Personalized Rituximab Treatment Based on Artificial Intelligence in Membranous Nephropathy (iRITUX) (iRITUX)

Study of Artificial Intelligence-based Personalized Rituximab Treatment Protocol in Membranous Nephropathy

Membranous nephropathy is an autoimmune disease affecting the kidney, and the most common cause of nephrotic syndrome in non-diabetic Caucasian adults. The course of this disease is highly variable from one individual to another, ranging from spontaneous remission to progressive chronic kidney disease.

The identification of autoantibodies - e.g., the phospholipase A2 receptor type 1 (PLA2R1) - has promoted the use of immunosuppressive drugs such as rituximab which is now a safe and effective first-line treatment for the management of membranous nephropathy. However, up to 40% of patients do not respond to a first course of rituximab treatment. In nephrotic patients, due to urinary drug loss, rituximab blood level is lower than in other autoimmune diseases treated with rituximab without proteinuria. This high urinary drug loss decreases the drug exposure, potentially explaining why rituximab regimen with low dose infusions (375 mg/m2) did not demonstrate efficacy after month-6 compared to a non-immunosuppressive antiproteinuric treatment in a previous study. In contrast, a regimen of two 1-g infusions two weeks apart was associated with a significantly greater remission rate after 6 months.

Recently, the investigators have shown that after two 1-g rituximab infusions, the rituximab blood level 3 months after the first rituximab infusion, was correlated with the likelihood of remission after 6 and 12 months of the rituximab treatment. Patients with positive rituximab blood level 3 months after treatment had a higher chance of remission at month-6 and at month-12 than patients with an undetectable rituximab level at month-3.

Nowadays, machine learning algorithms are increasingly used in medicine, especially in pharmacology, to predict the exposure to a drug, the initial dose to administer or the interval between two infusions.

The objective of this study is to use a machine learning algorithm predicting the risk of having an undetectable residual level of rituximab 3 months after treatment, in order to propose a personalized treatment management with early additional doses of rituximab for the patients at risk.

Study Overview

• Status: Recruiting
• Conditions: Membranous Nephropathy
• Intervention / Treatment: Drug: RiTUXimab Injection

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Céline FERNANDEZ; Phone Number: +33492038828; Email: fernandez.c3@chu-nice.fr
• Study Contact Backup: Name: Barbara SEITZ-POLSKI, MD, PhD; Phone Number: +33492038828; Email: seitz-polski.b@chu-nice.fr

Study Locations

• France
  • Besançon, France
    • Recruiting
    • CHU de Besançon
    • Principal Investigator: Thomas CREPIN
  • Bordeaux, France
    • Recruiting
    • CHU de Bordeaux - Hôpital Pellegrin
    • Principal Investigator: Claire Rigothier
  • Caen, France
    • Recruiting
    • CHu de Caen
    • Principal Investigator: Antoine LANOT
  • Créteil, France
    • Recruiting
    • AP-HP - Hôpital H. Mondor
    • Principal Investigator: Vincent Audard
  • Lyon, France
    • Recruiting
    • HCL - Hôpital E. Herriot
    • Principal Investigator: fitsum guebre-egziabher
  • Marseille, France
    • Recruiting
    • AP-HM - Hopital de La Conception
    • Principal Investigator: Noémie JOURDE-CHICHE
  • Nice, France
    • Recruiting
    • CHU de Nice
    • Principal Investigator: Barbara Seitz-Polski
    • Contact: Céline FERNANDEZ; Phone Number: 0492038828; Email: fernandez.c3@chu-nice.fr
    • Sub-Investigator: Maxime TEISSEYRE
  • Nîmes, France
    • Recruiting
    • CHU de Nîmes - Hôpital Carémeau
    • Principal Investigator: Olivier Moranne
  • Paris, France
    • Not yet recruiting
    • AP-HP - Hôpital Européen Georges Pompidou
    • Principal Investigator: Alexandre KARRAS
  • Paris, France
    • Not yet recruiting
    • AP-HP - Hôpital Necker
    • Principal Investigator: KNEBELMANN Bertrand
  • Toulouse, France
    • Recruiting
    • CHU de Toulouse - Hôpital Rangueil
    • Principal Investigator: Dominique CHAUVEAU
  • Tours, France
    • Recruiting
    • CHRU de Tours - Hôpital Bretonneau
    • Principal Investigator: Christelle BARBET
  • Valenciennes, France
    • Not yet recruiting
    • Ch de Valenciennes
    • Principal Investigator: Claire CATERY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Ongoing episode of membranous nephropathy diagnosed by the presence of anti-PLA2R1 antibodies detected by ELISA (≥ 14 RU/ml, EUROIMMUN): the result must be validated by the Coordination team before randomization.
• Nephrotic syndrome defined by proteinuria > 3.5 g/24h (or UPCR > 3.5 g/g) and serum albumin < 30 g/L at diagnosis
• Estimated Glomerular Filtration Rate (CKD-EPI formula) > 30 mL/min/1,73 m2
• Indication for rituximab treatment according to the KDIGO and French guidelines
• Non-immunosuppressive antiproteinuric treatment at stable dose for 2 weeks according to French guidelines, including a renin angiotensin aldosterone system inhibitor, a diuretic and a low-salt diet at maximal tolerated dose (i.e., absence of orthostatic hypotension and no increase in creatinine > 30%)

Exclusion Criteria:

• Secondary Membranous nephropathy related to cancer, infection, systemic lupus, drug
• Diagnosis of PLA2R1-associated Membranous nephropathy not confirmed by the Coordination team (validation mandatory for randomization)
• Pregnancy or breastfeeding
• Immunosuppressive treatment (including rituximab) in the 6 months preceding inclusion
• Presence of anti-rituximab antibodies detected by Central Lab
• Cancer under treatment
• Patients with active, severe infections
• Hypersensitivity to the active substance or excipients
• Patients severely immunocompromised
• Severe heart failure or severe, uncontrolled cardiac disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard-of-care; rituximab treatment 1gram x 2 (day-0, day-15)	Drug: RiTUXimab Injection; Dose administered will depend on randomisation and for experimental Arm on the risk of having undetectable rituximab level after 3 months
Experimental: Personalised treatment; personalized treatment based on the algorithm for assessing the risk of having undetectable rituximab level after 3 months: Patients with a risk between 0 and 50% will receive 1gram x2 (day-0, day-15); Patients with a risk between 51 and 75% will receive 1gram x 3 (day-0, day-15, day-30); Patients with a risk between 76 and 100% will receive 1gram x 4 (day-0, day-15, day-30, day-45)	Drug: RiTUXimab Injection; Dose administered will depend on randomisation and for experimental Arm on the risk of having undetectable rituximab level after 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission (complete or partial) after 6 months of rituximab initiation	Clinical remission (complete or partial) according to KDIGO and French guidelines: Complete: urine protein/creatinine ratio (UPCR) <0.3 g/g and serum albumin>30 g/L and Glomerular Filtration Rate (estimated by CKD-EPI formula) >60 ml/min/1.73m2; Partial: UPCR <3.5 g/g with a decrease >50% from baseline (i.e., at first rituximab infusion) and serum albumin improvement or normalization and stable serum creatinine (or increase <30%).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete clinical remission after 12 months of rituximab initiation	Complete remission: urine protein/creatinine ratio (UPCR) <0.3 g/g and serum albumin>30 g/L and Glomerular Filtration Rate (estimated by CKD-EPI formula) >60 ml/min/1.73m2	12 months
Partial clinical remission after 12 months of rituximab initiation	Partial remission: UPCR <3.5 g/g with a decrease >50% from baseline (i.e., at first rituximab infusion) and serum albumin improvement or normalization and stable serum creatinine (or increase <30%).	12 months
Immunological remission: anti-PLA2R1 depletion	Immunological remission: anti-PLA2R1 depletion (i.e., PLA2R1 titer < 14 RU/mL by ELISA method) at month-3, month-6 and month-12	12 months
Change in urine protein/creatinine ratio (UPCR)	Percentage of change in urine albumin/creatinine ratio (mg/g) from day-0 to month-3, month-6, month-9, month-12	12 months
Change in serum creatinine	Percentage of change in serum creatinine (μmol/L) from day-0 to month-3, month-6, month-9, month-12	12 months
Change in renal function	Percentage of change in Glomerular Filtration Rate estimated by CKD-EPI formula (mL/min/1.73m²) from day-0 to month-3, month-6, month-9, month-12	12 months
Change in the immunological status of the disease	Percentage of change in anti-PLA2R1 titer (RU/mL) by ELISA (EUROIMMUN Kit) from day-0 to month-3, month-6, month-9, month-12	12 months
Appearance of anti-drug antibodies after rituximab treatment	Serum anti-rituximab antibodies (ng/mL) at month-3, month-6, month-9, month-12	12 months
Rituximab underdosed patients	Percentage of patients with serum rituximab (μg/mL) >2 μg/mL 3 months after the last infusion	3 months
Serious adverse events	Occurence of Serious adverse events reported	84 months
Adaptation of symptomatic treatment	Number of dose modification of non-immunosuppressive anti-proteinuric treatment during study follow-up	84 months
Model improvement through machine learning	serum creatinine and serum albumin levels, weight, anti-PLA2R1 and rituximab level will be combined to report the risk of having undetectable rituximab level after 3 months (in %) at day-0, day-15, day-30, day-45, month-3, month-6	6 months
Effect of rituximab on immune profiles	Cytokine levels in pg/mL (IFN-γ, IFN-α, IL-12p70, IL-17A, IL-4, IL-5, IL-10, IL-1, IL-6) at day-0 and month-6	6 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice

Publications and helpful links

General Publications

• Teisseyre M, Destere A, Cremoni M, Zorzi K, Brglez V, Benito S, Bailly L, Fernandez C, Seitz-Polski B. Artificial intelligence-based personalised rituximab treatment protocol in membranous nephropathy (iRITUX): protocol for a multicentre randomised control trial. BMJ Open. 2025 Apr 2;15(4):e093920. doi: 10.1136/bmjopen-2024-093920.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2025
• Primary Completion (Estimated): August 31, 2031
• Study Completion (Estimated): September 30, 2031

Study Registration Dates

• First Submitted: February 27, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: September 5, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Autoimmune Diseases; Immune System Diseases; Glomerulonephritis; Nephritis; Glomerulonephritis, Membranous; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Rituximab
• Other Study ID Numbers: 22-APN-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: not planed

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No