Use of Immune Globulin Plus Rituximab for Desensitization in Highly HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation
Condition: End Stage Renal Disease
MeSH terms: Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This single center, Phase I/II, exploratory study has been modified to a safety/efficacy
      study providing all patients with IVIG and Rituximab. The trial will examine the safety and
      efficacy of human polyclonal IVIG 10%, when given at [2.0 gm/kgx2], + Rituximab 1gm to reduce
      donor-specific antibodies (DSA) to a level that is permissive for transplantation in 75
      subjects (adults only ages >18 yrs) who are highly-HLA sensitized and are awaiting deceased
      donor kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch
      will be performed. If acceptable crossmatches and DSA levels are seen, the patients will
      proceed to DD transplantation. Patients receiving transplants will receive an additional dose
      of IVIG at transplantation (within 10 days) and will receive additional doses of Rituximab 1g
      at 3M post transplant if DSA levels remain or become positive at 6M if de novo DSA occur.
      Patients who are desensitized and not transplanted at 9M after desensitization will have
      completed the study and can be treated as best judged by their physician.
    

Detailed description: 
      Organ transplantation offers the only hope for a normal life for patients with end-stage
      renal disease on dialysis. For 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. Intravenous gamma globulin (IVIG) can
      reduce or eliminate these antibodies in most patients and allow for successful
      transplantation. This breakthrough has allowed patients previously considered not
      transplantable to receive life-saving transplants. However, IVIG alone does not always
      eradicate the anti-HLA antibodies to a degree that will allow transplantation.

      In this study, the investigators propose additional treatment with rituximab, a humanized
      antibody directed at the CD20 antigen that is present on most B-cells. Both IVIG and
      rituximab are approved by the U.S. Food and Drug Administration (FDA) for numerous
      immunologic disorders and Non-Hodgkin's lymphoma, respectively. However, neither is approved
      by the FDA for desensitization of highly-HLA sensitized transplant patients. A previously
      conducted pilot study demonstrated IVIG + Rituximab can fill an important gap in the current
      therapeutic approach for management of highly sensitized patients and may become the standard
      therapy.

      Update: Study updated after observation that subjects transplanted after desensitization with
      IVIG alone experienced higher rates of antibody rejection and graft loss. The primary
      objective of this revised protocol will be to examine the safety and efficacy of IVIG 2gm/kg
      (maximum 140g) given on day#0 & day #30 plus Rituximab 1gm given on day #15. Transplanted
      patients will receive additional doses of Rituximab 1gm at 3 months post-transplant if donor
      specific antibody (DSA) levels remain or become positive or at 6M if de novo DSA occur. All
      transplanted patients who remain DSA negative, will not receive additional Rituximab. All
      transplanted patients will have a protocol biopsy at transplant and 12 months. All subjects
      will complete 5 visits in the pre-transplant phase of the study. Patients who are
      transplanted will have additional 5 post-transplant visits. The following are
      research-related procedures:

        1. Rituximab infusion.

        2. Kidney allograft biopsies (Intra-op, 12 months post-transplant)

        3. Rituximab level, HACA levels

        4. Immunologic biomarkers (CD19+, CD38+, CD27+)

      Although the investigator commonly uses both treatment regimens at Cedars-Sinai Medical
      Center, only the IVIG treatment is considered to be standard of care for highly
      HLA-sensitized patients. The investigational component of this study is the addition of the
      rituximab. Currently the study has been amended to a safety and efficacy study focusing on
      decreasing HLA antibodies pre-transplant and minimizing DSA post-transplant.
    

Intervention name(s): Rituxan
Intervention type(s): Biological
Intervention description(s): Rituximab (1gm) given on day# 15. Transplanted patients will receive an additional dose of Rituximab at 3M if DSA remains or 6M if denovo DSA present.
Other intervention name(s): Rituximab
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney transplant; highly sensitized