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

Membranous Nephropathy Clinical Trial

— iRITUX  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06341205
• Other study ID #: 22-APN-01
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: September 1, 2024
• Est. completion date: September 30, 2031

Study information

• Verified date: February 2024
• Source: Centre Hospitalier Universitaire de Nice
• Contact: Barbara SEITZ-POLSKI, MD, PhD
• Phone: +33492038828
• Email: seitz-polski.b[@]chu-nice.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: September 30, 2031
• Est. primary completion date: August 31, 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glomerulonephritis, Membranous
• Kidney Diseases
• Membranous Nephropathy

Intervention

Drug:
• RiTUXimab Injection
Dose administered will depend on randomisation and for experimental Arm on the risk of having undetectable rituximab level after 3 months

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nice

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Rituximab underdosed patients	Percentage of patients with serum rituximab (µg/mL) >2 µg/mL 3 months after the last infusion	3 months
Secondary	Serious adverse events	Occurence of Serious adverse events reported	84 months
Secondary	Adaptation of symptomatic treatment	Number of dose modification of non-immunosuppressive anti-proteinuric treatment during study follow-up	84 months
Secondary	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
Secondary	Effect of rituximab on immune profiles	Cytokine levels in pg/mL (IFN-?, IFN-a, IL-12p70, IL-17A, IL-4, IL-5, IL-10, IL-1, IL-6) at day-0 and month-6	6 months