To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL).
Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91.
Fifty-one European and Asian sites (tertiary referral centers, private ENT practices).
Two hundred fifty-six patients aged 18 to 65 years presenting within 72 hours following ISSNHL onset with mean hearing loss ≥ 40 dB and mean threshold ≥ 60 dB at the 3 worst affected contiguous test frequencies.
Single-dose intratympanic injection of AM-111 (0.4 or 0.8 mg/ml) or placebo; oral prednisolone as reserve therapy if hearing improvement < 10 dB at Day 7.
Hearing improvement to Day 28 was the primary efficacy endpoint; complete hearing recovery, frequency of reserve therapy used, complete tinnitus remission, improvement in word recognition were secondary endpoints. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events.
While the primary efficacy endpoint was not met in the overall study population, post-hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 0.4 mg/ml in patients with profound ISSNHL. The study drug and the administration procedure were well tolerated.
AM-111 provides effective otoprotection in case of profound ISSNHL. Activation of the JNK stress kinase, AM-111's pharmacologic target, seems to set in only following pronounced acute cochlear injury associated with large hearing threshold shifts.
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*Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
†ENT Hospital “Dr Dragiša MIšović-Dedinje”, Belgrade, Serbia
‡ENT Department, Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia
§Private ENT practice, Bad Schönborn, Germany
||Department of ENT, 10th Military Hospital, Bydgoszcz, Poland
¶Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan
#Private ENT practice, Olomouc, Czech Republic
**Department of Otolaryngology, Military Medical Academy, Sofia, Bulgaria
††Department of Otolaryngology, Thammasat University Hospital, Pathum Thani, Thailand
‡‡Auris Medical AG, Basel, Switzerland
Address correspondence and reprint requests to Thomas Meyer, Ph.D., Auris Medical AG, Dornacherstrasse 210, 4053 Basel, Switzerland. E-mail: firstname.lastname@example.org
The trial was registered on the EU Clinical Trials Register (EudraCT 2013-002077-21). It was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonisation and Good Clinical Practice guidelines. The study was approved by appropriate independent ethics committees and the competent national health authorities.
The study was supported in full by Auris Medical AG. H.S. received honoraria from the Sponsor as medical expert in discussions with a regulatory body as well as speaker at scientific symposia. T.M. is Chairman, CEO, and a major shareholder of Auris Medical AG's parent company.
The other authors disclose no conflicts of interest.