End Stage Renal Disease Clinical Trial
Official title:
Assessing Safety and Efficacy of Preoperative and Post-Transplant C1 Inhibitor (Berinert®) vs. Placebo in Recipients of a Renal Allograft From Deceased High Risk Donors and Its Impact on DGF and IRI
The use of C1INH (Berinert) in patients receiving deceased donor kidney transplants with high risk for delayed graft function (DGF) may show significant improvement in outcomes post transplant compared with patients that do not receive C1INH treatment. Complement activation has been detected in animal models and human kidneys with ischemic reperfusion injury (IRI) and inflammatory cell infiltrates. By blocking complement activation the investigators hope to improve kidney graft function post transplant in these recipients.
Early graft function has a long-term effect on graft survival. Poor early graft function and
delayed graft function (DGF) contributes to decreased short- and long-term patient and graft
survival, increased incidence of acute rejection, prolonged hospitalization, and higher costs
of transplantation. Although multiple factors contribute to the impaired graft function,
ischemia-reperfusion injury (IRI) is the underlying pathophysiology leading to poor early
graft function and DGF. A >35% incidence of DGF has remained constant over time despite
significant improvements in immunosuppressive strategies and patient management. This may be
due to increased use of kidneys from "extended-criteria" and/or non-heart-beating donors,
where even greater rates (>60%) of DGF have been reported.
More than 96,680 people are currently waiting for a kidney transplant in the United States
(United Network for Organ Sharing (UNOS); UNOS.org 3/22/13). Of the 15,092 kidney transplants
performed in the US in 2011, ~11,000 (62%) were from deceased donors. Of these, approximately
17% were from expanded-criteria donors. The USRDS reports that more than 50% of patients on
the waiting list are willing to accept a kidney from an expanded-criteria donor (ECD) or
donors after cardiac death (DCD).
From the investigators previous studies with C1INH (Berinert®) for prevention of antibody
mediated rejection (ABMR), the investigators noted that no patients developed ABMR during
treatment with C1INH, the investigators also noted a near significant reduction in DGF due to
IRI (ClinicalTrials.gov(NCT01134510), FDA Investigational New Drug (IND#): 14363). These
findings suggest an important role for complement in the mediation of IRI and that inhibition
of early complement activation using C1INH in patients receiving at risk kidneys for IRI
should reduce this costly and often devastating complication of kidney transplantation. In
addition, numerous other studies in animal models have shown dramatic improvements in IRI
models with the use of C1INH. Complement activation is detectable in animal and in human
kidneys models after IRI and experimental data suggests that use of C1INH prior to induction
of IRI significantly reduces IRI as well as inflammatory cell infiltrates. Based on this, the
investigators hypothesize that the use of C1INH in patients receiving deceased donor (DD)
kidney transplants with high risk for DGF will show significant reductions in DGF and
improved outcomes post-transplant compared with patients receiving DD transplants who do not
receive C1INH treatment. Here, the investigators propose to investigate the application of
pre-operative and post-transplant doses of C1INH (Berinert®) vs. placebo in adult subjects
receiving a DD renal allograft considered at high-risk for IRI and DGF. The investigators
hypothesize that C1INH treated patients will demonstrate improved function of the kidney
allograft compared to placebo, with equivalence in safety. The primary objectives of this
study are: Using a double blinded, placebo controlled format, the investigators will:
1. Evaluate and compare the safety of C1INH (50 units/kilogram, round to the nearest 500
unit) administered pre-transplant and 24 hrs post-transplant in recipients of kidney
allografts from high risk for IRI deceased donors.
The secondary objectives are to:
1. On the basis of safety and efficacy, determine appropriate Berinert® study dose for
Phase III investigation, and
2. Determine appropriate endpoint choice for Phase III investigation.
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