Yanovski 2011.

Methods	Parallel randomised controlled clinical trial, randomisation ratio 1:1, superiority design
Participants	Inclusion criteria: BMI ≥ 95th percentile according to the CDC 2000 growth charts for the US prepubertal or early pubertal (defined as breast Tanner stage I to III for girls; testes < 8 mL for boys) fasting hyperinsulinaemia, defined as fasting insulin ≥ 15 mU/mL, the 99th percentile for fasting insulin among 224 nonobese 6‐ to 12‐year‐old children studied as outpatients at the National Institutes of Health with the same insulin assay Exclusion criteria: impaired fasting glucose diabetic diagnosed renal, cardiac, endocrine, pulmonary or hepatic disease that might alter bodyweight baseline creatinine > 1 mg/dL and for ALT or AST > 1.5 times the upper limit of the laboratory normal range Diagnostic criteria: see above
Interventions	Intervention: metformin + dietitian‐administered weight‐reduction programme Comparator: placebo + dietitian‐administered weight‐reduction programme Number of trial centres: 1 Treatment before trial: no Titration period: once baseline assessments were completed, participant's trial medication dose was progressively increased according to a prespecified algorithm over a 3‐week period, starting with 500 mg twice daily and increasing to a maximum dose of 1000 mg twice daily
Outcomes	Outcomes reported in abstract of publication: BMI, bodyweight, BMI z score, fat mass, fasting plasma glucose, HOMA‐IR, adverse events
Study details	Run‐in period: no Trial terminated early: no
Publication details	Language of publication: English Commercial and noncommercial funding Publication status: peer‐reviewed journal
Stated aim for study	Quote from publication: "To determine whether metformin treatment causes weight loss and improves obesity related comorbidities in obese children, who are insulin resistant"
Notes	‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We randomly assigned participants in a 1:1 randomization ratio to receive metformin hydrochloride or placebo, twice daily with meals. Investigators assigned consecutive code numbers to participants from prespecified lists stratified by race/ethnicity, sex, and degree of pubertal development" Comment: an adequate randomisation method was used
Allocation concealment (selection bias)	Low risk	Quote: "The CRC Pharmaceutical Development Section used permuted blocks with stratification to generate allocations that translated code numbers into study group assignments by using a pseudo‐random number program and prepared identically appearing placebo and metformin capsules" Comment: allocation was concealed
Blinding of participants and personnel (performance bias) Objective outcomes	Low risk	Quote: "No participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments during the trial" Comment: both the participants and personnel were blinded
Blinding of participants and personnel (performance bias) Subjective outcomes	Low risk	Quote: "No participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments during the trial" Comment: both the participants and personnel were blinded
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Quote: "No participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments during the trial" Comment: both the participants and personnel were blinded
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	Quote: "No participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments during the trial" Comment: both the participants and personnel were blinded
Incomplete outcome data (attrition bias) Objective outcomes	Low risk	Quote: "We assessed efficacy in the intention‐to‐treat sample of all randomly assigned participants using a multiple imputation model for missing data under a missing‐at‐random assumption" Comment: low risk of attrition bias for objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes	Low risk	Quote: "We assessed efficacy in the intention‐to‐treat sample of all randomly assigned participants using a multiple imputation model for missing data under a missing‐at‐random assumption" Comment: low risk of attrition bias for subjective outcomes
Selective reporting (reporting bias)	Low risk	Comment: all outcomes reported from protocol
Other bias	Unclear risk	Comment: unclear if any other bias was present

"‐" denotes not reported.

ALR: adiponectin‐to‐leptin ratio; ALT: alanine transaminase; AST: aspartate transaminase; BMI: body mass index; BMIadj: adjusted body mass index: BMI‐SDS: body mass index standardised score; BMRadj: adjusted basal metabolic rate; CDC: Centers for Disease Control and Prevention; DBP: diastolic blood pressure; DEXA: dual energy X‐ray absorptiometry; FGIR: fasting glucose insulin ratio; HbA1c: glycosylated haemoglobin A1c; HOMA‐IR: homeostasis model assessment for insulin resistance index; hsCRP: highly sensitive C‐reactive protein; LOCF: last observation carried forward; min: minute; OGTT: oral glucose tolerance test; QUICKI: quantitative insulin check index; SBP: systolic blood pressure; SD: standard deviation; SDS: standard deviation score