Phase 3 N=551 Randomized Triple-blind Treatment

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

Severe Hypertriglyceridemia

Bottom Line

View on ClinicalTrials.gov: NCT03001817 ↗

Enrolled (actual)

551

Serious AEs

3.5%

Results posted

Nov 2022

Primary outcome: Primary: Percent Change of Fasting Triglyceride(TG) Levels From Baseline to Week 12 — -56.00; -7.97 Percent of Change — p=<0.0001

Study Design & Population

Study type: Interventional
Phase: Phase 3
Interventions: K-877 (Drug); Fenofibrate (Drug); Placebo (for K-877) (Drug); Placebo (for Fenofibrate) (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Kowa Research Institute, Inc.
Primary completion: Jun 2019

Outcome Measures

Outcome	Result	p-value
PRIMARY Percent Change of Fasting Triglyceride(TG) Levels From Baseline to Week 12	-56.00; -7.97	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Remnant Cholesterol	-52.95; -3.36	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in HDL-C	16.25; 4.00	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Apo A1	1.21; 2.13	0.5443
SECONDARY Percent Change From Baseline to Week 12 in Non-HDL-C	-16.07; 0.81	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Total Cholesterol	-11.26; 1.55	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in LDL-C	31.93; 1.01	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Free Fatty Acids (FFAs)	-19.07; 10.29	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Apo A2	15.30; 2.89	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Apo B	2.41; 3.73	0.4939
SECONDARY Percent Change From Baseline to Week 12 in Apo B48	-31.35; 22.62	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Apo B100	3.09; 2.76	0.8371
SECONDARY Percent Change From Baseline to Week 12 in Apo C2	0.00; 0.00	0.3415
SECONDARY Percent Change From Baseline to Week 12 in Apo C3	-39.56; 5.11	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Apo E	-28.48; 0.56	<0.0001 sig
SECONDARY Change From Baseline to Week 12 in Fibroblast Growth Factor 21 (FGF21)	196.97; 3.88	<0.0001 sig
SECONDARY Change From Baseline to Week 12 in hsCRP	-0.051; -0.100	0.7442
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (VLDL) Cholesterol-Large	-27.89; 5.99	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (VLDL) Cholesterol-Intermediate	-17.32; 4.70	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Very Low-Density Lipoprotein (VLDL) Cholesterol-Small	-4.13; 1.86	0.0374 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Intermediate Density Lipoproteins 1	4.47; 2.10	0.7429
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Intermediate Density Lipoproteins 2	15.50; 3.06	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins I	45.24; 1.04	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IIa	59.36; 0.75	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IIb	61.87; 1.26	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IIIa	33.08; 0.85	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IIIb	-1.50; 1.11	0.3669
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IVa	-24.88; -0.26	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IVb	-34.81; 5.60	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Low Density Lipoproteins IVc	-21.68; 4.65	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - High Density Lipoproteins 2b	-7.34; 2.04	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - High Density Lipoproteins 3 and 2a	-2.01; 1.76	0.0509
SECONDARY Percent Change From Baseline to Week 12 in Ion Mobility - Major LDL Particle Measurement	2.38; -0.06	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL & Chylomicron Particles	-37.93; 5.37	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL & Chylomicron Particles-Large	-48.58; 7.54	<.0001 sig
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL Particles-Medium	-33.57; 7.58	<.0001 sig
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL Particles-Small	0.90; -1.87	0.0647
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - LDL Particles (Total)	209.41; 51.43	0.0007 sig
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - Intermediate-density Lipoprotein (IDL) Particles	-5.52; -0.21	0.1399
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - LDL Particles-Large	27.54; 0.00	0.0122 sig
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - LDL Particles-Small	87.75; 23.85	0.0994
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Particles (Total)	2.87; -1.07	0.0904
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Particles-Large	0.27; 0.05	0.4346
SECONDARY Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Particles-Medium	-0.97; 0.02	0.1474
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Particles-Small	7.08; -2.42	0.0054 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL Particle Size	-5.70; 0.80	0.0002 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - LDL Particle Size	1.00; 0.01	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Particle Size	-1.14; 0.00	0.0118 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - Triglyceride (Total)	-48.78; 8.43	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - VLDL & Chylomicron Triglyceride	-49.06; 6.71	<.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipoprotein Fraction - HDL Cholesterol	-0.11; -4.63	0.2049
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of TG:HDL-C	-62.64; -11.22	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Total Cholesterol (TC):HDL-C	-25.84; -3.86	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Non-HDL-C:HDL-C	-30.79; -4.49	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of LDL-C:Apo B	30.90; -0.49	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Apo B:Apo A1	0.73; 2.47	0.9117
SECONDARY Percent Change From Baseline to Week 12 in Lipid and Lipoprotein Ratios of Apo C3:Apo C2	-24.84; 7.50	<0.0001 sig
SECONDARY Percent Change From Baseline to Week 52 in Fasting TG	-57.93; -55.45	—
SECONDARY Percent Change From Baseline to Week 52 in Remnant Cholesterol	-53.98; -49.11	—
SECONDARY Percent Change From Baseline to Week 52 in HDL-C	17.65; 19.35	—
SECONDARY Percent Change From Baseline to Week 52 in Apo A1	1.63; 3.48	—
SECONDARY Percent Change From Baseline to Week 52 in Non-HDL-C	-17.24; -15.71	—
SECONDARY Percent Change From Baseline to Week 52 in TC	-11.84; -9.93	—
SECONDARY Percent Change From Baseline to Week 52 in LDL-C	31.15; 36.84	—
SECONDARY Percent Change From Baseline to Week 52 in FFAs	-18.08; -13.64	—
SECONDARY Percent Change From Baseline to Week 52 in Apo A2	9.26; 12.31	—
SECONDARY Percent Change From Baseline to Week 52 in Apo B	0.93; 2.46	—
SECONDARY Percent Change From Baseline to Week 52 in Apo B48	-14.04; -5.22	—
SECONDARY Percent Change From Baseline to Week 52 in Apo B100	1.48; 1.97	—
SECONDARY Percent Change From Baseline to Week 52 in Apo C2	-8.70; -1.80	—
SECONDARY Percent Change From Baseline to Week 52 in Apo C3	-36.70; -30.77	—
SECONDARY Percent Change From Baseline to Week 52 in Apo E	-29.94; -30.67	—
SECONDARY Change From Baseline to Week 52 in FGF21	259.20; 207.50	—
SECONDARY Change From Baseline to Week 52 in hsCRP	0.000; -0.200	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - VLDL Cholesterol-Large	-33.43; -24.44	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - VLDL Cholesterol-Intermediate	-21.71; -11.70	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - VLDL Cholesterol-Small	-4.28; -3.23	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Intermediate Density Lipoproteins 1	4.44; 8.23	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Intermediate Density Lipoproteins 2	21.05; 21.09	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins I	48.52; 38.99	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IIa	64.54; 44.52	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IIb	58.07; 42.18	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IIIa	31.63; 30.84	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IIIb	0.34; 4.31	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IVa	-24.86; -15.38	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IVb	-35.58; -27.86	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Low Density Lipoproteins IVc	-24.00; -22.02	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - High Density Lipoproteins 2b	-9.54; -8.99	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - High Density Lipoproteins 3 and 2a	-3.58; -3.06	—
SECONDARY Percent Change From Baseline to Week 52 in Ion Mobility - Diameter of the Major LDL Particle	2.38; 1.56	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL & Chylomicron Particles	-39.09; -30.29	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL & Chylomicron Particles-Large	-51.64; -51.23	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL Particles-Medium	-34.20; -20.70	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL Particles-Small	0.00; 3.85	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - LDL Particles (Total)	193.00; 213.50	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - IDL Particles	-9.00; -6.50	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - LDL Particles-Large	25.50; 50.50	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - LDL Particles-Small	81.00; 138.00	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Particles	1.07; 1.38	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Particles-Large	0.10; -0.10	—
SECONDARY Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Particles-Medium	-0.80; -1.15	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Particles-Small	9.01; 6.37	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL Particle Size	-6.12; -6.70	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - LDL Particle Size	0.99; 0.51	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Particle Size	-1.15; -1.11	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - Triglyceride	-48.01; -48.29	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - VLDL & Chylomicron Triglyceride	-48.38; -47.69	—
SECONDARY Percent Change From Baseline to Week 52 in Lipoprotein Fraction - HDL Cholesterol	-3.88; -2.63	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of TG:HDL-C	-63.46; -65.21	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of TC:HDL-C	-27.21; -27.59	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Non-HDL-C:HDL-C	-30.63; -32.36	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of LDL-C:Apo B	28.03; 24.73	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Apo B:Apo A1	1.05; -1.76	—
SECONDARY Percent Change From Baseline to Week 52 in Lipid and Lipoprotein Ratios of Apo C3:Apo C2	-20.98; -13.99	—

Summary

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.

Eligibility Criteria

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);

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Data sourced from ClinicalTrials.gov (NCT03001817). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.