Rituximab in Kidney Transplantation
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
Purpose
The purpose of this study is to determine whether treatment with rituximab in people who develop new anti-HLA antibodies after kidney transplant will promote longer-term survival of the transplanted kidney.
| Condition | Intervention | Phase |
|---|---|---|
|
Kidney Transplantation Kidney Disease Kidney Failure, Chronic |
Drug: Rituximab |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- Stage 1 (Screening Study): Incidence and timing of alloantibody development [ Time Frame: During screening window of 3-60 months post-transplant ] [ Designated as safety issue: No ]
- Stage 2 (Pilot Study): test whether Rituximab (Rituxan®) therapy will decrease circulating anti-HLA antibodies by 50% [ Time Frame: At 12 months ] [ Designated as safety issue: No ]measured by LuminexTM platform with One Lambda LabScreenTM PRA Class I and II kit
- Patient survival (Pilot Study) [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]
- Incidence of graft loss (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
- Incidence of biopsy-proven post-transplant lymphoproliferative disease (PTLD) (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
- Loss of peritubular capillary (PTC) C4d staining on renal biopsy (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Degree and duration of B-cell depletion (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Frequencies of alloreactive T cells determined by ELISPOT (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Intragraft analysis of lineage specific markers and immunohistology to look at cellular infiltration (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Viral replication of polyoma virus, Epstein-Barr virus, and cytomegalovirus measured by PCR (Pilot Study) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Natural History of Screening Study [ Time Frame: During screening window of 3-60 months post-transplant ] [ Designated as safety issue: No ]
- Graft function at 3 and 5 years as measured by calculated GFR and serum creatinine
- Graft Survival at 3 and 5 years
- Evolution of Antibody Profile as measured by Anti-HLA Ab specifities and strength, and presence of MICA
- Incidence of Clinical Risk Factors During Screening Study [ Time Frame: During screening window of 3-60 months post-transplant ] [ Designated as safety issue: Yes ]
- Demographics and age
- Immunosuppression regimens
- Living-donor vs. Deceased-donor
- ECD vs. non-ECD
- Infections
- Rejections
- Incidence of Mechanistic Risk Factors During Screening Study [ Time Frame: During screening window of 3-60 months post-transplant ] [ Designated as safety issue: No ]
- Chemokines and Cytokines
- Inflammatory Markers
- Gene expression profiles in the blood
- Prevention of progressive chronic antibody mediated rejection by renal allograft biopsy [ Time Frame: 12 months ] [ Designated as safety issue: No ]
| Enrollment: | 757 |
| Study Start Date: | March 2006 |
| Estimated Study Completion Date: | December 2014 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Rituximab Arm
Enrollment into a Pilot study will occur after Stage 1. Adult participants (>18 years of age or older) will receive an intravenous infusion of 1000mg rituximab on Days 0 and 14. Pediatric participants (<18 years of age or younger) will receive an intravenous infusion of 375 mg/m2 rituximab (max. 500mg/m2) on Days 0, 8, 15, and 22. |
Drug: Rituximab
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
|
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. 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 new study will evaluate the safety and efficacy of rituximab in preventing organ rejection and promoting long-term survival of donor kidneys in people who undergo kidney transplantation.
The study will last 8 years. The study will enroll participants for 4 years, and patients will participate in the study for 2 to 5 years. 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 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:
- Adult participants, >18 years of age or older, will receive an intravenous infusion of 1000mg of rituximab at Days 0 and 14.
- Pediatric participants, <18 years of age or younger, will receive an intravenous infusion of 375 mg/m2 of rituximab at Days 0, 8, 15 and 22.
All participants will also receive standard of care immunosuppressive drugs. Adult participants, 18 years of age or older, will have 7-9 study visits over 12-24 months. Pediatric participants, 18 years of age or younger, 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.
Eligibility| Ages Eligible for Study: | 5 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Stage 1 Inclusion Criteria for All Participants:
- Participant 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 or Younger):
- Parent or guardian willing to provide informed consent
- Have received all childhood vaccinations prior to study entry
Stage 2 Inclusion Criteria for Pilot 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 IV venous 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 intravenous 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/mm3
- White blood cell count less than 3,000 cells/mm3
- AST or ALT 2.5 times the upper limit of normal at study entry
- Pregnant or breast-feeding
- Absolute neutrophil count less than 1000/mm3
Stage 2 Exclusion Criteria for Pediatric Participants (18 Years of Age or Younger):
- Positive test for parvovirus (B19) by PCR in the blood.
Contacts and Locations| United States, Alabama | |
| University of Alabama, Pediatric Nephrology | |
| Birmingham, Alabama, United States, 35294 | |
| University of Alabama | |
| Birmingham, Alabama, United States, 35294 | |
| United States, California | |
| University of California, San Francisco | |
| San Francisco, California, United States, 94143 | |
| United States, Florida | |
| University of Florida | |
| Gainesville, Florida, United States, 32601 | |
| United States, Illinois | |
| Northwestern University | |
| Chicago, Illinois, United States, 60611 | |
| University of Illinois | |
| Chicago, Illinois, United States, 60607 | |
| United States, Maryland | |
| University of Maryland | |
| Baltimore, Maryland, United States, 21201 | |
| United States, Massachusetts | |
| Brigham and Women's Hospital | |
| Boston, Massachusetts, United States, 02115 | |
| Massachusetts General Hospital | |
| Boston, Massachusetts, United States, 02114 | |
| Beth Israel Deaconess Medical Center | |
| Boston, Massachusetts, United States, 02215 | |
| Children's Hospital Boston | |
| Boston, Massachusetts, United States, 02115 | |
| United States, New Jersey | |
| Saint Barnabas Medical Center | |
| Livingston, New Jersey, United States, 07039 | |
| United States, Oregon | |
| Oregon Health Science University | |
| Portland, Oregon, United States, 97219 | |
| Legacy Transplant Services | |
| Portland, Oregon, United States, 97210 | |
| United States, Pennsylvania | |
| Children's Hospital of Philadelphia | |
| Philadelphia, Pennsylvania, United States, 19104 | |
| United States, Texas | |
| The Methodist Hospital | |
| Houston, Texas, United States, 77030 | |
| United States, Washington | |
| Children's Hospital and Regional Medical Center | |
| Seattle, Washington, United States, 98105 | |
| Principal Investigator: | Mohamed H. Sayegh, MD | Brigham and Women's Hospital |
| Principal Investigator: | William Harmon, MD | Children's Hospital Boston |
| Study Chair: | Anil Chandraker, MD | Brigham and Women's Hospital |
More Information
Additional Information:
Publications:
| Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT00307125 History of Changes |
| Other Study ID Numbers: | DAIT CTOT-02, CCTPT-02 |
| Study First Received: | March 23, 2006 |
| Last Updated: | April 30, 2013 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
|
Organ Transplantation Immunosuppression Renal Failure |
Additional relevant MeSH terms:
|
Kidney Diseases Kidney Failure, Chronic Renal Insufficiency Urologic Diseases Renal Insufficiency, Chronic Rituximab |
Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents |
ClinicalTrials.gov processed this record on May 19, 2013