| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with refractory or relapsing Takayasu Arteritis desease |
| Patients ayant réfractaire ou en rechute de l'artérite de Takayasu |
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| E.1.1.1 | Medical condition in easily understood language |
| INfliximab and TOcilizumab in Refractory/relapsing TAKayasu arteritis |
| Efficacite de l'Infliximab ou Tocilizumab dans la maladie de Takayasu réfractaire ou en rechute |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To obtain ≥ 70% of patients with prednisone ≤ 0.1mg/kg per day and inactive disease during 3 months at 6 months after randomization.
Proportion at 6 months after randomization of patients with prednisone ≤ 0.1mg/kg per day and sustained inactive disease from M3 to M6.
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Obtenir ≥ 70% des patients avec prednisone ≤ 0,1mg/kg par jour et maladie inactive pendant 3 mois à 6 mois après randomisation.
Proportion à 6 mois après la randomisation des patients avec prednisone ≤ 0,1 mg/kg par jour et maladie inactive de M3 à M6.
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| E.2.2 | Secondary objectives of the trial |
To compare, after randomization between the 2 arms.
Incidence of relapse between 3 and 6 months
Incidence of traitement failure at 3 months
Incidence of revascularization procedures (endovascular or surgical) required due to the disease
Cumulative dose of prednisone at 6 & 12 months
Incidence of adverse events at 6 & 12 months
Mean change in SF-36 quality-of-life values from randomization to 6 & 12 months
Proportion of new vascular lesions at 6 & 12 months
Incidence of relapse as defined by the NIH criteria between 3 and 6 months
Incidence of revascularization procedures (endovascular or surgical) from randomization to 6 months
Cumulative doses of prednisone in each arm at 6 & 12 months
Incidence of adverse events of grades III and IV at 6 & 12 months
Mean change in the quality of life questionnaire SF-36 from randomization to 6 & 12 months
Proportion of new vascular lesions at 6 & 12 months
Incidence of adverse event grade III or IV during 6 & 12 months
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Comparer après la randomisation entre les 2 bras:
Incidence des rechutes entre 3 et 6 mois
Incidence des procédures de revascularisation (endovasculaire ou chirurgicale) requises en raison de la maladie à 6 et 12 mois
Dose cumulative de prednisone à 6 et 12 mois
Incidence des événements indésirables 6 et 12 mois
Changement moyen des valeurs de la qualité de vie du SF-36 de la randomisation à 6 et 12 mois
Proportion de nouvelles lésions vasculaires à 6 & 12 mois
Rechute telle que définie par les critères des NIH entre 3 et 6 mois
Doses cumulatives de prednisone dans chaque groupe à 6 et 12 mois
Incidence d'événements indésirables de grades III et IV à 6 et 12 mois
Changement moyen dans le questionnaire sur la qualité de vie SF-36 de la randomisation à 6 et 12 mois
Proportion de nouvelles lésions vasculaires à 6 et 12 mois après la randomisation
Incidence d'événements indésirables de grade III ou IV pendant 6 et 12 mois.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis of Takayasu disease according to the international criteria of the American College of Rheumatology (ACR) (appendix 1)
o Age at disease onset < 40 years
o Claudication of extremities
o Decreased brachial artery pulse (one or both arteries)
o Blood pressure difference of >10mm Hg between the arms
o Bruit over subclavian arteries or aorta
Active disease according to the international criteria of the National Institute of Health (NIH) (appendix 2)
New onset or worsening of at least two of the following four criteria
o Systemic features
o Elevated erythrocyte sedimentation rate
o Features of vascular ischemia or inflammation
o Typical angiographic features
Refractory/relapsing disease
o Failure of disease to respond to daily corticosteroids therapy (1mg/kg/day for > 1month), i.e. disease still active
o Inability to taper corticosteroids below 10mg/day within 6 months
o Inability to discontinue corticosteroids after 1 year of treatment
o Relapse of disease after gradual decrease of corticosteroids therapy
Patients with one immunosuppressive agent (methotrexate, azathioprine, mercaptopurine or mycophenolate mofetil)
Age of 18 years or older
Weight 40 – 120 kg
Medical follow-up in a university or general hospital in France
Social insurance
Willing and able to provide written informed consent
Willing and able to comply with treatment and follow-up procedures required by the study protocol
For female subjects of child-bearing age, a negative serum pregnancy test
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. Adequate contraceptive measures include hormonal methods used for two or more cycles prior to Screening (e.g., oral contraceptive pills, contraceptive patch, or contraceptive vaginal ring), barrier methods (e.g., contraceptive sponge, diaphragm used in conjunction with contraceptive foam or jelly, or condom used in conjunction with contraceptive foam or jelly), intrauterine methods (IUD), sterilization (e.g., tubal ligation or a monogamous relationship with a vasectomized partner), and abstinence.
Chest X-ray results (postero-anterior and lateral) within 12 weeks prior to enrollment with no evidence of active tuberculosis, active infection, or malignancy
Tuberculosis assessment:
o Active Tuberculosis infection treatment achieved
o Completion of at least 3 weeks treatment for Latent Tuberculosis infection
o Negative tuberculin skin test (TST) or interferon-gamma release assay (IGRA) (e.g., QuantiFERON®-TB Gold or T-spot TB® Test)
A potential subject with a positive TST or IGRA at inclusion is eligible if her/his chest X-ray does not show evidence suggestive of active tuberculosis infection and there are no clinical signs and symptoms of pulmonary and/or extra-pulmonary tuberculosis infection. These subjects with a latent tuberculosis infection who have not already received a prophylactic tuberculosis treatment must agree in advance to complete such a treatment course. |
Age ≥ 18 ans
Consentement écrit et éclairé
Diagnostic de l'AT selon les critères internationaux de l'American College of Rheumatology (ACR) (Arend et al, 1990).
Maladie active selon les critères internationaux du National Institute of Health (NIH) (Kerr et al, 1994).
Patients avec un agent immunosuppresseur (méthotrexate, azathioprine ou mycophénolate mofétil).
Maladie réfractaire ou récidivante :
- Absence de réponse de la maladie au traitement quotidien aux corticostéroïdes (1 mg/kg/jour pendant > 1 mois), c'est-à-dire que la maladie est toujours active.
- Incapacité de réduire les corticostéroïdes en dessous de 10mg/jour dans un délai de 6 mois.
- Incapacité d'arrêter les corticostéroïdes après 1 an de traitement.
- Rechute de la maladie après une diminution graduelle du traitement aux corticostéroïdes.
Suivi médical dans un hôpital en France
Avoir la capacité et la volonté de donner un consentement éclairé par écrit et de se conformer aux exigences du protocole de l'étude.
Poids supérieur à 40 kg
Contraception efficace chez les femmes en âge de procréer
Aucun signe de tuberculose latente dans les antécédents médicaux, radiographie pulmonaire, test in vitro ou traitement de la tuberculose latente terminé.
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| E.4 | Principal exclusion criteria |
Active tuberculosis or untreated latent tuberculosis
Evidence of active infection (includes chronic infection)
Infection requiring treatment with antibiotics within 2 weeks prior to enrollment
Infection with human immunodeficiency virus (HIV), hepatitis C, or a positive hepatitis B surface antigen.
Pregnancy or lactation
Inability to comply with study guidelines
Inability to provide informed consent
Immunosuppressant type or dose modification within 30 days prior to enrollment
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
Severe renal insufficiency (creatinine clairance <30mL/min/1,73m2)
Hepatic dysfunction as shown by aspartate transaminase (AST) or alanine transaminase (ALT) levels >5‐fold the upper limit of normal
Heart failure ≥ stage III / IV NYHA,
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.
History of multiple sclerosis and/or demyelinating disorder
History of severe allergic or anaphylactic reactions to cyclophosphamide, interferon or infliximab and prednisone.
History of immediate hypersensitivity reaction to iodinated and gadolinium-based contrast media
Cytopenia: Hemoglobin < 8.5 g/dL, absolute neutrophil < 1.5 G/L, Platelet count < 80 G/L
Any live (attenuated) vaccine fewer than 4 weeks before enrolment. Recombinant or killed virus vaccines fewer than 2 weeks before enrolment.
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 6 months prior to enrollment
b-Past treatment with rituximab within the past 12 months, or past treatment with rituximab more than 12 months ago where the B lymphocytes count has not returned to normal at time of enrollment
c-Treatment with any systemic alkylating agents within 6 months prior to enrollment (e.g., cyclophosphamide, chlorambucil)
History of hypersensitivity to infliximab, other murine proteins, or to any of the excipients
Hypersensitivity to Tocilizumab or to any of the excipients
Lack of affiliation to a social security benefit plan (as a beneficiary or assignee)
Presence of any of the following disease processes:
o Microscopic polyangiitis
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Antécédent de traitement par anticorps monoclonaux
Infection aiguë traitée par antibiotiques dans les 30 derniers jours.
Tuberculose évolutive
infection par le VIH
Troubles démyélinisants préexistants ou d'apparition récente
Cancer ou trouble hématologique
Antécédents d’hypersensibilité à l’infliximab, aux autres protéines murines, ou à l’un des excipients
Hypersensibilité au Tocilizumab ou à l’un des excipients
Grossesse ou allaitement
Absence d'affiliation à un régime de sécurité sociale (en tant que bénéficiaire ou cessionnaire).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion at 6 months after randomization of patients with prednisone ≤ 0.1mg/kg per day and sustained inactive disease from M3 to M6. |
| Proportion à 6 mois après la randomisation des patients avec prednisone ≤ 0,1 mg/kg par jour et maladie inactive de M3 à M6. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months after randomization of patients |
6 mois après la randomisation des patients
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|
| E.5.2 | Secondary end point(s) |
Incidence of relapse as defined by the NIH criteria between 3 and 6 months.
Incidence of revascularization procedures (endovascular or surgical) from randomization to 6 months after randomization.
Cumulative doses of prednisone in each arm at 6 & 12 months after randomization.
Incidence of adverse events of grades III and IV at 6 & 12 months after randomization.
Mean change in the quality of life questionnaire SF-36 from randomization to 6 & 12 months after randomization.
Proportion of new vascular lesions at 6 & 12 months after randomization measured by angio-CT or MR angiography
Incidence of adverse event grade III or IV during 6 & 12 months after randomization.
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Incidence de rechute telle que définie par les critères des NIH entre 3 et 6 mois.
Incidence des procédures de revascularisation (endovasculaire ou chirurgicale) de la randomisation à 6 mois après la randomisation.
Doses cumulatives de prednisone dans chaque groupe à 6 et 12 mois après la randomisation.
Incidence d'événements indésirables de grades III et IV à 6 et 12 mois après la randomisation.
Changement moyen dans le questionnaire sur la qualité de vie SF-36 de la randomisation à 6 et 12 mois après la randomisation.
Proportion de nouvelles lésions vasculaires à 6 et 12 mois après la randomisation, mesurée par angio-scanner ou angiographie par résonnance magnétique.
Incidence d'événements indésirables de grade III ou IV pendant 6 et 12 mois après la randomisation. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
6 & 12 months after randomization
from randomization to 6 & 12 months after randomization. |
6 et 12 mois après la randomisation
De la randomisation à 6 et 12 mois après la randomisation |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
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