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

Acute Lung Injury 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 Subjects Undergoing Surgery for Congenital Heart Defects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02891837
• Other study ID #: CIT-003-01
• Secondary ID: 2016-002427-28
• Status: Completed
• Phase: Phase 3
• Start date: August 2016
• Est. completion date: July 2019

Study information

• Verified date: January 2023
• Source: Asklepion Pharmaceuticals, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 189
• Est. completion date: July 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Lung Injury
• Wounds and Injuries

Intervention

Drug:
• L-citrulline
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.

Other:
• Placebo
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.

Locations

Country	Name	City	State
Austria	LKH-Universitätsklinikum Graz Universitätsklinik für Kinder- und Jugendheilkunde	Graz
Austria	Medizinische Universität Wien, Klinik für Kinder- und Jugendheilkunde, Abteilung für Pädiatrische Kardiologie Kinderherzzentrum	Wien
Germany	Universitätsmedizin Göttingen	Göttingen
Germany	Medizinische Hochschule Hannover	Hanover
Germany	Klinik für Kinderkardiologie und angeborene Herzfehler. Deutsches Herzzentrum München - Klinik an der TU München	München
Germany	Universitätsklinik Tübingen, Kinderkardiologie Pulmonologie, Intensivmedizin	Tübingen
Israel	Wolfson Medical Center	H_olon
Israel	Rambam Health Care Center	Haifa
Israel	Sheba Medical Center	Ramat Gan
United States	Children's Hospital Colorado	Aurora	Colorado
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	The Children's Hospital at Montefiore	Bronx	New York
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Riley Hospital for Children at Indiana University	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Loma Linda University Children's Hospital	Loma Linda	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Columbia University Medical Center	New York	New York
United States	Advocate Children's Hospital	Oak Lawn	Illinois
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	University of California Davis Medical Center	Sacramento	California
United States	St Louis University, SSM Health Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Washington University School of Medicine/ St Louis Children's Hospital	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Asklepion Pharmaceuticals, LLC

Countries where clinical trial is conducted

United States,  Austria,  Germany,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	28 Days
Secondary	Length of Time on Mechanical Ventilation	The same definitions and analyses as described for the primary endpoint will be applied.	28 Days
Secondary	Length of Time on Positive Pressure Ventilation	The same definitions and analyses as described for the primary endpoint will be applied.	28 Days
Secondary	Length of Time of Inotrope Use	The same definitions and analyses as described for the primary endpoint will be applied.	28 days
Secondary	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).	Up to 48 hours after separation from CBP
Secondary	Hemodynamic Improvement: Heart Rate	Heart rate at hours 1, 2, 4, 12, 24 and 48.	2 Days
Secondary	Hemodynamic Improvement: Systemic Arterial Blood Pressure	Systemic arterial blood pressure at hours 1, 2, 4, 12, 24 and 48.	2 Days
Secondary	Hemodynamic Improvement: Oxygen Saturation	Oxygen saturation at hours 1, 2, 4, 12, 24 and 48.	2 Days
Secondary	Hemodynamic Improvement: Central Venous Pressure	Central venous pressure at hours 1, 2, 4, 12, 24 and 48.	2 Days
Secondary	Thoracotomy Output	The thoracotomy output is defined as the total volume of chest tube drainage recorded in cc prior to discontinuation of chest intubation. The total postoperative duration (in hours) that the chest tube is used will be calculated as the time from the end of the surgery to the time the chest tube is removed. If an additional chest tube is required or reinserted (until discharge from the hospital or at Day 28) the duration that the additional chest tube was used (from time of insertion to time of removal) will be added to the time the original chest tube was used for the total postoperative duration. If a subject did not use any chest tube the duration is set to 0. As a sensitivity analysis, subjects with no use of chest tube will be excluded. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed duration of chest tube drainage will be used.	28 Days
Secondary	Length of Time of Intubation	The length will be derived as the time in hours from separation from CPB until discontinuation of intubation. Any duration of re-use of intubation will continue to accrue. If a subject did not use any intubation the length is set to 0. As a sensitivity analysis, subjects with no use of intubations will be excluded. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed length of time on intubation will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of time on intubation of 28 days.; For the length of time on intubation the same analyses as described for the primary endpoint will be applied.	28 Days
Secondary	Length of Pediatric Intensive Care Unit (PICU) Stay	The length of PICU stay will be calculated as the total number of days postoperative until discharge from PICU. For subjects who died before discharge from PICU or before Day 28, respectively, the observed length of PICU stay will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of PICU stay of 28 days. For the length of PICU stay the same analyses as described for the primary endpoint will be applied.	28 Days
Secondary	Length of Time on Vasodilators	Length of time on vasodilators will be measured from first use following separation from bypass, until the subject is discharged from the hospital or at Day 28. The length will be derived as the time in hours from separation from CPB until discontinuation of all vasodilators.	28 Days
Secondary	Length of Hospitalization	The length of hospitalization will be calculated as the total number of days postoperative until discharge from the hospital. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed length of hospitalization will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of hospitalization of 28 days. The same analyses as described for the primary endpoint will be applied.	28 Days
Secondary	Patients With Plasma Concentrations of Citrulline	Plasma citrulline concentrations will be assessed in both treatment groups to determine the number of patients who reach the therapeutic sustained target plasma citrulline level of =100 µmol/L. Blood collection for assessment of plasma citrulline concentrations will be taken prior to surgery, during surgery, 30 minutes post-decannulation after CPB (prior to bolus and 5 minutes after bolus), at the specified post-operative time points (6h, 12h, 24h, 48h), and at hospital discharge or Day 28, whichever occurs first.	28 Days
Secondary	Occurrence of Adverse and Serious Adverse Events	Pre-treatment adverse events and treatment adverse events will be analyzed separately. The number of affected subjects will be reported.	28 Days
Secondary	Number of Patients With Refractory Hypotension	Refractory hypotension is defined as a 20% drop of mean arterial pressure (MAP) below specific age-related criteria for more than 30 minutes. The number of subjects with any refractory hypotension from end of surgery until 48 hours will be compared between groups.	2 Days