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

Study Overview
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Brief Summary
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We hypothesize that the anti-CD20 monoclonal antibody Rituximab will be more effective than MMF in maintaining remission in children with frequent relapsing or steroid dependent nephrotic syndrome who have had one relapse while receiving MMF. We will conduct a randomized study comparing two Rituximab infusions and continued MMF treatment. We plan to enroll 64 to have a comparater group of 58 (29 in each arm).

Detailed Description
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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.

Official Title
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Randomized Trial Comparing Rituximab Against Mycophenolate Mofetil in Children Wtih Refractory Nephrotic Syndrome (RAMP)

Conditions
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Frequent Relapsing Nephrotic Syndrome, Steroid Dependent Nephrotic Syndrome

Intervention / Treatment
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* Drug: Rituximab
* Drug: MMF


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Rituximab 375 mg/m2 will be administered intravenously on Study weeks 1 & 3. | Drug: Rituximab<br>* We hypothesize that the anti-CD20 monoclonal antibody Rituximab will be more effective in maintaining remission in children who have already had one relapse while receiving MMF<br>|
| Active Comparator: Mycophenolate Mofetil (MMF)<br>Mycophenolate Mofetil will be continued in the patients in the MMF arm at a standard oral dose of 600 mg/m2 PO, BID starting on Study week 1 and continuing for 12 months | Drug: MMF<br>* Subjects randomized to MMF, will continue MMF as scheduled by the investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse Free Survival |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse Free at 12 Months |  | 12 months |