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NCT Number: NCT06291103

Screening for Subclinical Antibody Mediated Rejection and Efficacy of Belatacept in the Context of de Novo Donor Specific Antibody After Kidney Transplantation (BELA-M-R)

Antibody mediated rejection (ABMR) is a major cause of graft loss after kidney transplantation (KT) and is mainly associated with preformed anti-HLA donor specific antibodies (DSAs) (phenotype 1) or de novo DSAs (dnDSAs) (phenotype 2). Preexisting DSA-associated ABMR have superior graft survival compared with dnDSA-associated ABMR, which could partly be explained by the fact that patients with de novo DSA-associated ABMR have biopsy later, when graft dysfunction and/or proteinuria are already present. ABMR is a progressive process with an early stage called subclinical ABMR (sABMR), in which histological lesions are present in the kidney graft without clinical graft dysfunction. These early lesions are now well recognized as risk factors for transplant glomerulopathy and poor graft survival in phenotype 1 ABMR (ref 5). The impact of sABMR associated with dnDSA at any time post-transplant has been less studied and reported. Recently, a retrospective multicenter study was published, within the Spiesser Group that included 123 patients without graft dysfunction who underwent graft biopsy because of the presence of dnDSA (One Lambda, MFI > 1000). Performing a kidney graft biopsy after dnDSA indentification without renal dysfunction leads to the diagnosis of active sABMR in 35 % of cases. Nevertheless, no effect of standard of care treatment in active sABMR was observed. Very recently, an expert consensus for the recommended treatment for ABMR after KT was published. It was conclude that the clear lack of evidence but a standard of care for ABMR was nevertheless defined. Therefore, the current proposal is to evaluate a new strategy for active sABMR, testing a conversion from calcineurin inhibitor (CNI) to belatacept associated with the recently recommended standard of care (SOC) compared to continuing CNI. Belatacept might help to manage nonadherence, decrease the toxicity of CNI on an endothelium already affected by microvascular inflammation, and reduce DSA titers.

The monitoring of dnDSA after KT and an indication graft biopsy in case of appearance, even in the absence of graft dysfunction, is not part of a routine clinical practice in all KT centers. This strategy could be a valuable option, in order to begin treatment of ABMR before graft dysfunction occurs, and therefore to improve prognosis associated with phenotype 2 ABMR. Parajuli et al.4 suggested that early diagnosis and treatment of sABMR with SOC, using DSA monitoring may improve outcomes after KT, but this is a retrospective and no-randomized study. This study will be the first prospective randomized study in the context of de novo DSA. The objective is to evaluate a new combination of treatment for ABMR in the context of dnDSA with subclinical lesions and in the same time may help to determine the real incidence of sABMR in KT recipients with subclinical dnDSA. The use of belatacept in the context of sABMR to improve the non-adherence and to decrease the endothelial toxicity had never been evaluated in a prospective way.

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Key information

Conditions

Kidney Transplant Rejection

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

CHU de ROUEN

Rouen, 76031, France

Location contact

Dominique Bertrand, Dr

CONTACT

[email protected]

02 32 88 54 52

Dominique Bertrand, Dr

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Screening inclusion criteria:
  • Kidney transplant recipient
  • Adult
  • De novo DSA (MFI > 1000 using the Luminex single antigen beads assay or positive with the manufacturer criteria according to the Luminex assay) absent on the day of kidney transplantation and in the sera prior to kidney transplantation
  • No clinical graft dysfunction at time of DSA detection (< 20 % variation of eGFR compared to last 3 months before detection and < 0,5 g/g proteinuria/creatinuria ratio)
  • Affiliation with, or beneficiary of a Social security (national health insurance) category
  • Person having read and understood the information letter and signed the consent form
  • Women of childbearing potential with effective contraception/very-effective contraception (Cf. CTFG) (oestro-progestatives or intra-uterine device or tubal ligation) and a negative blood pregnancy test.
  • Women surgically sterile (absence of ovaries and/or uterus)
  • Postmenopausal women: confirmation diagnostic (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit)
  • Randomization inclusion criteria:
  • Patients with active sABMR, according Banff 2019 classification, with very slight transplant glomerulogathy (cg = 0 or 1).

Exclusion criteria

  • Screening exclusion criteria:
  • Minor
  • Specific treatment for DSA occurrence before kidney graft biopsy: IVIG or rituximab or plasmapheresis or immunoabsorption
  • ABO incompatible kidney transplantation
  • Combined transplantation
  • Transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown.
  • Hypersensitivity to the active substance or to any of the excipients - Pregnant or parturient or breastfeeding woman or absence of contraception
  • Person deprived of liberty by an administrative or judiciary decision or person placed under judicial protection, under guardianship or supervision
  • Person consenting to the research participating to another trial
  • Medical history or psychological or sensorial abnormality prone to inhibit the subject to understand the conditions required for his/her participation to the protocol or unable him/her to give an informed consent
  • No signed ICF
  • Randomization exclusion criteria:
  • No sABMR or chronic active sABMR (cg > 1) on initial biopsy
  • History of severe opportunistic infection before randomization
  • Acute or chronic infection with HBV, HCV or HIV
  • EBV negative serology
  • History of post-transplant lymphoproliferative disorder.

Treatment and study plan

Conversion to Belatacep

Drug

CNI will be tapered within 3 months: 75 % of initial dose on the first month, 50 % on the second month, 25 % on the third month, and stopped and a conversion to Belatacept will be performed. It will be administered (6mg/kg) every 2W for the first 2 months and then every month until kidney graft survival.

Standard of care treatment (SOC regimen) with Tacrolimus

Drug

Tacrolimus will be continued until kidney graft survival with objective of whole blood through levels between 6 and 8 ng/mL

Primary outcomes

  1. The efficacy of belatacept combined with standard of care, compared to calcineurin inhibitors (CNI) combined with standard of care, among kidney transplant recipients with sABMR

    Time frame: over 12 months post-biopsy

    Proportion in each arm, at 12 months post randomization, of patients with:

    • decrease eGFR > 20% at 12 months post randomization, according to CKD-EPI formula
    • or bad features on 12-month protocol biopsy: cg > 1
    • or chronic active ABMR according Banff 2019 classification,
    • or < 50 % MFI reduction of DSA,
    • or proteinuria/creatinuria ratio > 0.5 g/g,
    • or death,
    • or graft loss.

Secondary outcomes

  1. Presence of chronic active ABMR

    Time frame: at 12 months post biopsy

    Presence of ABMR defined according to the Banff 2019 classification, assessed on the kidney graft biopsy

  2. Serum creatinine and calculation of eGFR

    Time frame: 12 months and 36 months post biopsy

    Assessment of renal function based on serum creatinine levels and estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula

  3. Proteinuria/creatininuria ratio

    Time frame: 12 months and 36 months post biopsy

    Evaluation of proteinuria using the proteinuria-to-creatininuria ratio measured on urine samples

  4. Significant Proteinuria

    Time frame: 12 months and 36 months post biopsy

    Proportion of patients presenting significant proteinuria, defined as a proteinuria-to-creatininuria ratio > 0.5

  5. Presence of Poor Prognostic Histological Features

    Time frame: 12 months post biopsy

    Presence of unfavorable histological features, defined as transplant glomerulopathy with cg score > 1 according to Banff 2019 classification

  6. Biopsy-Proven Acute T Cell-Mediated Rejection

    Time frame: From biopsy to 36 months post biopsy

    Incidence of biopsy-proven acute T cell-mediated rejection, classified according to the Banff 2019 criteria

  7. Donor-Specific Antibody (DSA) Mean Fluorescence Intensity (MFI)

    Time frame: 12 months post-biopsy and 36 months post-randomization

    Assessment of DSA MFI measured using a Luminex single antigen assay at 12 months post-V0 and collected from medical charts at 36 months post-randomization

  8. Insufficient Reduction in DSA MFI

    Time frame: 12 months post biopsy

    Proportion of patients presenting a reduction in DSA MFI of less than 50% compared to baseline values.

  9. Evaluation of Safety Outcomes (Adverse Events)

    Time frame: Until the end of the study

    Collection and analysis of adverse events, including but not limited to viral reactivations (BK virus, CMV, EBV viremia), cardiovascular events, and other clinically significant adverse events.

  10. Graft Loss and Death

    Time frame: 12 months and 36 months post biopsy

    Occurrence of graft loss and all-cause mortality, collected from medical charts.

  11. Renal Function and Proteinuria According to Initial Biopsy Groups

    Time frame: 12 months and 36 months post biopsy

    Comparison of serum creatinine, eGFR (CKD-EPI), and proteinuria-to-creatininuria ratio between patient groups defined according to the initial biopsy findings.

  12. Graft Loss and Death According to Initial Biopsy Groups

    Time frame: 12 months and 36 months post biopsy

    Comparison of graft loss and all-cause mortality between patient groups defined according to the initial biopsy findings.

  13. Incidence Rate of de novo Subclinical ABMR (sABMR)

    Time frame: From initial biopsy up to 12 months post biopsy

    Incidence rate of biopsy-proven subclinical ABMR (sABMR), defined according to Banff 2019 classification, in patients without sABMR at initial biopsy. The incidence will be expressed as the number of patients developing sABMR divided by the time elapsed between the initial biopsy and the first biopsy demonstrating sABMR.

Study contacts

Contact information is provided by the study sponsor or research team.

Dominique Bertrand, Dr

CONTACT

[email protected]

02 32 88 54 52

Sponsors and collaborators

Lead sponsor

University Hospital, Rouen

Other

Registry information

Acronym: BELA-M-R

Important dates

Study start
2026
Primary completion
2032
Study completion
2032
First posted
Mar 4, 2024
Registry last updated
Jun 9, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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