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

Background: Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL. Methods: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy. Results: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed. Conclusions: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids. Background 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 * Correspondence: tnakagawa@ent.kuhp.kyoto-u.ac.jp Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan Full list of author information is available at the end of the article Nakagawa et al. BMC Medicine 2010, 8:76 http://www.biomedcentral.com/1741-7015/8/76 © 2010 Nakagawa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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.