Clinical trial NCT03371095: Induction Therapy With Anti-TNFα vs Cyclophosphamide in Severe Behçet Disease
Official title: Multicenter, Randomized, Prospective Trial Comparing the Efficacy and Safety of Infliximab to That of Cyclophosphamide in Severe Behçet's Disease. ITAC : Induction Therapy With Anti-TNFα vs Cyclophosphamide in Severe Behçet Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Behcet's Disease
Vasculitis
Keywords: Behcet's Disease
Vasculitis
Biotherapy
immunosuppressant
Infliximab
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-12-13
Enrollment: 53
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.
* Chest X-ray results (postero-anterior and lateral) within 12 weeks prior to inclusion with no evidence of active Tuberculosis, active infection, or malignancy
* For female subjects of child-bearing age, a negative 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 and 6 months after stopping therapy. Adequate contraceptive measures include hormonal methods used for two or more cycles prior to Inclusion (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.
* 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)

Exclusion Criteria:

* Evidence of active Tuberculosis
* HIV or active HBV infection (HBs Ag+).
* Pregnancy or lactation
* Have been taking an oral daily dose of a glucocorticoid of more than 20 mg prednisone equivalent for more than 6 weeks continuously prior to the inclusion visit or taking more than 3000 mg methylprednisolone 4 weeks prior to the inclusion visit
* 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 malignancy within 5 years prior to Inclusion other than carcinoma in situ of the cervix or excised basal cell or squamous cell carcinoma of the skin.
* History of multiple sclerosis and/or demyelinating disorder
* History of severe allergic or anaphylactic reactions to cyclophosphamide or infliximab
* Infectious disease:

  * Infection requiring treatment with intravenous antibiotics within 2 weeks prior to Inclusion
  * History of recurrent infection
* Laboratory values assessed during Inclusion:

  * 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:

  * Treatment with systemic biologic therapy or with cyclophosphamide within 3 months prior to Inclusion
  * if on azathioprine, mycophenolate mofetil, or methotrexate at the time of inclusion, these drugs must be withdrawn prior to receiving the cyclophosphamide or infliximab dose on Day 1
* Any live (attenuated) vaccine within 4 weeks prior inclusion; recombinant or killed virus vaccines are permitted.
* 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

Primary outcomes:
measure: Complete clinical response
timeFrame: At week 22 after randomization
Secondary outcomes:
measure: Complete clinical response
timeFrame: At week 12 after randomization
measure: Complete clinical response
timeFrame: At week 48 after randomization
measure: Remission of CNS and/or cardiovascular involvement
timeFrame: At week 12 after randomization
measure: Remission of CNS and/or cardiovascular involvement
timeFrame: At week 22 after randomization
measure: Remission of CNS and/or cardiovascular involvement
timeFrame: At week 48 after randomization
measure: Percent meeting the target of ≤ 0.1 mg/day/kg of prednisone
timeFrame: At week 22 after randomization
measure: Percent meeting the target of ≤ 0.1 mg/day/kg of prednisone
timeFrame: At week 48 after randomization
measure: Mean dose of prednisone
timeFrame: At week 12 after randomization
measure: Mean dose of prednisone
timeFrame: At week 22 after randomization
measure: Mean dose of prednisone
timeFrame: At week 48 after randomization
measure: Cumulative dose of prednisone
timeFrame: At week 12 after randomization
measure: Cumulative dose of prednisone
timeFrame: At week 22 after randomization
measure: Cumulative dose of prednisone
timeFrame: At week 48 after randomization
measure: Time to response onset
timeFrame: At week 48 after randomization
measure: C-reactive protein
timeFrame: Every 4 weeks
measure: Time to relapse
timeFrame: At week 48 after randomization
measure: Rate of relapse
timeFrame: At week 48 after randomization
measure: Time to occurrence of worsening
timeFrame: At week 48 after randomization
measure: Rate of worsening
timeFrame: At week 48 after randomization
measure: Overall survival
timeFrame: At week 22 after randomization
measure: Overall survival
timeFrame: At week 48 after randomization
measure: Event Free Survival
timeFrame: At week 22 after randomization
measure: Event Free Survival
timeFrame: At week 48 after randomization
measure: Frequency of adverse clinical events
timeFrame: At week 22 after randomization
measure: Severity of adverse clinical events
timeFrame: At week 22 after randomization
measure: Change in quality of life
timeFrame: At week 12 after randomization
measure: Change in quality of life
timeFrame: At week 22 after randomization
measure: Changes in CNS involvement
timeFrame: At week 12 after randomization
measure: Changes in CNS involvement
timeFrame: At week 22 after randomization
measure: Changes in vascular involvement
timeFrame: At week 12 after randomization
measure: Changes in vascular involvement
timeFrame: At week 22 after randomization
measure: Changes in cardiological involvement
timeFrame: At week 12 after randomization
measure: Changes in cardiological involvement
timeFrame: At week 22 after randomization
measure: Serum concentration measurement of TNFa inhibitor at week 22
timeFrame: At week 12 after randomization
measure: Change in Behcet's Disease Current Activity Form
timeFrame: At week 12 after randomization
measure: Change in Behcet's Disease Current Activity Form
timeFrame: At week 22 after randomization
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHRU Amiens
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Bordeaux
country: France
facility: Hôpital Saint André
city: Boulogne-Billancourt
country: France
facility: CH Ambroise Paré
city: Caen
country: France
facility: CHU Caen
city: Créteil
country: France
facility: Henri Mondor Hospital
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Le Kremlin-Bicêtre
country: France
facility: CHU Bicêtre
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital de La Timone
city: Metz
country: France
facility: CH Metz
city: Paris
country: France
facility: CHU Bichat
city: Paris
country: France
facility: CHU Tenon
city: Paris
country: France
facility: Hôpital de La Pitié Salpetriere
city: Paris
country: France
facility: Hôpital Foch
city: Paris
country: France
facility: Hôpital Lariboisière
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Saint Louis
city: Poitiers
country: France
facility: CHU Poitiers
city: Rouen
country: France
facility: Hôpital Bois Guillaume
city: Saint-Denis
country: France
facility: CH Saint-Denis
city: Toulouse
country: France
facility: CHU Purpan
city: Valenciennes
country: France
facility: CH Valenciennes
Study officials:
References: