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

Ventricular Septal Defect Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05253209
• Other study ID #: CIT-CPB-003-02
• Status: Recruiting
• Phase: Phase 3
• Start date: June 29, 2022
• Est. completion date: February 10, 2024

Study information

• Verified date: August 2023
• Source: Asklepion Pharmaceuticals, LLC
• Contact: Gurdyal Kalsi, MD, MFPM
• Phone: +1 410.736.3750
• Email: gurdyal.kalsi[@]asklepionpharm.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 97
• Est. completion date: February 10, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Atrioventricular Septal Defect
• Endocardial Cushion Defects
• Heart Defects, Congenital
• Heart Septal Defects
• Heart Septal Defects, Atrial
• Heart Septal Defects, Ventricular
• Lung Injury
• Ventricular Septal Defect

Intervention

Drug:
• L-citrulline
Intravenous L-citrulline given for up to 48 hours
• Plasmalyte A
Intravenous Plasmalyte A given for up to 48 hours

Locations

Country	Name	City	State
United States	Children's Hospital of Colorado	Aurora	Colorado
United States	Children's of Alabama	Birmingham	Alabama
United States	Heart Center, Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital- The Heart Center	Columbus	Ohio
United States	Duke University Medical Center Surgical Office of Clinical Research (SOCR)	Durham	North Carolina
United States	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana
United States	University of Wisconsin-Madison	Madison	Wisconsin
United States	Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Seattle Children's Research Institute	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Asklepion Pharmaceuticals, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Intubation	Length of time on intubation	From separation from bypass until discontinuation of intubation or Day 28, whichever occurs first
Secondary	Early extubation	Frequency of extubation <12 hours after surgery	From end of surgery until 12 hours post-surgery
Secondary	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
Secondary	Duration of hospitalization	Number of post-operative days until discharge from hospital	From surgery until discharge from hospital or Day 28, whichever occurs first
Secondary	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
Secondary	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
Secondary	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
Secondary	Volume of chest tube drainage	Total amount of chest tube drainage (mL)	Duration of chest tube placement or Day 28, whichever occurs first
Secondary	Hemodynamic improvement (heart rate)	Changes in heart rate measurements.	1, 2, 4, 12, 24, and 48 hours post-dose
Secondary	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
Secondary	Hemodynamic improvement (oxygen saturation)	Changes in oxygen saturation measurements.	1, 2, 4, 12, 24, and 48 hours post-dose
Secondary	Hemodynamic improvement (central venous pressure)	Changes in oxygen saturation measurements.	1, 2, 4, 12, 24, and 48 hours post-dose
Secondary	Hemodynamic improvement (pulmonary arterial pressure)	Changes in PAP measurements (when available).	1, 2, 4, 12, 24, and 48 hours post-dose
Secondary	Arterial blood gasses (PaO2)	Changes in PaO2 measurements	Intra-operatively to Day 28
Secondary	Arterial blood gasses (PaCO2)	Changes in PaCO2 measurements	Intra-operatively to Day 28
Secondary	Arterial blood gasses (HCO3)	Changes in HCO3 measurements	Intra-operatively to Day 28
Secondary	Arterial blood gasses (pH)	Changes in pH measurements	Intra-operatively to Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	Adverse events	Incidence of adverse events and serious adverse events	Pre-operatively until Day 28
Secondary	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
Secondary	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
Secondary	Clinical laboratory values (Blood Haematocrit)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28
Secondary	Clinical laboratory values (Red Blood Cell Count)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28
Secondary	Clinical laboratory values (White Blood Cell Count)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28
Secondary	Clinical laboratory values (Blood Platelet Count)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28
Secondary	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
Secondary	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
Secondary	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
Secondary	Clinical laboratory values (Blood Lactate Dehydrogenase)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28
Secondary	Clinical laboratory values (Blood Activated Clotting Time)	Absolute values and the absolute and percentage changes from baseline.	Intra-operatively, Days 1, 2 and 28