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)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Vasculitis; Cryoglobulinemia
• Intervention / Treatment: Drug: Belimumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David Saadoun, MD PhD; Phone Number: 33 142499742; Email: david.saadoun@aphp.fr
• Study Contact Backup: Name: Matthieu RESCHE-RIGON, MD PhD; Phone Number: 33 142499742; Email: matthieu.resche-rigon@u-paris.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belimumab; Belimumab administered subcutaneously 200mg weekly from week 0 to week 24.	Drug: Belimumab; 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.
Placebo Comparator: Placebo; Placebo of Belimumab administered subcutaneously weekly from week 0 to week 24.	Drug: Placebo; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunomonitoring W4	deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description	Week 4
Immunomonitoring W24	deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description	Week 24
Immunomonitoring W48	deep immunophenotyping, cytokines production, clonal IgM memoryCD21-/low cells) description	Week 48
renal response W12	Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).	Week 12
renal response W24	Renal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatinuria <50 mg/mmol).	Week 24

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2021
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): March 1, 2025

Study Registration Dates

• First Submitted: November 9, 2020
• First Submitted That Met QC Criteria: November 9, 2020
• First Posted (Actual): November 16, 2020

Study Record Updates

• Last Update Posted (Actual): November 16, 2020
• Last Update Submitted That Met QC Criteria: November 9, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Vasculitis; Belimumab; Non-infectious; Cryoglobulinemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Vasculitis; Cryoglobulinemia; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Belimumab
• Other Study ID Numbers: APHP180351

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No