Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT)

Study Overview
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Brief Summary
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The primary objective of the study is to determine whether pemafibrate administered twice daily will delay the time to first occurrence of any component of the clinical composite endpoint of: nonfatal Myocardial Infarction (MI) nonfatal ischemic stroke coronary revascularization; or Cardio Vascular (CV) death.

Detailed Description
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A multi-regional clinical trial with participating sites in the following countries. India is being conducted under a previous protocol version due to regulatory requirements. Argentina Brazil Bulgaria Canada Colombia Czech Republic Denmark France Germany Hungary India Israel Japan Mexico Netherlands Poland Romania Russian Federation Slovakia South Africa Spain Ukraine United Kingdom United States

Official Title
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Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT)

Conditions
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Type2 Diabetes, Dyslipidemia

Intervention / Treatment
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* Drug: K-877
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fasting TG ≥ 200 mg/dL (2.26 mmol/L) and < 500 mg/dL (5.65 mmol/L) at Visit 1 (Screening/Enrollment Visit) or Visit 1.1 (Retest) HDL-C ≤ 40 mg/dL (1.03 mmol/L) at Visit 1 (Screening/Enrollment Visit) or Visit 1.1 (Retest) Type 2 diabetes of longer than 12 weeks duration documented in medical records, for example: local laboratory evidence through medical record review of elevated HbA1c (≥ 6.5% [48 mmol/mol]), elevated plasma glucose (fasting ≥ 126 mg/dL [7.0 mmol/L], 2-hour ≥ 200 mg/dL [11.1 mmol/L] during oral glucose tolerance testing, or random value ≥ 200 mg/dL with classic symptoms, or currently taking medication for treatment of diabetes; AND either Age ≥ 50 years if male or ≥ 55 years if female (primary prevention cohort); OR Age ≥ 18 years and established systemic atherosclerosis (secondary prevention cohort), defined as any 1 of the following: i. Prior MI or ischemic (non-hemorrhagic) stroke ii. Coronary angiographic lesion of ≥ 60% stenosis in a major epicardial vessel or ≥ 50% left main stenosis iii. Asymptomatic carotid disease with ≥ 70% carotid artery stenosis iv. Symptomatic carotid disease with ≥ 50% carotid artery stenosis v. Symptomatic lower extremity PAD (ie, intermittent claudication, rest pain, lower extremity ischemic ulceration, or major amputation with either ankle-brachial index ≤ 0.9 or other diagnostic testing [eg, toe-brachial index, angiogram, or other imaging study]) vi. Prior arterial revascularization procedure (including coronary, carotid, or peripheral angioplasty/stenting, bypass, or atherectomy/endarterectomy) Exclusion Criteria: Current or planned use of fibrates or agents with PPAR-α agonist activity (eg, saroglitazar) within 6 weeks (42 days) of Visit 1 (Screening/Enrollment Visit). Note: PPAR-γ agonists (eg, glizatones such as pioglitazone and rosiglitazone) are allowed Known sensitivity to PPAR-α agonists or tablet excipients Initiation of, or change in, current TG-lowering therapy within 12 weeks of Visit 1 (if applicable). Note: TG-lowering therapy is defined as niacin > 100 mg/day or dietary supplements or prescription omega-3 fatty acids > 1 g/day Type 1 diabetes mellitus

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>K-877 (pemafibrate) tablet twice daily. | Drug: K-877<br>* 0.2mg tablet<br>* Other names: pemafibrate;|
| Placebo Comparator: Control Group<br>Matching K-877 placebo tablet twice daily. | Drug: Placebo<br>* K-877 matching placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with first occurrence of nonfatal MI, nonfatal ischemic stroke, coronary revascularization, or CV death. |  | Through study completion, an average of 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of The 4-component composite endpoint of non-fatal MI, non-fatal ischemic stroke, hospitalization for unstable angina requiring unplanned coronary revascularization or cardiovascular death |  | Through study completion, an average of 4 years | 
| Time to first occurrence of the 3-component composite endpoint of non-fatal MI, non-fatal ischemic stroke, or cardiovascular death |  | Through study completion, an average of 4 years | 
| Time to first occurrence of any component of the primary endpoint or hospitalization for Heart failure (HF) |  | Through study completion, an average of 4 years | 
| Time to first occurrence of any component of the primary endpoint or all-cause mortality |  | Through study completion, an average of 4 years | 
| Time to first occurrence of any new or worsening Peripheral artery disease (PAD) | Any new or worsening Peripheral artery disease (PAD), defined as incidence of lower extremity revascularization, intermittent claudication, rest pain, lower extremity ischemic ulceration, or major amputation with either ankle-brachial index ≤ 0.9 or other diagnostic testing (eg, toe-brachial index, angiogram, or other imaging study) | Through study completion, an average of 4 years | 
| Time of first occurrence of individual endpoints and an analysis of total events | (evaluating time to occurrence of the first and all recurrent non-fatal MI, non-fatal ischemic stroke, coronary revascularization, or cardiovascular death). | Through study completion, an average of 4 years | 
| Incidence of cardiovascular events | Effect of pemafibrate vs placebo on cardiovascular events compared to known genetic polymorphisms in the PPARA gene | Up to 4 Years | 
| Lipid Endpoints | The change from Screening/Enrollment Visit (Visit 1) to Month 4 Visit (Visit 5) for the following lipid biomarkers: Total cholesterol (TC), Triglyceride(s) (TG), High-density lipoprotein cholesterol (HDL-C), non-HDL-C (calculated), Very low-density lipoprotein cholesterol (VLDL-C) (calculated), ApoA1, ApoC3, and ApoE | Week -3 to Month 4 (Visit 1 to Visit 5) | 
| Nonfasting Remnant Cholesterol Endpoint | The change from Randomization Visit (Visit 2) to Month 6 Visit (Visit 6) for nonfasting remnant cholesterol | Week 0 to Month 6 (Visit 2 to Visit 6) |