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

Sponsor

Asklepion Pharmaceuticals, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT02891837

Collaborator

(none)

192

Enrollment

Locations

Arms

Actual Duration (Months)

6.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lung Injury	Drug: L-citrulline Other: Placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

192 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

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

Actual Study Start Date :

Aug 1, 2016

Actual Primary Completion Date :

Jun 1, 2019

Actual Study Completion Date :

Jul 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	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.
Placebo Comparator: 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.	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.

Arm

Intervention/Treatment

Experimental: 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.

Drug: L-citrulline

Placebo Comparator: 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.

Other: Placebo

Outcome Measures

Primary Outcome Measures

A composite variable consisting of the longer of either (1) length of time on mechanical ventilation or (2) length of inotrope use. [28 Days]
The definition of mechanical ventilation shall include invasive mechanical ventilation or noninvasive mechanical ventilation including bilevel (biphasic) positive airway pressure or continuous positive airway pressure. The definition of inotrope use includes medications which are considered within the derivation of the total inotrope score (dopamine, dobutamine, milrinone, epinephrine, phenylephrine, norepinephrine). Length of time on mechanical ventilation & length of inotrope use will be measured until the subject is discharged from the hospital or until Day 28, whichever occurs first.

Secondary Outcome Measures

Length of time on mechanical ventilation [28 Days]
The same definitions and analyses as described for the primary endpoint will be applied.
Length of time on positive pressure ventilation [28 Days]
The same definitions and analyses as described for the primary endpoint will be applied.
Length of time of inotrope use [28 days]
The same definitions and analyses as described for the primary endpoint will be applied.
Inotrope score [28 Days]
Inotrope score will be 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 will be derived.
Hemodynamic Improvement [2 Days]
Hemodynamic evaluations include heart rate, systemic arterial blood pressure, oxygen saturation, and central venous pressure. The absolute changes from baseline at hours 1, 2, 4, 12, 24, and 48 will be compared between groups.
Hemodynamic Improvement: Heart Rate [2 Days]
Heart rate will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.
Hemodynamic Improvement: Systemic arterial blood pressure [2 Days]
Systemic arterial blood pressure will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.
Hemodynamic Improvement: Oxygen saturation [2 Days]
Oxygen saturation will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.
Hemodynamic Improvement: Central venous pressure [2 Days]
Central venous pressure will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.
Thoracotomy output [28 Days]
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.
Length of time of intubation [28 Days]
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.
Length of PICU stay [28 Days]
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.
Length of time on vasodilators [28 Days]
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.
Length of hospitalization [28 Days]
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.
Plasma concentrations of citrulline [28 Days]
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.
Occurrence of adverse and serious adverse events [28 Days]
Pre-treatment adverse events and treatment adverse events will be analyzed separately. AEs will be summarized by system organ class (SOC) and preferred term (PT) according to Medical Dictionary for Regulatory Activities (MedDRA). The number of events, as well as the number and rate of affected subjects will be reported. AEs (SOC and PT) will also be summarized by seriousness, as well as by severity and relationship to study medication.
Incidence of refractory hypotension [2 Days]
Refractory hypotension is defined as a 20% drop of 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.
Change from baseline in laboratory values [2 Days]
The laboratory analyses will be performed at the local hospital/institution laboratories. Reference ranges will be supplied by all appropriate laboratory facilities and used by the investigator to assess the laboratory data for clinical significance and pathological changes. Change from baseline in laboratory values (serum electrolytes, blood urea nitrogen [BUN], creatinine, complete blood count, LFTs, and ACT will be tabulated using summary tables listing descriptive measurements for all observed time points.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	Loma Linda University Children's Hospital	Loma Linda	California	United States	92354
3	University of California Davis Medical Center	Sacramento	California	United States	95817
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Children's National Medical Center	Washington	District of Columbia	United States	20010
6	Nicklaus Children's Hospital	Miami	Florida	United States	33155
7	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
8	Advocate Children's Hospital	Oak Lawn	Illinois	United States	60453
9	Riley Hospital for Children at Indiana University	Indianapolis	Indiana	United States	46202
10	The Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
11	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216-4505
12	St Louis University, SSM Health Cardinal Glennon Children's Hospital	Saint Louis	Missouri	United States	63104
13	Washington University School of Medicine/ St Louis Children's Hospital	Saint Louis	Missouri	United States	63110
14	The Children's Hospital at Montefiore	Bronx	New York	United States	10467
15	Columbia University Medical Center	New York	New York	United States	10032
16	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
17	Nationwide Children's Hospital	Columbus	Ohio	United States	43215
18	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
19	Seattle Children's Hospital	Seattle	Washington	United States	98105
20	University of Wisconsin	Madison	Wisconsin	United States	53792-1690
21	LKH-Universitätsklinikum Graz Universitätsklinik für Kinder- und Jugendheilkunde	Graz		Austria	8036
22	Medizinische Universität Wien, Klinik für Kinder- und Jugendheilkunde, Abteilung für Pädiatrische Kardiologie Kinderherzzentrum	Wien		Austria	1050
23	Universitätsmedizin Göttingen	Göttingen		Germany	37075
24	Medizinische Hochschule Hannover	Hanover		Germany	30625
25	Klinik für Kinderkardiologie und angeborene Herzfehler. Deutsches Herzzentrum München - Klinik an der TU München	München		Germany	80636
26	Universitätsklinik Tübingen, Kinderkardiologie Pulmonologie, Intensivmedizin	Tübingen		Germany	Tübingen
27	Rambam Health Care Center	Haifa		Israel	3109601
28	Wolfson Medical Center	H̱olon		Israel	5822012
29	Sheba Medical Center	Ramat Gan		Israel	5265601