Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease
Andrea Vambutas, … , Lisa Rosen, Elliot Goldofsky
Andrea Vambutas, … , Lisa Rosen, Elliot Goldofsky
Published August 18, 2014
Citation Information: J Clin Invest. 2014;124(9):4115-4122. https://doi.org/10.1172/JCI76503.
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Clinical Research and Public Health

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease

Abstract

BACKGROUND. Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals.

METHODS. We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period.

RESULTS. Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels.

CONCLUSION. We demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01267994.

FUNDING. NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Authors

Andrea Vambutas, Martin Lesser, Virginia Mullooly, Shresh Pathak, Gerald Zahtz, Lisa Rosen, Elliot Goldofsky

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Figure 3

Hearing thresholds (PTA and WRS) relative to IL-1β plasma levels in a phase I/II trial of anakinra for corticosteroid-resistant AIED (NCT01267994).

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Hearing thresholds (PTA and WRS) relative to IL-1β plasma levels in a ph...
At visit 1, anakinra (daily subcutaneous injectable medication) was instituted (↑) for the next 84 days, after which therapy was discontinued (↓). Interval audiograms were obtained at visits 2 (day 28), 3 (day 56), and 4 (day 84). The 180-day post-treatment observational period is shown in visits 5 (day 114), 6 (day 174), and 7 (day 264). The left axis shows PTA, plotted inversely, similar to an audiogram (lower numbers correspond to better hearing); solid lines denote active ears (blue, left; red, right), and dashed lines denote inactive ears. Numeric values show WRS for the active ear (blue, left; red, right), with a best possible score of 100. The right axis shows IL-1β plasma values (green). In some patients, after visit 4, anakinra treatment was reinstated for an additional 28 days (denoted by arrows) because of a decline in hearing. Institution of steroid therapy in patient LIJ-07 is denoted by a red arrow.