Clinical trial NCT02891837: L-citrulline for Prevention of Sequelae of Acute Lung Injury in Pediatrics Undergoing Cardiopulmonary Bypass for Heart Defects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Lung Injury
Keywords: L-citrulline
pediatric
Lung Injury
Bypass
Heart Defects
Clinical Sequelae
Lead sponsor: Asklepion Pharmaceuticals, LLC
Sponsor class: INDUSTRY
First posted: 2016-09-08
Enrollment: 189
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use.
timeFrame: 28 Days
Secondary outcomes:
measure: Length of Time on Mechanical Ventilation
timeFrame: 28 Days
measure: Length of Time on Positive Pressure Ventilation
timeFrame: 28 Days
measure: Length of Time of Inotrope Use
timeFrame: 28 days
measure: Inotrope Score
timeFrame: Up to 48 hours after separation from CBP
measure: Hemodynamic Improvement: Heart Rate
timeFrame: 2 Days
measure: Hemodynamic Improvement: Systemic Arterial Blood Pressure
timeFrame: 2 Days
measure: Hemodynamic Improvement: Oxygen Saturation
timeFrame: 2 Days
measure: Hemodynamic Improvement: Central Venous Pressure
timeFrame: 2 Days
measure: Thoracotomy Output
timeFrame: 28 Days
measure: Length of Time of Intubation
timeFrame: 28 Days
measure: Length of Pediatric Intensive Care Unit (PICU) Stay
timeFrame: 28 Days
measure: Length of Time on Vasodilators
timeFrame: 28 Days
measure: Length of Hospitalization
timeFrame: 28 Days
measure: Patients With Plasma Concentrations of Citrulline
timeFrame: 28 Days
measure: Occurrence of Adverse and Serious Adverse Events
timeFrame: 28 Days
measure: Number of Patients With Refractory Hypotension
timeFrame: 2 Days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Loma Linda
country: United States
facility: Loma Linda University Children's Hospital
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Oak Lawn
country: United States
facility: Advocate Children's Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University
state: Indiana
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: St Louis University, SSM Health Cardinal Glennon Children's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine/ St Louis Children's Hospital
state: Missouri
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Graz
country: Austria
facility: LKH-Universitätsklinikum Graz Universitätsklinik für Kinder- und Jugendheilkunde
city: Wien
country: Austria
facility: Medizinische Universität Wien, Klinik für Kinder- und Jugendheilkunde, Abteilung für Pädiatrische Kardiologie Kinderherzzentrum
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: München
country: Germany
facility: Klinik für Kinderkardiologie und angeborene Herzfehler. Deutsches Herzzentrum München - Klinik an der TU München
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen, Kinderkardiologie Pulmonologie, Intensivmedizin
city: Haifa
country: Israel
facility: Rambam Health Care Center
city: H̱olon
country: Israel
facility: Wolfson Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
Study officials:
affiliation: Asklepion Pharmaceuticals, LLC
name: Gurdyal Kalsi, MD
role: STUDY_DIRECTOR
References: