Phase 1/2 Dose-Escalation Study of Epoprostenol as Adjunct Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation (ECMO)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Safety and Maximum Tolerated Dose
研究概览
简要总结
Extracorporeal membrane oxygenation (ECMO) is a machine that temporarily supports the heart and/or lungs and is a critical rescue therapy for refractory cardiac and respiratory failure in pediatric populations. Despite technological advancements, the contact between blood and the artificial surface of the ECMO circuit often triggers blood clotting that requires blood thinning medications while on ECMO. The current standard of care is to use medications that have little effect on platelets, a part of the clotting system that can be activated by parts of the ECMO machine.
The goal of this clinical trial is to find the safest dose of a medication called epoprostenol (also known as Veletri) when it is given directly into the ECMO circuit and investigate its pharmacokinetics and effect on platelets for patients on ECMO. This medication is primarily used for the management of patients with pulmonary hypertension and does have a known side effect of decreasing platelet activation. This clinical trial is investigating what doses of this medication are safe in ECMO populations and if there is a measurable effect on platelet function with the trial doses. There is the possibility of direct benefit to the participant because if epoprostenol reduces platelet activation in the ECMO circuit it could potentially decrease ECMO circuit clotting events or reduce the need for escalation of other systemic blood thinning medications during the 48-hour infusion.
The main questions this study aims to answer are:
- What is the safest and maximum tolerated dose (MTD) of continuous intravenous (IV) epoprostenol when administered as an additional anticoagulant in pediatric patients receiving veno-arterial (V-A) or veno-venous (V-V) ECMO?
- How does epoprostenol move through the ECMO circuit?
- What is the effect of epoprostenol on platelet function at different doses?
Participants receiving V-V or V-A ECMO with at least 12 hours of stable blood pressures and 6 hours of blood thinning within clinical practice goal, who agree to participate, will receive a 48-hour infusion of epoprostenol with associated blood sampling and adverse event monitoring. The three doses of epoprostenol in this dose-escalation study are 4 ng/kg/min, 8 ng/kg/min, and 12 ng/kg/min. Starting with the lowest dose, each participant will receive one dose throughout the 48 hours with close monitoring for side effects. The 3 major side effects that are being tracked are: 1) effects on blood pressure, 2) effects on unexpected bleeding, and 3) effects on fluid in the lungs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Days 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≤ 17.5 years of age at the time of ECMO initiation.
- •Corrected Gestational Age ≥ 37 weeks at the time of ECMO initiation.
- •Admitted to the PICU, CICU, or NI/ICU requiring V-A or V-V ECMO support.
- •Receiving standard systemic anticoagulation with Unfractionated Heparin (UFH) or Bivalirudin
- •Written informed consent provided by the patient's parent or Legally Authorized Representative (LAR).
排除标准
- •Active bleeding: Any active bleeding requiring >20ml/kg or ≥2 Units of Packed Red Blood Cells in the prior 12 hours.
- •Known intracranial hemorrhage during acute hospitalization either prior to or during ECMO.
- •Severe coagulopathy: Platelet count < 50,000/ uL or Fibrinogen < 50 mg/dL at baseline.
- •Known or suspected qualitative platelet dysfunction disorder (congenital bleeding disorder)
- •Clinical Contraindication to vasodilation: Severe left ventricular outflow tract obstruction (e.g., HOCM, severe aortic stenosis, or post-capillary cause of pulmonary hypertension).
- •Prior major bleeding episode during current hospitalization including gastrointestinal bleed that required > 20ml/kg or ≥2 Units of PRBCs in a 12-hour period.
- •Known hypersensitivity to epoprostenol
- •Patients with known esophageal varices
- •Systemic prostacyclin therapy for pulmonary hypertension
- •Moribund clinical condition as assessed by the investigators and/or clinical team
- •Positive pregnancy test
- •Inability to achieve hemodynamic and anticoagulation stability as previously defined in the first 7 days of ECMO support.
研究组 & 干预措施
Statum B: 4 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum B: ≥ 10kg. Escalation will proceed independently within each stratum. The epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 4 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
Statum A: 8 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum A: < 10kg. Escalation will proceed independently within each stratum. For this arm the epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 8 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
Statum B: 8 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum B: ≥10kg. Escalation will proceed independently within each stratum. For this arm the epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 8 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
Statum A: 12 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum A: < 10kg. Escalation will proceed independently within each stratum. In this arm, the epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 12 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
Statum B: 12 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum B: ≥10kg. Escalation will proceed independently within each stratum. In this arm, the epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 12 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
Statum A: 4 ng/kg/min
Patients will be enrolled into two distinct strata based on weight: Stratum A: < 10kg. Escalation will proceed independently within each stratum. The epoprostenol infusion will start at 2 ng/kg/min and increase 2 ng/kg/min every 15 minutes to the goal dose of 4 ng/kg/min for the remainder of the study period or until other stopping criteria are met.
干预措施: Dose-escalation study of epoprostenol as adjunct anticoagulation in ECMO (Drug)
结局指标
主要结局
Safety and Maximum Tolerated Dose
时间窗: Within 72 hours of epoprostenol initiation
The primary outcome is to determine the MTD of continuous infusion epoprostenol, defined as a DLT rate ≥ 33.3% after a cohort has enrolled and study drug received. There are 3 DLTs defined for this study and will be followed for 24 hours after end of infusion: 1. Adverse Hemodynamic Effects - in the first 4 hours following target dose, sustained decreases in mean arterial pressure, increases in vasopressor/inotropic support, or administration of 40 mL/kg or \>2 L of fluid to treat hypotension; between 4-72h if any of the above hemodynamic changes occur, the independent medical monitor (IMM) will adjudicate 2. Clinically Significant Bleeding - adapted from ECMO-CENTRAL definitions for the duration of epoprostenol infusion 3. Clinically Significant Pulmonary Edema - in the first 4 hours following target dose and defined through combination of changes in lung ultrasound score and changes in oxygenation; between 4-72h if any of the above hemodynamic changes occur, the IMM will adjudicate
次要结局
- Determination of the Steady State Concentration of Epoprostenol Metabolites(Within 48 hrs of epoprostenol initiation)
- Population Pharmacokinetic Analysis(Within 48 hours of epoprostenol infusion)
- Thromboelastography (TEG) with platelet mapping(Within 48 hours of epoprostenol intiation)
- Light-transmission aggregometry(Within 48 hours of epoprostenol intiation)
- Platelet activation measurement through whole-blood flow cytometry(Within 48 hours of epoprostenol intiation)
研究者
Garrett Keim
Assistant Professor of Anesthesiology And Critical Care Medicine
Children's Hospital of Philadelphia