Effects of Rituximab and Mycophenolate Mofetil (MMF) on Highly Sensitized Patients Awaiting Renal Transplant
Condition: Kidney Failure, Chronic; Diabetic Nephropathies; Glomerulonephritis, IGA; Hypertension, Renal
MeSH terms: Kidney Diseases; Renal Insufficiency; Diabetic Nephropathies; Kidney Failure, Chronic; Glomerulonephritis; Glomerulonephritis, IGA; Hypertension, Renal; Hypertension
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a 12-month phase 2, prospective, open label study to evaluate the effect of rituximab
      with mycophenolate mofetil (MMF)on the PRA of 14 highly sensitized patients who just
      completed an 8 month trial of MMF treatment alone. PRA values obtained at study enrollment
      and at 6 and 12 months on combined therapy as well as the rates of transplant will be
      compared and evaluated using descriptive analysis.
    

Detailed description: 
      BACKGROUND: Patients who have been exposed to human tissue by prior transplants, blood
      transfusion or pregnancy may develop and maintain anti-bodies against these foreign human
      cells (SENSITIZATION). As a result of sensitization these patients are more likely to reject
      an organ donated from an individual who possesses a similar human cell marker
      (ANTIGENIC)profile. These sensitized patients will remain on the kidney transplant waiting
      list up to twice as long as those who are not pre-sensitized.

      The Panel of Reactive Antibodies (PRA) is a test panel used to measure the patient reactivity
      to human leukocyte cell antigens (HLA). A PRA of 75% means the patient reacted to 75% of the
      antigens on the panel. A high PRA indicates that the subject already has antibodies and is
      highly SENSITIZED. Spontaneous decreases in PRA titers rarely occur. Thus the probability of
      transplantation in sensitized patients is significantly decreased.

      RATIONALE for use of Rituximab:

      By reducing specific B-cell populations Rituximab is currently used as a treatment in
      auto-immune diseases such as lupus erythematosus and rheumatoid arthritis and some cancers
      such as B-cell non-Hodgkin's lymphoma. It has been reported to have a potential roll in
      decreasing anti-human lymphocyte (HLA) antibodies post transplant. More studies are needed to
      assess its possible benefit among pre-transplant patients. Vierira et al. ["Rituxan for
      reduction of anti-HLA antibodies in patients awaiting renal transplantation", Am J
      Transplantation 2002;2:A870] reported on the use of rituximab in sensitized patients. Nine
      patients on dialysis with a PRA > 50% were treated with rituximab (n=3 per group) at 50, 150,
      or 375mg/m2. No significant change was seen in WBC, hemoglobin, platelet count, chemistry,
      liver enzymes or CMV IgG titers. At three days and 6 months after infusion there was a
      decline in the B cell count compared to pre-infusion levels. In 44%, a decline in PRA was
      seen. The patients receiving the higher doses had a larger decrement in antibody titers.

      GENENTECH, INC. will provide Rituximab, labeled for investigational use. Rituximab is
      formulated for IV administration as a sterile product as a sterile, preservative-free liquid
      concentrate for intravenous (IV) administration.

      STUDY DESIGN: This is a 12-month phase 2, prospective, open label study to evaluate the
      effect of rituximab with mycophenolate mofetil (MMF)on the PRA of 14 highly sensitized
      patients who just completed an 8 month trial of MMF treatment alone. PRA values obtained at
      study enrollment and at 6 and 12 months on combined therapy as well as the rates of
      transplant will be compared and evaluated using descriptive analysis.

      Primary Endpoints: The number of subjects who experience a decrement from baseline in their
      Panel of Reactive Antibody values (PRA I, PRA II) or cPRA (calculated PRA when available) at:
      baseline, 6 and 12 months of study initiation.

      Secondary Endpoints: The number of subjects who received a transplant The number of subjects
      with a negative crossmatch if transplanted.

      STUDY POPULATION: Patients on the kidney transplant waiting list who are currently receiving
      hemodialysis and who have a Panel of Reactive Antibodies (PRA) titer levels over 50% after
      completing 8 months of mycophenolate mofetil (MMF) treatment alone.

      SCREENING: Subjects will be consented, then screened clinically for occurrence of infection,
      Tuberculosis exposure and for protective antibodies in response to prior vaccination.

      RITUXIMAB DOSAGE AND ADMINISTRATION: The Rituximab dose is 1000mg (1gm) given as a single
      I.V. infusion for 2 doses (days 1 and 15). No extra dosing will be given. Rituximab may be
      administered in an outpatient setting. Hypersensitivity reactions may occur. Premedication,
      consisting of acetaminophen (1gm) and diphenhydramine (50mg or equivalent dose) by mouth 30
      to 60 minutes prior to the start of an infusion will be considered before each infusion of
      Rituximab. Rituximab will not be re-administered after initial dose regimen.

      (MMF) Mycophenolate mofetil DOSAGE AND ADMINISTRATION: Dosing of MMF will continue at the
      highest tolerated dose the subject was taking at the completion of the parent study: "Highly
      Sensitized Patients: effects of mycophenolate mofetil (MMF) on anti- human lymphocyte
      antibody (HLA) levels in patients awaiting renal transplant". The dose will be adjusted
      according to standard practices, gastrointestinal tolerance and WBC count.

      CLINICAL AND LABORATORY SAFETY EVALUATIONS:

      SCREENING:

        -  Medical history and documentation of the rationale for treatment of the patient's
           disease with Rituximab.

        -  Pregnancy test (serum or urine) for women of childbearing potential must be done prior
           to initial Rituximab treatment date.

        -  Medical history to include: age, sex, prior transplant history, blood transfusion
           history, prior pregnancy history, history of autoimmune disease, infection history over
           the last 5 years, and immunization history.

        -  Physical examination, including vital signs, and performance status.

        -  Hematology (within 2 weeks of treatment): complete blood count (CBC) with differential
           and platelet count.

        -  Serum Chemistries: glucose, blood urea nitrogen, serum creatinine, uric acid, total
           bilirubin, alkaline phosphatase, low density lipoprotein, high density lipoprotein,
           total protein, albumin, aspartate aminotransferase(AST), alanine aminotransferase (ALT),
           and serum calcium.

        -  Serology Testing as appropriate: Hepatitis B, Hepatitis C, HIV

        -  IgG and IgM total antibody counts.

        -  Drug Monitoring: Baseline = pre-infusion. Serum drug levels for Ritux will also be
           measured for safety. Human Anti-Rituximab Antibody (HACA)is a test for presence of
           antibodies against rituximab.

        -  Lymphocyte Sub Group: A sub-group of type-B lymphocytes called 'CD-19 Cells' are
           specifically impacted by Rituximab and will be used as a marker of drug efficacy.

      ON GOING EVALUATIONS Post -Treatment:

      For safety the total IgG and IgM levels will be monitored and IgG supplemented if levels
      decrease below normal values. Additionally WBC counts that drop below 3.0 will result in
      changes in the MMF dose. If serious infections occur MMF will be discontinued. Patients will
      be followed for one year after initial rituximab infusion.

        -  Hematology: monitor CBC + differential weekly for 1 month then monthly

        -  Monthly: PRAs will be monitored monthly through the 12th month of the study. The
           standard PRA value is the sum of anti-bodies produced by 2 main groups of lymphocytes;
           Class I and Class II. We will have PRA I and PRA II antibody classes reported separately
           as well as PRA reporting using a calculation (cPRA).

        -  Quarterly: Serology Testing as appropriate: Hepatitis B, Hepatitis C, HIV, IgG and IgM
           total antibody counts.

        -  Monitor Serum Ritux and HACA levels at baseline, 6 months and 9 months.

        -  Monitor CD19+ B-cells at baseline, weeks 1, 2, 4, months 3, 6, 9 and 12.
    

Intervention name(s): Rituximab; Mycophenolate mofetil (MMF)
Intervention type(s): Drug; Drug
Intervention description(s): Rituximab dose is 1,000 mg given as an IV infusion every two weeks for 2 doses (days 1 and 15).; Cellcept is continued from prior study, taken 500 - 1,000 mg BID, P.O.
Other intervention name(s): Rituxan, Rituximab; mycophenolate mofetil, MMF, Cellcept
Intervention MeSH terms: Mycophenolic Acid; Rituximab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dialysis; Kidney; Renal; Nephropathy; Glomerulonephropathy; Immunosuppression; Graft; Compatibility; Transplant; Diabetes; Hypertension; Transplantation, Kidney