Rituximab in Progressive IgA Nephropathy

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. .

2.0 OBJECTIVES

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 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 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

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)

Inclusion Criteria:

- Any patient between the age of 18 and 70 years of age and able to give informed
consent

- GFR by Cockcroft-Gault or MDRD equations <90 mls/min and >30 mls/min

- Greater than or equal to 1000 mg of proteinuria/24 hours while on stable ACEi, ARB or
renin inhibitor therapy for 2 months. Patients receiving combination ACE or ARB or
ACEi and a renin inhibitor for 2 months will only require 500mg/24 hours

- 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

- Female patients with IgA will be considered eligible for study entry if they have a
negative urine or serum pregnancy test at the time of screening are agreeable to 2
years of contraception

- Biopsy proven IgA nephropathy and clinical features consistent with Henoch Schonlein
Purpura will be considered eligible for the study

- Able to swallow the 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, C or HIV

- 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

- History of Crohn's disease or Celiac Sprue

- Positive pregnancy test or breast feeding at time of study entry or unwilling to
comply with contraceptive measures

- Current or recent (within 30 days) exposure to any investigational drug

- Serum Cr >3.5 mg/dl or MDRD calculated GFR <30 mls/min

- Patients receiving >6 months therapy with oral prednisone or glucocorticoid
equivalent

- 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.

- 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 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