Clinical Trials Register

Summary
EudraCT Number:	2019-002334-36
Sponsor's Protocol Code Number:	2018/350/HP
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:	2019-08-30
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

2019-002334-36

A.3

Full title of the trial

VASCULAR AND RENAL IMPACT OF ENDOTHELIN-1 RECEPTOR BLOCKADE IN PATIENTS WITH RESISTANT ARTERIAL HYPERTENSION

IMPACT VASCULAIRE ET RENAL DU BLOCAGE DES RECEPTEURS DE L'ENDOTHELINE-1 CHEZ DES PATIENTS ATTEINTS D'HYPERTENSION ARTERIELLE RESISTANTE

A.3.1

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

VASCULAR AND RENAL IMPACT OF ENDOTHELIN-1 RECEPTOR BLOCKADE IN PATIENTS WITH RESISTANT ARTERIAL HYPERTENSION

IMPACT VASCULAIRE ET RENAL DU BLOCAGE DES RECEPTEURS DE L'ENDOTHELINE-1 CHEZ DES PATIENTS ATTEINTS D'HYPERTENSION ARTERIELLE RESISTANTE

A.3.2

Name or abbreviated title of the trial where available

ENDOTHELIN-2

A.4.1

Sponsor's protocol code number

2018/350/HP

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	CHU de Rouen
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	CHU de Rouen
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	CHU de Rouen
B.5.2	Functional name of contact point	POURCHER
B.5.3	Address:
B.5.3.1	Street Address	1 rue de Germont
B.5.3.2	Town/ city	ROUEN
B.5.3.4	Country	France
B.5.4	Telephone number	+33232888265
B.5.5	Fax number	+33232 88 8287
B.5.6	E-mail	secretariat.drc@chu-rouen.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	BOSENTAN MYLAN
D.2.1.1.2	Name of the Marketing Authorisation holder	MYLAN SAS
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	BOSENTAN MYLAN
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Resistant arterial hypertension

Hypertension artérielle résistante

E.1.1.1

Medical condition in easily understood language

Resistant arterial hypertension

Hypertension artérielle résistante

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10038466
E.1.2	Term	Renal hypertension and related conditions
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10038465
E.1.2	Term	Renal hypertensions
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10038464
E.1.2	Term	Renal hypertension
E.1.2	System Organ Class	10038359 - Renal and urinary 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

The main objective of the study is to assess the effect of ET-1 receptor antagonist administration during 8 weeks on endothelial function in patients with resistant hypertension.

L'objectif principal de l'étude est d'évaluer l'effet de l'administration d'un antagoniste des récepteurs de l'ET-1 pendant 8 semaines sur la fonction endothéliale de patients atteints d'hypertension artérielle résistante.

E.2.2

Secondary objectives of the trial

The secondary objectives are to assess the effect of the administration of an ET-1 receptor antagonist during 8 weeks:
- on systemic and central hemodynamics
- on local concentrations of endothelial factors during a sustained increase of the blood flow
- on the renal function of patients with resistant hypertension.

Les objectifs secondaires sont d'évaluer l'effet de l'administration d'un antagoniste des récepteurs de l'ET-1 pendant 8 semaines :
- sur l'hémodynamique systémique et centrale
- sur les concentrations locales des facteurs endothéliaux lors d'une augmentation soutenue du débit sanguin
- sur la fonction rénale de patients atteints d'hypertension artérielle résistante.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• age between 30 and 80 years old
• Patients with resistant hypertension defined according to the criteria recognized by the French Society of Hypertension (SFHTA): arterial pressure greater than or equal to 140 and / 90 mm Hg under triple antihypertensive trithérapie at optimal dose comprising at least one diuretic pendant at less than 4 weeks.
• Patients with resistant hypertension confirmed by self-measurement (≥135 / 85 mmHg on average) or by ambulatory blood pressure measurement (mean of 24h ≥130 / 80 mmHg).
• Hemoglobin level ≥ 12 g / dL
• For women of childbearing potential, reliable methods of contraception (as defined by the WHO-Pearl Index) should be used (hormonal contraception should not be the only contraceptive method used during bosentan treatment).
• For postmenopausal women: confirmatory diagnosis (non-medically induced amenorrhea for at least 12 months and age greater than 45, before the inclusion visit)
• Patient who read and understood the newsletter and signed the consent form
• Patient affiliated to a social security scheme

- Patients âgés de 30 à 80 ans
• Patients atteints d'hypertension artérielle résistante définie selon les critères reconnus par la société française d'hypertension artérielle (SFHTA) : pression artérielle supérieure ou égale à 140 et/ 90 mm Hg sous trithérapie antihypertensive à dose optimale comprenant au moins un diurétique pendant au moins 4 semaines.
• Patients ayant une hypertension artérielle résistante confirmée par automesure tensionnelle (≥135/85 mm Hg en moyenne) ou par mesure ambulatoire de la pression artérielle (moyenne des 24h ≥130/80 mm Hg).
• Taux d’hémoglobine ≥ 12 g/dL
• Pour les femmes en âge de procréer, des méthodes de contraception fiables (selon la définition de l’OMS-indice de Pearl) doivent être utilisées (une contraception hormonale ne doit pas être la seule méthode contraceptive utilisée pendant le traitement par bosentan).
• Pour les femmes ménopausées : diagnostic de confirmation (aménorrhée non médicalement induite depuis au moins 12 mois et âge supérieur à 45 ans, avant la visite d’inclusion)
• Patient ayant lu et compris la lettre d’information et signé le formulaire de consentement
• Patient affilié à un régime de sécurité sociale

E.4

Principal exclusion criteria

Patients aged 30 to 80 years
• Patients with hypertension • Patients with secondary arterial hypertension other than sleep apnea syndrome or chronic renal failure stage 2 or 3.
• Patients with hypertension greater than or equal to 180 and / or 110mmHg
• Chronic renal failure stage 4 and 5 (defined by DFG CKD-EPI <30
ml / min / 1,73m²)
• Renal transplant patient
• Orthostatic hypotension (decreased SBP> 20mmHg and / or DBP> 10mmHg occurring within 3 minutes of standing).
• Contra-indication to NATISPRAY 0.30 mg / dose, oral spray solution (including nitrate hypersensitivity) in accordance with the NATISPRAY SPC:
o shock, severe hypotension,
o in combination with sildenafil
o obstructive cardiomyopathy,
o inferior court inferior myocardial infarction with right ventricular extension, except in case of evidence of left ventricular failure,
o intracranial hypertension,

• Contra-indication to BOSENTAN MYLAN 62.5 mg and 125 mg film-coated tablets:
o Hypersensitivity to the active substance or to any of the excipients listed in the SPC
Moderate to severe hepatic insufficiency corresponding to class B or C of the Child-Pugh classification
o Serum levels of liver aminotransferases, ASAT and / or ALAT> 3 times the upper limit of normal at start of treatment (results less than 3 months old).
o Association with ciclosporin A
• Known allergy to cellulose
• Patients treated with: tacrolimus or sirolimus, fluconazole or other CYP2C9 or CYP3A4 inhibitors, glibenclamide, rifampicin, antiretroviral drugs including lopinavir + ritonavir, warfarin, simvastatin, ketoconazole, epoprostenol, sildenafil and digoxin
• Pregnant, breastfeeding woman, or woman of childbearing potential not using reliable methods of contraception (hormonal contraception should not be the only contraceptive method used during bosentan treatment) or no proven reliable effective contraception;
• Person deprived of liberty by an administrative or judicial decision or person placed under the protection of justice, under tutorship or curatorship
• Patient participating or having participated in the 4 weeks prior to inclusion in a clinical trial

•Patients ayant une hypertension artérielle secondaire autre qu'un syndrome d'apnée du sommeil ou une insuffisance rénale chronique stade 2 ou 3.
• Patients ayant une hypertension artérielle supérieure ou égale à 180 et/ou 110mmHg
• Insuffisance rénale chronique de stade 4 et 5 (définie par un DFG CKD-EPI<30ml/min/1,73m²)
• Patient transplanté rénal
• Hypotension orthostatique (diminution de la PAS > 20mmHg et/ou de la PAD >10 mmHg survenant dans les 3 minutes suivant un passage en position debout).
• Contre-indication au NATISPRAY 0,30 mg/dose, solution pour pulvérisation buccale (et notamment hypersensibilité aux dérivés nitrés) conformément au RCP du NATISPRAY :
o état de choc, hypotension sévère,
o en association au sildénafil
o cardiomyopathie obstructive,
o infarctus du myocarde de siège inférieur avec extension au ventricule droit, à la phase aiguë, sauf en cas de signe d'insuffisance ventriculaire gauche,
o hypertension intra-crânienne,
• Contre-indication au BOSENTAN MYLAN 62,5 mg et 125 mg, comprimé pelliculé :
o Hypersensibilité à la substance active ou à l’un des excipients mentionnés au RCP
o Insuffisance hépatique modérée à sévère correspondant à la classe B ou C de la classification de Child-Pugh
o Taux sériques des aminotransférases hépatiques, ASAT et/ou ALAT > 3 fois la limite supérieure de la normale à la mise en route du traitement (résultats datant de moins de 3 mois).
o Association à la ciclosporine A
• Allergie connue à la cellulose
• Patients traités par : tacrolimus ou sirolimus, fluconazole ou autres inhibiteurs du CYP2C9 ou CYP3A4, glibenclamide, rifampicine, médicaments antirétroviraux dont lopinavir + ritonavir, warfarine, simvastatine, kétoconazole, époprosténol, sildénafil et digoxine
• Femme enceinte, allaitante, ou femme en âge de procréer n’utilisant pas de méthodes fiables de contraception (une contraception hormonale ne doit pas être la seule méthode contraceptive utilisée pendant le traitement par bosentan) ou absence de contraception efficace fiable avérée;
• Personne privée de liberté par une décision administrative ou judiciaire ou personne placée sous sauvegarde de justice, sous tutelle ou curatelle
• Patient participant ou ayant participé dans les 4 semaines précédant son inclusion à un essai clinique

E.5 End points

E.5.1

Primary end point(s)

8-week change in amplitude of endothelium-dependent radial artery dilatation with sustained increase in blood flow

Variation en 8 semaines de l'amplitude de la dilatation endothélium-dépendante de l'artère radiale lors d'une augmentation soutenue du débit sanguin

E.5.1.1

Timepoint(s) of evaluation of this end point

8 weeks

8 semaines

E.5.2

Secondary end point(s)

- 8 week change in peripheral and central arterial pressures and arterial stiffness
- 8-week change in local concentrations of NO, EETs and ET-1 with sustained increase in blood flow
- Variation in 8 weeks of natriuresis and measured glomerular filtration rate (DTPA labeled by the technetium 99m)

- Variation en 8 semaines des pressions artérielles périphériques et centrales et de la rigidité artérielle
- Variation en 8 semaines des concentrations locales de NO, des EETs et d'ET-1 lors d'une augmentation soutenue du débit sanguin
- Variation en 8 semaines de la natriurèse et du débit de filtration glomérulaire mesuré (DTPA marqué par le techtétium 99m)

E.5.2.1

Timepoint(s) of evaluation of this end point

8 weeks

8 semaines

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

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

Yes

E.8.2.3

Other

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

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

LVLS

DVDP

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

Aucun

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

2020-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-02

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

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