Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy

NCT ID: NCT01508468

Last Updated: 2021-10-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-01-17
• Study Completion Date: 2016-08-31

Brief Summary

The Membranous Nephropathy is one of the most common cause of Nephrotic Syndrome of adults. In 2/3 of patients the cause of the disease is idiopathic. This can also be referred to as idiopathic membranous nephropathy (IMN).The most of these patients are treated by non immunosuppressive symptomatic treatment (NIST): antiproteinuric and antihypertensive blocking the rennin-angiotensine system. However, the patients resistant to antiproteinuric treatment risk to develop an end stage renal disease (ESRD).

Rituximab has been recently used in patients suffering of nephrotic syndrome related to IMN in four international studies. Rituximab appears effective and safe in reducing proteinuria in nearly 60% of patients.

The primary outcome of the investigators prospective randomized study is to determine whether or not the Rituximab associated with NIST is more effective than non immunologic symptomatic treatment alone in inducing long term remission of proteinuria.

Detailed Description

The IMN exposes patients to severe complications which engage the vital prognosis or Nephrotic Syndrome.

The development of well tolerated and effective pathogenesis linked therapies is needed to treat patients with idiopathic Membranous Nephropathy Rituximab, a monoclonal antibody (mAb) against the CD20 present on B cells, has been recently used in patients suffering of nephrotic syndrome related to IMN in four international studies. Rituximab appears effective and safe in reducing proteinuria in nearly 60% of patients.

However, no randomized controlled study has been published to date.

In a previous study, outcome of 28 patients treated with rituximab for idiopathic MN is analysed. Anti-PLA2R antibodies in serum and PLA2R antigen in kidney biopsy were assessed in 10 and 9 patients.

Proteinuria was significantly decreased by 56%, 62% and 87% at 3 months, 6 months and 12 months. At 6 months, 2 patients achieved full remission and 12 partial remission (overall renal response, 50%). At 12 months (n=23), complete remission was achieved in 6 patients and partial remission in 13 patients (overall renal response, 82,6%). Three patients suffered a relapse of nephrotic proteinuria 27 to 50 months after treatment. Univariate analysis suggested that the degree of renal failure (MDRD < 45/ml/min/1.73 m²) is an independent factor that predicts lack of response to rituximab. Anti-PLA2R antibodies were detected in serum in 10 patients, and PLA2R antigen in immune deposits in 8 of 9 patients. Antibodies became negative in all 5 responsive patients with available follow-up. In this retrospective study, a high rate of remission was achieved at 12 months after treatment.

Our trial is a Prospective randomized multicentric open label study. The 2 arms of the study are : Non Immunosuppressive Symptomatic Treatment (NIST) and Rituximab+ NIST Patients randomized to the Rituximab arm will receive 375 mg/m² on days 1 and 8 (+ NIST). Patients in the control arm will be treated only with Non Immunosuppressive Symptomatic Treatment (NIST).

The duration of participation per patient is 6 months for interventional study. An observational follow-up is performed at M9, M12, M18 & M24 for all patients included in study with lab data collection of test done during usual pathology follow-up.

A part of the diagnosis renal biopsy (performed usually as part of health care) is collected for all patients as for the purpose of central analysis.

Our Primary Outcome Measure is evaluation of efficacy of Rituximab associated with NIST in (IMN) in reducing the rate of proteinuria (patients with persistent urinary protein excretion rate ≥3,5g/24 h and albuminemia < 30g/l ).

Conditions

Idiopathic Membranous Nephropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

active comparator

Non Immunosuppressive Symptomatic Treatment (NIST). "No specific treatment" Converting Enzyme Inhibitor , Angiotensin II receptor antagonist, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin.

Group Type: ACTIVE_COMPARATOR

symptomatic treatment (Converting Enzyme inhibitor, Angiotensin II, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin)

Intervention Type: DRUG

Converting Enzyme inhibitor , Angiotensin II receptor antagonist, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin.

experimental

NIST and Rituximab: 500 Mg and 100Mg in solution to be diluted for IV infusion (Mabthera®)

Group Type: EXPERIMENTAL

experimental (Non Immunosuppressive Symptomatic Treatment (NIST) and Rituximab)

Intervention Type: DRUG

NIST and IV infusion of Rituximab 375mg/m² at day (1) and day (8)

Interventions

symptomatic treatment (Converting Enzyme inhibitor, Angiotensin II, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin)

Converting Enzyme inhibitor , Angiotensin II receptor antagonist, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin.

Intervention Type: DRUG

experimental (Non Immunosuppressive Symptomatic Treatment (NIST) and Rituximab)

NIST and IV infusion of Rituximab 375mg/m² at day (1) and day (8)

Intervention Type: DRUG

Other Intervention Names

symptomatic treatment (no specific); experimental

Eligibility Criteria

Inclusion Criteria

• At least 18 years old.
• Idiopathic Membranous nephropathy proved by renal biopsy
• Persistent urinary protein excretion rate ≥3,5g/24 h and albuminemia < 30g/l for at least 6 months with full dose of NIST
• Patient receiving a non immunosuppressive conventional treatment (antiproteinuric and antihypertensive blocking the rennin-angiotensine system, lipid-lowering statin) since at least 6 months.
• Patient has given its written consent
• Patient with social coverage (excepting AME)
• Use of an efficient contraception method for women in childbearing age.

Exclusion Criteria

• Secondary membranous nephropathy
• Patient already in a clinical trial
• Patient received an immunosuppressive treatment within 3 months before the study
• Patient with chronic renal disease defined by estimated GFR by MDRD formula under 30ml/mn/1,73m²
• Pregnancy and breastfeeding
• HIV infection, HCV and HBV active infection
• Severe or evolving infections.
• Allergy or hypersensitivity to Rituximab or any component

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karine Dahan, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique

Locations

Department of Nephrology , Tenon hospital - APHP

Paris, , France

Countries

France

References

von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.

Reference Type: DERIVED

PMID: 34778952 (View on PubMed)

Seitz-Polski B, Dahan K, Debiec H, Rousseau A, Andreani M, Zaghrini C, Ticchioni M, Rosenthal A, Benzaken S, Bernard G, Lambeau G, Ronco P, Esnault VLM. High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy. Clin J Am Soc Nephrol. 2019 Aug 7;14(8):1173-1182. doi: 10.2215/CJN.11791018. Epub 2019 Jul 24.

Reference Type: DERIVED

PMID: 31340979 (View on PubMed)

Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, Michel PA, Mihout F, Dussol B, Matignon M, Mousson C, Simon T, Ronco P; GEMRITUX Study Group. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol. 2017 Jan;28(1):348-358. doi: 10.1681/ASN.2016040449. Epub 2016 Jun 27.

Reference Type: DERIVED

PMID: 27352623 (View on PubMed)

Other Identifiers

AOM 10089

Identifier Type: OTHER

Identifier Source: secondary_id

P 100115

Identifier Type: -

Identifier Source: org_study_id