A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1972-x) contains supplementary material, which is available to authorized users.

The renaissance of complement therapeutics

“…This showed beneficial safety profiles after systemic administration and organ perfusion in phase I and phase IIb trials, and a large clinical study in kidney transplantation is ongoing in the UK 147,148 .…”

“…Patient stratification, tailored study design and selection of distinct targets might prove to be critical for the success of the approach. Several trials with eculizumab and plasma protease C1 inhibitor are ongoing, and the results of a large clinical study using Mirococept are eagerly awaited 147 . As the arsenal of promising candidate molecules reaching clinical stages increases, the goal of using complement drugs to prevent transplantation-related complications is becoming more achievable.…”

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

“…Gene polymorphism in the Ficolin 2 gene, another activator of the lectin-mediated complement pathway, increased the affinity to carbohydrates and is associated with a higher risk of DGF and acute rejection [39]. In a current study complement receptor 1 blocking is tested for prevention of DGF targeting complement effects mediated by C3d and C4b [40]. Inhibition of terminal complement activation using a C5 inhibitor resulted in reduced DGF in animal models [6].…”

The complex functioning of the complement system in xenotransplantation

“…There are two ways to reduce complement‐mediated injury to a graft, namely targeting complement molecules (a) during donor organ preservation, or (b) subsequently when any one of the three pathways is activated. For example, (a) Mirococept (APT070), a derivative of human CR1, is now under clinical trial for preventing IRI in kidney allografts during preservation . Annexin IV is expressed in grafts, and an anti‐annexin‐IV antibody tagged to a complement inhibitor (Crry) protected mouse cardiac allografts from IRI .…”

“…For example, (a) Mirococept (APT070), a derivative of human CR1, is now under clinical trial for preventing IRI in kidney allografts during preservation. 189 Annexin IV is expressed in grafts, 190 and an anti-annexin-IV antibody tagged to a complement inhibitor (Crry) protected mouse cardiac allografts from IRI. 191 (b) Many efforts have been made to directly target complement at sites of activation.…”