Adams COIN 2011.

Methods	Phase III open‐label RCT; n = 1630
Participants	Advanced colorectal cancer, first‐line therapy
Interventions	Arm A: mFOLFOX6 or CAPOX. Arm B: mFOLFOX6 with cetuximab or CAPOX with cetuximab. Arm C: intermittent mFOLFOX6 or CAPOX. Arm C excluded from analysis given comparisons would not yield information regarding efficacy of EGFR MAb.
Outcomes	Primary outcome: OS in participants with KRAS exon 2 WT tumours. Secondary outcomes: subgroup analyses for OS for KRAS/NRAS/BRAF status, OS for all participants, PFS, ORR, toxic effects.
Notes	Sponsored by MRC. TSM and RAA have received travel, accommodation, and lecture fees from Roche and Merck Serono. Median follow‐up 21 months in control arm, 23 months in cetuximab arm
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central telephone randomisation was done by the MRC Clinical Trials Unit, using the method of minimisation with a random element. The minimisation factors were hospital, WHO performance status, chemotherapy regimen, previous adjuvant chemotherapy, liver metastases, and peritoneal metastases. Participants were randomly assigned (1:1:1).
Allocation concealment (selection bias)	Low risk	Centralised randomisation after faxing details to central site (COIN protocol from MRC website)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Open‐label trial (but see below)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Open‐label trial. Participant symptoms were assessed by investigators throughout treatment but primary outcome (OS) is not affected by open‐label nature.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Equal dropout: in KRAS exon 2 WT population 33/358 in arm A, 26/357 arm B. Intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	All stated outcomes reported.
Other bias	Low risk	No other significant bias present.