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

NCT ID: NCT02891837

Last Updated: 2023-02-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 189 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2019-07-31

Brief 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.

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 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.

Conditions

Acute Lung Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

L-citrulline

Intervention Type: DRUG

• 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

• 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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Eligibility Criteria

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asklepion Pharmaceuticals, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gurdyal Kalsi, MD

Role: STUDY_DIRECTOR

Asklepion Pharmaceuticals, LLC

Locations

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

University of Mississippi Medical Center

Jackson, Mississippi, United States

St Louis University, SSM Health Cardinal Glennon Children's Hospital

St Louis, Missouri, United States

Washington University School of Medicine/ St Louis Children's Hospital

St Louis, Missouri, United States

Columbia University Medical Center

New York, New York, United States

The Children's Hospital at Montefiore

The Bronx, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

LKH-Universitätsklinikum Graz Universitätsklinik für Kinder- und Jugendheilkunde

Graz, , Austria

Medizinische Universität Wien, Klinik für Kinder- und Jugendheilkunde, Abteilung für Pädiatrische Kardiologie Kinderherzzentrum

Vienna, , Austria

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, , Germany

Rambam Health Care Center

Haifa, , Israel

Wolfson Medical Center

Holon, , Israel

Sheba Medical Center

Ramat Gan, , Israel

Countries

United States; Austria; Germany; Israel

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002427-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CIT-003-01

Identifier Type: -

Identifier Source: org_study_id