PCOSMIC 2010.

Methods	Multicentre RCT Setting: New Zealand Randomisation: double‐blind Number randomised: 171
Participants	Summary: metformin vs placebo in obese women, metformin and CC vs CC vs metformin in non‐obese women Inclusion criteria: women with PCOS according to Rotterdam consensus criteria Exclusion criteria: couples had undergone previous fertility treatment involving > 5 months' treatment with CC or metformin; tubal factor (at least 1 tube blocked); severe male factor (< 15 mil/mL); important medical disorders Obese women (BMI > 32 kg/m2): baseline characteristics: metformin (n = 32) vs placebo (n = 33) Mean age (SD) 29.5 (4.3) vs 29.2 (4.2) Mean BMI (SD) 38.0 (3.9) vs 37.6 (3.2) Mean total testosterone, nmol/L (SD) 2.62 (1.06) vs 2.76 (1.19) Mean fasting insulin, pmol/L (SD) 18.0 (12.7) vs 18.3 (10.8) Dropout: 7 (5 in placebo, 2 in metformin group) Non‐obese women (BMI: ≤ 32 kg/m2): baseline characteristics: metformin and CC (n = 35) vs metformin (n = 35) vs CC (n = 36) Mean age (SD) 29.2 (4.7) vs 28.9 (4.4) vs 28.2 (4.0) Mean BMI (SD) 26.9 (4.1) vs 26.5 (3.5) vs 26.2 (3.4) Mean total testosterone, nmol/L (SD) 2.89 (1.39) vs 2.92 (1.53) vs 2.97 (1.29) Mean fasting insulin, pmol/L (SD) 10.3 (6.5) vs 10.4 (6.5) vs 10.7 (6.0) Dropout: 9 (2 in metformin and CC, 3 in metformin and 4 in CC groups)
Interventions	Obese women were randomised to receive either metformin 500 mg 3/d (increasing dose over 2 weeks) or matching placebo Non‐obese women were randomised to receive either metformin 500 mg 3/d, CC 50 mg from day 2‐6 (increasing up to 150 mg over 3 months if no evidence of ovulation) or metformin 500 mg 3/d combined with CC 50 mg day 2‐6 (increasing up to 150 mg over 3 months if no evidence of ovulation) Duration: up to 6 months All study drugs were stopped once the participant was pregnant
Outcomes	Primary: live birth rate, gastrointestinal side effects Secondary: clinical pregnancy rate, ovulation: serum progesterone ≥ 25 nmol/L, miscarriage, multiple pregnancy, adverse effects: various pregnancy complications
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computerised block randomisation (blocks of 10)
Allocation concealment (selection bias)	Low risk	Quote: "allocation concealment was strictly maintained by a telephone call from the recruiting nurse to pharmacy, ...dispensing pre‐prepared drugs in a true third party randomisation"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis planned and protocol breach and losses to follow‐up were reported
Selective reporting (reporting bias)	Low risk	Protocol published and all outcomes reported. 3‐arm study, however data presented for all 3 arms clearly
Other bias	Low risk	No evidence of other bias