Clinical trial NCT03804359: Personalized Medicine for Membranous Nephropathy
Official title: Personalized Medicine for Membranous Nephropathy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Idiopathic Membranous Nephropathy
Keywords: Nephrotic Syndrome
PLA2R1-antibodies
Epitope spreading
Rituximab
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
First posted: 2019-01-15
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Clinical remission will be defined as a composite criterion combining (KDIGO definitions)
timeFrame: 6 months
Secondary outcomes:
measure: Immunological remission
timeFrame: 6 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU D'amiens Hôpital Sud
city: Besançon
country: France
facility: CHU Besançon
city: Brest
country: France
facility: Hôpital universitaire La Cavale Blanche
city: Caen
country: France
facility: CHU de Caen
city: Clermont-Ferrand
country: France
facility: CHU Gabriel Montpied
city: Créteil
country: France
facility: CHU Henri Mondor
city: Lille
country: France
facility: CHRU de LILLE
city: Lyon
country: France
facility: CHU de LYON NORD
city: Marseille
country: France
facility: AP-HM
city: Montpellier
country: France
facility: CHRU de Montpellier
city: Nantes
country: France
facility: CHU de NANTES
city: Nice
country: France
facility: Dr Barbara SEITZ-POLSKI
city: Nîmes
country: France
facility: CHU Carémeau
city: Paris
country: France
facility: Hôpital Necker
city: Paris
country: France
facility: Le Kremlin Bicêtre
city: Reims
country: France
facility: Hôpital de la maison blanche
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Tours
country: France
facility: CHU de Tours
Study officials:
affiliation: Centre Hospitalier Universitaire de Nice
name: Barbara SEITZ-POLSKI
role: PRINCIPAL_INVESTIGATOR
References:
citation: Simon N, Courouce AM, Lemarrec N, Trepo C, Ducamp S. A twelve year natural history of hepatitis C virus infection in hemodialyzed patients. Kidney Int. 1994 Aug;46(2):504-11. doi: 10.1038/ki.1994.301.
citation: Simon P, Ramee MP, Boulahrouz R, Stanescu C, Charasse C, Ang KS, Leonetti F, Cam G, Laruelle E, Autuly V, Rioux N. Epidemiologic data of primary glomerular diseases in western France. Kidney Int. 2004 Sep;66(3):905-8. doi: 10.1111/j.1523-1755.2004.00834.x.
citation: Ponticelli C. Membranous nephropathy. J Nephrol. 2007 May-Jun;20(3):268-87.
citation: Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010 Jul;56(1):157-67. doi: 10.1053/j.ajkd.2010.01.008. Epub 2010 Apr 8.
citation: Lassalle M, Ayav C, Frimat L, Jacquelinet C, Couchoud C; Au Nom du Registre REIN. The essential of 2012 results from the French Renal Epidemiology and Information Network (REIN) ESRD registry. Nephrol Ther. 2015 Apr;11(2):78-87. doi: 10.1016/j.nephro.2014.08.002. Epub 2014 Nov 1.
citation: Brglez V, Boyer-Suavet S, Zorzi K, Fernandez C, Fontas E, Esnault V, Seitz-Polski B. Personalized Medicine for PLA2R1-Related Membranous Nephropathy: A Multicenter Randomized Control Trial. Front Med (Lausanne). 2020 Aug 13;7:412. doi: 10.3389/fmed.2020.00412. eCollection 2020.