Discussion 
inflammation, dry eye disease, CFS
INFLAMMATION, DISEASE, PATHOPHYSIOLOGY, MAY, SECONDARY, KERATOCONJUNCTIVITIS SICCA, CORONAVIRUS, SEPARATION, DISEASES
The advent of topical cyclosporine into the therapeutic armamentarium available for patients with dry eye disease almost 2 decades ago was a significant advance in the treatment of keratoconjunctivitis sicca. Although approved specifically to increase tear production believed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, the broad effects of its antinflammatory action on the pathophysiology of the disease is now well recognized [We compared two dose levels of a proprietary formulation of MNP cyclosporine with Restasis™, a commonly used and widely available ophthalmic preparation of cyclosporine. The study enrolled patients between May 2019 and March 2020 and patient follow-up visits extended into September 2020. Hence the follow-up visits of many patients were disrupted by pandemic-related restrictions, leading to a greater number of patient drop-outs than previously anticipated. Nevertheless, the loss of patient numbers was evenly distributed across treatment arms. Moreover, the final sample size proved to be sufficient to detect a strong efficacy signal for all the treatment arms as well as to detect divergence among treatment arms.Paired t tests of follow-up data versus baseline values showed a strong efficacy signal (p ≤ 0.0005) for all treatment arms for all objective (CFS, STT, CLGS) and subjective measures of disease activity (OSDI, DESS), attesting to the sensitivity of the endpoints to therapeutic change.The primary efficacy endpoint, CFS, showed a superior outcome with the higher dose regimen of MNP cyclosporine (one drop of 0.05% twice daily) compared to Restasis™ at the same dose in the PP population at 12 weeks (p = 0.0026). The conclusion from this outcome was supported by outcomes documented for both objective and patient-reported outcomes in the secondary efficacy endpoints (STT p = 0.01; CLGS p = 0.02; OSDI p = 0.02) assessed for the same population at the same time point. All individual symptom scores also pointed to the same conclusion. The superiority signal was stronger for all objective endpoints on ANCOVA using baseline scores as the covariate. Thus, this study endorsed the hypothesis that manipulation of formulation characteristics can influence treatment outcomes and enhance the therapeutic value of topically administered cyclosporine in the management of dry eye disease.Superiority of efficacy of MNP cyclosporine over Restasis™ was not sustained at the lower dose of the test product (1 drop twice daily for 4 weeks and once daily thereafter). A separation between outcomes in the lower dose MNP cyclosporine and control arms was not evident at 12 weeks for any of the objective endpoints or for the patient-reported OSDI, and for only 2 of the 7 individual DES scores. Consequently, the higher dose of MNP cyclosporine was numerically more effective than the lower dose of the test product for all the endpoints, and the separation between the doses was statistically significant for STT and 4 of 7 individual symptom scores. Thus, this dose-finding study provides unambiguous data for the choice of dose in patients with moderate to severe keratoconjunctivitis sicca.We found no effect of treatment on BCVA or on use of tear substitutes. BCVA was close to 0.3 logMAR at baseline for each of the 3 treatment arms. Lack of appreciable improvement in visual acuity despite substantial improvements in the signs and symptoms of DED suggests that the deviation from normal vision seen in this patient population at baseline may not have been attributable to DED. The lack of reduction in use of tear substitutes is more difficult to explain. A 2019 review of studies with cyclosporine in DED [This study did not reveal any issues with safety or tolerability of the test product. All study treatments seemed to have been reasonably well tolerated. We could not detect any differences in toleration of the test product in comparison to the control group. This study failed to substantiate the hypothesis that differences in formulation characteristics would confer a superior local toleration profile on the test product. The sample size of this study may have been insufficient to detect differences in safety and tolerability of the study drugs.A number of limitations of this study may need to be kept in mind while interpreting the results. Foremost among these is perhaps the open-label design that may have permitted conscious and unconscious biases to affect subject selection and assessment of endpoints. Although the primary efficacy endpoint and two of the secondary endpoints were of an objective nature requiring precise or semi-precise readouts using instrumental techniques, the influence of bias cannot be entirely ruled out. Nevertheless, it would be reassuring to note that the main conclusions to be drawn from this study do not depend on those endpoints that may be expected to be more vulnerable to human bias, namely patient-reported outcomes and the CGET, although the patient-reported outcomes strongly support the results of objective endpoints. Indeed, it is interesting to note that the endpoint that could be considered the most susceptible to bias, namely CGET, did not return a categorical outcome.Another limitation of the study is the large number of patients that had to be excluded from the PP analysis, and the curtailment of efficacy analysis to the 12-week time-point, resulting from disruptions consequential to civic restrictions imposed due to the coronavirus pandemic. It is possible that a longer duration of follow-up for a larger set of patients could have narrowed the divergence between the two dose-levels of the test product and between the test and control groups by allowing more time for the slower-acting formulations to catch up with the lead group. On the other hand, it can be argued that the differences between treatment groups seen at 12 weeks in the present analysis may have been consolidated over a longer follow-up period. Further studies to test these hypotheses may be in order.It has been customary in ophthalmology, and other disciplines where diseases affecting paired units are the subject of analysis, to include only one unit (usually the more severely affected limb or member) from each individual in efficacy assessments. This is to ensure that each value included in the analysis is an independent data-point unrelated to the movement of other data-points. This is a necessary prerequisite to the proper use of common statistical tests of inference that are rendered invalid if this rule is overlooked, since the presence of interdependent values inappropriately inflates the true size of the sample [