Randomized Trial Comparing Rituximab Against Mycophenolate Mofetil in Children Wtih Refractory Nephrotic Syndrome

After screening, and eligibility criteria have been met, children with steroid dependent and
frequent relapsing nephrotic syndrome (SDNS and FRNS) will be enrolled into a 53 week study.
The study is comprised of 3 sections; screening, treatment, and followup.

Screening will be <4 weeks from Day 1/week 1. Treatment is Day 1/Week 1 and Day 15/Week 3.
Follow-Up is Week 7, Week 13, Week 19, Week 27 and Week 53. Participants will be randomized
by the study pharmacy between screening and treatment Day1. If participant is randomized to
Rituximab, then Treatment Day 15 will be based on tolerance of Rituximab infusion.

Safety assessments will occur at every visit beginning with Day 1.

Inclusion Criteria:

- SDNS or FRNS

- Complete remission, defined by absence of edema and 3 consecutive daily urine dipstick
readings of trace or negative for protein

- Must be taking MMF and have had at least one relapse while taking MMF in the prior 6
months that responded to corticosteroid treatment by re-entering complete remission at
least 2 weeks prior to study entry.

- BMI prior to onset of NS <99th percentile

- Age 1-18 years

- Estimated GFR >40 ml/min/1.73m² (by Modified Schwartz formula)

- Negative serum pregnancy test (for females who are tanner stage 4 or 5)

- Males and females of reproductive potential (sexually active in boys or post-menarche
in girls) must agree to use an acceptable method of birth control during treatment and
for twelve months (1 year) after completion of treatment

Exclusion Criteria:

- • Prior therapy with rituximab, tacrolimus or cyclosporine

- Prior therapy with cytotoxic agents in the past 90 days

- History of genetic defects known to directly cause nephrotic syndrome (i.e. NPHS2
(podocin), NPHS1 (nephrin), PLCE1, WT1)

- History of or concomitant severe, active infection (e.g. HIV, hepatitis B,
hepatitis C)

- History of diabetes mellitus

- History of organ or bone marrow transplant

- Secondary nephrotic syndrome (i.e. reflux nephropathy, IgA nephropathy, lupus
nephritis, etc)

- Live viral vaccines administered in the past 6 weeks (42 days)

- Participation in another therapeutic trial within 30 days of enrollment

- Allergy to study medications

- ANC < 1.5 x 103

- Hemoglobin: < 8.0 gm/dL

- Platelets: < 100,000/mm

- AST or ALT >2.5 x Upper Limit of Normal at the local institutions laboratory

- Positive Hepatitis B or C serology (Hep B Surface antigen, Hep B Core antibody,
and Hep C antibody)

- History of HIV infection

- Treatment with any investigational agent 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 randomization

- Previous treatment with Natalizumab (Tysabri®)

- Previous Treatment with Rituximab (Rituxan®)

- Known hypersensitivity to Rituximab, to any of its excipients, or to murine
proteins

- 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 other infection
(including tuberculosis or atypical mycobacterial disease, but excluding fungal
infections of nail beds) or 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

- Lack of peripheral venous access

- History of drug, alcohol, or chemical abuse within 6 months prior to screening

- Pregnant, lactating, or refusal of birth control in an adolescent of
child-bearing potential

- Concomitant malignancies or previous malignancies

- 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
complications

- Inability to comply with study and follow-up procedures

Patients who fail screening due to an abnormal laboratory parameter may be rescreened
within the next 6 months if the local PI believes that the abnormality was transient and
not related to a chronic underlying disease. Rescreening may only occur once and may not
occur within 2 weeks of the initial screen failure.

If a patient has a clinically significant laboratory abnormality, the PI will be asked to
define a follow-up plan (timing of repeating the laboratory test and/or additional
work-up).