Study to Evaluate the Efficacy and Safety of K-877 in Adult Patients With Fasting High Triglyceride Levels and Mild or Moderate Renal Impairment

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of K-877 in adult patients With Fasting High Triglyceride Levels ≥500 mg/dL and <2000 mg/dL and Mild or Moderate Renal Impairment.

Official Title
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A Phase 3, Multi-Center, Placebo-Controlled, Randomized, Double--Blind, 12-Week Study With a 40-Week, Active-Controlled, Open-Label Extension to Evaluate the Efficacy and Safety of K-877 in Adult Patients With Fasting Triglyceride Levels ≥500 mg/dL and <2000 mg/dL and Mild or Moderate Renal Impairment

Conditions
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Severe Hypertriglyceridemia

Intervention / Treatment
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* Drug: K-877
* Drug: Fenofibrate
* Drug: Placebo (for K-877)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand and willing to comply with all study requirements and procedures throughout the duration of the study and give written informed consent; Aged ≥18 years; Patients receiving moderate- or high-intensity statin therapy must meet one of the following criteria¹ unless they have any exceptional conditions (see inclusion criterion 4): Aged ≥21 years with clinical atherosclerotic cardiovascular disease (ASCVD) (history of acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary or other arterial 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); 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); 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 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; Patients currently on a low-intensity statin or not on a statin, must meet one of the following criteria; Patient does not meet any criteria for moderate- or high-intensity statin therapy listed above (see inclusion criteria, 3.a. through 3.d.); Patient does meet one or more criteria for moderate- or high-intensity statin therapy listed above (see inclusion criteria 3.a. through 3.d.); but the patient is not a candidate for moderate or high-intensity statin due to safety concerns, or due to partial or complete statin intolerance; or Patient does meet one or more criteria for moderate- or high intensity statin therapy listed above (see inclusion criteria 3.b. through 3.d., except for 3.a.); but the patient is not a candidate for moderate or high intensity statin for primary prevention after considering individual risk evaluation (e.g. current LDL C ≤70mg/dL) and patient preference; Fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) based on the mean of Visit 2 (Week -2) and Visit 3 (Week -1). Mild to moderate renal impairment eGFR >= 30mL/min/1.73 and < 90 mL/min/1.73 at Visit 1 Exclusion Criteria: 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), 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; Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); Patients with type 1 diabetes mellitus; 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);

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 12 Week Efficacy<br>K-877 or placebo comparator for 12 weeks | Drug: K-877<br> <br> Drug: Placebo (for K-877)<br> <br> |
| Active Comparator: 40 week extension<br>K-877 or fenofibrate comparator for 40 weeks | Drug: K-877<br> <br> Drug: Fenofibrate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fasting TG From Baseline to Week 12 |  | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 12 in Remnant Cholesterol |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in HDL-C |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo A1 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Non-HDL-C |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Total Cholesterol |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in LDL-C |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in FFAs |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo A2 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo B |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo B48 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo B100 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo C2 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo C3 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Apo E |  | 12 Weeks | 
| Change From Baseline to Week 12 in FGF21 |  | 12 Weeks | 
| Change From Baseline to Week 12 in hsCRP |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (VLDL Cholesterol-Large) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (VLDL Cholesterol-Intermediate) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (VLDL Cholesterol-Small) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Intermediate Density Lipoproteins 1) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Intermediate Density Lipoproteins 2) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins I) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IIa) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IIb) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IIIa) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IIIb) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IVa) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IVb) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Low Density Lipoproteins IVc) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (High Density Lipoproteins 2b) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (High Density Lipoproteins 3 and 2a) | Two lipoprotein subclasses, HDL3 and HDL2a, were analyzed together as one measurement without distinction. | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility (Diameter of the Major LDL Particle (Å)) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL & Chylomicron Particles) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL & Chylomicron Particles-Large) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL Particles-Medium) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL Particles-Small) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (LDL Particles) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (IDL Particles) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (LDL Particles-Large) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (LDL Particles-Small) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (HDL Particles) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (HDL Particles-Large) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (HDL Particles-Medium) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction (HDL Particles-Small) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL Particle Size) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (LDL Particle Size) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (HDL Particle Size) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (Triglyceride) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction (VLDL & Chylomicron Triglyceride) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipoprotein Fraction HDL Cholesterol (Total) |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of TG:HDL-C |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of TC:HDL-C |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Non-HDL-C:HDL-C |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of LDL-C:Apo B |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Apo B:Apo A1 |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Apo C3:Apo C2 |  | 12 Weeks | 
| Percent Change From Baseline to Week 52 in Fasting TG |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Remnant Cholesterol |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in HDL-C |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo A1 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Non-HDL-C |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in TC |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in LDL-C |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in FFAs |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo A2 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo B |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo B48 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo B100 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo C2 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo C3 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Apo E |  | 52 Weeks | 
| Change From Baseline to Week 52 in FGF21 |  | 52 Weeks | 
| Change From Baseline to Week 52 in hsCRP |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (VLDL Cholesterol-Large) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (VLDL Cholesterol-Intermediate) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (VLDL Cholesterol-Small) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Intermediate Density Lipoproteins 1) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Intermediate Density Lipoproteins 2) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins I) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IIa) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IIb) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IIIa) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IIIb) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IVa) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IVb) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Low Density Lipoproteins IVc) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (High Density Lipoproteins 2b) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (High Density Lipoproteins 3 and 2a) | Two lipoprotein subclasses, HDL3 and HDL2a, were analyzed together as one measurement without distinction. | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Ion Mobility (Diameter of the Major LDL Particle (Å)) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL & Chylomicron Particles) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL & Chylomicron Particles-Large) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL Particles-Medium) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL Particles-Small) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (LDL Particles) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (IDL Particles) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (LDL Particles-Large) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (LDL Particles-Small) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Particles) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Particles-Large) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Particles-Medium) |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Particles-Small) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL Particle Size) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (LDL Particle Size) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Particle Size) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (Triglyceride) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (VLDL & Chylomicron Triglyceride) | Two types of lipoprotein particles were analyzed together as one measurement without distinction. | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipoprotein Fraction (HDL Cholesterol) |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of TG:HDL-C |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of TC:HDL-C |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Non-HDL-C:HDL-C |  | 52 Weeks | 
| Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of LDL-C:Apo B |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Apo B:Apo A1 |  | 52 Weeks | 
| Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Apo C3:Apo C2 |  | 52 Weeks |