Rituximab Versus Mycophenolate Mofetil in Children With Steroid-dependent Idiopathic Nephrotic Syndrome.

NCT ID: NCT04585152

Last Updated: 2022-12-21

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 160 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-15
• Study Completion Date: 2023-09-30

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.

Conditions

Nephrotic Syndrome Steroid-Dependent

Keywords

nephrotic syndrome treatment; rituximab; Mycophenolate Mofetil

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rituximab biosimilar

Drug Name: Rituximab biosimilar monoclonal anti-CD20 antibody Why: Anti-body/antigen interaction results in cell apoptosis and reduced CD20 positive cell related activities (of note CD20 is mostly represented on B cells but also in Th17 cells) How: RTX IV: for dosage between 100 and 250 mg Rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg Rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg Rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Where: in Hospital When and how much: once; diluted in 1000 ml of normal saline.

Group Type: EXPERIMENTAL

Rituximab Biosimilar

Intervention Type: DRUG

for dosage between 100 and 250 mg Rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg Rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg Rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Mycophenolate mofetil

Drug Name: Mycophenolate Mofetil (MMF)

Why: selective and reversible inhibition of inosine monophosphate dehydrogenase with inhibition that particularly affects lymphocytes since they rely almost exclusively de novo purine synthesis Procedures: MMF 1,200 mg/m2 orally divided in 2 daily doses

Group Type: ACTIVE_COMPARATOR

Rituximab Biosimilar

Intervention Type: DRUG

for dosage between 100 and 250 mg Rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg Rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg Rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Interventions

Rituximab Biosimilar

for dosage between 100 and 250 mg Rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg Rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg Rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Intervention Type: DRUG

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

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 24 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bambino Gesù Hospital and Research Institute

OTHER

Sponsor Role: collaborator

Istituto Giannina Gaslini

OTHER

Sponsor Role: lead

Responsible Party

Gian Marco Ghiggeri MD, PhD

MD, director of Nephrology, Dialysis and Transplantation Unit

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

GianMarco Ghiggeri, MD

Role: PRINCIPAL_INVESTIGATOR

Istituto Giannina Gaslini

Locations

IRCCS G. Gaslini

Genova, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

GianMarco Ghiggeri, MD

Role: CONTACT

Phone: +39 010 56363523

Email: gmarcoghiggeri@gaslini.org

Francesca Lugani, MD, PhD

Role: CONTACT

Phone: +39 010 56363523

Email: francescalugani@gaslini.org

Facility Contacts

GianMarco Ghiggeri, MD

Role: primary

References

Larkins NG, Hahn D, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2024 Nov 8;11(11):CD002290. doi: 10.1002/14651858.CD002290.pub6.

Reference Type: DERIVED

PMID: 39513526 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34845071 (View on PubMed)

Other Identifiers

RTXvsMMF

Identifier Type: -

Identifier Source: org_study_id