PACE: Prostacyclin AntiCoagulation in ECMO

Phase 2Not Yet RecruitingNCT07837869

Garrett Keim44 enrolled

Overview

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: 1. 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? 2. How does epoprostenol move through the ECMO circuit? 3. 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.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: ALLMin age: 0 DaysMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≤ 17.5 years of age at the time of ECMO initiation. 2. Corrected Gestational Age ≥ 37 weeks at the time of ECMO initiation. 3. Admitted to the PICU, CICU, or NI/ICU requiring V-A or V-V ECMO support. 4. Receiving standard systemic anticoagulation with Unfractionated Heparin (UFH) or Bivalirudin 5. Written informed consent provided by the patient's parent or Legally Authorized Representative (LAR). Exclusion Criteria: 1. Active bleeding: Any active bleeding requiring \>20ml/kg or ≥2 Units of Packed Red Blood Cells in the prior 12 hours. 2. Known intracranial hemorrhage during acute hospitalization either prior to or during ECMO. 3. Severe coagulopathy: Platelet count \< 50,000/ uL or Fibrinogen \< 50 mg/dL at baseline. 4. Known or suspected qualitative platelet dysfunction disorder (congenital bleeding disorder) 5. Clinical Contraindication to vasodilation: Severe left ventricular outflow tract obstruction (e.g., HOCM, severe aortic stenosis, or post-capillary cause of pulmonary hypertension). 6. Prior major bleeding episode during current hospitalization including gastrointestinal bleed that required \> 20ml/kg or ≥2 Units of PRBCs in a 12-hour period. 7. Known hypersensitivity to epoprostenol 8. Patients with known esophageal varices 9. Systemic prostacyclin therapy for pulmonary hypertension 10. Moribund clinical condition as assessed by the investigators and/or clinical team 11. Positive pregnancy test 12. Inability to achieve hemodynamic and anticoagulation stability as previously defined in the first 7 days of ECMO support.

Outcomes

Primary Outcomes

Safety and Maximum Tolerated Dose

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

Time frame: Within 72 hours of epoprostenol initiation

Secondary Outcomes

Determination of the Steady State Concentration of Epoprostenol Metabolites

We will determine the steady-state concentration (Css) of epoprostenol metabolites in each patient. In a standard patient receiving drug by continuous infusion, Css is defined as: Css = R0/CL, where R0 is the rate of infusion and CL is the patient's clearance of the drug. In a patient on ECMO, clearance will include patient clearance (CLp) and sequestration of drug by the circuit (CLs). The half-life of epoprostenol metabolites is \~15 minutes, so our first PK sampling time point (4 hours) will allow evaluation of ongoing sequestration across the ECMO circuit, since the patient should be at steady state at this time. We will compare metabolite concentrations at the 3 sampling sites - pre-membrane, post-membrane, and patient (arterial) - to determine sequestration at this time point. It is expected that sequestration is saturable and will not be ongoing at 24 hours.

Time frame: Within 48 hrs of epoprostenol initiation

Population Pharmacokinetic Analysis

As an exploratory analysis, we will perform population PK (popPK) analysis using all available concentration data from enrolled patients. The objective of the popPK analysis is to develop metabolite-only models for each metabolite. Since parent drug concentrations will not be available, we will assume a two-compartment structure where drug is administered into the first (latent) compartment and only the 2nd compartment is observed. In this setup, k12 will represent formation of the metabolite. Because the fraction of parent drug converted to each metabolite will not be known, all PK parameters (CL, V) will be apparent parameters. As the data allows, more complex model structures will be explored. Covariate analysis will be used to statistically evaluate how factors relating to ECMO (flow rate, circuit age, etc.) and the patient (age, renal function, etc.) influence epoprostenol metabolite PK.

Time frame: Within 48 hours of epoprostenol infusion

Thromboelastography (TEG) with platelet mapping

To evaluate the effect of epoprostenol on platelet function within the ECMO circuit environment and patient, thromboelastography (TEG) with platelet mapping, focusing on the Maximum Amplitude (MA) parameter, will be measured at various timepoints during epoprostenol infusion.

Time frame: Within 48 hours of epoprostenol intiation

Light-transmission aggregometry

To evaluate the effect of epoprostenol on platelet function within the ECMO circuit environment and patient, light-transmission aggregometry against ADP, thrombin, TRAP, and CRP-A agonists will be utilized at various timepoints during epoprostenol infusion.

Time frame: Within 48 hours of epoprostenol intiation

Platelet activation measurement through whole-blood flow cytometry

To evaluate the effect of epoprostenol on platelet function within the ECMO circuit environment and patient, whole-blood flow cytometry for PAC-1, P-selectin, and CD41 at baseline and post-agonist stimulation will be measured at various timepoints during epoprostenol infusion:

Time frame: Within 48 hours of epoprostenol intiation

PACE: Prostacyclin AntiCoagulation in ECMO

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts