C1INH Inhibitor Preoperative and Post Kidney Transplant to Prevent DGF & IRI
Condition: End Stage Renal Disease; Kidney Failure; Delayed Graft Function; Ischemic Reperfusion Injury
MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Renal Insufficiency; Reperfusion Injury; Delayed Graft Function
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): C1 Esterase Inhibitor; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): C1 Esterase Inhibitor 50 units per kilogram intravenous infusion administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses; Placebo medication identical to study drug (C1 esterase inhibitor) volume will be administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses
Other intervention name(s): Berinert (C1INH); Normal Saline (0.9%NaCl)
Intervention MeSH terms: Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: ESRD (End Stage Renal Disease); CKD (Chronic Kidney Disease); Kidney Transplant; ECD; delayed graft function; chronic kidney disease; expanded-criteria donor; end stage renal disease