Intratympanic Sustained-Exposure Dexamethasone Thermosensitive Gel for Symptoms of Ménière's Disease: Randomized Phase 2b Safety and Efficacy Trial

Abstract

Objective: To evaluate safety and efficacy of a single intratympanic injection of OTO-104, sustained-exposure dexamethasone, in patients with unilateral Ménière's disease.

Study design: Randomized, double-blind, placebo-controlled, Phase 2b study over 5 months.

Setting: Fifty-two academic and community otolaryngology centers.

Patients: One hundred fifty four patients (77 per group) aged 18 to 85 years inclusive.

Intervention: Single intratympanic injection of OTO-104 (12 mg dexamethasone) or placebo.

Main outcome measures: Efficacy (vertigo) and safety (adverse events, otoscopy, audiometry, tympanometry).

Results: Primary endpoint (change from baseline in vertigo rate at Month 3) was not statistically significant (placebo [-43%], OTO-104 [-61%], P = 0.067). Improvements with OTO-104 were observed in prospectively defined secondary endpoints number of days with definitive vertigo, (Month 2 [P = 0.035], Month 3 [P = 0.030]), vertigo severity (Months 2-3, P = 0.046) and daily vertigo counts (Month 2, P = 0.042), and in some Short Form-36 (SF-36) subscales (Month 2 bodily pain P = 0.039, vitality P = 0.045, social functioning P = 0.025). No difference in tinnitus loudness or tinnitus handicap inventory (THI-25) was observed. OTO-104 was well tolerated; no negative impact on safety compared with placebo. Persistent tympanic membrane perforation was observed in two OTO-104 treated patients at study end.

Conclusion: OTO-104 was well-tolerated, did not significantly affect change from baseline in vertigo rate, but did reduce number definitive vertigo days, vertigo severity, and average daily vertigo count compared with placebo during Month 3. Results provide insight into analyzing for a vertigo treatment effect and support advancing OTO-104 into Phase 3 clinical trials for the treatment of Ménière's disease symptoms.

FIG. 1

CONSORT diagram. Patients were included in the treatment group to which they were randomized regardless of the actual study drug received.

FIG. 2

Percent change in vertigo rate during Month 3 from baseline (full analysis set). P = 0.067.

FIG. 3

Number of definitive vertigo days over 4 months^∗ (secondary endpoint). ^∗Prospectively defined poisson regression statistical model used to assess rate of definitive vertigo days within each monthly period. ^∗∗P = 0.035, ^∗∗∗P = 0.030.

FIG. 4

Change from baseline in vertigo severity score over 4 months^∗ (secondary endpoint). ^∗Prospectively defined data reported as change from baseline in vertigo severity score (total reported average vertigo score divided by the number of diary entries over the respective 28-day reporting period using a 5 point severity scale). ^∗∗P = 0.046.

FIG. 5

Change from baseline in average daily vertigo count over 4 months^∗ (exploratory analysis). ^∗Data reported as change from baseline in average daily vertigo count (average number of vertigo episodes reported in daily diary divided by the number of dairy entries in each respective study month). ^∗∗P = 0.042, ^∗∗∗P = 0.065.

FIG. 6

A, Summary level of the SF-36 change from baseline at Month 3—general health questionnaire (exploratory analysis). B, SF-36 general health questionnaire change from baseline at Month 3, subscales. ^∗P = 0.039, ^∗∗ P = 0.045, ^∗∗∗ P = 0.025. SF-36 indicates Short Form-36.