gie ne t hera p y i nitiate d ≤4 wee ks pri or t o t he Scree ni n g 
Vi sit. 
N ote: S u bjects w h o ha ve bee n o n a c o nsiste nt li d h ygie ne 
t hera py (ie, n o c ha n ge t o t he t ype of li d h y gie ne t hera p y  bei n g 
use d or t o t he fre q ue nc y of use) f or m ore t ha n 4 wee ks pri or t o 
t he Scree ni n g Visit are n ot e xcl u de d. H o we ver, t he y ca n n ot 
st o p or c ha n ge t his re gi me n f or t he d urati o n of t he st u d y. In 
a d diti o n, s u bjects w h o d o n ot c urre ntl y use li d h y g ie ne t hera py 
ca n n ot start f or t he d urati o n of t he st u d y .
3.
Wo me n of c hil d beari n g p ote ntial (t h ose w h o are n ot s ur gicall y  
sterilize d or p ost me n o pa usal f or at least 2 ye ars) ar e e xcl u de d
fr o m partici pati n g i n t he st u d y if t he y meet a n y
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
of t he 
f oll o wi n g c o n diti o ns:
a.
T he y  are c urre ntly pre g na nt, or pla n t o bec o me 
pre g na nt w hile partici pati n g i n t he st u d y , or
b.
T he y  ha ve a p ositi ve res ult o n a pre g na nc y test at t he 
Scree ni n g Visit, or
c.
T he y  are breast fee di n g
d.
Are n ot i n a gree me nt t o use a de q uate birt h c o ntr ol 
met h o ds t hr o u g h o ut t he st u d y

Pa ge 5 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
4.
H y perse nsiti vit y  t o t he use of a n y of t he st u d y pr o d ucts or 
aller g y t o a n y i n gre di e nt i n t he st u d y pr o d ucts
5.
Oc ular a b n or malities t hat c o ul d a d versel y  affect t he safety or 
efficac y o utc o me s uc h as:

E y eli d a n o malies t hat affect pr o per li d cl os u re or pr o per 
bli n k f u ncti o n (e g, ectr o pi o n or e ntr o pi o n)

C or neal dis or ders or a b n or malit y  s uc h as acti ve c or neal 
ulcer, c urre nt c or neal a brasi o n, kerat oc o n us or c or neal 
d y str o p hies w hic h are acti vel y c ha n gi n g or affect visi o n

Meta plasia of t he oc ular s urface

Hist or y  of c or neal er osi o n s yn dr o me or rec urre nt c or neal 
er osi o n s yn dr o me

Cli nicall y  si g nifica nt c or neal e pit helial a nteri or me m bra ne 
d y str o p h y (s u bjects wit h mi n or/i nsi g nifica nt pri mar y  
peri p heral c or neal e pit helial d y str o p h y ( n ot ce ntral 
d y str o p h y) wit h o ut a hist or y of c or neal er osi o n s y n dr o me 
ca n be i ncl u de d)

C urre nt fila me nt o us keratitis

E vi de nce of c or neal ne o vasc ularizati o n

A n y  hist or y of her pes si m ple x or her pes z oster keratitis
6.
U nc o ntr olle d acti ve s ys te mic diseases. T hese c o n diti o ns ma y  
i ncl u de b ut are n ot li mite d t o u nsta ble dia betes, t h y r oi d 
diseases, a ut oi m m u ne diseases, a n d/ or p o orl y c o ntr olle d 
h y perte nsi o n.
7.
Acti ve oc ular i nfecti o n ( bacterial, viral, or f u n gal) or acti ve 
i nfla m mati o n n ot ass ociate d wit h dr y e ye s uc h as u veitis, iritis, 
acti ve ble p haritis, acti ve aller gic c o nj u ncti vitis, etc.
8.
Cli nicall y  si g nifica nt c o n gesti ve heart fail ure, re nal fail ure, 
he patic d ys f u ncti o n, pre vi o us car di o vasc ular acci de nt ( C VA) 
wit h a si g nifica nt resi d ual m ot or or se ns or y  defect, pr o gressi ve 
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
ne ur ol o gic dis or ders ( e g, Par ki ns o nis m, de me ntias, M ulti ple 
Scler osis, u nsta ble ac q uire d seiz ure dis or ders, etc.)
9.
C urre nt or past partici pati o n i n a n y cli nical st u d y wit hi n 3 0 
da y s pri or t o t he Scree ni n g Vi sit
1 0. P u nctal pl u g i nserti o n or diat her m y  pr oce d ure i nitiate d wit hi n 
3 0 da y s pri or t o t he Scree ni n g Visit
1 1. Si g nifica nt ill nesses t hat c o ul d, i n t he o pi ni o n of t he 
I n v esti gat or, i nterfere wit h t he st u d y para meters

Pa ge 6 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
1 2. Use of a n y s ys te mic me dicati o n k n o w n t o ca use dr y e ye (e g,
a nti- hista mi nes, a nti-de pressa nts, a nti -ps y c h otics, etc.) f or less 
t ha n 1 m o nt h. T he d osi n g re gi me n s h o ul d n ot c ha n ge d uri n g 
t he st u d y.
1 3. C o ntact le ns use wit hi n 3 0 da y s pri or t o Scree ni n g Vi sit, or 
u n willi n g t o a v oi d c o ntact le ns use d uri n g t he c o urse of t he 
st u d y
1 4. U n willi n g t o a v oi d t he use of a d diti o nal artificial tear pr o d ucts 
( ot her t ha n t he assi g ne d st u d y pr o d uct ) t hr o u g h o ut t he c o urse 
of t he st u d y  peri o d
1 5. Hist or y  of oc ular or i ntra oc ular s ur ger y, e yeli d s ur ger y, 
kerat orefracti ve pr oce d ure, c or neal tra ns pla nt or seri o us oc ular 
tra u ma, wit hi n 6 m o nt hs pri or t o t he Scree ni n g Visit
1 6. I nitiati o n of a ny t o pical oc ular ( o ver -t he-c o u nter or prescri be d) 
me dicat i o n ( wit h t he e xce pti o n of artificial tears/ gels/ 
l u brica nts) ≤2 wee ks pri or t o t he Scree ni n g Visit
Assess me nts:
Scree ni n g :
T he f oll o wi n g assess me nts will be perf or me d e xcl usi vel y  at t he 
Scree ni n g Visit:

Sc hir mer I test wit h o ut a nest hesia 

I ntra oc ular press ure (I O P)

F u n d us e xa mi nati o n ( u n dilate d)
Effic ac y:

Pri mar y  en d p oi nt assess me nt : T F B U T

Sec o n dar y  en d p oi nt assess me nts: 
o
T F B U T
o
L L T ( L L T A U C1 2 0 at Da y 3 5)
o
Gl o bal Oc ular D isc o mf ort q uesti o n naire
S afet y:

A d verse eve nts ( A Es)

B C V A

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Slit -la m p e xa mi nati o n

Pa ge 7 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
N ote: F or eli gi ble st u d y s u bjects, all st u d y  assess me nts d uri n g eac h 
visit m ust be c o n d ucte d at t he sa me ti me of da y wit hi n ± 1 h o ur of t he 
start ti me of Visit 1 ( Baseli ne).
St atistic al Met h o ds:   
V ari a bles
Pri mar y  E n d p oi nt

C ha n ge fr o m baseli ne i n T F B U T at Da y 3 5 (assess me nt f or 
n o ni nferi orit y )
Sec o n dar y  E n d p oi nts

C ha n ge fr o m baseli ne i n T F B U T at Da y 3 5 (assess me nt f or 
s u peri orit y)

L L T A U C 1 2 0 at Da y 3 5

C ha n ge fr o m baseli ne i n Gl o bal Oc ular Disc o mf ort V A S sc ore 
at Da y 3 5
Safet y  Varia bles

A Es

B C V A

Slit -la m p e xa mi nati o n
Pl a n ne d A n al yses
T hree a nal ys is sets will be defi ne d f or t his st u d y. T he F ull A nal ys is 
Set ( FA S) will i ncl u d e all ra n d o mize d s u bjects w h o ha ve at least o ne 
p ost -baseli ne pri mar y  e n d p oi nt assess me nt. T he Per Pr ot oc ol Set 
( P P S) will c o nsist of F A S s u bjects w h o ha ve n o maj or pr ot oc ol 
de viati o ns. T he Safet y A nal y sis Set will i ncl u de all s u bjects e x p ose d 
t o p ost -ra n d o mizati o n st u d y pr o d uct. I n t he e ve nt of a ra n d o mizati o n 
or dis pe nsi n g err or , s u bjects i n t he Safet y A nal y sis Set will be 
a nal yz e d acc or di n g t o t he st u d y pr o d uct t he y recei ve d; h o we ver, 
s u bjects i n t he FA S will be a nal yz e d as ra n d o mize d (re gar dles s of t he 
st u d y pr o d uct t he y  recei ve d).
T he pri mar y  a n d sec o n dar y efficac y a nalys es will be perf or me d o n 
b ot h t he FA S a n d P P S wit h t he P P S pr o vi di n g pri mar y i nfere nce f or 
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
t he n o ni nferi ority h y p ot hesis a n d FA S pr o vi di n g pri mar y  i nfere nce f or 

Pa ge 8 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
t he s u peri orit y h y p ot heses.
T he st u d y  e ye will be t he w orst e ye at b aseli ne f or eac h para meter. If 
t he b aseli ne val ues are e q ui vale nt, t he ri g ht e y e will be selecte d.
T he a nal ys is of t he pri mar y efficac y para meter, c ha n ge fr o m b aseli ne
i n T F B U T at Da y 3 5 i n t he st u d y e ye, will be base d o n a mi xe d m o del. 
T he mi xe d m o del will i ncl u de ter ms f or baseli ne T F B U T , treat me nt, 
visit ( Da y  1 5, Da y 3 5), a n d treat me nt-b y -visit i nteracti o n. Esti mates of 
t he differe nce ( S Y S TA N E B A L A N C E - R E F R E S H O P TI V E
A d va nce d ) i n mea n c ha n ge fr o m baseli ne i n T F B U T bet wee n 
S Y S T A N E B A L A N C E a n d R E F R E S H O P TI V E A d va nce d a n d 
ass ociate d 9 5 % c o nfi de nce i nter val ( CI ) will be prese nte d. E vi de nce 
of n o ni nferi orit y will be dee me d esta blis he d if t he l o wer li mit of t he 
9 5 % CI  f or t he differe nce is a b o ve - 1. 0.
T he a nal ys is of t he sec o n dar y efficac y para meter L LT A U C 1 2 0 at 
Da y 3 5, c ha n ge fr o m baseli ne i n Gl o bal Oc ular Disc o mf ort VA S sc ore 
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
at Da y 3 5, a n d c ha n ge fr o m baseli ne i n T F B U T at Da y  3 5 will be 
base d o n a mi xe d m o del. T he mi xe d m o del will i ncl u de ter ms f or 
basel i ne para meter val ue, treat me nt, visit ( Da y  1 5, Da y 3 5), a n d 
treat me nt-b y -visit i nteracti o n. Esti mates of t he dif fere nce i n mea n 
c ha n ge fr o m baseli ne bet wee n S Y S TA N E B A L A N C E a n d R E F R E S H 
O P TI V E A d va nce d a n d ass ociate d 9 5 % CI will be pre se nte d. T he 
pri mar y  e n d p oi nt (ie, c ha n ge fr o m baseli ne i n T F B U T at Da y 3 5) a n d 
b ot h sec o n dar y  e n d p oi nts will be e val uate d f or s u peri orit y of 
S Y S T A N E B A L A N C E o ver R E F R E S H O P TI V E A d va nce d .
 
 
 T he mi xe d m o del will i ncl u de ter ms f or baseli ne par a meter 
val ue a n d treat me nt. Esti mates of t he dif fere nce i n mea n c ha n ge fr o m 
baseli ne bet wee n S Y S TA N E B A L A N C E a n d R E F R E S H O P TI V E
A d va nce d a n d ass ociate d 9 5 % CI will be prese nte d.
 
To  e ns ure o verall c o ntr ol of t he t ype I err or rate, t he sec o n dar y  
efficac y h y p ot heses will be rele va nt o nl y if t he pri mar y efficac y n ull 
h y p ot hesis is first rejecte d at t he 5 % le vel of si g nifica nce ( 2-s i de d). 
F oll o wi n g t he rejecti o n of t he pri mar y  efficac y n ull h yp ot hesis, t he 
sec o n dar y h yp ot heses will be teste d f oll o wi n g t he H oc h ber g testi n g 

Pa ge 9 of 5 0
S p o ns or:
Alc o n Researc h, Lt d.
6 2 0 1 S o ut h Free wa y
F ort W ort h, Te xas 
7 6 1 3 4- 2 0 9 9
Pr ot oc ol N u m ber: E X B 1 0 7 -P 0 0 1
pr oce d ure.
S afet y:
T he safet y a nal ys es will c o nsist of s u m maries of t he A Es a n d 
meas ure d safet y para meter data. T his will i nc l u de s u m maries of 
B C V A a n d slit-la m p i n a d diti o n t o A Es. T he statistics prese nte d f or 
eac h e n d p oi nt will be rele va nt t o t he meas ure of t he val ue, ie, w het her 
t he data are cate g orical or n u meric. C o nti n u o us meas ure me nts will be 
prese nte d usi n g n u m ber , mea n, sta n dar d de viati o n, mi ni m u m a n d 
ma xi m u m at eac h visit. Cate g orical meas ure me nts will be ta b ulate d 
wit h t he n u m ber a n d perce nt of s u bjects i n eac h cate g or y  at eac h visit. 
N o i nfere ntial testi n g will be perf or me d f or t he safet y  a nalys es.
S a m ple size j ustific ati o n:
T his st u d y  will ra n d o mize a p pr o xi matel y 2 2 0 s u bjects t o ac hie ve 2 0 0 
e val ua ble s u bjects i n a 1: 1 rati o bet wee n S Y S TA N E B A L A N C E a n d 
R E F R E S H O P TI V E A d va nce d . A t otal of 2 0 0 s u bjects pr o vi des 
a p pr o xi matel y 8 0 % p o wer t o reject t he n ull h yp o t hesis of i nferi ority 
of mea n c ha n ge fr o m baseli ne i n T F B U T at t he 0. 0 2 5 le vel of 
si g nifica nce ( 1-si de d), ass u mi n g a treat me nt  differe nce of 0. 0, a 
sta n dar d de viati o n of 2. 5, a n d a n o ni nferi orit y  mar gi n of 1. 0.
P o wer
Ass u me d 
sta n dar d de viati o n
Sa m ple size 
(t otal e val ua ble)
8 0 %
2. 5
2 0 0
2. 7 5
2 4 0
3. 0
2 8 6
9 0 %
2. 5
2 6 6
2. 7 5
3 2 0
3. 0
3 8 2
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7

Pa ge 1 0 of 5 0
1. 1 
A me n d me nts 
A me n d me nt 3
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
P ur p ose of A me n d me nt:  T he p ur p ose of t his a me n d me nt is t o wi de n t he ra n ge of 
U na nest hetize d Sc hir mer I T est sc ores w hic h are eli gi ble f or i ncl usi o n i nt o t he st u d y, t o 
re vise t he recr uit me nt tar gets o utli ne d i n Secti o n 8, t o re vise la n g ua ge i n Secti o n 1 0. 2. 1. 1 t o 
all o w f or patie nts t o be rescree ne d, t o all o w f or Tu m bli n g E c harts t o be use d t o assess B C VA 
i n t he S yn o psis, Secti o n 1 0. 2. 1. 1 ( Scree ni n g Visit), Secti o n 1 0. 2. 2 1 ( Ra n d o mizati o n Vi sit), 
Secti o n 1 0. 2. 2. 2 ( V isit 2), Secti o n 1 0. 2. 2. 3 ( Visit 4/ Fi nal Vi sit), a n d Secti o n 1 0. 3 
( U nsc he d ule d Visits), t o clarif y t he defi niti o n of t he Safety A nal ys is Set i n b ot h t he s yn o psis 
( u n der Pla n ne d A nal ys es) Secti o n 11. 2 ( A nal y sis Data Sets), a n d t o c orrect a n err or i n 
Secti o n 1 1. 3 ( De m o gra p hic a n d Baseli ne C haracter istics) w hic h descri bes t he race cate g ories 
c ollecte d as baseli ne varia bles.
Rati o nale:  T he c urre nt ra n ge of U na nest hetize d Sc hir mer I T est sc ores ( 5 – 1 0 m m, 
i ncl usi ve) ha ve ca use d a hi g h rate of scree n-fail ures f or partici pati n g sites i n t he st u d y, w h o 
ha ve li mite d met h o ds t o i m pr o ve t heir pre -scree ni n g. T he ne w ra n ge of 3 – 1 2 m m, i ncl usi ve, 
still re q uires patie nts t o ha ve s o me lacri mal f u ncti o n, a n d is wit hi n t he cli nicall y acce pte d 
ra n ge see n i n dr y e ye patie nts. Sites are e x perie nci n g var y i n g le vels of diffic ult y i n recr uiti n g 
t he tar get patie nts f or t his st u d y, s o site-s pecific recr uit me nt tar gets ha ve bee n ma de m ore 
fle xi ble t o ac hie ve t he tar get ra n d o mizati o n n u m bers f or t he e ntire st u d y wit hi n a li mite d 
recr uit me nt peri o d. I n n o n-E n glis h s pea ki n g c o u ntries, T u m bli n g E c harts ha ve bee n pr o vi de d 
t o assess B C VA i nstea d of E T D R S c harts. La n g ua ge i n Secti o n 1 0. 2. 1. 1 has bee n re vise d t o 
all o w patie nts t o be re -scree ne d if t he y ha ve a Sc hir mer sc ore w hic h re-q ualifies t he m base d 
o n t he re vise d i ncl usi o n c riteri o n. T he Safety A nal y sis Set s h o ul d o nl y ca pt ure patie nts t hat 
ha ve bee n e x p ose d t o o ne of t he t w o i n vesti gati o nal pr o d ucts i n t he treat me nt p hase, a n d 
s h o ul d n ot i ncl u de patie nts w h o ha ve ta ke n r u n-i n sali ne o nl y. T he list of Race cate g ories i n 
Secti o n 1 1. 3 pre vi o usl y  i ncl u de d a c o m ma w hic h c ha n ge d t he mea ni n g of “ Africa n 
A merica n” as a race cate g or y , a n d f urt her o mitte d t he cate g or y of “ Ot her,” alt h o u g h t his is 
ca pt ure d i n t he e C R F.

Pa ge 11 of 5 0
C urre nt St u d y  Stat us:
Case Re p ort F or m Re visi o n Re q uire d:
Ye s   
X
N o
I nf or me d C o nse nt M o dificati o ns Re q uire d: 
Ye s   
X
N o
A p plica ble I n vesti gat ors:
X
All
Selecte d (list bel o w)
Ite mize d C ha n ges: I ncl usi o n criteria # 3 has bee n u p date d t o rea d:
“M ust ha ve b ot h of t he f oll o wi n g i n at least o ne e y e at t he Scree ni n g Vi sit a n d Vi sit 1 ( Da y 
0):

T he s u m of 3 meas ures of T F B U T ≤ 1 5 sec o n ds, a n d

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
U na nest hetize d Sc hir mer I  test of ≥ 3 m m t o ≤ 1 2 m m ”
Secti o n 8 [ S U BJ E C T  P O P U LA T I ON ] will be re vise d t o: “ T he st u d y  p o p ulati o n i ncl u des 
a p pr o xi matel y 2 2 0 s u bjects t o be ra n d o mize d ( 2 0 0 e val ua ble s u bjects re q uire d) at 
a p pr o xi matel y 1 0 sites. U p t o 5 5 s u bjects ma y be recr uite d per site, a n d site recr uit me nt 
tar gets ma y var y base d o n site ca pa bilities, a vaila ble patie nt p o p ulati o n, a n d le n gt h of 
recr uit me nt peri o d.”
T he f oll o wi n g se nte nce has bee n delete d fr o m Secti o n 1 0. 2. 1. 1 [ Scree ni n g Visit ( Da y -1 4 t o 
Da y  -7)]: “ N o s u bjects ma y  be re-scree ne d if t he y fail e ntr y criteria f or a ny reas o n ot her t ha n 
t he re q uire d sta bilizati o n ti mefra mes i n t he e xcl usi o n criteria.” T he f oll o wi n g se n te nce has 
bee n a d de d: “ Als o, a patie nt ca n be re -scree ne d if t he y scree n-faile d d ue t o t he ori gi nal 
Sc hir mer I assess me nt e ntr y criteria a n d t he patie nt’ s ori gi nal Sc hir mer sc ore is n o w wit hi n 
t he ne w Sc hir mer I assess me nt e ntr y criteria wi n d o w.”
Secti o n 1 0. 2. 1. 1 [ Scree ni n g V isit ( Da y -1 4 t o Da y  -7)], P oi nt 6., s u b -b ullet # 1, Secti o n 
1 0. 2. 2. 1 [ Ra n d o mizati o n Visit ( Da y  0/ Baseli ne)], P oi nt 4., s u b-b ullet # 1, Secti o n 1 0. 2. 2. 2 
[ Visit 2 ( Da y 1 5 ± 3 da ys)], P oi nt 4., s u b-b ullet # 1, Secti o n 1 0. 2. 2. 3 [ Visit 3/ Fi nal Visit ( Da y  
3 5 ± 3 da ys)], P oi nt 4., s u b -b ullet # 1, a n d Secti o n 1 0. 3 [ U nsc he d ule d Visits] P oi nt 2., s u b -
b ullet # 1 ha ve all bee n re vise d t o rea d: “ B C V A m ust be meas ure d usi n g a n E T D R S or 
T u m bli n g E c hart at a dista nce of 3 or 4 meters usi n g t he letters rea d met h o d.”

Pa ge 1 2 of 5 0
S y n o psis [ Pla n ne d A nal yses] a n d Secti o n 1 1. 2 [ A nal y sis Data Sets]: T he Safety A nal ys is Set 
defi niti o n has bee n re vise d t o: “ T he Safet y  Anal ysis Set will i ncl u de all s u bjects e x p ose d t o 
p ost -ra n d o mizati o n st u d y pr o d uct.”
Secti o n 1 1. 3 [ De m o gra p hic a n d Baseli ne C haracteristics] c o ntai ns a n u p date t o t he b ullet 
p oi nt w hic h lists Race cate g ories. T his b ullet p oi nt has bee n u p date d t o rea d:

“ Race ( A merica n I n dia n or Alas ka Nati ve, Asia n, Blac k or Africa n A merica n, Nati ve 
Ha waiia n or Ot her Pacific Isla n d er, Ot her)”
A me n d me nt 2
P ur p ose of A me n d me nt:  To  m o dif y t he mi ni m u m a ge f or patie nts i n Si n ga p ore ( 2 1) a n d 
Ta i wa n (2 0 ) i n res p o nse t o fee d bac k fr o m l ocal a ut h orities. To  re place i nc orrect “ Da y 1” 
refere nce wit h c orrect “ Da y 0” refere nce i n statistical anal ys is secti o n.
Rati o nale:  T he I R Bs i n T ai wa n a n d Si n ga p ore pr o vi de d fee d bac k t hat per l ocal re g ulati o ns, 
t he mi ni m u m a ge of a d ult patie nts i n t hese c o u ntries are 2 0 a n d 2 1, res pecti vel y. T he gl o bal 
pr ot oc ol will be a me n de d t o a d dress t his mi ni m u m a ge pe r c o u ntr y b y m o dif yi n g i ncl usi o n 
criteria # 2. I n a pre vi o us versi o n of t he pr ot oc ol, a t y p o was i de ntifie d i n t he Statistical 
A nal y sis secti o n t hat err o ne o usl y referre d t o t he Da y 0 ti me p oi nt as “ Da y 1.” T his is bei n g 
c orrecte d i n t his a me n d me nt, as well.
C urre nt St u d y  Stat us: Si x sites i n U nite d States are o pe n a n d recr uiti n g patie nts. O ne site i n 
A ustralia is o pe n b ut has n ot y et recr uite d patie nts. Et hics C o m mittee a n d Healt h A ut h orit y 
a p pr o vals are i n t he fi nal sta ges i n Tai wa n a n d Si n ga p ore.
Case R e p ort F or m Re visi o n Re q uire d:
Ye s   
X
N o
I nf or me d C o nse nt M o dificati o ns Re q uire d: 
Ye s   
X
N o
A p plica ble I n vesti gat ors:
X
All
Selecte d (list bel o w)
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Ite mize d C ha n ges: I ncl usi o n Criteria # 2 will be u p date d t o rea d: “2. M ust be 1 8 y ears of a ge 
or ol der at t he ti me of i nf or me d c o nse nt [ patie nts i n Si n ga p ore m ust be 2 1 years of a ge or 
ol der a n d patie nts i n Tai wa n m ust be 2 0 years of a ge or ol der d ue t o l ocal re g ulati o ns]. ”
“ Da y 1” will be re place d wit h “ Da y 0” i n t he f oll o wi n g secti o ns:

Pa ge 1 3 of 5 0

Secti o n 1: S y n o psis, Assess me nts

Secti o n 1: S y n o psis, Statistical Met h o ds, Va ria bles

Secti o n 1: S y n o psis, Statistical Met h o ds, Pla n ne d A nal y ses


Secti o n 1 1. 4. 3. 2: A N A L Y SI S M E T H O D S
A me n d me nt 1
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
P ur p ose of A me n d me nt: To  re m o ve refere nce t o “ 0. 9 %” c o nce ntrati o n of sali ne s ol uti o n use d 
d uri n g r u n -i n p hase.
Rati o nale: A searc h of sali ne pr o d ucts a vaila ble gl o ball y deter mi ne d t hat t here were n o 
s uita ble 0. 9 % sali ne s ol uti o n pr o d ucts i n dicate d f or o p ht hal mic use i n all f o ur partici pati n g 
c o u ntries. As a res ult, sali ne s u p plies of dif fere nt c o nce ntrati o n, w hic h has a n o p ht hal mic use 
i n dicati o n, ha d t o be pr oc ure d f or use i n t his st u d y. T he sali ne re mai ns preser vati ve free, 
t heref ore, o nly t he refere nce t o “ 0. 9 %” has bee n re m o ve d. 
C urre nt St u d y  Stat us: Recr uit me nt has be g u n at t w o sites i n t he U S. Et hics C o m mittee a n d 
Healt h A ut h orit y s u b missi o ns are i n t he earl y sta ges i n A ustralia, Si n ga p ore, T ai wa n.
Ite mize d C ha n ges: Refere nce t o “ 0. 9 %” has bee n re m o ve d fr o m refere nces t o t he sali ne 
s ol uti o n i n t he f oll o wi n g secti o ns: 1 S Y N O P SIS, T a ble 2 - 1, Secti o n 9, Secti o n 9. 1, Secti o n 
9. 2, Secti o n 9. 3, Secti o n 9. 4, Secti o n 1 0. 1, a n d Secti o n 1 0. 2. 1. 1. 

Pa ge 1 4 of 5 0
2 
O V E R VI E W O F  S T U D Y P L A N
Ta ble 2 – 1
Sc he d ule of Assess me nts
Pr oce d ure/ Assess me nt 1
Scree ni n g 
Visit 1
( B aseli ne)
Visit 2 
Visit 3
( E xit)
E arl y 
E xit
U nsc he d ule d
D a y 
-1 4 t o - 7
D a y 0 
D a y 1 5
3 
d a ys
D a y 3 5 
3 
d a ys
I nf or me d c o nse nt
X
De m o gra p hics
X
Me dical hist or y
X
C ha n ges t o me dical c o n diti o ns
X   
X   
X   
X   
X
C o nc o mita nt me dicati o ns
X
C ha n ges t o c o nc o mita nt me dicati o ns
X   
X   
X   
X   
X
Uri ne pre g na nc y test 2
X
X   
X
I ncl usi o n/e xcl usi o n criteria
X
U n dilate d f u n d us e xa mi nati o n
X
U na nest hetize d Sc hir mer I test
X
I ntra oc ular press ure
X
Start r u n -i n p hase Sali ne
X 3
Dis pe nse r u n -i n p hase Sali ne
X
St o p r u n -i n p hase Sali ne 
X
C ollect r u n -p hase Sali ne e m pt y a n d 
u n use d b ottles
X
Ra n d o mizati o n 
X
Dis pe nse treat me nt p hase st u d y 
pr o d ucts ( S Y S T A N E B A L A N C E or 
R E F R E S H O P TI V E A d va nce d)
X   
X
X 4
C ollect treat me nt p hase st u d y 
pr o d ucts ( S Y S T A N E B A L A N C E or 
R E F R E S H O P TI V E A d va nce d)
X   
X   
X   
X 4
Oc ular Disc o mf ort assess me nt
X   
X   
X   
X 5
B C V A
X   
X   
X   
X   
X   
X
Slit -la mp e xa mi nati o n
X   
X   
X   
X   
X   
X
Tear fil m brea k -u p ti me
X   
X   
X   
X   
X 5
Li pi d la yer t hic k ness
X   
X   
X   
X 5
A d verse e ve nts
( b ot h v ol u nteere d a n d elicite d)
X   
X   
X   
X   
X   
X
Electr o nic data ca pt ure
X   
X   
X   
X   
X   
X
C o m plete e xit f or m
X   
X
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
1. F or eli gi ble st u d y s u bjects, all st u d y assess me nts d uri n g eac h visit m ust be c o n d ucte d at t he sa me ti me of da y wit hi n 
± 1 h o ur of t he start ti me of Visit 1 ( Baseli ne) . 
2. F or w o me n w h o are of c hil d beari n g p ote ntial.
3. Preser vati ve -free sali ne will be a d mi nistere d f or 7 t o 1 4 da ys pri or t o baseli ne i.e. fr o m Da y -1 4/ Da y -7 t o Da y -1. 
4. If necessar y.
5. T hese assess me nts s h o ul d o nl y be d o ne if st u d y s u bject e xits t he st u d y earl y pri or t o Da y 3 5 b ut has bee n o n mas ke d
treat me nt f or at least 1 4 da ys.

Pa ge 1 5 of 5 0
3 
A B B R E VI A TI O N S
A b bre vi ati o n 
Defi niti o n
A D E
A d verse de vice / dr u g eff ect
A D R
A d verse dr u g reacti o n
A E
A d verse e ve nt
A E F
A d verse e ve nt f or m 
B A K
Be n z al k o ni u m c hl ori de
A U C 1 2 0
Area u n der t he e pi der mal c o nce ntrati o n -ti me pr ofile
B C V A
Bes t-co rrecte d v is ual acu ity
C JD
C re utz feld t-Jac o b D isease
C R F
C ase re p ort fo r m
D E D
Dr y  e ye disease
D M P G -Na 
Di m y rist o yl p h os p hati d yl glycer ol
E D C
E lectr o nic da ta ca ptu re
E D T A
Et h y le ne dia mi ne tetra acetic aci d
E T D R S 
Ear ly treat me nt d iab etic reti n o path y st ud y
E X C
E xcl usi o n
F A S
F ull a nal ys is set
F D A
U S F o o d a n d Dr u g A d mi nistrati o n
F ID
F or m ul ati o n i dentifi catio n
G C P
G o o d cli nical pr actice
G T T
Dr o p
H IV
H u ma n i m m u n o deficie nc y vir us
IC H
Int er nati o nal C o nf ere nc e o n Har m o ni z ati o n
IE C
In d epe n de nt Et hics C o m m ittee
I N C
I ncl usi o n
IR B
Instit uti o n al Re vi ew B o ard
I RT
I nteracti ve res p o nse tec h n ol o g y
L L T
Li pi d la y er t hic k ness
M M R M 
Mi xe d m o del re peate d meas ures a nal ys is
M O P
Ma n ual of pr oce d ures
O D
Ri g ht e y e
O S
L e ft e y e
O U
B ot h e y es
P G
Pr o p y le ne gl yc ol
P P S
Per Pr ot oc ol Set
Q ID
F o ur ti mes a d a y
S A E
Seri o us a d verse ev e nt
S D
Sta n dar d de viati o n
T F B U T 
Te ar fil m brea k -u p ti me
V A S
Vi s ual a nal o g scale
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7

Pa ge 1 6 of 5 0
4 
T A B L E O F  C O N T E N T S
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
1 
S Y N O P SI S ................................ ............................................................................. 2
1. 1 
A me n d me nts ......................................................................................... 1 0
2 
O V E R VI E W O F S T U D Y  P LA N .......................................................................... 1 4
3 
A B B R E VI A TI O N S ............................................................................................... 1 5
4 
T A B L E O F C O N T E N T S ...................................................................................... 1 6
List of T a bles ............................................................................................................................ 1 8
List of Fi g ures .......................................................................................................................... 1 8
5 
I NT R O D U C TI O N ................................................................................................ 1 9
5. 1 
St u d y  Rati o nale a n d Bac k gr o u n d......................................................... 1 9
5. 2 
S y sta ne Bala nce .................................................................................... 1 9
5. 3 
K n o w n a n d P ote ntial Ris ks .................................................................. 2 0
5. 4 
P ote ntial Be nefits .................................................................................. 2 0
6 
E T HI C S ................................................................................................................ 2 1
7 
P R O T O C O L  AM E N D M E N T S
............................................................................ 2 2
8 
S U BJ E C T  P O P U LA T I ON .................................................................................... 2 2
9 
T R E A T M E N T S A D MI NI S T E R E D ...................................................................... 2 2
9. 1 
I de ntit y of St u d y Pr o d ucts.................................................................... 2 3
9. 2 
Usa ge .................................................................................................... 2 3
9. 3 
Acc o u nta bilit y  Pr oce d ures.................................................................... 2 4
9. 4 
S u bject C o nfi de ntialit y  a n d Met h o ds Use d t o Mi ni mize Bias.............2 4
1 0 
S T U D Y  P R O C E D U R E S...................................................................................... 2 5
1 0. 1 
O utli ne of St u d y ................................................................................... 2 5
1 0. 2 
Vi sits a n d E xa mi nati o ns ....................................................................... 2 7
1 0. 2. 1 
Sali ne R u n -i n P hase ( Da y - 1 4/-7 t o Da y  0).......................... 2 7
1 0. 2. 1. 1 
Scree ni n g V isit ( Da y -1 4 t o Da y  - 7)..................... 2 7
1 0. 2. 2 
Tr eat me nt P hase – Vi sit 1 t o Visit 3 / Da y  0 t o Da y 3 5........ 2 9
1 0. 2. 2. 1 
Ra n d o mizati o n, Vi sit 1 ( Da y 0/ Baseli ne) ............ 2 9
1 0. 2. 2. 2 
Vi sit 2 ( Da y 1 5 ± 3 da ys) ...................................... 3 1
1 0. 2. 2. 3 
Vi sit 3/ Fi nal Vi sit ( Da y 3 5 ± 3 da y s) .................... 3 2
1 0. 3 
U nsc he d ule d V isits............................................................................... 3 3

Pa ge 1 7 of 5 0
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
1 0. 4 
Disc o nti n ue d S u bjects .......................................................................... 3 4
1 0. 5 
Cli nical St u d y  Ter mi nati o n ................................................................... 3 5
1 1 
A N A L Y SI S P L A N ............................................................................................... 3 5
1 1 . 1 
S u bject E val ua bilit y .............................................................................. 3 5
1 1 . 2 
A nal y sis Data Sets ................................................................................ 3 5
1 1 . 3
De m o gra p hic a n d Baseli ne C haracteristics.......................................... 3 6
1 1 . 4 
Ef ficac y Anal ys es ................................................................................. 3 7
1 1 . 4. 1 
Pri mar y  Efficac y................................................................... 3 7
1 1 . 4. 1. 1 
Statistical H y p ot heses ........................................... 3 7
1 1 . 4. 1. 2 
A nal y sis Met h o ds ................................................. 3 7
1 1 . 4. 2 
Sec o n dar y  Efficac y............................................................... 3 8
1 1 . 4. 2. 1 
Statistical H y p ot heses ........................................... 3 8
1 1 . 4. 2. 2 
A nal y sis Met h o ds ................................................. 3 9
4 0
4 0
4 0
1 1 . 5 
Ha n dli n g of Missi n g Data .................................................................... 4 0
1 1 . 6 
M ulti plicit y ........................................................................................... 4 1
1 1 . 7 
Safet y  A nal y sis ..................................................................................... 4 1
1 1 . 8 
Healt h Ec o n o mics ................................................................................. 4 1
1 1 . 9 
I nteri m A nal ys es ................................................................................... 4 1
1 1 . 1 0 
Sa m ple Size J ustificati o n ...................................................................... 4 1
1 2 
C O L L E C TI O N O F C O M P L AI N T S ..................................................................... 4 2
1 2. 1 
Ge neral I nf or mati o n ............................................................................. 4 2
1 2. 2 
M o nit ori n g f or A d verse E ve nts ............................................................ 4 5
1 2. 3 
Pr oce d u res f or Rec or di n g a n d Re p orti n g............................................. 4 5
1 2. 4 
I nte nsity a n d Ca usalit y Assess me nts .................................................... 4 7
1 2. 5 
U n mas ki n g of t he St u d y  Inf or mati o n ................................................... 4 7
1 2. 6 
F oll o w -U p of Safet y I nf or mati o n......................................................... 4 8
1 2. 7 
Pre g na nc y  i n t he Cli nical St u d y........................................................... 4 8
1 3 
D A T A H A N D LI N G A N D A D MI NI S T R A TI V E R E Q UI R E M E N T S .................. 4 8
1 3. 1 
C o m pleti o n of S o urce D oc u me nts a n d Case Re p ort F or ms ................. 4 8
1 3. 2   
Data Re vie w a n d Clarificati o ns............................................................ 4 9
1 3. 3 
Re g ulat or y  D oc u me ntati o n a n d Rec or ds Rete nti o n .............................4 9

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1 4 
Refere nces ............................................................................................................. 5 0
List of Ta bles
Ta ble 2 – 1 
Sc he d ule of Assess me nts ................................................................................. 1 4
Ta ble 1 1 – 1 
Sa m ple Size Calc ulati o n .................................................................................. 4 2
List of Fi g ur es
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Fi g ure 1 0 - 1 
St u d y  Desi g n.................................................................................................... 2 6

Pa ge 1 9 of 5 0
5 
I N T R O D U C TI O N
5. 1 
St u d y R ati o n ale a n d B ac k gr o u n d
T he p ur p ose of t his st u d y is t o e val uate t he cli nical effecti ve ness of S Y S TA N E B A L A N C E 
c o m pare d t o R E F R E S H O P TI V E A d va nce d i n patie nts wit h dr y e ye ass ociate d wit h li pi d 
deficie nc y. 
Dr y  e ye disease ( D E D), als o calle d kerat oc o nj u ncti vitis sicca or dr y  e ye s y n dr o me, is a 
m ultifact orial disease of t he tears a n d oc ular s urface t hat res ults i n s y m pt o ms of disc o mf ort, 
vis ual dist ur ba nce, a n d tear fil m i nsta bilit y  wit h p ote ntial da ma ge t o t he oc ular s urface 
( Le m p 2 0 0 7). Dr y  e ye ma y affect i n di vi d uals wit h differi n g se verit y, fr o m mil d cases 
e x perie nci n g b ur ni n g a n d ot her s y m pt o ms of oc ular disc o mf ort, t o se vere cases wit h 
s u bsta ntiall y i m paire d visi o n. T he gl o bal pre vale nce of D E D re p orte d i n se veral lar ge st u dies 
ra n ges fr o m 5 % t o 3 5 % (S mit h 2 0 0 7 ); mei b o mia n gla n d d ys f u ncti o n ( o bstr ucti o n or gla n d 
dr o p o ut) has bee n re p orte d i n u p t o 7 0 % of dr y  e ye cases ( Sc ha u m ber g 2 0 1 1).
S Y S T A N E B A L A N C E is a li pi d- base d artificial tear dr o p a n d has bee n f or m ulate d wit h a 
pate nte d Li pitec h ™s yste m (c o nsisti n g of p h os p h oli pi ds a n d mi neral oil) t o hel p a d dress dr y  
e ye si g ns a n d s y m pt o ms ca use d b y a deficie nc y  i n t he li pi d la yer of t he tear fil m. P ote ntial 
be nefits of S Y S T A N E B A L A N C E i ncl u de i m pr o ve me nt i n cli nical meas ures relate d t o li pi d-
deficie nt tear fil m s uc h as i ncrease d tear fil m brea k-u p ti me ( T F B U T) a n d li pi d la yer 
t hic k ness ( L LT) , re d uce d oc ular s urface stai ni n g, re d ucti o n i n t he nee d f or hi g her d osi n g or 
e x pe nsi ve alter nati ve dr y e ye t hera pies, i m pr o ve me nt i n patie nt’s q uality of life a n d treat me nt 
satisfacti o n. A k e y  i n gre die nt i n t he Li pitec h sy ste m, p h os p h oli pi ds ( w hic h c o ntai n b ot h p olar 
a n d n o n -p olar gr o u ps) is a nat ural c o m p o ne nt of t he li pi d la y er of t he tear fil m w hic h hel ps t o 
pr o vi de sta bilit y  at t he i nterface bet wee n t he li pi d la yer a n d t he a q ue o us la yer. 
A ne w a d diti o n t o t he li pi d -bas e d s u b gr o u p of artificial tear pr o d ucts ( R E F R E S H O P TI V E
A d va nce d ) c o ntai ns cast or oil a n d is la u nc hi n g acr oss t he gl o be i n ke y gr o wt h mar kets. W hile 
t here are n o da ta c o m pari n g t he effecti ve ness of b ot h pr o d ucts, s u p ple m e nti n g t he li pi d la yer 
of patie nts w it h li pi d-deficie nt dr y  e ye wit h a ke y nat ural c o m p o ne nt ma y be a better 
alter nati ve i n i m pr o vi n g or pr ol o n gi n g t he i nte grit y of t he li pi d la yer.
T his st u d y is desi g ne d t o s h o w t hat t he cli nical be nefits of S Y S T A N E B A L A N C E will be at 
least n o ni nfer i or t o R E F R E S H O P TI V E A d va nce d . 
5. 2 
S yst a ne B al a nce
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Alc o n has de vel o pe d S Y S T A N E B A L A N C E L u brica nt E y e Dr o ps as a n artificial tear 
s u p ple me nt. T he f or m ulati o n is a n oil-i n-water e m ulsi o n c o ntai ni n g pr o p yl e ne gl yc ol as t he 

Pa ge 2 0 of 5 0
acti ve de m ulce nt , p oly q ua d ( p ol yq uarter ni u m -1) as t he preser vati ve, H P -G uar/ b orate gelli n g 
tec h n ol o g y, a n a ni o nic p h os p h oli pi d ( di m yrist o yl p h os p hati d yl gl ycer ol, D M P G -Na ) a n d 
et h yle ne dia mi ne tetra acetic aci d (E D T A) as a c helati n g a ge nt. S Y S T A N E B A L A N C E 
L u brica nt E y e Dr o p was first mar kete d i n t he U nite d Sta tes i n 2 0 0 8 a n d has s ol d o ver 
8 milli o n u nits w orl d wi de si nce its i ntr o d ucti o n t o t he mar ket. To  date, Alc o n has re gistere d 
S Y S T A N E B A L A N C E L u brica nt E y e Dr o ps w orl d wi de i n m ulti ple c o u ntries. 
5. 3 
K n o w n a n d P ote nti al Ris ks
D uri n g t h e cli nical de vel o p me nt of S Y S T A N E B A L A N C E , a si n gle n o n -seri o us a d verse dr u g 
reacti o n (A D R ) of mil d bl urre d visi o n was re p orte d. N o s y ste mic A D R was re p orte d i n a n y 
s u bject a d mi nistere d S Y S T A N E B A L A N C E i n t he cli nical st u dies perf or me d t o date . Si nce 
t he initial a p pr o val of t he S Y S T A N E fa mil y of pr o d ucts, l ocal oc ular si de effects ha ve bee n 
t he m ost c o m m o n t ypes of s p o nta ne o us re p orts o bser ve d t hr o u g h p ost mar keti n g
s ur veilla nce. Ot her m ost fre q ue nt A Es re p orte d were: e ye irritati o n, bl urre d visi o n, oc ular 
h y p ere mia, a n d e ye pai n. N o s p o nta ne o us re p ort has bee n o bser ve d at a fre q ue nc y  t hat w o ul d 
i n dicate a safety c o ncer n f or c o nti n ue d s u bject use of S Y S T A N E B A L A N C E.
O verall, t he occ urre nce of n o nse ri o us l ocal oc ular side ef fects wit h t he use of a t o pical oc ular 
l u brica nt li ke S Y S T A N E B A L A N C E is n ot u ne x pecte d es pecially i n s u bjects wit h a 
pre dis p osi n g ris k fact or (e g, dr y  e ye s u bjects) a n d d o n ot re prese nt a safet y  c o ncer n f or t he 
use of S Y S T A N E B A L A N C E.
5. 4 
P ote nti al Be nef its
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
S Y S T A N E B A L A N C E L u brica nt E y e Dr o ps is a m ulti d ose, artificial tear pr o d uct t hat has 
bee n s h o w n t o i m pr o ve t he si g ns a n d s y m pt o ms of dr y  e ye i n m ulti ple cli nical st u dies. T he 
pr o d uct has bee n s h o w n t o l u bricate t he oc ular s urface, s u p ple me nt a n d sta bil ize t he li pi d 
la yer of t he tear fil m, a n d re d uce e xcessi ve tear e va p orati o n, t here b y pr o vi di n g l o n g lasti n g 
relief fr o m dr y e ye s y m pt o ms s uc h as b ur ni n g a n d irrit ati o n.

Pa ge 2 1 of 5 0
6 
E T HI C S
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T his cli nical st u d y  will be c o n d ucte d i n acc or da nce wit h t he pri nci ples of t he Declarati o n of 
Helsi n ki, a n d i n c o m plia nce wit h t he I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H) E 6 
G o o d Cli nical Practice ( G C P) C o ns oli date d G ui deli ne a n d ot her re g ulati o ns as a p plica ble. 
T he I n vesti gat or a n d all cli nical st u d y  staff will c o n d uct t he cli nical st u d y i n c o m plia nce wit h 
t he pr ot oc ol. T he I n vesti gat or will e ns ure t hat 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 are q ualifie d t o perf or m t heir assi g ne d res p o nsi bilities t hr o u g h rele va nt e d ucati o n, 
trai ni n g, a n d e x perie nce.
Bef ore cli nica l st u d y i nitiati o n, t his pr ot oc ol, t he i nf or me d c o nse nt f or m, a n y ot her writte n 
i nf or mati o n gi ve n t o s u bjects, a n d a ny a d vertise me nts pla n ne d f or s u bject recr uit me nt m ust 
be a p pr o ve d b y a n I n de pe n de nt Et hics C o m mittee/Instit uti o nal Re vie w B oar d (I E C/I R B). 
T he I n vesti gat or m ust pr o vi de d oc u me ntati o n of t he I E C/I R B a p pr o val t o t he S p o ns or . T he 
a p pr o val m ust be date d a n d m ust i de ntif y  t he a p plica ble pr ot oc ol, a me n d me nts (if a ny), 
i nf or me d c o nse nt f or m, all a p plica ble recr uiti n g materials, writte n i nf or mati o n for s u bject, 
a n d s u bject c o m pe nsati o n pr o gra ms. T he I E C/IR B m ust be pr o vi de d wit h a c o p y  of t he 
pr o d uct m o n o gra p h or e q ui vale nt , a ny peri o dic safet y u p dates, a n d all ot her i nf or mati o n as 
re q uire d by l ocal re g ulati o n a n d/ or t he I E C/I R B. At t he e n d of t he st u d y, t he I n vesti gat or will 
n otif y  t he I E C/I R B a b o ut t he st u d y’s c o m pleti o n. T he I E C/IR B als o will be n otifie d if t he 
st u d y is ter mi nate d pre mat urel y. Fi nall y, t he I n vesti gat or will re p ort t o t he I E C/IR B o n t he 
pr o gress of t he st u d y at i nter vals sti p ulate d b y  t he IE C/I R B.
Vo l u ntar y i nf or me d c o nse nt will be o btai ne d fr o m e ver y s u bject pri or t o t he i nitiati o n of a n y 
scree ni n g or ot her st u d y-relate d pr oce d ures. T he I n vesti gat or m ust ha ve a defi ne d pr ocess f or 
o btai ni n g c o nse nt. S pecificall y, t he I n vesti gat or, or desi g nee, will e x plai n t he cli nical st u d y  t o 
eac h p ote ntial s u bject a n d t he s u bject m ust i n dicate v ol u ntar y  c o nse nt by si g ni n g a n d dati n g 
t he a p pr o ve d i nf or me d c o nse nt f or m. T he s u bject m ust be pr o vi de d a n o p p ort u nit y t o as k 
q uesti o ns of t he I n vesti gat or , a n d if re q uire d by l ocal re g ulati o n, ot her q ualifie d pers o n nel. 
T he I n vesti gat or m ust pr o vi de t he s u bject wit h a c o p y  of t he c o nse nt f or m writte n i n a 
la n g ua ge t he s u bject u n dersta n ds. T he c o nse nt d oc u me nt m ust meet all a p plica ble l ocal la ws 
a n d will pr o vi de s u bjects wit h i nf or mati o n re gar di n g t he p ur p ose, pr oce d ures, re q uire me nts, 
a n d restricti o ns of t he st u d y, al o n g wit h a ny k n o w n ris ks a n d p ote ntial be nefits ass ociate d 
wit h t he st u d y pr o d ucts, t he a vaila ble c o m pe nsati o n, a n d t he esta blis he d pr o visi o ns f or 
mai ntai ni n g c o nfi de ntialit y  of pers o nal, pr otecte d healt h i nf or mati o n. S u bjects will be t ol d 
a b o ut t he v ol u ntar y nat ure of partici pati o n i n t he st u d y a n d will be pr o vi de d wit h c o ntact 
i nf or mati o n f or t he a p pr o priate i n di vi d uals s h o ul d q uesti o ns or c oncer ns arise d uri n g t he 
st u d y. T he s u bject will als o be t ol d t hat his/ her rec or ds ma y be accesse d b y a p pr o priate 

Pa ge 2 2 of 5 0
a ut h orities a n d S p o ns or- desi g nate d pers o n nel. T he I n vesti gat or m ust kee p t he ori gi nal, si g ne d 
c o p y of t he c o nse nt a n d m ust pr o vi de a d u plicate c o p y t o eac h s u bject.
7 
P R O T O C O L  AM E N D M E N T S
M o dificati o n of t he pr ot oc ol is pr o hi bite d wit h o ut pri or writte n a gree me nt i n t he f or m of a 
pr ot oc ol a me n d me nt. All a me n d me nts will be create d b y  t he S p o ns or a n d m ust be a p pr o ve d 
b y  t he I E C/I R B pri or t o i m ple me ntati o n e xce pt w he n re q uire d t o miti gate i m me diate safety 
ris ks or w he n t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve re visi o ns. 
A me n d me nts ma y  necessitate t hat t he i nf or me d c o nse nt a n d ot her st u d y-relate d material be 
re vise d. If t he c o nse nt f or m is re vise d, all s u bjects c urre ntl y e nr olle d i n t he st u d y  ma y be 
re q uire d by t he I RB/I E C t o si g n t he a p pr o ve d, re vise d i nf or me d c o nse nt f or m.
8 
S U B J E C T P O P U L A TI O N
T he st u d y  p o p ulati o n i ncl u des a p pr o xi matel y 2 2 0 s u bjects t o be ra n d o mize d ( 2 0 0 e val ua ble 
s u bjects re q uire d) at a p pr o xi matel y 1 0 sites. U p t o 5 5 s u bjects ma y  be recr uite d per site, a n d 
site recr uit me nt tar gets ma y var y base d o n site ca pa bilities, a vaila ble patie nt p o p ulati o n, a n d 
le n gt h of recr uit me nt peri o d. To  partici pate i n the st u d y, s u bjects m ust be at least 1 8 y ears of 
a ge a n d e x hi bit dr y e ye s ym pt o ms . T he e x pecte d d urati o n of s u bject partici pati o n i n t he st u d y  
is a p pr o xi matel y 7 wee ks ( 4 9 da ys); u p t o 2 wee ks ( 1 4 da ys) d uri n g t he r u n -i n p hase a n d 5
wee ks ( 3 5 da ys) i n t he treat me nt p hase. T he c o m plete i ncl usi o n a n d e xcl usi o n criteria are 
prese nte d i n Secti o n 1.
9 
T R E A T M E N T S A D MI NI S T E R E D
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
S u bjects w h o meet t he eli gi bilit y  criteria will first be dis pe nse d Preser vati ve -Free Sa li ne t o be 
use d d uri n g t he r u n-i n peri o d bet wee n t he Scree n i n g Visit a n d Visit 1 (Baseli ne/ Da y  0).
At V isit 1, s u bjects w h o meet t he eli gi bilit y criteria (as deter mi ne d by t he re -e val uati o n of t he 
T F B U T assess me nt pri or t o ra n d o mizati o n) will be ra n d o mize d i n a 1: 1 ma n ner t o recei ve 
treat me nt wit h S Y S T A N E B A L A N C E L u brica nt E y e Dr o ps or R E F R E S H O P TI V E
A d va nce d L u brica nt E y e Dr o ps. T hr o u g h o ut t he st u d y , t he I n vesti gat or will be res p o nsi ble 
f or t he acc o u nti n g of all st u d y materials a n d will e ns ure t hat t he st u d y pr o d ucts are n ot use d 
i n a n u na ut h orize d ma n ner.
T his st u d y  is d o u ble-mas ke d. D esi g nate d u n mas ke d i n di vi d ual(s) at eac h site m ust be 
assi g ne d t o dis pe nse a n d reclai m t he mas ke d st u d y pr o d uct . U n mas ke d i n di vi d uals s h o ul d n ot 
be i n v ol ve d i n c o n d ucti n g a n y s u bject assess me nts. E xtre me ca uti o n s h o ul d be use d t o a v oi d 
p ote ntial u n mas ki n g of t he i n di vi d uals c o n d ucti n g s u bject assess me nts.

Pa ge 2 3 of 5 0
9. 1 
I de ntit y of St u d y Pr o d uct s
R u n -i n Pr o d uct :  
Preserva ti ve-F ree Sali ne S ol uti o n
Te st Pr o d uct:  
S Y S T A N E B A L A N C E
C o ntr ol Pr o d uct:  
R E F R E S H O P TI V E A d va nce d (m ulti d ose preser ve d f or m ulati o n)
Preser vati ve - Free Sali ne will be pr o vi de d f or t he r u n-i n p hase i n t he c o m mercially a vaila ble 
cart o n as a n o pe n -la bel pr o d uct. Mas ke d st u d y pr o d ucts will be s u p plie d i n c o m merciall y 
a p pr o ve d b ottles i n i de ntical c art o ns c o vere d wit h a p pr o ve d cli nical la beli n g. T he cart o n
la bels will c o ntai n, at a mi ni m u m, t he pr ot oc ol n u m ber a n d kit i de ntificati o n n u m ber .
S Y S T A N E B A L A N C E a n d R E F R E S H O P TI V E A d va nce d sh o ul d be st ore d i n acc or da nce 
wit h t he a p pr o ve d cli nical la beli n g. Pr o d uc ts are t o be s ha ke n ge ntl y  bef ore use , a n d t o a v oi d 
c o nta mi nati o n, t he ti p of t he c o ntai ner s h o ul d ne ver be t o uc he d t o a ny s urface. 
A site te m perat ure l o g will be mai ntai ne d t o d oc u me nt st ora ge c o n diti o ns of t he st u d y
pr o d uct s a n d will be ma de a vaila ble f or t he st u dy m o nit or t o i ns pect.
9. 2 
Us a ge
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
O pe n -la bel Preser vati ve -Free Sali ne e ye dr o ps will be pr o vi de d t o eac h s u bject i n s uf ficie nt 
q ua ntit y  t o acc o m m o date QI D d osi n g t hr o u g h o ut t he R u n-i n p hase. O ne kit of mas ke d st u d y
pr o d uct will be pr o vi de d t o eac h s u bject at t he ti me of ra n d o mizati o n ( Vi sit 1/ Da y  0) a n d a 
sec o n d kit will be pr o vi de d at Vi sit 2/Da y  1 5. E xtra kits of st u d y pr o d uct ma y  be s u p plie d as 
nee de d.
R u n -i n P hase: 
D uri n g t he r u n -i n p hase ( bet wee n t he Scree n i n g Visit a n d Vi sit 1), 
s u bjects will be gi ve n Preser vati ve -Free Sali ne e ye dr o ps a n d 
i nstr ucte d t o d ose eac h e ye wit h 1 dr o p, QI D.
Tr eat me nt P hase:
Da y  0 t o Da y 3 5
At V isit 1 ( Da y 0), s u bjects will be ra n d o mize d a n d will recei ve eit her 
S Y S T A N E B A L A N C E or R E F R E S H O P TI V E A d va nce d . S u bjects 
will be i nstr ucte d t o d ose eac h e ye wit h 1 dr o p, QI D ( wit h t he last 
d ose at be dti me , ie, n o later t ha n mi dni g ht ) fr o m Visit 1 t o Vi sit 3 
( Da y 0 – Da y  3 5).
T he first d ose of Preser vati ve -Free Sali ne e ye dr o ps will be self -a d mi nistere d b y t he s u bject 
at t he st u d y site a n d o bser ve d b y site staff t o c o nfir m t he s u bject is usi n g t he c orrect
a d mi nistrati o n tec h ni q ue.

Pa ge 2 4 of 5 0
9. 3 
Acc o u nt a bilit y Pr oce d ures
U p o n recei pt of t he r u n -i n Preser vati ve-Free Sali ne , t he test pr o d uct (S Y S T A N E B A L A N C E )
a n d t he c o ntr ol pr o d uc t (R E F R E S H O P TI V E A d va nce d ), t he I n vesti gat or or desi g nee will 
c o n d uct a n i n ve nt or y. Desi g nate d st u dy staf f will dis pe nse t he r u n-i n Preser vati ve-Free Sali ne 
t o all s u bjects w h o q ualif y f or t he st u d y. O n Vi sit 1 (Da y  0/ Baseli ne), s u bjects will ret ur n 
use d a n d u n use d c o ntai ners of r u n -i n Preser vati ve-Free Sali ne a n d sites will mai ntai n a n 
acc urate i n ve nt or y of t he vials of r u n-i n Preser vati ve-Free Sali ne ret ur ne d b y  t he s u bjects. 
If t he s u bject q ualifies f or t he st u d y, t he site will ra n d o mize t he s u bject usi n g a n electr o nic 
data ca pt ure ( E D C ) s yste m at Visit 1/ Baseli ne. T he site pers o n nel will pr o vi de t he mas ke d 
st u d y pr o d uct t o t he s u bject i n acc or da nce wit h t he i nteracti ve res p o nse tec h n ol o g y (I RT )
treat me nt kit n u m bers assi g ne d at Visit 1 a n d at Visit 2.
D uri n g t he st u d y , t he I n vesti gat or m ust mai ntai n rec or ds of st u d y pr o d uct s recei pt,
dis pe nsati o n a n d c ollecti o n f or eac h s u bject. S u bjects will be i nstr ucte d t o bri n g use d a n d 
u n use d vials of Preser vati ve -Free Sali ne t o t he Baseli ne Vi sit a n d t he mas ke d st u d y pr o d uct
t o all p ost -baseli ne visits. At V isit 3/ Da y  3 5 ( Fi nal Vi sit) or at Earl y E xit , all use d a n d u n use d 
st u d y pr o d uct s s h o ul d be ret ur ne d. S ites will mai ntai n a n acc urate i n ve nt or y of t he 
b ottles/ vials ret ur ne d by t he s u bjects. T his rec or d m ust be ma de a vaila ble t o t he st u d y 
m o nit or f or t he p ur p oses of verif y i n g t he acc o u nti n g of cli nical s u p plies. A n y  discre pa ncies 
a n d/ or deficie ncies bet wee n t he o bser ve d dis p ositi o n a n d t he writte n acc o u nt m ust be 
rec or de d al o n g wit h a n e x pla nati o n. 
At t he c o ncl usi o n of t he st u d y , t he I n vesti gat or will be res p o nsi ble f or ret ur ni n g all use d a n d 
u n use d st u d y pr o d ucts u nless ot her wise i nstr ucte d b y  t he S p o ns or.
9. 4 
S u bject C o nfi de nti alit y a n d Met h o ds Use d t o Mi ni mize Bi as
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n ymit y  is mai ntai ne d t hr o u g h o ut t he
c o urse of t he st u d y.  In partic ular , t he I n vesti gat or m ust kee p a n e nr oll me nt l o g wit h 
c o nfi de ntial i de ntif yi n g i nf or mati o n t hat c orres p o n ds t o t he s u bject n u m bers a n d i nitials of 
eac h st u d y partici pa nt. At t he e n d of t he cli nical st u d y , t he S p o ns or will c ollect a c o py of t he 
e nr oll me nt l o g wit h o ut a n y i de ntif yi n g s u bject i nf or mati o n. All d oc u me nts s u b mitte d t o t he 
S p o ns or will i de ntif y  t he s u bjects e xcl usi vel y b y n u m ber a n d de m o gra p hic i nf or mati o n. N o 
ot her pers o nall y i de ntif yi n g i nf or mati o n s h o ul d be tra ns mitte d t o t he S p o ns or .
T he i nte nt of mas ki n g is t o li mit t he occ urre nce of c o nsci o us a n d u nc o nsci o us bias i n t he 
c o n d uct a n d i nter pretati o n of t he cli nical st u d y. Bias c o uld arise fr o m t he i nfl ue nce t hat t he 
k n o wle d ge of a s pecific treat me nt assi g n me nt ma y ha ve o n t he recr uit me nt a n d all ocati o n of 

Pa ge 2 5 of 5 0
s u bjects, t heir s u bse q ue nt care, t he assess me nt of e n d p oi nts, t he ha n dli n g of wit h dra wals, 
a n d s o o n. T he esse ntial ai m of mas ki n g, t heref ore, is t o pre ve nt i de ntificati o n of t he st u d y 
pr o d uct s b y t he I n vesti gat or, s u bject, a n d ot hers ass ociate d wit h t he c o n d uct of t he st u d y u ntil 
all s uc h o p p ort u nities f or bias ha ve passe d.
T he R u n -i n P hase is o pe n-la bel a n d all s u bjects will use Preser vati ve -Free Sali ne e ye dr o ps 
f or at least 7 da ys. T h e Treat me nt P hase is d o u ble-mas ke d, wit h s u bjects ra n d o mize d t o 
recei ve eit her S Y S T A N E B A L A N C E or R E F R E S H O P TI V E A d va nce d f or t he d urati o n of 
t he 5 wee k treat me nt peri o d. T he I n vesti gat or , cli nical site staff (e xce pt desi g nate d u n mas ke d 
site pers o n nel), S p o ns or, a n d m o nit ors i n v ol ve d i n re p orti n g, o btai ni n g, a n d/ or re vie wi n g t he 
cli nical e val uati o ns will n ot be a ware of t he s pecific mas ke d st u d y pr o d uct be i n g 
a d mi nistere d. T his le vel of mas ki n g will be mai ntai ne d t hr o u g h o ut t he c o n d uct of t he st u d y. 
T he ra n d o mizati o n sc he me will be ge nerate d a n d mai ntai ne d b y  t he S p o ns or’s ( or desi g nee)
u n mas ke d pers o n nel w h o are n ot i n v ol ve d i n t he c o n d uct or a nal ys is of the st u d y. S u bjects 
will be assi g ne d ra n d o ml y  t o treat me nt gr o u ps via I RT wit h stratificati o n b y  site. T he s p o ns or 
st u d y s pecific pers o n nel will be mas ke d t hr o u g h o ut t he c o urse of t he st u dy.  O nce all st u dy 
data ha ve bee n vali date d a n d t he data base l oc ke d, i n di vi d ual s u bjects will be u n mas ke d. I n 
t he e ve nt of a me dical e mer ge nc y w here t he k n o wle d ge of s u bject treat me nt is re q uire d, a n 
i n di vi d ual In vesti gat or will ha ve t he a bilit y  t o u n mas k t he treat me nt assi g n me nt f or a s pecific 
s u bject.
Alt h o u g h t his is a d o u ble -mas ke d st u d y , at least 1 desi g nate d pers o n fr o m eac h cli nical site 
will be u n mas ke d. T his pers o n will be res p o nsi ble f or dis pe nsi n g, reclai mi n g, c o n d ucti n g 
i n ve nt or y, a n d will be a vaila ble t o a d dress a n y st u d y pr o d uct irre g ularities. T his i n di vi d ual 
w ill als o perf or m t he i nstillati o n of mas ke d st u d y  pr o d uct at Vi sit 1 ( Baseli ne), Vi sit 2 a n d 
Vi sit 3. Sites s h o ul d ma ke e ver y  eff ort t o ha ve t he sa me u n mas ke d o bser ver t hr o u g h o ut t he 
st u d y. 
1 0 
S T U D Y  P R O C E D U R E S
1 0. 1 
O utli ne of St u d y
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T his is a p ost -mar ket, pr os pecti ve, d o u ble -mas ke d, ra n d o mize d, m ultice nter , parallel-gr o u p 
st u d y wit h 2 treat me nt ar ms:
1.
S Y S T A N E B A L A N C E L u brica nt E y e D r o ps
2.
R E F R E S H O P TI V E A d va nce d L u brica nt E y e Dr o ps

Pa ge 2 6  of 5 0
S u bjects m ust e x hi bit  dr y  e ye s ym pt o ms t o be c o nsi dere d f or i ncl usi o n i n t his st u d y. T he 
st u d y c o nsists of 4 re q uire d visits: Scree n i n g Visit ( Da y -1 4 t o Da y  - 7), Vi sit 1 
( Da y 0/ Baseli ne), Visit 2 ( Da y 1 5) a n d Visit 3 ( Da y 3 5/ E n d of Treat me nt). 
Fi g ur e 1 0 - 1 
St u d y Desi g n
S u bjects will be s cree ne d f or eli gi bilit y at least 7 da ys pri or t o, b ut n o m ore t ha n 1 4 da ys 
(ie, Da y  -1 4 t o Da y  -7) pri or t o Visit 1 ( Baseli ne/ Da y 0) t o si m ulta ne o usl y be gi n t he Sali ne  
r u n-i n p hase. S u bjects w h o meet eli gi bilit y criteria at Scree ni n g will be as ke d t o d isc o nti n ue 
all artificial tears/l u brica nts/ gels/re wetti n g dr o ps a n d will be gi ve n a s u p pl y of Preser vati ve -
Free Sali ne  wit h i nstr ucti o ns t o a d mi nister 1 dr o p i n eac h e ye 4 ti mes per da y d uri n g t he r u n-
i n peri o d. A d diti o nall y , su bjects m ust disc o nti n ue c o nt act le ns wear at least 3 0 da y s bef ore 
Scree ni n g a n d a gree n ot t o wear c o ntact le nses f or t he d urati o n of t he st u d y. 
U p o n c o m pleti o n of t he r u n -i n peri o d, eli gi ble s u bjects will be ra n d o mize d t o eit her 
S Y S T A N E B A L A N C E or R E F R E S H O P TI V E  A d va nce d  at Visit 1 a n d ot her baseli ne  
e val uati o ns will be c o n d ucte d. A n a de q uate s u p pl y  of ra n d o mize d test pr o d uct (S Y S T A N E 
B A L A N C E ) a n d c o ntr ol pr o d uct ( R E F R E S H O P TI V E  A d va nce d ) will be dis pe nse d at Da y  0 
f or t he treat me nt peri o d ( Da y 0 – Da y  1 5 ). S u bjects will be i nstr ucte d t o i nstill 1 dr o p of t he 
assi g ne d test or c o ntr ol  pr o d uct i n eac h e ye, 4 ti mes per da y. At t he st u d y  visits d uri n g t he 
treat me nt p hase, t he u n mas ke d site pers o n nel will i nstill t he mas ke d st u d y  pr o d uct f or eac h 
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7

Pa ge 2 7 of 5 0
s u bject. A t Vi sit 2 ( Da y 1 5), a sec o n d kit will be dis pe nse d f or t he re mai ni n g treat me nt peri o d 
( Da y 1 5 – Da y  3 5).
1 0. 2 
Vi sits a n d E x a mi n ati o ns
S u bjects s h o ul d c o me i n f or all re g ularl y sc he d ule d visits (e ve n if a visit is “ o ut of wi n d o w”). 
Vi sit 3 (Da y  3 5) is critical f or e val uati n g t he s u bject’s res p o nse t o t hera py after c o m pleti n g 
t he desi g nate d d osi n g peri o d.
T he sc he d ule of st u d y  pr oce d ures/ assess me nts is prese nte d i n Ta ble 2 – 1. F or details of t he 
pr oce d ures use d a n d or der of assess me nts i n t his pr ot oc ol, refer t o t he ma n ual of pr oce d ure s 
(M O P ). F or eli gi ble st u d y  s u bjects, all st u d y assess me nts d uri n g eac h visit m ust be c o n d ucte d 
at t he sa me ti me of da y wit hi n ± 1 h o ur of t he start ti me of Visit 1 ( Baseli ne). A d verse e ve nts 
( A Es) will be c ollecte d fr o m t he ti me of i nf or me d c o nse nt, u ntil t he s u bject e xits t he st u d y . 
A ll A E s t hat are o bser ve d or re p orte d s h o ul d be rec or de d o n a n A E f or m as per Secti o n 1 2. 2
a n d re p orte d t o t he I R B/I E C, as re q uire d.
1 0. 2. 1 
S ali ne R u n -i n P h ase ( D a y -1 4 /- 7 t o D a y 0)
T he r u n -i n p hase i ncl u des t he d urati o n fr o m t he Scree ni n g Visit t o t he Baseli ne Vi sit ( Da y 0).
1 0. 2. 1. 1 
Scree ni n g V isit ( D a y -1 4 t o D a y -7)
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Scree ni n g pr oce d ures m ust be c o m plete d at t he Scree ni n g V isit. I nf or me d c o nse nt m ust be 
o btai ne d pri or t o c o n d ucti n g st u d y- s pecific Scree ni n g assess me nts. S u bjects w h o meet 
eli gi bilit y criteria at Scree ni n g will be gi ve n a s u p pl y of Preser vati ve -Free Sali ne t o be use d 
d uri n g t he 7 t o 1 4 da y  r u n-i n p hase . 
T he Scree ni n g p r oce d ures i ncl u de t he f oll o wi n g a n d m ust be c o m plete d i n t he or der st ate d 
bel o w:
1.
E x plai n t he p ur p ose a n d nat ure of t he st u d y,  a n d ha ve t he s u bject or le gally a ut h orize d 
re prese ntati ve rea d, si g n, a n d date t he I R B/IE C -a p pr o ve d i nf or me d c o nse nt d oc u me nt. 
A d diti o nall y , ha ve t he i n di vi d ual o btai ni n g c o nse nt fr o m t he s u bject a n d a wit ness, if 
a p plica ble, si g n a n d date t he i nf or me d c o nse nt d oc u me nt. Pr o vi de a p h ot oc o p y  of t he 
si g ne d d oc u me nt t o t he s u bject a n d place t he ori gi nal si g ne d d oc u me nt i n t he s u bject’s 
c hart.
2.
If t he s u bject c o nse nts, retrie ve t he 9-di git s u bject i de ntific ati o n n u m ber fr o m E D C.

Pa ge 2 8 of 5 0
3.
O btai n de m o gra p hic i nf or mati o n a n d me dical hist or y , i ncl u di n g i nf or mati o n o n all 
me dicati o ns use d wit hi n t he past 3 0 da y s. I ncl u de her bal t hera pies, vita mi ns, a n d all 
o ver -t he-c o u nter as well as prescri pti o n me dicati o ns.
4.
C o n d uct uri ne pre g na nc y test o n w o me n of c hil d beari n g p ote ntial. If t he test is 
p ositi ve, t he s u bject is i neli gi ble a n d m ust disc o nti n ue. A d diti o nall y , f or w o me n of 
c hil d beari n g p ote ntial, rec or d met h o d(s) of birt h c o ntr ol i n t he s u bject’s c hart. F or 
s urgi call y st erile or p ost -me n o pa usal w o me n, rec or d date of s ur gical sterilizati o n 
(t u bal li gati o n, hys terect o m y or bilateral o o p h orect o m y) or date of me n o pa use 
( defi ne d as 1 2 m o nt hs si nce last me nses).
5.
Scree n s u bjects f or pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria.
6.
T he f oll o wi n g assess me nts m ust be c o m plete d i n b ot h e y es ( O U) (see t he M O P
f or 
details re gar di n g eac h assess me nt a n d t he or der of testi n g ):

B C V A m ust be meas ure d usi n g a n E T D R S or T u m bli n g E c hart at a dista nce 
of 3 or 4 meters usi n g t he letters rea d met h o d. T he test ma y  be perf or me d 
usi n g t he s u bject’s hist orical c orrecti o n. Vis ual ac uit y  testi n g s h o ul d prece de 
a n y e xa mi nati o n re q uiri n g dia g n ostic dr ops (e g , dilati n g dr o ps) or c o ntact wit h 
t he e ye. B C V A m ust be ≥ 5 5 i n b ot h e yes f or t he s u bject t o q ualif y f or t he 
st u d y.

Slit -lam p e x a mi nati o n

U n dilate d f u n d us e xa mi nati o n

U na nest heti z e d Sc hir mer I t est usi n g t he stri ps 

T F B U T ri g ht e ye (O D ) × 3 , left e ye ( O S ) × 3

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
I ntra oc ular press ure
7. I f t he i nclusi o n/ e x clusi o n criteria are met, t he site staff will dis p ense t he a p pr o priate 
n u m ber of c o ntai ners of Preser vati ve -Free Sali ne e ye dr o ps t o pr o vi de QI D treat me nt 
f or t he r un- i n p hase .
8.
T he site staff will o bs erv e t he s u bject i nstill t he first d ose of Preser vati ve -Free Sali ne
w hil e at t his visit.
9.
S u bj ects will be i nstr ucte d t o d ose wit h 1 dr o p of Sali ne i n eac h e ye, 4 ti mes per d a y.
T h e last d ose s h o ul d be at b e dti me (ie, n o later t ha n mi d ni g ht).

Pa ge 2 9 of 5 0
1 0. S u bjects will be i nstr ucte d t o ret ur n use d a n d u n us e d c o ntai ners of Preser vati ve -Free 
Sali ne at t he ne xt visit ( Visit 1).
1 1. Rec or d a n y A E s t hat are o bser ve d or re p orte d.
1 2. Sc he d ule V isit 1 t o ta ke place 7 t o 1 4 da y s after t he Scree ni n g Visit.
1 3. Pr o vi de s u bjects wit h R u n -i n P hase D osi n g Instr u cti o ns car d a n d St u d y I n f or mati o n
car d.
1 4. E nt er t he s u bject i nf or mati o n a n d visit da ta i nt o t he E D C s yste m.
If, at t he Scree ni n g Visit, it is deter mi ne d t hat a s u bject di d n ot meet t he ti mefra me 
re q uire d f or sta bilizati o n of c hr o nic me dicati o ns or me dical hist or y, t he s u bject ma y be 
br o u g ht bac k at a later date t o re -atte m pt t he Scree ni n g pr ocess o nce t he ti mefra me (s) ha ve 
bee n ac hie ve d. Als o, a patie nt ca n be re- scree ne d if t he y scree n-faile d d ue t o t he ori gi nal 
Sc hir mer I assess me nt e ntr y criteria a n d t he patie nt’ s ori gi nal Sc hir mer sc ore is n o w 
wit hi n t he ne w Sc hir mer I assess me nt e ntr y  criteria wi n d o w.
1 0. 2. 2 
Tr e at me nt P h ase – Vi sit 1 t o Vi sit 3 / D a y 0 t o D a y 3 5
T he d urati o n of t he Tr eat me nt P hase is 3 5 da ys ie, fr o m Baseli ne Visit/ Visit 1 ( Da y 0) t o 
Vi sit 3 ( Da y 3 5). Ra n d o mizati o n t o a treat me nt gr o u p will be c o n d ucte d at Vi sit 1. Sites will 
ra n d o mize eac h s u bject usi n g t he E D C s yste m. T he u n mas ke d site pers o n nel will dis pe nse 
t he a p pr o priate mas ke d st u d y  pr o d uct kit.
Q ualif y i n g s u bjects will recei ve t heir first mas ke d st u d y pr o d uct kit at Visit 1 ( Da y 0). T he 
sec o n d kit will be dis pe nse d at t he V isit 2 ( Da y 1 5). H o we ver, s u bjects ma y ret ur n f or 
a d diti o nal kits if pre vi o us kits were l ost or destr o ye d.
1 0. 2. 2. 1 
R a n d o miz ati o n, Vi sit 1 ( D a y 0/ B aseli ne)
1.
O btai n i nf or mati o n o n a n y  c ha n ges i n me dical healt h a n d/ or t he use of c o nc o mita nt 
me dicati o ns.
2.
T he site staf f will perf or m acc o u nta bilit y , rec or d, a n d c ollect t he n u m ber of use d a n d 
u n use d c o ntai ners of S ali ne.
3.
S u bjects s h o ul d c o m plete t he f oll o wi n g q uesti o n naires:


A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Oc ular Disc o mf ort q uesti o n naire
4.
T he f oll o wi n g assess me nts m ust be c o m plete d O U (see t he M O P
f or details re gar di n g 
eac h assess me nt a n d t he or der of testi n g ). 

Pa ge 3 0 of 5 0

B C V A m ust be meas ure d usi n g a n E T D R S or T u m bli n g E c hart at a dista nce 
of 3 or 4 meters usi n g t he letters rea d met h o d. T he test ma y be perf or me d 
usi n g t he s u bject’s hist orical c orrecti o n. Vis ual ac uit y  testi n g s h o ul d prece de 
a n y e xa mi nati o n re q uiri n g dia g n ostic dr o ps (e g. dilati n g dr o ps) or c o ntact wit h 
t he e ye. B C V A m ust be ≥ 5 5 i n b ot h e y es f or t he s u bject t o q ualif y  f or t he 
st u d y.

Slit -lam p e x a mi nati o n 

L L T assess me nt s

T F B U T O D × 3, O S × 3

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
5.
Re -c o nfir m s u bject eli gi bilit y. Eli gi ble s u bjects m ust ha ve a T F B U T  (s u m of 
3 meas ures ≤ 1 5 sec o n ds at Scree ni n g a n d baseli ne i n t he sa me e ye(s)), a n d B C VA 
( ≥5 5 letters i n eac h e ye at Scree ni n g a n d baseli ne ). T he q ualif yi n g e ye wit h t he 
s h orter mea n T F B U T at baseli ne w o ul d be t he st u d y  e ye. T he sa me st u d y  e ye m ust 
als o ha ve q ualifie d at Scree ni n g.
6.
If t he s u bject d oes n o t q ualif y, t he visit s h o ul d st o p a n d t he s u bject s h o ul d be e xite d 
fr o m t he st u d y as a scree n fail ure.
7. If t he s u bject q ualifies, ra n d o mize t he s u bject a n d o btai n t he mas ke d st u d y pr o d uct kit 
n u m ber(s) t o be dis pe nse d. T he u n mas ke d site staff will retrie ve a n d dis pe nse t he 
assi g ne d mas ke d st u d y pr o d uct kit(s).
8.
T he u n mas ke d site staff will i nstill a si ng le dr o p of t he mas ke d test/c o ntr ol pr o d uct t hat 
was dis pe nse d t o t he s u bject i n eac h e y e. Mas ke d
site pers o n n el m ust n ot be prese nt
w hile t he b ottle of mas ke d test/c o ntr ol pr o d uct is re m o ve d fr o m t he kit a n d
a d mi nistere d.
9.
S u bjects will be i nstr ucte d t o d ose 1 dr o p of t he test/c o ntr ol pr o d uct i n eac h e ye QI D. 
T he last d ose s h o ul d be at be dti me (ie, n o later t ha n mi d ni g ht).
1 0. S u bjects will be i nstr ucte d t o retai n a n d ret ur n all use d a n d u n use d kits at t heir ne xt 
visit.
1 1. Rec or d a n y A Es t hat are o bser ve d or re p orte d, i ncl u di n g t h ose ass ociate d wit h c ha n ges 
i n c o nc o mita nt me dicati o n d osi n g.
1 2. Sc he d ule V isit 2 t o ta ke place 1 5 ± 3 da ys after Vi sit 1.

Pa ge 3 1 of 5 0
1 3. Pr o vi de s u bject wit h Tr eat me nt P hase D osi n g I nstr ucti o ns car d. Pr o vi de St u d y 
I nf or mati o n car d if ori gi nal car d is l ost or u na vaila ble.
1 4. E nter t he s u bject i nf or mati o n a n d visit data i nt o t he E D C s y ste m.
1 0. 2. 2. 2 
Vi sit 2 ( D a y 1 5 ± 3 d a ys)
1.
O btai n i nf or mati o n o n a n y  c ha n ges i n me dical health a n d/ or t he use of c o nc o mita nt 
me dicati o ns.
2.
T he u n mas ke d site staff will perf or m dr u g acc o u nta bilit y, rec or d, a n d c ollect t he kit(s) 
of mas ke d st u d y pr o d uct .
3.
S u bjects s h o ul d c o m plete t he f oll o wi n g q uesti o n naires:


Oc ular Disc o mf ort q ues ti o n naire
4.
T he f oll o wi n g assess me nts m ust be c o m plete d i n b ot h e y es ( O U) (see t he M O P
f or 
details re gar di n g eac h assess me nt a n d or der of testi n g ). 

T he B C V A m ust be meas ure d usi n g a n E T D R S or T u m bli n g E c hart at a 
dista nce of 3 or 4 meters usi n g t he letters rea d met h o d. T he test ma y be 
perf or me d usi n g t he s u bject’s hist orical c orrecti o n. Vis ual ac uit y  testi n g 
s h o ul d prece de a ny e xa mi nati o n re q uiri n g dia g n ostic dr o ps (e g. dilati n g dr o ps) 
or c o ntact wit h t he e y e. 

Slit -lam p e x a mi nati o n
5.
T he u n mas ke d site staff will i nstill a si ng le dr o p of t he mas ke d test/c o ntr ol pr o d uct t hat 
was dis pe nse d t o t he s u bject i n eac h e y e. Mas ke d
site pers o n n el m ust n ot be prese nt
w hile t he b ottle of mas ke d test/c o ntr ol pr o d uct is re m o ve d fr o m t he kit a n d
a d mi nistere d.
6.
T he f oll o wi n g assess me nts m ust be c o m plete d i n b ot h e y es ( O U) (see t he M O P
f or 
details re gar di n g eac h assess me nt a n d or der of testi n g ). 

L L T assess me nt

T F B U T assess me nt

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
7.
T he u n mas ke d site staff will dis pe nse a n a d diti o nal mas ke d st u d y pr o d uct kit.

Pa ge 3 2 of 5 0
8.
S u bjects will be i nstr ucte d t o c o nti n ue t o d ose 1 dr o p of t he test/c o ntr ol pr o d uct i n 
eac h e ye QI D. T he last d ose s h o ul d be at be dti me (ie, n o later t ha n mi d ni g ht).
9.
S u bjects will be i nstr ucte d t o retai n a n d ret ur n all use d a n d u n use d kits at t heir ne xt 
visit.
1 0. R ec or d a n y A Es that are o bser v e d or rep orte d, i ncl u di n g t h ose ass ociat e d wit h c han ges
i n c o nc o m ita nt me dicati o n d osi n g.
1 1. Sc he d ule Vi sit 3 t o ta ke place 3 5 ± 3 da ys after Vi sit 1.
1 2. Pr o vi de s u bject wit h T reat me nt P hase D osi n g I nstr ucti o ns car d a n d pr o vi de St u d y 
I nf or mati o n car d if ori gi nal car d is l ost or u na vaila ble.
1 3. E nter t he s u bject i nf or mati o n a n d visit data i nt o t he E D C s y ste m.
1 0. 2. 2. 3 
Vi sit 3/ Fi n al Vi sit ( D a y 3 5 ± 3 d a ys)
1.
O btai n i nf or m ati o n o n a n y c ha n ges i n me dical healt h a n d/ or t he use of c o nc o mita nt 
me dicati o ns.
2.
C o n d uct uri ne pre g na nc y test o n w o me n of c hil d beari n g p ote ntial. 
3.
S u bjects s h o ul d c o m plete t he f oll o wi n g q uesti o n naires:


Oc ular Disc o mf ort q uesti o n naire 
4.
T he f oll o wi n g assess me nts m ust be c o m plete d i n b ot h e y es ( O U) (see t he M O P
f or 
details re gar di n g eac h assess me nt a n d or der of testi n g ). 

T he B C V A m ust be meas ure d usi n g a n E T D R S or T u m bli n g E c hart at a 
dista nce of 3 or 4 meters usi n g t he letters rea d met h o d. T he test ma y  be 
perf or me d usi n g t he s u bject’s hist orical c orrecti o n. Vis ual ac uit y  testi n g 
s h o ul d prece de a ny e xa mi nati o n re q uiri n g dia g n ostic dr o ps (e g. dilati n g dr o ps) 
or c o ntact wit h t h e e ye. 

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Slit -lam p e x a mi nati o n
5.
T he u n mas ke d site staff will i nstill a si ng le dr o p of t he mas ke d test/c o ntr ol pr o d uct t hat 
was dis pe nse d t o t he s u bject i n eac h e y e. Mas ke d
site pers o n n el m ust n ot be prese nt
w hile t he b ottle of mas ke d test/c o ntr ol pr o d uct is re m o ve d fr o m t he kit a n d
a d mi nistere d.
6.
T he f oll o wi n g assess me nts m ust be c o m plete d O U (see t he M O P
f or details re gar di n g 
eac h assess me nt a n d or der of testi n g ). 

Pa ge 3 3 of 5 0

L L T assess me nts

T F B U T assess me nt

7.
T he u n mas ke d site staff will perf or m dr u g acc o u nta bilit y, rec or d, a n d c ollect all kit(s) 
of st u d y pr o d ucts.
8.
R ec or d a n y A Es that are o bser v e d or rep orte d, i ncl u di n g t h ose ass ociat e d wit h c han ges
i n c o nc o m ita nt me dicati o n d osi n g.
9.
E x it t he s u bject fro m t he st ud y.
1 0. E nt er t he s u bject i nf or mati o n a n d visit data i nt o t he E D C s ys te m.
1 0. 3 
U nsc he d ule d Vi sits
A n y  visit t hat occ urs bet wee n t he re g ularly sc he d ule d visits m ust be d oc u me nte d i n t he 
U nsc he d ule d V isit pa ges of t he case re p ort f or m ( C R F). D uri n g all u nsc he d ule d visits, t he 
f oll o wi n g pr oce d ures m ust be c o n d ucte d :
1.
O bt ai n i nf or mati on o n a n y c h a n ges i n me dic al hea lt h a n d/ or t he use of c on c o mita nt 
me dicati o ns.
2.
T he f oll o wi n g assess me nts m ust be c o m plete d O U (see t he M O P
f or details re gar di n g 
eac h assess me nt). 

B C V A m ust be meas ure d usi n g a n E T D R S or T u m bli n g E c hart at a dista nce 
of 3 or 4 meters usi n g t he letters rea d met h o d. T he test ma y  be perf or me d 
usi n g t he s u bject’s hist orical c orrecti o n. Vis ual ac uit y  testi n g s h o ul d prece de 
a n y e xa mi nati o n re q uiri n g dia g n ostic dr o ps (e g. dilati n g dr o ps) or c o ntact wit h 
t he e ye. 

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Slit -lam p e x a mi nati o n. 
3.
Rec or d a n y A Es t hat are o bser ve d or re p orte d, i ncl u di n g t h ose ass ociate d wit h c ha n ges 
i n c o nc o mita nt me dicati o n d osi n g.
4.
U n mas ke d site staf f will c ollect a n d dis pe nse mas ke d st u d y pr o d uct kits as necessar y.
Ot her assess me nts ma y b e d o ne at t he discreti o n of t he In vest i gat or t o a p pr o priate l ytreat t he 
s u bject. If t he s u bject is disc o nti n ui n g at t he u nsc h e d ule d visit, t he Ear l y E xit C R Fs s h o ul d be 
co m pl ete d rat her t ha n t he C R Fs f or a n U ns c h ed ule d Vi sit a n d t he ap pr o pri at e E x it pr o ced ure 
s h o ul d be c o m plete d as descri be d i n t he f oll o wi n g secti o ns. 

Pa ge 3 4 of 5 0
1 0. 4 
Disc o nti n ue d S u bjects
Disc o nti n ue d s u bjects are t h ose w h o wit h dra w or are wit h dra w n fr o m t he st u d y  after t he 
Scree ni n g V isit. S u bjects ma y disc o nti n ue fr o m t he st u d y at a n y ti me f or a n y reas o n. S u bjects 
ma y  als o be disc o nti n ue d fr o m t he st u d y at a n y ti me if, i n t he o pi ni o n of t he I n vesti gat or, 
t heir c o nti n ue d partici pati o n p oses a ris k t o t heir healt h. Disc o nti n ue d s u bjects will n ot be 
re place d (ie, t heir s u bject n u m bers will n ot be re-assi g ne d/re -use d).
S h o ul d a s u bject e x hi bit a n y  cli nicall y rele va nt si g ns, sy m pt o ms, or ot her cli nical 
o bser vati o ns t hat c o ul d be p ossi bl y  ass ociate d wit h s us pecte d se nsiti vit y or i nt olera nce t o o ne 
of t he st u d y  pr o d uct s, t he In vesti gat or m ust d oc u me nt t h ose o bser vati o ns o n a n A E F or m.
A n y  s u bject w h o e xits earl y fr o m t he st u d y (ie, pri or t o Da y 3 5) m ust u n der g o all t he 
pr oce d ures o utli ne d at Earl y  E xit i n Secti o n 0 .A d diti o nall y , t he E xit F or m m ust be c o m plete d 
a n d o ne of t he f oll o wi n g reas o ns f or disc o nti n uati o n m ust be i de ntifie d: 

Disc o nti n ue d d ue t o Scree n F ail ure

Disc o nti n ue d d ue t o A E

Disc o nti n ue d d ue t o Deat h

Disc o nti n ue d d ue t o L ost t o F oll o w U p

Disc o nti n ue d d ue t o N o n -C o m plia nce wit h St u d y  Dr u g

Disc o nti n ue d d ue t o P h ysicia n Decisi o n

Disc o nti n ue d d ue t o Pre g na nc y

Disc o nti n ue d d ue t o Pr ot oc ol V i olati o n

Disc o nti n ue d d ue t o St u d y  Ter mi nate d b y S p o ns or

Disc o nti n ue d d ue t o T ec h nical Pr o ble ms

Disc o nti n ue d st u d y  d ue t o Wi t h dra wal b y S u bject

A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Disc o nti n ue d d ue t o Ot her Reas o n (s pecif y )
Fi nall y , t o e ns ure t he safet y of all s u bjects w h o disc o nti n ue early,  In vesti gat ors s h o ul d assess 
eac h s u bject a n d, if necessar y, a d vise t he m of a ny t hera pies a n d/ or me dical pr oce d ures t hat 
mi g ht be nee de d t o mai ntai n t heir healt h.

Pa ge 3 5 of 5 0
1 0. 5 
Cli nic al St u d y Te r mi n ati o n
If t he cli nical st u dy is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or will i nf or m t he 
I n vesti gat or a n d t he re g ulat or y a ut h orities (if necessar y ) of t he ter mi na ti o n/ s us pe nsi o n a n d 
t he reas o n(s) f or t he ter mi nati o n/s us pe nsi o n. T he I n vesti gat or s h o ul d pr o m ptl y n otif y t he 
I E C/I R B of t he ter mi nati o n or s us pe nsi o n a n d of t he reas o ns. T he S p o ns or reser ves t he ri g ht 
t o cl ose t he st u d y site or ter mi nate t he st u d y i n its e ntiret y at a n y ti me, f or reas o na ble ca use. 
Reas o ns f or t he cl os ure of a st u d y site or ter mi nati o n of a st u d y m a y i ncl u de: 

S uc cessf ul c o m pleti o n of t he st u d y

T he s t u d y’s e nr oll me nt g oals are met

T he I n vesti gat or fails t o c o m pl y  wit h t he pr ot oc ol or G C P gui deli nes

Safet y  c o ncer ns

S uf ficie nt data s u g gesti n g lac k of efficac y

I na de q uate recr uit me nt of s u bjects b y  t he I n vesti gat or
T he I n vesti gat or ma y  als o ter mi nate t he st u d y at his/ her site f or reas o na ble ca use. If t he 
S p o ns or ter mi nates t he st u d y  f or safet y reas o ns, t he S p o ns or will i m me diatel y  n otif y t he 
I n vesti gat or(s) b y tele p h o ne a n d will s u bse q ue ntl y  pr o vi de writte n c o nfir mati o n of a n d 
i nstr ucti o ns f or st u d y ter mi nati o n. 
1 1 
A N A L Y SI S P L A N
1 1. 1 
S u bject E v al u a bilit y
All s u bjects w h o satisf y  t he i ncl usi o n a n d e xcl usi o n criteria, a n d w h o si g n t he i nf or me d 
c o nse nt f or m, will be c o nsi dere d e val ua ble. 
T he fi nal s u bject e val ua bilit y  will be deter mi ne d pri or t o brea ki n g t he c o de f or mas ke d 
treat me nt assi g n me nt a n d l oc ki n g t he data base. 
1 1. 2 
A n al ysis D at a Sets
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T hree a nal ys is sets will be defi ne d f or t his st u d y: t he Safety A nal ys is Set, F ull A nal y sis Set 
( FA S) a n d Per Pr ot oc ol Set ( P P S). 
T he F A S will i ncl u de all ra n d o mize d s u bjects w h o ha ve at least 1 p ost -baseli ne pri mar y  
e n d p oi nt assess me nt. 

Pa ge 3 6 of 5 0
T he P P S wil l c o nsist of FA S s u bjects w h o satisf y  all i ncl usi o n/e xcl usi o n criteria a n d w h o 
ha ve n o maj or pr ot oc ol de viati o ns, w hic h will be s pecifie d i n t he De viati o ns a n d E val ua bilit y 
Pla n ( D E P).  
T he Safet y A nal ys is Set will i ncl u de all s u bjects e x p ose d t o p ost -ra nd o mizati o n st u d y 
pr o d uct . 
T he pri mar y  a n d sec o n dar y efficac y a nalys es will be perf or me d o n b ot h t he FA S a n d P P S
wit h t he P P S pr o vi di n g t he pri mar y  i nfere nce f or t he n o ni nferi ority h y p ot hesis a n d t he FA S 
pr o vi di n g t he pri mar y  i nfere nce f or t he s u peri ority h y p ot heses.
I n t he e ve nt of a ra n d o mizati o n or dis pe nsi n g err or, s u bjects i n t he Safety A nal y sis Set will be 
a nal yz e d acc or di n g t o t he st u d y pr o d uct t he y recei ve d; h o we ver, s u bjects i n t he FA S will be 
a nal yz e d as ra n d o mize d (re gar dless of t he st u d y pr o d uct t he y recei ve d).
1 1. 3 
De m o gr a p hic a n d B aseli ne C h ar acteristics
De m o gra p hic c haracteristics will be s u m mariz e d b y tr eat me nt gr o u p. T h e f oll o wi n g 
de m o g rap hic ch ar acteristics will be s u m marize d for all d ata sets:
1.
C o nti n u o us baseli ne varia bles: a ge ( years)
2.
Cate g o rical baseli ne var ia bles:

A ge ( < 6 5, ≥ 6 5 ye ars)

Ge n der (fe male, male)

Et h nicit y  ( His pa nic, n ot His pa nic); a n d

Race ( A merica n I n dia n or Alas ka Nati ve, Asia n, Blac k or Africa n A merica n, 
Nati ve Ha waiia n or Ot her Pacific Isla n der , W hite, Ot her)
S u m m ar y statistics (sam ple siz e, mea n, me di a n, sta n dar d de v iati o n (S D ), mi ni m u m a n d 
ma x i m u m f or c o nti n u o us varia bl es a n d s am ple siz e, c o u nts a n d pe rce nta ges f or cat e gori cal 
varia bles) will be pr o vi de d b y tr eat me nt gr o u p . A listi n g of ra n d o mize d treat me nt assi g n me nt 
f or eac h s u bject, t heir e val ua bili t ystat us a n d de m o gra p h ic c haracteristics will be pr o vi de d .
Vi sit 1 ( Baseli ne/ Da y 0) s u m mar y statistics will be pre s ente d o v e rall a n d b y tr eatme nt gr o u p. 
Des cri pti ve statistics (sa m ple size, mean, S D, mi ni m u m a n d ma x i mu m) will be prese nte d b y
treat me nt at Vi sit 1 f or T FB U T , L L T A U C 1 2 0
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
, Gl o bal Oc ular Disc o mf ort V A S sc ore,
 B C VA, a n d slit-la m p e xa mi nati o n.

Pa ge 3 7 of 5 0
1 1. 4 
Effic ac y A n al yses
T he st u d y  e ye will be t he w orst e ye at baseli ne f or eac h para meter. If t he baseli ne val ues are 
e q ui vale nt, t he ri g ht e ye will be selecte d.
1 1. 4. 1 
Pri m ar y Effic ac y
T he pri mar y  o bjecti ve of t his st u d y is t o de m o nstrate n o ni nferi ority of S Y S TA N E 
B A L A N C E o ver R E R E S H O P TI V E A D V A N C E D usi n g T F B U T after 3 5 da ys of QI D d osi n g 
i n s u bjects wit h li pi d -deficie nt dr y  e ye.
T he pri mar y  e n d p oi nt is t he c ha n ge fr o m baseli ne at Da y 3 5 i n T F B U T . T he T F B U T will be 
assesse d at Visit 1 ( Da y 0), Vi sit 2 ( Da y 1 5), a n d Vi sit 3 ( Da y 3 5). 
1 1. 4. 1. 1 
St atistic al H y p ot heses
T he pri mar y  efficac y h yp ot hesis is t hat S Y S TA N E B A L A N C E is n o ni nferi or t o R E F R E S H 
O P TI V E A D V A N C E D wit h res pect t o t he c ha n ge fr o m baseli ne i n T F B U T  at Day 3 5 i n 
s u bjects wit h li pi d -deficie nt dr y e y e.
T he n ull a n d alt er nati ve h yp ot heses are:
H 0: μ   -    ≤ - 1
H 1: μ   -    > - 1
w here μ   a n d μ   de n ote t he mea n c ha n ge fro m baseli ne i n T F B U T at Da y 3 5 f or S Y S T A N E 
B A L A N C E a n d R E F R E S H O P TI V E A D V A N C E D, res pecti vel y.
T he n o ni nferi orit y mar gi n was c h ose n as 1 sec o n d o n t he basis t hat a n i ncrease of at least 
2 5 % i n t he baseli ne T F B U T  of a patie nt wit h li pi d-deficie nt dr y  e ye w o ul d be c o nsi dere d 
cli nicall y mea ni n gf ul si nce t he patie nt w o ul d bli n k less ofte n. Base d o n hist orical data, t he 
mea n T F B U T at baseli ne f or a patie nt wit h li pi d-deficie nt dr y  e ye is a p pr o xi matel y 4 
sec o n ds.
1 1. 4. 1. 2 
A n al ysis Met h o ds
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T he pri mar y  efficac y a nal ysis p o p ulati o n will be t he P PS.
T he a nal ys is of t he pri mar y efficac y para meter, c ha n ge fr o m baseli ne i n T F B U T  at Da y 3 5 i n 
t he st u d y e ye, will be base d o n a mi xe d m o del re peate d meas ures ( M M R M) a nal ys is. T he 
mi xe d m o del will i ncl u de ter ms f or baseli ne T F B U T , treat me nt ( S Y S TA N E B A L A N C E, 

Pa ge 3 8 of 5 0
R E F R E S H O P TI V E A d va nce d ), visit ( Da y 1 5, Da y 3 5), a n d treat me nt-b y - visit i nteracti o n. 
T he res p o nse varia ble is t he c ha n ge fr o m baseli ne i n T F B U T f or t he st u d y e ye.
A n u nst r uct ure d v ariance -c o vari a nce m atri x will be use d t o m o d el t he wit hi n -s u bject 
c orrel ati o n. If t he u nstr uc t ure d varia n ce- c o varian c e matri x res ults i n a lac k of c o n verge n ce 
t he n ot h er c o v ariance str uc t ures will be i n vesti gat e d.
Wi t hi n-treat me nt a n d esti mates of t he differe nce (S Y S T A N E B A L A N C E – R E F R E S H 
O P TI V E A d va nce d ) i n mea n c ha n ge fr o m baseli ne i n T F B U T bet wee n S Y S T A N E 
B A L A N C E a n d R E F R E S H O P TI V E A d va nce d a n d ass ociate d 9 5 % CI will be prese nte d. 
E vi de nce of n o ni nferi orit y will be dee me d esta blis he d if t he l o wer li mit of t he 9 5 % CI f or t he 
dif fere nce is a b o ve - 1. 0.
1 1. 4. 2 
Sec o n d ar y Effic ac y
T he s ec o n dar y efficac y o bjecti ves are:

To  de m o nstrate t hat S Y S T A N E B A L A N C E is s u peri or t o R E F R E S H O P TI V E A d va nce d 
usi n g T F B U T after 3 5 da ys of QI D d osi n g i n s u bjects wit h li pi d -deficie nt dr y  e ye.

To  e val uate c ha n ges i n L L TA U C 1 2 0 f oll o wi n g t he use of S Y S T A N E B A L A N C E vers us 
R E F R E S H O P TI V E A d va nce d after 3 5 da y s of QI D d osi n g i n s u bjects wit h li pi d -
deficie nt dr y  e ye.

To  e val uate c ha n ges i n Gl o bal Oc ular Disc o mf ort usi n g a V A S sc ore f oll o wi n g use of 
S Y S T A N E B A L A N C E vers us R E F R E S H O P TI V E A d va nce d after 3 5 da ys of QI D 
d osi n g i n s u bjects wit h li pi d -deficie nt dr y  e ye.
T he sec o n dar y  efficac y e n d p oi nts are:

C ha n ge fr o m baseli ne i n T F B U T at Da y 3 5 

L L T A U C 1 2 0 at Da y 3 5

C ha n ge fr o m baseli ne i n Gl o bal Oc ular Disc o mf ort V A S sc ore at Da y  3 5
1 1. 4. 2. 1 
St atistic al H y p ot heses
T he h y p ot heses f or t he sec o n dar y  a nalys is are:

S Y S T A N E B A L A N C E is s u peri or t o R E F R E S H O P TI V E A d va nce d wit h res pect t o 
c ha n ge fr o m baseli ne i n T F B U T at Da y 3 5

S Y S T A N E B A L A N C E is s u peri or t o R E F R E S H O P TI V E A d va nce d wit h res pect t o L L T 
A U C 1 2 0
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
at Da y 3 5

Pa ge 3 9 of 5 0

S Y S T A N E B A L A N C E is s u peri or t o R E F R E S H O P TI V E A d va nce d wit h res pect t o 
c ha n ge fr o m baseli ne i n Gl o bal Oc ular Disc o mf ort V A S sc ore at Da y  3 5
T he n ull a n d alter nati ve h y p ot heses f or t he first sec o n dar y e n d p oi nt are:
H 0:    -    ≤ 0
H 1:    -    > 0 w her e μ   a n d μ   de n ote t he mea n c han ge fr o m baseli ne i n T F B U T at 
Da y 3 5 f or S Y S T A N E B A L A N C E a n d R E F R E S H O P TI V E A d va nce d, res pecti vel y .
T he n ull a n d alter nati ve h y p ot heses f or t he sec o n d sec o n dar y e n d p oi nt are:
H 0:    -    ≤ 0
H 1:    -    > 0
w here μ   a n d μ   de n ote t he mea n L L T A U C 1 2 0 at Da y 3 5 f or S Y S T A N E B A L A N C E a n d 
R E F R E S H O P TI V E A d va nce d, res pecti vel y .
T he n ull a n d alter nati ve h y p ot heses f or t he t hir d sec o n dar y e n d p oi nt are:
H 0: µ S B - µO A 0
H 1: µ S B - µO A < 0
w here μ   a n d μ   de n ote t he mea n c ha n ge fr o m baseli ne i n V A S sc ore at Da y  3 5 f or 
S Y S T A N E B A L A N C E a n d R E F R E S H O P TI V E A d va nce d, res pecti vel y .
1 1. 4. 2. 2 
A n al ysis Met h o ds
T he a nal ys is of t he sec o n dar y efficac y para meter L L T A U C 1 2 0
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
at Da y 3 5, a n d c ha n ge fr o m 
baseli ne i n Gl o bal Oc ular Disc o mf ort VA S sc ore at Da y  3 5, a n d c ha n ge fr o m baseli ne of t he 
T F B U T at Da y 3 5 will be base d o n a M M R M. T he mi xe d m o del will i ncl u de ter ms f or 
baseli ne para meter val ues, treat me nt, visit ( Da y 1 5, Da y  3 5), a n d treat me nt-b y -visit 
i nteracti o n. Esti mates of t he differe nce i n mea n c ha n ge fr o m baseli ne bet wee n S Y S T A N E 
B A L A N C E a n d R E F R E S H O P TI V E A d va nce d a n d ass ociate d 9 5 % CIs will be prese nte d. 
Eac h e n d p oi nt will be e val uate d f or s u peri orit y of S Y S T A N E B A L A N C E o ver R E F R E S H 
O P TI V E A d va nce d. T he p- val ue fr o m t he o ne-si de d test less t ha n 0. 0 2 5 f or a dif fere nce i n 
fa v or of S Y S TA N E B A L A N C E will i n dicate s u peri orit y of S Y S T A N E B A L A N C E o ver 
R E F R E S H O P TI V E A d va nce d.

Pa ge 4 0 of 5 0
1 1. 5 
H a n dli n g of Missi n g D at a
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T he mi xe d -effects re peate d meas ures ( M M R M ) m o del a p pr oac h will be use d t o a nal yze t he 
c o nti n u o us varia bles. T he M M R M m o del is s uita ble f or l o n git u di nal data wit h missi n g val ues 

Pa ge 4 1 of 5 0
u n der t he missi n g at ra n d o m ( M A R ) ass u m pti o n. It is a li keli h o o d-base d a nal ysis t hat ca n 
pr o vi de vali d i nfere nce wit h o ut t he nee d f or e x plicit m o deli n g or i m p utati o n of missi n g data .
1 1. 6   
M ulti plicit y
To  e ns ure o verall c o ntr ol of t he t ype I err or rate, t he sec o n dar y  efficac y h y p ot heses will be 
rele va nt o nly if t he pri mar y ef ficac y n ull h y p ot hesis is first rejecte d at t he 5 % le vel of 
si g nifica nce ( 2-si de d). F oll o wi n g t he rejecti o n of t he pri mar y efficac y n ull h yp ot he sis, t he 
sec o n dar y h yp ot heses will be teste d f oll o wi n g t he H oc h ber g testi n g pr oce d ure.
 
1 1. 7 
S afet y A n al ysis
T he safet y e n d p oi nts i n t his st u d y are:

A Es

B C V A

Slit -la m p e xa mi nati o n (c or nea, le ns, iris a n d a nteri or c ha m ber)
T he safet y a nal ys es will c o nsist of s u m maries of t he A Es a n d meas ure d safet y  para meter 
data. T his will i ncl u de s u m maries of B C VA a n d slit-la m p i n a d diti o n t o A Es. T he statistics 
prese nte d f or eac h e n d p oi nt will be rele va nt t o t he meas ure of t he val ue, ie, w het her t he data 
are cate g orical or n u meric. C o nti n u o us meas ure me nts will be prese nte d usi n g n u m ber , mea n, 
sta n dar d de viati o n, mi ni m u m a n d ma xi m u m at eac h visit. Cate g orical meas ure me nts will be 
ta b ulate d wit h t he n u m ber a n d perce nt of s u bjects i n eac h cate g or y at eac h visit. N o 
i nfere ntial testi n g will be perf or me d f or t he safety a nal ys es.
1 1. 8 
He alt h Ec o n o mics
N ot a p plica ble.
1 1. 9 
I nteri m A n al yses
N ot a p plica ble.
1 1. 1 0 
S a m ple Size J ustific ati o n
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
I n t his st u d y, a p pr o xi matel y 2 2 0 s u bjects will be ra n d o mize d t o S Y S T A N E B A L A N C E or 
R E F R E S H O P TI V E A d va nce d i n a 1 : 1 rati o i n or der t o ac hie ve 2 0 0 e val ua ble s u bjects. A 
t otal of 2 0 0 s u bjects pr o vi des a p pr o xi matel y 8 0 % p o wer t o reject t he n ull h yp ot hesis of 

Pa ge 4 2 of 5 0
i nferi orit y of mea n c ha n ge fr o m baseli ne i n T F B U T at t he 0. 0 2 5 le vel of si g nifica nce 
( 1-si de d), ass u mi n g a treat me nt differe nce of 0. 0, a sta n dar d de viati o n of 2. 5, a n d a 
n o ni nferi orit y  mar gi n of 1. 0 sec o n d.
Ta ble 1 1 – 1 s h o ws t he sa m ple size re q uire d t o ac hie ve 8 0 % a n d 9 0 % p o wer wit h dif fere nt 
ass u me d val ues of sta n dar d de viati o n.
Ta ble 11 – 1 
S a m ple Size C alc ul ati o n
P o wer 
Ass u me d 
st a n d ar d de vi ati o n
S a m ple size 
(t ot al e v al u a ble)
8 0 %
2. 5
2 0 0
2. 7 5
2 4 0
3. 0
2 8 6
9 0 %
2. 5
2 6 6
2. 7 5
3 2 0
3. 0
3 8 2
1 2 
C O L L E C TI O N O F  C O M P L AI N T S
1 2. 1 
Ge ner al I nf or m ati o n
A d verse E ve nt 
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject w h o is a d mi nistere d a st u d y pr o d uct
re gar dless of w het her or n ot t he e ve nt has a ca usal relati o ns hi p wit h t he treat me nt. A n A E, 
t heref ore, ca n be a ny u nfa v ora ble or u ni nte n de d si g n (i ncl u di n g a n a b n or ma l la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y  ass ociate d wit h t he st u d y pr o d uct, w het her or n ot 
relate d t o t he treat me nt. I n cli nical st u dies, a n A E ca n i ncl u de a n u nt o war d me dical 
occ urre nce occ urri n g at a n y  ti me, i ncl u di n g r u n-i n or was h o ut peri ods, e ve n if n o st u d y 
pr o d uct has bee n a d mi nistere d. T he deter mi nati o n of cli nical rele va nce is base d u p o n t he 
me dical j u d g me nt of t he I n vesti gat or.
Q u alit y C o m pl ai nts 
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Deficie nc y  of a pr o d uct i ncl u des i na de q uac y wit h res pect t o its i de ntit y , q ualit y, d ura bilit y, 
relia bilit y, safety or perf or ma nce. N ote: T his defi niti o n i ncl u des malf u ncti o ns, use err ors, a n d 
i na de q uate la beli n g.

Pa ge 4 3 of 5 0

Malf u ncti o n is defi ne d as a fail ure of a pr o d uct t o meet its perf or ma nce s pecificati o ns or 
ot her wise perf or m as i nte n de d. Perf or ma nce s pecificati o ns i ncl u de all clai ms ma de i n t he 
la beli n g of t he pr o d uct. T he i nte n de d perf or ma nce of t he pr o d uct refers t o t he i nte n de d 
use f or w hic h it is la bele d or mar kete d.
Use err or is defi ne d as t he act or o missi o n of a n act t hat res ults i n a dif fere nt me dical de vice 
res p o nse t ha n i nte n de d b y ma n ufact urer or e x pecte d b y user.
A d verse Dr u g/ De vice Effect ( A D E)
A n A D E is defi ne d as a n A E relate d t o t he use of st u d y pr o d uct. N ote: T his defi niti o n 
i ncl u des A E s res ulti n g fro m i ns ufficie nt or i n a de q u ate i nstr ucti o ns f or use, de pl oy me nt, 
i m pl a nt ati o n, i nst all ati o n, or o per ati o n; a ny m alf u ncti o n; a n d use error or i nte nti o n al mis use 
of t he st u dy pro d uct .
Seri o us A d verse E ve nt ( S A E)
A d verse e ve nt t hat le d t o a n y  of t he f oll o wi n g:

Deat h

A seri o us deteri orati o n i n healt h t hat eit her res ulte d i n:
a.
A life-t hreate ni n g ill ness or i nj ur y.
N ote: Life -t hre ate ni n g me a ns t h at t he i n divi d u al w as at i m me di ate risk of de at h 
fro m t he eve nt as it occ u rre d, ie, it d oes n ot i ncl u de a n eve nt w hic h hy p ot hetic ally 
mi g ht h ave c a use d de at h h a d it occ urr e d i n a m ore severe f or m.
b.
A n y p ote ntiall y si g ht -t hreate ni n g e ve nt or per ma ne nt i m pair me nt t o a b o d y 
str uct ure or a b o dy f u ncti o n.
c.
I n- patie nt h os pitalizati o n or pr ol o n ge d h os pitalizati o n
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
N ote: Pl a n ne d h os pit aliz ati o n f or a p re-existi n g c o n diti o n, or a p roce d u re
re q uire d by t he cli nic al i nvesti g ati o n pl a n, wit h o ut seri o us deteri or ati o n i n 
he alt h, is n ot c o nsi der e d a S A E . I n ge ner al, h os pit aliz ati o n si g nifies t h at t he 
i n divi d u al re m ai ne d at t he h os pit al or e me rge ncy w a rd f or o bserv ati o n a n d/ or 
tre at me nt ( us u ally i nv olvi n g a n over ni g ht st ay) t h at w o ul d n ot h ave bee n 
a p pr o pri ate i n t he p hysici a n's office or a n o ut- p atie nt setti n g. C o m plic ati o ns t h at 
occ ur d uri n g h os pit aliz ati o n a re A Es. If a c o m plic ati o n p rol o n gs h os pit aliz ati o n 

Pa ge 4 4 of 5 0
or f ulfills a ny ot her seri o us criteri a, t he eve nt is seri o us. W he n i n d o u bt as t o 
w het her “ h os pit aliz ati o n ” occ ur re d, t he eve nt s h o ul d be c o nsi de re d seri o us.
d.
A me dical i nter ve nti o n t o pre ve nt a) or b), or a n y s urgi cal i nter ve nti o n.
e.
A n y  i n direct har m as a c o nse q ue nce of i nc orrect dia g n ostic test res ults w he n use d 
wit hi n ma n ufact urer's i nstr ucti o ns f or use.

Fetal distress, fetal deat h, or a c o n ge nital a b n or malit y  or birt h defect.
N ote: T his i ncl u des q ualit y c o m plai nts t hat mi g ht ha ve le d t o a S A E if:
a.
s uita ble acti o n ha d n ot bee n ta ke n or
b.
i nter ve nti o n ha d n ot bee n ma de or
c.
circ u msta nces ha d bee n less f ort u nate. T hese are ha n dle d u n der t he S A E re p orti n g 
s yste m.

Is a n i m p orta nt me dical e ve nt. A n i m p orta nt me dical e ve nt is a n e ve nt 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 b ut ma y be c o nsi dere d a n S A E 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, it 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 nt o ne of t he o utc o mes liste d i n t he 
defi niti o ns f or S A Es. E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ul t i n a s u bject’s h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de nc y  or dr u g a b use.
Seri o us P u blic He alt h T hr e at
A n y  e ve nt ty pe w hic h res ults i n i m mi ne nt ris k of deat h, seri o us deteri orati o n i n state of 
healt h, or seri o us ill ness t hat re q uires pr o m pt re me dial acti o n. T his w o ul d i ncl u de e ve nts t hat 
are of si g nifica nt a n d u ne x pecte d nat ure s uc h t hat t he y  bec o me alar mi n g as a p ote ntial p u blic 
healt h hazar d, e g, h u ma n i m m u n o deficie nc y  vir us ( HI V) or Cre utzfel dt-Jac o b Disease ( CJ D).
N o nseri o us a d verse e ve nt
A n y  A E t hat d oes n ot meet seri o us ness criteria descri be d a b o ve.
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
C o ntri b ut or y c a use (c a us alit y assess me nt)

Pa ge 4 5 of 5 0
I n assessi n g t he ass ociati o n of t he de vice/ pr o d uct t o t he e ve nt, t he f oll o wi n g s h o ul d be ta ke n 
i nt o acc o u nt:

T he o pi ni o n, base d o n a vaila ble e vi de nce, of healt hcare pr ofessi o nals

T he res ults of t he preli mi nar y  assess me nt of t he e ve nt

E vi de nce of pre vi o us, si milar e ve nts
T his j u d g me nt ma y  be diffic ult w he n t here are m ulti ple de vices/ pr o d ucts a n d dr u gs i n v ol ve d. 
I n c o m ple x sit uati o ns, it s h o ul d be ass u me d t hat t he de vice ma y ha ve ca use d or c o ntri b ute d t o 
t he e ve nt a n d t he M A N U FA C T U R E R S s h o ul d err o n t he si de of ca uti o n.
Refer e nce S afet y I nf or m ati o n
F or S A Es p ote ntiall y  q ualif yi n g e x pe dite d re p orti n g, t he f oll o wi n g will ser ve as t he refere nce 
safety i nf or mati o n f or t he p ur p oses of deter mi ni n g e x pecte d ness:

Pr o d uct La bel f or S Y S T A N E B A L A N C E
1 2. 2 
M o nit ori n g f or A d verse E ve nts
At eac h visit, after t he s u bject has ha d t he o p p ort u nit y t o s p o nta ne o usly me nti o n a n y 
pr o ble ms, t he I n vesti gat or s h o ul d i n q uire a b o ut A Es b y  as ki n g t he sta n dar d q uesti o ns:

“ Ha ve y o u ha d a n y healt h pr o ble ms si nce t he last st u d y  visit?”

“ Ha ve t here bee n a n y c ha n ges i n t he me dici nes y o u ta ke si nce t he last st u d y visit?” 
A Es s h o ul d be re p orte d f or a n y cli nicall y rele va nt c ha n ge i n c o nc o mita nt me dicati o n(s) t hat 
is t he res ult of a n u nt o war d ( u nfa v ora ble a n d u ni nte n de d) c ha n ge i n a s u bject’s me dical 
healt h.
C ha n ges i n a n y pr ot oc ol s pecific para meters a n d q uesti o n naires (if a p plica ble) e val uate d 
d uri n g t he st u d y are t o be re vie we d b y t he I n vesti gat or. A n y u nt o war d ( u nfa v ora ble a n d 
u ni nte n de d) c ha n ge i n a pr ot oc ol s pecific para meter or q uesti o n naire res p o nse t hat is 
cli nicall y rele va nt is t o be re p orte d as a n A E. T hese cli nicall y rele va nt c ha n ges will be 
re p orte d re gar dless of ca usalit y.
1 2. 3 
Pr oce d u res f or Rec or di n g a n d Re p orti n g
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
S u bse q ue nt t o si g ni n g a n i nf or me d c o nse nt f or m, all u nt o war d me dical occ urre nces t hat 
occ ur d uri n g t he c o urse of t he st u d y m ust be d oc u me nte d o n a n A d verse E ve nt F or m ( A E F). 
A se parate A E F m ust be file d o ut f or eac h e ve nt. W he n p ossi ble, si g ns a n d s y m pt o ms 

Pa ge 4 6 of 5 0
i n dicati n g a c o m m o n u n derl yi n g pat h ol o g y s h o ul d be d oc u me nte d as o ne c o m pre he nsi ve 
e ve nt. F or eac h rec or de d e ve nt, t he A E d oc u me nt ati o n m ust i ncl u de t he o nset date, o utc o me, 
res ol uti o n date (if e ve nt is res ol ve d), i nte nsit y, (ie, se verity), a n y acti o n wit h st u d y pr o d uct
ta ke n as a res ult of t he e ve nt, a n d a n assess me nt of t he A E’ s relati o ns hi p t o t he st u d y pr o d uct.
Re p orti n g Seri o us A d verse E ve nts 
All a v ail a ble i nf or m ati o n o n S A E (s) a n d a n y ot her ass oci ate d A E, if a p plic a ble, m ust be 
f or w ar de d t o t he st u d y S p o ns or i m me di atel y (ie, wit hi n 2 4 h o urs of t he I n vesti g at or’s or 
site’s k n o wle d ge of t he e ve nt) as f oll o ws: I n st u dies utilizi n g E D C, all a vaila ble i nf or mati o n 
f or t he S A E a n d a ny ass ociate d A E(s) m ust be e ntere d i m me diatel y i nt o t he E D C s yste m.
N O T E: S h o ul d t he E D C syste m bec o me n o n - o per ati o n al, t he site m ust c o m plete t he 
a p pr o pri ate p a per Seri o us A dverse Eve nt F or m. T he c o m plete d f or m is c o m m u nic ate d t o t he 
st u dy S p o ns or eit her by f ax at 
 or by e m ail at
 wit hi n 2 4 h o urs of t he I nvesti g at or’s or site’s a w are ness, 
h o wever, t he re p orte d i nf or m ati o n m ust be e ntere d i nt o t he E D C syste m o nce i t bec o mes 
o per ati o n al.
A d diti o nal i nf or mati o n f or a n y a p plica ble e ve nt is t o be re p orte d as s o o n as it bec o mes 
a vaila ble. A n y c o m plai nts fr o m t he s u bject o n a past e ve nt pre vi o us t o i nitiati o n of t he st u d y 
b ut t hat is res ol ve d at t he ti me of t he first visi t m ust be re p orte d t o Alc o n f oll o wi n g t he us ual 
p har mac o vi gila nce circ uit.
Re p orti n g Q u alit y C o m pl ai nts
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
A n y  malf u ncti o n or q ualit y c o m plai nt, w hic h occ urs d uri n g t his st u d y m ust be re p orte d 
wit hi n 1 0 cale n dar da y s via data e ntr y  wit hi n t he cli nical st u d y E D C s ys te m or b y fa x t o t he 
S p o ns or i n t he e ve nt t hat electr o nic data e ntr y  is n ot p ossi ble. See t he M O P
f or t he list of 
St u d y  Staff pers o n nel t o c o ntact.
T he I n vesti gat or will be as ke d t o deter mi ne w het her t he y  belie ve t he st u d y pr o d uct was 
ass ociate d wit h, or c o ntri b ute d t o, t he e ve nt. T his i nf or mati o n is t o be d oc u me nte d via data 
e ntr y wit hi n t he cli nical st u d y E D C s ys te m.
T he S p o ns or ’s Me dical Safety De part me nt is res p o nsi ble f or arc hi vi n g a n d s u b mitti n g all 
re p orta ble q ualit y c o m plai nts a n d A Es t o t he a p pr o priate re g ulat or y  a ut h orities.

Pa ge 4 7 of 5 0
1 2. 4 
I nte nsit y a n d C a us alit y Assess me nts
F or e v er y A E, t h e In ves tigat or m ust assess th e serio us ness, i nte nsit y (sev erity) a n d ca us ality 
(relati o ns hi p t o st u d y pr o d uct). S pecifi call y, e vents s h o ul d be classifie d as mil d, m o derate, or
se vere. T he assess ment of ca usali t ywill be bas e d u p o n t he cate g ories of re late d a n d n ot 
relate d. A n assess me nt of ca u sality will als o be perf or me d b y S p o ns or p h y sician utilizi n g t he
sa me d e fi niti o ns. T hese classificati o ns s h o ul d be base d o n t he f oll o wi n g defi niti o ns:
I ntensit y ( S e verit y):

Mil d 
A n e ve nt is mil d if t he s u bject is a war e of, b ut ca n easil y t olerate t he sig n or
s ym pt o m.

M o d erate A n e ve nt is m o d erat e if the sig n or s ym pt o m res ults i n dis c o mf ort sig nifi cant
e n o u g h t o ca use i nterfere nce wit h t he su bj ect’s us u al acti vities.

Se ver e   
A n e ve nt is se vere if t he si gn or s ym pt o m is i nca pacitati ng a nd res ults in t he
s u bject’s i nab ility t o w o r k o r e n ga ge i n t heir us ua l acti vities.
C a us ali t y:

Relate d   
A n A E c o nsi dered related t o t he use of t he st u d y pr o d uct.
A d v erse e vents classifie d as relate d m a y b e eit her d efinit el y relate d or p ossi bl y relate d w he re
a direct ca use a n d effect relatio ns h i p b e t wee n th e st u d y pr o d uct a n d the e ve nt has n ot be e n
de m o nstrat e d b ut there is a reas o na bl e p ossi bili t y t hat t he e ve nt was caus e d b y t h e st u d y 
pr o d uct .

N ot Relate d 
A n A E c o nsidere d u nrel at e d to t he use of t he st u d y pr o d uct. A d v erse
e ve nts classifie d as n ot related ma y e ither b e d efinit el y u nre late d or
si m ply u nli k el y t o be related (ie, t her e ar e ot h er more likel y ca uses f or
t he A E ).
F or a S A E re p orte d by a n In vesti gat or as n ot relate d t hat u p o n re vie w of t he a vaila ble data b y  
t he S p o ns or p h y sicia n is assesse d ( u p gra de d) t o be relate d, t he I n vesti gat or will recei ve a 
n otificati o n.
1 2. 5 
U n m as k i n g of t he St u d y I nf or m ati o n
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Mas ke d i nf or mati o n o n t he i de ntit y  of t he assi g ne d st u d y pr o d uct s h o ul d n ot be discl ose d 
d uri n g t he st u d y.  If t he treat me nt c o de nee ds t o be br o ke n i n t he i nterest of s u bject safety,  t he 
I n vesti gat or is e nc o ura ge d t o c o ntact a n a p pr opriate S p o ns or re prese ntati ve pri or t o 
u n mas ki n g t he i nf or mati o n if t here is s uf ficie nt ti me. De pe n di n g u p o n t he i n di vi d ual 

Pa ge 4 8 of 5 0
circ u msta nces (ie, me dical e mer ge nc y), t he c o de ma y be br o ke n pri or t o c o nta ct wit h t he 
S p o ns or . T he S p o ns or m ust be i nf or me d i n all cases i n w hic h t he c o de was br o ke n a n d of t he 
circ u msta nces i n v ol ve d. A d diti o nall y , t he S p o ns or ma y be re q uire d t o u n mas k t he 
i nf or mati o n i n or der t o f ulfill e x pe dite d re g ulat or y re p orti n g re q uire me nts.
1 2. 6 
F oll o w -U p of S afet y I nf or m ati o n
T he I n vesti gat or is res p o nsi ble f or a de q uate a n d safe me dical care of s u bjects d uri n g t he 
st u d y a n d f or e ns uri n g t hat a p pr o priate me dical care a n d rele va nt f oll o w -u p pr oce d ures are 
mai ntai ne d after t he st u d y. A n y a d diti o nal data fr o m t hese f oll o w- u p pr oce d ures m ust be 
d oc u me n te d a n d a vaila ble t o t he S p o ns or w h o will deter mi ne w he n t he data nee d t o be 
d oc u me nte d o n t he case re p ort f or ms.
1 2. 7  
Pre g n a nc y i n t he Cli nic al St u d y
Wo me n w h o are pre g na nt or breast -fee di n g are e xcl u de d fr o m partici pati o n i n t he st u d y. 
Wo me n of c hil d beari n g p ote ntial or w o me n c o nsi dere d p ost -me n o pa usal are n ot e xcl u de d 
fr o m t he st u d y as l o n g as a de q uate birt h c o ntr ol met h o ds are bei n g utilize d. All w o me n of 
c hil d beari n g p ote ntial are re q uire d t o use a de q uate birt h c o ntr ol met h o ds w hic h are 
s u m marize d i n t he prot oc ol’s e xcl usi o n criteria.
Pri or t o cli nical st u d y e nr oll me nt, fe male s u bjects of c hil d beari n g p ote ntial m ust be a d vise d 
of t he i m p orta nce of a v oi di n g pre g na nc y  d uri n g t he st u d y a n d t he p ote ntial ris ks ass ociate d 
wit h a n u ni nte nti o nal pre g na nc y . D uri n g the st u d y, fe male s u bjects are t o be i nstr ucte d t o 
c o ntact t he I n vesti gat or i m me diatel y if t he y s us pect t he y mi g ht be pre g na nt. S p o ns or m ust be 
c o ntacte d i m me diatel y,  treat me nt disc o nti n ue d, a n d t he s u bject e xite d fr o m t he st u d y.
I n a d diti o n, c o m plicati o ns of pre g na nc y  ma y be re p orta ble a n d will be deci de d o n a case b y 
case basis. A S p o ns or pre pare d f or m will be utilize d t o ca pt ure all pre g na nc y  relate d 
i nf or mati o n u ntil t he o utc o me of t he pre g na nc y.
1 3 
D A T A  H A N D LI N G A N D A D MI NI S T R A TI V E 
R E Q UI R E M E N T S
1 3. 1 
C o m pleti o n o f S o urce D oc u me nts a n d C ase Re p ort F or ms
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T he nat ure a n d l ocati o n of all s o urce d oc u me nts will b e i de ntifie d t o e ns ure t hat ori gi nal data 
re q uire d t o c o m plete t he C R Fs e xist a n d are accessi ble f or verificati o n b y t he site m o nit or. If 
electr o nic rec or ds are mai ntai ne d, t he met h o d of verificati o n m ust be deter mi ne d i n a d va nce 
of starti n g t he st u d y.  

Pa ge 4 9 of 5 0
At a mi ni m u m, s o urce d oc u me nts s h o ul d i ncl u de t he f oll o wi n g i nf or mati o n f or eac h s u bject:

S u bject i de ntificati o n ( na me, se x, race/et h nicit y)

D oc u me ntati o n of s u bje ct eli gi bilit y

Date of i nf or me d c o nse nt

Dates of visits

D oc u me ntati o n t hat pr ot oc ol s pecific pr oce d ures were perf or me d

Res ults of st u d y  para meters, as re q uire d by t he pr ot oc ol

St u d y me dicati o n acc o u nta bilit y  rec or ds

D oc u me ntati o n of A Es a n d ot her safet y para meters (if a p plica ble)

Rec or ds re gar di n g me dical hist ories a n d t he use of c o nc o mita nt t hera pies pri or t o a n d 
d uri n g t he st u d y

Date of st u d y c o m pleti o n a n d reas o n f or earl y disc o nti n uati o n, if a p plica ble
It is re q uire d t hat t he a ut h or of a n e ntr y i n t he s o urce d oc u me nts be i de ntifia ble. Direct access 
t o s o urce d oc u me ntati o n ( me dical rec or ds) m ust be all o we d f or t he p ur p ose of verif yi n g t hat 
t he data rec or de d o n t he C R F are c o nsiste nt wit h t he ori gi nal s o urce data. 
Case re p ort f or ms will be pr o vi de d t o t he sites (electr o nic); o nl y desi g nate d i n di vi d uals ma y 
c o m plete t he C R Fs. T he C R Fs will be s u b mitte d at re g ular i nter vals base d u p o n t he cli nical 
st u d y visit sc he d ule. It is e x pecte d t hat all data re p orte d will ha ve c orres p o n di n g e ntries i n t he 
s o urce d oc ume nts a n d t hat t he Pri nci pal I n vesti gat or will re vie w t he re p orte d data a n d certif y  
t hat t he C R Fs are acc urate a n d c o m plete. N o s u bject i de ntifiers s h o ul d be rec or de d o n t he 
C R Fs be y o n d s u bject n u m ber , a n d de m o gra p hic i nf or mati o n. 
1 3. 2   
D at a Re vie w a n d Cl arific ati o ns
T he C R F data will be re vie we d a gai nst t he s u bject’ s s o urce data by t he st u d y m o nit ors t o 
e ns ure c o m plete ness a n d acc urac y. After m o nit ori n g has occ urre d at t he cli nical sites a n d t he 
C R Fs ha ve bee n s u b mitte d, a d diti o nal data clarificati o ns a n d/ or a d diti o ns ma y  be nee de d. 
Data clarificati o ns a n d/ or a d diti o ns are d oc u me nte d a n d are part of eac h s u bject’ s C R Fs.
1 3. 3 
Re g ul at or y D oc u me nt ati o n a n d Rec or ds Rete nti o n
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
T he I n vesti gat or is re q uire d t o mai ntai n u p- t o-date, c o m plete re g ulat or y  d oc u me ntati o n as 
i n dicate d b y t he S p o ns or a n d t he I n vesti gat or ’s files will be re vie we d as part of t he o n g oi n g 

Pa ge 5 0 of 5 0
st u d y m o nit ori n g. Fi na ncial i nf or mati o n is n ot s u bject t o re g ulat or y i ns pecti o n a n d s h o ul d be 
ke pt se paratel y. 
A d diti o nall y , t he I n vesti gat or m ust kee p st u d y rec or ds a nd s o urce d oc u me nts u ntil t he 
S p o ns or pr o vi des writte n a p pr o val f or t heir destr ucti o n. If t he I n vesti gat or retires, rel ocates, 
or f or a n y ot her reas o n wit h dra ws fr o m res p o nsi bilit y  of kee pi n g t he st u d y rec or ds, t he 
S p o ns or m ust be n otifie d a n d s uita ble arra n ge me nts ma de f or rete nti o n of st u d y  rec or ds a n d 
s o urce d oc u me nts nee de d t o c o m pl y wit h nati o nal a n d i nter nati o nal re g ulati o ns ( ge nerally 
2 ye ars after disc o nti n ui n g cli nical de vel o p me nt or after t he l atest mar keti n g a p pr o val).
1 4 
Refere nces
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7
Le m p M A, Ba u d o ui n C, Ba u m J, D o g ur M, F o ul ks G N, et al. T he defi niti o n a n d 
classificati o n of dr y e ye disease: Re p ort of t he Defi niti o n a n d Classificati o n S u bc o m mittee of 
t he Inter nati o nal Dr y  E ye W or ks h o p . Oc ul S urf. 2 0 0 7; 5: 7 5- 9 2.
S mit h J A, Al beitz J, Be g le y C, Caffery B, Nic h ols K, Sc ha u m ber g D, et al. T he 
e pi de mi ol o g y of dr y e ye disease: Re p ort of t he E pi de mi ol o g y  S u bc o m mittee of t he 
I nter nati o nal Dr y E ye W or ks h o p . Oc ul S urf. 2 0 0 7 ; 5: 9 3– 1 0 7.
Sc ha u m ber g D A, Nic h ols JJ, Pa pas E B, T o n g L, Uc hi n o M, Nic h ols K K. T he i nter nati o nal 
w or ks h o p o n mei b o mia n gla n d d ys f u ncti o n: re p ort of t he s u bc o m mittee o n t he e pi de mi ol o g y 
of, a n d ass ociate d ris k fact ors f or , M G D. I n vest O p ht hal m ol Vis Sci. 2 0 11 ; 5 2( 4): 1 9 9 4- 2 0 0 5.

                                                                                                                
                                                                                     
D at e/ Ti m e 
( m m/ d d/ y y y y G M T): 
Si g n e d b y:
J u stifi c ati o n :
0 3/ 0 8/ 2 0 1 7 1 2: 4 7: 4 7
0 3/ 0 7/ 2 0 1 7 0 3: 1 6: 3 8
0 3/ 0 6/ 2 0 1 7 1 4: 2 0: 1 7
0 3/ 0 6/ 2 0 1 7 0 8: 2 0: 0 1
A l c o n - B usi n ess  Us e  O nl y  
 
Eff e cti v e  D at e:   
D o c u m e nt:   
V e rsi o n:   
St at us:   E f f e c t i v e
Pri nt e d  B y:  
Pri nt  D at e:   
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 1 7 8 3
P r o t o c o l  -  C l i n i c a l
0 9- Mar- 2 0 1 7