Rituximab Treatment to Block HLA Antibodies in Renal Transplant Recipients

Pilot Study of Rituximab Treatment to Inhibit HLA Antibodies in Renal Allograft Recipients

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.

Study Overview

• Status: Withdrawn
• Conditions: Kidney Insufficiency; Chronic Rejection
• Intervention / Treatment: Drug: Rituximab

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab; this study has only one arm as the treatment group	Drug: Rituximab; All subjects will be treated with Rituximab 1000 mg (1 g) intravenously on days 1 and 15.; Other Names: Rituxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Negative DSA by Luminex beads or ELISA	at 12 months post study medication
Lack of C4d deposition in peritubular capillary	on 12 month renal biopsy

Secondary Outcome Measures

Outcome Measure	Time Frame
Renal allograft function: Serum creatinine, Calculated creatinine clearance, Urine protein, Urine protein-creatinine ratio	12 months after study entry compared to the baseline
Change in chronic rejection pathology indices	on 12-month renal biopsy compared to baseline biopsy.

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Nina Tolkoff-Rubin, M.D., Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: December 1, 2005
• First Submitted That Met QC Criteria: December 1, 2005
• First Posted (Estimated): December 5, 2005

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Kidney transplantation; HLA
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 2005p001524