Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy

NCT03018535 | Unknown Phase 3

• 1 other identifier: EudraCT 2011 006115-59
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

Brief Summary

Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the disease in the majority of the patients. Additional autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described, including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO). The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of interventional studies show that 30-40% of the untreated patients with persistent nephrotic syndrome (NS) progress to end-stage renal disease (ESRD). The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide, capable to induce remission of protenuria in two-third of the patients. Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide, since it may be associated with adverse events, including bone marrow suppression, gonadal toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies highly effective but with a greater safety profile is desirable. Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent. There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational studies in IMN provided encouraging data; in addition, the drug seems well tolerated. Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing. The investigators propose this study in order to test, in a randomized controlled trial, the hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment. In addition, the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment. Finally, the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events

Conditions

Glomerulonephritis, Membranous

Outcome Measures

Primary Outcomes (1)

• change in probability of complete remission (proteinuria < 0.3 g/day) Primary Outcome Measures The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year (see Design and power considerations).

  The primary outcome measure is the change in probability of complete remission (proteinuria \< 0.3 g/day) at one year

  1 year

Secondary Outcomes (7)

• Change from baseline in proteinuria

  from randomization up to 36 months

• CR (Complete Remission) or PR (Partial Remission: Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g )

  from randomization up to 36 months

• Estimated Glomerular filtration rate (MDRD formula)

  from randomization up to 36 months

• Serum creatinine level (mg/dl)

  from randomization up to 36 months

• Frequency of and time to relapse of nephrotic syndrome

  up to 36 months

Study Arms (2)

RITUXIMAB

EXPERIMENTAL

1 g. IV of Rituximab on days 1 and 15

Drug: Rituximab

Corticosteroids and Cyclophosphamide

ACTIVE COMPARATOR

Month 1, 3 and 5: 1g IV methylprednisolone daily for 3 doses; oral methylprednisolone (0.4mg/kg/day) or prednisone (0.5/mg/kg/day); Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)

Drug: Methylprednisolone; Drug: Cyclophosphamide

Interventions

Rituximab DRUG

Rituximab,1 g IV, day 1 and day 15

Also known as: Mabthera, Rituxan

RITUXIMAB

Methylprednisolone DRUG

Methylprednisolone 1 g IV daily for 3 doses, then oral methylprednisolone (0.4 mg/kg/day) or oral prednisone (0.5mg/kg/day) for 27 days during Month 1, 3, 5.

Also known as: URBASON, SOLUMEDROL

Corticosteroids and Cyclophosphamide

Cyclophosphamide DRUG

Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days

Also known as: Cytoxan, Endoxan

Corticosteroids and Cyclophosphamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Biopsy-proven diagnosis of idiopathic MN performed within the past 24 months
• Proteinuria \> 3.5 g/24h on three 24-hour urine collection (once a week for 3 weeks)
• Estimated GFR (MDRD formula) ≥ 30ml/min/1.73m2 under ACEI/ARB therapy
• Post-menopausal females, or females surgically sterile or practicing a medically approved method of contraception (no birth-control pill)
• Three months of ACEI and/or ARB therapy before treatment
• Blood Pressure \<130/80 mm Hg
• HMG-CoA reductase inhibitor therapy
• Patients remaining with proteinuria \>3.5g/24h after 3 months of ACEI and/or ARB therapy and Blood Pressure \<130/80 mm Hg may be randomized to RTX / cyclical corticosteroid/alkylating-agent therapy without the need of the run-in/conservative phase of the study.

You may not qualify if:

• serum creatinine \>2.5 mg/dl; Estimated GFR \< 30 ml/min/1.73m2
• previous treatment with Rituximab, Steroids, Alkylating Agents, Calcineurin Inhibitors, Synthetic ACTH, MMF, Azathioprine
• Presence of active infection
• Secondary cause of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred \< 6 months prior to enrollment into the study
• Type 1 or 2 diabetes mellitus
• Pregnancy or nursing for safety reasons
• Renal vein thrombosis documented prior to entry by renal US or CT scan

Sponsors & Collaborators

• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia: lead
• University of Bari: collaborator
• Azienda Ospedaliera Brotzu: collaborator
• University of Messina: collaborator
• University of Milan: collaborator
• Universita di Verona: collaborator
• University of Chieti: collaborator
• University of Bologna: collaborator
• Azienda Sanitaria Locale Roma E: collaborator
• IRCCS Azienda Ospedaliero-Universitaria di Bologna: collaborator
• Regione Piemonte: collaborator
• University of Modena and Reggio Emilia: collaborator
• University of Pisa: collaborator
• University of Milano Bicocca: collaborator
• Humanitas Hospital, Italy: collaborator
• Azienda Ospedaliera Universitaria Policlinico: collaborator
• Fondazione Salvatore Maugeri: collaborator
• University of Bern: collaborator
• University of Alberta: collaborator
• Istituto Giannina Gaslini: collaborator

Study Sites (1)

Division of Nephrology, Montichiari Hospital, ASST Spedali Civili di Brescia

Montichiari, Brescia, 25018, Italy

Location

Related Publications (8)

• Glassock RJ. The pathogenesis of membranous nephropathy: evolution and revolution. Curr Opin Nephrol Hypertens. 2012 May;21(3):235-42. doi: 10.1097/MNH.0b013e3283522ea8.

  PMID: 22388552 BACKGROUND

• Cravedi P, Remuzzi G, Ruggenenti P. Rituximab in primary membranous nephropathy: first-line therapy, why not? Nephron Clin Pract. 2014;128(3-4):261-9. doi: 10.1159/000368589. Epub 2014 Nov 22.

  PMID: 25427622 BACKGROUND

• Murtas C, Bruschi M, Candiano G, Moroni G, Magistroni R, Magnano A, Bruno F, Radice A, Furci L, Argentiero L, Carnevali ML, Messa P, Scolari F, Sinico RA, Gesualdo L, Fervenza FC, Allegri L, Ravani P, Ghiggeri GM. Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin J Am Soc Nephrol. 2012 Sep;7(9):1394-400. doi: 10.2215/CJN.02170312. Epub 2012 Jul 5.

  PMID: 22773590 BACKGROUND

• Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995 Nov;48(5):1600-4. doi: 10.1038/ki.1995.453.

  PMID: 8544420 BACKGROUND

• Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007 Jun;18(6):1899-904. doi: 10.1681/ASN.2007020166. Epub 2007 May 9.

  PMID: 17494881 BACKGROUND

• 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.

  PMID: 34778952 DERIVED

• Scolari F, Delbarba E, Santoro D, Gesualdo L, Pani A, Dallera N, Mani LY, Santostefano M, Feriozzi S, Quaglia M, Boscutti G, Ferrantelli A, Marcantoni C, Passerini P, Magistroni R, Alberici F, Ghiggeri GM, Ponticelli C, Ravani P; RI-CYCLO Investigators. Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial. J Am Soc Nephrol. 2021 Apr;32(4):972-982. doi: 10.1681/ASN.2020071091. Epub 2021 Mar 1.

  PMID: 33649098 DERIVED

• Scolari F, Dallera N, Gesualdo L, Santoro D, Pani A, Santostefano M, Feriozzi S, Mani LY, Boscutti G, Messa P, Magistroni R, Quaglia M, Ponticelli C, Ravani P. Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial. BMJ Open. 2019 Dec 4;9(12):e029232. doi: 10.1136/bmjopen-2019-029232.

  PMID: 31806605 DERIVED

MeSH Terms

Conditions

Glomerulonephritis, Membranous

Interventions

Rituximab; Methylprednisolone; Methylprednisolone Hemisuccinate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• FRANCESCO SCOLARI, MD

  Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: DIRECTOR OF THE DIVISION OF NEPHROLOGY, MONTICHIARI HOSPITAL

Study Record Dates

• First Submitted: January 9, 2017
• First Posted: January 12, 2017
• Study Start: January 1, 2012
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: May 20, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)