Trial of Rituximab Given Pre-Transplant to Sensitised Live Donor Kidney Recipients

Study Overview
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Brief Summary
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About one third of prospective kidney transplant recipients have antibodies in their blood directed against the tissues of their only available kidney donor. Recently, desensitisation treatments when administered pre-transplant have allowed successful transplantation of these patients despite high rates of acute antibody mediated rejection (AAMR). The investigators propose to test in a randomised controlled trial whether rituximab, a monoclonal antibody that depletes B-lymphocytes, will safely lower antibody mediated rejection (AMR) rates when added to standard therapy. The investigators will also test whether rituximab enables more patients to achieve a negative crossmatch against their donor and thereby allow more transplants to proceed.

Detailed Description
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This study is designed to investigate in a prospective, randomised fashion whether a single intravenous dose of rituximab (375 mg/m2) given two weeks prior to transplant, in addition to standard therapy, will allow sensitised renal transplant subjects to achieve a negative CDC crossmatch and thereby proceed to live donor transplantation. We will also evaluate whether rituximab will reduce the number of AAMR episodes in the post-transplant period, compared to controls. All eligible subjects must have a positive T- and/or B-cell CDC or flow cytometry crossmatch and have donor-specific antibodies identified by solid-phase assay at screening. All subjects will receive a standard desensitisation regimen that includes plasma exchange/IVIG + MMF before and immediately after transplantation followed by a standard care immunosuppressive regimen (IL-2R antagonist, tacrolimus, mycophenolate mofetil [MMF] and corticosteroids) after transplantation.

Official Title
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A Prospective Open Label Randomised Multicentre Study Evaluating the Efficacy & Safety of Rituximab Given Pre-Transplant to Sensitised Renal Allograft Recipients in Addition to a Standard Desensitisation Regimen Consisting of PE/IVIG & MMF

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Rituximab
* Drug: Standard Care


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subjects, age > 18 years Subjects receiving a single organ renal transplant from a living donor Positive T-cell and/or B-cell crossmatch by complement dependent cytotoxicity (CDC) and/or positive flow cytometry crossmatch with confirmed donor-specific antibodies on solid-phase assay at screening. Positive CDC T-cell and/or B-cell crossmatch titre must be less than or equal to 1:64. Subjects capable of understanding the purposes and risks of the study and who can give written informed consent Exclusion Criteria at Study Entry (4 weeks prior to transplant): Primary renal transplant lost from acute rejection less than six months prior to randomisation Women of childbearing potential with a positive serum or urine pregnancy test or nursing mothers Subjects with history of malignancy (other than non melanoma skin cancer that has been totally excised with no recurrence for two years) Subjects with known contraindications to treatment with rituximab Subjects with haemoglobin < 8.5 g/dL, WBC value of < 3000/mm3 or a platelet count of < 50,000/mm3 that is unlikely to resolve prior to randomisation Subjects with a positive ABO crossmatch with donor Subjects with severe diarrhoea or other gastrointestinal disorders that might interfere with the ability to absorb oral medication and is unlikely to resolve prior to randomisation Subjects participating in another interventional clinical trial or requiring treatment with un-marketed investigational drugs or who would be expected to require other medications prohibited by the protocol Subjects who cannot be followed for the study duration Subjects with disorders or conditions that may interfere with the ability to comply with study procedures and/or requirements Additional Exclusion Criteria at Day -2 before Transplantation: All exclusion criteria as at study entry Positive T- and/or B-cell CDC crossmatch at Day -2

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Rituximab<br>* Single dose (375 mg/m2) of rituximab to be given intravenously (IV) 14 days prior to transplantation<br>* Other names: Mabthera;|
| Active Comparator: 2<br> | Drug: Standard Care<br>* Standard care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biopsy proven antibody mediated rejection |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination of donor specific antibodies (DSA) |  | Day - 2 , 7; Months 1, 3, 6, 9 and 12 | 
| C4d in biopsies |  | Day 7; Months 3 and 12 | 
| Plasma exchanges |  | Month 12 | 
| Death |  | Month 12 | 
| Treated rejection |  | Month 12 | 
| Graft loss |  | Months 3, 6 and 12 | 
| Treatment failure |  | Months 6 and 12 | 
| Calculation of glomerular filtration rate (GFR) |  | Months 1 - 12 | 
| Slope of 1/serum creatinine (Ser. Cr) |  | Months 6 and 12 | 
| 24-hour U protein |  | Months 3 and 12 | 
| Safety |  | Month 12 | 
| Cancer and infections |  | Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab, donor, sensitised, antibody, rejection