PRECEDENT 2013.

Methods	Phase II open‐label multicentre RCT; randomisation ratio EC145 (Vintafolide) + PLD to PLD was 2:1; recruitment between Sept 2008 and June 2010 in USA, Canada and Poland.
Participants	162 women with PR ROC (149 had measurable disease); ≥18 years; ECOG performance status of 0‐2; measurable disease; ≤ 2 prior systemic cytotoxic regimens and adequate organ function. Excluded if prior exposure to PLD, folate‐receptor (FR) targeted therapy or vinca‐containing compounds; recent surgery; serious comorbidities; concurrent malignancy.
Interventions	Arm 1 (100 women): EC145 (2.5 mg IV days 1,3 and 5, weeks 1 and 3, q4wk) + PLD (50 mg/m²) q4wk Arm 2 (49 women): PLD (50 mg/m²) IV q4wk EC145 is a folate‐linked vinca alkaloid. Premedication was optional, but considered not necessary for EC145 administration.
Outcomes	Primary: PFS assessed within 12 months following completion of accrual using RECIST and clinical findings Secondary: OS assessed within 18 months after PFS analysis; ORR; safety and tolerability; correlation between therapeutic response and 99mTc‐EC20 levels.
Notes	We contacted the investigators, who gave us access to their unpublished manuscript and provided us with additional unpublished data. The Independent radiologic committee (IRC) assessment in women with more than one CT scan correlation was 74%. PFS was not significantly different between the treatment groups for the IRC assessment except for the subgroup of folate‐receptor positive women. One woman in each group required growth factor support (unpublished data). Median OS was unusually long in the PLD only arm (16.8 months)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation 2:1 EC145/PLD:PLD. Stratified according to primary or secondary platinum resistance, treatment centre, and baseline CA‐125 (<200 versus ≥200 U/ml).
Allocation concealment (selection bias)	Low risk	Central randomisation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessment was based upon investigator assessment using RECIST criteria, however blinded assessment was performed by an IRC to check for investigator bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Censoring due to clinical progression was 12% and 10% for treatment arms respectively. Eight women in the EC145 arm were withdrawn from EC145 due to treatment related AEs (7.5%) but were included in ITT analyses. Women with non‐measurable disease (13) were included in the safety analyses but excluded from the survival analyses.
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported. Sensitivity analysis performed for primary outcome.
Other bias	Low risk	Baseline characteristics were similar between the arms except for the number of tumour lesions, which was greater in the EC145 arm, however this was not a prognostic factor for shorter PFS.