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CD38 mAb Induction + Azathioprine Maintenance for Chronic Active AMR in Kidney Transplant Recipients (CAZA)

16 de julho de 2026 atualizado por: wujianyong

A Multicenter Exploratory Clinical Study of Targeted NK Cell Inhibition for Transplant Kidney Chronic Active Antibody-Mediated Rejection (caABMR): Single Induction With CD38 Monoclonal Antibody Followed by Sequential Maintenance With Azathioprine

This multicenter, prospective, single-arm exploratory study evaluates the efficacy and safety of a novel sequential regimen for chronic active antibody-mediated rejection (caABMR) in kidney transplant recipients: single-dose CD38 monoclonal antibody (1800 mg subcutaneous) induction to deplete plasma cells and NK cells, followed by long-term maintenance with azathioprine (replacing mycophenolate mofetil) plus standard triple immunosuppression (steroid + calcineurin inhibitor). The regimen aims to control DSA-driven injury, stabilize or improve graft function (primary: eGFR decline slope), reduce DSA, improve pathology (Banff 2022), and minimize infection/nephrotoxicity risks associated with intensified or prolonged biologic therapy. Twenty patients across 6 Chinese transplant centers will be enrolled. CD38 mAb, azathioprine, key monitoring tests (HLA antibody, pharmacogenomics, immune profiling) are provided free by the study team (~40,000 RMB per patient). Ethics approved; informed consent obtained.

Visão geral do estudo

Status

Ainda não está recrutando

Condições

Intervenção / Tratamento

Descrição detalhada

Background: caABMR is the leading cause of late kidney allograft loss. Current therapies (plasmapheresis, IVIG, rituximab, bortezomib, long-term CD38 mAb) have limited efficacy, high recurrence, significant side effects, and high cost with no approved standard.

Rationale: CD38 mAb depletes antibody-producing plasma cells and pathogenic NK cells, rapidly lowering DSA and micro vascular inflammation. However, long-term monotherapy is costly and may increase infection risk. This study uses single induction dose + switch to azathioprine (safe, inexpensive, long-used in transplantation, suppresses NK activity) for durable, affordable maintenance. TPMT/NUDT15 genotyping guides personalized AZA dosing; serial NK cell monitoring targets <20/μL.

Design: Multicenter (6 centers), prospective, open-label, single-arm, exploratory (N=20).

Intervention: Baseline: CD38 mAb 1800 mg SC x1 + immediate switch MMF→AZA (dose per genotype: normal metabolizer 2-3 mg/kg/d; intermediate 0.6-2.4 mg/kg/d). Maintain triple IS (steroid + AZA + Tac target 5-7 ng/mL or CsA 150-250 ng/mL).

Tipo de estudo

Intervencional

Inscrição (Estimado)

20

Estágio

  • Não aplicável

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Contato de estudo

  • Nome: Chunchun Wei, MD
  • Número de telefone: +8613738053172
  • E-mail: 327530957@qq.com

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

  • Adulto
  • Adulto mais velho

Aceita Voluntários Saudáveis

Não

Descrição

Inclusion Criteria:

  1. Voluntary written informed consent.
  2. Age ≥18 years.
  3. Kidney transplant (living or deceased donor) ≥180 days prior.
  4. eGFR ≥30 mL/min/1.73 m² (CKD-EPI 2021).
  5. Currently on stable triple immunosuppression (CNI + MMF + steroid) for ≥4 weeks, no severe related adverse effects.
  6. Positive HLA Class I and/or Class II donor-specific antibodies (DSA).
  7. Transplant kidney biopsy meeting Banff 2022 criteria for chronic active antibody-mediated rejection (caABMR).
  8. TPMT/NUDT15 genotyping: non-homozygous mutant (normal or intermediate metabolizer).

Exclusion Criteria:

  1. Participating in another clinical trial.
  2. Age <18 years.
  3. Pregnant, breastfeeding, or inadequate contraception in females.
  4. ABO-incompatible transplant.
  5. TPMT/NUDT15 homozygous mutant genotype.
  6. Biopsy shows any of: T-cell mediated rejection (TCMR), new/recurrent severe thrombotic microangiopathy, or polyomavirus nephropathy.
  7. Received anti-rejection therapy in prior 3 months.
  8. Received other immunomodulatory monoclonal/polyclonal antibodies (anti-CD20, bortezomib, anti-C5, anti-IL-6/IL-6R) in prior 3 months.
  9. Total bilirubin >2×ULN or ALT/AST >2.5×ULN.
  10. Hemoglobin <8 g/dL.
  11. Platelets <100×10^9/L.
  12. WBC <3×10^9/L or neutrophils <1.5×10^9/L.
  13. Hypogammaglobulinemia: IgG <400 mg/dL.
  14. Active bacterial, viral, or fungal infection.
  15. Active malignancy requiring intensified immunosuppression.
  16. Latent or active tuberculosis.
  17. Live vaccine within 6 weeks of screening.
  18. History of alcohol or illicit drug abuse.
  19. Severe medical or psychiatric illness likely to impair study participation.
  20. Active hepatitis B.
  21. Known hypersensitivity to CD38 mAb, azathioprine, or study drug components, or severe drug allergy history.

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Tratamento
  • Alocação: N / D
  • Modelo Intervencional: Atribuição de grupo único
  • Mascaramento: Nenhum (rótulo aberto)

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Experimental: Experimental: CD38 mAb Induction + Azathioprine Sequential Maintenance

All enrolled caABMR patients receive:

  • Single subcutaneous injection of CD38 monoclonal antibody 1800 mg at baseline (Day 0).
  • Immediate conversion from mycophenolate mofetil to azathioprine (AZA), dosed according to TPMT/NUDT15 genotype and adjusted to achieve NK cell count <20/μL.
  • Continued standard triple immunosuppression: corticosteroid + azathioprine + tacrolimus (trough 5-7 ng/mL) or cyclosporine (trough 150-250 ng/mL).
  • Protocol-driven monitoring and 28-week surveillance biopsy. No control arm (single-arm exploratory design justified by lack of approved therapy and emerging evidence for CD38 targeting in AMR).
Biológico: CD38
Single 1800 mg subcutaneous injection at baseline to induce rapid depletion of plasma cells (source of DSA) and NK cells (key effectors of microvascular injury in caABMR). Marketed anti-CD38 mAb (off-label use in this indication).
Outros nomes:
  • CD38 mAb
  • anti-CD38 monoclonal antibody
Medicamento: Azathioprine (AZA)
Oral azathioprine maintenance (replaces mycophenolate), individualized starting dose 2.0-3.0 mg/kg/day (normal TPMT/NUDT15 metabolizer) or 30-80% reduced (intermediate metabolizer), titrated per serial NK cell counts and hematologic tolerance. Long-term NK suppression to maintain immune balance and protect graft.
Outros nomes:
  • AZA
  • Imuran (or generic)
Outro: Standard Triple Immunosuppression Maintenance
Continued per local practice with protocol targets

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Slope of estimated glomerular filtration rate (eGFR) decline
Prazo: Baseline through Week 28, planned assessments at weeks 0, 4, 8, 12, 16, 20, 24, 28
The primary efficacy endpoint is the slope of eGFR decline over 28 weeks, calculated from serial serum creatinine measurements (every 4 weeks) using the 2021 CKD-EPI equation. Serum creatinine is measured by enzymatic method or isotope dilution mass spectrometry. Slope is estimated via linear mixed-effects model or ordinary least-squares regression per patient, then summarized. Negative slope indicates ongoing graft loss; less negative or positive slope indicates stabilization or improvement of renal function after treatment.
Baseline through Week 28, planned assessments at weeks 0, 4, 8, 12, 16, 20, 24, 28

Medidas de resultados secundários

Medida de resultado
Descrição da medida
Prazo
Change in peripheral blood NK cell, T cell and B cell subset counts and percentages measured by flow cytometry
Prazo: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28
Quantitative detection of lymphocyte subpopulations (NK, T, B cells) in peripheral blood via flow cytometry; evaluate the absolute count and relative percentage changes at each follow-up time point.
Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28
Absolute and relative percentage change in estimated glomerular filtration rate calculated by CKD-EPI 2021 formula
Prazo: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28
Estimated glomerular filtration rate (eGFR) is calculated by the CKD-EPI 2021 formula. Both absolute value and relative percentage change of eGFR will be evaluated at all scheduled follow-up visits.
Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28
Percentage change in urine protein-to-creatinine ratio (UPCR)
Prazo: Baseline and Week 28
Urine protein-to-creatinine ratio (UPCR) measured in mg/g or mg/mmol. Urine protein is tested via pyrogallol red molybdate method, and creatinine is detected using sarcosine oxidase assay. The relative percentage change of UPCR is used to evaluate renal therapeutic efficacy.
Baseline and Week 28
Relative percentage change in donor-specific antibody (DSA) mean fluorescence intensity (MFI)
Prazo: Baseline, Week 8, Week 28
Donor-specific antibody MFI is detected via Luminex single-antigen bead assay. Relative percentage change from baseline will be calculated to evaluate the reduction of alloantibody levels.
Baseline, Week 8, Week 28
Change in Transplant Kidney Biopsy Pathology Scores (Banff 2022)
Prazo: Baseline, Week 28
Banff 2022 renal allograft pathology scoring system is applied for the interpretation of protocol kidney biopsy specimens. The scores include microcirculation inflammation, tubulitis, interstitial inflammation, chronic glomerulopathy, transplant glomerulitis and chronic arteriopathy. The pathological scores are recorded at screening baseline and week-28 follow-up biopsy. The variation of each individual Banff lesion score between two time-points will be analyzed. Higher Banff lesion scores represent more severe renal allograft injury.
Baseline, Week 28
Incidence of Acute Rejection (TCMR, AMR, or Mixed)
Prazo: Through Week 28
Cumulative incidence (%) of biopsy-proven acute rejection, including T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and mixed rejection, diagnosed according to Banff 2022 classification criteria.
Through Week 28
Patient overall survival rate
Prazo: Week 28
The proportion of subjects who remain alive without all-cause mortality at the designated follow-up time point
Week 28
Graft survival rate
Prazo: Week 28
Percentage of participants with functioning renal allograft, defined as no return to maintenance dialysis and no secondary kidney retransplantation
Week 28
Incidence of BK Virus (BKV) Infection
Prazo: Through Week 28
Cases of BK virus infection are categorized as BKV viruria (>10³ copies/mL), BKV viremia (≥10⁴ copies/mL), or biopsy-confirmed BKV nephropathy identified by renal histology combined with SV40 IHC or ISH staining. Cumulative incidence percentage will be calculated for each category.
Through Week 28
Incidence of Cytomegalovirus (CMV) Infection
Prazo: Through Week 28
Cytomegalovirus infection is defined as detectable CMV DNA ≥10³ copies/mL quantified via quantitative PCR (qPCR). Cumulative incidence percentage of affected subjects will be summarized.
Through Week 28
Incidence of Neutropenia
Prazo: Through Week 28
Neutropenia is stratified by absolute neutrophil count (ANC): mild ANC <1.5×10⁹/L, moderate ANC <1.0×10⁹/L, severe ANC <0.5×10⁹/L. Cumulative incidence percentage will be stratified by severity grades defined per NCI CTCAE or study protocol criteria.
Through Week 28

Outras medidas de resultado

Medida de resultado
Descrição da medida
Prazo
Outcome Measure Title：Incidence of injection-related adverse reactions
Prazo: Through Week 28
All infusion-related adverse events during the whole follow-up period will be recorded, including fever, chills, hypotension, dyspnea and other infusion-associated manifestations.
Through Week 28
Incidence of adverse events (AE) and serious adverse events (SAE)
Prazo: Through Week 28
The type, severity, relation to study medication and occurrence frequency of all adverse events and serious adverse events will be collected, according to CTCAE common terminology criteria.
Through Week 28
Incidence of liver function abnormalities
Prazo: Through Week 28
Liver function indexes including alanine transaminase, aspartate transaminase, total bilirubin will be tested regularly. Liver function abnormality is defined as laboratory elevation exceeding 3-fold upper limit of normal range.
Through Week 28
Incidence of all-cause hospitalization
Prazo: Through Week 28
All hospitalization events for any reason during follow-up will be documented, including the admission time, diagnosis and length of hospital stay.
Through Week 28

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

wujianyong

Investigadores

  • Investigador principal: Jianyong Wu, MD, Zhejiang University

Publicações e links úteis

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Publicações Gerais

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo (Estimado)

15 de julho de 2026

Conclusão Primária (Estimado)

15 de março de 2028

Conclusão do estudo (Estimado)

15 de março de 2028

Datas de inscrição no estudo

Enviado pela primeira vez

11 de julho de 2026

Enviado pela primeira vez que atendeu aos critérios de CQ

16 de julho de 2026

Primeira postagem (Real)

21 de julho de 2026

Atualizações de registro de estudo

Última Atualização Postada (Real)

21 de julho de 2026

Última atualização enviada que atendeu aos critérios de controle de qualidade

16 de julho de 2026

Última verificação

1 de julho de 2026

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • IIT20260074C-R1

Plano para dados de participantes individuais (IPD)

Planeja compartilhar dados de participantes individuais (IPD)?

NÃO

Informações sobre medicamentos e dispositivos, documentos de estudo

Estuda um medicamento regulamentado pela FDA dos EUA

Não

Estuda um produto de dispositivo regulamentado pela FDA dos EUA

Não

Essas informações foram obtidas diretamente do site clinicaltrials.gov sem nenhuma alteração. Se você tiver alguma solicitação para alterar, remover ou atualizar os detalhes do seu estudo, entre em contato com register@clinicaltrials.gov. Assim que uma alteração for implementada em clinicaltrials.gov, ela também será atualizada automaticamente em nosso site .

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