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Efficacy and Safety of AM-111 in the Treatment of Acute Sensorineural Hearing Loss: A Double-Blind, Randomized, Placebo-Controlled Phase II Study

Suckfuell, Markus*; Lisowska, Grazyna; Domka, Wojciech; Kabacinska, Anna§; Morawski, Krzysztof; Bodlaj, Robert; Klimak, Petr#; Kostrica, Rom**; Meyer, Thomas††

doi: 10.1097/MAO.0000000000000466
Sensorineural Hearing Loss & Tinnitus

Objective 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).

Study Design Prospective, double-blind, randomized, placebo-controlled study with follow-up visits on Days 3, 7, 30, and 90.

Setting Twenty-five European sites (academic tertiary referral centers, private ENT practices).

Patients 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.

Interventions 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.

Main Outcome Measures 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.

Results 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.

Conclusion 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.

*Department of ENT, Head and Neck Surgery, Martha Maria Hospital, Munich, Germany; †Department of Otolaryngology in Zabrze, Medical University of Silesia, Katowice; ‡Department of Otolaryngology, District Specialist Hospital, Rzeszow; §Department of Otolaryngology and ENT Oncology, Pomeranian Medical University, Szczecin; ∥Department of Otolaryngology, Medical University of Warsaw, Warsaw, Poland; ¶Private ENT practice, Lichtenfels, Germany; #Department of ENT, Head and Neck Surgery, Regional Hospital, Kladno; **Department of ENT, Head and Neck Surgery, Masaryk University, Brno, Czech Republic; and ††Auris Medical AG, Basel, Switzerland

Address correspondence and reprint requests to Thomas Meyer, Ph.D., Auris Medical AG, Falknerstrasse 4, 4001 Basel, Switzerland; E-mail:

The study was supported in full by Auris Medical AG. M. S. received honoraria from the Sponsor as medical expert in discussions with a regulatory body and as safety officer for an unrelated study. T. M. is the Managing Director and a major shareholder of Auris Medical AG.

The other authors disclose no conflicts of interest.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Acute or sudden hearing loss can be a frightening symptom of an inner ear dysfunction. It may be accompanied by other disturbing or unpleasant symptoms, such as tinnitus or vertigo, and frequently prompts an urgent medical visit (1). Triggers for acute sensorineural hearing loss (ASNHL) include acute acoustic trauma (AAT), barotrauma, head trauma, or drug exposure. Often, the precise etiology is unknown or may only be suspected, leading to a diagnosis of idiopathic sudden sensorineural hearing loss (ISSNHL).

Oxidative stress, alterations in stereocilia bundle, glutamate excitotoxicity, collapse of supporting cells, strial edema, or inflammatory response have been reported as pathophysiologic mechanisms underlying ASNHL (2–5). Its natural history is characterized by frequent partial or complete hearing recovery because of cellular defenses and intrinsic repair mechanisms such as neosynaptogenesis (6). However, part of the damage often is irreversible, resulting in permanent threshold shift (2). Recent animal data suggest that slow degeneration of spiral ganglion cells and delayed hearing loss may occur even despite complete short-term recovery (7,8).

Despite extensive research into the pathophysiology of ASNHL and considerable clinical interest, there still exists no treatment that has unequivocal evidence of efficacy for AAT (9) or ISSNHL (10–15). Given low evidence levels, ISSNHL guidelines refrain in general from prescribing treatments (1,16); considering the impact of hearing loss on quality of life, oral steroids, hyperbaric oxygen, or rheologics therapy are recommended as treatment options.

AM-111 (D-JNKI-1 gel for intratympanic injection; Auris Medical AG, Basel, Switzerland) is a 31–amino acid cell-permeable peptide, formulated in a biocompatible hyaluronic acid gel, that is being developed for topical treatment of ASNHL. AM-111’s effector domain has been derived from the scaffold protein islet-brain 1, which retains c-Jun N-terminal kinase (JNK) in the cytoplasm; it is coupled to the trans-activator of transcription (TAT) protein transduction domain (17). JNK is a member of the stress-activated group of mitogen-activated protein kinases involved in apoptosis after extracellular stress insults and inflammation (18). Its inhibition prevents formation of transcription complexes and further progress along the apoptotic pathway or activation of genes, which are encoding inflammatory molecules.

JNK is involved in apoptosis of stress-injured hair cells and spiral ganglia neurons (19,20), the principal mechanism of cell death in the cochlea after traumatic injury (21) or cochlear inflammation (22,23). Treatment with AM-111 was shown to be otoprotective in various models of cochlear insult: acute noise trauma (24–26), acute labyrinthitis (23), aminoglycoside ototoxicity (24), bacterial infection (27), cochlear ischemia (28), and cochlear implantation trauma (29). The breadth of AM-111’s therapeutic spectrum suggests a key role of JNK in ASNHL.

A small, randomized, double-blind, phase I/II study in victims of firecracker noise trauma previously showed that AM-111 at 0.4 or 2.0 mg/ml was well tolerated and provided first indications of potential efficacy (30). A larger phase II study aimed to evaluate AM-111’s efficacy and safety in ASNHL.

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Study Design and Participants

This was a multicenter, double-blind, randomized, placebo-controlled phase II study with 2 sequential dose cohorts (AM-111 2.0 mg/ml, “high dose”, and AM-111 0.4 mg/ml, “low dose”). The study involved 25 sites in Poland, Germany, and the Czech Republic and was registered on (NCT00802425). 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.

Eligible participants were to be aged 18 to 60 years and experienced ASNHL (unilateral ISSNHL, unilateral or bilateral AAT) with hearing loss of at least 30 dB and onset not more than 48 hours previously. The hearing loss was determined against a reference value: mean hearing threshold at the 3 most affected contiguous test frequencies (pure tone average [PTA]) less corresponding mean hearing threshold of the contralateral ear (31). In case of previously asymmetric hearing or bilateral ASNHL, thresholds from a previous audiogram or ISO-7029; 2000 norm values served as reference (2% and 3% of patients). The PTA frequencies determined at baseline remained fixed for all evaluations.

Exclusion criteria included history of Ménière’s disease, autoimmune or radiation-induced hearing loss, endolymphatic hydrops or fluctuating hearing loss, suspected perilymph fistula, membrane rupture or retrocochlear lesion, barotrauma, air-bone gap of greater than 20 dB in 3 contiguous frequencies, previous ASNHL incident within the past 6 weeks, and acute or chronic otitis media or otitis externa. Women who were breast feeding, pregnant, or who planned a pregnancy during the study or women of childbearing potential who declared being unwilling or unable to practice an effective method of contraception were excluded.

Written informed consent was obtained from each patient before the performance of any study-specific procedures.

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Randomization and Masking

At baseline (Day 0), study participants were randomized to receive AM-111 or placebo at a 2:1 ratio. The study drug formulation was identical in appearance for active and placebo doses and revealed no differences during administration. The study medication was provided to study sites in identical kits and sequentially numbered with an identifier for the study site and one for each patient. A separate randomization sequence was generated for each study site. The randomization was blocked in groups of 3 without revealing the block size to study staff. Study patients and investigators remained blinded throughout the entire study.

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The study consisted of a baseline assessment and 4 follow-up visits on Days 3, 7, 30, and 90. Baseline assessments included a general physical examination, vital signs, and a urine pregnancy test for women of childbearing age. At each study visit, pure tone hearing thresholds, speech discrimination at 60 and 80 dB, and subjective tinnitus loudness were determined. The primary efficacy end point was the PTA improvement from baseline to Day 7. Rapid amelioration must be the aim of any ASNHL therapy, and the course of recovery should become apparent already at this early time point without being influenced by any reserve therapy. The percentage improvement of PTA relative to baseline hearing loss and the percentage of patients with complete remission (PTA recovering to within 10 dB of the reference value) at Day 7 were coprimary endpoints.

Trained study personnel determined pure tone hearing thresholds for both ears at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz using the descending method of limits (air and bone conduction). Contralateral masking was required if the interaural difference in air-bone conduction was greater than 50 dB. Threshold was defined as the lowest audible level, measured twice for that patient. In case of no response because of profound hearing loss, threshold was set at 120 dB. Hearing loss was classified by baseline audiogram type (32) and initial PTA frequency range (low, medium, or high). Speech discrimination score (SDS) was determined for both ears as percentage of correct responses using 2 standard lists with 20 language-specific monosyllabic words each, presented randomly and with contralateral masking. Those patients reporting tinnitus were asked to rate its loudness “right now” on a numerical scale ranging from 0 (no tinnitus) to 10 (extremely loud).

The primary safety end point was the frequency of clinically relevant hearing deterioration in the treated ear, defined as threshold shift of 10 dB or greater from the baseline at the average of 3 contiguous test frequencies. Further safety assessments included vital signs, nystagmoscopy/nystagmography, otoscopy, and tympanometry.

Approximately 0.25 ml of the study drug was administered on Day 0 by intratympanic injection under local anesthesia through a small myringotomy with the patient’s head placed in a position tilted 45 degrees toward the unaffected ear. Patients remained in their reclined or supine position for approximately 30 minutes to allow for diffusion of the active substance into the cochlea. In case of bilateral AAT, only the worst affected ear was treated. Subjects whose PTA recovered less than 10 dB from baseline to Day 7 were given the option to receive oral prednisolone 50 mg (Ratiopharm, Ulm, Germany) b.i.d. for 5 days. Previous reports showed no difference in outcomes for corticosteroid therapy initiated within the first 24 hours or within the first week (32).

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Statistical Methods

The sample size was determined based on an expected effect size of 0.6, a 2-sided type I error rate of 5% and a statistical power of 80%. This resulted in a planned sample size of 102 patients per cohort (68 AM-111, 34 placebo), for a total of 204 patients.

Efficacy analyses were primarily performed on a modified “intention-to-treat” (mITT) analysis set (treated patients with PTA measured on Day 3 ± 1 or Day 7 + 4 days at most) and secondarily on the “per protocol” (PP) analysis set. The “safety population” analysis set included all patients who received an injection of the study medication. Random imputation was performed for missing PTA values at Days 7 and 30 and missing SDS values at Day 7 based on the preceding value and the mean change observed in the respective treatment group (mITT set).

For continuous efficacy end points, analysis of covariance (ANCOVA) models were used including treatment group and initial frequency range as class effects and baseline values of the respective endpoint as covariate. For the complete recovery rate, a logistic regression model was applied including treatment, initial frequency range, and baseline hearing loss as predictor variables. Initial frequency range was included in the models because spontaneous recovery has been reported to be more pronounced in the lower frequencies (32). All analyses of secondary efficacy end points were exploratory. Poolability of placebo data across the 2 dose cohorts was tested before primary efficacy analysis with an ANCOVA including cohort and initial frequency range as class effects and baseline hearing loss as covariate. The percentage of subjects with posttreatment remission of ASNHL-related tinnitus was compared using the Fisher exact test.

The frequency of patients meeting the primary safety end point was compared using the Fisher exact test within cohorts. The frequency of clinically relevant hearing loss was compared between treated and untreated ears applying McNemar’s test on symmetry.

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Patient Flow and Characteristics

The trial profile in accordance with the CONSORT statement (33) is shown in Figure 1. A total of 210 patients were screened, randomized, and treated; 11 patients (5%) were lost to follow-up, and 6 (3%) withdrew consent. Baseline demographics for the study population are presented in Table 1 and hearing characteristics in Table 2. Most patients were male (61%), experienced ISSNHL (92%), and had tinnitus as comorbidity (80%). On average, patients were treated 29 hours after ASNHL onset. The mean hearing loss at the 3 most affected test frequencies was 52.2 dB; the mean SDS was 52.3% (60 dB) and 67.6% (80 dB). Clinically relevant spontaneous nystagmus (defined as >5 beats/30 s) was observed in 7% of patients. Overall, baseline characteristics were similar for treatment groups.

FIG. 1

FIG. 1





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Efficacy Outcomes

Because the 90% confidence interval for the difference in mean PTA improvement was within the prespecified interval (±15 dB), placebo data from both cohorts were pooled for efficacy analyses. The global null hypothesis of no differences between treatment groups in PTA improvement from baseline to Day 7 could not be rejected: least square means were 24.0, 27.9, and 22.5 dB for the placebo, low-dose, and high-dose groups, respectively (p = 0.208). The study thus failed to meet its primary efficacy end point. There were also no significant differences between either dose levels of AM-111 compared with placebo for the coprimary endpoints and for the other follow-up visits.

Analysis of PTA improvement by hearing loss severity (34) revealed unexpectedly strong spontaneous recovery for lesser severities: by Day 7, placebo-treated patients enrolling with mild-to-moderate hearing loss (PTA <60 dB; n = 41) had recovered already 28.9 dB or 77% of their initial loss, whereas for patients with severe to profound hearing loss (PTA ≥60 dB; n = 30), it was only 17.3 dB or 24% (Figs. 2, A and B). ANCOVA revealed a statistically significant interaction term between treatment group and hearing loss severity subgroup (p = 0.04), indicating that the latter should be analyzed separately. Because mild-to-moderate hearing loss was essentially fully recovered by Day 90 (just 3 dB or 8.1% remained on average), further exploratory analyses focused on the severe-to-profound category, where a loss of 37.9 dB (52.6%) still remained (Table 3 for baseline characteristics).

FIG. 2

FIG. 2



ANCOVA in the severe-to-profound hearing loss subgroup demonstrated superiority of AM-111 0.4 mg/ml over placebo for the primary as well as the coprimary endpoints (Table 4). PTA improvement was 12.1 dB higher (p = 0.017), relative PTA improvement was 19.5 percentage points better (p = 0.021), and the frequency of complete recovery was 17.7 percentage points higher (logistic regression p = 0.044) for AM–111 0.4 mg/ml compared with placebo. ANCOVA for SDS also showed statistically significantly better improvement: 21.5 and 18.3 percentage points at 60 and 80 dB (p = 0.023 and 0.019, respectively). The high-dose group overall showed improvement between the low-dose and the placebo groups, without reaching statistical significance.



A clinically relevant and statistically significant therapeutic effect of AM-111 low-dose was apparent already at Day 3; it continued to Day 30 and leveled off somewhat by Day 90 but still remained clinically relevant (Table 5 and Fig. 3A). At Day 90, 42% of patients had achieved complete recovery versus 47% and 26% in the AM-111 high-dose and placebo groups, respectively. Sensitivity analysis showed that the therapeutic effect did not depend on early treatment: in patients who were treated only after 24 hours (72% of the subgroup), it actually was larger as spontaneous recovery decreased (Fig. 3B).



FIG. 3

FIG. 3

Multiple regression analysis showed AM-111 low-dose treatment consistently as single most important determinant of PTA or SDS improvement to Days 7 and 30. Other factors such as high-frequency hearing loss, AAT as etiology, partial or complete deafness, or spontaneous nystagmus tended to have negative effects, whereas ASNHL-related tinnitus or a flat audiogram had positive effects on hearing improvement; however, evidence levels were rather weak. The reserve therapy was administered most frequently in placebo patients (60%) and least often in the AM-111 low-dose group (31%). Prednisolone administration did not seem to have any particular effect on PTA improvement between Days 7 and 30 (Table 6).



Complete tinnitus remission was more frequent in severe-to-profound hearing loss patients receiving AM-111 low dose (56.0%, p = 0.045) and AM-111 high dose (48.3%, p = 0.152) than in the placebo group (26.1%).

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Safety and Tolerability Outcomes

There were no statistically significant differences between treatment groups for the primary safety endpoint at Day 7 or any other time point; the incidence of clinically relevant hearing deterioration over all visits was 14.5%, 12.5%, and 20.0% in the placebo, AM-111 low dose, and AM-111 high-dose groups, respectively. In the treated ear, it was observed more often than in the untreated contralateral ear on Days 3 and 7 (p < 0.05) but not on Day 30 or 90, pointing to still ongoing effects of the underlying pathology and/or transient effects of the myringotomy.

Adverse events (AEs) were reported by similar proportions of patients with no major differences in frequency, intensity, or relationship between treatment groups (Table 7). In the AM-111 high-dose group, there were a few more patients with continued worsening of symptoms in the first days after treatment that may be causally related to undiagnosed endolymphatic hydrops or retrocochlear dysfunction. At baseline, the incidence of clinically relevant spontaneous nystagmus, a negative prognostic factor (1,35), was highest in the high-dose group.



The majority of AEs were local, mild, or moderate in severity and concerned hearing and tinnitus. Detailed analysis of hearing deteriorations at Days 3 and 7 suggested most often the ongoing underlying pathology as cause; 3 cases were related to the myringotomy, and 1 case to middle ear infection (fully resolved). The majority of tinnitus-related AEs were observed only after Day 7 and thus considered unrelated. The number of patients with procedure-related AEs (ear discomfort or pain, incision site complications, middle ear infection) was less than 5%. By Day 7, the tympanic membrane was closed again in all but 7 patients (mild; subsequently fully resolved). Vital signs remained stable throughout the observation period, and the incidence of spontaneous nystagmus decreased in all treatment groups.

For 9 patients nonfatal serious AEs (SAEs) were recorded (2, 4, and 3 patients in the placebo, AM-111 low dose, and AM-111 high dose groups). All SAEs except two were considered unlikely related or not related, and all except two (diagnosis of internal auditory canal tumor and neurofibromatosis type II, not related) were recovered or recovering. The most common SAE was “deafness neurosensory,” as some severe to profound hearing loss patients with insufficient recovery, acute relapse, or ongoing deterioration were hospitalized in Poland for infusion therapy in line with customary medical practice.

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To our knowledge, this was the first large randomized controlled trial with a medication specifically developed for intratympanic treatment of ASNHL. The study demonstrated that AM-111 is well tolerated and safe. Whereas the study failed to demonstrate confirmatory efficacy in the whole study population, exploratory analyses revealed a statistically significant and clinically relevant effect of AM-111 0.4 mg/ml in the treatment of severe-to-profound ASNHL. Improvement in PTA and SDS was more rapid and more profound than for placebo, and complete hearing recovery and tinnitus remission were more frequent. The latter finding, which was not yet apparent in the previous smaller trial (30), suggests that preservation of sensory cochlear cells may prevent tinnitus and hearing loss at the same time. Outcomes with AM-111 compare favorably with published data from 2 recent well-designed ISSNHL trials with prednisolone in terms of safety and efficacy, which showed frequent side effects for oral and intratympanic administration (36) and no therapeutic benefit over placebo (37).

The present study gathered important new data on spontaneous hearing recovery, which is a key determinant for efficacy analysis. Although there is consensus that spontaneous recovery can be substantial in ASNHL (13), actually no reliable and detailed reference data have been available. Beside the absence of a generally accepted methodology for defining, measuring, and evaluating ASNHL (31), this has to be attributed mostly to the dearth of placebo-controlled studies (13). The largely unknown natural history coupled with fears of potentially irreversible damage through nontreatment has clearly deterred previous investigators from using a placebo control. In turn, observation of hearing recovery after steroid or other treatments may erroneously be interpreted as a therapeutic effect, although actually nothing but spontaneous recovery is occurring. A recent noncontrolled ISSNHL study with intratympanic methylprednisolone (average hearing loss, 81 dB) showed, for example, mean improvement of 32 dB over 3 months (38), whereas in the present study, under similar conditions, placebo-treated severe-to-profound hearing loss patients improved 33.5 dB.

As pointed out by earlier authors, spontaneous recovery may produce a “floor effect” in the evaluation of treatment effects (39). A minimum initial hearing loss should be set high enough to allow a treatment to actually exceed such floor effect—otherwise, a study may fail to detect a therapeutic benefit that is actually there (40). In retrospect, the minimum hearing loss of 30 dB at baseline was set too low for the early post-ASNHL stage that was evaluated in the present study, as patients were enrolled whose spontaneous recovery was impossible or difficult to beat in a clinically meaningful way. Adjustment for the level of initial hearing loss in the ANCOVA model served to reduce within-group variance but was not destined to control for a floor effect. A higher share of mild to moderate hearing loss and early treatment (≤12 hr from onset) cases in the placebo group compared with the active groups weighed further on the size of the treatment effect.

Another unexpected outcome from the present study was that the AM-111 0.4 mg/ml group initially appeared to show better improvement than the AM-111 2.0 mg/ml group. However, the difference was not statistically significant for absolute PTA improvement and much smaller or absent for the other efficacy outcomes. Results in the high-dose group may have been negatively influenced by a disproportionate share of patients with unfavorable prognostic factors (high-frequency hearing loss, spontaneous nystagmus, and age) or with continued worsening of symptoms in the beginning. The high dose may thus be considered as potentially equally effective.

In animal studies, the most effective AM-111 concentration was 0.2 to 0.4 mg/ml (25,28); at higher concentrations, the compound still had an otoprotective but decreasing effect (unpublished data). The latter may reflect dose-dependent inhibition of prosurvival effects of JNK as described elsewhere (41) or cell membrane perturbation by TAT (42). It may well be that in humans, 0.4 mg/ml lies on the ascending and 2.0 mg/ml on the descending slope of the dose-response curve. Hence, a concentration in between might provide additional therapeutic benefits. Further incremental benefits may also be achieved from repeated AM-111 administration because the acute stage of cochlear inflammation after ASNHL has been reported to last up to 1 week (4,43).

In conclusion, AM-111 seems to be a promising novel approach for treating ASNHL with a short local therapy that attenuates permanent hearing loss and tinnitus. Future clinical studies with AM-111 should focus on the severe-to-profound hearing loss population in the early post-ASNHL stage and further evaluate the optimum concentration and dose regimen. Although the present study revealed a very high spontaneous recovery rate in patients with mild-to-moderate hearing loss, the prognosis and hence the need for treatment would most likely be different for them if they presented only after 48 hours as natural repair processes continue to lose strength.

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The authors thank Neil Sanderson for proofreading the manuscript, Prof. Uwe Baumann for the support in specifying audiologic assessments and independent expert review of all audiology output, and Dr. Manfred Wargenau and Dr Frauke Friedrichs for the biostatistical contributions. The authors also thank all participating acute hearing loss patients who made this study possible and to all investigators and their staff: Germany—Robert Bodlaj, Lichtenfels; Andreas Haisch, Berlin; Florian Heimlich, Heidelberg; Jan Kiefer, Regensburg; Christian Otterstedde, Frankfurt; Friedemann Pabst, Dresden; Stefan Plontke, Tübingen; Hans Christoph Reeker, Velbert; Frank Reintjes, Braunschweig; Elfi Seeger-Schellerhoff, Porta Westfalica; Poland—Wojciech Domka, Rzeszow; Grazyna Gawlicka, Czestochowa; Anna Kabacinska, Szczecin; Ireneusz Kantor, Warsaw; Janusz Klatka, Lublin; Grazyna Lisowska, Zabrze; Krzysztof Morawski, Warsaw; Ewa Olszewska, Bialystok; Krzysztof Wilczynski, Wroclaw; Czech Republic—Viktor Chrobok, Hradec Kralove, Petr Klimak, Kladno; Rom Kostrica, Brno; Radek Langer, Mlada Boleslav, Arnost Pellant, Pardubice, Jaroslav Slípka, Pilsen.

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Acute acoustic trauma; Apoptosis; Idiopathic sudden sensorineural hearing loss; Intratympanic treatment; Otoprotection; Spontaneous recovery; Tinnitus

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