Personalized Medicine for Membranous Nephropathy

Study Overview
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Brief Summary
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Randomized, open label, multicentre (20 sites), prospective trial comparing the efficacy of two therapeutic strategies to obtain clinical remission 1 year after diagnosis of Idiopathic Membranous Nephropathy with nephrotic syndrome and anti-PLA2R1 (phospholipase A2 receptor 1) antibodies: GEMRITUX protocol: 6 months of symptomatic antihypertensive and antiproteinuric therapy, and if the nephrotic syndrome persists at month-6 (urinary protein/creatinine ratio (UPCR) remains > 3.5 g/g and albuminemia < 30 g/l), two 375 mg/m2 rituximab infusions at 1-week interval. Personalized treatment: restricted anti-CysR activity at inclusion : 6-month symptomatic antihypertensive and antiproteinuric treatment (KDIGO) restricted anti-CysR activity after 6 months of symptomatic treatment with persisting nephrotic syndrome (UPCR remains > 3.5 g/g and albuminemia < 30 g/l): two 375 mg/m2 rituximab infusions at 1-week interval; Anti-CTLD (C-type lectin domains ) 1/7 activity at inclusion or after 6 months with persisting nephrotic syndrome (UPCR remains > 3.5 g/g and albuminemia < 30 g/l): two 1g rituximab infusions at 2-week interval at month 0 and/or month 6.

Official Title
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Personalized Medicine for Membranous Nephropathy

Conditions
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Idiopathic Membranous Nephropathy

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or more Anti-PLA2R1 activity detected by ELISA or Euroimmune Immunofluorescence Assay Nephrotic syndrome defined by proteinuria > 3.5 g/24h (or UPCR > 3.5 g/g) and serum albumin < 30 g/L at diagnosis eGFR (CKD-EPI) > 30 ml/min/1,73 m2 at diagnosis Symptomatic treatment according to KDIGO guidelines: maximal tolerated dose of NIAT : Non Immunosuppressive Antiproteinuric Treatment (angiotensin-converting enzyme inhibitor and/or angiotensin 2 receptor blockers, diuretics and statins) Medical insurance Signed informed consent Having understood and accepted the need for long-term medical follow-up Woman of child-bearing age must be using an effective method of contraception Exclusion Criteria: Secondary Membranous Nephropathy: Membranous Nephropathy related to cancer, infectious, systemic lupus erythematosis, drug Anti-PLA2R1 antibodies not confirmed by central analysis (in this case the patient will be replaced) Pregnancy or breastfeeding Immunosuppressive treatment in the 3 last months Cancer under treatment Patient with complicated nephrotic syndrome that would require early immunosuppressive treatment (thrombosis, acute renal failure…) Patients with active, severe infections or active hepatitis B Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients Patients in a severely immunocompromised state Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease Patients unable to give an informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: GEMRITUX protocol<br>6 months of symptomatic antihypertensive and antiproteinuric therapy, and if the nephrotic syndrome persists at month-6 (urinary protein/creatinine ratio (UPCR) remains > 3.5 g/g and albuminemia < 30 g/l), two 375 mg/m2 rituximab infusions at 1-week interval. | |
| Experimental: Personalized treatment<br>restricted anti-CysR activity at inclusion : 6-month symptomatic antihypertensive and antiproteinuric treatment (KDIGO) restricted anti-CysR activity after 6 months of symptomatic treatment with persisting nephrotic syndrome (UPCR remains > 3.5 g/g and albuminemia < 30 g/l): two 375 mg/m2 rituximab infusions at 1-week interval; Anti-CTLD1/7 activity at inclusion or after 6 months with persisting nephrotic syndrome (UPCR remains > 3.5 g/g and albuminemia < 30 g/l): two 1g rituximab infusions at 2-week interval at month 0 and/or month 6. | Drug: Rituximab<br>* In the personalized arm, the patient will be treated in function of the CysR activity result during the inclusion visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical remission will be defined as a composite criterion combining (KDIGO definitions) | Complete clinical remission: urinary protein/creatinine ratio (UPCR)<0.3 g/g in spot morning urine samples and serum albumin > 35 g/L and eGFR (epidermal growth factor receptor) > 60 ml/min/1.73 m2 Partial clinical remission: UPCR < 3.5 g/g with a decrease greater than 50% from baseline and serum albumin > 30 g/L and increase of serum creatinine lower than 20% | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological remission | full PLA2R1 depletion measured by ELISA (titer<14RU (relative units) /ml) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nephrotic Syndrome, PLA2R1-antibodies, Epitope spreading, Rituximab