Tähtinen 2011.

Methods	Randomised ‐ yes, computerised random number generator with block length of 10 Concealment of allocation ‐ adequate Double‐blind ‐ yes Intention‐to‐treat (ITT) ‐ yes Loss to follow‐up ‐ described Design ‐ parallel
Participants	N ‐ 322 children (N = 319 children were included in analysis) Age ‐ between 6 months and 3 years Setting ‐ general practice: healthcare centre of Turku (Finland) Inclusion criteria ‐ acute otitis media (AOM) based on 3 criteria: (a) middle‐ear fluid had to be detected by means of pneumatic otoscopic examination that showed at least 2 of the following tympanic membrane findings: bulging position, decreased or absent mobility, abnormal colour or opacity not due to scarring, or air fluid interfaces; (b) at least 1 of the following acute inflammatory signs in the tympanic membrane had to be present: distinct erythematous patches or streaks or increased vascularity over full, bulging, or yellow tympanic membrane; (c) presence of acute symptoms such as fever, otalgia or respiratory symptoms Exclusion criteria ‐ ongoing antibiotic treatment; AOM with spontaneous perforation of the tympanic membrane; systemic or nasal steroid therapy within 3 preceding days; antihistamine, oseltamivir or a combination therapy within 3 preceding days; contraindication to penicillin or amoxicillin; presence of ventilation tube; severe infection requiring antibiotic treatment; documented Epstein‐Barr virus infection within 7 preceding days; Down's syndrome or other condition affecting middle‐ear diseases; known immunodeficiency Baseline characteristics ‐ balanced
Interventions	Tx ‐ amoxicillin‐clavulanate 40‐5.7 mg/kg daily in 2 doses for 7 days; N = 162 (N = 161 included in analysis) C ‐ matching placebo in 2 doses for 7 days; N = 160 (N = 158 included in analysis) Use of additional medication ‐ the use of analgesics and antipyretic agents was encouraged and the use of analgesic ear drops and decongestive nose drops or sprays was allowed
Outcomes	Primary outcome ‐ time to treatment failure (i.e. a composite endpoint consisting of 6 independent components: (a) no improvement in overall condition at day 2, (b) worsening of the child's overall condition at any time, (c) no improvement in otoscopic signs at day 7, (d) perforation of tympanic membrane at any time, (e) severe infection (e.g. mastoiditis or pneumonia) necessitating systemic open‐label antimicrobial treatment at any time, (f) any other reason for stopping the study drug at any time Secondary outcomes ‐ assessed by study physician ‐ (a) time to the initiation of rescue treatment; (b) time to development of contralateral AOM; ‐ diary symptom assessment; (c) resolution of symptoms; (d) use of analgesics Parents were given a diary to record symptoms, doses of study drugs and any other medications and adverse events First visit after enrolment (= day 0) was scheduled at day 2. End‐of‐treatment visit was scheduled at day 7
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computerised random number generator with block length of 10
Allocation concealment (selection bias)	Low risk	Concealment of allocation by the pharmacist (independent to trial team) by labelling the identical opaque study drug containers with allocation numbers; allocation list was kept at the paediatric infectious disease ward behind locked doors
Other bias	Low risk	ITT analysis ‐ yes, baseline characteristics ‐ balanced
Blinding of participants and personnel (performance bias)	Low risk	Placebo with same taste and appearance as amoxicillin‐clavulanate
Incomplete outcome data (attrition bias)	Low risk	Loss to follow‐up ‐ treatment: N = 1 (1%) and placebo: N = 2 (1%)