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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass 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 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.

Official Title
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A Phase III Double-Blind, Randomized, Placebo Controlled, Multi Center Clinical Study to Evaluate the Efficacy and Safety of Intravenous 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

Conditions
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Ventricular Septal Defect, Atrioventricular Septal Defect, Primum Atrial Septal Defect

Intervention / Treatment
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* Drug: L-citrulline
* Drug: Plasmalyte A


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>Patients will receive: an L-citrulline bolus of 150 mg/kg at the initiation of cardiopulmonary bypass the addition L-citrulline to maintain a steady state target concentration of approximately 100 μmol/L of L-citrulline during cardiopulmonary bypass an L-citrulline bolus of 10 mg/kg 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. Infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever occurs first. | Drug: L-citrulline<br>* Intravenous L-citrulline given for up to 48 hours<br>|
| Placebo Comparator: Placebo<br>Plasmalyte A administered to the same schedule as the active treatment arm. | Drug: Plasmalyte A<br>* Intravenous Plasmalyte A given for up to 48 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 in hours from separation from CPB until discontinuation of all mechanical ventilation including non-invasive support or Day 28, whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intubation | Length of time on intubation | From separation from bypass until discontinuation of intubation or Day 28, whichever occurs first | 
| Early extubation | Frequency of extubation <12 hours after surgery | From end of surgery until 12 hours post-surgery | 
| Positive pressure ventilation | Length of time on non-invasive mechanical ventilation | 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 | 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). | 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) | 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 | 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) | Duration of chest tube placement or Day 28, whichever occurs first | 
| Hemodynamic improvement (heart rate) | Changes in heart rate measurements. | 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. | 1, 2, 4, 12, 24, and 48 hours post-dose | 
| Hemodynamic improvement (oxygen saturation) | Changes in oxygen saturation measurements. | 1, 2, 4, 12, 24, and 48 hours post-dose | 
| Hemodynamic improvement (central venous pressure) | Changes in oxygen saturation measurements. | 1, 2, 4, 12, 24, and 48 hours post-dose | 
| Hemodynamic improvement (pulmonary arterial pressure) | Changes in PAP measurements (when available). | 1, 2, 4, 12, 24, and 48 hours post-dose | 
| Arterial blood gasses (PaO2) | Changes in PaO2 measurements | Intra-operatively to Day 28 | 
| Arterial blood gasses (PaCO2) | Changes in PaCO2 measurements | Intra-operatively to Day 28 | 
| Arterial blood gasses (HCO3) | Changes in HCO3 measurements | Intra-operatively to Day 28 | 
| Arterial blood gasses (pH) | Changes in pH measurements | Intra-operatively to Day 28 | 
| Plasma levels of L-citrulline to assess PK-PD (exposure-response) relationship | Measurement of plasma levels of L-citrulline | 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 | 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 | Total over duration of hospitalization or to Day 28 whichever occurs first | 
| Adverse events | Incidence of adverse events and serious adverse events | 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. | From the end of surgery until 48 hours after first dose | 
| Clinical laboratory values (Blood Hemoglobin and Total Bilirubin) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Haematocrit) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Red Blood Cell Count) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (White Blood Cell Count) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Platelet Count) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Sodium, Potassium, Calcium, Magnesium, Chloride) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Urea Nitrogen and Creatinine) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Lactate Dehydrogenase) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 | 
| Clinical laboratory values (Blood Activated Clotting Time) | Absolute values and the absolute and percentage changes from baseline. | Intra-operatively, Days 1, 2 and 28 |