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

Blindness and Low Vision Clinical Trial

— CECIBO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03841734
• Other study ID #: 18-AOIP-01
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: March 2019
• Est. completion date: March 2021

Study information

• Verified date: January 2019
• Source: Centre Hospitalier Universitaire de Nice
• Contact: Nathalie Tieulié, MD
• Phone: 04 92 03 90 19
• Email: tieulie.n[@]chu-nice.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 8
• Est. completion date: March 2021
• Est. primary completion date: March 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Arteritis
• Arteritis, Giant Cell
• Blindness
• Blindness and Low Vision
• Giant Cell Arteritis
• Polymyalgia Rheumatica
• Vision, Low

Intervention

Drug:
• treatment
8 patients will be treat with bosentan at 145 mg per day during 14 days

Locations

Country	Name	City	State
France	CH de Cannes	Cannes

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nice

Country where clinical trial is conducted

France, 

References & Publications (15)

Bienvenu B, Ly KH, Lambert M, Agard C, André M, Benhamou Y, Bonnotte B, de Boysson H, Espitia O, Fau G, Fauchais AL, Galateau-Sallé F, Haroche J, Héron E, Lapébie FX, Liozon E, Luong Nguyen LB, Magnant J, Manrique A, Matt M, de Menthon M, Mouthon L, Puéchal X, Pugnet G, Quemeneur T, Régent A, Saadoun D, Samson M, Sène D, Smets P, Yelnik C, Sailler L, Mahr A; Groupe d’Étude Français des Artérites des gros Vaisseaux, under the Aegis of the Filière 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. — View Citation

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. Review. French. — View Citation

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. — View Citation

González-Gay MA, García-Porrúa C, Llorca J, Hajeer AH, Brañas F, Dababneh A, González-Louzao C, Rodriguez-Gil E, Rodríguez-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. — View Citation

Lozano E, Segarra M, Corbera-Bellalta M, García-Martínez A, Espígol-Frigolé G, Plà-Campo A, Hernández-Rodríguez 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. — View Citation

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. Review. French. — View Citation

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. — View Citation

Narváez J, García-Gómez C, Álvarez L, Santo P, Aparicio M, Pascual M, López 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. Review. — View Citation

Planas-Rigol E, Terrades-Garcia N, Corbera-Bellalta M, Lozano E, Alba MA, Segarra M, Espígol-Frigolé G, Prieto-González S, Hernández-Rodríguez 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. — View Citation

Régent 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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med. 2003 Jul 10;349(2):160-9. Review. — View Citation

Weyand CM, Schönberger 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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Visual acuity calculated according to the Early Treatment Diabetic Retinopathy Study		3 months
Secondary	Visual acuity calculated according to the Early Treatment Diabetic Retinopathy Study		1 month
Secondary	Goldman's one-sided visual field		3 months
Secondary	Numbers of adverse event and serious adverse events		16 days