Hypothesis: In patients with progressive IgA nephropathy an intravenous infusion of 1000 mg of rituximab on Day 1 and Day 15 and Days 168 and 182 is superior to conventional therapy in reducing 24 hour proteinuria, and slowing progression of chronic kidney disease. Rituximab doses for pediatric patients will be 375mg/m² of rituximab on Days 1 and Day 15 and Days 168 and 182.
2.1 Primary Efficacy Endpoints:
Percentage of patients in each group achieving complete or partial response as defined below:
Complete Response: At 12 months
1. < 300 mg proteinuria/24 hours Pediatric Criteria: First morning void urine protein: creatinine ratio <0.3
2. No greater than a 10% reduction in baseline estimated GFR as determined by MDRD (4 point) formula Pediatric criteria: No greater than a 10% reduction in baseline estimated GFR as determined by Schwartz formula Partial Response: At 12 months
1) > 50% reduction in 24 hour proteinuria 2) No greater than a 25% reduction in baseline estimated GFR as determined by MDRD formula Pediatric criteria: No greater than a 25% reduction in baseline estimated GFR as determined by Schwartz formula No Response: At 12 months
1. A 50% reduction, unchanged or increasing proteinuria over baseline levels will be considered no response
2. A greater than a 30% reduction in baseline estimated GFR as determined by MDRD formula Pediatric criteria: A greater than a 25% reduction in baseline estimated GFR as determined by Schwartz formula
2.2 Primary Safety Endpoints:
- Incidence of Infusion Related Reactions: Defined as the development of hypotension, generalized pruritus, chills/rigors, angioedema and/or bronchospasm.
- Pulmonary Complications: Defined as a hypoxia, pulmonary infiltrates and/or acute respiratory failure
- Incidence of Major Infections: Defined as the development of pneumonia, complicated UTI/Pyelonephritis, Sepsis, and Meningitis.
- Development of Progressive Multifocal Leukoencephalopathy (PML)
2.3 Secondary Exploratory Efficacy Endpoints:
A) For patients in Groups 1 & 2 consenting to a repeat kidney biopsy at 12 months, a secondary endpoint will include the percentage of patients in experiencing a 25% increase in cortical fibrosis. The response rate will be semi-quantified by the change in cortical fibrosis as measured by changes in Sirius Red staining of interstitial collagen. A patient will be considered a complete or partial response or no response according to the following criteria:
Complete: Less than 10% rise in cortical fibrosis as measured by Sirius Red staining and digital image analysis Partial: Rising cortical fibrosis > 10% but less than 25% No Response: Greater than 25% rise in cortical fibrosis over baseline levels-(if patient consents to repeat kidney biopsy)
3.12 Clinical Criteria: Any patient 18 years of age or older and able to give informed consent and having proteinuria (> 1000 mg/24 hrs without ACE/ARB therapy; > 500 mg/24 hours on ACE or ARB therapy) with biopsy proven IgA nephropathy and the histologic features outlined in sections A, B &C of section 3.1.1 will be considered eligible for study enrollment.
Patients must be between the ages of 16 and 70 for all sites except Stanford University. The eligible age range at the Stanford University site will range from age 5-70. Patients must be able to give informed written consent. If the patients is less than 18 but older than 16, they can participate in the study provided that a parent or guardian signs an age-appropriate consent.
Pediatric-Specific Criteria: For patients being enrolled at the Stanford University site any patient age 5 years or greater with parental permission may be included in the study.
(For Stanford University site only: Stanford has extensive experience with pediatric, as young as one year of age, use of Rituximab in acute renal transplant rejection therefore request that the patients must be between the ages of 5 and 70.)
- Renal Insufficiency: Patients with stage II or III Chronic Kidney Disease (CKD) with estimated GFR by Cockcroft-Gault or MDRD equations < 90 mls/min and > 30 mls/min.
- Proteinuria: Patients excreting greater than or equal to 1000 mg of proteinuria/24 hours while on stable ACE or ARB therapy for 2 months. Patients receiving combination ACE or ARB will only require 500 mg/24 hours for study eligibility.
- Blood Pressure: Patients must have blood pressure <130/80 mmHg. The presence of hypertension is not required for study entry, but any patient requiring long term hypertensive medications must have blood pressure controlled <130-80 mmHg, to be considered eligible for the study .
- Gender: Female patients with IgA nephropathy will be considered eligible for study entry if they have a negative urine or serum pregnancy test at the time of screening. Patients wishing to be enrolled in the study must also be agreeable to 2 years of contraception.
- Henoch Schonlein Purpura (HSP): Patients with biopsy proven IgA nephropathy and clinical features consistent with Henoch Schonlein Purpura will be considered eligible for the study.
- Patient must be able to swallow the oral medications to be enrolled in the study.
3.1.3 Pediatric Inclusion Specifications
All children age 5 and older will be included if:
- Evidence of biopsy proven IgA Nephropathy
- Calculated creatinine clearance of greater than 30 mL/min/1.73m² (Schwartz's formula) and either of the following:
- 24 hour urine collection showing proteinuria greater than 1 g
- 24 hour urine protein creatinine ratio greater than 1 g
- First void morning spot urine protein creatinine ratio greater than 0.5g on ACEi and/or ARB treatment for 2 months
- With or without hypertension
Exclusion Criteria: Patients with any of the following criteria will NOT be considered eligible for study participation
- 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.
- Patients with 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).
- Patients with Child's Class C Cirrhosis.
- Patients with history of Crohn's disease or Celiac Sprue
- Positive pregnancy test or breast feeding at time of study entry. Patients unwilling to comply with contraceptive measures as outlined above.
- Current or recent (within 30 days) exposure to any investigational drug.
- Serum Cr > 3.5 mg/dl or MDRD calculated GFR < 30 mls/min or Schwartz GFR <30 ml/min/1.73m² in children
- Patients receiving > 6 months therapy with oral prednisone or glucocorticoid equivalent.
- Patients having received a live vaccine within 28 days of study enrollment.
General Safety & Laboratory Exclusion Criteria
- Patients with 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.
- Receipt of a live vaccine within 4 weeks prior to randomization
- Previous Treatment with Rituximab (MabThera® / Rituxan®)
- Previous treatment with 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
- 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
- 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
You will have a physical examination and routine blood and urine tests to determine if you are eligible to take part in the study. You will need to excrete greater than or equal to 1000 mg of protein in a 24-hour urine collection while on stable ACE or ARB therapy for 2 months. Patients receiving combination ACE or ARB will only require 500mg/24 hours for study eligibility.
Patients will be randomized to either treatment with rituximab plus conventional therapy (Group 1) or conventional therapy alone (Group 2) and will be followed for 12 months after enrollment. If you are randomized into the rituximab group at your Days 1, 15, 168, and 182 visits, you will have blood drawn for routine blood tests and will received an intravenous infusion of rituximab.
The study procedures will last about 12 months.
Last updated: 11/07/2012