Efficacy of Tocilizumab in association to steroids in giant cell arteritis with cerebro-vascular involvement patients (ToGiAS). A french prospective multicentre randomized versus placebo phase III trial (TOGIAC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14], Diseases [C] - Nervous System Diseases [C10]

Trial duration

24 Sep 2021 → 1 Aug 2025

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Association Robert Debré pour la Recherche Médicale · CHUGAI PHARMA France · ROCHE

External identifiers

EU CT number

2024-511906-21-00

EudraCT number

2020-000080-23

ClinicalTrials.gov

NCT04888221

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Assess the efficacy of tocilizumab to induce complete remission of GCA with cerebrovascular involvement (clinical, radiological) and absence of clinical and MRI ischemic stroke recurrence at 24 weeks.

Secondary objectives 8

1. Relapse-free survival
2. Time to remission
3. Serious adverse event-free survival
4. Neurovascular imaging improvement
5. Number and percentages of deaths
6. Number and percentages of patients with rankin score 0-1
7. Percentage of clinical and MRI ischemic stroke recurrence at 24 weeks. Influence of tocilizumab treatment on cumulative steroid dose at 24 weeks
8. Safety of tocilizumab assessed by adverse events

Conditions and MedDRA coding

Giant cell arteritis with Cerebro-vascular involvement

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age > 60 years
2. Diagnosis of : - GCA (according to ACR criteria or positive temporal artery biopsy) (de novo and/or relapse) - And neurovascular involvement: 􀂃 Defined by PET uptake of vertebral and/or carotid arteries (extra or intra cranial) or angioCT/MRI showing arterial involvement inconsistent with atherosclerosis 􀂃 Either Ischemic stroke (including TIA) in the vertebro-basilar or carotid territory (symptomatic arterial involvement) 􀂃 Without Ischemic stroke (including TIA) (asymptomatic arterial involvement)
3. Inclusion should be done  within 4 weeks after the stroke concerning the “symptomatic” patients  within 4 weeks after the diagnosis of GCA (or relapse) concerning the patients with asymptomatic neurovascular involvement.  Within 21 days after starting the corticosteroids
4. Signed Informed Consent Form
5. Affiliation to social security

Exclusion criteria 35

1. Other proven cause of stroke: atrial fibrillation, significant atheromatous stenosis of carotid or vertebro-basilar arteries
2. Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever was longer) of screening
3. Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to Campath (alemtuzumab), anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20 within 6 months before the baseline
4. Treatment with IV gamma globulin or plasmapheresis within 24 weeks of baseline
5. Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation within 2 months before the baseline
6. Previous treatment with tocilizumab (TCZ) within 6 months before the baseline
7. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or simultaneously with tocilizumab treatment
8. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil (MMF) within 4 weeks of baseline
9. Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks; or anakinra within 1 week of baseline
10. Previous treatment with tofacitinib within 2 months before the baseline
11. Treatment with cyclophosphamide within 24 weeks of baseline
12. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or to prednisone
13. 13. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, or gastrointestinal disease
14. Current liver disease, as determined by the investigator
15. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
16. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
17. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
18. Active TB requiring treatment within the previous 3 years (Patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years were eligible)
19. Primary or secondary immunodeficiency (history of or currently active)
20. Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that had been excised and cured)
21. History of alcohol, drug, or chemical abuse within 1 year prior to screening
22. Body weight >150 kg
23. Serum creatinine >1.4 mg/dL (124 µmol/L) in female patients and 1.6 mg/dL (141 µmol/L) in male patients
24. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)× 3 Upper limit of normal (ULN)>
25. Platelet count < 100 109/L (100,000/mm3)
26. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
27. White blood cells <3.0 x109/L (3000/mm3)
28. Absolute neutrophil count < 2.0 x 109/L (2000/mm3)
29. Absolute lymphocyte count < 0.5 X 109/L (500/mm3)
30. Positive hepatitis B surface antigen or hepatitis C antibody
31. Contraindication to aspirin, clopidogrel, steroids use, rifampicin and/or izoniazid
32. Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization, except arterial thrombectomy if necessary for ischemic stroke
33. Transplanted organs (except corneal transplant performed more than 3 months prior to screening)
34. Inability to provide informed consent
35. Participation in another interventional research

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is composite: complete remission of GCA with cerebrovascular involvement (clinical, biological, and PET uptake) including absence of clinical and MRI ischemic stroke recurrence at 24 weeks

Secondary endpoints 9

1. Relapse-free survival will be assessed at weeks 4, 12, 24 and 52
2. Time to remission will be assessed at weeks 4, 12, 24 and 52
3. Serious adverse event-free survival will be assessed at weeks 4, 12, 24 and 52
4. Neurovascular imaging improvement: angio-CT improvement of vasculitis lesions and /or improvement or disappearance of PET FDG uptake will be assessed at weeks 4, 12, 24 and 52
5. Number and percentages of deaths Relapse-free survival will be assessed at weeks 4, 12, 24 and 52
6. Number and percentages of patients with rankin score 0-1 Relapse-free survival will be assessed at weeks 4, 12, 24 and 52
7. Percentage of clinical and MRI ischemic stroke recurrence at 24 weeks
8. Influence of tocilizumab treatment on cumulative steroid dose at 24 weeks
9. Safety of tocilizumab assessed by adverse events (mostly nasopharyngitis, headache, hypertension, injection site reactions and serious adverse events (mostly upper respiratory tract infections, but also rare liver damage), neutropenia and hypercholesterolemia

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator

Locations

1 EU/EEA country · 8 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

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