Dataset Information

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

ABSTRACT: To evaluate safety and efficacy of a single intratympanic injection of OTO-104, sustained-exposure dexamethasone, in patients with unilateral Ménière's disease.Randomized, double-blind, placebo-controlled, Phase 2b study over 5 months.Fifty-two academic and community otolaryngology centers.One hundred fifty four patients (77 per group) aged 18 to 85 years inclusive.Single intratympanic injection of OTO-104 (12?mg dexamethasone) or placebo.Efficacy (vertigo) and safety (adverse events, otoscopy, audiometry, tympanometry).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.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.

SUBMITTER: Lambert PR

PROVIDER: S-EPMC5414596 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Lambert Paul R PR Carey John J Mikulec Anthony A AA LeBel Carl C

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 20161201 10

<h4>Objective</h4>To evaluate safety and efficacy of a single intratympanic injection of OTO-104, sustained-exposure dexamethasone, in patients with unilateral Ménière's disease.<h4>Study design</h4>Randomized, double-blind, placebo-controlled, Phase 2b study over 5 months.<h4>Setting</h4>Fifty-two academic and community otolaryngology centers.<h4>Patients</h4>One hundred fifty four patients (77 per group) aged 18 to 85 years inclusive.<h4>Intervention</h4>Single intratympanic injection of OTO-1 ...[more]

PMID: 27749754

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Project description:Glucocorticoids are the first-line treatment for sensorineural hearing loss, but little is known about the mechanism of their protective effect or the impact of route of administration. The recent development of hollow microneedles enables safe and reliable sampling of perilymph for proteomic analysis. Using these microneedles, we investigate the effect of intratympanic (IT) versus intraperitoneal (IP) dexamethasone administration on guinea pig perilymph proteome. Guinea pigs were treated with IT dexamethasone (n = 6), IP dexamethasone (n = 8), or untreated for control (n = 8) 6 h prior to aspiration. The round window membrane (RWM) was accessed via a postauricular approach, and hollow microneedles were used to perforate the RWM and aspirate 1 μL of perilymph. Perilymph samples were analyzed by liquid chromatography-mass spectrometry-based label-free quantitative proteomics. Mass spectrometry raw data files have been deposited in an international public repository (MassIVE proteomics repository at https://massive.ucsd.edu/) under data set # MSV000086887. In the 22 samples of perilymph analyzed, 632 proteins were detected, including the inner ear protein cochlin, a perilymph marker. Of these, 14 proteins were modulated by IP, and three proteins were modulated by IT dexamethasone. In both IP and IT dexamethasone groups, VGF nerve growth factor inducible was significantly upregulated compared to control. The remaining adjusted proteins modulate neurons, inflammation, or protein synthesis. Proteome analysis facilitated by the use of hollow microneedles shows that route of dexamethasone administration impacts changes seen in perilymph proteome. Compared to IT administration, the IP route was associated with greater changes in protein expression, including proteins involved in neuroprotection, inflammatory pathway, and protein synthesis. Our findings show that microneedles can mediate safe and effective intracochlear sampling and hold promise for inner ear diagnostics.

Project description:ObjectiveTo determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease.Study designsThree randomized, double-blind, placebo-controlled, multicenter studies of OTO-104 in patients with Ménière's disease.SettingThe United States and throughout Europe.PatientsIndividuals with Ménière's disease aged 18 to 85 years.InterventionsAll three studies were conducted according to a similar protocol, whereby after a 1-month lead-in period, eligible patients received a single intratympanic injection of either 12 mg OTO-104 (otic formulation of dexamethasone in thermosensitive poloxamer) or placebo (1:1) and were observed for 3 months.Main outcome measuresThe primary efficacy endpoint was measured by the number of definitive vertigo days (DVDs) at month 3. Secondary objective was OTO-104 safety and tolerability including adverse events, audiometry, tympanometry, and otoscopic examinations.ResultsAlthough OTO-104 demonstrated numerically greater reductions in DVD compared with placebo across all three studies, statistical significance versus placebo (primary efficacy endpoint) was only achieved in one study, the AVERTS-2 study (n = 174, p = 0.029). Secondary vertigo efficacy endpoints were statistically significant at month 3 in that study including vertigo severity, the effect of vertigo on daily activity (days at home sick or bedridden), and vertigo frequency. In the AVERTS-1 study, which did not meet the primary endpoint, a subgroup analysis of the 115 patients (69.7% of study population) who did not previously receive intratympanic steroid injections demonstrated that OTO-104 patients had significantly lower mean DVD at month 3 than patients receiving placebo (1.9 for OTO-104 versus 3.0 for placebo; p = 0.045). Importantly, a significant placebo response was observed across studies in Ménière's disease patients. OTO-104 and the intratympanic injection procedure were well tolerated.ConclusionsIn all three high-quality, randomized, double-blind, placebo-controlled, multicenter studies, a single intratympanic injection of 12 mg OTO-104 demonstrated numerically greater reductions in vertigo versus placebo in patients with Ménière's disease, but statistical separation from placebo was demonstrated in only one of the studies. OTO-104 was safe and well tolerated.(Otonomy, Inc. funded; NCT02717442, NCT02612337, NCT03664674).

Project description:Gentamicin is used as a therapeutic agent for Ménière's disease because of its vestibulotoxicity causing chemo-ablation of the vestibular sensory epithelia. Its use has increased in recent years. However, there is still no consensus about the dose regimen of gentamicin in the treatment of Ménière's disease. In this study two different dose regimen treatment protocols are compared in a placebo controlled study design. The primary objective is to quantify the treatment effect on dizziness, the secondary objective is hearing evaluation.We performed a randomized, double-blind, placebo-controlled study in adults with unilateral Ménière's disease according to the AAO-HNS guidelines resistant to conservative medication. Three groups received four injections, administered weekly (four intratympanic injections with 40 mg/mL gentamicin solution, two injections gentamicin solution and two injections of placebo in random order, or four injections with placebo). Outcome measures were the score on the Dizziness Handicap Inventory and pure tone audiometry (PTA). Intended follow-up was 2 years.During follow-up one patient exceeded the accepted amount of hearing loss. Further, enrollment was very slow (until 12 months between two patients) and new insights showed an apparent benefit of intratympanic gentamicin treatment (ITG). Therefore we performed an unscheduled interim analysis which showed that PTA threshold shifts reached the stopping criteria in two more patients. Because of this, this study was ended. Of the three patients with the significant PTA threshold shift two were enrolled in the gentamicin group.No conclusions can be drawn concerning doses regimens. Now that new publications have shown that ITG treatment can be an effective and safe treatment, a placebo-controlled randomized controlled trial may not pass the ethical committee because of these recent reports in literature. Still, a dose regimen study (without placebo) on ITG treatment needs to be performed.This trial was registered in The University Medical Center Utrecht/ Gelre hospital Apeldoorn. Protocol ID: 07/343, EudraCT number 2006-005913-37.

Dataset Information

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

Publications

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

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