Randomized Single-Masked Study of Preservative-Free Versus Preserved Hyaluronic Acid in Dry Eye Disease

Purpose: To compare the effects of preservative-free hyaluronic acid (PF HA) versus benzalkonium chloride-preserved hyaluronic acid (BAK HA) on symptoms and signs of dry eye disease (DED) using identical formulations except for preservative content. Methods: In this randomized, single-masked, 6-month trial, 47 patients with DED were randomized to receive PF HA or BAK HA. The primary outcome was the change in Ocular Surface Disease Index (OSDI) score from baseline to month 6. Secondary outcomes included non-invasive tear break-up time (NIBUT), Schirmer I test, fluorescein tear break-up time (TBUT), fluorescein corneal staining (FCS), lissamine green conjunctival staining (LCS), best-corrected visual acuity (BCVA), and instillation frequency. Continuous and ordinal outcomes were analyzed using linear mixed-effects and mixed-effects ordinal logistic regression models, respectively. Results: Forty-three patients completed the study. PF HA produced a greater OSDI score reduction than BAK HA (adjusted change, -14.36 vs. -9.42; P = 0.001), and ∼40% of PF HA-treated patients achieved normal OSDI scores at the final visit, compared with none in the BAK HA group. At the final visit, no significant between-group differences were observed for NIBUT, Schirmer I, TBUT, BCVA, FCS, or LCS. PF HA showed more favorable longitudinal changes in symptoms and selected signs, including OSDI (P < 0.001), NIBUT (P = 0.017), FCS (P = 0.002), and LCS (P < 0.001), indicating a treatment-by-time effect. PF HA was associated with lower instillation frequency (P < 0.001). Conclusions: Both formulations improved DED signs and symptoms. PF HA provided greater symptomatic relief and showed more favorable longitudinal changes. Translational Relevance: These findings support the translation of experimental knowledge regarding preservative-induced ocular surface toxicity into evidence-based therapeutic decisions for long-term patient care.