Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Phase 3 Trials of Thermosensitive Ciprofloxacin Gel for Middle Ear Effusion in Children with Tubes.

OBJECTIVE: To investigate the efficacy, safety, and microbiology of a thermosensitive otic suspension of ciprofloxacin (OTO-201) in children with bilateral middle ear effusion undergoing tympanostomy tube placement. STUDY DESIGN: Two randomized, double-blind, sham-controlled phase 3 trials. Patients were randomized to intratympanic OTO-201 or sham. SETTING: Children with bilateral middle ear effusion undergoing tympanostomy tube placement. SUBJECTS/METHODS: Studies evaluated 532 patients (6 months to 17 years old) in a combined analysis of efficacy (treatment failure: presence of otorrhea, otic or systemic antibiotic use, lost to follow-up, missed visits), safety (audiometry, otoscopy, tympanometry), and microbiology. RESULTS: There was a lower cumulative proportion of treatment failures in patients receiving OTO-201 vs tympanostomy tubes alone (1) on days 4, 8, 15, and 29; (2) on day 15, primary end point (23.0% vs 45.1%; age-adjusted odds ratio, 0.341; P < .001; reduction in relative risk, 49%); and (3) on day 15, blinded-assessor otorrhea treatment failure (7.0% vs 19.4%; age-adjusted odds ratio, 0.303; P < .001; reduction in relative risk, 64%). Per-protocol and subgroup analyses (baseline demographics, pathogen type, culture status, effusion type, microbiologic response) supported these findings. There were no drug-related serious adverse events; the most frequent treatment-emergent adverse events in both groups were pyrexia, postoperative pain, nasopharyngitis, cough, and upper respiratory tract infection. OTO-201 administration had no evidence of increased tube occlusion and no negative effect on audiometry, tympanometry, or otoscopy. CONCLUSIONS: Combined analysis of 2 phase 3 trials demonstrated a lower cumulative proportion of treatment failures through day 15 compared with TT alone when OTO-201 was administered intratympanically for otitis media with bilateral middle ear effusion at time of tympanostomy tube placement.

Safety and Efficacy of Intratympanic Ciprofloxacin Otic Suspension in Children With Middle Ear Effusion Undergoing Tympanostomy Tube Placement: Two Randomized Clinical Trials.

IMPORTANCE: Otorrhea after tympanostomy tube placement (TTP) in children is common. Although not approved by the US Food and Drug Administration, antibiotic ear drops are routinely used intraoperatively and prescribed for multidose, multiday postoperative administration by caregivers. OBJECTIVE: To investigate the safety and efficacy of a single-dose intratympanic, intraoperative, thermosensitive, otic suspension of ciprofloxacin (OTO-201) in children requiring TTP. DESIGN, SETTING, AND PARTICIPANTS: Two identically designed, prospective, double-blind, sham-controlled, multicenter phase 3 randomized clinical trials included 532 patients aged 6 months to 17 years with middle ear effusions. Patients with confirmed bilateral effusions on the day of TTP were randomized to TTP alone or to TTP with OTO-201 injection. Children underwent a 28-day observation period. Data were collected from November 14, 2013, to June 3, 2014. Final follow-up was completed on June 16, 2014, and intent-to-treat data were analyzed from June 10 to August 27, 2014. MAIN OUTCOMES AND MEASURES: Efficacy was assessed as treatment failure, including the presence of otorrhea, use of otic or systemic antibiotics, loss to follow-up, or missed visits. Safety was assessed for serious adverse events and treatment-emergent adverse events using audiometry, otoscopy, and tympanometry. RESULTS: Among the 532 patients included in the trials, 175 were randomized to TTP only and 357 to OTO-201 treatment (304 boys [57.1%]; 228 girls [42.9%]; mean [SD] age, 2.4 [2.1]). At day 15, the cumulative proportion of treatment failures (primary end point) was 24.6% (44 of 179 patients) in trial 1 and 21.3% (38 of 178 patients) in trial 2 in the OTO-201 groups vs 44.8% (39 of 87 patients) in trial 1 and 45.5% (40 of 88 patients) in trial 2 in the TTP-alone groups. At day 15 otorrhea-only treatment failures in trial 1 included 21 of 179 (11.7%) in the OTO-201 group vs 22 of 87 (25.3%) in the TTP-only group; in trial 2, 17 of 178 (9.6%) in the OTO-201 group vs 29 of 88 (33.0%) in the TTP-only group. The odds of otorrhea-only failure were significantly reduced in the OTO-201 groups compared with the TTP-only groups in both trials (age-adjusted odds ratios, 0.38 [95% CI, 0.19-0.75] and 0.19 [95% CI, 0.09-0.38]; P < .001 for both trials, post hoc analysis). No drug-related serious adverse events were seen, and most adverse events were mild or moderate. No evidence of increased tube occlusion and no negative effect on results of audiometry, tympanometry, or otoscopy were noted with OTO-201 administration. CONCLUSIONS AND RELEVANCE: Two large phase 3 randomized clinical trials demonstrate the safety and efficacy of a single intraoperative administration of OTO-201 for middle ear effusion at the time of TTP. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01949142 and NCT01949155.

Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery.

OBJECTIVE: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. METHODS: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). RESULTS: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control (P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. CONCLUSIONS: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea.

A randomized, double-blind, placebo-controlled clinical study to assess safety and clinical activity of OTO-104 given as a single intratympanic injection in patients with unilateral Ménière's disease.

OBJECTIVE: To evaluate the safety, tolerability, and clinical activity of a single intratympanic injection of OTO-104, sustained-release dexamethasone formulation, in patients with unilateral Ménière's disease. STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled, dose-escalation study of 16 weeks' (4-wk lead-in before dosing; 12-wk follow-up after dosing) duration for each patient. SETTING: Fifteen centers (physician offices and academic or tertiary referral centers). PATIENTS: Forty-four patients aged 22 to 75 years. INTERVENTION: Single intratympanic injection of OTO-104 (3 or 12 mg) or placebo. MAIN OUTCOME MEASURES: Safety and tolerability were assessed via adverse event reports, otoscopy, audiometry, and tympanometry. Clinical activity was assessed primarily as changes in vertigo frequency. RESULTS: OTO-104 was well tolerated, with no impact on hearing function. Plasma levels were observed in a few patients and were barely quantifiable. The most frequently reported adverse event considered related to investigational product was tympanic membrane perforation; no clinical sequelae were associated with these perforations and all were graded mild or moderate. At Month 3, the observed mean ± standard deviation (SD) change from baseline in vertigo frequency was -0.124 ± 0.153, -0.147 ± 0.166, and -0.211 ± 0.153 for the placebo, 3-mg OTO-104, and 12-mg OTO-104 groups, respectively; corresponding to 42%, 56% and 73% reductions in vertigo frequency, respectively. Similar results were observed for tinnitus, measured by the Tinnitus Handicap Inventory (THI-25). CONCLUSION: OTO-104 was safe and well tolerated. Although the sample size was small, the data suggest 12 mg of OTO-104 was associated with a clinically meaningful reduction in vertigo frequency compared to placebo 3 months after treatment.

Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses. METHODS: The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo-controlled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure). RESULTS: A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy. CONCLUSION: The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.

Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for > or = 3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. RESULTS: A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. CONCLUSION: In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.