Vascepa to Accelerate Lipoprotein Uptake and Elimination
Condition: Lipid Disorder; Triglycerides High; Dyslipidemias
MeSH terms: Dyslipidemias; Lipid Metabolism Disorders
Intervention: Icosapent Ethyl 1000 MG [Vascepa]
Intervention description: Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22H34O2 and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate.
Intervention MeSH terms: Eicosapentaenoic acid ethyl ester
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel, randomized, controlled mechanistic pilot/feasibility experiment focused on elucidating detailed mechanism of action for apolipoprotein turnover kinetics changes using intravenous infusions of stable isotopes in a clinical/translational metabolic unit.
Masking: Double (Investigator, Outcomes Assessor)
Masking description: Reference therapy is usual care, so the subject and coordinators are unblinded to assignment, but investigators and outcomes assessors are blinded to assignment.
Enrollment: 20.0
Sex: All
Minimum age: 21 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study is a Phase 1 pilot/feasibility mechanistic experiment to help clarify the
      mechanism of action of an EPA-rich fish oil preparation, icosapent ethyl, on lipid changes in
      statin-treated patients with residual triglyceridemia.
    

Eligibility criteria:

        Inclusion Criteria:

        - 1. Triglyceridemia, defined as:

          1. statin-treated TG > 200 mg/dL -and/or-

          2. statin-treated TG > 150 mg/dL -plus- statin-treated HDL < 45 [men] or < 55 [women] 2.
             Self-reported Caucasian-majority race, defined as 3 out of 4 grandparents Caucasian 3.
             Subjects between the ages of 21 and 75 years of age inclusive 4. Ability to understand
             and agree to informed consent 5. Are reliable and willing to make themselves available
             for the duration of the study, comply with study procedures, agree not to participate
             in other clinical experiments, and agree not to donate blood products during the study

             Exclusion Criteria:

               -  1. Diagnosis of idiopathic or otherwise active diabetes: History of resolved
                  gestational or drug-induced diabetes is acceptable, but history Type I or Type II
                  diabetes are exclusionary.

                  2. Use of medications indicated for the treatment of diabetes within 6 weeks of
                  the first experimental visit (see Prohibited Treatments) 3. History of a
                  myocardial infarction (MI), unstable angina leading to hospitalization, coronary
                  artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI),
                  uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient
                  ischemic attack, carotid revascularization, endovascular procedure or surgical
                  intervention within 6 months of baseline.

                  4. Known inefficacy to TG-lowering doses of fish oils (e.g. >= 4 caps daily of
                  prescription fish oil or >= 6 caps daily of supplemental fish oil).

                  5. TG > 500 mg/dL as the average of valid, statin-treated values 6. BMI > 40
                  kg/m2 7. BMI < 20 kg/m2 8. Evidence of previously undiagnosed diabetes: Average
                  fasting glucose during screening > 125 mg/dL 9. Known familial lipoprotein lipase
                  impairment or deficiency (Fredrickson Type I), Apo C II deficiency, or familial
                  dysbetalipoproteinemia (Fredrickson Type III).

                  10. Severe allergy to fish, unless non-allergic response to fish oil is
                  established (n.b. most fish allergies are to the proteins as opposed to the fats,
                  so with highly-purified oils the risk of a true allergy is remote).

                  11. Known intolerance or contraindication to Vascepa, and if the former is
                  unknown, known intolerance or contraindication to fish oil 12. Any surgical or
                  medical condition that may interfere with absorption, distribution, metabolism,
                  or excretion of EPA or DHA.

                  13. History of extreme triglyceridemia (TG > 1000 mg/dL) or pancreatitis from
                  triglyceridemia, regardless of whether it is currently controlled.

                  14. Medical condition that would prohibit fasting (e.g. diagnosis of insulinoma
                  or postabsorptive hypoglycemia).

                  15. Significant disinclination to dairy products (e.g. lactose intolerance,
                  inviolable dietary restrictions). All participants will receive a test dose of
                  the fat challenge during the screening visit, which consists of heavy cream and
                  lactase enzyme. Many people with lactose intolerance successfully avert symptoms
                  by correcting their lactase deficiency with lactase supplements. We will allow
                  these people to participate because we will allow them to take their preferred
                  brand and dose of lactase supplement beyond the lactase in the fat challenge if
                  needed. However, we still require that they are able to tolerate the test dose
                  given during screening.

                  16. History of a non-skin malignancy within the previous 5 years. 17.
                  Uncontrolled thyroid disease. 18. Any major active rheumatologic, pulmonary, or
                  dermatologic disease or inflammatory condition.

                  19. Major surgery within the previous 6 weeks. 20. Subjects who have undergone
                  any organ transplant. 21. History of illicit drug use within the past 3 years, or
                  regular alcohol use of greater than 14 drinks per week. For clarity, illicit
                  substances are per Federal law or regulations in effect at the time of first
                  approval of this protocol.

                  22. Women who are breast-feeding. 23. Women of childbearing potential must have a
                  negative urine pregnancy test at screening and baseline visits and be willing to
                  have additional urine pregnancy tests during the study.

                  24. Sexually active subjects (both women and men) must be willing to use a
                  medically accepted method of contraception from screening visit until month after
                  last dose of study drug 25. Significant or unstable medical or psychological
                  conditions, including known or suspected personality disorders, that could
                  compromise the subject's safety or successful participation in the study in the
                  opinion of the investigator.

                  26. Subject-reported history of HIV and/or use of HIV medications 27. History of
                  symptomatic gallstone disease unless definitively treated (e.g. condition
                  successfully treated with cholecystectomy without recurrent or residual biliary
                  disease).

                  28. History of bariatric surgery or other major gastrointestinal surgery
                  associated with major disruptions to drug absorption.

                  29. Anticipation of major surgery during the screening or treatment periods of
                  the study 30. Participants with the following conditions will opt out of heparin
                  exposure for lipase determinations, but will be allowed to participate in the
                  overall protocol.

                  31. History of intolerance or adverse reaction to therapeutic or sub-therapeutic
                  heparin regimens 32. History of intracerebral hemorrhage 33. History of
                  significant GI bleed, unless definitively treated without recurrence 34. Women
                  with dysfunctional uterine bleeding 35. Individuals with clinically-significant
                  coagulopathy at screening 36. Individuals with clinically-significant
                  thrombocytopenia at screening 37. Hemoglobin < 12 g/dL at screening 38. Mean
                  corpuscular volume (MCV) < 80 fL or > 100 fL at screening 39. Donation of whole
                  blood within 8 weeks prior to the first experimental visit. Participation in the
                  screening phase is permitted.

                  40. History of inherent unremediable risks for anemia, such as
                  hemoglobinopathies, hemolytic disorders, and bleeding disorders, regardless of
                  whether their hemoglobin is currently normal.

                  41. History of a large-volume gastrointestinal (GI) bleeding, such as a bleed
                  that required ER evaluation or admission, required acute endoscopic or surgical
                  management, was managed by blood transfusion, or caused anemia.

                  42. History of NSAID-mediated peptic ulcer disease is excluded, irrespective of
                  current medical treatment. A history of peptic ulcer disease from H. pylori does
                  not exclude participation provided H. pylori was successfully eradicated. Other
                  causes of peptic ulcer disease may be allowable, especially if definitively
                  treated or the risk of recurrence is otherwise low.

                  43. Chronic, untreated conditions that predispose to anemia, such as significant
                  iron or B vitamin malabsorption, persistent menorrhagia, or other chronic or
                  intermittent bleeding.

                  44. Participation in an investigational drug study concurrently; participants who
                  previously completed an investigational drug study cannot participate in the
                  first experimental visit until at least 6 weeks after the final dose given during
                  the previous investigational drug study. For the purposes of this exclusion, an
                  investigational drug is a new chemical entity or a pharmaceutical investigated to
                  support an initial new drug application. Furthermore, herbal or other supplements
                  already deemed "generally regarded as safe" or legally sold in the U.S. would not
                  be considered an investigational drug.

                  45. Use of medications indicated for the treatment of diabetes within 6 weeks of
                  the first experimental visit 46. Daily therapy with non-statin lipid-altering
                  medications within 6 weeks of the first experimental visit is exclusionary,
                  including long-term therapy with the agents listed below. Subjects may wash off
                  these medications so long as the first experimental visit occurs at least 6 weeks
                  after chronic therapy ceases. Following a washout period, fasting lipids will be
                  repeated prior to the first experimental visit to assure that these are not
                  exclusionary as defined above.

                    1. Niacin > 100 mg/ day: (Niacor®, Slo-Niacin®, Niaspan®, Advicor®, Simcor®,
                       Inositol Hexanicotinate, or supplemental niacin).

                    2. Fibrates: gemfibrozil (Lopid®), fenofibrate (Antara®, Lofibra®, Tricor®,
                       Triglide®), fenofibric acid (Trilipix®, Certriad®).

                    3. Enterically active lipid altering drugs: colestipol (Colestid®),
                       cholestyramine (Questran®), colesevelam (Welchol®), ezetimibe (Zetia®,
                       Vytorin®), orlistat (Xenical®, Ali®).

                    4. Prescription fish oil: Vascepa®, Epanova®, Lovaza® (nee Omacor®)

                    5. Supplemental omega-3-enriched oils: flaxseed, fish, or algal oils

                    6. Foods enriched with omega-3 fatty acids

                    7. Consumption of up to 2 servings per week of fish is acceptable 47.
                       Lipid-altering supplements

                    1. Sterol/stanol products (e.g. CholestOff), policosanols

                    2. Dietary fiber supplements, including >2 teaspoons of Metamucil® or psyllium
                       containing supplements per day

                    3. Garlic supplements or soy isoflavones supplements

                    4. Supplemental vitamin B5 or related compounds unless part of a multi-vitamin

                    5. As above, red yeast statin will be switched to a GMP prescription statin

                    6. Any other medications, herbal products, or dietary supplements with known or
                       potential lipid-altering effects 48. Anticoagulant therapy (except aspirin)

                    1. Warfarin

                    2. Rivaroxiban

                    3. Apixaba

                    4. Dabigantran 49. Anti-obesity medications or their components

                    1. Orlistat (Xenical)

                    2. Lorcaserin (Belviq)

                    3. Phentermine plus extended-release topiramate (Qsymia)