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A Multicenter, Randomized, Prospective, Open-Label Trial of Rituximab in the Treatment of Progressive IgA Nephropathy
Sponsored by: Genentech, Inc.
Principal Investigator: Patrick Nachman, MD
The purpose of this study is to compare the ability of Rituximab to standard therapy (tight blood pressure control and fish oil) in lowering protein in the urine in patients with IgA nephropathy, and to examine the side effects occurring with Rituximab. Approximately 50 patients (5 for UNC Kidney Center) will be randomized to Rituximab in addition to standard therapy vs. standard therapy alone in an open-label multicenter controlled trial. Patients randomized to the Rituximab group will receive a total of 4 doses on days #1; 15; 168 and 182. Standard therapy will consist of combination ACE inhibitors and ARBs to achieve a BP goal of 125/75 (MAP 90 mm Hg) and Omega-3 Fatty Acid Fish Oil Supplements, 3.6 gm EPA/day. Patients will be followed for a total of 12 months.
Inclusion Criteria:
Note: All eligible patients will have undergone a renal biopsy compatible with a diagnosis of IgA nephropathy within 12 months of study entry. The diagnostic criteria for IgA nephropathy are as follows:- Age 18-70
- Light microscopy demonstrating mesangial matrix expansion with mesangial cell hypercellularity defined as 5 or more mesangial cells per stalk
- Mesangial immunohistologic staining positive for IgA antibodies and is considered by the renal pathologist to be predominant over concurrent staining for IgG and IgM
- Presence of mesangial immune complexes on electron microscopy with or without the presence of podocyte foot plate effacement.
- Endocapillary proliferation, karyorrhexis or cellular crescents must be present in less than 10% of glomeruli on initial renal biopsy
- Renal Insfficiency: stage II or III CKD with estimated GFR (by Cockcroft-Gault or MDRD Equations) <90mls/min and >30mls/min
- Blood Pressure: BP <130/80 mmHg. Any patient needing long term hypertensive meds must have BP controlled <130/80 mmHg to be considered eligible.
- Gender: Females with IgA nephropathy must have a negative urine or serum pregnancy test at screening and must be agreeable to 2 years of contraception.
- Henoch Schonlein Purpura (HSP): eligible if have biopsy proven IgA Nephropathy.
- Patient must be able to swallow oral medications
Exclusion Criteria:
- Clinical and histologic evidence of IgA predominant Lupus nephritis.
- Clinical and histologic evidence of idiopathic IgA forms of membranoproliferative glomerulonephritis.
- Clinical evidence of cirrhosis, chronic active liver disease or known infection with hepatitis B or hepatitis C (patients will be serologically screened prior to study entry).
- Estimated GFR <30 ml/min/1.73m2 at the time of screening.
- Greater than 50% glomerular senescence or cortical scarring on renal biopsy.
- Active systemic infection or history of serious infection within one month of entry.
- Known infection with HIV, (patients will be serologically screened prior to study entry).
- Child’s Class C Cirrhosis.
- History of Crohn’s disease or Celiac Sprue
- Pregnancy (a negative serum or urine pregnancy test will be performed for all women of childbearing potential no later than 7 days prior to treatment) or lactation. Unwilling to take contraception for 2 years.
- Current or recent (within 30 days) exposure to any investigational drug.
- Serum Cr >3.5mg/dl or MDRD calculated GFR <30mls/min (Schwartz GFR <30 ml/min/1.73m² in children)
- Receiving > 6 months therapy with oral prednisone or glucocorticoid equivalent.
- Received a live vaccine within 28 days of study enrollment.
- Anaphylaxis and/or known allergic reactions to Rituximab
- Hemoglobin: < 8.5 gm/dL
- Platelets: < 100,000/mm
- AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.
- Previous Treatment with Rituximab (MabThera® / Rituxan®) or Natalizumab (Tysabri®)
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- History of recurrent significant infection or history of recurrent bacterial infections
- Known active bacterial, viral fungal mycobacterial or atypical mycobacterial infections, but excluding fungal infections of nail beds.
- Any major episode of infection requiring hospitalization or treatment with I.V. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
- Ongoing use of high dose steroids (>10 mg/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 screening
- Concomitant or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- History of psychiatric disorder that would interfere with normal participation in this protocol
- Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication
- Inability to comply with study and follow-up procedures
For more information, please contact:
Anne Froment
(919) 966-2561 ext 247
anne_froment@med.unc.edu
