Safety and Efficacy of Eculizumab in High-risk TA-TMA

Официальное название

The Safety and Efficacy of Eculizumab for High-risk Transplant-associated Thrombotic Microangiopathy.

Обзор

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.

Подробное описание

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

Dosing frequency:

Loading phase (first 5 doses) First 5 doses: 1 dose every 48 hours × 2 doses, then 1 dose every 72 hours × 3 doses Induction phase (subsequent 4 doses) Subsequent 4 doses: once weekly for 4 weeks Maintenance phase Once every 2 weeks, continued up to 24 weeks

Dose adjustment principles:

Based on eculizumab trough concentration (target ≥100 μg/mL), CH50 level (\<10% of the lower limit of normal), and sC5b-9 target: \<244 ng/mL

Monitoring frequency:

Loading phase: daily monitoring Induction and maintenance phases: monitoring prior to each dose

Вмешательства

• Препарат Eculizumab
  Dosing Regimen Weight-based induction therapy: Eculizumab 10-\<40 kg: 600 mg * 40 kg: 900 mg Dosing frequency: Loading phase (first 5 doses) First 5 doses: 1 dose every 48 hours × 2 doses, then 1 dose every 72 hours × 3 doses Induction phase (subsequent 4 doses) Subsequent 4 doses: once weekly for 4 weeks Maintenance phase Once every 2 weeks, continued up to 24 weeks Dose adjustment principles: Based on eculizumab trough concentration (target ≥100 μg/mL), CH50 level (\<10% of the lower li

Первичные конечные точки

• 6-month overall survival rate after diagnosis of TA-TMA [Срок оценки: 6 months after diagnosis of TA-TMA]

Вторичные конечные точки (9)

• Complete TMA response (cTMA-R) [Срок оценки: 26-week treatment period]
• Cumulative incidence and recovery rate of MODS at 6 months after diagnosis of TA-TMA [Срок оценки: 6 months after diagnosis of TA-TMA]
• 1-year overall survival rate after HSCT [Срок оценки: 1 year (365 days) from the date of hematopoietic stem cell infusion]
• 1-year non-relapse mortality (NRM) after HSCT [Срок оценки: 1-year (365-day) after transplantation.]
• Organ-specific functional recovery (kidney, lung, cardiovascular, etc.) [Срок оценки: 6 months after diagnosis of TA-TMA]
• Safety assessments (infection, infusion-related reactions, etc. [Срок оценки: 6 months after diagnosis of TA-TMA]
• Maximum Plasma Concentration [Cmax] of eculizumab [Срок оценки: 6 months after diagnosis of TA-TMA]
• Safety assessments (CD3+ T cells, CD19+ B cells, CD56+ NK cells) [Срок оценки: 6 months after diagnosis of TA-TMA]
• Minimum Plasma Concentration [Cmin] of eculizumab [Срок оценки: 6 months after diagnosis of TA-TMA]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 8 центров

• Xiangya Hospital of Central South University — Чанша
• Sir Run Run Shaw Hospital, Zhejiang University School of Medicine — Ханчжоу
• The First Affiliated Hospital, Zhejiang University School of Medicine. — Ханчжоу
• The Second Affiliated Hospital of Zhejiang University School of Medicine — Ханчжоу
• Jinhua Central Hospital — Jinhua
• The Affiliated People's Hospital of Ningbo University — Ningbo
• The First Affiliated Hospital of Ningbo University — Ningbo
• The First Affiliated Hospital of Wenzhou Medical University — Wenzhou

Идентификаторы

NCT: NCT07707687 · ZJU-TA-TMA

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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