32, P = 0.005; grade 4 = 0.77, P = 0.001) [66]. Although there was a clinically relevant improvement in DED symptoms from baseline the Cyclokat and cationic emulsion vehicle treatment arms, no statistically significant differences were observed at month 6 for the mean Adriamycin price change in the global score of ocular discomfort, the DED symptom

coprimary efficacy endpoint. However, there was a statistically significant improvement in symptoms for patients achieving a ≥25% improvement in the VAS score (50.21% versus 41.94%, P = 0.048). The difficulty in demonstrating the benefit of Cyclokat over Inhibitors,research,lifescience,medical its cationic emulsion vehicle was in part attributed to the efficacy of the vehicle itself in improving the symptoms of DED as demonstrated in clinical trials for Cationorm. Additionally, the symptoms coprimary endpoint result can be related to poor correlation between dry eye disease signs and symptoms. At baseline in the Siccanove study, while the mean VAS scores increased with the severity of the CFS, the correlation Inhibitors,research,lifescience,medical between the VAS score, as an expression of DED symptoms, and the CFS grade, as an expression Inhibitors,research,lifescience,medical of a DED sign, at baseline was low (Spearman’s correlation coefficient = 0.23) due to the wide variability in the severity of patient

reported symptoms. Similarly at month 6 the statistical correlation between mean change in CFS grade and VAS score was low (Spearman’s correlation coefficient = 0.094) with only approximately 68% of patients showing Inhibitors,research,lifescience,medical concordance in the direction of change in CFS grade and DED symptoms [65]. Although a poor concordance between dry eye disease signs and symptoms has been recognized in the literature, improvement in both signs and symptoms is an expected outcome in randomized clinical trials investigating new DED treatments. Hence several drugs having shown promise for improving DED have failed due to the inability to demonstrate a statistically significant improvement in signs and symptoms of dry eye disease Inhibitors,research,lifescience,medical using coprimary efficacy endpoints. Fortunately,

sign and symptom composite responder endpoints, used in registration trial supporting the approval of new treatments for other chronic inflammatory diseases, provide an alternate method to satisfy the requirement of regulatory authorities. The methodological approach and of composite responder analysis avoids issues related to high variability when following mean change of signs and symptoms as discontinuous variables. By focusing only on within-patient’s improvements, the composite responder approach could resolve the concern related to the poor correlation between signs and symptoms in evaluating the efficacy of new treatment for DED. As such a pivotal phase III trial, the Sansika study, utilizing a composite responder analysis at month 6, has been initiated to evaluate the efficacy of Cyclokat in patients with severe dry eye disease. 6.