Clinical Efficacy and Safety of AM‐101 in the Treatment of Acute Tinntius

Abstract

Objectives: Glutamate excitotoxicity following cochlear trauma can trigger aberrant excitation of the auditory neurons, resulting in tinnitus. AM-101, a small molecule NMDA receptor antagonist, has shown evidence of preventing onset of tinnitus in animal models of cochlear trauma after intratympanic delivery. We present the results of the European and U.S. phase II clinical trials. Methods: Three hundred and twenty subjects with persistent tinnitus were enrolled in a double blind placebo controlled trial of AM-101. Efficacy endpoints included change in subjective tinnitus loudness, annoyance, sleep difficulties, the THI-12 questionnaire, and minimum masking level and loudness match. A patient global impression of change assessed the change in tinnitus severity over the study duration. Results: A dose dependent and statistically significant improvement of tinnitus loudness, annoyance, sleep difficulties, and the THI-12 over placebo could be demonstrated in subjects with tinnitus following acute noise trauma or otitis media. The improvement was most pronounced in the AM-101 810 µg/mL treatment group and continued to increase to Day 90 of the study. In contrast, the subgroup of sudden hearing loss related tinnitus did not show an improvement in tinnitus. The study drug was well tolerated. Conclusions: The study established human proof of concept for application of AM-101 in the treatment of tinnitus arising from cochlear glutamate excitotoxicity. Local delivery of AM-101 in a defined patient population in the acute stage of injury allows for a substantial and persisting attenuation of tinnitus with minimal systemic exposure and side effects.