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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
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.
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.
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).
389
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.
Table 2.
Analysis
population
PP
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.
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
Placebo
1.0%
Bepo
1.5%
Bepo
Placebo
PP
1.5%
Bepo
Baseline
Severe Itch PP
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
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
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.
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