Evaluation of Bosentan, Prednisone, and Prednisolone in the Management of Newly Diagnosed or Relapsing Giant Cell Arteritis

Trial ID: 2024-517030-17-00
Protocol: APHP200041
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Giant cell arteritis

Objectives

The primary objective of this study is to evaluate the benefit of an additional 3 months of **bosentan** therapy in patients treated with glucocorticoids (GC) for newly diagnosed or relapsing **Giant Cell Arteritis** (GCA), after 52 weeks of follow-up. This is clinically relevant as it aims to determine the potential extended therapeutic effects of bosentan in managing GCA, which could influence treatment protocols and improve patient outcomes.

Secondary objectives include:

To compare the occurrence of new ischemic events.
To compare the proportion of patients in remission without prednisone at week 52 between bosentan and a reference group.
To compare the proportion of patients in remission with ≤5 mg/day of prednisone at week 52 between bosentan and a reference group.
To assess the glucocorticoid-sparing effect of bosentan in the treatment of GCA.
To assess the effect of bosentan on quality of life.
To compare the proportion of patients in remission at year 2 and the relapse rate from year 1 to year 2.
To compare the number of patients still receiving glucocorticoids at year 2.
To assess the safety of bosentan in the treatment of GCA.
To assess the effect of bosentan on the frequency of glucocorticoid-related side effects.

Participants

The clinical trial involves participants diagnosed with **Giant-cell arteritis** (GCA), either newly diagnosed or experiencing a relapse. The study population includes both male and female subjects, with an age range starting from 50 years and above, as the disease onset criteria specify a minimum age of 50. Participants are required to have a history of elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels, along with specific cranial symptoms or evidence of large vessel vasculitis. The trial does not focus on a vulnerable population, and both menopausal and non-menopausal women are included, provided they adhere to specific contraceptive measures and testing requirements. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the presence of active GCA symptoms within four weeks prior to randomization. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **bosentan** in the treatment of newly diagnosed or relapsing **giant cell arteritis** (GCA). This is a Phase 4, randomized, double-blind, controlled trial. The study aims to assess the benefit of an additional 3 months of bosentan therapy in patients already receiving glucocorticoids (GC) for GCA, with a follow-up period of 52 weeks. The trial is expected to commence recruitment on July 1, 2025, and conclude by July 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, medical history, and signs of active GCA. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with primary endpoints including failure-free survival at week 52. Secondary endpoints will assess the proportion of new ischemic events, remission rates with and without prednisone, and quality of life metrics at weeks 26 and 52.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including the occurrence of a relapse or inability to reduce GC dosage as per the predefined schedule. Participants will also attend an end-of-study visit to evaluate overall outcomes and any adverse events experienced during the trial. The study will utilize oral administration of bosentan, prednisone, and prednisolone, with specific dosing regimens tailored to each participant's treatment plan.

Treatment

The clinical trial involves the administration of **BOSENTAN**, a chemical compound used in the treatment of Giant Cell Arteritis. BOSENTAN is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 250 mg, with a total maximum dose of 23,625 mg over a treatment period of up to 16 weeks. The administration schedule is designed to ensure optimal therapeutic outcomes, and participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to BOSENTAN, the trial includes the use of **PREDNISONE** as a non-experimental treatment. PREDNISONE is administered in tablet form, also via the oral route. The maximum daily dose for PREDNISONE is 40 mg, with a total maximum dose of 3,150 mg over a 52-week treatment period. This medication serves as a standard-of-care therapy, and its administration is carefully monitored to maintain consistency and evaluate its effects in conjunction with BOSENTAN.

Furthermore, **PREDNISOLONE** is included in the study as another non-experimental treatment. Like PREDNISONE, PREDNISOLONE is administered orally in tablet form. The dosing schedule for PREDNISOLONE mirrors that of PREDNISONE, with a maximum daily dose of 40 mg and a total maximum dose of 3,150 mg over a 52-week period. The inclusion of PREDNISOLONE allows for a comprehensive assessment of its therapeutic impact alongside BOSENTAN and PREDNISONE.

Efficacy

The efficacy of the clinical trial titled "BOSICART - Bosentan in the treatment of Giant Cell Arteritis" will be assessed using both primary and secondary endpoints. The primary endpoint is **failure-free survival** at week 52, where a failure is defined by the occurrence of a relapse or the inability to decrease glucocorticoids (GC) according to the predefined schedule. Secondary endpoints include the proportion of new ischemic events at week 52, the proportion of patients in remission without prednisone at week 52, and the proportion of patients in remission with prednisone ≤5 mg/day at week 52. Additionally, the cumulative dose of prednisone at week 52 and quality of life, measured by the Health Assessment Questionnaire (HAQ) and SF-36 at weeks 26 and 52, will be evaluated. The proportion of patients in remission at year 2 and the proportion of patients receiving GC at year 2 will also be assessed.

The planned methods for measuring and collecting these efficacy parameters involve validated scales and patient-reported outcomes. The quality of life will be specifically measured using the HAQ and SF-36 instruments. The analysis will compare the occurrence of new ischemic events and the proportion of patients in remission between those treated with bosentan and a reference group. The trial will also assess the GC-sparing effect of bosentan in the treatment of Giant Cell Arteritis and its impact on quality of life. The frequency and type of side effects within one year after inclusion will be monitored as part of the secondary objectives.

Inclusion and Exclusion Criteria

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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): 1. Age ≥50 years at disease onset 2. History of erythrocyte sedimentation rate (ESR) ≥ 50 mm/h or CRP ≥ 20 mg/L (not mandatory if TAB is positive: see below) 3. 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) 4. 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: o 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 o or PET scan: ≥ grade 2 (from 0 to 3) tracer uptake on large arteries
At least a sign of active GCA within the 4 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: o 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) o unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness o 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.

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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
Pregnant or breastfeeding woman
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: o Tocilizumab or methotrexate or secukinumab within 12 weeks preceding inclusion o Cell-depleting agents (i.e., anti-CD20) o Alkylating agents including cyclophosphamide o Hydroxychloroquine, cyclosporine A, dapsone, azathioprine, mycophenolate mofetil or janus kinase inhibitors within 4 weeks preceding inclusion o Tumor necrosis factor inhibitors within 8 weeks preceding inclusion o 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: o Active hepatitis B or C o HIV infection