ODYSSEY OPTIONS I

Methods	Type of RCT: 2:1 parallel‐group, double‐blind, stratified, permuted‐block designed RCT Settings: outpatient care Duration: 24 weeks Start and stop dates: NA
Participants	Number of participants: 355 Number lost to follow‐up: 10 Women: 124 (35%) Age (SD), years: 63 (10) History of CVD: 200 (56%) FH participants: 31 (9%) Participants with history of CVD and LDL‐C levels ≥ 70 mg/dL, or CVD risk factors and LDL‐C ≥ 100 mg/dL
Interventions	Background therapy: 24 weeks 20 or 40 mg of baseline atorvastatin and National Cholesterol Education Program Adult Treatment Panel III Randomised therapy: alirocumab versus 10 mg ezetimibe per day, or 20 or 40 mg atorvastatin, or for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg Alirocumab dose: 75 mg alirocumab every 2 weeks, with uptitration of alirocumab to 150 mg at week 12. Resulting in a 2‐week equivalent dose of 75 mg to 150 mg Resulting in 7 groups 20 mg atorvastatin plus 75 mg alirocumab every 2 weeks 20 mg atorvastatin plus 10 mg ezetimibe every day 20 mg atorvastatin plus 20 mg atorvastatin every day 40 mg atorvastatin plus 75 mg alirocumab every 2 weeks 40 mg atorvastatin plus 10 mg ezetimibe every day 40 mg atorvastatin plus 40 mg atorvastatin every day 40 mg of rosuvastatin All blinded with placebo alirocumab and over‐encapsulated tables for ezetimibe, atorvastatin, and rosuvastatin
Outcomes	CVD, lipids, any adverse events, all‐cause mortality
Notes	Unless otherwise specified, comparisons are made of alirocumab therapy vs pooled other therapies Fasting blood samples were collected in the morning LDL‐C was calculated using the Friedewald formula Lipoprotein(a) was analysed using an immunoradiometric assay on the Siemens BNII NCT01730040
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised interactive voice‐response system or interactive Web‐response system
Allocation concealment (selection bias)	Low risk	Permuted‐block design and central allocation
Blinding of participants and personnel (performance bias) LDL‐C	Low risk	Both were blinded
Blinding of outcome assessment (detection bias) LDL‐C	Low risk	Central laboratory
Incomplete outcome data (attrition bias) All outcomes	Low risk	4 (3.85%) participants in the alirocumab arm had missing lipids measurements compared with 6 (2.39%) in the comparator arm. Additionally, mixed‐effects (ANCOVA) models were used
Selective reporting (reporting bias)	Low risk	Reports on protocol‐defined endpoints
Other bias	High risk	Funded by Sanofi and Regeneron