Clinical Trials Register

Summary
EudraCT Number:	2019-004243-74
Sponsor's Protocol Code Number:	CPRC2018/EVATRAN-GIRERD/JL
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-03-31
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2019-004243-74

A.3

Full title of the trial

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:
EVATRAN (The effect of Eplerenone on the evolution of Vasculopathy in renal transplant patients).

Essai randomisé en cross-over du blocage du récepteur minéralocorticoïde par l’éplérénone sur l’évolution de la rigidité artérielle des patients greffés rénaux au-delà d’un an : EVATRAN (effet de la l’Eplérénone sur l’évolution de la VAsculopathie du patient TRANsplanté rénal)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

EVATRAN: Evaluation of the impact of Eplerenone on the VAscular stiffness in kidney TRANsplant récipients

EVATRAN: Etude de l’effet de l’Eplérénone sur l’évolution de la VAsculopathie du patient TRANsplanté rénal

A.3.2

Name or abbreviated title of the trial where available

EVATRAN

A.4.1

Sponsor's protocol code number

CPRC2018/EVATRAN-GIRERD/JL

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Centre Hospitalier Régional Universitaire de Nancy
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Centre Hospitalier Régional Universitaire de Nancy
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre Hospitalier Régional Universitaire de Nancy
B.5.2	Functional name of contact point	Study project manager
B.5.3	Address:
B.5.3.1	Street Address	Rue du Morvan
B.5.3.2	Town/ city	VANDOEUVRE-LES-NANCY
B.5.3.3	Post code	54511
B.5.3.4	Country	France
B.5.4	Telephone number	3303.83.15.52.78
B.5.5	Fax number	3303.83.15.74.51
B.5.6	E-mail	dripromoteur@chru-nancy.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	INSPRA 25 mg or his generics
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Inspra 25 mg or his generics
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EPLERENONE
D.3.9.1	CAS number	107724-20-9
D.3.9.4	EV Substance Code	SUB06574MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with a kidney transplantation for more than one year and on cyclosporine

Patient transplanté rénal depuis au moins un an et sous ciclosporine

E.1.1.1

Medical condition in easily understood language

Patients with a kidney transplantation for more than one year and on cyclosporine

Patient transplanté rénal depuis au moins un an et sous ciclosporine

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10047065
E.1.2	Term	Vascular disorders
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the impact of a six month administration of eplerenone on arterial stiffness, among stable kidney transplant patients on cyclosporine, transplanted for at least one year

Evaluer l’impact de l’administration pendant 6 mois de l’éplérénone sur la rigidité artérielle des patients transplantés rénaux stables, greffés depuis au moins un an sous ciclosporine.

E.2.2

Secondary objectives of the trial

To evaluate the impact of a 6 months administration of eplerenone among kidney transplant patients on cyclosporine :
1. the central blood pressure profile after 6 months of treatment
2. the peripheral blood pressure profile after 3 and 6 months of treatment
3. the carotid intima-media thickness after 6 months of treatment
4. left ventricular hypertrophy after 6 months of treatment
5. oxidative stress after 6 months of treatment
6. endothelial dysfunction after 6 months of treatment
7. the graft function throughout the course of treatment
8. the risk of life-threatening hyperkalaemia throughout the course of treatment
9. the risk of acute renal failure throughout the course of treatment

Evaluer l’impact de l’administration pendant 6 mois de l’éplérénone chez des patients transplantés rénaux sous cyclosporine sur :
1. le profil tensionnel central après 6 mois de traitement ;
2. le profil tensionnel périphérique après 3 et 6 mois de traitement ;
3. l’épaisseur intima-media carotidienne après 6 mois de traitement ;
4. l’hypertrophie ventriculaire gauche après 6 mois de traitement ;
5. Le stress oxydatif après 6 mois de traitement ;
6. La dysfonction endothéliale après 6 mois de traitement ;
7. la fonction du greffon durant toute la durée du traitement ;
8. le risque d’hyperkaliémie menaçante durant toute la durée du traitement ;
9. le risque d’insuffisance rénale aigüe durant toute la durée du traitement.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female ≥ 50 years of age ;
• Patient who had a kidney transplant at least one year prior to inclusion;
• Patient treated with 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 who signed informed consent;
• Patient affiliated with to beneficiary of a social security system.

• Hommes ou femmes âgés > ou = 50 ans ;
• Patient transplanté rénal depuis au moins un an ;
• Patient sous ciclosporine ;
• Patient dont la situation clinico-biologique est stable depuis au moins trois mois : absence de modification du traitement ayant un impact sur la pression artérielle (hors immunosuppresseurs) depuis 3 mois, absence de rejet aigu diagnostiqué dans les 3 mois ;
• Patient ayant un DFG estimé selon la formule CKD-EPI ≥30mL/min/1,73m2 ;
• Patient avec PAS périphérique≥110mmHg, quelle que soit l’existence ou non d’un traitement antihypertenseur (y compris IEC ou sartan) ;
• Patient ayant signé le consentement éclairé ;
• Patient affilié à régime de sécurité sociale ou bénéficiaire d’un tel régime.

E.4

Principal exclusion criteria

• Patient with documented kalemia ≥ 5mmol/L in the last 15 days,
• Bicarbonate blood level <20mmol/L with or without documented supplementation in the last 15 days,
• Patient undergoing mineralocorticoid receptor antagonism or with a formal indication to receive this treatment;
• Indication for a combination of ACE inhibitor and sartan or renin inhibitor (each of which is authorized separately);
Patient undergoing digoxin medication,
• Known hypersensitivity or allergy to eplerenone and its excipients;
• Patient with severe hepatic impairment (Child-Pugh Class C);
Patient treated with potent CYP3A4 inhibitor,
Patient with known galactose intolerance, lactase Lapp deficiency, or glucose, galactose malabsorption syndrom,
• Patient participating in other interventional research;
• Female with a desire of pregnancy for the next 15 months;
• Female 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, curatorship, 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-

• Patient ayant une kaliémie ≥ 5mmol/L datant de moins de 15 jours;
• Taux de bicarbonate sanguin < 20mmol/L avec ou sans supplémentation documenté datant de moins de 15 jours;
• Patient sous antagoniste du récepteur minéralocorticoïde ou avec indication formelle à recevoir ce traitement ;
• Indication impérative d’une combinaison d’IEC et sartan ou inhibiteur de rénine (chacun d’entre eux étant autorisé séparément) ;
Patient sous digoxine,
• Hypersensibilité ou allergie connue à l’éplérénone et à ses excipients ;
• Patient avec une insuffisance hépatique sévère (Classe Child-Pugh C) ;
• Patient en cours de traitement par un inhibiteur puissant du CYP3A4 ;
• Patient connu pour présenter une intolérance au galactose, un déficit en lactase de Lapp ou un syndrome de malabsorption du glucose ou du galactose.
• Patient participant à une autre recherche interventionnelle ;
• Femme ayant un désir de grossesse dans les 15 mois ;
• Femme en âge de procréer ne disposant pas de moyen de contraception efficace ;
• Personnes visées aux articles L. 1121-5, L. 1121-7 et L1121-8 du code de la santé publique.
- Femme enceinte, parturiente ou mère qui allaite ;
- Personne majeure faisant l'objet d'une mesure de protection légale (tutelle, curatelle, sauvegarde de justice) ;
- Personne majeure hors d'état d'exprimer son consentement et qui ne font pas l'objet d'une mesure de protection juridique ;
- Personnes privées de liberté par une décision judiciaire ou administrative ;
- Personnes faisant l'objet de soins psychiatriques en vertu des articles L. 3212-1 et L. 3213-1.

E.5 End points

E.5.1

Primary end point(s)

Evolution of pulse wave velocity (PWV in m/s) adjusted to the blood pressure measured by Sphygmocor®, after 6 months of treatment with eplerenone.

Evolution de la vélocité de l’onde de pouls (VOP en m/s) ajustée sur la pression artérielle mesurée par Sphygmocor®, après 6 mois de traitement par éplérénone.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after treatment with eplerenone

6 mois après traitement par éplérénone

E.5.2

Secondary end point(s)

The secondary objectives will be the evaluation based on evolution after six months of treatment with eplerenone of:
1. Central Systolic Blood Pressure (CSPc), Central Diastolic Blood Pressure (CDAb), Central Pulsed Pressure (CPp), Index of Increase (Aix in %), measured by Sphygmocor® (Atcor medical) applanation tonometry;
2. Peripheral systolic blood pressure (PASp in mmHg), peripheral diastolic blood pressure (PADp in mmHg), peripheral pulse pressure (PPp in mmHg)
3. Intima-media thickness (in mm) measured by Echotracking (ART.LAB, ESAOTE®) ;
4. Left ventricular mass (LVM in g/m2) measured by cardiac ultrasound;
5. Biological markers of oxidative stress (plasma Isoprostane and Malondialdehyde (MDA)) ;
6. Biological markers of endothelial dysfunction (endothelin, soluble endothelium selectin (sE-selectin), von Willebrand factor;
7. Graft function measured by blood creatinine (in micromol/L) with estimation of glomerular filtration rate (DFGe in mL/min/1.73m2 ) according to the CKD-EPI formula as well asproteinuria measured by the ratio proteinuria/creatininuria (in mg/g). The percentage of patients with DFG ≥ 90, 60-89, 45-59, 30-44, 15-29, <15ml/min/1.73m2 will also be evaluated, as well as the percentage of patients with ratio proteinuria/creatininuria <500; 500-1000, 1000-2000, 2000-3000, >3000.

Each variable corresponding to criteria 1 to 4 will be evaluated by the difference in value between the start and end of treatment (absolute change), as well as the percentage change (relative change).

Secondary Objectives 8 and 9 will be evaluated by :
8. the occurrence of hyperkalemia ≥ 5.5 mmol/L and the number of hyperkalemias during hyperkalemia follow-up between 5 - 5.49; 5.5 - 6; >6mmol/L ;
9. the risk of acute renal failure defined as an increase in creatinine of more than 50%.

Les objectifs secondaires 1 à 7 seront évalués par l’évolution après 6 mois de traitement par éplérénone:
1. De la pression artérielle systolique centrale (PASc), la pression artérielle diastolique centrale (PADc), la pression pulsée centrale (PPc), l’index d’augmentation (Aix en %), mesurées par tonométrie d’aplanation Sphygmocor® (Atcor medical) ;
2. De la pression artérielle systolique périphérique (PASp en mmHg), la pression artérielle diastolique périphérique (PADp en mmHg), la pression pulsée périphérique (PPp en mmHg) ;
3. De l’épaisseur intima-media (en mm) mesurée par Echotracking (ART.LAB, ESAOTE®) ;
4. De la masse ventriculaire gauche (MVG en g/m2) mesurée en échographie cardiaque ;
5. Des marqueurs biologiques de stress oxydatif (Isoprostane et Malondialdéhyde (MDA) plasmatiques) ;
6. Des marqueurs biologiques de dysfonction endothéliale (endothéline, soluble endothelium selectin (sE-selectin), von Willebrand factor ;
7. De la fonction du greffon mesurée par la créatinine sanguine (en micromol/L) avec estimation du débit de filtration glomérulaire (DFGe en mL/min/1.73m2) selon la formule CKD-EPI, ainsi que la protéinurie mesurée par le ratio protéinurie/créatininurie (en mg/g). Le pourcentage de patients avec DFG ≥ 90, 60-89, 45-59, 30-44, 15-29, <15ml/min/1,73m2 sera également évalué, ainsi que le pourcentage de patients avec ratio protéinurie/créatininurie (en mg/g) <500 ; 500-1000, 1000-2000, 2000-3000, >3000.

Chaque variable correspondant aux critères 1 à 4 sera évaluée par la différence de valeur entre le début et la fin du traitement (variation absolue), ainsi que par le pourcentage de variation (variation relative).

Les objectifs secondaires 8 et 9 seront évalués par :
8. l’occurrence d’une hyperkaliémie ≥ 5.5 mmol/L et le nombre d’hyperkaliémies au cours du suivi d’une hyperkaliémie entre 5 - 5,49 ; 5,5 - 6 ; >6mmol/L ;
9. le risque d’insuffisance rénale aigüe définie par une majoration de la créatinine de plus de 50%.

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary objectives will be based on evolution after six months of treatment with eplerenone.

Les objectifs secondaires seront évalués par l’évolution après 6 mois de traitement par éplérénone.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Patient sans traitement par éplérénone

patient without eplerenone administration

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visite of last patient (LVLS) which will take place 2 to 3 days after the last dose

Dernière visite du dernier patient inclus dans l'étude réalisée 2 a 3 jours après dernière prise

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

none

prise en charge usuelle à la fin de participation du patient

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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