RITUXIMAB for Membranous nephropathy

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years"}
• {"criterion_text":"- Ongoing episode of membranous nephropathy diagnosed either by: the presence of anti-PLA2R1 or anti-THSD7A antibodies, or renal biopsy"}
• {"criterion_text":"- Nephrotic syndrome defined by proteinuria > 3.5 g/24h (or UPCR > 3.5 g/g) and serum albumin < 30 g/L at screening"}
• {"criterion_text":"- Indication for rituximab treatment according to the KDIGO or French guidelines"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Estimated Glomerular Filtration Rate CKD-EPI > 30 mL/min/1,73 m²"}

Exclusion criteria

• {"criterion_text":"- Secondary membranous nephropathy related to cancer, infection, systemic lupus, drug"}
• {"criterion_text":"- Patient refusing to follow the algorithm recommendation approved by their referring nephrologist"}
• {"criterion_text":"- Patient who, in the opinion of the investigator, cannot receive the treatment recommended by the iRITUX algorithm (safety or compliance reasons)"}
• {"criterion_text":"- Pregnancy or breastfeeding"}
• {"criterion_text":"- Immunosuppressive treatment (including rituximab) in the 6 months preceding inclusion"}
• {"criterion_text":"- Presence of anti-rituximab antibodies detected by Central Lab (if negative result available within 6 weeks before screening, or if the patient is naïve of rituximab treatment, the patient is eligible)"}
• {"criterion_text":"- Cancer under treatment"}
• {"criterion_text":"- Patients with active, severe infections"}
• {"criterion_text":"- Hypersensitivity to the active substance or excipients"}
• {"criterion_text":"- Patients severely immunocompromised who, in the opinion of the investigator, cannot receive more than two 1-gram doses of rituximab"}
• {"criterion_text":"- Severe heart failure or severe, uncontrolled cardiac disease"}

Primary endpoints

• {"endpoint_text":"- Clinical remission (complete or partial) according to KDIGO or French guidelines: - Complete: urine protein/creatinine ratio (UPCR) <0.3 g/g and serum albumin>30 g/L - Partial: UPCR <3.5 g/g with a decrease >50% from baseline (i.e., at first rituximab infusion) and serum albumin improvement or normalization","definition_or_measurement_approach":"Clinical remission defined per KDIGO or French guidelines: Complete = UPCR <0.3 g/g and serum albumin >30 g/L; Partial = UPCR <3.5 g/g with >50% decrease from baseline and serum albumin improvement or normalization."}

Secondary endpoints

• {"endpoint_text":"- Complete clinical remission at month-12 according to KDIGO or French guidelines","definition_or_measurement_approach":"Assessment of complete clinical remission at month 12 per KDIGO/French guidelines."}
• {"endpoint_text":"- Partial clinical remission at month-12 according to KDIGO or French guidelines","definition_or_measurement_approach":"Assessment of partial clinical remission at month 12 per KDIGO/French guidelines."}
• {"endpoint_text":"- Immunological remission: If membranous nephropathy anti-PLA2R1 associated: anti-PLA2R1 depletion (i.e., PLA2R1 titer < 14 RU/mL by ELISA EUROIMMUN kit) at month-3, month-6, month-12 ✓ If membranous nephropathy anti-THSD7A associated: anti-THSD7A depletion (i.e., positive or negative immunofluorescence)","definition_or_measurement_approach":"Immunological remission measured by anti-PLA2R1 ELISA (<14 RU/mL) at M3, M6, M12 for PLA2R1-associated disease; anti-THSD7A depletion by immunofluorescence for THSD7A-associated disease."}
• {"endpoint_text":"- Percentage of change in urine protein/creatinine ratio (UPCR) (g/g) and urine albumin/creatinine ratio (mg/g) from day-0 to month-3, month-6, month-9, month-12","definition_or_measurement_approach":"Relative change in UPCR and urine albumin/creatinine ratio between baseline (day 0) and specified follow-up months."}
• {"endpoint_text":"- Percentage of change in serum creatinine (μmol/L) and Glomerular Filtration Rate estimated by CKD-EPI formula (mL/min/1.73m²) from day-0 to month-3, month-6, month-9, month-12","definition_or_measurement_approach":"Relative change in serum creatinine and eGFR (CKD-EPI) between baseline and follow-up timepoints."}
• {"endpoint_text":"- 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 (membranous nephropathy anti-PLA2R1 associated only)","definition_or_measurement_approach":"Percent change in anti-PLA2R1 titer measured by EUROIMMUN ELISA at specified timepoints for PLA2R1-associated patients."}
• {"endpoint_text":"- Serum anti-rituximab antibodies (ng/mL) at month-3, month-6, month-9, month-12","definition_or_measurement_approach":"Measurement of serum anti-rituximab antibodies (ng/mL) at indicated months."}
• {"endpoint_text":"- Percentage of patients with serum rituximab (μg/mL) >2 μg/mL 3 months after the last infusion","definition_or_measurement_approach":"Proportion of patients with serum rituximab >2 μg/mL at 3 months post-last infusion."}
• {"endpoint_text":"- Serious adverse events related to treatment during study follow-up","definition_or_measurement_approach":"Recording and attribution of serious adverse events related to study treatment during follow-up."}
• {"endpoint_text":"- Modification of non-immunosuppressive anti-proteinuric treatment during study follow-up","definition_or_measurement_approach":"Documentation of changes to non-immunosuppressive antiproteinuric therapies during follow-up."}
• {"endpoint_text":"- Pharmacokinetics in all patients with serum creatinine and serum albumin levels, weight, anti- PLA2R1 and rituximab level at day-0, day-15, day-30, day-45, month-3, month-6","definition_or_measurement_approach":"PK assessments including serum rituximab levels and relevant covariates (creatinine, albumin, weight, anti-PLA2R1) at listed timepoints."}
• {"endpoint_text":"- Correlation between epitope spreading at day-0 and response to treatment in both groups (in PLA2R1 and THSD7A positive patients).","definition_or_measurement_approach":"Analysis of correlation between baseline epitope spreading and treatment response in PLA2R1/THSD7A positive patients."}
• {"endpoint_text":"- Predictive rate (%) of the algorithm for rituximab underdosing (i.e. serum level <2 mg/ml at month-3) in the control group (i.e. patients treated according to the standard-of-care strategy).","definition_or_measurement_approach":"Calculation of algorithm predictive performance (percentage) for underdosing (serum <2 μg/mL at M3) in control group."}
• {"endpoint_text":"- Correlation between urine rituximab levels at day-15 and disease severity (defined as lowering of estimated glomerular filtration rate, proteinuria), drug exposure (measured with serum rituximab level), clinical response (partial or complete as defined above), immunological response (negative anti-PLA2R1 titer)","definition_or_measurement_approach":"Correlation analyses between urine rituximab at D15 and severity, serum exposure, clinical and immunological responses."}
• {"endpoint_text":"- Pharmacokinetics in all patients with serum creatinine and serum albumin levels, weight, anti- PLA2R1 and rituximab level at day-0, day-15 (predose and postdose), day-30, day-45, month-3, month-6","definition_or_measurement_approach":"PK sampling including predose and postdose at D15 and other timepoints as listed."}
• {"endpoint_text":"- Immunophenotying of B cells subsets as follows: naïve cells (CD19+CD27-IgD+), non-switched memory cells (CD19+CD27+IgD+), switched memory cells (CD19+CD27+IgD-), double negative cells (CD19+CD27-IgD), transitional cells (CD19+CD38++CD27-IgD+) and plasmablasts (CD19+CD38++CD27+IgD-), expressed as the percentage of total lymphocytes.","definition_or_measurement_approach":"Flow cytometry immunophenotyping of B-cell subsets expressed as percent of total lymphocytes."}
• {"endpoint_text":"- Immunophenotying of T cells subsets as follows: T helper cells (CD3+CD4+), cytotoxic T lymphocytes (CD3+ CD8+), regulatory T cells (CD3+ CD4+ Foxp3+ CD25high), Th1 cells (CD3+ CD4+ T-bet +) and Th17 cells (CD3+ CD4+ RORγt +).","definition_or_measurement_approach":"Flow cytometry immunophenotyping of T-cell subsets as specified."}
• {"endpoint_text":"- 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 (Nice patients only). 19. Optional: stools biorepository samples","definition_or_measurement_approach":"Measurement of listed cytokines in pg/mL at D0 and M6 (Nice sites only)."}
• {"endpoint_text":"- Optional: stools biorepository samples will be collected at Day-0 and Month-6 visits for future exploratory biomarker analysis to better understand disease and the impact of the microbiota on the treatment response (Nice patients only).","definition_or_measurement_approach":"Optional stool sample collection at D0 and M6 at specified site(s) for future exploratory biomarker analyses."}

France

Earliest CTIS Part Ii Submission Date

29-08-2024

Latest Decision Or Authorization Date

20-02-2026

Processing Time Days

540

Number Of Sites

15

Number Of Participants

130

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Nice

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France