Pijnlijk Loopoor Therapie Studie

Rationale: Around 15-20% of children with AOM present with ear discharge due to a spontaneous perforation of the eardrum (AOMd). Since oral antibiotics effectively reduce ear pain and/or fever in children with AOMd, current guidance recommends general practitioners (GPs) to consider oral antibiotics for these children. However, oral antibiotics put children at risk for adverse effects and increase the risk of antimicrobial resistance. In children with AOMd, the perforation of the eardrum provides an opportunity to instill topical antibiotics directly into the middle ear without exposing children to systemic side effects and putting less selective resistance pressure on bacteria. Evidence on its effectiveness in children with AOMd is, however, lacking. We hypothesise that antibiotic-corticosteroid eardrops are non-inferior to oral antibiotics in resolving ear pain and fever at day 3 (72 hours after randomisation) in children aged 6 months to 12 years visiting their GP with AOMd and either ear pain or fever or both.



Objective: To establish the clinical and cost-effectiveness of antibiotic-corticosteroid eardrops as compared with oral antibiotics in children with AOMd.



Study design: A primary care based, open, randomised controlled non-inferiority trial.



Study population: Children aged 6 months to 12 years whose parents are consulting their GP because of AOMd and either ear pain or fever or both.



Intervention: Children will be randomly allocated to either 1) hydrocortisone-bacitracin-colistin (Bacicoline-B®) eardrops, five drops, three times per day in the discharging ear(s) for 7 days or 2) amoxicillin suspension or tablets 50 mg per kilogram body weight per day, divided over three oral doses for 7 days.



Main study parameters/endpoints: The primary outcome is the proportion of children without ear pain and fever at day 3. Secondary outcomes are ear pain intensity/severity; fever intensity/severity; ear discharge; time to resolution of total symptoms; persistent eardrum perforation; middle ear effusion; adverse events; disease-specific quality of life; antibiotic consumption; AOM recurrences; costs and cost-effectiveness; antimicrobial resistance.



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Participants will be followed for a total of 3 months. This includes a baseline visit, a telephone call at day 3 and a follow-up visit at 2 weeks. Parents of participating children will be asked to record their child’s symptoms in a daily diary during the first 2 weeks and a weekly diary afterwards. At the baseline and the 2 weeks home visits, otoscopy and tympanometry (at 2 weeks only) will be performed and otorrhoeal, nasopharyngeal and faecal samples will be collected. At 3 months, a faecal sample will be collected. Data collection methods and associated burden to participants have been extensively discussed with our parent panel. The proposed methods were judged both feasible and acceptable by our parent panel and have been successfully applied in our previous trial.

Children allocated to eardrops will not be exposed to systemic adverse effects associated with oral antibiotics and may be at lower risk of developing antimicrobial resistance. A potential risk is that children may experience a prolonged disease course and might need subsequent treatment with oral antibiotics if antibiotic-corticosteroid eardrops appear to be inferior to oral antibiotics. We however do not anticipate large differences in treatment failures between the two active treatment groups given the difference (30%) observed between oral antibiotics and placebo or no treatment in previous trials.

The main risk of eardrops is potential ototoxicity. Although the hydrocortisone-bacitracin-colistin eardrops do not contain an aminoglycoside, there still is a risk. However, based on current available literature and recent data from the Netherlands Pharmacovigilance Centre, the risk of ototoxicity associated with the use of eardrops is considered at most similar but probably lower than the risk of ototoxicity related to the middle ear infection itself. Both the Dutch College of General Practitioners and the Dutch ENT Society have balanced benefits and risks of using these eardrops in children with an active middle ear infection and concluded that the (potential) benefits outweigh the risks. Current status: Ongoing (restart trial september 2021).

We hypothesise that antibiotic-corticosteroid eardrops are non-inferior to oral antibiotics in resolving ear pain and fever at day 3 (72 hours after randomisation) in children aged 6 months to 12 years visiting their GP with AOMd and either ear pain or fever or both.

Primary outcome: day 3

Secondary outcomes: 0-3 days, 2 weeks, 3 months

Children will be randomly allocated to either 1) hydrocortisone-bacitracin-colistin (Bacicoline-B®) eardrops, five drops, three times per day in the discharging ear(s) for 7 days or 2) amoxicillin suspension or tablets 50 mg per kilogram body weight per day, divided over three oral doses for 7 days.