The Effect of Eplerenone on the Evolution of Vasculopathy in Renal Transplant Patients. (EVATRAN)

A Randomized Crossover Clinical Trial Regarding the Blockage of the Mineralocorticoid Receptor Using Eplerenone on the Evolution of Arterial Stiffness in Kidney Patients One Year After Transplant

Cardiovascular (CV) pathologies are the leading cause of death in kidney transplant patients.Arterial stiffness is a prognostic factor for CV mortality in kidney transplantation. Despite a reduced CV risk in transplant kidney patients in comparison to patients in dialysis, CV mortality among kidney transplant patients is much higher than the general population.

After renal transplantation, the cardiac and vascular anomalies observed in chronic end-stage renal disease are partially improved because of restored normal kidney function and withdrawal from dialysis.

However, patients are exposed to immunosuppressive drugs, in particular calcineurin inhibitors, which can be associated with vascular toxicity, either directly or by promoting the appearance of hypertension, diabetes, or dyslipidemia.The pathophysiology of arterial stiffness in kidney transplantation is complex and multifactorial.

Calcineurin inhibitors are likely to play an important role in the persistence of increased arterial stiffness in transplant patients in whom renal function has been restored. Indeed, the discontinuation of anti-calcineurins in favour of other molecules .is associated with a decrease of arterial stiffness.

Preclinical work has shown that the vascular toxicity of cyclosporine is mediated by activation of the mineralocorticoid receptor in smooth muscle cells. The involvement of the mineralocorticoid receptor in the onset of arterial stiffness is also well demonstrated in non-transplanted subjects.

Blocking the mineralocorticoid receptor in patients under cyclosporine may reduce their arterial stiffness and in and consequently improve their CV prognosis.

Studies have show a good safety in kidney transplant patients. This pilot study proposes to examine, for the first time, the impact of treatment with a mineralocorticoid receptor antagonist on the evolution of arterial stiffness in renal transplant patients on calcineurin inhibitors.

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplantation for More Than One Year; Patients With a Kidney Transplantation on Cyclosporine
• Intervention / Treatment: Drug: Eplerenone 50mg/day (cross over design); Other: Period without eplerenone (cross over design)

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sophie GIRERD, MD-phD; Phone Number: +33 (0) 3 83 15 73 22; Email: s.girerd@chru-nancy.fr

Study Locations

• France
  • Vandœuvre-lès-Nancy, France, 54500
    • Recruiting
    • CHRU de Nancy
    • Contact: Sophie GIRERD, MD; Phone Number: +33 (0) 3 83 15 73 22; Email: s.girerd@chru-nancy.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women ≥ 50 years of age;
• Patient who had a kidney transplant at least one year prior to inclusion;
• Patient on cyclosporine;
• Patient whose clinical-biological state has been stable for at least 3 months: no change in treatment with an impact on blood pressure (excluding immunosuppressive drug) for 3 months, no acute rejection diagnosed within 3 months;
• Patient with a glomerular filtration rate estimated according to the formula CKD-EPI ≥30mL/min/1.73m2;
• Patient with a peripheral PAS≥110mmHg, irrespective of the presence or not of an antihypertensive therapy (including ACE inhibitors or sartan) ;
• Patient with signed informed consent;
• Patient affiliated with or beneficiary of a social security system.

Exclusion Criteria:

• Patient with documented kalemia ≥ 5mmol/L in the last 15 days;
• Patient undergoing mineralocorticoid receptor antagonism or with a formal indication to receive this treatment;
• Bicarbonate blood level <20mmol/L with or without documented supplementation in the last 15 days.
• Indication for a combination of ACE inhibitor and sartan (each of which is authorized separately);
• Patient under another potassium sparing diuretics;
• Patient under digoxine;
• Sodium polystyrene sulfonate contraindication;
• Known hypersensitivity or allergy to eplerenone and its excipients;
• Patient with severe hepatic impairment (Child-Pugh Class C);
• Patient under CYP3A4 inhibitor;
• know intolerance to Galactose, a Lapp lactase deficiency or galactose malabsorption syndrome;
• Patient participating in other interventional research;
• Woman with a desire of pregnancy within 15 months;
• Woman of childbearing age without effective contraception;
• Persons referred to in Articles L. 1121-5, L. 1121-7 and L1121-8 of the Public Health Code :
• Pregnant women, parturient women or nursing mothers ;
• Adult person subject to a legal protection measure (guardianship, curator, judicial safeguard);
• Adults person who is unable to give consent and who is not subject to a legal protection measure;
• Persons deprived of their liberty by a judicial or administrative decision;
• Persons subject to psychiatric care pursuant to articles L. 3212-1 and L. 3213-1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Eplerenone group A (cross over design); Patient will receive eplerenone 50mg/day taken orally for 6 months, followed by a 8 to 10 weeks wash-out period, then a 6-month period without eplerenone, until the end of the study.	Drug: Eplerenone 50mg/day (cross over design); Eplerenone 50mg/day for 6 months followed; Other: Period without eplerenone (cross over design); 6-month period without eplerenone
Active Comparator: Eplerenone group B (cross over design); Eplerenone-free for 6 months, followed by a 8 to 10 weeks wash-out period, then a 6-month period in which patients will receive eplerenone 50 mg/day as a single dose taken orally.	Drug: Eplerenone 50mg/day (cross over design); Eplerenone 50mg/day for 6 months followed; Other: Period without eplerenone (cross over design); 6-month period without eplerenone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evolution of pulse wave velocity (PWV in m/s) adjusted to the blood pressure	After 6 months of treatment with eplerenone

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of Central Systolic Blood Pressure (CSPc)		After 6 months of treatment with eplerenone
Evolution of central Diastolic Blood Pressure (CDAb)		After 6 months of treatment with eplerenone
Evolution of Central Pulsed Pressure (CPp)		After 6 months of treatment with eplerenone
Evolution of Augmentation index (Aix in %)		After 6 months of treatment with eplerenone
Evolution peripheral systolic blood pressure (PASp in mmHg)		After 6 months of treatment with eplerenone
Evolution of peripheral diastolic blood pressure (PADp in mmHg)		After 6 months of treatment with eplerenone
Evolution of peripheral pulse pressure (PPp in mmHg)		After 6 months of treatment with eplerenone
Evolution of Intima-media thickness (in mm)		After 6 months of treatment with eplerenone
Evolution of left ventricular mass (LVM in g/m2)		After 6 months of treatment with eplerenone
Evolution of biological markers of oxidative stress (plasma Isoprostane)		After 6 months of treatment with eplerenone
Evolution of biological markers of oxidative stress (Malondialdehyde)		After 6 months of treatment with eplerenone
Evolution of Biological markers of endothelial dysfunction (endothelin)		After 6 months of treatment with eplerenone
Evolution of biological markers of endothelial dysfunction (soluble endothelium selectin (sE-selectin))		After 6 months of treatment with eplerenone
Evolution of biological markers of endothelial dysfunction (von Willebrand factor)		After 6 months of treatment with eplerenone
Evolution of graft function	measured by creatinine (in micromol/L) with estimation of glomerular filtration rate (eGFR in mL/min/1.73m2 ) according to the CKD-EPI formula.	After 6 months of treatment with eplerenone
Evolution of proteinuria	measured by the ratio proteinuria/creatinuria (in mg/g)	After 6 months of treatment with eplerenone
Percentage of patients with DFG ≥ 90, 60-89, 45-59, 30-44, 15-29 <15ml/min/1,73m2		After 6 months of treatment with eplerenone
Percentage of patient with ratio proteinuria/creatinuria (en mg/g) <500 ; 500-1000, 1000-2000, 2000-3000, >3000		After 6 months of treatment with eplerenone
hyperkalemia occurence ≥ 5.5 mmol/L		during 6 month of treatment with eplerenone
Number of hyperkalemia	number of hyperkalemias during hyperkalemia follow-up between 5 - 5.49; 5.5 - 6; >6mmol/L	during 6 month of treatment with eplerenone
increase of creatinine of more than 50%	Evaluation of risk of acute renal failure defined as an increase in creatinine of more than 50%	during 6 month of treatment with eplerenone

Collaborators and Investigators

• Sponsor: Pr. Nicolas GIRERD
• Investigators: Study Chair: Nicolas GIRERD, MD-Phd, Central Hospital, Nancy, France; Principal Investigator: Sophie GIRERD, MD-PhD, Central Hospital, Nancy, France

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2021
• Primary Completion (Anticipated): March 1, 2026
• Study Completion (Anticipated): March 1, 2026

Study Registration Dates

• First Submitted: June 25, 2020
• First Submitted That Met QC Criteria: June 25, 2020
• First Posted (Actual): June 30, 2020

Study Record Updates

• Last Update Posted (Actual): August 19, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone
• Other Study ID Numbers: 2019-004243-74

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No