Bosentan in the Treatment of Giant Cell Arteritis

Phase 2

Not yet recruiting

• Conditions: Giant Cell Arteritis (GCA)
• Interventions: Drug: Bosentan; Drug: Glucocorticoids

• Registration Number: NCT06957002
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

The purpose of this study is to determine whether a treatment with 3 months of bosentan associated to standard therapy might be superior to glucocorticoids alone in term of failure free survival at 12 months

Detailed Description

Giant cell arteritis (GCA) is the most common vasculitis in individuals over the age of 50. It is characterized by inflammation of large vessels, including the aorta and its main branches. Patients experience headaches, scalp tenderness, joint pain, and general symptoms such as weight loss, fatigue, and fever. More rarely, unilateral or bilateral visual acuity is impaired. At the biological level, an increase in inflammatory markers, such as C-reactive protein (CRP), is observed.

Glucocorticoids (GCs) are the cornerstone of GCA treatment and are usually administered for 12 to 18 months to prevent relapse, sometimes longer. However, most patients develop significant adverse effects associated with GCs, including hypertension, arterial disease, diabetes, osteoporosis, and infections. As a result, various strategies targeting the inflammatory process have been developed to reduce GC use. For example, methotrexate has been shown to be a modestly effective GC-sparing treatment. A 12-month course of tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist, has also been shown to induce and maintain remission of GCA, with a significant GC-sparing effect. However, only 45% of patients remained in long-term remission after discontinuing tocilizumab.

In patients with GCA, in addition to lymphocyte (white blood cell) activation, the investigator observed increased proliferative properties of vascular smooth muscle cells (VSMCs), obtained from temporal artery biopsies at the time of diagnosis. This proliferation and migration of VSMCs are promoted by endothelin-1 (ET-1), a molecule expressed in the walls of diseased arteries. Thus, ET-1 contributes to vessel lumen narrowing and complete obstruction. It was found that plasma ET-1 concentrations were higher in patients with visual ischemic complications. Additionally, an association was found between endothelin expression in temporal artery biopsies at baseline and therapeutic response at month six.

Bosentan has been marketed since 2002 for the management of patients with pulmonary arterial hypertension. This vasodilating drug is an endothelin (ET-1) receptor antagonist.

The investigator hypothesize that a 3-month course of treatment with bosentan, an endothelin receptor antagonist, combined with standard therapy, could be more effective than glucocorticoids (GCs) alone, reducing the risk of relapse and the current adverse effects, thereby improving relapse-free survival at 12 months.

Study Timeline

• Study First Submitted: 2025-03-24
• Study First Submitted QC: 2025-04-25
• Status Verified: 2025-05
• Study First Posted: 2025-05-04
• Last Update Submitted: 2025-05-09
• Last Update Posted: 2025-05-14
• Study Start: 2025-09
• Primary Completion: 2029-09
• Study Completion: 2029-09

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

Not provided

Exclusion Criteria

• Patients under maintenance of justice, wardship or legal guardianship

• Patient unable to give written informed consent prior to participation in the study

• Patients included in other investigational therapeutic study within the previous 3 months

• Patients suspected not to be observant to the proposed treatments

• Weight <40 Kg or > 100 Kg

• Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C. History of chronic alcohol abuse (consumption > 20 g/day)

• Severe chronic heart failure or severe systolic dysfunction

• Recent (< 3 months) or incoming surgery requiring a general anaesthesia

• History of stem cell or organ transplantation (except corneas if performed more than 3 months prior inclusion)

• Hypersensitivity to bosentan or one of its excipients

• Prior treatment with any of the following:

  • Tocilizumab or methotrexate or secukinumab within 12 weeks preceding inclusion
  • Cell-depleting agents (i.e., anti-CD20)
  • Alkylating agents including cyclophosphamide
  • Hydroxychloroquine, cyclosporine A, dapsone, azathioprine, mycophenolate mofetil or janus kinase inhibitors within 4 weeks preceding inclusion
  • Tumor necrosis factor inhibitors within 8 weeks preceding inclusion
  • Anakinra within 1 week preceding inclusion

• Ongoing treatment with glibenclamide, fluconazole and rifampicin. Concomitant administration of both a CYP3A4 inhibitor or a CYP2C9 inhibitor

• Long-course systemic glucocorticoid therapy for other conditions than GCA or PMR

• Laboratory abnormalities: AST or ALT >3 x upper limit of normal (ULN)

• Infections:

  • Active hepatitis B or C
  • HIV infection

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bosentan + Glucocorticoids	Bosentan	Bosentan : 62.5 mg bid for 4 weeks and 125 mg bid during 9 additional weeks Glucocorticoids : prespecified GC tapering schedule
Glucocorticoids	Glucocorticoids	prespecified GC tapering schedule

Primary Outcome Measures

Name	Time	Method
Failure free survival at Week 52	12 months ( Week 52)	A failure is defined by the occurrence of a relapse or the impossibility to decrease Glucocorticoids according to the predefined scheduled Glucocorticoids scheme.

Secondary Outcome Measures

Name	Time	Method
Exploratory criteria	At the beginning of the study and in both groups at Week 13 and Week 52	Compare the remodeling cytokines (pentraxin 3, osteoprotegerin, osteopontin, osteocalcin, thrombomodulin, HGF, endothelin, IL-6, TGF-β MMP-3)
Frequency and type of side effects	within 1 year after inclusion	Frequency and type of side effects
Proportion of new ischemic event	12 months (Week 52)
Proportion of patients in remission without prednisone	12 months (Week 52)	Proportion of patients in remission without prednisone
Proportion of patients in remission with prednisone ≤5 mg/day	12 months (Week 52)
Cumulative dose of prednisone	12 months (Week 52)
Proportion of patient in remission	2 years	Proportion of patient in remission
Proportion of patients relapsing	year 1 to year 2	Proportion of patients relapsing
Proportion of patients receiving Glucocorticoids	2 years
Quality of life measured by the "Health Assessment Questionnaire" (HAQ)	at Week 26 and Week 52	HAQ (Health Assessment Questionnaire) is a functional disability tool specific to rheumatoid arthritis. The assessment covers the past week and 8 domains of physical activity. For each area of activity, 2 to 3 items are described. Each item can be modified with aids. Only items with a specified response or aid are taken into account. Scores range from 0 (no impact) to 3 (maximum impact).
Quality of life measured by the "Short Form 36 Questionnaire" (SF36)	at Week 26 and Week 52	To score the SF-36, scales are standardized with a scoring algorithm or by the SF-36 (v2) scoring software to obtain a score ranging from 0 to 100. Higher scores indicate better health status, and a mean score of 50 has been articulated as a normative value for all scales

Trial Locations

Locations (1)

Unité de Recherche Clinique, Entrepôts de données et Pharmacologie GHU Paris Centre; 🇫🇷 Paris, France