Siqueira 2016

Methods	Double‐blinded RCT, 30 days' treatment with 1‐year duration of follow‐up
Participants	Setting: children belonging to families from low economic and social classes who do not have access to the private health system or additional health care, or both, at Petropolis, Rio de Janeiro, Brazil Participants: 600; 200 randomised to InfluBio, 200 to homeopathic complex, and 200 to placebo Recruitment method: Brazilian Public Health System in Petropolis (BPHSP), Rio de Janeiro Withdrawals and exclusions: InfluBio: 55 lost to follow‐up, 145 analysed Homeopathic complex: 51 lost to follow‐up, 149 analysed Placebo: 49 lost to follow‐up, 151 analysed Age range: 1 to 5 years Gender: 42.3% female for homeopathic complex, 48.3% female for placebo, and 42.8% female for InfluBio for those who completed the study Eligibility criteria: Inclusion criteria: no apparent disease Exclusion criteria: history of wheezing and asthma, HIV infection, immunodeficiency; type I diabetes, malignancies, corticosteroid treatment; congenital anomalies, liver disease, history of at least 1 episode of respiratory infection in the 30 days prior to the beginning of the study
Interventions	2 different homeopathic medicinal products versus placebo Each test solution was administered by the child’s tutor twice a day, for 30 days, in April. The dosage applied was 1 drop/year of age; the sample had been previously diluted in a tablespoon of filtered water. Homeopathic product 1: InfluBio was prepared from purified influenza virus sample A/Victoria/3/75 (H3N2), provided by the Virus Surface Structure Laboratory at the Federal University of Rio de Janeiro, Brazil. Briefly, 1 mL of this infectious virus suspension at 0.240 HAU/25 mL was diluted in 9 mL of sterile distilled water in order to make the first dilution (1:10 dilution) following Brazilian Homeopathic Pharmacopea. This 1:10 sample was submitted to 100 mechanical succussions for 33 s (approximately 3 Hz), originating the first potency, which was named decimal (1 dH, 10_1). This procedure was successively repeated to obtain biotherapy 30 dH (10_30 ), which was denominated InfluBio. Homeopathic product 2: a homeopathic complex composed of bacterial strains (Streptococcus and Staphylococcus) and inactivated influenza virus, prepared following the same homeopathic procedures as above until the 30 dH potency, which corresponds to a dilution of 10_30. This medicine is used routinely in patients in the BPHSP for the prophylaxis and treatment of diseases of the upper respiratory tract. Placebo: the placebo was the biotherapy vehicle, i.e. ethanol 30% (volume per volume), which is commonly employed as a vehicle for homeopathic medicines.
Outcomes	Number of episodes of influenza and ARTI in 1 year (2009 to 2010) To characterise the number of influenza and ARTI episodes, at least 2 of the following symptoms had to be present: fever (temperature > 37.8 °C), runny nose, prostration, myalgia, headache, and cough. Duration, in days, of influenza and ARTI symptoms (not reported in results) Adverse events (not reported in results)
Notes	Partly sponsored by FAPERJ and Instituto Roberto Costa, and Coorenacao de Aperfeicoamento de Pessoal de Nival Superior granted the author a PhD scholarship.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The children were randomised followed a numbered list to three intervention groups (Homeopathic Complex, Placebo, and InfluBio), with 200 patients each (1:1:1), block sizes of 6, using Epi Info software” (p. 73) Comment: robust method of allocation concealment was likely used, however meaning of "randomised following a numbered list" is unclear.
Allocation concealment (selection bias)	Low risk	Quote: “Following this list, and also to guarantee concealment, independent pharmacists dispensed the test solutions to the health agents who gave the solutions to child’s parent or guardian. During the study, neither the families nor the health agents and doctors knew which solution was being given to each child. To this effect, we created a random code of letters (A, B, C) to identify the solutions, which was kept under the custody of the general coordinator of the research.” (p. 73) “All solutions were identical in appearance and taste.” (p. 74) Comment: robust method of allocation concealment used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “The following groups were blinded: the patients and their guardians; physicians; health agents; and the researchers who performed the data analysis. The physicians (n = 300) and health agents (n = 400) were trained according to an established protocol, which was identical to each child.” (p. 73) Comment: robust method of blinding used.
Blinding of outcome assessment (detection bias) Patient reported outcomes	Low risk	Quote: “The following groups were blinded: the patients and their guardians; physicians; health agents; and the researchers who performed the data analysis. The physicians (n = 300) and health agents (n = 400) were trained according to an established protocol, which was identical to each child.” (p. 73) Comment: robust method of blinding used.
Blinding of outcome assessment (detection bias) Practitioner outcome assessors	Low risk	Quote: “The following groups were blinded: the patients and their guardians; physicians; health agents; and the researchers who performed the data analysis. The physicians (n = 300) and health agents (n = 400) were trained according to an established protocol, which was identical to each child.” (p. 73) Comment: robust method of blinding used.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: “Of the 600 children selected for the study, 445 (74.17%) children finished it and 155 (25.83%) children were classified as dropouts, since they quit during the research period. The main reasons for this loss were change of residence or adhesion to private health insurance plans.” (p. 74) Comment: Reasons for loss to follow‐up mentioned in a general sense, but no specific numbers for each group. Note that baseline demographic data are only provided for the 445 children who completed the study, not the 145 dropouts. Intention‐to‐treat analysis planned for in methods, but those lost to follow‐up were not part of the study flowchart (Figure 1); were not included in the baseline characteristics (Table 1); were not included in Table 2 analysis of number of flu and ARTIs symptomatic episodes in the first year postintervention; and the key outcome data in Figure 2 are presented in such a way that it is unclear if ITT analysis was actually used.
Selective reporting (reporting bias)	High risk	Results focus on arbitrary cut‐off of 3 or more flu and ARTI episodes for comparison between groups, a benchmark that was not set prospectively in the methods. Results do not provide mean numbers of ARTIs, however these can be approximately calculated from the data in Table 2. Outcomes listed in methods but not reported in results: Duration, in days, of flu and ARTI symptoms Adverse events Regarding adverse events, the results state "It is important to point out that no discomfort or death induced by the use of test solutions were reported by the children’s families during the period of this clinical trial." (p. 75), however no data on adverse events are provided. Results include mention of increase in ARTI episodes in first 2 months in the placebo group, but no data presented, and this was not mentioned in the methods.
Other bias	Unclear risk	Analysis more difficult given combination of influenza and URTIs into 1 study. Use of diagnostic criteria (at least 2 of the following symptoms had to be present: fever (temperature > 37.8 °C), runny nose, prostration, myalgia, headache, and cough) does not specifically select for episodes of influenza or URTI. Very low total number of ARTIs during the 12‐month follow‐up period (compared to the year before and to known incidence data for childhood ARTI). This suggests the monthly assessments to check for URTI may not have picked up all cases. Declaration: none of the authors have a conflict of interest.