L-citrulline for Prevention of Sequelae of Acute Lung Injury in Pediatrics Undergoing Cardiopulmonary Bypass for Heart Defects

Asklepion Pharmaceuticals, LLC189 enrolled

Overview

The purpose of this study is to determine whether L-citrulline is effective and safe in the prevention of clinical sequelae of Acute Lung Injury in pediatric subjects undergoing surgery for congenital heart defects.

This is a randomized, double-blind, placebo controlled, multicenter study that will compare the efficacy and safety of L-citrulline versus placebo in subjects undergoing surgery for congenital heart defects. Eligible subjects 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 in this study. Each enrolled subject will be randomized to receive either L-citrulline or placebo throughout all administrations in the study. Subjects will receive an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass, the addition of L-citrulline at a concentration of 200 μmol/L or placebo given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L. L-citrulline bolus of 20 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hr continuous L-citrulline infusion or placebo for up to 48 hours. The study drug or placebo infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever comes first. Subjects will be followed until Day 28 or discharge from the hospital, whichever comes first. For subjects discharged prior to Day 28, a final assessment via telephone will be conducted at Day 28.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Enrollment

189

Conditions

Acute Lung Injury

Interventions

L-citrullineDRUG

* Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * Addition of study medication at a concentration of 200 μmol/L given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.

PlaceboOTHER

* Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass; * Addition of placebo matched for volume given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations during bypass; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.

Eligibility

Sex: ALLMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects, parents, or legal guardian of the subject who are willing and able to sign informed consent * Male and female subjects aged ≤18 years of age * Infants, children and adolescents undergoing cardiopulmonary bypass (CPB) for repair of a large unrestrictive VSD, an ostium primum ASD, or a partial or complete AVSD * Pre-operative echocardiogram which confirms the cardiovascular anatomy and defect to be surgically repaired Exclusion Criteria: * Evidence of pulmonary artery or vein abnormalities on the pre-operative echocardiogram that will not be addressed surgically. Specific abnormalities excluded include the following: * 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 intravenous 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; Females of child-bearing potential must be willing to participate an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device) * Any condition which, in the opinion of the investigator, might interfere with the study objectives * 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

Locations (29)

Outcomes

Primary Outcomes

A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use.

Mechanical ventilation (MV) = invasive or noninvasive MV incl. bilevel (biphasic) positive airway pressure or continuous positive airway pressure. Inotrope use = medications considered within the derivation of total inotrope score (dopamine, dobutamine, milrinone, epinephrine, phenylephrine, norepinephrine). Both measures recorded until earliest of subject hospital discharge or Day 28.

Time frame: 28 Days

Secondary Outcomes

Length of Time on Mechanical Ventilation

The same definitions and analyses as described for the primary endpoint will be applied.

Time frame: 28 Days

Length of Time on Positive Pressure Ventilation

The same definitions and analyses as described for the primary endpoint will be applied.

Time frame: 28 Days

Length of Time of Inotrope Use

The same definitions and analyses as described for the primary endpoint will be applied.

Time frame: 28 days

Inotrope Score

Inotrope score is reflective of the pharmacological support required by the cardiovascular system and is a good predictor of mortality and morbidity in patients undergoing bypass surgery. A lower inotrope score represents less pharmacological support and would indicate a lower risk for a poor clinical outcome. Therefore, any treatment effect would be indicated by a lower inotrope score in the citrulline group when compared to the placebo group. In this study, the score was calculated each hour post-operatively from the time of separation from bypass until the completion of study drug. Additionally, the total inotrope score over time until Day 28 or hospital discharge was derived. Inotrope score was calculated using the following formula: Total inotrope score = Dopamine dose (µg/kg/min) + Dobutamine dose (µg/kg/min) + 10 \* Milrinone dose (µg/kg/min) + 100 \* Epinephrine dose (µg/kg/min) + 100 \* Phenylephrine dose (µg/kg/min) + 100 \* Norepinephrine dose (µg/kg/min).

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

University of Alabama

Birmingham, Alabama, United States

Loma Linda University Children's Hospital

Loma Linda, California, United States

University of California Davis Medical Center

Sacramento, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Nicklaus Children's Hospital

Miami, Florida, United States

Arnold Palmer Hospital for Children

Orlando, Florida, United States

Advocate Children's Hospital

Oak Lawn, Illinois, United States

Riley Hospital for Children at Indiana University

Indianapolis, Indiana, United States

The Johns Hopkins Hospital

Baltimore, Maryland, United States

...and 19 more locations