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

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

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.

Study Overview

• Status: Terminated
• Conditions: Atrioventricular Septal Defect; Ventricular Septal Defect; Primum Atrial Septal Defect
• Intervention / Treatment: Drug: L-citrulline; Drug: Plasmalyte A

Detailed Description

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
• Enrollment (Actual): 64
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's of Alabama
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Heart Center, Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Surgical Office of Clinical Research (SOCR)
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43215
      • Nationwide Children's Hospital- The Heart Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Research Institute
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-4108
      • University of Wisconsin-Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active; 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; Intravenous L-citrulline given for up to 48 hours
Placebo Comparator: Placebo; Plasmalyte A administered to the same schedule as the active treatment arm.	Drug: Plasmalyte A; Intravenous Plasmalyte A given for up to 48 hours

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Asklepion Pharmaceuticals, LLC
• Investigators: Principal Investigator: Christopher Mastropietro, MD, FCCM, Riley Hospital for Children at Indiana University Health; Study Director: Gurdyal Kalsi, MD, MFPM, Asklepion Pharmaceuticals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2022
• Primary Completion (Actual): May 10, 2024
• Study Completion (Actual): May 10, 2024

Study Registration Dates

• First Submitted: January 24, 2022
• First Submitted That Met QC Criteria: February 21, 2022
• First Posted (Actual): February 23, 2022

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 13, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Wounds and Injuries; Congenital Abnormalities; Cardiovascular Abnormalities; Thoracic Injuries; Heart Septal Defects; Heart Septal Defects, Atrial; Heart Defects, Congenital; Acute Lung Injury; Lung Injury; Heart Septal Defects, Ventricular; Endocardial Cushion Defects; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: CIT-CPB-003-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No