Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies

This study has been completed.
Sponsor:
Collaborators:
Clinical Trials in Organ Transplantation
Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00307125
First received: March 23, 2006
Last updated: March 11, 2015
Last verified: March 2015
  Purpose

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.


Condition Intervention Phase
Kidney Transplant
Kidney Transplant Recipient
Graft Function/Survival
de Novo HLA Antibodies Development
Drug: Rituximab plus immunosuppression
Drug: Placebo plus immunosuppression
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel 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:
  • During Screening Phase: Incidence of Alloantibody Development [ Time Frame: During screening window of 3-60 months post kidney transplant ] [ Designated as safety issue: No ]
    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 [ Time Frame: During screening window of 3-60 months post kidney transplant ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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:
  • Number of Deaths 12 Months Post Treatment Initiation [ Time Frame: 12 months post treatment initiation ] [ Designated as safety issue: No ]
    Number of participant deaths within 12 months post treatment initiation

  • Number of Participants Experiencing Graft Loss 12 Months Post Treatment Initiation [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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 Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD) [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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 Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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 Viral Replication of Cytomegalovirus (CMV) [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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 Participants With Evidence of Viral Replication of Epstein-Barr Virus (EBV) [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Viral Replication of Polyomavirus (BKV) [ Time Frame: 1 year post treatment initiation ] [ Designated as safety issue: No ]
    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.


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: 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.

Drug: Rituximab plus immunosuppression

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.

Other Names:
  • Rituxan®
  • MabThera®
  • anti-CD20
Placebo Comparator: 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.

Drug: Placebo plus immunosuppression

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.

Other Name: Placebo for rituximab

  Show Detailed Description

  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:

  • 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

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 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.
  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
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
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
Clinical Trials in Organ Transplantation
Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)
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
Results First Received: February 27, 2015
Last Updated: March 11, 2015
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
Graft function/survival
Immunosuppression
anti-CD20 (rituximab)

Additional relevant MeSH terms:
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 21, 2015