Pedrero‐Escalas 2016

Methods	RCT, double‐blinded, controlled study, 3 months treatment
Participants	Setting: tertiary healthcare hospital in Spain Participants: 95; 45 randomised to homeopathy, 50 to placebo Recruitment method: participants were referred to tertiary healthcare hospital by primary care paediatricians who had diagnosed otitis media with effusion, using simple otoscopy. Withdrawals and exclusions: 2 participants failed/abandoned prior to commencement; 3/45 homeopathy participants withdrew (1 voluntary withdrawal, 1 due to adverse effects, 1 due to surgical procedure); and 6/50 placebo participants withdrew (1 voluntary withdrawal, 4 due to adverse effects, 1 due to surgical procedure). Age range: 2 months to 12 years Gender: 63% male in experimental; 64% male in placebo Eligibility criteria: Inclusion criteria: otitis media with effusion diagnosed by pneumatic otoscopy examination Exclusion criteria: neonatal screening fail, receptive language disorder, neuro‐sensorial hearing loss, autism, craniofacial abnormalities, Down syndrome; middle or internal ear malformation, ciliary motility disorders, cholesteatoma, acute mastoiditis, acute otitis media; recent vaccination (< 30 days); obstructive sleep apnoea; tympanic perforation; tympanostomy tubes or adenoidectomy; lactose or glucose intolerance; treating asthma; corticosteroid, antihistamine, or mucolytic therapy
Interventions	Homeopathic medicinal product versus placebo Homeopathic product: for 3 months children received 2 homeopathic treatments: homeopathic treatment A (Agraphis nutans 5CH and Thuya occidentalis 5CH) at a dosage of 5 granules of each, once a day, preferably in the evening, and homeopathic treatment B (Kalium muriaticum 9CH and Arsenicum iodatum 9CH) at a dosage of 5 granules, twice a day. Placebo: the placebo group received placebo treatment instead of the homeopathy treatment. Boiron Laboratories prepared the homeopathy and placebo treatments, following European Good Manufacturing Practice (EGMP) requirements. Both groups received aerosol therapy (model Apex Mini‐Nebe 230V‐50Hrz 0.6A) consisting of 1 session every 24 hours for 20 days of 1 vial ambroxol hydrochloride (7.5 mg/mL), 1 vial budesonide (0.25 mg/mL suspension), and 2 mL physiological saline for 45 days.
Outcomes	Outcomes: Presence of OME versus absence of OME (assessed via PNO) Recovery (PNO changed from negative in first visit to positive in third visit) Recurrence (after positive PNO in second visit, changed to negative PNO in third visit) Acute otitis media Eardrum perforation Mastoiditis Adverse events Note that occurrence of AOM is the only outcome relevant to this review of ARTI.
Notes	Funding: Laboratorios Boiron Spain Avda
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “A double blind, placebo‐controlled, and randomised parallel group study” (p. 218); “Treatment assignment was set up with a permuted‐block randomisation algorithm and a masking plan was followed to guarantee the double‐blindness.” (p. 218) Comment: robust method of random sequence generation used. Note differences in baseline demographics. “The groups were homogeneous at baseline except for the variable 'school absenteeism for otological causes' and 'the number of Acute otitis media in the previous year.'" (p. 219) "Therefore a univariate and multivariate regression analysis was performed for baseline adjustment and to ascertain whether this disparity affected the results of the study. The odds ratio (OR) and the adjusted OR were obtained for each of these 2 variables, and it was found that both OR were of the same magnitude and were not confounding factors.” Note: no data provided for the above statement.
Allocation concealment (selection bias)	Low risk	Quote: “...a masking plan was followed...” (p. 218) Comment: no statement assuring similarity in appearance/taste/smell of homeopathic treatment and placebo treatment. However, methods state there was a masking plan.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Likely to be adequately double‐blinded given reference to a masking plan
Blinding of outcome assessment (detection bias) Patient reported outcomes	Low risk	Likely to be adequately double‐blinded given reference to a masking plan
Blinding of outcome assessment (detection bias) Practitioner outcome assessors	Low risk	Quote: “Tympanometry examination was performed in the three visits to support the diagnosis of PNO.” “The patient's follow‐up was always performed by the same clinician who had included the patient in the study.” “A masking plan was followed to guarantee the double‐blindness.” (p. 219) Comment: likely to be adequately double‐blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal numbers were low, and all were explained.
Selective reporting (reporting bias)	Low risk	Quote: “There were no changes to the trial design before starting recruitment that could have affected the trial quality.”(p. 218) Comment: low risk of reporting bias, all outcomes described in methods are reported in results.
Other bias	Low risk