GAUSS‐3.

Study characteristics
Methods	Type of RCT: 1:1 parallel‐group, double‐blind RCT (after a run‐in phase) Settings: outpatient care Duration: 24 weeks (6 months) Start and stop dates: February 2016 and August 2017
Participants	Number of participants: 291 (in phase B, after the run‐in phase), statin intolerant participants Number lost to follow‐up: 2  Women: 106 (49%) Mean age (SD), years: 59 (10) History of CVD: unknown Participants with FH: NA Inclusion criteria Men or women 18–80 years of age Inability to tolerate atorvastatin 10 mg and any other statin at any dose or, alternatively, ≥ 3 statins, with 1 at the lowest mean daily starting dose and 2 other statins at any dose. The lowest mean starting dose was defined as rosuvastatin 5 mg, simvastatin 10 mg, pravastatin 40 mg, lovastatin 20, fluvastatin 40 mg, or pitavastatin 2 mg For people with diagnosed CHD, lipid inclusion criteria required LDL‐C ≥ 100 mg/dL. People without CHD were required to have LDL‐C ≥ 130 mg/dL with ≥ 2 risk factors, ≥ 160 mg/dL with ≥ 1 risk factors, or ≥ 190 mg/dL with 0 additional risk factors. Exclusion criteria Myocardial infarction, unstable angina, coronary revascularisation, or stroke within 3 months before randomisation  Personal or family history of hereditary muscular disorders Moderate‐to‐severe heart failure or uncontrolled cardiac arrhythmia Recently diagnosed or poorly controlled diabetes Hypertension or hyper/hypothyroidism Known active infection Major haematological, renal, hepatic, metabolic, gastrointestinal, or endocrine dysfunction
Interventions	Background therapy: none Randomised therapy: evolocumab vs ezetimibe (10 mg) Evolocumab dose: 420 mg/4 weeks
Outcomes	CVD, all‐cause mortality
Notes	Funded by Amgen
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central computerised system.
Allocation concealment (selection bias)	Low risk	Central allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Central laboratory and blinded adjudication.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 participants were lost to follow‐up.
Selective reporting (reporting bias)	Low risk	Reported most endpoints.
Other bias	Low risk	No concerns outside the assessed risk of bias domains.