Evaluation of Desensitization Protocols in HLA-incompatible Kidney-transplant Candidates

Study Overview
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Brief Summary
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Kidney transplantation is the best renal-replacement in the setting of end-stage renal disease. However, some transplant candidates have developed anti-HLA alloantibodies (human leukocyte antigen). When they are numerous and when their strength assessed by mean fluorescence intensity (MFI) is high it is very complicated to find-out a suitable kidney allograft against which the recipient has a negative cross-match. In such a case the only hope for the patient is desensitization therapy, whereby the treatment will decrease anti-HLA alloantibodies below a threshold, i.e. MFI < 3,000, enabling kidney transplantation without risking antibody-mediated rejection. Desensitization relies on i) apheresis technics in order to withdraw circulating anti-HLA antibodies, and ii) immunosuppression, i.e. rituximab or tocilizumab, targeting B-lymphocytes, and tacrolimus/mycophenolic acid/steroids targeting T-cells. The type of apheresis is guided by the pre-desensitization MFI of anti-HLA alloantibodies, e.g. double filtration plasmapheresis or semispecific immunoadsorption. Likely the choice between rituximab and tocilizumab depends also on predesensitization anti-HLA antibody MFIs. At the end of the desensitization process, the patient will be able to get a kidney transplant either from a live-donor or from a deceased donor.

Official Title
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Evaluation of Desensitization Protocols in HLA-incompatible Kidney-transplant Candidates

Conditions
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End-stage Renal Disease, Kidney Transplantation, Hla-incompatible Kidney Transplant Candidates

Intervention / Treatment
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* Drug: visits of tocilizumab injection (every 4 weeks, up to 5 visits)
* Drug: Rituximab 375 mg/m2 at Day-30
* Drug: Rituximab 375 mg/m2 at Day-15 (only for donors living)
* Other: Transplant Day-0


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients on the kidney transplant list, waiting for a first or repeat transplant Presence of anti HLA antibodies either class I and/or II Sensitized against a potential living donor or have been on the waiting list for at least 3 years and having no potential live-donor Patients eligible for desensitization will receive either rituximab alone, or rituximab plus apheresis, or tocilizumab before rituximab Normal recent (<6 months) cardiac workup Vaccinated against pneumococcus and meningococcus B and C Willingness of the patient to undergo the desensitization process and Express consent of the patient for women of childbearing age, effective contraception or abstinence Affiliated to a social security scheme or of such a scheme Exclusion Criteria: Active underlying infections or neoplasia Pregnant women, parturient or breastfeeding Subject in exclusion period of another study Subject under administrative or judicial control Subject who cannot be contacted in an emergency Rituximab contra indication: hypersensitivity (to active substance or murine protein), active and severe infections, patients in a severely immunocompromised state, severe heart failure or severe, uncontrolled cardiac disease. Tocilizumab contra indication: hypersensitivity, active and severe infections. Apheresis contra indication: active and severe infection, untreated or instable coagulation disorders, unstable coronary disease, recent stroke, hemodynamic instability.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Desensitization with Tocilizumab and rituximab (MFI >15000)<br> | Drug: visits of tocilizumab injection (every 4 weeks, up to 5 visits)<br>* every 4 weeks, up to 5 visits (D-170, D-142, D-114, D-86, D-58).<br>Drug: Rituximab 375 mg/m2 at Day-30<br>* Rituximab 375 mg/m2 at Day-30<br>Drug: Rituximab 375 mg/m2 at Day-15 (only for donors living)<br>* Rituximab 375 mg/m2 at Day-15<br>Other: Transplant Day-0<br>* TRANSPLANTATION<br>|
| Other: Desensitization with Rituximab only (MFI<15000)<br> | Drug: Rituximab 375 mg/m2 at Day-30<br>* Rituximab 375 mg/m2 at Day-30<br>Drug: Rituximab 375 mg/m2 at Day-15 (only for donors living)<br>* Rituximab 375 mg/m2 at Day-15<br>Other: Transplant Day-0<br>* TRANSPLANTATION<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of the results of the strategy of desensitization in patients who will access to kidney transplantation from deceased or living donors. | Decrease of MFI for highest donor-specific alloantibody (DSA) between start and end of desensitization for every patient in each category | at day 1 start of desensitization, at day 0 of Graft | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Desensitization efficacy with regards to DSA decrease and kidney transplantation | MFI for highest DSAs for each group | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | 
| impairment of DSA synthesis | Decrease in peripheral plasma cells and plasmablasts of >50% | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | 
| Impairment of immune response | Decrease in complement factors of >25% | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | 
| Incidence of treatment desensitization protocols, emergent adverse events (safety and Tolerability) | Emergent adverse events to the desensitization therapy will be carefully monitored during the treatment period and within the following three months. | Day-198, at day-30 Graft, at day-15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-HLA alloantibodies, Desensitization therapy, Tocilizumab, Rituximab