Efficacy and Safety of Single-dose Zuberitamab in the Initial Episode of Paediatric Steroid-sensitive Nephrotic Syndrome: A Multicenter Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 120
- 试验地点
- 9
- 主要终点
- Relapse-free survival time within 12 months after randomization
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Zuberitamab + Standard corticosteroid treatment
Zuberitamab plus standard corticosteroid treatment: Zuberitamab 375 mg/m2 (max 500 mg) as a single IV dose after remission. Premedication 30 min prior includes oral antipyretic and antihistamine and IV methylprednisolone 1.6 mg/kg (max 48 mg); oral steroid withheld on infusion day. Standard corticosteroid treatment consists of oral prednisone/prednisolone per protocol taper. TMP-SMZ prophylaxis (TMP 3 mg/kg on alternate days, max SMZ 960 mg) is administered until CD19 recovery. Relapse is managed per protocol with corticosteroid re-induction and possible repeat zuberitamab after remission. Permitted and prohibited concomitant medications are the same as in the comparator arm.
干预措施: standard corticosteroid treatment (Drug)
Standard corticosteroid treatment Only
Standard corticosteroid treatment: oral prednisone/prednisolone 2 mg/kg/day (max 60 mg) for 6 weeks, followed by 1.5 mg/kg (max 40 mg) on alternate days for 6 weeks, then discontinue. No zuberitamab, TMP-SMZ prophylaxis, or infusion premedication is given during initial treatment. Relapse is managed per protocol with corticosteroid re-induction; participants may receive zuberitamab after remission is re-achieved according to predefined criteria. Permitted concomitant medications include antihypertensives, calcium supplementation, anti-infective agents, antihistamines, anticoagulants, IVIG, hepatoprotective agents, glucose-lowering medications, and ophthalmic treatments. Prohibited therapies include other immunosuppressants (rituximab, CNIs, MMF, cyclophosphamide, plasma exchange) and Chinese herbal medicines for nephrotic syndrome (e.g., Huangkui, Huaiqihuang, Tripterygium). Live vaccines are prohibited during B-cell depletion.
干预措施: standard corticosteroid treatment (Drug)
Zuberitamab + Standard corticosteroid treatment
Zuberitamab plus standard corticosteroid treatment: Zuberitamab 375 mg/m2 (max 500 mg) as a single IV dose after remission. Premedication 30 min prior includes oral antipyretic and antihistamine and IV methylprednisolone 1.6 mg/kg (max 48 mg); oral steroid withheld on infusion day. Standard corticosteroid treatment consists of oral prednisone/prednisolone per protocol taper. TMP-SMZ prophylaxis (TMP 3 mg/kg on alternate days, max SMZ 960 mg) is administered until CD19 recovery. Relapse is managed per protocol with corticosteroid re-induction and possible repeat zuberitamab after remission. Permitted and prohibited concomitant medications are the same as in the comparator arm.
干预措施: Zuberitamab (Biological)
结局指标
主要结局
Relapse-free survival time within 12 months after randomization
时间窗: From randomization until first relapse or 12 months after randomization, whichever occurs first.
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.
次要结局
- Relapse-Free Survival Rate at 12 Months Post-Randomization(12 months post-randomization.)
- Relapse-Free Survival Rate at 6 Months Post-Randomization(6 months post-randomization.)
- Cumulative Steroid Dose at 12 Months Post-Randomization(12 months post-randomization.)
- Change From Baseline in Serum Creatinine (Renal Function) at 12 Months(From baseline to 12 months post-randomization.)
- Change From Baseline in Serum Creatinine at the Time of Relapse(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(From baseline to 12 months post-randomization)
- Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scores at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scores at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Systolic Blood Pressure Z-scores at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in systolic Blood Pressure Z-scores at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in diastolic Blood Pressure Z-scores at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in diastolic Blood Pressure Z-scores at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Height Z-scores at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Height Z-scores at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Weight Z-scores at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Weight Z-scores at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Laboratory Blood Parameters (Hemoglobin) at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Laboratory Blood Parameters (Hemoglobin Levels) at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Laboratory Blood Parameters (Serum Albumin) at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Laboratory Blood Parameters (Serum Albumin) at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Change From Baseline in Laboratory Blood Parameters (Total Cholesterol) at 12 Months(From baseline to 12 months post-randomization)
- Change From Baseline in Laboratory Blood Parameters (Total Cholesterol) at the Time of Relapse(From baseline to the date of documented disease relapse (up to 12 months))
- Time to CD19+ B-Cell Recovery(From baseline to 12 months post-randomization)
- T-cell Immunophenotyping(Baseline, 1 month, 3 months, 6 months and 12 months after randomization.)
- B-cell Immunophenotyping(Baseline, 1 month, 3 months, 6 months and 12 months after randomization.)
- Cytokine Profiling(Baseline, 1 month, 3 months, 6 months and 12 months after randomization.)
- Incidence and Severity of Adverse Events (AEs)(From randomization through study completion, up to 12 months.)