Different Immunosuppressive Treatment in iMN

Study Overview
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Brief Summary
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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
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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.

Official Title
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Different Immunosuppressive Treatment in Idiopathic Membranous Nephropathy: a Prospective Cohort

Conditions
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Idiopathic Membranous Nephropathy

Intervention / Treatment
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* Drug: Prednisone
* Drug: Cyclophosphamide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cyclophosphamide and prednisone<br>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. | Drug: Prednisone<br>* 1mg/kg/d p.o.which will be tapered after 2 months and discontinued over a 6-12 month period.<br>Drug: Cyclophosphamide<br>* 1-2mg/kg/d p.o. with a target accumulated dose of 12g.<br>* Other names: CTX;|
| Active Comparator: Rituximab<br>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. | Drug: Rituximab<br>* 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.<br>* Other names: CD20 antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| complete remission on 6, 12, 18 and 24 month | complete remission on 6, 12, 18 and 24 month | 6, 12, 18 and 24 months | 
| 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 | 
| change of estimated glomerular filtration rate (eGFR) | change of estimated glomerular filtration rate (eGFR) from baseline | 24 months | 
| serum creatinine increase ≥50 percent from baseline | proportion of patients with increase of serum creatinine ≥50 percent from baseline | 24 months | 
| 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 | 
| anti-PLA2R levels | Auto-antibody to the M-type phospholipase A2 receptor (PLA2R) | baseline and 3, 6, 9, 12, 18, 24 months | 
| CD19+ B cell count | CD19+ B cell count | baseline and 3, 6, 9, 12, 18, 24 months | 
| Adverse events | Adverse events | through the study completion until 24 months |