RItuximab From the FIRst Episode of Idiopathic Nephrotic Syndrome

NCT03970577 | Unknown Phase 2 DMC

• 2 other identifiers: P170922J2018-003437-15
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 1

Brief Summary

Minimal change nephrotic syndrome (MCNS) is an acquired glomerular disease characterized by massive proteinuria occurring in the absence of glomerular inflammatory lesions or immunoglobulin deposits. MCNS represents a frequent cause of nephrotic syndrome (NS) in adults (10% to 25% of cases). The disease typically takes a chronic course characterized by frequent relapses. Until now, exclusive oral steroid therapy at the dose of 1mg/kg/day (max 80 mg/day) for a minimum of 4 weeks and a maximum of 16 weeks (as tolerated) constitutes the first line treatment of adults with MCNS. Despite of successful remission of initial episode, previous case series showed that 56%-76% of patients experience at least one relapse after steroid-induced remission. The recent MSN trial prospectively showed that 57.9% and 70% of adult patients were in complete remission (CR) after 4 and 8 weeks of oral steroids therapy (1mg/kg/day). Among them, 23.1% of patients displayed at least one relapse episode (after one year-follow-up). Although well tolerated, side effects are common in patients with prolonged and/or repeated courses of steroids and alternative regimens seem highly suitable to reduce the risk of subsequent relapse. Rituximab has recently emerged as a promising therapeutic option in patients with steroids dependent-MCNS. In a multicenter, double-blind, randomized, placebo-controlled trial in children with frequent relapse or with steroid dependent NS, the authors found that the median relapse free period was significantly longer in the Rituximab group than in the placebo group without significant differences concerning serious adverse events. To our knowledge, its use has never been investigated for the initial episode of MCNS with the aim to reduce the subsequent risk of relapse that is a major concern in the management of MCNS patients. The main objective is to demonstrate, from initial episode of MCNS in adults, once complete remission has occurred, that the use of Rituximab (two injections separated by one week 375mg/m2, with definitive steroids withdrawal after 9 weeks of treatment) may reduce the risk of subsequent MCNS relapse after 12 months of follow-up and may be a safe and an efficient treatment regimen. The study will be a single stage phase IIb, randomized, open-label, parallel group, in a 1:1 ratio, active controlled, multicenter trial testing the efficacy and safety of two injections of Rituximab separated by one week 375mg/m2 from initial episode of biopsy-proven MCNS in adults. Since Rituximab therapy (when initiated in a context of steroid dependency MCNS) seems to be more effective in patients with complete remission and because of recent data from MSN trial showing that 70% of patients were in complete remission of nephrotic syndrome after 8 weeks of steroids, we decided to maximize the potential benefit, to perform randomization of patients after 8 weeks of steroid treatment. A potential risk factor of relapse is the time of CR occurrence, and because some patients reach CR at 4 weeks and others at 8 weeks, a randomization (1:1) with minimization strategy will be done in order to balance this factor between arms. The primary endpoint will be the incidence of MCNS relapse during the 12 months following randomization defined by the recurrence of nephrotic syndrome (urine protein/creatinine ratio (UPCR) ≥ 300mg/mmol and decreased albumin level (\< 30 g/L) in a patient who was in complete remission. Rituximab is currently considered as an effective therapeutic option to maintain remission in patients with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). The goal of this prospective study is to determine the potential interest of the use of Rituximab from the initial episode of MCNS to reduce the risk of subsequent relapse, that is a major concern in the management of MCNS patients.

Conditions

Minimal Change Nephrotic Syndrome (MCNS)

Keywords

Minimal Change Nephrotic syndrome; Rituximab; Relapse rate

Outcome Measures

Primary Outcomes (1)

• Incidence of MCNS relapse during the 12 months following randomization

  defined by the recurrence of nephrotic syndrome (urine protein/creatinine ratio (UPCR) ≥ 300mg/mmol and decreased albumin level (\< 30 g/L) in a patient who was in complete remission

  12 months following randomization

Secondary Outcomes (5)

• The relapse rate

  18 months after randomization

• Type of adverse events (AEs) and serious adverse events (SAEs)

  18 months

• Frequency of adverse events (AEs) and serious adverse events (SAEs)

  18 months

• Severity of adverse events (AEs) and serious adverse events (SAEs) assessed by the CTCAE version 4.0

  18 months

• Treatment Burden questionnaire (TBQ) © (Ravaud et al, 2012)

  4 weeks before randomization, 1 week after randomization and 16 weeks after randomization

Study Arms (2)

Rituximab treatment

EXPERIMENTAL

Two injections of Rituximab (375mg/m2) separated by one week (one at time of randomization and the other one week after) and definitive withdrawal of steroid at the time of second injection of Rituximab (for a total steroids exposure of 9 weeks)

Drug: Rituximab

Oral steroid treatment

ACTIVE COMPARATOR

The patients will continue exclusive oral steroid treatment, that will be progressively tapered, for a total of 24 weeks (by taking into account the initial oral steroid therapy administered during 8 weeks and the oral steroid treatment given after randomization). Each patient will be followed up until 18 months after randomization. The patient will have study visits at inclusion, 4 weeks and 8 weeks after inclusion. At the time of randomization, patients who will have reached CR of MCNS will be allocated in test or control group and will be followed up similarly: visits at 1, 4, 16, 24 weeks, 12 and 18 months after randomization.

Drug: Prednisone

Interventions

Rituximab DRUG

Two injections of Rituximab (375mg/m2) separated by one week (one at time of randomization and the other one week after) and definitive withdrawal of steroid at the time of second injection of Rituximab (for a total steroids exposure of 9 weeks)

Also known as: Mabthéra

Rituximab treatment

Prednisone DRUG

exclusive oral steroid therapy (progressively tapered with the same procedure for all patients) for a total exposure of 24 weeks (taking into account the initial oral steroid therapy administered during 8 weeks in addition with the oral steroid treatment given after randomization). Each patient will be followed up until 18 months after randomization.

Also known as: Cortancyl

Oral steroid treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient aged ≥ 18 years
• First episode of Minimal change nephrotic syndrome defined as albumin level \< 30 g/L and urine protein/creatinine ratio (UCPR) ≥ 300mg/mmol
• Biopsy-proven MCNS defined on renal biopsy examination by the presence of minimal change glomerular lesions and absence of segmental sclerosis by light microscopy, negative immunofluorescence, or presence of IgM deposits into the mesangium
• Signed informed consent to participate in the study
• Patients who are affiliated with the French health care system

You may not qualify if:

• Previous administration of Rituximab therapy
• MCNS resulting from a secondary process (lymphoid disorders or malignant disease) or potentially related to treatment known to be associated with MCNS occurrence (Lithium, Interferon, non-steroidal anti-inflammatory drugs)
• Patients with acute infections or chronic active infections
• Positive serological screening test for HIV, B or C hepatitis
• Positive immunological tests for antinuclear and anti-DNA antibodies
• Usual contraindication to steroid or Rituximab
• Immunosuppressed patients, patients with a severe immune deficit
• Patients with hypersensitivity to a monoclonal antibody or biological agents
• Patients with a known allergy to steroid and its excipients or to Rituximab and its excipients or to acetaminophen and its excipients or to cetirizine and its excipients or to protein of murine origin
• Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
• Patients who have white blood cell count ≤4,000/mm3,
• Patients who have platelet count ≤100,000/mm3,
• Patients who have haemoglobin level \<9g/dL,
• Patients who have SGOT or SGPT or bilirubin level greater than 3 times the upper limit of normal
• Patients who have serum creatinine level \>150 µmol/l,

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

AUDARD

Créteil, 94320, France

RECRUITING

Related Publications (2)

• Gauckler P, Matyjek A, Kapsia S, Marinaki S, Quintana LF, Diaz MM, King C, Griffin S, Ramachandran R, Odler B, Eller K, Artan AS, Mirioglu S, Busch M, Schaepe M, Turkmen K, Cheung CK, Pepper RJ, Juarez GF, Pascual J, Aunon P, Garcia-Carro C, Rodriguez A, Alberici F, Luzardo L, Chebotareva N, Schonermarck U, Fernandez L, Radhakrishnan J, Guaman K, Peleg Y, Hoisnard L, Audard V, Papasotiriou M, Krnanska N, Tesar V, Hruskova Z, Bruchfeld A, Stangou M, Lioulios G, Faguer S, Ribes D, Salhi S, Windpessl M, Galesic K, Crnogorac M, Zagorec N, Mayer G, Kronbichler A; RITERM Study Team. Long-Term Outcomes of Rituximab-Treated Adult Patients with Podocytopathies. J Am Soc Nephrol. 2025 Apr 1;36(4):668-678. doi: 10.1681/ASN.0000000520. Epub 2024 Oct 16.

  PMID: 39431468 DERIVED

• Christian MT, Maxted AP. Optimizing the corticosteroid dose in steroid-sensitive nephrotic syndrome. Pediatr Nephrol. 2022 Jan;37(1):37-47. doi: 10.1007/s00467-021-04985-1. Epub 2021 Feb 20.

  PMID: 33611671 DERIVED

MeSH Terms

Conditions

Nephrosis, Lipoid

Interventions

Rituximab; Prednisone

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)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Vincent AUDARD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Vincent AUDARD, MD, PhD

CONTACT

+33(1)49 81 44 46; vincent.audard@aphp.fr

Dil SAHALI, MD,PhD

CONTACT

+33 (1) 49 81 25 37; dil.sahali@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study will be a single stage phase IIb, randomized, open-label, parallel group, in a 1:1 ratio, active controlled, multicenter trial testing the efficacy and safety of two injections of Rituximab separated by one week (375mg/m2) from initial episode of MCNS in adults. The control arm is a standard regimen of oral steroid alone (progressively tapered within 24 weeks). At inclusion, all patients will receive oral steroid therapy (Prednisone, 1mg/kg/day, maximum 80 mg/day). For patients without complete remission after 4 weeks of treatment, prednisone will be continued at the same dose until the 8th week. For patients with complete remission after 4 weeks of treatment, doses of prednisone will be progressively reduced between the 4th and the 8th week (0.06 mg/kg by week). Patients who reach complete remission by 8 weeks after inclusion will be randomized at this time to receive either Rituximab (experimental group) or the standard steroid regimen (control group).

Study Record Dates

• First Submitted: April 15, 2019
• First Posted: May 31, 2019
• Study Start: July 29, 2020
• Primary Completion: November 29, 2023
• Study Completion: November 29, 2023
• Last Updated: July 13, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)