Study design
This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion after verification of the inclusion criteria listed in the following section. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo.
Participants
Inclusion criteria
Graft recipients on chronic hemodialysis aged 18 or older will be eligible for inclusion if they:
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Sign the informed consent for study participation
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Are about to receive a single or a dual kidney graft from an ECD (brain-dead donor aged > 60 years or aged 50–59 years with 2+ characteristics among vascular cause of death, medical history of hypertension or serum creatinine > 130 μmol/L) regardless of machine perfusion use and graft rank
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Are affiliated with a medical care system.
Exclusion criteria
Graft recipients will be excluded if they have any of the following conditions:
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Are about to receive multiple organ transplantation involving organs other than kidney
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Are on chronic peritoneal dialysis
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Are not yet on dialysis and are about to receive a preemptive KT
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Have a known hypersensitivity or allergy to eplerenone, its excipients, or lactose
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Have severe cirrhosis (Child-Pugh class C)
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Are receiving potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and/or nefazodone)
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Are receiving a graft from a donor treated with an MRA (spironolactone or eplerenone)
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Have a known hypersensitivity or allergy to iodine contrast products (since iohexol will be used for GFR quantification)
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Have thyrotoxicosis,
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Have undergone human leukocyte antigen (HLA) desensitization
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Are pregnant or do not use an effective means of contraception (for women)
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Are a patient under judicial protection
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Are a patient under tutorship or legal guardianship
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Are already participating in another medical research study.
Participant recruitment
Patients will be included during their hospitalization for KT. The study will be explained to the patients fulfilling the inclusion criteria at admission. Patients will receive a written information document and will have a time delay to decide if they wish to be included in the study (see Additional files 2 and 3). Note that this time delay may be shorter when compared to clinical trials performed in other settings, as the KT may be performed within a few hours after the patient’s admission. There is no minimal prespecified time delay: it is the investigator’s responsibility to ensure that patients had sufficient time to rightfully decide to participate in the study. Inclusion and randomization will be performed when KT scheduling is confirmed, i.e., in the absence of any contraindication for the KT, either related to the recipient, to the graft, or to an immunological issue based on daily or virtual cross-match.
Randomization
Randomization will be provided via the Cleanweb™ system based on a prespecified randomization list using blocks, stratified on centers and machine perfusion use.
Interventions
Timing of administration of the study treatment
The first administration of the study treatment (eplerenone 25 mg or placebo) will be performed within 2 h prior to patient departure to the operating room, usually at the same time as the first administration of immunosuppressive therapy (H0). See Fig. 1. Of note, treatment will be initiated only if a dosage of serum potassium ≤5 mmol/L within the previous 12 h is available.
The remaining study treatment units will be given every 12 h for 4 days; thus, eight treatment units (H0, H12, H24, H36, H48, H60, H72, H84) will ultimately be administered to the patients.
Posology change
No change in treatment dose is planned. If patients experience clinically significant hyperkalemia, treating physicians will apply local protocols (e.g., administer potassium-binding resins, correct metabolic acidosis, and/or schedule a dialysis session).
Premature discontinuation of the study treatment
Study treatment will be discontinued if allergy to eplerenone or excipients is suspected. If the study treatment is discontinued, patients will be followed until the end of the study period. Hyperkalemia will not trigger treatment discontinuation.
Appropriate administration of treatment units
Blister packs will be returned to the hospital pharmacy to verify treatment administration.
Unblinding modalities
Unblinding will be authorized in patients for whom knowing treatment allocation will eventually lead to a modification in management and care. Investigators can call the 24/7 phone number of the Poison Control Center in charge of the study to request unblinding.
Concomitant medication
During the study treatment administration phase (i.e., 4 days), patients cannot receive angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs) and/or renin inhibitors and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and/or potassium-sparing diuretics and/or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, clarithromycin, ritonavir, nelfinavir, etc.).
Concomitant use of cyclosporine or tacrolimus is allowed.
If needed, potassium supplementation is allowed in patients with hypokalemia due to hypokalemic polyuria following graft recovery or loop diuretic use. A close monitoring of serum potassium levels and renal function will be mandatory.
The choice of immunosuppressive therapy modalities and use of dialysis after transplant is left to the discretion of the treating physicians, and the participating centers may use their usual standard practices. The study treatment is considered as a supplementary intervention to improve graft function irrespective of the immunosuppressive regimen.
Study outcomes
The primary outcome of the study is graft function at 3 months assessed by GFR (mL/min/1.73m2) using iohexol clearance. Two hours after intravenous injection of 3.235 × 106 μg iohexol, 5-mL blood samples will be collected every 30 min for 2.5 h. After centrifugation at room temperature (2500 g for 10 min), the plasma will be stored at − 20° until high performance liquid chromatography (HPLC) measurement of iohexol concentration using an ODS C18 ultrasphere Beckman Coulter column 5 μm × 4.6 mm × 250 mm and an ultraviolet spectrophotometer detector at 240 nm (Shimadzu France, Champs s/Marne, France) as previously reported [19]. The plasma clearance of iohexol will be determined by the one-compartment model from the area under the curve of iohexol elimination from the plasma with the formula: Clearance (Cl) = dose/area under curve (AUC). The area will be corrected for the early distribution phase according to Bröchner-Mortensen; the corrected Cl calculated as (0.990778 × Cl) – (0.001218 × Cl) [20] will be used as the actual primary endpoint.
In patients with primary non-function (defined by the necessity for dialysis at 3 months post-KT), an arbitrary value of 5 mL/min will be used as GFR.
Secondary outcomes include:
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1.
The proportion of patients with either dialysis dependency or a GFR < 30 mL/min/1.73m2 at 3 months
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2.
The time delay for graft recovery assessed by:
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The proportion of patients with a DGF defined by the necessity of one or more dialysis sessions during the 7 days following KT
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The proportion of patients with immediate (defined by a serum creatinine < 30 mg/L at 7 days post-KT), slow (defined by a serum creatinine > 30 mg/L at 7 days post-KT without dialysis requirement), or DGF (defined by the necessity of one or more dialysis sessions during the 7 days following KT)
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3.
Twenty-four hour proteinuria and microalbuminuria levels at 3 months
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4.
The occurrence of hyperkalemia > 6 mmol/L during the first week following KT
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5.
The length of hospital stay for the KT (days)
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6.
The occurrence of biopsy-proven acute rejection in the first 3 months following KT
In addition, estimated GFR (eGFR, using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula), graft, and patient survival data will be collected at 1, 3, and 10 years via the French national database of organ recipients (CRISTAL, Agence de la Biomédecine).
Study visits
As presented in Fig. 2, study visits will be performed daily until day 7, then at day 28, and finally at 3 months post-KT for the measurement of the primary outcome. Blood and urinary biological samples retrieved for biobanking purposes will be drawn at day 0 (randomization), day 1, day 7, day 28, and at 3 months.
Adverse effects
The potassium level will be closely monitored throughout the treatment administration period. The serum potassium level must be verified as being ≤ 5 mmol/L in the 12 h prior to the first administration of eplerenone or placebo. Thereafter, the serum potassium level will be measured 6 h after the end of vascular clamping and subsequently twice a day until 48 h after the last administration of treatment (eplerenone or placebo). Thereafter, serum potassium levels will be monitored as typically performed in usual care.
Moreover, patients included in the study will receive the usual care performed during the post-operative KT period, including clinical workups (i.e., measurement of blood pressure, heart rate, and diuresis) as well as biological workups (serum creatinine, hemogram). All adverse events related to iohexol clearance will also be recorded.
Recording of serious adverse events (SAEs) will conform to Good Clinical Practice standards and will be in accordance with French regulation. Suspected unexpected SAEs/reactions will be reported by the attending physician to the sponsor immediately upon first awareness of their existence. It will be the responsibility of the investigators to collect all adverse events (either serious or non-serious) in the case report form (CRF) of the trial, during the follow-up of the patient. Adverse events (either serious or non-serious) will be collected until 48 h after the 3 months visit of the study. Every hyperkalemia episode leading to a supplementary dialysis session will be considered as an SAE. The half-life of eplerenone is short (4 h), and its administration two times a day (b.i.d.) allows its easy discontinuation in case of a non-anticipated adverse event.
Statistical analysis plan
Sample size and power calculation
According to French statistical data (https://www.agence-biomedecine.fr/annexes/bilan2016/donnees/organes/06-rein/synthese.htm), the mean eGFR at 3 months among patients receiving a kidney graft from an ECD is 42 mL/min. Inclusion of 126 patients will allow identifying of a difference of 7 mL/min/1.73 m2 between the two groups (42 mL/min/1.73 m2 in the placebo group and 49 mL/min/1.73 m2 in the eplerenone group), with a standard deviation of 14 mL/min, a two-sided alpha risk of 5%, and a beta risk of 20% (power 80%). Since it is anticipated that 5% of patients could be included but not randomized or could withdraw their consent, we will target the inclusion of 132 patients.
Statistical analysis
The primary outcome, which is to compare the mean measured GFR between the two groups, will be analyzed by a t test for independent samples, after verifying the normality of GFR distribution in each group. In case of non-normality, the non-parametric Mann-Whitney test will be used. An analysis adjusted on stratification factors will then be performed to avoid clustering effects arising from stratification [21].
Secondary outcomes 1, 2, 4, and 6 will be analyzed by a chi-squared test. Secondary outcomes 3 and 5 will be analyzed with a non-parametric Mann-Whitney test for independent groups, given that the distribution of proteinuria levels and length of hospital stay are most likely non-normal.
In the event of clinically significant differences between baseline characteristics of the patients of the two groups, possibly observed despite randomization due to the moderate number of patients in this trial, some explanatory analyses adjusted for these parameters and on stratification factors will be performed and presented in the publication. Linear regression will be used for continuous variables and logistic regression for dichotomous variables.
The results of the trial will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) Statement (see Additional file 1).
Ethical issues
Ethics Committee approval
This study follows the principles of the Declaration of Helsinki and is in accordance with Good Clinical Practice and French regulation. The trial has been approved by the French Health Authorities (Agence nationale de la sécurité du médicament et des produits de santé: ANSM) and the appropriate Ethics Committee (Comité de Protection des Personnes: CPP Est III).
Information and consent forms
The patients are included on the basis of written information and upon signing an informed consent form (see Additional files 2 and 3). The informed consent form specifies that the patient can withdraw from the study at any time without any prejudice with regard to current or future medical treatment.
Interim analyses and study termination rules
An independent Data Safety and Monitoring Board (DSMB) comprising four international experts in kidney transplantation, biostatistics, and pharmacology (Prof. M. Kessler, Prof. D. Anglicheau, Dr. E. Gayat, and Dr. S. Crepin) will be responsible for ensuring the safety of the trial and for monitoring the progress of the research in accordance with the protocol. SAEs will be monitored during DSMB sessions, blinded for the randomization arm. No interim analysis is planned. The DSMB may decide to terminate the trial early for the following reasons: detection of adverse events, poor data quality, low levels of implementation, fraud, or new information which would rule the trial unnecessary, futile, or unethical.
Data quality and regulatory issues
Monitoring of the study
The sponsor of the study — the Nancy University Hospital (Direction de la recherche, CHRU Nancy, Rue du Morvan, 54500 Vandoeuvre les Nancy; phone: 33 3.83.15.52.85, fax: 33 3.83.15.74.51) — will monitor (via quality control and audits) the study in all sites to ensure that compliance with the protocol and applicable regulations is maintained and that data are collected in a timely, accurate, and complete manner. All SAEs will be reported to the French regulatory agency (Agence nationale de la sécurité du medicament et des produits de santé: ANSM). The sponsor will provide yearly security reports to the French regulatory agency and the Ethics Committee.
Data management of the study
Clinical data management is performed at the Nancy Clinical Investigation Center using the Ennov Clinical® v7.5 Electronic Data Capture solution. Individual and secured access is provided to remote users who performed the data entry on the electronic CRF. Edit verifications are performed according to the Data Validation Plan. After database lock, the data will be provided as SAS® files to the statistical team for data analysis under the leadership of the trial’s methodologist.
Data interpretation issues
A steering committee comprising the two co-principal investigators (Dr. F. Jaisser, Dr. S. Girerd), the methodologist of the trial (Dr. N. Girerd), and Prof. P. Rossignol and Prof. L. Frimat will be in charge of the analysis and interpretation of the data as well as manuscript drafting and editing. The sponsor and funders will not have ultimate authority on the decision to submit the report to publication.