Palomba 2005.

Methods	Randomised, prospective, double‐blinded, multi‐centre trial Method of randomisation: computer‐generated randomisation list; further details unknown Duration, timing and location of the trial: unknown Sample size calculation was performed. 70 women were randomised. Three cycles per participant Ratio between metformin and placebo: 1:1 Intention‐to‐treat analysis was performed.
Participants	70 non‐obese insulin‐resistant primary infertile women with clomiphene‐resistant PCOS Mean age (±SD) was 26.2 (2.7) for the metformin group and 26.9 (2.8) for the placebo group. Body mass index (±SD) was 26.5 (2.7) and 26.4 (2.5), respectively. Duration of infertility (±SD) was 26.1 (4.7) and 24.8 (4.9) months, respectively. Infertility workup consisted of endocrinology, vaginal ultrasonography and semen analysis. Fasting glucose and insulin levels were measured, and a glucose tolerance test was performed. Each woman received 75 grams of glucose, and at 30, 60, 90 and 120 minutes, glucose and insulin concentrations were determined.
Interventions	The women took metformin 850 mg 2 times daily or placebo for 3 months. After 3 months, ovulation induction was started. Metformin or placebo was continued during ovarian stimulation with FSH and was stopped when women conceived. All women underwent ovulation induction according to a low‐dose step‐up protocol, started with 75 IU hpFSH (fostimon) for 14 days. If no ovarian response was detected, this dose was increased by 37.5 IU hpFSH each week until follicular development was observed on ultrasonography. Maximum dose was 225 IU daily. Treatment was discontinued if no follicular response was detected after 35 days of treatment, or if more then 3 follicles > 14 mm were present. hCG was given when the diameter of the dominant follicle was > 17 mm.   Women with PCOS who in previous ovulation induction failed to ovulate underwent timed intercourse, whereas those who were ovulating who did not conceive underwent intrauterine insemination.
Outcomes	(Ongoing) pregnancy rate per woman OHSS Cycle cancellation Ovulation rate Number of oocytes produced per cycle Monofollicular development and multi‐follicular development. Miscarriage rate per woman Live birth rate Quantity of gonadotrophins used per woman per cycle (total dose in IU (international units)) Duration (days) of ovarian stimulation per woman per cycle Serum oestradiol level on the day of hCG trigger injection
Notes	PCOS: Diagnosis was based on National institutes of Health criteria (Zawadski and Dunaif, 1992). Insulin resistance was defined according to Legro et al (1998). Clomiphene‐resistant: failure to ovulate or conceive, ovulating during 6 previous cycles of clomiphene citrate with incremental doses of clomiphene citrate up to 150 mg/d for 5 days alone or in combination with metformin (1700 mg daily)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed by computer‐generated randomisation list.
Allocation concealment (selection bias)	Unclear risk	No further information was provided.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Women and operators were blinded for the whole treatment period. Drug and placebo were packaged in identical form in the pharmacy and were labelled according to participant number.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Women and operators were blinded for the whole treatment period. Drug and placebo were packaged in identical form in the pharmacy and were labelled according to participant number.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No indication of loss to follow‐up or drop‐out was reported. All randomised women were included in the analysis.
Selective reporting (reporting bias)	Low risk	All outcomes described in the Methods section were reported.
Other bias	Unclear risk	Obese women were excluded.