Rituximab or Cyclophosphamide Combined With Steroids in Idiopathic Membranous Nephropathy

Study Overview
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Brief Summary
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This wasa prospective, multicenter, randomized, controlled trial. Patients with idiopathic membranous nephropathy (IMN) were randomly divided into intervention or control group. Intervention group was given rituximab combined with steroid in induction therapy. After 6 months, patients in the rituximab treatment group who had decreased 24h urinary protein by >25% but did not achieve CR were given rituximab maintenance therapy. Patients in control group were treated with cyclophosphamide combined with prednisolone.The response rate at 24 months (including the proportion of participants with complete and partial responses at 24 months after enrollment) was measured.

Detailed Description
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Study design A randomized, controlled, multicenter clinical study Outcomes Primary objective To evaluate the efficacy of rituximab or cyclophosphamide combined with steroids in the treatment of idiopathic membranous nephropathy Secondary Objectives The safety of rituximab or cyclophosphamide combined with steroids in idiopathic membranous nephropathy; Primary outcome The response rate at 24 months (including the proportion of participants with complete and partial responses at 24 months after enrollment); Secondary outcomes Response rates at 6 and 12 months (including the proportion of participants with complete response, near-complete response, and partial response at 6 and 12 months after enrollment); The proportion of patients without recurrence at 12 months and 24 months; The median recurrence time; Recurrence frequency; Cumulative dose of glucocorticoid; CD19+ cell count, anti-PLA2R antibody expression level; Incidence of adverse events; Study population 72 patients,male or female, with idiopathic membranous nephropathy (IMN), 36 in each arm. Description of the study intervention Intervention group: rituximab combined with steroid treatment group: 36 cases. The patients were pretreated with diphenhydramine and dexamethasone 30-60 minutes before rituximab infusion. Induction therapy: Rituximab iv infusion 1g, d1, d15, additional glucocorticoid treatment, oral prednisolone, initial dose 0.5mg/(KGD), once a day, after 8 weeks of treatment, reduced by 5mg every 2-4 weeks, until 0.25mg/kg, this dose was maintained for 8 weeks, then reduced by 2.5mg every 2-4 weeks, until drug withdrawal, The course of treatment was about 24 weeks; - Maintenance therapy after 6 months: Patients who achieved CR did not need maintenance therapy; Patients whose 24-hour proteinuria decreased by >25% but did not achieve CR were given an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count). Patients whose 24-hour proteinuria decreased less than 25% did not need to continue drug treatment, and were considered as treatment failure and withdrawn from the trial. Control group: Treated with Italian protocol, namely cyclophosphamide-steroid alternating cycle treatment,36 cases. - Treatment regimen: Methylprednisolone 0.5-1.0 g/d was given intravenously for the first 3 days of month 1, 3, and 5, followed by oral prednisone 0.5mg/(kg·d) for 27 days, and cyclophosphamide 2.0mg/(kg·d) for 30 days at month 2, 4, and 6. -Maintenance therapy after 6 months: Patients who achieved CR or whose 24h urinary protein decreased by >25% but did not achieve CR did not need maintenance treatment, and were followed up. Patients with 24h proteinuria decreased less than 25% did not need to continue to use drugs, and were considered as treatment failure and withdrawn from the trial. Duration of study: The entire clinical study duration was 36 months from the date of program initiation. Duration of visits: Long-term follow-up

Official Title
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Clinical Study of Rituximab or Cyclophosphamide Combined With Steroids in the Treatment of Idiopathic Membranous Nephropathy

Conditions
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Idiopathic Membranous Nephropathy

Intervention / Treatment
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* Drug: Rituximab
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18-75 years; Patients diagnosed as idiopathic membranous nephropathy (IMN) by renal biopsy within 24 months before enrollment; (3) Proteinuria > 3.5g/d for 3 consecutive days (once a week for 3 consecutive weeks); 4, serum albumin < 35 g/L; 5, assess glomerular filtration rate (eGFR) ≥30ml/min/1.73m2(calculated according to CKD-EPI formula); 6, ACEI or ARB treatment for at least 2 months, blood pressure <140/90 MMHG; 7, if female, must be postmenopausal or postoperative infertility or use of medical contraception (considering the potential risk of thromboembolism in patients with kidney disease); 8, the subject voluntarily signed the informed consent; Exclusion Criteria: Patients with type 1 diabetes or type 2 diabetes and diabetic nephropathy; Patients with secondary membranous nephropathy and any active infections (such as hepatitis B and C, systemic lupus erythematosus, drug therapy, malignancy, and other secondary causes, should be tested for HIV, hepatitis B, and C before enrollment); Previous treatment with rituximab, steroids, alkylating agents, calcineurin inhibitors, synthetic ACTH, mycophenolate mofetil (MMF), and azathioprine; Receipt of any other study medication (within the last month); Allergies or a history of allergies to any known interventional drug or any of its components (including excipients); Resistance to rituximab or cyclophosphamide; Presence of active infection; A history of immunodeficiency, including other acquired or congenital immunodeficiency diseases, or organ transplantation; Pregnancy or lactation; 10, a history of mental illness; 11, laboratory tests meeting the following criteria need to be excluded: （1） Hemoglobin <80g/L; （2） Platelet < 80 x 109/ L; （3） Neutrophil < 1.0×109/ L; （4） Aspartate aminotransferase (AST) or amino acid aminotransferase (ALT) >2.5× upper limit of normal except in relation to the primary disease; 12. Any patient judged by the investigator to be ineligible for enrollment in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: Intervention arm<br>Rituximab combined with steroid treatment group | Drug: Rituximab<br>* Induction therapy: Rituximab iv infusion 1g, d1, d15, additional glucocorticoid treatment, oral methylprednisolone, initial dose 0.5mg/(KGD), once a day, after 8 weeks of treatment, reduced by 5mg every 2 4 weeks, until 0.25mg/kg, this dose was maintained for 8 weeks, then reduced by 2.5mg every 2 4 weeks, until drug withdrawal, The course of treatment was about 24 weeks; Maintenance therapy after 6 months Patients who achieved CR did not need maintenance therapy; Patients whose 24-hour proteinuria decreased by >25% but did not achieve CR were given an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count). Patients whose 24-hour proteinuria decreased less than 25% did not need to continue drug treatment, and were considered as treatment failure and withdrawn from the trial.<br>* Other names: Intervention arm;|
| Active Comparator: Control arm<br>Cyclophosphamide-steroid alternating cycle treatment | Drug: Cyclophosphamide<br>* Control group (treated with Italian protocol, namely cyclophosphamide-steroid alternating cycle treatment) : - Treatment regimen: Methylprednisolone 0.5-1.0 g/d was given intravenously for the first 3 days of month 1, 3, and 5, followed by oral prednisone 0.5mg/(kg·d) for 27 days, and cyclophosphamide 2.0mg/(kg·d) for 30 days at month 2, 4, and 6. -Maintenance therapy after 6 months: Patients who achieved CR or whose 24h urinary protein decreased by >25% but did not achieve CR did not need maintenance treatment, and were followed up. Patients with 24h proteinuria decreased less than 25% did not need to continue to use drugs, and were considered as treatment failure and withdrawn from the trial.<br>* Other names: Control arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The response rate at 24 months | including the proportion of participants with complete and partial responses at 24 months after enrollment | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates at 6 and 12 months | Including the proportion of participants with complete response, near-complete response, and partial response at 6 and 12 months after enrollment | up to 12 months | 
| The proportion of patients without recurrence | The proportion of patients without recurrence at 12 months and 24 months | up to 24 months | 
| The median recurrence time | The median recurrence time | Through study completion, an average of 2 years | 
| Recurrence frequency | Recurrence frequency of the patients | Through study completion, an average of 2 years | 
| CD19+ cell count, anti-PLA2R antibody expression level | CD19+ cell count, anti-PLA2R antibody expression level | Through study completion, an average of 2 years | 
| Incidence of adverse events | Incidence of adverse events | Through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rituximab, idiopathic membranous nephropathy, cyclophosphamide, steroids, remission