24-Hour Intraocular Pressure Control with

Fixed-dose Combination Brinzolamide

1%/Brimonidine 0.2%
A Multicenter, Randomized Trial
Robert N. Weinreb, MD,1 Jason Bacharach, MD,2 Robert D. Fechtner, MD,3 Malik Y. Kahook, MD,4
David Wirta, MD,5 Steve Burmaster, PhD,6 Xiangyi Meng, PhD,7 Douglas A. Hubatsch, MSc6

Purpose: To determine the intraocular pressure (IOP)-lowering effect of fixed-combination brinzolamide 1%/
brimonidine 0.2% (BBFC) over a 24-hour period.
Design: Prospective, multicenter, double-masked, parallel-group clinical trial conducted at 16 academic and
nonacademic sites in the United States.
Participants: Subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT) aged
18 years with
mean baseline IOP measurements in at least 1 eye of
21 and <28 mmHg.
Methods: Duplicate mean pneumatonometer IOP measurements were collected every 2 hours over a 24-
hour period in controlled light conditions in overnight facilities. Daytime (8 AMe8 PM) and nocturnal (10 PMe6
AM) IOP measurements were collected in a sitting or supine position, respectively. Baseline 24-hour IOP was
measured in untreated subjects after a washout (up to 4 weeks) and eligibility phase. After the baseline visit,
participants were randomized 1:1 to receive masked BBFC or vehicle, 1 drop 3 times daily (8 AM, 3 PM, and 10 PM)
for 4 weeks. At week 4, IOP measurements were repeated in both groups under the same conditions.
Main Outcome Measure: Mean change from baseline in 24-hour IOP at week 4.
Results: Of 125 participants randomized, 123 (98%; BBFC, n ¼ 62; vehicle, n ¼ 61) completed the study. No
subjects randomized to BBFC discontinued the study. At week 4, BBFC-treated eyes had significantly reduced
mean 24-hour IOP vs. vehicle (least squares mean difference [95% confidence interval]: 2.5 [3.3, 1.7]; P <
0.001); daytime (3.4 [4.3, 2.6]; P < 0.001) and nocturnal (1.2 [2.3, 0.0]; P ¼ 0.053) reductions were
observed. Mean change from baseline was significantly different between BBFC- and vehicle-treated eyes at all
daytime points and 3 of 5 nocturnal time points (10 PM, 12 AM, and 6 AM; secondary end point). The frequency of
adverse events was similar between treatment groups; in the BBFC arm, ocular hyperemia, corneal abrasion, and
dysgeusia were the most frequently reported, consistent with events described in the drug label.
Conclusions: This large, multicenter study of 24-hour IOP control with BBFC met its primary end point;
BBFC demonstrated significantly superior 24-hour IOP-lowering efficacy versus vehicle after 4 weeks of 3-times-
daily treatment in subjects with OAG or OHT. Ophthalmology 2018;-:1e10 ª 2018 by the American Academy of
Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

Elevated intraocular pressure (IOP) is a major risk factor for
the progression of open-angle glaucoma (OAG).1 Lowering
IOP is the only effective approach for slowing glaucomatous
progression and reducing the associated risk of vision loss.2-4
To reach and maintain their target IOP, patients with OAG
and ocular hypertension (OHT) frequently require multiple
IOP-lowering medications;3 however, patient compliance
and persistence with IOP-lowering medications are
common problems.5 Fixed-dose combination medications
have become increasingly popular because of their enhanced
efficacy and potential to improve patient adherence to
treatment as a result of the simpler dosing schedule.6 The
fixed-dose combination brinzolamide 1%/brimonidine
0.2% (BBFC, SIMBRINZA; Alcon, Fort Worth, TX) is
approved in the United States as a 3 times daily (TID)
therapy for the reduction of elevated IOP in adult patients
with OAG or OHT7 and as a twice-daily therapy in the rest of
the world for those patients with OAG or OHT for whom
monotherapy provides insufficient IOP reduction.8 In 2
phase 3 studies, BBFC dosed TID demonstrated
significantly superior IOP-lowering efficacy compared with
brinzolamide 1% or brimonidine 0.2% monotherapy in
subjects with OAG or OHT, with a safety profile that was
consistent with the individual components.9-11 Fixed-dose
combination brinzolamide 1%/brimonidine 0.2% has also
been shown to be an efficacious adjunctive agent to

ª 2018 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ophtha.2018.10.040 1

This is an open access article under the CC BY-NC-ND license ISSN 0161-6420/18
(http://creativecommons.org/licenses/by-nc-nd/4.0/). Published by Elsevier Inc.
 Ophthalmology Volume -, Number -, Month 2018
Figure 1. Study design. BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%; E1 ¼ first eligibility visit; E2 ¼ second eligibility visit;
IOP ¼ intraocular pressure; TID ¼ 3 times daily.
prostaglandin analogs, providing statistically significant and
clinically relevant IOP reduction beyond that achieved with
prostaglandin monotherapy.12,13
Nocturnal efficacy of an IOP-lowering drug may differ
from its daytime efficacy.14,15 Although the IOP-lowering
efficacy of BBFC over the daytime hours has been well
demonstrated, there is a paucity of data regarding the
efficacy of BBFC in maintaining IOP lowering over the
entire 24-hour period, particularly during nocturnal hours.
We report the results from a large, multicenter study of IOP
measured over a 24-hour period in a standardized fashion.
This multicenter 24-hour IOP control efficacy and safety
trial was designed to investigate the ability of BBFC,
compared with vehicle, to control IOP over a 24-hour period
after 4 weeks of TID topical ocular therapy.
Methods
Study Design and Participants
This was a prospective, multicenter, double-masked, randomized,
parallel-group efficacy and safety study conducted at 16 trial sites
(academic and nonacademic) in the United States between May
2016 and January 2017 (http://www.clinicaltrials.gov,
NCT02770248) (Fig 1).
Eligibility for study entry was based on 2 eligibility visits: the
first eligibility visit (E1) and the second eligibility visit (E2) (3e5
days after E1) (Fig 1). Eligible subjects were aged
18 years, were
diagnosed with OAG or OHT, and had mean baseline IOP
measurements in at least 1 eye (study eye) of
21 and <28
mmHg at 8 AM at both E1 and E2. Before E1, subjects
underwent washout of prestudy IOP-lowering medication for up
to 30 days based on the duration of action and drug half-life of the
medication being taken. To minimize potential risk to patients due
to IOP elevations during the washout period, at the discretion of the
investigator, subjects were permitted to use open-label 1% brin-
zolamide ophthalmic suspension (AZOPT, Alcon Laboratories,
Inc., Fort Worth, TX) during the washout period until 5 days before
E1 (minimum washout period for brinzolamide). After discontin-
uation of open-label brinzolamide 5 days before E1, subjects were
2
required to remain without IOP-lowering therapy through E2.
Exclusion criteria included any form of glaucoma other than OAG
or OHT; central cornea thickness <500 or >620 mm; Schaffer
angle Grade <2 in either eye; cup-to-disc ratio >0.8 (horizontal or
vertical) in either eye; chronic, recurrent, or severe inflammatory
eye disease (e.g., scleritis, uveitis, herpes keratitis); severe central
visual field loss in either eye; ocular trauma or surgery 6 months
before screening; ocular laser surgery, infection, or inflammation
3 months before screening; clinically significant or progressive
retinal disease such as retinal degeneration, diabetic retinopathy, or
retinal detachment; best-corrected visual acuity score <55 Early
Treatment Diabetic Retinopathy Study letters (equivalent to w20/
80 Snellen, 0.60 logarithm of the minimum angle of resolution, or
0.25 decimal) in either eye; and any other ocular pathology
(including severe dry eye) that precluded administration of the
active treatment.
At E2, subjects were randomized centrally using a randomiza-
tion schedule pregenerated by the sponsor statistician and retrieved
from the site-specific electronic Interactive Response Technology
system. Subjects were randomized 1:1 to masked BBFC or vehicle
(as a control), with randomization stratified according to baseline
IOP (24 or >24 mmHg). Masked treatment was not administered
until the conclusion of the 24-hour baseline visit (visit 3). The
subject, study principal investigator, and personnel conducting the
study were masked to treatment. At visit 3, duplicate, mean,
pneumatonometer (Reichert Model 30, Depew, NY) IOP
measurements in each eye were collected every 2 hours over a
24-hour period to ascertain baseline IOP values. Blood pressure
measurements were also collected every 2 hours after a 5-minute
interval following IOP measurement. At the conclusion of visit
3, masked treatment was administered as 1 drop TID (8 AM, 3 PM,
and 10 PM) for 4 weeks. At week 4, subjects participated in the
second 24-hour visit, with IOP and blood pressure collected every
2 hours (visit 5) under the same conditions, with measurements
collected before the 8 AM and 10 PM treatment administrations; the
3 PM administration did not coincide with IOP and blood pressure
measurements.
During the daytime period (8 AMe8 PM), IOP and blood
pressure measurements were collected in a sitting position; subjects
were required to sit upright approximately 15 to 30 minutes before
and during the measurement period. During the nocturnal period
(10 PMe6 AM), IOP and blood pressure measurements were
 Weinreb et al 
24-Hour IOP Control with BBFC
collected in a supine position in a sleep laboratory; subjects were
required to remain supine approximately 30 minutes before and
during the collection period. Lights were darkened (<10 lux) from
9:30 PM to after the 6 AM assessment was completed. Subjects were
awakened gently and briefly to assist the nocturnal measurements
while maintaining low-light conditions to ensure minimal
disruption.
After 2 weeks of treatment, subjects participated in a safety visit
(visit 4). At this visit, IOP was assessed at 8 AM, and subjects were
asked about any treatment-emergent adverse events (AEs), defined
as any unfavorable or unintended sign, symptom, or disease
temporally associated with the study treatment. Other safety
assessments at this visit included best-corrected visual acuity,
blood pressure, heart rate, biomicroscopy, and visual field loss.
Study Objectives
The primary objective was to evaluate differences between BBFC
and vehicle in mean change from baseline in 24-hour IOP at week
4. The secondary objectives were (1) to evaluate differences
between treatments in mean change from baseline at week 4 in
daytime (8 AM e8 PM) and nocturnal (10 PMe6 AM) IOP and (2) to
evaluate differences between treatments in mean change from
baseline in IOP for each time point at week 4. Exploratory
objectives included the evaluation of ocular perfusion pressure
(over 24 hours, daytime, nocturnal, and individual time points) at
week 4. The difference between treatments in the percentage of
subjects who responded to treatment, defined as those who expe-
rienced a reduction in IOP from baseline to week 4 of
20%, was
evaluated as a post hoc exploratory objective.
Standard Protocol Approvals, Registrations, and
Consents
The study was approved by an Independent Ethics Committee/
Institutional Review Board in accordance with the Health Insur-
ance Portability and Accountability Act regulations and was con-
ducted according to the International Conference on
Harmonization Guidelines for Good Clinical Practice and the
Declaration of Helsinki. At the time of enrollment, each subject
provided written informed consent.
Sample Size and Power Calculations
Before study commencement, a statistical power analysis
determined that, assuming a dropout rate of 5%,
53 subjects per
treatment group should be randomized to ensure that the number of
evaluable subjects in the primary efficacy analysis was sufficient to
maintain 80% power to detect a difference in mean change from
baseline in 24-hour IOP of 2 mmHg between the treatment groups.
The calculation was based on the assumption of a common
standard deviation for change from baseline in mean 24-hour IOP
of 3.5 mmHg and the use of a 2-sample, 2-sided t test performed at
the alpha ¼ 0.05 level of significance.
Statistical Analysis
A fixed-sequence testing procedure was used for hypothesis testing
of primary and secondary end points. Significance for a compari-
son was claimed only if the null hypothesis was rejected for the
previous end point in the series. The testing order (all based on IOP
at week 4) was the (1) difference between treatments in mean
change from baseline in 24-hour IOP; (2) difference between
treatments in mean change from baseline in daytime IOP; and (3)
difference between treatments in mean change from baseline in
nocturnal IOP. An analysis of covariance model with terms for
treatment and baseline IOP stratum was used to compare change
from baseline in 24-hour IOP. Within-treatment associated means
and 2-sided 95% confidence intervals (CIs) were provided for each
treatment group and for the difference between treatment groups
(BBFC vs. vehicle). Evidence of efficacy was established if the
upper bound of the 95% CI on the difference in mean change from
baseline in 24-hour IOP at week 4 was <0. A mixed-model,
repeated-measures analysis with terms for treatment, baseline
IOP stratum, time point, and treatment by time point interaction
was used to compare IOP to week 4 at each time point. Several
covariance structures were considered. Estimates of the
differences, 95% CIs, and P values were provided. For the post hoc
response analysis, the following were examined: (1) reductions at
the different daytime time points; (2) reductions at the different
nocturnal time points; and (3) repeated measurement analysis of all
daytime and nocturnal time points. P values for post hoc and
exploratory analyses were generated for hypothesis generation
purpose only.
The primary analysis data set for efficacy evaluations was the
full-analysis set, which included all randomized subjects who
received
1 dose of study therapy and had
1 on-treatment IOP
measurement. The per-protocol set was also examined as a
supportive analysis for the primary and secondary end points and
the post hoc response analysis (only hypothesis-generating statis-
tics are provided; no inferential conclusions should be drawn on
the basis of the per-protocol analysis). Safety variables were
summarized using descriptive statistics.
Results
Subjects
A total of 162 subjects were screened, of whom 125 were randomized
into the study. Baseline IOP measurement of <21 or
28 mmHg was
the main reason for screen failure (n ¼ 19/37 [51%]; 89% of subjects
failing to meet IOP qualification criteria failed at E1). Of the 125
subjects randomized, 123 (98%) completed the study (Fig 2). Two
subjects randomized to vehicle discontinued from the study: 1
because of experiencing 2 serious AEs (SAEs) (thrombocytopenia
and sepsis) and 1 after randomization but before receiving masked
treatment. Therefore, the safety population comprised 124 subjects
who were exposed to
1 dose of study treatment and had a post-
treatment study visit. Subject demographics and disease character-
istics at baseline were generally similar in both treatment groups
(Table 1).
Mean Change from Baseline in 24-Hour
Intraocular Pressure at Week 4
From baseline to week 4, the 24-hour least squares (LS) mean IOP
change of 3.1 mmHg in BBFC-treated eyes was significantly
greater than the 0.6 mmHg change observed in vehicle-treated eyes
(LS mean difference, 2.5; 95% CI, 3.3 to 1.7; P < 0.001;
Fig 3A). A similar trend was also observed in the per-protocol set
(Fig 3B).
Mean change from baseline in daytime and nocturnal IOP at week
4 of BBFC treatment resulted in reductions in both daytime (8 AMe8
PM) and nocturnal (10 PMe6 AM) IOP compared with vehicle. During
the daytime, the LS mean change for BBFC- and vehicle-treated eyes
was 3.9 and 0.5 mmHg, respectively (LS mean difference 3.4;
95% CI, 4.3 to 2.6; P < 0.001) (Fig 4A). During the nocturnal
period, the LS mean change for BBFC- and vehicle-treated eyes
was 1.9 and 0.7 mmHg, respectively (LS mean difference 1.2;
95% CI, 2.3 to 0.0; P ¼ 0.053) (Fig 4A). In general, the trends in the
per protocol set were similar to those seen in the full-analysis set,
with a more marked difference in mean change from baseline in
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 Ophthalmology Volume -, Number -, Month 2018

Figure 2. Subject disposition in the 24-hour intraocular pressure (IOP) control study with fixed-dose combination brinzolamide 1%/brimonidine 0.2%
(BBFC). aSubject withdrew consent. bFull-analysis set served as the primary analysis set for all primary, secondary, and exploratory efficacy analyses; included
all randomized subjects who received
1 dose of study therapy; and had
1 on-treatment IOP measurement. cPer-protocol set defined as a subset of the full-
analysis set, excluding all subjects who had critical, predefined deviation criteria that could affect key study end points (noncompliance was the main reason
for exclusion from the per-protocol set). dSafety set comprised all subjects exposed to BBFC or vehicle. Two subjects were administered both treatments
(BBFC and vehicle); for safety, they are grouped under the first administered treatment. SAE ¼ serious adverse event.

Table 1. Subject Demographics and Baseline Characteristics

BBFC (n [ 62) Vehicle (n [ 61) Total (N [ 123)

Age, mean (SD), yrs 67.5 (8.5) 63.6 (11.2) 65.5 (10.1)
Sex, n (%)
Male 24 (39) 20 (33) 44 (36)
Female 38 (61) 41 (67) 79 (64)
Age category, n (%), yrs
<50 1 (2) 5 (8) 6 (5)
50e64 24 (39) 24 (39) 48 (39)

65 37 (60) 32 (53) 69 (56)
Race, n (%)
White 37 (60) 28 (46) 65 (53)
Black or African American 19 (31) 28 (46) 47 (38)
Asian 3 (5) 4 (7) 7 (6)
Other 3 (5) 1 (2) 4 (3)
Iris color, n (%)
Blue 14 (23) 9 (15) 23 (19)
Brown 37 (60) 44 (72) 81 (66)
Green 3 (5) 1 (2) 4 (3)
Hazel 8 (13) 7 (12) 15 (12)
Baseline IOP, mean (SD), mmHg 24.5 (2.3) 24.6 (2.6) 24.5 (2.4)
Baseline IOP category, n (%)
24 mmHg 31 (50) 32 (53) 63 (51)
>24 mmHg 31 (50) 29 (48) 60 (49)
Diagnosis, n (%)
OHT 20 (32) 14 (23) 34 (28)
OAG* 42 (68) 47 (77) 89 (72)
Baseline corneal thickness, mean (SD), mm 552.6 (32.2) 553.9 (29.2) 553.2 (30.6)

BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%; IOP ¼ intraocular pressure; OAG ¼ open-angle glaucoma; OHT ¼ ocular hyper-
tension; SD ¼ standard deviation.
*Includes those subjects with a diagnosis of OAG or primary OAG recorded in the electronic case report form. Subjects with OAG: BBFC, n¼26 (42%);
vehicle, n¼30 (49%). Subjects with primary OAG: BBFC, n¼16 (26%); vehicle, n¼17 (28%). Percentages may not add up to 100 because of rounding.

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 Weinreb et al 
24-Hour IOP Control with BBFC
Figure 3. The 24-hour intraocular pressure (IOP) change from baseline at
week 4 in (A) full-analysis set and (B) per-protocol set. aChange from
baseline (day 0) in 24-hour IOP at week 4, calculated by averaging the
change from baseline across all time points. Only descriptive statistics are
presented for the per-protocol set. BBFC ¼ fixed-dose combination brinzo-
lamide 1%/brimonidine 0.2%; CI ¼ confidence interval; LS ¼ least squares.
nocturnal IOP between BBFC and vehicle groups than observed in
the full-analysis set (Fig 4B).
Mean Intraocular Pressure Change from Baseline
for Individual Time Points at Week 4
Examination of the change from baseline in IOP at week 4 for each
time point showed that the LS mean change between BBFC- and
vehicle-treated eyes was notably different at all daytime time
points, as well as at 3 of the 5 nocturnal time points (Fig 5). At
week 4, BBFC reduced mean IOP from baseline by 14% to 22%
during the daytime period and by 6% to 9% during the nocturnal
period (Table 2).
Exploratory Analysis of Mean Ocular Perfusion
Pressure at Week 4
Fixed-combination brinzolamide 1%/brimonidine 0.2% performed
similarly to vehicle with no negative effect on ocular perfusion
pressure (during the 24-hour, daytime, or nocturnal periods) after 4
weeks of treatment (Fig 6). For treatment comparisons (in terms of
a rate of 20% ocular perfusion pressure reduction), the post hoc
power estimations were 86%, 99%, 99%, 49%, 97%, 99%, and
38% at each daytime time point, respectively (8 AMe8 PM). The
estimated powers were 26%, 35%, 41%, 3%, and 8% at each
nocturnal time point, respectively (10 PMe6 AM).
Post Hoc Analysis of Response at Week 4
A notable difference was seen in the percentage of BBFC- and
vehicle-treated subjects experiencing a response (
20% IOP
reduction from baseline to week 4) during the daytime period (Fig
7). A difference was also observed at 10 PM, 12 AM, and 2 AM (Fig 7).
Safety and Tolerability
Over the course of the study, 26 subjects experienced at least 1
treatment-emergent AE (BBFC, n ¼ 15, 23%; vehicle, n ¼ 11,
18%), most of which were eye disorders (Table 3). The overall
frequency of AEs was similar between the 2 treatment groups
and was consistent with events described in the drug label.7
The most frequent AEs that occurred in subjects receiving
BBFC included ocular hyperemia (5%), corneal abrasion (3%),
and dysgeusia (3%). Two vehicle-treated subjects (3%) experi-
enced a total of 3 nonfatal SAEs: one subject experienced
worsening hemorrhoids and did not discontinue treatment, and 1
subject experienced an SAE of thrombocytopenia and an SAE of
sepsis and exited the study after visit 3. No BBFC-treated
subjects discontinued from the study, and no deaths were
reported.
Discussion
Twenty-fourehour studies of IOP control are typically
conducted as single-center trials. The current study was a
large, multicenter, randomized, double-masked trial to
evaluate the effect of an IOP-lowering medication over a
24-hour period in subjects diagnosed with OAG or OHT.
After 4 weeks of TID treatment, BBFC demonstrated
significantly superior 24-hour IOP-lowering efficacy
compared with vehicle. Fixed-combination brinzolamide
1%/brimonidine 0.2% treatment also lowered IOP to a
greater extent than vehicle during the daytime and nocturnal
time periods, although the reduction in LS mean IOP of 1.2
mmHg with BBFC vs. vehicle did not achieve statistical
significance in the nocturnal period in the full-analysis set.
However, it is noted that in landmark studies, each 1 mmHg
lowering of IOP was associated with a 10% reduction in the
risk of glaucomatous progression.16,17
Previous studies have shown that peaks in IOP in
subjects with glaucoma or OHT frequently occur during the
nighttime period with the participant in the supine posi-
tion.18-20 Although a small, single-center pilot study inves-
tigating the ocular hypotensive efficacy of netarsudil in
subjects with OAG or OHT (n ¼ 12) over a 24-hour period
found that the IOP-lowering efficacy was approximately
equal in both the nocturnal and daytime periods (3.5 mmHg
reduction vs. baseline; measured in the habitual position),21
other 24-hour IOP control studies have shown that a number
of current glaucoma medications typically have no efficacy,
or reduced efficacy, at nighttime.20,22-26 A comparative
study of dorzolamide/timolol-fixed combination and
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 Ophthalmology Volume -, Number -, Month 2018

Figure 4. Daytime and nocturnal intraocular pressure (IOP) change from baseline at week 4 in (A) full-analysis set and (B) per-protocol set. aChange from
baseline (day 0) in 24-hour IOP at week 4, calculated by averaging the change from baseline across all daytime or nocturnal time points. Only descriptive
statistics are presented for the per-protocol set. BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%; CI ¼ confidence interval; IOP ¼
intraocular pressure; LS ¼ least squares.

brimonidine/timolol-fixed combination (BTFC) in primary comparing the 24-hour effects of BBFC and the b-blocker
OAG demonstrated that although both fixed-combination timolol in subjects with OAG and OHT, after 4 weeks
medications significantly reduced 24-hour IOP, of treatment, mean IOP was significantly reduced in
dorzolamide/timolol-fixed combination was superior to
BTFC at 2 individual time points: 6 PM, near the trough
efficacy of brimonidine, and 2 AM, during the overnight
period when brimonidine has been shown to have a weaker
effect.27 It should be noted that in this comparative study,
both daytime and nocturnal IOP were measured in the
sitting position, which may not account for postural
differences in IOP over 24 hours when measured in the
habitual position.27
The IOP-lowering efficacy of BBFC during daytime hours
has been well documented. In 2 multicenter, phase 3 studies,
BBFC TID treatment demonstrated efficacy in IOP lowering
(8 AMe5 PM at month 3) that was significantly greater than
that observed with the individual components of the product
and with similar safety and tolerability in subjects with OAG Figure 5. Least squares mean intraocular pressure (IOP) at week 4 for each
and OHT.9-11 However, there has been a lack of data char- time point (full-analysis set). P values for fixed-dose combination brinzolamide
acterizing the effect of BBFC in maintaining IOP lowering 1%/brimonidine 0.2% (BBFC) vs. vehicle are descriptive only: *P < 0.05;
during the 24-hour period, particularly in the nighttime hours. **P < 0.01; ***P < 0.001. Arrows indicate dosing times: 8 AM, 3 PM, and 10 PM.
In a prospective, open-label, single-center, randomized trial CI ¼ confidence interval; IOP ¼ intraocular pressure; LS ¼ least squares.

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 Weinreb et al 
24-Hour IOP Control with BBFC

Table 2. Percent Change from Baseline Intraocular Pressure at Week 4 for Each Time Point (Full-Analysis Set)

BBFC (n [ 62) Vehicle (n [ 61)

Mean IOP (SD) Mean IOP (SD)
Percent Change Percent Change
Timepoint Baseline Week 4 from Baseline Baseline Week 4 from Baseline
Daytime
8 AM 23.8 (3.1) 20.5 (3.5) 14 24.3 (3.9) 23.8 (4.8) 2
10 AM 23.2 (3.4) 18.1 (3.9) 22 23.3 (4.4) 22.7 (4.4) 3
12 PM 23.3 (3.9) 19.3 (3.6) 17 23.1 (4.2) 22.9 (4.3) 1
2 PM 23.4 (3.6) 20.1 (3.7) 14 22.8 (4.0) 22.2 (4.6) 3
4 PM 22.5 (3.9) 18.5 (3.8) 18 22.9 (4.6) 22.4 (5.1) 2
6 PM 22.5 (3.7) 18.0 (3.7) 20 22.8 (4.1) 22.5 (4.0) 1
8 PM 22.4 (4.3) 19.0 (3.7) 15 22.1 (4.1) 21.4 (4.2) 3
Nocturnal
10 PM 24.6 (5.2) 22.6 (4.1) 8 24.8 (3.6) 24.2 (3.9) 2
12 AM 23.7 (4.5) 21.9 (3.7) 8 24.5 (4.3) 23.7 (4.0) 3
2 AM 25.3 (5.1) 23.0 (4.0) 9 24.6 (4.5) 24.1 (3.9) 2
4 AM 25.3 (5.2) 23.8 (4.4) 6 25.4 (4.6) 24.5 (4.7) 4
6 AM 25.9 (5.4) 23.9 (3.8) 8 26.6 (4.6) 26.0 (4.9) 2

BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%; IOP ¼ intraocular pressure; SD ¼ standard deviation.

BBFC-treated eyes throughout the 24-hour period (2.0
mmHg vs. baseline; 0.7 mmHg vs. timolol).6 Treatment
with BBFC significantly lowered IOP during both the
daytime and nocturnal periods, achieving a significantly
greater IOP reduction than timolol, which failed to
demonstrate IOP-lowering efficacy at night.6 Consistent
with this 24-hour IOP-lowering effect, in the current study,
mean 24-hour IOP was reduced by 2.5 mmHg in BBFC-
treated eyes at week 4 (vs. vehicle). Treatment with BBFC
also provided consistent daytime IOP control, demonstrating
notable IOP reduction vs. vehicle across all time points, as
well as at most nocturnal time points. In the 2 pivotal phase 3
trials comparing BBFC with its component medications over
3 months, reductions in IOP from baseline in the BBFC
group across visits and time points ranged from 23% to 35%
(5.5e8.9 mmHg); mean baseline IOP ranged from 23.2 to
27.2 mmHg.9-11 A lower magnitude of IOP reduction
in BBFC-treated eyes was seen in the current study
(14%e22% [3.3e5.1 mmHg] across daytime time points),
with the lower mean baseline IOP likely to be a factor
(22.4e23.8 mmHg). It is possible that variations in patient
population, drug dosing, or study design may account for
differences in the magnitude of mean 24-hour IOP reduction
observed in the current study compared with studies of other
classes of glaucoma medication, but it is not possible to draw
conclusions in the absence of a head-to-head comparison.
Fixed-dose combination brinzolamide 1%/brimonidine
0.2% was the first noneb-blockerecontaining fixed-
combination glaucoma medication to be approved in the
United States.9,11 Although BBFC may be better tolerated
in pulmonary or cardiac conditions, the brimonidine
component may have the potential to affect arterial blood
pressure.6 Low ocular perfusion pressure has been
proposed as a risk factor for glaucomatous damages;28,29

Figure 6. Mean ocular perfusion pressure at baseline and after 4 weeks of treatment during the 24-hour, daytime, and nocturnal periods. In this exploratory
analysis, ocular perfusion pressure was defined as 2/3  (diastolic blood pressure þ 1/3 [systolic blood pressure  diastolic blood pressure]  intraocular
pressure). BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%; SD ¼ standard deviation.

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 Ophthalmology Volume -, Number -, Month 2018

Figure 7. Analysis of response at week 4 (full-analysis set). aCalculated as a percentage of the total number of subjects evaluable in the fixed-dose com-
bination brinzolamide 1%/brimonidine 0.2% (BBFC) and vehicle arms (n ¼ 62 and n ¼ 61, respectively, unless otherwise specified). bP values for BBFC
versus vehicle are for descriptive purposes only. cn ¼ 61 subjects evaluable. dn ¼ 60 subjects evaluable. Arrows indicate dosing times: 8 AM, 3 PM, and 10 PM.
CI ¼ confidence interval; IOP ¼ intraocular pressure; OR ¼ odds ratio.

because ocular perfusion pressure may be altered by
changes in mean arterial blood pressure or IOP, treatments
affecting these parameters may have an impact on ocular
perfusion pressure. In the BBFC pivotal phase 3 trials,
cardiovascular parameters (resting pulse and mean systolic
and diastolic blood pressures) in the BBFC group were
similar to those from the brimonidine group, demon-
strating a modest, clinically insignificant decline.9,10 In the
current study, BBFC did not adversely affect baseline
ocular perfusion pressure after 4 weeks of treatment during
any of the study periods (24-hour, daytime, or nocturnal;
exploratory analyses; only descriptive statistics are pre-
sented) and demonstrated a safety profile consistent with
the individual components.
Treatment with BBFC administered TID demonstrated
superior 24-hour IOP-lowering efficacy compared with
vehicle over 4 weeks in subjects with OAG or OHT. Fixed-
dose combination brinzolamide 1%/brimonidine 0.2%
reduced IOP during both the daytime and the nocturnal
periods with no new safety signals identified.
Study Limitations
This study has some limitations. Many of the clinical sites
established their 24-hour research units specifically for this
study; in contrast with the typical clinic setting of daytime
assessments, the nocturnal testing was conducted in
overnight facilities under low-light conditions by trained but
relatively inexperienced personnel. The most widely used
method of IOP measurement is Goldmann applanation
tonometry, whereas the current study (and the aforemen-
tioned 24-hour studies) used a pneumatonometer. Nocturnal

Table 3. Subjects with Treatment-Emergent Adverse Events (
3% of Subjects in the Safety Population)

Primary System Organ Class Preferred Term BBFC (n [ 64) Vehicle (n [ 60) Total (N [ 124)
Any event, n (%) 15 (23) 11 (18) 26 (21)
Eye disorders, n (%) 4 (6) 8 (13) 12 (10)
Conjunctival hyperemia 0 (0) 4 (7) 4 (3)
Eye pruritus 0 (0) 2 (3) 2 (2)
Ocular hyperemia 3 (5) 1 (2) 4 (3)
Injury and procedural complications, n (%) 3 (5) 0 (0) 3 (2)
Corneal abrasion 2 (3) 0 (0) 2 (2)
Nervous system disorders, n (%) 2 (3) 1 (2) 3 (2)
Dysgeusia (bad taste) 2 (3) 0 (0) 2 (2)

BBFC ¼ fixed-dose combination brinzolamide 1%/brimonidine 0.2%.

Adverse events with start date on or after the date of first administration of Investigational product in study eye. The “Preferred Term” rows represent the
number of subjects with events. The summary rows for “Primary System Organ Class” and “Any Event” represent subject counts. Percentages for treatment
given are based on the number of subjects in safety set in specific treatment group. Medical Dictionary for Regulatory Activities version 16 has been used for
the reporting of AEs. Percentages may not add up to 100 because of rounding.

8
 Weinreb et al 
24-Hour IOP Control with BBFC
measurements are potentially further affected by several
factors, including the complexities of tonometer use in the
nighttime hours and low-ambient lighting.
An additional limitation is that efficacy was evaluated in
the eye with the higher mean IOP at eligibility visits E1 and
E2 (designated the “worse” eye); thus, the magnitude of IOP
reduction observed in the treatment groups may be greater
than would be observed in a clinical setting. However, both
treatment groups were analyzed using this approach,
reducing the potential to introduce bias.
Additionally, the short duration of this study means that
delayed AEs may not be discovered; eye allergy has been
reported when using brimonidine alone and may be delayed
for up to 15 months after treatment is started.30
In conclusion, this large, multicenter study of 24-hour
IOP control with BBFC met its primary endpoint; BBFC
demonstrated significantly superior 24-hour IOP-lowering
efficacy versus vehicle following 4 weeks of 3-times-daily
treatment in subjects with OAG or OHT.
Acknowledgments
Editorial and medical writing support of the manuscript and the
Journal’s article processing charges were funded by Novartis
Pharmaceuticals Corporation. The authors thank Julie Clark and
Ned Masin of Novartis Pharmaceuticals Corporation (East Han-
over, NJ), who reviewed the article during the early stages of
development; John Peterson, formerly of Novartis Pharmaceuti-
cals Corporation (East Hanover, NJ), who reviewed the article
during the early stages of development and supported in the
preparation and interpretation of the study data; and Jessica
Donaldson-Jones of Fishawack Communications Ltd. (Abingdon,
UK), who provided manuscript drafting, editorial, and medical
writing support. All named authors meet the International
Committee of Medical Journal Editors criteria for authorship for
this manuscript, take complete responsibility for the integrity of
the work, and have given final approval for the version to be
published.
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Footnotes and Financial Disclosures
Originally received: February 15, 2018.
Final revision: October 19, 2018.
Accepted: October 29, 2018.
Available online: ---. Manuscript no. 2018-389.
1 participated in the data analysis and interpretation, and preparation, review,
Hamilton Glaucoma Center and Shiley Eye Institute, University of Cali-
fornia San Diego, San Diego, California.
2 The State University of New York, University of Colorado, and University
North Bay Eye Associates Inc., Petaluma, California.
3
Department of Ophthalmology, SUNY Upstate Medical University, Syr-
acuse, New York.
4
Department of Ophthalmology, University of Colorado School of Medi-
cine, Aurora, Colorado.
5 Independent Ethics Committee/Institutional Review Board approved the
Aesthetic Eye Care Institute & Eye Research Foundation, Newport Beach,
California.
6
Novartis Pharmaceuticals Corporation, Fort Worth, Texas.
7 the time of enrollment, each subject provided written informed consent.
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Presented as a poster at: the American Academy of Ophthalmology Annual
Meeting, New Orleans, Louisiana, November 11e14, 2017.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): R.N.W.: Grant/
research support Genentech, Heidelberg Engineering, Konan, Meditec-
Zeiss, National Eye Institute, Optos, Optovue, Quark, Tomey, Topcon;
Consultant/advisor Aires Pharma, Alcon, Allergan, Bausch & Lomb,
Eyenovia, Novartis, Sensimed, Unity; Patents/royalties for intellectual
property Toromedes.
J.B.: Consultant and/or lecture fees Aerie Pharmaceuticals, Inc., Alcon,
Allergan, Bausch & Lomb, Glaukos; Stockholder Injectsense.
R.D.F.: Consultant/advisor Alcon, Allergan, ForSight VISION5, Glaukos,
Novartis, Santen Pharmaceutical Co., Ltd., Zeiss; Grant/research support
Aerie Pharmaceuticals, Inc.
M.Y.K.: Grant/research support Allergan, Bausch & Lomb, Roche;
Consultant/advisor Alcon, Allergan; Patents/royalties for intellectual prop-
erty Aurea Medical, ClarVista Medical, Johnson Vision, New World
Medical, ShapeTech.
D.W.: Financial support Aerie Pharmaceuticals, Inc., Alcon/Novartis,
Allergan, Kala, Shire.
S.B., X.M., and D.A.H.: Employees Novartis Pharmaceuticals Corporation.
10
27. Konstas AG, Quaranta L, Yan DB, et al. Twenty-four hour
efficacy with the dorzolamide/timolol-fixed combination
compared with the brimonidine/timolol-fixed combination
in primary open-angle glaucoma. Eye (Lond). 2012;26:
80e87.
28. Leske MC. Ocular perfusion pressure and glaucoma: clinical
trial and epidemiologic findings. Curr Opin Ophthalmol.
2009;20:73e78.
29. Quaranta L, Katsanos A, Russo A, et al. 24-hour intraocular
pressure and ocular perfusion pressure in glaucoma. Surv
Ophthalmol. 2013;58:26e41.
30. Watts P, Hawksworth N. Delayed hypersensitivity to brimo-
nidine tartrate 0.2% associated with high intraocular pressure.
Eye. 2002;16:132e135.
Sponsored by Alcon Research, Ltd. (Fort Worth, TX), an affiliate of
Novartis Pharmaceuticals Corporation (East Hanover, NJ). The sponsor
participated in the design of the study, conducting the study, data collection,
data management, and interpretation. Novartis Pharmaceuticals Corporation
and approval of the manuscript.
of California San Diego are supported in part by unrestricted grants from
Research to Prevent Blindness (New York, NY). Some grants have been
applied to administrative and scientific support, but exclude any payment
for authoring the manuscript.
HUMAN SUBJECTS: Human subjects were included in this study. An
study. All research adhered to the tenets of the Declaration of Helsinki and
was conducted according to the International Conference on Harmonization
Guidelines for Good Clinical Practice and the Declaration of Helsinki. At
No animal subjects were used in this study.
Author Contributions:
Conception and design: Weinreb, Fechtner, Kahook, Hubatsch
Analysis and interpretation: Weinreb, Bacharach, Fechtner, Kahook, Wirta,
Burmaster, Meng, Hubatsch
Data collection: Bacharach, Kahook, Wirta, Burmaster, Hubatsch
Obtained funding: Weinreb, Bacharach, Fechtner, Kahook, Wirta, Bur-
master, Meng, Hubatsch
Overall responsibility: Weinreb, Bacharach, Fechtner, Kahook, Wirta,
Burmaster, Meng, Hubatsch
Abbreviations and Acronyms:
AE ¼ adverse event; BBFC ¼ fixed-dose combination brinzolamide 1%/
brimonidine 0.2%; BTFC ¼ brimonidine/timolol-fixed combination;
CI ¼ confidence interval; E1 ¼ first eligibility visit; E2 ¼ second eligibility
visit; IOP ¼ intraocular pressure; LS ¼ least squares; OAG ¼ open-angle
glaucoma; OHT ¼ ocular hypertension; SAE ¼ serious adverse event;
TID ¼ 3 times daily.
Correspondence:
Robert N. Weinreb, MD, Hamilton Glaucoma Center and Shiley Eye
Institute, University of California San Diego, San Diego, CA 92093-0946.
E-mail: hiiop@aol.com.