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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Idiopathic Membranous Nephropathy

Intervention / Treatment
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* Drug: Rituximab
* Drug: cyclosporine


Participation Criteria
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Eligibility Criteria
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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.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab monotherapy<br>Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to the CD19+ B cells count. | Drug: Rituximab<br>* 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.<br>* Other names: CD20 antibody;|
| Experimental: Rituximab combined with cyclosporine<br>Rituximab 1000mg I.V. on Days 1 and 181, and will be retreated or not on Days 15 and 195 according to CD19+ B cells count. cyclosporine (CsA) will be started at a dose of 3mg/kg/day p.o. divided into 2 equal doses given at 12 hour intervals. Doses of CsA will be adjusted according to the blood levels of CsA. CsA will be tapered after 6 months and discontinued over a 3 month period. | Drug: Rituximab<br>* 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.<br>* Other names: CD20 antibody;Drug: cyclosporine<br>* 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.<br>* Other names: CsA;|

What is the study measuring?
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Primary Outcome Measures

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Change of estimated glomerular filtration rate (eGFR) | Change of eGFR from baseline to 24 months | 24 months | 
| Serum creatinine increase≥50 percent from baseline | proportion of patients with increase of serum creatinine ≥50 percent from baseline | 24 months | 
| 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 | 
| Anti-PLA2R titer | Auto-antibodies to the M-type phospholipase A2 receptor(PLA2R) | baseline and 3, 6, 9, 12, 18, 24 months | 
| The number of CD19+B cells | CD19+ B cells | baseline and 3, 6, 9, 12, 18, 24 months | 
| 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 | 
| Adverse events | adverse events | through study completion until 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab, cyclosporine, idiopathic membranous nephropathy