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

Abstract

Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

Trial registration: ClinicalTrials.gov NCT01803646.

Keywords: AM-101; anesthetic; cochlea; hearing loss; intratympanic; local tolerance; otitis media; safety; tinnitus; traumatic; treatment.

Figures

Figure 1.

Patient flowchart for the TACTT2 trial.

Figure 2.

Frequency of use of tympanopunction (puncturing of eardrum), tympanotomy, or application through a preexisting ventilating tube (1392 administrations in total).

Figure 3.

Choice of local anesthetic for numbing of eardrum prior to intratympanic drug delivery (1392 administrations in total).

Figure 4.

Frequency of clinically relevant hearing loss in treated ear(s) (threshold shift ≥15 dB in any 2 contiguous test frequencies from baseline). (a) Air conduction hearing thresholds and (b) bone conduction hearing thresholds. n = 323. FUV, follow-up visit.

Figure 5.

Frequency of clinically relevant hearing loss in treated and untreated ears in unilaterally treated subjects (≥15 dB air conduction in any 2 contiguous test frequencies from baseline). (a) AM-101 group (n = 111); (b) placebo group (n = 72). FUV, follow-up visit.

Figure 6.

Frequency of clinically relevant hearing loss in treated and untreated ears in unilaterally treated subjects (≥15 dB bone conduction in any 2 contiguous test frequencies from baseline). (a) AM-101 group (n = 109); (b) placebo group (n = 72). FUV, follow-up visit.