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) (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, we published a retrospective multicenter study 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, we did not observe any effect of standard of care treatment in active sABMR. Very recently, an expert consensus for the recommended treatment for ABMR after KT was published. They concluded the clear lack of evidence but a standard of care for ABMR was nevertheless defined. Therefore, we propose 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. We will 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Kidney Transplant Rejection
• Intervention / Treatment: Drug: Conversion to Belatacep; Drug: Standard of care treatment (SOC regimen) with Tacrolimus

• Study Type: Interventional
• Enrollment (Estimated): 290
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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)

2. Randomization inclusion criteria:

   • Patients with active sABMR, according Banff 2019 classification, with very slight transplant glomerulogathy (cg = 0 or 1).

Exclusion Criteria:

1. 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

2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; - Experimental arm: conversion to Belatacept 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.	Drug: Conversion to Belatacep; 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.
Active Comparator: Control; - Control arm: Standard of care treatment (SOC regimen) with Tacrolimus Tacrolimus will be continued until kidney graft survival with objective of whole blood through levels between 6 and 8 ng/mL	Drug: Standard of care treatment (SOC regimen) with Tacrolimus; Tacrolimus will be continued until kidney graft survival with objective of whole blood through levels between 6 and 8 ng/mL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	over 12 months post-biopsy

Collaborators and Investigators

• Sponsor: University Hospital, Rouen

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): March 1, 2031
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: February 26, 2024
• First Submitted That Met QC Criteria: February 26, 2024
• First Posted (Estimated): March 4, 2024

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 2022/0342/HP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No