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

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ClinicalTrials.gov Identifier: NCT00307125

Recruitment Status : Completed

First Posted : March 27, 2006

Results First Posted : March 23, 2015

Last Update Posted : March 23, 2015

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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)

Study Description

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.

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

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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:

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.
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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	757 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Study Start Date :	March 2006
Actual Primary Completion Date :	December 2012
Actual Study Completion Date :	December 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

Genetic and Rare Diseases Information Center resources: Chronic Graft Versus Host Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

During Screening Phase: Incidence of Alloantibody Development [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Secondary Outcome Measures :

Number of Deaths 12 Months Post Treatment Initiation [ Time Frame: 12 months post treatment initiation ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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.

Eligibility Criteria

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Ages Eligible for Study:	5 Years to 70 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00307125

Locations

Show 17 study locations

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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
University of Illinois
Chicago, Illinois, United States, 60607
Northwestern University
Chicago, Illinois, United States, 60611
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Children's Hospital Boston
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

National Institute of Allergy and Infectious Diseases (NIAID)

Clinical Trials in Organ Transplantation

Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)

Investigators

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Principal Investigator:	Mohamed H. Sayegh, MD	Brigham and Women's Hospital
Principal Investigator:	William Harmon, MD	Boston Children's Hospital
Study Chair:	Anil Chandraker, MD	Brigham and Women's Hospital

More Information

Additional Information:

Click here for the Clinical Trials in Organ Transplantation (CTOT) public Web site This link exits the ClinicalTrials.gov site

Publications:

Lee PC, Terasaki PI, Takemoto SK, Lee PH, Hung CJ, Chen YL, Tsai A, Lei HY. All chronic rejection failures of kidney transplants were preceded by the development of HLA antibodies. Transplantation. 2002 Oct 27;74(8):1192-4. doi: 10.1097/00007890-200210270-00025.

Mauiyyedi S, Colvin RB. Humoral rejection in kidney transplantation: new concepts in diagnosis and treatment. Curr Opin Nephrol Hypertens. 2002 Nov;11(6):609-18. doi: 10.1097/00041552-200211000-00007.

Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003 Apr 15;75(7):1034-40. doi: 10.1097/01.TP.0000055833.65192.3B.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fishman JA, Ikle DN, Wilkinson RA. Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study. Transpl Int. 2017 Jul;30(7):689-694. doi: 10.1111/tri.12959. Epub 2017 May 2.

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Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00307125
Other Study ID Numbers:	DAIT CTOT-02 CCTPT-02 ( Other Identifier: NIAID )
First Posted:	March 27, 2006 Key Record Dates
Results First Posted:	March 23, 2015
Last Update Posted:	March 23, 2015
Last Verified:	March 2015

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):


Organ Transplantation Graft function/survival Immunosuppression anti-CD20 (rituximab)

Additional relevant MeSH terms:

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Rituximab Antineoplastic Agents, Immunological Antineoplastic Agents	Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents

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