Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial

Sudden sensorineural hearing loss (SSHL) is a condition in which an individual experiences hearing loss of at least 30 dB over at least three test frequencies in one ear within a period of 3 days [1]. Some patients recover completely without medical intervention, often within the first 3 days. Others get better slowly over a 1-week or 2-week period, which is known as 'spontaneous recovery' [1]. Although a good recovery is likely, 15% of patients with SSHL experience hearing loss that worsens over time. Approximately 40,000 new cases of SSHL occur each year in the US [1], and 35,000 patients with SSHL consult a doctor each year in Japan [2]. SSHL can affect anyone; however, for reasons that so far remain unknown, it is most often reported in people aged between 30 and 60 years. The most common therapy for SSHL is the systemic application of glucocorticoids. Unfortunately, about 20% of patients do not respond to this treatment [3].

Based on these findings, researchers have sought alternative therapeutic options for SSHL. Protecting auditory hair cells and primary neurons from irreversible degeneration is a practical strategy, as inner ear cells have limited regeneration capacity [4]. Recent improvements in our understanding of the role of growth factors in the maintenance of mature peripheral auditory systems have led to numerous attempts to define ways to reduce auditory hair cell and neuron degeneration, which have indicated that some growth factors have potential for the treatment of SSHL [5‐8]. However, growth factors have not yet been used for this purpose in a clinical setting, as several obstacles have hindered their progress. Safe and effective methods for the sustained delivery of growth factors to the inner ear need to be developed to facilitate their clinical application. As a solution to this problem, we used gelatin hydrogels as a vehicle to deliver growth factors to the inner ear [9]. Gelatin hydrogels consist of gelatin polymers that are electrostatically complexed with growth factors [10]. The growth factors are released by the enzymatic degradation of the gelatin polymers after application. Our focus was on insulin-like growth factor 1 (IGF1), which has been approved for clinical application. We conducted a series of animal experiments, which revealed that topical IGF1 application via gelatin hydrogels significantly improved hearing by protecting auditory hair cells against damage caused by intense noise exposure [11] or ischaemic injury [12]. Moreover, no adverse events were observed in animals following the local application of IGF1 via gelatin hydrogels [11].

Here, we report on a prospective clinical trial of topical IGF1 application through gelatin hydrogels for the treatment of glucocorticoid-resistant SSHL, which was intended to provide preliminary estimates of variables for generating hypotheses for more specific studies using randomised trials when appropriate. Systemic glucocorticoid application has been regarded as a primary treatment of choice for SSHL. We recruited patients with SSHL that showed no recovery to systemic glucocorticoid administration as subjects in the present study.

In all, 26 patients fulfilled the inclusion criteria, 1 of whom was excluded before the test treatment because of a diagnosis of functional hearing loss. In total, 25 patients (13 women and 12 men) were treated in accordance with the study protocol, and data for assessment of the primary and secondary outcomes were available for all patients. The median age at registration was 49 years (range 23-72 years). Comorbidities were found in 22 of the 25 patients (88%), and 18 of the 25 patients (72%) had a history of previous diseases. None of the comorbidities or previous diseases presented were directly associated with SSHL. None of the patients had family histories of SSHL. All 25 patients complained of associated symptoms: 22 (88%) complained of tinnitus, 19 (76%) had a feeling of ear fullness and 14 (56%) complained of dizziness. The median interval between the onset of SSHL and the initiation of the test treatment was 23 days (range 15-32 days). The mean hearing level at registration was 81.2 dB (95% confidence interval (CI), 71.2 to 91.1).

A summary of the hearing recovery according to pure-tone audiometry for all of the patients is shown in Table 2. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of the patients showed hearing improvement. The null hypothesis for the primary outcome was not rejected. Of the 25 patients, 0 showed complete recovery, 1 (4%) showed marked recovery, 11 (44%) showed slight recovery and 13 (52%) showed no recovery at 12 weeks. None of the patients who were treated more than 26 days after the onset of SSHL showed hearing improvement. At 24 weeks after the test treatment, the proportion of patients showing hearing improvement was 56% (95% CI 35% to 76%; P = 0.015), showing that the null hypothesis was rejected for the data at 24 weeks. Of the 25 patients, none showed complete recovery, 1 (4%) showed marked recovery, 13 (52%) showed slight recovery, and 11 (44%) showed no recovery. Two patients showed a hearing improvement of less than 10 dB at 12 weeks after the treatment, but an improvement of 10 dB at 24 weeks.

No serious adverse events associated with the test treatment occurred, although any adverse events were recorded in all of 25 patients to be evaluated. Adverse events with an incidence rate of more than 20% included dizziness (44%), nausea (24%), otitis externa (32%), common cold (20%) and otitis media (28%). All adverse events disappeared within the observation period. Except for two patients, the dizziness appeared either on the day of local IGF1 application or on the next day, and continued for a mean of 6.4 days (range 1-20 days). In all patients, the dizziness appeared after the test treatment. In one patient, dizziness appeared 2 months after the test treatment and continued for 4 months. In another patient, dizziness appeared 7 days after the application and disappeared 2 days later. Otitis media was found in 7 of the 25 (28%) patients, and was cured within a mean of 9.4 days (range 2-17 days). Exacerbation of tinnitus appeared in two patients at 29 and 33 days after the test treatment, respectively. None of the patients showed residual perforation of the tympanic membrane or additional hearing loss over 10 dB.

Hearing loss is common, affecting about 5% to 6% of the population of the USA [1]. SSHL is one of the most common clinical conditions encountered by otolaryngologists, although it is less common than age-related hearing loss. National surveys have demonstrated the incidence of SSHL to be 5-30 per 100,000 per year [2, 16, 17]. Systemic application of glucocorticoids has been used as a standard therapy, although the supporting evidence is weak. Although systemic glucocorticoid application results in hearing recovery in some patients with SSHL, approximately 20% show no recovery [3]. Alternative therapeutic treatment options for SSHL have thus been eagerly sought. Against this background, we began developing topical IGF1 treatments using gelatin hydrogels in animal models [5, 11, 12], followed by a clinical trial to investigate their safety and efficacy for use in patients with SSHL. Some studies have indicated that SSHL develops when the inner ear does not receive a sufficient oxygen supply [18]. Consequently, hyperbaric oxygen treatment has been used as an alternative option for the treatment of SSHL [19, 20]. At Kyoto University Hospital, hyperbaric oxygen therapy has been used as a secondary treatment of choice for glucocorticoid-resistant SSHL [14]. We thus used the proportion of patients with glucocorticoid-resistant SSHL showing hearing recovery following hyperbaric oxygen therapy as a historical control.

Here, we report hearing recovery according to pure-tone audiometry and incidence of adverse events following topical IGF1 application using gelatin hydrogels in patients with SSHL enrolled in a single arm, non-randomised and open trial. Topical IGF1 treatment resulted in hearing recovery in approximately half of the patients with SSHL that had not responded to systemic glucocorticoid application, although the null hypothesis was rejected at 24 weeks after the test treatment but not at 12 weeks. In addition, no serious adverse events were observed during the 24-week observation period. The results indicated that the topical IGF1 application using gelatin hydrogels was safe, and had equivalent or superior efficiency to the hyperbaric oxygen therapy that was used as a historical control; this suggests that the efficacy of topical IGF1 application using gelatin hydrogels for SSHL that is resistant to systemic glucocorticoid treatments should be evaluated using randomised clinical trials.

Spontaneous recovery occurs in 40% to 65% of patients with SSHL [21, 22], which makes it difficult to examine the exact therapeutic effects of interventions. It is therefore important either to eliminate patients with spontaneous recovery from such trials or to include a placebo control. In the present study, the test treatment was initiated in all patients more than 14 days (mean 23 days; range 15-32 days) after the onset of SSHL. In most cases, spontaneous recovery occurs within 14 days of onset [21]. We therefore consider spontaneous recovery to have had a negligible influence on the present results.

As a secondary treatment of choice for SSHL, intratympanic injection of glucocorticoids has gained considerable attention, because it seems to deliver a high concentration of glucocorticoids to the inner ear [23]. In addition, local application can reduce the total amount of glucocorticoids that needs to be applied, leading to a reduced risk of adverse events [24]. However, this approach remains controversial, because the criteria used to judge its efficacy differ in the literature. Haynes et al. [25] reviewed the literature on the intratympanic injection of glucocorticoids for SSHL after the failure of systemic treatment, and re-estimated the hearing recovery based on their own criteria, according to which a 20 dB improvement as indicated by pure-tone audiometry or a 20% improvement in discrimination was considered to be a successful therapeutic intervention. The recovery rates according to their criteria were 0% to 40%. When these criteria for successful intervention were applied to the data from the present study, the recovery rate was 24%, suggesting that the efficacy of topical IGF1 treatment using gelatin hydrogels might be equivalent to that of the intratympanic injection of glucocorticoids. We therefore recommend that the efficacy of topical IGF1 treatment using gelatin hydrogels should be evaluated in a randomised clinical trial, and its effectiveness for SSHL should be compared with that of the intratympanic injection of glucocorticoids.

The present results indicate the safety and efficacy of the use of topical IGF1 treatment using gelatin hydrogels for SSHL resistant to systemic glucocorticoid treatments. A double-blinded, randomised clinical study could clarify these findings. However, there are ethical obstacles to the use of double-blinded, randomised clinical trials for SSHL. For instance, the time from the onset of SSHL to the start of treatment has been regarded as important for the outcome, with prompt treatment preventing the development of irreversible auditory pathological changes. In addition, systemic glucocorticoid treatments have widely been accepted as a standard therapy for SSHL, and have led to improvement in some patients [26]. Hence, there would be ethical difficulties in not offering patients treatment with systemic glucocorticoids. Moreover, topical IGF1 application using gelatin hydrogels requires the use of surgical procedures, which would make it difficult to test in a double-blinded study. Therefore, as a next step, we will conduct a randomised clinical trial to compare the efficacy of topical IGF1 treatment using gelatin hydrogels with that of the intratympanic injection of glucocorticoids in patients with SSHL that is resistant to systemic glucocorticoids; it is hoped that this might clarify the efficacy of topical IGF1 treatment using gelatin hydrogels.