REDUCE‐IT (NCT01492361) is a phase 3b, international, multicenter, prospective, randomized, double‐blinded, placebo‐controlled, parallel‐group trial of icosapent ethyl 4 g/d (2 g twice daily with food) vs placebo (Figure). The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in patients at elevated CV risk concurrently treated with statins. Inclusion and exclusion criteria are listed in Table 1 and Table 2 , respectively. Men or women age ≥45 years with established CVD (CV risk stratum 1, Table 1 ) or age ≥50 years with diabetes mellitus in combination with 1 additional risk factor for CVD (CV risk stratum 2, Table 1 ) were eligible for inclusion. Fasting TG levels ≥150 mg/dL and <500 mg/dL were required. A study amendment was made during the early part of the trial, increasing the lower end of the fasting TG level from ≥150 mg/dL to ≥200 mg/dL, to increase enrollment of patients with more significant TG elevations. LDL‐C levels needed to be >40 mg/dL and ≤100 mg/dL, with patients on stable statin therapy (± ezetimibe) for ≥4 weeks prior to the LDL‐C and TG qualifying measurements for randomization.
The primary endpoint is a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of CV death, nonfatal MI, or nonfatal stroke. Several other secondary, tertiary, and exploratory endpoints are being assessed (Table3 ), which were designed to provide additional insights into the potential effects of EPA therapy on various outcomes and in distinct high‐risk patient populations.
The sample‐size calculation was based on a hazard ratio assumption of 0.85. Therefore, 1612 events would be required to have approximately 90% power with a 1‐sided α‐level of 2.5% and with 2 interim analyses. This results in a total target sample size of 7990 patients. Approximately 70% of randomized patients were to be in CV risk stratum 1 (established CVD) and approximately 30% of randomized patients were to be in CV risk stratum 2 (high‐risk primary prevention defined by diabetes mellitus and other risk factors). Randomization was stratified by CV risk strata, ezetimibe use, and by geographical region.
The first patient was randomized on November 28, 2011. Protocol amendment 1 (May 2013) changed the lower limit of TG levels for entry into the trial from 150 mg/dL to 200 mg/dL, as a majority of the steering committee members felt that those were the patients most likely to benefit from TG lowering. Protocol amendment 2 (July 2016) designated the composite of hard major adverse cardiovascular events (CV death, nonfatal MI, nonfatal stroke) as the “key secondary endpoint” per suggestions from the FDA with steering committee concordance. The last patient was randomized on August 4, 2016. Approximately 8000 patients have been randomized at approximately 470 centers worldwide (see Supporting Information, Appendix, in the online version of this article). Follow up will continue in this event‐driven trial until approximately 1612 adjudicated primary efficacy endpoint events have occurred. This study is being conducted in accordance with a special protocol assessment agreement with the FDA.
The primary endpoint is a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of CV death, nonfatal MI, or nonfatal stroke. Several other secondary, tertiary, and exploratory endpoints are being assessed (Table
The sample‐size calculation was based on a hazard ratio assumption of 0.85. Therefore, 1612 events would be required to have approximately 90% power with a 1‐sided α‐level of 2.5% and with 2 interim analyses. This results in a total target sample size of 7990 patients. Approximately 70% of randomized patients were to be in CV risk stratum 1 (established CVD) and approximately 30% of randomized patients were to be in CV risk stratum 2 (high‐risk primary prevention defined by diabetes mellitus and other risk factors). Randomization was stratified by CV risk strata, ezetimibe use, and by geographical region.
The first patient was randomized on November 28, 2011. Protocol amendment 1 (May 2013) changed the lower limit of TG levels for entry into the trial from 150 mg/dL to 200 mg/dL, as a majority of the steering committee members felt that those were the patients most likely to benefit from TG lowering. Protocol amendment 2 (July 2016) designated the composite of hard major adverse cardiovascular events (CV death, nonfatal MI, nonfatal stroke) as the “key secondary endpoint” per suggestions from the FDA with steering committee concordance. The last patient was randomized on August 4, 2016. Approximately 8000 patients have been randomized at approximately 470 centers worldwide (see Supporting Information, Appendix, in the online version of this article). Follow up will continue in this event‐driven trial until approximately 1612 adjudicated primary efficacy endpoint events have occurred. This study is being conducted in accordance with a special protocol assessment agreement with the FDA.