Jacobs 2016

Methods	A parallel assignment RCT of homeopathy treatment for URTI
Participants	263 children diagnosed with URTI Setting: University of Washington Medical Center, Roosevelt Pediatric Care Center, Seattle, WA, USA Participants: 263; 128 randomised to homeopathy, 133 to placebo Recruitment method: parents approached in primary care practice, but method of recruitment not stated. Withdrawals and exclusions: of 263 randomised participants, 1 was excluded before commencing treatment due to a positive strep culture at enrolment, and 1 was excluded due to age over 5 years at enrolment. Symptom diaries were returned by 163 participants, and 155 returned dosage logbooks; 244 completed phone follow‐up at 7 to 10 days post‐index visit (i.e. 17 were lost to phone follow‐up). Age range: 2 to 5 years Gender: 48% female Eligibility criteria: Inclusion criteria: clinical diagnosis of URTI, duration of symptoms less than 7 days, parent who spoke English Exclusion criteria: history of asthma, on any prescribed medication, prescribed any medication other than acetaminophen or ibuprofen at index visit, use of homeopathic remedy within 48 hours of index visit
Interventions	Homeopathy (5 mL up to 6 times daily as needed for cold symptoms of commercial liquid formulation Hyland's Cold 'n Cough 4 Kids, which contains: Allium Cepa 6X Hepar Sulph Calc 12X Natrum Muriaticum 6X Phosphorous 12X Pulsatilla 6X Sulphur 12X Hydrastis 6X (6X potency means a 1:10 dilution 6 successive times, 12X is the same dilution 12 times)). Ingredients were added to a liquid preparation that included Glycyrrhiza extract as sweetener. Placebo (5 mL placebo liquid up to 6 times daily as needed). Placebo was similar in appearance, with some similarity of taste (liquid preparation included Glycyrrhiza extract as sweetener).
Outcomes	The parent‐scored outcomes were as follows. Overall symptom severity at 7‐ to 10‐day follow‐up. (Change in cold symptoms of child during the 7 to 10 days after the index visit for a URTI. Parents assessed severity of 4 symptoms (runny nose, cough, sneeze, and congestion) in their child using a 4‐point scale for each symptom, 0 = none to 3 = severe. Cold score is the sum of scores for each symptom (0 to 12). Parents assessed cold score at baseline, twice daily on study days 1 to 3, and at the 7‐ to 10‐day follow‐up.) Adverse events. (Parents were asked to record any side effects after each dose of study medications. Parents were also asked about side effects during follow‐up phone call.) Change in severity of cold symptoms 1 hour after a dose. (Parents measured change in runny nose, cough, nasal congestion, and sneezing severity 1 hour after administering a dose of study medication up to the first 10 doses of study medication. Change in symptom was rated on a 7‐point scale (from 0 to 6), with 0 indicative of the symptom being much worse and 6 indicative of the symptom being much improved. The unit of analysis for each outcome was doses of medication. Each participant could contribute data on 0 to 10 doses.) Change in non‐specific symptoms 1 hour after a dose. (Parents measured change in severity of irritability, lethargy, fussiness, and appetite 1 hour after administering a dose of study medication up to the first 10 doses of study medication. Change in symptom was rated on a 7‐point scale (0 to 6), with 0 indicative of the symptom being much worse and 6 indicative of the symptom being much improved. The unit of analysis for each outcome was doses of medication. Each participant could contribute data on 0 to 10 doses.) Change in functional status of child at 5‐ to 10‐day follow‐up. (Change in functional status of child at the 5‐ to 10‐day phone follow‐up after the index visit for a URTI. Parents rated 5 activities (vigorous activity, activities that require concentration, activities with family or friends, appetite, and sleep) once daily on study days 1 to 5 in their child and again at the 5‐ to 10‐day follow‐up.) Change in health status at 5‐ to 10‐day follow‐up. (Change in health status of child during the 5 to 10 days after the index visit for a URTI. Parents rated health status on 1‐to‐10 scale, with 1 indicating perfect health and 10 indicating very sick. Health status was rated once daily on study days 1 to 3 and again at the 5‐ to 10‐day follow‐up.)
Notes	Sponsors and collaborators: University of Washington, Standard Homeopathic Company
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Each participant was consecutively assigned a unique study identification number and the parent was provided a bottle of study medication with the corresponding identification number. The contents, either the homeopathic syrup or a placebo, were assigned using a computerized randomisation sequence in blocks of four by the University of Washington Investigational Drug Service, which labelled all of the medication bottles.” (p. 230) Comment: robust random sequence generation method used.
Allocation concealment (selection bias)	Low risk	Quote: “The parent was provided a bottle of study medication with the corresponding identification number... the University of Washington Investigational Drug Service... labelled all of the medication bottles.” (p. 230) “The homeopathic syrup and placebo were identical in appearance, smell and taste.” (p. 230) Comment: robust allocation concealment method used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Given robust allocation concealment and all reporting of outcomes done by parents, risk of performance bias is likely to be low.
Blinding of outcome assessment (detection bias) Patient reported outcomes	Low risk	Given robust allocation concealment and all reporting of outcomes done by parents, risk of performance bias is likely to be low.
Blinding of outcome assessment (detection bias) Practitioner outcome assessors	Low risk	Not applicable ‐ no practitioner outcome assessments
Incomplete outcome data (attrition bias) All outcomes	High risk	Symptom diary‐based outcomes subject to high risk of attrition bias, as only 162 of 261 participants returned symptom diaries. While the baseline demographics between "Didn’t return symptom diary" and "Returned symptom diary" groups showed no significant differences, there is a reasonable likelihood that failure to return symptom diary may have been associated with some differences in illness progression or participant/family characteristics. The small number of participants who returned symptom diaries also results in inadequate power for the relevant outcomes. Phone follow‐up outcomes subject to less risk of attrition bias: 244 of 261 participants completed phone follow‐up. Note that none of the phone follow‐up‐based outcomes showed any significant results.
Selective reporting (reporting bias)	Unclear risk	There were several planned outcomes for which no results were reported; time off school for children and days off work for parents are not mentioned in results. Results with positive outcomes (e.g. diary symptom scores at assessment points 1 and 2) are described in detail, while for some results with negative outcomes (e.g. composite cold scores at 5‐ to 10‐day follow‐up, functional outcomes at 5‐ to 10‐day follow‐up) no actual data are provided in the results.
Other bias	Low risk	Sponsor: Standard Homeopathic Company Quote: "The only disclosure restriction on the Principal investigators is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo." Conflict of interest statement: "Dr Jacobs served in the past as a consultant for Standard Homeopathic Company." (p. 234)