TRIBECA - 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 after RItuximab with BElimumab in mixed Cryoglobulinemia Associated vasculitis)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

20 Oct 2021 → ongoing

Decision date (initial)

2024-11-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

GSK

External identifiers

EU CT number

2024-516237-12-00

EudraCT number

2020-004519-29

ClinicalTrials.gov

NCT04629144

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To evaluate efficacy of belimumab compared to placebo in patients with mixed non-infectious active cryoglobulinemia vasculitis.

Secondary objectives 13

1. • Safety and tolerability of treatments as assessed by frequency and severity of adverse clinical events
2. Complete, partial (improvement in some but not all organs involved at baseline) and non-clinical (no clinical improvement) response rate
3. Rate of complete renal response
4. • Rate of cryoglobulinemia clearance
5. • Rate of negativation of rheumatoid factor activity
6. • Rate of normalization of C4 complement level
7. Early failure rate at W5 (non clinical response at W5)
8. Clinical relapse rate and the time to relapse between the two treatments groups,
9. Cumulative dose of corticosteroids received between the two treatments groups
10. • Evolution of gammaglobulin and of CD19+ B cells levels
11. Quality of life scores (SF-36) (Appendix 1) between the two treatment groups,
12. Rate of infections (severe or not) and other complications (lymphoma.)
13. • BVAS activity score (Appendix 2)

Conditions and MedDRA coding

Cryoglobulinemia vasculitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Age ≥ 18 years
2. 2. Written inform consent
3. 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. and 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. 4. Affiliated to National French social security system
5. 5. Having received Rituximab as induction therapy within 6 weeks (1 to 4 infusions, dose at the discretion of the investigator)
6. 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. 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: a. 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 b. 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 o 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. 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: - 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.
9. 9. Neutrophils (ANC) >1x109/L,

Exclusion criteria 18

1. 1. Patient with a vasculitis unrelated to cryoglobulinemia
2. 2. Patient with non active cryoglobulinemia vasculitis, at initiation of rituximab. Patients with mixed inactive vasculitis following rituximab administration may be included.
3. 3. Excluded concomitant medications a. 365 days Prior to Investigational Medicinal Product (Belimumab or placebo) ):c. Intravenous cyclophosphamide 30 Days Prior to Investigational Medicinal Product (Belimumab or placebo): (or 5 half lives, whichever is greater) o Any non-biologic investigational agent (Investigational agent applies to any drug not approved for sale in the country in which it is being use) d. Live vaccines within 30 days prior to baseline or concurrently with Investigational Medicinal Product (Belimumab or placebo): o 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 b. 180 Days Prior to Investigational Medicinal Product (Belimumab or placebo)
4. 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. 5. Have a Progressive multifocal leukoencephalopathy
6. 6. 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
7. 7. Have a history of a primary immunodeficiency
8. 8. Have a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
9. 9. Infection history: a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus,) b. 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.
10. 10. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior the inclusion visit
11. 11. Have a historically positive HIV test according to results obtained within 3 months prior to inclusion visit
12. 12. Hepatitis status according to results obtained within 3 months prior to inclusion visit: a. Positive test for hepatitis B RNA b. Positive test for Hepatitis C RNA
13. 13. 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
14. 14. If Women of Child Bearing Potential (WCBP) are included please see special instructions in Inclusion criteria
15. 15. Pregnant or breast feeding women
16. 16. Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study
17. 17. Patients under legal protection or unable to consent
18. 18. Participation to another interventional study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete clinical response rate of vasculitis symptoms at week (W) 25 with oral corticosteroid withdrawal (prednisone (or prednisolone, only if prednisone is out of stock in the market) at 0 mg/day) at week (W) 12.

Secondary endpoints 1

1. •Safety and tolerability of treatments as assessed by frequency and severity of adverse clinical events at W25 and at W48 •Complete, partial and non-clinical response rate at W13, W25 and at W48. •Complete renal response rate at W13, W25 and W48 • Rate of cryoglobulinemia clearance, of negativation of rheumatoid factor activity and of normalization of C4 complement level at W13, W25 and at W48 •Rate of early failures (non clinical response at W5)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

SAADOUN David

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Razika GUIZEM

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications