A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects

Phase 3TerminatedNCT05253209

Asklepion Pharmaceuticals, LLC64 enrolled

Overview

This is a randomized, double-blind, placebo controlled, multicenter study to compare the efficacy and safety of L-citrulline versus placebo in patients undergoing surgery for congenital heart defects. Eligible patients undergoing repair of a large unrestrictive ventricular septal defect (VSD), a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial septal defect (primum ASD) will be eligible for enrollment.

This is a randomized, double-blind, placebo controlled, multicenter study that will compare the efficacy and safety of L- citrulline versus placebo in patients undergoing surgery for congenital heart defects. Eligible patients undergoing repair of a large unrestrictive ventricular septal defect (VSD), a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial septal defect (primum ASD) will be eligible for enrollment. Each enrolled patient will be randomized to receive either L citrulline or placebo throughout all administrations in the study. Patients will receive: 1. an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass 2. the addition L-citrulline or placebo to maintain a steady state target concentration of approximately 100 μmol/L of L-Citrulline or placebo during cardiopulmonary bypass 3. an L-citrulline bolus of 10 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 µmol/L. The study drug or placebo infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever occurs first. Patients will be followed until Day 28 or discharge from the hospital, whichever occurs first. For patients discharged prior to Day 28, a final assessment via telephone will be conducted at Day 28.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

Eligibility

Sex: ALLMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients, parents, or legal guardian willing and able to sign informed consent * Male and female subjects aged ≤18 years of age (females of child-bearing potential willing to practice an acceptable form of birth control) * Patients undergoing cardiopulmonary bypass for repair of a large unrestrictive ventricular septal defect, an ostium primum/secundum atrial septal defect, or a partial or complete atrioventricular septal defect * Pre-operative echocardiogram confirming cardiovascular anatomy and defect to be repaired Exclusion Criteria: * Evidence of pulmonary artery or vein abnormalities that will not be addressed surgically. Specific abnormalities excluded include: * significant pulmonary artery narrowing not amenable to surgical correction * previous pulmonary artery stent placement * significant left sided AV valve regurgitation not amenable to surgical correction * pulmonary venous return abnormalities not amenable to surgical correction * pulmonary vein stenosis not amenable to surgical correction * Preoperative requirement for mechanical ventilation or IV inotrope support * Presence of fixed or idiopathic pulmonary hypertension (i.e. Eisenmenger's Syndrome) prior to surgical repair * Pre-operative use of medications to treat pulmonary hypertension * Pregnancy; Sexually active females of child-bearing potential must be willing to practice an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device) * Participation in another clinical trial within 30 days of Screening or while participating in the current study, including the 28 days of follow-up post study drug administration. * Any condition which, in the opinion of the investigator, might interfere with the study objectives

Locations (10)

Children's of Alabama

Birmingham, Alabama, United States

Children's Hospital of Colorado

Aurora, Colorado, United States

Heart Center, Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, United States

Cardinal Glennon Children's Hospital

St Louis, Missouri, United States

Duke University Medical Center Surgical Office of Clinical Research (SOCR)

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Nationwide Children's Hospital- The Heart Center

Columbus, Ohio, United States

Seattle Children's Research Institute

Seattle, Washington, United States

University of Wisconsin-Madison

Madison, Wisconsin, United States

Outcomes

Primary Outcomes

Post-operative need for mechanical ventilation

Mechanical ventilation is defined as invasive and non-invasive mechanical ventilation including bilevel positive airway pressure (BPAP), continuous positive airway pressure (CPAP)

Time frame: Time in hours from separation from CPB until discontinuation of all mechanical ventilation including non-invasive support or Day 28, whichever occurs first

Secondary Outcomes

Intubation

Length of time on intubation

Time frame: From separation from bypass until discontinuation of intubation or Day 28, whichever occurs first

Early extubation

Frequency of extubation \<12 hours after surgery

Time frame: From end of surgery until 12 hours post-surgery

Positive pressure ventilation

Length of time on non-invasive mechanical ventilation

Time frame: Time in hours from separation from CPB until discontinuation of all non-invasive mechanical ventilation or Day 28, whichever occurs first

Duration of hospitalization

Number of post-operative days until discharge from hospital

Time frame: From surgery until discharge from hospital or Day 28, whichever occurs first

Use of inotropes

Duration of inotrope use (e.g., dopamine, dobutamine, milrinone, epinephrine, phenylephrine and/or norepinephrine).

Time frame: Measured from first use until discharge or Day 28, whichever occurs first

Use of vasodilators

Duration of vasodilator use (e.g., nitroprusside, nitroglycerin, and nicardipine)

Time frame: Measured from first use until discharge or Day 28, whichever occurs first

Duration of chest tube placement

Total post-operative time chest tube is used

Time frame: From the end of the surgery to the time the chest tube is removed or Day 28, whichever occurs first

Volume of chest tube drainage

Total amount of chest tube drainage (mL)

Time frame: Duration of chest tube placement or Day 28, whichever occurs first

Hemodynamic improvement (heart rate)

Changes in heart rate measurements.

Time frame: 1, 2, 4, 12, 24, and 48 hours post-dose

Hemodynamic improvement (systemic arterial blood pressure)

Changes in systemic arterial systolic and diastolic blood pressure measurements.

Time frame: 1, 2, 4, 12, 24, and 48 hours post-dose

Hemodynamic improvement (oxygen saturation)

Changes in oxygen saturation measurements.

Time frame: 1, 2, 4, 12, 24, and 48 hours post-dose

Hemodynamic improvement (central venous pressure)

Changes in oxygen saturation measurements.

Time frame: 1, 2, 4, 12, 24, and 48 hours post-dose

Hemodynamic improvement (pulmonary arterial pressure)

Changes in PAP measurements (when available).

Time frame: 1, 2, 4, 12, 24, and 48 hours post-dose

Arterial blood gasses (PaO2)

Changes in PaO2 measurements

Time frame: Intra-operatively to Day 28

Arterial blood gasses (PaCO2)

Changes in PaCO2 measurements

Time frame: Intra-operatively to Day 28

Arterial blood gasses (HCO3)

Changes in HCO3 measurements

Time frame: Intra-operatively to Day 28

Arterial blood gasses (pH)

Changes in pH measurements

Time frame: Intra-operatively to Day 28

Plasma levels of L-citrulline to assess PK-PD (exposure-response) relationship

Measurement of plasma levels of L-citrulline

Time frame: Pre-surgery, 6, 12, 24 and 48 hours after first dose

Health Economics: mechanical ventilation

Measured as cost per day and expressed as incremental cost per quality adjusted life year (QALY) gained

Time frame: Total over duration of hospitalization or to Day 28 whichever occurs first

Health Economics: duration of hospitalisation

Measured as total cost of hospitalisation expressed as incremental cost per quality adjusted life year (QALY) gained

Time frame: Total over duration of hospitalization or to Day 28 whichever occurs first

Adverse events

Incidence of adverse events and serious adverse events

Time frame: Pre-operatively until Day 28

Incidence of refractory hypotension

Number of subjects with any refractory hypotension. Defined as a drop of \>20% in mean arterial pressure for \>30 minutes.

Time frame: From the end of surgery until 48 hours after first dose

Clinical laboratory values (Blood Hemoglobin and Total Bilirubin)