ENDOTHELION Study Group: Effect of Bosentan in NAION Patients (ENDOTHELION)

Effect of Bosentan in Patients With Non Arteritic Ischemic Optic Neuropathy

Acute ischemic optic neuropathy are the second leading cause of optic neuropathy after glaucoma in the population aged over 50 years. The visual prognosis of the condition is unfavorable in the great majority of cases, with significant effects on the visual field and vision. The severity of the unilateral condition is also associated with bilateralization in 15% at 5 years. There is no effective treatment for the acute phase of the disease or to reduce the rate of bilateralization. In this context, it is essential to develop new therapeutic strategies in the acute phase of the disease to reduce the anatomical optic nerve damage.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Optic Neuropathy
• Intervention / Treatment: Drug: bosentan; Drug: placebo

Detailed Description

The main objective of our study will be to compare the treatment with bosentan to placebo for 8 weeks for recovery anatomical criteria (RFNL in OCT, optic atrophy) and functional (visual acuity, visual field). The primary endpoint will be the improvement of the visual field, a major criterion of the affected visual function in this disease.

The evaluation of bosentan will mainly after 8 weeks of treatment in order to assess the effectiveness of drug treatment in the absence of continuous positive airway pressure (set up after three months if necessary, feasible confounding factor for the evaluation of results ), the period of three months is sufficient to assess the anatomical and functional recovery (disappearance of papilledema).

• Study Type: Interventional
• Enrollment (Anticipated): 86
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Christophe Pr CHIQUET, Prof, MD, PhD; Email: CChiquet@chu-grenoble.fr
• Study Contact Backup: Name: BOUZEID Mayssam, PhD; Phone Number: +33 476766660; Email: mbouzeid@chu-grenoble.fr

Study Locations

• France
  • Angers, France, 49100
    • Recruiting
    • University hospital of Angers
    • Contact: Philippe GOHIER, MD; Phone Number: 0241353274; Email: phgohier@chu-angers.fr
    • Sub-Investigator: Frédéric GAGNADOUX, MD
    • Sub-Investigator: Pascaline PRIOU, MD
    • Principal Investigator: Philippe GOHIER, MD
  • Bordeaux, France, 33000
    • Terminated
    • University Hospital of Bordeaux
  • Grenoble, France, 38043
    • Recruiting
    • CHU de Grenoble
  • Grenoble, France, 38043
    • Recruiting
    • University Hospital of Grenoble Michallon
    • Contact: Christophe CHIQUET, MD; Phone Number: 04 76 76 55 16; Email: CChiquet@chu-grenoble.fr
    • Sub-Investigator: Jean-Louis PEPIN, MD
    • Sub-Investigator: Sandrine LAUNOIS-ROLLINAT, MD
    • Sub-Investigator: Bertrand TOUSSAINT, MD
    • Sub-Investigator: Olivier ORMEZZANO, MD
    • Principal Investigator: Christophe CHIQUET, MD
    • Sub-Investigator: Claire GAILLARD-GROLEAS, MD
  • Paris, France, 75019
    • Recruiting
    • Ophtalmological fondation of Rothschild + Bichat Hospital
    • Contact: Catherine VIGNAL, MD; Phone Number: 0148036222; Email: cvignal@fo-rothschild.fr
    • Sub-Investigator: Cédric LAMIREL, MD
    • Sub-Investigator: Marie-Pia ORTHO, MD
    • Principal Investigator: Catherine VIGNAL, MD
  • Paris, France
    • Recruiting
    • Centre National d'Ophtalmologie XV-XX
    • Principal Investigator: Catherine VIGNAL, MD
    • Contact: Catherine VIGNAL, MD; Email: cvignal@club-internet.fr
    • Sub-Investigator: Emmanuel HERON, MD
  • Saint-Etienne, France, 42055
    • Recruiting
    • University Hospital of Saint-Etienne
    • Contact: Philippe GAIN, MD; Phone Number: 0477127793; Email: philippe.gain@univ-st-etienne.fr
    • Contact: Claire GUILLEMOT, MD; Phone Number: 0673169519; Email: claire.guillemot@gmail.com
    • Principal Investigator: Gilles THURET, MD
    • Sub-Investigator: philippe GAIN, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non arteritic ischemic optic neuropathy (NAION) with onset < 21 days
• Age ≥ 50 years old
• Signed informed consent form
• Patients affiliated with a national health insurance scheme or beneficiaries of such a scheme

Exclusion Criteria:

• Pregnant women, women in labour or breast-feeding mother
• Patients with other acute or chronic intercurrent ocular pathology interfering with visual acuity or visual field (diabetes, drug-induced or other retinopathy, other optic neuropathy including uni- or contralateral glaucoma and/or intraocular pressure > 30 mmHg, advanced cataract, corneal opacities, amblyopia < 5/10, severe myopia > -6 diopters, retinal disease)
• Simultaneous bilateral NAAION, 1 month apart or less
• Signs that may raise suspicion of other inflammatory neuropathy: arterial NAAION (Horton's disease), pain on eye movement or any signs suggestive of optic neuritis, known diagnosis of multiple sclerosis, history of inflammatory optic neuropathy (homo- or ipsi-lateral). A temporal artery biopsy should be performed if there are symptoms suggestive of Horton's disease, or if there is pale and/or diffuse edema, or obliteration of the associated central retinal artery.
• Patients with systolic blood pressure below 100 mmHg
• Patient with orthostatic hypotension (20 mmHg drop in SBP and/or 10 mmHg drop in DBP when moving to a standing position)
• Neurological history of vascular or tumour-related changes to the visual field or other optic neuropathy
• Systemic inflammatory disease
• Known allergy to bosentan
• Patients with moderate to severe hepatic impairment (Child-Pugh class B or C), biliary cirrhosis (serum levels of liver aminotransferases, aspartate aminotransferases (ASAT) and/or alanine aminotransferases (ALAT), greater than three times the upper limit of normal, bilirubin greater than twice normal)
• Estimated glomerular filtration rate (GFR) < 30 ml/min/1.73 m2
• Patients treated with drugs whose efficacy may be reduced by activation of cytochrome P450, 2C9, 3A4 and 2C19 isoenzymes
• Patients treated with amiodarone
• Patient treated with systemic corticosteroids (background treatment or treatment initiated at the time of NAAION diagnosis)
• Person deprived of liberty by judicial or administrative decision, adult protected by law, hospitalized person
• Ongoing participation in another clinical research study or in the exclusion period of another clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; Bosentan at a dose of 125 mg two times daily, will be administered orally, twice a day, during eight weeks	Drug: bosentan; treatment by bosentan or placebo is randomized , 125 mg twice a day
Placebo Comparator: Placebo; placebo drug , twice a day, during eight weeks	Drug: placebo; treatment by bosentan or placebo is randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean deviation of automated visual field	Humphrey 30-2 SITA-standard	3 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
visual acuity	ETDRS scale	6, 12 and 24 month
optic nerve fiber layer thickness	OCT measurement	3, 6, 12 and 24 month
mean deviation of automated visual field for healthy eye and NAION eye	Humphrey 30-2	3, 6, 12 and 24 month
inflammatory marker and prepro-endothelin dosing	RANTES, MCP-1, TNF-α, INF-γ, IL-6, IL-10 and TGF-β	3 month
mean deviation of automated visual field for controlateral eye	Humphrey 30-2 sita-standard	24 month
VFQ-25 score	VFQ-25 quality of life	3 and 12 month
rate of bilateral occurence of NAION	rate of bilateralization	at 24 month visit

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Investigators: Principal Investigator: Christophe Pr CHIQUET, Prof, MD, PhD, University Hospital, Grenoble

Publications and helpful links

General Publications

• Chiquet C, Vignal C, Gohier P, Heron E, Thuret G, Rougier MB, Lehmann A, Flet L, Quesada JL, Roustit M, Milea D, Pepin JL; ENDOTHELION group. Treatment of nonarteritic anterior ischemic optic neuropathy with an endothelin antagonist: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy)-a multicentre randomised controlled trial protocol. Trials. 2022 Oct 29;23(1):916. doi: 10.1186/s13063-022-06786-9.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: December 5, 2014
• First Submitted That Met QC Criteria: February 24, 2015
• First Posted (Estimate): March 3, 2015

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 4, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Bosentan
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Eye Diseases; Cranial Nerve Diseases; Optic Nerve Diseases; Optic Neuropathy, Ischemic; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: 2014-000848-14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No