Trial record 1 of 26 for:    B-Cell Depletion by anti-CD20
Previous Study | Return to List | Next Study

Rituximab in Kidney Transplantation

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00307125
First received: March 23, 2006
Last updated: November 4, 2013
Last verified: November 2013
  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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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 ]
    1. Graft function at 3 and 5 years as measured by calculated GFR and serum creatinine
    2. Graft Survival at 3 and 5 years
    3. 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 ]
    1. Demographics and age
    2. Immunosuppression regimens
    3. Living-donor vs. Deceased-donor
    4. ECD vs. non-ECD
    5. Infections
    6. 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 ]
    1. Chemokines and Cytokines
    2. Inflammatory Markers
    3. 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
Study Completion Date: December 2012
Primary Completion Date: December 2012 (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
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00307125

Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
University of Alabama, Pediatric Nephrology
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
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, New Jersey
Saint Barnabas Medical Center
Livingston, New Jersey, United States, 07039
United States, Oregon
Legacy Transplant Services
Portland, Oregon, United States, 97210
Oregon Health Science University
Portland, Oregon, United States, 97219
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
Sponsors and Collaborators
Investigators
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: November 4, 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
Renal Insufficiency, Chronic
Urologic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014