Eculizumab for Prevention of Delayed Graft Function (DGF) in Kidney Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of Eculizumab in the prevention of Delayed Graft Function following deceased donor kidney transplantation. Based on experimental data and supportive observations in humans associating complement gene upregulation with ischemic reperfusion (IR) injury, it is hypothesized that C5 cleavage is a key step in the pathogenesis of ischemic reperfusion injury following transplantation. It is further hypothesized that Eculizumab, a humanized monoclonal antibody that blocks C5 cleavage in humans will be an effective prophylactic agent to prevent IR injury in high risk recipients. This trial is a prospective, randomized study to test the efficacy of eculizumab vs. placebo given once at the time of transplantation and once again 24 hours later in preventing delayed graft function in first adult recipients of deceased donor kidneys.

Official Title
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Eculizumab for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplantation

Conditions
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Delayed Graft Function, Kidney Transplantation, Complement Activity

Intervention / Treatment
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* Drug: Eculizumab
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Weight > 40 kg Male or Female Recipient of first deceased donor kidney Able to provide written informed consent Transplant candidate as per site specific guidelines Dialysis dependent renal failure (initiated more than 2 months prior to transplant) Recipients of kidneys defined as: Extended Criteria Donor (ECD) kidney with brain death: Kidney donors 60 years of age or older; or donors aged 50-59 years and have two of the following features: Hypertension, terminal serum creatinine > 1.5 mg/dL, or death from cerebrovascular accident (CVA), OR Standard Criteria Donor (SCD) kidney with actual cold ischemia time (CIT) 18 - 40 hours Exclusion Criteria: Patient is planned to receive a multi-organ transplant Kidney from donor < 6 years of age Dual kidney transplant (from same donor, including en bloc) Living donor kidney transplant Recipients with donor-specific anti-HLA antibodies of more than 3,000 MFI Participation in another investigational drug study Recipient BMI > 40 ABO incompatible DCD (donor with cardiac death) Donor Women who are pregnant or breast-feeding Women of child bearing potential who are unable or unwilling to use a medically acceptable form of contraception (defined as the use of oral, injected or implanted hormonal methods of contraception, intrauterine device (IUD)or intrauterine system (IUS), barrier methods of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository) Patients with HBsAg-positive status, HCV infection, or HIV infection Patients with atypical hemolytic uremic syndrome (aHUS) or C3 glomerulonephritis (C3GN) Active bacterial or other infection which is clinically significant in the opinion of the investigator Patients with history of splenectomy Patients with history of meningococcal disease Patients allergic to or unable to tolerate Ciprofloxacin Patients unable or unwilling to receive vaccination against meningitis prior to study drug administration Patients with a known or suspected hereditary complement deficiency Patients with a history of cancer (other than non melanoma skin cancers) within the last five years Donors of more than 70 years of age Subjects with a psychiatric or physical illness which in the opinion of the Investigator would interfere with their ability to participate in the study.

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: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eculizumab<br>Eculizumab 1200 mg (diluted in Sodium Chloride (NaCl) to 5mg/mL, volume = 240 mL) will be given intraoperatively at the time of transplantation prior to reperfusion of the renal allograft and again at 900 mg (diluted in NaCl to 5mg/mL, volume = 180 mL) 12-24 hours post-transplantation | Drug: Eculizumab<br> <br> * Other names: Soliris;|
| Placebo Comparator: Normal Saline<br>Administered at same volume and time as Experimental arm | Drug: Normal Saline<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodialysis | The need of at least one dialysis treatment during the first 7 days after transplantation excluding: (i) requirement for a single dialysis session indicated for hyperkalemia (ii) hyperacute rejection, renal arterial and/or venous thrombosis, obstructive uropathy, recurrence of primary disease, and early thrombotic microangiopathy | 7 days post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate (GFR) | Estimated GFR as determined from the 4-variable MDRD (Modified Diet in Renal Disease) equation on days 7, 30, 90 and 180 post-transplantation | 6 months post-transplantation | 
| Hemodialysis | Number of dialysis sessions at 30 days and 8 weeks post-transplantation | 8 weeks post-transplantation | 
| Primary Non-function | The incidence of primary non-function (PNF) defined as the need for dialysis-dependency for more than 8 weeks | 8 weeks post-transplantation | 
| Graft Rejection | Incidence of graft rejection within 6 months | 6 months post-transplantation | 
| Patient Survival | Patient survival at 12 months post-transplantation | 12 months post-transplantation | 
| Graft Survival | Death censored graft survival at 12 months post-transplantation | 12 months post-transplantation | 
| Serum Creatinine | Change from baseline in serum creatinine and serum creatinine concentration at 24, 48 and 72 hours post-transplantation | 3 days post-transplantation | 
| Urine Output | Percentage of patients with total 24-hour urine output of more than 500 mL on post-transplantation days 2 and 3 | 3 days post-transplantation | 
| Biomarkers | Absolute levels of biomarkers associated with acute renal injury | 6 months post-transplantation | 
| Qualified Delayed Graft Function (qDGF) | The incidence of qDGF defined as the requirement for dialysis for any reason in the first 7 days post-transplantation | 7 days post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Transplantation, Delayed Graft Function