INTOReTAK - Multicentre, randomized, prospective trial evaluating the efficacy and safety of Infliximab to tocilizumab in refractory or relapsing Takayasu arteritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

4 Feb 2021 → ongoing

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ministry of Health - PHRC

External identifiers

EU CT number

2024-512229-10-00

EudraCT number

2018-003753-13

ClinicalTrials.gov

NCT04564001

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To obtain, by arm, ≥ 70% of patients at 6 months post-treatment with prednisone (or the prednisolone) ≤ 0.1mg/kg per day and inactive disease during the last 3 months.

Secondary objectives 7

1.  To estimate the incidence of relapse between 3 and 6 months post-treatment in each arm
2.  To estimate the incidence of traitement failure at 3 months post-treatment in each arm
3.  To estimate the incidence of revascularization procedures (endovascular or surgical) required due to the disease at 6 & 12 post-treatment in each arm
4.  To estimate the cumulative dose of prednisone(or the prednisolone) at 6 & 12 months post-treatment in each arm
5.  To estimate the incidence of adverse events at 6 & 12 months post-treatment in each arm
6.  To estimate the mean change in SF-36 quality-of-life values from Day1 of treatment to 6 & 12 months post-treatment in each arm
7.  To estimate the proportion of new vascular lesions at 6 & 12 months post-treatment in each arm measured by angio-computorized tomography or magnetic resonance imaging angiography.

Conditions and MedDRA coding

Takayasu arteritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1.  Diagnosis of Takayasu arteritis (see protocol)
2.  Medical follow-up in a university or general hospital in France
3.  Social insurance
4.  Willing and able to provide written informed consent
5.  Chest X-ray results (postero-anterior and lateral) or chest CT within 12 weeks prior to the inclusion & randomization visit with no evidence of active tuberculosis, active infection, or malignancy
6.  Tuberculosis assessment meeting one of the following conditions (see protocol)
7.  Negative human immunodeficiency virus (HIV) serology, negative hepatitis C RNA, and hepatitis B surface antigen within 3 months.
8.  Willing and able to comply with treatment and follow-up procedures required by the study protocol
9.  For female subjects of child-bearing age, a negative serum pregnancy test and no pregnancy plans within 12 months.
10.  For subjects with reproductive potential, a willingness to use contraceptive measures adequate to prevent the subject or the subject’s partner from becoming pregnant during the study.
11.  Active disease according to the international criteria of the National Institute of Health (NIH) (appendix 2) - see protocol
12.  Refractory/relapsing disease or symptomatic severe arterial involvement
13.  For Refractory/relapsing disease, patients with one immunosuppressive agent (methotrexate, azathioprine, mercaptopurine or mycophenolate mofetil, leflunomide, ciclosporine, hydroxychloroquine) with no change in dosage within the last 30 days unless allergy/intolerance or contraindication to immunosuppressive agents.
14.  Age of 15 years or older
15.  Weight 40 – 120 kg
16.  For symptomatic severe arterial involvement, patients with one immunosuppressive agent (methotrexate, azathioprine, mercaptopurine or mycophenolate mofetil, leflunomide, ciclosporine, hydroxychloroquine) unless allergy/intolerance or contraindication to immunosuppressive agents.

Exclusion criteria 21

1.  Active tuberculosis or latent tuberculosis infection currently treated less than 3 weeks
2.  Evidence of active infection (includes chronic infection)
3.  Infection requiring treatment with antibiotics within 2 weeks prior to the inclusion & randomization visit
4.  Infection with positive human immunodeficiency virus (HIV) serology, positive hepatitis C RNA, or a positive hepatitis B surface antigen.
5.  Pregnancy or lactation
6.  Inability to comply with study guidelines
7.  Inability to provide informed consent
8.  Alcohol or drug abuse, that, in the investigator’s opinion, could prevent a subject from fulfilling the study requirements or that would increase the risk of study procedures
9.  Severe renal insufficiency (creatinine clairance <30mL/min/1,73m2)
10.  Hepatic dysfunction as shown by aspartate transaminase (AST) or alanine transaminase (ALT) levels >5‐fold the upper limit of normal
11.  Heart failure ≥ stage III / IV NYHA,
12.  History of any malignant neoplasm except adequately treated basal or squamous cell carcinoma of the skin, or solid tumors treated with curative therapy and disease free for at least 5 years.
13.  History of multiple sclerosis and/or demyelinating disorder
14.  History of severe allergic or anaphylactic reactions to infliximab, any chimeric murine monoclonal antibody, tocilizumab, and their respective excipients or prednisone (or the prednisolone).
15.  History of immediate hypersensitivity reaction to iodinated and gadolinium-based contrast media
16.  Cytopenia: Hemoglobin < 8.5 g/dL, absolute neutrophil < 1.5 G/L, Platelet count < 80 G/L
17.  Any live (attenuated) vaccine fewer than 4 weeks before enrolment. Recombinant or killed virus vaccines fewer than 2 weeks before the inclusion & randomization visit.
18.  Use of the following systemic treatments during the specified periods: a.Treatment with biologic therapy (infliximab, adalimumab, certolizumab pegol, golimumab, anakinra, tocilizumab, etanercept, abatacept, ixekizumab, secukinumab, ustekinumab, alemtuzumab) within 3 months prior to the inclusion & randomization visit b. Past treatment with rituximab within the past months, or past treatment with rituximab more than months ago where the B lymphocytes count has not returned to normal at time of the inclusion & randomization visit c. Treatment with any systemic alkylating agents within 3 months prior to the inclusion & randomization visit (e.g., cyclophosphamide, chlorambucil)
19.  Indication to initiate infliximab or tocilizumab for another active disease than Takayasu arteritis
20.  Lack of affiliation to a social security benefit plan (as a beneficiary or assignee)
21.  Presence of any of the following on-ongoing and on-treatment disease processes: o Microscopic polyangiitis o Granulomatosis with polyangiitis o Eosinophilic granulomatosis with polyangiitis o Polyarteritis nodosa o Cogan’s syndrome o Behcet’s disease o Kawasaki’s disease o Atypical mycobacterial infections o Deep fungal infections o Lymphoma, lymphomatoid granulomatosis, or other type of malignancy tha mimics vasculitis o Cryoglobulinemic vasculitis o Systemic lupus erythematosus o Rheumatoid arthritis o Mixed connective tissue disease or any overlap autoimmune syndrome o Known constitutive immunodeficiency

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion at 6 months after Day1 of treatment, of patients with prednisone (or the prednisolone) ≤ 0.1mg/kg per day and sustained inactive disease from M3 to M6 and same biological therapy from Day1 of treatment among the randomized patients in the same arm.

Secondary endpoints 10

1.  Incidence of relapse as defined by the NIH criteria between M3 and M6 after Day1 of treatment.
2.  Incidence of traitement failure at M3 after Day1 of treatment i.e disease still active according to the NIH criteria
3.  Proportion at 6 months after Day1 of treatment of patients with prednisone (or the prednisolone) ≤ 0.1mg/kg per day and sustained inactive disease (modified NIH score (without criterion 3) ≤ 1) from M3 to M6 and same biological therapy from Day1 of treatment among the randomized patients in the same arm.
4.  Incidence of relapse as defined by the modified NIH criteria (without criterion 3) ≥2 between M3 and M6 after Day1 of treatment.
5.  incidence of traitement failure at M3 after Day1 of treatment i.e disease still active according to the modified NIH criteria (without criterion 3) ≥2
6.  Incidence of revascularization procedures (endovascular or surgical) from Day1 of treatment to M6 and M12 after Day1 of treatment
7.  Cumulative doses of prednisone (or the prednisolone) in each arm at M6 and M12 after Day1 of treatment
8.  Incidence of adverse events of grades III or IV at M6 and M12 after Day1 of treatment
9.  Mean change in the quality of life questionnaire SF-36 from D1 of treatment to M6 and M12 after treatment
10.  Proportion of new vascular lesions at M6 and M12 after Day1 of treatment assessed by angio-CT or MR angiography

Investigational products

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

Test 2

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

Pr Tristan MIRAULT

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Touria EL AAMRI

Locations

1 EU/EEA country · 18 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 10 files

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

Application history

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