Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study.
To evaluate the efficacy and safety of AM-111, a c-Jun N-terminal Kinase (JNK) ligand, in patients with acute sensorineural hearing loss (ASNHL). Prospective, double-blind, randomized, placebo-controlled study with follow-up visits on Days 3, 7, 30, and 90. Twenty-five European sites (academic tertiary referral centers, private ENT practices). Approximately 210 patients aged 18 to 61 years presenting within 48 hours after acute acoustic trauma or idiopathic sudden sensorineural hearing loss with mean hearing loss of 30 dB or greater at the 3 most affected contiguous test frequencies. Single-dose intratympanic injection of AM-111 (0.4 or 2.0 mg/ml) or placebo; optionally, oral prednisolone if hearing improvement was less than 10 dB at Day 7. Efficacy was assessed by absolute hearing improvement (primary end point, Day 7), percentage hearing improvement, complete hearing recovery, speech discrimination improvement, and complete tinnitus remission. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events. The study failed to demonstrate a treatment benefit for the entire study population because mild-to-moderate ASNHL cases showed unexpectedly strong spontaneous recovery. In severe-to-profound ASNHL patients (threshold ≥60 dB), AM-111 0.4 mg/ml showed statistically significant, clinically relevant, and persistent improvements in hearing and speech discrimination and higher tinnitus remission compared with placebo. The study drug and the intratympanic injections were well tolerated. The study established proof of concept for AM-111 in the treatment of severe-to-profound ASNHL. Control for spontaneous hearing recovery is essential for ASNHL studies.