The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation
Condition: Antibody-mediated Rejection; Hyperacute Rejection of Cardiac Transplant; Left Ventricular Dysfunction; Cardiac Allograft Vasculopathy; Heart Graft Dysfunction
MeSH terms: Ventricular Dysfunction; Ventricular Dysfunction, Left
Study type: Interventional
Phase: Phase 3

Summary: 
      All individuals who receive a heart transplant are at risk for developing antibody-mediated
      rejection (AMR). An antibody is a protein produced by the body's immune system when it
      detects a foreign substance, called an antigen. The mechanism of an antibody is to attack an
      antigen. In antibody mediated rejection, antibodies will attack the transplanted heart,
      causing injury to the heart. The purpose of this investigation is to determine if a study
      drug, called eculizumab (Soliris), is safe to use in heart transplant recipients, and
      determine if it reduces risk of antibody-mediated rejection.
    

Detailed description: 
      The growing proportion of sensitized cardiac recipients presents an additional challenge to
      the transplant practitioner attempting to minimize the occurrence of antibody mediated
      rejection (AMR). Patients pre-exposed or "sensitized" to antigen exposing events (i.e.: blood
      transfusions, multiple pregnancies, prior organ transplantations, ventricular support
      devices) are more likely to both possess preformed and develop de-novo antibodies. Sensitized
      patients with panel reactive antibodies > 25% are at risk for increased risk of rejection,
      development of cardiac allograft vasculopathy and increased mortality after heart
      transplantation.

      A central component of antibody-mediated cell injury is complement activation. The inhibition
      of terminal complement activation may be the missing link to decreasing possibly both
      complement-mediated AMR and cellular rejection (CR) by inhibiting both the inflammatory
      effects of both circulating antibodies and cytokine induced cell death.

      Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with
      high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation
      of the terminal complement complex C5b-9. By this mechanism, eculizumab (Soliris®) inhibits
      terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria
      patients.

      This study is a non-randomized, open-label, investigator-initiated safety and efficacy trial
      investigating the de-novo use of eculizumab alongside conventional therapy to prevent
      antibody mediated rejection. The duration of the study will include an open enrollment period
      and at least 12 months of follow-up (post-transplant). We will consent up to 45 eligible
      patients, highly "sensitized", with a panel reactive antibody score greater than 70%, who are
      not previously or currently enrolled in another ongoing trial. Of these 45 participants, up
      to 20 of these patients will be treated with eculizumab (Solaris), the study drug. The use of
      eculizumab will be un-blinded to all study and research practitioner participants.
    

Intervention name(s): Eculizumab
Intervention type(s): Drug
Intervention description(s): At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses.
On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion.
On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days.
On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit.
On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit.
Other intervention name(s): Soliris
Intervention MeSH terms: Eculizumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: cardiac transplantation; immunosuppression; acute cellular rejection; antibody mediated rejection; sensitization; antibody production in cardiac patients; panel reactive antibodies; desensitization strategies in heart transplant patients; complement activation; complement c3d and c4d deposition; terminal complement inhibition; complement C5 binding; Eculizumab; monoclonal antibody; donor specific antibodies