Efficacy and Safety of Belimumab in the Treatment of Non-infectious Active Cryoglobulinemia Vasculitis Compared to Placebo. TRIBECA STUDY (Treatment nd BElimumab in Cryoglobulinemia Associated Vasculitis)

Multicenter Randomized Double-blind Study Comparing the Efficacy and Safety of Belimumab in the Treatment of Non-infectious Active Cryoglobulinemia Vasculitis Compared to Placebo. TRIBECA STUDY (Treatment nd BElimumab in Cryoglobulinemia Associated Vasculitis)

Cryoglobulinemia vasculitis (CV) is a systemic immune-mediated small vessel vasculitis. Rituximab proved effective on main vasculitis signs, with a complete clinical response of 65%. However, CV relapse is noted in up to 40% of patients. Following rituximab, serum Blys concentration significantly increased and may favor relapses. Tribeca is a multicentre randomized controled study comparing safety and efficacy of belimumab to placebo in non infectious cryoglobulinemia vasculitis.

Inclusion Criteria:

The eligibility criteria will be checked at the inclusion/randomization visit. Patients meeting the following criteria may be included in the study:

1. Age > 18 years

2. Written inform consent

3. Active mixed cryoglobulinemia vasculitis, at initiation of rituximab, define by a. a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement , b. history of positive cryoglobulinemia and/or positive Rheumatoid factor associated with low C4 complement level , and/or a monoclonal component (IgM Kappa) and/or a histologal proof of vasculitis in the affected organs

4. Affiliated to National French social security system

5. Having received Rituximab as induction therapy within 6 weeks (1 to 4 infusions, dose at the discretion of the investigator)

6. Female subjects of childbearing potential must have a negative serum or urinary pregnancy test at inclusion visit, and confirmed monthly while in study, out to at least 92 days (5 half lives) post last dose.

7. For subjects with reproductive potential (male or female), a willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study from 2 weeks prior to administration of the 1st dose of study agent until 92 days after the last dose of study agent. Therefore the subjects agree to 1 of the following:

   1. Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 92 days after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception) OR

   2. Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 92 days after the last dose of study agent o Oral contraceptive, either combined or progestogen alone o Injectable progestogen o Implants of levonorgestrel or etonogestrel o Estrogenic vaginal ring o Percutaneous contraceptive patches o Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the product label

      o Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records

      • Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception.

8. HIV negative serology ; negative HBs Ag test and HBc Ab test; HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion:

   o In case of negative AgHBs and positive HBc Ab test, HBV DNA test must be negative; AND Hepatitis B surveillance should be started (monthly HBsAg and HBV DNA testing for the duration of the study treatment and at least every 12 weeks after treatment is discontinued for the duration of study treatment. In addition, antiviral prophylaxis should be started before the first administration of the study treatment and continued until 12 months after completion of study treatment; HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion

9. neutrophils (ANC) >1x109/L

Exclusion criteria :

Subjects will be not included from the study if they meet any of the following criteria:

1. Patient with a vasculitis unrelated to cryoglobulinemia

2. Patient with non active cryoglobulinemia vasculitis, at initiation of rituximab. Patients with mixed inactive vasculitis following rituximab administration may be included.

3. Excluded concomitant medications:

   1. 365 days Prior to Investigational Medicinal Product (Belimumab or placebo):: Any biologic investigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131) Investigational agent applies to any drug not approved for sale in the country in which it is being used
   2. 180 Days Prior to Investigational Medicinal Product (Belimumab or placebo):: Intravenous cyclophosphamide
   3. 30 Days Prior to Investigational Medicinal Product (Belimumab or placebo): (or 5 half lives, whichever is greater) Any non-biologic investigational agent Investigational agent applies to any drug not approved for sale in the country in which it is being use
   4. Live vaccines within 30 days prior to baseline or concurrently with Investigational Medicinal Product (Belimumab or placebo)

4. Have a history of malignant neoplasm within the last 5 years, other than carcinoma in situ of the cervix or excised basal cell, squamous cell carcinoma of the skin and low grade hemopathy with no indication for a specific treatment

5. Have evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk

6. Have a Progressive multifocal leukoencephalopathy

7. Have a history of a primary immunodeficiency

9. Have a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant

10. Infection history:

• Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus

• Infection requiring hospitalization and/or use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of the inclusion visit.

  11. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior to the inclusion visit

  12. Have a historically positive HIV test according to results obtained within 3 months prior to inclusion visit

  13. Hepatitis status according to results obtained within 3 month prior to inclusion visit :

• Positive test for hepatitis B RNA

• Positive test for Hepatitis C RNA

  14. Have a history of a hypersensitivity or an anaphylactic reaction to parenteral administration of Belimumab, corticosteroids or any excipients of the treatments administered during the study

  15. If Women of Child Bearing Potential (WCBP) are included please see special instructions in Inclusion criteria

  16. Pregnant or breast feeding women

  17. Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study

  18. Patients under legal protection or unable to consent

  19. Participation to another interventional study