Study of the Benefit of Early Treatment With an Endothelin Inhibitor (Bosentan) in Patients With Sudden Blindness Due to Giant Cell Arteritis: CECIBO

NCT03841734 | Unknown Phase 3

• 1 other identifier: 18-AOIP-01
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Giant cell arteritis , also named Horton's disease, is the most common vasculitis in subjects over 50 years old. The incidence increases with age : from 188 to 290 cases per million inhabitants per year, with a North-South gradient. The major risk of Horton's disease is blindness, unilateral, occurring in 15 to 20% of cases, sometimes preceded by episodes of transient amaurosis. The decrease in visual acuity is often brutal, irreversible and bilateral in 25 to 50% of cases. The mechanism of this blindness is an arterial ischemia: Acute Anterior Ischemic Optic Neuropathy acute anterior ischaemic optic neuropathy (90%), acute retro-bulbar ischaemic optic neuropathy (5%), occlusion of the central artery of the retina (5%). The pathogenesis of this brutal ischemia is not fully understood. One of the hypotheses suggests that, during stimulation by an antigen of the environment, preactivated dendritic cells of the arterial wall would stimulate T lymphocytes. These will recruit cells that cause an inflammatory infiltrate polymorphic predominant at the media level. These lesions may be accompanied by destruction of the internal elastic lamina, with inconstant but pathognomonic presence of multinucleated giant cells. All arteries with internal elastic lamina can be affected by parietal inflammation, which results in stenosis and occlusion, explaining the ischemia. The visual loss is usually abrupt and very severe, leaving the patient with definitely very low or no residual visual acuity. Conventional treatment currently recommended includes systemic corticosteroid therapy at 1 mg / kg / day, preceded or not by 500 mg pulses of methylprednisolone , and associated with antiplatelet and anticoagulant therapy (LMWH). Despite the decline in visual acuity thus occurred is then always final. Certainly loss of vision has a major impact on the quality of life of patients. Apart from this lymphocytic inflammation, a process of vascular remodeling is at the origin of the vascular occlusion phenomenon. The endothelin system is a family of amino acids including 3 members: ET1, ET2 and ET3. ET1 is a potent vasoconstrictor. ET1 receptors (ETA and ETB) are expressed in the arteries of patients with giant cell arteritis . The expression of ET1 associated with proliferation of muscle cells in arteries will decrease under the effect of endothelin inhibitors. This has been shown during treatment of pulmonary hypertension. In giant cell arteritis , the endothelin system continues to be very active up to 8 days despite the introduction of systemic corticosteroids. Bosentan is a mixed endothelin receptor antagonist with affinity for both ETA and ETB receptors. This inhibitor is used in treatment of pulmonary artery hypertension, digital ulcerations of systemic sclerosis and critical peripheral arterial ischemia.

Conditions

Arteritis, Giant Cell; Blindness and Low Vision

Outcome Measures

Primary Outcomes (1)

• Visual acuity calculated according to the Early Treatment Diabetic Retinopathy Study

  3 months

Secondary Outcomes (3)

• Visual acuity calculated according to the Early Treatment Diabetic Retinopathy Study

  1 month

• Goldman's one-sided visual field

  3 months

• Numbers of adverse event and serious adverse events

  16 days

Study Arms (1)

Treatment bosentan

EXPERIMENTAL

Drug: treatment

Interventions

treatment DRUG

8 patients will be treat with bosentan at 145 mg per day during 14 days

Treatment bosentan

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Decreased visual acuity (BVA) \<5 days, regardless of degree of severity, abrupt onset in the context of newly diagnosed or suspected Horton's disease at this loss of visual acuity
• Able to sign the consent
• Affiliated to the social security system
• Already under conventional treatment of Horton's disease or the: requiring: Corticosteroids and + - anti-platelet aggregators and / or LMWH at the discretion of the referring physician for its vasculitis and + - immunosuppressive or biotherapy if necessary.

You may not qualify if:

• Underlying hepatocellular insufficiency known
• Patient under guardianship or curator
• Hypersensitivity to the active substance or to any of the excipients
• Moderate to severe hepatic insufficiency corresponding to class B or C of the Child-Pugh classification
• Any other ophthalmological pathology explaining the sudden drop in vision: retinal detachment, retinal hemorrhage, posterior uveitis, nonarteritic arterial occlusion, cortical stroke
• Serum levels of hepatic aminotransferases, aspartate aminotransferases (ASTs) and / or alanine aminotransferases (ALATs), greater than 3 times the upper limit of normal before start of treatment
• Patient under treatment with cyclosporine A, antiretrovirals, glibenclamide or Rifampicin.
• Pregnant or lactating women

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nice: lead

Study Sites (1)

CH de Cannes

Cannes, France

Location

Related Publications (15)

• Chaigne-Delalande S, de Menthon M, Lazaro E, Mahr A. [Giant-cell arteritis and Takayasu arteritis: epidemiological, diagnostic and treatment aspects]. Presse Med. 2012 Oct;41(10):955-65. doi: 10.1016/j.lpm.2012.07.011. Epub 2012 Aug 31. French.

  PMID: 22940467 BACKGROUND

• Watelet B, Samson M, de Boysson H, Bienvenu B. Treatment of giant-cell arteritis, a literature review. Mod Rheumatol. 2017 Sep;27(5):747-754. doi: 10.1080/14397595.2016.1266070. Epub 2017 Jan 13.

  PMID: 27919193 BACKGROUND

• Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008 Jul 19;372(9634):234-45. doi: 10.1016/S0140-6736(08)61077-6.

  PMID: 18640460 BACKGROUND

• Gonzalez-Gay MA, Garcia-Porrua C, Llorca J, Hajeer AH, Branas F, Dababneh A, Gonzalez-Louzao C, Rodriguez-Gil E, Rodriguez-Ledo P, Ollier WE. Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients. Medicine (Baltimore). 2000 Sep;79(5):283-92. doi: 10.1097/00005792-200009000-00001.

  PMID: 11039076 BACKGROUND

• Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med. 2003 Jul 10;349(2):160-9. doi: 10.1056/NEJMra022694. No abstract available.

  PMID: 12853590 BACKGROUND

• Bienvenu B, Ly KH, Lambert M, Agard C, Andre M, Benhamou Y, Bonnotte B, de Boysson H, Espitia O, Fau G, Fauchais AL, Galateau-Salle F, Haroche J, Heron E, Lapebie FX, Liozon E, Luong Nguyen LB, Magnant J, Manrique A, Matt M, de Menthon M, Mouthon L, Puechal X, Pugnet G, Quemeneur T, Regent A, Saadoun D, Samson M, Sene D, Smets P, Yelnik C, Sailler L, Mahr A; Groupe d'Etude Francais des Arterites des gros Vaisseaux, under the Aegis of the Filiere des Maladies Auto-Immunes et Auto-Inflammatoires Rares. Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis (GEFA). Rev Med Interne. 2016 Mar;37(3):154-65. doi: 10.1016/j.revmed.2015.12.015. Epub 2016 Jan 29.

  PMID: 26833145 BACKGROUND

• Weyand CM, Schonberger J, Oppitz U, Hunder NN, Hicok KC, Goronzy JJ. Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes. J Exp Med. 1994 Mar 1;179(3):951-60. doi: 10.1084/jem.179.3.951.

  PMID: 8113687 BACKGROUND

• Terrades-Garcia N, Cid MC. Pathogenesis of giant-cell arteritis: how targeted therapies are influencing our understanding of the mechanisms involved. Rheumatology (Oxford). 2018 Feb 1;57(suppl_2):ii51-ii62. doi: 10.1093/rheumatology/kex423.

  PMID: 29982777 BACKGROUND

• Lozano E, Segarra M, Corbera-Bellalta M, Garcia-Martinez A, Espigol-Frigole G, Pla-Campo A, Hernandez-Rodriguez J, Cid MC. Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events. Ann Rheum Dis. 2010 Feb;69(2):434-42. doi: 10.1136/ard.2008.105692. Epub 2009 Mar 15.

  PMID: 19289383 BACKGROUND

• Dimitrijevic I, Andersson C, Rissler P, Edvinsson L. Increased tissue endothelin-1 and endothelin-B receptor expression in temporal arteries from patients with giant cell arteritis. Ophthalmology. 2010 Mar;117(3):628-36. doi: 10.1016/j.ophtha.2009.07.043. Epub 2009 Dec 24.

  PMID: 20036012 BACKGROUND

• Planas-Rigol E, Terrades-Garcia N, Corbera-Bellalta M, Lozano E, Alba MA, Segarra M, Espigol-Frigole G, Prieto-Gonzalez S, Hernandez-Rodriguez J, Preciado S, Lavilla R, Cid MC. Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis. Ann Rheum Dis. 2017 Sep;76(9):1624-1634. doi: 10.1136/annrheumdis-2016-210792. Epub 2017 Jun 12.

  PMID: 28606962 BACKGROUND

• Regent A, Ly KH, Groh M, Khifer C, Lofek S, Clary G, Chafey P, Baud V, Broussard C, Federici C, Labrousse F, Mesturoux L, Le Jeunne C, Vidal E, Brezin A, Witko-Sarsat V, Guillevin L, Mouthon L. Molecular analysis of vascular smooth muscle cells from patients with giant cell arteritis: Targeting endothelin-1 receptor to control proliferation. Autoimmun Rev. 2017 Apr;16(4):398-406. doi: 10.1016/j.autrev.2017.02.006. Epub 2017 Feb 14.

  PMID: 28232168 BACKGROUND

• Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, Wigley FM, Black CM, Fessler BJ, Merkel PA, Pope JE, Sweiss NJ, Doyle MK, Hellmich B, Medsger TA Jr, Morganti A, Kramer F, Korn JH, Seibold JR. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2011 Jan;70(1):32-8. doi: 10.1136/ard.2010.130658. Epub 2010 Aug 30.

  PMID: 20805294 BACKGROUND

• Narvaez J, Garcia-Gomez C, Alvarez L, Santo P, Aparicio M, Pascual M, Lopez de Recalde M, Borrell H, Nolla JM. Efficacy of bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): A case series and review of the literature. Medicine (Baltimore). 2016 Nov;95(48):e5511. doi: 10.1097/MD.0000000000005511.

  PMID: 27902617 BACKGROUND

• Ly KH, Liozon E, Fauchais AL, Vidal E. [Pathophysiology of giant cell arteritis]. Rev Med Interne. 2013 Jul;34(7):392-402. doi: 10.1016/j.revmed.2013.02.037. Epub 2013 Mar 23. French.

  PMID: 23528439 RESULT

MeSH Terms

Conditions

Giant Cell Arteritis; Blindness; Vision, Low

Interventions

Therapeutics

Condition Hierarchy (Ancestors)

Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Vasculitis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Vision Disorders; Sensation Disorders; Neurologic Manifestations; Eye Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Nathalie Tieulié, MD

  Centre Hospitalier Universitaire de Nice

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nathalie Tieulié, MD

CONTACT

04 92 03 90 19; tieulie.n@chu-nice.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2019
• First Posted: February 15, 2019
• Study Start: March 1, 2019
• Primary Completion: March 1, 2019
• Study Completion: March 1, 2021
• Last Updated: February 15, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)