Fleming 2002.

Methods	RCT Setting: UK Method of randomisation: computer‐generated randomisation by pharmacy in blocks of 4 Blinding: double‐blind Number randomised: 94
Participants	Summary: metformin vs placebo in obese PCOS women Inclusion criteria: PCOS (oligomenorrhoea < 8 cycles/year, exclusion of other endocrinopathy, US finding of PCOS) Age < 35 years Exclusion criteria: diabetes mellitus, adrenal hyperplasia, thyroid dysfunction, hyperprolactinaemia, medication likely to influence hormonal profiles Baseline characteristics of each group metformin (n = 39) vs placebo (n = 26): mean age (+/‐ SD) 28.6 (5.8), 29.2 (5.6) mean BMI (± SD) 34.2 (8.6), 35.0 (8.2) mean fasting insulin mIU/L (± SD) 16.7 (12.7), 18.4 (13.6) mean total testosterone mol/L (± SD) 3.0 (1.5), 3.8 (1.6) mean fasting glucose nmol/L (CIs) 5.05 (4.87‐5.23), 4.93 (4.81‐5.05) Dropouts: 30 (32%), with 22 in the treatment arm and 8 in the placebo, mainly due to gastrointestinal side effects in metformin group. Overall, 58% of the metformin arm completing the trial and 83% of the placebo arm. Included in ITT analysis
Interventions	Main intervention: 1 of metformin 850 mg 2/d, placebo Duration: 12‐16 weeks Co‐interventions: 1st week of treatment at 850 mg 1/d
Outcomes	Primary: gastrointestinal side effects Secondary: clinical pregnancy, ovulation: by twice‐weekly serum oestradiol. Where oestradiol > 300 pmol/L, LH and progesterone (> 8 nmol/L in ≥ 2 successive samples defined ovulation*) were determined, BMI, testosterone, fasting glucose, fasting insulin
Notes	Diagnostic criteria different to other trials ‐ using US not hyperandrogaenemia (although 90% did have raised androgens, and mean entry‐FAI 10 with 5% CI 8.6). Subgroup analysis showed that those who ovulated in response to metformin had significantly lower androgens. High rate of background ovulation (64% on placebo ovulated at some stage) *Information not in the original paper kindly provided by the study author
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation by pharmacy in blocks of 4
Allocation concealment (selection bias)	Low risk	Remote allocation. Identical metformin and placebo tablets. Randomisation code kept in the pharmacy department until the end of the trial
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The trial was described as double‐blind although the details of this were not explained
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The trial was described as double‐blind although the details of this were not explained
Incomplete outcome data (attrition bias) All outcomes	High risk	Dropouts: 30 (32%), with 22 in the treatment arm and 8 in the placebo, mainly due to gastrointestinal side effects in metformin group. Overall, 58% of the metformin arm completed the trial and 83% of the placebo arm.
Selective reporting (reporting bias)	Unclear risk	Insufficient information in the study
Other bias	Low risk	No evidence of other bias