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Safety & Efficacy of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection

2014-08-27 03:13:16 | BioPortfolio

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 AMR and chronic AMR (CAMR) remain significant problems. Recent data suggests that addition of Berinert (C1 Inhibitor) to post-transplant treatment regimen may significantly reduce incidence of AMR.

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 12 months to assess safety and efficacy of the study protocol.

Description

Single center, Phase I/II, exploratory study will use an open labeled design. 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 IVIG + rituximab and/or plasmapheresis and are awaiting LD/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 antibodies may result naturally or from previous pregnancy, transfusions, or prior transplants.) If acceptable crossmatches and DSA levels are seen after desensitization, the patients will proceed to LD/DD transplantation. Patients receiving transplants will have pre-transplant labs obtained for C1 INH levels, C3 and C4 at transplant. In addition to the standard post-transplant immunosuppressive protocol, participating patients will receive 20U/kg C1 INH QD X3, then twice weekly X 3 weeks. At the end of the treatment, a protocol biopsy will be performed to assess the allograft for evidence of AMR, including C4d staining. Since ~25% of HS patients experience AMR post-transplant and 85% of these AMR 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 6M to assess allograft function and AMR episodes as well as DSA.

The subjects will be followed to determine the proportion who develop evidence of AMR within 6M 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 12 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.

Study Design

Control: Historical Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Kidney Transplantation

Intervention

C1 Esterase Inhibitor

Location

Cedars-Sinai Medical Center
Los Angeles
California
United States
90048

Status

Not yet recruiting

Source

Cedars-Sinai Medical Center

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:13:16-0400

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Medical and Biotech [MESH] Definitions

The end-stage of CHRONIC RENAL INSUFFICIENCY. It is characterized by the severe irreversible kidney damage (as measured by the level of PROTEINURIA) and the reduction in GLOMERULAR FILTRATION RATE to less than 15 ml per min (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002). These patients generally require HEMODIALYSIS or KIDNEY TRANSPLANTATION.

The transference of a kidney from one human or animal to another.

General dysfunction of an organ occurring immediately following its transplantation. The term most frequently refers to renal dysfunction following KIDNEY TRANSPLANTATION.

Preparative treatment of transplant recipient with various conditioning regimens including radiation, immune sera, chemotherapy, and/or immunosuppressive agents, prior to transplantation. Transplantation conditioning is very common before bone marrow transplantation.

A complication of kidney diseases characterized by cell death involving KIDNEY PAPILLA in the KIDNEY MEDULLA. Damages to this area may hinder the kidney to concentrate urine resulting in POLYURIA. Sloughed off necrotic tissue may block KIDNEY PELVIS or URETER. Necrosis of multiple renal papillae can lead to KIDNEY FAILURE.

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