B-Cell Depletion by Anti-CD20 (Rituximab) in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies Will Result in Inhibition of Alloantibody Production and Attenuation of Chronic Humoral Rejection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 757
- 试验地点
- 34
- 主要终点
- During Screening Phase: Incidence of Alloantibody Development
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Pilot Phase-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.
干预措施: Placebo plus immunosuppression (Drug)
Pilot Phase-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.
干预措施: Rituximab plus immunosuppression (Drug)
结局指标
主要结局
During Screening Phase: Incidence of Alloantibody Development
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Number of Participants Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD)(1 year post treatment initiation)
- Number of Participants With Viral Replication of Cytomegalovirus (CMV)(1 year post treatment initiation)
- Number of Deaths 12 Months Post Treatment Initiation(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 Viral Replication of Polyomavirus (BKV)(1 year post treatment initiation)
- Number of Participants Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy(1 year post treatment initiation)
- Number of Participants With Evidence of Viral Replication of Epstein-Barr Virus (EBV)(1 year post treatment initiation)