General practice / Family do

Topical or oral antibiotics for children with acute otitis media presenting with ear discharge: study protocol of a randomised controlled non-inferiority trial

Loading

  1. http://orcid.org/0000-0003-3413-1423Saskia Hullegiei,
  2. http://orcid.org/0000-0002-1446-9614Roderick P Venekamp1,
  3. Thijs One thousand A van Dongenone,
  4. Sanne Muldertwo,
  5. Willem van Schaik3,
  6. Chiliad Ardine de Witi,iv,
  7. Alastair D Hay5,
  8. http://orcid.org/0000-0003-3664-1873Paul Piffling6,
  9. http://orcid.org/0000-0002-5127-4509Michael V Moorevi,
  10. Elisabeth A M Sanders7,viii,
  11. Marc J One thousand Bonten1,9,
  12. Debby Bogaert7,10,
  13. Anne GM Schilderone,11,12,
  14. Roger A G J Damoiseaux1
  1. i Julius Middle for Health Sciences and Primary Intendance, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2 Parent and PPI contributor, Utrecht, kingdom of the netherlands
  3. 3 Found of Microbiology and Infection, University of Birmingham, Birmingham, UK
  4. four Centre for Nutrition, Prevention and Healthcare, National Plant of Public Health and the Surround (RIVM), Bilthoven, The Netherlands
  5. 5 Centre for Academic Main Care, Schoolhouse of Social and Community Medicine, University of Bristol, Bristol, Great britain
  6. half-dozen Primary Care Population Science and Medical Teaching, Aldemoor Health Centre, University of Southampton, Southampton, UK
  7. vii Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Heart Utrecht, Utrecht, The Netherlands
  8. 8 Centre for Communicable diseases Control, National Found of Public Health and the Environment (RIVM), Bilthoven, Holland
  9. 9 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
  10. ten Centre for Inflammation Research, Queen's Medical Research Found, Academy of Edinburgh, Edinburgh, U.k.
  11. 11 National Institute for Health Research Academy College London Hospitals Biomedical Research Centre, London, United kingdom of great britain and northern ireland
  12. 12 evidENT, Ear Institute, Academy Higher London, London, Uk
  1. Correspondence to Ms Saskia Hullegie; due south.hullegie{at}umcutrecht.nl

Abstract

Background Effectually 15%–20% of children with acute otitis media present with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd). Current guidance recommends clinicians to consider oral antibiotics as first-line treatment in this condition. The opening in the eardrum even so should allow topical antibiotics to enter the centre ear straight. Local administration of antibiotics does not expose children to systemic side effects and may put less selective resistance force per unit area on bacteria. Prove on the effectiveness of this approach in children with AOMd is defective.

Methods and analysis A primary intendance-based, open, individually randomised, controlled, non-inferiority trial. The trial aims to recruit 350 children aged 6 months to 12 years with AOMd and ear pain and/or fever. Participants will be randomised to seven days of hydrocortisone-bacitracin-colistin eardrops five drops three times daily or amoxicillin oral interruption l mg/kg body weight per day, divided over iii doses. Parents will go on a daily diary of AOM symptoms, agin events and complications for two weeks. In add-on, they will record AOM recurrences, healthcare utilisation and societal costs for three months. The primary issue is the proportion of children without ear hurting and fever at day 3. Secondary outcomes include ear pain and fever intensity/severity; days with ear belch; eardrum perforation at ii weeks; adverse events during first 2 weeks; costs; and price effectiveness at 2 weeks and 3 months. The chief analyses volition be intention-to-care for and per-protocol analyses will be conducted every bit well.

Ideals and dissemination The medical inquiry ideals committee Utrecht, The Netherlands has given ethical approving (17-400/Chiliad-M). Parents/guardians of participants will provide written informed consent. Study results volition exist submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings.

Trial registration number Holland National Trial Register; NTR6723. Date of registration: 27 November 2017.

  • acute otitis media
  • ear belch
  • oral antibiotics
  • antibiotic-corticosteroid eardrops
  • antimicrobial resistance

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access commodity distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work not-commercially, and license their derivative works on different terms, provided the original piece of work is properly cited, appropriate credit is given, whatever changes fabricated indicated, and the use is non-commercial. Encounter: http://creativecommons.org/licenses/by-nc/four.0/.

Statistics from Altmetric.com

  • acute otitis media
  • ear discharge
  • oral antibiotics
  • antibiotic-corticosteroid eardrops
  • antimicrobial resistance

Strengths and limitations of this study

  • The pragmatic, open-label design of our trial enhances the applicability of the findings to daily practice.

  • The pragmatic design is virtually suited to address key secondary outcomes such as antibiotic consumption during the first 2 weeks and cost-effectiveness in everyday practice.

  • The open up-label blueprint may introduce bias caused by the awareness of treatment assignment.

Introduction

Acute otitis media (AOM) is ane of the most mutual childhood infections and an of import reason for doctor consultations and antibiotic prescribing.1 2 Approximately 15%–twenty% of children with AOM nowadays with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd).3 iv Contrary to widespread beliefs, children with AOMd accept similar levels of ear hurting and are more unwell at presentation than those without ear discharge.iii iv These children likewise have a poorer prognosis with higher rates of ear pain and/or fever at 3–7 days and more than AOM recurrences and hearing problems at three months than children presenting with AOM without ear belch.3 iv They also benefit more than from oral antibiotics than those with AOM without ear discharge: number needed to care for to accomplish resolution of ear pain and/or fever at days 3–7: three versus 8, respectively.3 Based on this bear witness, current guidelines recommend full general practitioners (GPs) to consider an firsthand oral antibiotic prescribing strategy for children with AOMd.five vi Oral antibiotics, yet, expose children to systemic side furnishings such every bit diarrhoea, vomiting and rash7 and routine use of oral antibiotics in common infections such as AOM contributes to emergence of antimicrobial resistance.8 ix Culling handling strategies for AOM are therefore urgently needed.

In children with AOMd, the perforation should allow topical antibiotics to enter the middle ear directly. Topical antibody treatment does non betrayal children to systemic side effects and may put less selective resistance pressure on commensal microbes.10 11 We have shown that in children with acute ear belch in the presence of ventilation tubes (grommets) antibiotic-corticosteroid eardrops are clinically much more effective and less costly than oral antibiotics.12 xiii Topical antibiotics may therefore likewise exist an constructive treatment strategy in children with AOMd. And then far, show to back up this hypothesis is lacking.fourteen 15 Our trial aims to provide this primal evidence.

Objective

The aim of this randomised controlled trial is to constitute whether treatment with antibiotic-corticosteroid eardrops is not-inferior to treatment with oral antibiotics in children aged half-dozen months to 12 years presenting to their GP with AOM with astute ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd).

The objectives are to determine the:

  • Effectiveness of antibody-corticosteroid eardrops versus oral antibiotics in terms of:

    • The proportion of children without ear hurting and fever at day 3;

    • Severity and duration of ear hurting, fever, ear discharge;

    • Time to resolution of full symptoms;

    • Heart ear effusion (MEE) and eardrum perforation at 2 weeks;

    • Otitis media (OM)-specific quality of life (QoL) at 2 weeks and 3 months;

    • Antibiotic consumption during the showtime two weeks and at 3 months and AOM recurrences at 3 months;

    • Adverse events during the commencement 2 weeks;

  • Costs and cost-effectiveness of antibiotic-corticosteroid eardrops versus oral antibiotics;

  • Prevalence of bacteria and viruses in otorrhoea and nasopharyngeal samples of children with AOMd before and later treatment and the antimicrobial susceptibility profile of the bacteria;

  • Impact of the handling regimens on antimicrobial resistance genes in the man gut.

Methods and analyses

Study design and setting

An open up, individually randomised, controlled, non-inferiority trial in 350 children aged 6 months to 12 years presenting to their GP with AOMd. Children volition exist randomly allocated to seven days treatment with either: (one) antibiotic-corticosteroid (hydrocortisone–bacitracin–colistin) eardrops or (2) oral antibiotics (amoxicillin interruption). Follow-upward will be 3 months.

At trial starting time, in December 2017, we anticipated a 2-year trial recruitment period. Approximately 250 GPs in the region of Utrecht, The Netherlands, agreed to recruit children to the trial. Due to the COVID-19 related infection command measures, we anticipate a relatively depression AOM incidence during trial recommencement. To run across the required sample size, we will recruit additional general practices to the trial. Farther details on the trial status are outlined in the 'electric current study status' section below.

Participants

Children aged 6 months to 12 years presenting to their GP with recent onset AOMd in ane or both ears and either ear pain or fever or both. Children with grommets in place and those with a pre-existing perforation of the eardrum are excluded. For detailed inclusion and exclusion criteria, see box ane.

Box 1

Full list of inclusion and exclusion criteria

Inclusion criteria:

Children aged half-dozen months to 12 years whose parents are consulting the general practitioner (GP) with acute otitis media (AOM) and ear belch in ane or both ears (≤ seven days elapsing) and either parent-reported ear pain in the previous 24 hours or fever (child'south body temperature of ≥ 38.0°C in the previous 24 hours equally reported by parents or as measured by the GP during consultation) or both.

Exclusion criteria:

Children will be excluded from participation if they;

  1. Are systemically very unwell and require firsthand oral antibiotics or immediate hospitalisation (eg, child has signs and symptoms of serious illness and/or complications such equally mastoiditis/meningitis);

  2. Are at loftier risk of serious complications including children with known immunodeficiency other than partial IgA or IgG2 deficiencies, craniofacial malformation such as cleft palate, children with Down syndrome, previous ear surgery other than grommet insertion;

  3. Accept grommets in place;

  4. Have a pre-existing perforation of the eardrum;

  5. Had a prior AOM episode (with or without ear discharge) in previous 28 days;

  6. Used oral antibiotics or topical antibiotics in previous 2 weeks;

  7. Have a known allergy or sensitivity to oral amoxicillin or hydrocortisone-bacitracin-colistin;

  8. Take already participated in this trial.

AOM presenting with ear discharge due to a spontaneous tear or perforation of the eardrum (AOMd) is defined as the presence of acute-onset of otoscopically confirmed otorrhoea together with other symptoms of an astute infection such as ear pain and/or fever, and/or irritability.

Inclusion and baseline assessments

Figure one depicts a menstruum diagram of study procedures. Participating GPs inform parents of potentially eligible children about the trial, take consent for sharing their contact details with the research team at the UMC Utrecht and provide a study data alphabetic character. Members of the research team contact parents past phone to provide detailed information about the trial. If parents provisionally agree to participate and if the child meets the eligibility criteria, a home visit by the trial doc is scheduled for the aforementioned solar day.

At this visit, the trial doctor takes written informed consent from parents/guardians, collects baseline demographic and illness-specific data, records otoscopic findings and takes otorrhoea, nasopharynx and faeces samples. Parents volition complete an OM-specific QoL questionnaire on behalf of their kid.

Study group assignment

An independent information manager generates a figurer-generated randomisation sequence with stratification according to age (<ii vs ≥ii years) and laterality (unilateral vs bilateral AOM at baseline). At the decision of the baseline home visit, the trial md accesses a trial randomisation website for concealed study-group assignment. The assignment will exist balanced in a i:1 ratio for the two report groups:

  1. Hydrocortisone–bacitracin–colistin (Bacicoline-B) eardrops, five drops, three times per day in the discharging ear(due south) for 7 days; or

  2. Amoxicillin, fifty mg/kg of body weight per day, divided over three doses administered orally for 7 days.

Hydrocortisone–bacitracin–colistin eardrops are the most widely used commercially available eardrops in the Netherlands that do non incorporate a potentially ototoxic aminoglycoside. The combination of antibiotics in these eardrops covers the spectrum of leaner most ofttimes plant in AOM.sixteen 17 We accept chosen an eardrop that also contains a corticosteroid since the available evidence from children with grommets suggests that topical treatment with a combination of antibiotics and a corticosteroid might be more effective than topical antibiotics alone in resolving acute ear belch.18 19 Hydrocortisone–bacitracin–colistin eardrops were also used in our previous trial in children with acute ear belch in the presence of ventilation tubes (grommets).12 Parents of children assigned to the antibody-corticosteroid eardrops grouping will be shown how to remove any visible ear discharge with a tissue and apply the drops while tilting their child's head to one side, and to apply tragal pressure (tragal pumping).20

Amoxicillin is listed as outset-line antibody for AOM in children in virtually European guidelines, including the Netherlands.6 21 Based on the current antimicrobial resistance profiles in the Netherlands, the clinical practise guideline refers to the Dutch Paediatric Formulary which recommends a dosage of 50 mg/ kg of body weight per day, divided over three doses for 7 days.half-dozen 22

The report team volition notify the GP and local pharmacist almost the outcome of the randomisation. During follow-up, parents and GPs are encouraged to manage AOM recurrences according to current Dutch clinical do guidance,6 but any treatment decisions will be up to the GPs' discretion. Beingness a pragmatic trial, no restrictions in concurrent treatment will be applied and any concurrent treatments will be captured in the daily symptom diary.

Follow-up data collection

Participants will be followed for iii months. Parents will go along a daily diary of AOM-related symptoms including fever recordings and ear pain scores, use of written report and other medication, adverse events and complications of AOM for 2 weeks. Thereafter, they will proceed a weekly diary recording AOM recurrences, GP consultations, prescribed and over-the-counter (OTC) medication, hospital admissions and societal costs for AOM for three months. A telephone phone call will be scheduled at day three to answer any remaining questions about the study, to optimise compliance to the diary and to capture data on our nigh critical parent-reported outcomes. A follow-upwardly visit at the kid's dwelling house will exist scheduled at 2 weeks to check diary data for accuracy, perform otoscopy and tympanometry and sample otorrhoea (where possible), nasopharynx and faeces samples. Parents will consummate OM-specific QoL and productivity loss questionnaires at ii weeks and at 3 months. Parents will also send a faeces sample to the laboratory for analysis at iii months.

Validated questionnaires

Parents written report the presence and severity of their kid's symptoms using a validated seven-point Likert scale.23 24 OM-specific QoL of the child will be assessed using the parent-reported OM-6 questionnaire, a 6-item questionnaire recording ear-related problems in the previous menstruum.25 An adapted version of the iMTA Productivity Cost Questionnaire (iPCQ) is used to capture parental productivity losses due to AOM26

Temperature measurement

Parents measure their child'due south temperature two times per twenty-four hour period (morning and evening) with a tympanic membrane thermometer in the unaffected ear.27 In children aged below two years and in those with bilateral ear discharge, temperature is measured rectally. To standardise measurements, a written report thermometer volition be provided. The definition of 'no fever' at twenty-four hours iii (primary outcome) is a temperature recording below 38.0°C both in the morn and evening.6

Eardrum perforation

Otoscopy will be used to assess the integrity of the eardrum at 2 weeks. In case of inconclusive otoscopy results, tympanometry results will exist used.

MEE assessment

A diagnostic algorithm combining tympanometry and otoscopy will be used to diagnose MEE at ii weeks.28

Collection and analyses of otorrhoea and nasopharynx samples

The otorrhoea and nasopharynx samples are collected using a flexible applicator swab with flocked nylon fibre tip.29 The swabs will be immediately transported to the microbiology laboratory of the UMC Utrecht where they volition be stored at −eighty°C until further analysis.

Collection and analyses of faeces samples

The baseline, 2-calendar week and 3-month faeces samples are collected using the OMNIgene●GUT (OMR-200), a trademark of Deoxyribonucleic acid Genotek, Ottawa, Canada. Parents volition ship the 3-month faeces samples by mail. If faeces samples cannot be collected during the baseline and two-week dwelling house visit, we volition provide the parents with a collection kit and send envelop, so parents tin can collect and send the faeces samples by mail at their earliest convenience. Samples will be stored at −fourscore°C at the microbiology laboratory of the UMC Utrecht until analysis for detection and quantification of the dynamics of bacterial genes that confer resistance to the antibiotics used in our trial.30

Chief and secondary outcomes

The primary effect is the proportion of children without ear pain (ear hurting score 0 on the 0–6 Likert calibration) and fever (body temperature of 38.0°C or higher) at mean solar day 3 (72 hours later randomisation).

Secondary outcomes are the proportion of children with at most balmy ear hurting (ear pain score less than iii on the 0–half dozen Likert Scale) at 24-hour interval 3; mean ear pain score over days 0–3, number of days with ear pain (ear pain score 1 or college on the 0–6 Likert scale); hateful body temperature over days 0–iii; number of days with fever (body temperature of 38.0°C or higher) during the first ii weeks; the proportion of children with parent-reported ear discharge at day 3; number of days with parent-reported ear belch at twenty-four hours 3 and during the first two weeks; proportion of children with otoscopically confirmed ear discharge at 2 weeks; time to resolution of total symptoms (time to all of pain, fever, discharge, being unwell, sleep disturbance, and distress/crying being rated 0 or 1 on the Likert scale); MEE and proportion of children with otoscopically confirmed eardrum perforation at ii weeks; OM-specific QoL at baseline, 2 weeks and 3 months; antibiotic consumption during the first 2 weeks and at 3 months; number of AOM recurrences at 3 months; number of adverse events during the commencement 2 weeks; costs and cost-effectiveness at 2 weeks and 3 months; the prevalence of viruses and leaner in otorrhoea and nasopharynx samples at baseline and 2 weeks; the antimicrobial susceptibility profiling of the bacteria and the impact of the treatment regimens on antimicrobial resistance genes in the homo gut; microbiome profile of nasopharynx at baseline and two weeks.

Sample size calculation

The main aim is to demonstrate that antibiotic-corticosteroid eardrops are non-inferior to oral antibiotics in relieving ear pain and fever at day iii. The proportion of children without ear pain and fever at day 3 is expected to exist 65% in the oral antibiotics group and effectually 35% if placebo or no treatment would exist trialled.3 Our parent console assisted in defining the not-inferiority margin by advising on the maximum difference in primary effect that they would regard equally unimportant. Following these discussions, the clinically acceptable non-inferiority margin is set at 15%; that is, l% of the difference (30%) observed between oral antibiotics and placebo or no treatment in before trials.3 Taking 50% of such a divergence is also a widely-accepted method to determine the non-inferiority margin.31 32 Testing significance at a i-sided 0.025 level (α) and using a power of fourscore% (β 0.20), each treatment arm should include at to the lowest degree 159 children to demonstrate that the upper limit of the i-sided 97.5% CI (or equivalently a two-sided 95% CI) of the difference in handling effect for the primary outcome does not exceed the predefined not-inferiority margin of fifteen%. To allow for a maximum of 10% loss to follow-upward, we aim to randomise 350 children.

Statistical assay

Primarily, all analyses will be performed according to the intention-to-treat principle. Per-protocol analyses will also be conducted as well because of its importance in non-inferiority trials.33 All analyses will be performed blinded with respect to study-group assignment and analysis and presentation of results will be in accord with the Consolidated Standards of Reporting Trials guidelines.34 35

Clinical effectiveness

Nosotros will use descriptive statistics to describe the baseline characteristics trial population; we will nowadays ways and SD for normally distributed continuous variables, medians and IQRs for non-normally distributed continuous variables, and numbers with percentages for categorical variables.

The chief event volition be analysed with binomial logistic regression model including treatment group and effectiveness of oral antibiotics versus antibody-corticosteroid eardrops will be expressed as relative risk and absolute risk difference with accompanying 95% CIs. This latter will enable united states of america to judge whether not-inferiority has been demonstrated, in detail whether the upper limit of the 2-sided 95% CI exceeds the predefined not-inferiority margin of 15%. In adapted analyses, stratification factors and other important prognostic factors (baseline ear pain score, duration of ear pain prior to enrolment) will be added to the model. Subgroup effects co-ordinate to age (<ii vs ≥2 years) and laterality (unilateral vs bilateral AOM at baseline) will exist evaluated by including an interaction term (treatment*age) in the model.

In sensitivity analyses, nosotros will impute for missing baseline and outcome data using multiple imputation techniques.36 37 In farther sensitivity analysis, we will appraise whether results differ when defining the absence of fever for the master event as parental fever score 0 or 1 on the 0–6 Likert calibration at solar day three (instead of the kid's torso temperature recordings as specified above).

In secondary analysis, we will utilise log binomial regression analyses for dichotomous variables, Poisson regression analyses for count variables, and linear regression analyses for continuous variables, where applicable corrected for repeated measurements. For these analyses, the comparing betwixt handling groups will exist expressed as risk ratios, rate ratios, and mean differences, respectively; all with 95% CIs. Kaplan-Meier curves will be plotted for duration of symptoms and log-rank tests for differences betwixt groups.

Toll-effectiveness assay

A societal perspective will be used for this analysis, that is, medical and not-medical costs volition exist taken into account. We will use a short-time horizon for all analyses and therefore, all costs volition be presented undiscounted.

Beginning, effectiveness volition be assessed: the main clinical effectiveness event will be symptom (ear pain and fever) resolution. Similar to our previous trials in this field, nosotros will not apply quality-adjusted life-years (QALYs) every bit the nature of the status (cocky-limiting in the vast majority of the children and of relatively brusk duration) does not impact importantly on QALYs.12

Second, costs will be calculated; all costs will be estimated at the patient level by multiplying resource utilize with cost estimates per unit of measurement of resources use. Cost prices will be estimated according to guidelines for economic evaluation in healthcare research or taken from standard reference lists, every bit far as possible.38 39 Costs of medication use will exist retrieved from the Dutch formulary and a pharmacist'due south fee will be added for every prescription.38 40 Costs of OTC and complementary medicines will be calculated per day, based on current average retail prices. Costs of consulting a GP or a medical specialist, and hospitalisations will be based on current Dutch guidelines for pharmacoeconomic evaluation38 or charges if no other estimates are available. Costs of diagnostic tests will also be derived from the Dutch guidelines for pharmacoeconomic evaluation.38 Costs of surgical procedures volition exist based on a previous Dutch costing written report.41 Costs associated with absence from work will be retrieved from the completed iPCQ.26 The hourly price estimate for childcare volition exist derived from the Dutch National Institute for Family Finance Data.42 Travel expenses volition be calculated for healthcare visits following the Dutch guideline for pharmacoeconomic evaluation.38 Overall costs volition exist compared beyond the treatment groups, and where relevant, differences volition be calculated, including 95% CIs. Finally, we will compare differences in costs between handling groups to differences in clinical effects between groups by calculating incremental cost-effectiveness ratios (ICERs). ICERs volition indicate the incremental cost per day with ear pain and fever avoided when comparing antibiotic-corticosteroid eardrops with oral antibiotics, both in the short (14 days) and long term (3 months). Doubtfulness will be addressed in a probabilistic sensitivity assay by means of bootstrapping. Results will be presented using incremental price-effectiveness planes and cost-effectiveness acceptability curves.

Ethics and dissemination

The study is conducted according to the principles of the Announcement of Helsinki (10th version, October 2013), in accordance with the Medical Research Involving Homo Subjects Human action (WMO) and the principles of Good Clinical Practice. The medical research ethics committee Utrecht, The Netherlands has approved the protocol (protocol number 17-400/1000-G). The trial doctor will take written informed consent (see online supplemental file i) from both parents/guardians. Regular trial audits including checks on source data verification, accurateness, validity and completeness of informed consent forms and captured data will be performed by a clinical enquiry associate of Julius Clinical, an independent clinical research arrangement. Nosotros have not established a data safe monitoring board and refrain from conducting any interim analysis for safety or superiority/futility since we neither expect whatsoever safety bug nor large differences in treatment failures between the two active handling groups given the deviation (30%) observed between oral antibiotics and placebo or no handling in previous trials.2 12However, in accord to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is sufficient basis that continuation of the report will jeopardise subject wellness or safety. The information direction section of the Julius Center for Wellness Sciences and Primary Care of the UMC Utrecht will be responsible for handling and storage of the data using innovative software applications like SLIM (Study Logistic and Information Management System) and Enquiry Online. On completion of the trial, data volition be stored for a minimum of 15 years at a central data drive at the Julius Center and volition only exist made available for use by third parties on request and blessing of the principle investigator (professor RAMJD).

Supplemental material

Dissemination plan

Nosotros will publish study results in peer reviewed scientific journals and nowadays at relevant (inter)national scientific meetings. We will work with our parent panel to help translate the findings of the trial and harness their resources for dissemination to the lay public.

Patient and public involvement

For this trial, nosotros accept established a console of eight parents. This panel provided input to the design of the trial including the sample size calculation by advising on the clinically acceptable non-inferiority margin and the outcome measures by proposing additional outcomes of interest such as being unwell and sleep disturbance, and commented on the recruitment strategy and patient information letter. Ane of the parent panel members is a coapplicant on the grant application and coauthor on this paper. The parent panel will be actively involved throughout all critical stages of the trial through regular parent console meetings. They volition work with us throughout the recruitment phase, volition exist involved in reporting the trial results, and will exist ultimately key to pull the evidence into mainstream clinical practice.

Current study status

The first participant was enrolled in the trial on 13 Dec 2017. On viii Baronial 2018 with 34 participants beingness enrolled, trial recruitment was put on hold due to supply issues of hydrocortisone–bacitracin–colistin eardrops. These drops are available again since early on 2021. Our funding body, holland Organisation for Health Research and Development (ZonMw), has approved the trial to reopen in September 2021. Nosotros expect information drove to exist completed by the end of 2023 with trial results existence available past March 2024.

Discussion

This trial is one of the first to compare the effectiveness of topical with oral antibiotics in children with AOMd. The simply other trial in this field is conducted in UK primary care (Runny Ear STudy). This study has been designed in close collaboration with members of the Dutch report team to enable future meta-analysis by harmonising design, outcomes and issue measure instruments.14 15 The UK-based trial has stopped prematurely due to problems with the electronic health record system platform which resulted in low recruitment (n=22) and failure to reach the predefined sample size.43

With obvious theoretical advantages of topical over oral antibiotic treatment and the lack of direct evidence, farther research is needed to found whether with AOMd can effectively be treated with topical antibiotics. Our trial will not but provide this key evidence, but as well establish the impact of the two antibiotic treatment strategies on microbiome composition and antimicrobial resistance. The pragmatic, open-label design of our trial enhances the applicability of the findings to daily practice and is most suited to address key secondary outcomes such as antibody consumption during the first 2 weeks and toll-effectiveness in everyday exercise. This would be much more than difficult to determine realistically in a blinded written report where children in both groups would receive oral suspension and ear drops. The lack of blinding might, however, introduce bias caused by the awareness of treatment consignment which may be particularly problematic in trials with subjective outcomes. However, both study groups receive an agile handling, our parent console had no strong behavior or preferences for ane treatment over the other, and a recent meta-epidemiological study institute no evidence for a difference in estimated treatment issue between blinded and not-blinded trials.44 Another limitation of our study is, that we practise not capture data on the prevalence of longer term complications such as the presence of otoscopically confirmed MEE or chronic suppurative OM at 3 months. We, yet, will collect information well-nigh AOM-related specialist referrals, hospitalisation and/or surgery during the 3 months follow-up period, which provide information on the occurrence of AOM sequelae in the short and long terms.

Ethics statements

Patient consent for publication

Acknowledgments

Nosotros gratefully give thanks our parent console for their valuable input and all children and parents who participated in our trial thus far.

Supplementary materials

  • Supplementary Data

    This web only file has been produced past the BMJ Publishing Group from an electronic file supplied past the author(s) and has non been edited for content.

    • Data supplement one

Request Permissions

If you wish to reuse any or all of this article delight use the link below which will have yous to the Copyright Clearance Centre's RightsLink service. You will be able to get a quick toll and instant permission to reuse the content in many different ways.

Copyright information:

© Author(due south) (or their employer(s)) 2021. Re-use permitted nether CC Past-NC. No commercial re-utilise. Run across rights and permissions. Published past BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access commodity distributed in accordance with the Creative Commons Attribution Not Commercial (CC BY-NC four.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on dissimilar terms, provided the original piece of work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/past-nc/four.0/.