Different Immunosuppressive Treatment in iMN

Idiopathic Membranous Nephropathy Clinical Trial

Official title:

Different Immunosuppressive Treatment in Idiopathic Membranous Nephropathy: a Prospective Cohort

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04745728
• Other study ID #: iMN cohort
• Status: Recruiting
• Phase: Phase 3
• Start date: April 14, 2021
• Est. completion date: March 2027

Study information

• Verified date: April 2022
• Source: Peking Union Medical College Hospital
• Contact: Sanxi Ai
• Phone: 18811054896
• Email: sanxiai[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to compare the 24 month remission of different immunosuppressive therapies in the treatment of idiopathic membranous nephropathy (iMN)

Description:

To date, the first-line immunosuppressive immunosuppressive therapy of iMN includes corticosteroids combined with cyclophosphamide or rituximab (RTX). In recent randomized trials (MENTOR, GEMRITUX), the long-term remission rate of RTX is about 60%, which is similar to the remission rate of cyclophosphamide combined with corticosteroids in early studies. But there is only one published randomized trial (STARMEN) comparing the efficacy of the two protocols head-to-head. In STRAMEN trial, the long-term remission rate of cyclophosphamide+corticosteroids group was 83%, which was significantly higher than the that (58%) of the tacrolimus-RTX group. But in STRAMEN trial, only one single dose of RTX was given which might influence the efficacy of the tacrolimus-RTX arm. Therefore, head-to-head comparison of RTX (more than one dose) and cyclophosphamide+corticosteroid is needed. The optimal dose of RTX in the treatment of iMN is unclear. In MENTOR trial, RTX was given 1g on D1 and D15, and the rate of complete remission at 6 month was 0, so RTX was repeated at 6 month. Based on the experience of our center, most patients need at least one repeated dose of RTX at 6 month.

Based on the previous rationale, the investigators designed this study to compare the efficacy of cyclophosphamide plus corticosteroids with RTX in the treatment of iMN.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: March 2027
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• idiopathic membranous nephropathy

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

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

• Angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for = 3 months with controlled blood pressure prior to beginning of immunosuppressive therapy or if patients are intolerant to ACEI/ARB.

• proteinuria =4g/24h and decreased = 50% from baseline

Exclusion Criteria:

• presence of active infection or a secondary cause of membranous nephropathy

• proteinuria associated with diabetic nephropathy

• pregnancy or breast feeding

• history of resistance to rituximab or alkylating agents or corticosteroid

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

Related Conditions & MeSH terms

• Glomerulonephritis, Membranous
• Idiopathic Membranous Nephropathy
• Kidney Diseases

Intervention

Drug:
• Prednisone
1mg/kg/d p.o.which will be tapered after 2 months and discontinued over a 6-12 month period.
• Cyclophosphamide
1-2mg/kg/d p.o. with a target accumulated dose of 12g.
• Rituximab
1000mg I.V. on D1 and at 6 month. After 6 month, in patients with response but not complete remission, Rituximab could be stopped or repeated with a 6 month-interval (12 month, 18 month, 24 month) until complete remission. Rituximab 1000mg I.V. will be repeated on the 15th day of each Rituximab infusion if CD19+ B cell count>5/ul.

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital

Country where clinical trial is conducted

China, 

References & Publications (6)

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. — View Citation

Dahan K, Johannet C, Esteve E, Plaisier E, Debiec H, Ronco P. Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody. Kidney Int. 2019 Jan;95(1):233-234. doi: 10.1016/j.kint.2018.08.045. — 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

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	complete or partial remission on 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 urine protein=50% plus urine protein =3.5g/24h but >0.5g/24h	24 months
Secondary	complete or partial remission on 6, 12 and 18 month	complete or partial remission on 6, 12 and 18 month	6, 12 and 18 months
Secondary	complete remission on 6, 12, 18 and 24 month	complete remission on 6, 12, 18 and 24 month	6, 12, 18 and 24 months
Secondary	time to complete or partial remission	time to complete or partial remission	from date of treatment until the date of first documented remission, up to 24 months
Secondary	change of estimated glomerular filtration rate (eGFR)	change of estimated glomerular filtration rate (eGFR) from baseline	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	rate of relapse	proportion of patients with relapse. Relapse is defined as development of urine protein >3.5g/24h following complete or partial remission.	12, 18, 24 months
Secondary	anti-PLA2R levels	Auto-antibody to the M-type phospholipase A2 receptor (PLA2R)	baseline and 3, 6, 9, 12, 18, 24 months
Secondary	CD19+ B cell count	CD19+ B cell count	baseline and 3, 6, 9, 12, 18, 24 months
Secondary	Adverse events	Adverse events	through the study completion until 24 months