Vascular and Renal Impact of ENDOTHELIN-1 Receptor Blockade in Patients with Uncontrolled Arterial Hypertension - ENDOTHELIN-2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Rouen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

Decision date (initial)

2024-08-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515928-36-00

EudraCT number

2019-002334-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

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 uncontrolled hypertension.

Secondary objectives 3

1. Evaluate the effect of administration of an ET-1 receptor antagonist for 8 weeks on systemic and central hemodynamics
2. Evaluate the effect of administration of an ET-1 receptor antagonist for 8 weeks on local concentrations of endothelial factors during a sustained increase in blood flow
3. Evaluate the effect of administration of an ET-1 receptor antagonist for 8 weeks on renal function and natriuresis.

Conditions and MedDRA coding

Uncontrolled arterial hypertension

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. age between 30 and 80 years old
2. Patients with uncontrolled 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 in a medical clinic.
3. Patients with uncontrolled hypertension confirmed by selfmeasurement (≥135 / 85 mmHg on average) or by ambulatory blood pressure measurement (mean of 24h ≥130 / 80 mmHg).
4. Hemoglobin level > 11 g / dL
5. 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).
6. For postmenopausal women: confirmatory diagnosis (non-medically induced amenorrhea for at least 12 months and age greater than 45, before the inclusion visit)
7. Patient who read and understood the newsletter and signed the consent form
8. Patient affiliated to a social security scheme

Exclusion criteria 19

1. Patients with secondary hypertension other than sleep apnea syndrome or stage 2 or 3 chronic renal failure. Are sought: - stenosis of the renal arteries for subjects under 50 years old. - primary hyperaldosteronism, an endocrine cause (hypercortisolism, pheochromocytoma), a toxic cause (consumption of glycerrhizide, cannabis drugs, heroin, treatments with anti-inflammatories, corticosteroids), a genetic cause (Liddle syndrome) for subjects under the age of 40 years.
2. Patients with arterial hypertension greater than or equal to 180/110 mmHg associated with symptoms suggesting the diagnosis of malignant hypertension.
3. Chronic renal failure stages 4 and 5 (defined by a CKD-EPI GFR < 30 ml/min/1.73m² less than 3 months old)
4. Renal transplant patient
5. Patient with a history of stroke, TIA, acute coronary syndrome or hospitalization for heart failure in the 3 to 6 months preceding the inclusion visit.
6. Patient with chronic heart failure NYHA III-IV.
7. Early initiation of treatment with hematopoietic growth factors (HCF)
8. Patient with a confirmed potassium level < 3.5 mEq/L or > 5.5 mEq/L
9. Patient with viral liver disease
10. Patient with unbalanced diabetes (HbA1c >7.5%)
11. Patient with proteinuria > 1g/g creatininuria
12. Orthostatic hypotension (decrease in SBP > 20mmHg and/or DBP >10 mmHg occurring within 3 minutes following standing).
13. Contraindication to NATISPRAY 0.30 mg/dose, solution for oral spray: - Hypersensitivity to nitrates or to one of the excipients. - State of shock, severe hypotension. - In combination with sildenafil, taladafil, vardenafil, avanafil and riociguat. - Obstructive cardiomyopathy. - Lower site myocardial infarction with extension to the right ventricle, in the acute phase, except in cases of signs of left ventricular failure. - Intracranial hypertension.
14. Contraindication to BOSENTAN VIATRIS 62.5 mg and 125 mg, film-coated tablet: - Hypersensitivity to the active substance or to one of the excipients mentioned in the SmPC. - Moderate to severe hepatic impairment corresponding to class B or C of the Child-Pugh classification. - Serum levels of hepatic aminotransferases, AST and/or ALT > 3 times the upper limit of normal at the start of treatment (results less than 3 months old). - Association with cyclosporin A.
15. Known allergy or intolerance to cellulose.
16. Patients treated with: tacrolimus or sirolimus, ciclosporin, fluconazole or other CYP2C9 or CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, clarithromycin, erythromycin, telithromycin), glibenclamide, antiretroviral drugs including lopinavir + ritonavir, warfarin, simvastatin, enol , sildenafil, digoxin, rifampin, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone.
17. Premenopausal woman whose contraception is contraception other than a copper intrauterine device.
18. Person deprived of liberty by an administrative or judicial decision or person placed under judicial protection, guardianship or curatorship.
19. Patient participating or having participated in the 4 weeks preceding inclusion in a clinical trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 8-week change in amplitude of endothelium-dependent radial artery dilatation with sustained increase in blood flow

Secondary endpoints 3

1. 8 week change in peripheral and central arterial pressures and arterial stiffness
2. 8-week change in local concentrations of NO, EETs and ET-1 with sustained increase in blood flow
3. Variation in 8 weeks of natriuresis and measured glomerular filtration rate (DTPA labeled by the technetium 99m)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Rouen

Sponsor organisation

Centre Hospitalier Universitaire Rouen

Address

1 Rue De Germont, Bp 96031 Bp 96031

City

Rouen Cedex

Postcode

76031

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Public contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications