Dornase Alfa Ototoxic Effects in Animals and Efficacy in the Treatment of Clogged Tympanostomy Tubes in Children: A Preclinical Study and a Randomized Clinical Trial

Abstract

Importance: Many treatments for clogged tympanostomy tubes (TTs) have been proposed, but none have met scientific rigor for safety and efficacy, including the popular empirical use of ototopical antibiotic drops. Dornase alfa, a recombinant molecule with the unique property of cleaving DNA, may be ideal in treating clogged TTs because both middle-ear effusion and the plug are abundant with DNA.

Objective: To investigate the ototoxic effects of dornase alfa in a chinchilla model and its efficacy in a clinical trial in children with clogged TTs.

Design, setting, and participants: The safety profiles of dornase alfa (full-strength and 1:10 strength) were evaluated in chinchilla middle ears using serial auditory brainstem response. The efficacy of ototopical dornase alfa (full-strength) was evaluated in children with clogged TTs in a prospective, single-blind randomized clinical trial. The animal study included 21 chinchillas and was conducted at Loma Linda University, Loma Linda, California, and the clinical trial was conducted at Children's Hospital Colorado, Aurora. A total of 40 children (50 ears with tubes) were enrolled.

Interventions: In the animal study, chinchillas were assigned to 3 groups: controls (saline), full-strength dornase alfa, or 1:10 dornase alfa dilution. Children were randomly assigned to receive either topical dornase alfa or ofloxacin for clogged TT, 5 drops each ear twice a day for 7 days.

Main outcomes and measures: Animal study: Auditory brainstem responses. Randomized trial of children participants: The primary outcome was patency of TT at day 14 assessed by otoscopy and tympanometry.

Results: The chinchilla study showed similar auditory brainstem response degradation during a 6-hour period between the control (n = 5) and treatment groups (n = 21). In the clinical trial, a total of 40 clogged TTs (in 33 children, including 25 boys [76%]; mean age, 4.3 years; median [range] age, 3.4 [1.0-14.3] years) were analyzed. The number of unclogged TTs was higher in the dornase alfa group (13 [59%]) compared with the ofloxacin group (8 [44%]), with a difference of 15% (odds ratio, 1.8; 95% CI, 0.54-6.72).

Conclusions and relevance: The chinchilla model suggests that dornase alfa is likely nonototoxic. The pilot clinical trial failed to show efficacy of dornase alfa to unclog TTs. With the difference seen between the treatment groups, a sample size estimate could be calculated for a future large-scale trial.

Trial registration: ClinicalTrials.gov identifier: NCT00419380.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chan reports receiving personal fees from Otonomy Inc. No other disclosures were reported.

Figures

Figure.. CONSORT Flow Diagram of Participants in the Clinical Trial

TT indicates tympanostomy tube.