Eric A Mair1, Albert H Park2, Debra Don3, Jeffrey Koempel3, Moraye Bear4, Carl LeBel5. 1. Charlotte Eye, Ear, Nose, and Throat Associates, PA, Charlotte, North Carolina. 2. Department of Surgery and Pediatrics, University of Utah, Salt Lake City3Department of Pediatrics, University of Utah, Salt Lake City. 3. Department of Otolaryngology-Head and Neck Surgery, Children's Hospital Los Angeles, Los Angeles, California. 4. Forsythe and Bear, LLC, Woodlands, California. 5. Otonomy, Inc, San Diego, California.
Abstract
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.
RCT Entities:
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.
Authors: Albert H Park; David R White; Jonathan R Moss; Moraye Bear; Carl LeBel Journal: Otolaryngol Head Neck Surg Date: 2016-05-17 Impact factor: 3.497