Efficacy and Safety of Belimumab Versus Placebo in Non-Infectious Active Cryoglobulinemia Vasculitis: A Randomized, Double-Blind, Multicenter Study
- Trial ID
- 2024-516237-12-00
- Protocol
- APHP180351
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of belimumab compared to placebo in patients with mixed non-infectious active **cryoglobulinemia vasculitis**. This is clinically relevant as it aims to determine the potential of belimumab to improve patient outcomes in a condition characterized by inflammation of blood vessels due to cryoglobulins, which can lead to significant morbidity.
Secondary objectives include:
- Assessing the safety and tolerability of treatments by monitoring the frequency and severity of adverse clinical events.
- Evaluating response rates, including complete, partial, and non-clinical responses.
- Determining the rate of complete renal response.
- Measuring the rate of cryoglobulinemia clearance.
- Assessing the rate of negativation of rheumatoid factor activity.
- Evaluating the rate of normalization of C4 complement level.
- Determining early failure rate at week 5.
- Comparing clinical relapse rates and time to relapse between treatment groups.
- Measuring the cumulative dose of corticosteroids received between treatment groups.
- Monitoring the evolution of gammaglobulin and CD19+ B cells levels.
- Comparing quality of life scores (SF-36) between treatment groups.
- Assessing the rate of infections and other complications, such as lymphoma.
- Evaluating the BVAS activity score.
Participants
The clinical trial involves participants diagnosed with **cryoglobulinemia vasculitis**, a condition characterized by clinically active vasculitis with potential involvement of skin, joints, renal, peripheral nerve, central neurological, digestive, pulmonary, and/or cardiac systems. The study population includes both male and female subjects aged 18 years and older. Participants are required to have received Rituximab as induction therapy within six weeks prior to the study. The trial does not include a vulnerable population. Participants must be affiliated with the National French social security system and meet specific health criteria, including negative serology for HIV, HBs Ag, and HCV, or negative HCV RNA if HCV serology is positive. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as contraceptive measures are required for subjects with reproductive potential to prevent pregnancy during the study period. The selection criteria ensure that participants have a history of positive cryoglobulinemia and/or positive Rheumatoid factor associated with low C4 complement level, and/or a monoclonal component (IgM Kappa), and/or histological proof of vasculitis in affected organs.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **belimumab** compared to a placebo in patients with mixed non-infectious active **cryoglobulinemia vasculitis**. This is a multicenter, randomized, double-blind, controlled study. Participants will be randomly assigned to receive either belimumab or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature. The trial is expected to last until November 2024, with participant involvement spanning approximately 48 weeks.
The study will include several key visits. The initial inclusion visit will serve as a screening to confirm eligibility based on criteria such as age, medical history, and prior treatment with rituximab. Participants must have received rituximab as induction therapy within six weeks prior to the study. Follow-up visits will occur at regular intervals to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. These visits will include assessments at weeks 13, 25, and 48, with the primary endpoint being the complete clinical response rate of vasculitis symptoms at week 25, alongside oral corticosteroid withdrawal by week 12. Secondary endpoints will evaluate safety, tolerability, and various response rates at weeks 13, 25, and 48.
The end-of-study visit will conclude the trial for each participant, ensuring all necessary data is collected and any final assessments are completed. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study protocols, or if the investigator deems it necessary for their safety. The trial's design and procedures are structured to maintain scientific rigor while prioritizing participant safety and data integrity.
Treatment
The clinical trial involves the administration of **Benlysta**, a pharmaceutical product containing the active substance **belimumab**. Benlysta is provided as a 200 mg **solution for injection** in a pre-filled syringe. The medication is administered via **subcutaneous injection**. The maximum daily dose is 200 mg, with a total maximum dose of 4800 mg over the treatment period. The treatment duration is set for a maximum of 24 weeks. The product is manufactured by GlaxoSmithKline (Ireland) Limited and is classified under the ATC code L04AA26. The active substance, belimumab, is a protein of non-human origin, specifically categorized as "Protein - Other".
The study also includes a **placebo** comparator, which is designed to match the Benlysta formulation in appearance but does not contain the active substance belimumab. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as Benlysta, via subcutaneous injection, to ensure consistency in the administration process across all study participants.
Efficacy
The efficacy of **belimumab** in the treatment of non-infectious active cryoglobulinemia vasculitis will be assessed through a series of predefined endpoints. The primary endpoint is the complete clinical response rate of vasculitis symptoms at week 25, with the withdrawal of oral corticosteroids (prednisone or prednisolone) to 0 mg/day by week 12. Secondary endpoints include the safety and tolerability of treatments, assessed by the frequency and severity of adverse clinical events at weeks 25 and 48, as well as complete, partial, and non-clinical response rates at weeks 13, 25, and 48. Additionally, the complete renal response rate and the rate of cryoglobulinemia clearance, negativation of rheumatoid factor activity, and normalization of C4 complement level will be evaluated at weeks 13, 25, and 48. The rate of early failures, defined as non-clinical response at week 5, will also be measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Written inform consent
- 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
- Affiliated to National French social security system
- Having received Rituximab as induction therapy within 6 weeks (1 to 4 infusions, dose at the discretion of the investigator)
- 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.
- 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.
- 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.
- Neutrophils (ANC) >1x109/L,
Exclusion Criteria
- Patient with a vasculitis unrelated to cryoglobulinemia
- Patient with non active cryoglobulinemia vasculitis, at initiation of rituximab. Patients with mixed inactive vasculitis following rituximab administration may be included.
- 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)
- 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
- 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 history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
- 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.
- 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
- Have a historically positive HIV test according to results obtained within 3 months prior to inclusion visit
- 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
- 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
- If Women of Child Bearing Potential (WCBP) are included please see special instructions in Inclusion criteria
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 20 Oct 2021 | 52 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Benlysta 200 mg solution for injection in pre-filled syringe. | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 200 | 24 | PRD5568803 |
Placebo of belimumab | Placebo | N/A | — | — | — | N/A |