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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) (TRIBECA)

Primary Purpose

Vasculitis, Cryoglobulinemia

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Belimumab
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Vasculitis focused on measuring Belimumab, Vasculitis, Cryoglobulinemia, Non-infectious

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age > 18 years
  • Written inform consent
  • Active cryoglobulinemia vasculitis define by positive cryoglobulinemia and a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement (no histological evidence needed if presence of purpura demonstrated),
  • Affiliated to National French social security system
  • Having received Rituximab as induction therapy within 6 weeks
  • Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.

Therefore, these women must have a negative serum pregnancy test at screening, and confirmed monthly while in study, out to at least 4 months (5 half lives) post last dose and agree to 1 of the following:

  • Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks 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
  • 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 16 weeks after the last dose of study agent

    • Oral contraceptive, either combined or progestogen alone
    • Injectable progestogen
    • Implants of levonorgestrel or etonogestrel
    • Estrogenic vaginal ring
    • Percutaneous contraceptive patches
    • Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the product label
    • 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.
  • HIV negative serology ; negative HBs Ag test and HBc Ab test; HCV negative serology or negative HCV RNA if positive HCV serology
  • Adequate haematological status:

    • neutrophils (ANC) >1x109/L;

Exclusion Criteria:

  • Patient with a vasculitis unrelated to cryoglobulinemia
  • Patient with non active cryoglobulinemia vasculitis,
  • Patient with immunosuppressant introduced or increased in the month prior to the inclusion, (except Rituximab)
  • Patients receiving corticosteroid therapy > 0.5 mg/kg/d > 1 month before the inclusion or > 1 mg/kg/d >2 weeks before inclusion or taking more than 3000 mg methylprednisolone 4 weeks prior to the inclusion visit
  • Excluded concomitant medications (except Rituximab) :
  • 365 days Prior to Belimumab:

    • 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
  • 180 Days Prior to Belimumab:

    • Intravenous cyclophosphamide

      • If concomitant use with cyclophosphamide, enhanced safety monitoring required.
  • Serum IgG levels should be measured monthly in this situation
  • Benlysta should be discontinued in subjects with serum IgG levels <250 mg/dL associated with a severe or serious infection
  • 30 Days Prior to Belimumab (or 7 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
  • Live vaccines within 30 days prior to baseline or concurrently with belimumab
  • Have a history of malignant neoplasm within the last 5 years
  • Have a Progressive multifocal leukoencephalopathy
  • .
  • 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
  • Have a history of a primary immunodeficiency
  • Have a significant IgG deficiency (IgG level < 400 mg/dL)
  • Have a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
  • • Have an IgA deficiency (IgA level < 10 mg/dL
  • 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 Day 0.
    • Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior to Day 0
  • Have a historically positive HIV test or test positive at screening for HIV
  • Hepatitis status:

    • Serologic evidence of current or past Hepatitis B (HB) infection based on the results of testing for HBsAg and HBcAb as follows:
  • Patients positive for HBsAg or HBcAb are excluded

    • Positive test for Hepatitis C RNA
  • Have a history of a hypersensitivity or an anaphylactic reaction to parenteral administration of Belimumab or Rituximab, corticosteroids or any excipients of the treatments administered during the study
  • If Women of Child Bearing Potential (WCBP) are included please see special instructions above
  • Pregnant or breast feeding women
  • Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study
  • Patients under legal protection or unable to consent
  • Participation to another interventional study

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Belimumab

    Placebo

    Arm Description

    Belimumab administered subcutaneously 200mg weekly from week 0 to week 24.

    Placebo of Belimumab administered subcutaneously weekly from week 0 to week 24.

    Outcomes

    Primary Outcome Measures

    Complete clinical response rate W24
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. The skin and articular remissions are evaluated clinically. Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol, ). Neurological remission is evaluated clinically and electrophysiologically. Digestive remission is evaluated clinically, by endoscopy and/or by Xray. Complete remission of all baseline abnormalities is required to define digestive remission. Cardiac remission is evaluated clinically (improvement of chest pains and other cardiac events), electrically (disappearance of abnormalities indicating acute myocardial suffering on EKG) and biologically (normalization of muscular enzymes). Complete remission of all baseline abnormalities is required to define cardiac remission.

    Secondary Outcome Measures

    Safety W24
    Frequency and severity of adverse clinical events
    Safety W48
    Frequency and severity of adverse clinical events
    Response W12
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Response W24
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Response W48
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Rate of cryoglobulinemia clearance W12
    cryoglobulinemia clearance
    Rate of cryoglobulinemia clearance W24
    cryoglobulinemia clearance
    Rate of cryoglobulinemia clearance W48
    cryoglobulinemia clearance
    rheumatoid factor activity W12
    negativation of rheumatoid factor activity
    rheumatoid factor activity W24
    negativation of rheumatoid factor activity
    rheumatoid factor activity W48
    negativation of rheumatoid factor activity
    C4 complement level W12
    normalization of C4 complement level
    C4 complement level W24
    normalization of C4 complement level
    C4 complement level W48
    normalization of C4 complement level
    Early failures
    Rate of early failures (non clinical response at W4) Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol,).
    Clinical relapse rate W48
    Relapse is defined as de novo appearance or recurrence of a manifestation of cryoglobulinemia vasculitis
    Prednisone W24
    Cumulative dose of prednisone
    Prednisone W48
    Cumulative dose of prednisone
    Quality of life W24
    Quality of life score SF-36. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. To calculate the scores it is necessary to purchase special software for the commercial version, but no special software is needed for the RAND-36 version. Pricing depends on the number of scores that the researcher needs to calculate. The eight sections are: vitality physical functioning bodily pain general health perceptions physical role functioning emotional role functioning social role functioning mental health
    Quality of life W48
    Quality of life score SF-36. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. To calculate the scores it is necessary to purchase special software for the commercial version, but no special software is needed for the RAND-36 version. Pricing depends on the number of scores that the researcher needs to calculate. The eight sections are: vitality physical functioning bodily pain general health perceptions physical role functioning emotional role functioning social role functioning mental health
    Infections
    Rate of infections
    BVAS activity W12
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.
    BVAS activity W24
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.
    BVAS activity W48
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.

    Full Information

    First Posted
    November 9, 2020
    Last Updated
    November 9, 2020
    Sponsor
    Assistance Publique - Hôpitaux de Paris
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04629144
    Brief Title
    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)
    Acronym
    TRIBECA
    Official Title
    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)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2020
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 1, 2021 (Anticipated)
    Primary Completion Date
    June 1, 2024 (Anticipated)
    Study Completion Date
    March 1, 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Assistance Publique - Hôpitaux de Paris

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Vasculitis, Cryoglobulinemia
    Keywords
    Belimumab, Vasculitis, Cryoglobulinemia, Non-infectious

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare Provider
    Allocation
    Randomized
    Enrollment
    48 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Belimumab
    Arm Type
    Experimental
    Arm Description
    Belimumab administered subcutaneously 200mg weekly from week 0 to week 24.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo of Belimumab administered subcutaneously weekly from week 0 to week 24.
    Intervention Type
    Drug
    Intervention Name(s)
    Belimumab
    Intervention Description
    Belimumab administered subcutaneously 200mg weekly from week 0 to week 24. Both arms will have the same corticosteroid tapering scheme, with an initial dose of 60 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: 60 mg/day week (W)0-W4, 40 mg/day W4-W6 30 mg/day W6-W8, 20 mg/day W8-W10, 15 mg/day W10-W12, 10 mg/day W12-W14, 7.5 mg/day W14-W16, 5 mg/day W16-W18 2.5mg/day W18-W20. Stopping glucocorticoid therapy at W20 At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Both arms will have the same corticosteroid tapering scheme, with an initial dose of 60 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: 60 mg/day week (W)0-W4, 40 mg/day W4-W6 30 mg/day W6-W8, 20 mg/day W8-W10, 15 mg/day W10-W12, 10 mg/day W12-W14, 7.5 mg/day W14-W16, 5 mg/day W16-W18 2.5mg/day W18-W20. Stopping glucocorticoid therapy at W20 At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
    Primary Outcome Measure Information:
    Title
    Complete clinical response rate W24
    Description
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. The skin and articular remissions are evaluated clinically. Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol, ). Neurological remission is evaluated clinically and electrophysiologically. Digestive remission is evaluated clinically, by endoscopy and/or by Xray. Complete remission of all baseline abnormalities is required to define digestive remission. Cardiac remission is evaluated clinically (improvement of chest pains and other cardiac events), electrically (disappearance of abnormalities indicating acute myocardial suffering on EKG) and biologically (normalization of muscular enzymes). Complete remission of all baseline abnormalities is required to define cardiac remission.
    Time Frame
    Week 24
    Secondary Outcome Measure Information:
    Title
    Safety W24
    Description
    Frequency and severity of adverse clinical events
    Time Frame
    Week 24
    Title
    Safety W48
    Description
    Frequency and severity of adverse clinical events
    Time Frame
    Week 48
    Title
    Response W12
    Description
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Time Frame
    Week 12
    Title
    Response W24
    Description
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Time Frame
    Week 24
    Title
    Response W48
    Description
    The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse. Partial clinical response The partial clinical response is defined by the improvement and / or remission of more than half of the organ involvement present at baseline and the absence of clinical relapse. No clinical response Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol).
    Time Frame
    Week 48
    Title
    Rate of cryoglobulinemia clearance W12
    Description
    cryoglobulinemia clearance
    Time Frame
    Week 12
    Title
    Rate of cryoglobulinemia clearance W24
    Description
    cryoglobulinemia clearance
    Time Frame
    Week 24
    Title
    Rate of cryoglobulinemia clearance W48
    Description
    cryoglobulinemia clearance
    Time Frame
    Week 48
    Title
    rheumatoid factor activity W12
    Description
    negativation of rheumatoid factor activity
    Time Frame
    Week 12
    Title
    rheumatoid factor activity W24
    Description
    negativation of rheumatoid factor activity
    Time Frame
    Week 24
    Title
    rheumatoid factor activity W48
    Description
    negativation of rheumatoid factor activity
    Time Frame
    Week 48
    Title
    C4 complement level W12
    Description
    normalization of C4 complement level
    Time Frame
    Week 12
    Title
    C4 complement level W24
    Description
    normalization of C4 complement level
    Time Frame
    Week 24
    Title
    C4 complement level W48
    Description
    normalization of C4 complement level
    Time Frame
    Week 48
    Title
    Early failures
    Description
    Rate of early failures (non clinical response at W4) Patients with no clinical response at W4 will be defined by worsening of ulcers or cutaneous necrosis, worsening peripheral neurological involvement or by persistence of active renal involvement defined by persistence of proteinuria> 1.5 g / 24h or proteinuria/creatinuria <150 mg/mmol,).
    Time Frame
    Week 4
    Title
    Clinical relapse rate W48
    Description
    Relapse is defined as de novo appearance or recurrence of a manifestation of cryoglobulinemia vasculitis
    Time Frame
    Week 48
    Title
    Prednisone W24
    Description
    Cumulative dose of prednisone
    Time Frame
    Week 24
    Title
    Prednisone W48
    Description
    Cumulative dose of prednisone
    Time Frame
    Week 48
    Title
    Quality of life W24
    Description
    Quality of life score SF-36. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. To calculate the scores it is necessary to purchase special software for the commercial version, but no special software is needed for the RAND-36 version. Pricing depends on the number of scores that the researcher needs to calculate. The eight sections are: vitality physical functioning bodily pain general health perceptions physical role functioning emotional role functioning social role functioning mental health
    Time Frame
    Week 24
    Title
    Quality of life W48
    Description
    Quality of life score SF-36. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. To calculate the scores it is necessary to purchase special software for the commercial version, but no special software is needed for the RAND-36 version. Pricing depends on the number of scores that the researcher needs to calculate. The eight sections are: vitality physical functioning bodily pain general health perceptions physical role functioning emotional role functioning social role functioning mental health
    Time Frame
    Week 48
    Title
    Infections
    Description
    Rate of infections
    Time Frame
    Week 48
    Title
    BVAS activity W12
    Description
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.
    Time Frame
    Week 12
    Title
    BVAS activity W24
    Description
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.
    Time Frame
    Week 24
    Title
    BVAS activity W48
    Description
    BVAS activity score as defined in Flossmann, Oliver, et al. "Development of comprehensive disease assessment in systemic vasculitis." Postgraduate medical journal 84.989 (2008): 143-152.
    Time Frame
    Week 48
    Other Pre-specified Outcome Measures:
    Title
    Immunomonitoring W4
    Description
    deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
    Time Frame
    Week 4
    Title
    Immunomonitoring W24
    Description
    deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
    Time Frame
    Week 24
    Title
    Immunomonitoring W48
    Description
    deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description
    Time Frame
    Week 48
    Title
    renal response W12
    Description
    Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).
    Time Frame
    Week 12
    Title
    renal response W24
    Description
    Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).
    Time Frame
    Week 24

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age > 18 years Written inform consent Active cryoglobulinemia vasculitis define by positive cryoglobulinemia and a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement (no histological evidence needed if presence of purpura demonstrated), Affiliated to National French social security system Having received Rituximab as induction therapy within 6 weeks Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%. Therefore, these women must have a negative serum pregnancy test at screening, and confirmed monthly while in study, out to at least 4 months (5 half lives) post last dose and agree to 1 of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks 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 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 16 weeks after the last dose of study agent Oral contraceptive, either combined or progestogen alone Injectable progestogen Implants of levonorgestrel or etonogestrel Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the product label 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. HIV negative serology ; negative HBs Ag test and HBc Ab test; HCV negative serology or negative HCV RNA if positive HCV serology Adequate haematological status: neutrophils (ANC) >1x109/L; Exclusion Criteria: Patient with a vasculitis unrelated to cryoglobulinemia Patient with non active cryoglobulinemia vasculitis, Patient with immunosuppressant introduced or increased in the month prior to the inclusion, (except Rituximab) Patients receiving corticosteroid therapy > 0.5 mg/kg/d > 1 month before the inclusion or > 1 mg/kg/d >2 weeks before inclusion or taking more than 3000 mg methylprednisolone 4 weeks prior to the inclusion visit Excluded concomitant medications (except Rituximab) : 365 days Prior to Belimumab: 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 180 Days Prior to Belimumab: Intravenous cyclophosphamide If concomitant use with cyclophosphamide, enhanced safety monitoring required. Serum IgG levels should be measured monthly in this situation Benlysta should be discontinued in subjects with serum IgG levels <250 mg/dL associated with a severe or serious infection 30 Days Prior to Belimumab (or 7 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 Live vaccines within 30 days prior to baseline or concurrently with belimumab Have a history of malignant neoplasm within the last 5 years Have a Progressive multifocal leukoencephalopathy . 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 Have a history of a primary immunodeficiency Have a significant IgG deficiency (IgG level < 400 mg/dL) Have a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant. • Have an IgA deficiency (IgA level < 10 mg/dL 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 Day 0. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior to Day 0 Have a historically positive HIV test or test positive at screening for HIV Hepatitis status: Serologic evidence of current or past Hepatitis B (HB) infection based on the results of testing for HBsAg and HBcAb as follows: Patients positive for HBsAg or HBcAb are excluded Positive test for Hepatitis C RNA Have a history of a hypersensitivity or an anaphylactic reaction to parenteral administration of Belimumab or Rituximab, corticosteroids or any excipients of the treatments administered during the study If Women of Child Bearing Potential (WCBP) are included please see special instructions above Pregnant or breast feeding women Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study Patients under legal protection or unable to consent Participation to another interventional study
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    David Saadoun, MD PhD
    Phone
    142499742
    Ext
    33
    Email
    david.saadoun@aphp.fr
    First Name & Middle Initial & Last Name or Official Title & Degree
    matthieu resche-rigon, MD PhD
    Phone
    142499742
    Ext
    33
    Email
    matthieu.resche-rigon@u-paris.fr

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided

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    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)

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