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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Condition or disease | Intervention/treatment | Phase |
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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 (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 |

Arm | Intervention/treatment |
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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:
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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 |
- 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.
- 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.

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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 |
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.

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

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 |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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 |
Organ Transplantation Graft function/survival Immunosuppression anti-CD20 (rituximab) |
Rituximab Antineoplastic Agents, Immunological Antineoplastic Agents |
Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents |