Cardiovascular Diseases Clinical Trial
— MAGNETICOfficial title:
Physiopathological Study of Genetic Modulation of Cardiovascular Effect of PPAR-Alpha Activation (MAGNETIC-PPARA)
NCT number | NCT05542147 |
Other study ID # | AOP2225 |
Secondary ID | |
Status | Recruiting |
Phase | N/A |
First received | |
Last updated | |
Start date | July 3, 2022 |
Est. completion date | December 31, 2024 |
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.
Status | Recruiting |
Enrollment | 200 |
Est. completion date | December 31, 2024 |
Est. primary completion date | December 31, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Italy | University Hospital of Padova | Padova | Padua |
Lead Sponsor | Collaborator |
---|---|
Mario Luca Morieri |
Italy,
Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, Hastings T, Buranasupkajorn P, Motsinger-Reif AA, Rotroff DM, Sigal RJ, Marcovina SM, Kraft P, Buse JB, Wagner MJ, Gerstein HC, Mychaleckyj JC, Pare G, Doria A. Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial. Diabetes Care. 2018 Nov;41(11):2404-2413. doi: 10.2337/dc18-0709. Epub 2018 Sep 27. — View Citation
Morieri ML, Shah H, Doria A; the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Genetic Study Group. Variants in ANGPTL4 and the Risk of Coronary Artery Disease. N Engl J Med. 2016 Dec 8;375(23):2304-2305. doi: 10.1056/NEJMc1607380. No abstract available. — View Citation
Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, Gao H, Lovato L, Prudente S, Pandolfi A, Pezzolesi MG, Sigal RJ, Pare G, Marcovina SM, Rotroff DM, Patorno E, Mercuri L, Trischitta V, Chew EY, Kraft P, Buse JB, Wagner MJ, Cresci S, Gerstein HC, Ginsberg HN, Mychaleckyj JC, Doria A. PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid. Diabetes. 2020 Apr;69(4):771-783. doi: 10.2337/db19-0973. Epub 2020 Jan 23. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Arterial Stiffness - Augmentation Index (AI) | Differences in fenofibrate induced-changes in AI across rs6008845 genotypes | Baseline and 12 weeks | |
Other | Haematopoietic stem/progenitor cells (HSPCs) | Differences in fenofibrate induced-changes in circulating levels of HSPC across rs6008845 genotypes. | Baseline and 12 weeks | |
Primary | Endothelial Function | 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 | Arterial Stiffness - Pulse Wave Velocity (PWV) | Differences in fenofibrate induced-changes in PWV across rs6008845 genotypes. [PWV is directly associated with risk of cardiovascular disease] | baseline and 12 weeks | |
Secondary | Endothelial progenitor cells (EPCs) | Differences in fenofibrate induced-changes in circulating levels of EPC across rs6008845 genotypes. | baseline and 12 weeks | |
Secondary | Inflammatory markers and chemokines | Differences in fenofibrate induced-changes in CCL11, CCL27 sVCAM, sE-Selectin, Endothelin-1 across rs6008845 genotypes. | baseline and 12 weeks | |
Secondary | Platelet aggregation induced by adenosine diphosphate (ADP) | 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 | |
Secondary | Platelet aggregation induced by arachidonic acid | 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 |
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