Safety and Efficacy of Intratympanic Ciprofloxacin Otic Suspension in Children With Middle Ear Effusion Undergoing Tympanostomy Tube Placement: Two Randomized Clinical Trials | Medical Devices and Equipment | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Figure.  CONSORT Flow Diagram
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.

Table 1.  Baseline Demographic and Disease Characteristics in the Intent-to-Treat Population
Baseline Demographic and Disease Characteristics in the Intent-to-Treat Population
Table 2.  Cumulative Proportion and Analysis of Treatment Failures and Treatment Failure Causes
Cumulative Proportion and Analysis of Treatment Failures and Treatment Failure Causes
Table 3.  Summary of TEAEs by System Organ Classa
Summary of TEAEs by System Organ Classa
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Ah-Tye  C, Paradise  JL, Colborn  DK.  Otorrhea in young children after tympanostomy-tube placement for persistent middle-ear effusion: prevalence, incidence, and duration.  Pediatrics. 2001;107(6):1251-1258.PubMedGoogle ScholarCrossref
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Rosenfeld  RM, Schwartz  SR, Pynnonen  MA,  et al.  Clinical practice guideline: Tympanostomy tubes in children.  Otolaryngol Head Neck Surg. 2013;149(1)(suppl):S1-S35.PubMedGoogle ScholarCrossref
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van Dongen  TM, van der Heijden  GJ, Venekamp  RP, Rovers  MM, Schilder  AG.  A trial of treatment for acute otorrhea in children with tympanostomy tubes.  N Engl J Med. 2014;370(8):723-733.PubMedGoogle ScholarCrossref
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Wang  X, Fernandez  R, Tsivkovskaia  N,  et al.  OTO-201: nonclinical assessment of a sustained-release ciprofloxacin hydrogel for the treatment of otitis media.  Otol Neurotol. 2014;35(3):459-469.PubMedGoogle ScholarCrossref
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Mair  EA, Moss  JR, Dohar  JE, Antonelli  PJ, Bear  M, LeBel  C.  Randomized clinical trial of a sustained-exposure ciprofloxacin for intratympanic injection during tympanostomy tube surgery.  Ann Otol Rhinol Laryngol. 2016;125(2):105-114.PubMedGoogle ScholarCrossref
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Original Investigation
May 2016

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

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
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

Introduction

Children with recurrent acute or chronic otitis media with effusion may need tympanostomy tube placement (TTP), which is the most common pediatric ambulatory surgery in the United States.1 A complication after TTP may be postoperative otorrhea.2,3 Although antibiotic drops are used intraoperatively, they are not approved by the US Food and Drug Administration for this indication. Topical antibiotic eardrops for children with uncomplicated acute postoperative otorrhea4 have been shown to reduce the incidence of this complication.5 Availability of a single-dose antibiotic approved by the US Food and Drug Administration for intratympanic administration during TTP by otolaryngologists could ensure application of antibiotics to the middle ear.

In the present trials, a suspension of ciprofloxacin microparticles in a buffered solution containing a thermosensitive polymer, poloxamer 407 (OTO-201) (OTIPRIO; Otonomy, Inc), was administered intraoperatively to pediatric patients with bilateral middle ear effusion (MEE) requiring TTP. When OTO-201 is exposed to the body temperature in the middle ear, it quickly transitions from a liquid to a gel, allowing the suspended ciprofloxacin microparticles to be solubilized over time. In a preclinical study,6 OTO-201 provided sustained exposure of ciprofloxacin to the middle ear for 1 to 2 weeks after a single administration. The purpose of both phase 3 trials was to assess the efficacy, safety, and tolerability of OTO-201 in pediatric patients with bilateral MEE requiring TTP.

Methods
Trial Designs

Two identical, prospective, double-blind, sham-controlled multicenter phase 3 randomized clinical trials assessed the effectiveness, safety, and tolerability of OTO-201 in pediatric patients (age range, 6 months to 17 years) with bilateral MEE requiring TTP. The individual trials were approved by institutional review boards or research ethics boards of 25 sites or Schulman Associates, Cincinnati, Ohio, which was the central institutional review board for 35 sites. Both trials were conducted in compliance with the applicable regulatory requirements, the Declaration of Helsinki,7 and the International Conference on Harmonisation Guidance on Good Clinical Practice.8 All patients or their caregivers provided written informed consent. The trial protocols are available in the Supplement.

Randomization and Trial Intervention

In both trials, patients were randomized to receive OTO-201 or sham treatment (TTP alone) intraoperatively using a 2:1 allocation ratio stratified by age (6 months to 2 years or >2 years) (Figure). A permuted-block randomization algorithm was used to generate the patient’s randomized treatment assignment. Eligible patients were randomized to treatment on the day of surgery (day 1) before TTP. All persons involved in the trials (trial staff, caregivers, and patients) other than the qualified health care professional who prepared the study drug and the surgeon who administered OTO-201 or sham treatment were blinded to treatment randomization.

Key inclusion criteria were age 6 months to 17 years, a clinical diagnosis of bilateral MEE requiring TTP, and ability to provide assent for participation in the trial (for younger patients their caregiver provided written informed consent and Health Insurance Portability and Accountability Act documents). Key exclusion criteria were history of ear or mastoid surgery; designation for any other surgical procedure that would occur concurrently with TTP; history of sensorineural hearing loss, chronic or recurrent bacterial infections, tympanic membrane perforation, immunodeficiency disease, or abnormality of the tympanic membrane or middle ear; use of topical nonsteroidal otic agents within 1 day of randomization; use of a topical or otic corticosteroid within 3 days of randomization or a systemic corticosteroid within 7 days of randomization; any infection requiring systemic antimicrobial or antifungal agents; use of topical or systemic antimicrobial or antifungal agents before approximate washout intervals; concurrent use of oral anti-inflammatory agents; history of allergy to ciprofloxacin; menarche or postmenarche (among girls); and being the sibling of or residing in the same household as another participant.

Before the study drug was administered, an MEE culture specimen and the remaining middle ear fluid were aspirated. Each 6-mg dose (6%, 60 mg/mL [weight to volume ratio] in poloxamer 407) of OTO-201, selected on the basis of results from a phase 1b clinical trial,9 was given as a single 0.1-mL intratympanic injection. For sham injections (TTP only), the syringe was empty. Patients visited the trial center on days 4, 8, 15, and 29 for safety and efficacy assessments. Patients received reimbursement for travel expenses. Data were collected from November 14, 2013, to June 3, 2014, and final follow-up was completed on June 16, 2014.

Trial Outcomes
Populations

The planned sample size of 264 patients was derived in each trial using the methods described in the Statistical Analysis subsection and clinical experience from the phase 1b trial.9 The following 4 analysis sets were used for the statistical analyses: (1) safety analysis consisted of all exposed patients undergoing analysis according to the actual treatment received (OTO-201 or TTP alone); (2) full analysis for efficacy was the intent-to-treat set and consisted of all randomized patients undergoing analysis according to the treatment group to which they were randomized; (3) per protocol was used as a sensitivity analysis of the primary efficacy end point and consisted of all patients without major protocol deviations (eg, excludes patients with visits outside the study follow-up window or missed visits or who were lost to or unavailable for follow-up) who had external otorrhea based on results of the ear examination at days 4, 8, 15, and 29; and (4) microbiologic evaluation included patients whose baseline bacteriologic sample was positive for Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. The effusion type for each ear was categorized as absent, serous, purulent, sanguineous, or mucoid.

Efficacy Assessments

The efficacy of OTO-201 was assessed by the cumulative proportion of treatment failures through day 29 (primary end point, day 15). Treatment failure was defined as one of the following, whichever occurred first: (1) the presence of postoperative otorrhea in one or both ears noted by a blinded assessor (a health care professional who was not present during surgery or involved in the preparation of the study drug) during the visual external ear examination on or after 3 postoperative day (day 4); (2) the patient received otic antibiotic drops any time after surgery and before otorrhea confirmation by the blinded assessor; (3) the patient received a systemic antibiotic any time after surgery and before confirmation of otorrhea by the blinded assessor; (4) loss to follow-up; or (5) the patient did not return to the clinic for a blinded assessment.

In both trials, the assessment of postoperative otorrhea (a visual external ear examination) for the efficacy end point occurred on days 4, 8, 15, and 29 by a blinded assessor in addition to the otoscopic examination performed by an unblinded investigator. If otorrhea in either ear was confirmed by the blinded assessor on or after 3 postoperative days (day 4), a specimen for culture was obtained and the patient was eligible to receive ciprofloxacin and dexamethasone10 (4 drops twice a day in both ears for 7 days). Regardless of otorrhea status, all patients were asked to continue all trial assessments, including continued assessment by the blinded assessor.

An effusion sample was collected for microbiologic culture, sensitivity, and exploratory microbiologic testing at the time of surgery. A culture specimen was also collected at subsequent visits if the blinded assessor noted otorrhea on results of the external examination; a culture specimen was not collected if the blinded assessor reported no otorrhea for the patient.

Other key secondary efficacy end points included the cumulative proportion of treatment failures at days 4, 8, and 29, including day 29 in the per-protocol population, according to defined causes of treatment failure. The cumulative proportion of otorrhea-only treatment failures performed as a post hoc analysis was derived from 1 of the following 2 causes: (1) otorrhea was identified by the blinded assessor or (2) otic or systemic antibiotics had been prescribed for the patient for documented otorrhea-related signs through day 15. The cumulative proportion of treatment failures through day 15 was also analyzed for the per-protocol population in the same manner as the primary end point as a sensitivity analysis.

Safety Assessments

Safety assessments included treatment-emergent adverse events (TEAEs), otoscopy for the presence of bilateral effusion, audiometric testing, tympanometry, evaluation of tube occlusion, physical examination, and vital sign measurement. Adverse events were classified using standard terminology (ie, system organ class and preferred term) according to the Medical Dictionary for Regulatory Activities code (version 16.1).11

For children able to complete audiometric testing (typically ≥4 years of age), hearing was assessed at screening and days 15 and 29. The audiologist determined the most appropriate test method (visual reinforcement audiometry, conditioned play audiometry, or conventional). The degree of hearing loss was calculated using the pure-tone average (PTA) (the sum of the threshold levels in decibels obtained for 500, 1000, 2000, and 4000 Hz divided by the number of thresholds obtained) and categorized as normal hearing (0- to 15-dB) or slight (16- to 25-dB), mild (26- to 40-dB), moderate (41- to 55-dB), moderate to severe (56- to 70-dB), severe (71- to 90-dB), or profound (>90-dB) hearing loss. Shifts from screening in PTA for air conduction, bone conduction, and the air-bone gap, which depicts shifts in the air-bone gap of no greater than 10 vs greater than 10 dB, were calculated for each ear, each frequency, and each treatment group at each postbaseline assessment when possible.

Statistical Analysis

Intent-to-treat data were analyzed from June 10 to August 27, 2014. The cumulative proportion of treatment failures at each time point through day 29 was analyzed using the Cochran-Mantel-Haenszel test stratified by age (6 months to 2 years vs >2 years) to determine whether the adjusted odds ratio (OR) was equal to 1.0 (ie, no association between treatment and outcome), at the 2-tailed level of α = .05 for the full analysis set. Estimates of the strength of association were provided using the adjusted relative risk and adjusted OR with associated 95% CIs. The cumulative proportions presented were not adjusted for age. The cumulative proportion of otorrhea-only treatment failures and the per-protocol population as a sensitivity analysis of the primary end point underwent similar analyses. For the primary end point, an additional sensitivity analysis used multiple imputation of data for patients who missed a visit or were lost to follow-up. For this analysis, binary failure status for missing data was imputed at each visit and then transformed to cumulative failure through day 15.12,13

Results

A total of 532 children with MEE requiring TTP were randomized and participated in the trials from November 14, 2013, to June 3, 2014 (Table 1 and Figure). Trial 1 was conducted by 28 investigators (25 centers in the United States and 4 centers in Canada; 1 investigator was the principal investigator at 2 centers). Trial 2 was conducted by 19 investigators (18 centers in the United States and 1 center in Canada).

Patients and Baseline Characteristics

In both trials, a total of 532 patients (266 in each trial) were randomized (179 and 178 patients to the OTO-201 groups and 87 and 88 patients to the TTP-alone groups in trials 1 and 2, respectively; Figure). A total of 6 patients discontinued prematurely (in trial 1, 1 in the TTP-alone group and 3 in the OTO-201 group; in trial 2, 2 in the OTO-201 group). The reasons for discontinuation included loss to follow-up, withdrawal by the caregiver, and protocol deviation (Figure). Most patients in both trials were aged 6 months to 2 years (trial 1, 109 of 179 [60.9%] in the OTO-201 group and 53 of 87 [60.9%] in the TTP-alone group; trial 2, 111 of 178 [62.4%] in the OTO-201 group and 53 of 88 [60.2%] in the TTP-alone group).

Baseline effusion types were generally balanced across all groups (Table 1). For all children, at least 1 ear with a positive baseline finding for MEE cultures in the OTO-201 group vs the TTP group was identified with 1 of the 5 main middle ear pathogens typically mentioned previously (see the Populations subsection of the Methods section’s Trial Outcomes subsection).

Efficacy

In all-cause treatment failures, the proportion at each visit through day 29 was lower in the OTO-201 groups compared with the TTP-alone groups in both trials (Table 2). The primary end point of cumulative proportion of treatment failures at day 15 was 24.6% (44 of 179) in trial 1 and 21.3% (38 of 178) in trial 2 for patients in the OTO-201 groups compared with 44.8% (39 of 87) in trial 1 and 45.5% (40 of 88) in trial 2 for patients in the TTP-alone groups (ORs for OTO-201 vs TTP, 0.39 (95% CI, 0.22-0.68) and 0.30 (95% CI, 0.17-0.53), respectively; P < .001 for both). Reduced proportions of treatment failures for the OTO-201 dose groups compared with the TTP groups were apparent as early as day 4, when 16 of 179 (8.9%) in trial 1 and 9 of 178 (5.1%) in trial 2 for patients in the OTO-201 groups were considered have treatment failures vs 21 of 87 (24.1%) in trial 1 and 25 of 88 (28.4%) in trial 2 for patients in the TTP-alone groups for trials 1 and 2, respectively (Table 2). Because the trials were not powered to test for differences between age strata, the numbers of patients were smaller, with approximately 60% constituting the younger stratum. In the younger stratum, the observed treatment effect was statistically significant (OR, 0.39 [95% CI, 0.20-0.76; P = .005] in trial 1; OR, 0.20 [95% CI, 0.10-0.41; P < .001] in trial 2). In the older stratum, although differences did not reach statistical significance, the direction of the ORs was consistent with a positive OTO-201 effect (OR, 0.39 [95% CI, 0.15-1.02; P = .051] in trial 1; OR, 0.70 [95% CI, 0.24-2.04; P = .51] in trial 2). The treatment effect in the older stratum was even stronger when the 2 trials were combined (OR, 0.51 [95% CI, 0.25-1.04; P = .06]). Similarly, the cumulative proportion of treatment failures due to otorrhea on day 15 as documented during the external ear examination by the blinded assessor or the need for prescription of an otic or systemic antibiotic with documented evidence of otorrhea was lower in the OTO-201 group than the TTP-alone group in trial 1 (21 of 179 [11.7%] vs 22 of 87 [25.3%; OR 0.38; 95% CI, 0.19-0.75; number needed to treat, 7; P = .004) and trial 2 (17 of 178 [9.6%] vs 29 of 88 [33.0%]; OR, 0.19; 95% CI, 0.09-0.38; number needed to treat, 4; P < .001).

The sensitivity analysis of the primary efficacy end point using the per-protocol analysis (randomized patients who adhered to the protocol and excluded patients with out-of-window or missed visits or those lost to follow-up) showed findings similar to those of the primary analysis and provided strong support for the primary analysis (Table 2). The cumulative proportion of patients with designated treatment failures in the per-protocol analysis through day 15 resulted in a statistically significant treatment effect in favor of OTO-201 compared with TTP alone in trial 1 (18 of 148 [12.2%] vs 27 of 70 [38.6%]; OR, 0.21; 95% CI, 0.10-0.43; P < .001) and in trial 2 (27 of 159 [17.0%] vs 29 of 74 [39.2%]; OR, 0.28; 95% CI, 0.15-0.55; P < .001) (Table 2). The reduction in the relative risk for treatment failure in the OTO-201 groups compared with TTP-alone groups in the per-protocol population was 68% in trial 1 and 57% in trial 2. The sensitivity analysis of the primary efficacy end point using multiple imputation through day 15 for missed visits and patients lost to follow-up also provided strong support for the primary analysis (Table 2).

Safety

In both trials, no serious or life-threatening adverse events related to the study drug occurred, and no TEAEs resulted in patient discontinuation from either trial. Most adverse events were mild or moderate in severity. The proportions of patients who experienced TEAEs were 87 of 179 (48.6%) for trial 1 and 102 of 178 (57.3%) in trial 2 among the OTO-201 groups and 48 of 86 (55.8%) in trial 1 and 47 of 87 (54.0%) in trial 2 among the TTP-alone groups (Table 3). The most frequent TEAEs for the OTO-201 and TTP-alone groups were nasopharyngitis, irritability, and rhinorrhea. In both trials, the types of events in the OTO-201 groups were similar to those observed in the TTP-alone groups and were expected for this type of administration and procedure in a pediatric population. Three serious adverse events (including gastroenteritis and bronchiolitis in 3 patients in the OTO-201 group) and 1 severe TEAE (hypoglycemia in 1 patient in the OTO-201 group) were reported in trial 1; all adverse events were resolved and deemed not related to the study drug. Two severe TEAEs (respiratory syncytial virus infection in 1 patient in the OTO-201 group and sinusitis in 1 patient in the TTP group) were reported in trial 2; both TEAEs were deemed not related to the study drug. No clinically meaningful changes in results of laboratory evaluations, vital signs, or tympanostomy tube status were noted in either trial.

Overall, no drug-related effects were detected on results of otoscopic examinations, audiometric analyses, or tympanometry. At least 94% of evaluated tympanostomy tubes were patent at each trial visit, and no differences were seen in either trial between the 2 treatment groups. At screening, most of the ears in the OTO-201 and TTP-alone groups had a tympanometry category of B, with normal canal volume. At day 29, most of the ears in each treatment group had a tympanogram with a large volume, consistent with the presence of a patent tube.

The most frequent type of shift in PTA category at any visit was from mild to normal for the OTO-201 groups in both trials (trial 1 range, 24.4%-36.6%; trial 2 range, 33.3%-39.5%) and for the TTP-alone groups in trial 2 (range, 29.2%-44.0%), and slight to normal for the TTP-alone group in trial 1 (range, 33.3%-41.7%). Pure-tone audiometry shifts from mild to moderate severity from screening to day 29 were observed in individual ears and therefore were infrequent; most of the ears of the patients who had higher PTA shifts were found to have an effusion.

In both trials, most if not all ears evaluated in the OTO-201 and TTP-alone groups had a normal bone conduction category in the left, right, and nonspecific ear at screening and days 15 and 29. Proportions of ears with air-bone gap improvement in either ear or in a nonspecific ear (shifts in air-bone gap from >10 dB at screening to ≤10 dB at day 29) were larger in the OTO-201 groups than in the TTP-alone groups at most frequencies.

Discussion

The placement of TTPs is routinely performed in children to eliminate persistent middle ear fluid and diminish the frequency and severity of ear infections after long-term oral antibiotic therapy. In these 2 identical phase 3 clinical trials comparing OTO-201 and TTP alone, the primary, secondary, and sensitivity analyses indicated that OTO-201 may be an effective treatment for pediatric patients with bilateral MEE who require TTP. A lower cumulative proportion of treatment failures at days 4, 8, 15 (primary end point), and 29 were noted in the patients who received OTO-201 compared with TTP alone in both trials. The sensitivity analyses of the cumulative proportion of treatment failures in the per-protocol population at day 15 and multiple imputation analysis of missed visits and loss to follow-up through day 15 provided strong support for the primary efficacy results. A post hoc analysis of the cumulative proportion of otorrhea-only treatment failures (documented otorrhea by a blinded assessor or the need for prescription of otic or systemic antibiotics with documented otorrhea) also supported the primary efficacy results. Clear improvements in efficacy regardless of any baseline demographic data, such as age, sex, effusion type, or culture status, were shown after OTO-201 dosing.

No drug-related serious adverse events were seen in either trial. Most of the adverse events were mild or moderate in severity and were expected for this type of administration and procedure in a pediatric population. No evidence of increased tube occlusion and no negative effect on the audiometry, tympanometry, or otoscopy results were noted after OTO-201 administration.

As in all trials, the research has some limitations, such as the exclusion of concurrent surgical procedures and caregiver or patient centricity measures. Research that could provide insight into the benefits of OTO-201 on caregiver or patient centricity measures would align with the evolving initiatives at the Patient-Centered Outcomes Research Institute.14 Caregiver surveys and validated tools beyond the 6-item quality-of-life survey used previously15 could be relevant in this patient setting.

Conclusions

In both trials, OTO-201 was administered via intratympanic injection by an otolaryngologist and has been shown in a preclinical trial6 to result in middle ear drug concentrations with sustained exposure for as long as 2 weeks. A single intraoperative application of OTO-201 may be a safe and effective treatment for MEE at the time of TTP. Two phase 3 clinical trials demonstrated that a single-dose intraoperative intratympanic administration of OTO-201, a thermosensitive otic suspension of ciprofloxacin, may be a safe and effective treatment for MEE at the time of TTP.

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Article Information

Corresponding Author: Eric A. Mair, MD, Charlotte Eye, Ear, Nose, and Throat Associates, PA, 6035 Fairview Rd, Charlotte, NC 28210 (emair@ceenta.com).

Accepted for Publication: November 5, 2015.

Published Online: March 17, 2016. doi:10.1001/jamaoto.2016.0001.

Author Contributions: Dr LeBel and Ms Bear had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mair, Bear, LeBel.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mair, Koempel, LeBel.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bear, LeBel.

Obtained funding: LeBel.

Administrative, technical, or material support: Mair, Park, Koempel, Bear, LeBel.

Study supervision: Mair, Park, LeBel.

Conflict of Interest Disclosures: Dr Mair reported participating as an investigator in the trials and receiving financial compensation for medical consultation from Otonomy, Inc, but not related to his role in these trials. Dr Park reports participating as an investigator in the trials. Dr Don reported providing technical guidance on the trials and receiving financial compensation for medical consultation from Otonomy, Inc, but not related to her role in these trials. Dr Koempel reported participating as an investigator in the trials and providing technical guidance. Ms Bear reported employment as a statistical consultant by Otonomy, Inc. Dr LeBel reported employment by Otonomy, Inc, and being involved the trials’ design and operation. No other disclosures were reported.

Funding/Support: This study was supported by Otonomy, Inc.

Role of the Funder/Sponsor: The funding source, Otonomy, Inc, was responsible for the design and conduct of the study and collection, management, analysis, and interpretation of the data. Preparation, review, or approval of the manuscript and decision to submit the manuscript for publication was the responsibility of the authors, including those authors who are from Otonomy, Inc.

Previous Presentations: This paper was presented in part at the Annual Meeting of the American Society of Pediatric Otolaryngology; April 24, 2015; Boston, Massachusetts; and the 18th Annual International Symposium on Recent Advances in Otitis Media; June 8, 2015; National Harbor, Maryland.

Additional Information: The following principal investigators participated in the trials: Thomas Andrews, MD, Pediatric Otolaryngology Head and Neck Surgery (HNS), Odessa and Tampa, Florida; John Ansley, MD, Carolina Ear, Nose and Throat (ENT), Orangeburg, South Carolina; Michael Armstrong, MD, Richmond ENT, Richmond, Virginia; Kevin Braat, MD, ENT and Allergy Associates, Southampton and Riverhead, New York; Robert Bridge, MD, Precision Trials, Phoenix, Arizona; Matthew Brown, MD, Iowa Head and Neck, Des Moines; John Byers, MD, Greensboro ENT, Greensboro, North Carolina; Felizardo Camilon, MD, Orange, California; Kenny Chan, MD, Children’s Hospital Colorado, Aurora; Dary Costa, MD, St Louis University, St Louis, Missouri; David Darrow, MD, DDS, Children’s Hospital of the King’ Daughters, Norfolk, Virgina; Franklin Douglis, MD, Conroe, Spring, and Cleveland, Texas; Ann Edmunds, MD, PharmD, Omaha ENT Clinic, Omaha, Nebraska; Dale Ehmer, MD, ENT Associates of Texas, McKinney, Frisco, and Plano; Eduard Eksteen, MD ChB, MacKenzie HSc Centre, University of Alberta, Edmonton, Canada; Samuel Engel, MD, MPH, Coastal ENT, Neptune, New Jersey; David Evans, MD, Sacramento ENT Surgical and Medical Group, Sacramento, California; Michael Friedman, MD, Chicago ENT, Chicago, Illinois; Avlon Glaser, MD, ENT and Allergy Associates, Hoboken and Rutherford, New Jersey; Steven Goudy, MD, Vanderbilt University Medical Center, Nashville, Tennessee; Rob Hekkenberg, MD, FRCSC, ENT Health Corp, Barrie, Ontario, Canada; David Karas, MD, Connecticut Pediatric Otolaryngology, North Haven and Madison; Jeffrey Koempel, MD, MBA, Children’s Hospital LA, Los Angeles, California; Fredrick Kozak, MD, Pediatric ENT Clinic BC Children’s Hospital, Vancouver, British Columbia, Canada; Brent Lanier, MD, CPI, Central California Clinical Research, Fresno; Bryan Keith Lansford, MD, NEA Baptist Clinic, Jonesboro, Arkansas; Kenneth Lee, MD, PhD, Children’s at Legacy Pediatric Otolaryngology-HNS, Plano, Texas; Darren Leitao, MD, FRCSC, Pediatric Otolaryngology-HNS, University of Manitoba, Winnipeg, Canada; Eric Mair, MD, Charlotte Eye, Ear, Nose, and Throat Associates, PA, Charlotte, North Carolina; Scott Manthei, DO, Westfield Nevada Eye and Ear, Henderson; Timothy Martin, MD, Children’s Hospital of Wisconsin, Milwaukee; Kenneth Maxwell, MD, Piedmont ENT Associates, Winston-Salem, North Carolina; John McClay, MD, Frisco ENT for Children, Dallas, Texas; Mark Mehle, MD, Clinical Research Solutions, Middleburg Heights, Ohio; Timothy Melson, MD, Shoals Medical Trials, Inc, Sheffield, Alabama; Steven Miller, MD, Intermountain ENT Specialists, Salt Lake City, Utah; Jonathan Moss, MD, Charlotte Eye, Ear, Nose, and Throat Associates, PA. Matthews, North Carolina; Albert Park, MD, University of Utah Primary Children’s Hospital, Salt Lake City; Michael Parker, MD, PMG Research of Wilmington, Wilmington, North Carolina; Sundip Patel, MD, ENT for Children Clinical Office, Dallas and North Richland Hills, Texas; Michael Poole, MD, PhD, Georgia Ear Associates, Savannah; Gresham Richter, MD, University of Arkansas Children’s Hospital, Little Rock; J. Lewis Romett, MD, Colorado ENT & Allergy, Colorado Springs; Jeffrey Rosenbloom, MD, Alamo ENT, LLC, San Antonio, Texas; Scott Schoem, MD, Connecticut Children’s Medical Center, Hartford; Doron Sommer, MD, McMaster University Medical Centre, Hamilton, Ontario, Canada; Peter Spafford, MD, FRCS, Wall Street ENT Clinic, Saskatoon, Saskatchewan, Canada; Zorik Spektor, MD, Center for Pediatric ENT, Boynton Beach, Florida; Charles Syms, MD, Ear Medical Group, San Antonio, Texas; Donald Welsh, MD, Advanced ENT and Allergy, Louisville, Kentucky; David White, MD, Medical University of South Carolina, Charleston; Ramzi Younis, MD, Bascom Palmer Eye Institute, Miami, Florida; and Jacob Zeiders, MD, MS, South Florida Pediatric Otolaryngology, Ft Lauderdale.

Additional Contributions: We thank the patients and their caregivers for their participation in these phase 3 trials, the clinical trial site staff members, trial coordinators, statisticians, nursing and supporting staff, the Rho, Inc, project managers, trial monitors, and remaining members of the trial teams. Donna Simcoe, MS, MBA, Simcoe Consultants, Inc, developed an early draft of the manuscript based on conversations with the authors, for which she was compensated; this work was funded by Otonomy, Inc.

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