Rituximab Treatment to Block HLA Antibodies in Renal Transplant Recipients

Mass General Brigham

Status and phase

Withdrawn

Phase 2

Phase 1

Conditions

Chronic Rejection

Kidney Insufficiency

Treatments

Drug: Rituximab

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00261547

2005p001524

Details and patient eligibility

About

The purpose of this study is to determine if administration of rituximab blocks the development of donor specific antibodies (DSA) in transplant recipients who have developed renal dysfunction and DSA after renal transplant. It is hoped that by blocking DSA production renal function will stabilize or improve.

Full description

A long established risk factor for late renal allograft loss is the development of DSA. Recent studies from our group and others have shown that these antibodies are probably responsible for chronic rejection by attacking the vascular endothelium and fixing complement (detected as C4d in renal biopsies). Studies in humans and monkeys have shown that circulating antibody and complement deposition precede the development of chronic graft injury. Interruption of antibody production is a potential beneficial strategy to prevent late graft loss from this mechanism.

Therapeutic regimens that have been used in an attempt to deplete HLA or ABO antibodies include plasmapheresis, IVIg, tacrolimus and mycophenolate mofetil (MMF), and anti-CD20 (rituximab). Of these regimens, the most specific is anti-CD20, rituximab (rituxan), a therapy now FDA approved for B cell proliferative diseases. Although initially introduced for the treatment of neoplasm, the humoral immunosuppressant effects of rituximab have been shown to have clinical significance. Rituximab interferes with both primary and secondary humoral responses by eliminating B-cells prior to antigen exposure, thus interfering with differentiation into antibody secreting cells and specific antibody production.

Sex

All

Ages

18 to 64 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Recipient of a primary cadaver or living donor renal allograft
18-64 years of age
At least 6 months and no more than 10 years post renal transplant
Serum clearly positive for defined DSA
Renal biopsy positive for C4d staining within 28 days before study Day 1 treatment
Blood positive for Cd 19/20 cells at greater than/equal to 50 % of lower limit of normal
Baseline serum creatinine 1.7-3.0 mg/dl
On stable doses of tacrolimus and MMF for at least 1 month prior to study entry
Able and willing to sign IRB approved consent form and comply with the requirements of the screen, treatment and follow-up phase of the protocol
Negative serum pregnancy test (women of child bearing potential)
Men and women of reproductive potential agree to use an acceptable method of birth control during treatment, for twelve months after treatment completion, or until B cell counts return to normal, whichever is longer

Exclusion criteria

Hemoglobin: < 8.5 gm/dL
Platelets: < 100.00/mm
White blood cell count: < 3000/mm3
AST or ALT . 2.5 x Upper Limit of Normal unless related to primary disease
Positive Hepatitis B or C serology
History of positive HIV
Treatment with any investigational agen within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)
Receipt of a live vaccine within 4 weeks prior to study entry
Previous treatment with rituximab (rituxan)
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
History of recurrent infections
Known active bacterial, viral, fungal, mycobacterial or other infection or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
Ongoing use of high dose steroids (>10mg/day) or unstable steroid dose in the past 4 weeks.
Lack of peripheral venous access
History of drug, alcohol or chemical abuse within 6 months prior to screen
Pregnancy or lactation
Concomitant malignancies or previous malignancies
History of psychiatric disorder that would interfere with normal participation in this protocol
Significant cardiac or pulmonary disease
Any other disease, metabolic dysfunction, physical examination finding or clinical lab finding giving reasonable suspicion of disease or condition that contraindicates use of an investigational drug or that may affect the interpretation of the results or render subject a high rist from treatment complications
Inability to comply with study and follow-up procedures