E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hypertriglyceridemia |
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E.1.1.1 | Medical condition in easily understood language |
High triglyceride levels in the blood |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020870 |
E.1.2 | Term | Hypertriglyceridemia |
E.1.2 | System Organ Class | 100000004861 |
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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 |
The primary objectives of the study are:
• To determine the efficacy of Epanova 2 g daily compared to olive oil 2 g daily for 12 weeks in lowering serum triglyceride (TG) levels in subjects with severe hypertriglyceridemia (TG levels ≥500 mg/dL [5.65 mMol/L] and <2500 mg/dL [28.25 mMol/L])
• To determine the safety and tolerability of Epanova. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To determine the effect of Epanova 2 g daily compared to olive oil 2 g daily for 12 weeks in lowering serum TG levels in subjects with at least 1 qualifying TG >885 mg/dL (10 mMol/L) and <2500 mg/dL (28.25 mMol/L);
• To determine the effects of Epanova 2 g daily compared to olive oil 2 g daily for 12 weeks in lowering TG levels in subjects with Fredrickson Type V hyperlipidemia (TG/very low-density lipoprotein cholesterol [VLDL-C] ≥6);
• To determine the effect of Epanova on non-high-density lipoprotein cholesterol (non-HDL-C) and high-density lipoprotein cholesterol (HDL-C). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (5.65 mMol/L) and <2500 mg/dL (28.25 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;
6. Willingness to maintain current physical activity level and follow the TLC diet throughout the study. |
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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;
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 Visit 1;
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 in the 4 weeks prior to Visit 1;
8. History of hospitalization for pancreatitis in the last 5 years;
9. Uncontrolled diabetes (hemoglobin A1c >10%);
10. Uncontrolled hypothyroidism or thyroid-stimulating hormone >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) at two consecutive visits prior to randomization at Visit 3;
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal;
17. Exposure to any investigational product within 4 weeks of Visit 1; 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is percent change in TG from baseline to Week 12 endpoint.
The primary efficacy variable will also be evaluated for the following subgroups:
• Subjects with at least 1 qualifying TG >885 mg/dL (10 mMol/L) and
• Subjects with Fredrickson Type V (TG/VLDL-C ≥6).
Safety assessments will include adverse events, clinical laboratory parameters (chemistry, hematology, and urinalysis), 12-lead ECGs, vital signs, and physical examinations. Additionally, serious adverse events (SAEs) and adverse events leading to discontinuation will be recorded. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For lipid parameters (TG, non-HDL-C, HDL-C, TC, LDL-C, VLDL-C, and TC:HDL-C ratio) baseline will be defined as the mean of the measurement at Visit 3 (Week 0) and the last 2 qualifying measurements from Visits 1, 1a, 2, and 2a. Week 12 endpoint will be defined as the average of the measurements at Visit 5 (Week 10) and Visit 6 (Week 12). If both the Visit 5 (Week 10) measurement and the Visit 6 (Week 12) measurement are missing, Week 12 endpoint will be defined as the last measurement after the first dose of study drug.
All analyses of safety during the double-blind period will be conducted on the safety population. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy variables are percent changes in non-HDL-C and HDL-C from baseline to Week 12 endpoint.
The tertiary efficacy parameters include:
• Percent changes in LDL-C, TC, VLDL-C, and TC:HDL-C ratio from baseline to Week 12 endpoint;
• Percent changes in apo A-I, apo A-V, apo B, apo C-III, and RLP-C from baseline to Week 12 endpoint;
• Percent changes in Lp(a) and Lp-PLA2 from baseline to Week 12 endpoint;
• Changes in adiponectin and leptin from baseline to Week 12 endpoint; and
• Change in plasma concentrations and RBC membrane content of fatty acids including EPA, DHA, AA, and DPA from baseline to Week 12 endpoint. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For lipid parameters (TG, non-HDL-C, HDL-C, TC, LDL-C, VLDL-C, and TC:HDL-C ratio) baseline will be defined as the mean of the measurement at Visit 3 (Week 0) and the last 2 qualifying measurements from Visits 1, 1a, 2,
and 2a. Week 12 endpoint will be defined as the average of the measurements at Visit 5 (Week 10) and Visit 6 (Week 12). If both the Visit 5 (Week 10) measurement and the Visit 6 (Week 12) measurement are missing, Week 12 endpoint will be defined as the last measurement after the first dose of study drug.
For all other efficacy parameters, baseline will be the Visit 3 (Week 0) measurement, and Week 12 endpoint will be the Visit 6 (Week 12) measurement. If the Week 12 measurement is missing, Week 12 endpoint will be the last measurement after the first dose of study drug. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 | No |
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 |
Canada |
Denmark |
Netherlands |
Czech Republic |
Hungary |
Russian Federation |
United States |
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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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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 | 10 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |