| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe hypertriglyceridemia [fasting TG levels >=500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020667 |
| E.1.2 | Term | Hyperlipidemia |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
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| E.2.2 | Secondary objectives of the trial |
* 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);
* 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);
* 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
* To determine the plasma concentrations of K-877 for the purpose of use in population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and willing to comply with all study requirements and procedures
throughoutthe 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 lipid-altering 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 outside the required range for entry into the study but is
≥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. Normal renal function (i.e., estimated glomerular filtration rate [eGFR] ≥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,
o They are not breastfeeding,
o They do not plan to become pregnant during the study, and
o They are taking adequate contraception (see inclusion criterion 9);
9. Women of childbearing potential must have a negative serum pregnancy test at Visit 1 (Week -8
or Week -6), a negative urine pregnancy test at Visit 4 (Day 1), and must agree to use an effective method of avoiding pregnancy from screening to the end of the study and for 30 days
following their last dose of study drug, unless their sexual partner is surgically sterile.
Effective methods of avoiding pregnancy are those contraceptive methods with a Pearl index of <1
used consistently and correctly (including implantable contraceptives, injectable contraceptives,
oral contraceptives, transdermal contraceptives, or intrauterine devices); and
10. Women are not considered to be of childbearing potential if they meet at least 1 of the
following 2 criteria as documented by the Investigator:
o They have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at a minimum of 1 menstrual cycle prior to signing the informed consent form; or
o They are post-menopausal: for women ≥55 years of age, defined as ≥1 year since their last
menstrual period, or for women <55 years of age, defined as ≥1 year since their last
menstrual period and have a follicle-stimulating hormone level in the central laboratory’s
normal range for post-menopausal phase.
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| E.4 | Principal 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), 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;
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,
10. Patients who are receiving dialysis at Visit 1 (Week -8 or Week -6) or who have had a kidney transplant, regardless of renal function;
11. Patients with active liver disease, or severe hepatic disorders
12. 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;
13. Known familial lipoprotein lipase impairment or deficiency (Fredrickson Type I), Apo C2 deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III);
14. History of malignancy, except patients who have been disease-free for >5 years prior to Visit 1 (Week -8 or Week -6), or whose only malignancy has been basal or squamous cell skin carcinoma;
15. History of bariatric surgery;
16. Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg after 5 minutes of resting during screening or Visit 4 (Day 1);
17. Positive hepatitis B surface antigen or hepatitis C virus antibody serology
18. Known to be infected with human immunodeficiency virus (HIV) 1 or HIV 2;
19. Known hypersensitivity or intolerance to fibrates or peroxisome proliferator-activated receptor-α agonists;
20. Anticipation of major surgery during the study;
21. Treatment with chronic prescription pharmacotherapy for metabolic or cardiovascular disease management or risk factor modification that has not been stable for ≥4 weeks prior to Visit
1 (Week -8 or Week -6);
22. Ongoing treatment with weight loss drugs ;
23. Ongoing treatment with cyclosporine, rifampin, or other strong inhibitors of organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3;
24. Treatment with tamoxifen, estrogens, or progestins that has not been stable for ≥4 weeks prior to the first TG qualifying visit (Visit 2 [Week -2]);
25. Use of all systemic corticosteroids.
26. Clinical evidence of hypothyroidism, thyroid hormone therapy that is not stable for ≥4 weeks prior to the first TG qualifying visit (Visit 2 [Week -2]), or patients with the following thyroid-stimulating hormone (TSH) and thyroxine (T4) levels at Visit 1 (Week -8 or Week -6):
o For patients not on replacement therapy:
ƒ TSH >1.5 × upper limit of normal (ULN), or
ƒ T4 outside of the normal range and TSH >1.0 × ULN and ≤1.5 × ULN;
o For patients on replacement therapy:
ƒ TSH outside of the normal range;
27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × ULN at Visit 1 (Week -8 or Week -6);
28. Total bilirubin ≥2 × ULN at Visit 1 (Week -8 or Week -6), unless due to Gilbert’s syndrome;
29. Unexplained creatine kinase (CK) concentration >3 × ULN or CK elevation due to known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1 (Week -8 or Week -6);
30. Participation in another clinical trial involving an investigational agent within 30 days prior to Visit 1 (Week -8 or Week -6);
31. History of illicit drug use or alcohol abuse within 1 year prior to Visit 1 (Week -8 or Week -6);
32. Patients who have previously received K-877; or
33. Any condition or therapy, which, in the opinion of the Investigator, might pose a risk to the patient or make participation in the study not in the best interest of the patient.
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| E.5 End points |
| E.5.1 | 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.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | 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 high-sensitivity
C-reactive 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, non-HDL-C: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, non-HDL-C: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 145 mg
(in the 40-week Extension Period), change from Visit 7 (Week 12) in efficacy and safety variables
will also be explored.
The exploratory efficacy endpoints for the 12-week Efficacy Period include the following:
• Change from baseline to Week 12 in selected biomarkers suggestive of hepatic inflammation and
fibrosis, including cytokeratin-18 (CK-18), ferritin, hyaluronic acid, tumor necrosis factor alpha
(TNF-α), type IV collagen, and adiponectin.
The exploratory efficacy endpoints for the 40-week Extension Period include the following:
• Change from baseline to Week 52 in selected biomarkers suggestive of hepatic inflammation and
fibrosis, including CK-18, ferritin, hyaluronic acid, TNF-α, type IV collagen, and adiponectin.
Safety:
Safety assessments include adverse events (AEs), clinical laboratory measurements
(chemistry, hematology, coagulation profile, endocrinology, and urinalysis), 12-lead
electrocardiograms (ECGs), vital signs (heart rate, respiratory rate, and blood pressure), and
physical examinations. Pharmacokinetics/Pharmacodynamics:
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be used for
population
PK analysis and PK/PD analysis.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belarus |
| Canada |
| Georgia |
| Hungary |
| Russian Federation |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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