Induction Therapy With Anti-TNFα vs Cyclophosphamide in Severe Behçet Disease

NCT03371095 | Completed Phase 3

• 1 other identifier: P160932J
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 27

Brief Summary

Behçet's disease (BD) is a systemic vasculitis of arterial and venous vessels of any size, involving young patients (from 15 to 45 years). BD significantly increases morbidity and mortality. Therapeutic management of BD depends on the clinical presentation and organ involved. Although colchicine, nonsteroidal antiinflammatory agents and topical treatments are often sufficient for mucocutaneous and joint involvement, more aggressive approach with immunosuppressive agents is warranted for severe manifestations. Early recognition and vigorous use of immunosuppressives with high dose steroids have changed the prognosis of patients with severe BD. BD is a severe systemic vasculitis leading to blindness in up to 20% at 4 years and a 5-year mortality rate of 15% in patients with major vessel or neurological involvement. Cyclophosphamide has been used for life-threatening BD for 40 years. However, the outcome of severe complications of BD is poor. The European League Against Rheumatism (EULAR) recommendation for the management of BD advocated cyclophosphamide plus glucocorticoids for life-threatening manifestations (i.e neurological and/or major vessel involvement). TNFa antagonists have been used with success in severe and/or resistant cases. In addition, the incidence of blindness in BD has been dramatically reduced in the recent years with the use of anti-TNF. However, there is no firm evidence or randomized controlled trials directly addressing the best induction immunosuppressive therapy in severe BD manifestations. The investigators therefore aimed to assess the best induction therapy in severe and difficult to treat BD patients. The investigators hypothesize that up to 70% of the patients with life-threatening manifestations of BD receiving these compounds \[anti-TNFa or cyclophosphamide\] will achieve a complete remission of BD at 6 months and with less than 0.1 mg/kg/day of prednisone. ITAC, is the first randomized prospective, head to head study, comparing infliximab, to cyclophosphamide in severe manifestations of BD. There is no firm evidence or randomized controlled trials directly addressing the best induction immunosuppressive therapy in severe BD. Cyclophosphamide failed to demonstrate sustainable remission over 70 % of life threatening BD cases. There is little published information on use of immunosuppressants other than cyclophosphamide for severe BD. TNFa antagonists have been used with success in severe and/or resistant cases. TNFa expression correlates with BD activity and other immunological data provide a strong rationale for targeting BD with biologics. Despite a strong rationale, these compounds are not yet approved in BD, which guarantees the innovative nature of this study that aims selecting or dropping any arm when evidence of efficacy already exists.

Conditions

Behcet's Disease; Vasculitis

Keywords

Behcet's Disease; Vasculitis; Biotherapy; immunosuppressant; Infliximab

Outcome Measures

Primary Outcomes (1)

• Complete clinical response

  The complete clinical response is defined by the remission of all affected organs involved at baseline with a prednisone ≤ 0.1mg/kg per day

  At week 22 after randomization

Secondary Outcomes (36)

• Complete clinical response

  At week 12 after randomization

• Complete clinical response

  At week 48 after randomization

• Remission of CNS and/or cardiovascular involvement

  At week 12 after randomization

• Remission of CNS and/or cardiovascular involvement

  At week 22 after randomization

• Remission of CNS and/or cardiovascular involvement

  At week 48 after randomization

Study Arms (2)

Infliximab

EXPERIMENTAL

Infliximab 5mg/kg intravenously at week 0, 2, 6, 12, and 18

Drug: Infliximab

Cyclophosphamide

ACTIVE COMPARATOR

Cyclophosphamide 0.7g/m2 up to 1.2g/m2 intravenously at week 0, 4, 8, 12, 16 and 20

Drug: Cyclophosphamide

Interventions

Infliximab DRUG

Use of infliximab instead of cyclophosphamide

Infliximab

Cyclophosphamide DRUG

Use of cyclophosphamide

Cyclophosphamide

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 12 years old
• Written inform consent (Informed Consent should be obtained from the legal guardian in accordance with regional laws or regulations for patients 12 to 17 years of age)
• Diagnosis of BD according to international criteria for BD (ICBD) (see Appendix 1).
• Life threatening active BD defined as 1 of the following disease categories and according to the validated international definition:
• Major vessel disease: arterial aneurysms or arterial stenosis, myocarditis and/or major deep vein thrombosis (i.e. inferior vena cava, superior vena cava, cardiac cavity thrombosis, pulmonary embolism, supra-hepatic vessels, renal and mesenteric vessels). Diagnosis of major vessel involvement will be done using vascular doppler sonography, echocardiography, angio-CT scan and/or cardiac magnetic resonance imaging (MRI).
• Central nervous system involvement: encephalitis or meningoencephalitis or myelitis. The diagnosis of neuro-Behçet's (CNS involvement) will be based on objective neurological symptoms that were associated with neuroimaging (CNS and/or medullar MRI) findings suggestive of BD-related CNS involvement. Cerebrospinal fluid (CSF) findings showing aseptic inflammation may be associated.
• For female subjects of child-bearing age, a negative pregnancy test
• A potential subject with a positive interferon-gamma release assay (IGRA) (e.g., QuantiFERON®-TB Gold or T-spot TB® Test) or a positive tuberculin skin test (≤6 months) is eligible if her/his chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease and there are no clinical signs and symptoms of pulmonary and/or extra-pulmonary TB disease. These subjects with a latent TB infection who have not already received a prophylactic TB treatment must agree in advance to complete such a treatment course.
• HIV negative serology and negative HBs Ag test (≤1 month)

You may not qualify if:

• Evidence of active Tuberculosis
• HIV or active HBV infection (HBs Ag+).
• Pregnancy or lactation
• Alcohol or drug dependance
• Severe renal (creatinine clearance \<30ml/min/1,73m2) or pre-existing hemorrhagic cystitis or liver insufficiency (hepatic encephalopathy) or urinary obstruction
• Heart failure ≥ stage III / IV NYHA,
• History of multiple sclerosis and/or demyelinating disorder
• History of severe allergic or anaphylactic reactions to cyclophosphamide or infliximab
• Infectious disease:
• History of recurrent infection
• Hemoglobin \< 8 g/dL
• WBC \< 2.0 x 103/mm3
• Platelet count \< 70 x 103/mm3
• Use of the following systemic treatments during the specified periods:
• Lack of affiliation to a social security benefit plan (as a beneficiary or assignee), patients affiliated to universal medical coverage (CMU) are eligible for the study

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (27)

CHRU Amiens

Amiens, France

Location

Hôpital Avicenne

Bobigny, France

Location

CHU Bordeaux

Bordeaux, France

Location

Hôpital Saint André

Bordeaux, France

Location

CH Ambroise Paré

Boulogne-Billancourt, France

Location

CHU Caen

Caen, France

Location

Henri Mondor Hospital

Créteil, France

Location

CHU Dijon

Dijon, France

Location

CHU Grenoble

Grenoble, France

Location

CHU Bicêtre

Le Kremlin-Bicêtre, France

Location

CHRU Lille

Lille, France

Location

Hôpital de la Croix Rousse

Lyon, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

Hôpital de La Timone

Marseille, France

Location

CH Metz

Metz, France

Location

CHU Bichat

Paris, France

Location

CHU Tenon

Paris, France

Location

Hôpital de La Pitié Salpetriere

Paris, France

Location

Hôpital Foch

Paris, France

Location

Hôpital Lariboisière

Paris, France

Location

Hôpital Saint Antoine

Paris, France

Location

Hôpital Saint Louis

Paris, France

Location

CHU Poitiers

Poitiers, France

Location

Hôpital Bois Guillaume

Rouen, France

Location

CH Saint-Denis

Saint-Denis, France

Location

CHU Purpan

Toulouse, France

Location

CH Valenciennes

Valenciennes, France

Location

MeSH Terms

Conditions

Behcet Syndrome; Vasculitis

Interventions

Infliximab; Cyclophosphamide

Condition Hierarchy (Ancestors)

Mouth Diseases; Stomatognathic Diseases; Uveitis, Anterior; Panuveitis; Uveitis; Uveal Diseases; Eye Diseases; Vascular Diseases; Cardiovascular Diseases; Hereditary Autoinflammatory Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vascular

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2017
• First Posted: December 13, 2017
• Study Start: May 25, 2018
• Primary Completion: December 24, 2021
• Study Completion: April 11, 2022
• Last Updated: July 3, 2023

Record last verified: 2017-12

Locations

FR (27)