Epanova® for Lowering Very High Triglycerides II (EVOLVE II)

This is a double-blind, randomized, olive oil-controlled study to investigate the efficacy and safety of Epanova as an adjunct therapy to diet for reduction of TG levels in subjects with severe hypertriglyceridemia. The study consists of an approximately 8-week screening period that includes a diet and lifestyle stabilization and washout period and a 12-week treatment period.

\[During the screening period and treatment period, all visits are to be within ±3 days of the scheduled time.\]

Screening Period:

Visit 1 will occur at Week -8 for subjects requiring washout and/or statin, cholesterol-absorption inhibitor (CAI), or statin-CAI stabilization. This includes subjects who:

* Were previously on omega-3 drugs/supplements;
* Require adjustment to or addition of permitted statins, CAI, or statin-CAI combination;
* Have not been on a permitted stable dose of statin, CAI, or statin-CAI combination for at least 4 weeks prior to Visit 1; and/or
* Need to washout of bile acid sequestrants, fibrates, niacin, and other supplements known to alter lipid metabolism.

For these subjects who require washout and/or statin, CAI, or statin-CAI stabilization, at Visit 1 (Week -8) screening procedures will be performed. Subjects will return at Visit 1a (Week -2) for their first qualifying lipid measurement.

For subjects not requiring washout, Visit 1 will occur at Week -2. All screening procedures will be performed at this visit including the first qualifying lipid measurement.

At Visit 2 (Week -1), all subjects will return for their second lipid qualifying measurement. If at Visit 2 the subject does not have an average TG ≥500 mg/dL (6 mmol/L) and \<2500 mg/dL (28 mmol/L), the TG measurement may be repeated one additional time after Visit 2 (Visit 2a). The subject's qualifying measurement would be the average of Visit 1 or 1a + Visit 2 + Visit 2a (repeat measurement).

To be eligible for randomization, the subject must have a qualifying TG ≥500 mg/dL (6 mmol/L) and \<2500 mg/dL (28 mmol/L). Of the total number of subjects, approximately 50% will have a qualifying TG \>885 mg/dL (10 mmol/L) and \<2500 mg/dL (28 mmol/L). Once approximately 50% of the total subjects has been reached for each TG group, enrollment of subjects with that specific TG criterion will stop. Subjects will be equally allocated to each treatment group.

\[At the screening visit, all subjects will receive counseling regarding the National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes (TLC) diet and will receive basic instructions on how to follow this diet. See Appendix C.\]

Treatment Period:

At Visit 3 (Week 0), approximately 116 subjects will be randomized in a 1:1 ratio to receive daily olive oil 2 g or Epanova 2 g. Subjects will be stratified by lipid-altering drugs to ensure a balanced allocation of subjects who are users and non-users of the following permitted lipid-altering drugs in each treatment group: statin, CAI, or statin-CAI combination. During the treatment period, subjects will return to the site at Visit 4 (Week 6), Visit 5 (Week 10), and Visit 6 (Week 12) for efficacy and safety evaluations.

Eligibility Criteria:
Inclusion Criteria:

1. Understanding of the study procedures, willingness to adhere to the study schedule, and agreement to participate in the study by giving written informed consent prior to screening;
2. Willing to use an appropriate and effective method of contraception;
3. Qualifying (average of Visit 1 or 1a + Visit 2 + Visit 2a \[repeat measurement\]) serum TG ≥500 mg/dL (6 mMol/L) and \<2500 mg/dL (28 mMol/L);
4. Body mass index ≥20 kg/m2;
5. Untreated dyslipidemia or dyslipidemia treated with a statin, CAI, or statin-CAI combination that has been stable for 6 weeks prior to randomization; and
6. Willingness to maintain current physical activity level and follow the TLC diet throughout the study.

Exclusion Criteria:

1. Allergy or intolerance to omega-3 fatty acids, omega-3-acid ethyl esters, or fish;
2. Known lipoprotein lipase impairment;
3. Known non-responder to omega-3 or fenofibrate therapy;
4. Use of any prescription medications containing EPA and/or DHA (eg, Lovaza® or Vascepa®) within 8 weeks prior to randomization. Up to 1 g capsule/day of an omega-3 dietary supplement will be permitted;
5. Unable to discontinue use of bile acid sequestrants, fibrates or niacin (other than niacin-containing vitamins \<200 mg), or any supplement used to alter lipid metabolism including but not limited to dietary fiber supplements, red rice yeast supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or policosanols at screening;
6. Use of tamoxifen, estrogens, or progestins that has not been stable for \>4 weeks at screening or is unstable prior to randomization;
7. Use of oral or injected corticosteroids or anabolic steroids prior to randomization;
8. History of hospitalization for pancreatitis in the last 5 years;
9. Uncontrolled diabetes (hemoglobin A1c \[HbA1c\] \>10%);
10. Uncontrolled hypothyroidism or thyroid-stimulating hormone (TSH) \>5 mIU/L;
11. History of cancer (other than basal cell carcinoma) in the past 2 years;
12. Cardiovascular event (ie, myocardial infarction, acute coronary syndrome, new onset angina, stroke, transient heart attack, unstable congestive heart failure requiring a change in treatment), revascularization procedure or vascular surgery within 6 months of randomization;
13. Use of simvastatin 80 mg or Vytorin 10/80 mg;
14. Recent history (within 6 months of randomization) of significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal, or immunologic disease;
15. Poorly controlled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg);
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 × the upper limit of normal (ULN); if ALT/AST is \>3 × ULN, the levels have been stable for 3 months and are \<5 × ULN;
17. Exposure to any investigational product within 4 weeks of randomization; or
18. Any condition or therapy which, in the opinion of the Investigator, might pose a risk to the subject or make participation in the study not in the subject's best interest.