Clinical trial NCT04585152: Rituximab Versus Mycophenolate Mofetil in Children With Steroid-dependent Idiopathic Nephrotic Syndrome.
Official title: Randomized Controlled Trial Comparing Rituximab to Mycophenolate Mofetil in Children With Steroid-dependent Idiopathic Nephrotic Syndrome.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Nephrotic Syndrome Steroid-Dependent
Keywords: nephrotic syndrome treatment
rituximab
Mycophenolate Mofetil
Lead sponsor: Istituto Giannina Gaslini
Sponsor class: OTHER
Collaborators: name: Bambino Gesù Hospital and Research Institute
First posted: 2020-10-14
Enrollment: 160
Sex: ALL
Minimum age (years): 3
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The RTX-MMF 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
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Comparison between RTX and MMF, considering remission intervals (in months) in the two cohorts
timeFrame: 12-24 months
Secondary outcomes:
measure: RTX safety by evaluation and documentation of side effects measuring frequency and severity of any treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 36 months
Other outcomes:
measure: Biomarkers of immune competence: mononuclear cells (PBMCs) by cytometry, serum immunoglobulin
timeFrame: 36 months
Locations:
city: Genova
country: Italy
facility: IRCCS G. Gaslini
Study officials:
affiliation: Istituto Giannina Gaslini
name: GianMarco Ghiggeri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lugani F, Angeletti A, Ravani P, Vivarelli M, Colucci M, Caridi G, Verrina E, Emma F, Ghiggeri GM. Randomised controlled trial comparing rituximab to mycophenolate mofetil in children and young adults with steroid-dependent idiopathic nephrotic syndrome: study protocol. BMJ Open. 2021 Nov 29;11(11):e052450. doi: 10.1136/bmjopen-2021-052450.