Genetic-Dependent Cardiovascular Response to PPAR-Alpha Agonist Fenofibrate (MAGNETIC)

January 19, 2024 updated by: Mario Luca Morieri

Physiopathological Study of Genetic Modulation of Cardiovascular Effect of PPAR-Alpha Activation (MAGNETIC-PPARA)

Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-a) agonist known to improve diabetic dyslipidemia, has been proposed as a drug to prevent cardiovascular disease (CVD) in type 2 diabetes (T2D). However, the results of clinical trials have been mixed. Supporting the hypothesis that these disappointing results hide a genetic heterogeneity in the CVD response to fenofibrate, a common genetic variant (rs6008845) in the gene coding for PPAR-a has been found to dramatically influence the ability of this drug to reduce CVD events in the ACCORD Lipid trial (PMID:31974142).

The aim of this study is to validate these findings by dissecting the pathways and mechanism through which this variant exerts such a modulatory effect, by means of a randomized clinical trial.

If successful, this project will pave the way to a precision medicine approach to prescribe fenofibrate optimally, offering a cardio-protective drug to those patients that are most likely to experience a robust benefit from this medication.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The main hypothesis of this study is that underlying genetic heterogeneity in the CV response to fibrates can successfully identify subjects with a consistent benefit from this treatment. Supporting this postulate a common genetic variant (rs6008845) in the gene coding for PPAR-alpha has been found to dramatically influence the ability of this drug to reduce CVD events.

This genetic modulation of fenofibrate effectiveness has been found in whites, validated in black participants in the ACCORD Lipid trial, and then replicated in external cohorts. Interestingly, the genetic effect was independent of fenofibrate-induced changes in plasma lipids, suggesting a more complex mechanism of action of fibrates. (PMID:31974142).

Through this randomized study, subjects carrying the different rs6008845 genotypes (TT, TC, CC) will be randomized to receive fenofibrate or placebo for 12 weeks.

The specific aims are:

  • To replicate the previous "rs6008845 by fenofibrate" interaction on MACE, testing the fenofibrate-induced changes in endothelial function, arterial stiffness, and markers of endothelium damage.
  • To evaluate whether the fenofibrate-induced change on circulating biomarkers is modulated by rs6008845 genotypes. This will provide insight into the mechanism(s) behind the rs6008845 modulation of fenofibrate effectiveness by the identification of circulating biomarkers mirroring this genetic effect. Different known actions of fenofibrate, beyond lipid-lowering effects, such as fenofibrate anti-inflammatory and anti-platelet effects will be evaluated.

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
    • Padua
      • Padova, Padua, Italy, 35128
        • Recruiting
        • University Hospital of Padova
        • Contact:
          • Mario Luca Morieri

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Type 2 diabetes with previous cardiovascular events or at least one CV risk factor (hypertension, obesity, smoke, age>65 years)
  • HbA1c < 8%
  • Triglycerides < 200 mg/dl
  • On statin treatments and with LDLcholesterol < 100 mg/dl or at maximum statin-tolerated dose
  • European ancestry (rational: given the relatively small sample size and the ancestry-differences in allele frequency of rs6008845 T allele [i.e. from 65% in whites to 20% in blacks subjects) this criteria allows to limit ethnic-confounding factors that would reduce the probability of success of this physiopathological study aiming to dissect the mechanism of the genetic modulation of fenofibrate effectiveness).

Exclusion Criteria:

  • CKD III stage with eGFR<60 ml/min/1.73
  • Uncontrolled hypertension with systolic blood pressure > 170 mmHg at enrollment.
  • Hereditary muscle disorders
  • Uncontrolled hypothyroidism
  • Elevated alcohol consumption
  • Hepatic failure
  • Allergy to fenofibrate or excipients
  • Acute / chronic pancreatitis
  • Pregnancy and lactation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fenofibrate
1 tablet per day per 12 weeks
Drug: Fenofibrate 145 mg
1 tablet per day
Other Names:
  • Fenofibrate
Placebo Comparator: Placebo
1 tablet per day per 12 weeks
Drug: Placebo
1 tablet per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endothelial Function
Time Frame: baseline and 12 weeks
Differences in fenofibrate induced-changes in Reactive Hyperemia Index (RHI) across rs6008845 genotypes. [RHI is a non-invasive measure of endothelial function, and it is inversely associated with risk of cardiovascular disease].
baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Arterial Stiffness - Pulse Wave Velocity (PWV)
Time Frame: baseline and 12 weeks
Differences in fenofibrate induced-changes in PWV across rs6008845 genotypes. [PWV is directly associated with risk of cardiovascular disease]
baseline and 12 weeks
Endothelial progenitor cells (EPCs)
Time Frame: baseline and 12 weeks
Differences in fenofibrate induced-changes in circulating levels of EPC across rs6008845 genotypes.
baseline and 12 weeks
Inflammatory markers and chemokines
Time Frame: baseline and 12 weeks
Differences in fenofibrate induced-changes in CCL11, CCL27 sVCAM, sE-Selectin, Endothelin-1 across rs6008845 genotypes.
baseline and 12 weeks
Platelet aggregation induced by adenosine diphosphate (ADP)
Time Frame: baseline and 12 weeks
Anti-platelet effects will be evaluated as the differences in fenofibrate induced-changes in platelet aggregation induced by adenosine diphosphate (ADP) (i.e. ADPtest) across rs6008845 genotypes.
baseline and 12 weeks
Platelet aggregation induced by arachidonic acid
Time Frame: baseline and 12 weeks
Anti-platelet effects will be evaluated as the differences in fenofibrate induced-changes in platelet aggregation induced by arachidonic acid (ASPI test) across rs6008845 genotypes.
baseline and 12 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Arterial Stiffness - Augmentation Index (AI)
Time Frame: Baseline and 12 weeks
Differences in fenofibrate induced-changes in AI across rs6008845 genotypes
Baseline and 12 weeks
Haematopoietic stem/progenitor cells (HSPCs)
Time Frame: Baseline and 12 weeks
Differences in fenofibrate induced-changes in circulating levels of HSPC across rs6008845 genotypes.
Baseline and 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mario Luca Morieri

Investigators

  • Principal Investigator: Mario Luca Morieri, MD PhD, University Hospital of Padova

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 3, 2022

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

September 8, 2022

First Submitted That Met QC Criteria

September 13, 2022

First Posted (Actual)

September 15, 2022

Study Record Updates

Last Update Posted (Actual)

January 22, 2024

Last Update Submitted That Met QC Criteria

January 19, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AOP2225

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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