Clinical Trials Register

Summary
EudraCT Number:	2016-003818-26
Sponsor's Protocol Code Number:	K-877-302
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-04-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2016-003818-26

A.3

Full title of the trial

Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with diabeTes (PROMINENT)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

K-877-302

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kowa Research Institute, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Kowa Research Institute, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IQVIA
B.5.2	Functional name of contact point	Regulatory Department
B.5.3	Address:
B.5.3.1	Street Address	East Point Business Park, Estuary House, Fairview
B.5.3.2	Town/ city	Dublin 3
B.5.3.3	Post code	DO3 Y6A2
B.5.3.4	Country	Ireland
B.5.6	E-mail	IQVIA-VHP@iqvia.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pemafibrate
D.3.2	Product code	K-877
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pemafibrate
D.3.9.1	CAS number	848259–27–8
D.3.9.2	Current sponsor code	K-877
D.3.9.3	Other descriptive name	K-877
D.3.9.4	EV Substance Code	SUB119482
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Reduction of cardiovascular events in patients with Type II Diabetes

E.1.1.1

Medical condition in easily understood language

Diabetic patients with cardiovascular events

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10012654
E.1.2	Term	Diabetic complications cardiovascular
E.1.2	System Organ Class	100000004860

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary scientific aim of the PROMINENT study is to assess whether treatment with the selective peroxisome proliferator activated receptor modulator alpha (SPPARM-α), 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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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.

E.4

Principal exclusion criteria

1. Current or planned use of fibrates or agents with potent peroxisome proliferator activated receptor (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
2. Known sensitivity to PPAR-α 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 life expectancy < 3 years, which might prevent the participant from completing the study
26.Any factors likely to limit adherence to the study medications and procedures, such as substance abuse, dementia, plans to move within the next 2 years, and/or history of noncompliance with medication or scheduled appointments, and
27.Participation in another clinical study at the time of informed consent, or has received an investigational drug within 90 days before signing the informed consent for this study.

E.5 End points

E.5.1

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Variable as event driven

E.5.2

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..

E.5.2.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Argentina

Brazil

Canada

Colombia

India

Israel

Japan

Mexico

South Africa

United States

France

Poland

Bulgaria

Netherlands

Romania

Spain

Czechia

Germany

Denmark

Hungary

Russian Federation

Slovakia

Ukraine

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

Post-study Safety Call up to 30 days after the Common Study End Date (CSED) Visit. The CSED Visit will occur after 1,304 adjudicated and confirmed primary endpoint events have accrued.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

4000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

6000

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

405

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3903

F.4.2.2

In the whole clinical trial

10000

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of care, not provided by Sponsor.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-04-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-06-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-07-27

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