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

NCT ID: NCT00307125

Last Updated: 2015-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 757 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-03-31
• Study Completion Date: 2012-12-31

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.

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:

1. 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.

2. 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.

Conditions

Kidney Transplant; Kidney Transplant Recipient; Graft Function/Survival; de Novo HLA Antibodies Development

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Rituximab plus immunosuppression

Intervention Type: DRUG

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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo plus immunosuppression

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Rituxan®; MabThera®; anti-CD20; Placebo for rituximab

Eligibility Criteria

Inclusion Criteria

• 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

• Parent or guardian willing to provide informed consent
• Have received all childhood vaccinations prior to study entry

• 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

Exclusion Criteria

• 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.

• 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

• Positive test for parvovirus (B19) by PCR in the blood.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical Trials in Organ Transplantation

NETWORK

Sponsor Role: collaborator

Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)

UNKNOWN

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mohamed H. Sayegh, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

William Harmon, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Anil Chandraker, MD

Role: STUDY_CHAIR

Brigham and Women's Hospital

Locations

University of Alabama, Pediatric Nephrology

Birmingham, Alabama, United States

University of Alabama

Birmingham, Alabama, United States

University of California, San Francisco

San Francisco, California, United States

University of Florida

Gainesville, Florida, United States

University of Illinois

Chicago, Illinois, United States

Northwestern University

Chicago, Illinois, United States

University of Maryland

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Saint Barnabas Medical Center

Livingston, New Jersey, United States

Legacy Transplant Services

Portland, Oregon, United States

Oregon Health Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

The Methodist Hospital

Houston, Texas, United States

Children's Hospital and Regional Medical Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 12438971 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12394606 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12698094 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28346714 (View on PubMed)

Related Links

http://www.ctotstudies.org

Click here for the Clinical Trials in Organ Transplantation (CTOT) public Web site

Other Identifiers

CCTPT-02

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT CTOT-02

Identifier Type: -

Identifier Source: org_study_id