Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01508468
First received: December 9, 2011
Last updated: February 26, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Idiopathic Membranous Nephropathy
Drug: symptomatic treatment (Converting Enzyme inhibitor, Angiotensin II, Anti-renin, Aldosterone antagonist diuretic, Beta blocker, Calcium inhibitor, statin)
Drug: experimental (Non Immunosuppressive Symptomatic Treatment (NIST) and Rituximab)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (IMN)

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Evaluation of efficacy of Rituximab associated with Non Immunosuppressive Symptomatic Treatment (NIST) in (IMN) in reducing the rate of proteinuria (patients with persistent urinary protein excretion rate ≥3,5g/24 h and albuminemia < 30g/l ) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Evaluation of efficacy of Rituximab associated with Non Immunosuppressive Symptomatic Treatment (NIST) in (IMN) in reducing the rate of proteniuria


Secondary Outcome Measures:
  • Effect of Rituximab on the progression of chronic renal disease [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Effect of Rituximab on the progression of chronic renal disease by measuring :

    • Percentage of proteinuria variation at 6 months
    • Percentage of nephrotic syndrome complication: measuring serum creatinine and glomerular filtration rate (GFR) at 6 months, infections, hydrops, vein thrombosis, arterial thrombosis.

  • Evaluation of Rituximab tolerance in IMN [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

    Evaluation of Rituximab tolerance in IMN :

    -Percentage of serious allergic reaction after Rituximab infusion "drop in blood pressure and/or bronchospasm"


  • serologic diagnosis with identification of anti-NEP and anti-PLA2R antibodies in IMN before and after treatment with Rituximab [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    serologic diagnosis with identification of anti-NEP and anti-PLA2R antibodies in IMN before and after treatment with Rituximab

  • genetic analysis [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    genetic analysis Study of the alleles "HLA-DQA1 and PLA2R1" situated respectively on chromosomes 6p21 and 2q24.

  • Lymphocyte CD19 dosing at month 3 and month 6. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Lymphocyte CD19 dosing at month 3 and month 6.


Estimated Enrollment: 80
Study Start Date: January 2012
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
Drug: 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.
Other Name: symptomatic treatment (no specific)
Experimental: experimental
NIST and Rituximab: 500 Mg and 100Mg in solution to be diluted for IV infusion (Mabthera®)
Drug: experimental (Non Immunosuppressive Symptomatic Treatment (NIST) and Rituximab)
NIST and IV infusion of Rituximab 375mg/m² at day (1) and day (8)
Other Name: experimental

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.

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 ).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • At least 18 years old.
  • Idiopathic Membranous nephropathy proved by renal biopsy (performed less than 2 years)
  • 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 45ml/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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01508468

Contacts
Contact: Karine Dahan, MD + 33 (0) 1 56 01 66 39 karine.dahan@tnn.aphp.fr

Locations
France
Department of Nephrology , Tenon hospital - APHP Recruiting
Paris, France
Contact: Karine Dahan, MD    + 33 (0) 1 56 01 66 39    karine.dahan@tnn.aphp.fr   
Principal Investigator: Karine Dahan, MD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Karine Dahan, MD Assistance Publique
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01508468     History of Changes
Other Study ID Numbers: P 100115, AOM 10089
Study First Received: December 9, 2011
Last Updated: February 26, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: French Data Protection Authority

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Rituximab
membranous nephropathy
anti-PLA2R antibody

Additional relevant MeSH terms:
Glomerulonephritis, Membranous
Kidney Diseases
Glomerulonephritis
Nephritis
Urologic Diseases
Autoimmune Diseases
Immune System Diseases
Adrenergic beta-Antagonists
Aldosterone Antagonists
Angiotensin II
Diuretics
Enzyme Inhibitors
Rituximab
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Angiotensin Receptor Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Natriuretic Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 24, 2014