Key words: Conjunctival allergen challenge – Levocabastine – Ocular allergy – Olopatadine
SUMMARY
Objective: To compare the efficacy of olopatadine and levocabastine in reducing ocular allergic itching and vascular hyperemia (redness) induced by conjunctival allergen challenge.
Research design and methods: The study was a randomized, double- masked, contralateral study using the conjunctival allergen challenge (CAC) model. At Visit 1, subjects with a positive allergen skin test and a history of allergic conjunctivitis were administered increasing concentrations of allergen until at least a moderate grade 2 ocular itching and conjunctival redness response was obtained in both eyes. Allergic signs were graded on standardized 0- 4 scales. Subjects who reacted positively were re-challenged at Visit 2 with the pre-determined concentration of allergen. Subjects who again responded with at least a grade 2 bilateral ocular itching and conjunctival redness score at Visit 2 were eligible for drug evaluation. At Visit 3, subjects received olopatadine in one eye and levocabastine in the contralateral eye according to a computer- generated randomization scheme generated prior to commencement of the study. Ocular discomfort was then graded in both eyes. Subjects were bilaterally challenged with the predetermined concentration of allergen 27 min after topical drug administration, such that the first post-challenge assessment was made 30 min post-drug instillation. Allergic signs and symptoms were evaluated at 3 min, 10 min, and 20 min post-challenge and safety and efficacy analyses were performed.
Results: Sixty-eight subjects received study drug and were included in the safety and efficacy analyses. Ocular itching scores for olopatadine were significantly lower than levocabastine at 3 min and 10min post-challenge (p
Conclusion: Olopatadine treated eyes had significantly less itching and redness than levocabastine treated eyes after conjunctival allergen challenge. Olopatadine was also associated with less discomfort upon instillation than levocabastine.
Introduction
The signs and symptoms of allergic conjunctivitis can be inhibited by modulating the allergic process at various levels ranging from tear dilution, to local vascular constriction, to inhibition of mediator activity after release, and, ultimately, inhibiting the mast cell from reacting in the presence of a sensitizing agent. The most non-specific of these is washing and dilution of antigen and mediators from the eye with tear substitutes. The notable anti-allergic benefit received from topical placebo in clinical ocular allergic trials can be attributed to this cleansing effect. Pharmacologie agents used for allergy therapy can be topical alpha-adrenergic agonists, which act to locally constrict blood vessels in the conjunctiva and whiten the eye^sup 1-3^. However, these agents have a limited duration of action; considering their indicated dosing frequency, they may not provide all-day coverage for prevention of allergy signs and symptoms. These agents should also be used with caution since a rebound effect may be demonstrated with topical ocular use. Vasoconstrictors are usually used in association with topical H^sub 1^ histamine receptor antagonists that competitively block histamine receptors on nerve endings and vascular tissue, thus inhibiting ocular itching, as well as redness and swelling in the more powerful and newer agents. Histamine is known to be the quintessential mediator responsible for the signs and symptoms of seasonal and perennial allergic conjunctivitis4,5.
Levocabastine 0.05% (Livostin* 0.05% levocabastine hydrochloride ophthalmic suspension, Novartis Ophthalmics, East Hanover, NJ) is a topical ocular H^sub 1^ antihistamine indicated for the relief of the signs and symptoms of seasonal allergic conjunctivitis. Clinical studies have shown the duration of action to be at least four hours6,7 and the recommended dose is one drop instilled in each eye four times per day8.
Prevention of mast cell degranulation is the ultimate goal in the pharmacological intervention of allergy. Topical mast cell stabilizers available for use in the eye, such as cromolyn sodium, nedocromil, pemirolast, and lodoxamide tromethamine, act by inhibiting degranulation of the mast cell and release of pro- inflammatory mediators of allergic conjunctivitis. The mast cell is known to play a primary role in the pathogenesis of immediate hypersensitivity reactions9-13. Allergens bind to IgE antibodies on the mast cell surface, causing changes in membrane calcium transit that lead to disruption of the cell membrane and spilling of the mast cells’ contents into the extracellular space. Mast cell stabilizers are thought to interfere with this calcium step in cell membrane destabilization. Clinical benefit is derived from these agents if used prophylactically, so these agents should be used for a loading period prior to allergen exposure.
Olopatadine 0.1% (Patanol[dagger] olopatadine hydrochloride ophthalmic solution 0.1%, Alcon Laboratories, Fort Worth, TX) was the first topical ocular anti-allergy agent developed specifically for use in the eye. It confers a dual mechanism of action, acting as an H^sub 1^ receptor antagonist and stabilizer of conjunctival mast cells. Due to this unique dual activity, olopatadine can bind to conjunctival H^sub 1^ receptors, inhibiting histamine’s immediate vascular and neuronal activity and providing rapid relief of itching, redness, and swelling. Simultaneously, the molecule also stabilizes conjunctival mast cells to prevent further waves of mast cell activation and degranulation. Clinical data indicate that the duration of action of olopatadine 0.1% is at least 12 h^sup 14^. Product labeling recommends one drop two times per day, or every 6h- 8h8.
Evaluation of the clinical efficacy of ocular anti-allergy therapies can be a difficult process due to the variety of environmental factors that influence the ocular allergic response. Conjunctival allergen challenge (CAC) has been validated as a standard allergic conjunctivitis model15 that reliably produces the signs and symptoms of the disease in a consistent and reproducible manner for all subjects16-21. The strict grading system with photographic documentation mitigates the subjectivity of rating signs and symptoms. The CAC model is ideal for evaluating the onset and duration of action of anti-allergic drugs.
In the present study, the efficacy of olopatadine was compared to levocabastine in the treatment of ocular itching and redness elicited by conjunctival allergen challenge. Since levocabastine has a shorter duration of action6,7, only time points within one hour of medication dosing were evaluated, as both drugs should have been at peak activity at these times.
Subjects and methods
Subjects
This was a randomized, double-masked, single-center study. The investigators obtained Institutional Review Board (IRB) approval for both the protocol and informed consent before study initiation. Subjects with a history of seasonal allergic conjunctivitis and a positive diagnostic test for allergic disease (skin test) for grasses, trees, cat hair and dander, or ragweed within the previous 24 months were eligible for enrolment.
During the course of the study, and for appropriate wash-out periods, subjects were not allowed to use any other eye drops or systemic medications that could affect the outcome of the study (ie. topical or systemic antihistamines, mast cell stabilizers, or corticosteriods). Subjects were excluded if any systemic or ocular diseases were present that could have interfered with the conduct of the study. In addition, all subjects were at least 18 years of age and had no known sensitivity to any of the medications used in the study.
At the first study visit, subjects read and signed the IRB- approved consent form. Inclusion/exclusion criteria were verified for each subject and medical and medication history was collected onto the appropriate case report forms. Since pregnancy was an exclusion criterion, women of childbearing potential were given a pregnancy test. Clinical research staff were responsible for data collection on forms, and the same ophthalmologist was assigned to evaluate subjects at all three visits.
Each subject received a visual acuity evaluation, a fundus examination and a biomicroscopic slit-lamp examination of the ocular surface, cornea, anterior chamber, and iris. Gross and biomicroscopic examination allowed evaluation of baseline ocular redness in conjunctival, ciliary and episcleral vessel beds assessed separately on a standardized grading scale ranging from 0 (none) to 4 (extremely severe). Itching was graded by subjects on a scale of 0 (none) to 4 (severe).
Subjects who presented with any itching or with redness greater than grade 1 in either eye in any vessel bed at baseline were ineligible to continue in the study.
The threshold concentration of allergen needed to elicit a sufficient (bilateral grade 2 redness and itching) allergic reaction wa\s determined as previously described16 and confirmed at Visit 2. At the end of Visits 1 and 2, one or two drops of a commercially available antihistamine/decongestant combination (usually VasoconA) were instilled into each eye for relief of allergic signs and symptoms when necessary for relief of any temporary discomfort from allergen challenge.
After 14 3 days, subjects returned for the Visit 3 drug evaluation. Visual acuity was determined and the ocular surface, cornea, anterior chamber, and iris were evaluated as at previous visits. Subjects who presented with any itching or redness greater than grade 1 in either eye were ineligible for the study. Qualifying subjects were then randomly assigned to receive olopatadine 0.1% hydrochloride ophthalmic solution (Alcon Laboratories; Fort Worth, TX) in either the right or left eye and levocabastinc 0.05% hydrochloride ophthalmic suspension (Novartis; East Hanover, NJ) in the contralateral eye. Randomization schedules were computer generated by an independent technician. Two drops of masked study drug from a bottle labeled ‘Right Eye’ were instilled in the right eye and two drops of study drug from a bottle labeled ‘Left Eye’ were instilled in the left eye according to the randomization table. Immediately after drug instillation, ocular discomfort was recorded, if present, as an adverse event.
Twenty-seven minutes after drug instillation, subjects were challenged in each eye with the allergen concentration determined at Visit 1 and confirmed at Visit 2. This time point was chosen such that the post-allergen challenge evaluations 3 min, 10 min, and 20min after CAC occurred 30 min, 37 min, and 47 min after drug administration. This protocol assured that both drugs were assessed at their peak activity, ocular itching and redness were evaluated as at Visits 1 and 2. At the end of Visit 3, subjects received one or two drops of an antihistamine/decongestant for relief of allergic signs and symptoms if necessary.
Adverse events, both spontaneous and solicited, were recorded throughout the study. Adverse events were defined as any untoward changes from baseline in a subject’s ophthalmic or medical health, with the exception of the efficacy parameters (itching and redness). Specific safety parameters included visual acuity, ocular surface, cornea, anterior chamber, iris, and fundus evaluations.
Statistical Analysis
The primary efficacy variables evaluated in the study were itching and redness. While chemosis, lid swelling, and tearing are all signs and symptoms that significantly decrease with anti- allergy therapy, itching and redness are the sign and symptom of primary concern to patients and in previous studies have demonstrated the greatest significant change from control values. A sum redness score was calculated from the conjunctival, ciliary, and episcleral redness scores as previously described16. Statistically significant differences between the treatment arms were identified.
Analyses of variance were conducted with a 0.05 probability of a type 1 error. The software program, SAS v6.12, was used by an impartial external statistician for analyses of itching, conjunctival, ciliary, and episcleral redness, and sum redness scores. Descriptive statistics were provided for each of the variables. The demographic characteristics of subjects in each treatment group (i.e., age, sex, race, iris color) were tabulated.
Results
Sixty-eight (68) subjects completed the study: mean age was 37 years with a range of 18 years-67 years; 54.4% (37) subjects were male and 45.6% (31) were female. All subjects were Caucasian.
Olopatadine treated eyes had significantly less itching (analysis of variance, p
Similar results were obtained for redness. Conjunctival, episcleral and ciliary hyperemia were all significantly less (p ≤ 0.002) in olopatadine-treated eyes than in levocabastine- treated eyes at 3 min, 10 min, and 20min post-challenge (Table 1). The sum redness score was also significantly less at all three time points postchallenge (p
Adverse events related to olopatadine and levocabastine were mild and easily tolerable. No serious adverse events occurred during the study, and no subject was discontinued from the study due to an adverse event. Of the 68 subjects, one (1.5%) experienced ocular pruritis after drug administration. This was categorized as possibly related to the use of levocabastine. No ocular adverse events, other than discomfort, were noted. No clinically significant decrease in visual acuity or changes in ocular signs were observed.
A spontaneous complaint of burning or stinging was more frequent immediately after levocabastine versus olopatadine administration. Of the 68 subjects who were exposed to both drugs, three (4.41%) reported ocular discomfort in the olopatadine eye and 18 (26.5%) in the levocabastine treated eye. These data were not analyzed statistically.
Figure 1. Average itching score: olopatadine was significantly more effective than levocabastine in reducing ocular itching at 3 min and 10min after drug instillation (*p ≤ 0.001). The standardized scale on which subjects rated their ocular itching ranged from 0 (none) to 4 (severe)
Discussion
Conjunctival hyperemia and itching are the defining sign and symptom of ocular allergy. Itching, in particular, is the hallmark of ocular allergy; in the absence of all other signs, the presence of ocular itching is considered diagnostic for allergy. The results of this clinical trial demonstrate that olopatadine causes a greater reduction in peak ocular itching than levocabastine. Ocular redness, determined as the sum redness score, or in individual vascular beds (conjunctival, ciliary, episcleral) was also significantly less in olopatadine versus levocabastine treated eyes. Redness can be considered a more general outcome of mast cell degranulation, since vascular dilation and leakage is elicited not only by histamine but also through the contribution of a variety of inflammatory mediators. The greater efficacy of olopatadine in reducing redness in all quadrants and at all time points may be due to mast cell stabilization and histamine receptor blockage eliciting a greater impact on inhibition of the histamine-mediated allergic response.
Ophthalmic antihistamines have greatly evolved over the last 20years. Traditionally, first generation molecules such as antazoline and pheniramine were uncomfortable upon instillation, with weak and non-specific histamine receptor binding leading to ocular drying, little efficacy and a short (2h) duration of effect. Levocabastine was a welcome improvement to these molecules since it offered a more comfortable formulation and a longer-acting and more efficacious treatment. This pharmacological evolution continued with the introduction of olopatadine, shown in pre-clinical and clinical studies to be a highly selective, potent, and long acting H^sub 1^ antagonist as well as a stabilizer of mast cells22,23. Its clinical efficacy in preventing mast cell degranulation has been documented by significant decreases in tear histamine levels, neutrophils, eosinophils, lymphocytes, and ICAM 1 expression in olopatadine- treated eyes after allergen challenge24. In comparative CAC trials similar to the present study, olopatadine was shown to be more effective in reducing the signs and symptoms of allergy than systemic loratadine25, nedocromil (mast cell stabilizer)26, loteprednol (corticosteroid)27, azelastine28, ketotifen29 and epinastine30 (dual mechanism molecules).
Table 1. Mean ( standard deviation of the mean) ocular redness scores in olopatadine and levocabastine-treated eyes 3 min, 10 min, and 20 min after conjunctival allergen challenge of sensitized individuals (N = 68)
Figure 2. Average redness score: olopatadine was significantly more effective than levocabastine in reducing ocular redness 3 min, 10 min, and 20 min after drug instillation (*p
Levocabastine is widely used throughout the world, and yet a direct comparison of olopatadine with levocabastine had never been performed. In clinical allergic conjunctivitis trials, levocabastine has been shown to have comparable activity to azelastine31 and lodoxamide32 and to be not significantly different from epinastine33.
Subjects complained of ocular discomfort with less frequency in the olopatadine versus levocabastine treated eyes. This greater comfort may be a clinical advantage in children or other particularly sensitive individuals such as dry eye patients with allergy.
In summary, olopatadine and levocabastine were both safe and well tolerated. One drop of olopatadine was shown at time points within one hour of drug administration to be significantly more effective than levocabastine in reducing ocular itching and redness induced by conjunctival allergen challenge.
Acknowledgments
This study was supported by an unrestricted research grant from Alcon Laboratories, Inc., Fort Worth, Texas.
* Livostin is a registered tradename of Novartis Ophthalmics, East Hanover, NJ
[dagger] Patanol is a registered tradename of Alcon Laboratories, Fort Worth, TX
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-2707_4, Accepted for publication: 08 August 2004
Published Online: 16 November 2004
doi:10.1185/030079904X5724
Mark B. Abelson1,2,3 and Jack V. Greiner2,3
1 Ophthalmic Research Associates, North Andover, MA, USA
2 Schepens Eye Research Institute, Boston, MA, USA
3 Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
Address for correspondence: Dr Jack V. Greiner, Ophthalmic Research Associates, 863 Turnpike St., North Andover, MA 01845, USA
Copyright Librapharm Dec 2004
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