Zuberitamab in the First Episode of Paediatric Nephrotic Syndrome

Phase 3Not Yet RecruitingNCT07765914

Children's Hospital of Fudan University120 enrolled

Overview

The goal of this clinical trial is to learn whether adding Zuberitamab to standard corticosteroid therapy can help prevent relapse in children and adolescents aged 1 to 18 years with newly diagnosed steroid-sensitive nephrotic syndrome (SSNS). It will also learn about the safety of Zuberitamab. The main questions it aims to answer are: * Does Zuberitamab plus standard corticosteroid therapy prolong the time to first relapse compared with standard corticosteroid therapy alone? * What medical problems do participants experience during treatment? Researchers will compare Zuberitamab plus standard corticosteroid therapy to standard corticosteroid therapy alone to see whether adding Zuberitamab improves disease control. Participants will: * Receive standard corticosteroid treatment for approximately 12 weeks, with or without a single intravenous infusion of Zuberitamab after achieving remission * Take preventive antibiotics if they are in the Zuberitamab group * Test their urine daily at home using dipsticks and record results in a diary * Visit the clinic for regular checkups and blood and urine tests during follow-up for up to 12 months

Primary nephrotic syndrome (PNS) is the most common glomerular disease in children. Although 80-90% of affected children achieve complete remission after initial corticosteroid therapy and are classified as having steroid-sensitive nephrotic syndrome (SSNS), most experience disease relapse within the first year after onset. Approximately half subsequently develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), requiring prolonged exposure to corticosteroids and additional immunosuppressive agents. Recurrent relapses and long-term immunosuppressive treatment are associated with substantial morbidity, including infection, impaired growth and development, metabolic complications, nephrotoxicity, and reduced quality of life. B-cell depletion therapy has emerged as an effective strategy for relapsing nephrotic syndrome. Rituximab, an anti-CD20 monoclonal antibody, has demonstrated the ability to reduce relapse rates and maintain remission in children with FRNS/SDNS, even after withdrawal of corticosteroids and other immunosuppressive agents. Based on accumulating evidence, rituximab has been incorporated into international treatment guidelines. Building upon extensive clinical experience with rituximab, our group initiated an investigator-sponsored multicenter study evaluating early rituximab treatment in children with newly diagnosed SSNS. Long-term follow-up from this study suggested potential benefits in preventing relapse and demonstrated an acceptable safety profile. Zuberitamab is a next-generation anti-CD20 monoclonal antibody developed through molecular engineering of rituximab. Compared with rituximab, preclinical studies have demonstrated enhanced antibody-dependent cellular cytotoxicity (ADCC), a larger steady-state volume of distribution, and more sustained B-cell depletion. Zuberitamab was approved in China in 2023 for the treatment of CD20-positive diffuse large B-cell lymphoma. In addition, its use in kidney diseases has been reported in retrospective cohort studies and other early clinical experiences, including patients with membranous nephropathy. However, evidence regarding its efficacy and safety in glomerular diseases, particularly in paediatric nephrotic syndrome, remains limited. Current treatment strategies for childhood nephrotic syndrome primarily focus on managing relapses after they occur rather than preventing them during the early phase of disease. Whether early intervention with a potent anti-CD20 monoclonal antibody can modify the disease course and reduce future relapses remains uncertain. This study is designed to evaluate the efficacy and safety of early Zuberitamab administration in combination with standard corticosteroid therapy in children with newly diagnosed steroid-sensitive nephrotic syndrome. This is a multicenter, open-label, randomized controlled trial conducted across nine pediatric nephrology centers in China. Children with newly diagnosed steroid-sensitive nephrotic syndrome (SSNS) who achieve remission following standard corticosteroid treatment will be randomized at weeks 4-5 after remission to receive either Zuberitamab plus standard corticosteroid treatment or standard corticosteroid treatment alone. Participants will be followed prospectively for up to 12 months to assess disease relapse, cumulative corticosteroid exposure, safety outcomes, kidney function, and health-related quality of life. The study aims to determine whether early addition of Zuberitamab at weeks 4-5 after remission, compared with standard corticosteroid treatment alone, can prolong time to first relapse within 12 months.

Interventions

ZuberitamabBIOLOGICAL

Zuberitamab is administered as a single intravenous infusion at a dose of 375 mg/m² (maximum 500 mg) following achievement of steroid-sensitive remission. To reduce the risk of infusion-related reactions, premedication is administered approximately 30 minutes before infusion and may include: * Acetaminophen or ibuprofen; * Cetirizine, cyproheptadine, loratadine, or equivalent antihistamines; * Intravenous methylprednisolone 1.6 mg/kg (maximum 48 mg). Participants receiving zuberitamab also receive prophylactic trimethoprim-sulfamethoxazole (TMP 3 mg/kg every other day; maximum SMZ dose 960 mg every other day) until B-cell recovery. Infusion-related reactions are managed according to protocol-defined procedures, including infusion rate reduction, temporary interruption, permanent discontinuation when clinically indicated, and appropriate supportive therapy.

standard corticosteroid treatmentDRUG

standard corticosteroid treatment administered orally to treat steroid-sensitive nephrotic syndrome: 6 weeks at 2 mg/kg (max 60 mg/day), then alternate day steroid 1.5 mg/kg (max 40 mg on alternate days) for 6 weeks.

Eligibility

Sex: ALLMin age: 1 YearMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Newly diagnosed steroid-sensitive nephrotic syndrome (SSNS) according to the 2023 IPNA criteria, who achieved complete remission after steroid induction therapy prior to study entry, defined as UPCR (based on first morning void or 24 h urine sample) \<= 20 mg/mmol (0.2 mg/mg), or negative or trace dipstick on three or more consecutive days. * An estimated glomerular filtration rate \>= 90 mL/min/ 1.73 m2 at study entry. * Peripheral blood CD20+ (detected as CD19+) cells \>= 1% of total lymphocytes. * No use of other immunosuppressants within 3 months prior to study entry, other than steroids for nephrotic syndrome. Exclusion Criteria: * Known etiology including congenital nephrotic syndrome, IgA nephropathy, Henoch-Schönlein purpura nephritis, lupus nephritis, or other secondary nephrotic syndromes. * Patients exhibiting any of the following abnormal clinical laboratory values: leukopenia (white blood cells \<= 3.0 × 10\^9/L), absolute neutrophil count \< 1.5 × 10\^9/L; moderate to severe anemia (hemoglobin \< 9.0 g/dL); thrombocytopenia (platelet count \< 100 × 10\^12/L); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 times the upper limit of normal; positive for any autoimmune markers (ANA, ENA, ANCA, etc.) or decreased complement C3 levels. * Evidence of the following infections: severe or opportunistic infection within the previous 6 months (active tuberculosis or history of tuberculosis or suspected tuberculosis; chronic active infections such as EBV, CMV; active hepatitis B presentation or history, or hepatitis C or hepatitis B virus carrier; HIV infection; or other active viral infections). * Receipt of live vaccine within one month prior to study entry. * History of previous use of biological agents. * Current examination suggestive of heart failure, severe arrhythmia, angina pectoris (CTCAE Grade 4), or uncontrolled blood pressure. * Severe diseases of vital organs such as the brain or liver, or suffering from hematological or endocrine system disorders. * Diagnosis of co-existing autoimmune diseases, primary immunodeficiency, or malignancy. * History of organ transplantation (excluding cornea and hair transplants). * Known allergy to methylprednisolone, Zuberitamab injection active ingredients or any excipients, sulfamethoxazole (or a contraindication to this drug due to G6PD deficiency). * Investigator's judgment that the patient is unsuitable for participation in this study (e.g., patient is highly likely to be lost to follow-up or provide false results, such as alcohol dependence or psychiatric illness).

Locations (9)

Children's Hospital of Fudan University

Shanghai, Shanghai Municipality, China

Second Xiangya Hospital of Central South University

Changsha, China

Guiyang Maternal and Child Health Care Hospital

Guiyang, China

Shanghai Children's Hospital

Shanghai, China

Shanghai Children's Medical Center

Shanghai, China

Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Shanghai, China

Wuhan Children's Hospital

Wuhan, China

Wuxi Women's & Children's Hospital

Wuxi, China

Xiamen Maternity & Child Care Hospital

Xiamen, China

Outcomes

Primary Outcomes

Relapse-free survival time within 12 months after randomization

Time from randomization to the first confirmed disease relapse during the 12-month follow-up period. Participants without relapse will be censored at the date of the last available assessment. Relapse is defined according to the 2023 International Pediatric Nephrology Association (IPNA) criteria as urine dipstick protein ≥3+ (≥300 mg/dL) or urine protein-to-creatinine ratio (UPCR) ≥200 mg/mmol (≥2 mg/mg) on a spot urine sample for three consecutive days, with or without edema, in a participant who previously achieved complete remission.

Time frame: From randomization until first relapse or 12 months after randomization, whichever occurs first.

Secondary Outcomes

Relapse-Free Survival Rate at 12 Months Post-Randomization

The proportion of participants who remain free from disease relapse at 12 months after randomization.

Time frame: 12 months post-randomization.

Relapse-Free Survival Rate at 6 Months Post-Randomization

The proportion of participants who remain free from disease relapse at 6 months after randomization.

Time frame: 6 months post-randomization.

Cumulative Steroid Dose at 12 Months Post-Randomization

The total amount of steroid medication (prednisolone) taken by participants from randomization until 12 months.

Time frame: 12 months post-randomization.

Change From Baseline in Serum Creatinine (Renal Function) at 12 Months

Change from baseline in serum creatinine levels to assess renal function.

Time frame: From baseline to 12 months post-randomization.

Change From Baseline in Serum Creatinine at the Time of Relapse

Change from baseline in serum creatinine levels measured at the acute phase of disease relapse.

Time frame: From baseline to the date of documented disease relapse (up to 12 months).

Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 12 Months

Change from baseline in eGFR, calculated using an appropriate pediatric formula (e.g., the modified Schwartz formula), to assess renal function.