Importance: Muscle-related statin intolerance is reported by 5%to 20%of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420mg monthly) or oral ezetimibe (10mg daily). Main Outcome and Measures: Coprimary end pointswere the mean percent change in LDL-C level from baseline to the mean ofweeks 22 and 24 levels and from baseline toweek 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9]mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72]mg/dL). For the mean ofweeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7%(95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5%(95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P