Conditions: Open-Angle Glaucoma Ocular Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 290
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% (dosed twice per day (BID)) when added to a prostaglandin analogue (PGA) in subjects with open-angle glaucoma or ocular hypertension.

Detailed description:
This study consisted of 2 sequential phases: Screening/Eligibility Phase, followed by a Masked Treatment Phase (Phase II). Subjects were assigned into one of 3 PGA therapy groups for the duration of the study, based upon commercial availability.

Arms:
arm 1: Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days arm 2: Brinz/brim vehicle, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days

Interventions: intervention 1: Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension intervention 2: Brinz/brim vehicle intervention 3: Prostaglandin analogue
Intervention descriptions: intervention 1: None intervention 2: Inactive ingredients used as a placebo for masking purposes intervention 3: None

Protocol document:
Prot_001.pdf: 
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a Novartis company 
 
Short Title 
 
Simbrinza BID Adjunctive to PGA 
 
Long Title 
 
Additive Effect of Twice Daily Brinzolamide 1% /Brimonidine 0.2% Fixed 
Dose Combination as an Adjunctive Therapy to a Prostaglandin Analogue 
 
TDOC-0050474 Version 1.0 replaces TDOC-0018786 Version 1.0 (11-Mar-2015) 
 
Protocol Number: 
Study Phase: 
Sponsor Name and 
Address: 
 
Investigational Product: 
 
 
US IND# / EudraCT 
Indication Studied: 
GLH694-P001 / NCT02419508 
4 
Alcon Research, Ltd. 
6201 South Freeway 
Fort Worth, Texas 76134-2099 
SIMBRINZA™ 
Brinzolamide 1%/Brimonidine 0.2% tartrate ophthalmic 
suspension 
2015-000736-15 
Ocular Hypertension 
Open Angle Glaucoma 


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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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1 
SYNOPSIS 
Sponsor: 
Alcon Research, Ltd. 
6201 South Freeway 
Fort Worth, Texas 
76134-2099 
 
 
Protocol Number: GLH694-P001 
Investigational 
Product: 
SIMBRINZA ™ 
Brinzolamide 1%/ 
Brimonidine 0.2% tartrate 
ophthalmic suspension 
Study Phase: 
1 
2 
3 
 4 
N/A 
 
Active Ingredient: 
Brinzolamide 1%/Brimonidine 0.2% 
Protocol Title: 
Additive Effect of Twice Daily Brinzolamide 1% /Brimonidine 
0.2% Fixed Dose Combination as an Adjunctive Therapy to a 
Prostaglandin Analogue 
Investigator(s)/ No. of Sites: Multicenter, approximately 33 sites 
No. of Subjects 
Approximately 280 subjects enrolled, 180 subjects randomized, 
162 subjects evaluable 
Duration of Treatment: 
Approximately 42 days 
Study Population: 
Adult subjects with open-angle glaucoma or ocular hypertension 
who require multiple pharmaceutical therapy for control of IOP or 
with inadequately controlled IOP while on a PGA monotherapy. 
Objective(s): 
To demonstrate the additive IOP lowering effect of Brinzolamide 
1%/Brimonidine 0.2% (dosed BID) when added to a PGA in 
patients with open-angle glaucoma or ocular hypertension. 
Methodology: 
Multicenter, randomized, double-masked, parallel-group study 
Treatments: 
Investigational Product: 
SIMBRINZA® 
Brinzolamide/Brimonidine tartrate 
ophthalmic suspension 1%/0.2% 
Route of Administration: Topical ocular drops 
Duration of Treatment: 
Approximately 42 days 
 
Dosage: 
1 drop instilled 2 times per day in 
affected eye(s) (09:00 and 21:00) 
 
 
 
Prostaglandin analogues: TRAVATAN PQ (Travoprost 


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Sponsor: 
Alcon Research, Ltd. 
6201 South Freeway 
Fort Worth, Texas 
76134-2099 
Protocol Number: GLH694-P001 
 
 
 
ophthalmic solution preserved with 
Polyquad) 0.004% 
XALATAN (Latanoprost) 0.005% 
LUMIGAN (Bimatoprost) 0.01% 
Route of Administration: Topical ocular drops 
Duration of Treatment: 
Run-in period followed by treatment 
for approximately 42 days 
Dosage: 
1 drop instilled once per day in 
affected eye(s) in the evening 
Control Article: 
Brinz/Brim Vehicle 
Route of Administration: Topical ocular drops 
Duration of Treatment: 
Approximately 42 days 
Dosage: 
1 drop instilled 2 times per day in 
affected eye(s) (09:00 and 21:00) 
Subject Selection: 
Inclusion Criteria: 
1. Subjects 18 years of age or older, of any race/ethnicity, 
diagnosed with either open-angle glaucoma (including 
open-angle glaucoma with pseudoexfoliation or pigment 
dispersion) or ocular hypertension. 
 
2. After signing the Informed Consent Form, subjects 
previously on combination therapy must simultaneously 
initiate study-specific PGA therapy and must be washed 
out of all other adjunctive medications (miotics and 
oral/topical carbonic anhydrase inhibitors, 5 days; alpha 
and alpha/beta agonists, 14 days; beta-antagonists, 28 
days) prior to Eligibility Visit 1. 
 
Subjects who were previously on one of the study-specific 
branded PGA monotherapy for at least 28 days prior to the 
Screening Visit should also be considered potential study 
candidates (see MOP section 5.1.1.1 for possible 
screening/washout scenarios). 


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Alcon Research, Ltd. 
6201 South Freeway 
Fmt Worth, Texas 
Protocol Number: GLH694-P001 
76134-2099 
 
 
 
 
3. Qualifying Mean IOP measmements (after washout) at 
both the Eligibility 1 and 2 Visits in at least 1 eye (the 
same eye[s]) must be 19 and < 32 mmHg at 09:00. 
 
4. Must be able to understand and sign an info1med consent 
fo1m that has been approved by an Institutional Review 
Board/Ethics Committee. 
 
5. Willing and able to attend all study visits. 
Exclusion Criteria: 
1. 
Women of childbearing potential, defined as all 
women who are not postmenopausal for at least 1 year 
or less than 6 weeks since sterilization, are excluded 
from participation if: 
a. they are cmTently pregnant, or 
b. have a positive result on the urine pregnancy test at 
Screening, or 
c. intend to become pregnant during the study period, 
or 
d. are breast-feeding, or 
e. are not in agreement to use adequate biit h control 
methods to prevent pregnancy throughout the study 
(further definition can be found in Section 12.7). 
 
 
Effective contraceptive measures include: 
• 
Total abstinence (when this is in line with the 
prefen ed and usual lifestyle of the subject). 
Periodic abstinence (eg, calendar, ovulation, 
symptothe1mal, postovulation methods) and 
withdrawal are not acceptable methods of 
contraception 
• 
Female sterilization (have had surgical bilateral 
oophorectomy with or without  hysterectomy) 
or tubal ligation at least 6 weeks before 
Baseline. In case of oophorectomy alone, only 
when the reproductive status of the woman has 


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Alcon Research, Ltd. 
6201 South Freeway 
Fmt Worth, Texas 
Protocol Number: GLH694-P001 
76134-2099 
 
 
been confnmed by follow up hormone level 
assessment 
• 
Male sterilization (at least 6 months prior to 
Baseline). For female subjects in the study, the 
vasectomized male partner should be the sole 
pa1tn er for that subject 
• 
Use of oral, injected or implanted hmm onal 
methods of contraception or other form s of 
hmm onal contraception that have comparable 
efficacy (failure rate <l%), for example 
hmmone vaginal ring or transdermal hmmone 
contraception 
• 
Placement of an intrauterine device (IUD) or 
intrauterine system (IUS) 
 
2. 
Any fo1m of glaucoma other than open-angle glaucoma 
or ocular hype1tension. 
 
3. 
Central cornea thickness (CCT) greater than 620 µm as 
measured by pachymetly in either eye (see MOP for 
fmther details). 
 
4. 
Schaffer angle Grade < 2 in either eye, as measured by 
gonioscopy (extreme nan ow angle with complete or 
partial closure). 
 
5. 
Cup/disc ratio greater than 0.80 (horizontal or ve1tical 
measurement) in either eye. 
 
6. 
Severe centr·al visual fi eld loss in either eye or field 
loss threatening fixation in either eye. 
 
Severe centr·al visual fi eld loss is de fined as a 
se nsiti vity of less than or equal to 10 dB in at least 2 of 
the 4 visual field test points closest to the point of 
fixation. 


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Version: 3.0; 
Alcon Research, Ltd. 
6201 South Freeway 
Fort Worth, Texas 
76134-2099 
Protocol Number: GLH694-P001 
 
 
7. 
Chronic, recurrent or severe inflammatory eye disease 
(eg, scleritis, uveitis, herpes keratitis) in either eye. 
 
8. 
Ocular trauma in either eye within the past 6 months 
prior to the Screening visit. 
 
9. 
Ocular infection or ocular inflammation in either eye 
within the past 3 months prior to the Screening visit. 
 
10. 
Clinically significant or progressive retinal disease 
such as retinal degeneration, diabetic retinopathy, or 
retinal detachment in either eye. 
 
11. 
Best-corrective visual acuity score worse than 55 
ETDRS letters (equivalent to approximately 20/80 
Snellen, 0.60 logMAR or 0.25 decimal) in either eye. 
 
12. 
Other ocular pathology (including severe dry eye) in 
either eye that may, in the opinion of the Investigator, 
preclude the safe administration of a topical ocular 
alpha-adrenergic agonist and/or topical ocular carbonic 
anhydrase inhibitor and/or topical ocular PGA. 
 
13. 
Intraocular surgery in either eye within the past 6 
months prior to the Screening visit. 
 
14. 
Ocular laser surgery in either eye within the past 3 
months prior to the Screening visit. 
 
15. 
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. 
History of active, severe, unstable or uncontrolled 
cardiovascular (eg, coronary insufficiency, 


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Protocol Number: GLH694-P001 
 
 
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. 
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. 
Therapy with another investigational agent within 30 
days prior to the Screening visit. 
 
22. 
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 (ie, β-adrenergic blocking agents). The dosing 
regimen of these medications should not change during 
the study. 
 
23. 
Hypersensitivity to alpha-adrenergic agonist drugs, 
topical or oral carbonic anhydrase inhibitors, 
prostaglandins, sulfonamide derivatives, or to any 
component of the study medications in the opinion of 
the Investigator. 
 
24. 
Use of any additional topical or systemic ocular 
hypotensive medication in either eye during the study. 


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Alcon Research, Ltd. 
6201 South Freeway 
Protocol Number: GLH694-P001 
 
 
Fmt Worth, Texas 
76134-2099 
25. 
Subjects who cannot safely discontinue all 
glucocmticoids administered by any route prior to the 
Eligibility 1 visit and continue to not use during the 
study. 
 
Steroid washout duration: 
a. 
Chronic therapy - 4 weeks 
b. 
Intennittent therapy-2 weeks 
 
 
26. 
Subjects who, in the opinion of the Investigator, cannot 
discontinue all !OP-lowering ocular medication(s) 
except the study provided PGA therapy per the 
appropriate washout schedule prior to the Eligibility 1 
visit. 
 
27. 
Mean IOP 2'.: 32mmHg at any time point, in either eye, 
during the Screening/Eligibility Phase. 
 
 
 
 
 
Assessments: 
The Medical Director may declare any subject ineligible for a 
valid medical reason. 
Primary Efficacy: 
• 
Mean change from baseline (on PGA) in diurnal IOP 
(mean of 09:00 and 11:00 time points) at Week 6 
Secondary Efficacy: 
• 
Mean diurnal IOP at Week 6 
• 
Mean percentage change from baseline in diurnal IOP at 
Week6 
• 
Mean change from baseline in IOP at 11:00 at Week 6 
• 
Mean percentage change from baseline at 11:00 at Week 6 
• 
Mean change from baseline in IOP at 09:00 at Week 6 
• 
Mean percentage change from baseline at 09:00 at Week 6 
 
 


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Version: 3.0; 
Alcon Research, Ltd. 
6201 South Freeway 
Protocol Number: GLH694-P001 
 
 
Fort Worth, Texas 
76134-2099 
Safety: 
Automated perimetry, fundus parameters, best-corrected visual 
acuity (BCVA), slit-lamp exam, blood pressure, pulse rate and 
adverse events. 
 
Statistical Methods: 
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 09:00 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. 
Randomization will be stratified according to region and type of 
PGA (Lumigan, Xalatan, Travatan). 
 
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 1 of the 2 scheduled on-treatment 
visits. The Safety set will consist of all who received a dose of 


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Alcon Research, Ltd. 
6201 South Freeway 
Protocol Number: GLH694-P001 
Fmt Worth, Texas 
76134-2099 
 
 
study medication. 
 
 
Primaiy Efficacy: 
The prima1y efficacy analysis will be an assessment of differences 
between treatments in mean change from baseline in diurnal IOP 
at Week 6 (subject IOP averaged over the 09:00 and 11:00 time 
points). The null and alternative hypotheses for the ptimaiy 
analysis ai·e: 
 
 
Ho: µ BrinzBrim+PGA = µ Vehicle+PGA 
H1: µ BrinzBrim+PGA -# µ v ehicle+PGA 
 
where µsrinzBrim+PGArefers to mean diurnal IOP change from 
baseline for subjects randomized to receive brinzolamide / 
brimonidine plus PGA, and µ v ehicie+PGArefers to mean diurnal IOP 
change from baseline for subjects randomized to receive Vehicle 
plus PGA. The treatment difference in mean diurnal IOP change 
from baseline will be tested based on the least squares means 
derived from a repeated measures mixed model. This model will 
include fixed effects of treatment, visit, type of PGA, region, and 
the interaction of treatmentand visit; the baseline diurnal IOP as a 
covai·iate; and the random effect of subject within the subject's 
treatment, region, and type of PGA. 
 
Secondaiy efficacy: 
Analyses of treatment differences of seconda1y endpoints will use 
the same methods as those for the prima1y endpoint. Hypothesis 
tests will use the same null and alternative hypotheses as above, 
with µ representing the mean for the variable being tested. 
 
A closed step-down testing procedure will be used for hypothesis 
testing of prima1y and seconda1y endpoints; therefore, no 
multiplicity adjustment is needed. The testing order (all based on 
IOP at Week 6) will be 
• 
Difference between treatments in mean change from 
baseline in diurnal IOP 


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Alcon Research, Ltd. 
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Protocol Number: GLH694-P001 
Fmt Worth, Texas 
76134-2099 
 
 
• 
Difference between treatments in mean diurnal IOP 
• 
Difference between treatments in mean percentage diurnal 
IOP change from baseline 
• 
Difference between treatmentsin 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 09:00 
• 
Difference between treatments in percentage IOP change 
from baseline at 09:00 
 
 
Significance for a comparison will be claimed only if the null 
hypothesis is rejected (p < 0.05) for the previous endpoint in this 
senes. 
 
 
 
Sample Size Justification: 
With 81 evaluable subjects per treatment group in the primary 
efficacy analysis, there is at leas t 90% power to detect a difference 
in mean change from base line in dimn al IOP at Week 6 IOP of 
2.0 mmHg between the treatment groups. This calculation is based 
on the assumption of a common standard deviation for mean 
change from baseline in diurnal IOP as small as 3.5 mmHg and as 
large as 3.9 mmHg and the use of a two-sample two-sided t-test 
performed at the a=0.05 level of significance. 
 
Assmning a drop-out rate of 10%, approximately 90 subjects per 
treatment group will be randomized to ensure the required number 
of evaluable subjects in the final efficacy analysis. 


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Version: 3.0; 
 
 
X 
X 
X 
1.1 
Amendments 
Amendment 2 
 
1. Remove 16:00 IOP collection time point at all visits. 
 
Rationale: The 12-hr trough and 2-hr peak effects of Simbrinza are seen at 9:00 and 11:00, 
respectively, and are the critical measurement time points for the study. The 16:00 time point 
provides further daytime data but is proving to be a major barrier to recruitment. Removing 
the late day 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 (9:00 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. 
 
 
2. Reduce E1 & E2, 09:00 am, IOP inclusion criteria (#3) from ≥ 21 and < 32 mmHg to 
≥ 19 and < 32 mmHg. 
 
Rationale: 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. 
 
 
 
Case Report Form Revision Required: 
Yes 
No 
 
Informed Consent Modifications Required: 
Yes 
No 
 
Applicable Investigators: 
All 
Selected (list below) 
 
 
Itemized Changes: 
 
Itemized Changes: Additions/modifications are noted in bold, italics. Deletions are noted with 
a strikethrough. 


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Version: 3.0; 
 
 
I. 
Reduction of E1 and E2 (09:00) IOP inclusion criteria from ≥ 21 and < 32 mmHg 
to ≥ 19 and < 32 mmHg: 
 
• Synopsis, Inclusion Criteria, #3 – 
the Eligibility 1 and 2 Visits in at least 1 eye (the same eye[s]) must be ≥ 19 21 and 
< 32 mmHg at 09:00. 
 
• Synopsis, 
 
 
• Subject Population, 8 – 
in at least 1 eye (study eye) ≥ 19 21 and < 32 mmHg at 2 consecutive visits 
(Eligibility 1 and Eligibility 2) 
 
• Duration of Exposure, 9.2.2 – 
and present with uncontrolled IOP (≥ 19 21 mmHg) at Screening may skip the 28 
day run-in 
 
• Table 10-1, Study Plan by Treatment Group – 
Mean IOP for both Eligibility Visits must be: ≥ 19 21 mmHg and < 32 mmHg 
 
• Table 10-3, Activity for Eligibility 1 and Eligibility 2 Visits – 
Mean IOP must be ≥ 19 21 and < 32 mmHg 
 
• Demographics and Baseline Characteristics, 11.3 and Baseline Characteristics, 11.3.2- 
In addition, baseline IOP (19 21-26 mmHg, 27-32 mmHg) 
• Subgroup Analysis Methods, 11.4.1.2.1 – 
sex, race, baseline IOP (19 21-26 mmHg, 27-32 mmHg), 
 
• 
 
 
 
II. 
Remove 16:00 IOP collection time point at all visits. 
 
• Synopsis, Primary efficacy – 


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Version: 3.0; 
 
 
Mean change from baseline (on PGA) in diurnal IOP (mean of 09:00, and 11:00 
and 16:00 time points) at Week 6 
 
• Removal of 16:00 visits and assessments previously completed at 16:00 will be 
completed at 11:00 time point in the following tables: 
1. Overview of Study Plan, 2 – 
2. Table 10-3, Activity for Eligibility 1 and Eligibility 2 Visits – 
3. Table 10-4, Activities for Week 2 and Week 6 (Exit) Visits – 
 
• Eligibility 1 and Eligibility 2 Visits, 10.2.2 – 
ELIGIBILITY 1 AND ELIGIBILITY 2 VISITS: [09:00 (+/-30 MIN) AND 11:00 (+/- 
30 MIN), AND 16:00 (+/- 30 MIN) EXAMINATIONS] 
 
• Week 2 and Week 6 Visits, 10.2.3 – 
WEEK 2 AND WEEK 6 (EXIT) VISITS: [09:00 (+/- 30 MIN) AND 11:00 (+/- 30 
MIN), AND 16:00 (+/- 30 MIN) EXAMINATIONS] 
 
 
 
III. 
Summary statistical changes in absence of 16:00 IOP time point 
 
The following sections contain text as described below: 
1. Synopsis, Secondary Efficacy – 
2. Secondary Efficacy, 11.4.2 – 
3. Multiplicity, 11.6 – 
 
Changed from: 
• 
Mean change from baseline in IOP for each time point (09:00, 11:00, 16:00) at Week 
  
6 
 
• 
Mean percentage change from baseline in IOP for each time point (09:00, 11:00, 
  
16:00) at Week 6 
 
Changed to: 
• 
Mean change from baseline in IOP at 11:00 at Week 6 
• 
Mean percentage change from baseline at 11:00 at Week 6 
• 
Mean change from baseline in IOP at 09:00 at Week 6 
• 
Mean percentage change from baseline at 09:00 at Week 6 


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IV. 
Additional changes 
 
• 
Clarified of exclusion 27, Synopsis - 
Mean IOP 2': 32 mmHg at any time point, in either eye, dming the 
Screening/Eligibility Phase. 
 
 
• 
Remove Medical Monitor, Synopsis, Exclusion - 
Changed from: The Medical Moai.tor may declare any subject ineligible for a valid 
medical reason. 
Changed to: The Medical Director may declare any subject ineligible for a valid 
medical reason. 
 
 
• 
Removal of identifying specific participating regions, Synopsis and Sections 11.4 & 
11.4.3 - 
 
 
 
If both eyes are equal then the right eye will be selected for analysis. Randomization 
will be stratified according to region (EU (EHrope, AHst rn.lia), LACA. t (Latia 
Ameriea, Csa ada)) and type of PGA therapy. 
Age categ01y: <50, 50-65, >65; Sex; Race; regioa (EU (EHrnpe, AHstrnlia), L l\.CM t 
(L atifl Araeriea, C aliada)) 
 
 
• 
Subject Confidentiality and Methods used to Minimize Bias, 9.4 - 
The Investigator must ensure that the subject's anonymity is maintained throughout 
the comse of the study. In part ic ul ar, the Investigator must keep aa eRn >Um  eat a 
subject log with confidential identifying infonnation that con esponds to the subject 
number, subject name and medical ID number s aad initials of each study 
part icipant. At the end of the clinical study, the Sponsor will collect a copy of the 
el.'lfo llraea t s ubje c t log w i tho u t any identifying subject inf01mation. All documents 
submitted to the Sponsor will identify the subjects exclusively by number aaa 
d em og rap bi e in fo rm at ioR. No other personally identifying inform at io n sho ul d be 
transmitted to the Sponsor. 


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Page 17 of 66 
 
 
 
 
• 
Screen Visit (Day -28), 10.2.1, item no. 18 - 
Schedule the subject to return in 28 days ( 
, +1 day) for the Eligibility 1 Visit. 
 
 
• 
WEEK 2 AND WEEK 6 (EXIT) VISITS, 10.2.3 - 
Note: The Week 6 Visit should be conducted 42 days (4---J-- ±3 d ays) following the 
Eligibility 2 Vi.sit. 
 
 
• 
Sampl e Size Justification, Synopsis and Section 11.10 - 
This calculation is based on the assumption of a common standard deviation for mean 
change from baseline in diurnal IOP as small as 3.5 mmHg and as large as  3.9 mmHg 
and the use of a two-sample two-sided t-test performed at the a =0.0 5 leve l of signifi 
cance. 
 
• 
Efficacy Analyses, 11.4 - 
Unless otherw ise spe c ified , all stati stie aJ aBalyses significant testing will be at the 
5% level (two-sided) at the 5% level. 
 
 
• 
Adverse Section is updated; 
o Procedures for Recording and Reporting AEs and SAEs, 12.3 - 
Any pre-existing medical conditions or signs/symptomspresent in a subject 
prior to the start of the study (ie,before informed consent is signed) should 
be recorded in the baseline history section of the CRF.Any medical 
occurrences having an onset after informed consent but prior to the start of 
study treatment (ie, initiation of treatment with test article) should also be 
recorded in the baseline history section within the CRF. 
o Serious Adverse Events, 12.3 - 
 
 1J0ns0rCentaet
 
Gasiness aK NamlJe F 
Ema il 


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Version: 3.0; 
 
 
X 
X 
X 
Amendment 1 
 
TDOC-0050474 Version 1.0 replaces TDOC-0018786 Version 1.0 (11-Mar-2015) 
 
Due to changes in document management system, tables have been re-numbered. 
 
Purpose of Amendment: The primary purpose of this amendment is to implement required 
changes received from regulatory authorities. 
 
Rationale: Clarification of women of childbearing potential, effective contraception methods, 
storage of PGAs, and safety reporting timeframe. 
 
Current Study Status: No subjects have been enrolled at the time of this amendment. 
 
Case Report Form Revision Required: 
Yes 
No 
 
Informed Consent Modifications Required: 
Yes 
No 
 
Applicable Investigators: 
All 
Selected (list below) 
 
 
Itemized Changes: 
 
1. Title Page 
 
Added: TDOC-0050474 Version 1.0 replaces TDOC-0018786 Version 1.0 (11-Mar- 
2015) 
 
2. Section 1: Synopsis – Treatments 
Changed from: Investigational Product 
Changed to: Prostaglandin Analogues 
3. Section 1: Synopsis – Exclusion Criterion #1 
 
Modified from: 
Women of childbearing potential (who are not postmenopausal for at least 1 year or 
surgically sterile) are excluded from participation if they are currently pregnant, have 
a positive result on the urine pregnancy test at Screening, or intend to become 
pregnant during the study period; are breast-feeding; are not in agreement to use 
adequate birth control methods to prevent pregnancy throughout the study (see MOP 
for further details). 


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Modified to: 
Women of childbearing potential, defined as all women who are not postmenopausal 
for at least 1 year or less than 6 weeks since sterilization, are excluded from 
participation if: 
a. 
they are currently pregnant, or 
b. 
have a positive result on the urine pregnancy test at Screening, or 
c. 
intend to become pregnant during the study period, or 
d. 
are breast-feeding, or 
e. 
are not in agreement to use adequate birth control methods to prevent 
pregnancy throughout the study (further definition can be found in 
Section 12.7) 
 
Effective contraceptive measures include: 
• 
Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject). Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not 
acceptable methods of contraception 
• 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least 6 weeks before Baseline. 
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment 
• 
Male sterilization (at least 6 months prior to Baseline). For female 
subjects in the study, the vasectomized male partner should be the sole 
partner for that subject 
• 
Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
 
 
4. Section 3: Abbreviations 
 
Added: 
IMP – Investigational Medicinal Product 
IP – Investigational Product 
PSD – Pattern Standard Deviation 
SBP – Systolic Blood Pressure 
VF – Visual Field 


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5. Section 5.1: Study Rationale and Background 
 
Added the following statement to the end of this section: 
A summary of the known and potential risks and benefits associated with 
SIMBRINZA and Prostaglandin Analogues can be found in the Summary of Product 
Characteristics (SmPC) or Product Information equivalent. 
 
6. Section 9.1: Identity of Study Treatments 
 
Added: or 8 mL 
 
7. Section 9.1: Identity of Study Treatments 
 
Modified 2nd paragraph from: 
TRAVATAN, XALATAN, and LUMIGAN are unmasked medications provided by the 
Sponsor. TRAVATAN should be securely stored according to the label. Once the 
bottle is opened, it should be discarded after 4 weeks from first opening. XALATAN 
should be protected from light. Unopened XALATAN must be stored under 
refrigeration at 2-8ºC (36-46ºF) and opened XALATAN may be stored in 
temperatures up to 25ºC (77ºF) and is viable for 6 weeks. LUMIGAN should be 
securely stored according to the label. Once the bottle is opened, it should be 
discarded after 4 weeks from first opening. 
 
Modified 2nd paragraph to: 
PGAs will be unmasked (open labeled) product. TRAVATAN, XALATAN, and 
LUMIGAN are unmasked medications provided by the Sponsor. Storage of PGAs 
should be in accordance with the country product labeling. 
 
8. Section 12.1: General Information 
 
Added: The determination of clinical relevance is based upon the medical judgment of 
the Investigator 
 
9. Section 12.2: Monitoring for Adverse Events 
 
Modified last statement of 1st paragraph from: 
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 following exposure 
to the study treatment. 


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Modified last statement of 1st paragraph to: 
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. 
 
10. Section 12.3: Procedures for Recording and Reporting AEs and SAEs 
 
Modified from: (ie, within one working day of the Investigator’s or site’s knowledge 
of the event) 
 
Modified to: (ie, within 24 hours of the Investigator’s or site’s knowledge of the 
event) 
 
11. Section 12.6: Follow-Up of Subjects with Adverse Events 
 
Removed the last sentence: 
All AEs (serious and non-serious) received 1 month after subject’s last visit will be 
considered and processed as spontaneous events (following the usual 
pharmacovigilance circuit). 
 
12. Section 12.6: Follow-Up of Subjects with Adverse Events 
 
Modified 1st paragraph to read as follows: 
Women who are pregnant or breast-feeding are excluded from participation in the 
study. Women of childbearing potential are not excluded from the study as long as 
adequate birth control methods are being utilized or women considered post- 
menopausal. 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 (e.g. 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 and should be used during the study. 


 
 
 
 
 
Page 22 of 66 
 
2 
OVERVIEW OF STUDY PLAN 
 
 
Activity 
Screen 
Eligibility 1a 
Eligibility 2 
(3-8 days from 
Eligibility Visit 1) 
Week 2 
(14 ± 3 days from 
Eligibility 2) 
Week 6 (Exit) Visit 
(42 ± 3 days from 
Eligibility 2) 
UNSC 
Visit 
Early 
Exit b 
09:00 
11:00 
09:00 
11:00 
09:00 
11:00 
09:00 
11:00 
Informed Consent c 
X 
Demographics 
X 
Med Hx & Con. Meds 
X 
Change in Med Hx/Con 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
Urine Pregnancy Test d 
X f 
X f 
X f 
Best-Corrected VA 
X 
X 
X 
X 
X 
X 
X 
Automated Perimetry 
X e 
X f 
X f 
Slit-Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
IOP (Goldmann) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
Pachymetry 
X 
Dilated Fundus Exam 
X 
X 
X 
X 
Blood Pressure & Pulse 
Rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Meds 
X 
X 
Instill Study Meds in Office 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Study Meds 
X 
X 
X 
X 
Exit Subject & 
Complete Exit Form 
X 
X 
a E1 should be conducted from 1 to 29 days after Screening, according to the run-in/washout schedule 
b Perform assessments on subjects who discontinue study participation prior to Week 6 visit. 
c Must be signed/dated before study procedures are performed. 
d Required on all female subjects of childbearing potential. 
e At Screening (preferably) or in between Screening and E2 
f May be conducted anytime during the visit. 
 
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3 
ABBREVIATIONS 
 
AC 
Anterior chamber 
ADR 
Adverse drug reaction 
AE 
Adverse event 
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 
Con Meds 
Concomitant medications 
CRF 
Case report form 
dB 
Decibel 
E1 
Eligibility 1 
E2 
Eligibility 2 
CRF 
Case report form 
EDC 
Electronic data capture 
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 
HIPAA 
Health insurance portability and accountability act 
Hx 
History 
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 
IWRS 
Inter-active web response system 
LOCF 
Last observation carried forward 
logMAR 
Log10 of the minimum angle of resolution 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
Med Hx 
Medical history 
Meds 
Medications 
mg 
Milligram 


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mm 
Millimeter 
mmHg 
Millimeters of mercury 
MOP 
Manual of procedures 
N/A 
Not applicable 
NCR 
Not clinically relevant 
NDA 
New Drug Application 
NSAID 
Non-steroidal anti-inflammatory drug 
OAG 
Open-angle glaucoma 
OC 
Observed case 
OD 
Right eye 
OHT 
Ocular hypertension 
OS 
Left eye 
OU 
Both eyes 
PGA 
Prostaglandin analogue 
PI 
Principal investigator 
PPS 
Per protocol set 
PQ 
Polyquad 
PSD 
Pattern Standard Deviation 
QA 
Quality assurance 
QD 
Once a day 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
SAS statistical software, SAS Institute Inc., Cary, NC 
SBP 
Systolic Blood Pressure 
TID 
Three times a day 
US 
United States 
VF 
Visual Field 


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4 
TABLE OF CONTENTS 
Additive Effect of Twice Daily Brinzolamide 1% /Brimonidine 0.2% Fixed Dose 
Combination as an Adjunctive Therapy to a Prostaglandin Analogue .................... 1 
1 
SYNOPSIS ............................................................................................................. 3 
1.1 
Amendments ..................................................................................................... 13 
2 
OVERVIEW OF STUDY PLAN .......................................................................... 22 
3 
ABBREVIATIONS ................................................................................................... 23 
4 
TABLE OF CONTENTS ...................................................................................... 25 
List of Tables....................................................................................................................................... 27 
5 
INTRODUCTION ................................................................................................ 28 
5.1 
Study Rationale and Background ..................................................................... 28 
5.2 
Known and Potential Risks ............................................................................... 29 
5.3 
Potential Benefits .............................................................................................. 31 
6 
ETHICS ................................................................................................................ 33 
7 
PROTOCOL AMENDMENTS............................................................................. 34 
8 
SUBJECT POPULATION ........................................................................................... 34 
9 
TREATMENTS ADMINISTERED ...................................................................... 34 
9.1 
Identity of Study Treatments ............................................................................ 35 
9.2 
Usage ................................................................................................................ 35 
9.2.1 
Route of Administration ............................................................................... 35 
9.2.2 
Duration of Exposure .................................................................................... 36 
9.2.3 
Methods Used to Determine Dosage ............................................................ 36 
9.3 
Accountability Procedures ................................................................................ 36 
9.4 
Subject Confidentiality and Methods Used to Minimize Bias ......................... 36 
10 
STUDY PROCEDURES ...................................................................................... 37 
10.1 
Outline of Study ............................................................................................... 37 
10.2 
Visits and Examinations ................................................................................... 39 
10.2.1 
SCREENING VISIT (DAY -28) ................................................................... 39 
10.2.2 
ELIGIBILITY 1 AND ELIGIBILITY 2 VISITS: [09:00 (+/-30 MIN) AND 
11:00 (+/- 30 MIN) EXAMINATIONS] ......................................................... 42 


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10.2.3 
WEEK 2 AND WEEK 6 (EXIT) VISITS: [09:00 (+/- 30 MIN) AND 11:00 
(+/- 30 MIN) EXAMINATIONS] ................................................................... 44 
10.3 
Unscheduled Visits ............................................................................................... 46 
10.4 
Discontinued Subjects ...................................................................................... 46 
10.5 
Clinical Study Termination ............................................................................... 47 
11 
ANALYSIS PLAN ................................................................................................ 48 
11.1 
Subject Evaluability .......................................................................................... 48 
11.2 
Analysis Data Sets ............................................................................................ 48 
11.2.1 
Full Analysis Sets ......................................................................................... 48 
11.2.2 
Per Protocol Set ............................................................................................ 49 
11.2.3 
Safety Set ...................................................................................................... 49 
11.3 
Demographic and Baseline Characteristics ...................................................... 49 
11.3.1 
Demographic Characteristics ........................................................................ 49 
11.3.2 
Baseline Characteristics ................................................................................ 49 
11.4 
Efficacy Analyses ............................................................................................. 50 
11.4.1 
Primary Efficacy ........................................................................................... 50 
11.4.1.1 
Statistical Hypotheses ............................................................................... 50 
11.4.1.2 
Analysis Methods...................................................................................... 51 
11.4.1.2.1 
SUBGROUP ANALYSIS METHODS ................................................. 51 
11.4.2 
Secondary Efficacy ....................................................................................... 51 
11.4.2.1 
Statistical Hypotheses ............................................................................... 52 
11.4.2.2 
Analysis Methods...................................................................................... 52 
52 
53 
53 
11.5 
Handling of Missing Data ................................................................................. 53 
11.6 
Multiplicity ....................................................................................................... 53 
11.7 
Safety Analysis ................................................................................................. 54 
11.8 
Health Economics ............................................................................................. 54 
11.9 
Interim Analyses ............................................................................................... 54 
11.10 
Sample Size Justification .................................................................................. 54 
12 
ADVERSE EVENTS ............................................................................................ 56 
12.1 
General Information ......................................................................................... 56 
12.2 
Monitoring for Adverse Events ........................................................................ 56 
12.3 
Procedures for Recording and Reporting AEs and SAEs ................................. 56 


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12.4 
Intensity and Causality Assessments ................................................................ 60 
12.5 
Unmasking of the Study Treatment .................................................................. 60 
12.6 
Follow-Up of Subjects with Adverse Events .................................................... 61 
12.7 
Pregnancy in the Clinical Trial ............................................................................ 61 
13 
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS ................... 62 
13.1 
Completion of Source Documents and Case Report Forms ............................. 62 
13.2 
Data Review and Clarifications ........................................................................ 63 
13.3 
Regulatory Documentation and Records Retention ......................................... 63 
13.4 
Quality Assurance and Quality Control ............................................................ 63 
14 
References ............................................................................................................. 64 
List of Tables 
Table 10–1 
Study Plan by Treatment Groups ..................................................................... 38 
 
Table 10–2 
Ocular Hypotensive Medication Washout Schedule ........................................ 39 
Table 10–3 
Activities for Eligibility 1 and Eligibility 2 Visits ............................................. 42 
Table 10–4 
Activities for Week 2 and Week 6 (Exit) Visits ................................................. 45 


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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 patients 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 subjects 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 5 almost 40% of patients needed 2 or 
more medications to achieve their target IOP (Kass et al 2002), and in the Collaborative Initial 
Glaucoma Treatment Study (CIGTS) after year 2 more than 75% of patients needed 2 or more 
medications to reach their target IOP (Lichter et al 2001). 
 
It is well known that the complexity of treatment (doses per day, number of bottles) can affect 
patient adherence to medications. To this end, combination therapies with drugs of differing 
but complementary mechanisms of action may simplify treatment for patients and offer other 
potential benefits such as eliminating a required waiting time between the two instillations in 
order to avoid drug washout or they may also decrease exposure to preservatives such as 


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benzalkonium chloride, which is known to have adverse effects on the ocular surface and to 
increase treatment side effects (Baudouin 2010). 
 
In addition to the potential clinical benefits, the cost of fixed combination therapy may be  less 
than the combined cost of the component medications in many countries (Rylander 2008). 
Studies have shown that the direct costs (visits, surgeries, medications, etc) and indirect costs 
(visual impairment, social rehabilitation, etc) of glaucoma increase with elevated IOP, disease 
progression, late stages of the disease, and poor adherence and persistence (Oostenbrink 2001, 
Lee 2006). By increasing the subject’s compliance and IOP control, fixed combination therapy 
could also potentially decrease the direct and indirect costs of glaucoma. 
 
SIMBRINZA is a fixed dose combination IOP-lowering topical therapy comprised of 
Brinzolamide (1% or 10mg/mL) and Brimonidine tartrate suspension (0.2% or 2 mg/mL). 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 for reducing/decreasing elevated intraocular pressure (IOP) in adult patients with 
open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP 
reduction. 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 for the same indication. 
 
A summary of the known and potential risks and benefits associated with SIMBRINZA and 
Prostaglandin Analogues can be found in the Summary of Product Characteristics (SmPC) or 
Product Information equivalent. 
 
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). 
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 concern for the use of SIMBRINZA. The 
development of fatigue/drowsiness may impair a person’s ability to 


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operate a motor vehicle or machinery. Patients 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 patients 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 patients 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 patients 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 patients, or in conditions where the cornea is 
compromised. 
 
 
 
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. 


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Overall, no additional risks were identified with the use of SIMBRINZA relative to the known 
risks of the individual components. 
 
Prostaglandin Analogues 
 
The most frequent adverse event associated with the use of topical ocular PGAs is hyperemia. 
Hyperemia generally occurs at the onset of use and generally subsides or resolves over time 
without the addition of concomitant therapy or resolves with discontinued use of the PGA. 
Other common adverse events associated with this class of medicinal product include 
periocular skin hyperpigmentation or discolouration, iris hyperpigmentation, and changes in 
eyelash length, thickness, pigmentation, and/or number of lashes. These changes generally 
occur after several months to years of dosing and usually do not require the addition of 
concomitant therapy. In addition, these adverse events usually resolve with the discontinued 
use of the medication (with the exception of iris hyperpigmentation, which is most likely 
permanent). 
 
Less common or rare adverse events with a possible association to the use of a topical ocular 
PGAs include cystoid macular edema, anterior chamber inflammation (ie, anterior uveitis, 
iritis, and iridocyclitis), and herpes simplex keratitis. The occurrence of cystoid macular edema 
in patients dosing with a PGA has been reported at a low incidence. It appears that this event 
is more likely to occur in patients with predisposing risk factors (aphakia, pseudophakia with 
a ruptured posterior capsule during surgery, history of uveitis, or retinal inflammatory or 
vascular disease). Caution is advised with the use of a topical ocular PGA in patients with 
predisposing risk factors. Anterior chamber inflammation and herpes simplex keratitis have 
been reported at a low incidence in patients dosing with a topical ocular PGA. These events 
have been reported in both patients with risk factors for the development of these conditions 
and in patients with no known risk factors. Prescribing physicians should be aware of the 
possible development of these conditions (Alm 2008, Cracknell 2009). 
 
5.3 
Potential Benefits 
SIMBRINZA 
 
Results from clinical studies evaluating brinzolamide/brimonidine administered TID or BID 
show that the IOP-lowering efficacy of the fixed combination is statistically superior to each 
of its individual components (Katz 2013, Nguyen 2013, Aung 2014). An additional multicenter 
clinical study has shown that the IOP lowering efficacy of the brinzolamide/brimonidine 
administered BID (fixed combination) is noninferior to the individual components 
administered concomitantly (unfixed combination) (Gandolfi 2014). 


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There are several potential benefits to SIJ\ifBRIN ZA fi xed co m bin at ion therapy such as: 
 
• 
an IOP lowering effect of up to 35% (Aung 2014, Gandolfi 2014, Katz 2013, Nguyen 
2013) 
 
• 
a safety profile that is consistent with that of the individual components (Aung 2014, 
Gandolfi 2014, Katz 2013, Nguyen 2013, Whitson 2013) 
 
• 
a lower exposure to preservatives versus the individual components 
 
• 
the potential for increased subject adherence (Higgenbotham 2010, Schwartz 2010) 
versus the dosing the individual components concomitantly 
 
• 
an alternative therapy option for subjects in whom therapy with beta-blockers 1s 
contraindicated, 
 
which all contribute to a positive benefit:risk profile for subjects. 
 
P1·ostaglandin Analogues 
 
Prostag landin analogs are effective in lowering IOP and have often replaced p bl oc ker s as 
first-line therapy in lowering intraocular pressure. In some patients however, target IOPs will 
not be reached and an adjunctive therapy will be required. 
 
Alcon is investigating the effectiveness of SIMBRINZA, dosed twice daily, as an adjunctive 
therapy to a prostaglandin analogue in subjects who require fmther IOP lowering. This 
combination of medications may expand the treatment options available to  both clinicians  and 
subjects in whom a PGA alone does not provide sufficient IOP lowering. 


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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. 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 
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 


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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 180 subjects to be randomized at approximately 
35 sites. Competitive enrollment is acceptable with no more than 27 subjects at any one site. 
To participate in the study, subjects must have been on branded PGA [Travatan (travoprost), 
Xalatan (latanoprost), or Lumigan (bimatoprost)] monotherapy for at least 4 weeks (28 days) 
and have a mean IOP measurement at 09:00 in at least 1 eye (study eye) ≥ 19 and < 32 mmHg 
at 2 consecutive visits (Eligibility 1 and Eligibility 2). The expected duration of subject 
participation in the study is approximately 11 weeks (5 visits). The complete  inclusion and 
exclusion criteria are presented in Section 1. 
 
9 
TREATMENTS ADMINISTERED 
At the Screening Visit, the PI will assign subjects into one of 3 prostaglandin analogue therapy 
groups [Travatan (travoprost), Xalatan (latanoprost), or Lumigan (bimatoprost)]. Assuming the 
subject qualifies, each subject will remain on PGA (selected at Screening Visit) throughout the 
duration of the study. 
 
For randomization into the study, subjects will be randomly assigned through IRT; a generated 
subject number automatically populated in the EDC system. Subjects will be randomized in a 
1:1 manner to receive treatment with either SIMBRINZA and designated PGA or Vehicle and 
designated PGA. Throughout the study, the Investigator will be responsible for the accounting 
of all study drugs and will ensure that the study products are not used in any unauthorized 
manner. 


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9.1 
Identity of Study Treatments 
 
Investigational Group: 
Control Group: 
SIMBRINZA+ PGA 
Vehicle + PGA 
 
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 or 8 mL with 
SIMBRINZA or Vehicle. Masked Investigational Products (SIMBRINZA or Vehicle) should 
be securely stored in accordance with the label. 
 
PGAs will be unmasked (open labeled) product. TRAVATAN, XALATAN, and LUJ\.1IGAN 
are unmasked medications  provided  by  the  Sponsor.  Storage  of  PGAs  should  be  in 
accordance with the countJ.y pro du ct labe lin g. 
 
A te m perat ur e log w ill be m aintai n e d 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 
One drop of masked IP is to be applied topically to the eye at 09:00 (± 30 min) and 21:00 
 
(± 30 min). 
 
One drop of PGA is to be applied topically to the eye daily in the evening. 
 
The study medications should be dosed in both eyes unless there is a potential safety issue to 
the subject in the opinion of the Investigator. 
 
Subjects should be reminded to: 
 
• 
Shake the masked IP prior to instillation, 
 
• 
If evening instillation of both !OP-lowering medications occurs at the same time, 
instill the PGA first, wait 15 minutes, then instill the masked IP, and 
 
• 
Attempt to consistently instill both PGA and masked IP at approximately the same 
time each evening. 


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• Return all used and unused bottles at each visit. 
 
9.2.2 
Duration of Exposure 
All subjects in the study will receive PGAs for the duration of the study, including run- 
in/washout, eligibility,and maskedtreatment periods. 
 
Exception - subjects who were previously prescribed one of the study-specific branded PGAs 
as monotherapy (ie, TRAVATAN PQ  0.004%,  XALATAN 0.005%,  or  LUMIGAN 0.01%) 
and present with uncontrolled IOP ( 19 mmHg) at Screening may skip the 28 day run -in 
period if documentation exists in the subject's medical chart co nfirm ing use of the study 
specific PGAmonotherapyfor at least 4 weeks (28 days) immediately prior to screening. 
 
Masked SIMBRINZAor Vehicle will be received at the E2 Visit following randomization for 
the 42 day treatment phase. 
 
9.2.3 
Methods Used to Determine Dosage 
The dosage and BID dosing regimen for SIMBRINZA is based on the dosage and dosing 
regimen of the marketed product. The dosage and QD dosing regimen for TRAVATAN 
0.004%, or XALATAN 0.005%, or LUMIGAN 0.01% are based on the dosage and dosing 
regimen of these marketed PGA analogues. 
 
9.3 
Accountability Procedures 
Upon receipt  of unmasked TRAVATAN 0.004%, and XALATAN 0.005%,  and LUMIGAN 
0.01% and masked IP from the Sponsor, the Investigator or designee will conduct an 
inventmyof all products. Designated study staff will provide the  study dtugs to  the subjects in 
accordance with their EDC assigned subject numbers and the randomization schedule. During 
the study, the Investigator must maintain records of study treatment dispensation and 
collectionof PGAs and masked IP for each subject. This record must be made available to the 
study monitor for the purposes of verifying  the accounting of clinical supplies. Any 
discrepancies and/or deficiencies between the observed disposition and the written account 
must be recorded along with an explanation. At the conclusion of the study, the Investigator will 
be responsible for returning all used and unused study supplies unless otherwise instructed by 
the Sponsor. 
 
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 


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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, PGA therapy is open labeled and will be dosed 
during the run-in/washout phase (Screening Visit through E2) and for the duration of the 
masked treatment period 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. 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 or PGA. Kits containing PGA will also 
be labeled to identify the PGA, protocol and kit numbers. 
 
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 open-angle glaucoma and/or ocular hypertension who are insufficiently 
controlled on monotherapy or are already on multiple 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 and a Run- 
in/Washout phase 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 at Week 2 and Week 6 (Exit Visit) as shown in Table 10-1. 


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Table 10–1 
Study Plan by Treatment Groups 
 
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 + PGA 
(TRAVATAN PQ 0.004%, 
or XALATAN 0.005%, or 
LUMIGAN 0.01%) 
Begin dosing with PGA at 
bedtime on the evening of the 
screening visit 
& 
Washout of all other IOP- 
lowering medications if on 
multiple therapies 
SIMBRINZA BID 
(09:00 & 21:00) 
and 
PGA QD 
Mean IOP for both Eligibility 
Visits must be: 
≥ 19 mmHg and < 32 mmHg 
in at least 1 eye at 
09:00 time point 
(while on PGA monotherapy) 
The same eye(s) must qualify 
at both 09:00 time points. 
(at bedtime) 
Vehicle + PGA 
(TRAVATAN PQ 0.004%, 
or XALATAN 0.005%, or 
LUMIGAN 0.01%) 
Vehicle BID 
(09:00 & 21:00) 
and 
PGA QD 
The mean IOP in either eye must 
not be greater than or equal to 
32 mmHg at any time point. 
(at bedtime) 
 
 
Following the screening procedures and the initial evaluation of inclusion and exclusion 
criteria, subjects not on a study specific branded PGA for at least 28 days prior to Screening, 
will start the appropriate run-in period to ensure documented use of the PGA for a minimum 
of 28 days. Simultaneously, subjects on multiple IOP-lowering medications will start the 
appropriate washout period based on the type of ocular hypotensive medication as described 
in Table 10-2. 


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Table 10-2 
Ocular Hypotensive MedicationWashout Schedule 
 
Type of Ocular Hypotensive Medication* 
Washout Pe1i od* 
Screening to Eligibility 
1 Visit 
Miotics and Oral/Topical Carbonic Anhydrase Inhibitors (CAI) 
5 days ± 1 day 
Alpha and alpha/beta agonists 
14 days ± 1 day 
Beta-antagonists and Prostaglandin Analogues 
(with the exception of study-specific PGA) 
28 days ± 1 day 
Combination Dmgs 
(use longest wash-out period of individual components) 
Up to 28 days ± 1 day 
 
 
10.2 
Visits and Examinations 
All procedures and the coITes pondent sc or ing must be perform ed as detailed in the Manual of 
Procedures (MOP). 
 
10.2.1 
SCREENING VISIT (DAY -28) 
The intent of the Washout phase is to determine intraocular pressure at the Eligibility 1 
and Eligibility 2 Visits while only on PGA analogue monotherapy (PGA baseline). 
 
If in the opinion of the Investigator, the subject can stop all !OP-lowering medications and 
simultaneously start TRAVATAN 0.004 % , or XALATAN 0.005 %, or LUMIGAN 0.01% 
monotherapy for the specified washout, it would be preferable. 
 
However, it may be in the interest of the subject to continue concomitant therapy with a CAI 
(eg, PGA therapy and AZOPT) and stop AZOPT therapy at least 5 days prior to El visit while 
continuing daily PGA analogue therapy. 
Additionally, there may be other subjects who were previously prescribed TRAVATAN 
0.004%, or XALATAN 0.005 %, or LUMIGAN 0.01% monotherapy and return to the site 
with uncontrolled IOP as defined in the eligibility criteria. These subjects do not need an 
additional 28 day run-in period with PGA. If all other Inclusion/Exclusion  criteria are met, 
the Eligibility 1 Visit may occur promptly (within - 1-5 days as convenient for site and 
subject). 


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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. Indicate Investigator-designated PGA that subject will be assigned. 
5. Screen the subject for protocol inclusion/exclusion criteria as per Section 1. 
6. 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. 
7. Perform a urine pregnancy test if the subject is a woman of childbearing potential. 
8. Perform pulse and blood pressure measurements. 
9. Assess best-corrected visual acuity (BCVA), OU. 
10 Conduct automated perimetry, OU. 
11 Perform a slit-lamp examination (biomicroscopy), OU. 
12 Perform Goldmann applanation tonometry, OU. 
13 Conduct gonioscopy, OU. 
14 Perform pachymetry, OU. 
15 Perform a dilated fundus examination, OU. 
16 Washout concomitant ocular hypotensive medication(s) 
Instruct subjects who qualify for the study and are on additional ocular hypotensive 
medication(s) other than a study branded PGA to discontinue the prescribed IOP- 
lowering medication(s). Subjects must be able to discontinue use of concomitant IOP-
lowering medication(s) based on the appropriate schedule (see Table 10.1.-2), but 
remain on TRAVATAN 0.004%, or XALATAN 0.005%, or LUMIGAN 0.01% 
monotherapy throughout the duration of the study. The washout period of longest 
duration should be used when the subject is taking multiple ocular hypotensive 
medications for more than 1 class. 


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17 Dispense TRAVATAN 0.004%, or XALATAN 0.005%, or LUMIGAN 0.01% at the 
Screening Visit. 
Instruct each subject to instill the medication daily at bedtime, OU. Instill the first 
dose of the study specific branded PGA on the evening of the Screening Visit and 
continue instillation for the duration of the run-in/washout phase (up to 29 days). 
Exception: The Run-in/Washout Phase duration may be reduced for those subjects 
who demonstrate uncontrolled IOP and were on TRAVATAN 0.004%, or XALATAN 
0.005%, or LUMIGAN 0.01% monotherapy for at least 28 days prior to the Screening 
Visit. 
18 Schedule the subject to return in 28 days (+1 day) for the Eligibility 1 Visit. 
(See exception above for those uncontrolled subjects previously prescribed 
TRAVATAN 0.004%, or XALATAN 0.005%, or LUMIGAN 0.01% monotherapy) 
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. 


 
0 
t,1 = I 
= = 
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., 
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.... 
...... 
>
=
.... 0 
Page 42 of 66 
 
 
10.2.2 
ELIGIBILITY 1 AND ELIGIBILITY 2 VISITS: [09:00 (+/-30 MIN) AND 11:00 (+/- 30 MIN)                         
EXAMINATIO NS] 
Table 10-3 
Activities for Eligibility1 and Eligibility 2 Visits 
 
 
 
 
 
VJ 
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Activity 
Eligibility1 (El ) 
Visit 
Eligibility 2 (E2) 
Visit 
09:00
11:00 
09:00 
11:00 
Docmnent that the subject has daily administered PGA therayp for 28 days. 
X 
Document date and time of last instillation. 
RESCHEDULEthe visit if the subjectdid not dose the previous evening. 
X 
X 
Update Medical Hist0y1 /Concomitant Medications 
X 
X 
X 
X 
Obtain Blood Pressme and Pulse Rate 
X 
X 
X 
X 
Perfonn BCVA, OU 
X 
X 
Perf01m slit lamp exam (Aqueous cells, aqueous flare, lens, status ofl ens), OU 
X 
X 
Measme IOP (Goldmann), OU 
Mean JOP must be;;::19 and< 32mmHgin atleast one (same) eye(s) at 09:00. 
Mean IOP must be less than 32 mmHg in either eye at all time points. 
The mean JOP is defined as the average of two or more JO P read ings in the sam e eye . 
X 
X 
X 
X 
Schedule the subject to return for the Eligibility 2 Visit (E2) in 3-8 days following El Visit prior 
to 09:00 
X 
Verify i11cl u s ionlex     c lu  s ion criteria. 
Only subjects meetinR all requirements can be randomized 
Randomize the subject upon confirmation of eligibility. 
X 
Dispense to the subject the conesponding masked study medications and 
PGA kits, document in the dispensing logs. 
X 
Instrnct the subject to sta1tdosing the same evening. For subjects wearing contact lenses, 
instrnct them to remove the lenses before the instillation of the study medication & wait 
approximately 15 minutes after dose before insettin g the lenses again. 
PGA analogue - Daily dosing at bedtime. 
Masked IP - BID dosing at 09:00 and 21:00 (± 30 minutes) 
X 
Schedule the successfully randomized subject to retmn for the Week 2 Visit in 14 ±3 days 
following E2 Visit prior to 09:00 (± 30 minutes). 
X 


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NOTE: 
 
• 
The Eli gibility 1 Visit should be cond ucted 1-29 days following the Screening Visit 
based on the n m-in/washout period. 
 
• 
The Eligibility 2 Visit should be conducted 3-8 days following the Eligibility 1 Visit. 
 
• 
The PGA and Masked IP should be dosed in both eyes unless there is a potential 
safety issue to the subject in the opinion of the Investigator. 
 
At the end of the Eligibility 2 Visit, if the subject qualifies to continue in the study, use 
EDC to randomize the subject. The IRT system will return the assigned kit numbers for the 
PGA therapy and the masked study treatment to be dispensed to the subject. Once the 
EDC/IRT assigns kit numbers, dispense the kit numbers assigned to the subject. 
 
Dosing instrnctions should be provided to the subject as follows: 
 
a) Subjects wearing contact lenses should remove the lenses before instillation of 
either medication. Following instillation of the study medications, the subject should 
wait approximately 15 minutes after the last dose before  re-inse11ing lenses. 
b) MUST shake masked IP before use. Instill 1 drop of masked study medication in 
each affected eye daily at 09:00 (± 30 min) and 21:00 (± 30 min) for 
approximately 6 weeks. 
 
c) Instill 1 drop of PGA in each affected eye daily at bedtime for approximately 6 
weeks. 
 
d) If instillation of the PGA and masked IP occurs at approximately the same time; 
 
1. 
Instill PGA first 
 
11. 
Wait approximately 15 minutes before instilling masked IP 
 
111. 
Attempt to instill study medications at the same time each evening 
 
At the Eligibility 2 visit, schedule the subject to return in 14 days (± 3 days) in the morning 
prior to 09:00 (± 30 minutes) for the Week 2 Visit. 


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Note: Contact the sub;ect the day prior to the Week 2 and Week 6 Visits to remind the subject 
to: 
 
• 
instill the dose of PGA at bedtime and masked study medication at 21:00 (± 30 
minutes) the night prior to the visit, 
 
• 
remove contact lenses prior to instillation of study medications and wait 15 minutes 
before inserting the lenses again 
 
• 
DO NOT dose the masked IP the morning of the study vi sit. The morning dose will 
be instilled in the office after the 09:00 !OP measurement. 
 
• 
DO NOT discard any unused or empty bottles, 
 
• 
bring all PGA and masked IP study medication bottles to the study visit, 
 
• 
bring contact lenses or glasses with them to the study visit if they wear them 
 
10.2.3 
WEEK 2 AND WEEK 6 (EXIT) VISITS: [09:00 (+/- 30 MIN) 
AND 11:00 (+/- 30 MIN) EXAMINATIONS] 
NOTE: 
 
The Week 2 Visit should be conducted 14 days (± 3 days) following the Eligibility 2 Visit. 
The Week 6 Visit should be conducted42 days (± 3 days) following the Eligibility 2 Visit. 


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Table 10–4 
Activities for Week 2 and Week 6 (Exit) Visits 
 
Activity 
Week 2 Visit 
Week 6 (Exit) Visit 
09:00 
11:00 
09:00 
11:00 
Document date and time of last instillation. 
RESCHEDULE the visit if the subject did not dose the 
previous evening or if the subject has already dosed the 
morning dose. 
X 
X 
Document any changes in Medical History and 
Concomitant Medications 
X 
X 
X 
X 
Perform a urine pregnancy test if subject is female of 
child bearing age 
[X] 
Obtain Blood Pressure and Pulse Rate 
X 
X 
X 
X 
Perform BCVA, OU 
X 
X 
Perform slit lamp exam (Aqueous cells, aqueous flare, 
lens, status of lens), OU 
X 
X 
Perform Goldmann applanation tonometry, OU. 
Record time of IOP measurements 
X 
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 
X 
Approximately 15 minutes after the IOP measurements, 
instill the masked IP in the office. Record the time of 
instillation by the site. 
X 
X 
Perform 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 
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 


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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. 
 
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. 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 following sections). 
 
10.4 
Discontinued Subjects 
Discontinued subjects are those who withdraw or are withdrawn from the study after the 
Screening Visit. 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 


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of the study treatments, the Investigator must document those obse1vations on an Adverse 
Event (AE) Fo1m. 
Any subject who exits early from the study must undergo all procedures outlined at Week 6. 
Additionally, the Exit F01m mu st be compl eted an d one of the following reasons for 
discontinuation must be identified: 
 
• 
 
Discontinued Study due to Screen Failure 
• 
 
Discontinued Study due to Adverse Event 
• 
 
Discontinued Study due to Death 
• 
 
Discontinued Study due to Lack of Efficacy 
• 
 
Discontinued Study due to Lost to Follow Up 
• 
 
Discontinued Study due to Non-Compliance with Study Drng 
• 
 
Discontinued Study due to Physician Decision 
• 
 
Discontinued Study due to Pregnancy 
• 
 
Discontinued Study due to Progressive Disease 
• 
 
Discontinued Study due to Protocol Violation 
• 
 
Discontinued Study due to Study Te1mi nated by Sponsor 
• 
 
Discontinued Study due to Technical Problems 
• 
 
Discontinued Study due to Withdrawal by Subject 
• 
 
Discontinued Study due to Other Reasons 
 
Finally, to ensure the safety of all subjects who discontinue early, Investigators should assess 
each subject and, if necessa1y, advise them of any therapies and/or medical procedures that 
might be needed to maintain their health. 
 
10.5 
Clinical Study Termination 
If the clinical study is prematurely te1minated or suspended, the Sponsor will infmm the 
Investigator and the regulat01y autho riti es of the te1mi nation/ suspension and the reason(s) 
for the te1mi nation/suspension. The Investigator should promptly notify the IEC/IRB of the 
te1mi nation or suspension and of the reasons. The Sponsor rese1ves the right to close the 
investigational site or te1minate the study in its entirety at any time, for reasonable cause. 
Reasons for the closure of an investigational site or te1mination of a study may include: 
 
• 
Successful completion of the study 
 
• 
The study's enrollment goals are met 


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• 
The Investigator fails to comply with the protocol or GCP guidelines 
 
• 
Safety concerns 
 
• 
Sufficient data suggesting lack of efficacy 
 
• 
Inadequate recruitment of patients/subjects by the Investigator 
 
The Investigator also may tenninate the study at his/her site for reasonable cause. If the Sponsor 
terminates the study for safety reasons, it will immediately notify the Investigator(s) by 
telephone and subsequently will provide written confinnation of and instructions for study 
tennination. 
 
11 
ANALYSIS PLAN 
11.1 
Subject Evaluability 
The fmal subject evaluability will be detennined prior to breaking the code for masked 
treatment assignment and locking the database. 
 
All subjects who consented to participate in the study will be evaluated in the pre-treatment safety 
analysis set. All subjects who are randomized and receive a dose of investigational product will 
be evaluable for the t1eatment-emergent safety analysis set. All subjects who receive study 
medication and who complete at least  1 scheduled on-therapy study visit  will  be evaluated in 
the full analysis set. All subjects who receive the study medication to which they were randomly 
assigned, satisfy pre-randomization inclusion/exclusion criteria, and who complete at least 1 
scheduled on-therapy study visit will be evaluated in the per protocol analysis set. In addition, 
individual subject visits and data points that do not satisfy protocol criteria may be excluded from 
the per protocol analysis set. The final subject evaluability will be deten nined prior to breaking 
the code for masked treatment assignment and locking the database. 
 
11.2 
Analysis Data Sets 
11.2.1 
Full Analysis Sets 
 
The full analysis set (FAS) is the primaiy analysis set for the study; all primaiy, secondaiy 
 efficacy analyses will be based on the FAS. 
All subjects who receive study medication and who complete at least 1 scheduled on-therapy 
study visit will be evaluated in the full analysis set. 


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11.2.2 
Per Protocol Set 
The per protocol set (PPS) will be evaluated only for the primary efficacy endpoint to confirm 
results from the FAS. 
 
All subjects who receive the study medication to which they were randomly assigned, satisfy 
pre-randomization inclusion/exclusion criteria, and who complete at least 1 scheduled on- 
therapy study visit will be evaluated in the per protocol analysis set. In addition, individual 
subject visits and data points that do not satisfy protocol criteria may be excluded from the per 
protocol analysis set. 
 
11.2.3 
Safety Set 
There will be two safety analysis sets – pre-treatment safety analysis set and treatment- 
emergent safety analysis set. The pre-treatment safety analysis set will include all subjects who 
consented to participate in the study. The pre-treatment safety analysis set will be the set used 
to summarize the occurrence of adverse experiences prior to exposure of investigational 
product. The treatment-emergent safety analysis set will be used for each of the safety 
parameters and adverse events occurring after exposure to investigational product. 
 
11.3 
Demographic and Baseline Characteristics 
Subject characteristics summaries include tables and listings such as demographics (age, 
gender, race, ethnicity, iris color, and region) and baseline characteristics (baseline IOP by time 
point, baseline diurnal IOP, baseline IOP category (19-26 mmHg, 27-32 mmHg), prostaglandin 
analogue (PGA) run-in monotherapy, corneal thickness, and diagnosis) for all analysis sets 
(safety, FAS, and PPS). 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. 
 
11.3.1 
Demographic Characteristics 
Age will be summarized as a continuous variable as well as categorically (< 65, ≥ 65 and 
furthermore as < 50, 50-64, ≥ 65). In addition, sex, race, ethnicity, iris color and region will be 
summarized as categorical variables. 
 
11.3.2 
Baseline Characteristics 
Baseline IOP by time point, diurnal baseline IOP, and corneal thickness will be summarized as 
continuous variables. In addition, baseline IOP (19-26 mmHg, 27-32 mmHg), PGA run-in 


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mono therapy (Lumigan, Xalatan, Travatan), and corneal thickness categ01y ( 0.55 mm, 
>0.55 to 0.60 mm and >0.60 mm) will be summarizedas categolical variables. 
 
11.4 
Efficacy Analyses 
Unless othe1wise specified, all significant testing will be at the 5% level (two-sided). 
 
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 set will consist of all who received a dose of  study medication. 
 
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 sh1dy 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 09:00 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. Randomization will be stratified according to region and type of PGA therapy. 
 
Note that baseline conesponds to a visit where subjects are cmTently taking a PGA 
monotherapy 
 
11.4.1 
Primary Efficacy 
The prima1y objective of this study is to demonstrate the additive effect of brinzolamide 1% 
/brimonidine 0.2% in subjects with either open angle glaucoma or ocular hype1iension who 
are cmTently on prostaglandin analogue monotherapy. 
 
The prima1y endpoint is: 
 
• 
Mean change from baseline in diurnal IOP at Week 6 
 
The prima1y efficacy analysis will be an assessment of differences between treatments in mean 
change from baseline in diurnal IOP at Week 6 (patient IOP averaged over the 09:00 and 11:00 
time points). 
 
11.4.1.1 
Statistical Hypotheses 
The null and alternative hypotheses for the primary analysis are: 


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H0: μBrinzBrim+PGA = μVehicle+PGA 
H1: μBrinzBrim+PGA ≠ μVehicle+PGA 
where μBrinzBrim+PGA refers to mean diurnal IOP change from baseline for subjects randomized 
to receive brinzolamide / brimonidine plus PGA, and μVehicle+PGA refers to mean diurnal IOP 
change from baseline for subjects randomized to receive Vehicle plus PGA. 
 
Thus, success reflects a greater reduction in mean diurnal IOP change from baseline at Week 6 
for the adjunctive therapy (brinzolamide / brimonidine plus PGA) relative to Vehicle plus PGA. 
 
11.4.1.2 
Analysis Methods 
The treatment difference in mean diurnal IOP change from baseline will be examined with a 
pair-wise test at each scheduled on-therapy visit with Week 6 as the primary endpoint. The 
treatment difference in mean diurnal IOP change from baseline at Week 6 will be tested based 
on the least squares means derived from a repeated measures mixed model. This model will 
include fixed effects of treatment, visit, type of PGA, region, and the interaction of treatment 
and visit; the baseline diurnal IOP as a covariate; and the random effect of subject within the 
subject’s treatment, region, and type of PGA. 
 
Descriptive statistics will also be presented for the primary endpoint at Week 6. 
 
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. 
 
11.4.1.2.1 
SUBGROUP ANALYSIS METHODS 
Planned subgroup analyses will assess the impact of sites and demographic subgroups on 
overall study results and assess the efficacy in each subgroup. Subgroups of sites, age category 
(< 65, ≥ 65 and furthermore as < 50, 50-64, ≥ 65), sex, race, baseline IOP (19-26 mmHg, 27-
32 mmHg), PGA run-in monotherapy (Lumigan, Xalatan, Travatan), corneal thickness 
category (≤0.55 mm, > 0.55 to 0.60 mm and > 0.60 mm) will be summarized descriptively (N, 
mean, standard deviation) for the primary end point. 
 
11.4.2 
Secondary Efficacy 
The secondary endpoints are 


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• 
Mean dimn al IOP at Week 6 
 
• 
Mean percentage change from baseline in dimnal IOP at Week 6 
 
• 
Mean change from baseline in IOP at 11:00 at Week 6 
 
• 
Mean percentage change from baseline in IOP at 11:00 at Week 6 
 
• 
Mean change from baseline in IOP at 09:00 at Week 6. 
 
• 
Mean percentage change from baseline in IOP at 09:00 at Week 6. 
 
11.4.2 .1 
Stati stical Hypothe ses 
The null and alternative hypotheses for each of the secondary analyses are: 
 
 
 
 
where µBrinzBrim+PGArefe rs to th e m ea n o f eac h seco nd a1y endpo in t for subjects randomized to 
receive brinzolamide / brimonidine plus PGA, and µvehicie+PGA refe rs to the m ea n o f the same 
endpoint in the con esponding group of subjects randomized to receive Vehicle plus PGA. 
 
Thus, success reflects a greater mean estimate for the adjunctive therapy (brinzolamide / 
brimonidine plus PGA) relative to Vehicle plus PGA in each secondaiy endpoint comparison. 
 
11.4.2.2 
Analysis Methods 
Analyses of treatment differences of secondaiy endpoints will use the same methods as those 
for the prima1yendpoint. Hypothesis tests will use the same null and alternative hypotheses 
as above, with µ representing the mean for the variable being tested. 
 
Descriptive statistics will also be repo1ted for each of the seconda1yendpoints. 
 


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11.5 
Handling of Missing Data 
The primary, secondary, 
efficacy analyses will be based on an observed case 
(OC) analysis. The statistical model that will be employed and its associated analysis is one 
that is robust to data that are missing at random (MAR). 
 
11.6 
Multiplicity 
A closed step-down testing procedure will be used for hypothesis testing of primary and 
secondary endpoints; therefore no multiplicity adjustment is needed. The testing order (all 
based on IOP at Week 6) will be: 


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• 
Difference between treatments in mean change from baseline in diurnal IOP 
 
• 
Difference between treatments in mean diurnal IOP 
 
• 
Difference between treatments in mean percentage diurnal 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 09:00 
 
• 
Difference between treatments in IOP change from baseline for each time point 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. 
 
11.7 
Safety Analysis 
The safety endpoints in this study are automated perimetty, fundus parameters, best-con ected 
visual acuity (BCVA), slit-lamp exam, blood pressure, pulse rate and adverse events. 
 
The safety analyses will consist of descriptive summaries of the data as relevant to  the scale of 
data, eg, frequency and percents for adverse events, and mean changes from baseline as 
appropriate. 
 
11.8 
Health Economics 
Not applicable. 
 
11.9 
Interim Analyses 
Not applicable. 
 
11.10 
Sample Size Justification 
With 81 evaluable subjects per treatment group in the primaiy efficacy analysis, there is at 
least 90% power to detect a 2.0 mmHg difference in mean cha nge from baseline in diurnal 
IOP at Week 6 betweenthe treatment groups. This calculation is based on the assumption of a 
common standard deviation for mean change from baseline in diurnal IOP as small as 3.5 
mmHg and as large as 3.9 mmHg and the use of a two-sample two-sided t-test performed at 
the a=0 .05 level of significance. 


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Assuming a drop-out rate of 10%, approximately 90 subjects per treatment group will be 
randomized to ensure the required number of evaluable subjects in the final efficacy analysis. 


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12 
ADVERSE EVENTS 
12.1 
General Information 
An Adverse Event (AE) is any untoward medical occurrence in a subject who is administered 
a study treatment regardless of whether or not the event has a causal relationship with the 
treatment. An AE, therefore, can be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the study treatment, 
whether or not related to the treatment. In clinical studies, an AE can include an untoward 
medical occurrence occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered. The determination of clinical relevance is based upon the 
medical judgment of the Investigator. 
 
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 
Any pre-existing medical conditions or signs/symptoms present in a subject prior to the start 
of the study (ie, before informed consent is signed) should be recorded in the baseline history 
section of the CRF. Any medical occurrences having an onset after informed consent but 
prior to the start of study treatment (ie, initiation of treatment with test article) should also 
be recorded in the baseline history section within the CRF. 


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Subsequent to signing an informed consent form, all untoward medical occunences that 
occm dming the course of the study must be documented on an Adverse Event Fo1m (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 assessmentof 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 cunent hospitalization, is not disabling, etc.). All 
adverse events must be repmted regardless of whether or not they are related to the study 
treatment. 
 
For nonselious adverse events, an AEF containing all available info1mation will be 
collected on a routine basis according to instructions provided by the study sponsor. 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any adverse experience that meets any of the 
following clitelia: 
 
• 
Results in death. 
 
• 
Is life-threatening. 
 
NOTE: Life-threatening means that the subject was at immediate risk of death from the 
reaction as it occurred, ie, it does not include a reaction which hypothetically might 
have caused death had it occurred in a more severe form. 
 
• 
Requires hospitalization or prolongation of existing hospitalization. 
 
NOTE: In general, hospitalization signifies that the individual remained at the hospital 
or emergency ward for observation and/or treatment (usually involving an overnight 
stay) that would not have been appropriate in the physician's office or an out-patient 
setting. Complications that occur during hospitalizatoi n are AEs. 


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If a complicati on prolongs hospitalization or fulfills any other serious criteria, the event 
is serious. When in doubt as to whether " hospitalization" occurred, the event should be 
considered serious. 
 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disrnption of a person's ability to conduct n01mal life functions. 
 
NOTE: The term disability means a substantial disruption of a person :S, ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma (eg, sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial disruption. 
 
• 
Is a congenital anomaly/bilth defect. 
 
• 
Is an import ant medical event. An impmt ant medical event is an event that may not 
result in death, be life- threatening, or requil·e hospitalization but may be considered 
an  SAE  whe, n   based  upon  appropriate  medical  judgment,  it  may  jeopardize  the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed 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 drng dependency or drng abuse. 
 
All available information on a serious adverse event(s) and any other associated AE, if 
applicable, must be forwa1·ded to th e stud y Spon sor imm ediatel y (ie, w ithin 24 ho 
urs of the Investigator's or site's knowledge of the event) as follows: 
• In studies utilizing EDC (electronic data capture), all available info1mation 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   
faxed   to   the   study Sponsor  at 
within 24 hours of the 
Investigator's or sites awareness; however, the reported information must be entered into 
the EDC system once it becomes operational (Table 12-1). 


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• 
Additional information for any applicable event is to be rep01ted 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 repo1ted to Alcon following the usual 
pha1macovigilance circuit. 
 
 
In addition to the reporting of serious adverse events to the study sponsor, the SAE 
must be 1·eport ed to the IRB / IE C according to their requirements. 
Sponsor representatives and their contact inf01mation are provided in the Manual of 
Procedures that accompanies this protocol. 
 
If the SAE was due to a hospitalization of the subject, a copy of the discharge summa1y is 
to be fo1warded 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 laborato1y tests also may be requested. Fmt her, depending upon the nature of 
the SAE, the Sponsor may request copies of applicable p01tions of the subject's medical 
records. 
An assessment of seriousness will also be performed for all adverseevents by a study 
Sponsor physician utilizing the same criteria. If an adverse event repo1t ed 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. 
 
 
 
Safe ty Events of Special Interest 
 
In addition, the following cases will be collected and forwarded to the study Sponsor 
within 24 hours: 
 
• 
Pregnancy exposmes to the medicinal product. 
• 
Overdose, abuse and misuse cases. 
• 
Lack of efficacy cases (based upon Investigator's clinical judgment). 
• Medication enors. 
 
Theseevents may be reported on the AE form in the EDC system. 


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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). 
 
An assessment of causality will also be performed by a study sponsor physician utilizing 
the same definitions. 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 


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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 
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 are not excluded from the study as long as adequate birth 
control methods are being utilized or women considered post-menopausal. 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 (e.g. 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 and should be used during the study. 
 
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 patients 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 patient exited from the study. 


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Although not necessarily adverse, for the purposes of this trial, pregnancies will be reported 
on the adverse event form. In addition, complications of pregnancy may be reportable and 
will be decided on a case 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/ethnicity) 
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 (paper or 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. 


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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 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). 
 
13.4 
Quality Assurance and Quality Control 
The Sponsor will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure the trial is conducted and data are generated, documented and 
reported in compliance with the protocol, GCP and applicable regulatory requirements. The 
Sponsor will secure agreement from all involved parties to ensure direct access to all trial 
related sites, source data and documents, and reports for the purpose of monitoring and auditing 
by the Sponsor, and inspection by domestic and foreign regulatory authorities. Quality control 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. Agreements made by the Sponsor with the Investigator/Institution and any 
other parties involved in the clinical trial will be provided in writing as part of the protocol or 
as a separate agreement. 


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14 
References 
Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. 
Surv Ophthalmol 2008;53:S93-105. 
 
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. 
 
Baudouin C, Labbe A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the 
good, the bad, and the ugly. Prog Retin Eye Res. 2010;29(4):312-34. 
 
Cracknell KPB, Grierson I. Prostaglandin analogues in the anterior eye: Their pressure 
lowering action and side effects. Exp Eye Res 2009;88:786-91. 
 
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. 
 
Lee PP, Walt JG, Doyle JJ, Kotak SV, Evans SJ, Budenz DL, et al. A multicenter, retrospective 
pilot study of resource use and costs associated with severity of disease in glaucoma. Arch 
Ophthalmol. 2006;124(1):12-9. 


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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. 
 
Oostenbrink JB, Rutten-van Molken MP, Sluyter-Opdenoordt TS. Resource use and costs of 
patients with glaucoma or ocular hypertension: a one-year study based on retrospective chart 
review in the Netherlands. J Glaucoma. 2001;10(3):184-91. 
 
Rolando M, Brezzo G, Giordano P, Campagna P, Burlando S, Calabria G. The effect of 
different benzalkonium chloride concentrations on human normal ocular surface: a controlled 
prospective impression cytology study. In: Van Bijsterweld OP, Lemp MA, Spinelli D, eds. 
The Lacrimal System. Amsterdam: Kagler & Ghedini; 1991. p. 89–91. 
 
Rylander NR, Vold SD. Cost analysis of glaucoma medications. Am J Ophthalmol. 
2008;145(1):106-13. 
 
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. 


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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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03/28/2017 18:04:27 
03/28/2017 17:19:42 
03/27/2017 17:55:04 
 
Justification: 
 
Signed by: 
Date/Time 
(mm/dd/yyyy GMT): 

SAP_000.pdf: 
Short Title:
Statistical Analysis Plan CQVJ499A2401( Alcon 
GLH694-P001) / NCT02419508
Full Title:
Statistical Analysis Plan CQVJ499A2401( Alcon 
GLH694-P001)
Protocol Title:
Additive 
Effect 
of 
Twice 
Daily 
Brinzolamide 
1% 
/Brimonidine 0.2% fixed dose combination as an adjunctive 
therapy to a prostaglandin analogue
Project Number:
CQVJ499A2401( Alcon GLH694-P001) 
Protocol TDOC Numbers:
TDOC-0051182 & TDOC-0050474
Author:
 Lead Statistician
Version:
Amendment 3.0, 06MAR2018
Approvals:
See last page for electronic approvals.
Job Notes:
This version of the Statistical Analysis Plan is based on Version 3.0, of the study protocol
TDOC-0050474.
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Page 2
Executive Summary:
Key Objectives:
The primary objective of this study is to demonstrate the additive effect of twice daily 
brinzolamide 1% / brimonidine 0.2% (SIMBRINZA) in subjects with either open-angle 
glaucoma or ocular hypertension who are currently on a prostaglandin analogue monotherapy 
(PGA).
Decision Criteria for Study Success:
Success will be declared if the primary efficacy null hypothesis is rejected at the 5% level of 
significance (two-sided) in favor of adjunctive therapy (SIMBRINZA plus PGA) relative to 
PGA alone.  Success reflects greater mean reduction at Week 6 from baseline in diurnal IOP 
for the adjunctive therapy relative to PGA alone.
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Page 3
Table of Contents
Statistical Analysis Plan CQVJ499A2401( Alcon GLH694-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...........................................................................................................7
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.......................................................................................13
5.1
Safety Endpoints...............................................................................................13
5.2
Safety Hypotheses ............................................................................................14
5.3
Statistical Methods for Safety Analyses...........................................................14
5.3.1
Extent of Exposure .......................................................................................14
5.3.2
Automated Perimetry ...................................................................................15
5.3.3
Fundus Parameters .......................................................................................15
5.3.4
Best Corrected Visual Acuity (BCVA) .........................................................16
5.3.5
Slit Lamp Examination (SLE)......................................................................16
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5.3.6
Vital Signs (Blood Pressure, Pulse Rate) .....................................................17
5.3.7
Treatment-Emergent Adverse Events...........................................................17
5.4
Interim Analysis for Safety...............................................................................18
6
Pharmacokinetic Analysis Strategy ......................................................................18
7
Analysis Strategy for Other Endpoints.................................................................18
8
Sample Size and Power Calculations ...................................................................18
9
References ............................................................................................................19
10
Revision History...................................................................................................19
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 ...........................11
Table .11–1
Measurement Scales for Ophthalmic Assessments..........................................23
Table .11–2
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 effect of brinzolamide 1%/ 
brimonidine 0.2% (SIMBRINZA) in subjects with either open-angle glaucoma or ocular 
hypertension who are currently on a prostaglandin analogue monotherapy.
1.2
Study Description
The study is a 6 week, multicenter, parallel group study in subjects with 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 and Run-In/Washout 
Phase followed by 2 Eligibility Visits (E1 & 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).
Table .1–1
Study Plan by Treatment Groups
Study Phase
Treatment Group
Phase I
(Screening/Eligibility Phase)
Phase II
(Treatment  Phase)
Screening and Eligibility Visits
Week 2 and Week 6 (Exit) Visits
SIMBRINZA + PGA
(TRAVATAN PQ 0.004%, or
XALATAN 0.005%, or 
LUMIGAN 0.01%)
Begin dosing with PGA analogue at 
bedtime on the evening of the 
screening visit
&
Washout of all other IOP-lowering 
medications
In at least one eye* Mean IOP at
each Eligibility Visit  at 9:00 Hrs 
time point must be:
≥ 19 mmHg and < 32 mmHg
(while on PGA monotherapy)
*This qualifying eye must be the 
same eye for each Eligibility Visit
The mean IOP in either eye must 
not be greater than or equal to 
32 mmHg at any time point.
SIMBRINZA BID
(09:00 and 21:00 Hrs)
PGA QD
(at bedtime)
Vehicle +  PGA
(TRAVATAN PQ 0.004%, or
XALATAN 0.005%, or 
LUMIGAN 0.01%)
Vehicle BID
(09:00 and 21:00 Hrs)
PGA QD
(at bedtime)
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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 implemented in an Interactive Response Technology 
(IRT) system. Each subject number will be associated with treatment groups according to a 
random process. 
The randomization will be stratified by study region and type of PGA therapy (LUMIGAN, 
XALATAN or TRAVATAN). For each of the three study-specific PGA types within each 
region, subjects will be randomized 1:1 to SIMBRINZA or vehicle, to ensure balanced 
treatment assignment within each region and PGA type.
1.4
Masking
This study is double-masked with subjects randomized to use SIMBRINZA or vehicle for a 
duration of approximately 42 days. However, PGA 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. 
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. Each kit will 
contain 1 bottle of masked IP or PGA. Kits containing PGA will also be labeled to identify 
the PGA, protocol and kit numbers. This level of masking will be maintained throughout the 
conduct of the study.
1.5
Interim Analysis
No interim analyses are planned for this study.
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2
Analysis Sets
2.1
Efficacy Analysis Sets
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 set.  For example if a subject is given SIMBRINZA plus PGA
when they were randomly assigned to receive Vehicle plus PGA, the subject will be analyzed 
according to the randomization schedule (i.e. Vehicle plus PGA) regardless of which 
treatment was actually received (SIMBRINZA plus PGA). 
The per protocol set (PPS) will be evaluated only for the primary efficacy endpoint to 
confirm results from the FAS.  
PPS is a subset of the FAS and excludes all subjects who have met any of the critical 
deviation criteria identified in the Deviation and Evaluability Plan (DEP). In addition, 
individual subject visits and data points with critical deviations may be excluded from the
analysis involving the PPS. Evaluability for all subjects will be determined prior to breaking 
the code for masked treatment assignment.
The primary analysis set for all primary, secondary and 
analyses will be the full
analysis set (FAS). 
2.2
Safety Analysis Set
Safety analyses will be conducted using the Safety Set defined to include all subjects who 
received a dose of masked IP (i.e. not the run-in medication).  In the safety set subjects will 
be categorized under the actual treatment received. Subjects who took incorrect study 
treatment will be included in the group corresponding to the first treatment received.
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, gender, race, ethnicity, iris color and 
region)
and baseline characteristics ( baseline diurnal IOP, baseline IOP category :19-26 
mmHg, 27-32 mmHg, assigned PGA monotherapy, corneal thickness and diagnosis) . 
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Demographic and baseline characteristics will be reported for the FAS, while disposition 
table for all screened subjects. 
Listings for treatment assignment by investigator, screen failures by reason, subjects who 
terminated early from the study or discontinued treatment, and subjects excluded from key 
analysis sets will be reported. 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.  Diurnal baseline IOP and corneal thickness will be 
summarized as continuous variables.  In addition, baseline IOP category (19-26 mmHg, 27-
32 mmHg), assigned PGA monotherapy, corneal thickness (≤ 0.55 mm, > 0.55 mm to 0.60 
mm and > 0.60 mm and diagnosis will be summarized as categorical variables.
4
Efficacy Analysis Strategy
The efficacy assessment between treatment groups will be analyzed based on the FAS. If not 
otherwise specified, all significance testing will be at the 5% level (two-sided).
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 AM 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 AM averaged across the 2 eligibility visits. If both eyes are equal then the right eye will 
be selected for analysis.
Note: For IOP measurements, baseline corresponds to the average of 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 diurnal IOP at Week 6 
(subject IOP changes from baseline averaged over the 09:00 and 11:00 Hrs. time points). 
Secondary Endpoints
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Pa ge 9

M ea n di ur nal I O P (s u bject I O P a vera ge d o ver t he 0 9: 0 0 a n d 1 1 : 0 0 Hr . ti me p oi nts) t o 
We e k 6

M ea n di ur nal I O P perce nt c ha n ge fr o m baseli ne (s u bject I OP perce nt c ha n ge fr o m 
baseli ne a v era ge d o ver t he 0 9: 0 0 a n d 1 1 : 0 0 Hr. ti me p oi nts) t o We e k 6.

Mea n c ha n ge fr o m baseli ne i n I O P at 1 1 : 0 0 at Wee k 6

Mea n perce nt a ge c ha n ge fr o m baseli ne i n I O P at 1 1 : 0 0 at Wee k 6

Mea n c ha n ge fr o m baseli ne i n I O P  at 9 : 0 0 at Wee k 6

Mea n perce nta ge c ha n ge fr o m b aseli ne i n I O P at 9: 0 0 at Wee k 6
4. 2
Effic ac y 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:  μSI M B RI N Z A + P G A = μ Ve hicle + P G A  
H 1:  μSI M B RI N Z A + P G A ≠ μ Ve hicle + P G A
w here 
μ Bri nz Bri m + P G A
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 SI M B RI N Z A pl us P G A, a n d μ Ve hicle + P G A 
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:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 3 3 7
1 2- Mar- 2 0 1 8
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 Ve hicle pl us P G A.  
T h us, s uccess reflects greater mea n re d ucti o n i n di ur nal I O P c ha n ge fr o m baseli ne at Wee k 6 
f or t he a dj u ncti ve t hera p y ( SI M B RI N Z A pl us P G A ) relati ve t o P G A al o ne.  T his is e vi de nce d 
b y  greater mea n di ur nal I O P c ha n ge fr o m baseli ne w hic h c orres p o n ds wit h t he mea n c ha n ge 
fr o m baseli ne val ue bei n g “ m ore” i n t he a dj u ncti ve t hera p y gr o u p.


Page 10
The null and alternative hypotheses for the secondary endpoints are:
H0:  μSIMBRINZA+PGA =  μVehicle+PGA 
H1:  μSIMBRINZA+PGA  ≠  μVehicle+PGA
where μBrinzBrim+PGA refers to mean of each secondary endpoint for subjects randomized to 
receive SIMBRINZA plus PGA, and μVehicle+PGA refers to mean of the same endpoint in the 
corresponding group of subjects randomized to receive Vehicle plus PGA.  Thus, success
reflects greater mean estimate for the adjunctive therapy relative to PGA alone.
4.3
Statistical Methods for Efficacy Analyses
All endpoints will be summarized using standard descriptive summary statistics, on the FAS, 
consistent with the type of variable (continuous vs. categorical).
Primary Analysis
Treatment differences in mean diurnal IOP change from baseline will be examined with a 
pair-wise test at each scheduled on-therapy visit with Week 6 as the primary endpoint.
Pair-wise tests will be based on the least squares means derived from using a mixed model 
repeated measures analysis (MMRM).  The model will include factors for PGA, region, 
treatment, visit, and treatment by visit interaction. Baseline diurnal IOP will be included in 
the model as a covariate.
Covariance structures such as unstructured (UN), variance components (VC), compound 
symmetry (CS), autoregressive [AR(1)], and Toeplitz (Toep) will be considered. The best 
fitting structure, based on Akaike Information Criterion (AIC) will be selected. Within-
treatment and between treatment estimates of mean change from baseline in mean diurnal 
IOP, the associated standard error, 95% confidence interval and p-value will be provided.
SAS pseudo-code is provided in the Appendix (see Section 11.1.).
The primary analysis will be based on the FAS and repeated on the PPSsubjects .
Secondary Analyses
Analysis of treatment differences of all secondary endpoints, outlined below, will use the 
same methods as those for the primary endpoint and it will be based on the FAS. 
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Pa ge 1 1

Mea n di ur nal I O P (s u bject I O P a vera ge d o ver t he 0 9: 0 0 a n d 1 1: 0 0 Hr s. ti me p oi nts) 
t o Wee k 6

Mea n d i ur nal I O P perce nt c ha n ge fr o m baseli ne (s u bject I OP perce nt 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 Hr s. ti me p oi nts) t o Wee k 6.

Mea n c ha n ge fr o m baseli ne i n I O P at 1 1: 0 0
at Wee k 6

Mea n perce nt a ge c ha n ge fr o m baseli ne i n I O P at 1 1: 0 0 at Wee k 6

Mea n c ha n ge fr o m baseli ne i n I O P at 9: 0 0
at Wee k 6

Mea n perce nt a ge c ha n ge fr o m baseli ne i n I O P at 9: 0 0 at Wee k 6
Ta ble 4 -1 s u m marizes t he ke y  efficac y a nalys es.
Ta ble 4 – 1
S u m m ar y of A n al ysis S tr ate g y f or Ke y Effic ac y E n d p oi nt s
E n d p oi nt
Mai n 
vs. 
Se nsiti vit y  
A p pr oac h †
Stati stical 
Met h o d
‡
A nal y sis
Set
Missi n g 
Data 
A p pr oac h
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:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 3 3 7
1 2- Mar- 2 0 1 8


Page 12
Primary
Mean change from baseline in 
diurnal IOP at Week 6 (subject 
changes from baseline IOP 
averaged over the 09:00 and
11:00 Hrs time points)
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean change from baseline in 
diurnal IOP at Week 6 
S
MMRM§
PP
Likelihood-
based ignorable 
analysis
Secondary
Mean diurnal IOP (subject IOP 
change from baseline averaged 
over the 09:00 and 11:00 Hrs 
time points) to Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean diurnal IOP percent 
change from baseline (subject 
IOP 
percent 
change 
from 
baseline averaged over the 
09:00
and
11:00
Hrs time 
points) to Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean change from baseline in
IOP at 11:00 at Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean percent change from 
baseline in IOP at 11:00 at 
Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean change from baseline in
IOP at 9:00 at Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
Mean percentage change from 
baseline in IOP at 9:00 at 
Week 6
M
MMRM§
FAS
Likelihood-
based ignorable 
analysis
†M=Main analysis approach; S=Sensitivity analysis approach
‡Further details on statistical models are outlined above in 4.3.
§Mixed models with repeated measures 
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Pa ge 1 3
4. 4
M ulti plicit y S tr ate g y
To  ens ure t ype I err or is c o ntr olle d o ver t he set of st u d y hy p ot heses at t he 5 % le vel of 
si g nifica nce (t w o-si de d), a fi xe d se q ue nce testi n g strate g y will be e m pl o ye d. T he testi n g 
or der (all ef ficac y e n d p oi nts at We e k 6) will be:

Dif fere 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 mea n di ur nal I O P

Dif fere nce bet wee n treat me nts i n mea n perce nta ge di ur nal I O P cha n ge fr o m 
baseli ne

Dif fere nce bet wee n treat me nts i n I OP c ha n ge fr o m baseli ne at 11: 0 0

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 

Dif fere nce bet wee n treat me nts i n IO P  c ha n ge fr o m baseli ne at 9: 0 0

Differe 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 9: 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 i n t his series.
4. 5
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
T he pri mar y  en d p oi nt will be s u m marize d descri pti vel y  (N, mea n, sta n dar d de viati o n) , b y  
treat me nt, i n su b gr o u ps of a ge cate g or y (< 6 5, ≥6 5 a n d f urt her m ore as < 5 0, 5 0- 6 4, ≥6 5) , se x, 
race, baseli ne I OP (1 9- 2 6 m m H g, 2 7 - 3 2 m m H g ), re gi o n, P G A  ru n- i n m o n ot hera p y , a n d 
c or neal t hic k ness (≤ 0. 5 5 m m, > 0. 5 5 m m t o 0. 6 0 m m a n d > 0. 6 0 m m ).
I n ad diti o n, descri pti ve s u m mar y statistics will be pr o vi de d for s u bjects wit h
1 6: 0 0 I O P 
meas ure me nts o n t he f oll o wi n g e n d p oi nts:

I O P at eac h visit a n d ti me p oi nt

C ha n ge fr o m baseli ne i n I O P  at eac h visit a n d ti me p oi nt

Di ur nal I O P  at Wee k 6

C ha n ge fr o m baseli ne i n di ur nal I O P  at Wee k 6
4. 6
I nteri m A n al ysis f or  Effic ac y
N ot a p plica ble.
5
S afet y A n al ysis S tr ate g y
5. 1
S afet y E n d p oi nts
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:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 3 3 7
1 2- Mar- 2 0 1 8
T he safet y e n d p oi nts are:


Pa ge 1 4

E xte nt of e x p os ure

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 VA)

Slit -la m p e xa m

Vi tal Si g ns ( Bl o o d press ure, P ulse rate )

A d verse e ve nts
Rele va n t meas ure me nt scales f or safety e n d p oi nts ( Ta ble 1 0. 2- 1) a n d a st u d y pla n f or t he 
pla n ne d assess me nts/ pr oce d ures ( Ta ble 1 0.2- 2) are prese nte d i n t he A p pe n di x.
5. 2
S afet y H y p ot heses
T here are n o f or mal safet y  h yp ot heses i n t his st u d y. T he f oc us of t he safet y a nal ys is will be a 
c o m pre he nsi ve descri pti ve assess me nt o f t he occ urre nce a n d c haracteristics of a d verse e ve nts 
as well as t he ot her safet y e n d p oi nts.
5. 3
St atistic al Met h o ds f or S afet y A n al yses
All a nal y ses will be perf or me d o n t he safet y set. .
5. 3. 1
E xte nt of E x p os ure
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:  
4 . 0 ;  M o s t - R e c e n t ;  E f f e c t i v e ;  C U R R E N T
T D O C - 0 0 5 0 3 3 7
1 2- Mar- 2 0 1 8
E xte nt of e x p os ure t o i n vesti gati o nal pr o d uct is calc ulate d as d urati o n of e x p os ure t o mas ke d 
I P recei ve d .  F or all ra n d o mize d s u bjects e x p ose d t o mas ke d I P, d urati o n of e x p os ure is 
defi ne d as t he last da y  of e x p os ure t o mas ke d I P mi n us t he first da y  of e x p os ure t o mas ke d I P
pl us 1 da y.  I n t he e ve nt t hat t he last da y of e x p os ure is u n k n o w n, t he date of last c o ntact wit h 
t he s u bject will be use d. T he first i nstillati o n of i n vesti gati o nal pr o d uct is sc he d ule d t o occ ur 
o n t he e ve ni n g of t he Eli gi bilit y  2 Vi sit a n d t he last i nstillati o n of i n vesti gati o nal pr o d uct is 
sc he d ule d t o occ ur at t he We e k 6 Vi sit ( Da y 42) f oll o wi n g t he 0 9: 0 0 Hr . I OP meas ure me nt .  
A d diti o nall y , s u bjects e x p ose d t o i n vesti gati o nal pr o d uct wit h n o visits after Da y  1 or n o date 
of last c o ntact will ha ve t heir e xte nt of e x p os ure d oc u me nte d as 1 d a y. E xte nt of e x p os ure 
will be s u m marize d as a c o nti n u o us meas ure ( N, mea n, me dia n, sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) a n d b y c o u nts a n d perce nta ges of s u bjects i n t he f oll o wi n g cate g ories: 0 d a y s, 
1 t o 1 7 da y s, 1 8 t o 4 5 da ys a n d > 4 5 da ys.
E xte nt of e x p os ure will be prese nte d o verall a n d b y de m o gra p hic c haracteristics ( a ge, ge n der , 
race, et h nicit y, a n d a ge cate g ories (< 6 5 years a n d ≥ 6 5 y ears a n d < 5 0, 5 0 -6 4, ≥6 5 ).


Page 15
5.3.2
Automated Perimetry
Visual fields will be conducted at the Screening and the last visit at 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 worse eye at the parameter level. 
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), and 
Corrected Loss Variance (CLV), dependent upon the visual field device used.  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.
5.3.3
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 Study Table 11-1in the Appendix 
for the scale of each parameter). The dilated fundus examination will be conducted at the 
Screening and Week 6/Exit 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.
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5.3.4
Best Corrected Visual Acuity (BCVA)
Best corrected visual acuity will be assessed at the Screening, Eligibility 1 (09:00 Hr.), 
Eligibility 2 (09:00 Hr.), Week 2 (09:00 Hr.) and Week 6 (09:00 Hr.)/Exit Visits.  Baseline 
will be defined as the last BCVA measurement prior to exposure to the masked IP (i.e. 
Eligibility 2 (09:00 Hr.)). 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).  
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 worse 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. 
5.3.5
Slit Lamp Examination (SLE) 
A SLE will be performed at the Screening, Eligibility 1 (09:00 Hr. ), Eligibility 2 (09:00 Hr.), 
Week 2 (09:00 Hr.), and Week 6 (09:00 Hr.)/Exit Visits.  Baseline will be defined as the last 
SLE measurement prior to exposure to masked IP (i.e. Eligibility 2 (09:00 Hr.)). The analysis 
of the SLE will consist of increases from baseline in the presence of aqueous flare/cells and 
lens (Table 11-1 ). For each slit-lamp parameter, the eye showing the largest increase in slit-
lamp grade from baseline to any visit 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 will 
be presented. 
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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. 
5.3.6
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. The statistics will be given for the 
actual parameter value. In addition, number and percentage of subjects with abnormal vital 
signs by visit and time point. A shift table from baseline will be presented for each parameter
collected. For this purpose 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.
A patient listing with data at baseline and each study visit for each parameter as well as , a
listing with data for each abnormal cardiovascular finding will be provided. 
Finally, a patient listing corresponding to this shift in cardiovascular parameters will be 
presented for the overall safety population. 
5.3.7
Treatment-Emergent Adverse Events
The applicable definition of an Adverse Event (AE) is in the study protocol. In the outputs, it 
will be referred to as treatment-emergent adverse events. Any pre-existing medical condition 
or signs/symptoms present in a subject prior to the start of the study (i.e., before informed 
consent is signed) should be recorded in the baseline history section of the CRF.  Any 
medical occurrences having an onset after informed consent but prior to the start of study 
treatment (i.e., initiation of treatment with test article) should also be recorded in the baseline 
history section within the CRF.  These occurrences 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 
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any event already present that worsens following exposure to masked IP. The period for 
treatment-emergent AE analysis starts from exposure to the masked IP to study exit.
Descriptive summaries (n and %) for treatment-emergent AEs will be presented by system 
organ class and preferred term. In addition reports will be generated for the most frequent 
treatment-emergent AEs (with incidence of 1% in one or both treatment groups), ocular AEs, 
non-ocular AEs, treatment-related AEs, serious AEs and AEs resulting in treatment 
discontinuation. 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. These reports will be supported by subject listings, as 
necessary.  
A table and listing will report deaths. 
Only subject listings 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.
5.4
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 81 evaluable subjects per treatment group in the primary efficacy analysis, there is at 
least 90% power to detect a difference in mean change from baseline in diurnal IOP at Week 
6 of 2.0 mmHg between the treatment groups. This calculation is based on the assumption of 
a common standard deviation for mean change from baseline in diurnal IOP as small as 3.5 
mmHg and as large as 3.9 mmHg and the use of a two-sample two-sided t-test performed at 
the α=0.05 level of significance. 
Assuming a drop-out rate of 10%, approximately 90 subjects per treatment group will be 
enrolled to ensure the required number of evaluable subjects in the primary efficacy analysis.
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Subjects will be randomized in a 1:1 ratio to receive either SIMBRINZA and designated 
PGA or Vehicle and designated PGA
9
References
None.
10
Revision History
This is the first revision (Version 2.0) to the Statistical Analysis Plan for this study. This 
version of the Statistical Analysis Plan is based on Version 1.0 of the study protocol recreated 
as TDOC-0050474. This is the first revision to the original protocol with a reference number 
of TDOC-0018786.
2. Table .1–1, Study Plan by Treatment Groups, updated to align with revised protocol 
criteria for the Mean IOP Visit requirement of < 32 rather than ≤ 32 at the eligibility 
visits.
 
 
 
Amendment 2
This is the second revision (Version 3.0) to the Statistical Analysis Plan for this study. This 
version of the Statistical Analysis Plan is based on Version 3.0 of the study protocol recreated 
as TDOC-0050474. This is the third revision to the original protocol with a reference number 
of TDOC-0018786.
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1.
2. Global change: Remove 16:00 IOP collection time point at all visits.
3. Global change: Reduce E1 & E2, 09:00 am, IOP inclusion criteria (#3) from ≥ 21 and 
< 32 mmHg to ≥ 19 and < 32 mmHg.
4. Changed Secondary Endpoints from 
o
Mean change from baseline in IOP for each time point (9:00, 11:00, 16:00) at 
Week 6
o
Mean percentage change from baseline in IOP to Week 2 for each time point
(9:00, 11:00, 16:00) at Week 6
to
o
Mean change from baseline in IOP at 11:00 at Week 6
o
Mean percentage change from baseline in IOP at 11:00 at Week 6
o
Mean change from baseline in IOP at 9:00 at Week 6
o
Mean percentage change from baseline at 9:00 at Week 6
5. Removed identification of  specific participating regions, i.e., (EU (Europe, 
Australia), LACAN (Latin America, Canada))
6. Revised wording in Sample Size Justification to add phrase “change from baseline in 
diurnal” after “standard deviation from mean”
7. Changed wording in Efficacy Analysis sentence from
o
Unless otherwise specified, all statistical analyses will be at the 5% level 
to
o
Unless otherwise specified, all significance testing will be at the 5% level 
(two-sided)
8. Updated Adverse Events section
9. Added subset analysis of subjects with 16:00 IOP measurements
10. Study Plan updated to only include 9:00 and 11:00 time points
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Amendment 3
Minor editing changes were made following dry run meeting and to harmonize the analysis 
plan with the TLF ( mock up tales ) document.  
1.
2. Patients were replaced with subjects .
3. Section 2.2 the pre-treatment analysis set was deleted. 
4. Section 3 text change to specify that the baseline and demographic characteristics will 
not be reported for all analysis sets but only for the FAS. Baseline values will not be 
reported by time point. 
5. Section 4.3 and 4.5 , 5.3.6 some minor rewording but not content change.  
6. Section 5.3 changed to delete the reporting of all safety analysis by age subgroup. The 
reporting of each safety parameter will be discussed in the appropriate section. 
7. Section 5.3.1 a second age group (<50, 50-64, ≥65) for subgroup analysis has been 
added. 
8. All listing details were delete the variables reported in each listing are in the TFL 
shell document.  
9. Adverse event were replaced by treatment emergent adverse event to be consistent 
with the TLF document. 
10. Section 5.3.7 a deaths listing and table has been added. 
11. Section 5.3.2 definition of the baseline has been updated to harmonized to what used 
in the TLF documentation. 
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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 4.3.1.:
proc mixed data = dataset noclprint order=internal;
      
class treatment visit subject pga region;
model  dIOPchange = baselineIOP pga region treatment | visit;
repeated visit/ type=UN subject=subject(treatment);
         lsmeans treatment  visit;
         lsmeans treatment*visit/ slice=visit cl diff;      
run;
The comparisons will be extracted from the SAS statement “lsmeans treatment*visit/ 
slice=visit cl diff” at Week 6. 
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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
Study Plan
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Date/Time 
(mm/dd/yyyy GMT):
Signed by:
Justification:
03/12/2018 09:55:08
03/09/2018 04:57:41
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