Exploratory Study of the Effects of Omega-3-acid Ethyl Esters on the Lipid and Lipoprotein Profile in the Blood

Study Overview
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Brief Summary
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The purpose of this study is to explore the effects of 8-week treatment with omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood in hyperlipidemic patients receiving a HMG-CoA reductase inhibitor by use of HPLC in comparison with the control group of patients not treated with omega-3-acid ethyl esters.

Detailed Description
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This study was designed to explore the effects of omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood in hyperlipidemic patients receiving a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor in comparison with the control group of patients not treated with omega-3-acid ethyl esters in an unblinded manner by use of high performance liquid chromatography (HPLC) using highly-sensitive gel filtration columns, which is a technique for analyzing lipoprotein. Study participants who gave consent and were assessed as eligible in the eligibility assessment will be stratified by the factors of fasting triacylglycerol (TG; <300 mg/dL or 300 mg/dL≤) and age (<65 years or 65 years≤) at the start of the screening period and allocated to either the group treated with omega-3-acid ethyl esters or the group not treated with omega-3-acid ethyl esters (1:1 ratio).

Official Title
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Exploratory Study of the Effects of Omega-3-acid Ethyl Esters on the Lipid and Lipoprotein Profile in the Blood

Conditions
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Hyperlipidemia

Intervention / Treatment
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* Drug: TAK-085
* Other: Not treated with omega-3-acid ethyl esters


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants diagnosed as hyperlipidemia. Participants constantly receiving a HMG-CoA reductase inhibitor at a stable dose for at least 4 weeks at the start of the observation period. Participants with fasting TG of 150≤ to <400 mg/dL measured at the start of the observation period at Visit 1 (Week -4). Participants who, in the opinion of the principal investigator or the investigator, are capable of understanding the content of the clinical study and complying with the study protocol requirements. Participants who can provide written informed consent prior to the conduction of the clinical study procedures. Participants aged ≥20 years at the time of informed consent at Visit 1 (Week -4). Exclusion Criteria: Participants who had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous hemorrhage) within 24 weeks prior to the start of the observation period, or those who concurrently have the above disorders. Participants who had thyroid disorders (hyperthyroidism or hypothyroidism) within 24 weeks prior to the start of the observation period, those who concurrently have the above disorders, or those who are orally receiving a therapeutic drug for thyroid disorder. Participants in whom the type of HMG-CoA reductase inhibitors was changed within 12 weeks prior to the start of observation period. Participants who received an eicosapentaenoic acid (EPA) preparation or an EPA/docosahexaenoic acid (DHA) preparation (including supplements) within 12 weeks prior to the start of observation period. Participants who started antidyslipidemic agents within 4 weeks prior to the start of observation period. Participants with severe hepatic impairment (e.g., Child-Pugh classification C). Participants who were previously diagnosed as lipoprotein lipase deficiency or apoprotein C-II deficiency. Participants who are concurrently having Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), or serum dysproteinemia. Diabetic participants who are currently receiving thiazolidine or insulin. Participants who are concurrently having hypertension of grade IIINote 1). Note 1: Participants with systolic blood pressure of ≥180 mm Hg or diastolic blood pressure of ≥110 mm Hg regardless of treatment with antihypertensive drugs. Participants who are habitual drinkers drinking an average of over 100 mL per day (expressed in terms of quantity of alcohol), or participants with or with a history of drug abuse or addiction. Pregnant, lactating or postmenopausal women. Participants with a history of hypersensitivity or allergy for omega-3-acid ethyl esters. Participants participating in other clinical studies. Participants assessed ineligible in the study by the principal investigator or the investigator.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-085 4g<br>A dose of 2 g of omega-3-acid ethyl esters (TAK-085) capsule is orally administered immediately after meal twice a daily (totally 4g per a day) for 8 weeks, plus a stable HMG-CoA reductase inhibitor regimen (started ≥4 weeks prior to informed consent) at a consistent dose. | Drug: TAK-085<br>* Omega-3-acid ethyl esters (TAK-085) capsule<br>|
| Experimental: Control Group<br>Stable HMG-CoA reductase inhibitor regimen at a consistent dose only. | Other: Not treated with omega-3-acid ethyl esters<br>* Not treated with omega-3-acid ethyl esters<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Changes From Baseline in Concentration of Major 4 Lipid Constituents in Small Dense Low Density Lipoprotein (sdLDL) Fraction | Major 4 lipid constituents refer to cholesterol, triglycerides, free cholesterol, and phospholipid. The reported data are percent of change from baseline in concentration of the each lipid constituents in sdLDL fraction at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Triglycerides (TG) to Cholesterol Ratio in sdLDL Fraction | Reported data are percent of change from baseline in in TG to cholesterol ratio in sdLDL fraction at Week 4 and Week 8. | Baseline, Week 4, and Week 8 | 
| Percent Change From Baseline in Mean Particle Sizes of Small Dense Low Density Lipoprotein-cholesterol (sdLDL-C) and Low Density Lipoprotein-cholesterol (LDL-C) Monitored by Major 4 Lipid Constituents | Reported data are percent of change from baseline in mean particle sizes of sdLDL-C and LDL-C monitored by major 4 lipid constituents (cholesterol, triglycerides, free cholesterol, and phospholipid) at Week 4 and Week 8. Here the data were consolidated from results of the two outcome measures (Change in mean particle sizes of sdLDL-C and Change in mean particle sizes of LDL-C) on initial registration information (see History of Change of registration) because sdLDL-C refers to LDL-C which is smaller particle size and heavier density. | Baseline, Week 4, and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Changes From Baseline in Concentration of Major 4 Lipid Constituents in Chylomicron (CM) Fraction | Major 4 lipid constituents refer to cholesterol, triglycerides, free cholesterol, and phospholipid. The reported data are percent of change from baseline in concentration of the each lipid constituents in CM fraction at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Concentration of Major 4 Lipid Constituents in Very Low-density Lipoprotein (VLDL) Fraction | Major 4 lipid constituents refer to cholesterol, triglycerides, free cholesterol, and phospholipid. The reported data are percent of change from baseline in concentration of the each lipid constituents in VLDL Fraction at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Concentration of Major 4 Lipid Constituents in Low-density Lipoprotein (LDL) Fraction | Major 4 lipid constituents refer to cholesterol, triglycerides, free cholesterol, and phospholipid. The reported data are percent of change from baseline in concentration of the each lipid constituents in LDL Fraction at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Concentration of Major 4 Lipid Constituents in High-density Lipoprotein (HDL) Fraction | Major 4 lipid constituents refer to cholesterol, triglycerides, free cholesterol, and phospholipid. The reported data are percent of change from baseline in concentration of the each lipid constituents in HDL Fraction at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Concentration of Fatty Acids in Total Lipids | Fatty acids refer to the following 24 acids; Lauric acid, Myristic acid, Myristoleic acid, Palmitic acid, Palmitoleic acid, Stearic acid, Oleic acid, Linoleic acid, Gamma-linolenic acid, Linolenic acid, Arachic acid, Eicosenoic acid, Eicosadienoic acid, 5-8-11 Eicosatrienoic acid, Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Behenic acid, Erucic acid, Docosatetraenoic acid, Docosapentaenoic acid, Lignoceric acid, Docosahexaenoic acid, and Nervonic acid. The reported data are percent of change from baseline in concentration of these fatty acids in total lipids at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Eicosatrienoic Acid to Arachidonic Acid (T/T) Ratio in Total Lipids | The reported data are percent of change from baseline in T/T ratio in total lipids at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Eicosapentaenoic Acid to Arachidonic Acid (EPA/AA) Ratio in Total Lipids | The reported data are percent of change from baseline in EPA/AA ratio in total lipids at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Eicosapentaenoic Acid Plus Docosahexaenoic Acid to Arachidonic Acid (EPA+DHA/AA) Ratio in Total Lipids | The reported data are percent of change from baseline in EPA+DHA/AA ratio in total lipids at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Changes From Baseline in Docosahexaenoic Acid to Arachidonic Acid (DHA/AA) Ratio in Total Lipids | The reported data are percent of change from baseline in DHA/AA ratio in total lipids at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Change From Baseline in Mean Concentration of sd LDL-C in Total Lipids | There were no reporting data for this outcome measure because the data of change in mean concentration of sdLDL-C in total lipids were not collected and analyzed in this study finally. So here the data input for this outcome measure are NA for each arm. | Baseline, Week 4 and Week 8 | 
| Percent Change From Baseline in Concentration of Lipids in the Blood | Lipids on this outcome measure include Total cholesterol, Triacylglycerol (TG), HDL-C, non-HDL, and Remnant lipoprotein cholesterol (RemL-C). Reported data are percent of change in concentration of these lipids in the blood at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Change From Baseline in Concentration of Apolipoproteins in the Blood | Apolipoproteins on this outcome measure include Apolipoprotein AI, AII, B, B-48, B-100, CII, CIII, CII/III, and E. Reported data are percent of change in concentration of these apolipoproteins in the blood at Week 4 and Week 8. | Baseline, Week 4 and Week 8 | 
| Percent Change From Baseline in Lipoprotein Particle Numbers in the Blood | Reported data were percent of changes from baseline in lipoprotein particle numbers in the blood for 4 fractions (CM, VLDL, LDL, and HDL fractions). Data for this outcome measure was reported instead of the outcome measure title of Change from Baseline in particle number of lipids, apoprotein and lipoprotein on registration module (see History of Change of registration). | Baseline, Week 4 and Week 8 |