Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection
Condition: Kidney Transplantation
MeSH terms: Angioedemas, Hereditary
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Organ transplantation offers the only hope for a normal life for patients with end-stage
      renal disease on dialysis (ESRD). For the highly-sensitized patient, patients with antibodies
      to human leukocyte antigens (HLA), transplantation is extremely difficult or impossible since
      pre-formed antibodies will cause severe rejection and loss of transplanted organs.
      Approximately 30% of the transplant list in the U.S. is considered sensitized (have
      detectable antibodies to HLA antigens). These anti-HLA (anti-Human Leukocyte Antigen
      antibodies) pose a significant barrier to transplantation that has recently been successfully
      addressed using desensitization therapies with IVIG, rituximab and/or plasmapheresis (PE).
      Despite the success of these therapies, post-transplant antibody mediated rejection (AMR) and
      chronic Antibody Mediated Rejection (CAMR) remain significant problems. Recent data suggests
      that addition of Berinert (C1 Inhibitor) to post-transplant treatment regimen may
      significantly reduce incidence of Antibody Mediation Rejection.

      Twenty highly-sensitized patients who have undergone desensitization treatment and are
      awaiting kidney transplant will be enrolled in the study. Once transplanted these patients
      will be started on the standard of care post-transplant immunosuppressive protocol. In
      addition patients will receive Berinert 20 units/ kg daily x 3 days, then twice weekly x 3
      weeks. At the end of Berinert treatment a kidney biopsy will be performed. Subjects will be
      followed for 6 months to assess safety and efficacy of the study protocol.
    

Detailed description: 
      Single center, Phase I/II, randomized The trial will examine the safety and efficacy of human
      C1 INH given post-transplant to reduce or prevent complement-dependent, antibody-mediated
      rejection (AMR) in 20 subjects (adult) who are highly-HLA sensitized (HS),(Panel Reactive
      Antibodies >30% (PRA), have undergone desensitization with intravenous immunoglobin (IVIG) +
      rituximab and/or plasmapheresis and are awaiting Living donor (LD)/ Deceased Donor (DD)
      kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch will
      be performed to detect anti-HLA antibodies and donor-specific anti-HLA antibodies (DSA) which
      are associated with acute rejection or graft loss. (These anti-HLA (anti-Human Leukocyte
      Antigen antibodies) antibodies may result naturally or from previous pregnancy, transfusions,
      or prior transplants.) If acceptable crossmatches and Donor Specific Antibody levels are seen
      after desensitization, the patients will proceed to Living Donor/Deceased Donor
      transplantation. Patients receiving transplants will have pre-transplant labs obtained for C1
      INH levels, Complement 3 (C3) and Complement 4 (C4) at transplant. In addition to the
      standard post-transplant immunosuppressive protocol, participating patients will receive
      placebo or 20 Units/kg C1 INH twice weekly X 4 weeks. At the end of the treatment, a protocol
      biopsy will be performed to assess the allograft for evidence of Antibody Mediated Rejection,
      including C4d staining. Since ~25% of highly sensitized patients experience Antibody Mediated
      Rejection post-transplant and 85% of these Antibody Mediated Rejection episodes occur in the
      1st post-transplant month, we feel the assessment of the potential impact of C1 INH therapy
      is best assessed in this time period. After completion of the C1 INH therapy, patients will
      be followed for an additional 6 month to assess allograft function and Antibody Mediated
      Rejection episodes as well as Donor Specific Antibodies.

      The subjects will be followed to determine the proportion who develop evidence of Antibody
      Mediated Rejection within 6 month of completion of the study. In addition we will asses the
      transplanted patients to determine the number who sustain a viable and functioning kidney
      allograft for 6 months. All subjects will be evaluated on an intent-to-treat basis. The
      subject accrual rate will be limited to no more than five subjects per month in the initial
      three months to assure safety to all subjects. Repeat laboratories will be performed at the
      completion of C1 INH therapy to determine effect on levels and correlation with any potential
      events.
    

Intervention name(s): C1 Esterase Inhibitor; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): C1 Esterase Inhibitor 20 units/kg twice weekly x 4 weeks; NS (comparable volume as intervention) twice weekly x 4wks
Other intervention name(s): Berinert
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: Treatment
Keywords: Kidney transplantation