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JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 27, Number 4, 2011


Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2011.0005

Prolonged Effectiveness of Bepotastine Besilate


Ophthalmic Solution for the Treatment of Ocular
Symptoms of Allergic Conjunctivitis
Jon I. Williams,1 Kathryn S. Kennedy,2 James A. Gow,1 Gail L. Torkildsen,3 Mark B. Abelson,46
Paul J. Gomes,4 and Timothy R. McNamara,1 for the Bepotastine Besilate Ophthalmic Solutions Study Group

Abstract
Purpose: This clinical trial evaluated the safety and effectiveness of bepotastine besilate ophthalmic solutions
1.0% and 1.5% compared with placebo for the treatment of ocular itching and conjunctival hyperemia (redness)
using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis when dosed 16 h before a CAC
test.
Methods: Subjects with a history of allergic conjunctivitis were assigned to receive placebo or bepotastine
besilate ophthalmic solution 1.0% or 1.5% in a single-center, randomized, placebo-controlled clinical trial. Eligible subjects (n = 107) aged 10 years and older with a history of allergic conjunctivitis who had a reproducible
positive reaction to a CAC were enrolled and dosed with test agent. The primary trial objectives included
assessment of ocular itching and conjunctival redness at 16 h after instillation of test agent. Reductions in several
CAC-induced secondary symptoms and signs of allergic conjunctivitis were also evaluated for tearing, ciliary
and episcleral redness, eyelid swelling, chemosis, and mucous discharge.
Results: Bepotastine besilate ophthalmic solution 1.5% demonstrated clinical effectiveness and statistical significance in comparison to placebo for the reduction in CAC-induced ocular itching 16 h after drug administration. Bepotastine besilate ophthalmic solution 1.0% also achieved statistical significance in comparison to
placebo for reducing ocular itching at all time points 16 h after dosing. Statistically significant reduction (P 0.05)
was additionally seen in this CAC test for the secondary ocular efficacy variable of allergen-induced tearing for
bepotastine besilate ophthalmic solution 1.5%. No clinical benefit was seen for reducing the coprimary efficacy
variable of conjunctival redness with the CAC model of allergic conjunctivitis.
Conclusions: Bepotastine besilate ophthalmic solution 1.5% produced predefined clinically meaningful reduction in CAC-induced ocular itching and tearing in a single-site trial and was more effective than bepotastine
besilate ophthalmic solution 1.0% and placebo for reducing ocular itching in a CAC test 16 h after dosing.

Introduction

llergic conjunctivitis is a common ocular atopic


disorder affecting as much as 20% of the population in
the Western world.1 The quintessential ocular symptom of
allergic conjunctivitis is ocular itching, and the ocular sign of

conjunctival hyperemia (redness) is also frequently present.


Other common signs and symptoms include chemosis, lid
swelling, watery eyes, mucous discharge, and nasal symptoms.1 This allergic disorder is frequently associated with
seasonal pollen sensitivity, although perennial forms exist
associated with exposure to mites, molds, or animal dander.

Data were presented in part and in poster presentation format at the 65th Annual Meeting of the American Academy of Allergy Asthma &
Immunology, March 1317, 2009, in Washington, DC; the 35th Annual Meeting of the American Society for Cataract and Refractive Surgery,
April 38, 2009, in San Francisco, CA; and the 67th Annual Meeting of the American College of Asthma, Allergy & Immunology, November
510, 2009, in Miami, FL.
1
ISTA Pharmaceuticals Inc., Irvine, California.
2
Statistics and Data Corporation, Tempe, Arizona.
3
Andover Eye Associates, Andover, Massachusetts.
4
Ora, Inc., Andover, Massachusetts.
5
Schepens Eye Research Institute, Boston, Massachusetts.
6
Harvard Medical School, Boston, Massachusetts.

385

386
While the roles of many preformed and newly formed mediators of allergy are continuously being discovered, histamine has remained the fulcrum of the immediate ocular
allergic reaction.1,2 The ocular allergic reaction is driven by
an IgE-activated mast cell degranulation that leads to histamine release and binding of histamine to its cognate H1 and
H2 receptors on conjunctival nerves and blood vessels, resulting in the ocular itching, redness, swelling, and watery
eyes that principally define the ocular allergic reaction. The
short- and long-term effects of histamine release affects
nerves and vasculature, epithelial cells, fibroblasts, and other
constitutively maintained cells in ocular tissues.3
Antagonism of histaminereceptor interactions is frequently used to treat ocular allergies, which leads to improvement in ocular itching and in redness, decreased
swelling of the eyelids and conjunctiva, as well as reduction
in watery eyes due to allergen exposure. These favorable
effects can be provided by antihistamine medications formulated for ophthalmic use. The latest-generation ophthalmic antihistamines are noted for having multiple
mechanisms of action4 that may allow for a longer duration
of activity than older antihistamines and fewer side effects.
Bepotastine besilate is one of the newer generation antihistamines, and is a selective H1 receptor antagonist and
mast cell stabilizer with demonstrated preclinical and clinical
effectiveness.57 Bepotastine has been shown to stabilize
mast cells,710 inhibit eosinophil migration,5,6 block the synthesis and release of newly formed mediators such as
leukotrienes7,11 and interleukin-5,12,13 and reduce the inflammatory effects of exogenously applied mediators such as
histamine and platelet activating factor.8 The clinical effectiveness and safety of bepotastine besilate as an oral medication for treating multiple allergic conditions were
demonstrated in multiple clinical trials in Japan.1420 In 2000,
an oral formulation of bepotastine besilate was approved in
Japan for the treatment of allergic rhinitis, and in 2002 the
indication was expanded to the management of urticaria and
pruritus associated with skin diseases.21 Evaluation of the
clinical effectiveness and safety of bepotastine besilate as an
ophthalmic solution using the well-established conjunctival
allergen challenge (CAC) clinical model of allergic conjunctivitis subsequently has been conducted.22,23 As a result of
positive outcomes in CAC trials and a favorable safety profile, bepotastine besilate ophthalmic solution 1.5% was recently approved in the United States for treating itching
associated with the signs and symptoms of allergic conjunctivitis when dosed twice daily.
The CAC is a standardized and reproducible clinical
method of inducing an ocular allergic reaction and evaluating the effects of ophthalmic antiallergy medications in a
controlled clinical setting. Although the CAC methodology
does not directly address the action of compounds as a mast
cell stabilizer in human conjunctiva, the CAC has been validated by use in clinical trials with earlier generation ophthalmic agents that were subsequently approved by the U.S.
Food and Drug Administration (FDA).2428 Positive results
have been demonstrated in 2 well-controlled CAC clinical
trials (one single site, one multisite) for the primary endpoints of ocular itching and conjunctival redness when assessed 15 min and 8 h after instillation of bepotastine besilate
ophthalmic solutions,22,23 and for the relief of nonocular allergic symptoms, including nasal congestion and rhinorrhea.29 Those clinical trial results led to the approval of

WILLIAMS ET AL.
Bepreve (bepotastine besilate ophthalmic solution) 1.5% in
September 2009 by the FDA for the treatment of ocular
itching associated with the signs and symptoms of allergic
conjunctivitis.30
The single-site CAC clinical trial tested the hypothesis that
bepotastine besilate ophthalmic solution 1.0% or 1.5% may
reduce the primary efficacy variables of CAC-induced ocular
itching and conjunctival redness with sustained clinical tolerability compared with placebo for at least 8 h duration. An
additional primary aim addressed in this article was to examine any prolonged beneficial effects seen in the single-site
CAC clinical trial 16 h after dosing of bepotastine besilate
ophthalmic solutions 1.0% and 1.5% compared with placebo
for treating ocular allergic responses. It was postulated that
successful demonstration for reduction in CAC-induced ocular allergic responses at 16 h postdosing with bepotastine
besilate ophthalmic solution 1.0% or 1.5% might potentially
support once daily dosing by allergic conjunctivitis patients.

Methods
Clinical trial design and medications
This was a single-center, double-masked, randomized,
placebo-controlled clinical trial. The first 2 clinical trial visits
were screening visits to identify subjects with a reproducible
and consistent response to an ocular test allergen. Efficacy
was then determined by inhibition of the allergic reaction
induced by a CAC test 16 h, 8 h, and 15 min after test agent
instillation at successive trial visits.
The test agents were placebo (vehicle), bepotastine besilate ophthalmic solution 1.0%, and bepotastine besilate
ophthalmic solution 1.5%. Both bepotastine besilate formulations and placebo were identically supplied and labeled
and were double-masked as to bottle content from subjects
and investigators.

Clinical trial requirements/guidelines


The clinical trial protocol and informed consent form were
approved by an independent institutional review board
(IntegReview, Austin, TX) before initiation of the clinical
trial. The clinical trial was registered on the clinicaltrials.gov
Web site (NCT00424398). All trial visits for enrolled subjects
were performed in a single outpatient ophthalmic clinic
setting (Andover Eye Associates, Andover, MA) between
March 1, 2007, and April 4, 2007. Before any clinical trial
procedures, a signed informed consent (and assent if the
subject was < 18 years of age), and a signed Health Insurance
Portability and Accountability Act form were obtained from
all subjects. The clinical trial was conducted in accordance
with International Conference on Harmonisation Good
Clinical Practice guidelines, the World Medical Association
Declaration of Helsinki (1996 version), and applicable regulatory requirements. This was a prospective, placebocontrolled CAC clinical trial. All ophthalmic examinations
and trial-related procedures were performed by clinically
trained researchers with experience with CAC methodology.

Criteria for clinical trial participation


Subjects had to meet the following inclusion criteria to be
eligible for participation in the clinical trial: (1) be at least 10
years of age and of either sex and any race; (2) have provided

BEPOTASTINE BESILATE AND OCULAR ALLERGY


written informed consent (and assent if applicable); (3) have
negative pregnancy test from all women of childbearing
potential, as well as a medically acceptable form of birth
control for the designated period; (4) have a positive history
of ocular allergies and a positive skin test reaction to cat hair,
cat dander, grasses, ragweed, and/or trees within the past 24
months; (5) have best-corrected visual acuity of 0.7 logMAR
or better using an Early Treatment Diabetic Retinopathy
Study (ETDRS) chart; (6) have positive bilateral CAC reaction within 10 min of allergen instillation at visits 1 and 2;
and (7) avoid disallowed medication and contact lens wear
for the designated period.
The presence of any of the following conditions prohibited
entry into the trial: (1) known contraindications to trial
medication(s) or their components; (2) any systemic or ocular
condition that could have affected a subjects safety or trial
parameters; (3) ocular surgery within 3 months of visit 1 or
refractive surgery within the past 6 months; (4) signs of active allergic conjunctivitis at the start of any visit; (5) use of
disallowed topical or systemic medications during the designated period; (6) use of an investigational drug or device
within 30 days of the trial or concurrently enrolled in another
trial; and (7) being a woman who was pregnant, planning a
pregnancy, lactating, or not using a medically acceptable
form of birth control for the designated period.
Subjects who met these initial entry criteria and did not
meet any exclusion criterion at visit 1 then underwent trial
screening procedures.

Clinical trial visits


Visit 1 (day - 21 3): allergen titration CAC. Eligible subjects underwent a titration CAC with 1 drop of allergen (e.g.,
Timothy grass or cat dander) instilled bilaterally in the
conjunctival cul de sac at the weakest dilution. If the subject
failed to react within 10 min, increasingly concentrated doses
of the allergen were instilled bilaterally at 10-min intervals
until a positive reaction was elicited (score of 2 for ocular
itching and 2 for redness in the conjunctival vessel bed in
each eye). Subjects who did not meet this qualification were
discontinued from screening. Upon completion of the CAC,
an ocular examination was performed on each subject that
included distance visual acuity using an ETDRS vision chart,
slit lamp biomicroscopy, intraocular pressure, and funduscopy through dilated pupils.
Visit 2 (day - 14 3): allergen confirmation CAC. A confirmatory CAC was performed bilaterally with the same allergen and concentration that elicited the adequate allergic
response at visit 1. Subjects who reacted positively in both
eyes as defined for visit 1 for at least 2 out of 3 time points
within this 20 min interval continued in the clinical trial; all
other subjects were discontinued from the clinical trial.
Ocular itching was graded by subjects at 3, 5, and 7 min postCAC, and conjunctival redness was graded by the investigator at 7, 15, and 20 min post-CAC.
Visit 3A (day 0): 16 h duration of action dosing. After
updating a subjects medical and medication history, the
distance visual acuity using ETDRS and slit lamp biomicroscopic examinations were performed. Baseline ocular allergic symptomatology also was assessed. Eligible subjects
were enrolled into 1 of 3 treatment groups according to a

387
computer-generated randomization code to receive placebo,
bepotastine besilate ophthalmic solution 1.0%, or bepotastine
besilate ophthalmic solution 1.5%. No attempt was made to
stratify the randomization process. A trained technician instilled 1 drop from the subjects double-masked test agent
bottle onto each eye. After 15 min, a safety (visual acuity and
biomicroscopy) examination was performed in subjects < 18
years of age. All subjects were told to return *15.5 h after
drug instillation for the visit 3B CAC.
Visit 3B (day 1): 16 h duration of action CAC. Sixteen hours
( 30 min) after drug or placebo instillation, subjects at visit
3B received 1 drop of the allergen solution bilaterally. Ocular
itching was graded by the subjects at 3, 5, and 7 min postchallenge and conjunctival redness was graded by the investigator at 7, 15, and 20 min postchallenge. Grades for
secondary ocular efficacy variables (tearing, ciliary and
episcleral redness, eyelid swelling, chemosis, and mucous
discharge) were also determined.
Details of visit 4 and visit 5 procedures and effectiveness
outcomes, including study exit procedures, have been previously described.22,23,29 In brief, subjects received 1 drop of
assigned test agent in each eye at visit 4 (day 14 3), and then
a CAC test was performed 8 h after the test agent instillation.
At visit 5 (day 28), enrolled female subjects capable of becoming pregnant received a second urine pregnancy test. All
subjects then received a third and final drop of assigned test
agent in each eye. Fifteen minutes after test agent instillation
at visit 5, a CAC test was performed and subjects were exited
from the clinical trial. Grading of ocular itching, conjunctival
redness, and all secondary efficacy variables was conducted
for visit 4 and visit 5 as at visit 3B.

Efficacy and safety assessments


Primary ocular efficacy variables were subject-assessed
ocular itching and physician-assessed conjunctival redness.
Severity scales for both variables were based on a 5-point (0
4 U) standardized scale, with half-unit increments allowed.25
Tearing and ocular mucous discharge as ocular secondary
efficacy variables were graded as present or absent.
Safety assessments included distance visual acuity using
an ETDRS chart and slit lamp biomicroscopy performed at
the beginning of each visit. For enrolled subjects under the
age of 18, these assessments were also performed 15 min
postdrug instillation at visit 3A. The intraocular pressure and
funduscopy through dilated pupils examinations were conducted after efficacy assessments at visit 1 and at the last trial
visit. Treatment emergent adverse events (AEs; reported,
elicited, or observed) were recorded at visit 3A and 3B as
well as at later study visits.

Data analysis and statistical methods


Demographic and baseline medical history data were
summarized descriptively. For quantitative baseline demographic variables, summaries included the mean, median,
and standard deviation, and were analyzed using a 2-sided
t-test. Qualitative demographic variables were summarized
using counts and percentages, and were analyzed using
Fishers exact test.
The prospectively defined primary analysis population
was the per protocol (PP) population. Subjects had to attend

388
visit 3A and 3B or visit 4 and also had to attend visit 5 to be
considered for the PP population. An alternative analysis
population evaluated for significant changes in efficacy
outcomes was the intent-to-treat (ITT) population with last
observation carried forward (LOCF) for imputation of
missing data. The Wilcoxon rank sum test was used to
compare outcomes for the primary efficacy variables of ocular itching and conjunctival redness between each active
treatment group and the placebo group in the primary
analysis population at each observation time point for visit
3B, the CAC test occurring 16 h after instillation of test
agents. The significance levels used to assess the P values for
the primary efficacy variables were adjusted for multiple
comparisons using conservative Bonferroni corrections to
recognize multiple bepotastine besilate concentrations and
2 potential duration of actions, efficacy at 16 h assessed at
visit 3B or efficacy at 8 h assessed at visit 4. As a predefined
result, treatment differences for either primary efficacy
variable therefore were considered statistically significant
at a (2-sided) 0.0125 when observed at a majority of observation time points. Since secondary efficacy variables
were considered nonvalidated surrogates for possible clinical
activity, P values determined for all secondary efficacy variables other than allergen-induced tearing and ocular mucous discharge were calculated by the Wilcoxon rank sum
test and were adjusted by the false discovery rate method.31
Statistical significance for allergen-induced tearing and ocular mucous discharge was evaluated using generalized linear
models, treating each subject as a cluster. Statistical significance for all secondary efficacy variables required a (2-sided)
0.05 at all observation time points.
A treatment group response considered clinically meaningful required achievement of clinical significance at a majority of observation time points, as well as statistical
significance. Clinical significance at each time point was defined as a 1.0-U difference between bepotastine besilate
ophthalmic solution (1.0% or 1.5%)treated eyes and placebotreated eyes, applicable for all primary and secondary efficacy
variables except tearing and mucous discharge. For allergeninduced tearing and mucous discharge, clinical significance
was equated to statistical significance.
Additional analyses were performed to examine the clinical and statistical significance for the coprimary endpoints of
ocular itching and conjunctival redness for the subset of
subjects who experienced grade 3 or greater itching at
screening visit 2 in 1 or both eyes, or received a total redness
score of 4.5 or greater summed for both eyes. Fishers exact
test was used to compare the proportion of subjects from
each treatment group who achieved a mean itching grade of
0 to 0.5-U, etc at all post-CAC time points within the PP
study population. This analysis was also performed for the
subjects who were more severely affected by a CAC, having
an itching grade of 3 or greater in 1 or both eyes at any time
point at visit 2.
Assuming the standard deviation of the mean scores for
ocular itching and conjunctival redness were each 1.0-U for
all 3 treatment groups (based on the results of previous CAC
studies with ophthalmic antihistamines), a sample size of 23
subjects per group was anticipated to have > 85% power at a
post-CAC time point to detect a true mean score difference of
1.0-U between any 2 groups using a 2 sample t-test. Given
the nonparametric nature of measures for primary and secondary efficacy endpoints, and with the anticipation of an

WILLIAMS ET AL.
approximate 10% drop-out rate, 30 subjects per treatment
group was used as a target enrollment guide.

Results
Subject sample characteristics
A total of 179 subjects were screened and 107 were enrolled and randomly assigned a masked test agent: 36 subjects to each of placebo and bepotastine besilate ophthalmic
solution 1.0% and 35 subjects to bepotastine besilate ophthalmic solution 1.5%. Of those enrolled, 102 completed the
clinical trial including attendance at visit 3A and 3B, of
whom 3 subjects committed protocol violations that removed them from consideration for the PP population. This
left 34 subjects in the placebo group, 35 subjects in the bepotastine besilate ophthalmic solution 1.0% group, and 30
subjects in the bepotastine besilate ophthalmic solution 1.5%
group comprising the PP population with data for the 16 h
duration of action (i.e., visit 3A and 3B). The subject demographics among all subjects were well balanced for bepotastine besilate ophthalmic solution 1.0% and 1.5% compared
with placebo for age, gender, race, and iris color (Table 1).

Efficacy variable outcomes


Ocular itching. For reduction in CAC-induced ocular
itching, both bepotastine besilate ophthalmic solutions 1.0%
and 1.5% achieved statistical significance in comparison to
placebo at all time points 16 h after dosing in both the PP
population (P < 0.001) and the ITT population with LOCF
(P 0.001) with LOCF (Table 2). Bepotastine besilate ophthalmic solution 1.5%, but not bepotastine besilate ophthalmic solution 1.0%, also achieved clinical significance in
comparison to placebo in the PP population for the reduction
of ocular itching at all time points 16 h after dosing.
An analysis was performed to determine the proportion of
subjects in each group that evidenced a 2.0-U, etc reduction
in itching scores compared with their screening visit scores
within the PP population, as well as for the subgroup of
subjects in the PP population with the most severe itching
(defined as an ocular itch score of 3 or more in each eye at a
screening visit 2 time point). Within the PP population,
40.0% of subjects in the bepotastine besilate ophthalmic solution 1.5% group experienced a 2.0-U reduction for at least 1
post-CAC time point at visit 3B compared with 34.3% of
those in the bepotastine besilate ophthalmic solution 1.0%
group and 5.9% in the placebo group, demonstrating a dosedependent reduction in itch. Of those in the severe itching
subpopulation, a 2.0-U reduction in eye itching scores for at
least 1 post-CAC time point was measured in 8.7% of the
placebo group compared with 37.5% and 43.5% of the bepotastine besilate ophthalmic solution 1.0% and 1.5% group
subjects, respectively (Fig. 1). In both the PP population and
severe itching subpopulation, the greater number of subjects
that experienced 2.0-U reductions in itching scores with either bepotastine besilate ophthalmic solution (1.0% or 1.5%)
treatment compared with placebo was statistically significant
(P = 0.001 and P = 0.008, respectively).
Given that subject enrollment required an ocular itching
score of 2.0-U or greater at visit 1 and visit 2, a 2.0-U
reduction in itching would be expected to produce near
complete elimination of ocular itching. Figure 2 illustrates
the proportion of subjects that achieved complete or near

BEPOTASTINE BESILATE AND OCULAR ALLERGY


Table 1.

389

Demographic Information of Enrolled Patients (Intent-to-Treat Population)

No. of subjects randomized


Mean age ( SD) (years)
Range of ages (years)
> 18 years of age, N (%)
18 years of age, N (%)
P valuea
Gender, N (%)
Female
Male
P value
Race, N (%)
Caucasian
African-American
Asian
Other
P value
Iris color, N (%)
Blue
Brown
Green
Hazel
P value

Placebo

Bepotastine besilate
ophthalmic solution 1.0%

Bepotastine besilate
ophthalmic solution 1.5%

36
40.9 ( 11.4)
13.065.0
34 (94.4)
2 (5.6)

36
39.9 ( 15.2)
12.064.0
33 (91.7)
3 (8.3)
0.75

35
44.3 ( 16.0)
11.073.0
33 (94.3)
2 (5.7)
0.31

17 (47.2)
19 (52.8)

14 (38.9)
22 (61.1)
0.63

18 (51.4)
17 (48.6)
0.81

33
1
2
0

(91.7)
(2.8)
(5.6)
(0.0)

35 (97.2)
0 (0.0)
0 (0.0)
1 (2.8)
0.36

31 (88.6)
1 (2.9)
0 (0.0)
3 (8.6)
0.15

12
19
2
3

(33.3)
(52.8)
(5.6)
(8.3)

11 (30.6)
15 (41.7)
3 (8.3)
7 (19.4)
0.51

11 (31.4)
17 (48.6)
1 (2.9)
6 (17.1)
0.72

a
P value for age as a continuous variable was calculated by 2 sample t-test. All other P values were calculated using Fishers exact test.
SD, standard deviation.

complete elimination of ocular itch (score of 0 or 0.5-U) 16 h


after dosing at a post-CAC time point. A greater number of
subjects receiving either bepotastine besilate ophthalmic solution achieved complete or nearly complete elimination of
itch following a CAC compared with placebo in both the PP
population (P < 0.001) and the baseline severe itching subpopulation (P = 0.005). For both study populations, the degree of reduction or elimination of ocular itching was greater
in the bepotastine besilate ophthalmic solution 1.5% group
relative to results for the bepotastine besilate ophthalmic
solution 1.0% group, although the differences were not statistically significant (P > 0.05).
Conjunctival redness. Bepotastine besilate ophthalmic solution 1.0% was statistically superior (P 0.012) to placebo
for reducing mean conjunctival redness only at the 7 min

Table 2.

time point 16 h after dosing in both the PP population and


the ITT population with LOCF. However, there were no
clinically significant (i.e., 1.0-U) differences in conjunctival
redness between bepotastine besilate ophthalmic solutions
(1.0% or 1.5%) and placebo at any time point 16 h after
dosing.
Tearing (lacrimation). Shown in Table 3 is the proportion
of subjects eyes with allergen-induced tearing absent at all
post-CAC time points exclusively for those subjects that
had tearing eyes observed during screening visit 2. A dose
relationship was found for the relative reduction in allergeninduced tearing measured between screening and 16 h
postdosing. The placebo group had a 27.5% reduction in eyes
with tearing present at baseline, compared with a 51.2% reduction in the bepotastine besilate ophthalmic solution 1.0%

Conjunctival Allergen Challenge at 16 H Postdosing


Difference in mean itching scores
(placeboactive)

Analysis
population
PP

ITT with LOCF

Time of itching
assessment after a CAC

Bepotastine besilate
ophthalmic solution 1.0%

Bepotastine besilate
ophthalmic solution 1.5%

3 min
5 min
7 min
3 min
5 min
7 min

0.7a
0.9a
0.9a
0.7a
0.8a
0.9a

1.0a
1.1a
1.1a
0.8a
0.9a
0.8a

Difference in mean itching scores in the PP and the ITT with LOCF populations.
a
P 0.001.
CAC, conjunctival allergen challenge; ITT, intent-to-treat; LOCF, last observation carried forward; PP, per protocol.

390

WILLIAMS ET AL.

% With Complete or Nearly Complete Clearance


of Itching Post-CAC (average eye score combined)

50%

45%
40%
35%

30%
25%
20%
15%
10%
5%
0%
Placebo

1.0%
Bepo

1.5%
Bepo

Placebo

PP

FIG. 1. Percent of subjects with 2-U improvement in ocular


itching scores (placeboactive) at 1 or more observation time
points relative to visit 2 screening values. Changes in ocular
itching scores were pair-matched for each subject by eye and
observation time point at 16 h after dosing with masked
medication. Results for left and right eyes were averaged. PP,
per protocol population.
group (P 0.05 relative to placebo) and an 85.7% reduction in
the bepotastine besilate ophthalmic solution 1.5% group
(P < 0.0001 relative to placebo). There was also a significantly
greater reduction of tearing in the bepotastine besilate ophthalmic solution 1.5% group as compared with the bepotastine besilate ophthalmic solution 1.0% group (P = 0.0046).
In general, regardless of whether or not subjects experienced allergen-induced tearing at visit 2, there was less
tearing in both bepotastine besilate ophthalmic solution
groups as compared with placebo at all 3 post-CAC time
points at visit 3B, in both the PP population and the ITT
population with LOCF. In the PP population in particular,
there were between 3.1% and 9.4% tearing eyes in the bepotastine besilate ophthalmic solution 1.5% group as compared with between 36.8% and 47.1% tearing eyes in the
placebo group, and the differences were statistically significant at each time point (P < 0.001). Tearing in the bepotastine
besilate ophthalmic solution 1.0% group ranged between
20.0% and 24.3%, and also was significantly less than the
placebo group 7 and 15 min post-CAC (P 0.030).

1.5%
Bepo

Baseline
Severe Itch PP

* P 0.05 relative to Placebo


FIG. 2. Percent of subjects with complete or nearly complete clearance of itching post-CAC at 1 or more observation
time points 16 h after dosing. Results for left and right eyes
were averaged. PP, per protocol population.
mic solution 1.0% group and by 3 subjects in the bepotastine
besilate ophthalmic solution 1.5% group. All 9 subjects reported this event as mild or moderate.

Discussion
Bepotastine besilate ophthalmic solutions 1.0% and 1.5%
were both previously reported to be effective for the reduction of ocular itching in this double-masked, single-site trial
for at least 8 h using the CAC model of allergic conjunctivitis.22,23 The data analyses presented here for bepotastine
besilate ophthalmic solution 1.5% also show clinical success
( 1.0-U improvement relative to placebo; P < 0.001) in reducing ocular itching when challenged 16 h after drug delivery, suggesting the possibility of a once daily dosing
regimen. It appears that the higher bepotastine besilate
Table 3. Percent of Eyes with Tearing Present
at Screening and Percent Cleared Relative
to Baseline at 16 H After Dosing with Medication

Safety
The safety population (n = 107) was defined as subjects
who received at least 1 dose of test agent. A total of 5 ocular
AEs were reported, 2 originating from the bepotastine besilate ophthalmic solution 1.5% group (eye irritation and
conjunctival cyst) and 3 from the placebo group (eye irritation and foreign body sensation). Eighteen subjects reported
29 nonocular AEs (Table 4). Fourteen of these nonocular AEs
were classified as related to treatment, reported by 9 subjects.
Unpleasant or bitter drug taste was reported upon eyedrop
instillation by 6 subjects in the bepotastine besilate ophthal-

1.0%
Bepo

Placebo
Bepotastine
besilate ophthalmic
solution 1.0%
Bepotastine
besilate ophthalmic
solution 1.5%
a

Baseline, visit
2 (tearing eyes/
total eyes)

16 h duration of
action, visit 3B
(nontearing eyes/
visit 2 tearing eyes)

58.8% (40/68)
61.4% (43/70)

27.5% (11/40)
51.2% (22/43)a

46.7% (28/60)

85.7% (24/28)b,c

P 0.05 relative to placebo.


P 0.0001 relative to placebo.
c
P 0.005 relative to bepotastine besilate ophthalmic solution 1.0%.
P values calculated using Fishers exact test.
b

BEPOTASTINE BESILATE AND OCULAR ALLERGY


Table 4.

Treatment-Emergent Nonocular
Adverse Events

AE
Total nonocular
AEs
Dysgeusia
Respiratory,
thoracic,
mediastinal
disorders (all)
Gastrointestinal
disorders (all)
Nasopharyngitis
Lymphadenopathy
Anxiety
Cyst removal

Placebo
(n = 36)

Bepotastine
besilate
ophthalmic
solution 1.0%
(n = 36)

Bepotastine
besilate
ophthalmic
solution 1.5%
(n = 35)

2 (5.6%)

9 (25.0%)

7 (20.0%)

0
1 (2.8%)

6 (16.7%)
1 (2.8%)

3 (8.6%)
3 (8.6%)

1 (2.8%)

2 (5.7%)

0
0
0
0

2 (5.6%)
1 (2.8%)
0
1 (2.8%)

0
0
1 (2.9%)
0

AE, adverse event.

concentration provided the potency required to achieve this


clinically significant effect for up to 16 h. Subgroup analyses
for the present clinical trial revealed a dose-dependent improvement in ocular itching that was statistically significant
among subjects with more severe ocular itching scores at
screening as well as for all subjects when treated with either
concentration of bepotastine besilate ophthalmic solution.
This finding has important implications since increased severity of allergic conjunctivitis symptoms can lead to a more
refractory therapeutic response. Bepotastine besilate ophthalmic solutions therefore appear to offer an efficacious and
rapid therapy for the severely allergic patient, which may
allow such severe patients to avoid or reduce steroid use and
thereby minimize the detrimental effects associated with
those drugs.32 Based on the analysis of AEs from this trial,
both concentrations of bepotastine besilate ophthalmic solution also were safe and well tolerated. Ocular AEs in this
clinical trial were minimal and did not include any instances
of dry eye.
Results of this clinical trial are comparable to previous
clinical trials of bepotastine besilate as a systemic medication
in treating itching associated with other allergic conditions.13,16,3337 Statistical significance for reduced itching was
seen in the multicenter CAC trial for both bepotastine besilate ophthalmic solutions (1.0% and 1.5%) compared with
placebo for the 16-h CAC test (P < 0.0055 at all time points),
but a 1.0-U improvement in ocular itching compared with
placebo was not demonstrable for either bepotastine besilate
formulation and clinical benefit was not seen for reducing
conjunctival redness.
Lacrimation is a major problem in patients with allergic
rhinoconjunctivitis. A cross-sectional survey of patients
(n = 447) with allergic rhinitis and their physicians showed
that at the time of their consultation, 44.0% of patients were
suffering from both nasal and ocular symptoms.38 Furthermore, 13.6% of patients reported itchy, red eyes, or watery
eyes as their most troublesome symptom.38 An ocular allergy
treatment for tearing or watery eyes that did not induce dry
eye side effects would address the needs of such patients.

391
The data presented here therefore demonstrate that both
bepotastine besilate ophthalmic solutions (1.0% and 1.5%)
have possible clinical value by virtue of showing significant
activity for reducing allergen-induced excessive tearing or
watery eyes in the CAC model.
Sisler et al.39 reported in 1982 that the lacrimal drainage
system included valves assuring the progression of tears in 1
direction; secretions pumped from the lacrimal gland are
distributed over the ocular conjunctiva and drain from the
ocular surface through the punctum; the punctum carries
secretions to the common canaliculus, moving then to the
lacrimal sac and nasolacrimal duct, where secretions drain
into the nose. This one-way drainage hypothesis is supported by a conjunctival and nasal allergen challenge study
suggesting that lacrimal secretions gained access to the nose
through the nasolacrimal duct but nasal secretions could not
reach the eye.40 Therefore, it is likely that CAC-induced inflammation causing nasal congestion might block the
drainage of tears through the nasolacrimal duct and lead to
excessive watery eyes. It is notable that in the present study,
the dose-dependent reduction in watery eyes observed 16 h
after treatment in subjects receiving bepotastine ophthalmic
solution 1.0% and 1.5% correlates with previously published
results demonstrating statistically significant reductions
(P 0.01) in nasal congestion and rhinorrhea with bepotastine besilate ophthalmic solution 1.5% 16 h after subject
dosing.29 Further studies appear warranted to better understand the relationship between CAC-induced tear production and the actions of H1 receptor antagonists such as
bepotastine besilate ophthalmic solutions.
The CAC model has been accepted by the FDA as a
standardized and reproducible means of evaluating the efficacy and duration of action of ophthalmic antiallergic
agents.41,42 At a CAC visit, the test agent is instilled into the
conjunctival cul de sac of subjects with a history of allergic
conjunctivitis. At a predetermined time later, an allergen is
instilled to induce an ocular allergic response intended to be
similar across all subjects. Changes in the signs and symptoms resulting from the allergen challenge are graded according to standardized severity scales at predetermined
time points, allowing for relatively precise comparisons of
the effects of ocular allergy drugs among subjects and the
reproducibility of effects for any 1 subject. The scales and
grading procedures also afford the sensitivity needed for
drug onset of action and duration of action clinical studies, in
comparison to either placebo or to an active comparator.
However, the CAC model does have study limitations. To
avoid interference by seasonal allergens, CAC clinical trials
are often conducted outside the allergy season. Exposure to
high concentrations of different allergens in the CAC model
and study designs that emphasize prevention rather than
treatment of allergic symptoms may be seen as limitations of
the model. However, the more numerous drawbacks inherent in a seasonal allergic conjunctivitis trial, such as dayto-day variability of allergen exposure and differences in
intersubject symptoms, are resolved by the use of this model.
In conclusion, this CAC clinical trial demonstrates the
potential of once daily dosing with bepotastine besilate
ophthalmic solutions. Since patient treatment, adherence,
and quality of life are important issues in allergic diseases,
the benefits of once daily dosing are considerable. Studies in
other therapeutic areas indicate that a key factor in treatment
adherence is the prescribed dosing schedule for a drug.4345

392
Suboptimal adherence to treatment regimens results in reduced clinical benefits and diminished quality of life for
many patients, especially those with persistent allergies,
contact lens wearers, and children. Interestingly, patient
adherence has been shown to double when drug regimens
decrease from twice a day to once a day.46 Bepotastine besilate ophthalmic solutions 1.0% and 1.5% have been shown
in this CAC trial to be safe and effective topical therapies that
provide potent relief of ocular itching in the CAC model of
allergic conjunctivitis for at least 16 h. Further clinical research to explore alternative dosing regimens with bepotastine besilate ophthalmic solution 1.5%, the approved
ophthalmic antihistamine, in patients having allergic conjunctivitis therefore may be warranted.

Acknowledgments
The authors would like to thank Mauricio Munoz and
Randi L. Rohlman of ISTA Pharmaceuticals, Inc., for assistance in editing the article.

Author Disclosure Statement


This clinical trial was funded by a grant from ISTA
Pharmaceuticals, Inc. The authors have made the following
financial disclosures: J.I.W., J.A.G., and T.R.M. are employees
of ISTA Pharmaceuticals, Inc.; K.S.K. is an employee of
Statistics and Data Corporation; no competing financial interests exist. G.L.T. is an employee of Andover Eye Associates, and P.J.G and M.B.A. are employees of Ora, Inc.; they
have no competing financial interests to disclose.

References
1. Abelson, M.B., Smith, L., and Chapin, M. Ocular allergic
disease: mechanisms, disease subtypes, treatment. Ocul.
Surf. 1:127149, 2003.
2. Abelson, M.B., and Allansmith, M.R. Histamine in the eye.
In: Silverstein A, OConnor G, eds. Immunology and Immunopathology of the Eye. New York: Masson Publishing,
1979:362364.
3. Leonardi, A. Role of histamine in allergic conjunctivitis. Acta
Ophthalmol. Scand. Suppl. 230:1821, 2000.
4. Leonardi, A. Emerging drugs for ocular allergy. Expert Opin.
Emerg. Drugs. 10:505520, 2005.
5. Sakai, A., Kikuchi, M., Yato, N., et al. Inhibitory effect of
betotastine besilate on antigen-induced airway eosinophil
infiltration and peripheral blood eosinophilia in mice. Arzneimittelforschung 47:954958, 1997.
6. Ukai, K., Takeuchi, M., and Masuda, S. Clinical pharmacological study of antiallergic agent TAU-184 (bepotastine
besilate)the effect on counting of eosinophils in nasal
discharge, and the patency improvement of nasal cavity [in
Japanese]. J. Clin. Ther. Med. 13:14011412, 1997.
7. Yato, N., Murata, T., Saito, N., et al. Anti-allergic activity of
betotastine besilate (TAU-284), a new anti-allergic drug [in
Japanese]. Folia Pharmacol. Jpn. 110:1929, 1997.
8. Ueno, M., Inagaki, N., Nagai, H., and Koda, A. Antiallergic
action of betotastine besilate (TAU-284) in animal models: a
comparison with ketotifen. Pharmacology 57:206214, 1998.
9. Honda, H., Murata, K., Hamazaki, A., et al. Inhibitory effect
on anaphylactic reaction and histamine-antagonizing action
[in guinea pigs] of betotastine besilate (TAU-284), a novel
anti-allergic drug [in Japanese]. Jpn. Pharmacol. Ther. 25:
879888, 1997.

WILLIAMS ET AL.
10. Sakamoto, O., Okanari, E., and Ueno, H. Suppression effects
of the novel drug betotastine besilate (TAU-284) on experimental asthmatic reactions in guinea pigs [in Japanese].
Jpn. J. Pharmacol. Ther. 25:889894, 1997.
11. Andoh, T., and Kuraishi, Y. Suppression by bepotastine
besilate of substance P-induced itch-associated responses
through the inhibition of the leukotriene B4 action in mice.
Eur. J. Pharmacol. 547:5964, 2006.
12. Kaminuma, O., Ogawa, K., Kikkawa, H., et al. A novel antiallergic drug, betotastine besilate, suppresses interleukin-5
production by human peripheral blood mononuclear cells.
Biol. Pharm. Bull. 21:411413, 1998.
13. Ohashi, Y. Immunological study of a second-generation
antihistamine drugthe effects of bepotastine besilate on
cytokine production from the peripheral blood mononuclear
cells in cedar pollen allergy patients [in Japanese]. Prog. Med.
24:157159, 2004.
14. Maruta, H., Nagata, M., Koga, H., and Tajiri, S. Clinical
evaluation of bepotastine besilate (Talion tablets) on chronic
urticaria [in Japanese]. J. New Rem. Clin. 53:576582, 2004.
15. Takahashi, H., Ishida-Yamamoto, A., and Iizuka, H. Effects
of bepotastine, cetirizine, fexofenadine, and olopatadine on
histamine-induced wheal-and flare-response, sedation, and
psychomotor performance. Clin. Exp. Dermatol. 29:526532,
2004.
16. Ishibashi, Y., Harada, S., and Niimura, M. Early phase II
study of TAU-284 (betotastine besilate) on chronic urticaria
[in Japanese]. J. Clin. Ther. Med. 13:11991215, 1997.
17. Ishibashi, Y., Harada, S., and Niimura, M. Late phase II
study of TAU-284 (betotastine besilate) on chronic urticaria optimal dose finding study by double-blind technique [in
Japanese]. J. Clin. Ther. Med. 13:12371257, 1997.
18. Horikawa, T., Harada, S., and Tamura, S. The clinical efficacy
of bepotastine besilate in relation to senile dermal pruritus:
usage testing [in Japanese]. Sci. Skin. 4:475480, 2005.
19. Kawana, S., Niimi, Y., and Higashi, N. Kikuchi, I. Effectiveness and safety investigation of bepotastine besilate
(Talion tablets) in patients with atopic dermatitis [in Japanese]. J. New Rem. Clin. 54:13251331, 2005.
20. Ohta, N., Akasuka, N., Saito, F., et al. The effect of prophylactic treatment with bepotastine in patients with Japanese
cedar pollinosis [in Japanese]. Pract. Otol. 95:531537, 2002.
21. TALION [package insert]. Osaka, Japan: Tanabe Seiyaku
Co., Ltd., 2009.
22. Abelson, M.B., Torkildsen, G.L., Williams, J.I., et al. A single
center, double-masked, randomized, placebo-controlled
evaluation of the onset and duration of action of the
ophthalmic antihistamine bepotastine besilate 1.0% and
1.5% in the conjunctival allergen challenge model of allergic
conjunctivitis. Clin. Ther. 31:19081921, 2009.
23. Macejko, T.T., Bergmann, M.T., Williams, J.I., et al. Multicenter clinical evaluation of bepotastine besilate ophthalmic
solution 1.0% and 1.5% to treat allergic conjunctivitis Am.
J. Ophthalmol. 150:122127, 2010.
24. Abelson, M.B., and Spitalny, L. Combined analysis of two
studies using the conjunctival allergen challenge model to
evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am. J. Ophthalmol.
125:797804, 1998.
25. Abelson, M.B. Evaluation of olopatadine, a new ophthalmic
antiallergic agent with dual activity, using the conjunctival
allergen challenge model. Ann. Allergy Asthma Immunol.
81:211218, 1998.
26. Abelson, M.B., Chapin, M.J., Kapik, B.M., and Shams, N.B.
Efficacy of ketotifen fumarate 0.025% ophthalmic solution

BEPOTASTINE BESILATE AND OCULAR ALLERGY

27.

28.

29.

30.
31.

32.
33.

34.

35.

36.
37.

38.
39.

compared with placebo in the conjunctival allergen challenge model. Arch. Ophthalmol. 121:626630, 2003.
Abelson, M.B., Gomes, P., Crampton, H.J., et al. Efficacy and
tolerability of ophthalmic epinastine assessed using the
conjunctival antigen challenge model in patients with a
history of allergic conjunctivitis. Clin. Ther. 26:3547, 2004.
Abelson, M.B., Gomes, P.J., Pasquine, T., et al. Efficacy of
olopatadine ophthalmic solution 0.2% in reducing signs and
symptoms of allergic conjunctivitis. Allergy Asthma Proc.
28:427433, 2007.
Torkildsen, G.L., Williams, J.I., Gow, J.A., et al. Bepotastine
besilate ophthalmic solution for the relief of nonocular
symptoms provoked by conjunctival allergen challenge.
Ann. Allergy Asthma Immunol. 105:5764, 2010.
BEPREVE [package insert]. Irvine, CA ISTA Pharmaceuticals, Inc. 2010.
Rosner, B. Comparisons of specific groups in one-way ANOVA, In: Rosner, B., ed. Fundamentals of Biostatistics, 6th ed.
Boston: Duxbury Press; 2005; p. 564582.
[No authors listed] Drugs for allergic disorders. Med. Lett.
8:918, 2010.
Tanaka, T., Miyazaki, S., and Ishikawa, K. The usefulness of
Talion in relation to nasal congestion in allergic rhinitis [in
Japanese]. Prog. Med. 24:20372044, 2004.
Kimitsuki, T., Horinouchi, K., Toyama, K., et al. Investigation of the effectiveness of bepotastine besilate (Talion tablets) on patients with ear itchiness. Jibi Rinsho. 51:131136,
2005.
Shimochi, H. SNJ-1773 Phase II trialclinical pharmacology
trial for patients with allergic conjunctivitis during the free
interval. Senju Clinical Trial Report SNJ-TO-03, 2004.
Shimoji, H. SNJ-1773 Phase 1 clinical study (repeated instillation study) Senju Clinical Study Report SNJ-TO-02, 2003.
Ikemura, H. SNJ-1772 Phase II trial. Exploratory test on allergic conjunctivitis. Senju Study Summary Report SNJ-TO-04,
2005.
Schatz, M. A survey of the burden of allergic rhinitis in the
USA. Allergy 62 Suppl 85:916, 2007.
Sisler, H.A. One-way flow in the lacrimal drainage system:
determinants from the basic sciences. Ann. Ophthalmol.
14:7677, 1982.

393
40. Spangler, D.L., Abelson, M.B., Ober, A., and Gomes, P.J.
Randomized, double-masked comparison of olopatadine
ophthalmic solution, mometasone furoate monohydrate
nasal spray, and fexofenadine hydrochloride tablets using
the conjunctival and nasal allergen challenge models. Clin.
Ther. 25:22452267, 2003.
41. Abelson, M.B., and Loeffler, O. Conjunctival allergen challenge: models in the investigation of ocular allergy. Curr.
Allergy Asthma Rep. 3:363368, 2003.
42. Abelson, M.B., Chambers, W.A., and Smith, L.M. Conjunctival allergen challenge: A clinical approach to studying allergic conjunctivitis. Arch. Ophthalmol. 108:8488,
1990.
43. Guest, J.F., Davie, A.M., Ruiz, F.J., and Greener, M.J.
Switching asthma patients to a once-daily inhaled steroid
improves compliance and reduces healthcare costs. Prim.
Care Respir. J. 14:8898, 2005.
44. Schenker, H., Maloney, S., Liss, C., et al. Patient preference,
efficacy, and compliance with timolol maleate ophthalmic
gel-forming solution versus timolol maleate ophthalmic solution in patients with ocular hypertension or open-angle
glaucoma. Clin. Ther. 21:138147, 1999.
45. Claxton, A.J., Cramer, J., and Pierce, C. A systematic review
of the associations between dose regimens and medication
compliance. Clin. Ther. 23:12961310, 2001.
46. Granger, A.L., Fehnel, S.E., Hogue, S.L., et al. An assessment
of patient preference and adherence to treatment with
Wellbutrin SR: a web-based survey. J. Affect Disord. 90:217
221, 2006.

Received: January 14, 2011


Accepted: April 30, 2011
Address correspondence to:
Dr. Jon I. Williams
ISTA Pharmaceuticals, Inc.
50 Technology Drive
Irvine, CA 92618-2301
E-mail: jwilliams@istavision.com

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