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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\u2009kHz. 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                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200915, 1 site) there were no severe nor serious adverse events. In Phase IIa (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200944, 3 sites) the average pure-tone threshold across 2,4,8\u2009kHz did not change from baseline to 6 and 12 weeks (estimated change \u22120.87\u2009dB; 95% CI \u22122.37 to 0.63;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.252 and \u22120.46\u2009dB; 95% CI \u22121.94 to 1.03;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.545, 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\u2019s primary endpoint was not met.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-45784-0","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T04:02:28Z","timestamp":1709265748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["A phase I\/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss"],"prefix":"10.1038","volume":"15","author":[{"given":"Anne G. 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