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)

NCT ID: NCT04629144

Last Updated: 2024-06-26

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-20
• Study Completion Date: 2025-10-20

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.

Conditions

Vasculitis; Cryoglobulinemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Belimumab

Belimumab administered subcutaneously 200mg weekly from week 1 to week 24.

Group Type: EXPERIMENTAL

Belimumab

Intervention Type: DRUG

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.

Placebo

Placebo of Belimumab administered subcutaneously weekly from week 1 to week 24.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

Belimumab

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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: DRUG

Eligibility Criteria

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

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CH Blois

Blois, , France

Site Status: RECRUITING

CHU (Haut-Lévêque)

Bordeaux, , France

Site Status: RECRUITING

CHU Caen

Caen, , France

Site Status: RECRUITING

Hopital Henri Mondor

Créteil, , France

Site Status: NOT_YET_RECRUITING

Hopital Bicetre

Le Kremlin-Bicêtre, , France

Site Status: RECRUITING

CHU Lille

Lille, , France

Site Status: RECRUITING

CHU La Conception

Marseille, , France

Site Status: RECRUITING

CHU Nantes

Nantes, , France

Site Status: RECRUITING

CH Nimes

Nîmes, , France

Site Status: RECRUITING

Hopital de La Pitié Salpetriere AP-HP

Paris, , France

Site Status: RECRUITING

Hopital Européen Georges Pompidou

Paris, , France

Site Status: RECRUITING

Hopital Necker

Paris, , France

Site Status: RECRUITING

Hopital Saint Antoine

Paris, , France

Site Status: RECRUITING

Hopital Saint Louis

Paris, , France

Site Status: RECRUITING

Hopital Tenon

Paris, , France

Site Status: RECRUITING

CHU Starsbourg

Strasbourg, , France

Site Status: RECRUITING

Hopital Foch

Suresnes, , France

Site Status: RECRUITING

CHU Toulouse

Toulouse, , France

Site Status: RECRUITING

CHU Tours

Tours, , France

Site Status: RECRUITING

CHU Valenciennes

Valenciennes, , France

Site Status: RECRUITING

Countries

France

Central Contacts

David Saadoun, MD PhD

Role: CONTACT

david.saadoun@aphp.fr

142499742 ext. 33

Jérôme Lambert, MD PhD

Role: CONTACT

jerome.lambert@u-paris.fr

142499742 ext. +33

Facility Contacts

Bertrand Lioger, MD

Role: primary

Estibaliz Lazaro, MD

Role: primary

Achille Aouba, MD

Role: primary

Marc Michel, MD

Role: primary

Xavier Mariette, MD

Role: primary

Eric Hachulla, MD

Role: primary

Gilles Kaplanski, MD

Role: primary

Antoine Neel, MD

Role: primary

Olivier Moranne, MD

Role: primary

David Saadoun, MD PhD

Role: primary

Alexandre Karras, MD

Role: primary

Aurélie Hummel, MD

Role: primary

Arsene Mekinian, MD

Role: primary

Baptiste Hervier, MD

Role: primary

Jean-Jacques Boffa, MD

Role: primary

Jacques Eric Gottenberg, MD

Role: primary

Felix Ackermann, MD

Role: primary

Stanislas Faguer, MD

Role: primary

Alexandra Audemard, MD

Role: primary

Thomas Quemeneur, MD

Role: primary

Other Identifiers

APHP180351

Identifier Type: -

Identifier Source: org_study_id