Pemafibrate to reduce risk of cardiovascular events in patients with diabetes.

• Register: EUCTR
• Last refreshed on: 2 May 2022
• Main ID: EUCTR2016-003818-26-SK
• Date of registration: 30/01/2017
• Prospective Registration: Yes
• Primary sponsor: Kowa Research Institute, Inc.
• Public title: Pemafibrate to reduce risk of cardiovascular events in patients with diabetes.
• Scientific title: Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with diabeTes (PROMINENT)
• Date of first enrolment: 16/03/2017
• Target sample size: 10000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003818-26
• 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: no 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

Argentina, Brazil, Bulgaria, Canada, Colombia, Czech Republic, Czechia, Denmark, France, Germany, Hungary, India, Israel, Japan, Mexico, Netherlands, Poland, Romania, Russian Federation, Slovakia, South Africa, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: David Sojka
• Affiliation: IQVIA

• Name: David Sojka
• Affiliation: IQVIA

Key inclusion & exclusion criteria

Inclusion criteria:
1. 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)
2. HDL-C = 40 mg/dL (1.03 mmol/L) at Visit 1 (Screening/Enrollment Visit) or Visit 1.1 (Retest)
3. 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
a) Age = 50 years if male or = 55 years if female (primary prevention cohort); OR
b) 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 peripheral artery disease (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)
4. In addition, by Visit 1 (Screening/Enrollment Visit), participants must be either:
a) Receiving treatment with a stable dose (ie, for at least 12 weeks) of a qualifying moderate- to high intensity statin (atorvastatin = 40 mg/day, rosuvastatin = 20 mg/day, simvastatin = 40 mg/day*, or pitavastatin 4 mg/day); or
b) Have evidence of LDL-C = 70 mg/dL (1.81 mmol/L) by local laboratory determination within the previous 12 months#, or
c) Statin intolerant+ and have evidence of LDL-C = 100 mg/dL (2.59 mmol/L) by local laboratory determination within the previous 12 months.
* Participants enrolled on simvastatin > 40 mg/day must have been taking and tolerating that dose for at least 12 months.
# If untreated or on stable dosing (ie, for at least 12 weeks) of another lipid-lowering regimen that may include a statin with or without ezetimibe and/or a PCSK9 inhibitor
+ Statin intolerance is defined as: the inability to tolerate at least 2 statins: 1 statin at the lowest daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), AND another statin at any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping, that begins or increases during statin therapy and stops when statin therapy is discontinued. Participants not receiving a daily regimen of a statin (e.g., 1-3 times weekly) could also be considered “statin intolerant” if they cannot tolerate a cumulative weekly statin dose of 7 times the lowest approved tablet size, and the criteria outlined above are also met.
5. Ability to understand and comply with study procedures and give written informed consent.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Nu
Exclusion criteria:
1. Current or planned use of fibrates or agents with potent peroxisome proliferator activated receptor (PPAR)-a agonist activity (eg, saroglitazar) within 6 weeks (42 days) of Visit 1 (Screening/Enrollment Visit). Note: PPAR-? agonists (eg, glizatones such as pioglitazone and rosiglitazone) are allowed
2. Known sensitivity to PPAR-a agonists or tablet excipients
3. 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
4. Type 1 diabetes mellitus
5.Uncontrolled diabetes mellitus as defined by a HbA1c > 9.5% [80 mmol/mol] at Visit 1 (Screening/Enrollment Visit)
6.Untreated or inadequately treated hypothyroidism [thyroid stimulating hormone (TSH) > 2.0 X the upper limit of normal (ULN) or free thyroxine (T4) = ULN] or hyperthyroidism; controlled thyroid disease (permitted) requires normal TSH and stable therapy for at least 4 weeks
7. Recent CVD event (eg, MI or stroke) within 8 weeks of Visit 2 (Randomization Visit)
8. Recent or planned vascular intervention within 8 weeks of Visit 2
9. New York Heart Association Class IV heart failure (HF)
10. Known homozygous familial hypercholesterolemia (heterozygous is permitted) or familial hypoalphalipoproteinemia
11.Documented previous occurrence of myositis/myopathy
12.Unexplained creatine kinase (CK) > 5 X ULN
13.Liver disease defined as cirrhosis or Child-Pugh class B and C, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 X ULN
14.Biliary obstruction or hyperbilirubinemia (ie, total bilirubin > 2 X ULN, except with a documented diagnosis of Gilbert’s disease)
15.Chronic renal insufficiency, defined by an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or kidney transplant, regardless of renal function
16.Unexplained anemia (hematocrit = 30%)
17.Uncontrolled hypertension (seated systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg) at Visit 2 (Randomization Visit).
18.History of chronic active hepatitis B or hepatitis C, or known infection with HIV; participants with documented hepatitis C resolution after treatment are permitted
19.Active malignancy, except non-melanoma skin cancer or carcinoma in situ of the cervix, within the last 2 years.
20.Prior organ transplant or any condition likely to lead to organ transplantation in the next 5 years
21.Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of organic anion transporting polypeptides (OATP)1B1, or OATP1B3
22.History of alcoholism or unwillingness to limit alcohol intake to < 15 alcoholic beverages (or units) per week or < 5 alcoholic beverages (or units) during a single occasion for men and < 8 alcoholic beverages (or units) per week or < 4 alcoholic beverages (or units) during a single occasion for women during the study period. Note: One alcoholic beverage (unit) is defined as 12 oz. (350 mL) of beer, 5 oz. (150 mL) of wine, or 1.5 oz. (45 mL) of liquor
23.History of hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
24.Women who are pregnant, lactating, planning to be pregnant or lactating during the study period, or WOCP who are not using an acceptable method of contraception
25.A medical condition, other than vascular disease, with l

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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Reduction of cardiovascular events in patients with Type II Diabetes
MedDRA version: 20.0 Level: HLT Classification code 10012654 Term: Diabetic complications cardiovascular System Organ Class: 100000004860

Intervention(s)

Product Name: Pemafibrate
Product Code: K-877
Pharmaceutical Form: 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: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The primary scientific aim of the PROMINENT study is to assess whether
treatment with the selective peroxisome proliferator activated receptor
modulator alpha (SPPARM-a), pemafibrate, will prevent myocardial
infarction (MI), ischemic stroke, coronary revascularization, and
cardiovascular (CV) death in adults with type 2 diabetes (T2D) who have
elevated triglycerides (TG) and low high-density lipoprotein cholesterol
(HDL-C) levels and are at high risk for future CV events.
Specifically, the primary objective of the study is to determine whether
pemafibrate administered at a dose of 0.2 mg twice daily will delay the
time to first occurrence of any component of the clinical composite
endpoint of:
•nonfatal MI;
•nonfatal ischemic stroke;
•coronary revascularization; or
•CV death.

Secondary Objective: The secondary scientific aim of this study is to investigate 1) the efficacy (time to first occurrence) of a number of secondary CV and diabetes-related vascular and nonvascular endpoints in the study population, and 2) the efficacy (as measured by the percent change from baseline) for a number of lipid measures.

Timepoint(s) of evaluation of this end point: Variable as event driven

Primary end point(s): The primary efficacy endpoint is the time from randomization to the first
occurrence of any component of the clinical composite endpoint of:
•Nonfatal MI
•Nonfatal ischemic stroke
•Coronary revascularization
•Cardiovascular death

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Variable with exception of the following carried out at specific visits:
The change from Screening/Enrollment Visit (Visit 1) to Month 4 Visit (Visit 5) for the following lipid biomarkers: TC, TG, HDL-C, non-HDL-C (calculated), VLDL-C (calculated), ApoA1, ApoC3, and ApoE; and
• The change from Randomization Visit (Visit 2) to Month 6 Visit (Visit 6) for non-fasting remnant cholesterol

Secondary end point(s): The group A (clinical) endpoints are 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
- The 3-component composite endpoint of non-fatal MI, non-fatal
ischemic stroke, or cardiovascular death
- Any component of the primary endpoint or hospitalization for HF
- Any component of the primary endpoint or all-cause mortality
- Any new or worsening 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)
- Time of first occurrence of individual endpoints and an analysis of total
events (evaluating time to occurrence of the first and all recurrent nonfatal
MI, non-fatal ischemic stroke, coronary revascularization, or
cardiovascular death).
- Additionally, as a prespecified secondary analysis, evidence of any
genetic effect modification that may relate to pemafibrate and incident
cardiovascular events will be evaluated. In particular, whether the effect
of pemafibrate as compared with placebo on cardiovascular events
differs according to known genetic polymorphisms in the PPARA gene
(such as, but not limited to rs6008845), will be assessed.
The group B (lipid) endpoints are:
• The change from Screening/Enrollment Visit (Visit 1) to Month 4 Visit
(Visit 5) for the following lipid biomarkers: TC, TG, HDL-C, non-HDL-C
(calculated), VLDL-C (calculated), ApoA1, ApoC3, and ApoE; and
• The change from Randomization Visit (Visit 2) to Month 6 Visit (Visit 6)
for non-fasting remnant cholesterol
* VLDL-C will be calculated as TC minus HDL-C minus LDL-C, where LDLC
is measured by a direct homogenous method.

Secondary ID(s)

K-877-302

Source(s) of Monetary Support

Kowa Research Institute, Inc.

Ethics review

Status: Approved
Approval date: 15/02/2017
Contact: