Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis

Abstract

PURPOSE: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from loss of corneal innervation. DESIGN: Phase II multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with stage II (moderate) or stage III (severe) NK in one eye. METHODS: The REPARO Phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study drug, while efficacy was by intention to treat. MAIN OUTCOME MEASURES: Corneal healing (defined as <0.5 mm maximum diameter of fluorescein staining in the lesion area) was assessed in clinical pictures by masked central readers at week 4 (primary efficacy endpoint) and week 8 (key secondary endpoint) of controlled treatment. Corneal healing was also assessed post hoc by masked central readers using a more conservative measure (0 mm staining in the lesion area and no other persistent staining). RESULTS: At week 4 (primary endpoint), 19.6% of vehicle-treated patients achieved corneal healing (<0.5 mm lesion staining), vs. 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI] 15.88–54.71; P<0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI 18.96–57.83; P<0.001). At week 8 (key secondary endpoint), 43.1% of vehicle-treated patients achieved <0.5 mm lesion staining, vs. 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI 11.25–51.49; P<0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI 10.60–51.13, P<0.002). Post hoc analysis of corneal healing by the more conservative measure (0 mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. Over 96% of patients healed after controlled rhNGF treatment remained recurrence-free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. CONCLUSIONS: Topical rhNGF is safe, and more effective than vehicle in promoting healing of moderate-to-severe NK.

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ORCID for Parwez Hossain: orcid.org/0000-0002-3131-2395

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