Compare Efficacy and Safety of Repeated Courses of Rituximab to That of Maintenance Mycophenolate Mofetil Following Single Course of Rituximab Among Children With Steroid Dependent Nephrotic Syndrome

Study Overview
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Brief Summary
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The aim of the RITURNS II study is to evaluate the efficacy and safety of Repeat courses of Rituximab to that of maintenance Mycophenolate Mofetil following single course of Rituximab in maintaining remission over 24 months among Children with Steroid Dependent Nephrotic Syndrome (SDNS).

Detailed Description
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The vast majority of children with idiopathic nephrotic syndrome respond well to corticosteroid treatment. However, as many as 70% experience at least one relapse, and 30% develop a more complicated course with frequent relapses (FRNS) with or without steroid dependency (SDNS). Extended steroid exposure in these children often results in long-term complications. The management of patients with SDNS is challenging and expensive. Relapses may lead to serious complications, e.g. related to anasarca, hypertension, life threatening infections (peritonitis, pneumonia, meningitis), thrombosis and malnutrition. Repeated courses or even continuous steroid treatment lead to considerable medication related toxicity and morbidity. The goal of treatment is to reduce the rate of relapses, the cumulative dose of corticosteroids, and the incidence of serious complications. Various prospective studies suggest that Rituximab, a B cell depleting monoclonal antibody, could be a safe and effective alternative to steroid or immunosuppressants to achieve and maintain remission in this population. Single rituximab infusion have been shown to be efficacious for 6 to 12 months and the side effect profile observed to date is very benign but after 6-8 months there was relapse due to regeneration of B-lymphocytes, hence for maintenance of remission MMF has been considered. In spite of good initial response, rituximab responders always remain prone to further relapse with regeneration of B lymphocytes, necessitating either repeat course of rituximab or addition of another steroid-sparing immunosuppressant. Reports suggest efficacy of rituximab may vary depending on disease pathology, clinical course, and simultaneous use of other immunosuppressants. The aim of the RITURNS II study is to evaluate the efficacy and safety of Repeat courses of Rituximab to that of maintenance Mycophenolate Mofetil following single course of Rituximab in maintaining remission over 24 months among Children with Steroid Dependent Nephrotic Syndrome (SDNS).

Official Title
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Randomized Clinical Trial to Compare Efficacy and Safety of Repeated Courses of Rituximab to That of Maintenance Mycophenolate Mofetil Following Single Course of Rituximab in Maintaining Remission Over 24 Months Among Children With Steroid Dependent Nephrotic Syndrome

Conditions
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Steroid-Dependent Nephrotic Syndrome

Intervention / Treatment
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* Drug: Rituximab
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Children between 3 and 16 years with SDNS. Minimal Change disease/ FSGS/MesPGN as per Kidney Biopsy report. Estimated glomerular filtration rate (eGFR) >80 ml/min per 1.73 m2 at study entry. Remission at study entry (Urine albumin nil or trace (or proteinuria <4 mg/m2/h) for 3 consecutive early morning specimens). Not received any steroid sparing agent previously. Parents willing to give informed written and audiovisual consent. Ability to swallow tablet. Exclusion Criteria Known etiology (e.g., lupus erythematosus, IgA nephropathy, amyloidosis, malignancy, other secondary forms of NS). Patients with severe leukopenia (leukocytes <3.0× 1000 cells/mm3), severe anemia (haemoglobin <8.9 g/dl), thrombocytopenia (platelet <100.0 × 1000 cells/mm3) or deranged liver function tests (AST or ALT to >50 IU/L ) at enrolment. Known active chronic infection (tuberculosis, HIV, hepatitis B or C). Live vaccination within one month prior to screening.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 16 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: Repeated Courses of Rituximab Only<br>First course Course Rituximab at Randomization. Prophylactic 2nd and 3rd course rituximab re-administration will be done at 8 months and 16 months of follow-up if B cell count normalize. | Drug: Rituximab<br>* First course Course Rituximab at Randomization.<br>|
| Active Comparator: Rituximab and Mycophenolate Mofetil<br>First course Course Rituximab at Randomization. Addition of Maintenance Mycophenolate Mofetil from 4 Month onwards. | Drug: Rituximab<br>* First course Course Rituximab at Randomization.<br>Drug: Mycophenolate Mofetil<br>* Addition of Maintenance Mycophenolate Mofetil from 4 Month onwards<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the time to first relapse or death (whichever occurs first) till end of study (follow-up phase of 24 months) |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative prednisolone requirement (mg/kg/yr) over the first 12 and 24 months, respectively. |  | 12 and 24 months | 
| Number and severity of adverse events |  | 0-24 months | 
| Number of relapses within months 0-24, 0-12 and 12-24, respectively |  | months 0-24, 0-12 and 12-24 |