Comparative Efficacy of Methotrexate Versus Tocilizumab in Giant Cell Arteritis: A Multicenter, Randomized, Controlled Trial
- Trial ID
- 2024-512269-14-00
- Protocol
- METOGiA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of 52 weeks of Methotrexate (MTX) versus 52 weeks of Tocilizumab (TCZ) for the treatment of Giant Cell Arteritis (GCA), following 78 weeks of follow-up. This comparison is clinically relevant as it aims to determine the most effective treatment strategy for managing GCA, a condition that can lead to serious complications if not adequately controlled.
Secondary objectives include:
- Comparing the efficacy of 12 months of MTX versus 12 months of TCZ after 52 and 104 weeks of follow-up.
- Describing the number of patients needed to treat to avoid one relapse at weeks 52, 78, and 104.
- Comparing the proportion of patients in remission without prednisone and with ≤5 mg/day of prednisone at weeks 52, 78, 104, and 156.
- Assessing the glucocorticoid-sparing effect of MTX and TCZ in the treatment of GCA.
- Evaluating the effect of MTX and TCZ on quality of life and tiredness.
- Comparing the time to relapse or deviation from the scheduled regimen of prednisone between the TCZ and MTX groups.
- Assessing the safety of MTX and TCZ in the treatment of GCA.
- Evaluating the effect of MTX and TCZ on the frequency of glucocorticoid-related side effects.
- Estimating and comparing the mean cost per patient and the marginal cost between weeks 52 and 78 for each strategy.
- Assessing the effect of MTX and TCZ on T-cell polarization and the IL-6 pathway.
Participants
The clinical trial focuses on individuals diagnosed with **Giant Cell Arteritis** (GCA), a condition characterized by inflammation of the blood vessels. The study population includes both male and female participants, with an age range of 50 years and older, reflecting the typical onset age for GCA. Participants are required to have active GCA within six weeks before randomization, as indicated by specific clinical markers such as elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels, along with cranial symptoms or polymyalgia rheumatica (PMR) symptoms. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include written consent and affiliation with a social security system, ensuring that participants meet the revised diagnostic criteria for GCA. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **methotrexate** versus **tocilizumab** in the treatment of **giant cell arteritis** (GCA). This is a multicenter, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial will span a total duration of 78 weeks, with the primary objective being to assess the percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of **prednisone** at week 78. Secondary endpoints include the percentage of patients in remission without prednisone at various time points, quality of life assessments, and the frequency of side effects.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of GCA, and active disease status. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted at weeks 0, 12, 28, 52, and 78. The end-of-study visit will occur at week 78, marking the conclusion of the participant's involvement in the trial.
The expected length of participant involvement is approximately 78 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or deviation from the study protocol. The trial will utilize **CORTANCYL** (prednisone) as an auxiliary treatment, with a maximum daily dose of 40 mg and a total treatment period of 41 weeks. **Folic acid** and **methotrexate** will be administered as comparator and test products, respectively, with specific dosing regimens and treatment periods outlined in the protocol. The trial aims to provide comprehensive data on the comparative effectiveness of the two treatment strategies for GCA.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **CORTANCYL** is utilized in three different dosages: 20 mg, 5 mg, and 1 mg. Each form is a **tablet** containing the active substance **prednisone**, a chemical compound. The tablets are administered orally with a maximum daily dose of 40 mg and a total dose not exceeding 450 mg over a treatment period of 41 weeks. The pharmaceutical form is a scored tablet, allowing for dose adjustments as necessary.
**FOLIC ACID** is included as an auxiliary treatment in the form of a **tablet**. It is administered orally with a maximum daily dose of 10 mg and a total dose of up to 520 mg over a 52-week period. Folic acid serves as an anti-anaemic preparation, supporting the primary treatment regimen.
**RoActemra**, containing the active substance **tocilizumab**, is provided as a 162 mg solution for injection in a pre-filled syringe. This protein-based medication is administered subcutaneously with a maximum daily dose of 162 mg and a total dose of 8424 mg over 52 weeks. RoActemra is a key component of the trial, serving as a comparator to evaluate its efficacy against other treatments.
**METHOTREXATE** is administered as a solution for injection, with the active substance being a chemical compound. It is delivered subcutaneously with a maximum daily dose of 20 mg and a total dose of 1025 mg over a 52-week period. Methotrexate functions as an immunosuppressant, playing a critical role in the trial's objective to assess its effectiveness in treating giant cell arteritis.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of methotrexate versus tocilizumab over a 52-week treatment period, with a follow-up duration of 78 weeks.
Efficacy
The efficacy of the clinical trial comparing **methotrexate** (MTX) and **tocilizumab** (TCZ) for the treatment of Giant Cell Arteritis (GCA) will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of prednisone at week 78. Secondary endpoints include the percentage of patients alive without relapse at weeks 52 and 104, the number of patients needed to treat to avoid one relapse at weeks 52, 78, and 104, and the percentage of patients in remission without prednisone at weeks 52, 78, 104, and 156.
Additional secondary endpoints involve the cumulative dose of prednisone, quality of life measured by HAQ and SF36, and tiredness measured by FACIT-Fatigue at specified timepoints. The trial will also evaluate the time to relapse or deviation from the scheduled regimen, frequency and type of side effects, and incremental costs between the two strategies. Immunological parameters such as the percentage of Th1, Th17, and Treg cells among total CD4+ T cells, and serum concentrations of IL-6, soluble IL-6R, and soluble gp130 will be measured at various timepoints using flow cytometry and Luminex, respectively.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written consent
- Affiliation to a social security system
- 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))
- 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
- Uncontrolled psychotic state
- Patient unable to give his/her consent
- Premenopausal women (menopause is defined as amenorrhea for more than 12 consecutive months)
- Non-compliant patients
- Weight<40 Kg or >100Kg
- Patients under maintenance of justice, wardship or legal guardianship
- History of intoxication (alcohol or medication) requiring hospitalization within 12 months before inclusion
- Current chronic alcohol abuse (consumption > 20g/day)
- Recent or incoming surgery within 12 months after inclusion
- History of stem cell or organ transplantation (except corneas performed more than 3 months prior inclusion)
- Primary or secondary immunodeficiency
- Hypersensitivity to methotrexate or tocilizumab, one of its excipients or another human or murine monoclonal antibody
- History of diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal tract condition that might predispose to bowel perforation
- Patient refusing to sign methotrexate safety contract
- 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
- Long-term systemic glucocorticoid therapy ((except dermocorticoids and inhaled corticoids) for other conditions than GCA or PMR
- Patient with ≥3 prior glucocorticoid systematic therapies for another disease than GCA or PMR within the 6 months before inclusion
- Long-term treatment with sulfamethoxazole/trimethoprim (Bactrim®)
- Live vaccine administered within 30 days before inclusion
- 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]
- Laboratory abnormalities, within 12 months before inclusion : positive HBs antigen or positive HCV antibodies
- History of viral hepatitis B or C (chronic or acute)
- HIV infection
- 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)
- Proven infection requiring oral antibiotics within 14 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)
- Prior history of histoplasmosis or listeriosis
- Active tuberculosis
- 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.
- 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 27 Jan 2020 | 230 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RoActemra 162 mg solution for injection in pre-filled syringe. | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 162 | 52 | PRD1576593 |
FOLIC ACID | Other | — | ORAL USE | 10 | 52 | SUB07774MIG |
CORTANCYL 5 mg, comprimé sécable | Other | COMPRIMÉ SÉCABLE | ORAL USE | 40 | 41 | PRD9995015 |
METHOTREXATE | Test | — | SUBCUTANEOUS USE | 20 | 52 | SUB08856MIG |
CORTANCYL 1 mg, comprimé | Other | COMPRIMÉ | ORAL USE | 40 | 41 | PRD9995013 |
CORTANCYL 20 mg, comprimé sécable | Other | COMPRIMÉ SÉCABLE | ORAL USE | 40 | 41 | PRD9995017 |