BE-MOBILYZED: BElimumab to MOBIlise memory B-cells from secondary LYmhoid organs to improve memory B-cell HLA-specificity profiling to support delisting for transplant access in highly-sensitiZED.
- Trial ID
- 2023-508116-32-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effects of belimumab on the antigen-specificity profile of circulating HLA-specific memory B-cells to facilitate delisting and enable improved and safer transplant access in highly-sensitized patients. This objective addresses a critical clinical challenge in managing highly-sensitized renal transplant candidates, where accurate assessment of HLA immunization is essential for optimizing organ allocation while minimizing the risk of antibody-mediated rejection.
The secondary objectives include:
• To investigate the effects of a delisting strategy which accounts for circulating mobilized memory B-cells on the probability of donor organ allocation.
• To investigate transplant outcomes, including graft survival, rejection rates and overall patient survival in patients transplanted with donor kidneys which express HLA-specificities which were delisted as unacceptable antigen.
• To investigate the concordance of the antigen specificity profile of circulating HLA-specific memory B-cells of tests before treatment with belimumab, compared to on-treatment.
• To investigate the effects of belimumab on MFI levels of anti-HLA antibodies produced by supernatants of stimulated circulating memory B-cells.
• To investigate the effects of belimumab on MFI levels of anti-HLA antibodies in plasma.
• To investigate the long-term post-treatment effects of belimumab on the antigen-specificity profile of circulating HLA-specific memory B-cells.
• To investigate the effects of belimumab on plasma BAFF levels.
• To investigate the effects of belimumab on phenotypically distinct B-cell subsets in the peripheral circulation.
• To investigate the impact of belimumab-mediated BAFF inhibition on the transcriptional landscape of B-cells.
• To investigate the adverse event rate, serious adverse event rate and SUSAR rate of a four-week course of subcutaneous belimumab within a population of highly-sensitized renal transplant candidates.
Participants
The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consists of **adults** aged **18 to 75 years** who are candidates for **kidney transplantation**. Both **male** and **female** subjects are eligible for enrollment. Participants are classified as **highly-sensitized**, defined by either a probability of 2% or less of being matched with a donor organ within the Eurotransplant Kidney Allocation System or a probability of 0.5% or less within the Eurotransplant AM-program for those who qualify. The trial addresses conditions including **antibody-mediated rejection** of renal grafts and high **HLA-immunization** in transplant candidates. Female participants of childbearing potential must not be pregnant or nursing and must agree to use proper contraception during the study. The trial population was selected based on transplant candidacy status, degree of sensitization, and willingness to comply with the study protocol. No vulnerable populations are included in this study.
Plans and Procedures
This is a Phase 4, low-intervention clinical trial investigating the effects of belimumab on the antigen-specificity profile of circulating HLA-specific memory B-cells in highly-sensitized kidney transplant candidates. The study employs an interventional design to evaluate whether belimumab treatment can mobilize memory B-cells from secondary lymphoid organs, thereby improving HLA-specificity profiling and supporting delisting procedures for improved and safer transplant access. The trial addresses two primary medical conditions: antibody-mediated rejection of renal grafts and high HLA-immunization in transplant candidates, both classified as rare diseases.
The investigational medicinal product is Benlysta 200 mg solution for injection in pre-filled syringe, containing the active substance belimumab, administered via the subcutaneous route. The maximum daily dose is 200 mg, with a maximum total dose of 800 mg administered over a treatment period of 4 weeks. The product remains pharmaceutically identical to the authorized Benlysta formulation, with trial-specific labeling applied in accordance with Annex VI Regulation (EU) No 536/2014, including trial code, sponsor information, and the statement "For clinical trial use only".
Eligible participants include adults aged 18 to 75 years who are candidates for kidney transplantation and classified as highly-sensitized, defined by either a probability of ≤2% of being matched with a donor organ within the Eurotransplant Kidney Allocation System (ETKAS) or ≤0.5% probability within the Eurotransplant AM-program. Additional inclusion criteria require participants to provide informed consent, demonstrate willingness and ability to comply with the protocol, and, for female subjects, meet specific requirements regarding pregnancy status and contraception use. Female participants must not be pregnant or nursing, as confirmed by negative pregnancy testing at screening, or must be of non-child-bearing potential, or agree to use proper contraception if of child-bearing potential.
The primary endpoint assesses the difference between baseline and after 4 weeks of belimumab therapy in the number of HLA-specificities with targeted antibodies produced by supernatants of stimulated memory B-cells, detected through Luminex single antigen bead analysis. Secondary endpoints include evaluation of changes in unacceptable HLA-specificities, virtual panel reactive antibody (vPRA), and frequency of matching donors within the Eurotransplant region following delisting. Additional secondary outcomes measure clinical events such as rejection, donor-specific antibody (DSA) development, graft loss, or mortality in transplanted patients, concordance in memory analysis results, changes in mean fluorescence intensity (MFI) levels of targeted antibodies in both memory B-cell supernatants and plasma, durability of treatment effects at 12 and 36 weeks post-treatment, serum BAFF levels, phenotypically distinct B-cell subsets in peripheral circulation, differential gene expression and pathway enrichment analysis of sorted B-cell populations, and comprehensive safety assessments including adverse events and serious adverse events.
The trial duration extends from the estimated recruitment start date of September 1, 2025, to the estimated end date of November 1, 2027. Participant involvement encompasses a screening visit for eligibility assessment, baseline evaluations, a 4-week treatment period with belimumab administration, and follow-up visits at 12 and 36 weeks after completion of treatment. Safety monitoring continues for 84 days following the treatment period for adverse events and extends to 40 weeks for serious adverse events, with reporting of suspected unexpected serious adverse reactions (SUSARs) continuing until the end of study. The protocol includes provisions for temporary or permanent discontinuation of treatment based on predefined stop criteria, with adverse events leading to treatment discontinuation described separately in the safety analysis.
Treatment
The investigational medicinal product utilized in this clinical trial is **Benlysta** 200 mg solution for injection in **pre-filled syringe**. The active substance is **belimumab**, a protein-based therapeutic agent. The pharmaceutical form consists of a solution for injection supplied in a pre-filled syringe delivery system. The route of administration is **subcutaneous injection**. The maximum daily dose is 200 mg, with a maximum total dose of 800 mg administered over a treatment period of 4 weeks. The medicinal product is supplied without labeling by the manufacturer, and the trial site performs labeling in accordance with the Summary of Product Characteristics for Benlysta. Additional labeling compliant with Annex VI Regulation (EU) No 536/2014 is applied, including trial code, sponsor or investigator identification, and the statement "For clinical trial use only". No modifications to the formulation, strength, pharmaceutical form, or primary packaging of the authorized product are undertaken, ensuring the investigational medicinal product remains pharmaceutically identical to the authorized Benlysta product. The marketing authorization number is EU/1/11/700/006, and the product is authorized by GLAXOSMITHKLINE (IRELAND) LIMITED.
Efficacy
Efficacy will be assessed through multiple parameters evaluating the impact of belimumab on HLA-specific memory B-cell profiles and transplant eligibility outcomes. The primary endpoint is the difference between baseline and after 4 weeks of belimumab therapy in the number of HLA-specificities with targeted antibodies as produced by supernatants of stimulated memory B-cells, detected through Luminex single antigen bead analysis. Secondary endpoints include the difference between baseline and after delisting in the number of unacceptable HLA-specificities, the virtual panel reactive antibody (vPRA), and the frequency of matching donors within the Eurotransplant region, as calculated through online available Eurotransplant calculator tools. Additional secondary endpoints encompass the number of rejection, donor-specific antibody (DSA) development, graft loss, or mortality events in patients who were transplanted after the delisting procedure. The difference in concordant positive antigens in memory analysis between the two pretreatment assays and the two on-treatment assays will be evaluated. Changes in mean fluorescence intensity (MFI) levels of targeted antibodies as produced by supernatants of stimulated memory B-cells and in plasma will be assessed at baseline and after 4 weeks of belimumab therapy, detected through Luminex single antigen bead analysis. The difference between 4 weeks of belimumab therapy and 12 and 36 weeks thereafter in the number of HLA-specificity specificities with targeted antibodies as produced by supernatants of stimulated memory B-cells will be measured. Serum BAFF levels in peripheral blood will be evaluated before, during, and after belimumab treatment. Phenotypically distinct B-cell subsets in the peripheral circulation will be assessed at baseline, during 4 weeks of belimumab treatment, and 36 weeks thereafter, as measured through flow-cytometry and ELISPOT assays. Differential gene expression and pathway enrichment analysis of sorted B-cell populations will be conducted at baseline, during 4 weeks of belimumab treatment, and 36 weeks thereafter.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults within the age group ≥18 and ≤75 years
- Candidate for a kidney transplant
- Highly-sensitized as determined by either: ≤2% probability of being matched with a donor organ within the Eurotransplant Kidney Allocation System (ETKAS) OR ≤0,5 % probability of being matched with a donor organ within the Eurotransplant AM-program, if patients qualify to be included in this program.
- Provided informed consent to participation in this study
- Willingness and ability to comply with the protocol of this study
- Female subjects are eligible to enter the study if they are:Not pregnant or nursing, as indicated by a negative pregnancy test at screening. OR Of non-child-bearing potential (i.e. after hysterectomy, postmenopausal, bilateral ovariectomy or documented bilateral tubal ligation or other permanent female sterilization procedure) OR In agreement to not become pregnant in case she is of child-bearing potential and use proper contraception.
Exclusion Criteria
- Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG, corrected for ESRD.
- Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA <0.1 g/L).
- Having received any vaccination within 3 months before screening.
- Enrolled in another clinical trial investigating an investigational drug or device at the time of belimumab treatment and delisting. However, participation in a desensitisation trial after the primary outcome is assessed is allowed.
- Previous administration of any of the following agents within 365 days from the screening day: BAFF-inhibitors (e.g. Belimumab, Tabalumab), Monoclonal antibodies targeting CD20 (e.g. Rituximab), Monoclonal antibodies targeting CD52 (e.g. Alemtuzumab), Lymphocyte depleting agents (e.g. rATG, ATGAM), IL6-inhibitors or IL6-IL6R modulators (e.g. Tocilizumab, Clazakizumab), Proteosome inhibitors (e.g. Bortezomib).
- Previous administration of high-dose corticosteroids (>50mg of prednisolone or equivalent per day) within 90 days from the screening day.
- Active infection at time of screening with any of the following: Hospitalization for treatment within previous 30 days from the screening day. OR Current use of parenteral (intravenous or intramuscular) antibiotics (including anti-bacterial, anti-viral, anti-fungal or anti-parasitic agents). OR Current serologic evidence of viral hepatitis defined as: patients positive for HbsAg or HBcAb or a positive hepatitis C antibody test not treated with antiviral medication.
- Uncontrolled HIV infection as defined by CD4 count below 250 cells/mm³ and/or detectable viremia.
- History of a primary immunodeficiency including complement-deficiencies.
- Have a neutrophil count < 1.5x10E9/L.
- Have a current indication for a blood product transfusion at the time of screening or have a high likelihood that a patient may require a blood transfusion during the treatment phase of this study, in the opinion of the investigator.
- Have a significant history of infections that in the opinion of the investigator would make the patient unsuitable for participation in the study.
- Have a history of an anaphylactic or otherwise severe allergic reaction to parenteral administration of human or murine proteins or monoclonal antibodies.
- Have an active malignant neoplasm or a history of one in the last 5 years, with the exception of basal cell or squamous cell carcinoma of the skin which was treated with local resection only or carcinoma in situ of the uterine cervix treated locally with no evidence of metastatic disease for 3 years.
- Have evidence of psychiatric illness that in the opinion of the investigator would make the patient unsuitable for participation in the study.
- Have any other abnormal laboratory value or intercurrent medical illness that in the opinion of the investigator would make the patient unsuitable for participation in the study.
- Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 01 Sept 2025 | — |
| Netherlands | — | — | 25 |
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 | 200 | 4 | PRD5568803 |