MEthotrexate versus TOcilizumab for treatment of GIant cell Arteritis: a multicenter, randomized, controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Dijon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

27 Jan 2020 → ongoing

Decision date (initial)

2024-03-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-512269-14-00

EudraCT number

2018-002826-22

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare the efficacy of 52 weeks of MTX versus that of 52 weeks of TCZ for the treatment of GCA, after 78 weeks of follow-up.

Secondary objectives 13

1. To compare the efficacy of 12 months of MTX versus that of 12 months of TCZ for the treatment of GCA after 52 and 104 weeks (W104; 2 years) of follow-up
2. To describe the number of patients needed to treat to avoid 1 relapse at W52, 78 and 104
3. To compare (TCZ-group vs. MTX-group) the proportion of patients in remission without prednisone at W52, 78, 104 and 156
4. To compare (TCZ-group vs. MTX-group) the proportion of patients in remission with ≤5 mg/day of prednisone at W52, 78, 104 and 156
5. To assess the GC-sparing effect of MTX and TCZ in the treatment of GCA
6. To assess the effect of MTX and TCZ on quality of life
7. To assess the effect of MTX and TCZ on tiredness
8. To compare (TCZ-group vs MTX-group) time to relapse or deviation from the scheduled regimen of prednisone
9. To assess the safety of MTX and TCZ in the treatment of GCA
10. To assess the effect of MTX and TCZ on the frequency of GCrelated side effects
11. To estimate and compare the mean cost per patient associated with each of the two strategies at W52 and W78
12. To estimate and compare the marginal cost between W52 and W78 of each strategy
13. To assess the effect of MTX and TCZ on T-cell polarization and on the IL-6 pathway

Conditions and MedDRA coding

GIant cell Arteritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Written consent
2. Affiliation to a social security system
3. 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))
4. 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 29

1. Uncontrolled psychotic state
2. Patient unable to give his/her consent
3. Premenopausal women (menopause is defined as amenorrhea for more than 12 consecutive months)
4. Non-compliant patients
5. Weight<40 Kg or >100Kg
6. Patients under maintenance of justice, wardship or legal guardianship
7. History of intoxication (alcohol or medication) requiring hospitalization within 12 months before inclusion
8. Current chronic alcohol abuse (consumption > 20g/day)
9. Recent or incoming surgery within 12 months after inclusion
10. History of stem cell or organ transplantation (except corneas performed more than 3 months prior inclusion)
11. Primary or secondary immunodeficiency
12. Hypersensitivity to methotrexate or tocilizumab, one of its excipients or another human or murine monoclonal antibody
13. History of diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal tract condition that might predispose to bowel perforation
14. Patient refusing to sign methotrexate safety contract
15. 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
16. Long-term systemic glucocorticoid therapy ((except dermocorticoids and inhaled corticoids) for other conditions than GCA or PMR
17. Patient with ≥3 prior glucocorticoid systematic therapies for another disease than GCA or PMR within the 6 months before inclusion
18. Long-term treatment with sulfamethoxazole/trimethoprim (Bactrim®)
19. Live vaccine administered within 30 days before inclusion
20. 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]
21. Laboratory abnormalities, within 12 months before inclusion : positive HBs antigen or positive HCV antibodies
22. History of viral hepatitis B or C (chronic or acute)
23. HIV infection
24. 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)
25. Proven infection requiring oral antibiotics within 14 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)
26. Prior history of histoplasmosis or listeriosis
27. Active tuberculosis
28. 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.
29. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of prednisone at week 78 (W78).

Secondary endpoints 14

1. Percentage of patients alive without relapse after initial remission or deviation from the scheduled regimen of prednisone at W52 and 104
2. 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.
3. Percentage of patients in remission without prednisone at W52, 78, 104 and 156
4. Percentage of patients in remission with prednisone ≤5 mg/day at W52, 78, 104 and 156
5. Cumulative dose of prednisone at W52, 78, 104 and 156
6. Quality of life measured by HAQ and SF36 at W 28, 52, 104 and 156
7. Tiredness measured by FACIT-Fatigue at W28, 52, 104 and 156
8. Time to relapse or deviation from the scheduled regimen of prednisone
9. Frequency and type of side effects within 3 years after inclusion
10. Frequency of GCrelated side effects within 3 years after inclusion
11. Incremental costs between the two strategies at W52 and W78
12. Marginal costs of both strategies between W52 and W78
13. 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)
14. Serum concentrations of IL-6, soluble IL-6R and soluble gp130 by Luminex at W0, W12, W28, W52, W78 and in case of relapse.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Dijon

Sponsor organisation

Centre Hospitalier Universitaire De Dijon

Address

1 Boulevard Jeanne D Arc, Bp 77908 Bp 77908

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de Projet Recherche

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de Projet Recherche

Locations

1 EU/EEA country · 41 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications