Clinical trial: MEthotrexate Versus TOcilizumab for Treatment of GIant Cell Arteritis: a Multicenter, Randomized, Controlled Trial (NCT03892785)

Eligibility criteria:
Inclusion Criteria:

          -  Written consent

          -  Affiliation to a social security system

          -  Diagnosis of GCA, as defined by the revised GCA diagnosis criteria:44

               -  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)

          -  unequivocal symptoms of polymyalgia rheumatica (PMR)

             o 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)

          -  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

               -  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 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:

               -  AST or ALT >1.5 x upper limit of normal (ULN)

               -  total bilirubin >ULN

               -  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]

               -  positive HBs antigen or positive HCV antibodies

          -  Infections:

               -  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)
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 50 Years old.


Patient description (medical language): A 61-year-old man comes to the emergency department complaining of an acute vision disturbance. He had an episode of vision disturbance in the right eye that occurred suddenly and resolved spontaneously in 15 minutes. He also has right jaw pain while chewing.  He also complains of fatigue and hip muscle aches over the last several months.  The patient has a history of mild hyperlipidemia that has been controlled by diet and lifestyle modifications.  On examination, his blood pressure is 130/70 mm Hg and pulse is 66/min.  Neurological examination is unremarkable.  Visual examination is also normal. ESR is 103 mm/h. Temporal artery biopsy shows multinuclear giant cells and internal elastic membrane fragmentation.

Patient description (patient's own words): I’m a 61-year-old man and I came to the ER because I had a sudden episode where I couldn’t see out of my right eye. It only lasted about 15 minutes and went away on its own but it really scared me. I’ve also been having pain in my right jaw when I chew. For the past few months I’ve felt really tired and noticed my hips ache a lot. I have a history of mild cholesterol issues but I’ve been managing that with my diet and lifestyle. When the doctors checked me my blood pressure and pulse were normal and my vision and neurological exams didn’t show anything wrong. However they ran some tests and said my ESR levels were very high and a biopsy of my temporal artery showed some inflammation and damage.

Does the patient match the trial criteria? Entailment