Amoxicillin-clavulanate Versus Amoxicillin Versus Placebo in Acute Otitis Media in Children

Background Although acute otitis media (AOM) is very common among young children, the evidence concerning its proper treatment is scarce and rather old. Amoxicillin is the most common treatment of AOM in everyday practice. Still, placebo-controlled, high-quality trials on amoxicillin are missing and amoxicillin has not been compared with amoxicillin - clavulanate. We have thus designed a parallel-grouped triple-blinded randomized controlled superiority trial concerning the efficacy of amoxicillin, amoxicillin-clavulanate or placebo in the treatment of AOM. We use commercially available products as study medicines.

Methods The study is a randomized, triple-blind, placebo-controlled clinical trial comparing the efficacy of amoxicillin with placebo and amoxicillin-clavulanic acid in the treatment of acute otitis media in children. Patients, children 6-35 months of age with the diagnosis of AOM and passing predefined inclusion and exclusion criteria, will be recruited from primary care. Three research centers are recruiting: Mikkeli, Kuopio and Turku.

The aims of this project are to find out:

1\) Is amoxicillin superior to placebo in treatment of childhood acute otitis media? 2) Is amoxicillin clavulanic acid superior to amoxicillin in treatment of childhood acute otitis media? 3) What is the effect of antibiotic treatments, either with amoxicillin or amoxicillin-clavulanate in comparison to placebo, on the recovery of AOM in relation to the harms? 4) What is the effect of different risk factors (e.g. age, history of otitis, exposure to tobacco smoke, lack of breastfeeding, use of a pacifier, unilateral/bilateral episode) on the recovery of AOM? 5) Is there a difference in the course of AOM in different viral upper respiratory tract infections? 6) What is the impact of nasopharyngeal carriage of otopathogenic bacteria on the course of AOM? 7) What is the effect of antimicrobial treatment of AOM on the carriage of nasopharyngeal bacteria compared to placebo? The primary outcome in this trial are the symptoms of the child having AOM, measured with the newly validated AOM SOS symptom score 6.0. The primary analyses will be performed with generalized estimation equations (GEE) as proposed by the developing team of AOM-SOS v6.0. Secondary and other outcomes are collected along newly reported Core Outcome Set for AOM. To avoid type 1 error, secondary outcomes are analyzed with serial gatekeeping strategy.

To follow the needs for research on antimicrobial treatment, we have planned to perform, in addition to traditional intention to treat and per protocol analyses, also DOOR (Desirability of Outcome Ranking) -analyses. These analyses help to appraise the benefit/harm -balance of various treatments.

For sample size calculations the mean SD of the AOM-SOS v6.0 is supposed to be 12 points and the mean clinically important difference (MID) 5 points. With an assumed loss of 10%, altogether 219 children will be recruited.

All patients will be randomized to receive one of the following treatments per orally:

1. Amoxicillin

\- The dose of amoxicillin is 40-50 mg/kg/day divided into two daily doses for 7 days
2. Amoxicillin-clavulanate

\- The dose is as amoxicillin 40-50mg/kg/day divided into two daily doses for 7 days
3. Placebo

* The dose of placebo is comparable to the active study medical products.
* The product is commercially available mixture (SyrSpend) The parents are instructed to keep an electric daily symptom diary (AOM SOS score v6.0) of their child's symptoms, and any potential harm to the child caused by the medication. The subjects will attend the study clinic 2-4 days and 7-9 days after the recruitment. At both visits, the study physician will interview the parent or the legal guardian and the child will undergo a clinical examination including pneumatic video-otoscopy and tympanometry. The video-otoscopy and tympanometry findings will be recorded and the diagnoses validated afterwards.

A polyester fiber swab sample is taken from the nasopharynx of all children to detect respiratory viruses and bacteria both at recruitment and at 7-9 day visit (Multiplex-PCR).

Study clinic visits continue weekly until symptoms, inflammatory changes in the tympanic membrane, middle ear effusion and/or tympanometry have normalized. In case of prolonged effusion (>3 months), the child is referred to an otolaryngologist.

Impact The trial will produce important and highly needed knowledge for the treatment of the most common pediatric infectious disease, where antimicrobial treatment is used. The project will result in three doctoral dissertations and several other publications. In addition, a large amount of material will be generated for further research.

• Amoxicillin (Drug): Amoxicillin administered twice daily for seven days
• Amoxicillin + Clavulanate (Drug): Amoxicillin-clavunate administered twice daily for seven days
• Placebo (Drug): Placebo administered twice daily for seven days

Primary outcomes

• Symptoms of the child [From enrollment to the day 14 of the follow-up]: Daily AOM-SOS score version 6.0. measured by the parents. The treatment effectiveness measured as risk ratios and generalized estimation equations (GEE) are used to convert the daily mean comparisons into relative effect estimates.

Secondary outcomes

• Time to treatment failure [From enrollment to the day 10 of the follow-up]: Treatment failure is a composite endpoint, consisting of six independent components: 1. no improvement in overall condition by the first scheduled visit (day 2-4) (i.e., unless parents thought that their child's overall condition was improving, the case was categorized as treatment failure), 2. a worsening of the child's overall condition at any time, 3. no improvement in otoscopic signs by the end-of treatment visit on day 7-9, 4. perforation of the tympanic membrane or severe infection (e.g., mastoiditis or pneumonia) at any time 5. necessitating systemic open-label antimicrobial treatment at any time, 6. any other reason for stopping the study drug (e.g., an adverse event or nonadherence to the study drug) at any time.
• The duration of middle ear effusion [From enrollment until the ear is cured and effusion vanished. If effusion persist for 3 months, the follow up is discontinued and the child is referred to ENT specialist.]: The duration of middle ear effusion is measured with video-otoscopy and tympanometry at physician visits
• The mean number of pain medication doses [From enrollment to day 7 of the follow up]: The parents give the amount of pain medication doses daily by MyCap (REDCap) system
• The mean AOM-SOS score value [the first 7 days after randomization]: The mean AOM-SOS score values in each group
• Contralateral AOM [the first 7 days after randomization]: The proportions of children with development of contralateral AOM during the treatment

Other outcomes

• Side effects [the first 7 days after randomization]: The proportions of children with side effects (for ex. diarrhea, rash)
• AOM recurrences [12 months from enrollment]: The mean number of AOM recurrences after the trial in the next 12 months, data collected from patient records, Kanta
• Missed days from day care and work [The first 7 days after randomization]: The mean number of missed days from day care (participants) and work (parents) during the first 7 days after randomization
• Nasopharyngeal colonization of otopathogens and the composition and function of nasopharyngeal microbiome [The first 7 days after randomization]: The proportion of children with nasopharyngeal colonization of otopathogens and the composition and function of nasopharyngeal microbiome before and after the treatment
• The effect of nasopharyngeal viruses in the course of AOM [The first 14 days after randomization]: The proportions of children with no improvement of overall condition by the first scheduled control visit (day 2-4), with no improvement of otoscopic signs (7-9 day visit) and with middle ear effusion at days 2, 7 and 14) along viral findings in the nasopharyngeal samples
• Need of rescue antibiotics [The first 14 days after randomization]: The proportions of children needing rescue antibiotics, with spontaneous perforation and with middle ear effusion at days 2, 7 and 14 along nasopharyngeal otopathogen findings
• Risk factors [The first 14 days after randomization]: The effect of risk factors (age, history of otitis, exposure to tobacco smoke, lack of breastfeeding, use of a pacifier, daycare, unilateral/bilateral episode) on the course of AOM

Sex: All, ages: 6 Months to 35 Months

Inclusion Criteria:

* acute otitis media along the diagnostic criteria:

  1. The child has acute symptoms, such as fever, ear pain, or respiratory symptoms
  2. Tympanic membrane shows in otoscopy at least one of the following acute inflammatory signs:
* intense erythematous patches or streaks over full tympanic membrane
* bulging tympanic membrane 3. The presence of middle-ear effusion, established either by
* decreased or absent mobility in pneumatic otoscopy,
* flat tympanogram (B) or
* air-fluid interfaces behind full or bulging tympanic membrane

Exclusion Criteria:

* complicated AOM

  * mastoiditis, facial palsy, inner ear infection
  * spontaneous perforation of the tympanic membrane
* known allergy to aminopenicillins
* known severe allergy to other beta-lactam antibiotics
* antibiotic treatment for another infectious disease, present or during two preceding weeks
* tympanostomy tube or chronic perforation of the tympanic membrane
* anatomic defect or anomaly affecting the susceptibility to AOM
* immune defect, either primary or secondary
* severe chronic kidney disease
* known hearing defect

NIH grants: 2025