Clinical trial NCT00261547: Rituximab Treatment to Block HLA Antibodies in Renal Transplant Recipients
Official title: Pilot Study of Rituximab Treatment to Inhibit HLA Antibodies in Renal Allograft Recipients
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Chronic Rejection
Kidney Insufficiency
Keywords: Kidney transplantation
HLA
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2005-12-05
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Negative DSA by Luminex beads or ELISA
timeFrame: at 12 months post study medication
measure: Lack of C4d deposition in peritubular capillary
timeFrame: on 12 month renal biopsy
Secondary outcomes:
measure: Renal allograft function: Serum creatinine, Calculated creatinine clearance, Urine protein, Urine protein-creatinine ratio
timeFrame: 12 months after study entry compared to the baseline
measure: Change in chronic rejection pathology indices
timeFrame: on 12-month renal biopsy compared to baseline biopsy.
Other outcomes:
Locations:
Study officials:
affiliation: Massachusetts General Hospital
name: Nina Tolkoff-Rubin, M.D.
role: PRINCIPAL_INVESTIGATOR
References: