Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMN

Idiopathic Membranous Nephropathy Clinical Trial

Official title:

A Multicenter Randomized Controlled Trial of Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of Idiopathic Membranous Nephropathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04743739
• Other study ID #: iMN RTX plus CsA
• Status: Recruiting
• Phase: Phase 3
• Start date: April 14, 2021
• Est. completion date: March 2025

Study information

• Verified date: May 2021
• Source: Peking Union Medical College Hospital
• Contact: Sanxi Ai, Doctor
• Phone: 18811054896
• Email: sanxiai[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to determine whether or not cyclosporine (CsA) combined with RTX is more effective than RTX alone in the treatment of idiopathic membranous nephropathy (iMN).

Description:

To date, the first-line immunosuppressive therapy of iMN includes corticosteroids combined with cyclophosphamide or Rituximab (RTX) which has been used more and more widely due to superior safety profiles. But the long term remission rate of RTX monotherapy is only 60% and it takes effect relatively slowly.

2 pilot studies reported that the combination therapy of cyclosporine (CsA) and RTX had better efficacy for inducing remission for iMN, with the long term remission rate up to 85%. CsA and RTX may have synergistic effect in the treatment of iMN because they have different time of action and different effects on the immune system and podocytes.

Based on the previous rationale, the investigators designed this trial to determine whether combination of CsA and RTX is more effective than RTX alone in the treatment of iMN.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 126
• Est. completion date: March 2025
• Est. primary completion date: March 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• idiopathic MN with or without diagnostic biopsy

• Female, must be post-menopausal, sterile or have effective method of contraception

• must be off steroid or mycophenolate mofetil for >1 month and alkylating agents for > 6 months

• Angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for =3 months prior to randomization with controlled blood pressure or if patients is intolerant to ACEI/ARB

• proteinuria =4g/24h using the average from two 24-hour urine samples collected within 2 weeks of each other, and decreased =50% from baseline.

• estimated glomerular filtration rate (eGFR) =40ml/min/1.73m2

Exclusion Criteria:

• presence of active infection or a secondary cause of MN

• diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy.

• pregnancy or breast feeding

• history of resistance to CsA or other calcineurin inhibitors(CNI), RTX or alkylating agents.

• Patients who previously achieved remission after treatment of CNI, RTX or alkylating agents but relapsed off CNI after 3 months, or relapsed off RTX or alkylating agents after 6 months, are eligible.

Related Conditions & MeSH terms

• Glomerulonephritis, Membranous
• Idiopathic Membranous Nephropathy
• Kidney Diseases

Intervention

Drug:
• Rituximab
Rituximab 1000mg, I.V. on Days 1 and 181, and will be retreated or not at Days 15 and 195 according to the CD19+ B cell count.
• cyclosporine
cyclosporine (CsA) will be started at a dose of 3mg/kg/d and adjusted according to the blood levels of the CsA. CsA will be tapered after 6 months and discontinued over a three month period.

Locations

Country	Name	City	State
China	Beijing Luhe Hospital, Capital Medical University	Beijing	Beijing
China	Beijing Tongren Hospital, Capital Medical University	Beijing	Beijing
China	Fuwai Hospital, Chinese Academy of Medical Sciences	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Nanyang Nanshi Hospital, Henan University	Nanyang	Henan
China	The Seventh Affiliated Hospital, Sun Yat-sen University	Shenzhen	Shenzhen
China	The First Affiliated Hospital of Xinjiang Medical University	Urumqi	Xinjiang

Sponsors (8)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Beijing Tongren Hospital, Chinese Academy of Medical Sciences, Fuwai Hospital, First Affiliated Hospital of Xinjiang Medical University, Nanyang Nanshi Hospital of Henan University, Shanghai Fosun Pharmaceutical Development Co, Ltd., The Luhe Teaching Hospital of the Capital Medical University, The Seventh Affiliated Hospital, Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (10)

Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2;361(1):11-21. doi: 10.1056/NEJMoa0810457. — View Citation

Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, Ponticelli C, Saito T, Choukroun G, Nachman P, Praga M, Yoshikawa N. Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations. Kidney Int. 2007 Dec;72(12):1429-47. Epub 2007 Sep 26. — View Citation

Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008 Sep;14(9):931-8. doi: 10.1038/nm.1857. — View Citation

Fernández-Juárez G, Rojas-Rivera J, Logt AV, Justino J, Sevillano A, Caravaca-Fontán F, Ávila A, Rabasco C, Cabello V, Varela A, Díez M, Martín-Reyes G, Diezhandino MG, Quintana LF, Agraz I, Gómez-Martino JR, Cao M, Rodríguez-Moreno A, Rivas B, Galeano C, Bonet J, Romera A, Shabaka A, Plaisier E, Espinosa M, Egido J, Segarra A, Lambeau G, Ronco P, Wetzels J, Praga M; STARMEN Investigators. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int. 2021 Apr;99(4):986-998. doi: 10.1016/j.kint.2020.10.014. Epub 2020 Nov 7. — View Citation

Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, Jefferson JA, Gipson PE, Rizk DV, Sedor JR, Simon JF, McCarthy ET, Brenchley P, Sethi S, Avila-Casado C, Beanlands H, Lieske JC, Philibert D, Li T, Thomas LF, Green DF, Juncos LA, Beara-Lasic L, Blumenthal SS, Sussman AN, Erickson SB, Hladunewich M, Canetta PA, Hebert LA, Leung N, Radhakrishnan J, Reich HN, Parikh SV, Gipson DS, Lee DK, da Costa BR, Jüni P, Cattran DC; MENTOR Investigators. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019 Jul 4;381(1):36-46. doi: 10.1056/NEJMoa1814427. — View Citation

Polanco N, Gutiérrez E, Covarsí A, Ariza F, Carreño A, Vigil A, Baltar J, Fernández-Fresnedo G, Martín C, Pons S, Lorenzo D, Bernis C, Arrizabalaga P, Fernández-Juárez G, Barrio V, Sierra M, Castellanos I, Espinosa M, Rivera F, Oliet A, Fernández-Vega F, Praga M; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010 Apr;21(4):697-704. doi: 10.1681/ASN.2009080861. Epub 2010 Jan 28. — View Citation

Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136-42. Review. — View Citation

Segarra A, Praga M, Ramos N, Polanco N, Cargol I, Gutierrez-Solis E, Gomez MR, Montoro B, Camps J. Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients. Clin J Am Soc Nephrol. 2009 Jun;4(6):1083-8. doi: 10.2215/CJN.06041108. Epub 2009 May 28. — View Citation

van den Brand JAJG, Ruggenenti P, Chianca A, Hofstra JM, Perna A, Ruggiero B, Wetzels JFM, Remuzzi G. Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy. J Am Soc Nephrol. 2017 Sep;28(9):2729-2737. doi: 10.1681/ASN.2016091022. Epub 2017 May 9. — View Citation

Waldman M, Beck LH Jr, Braun M, Wilkins K, Balow JE, Austin HA 3rd. Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. Kidney Int Rep. 2016 Jul;1(2):73-84. Epub 2016 Jun 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	complete remission (CR) or partial remission (PR) at 24 month	complete or partial remission at 24 month. complete remission is defined as urine protein=0.5g/24h and serum albumin=3.5g/dl. Partial remission is defined as reduction in baseline urine protein =50% plus urine protein=3.5g/24h but >0.5g/24h	24 months after randomization
Secondary	complete remission (CR) or partial remission (PR) on 6 month, 12 month, 18 month	complete or partial remission on month 6, 12 and 18	6, 12, 18 months after randomization
Secondary	complete remission (CR) on 6, 12, 18, 24 month	complete remission on month 6, 12, 18 and 24	6, 12, 18, 24 months after randomization
Secondary	Time to complete remission (CR) or partial remission (PR)	Time to complete or partial remission	from date of randomization until the date of first remission, assessed up to 24 months
Secondary	Change of estimated glomerular filtration rate (eGFR)	Change of eGFR from baseline to 24 months	24 months
Secondary	Serum creatinine increase=50 percent from baseline	proportion of patients with increase of serum creatinine =50 percent from baseline	24 months
Secondary	Proportion of patients with relapse	Rate of relapse. Relapse is defined as development of nephrotic range proportion of patients with relapse. Relapse is defined as development of proteinuria>3.5g/24h following CR or PR.	12,18,24 months
Secondary	Anti-PLA2R titer	Auto-antibodies to the M-type phospholipase A2 receptor(PLA2R)	baseline and 3, 6, 9, 12, 18, 24 months
Secondary	The number of CD19+B cells	CD19+ B cells	baseline and 3, 6, 9, 12, 18, 24 months
Secondary	Quality of life measured by kidney disease and quality of life (KDQOL-36)	KDQOL-36 includes 36 questions which are scored positively (higher score indicating better quality of life) on a 0-100 scale using developer-recommended scoring.	baseline, 12 and 24 month
Secondary	Adverse events	adverse events	through study completion until 24 months