Severe hypertriglyceridemia [fasting TG levels >=500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and mild or moderate renal impairment. MedDRA version: 20.0 Level: LLT Classification code 10020667 Term: Hyperlipidemia System Organ Class: 100000004861
Conditions
Sponsors
Kowa Research Institute, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Able to understand and willing to comply with all study requirements and procedures throughout the duration of the study and give written informed consent; 2. Aged >=18 years; 3. Patients receiving statin therapy must meet one of the following criteria1: o Aged >=21 years with clinical atherosclerotic cardiovascular disease (ASCVD) (history of acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary revascularization, stroke, transient ischemic attack [TIA] presumed to be of atherosclerotic origin, or peripheral arterial disease or revascularization), on a high-intensity statin (or moderate-intensity statin if not a candidate for high-intensity statin due to safety concerns); o Aged >=21 years with a history of LDL-C >=190 mg/dL, which is not due to secondary modifiable causes, on a high-intensity statin (or moderate-intensity statin if not a candidate for high-intensity statin due to safety concerns); o Aged 40 to 75 years, inclusive, without clinical ASCVD but with diabetes and a history of LDL-C of 70 to 189 mg/dL, inclusive, on a moderate- or high-intensity statin; or o Aged 40 to 75 years, inclusive, without clinical ASCVD or diabetes, with a history of LDL-C of 70 to 189 mg/dL, inclusive, with estimated 10-year risk for ASCVD of >=7.5% by the Pooled Cohort Equation on a moderate- or high-intensity statin; 4. Patients not currently on statins, must not meet the criteria for statin therapy listed above (see inclusion criterion 3); 5. Not on lipid-altering therapy other than statins, ezetimibe, or PCSK9 inhibitors at randomization; o For patients currently on statins, ezetimibe, or PCSK9 inhibitors at screening, statin, ezetimibe, or PCSK9 inhibitor dose(s) must be stable for >=6 weeks prior to Visit 1 (Week -8 or Week -6); and o Patients on lipid-altering medications other than statins, ezetimibe, or PCSK9 inhibitors (e.g., bile acid sequestrants, fibrates, niacin [>100 mg/day], omega-3 fatty acids [>1000 mg/day], or any supplements used to alter lipid metabolism including, but not limited to, red rice yeast supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or policosanols) at the time of screening must be able to safely discontinue all such lipidaltering therapy at Visit 1 (Week -8 or Week -6); 6. Fasting TG levels >=500 mg/dL (5.65 mmol/L) and =450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L), an additional TG measurement can be collected 1 week later at Visit 3.1. If a third measurement is made at Visit 3.1, entry into the study is based on the mean of the values from Visit 2, Visit 3, and Visit 3.1; 7. Mild to moderate renal impairment (eGFR ³30 mL/min/1.73 m2 and <90 mL/min/1.73 m2) at Visit 1 (Week -8 or Week -6); o eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (2009); 8. Women of childbearing potential may be considered for enrollment if all of the following criteria are met: o They are not pregnant,
Exclusion criteria
Exclusion criteria: 1. Patients who will require lipid-altering treatments other than study drugs (K-877 or fenofibrate), statins, ezetimibe, or PCSK9 inhibitors during the course of the study. These include bile acid sequestrants, non-study fibrates, niacin (>100 mg/day), omega3 fatty acids (>1000 mg/day), or any supplements used to alter lipid metabolism including, but not limited to, red rice yeast supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or policosanols; 2. Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); 3. Patients with type 1 diabetes mellitus; 4. Patients with newly diagnosed (within 3 months prior to Visit 2 [Week -2]) or poorly controlled type 2 diabetes mellitus (T2DM), defined as hemoglobin A1c >9.5% at Visit 1 (Week -8 or Week -6); 5. Patients who are receiving insulin or insulin analogue treatment, except for basal insulin therapy with a single insulin that has been stable for >=4 weeks prior to Visit 1 (Week -8 or Week -6); 6. History of stroke (including TIA), myocardial infarction or unstable angina pectoris, life-threatening arrhythmia, or revascularization within 6 months prior to Visit 1 (Week -8 or Week -6); 7. Patients with symptomatic heart failure (New York Heart Association Class III or IV); 8. History of chronic pancreatitis or hospitalization for acute pancreatitis within the preceding 5 years; 9. History of gallbladder disease, unless treated with cholecystectomy or the Investigator considers the gallbladder disease not clinically significant, such that it will not impact patient safety; 10. Patients with severe renal impairment (i.e., eGFR 5 years prior to Visit 1 (Week -8 or Week -6), or whose only malignancy has been basal or squamous cell skin carcinoma; 16. History of bariatric surgery; 17. Systolic blood pressure >=160 mmHg and/or diastolic blood pressure >=100 mmHg after 5 minutes of resting during screening or Visit 4 (Day
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice daily compared to placebo from baseline to Week 12 in lowering fasting TG levels in patients with fasting TG levels >=500 mg/dL (5.65 mmol/L) and =500 mg/dL (5.65 mmol/L) and =500 mg/dL (5.65 mmol/L) and =500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and mild or moderate renal impairment; and * To determine the plasma concentrations of K-877 for the purpose of use in population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis. ; Primary end point(s): The primary efficacy endpoint is the percent change in fasting TG from baseline to Week 12. Baseline for TG will be defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) measurements. ;Timepoint(s) of evaluation of this end point: 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoints for the 12-week Efficacy Period include the following: • Percent change from baseline to Week 12 in remnant cholesterol (calculated as total cholesterol [TC] – low-density lipoprotein C [LDL C] – high-density lipoprotein C [HDL-C]), HDL-C, apolipoprotein (Apo) A1, and non-HDL-C; o Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; • Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; • Change from baseline to Week 12 in fibroblast growth factor 21 (FGF21) and highsensitivity Creactive protein (hsCRP), and percent change from baseline to Week 12 in ion mobility analysis and lipoprotein fraction (nuclear magnetic resonance [NMR]); and • Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of TG:HDL-C, TC:HDL-C, nonHDLC:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and Apo C3:Apo C2. The secondary efficacy endpoints for the 40-week Extension Period include the following: • Percent change from baseline to Week 52 in fasting TG; • Percent change from baseline to Week 52 in remnant cholesterol (calculated as TC - LDL C - HDL-C), HDL-C, Apo A1, and non-HDL-C; o Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; • Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; • Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from baseline to Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and • Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of TG:HDL-C, TC:HDL-C, nonHDLC:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and A | — |
Countries
Belarus, Canada, Czech Republic, Georgia, Hungary, Poland, Russian Federation, Ukraine, United States
Contacts
Public ContactLourdes Herreros
Medpace Spain
Outcome results
None listed