Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation

Study Overview
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Brief Summary
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This study is designed to assess the effectiveness of eculizumab in recipients of kidney transplantation with donor-specific antibodies (DSA) and worsening kidney function and to assess if eculizumab improves endothelial cell injury in the kidney. The investigators hypothesize that complement inhibition with eculizumab will reduce allograft injury, resulting from less complement-mediated injury of endothelial cells and less endothelial cell activation.

Detailed Description
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This study will address the clinical challenge that currently exists in the management of kidney transplant recipients who have developed de novo DSA, have deteriorating graft function, yet have no established treatment alternative. This is a randomized, open-label, pilot intervention trial. Post transplant patients with deteriorating renal function (defined as 20% reduction in GFR) will be screened for the development of DSA and biopsied for the presence of C4d deposition. All patients with DSA and those meeting inclusion/exclusion criteria will undergo protocol renal biopsy and will be assessed for C4d deposition. Participants will be randomized to treatment with eculizumab plus standard of care (SOC) or SOC only. Randomization will be stratified by C4d status (C4d+/C4d-) with 10 subjects (7 eculizumab, 3 SOC only) in each stratum. Eculizumab is an antibody that has been developed to inhibit the complement protein C5. Eculizumab will be delivered via IV according to the following schedule: Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks

Official Title
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Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial

Conditions
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Kidney; Complications, Allograft

Intervention / Treatment
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* Drug: eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Kidney transplant recipients greater than 6 months from the date of transplant Must be on standard immunosuppression: tacrolimus, mycophenolate mofetil, prednisone and have stable tacrolimus trough levels over past 3 months Deteriorating renal function, as defined by 20% reduction in GFR (MDRD calculation) Presence of DSA, as defined as MFI > 1100 Renal biopsy demonstrating no diffuse, irreversible end-stage organ injury (i.e. stage IV Fibrosis) Renal biopsy demonstrating C4d deposition (stratum 1) or no C4d deposition (stratum 2) Exclusion Criteria: History of CMV, BK, HSV or other viral infections History of chronic, recurrent bacterial infections Evidence of tubulitis on renal biopsy or other morphological features of acute cellular rejection or acute humoral rejection Renal biopsy demonstrating diffuse, irreversible end-stage organ injury Absolute GFR < 25 (MDRD calculation) Inability to provide informed consent History of poor vascular access Refusal to use double barrier contraception during study participation Patients actively enrolled in other clinical trials

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eculizumab<br>eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) | Drug: eculizumab<br>* Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks<br>* Other names: Soliris;|
| No Intervention: no additional therapy<br>patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline eGFR (Estimated Glomerular Filtration Rate) |  | Baseline | 
| Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Primary statistical analysis of change from baseline was conducted with mixed effects modeling providing calculated estimates. | Months 2,3,4,5,6 | 
| Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | These data were calculated by mean 6-month eGFR minus baseline mean eGFR divided by baseline eGFR. Presented below are the between groups results. These results were derived from the results in the outcome Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic kidney allograft injury, complement protein, eculizumab, Kidney transplantation