Cryoglobulinemia, Vasculitis
Conditions
Keywords
Belimumab, Vasculitis, Cryoglobulinemia, Non-infectious
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.
Interventions
DRUGBelimumab
Belimumab administered subcutaneously 200mg weekly from week 1 to week 24. Both arms will have the same corticosteroid tapering scheme, with an initial dose of 30 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: * 30 mg/day week (W)0-W2, * 20 mg/day W2-W4 * 15 mg/day W4-W6, * 10 mg/day W6-W8, * 5 mg/day W8-W10 Between W10-W12 the strategy for stopping glucocorticoids is left to the investigator's discretion. Stopping glucocorticoid therapy at W12. At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
DRUGPlacebo
Both arms will have the same corticosteroid tapering scheme, with an initial dose of 30 mg/day. The following schedule of reduction of prednisone will apply to both groups as long as the disease is inactive: * 30 mg/day week (W)0-W2, * 20 mg/day W2-W4 * 15 mg/day W4-W6, * 10 mg/day W6-W8, * 5 mg/day W8-W10 Between W10-W12 the strategy for stopping glucocorticoids is left to the investigator's discretion. Stopping glucocorticoid therapy at W12. At each step, the prednisone dose will be reduced only in the absence of signs of vasculitis activity.
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete clinical response rate at week 25 with corticosteroid withdrawal at week 12 | Week 25 | Complete clinical response is defined by remission of all affected organs involved at baseline and the absence of clinical relapse. * Skin and articular remissions * Renal remission * Neurological remission * Digestive remission * Cardiac remission * Central nervous system remission * Pulmonary remission |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| C4 complement level W13 | Week 13 | normalization of C4 complement level |
| CD19+ | Baseline | — |
| Quality of life W25 | Week 25 | 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 | Week 48 | 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 | Week 48 | Rate of infections |
| BVAS activity W48 | Week 48 | 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. |
| Safety W25 | Week 25 | Frequency and severity of adverse clinical events |
| Safety W48 | Week 48 | Frequency and severity of adverse clinical events |
| Response W13 | Week 13 | 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 W25 | Week 25 | 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 | Week 48 | 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 W13 | Week 13 | cryoglobulinemia clearance |
| Rate of cryoglobulinemia clearance W25 | Week 25 | cryoglobulinemia clearance |
| Rate of cryoglobulinemia clearance W48 | Week 48 | cryoglobulinemia clearance |
| rheumatoid factor activity W13 | Week 13 | negativation of rheumatoid factor activity |
| rheumatoid factor activity W25 | Week 25 | negativation of rheumatoid factor activity |
| rheumatoid factor activity W48 | Week 48 | negativation of rheumatoid factor activity |
| C4 complement level W25 | Week 25 | normalization of C4 complement level |
| C4 complement level W48 | Week 48 | normalization of C4 complement level |
| Early failures | Week 5 | Rate of early failures (non clinical response at W5) 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 | Week 48 | Relapse is defined as de novo appearance or recurrence of a manifestation of cryoglobulinemia vasculitis |
| BVAS activity W13 | Week 13 | 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 W25 | Week 25 | 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. |
| Prednisone W25 | Week 25 | Cumulative dose of prednisone |
| Prednisone W48 | Week 48 | Cumulative dose of prednisone |
| Gammaglobulin | Baseline | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunomonitoring W48 | Week 48 | deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description |
| renal response W13 | Week 13 | Renal remission is evaluated biologically (proteinuria \<0.5g/24h or proteinuria/creatinuria \<50 mg/mmol). |
| renal response W25 | Week 25 | Renal remission is evaluated biologically (proteinuria \<0.5g/24h or proteinuria/creatinuria \<50 mg/mmol). |
| Immunomonitoring W25 | Week 25 | deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description |
| Immunomonitoring W13 | Week 13 | deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description |
Countries
France
Contacts
Primary ContactDavid Saadoun, MD PhD
Backup ContactJérôme Lambert, MD PhD
Outcome results
None listed