A study of K-877 in adults with high triglycerides and reduced kidney function.

• Register: EUCTR
• Last refreshed on: 13 July 2020
• Main ID: EUCTR2016-001518-39-PL
• Date of registration: 09/02/2017
• Prospective Registration: Yes
• Primary sponsor: Kowa Research Institute, Inc.
• Public title: A study of K-877 in adults with high triglycerides and reduced kidney function.
• Scientific title: 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
• Date of first enrolment: 04/04/2017
• Target sample size: 422
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001518-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belarus, Bulgaria, Czech Republic, Georgia, Hungary, Poland, Russian Federation, Ukraine, United States

Contacts

• Name: Lourdes Herreros
• Affiliation: Medpace Spain

• Name: Lourdes Herreros
• Affiliation: Medpace Spain

Key inclusion & exclusion 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 moderate or high-intensity statin therapy must meet one of the following criteria1 unless they have any exceptional conditions:
a) 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);
b) 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);
c) 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
d) 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 currently on a low-intensity statin or not on a statin, must meet one of the following criteria:
a) Patient does not meet any criteria for moderate- or high intensity statin therapy listed above (see inclusion criteria 3 a throught 3d);
b) 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 (including, but not limited to, examples in Appendix B), or due to partial or complete statin intolerance;
c) 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 (see Appendix B);
5. Not on lipid-altering therapy other than statins, ezetimibe, or PCSK9 inhibitors at randomization;
a) 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
b) 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 <2000 mg/dL (22.60 mmol/L) based on the mean of Visit 2 (Week -2) and Visit 3 (Week -1). Note: In cases in which a patient’s mean TG level from Visit 2 and Visit 3 falls o
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;
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;
5. Patients who are receiving insulin or insulin analogue treatment, except for patients on fixed-dose regimens insulin for =4 weeks prior to Visit 1;
6. History of stroke (including TIA), myocardial infarction or unstable angina pectoris, life-threatening arrhythmia, or coronary revascularization within 6 months prior to Visit 1;
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 <30 mL/min/1.73 m2) at Visit 1 or on more than one occasion in the 6 months prior to Visit 1; eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (2009);
11. Patients who are receiving dialysis at Visit 1 or who have had a kidney transplant, regardless of renal function;
12. Patients with active, severe liver disease impacting hepatic function (e.g.hepatic cirrhosis, Child-Pugh grade B or C). Faty liver disease or nonalcoholic steatohepatitis in Child-Pugh category A is permitted;
13. History or evidence of major and clinically significant cardiovascular, pulmonary, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic disease that would interfere with the conduct of the study or interpretation of the data;
14. Known familial lipoprotein lipase impairment or deficiency (Fredrickson Type I), Apo C2 deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III);
15. History of malignancy, except patients who have been disease-free for >5 years prior to Visit 1, 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 at Visit 1;
18. Positive hepatitis B surface antigen(HBsAg) or positive hepatitis C virus (HCV) antibody serology with detectable HCV ribonucleic acid (RNA):
a) Patients with a history of hepatitis B vaccination (Anti-HBs antibody positive) without a history of hepatitis B infection (HBsAg negative) are eligible;
b) Patients with negative HCV RNA and no evidence of active hepatitis C infection, no evidence of liver dysfunction, and who are not on a direct acting antiviral are eligible;
19. Known to be infected with human immunodeficiency virus (HIV) 1 or HIV 2;
20. Known hypersensitivity or intolerance to fib

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

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: 20.1 Level: LLT Classification code 10020667 Term: Hyperlipidemia System Organ Class: 100000004861

Intervention(s)

Product Name: K-877
Product Code: K-877
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Pemafibrate
CAS Number: 848259-27-8
Current Sponsor code: K-877
Other descriptive name: K-877
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.2-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Fenofibrate
Product Name: Fenofibrate
Product Code: Fenofibrate
Pharmaceutical Form: Tablet
INN or Proposed INN: FENOFIBRATE
CAS Number: 49562-28-9
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 48-

Trade Name: Fenofibrate
Product Name: Fenofibrate
Product Code: Fenofibrate
Pharmaceutical Form: Tablet
INN or Proposed INN: FENOFIBRATE
CAS Number: 49562-28-9
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 145-

Primary Outcome(s)

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.

Secondary Objective: Secondary Objectives:
The secondary objectives of the study are the following:
* To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in lowering fasting TG levels in patients with fasting TG levels >=500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and mild or moderate renal impairment;
* To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and Week 52 in altering lipid parameters in patients with fasting TG levels >=500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and mild or moderate renal impairment;
* To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with fasting TG levels >=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.

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 <2000 mg/dL (22.60 mmol/L) and mild or moderate renal impairment.

Timepoint(s) of evaluation of this end point: 12 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 12, 40 or 52 weeks

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 Apo C3:Apo C2.
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol 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. Baseline for all other efficacy and safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, the last measurement prior to the first dose of randomized study drug will be used.
For patients randomized to receive placebo (in the 12-week Efficacy Period) and fenofibrate (in the 40 week Extension Period), change from Visit 7 (Week 12) in efficacy and safety variables will also be explored.

For completion of secondary endpoints please refer to the protocol (V1.0, 13 Sep 2016).

Secondary ID(s)

2016-001518-39-HU

K-877-303

Source(s) of Monetary Support

Kowa Research Institute, Inc.

Ethics review

Status: Approved
Approval date: 14/02/2017
Contact:

Results

• Results available: Yes
• Date Posted: 05/07/2020
• Date Completed: 05/07/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001518-39/results