E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hypertriglyceridemia defined as serum triglyceride (TG) values ≥500 and <2000 mg/dL (≥5.65 mmol/L and <22.60 mmol/L). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020870 |
E.1.2 | Term | Hypertriglyceridemia |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy and safety of Epanova in 332 subjects with severe hypertriglyceridemia defined as serum triglyceride (TG) values ≥500 and <2000 mg/dL (≥5.65 mmol/L and <22.60 mmol/L). The primary efficacy analyses will evaluate the effects of each dose of Epanova, relative to placebo, on fasting serum TG levels after 12 weeks of treatment. The primary safety and tolerability evaluation will be the review of the adverse events at each dose, compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the effects of each dose of Epanova on fasting levels of non-high-density lipoprotein cholesterol (non-HDL-C) and high-density lipoprotein cholesterol (HDL-C). The tertiary objectives are to assess and or evaluate the effects of each dose of Epanova on other lipid parameters including total cholesterol (TC), LDL-C, TC : HDL-C ratio, and very low-density lipoprotein (VLDL) cholesterol; apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), apolipoprotein C-III (apo C–III), and remnant lipoprotein cholesterol (RLP-C); lipoprotein particles (sizes, concentrations and subfractions for VLDL, LDL and HDL); HbA1c; the proportion of subjects who achieve TG <500 mg/dL at Week 12; plasma EPA, DHA, and arachidonic acid (AA); lipoprotein-associated phospholipase A2 (Lp-PLA2) and high sensitivity C-reactive protein (hs-CRP); other safety parameters including blood pressure, routine chemistry and hematology tests, urinalyses, and electrocardiograms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women, ≥18 years of age. 2. Serum TG values in the range ≥500 mg/dL and <2000 mg/dL (≥5.65 mmol/L and <22.60 mmol/L) for the average of Visits 2 and 3 (Weeks -2 and -1). Repeat of Visit 3 test is allowed (Visit 3a), and the average of Visit 2 (Week -2) + Visit 3 (Week -1) + Visit 3a (repeat visit) is used as the criterion. 3. Body mass index ≥20 kg/m2. 4. Untreated dyslipidemia, or use of a statin or cholesterol absorption inhibitor, or their combination, if stable for 6 weeks at Visit 2 (Week -2) and prior to randomization. 5. Willing to restrict consumption of fish to no more than twice per week during the study. 6. Willingness to maintain current activity level and follow TLC diet. |
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E.4 | Principal exclusion criteria |
1. Allergy or intolerance to omega-3 fatty acids, omega-3-acid ethyl esters, or fish. 2. Known lipoprotein lipase impairment or deficiency or apolipoprotein C-II deficiency or familial dysbetalipoproteinemia. 3. Unable to discontinue use of omega-3 drugs/supplements at Week -8 (Visit 1). 4. 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 Week -4 (Visit 1). 5. Women who are pregnant, lactating, or planning to become pregnant. Women of childbearing potential who are not using acceptable contraceptive methods. A woman is considered of childbearing potential if she is not surgically sterile or is less than 1 year since last menstrual period. Examples of acceptable contraceptive methods include abstinence, intrauterine device (IUD) or double barrier method. Estrogen-containing contraceptives are excluded. 6. Use of tamoxifen, estrogens or progestins that has not been stable for >4 weeks at Visit 1, or is unstable prior to randomization. 7. Use of oral or injected corticosteroids or anabolic steroids at Visit 1 or prior to randomization. 8. History of pancreatitis. 9. History of symptomatic gallstone disease, unless treated with cholecystectomy. 10. Uncontrolled diabetes (HbA1c ≥9). 11. Uncontrolled hypothyroidism or thyroid stimulating hormone (TSH) >5 mIU/L. 12. History of cancer (other than basal cell carcinoma) in the past 2 years. 13. Cardiovascular event (i.e., myocardial infarction, acute coronary syndrome, new onset angina, stroke, transient ischemic attack, unstable congestive heart failure requiring a change in treatment) or revascularization procedure within prior six months at Visit 1, or prior to randomization. 14. Use of anticoagulants (e.g. warfarin [Coumadin®], coumarin, heparin, enoxaparin, clopidogrel). 15. Presence of an aortic aneurysm or resection of an aortic aneurysm within prior six months at Visit 1, or prior to randomization. 16. Recent history (within prior six months at Visit 1 or prior to randomization) of significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal or immunologic disease. 17. Poorly controlled hypertension (resting blood pressure ≥160 mm Hg systolic and/or ≥100 mm Hg diastolic) at two consecutive visits prior to randomization at Visit 4. 18. Any of the following laboratory criteria: serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN), fasting serum glucose >200 mg/dL, calculated glomerular filtration rate (GFR) <30 ml/min, platelet counts <60 x 109/L, or hemoglobin <10.0 g/dL. 19. Recent history (past 12 months) of drug abuse or alcohol abuse. Alcohol abuse will be defined as >14 drinks per week (1 drink = 12 oz beer, 5 oz wine, or 1.5 oz hard liquor). 20. Exposure to any investigational product within 4 weeks prior to Visit 1, or prior to randomization. 21. Presence of 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for each arm is the percent change in TG levels from baseline (average of Weeks -2, -1 and 0) to the end-of-treatment (average of Weeks 10 and 12).
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is defined as the last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |