ODYSSEY ALTERNATIVE

Methods	Type of RCT: 1:1 parallel‐group RCT, with stratification for CVD history Settings: outpatient care Duration: 24 weeks Start and stop dates: 09/2012 and 09/2016
Participants	Number of participants: 251 (excluding 63 participants in an atorvastatin rechallenge arm) Number lost to follow‐up: 80 Women: 114 (45%) Age (SD), years: 63 (10) History of CVD: 115 (46%) FH participants: 38 (15%) Participants with primary hypercholesterolaemia and moderate, high, or very high CV risk, who are intolerant to statins 377 participants with a history of statin intolerance, and of moderate, high, or very high CV risk. Moderate CV risk defined as SCORE risk of 1% or more but lower than 5%; high risk defined as score risk of 5% or more, or moderate chronic kidney disease, diabetes without target organ damage heFH; very high risk defined as history of documented CHD, ischaemic stroke, peripheral artery disease, TIA, abdominal aortic aneurysm, or carotid artery stent procedure, or carotid endarterectomy or carotid artery stent procedure, or renal artery stenosis or renal artery stent procedure or diabetes with target organ damage
Interventions	Background therapy: National Cholesterol Education Program Adult Treatment Panel III therapeutic lifestyle changes diet. Participants were allowed to continue to use bile acid, nicotinic acid, fenofibrate, or mega‐3 acid Randomised therapy: alirocumab and placebo vs daily 10 mg ezetimibe or 20 mg atorvastatin and placebo Alirocumab dose: 24 weeks 75 mg alirocumab every 2 weeks, with uptitration of alirocumab to 150 mg every 2 weeks at week 12. Resulting in a 2‐week equivalent dose of 75 mg to 150 mg
Outcomes	MACE, lipids, any adverse events, all‐cause mortality
Notes	Atorvastatin arm was included as a re‐challenge experiment. Main analysis focuses on alirocumab vs ezetimibe (151 participants) LDL‐C was calculated using the Friedewald formula NCT01709513
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Low risk	Permuted‐block design and central allocation
Blinding of participants and personnel (performance bias) LDL‐C	Low risk	Placebo‐controlled, patients self‐administered. Unclear if staff was also blinded. Any potential unblinding of staff would be unlikely to result in bias in association with biomarkers
Blinding of outcome assessment (detection bias) LDL‐C	Low risk	Lipid parameters assessed at central blinded laboratory
Incomplete outcome data (attrition bias) All outcomes	High risk	36 (28.6%) participants in the alirocumab arm had missing lipid measurements compared with 44 (36.1%) in the ezetimibe arm. Potenially, these "missing" participants simply did not make the required follow‐up time (24 weeks) owing to late enrolment; without specific description of the reason for these lower numbers, some concern is warranted
Selective reporting (reporting bias)	Unclear risk	Full paper has not yet been published
Other bias	High risk	Funded by Sanofi and Regeneron