MAGNETIC: Genetic-Dependent Cardiovascular Response to PPAR-Alpha Agonist Fenofibrate

Sponsor

Mario Luca Morieri (Other)

Overall Status

Recruiting

CT.gov ID

NCT05542147

Collaborator

(none)

200

Enrollment

Location

Arms

Anticipated Duration (Months)

6.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Cardiovascular Diseases Pharmacogenomic Drug Interaction	Drug: Fenofibrate 145 mg Drug: Placebo	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

Single-blinded for treatment (Participant), double-blinded for genetics (Participant and Investigator)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jul 3, 2022

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Endothelial Function [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].

Secondary Outcome Measures

Arterial Stiffness - Pulse Wave Velocity (PWV) [baseline and 12 weeks]
Differences in fenofibrate induced-changes in PWV across rs6008845 genotypes. [PWV is directly associated with risk of cardiovascular disease]
Endothelial progenitor cells (EPCs) [baseline and 12 weeks]
Differences in fenofibrate induced-changes in circulating levels of EPC across rs6008845 genotypes.
Inflammatory markers and chemokines [baseline and 12 weeks]
Differences in fenofibrate induced-changes in CCL11, CCL27 sVCAM, sE-Selectin, Endothelin-1 across rs6008845 genotypes.
Platelet aggregation induced by adenosine diphosphate (ADP) [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.
Platelet aggregation induced by arachidonic acid [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.

Other Outcome Measures

Arterial Stiffness - Augmentation Index (AI) [Baseline and 12 weeks]
Differences in fenofibrate induced-changes in AI across rs6008845 genotypes
Haematopoietic stem/progenitor cells (HSPCs) [Baseline and 12 weeks]
Differences in fenofibrate induced-changes in circulating levels of HSPC across rs6008845 genotypes.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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