The Safety and Efficacy of Eculizumab for High-risk Transplant-associated Thrombotic Microangiopathy.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 8
- 主要终点
- 6-month overall survival rate after diagnosis of TA-TMA
研究概览
简要总结
High-risk, complement-mediated, untreated transplant-associated thrombotic microangiopathy (hrTA-TMA) carries a very poor prognosis due to multiple organ dysfunction syndrome (MODS). The complement C5 inhibitor eculizumab has shown promising efficacy in children with hrTA-TMA, but has not been prospectively studied in adult allogeneic hematopoietic stem cell transplantation (HSCT) recipients. The investigators plan to conduct the first multicenter prospective study in adults to evaluate eculizumab as an early targeted intervention for hrTA-TMA. The investigators hypothesize that eculizumab will more than double the survival rate of hrTA-TMA in adult HSCT recipients compared with untreated hrTA-TMA patients from our previous study, who will serve as historical controls. Inclusion criteria are a confirmed diagnosis of TA-TMA with at least one of the following hrTA-TMA features: random urine protein-to-creatinine ratio (rUPCR) ≥2 mg/mg, multiple organ dysfunction syndrome (MODS), or elevated plasma IL-10 (≥2× upper limit of normal). The primary endpoint is survival at 6 months after diagnosis of hrTA-TMA. Secondary endpoints are the cumulative incidence of MODS at 6 months after diagnosis of hrTA-TMA, and 1-year post-transplant survival. The eculizumab regimen consists of an intensive loading dose, an induction dose, and a maintenance dose, with a total treatment duration of up to 24 weeks. This study aims to investigate the safety and efficacy of eculizumab in the treatment of high-risk TA-TMA.
详细描述
High-risk, complement-mediated, untreated transplant-associated thrombotic microangiopathy (hrTA-TMA) carries a very poor prognosis due to multiple organ dysfunction syndrome (MODS). The complement C5 inhibitor eculizumab has shown promising efficacy in children with hrTA-TMA, but has not been prospectively studied in adult allogeneic hematopoietic stem cell transplantation (HSCT) recipients. The investigators plan to conduct the first multicenter prospective study in adults to evaluate eculizumab as an early targeted intervention for hrTA-TMA. The investigators hypothesize that eculizumab will more than double the survival rate of hrTA-TMA in adult HSCT recipients compared with untreated hrTA-TMA patients from our previous study, who will serve as historical controls. Inclusion criteria are a confirmed diagnosis of TA-TMA with at least one of the following hrTA-TMA features: random urine protein-to-creatinine ratio (rUPCR) ≥2 mg/mg, multiple organ dysfunction syndrome (MODS), or elevated plasma IL-10 (≥2× upper limit of normal). The primary endpoint is survival at 6 months after diagnosis of hrTA-TMA. Secondary endpoints are the cumulative incidence of MODS at 6 months after diagnosis of hrTA-TMA, and 1-year post-transplant survival. The eculizumab regimen consists of an intensive loading dose, an induction dose, and a maintenance dose, with a total treatment duration of up to 24 weeks. This study aims to investigate the safety and efficacy of eculizumab in the treatment of high-risk TA-TMA.
Dosing Regimen
Weight-based induction therapy:
Eculizumab 10-<40 kg: 600 mg
- 40 kg: 900 mg
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years.
- •Patients who have undergone hematopoietic stem cell transplantation for any indication within 12 months prior to enrollment.
- •Meet the diagnostic criteria for TA-TMA within ≤14 days prior to enrollment (at least 4 of the following 7 criteria present simultaneously):① Lactate dehydrogenase (LDH) above the age-adjusted upper limit of normal;② Presence of schistocytes on peripheral blood smear;③ New-onset thrombocytopenia or requirement for platelet transfusions;④ New-onset anemia or requirement for red blood cell transfusions;⑤ Hypertension;⑥ Random urine protein-to-creatinine ratio (rUPCR) ≥1 mg/mg;⑦ Elevated plasma soluble C5b-9 (sC5b-9) level (≥244 ng/mL).
- •Meet the criteria for high-risk TA-TMA (presence of any of the following):① Proteinuria (rUPCR ≥2 mg/mg);②Multiple organ dysfunction syndrome (MODS);③ Elevated IL-10 (≥2× upper limit of normal [ULN]).
- •Meet the following condition: TA-TMA has not resolved after ≥72 hours of management of triggering factors/conditions, including: ① Discontinuation or dose reduction of inciting medications (e.g., calcineurin inhibitors, CNI); ② Treatment of any underlying infection; ③ Treatment of underlying acute graft-versus-host disease (aGVHD).
- •Provide written informed consent.
排除标准
- •Known hypersensitivity to eculizumab.
- •Uncontrolled severe infection (including meningococcal infection).
- •Prior treatment with complement inhibitors.
- •Known hereditary or acquired ADAMTS13 deficiency (activity <10%).
- •Disseminated intravascular coagulation (DIC).
- •Respiratory failure (any cause) requiring mechanical ventilation, occurring within 72 hours prior to enrollment.
- •Acute and/or chronic heart failure with ejection fraction ≤40%.
- •Expected survival <48 hours.
- •Any subject who, in the investigator's opinion, is not suitable for participation in this study.
结局指标
主要结局
6-month overall survival rate after diagnosis of TA-TMA
时间窗: 6 months after diagnosis of TA-TMA
This endpoint is defined as the proportion of patients who survive for 6 months (180 days) from the date of TA-TMA diagnosis among all enrolled patients with confirmed TA-TMA in the study population.
次要结局
- Complete TMA response (cTMA-R)(26-week treatment period)
- Cumulative incidence and recovery rate of MODS at 6 months after diagnosis of TA-TMA(6 months after diagnosis of TA-TMA)
- 1-year overall survival rate after HSCT(1 year (365 days) from the date of hematopoietic stem cell infusion)
- 1-year non-relapse mortality (NRM) after HSCT(1-year (365-day) after transplantation.)
- Organ-specific functional recovery (kidney, lung, cardiovascular, etc.)(6 months after diagnosis of TA-TMA)
- Safety assessments (infection, infusion-related reactions, etc.(6 months after diagnosis of TA-TMA)
- Maximum Plasma Concentration [Cmax] of eculizumab(6 months after diagnosis of TA-TMA)
- Safety assessments (CD3+ T cells, CD19+ B cells, CD56+ NK cells)(6 months after diagnosis of TA-TMA)
- Minimum Plasma Concentration [Cmin] of eculizumab(6 months after diagnosis of TA-TMA)
研究者
Yi Luo
Professor
First Affiliated Hospital of Zhejiang University