Rituximab in the First Episode of Paediatric Nephrotic Syndrome

Study Overview
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Brief Summary
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The study will be a randomized, open-label trial in children with the initial episode of SSNS and whose state of complete remission after received standard prednisolone, to determine whether rituximab (a single intravenous infusion of 375 mg/m2) would be noninferior to corticosteroid alone in maintaining complete disease remission during 12-month of follow-up.

Detailed Description
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The 12-month relapse-free survival rate is less than 30% in steroid-sensitive nephrotic syndrome (SSNS) children after the standard corticosteroid therapy, with approximately half becoming frequent relapsers or steroid dependent and necessitating the need for alternative immunosuppressive agents. The first relapse of SSNS most occurs within 6-12 months of onset, and contemporary cohorts suggest up to 16-42% of children with SSNS continue to have relapses in adulthood. Rituximab and rituximab biosimilar appear effective in reducing the relapse in children with frequent relapse or steroid dependent nephrotic syndrome. Accordingly, we hypothesize in paediatric SSNS, rituximab added to guideline-recommended corticosteroid therapy is noninferior to corticosteroid alone for maintaining remission for the first year of onset, expected to improve long-term outcomes. An open-label, single-arm, multicentre trial was performed at eight centers in China with a 12-month follow-up (NCT04783675). The study found that in children with the initial episode of SSNS, rituximab appears to be an effective and safe treatment for maintaining disease remission. The goal of this prospective study is to determine whether rituximab (a single intravenous infusion of 375 mg/m2) would be noninferior to corticosteroid alone in maintaining complete disease remission during 12-month of follow-up. The study will be a randomized, open-label, parallel group, in a 1:1 ratio, active controlled, multicenter trial.

Official Title
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Efficacy and Safety of Single-dose Rituximab Biosimilar in the Initial Episode of Paediatric Steroid-sensitive Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial

Conditions
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Steroid-Sensitive Nephrotic Syndrome

Intervention / Treatment
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* Drug: Rituximab
* Drug: Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children between 1 and 18 years with Steroid-Sensitive Nephrotic Syndrome (nephrotic-range proteinuria and either hypoalbuminemia or edema when albumin level is not available) Estimated glomerular filtration rate (eGFR) ≥90 ml/min per 1.73 m2 at study entry Remission at study entry the cluster of differentiation antigen 20 (CD20) positive cells in peripheral blood ≥1% total lymphocytes No immunosuppressive agents have been used within 3 months of enrolment, except for the use of corticosteroid to treat nephrotic syndrome Provision of consent by a legal representative using a document approved by the institutional review board after receiving an adequate explanation of this clinical trial. For children ages 8-18, written assent is required using age-appropriate and background-appropriate documents Exclusion Criteria: Diagnosis of secondary NS Patients showing one of the following abnormal clinical laboratories values: leukopenia (white blood cell count ≤3.0*109/L); moderate and severe anemia (hemoglobin <9.0g/dL); thrombocytopenia (platelet count <100*1012/ L); positivity of autoimmunity tests (ANA, Anti DNA antibody, ANCA) or reduced C3 levels; Alanine aminotransferase or aspartate aminotransferase > 2.5× upper limit of normal value Presence of severe or chronic infections within 6 months before assignment: tuberculosis or in whom tuberculosis is suspected; Epstein-Barr virus or cytomegalovirus; hepatitis B or hepatitis C or hepatitis B virus carrier, human immunodeficiency virus or other active viral infections Live vaccination within last month Patients with poorly controlled hypertension Patients with severe brain, heart, liver, and other important organs, as well as blood and endocrine system diseases Presence or history of autoimmune diseases, primary immunodeficiency, or tumor Patients with a known allergy to Rituximab and its excipients Assessed to be unfit for participation by the investigators (patients highly likely to be lost to follow-up or provide inaccurate data, for example, patients with alcohol or other substance misuse disorders, and patients with psychological disorders)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Rituximab<br>Rituximab (375 mg/m2) will be given as a single intravenous infusion after remission. The prednisolone at a dose of 2 mg/kg per day (maximum 60 mg in single or divided doses) for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks; therapy is then discontinued. | Drug: Rituximab<br>* Rituximab 375 mg/m2 added to guideline-recommended corticosteroid therapy<br>* Other names: rituximab biosimilar (HANLIKANG®, Shanghai Henlius Biotech, Inc. China);Drug: Corticosteroid<br>* guideline-recommended corticosteroid therapy<br>* Other names: prednisolone/prednisone;|
| Other: Routine Therapy<br>The prednisolone at a dose of 2 mg/kg per day (maximum 60 mg in single or divided doses) for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks; therapy is then discontinued. | Drug: Corticosteroid<br>* guideline-recommended corticosteroid therapy<br>* Other names: prednisolone/prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year relapse-free survival rate | The rate of no relapse within 1 year. Relapse definition: recurrence of nephrotic-range proteinuria, urine protein/creatinine ratio ≥2 mg/mg or dipstick ≥3+ on 3 consecutive days in the first morning samples. | 1-year after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to relapse (days) | Number of days from randomization to occurrence of first relapse. Relapse definition: recurrence of nephrotic-range proteinuria, urine protein/creatinine ratio ≥2 mg/mg or dipstick ≥3+ on 3 consecutive days in the first morning samples. | 1-year after randomization | 
| Peripheral blood T cell subsets | It is a repeat measured variable. Using fluorescence-activated cell sorting, peripheral blood T cells subsets will be studied as percentages and absolute counts. | At basline, 1,3,6,9,12 months after randomization | 
| Peripheral blood B cell subsets | It is a repeat measured variable. Using fluorescence-activated cell sorting, peripheral blood B cells subsets will be studied as percentages and absolute counts. | At basline, 1,3,6,9,12 months after randomization | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | It is a binary variable (1/0). The variable would be setted as 1 if any adverse events occurs including infusion- related reactions, infection (upper respiratory tract infection, hepatitis B virus reactivation, herpes zoster infection, pneumocystis pneumonia, etc), persistent hypogammaglobulinaemia, encephalopathy, severe neutropenia, fatal pulmonary fibrosis, ulcerative colitis, Crohn's disease and fulminant myocarditis etc. Adverse events will be graded according to the Common Terminology Criteria for Adverse Events | 1-year after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab, Children, Relapse