Randomized Trial Comparing Rituximab Against Mycophenolate Mofetil in Children Wtih Refractory Nephrotic Syndrome
Condition: Frequent Relapsing Nephrotic Syndrome; Steroid Dependent Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Syndrome
Intervention: Rituximab; MMF
Intervention description: 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; Subjects randomized to MMF, will continue MMF as scheduled by the investigator
Intervention MeSH terms: Rituximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 1 Year
Maximum age: 18 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        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).