Cardiovascular Disease, Hypertriglyceridemia
Conditions
Keywords
dyslipidemia, hyperlipidemia, cardiovascular risk
Brief summary
The primary objective is to evaluate the efficacy of adding Epanova (2 g or 4 g daily) to an optimal statin monotherapy for lowering non-high-density lipoprotein (non-HDL) cholesterol in subjects with persistent hypertriglyceridemia and high risk for cardiovascular disease.
Detailed description
The primary efficacy variable is serum non-HDL cholesterol. The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/day and 4g/day Epanova groups. Baseline is defined as the average of Visits 2, 3 and 4 (Weeks -2, -1 and 0) and end-of-treatment is the average of Visits 5 and 6 (Weeks 5 and 6).
Interventions
DRUGOlive oil, 4g
Olive oil: 4 x 1 g capsule daily for 6 weeks + prescription statin
DRUGomega-3-carboxylic acids, 2g
Epanova: 2 x 1 g capsule + olive oil 2 x 1 g capsule daily for 6 weeks + prescription statin
DRUGomega-3-carboxylic acids, 4g
Epanova: 4 x 1 g capsule daily for 6 weeks + prescription statin
Sponsors
Omthera Pharmaceuticals, Inc
Medpace, Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men or women, ≥18 years of age. 2. Fasting triglyceride (TG) level ≥200 mg/dL and \<500 mg/dL. 3. The subject is a high risk for a future cardiovascular event. 4. The subject is treated with a statin and at or near LDL-C goal.
Exclusion criteria
1. Allergy or intolerance to omega-3 fatty acids and omega-3-acid ethyl esters. 2. Use of fibrates, bile acid sequestrants, or niacin or its analogues (greater than 200 mg/d) during screening. 3. Use of simvastatin 80 mg or Vytorin10/80 mg during screening. 4. Use of any eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) products. 5. Use of any supplement for the purpose of lowering plasma cholesterol during screening. 6. Use of weight loss drugs or programs during screening. 7. Use of erythromycin, telithromycin, clarithromycin, cyclosporine, itraconazole, ketoconazole, protease inhibitors, or nefazodone during screening. 8. Use of anticoagulants during screening. 9. Use of oral or injected corticosteroids during screening. 10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for \>4 weeks at Visit 1, or is unstable during screening. 11. Use of \>750 mL/d grapefruit juice during screening. 12. Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II deficiency or familial dysbetalipoproteinemia. 13. History of pancreatitis. 14. Type I diabetes mellitus, use of insulin, or HbA1c \>10% at Visit 1. 15. Poorly controlled hypertension 16. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) \>1.5xULN at Visit 2. 17. Recent history or current significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal or immunologic disease. 18. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within the previous two years. 19. Females who are pregnant, planning to be pregnant during the study period, lactating, or women of childbearing potential who are not using an acceptable method of contraception. 20. Creatine kinase \>5.0 times upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 times ULN at Visit 2. 21. Current or recent history (past 12 months) of drug or alcohol abuse. 22. Exposure to any investigational agent within 4 weeks prior to Visit 1. 23. Any other condition the investigator believes would interfere with the subject's ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the subject at undue risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Non-HDL Cholesterol | 6 weeks | The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/day and 4g/day Epanova groups. |
Countries
United States
Participant flow
Recruitment details
The enrollment period started August 2011 and the last subject visit was May 2012. All subjects were qualified at the clinical site and eligibility was determined by each PI (96 sites)
Pre-assignment details
Subjects underwent 6-week washout and diet stabilization period, discontinued use of any non-statin lipid therapies, continued their current statin regimen, and followed the NCEP TLC diet. Men and women considered to be at high risk for atherosclerotic CVD and who had high serum TG (≥200 mg/dL and \<500 mg/dL) were eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Epanova, 2 g omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids + placebo : omega-3-carboxylic acids 2 x 1 g capsule + placebo 2 x 1 g capsule daily for 6 weeks | 215 |
| Epanova, 4 g omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids: omega-3-carboxylic acids 4 x 1 g capsule daily for 6 weeks | 216 |
| Placebo placebo, 1 g capsule
placebo : 4 x 1 g capsule daily for 6 weeks | 215 |
| Total | 646 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 |
| Overall Study | Noncompliance | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Epanova, 4 g | Placebo | Epanova, 2 g | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 75 Participants | 91 Participants | 77 Participants | 243 Participants |
| Age, Categorical Between 18 and 65 years | 141 Participants | 124 Participants | 138 Participants | 403 Participants |
| Age, Continuous | 60.1 years STANDARD_DEVIATION 9.23 | 61.5 years STANDARD_DEVIATION 9.64 | 60.9 years STANDARD_DEVIATION 9.95 | 60.8 years STANDARD_DEVIATION 9.61 |
| Region of Enrollment United States | 216 participants | 215 participants | 215 participants | 646 participants |
| Sex: Female, Male Female | 79 Participants | 93 Participants | 92 Participants | 264 Participants |
| Sex: Female, Male Male | 137 Participants | 122 Participants | 123 Participants | 382 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 215 | 36 / 216 | 5 / 215 |
| serious Total, serious adverse events | 3 / 215 | 1 / 216 | 3 / 215 |
Outcome results
Primary
Serum Non-HDL Cholesterol
The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/day and 4g/day Epanova groups.
Time frame: 6 weeks
Population: The Intent-to-Treat (ITT) Population was comprised of all subjects who were randomized. In the event that randomized subjects terminated before treatment or had no post-treatment efficacy assessments, a modified ITT Population was implemented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Epanova 2 g | Serum Non-HDL Cholesterol | -3.86 Percent change from baseline |
| Epanova 4 g | Serum Non-HDL Cholesterol | -6.91 Percent change from baseline |
| Placebo | Serum Non-HDL Cholesterol | -0.91 Percent change from baseline |
p-value: <0.05ANCOVA
p-value: <0.0001ANCOVA