A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA * Intervention Trial)
- Conditions
- 10011082cardiovascular diseaseheart and vessel disease10047066
- Registration Number
- NL-OMON46966
- Lead Sponsor
- Amarin Pharma Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 1700
Inclusion Criteria:
1. Fasting TG levels of *200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L).
2. LDL-C > 40 mg/dL (1.04 mmol/L) and * 100 mg/dL (2.60 mmol/L) and on stable therapy with a statin (with or without ezetimibe), for at least 4 weeks prior to the LDL-C/TG baseline qualifying measurements for randomization.
* Stable therapy is defined as the same daily dose of the same statin for at least 28 days before the lipid qualification measurements (TG and LDL-C) and, if applicable, the same daily dose of ezetimibe for at least 28 days before the lipid qualification measurements (TG and LDL-C). Patients who have their statin therapy or use of ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose changed at Visit 1, will need to go through a stabilization period of at least 28 days since initiation/change and have their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1).
* Statins may be administered with or without ezetimibe.
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients do not qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) is allowed. For some patients, because they need to stabilize medications and/or need to washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the stabilization/washout period.
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV Risk Category 2). The CV risk categories are defined as follows:
CV Risk Category 1: defined as men and women *45 years of age with one or more of the following:
o Documented coronary artery disease (CAD; one or more of the following primary criteria must be satisfied):
* Documented multi vessel CAD (>50% stenosis in at least two major epicardial coronary arteries * with or without antecedent revascularization);
* Documented prior MI;
* Hospitalization for high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) (with objective evidence of ischemia: ST-segment deviation or biomarker positivity).
o Documented cerebrovascular or carotid disease (one of the following primary criteria must be satisfied):
* Documented prior ischemic stroke;
* Symptomatic carotid artery disease with *50% carotid arterial stenosis;
* Asymptomatic carotid artery disease with *70% carotid arterial stenosis per angiography or duplex ultrasound;
* History of carotid revascularization (catheter-based or surgical).
o Documented peripheral arterial disease (PAD; one or more of the following primary criteria must be satisfied):
* Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication;
* History of aorto-iliac or peripheral arterial intervention (catheter-based or surgical).
OR
CV Risk Category 2: defined as patients with:
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND
2. Men and women *50 years of age AND
3. One of the following at Visit 1 (additional risk factor for CVD):
* Men *55 years of age and Women *65 years of age;
* Cigarette smoker or stopped smoking within 3 months before Visit 1;
* Hypertension (blood pressure *140 mmHg systolic OR *90 mmHg diastolic) or on antihypertensive medication;
* HDL-C *40 mg/dL for men
Exclusion Criteria:
1. Severe (New York Heart Association [NYHA] class IV) heart failure.
2. Any life-threatening disease expected to result in death within the next 2 years (other than CVD).
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x the upper limit of normal (ULN), or biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN).
4. Hemoglobin A1c >10.0% at screening (Visit 1). If patients fail this criterion (HbA1c >10.0%) at Visit 1, they may have their antidiabetic therapy optimized and be retested at Visit 1.1.
5. Poorly controlled hypertension: blood pressure *200 systolic mmHg OR *100 mmHg diastolic (despite antihypertensive therapy).
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-cardiac major surgical procedure. Patients can be (re)evaluated for participation in the trial (starting with Visit 1.1) after their recovery from the intervention/surgery.
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III).
8. Participation in another clinical trial involving an investigational agent within 90 days prior to screening (Visit 1). Patients cannot participate in any other investigational medication or medical device trial while participating in this study (participation in a registry or observational study without additional therapeutic intervention is allowed).
9. Intolerance or hypersensitivity to statin therapy.
10. Known hypersensitivity to any ingredients of the study product or placebo (refer to Table 5); known hypersensitivity to fish and/or shellfish.
11. History of acute or chronic pancreatitis.
12. Malabsorption syndrome and/or chronic diarrhea (Note: patients who have undergone gastric/intestinal bypass surgery are considered to have malabsorption, hence are excluded; patients who have undergone gastric banding are allowed to enter the trial).
13 Non-study drug related, non-statin, lipid-altering medications, supplements or foods:
* Patients are excluded if they used niacin >200 mg/day or fibrates during the screening period (after Visit 1) and/or plan to use during the study; patients who are taking niacin> 200 mg/day or fibrates during the last 28 days before Visit 1 need to go through washout of at least 28 days after their last use and have their qualifying lipids measured (TG and LDL-C) after the washout period (Visit 1.1).
* Patients are excluded if they take any omega-3 fatty acid medications (prescription medicines containing EPA and/or docosahexaenoic acid [DHA]) during the screening period (after Visit 1) and/or plan to use during the treatment/follow-up period of the study. To be eligible for participation in the study, patients who are taking omega-3 fatty acid medications during the last 28 days before Visit 1 (except patients in the Netherlands), need to go through a washout period of at least 28 days after their last use and have their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1);
* For patients in The Netherlands only: patients being treated with omega-3 fatty acid medications containing EPA and/or DHA are excluded; no washout is allowed.
* Patients are excluded if they use dietary supplements containing omega-3 fatty acids (e.g.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy endpoint is the time from randomization to the first<br /><br>occurrence of any component of the composite of the following clinical events:<br /><br>* CV death;<br /><br>* Nonfatal MI (including silent MI; ECGs will be performed annually for the<br /><br>detection of silent MIs);<br /><br>* Nonfatal stroke;<br /><br>* Coronary revascularization;<br /><br>* Unstable angina determined to be caused by myocardial ischemia by<br /><br>invasive/non-invasive testing and requiring emergent hospitalization.<br /><br>The first occurrence of any of these major adverse cardiovascular events during<br /><br>the follow-up period of the study will be included in the incidence.</p><br>
- Secondary Outcome Measures
Name Time Method