METHOTREXATE for Giant cell arteritis

Inclusion criteria

• {"criterion_text":"- Written consent\n- Affiliation to a social security system\n- Diagnosis of GCA, as defined by the revised GCA diagnosis criteria : Age ≥50 years at disease onset / AND History of erythrocyte sedimentation rate (ESR) ≥50 mm/h OR CRP≥20 mg/L (not mandatory if TAB is positive: see below) / AND 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) OR unequivocal symptoms of polymyalgia rheumatica (PMR) / AND 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) OR Evidence of large vessel vasculitis (aorta and/or epiaortic arteries) : (angio-CT or angio-MRI: thickened arterial wall (≥2mm for the aorta and ≥1mm for epiaortic arteries) and/or contrast-enhanced arteries in T1-weighted sequences) - (PET scan: grade 3 tracer uptake of the arterial wall (grade 3 = arterial SUVmax superior to the SUVmax of the liver))\n- Active GCA within 6 weeks before randomization. Active GCA is defined by ESR ≥30 mm/h or CRP ≥10 mg/L and at least one of the following: ≥1 unequivocal cranial symptom(s) of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication) / ≥1 unequivocal symptom(s) of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness / any other feature(s) judged by the clinical investigator to be consistent with GCA or PMR flares"}

Exclusion criteria

• {"criterion_text":"- Uncontrolled psychotic state\n- History of stem cell or organ transplantation (except corneas performed more than 3 months prior inclusion)\n- Primary or secondary immunodeficiency\n- Hypersensitivity to methotrexate or tocilizumab, one of its excipients or another human or murine monoclonal antibody\n- History of diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal tract condition that might predispose to bowel perforation\n- Patient refusing to sign methotrexate safety contract\n- Prior treatment with any of the following: Tocilizumab or methotrexate within 12 weeks before inclusion - Treatment with rituximab or other anti-CD20 agent within one year before inclusion - Treatment with cyclophosphamide within one year before inclusion - Hydroxychloroquine, cyclosporine A, dapsone, azathioprine, mycophenolate mofetil or janus kinase inhibitors within 4 weeks before inclusion - Tumor necrosis factor inhibitors within 8 weeks (infliximab) or 2 weeks (adalimumab or etanercept) before inclusion - Anakinra within 1 week before inclusion\n- Long-term systemic glucocorticoid therapy ((except dermocorticoids and inhaled corticoids) for other conditions than GCA or PMR\n- Patient with ≥3 prior glucocorticoid systematic therapies for another disease than GCA or PMR within the 6 months before inclusion\n- Long-term treatment with sulfamethoxazole/trimethoprim (Bactrim®)\n- Live vaccine administered within 30 days before inclusion\n- Patient unable to give his/her consent\n- Laboratory abnormalities, within 72h before inclusion : AST or ALT >1.5 x upper limit of normal (ULN) - total bilirubin >20 µmol/L (12 mg/L) - platelets<100 G/L - leukocytes <3 G/L - neutropenia <1.5 G/L - lymphopenia <0.5 G/L - haemoglobin <8 g/dL (not related to GCA activity) - clearance of creatinine <30 ml/min/1,73 m2 [CKD EPI 2009]\n- Laboratory abnormalities, within 12 months before inclusion : positive HBs antigen or positive HCV antibodies\n- History of viral hepatitis B or C (chronic or acute)\n- HIV infection\n- Persistent infection or severe infection requiring hospitalization or intravenous antibiotics within 30 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)\n- Proven infection requiring oral antibiotics within 14 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)\n- Prior history of histoplasmosis or listeriosis\n- Active tuberculosis\n- Latent tuberculosis (diagnosis based on history of non-treated contact, opacity with a diameter greater than 1 cm on chest radiography, or positive in vitro test: Quantiferon Gold® or T-Spot-TB®). NB: a history of tuberculosis for which treatment is over and was correctly precribed regarding usual recommendations is not an exclusion criteria, whatever the results of Quantiferon Gold® or T-Spot-TB® tests.\n- Unstable or poorly controlled, acute or chronic disease, not due to GCA, and which contraindicates tocilizumab or methotrexate: Recurrent infections, unstable ischemic heart disease, renal failure (creatinine clearance <30 ml/min/1,73 m2 [CKD EPI 2009]), liver failure, current liver disease, heart failure ≥ NYHA stage III/IV, respiratory failure - Neoplasia < 5 years, (except for in situ cervical cancer and skin carcinoma, except melanoma, with R0 resection)\n- Premenopausal women (menopause is defined as amenorrhea for more than 12 consecutive months)\n- Non-compliant patients\n- Weight<40 Kg or >100Kg\n- Patients under maintenance of justice, wardship or legal guardianship\n- History of intoxication (alcohol or medication) requiring hospitalization within 12 months before inclusion\n- Current chronic alcohol abuse (consumption > 20g/day)\n- Recent or incoming surgery within 12 months after inclusion"}

Primary endpoints

• {"endpoint_text":"- Percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of prednisone at week 78 (W78).","definition_or_measurement_approach":"Proportion of patients alive and without relapse after achieving initial remission and without deviation from the scheduled prednisone taper regimen, assessed at Week 78 (W78)."}

Secondary endpoints

• {"endpoint_text":"- Percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of prednisone at W52 and 104","definition_or_measurement_approach":"Proportion of patients alive without relapse or deviation from prednisone regimen assessed at Weeks 52 and 104."}
• {"endpoint_text":"- Number of patients needed to treat to avoid 1 relapse at W52, 78 and 104, and will be calculated as 1/ absolute risk reduction, that is the difference between the relapse rate in TCZ group and the relapse rate in the MTX group.","definition_or_measurement_approach":"Calculated as 1 / absolute risk reduction (difference in relapse rates between TCZ and MTX groups) at Weeks 52, 78 and 104."}
• {"endpoint_text":"- Percentage of patients in remission without prednisone at W52, 78, 104 and 156","definition_or_measurement_approach":"Proportion of patients in remission and not receiving prednisone at Weeks 52, 78, 104 and 156."}
• {"endpoint_text":"- Percentage of patients in remission with prednisone ≤5 mg/day at W52, 78, 104 and 156","definition_or_measurement_approach":"Proportion of patients in remission receiving prednisone ≤5 mg/day at Weeks 52, 78, 104 and 156."}
• {"endpoint_text":"- Cumulative dose of prednisone at W52, 78, 104 and 156","definition_or_measurement_approach":"Total cumulative prednisone dose received by each patient, measured and aggregated at Weeks 52, 78, 104 and 156."}
• {"endpoint_text":"- Quality of life measured by HAQ and SF36 at W 28, 52, 104 and 156","definition_or_measurement_approach":"Quality of life assessed using HAQ and SF-36 instruments at Weeks 28, 52, 104 and 156."}
• {"endpoint_text":"- Tiredness measured by FACIT-Fatigue at W28, 52, 104 and 156","definition_or_measurement_approach":"Fatigue measured using the FACIT-Fatigue scale at Weeks 28, 52, 104 and 156."}
• {"endpoint_text":"- Time to relapse or deviation from the scheduled regimen of prednisone","definition_or_measurement_approach":"Time-to-event endpoint measuring time from randomization to relapse or first deviation from the scheduled prednisone taper regimen."}
• {"endpoint_text":"- Frequency and type of side effects within 3 years after inclusion","definition_or_measurement_approach":"Count and classification of adverse events and their types occurring up to 3 years after inclusion."}
• {"endpoint_text":"- Frequency of GCrelated side effects within 3 years after inclusion","definition_or_measurement_approach":"Frequency of glucocorticoid-related adverse effects recorded up to 3 years after inclusion."}
• {"endpoint_text":"- Incremental costs between the two strategies at W52 and W78","definition_or_measurement_approach":"Economic endpoint comparing incremental costs per patient between MTX and TCZ strategies at Weeks 52 and 78."}
• {"endpoint_text":"- Marginal costs of both strategies between W52 and W78","definition_or_measurement_approach":"Economic endpoint assessing marginal costs of each strategy between Weeks 52 and 78."}
• {"endpoint_text":"- Percentage of Th1 (CD4+IFN-γ+), Th17 (CD4+IL-17+) and Treg (CD4+CD25highFoxP3+) cells among total CD4+ T cells and levels of expression of IL-6R and Gp130 by CD4+ T cells, measured by flow cytometry at W0, W12, W28, W52, W78 and in case of relapse (limited to 5 centers)","definition_or_measurement_approach":"Immunophenotyping by flow cytometry at specified visits (W0, W12, W28, W52, W78 and at relapse) limited to 5 centers; reports percentages of T-cell subsets and expression levels of IL-6R and gp130."}
• {"endpoint_text":"- Serum concentrations of IL-6, soluble IL-6R and soluble gp130 by Luminex at W0, W12, W28, W52, W78 and in case of relapse.","definition_or_measurement_approach":"Biomarker measurement of serum IL-6, soluble IL-6R and soluble gp130 using Luminex at specified visits and at relapse."}

France

Earliest CTIS Part Ii Submission Date

27-02-2024

Latest Decision Or Authorization Date

20-04-2026

Processing Time Days

783

Number Of Sites

41

Number Of Participants

230

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Dijon

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France