Clinical trial NCT04743739: Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMN
Official title: A Multicenter Randomized Controlled Trial of Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of Idiopathic Membranous Nephropathy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Idiopathic Membranous Nephropathy
Keywords: Rituximab
cyclosporine
idiopathic membranous nephropathy
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Beijing Tongren Hospital
name: Chinese Academy of Medical Sciences, Fuwai Hospital
name: The Luhe Teaching Hospital of the Capital Medical University
name: The Seventh Affiliated Hospital of Sun Yat-sen University
name: First Affiliated Hospital of Xinjiang Medical University
name: Nanyang Nanshi Hospital of Henan University
name: Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
First posted: 2021-02-08
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: complete remission (CR) or partial remission (PR) at 24 month
timeFrame: 24 months after randomization
Secondary outcomes:
measure: complete remission (CR) or partial remission (PR) on 6 month, 12 month, 18 month
timeFrame: 6, 12, 18 months after randomization
measure: complete remission (CR) on 6, 12, 18, 24 month
timeFrame: 6, 12, 18, 24 months after randomization
measure: Time to complete remission (CR) or partial remission (PR)
timeFrame: from date of randomization until the date of first remission, assessed up to 24 months
measure: Change of estimated glomerular filtration rate (eGFR)
timeFrame: 24 months
measure: Serum creatinine increase≥50 percent from baseline
timeFrame: 24 months
measure: Proportion of patients with relapse
timeFrame: 12，18，24 months
measure: Anti-PLA2R titer
timeFrame: baseline and 3, 6, 9, 12, 18, 24 months
measure: The number of CD19+B cells
timeFrame: baseline and 3, 6, 9, 12, 18, 24 months
measure: Quality of life measured by kidney disease and quality of life (KDQOL-36)
timeFrame: baseline, 12 and 24 month
measure: Adverse events
timeFrame: through study completion until 24 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Fuwai Hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Beijing
country: China
facility: Beijing Tongren Hospital， Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Luhe Hospital, Capital Medical University
state: Beijing
city: Nanyang
country: China
facility: Nanyang Nanshi Hospital, Henan University
state: Henan
city: Shenzhen
country: China
facility: The Seventh Affiliated Hospital, Sun Yat-sen University
state: Shenzhen
city: Urumqi
country: China
facility: The First Affiliated Hospital of Xinjiang Medical University
state: Xinjiang
Study officials:
affiliation: Peking Union Medical College Hospital
name: Yan Qin, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Polanco N, Gutierrez E, Covarsi A, Ariza F, Carreno A, Vigil A, Baltar J, Fernandez-Fresnedo G, Martin C, Pons S, Lorenzo D, Bernis C, Arrizabalaga P, Fernandez-Juarez G, Barrio V, Sierra M, Castellanos I, Espinosa M, Rivera F, Oliet A, Fernandez-Vega F, Praga M; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Espanola de Nefrologia. 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.
citation: 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.
citation: Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136-42. doi: 10.1016/0167-5699(92)90111-J.
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.
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. doi: 10.1038/sj.ki.5002553. Epub 2007 Sep 26.
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, Juni 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.
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.
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.
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. doi: 10.1016/j.ekir.2016.05.002. Epub 2016 Jun 11.
citation: Fernandez-Juarez G, Rojas-Rivera J, Logt AV, Justino J, Sevillano A, Caravaca-Fontan F, Avila A, Rabasco C, Cabello V, Varela A, Diez M, Martin-Reyes G, Diezhandino MG, Quintana LF, Agraz I, Gomez-Martino JR, Cao M, Rodriguez-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.