Multicentre, Randomized, Prospective Trial Evaluating the Efficacy and Safety of Infliximab to Tocilizumab in Refractory or Relapsing Takayasu Arteritis

NCT04564001 | Unknown Phase 2 DMC

• 1 other identifier: P160909
• Study Type: interventional
• Target: 50
• Locations: 0 countries
• Sites: N/A

Brief Summary

Takayasu arteritis (TA) is a vasculitis of unknown origin, resulting in progressive thickening and stenosis of large and medium arteries (the aorta and its major branches, and the pulmonary arteries). First line therapy of TA consists of high dose corticosteroids (CS). Between 20 and 50% of cases respond to CS alone, with subsequent resolution of symptoms and stabilization of vascular abnormalities. Although second-line agents (methotrexate, azathioprine, mercaptopurine, mycophenolate mofetil) may result in initial remission, relapses remain common when prednisone is tapered. Thus, 50% of CS-resistant or relapsing TA patients may achieve sustained remission with the addition of methotrexate. During the last decade, biologics such as anti-tumor necrosis factor alpha (anti-TNFα) and anti-interleukin-6 (anti-IL-6) have been used as third-line treatment in refractory or relapsing TA. Almost 90% of CS-methotrexate resistant TA cases responded to infliximab, an anti-TNFα, and sustained remission was obtained in 37 to 76% of the cases. Tocilizumab, an anti-IL-6 has given similar results with 68% of sustained remission in refractory TA. Irrespective of classical cardiovascular risk factors, the systemic inflammation and CS use play a pivotal role in the occurrence of cardiovascular thrombotic events (CVEs). As CVEs overlap with TA complications it is primordial to drastically taper CS in that vasculitis. We therefore hypothesize that Infliximab or Tocilizumab can achieve a remission in more than 70% of refractory/relapsing TA cases to CS associated to a second-line agent. INTOReTAK, first randomized prospective study in TA, has an original design testing Infliximab and Tocilizumab propensity to achieve over 70% of sustained remission in refractory/relapsing TA and evaluating jointly the 2 arms. The primary objective of this study is to obtain, by arm, ≥ 70% of patients at 6 months after randomization with prednisone ≤ 0.1mg/kg per day and inactive disease (NIH score ≤ 1) during the last 3 months.

Conditions

Takayasu Arteritis

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with prednisone ≤ 0.1mg/kg per day and sustained inactive disease (NIH score ≤ 1) from M3 to M6 and same biological therapy from randomization

  at 6 months after randomization

Secondary Outcomes (12)

• Incidence of relapse as defined by the NIH criteria

  between 3 and 6 months

• Incidence of traitement failure

  at 3 months after randomization

• Incidence of revascularization procedures

  at 6 months after randomization

• Incidence of revascularization procedures

  at 12 months after randomization

• Cumulative doses of prednisone

  at 6 months after randomization

Study Arms (2)

A ( Infliximab)

EXPERIMENTAL

Infliximab 5mg/kg intravenously at week 0; 2; 6; 14; 22 following prescription recommendations

Drug: Infliximab

B (Tocilizumab)

EXPERIMENTAL

Tocilizumab : 8mg/kg intravenously at week 0; 4; 8; 12; 16; 20; 24 following prescription recommendations

Drug: Tocilizumab

Interventions

Infliximab DRUG

Patients will receive infliximab 5mg/kg intravenously at week 0; 2; 6; 14; 22 in arm A

A ( Infliximab)

Tocilizumab DRUG

Patients will receive tocilizumab 8mg/kg intravenously at week 0; 4; 8; 12; 16; 20; 24 in arm B

B (Tocilizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Takayasu disease according to the international criteria of the American College of Rheumatology (ACR)
• Age at disease onset \< 40 years
• Claudication of extremities
• Decreased brachial artery pulse (one or both arteries)
• Blood pressure difference of \>10mm Hg between the arms
• Bruit over subclavian arteries or aorta
• Active disease according to the international criteria of the National Institute of Health (NIH)
• New onset or worsening of at least two of the following four criteria
• Systemic features
• Elevated erythrocyte sedimentation rate
• Features of vascular ischemia or inflammation
• Typical angiographic features
• Refractory/relapsing disease
• Failure of disease to respond to daily corticosteroids therapy (1mg/kg/day for \> 1month), i.e. disease still active
• Inability to taper corticosteroids below 10mg/day within 6 months

You may not qualify if:

• 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 infliximab, any chimeric murine monoclonal antibody, tocilizumab, and their respective excipients or prednisone

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

Takayasu Arteritis

Interventions

Infliximab; tocilizumab

Condition Hierarchy (Ancestors)

Aortic Arch Syndromes; Aortic Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Vasculitis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Tristan MIRAULT

CONTACT

+33156093051; tristan.mirault@aphp.fr

Matthieu Resche-Rigon

CONTACT

+33142499742; matthieu.resche-rigon@univ-paris-diderot.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2020
• First Posted: September 25, 2020
• Study Start: September 1, 2020
• Primary Completion: February 1, 2021
• Study Completion: September 1, 2023
• Last Updated: September 25, 2020

Record last verified: 2020-09