Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies
- Conditions
- Kidney Transplant RecipientKidney TransplantGraft Function/Survivalde Novo HLA Antibodies Development
- Interventions
- Drug: Placebo plus immunosuppression
- Registration Number
- NCT00307125
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 757
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pilot Phase-Rituximab plus immunosuppression Rituximab plus immunosuppression Enrollment into a Stage 2 pilot treatment study will occur after Stage 1. Adult Rituximab Dosing (Subjects \> 18 years): 1000 mg on days 0 and 14; Pediatric Rituximab Dosing (Subjects \<\\=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. Pilot Phase-Placebo plus immunosuppression Placebo plus immunosuppression Adult Placebo Dosing (Subjects \>18 years): 1000 mg on days 0 and 14; Pediatric Placebo 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.
- Primary Outcome Measures
Name Time Method During Screening Phase: Incidence of Alloantibody Development During screening window of 3-60 months post kidney transplant Data were analyzed for 653 participants from the screening phase of the study. This outcome looked at the number of kidney transplant recipients that developed de novo HLA antibodies (anti-HLA Ab) post-transplant. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection.
During Screening Phase: Timing of Alloantibody Development During screening window of 3-60 months post kidney transplant Data were analyzed for 653 participants from the screening phase of the study. Of these, 79 (12%) developed de novo HLA-antibodies (anti-HLA Ab). This outcome looks at the average length of time (interval) from post kidney transplant until development of alloantibody. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection
Number of Participants With 50 Percent (%) Decrease in Circulating Anti-Human Leukocyte Antigen (HLA) Antibodies 1 year post treatment initiation Number of participants with 50% decrease in circulating anti-HLA antibodies at any time within the first 12 months post kidney transplant by LuminexTM Beads Method. Luminex assays for quantitation and detection of cytokine and signal transduction proteins. Presence of circulating antibodies is indicative of the transplant recipient's immune system responding to the transplanted organ as a foreign object or infection.
- Secondary Outcome Measures
Name Time Method Number of Participants Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD) 1 year post treatment initiation Number of participants with PTLD within 12 month post treatment initiation. Diagnosis of PTLD was made by B cell proliferation after therapeutic immunosuppression.
Number of Participants With Viral Replication of Cytomegalovirus (CMV) 1 year post treatment initiation Number of participants with viral replication of CMV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of viral replication is indicative of active CMV infection.
Number of Deaths 12 Months Post Treatment Initiation 12 months post treatment initiation Number of participant deaths within 12 months post treatment initiation
Number of Participants Experiencing Graft Loss 12 Months Post Treatment Initiation 1 year post treatment initiation Number of participants with graft loss, defined as the need for dialysis for greater than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure within 12 month post treatment initiation
Number of Participants With Viral Replication of Polyomavirus (BKV) 1 year post treatment initiation Number of participants with viral replication of BKV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of viral replication is indicative of a BKV infection. Polyomavirus BK is a significant pathogen in transplant recipients.
Number of Participants Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy 1 year post treatment initiation Number of participants with loss of PTC C4d staining on kidney (renal) biopsy within 12 months post treatment initiation. PTC C4d staining on biopsy indicates organ rejection.
Number of Participants With Evidence of Viral Replication of Epstein-Barr Virus (EBV) 1 year post treatment initiation Number of participants with positive viral replication of EBV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of EBV viral replication is indicative of active infection.
Trial Locations
- Locations (17)
University of Illinois
🇺🇸Chicago, Illinois, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
University of Alabama, Pediatric Nephrology
🇺🇸Birmingham, Alabama, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Children's Hospital Boston
🇺🇸Boston, Massachusetts, United States
Children's Hospital and Regional Medical Center
🇺🇸Seattle, Washington, United States
University of Alabama
🇺🇸Birmingham, Alabama, United States
The Methodist Hospital
🇺🇸Houston, Texas, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Oregon Health Science University
🇺🇸Portland, Oregon, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Legacy Transplant Services
🇺🇸Portland, Oregon, United States