- Email: [email protected]
A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model
CLINICALTHERAPEUTICS"NOL.22,NO.7,2000
A Comparison of the Relative Efficacy and Clinical Performance of Olopatadine Hydrochloride 0.1% Ophthalmic Solution and Ketotifen Fumarate 0.025 % Ophthalmic Solution in the Conjunctival Antigen Challenge Model Gregg J. Berdy, MD, ‘J Dennis L. Spangler, MD,3 George Bensch, MD,4 Susan S. Berdy, MD,5 and Robert C. Brusatti, OD2 ‘Departmen t of 0 p hthalmology, Washington University School of Medicine, St. L.ouis, and 20phthalmology Associates, Creve Coeur, Missouri, 3Atlanta Allergy and Asthma Clinic, Atlanta, Georgia, 4Allergy, Immunology and Asthma Group, Stockton, California, and SDepartment of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri ABSTRACT Objective: The purpose of this study was to compare the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. Methods: This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Of the 53 subjects screened, 32 were enrolled and completed the study. The study comprised 3 visits. Primary efficacy variables were ocular itching (assessed at visits 2 and 3) and subject satisfaction (assessed at visit 3). Tolerability variables were slit-lamp findings (all visits), visual acuity (all visits), ocular comfort after drug instillation (visit 3), and adverse events (visits 2 and 3). At visit 1, the antigen concentration that elicited a positive ocular allergic response was determined, and this concentration was confirmed at visit 2. Subjects graded itching on a 5-point scale at 3, 5, and 10 minutes postchallenge. The scores from this visit were used as baseline scores and compared with scores from visit 3 to determine drug efficacy. At visit 3, subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and 1 drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Following drug instillation, the subjects assessed the comfort level in each eye. Twelve hours after instillation, subjects were challenged with the antigen concentration that elicited a positive response at the previous visits. Itching was subjectively graded at 3, 5, and 10 minutes postchallenge. Subjects were asked to choose which therapy they were more satisfied with. Accepted for publication May 17, 2000. Printed in the USA. Reproduction in whole
826
or part is not permitted.
0149.2918/00/$19.00
G.J. BERDY
ET AL.
Results: Twelve hours after administration, efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; PcO.05). Olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen immediately after drug instillation (1.25 vs 2.09; P < 0.05) and 12 hours later, as measured by patient ratings of ocular comfort. Of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine than with ketotifen. Conclusions: Olopatadine is more effective than ketotifen in reducing the itching associated with allergic conjunctivitis in the antigen challenge model. Olopatadine caused less ocular discomfort than ketotifen and was preferred by -3 times as many patients as was ketotifen. Key words: olopatadine, ketotifen, conjunctival allergen challenge, ocular allergy. (CZin Z’her. 2000;22:826-833) INTRODUCTION The prevalence of allergic disease, including allergic sinusitis, allergic rhinitis, and ocular allergy, is currently estimated at 20% worldwide and is increasing.’ This trend has stimulated interest in ocular antiallergic therapy, resulting in the development of new, more potent agents that effectively control the disease.2 Ocular allergy is a complex disease that can have both acute and chronic forms3 An estimated 90% of patients with ocular allergy experience seasonal allergic conjunctivitis (SAC) or perennial allergic conjunctivitis and may experience allergic sinusitis and/or rhinitis in addition to ocular symptoms. Although ocular allergy does not threaten vision, the symptoms can be ex-
tremely irritating and can substantially affect quality of life. SAC is a type I hypersensitivity reaction in which antigens bind to specific immunoglobulin (IgE) receptors on conjunctival mast cells, resulting in their degranulation and a subsequent release of inflammatory mediators. The most important of these mediators is histamine. Histamine binds to Hi receptors, which results in ocular redness, itching, and chemosis, as well as swelling of the eyelids. Several classes of ocular allergy medications inhibit the pro-allergic/proinflammatory activities of immune cells4 A new class of antiallergic agents combines the 2 primary mechanisms of action attributed to these compounds: mast cell stabilization and histamine H,-receptor inhibition.5 These drugs are particularly effective in the treatment of ocular allergy because they provide immediate relief of symptoms through histamine antagonism, which traditional mast cell stabilizers do not, and also moderate the disease by preventing mast cell degranulation. Currently, there are 2 agents approved in the United States that fall into this class: olopatadine hydrochloride 0.1 %* and ketotifen fumarate 0.025%.+ Both olopatadine” and ketotifen’ have been shown to be clinically efficacious and well tolerated. The purpose of this study was to compare their efficacy in relieving symptoms of ocular allergy 12 hours after drug administration in a conjunctival antigen challenge model. Patients’ comfort level immediately after instillation of each ophthalmic formulation and patient satisfaction with the treatment were also assessed. *Trademark: Patanol@ (Alcon Laboratories, Worth, Texas). +Trademark: Zaditor@ (CIBA%ion, Duluth,
Inc., Fort Georgia).
827
CLINICAL
PATIENTS AND METHODS This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Subjects were recruited from a database of patients who were previously involved in ocular allergy studies. Of the 53 subjects screened, 32 were enrolled and completed the study; 17 subjects did not meet the inclusion criteria and 4 were lost to follow-up. The study was approved by the Western Institutional Review Board, and written informed consent was obtained from all subjects. Visit I: Baseline Screening (Day 0) This study followed a standardized antigen challenge protocol8 Demographic data and visual acuity (Early Treatment Diabetic Retinopathy Study) were recorded. A urine pregnancy test was given to all women of childbearing potential. A slitlamp examination was performed to exclude all subjects with baseline ocular redness (redness in any vessel bed rated >l on a 5-point scale, where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = unusually severe) or any itching in either eye. Subjects were not allowed to use any eyedrops (except those instilled by study technicians) for the duration of the study, have any active ocular disease, or use any systemic medication that could affect the outcome of the study (eg, antihistamines or corticosteroids). A conjunctival antigen challenge (CAC) was performed bilaterally with an allergen to which the subject tested positive in a skin test, or had reacted to in a previous study. The allergen concentration was increased until a positive reaction was elicited bilaterally (redness graded 22 in any vessel bed and itching 828
THERAPEUTICS”
graded 22). Any subject who did not react positively was excluded from the study. Itching was graded on a 5-point scale (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = unusually severe) by the subject at 3, 5, and 10 minutes after the CAC. If needed, the subject received a dose of a currently marketed topical ophthalmic antiallergic agent (pheniramine maleate 0.3%/naphazoline hydrochloride 0.025% ophthalmic solution*) to relieve any immediate discomfort caused by the allergic reaction. Visit 2: Confirmation Results (Day 7 -c2)
of Allergen Test
Medical and medication history were updated and visual acuity was recorded. A slit-lamp examination was performed to exclude subjects with baseline conjunctival redness (redness graded ~1 in any vessel bed) or any itching in either eye. The CAC was again performed bilaterally using the allergen concentration that elicited a positive reaction at the previous visit. Any subject who did not react positively was excluded from the study. Itching was graded as previously described. Again, if needed, the subject received a dose of a currently marketed topical antiallergic agent to relieve any immediate discomfort caused by the allergic reaction. Visit 3: Drug Evaluation (Day 21 f 3) Medical and medication histories were updated and visual acuity was recorded. A slit-lamp examination was performed to exclude subjects with active allergic conjunctivitis (redness graded 21 in any vessel bed or any itching in either eye). *Trademark: Fort Worth,
Naphcon@ Texas).
A (Alcon
Laboratories,
Inc.,
G.J. BERDY
ET AL.
Subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and 1 drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Immediately after drug instillation, subjects were asked to grade, on a 9-point scale (0 = comfortable and 8 = uncomfortable), the comfort level in each eye. Twelve hours after instillation, a CAC was performed using the concentration that elicited positive responses at visits 1 and 2. Itching was subjectively graded as previously described. Following the subjective assessment of itching, subjects completed a Quality of Life Assessment. Subjects were then asked which drop they preferred. Again, if needed, subjects were administered a dose of a currently marketed, ophthalmic antiallergic preparation to relieve any immediate discomfort caused by the challenge. Statistical Analysis Data from all subjects who received drug were considered evaluable for comfort and efficacy analyses. Mean itching scores at visit 3 were compared between treatments. Mean efficacy scores provided a measure of clinical efficacy of a drug treatment for ocular itching. It was defined as the difference between the mean itching score at visit 2 (baseline) and the mean itching score at visit 3. Mean ocular comfort scores at visit 3 immediately following instillation of the drops were compared between treatments. Paired t tests were performed on the mean itching, efficacy, and ocular comfort score comparisons at each time point. Two-sided statistical tests were used, and P 5 0.05 was considered statistically significant.
RESULTS Olopatadine was significantly more effective than ketotifen at all time points (3, 5, and 10 minutes) in reducing the itching induced by the CAC (P < 0.05) (Figure 1). Compared with baseline scores of itching (visit 2), the mean efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; P < 0.05) (Figure 2). When subjects were asked to grade (on a scale from 0 to 8) the comfort level in each eye immediately following drug instillation, olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen ( 1.25 vs 2.09; P < 0.05) (Figure 3). After administration of the ophthalmic drops, subjects were asked to state which eye was more comfortable. This subjective evaluation was done before the antigen challenge and was designed to measure only the ocular tolerability of the drop. Of the 22 subjects who had a preference, 16 (73%) identified olopatadine and 6 (27%) identified ketotifen as the more tolerable (ie, causing less ocular discomfort) formulation. At the conclusion of the study, subjects were asked to identify the product that was more satisfactory in terms of efficacy and comfort. Again, of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine and 6 (27%) were more satisfied with ketotifen. DISCUSSION The mast cell stabilizer/antihistamine combination is the newest drug class in ocular allergy therapy.4 These drugs are effective in reducing the itching associated with the acute phase of ocular allergy, preventing subsequent mast cell ac-
829
CLINICAL
THERAPEUTICS@
W Olopatadine Ketotifen
2.5
2.0 s? 8 * 7
1.5
2
g s
1.0
2 0.5
0 3
5
10
Time (min) Postchallenge
Figure 1. Mean itching scores for eyes treated with olopatadine versus ketotifen at 3, 5, and 10 minutes postchallenge (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = unusually severe). Challenge was conducted 12 hours after drug instillation. Mean itching scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). U Olopatadine Ketotifen
$ 03
2.5
6
2.0
.-2 =
1.5
s a, 2
1.0 0.5
3
5
10
Time (min) Postchallenge
Figure 2. Mean efficacy scores for eyes treated with olopatadine versus ketotifen at 3, 5, and 10 minutes postchallenge. Efficacy score is defined as the difference between the mean itching score at visit 2 (untreated baseline) and the mean itching score at visit 3 (after drug treatment). Mean efficacy scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). 830
G.J. BERDY ET AL.
Olopatadine
Ketotifen
Figure 3. Mean comfort scores immediately following drug instillation (0 = comfortable and 8 = uncomfortable). Mean comfort scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). tivation, and, potentially, inhibiting or minimizing late-phase reactions.5-7g9 The currently approved indication for olopatadinelo and ketotifentt is the treatment of itching associated with allergic conjunctivitis. Although the efficacy and tolerability of these 2 agents have been demonstrated in clinical studies,5*6 the results of the present study indicate that there are differences in effectiveness and tolerability between these agents, as measured by subjective evaluations of ocular comfort. In this antigen challenge model, olopatadine was shown to be significantly more effective than ketotifen (P < 0.05) in reducing ocular itching induced by a conjunctival antigen 12 hours after instillation. This differential effect on itching suggests that olopatadine binds to a significantly higher number of H, receptors than does ketotifen, since the ability of an ocular allergy medication to relieve itching is mediated solely by H, receptors on nerve cells.‘* Although preclinical data on
the HI-receptor binding of these drugs is important in drug development, the antigen challenge model provides the clinical relevance needed to evaluate the efficacy of these H,-receptor antagonists in viva.* In a study comparing these 2 drugs in the environmental model, olopatadine used twice daily was found to be more effective in controlling itching over a 14day period (Alejandro J. Aguilar, Buenos Aires, Argentina, personal communication, September 13, 1999). This study used the 0.05% concentration of ketotifen (available in Japan and South America) and not the 0.025% concentration approved in the United States. Yet even at this higher dose, ketotifen’s clinical efficacy at 12 hours postdose was inferior to that of olopatadine. This difference in efficacy may be explained by the greater bioavailability of olopatadine or its superior ability to stabilize mast cells. Furthermore, histamine antagonism by ketotifen appears to be biphasic, whereas 831
CLINICAL THERAPEUTICS”
olopatadine is known to inhibit histamine release in a dose-dependent manner.5v9 Another important finding of this study was the subjects’ superior comfort level with olopatadine versus ketotifen. These results confirmed those of a previous “forced choice” study, which reported that 100% of subjects were more comfortable with olopatadine than with ketotifen (Jo& Domingo Luna, MD, Fundacion VER Casilla de Correo, Cordoba, Argentina, personal communication, November 24,1999). The superior comfort level with olopatadine reported by subjects in the present study may indicate an increased likelihood of patient compliance, which may lead to better control of the allergic disease. When subjects were further questioned as to their overall satisfaction with the ophthalmic formulations in terms of efficacy and comfort, the majority of subjects who indicated a preference preferred olopatadine. The longterm efficacy of these formulations in relieving symptoms of allergic conjunctivitis as well as patient satisfaction with these products should be studied in an environmental model to confii these results. CONCLUSIONS Both olopatadine and ketotifen are approved for the relief of ocular itching associated with allergic conjunctivitis. In this study, olopatadine was shown to be more effective and cause less ocular discomfort than ketotifen in the conjunctival antigen challenge model of allergic conjunctivitis, as measured by subjective ratings of efficacy and comfort. ACKNOWLEDGMENT This paper was supported by a grant from Alcon Laboratories, Inc., Fort Worth, Texas. 832
Address correspondence to: Gregg J. Berdy, MD, Ophthalmology Associates, 456 North New Ballas Rd., Suite 386, Creve Coeur, MO 63 14 1. REFERENCES 1. Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr Allergy. 1987;21:l-20. 2. Yanni JM, Sharif NA, Gamache DA, et al.
A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: Effects of new topical ocular drugs. Acta Ophthalmol Stand. 1999;77: 33-37. 3. Collum LM, Kilmartin DJ. Acute allergic conjunctivitis. In: Abelson MB, ed. Allergic Diseases of the Eye. Philadelphia, Pa:
WB Saunders;2000: 108-132. 4. Berdy GJ, Abelson MB. Antihistamines
and mast cell stabilizersin allergic ocular disease.In: Albert DM, Jakobiec FA, eds. Principles
and Practice
of Ophthalmol-
ogy. Philadelphia,Pa:WB Saunders;2ooO: 306-318. 5. Yanni JM, Miller ST, Gamache DA, et al.
Comparative effects of topical ocular antiallergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol. 1997; 79541-545. 6. Abelson MB. Evaluation of olopatadine, a
new ophthalmic antiallergic agent with dual activity, using the conjunctival atlergen challenge model. Ann Allergy Asthma Immunol. 1998;81:211-218. 7. Femandez M, Wong E, Oehling A. Retro-
spective study of ketotifen protective action in different allergopathies. Allergol lmmunopathol (Madr). 1987;15:369-373.
G.J. BERDY
ET AL.
8. Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge: A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990;108:84-88. 9. Yanni JM, Stephens DJ, Miller ST, et al. The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther. 1996;12:389-400.
10. Patanol@ [package insert]. Fort Worth, Tex: Alcon Laboratories, Inc; 1999. 11. Zaditof [package insert]. CIBA Vision: 1999.
Duluth,
Ga:
12. Abelson MB, Udell IJ, Aliansmith MR, et al. Allergic and toxic reactions. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Philadelphia, Pa: WB Saunders; 2000:78 l-802.
833
A Comparison of the Relative Efficacy and Clinical Performance of Olopatadine Hydrochloride 0.1% Ophthalmic Solution and Ketotifen Fumarate 0.025 % Ophthalmic Solution in the Conjunctival Antigen Challenge Model Gregg J. Berdy, MD, ‘J Dennis L. Spangler, MD,3 George Bensch, MD,4 Susan S. Berdy, MD,5 and Robert C. Brusatti, OD2 ‘Departmen t of 0 p hthalmology, Washington University School of Medicine, St. L.ouis, and 20phthalmology Associates, Creve Coeur, Missouri, 3Atlanta Allergy and Asthma Clinic, Atlanta, Georgia, 4Allergy, Immunology and Asthma Group, Stockton, California, and SDepartment of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri ABSTRACT Objective: The purpose of this study was to compare the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. Methods: This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Of the 53 subjects screened, 32 were enrolled and completed the study. The study comprised 3 visits. Primary efficacy variables were ocular itching (assessed at visits 2 and 3) and subject satisfaction (assessed at visit 3). Tolerability variables were slit-lamp findings (all visits), visual acuity (all visits), ocular comfort after drug instillation (visit 3), and adverse events (visits 2 and 3). At visit 1, the antigen concentration that elicited a positive ocular allergic response was determined, and this concentration was confirmed at visit 2. Subjects graded itching on a 5-point scale at 3, 5, and 10 minutes postchallenge. The scores from this visit were used as baseline scores and compared with scores from visit 3 to determine drug efficacy. At visit 3, subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and 1 drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Following drug instillation, the subjects assessed the comfort level in each eye. Twelve hours after instillation, subjects were challenged with the antigen concentration that elicited a positive response at the previous visits. Itching was subjectively graded at 3, 5, and 10 minutes postchallenge. Subjects were asked to choose which therapy they were more satisfied with. Accepted for publication May 17, 2000. Printed in the USA. Reproduction in whole
826
or part is not permitted.
0149.2918/00/$19.00
G.J. BERDY
ET AL.
Results: Twelve hours after administration, efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; PcO.05). Olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen immediately after drug instillation (1.25 vs 2.09; P < 0.05) and 12 hours later, as measured by patient ratings of ocular comfort. Of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine than with ketotifen. Conclusions: Olopatadine is more effective than ketotifen in reducing the itching associated with allergic conjunctivitis in the antigen challenge model. Olopatadine caused less ocular discomfort than ketotifen and was preferred by -3 times as many patients as was ketotifen. Key words: olopatadine, ketotifen, conjunctival allergen challenge, ocular allergy. (CZin Z’her. 2000;22:826-833) INTRODUCTION The prevalence of allergic disease, including allergic sinusitis, allergic rhinitis, and ocular allergy, is currently estimated at 20% worldwide and is increasing.’ This trend has stimulated interest in ocular antiallergic therapy, resulting in the development of new, more potent agents that effectively control the disease.2 Ocular allergy is a complex disease that can have both acute and chronic forms3 An estimated 90% of patients with ocular allergy experience seasonal allergic conjunctivitis (SAC) or perennial allergic conjunctivitis and may experience allergic sinusitis and/or rhinitis in addition to ocular symptoms. Although ocular allergy does not threaten vision, the symptoms can be ex-
tremely irritating and can substantially affect quality of life. SAC is a type I hypersensitivity reaction in which antigens bind to specific immunoglobulin (IgE) receptors on conjunctival mast cells, resulting in their degranulation and a subsequent release of inflammatory mediators. The most important of these mediators is histamine. Histamine binds to Hi receptors, which results in ocular redness, itching, and chemosis, as well as swelling of the eyelids. Several classes of ocular allergy medications inhibit the pro-allergic/proinflammatory activities of immune cells4 A new class of antiallergic agents combines the 2 primary mechanisms of action attributed to these compounds: mast cell stabilization and histamine H,-receptor inhibition.5 These drugs are particularly effective in the treatment of ocular allergy because they provide immediate relief of symptoms through histamine antagonism, which traditional mast cell stabilizers do not, and also moderate the disease by preventing mast cell degranulation. Currently, there are 2 agents approved in the United States that fall into this class: olopatadine hydrochloride 0.1 %* and ketotifen fumarate 0.025%.+ Both olopatadine” and ketotifen’ have been shown to be clinically efficacious and well tolerated. The purpose of this study was to compare their efficacy in relieving symptoms of ocular allergy 12 hours after drug administration in a conjunctival antigen challenge model. Patients’ comfort level immediately after instillation of each ophthalmic formulation and patient satisfaction with the treatment were also assessed. *Trademark: Patanol@ (Alcon Laboratories, Worth, Texas). +Trademark: Zaditor@ (CIBA%ion, Duluth,
Inc., Fort Georgia).
827
CLINICAL
PATIENTS AND METHODS This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Subjects were recruited from a database of patients who were previously involved in ocular allergy studies. Of the 53 subjects screened, 32 were enrolled and completed the study; 17 subjects did not meet the inclusion criteria and 4 were lost to follow-up. The study was approved by the Western Institutional Review Board, and written informed consent was obtained from all subjects. Visit I: Baseline Screening (Day 0) This study followed a standardized antigen challenge protocol8 Demographic data and visual acuity (Early Treatment Diabetic Retinopathy Study) were recorded. A urine pregnancy test was given to all women of childbearing potential. A slitlamp examination was performed to exclude all subjects with baseline ocular redness (redness in any vessel bed rated >l on a 5-point scale, where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = unusually severe) or any itching in either eye. Subjects were not allowed to use any eyedrops (except those instilled by study technicians) for the duration of the study, have any active ocular disease, or use any systemic medication that could affect the outcome of the study (eg, antihistamines or corticosteroids). A conjunctival antigen challenge (CAC) was performed bilaterally with an allergen to which the subject tested positive in a skin test, or had reacted to in a previous study. The allergen concentration was increased until a positive reaction was elicited bilaterally (redness graded 22 in any vessel bed and itching 828
THERAPEUTICS”
graded 22). Any subject who did not react positively was excluded from the study. Itching was graded on a 5-point scale (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = unusually severe) by the subject at 3, 5, and 10 minutes after the CAC. If needed, the subject received a dose of a currently marketed topical ophthalmic antiallergic agent (pheniramine maleate 0.3%/naphazoline hydrochloride 0.025% ophthalmic solution*) to relieve any immediate discomfort caused by the allergic reaction. Visit 2: Confirmation Results (Day 7 -c2)
of Allergen Test
Medical and medication history were updated and visual acuity was recorded. A slit-lamp examination was performed to exclude subjects with baseline conjunctival redness (redness graded ~1 in any vessel bed) or any itching in either eye. The CAC was again performed bilaterally using the allergen concentration that elicited a positive reaction at the previous visit. Any subject who did not react positively was excluded from the study. Itching was graded as previously described. Again, if needed, the subject received a dose of a currently marketed topical antiallergic agent to relieve any immediate discomfort caused by the allergic reaction. Visit 3: Drug Evaluation (Day 21 f 3) Medical and medication histories were updated and visual acuity was recorded. A slit-lamp examination was performed to exclude subjects with active allergic conjunctivitis (redness graded 21 in any vessel bed or any itching in either eye). *Trademark: Fort Worth,
Naphcon@ Texas).
A (Alcon
Laboratories,
Inc.,
G.J. BERDY
ET AL.
Subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and 1 drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Immediately after drug instillation, subjects were asked to grade, on a 9-point scale (0 = comfortable and 8 = uncomfortable), the comfort level in each eye. Twelve hours after instillation, a CAC was performed using the concentration that elicited positive responses at visits 1 and 2. Itching was subjectively graded as previously described. Following the subjective assessment of itching, subjects completed a Quality of Life Assessment. Subjects were then asked which drop they preferred. Again, if needed, subjects were administered a dose of a currently marketed, ophthalmic antiallergic preparation to relieve any immediate discomfort caused by the challenge. Statistical Analysis Data from all subjects who received drug were considered evaluable for comfort and efficacy analyses. Mean itching scores at visit 3 were compared between treatments. Mean efficacy scores provided a measure of clinical efficacy of a drug treatment for ocular itching. It was defined as the difference between the mean itching score at visit 2 (baseline) and the mean itching score at visit 3. Mean ocular comfort scores at visit 3 immediately following instillation of the drops were compared between treatments. Paired t tests were performed on the mean itching, efficacy, and ocular comfort score comparisons at each time point. Two-sided statistical tests were used, and P 5 0.05 was considered statistically significant.
RESULTS Olopatadine was significantly more effective than ketotifen at all time points (3, 5, and 10 minutes) in reducing the itching induced by the CAC (P < 0.05) (Figure 1). Compared with baseline scores of itching (visit 2), the mean efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; P < 0.05) (Figure 2). When subjects were asked to grade (on a scale from 0 to 8) the comfort level in each eye immediately following drug instillation, olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen ( 1.25 vs 2.09; P < 0.05) (Figure 3). After administration of the ophthalmic drops, subjects were asked to state which eye was more comfortable. This subjective evaluation was done before the antigen challenge and was designed to measure only the ocular tolerability of the drop. Of the 22 subjects who had a preference, 16 (73%) identified olopatadine and 6 (27%) identified ketotifen as the more tolerable (ie, causing less ocular discomfort) formulation. At the conclusion of the study, subjects were asked to identify the product that was more satisfactory in terms of efficacy and comfort. Again, of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine and 6 (27%) were more satisfied with ketotifen. DISCUSSION The mast cell stabilizer/antihistamine combination is the newest drug class in ocular allergy therapy.4 These drugs are effective in reducing the itching associated with the acute phase of ocular allergy, preventing subsequent mast cell ac-
829
CLINICAL
THERAPEUTICS@
W Olopatadine Ketotifen
2.5
2.0 s? 8 * 7
1.5
2
g s
1.0
2 0.5
0 3
5
10
Time (min) Postchallenge
Figure 1. Mean itching scores for eyes treated with olopatadine versus ketotifen at 3, 5, and 10 minutes postchallenge (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = unusually severe). Challenge was conducted 12 hours after drug instillation. Mean itching scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). U Olopatadine Ketotifen
$ 03
2.5
6
2.0
.-2 =
1.5
s a, 2
1.0 0.5
3
5
10
Time (min) Postchallenge
Figure 2. Mean efficacy scores for eyes treated with olopatadine versus ketotifen at 3, 5, and 10 minutes postchallenge. Efficacy score is defined as the difference between the mean itching score at visit 2 (untreated baseline) and the mean itching score at visit 3 (after drug treatment). Mean efficacy scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). 830
G.J. BERDY ET AL.
Olopatadine
Ketotifen
Figure 3. Mean comfort scores immediately following drug instillation (0 = comfortable and 8 = uncomfortable). Mean comfort scores were compared using a paired, 2-sided t test (*P < 0.05 vs ketotifen). tivation, and, potentially, inhibiting or minimizing late-phase reactions.5-7g9 The currently approved indication for olopatadinelo and ketotifentt is the treatment of itching associated with allergic conjunctivitis. Although the efficacy and tolerability of these 2 agents have been demonstrated in clinical studies,5*6 the results of the present study indicate that there are differences in effectiveness and tolerability between these agents, as measured by subjective evaluations of ocular comfort. In this antigen challenge model, olopatadine was shown to be significantly more effective than ketotifen (P < 0.05) in reducing ocular itching induced by a conjunctival antigen 12 hours after instillation. This differential effect on itching suggests that olopatadine binds to a significantly higher number of H, receptors than does ketotifen, since the ability of an ocular allergy medication to relieve itching is mediated solely by H, receptors on nerve cells.‘* Although preclinical data on
the HI-receptor binding of these drugs is important in drug development, the antigen challenge model provides the clinical relevance needed to evaluate the efficacy of these H,-receptor antagonists in viva.* In a study comparing these 2 drugs in the environmental model, olopatadine used twice daily was found to be more effective in controlling itching over a 14day period (Alejandro J. Aguilar, Buenos Aires, Argentina, personal communication, September 13, 1999). This study used the 0.05% concentration of ketotifen (available in Japan and South America) and not the 0.025% concentration approved in the United States. Yet even at this higher dose, ketotifen’s clinical efficacy at 12 hours postdose was inferior to that of olopatadine. This difference in efficacy may be explained by the greater bioavailability of olopatadine or its superior ability to stabilize mast cells. Furthermore, histamine antagonism by ketotifen appears to be biphasic, whereas 831
CLINICAL THERAPEUTICS”
olopatadine is known to inhibit histamine release in a dose-dependent manner.5v9 Another important finding of this study was the subjects’ superior comfort level with olopatadine versus ketotifen. These results confirmed those of a previous “forced choice” study, which reported that 100% of subjects were more comfortable with olopatadine than with ketotifen (Jo& Domingo Luna, MD, Fundacion VER Casilla de Correo, Cordoba, Argentina, personal communication, November 24,1999). The superior comfort level with olopatadine reported by subjects in the present study may indicate an increased likelihood of patient compliance, which may lead to better control of the allergic disease. When subjects were further questioned as to their overall satisfaction with the ophthalmic formulations in terms of efficacy and comfort, the majority of subjects who indicated a preference preferred olopatadine. The longterm efficacy of these formulations in relieving symptoms of allergic conjunctivitis as well as patient satisfaction with these products should be studied in an environmental model to confii these results. CONCLUSIONS Both olopatadine and ketotifen are approved for the relief of ocular itching associated with allergic conjunctivitis. In this study, olopatadine was shown to be more effective and cause less ocular discomfort than ketotifen in the conjunctival antigen challenge model of allergic conjunctivitis, as measured by subjective ratings of efficacy and comfort. ACKNOWLEDGMENT This paper was supported by a grant from Alcon Laboratories, Inc., Fort Worth, Texas. 832
Address correspondence to: Gregg J. Berdy, MD, Ophthalmology Associates, 456 North New Ballas Rd., Suite 386, Creve Coeur, MO 63 14 1. REFERENCES 1. Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr Allergy. 1987;21:l-20. 2. Yanni JM, Sharif NA, Gamache DA, et al.
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