Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

Abstract

Inhibition of cochlear N-methyl-<smlcap>D</smlcap>-aspartate (NMDA) receptors with AM-101, a small molecule antagonist delivered by intratympanic injection, represents a novel approach to treat acute tinnitus triggered by glutamate excitotoxicity. An earlier double-blind, randomized, placebo-controlled phase II clinical trial (TACTT0) had demonstrated a significant and dose-dependent improvement in tinnitus triggered by acute acoustic trauma or otitis media from baseline to day 90. A second phase II trial (TACTT1) now sought to evaluate the most appropriate dose regimen for this treatment. Outcomes from the TACTT1 trial showed no significant difference in tinnitus improvement between a single-dose treatment and a dose regimen comprising three doses over 2 weeks. Taken together, three injections over 3 consecutive days showed the best results in the two phase II trials, suggesting that repeated and concentrated inhibition of cochlear NMDA receptors provides best treatment effects, while keeping the procedural impact on patients short.

Safety of Repeated‐Dose Intratympanic Injections with AM‐101 in Acute Inner Ear Tinnitus

“…The previous trials had shown good tolerance of the treatment with no impact on hearing; adverse events that were predominantly local, ear related, and transient; and minimal systemic exposure. 5 , 6 Based on almost 1400 intratympanic injections, the present study confirmed the favorable safety profile.…”

“…The use of phenol was not recommended based on prior study experience. 6 Prior to study drug administration, any remaining anesthetic had to be suctioned off. The injection was to be performed in the posterior-inferior quadrant or, alternatively, in the anterior-inferior quadrant.…”

“…The phase 3 trial TACTT2 (Efficacy and Safety of AM-101 in the Treatment of Acute Peripheral Tinnitus 2) was designed to assess the safety and efficacy of AM-101 (esketamine otic gel; Auris Medical AG, Basel, Switzerland) in acute peripheral tinnitus. AM-101 had previously been tested in 1 phase 1/2 4 and 2 phase 2 trials 5 , 6 involving >900 injections. Administered in single or triple doses at concentrations of up to 0.81 mg/mL, the study drug had been well tolerated in these previous trials, and only small traces of the active substance and its primary metabolite had been detected in plasma, confirming the minimal systemic exposure afforded by the intratympanic approach.…”

Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans

“…We did not observe large consistent decreases for the MML or loudness match measures. Use of psychoacoustic measures such as the MML have been problematic in earlier studies 39 , 40 and loudness matching is known to be subject to learning effects 41 . In this study, there was high variability in MML measurements across baselines with an average difference of 7.4 dB (range 6.2 to 29 dB), making interpretation of the results difficult.…”

Evidence and evidence gaps in tinnitus therapy

“…In another study performed afterwards in 2015 on this NMDA antagonist, the best dosage was found [49]: in 16 centers in the USA and Europe, 85 patients who had tinnitus for not longer than 3 months after noise-induced hearing loss, barotrauma, acute middle ear infection, or middle ear surgery, underwent intratympanic injection of the drug or placebo in the context of a phase II study conducted in a double-blind, randomized, and placebo-controlled way. Half of the patients received one treatment, the others had 3 injections in weekly intervals (placebo or AM-101).…”