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Original Investigation |

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

Eric A. Mair, MD1; Albert H. Park, MD2,3; Debra Don, MD4; Jeffrey Koempel, MD, MBA4; Moraye Bear, MA, MS5; Carl LeBel, PhD6
[+] Author Affiliations
1Charlotte Eye, Ear, Nose, and Throat Associates, PA, Charlotte, North Carolina
2Department of Surgery and Pediatrics, University of Utah, Salt Lake City
3Department of Pediatrics, University of Utah, Salt Lake City
4Department of Otolaryngology–Head and Neck Surgery, Children’s Hospital Los Angeles, Los Angeles, California
5Forsythe and Bear, LLC, Woodlands, California
6Otonomy, Inc, San Diego, California
JAMA Otolaryngol Head Neck Surg. 2016;142(5):444-451. doi:10.1001/jamaoto.2016.0001.
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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

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Figure.
CONSORT Flow Diagram

Patients excluded after eligibility assessment may have been excluded for multiple reasons. The safety analysis set included all patients who received the study drug (6 mg of ciprofloxacin otic suspension [OTO-201]) or tympanostomy tube placement (TTP) alone. The per-protocol analysis set included all randomized patients without major protocol deviations and who had external examination of the ears for otorrhea at days 4, 8, and 15. The microbiologic evaluation set included all randomized patients whose baseline bacteriologic sample was positive for at least 1 of 5 organisms. The safety analysis set is displayed by the treatment the patient received. All other analysis sets are displayed by the treatment to which the patient was randomized.

aMay have been excluded for multiple reasons.

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