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Different Immunosuppressive Treatment in iMN

Primary Purpose

Idiopathic Membranous Nephropathy

Status
Recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Prednisone
Cyclophosphamide
Rituximab
Sponsored by
Peking Union Medical College Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Idiopathic Membranous Nephropathy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Peking Union Medical College HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

cyclophosphamide and prednisone

Rituximab

Arm Description

Prednisone will be given at 1mg/kg/d p.o. and will be tapered after 2 months and discontinued over a 6-12 month period. Cyclophosphamide will be given at 1-2mg/kg/d p.o. with a target accumulated dose of 12g. Azathioprine or mycophenolate mofetil are optional which could be given for a short period of time (<6 months)after discontinuation of cyclophosphamide if patients do not remit at 6 month.

Rituximab 1000mg I.V. on Day1 and at 6 month. After 6 months, in patients with response but without 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 given on the 15th day after each Rituximab infusion if CD19+ B cell count>5/ul on the 15th day. Calcineurin inhibitors (CNI) are optional but should be tapered after 6 months and discontinued after 9 months.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

complete or partial remission on 6, 12 and 18 month
complete or partial remission on 6, 12 and 18 month
complete remission on 6, 12, 18 and 24 month
complete remission on 6, 12, 18 and 24 month
time to complete or partial remission
time to complete or partial remission
change of estimated glomerular filtration rate (eGFR)
change of estimated glomerular filtration rate (eGFR) from baseline
serum creatinine increase ≥50 percent from baseline
proportion of patients with increase of serum creatinine ≥50 percent from baseline
rate of relapse
proportion of patients with relapse. Relapse is defined as development of urine protein >3.5g/24h following complete or partial remission.
anti-PLA2R levels
Auto-antibody to the M-type phospholipase A2 receptor (PLA2R)
CD19+ B cell count
CD19+ B cell count
Adverse events
Adverse events

Full Information

First Posted
February 4, 2021
Last Updated
April 18, 2022
Sponsor
Peking Union Medical College Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04745728
Brief Title
Different Immunosuppressive Treatment in iMN
Official Title
Different Immunosuppressive Treatment in Idiopathic Membranous Nephropathy: a Prospective Cohort
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 14, 2021 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking Union Medical College Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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)
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Membranous Nephropathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
cyclophosphamide and prednisone
Arm Type
Active Comparator
Arm Description
Prednisone will be given at 1mg/kg/d p.o. and will be tapered after 2 months and discontinued over a 6-12 month period. Cyclophosphamide will be given at 1-2mg/kg/d p.o. with a target accumulated dose of 12g. Azathioprine or mycophenolate mofetil are optional which could be given for a short period of time (<6 months)after discontinuation of cyclophosphamide if patients do not remit at 6 month.
Arm Title
Rituximab
Arm Type
Active Comparator
Arm Description
Rituximab 1000mg I.V. on Day1 and at 6 month. After 6 months, in patients with response but without 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 given on the 15th day after each Rituximab infusion if CD19+ B cell count>5/ul on the 15th day. Calcineurin inhibitors (CNI) are optional but should be tapered after 6 months and discontinued after 9 months.
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
1mg/kg/d p.o.which will be tapered after 2 months and discontinued over a 6-12 month period.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
CTX
Intervention Description
1-2mg/kg/d p.o. with a target accumulated dose of 12g.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
CD20 antibody
Intervention Description
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.
Primary Outcome Measure Information:
Title
complete or partial remission on 24 month
Description
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
Time Frame
24 months
Secondary Outcome Measure Information:
Title
complete or partial remission on 6, 12 and 18 month
Description
complete or partial remission on 6, 12 and 18 month
Time Frame
6, 12 and 18 months
Title
complete remission on 6, 12, 18 and 24 month
Description
complete remission on 6, 12, 18 and 24 month
Time Frame
6, 12, 18 and 24 months
Title
time to complete or partial remission
Description
time to complete or partial remission
Time Frame
from date of treatment until the date of first documented remission, up to 24 months
Title
change of estimated glomerular filtration rate (eGFR)
Description
change of estimated glomerular filtration rate (eGFR) from baseline
Time Frame
24 months
Title
serum creatinine increase ≥50 percent from baseline
Description
proportion of patients with increase of serum creatinine ≥50 percent from baseline
Time Frame
24 months
Title
rate of relapse
Description
proportion of patients with relapse. Relapse is defined as development of urine protein >3.5g/24h following complete or partial remission.
Time Frame
12, 18, 24 months
Title
anti-PLA2R levels
Description
Auto-antibody to the M-type phospholipase A2 receptor (PLA2R)
Time Frame
baseline and 3, 6, 9, 12, 18, 24 months
Title
CD19+ B cell count
Description
CD19+ B cell count
Time Frame
baseline and 3, 6, 9, 12, 18, 24 months
Title
Adverse events
Description
Adverse events
Time Frame
through the study completion until 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sanxi Ai
Phone
18811054896
Email
sanxiai@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Yan Qin
Email
qinyanbeijing@126.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yan Qin
Organizational Affiliation
Peking Union Medical College Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Peking Union Medical College Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sanxi Ai
Email
sanxiai@163.com
First Name & Middle Initial & Last Name & Degree
Yan Qin
Email
qinyanbeijing@126.com
First Name & Middle Initial & Last Name & Degree
Yan Qin
First Name & Middle Initial & Last Name & Degree
Qi Miao

12. IPD Sharing Statement

Citations:
PubMed Identifier
20110379
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.
Results Reference
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PubMed Identifier
27352623
Citation
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.
Results Reference
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PubMed Identifier
31269364
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.
Results Reference
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PubMed Identifier
28487395
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.
Results Reference
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PubMed Identifier
33166580
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.
Results Reference
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PubMed Identifier
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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. No abstract available.
Results Reference
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Different Immunosuppressive Treatment in iMN

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