Conditions: Open-angle Glaucoma Ocular Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 173
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the additive intraocular pressure (IOP) lowering effect of Brinzolamide 1%/Brimonidine 0.2% (SIMBRINZA®) dosed twice daily (BID) when added to Travoprost 0.004%/Timolol 0.5% (DUOTRAV®) in subjects with open-angle glaucoma or ocular hypertension.

Detailed description:
This study is divided into 2 sequential phases for a total of 5 visits. Phase I of the study is the open-labeled Screening/Eligibility Phase, which includes a Screening Visit followed by 2 Eligibility Visits. Phase II of the study is the randomized, double-masked Treatment Phase, which includes 2 on-therapy visits: Visit 4 (at Week 2) and Visit 5 (Week 6, Exit Visit).

Arms:
arm 1: Brinzolamide 1%/brimonidine tartrate 0.2% ophthalmic suspension, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00 hrs) plus travoprost 0.004%/timolol 0.5% solution, 1 drop instilled in the affected eye(s) daily in the morning (at 9:00) or in the evening (at 21:00) for 42 days (Treatment Phase) arm 2: Brinzolamide/brimonidine vehicle, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00 hrs) plus travoprost 0.004%/timolol 0.5% solution, 1 drop instilled in the affected eye(s) daily in the morning (at 9:00) or in the evening (at 21:00) for 42 days (Treatment Phase)

Interventions: intervention 1: Brinzolamide 1%/brimonidine tartrate 0.2% ophthalmic suspension intervention 2: Brinzolamide/brimonidine vehicle intervention 3: Travoprost 0.004%/timolol 0.5% solution
Intervention descriptions: intervention 1: None intervention 2: Inactive ingredients used as placebo comparator intervention 3: 1 drop instilled in the affected eye(s) daily in the morning (at 9:00) or in the evening (at 21:00) for up to 10 days during the Screening/Eligibility Phase and 42 days during the Treatment Phase

Protocol document:
Prot_000.pdf: 
Page 1 of 71
a Novartis company
Short Title
Safety and Efficacy of SIMBRINZA BID as an Adjunctive to DUOTRAV
Long Title
Safety and Efficacy with Twice Daily Brinzolamide 1% / Brimonidine 0.2%
(SIMBRINZA) as an Adjunctive Therapy to Travoprost 0.004% / Timolol 
0.5% (DUOTRAV)
Protocol Number:
Study Phase:
Sponsor Name and 
Address:
Investigational Product:
US IND# / EudraCT
Indication Studied:
GLJ576-P001/ NCT02730871
4
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 76134-2099
SIMBRINZA
Brinzolamide 1% (10 mg/mL)/Brimonidine 0.2% (2 mg/mL) eye 
drops suspension
2016-000176-20
Ocular Hypertension
Open Angle Glaucoma
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Page 2 of 71
Investigator Agreement:
I have read the clinical study described herein, recognize its 
confidentiality, and agree to conduct the described trial in 
compliance with Good Clinical Practices (GCP), the ethical 
principles contained within the Declaration of Helsinki, this 
protocol, and all applicable regulatory requirements. 
Additionally, I will comply with all procedures for data recording 
and reporting, will permit monitoring, auditing, and inspection of 
my research center, and will retain all records until notified by 
the Sponsor.
Principal Investigator:
Signature
Date
Name:
Address:
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Page 3 of 71
1
SYNOPSIS
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number:GLJ576-P001
Investigational 
Product:
SIMBRINZA
Brinzolamide 1%/
Brimonidine 0.2% eye drops 
suspension
Study Phase:
1
2
3
4
N/A
Active Ingredient:                 Brinzolamide 1% (10 mg/mL)//Brimonidine 0.2% (2 mg/mL)
Protocol Title:
Safety and Efficacy with Twice Daily Brinzolamide 1% / 
Brimonidine 0.2% (SIMBRINZA) as an Adjunctive Therapy 
to Travoprost 0.004% / Timolol 0.5% (DUOTRAV)
Investigator(s)/ No. of Sites: Multicenter, approximately 40 sites
Center Location(s)/ 
Europe, Asia, Latin America, and Canada
No. of Subjects: 
Approximately 300 subjects enrolled, 240 subjects randomized,
216 subjects evaluable
Duration of Treatment:       Approximately 42 days
Study Population:                Adults with open-angle glaucoma or ocular hypertension on 
DUOTRAV (Travoprost 0.004%/Timolol 0.5%) solution therapy 
who may benefit from further IOP lowering (IOP ≥ 19 and ≤28 
mmHg in the study eye)
Objective(s):
To demonstrate the additive IOP lowering effect of Brinzolamide 
1%/Brimonidine 0.2% (dosed BID) when added to Travoprost 
0.004%/Timolol 0.5% solution in subjects with open-angle 
glaucoma or ocular hypertension
Methodology:
Multicenter, randomized, double-masked, parallel-group study
Treatments:
Investigational Product:
SIMBRIMZA
(Brinzolamide 1% (10 mg/mL)/ 
Brimonidine 0.2% (2 mg/mL))
Route of Administration:
Topical ocular drops
Duration of Treatment:
Approximately 42 days
Dosage:
1 drop instilled 2 times per day in
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Page 4 of 71
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number:GLJ576-P001
affected eye(s) (09:00 and 21:00 hrs)
Background Medication:
DUOTRAV
(Travoprost 0.004% (40 µg/mL)/ 
Timolol 0.5 % (5 mg/mL))
Route of Administration:
Topical ocular drops
Duration of Treatment:
Up to 10 days for eligibility and 
approximately 42 days after 
randomization 
Dosage:
1 drop instilled once per day in
affected eye(s) (09:00 or 21:00 hr) 
Control Article:
Brinzolamide/Brimonidine Vehicle
Duration of Treatment:
Approximately 42 days
Dosage:
1 drop instilled 2 times per day in
affected eye(s) (09:00 and 21:00 hrs)
Subject Selection:
Inclusion Criteria:
1. Subjects 18 years of age or older, of any race, diagnosed with 
either open-angle glaucoma (including pseudoexfoliation or 
pigment dispersion glaucoma) or ocular hypertension
2. Subjects currently on treatment with Travoprost 0.004% 
/Timolol 0.5% prescribed as approved in the country, on morning 
or evening dosing for at least 28 days prior to screening and that in 
the opinion of the Investigator may benefit from further IOP 
lowering. Subjects must remain on either their morning or evening 
dosing for the duration of the study.
3. Qualifying mean IOP measurements at both the Eligibility 1 
and Eligibility 2 visits, in at least 1 eye (the same eye(s) ≥ 19 and 
≤28 mmHg at 9:00 while on a Travoprost 0.004%/ Timolol 0.5% 
solution
4. Must be able to understand and sign an informed consent form 
that has been approved by an Institutional Review Board/Ethics 
Committee
5. Willing and able to attend all study visits.
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2.0; Most-Recent; Effective; CURRENT
TDOC-0051572
Protocol - Clinical
10-Apr-2017


Pa ge 5 of 7 1
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: G L J 5 7 6 -P 0 0 1
E xcl usi o n Criteria:
1.
W o me n of c hil d beari n g p ote ntial ( W O C B P), defi ne d as all 
w o me n w h o are n ot p ost me n o pa usal f or at least 1 y ear or less 
t ha n 6 wee ks si nce sterilizati o n, are e xcl u de d fr o m 
partici pati o n if:
a.
t he y are c urre ntl y pre g na nt, or
b.
ha ve a p ositi ve res ult o n t he uri ne pre g na nc y  test at 
Scree ni n g, or 
c.
i nte n d t o bec o me pre g nant d uri n g t he st u d y peri o d, or
d.
are breast -fee di n g, or 
e.
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 o pre ve nt pre g na nc y  t hr o u g h o ut t he st u d y.
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 as 
f oll o ws:

T otal a bsti ne nce ( w he n t his is i n li ne wit h t he 
preferre d a n d us ual lifest y le of t he s u bject). Peri o dic 
a bsti ne nce (e g, cale n dar, o v ulati o n, s ym pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n

Fe male sterilizati o n ( ha ve ha d s ur gical bilateral 
o o p h orect o m y wit h or wit h o ut h y sterect o m y) or 
t u bal li gati o n at least 6 wee ks bef ore Baseli ne. I n 
case of o o p h orect o m y al o ne, o nl y  w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n 
c o nfir me d b y f ol l o w u p h or m o ne le vel assess me nt

Male sterilizati o n (at least 6 m o nt hs pri or t o 
Baseli ne). F or fe male s u bjects i n t he st u d y , t he 
vasect o mize d male part ner s h o ul d be t he s ole part ner 
f or t hat s u bject

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Use of oral, i njecte d or i m pla nte d h or m o nal met h o ds 
of c o ntrace pti o n or ot her f or ms of h or m o nal 
c o ntrace pti o n t hat ha ve c o m para ble efficac y  (fail ure 
rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or 


Pa ge 6 of 7 1
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: G L J 5 7 6 -P 0 0 1
tra ns der mal h or m o ne c o ntrace pti o n

Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne 
s yste m (I U S)
2.
S u bjects wit h a n y  f or m of gla uc o ma ot her t ha n o pe n-a n gle 
gla uc o ma or oc ular h y perte nsi o n.
3.
S u bjects wit h ce ntral c or nea t hic k ness ( C C T) greater t ha n 6 2 0 
µ m as meas ure d b y pac h y metr y i n eit her e y e (see M O P f or 
f urt her details).
4.
S u bjects wit h Sc haffer a n gle Gra de < 2 i n eit her e y e, as 
meas ure d b y g o ni osc o p y (e xtre me narr o w a n gle wit h c o m plete 
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
or partial cl os ure).
5.
S u bjects wit h c u p/ disc rati o greater t ha n 0. 8 0 ( h oriz o ntal or 
vertical meas ure me nt) i n eit her e y e.
6.
S u bjects wit h se vere ce ntral vis ual fiel d l oss i n eit h er e ye or 
fiel d l oss t hreate ni n g fi xati o n i n eit her e ye. 
7.
S u bjects wit h c hr o nic, rec urre nt or se vere i nfla m mat or y  e ye 
disease (e g, scleritis, u veitis, her pes keratitis) i n eit her e y e.
8.
S u bjects wit h oc ular tra u ma i n eit her e y e wit hi n t he past 6 
m o nt hs pri or t o t he Scree ni n g visit.
9.
S u bjects wit h oc ular i nfecti o n or oc ular i nfla m mati o n i n eit her 
e ye wit hi n t he past 3 m o nt hs pri or t o t he Scree ni n g visit.
1 0. S u bjects wit h cli nicall y  si g nifica nt or pr o gressi ve reti nal 
disease s uc h as reti nal de ge nerati o n, dia bet ic reti n o pat h y, or 
reti nal detac h me nt i n eit her e ye.
1 1. S u bjects wit h best- c orrect e d vis ual ac uit y  sc ore w orse t ha n 5 5
E T D R S letters (e q ui vale nt t o a p pr o xi matel y  2 0/ 8 0 S nelle n, 
0. 6 0 l o g M A R or 0. 2 5 deci mal) i n eit her e y e.
1 2. S u bjects wit h o t her oc ular pat h ol o g y (i ncl u di n g se vere dr y 
e ye) i n eit her e ye t hat ma y, i n t he o pi ni o n of t he I n vesti gat or, 
precl u de t he safe a d mi nistrati o n of a n y st u d y me dicati o n.


Page 7 of 71
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number:GLJ576-P001
13. Subjects with intraocular surgery in either eye within the past 
6 months prior to the Screening visit.
14. Subjects with ocular laser surgery in either eye within the past 
3 months prior to the Screening visit.
15. Subjects with any abnormality preventing reliable applanation 
tonometry in either eye.
16. Any other conditions including severe illness which would 
make the subject, in the opinion of the Investigator, unsuitable 
for the study.
17. Subjects with recent (within 4 weeks of the Eligibility 1 Visit) 
use of high dose (> 1 gm daily) salicylate therapy.
18. Subjects with history of active, severe, unstable or 
uncontrolled cardiovascular (eg, coronary insufficiency, 
hypertension, Raynaud’s phenomenon, orthostatic 
hypotension, thromboangiitis obliterans), cerebrovascular (eg, 
cerebral insufficiency), hepatic, or renal disease that would 
preclude the safe administration of a topical alpha-adrenergic 
agonist or carbonic anhydrase inhibitor in the opinion of the 
Investigator
19. Subjects with current or anticipated treatment with any 
psychotropic drugs that augment an adrenergic response (eg, 
desipramine, amitriptyline).
20. Concurrent use of a monoamine oxidase inhibitor.
21. Study participants with asthma, history of asthma, or severe 
chronic obstructive pulmonary disease
22. Therapy with another investigational agent within 30 days 
prior to the Screening Visit.
23. Subjects with less than 30 days stable dosing regimen before 
the Screening Visit of any medications (excluding the IOP
lowering treatments) or substances administered by any route 
and used on a chronic basis that may affect IOP (eg, β-
adrenergic blocking agents). The dosing regimen of these 
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TDOC-0051572
Protocol - Clinical
10-Apr-2017


Pa ge 8 of 7 1
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: G L J 5 7 6 -P 0 0 1
me dicati o ns s h o ul d n ot c ha n ge d uri n g t he st u d y.
2 4. S u bjects wit h h y perse nsiti vit y  t o al p ha-a dre ner gic a g o nist 
dr u gs, t o pical or oral C AIs, P G As, ti m ol ol, s ulf o na mi de 
deri vati ves, or t o a n y c o m p o ne nt of t he st u d y me dicati o ns i n 
t he o pi ni o n of t he I n vesti gat or.
2 5. Use of a n y a d diti o nal t o pical or s ys te mic oc ular h yp ote nsi ve 
me dicati o n i n eit her e y e d uri n g t he st u d y.
2 6. S u bjects w h o ca n n ot safel y  disc o nti n ue all gl uc oc ortic oi ds 
a d mi nistere d b y a n y r o ute pri or t o t he Eli gi bilit y Visit 1 a n d 
c o nti nue t o n ot use d uri n g t he st u d y.
Ster oi d was h o ut d urati o n:
a.
C hr o nic t hera p y – 4 wee ks
b.
I nter mitte nt t hera py - 2 wee ks
2 7. Mea n I O P > 2 8 m m H g at a n y  ti me p oi nt i n eit her e ye d uri n g 
t he Scree ni n g/ Eli gi bilit y P hase.
T he Me dical M o nit or ma y declare a n y s u bject i neli gi ble f or a 
vali d me dical reas o n.
Assess me nts:
Pri m ar y Effic ac y:
C ha n ge fr o m baseli ne i n di ur nal I O P ( mea n of c ha n ges at 0 9: 0 0
a n d 1 1: 0 0 ti me p oi nts) at Wee k 6 .
Sec o n d ar y Effic ac y :

Di ur nal I O P at Wee k 6 

Perce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6

I O P c ha n ge fr o m baseli ne at Wee k 6 at 1 1: 0 0 hrs

Perce nta ge c ha n ge fr o m baseli ne i n I O P at Wee k 6 at 1 1: 0 0 
hrs

I O P c ha n ge fr o m baseli ne at Wee k 6 at 0 9: 0 0 hrs

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Perce nta ge c ha n ge fr o m baseli ne i n I O P at Wee k 6 at 0 9: 0 0 


Page 9 of 71
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number:GLJ576-P001
hrs
Safety:
Automated perimetry, fundus parameters, best-corrected visual
acuity (BCVA), slit-lamp exam, blood pressure, pulse rate and
adverse events
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Protocol - Clinical
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Page 10 of 71
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number:GLJ576-P001
Statistical Methods:
One eye from each patient will be chosen as the study eye and 
only the study eye will be used for analysis. If only 1 of a patient’s 
eyes is dosed, the dosed eye will be selected as the study eye. If 
both eyes are dosed, the worse evaluable eye will be selected as 
the study eye. Worse eye is defined as the eye with the higher IOP 
at 9:00 averaged across the 2 eligibility visits. If both eyes are 
equal then the worse eye will be defined as the eye with the higher 
IOP at 11:00 averaged across the 2 eligibility visits. If both eyes 
are equal then the right eye will be selected for analysis.
Analysis sets:
Efficacy analyses will be based on the Full Analysis Set (FAS), 
defined as all randomized subjects who received a dose of study 
medication and had at least one of the two scheduled on-treatment 
visits. The Safety Analysis Set will consist of all who received a 
dose of study medication.
Primary Efficacy:
The primary efficacy analysis will be an assessment of differences 
between treatments in mean change from baseline in diurnal IOP 
at Week 6 (change in patient IOP averaged over the 09:00 and
11:00 time points). The null and alternative hypotheses for the 
primary analysis are:
H0:  μBrinzBrim+ DUOTRAV  = μVehicle+ DUOTRAV
H1:  μBrinzBrim+ DUOTRAV ≠ μVehicle+ DUOTRAV
where μBrinzBrim+ DUOTRAV refers to mean diurnal IOP change from 
baseline for subjects randomized to receive brinzolamide / 
brimonidine plus Travoprost 0.004%/ Timolol 0.5%, and 
μVehicle+DUOTRAV refers to mean diurnal IOP change from baseline 
for subjects randomized to receive Vehicle plus Travoprost 
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Document:  
Version:  
Status:  
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Print Date:  
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2.0; Most-Recent; Effective; CURRENT
TDOC-0051572
Protocol - Clinical
10-Apr-2017


Pa ge 11 of 7 1
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: G L J 5 7 6 -P 0 0 1
0. 0 0 4 %/ ti m ol ol 0. 5 % . T he treat me nt differe nce i n mea n di ur nal 
I O P c ha n ge fr o m baseli ne will be teste d base d o n t he least s q uares 
mea ns deri ve d fr o m a n a nal ysis of c o variance m o del. T his m o del 
will i ncl u de treat me nt as a fi xe d ef fect a n d baseli ne 0 9: 0 0 I O P  as a 
c o variate.
Sec o n d ar y effic ac y :
H y p ot hesis tests of all sec o n dar y  efficac y e n d p oi nts will use t he 
sa me n ull a n d alter nati ve h yp ot heses as a b o ve, wit h µ re prese nti n g 
t he mea n f or t he varia ble bei n g teste d. A nal y ses of treat me nt 
dif fere nces i n di ur nal I O P a n d perce nt di ur nal I O P c ha n ge at Wee k 
6 will use t he sa me met h o ds as t h ose f or t he pri mar y  e n d p oi nt. 
A nal y ses of treat me nt differe nces i n I O P c ha n ge a n d perce nt I O P 
cha n ge at eac h Wee k 6 ti me p oi nt will utilize a re peate d meas ures 
mi xe d m o del wit h fi xe d effects of treat me nt, ti me p oi nt, a n d t he 
i nteracti o n of treat me nt a n d ti me p oi nt; a n d t he baseli ne 0 9: 0 0 I O P  
as a c o variate .
A gate -kee pi n g strate g y  will be e m pl o ye d t o e ns ure o verall c o ntr ol 
of t he t y pe 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 yp ot hesis is first 
rejecte d at t he 5 % le vel of si g nifica nce (t w o-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 hesis, eac h sec o n dar y  
h y p ot hesis will be teste d f oll o wi n g t he or der of t he h y p ot heses as 
liste d bel o w. Eac h h yp ot hesis will be rele va nt o nl y  if t he 
prece di n g h y p ot heses ha ve bee n rejecte d at t he 5 % le vel of 
si g nifica nce (t w o-si de d). T he testi n g or der (all base d o n I O P  at 
We e k 6) will be:

Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne  
i n di ur nal I O P

Differe nce bet wee n treat me nts i n di ur nal I O P

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Differe nce bet wee n treat me nts i n perce nta ge di ur nal I O P 
c ha n ge fr o m baseli ne 


Pa ge 1 2 of 7 1
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: G L J 5 7 6 -P 0 0 1

Differe nce b et wee n treat me nts i n IO P c ha n ge fr o m baseli ne at 
1 1: 0 0 hrs

Differe nce be t wee n treat me nts i n perce nta ge I O P c ha n ge fr o m 
baseli ne at 1 1: 0 0 hrs 

Differe nce bet wee n treat me nts i n I O P c ha n ge fr o m baseli ne at 
0 9: 0 0 hrs

Differe nce bet wee n treat me nts i n perce nta g e I O P c ha n ge fr o m 
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
baseli ne at 0 9: 0 0 hrs
Si g nifica nce f or a c o m paris o n will be clai me d o nl y if t he n ull 
h y p ot hesis is rejecte d ( p < 0. 0 5) f or t he pre vi o us e n d p o i nt i n t his 
series. 
Descri pti ve statistics will be calc ulate d f or t he pri mar y  a n d 
sec o n dar y e n d p oi nts at baseli ne a n d Wee k 6. 
O nl y  descri pti ve statistics will be calc ulate d f or t he 
 
varia bles .
T his st u d y  will i nc or p orate a n i nteri m a nalys is f or efficac y 
assess me nt w he n 5 0 % of t he t otal pla n ne d s u bjects ha ve 
c o m plete d or disc o nti n ue d fr o m t he st u d y. T he o bjecti ve of t he 
i nteri m a nal ysis is t o pr o vi de a n o p p ort u nit y f or earl y rejecti o n of 
t he n ull h yp ot hesis t hat t here is n o dif fere nce i n di ur nal I O P 
c ha n ge fr o m baseli ne bet wee n bri nz ola mi de / bri m o ni di ne pl us 
Tr a v o pr ost 0. 0 0 4 %/ Ti m ol ol 0. 5 % a n d ve hicle pl us Tr a v o pr ost 
0. 0 0 4 %/ T i m ol ol 0. 5 %. I n or der t o e ns ure Ty pe 1 err or is 
a de q uatel y c o ntr olle d at t he 5 % le vel of si g nifica nce (t w o -si de d), 
a p- val ue b o u n dar y will be e m pl o y e d, s pecificall y, t he Ha ybittle -
Pet o b o u n dar y  ( Ha ybittle 1 9 7 1) . T he H a y bittle -Pet o b o u n dar y  
e ns ures t hat t he st u d y st o ps f or efficac y o nl y if t here is 
o ver w hel mi n g e vi de nce of ef ficac y.


Pa ge 1 3 of 7 1
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: G L J 5 7 6 -P 0 0 1
S a m ple Size J ustific ati o n:
Wi t h 1 0 8 e val ua ble s u bjects per treat me nt gr o u p i n t he pri mar y 
efficac y a nal ys is, t here is at least 8 0 % p o wer t o detect a differe nce 
i n mea n c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6 I O P of 1. 5 
m m H g bet wee n t he treat me nt gr o u ps. H o we ver , t he re q uire d 
sa m ple size t o attai n t he sa me p o wer is 2 8 s u bjects per ar m if t he 
dif fere nce is 3. 0 m m H g bet wee n treat me nt gr o u ps as s u g geste d by 
e x pert o pi ni o n. B ot h calc ulati o n s are base d o n t he ass u m pti o n of a 
c o m m o n sta n dar d de viati o n f or mea n of 3. 9 m m H g a n d t he use of 
a t w o-sa m ple t w o-si de d t-test perf or me d at t he α = 0. 0 5 le vel of 
si g nifica nce.
Ass u mi n g a dr o p - o ut rate of 1 0 %, a p pr o xi matel y 1 2 0 s u bjects per 
treat me nt gr o u p will be e nr olle d t o e ns ure t he re q uire d n u m ber of 
e val ua ble s u bjects i n t he fi nal efficac y a nalys is.
To  miti gate t he u ncertai nt y a b o ut t he e x pecte d treat me nt 
dif fere nce, a t w o-l o o k desi g n wit h Ha y bittle -Pet o b o u n daries will 
be use d. T h us, t his st u d y will i nc or p orate a n i nteri m a nal ysis f or 
efficac y assess me nt w he n 5 0 % of t otal pla n ne d s u bjects ha ve 
c o m plete d or disc o nti n ue d fr o m t he st u d y. T he p o wer t o reject t he 
n ull h y p ot hesis at t he si n gle i nteri m a nal ys is w he n 5 0 % of 
s u bjects ha ve c o m plete d or disc o nti n ue d t he st u d y is 2 8. 2% if t he 
e x pecte d mea n differe nce is 1. 5 a n d 9 2. 2 % if t he e x pecte d mea n 
dif fere nce is 3. 0.
L o o k 
#
S a m pl e 
Si z e
Effi c a c y  
p- v al u e
P- v al u e 
B o u n d ar y
E xit Pr o b a biliti e s
= 0
= 1. 5
= 3. 0
1
1 0 8
0. 0 1 
0. 0 1 
0. 0 1
0. 2 8 2 
0. 9 2 2
2
2 1 6
0. 0 4 5 
0. 0 4 5
0. 0 4
0. 5 1 7 
0. 0 7 8
S u m  of E xit Pr o b a biliti e s
0. 0 5 0 
0. 7 9 9
1
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7


Page 14 of 71
1.1
Amendments
Amendment 1
1.
Lower the qualifying IOP criteria at both the Eligibility 1 and Eligibility 2 visits from ≥      
21 and ≤ 28 mmHg at 09:00 to ≥ 19 and ≤ 28 mmHg at 09:00.
Rationale: Screen failures due to lower IOPs on Duotrav than the ≥21 mmHg cutoff is high.  
Reducing the entry IOP by 2 mmHg will allow more patients to be eligible for the study while 
maintaining an IOP baseline that will allow a reasonable efficacy effect to be observed.  This 
lowering of inclusion IOP will not have a major effect on the study outcome parameters and 
the baseline IOP values will decrease proportionately.  The study is powered appropriately to 
test for treatment effects between the study arms.
2.
Remove the 15:00 IOP measurement time point at all study visits.
Rationale: The 12-hr trough and 2-hr peak effects of Simbrinza are seen at 09:00 and 11:00, 
respectively, and are the critical measurement time points for the study.  The 15:00 time point 
provides further daytime data but is proving to be a major barrier to recruitment.  Removing 
the late day 15:00 time point and reducing the patient commitment from ~ 7 hrs to ~ 3 hrs will 
facilitate recruitment.  Removing this time point will not affect the scientific integrity of the 
study since the 12- hr trough (09:00 IOP) and 2-hr peak (11:00 IOP) are being captured and 
provide the key IOP fluctuation values.  Further, the statistical design remains intact and valid 
since it is based on differences between treatment arms and the amendment affects 
measurements in both arms equally.
3.
Allow subjects currently on treatment with Travoprost 0.004% /Timolol 0.5% for at 
least 28 days prior to screening in the morning or evening to be eligible for the study.
Rationale: There is broad variability globally on the Duotrav on label dosing schedule 
(morning vs. evening dosing).  Allowing both, where on label, will allow for all Duotrav dosed 
patients to be considered.  Additionally, studies have shown that the IOP lowering from 
Duotrav is similar statistically between AM and PM dosing and therefore the dosing time will 
not bias the study results.  A planned descriptive analysis will be done (if patient numbers 
allow) to compare the effects of AM vs. PM dosing.
4.
Incorporate an interim analysis for efficacy assessment when 50% of the total planned 
subjects have completed or discontinued form the study.
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Page 15 of 71
Rationale: The combination of Simbrinza + Duotrav has not been studied previously and as 
such, the study was powered to show a 1.5 mmHg difference between study arms.  However, 
since the launch of Simbrinza, clinical experience has increased and expert opinion has 
suggested it may be more than 1.5 mmHg.  To minimize unnecessary patient enrollment in the 
trial, an interim analysis has been added at 50% completion to test for statistical differences 
between treatments.  If it is achieved, the study enrollment will stop and patients in the study 
will complete their visits.  This analysis has no effect on patient safety nor does it change the 
assessments or study design.
5.
Provide clarification to exclusion criteria # 27.
6.
Allow for re-screening with defined criteria.
7.
Update Statistical Analysis associated with the change in eligibility criteria.
8.
Define procedure/assessment windows.
9.
Update administrative information and correct minor errors from Protocol Version 1.0.
Current Study Phase: Execution Phase
Case Report Form Revision Required:
X Yes
No
Informed Consent Modifications Required:
X Yes
No
Applicable Investigators:
X All
Selected (list below)
Itemized Changes: Additions/modifications are noted in bold, italics. Deletions are noted 
with a strikethrough.
1.
Lower the qualifying IOP criteria at both the Eligibility 1 and Eligibility 2 visits from ≥ 
21 and ≤ 28 mmHg at 09:00 to ≥ 19 and ≤ 28 mmHg at 09:00.
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Page 16 of 71
•
Synopsis, Study Population
Adults with open-angle glaucoma or ocular hypertension on DUOTRAV 
(Travoprost 0.004%/Timolol 0.5%) solution therapy who may benefit from 
further IOP lowering (IOP ≥ 21 19 and ≤28 mmHg in the study eye)
•
Synopsis, Subject Selection, Inclusion Criteria #3
Qualifying mean IOP measurements at both the Eligibility 1 and Eligibility 2 
visits, in at least 1 eye (the same eye(s) ≥ 21 19 and ≤ 28 mmHg at 9:00 while 
on a Travoprost 0.004%/ Timolol 0.5% solution
•
Synopsis, Assessments, 
, Baseline IOP
Baseline IOP: 21 19-24 mmHg, >24-28 mmHg
•
Section 8 – Subject Population
To participate in the study, subjects must have a mean IOP measurement at 
09:00 in at least 1 eye (same eye, study eye) ≥ 21 19 and ≤ 28 mmHg at 2 
consecutive visits (Eligibility 1 and Eligibility 2).
•
Section 10, Table 10-1, Study Plan by Treatment Group
Mean  IOP  for  both  Eligibility Visits  must  be: ≥ 21 19 mmHg and ≤ 28 
mmHg in at least 1 eye at 09:00 time point
•
Section 10.2.2., Visit 2 (Eligibility 1) and Visit 3 (Eligibility 2), Table 10-2
Mean IOP must be ≥ 21 19 and ≤ 28 mmHg in at least one (same) eye(s) at 
09:00.
•
Section 11.3 – Demographic and Baseline Characteristics
Subject characteristics summaries include tables and listings such as 
demographics (age, gender, race, iris color, and region) and baseline 
characteristics (baseline IOP by time point, baseline diurnal IOP, baseline IOP 
category (21 19-24 mmHg, >24-28 mmHg), and diagnosis for all analysis sets 
(safety and FAS).
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Page 17 of 71
•
Section 11.3.2. – Baseline Characteristics
Baseline IOP by time point and diurnal baseline IOP will be summarized as 
continuous variables. In addition, baseline IOP (21 19-24 mmHg, >24-28 
mmHg), will be summarized as a categorical variables.
•
Section 11.4.1.2.1. – Subgroup Analysis Methods
Subgroups of age category (< 50, 50-65, >65), sex, race (Caucasian, Black, 
Asian, Hispanic, Other), baseline IOP (21 19-24 mmHg, >24-28 mmHg) and 
region (EMEA, Asia, ,LACAR, ) will be summarized descriptively (N, mean, 
standard deviation) for the primary end point.
•
Section 11.4.2.2.1. – Subgroup Analysis Methods
Subgroups of age category (< 50, 50-65, > 65), sex, race (Caucasian, Black, 
Asian, Hispanic, Other), baseline IOP (21 19-24 mmHg, >24-28 mmHg), and 
region (EMEA, Asia, LACAR) will be summarized descriptively (N, mean, 
standard deviation) for the secondary endpoints.
•
2.
Remove the 15:00 IOP measurement time point at all study visits.
•
Synopsis, Assessments, Primary Efficacy
Change from baseline in diurnal IOP (mean of changes at 09:00 and 11:00 and 
15:00 time points) at Week 6.
•
Synopsis, Statistical Methods, Primary Efficacy
The primary efficacy analysis will be an assessment of differences between 
treatments in mean change from baseline in diurnal IOP at Week 6 (change in 
patient IOP averaged over the 09:00 and 11:00, and 15:00 time points).
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Page 18 of 71
•
Section 2 – Overview of Study Plan
IOP (09:00, 11:00, 15:00)
•
Section 10.2.2., Visit 2 (Eligibility 1) and Visit 3 (Eligibility 2), Table 10-2
VISIT 2 (ELIGIBILITY 1) & VISIT 3 (ELIGIBILITY 2): [09:00 (+/-30 MIN), 
11:00 (+/- 30 MIN), AND 15:00 (+/- 30 MIN) EXAMINATIONS
•
Section 10.2.3., Visit 4 (Week 2) and Visit 5 (Week 6, Exit), Table 10-3
VISIT 4 (WEEK 2) & VISIT 5 (WEEK 6, EXIT): [09:00 (+/-30 MIN), 11:00 
(+/- 30 MIN), AND 15:00 (+/- 30 MIN) EXAMINATIONS
•
Section 11.4.1. Primary Efficacy
The primary efficacy analysis will be an assessment of differences between 
treatments in mean change from baseline in diurnal IOP at Week 6 (patient IOP 
change from baseline averaged over the 09:00 and 11:00, and 15:00 time 
points).
3.
Allow subjects currently on treatment with Travoprost 0.004% /Timolol 0.5% for at 
least 28 days prior to screening in the morning or evening to be eligible for the study.
•
Synopsis, Background Medication, DUOTAV Dosage
1 drop instilled once per day in affected eye(s) (09:00 or 21:00 hr) 
•
Synopsis, Subject Selection, Inclusion Criteria #2
Subjects currently on treatment with Travoprost 0.004% /Timolol 0.5% 
prescribed as approved in the country, on morning or evening dosing for at 
least 28 days prior to screening, and that in the opinion of the Investigator may 
benefit from further IOP lowering. Subjects must remain on either their 
morning or evening dosing for the duration of the study.
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Page 19 of 71
•
Section 2. - Overview of Study Plan, footnote
* Visit 1 and 2 may be combined if the subject IOP was measured at 09:00, 
DUOTRAV taken on the previous morning at 09:00 ± 1hr or evening at 21:00 
± 1hr
•
Section 8 – Subject Population
To participate in the study, subjects must be on DUOTRAV (travoprost 0.004% 
/ timolol 0.5 %) solution therapy for at least 4 weeks (28 days) dosing either in 
the morning or evening prior to screening.
•
Section 9 – Treatments Administered
At the Screening Visit, the PI will confirm that subjects have been on 
continuous morning or evening DUOTRAV (travoprost 0.004% / timolol 0.5 
%) therapy for at least 28 days. If qualified, each subject will continue with 
open label study DUOTRAV, dosed at approximately the same time (evening 
or morning) for the duration of the study.
•
Section 9.2.1. – Route of Administration
During the time the subject is in the study, the supplied DUOTRAV will be 
used, according to the morning or evening regimen followed prior to 
Screening. One drop is to be applied topically to the eye(s) daily in the 
morning (at 9:00± 30 min) or in the evening (at 21:00 ± 30 min) 
•
Section 9.2.2. – Duration of Exposure
Subject’s medical chart should confirm the use of the morning or evening dose 
of DUOTRAV (travoprost 0.004% / timolol 0.5 %) for at least 4 weeks (28 
days) immediately prior to screening.
•
Section 10, Table 10-1, Study Plan by Treatment Group
Begin dosing with study supplied DUOTRAV at 09:00 21:00 ±30min on the 
evening of the screening visit if subject dosed with Duotrav in the evenings 
prior to Screening, or begin dosing with study supplied DUOTRAV at 09:00 
±30min the following day after Screening if subject dosed with Duotrav in the 
mornings prior to Screening.
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Page 20 of 71
At Screening Visit the investigator should document that the subject has been 
previously on morning or evening DUOTRAV solution therapy for at least 28 
days prior to Screening Visit. 
•
Section 10.2.1 – Visit 1 – Screening, Step #11, Step #15, Step #16
•
Step 11. Perform Goldmann applanation tonometry OU
*if subjects IOP was measured at 09:00, DUOTRAV taken on the 
previous morning at 09:00 ± 1 hr or evening  at 21:00 ± 1 hr and all 
other study assessments can be completed as per protocol for Visit 1 
(Screening) and Visit 2 (E1), then Visit 1 and Visit 2 can be combined
•
Step 15. Instruct each subject to instill DUOTRAV daily at 
either 09:00 or 21:00 ±30 min, OU. 
Reminder: Investigator must document that subjects are currently on 
morning or evening dosing for at least 28 days prior to the Screening 
Visit. The same DUOTRAV dosing schedule must be followed for the 
entire study (morning or evening dosing.)
•
Step 16. Schedule the subject to return 1-5 days for the 
Eligibility 1 Visit (Visit 2).
*if subjects IOP was measured at 09:00, DUOTRAV taken on the 
previous morning at 09:00 ± 1 hr or evening  at 21:00 ± 1 hr and all 
other study assessments can be completed as per protocol for Visit 1 
(screening) and Visit 2 (E1), then Visit 1 and Visit 2 can be combined.
•
Section 10.2.2., Visit 2 (Eligibility 1) and Visit 3 (Eligibility 2), Table 10-2
•
Reconfirm that it is documented that the subject has 
administered morning or evening dose of DUOTRAV therapy daily for 
28 days.
•
RESCHEDULE the visit if the subject did not dose the previous 
morning or evening.
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Pa ge 2 1 of 7 1
•
D U O T R A V – Dail y  d osi n g i n t he m or ni n g or i n e ve ni n g (0 9: 0 0 
or 2 1: 0 0 ± 3 0 mi n). 
•
T he V isit 2 ( Eli gi bilit y 1 Visit) s h o ul d be c o n d ucte d 1-5 da y s 
f oll o wi n g t he Scree ni n g Visit or ca n be c o m bi ne d if t he s u bjects I O P 
was meas ure d at 0 9: 0 0 ± 3 0 mi n, D U O T R A V was ta ke n at 0 9: 0 0 ± 1 hr 
o n t he previ o us m or ni n g or at 2 1: 0 0 ± 1 hr o n t he pre vi o us e ve n i n g a n d 
all ot her st u d y assess me nts ca n be c o m plete d as per pr ot oc ol f or V 1 
(scree ni n g).
•
D osi n g i nstr ucti o ns s h o ul d be pr o vi de d t o t he s u bject as f oll o ws:
•
c) C o nti n ue wit h 1 dr o p of D U O T R AV i n eac h affecte d e ye daily 
at eit her 0 9: 0 0 ± 3 0 mi n or 2 1: 0 0 ± 3 0 mi n f or a p pr o xi matel y  6 wee ks.
R E MI N D E R: C o ntact t he s u bject pri or t o t he We e k 2 a n d We e k 6 Visits 
t o re mi n d t he s u bject t o:
• 
i nstill t he d ose of D U O T R AV at 0 9: 0 0 ( ± 3 0 mi n utes) or 2 1: 0 0 
( ± 3 0 mi n utes) a n d mas ke d st u d y me dicati o n at 2 1: 0 0 ( ± 3 0 mi n utes) t he 
ni g ht d ay pri or t o t he visit,
•
D O N O T d ose t he mas ke d I P or t he D U O T R AV 0 9: 0 0 m or ni n g 
d ose t he m or ni n g of t he st u d y visit. T he m or ni n g d ose of b ot h t he 
m as ke d I P  a n d D U O T R AV will be i nstille d i n t he of fice after t he 0 9: 0 0 
I O P meas ure me nt.
•
Secti o n 1 0. 2. 3, V isit 4 ( Wee k 2) a n d Vi sit 5 ( Wee k 6, E xit), Ta ble 1 0 - 3
•
R E S C H E D U L E t he visit if t he s u bject di d n ot d ose t he pre vi o us 
e ve ni n g or if t he s u bject has alrea d y d ose d t he m or ni n g d ose of 
D U O T R A V a n d/ or t he m as ke d I P.
•
A p pr o xi matel y  1 5 mi n utes after t he I O P meas ure me nts, i nstill 
t he mas ke d I P a n d t he D U O T R AV m or ni n g d ose f or s u bjects usi n g t he 
m or ni n g re gi me n i n t he office.
4.
I nc or p orate a n i nteri m a nal ysis f or efficac y assess me nt w he n 5 0 % of t he t otal pla n ne d 
s u bjects ha ve c o m plete d or disc o nti n ue d f or m t he st u d y.

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
S y n o psis, St atistic al Met h o ds ; Secti o n 1 1. 9


Pa ge 2 2 of 7 1
T his st u dy will i nc or p or ate a n i nteri m a n alysis f or effic acy assess me nt 
w he n 5 0 % of t he t ot al pl a n ne d s u bjects h ave c o m plete d or 
disc o nti n ue d fr o m t he st u dy. T he o bjective of t he i nteri m a n alysis is t o
pr ovi de a n o p p ort u nity f or e arly rejecti o n of t he n ull hy p ot hesis t h at 
t here is n o differe nce i n di ur n al I O P c h a n ge fr o m b aseli ne bet wee n 
bri nz ol a mi de / bri m o ni di ne pl us Tr av o pr ost 0. 0 0 4 %/ Ti m ol ol 0. 5 % 
a n d ve hicle pl us Tr av o pr ost 0. 0 0 4 %/ Ti m ol ol 0. 5 %. I n or der t o e ns ure 
Ty pe 1 err or is a de q u ately c o ntr olle d at t he 5 % level of si g nific a nce 
(t w o-si de d), a p- v al ue b o u n d ary will be e m pl oye d, s pecific ally, t he 
H ay bittle - Pet o b o u n d ary ( H ay bittle 1 9 7 1). T he H ay bittle -Pet o
b o u n d ary e ns ures t h at t he st u dy st o ps f or effic acy o nly if t here is 
over w hel mi n g evi de nce of effic acy.

S y n o psis, S a m ple Size J ustific ati o n ; Secti o n 11. 1 0
Wi t h 1 0 8 e val ua ble s u bjects per treat me nt gr o u p i n t he pri mar y efficac y 
a nal ys is, t here is at least 80 % p o wer t o detect a dif fere nce i n mea n 
c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6 I OP of 1. 5 m m H g 
bet wee n t he treat me nt gr o u ps. H o wever , t he re q uire d s a m ple size t o 
att ai n t he s a me p o wer is 2 8 s u bjects per ar m if t he differe nce is 3. 0 
m m H g bet wee n tre a t me nt gr o u ps as s u g geste d by e x pert o pi ni o n. B ot h
calc ulati o n s are base d o n t he ass u m pti o n of a c o m m o n sta n dar d 
de viati o n f or mea n of 3. 9 m m H g a n d t he use of a t w o -sa m ple t w o-si de d 
t-test perf or me d at t he α = 0. 0 5 le vel of si g nifica nce.
To  miti g ate t he u ncert ai nty a b o ut t he e x pecte d tre at me nt differe nce, a 
t w o-l o o k desi g n wit h H ay bittle -Pet o b o u n d aries will be use d. T h us, 
t his st u dy will i nc or p or ate a n i nteri m a n alysis f or effic acy assess me nt 
w he n 5 0 % of t ot al pl a n ne d s u bjects h ave c o m plete d or disc o nti n ue d 
fr o m t he st u dy. T he p o wer t o reject t he n ull hy p ot hesis at t he si n gle 
i nteri m a n alysis w he n 5 0 % of s u bjects h ave c o m plete d or disc o nti n ued 
t he st u dy is 2 8. 2% if t he e x pecte d me a n dif fere nce is 1. 5 a n d 9 2. 2%, if 
t he e x pecte d me a n differe nce is 3. 0.
L o o k 
#
S a m pl e 
Si z e
Effi c a c y  
p- v al u e
P- v al u e 
B o u n d ar y
E xit Pr o b a biliti e s
= 0
= 1. 5
= 3. 0
1
1 0 8
0. 0 1 
0. 0 1 
0. 0 1
0. 2 8 2 
0. 9 2 2
2
2 1 6
0. 0 4 5 
0. 0 4 5
0. 0 4
0. 5 1 7 
0. 0 7 8
S u m  of E xit Pr o b a biliti e s
0. 0 5 0 
0. 7 9 9
1
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7


Pa ge 2 3 of 7 1

Secti o n 1 0. 5, Cli nic al St u d y Te r mi n ati o n
A d de d te xt:
Reas o ns f or t he cl os ure of a n i n vesti gati o nal site or ter mi nati o n of a 
st u d y ma y i ncl u de:
I nteri m a n alysis res ults met pre-s pecifie d st o p pi n g r ule

Secti o n 1 4, Refer e nces
L a n K K G, De Mets D L. Discrete se q ue nti al b o u n d aries f or cli nic al 
tri als. Bi o metri k a. 1 9 8 3. 7 0( 3): 6 5 9 - 6 3.
5.
Pr o vi de clarificati o n t o e xcl usi o n criteria # 2 7

S y n o psis, S u bject Selecti o n, E xcl usi o n Criteri a # 2 7
M ea n I O P > 2 8 m m H g at a n y ti me p oi nt i n eit her eye d uri n g t he 
Scree ni n g/ Eli gi bilit y  P hase.
6.
All o w f or re -scree ni n g wit h defi ne d criteria.

Secti o n 8 – S u bject P o p ul ati o n
A s u bject m ay be re -scree ne d if t hey scree n f aile d d ue t o eli gi bility 
criteri a defi ne d i n t he ori gi n al ve rsi o n of t he pr ot oc ol. Refer t o t he 
C R F C o m pleti o n G ui deli nes f or f urt her i nf or m ati o n o n E D C 
d oc u me nt a ti o n g ui d a nce.
7.
U p date Statistical A nal ys is ass ociate d wit h t he c ha n ge i n eli gi bilit y criteria:

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
S y n o psis, Assess me nts, Sec o n d ar y Effic ac y
C h a n ge d fr o m:


Pa ge 2 4 of 7 1

Di ur nal I O P at Wee k 6 

Perce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6

I O P c ha n ge fr o m baseli ne at Wee k 6 f or eac h ti me p oi nt ( 0 9: 0 0, 1 1: 0 0, 
1 5: 0 0 hrs )

Perce nta ge c ha n ge fr o m baseli ne i n I O P at Wee k 6 f or eac h ti me p oi nt 
C h a n ge d t o:

Di ur nal I O P at Wee k 6 

Perce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P  at We e k 6

I O P c ha n ge fr o m baseli ne at We e k 6 for eac h ti me p oi nt ( 0 9: 0 0, at 1 1 : 0 0
1 5: 0 0 hrs

Perce nta ge c ha n ge fr o m baseli ne i n I O P at Wee k 6 f or eac h ti me p oi nt at 
11 : 0 0 hrs

I O P c h a n ge fr o m b aseli ne at We e k 6 at 0 9: 0 0 hrs

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Perce nt a ge c h a n ge fr o m b aseli ne i n I O P  at We e k 6 at 0 9: 0 0 hrs


Pa ge 2 5 of 7 1
o
S y n o psis, St atisti c al Met h o ds, Sec o n d ar y Effic ac y
C h a n ge d fr o m:
T he testi n g or der (all base d o n I O P  at Wee k 6) will be:

Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne  i n di ur nal 
I O P

Differe nce bet wee n treat me nts i n di ur nal I O P

Differe nce bet wee n treat me nts i n perce nta ge di ur nal I O P c ha n ge fr o m 
baseli ne 

Differe nce bet wee n treat me nts i n I O P c ha n ge fr o m baseli ne f or eac h ti me 
p oi nt

Differe nce be t wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne f or 
eac h  ti me p oi nt (0 9: 0 0, 1 1: 0 0, 1 5: 0 0)
C h a n ge d t o:
T he testi n g or der (all base d o n I O P  at Wee k 6) will be:

Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne  i n di ur nal 
I O P

Differe nce bet wee n treat me nts i n di ur nal I O P

Differe nce bet wee n treat me nts i n perce nta ge di ur nal I O P c ha n ge fr o m 
baseli ne 

Differe nce bet wee n treat me nts i n I O P c ha n ge fr o m baseli ne f or eac h ti me 
p oi nt at 1 1: 0 0 hrs

Differe nce be t wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne at 
1 1: 0 0 hrs f or eac h  ti me p oi nt ( 09: 0 0, 1 1: 0 0, 1 5: 0 0)

Differe nce bet wee n tre at me nts i n I O P c h a n ge fr o m b a seli ne at 0 9: 0 0 hrs

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Differe nce bet wee n tre at me nts i n perce nt a ge I O P c h a n ge fr o m b aseli ne at 
9: 0 0 hrs


Pa ge 2 6 of 7 1
o
Secti o n 1 1. 4, Effic ac y A n al ysis
C h a n ge d fr o m :
U nless ot her wise s pecifie d, all statistical a nal y ses will be t w o-si de d at t he 5 % 
le vel.
C h a n ge d t o:
U nless ot her wise s pecifie d, all statistical a nal yses si g nific a nce testi n g will be 
at t he 5 % si g nific a nce level t w o-si de d at t he 5 % le vel.
o
Secti o n 1 1. 4. 2. – Sec o n d ar y Effic ac y
C h a n ge d fr o m:
T he sec o n dar y  e n d p oi nts are: 

Di ur nal I O P at Wee k 6

Perce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6

C ha n ge fr o m baseli ne i n I O P f or eac h ti me p oi nt ( 0 9: 0 0, 1 1: 0 0, 1 5: 0 0) at 
Wee k 6 

Perce nta ge c ha n ge fr o m baseli ne i n I O P f or eac h ti me p oi nt ( 0 9: 0 0, 1 1: 0 0, 
1 5: 0 0) at Wee k 6
C h a n ge d t o:
T he sec o n dar y  e n d p oi nts are: 

Di ur nal I O P at Wee k 6

Perce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 

C ha n ge fr o m baseli ne i n I O P f or eac h ti me p oi nt ( 0 9: 0 0, at 1 1: 0 0 hrs
1 5: 0 0) at Wee k 6 

Perce nta ge c ha n ge fr o m baseli ne i n I O P f or eac h ti me p oi nt ( 0 9: 0 0, 1 1: 0 0, 
1 5: 0 0) at 1 1: 0 0 hrs at Wee k 6
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7


Pa ge 2 7 of 7 1

C h a n ge fr o m b aseli ne i n I O P at 0 9: 0 0 hrs at Wee k 6 

Perce nt a ge c h a n ge fr o m b aseli ne i n I O P at 0 9: 0 0 hrs at Wee k 6

Secti o n 1 1. 6 – M ulti plicit y
C h a n ge d fr o m:
T he testi n g or der (all base d o n I O P at Wee k 6) will be:

Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne i n di ur nal I O P 

Dif fere nce bet wee n treat me nts i n di ur nal IO P

Dif fere nce bet wee n treat me nts i n perce nta ge di ur nal I O P c ha n ge fr o m 
baseli ne 

Dif fere nce bet wee n treat me nts i n IO P  c ha n ge fr o m baseli ne f or eac h ti me 
p oi nt

Dif fere nce bet wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne f or 
eac h  ti me p oi nt (0 9: 0 0, 1 1: 0 0, 1 5: 0 0)
Si g nifica nce f or a c o m paris o n will be clai me d o nl y if t he n ull h y p ot hesis is 
rejecte d ( p < 0. 0 5) f or t he pre vi o us e n d p oi nt in t his series. S uccess f or t he 
last t w o e n d p oi nts will be defi ne d as 
p < 0. 0 5 f or at least 2 of t he 3 ti me p oi nts.
C h a n ge d t o:
T he testi n g or der (all base d o n I O P at Wee k 6) will be:

Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne i n di ur nal I O P 

Dif fere nce bet wee n treat me nts i n di ur nal IO P

Dif fere nce bet wee n treat me nts i n perce nta ge di ur nal I O P c ha n ge fr o m 
baseli ne 

Dif fere nce bet wee n treat me nts i n IO P  c ha n ge fr o m baseli ne f or eac h ti me 
p oi nt at 11: 0 0 hrs
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7


Pa ge 2 8 of 7 1

Dif fere nce bet wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne f or 
eac h  ti me p oi nt ( 0 9: 0 0, 11: 0 0, 1 5: 0 0) at 11: 0 0 hrs

Dif fere nce bet wee n tre at me nts i n I O P c h a n ge fr o m b aseli ne at 0 9: 0 0 hrs

Dif fere nce bet wee n tre at me nts i n perce nt a ge I O P c h a n ge fr o m b aseli ne at 
0 9: 0 0 hrs
Si g nifica nce f or a c o m paris o n will be clai me d o nl y if t he n ull h y p ot hesis is 
rejecte d ( p < 0. 0 5) f or t he pre vi o us e n d p oi nt i n t his series. S uccess f or t he last 
t w o e n d p oi nts will be defi ne d as p < 0. 0 5 f or at least 2 of t he 3 ti me p oi nts.
8.
Defi ne pr oce d ure/assess me nt wi n d o ws:

Secti o n 2. - O ver vie w of St u d y Pl a n, Pr oce d ure/ Assess me nt
I O P ( 0 9: 0 0, 1 1: 0 0, 1 5: 0 0) ± 3 0 mi n utes
9.
U p date a d mi nistrati ve i nf or mati o n a n d c orrect mi n or err ors fr o m Pr ot oc ol V ersi o n 1. 0:

S y n o psis, N o. of Sites:
M ultice nter, a p pr o xi matel y  3 0 4 0 sites

Secti o n 8 - S u bject P o p ul ati 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 4 0 s u bjects t o be ra n d o mize d at 
a p pr o xi matel y 3 0 4 0 sites gl o bally.

Secti o n 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
C h a n ge d Fr o m:
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 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 y i 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 p y 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. 


Pa ge 2 9 of 7 1
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 y i 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.
C h a n ge d To :
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 a s u bject 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 ber, s u bject n a me a n d 
me dic al I D n u m ber s 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 p y of t he e nr oll me nt 
s u bject l o g wit h o ut a ny 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.

Secti o n 1 0. 2. 3. Vi sit 4 ( Wee k 2), Ta ble 1 0 - 3, Acti vities f or  Wee k 2 a n d We e k 6 
( E xit) Visits
Err or  C orrecti o n
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
- Re m o val of 1 1: 0 0 assess me nt s fr o m Visit 4 ( Wee k 2); 
assess me nt s n ot c ollecte d at 11: 0 0 at Vi sit


Page 30 of 71
2
OVERVIEW OF STUDY PLAN
Nominal Time ± Visit Window Limits
Visit 1*
Screening
Visit 2*
Eligibility 1
Visit 3
Eligibility 2
(Randomization)
Visit 4
Visit 5
Exit
Unscheduled
Visit
Early 
Exita
Procedure/ 
Assessment
1-5 days 
after 
Screening
3-5 days from E1
Day 14± 
3 Days 
from E2
Day 42 ± 
5 Days 
from E2
Informed Consent b
X
Demographics
X
Medical History
X
Concomitant 
Medications
X
Changes in 
concomitant meds
X
X
X
X
X
X
Inclusion/Exclusion
X
Urine Pregnancy 
Test c
X
X
X
BCVA
X
X1
X1
X1
X1
X
X
Slit-Lamp 
Biomicroscopy
X
X1
X1
X
X1
X
X
Corneal thickness
(packymetry)
X
Angle width 
screening 
(Gonioscopy)
X
Dilated Fundus 
Exam
X
X
X
X
Visual field 
assessment
(Automated 
perimetry)
Xd
Xe
Xe
IOP
X
X2
X
X
IOP (09:00, 11:00)
+/- 30 minutes
X
X
X
Blood Pressure
X
X2
X
X
Blood Pressure 
(09:00, 11:00)
X
X
X
Pulse rate
X
X2
X
X
Pulse Rate (09:00, 
11:00)
X
X
X
Dispense study meds
X
X
Instill Meds in office
X
X
Alcon - Business Use Only 
 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
2.0; Most-Recent; Effective; CURRENT
TDOC-0051572
Protocol - Clinical
10-Apr-2017


Page 31 of 71
* Visit 1 and 2 may be combined if the subject IOP was measured at 09:00, DUOTRAV taken on the 
previous morning at 09:00 ± 1hr or evening at 21:00 ± 1hr and all other study assessments can be 
completed as per protocol
1 morning only
2 09:00 ± 2 hrs
a Perform assessments on subjects who discontinue study participation prior to Week 6 visit.
b Must be signed/dated before study procedures are performed.
c Required on all female subjects of childbearing potential.
d VF can have been performed 30 days before Screening to E2 visit
e May be conducted anytime during the visit.
Visit 1*
Screening
Visit 2*
Eligibility 1
Visit 3
Eligibility 2
(Randomization)
Visit 4
Visit 5
Exit
Unscheduled
Visit
Early 
Exita
Adverse Events
(Both Volunteered 
and Elicited)
X
X
X
X
X
X
X
Collect Study Meds
X
X
Exit patient & 
Complete Exit Form
X
X
Alcon - Business Use Only 
 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
2.0; Most-Recent; Effective; CURRENT
TDOC-0051572
Protocol - Clinical
10-Apr-2017


Page 32 of 71
3
ABBREVIATIONS
Abbreviation
Definition
AC
Anterior chamber
ADR
Adverse drug reaction
AE
Adverse event
AEF
Adverse event Form
AMP
Adenosine monophosphate
BAK
Benzalkonium chloride
BCVA
Best-corrected visual acuity
BID
Twice a day
BP
Blood pressure
CAI
Carbonic anhydrase inhibitor
CFR
Code of Federal Regulation
IB
Investigator’s brochure
CIGTS
Collaborative Initial Glaucoma Treatment Study
Con Meds
Concomitant medications
CRF
Case report form
dB
Decibel
DUOTRAV
Travoprost (0.004% or 40µg/mL and Timolol (0.5 % or 
E1
Eligibility 1
E2
Eligibility 2
CRF
Case report form
EDC
Electronic data capture
EMEA
European Medicines Agency
ETDRS
Early treatment diabetic retinopathy study
EudraCT
European clinical trials database
FAS
Full analysis set
FDA
US Food and Drug Administration
GCP
Good clinical practice
ICF
Informed consent form
ICH
International conference on harmonization
IEC
Independent ethics committee
IMP
Investigational Medicinal Product
IOP
Intraocular pressure
IP
Investigational Product
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intra-uterine device
LACAR
Latan America and Canada
logMAR
Log10 of the minimum angle of resolution
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
Med Hx
Medical history
Alcon - Business Use Only 
 
Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
Print Date:  
Effective
2.0; Most-Recent; Effective; CURRENT
TDOC-0051572
Protocol - Clinical
10-Apr-2017


Page 33 of 71
Meds
Medications
mg
Milligram
mm
Millimeter
mmHg
Millimeters of mercury
MOP
Manual of procedures
N/A
Not applicable
NCR
Not clinically relevant
NDA
New Drug Application
OAG
Open-angle glaucoma
POAG
Primary Open-Angle Glaucoma
OC
Observed case
OD
Right eye
OHT
Ocular hypertension
OS
Left eye
OU
Both eyes
PI
Principal investigator
PQ
Polyquatemium-1
QA
Quality assurance
QD
Once a day
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
SAS statistical software, SAS Institute Inc., Cary, NC
SIMBRINZA
Brinzolamide (1% or 10mg/mL) and Brimonidine (0.2% 
or 2 mg/mL) eye drops suspension
SBP
Systolic Blood Pressure
SmPC
Summary of Product Characteristics
VF
Visual Field
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4
TABLE OF CONTENTS
Safety and Efficacy with Twice Daily Brinzolamide 1% / Brimonidine 0.2% (SIMBRINZA) as 
an Adjunctive Therapy to Travoprost 0.004% / Timolol 0.5% (DUOTRAV) ..........1
1
SYNOPSIS ...............................................................................................................3
1.1
Amendments.......................................................................................................14
2
OVERVIEW OF STUDY PLAN............................................................................30
3
ABBREVIATIONS.................................................................................................32
4
TABLE OF CONTENTS........................................................................................34
5
INTRODUCTION..................................................................................................37
5.1
Study Rationale and Background .......................................................................37
5.2
Known and Potential Risks ................................................................................38
5.3
Potential Benefits................................................................................................41
6
ETHICS ..................................................................................................................42
7
PROTOCOL AMENDMENTS ..............................................................................43
8
SUBJECT POPULATION......................................................................................43
9
TREATMENTS ADMINISTERED........................................................................43
9.1
Identity of Study Treatments ..............................................................................44
9.2
Usage ..................................................................................................................44
9.2.1
Route of Administration .................................................................................44
9.2.2
Duration of Exposure .....................................................................................45
9.2.3
Methods Used to Determine Dosage..............................................................45
9.3
Accountability Procedures..................................................................................45
9.4
Subject Confidentiality and Methods Used to Minimize Bias ...........................46
10
STUDY PROCEDURES ........................................................................................46
10.1
Outline of Study .................................................................................................46
10.2
Visits and Examinations .....................................................................................47
10.2.1
VISIT 1 (Screening) .......................................................................................48
10.2.2
VISIT 2 (ELIGIBILITY 1) & VISIT 3 (ELIGIBILITY 2): [09:00 (+/-30 
MIN), 11:00 (+/- 30 MIN) EXAMINATIONS] .............................................50
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10.2.3
VISIT 4 (WEEK 2) & VISIT 5 (WEEK 6, EXIT): [09:00 (+/-30 MIN), 11:00 
(+/- 30 MIN) EXAMINATIONS] ..................................................................52
10.3
Unscheduled Visits .............................................................................................53
10.4
Discontinued Subjects ........................................................................................54
10.4.1
Screen Failure Subjects ..................................................................................55
10.5
Clinical Study Termination.................................................................................55
11
ANALYSIS PLAN .................................................................................................56
11.1
Subject Evaluability............................................................................................56
11.2
Analysis Data Sets..............................................................................................56
11.2.1
Full Analysis Set.............................................................................................56
11.2.2
Safety Analysis Set.........................................................................................56
11.3
Demographic and Baseline Characteristics........................................................56
11.3.1
Demographic Characteristics..........................................................................57
11.3.2
Baseline Characteristics..................................................................................57
11.4
Efficacy Analysis................................................................................................57
11.4.1
Primary Efficacy.............................................................................................57
11.4.2
Secondary Efficacy.........................................................................................58
60
11.5
Handling of Missing Data ..................................................................................60
11.6
Multiplicity.........................................................................................................60
11.7
Safety Analysis ...................................................................................................61
11.8
Health Economics...............................................................................................61
11.9
Interim Analyses.................................................................................................61
11.10
Sample Size Justification....................................................................................62
12
ADVERSE EVENTS..............................................................................................62
12.1
General Information ...........................................................................................62
12.2
Monitoring for Adverse Events ..........................................................................63
12.3
Procedures for Recording and Reporting AEs and SAEs...................................63
12.4
Intensity and Causality Assessments..................................................................66
12.5
Unmasking of the Study Treatment....................................................................66
12.6
Follow-Up of Subjects with Adverse Events......................................................67
12.7
Pregnancy in the Clinical Trial...........................................................................67
13
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS ....................68
13.1
Completion of Source Documents and Case Report Forms...............................68
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13.2
Data Review and Clarifications..........................................................................68
13.3
Regulatory Documentation and Records Retention ...........................................69
14
References...............................................................................................................70
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5
INTRODUCTION
5.1
Study Rationale and Background
Glaucoma is a group of progressive optic neuropathies caused by the degeneration and death 
of retinal ganglion cells and the axons that form the optic nerve that may lead visual field 
deterioration if left untreated (Weinreb 2004).
The biological mechanisms of the retinal ganglion cell degeneration are not precisely known, 
but risk factors for glaucoma and disease progression have been identified, such as elevated 
intraocular pressure (IOP), race, age, vascular disease and family history. However, elevated 
IOP is the only modifiable risk factor hence all treatment is targeted towards lowering IOP.
Although uncontrolled glaucoma may lead to optic nerve atrophy and blindness, glaucoma is 
often associated with a reduced quality of life even before blindness occurs (Wilson 1998, Wu 
2008). The primary goal of glaucoma treatment, therefore, is to preserve the subject’s visual 
function and quality of life. Physicians often follow a stepwise management strategy that aims 
to maximize IOP lowering while minimizing adverse events.
Typically treatment is initiated with a topical monotherapy such as a prostaglandin analogue or 
beta blocker. If the initial therapy is inadequate or poorly tolerated, additional therapies can be 
added on or subjects can be switched to an alternate therapy. Among the various treatment 
options currently available, prostaglandin analogues (PGAs) are often preferred as initial 
monotherapy because of their IOP lowering efficacy, low frequency of systemic side effects, 
and lower frequency of instillation compared with older therapies. Indeed, PGAs have largely 
replaced topical beta-blockers as first-line monotherapy over the past 10 years (Nasser 2006, 
Stewart 2008, Stewart 2005).
Despite the efficacy of the PGAs, a significant proportion of patients will fail on monotherapy 
and will require more than one medication to reach a target IOPs (IOP at which optic nerve 
damage will not progress). In the Ocular Hypertension Treatment Study (OHTS) by year five
almost 40% of subjects needed two or more medications to achieve their target IOP (Kass 
2002), and in the Collaborative Initial Glaucoma Treatment Study (CIGTS) after year two, 
more than 75% of subjects needed two or more medications to reach their target IOP (Lichter 
2001). As such, clinicians often add on therapy or, switch to fixed dose combinations to better 
manage the disease
One of the commonly used topical IOP lowering combination drugs used to treat elevated IOP 
is DUOTRAV. A fixed dose combination eye drop containing a topical prostaglandin 
analogue, travoprost 40 µg/mL, and a topical beta-adrenergic receptor blocking agent, timolol 
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5 mg/mL, which lower lOP by complementary mechanisms of action. The safety and efficacy 
of both travoprost and timolol have been established as single and adjunctive therapy in well-
controlled clinical studies in thousands of patients diagnosed with open-angle glaucoma or 
ocular hypertension. A summary of the known and potential risks and benefits associated with 
DUOTRAV can be found in the Summary of Product Characteristics (SmPC) or Product 
Information equivalent.
SIMBRINZA is a fixed dose combination eye drop suspension comprised of a carbonic 
anhydrase Inhibitor (CAI), brinzolamide (1% or 10mg/mL), and an Alpha agonist, brimonidine 
(0.2% or 2 mg/mL) which lower lOP by complementary mechanisms of action. In July 2014, 
brinzolamide/brimonidine fixed combination received marketing approval in the EU-27 
member states with a 2 times per day (BID) dosing regimen under the trade name of 
SIMBRINZA. Earlier, in April 2013, brinzolamide/brimonidine fixed combination received 
marketing approval in the United States with 3 times per day (TID) dosing under the trade 
name of SIMBRINZA. A summary of the known and potential risks and benefits associated 
with SIMBRINZA can be found in the Summary of Product Characteristics (SmPC) or Product 
Information equivalent
The fixed dose combination of both DUOTRAV and SIMBRINZA, are effective, subjects may 
require further IOP lowering because of disease progression. However, the complexity of 
treatments (doses per day, number of bottles) has been shown to affect patient adherence to 
medications and often precludes adding further therapies; indeed, clinicians often plan for a 
surgical intervention when a third bottle is added to the treatment regime. 
With the approval of SIMBRINZA, clinicians have the option of managing glaucoma with all 
4 classes of medications (PGAs, beta blockers, CAIs and alpha agonists) thereby providing 
maximal medical therapy in 2 bottles with 3 drops/day. However, as some of these medications 
have a similar mechanism of action (inhibit production or increase flow), the IOP lowering that 
may be achieved as monotherapy, may be even lower when used together. This study will 
therefore investigate the additive IOP lowering effect achieved when SIMBRINZA is used 
adjunctively to DUOTRAV in patients with OAG or OH after 6 weeks of treatment.
5.2
Known and Potential Risks
SIMBRINZA (brinzolamide 1%/brimonidine 0.2%)
The most common ocular adverse drug reactions (ADRs) reported in clinical studies with the 
use of the fixed combination SIMBRINZA were hyperemia, visual disturbances, ocular 
discomfort, and the development of ocular allergic type reactions (Aung 2014, Gandolfi 2014). 
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These types of ADRs are known nonserious risks associated with the use of one or both of the 
individual components. Common systemic ADRs reported included dysgeusia, oral dryness, 
and fatigue/drowsiness. Like common ocular ADRs, these systemic events are known class 
effects of one or both of the individual components. While a bitter taste and dry mouth may be 
unpleasant, neither adverse reaction poses a safety issue for the use of SIMBRINZA. The 
development of fatigue/drowsiness may impair a person’s ability to operate a motor vehicle or 
machinery. Subjects should be advised of this possible risk while using SIMBRINZA.
Decreased blood pressure and/or pulse rate have also been identified as systemic risks 
associated with the use of an alpha-2 adrenergic agonist (Kable 2000, Kamibayashi 2000). The 
use of brimonidine tartrate 2 mg/mL has been associated with minimal decreases in blood 
pressure. Some subjects who dosed with SIMBRINZA experienced decreases in blood 
pressure similar to those observed with the use of brimonidine as monotherapy.
With topical ocular carbonic anhydrase inhibitors (CAI) such as brinzolamide, there is an 
increased potential for developing corneal edema in subjects with low endothelial cell counts. 
No reports of corneal edema have been reported to date in clinical trials with the use of 
SIMBRINZA (dosed BID or TID). Carbonic anhydrase inhibitors may also produce acid-base 
and electrolyte alterations. This is more likely with the use of an oral CAI (eg, acetazolamide); 
however, since brinzolamide is absorbed systemically, there is a potential risk for the 
development of acid-base and electrolyte alterations with the use of SIMBRINZA. This risk is 
higher in subjects concomitantly dosing with high dose salicylate therapy. No report of an 
acid-base or electrolyte alteration associated with the use of SIMBRINZA has been reported to 
date in clinical trials.
The brinzolamide component of the fixed combination is a sulfonamide and although it is 
administered as a topical ocular drug, it is absorbed systemically. Therefore, the same types of 
adverse reactions that are attributable to sulfonamides may occur with topical ocular 
administration of SIMBRINZA. Rare fatalities have occurred with systemic use of 
sulfonamides. Sulfonamide reactions have not been reported to date with the use of Simbrinza
in clinical trials.
Simbrinza is preserved with benzalkonium chloride (BAK). BAK has been reported to cause 
punctate keratopathy and/or ulcerative keratopathy. Close monitoring is required with frequent 
or prolonged use in dry eye subjects, or in conditions where the cornea is compromised. The 
BAK concentration of SIMBRINZA is lower 
 relative to the BAK concentration in 
each of the individual components (0.1 mg for brinzolamide 10 mg/mL and 0.05 mg for 
brimonidine 2 mg/mL).
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Pharmacokinetic data did not indicate a systemic pharmacokinetic drug-drug interaction 
between the individual active components in SIMBRINZA. Systemic concentrations of the 
individual active components after dosing with SIMBRINZA were similar to the systemic 
concentrations after dosing with the individual components.
Overall, no additional risks were identified with the use of SIMBRINZA relative to the known 
risks of the individual components.
DUOTRAV (Travoprost 0.004% / Timolol 0.5 %)
Like other topically applied IOP lowering medications, travoprost and timolol are absorbed 
systemically. Due to the beta-adrenergic component of timolol, the same types of 
cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic 
blocking medicinal products may occur. The incidence of systemic ADRs after topical 
ophthalmic administration is lower than for systemic administration.
In clinical studies involving 2170 subjects treated with DUOTRAV the most frequently 
reported treatment-related adverse reaction was ocular hyperaemia 
Other common adverse events associated with this class of medicinal product include: punctate 
keratitis, eye pain, visual disturbance, vision blurred, dry eye, eye pruritus, ocular discomfort 
and eye irritation.
Less common or rare adverse reactions include: keratitis, iritis, conjunctivitis, anterior 
chamber inflammation, blepharitis, photophobia, visual acuity reduced, asthenopia, eye 
swelling, corneal erosion, meibomianitis, conjunctival hemorrhage, eyelid margin crusting, 
trichiasis, distichiasis. lacrimation increased, erythema of eyelid, growth of eyelashes eye 
allergy, conjunctival edema, eyelid edema, bradycardia, arrhythmia, heart rate irregular, 
hypertension, hypotension, dyspnea, postnasal drip, dysphonia, bronchospasm, cough, throat 
irritation, oropharyngeal pain, nasal discomfort, dermatitis contact, hypertrichosis, urticaria, 
skin discoloration, alopecia, skin hyperpigmentation (periocular), pain in extremity, 
chromaturia, thirst, fatigue, alanine aminotransferase increased, aspartate aminotransferase 
increased, hypersensitivity, nervousness, dizziness, and headache.
No specific drug interaction studies have been performed with travoprost or timolol. There is a 
potential for additive effects resulting in hypotension and/or marked bradycardia when 
ophthalmic beta blocker solution is administered concomitantly with oral calcium channel 
blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis 
glycosides, parasympathomimetics, guanethidine. The hypertensive reaction to sudden 
withdrawal of clonidine can be potentiated when taking beta-blockers. 
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Pa ge 4 1 of 7 1
P ote ntiate d s y ste mic beta- bl oc ka de (e g, decrease d heart rate, de pressi o n) has bee n re p orte d 
d uri n g c o m bi ne d treat me nt wit h C Y P 2 D 6 i n hi bit ors ( e g, q ui ni di ne, fl u o xeti ne, par o xeti n e) a n d 
ti m ol ol. M ydriasis res ulti n g fr o m c o nc o mita nt use of o p ht hal mic beta -bl oc kers a n d a dre nali ne 
(e pi ne p hri ne) has bee n re p orte d occasi o nall y. Beta-bl oc kers ma y  i ncrease t he h yp o gl yc ae mic 
effect of a nti dia betic me dici nal pr o d ucts. Beta- bl oc kers ca n mas k t he si g ns a n d s ym pt o ms of 
h y p o gl yc e mia.
5. 3
P ote nti al Be nefits
SI M B RI N Z A
Res ults fr o m cli nical st u dies e val uati n g bri nz ola mi de/ bri m o ni di ne a d mi nistere d TI D or BI D 
s h o w t hat t he I O P l o weri n g efficac y of t he fi xe d c o m bi nati o n is statisticall y s u peri or t o eac h of 
its i n di vi d ual c o m p o ne nts ( Katz 2 0 1 3, N g uye n 2 0 1 3, A u n g 2 0 1 4). A n a d diti o nal m ultice nter 
cli nical st u d y has s h o w n t hat t he I O P l o weri n g efficac y of t he bri nz ola mi de/ bri m o ni di ne 
a d mi nistere d BI D (fi xe d c o m bi nati o n) is n o ni nferi or t o t he i n di vi d ual c o m p o n e nts 
a d mi nistere d c o nc o mita ntl y  ( u nfi xe d c o m bi nati o n) ( Ga n d olfi 2 0 1 4).
T here are se veral p ote ntial be nefits t o SI M B RI N Z A
fi xe d c o m bi nati o n t hera p y s uc h as:
a n I O P l o weri n g effect of u p t o 3 5 % ( A u n g 2 0 1 4, Ga n d olfi 2 0 1 4, Katz 2 0 1 3, N g u ye n 
2 0 1 3)
a safety pr ofile t hat is c o nsiste nt wit h t hat of t he i n di vi d ual c o m p o ne nts ( A u n g 2 0 1 4, 
Ga n d olfi 2 0 1 4, Katz 2 0 1 3, N g u ye n 2 0 1 3, W hits o n 2 0 1 3)
a l o wer e x p os ure t o preser vati ves vers us t he i n di vi d ual c o m p o ne nts
t he p ote ntial f or i ncrease d s u bject a d here nce ( Hi g ge n b ot ha m 2 0 1 0, Sc h wartz 2 0 1 0) 
vers us t he d osi n g t he i n di vi d ual c o m p o ne nts c o nc o mita ntl y
a n alter nati ve t hera p y o pti o n f or s u bjects i n w h o m t hera p y wit h b eta-bl oc kers is 
c o ntrai n dicate d.
D U O T R A V
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
D U O T R A V (tra v o pr ost 0. 0 0 4 % / ti m ol ol 0. 5 %) is effecti ve i n l o weri ng I O P a n d ha ve ofte n 
re place d β-bl oc kers a n d P G As . I n s o me s u bjects h o we ver, tar get I O Ps will n ot be reac he d a n d 
a n a dj u ncti ve t hera p y will be re q uire d.
T he a p pr o val of SI M B RI N Z A gi ves cli nicia ns t he o pti o n t o ma na ge t he disease wit h 4 classes 
of me dicati o ns ( P G As, beta bl oc kers, C AIs a n d al p ha a g o nists) usi n g 3 dr o p s/ da y. 


Page 42 of 71
Nevertheless, as some of these medications have the same mechanism of action, the IOP 
lowering they may achieve as a monotherapy may be even lower when used together. 
Alcon is investigating the effectiveness of SIMBRINZA, dosed twice daily, as an adjunctive 
therapy to DUOTRAV in subjects who require further IOP lowering. This combination of 
medications may expand the treatment options available to both clinicians and subjects in 
whom DUOTRAV alone does not provide sufficient IOP lowering.
6
ETHICS
This clinical study will be conducted in accordance with the principles of the Declaration of 
Helsinki, and in compliance with the International Conference on Harmonization (ICH) E6 
Good Clinical Practice (GCP) Consolidated Guideline and other regulations as applicable. The 
Investigator and all clinical study staff will conduct the clinical study in compliance with the 
protocol. The Investigator will ensure that all personnel involved in the conduct of the study 
are qualified to perform their assigned responsibilities through relevant education, training, and 
experience.
Before clinical study initiation, this protocol, the informed consent form (and assent form, if 
applicable), any other written information given to subjects, and any advertisements planned 
for subject recruitment must be approved by an Independent Ethics Committee/Institutional 
Review Board (IEC/IRB). The Investigator must provide documentation of the IEC/IRB 
approval to the Sponsor. The approval must be dated and must identify the applicable protocol, 
amendments (if any), informed consent form, assent form (if any), all applicable recruiting 
materials, written information for subject, and subject compensation programs, if any. The 
IEC/IRB must be provided with a copy of the Investigator’s Brochure, any periodic safety 
updates, and all other information as required by local regulation and/or the IEC/IRB. At the 
end of the study, the Investigator will notify the IEC/IRB about the study’s completion. The 
IEC/IRB also will be notified if the study is terminated prematurely. Finally, the Investigator 
will report to the IEC/IRB on the progress of the study at intervals stipulated by the IEC/IRB.
Voluntary informed consent will be obtained from every subject (and/or legal representative, as 
applicable) prior to the initiation of any screening or other study-related procedures. The 
Investigator must have a defined process for obtaining consent. Specifically, the Investigator, 
or designee, will explain the clinical study to each potential subject and the subject must 
indicate voluntary consent by signing and dating the approved informed consent form. The 
subject must be provided an opportunity to ask questions of the Investigator, and if required by 
local regulation, other qualified personnel. The Investigator must provide the subject with a 
copy of the consent form written in a language the subject understands. The consent document 
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must meet all applicable local laws and will provide subjects with information regarding the 
purpose, procedures, requirements, and restrictions of the study, along with any known risks 
and potential benefits associated with the investigational product, the available compensation, 
and the established provisions for maintaining confidentiality of personal, protected health 
information. Subjects will be told about the voluntary nature of participation in the study and 
will be provided with contact information for the appropriate individuals should questions or 
concerns arise during the study. The subject also will be told that their records may be accessed 
by appropriate authorities and Sponsor-designated personnel. The Investigator must keep the 
original, signed copy of the consent and must provide a duplicate copy to each subject.
7
PROTOCOL AMENDMENTS
Modification of the protocol is prohibited without prior written agreement in the form of a 
protocol amendment. All amendments will be created by the Sponsor and must be approved by 
the IEC/IRB prior to implementation except when required to mitigate immediate safety risks 
or when the changes involve only logistical or administrative revisions. 
Amendments may necessitate that the informed consent and other study-related material be 
revised. If the consent form is revised, all subjects currently enrolled in the study may be 
required by the IRB/IEC to sign the approved, revised informed consent form.
8
SUBJECT POPULATION
The study population includes approximately 240 subjects to be randomized at approximately 
40 sites globally. Enrollment will be competitive. To participate in the study, subjects must be 
on DUOTRAV (travoprost 0.004% / timolol 0.5 %) solution therapy for at least 4 weeks (28 
days) either in the morning or evening prior to screening, have a mean IOP measurement at 
09:00 in at least 1 eye (same eye, study eye) ≥ 19 and ≤ 28 mmHg at 2 consecutive visits 
(Eligibility 1 and Eligibility 2). A subject may be re-screened if they screen failed due to 
eligibility criteria defined in the original version of the protocol. Refer to the CRF Completion 
Guidelines for further information on EDC documentation guidance. The expected duration of 
subject participation in the study is approximately 8 weeks (42 days, 5 visits). The complete 
inclusion and exclusion criteria are presented in Section 1.
9
TREATMENTS ADMINISTERED
At the Screening Visit, the PI will confirm that subjects have been on continuous morning or 
evening DUOTRAV (travoprost 0.004% / timolol 0.5 %) therapy for at least 28 days. If
qualified, each subject will continue with open label study DUOTRAV, dosed at 
approximately the same time (evening or morning) for the duration of the study.
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For randomization into the study, subjects will be randomly assigned through IRT; a generated 
subject number will be automatically populated in the EDC system. Subjects will be 
randomized in a 1:1 manner to receive treatment with either SIMBRINZA or Vehicle
adjunctively to their DUOTRAV therapy. Throughout the study, the Investigator will be 
responsible for the accounting of all study medications and will ensure they are not used in any 
unauthorized manner.
9.1
Identity of Study Treatments
Investigational Product (IP): 
SIMBRINZA
Control Group:
Vehicle 
Background Medication: 
DUOTRAV
SIMBRINZA and Vehicle will be supplied in identical opaque DROP-TAINER bottles with 
masked labels indicating that the product is for investigational use only, and will be identified 
both by kit and protocol number. Each bottle will be filled to a volume of 5 mL with 
SIMBRINZA or Vehicle. Masked Investigational Products (SIMBRINZA or Vehicle) should 
be securely stored in accordance with the label. The Investigational and Vehicle Products will 
be provided in identical packaging with identical labels. The labels will include the protocol 
number, a statement that the products are for investigational use only and any other 
information required per local regulation
DUOTRAV will be provided open label by the Sponsor for the clinical trial following local 
country regulations. 
A temperature log will be maintained at each investigational site documenting appropriate 
storage conditions of the investigational products and will be made available for the study 
monitor to inspect.
9.2
Usage
9.2.1
Route of Administration
During the time the subject is in the study, the supplied DUOTRAV will be used according to 
the morning or evening regimen followed prior to Screening. One drop is to be applied 
topically to the eye(s) daily in the morning (at 09:00 ± 30 min) or in the evening (at 21:00 ± 30
min). 
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Pa ge 4 5 of 7 1
O ne dr o p of mas ke d I P is t o be a p plie d t o picall y  t o t he e ye(s) at 0 9: 0 0 ( ± 3 0 mi n) a n d 2 1: 0 0 ( ± 
3 0 mi n).
T he st u d y  me dicati o ns s h o ul d be d ose d i n b ot h e yes u nless t here is a p ote ntial safety iss ue t o 
t he s u bject ( or is u n necessar y) i n t he o pi ni o n of t he I n vesti gat or. S u bjects s h o ul d be re mi n de d 
t o:
Ge ntl y  sha ke t he mas ke d I P pri or t o i nstillati o n,
As e ve ni n g i nstillati o n of b ot h I O P -l o weri n g me dicati o ns occ urs at t he sa me ti me, i nstill t he 
D U O T R A V first, wait 1 5 mi n utes, a n d t he n i nstill t he mas ke d I P.
9. 2. 2
D ur ati o n of E x p os ure
S u bject’s me dical c hart s h o ul d c o nfir m t he use of t he m or ni n g or e ve ni n g d ose of D U O T R A V
(tra v o pr ost 0. 0 0 4 % / ti m ol ol 0. 5 %) f or at least 4 wee ks ( 2 8 da ys) i m me diatel y pri or t o 
scree ni n g.
Mas ke d
I P (SI M B RI N Z A
or Ve hicle ) will be recei ve d at Visit 3 ( Eli gi bilit y  2 visit) f oll o wi n g 
ra n d o mizati o n f or t he 4 2 ± 5 da y s treat me nt p hase.
9. 2. 3
Met h o ds Use d t o Deter mi ne D os a ge
T he d osa ge a n d BI D d osi n g re gi me n f or SI M B RI N Z A
i n t his st u d y is base d o n t he d osa ge a n d 
d osi n g re gi me n of t he mar kete d pr o d uct. 
T he d osa ge a n d Q D d osi n g re gi me n f or D U O T R A V is base d o n t he d osa ge a n d d osi n g 
re gi me n of t he mar kete d pr o d uct.
9. 3
Acc o u nt a bilit y Pr oce d ures
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
U p o n recei pt of mas ke d I P fr o m t he S p o ns or, 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 of all pr o d ucts. Desi g nate d st u d y staff will pr o vi de t he st u d y dr u gs t o t he s u bjects i n 
acc or da nce wit h t heir Electr o nic Data Ca pt ure ( E D C ) assi g ne d s u bject n u m bers a n d t he 
ra n d o mizati o n sc he d ule. 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 dy 
treat me nt dis pe nsati o n a n d c ollecti o n of mas ke d I P f or eac h s u bject. 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 yi 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 dy s u p plies u nless
ot her wise i nstr ucte d b y t he S p o ns or .


Page 46 of 71
9.4
Subject Confidentiality and Methods Used to Minimize Bias
The Investigator must ensure that the subject’s anonymity is maintained throughout the course 
of the study. In particular, the Investigator must keep a subject log with confidential identifying 
information that corresponds to the subject number, subject name and medical ID number of 
each study participant. At the end of the clinical study, the Sponsor will collect a copy of the 
subject log without any identifying subject information. All documents submitted to the 
Sponsor will identify the subjects exclusively by number. No other personally identifying 
information should be transmitted to the Sponsor.
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 
knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of end points, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the Investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias have passed.
This study is double-masked, with subjects randomized to use SIMBRINZA or Vehicle for the 
duration of approximately 42 days. However, DUOTRAV solution therapy is open labeled and 
will be dosed for the duration of the masked treatment period of approximately 42 days but 
also during the screening and Eligibility periods. The Investigator, subject, Sponsor, and 
monitors involved in reporting, obtaining, and/or reviewing the clinical evaluations will not be 
aware of the specific masked treatment (SIMBRINZA or Vehicle) being administered. This 
level of masking will be maintained throughout the conduct of the study. Both SIMBRINZA
and Vehicle will be provided in identical masked bottles labeled with the protocol and kit 
numbers. Each kit will contain 1 bottle of masked IP.
The randomization scheme will be generated and maintained by the Sponsor. Only once all 
study data have been verified, validated and the database locked, will individual subjects be 
unmasked. In the event of a medical emergency where the knowledge of subject treatment is 
required, an individual Investigator will have the ability to unmask the treatment assignment 
for a specific subject.
10
STUDY PROCEDURES
10.1
Outline of Study
The study is a 6 week, multicenter, randomized, double-masked, 2-arm, parallel-group study in 
subjects with primary open-angle glaucoma and/or ocular hypertension on travoprost 0.004% / 
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timolol 0.5 % who may benefit from further IOP lowering medications. The study is divided 
into 2 sequential phases for a total of 5 visits. Phase I of the study is the open-labeled 
Screening/Eligibility Phase, which includes a Screening Visit followed by 2 Eligibility Visits 
(E1 and E2). Phase II of the study is the randomized, double-masked treatment phase (Masked 
Treatment Phase) which includes 2 on-therapy visits: Visit 4 (at Week 2) and Visit 5 (Week 6, 
Exit Visit) as shown in Table 10-1.
Table 10–1                Study Plan by Treatment Groups
At Screening Visit the investigator should document that the subject has been previously on 
morning or evening DUOTRAV solution therapy for at least 28 days prior to Screening Visit.
10.2
Visits and Examinations
All procedures and the correspondent scoring must be performed as detailed in the Manual of
Procedures (MOP).
Treatment Group
Study Phase
Phase I
(Screening/Eligibility Phase)
Phase II
(Masked Treatment 
Phase)
Screening and Eligibility Visits
Week 2 and Week 6 (Exit) 
Visits
SIMBRINZA + DUOTRAV
Begin dosing with study supplied 
DUOTRAV at 21:00 ±30min on 
the evening of the screening visit if 
the subject dosed with DUOTRAV
in the evenings prior to Screening, 
or begin dosing with study supplied 
DUOTRAV at 09:00 ±30min the 
following day after Screening if the 
subject dosed with DUOTRAV in 
the mornings prior to Screening.
Mean IOP for both Eligibility
Visits must be:
≥ 19 mmHg and ≤ 28 mmHg
in at least 1 eye at
09:00 time point
The same eye(s) must qualify at 
both 09:00 time points.
SIMBRINZA BID (09:00 
& 21:00)±30min and
DUOTRAV QD 
09:00±30min or 
21:00±30min
Vehicle + DUOTRAV
Vehicle BID (09:00 & 
21:00) ±30min and
DUOTRAV QD 
09:00±30min or 
21:00±30min
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10.2.1
VISIT 1 (Screening)
Subjects who were previously on travoprost 0.004% / timolol 0.5 % for at least 28 days 
(documented) prior to Screening Visit and, in the opinion of the Investigator, may benefit from 
further IOP lowering are candidates to be screened (Visit 1/ Screening). If all other 
Inclusion/Exclusion criteria are met, the Eligibility 1 (Visit 2) may occur promptly (within ~1-
5 days as convenient for site and subject).
1.
Explain the purpose, nature, and conduct of the study
2.
Complete the Informed Consent process before any screening procedures are 
performed
3.
Register the subject in EDC and obtain the subject number
4.
Screen the subject for protocol inclusion/exclusion criteria as per Section 1
5.
Document demographic information, medical history, and concomitant
medications including information on all medications used within the past
30 days. Include herbal therapies, vitamins, and all over-the-counter as well
as prescription medications
6.
Perform a urine pregnancy test if the subject is a woman of childbearing 
potential
7.
Perform pulse and blood pressure measurements
8.
Assess BCVA, OU
9.
Conduct visual field assessment (automated perimetry) OU
10. Perform a slit-lamp examination (biomicroscopy), OU
11. Perform Goldmann applanation tonometry, OU
*if subjects IOP was measured at 09:00, DUOTRAV taken on the previous 
morning at 09:00 ± 1 hr or evening at 21:00 ± 1 hr and all other study 
assessments can be completed as per protocol for Visit 1 (Screening) and Visit 2 
(E1), then Visit 1 and Visit 2 can be combined
12. Conduct gonioscopy, OU
13. Perform pachymetry, OU
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14. Perform a dilated fundus examination (Fundoscopy), OU
   15. Instruct each subject to instill DUOTRAV daily at either 09:00 or 21:00 ±30 
min, OU. 
Reminder: Investigator must document that subjects are currently on morning 
or evening dosing for at least 28 days prior to the Screening Visit. The same 
DUOTRAV dosing schedule must be followed for the entire study (morning or 
evening dosing).
  16. Schedule the subject to return in 1-5 days for the Eligibility 1 Visit (Visit 2)
*if subjects IOP was measured at 09:00, DUOTRAV taken on the previous 
morning at 09:00 ± 1 hr or evening at 21:00 ± 1 hr and all other study 
assessments can be completed as per protocol for Visit 1 (screening) and Visit 2 
(E1), then Visit 1 and Visit 2 can be combined.
Instruct Subjects who wear contact lenses to remove lenses before dosing, and 
reinsert lenses no sooner than 15 min post-instillation. Subjects should be 
reminded to wear or bring their glasses on study visit days.
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Pa ge 5 0 of 7 1
1 0. 2. 2
VI SI T  2 ( E LIGI BI LI T Y  1) & VI SI T 3 ( E LI GI BI LI T Y  2): [ 0 9: 0 0 (+/ -3 0 MI N), 1 1: 0 0 ( +/ - 3 0 MI N) 
E X A MI N A TI O N S]
T a ble 1 0 – 2                Acti vities f or Eli gi bilit y 1 a n d Eli gi bilit y 2 V isits
A cti vit y
Visit 2 - Eli gi bilit y 1 ( E 1)
Visit 3 - Eli gi bilit y 2 ( E 2)
0 9: 0 0 
1 1: 0 0
0 9: 0 0 
1 1: 0 0
Rec o nfir m t hat it is d oc u me nte d t hat t he s u bject has a d mi nistere d m or ni n g or e ve ni n g 
d ose of D U O T R A V t hera p y dail y f or 2 8 da ys.
X
D oc u me nt date a n d ti me of last i nstillati o n.
R E S C H E D U L E t he visit if t he s u bject di d n ot d ose t he pre vi o us mo r ni n g or e ve ni n g 
( 2 1: 0 0 mi mi n).
X
X
U p date Me dical
Hist or y / C o nc o mita nt Me dicati o ns
X
X
X
X
O btai n Bl o o d Press ure a n d P ulse Rate
X
X
X
X
Perf or m B C V A, O U
X
X
Perf or m slit-l a mp e xa m ( Aq ue o us cells, a q ue o us flare, le ns, stat us of le ns), O U
X
X
Meas ure
I O P ( G ol d ma n n), O U
Me a n I OP m us t be 1 9 a n d ≤2 8 m m H g i n at le ast o ne (s a me) eye(s) at 0 9: 0 0.
Me a n I O P m ust be less t h a n 2 8 m m H g i n eit her eye at al l ti me p oi nts.
( T he me a n I O P is defi ne d as t he aver a ge of t w o or m ore I O P re a di n gs i n t he s a me
eye).
X
X
X
X
Sc he d ule t he s u bject t o ret ur n f or Visit 3- Eli gi bilit y 2 ( E 2) i n 3- 5 da ys f oll o wi n g E 1
Visit pri or t o 0 9: 0 0
Verify i ncl usi o n/e xcl usi o n crit eri a.
O nly s u bjects meeti n g all re q uire me nts c a n be r a n d o miz e d
Ra n d o mize t he s u bject u p o n c o nfir mati o n of eli gi bilit y.
X
Dis pe nse t o t he s u bject t he c orres p o n di n g ma s ke d st u d y me dicati o n, d oc u me nt i n t he
dis pe nsi n g l o gs.
X
F or s u bjects we ari n g c o ntact le nses, i nstr uct t he m t o r em o ve t he le nses bef ore t he
i nstillati o n of t he st u d y me dicati o n & wait a p pr o xi matel y 1 5 mi n utes after d ose bef ore
i nserti n g t he le nses a gai n.
D U O T R A V – Dail y d osi n g i n t he m or ni n g or e ve ni n g ( 0 9: 0 0 or 2 1: 0 0 ± 3 0 mi n).
Mas ke d
I P – BI D d osi n g at 0 9: 0 0 ± 3 0 mi n a n d 2 1: 0 0 ± 3 0 mi n
X
Sc he d ule t he s uccessf ull y ra n d o mize d s u bject t o ret ur n f or Visit 4 ( Wee k 2 Visit) i n 1 4
± 3 da ys f oll o wi n g E 2 Visit pri or t o 0 9: 0 0 ( ± 3 0 mi n)
X
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  
 
 
Pri nte d B y:   
  
  
  
 
     
Pri nt Date:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 / 1 0 / 2 0 1 7  1 0 : 0 3 : 0 7  A M
 
E f f e c t i v e
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l


Pa ge 5 1 of 7 1
N O T E:
T he Visit 2 ( Eli gi bilit y  1 Visit) s h o ul d be c o n d ucte d 1-5 da y s f oll o wi n g t he Scree ni n g Visit 
or ca n be c o m bi ne d if t he s u bject s I O P was meas ure d at 0 9: 0 0 ± 3 0 mi n, D U O T R A V was ta ke n 
at 0 9: 0 0 ± 1 hr o n t he pre vi o us m or ni n g or 2 1: 0 0 ± 1 hr o n t he pre vi o us e ve ni n g a n d all ot her 
st u d y assess me nts ca n be c o m plete d as per pr ot oc ol f or V 1 (scree ni n g)
T he Visit 3 ( Eli gi bilit y  2 Visit) s h o ul d be c o n d ucte d 3-5 da y s f oll o wi n g t he Eli gi bilit y 1 
Visit.

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
D U O T R A V a n d Mas ke d IP s h o ul d be d ose d i n b ot h e y es u nless t here is a p ote ntial safet y 
iss ue ( or is u n necessar y) t o t he s u bject i n t he o pi ni o n of t he I n vesti gat or.
At t he e n d of t he Eli gi bilit y  2 Visit, if t he s u bject q ualifies t o c o nti n ue i n t he st u d y, use E D C t o 
ra n d o mize t he s u bject. T he IR T s ys te m will ret ur n t he assi g ne d kit n u m bers f or t he mas ke d 
st u d y treat me nt t o be dis pe nse d t o t he s u bject. O nce t he E D C/I R T assi g ns kit n u m bers, 
dis pe nse t he kit n u m bers assi g ne d t o t he s u bj ect.
D osi n g i nstr ucti o ns s h o ul d be pr o vi de d t o t he s u bject as f oll o ws:
a)
S u bjects weari n g c o ntact le nses s h o ul d re m o ve t he le nses bef ore i nstillati o n of eit her 
me dicati o n. F oll o wi n g i nstillati o n of t he st u d y  me dicati o ns, t he s u bject s h o ul d wait 
a p pr o xi matel y 1 5 mi n utes after t he last d ose bef ore re -i nserti n g le nses.
b)
M U S T ge ntl y s ha ke mas ke d IP bef ore use. I nstill 1 dr o p of mas ke d st u d y me dicati o n i n 
eac h affecte d e ye dail y at  0 9: 0 0 ( ± 3 0 mi n) a n d 2 1: 0 0 ( ± 3 0 mi n) f or a p pr o xi matel y 6 
wee ks. 
c)
C o nti n ue wit h 1 dr o p of D U O T R A V i n eac h affecte d e ye dail y at eit her 0 9: 0 0 ± 3 0 mi n 
or 2 1: 0 0 ± 3 0 mi n f or a p pr o xi matel y 6 wee ks.
d)
If i nstillati o n of D U O T R A V a n d mas ke d I P occ urs at a p pr o xi matel y t he sa me ti me;
i.
I nstill D U O T R A V first
ii.
Wait a p pr o xi matel y  1 5 mi n utes bef ore i nstillin g mas ke d I P
iii.
Atte m pt t o i nstill st u d y  me dicati o ns at t he sa me ti me eac h e ve ni n g


Pa ge 5 2 of 7 1
At t he Eli gi bilit y  2 Visit, sc he d ule t he s u bject t o ret ur n i n 1 4 da ys ( ± 3 da ys) i n t he m or ni n g
pri or t o 0 9: 0 0 ( ± 2 h o urs ) f or Visit 4 ( Wee k 2 Visit).
R E MI N D E R: C o nt act t he s u bject pri or t o t he Week 2 a n d Week 6 Visits t o re mi n d t he s u bject 
t o:
i nstill t he d ose of D U O T R A V at 0 9: 0 0 ( ± 3 0 mi n utes) or 2 1: 0 0 ( ± 3 0 mi n utes) a n d m aske d 
st u dy me dic ati o n at 2 1: 0 0 ( ± 3 0 mi n utes) t he d ay pri or t o t he visit,
re m ove c o nt act le nses pri or t o i nstill ati o n of st u dy me dic ati o ns a n d w ait 1 5 mi n utes bef ore 
i nserti n g t he le nses a g ai n
D O N O T d ose t he m as ke d I P or t he D U O T R A V 0 9: 0 0 m or ni n g d ose t he m or ni n g of t he 
st u dy visit. T he m or ni n g d ose of b ot h t he m aske d I P a n d D U O T R A V will be i nsti lle d i n t he 
office after t he 0 9: 0 0 I O P me as ure me nt.
D O N O T disc ar d a ny u n use d or e m pty b ottles,
bri n g all m aske d I P st u dy me dic ati o n b ottles t o t he st u dy visit,
bri n g c o nt act le nses or gl asses wit h t he m t o t he st u dy visit if t hey we ar t he m
1 0. 2. 3
VI SI T  4 ( W E E K 2) & VI SI T  5 ( W E E K 6, E XI T): [ 0 9: 0 0 ( +/-3 0 
MI N), 1 1: 0 0 ( +/ - 3 0 MI N ) E X A MI N A TI O N S]
T a ble 1 0 – 3                Acti vities f or W ee k 2 a n d
Wee k 6 ( E xit) V isits
Acti vit y
Visit 4 ( Wee k 2)
Visit 5 ( Wee k 6 )/( E xit) 
0 9: 0 0
0 9: 0 0 
1 1: 0 0
D oc u me nt date a n d ti me of last i nstillati o n.
R E S C H E D U L E t he visit if t he s u bject di d n ot d ose t he 
pre vi o us e ve ni n g o r if t he s u bject has alrea d y d ose d t he 
m or ni n g d ose.
X
X
D oc u me nt a n y c ha n ges i n Me dical Hist or y a n d
C o nc o mita nt Me dicati o ns
    X
X
X
Perf or m a uri ne pre g na nc y test if s u bject is fe male of
c hil d beari n g a ge
X
O btai n Bl o o d Press ure a n d P ulse Rate
  X
X
X
Perf or m B C V A, O U
X
X
Perf or m slit -la m p e xa m (A q ue o us cells, a q ue o us flare,
le ns, stat us of le ns), O U
X
X
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7


Page 53 of 71
Activity
Visit 4 (Week 2)
Visit 5 (Week 6 )/(Exit) 
09:00
09:00
11:00
Perform Goldmann applanation tonometry, OU.
Record time of IOP measurements
X
X
X
For subjects who wear contact lenses: remind them to 
remove contact lenses before dosing and re-insert lenses 
no sooner than 15 minutes following instillation of the 
study medication.
X
X
Approximately 15 minutes after the IOP measurements, 
instill the masked IP and the DUOTRAV morning dose 
for subjects using the morning regimen in the office. 
Record the time of instillation by the site.
X
X
Perform visual field assessment (automated perimetry), 
OU
[X]
Perform dilated fundus exam. Assess vitreous, 
retina/macula/choroid, and optic nerve, including 
cup/disc ratio, OU
X
Complete Adverse Event Forms if applicable. Report all 
serious events to Alcon within 24 hours of the 
Investigator’s knowledge of the event and to the IRB, 
according to their requirements.
X
X
X
Schedule the subject to return for the next planned visit 
approximately 09:00 (± 30 min before the morning 
instillation)
X
Collect the study medications. Complete subject’s drug 
dispensing log.
X
Complete the Exit Form and exit the subject from the
study
X
[X]: Any time
NOTE:
The visit 4 (Week 2 Visit) should be conducted 14 days (± 3 days) following the Eligibility 2 Visit.
The visit 5 (Week 6 Visit) should be conducted 42 days (± 5 days) following the Eligibility 2 Visit
10.3
Unscheduled Visits
Any visit that occurs between the regularly scheduled visits must be documented in the 
Unscheduled Visit pages of the CRF. During all unscheduled visits, the following procedures 
should be conducted if at all possible:
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Obtain blood pressure and pulse rate.
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3. The following, if conducted, must be completed in the order they are listed in both eyes:
a. BCVA,
b. Slit-lamp exam,
c. IOP, and
d. Dilated Fundus exam.
4. Assess and document adverse events reported or observed.
5. The unmasked site staff will dispense extra kits as necessary.
Other assessments may be done at the discretion of the Investigator to appropriately treat the 
subject. Any additional assessments will be documented at the unscheduled visit and medical 
records. If the subject is discontinuing at the unscheduled visit, the Early Exit CRFs should be 
completed rather than the CRFs for the Unscheduled Visit and the appropriate Exit procedures 
should be completed (see sections 10.4 and 10.5).
10.4
Discontinued Subjects
Discontinued subjects are those who withdraw or are withdrawn from the study after being 
successfully randomized into the study. Subjects may discontinue from the study at any time 
for any reason. Subjects may also be discontinued from the study at any time if, in the opinion 
of the Investigator, their continued participation poses a risk to their health. Discontinued 
subjects will not be replaced (ie, their subject numbers will not be re-assigned/re-used).
Should a subject exhibit any clinically relevant signs, symptoms, or other clinical observations 
that possibly could be associated with suspected sensitivity or intolerance to one of the study 
treatments, the Investigator must document those observations on an Adverse Event (AE) 
Form.
Any subject who exits early from the study must undergo all procedures outlined at Week 6. 
Additionally, the Exit Form must be completed and one of the following reasons for 
discontinuation must be identified:
• Discontinued Study due to Adverse Event
• Discontinued Study due to Death
• Discontinued Study due to Lack of Efficacy
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Pa ge 5 5 of 7 1
• Disc o nti n ue d St u d y d ue t o Lost t o F oll o w U p
• Disc o nti n ue d St u d y 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 St u d y d ue t o P h ysicia n Decisi o n
• Disc o nti n ue d St u d y d ue t o Pre g na nc y
• Disc o nti n ue d St u d y  d ue t o Pr ot oc ol Vi olati o n
• Disc o nti n ue d St u d y 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 St u d y  d ue t o Wit h dra wal b y S u bject
• Disc o nti n ue d St u d y d ue t o Ot her Reas o ns
1 0. 4. 1
Scree n F ail ure S u bjects
Scree n fail ures a re t h ose s u bjects w h o, after I C F is si g ne d, d o n ot q ualif y  f or t he st u d y a n d 
t heref ore are N O T ra n d o mize d. O nl y  a vaila ble i nf or mati o n fr o m scree ni n g a n d E 1 & E 2 V isits 
are c ollecte d i n E D C f or t h ose s u bjects 
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 of t he ter mi nati 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 om ptl y  n otif y t he I E C/IR 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 
i n vesti gati o nal 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 n i n vesti ga ti o nal site or ter mi nati o n of a st u dy ma y  i ncl u de: 

S uccessf ul c o m pleti o n of t he st u d y

T he st 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 g ui 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

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
I nteri m a nalys is res ults met pre-s pecifie d st o p pi n g r ule
T he I n vesti gat or als o ma y 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, it will i m me diatel y  n otif y t he I n vesti gat or(s) 


Page 56 of 71
by telephone and subsequently will provide written confirmation of and instructions for study 
termination.
11
ANALYSIS PLAN
11.1
Subject Evaluability
The final subject evaluability will be determined prior to breaking the code for masked 
treatment assignment and locking the database. 
11.2
Analysis Data Sets
11.2.1
Full Analysis Set
The full analysis set (FAS) is the primary analysis set for the study; all primary, secondary 
 
 analyses will be based on the FAS.
All randomized subjects who receive study medication and who complete at least 1 scheduled 
on-therapy study visit will be evaluated in the full analysis set.
11.2.2
Safety Analysis Set
Safety analyses will be conducted using the safety analysis set on a treatment-emergent basis. 
The safety analysis set will be used for each of the safety parameters and adverse events (AEs) 
occurring after exposure to investigational products administered during this study. 
Safety data is to be collected for each subject beginning at the time of informed consent. 
Should any AEs occur prior to investigational products exposure, these AEs will be presented 
separately from those treatment-emergent AEs considered in the safety analysis. 
11.3
Demographic and Baseline Characteristics
Subject characteristics summaries include tables and listings such as demographics (age, 
gender, race, iris color, and region) and baseline characteristics (baseline IOP by time point, 
baseline diurnal IOP, baseline IOP category (19-24 mmHg, >24-28 mmHg), and diagnosis for 
all analysis sets (safety and FAS). All descriptive summary statistics will be displayed with n 
and % for categorical data, and with mean, standard deviation, median, minimum, and 
maximum for continuous data. Tables will be presented by treatment and overall.
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Print Date:  
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TDOC-0051572
Protocol - Clinical
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Pa ge 5 7 of 7 1
1 1. 3. 1
De m o gr a p hic C h ar acteristics
A ge will be s u m marize d as a c o nti n u o us varia ble as well as cate g oricall y  ( < 6 5, ≥6 5 a n d 
f urt her m ore as < 5 0, 5 0-6 4, ≥6 5). I n a d diti o n, se x , race, iris c ol or a n d re gi o n will be 
su m marize d as cate g orical varia bles.
1 1. 3. 2
B aseli ne C h ar acteristics
Baseli ne I O P by ti me p oi nt a n d di ur nal baseli ne I O P will be s u m marize d as c o nti n u o us 
varia bles. I n a d diti o n, baseli ne I O P ( 1 9- 2 4 m m H g, > 2 4 -2 8 m m H g ), will be s u m marize d as a
cate g orical varia bles.
D U O T R A V t ype ( P Q or B A K f or m ulati o ns) will be als o c ollecte d at baseli ne f or eac h 
i n di vi d ual s u bject.
1 1. 4
Effic ac y A n al ysis
U nless ot her wise s pecifie d, all si g nifica nce testi n g will be at t he 5 % si g nifica nce le vel t w o-
si de d.
Efficac y  a nalys es will be base d o n t he F ull A nal ysis Set ( F A S), defi ne d as all ra n d o mize d 
s u bjects w h o recei ve d a d ose of st u d y me dicati o n a n d ha d at least o ne of t he t w o sc he d ule d o n-
t hera py visits. 
O ne e y e fr o m eac h patie nt will be c h ose n as t he st u d y  e ye a n d o nl y t he st u d y  e ye will be use d 
f or a nalys is. If onl y 1 of a patie nt’s e y es is d ose d, t he d ose d e ye will be selecte d as t he st u d y 
e ye. If b ot h e yes are d ose d, t he w orse e val ua ble e ye will be selecte d as t he st u d y  e ye. W orse 
e ye is defi ne d as t he e ye wit h t he hi g her I O P at 0 9: 0 0 a vera ge d acr oss t he 2 eli gi bilit y  visits. If 
b ot h e y es are e q ual t he n t he w orse e ye will be defi ne d as t he e ye wit h t he hi g her I O P at 1 1: 0 0 
a vera ge d acr oss t he 2 eli gi bilit y  visits. If b ot h e yes are e q ual t he n t he ri g ht e y e will be selecte d 
f or a nalys is.
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 t he a d diti ve effect of bri nz ola mi de 1 % 
/ bri m o ni di ne 0. 2 % i n s u bjects wit h eit her o pe n-a n gle gla uc o ma or oc ular h yperte nsi o n w h o are 
c urre ntl y o n D U O T R A V (tra v o pr ost 0. 0 0 4 % / ti m ol ol 0. 5 %).
T he pri mar y  e n d p oi nt is:

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
C h a n ge fr o m baseli ne i n di ur nal I O P at Wee k 6 


Pa ge 5 8 of 7 1
T he pri mar y  efficac y a nal ysis will be a n assess me nt of differe nces bet wee n treat me nts i n mea n 
c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6 ( patie nt I O P c ha n ge fr o m baseli ne a vera ge d 
o ver t he 0 9: 0 0 a n d 1 1 : 0 0 ti me p oi nts).
1 1. 4. 1. 1
St atistic al H y p ot heses
T he n ull a n d alter nati ve h y p ot heses f or t he pri mar y a nal ys is are:
H 0: μBri nz Bri m + D U O T R A V = μ Ve hicle + D U O T R A V
H 1: μBri nz Bri m + D U O T R A V ≠ μ Ve hicle + D U O T R A V
w here μ Bri nz Bri m + D U O T R A V refers t o mea n di ur nal I OP c ha n ge fr o m baseli ne f or s u bjects 
ra n d o mize d t o recei ve bri nz ola mi de / bri m o ni di ne pl us D U O T R A V , a n d μVe hicle + D U O T R A V refers t o 
mea n di ur nal I O P c ha n ge fr o m baseli ne f or s u bjects ra n d o mize d t o recei ve Ve hicle pl us 
D U O T R A V . 
T h us , s uccess reflects a greater re d ucti o n i n mea n di ur nal I O P fr o m baseli ne at Wee k 6 f or t he 
a dj u ncti ve t hera p y ( bri nz ola mi de / bri m o ni di ne pl us D U O T R A V ) relati ve t o Ve hicle pl us D U O T R A V .
1 1. 4. 1. 2
A n al ysis Met h o ds
T he treat me nt differe nce i n mea n di ur nal I O P c ha n ge f r o m baseli ne at Wee k 6 will be teste d 
base d o n t he least s q uares mea ns deri ve d fr o m a n a nal ys is of c o varia nce m o del. T his m o del 
will i ncl u de treat me nt as a fi xe d effect a n d t he baseli ne 9: 0 0 I O P as a c o variate; 
Descri pti ve statistics will als o be prese nte d f or t he pri mar y  e n d p oi nt at Wee k 6. 
1 1. 4. 1. 2. 1
S u b gr o u p A n al ysis Met h o ds
Pla n ne d s u b gr o u p a nal ys es will assess t he i m pact of sites a n d de m o gra p hic s u b gr o u ps o n 
o verall st u d y  res ults a n d assess t he efficac y i n eac h s u b gr ou p. S u b gr o u ps of a ge cate g or y          
( < 5 0, 5 0 - 6 5, >6 5), se x, race (Ca ucasia n, Blac k, Asia n, His pa nic, Ot her) , baseli ne I O P ( 1 9- 2 4 
m m H g, > 2 4 -2 8 m m H g ) a n d re gi o n ( E M E A, Asia, , L A C A R, ) will be s u m marize d 
descri pti vel y ( N, mea n, sta n dar d de viati o n) f or t he pri mar y  e n d p oi nt.
1 1. 4. 2
Sec o n d ar y Effic ac y
T he sec o n dar y  e n d p oi nts are:
D i ur nal I O P at Wee k 6

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
P erce nta ge c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6


Pa ge 5 9 of 7 1
C ha n ge fr o m baseli ne i n I O P at 1 1: 0 0 hrs at Wee k 6 
P erce nta ge c ha n ge fr o m baseli ne i n I O P at 1 1: 0 0 hrs at Wee k 6
C ha n ge fr o m baseli ne i n I O P at 0 9: 0 0 hrs at Wee k 6
Perce nta ge c ha n ge fr o m baseli ne i n I O P at 0 9: 0 0 hrs at Wee k 6
1 1. 4. 2. 1
St atistic al H y p ot heses
T he n ull a n d alter nati ve h y p ot heses f or a nal ys is of t he sec o n dar y e n d p oi nts are:
H 0: μBri nz Bri m + D U O T R A V = μ Ve hicle + D U O T R A V
H 1: μBri nz Bri m + D U O T R A V ≠ μ Ve hicle + D U O T R A V
w here μ Bri nz Bri m + D u otra v refers t o t he mea n of eac h sec o n dar y e n d p oi nt f or s u bjects ra n d o mize d 
t o recei ve bri nz ola mi de / bri m o ni di ne pl us D U O T R A V , a n d μVe hicle + D U O T R A V refers t o t he mea n of 
t he sa me e n d p oi nt i n t he c orres p o n di n g gr o u p of s u bjects ra n d o mize d t o recei ve Ve hicle pl us 
D U O T R A V .
1 1. 4. 2. 2
A n al ysis Met h o ds
A nal y ses of treat me nt differe nces i n di ur nal I O P a n d perce nt di ur nal I O P c ha n ge at Wee k 6 
will use t he sa me met h o ds as t h ose f or t he pri mar y e n d p oi nt. A nal y ses of treat me nt differe nces 
i n IO P c ha n ge a n d perce nt I O P c ha n ge at eac h Wee k 6 ti me p oi nt will utilize a re peate d 
meas ures mi xe d m o del wit h fi xe d effects of treat me nt, ti me p oi nt, a n d t he i nteracti o n of 
treat me nt an d ti me p oi nt , a n d t he baseli ne 0 9: 0 0 I O P as a c o variate .
Descri pti ve statistics will als o be re p orte d f or eac h of t he sec o n dar y  e n d p oi nts.
1 1. 4. 2. 2. 1
S u b gr o u p A n al ysis Met h o ds
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Pla n ne d s u b gr o u p a nal ys es will assess t he i m pact of sites a n d de m o gra p hic s u b gr o u ps o n 
o v erall st u d y res ults a n d assess t he efficac y i n eac h s u b gr o u p. S u b gr o u ps of a ge cate g or y 
( < 5 0, 5 0- 6 5, > 6 5), se x, race (Ca ucasia n, Blac k, Asia n, His pa nic, Ot her) , baseli ne I O P (1 9- 2 4 
m m H g, > 2 4 -2 8 m m H g), a n d re gi o n ( E M E A, Asia, L A C A R) will be s u m marize d de scri pti vely 
( N, mea n, sta n dar d de viati o n) f or t he sec o n dar y e n d p oi nts.


Pa ge 6 0 of 7 1
1 1. 5
H a n dli n g of Missi n g D at a
T he pri mar y , sec o n dar y, 
 efficac y a nalys es will be base d o n a n o bser ve d case 
( O C) a nalys is. T he statistical m o del t hat will be e m pl o ye d a n d its ass ociate d a nal ys is is o ne 
t hat is r o b ust t o data t hat are missi n g at ra n d o m ( M A R).
1 1. 6  
M ulti plicit y
A gate -kee pi n g strate g y  will be e m pl o ye d t o e ns ure o verall c o ntr ol of t he t y p e I  err or rate. T he 
sec o n dar y efficac y h yp ot heses will be rele va nt o nl y if t he pri mar y  efficac y n ull h yp ot hesis is 
first rejecte d at t he 5 % le vel of si g nifica nce (t w o-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 y p ot hesis, eac h sec o n dar y  h yp ot hesis will be teste d f oll o wi n g t he or der of t he 
h y p ot heses as liste d bel o w. Eac h hy p ot hesis will be rele va nt o nl y if t he prece di n g h y p ot heses 
ha ve bee n rejecte d at t he 5 % le vel of si g nifica nce (t w o -si de d). T he testi n g or der (all base d o n 
I O P at Wee k 6) will be:

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Differe nce bet wee n treat me nts i n mea n c ha n ge fr o m baseli ne i n di ur nal I O P 


Pa ge 6 1 of 7 1

Dif fere nce bet wee n treat me nts i n di ur nal IO P

Dif fere nce bet wee n treat me nts i n perce nta ge di ur nal I O P c ha n ge fr o m baseli ne 

Dif fere nce bet wee n treat me nts i n IO P  c ha n ge fr o m baseli ne at 11: 0 0 hrs

Dif fere nce bet wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne at 11: 0 0 hrs

Dif fere nce bet wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne at 11: 0 0 hrs

Dif fere nce bet wee n treat me nts i n IO P  c ha n ge fr o m baseli ne at 0 9: 0 0 hrs

Dif fere nce bet wee n treat me nts i n perce nta ge I O P c ha n ge fr o m baseli ne at 0 9: 0 0 hrs
Si g nifica nce f or a c o m paris o n will be clai me d o nl y if t he n ull h y p ot hesis is rejecte d ( p < 0. 0 5) 
f or t he pre vi o us e n d p oi nt i n t his series.
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 vis ual fiel d (a ut o mate d peri metr y), f u n d us para meters, 
best -c orrecte d vis ual ac uit y ( B C V A), slit-la m p e xa m, bl o o d press ure, p ulse rate a n d a d verse 
e ve nts.
T he safet y a nal ys es will c o nsist of descri pti ve s u m maries of t he data as rele va nt t o t he sc ale of 
data, e g, fre q ue ncies a n d perce nt a ges f or a d verse e ve nts, a n d mea n c ha n ges fr o m baseli ne as 
a p pr o priate
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
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
A n i nteri m a nal ys is f or efficac y assess me nt will be perf or me d w he n 5 0 % of t otal pla n ne d 
s u bjects ha ve c o m plete d disc o nti n ue d fr o m t he st u d y . T he o bjecti ve of t he i nteri m a nalys is is 
t o pr o vi de o p p ort u nit y f or early rejecti o n of t he n ull of h y p ot hesis of n o differe nce i n mea n 
c ha n ge fr o m baseli ne i n di ur nal I O P at Wee k 6 bet wee n treat me nt gr o u ps. I n o r der t o e ns ure 
T y pe 1 err or is a de q uatel y  c o ntr olle d at t he 5 % le vel of si g nifica nce (t w o-si de d) a p- val ue 
b o u n dar y will be e m pl o ye d, i n partic ular, t he Ha y bittle -Pet o b o u n dar y  ( Ha ybittle 1 9 7 1) . T he 
H a y bittle -Pet o b o u n dar y  e ns ures t hat t he st u d y st o ps f or efficac y o nly if t here is o ver w hel mi n g 
e vi de nce of efficac y.


Pa ge 6 2 of 7 1
1 1. 1 0
S a m ple Size J ustific ati o n
Wit h 1 0 8 e val ua ble s u bjects per treat me nt gr o u p i n t he pri mar y  efficac y a nal ysis, t here is at 
least 8 0 % p o wer t o detect a 1. 5 m m H g differe nce i n mea n c ha n ge fr o m baseline i n di ur nal I O P 
at Wee k 6 bet wee n t he treat me nt gr o u ps. H o we ver , t he re q uire d sa m ple size t o attai n t he sa me 
p o wer is 2 8 s u bjects per ar m if t he differe nce is 3. 0 m m H g bet wee n treat me nt gr o u ps (as 
s u g geste d by e x pert o pi ni o n). B ot h calc ulati o n s are base d o n t he ass u m pti o n of a c o m m o n 
sta n dar d de viati o n f or mea n of 3. 9 m m H g a n d t he use of a t w o-sa m ple t w o-si de d t-test 
perf or me d at t he α = 0. 0 5 le vel of si g nifica nce. 
Ass u mi n g a dr o p -o ut rate of 1 0 %, a p pr o xi matel y  1 2 0 s u bjects per treat me nt gr o u p will be 
ra n do mize d t o e ns ure t he re q uire d n u m ber of e val ua ble s u bjects i n t he fi nal efficac y  a nalys is.
To  miti gate t he u ncertai nt y a b o ut t he e x pecte d treat me nt differe nce, a t w o-l o o k desi g n wit h 
H a y bittle -Pet o b o u n daries will be use d. T h us, t his st u d y will i nc or p orat e a n i nteri m a nal ysis 
f or efficac y assess me nt w he n 5 0 % of t otal pla n ne d s u bjects ha ve c o m plete d or disc o nti n ue d 
fr o m t he st u d y. T he p o wer t o reject t he n ull hy p ot hesis at t he si n gle i nteri m a nal ys is w he n 5 0 % 
of s u bjects ha ve c o m plete d o r disc o nti n ue d t he st u d y is 2 8. 2% if t he e x pecte d mea n dif fere nce 
is 1. 5 a n d 9 2. 2 %, if t he e x pecte d mea n dif fere nce is 3. 0.
L o o k 
#
S a m pl e 
Si z e
Effi c a c y  
p- v al u e
P- v al u e 
B o u n d ar y
E xit Pr o b a biliti e s
= 0
= 1. 5
= 3. 0
1
1 0 8
0. 0 1 
0. 0 1 
0. 0 1
0. 2 8 2 
0. 9 2 2
2
2 1 6
0. 0 4 5 
0. 0 4 5
0. 0 4
0. 5 1 7 
0. 0 7 8
S u m  of E xit Pr o b a biliti e s
0. 0 5 0 
0. 7 9 9
1
1 2
A D V E R S E E V E N T S
1 2. 1
Ge ner al I nf or m ati o n
A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
A n A d verse E ve nt ( 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 treat me nt 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 n y 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 mal 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  
treat me nt, 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 o ds, e ve n 
if n o st u d y treat me nt 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 ve sti gat or.


Page 63 of 71
12.2
Monitoring for Adverse Events
At each visit, after the subject has had the opportunity to spontaneously mention any problems, 
the Investigator should inquire about AEs by asking the standard questions:
•
“Have you had any health problems since your last study visit?”
•
“Have there been any changes in the medicines you take since your last study visit?”
AEs should be reported for any clinically relevant change, as determined by the Investigator, 
in concomitant medication(s) that is the result of an untoward (unfavorable and unintended) 
change in a subject's medical health. 
Changes from baseline in any protocol-specific ocular or systemic parameter evaluated during 
the study are to be reviewed by the Investigator. In addition, the subject’s responses to any 
questionnaire utilized during the study are to be reviewed by the Investigator. Any untoward 
(unfavorable and unintended) change in a protocol-specific parameter or questionnaire 
response that is clinically relevant, in the opinion of the Investigator, is to be reported as an 
AE. These clinically relevant changes will be reported regardless of causality.
12.3
Procedures for Recording and Reporting AEs and SAEs
Subsequent to signing an informed consent form, all untoward medical occurrences that 
occur during the course of the study must be documented on an Adverse Event Form (AEF). 
A separate AEF must be filled out for each event. When possible, signs and symptoms 
indicating a common underlying pathology should be documented as one comprehensive 
event. For each recorded event, the AE documentation must include the onset date, 
outcome, resolution date (if event is resolved), intensity (ie, severity), any action with study 
treatment taken as a result of the event, and an assessment of the adverse event’s 
relationship to the study treatment.
Nonserious Adverse Events
A nonserious AE is defined as any untoward change in a subject's medical health that does 
not meet serious criteria noted below (eg, is not life-threatening, does not require 
hospitalization, does not prolong a current hospitalization, is not disabling, etc.).
All adverse events must be reported regardless of whether or not they are related to the 
study treatment.
Non-serious AEs must be reported in the EDC system within 10 calendar days of the 
Investigator’s or site’s knowledge of the event.
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Pa ge 6 4 of 7 1
Seri o us A d verse E ve nts
A serio us a d verse e v e nt (S A E ) is defi ne d as a ny ad verse e x p erie nce t hat m eets a ny of the 
f oll o wi n g criteria:

Res ult s i n d eat h.

Is life-t hreate ni n g.
N O T E: Life -t hre ate ni n g me a ns t h at the s u b ject w as at i m me di ate risk of de at h fr o m 
t he re acti o n a s it occ urre d, ie, it d oes n o t i ncl u de a re acti o n w hic h h yp ot hetic a lly mi g ht 
h ave c a use d de at h h a d it oc c urre d i n a m ore severe for m.

Re q uires h o s pitalizati o n or p rol o n gati o n of e xisti n g h os pital izati o n.
N O T E: I n ge ner al, h os pit aliz ati o n si g nifies t ha t t he i n divi d ua l rem ai ne d a t the h os pit a l 
or emer ge n cy w ard f or o bserv a ti o n a n d/ or tre at me nt ( us u al l y i nv olvin 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 h ysici a n's office o r a n o ut- p atie nt 
setti n g. C om pli c atio ns t h at occ u r d uri n g h o s pit aliz ati o n ar e A Es.
If a c o m p lic ati o n prol o n gs h os p it aliz ati o n or fulf ills a ny o t her seri o us criteri a, t he event is 
seri o us. Whe n i n d o u bt as t o w het her “ h os pi tal iz ati on ” occ urr e d, t he event s h o ul d be 
c o nsi dere d serio us.

Res ul ts i n p ersiste nt or si g nifica nt d isa bility/i n c apac it y. Disa bilit y is d efi ne d as a 
s ub sta n tial disr u pti o n of a pers o n’s a bilit y t o c o n du ct n orm al life fu ncti o ns.
N O T E: T he ter m dis a bility me a ns a s u bst a nti al disr u pti o n of a pers o n’s abil ity t o
c o nd uct n or m al life f u ncti o ns. T his d efi niti on is n ot i nte n de d t o i ncl ude ex pe rie nces of 
rel atively m i n or m e dic al si gn ific a nce s uc h as u nc o m plic ate d he a dac he, n a use a,
v o mitin g, di a rr he a, i nfl ue nz a, or acci de nt a l tr au m a (e g, s pr aine d a nkle) w hic h m ay 
i nterfere or prevent every d ay life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta nt i al 
dis r u pti o n.

Is a c o n ge nital a n om al y/ birt h defect.

A lc o n - B usi ness Use O nl y  
 
Effecti ve D ate:  
D oc u me nt:  
Versi o n:  
St at us:  E f f e c t i v e
Pri nte d B y:  
Pri nt Date:  
2 . 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 5 7 2
P r o t o c o l  -  C l i n i c a l
1 0- A pr- 2 0 1 7
Is a n im p orta nt m e dical e ve n t. A n im p orta nt me dical e ve nt is a n e ve nt t h at m a 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 m a 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 pria te m e dical j u d g me nt, it m a y je o pa rdize t h e s u bject 
a n d m a y re q uire m e dical or s u r gical in ter ven ti o n t o pre ve nt o ne of t he o utc om es liste d 


Page 65 of 71
in the definitions for SAEs. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in a subject’s hospitalization, or the 
development of drug dependency or drug abuse.
All available information on a serious adverse event(s) and any other associated AE, if
applicable, must be forwarded to the study Sponsor immediately (ie, within 24 hours 
of the Investigator’s or site’s knowledge of the event) as follows:
In studies utilizing EDC (electronic data capture), all available information for the SAE 
and any associated AE(s) must be entered immediately into the EDC system.
NOTE: Should the Electronic Data Capture (EDC) system become non-operational, the 
site must complete the appropriate paper Serious Adverse Event Form. The completed form
is communicated to the study Sponsor either by fax at 
or by email at 
  within 24 hours of the Investigator’s or site’s awareness,
however, the reported information must be entered into the EDC system once it becomes 
operational.
Additional information for any applicable event is to be reported as soon as it becomes 
available. Any complaints from the subject on a past event previous to initiation of the 
study but that is resolved at the time of the first visit must be reported to Alcon following 
the usual pharmacovigilance circuit.
In addition to the reporting of serious adverse events to the study sponsor, the SAE 
must be reported to the IRB / IEC according to their requirements.
Sponsor representatives and their contact information are provided in the Manual of 
Procedures (MOP) that accompanies this protocol.
If the SAE was due to a hospitalization of the subject, a copy of the discharge summary is 
to be forwarded to the study Sponsor as soon as it becomes available. In addition, a letter 
from the Investigator that summarizes the events related to the case as well as results of any
relevant laboratory tests also may be requested. Further, depending upon the nature of the 
SAE, the Sponsor may request copies of applicable parts of the subject’s medical records.
An assessment of seriousness will also be performed for all adverse events by a study
Sponsor physician utilizing the same criteria. If an adverse event reported for an
Investigator’s subject is upgraded to a serious adverse event by a study Sponsor 
physician, the Investigator will receive a notification by the study Sponsor.
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12.4
Intensity and Causality Assessments
For every AE, the Investigator must assess the seriousness, intensity (severity) and causality 
(relationship to study treatment). Specifically, events should be classified as mild, moderate, 
or severe. The assessment of causality will be based upon the categories of related and not 
related. These classifications should be based on the following definitions:
Intensity (Severity):
Mild
An event is mild if the subject is aware of, but can easily tolerate the sign
or symptom.
Moderate
An event is moderate if the sign or symptom results in discomfort
significant enough to cause interference with the subject’s usual activities.
Severe
An event is severe if the sign or symptom is incapacitating and results in the 
subject’s inability to work or engage in their usual activities.
Causality:
Related
Adverse events classified as related may be either definitely related or 
possibly related where a direct cause and effect relationship between the
study treatment and the event has not been demonstrated but there is a 
reasonable possibility that the event was caused by the study treatment.
Not Related
Adverse events classified as not related may either be definitely unrelated 
or simply unlikely to be related (ie, there are other more likely causes for 
the adverse event).
For a serious adverse event reported by an Investigator as not related that upon review of 
the available data by the study sponsor physician is assessed (upgraded) to be related, the 
Investigator will receive a notification.
12.5
Unmasking of the Study Treatment
Masked information on the identity of the assigned test article will be provided for each
subject. If the treatment code needs to be broken in the interest of subject safety, the
Investigator is encouraged to contact an appropriate study sponsor representative prior to 
unmasking if there is sufficient time. Dependent upon the individual circumstances (ie, 
medical emergency), the code may be broken prior to contact with the Sponsor. The 
study Sponsor must be informed in all cases in which the code was broken and of the 
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Page 67 of 71
circumstances involved.
Additionally, the Sponsor may be required to unmask the subject if the AE meets criteria of a 
Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfill expedited 
regulatory reporting requirements.
12.6
Follow-Up of Subjects with Adverse Events
The Investigator is responsible for adequate and safe medical care of subjects during the 
trial and for ensuring that appropriate medical care and relevant follow-up procedures 
are maintained after the trial. Any additional data from these follow-up procedures must 
be documented and available to the Sponsor who will determine when the data need to 
be documented on the case report forms.
12.7
Pregnancy in the Clinical Trial
Women who are pregnant or breast-feeding are excluded from participation in the study. 
Women of childbearing potential or women considered post-menopausal are not 
excluded from the study as long as adequate birth control methods are being utilized. 
Women of childbearing potential are defined as all women physiologically capable of 
becoming pregnant, following menarche and until becoming post-menopausal unless 
permanently sterile. Women are considered post-menopausal if they have had 12 months 
of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential. 
All women of childbearing potential are required to use adequate birth control methods 
which are summarized in the protocol’s exclusion criteria.
Prior to clinical trial enrollment, female subjects of childbearing potential must be 
advised of the importance of avoiding pregnancy during the trial and the potential risks 
associated with an unintentional pregnancy. During the trial, female subjects are to be 
instructed to contact the Investigator immediately if they suspect they might be pregnant. 
Alcon must be contacted immediately, treatment discontinued, and the subject exited 
from the study. 
In addition, complications of pregnancy may be reportable and will be decided on a case 
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Page 68 of 71
by case basis. A Sponsor prepared form will be utilized to capture all pregnancy related 
information until the outcome of the pregnancy.
13
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS
13.1
Completion of Source Documents and Case Report Forms
The nature and location of all source documents will be identified to ensure that original data 
required to complete the CRFs exist and are accessible for verification by the site monitor. If 
electronic records are maintained, the method of verification must be determined in advance of 
starting the study. At a minimum, source documents should include the following information 
for each subject:
Subject identification (name, sex, race)
Documentation of subject eligibility
Date of informed consent
Dates of visits
Documentation that protocol specific procedures were performed
Results of study parameters, as required by the protocol
Trial medication accountability records
Documentation of AEs and other safety parameters (if applicable)
Records regarding medical histories and the use of concomitant therapies prior to and during 
the study
Date of trial completion and reason for early discontinuation, if applicable
It is required that the author of an entry in the source documents be identifiable. Direct access 
to source documentation (medical records) must be allowed for the purpose of verifying that 
the data recorded on the CRF are consistent with the original source data. 
CRFs will be provided to the sites (electronic); only designated individuals may complete the 
CRFs. The CRFs will be submitted at regular intervals based upon the clinical trial visit 
schedule. It is expected that all data reported will have corresponding entries in the source 
documents and that the Principal Investigator will review the reported data and certify that the 
CRFs are accurate and complete. No subject identifiers should be recorded on the CRFs 
beyond subject number, and demographic information. 
13.2
Data Review and Clarifications
The CRF data will be reviewed against the subject’s source data by the study monitors to 
ensure completeness and accuracy. After monitoring has occurred at the clinical sites and the 
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Page 69 of 71
CRFs have been submitted, additional data clarifications and/or additions may be needed. Data 
clarifications and/or additions are documented and are part of each subject’s CRFs.
13.3
Regulatory Documentation and Records Retention
The Investigator is required to maintain up-to-date, complete regulatory documentation as 
indicated by the Sponsor and the Investigator’s files will be reviewed as part of the ongoing 
study monitoring. Financial information is not subject to regulatory inspection and should be 
kept separately. 
Additionally, the Investigator must keep study records and source documents until the Sponsor 
provides written approval for their destruction. If the Investigator retires, relocates, or for any 
other reason withdraws from responsibility of keeping the study records, the Sponsor must be 
notified and suitable arrangements made for retention of study records and source documents 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the latest marketing approval).
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14
References
Aung T, Laganovska G, Paredes TJH, Branch J, Tsorbatzoglou A, Goldberg, I. Twice-Daily 
Brinzolamide/Brimonidine Fixed Combination versus Brinzolamide or Brimonidine in Open-
Angle Glaucoma or Ocular Hypertension. Ophthalmology 2014;121(12):2348-55.
Gandolfi SA, Lim J, Sanseau AC, Restrepo JCP, Hamacher T. Randomized Trial of 
Brinzolamide/Brimonidine versus Brinzolamide Plus Brimonidine for Open-Angle Glaucoma 
or Ocular Hypertension. Adv Ther 2014; 31(2):1213-27.
Higginbotham EJ, Hansen J, Davis EJ, Walt JG, Guckian A. Glaucoma medication persistence 
with a fixed combination versus multiple bottles. Curr Med Res Opin. 2009;25(10):2543-7.
Kable JW, Murrin LC, Bylund DB. In vivo gene modification elucidates subtype-specific 
functions of alpha(2)-adrenergic receptors. J Pharmacol Exp Ther. 2000;293(1):1-7.
Kamibayashi T, Maze M. Clinical uses of α2-adrenergic agonists. Anesthesiology. 
2000;93:1345-9.
Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a 
randomized trial determines that topical ocular hypotensive medication delays or prevents the 
onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–13.
Katz G, Dubiner H, Samples J, Vold S, Sall K. Three-Month Randomized Trial of Fixed-
Combination Brinzolamide, 1% and Brimonidine, 0.2%. JAMA Ophthalmol. 2013; 
131(6):724-30.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983. 
70(3):659-63.
Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative 
Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or 
surgery. Ophthalmology. 2001;108:1943–53.
Nasser QJ, Stewart WC. Glaucoma treatment and diagnostic trends. Rev Ophthalmol. 
2006;13:87-93.
Nguyen QH, McMenemy MG, Realini T, Whitson J, Goode SM. Phase 3 Randomized 3-
Month Trial with an Ongoing 3-Month Safety Extension of Fixed-Combination Brinzolamide 
1%/Brimonidine 0.2%. Journal of Ocular Pharmacology and Therapeutics. 2013;29(3):290-7.
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Summer A, Tielsch JM. Relationship between intraocular pressure and primary open angle 
glaucoma among white and black Americans. Arch Ophthalmology 1991;109:1090-95.
Schwartz GF, Pate VD, Burk C, Bennett T. Patient persistency with topical glaucoma therapy 
is higher with fixed dose brimonidine/timolol than with two-bottle combinations. Association 
of Research in Vision and Ophthalmology; 2010:185. (Abstract).
Stewart WC, Stewart JA, Nelson LA, Kruft B. Physician attitudes regarding prostaglandin 
treatment for glaucoma in the United States and Europe. Eur J Ophthalmol. 2008;18(2):199 
204.
Stewart WC, Jenkins JN, Stewart JA. Survey assesses prostaglandin use. Rev Ophthalmol. 
2005;12:Article 844.
Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363(9422):1711-20. 
Whitson JT, Realini T, Nguyen QH, McMenemy MG, Goode SM. Six-month results from a 
Phase III randomized trial of fixed-combination brinzolamide 1% + brimonidine 0.2% versus 
brinzolamide or brimonidine monotherapy in glaucoma or ocular hypertension. Clinical 
Ophthalmology 2013; 7:1053-60.
Wilson MR, Coleman AL, Yu F, Bing EG, Sasaki IF, Berlin K, et al. Functional status and 
well-being in patients with glaucoma as measured by the Medical Outcomes Study Short 
Form-36 questionnaire. Ophthalmology. 1998;105(11):2112-6.
Wu Sy, Hennis A, Nemesure B, at al. Impact of glaucoma, lens opacities, and cataract surgery 
on visual functioning and related quality of Life the Barbados Eye Studies. Invest Ophthalmol 
Vis Sci 2008; 49:1333-8.
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Date/Time 
(mm/dd/yyyy GMT):
Signed by:
Justification:
04/10/2017 13:21:09
04/07/2017 21:02:02
04/07/2017 09:16:51
04/06/2017 16:51:31
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SAP_001.pdf: 
Page 1 of 26
Short Title:
Statistical Analysis Plan 
GLJ576-P001/ NCT02730871
Full Title:
Statistical Analysis Plan 
CQVJ499A2402 (GLJ576-P001) 
Protocol Title:
Safety and Efficacy with Twice Daily Brinzolamide 1% / 
Brimonidine 0.2% (SIMBRINZA) as an Adjunctive Therapy to 
Travoprost 0.004% / Timolol 0.5% (DUOTRAV)
Protocol TDOC Number:
TDOC-0051572
Author:
Trial Statistician
Template Version:
Version 4.0, approved 16MAR2015
Approvals:
See last page for electronic approvals.
Job Notes:
This is the third version (Version 3.0) Statistical Analysis Plan for this study. This version of 
the Statistical Analysis Plan is based on Version 2.0, of the study protocol TDOC-0051572.
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Page 2 of 26
Executive Summary:
Key Objectives:
The primary objective of this study is to demonstrate the additive IOP lowering effect of 
Brinzolamide 1%/Brimonidine 0.2% (dosed BID) when added to Travoprost 0.004%/Timolol
0.5% in subjects with either open-angle glaucoma or ocular hypertension who are currently 
on DUOTRAV (Travoprost/Timolol).
Decision Criteria for Study Success:
A success will be declared if the primary efficacy null hypothesis is rejected in favor of 
adjunctive therapy (SIMBRINZA plus DUOTRAV) relative to DUOTRAV alone.  Success 
reflects greater mean reduction at Week 6 from baseline in IOP for the adjunctive therapy 
relative to DUOTRAV alone.
This study incorporates an interim analysis when 50% of the total planned subjects have 
completed or discontinued from the study. Thus, study success may be declared at the interim 
analysis or after the total planned subjects have completed or discontinued.
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Table of Contents
Statistical Analysis Plan CQVJ499A2402 (GLJ576-P001).......................................................1
Table of Contents.......................................................................................................................3
List of Tables..............................................................................................................................4
1
STUDY OBJECTIVES AND DESIGN .................................................................5
1.1
Study Objectives.....................................................................................5
1.2
Study Description...................................................................................5
1.3
Randomization........................................................................................6
1.4
Masking..................................................................................................6
1.5
Interim Analysis .....................................................................................6
2
ANALYSIS SETS ..................................................................................................6
2.1
Efficacy Analysis Sets............................................................................7
2.2
Safety Analysis Set.................................................................................7
2.3
Pharmacokinetic Analysis Set ................................................................7
3
SUBJECT CHARACTERISTICS AND STUDY CONDUCT SUMMARIES .....7
4
EFFICACY ANALYSIS STRATEGY ...................................................................8
4.1
Efficacy Endpoints .................................................................................8
4.2
Efficacy Hypotheses...............................................................................9
4.3
Statistical Methods for Efficacy Analyses............................................10
4.4
Multiplicity Strategy.............................................................................13
4.5
Subgroup Analyses and Effect of Baseline Factors..............................13
4.6
Interim Analysis for Efficacy ...............................................................13
5
SAFETY ANALYSIS STRATEGY......................................................................14
5.1
Safety Endpoints...................................................................................14
5.2
Safety Hypotheses ................................................................................15
5.3
Statistical Methods for Safety Analyses...............................................15
5.3.1
Extent of Exposure ...............................................................15
5.3.2
Adverse Events.....................................................................16
5.3.3
Automated Perimetry ...........................................................16
5.3.4
Fundus Parameters ...............................................................17
5.3.5
Best Corrected Visual Acuity (BCVA) .................................17
5.3.6
Slit-Lamp Biomicroscopy ....................................................18
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Page 4 of 26
5.3.7
Vital Signs (Blood Pressure, Pulse Rate) .............................19
5.4
Interim Analysis for Safety...................................................................19
6
PHARMACOKINETIC ANALYSIS STRATEGY..............................................19
7
ANALYSIS STRATEGY FOR OTHER ENDPOINTS .......................................19
8
SAMPLE SIZE AND POWER CALCULATIONS .............................................19
9
REFERENCES.....................................................................................................20
10
REVISION HISTORY .........................................................................................20
11
Appendix ..............................................................................................................22
11.1
SAS Pseudo-code .................................................................................22
11.2
Study Tables for Reference ..................................................................23
List of Tables
Table 1–1
Study Plan by Treatment Groups.......................................................................5
Table 4–1
Summary of Analysis Strategy for Key Efficacy Endpoints ...........................12
Table 11–1
Measurement Scales for Ophthalmic Assessments..........................................23
Table 11-2
Overview of Study Plan...................................................................................24
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1
STUDY OBJECTIVES AND DESIGN
1.1
Study Objectives
The primary objective of this study is to demonstrate the additive IOP lowering effect of 
Brinzolamide 1% / Brimonidine 0.2% (dosed BID) when added to Travoprost 0.004% /
Timolol 0.5% solution in subjects with either open-angle glaucoma or ocular hypertension 
who are currently on DUOTRAV (Travoprost 0.004%/Timolol 0.5%).
1.2
Study Description
The study is a 6 week, multicenter, parallel group study in subjects with primary open-angle 
glaucoma and/or ocular hypertension and is divided into 2 sequential phases. Phase I of the 
study is the open-label Screening/Eligibility Phase, which includes a Screening Visit
followed by 2 Eligibility Visits (E1 and E2). Phase II of the study is a randomized, double-
masked treatment phase which includes on-therapy visits at Week 2 and Week 6 (Exit Visit) 
as shown in Table 1–1.
Table 1–1
Study Plan by Treatment Groups
Study Phase
Treatment Group
Phase I
(Screening/Eligibility Phase)
Phase II
(Masked Treatment  Phase)
Screening and Eligibility Visits
Week 2 and Week 6 (Exit) Visits
SIMBRINZA + DUOTRAV
Begin dosing with DUOTRAV at 
21:00 ±30 min on the evening of the 
screening visit if the subject dosed 
with DUOTRAV in the evenings 
prior to Screening, or begin dosing
with DUOTRAV at 9:00 ±30 min
the following day after Screening if 
the subject dosed with 
DUUOTRAV in the mornings prior 
to Screening.
Mean IOP for both Eligibility
Visits must be:
≥ 19 mmHg and ≤28 mmHg
in at least one eye at 
09:00 time point
The same eye(s) must qualify at 
both 09:00 time points.
The mean IOP in either eye must 
not be greater than 28 mmHg at any 
time point.
SIMBRINZA BID
(09:00 and 21:00) ±30 min 
And
DUOTRAV QD
(09:00 or 21:00) ±30 min
Vehicle + DUOTRAV
Vehicle BID
(09:00 and 21:00) ±30 min
And
DUOTRAV QD
(09:00 or 21:00) ±30 min
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1.3
Randomization
A member of the Randomization Programming group at Alcon who is not part of the study 
team will generate the randomized allocation schedule(s) for masked Investigational Product 
(IP) assignment. Randomization will be central (no stratification for site) and implemented 
via Interactive Response Technology (IRT) system. Each subject number will be associated 
with treatment groups according to a random process. Subjects will be randomized in a 
1:1 manner to receive treatment with either SIMBRINZA or Vehicle adjunctively to their 
DUOTRAV therapy.
1.4
Masking
This study is double-masked with subjects randomized to use SIMBRINZA or Vehicle for a
duration of approximately 42 days. The Investigator, subject, Sponsor, and monitors involved
in reporting, obtaining, and/or reviewing the clinical evaluations will not be aware of the 
specific masked treatment (SIMBRINZA or Vehicle) being administered. Both SIMBRINZA 
and Vehicle will be provided in identical masked bottles labeled with the protocol and kit 
numbers. This level of masking will be maintained throughout the conduct of the study. 
However, DUOTRAV therapy is open labeled and will be dosed during the Phase I 
(Screening Visit through E2) and for the duration of Phase II of the study.
1.5
Interim Analysis
An interim analysis for efficacy is planned when 50% of the total planned subjects have 
completed or discontinued from the study. The objective of the interim analysis is to provide 
opportunity for early rejection of the null hypothesis that there is no difference in mean IOP 
change from baseline between SIMBRINZA and Vehicle adjunctive to DUOTRAV. A 
detailed description of the planned interim efficacy analysis is in Section 4.6. Study 
enrollment may be ongoing at the time of interim analysis. Masking to treatment assignment 
will be maintained at all investigational sites. Subject-level unmasking will be restricted to an 
internal unmasked statistician and statistical programmer performing the interim analysis.
2
ANALYSIS SETS
The final subject evaluability for all analysis sets will be determined prior to breaking the 
code for masked treatment assignment and locking the database.
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2.1
Efficacy Analysis Sets
The primary analysis set for all primary, secondary 
efficacy analyses will be 
the full analysis set (FAS). 
All randomized subjects with a baseline assessment and who complete at least 1 scheduled 
on-therapy study visit will be evaluated in the full analysis set. Subjects will be analyzed as 
randomized in the FAS. For example, if a subject is given SIMBRINZA plus DUOTRAV
when they were randomly assigned to receive Vehicle plus DUOTRAV, the subject will be 
analyzed according to the randomization schedule (i.e. Vehicle plus DUOTRAV) regardless 
of which treatment was actually received (SIMBRINZA plus DUOTRAV). 
The Per Protocol Analysis Set (PPS) is a subset of all randomized subjects and excludes all 
data which have met any of the critical deviation criteria identified in the Deviations and 
Evaluability Plan (DEP). In addition, individual subject visits and data points with critical 
deviations may be excluded from the analyses involving the PPS. The Per Protocol Set (PPS) 
will be evaluated only for the primary efficacy endpoint to confirm results from the FAS.
2.2
Safety Analysis Set
Safety analyses will be conducted using the safety analysis set on a treatment-emergent basis. 
The safety analysis set includes all subjects who received a dose of IP during the masked 
treatment phase.
For treatment-emergent safety analyses, subjects will be categorized under the actual 
treatment received.
Safety data is to be collected for each subject beginning at the time of informed consent. 
Adverse events (AEs) that occur prior to exposure to investigational products will be 
presented separately from the treatment-emergent AEs.
2.3
Pharmacokinetic Analysis Set
Not Applicable. 
3
SUBJECT CHARACTERISTICS AND STUDY CONDUCT 
SUMMARIES
Subject characteristics and study conduct summaries include tables and listings such as 
subject disposition table, demographic tables (age, sex, race, ethnicity, iris color and region)
and baseline characteristics (baseline IOP, baseline IOP category (< 19 mmHg, 19-24 mmHg, 
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> 24-28 mmHg) and diagnosis, for all analysis sets (efficacy and safety). Listings for 
treatment assignment, screen failures, subjects who terminated early from the study or 
discontinued treatment, and subjects excluded from key analysis sets will be generated. All 
descriptive summary statistics will be displayed with n and % for categorical data, and with 
mean, standard deviation, median, minimum, and maximum for continuous data. Tables will 
be presented by treatment and overall.
Age will be summarized as a continuous variable as well as categorically (< 65, ≥65 and 
furthermore as < 50, 50-64, ≥65). In addition, gender, race, ethnicity, iris color and region 
will be summarized as categorical variables.
4
EFFICACY ANALYSIS STRATEGY
The efficacy assessment between treatment groups will be analyzed based on the FAS. 
Significance testing will be at the significance level dependent upon the time of analysis 
(interim or final) as determined by the Haybittle-Peto boundary.
One eye from each subject will be chosen as the study eye and only the study eye will be 
used for analysis. If only 1 of a subject’s eyes is dosed, the dosed eye will be selected as the 
study eye. If both eyes are dosed, the worse evaluable eye will be selected as the study eye. 
Worse eye is defined as the eye with the higher IOP at 9:00 averaged across the 2 eligibility 
visits. If both eyes are equal then the worse eye will be defined as the eye with the higher IOP 
at 11:00 averaged across the 2 eligibility visits. If both eyes are equal then the right eye will 
be selected for analysis.
For time-specific IOP measurements, baseline corresponds to the average of subject time-
matched IOP measurements at E1 and E2 visits on the study visit schedule.
4.1
Efficacy Endpoints
Primary Endpoint
The primary efficacy endpoint will be mean change from baseline in IOP at Week 6 (subject 
IOP changes from baseline averaged over the 09:00 and 11:00 time points).
Secondary Endpoints

Mean IOP at Week 6

Mean Percentage change from baseline in IOP at Week 6

Mean IOP change from baseline at Week 6 at 11:00.
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
Mean Percentage change from baseline in IOP at Week 6 at 11:00

Mean IOP change from baseline at Week 6 at 9:00

Mean Percentage change from baseline in IOP at Week 6 at 9:00
4.2
Efficacy Hypotheses
The null and alternative hypotheses for the primary analysis are:
H0:  μSIMBRINZA+DUOTRAV = μVehicle+DUOTRAV 
H1:  μSIMBRINZA+DUOTRAV ≠ μVehicle+DUOTRAV
where μSIMBRINZA+DUOTRAV refers to mean IOP change from baseline for subjects randomized 
to receive SIMBRINZA plus Travoprost 0.004% / Timolol 0.5%, and μVehicle+DUOTRAV refers to 
mean IOP change from baseline for subjects randomized to receive Vehicle plus 
Travoprost 0.004% / Timolol 0.5%.
Thus, success will be evidenced by a greater reduction in mean IOP change from baseline at 
Week 6 for the adjunctive therapy (SIMBRINZA plus DUOTRAV) relative to Vehicle plus 
DUOTRAV.
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The null and alternative hypotheses for the secondary endpoints are:
H0:  μSIMBRINZA+DUOTRAV  =  μVehicle+DUOTRAV 
H1:  μSIMBRINZA+DUOTRAV  ≠  μVehicle+DUOTRAV
where μSIMBRINZA+DUOTRAV refers to mean of each secondary endpoint for subjects 
randomized to receive SIMBRINZA plus DUOTRAV, and μVehicle+DUOTRAV refers to mean of 
the same endpoint in the corresponding group of subjects randomized to receive Vehicle plus 
DUOTRAV.
4.3
Statistical Methods for Efficacy Analyses
Primary Analysis
Treatment difference in mean IOP change from baseline will be examined based on the least 
squares means derived from an analysis of covariance model. The model will have IOP 
change from baseline as response variable and include fixed effect terms for baseline and 
treatment. The baseline term will be the average of the 9:00 AM and the 11:00 AM IOP 
measurements at the two eligibility visits. Change from baseline in IOP is calculated by 
taking the difference at each time point between the Week 6 value and the baseline value 
(averaged over the two eligibility visits) and then averaging the available differences. Within-
group estimates of the mean change from baseline and associated two-sided 95% confidence 
intervals will be presented. Estimates of the difference in mean change from baseline in IOP 
between SIMBRINZA and Vehicle and associated two-sided 95% confidence interval will 
also be presented.
Evidence of efficacy will be deemed established if a reduction in mean IOP is greater for 
SIMBRINZA than for Vehicle, with the associated p-value less than specified by the 
Haybittle-Peto boundary (see table in Section 8). Note that a negative difference 
(SIMBRINZA minus Vehicle) in mean change from baseline in IOP indicates greater 
reduction in IOP from baseline in favor of SIMBRINZA. Primary inference will be based on 
the FAS. The primary analysis will be repeated on the PPS to investigate sensitivity of 
including subjects who do not completely conform to protocol requirements. 
SAS pseudo-code is provided in the Appendix (see Section 11.1).
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Secondary Analyses
Analyses of IOP at Week 6 and percentage change from baseline in IOP at Week 6 will use 
the same statistical methods employed for the primary endpoint.
Mean IOP at Week 6 is calculated by averaging the IOP measurements at both Week 6 time 
points (9:00 and 11:00).
At the subject level, IOP percentage change from baseline is constructed as follows:

Obtain percentage differences from baseline for each of the 2 time point-matched IOPs 
at Week 6 (e.g. [(IOP Week 6 09:00 minus baseline IOP 09:00) / baseline IOP)]*100
and similarly for the 11:00 time point)

Obtain mean of the percentage changes from baseline at Week 6 
Analyses of IOP change and percent IOP change at each Week 6 time point will be based on a 
mixed model repeated measures (MMRM) with fixed effects of treatment, time point, and the 
interaction of treatment and time point; and the baseline (averaged over the eligibility visits) 
as a covariate.
Covariance structures such as unstructured (UN) will be used. Within-group estimates of the 
mean change from baseline and associated two-sided 95% confidence intervals will be 
presented. Note that a negative difference (SIMBRINZA minus Vehicle) in mean change 
from baseline in IOP indicates greater reduction in IOP from baseline in favor of 
SIMBRINZA.
SAS pseudo-code is provided in the Appendix (see Section 11.1).
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Table 4–1 summarizes the primary and secondary efficacy analyses.
Table 4–1
Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint
Main vs. 
Sensitivity 
Approach
Statistical 
Methoda
Analysis
Set
Missing Data 
Approach
Primary
Mean change from baseline in IOP 
at Week 6 (subject changes from
baseline IOP averaged over the 
09:00 and 11:00 measurements)
M
ANCOVAb
FAS
Likelihood-
based ignorable 
analysis
Mean Change from baseline in IOP 
at Week 6(subject changes from 
baseline IOP averaged over the 
09:00 and 11:00 measurements)
S
ANCOVAb
PPS
Likelihood-
based ignorable 
analysis
Secondary
Mean IOP at Week 6 (subject IOP 
averaged over the 09:00 and 11:00
measurements) 
M
ANCOVAb
FAS
Likelihood-
based ignorable 
analysis
Mean Percentage change from 
baseline in IOP at Week 6 (subject 
IOP percent change from baseline 
averaged over the 09:00 and 11:00
measurements)
M
ANCOVAb
FAS
Likelihood-
based ignorable 
analysis
Mean Change from baseline in IOP 
at Week 6 at 11:00
M
MMRMc
FAS
Likelihood-
based ignorable 
analysis
Mean Percentage change from 
baseline in IOP at Week 6 at 11:00
M
MMRMc
FAS
Likelihood-
based ignorable 
analysis
Mean Change from baseline in IOP 
at Week 6 at 9:00
M
MMRMc
FAS
Likelihood-
based ignorable 
analysis
Mean Percentage change from 
baseline in IOP at Week 6 at 9:00
M
MMRMc
FAS
Likelihood-
based ignorable 
analysis
M=Main analysis approach; S=Sensitivity analysis approach
aFurther details on statistical models are outlined above in 4.3.
bAnalysis of covariance with fixed effect for treatment, and baseline IOP as covariate
cMixed models with fixed effects of treatment, time point, and the interaction of treatment and time point; 
        with time matched baseline IOP as a covariate, and unstructured covariance structure
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4.4
Multiplicity Strategy
A gate-keeping strategy will be employed to ensure overall control of the type I error rate. 
The secondary efficacy hypotheses will be relevant only if the primary efficacy null 
hypothesis is first rejected at the level of significance (two-sided) dictated by the Haybittle-
Peto boundary (see Section 8) at the interim or final analysis. Following the rejection of the 
primary efficacy null hypothesis, each secondary hypothesis will be tested following the 
order of the hypotheses as listed below. Each hypothesis will be relevant only if the preceding 
hypotheses have been rejected at the 5% level of significance (two-sided). The testing order 
(all based on IOP at Week 6) will be:

Difference between treatments in mean change from baseline in IOP

Difference between treatments in IOP

Difference between treatments in percentage IOP change from baseline

Difference between treatments in IOP change from baseline at 11:00

Difference between treatments in percentage IOP change from baseline at 11:00

Difference between treatments in IOP change from baseline at 9:00

Difference between treatments in percentage IOP change from baseline at 9:00
Significance for a comparison will be claimed only if the null hypothesis is rejected 
(p < 0.05) for the previous endpoint in this series.
4.5
Subgroup Analyses and Effect of Baseline Factors
Subgroup analyses of IOP endpoints will be presented by treatment group to assess the 
consistency of treatment effect across various subgroups. 
The primary endpoint (mean change in IOP at Week 6) will be summarized descriptively (N, 
mean, standard deviation), by treatment, in the following subgroups: age category (< 65, ≥65
and furthermore as < 50, 50-64, ≥65), sex, race, baseline IOP (19-24 mmHg, 
> 24-28 mmHg), and region (EMEA = Belgium, Germany, Greece, Italy, Poland, Spain, UK; 
Asia = S. Korea, Malaysia, Taiwan, Australia; LACAR = Argentina, Chile, Colombia).
4.6
Interim Analysis for Efficacy
As previously stated, this study will incorporate an interim analysis for efficacy assessment 
when 50% of the total planned subjects have completed or discontinued from the study. The 
objective of the interim analysis is to provide an opportunity for early rejection of the null 
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hypothesis that there is no difference in IOP change from baseline between SIMBRINZA
plus DUOTRAV and Vehicle plus DUOTRAV. In order to ensure Type I error is adequately 
controlled at the 5% level of significance (two-sided), a p-value boundary will be employed, 
specifically, the Haybittle-Peto boundary (Haybittle 1971). The Haybittle-Peto boundary 
ensures that the study stops for efficacy only if there is overwhelming evidence of efficacy. 
The statistical method for efficacy at the interim analysis is the same as in Section 4.3. The 
primary analysis will be performed on all subjects who have completed or discontinued the 
study at the time of the interim analysis. Subjects who are enrolled and ongoing at the time of 
the interim time point will not contribute to the primary analysis. The p-value obtained from 
the primary analysis will be evaluated against the p-value boundary as listed in Section 8. 
The study will stop for efficacy if the p-value boundary is crossed with respect to the analysis 
of the primary endpoint. If the boundary is not crossed, the study will continue to conclusion.
If the efficacy stopping rule is met at the interim analysis, the main analysis for the primary 
hypothesis is the interim analysis. Analysis for the primary endpoint including subjects that 
did not contribute to the interim analysis but had been randomized at the time of the interim 
analysis (i.e. over-runs) will be reported as a supportive analysis. The main analysis for the 
secondary hypotheses will be based on the FAS population at the end of the study (i.e. 
subjects in the interim analysis plus over-runs).
Following a significant primary analysis at the interim analysis, the secondary hypotheses 
will be tested at the 5% two-sided level of significance. Testing will proceed in the order 
listed in Section 4.4. If the primary analysis is not significant at the interim analysis, the 
secondary endpoints will be tested, following a significant primary final analysis, at the 
reduced alpha as listed in Section 8 and in the order listed in Section 4.4.
5
SAFETY ANALYSIS STRATEGY
5.1
Safety Endpoints
The safety endpoints are:

Extent of exposure

Automated perimetry

Fundus parameters

Best-corrected visual acuity (BCVA)

Slit-lamp biomicroscopy examination
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
Vital Signs (blood pressure, pulse rate)

Adverse events
Relevant measurement scales for safety endpoints (Table 11–1) and a study plan for the 
planned assessments/procedures (Table 11-2) are presented in Section 1.
5.2
Safety Hypotheses
There are no formal safety hypotheses in this study. The focus of the safety analysis will be a 
comprehensive descriptive assessment of the occurrence and characteristics of adverse events 
as well as the other safety endpoints.
5.3
Statistical Methods for Safety Analyses
All analyses will be performed on the safety set overall by treatment unless otherwise noted. 
Selected safety analyses will also be presented by two sets of age categories [both 
(18-64 years and ≥ 65 years) and (18-49, 50-64, ≥65)]. The safety analyses will consist of 
descriptive summaries of the data as relevant to the scale of data, eg, frequencies and 
percentages for adverse events, and mean changes in IOP from baseline as appropriate.
5.3.1
Extent of Exposure
Extent of exposure to investigational product is calculated as duration of exposure to masked 
IP received. For all randomized subjects exposed to masked IP, duration of exposure is 
defined as the last day of exposure to masked IP minus the first day of exposure to masked IP 
plus 1 day. In the event that the last day of exposure is unknown, the date of last contact with 
the subject will be used. The first instillation of investigational product is scheduled to occur 
on the evening of the Eligibility 2 Visit and the last instillation of investigational product is 
scheduled to occur at the Week 6 Visit (Day 42) following the 09:00 IOP measurement. 
Additionally, subjects exposed to investigational product with no visits after Day 1 or no date 
of last contact will have their extent of exposure documented as 1 day. Extent of exposure 
will be summarized as a continuous measure (N, mean, median, standard deviation, minimum 
and maximum) and by counts and percentages of subjects in the following categories: 0 days, 
1 to 17 days, 18 to 42 days and > 42 days.
Extent of exposure will be presented overall and by demographic characteristics (age, sex, 
race, and age categories [both (18-64 years and ≥ 65 years) and (18-49, 50-64, ≥65)]) for the 
safety analysis set.
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5.3.2
Adverse Events
The applicable definition of an Adverse Event (AE) is in the study protocol. All AEs 
occurring from when a subject signs informed consent to when a subject exits the study will 
be accounted for. Analysis and presentation of AEs occurring prior to the exposure to the 
masked IP will be separated from those occurring after treatment exposure where a 
comparative evaluation of treatment-emergent AEs is intended. A treatment-emergent AE is 
an event not present prior to exposure to masked IP or any event already present that worsens 
following exposure to masked IP. The period for treatment-emergent AE analysis starts from 
first exposure to the masked investigational product to 30 days after cessation of study 
treatment. Any event occurring after the treatment-emergent period will be considered post-
treatment. 
Descriptive summaries (n and %) for AEs will be presented by system organ class and 
preferred term and by preferred term only. In addition to an overall presentation of all AEs, 
reports will be generated for special classes of AEs such as most frequent AEs (defined as 
AEs with incidence of 1% in one or both treatment groups), ocular AEs, nonocular AEs, 
treatment-related AEs, serious AEs, and AEs resulting in treatment discontinuation. Selected
AE analyses (all treatment-emergent ocular AEs and all nonocular AEs) will be presented by 
both sets of age categories (18-64 years and ≥ 65 years) and (18-49, 50-64, ≥65).
Presentation of ocular AEs will be overall, i.e. event occurring in one eye or both eyes will be 
counted once with respect to the subject level counts, but will be counted each time for the 
number of events. Ocular adverse events will be presented by subgroups (Age, Race, Gender, 
Ethnicity and Region). These reports will be supported by subject listings, as necessary.
A listing will be provided for AEs that occur after signing informed consent but prior to 
randomization and exposure to at least 1 dose of the masked IP. This listing will comprise all 
events occurring during this period in any subject who consented to participate in the study.
5.3.3
Automated Perimetry
Visual field assessments will be conducted at the Screening (Visit 1) and the Week 6/Exit
visits. Baseline will be defined as the last measurement prior to exposure to the masked IP 
(i.e. Screening). The analysis eye will be selected as the average of each subject’s right and 
left dosed eyes. If only one eye is dosed then this eye will be analyzed. Analysis of visual 
fields will use the data from the selected eye(s). 
Separate analyses will be performed for each visual field device used. The analyses will 
include Mean Deviation, Mean Defect, Corrected Pattern Standard Deviation (CPSD) or 
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PSD, and Corrected Loss Variance (CLV), dependent upon the visual field device used (see 
Manual of Procedures Section 4.2 for details). Observed values and change from baseline 
values for the selected eye(s) will be presented descriptively (N, mean, median, standard 
deviation, minimum, and maximum) at each post-baseline visit including exit for each 
treatment.
5.3.4
Fundus Parameters
A dilated fundus examination will be performed to evaluate the health of the vitreous; 
retina/macula/choroid, optic nerve, and cup/disc ratio (see Table 11–1 in the Appendix for the 
scale of each parameter). The dilated fundus examination will be conducted at the Screening
(Visit 1) and Week 6/ Exit (Visit 5) visits. Baseline will be defined as the last measurement 
prior to exposure to investigational product (i.e. Screening). 
For each fundus parameter, excluding cup/disc ratio, the worse eye will be used in the 
analysis. The worse eye is the dosed eye with the largest increase from baseline. If both 
dosed eyes have the same amount of increase, then the right eye will be selected. Note that 
the worse eye will be chosen on the parameter level, therefore it is possible that a given 
subject would have both eyes declared as worse eye (e.g. the right eye for retina and left eye 
for optic nerve). 
For each dilated fundus parameter, counts and percentages of subjects who experience an 
increase from baseline to exit visit will be presented. A listing will be provided which 
presents all subjects with an increase in any fundus parameter at any visit compared to the 
grade for the same eye at baseline. 
For cup/disc ratio, the analysis eye will be selected as the average of each subject’s right and 
left dosed eyes. If only one eye is dosed then this eye will be the selected eye. Analysis of 
cup/disc ratio will use the data from the selected eye(s). Observed values and change from 
baseline values for the selected eye(s) will be presented descriptively (N, mean, median, 
standard deviation, standard error, minimum, and maximum), by vertical and horizontal axes, 
at each study visit including exit for each treatment.
5.3.5
Best Corrected Visual Acuity (BCVA)
Best corrected visual acuity will be assessed at the Screening, Eligibility 1 (09:00 hours), 
Eligibility 2 (09:00 hours), Week 2 (09:00 hours) and Week 6 (09:00 hours)/Exit Visits.
Baseline will be defined as the last BCVA measurement prior to exposure to the masked IP 
(i.e. Eligibility 2 (09:00 hours)). The analysis eye will be selected as the eye with the largest 
decrease in the number of letters read from baseline to any visit (scheduled or unscheduled).
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If both study eyes have the same level of worsening, the right eye will be selected. Analysis 
of BCVA will use the data from the selected eye. 
Observed values and change from baseline values for the selected eye will be presented 
descriptively (N, mean, median, standard deviation, standard error, minimum, and maximum) 
at each study visit for each treatment. A plot of mean change in BCVA by study visit and by 
treatment with error bars representing +/- 1 standard error will be presented using the selected 
eye. The x-axis will be study visit and the y-axis will be the change in BCVA from baseline. 
Counts and percentages of subjects who experience pre-specified category of change from 
baseline to last on-treatment BCVA assessment or to any visit will be presented according to 
the following categories: ≥15 letter increase, 10-14 letter increase, 5-9 letter increase, no 
change (+/- 4), 5-9 letter decrease, 10-14 letter decrease, ≥15 letter decrease. For change to 
any visit, a subject will be counted only in the category that represents their worst change 
from baseline across all post-baseline assessments.
A listing will be provided which presents all subjects with a ≥15 letter decrease in BCVA 
from baseline to any visit.
5.3.6
Slit-Lamp Biomicroscopy
A slit-lamp examination (SLE) will be performed at the Screening, Eligibility 1 (09:00), 
Eligibility 2 (09:00), Week 2 (09:00), and Week 6 (09:00)/Exit Visits. Baseline will be 
defined as the last SLE measurement prior to exposure to masked IP (i.e. Eligibility 2 
(09:00)). The analysis of the SLE will consist of increases from baseline in the presence of 
aqueous flare/cells and lens (see Table 11–1 in the Appendix for the scale of each parameter). 
For each slit-lamp parameter, the eye showing the largest increase in slit-lamp grade from 
baseline to any visit (scheduled or unscheduled) will be used in the analysis. If both eyes 
have the same amount of increase, then the right eye will be selected. Note that the worse eye 
will be chosen at the parameter level; therefore it is possible that a given subject may not 
have the same worse eye for all parameters. The analysis of slit-lamp parameters will include 
the counts and percentages of subjects who experience an increase from baseline to any visit 
attended. In addition, a shift table showing slit-lamp grade at baseline relative to each 
scheduled post-baseline visit will be presented for each parameter.
A listing will be provided which presents all subjects with an increase in any slit-lamp 
parameter at any visit compared to the grade of the same eye at baseline.
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5.3.7
Vital Signs (Blood Pressure, Pulse Rate)
Blood pressure and pulse rate will be evaluated at Screening, and every time point at E1, E2,
Week 2, and Week 6/Exit Visits. The proximal baseline measurement for vital signs will be 
the average of the E1 and E2 Visits. For systolic and diastolic blood pressure, two 
measurements will be obtained at each Eligibility visit and the average pressure will be used 
for that visit. If the first two readings differ by more than 5 mmHg, a third reading will be 
taken and the average of the three values will be used. If three readings are available 
regardless of the above criteria (first two readings differ by more than 5 mmHg), the average 
of the three values will be used. A graphical representation of the mean actual parameter 
value over time by treatment will be provided.
Descriptive statistics (mean, standard deviation, N) by treatment group will be provided for 
each cardiovascular parameter at each scheduled visit and time point. The statistics will be 
given for the actual parameter value. A subject listing will be provided which contains data at 
baseline and each study visit and time point for each cardiovascular parameter. 
Also, a subject listing will be provided which contains data for each abnormal cardiovascular 
finding. Each value will be categorized as low, normal, or high using the following normal 
ranges for subjects 18 or more years of age: pulse - 60 to 100 bpm; systolic blood pressure -
100 to 140 mm Hg, diastolic blood pressure - 60 to 90 mm Hg. 
Finally, a subject listing corresponding to this shift in cardiovascular parameters will be 
presented for the overall safety population. 
5.4
Interim Analysis for Safety
Not applicable.
6
PHARMACOKINETIC ANALYSIS STRATEGY
Not applicable.
7
ANALYSIS STRATEGY FOR OTHER ENDPOINTS
Not applicable.
8
SAMPLE SIZE AND POWER CALCULATIONS
With 108 evaluable subjects per treatment group in the primary efficacy analysis, there is at 
least 80% power to detect a 1.5 mmHg difference in mean change from baseline in IOP at 
Week 6 between the treatment groups. However, the required sample size to attain the same 
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power is 28 subjects per arm if the difference is 3.0 mmHg between treatment groups as 
suggested by expert opinion.  Both calculations are based on the assumption of a common 
standard deviation for mean IOP of 3.9 mmHg and the use of a two-sample two-sided t-test 
performed at the α=0.05 level of significance.
To mitigate the uncertainty about the expected treatment difference, a two look design with 
Haybittle-Peto boundaries will be used. Thus, this study will incorporate an interim analysis
for efficacy assessment when 50% of total planned subjects have completed or discontinued 
from the study. The power to reject the null hypothesis at the single interim analysis when 
50% of subjects have completed or discontinued the study is 28.2% if the expected mean 
difference is 1.5 and 92.2% if the expected mean difference is 3.0.
Look #
Sample 
Size
Efficacy 
p-value
P-value 
Boundary
Exit Probabilities
δ=0
δ=1.5
δ=3.0
1
108
0.01
0.01
0.01
0.282
0.922
2
216
0.045
0.045
0.04
0.517
0.078
Sum of Exit Probabilities
0.05
0.799
1
Assuming a drop-out rate of 10%, approximately 120 subjects per treatment group will be 
randomized to ensure the required number of evaluable subjects in the final efficacy analysis.
Subjects will be randomized in a 1:1 ratio to receive either SIMBRINZA and DUOTRAV or 
Vehicle and DUOTRAV.
9
REFERENCES
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-63.
10
REVISION HISTORY
This is the second version (Version 2.0) Statistical Analysis Plan for this study. This version 
of the Statistical Analysis Plan is based on Version 2.0, of the study protocol TDOC-0051572.
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Amendment #1
1. Changed author from 
 to 
2. Lowered the qualifying IOP criteria at both the Eligibility 1 and Eligibility 2 visits 
from ≥21 and ≤28 mmHg at 9:00 to ≥19 and ≤28 mmHg at 9:00.
3. Removed the 15:00 IOP measurement time point at all study visits.
4. Allowed subjects currently on treatment with Travoprost 0.004%/Timolol 0.5% for at 
least 28 days prior to screening in the morning or evening to be eligible for the study.
5. Incorporated an interim analysis for efficacy assessments when 50% of the total 
planned subjects have been completed or discontinued from the study.
6. Updated Statistical Analysis associated with the change in eligibility criteria.
Amendment #2
1. Changed author from 
 to 
.
2. Dummy SAS codes are moved to Appendix.
3. All listing details were delete and the variables reported in each listing are in the TFL 
shell document.  
4. To test efficacy endpoints unstructured covariance (COV = “UN”) will be used.
5. The baseline value used in the model as covariate was changed to the average of 9:00 
Hr and 11:00 Hr values instead of the 09:00 AM IOP (averaged over the eligibility 
visits) to be consistent with the calculation of the primary endpoint.
6. Removed subgroup analysis (w.r.t. age, sex, baseline IOP category) of secondary 
efficacy end points. 
7.
8. Categorization by Duotrav type is removed as relevant information is not collected in 
CRF. 
9. The plot reporting the percentage of subjects achieving IOP target will be reported by 
treatment group was removed. 
10. For cup/disc ratio, the analysis eye will be selected as the average of each subject’s 
right and left dosed eyes instead of the worst eye.
11. Minor edits of the text throughout the document. 
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11
Appendix
11.1
SAS Pseudo-code
SAS pseudo-code such as the following will be used to implement the procedures described
in Section 4.3 for the primary endpoint:
proc mixed data = dataset;
      
class treatment subject;
model  dIOPchange = baselineIOP treatment / ddfm=KR;
         lsmeans treatment / cl diff
ods output diffs = diffs lsmeans = lsmeans; 
run;
SAS pseudo-code such as the following will be used to implement the procedures described 
in Section 4.3, for the secondary endpoint:
proc mixed data = dataset;
      
class treatment timepoint subject;
model  IOPchange = baselineIOP treatment | timepoint/ ddfm=KR;
repeated timepoint/ type=UN subject=subject;
         lsmeans treatment* timepoint/ cl diff;
ods output diffs = diffs lsmeans = lsmeans;
run;
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11.2
Study Tables for Reference
Table 11–1
Measurement Scales for Ophthalmic Assessments
Assessment
Scale
Parameter
Slit-Lamp Exam
0 – None
1 – Faint
2 – Moderate
3 – Marked
4 – Intense 
Aqueous Flare
Grade 0.0 – <1 cells
Grade 0.5 – 1 to 5 cells
Grade 1 – 6 to 15 cells
Grade 2 – 16 to 25 cells
Grade 3 – 26 to 50 cells
Grade 4  – >50 cells
Aqueous Cells
0 – Phakic
1 – Pseudophakic
2 – Aphakic 
Lens
0 – No opacity
1 – Any opacity 
2 – Worsening of opacity
3 – Not Evaluable
Status of Lens
Fundus Parameters
0 – Absence of any opacity
1 – Presence of opacity in the vitreous
Vitreous
0 – Normal. No evidence of previous 
inflammation or structural change
1 – Evidence of previous inflammation, 
now quiet; or previous structural change, 
now stable
2 – Evidence of active inflammatory 
process or acute structural change
Retina
Macula
Choroid
0 – Normal. No damage
1 – Mild optic nerve damage, secondary to 
glaucoma including any rim loss (sloping 
or thinning)
2 – Moderate optic nerve damage, 
including cupping to disc margin at one or 
more points
3 – Severe optic nerve damage, nearly total 
cupping, only nasal rim or less present
Optic Nerve
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Table 11-2
Overview of Study Plan
Nominal Time ± Visit Window Limits
Visit 1*
Screening
Visit 2*
Eligibility 1
Visit 3
Eligibility 2
(Randomization)
Visit 4
Visit 5
Exit
Unscheduled
Visit
Early
Exita
Procedure/ Assessment
1-5 days after 
Screening
3-5 days from E1
Day 14± 
3 Days from 
E2
Day 42 ± 
5 Days from 
E2
Informed Consent b
X
Demographics
X
Medical History
X
Concomitant Medications
X
Changes in Concomitant Meds
X
X
X
X
X
X
Inclusion/Exclusion
X
Urine Pregnancy Test c
X
X
X
BCVA
X
X1
X1
X1
X1
X
X
Slit-Lamp Biomicroscopy
X
X1
X1
X
X1
X
X
Corneal Thickness
(Pachymetry)
X
Angle Width Screening
(Gonioscopy)
X
Dilated Fundus Exam
X
X
X
X
Visual Field Assessment
(Automated perimetry)
Xd
Xe
Xe
IOP
X
X2
X
X
IOP (9:00, 11:00) +/- 30 minutes
X
X
X
Blood Pressure
X
X2
X
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Nominal Time ± Visit Window Limits
Visit 1*
Screening
Visit 2*
Eligibility 1
Visit 3
Eligibility 2
(Randomization)
Visit 4
Visit 5
Exit
Unscheduled
Visit
Early
Exita
Procedure/ Assessment
1-5 days after 
Screening
3-5 days from E1
Day 14± 
3 Days from 
E2
Day 42 ± 
5 Days from 
E2
Blood Pressure (9:00, 11:00)
X
X
X
Pulse Rate
X
X2
X
Pulse Rate (9:00, 11:00)
X
X
X
Dispense Study Meds
X
X
Instill Meds in Office
X
X
Adverse Events
(Both Volunteered and Elicited)
X
X
X
X
X
X
X
Collect Study Meds
X
X
Exit Subject & Complete Exit 
Form
X
X
* Visit 1 and 2 may be combined if the subject IOP was measured at 9:00, DUOTRAV taken on the previous morning at 9:00 ± 1hour or evening at 21:00 ± 1hour 
and all other study assessments can be completed as per protocol.
1 morning only
2 9:00 ± 2 hours
a Perform assessments on subjects who discontinue study participation prior to Week 6 visit.
b Must be signed/dated before study procedures are performed.
c Required on all female subjects of childbearing potential.
d VF can have been performed 30 days before Screening to E2 visit
e May be conducted anytime during the visit.
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Date/Time 
(mm/dd/yyyy GMT):
Signed by:
Justification:
07/23/2018 20:58:53
07/23/2018 20:13:23
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