Rituximab Versus Mycophenolate Mofetil in Children With Steroid-dependent Idiopathic Nephrotic Syndrome.
Rituximab Versus Mycophenolate Mofetil in Children With Steroid-dependent Idiopathic Nephrotic Syndrome.
Anti-CD20 monoclonal antibodies are emerging as the steroid-sparing therapy of choice for
 nephrotic syndrome.This Randomized Clinical Trial seeks to evaluate whether Rituximab
 biosimilar maintains drug-free disease remission in patients with steroid-dependent nephrotic
 syndrome for 12-24 months and verify its superiority vs. mycophenolate mofetil (1,200 mg/m2
 orally in 2 daily doses). The investigators will compare the risk of relapse to test this
 hypothesis (primary outcome). Secondary objectives will include assessing short- and
 long-term side-effects and developing specific biomarkers of sensitivity to therapy. Patients
 will be recruited, treated and followed at IRCCS G Gaslini and IRCCS Bambino Gesù where
 laboratory studies will be performed at in-site facilities.
Idiopathic nephrotic syndrome (NS) is a podocyte renal disease characterized by loss of the
 impermeability functions versus circulating proteins, causing severe proteinuria and
 hypo-albuminaemia with edema. According to 2019 KDIGO guidelines administration of low-dose
 prednisone is suggested to maintain remission in SDNS (steroid dependant nephrotic syndrome),
 and mycophenolate mofetile (MMF) or calcineurin inhibitors (CNI) or Rituximab as
 corticosteroid-sparing agents for children who develop serious corticosteroid-related adverse
 effects. Given the toxicity of cyclophosphamide and CNI in long-term administration, there is
 the need to clarify which is, between MMF and rituximab, the most effective approach.

 The RTX vs MMF trial is an open-label, two-parallel-arm, controlled and randomized clinical
 trial testing the superiority of RTX over MMF (1,200 mg/m2 orally in two daily doses) in
 maintaining steroid free disease remission in patients with SDNS.

 Eligible participants are children and young adults (age between 3 and 24 years) with
 nephrotic syndrome who are dependent on prednisone 0.3-1mg/Kg/day and have received
 prednisone for at least six months before enrolment. Previous treatment with MMF will be
 allowed. All participants will enter a 45 days run-in period, during which children treated
 with steroids alone will start MMF and will taper steroids after 15 days by 0.3 mg/kg per
 week until complete withdrawal. Patients already receiving MMF alone will continue the
 treatment. During the same period, instruction on urine collection and dipstick readings will
 be carefully reviewed and compliance assessed. After run-in period, children will be
 randomized to either the intervention arm (Rituximab, 375 mg/m2) or the comparator arm
 (continuing or starting MMF). In the intervention arm, 1 month after infusion MMF will be
 decreased by 50% and withdrawn within 2 additional weeks, whereas MMF will be maintained in
 the comparator. All patients will be followed for up to 24 months. In case of relapses during
 this period (see outcome section for definition) patients will be treated with oral
 prednisone (60 mg/sqm day). Following remission, steroids will be maintained at the initial
 dose for 7 days and then tapered off by 0.3 mg/kg per week until complete withdrawal in
 patients of the MMF arm. Patients of the intervention arm will instead be treated with
 another infusion of RTX (same dose) immediately following steroid-induced remission. After
 infusion of RTX, steroids will be maintained at the initial dose for 7 days and then tapered
 off by 0.3 mg/kg per week until complete withdrawal. In this way relapsed patients in both
 arms will receive the same cumulative dose of prednisone. In case following relapse of
 proteinuria patients fail to respond to prednisone (they will terminate the study and be
 considered as treatment failure). The study allows drop-in from one arm to the other after 2
 relapses (i.e., investigators will be allowed to use RTX in the comparator arm and vice versa
 MMF in intervention arm). The economic balance will be calculated on the basis of RTX doses
 needed to maintain remittance.

 All patients will be followed for 24 months. In person visits will occur at enrollment, at T0
 (infusion), after 1 month and every 3/6 months later.

 The investigators are going to enroll 160 patients.
Inclusion Criteria:

 -  Age between 3 and 24 years

 -  Prednison dependent steroid syndrome 0.3-1mg/Kg/day and receive prednisone for at
 least six months before enrolment. Steroid dependence is defined by two consecutive
 relapse during corticosteroid therapy or within 14 days of ceasing therapy.

 -  Ability to provide consent and assent: parents'/guardian's written informed consent,
 and child's assent given before any study-related procedure not part of the subject's
 normal medical care, with the understanding that consent may be withdrawn by the
 subject any time without prejudice to his or her future medical care.

 Exclusion Criteria:

 -  Positivity to autoimmunity tests (ANA, nDNA, ANCA)

 -  Reduction of C3 levels.

 -  eGFR<90/ml/min/1,73 m2 valuated according to revised Bedside Schwartz Formula for
 patients between 2 and 17 years and with CKD-EPI Creatinine 2009 Equation for 18 years
 old patients.

 -  Pregnancy

 -  Neoplasm

 -  Infections: previous or actual HBV (with HBeAb positivity) or HCV infection CD20 B
 lymphocytes count <2,5%

 -  Treatment with Rituximab in the last 6 months