Efficacy of Anti-CD20 Antibodies (Rituximab Biosimilar) in the Treatment of Childhood Steroid-dependent Nephrotic Syndrome
Efficacy of Anti-CD20 Antibodies (Rituximab Biosimilar) in the Treatment of Childhood Steroid-dependent 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 patientswith steroid-dependent nephrotic syndrome for 12-24
 months and verify its superiority vs. mycophenolate mofetil, the reference standard therapy.
 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 characterized by proteinuria and hypoalbuminemia
 associated with dyslipidemia and hypercoagulability. Oral corticosteroids are the cornerstone
 of therapy and induce disease remission in approximately 90% of cases. However, up to 85% of
 patients relapse and many develop steroid dependence (SDNS), requiring prolonged dose of
 steroids to maintain remission. Clinical practice guidelines (KDIGO) suggest using low-dose
 prednisone to maintain remission in SDNS and Mycophenolate Mofetil (MMF) or calcineurin
 inhibitors (CNI) as corticosteroid-sparing agents for children who develop steroid adverse
 effects. Given the toxicity of all these drugs (steroids, CNI and MMF), there is a need to
 investigate alternative options. Recent evidence supports the use of chimeric anti-CD20
 monoclonal antibodies in simple SDNS (Rituximab, RTX).

 The RTX4 trial is an open-label, two-parallel-arm, controlled and randomized clinical trial
 testing the superiority of RTX over MMF 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 1,200 mg/1,73 sqm orally in 2 daily doses 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,
 375mg/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 3 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 occure at enrollment, at
 T0 (infusion), after 1 month and every 3/6 months later.

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

 To be eligible for inclusion into this study, participants will have to fulfil the
 following 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:

 Children will be excluded if any of the following criteria apply:

 -  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 or cyclophosphamide in the last 6 months