ORIGIN 2012

Methods	Outcome Reduction With Initial Glargine Intervention (ORIGIN) RCT, 2 × 2 factorial, (capsule of n‐3 fatty acids or placebo), 72 months Summary risk of bias: low
Participants	People at high risk of CV events with impaired fasting glucose, impaired glucose tolerance or diabetes N: 6319 intervention, 6292 control. (analysed, intervention: 6281 control: 6255) Level of risk for CVD: moderate Men: 65.4% intervention, 64.7% control Mean age in years (SD): 63.5 (7.8) intervention, 63.6 (7.9) control Age range: unclear, eligible if aged ≥ 50 years Smokers: current smokers 12.1% intervention, 12.6% control Hypertension: 78.7% intervention, 80.3% control Medications taken by at least 50% of those in the control group: ACE inhibitor or ARB, aspirin or other antiplatelet, beta‐blocker, statin, glucose‐lowering drug Medications taken by 20%‐49%: calcium‐channel blocker Medications taken by some, but less than 20%: thiazide diuretics, anticoagulant Location: 40 study locations in Europe and the Americas Ethnicity: unclear
Interventions	Type: supplement capsule (Omacor) Comparison: EPA + DHA vs MUFA Intervention: 1 gelatin capsule/d Omacor containing at least 900 mg ethyl esters of n‐3 fats (465 mg EPA + 375 mg DHA). Dose: 0.84 g/d EPA + DHA Control: 1 × 1 g gelatin capsule/d olive oil Compliance: methods of assessment unclear, but reported that "rates of adherence to the study‐drug regimen were similar in the two groups with 96% of patients continuing to receive the study drug at 1 year ... and 88% at the end of the study". Length of intervention: 74 months mean follow‐up (median 6.2 years)
Outcomes	Main study outcome: composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke Dropouts: 38 intervention, 37 control (some of the remainder did not have final outcome status, were lost or withdrew consent, but were included in analysis) Available outcomes: mortality, CV mortality, fatal arrhythmia, MI, stroke, heart failure, angina, revascularisation, breast cancer, cancer diagnoses and cancer deaths, BP, lipids (HbA1c given as medians only) Response to contact: yes but no data provided
Notes	The other 2 × 2 assignment was to insulin glargine versus standard care, and is not discussed here. Results are reported here for the trial duration and not the follow‐up post trial (the ORIGIN and Legacy Effects, ORIGINALE). Study funding: Sanofi Aventis, Omacor provided by Pronova Biocare
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomized by an automated telephone randomization system (using randomly varying block sizes)"
Allocation concealment (selection bias)	Low risk	As above
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study described as "double blind" and placebo described as identical. Blinding of patients, investigators, local and central trials personnel described. However, no information provided as to the capsule's smell and taste
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "all primary and secondary outcomes were adjudicated with the use of prespecified definitions by a committee whose members were unaware of study‐group assignments"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Almost all participants were included in outcomes
Selective reporting (reporting bias)	Low risk	NCT00069784 – registered October 2003, study started August 2003, final data collection December 2011. Most outcomes appear to have been reported in various publications (cardiovascular events only reported by glargine randomisation).
Attention	Low risk	No suggestion of differences between groups
Compliance	Unclear risk	Methods of assessment unclear, but reported that "rates of adherence to the study‐drug regimen were similar in the two groups with 96% of patients continuing to receive the study drug at 1 year ... and 88% at the end of the study"
Other bias	Low risk	None noted