Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies
Condition: Kidney Transplant; Kidney Transplant Recipient; Graft Function/Survival; de Novo HLA Antibodies Development
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether treatment with rituximab (anti-CD20,
      Rituxan®, MabThera®) in individuals who develop new anti-HLA antibodies after renal (kidney)
      transplant will promote longer-term survival of the transplanted kidney.The pilot study
      compares the use of rituximab (Rituxan®) + site-specific standard immunosuppression to
      placebo + site-specific standard immunosuppression in the treatment of circulating anti-HLA
      antibodies in subjects who develop de novo anti-HLA antibodies between 3-36 months after
      transplant.
    

Detailed description: 
      Organ rejection occurs when a patient's body does not recognize the new organ and attacks it.
      Data suggest that the development of anti-human leukocyte antigen (HLA) antibodies is an
      early clinical indication that organ rejection may occur. Rituximab is a genetically
      engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to
      deplete B cells when administered intravenously; it is FDA-approved for the treatment of
      non-Hodgkin's lymphoma; Chronic Lymphocytic Leukemia (CLL); and Rheumatoid Arthritis (RA) in
      combination with methotrexate in adult patients with moderately-to severely-active RA who
      have inadequate response to one or more TNF antagonist therapies.

      In a previous small study, kidney transplant patients with either acute humoral rejection
      (AHR) or chronic humoral rejection (CHR) were given rituximab and other antilymphocyte
      therapy. Patients with AHR had lower or undetectable levels of circulating anti-HLA
      antibodies after study treatment, and patients with CHR had a sustained decrease of anti-HLA
      antibodies to undetectable after 6 to 9 months.

      This study will evaluate the safety and efficacy of rituximab in 1.)preventing organ
      rejection and 2.)promoting long-term survival of donor kidneys in people who undergo kidney
      transplantation.

      This study involves two stages:

        1. Stage 1 begins 3 to 36 months after transplant. During Stage 1, blood collection will
           occur every 3 months for up to 36 months after transplant to test for anti-HLA
           antibodies. When these antibodies are detected twice within 1 month, the patient will
           undergo a baseline kidney biopsy and have his or her glomerular filtration rate (GFR)
           measured to determine kidney function. If a patient meets certain study criteria, he or
           she will enter Stage 2 (Pilot Treatment Study).

           If anti-HLA antibodies are not detected in a patient's blood during Stage 1, the
           patient's participation will be complete.

        2. In Stage 2, patients will receive site-specific standard immunosuppression plus
           randomization to either rituximab or placebo:

             -  Adult dosing (>18 years of age), will receive an intravenous infusion of 1000mg of
                rituximab on Days 0 and 14.

             -  Pediatric dosing (<\= than 18 years of age) will receive an intravenous infusion of
                375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses of rituximab on Days 0, 8, 15 and
                22.

      Adult participants will have 7-9 study visits over 12-24 months. Pediatric participants will
      have 9-11 study visits over 12-24 months. A physical exam, medication history, adverse events
      assessment, and blood and urine collection will occur at all visits. A biopsy of the kidney
      transplant will occur at Stage 2 entry and Month 12.

      Note: Prior to January 2010, Stage 2 of this was a double-blind (double-masked) randomized
      pilot treatment study. As of January 2010 and beyond:

        -  subjects were no longer being recruited in the placebo treatment arm

        -  all treatment assignments were unblinded and an open-label design commenced; therefore,
           medication assignments were open to the study participants as well as to the site
           clinical team.

        -  all study subjects who participated in the study prior to this change were informed of
           the change

        -  all subjects who were randomized to the placebo-controlled arm and continued to meet the
           pilot study eligibility criteria were provided the option to participate in the pilot
           treatment study.
    

Intervention name(s): Rituximab plus immunosuppression; Placebo plus immunosuppression
Intervention type(s): Drug; Drug
Intervention description(s): Genetically engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to deplete B cells when administered intravenously. Generally used in the treatment of non-Hodgkin's lymphoma
Standard immunosuppression is site-specific.; Placebo dosing: Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).
Standard immunosuppression is site-specific.
Other intervention name(s): Rituxan®; MabThera®; anti-CD20; Placebo for rituximab
Intervention MeSH terms: Rituximab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Organ Transplantation; Graft function/survival; Immunosuppression; anti-CD20 (rituximab)