Efficacy of Anti-CD20 Antibodies (Rituximab Biosimilar) in the Treatment of Childhood Steroid-dependent Nephrotic Syndrome

NCT04402580 | Terminated Phase 2 DMC

• 1 other identifier: RTX4
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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 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

Conditions

Nephrotic Syndrome Steroid-Dependent

Keywords

nephrotic syndrome treatment; rituximab; Mycophenolate Mofetil

Outcome Measures

Primary Outcomes (1)

• Comparison between RTX and MMF, considering number of partecipants and relative relapses in the two cohorts

  The first expected result of the project is the demonstration that a single infusion of RTX is more likely than MMF to maintain remission of NS for 12-24 months in children with primary SDNS. In order to evaluate the remission, all the partecipats will document their proteinuria, relapse is defined by uPCR ≥2000 mg/g (≥ 200 mg/mmol) or \> 3+ protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171) and complete remission is defined by uPCR \<200 mg/g (\<20 mg/mmol) or o1+ of protein on urine dipstick for 3 consecutive days (KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney International Supplement, 2012 2, 163-171).

  12-24 months

Secondary Outcomes (1)

• RTX safety by evaluation and documentation of side effects

  36 months

Other Outcomes (1)

• Biomarkers of response to RTX and evaluation of immune competence in patients treated with RTX vs. patients treated with MMF

  36 months

Study Arms (2)

Rituximab biosimilar

EXPERIMENTAL

* 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.

Drug: Rituximab Biosimilar

Mycophenolate Mofetil

ACTIVE COMPARATOR

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/1,73 sqm orally divided in 2 daily doses

Drug: Mycophenolate Mofetil

Interventions

Rituximab Biosimilar 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.

Rituximab biosimilar

Mycophenolate Mofetil DRUG

1,200 mg/1,73 sqm orally divided in 2 daily doses

Mycophenolate Mofetil

Eligibility Criteria

• Age: 3 Years - 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Istituto Giannina Gaslini: lead
• Bambino Gesù Hospital and Research Institute: collaborator

Study Sites (1)

IRCCS Istituto Giannina Gaslini

Genova, 16148, Italy

Location

Related Publications (2)

• 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.

  PMID: 39513526 DERIVED

• Ravani P, Lugani F, Drovandi S, Caridi G, Angeletti A, Ghiggeri GM. Rituximab vs Low-Dose Mycophenolate Mofetil in Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults: A Randomized Clinical Trial. JAMA Pediatr. 2021 Jun 1;175(6):631-632. doi: 10.1001/jamapediatrics.2020.6150.

  PMID: 33616641 DERIVED

MeSH Terms

Conditions

Nephrotic Syndrome

Interventions

Mycophenolic Acid

Condition Hierarchy (Ancestors)

Nephrosis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Study Officials

• Gianmarco Ghiggeri, MD

  IRCCS Istituto Giannina Gaslini

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, director of Nephrology, Dialysis and Transplantation Unit

Model Details: 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

Study Record Dates

• First Submitted: May 13, 2020
• First Posted: May 27, 2020
• Study Start: July 1, 2019
• Primary Completion: August 31, 2020
• Study Completion: August 31, 2020
• Last Updated: September 14, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share

Locations

IT (1)