Study of Rituximab Monotherapy on Children With New-onset Nephrotic Syndrome: A Randomized Controlled Trial

Study Overview
=================
Brief Summary
-----------------
The main objective is to evaluate the effectiveness of Rituximab monotherapy versus steroid therapy on children with new-onset nephrotic syndrome within the 52-week follow-up.

Detailed Description
-----------------
Nephrotic syndrome(NS) -------the most common glomerular disease in children. Steroid, as the mainstream therapy for decades, many patients suffer from adverse effects of it, such as growth impacted, fat, and glaucoma.There is a urgent need for Steroid-sparing therapy. Rituximab, as a chemical monoclonal antibody against the cluster of differentiation antigen 20(CD20), has proved to be effective in patients with frequent-relapse/steroid-dependent NS. It has also been reported to be effective in six adult patients with new-onset NS. Rituximab mono-therapy in new-onset pediatric NS patients is still unclear.

Official Title
-----------------
Study of Rituximab Monotherapy VS Steroid Therapy on Children With New-onset Nephrotic Syndrome: A Randomized Controlled Trial

Conditions
-----------------
Nephrotic Syndrome in Children, Rituximab

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Steroid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: New-onset idiopathic nephrotic syndrome Glomerular filtration rate (eGFR) ≥90 ml/min per 1.73 m2 at study entry. Exclusion Criteria: Glomerular hematuria: Urine red blood cell counts≥ 10/high power field(HP), ≥ 3 times within 2 weeks; Continuous hypocomplementaemia(< 0.9g/L) ; Repeated or persistent Hypertension(systolic and/or diastolic blood pressures measured greater than the 95th percent of blood pressure in children matching sex, age and height ≥3 different time points) Diagnosis of secondary NS, such as secondary to Systemic Lupus Erythematosus, Immunoglobulin A Vasculitis(IgAV), diabetes, Hepatitis B virus(HBV) infection, etc. Complicated with other kidney diseases, such as multiple renal cysts, ANCA vasculitis, urinary system abnormalities, etc; With a family history of nephrotic syndrome, chronic glomerulonephritis, uremia, or other kidney diseases; Other monogenic genetic diseases known as the effect the condition of nephrotic syndromes, such as Wilms' tumor 1(WT1), NPHS2, LAMB2, PLCE1, etc. Congenital or acquired immunodeficiency, or patients with active tuberculosis, active Epstein-Barr virus and cytomegalovirus(CMV), acute hepatitis B, hepatitis C, HIV infection, deep fungal infection or other active infections. Laboratory indicators were abnormal, such as moderate or severe neutropenia(≤1000/μL)， moderate or severe anemia(hemoglobin<9.0g/dL), Thrombocytopenia (platelet count<100* 10^12/L) or with abnormal hepatic function (Alaninetransaminase(ALT), aspartate Aminotransferase(AST) or bilirubin >2.5*upper limit of normal value and continue to increase for 2 weeks); Steroid or immunosuppressive medicine for other diseases within 3 months, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, tripterygium wilfordii, etc. With tumor, severe cardiac failure, severe hepatologic diseases, hematological diseases, or other severe system diseases. Patients who are known to be allergic to rituximab; History of transplantation, excluding cornea or hair transplantation; The attenuated live vaccine was inoculated within 1 month before enrollment; Patients who participated in other clinical trials within three months before enrollment; Patients are not suitable for inclusion in the trial by any investigator.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 Group<br>Rituximab dose: 4 doses of 375 mg/m2 rituximab at 1-week intervals( within +7 days). | Drug: Rituximab<br>* Rituximab dose: 4 doses of 375 mg/m2 rituximab at 1-week intervals( within +7 days), associated with trimethoprim-sulfamethoxazole(25-50 mg/kg/day orally twice per day, 3 days per week. If the patient is not allergic) for three months from the first rituximab dosing date(Day 1). Four doses of rituximab are necessary whether the patient achieves complete remission.<br>|
| Active Comparator: Steroid Group<br>Daily oral prednisone/prednisolone 2 mg/kg/d (maximum 60 mg/d) for 6 weeks followed by alternate day prednisone/prednisolone, 1.5 mg/kg (maximum of 50 mg), for other 6 weeks. | Drug: Steroid<br>* Daily oral prednisone/prednisolone 2 mg/kg/d (maximum 60 mg/d) for 6 weeks followed by alternate day prednisone/prednisolone, 1.5 mg/kg (maximum of 50 mg), for other 6 weeks. Vitamin D and calcium(adjusted according to the blood calcium level) were administered for three months.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival time(day) after first complete remission | The time from complete remission to the first relapse during the whole 52-week follow-up in patients who achieve complete remission within 6 weeks. In order to evaluate the remission, all the participants will document their proteinuria. Relapse is defined by first-morning urine dipstick ≥3+ on three or more consecutive days, 24-h PCR≥2.0g/g, or 24-h urine protein ≥ 50mg/kg, with or without edema after complete remission(KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). Complete remission is defined by the first morning or 24h PCR ≤ 0.2g/g (or negative or trace dipstick) on three or more consecutive occasions(KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). | From complete remission to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission of nephrotic syndrome | Complete remission is defined by the first morning or 24h PCR ≤ 0.2g/g (or negative or trace dipstick) on three or more consecutive occasions (KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). It will be recorded as 1 when patients achieve complete remission, or as 0. | From admission day to 6 weeks | 
| Inefficiency of nephrotic syndrome | Inefficiency is defined as patients still have nephrotic-range proteinuria(first-morning urine dipstick ≥3+dipstick, 24-h PCR≥2.0g/g, or 24-h urine protein ≥ 50mg/kg) after 6-week treatment. | From admission day to 6 weeks | 
| The time(day) to first complete remission | The time(day) from the first medicine administration to complete remission within 6 weeks.Complete remission is defined by the first morning or 24h PCR ≤ 0.2g/g (or negative or trace dipstick) on three or more consecutive occasions (KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). | From admission day to 6 weeks | 
| Relapse of nephrotic syndrome | Relapse is defined as patients who have first-morning urine dipstick ≥3+ on three or more consecutive days, 24-h PCR≥2.0g/g, or 24-h urine protein ≥ 50mg/kg, with or without edema after complete remission(KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases). It will be recorded as 1 when patients have a relapse, or as 0. | From admission day to 52 weeks | 
| Cumulative prednisone dosage of each individual (milligrams per kilogram per year) | The total dosage of prednisone for each individual from the beginning to the end of the trial. | From admission day to 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rituximab, Glucocorticosteroids