Journal of the Formosan Medical Association (2011) 110, 690e694 Available online at www.sciencedirect.com journal homeage: www.jfma-online.com ORIGINAL ARTICLE A double-masked study to comare the efficacy and safety of toical cromolyn for the treatment of allergic conjunctivitis Yao-lin Liu, Fung-Rong Hu, I-Jong Wang, Wei-Li Chen, Yu-Chih Hou* Deartment of Ohthalmology, National Taiwan University Hosital, College of Medicine, National Taiwan University, Taiei, Taiwan Received 10 March 2010; received in revised form 28 Aril 2010; acceted 3 Setember 2010 KEYWORDS allergic conjunctivitis; cromolyn; ocular condition; reservative Background/Purose: To comare the efficacy and safety of toical cromolyn between with and without reservative for the treatment of allergic conjunctivitis. Methods: A double-masked study was erformed in atients with allergic conjunctivitis. Each cromolyn sodium 2% ohthalmic solution with or without 0.01% benzalkonium chloride (BAK) was randomized to aly on either eye. The efficacy and safety were evaluated every other week by a questionnaire about ocular itching, redness and foreign body sensation, and objective scores of conjunctival redness, chemosis, cornea erosion and discharge using slit-lam biomicroscoy. An overall resonse was also rated by hysician s imression. Results: A total of 37 subjects were enrolled in this study but only 33 comleted the study. All of subjective questionnaire scores showed a significant imrovement after treatment in both grous. Objective score of redness significantly decreased after treatment in either grous but not chemisos or discharge. After 4-week treatment, corneal erosion diminished significantly in the grou without reservative but not in the grou with 0.01% BAK. There was no significant difference between with and without 0.01% BAK grous in each subjective or objective score. No adverse effect related with medication was observed. Conclusion: Cromolyn 2 % ohthalmic solution was effective and safe to treat allergic conjunctivitis. A short-term use of cromolyn 2 % ohthalmic solution with 0.01% BAK would not cause any significant toxicity in atients with allergic conjunctivitis. Preservative-free cromolyn may be beneficial to the comromised eyes or eyes required of long-term medication. Coyright ª 2011, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. * Corresonding author. Deartment of Ohthalmology, National Taiwan University Hosital, College of Medicine, National Taiwan University, 7, Chung-Shan South Road, Taiei, Taiwan. E-mail address: ychou51@ntu.edu.tw (Y.-C. Hou). 0929-6646/$ - see front matter Coyright ª 2011, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. doi:10.1016/j.jfma.2011.09.004
Comarison of cromolyn for allergic conjunctivitis treatment 691 Allergic conjunctivitis is the most common form of ocular allergic disease, affecting 5%e20% of the oulation. 1 Other tyes of ocular allergies include vernal and atoic keratoconjunctivitis. Although these occur less frequently, they are more severe than seasonal or erennial allergic conjunctivitis. Perennial allergic conjunctivitis is characterized by the resence of itching, redness, swelling, tearing, and mucous discharge throughout the year. Allergic conjunctivitis is induced by immunoglobulin E (IgE)-mediated, tye 1 hyersensitivity reactions that involve histamine from degranulated mast cells. 2 Mast cell degranulation also releases a cascade of allergic and inflammatory mediators. 3 Histamine has been shown to induce itching in the ocular surface through H1 recetors and redness through both H1 and H2 recetors. 4 Itching is one of the major symtoms of allergic conjunctivitis, and it has a dramatic effect on a atient s quality of life. In addition, erennial allergic conjunctivitis is often accomanied by the nasal symtoms of rhinitis. The most common cause of allergic conjunctivitis is the household dust mite (Dermatohagoides teronyssinus). 2 The treatment otions for atients with allergic conjunctivitis include antihistamines, toical mast cell stabilizers, toical antihistamine-mast cell stabilizers, nonsteroidal antiinflammatory drugs, and corticosteroids. 5 Cromolyn sodium, a mast cell stabilizer, is a good substitute for toical steroids for mild to moderate allergic eye diseases because of its steroid-saring effect and good efficacy. 6 Cromolyn is oorly absorbed systemically when used toically and therefore has an excellent safety record. 7 Cromolyn sodium acts by inhibiting both the degranulation of sensitized mast cells and the release of histamine from the conjunctival mast cells. Cromolyn sodium 2% ohthalmic solution has been used for the treatment of allergic ocular disease. 8 Most of these ohthalmic solutions contain reservatives to revent contamination. It is well known that reservatives can cause ocular irritation and tissue damage. 9e12 Therefore, a formulation containing the active ingredient without any reservative has been develoed. The key alternative method to accomlish this goal is to ack the ohthalmic solution in an asetic bottle. Allergo-COMOD [Ursaharm Arzneimittel GmbH & Co. KG, Germany] is a sterile reservative-free ohthalmic solution containing cromolyn sodium. The objective of this study is to comare the efficacy and safety of cromolyn sodium without reservative (Allergo-COMOD) to that with reservative (Allergocrom [Ursaharm Arzneimittel GmbH & Co. KG, Germany]) in atients with allergic conjunctivitis after treatment for 4 weeks. Patients and methods Patients were recruited from the outatient clinic at the Deartment of Ohthalmology, National Taiwan University. The atients (18e70 years of age) had seasonal or erennial allergic conjunctivitis, which was diagnosed on the basis of their allergy history, and at least one of the following bilateral symtoms and signs: itching, tearing, eyelid swelling, conjunctival hyeremia, chemosis, or conjunctival aillary reaction. Patients were excluded from the study if they had any history of ocular surgery, asthma, diabetic retinoathy, or rheumatoid arthritis, or if they were regnant, lactating, or hyersensitive to cromolyn. Toical corticosteroids, nonsteroidal anti-inflammatory drugs, antihistamines, other mast cell stabilizers, immunosuressants, and vasoconstrictors were rohibited during the study eriod. If these toical medications had been used before, a washout eriod of 7 days was required. The trial was conducted in accordance with the Declaration of Helsinki, and it was aroved by the Institutional Review Board of the Research Ethics Committee at National Taiwan University Hosital in Taiwan. The study was exlained well to all articiants and written informed consent was obtained. This was a randomized, double-masked, and arallel study to comare the efficacy and safety of cromolyn sodium 2% ohthalmic solution with reservative to that without reservative for the treatment of atients with allergic conjunctivitis. The study eriod for each atient was 5 weeks, including a screening/washout eriod of 1 week (at Visit 1) and a treatment eriod of 4 weeks. Each atient was required to make four visits. At Visit 2, eligible atients were randomized to receive Allergo-COMOD (without reservative) in one eye and Allergocrom with 0.01% benzalkonium chloride (BAK) reservative in the fellow eye four times daily in a double-masked fashion for 4 weeks. The study was double-masked to ensure that the investigators exectations would not influence the assessment of the clinical resonse. The randomization table and codes were rovided by individuals who acked and labeled the study medication. The randomization codes laced in enveloes were generated according to the randomization table and were distributed to the study site before the initiation of the study; they were only oened by the investigator under an emergency situation. The atients were randomized in balanced blocks with an equal robability of receiving the study drug in the left eye (with the control drug in the right eye) or the study drug in the right eye (with the control drug in the left eye). Randomization schedules were generated at 1:1 ratio. Pretreatment and ost-treatment subjective evaluations of the atients were conducted using a questionnaire on ocular itching, redness, and foreign body sensation, which were rated on a 10-oint scale from 0 Z none to 9 Z severe. The hysician used slit-lam biomicroscoy to determine the scores of the intensity of conjunctival redness, chemosis, corneal erosion, and discharge on a 5- oint scale consisting of 1 unit increments: 0 Z normal and 4 Z comlete involvement. The overall resonse was rated according to the hysician s imression at each visit (0 Z clinical cure, 1 Z satisfactory clinical resonse, 2 Z slight clinical imrovement, 3 Z clinically unchanged, 4 Z slightly clinically worse, and 5 Z significantly clinically worse). The efficacy of the treatment was evaluated by the net change in the sum of the scores at the last visit comared to the baseline scores. The efficacy was analyzed for the intent-to-treat (ITT) and safety oulations. The ITT oulation included all randomized atients who received at least one dose of both study medications and who had at least one ostbaseline assessment for the rimary efficacy variable regardless of their comliance with the rotocol. The safety oulation included all randomized atients who received at least one dose of both study medications. The efficacy evaluation was erformed on the ITT oulation. For atients who
692 Y.-l. Liu et al. used a rohibited agent before the termination of the study, only the efficacy data obtained before the use of that agent were included in the efficacy analysis. Safety endoints were analyzed using the safety oulation. Statistical method Since the oulation is so small and the evaluation methodology only from 0e10 or 0e5, the way to test treatment difference between the grou without reservative and the grou with 0.01% BAK changed to the Wilcoxon Rank Sum test to avoid the normal distribution inadequate. We adoted the SAS Version 8.1 [SAS institute Inc.], with rocedure NPAR1WAY to test collecting data. Descritive statistics, such as mean and standard deviation, were calculated by the UNIVARIATE rocedure. A value < 0.05 was considered significant. Results A total of 37 atients were enrolled in this study after screening 42 otential candidates. Thirty-three atients comleted the study and 4 droed out. The reasons for droing out included adverse events (two atients), loss of follow-u (one atient), and rotocol violation (one atient). For the safety evaluation, the adverse events in these two atients were not related to the test treatment. No abnormal hysical examination or vital signs were detected throughout the study. A total of 34 atients (age, 39.2 13.5 years) satisfied the definition of the ITT oulation and were included in the ITT analysis. A total of 35 atients satisfied the definition of safety oulation and were included in the safety analysis. The effect of the grou without reservative was comared with the grou with 0.01% BAK using the rimary variable. As illustrated in Table 1, the mean baseline scores were 8.91 5.87 and 9.15 5.83 for the grous without reservative and with 0.01% BAK, resectively, and no significant differences existed between the two grous at baseline ( Z 0.883). At Visit 3, the changes in the mean atients diary scores from baseline were e4.05 5.06 and e4.71 5.51 for the treatment without reservative and with BAK grous, resectively, with significant difference ( < 0.001) in both the grous. This suggested that the symtoms imroved after the treatment in both the grous. At Visit 4, the changes in the mean score from baseline Table 1 Change in atient scores from baseline. V2 (baseline, Day 0) Mean SD 8.91 5.87 9.15 5.83 0.883 V3 change from baseline (Week 2) Mean SD 4.05 5.06 4.71 5.51 0.840 V4 change from baseline (Week 4) Mean SD 5.04 5.45 5.79 5.82 0.817 were e5.04 5.45 and e5.79 5.82 for treatment without reservative and for treatment with reservative grous, resectively. This indicated that after 4 weeks of treatment, symtoms of atients in both the grous further imroved. The diary scores of each atient, including scores for ocular itching, redness, and foreign body sensation, were significantly different before and after treatment ( < 0.01). However, the mean change in the scores from the baseline did not differ significantly between the two grous at Visits 3 and 4, indicating that both the treatments can relieve the symtoms of allergic conjunctivitis. Table 2 shows that the mean scores of conjunctival redness, corneal erosion, chemosis, and discharge rated by the hysician did not differ significantly between the two grous at baseline Visit 2. At follow-u Visits 3 and 4, the mean comosite sign scores were all decreased and the redness scores were esecially reduced. Statistical analysis between the scores at baseline Visit 2 and treatment Visits 3 and 4 revealed a significant difference in redness but not in chemosis or discharge. The score for corneal erosion did Table 2 Change in the hysician s rating from baseline on the intensity using slit-lam images. V2 (baseline, Day 0) Mean SD 1.68 0.59 1.65 0.54 0.743 Corneal crosion Mean SD 0.50 0.75 0.38 0.60 0.625 Mean SD 0.06 0.24 0.06 0.24 1.00 Mean SD 0.11 0.32 0.11 0.32 1.00 V3 change from baseline (Week 2) Mean SD 0.50 0.51 0.50 0.51 0.676 Corneal erosion Mean SD 0.15 0.50 0.06 0.60 0.853 Mean SD 0.06 0.24 0.06 0.24 1.00 Mean SD 0.09 0.38 0.06 0.24 0.332 V4 change from baseline (Week 4) Mean SD 1.06 0.95 0.94 1.04 0.343 Corneal erosion Mean SD 0.21 0.64 0.15 0.66 0.516 Mean SD 0.00 0.43 0.00 0.43 1.00 Mean SD 0.06 0.42 0.00 0.35 0.100
Comarison of cromolyn for allergic conjunctivitis treatment 693 not differ significantly between baseline Visit 2 and treatment Visits 3 and 4 in either grou, excet for a marginal statistical difference in the corneal erosion at treatment Visit 4 in the grou without reservative ( Z 0.035). However, no significant difference was observed between the two grous in all the four scales. Regarding the hysicians imression scale, the grou without reservative was not significantly suerior to the grou with 0.01% BAK, but both the grous exhibited significant imrovement (Table 3). Discussion In allergic conjunctivitis, mast cells lay an imortant role in allergen-induced inflammation. Mast-cell degranulation could cause abrut release of histamine and trytase, which induces ocular itching, vasodilatation, and increased vascular ermeability. Cromolyn sodium is a mast cell stabilizer and can inhibit the degranulation of sensitized mast cells and reduce the release of histamine by reventing calcium influx across the cell membrane. In our study, both grous showed marked reduction in ocular itching, redness, and foreign body sensation in atients with allergic conjunctivitis. For the second efficacy endoint, which measured the change in the hysicians rating from the baseline, conjunctival redness and corneal erosion imroved in both the treatment grous, but chemosis and discharge did not imrove. Because the baseline scores for chemosis and discharge were already low before treatment, the difference in the scores before and after treatment would not be significant. In our study, the evaluation from atients and the hysician showed that both the treatments were effective for allergic conjunctivitis and could reduce conjunctival redness and subjective symtoms. Both the treatments were safe and well tolerated without significant difference. The results demonstrated that cromolyn 2% ohthalmic solution was effective for treating allergic conjunctivitis. Preservatives in toical ohthalmic medications revent microbial soilage of harmaceutical rearations. They are essential for sterility because the atients may touch the oening of the containers with fingers, eyelids, cilia, conjunctiva, or cornea. However, ohthalmic reservatives may also damage ocular tissues. Preservatives are otentially cytotoxic to conjunctival and corneal eithelial cells by alteration of membrane integrity or cellular metabolism. 10 BAK, a commonly used reservative, induces the loss of mircovilli from the surface cells of cornea at low concentrations, and at higher concentrations, it causes cell desquamation. 11e13 The damages lead to the disrution of the Table 3 Change in the hysicians imression scores from baseline. Visit 3 (Week 2) Mean SD 1.85 0.42 1.76 0.50 0.423 Visit 4 (Week 4) Mean SD 1.21 0.65 1.12 0.65 0.570 stability of the tear film 14,15 and the integrity of the corneal eithelium 16 and also increase ocular surface inflammation. 17,18 Adverse effects, such as burning sensation, foreign body sensation, and conjunctival hyeremia, will become more significant, esecially in atients with dry eyes and glaucoma who need frequent, long-term, and sometimes multile toical medications containing the reservatives. 19,20 Aart from the imact on corneal and conjunctival eithelial cells, BAK has also been demonstrated to be cytotoxic to endothelial cells in in vitro studies. 21 When clinicians rescribe long-term toical solutions, this should be taken into consideration in high-risk cases, such as those with low endothelial cell density and extensive eithelial damage. Our study did not reveal any significant differences in the subjective and objective evaluation between cromolyn 2% ohthalmic solution without reservative and that with 0.01% BAK in the 1-month eriod. This indicates that for normal frequency and short-term use, cromolyn 2% ohthalmic solution with 0.01% BAK is safe for most atients with allergic conjunctivitis and would not cause significant corneal erosion or other toxicity. Since the toxicity of BAK is well documented, the lack of significant differences in subjective and objective evaluation between the solution with BAK and that without BAK may be due to the relatively short duration of our trial. In our study, the case number was relatively small and the range of evaluated score was also narrow. It is robable not easy to detect the difference between two grous. The short-term use of cromolyn 2% ohthalmic solution with 0.01% BAK for 4 weeks may not be long enough to resent the toxicity of BAK. Therefore, in acute or seasonal allergic conjunctivitis, there is no significant benefit in choosing the more costly reservativefree cromolyn over reservative-containing cromolyn if it is used for less than 1 month. However, corneal erosion significantly decreased in the grou without reservative but not in the grou with 0.01% BAK after the 4-week treatment. This may suggest that reservative-free eye dros could be more beneficial to treat erennial or severe allergic conjunctivitis, which requires long-term toical cromolyn treatment or multile drug combinations, and they may ossibly reduce BAK-induced ocular damages in more vulnerable conditions such as in dry eyes, in limbal insufficiency, or under long-term antiglaucoma medication. Our study rovides ractical information for the clinicians in the treatment of allergic conjunctivitis with cromolyn 2% ohthalmic solution. 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