Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis
Authors: Stefano Bonini, Alessandro Lambiase, Paolo Rama, Francesco Sinigaglia, Marcello Allegretti, Wendy Chao, Flavio Mantelli, Stefano Bonini, Alessandro Lambiase, Paolo Rama, Elisabeth Messmer, Pasquale Aragona, Gerd Geerling, Leonardo Mastropasqua, Rita Mencucci, John Dart, Andrea Leonardi, Jesus Montero, Maurizio Rolando, Thomas Reinhard, Claus Cursiefen, Jaime Etxebarria, Eric Gabison, Jacek P. Szaflik, Nacim Bouheraoua, Maria De La Paz, Maite Sainz de la Maza, Edward Wylegala, Francisco Figueiredo, Paolo Fogagnolo, Parwez Hossain, Katrin Lorenz, Pierre-Yves Robert, José Benitez del Castillo, Catherine Creuzot-Garcher, Friedrich Kruse, François Malecaze, Jesús Merayo-Lloves, Saaeha Rauz, Jorge Alio, Fiona Carley, Ramaesh Kanna, Carina Koppen, Janos Nemeth, Joaquim Neto Murta, Luis Torrao
Journal: Ophthalmology (2018)

PurposeTo 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 impaired corneal innervation.DesignPhase II multicenter, randomized, double-masked, vehicle-controlled trial.ParticipantsPatients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye.MethodsThe REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/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 treatment, whereas efficacy was by intention to treat.Main Outcome MeasuresCorneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining).ResultsAt week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 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 end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 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. More than 96% of patients who 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.ConclusionsTopical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK.