Study to Evaluate the Efficacy and Safety of K-877 in Adult Patients With Fasting High Triglyceride Levels and Normal Renal Function

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 normal renal function.

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, Double-Blind 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 Normal Renal Function

Conditions
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Severe Hypertriglyceridemia

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


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, criterion 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; 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 twice daily for 12 weeks | Drug: K-877<br> <br> Drug: Placebo (for K-877)<br> <br> |
| Active Comparator: 40 Week Extension<br>K-877 with placebo matching fenofibrate or fenofibrate with placebo matching K-877 for 40 weeks | Drug: K-877<br> <br> Drug: Fenofibrate<br> <br> Drug: Placebo (for K-877)<br> <br> Drug: Placebo (for Fenofibrate)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change of Fasting Triglyceride(TG) Levels 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 Free Fatty Acids (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 Fibroblast Growth Factor 21 (FGF21) |  | 12 Weeks | 
| Change From Baseline to Week 12 in hsCRP |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (VLDL) Cholesterol-Large |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (VLDL) Cholesterol-Intermediate |  | 12 Weeks | 
| Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (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 - Major LDL Particle Measurement |  | 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 | 
| Percent 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 | 
| Change From Baseline to Week 12 in Lipoprotein Fraction - LDL Particles (Total) |  | 12 Weeks | 
| Change From Baseline to Week 12 in Lipoprotein Fraction - Intermediate-density Lipoprotein (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 (Total) |  | 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 | 
| Percent 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 (Total) |  | 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 |  | 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 Total Cholesterol (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 | 
| Percent 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 |  | 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 | 
| Percent 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 | 
| Change From Baseline to Week 52 in Lipoprotein Fraction - LDL Particles (Total) |  | 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 | 
| Percent 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 | 
| Percent 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 |