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A comparison of the efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and cromolyn sodium 2% ophthalmic solution in seasonal allergic conjunctivitis
CLINICAL
THERAPEUTICSVVOL.
24, NO. IO,2002
A Comparison of the Efficacy and Tolerability of Olopatadine Hydrochloride 0.1% Ophthalmic Solution and Cromolyn Sodium 2% Ophthalmic Solution in Seasonal Allergic Conjunctivitis Constance H. Kateluris, MD,’ Giorgio Ciprandi, MD,2 Luc Missotten, MD,3 E Dare11 Turner, PhD,4 Donata Bertin, PhD,4 and Gilles Berdeaux, MD,4 for the International Olopatadine Study Group* ‘Department of Clinical Immunology and Allergy, Westmead Hospital, Sydney, Australia, 2Universitci degli Studi, Genova, Italy, “U.Z. Sint Rafael, Leuven, Belgium, and 4Alcon Research Ltd, Fort Worth, Texas
ABSTRACT Background: Treatments for allergic conjunctivitis have various mechanisms of action. Cromolyn sodium stabilizes conjunctival mast cells by preventing calcium influx across the cell membrane, whereas olopatadine hydrochloride is both an antihistamine and a mast cell stabilizer. Objective: This study compared the efficacy and tolerability of olopatadine and cromolyn in controlling the ocular signs and symptoms of seasonal allergic conjunctivitis. Methods: This was a multicenter, randomized, double-masked, parallel-group trial. One group instilled olopatadine 0.1% ophthalmic solution and placebo BID, and the other instilled cromolyn 2% ophthalmic solution QID, both for 6 weeks. The formulation of cromolyn used in this study is currently available only in Europe and Australia. Results: The intent-to-treat efficacy and safety analyses included 185 patients, 9 1 in the olopatadine group and 94 in the cromolyn group. At 30 minutes after the first instillation, respective decreases of -30% and -20% were reported in self-rated ocular itching and redness with both treatments; by 4 hours, itching had decreased by -38% in both groups. Differences between treatments were not statistically significant. At 4 hours, redness had decreased by -38% and -26% in the respective treatment groups. By day 42, both treatments had produced significant reductions from baseline in ocular signs and symptoms; however, the reductions in itching and redness were significantly greater with olopatadine compared *Members
of the International
Olopatadine
Study Group are listed in the Acknowledgments.
Accepted for publication June 26, 2002 Printed In the USA. Reproduction
0149.29
18/02/$19.00
in whole or part is not permitted.
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with cromolyn (both variables, P < 0.05). The difference in physicians’ impression of overall improvement on days 30 and 42 significantly favored olopatadine over cromolyn (both days, P < 0.05). Most patients (62.2%) had reacted positively to grass pollen at baseline. The regression slopes correlating itching and redness with pollen count were 5 times lower for olopatadine compared with cromolyn (P = 0.002 and P = 0.016. respectively), indicating that olopatadine’s efficacy increased as the pollen count increased. Conclusions: Six weeks’ instillation of olopatadine 0.1% ophthalmic solution BID had a significantly greater effect on the ocular signs and symptoms of allergic conjunctivitis compared with 6 weeks’ instillation of cromolyn 2% ophthalmic solution QID. Both treatments were well tolerated by patients in all age groups; however, olopatadine appeared to have better local tolerability in children aged < 11 years. Key words: allergic conjunctivitis, eye drops, olopatadine hydrochloride, cromolyn sodium. (C/in Thel: 2002;24: 15611575)
INTRODUCTION The occurrence of seasonal allergic conjunctivitis (SAC) coincides with the pollen season. SAC accounts for more than half of all patients with ocular allergy, many of whom have ocular symptoms only.‘-” Current treatments for allergic conjunctivitis fall into 3 main classes: stabilizers of the mast cell membrane (eg, cromolyn sodium, lodoxamide tromethamine) that prevent degranulation and consequent mediator release; agents that block cytokine production (eg, steroids) or prostaglandin formation (eg, nonsteroidal anti-inflammatory drugs);
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and antihistamines that antagonize histamine binding to H, receptors.” Olopatadine hydrochloride 0. I % ophthalmic solution* is a topical antiallergic agent that possesses multiple distinct mechanisms of action. It is an antihistamine with high affinity and selectivity for the histamine H, receptor and a mast cell stabilizer that inhibits the release of histamine and other proinflammatory mediators such as tumor necrosis factor-alpha from human conjunctival mast cells.“~’ It has shown activity in the conjunctival allergen challenge model9 and has an onset of action within minutes and a duration of action of X3 hours.“’ The efficacy and tolerability of olopatadine 0.1% ophthalmic solution administered BID for 2 weeks have been demonstrated in comparative studies in patients with SAC and perennial allergic conjunctivitis.” This study compared the efficacy and tolerability of olopatadine 0.1% ophthalmic solution BID with those of cromolyn 2% ophthalmic solution’ QID in patients with moderate to severe SAC. Cromolyn 2% ophthalmic solution is a mast cell stabilizer available in Europe and Australia for the treatment of allergic ocular disease. There is evidence in the literature that the efficacy of cromolyn is concentration dependent, with a 1% solution having no effect, a 2% solution having a possible effect, and a 4% solution having a probable effect. ’ 2-20The dosage and administration of cromolyn 2% ophthalmic solution used in this study were based on the instructions in the package insert.” The 6-week study duration was
*Trademark: Patanol’ (Alcon Laboratories, Inc.. Fort Worth, Texas). ‘Trademark: Opticrom@ (Fison\ Pharmaceuticals Brussels. Belgium).
C.H. KATELARIS
ET AL.
regarded as sufficient for evaluating the tolerability of topical treatments for SAC.
PATIENTS
AND METHODS
Znclusion and Exclusion
Criteria
Patients aged 24 years of either sex and any race were eligible for the study if they had a history of allergic conjunctivitis for at least 1 allergy season; reacted positively to 21 common local pollen on a skin test at screening or in the previous 12 months; and complained of itching (rated 4) and redness (slit-lamp image rated 12) in both eyes. Patients were excluded from the study for the following reasons: previous or current ocular disorders other than allergic conjunctivitis and nasolacrimal drainage malfunction; known sensitivity to any component of the study medications, including benzalkonium chloride; use of medication from 1 week before the study through its completion that could confound interpretation of the results (eg, steroids or nonsteroidal anti-inflammatory drugs, mast cell inhibitors, topical ocular vasoconstrictors); participation in other drug studies during the previous month; inability to discontinue contact lens use from 3 days before the study through its completion; pregnancy or lactation; and inadequate contraception in women of childbearing potential. The study was conducted in compliance with the principles of the Declaration of Helsinki as modified in Hong Kong, September 1989, and was approved by the appropriate ethics committees. Written informed consent was obtained from patients or their legal guardians. The good clinical practice guidelines were observed throughout.
Study Procedures This was a 6-week, multicenter, randomized, double-masked, parallel-group study. A computer-generated randomization schedule was used to assign sequential patients to the study treatments in an equal ratio. The 2 study regimens were ( 1) olopatadine 0.1% ophthalmic solution instilled in the morning and evening and placebo (olopatadine vehicle) instilled at noon and in the afternoon (olopatadine group), and (2) cromolyn 2% ophthalmic solution instilled at the same 4 times as olopatadine and placebo (cromolyn group). Double-masking was ensured through the use of identical opaque bottles and similarappearing contents and labeling. The patient (or guardian, in the case of a child) administered study medication by retracting the lower eyelid and instilling 1 drop of ophthalmic solution; if the drop missed the eye, the procedure was repeated. Any previous medication for allergic conjunctivitis was stopped at the screening visit, with a washout period of 21 week. Concomitant paracetamol (acetaminophen) and pseudoephedrine hydrochloride were allowed during the study. Clinic visits were scheduled for days 0 (enrollment, randomization, and start of treatment), 3,7, 14,30, and 42 (last day of treatment). A final follow-up visit took place 2 to 3 days after the end of treatment. The primary efficacy variables, ocular itching and conjunctival redness, were assessed by the investigators at each visit. The frequency of itching was rated on a 5-point scale: 0 = none, 1 = rarely (once), 2 = occasionally (at least once on 2 days), 3 = frequently (at least once every day), and 4 = very frequently (22 times each day). In addition, investigators compared slit-lamp images obtained at each visit
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CLINICAL THERAPEUTICS0
with standard reference photographs and assessed conjunctival redness on a 9-point scale consisting of 0.5~unit increments from 0 (normal) to 4 (total involvement). Secondary efficacy variables were chemosis and eyelid swelling (slit-lamp assessment, rated as described in the preceding paragraph). In addition, investigators compared patients’ overall clinical condition at each visit with that at study entry and rated change on the physicians’ impression scale: 0 = clinical cure, 1 = satisfactory clinical response, 2 = slight clinical improvement, 3 = clinically unchanged, 4 = slightly clinically worse, and 5 = significantly clinically worse. Patients kept a diary in which they rated the intensity of ocular itching and redness, each on a IO-point scale from 0 = none to 9 = severe. Patients’ ratings were recorded at 30 minutes, 1 hour, and 4 hours after the first instillation of treatment and before every dose on days 1 to 14 and days 30 to 42. Daily grain counts for the most common local pollens were obtained from pollen collection stations and included in a pollen allergy profile specific to each patient’s location. Safety variables included adverse events and ocular changes. An adverse event was defined as a clinically relevant change from baseline (expected or unexpected), excluding events related to disease progression (eg, signs and symptoms of allergy) or concomitant illness. Visual acuity (Snellen chart) was tested and pupil diameter measured at all visits. On days 0 and 42, intraocular pressure was measured by Goldmann applanation tonometry, and nondilated fundus examinations of the vitreous, retina, macula, choroid, optic nerve, and disc pallor were performed. Patients were assessed regularly and could be with-
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drawn from the study if, in the investigator’s opinion, their allergic reaction was not adequately controlled.
Statistical Methods The statistical objectives of this study were to demonstrate the noninferiority of olopatadine 0.1% ophthalmic solution to cromolyn 2% ophthalmic solution and, if noninferiority was demonstrated, the possible superiority of olopatadine. The decisions employed a clinically relevant difference in investigator-rated efficacy of >0.5 unit (SD of 1) as the threshold for noninferiority for both primary efficacy variables. It was determined that to ensure 86 evaluable patients per treatment group and achieve >90% power, it would be necessary to enroll 200 patients. Treatment differences were evaluated using a 2-tailed t test (a = 0.05). All patients who received medication were included in the intent-to-treat and safety analyses. Patients who received medication and satisfied all selection criteria and did not violate the study protocol on follow-up evaluations were included in the perprotocol analyses. In the latter analyses, data from patients who had been discontinued because of treatment failure were carried forward from the final visit. It was determined that olopatadine 0.1% ophthalmic solution would be declared noninferior to cromolyn 2% ophthalmic solution if the per-protocol analyses of primary efficacy ratings showed an upper 95% confidence limit for the mean difference that was less than the smallest rateable increment (0.5 unit). Olopatadine would be declared superior to cromolyn if the intent-to-treat analyses of primary efficacy ratings resulted in an upper 95% confidence limit for the mean difference
C.H. KATELARIS
ET AL.
that was less than zero.22,23 Treatments were compared and CIs estimated by repeated-measures analysis of variance (PROC MIXED, SAS for Windows version 6.12, SAS Institute Inc, Cary, N.C.) applied to all efficacy parameters. For the intent-to-treat data set and all variables except patients’ diary data, exact P values were corrected for repeated measures using Hommel’s procedure,24 which controlled the type I error rate at 0.05. Interactions between the treatments and sex, race, and iris color were examined with respect to itching, redness, and time comparisons with baseline using a 2-sample r test. A log-rank test was used to compare the 2 treatment groups in terms of the probability that 1 symptom of redness and 1 of itching (physicians’ impression scale) were unchanged or worsened in both eyes between days 7 and 42 compared with baseline. Treatments were also compared by logistic regression in terms of the probability of there being at least 1 day without symptoms (patients’ diaries), with time, treatment, and their interaction as factors. Comparison of baseline characteristics between treatment groups used the chisquare test. Safety analyses used the Fisher exact test for changes in visual acuity, a 2-sample t test for changes in intraocular pressure, and repeated-measures analysis of variance for changes in pupil diameter. An exploratory analysis examined the possibility of a correlation between efficacy parameters and Graminaceae (grass) pollen counts. Only patients who had a documented sensitivity to grass pollens were included in this analysis. The model tested for slope homogeneity between treatments using analysis of covariance (compound symmetrical structure, common intercept) with y (itching or redness scores) predicted by x (grass pollen count
as a covariate of treatments at 2 levels + random effect of patients, nested within treatments, with repeated measures on patients + error term).25,26
RESULTS A total of 188 patients were enrolled at 15 centers in 6 European countries and Australia. All were randomized to treatment (93 olopatadine, 95 cromolyn), but 3 patients (2 olopatadine, 1 cromolyn) did not use the assigned medication. Hence, 185 patients (91 olopatadine, 94 cromolyn) were included in the intent-to-treat efficacy and safety analyses. Sixteen additional patients were excluded because of protocol violations, including 10 who did not meet the selection criteria of symptoms in both eyes or a positive skin test result (7 olopatadine, 3 cromolyn). Thus, the per-protocol efficacy analysis included 169 patients (82 olopatadine, 87 cromolyn). The treatment groups were comparable in terms of baseline characteristics (Table I) and ocular itching, redness, chemosis, and swelling (Table II). The mean exposure to treatment was 39 days in both groups. The upper 95% confidence limit for the mean difference between groups was ~0.5 unit for both primary efficacy variables, ocular itching and conjunctival redness, from day 3 to day 42 (per-protocol data not shown). Hence, olopatadine 0.1% ophthalmic solution BID was not inferior to cromolyn 2% ophthalmic solution QID at any visit. Moreover, from days 14 through 42 (itching) and on day 42 (redness), the upper 95% confidence limit was 10 unit. Therefore, on these days, olopatadine was statistically superior to cromolyn in terms of both variables (P < 0.05) (Table II, Figure 1). This finding was supported by sig-
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CLlNICAL THERAPEUTICS”
Table I. Baseline characteristics
of the intent-to-treat
population. Olopatadine
Characteristic
All Patients (N = 185)
Hydrochloride 0.1% (n = 91)
Cromolyn Sodium 2% (n = 94)
35.0 (20.21) 4-71
33.0 (19.38) 4-77
36.8 (20.91) 4-75
103 (55.7) 82 (44.3)
51 (56.0) 40 (44.0)
52 (55.3) 42 (44.7)
172 2 9 2
(93.0) (1.1) (4.9) (1.1)
84 (92.3) l(l.1) 4 (4.4) 2 (2.2)
88 (93.6) 1 (1.1) 5 (5.3) 0 (0.0)
83 (44.9) 42 (22.7) 1.5 (8.1) 35 (18.9) 10 (5.4)
38 (41.8) 19 (20.9) 9 (9.9) 21 (23.1) 4 (4.4)
45 (47.9) 23 (24.5) 6 (6.4) 14 (14.9) 6 (6.4)
Age,Y Mean (SD) Range Sex, no. (%) Male Female Race, no. (%) White Black Asian Other Iris color, no. (%) Brown Hazel Green Blue Grey There were no statistically
significant
differences
between groups.
nificant between-group differences on days 30 and 42 for itching and on day 42 for redness (all, P < 0.05, per-protocol analyses) (Table II). Furthermore, olopatadine was superior to cromolyn on the physicians’ impression scale on days 30 and 42 (both, P < 0.05, per-protocol analyses) (Figure 2). In the subgroup analyses of the primary efficacy variables by baseline characteristics, there were no significant interactions of treatments with sex, race, or iris color. However, there was a significant interaction between treatment and age with respect to redness: children aged
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ure 3). The result for itching did not reach statistical significance. At every visit between days 3 and 42, olopatadine significantly reduced itching, redness, chemosis, and eyelid swelling from baseline (P < 0.05) (Table II). On day 42, decreases from baseline in all 4 efficacy variables were greater with olopatadine (range, 67.5%-76.7%) than with cromolyn (range, 43.0%-74.8%). After the first instillations of olopatadine and cromolyn on day 0, self-rated ocular itching and redness decreased rapidly. The effects were statistically significant (P< 0.05). At 30 minutes, itching and redness had decreased by -30% and -2O%, respectively, in both groups; at 4 hours, itching had decreased -38% in both groups. At 4 hours, ocular redness had decreased by
C.H. KATELARIS ET AL.
Table II. Mean investigator-rated ocular symptom scores and physicians’ scores (per-protocol data).
impression
scale
Day 0 Variable Primary symptoms Itching* Olopatadine 0.1% Cromolyn 2% Redness4 Olopatadine 0.1% Cromolyn 2% Secondary symptoms Chemosiss Olopatadine 0.1% Cromolyn 2% Eyelid swellings Olopatadine 0.1% Cromolyn 2% Physicians’ impression Olopatadine 0.1% Cromolyn 2%
(Baseline)
Day 3
Day I
Day 14
Day 30
Day 42
4.00 4.00
2.75+ 3.04+
2.41+ 2.13+
1.93++ 2.42+
1.47+i 2.03+
1.30+t 1.88*
2.51 2.51
1.63+ 1.751
1.30’ 1.49+
0.98+ 1.15’
0.86+ 1.03’
0.69+* 0.94’
1.08 0.95
0.68+
0.69’
0.54+ 0.551
0.36+ 0.45+
0.30+ 0.34+
0.28+ 0.28’
1.03
0.61+ 0.66+
0.53: 0.46+
0.34+ 0.37+
0.25’ 0.33’
0.24+ 0.26+
1.74 1.95
1.58 1.75
1.29 1.53
1.011 1.37
0.89* 1.19
1.03 scale”
*Frequency of itching was rated on a 5-point scale: 0 = none, I = rarely, 2 = occasionally,
3 = frequently, and 4 = very frequently. +P < 0.05 versus baseline. +P < 0.05 versus cromolyn. SRated on a 9-point scale from 0 to 4 (OS-unit increments), with higher numbers indicating greater severity. “Scale: 0 = clinical cure, 1 = satisfactory clinical response, 2 = slight clinical improvement, 3 = clinically unchanged, 4 = slightly clinically worse, and 5 = significantly clinically worse.
-38% with olopatadine and -26% with cromolyn. Olopatadine-treated patients had a 14% lower probability of having at least I itching symptom and 1 redness symptom in both eyes that were unchanged or worsened at day 42 compared with baseline (P < 0.04, log-rank test). Based on patients’ diary entries, the likelihood of a day without eye redness and itching was 1.6 times greater on most days in patients treated with olopatadine compared with those treated with cro-
molyn (P < O.OOl), and this difference was constant over time. Data were obtained during the high season for grass pollens, which were abundant at all study sites and were the most common cause of allergy. The pollen counts were comparable for the 2 treatment groups (Table III). At baseline, 115 of 185 patients (62.2%) reacted positively to grass pollens. Other pollens accounted for 134 allergic responses each and were not analyzed further, as this number was too small for meaningful slope analysis.
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CLINICAL THERAPEUTICS”
A
0 ( Baseline
e
Olopatadine
-t
Cromolyn sodium 2%
hydrochloride
I
I
I
I
I
I
7
14
21
28
35
42
Day
B
0.5 1
0 1 Baseline
I
I
I
I
I
I
7
14
21
28
35
42
Day
Figure 1. Mean (A) itching and (B) redness scores (per-protocol
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data set). *P < 0.05.
0.1%
C.H. KATELARIS
ET AL.
Baseline
i
2’1
14
q
Olopatadine
A-
Cromolyn sodium 2%
hydrochloride
0.1%
28
Day
Figure 2. Mean physicians’
impression
scale score (per-protocol
The relationship between grass pollen counts and ocular symptoms is shown in Figure 4. The regression slopes (b) correlating itching with pollen counts were 5 times lower for the olopatadine group (b = 0.002) than for the cromolyn group (b = 0.0 13) (P = 0.002). The regression slopes correlating redness with pollen counts were also 5 times lower for the olopatadine group (b = 0.001) than for the cromolyn group (b = 0.006) (P = 0.016). Four patients in the olopatadine group experienced 4 treatment-related ocular adverse events that consisted of ocular discharge, stinging, and blurred vision. Systemic adverse events judged related to treatment were dry nose and taste perversion in 2 patients. No event was serious and no patient was discontinued from the study. In the cromolyn group, 5 patients experienced 6 treatment-related ocular adverse events that consisted of dry eye, stinging, pruritus, and lacrimation. Two patients were withdrawn from the study because of symptoms that coincided with instillation of cromolyn: eye and mouth
data set).
*P< 0.05.
dryness in 1 patient, ocular stinging and lacrimation in the other. Two additional patients experienced 2 nonocular adverse events, headache and dry mouth, in relation to cromolyn treatment. Changes from baseline in visual acuity, pupil diameter, intraocular pressure, and fundus parameters were clinically unimportant and did not differ significantly between treatment groups.
DISCUSSION When antigens bind to immunoglobulin E molecules in the conjunctival mast cell membrane, this induces a sequence of events that causes vesicles to release proinflammatory mediators, including histamine and various cytokines.27128 Released histamine binds to H, receptors on conjunctival mast cells and epithelial cells, increasing phosphatidylinositol tumover and stimulating further release of proinflammatory mediators.29 Cromolyn stabilizes conjunctival mast cells by preventing calcium influx across the cell
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CLINICAL
THERAPEUTICS@’
0 Olopatadinehydrochloride 0.1% n Cromolyn sodium 2%
12-17 Age
4-11
Figure
3. Least-square *P = 0.002.
1570
16-64
265
(~1
mean scores for (A) itching
membrane,4,‘9 whereas olopatadine is both an antihistamine and a mast cell stabilizer. In terms of the primary efficacy variables, olopatadine 0.1% ophthalmic solution was more effective in reducing ocular itching and redness at all time points compared with cromolyn 2% ophthalmic solution. The superiority of olopatadine may have been related to olopatadine’s high affinity for the histamine H, receptor,
265
(~1
12-17 Age
16-64
and (B) redness,
with 95% CIs.
where it acts as a selective, noncompetitive inhibitorss30 and therefore attenuates the secondary release of proinflammatory mediators induced by histamine. The results of this study were consistent with the known efficacy of cromolyn 2% ophthalmic solution.“-“” Both treatments produced relief of ocular itching and redness 30 minutes after the first instillation (patient rated); this finding is not surpris-
C.H. KATELARIS ET AL.
ing and probably reflects temporary relief of symptoms by the mechanical irrigation effect of instillation. However, at 4 hours after instillation of olopatadine and cromolyn, redness had decreased by -38% and -26%, respectively, consistent with a fast-acting antihistaminic effect of olopatadine that may not be provided by cromolyn. By day 42, mean scores on the physicians’ impression scale were reduced with both treatments. This finding probably reflects the natural course of SAC, as pollen counts in the atmosphere showed a parallel decrease during the final 4 weeks of the study. It is therefore possible that this decrease in pollen counts contributed to symptom improvement. However, physicians’ impression scale scores were significantly higher for olopatadine (P < 0.05) which also may be explained by the synergy of olopatadine’s antihistaminic and mast cell-stabilizing effects compared with cromolyn’s single pharmacologic action. Similarly, the patient diary data showed that a day without ocular itching and redness was significantly more likely in patients treated with olopatadine compared with cromolyn. The pollen data support the superiority of olopatadine 0.1% ophthalmic solution to cromolyn 2% ophthalmic solution. The signs and symptoms of SAC are relatively short lived and depend on environmental conditions (mainly pollen levels). In the slope analysis, it was assumed that the amount of pollen in the atmosphere was roughly predictive of the exposure to pollen of a group of patients and that atmospheric pollen was predictive of the manifestation of an allergic response in this group. The slope analysis aligned the data on signs and symptoms with pollen level rather than with time in the study, as in the analysis of clinical trial results. The
Table III. Patients with a positive reaction at baseline, by pollen type. Pollen Type Graminaceae Ash Birch Olive Alder Plantain Wall pellitory Altemaria Willow Cypress Plane Mugwort Ragweed
No. of Patients 115 34 30 29 26 26 24 23 17 15
0
slope analysis used in this study tested whether the treatments controlled the allergic response to pollen in the environment. Specifically, it tested the hypothesis that the relationship (ie, the slope) between pollen counts and the allergic response was different between treatment groups. The test of homogeneity of slope recognizes that no difference is expected between treatments when pollen levels are low, but that a difference is expected when pollen levels are high. Under this test, a placebo or ineffective drug would have a positive slope, indicating an increase in signs and symptoms with increases in pollen counts. On the other hand, a perfect drug would have a slope of zero, indicating that when pollen levels are high, signs and symptoms are no greater than when pollen levels are low. In this study, the regression slopes predicting itching and redness based on pollen counts were 5 times lower for olopatadine than for cromolyn (itching, P = 0.002; redness, P = 0.016).
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CLINICAL THERAPEUTICS”
Olopatadine hydrochloride - - Cromolyn sodium 2%
/
,
’
0.1%
/ , Slope = 0.013
Grass Pollen Count (grains/m3)
3-
_ - - -
2__-_1
0
-
-
_
-
-
-
_ - - -
-&pe
= 0.006
__--
I 50
I
I 150
100
Slope = O.OOl+
I 200
Grass Pollen Count (grains/m3)
Figure 4. Correlation between grass pollen count and symptoms of (A) itching and (B) redness. *Slope difference, P = 0.002; ‘slope difference, P = 0.016.
A significant interaction between treatment and age was noted in the mean redness score, which was 2 times lower in children aged ~11 years who received olopatadine compared with those who received cromolyn (P = 0.002). Previous studies have reported that olopatadine 0.1% ophthalmic solution was superior to ketotifen fumarate 0.5% in patients with allergic conjunctivitis” and superior to
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nedocromil sodium 2% in the human conjunctival allergen challenge model,” particularly in terms of comfort on instillation. The greater local tolerability of olopatadine eyedrops may promote better compliance with repeated instillation in young children, although further research is necessary to test this hypothesis. Both treatments were well tolerated in patients with SAC of all ages.
C.H. KATELARIS ET AL.
CONCLUSIONS The signs and symptoms of SAC improved progressively with 6 weeks’ instillation of olopatadine 0.1% ophthalmic solution BID and cromolyn 2% ophthalmic solution QID. However, olopatadine provided consistently greater efficacy and significantly greater control of itching and redness when pollen counts were highest. Both treatments were well tolerated by patients in all age groups, although olopatadine appeared to have better local tolerability in children aged < 11 years.
ACKNOWLEDGMENTS The International Olopatadine Study Group consisted of the following, by country: Australia: Daniel Czarny, MD, John H. Hall, MD, Constance H. Katelaris, MD, Fiona E. McCurrach, MD, Paul Mitchell, MD, Richard J. Stawell, MD, George Thomson, MD, John Weiner, MD, Robert H. West, MD; Belgium: Frank M.R. Goes, MD, Christiane MarechalCourtois, MD, Luc Missotten, MD, Sayeh B. Pourjavan, MD, Agnes Riviere, MD; France: Dominique Bremond, MD, Philippe Verin, MD; Ireland: Amanda Collum, MD, Luis M.T. Collum, MD, Colin Hurley, MD, Joanne Kearney, MD, Kavita P. Khurana, MD, Yeok-See Ooi, MD; Italy: Piera M. Cerqueti, MD, Giorgio Ciprandi, MD, Andrea Leonardi, MD, Gabriella J. Orsoni, MD, Antonio Secchi, MD; Netherlands: Marc de Smet, MD, Frans Meijer, MD, Monica T.I? Odenthal, MD, Erik Reinders, MD; Spain: Dolores S. Dominguez, MD, J&us M. Iruzubieta, MD, Carlos R. Lapuente, MD, Esther C. Lopez, MD, Ana M. Palmer, MD, Juan C. Parra, MD, Jose F. Peiro, MD, Mariano R. Sans, MD.
This article was written in collaboration with Robert Pigache, MD.
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and comfort of olopatadine hydrochloride 0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model. Clin Thez 2000;22:1462-1472. MB, Spitalny L. Combined 10. Abelson analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am .I Ophthalmol. 1998; 125:797-804. 11. Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Actu Ophthalmol Stand Suppl. 2000;78:52-55. 12. Frankland AW, Walker SR. A clinical comparison of topical clobetasone butyrate and sodium cromoglycate in allergic conjunctivitis. ClinAllergy. 1981;11:473-478. 13. Allansmith MR. Pathology and treatment of giant papillary conjunctivitis. 1. The U.S. perspective. Clin 7’her: 1987;9:443450. 14 Foster CS. Evaluation of topical cromolyn sodium in the treatment of vernal keratoconjunctivitis. Ophthalmology. 1988;95: 194-201. 15 Ciprandi G, Cerqueti PM, Sacca S, et al. Levocabastine versus cromolyn sodium in the treatment of pollen-induced conjunctivitis. Ann Allergy. 1990;65:156-158. 16 Azevedo M, Castel-Branco MG, Oliveira JF, et al. Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy. 1991;21:689-694. 17 El Hennawi M. A double blind placebo controlled group comparative study of
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ophthalmic sodium cromoglycate and nedocromil sodium in the treatment of vernal keratoconjunctivitis. Br / Ophthalmol. 1994;78:365-369. 18. Calonge M, Montero JA, Herreras JM, et al. Efficacy of nedocromil sodium and cromolyn sodium in an experimental model of ocular allergy. Ann Allergy Asthma Immunol. 1996;77: 124-I 30. 19. Akman A, Irkec M, Orhan M. Effects of lodoxamide, disodium cromoglycate and fluorometholone on tear leukotriene levels in vernal keratoconjunctivitis. Eye. 1998;12:291-295, 20. Avunduk AM, Avunduk MC, Kapicioglu Z, et al. Mechanisms and comparison of anti-allergic efficacy of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis. Ophthalmology. 2000;107:1333-1337. 21. Opticrom 2%@ [package insert]. Brussels: Fisons Pharmaceuticals; 1993. 22. Points to Consider on BiostatisticaU Methodological Issues Arising from Recent CPMP Discussions on Licensing Applications: Superiority, Non-inferiority and Equivalence. Document CPMP/EWP/ 482/99. London: Committee for Proprietary Medicinal Products; September 23, 1999. 23. Morikawa T, Yoshida M. A useful testing strategy in phase III trials: Combined test of superiority and test of equivalence. .I Biopharm Stat. 1995;5:297-306. 24. Hommel G. A comparison of two modified Bonferroni procedures. Biometrika. 1988;75:383-386. 25. Milliken GA, Johnson DE. Designed experiments. In: Analysis of Messy Data. Vol 1. London: Chapman and Hall; 1994.
C.H. KATELARIS ET AL.
26. Littell R, Milliken GA, Stroup W, Wolfinger R. Test the equality of slopes. In: SAS System for Mixed Models. Caty, NC: SAS Institute Inc; 1996. 27. Allansmith MR. The Eye and Zmmunology. St Louis: Mosby; 1982.
30. el-Defrawy S, Jackson WB. New directions in therapy for ocular allergy. Inf Ophthalmol Clin. 1996;36:25-44. AC. Group compara31. Lindsay-Miller tive trial of 2% sodium cromoglycate (Opticrom) with placebo in the treatment of seasonal allergic conjunctivitis. Clin Allergy. 1979;9:271-275.
28. Macleod JD, Anderson DF, Baddeley SM, et al. Immunolocalization of cytokines to mast cells in normal and allergic conjunctiva. Clin Exp Allergy. 1997;27:13281334.
32. Kray KT, Squire EN Jr, Tipton WR, et al. Cromolyn sodium in seasonal allergic conjunctivitis. J Allergy Clin Immunol. 1985; 76:623-627.
29. Yanni JM, Weimer LK, Sharif NA, et al. Inhibition of histamine-induced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol. 1999;117:643-647.
0, Eliasson E, 33. Montan P, Zetterstrom Stromquist LH. Topical sodium cromoglycate (Opticrom) relieves ongoing symptoms of allergic conjunctivitis within 2 minutes. Allergy. 1994;49:637-640.
Address correspondence to: Constance H. Katelaris, Hawkesbury Road, Westmead NSW 2145, Australia.
MD, Westmead Hospital, 308/151
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THERAPEUTICSVVOL.
24, NO. IO,2002
A Comparison of the Efficacy and Tolerability of Olopatadine Hydrochloride 0.1% Ophthalmic Solution and Cromolyn Sodium 2% Ophthalmic Solution in Seasonal Allergic Conjunctivitis Constance H. Kateluris, MD,’ Giorgio Ciprandi, MD,2 Luc Missotten, MD,3 E Dare11 Turner, PhD,4 Donata Bertin, PhD,4 and Gilles Berdeaux, MD,4 for the International Olopatadine Study Group* ‘Department of Clinical Immunology and Allergy, Westmead Hospital, Sydney, Australia, 2Universitci degli Studi, Genova, Italy, “U.Z. Sint Rafael, Leuven, Belgium, and 4Alcon Research Ltd, Fort Worth, Texas
ABSTRACT Background: Treatments for allergic conjunctivitis have various mechanisms of action. Cromolyn sodium stabilizes conjunctival mast cells by preventing calcium influx across the cell membrane, whereas olopatadine hydrochloride is both an antihistamine and a mast cell stabilizer. Objective: This study compared the efficacy and tolerability of olopatadine and cromolyn in controlling the ocular signs and symptoms of seasonal allergic conjunctivitis. Methods: This was a multicenter, randomized, double-masked, parallel-group trial. One group instilled olopatadine 0.1% ophthalmic solution and placebo BID, and the other instilled cromolyn 2% ophthalmic solution QID, both for 6 weeks. The formulation of cromolyn used in this study is currently available only in Europe and Australia. Results: The intent-to-treat efficacy and safety analyses included 185 patients, 9 1 in the olopatadine group and 94 in the cromolyn group. At 30 minutes after the first instillation, respective decreases of -30% and -20% were reported in self-rated ocular itching and redness with both treatments; by 4 hours, itching had decreased by -38% in both groups. Differences between treatments were not statistically significant. At 4 hours, redness had decreased by -38% and -26% in the respective treatment groups. By day 42, both treatments had produced significant reductions from baseline in ocular signs and symptoms; however, the reductions in itching and redness were significantly greater with olopatadine compared *Members
of the International
Olopatadine
Study Group are listed in the Acknowledgments.
Accepted for publication June 26, 2002 Printed In the USA. Reproduction
0149.29
18/02/$19.00
in whole or part is not permitted.
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CLINICAL THERAPEUTICS”
with cromolyn (both variables, P < 0.05). The difference in physicians’ impression of overall improvement on days 30 and 42 significantly favored olopatadine over cromolyn (both days, P < 0.05). Most patients (62.2%) had reacted positively to grass pollen at baseline. The regression slopes correlating itching and redness with pollen count were 5 times lower for olopatadine compared with cromolyn (P = 0.002 and P = 0.016. respectively), indicating that olopatadine’s efficacy increased as the pollen count increased. Conclusions: Six weeks’ instillation of olopatadine 0.1% ophthalmic solution BID had a significantly greater effect on the ocular signs and symptoms of allergic conjunctivitis compared with 6 weeks’ instillation of cromolyn 2% ophthalmic solution QID. Both treatments were well tolerated by patients in all age groups; however, olopatadine appeared to have better local tolerability in children aged < 11 years. Key words: allergic conjunctivitis, eye drops, olopatadine hydrochloride, cromolyn sodium. (C/in Thel: 2002;24: 15611575)
INTRODUCTION The occurrence of seasonal allergic conjunctivitis (SAC) coincides with the pollen season. SAC accounts for more than half of all patients with ocular allergy, many of whom have ocular symptoms only.‘-” Current treatments for allergic conjunctivitis fall into 3 main classes: stabilizers of the mast cell membrane (eg, cromolyn sodium, lodoxamide tromethamine) that prevent degranulation and consequent mediator release; agents that block cytokine production (eg, steroids) or prostaglandin formation (eg, nonsteroidal anti-inflammatory drugs);
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and antihistamines that antagonize histamine binding to H, receptors.” Olopatadine hydrochloride 0. I % ophthalmic solution* is a topical antiallergic agent that possesses multiple distinct mechanisms of action. It is an antihistamine with high affinity and selectivity for the histamine H, receptor and a mast cell stabilizer that inhibits the release of histamine and other proinflammatory mediators such as tumor necrosis factor-alpha from human conjunctival mast cells.“~’ It has shown activity in the conjunctival allergen challenge model9 and has an onset of action within minutes and a duration of action of X3 hours.“’ The efficacy and tolerability of olopatadine 0.1% ophthalmic solution administered BID for 2 weeks have been demonstrated in comparative studies in patients with SAC and perennial allergic conjunctivitis.” This study compared the efficacy and tolerability of olopatadine 0.1% ophthalmic solution BID with those of cromolyn 2% ophthalmic solution’ QID in patients with moderate to severe SAC. Cromolyn 2% ophthalmic solution is a mast cell stabilizer available in Europe and Australia for the treatment of allergic ocular disease. There is evidence in the literature that the efficacy of cromolyn is concentration dependent, with a 1% solution having no effect, a 2% solution having a possible effect, and a 4% solution having a probable effect. ’ 2-20The dosage and administration of cromolyn 2% ophthalmic solution used in this study were based on the instructions in the package insert.” The 6-week study duration was
*Trademark: Patanol’ (Alcon Laboratories, Inc.. Fort Worth, Texas). ‘Trademark: Opticrom@ (Fison\ Pharmaceuticals Brussels. Belgium).
C.H. KATELARIS
ET AL.
regarded as sufficient for evaluating the tolerability of topical treatments for SAC.
PATIENTS
AND METHODS
Znclusion and Exclusion
Criteria
Patients aged 24 years of either sex and any race were eligible for the study if they had a history of allergic conjunctivitis for at least 1 allergy season; reacted positively to 21 common local pollen on a skin test at screening or in the previous 12 months; and complained of itching (rated 4) and redness (slit-lamp image rated 12) in both eyes. Patients were excluded from the study for the following reasons: previous or current ocular disorders other than allergic conjunctivitis and nasolacrimal drainage malfunction; known sensitivity to any component of the study medications, including benzalkonium chloride; use of medication from 1 week before the study through its completion that could confound interpretation of the results (eg, steroids or nonsteroidal anti-inflammatory drugs, mast cell inhibitors, topical ocular vasoconstrictors); participation in other drug studies during the previous month; inability to discontinue contact lens use from 3 days before the study through its completion; pregnancy or lactation; and inadequate contraception in women of childbearing potential. The study was conducted in compliance with the principles of the Declaration of Helsinki as modified in Hong Kong, September 1989, and was approved by the appropriate ethics committees. Written informed consent was obtained from patients or their legal guardians. The good clinical practice guidelines were observed throughout.
Study Procedures This was a 6-week, multicenter, randomized, double-masked, parallel-group study. A computer-generated randomization schedule was used to assign sequential patients to the study treatments in an equal ratio. The 2 study regimens were ( 1) olopatadine 0.1% ophthalmic solution instilled in the morning and evening and placebo (olopatadine vehicle) instilled at noon and in the afternoon (olopatadine group), and (2) cromolyn 2% ophthalmic solution instilled at the same 4 times as olopatadine and placebo (cromolyn group). Double-masking was ensured through the use of identical opaque bottles and similarappearing contents and labeling. The patient (or guardian, in the case of a child) administered study medication by retracting the lower eyelid and instilling 1 drop of ophthalmic solution; if the drop missed the eye, the procedure was repeated. Any previous medication for allergic conjunctivitis was stopped at the screening visit, with a washout period of 21 week. Concomitant paracetamol (acetaminophen) and pseudoephedrine hydrochloride were allowed during the study. Clinic visits were scheduled for days 0 (enrollment, randomization, and start of treatment), 3,7, 14,30, and 42 (last day of treatment). A final follow-up visit took place 2 to 3 days after the end of treatment. The primary efficacy variables, ocular itching and conjunctival redness, were assessed by the investigators at each visit. The frequency of itching was rated on a 5-point scale: 0 = none, 1 = rarely (once), 2 = occasionally (at least once on 2 days), 3 = frequently (at least once every day), and 4 = very frequently (22 times each day). In addition, investigators compared slit-lamp images obtained at each visit
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CLINICAL THERAPEUTICS0
with standard reference photographs and assessed conjunctival redness on a 9-point scale consisting of 0.5~unit increments from 0 (normal) to 4 (total involvement). Secondary efficacy variables were chemosis and eyelid swelling (slit-lamp assessment, rated as described in the preceding paragraph). In addition, investigators compared patients’ overall clinical condition at each visit with that at study entry and rated change on the physicians’ impression scale: 0 = clinical cure, 1 = satisfactory clinical response, 2 = slight clinical improvement, 3 = clinically unchanged, 4 = slightly clinically worse, and 5 = significantly clinically worse. Patients kept a diary in which they rated the intensity of ocular itching and redness, each on a IO-point scale from 0 = none to 9 = severe. Patients’ ratings were recorded at 30 minutes, 1 hour, and 4 hours after the first instillation of treatment and before every dose on days 1 to 14 and days 30 to 42. Daily grain counts for the most common local pollens were obtained from pollen collection stations and included in a pollen allergy profile specific to each patient’s location. Safety variables included adverse events and ocular changes. An adverse event was defined as a clinically relevant change from baseline (expected or unexpected), excluding events related to disease progression (eg, signs and symptoms of allergy) or concomitant illness. Visual acuity (Snellen chart) was tested and pupil diameter measured at all visits. On days 0 and 42, intraocular pressure was measured by Goldmann applanation tonometry, and nondilated fundus examinations of the vitreous, retina, macula, choroid, optic nerve, and disc pallor were performed. Patients were assessed regularly and could be with-
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drawn from the study if, in the investigator’s opinion, their allergic reaction was not adequately controlled.
Statistical Methods The statistical objectives of this study were to demonstrate the noninferiority of olopatadine 0.1% ophthalmic solution to cromolyn 2% ophthalmic solution and, if noninferiority was demonstrated, the possible superiority of olopatadine. The decisions employed a clinically relevant difference in investigator-rated efficacy of >0.5 unit (SD of 1) as the threshold for noninferiority for both primary efficacy variables. It was determined that to ensure 86 evaluable patients per treatment group and achieve >90% power, it would be necessary to enroll 200 patients. Treatment differences were evaluated using a 2-tailed t test (a = 0.05). All patients who received medication were included in the intent-to-treat and safety analyses. Patients who received medication and satisfied all selection criteria and did not violate the study protocol on follow-up evaluations were included in the perprotocol analyses. In the latter analyses, data from patients who had been discontinued because of treatment failure were carried forward from the final visit. It was determined that olopatadine 0.1% ophthalmic solution would be declared noninferior to cromolyn 2% ophthalmic solution if the per-protocol analyses of primary efficacy ratings showed an upper 95% confidence limit for the mean difference that was less than the smallest rateable increment (0.5 unit). Olopatadine would be declared superior to cromolyn if the intent-to-treat analyses of primary efficacy ratings resulted in an upper 95% confidence limit for the mean difference
C.H. KATELARIS
ET AL.
that was less than zero.22,23 Treatments were compared and CIs estimated by repeated-measures analysis of variance (PROC MIXED, SAS for Windows version 6.12, SAS Institute Inc, Cary, N.C.) applied to all efficacy parameters. For the intent-to-treat data set and all variables except patients’ diary data, exact P values were corrected for repeated measures using Hommel’s procedure,24 which controlled the type I error rate at 0.05. Interactions between the treatments and sex, race, and iris color were examined with respect to itching, redness, and time comparisons with baseline using a 2-sample r test. A log-rank test was used to compare the 2 treatment groups in terms of the probability that 1 symptom of redness and 1 of itching (physicians’ impression scale) were unchanged or worsened in both eyes between days 7 and 42 compared with baseline. Treatments were also compared by logistic regression in terms of the probability of there being at least 1 day without symptoms (patients’ diaries), with time, treatment, and their interaction as factors. Comparison of baseline characteristics between treatment groups used the chisquare test. Safety analyses used the Fisher exact test for changes in visual acuity, a 2-sample t test for changes in intraocular pressure, and repeated-measures analysis of variance for changes in pupil diameter. An exploratory analysis examined the possibility of a correlation between efficacy parameters and Graminaceae (grass) pollen counts. Only patients who had a documented sensitivity to grass pollens were included in this analysis. The model tested for slope homogeneity between treatments using analysis of covariance (compound symmetrical structure, common intercept) with y (itching or redness scores) predicted by x (grass pollen count
as a covariate of treatments at 2 levels + random effect of patients, nested within treatments, with repeated measures on patients + error term).25,26
RESULTS A total of 188 patients were enrolled at 15 centers in 6 European countries and Australia. All were randomized to treatment (93 olopatadine, 95 cromolyn), but 3 patients (2 olopatadine, 1 cromolyn) did not use the assigned medication. Hence, 185 patients (91 olopatadine, 94 cromolyn) were included in the intent-to-treat efficacy and safety analyses. Sixteen additional patients were excluded because of protocol violations, including 10 who did not meet the selection criteria of symptoms in both eyes or a positive skin test result (7 olopatadine, 3 cromolyn). Thus, the per-protocol efficacy analysis included 169 patients (82 olopatadine, 87 cromolyn). The treatment groups were comparable in terms of baseline characteristics (Table I) and ocular itching, redness, chemosis, and swelling (Table II). The mean exposure to treatment was 39 days in both groups. The upper 95% confidence limit for the mean difference between groups was ~0.5 unit for both primary efficacy variables, ocular itching and conjunctival redness, from day 3 to day 42 (per-protocol data not shown). Hence, olopatadine 0.1% ophthalmic solution BID was not inferior to cromolyn 2% ophthalmic solution QID at any visit. Moreover, from days 14 through 42 (itching) and on day 42 (redness), the upper 95% confidence limit was 10 unit. Therefore, on these days, olopatadine was statistically superior to cromolyn in terms of both variables (P < 0.05) (Table II, Figure 1). This finding was supported by sig-
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CLlNICAL THERAPEUTICS”
Table I. Baseline characteristics
of the intent-to-treat
population. Olopatadine
Characteristic
All Patients (N = 185)
Hydrochloride 0.1% (n = 91)
Cromolyn Sodium 2% (n = 94)
35.0 (20.21) 4-71
33.0 (19.38) 4-77
36.8 (20.91) 4-75
103 (55.7) 82 (44.3)
51 (56.0) 40 (44.0)
52 (55.3) 42 (44.7)
172 2 9 2
(93.0) (1.1) (4.9) (1.1)
84 (92.3) l(l.1) 4 (4.4) 2 (2.2)
88 (93.6) 1 (1.1) 5 (5.3) 0 (0.0)
83 (44.9) 42 (22.7) 1.5 (8.1) 35 (18.9) 10 (5.4)
38 (41.8) 19 (20.9) 9 (9.9) 21 (23.1) 4 (4.4)
45 (47.9) 23 (24.5) 6 (6.4) 14 (14.9) 6 (6.4)
Age,Y Mean (SD) Range Sex, no. (%) Male Female Race, no. (%) White Black Asian Other Iris color, no. (%) Brown Hazel Green Blue Grey There were no statistically
significant
differences
between groups.
nificant between-group differences on days 30 and 42 for itching and on day 42 for redness (all, P < 0.05, per-protocol analyses) (Table II). Furthermore, olopatadine was superior to cromolyn on the physicians’ impression scale on days 30 and 42 (both, P < 0.05, per-protocol analyses) (Figure 2). In the subgroup analyses of the primary efficacy variables by baseline characteristics, there were no significant interactions of treatments with sex, race, or iris color. However, there was a significant interaction between treatment and age with respect to redness: children aged
1566
ure 3). The result for itching did not reach statistical significance. At every visit between days 3 and 42, olopatadine significantly reduced itching, redness, chemosis, and eyelid swelling from baseline (P < 0.05) (Table II). On day 42, decreases from baseline in all 4 efficacy variables were greater with olopatadine (range, 67.5%-76.7%) than with cromolyn (range, 43.0%-74.8%). After the first instillations of olopatadine and cromolyn on day 0, self-rated ocular itching and redness decreased rapidly. The effects were statistically significant (P< 0.05). At 30 minutes, itching and redness had decreased by -30% and -2O%, respectively, in both groups; at 4 hours, itching had decreased -38% in both groups. At 4 hours, ocular redness had decreased by
C.H. KATELARIS ET AL.
Table II. Mean investigator-rated ocular symptom scores and physicians’ scores (per-protocol data).
impression
scale
Day 0 Variable Primary symptoms Itching* Olopatadine 0.1% Cromolyn 2% Redness4 Olopatadine 0.1% Cromolyn 2% Secondary symptoms Chemosiss Olopatadine 0.1% Cromolyn 2% Eyelid swellings Olopatadine 0.1% Cromolyn 2% Physicians’ impression Olopatadine 0.1% Cromolyn 2%
(Baseline)
Day 3
Day I
Day 14
Day 30
Day 42
4.00 4.00
2.75+ 3.04+
2.41+ 2.13+
1.93++ 2.42+
1.47+i 2.03+
1.30+t 1.88*
2.51 2.51
1.63+ 1.751
1.30’ 1.49+
0.98+ 1.15’
0.86+ 1.03’
0.69+* 0.94’
1.08 0.95
0.68+
0.69’
0.54+ 0.551
0.36+ 0.45+
0.30+ 0.34+
0.28+ 0.28’
1.03
0.61+ 0.66+
0.53: 0.46+
0.34+ 0.37+
0.25’ 0.33’
0.24+ 0.26+
1.74 1.95
1.58 1.75
1.29 1.53
1.011 1.37
0.89* 1.19
1.03 scale”
*Frequency of itching was rated on a 5-point scale: 0 = none, I = rarely, 2 = occasionally,
3 = frequently, and 4 = very frequently. +P < 0.05 versus baseline. +P < 0.05 versus cromolyn. SRated on a 9-point scale from 0 to 4 (OS-unit increments), with higher numbers indicating greater severity. “Scale: 0 = clinical cure, 1 = satisfactory clinical response, 2 = slight clinical improvement, 3 = clinically unchanged, 4 = slightly clinically worse, and 5 = significantly clinically worse.
-38% with olopatadine and -26% with cromolyn. Olopatadine-treated patients had a 14% lower probability of having at least I itching symptom and 1 redness symptom in both eyes that were unchanged or worsened at day 42 compared with baseline (P < 0.04, log-rank test). Based on patients’ diary entries, the likelihood of a day without eye redness and itching was 1.6 times greater on most days in patients treated with olopatadine compared with those treated with cro-
molyn (P < O.OOl), and this difference was constant over time. Data were obtained during the high season for grass pollens, which were abundant at all study sites and were the most common cause of allergy. The pollen counts were comparable for the 2 treatment groups (Table III). At baseline, 115 of 185 patients (62.2%) reacted positively to grass pollens. Other pollens accounted for 134 allergic responses each and were not analyzed further, as this number was too small for meaningful slope analysis.
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CLINICAL THERAPEUTICS”
A
0 ( Baseline
e
Olopatadine
-t
Cromolyn sodium 2%
hydrochloride
I
I
I
I
I
I
7
14
21
28
35
42
Day
B
0.5 1
0 1 Baseline
I
I
I
I
I
I
7
14
21
28
35
42
Day
Figure 1. Mean (A) itching and (B) redness scores (per-protocol
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data set). *P < 0.05.
0.1%
C.H. KATELARIS
ET AL.
Baseline
i
2’1
14
q
Olopatadine
A-
Cromolyn sodium 2%
hydrochloride
0.1%
28
Day
Figure 2. Mean physicians’
impression
scale score (per-protocol
The relationship between grass pollen counts and ocular symptoms is shown in Figure 4. The regression slopes (b) correlating itching with pollen counts were 5 times lower for the olopatadine group (b = 0.002) than for the cromolyn group (b = 0.0 13) (P = 0.002). The regression slopes correlating redness with pollen counts were also 5 times lower for the olopatadine group (b = 0.001) than for the cromolyn group (b = 0.006) (P = 0.016). Four patients in the olopatadine group experienced 4 treatment-related ocular adverse events that consisted of ocular discharge, stinging, and blurred vision. Systemic adverse events judged related to treatment were dry nose and taste perversion in 2 patients. No event was serious and no patient was discontinued from the study. In the cromolyn group, 5 patients experienced 6 treatment-related ocular adverse events that consisted of dry eye, stinging, pruritus, and lacrimation. Two patients were withdrawn from the study because of symptoms that coincided with instillation of cromolyn: eye and mouth
data set).
*P< 0.05.
dryness in 1 patient, ocular stinging and lacrimation in the other. Two additional patients experienced 2 nonocular adverse events, headache and dry mouth, in relation to cromolyn treatment. Changes from baseline in visual acuity, pupil diameter, intraocular pressure, and fundus parameters were clinically unimportant and did not differ significantly between treatment groups.
DISCUSSION When antigens bind to immunoglobulin E molecules in the conjunctival mast cell membrane, this induces a sequence of events that causes vesicles to release proinflammatory mediators, including histamine and various cytokines.27128 Released histamine binds to H, receptors on conjunctival mast cells and epithelial cells, increasing phosphatidylinositol tumover and stimulating further release of proinflammatory mediators.29 Cromolyn stabilizes conjunctival mast cells by preventing calcium influx across the cell
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CLINICAL
THERAPEUTICS@’
0 Olopatadinehydrochloride 0.1% n Cromolyn sodium 2%
12-17 Age
4-11
Figure
3. Least-square *P = 0.002.
1570
16-64
265
(~1
mean scores for (A) itching
membrane,4,‘9 whereas olopatadine is both an antihistamine and a mast cell stabilizer. In terms of the primary efficacy variables, olopatadine 0.1% ophthalmic solution was more effective in reducing ocular itching and redness at all time points compared with cromolyn 2% ophthalmic solution. The superiority of olopatadine may have been related to olopatadine’s high affinity for the histamine H, receptor,
265
(~1
12-17 Age
16-64
and (B) redness,
with 95% CIs.
where it acts as a selective, noncompetitive inhibitorss30 and therefore attenuates the secondary release of proinflammatory mediators induced by histamine. The results of this study were consistent with the known efficacy of cromolyn 2% ophthalmic solution.“-“” Both treatments produced relief of ocular itching and redness 30 minutes after the first instillation (patient rated); this finding is not surpris-
C.H. KATELARIS ET AL.
ing and probably reflects temporary relief of symptoms by the mechanical irrigation effect of instillation. However, at 4 hours after instillation of olopatadine and cromolyn, redness had decreased by -38% and -26%, respectively, consistent with a fast-acting antihistaminic effect of olopatadine that may not be provided by cromolyn. By day 42, mean scores on the physicians’ impression scale were reduced with both treatments. This finding probably reflects the natural course of SAC, as pollen counts in the atmosphere showed a parallel decrease during the final 4 weeks of the study. It is therefore possible that this decrease in pollen counts contributed to symptom improvement. However, physicians’ impression scale scores were significantly higher for olopatadine (P < 0.05) which also may be explained by the synergy of olopatadine’s antihistaminic and mast cell-stabilizing effects compared with cromolyn’s single pharmacologic action. Similarly, the patient diary data showed that a day without ocular itching and redness was significantly more likely in patients treated with olopatadine compared with cromolyn. The pollen data support the superiority of olopatadine 0.1% ophthalmic solution to cromolyn 2% ophthalmic solution. The signs and symptoms of SAC are relatively short lived and depend on environmental conditions (mainly pollen levels). In the slope analysis, it was assumed that the amount of pollen in the atmosphere was roughly predictive of the exposure to pollen of a group of patients and that atmospheric pollen was predictive of the manifestation of an allergic response in this group. The slope analysis aligned the data on signs and symptoms with pollen level rather than with time in the study, as in the analysis of clinical trial results. The
Table III. Patients with a positive reaction at baseline, by pollen type. Pollen Type Graminaceae Ash Birch Olive Alder Plantain Wall pellitory Altemaria Willow Cypress Plane Mugwort Ragweed
No. of Patients 115 34 30 29 26 26 24 23 17 15
0
slope analysis used in this study tested whether the treatments controlled the allergic response to pollen in the environment. Specifically, it tested the hypothesis that the relationship (ie, the slope) between pollen counts and the allergic response was different between treatment groups. The test of homogeneity of slope recognizes that no difference is expected between treatments when pollen levels are low, but that a difference is expected when pollen levels are high. Under this test, a placebo or ineffective drug would have a positive slope, indicating an increase in signs and symptoms with increases in pollen counts. On the other hand, a perfect drug would have a slope of zero, indicating that when pollen levels are high, signs and symptoms are no greater than when pollen levels are low. In this study, the regression slopes predicting itching and redness based on pollen counts were 5 times lower for olopatadine than for cromolyn (itching, P = 0.002; redness, P = 0.016).
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CLINICAL THERAPEUTICS”
Olopatadine hydrochloride - - Cromolyn sodium 2%
/
,
’
0.1%
/ , Slope = 0.013
Grass Pollen Count (grains/m3)
3-
_ - - -
2__-_1
0
-
-
_
-
-
-
_ - - -
-&pe
= 0.006
__--
I 50
I
I 150
100
Slope = O.OOl+
I 200
Grass Pollen Count (grains/m3)
Figure 4. Correlation between grass pollen count and symptoms of (A) itching and (B) redness. *Slope difference, P = 0.002; ‘slope difference, P = 0.016.
A significant interaction between treatment and age was noted in the mean redness score, which was 2 times lower in children aged ~11 years who received olopatadine compared with those who received cromolyn (P = 0.002). Previous studies have reported that olopatadine 0.1% ophthalmic solution was superior to ketotifen fumarate 0.5% in patients with allergic conjunctivitis” and superior to
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nedocromil sodium 2% in the human conjunctival allergen challenge model,” particularly in terms of comfort on instillation. The greater local tolerability of olopatadine eyedrops may promote better compliance with repeated instillation in young children, although further research is necessary to test this hypothesis. Both treatments were well tolerated in patients with SAC of all ages.
C.H. KATELARIS ET AL.
CONCLUSIONS The signs and symptoms of SAC improved progressively with 6 weeks’ instillation of olopatadine 0.1% ophthalmic solution BID and cromolyn 2% ophthalmic solution QID. However, olopatadine provided consistently greater efficacy and significantly greater control of itching and redness when pollen counts were highest. Both treatments were well tolerated by patients in all age groups, although olopatadine appeared to have better local tolerability in children aged < 11 years.
ACKNOWLEDGMENTS The International Olopatadine Study Group consisted of the following, by country: Australia: Daniel Czarny, MD, John H. Hall, MD, Constance H. Katelaris, MD, Fiona E. McCurrach, MD, Paul Mitchell, MD, Richard J. Stawell, MD, George Thomson, MD, John Weiner, MD, Robert H. West, MD; Belgium: Frank M.R. Goes, MD, Christiane MarechalCourtois, MD, Luc Missotten, MD, Sayeh B. Pourjavan, MD, Agnes Riviere, MD; France: Dominique Bremond, MD, Philippe Verin, MD; Ireland: Amanda Collum, MD, Luis M.T. Collum, MD, Colin Hurley, MD, Joanne Kearney, MD, Kavita P. Khurana, MD, Yeok-See Ooi, MD; Italy: Piera M. Cerqueti, MD, Giorgio Ciprandi, MD, Andrea Leonardi, MD, Gabriella J. Orsoni, MD, Antonio Secchi, MD; Netherlands: Marc de Smet, MD, Frans Meijer, MD, Monica T.I? Odenthal, MD, Erik Reinders, MD; Spain: Dolores S. Dominguez, MD, J&us M. Iruzubieta, MD, Carlos R. Lapuente, MD, Esther C. Lopez, MD, Ana M. Palmer, MD, Juan C. Parra, MD, Jose F. Peiro, MD, Mariano R. Sans, MD.
This article was written in collaboration with Robert Pigache, MD.
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Address correspondence to: Constance H. Katelaris, Hawkesbury Road, Westmead NSW 2145, Australia.
MD, Westmead Hospital, 308/151
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