Effectiveness of analgesic ear drops as add-on treatment to oral analgesics in children with acute otitis media: a pragmatic randomised controlled trial

BACKGROUND AND RATIONALE Acute otitis media (AOM) is a common condition of childhood and a major cause of primary care consultation and antibiotic prescribing. Ear pain is the most prominent symptom of AOM and central to children’s and parents’ illness experience. Evidence of effectiveness for interventions to control the pain and reduce reliance on antibiotics is urgently needed. Recently, we showed that an educational intervention to improve pain management in children with AOM led to an increase in oral analgesic use, in particular ibuprofen, but this neither resulted in lower parent-reported ear pain scores nor less antibiotic use. We also conducted a randomised controlled trial providing some evidence that analgesic ear drops can reduce ear pain and antibiotic consumption in children with AOM, but the trial was closed early due to medicine supply issues (a different medicine) resulting in the need for further high-quality evidence on their effectiveness, as highlighted in the “Nationale Onderzoeksagenda Huisartsgeneeskunde”: 4.5.3-ICPC H-ID433. AIM To investigate whether analgesic ear drops as added to usual (oral analgesic) care provide superior ear pain relief over ‘care as usual’ in children presenting to primary care with AOM and ear pain. PRIMARY RESEARCH QUESTION Do lidocaine ear drops as added to usual (oral analgesic) care provide superior parent-reported ear pain relief over the first three days compared to usual care in children with a general practitioner (GP)-diagnosis of AOM and ear pain? DESIGN Pragmatic, two arm, individually randomised, open, superiority trial with cost-effectiveness analysis and nested qualitative investigation in general practices in the Netherlands with a follow-up of 4 weeks. STUDY POPULATION Children aged 1-6 years with a GP-diagnosis of AOM and ear pain. Excluded: children with (suspected) non-intact tympanic membrane (perforation or tubes) with/without otorrhoea, those who are very unwell or require hospital admission, children with Down’s syndrome, craniofacial malformation, immunodeficiency and sensitivity to study medicine. INTERVENTIONS Lidocaine ear drops (Otalgan®) 1-2 drops up to six times daily for a maximum of 7 days with usual (oral analgesic) care versus usual care. Concealed study group assignment using a computer-generated randomisation sequence stratified for age (<2 years vs 2 years and above), AOM laterality (unilateral vs bilateral), and AOM baseline prescribing (yes vs no) will take place at the child’s home after the parent left the general practice (so after GP’s antibiotic prescribing decision and advice on oral analgesic use). The study physician will not provide management advice other than instructions about the use of lidocaine ear drops to parents of children randomly allocated to the intervention group. PRIMARY OUTCOME Mean parent-reported ear pain score (using a 0-10 validated numerical rating scale) over the first three days. SECONDARY OUTCOMES Antibiotic consumption, number of days with ear pain, overall symptom burden, oral and topical analgesic use, GP reconsultations with/without subsequent antibiotic prescribing, generic and disease-specific quality of life, adverse events, complications of AOM, cost-effectiveness, and parents’ and GPs’ views of treatment acceptability, usability and satisfaction. SAMPLE SIZE In our recent trial, the mean parent-reported ear pain score (0-10 scale) over the first three days was 4.36 (SD 2.12) among those allocated to usual care. To detect a clinically meaningful reduction of 20% with 90% power and at a 5% significance level, 126 children per group will be needed. To allow for 20% attrition, we aim to include a total of 300 participants. This will also provide 89% power to detect a 20% difference in the proportion of children consuming antibiotics (anticipating 47% of children consuming antibiotics in the usual care group as with our recent trial). STATISTICAL ANALYSIS Analyses will be performed according to the ITT principle. The primary outcome will be analysed with a linear mixed model with a GEE type matrix for repeated measurements adjusted for a-priori specified prognostic variables and stratification factors. In sensitivity analyses, we will use multiple imputation techniques. In secondary analyses, we will use Poisson regression analyses for count variables, log binomial regression analyses for dichotomous variables, and linear regression analyses for continuous variables. ECONOMIC EVALUATION Using a societal perspective, incremental cost-effectiveness ratios will be calculated by dividing the additional cost per additional 1 point reduction in mean ear pain score over the first three days for the lidocaine ear drops group vs control group. Uncertainty will be addressed by means of two-stage non-parametric bootstrap sampling. The final results will be presented using incremental cost-effectiveness planes and cost-effectiveness acceptability curves. TIME SCHEDULE March 2021-March 2025; 48 months.