TocilizuMab discontinuAtion in GIant Cell Arteritis

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

2 Apr 2024 → ongoing

Decision date (initial)

2023-08-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

After 26 weeks of follow-up, to compare the efficacy on relapse-free survival of immediate versus gradual discontinuation over 24 weeks of tocilizumab.

Secondary objectives 6

1. Compare, between the 2 therapeutic strategies: 1. relapse-free survival at 52 and 78 weeks of follow-up. - 2. Corticosteroid use - 3. quality of life - 4. fatigue - 5. proportion of patients in remission without prednisone at W26, W52 and W78 - 6. the proportion of patients in remission with a dose ≤5 mg/day of prednisone at W26, W52, and W78
2. Identify factors associated with the risk of relapse after initiation of the discontinuation strategy (immediate or gradual discontinuation)
3. Assess tolerance in both groups
4. Assess the frequency of steroid-related side effects in both groups.
5. Immunomonitoring: Evaluate the effect of the discontinuation strategy on cytokine profile, T cell polarization and IL-6 pathway activation (limited number of centers)
6. Imaging: Evaluate the performance of 18 FDG PET scans in predicting the risk of relapse

Conditions and MedDRA coding

Giant Cell Arteritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written consent
2. Diagnosis of GCA, defined by the following criteria: Age ≥50 years at diagnosis
3. Diagnosis of GCA, defined by the following criteria: History of ESR ≥50 mm/h OR CRP ≥20 mg/L (optional criterion if temporal artery biopsy (TAB) is positive).
4. Diagnosis of GCA, defined by the following criteria: at least one of the following clinical criteria: -At least one unequivocal sign of GCA (recent headache, scalp hyperesthesia, jaw claudication, temporal artery abnormality, visual disturbances of ischemic origin) -Clinical sign(s) of polymyalgia rheumatica (PR)
5. Diagnosis of GCA, defined by the following criteria: at least one of the following criteria during GCA follow-up: -TAB consistent with the diagnosis of GCA (non-necrotizing vasculitis with a mononuclear cell-rich inflammatory infiltrate or presence of granulomas, with or without multinuclear giant cells) -Evidence of temporal artery vasculitis by echo-Doppler of the temporal arteries (unilateral or bilateral halo sign) -Evidence of vasculitis of at least one large vessel by imaging (o angio-CT or angio-MRI: arterial wall thickening (≥2mm for aorta; ≥1mm for supra-aortic trunks and upper extremity arteries, ≥0.6mm for the cephalic artery, ...) and/or T1-weighted contrast. - o PET: grade 2 or 3* hypermetabolism of the wall of at least one large vessel (aorta, supra-aortic trunks, cephalic vessels, upper extremity arteries) (*i.e., arterial SUVmax ≥ liver SUVmax))
6. GCA in remission for at least 12 weeks before randomisation (remission = absence of symptoms due to GCA AND CRP ≤10 mg/L)
7. TCZ treatment (IV or SC) or biosimilar initiated 12 to 36 months prior to randomization
8. TCZ treatment (IV or SC) or biosimilar not interrupted more than 12 weeks in the 12 months prior to randomization
9. Treatment with subcutaneous TCZ (162 mg/week) or biosimilar for at least 12 consecutive weeks prior to randomization
10. Treatment with corticoids stopped at least 12 weeks before randomization (hydrocortisone treatment ≤20 mg/day is possible if given at a stable dose for the duration of the study)
11. Biological workup dating from less than 6 weeks on the day of randomization, showing good tolerance of tocilizumab: o AST and ALT < 1.5 x upper limit of normal (ULN) o Hemoglobin >8 g/dL o Platelets >100 G/L o Neutrophils >1 G/L o Lymphocytes >0.5 G/L

Exclusion criteria 18

1. Person who is not affiliated with the national health insurance system
2. Recent or scheduled surgery within 6 months of randomization
3. History of organ or hematopoietic marrow transplantation (except corneal transplantation performed at least 12 weeks prior to randomization)
4. Primary or secondary immune deficiency
5. Concomitant treatment with any of the following: - Methotrexate, leflunomide, cyclosporin A, azathioprine, mycophenolate mofetil, Janus kinase inhibitors, abatacept, secukinumab, anti-TNF-α, anakinra, ustekinumab, or any other immunosuppressive drug within 12 weeks prior to randomization - Rituximab or other anti-CD20 agent within 1 year prior to randomization - Cyclophosphamide in the year prior to randomization
6. History of long-term corticosteroid therapy for conditions other than GCA or PPR. (NB: dermocorticoids, inhaled corticosteroids, and corticosteroid joint infiltrations are allowed during the study)
7. Patient who has previously received ≥3 courses of oral corticosteroids for a disease other than GCA or RRP within 6 months prior to randomization
8. Ongoing anti-tuberculosis treatment at the time of randomization
9. Infections: - Current viral hepatitis B or C - Ongoing HIV infection - Severe infection requiring hospitalization within 30 days prior to randomization
10. Any unstable or poorly controlled condition or disease, acute or chronic, not related to GCA, and considered a contraindication to tocilizumab therapy in the opinion of the investigator
11. Person subject to a measure of legal protection (guardianship, tutorship)
12. Neoplasia < 5 years, (except cervical cancer in situ and skin carcinoma, except melanoma, with R0 resection)
13. Person subject to a court order
14. Patient unable to give consent
15. Person who does not speak French
16. Pre-menopausal women (menopause = amenorrhea of more than 12 consecutive months)
17. Uncontrolled psychotic state
18. History of drug or alcohol intoxication requiring hospitalization within 12 months prior to randomization

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Relapse-free survival in both groups (immediate vs. gradual discontinuation) at 26 weeks of follow-up, defined as the time from S0 (start of immediate/progressive discontinuation strategy) to relapse or death (any cause), whichever occurs first.

Secondary endpoints 6

1. 1. Relapse-free survival in both groups (immediate vs. gradual discontinuation) at W52 and W78 - 2. Cumulative prednisone dose at W26, W52 and W78 - 3. Quality of life scores (HAQ, SF-36) at W0, W12, W26, W52 and W78 - 4. FACIT-Fatigue score at W0, W12, W26, W52 and W78 - 5. Percentage of patients in remission without prednisone at W26, W52 and W78 - 6. Percentage of patients in remission with prednisone dose ≤5 mg/day at W26, W52 and W78
2. Factors associated with relapse-free survival at 26, 52, 78 weeks of follow-up. Potential relapse factors will include all relevant variables such as demographic, clinical and biological data related to GCA (gender, age, large vessel involvement, CRP, fibrinogen, IL-6), duration of TCZ treatment before inclusion, relapse status before inclusion.
3. Frequency and type of adverse events in both groups during the first 78 weeks after inclusion
4. Frequency of corticosteroid-related side effects (GTI score [Appendix 1] at baseline and at 52 weeks) in both groups
5. Immunomonitoring : a.Serum concentrations of haptoglobin, orosomucoid, CXCL10, IFN-γ, GM-CSF, IL-6, soluble IL-6R, and soluble gp130 measured by Luminex® at W0, W12, W26, and W52, and at relapse. - b. Percentage of Th1 (CD4+ IFN-γ+), Th17 (CD4+ IL-17+) and Treg (CD4+ CD25high FoxP3+) cells among total CD4+ T cells and expression levels of IL-6R and Gp130 by CD4+ T cells, measured by flow cytometry at W0, W12 and W26 and in case of relapse (limited to 5 centers: Dijon, Mâcon, Cochin, Metz, Nancy)
6. Imaging: calculation of the vascular score (PETVAS50) measured by 18FDG PET scan to predict the risk of relapse at week 78. The PET scan will be performed between screening and randomization (centers able to perform the examination and send the anonymized images to Pr Jean-Louis Alberini [Georges François Leclerc Center, Dijon] for centralized review)

Investigational products

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

Test 2

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 projets recherche

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

chef de projets recherche

Locations

1 EU/EEA country · 43 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 12 files

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

Application history

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