Combined Analysis of Two Studies Using
`the Conjunctival Allergen Challenge Model
`to Evaluate Olopatadine Hydrochloride,
`a New Ophthalmic Antiallergic Agent
`With Dual Activity
`
`MARK B. ABELSON, MD, AND LAWRENCE SPITALNY, MD
`
`● PURPOSE: To evaluate the effectiveness and
`safety of olopatadine hydrochloride and to deter-
`mine its optimal concentration and the onset and
`duration of action for treating allergic conjuncti-
`vitis. Olopatadine is a new topical ophthalmic
`antiallergic agent that demonstrates activity as
`both an antihistamine and a mast cell stabilizer.
`Two double-masked, randomized, placebo-con-
`trolled, contralateral eye comparison studies were
`conducted using the conjunctival allergen chal-
`lenge model.
`● METHODS: A total of 169 subjects received
`0.05% or 0.1% olopatadine. Study subjects were
`healthy adult men and women with a history of
`active allergic conjunctivitis within the previous
`two seasons but not receiving current treatment.
`With an allergen dose that produced signs and
`symptoms of allergic conjunctivitis at visits 1 and
`2, the conjunctival allergen challenge was per-
`formed 27 minutes after study drug administration
`at the third visit (onset-of-action challenge) and at
`8 hours after study drug administration at the
`
`Accepted for publication Oct 9, 1997.
`From Ophthalmic Research Associates, Inc, North Andover, and the
`Departments of Ophthalmology, Harvard Medical School, and Immu-
`nology, Schepens Eye Research Institute, Boston, Massachusetts (Dr
`Abelson); and Phoenix Eye Clinic, Phoenix, Arizona (Dr Spitalny).
`This study was supported by a grant from Alcon Laboratories, Fort
`Worth, Texas.
`Reprint requests to Mark B. Abelson, MD, Ophthalmic Research
`Associates, Inc, 863 Turnpike St, Ste 224, North Andover, MA 01845;
`fax: (978) 689-0020.
`
`fourth visit (duration-of-action challenge). Ol-
`opatadine was administered in one eye and placebo
`in the opposite eye. Itching and redness were
`scored for both eyes at 3, 10, and 20 minutes after
`the conjunctival allergen challenge.
`● RESULTS: Both 0.05% and 0.1% concentrations
`of olopatadine were significantly (P < .05) more
`effective than placebo in inhibiting itching and
`redness at all evaluations when administered 27
`minutes or 8 hours before the conjunctival aller-
`gen challenge. There were no serious or drug-
`related ocular or nonocular adverse events in
`either study.
`● CONCLUSION: These findings demonstrate the
`rapid and prolonged (at least 8 hours) ocular
`antiallergic action of olopatadine.
`(Am J Oph-
`thalmol 1998;125:797–804. © 1998 by Elsevier
`Science Inc. All rights reserved.)
`
`A LLERGIC CONJUNCTIVITIS IS A CONDITION
`
`that occurs seasonally or perennially in re-
`sponse to environmental allergens. Ocular
`itching is the hallmark symptom of allergic conjunc-
`tivitis and is often the most troublesome for the
`patient.1 Other symptoms and signs of allergic
`conjunctivitis include ocular redness, tearing, mu-
`cus production, foreign body sensation, chemosis,
`and lid edema. In its mildest form, the signs and
`symptoms may be self-limiting.2 However, often the
`signs and symptoms of allergic conjunctivitis are
`
`0002-9394/98/$19.00
`PII S0002-9394(98)00044-0
`
`© 1998 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED.
`
`797
`
`APOTEX EX1033
`
`Page 1
`
`

`
`recurrent, waxing and waning, and may be accom-
`panied by other allergic manifestations, such as
`allergic rhinitis.
`Orally administered H1 antihistamines and other
`systemic antiallergic agents have little effect on the
`ocular manifestations of allergies.1 Instead, topical
`ophthalmic agents should be prescribed. Currently
`available topical antiallergic agents include H1 an-
`tihistamines, such as levocabastine (Livostin; CIBA
`Vision, Duluth, Georgia); H1 antihistamine-vaso-
`constrictor combinations, such as antazoline-napha-
`zoline (Vasocon-A; CIBA Vision) and naphazoline-
`pheniramine (Naphcon-A; Alcon, Fort Worth,
`Texas); mast cell stabilizing agents, such as cro-
`molyn sodium (Crolom; Baush & Lomb, Tampa,
`Florida) and lodoxamide (Alomide; Alcon); and
`nonsteroidal anti-inflammatory drugs (NSAIDs),
`such as ketorolac tromethamine (Acular; Allergan,
`Irvine, California). Topical corticosteroids are re-
`served for severe, refractory cases of ocular allergic
`disease such as vernal or atopic keratoconjunctivitis
`because these agents can be associated with serious
`side effects, particularly increased intraocular pres-
`sure.1
`Mast cells, which are abundant in the human
`conjunctiva,3 play a central role in the pathogenesis
`of allergic conjunctivitis. When an airborne aller-
`gen, such as pollen, animal dander, or dust, enters
`the eye of an allergic individual, it traverses the
`conjunctival epithelium and initiates a chain of
`events which lead to degranulation of mast cells and
`release of preformed chemical mediators, including
`histamine, eosinophil chemotactic factor, and
`tryptase.4 In addition, the arachidonic acid biosyn-
`thetic pathway is activated, yielding prostaglandins
`and leukotrienes. During the ocular allergic re-
`sponse there are also documented local elevations in
`kinins, which are potent vasoactive peptides; leuko-
`trienes C4 and D4; and albumin, indicating striking
`increases in vascular permeability.4,5 Experimen-
`tally, selective stimulation of ocular histamine H1
`receptors results in ocular itching.6 Selective stim-
`ulation of ocular H2 receptors has been reported to
`produce vasodilation of conjunctival vessels without
`itching.7 However, H2 stimulation effects are con-
`troversial.8 In a clinical setting, most of the ocular
`H1 antihistamines are more effective in relieving
`ocular itching than redness.9 Topical mast cell
`
`stabilizing agents are less effective in relieving
`itching.10
`Olopatadine hydrochloride is a new topical oph-
`thalmic antiallergic agent currently under evalua-
`tion for use in treating allergic conjunctivitis. In
`preclinical testing, olopatadine showed prolonged,
`selective antihistaminic activity in addition to in-
`hibition of mediator release from human mast cells
`in vitro.11 Because of its dual activity as an antihis-
`tamine and mast cell stabilizer, it is projected to
`have both rapid onset and prolonged duration of
`action.
`This report presents the combined analysis of two
`studies in which the conjunctival allergen challenge
`test was used to evaluate the effectiveness and safety
`of olopatadine, to determine its optimal concentra-
`tion and the onset and duration of action for
`treating allergic conjunctivitis. The conjunctival
`allergen challenge is a validated model for studying
`allergic conjunctivitis. It provides standardized, re-
`producible results, thereby avoiding the variability
`in symptoms and signs inherent in the naturally
`occurring condition.5,10,12 Study 1 evaluated four
`concentrations of olopatadine (0.01%, 0.05%,
`0.1%, and 0.15%), and study 2 evaluated the two
`most effective concentrations (0.05% and 0.1%)
`identified in study 1. The results of a combined
`analysis for olopatadine concentrations of 0.05%
`and 0.1% are presented here. Both studies were
`double-masked,
`randomized,
`placebo-controlled
`contralateral eye comparison studies.
`
`SUBJECTS AND METHODS
`
`BOTH STUDIES ENROLLED ADULT SUBJECTS (18 YEARS
`of age or older), of either sex and any race, with a
`history of active allergic conjunctivitis within the
`previous two seasons but not receiving current
`treatment with topical or systemic medications.
`Subjects had to have proven allergies demonstrated
`by positive results on skin prick, radioallergosorbent
`test, or conjunctival allergen challenge within the
`previous 24 months, or demonstrated by a positive
`skin prick test or radioallergosorbent test at the time
`of study enrollment.
`The presence of any ophthalmic abnormality was
`cause for exclusion from the study,
`including a
`
`798
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`JUNE 1998
`
`Page 2
`
`

`
`history of dry eye syndrome, blepharitis, follicular
`conjunctivitis, iritis, or preauricular lymphadenop-
`athy; bacterial or viral ocular infection; history of
`ocular herpes virus infection; or history of retinal
`detachment, diabetic retinopathy, or any poten-
`tially progressive retinal disease. Subjects using oph-
`thalmic medications requiring longer than a 1-week
`washout were not included in the study. Contact
`lens wear was not permitted within 72 hours before
`the first visit and during the entire study period. The
`regular use during the study of any topical ophthal-
`mic solution, including tear substitutes, was prohib-
`ited, as was the use of any topical medication within
`1 week of the start of the study. Subjects were
`excluded from the study if they showed symptoms or
`signs of allergic conjunctivitis (any itching or a
`score of higher than 1 for redness in any one of the
`three vessel beds) at each of the baseline examina-
`tions at the first, second, or third visits. Further-
`more, to remain in the study, enrolled subjects had
`to have a positive conjunctival allergen test on
`rechallenge (at the second visit), as demonstrated
`by a score of at least 2 for itching and at least 2 for
`redness in one or more of three vessel beds (ciliary,
`episcleral, and conjunctival). Criteria for scoring of
`ocular symptoms and signs are listed in the Appen-
`dix.
`Other exclusion criteria were as follows: presence
`of any significant illness that could interfere with
`the study, particularly an autoimmune disease such
`as rheumatoid arthritis, which can be associated
`with dry eye syndrome; history of cardiovascular,
`hepatic, or renal disease, with the exception of
`controlled hypertension; known alcohol or drug
`abuse; use of any systemic medication that could
`interfere with the study, including monoamine ox-
`idase inhibitors, nonsteroidal anti-inflammatory
`agents, mast cell stabilizers, antihistamines, or cor-
`ticosteroids; use of an oral or topical investigational
`drug or device within 30 days before receipt of study
`medication; history of allergy or sensitivity to any
`ophthalmic drug, including preservatives; and preg-
`nancy or lactation. Women of childbearing poten-
`tial were required to have a negative pregnancy test
`before entering the study and to use adequate birth
`control during the study. All prohibited systemic
`medications were to be discontinued 72 hours be-
`
`fore the start of the study and not used throughout
`the study.
`The experimental design was similar for studies 1
`and 2. Both were randomized, double-masked, pla-
`cebo-controlled, parallel group studies using a con-
`tralateral eye comparison. Both studies enrolled
`adult outpatients at a single center. The first visit
`served as the screening visit and also, for subjects
`who fulfilled initial eligibility requirements, as the
`occasion to identify an antigen and dose that
`elicited a positive response on the conjunctival
`allergen challenge. A confirmatory conjunctival
`allergen challenge was performed at the second
`visit, which was to occur within 30 days of the first
`visit in study 1 and within 5 to 9 days of the first
`visit in study 2. The onset-of-action challenge was
`performed during the third visit and the duration-
`of-action challenge was performed during the fourth
`visit. In the onset-of-action challenge, allergen was
`instilled 27 minutes after instillation of the study
`medication. In the duration-of-action challenge,
`allergen was instilled 8 hours after instillation of the
`study medication. These time frames were chosen
`based on preclinical data.11 For onset-of-action,
`these data suggest that, while the antiallergic activ-
`ity of olopatadine begins within minutes of use, its
`peak activity would be most evident when evaluated
`30 minutes after instillation. Therefore, the allergen
`was instilled at 27 minutes after instillation of
`olopatadine, with the first evaluation point 3 min-
`utes thereafter. The third visit was scheduled 14
`days after the second visit in both studies, and visits
`3 and 4 were separated by 7 ⫾ 2 days in study 1 and
`14 days in study 2.
`Enrolled subjects were randomly assigned to re-
`ceive 0.05% or 0.1% olopatadine in one eye and
`placebo (vehicle for olopatadine) in the contralat-
`eral eye in a masked fashion. Assignment of the eye
`to receive active medication was random.
`Ophthalmic examinations were performed during
`the screening visit and at the start of subsequent
`visits. Ophthalmic examinations included vision
`assessment (best corrected on Snellen chart), scor-
`ing of ocular itching, and slit-lamp examination to
`assess conjunctival redness, cornea, anterior cham-
`ber, and iris. In addition, funduscopy was performed
`at screening. Pupil size was recorded at the third
`visit of study 1 at the baseline examination and just
`
`VOL. 125, NO. 6
`
`COMBINED ANALYSIS OF TWO STUDIES
`
`799
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`Page 3
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`

`
`before the conjunctival allergen challenge. In study
`2, measurement of pupil size was performed at the
`baseline ophthalmic examination for each visit and
`just before the conjunctival allergen challenge on
`the third and fourth visits.
`On the second visit and subsequent visits, any
`subject showing signs of allergic conjunctivitis (red-
`ness score of greater than 1 or any itching) at
`baseline was asked to return for another visit within
`1 week. At all visits, subjects with positive reactions
`to the conjunctival allergen challenge received,
`upon request, one or two drops of an ophthalmic
`antiallergic agent for relief of symptoms when the
`evaluation period had ended.
`Study protocols were designed in accordance with
`the tenets of the Declaration of Helsinki and ap-
`proved by the appropriate Institutional Review
`Board. Written informed consent was obtained from
`each subject after the nature and possible conse-
`quences of the study were explained.
`During the first visit, a complete medical history
`was recorded and the screening examination was
`done. After providing written consent, subjects who
`fulfilled entry criteria underwent a pregnancy test
`(female subjects of childbearing potential), a com-
`plete ophthalmic examination, and a skin prick or
`radioallergosorbent test (those subjects without doc-
`umented positive response to allergy testing within
`the prior 24 months).
`A bilateral conjunctival allergen challenge titra-
`tion test was then conducted to determine the
`appropriate allergen and dilution for subsequent
`tests. Each subject was challenged with weeds,
`grasses, trees, or animal dander based on previously
`documented allergic sensitivity. One 25-␮l drop of
`the lowest dilution (19 allergen units [AU] per 25
`␮l) of the chosen allergen was administered into
`each eye. If no reaction occurred within 10 minutes,
`increasing concentrations of allergen were adminis-
`tered every 10 minutes until a positive reaction was
`elicited. A positive reaction upon conjunctival al-
`lergen challenge was defined as a score of at least 2
`for redness and 2 for itching 5 to 10 minutes after
`allergen administration. If the subject tested nega-
`tive with the first allergen, another allergen was
`administered in the same manner. The dilution and
`type of allergen that elicited a positive response was
`used for subsequent conjunctival allergen challenge
`
`tests. Subjects who failed to respond to any of the
`allergens were excluded from the study.
`A confirmatory conjunctival allergen challenge
`was performed during the second visit, with the final
`allergen and dilution that elicited a score of at least
`2 for redness and itching at the first visit. Redness of
`each of three vessel beds and itching were scored
`and recorded at 3, 10, and 20 minutes after con-
`junctival allergen challenge. If a redness score of at
`least 2 in at least one vessel bed and an itching score
`of at least 2 were present at least at one time point,
`the subject was deemed eligible for the study.
`The onset of drug action was evaluated at the
`third visit in both studies. Subjects were randomized
`to receive one drop of olopatadine (at a concentra-
`tion of 0.05% or 0.1%) in one eye and one drop of
`placebo in the other eye according to the random-
`ization for treatment arm and eye. The concentra-
`tion of allergen determined at the first visit and
`confirmed at the second visit was used for the
`challenge. Pupil size was recorded immediately be-
`fore the conjunctival allergen challenge. The con-
`junctival allergen challenge was performed 27 min-
`utes after study drug instillation. The signs and
`symptoms of allergic conjunctivitis were scored, as
`previously described, at 3, 10, and 20 minutes after
`allergen administration.
`The duration of drug action was evaluated at the
`fourth visit in both studies. Subjects received one
`drop of olopatadine solution in one eye and one
`drop of placebo in the opposite eye. The concen-
`tration of allergen determined at the first visit and
`confirmed at the second visit was used for the
`challenge. The conjunctival allergen challenge was
`performed 8 hours after study drug instillation in
`both studies. In study 2, the conjunctival allergen
`challenge was performed immediately after taking
`the pupil size measurement. Itching and redness
`were then scored at 3, 10, and 20 minutes after the
`conjunctival allergen challenge. Subjects completed
`an exit form and all female subjects of childbearing
`potential underwent a pregnancy test at the end of
`the final visit.
`The conjunctival allergen challenge was con-
`ducted using one of four common allergens, namely,
`grasses, weeds, animal dander, or trees: Kentucky
`bluegrass (Poa pratensis); short ragweed (Ambrosia
`artemisiifolia); cat dander (Felis domesticus); and elm
`
`800
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`JUNE 1998
`
`Page 4
`
`

`
`TABLE 1. Patient Demographics
`
`Olopatadine
`
`No. of subjects
`Sex (no. [%])
`Male
`Female
`Age (yrs)
`Mean
`Range
`Race (no. [%])
`White
`Black
`Asian
`Other
`Iris (no. [%])
`Brown
`Blue
`Hazel
`Green
`
`0.05%
`
`84
`
`30 (36)
`54 (64)
`
`39
`18–80
`
`77 (92)
`1 (1)
`0 (0)
`6 (7)
`
`30 (36)
`22 (26)
`4 (5)
`28 (33)
`
`0.1%
`
`85
`
`33 (39)
`52 (61)
`
`38
`19–75
`
`79 (93)
`2 (2)
`1 (1)
`3 (4)
`
`38 (45)
`16 (19)
`9 (11)
`22 (26)
`
`All
`Subjects
`
`169
`
`63 (37)
`106 (63)
`
`39
`18–80
`
`156 (92)
`3 (2)
`1 (1)
`9 (5)
`
`68 (40)
`38 (22)
`13 (8)
`50 (30)
`
`(Ulmus americana). Serial dilutions were made from
`allergen stock solutions containing 100,000 AU per
`mL, resulting in seven test dilutions ranging from 19
`to 1250 AU per 25-␮l dose of allergen. Phosphate-
`buffered saline solution was used as the diluent.
`Olopatadine ophthalmic solution and placebo (ve-
`hicle for olopatadine ophthalmic solution) were
`supplied by Alcon Laboratories.
`Safety assessments of olopatadine for studies 1
`and 2 included recording of both spontaneous and
`solicited adverse events throughout the study peri-
`ods. Adverse events were defined as any changes
`from baseline in a subject’s ophthalmic or medical
`health. The onset, duration, severity, and outcome
`of each adverse event were recorded. Serious ad-
`verse events were noted, and the relation of all
`adverse events to study drug administration was
`classified as definitely unrelated, unlikely, possible,
`probable, or definitely related. Serious events were
`defined as events that caused or prolonged hospital-
`ization, were life- or sight-threatening, or were fatal
`or permanently disabling. In addition, a congenital
`anomaly, cancer, or overdose was defined as a
`serious adverse event.
`A sign rank test was used to compare the primary
`efficacy variables,
`itching and redness,
`for each
`concentration of olopatadine with contralateral pla-
`
`cebo (paired sample) at each evaluation time after
`the conjunctival allergen challenge. The sum of
`scores for ciliary, conjunctival, and episcleral red-
`ness was used for the redness scoring.
`SAS version 6.1 (SAS Institute, Cary, North
`Carolina) was used for all calculations. Summary
`statistics were provided for each of the variables in
`the analyses. All hypothesis tests were conducted
`with a 0.05 probability of a type 1 error.
`
`RESULTS
`
`STUDY 1 EVALUATED FOUR CONCENTRATIONS OF OL-
`opatadine (0.01%, 0.05%, 0.1% and 0.15%). In
`preclinical tests, an olopatadine concentration of
`0.01% was the minimum effective dose, producing a
`50% inhibition (EC50) of histamine-stimulated vas-
`cular permeability in guinea pig conjunctiva when
`used at least 15 minutes before challenge. The EC50
`concentrations at 8 and 24 hours were 0.04% and
`0.11%, respectively.11 A concentration of 0.15%
`represents the upper limit of solubility of olopata-
`dine. Study 2 evaluated two concentrations of
`olopatadine (0.05% and 0.1%). Because the 0.01%
`and 0.15% concentrations were not the strongest
`candidates for a clinical formulation, and for ease of
`comparison of data, findings presented here from
`study 1 include only those for the 0.05% and 0.1%
`concentrations.
`A total of 169 subjects was enrolled in the two
`studies. Of those, 84 subjects were randomly as-
`signed to receive 0.05% olopatadine, and 85 sub-
`jects were randomly assigned to receive 0.1% ol-
`opatadine. Demographic data and eye color were
`similar for the two treatment groups. The mean age
`of study subjects was 38 years (range, 18 to 80
`years). A tabular summary of demographic data for
`both studies combined is presented in Table 1.
`All subjects in both studies received drug and
`were evaluable for the safety analyses. The efficacy
`analyses for the 27-minute and 8-hour conjunctival
`allergen challenges included those subjects who
`completed that particular visit. One subject in the
`0.05% olopatadine treatment group missed the third
`visit (onset-of-action challenge), and one subject in
`the 0.1% olopatadine treatment group was not
`evaluable at the fourth visit (duration-of-action
`
`VOL. 125, NO. 6
`
`COMBINED ANALYSIS OF TWO STUDIES
`
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`Page 5
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`

`
`FIGURE. Differences between itching (top) and redness (bottom) scores for 0.05% and 0.1% olopatadine-treated
`eyes compared with respective placebo-treated eyes. These differences were statistically significant (P < .05) at all
`time points after conjunctival allergen challenge. Positive difference values indicate that the placebo eye was worse.
`
`challenge) because of baseline redness scores greater
`than 1. In addition, 13 subjects, six in the 0.05%
`treatment group and seven in the 0.1% treatment
`group, discontinued the study before the fourth
`visit. Of those 13 subjects, five discontinued because
`of an adverse event unrelated to treatment (four in
`the 0.05% group, one in the 0.1% group); six
`discontinued for personal reasons (two in the 0.05%
`group, four in the 0.1% group); and two for other
`reasons not related to the use of the study drugs
`(both in the 0.1% group). Therefore, the efficacy
`analyses included 83 and 85 subjects for the 0.05%
`and 0.1% concentrations, respectively, at the third
`visit, and 77 and 78 subjects, respectively, at the
`fourth visit.
`Both concentrations of olopatadine were signifi-
`
`cantly more effective than placebo in inhibiting
`signs of allergic conjunctivitis when administered
`either 27 minutes or 8 hours before conjunctival
`allergen challenge (Figure). The mean itching and
`redness (the sum of scores for ciliary, conjunctival,
`and episcleral redness) scores were significantly
`(P ⬍ .05) lower in olopatadine-treated eyes com-
`pared with placebo-treated eyes at all time points (3,
`10, and 20 minutes) after the 27-minute and 8-hour
`challenges (Tables 2 and 3).
`There were no serious adverse events and no
`ocular or nonocular adverse events rated as possibly,
`probably, or definitely drug-related in either study.
`In study 2, five subjects were discontinued from the
`study before the fourth visit because of a nonserious,
`non–drug-related adverse event (influenza, back
`
`802
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
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`
`Page 6
`
`

`
`TABLE 2. Mean Itching and Redness Scores for the Onset-of-Action Challenge (Visit 3)
`
`Olopatadine 0.05%
`SEM
`Placebo for 0.05%
`SEM
`Olopatadine 0.1%
`SEM
`Placebo for 0.1%
`SEM
`
`N
`
`83
`
`83
`
`85
`
`85
`
`Mean (SD) Itching Scores
`
`Mean (SD) Redness Scores*
`
`3 min
`
`10 min
`
`20 min
`
`3 min
`
`10 min
`
`20 min
`
`0.52† (0.8)
`0.09
`1.86 (1.1)
`0.12
`0.57† (1)
`0.1
`1.96 (1)
`0.11
`
`0.42† (0.7)
`0.08
`2.14 (1.1)
`0.11
`0.58† (1)
`0.1
`2.32 (1)
`0.11
`
`0.34† (0.7)
`0.08
`1.8 (1.1)
`0.12
`0.44† (0.8)
`0.08
`1.69 (1)
`0.12
`
`1.42† (1.5)
`0.16
`3.4 (2.3)
`0.25
`1.41† (1.6)
`0.18
`3.75 (2.4)
`0.26
`
`2.87† (2.3)
`0.26
`5.54 (2.3)
`0.25
`3.19† (2.4)
`0.26
`6.06 (1.9)
`0.21
`
`3.2† (2.4)
`0.26
`5.52 (2.3)
`0.25
`3.66† (2.5)
`0.27
`5.82 (2.2)
`0.23
`
`*Mean redness scores constitute the sum of redness scores (0 to 4) from three vessel beds; therefore, the possible range is 0 to 12.
`†P ⫽ .0001 for comparison with placebo.
`
`TABLE 3. Mean Itching and Redness Scores for the 8-Hour Challenge (Visit 4)
`
`Olopatadine 0.05%
`SEM
`Placebo for 0.05%
`SEM
`Olopatadine 0.1%
`SEM
`Placebo for 0.1%
`SEM
`
`N
`
`77
`
`77
`
`78
`
`78
`
`Mean (SD) Itching Scores
`
`Mean (SD) Redness Scores*
`
`3 min
`
`10 min
`
`20 min
`
`3 min
`
`10 min
`
`20 min
`
`0.56† (0.7)
`0.08
`1.73 (1.1)
`0.12
`0.56† (0.8)
`0.09
`1.81 (0.9)
`0.1
`
`0.49† (0.7)
`0.08
`1.96 (1)
`0.12
`0.58† (0.8)
`0.09
`1.98 (1)
`0.11
`
`0.37† (0.6)
`0.07
`1.5 (1)
`0.11
`0.47† (0.8)
`0.09
`1.49 (1.1)
`0.12
`
`2.38† (1.8)
`0.2
`3.73 (2.2)
`0.25
`2.13† (1.9)
`0.21
`3.63 (2.1)
`0.23
`
`4.43† (2.3)
`0.26
`5.52 (2.3)
`0.26
`4.26† (2.1)
`0.24
`5.67 (1.7)
`0.19
`
`4.71† (2.5)
`0.29
`5.66 (2.2)
`0.26
`4.52† (2.1)
`0.24
`5.56 (1.8)
`0.21
`
`*Mean redness scores constitute the sum of redness scores (0 to 4) from three vessel beds; therefore, the possible range is 0 to 12.
`†P ⫽ .0001 for comparison with placebo.
`
`pain, spontaneous bone fracture, or sinusitis). Over-
`all, in study 1, three subjects experienced adverse
`events, none related to administration of study drug
`or placebo. Overall, in study 2, 10 of 60 subjects
`(16.7%) in the 0.05% olopatadine treatment group
`and nine of 60 subjects (15%) in the 0.1% olopatadine
`treatment group experienced adverse events, none
`related to administration of study drug or placebo. No
`clinically significant worsening in ocular signs, de-
`crease in visual acuity, or increase or decrease in pupil
`diameter occurred during either study.
`
`DISCUSSION
`
`TOPICAL OLOPATADINE SOLUTION WAS EFFECTIVE IN
`counteracting the ocular itching and in preventing
`
`the redness produced by allergen administration in
`the conjunctival allergen challenge. Both 0.05%
`and 0.1% concentrations of olopatadine showed
`rapid and prolonged action, producing significant
`(P ⬍ .05) reductions in itching and redness scores,
`compared with placebo, at all time points when
`administered 27 minutes or 8 hours before the
`conjunctival allergen challenge.
`Based on results of these studies, the duration of
`the ocular antiallergic action of olopatadine is at
`least 8 hours. This lengthy duration of action allows
`for twice daily administration, a schedule that is
`convenient for patients and should be associated
`with good patient compliance. The recommended
`administration schedule for most currently available
`ocular antiallergic agents such as levocabastine,
`lodoxamide, and ketorolac is four times daily.13
`
`VOL. 125, NO. 6
`
`COMBINED ANALYSIS OF TWO STUDIES
`
`803
`
`Page 7
`
`

`
`APPENDIX. Scoring of Ocular Symptoms and Signs*
`
`Score
`
`Description
`
`Itching (Scored by Subject)
`
`1.0
`
`0.0 None
`0.5
`Intermittent tickling sensation, possibly localized in corner
`of eye
`Intermittent tickling sensation, involving more than corner
`of eye
`Intermittent all-over tickling sensation
`1.5
`2.0 Mild, continuous itch (can be localized) without desire
`to rub
`2.5 Moderate, diffuse continuous itch with desire to rub
`3.0
`Severe itch with desire to rub
`3.5
`Severe itch, improved with minimal rubbing
`4.0
`Incapacitating itch with irresistible urge to rub
`
`Regional Redness—Ciliary, Episcleral, and Conjunctival Vessels
`0.0 None; normal, quiet eye
`1.0 Mild; slightly dilated blood vessels; vessel color pink;
`can be quadrantic
`2.0 Moderate; more apparent dilation of blood vessels;
`vessel color more intense (redder); involves most of
`vessel bed
`Severe; numerous and obvious dilated blood vessels;
`color deep red in absence of chemosis, may be less
`red or pink in presence of chemosis; not quadrantic
`Extremely severe; large, numerous dilated blood vessels
`characterized by unusually severe deep red color,
`which involves entire vessel bed
`
`3.0
`
`4.0
`
`*Increments of 0.5 were allowed for each variable.
`
`Both the 0.05% and 0.1% concentrations of
`olopatadine showed similar antiallergic activity in
`these studies. Olopatadine was well-tolerated by all
`subjects in both study 1 and study 2. No subject
`reported an ocular or nonocular adverse event
`considered to be related to administration of ol-
`opatadine or placebo.
`these two double-
`The combined results of
`masked, randomized, placebo-controlled studies in-
`dicate that olopatadine is an effective ocular anti-
`
`allergic agent with a rapid onset and prolonged
`duration of action with excellent tolerability. A
`0.05% or 0.1% concentration of olopatadine admin-
`istered twice daily was shown to be effective for
`treatment of allergic conjunctivitis.
`
`REFERENCES
`
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`ments, and author responses are posted.
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`804
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`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`JUNE 1998
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`Page 8