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

NCT02891837 | Completed Phase 3 Results DMC

• 2 other identifiers: CIT-003-012016-002427-28
• Study Type: interventional
• Target: 189
• Locations: 4 countries
• Sites: 29

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.

Conditions

Acute Lung Injury

Keywords

L-citrulline; pediatric; Lung Injury; Bypass; Heart Defects; Clinical Sequelae

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• Length of Time on Mechanical Ventilation

  28 Days

• Length of Time on Positive Pressure Ventilation

  28 Days

• Length of Time of Inotrope Use

  28 days

• Inotrope Score

  Up to 48 hours after separation from CBP

• Hemodynamic Improvement: Heart Rate

  2 Days

Study Arms (2)

L-citrulline

EXPERIMENTAL

* 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.

Drug: L-citrulline

Placebo

PLACEBO COMPARATOR

* 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.

Other: Placebo

Interventions

L-citrulline 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.

L-citrulline

Placebo 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.

Placebo

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Asklepion Pharmaceuticals, LLC: lead

Study Sites (29)

University of Alabama

Birmingham, Alabama, 35233, United States

Location

Loma Linda University Children's Hospital

Loma Linda, California, 92354, United States

Location

University of California Davis Medical Center

Sacramento, California, 95817, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Nicklaus Children's Hospital

Miami, Florida, 33155, United States

Location

Arnold Palmer Hospital for Children

Orlando, Florida, 32806, United States

Location

Advocate Children's Hospital

Oak Lawn, Illinois, 60453, United States

Location

Riley Hospital for Children at Indiana University

Indianapolis, Indiana, 46202, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216-4505, United States

Location

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

St Louis, Missouri, 63104, United States

Location

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

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

The Children's Hospital at Montefiore

The Bronx, New York, 10467, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43215, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792-1690, United States

Location

LKH-Universitätsklinikum Graz Universitätsklinik für Kinder- und Jugendheilkunde

Graz, 8036, Austria

Location

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

Vienna, 1050, Austria

Location

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Klinik für Kinderkardiologie und angeborene Herzfehler. Deutsches Herzzentrum München - Klinik an der TU München

München, 80636, Germany

Location

Universitätsklinik Tübingen, Kinderkardiologie Pulmonologie, Intensivmedizin

Tübingen, Tübingen, Germany

Location

Rambam Health Care Center

Haifa, 3109601, Israel

Location

Wolfson Medical Center

Holon, 5822012, Israel

Location

Sheba Medical Center

Ramat Gan, 5265601, Israel

Location

MeSH Terms

Conditions

Acute Lung Injury; Lung Injury

Interventions

Citrulline

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Thoracic Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins

Limitations and Caveats

Data were significantly skewed due to differences in standard of care between US and non-US. The US dataset met the primary endpoint due to consistent early extubation in the OR. L-Citrulline promoted early extubation, reduced ventilator time \& inotrope use in the US population. Post-hoc analyses gave a significant primary endpoint with an L-Citrulline therapeutic window of 100 µmol ±20% steady state concentration. A second Phase 3 RCT to be conducted in the US alone should confirm this result.

Results Point of Contact

• Title: Gurdyal Kalsi, MD, MFPM (Hon)
• Organization: Asklepion Pharmaceuticals, LLC

gurdyal.kalsi@asklepionpharm.com

+1 410.736.3750

Study Officials

• Gurdyal Kalsi, MD

  Asklepion Pharmaceuticals, LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2016
• First Posted: September 8, 2016
• Study Start: August 1, 2016
• Primary Completion: June 1, 2019
• Study Completion: July 1, 2019
• Last Updated: February 23, 2023
• Results First Posted: February 23, 2023

Record last verified: 2023-01

Locations

AU (2); DE (4); IL (3); US (20)