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 Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Vasculitis, Cryoglobulinemia

Intervention / Treatment
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* Drug: Belimumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belimumab<br>Belimumab administered subcutaneously 200mg weekly from week 0 to week 24. | Drug: Belimumab<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo of Belimumab administered subcutaneously weekly from week 0 to week 24. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety W24 | Frequency and severity of adverse clinical events | Week 24 | 
| Safety W48 | Frequency and severity of adverse clinical events | Week 48 | 
| 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). | Week 12 | 
| 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). | Week 24 | 
| 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). | Week 48 | 
| Rate of cryoglobulinemia clearance W12 | cryoglobulinemia clearance | Week 12 | 
| Rate of cryoglobulinemia clearance W24 | cryoglobulinemia clearance | Week 24 | 
| Rate of cryoglobulinemia clearance W48 | cryoglobulinemia clearance | Week 48 | 
| rheumatoid factor activity W12 | negativation of rheumatoid factor activity | Week 12 | 
| rheumatoid factor activity W24 | negativation of rheumatoid factor activity | Week 24 | 
| rheumatoid factor activity W48 | negativation of rheumatoid factor activity | Week 48 | 
| C4 complement level W12 | normalization of C4 complement level | Week 12 | 
| C4 complement level W24 | normalization of C4 complement level | Week 24 | 
| C4 complement level W48 | normalization of C4 complement level | Week 48 | 
| 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,). | Week 4 | 
| Clinical relapse rate W48 | Relapse is defined as de novo appearance or recurrence of a manifestation of cryoglobulinemia vasculitis | Week 48 | 
| Prednisone W24 | Cumulative dose of prednisone | Week 24 | 
| Prednisone W48 | Cumulative dose of prednisone | Week 48 | 
| 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 | Week 24 | 
| 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 | Week 48 | 
| Infections | Rate of infections | Week 48 | 
| 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. | Week 12 | 
| 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. | Week 24 | 
| 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. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Belimumab, Vasculitis, Cryoglobulinemia, Non-infectious