Author's Response to comments on: “Comparison of postoperative cyclosporine 2.0% versus betamethasone 0.1% eye drops following trabeculectomy: A randomized clinical trial”

Dear Editor, We would like to thank the authors for their thoughtful comments and their interest in our article titled “Comparison of postoperative cyclosporine 2.0% versus betamethasone 0.1% eye drops following trabeculectomy: A randomized clinical trial.” Their engagement with our work is sincerely appreciated. Regarding the blinding process in our triple-masked design, we agree that the difference in physical appearance between cyclosporine A 2% (milky-white emulsion) and betamethasone 0.1% (clear solution) represents a potential limitation. To minimize the risk of unmasking, all study medications were prepared by an independent pharmaceutical company in identical bottles and packaging, labeled only as “A” or “B,” without any indication of their contents. Patients were informed that they could receive either cyclosporine A or a corticosteroid but were not informed about potential differences in appearance. In routine ophthalmic practice, many commonly used topical medications—including prednisolone acetate suspensions and several glaucoma medications such as dorzolamide-containing combinations—are also opaque or milky. This familiarity reduces the likelihood that patients, particularly those with average health literacy, would reliably distinguish allocation based solely on drop appearance. Furthermore, the surgeon, examining ophthalmologist, and data analyst remained masked throughout the randomized phase, which we believe substantially preserved the integrity of the triple-masked design. With respect to tolerability and adverse effects, we acknowledge that the study was not primarily designed as a detailed safety or tolerability trial and did not include a dedicated, structured tolerability questionnaire specific to cyclosporine A 2%. This is a limitation. Nonetheless, throughout follow-up, patients were routinely questioned about ocular symptoms, and common surface-related complaints—such as burning sensation and conjunctival hyperemia—were graded and analyzed. No patient in the cyclosporine A 2% group discontinued treatment because of intolerance, and the frequency and severity of burning sensation or conjunctival hyperemia were not significantly higher compared with the betamethasone group during the masked period. As many of our patients had prior exposure to glaucoma medications known to produce substantial ocular discomfort, such as dorzolamide-containing formulations, it is likely that their previous experiences influenced their perception and tolerance of transient irritation from cyclosporine. This may partly explain why higher-concentration cyclosporine A 2% was overall well accepted in this cohort. With regard to patient compliance, all participants were managed in a tertiary glaucoma clinic with close postoperative follow-up. At each scheduled visit, use of the study medications was reviewed, patients were asked about their adherence and any difficulties, and deviations were addressed promptly. Although no objective adherence measures (such as electronic monitoring or bottle weighing) were employed, we did not encounter evidence of systematic non-compliance or differential adherence between the two groups, and no participant was withdrawn for non-adherence. We agree that future studies would benefit from incorporating more formal adherence metrics, along with more granular assessment of tolerability and adverse events, especially when evaluating higher concentrations of cyclosporine A. We appreciate the opportunity to clarify these points and fully agree that further research—ideally with larger sample sizes, standardized tolerability assessment, and objective adherence monitoring—will be valuable in more definitively establishing the role of cyclosporine A 2% as a steroid-sparing strategy following trabeculectomy.