Eplerenone Impact on Echocardiographic Abnormalities in Kidney Transplant Recipients Under Calcineurin Inhibitors: A Randomized Controlled Trial
- Trial ID
- 2024-515860-29-00
- Protocol
- 2019PI092
- Sponsor
- CHRU De Nancy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized controlled trial is to evaluate the impact of a 36-week administration of **eplerenone** on a hierarchical composite endpoint, which includes major cardiovascular events and cardiac structural changes in kidney transplant recipients who have been receiving calcineurin inhibitors for more than one year. This is clinically relevant as it aims to determine the potential benefits of mineralocorticoid receptor blockade in reducing cardiovascular complications, which are a significant concern in this patient population.
Secondary objectives include assessing the impact of eplerenone on various parameters in the same patient group:
- Left ventricular systolic and diastolic cardiac function
- Peripheral blood pressure
- Natriuretic peptides
- Biomarkers of fibrosis
- Endothelial dysfunction
- Graft function
- Risk of severe hyperkalaemia
- Risk of acute renal failure
- Association of biological characteristics with echocardiographic characteristics in both randomized and non-randomized patients
Participants
The clinical trial involves **kidney transplant** recipients who have been on calcineurin inhibitors for more than one year. The study population includes both male and female participants aged 18 years and older. Participants are required to have a stable clinical and biological status for at least three months, with no recent changes in treatment affecting blood pressure and no acute graft rejection within the same period. They must also have a glomerular filtration rate (GFR) of at least 40 ml/min/1.73m², measured within the last month, and specific echocardiographic abnormalities. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants involved in the study. Participants are expected to maintain their current lifestyle, including any antihypertensive treatment, as long as it does not interfere with the trial's objectives. The selection criteria ensure that participants are suitable for assessing the impact of eplerenone on cardiovascular outcomes and cardiac structural changes.
Plans and Procedures
The clinical trial is designed as a **randomized, controlled** study to evaluate the impact of **eplerenone**, a mineralocorticoid receptor antagonist, on echocardiographic abnormalities in patients who have undergone **kidney transplantation** and are receiving calcineurin inhibitors. The trial will span a total duration of 36 weeks, with participants receiving a maximum daily dose of 50 mg of eplerenone administered orally. The primary objective is to assess the effect of eplerenone on a hierarchical composite endpoint, which includes major cardiovascular events and cardiac structural changes. The primary endpoint will be evaluated using the win ratio method, prioritizing death or hospitalization for heart failure or acute coronary syndrome, followed by variations in indexed left ventricular mass and left atrial volume.
Participants will be involved in the study for the entire 36-week period unless early termination is warranted due to adverse events, non-compliance, or withdrawal of consent. The study will commence with an inclusion visit, where eligibility criteria such as age, stable clinical and biological status, and specific echocardiographic abnormalities will be confirmed. Follow-up visits will occur at 12 and 36 weeks to monitor the evolution of parameters such as systolic function, blood pressure, Nt-ProBNP concentration, collagen biomarkers, and endothelial dysfunction markers. The end-of-study visit will coincide with the 36-week follow-up, where the primary and secondary endpoints will be assessed.
Inclusion criteria require participants to be adults aged 18 or older, with a stable renal transplant for at least one year, and on long-term ciclosporin or tacrolimus therapy. Participants must have a stable clinical and biological situation for at least three months, with no recent changes in treatment affecting blood pressure or acute graft rejection. Exclusion criteria are not explicitly detailed in the provided data. The trial is not categorized as low intervention and is classified as a phase 3 study, emphasizing the necessity to evaluate the treatment's impact on echocardiographic abnormalities in this patient population.
Treatment
The clinical trial involves the administration of **Eplerenone**, a pharmaceutical agent classified as an antagonist of aldosterone. The experimental medication is provided in the form of a **tablet** and is administered **orally**. The maximum daily dosage of Eplerenone is set at 50 mg, with a total maximum dose of 12.6 grams over the course of the study. The treatment period is defined as 36 weeks. The medication is packaged in a box containing 50 tablets, specifically labeled for the trial. Eplerenone is a chemically derived active substance, identified by the code SUB06574MIG, and is not formulated for pediatric use.
In this study, Eplerenone is evaluated for its impact on echocardiographic abnormalities in kidney graft recipients who are under treatment with calcineurin inhibitors, such as cyclosporine or tacrolimus. The trial aims to assess the effect of Eplerenone on a composite endpoint that includes major cardiovascular events and cardiac structural changes. The study does not involve any non-experimental treatments such as a placebo or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
Efficacy
Efficacy in this clinical trial will be assessed through a hierarchical composite endpoint evaluated at 36 weeks. The primary endpoint includes, in order of priority: death or hospitalization for heart failure or acute coronary syndrome, variation in indexed left ventricular mass (LVMi), and variation in indexed left atrial volume. The win ratio method will be employed to evaluate these criteria. Secondary endpoints will include the evolution of parameters of systolic function such as left ventricular ejection fraction (LVEF) and strain, remodeling of left ventricular and atrial volumes, and filling pressures including E/e', deceleration time, and pulmonary artery systolic pressure (PAPs) at 36 weeks. Additionally, the evolution of peripheral systolic and diastolic blood pressure, peripheral pulse pressure, and Nt-ProBNP concentration will be measured at randomization, 12 weeks, and 36 weeks. Biomarkers of collagen (PICP and PIIINP) and endothelial dysfunction (endothelin, soluble endothelium selectin, von Willebrand factor) will also be assessed at these timepoints. Graft function will be evaluated using serum creatinine levels and estimated glomerular filtration rate (eGFR) according to the CKD-EPI formula, alongside proteinuria measurements. The occurrence of hyperkalemia and the risk of acute renal failure, defined by an increase in creatinine greater than 50% during the 36-week follow-up, will also be monitored. These assessments will provide comprehensive data on the impact of eplerenone on cardiovascular and renal outcomes in kidney transplant recipients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men or women ≥ 18 years of age.
- Person who has undergone a prior clinical examination suitable for the clinical trial.
- Renal transplant patient for at least one year.
- Patient on long-term ciclosporin or tacrolimus therapy.
- Patient with a clinical and biological situation stable for at least three months: no change in treatment with a potential impact on blood pressure for 3 months (excluding immunosuppressive therapy) and no acute graft rejection diagnosed within 3 months
- Patient with a GFR estimated according to the CKD-EPI formula ≥40ml/min/1.73m2 less than one month old.
- Patient with peripheral SBP≥110mmHg, regardless of whether or not antihypertensive treatment (including ACE inhibitor or sartan) is being used.
- With the following echocardiographic abnormalities on trans-thoracic echocardiography performed at inclusion: - Indexed LV mass > 88 g/m2 in women or > 102 g/m2 in men, - And/or Left atrial volume > 34 ml/m2.
- Patient signed informed consent.
- Patient affiliated to a social security scheme or beneficiary of such a scheme.
Exclusion Criteria
- Patient transplanted more than 5 years.
- Patient in permanent atrial fibrillation.
- Patient with valve disease grade 3 or higher.
- A patient whose risk of mortality is considered to be very high in the following year.
- Patients with documented kalaemia ≥ 5mmol/L in the month before or on long-term potassium chelating resins.
- Blood bicarbonate level < 20mmol/L with or without documented supplementation in the month before.
- Patient under mineralocorticoid receptor antagonist or with formal indication to receive this treatment.
- Patient receiving another potassium-sparing diuretic.
- Patients receiving a combination of ACE inhibitors and sartan.
- Patients treated with digoxin.
- Left ventricular ejection fraction <40% on echocardiography at inclusion.
- Planned ligature of the arteriovenous fistula in the coming year.
- Known hypersensitivity or allergy to eplerenone and its excipients.
- Patients with severe hepatic impairment (Child-Pugh class C).
- Patient treated with a potent CYP3A4 inhibitor (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone).
- Patients with known galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome.
- Patients with a contraindication to Kayexalate: history of hypersensitivity to polystyrene sulphonate resins, obstructive intestinal pathology or laxative treatment with sorbitol.
- A woman of childbearing age without an effective contraceptive device : A woman is considered to be of childbearing age, i.e., fertile, from the onset of her first menstruation until she becomes menopausal, unless she is permanently sterile. An effective contraceptive method is considered to be: estrogen-progestogen hormonal contraception that inhibits ovulation, administered orally, intravaginally, or transdermally; or progestogen-only hormonal contraception that inhibits ovulation, administered orally, by injection, or implant; or intrauterine device (IUD) or hormonal IUD; or tubal ligation; or male partner with vasectomy; or sexual abstinence.
- Women wishing to become pregnant within 12 months.
- Patient taking part in other therapeutic interventional research.
- Pregnant woman, parturient or breast-feeding mother
- Minor child (not emancipated)
- An adult subject to a legal protection measure (guardianship, curatorship, safeguard of justice)
- Persons deprived of their liberty by a judicial or administrative decision.
- Patient unable to express consent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 02 May 2025 | 132 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
EPLERENONE | Test | — | ORAL | 50 | 36 | SUB06574MIG |