Poor Correlation Between Dry Eye Disease (DED) Signs and Symptoms in a Phase III Randomized Clinical Trial

Abstract

Purpose: : DED is a multifactorial disease of the tears associated with inflammation of the ocular surface. The diagnosis and treatment of DED relies on clinical signs and subjective patient symptoms common to other ocular surface conditions. Although a poor concordance between DED signs and symptoms has been recognized in the literature, improvement in both DED signs and symptoms is an expected outcome in randomized clinical trials investigating new DED treatments.

Methods: : The Siccanove study was a 6 month phase III, multicenter, randomized, controlled, double-masked trial of NOVA22007 (cyclosporine 0.1% ophthalmic cationic emulsion) administered once daily versus its emulsion vehicle in 492 patients with moderate to severe DED (grade 2-4 corneal fluorescein staining, CFS, on the modified Oxford scale). The primary objective of the study was to demonstrate superiority of NOVA22007 on both a DED sign (mean change in CFS) and DED symptoms (mean change in global score of ocular discomfort using a visual analog scale, VAS), the co-primary efficacy endpoints at month 6.

Results: : Statistically significant improvements in CFS were observed at 1, 3 and 6 months in NOVA22007 treated patients. Despite noticeable improvements in the mean VAS score from baseline no statistically significant difference was observed compared to the emulsion vehicle at month 6. Analysis of the study data revealed considerable variability in VAS score across the range of CFS scores highlighting the poor correlation between DED signs and symptoms. At month 6, 56% of patients showed improvement in both CFS and VAS scores. Paradoxically, 15% of patients showed worsening on the VAS despite improvement in the CFS score and 18% showed improved VAS scores in the presence of no change or worsening of the CFS score. The Spearman’s correlation coefficient between the mean change in keratitis and ocular discomfort was low, 0.094.

Conclusions: : The discordance between DED signs and symptoms in patients with moderate to severe DED observed in the Siccanove study underscores the regulatory challenge of simultaneously achieving statistically significant outcomes for both DED signs and symptoms in randomized, controlled clinical trials evaluating pharmacologic therapies for DED.

Clinical Trial: : http://www.clinicaltrials.gov NCT00814515

Keywords: cornea: tears/tear film/dry eye • clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials • cyclosporine