Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies

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:

• 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.

• 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.