Bosentan in the Treatment of Giant Cell Arteritis. Multicenter, Randomized, Controlled, Superiority Phase II Trial Comparing a Combination of Bosentan and Glucocorticoids Versus Glucocorticoids Alone in the Treatment of Patients With GCA
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Failure free survival at Week 52
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion Criteria :
- •Patients having given their written informed consent prior to participation in the study
- •Patients affiliated with social security or CMU (profit or being entitled)
- •Diagnosis of GCA, as defined by the revised GCA diagnosis criteria. Patients must satisfy criteria 1-2-3 and 4 (irrespective of time):
- •Age ≥50 years at disease onset
- •History of erythrocyte sedimentation rate (ESR) ≥ 50 mm/h or CRP ≥ 20 mg/L (not mandatory if TAB is positive: see below)
- •At least one of the following:
- •unequivocal cranial symptoms of GCA (new onset headache, scalp tenderness, jaw claudication, temporal artery abnormality, ischemia-related vision loss)
- •unequivocal symptoms of polymyalgia rheumatica (PMR)
- •At least one of the following:
- •Temporal artery biopsy (TAB) compatible with the diagnosis of GCA (non-necrotizing vasculitis with a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells)
- •Evidence of large vessel vasculitis:
- •angio-CT or angio-MRI: thickened and/or contrast-enhanced arteries especially aorta (≥2mm) and epiaortic arteries (≥1mm) and contrast enhanced arteries in T1-weighted sequences
- •or PET scan: ≥ grade 2 (from 0 to 3) tracer uptake on large arteries
- •At least a sign of active GCA within the 2 weeks prior to randomisation. Active GCA is defined by ESR ≥30 mm/h or CRP ≥10 mg/L and at least one of the following:
- •unequivocal cranial symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication)
- •unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness
- •other features judged by the clinical investigator to be consistent with GCA or PMR flares
- •Menopausal women (no gynaecological cycle over the past two years), or women who had a gynaecological cycle within previous 24 months (non-menopausal women) only if they have (1) an effective non hormonal contraceptive method throughout study and (2) a negative urinary beta-hCG test at inclusion.
排除标准
- •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
研究组 & 干预措施
Bosentan + Glucocorticoids
Bosentan : 62.5 mg bid for 4 weeks and 125 mg bid during 9 additional weeks Glucocorticoids : prespecified GC tapering schedule
干预措施: Bosentan (Drug)
Glucocorticoids
prespecified GC tapering schedule
干预措施: Glucocorticoids (Drug)
结局指标
主要结局
Failure free survival at Week 52
时间窗: 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.
次要结局
- Frequency and type of side effects(within 1 year after inclusion)
- Exploratory criteria(At the beginning of the study and in both groups at Week 13 and Week 52)
- 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 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 patients relapsing(year 1 to year 2)
- Proportion of patients receiving Glucocorticoids(2 years)
- Quality of life measured by the "Health Assessment Questionnaire" (HAQ)(at Week 26 and Week 52)
- Quality of life measured by the "Short Form 36 Questionnaire" (SF36)(at Week 26 and Week 52)