Exploratory Study of the Effect of Omega-3-acid Ethyl Esters (TAK-085) on Vascular Endothelial Function in Patients With Hyperlipidemia by Flow Mediated Dilation

Study Overview
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Brief Summary
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The purpose of this study is to explore the effects of omega-3-acid ethyl esters (TAK-085) on vascular endothelial function when administered for 8 weeks, as measured by FMD, in patients with hyperlipidemia.

Detailed Description
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This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of administration of omega-3-acid ethyl esters (TAK-085) [2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks] on vascular endothelial function, as measured by flow-mediated dilation (FMD), in patients receiving a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent hypertriglyceridemia. Considering the potential bias by factors that affect FMD between treatment groups, stratified allocation will be performed with fasting triglyceride (TG) level as a factor.

Official Title
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Exploratory Study of the Effect of Omega-3-acid Ethyl Esters on Vascular Endothelial Function in Patients With Hyperlipidemia by Flow Mediated Dilation

Conditions
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Hyperlipidemia

Intervention / Treatment
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* Drug: TAK-085


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with the diagnosis of hyperlipidemia and receiving instructions for lifestyle improvement Participants with a fasting TG level of 150 -499 mg/dL at Visit 1 after informed consent (Day -29 to Day -1 before start of study drug administration) Participants receiving a stable dose of HMG-CoA reductase inhibitor therapy continuously for at least 4 weeks before informed consent at Visit 1 (Day -29 to Day -1 before start of study drug administration) Male or postmenopausal female participants Participants who, in the opinion of the principal investigator or the investigator, are capable of understanding the content of the clinical research and complying with the research protocol requirements. Participants who can provide written informed consent prior to the conduction of the clinical research procedures Participants aged ≥20 years at the time of informed consent at Visit 1(Day -28 to Day 0 before the start of study drug administration) Exclusion Criteria: Participants with a history of revascularization or those have had coronary artery disease (a definitive diagnosis of myocardial infarction, angina) within 24 weeks before informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) Participants who have undergo aortic aneurysmectomy within 24 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or those with concurrent aortic aneurysm Participants who have had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous hemorrhage) within 24 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or those who concurrently have the above disorders Participant with a fasting FMD level of 0% measured at the start of study drug administration at Visit 2 (Day -15 to Day -1 before the start of study drug administration) Participants in whom the type and dosage of HMG-CoA reductase inhibitors, antidiabetic drugs and antihypertensive drugs have been changed within 4 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) Participants who have started anti dyslipidemic agents within 4 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) Participants requiring a change in the dose of dyslipidemia therapeutic, antidiabetic, or antihypertensive drugs during the period between informed consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) and the start of study drug administration at Visit 2 (Day -15 to Day -1 before the start of study drug administration) Participants with severe hepatic dysfunction Participants with severe renal dysfunction (as an indicator, CKD category ≥G3b, equivalent to an A3) Participants who have been diagnosed with pancreatitis Participants who have been diagnosed with lipoprotein lipase deficiency, apoprotein C-II deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, or familial type III hyperlipidemia Participants with concurrent Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), serum dysproteinemia, or hypothyroidism Participants with symptomatic Peripheral Arterial Disease (PAD) Participants with concurrent hypertension of grade II or higher Note 1) Note 1: Participants with systolic blood pressure of ≥160 mm Hg or diastolic BP of ≥100 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 Note 2) Participants with a history of hypersensitivity or allergy for omega-3-acid ethyl esters- Participants who smoke Participants participating in other clinical studies Participants who have been determined to be ineligible as subjects 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 2g<br>A dose of 2 grams of omega-3-acid ethyl esters (TAK-085) will be orally administered once a day immediately after meal. | Drug: TAK-085<br>* TAK-085 capsules<br>|
| Experimental: TAK-085 4g<br>A dose of 4 grams of omega-3-acid ethyl esters (TAK-085) will be orally administered twice a day immediately after meal. | Drug: TAK-085<br>* TAK-085 capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow-mediated Dilation (FMD) With Fasting State at Baseline, Week 4 and Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | Prior to meal at Baseline, Week 4, and Week 8 | 
| Change From Baseline in FMD With Fasting State at Week 4 and Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in FMD With Fasting State at Baseline, Week 4 and Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | Prior to meal at Baseline and Week 4, and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FMD With 4-Hours Postprandial State at Baseline and Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | 4-hours after meal at Baseline and Week 8 | 
| Change From Baseline in FMD With 4-Hours Postprandial State at Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | 4-hours after meal at Baseline and Week 8 | 
| Percent Change From Baseline in FMD With 4-Hours Postprandial State at Week 8 | FMD refers to dilation (widening) of an artery when blood flow increases in that artery. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound. FMD was calculated by the value of Maximum diastolic vessel size minus vessel size at rest, divided by vessel size at rest, described with percentage. | 4-hours after meal at Baseline and Week 8 | 
| Triglyceride (TG) Level With Fasting State at Baseline, Week 4, and Week 8 |  | Prior to meal at Baseline, Week 4, and Week 8 | 
| Change From Baseline in TG Level With Fasting State at Week 4 and Week 8 |  | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in TG Level With Fasting State at Week 4 and Week 8 |  | Prior to meal at Baseline and Week 4, and Week 8 | 
| TG Level With 4-Hours Postprandial State at Baseline, Week 4 and Week 8 |  | 4-hours after meal at Baseline, Week 4, and Week 8 | 
| Change From Baseline in TG Level With 4-Hours Postprandial State at Week 4 and Week 8 |  | 4-hours after meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in TG Level With 4-Hours Postprandial State at Week 4 and Week 8 |  | 4-hours after meal at Baseline and Week 4, and Week 8 | 
| Dihomo-gamma-linolenic Acid Concentration With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the observation value at each point. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in Dihomo-gamma-linolenic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in Dihomo-gamma-linolenic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in Dihomo-gamma-linolenic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in Dihomo-gamma-linolenic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Arachidonic Acid Concentration With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the observation value at each point. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in Arachidonic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in Arachidonic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in Arachidonic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in Arachidonic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Eicosapentaenoic Acid Concentration With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the observation value at each point. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in Eicosapentaenoic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in Eicosapentaenoic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in Eicosapentaenoic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in Eicosapentaenoic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Docosahexaenoic Acid Concentration With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the observation value at each point. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in Docosahexaenoic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in Docosahexaenoic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in Docosahexaenoic Acid Concentration With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in Docosahexaenoic acid at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Eicosapentaenoic Acid to Arachidonic Acid (EPA/AA) Ratio With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in EPA/AA Ratio With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in EPA/AA Ratio at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in EPA/AA Ratio With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in EPA/AA Ratio at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Docosahexaenoic Acid to Arachidonic Acid (DHA/AA) Ratio With Fasting State at Baseline, Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. | Prior to meal at Baseline, Week 4 and Week 8 | 
| Change From Baseline in DHA/AA Ratio With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the change from baseline in DHA/AA ratio at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Percent Change From Baseline in DHA/AA Ratio With Fasting State at Week 4 and Week 8 | Samples for plasma fatty acid fractions (Dihomo-gamma-linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Docosahexaenoic acid, EPA/AAratio, and DHA/AAratio) were taken under the fasting condition. Reported data was the percent change from baseline in DHA/AA ratio at each time point. | Prior to meal at Baseline and Week 4, and Week 8 | 
| Number of Participants Reporting One or More Adverse Events (AEs) |  | Up to Week 8 | 
| Number of Participants Reporting One or More AEs Related to Body Weight |  | Up to Week 8 | 
| Number of Participants Reporting One or More AEs Related to Blood Pressure in the Sitting Position |  | Up to Week 8 | 
| Number of Participants Reporting One or More AEs Related to Pulse in the Sitting Position |  | Up to Week 8 | 
| Number of Participants Reporting One or More AEs Related to Laboratory Tests of Fasting Plasma Glucose |  | Up to Week 8 |