Clinical trial NCT00307125
Conditions: Kidney Transplant Kidney Transplant Recipient Graft Function/Survival de Novo HLA Antibodies Development
Keywords: Organ Transplantation Graft function/survival Immunosuppression anti-CD20 (rituximab)
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2006-03-01; Completion date: 2012-12-01
Enrollment: 757 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Rituximab plus immunosuppression intervention 2: Placebo plus immunosuppression
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents: