A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss.

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change -0.87 dB; 95% CI -2.37 to 0.63; P = 0.252 and -0.46 dB; 95% CI -1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial's primary endpoint was not met.

Audiological findings in professionals exposed to music and their relation with tinnitus.

Professional musicians are at high risk of developing tinnitus due to their over-exposure to music at both occupational and recreational level. This is a 5-year long prospective case series study performed in the Musicians/Performing Arts Medicine Clinic of the 1st Otorhinolaryngology Department of the National and Kapodistrian University of Athens. A total of 274 professional musicians underwent thorough medical history, history of music exposure, assessment of the impact their hearing status has on their professional life (Musicians Hearing Handicap Index), behavioral (Pure Tone Audiometry, standard and extended high frequency) and objective audiometric tests (TEOAE and DPOAE). Standard pure tone audiometry thresholds were correlated with the presence of tinnitus only at high frequencies. Musicians with tinnitus had a clinical and significant higher MHHI score and the incidence of tinnitus was significantly higher in participants suffering from musculoskeletal disease and those with abnormal PTA. Participants' hours of practice were similar in those with tinnitus and those without. The tinnitus group (and in order of descending effect size) had significantly worse thresholds in high frequency audiometry (≥3000Hz) as well as lower signal to noise ratios in DPOAE at almost all frequencies and in TEOAE at high frequencies (2.8 and 4kHz). A subgroup analysis of the musicians with normal PTA, showed that those with tinnitus showed elevated thresholds in the extended high frequency. In conclusion, tinnitus occurrence in musicians with normal audiogram is potentially correlated with high frequency hearing loss and impaired otoacoustic emissions and these two examinations should be considered in this group.