Abstract
BackgroundDelayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation.Methods/designEMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5–25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events.DiscussionThe EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique ‘cytotopic’ property that permits its retention in the organ microvasculature.Trial registrationISRCTN registry, ISRCTN49958194. Registered on 3 August 2012.
Highlights
Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation
The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation
In the last two decades the incidence of DGF has significantly increased, probably due to the use of expanded criteria donors (ECDs) and donation after circulatory death (DCD) donors [2]. This common complication of renal transplantation is associated with detrimental effects on both short- and long-term graft outcomes as it is linked to increased rates of acute rejection and chronic allograft nephropathy
Summary
In the last two decades the incidence of DGF has significantly increased, probably due to the use of expanded criteria donors (ECDs) and DCD donors [2]. Considerable progress has been made in the understanding of the molecular mechanisms implicated in the pathogenesis of acute kidney injury that frequently leads to DGF [1] In this regard, various interventions for the prevention and treatment of DGF are currently under evaluation in the preclinical and clinical settings. Kidney delivery techniques have the advantage of selectively inhibiting the local inflammatory processes of IRI, and at the same time they minimise the risk of systemic side effects. To our knowledge, this is the first clinical trial to implement this innovative method of ex vivo administration of a cytotopic complement inhibitor (Mirococept) in renal transplantation. Abbreviations APT070: Mirococept; BPAR: Biopsy-proven acute rejection; CIT: Cold ischaemia time; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CR1: Complement receptor 1; CRF: Case Report Form; CRP: C-reactive protein; DBD: Donation after Brain Death; DCD: Donation after Circulatory Death; DGF: Delayed graft function; eGFR: Estimated glomerular filtration rate; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; HLA: Human leukocyte antigen; IMP: Investigational medicinal product; IRI: Ischaemia reperfusion injury; KHP-CTO: King’s Health Partners Clinical Trials Office; MAC: Membrane attack complex; MDRD: Mean calculated GFR; MHRA: Medicines and Healthcare products Regulatory Agency; MRC: Medical Research Council; NAG: N-acetyl-β-D-glucosaminidase; NGAL: Neutrophil gelatinase-associated lipocalin; Pbo: Placebo; PTLD: Post-transplant lymphoproliferative disorder; RBP: Retinol binding protein; RCA: Regulators of complement activation; REC: Research Ethics Committee; SDMA: Symmetric dimethylarginine; SPC: Summary of Product Characteristics; UTI: Urinary tract infection
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