Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies
Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies
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.
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.
Stage 1 Inclusion Criteria for All Participants:

 -  Willing to provide informed consent

 -  Previously diagnosed end stage renal disease (ESRD)

 -  Received kidney transplant within 3 and 36 months of study entry

 -  Willing to comply with the study protocol

 -  Willing to use acceptable forms of contraception during the study and for 12 months
 following rituximab/placebo therapy

 -  Willing to refrain from breastfeeding during the study and for 12 months following
 rituximab therapy

 Stage 1 Inclusion Criteria for Pediatric Participants (<\=18 Years of Age):

 -  Parent or guardian willing to provide informed consent

 -  Have received all childhood vaccinations prior to study entry

 Stage 2 Inclusion Criteria for Pilot Treatment Study:

 -  Three to 39 months post-transplant

 -  Developed new antibodies detected at two time points within 1 month between 3 to 36
 months post-transplant

 -  Negative pregnancy test

 Stage 1 Exclusion Criteria for All Participants:

 -  Recipient of a kidney from a donor older than 70 years of age

 -  Multi-organ transplant

 -  History of organ transplantation other than current kidney transplantation

 -  Previous treatment with rituximab

 -  History of severe allergic reactions to monoclonal antibodies

 -  History of allergic reaction to iodine glomerular filtration rate (GFR) assay

 -  Lack of intravenous (IV) access

 -  Sensitized to greater than 5% Panel Reactive Antibody (PRA) within 12 weeks prior to
 transplant

 -  History of recurrent bacterial or other significant infections

 -  Known active bacterial, viral, fungal, mycobacterial, or other infection (including
 tuberculosis [TB] or atypical mycobacterial disease) or any major episode of infection
 requiring hospitalization or treatment with IV antibiotics within 4 weeks of study
 entry. Patients with fungal infections of nail beds are not excluded.

 -  HIV infected

 -  Surface antigen positive for hepatitis B virus (HBV)

 -  Antibody positive for hepatitis C virus (HCV)

 -  History of drug, alcohol, or chemical abuse within 6 months prior to study entry

 -  History of cancer. Patients with adequately treated in situ cervical carcinoma or
 adequately treated basal or squamous cell carcinoma of the skin are not excluded.

 -  Clinically significant cardiovascular or pulmonary disease

 -  Evidence of urinary tract obstruction causing decreased kidney function, unless
 corrected by study entry

 -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
 laboratory finding that would contraindicate use of an investigational drug, may
 affect interpretation of study results, or put the patient at high risk for treatment
 complications

 -  History of psychiatric disorder that may interfere with participation in the study

 -  History of nonadherence to prescribed regimens

 -  Use of other investigational drugs within 4 weeks of study entry

 -  Received any licensed or investigational live attenuated vaccine within 2 months of
 study entry.

 Stage 2 Exclusion Criteria for All Participants:

 -  Previous treatment with rituximab

 -  Immunoglobulin Levels <500mg/dL (Combined IgM, IgG, IgA, IgE, IgD)

 -  History of severe allergic reactions to monoclonal antibodies

 -  History of cancer. Patients with adequately treated in situ cervical carcinoma or
 adequately treated basal or squamous cell carcinoma of the skin are not excluded.

 -  Active systemic infection at the time of entry into Stage 2

 -  Recurrent or de novo glomerular disease or Banff Grade III chronic rejection other
 than chronic humoral rejection (CHR) indicated in baseline kidney biopsy
 post-transplant

 -  History of post-transplant lymphoproliferative disease (PTLD)

 -  Serum creatinine of 3.0 mg/dl or greater OR GFR less than 25 ml/min at the time of
 entry into Stage 2

 -  Hemoglobin less than 8.5 g/dl

 -  Platelets less than 80,000 cells/mm^3

 -  White blood cell count less than 3,000 cells/mm^3

 -  AST or ALT 2.5 times the upper limit of normal at study entry

 -  Pregnant or breast-feeding

 -  Absolute neutrophil count less than 1000/mm^3

 Stage 2 Exclusion Criteria for Pediatric Participants (<\=18 Years of Age):

 -  Positive test for parvovirus (B19) by PCR in the blood.