Acute Lung Injury
Conditions
Keywords
L-citrulline, pediatric, Lung Injury, Bypass, Heart Defects, Clinical Sequelae
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.
Interventions
DRUGL-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.
OTHERPlacebo
* 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.
Sponsors
Asklepion Pharmaceuticals, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use. | 28 Days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 48 hours after separation from CBP | 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). |
| Hemodynamic Improvement: Heart Rate | 2 Days | Heart rate at hours 1, 2, 4, 12, 24 and 48. |
| Hemodynamic Improvement: Systemic Arterial Blood Pressure | 2 Days | Systemic arterial blood pressure at hours 1, 2, 4, 12, 24 and 48. |
| Hemodynamic Improvement: Oxygen Saturation | 2 Days | Oxygen saturation at hours 1, 2, 4, 12, 24 and 48. |
| Hemodynamic Improvement: Central Venous Pressure | 2 Days | Central venous pressure at hours 1, 2, 4, 12, 24 and 48. |
| 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 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 Pediatric Intensive Care Unit (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. |
| Patients With 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. The number of affected subjects will be reported. |
| Number of Patients With Refractory Hypotension | 2 Days | 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. |
| 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. |
Countries
Austria, Germany, Israel, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 99 |
| 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.
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. | 90 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | L-citrulline |
|---|---|---|---|
| Age, Customized All patients | 18.4 Months STANDARD_DEVIATION 29.2 | 19.5 Months STANDARD_DEVIATION 31.6 | 17.4 Months STANDARD_DEVIATION 26.9 |
| Age, Customized US Patients off mechanical ventilation in ≤48 hours | 16.9 Months STANDARD_DEVIATION 28.6 | 17.3 Months STANDARD_DEVIATION 29.1 | 16.6 Months STANDARD_DEVIATION 28.4 |
| Age, Customized US Patients off mechanical ventilation in >48 hours | 7.8 Months STANDARD_DEVIATION 9.4 | 9.0 Months STANDARD_DEVIATION 11.9 | 6.6 Months STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) All patients Hispanic or Latino | 20 Participants | 12 Participants | 8 Participants |
| Ethnicity (NIH/OMB) All patients Not Hispanic or Latino | 168 Participants | 77 Participants | 91 Participants |
| Ethnicity (NIH/OMB) All patients Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) USA patients Hispanic or Latino | 13 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) USA patients Not Hispanic or Latino | 98 Participants | 45 Participants | 53 Participants |
| Ethnicity (NIH/OMB) USA patients Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Europe | 11 participants | 6 participants | 5 participants |
| Region of Enrollment Israel | 41 participants | 22 participants | 19 participants |
| Region of Enrollment United States | 137 participants | 71 participants | 66 participants |
| Sex: Female, Male All patients Female | 98 Participants | 53 Participants | 45 Participants |
| Sex: Female, Male All patients Male | 91 Participants | 37 Participants | 54 Participants |
| Sex: Female, Male USA patients Female | 56 Participants | 32 Participants | 24 Participants |
| Sex: Female, Male USA patients Male | 56 Participants | 22 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 99 | 0 / 90 | 0 / 76 | 0 / 58 | 0 / 23 | 0 / 13 | 0 / 71 | 0 / 54 | 1 / 19 | 0 / 12 |
| other Total, other adverse events | 68 / 99 | 61 / 90 | 48 / 76 | 30 / 58 | 20 / 23 | 10 / 13 | 46 / 71 | 29 / 54 | 15 / 19 | 8 / 12 |
| serious Total, serious adverse events | 11 / 99 | 6 / 90 | 5 / 76 | 2 / 58 | 7 / 23 | 4 / 13 | 2 / 71 | 2 / 54 | 4 / 19 | 3 / 12 |
Outcome results
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use. | 3351.1 Minutes | Standard Deviation 5230.8 |
| Placebo | A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use. | 3549.6 Minutes | Standard Deviation 6069.1 |
p-value: 0.493Wilcoxon (Mann-Whitney)
Secondary
Hemodynamic Improvement: Central Venous Pressure
Central venous pressure at hours 1, 2, 4, 12, 24 and 48.
Time frame: 2 Days
Population: Modified FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 12 hours | 9.7 Millimeters of mercury | Standard Deviation 4.1 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 72 hours | 10.3 Millimeters of mercury | Standard Deviation 5.6 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 24 hours | 10.9 Millimeters of mercury | Standard Deviation 5.4 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 4 hours | 13.1 Millimeters of mercury | Standard Deviation 23.7 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 48 hours | 11.8 Millimeters of mercury | Standard Deviation 6.2 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | 1 hour | 10.2 Millimeters of mercury | Standard Deviation 20.1 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 48 hours | 9.6 Millimeters of mercury | Standard Deviation 8.3 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 72 hours | 13.2 Millimeters of mercury | Standard Deviation 23.9 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 4 hours | 13.2 Millimeters of mercury | Standard Deviation 27.4 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 12 hours | 9.0 Millimeters of mercury | Standard Deviation 3.6 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 24 hours | 9.8 Millimeters of mercury | Standard Deviation 3.6 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | 1 hour | 12.9 Millimeters of mercury | Standard Deviation 28 |
Secondary
Hemodynamic Improvement: Heart Rate
Heart rate at hours 1, 2, 4, 12, 24 and 48.
Time frame: 2 Days
Population: Modified FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Heart Rate | 1 hour | 80.1 Beats per minute | Standard Deviation 67.9 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | 2 hours | 111.2 Beats per minute | Standard Deviation 45.7 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | 4 hours | 130.4 Beats per minute | Standard Deviation 27.7 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | 12 hours | 120.9 Beats per minute | Standard Deviation 22 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | 24 hours | 122.2 Beats per minute | Standard Deviation 22.2 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | 48 hours | 125.9 Beats per minute | Standard Deviation 18.7 |
| Placebo | Hemodynamic Improvement: Heart Rate | 24 hours | 118.3 Beats per minute | Standard Deviation 14.9 |
| Placebo | Hemodynamic Improvement: Heart Rate | 1 hour | 83.6 Beats per minute | Standard Deviation 60.1 |
| Placebo | Hemodynamic Improvement: Heart Rate | 12 hours | 161.9 Beats per minute | Standard Deviation 17.6 |
| Placebo | Hemodynamic Improvement: Heart Rate | 2 hours | 116.0 Beats per minute | Standard Deviation 46.7 |
| Placebo | Hemodynamic Improvement: Heart Rate | 48 hours | 125.4 Beats per minute | Standard Deviation 21 |
| Placebo | Hemodynamic Improvement: Heart Rate | 4 hours | 133.5 Beats per minute | Standard Deviation 20.1 |
Secondary
Hemodynamic Improvement: Oxygen Saturation
Oxygen saturation at hours 1, 2, 4, 12, 24 and 48.
Time frame: 2 Days
Population: Modified FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 1 hour | 97.2 Percentage of hemoglobin bound to oxygen | Standard Deviation 7.9 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 2 hours | 98.6 Percentage of hemoglobin bound to oxygen | Standard Deviation 4.6 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 4 hours | 98.5 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.1 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 12 hours | 97.9 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.4 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 24 hours | 97.1 Percentage of hemoglobin bound to oxygen | Standard Deviation 4 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | 48 hours | 97.6 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.8 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 24 hours | 97.6 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.7 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 1 hour | 95.7 Percentage of hemoglobin bound to oxygen | Standard Deviation 15.8 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 12 hours | 97.6 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.6 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 2 hours | 97.6 Percentage of hemoglobin bound to oxygen | Standard Deviation 10.7 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 48 hours | 97.8 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.6 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | 4 hours | 98.1 Percentage of hemoglobin bound to oxygen | Standard Deviation 2.7 |
Secondary
Hemodynamic Improvement: Systemic Arterial Blood Pressure
Systemic arterial blood pressure at hours 1, 2, 4, 12, 24 and 48.
Time frame: 2 Days
Population: Modified FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 1 hour | 18.4 Millimeters of mercury | Standard Deviation 16.2 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 2 hours | 31.7 Millimeters of mercury | Standard Deviation 17.9 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 4 hours | 42.4 Millimeters of mercury | Standard Deviation 12.1 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 12 hours | 39.7 Millimeters of mercury | Standard Deviation 12.1 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 24 hours | 41.0 Millimeters of mercury | Standard Deviation 12.2 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 48 hours | 40.3 Millimeters of mercury | Standard Deviation 15.8 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 24 hours | 40.1 Millimeters of mercury | Standard Deviation 10.8 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 1 hour | 15.3 Millimeters of mercury | Standard Deviation 14.9 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 12 hours | 40.7 Millimeters of mercury | Standard Deviation 10.6 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 2 hours | 32.5 Millimeters of mercury | Standard Deviation 18.2 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 48 hours | 42.1 Millimeters of mercury | Standard Deviation 11.6 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | 4 hours | 42.1 Millimeters of mercury | Standard Deviation 12.3 |
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).
Time frame: Up to 48 hours after separation from CBP
Population: All patients (mFAS)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Inotrope Score | 24 hours after separation from CBP | 2143.0 µg/kg/min | Standard Deviation 12376.4 |
| L-citrulline | Inotrope Score | 20 hours after separation from CBP | 3254.9 µg/kg/min | Standard Deviation 16449.3 |
| L-citrulline | Inotrope Score | 25 hours after separation from CBP | 2142.8 µg/kg/min | Standard Deviation 12376.4 |
| L-citrulline | Inotrope Score | 12 hours after separation from CBP | 5983.5 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 26 hours after separation from CBP | 2142.8 µg/kg/min | Standard Deviation 12376.4 |
| L-citrulline | Inotrope Score | 5 hours after separation from CBP | 6044.0 µg/kg/min | Standard Deviation 39567 |
| L-citrulline | Inotrope Score | 27 hours after separation from CBP | 2041.4 µg/kg/min | Standard Deviation 2004.9 |
| L-citrulline | Inotrope Score | 28 hours after separation from CBP | 2041.1 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 13 hours after separation from CBP | 5983.1 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 29 hours after separation from CBP | 2041.1 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 2 hours after separation from CBP | 5076.2 µg/kg/min | Standard Deviation 38880 |
| L-citrulline | Inotrope Score | 30 hours after separation from CBP | 2041.1 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 14 hours after separation from CBP | 3255.8 µg/kg/min | Standard Deviation 16449.2 |
| L-citrulline | Inotrope Score | 31 hours after separation from CBP | 2040.9 µg/kg/min | Standard Deviation 12352.6 |
| L-citrulline | Inotrope Score | 6 hours after separation from CBP | 5983.5 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 32 hours after separation from CBP | 2041.0 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 15 hours after separation from CBP | 3255.8 µg/kg/min | Standard Deviation 16449.2 |
| L-citrulline | Inotrope Score | 33 hours after separation from CBP | 2041.1 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 46 hours after separation from CBP | 1012.1 µg/kg/min | Standard Deviation 7071.9 |
| L-citrulline | Inotrope Score | 34 hours after separation from CBP | 2041.0 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 16 hours after separation from CBP | 3255.4 µg/kg/min | Standard Deviation 16449.2 |
| L-citrulline | Inotrope Score | 35 hours after separation from CBP | 2040.9 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 7 hours after separation from CBP | 5983.3 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 36 hours after separation from CBP | 2041.1 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 17 hours after separation from CBP | 3255.7 µg/kg/min | Standard Deviation 16449.2 |
| L-citrulline | Inotrope Score | 37 hours after separation from CBP | 2040.9 µg/kg/min | Standard Deviation 12352.5 |
| L-citrulline | Inotrope Score | 8 hours after separation from CBP | 5983.2 µg/kg/min | Standard Deviation 2007.7 |
| L-citrulline | Inotrope Score | 38 hours after separation from CBP | 2040.9 µg/kg/min | Standard Deviation 12352.6 |
| L-citrulline | Inotrope Score | 18 hours after separation from CBP | 3255.4 µg/kg/min | Standard Deviation 16449.2 |
| L-citrulline | Inotrope Score | 39 hours after separation from CBP | 2040.9 µg/kg/min | Standard Deviation 12352.6 |
| L-citrulline | Inotrope Score | 3 hours after separation from CBP | 5983.4 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 40 hours after separation from CBP | 1012.5 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 19 hours after separation from CBP | 3254.9 µg/kg/min | Standard Deviation 16449.3 |
| L-citrulline | Inotrope Score | 41 hours after separation from CBP | 1012.5 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 9 hours after separation from CBP | 5983.4 µg/kg/min | Standard Deviation 39369.2 |
| L-citrulline | Inotrope Score | 42 hours after separation from CBP | 1012.5 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 1 hour after separation from CBP | 1691.6 µg/kg/min | Standard Deviation 11420.8 |
| L-citrulline | Inotrope Score | 43 hours after separation from CBP | 1012.4 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 21 hours after separation from CBP | 2143.6 µg/kg/min | Standard Deviation 12376.3 |
| L-citrulline | Inotrope Score | 44 hours after separation from CBP | 1012.4 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 10 hours after separation from CBP | 5983.0 µg/kg/min | Standard Deviation 39369.3 |
| L-citrulline | Inotrope Score | 45 hours after separation from CBP | 1012.3 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 22 hours after separation from CBP | 2143.2 µg/kg/min | Standard Deviation 12376.3 |
| L-citrulline | Inotrope Score | 4 hours after separation from CBP | 6044.1 µg/kg/min | Standard Deviation 39566.9 |
| L-citrulline | Inotrope Score | 47 hours after separation from CBP | 1012.1 µg/kg/min | Standard Deviation 7071.8 |
| L-citrulline | Inotrope Score | 23 hours after separation from CBP | 2143.2 µg/kg/min | Standard Deviation 12376.3 |
| L-citrulline | Inotrope Score | 48 hours after separation from CBP | 1012.1 µg/kg/min | Standard Deviation 7071.9 |
| L-citrulline | Inotrope Score | 11 hours after separation from CBP | 5983.1 µg/kg/min | Standard Deviation 39369.2 |
| Placebo | Inotrope Score | 30 hours after separation from CBP | 2004.7 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 27 hours after separation from CBP | 12352.5 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 1 hour after separation from CBP | 583.6 µg/kg/min | Standard Deviation 4879 |
| Placebo | Inotrope Score | 2 hours after separation from CBP | 537.1 µg/kg/min | Standard Deviation 4870.3 |
| Placebo | Inotrope Score | 3 hours after separation from CBP | 1258.2 µg/kg/min | Standard Deviation 11744 |
| Placebo | Inotrope Score | 4 hours after separation from CBP | 1257.4 µg/kg/min | Standard Deviation 11744.1 |
| Placebo | Inotrope Score | 5 hours after separation from CBP | 1257.3 µg/kg/min | Standard Deviation 11744.1 |
| Placebo | Inotrope Score | 6 hours after separation from CBP | 1243.4 µg/kg/min | Standard Deviation 11677.9 |
| Placebo | Inotrope Score | 8 hours after separation from CBP | 39369.2 µg/kg/min | Standard Deviation 13688.2 |
| Placebo | Inotrope Score | 9 hours after separation from CBP | 2007.1 µg/kg/min | Standard Deviation 13688.3 |
| Placebo | Inotrope Score | 10 hours after separation from CBP | 2007.0 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 11 hours after separation from CBP | 2007.0 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 12 hours after separation from CBP | 2006.8 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 13 hours after separation from CBP | 2006.7 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 14 hours after separation from CBP | 2006.6 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 15 hours after separation from CBP | 2006.5 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 16 hours after separation from CBP | 2006.6 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 17 hours after separation from CBP | 2006.5 µg/kg/min | Standard Deviation 13688.4 |
| Placebo | Inotrope Score | 18 hours after separation from CBP | 2006.2 µg/kg/min | Standard Deviation 13688.5 |
| Placebo | Inotrope Score | 19 hours after separation from CBP | 2006.1 µg/kg/min | Standard Deviation 13688.5 |
| Placebo | Inotrope Score | 20 hours after separation from CBP | 2005.7 µg/kg/min | Standard Deviation 13688.5 |
| Placebo | Inotrope Score | 21 hours after separation from CBP | 2107.8 µg/kg/min | Standard Deviation 13707.6 |
| Placebo | Inotrope Score | 22 hours after separation from CBP | 2005.7 µg/kg/min | Standard Deviation 13688.5 |
| Placebo | Inotrope Score | 23 hours after separation from CBP | 2005.6 µg/kg/min | Standard Deviation 13688.6 |
| Placebo | Inotrope Score | 24 hours after separation from CBP | 2005.3 µg/kg/min | Standard Deviation 13688.6 |
| Placebo | Inotrope Score | 25 hours after separation from CBP | 2005.2 µg/kg/min | Standard Deviation 13688.6 |
| Placebo | Inotrope Score | 26 hours after separation from CBP | 2004.9 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 28 hours after separation from CBP | 2005.4 µg/kg/min | Standard Deviation 13688.6 |
| Placebo | Inotrope Score | 29 hours after separation from CBP | 2004.7 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 7 hours after separation from CBP | 1243.4 µg/kg/min | Standard Deviation 11677.9 |
| Placebo | Inotrope Score | 31 hours after separation from CBP | 2004.6 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 32 hours after separation from CBP | 2004.7 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 33 hours after separation from CBP | 2004.6 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 34 hours after separation from CBP | 2004.6 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 35 hours after separation from CBP | 2004.4 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 36 hours after separation from CBP | 2004.5 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 37 hours after separation from CBP | 2004.4 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 38 hours after separation from CBP | 2004.4 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 39 hours after separation from CBP | 2004.3 µg/kg/min | Standard Deviation 13688.7 |
| Placebo | Inotrope Score | 40 hours after separation from CBP | 2004.3 µg/kg/min | Standard Deviation 13688.8 |
| Placebo | Inotrope Score | 41 hours after separation from CBP | 1282.1 µg/kg/min | Standard Deviation 8736.4 |
| Placebo | Inotrope Score | 42 hours after separation from CBP | 780.0 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 43 hours after separation from CBP | 779.9 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 44 hours after separation from CBP | 780.1 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 45 hours after separation from CBP | 780.0 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 46 hours after separation from CBP | 780.0 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 47 hours after separation from CBP | 780.0 µg/kg/min | Standard Deviation 7378.4 |
| Placebo | Inotrope Score | 48 hours after separation from CBP | 779.8 µg/kg/min | Standard Deviation 7378.4 |
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Hospitalization | 7.1 Days | Standard Deviation 5.1 |
| Placebo | Length of Hospitalization | 3.9 Days | Standard Deviation 3.9 |
p-value: 0.3681Wilcoxon (Mann-Whitney)
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Pediatric Intensive Care Unit (PICU) Stay | 6.3 Days | Standard Deviation 8.5 |
| Placebo | Length of Pediatric Intensive Care Unit (PICU) Stay | 6.5 Days | Standard Deviation 9.2 |
p-value: 0.7572Wilcoxon (Mann-Whitney)
Secondary
Length of Time of Inotrope Use
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time of Inotrope Use | 2726.4 Minutes | Standard Deviation 3637.5 |
| Placebo | Length of Time of Inotrope Use | 3167.3 Minutes | Standard Deviation 6035.2 |
p-value: 0.8678Wilcoxon (Mann-Whitney)
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time of Intubation | 1600.4 Minutes | Standard Deviation 4488.9 |
| Placebo | Length of Time of Intubation | 1303.9 Minutes | Standard Deviation 4408.3 |
p-value: 0.6422Wilcoxon (Mann-Whitney)
Secondary
Length of Time on Mechanical Ventilation
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Mechanical Ventilation | 2398.4 Minutes | Standard Deviation 2031.8 |
| Placebo | Length of Time on Mechanical Ventilation | 5236.9 Minutes | Standard Deviation 4714.7 |
Secondary
Length of Time on Positive Pressure Ventilation
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Positive Pressure Ventilation | 2018.7 Minutes | Standard Deviation 4918.5 |
| Placebo | Length of Time on Positive Pressure Ventilation | 1285.6 Minutes | Standard Deviation 2354.8 |
p-value: 0.1924Wilcoxon (Mann-Whitney)
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Vasodilators | 1668.4 Minutes | Standard Deviation 5751.6 |
| Placebo | Length of Time on Vasodilators | 611.3 Minutes | Standard Deviation 1212.5 |
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.
Time frame: 2 Days
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-citrulline | Number of Patients With Refractory Hypotension | 0 Participants |
| Placebo | Number of Patients With Refractory Hypotension | 0 Participants |
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.
Time frame: 28 Days
Population: The analysis of AEs included all patients who were randomized, underwent surgery and received study medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 68 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 19 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 68 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 11 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 6 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 62 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 61 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 12 Participants |
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.
Time frame: 28 Days
Population: All patients (mFAS)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 0 - Intra-Op | 2179.6 umol/L | Standard Deviation 1046.8 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 0 - 12 hours | 123.8 umol/L | Standard Deviation 41.3 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 0 - 0 hours (post bolus) | 1387.8 umol/L | Standard Deviation 4957.5 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 0 - 0 hours (prior to bolus) | 1808.9 umol/L | Standard Deviation 12549.4 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 2 - 48 hours | 68.2 umol/L | Standard Deviation 44.9 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 0 - 6 hours | 146.6 umol/L | Standard Deviation 67.3 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 28/ Discharge | 21.9 umol/L | Standard Deviation 29.5 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Day 1 - 24 hours | 102.1 umol/L | Standard Deviation 42.6 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 28/ Discharge | 16.9 umol/L | Standard Deviation 6.2 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 0 - Intra-Op | 26.4 umol/L | Standard Deviation 9.1 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 0 - 0 hours (prior to bolus) | 27.6 umol/L | Standard Deviation 11.3 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 0 - 0 hours (post bolus) | 27.8 umol/L | Standard Deviation 11.6 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 0 - 6 hours | 20.3 umol/L | Standard Deviation 10.2 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 0 - 12 hours | 18.5 umol/L | Standard Deviation 8.4 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 1 - 24 hours | 14.9 umol/L | Standard Deviation 6.8 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Day 2 - 48 hours | 12.1 umol/L | Standard Deviation 5.8 |
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.
Time frame: 28 Days
Population: Modified FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Thoracotomy Output | 206.41 Milliliters | Standard Deviation 137.26 |
| Placebo | Thoracotomy Output | 198.94 Milliliters | Standard Deviation 143.85 |
Post Hoc
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. Note: data are reported for post-hoc analyses based on a modified full analysis set (mFAS) targeting the US population for a 48-hour treatment period. Analysis method used was quartiles based, but followed prescribed statistical analysis plan methods. This is because chosen endpoints did not appear to be valid in the ex-US population due to differences in physician decision making. In the US, extubation occurs as soon as a patient's physical condition permits (only more severely ill children remain on mechanical ventilation); conversely, in ex-US sites, children remain on mechanical ventilation.
Time frame: 28 Days
Population: Only data from US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use. | 1484.9 Minutes | Standard Deviation 1317.1 |
| Placebo | A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use. | 1730.7 Minutes | Standard Deviation 1435.5 |
Comparison: H0: Composite endpoint in L-citrulline group = placebo group H1: Composite endpoint in L-citrulline group ≠ placebo group H0 tested using Wilcoxon-rank-sum test. Significance level = 1% (2-sided).p-value: 0.15695% CI: [-88, 626]Wilcoxon (Mann-Whitney)
Comparison: Post hoc analyses were done for US patients on mechanical ventilation for \<=48 hours. For all post hoc analyses a significance level of 5% was applied.p-value: 0.162795% CI: [-335.5, 1961.6]t-test, 2 sided
Post Hoc
Hemodynamic Improvement: Central Venous Pressure
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.
Time frame: 2 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after treatment | -10.0 Millimeters of mercury | Standard Deviation 48.8 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after treatment | -6.5 Millimeters of mercury | Standard Deviation 47.4 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after treatment | 6.7 Millimeters of mercury | Standard Deviation 36.5 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after treatment | -10.4 Millimeters of mercury | Standard Deviation 58.6 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after treatment | -0.1 Millimeters of mercury | Standard Deviation 11.2 |
| L-citrulline | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after treatment | -5.3 Millimeters of mercury | Standard Deviation 17.3 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after treatment | -8.3 Millimeters of mercury | Standard Deviation 43.9 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after treatment | -6.8 Millimeters of mercury | Standard Deviation 45 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after treatment | -7.7 Millimeters of mercury | Standard Deviation 41.1 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after treatment | -5.2 Millimeters of mercury | Standard Deviation 43.8 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after treatment | 6.2 Millimeters of mercury | Standard Deviation 20.8 |
| Placebo | Hemodynamic Improvement: Central Venous Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after treatment | -5.2 Millimeters of mercury | Standard Deviation 41.7 |
Comparison: Values at 48 hours post-surgery start for all US patients on ventilation for ≤48 hours are presented.~Treatment group, baseline values and site were included as fixed factors, site\*treatment as interaction terms in this ANOVA. The normality assumption of residuals is critical for all considered timepoints. Please interpret results with caution.p-value: 0.0326ANOVA
Comparison: Values at 48 hours post-surgery start for ALL patients on ventilation for ≤48 hours are presented.~Treatment group, baseline values and site were included as fixed factors, site\*treatment as interaction terms in this ANOVA. The normality assumption of residuals is critical for all considered timepoints. Please interpret results with caution.p-value: 0.0026ANOVA
Post Hoc
Hemodynamic Improvement: Heart Rate
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.
Time frame: 2 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | -43.9 Beats per minute | Standard Deviation 78.6 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | -14.1 Beats per minute | Standard Deviation 50 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 10.0 Beats per minute | Standard Deviation 27.3 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 1.8 Beats per minute | Standard Deviation 19.6 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | 3.1 Beats per minute | Standard Deviation 21.3 |
| L-citrulline | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 5.8 Beats per minute | Standard Deviation 21.2 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | 3.3 Beats per minute | Standard Deviation 20.3 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | -40.6 Beats per minute | Standard Deviation 66.4 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 5.4 Beats per minute | Standard Deviation 16.5 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | 1.1 Beats per minute | Standard Deviation 43 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 7.1 Beats per minute | Standard Deviation 26.6 |
| Placebo | Hemodynamic Improvement: Heart Rate | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 18.5 Beats per minute | Standard Deviation 24.9 |
Post Hoc
Hemodynamic Improvement: Oxygen Saturation
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.
Time frame: 2 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | 1.3 Percentage of hemoglobin bound to oxygen | Standard Deviation 6.2 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | 2.3 Percentage of hemoglobin bound to oxygen | Standard Deviation 9.4 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 1.4 Percentage of hemoglobin bound to oxygen | Standard Deviation 8.8 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 0.8 Percentage of hemoglobin bound to oxygen | Standard Deviation 8.4 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | -0.2 Percentage of hemoglobin bound to oxygen | Standard Deviation 9.9 |
| L-citrulline | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 0.4 Percentage of hemoglobin bound to oxygen | Standard Deviation 9.6 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | 0.2 Percentage of hemoglobin bound to oxygen | Standard Deviation 8.4 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | -1.8 Percentage of hemoglobin bound to oxygen | Standard Deviation 18.2 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 0.7 Percentage of hemoglobin bound to oxygen | Standard Deviation 8.7 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | 1.5 Percentage of hemoglobin bound to oxygen | Standard Deviation 9 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 1.1 Percentage of hemoglobin bound to oxygen | Standard Deviation 10.3 |
| Placebo | Hemodynamic Improvement: Oxygen Saturation | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 0.7 Percentage of hemoglobin bound to oxygen | Standard Deviation 9.4 |
Post Hoc
Hemodynamic Improvement: Systemic Arterial Blood Pressure
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.
Time frame: 2 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | -17.9 Millimeters of mercury | Standard Deviation 13.2 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | -3.8 Millimeters of mercury | Standard Deviation 19.1 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 7.3 Millimeters of mercury | Standard Deviation 12.5 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 6.6 Millimeters of mercury | Standard Deviation 11.7 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | 8.8 Millimeters of mercury | Standard Deviation 12.9 |
| L-citrulline | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 6.5 Millimeters of mercury | Standard Deviation 17.9 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after surgery start | 8.4 Millimeters of mercury | Standard Deviation 11.4 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after surgery start | -22.3 Millimeters of mercury | Standard Deviation 17.1 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after surgery start | 7.2 Millimeters of mercury | Standard Deviation 13.1 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after surgery start | -4.0 Millimeters of mercury | Standard Deviation 17.8 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after surgery start | 7.6 Millimeters of mercury | Standard Deviation 14.5 |
| Placebo | Hemodynamic Improvement: Systemic Arterial Blood Pressure | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after surgery start | 8.9 Millimeters of mercury | Standard Deviation 13.5 |
Post Hoc
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).
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 13 hours after separation from CBP | 3.3 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 25 hours after separation from CBP | 1.8 µg/kg/min | Standard Deviation 2.6 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 7 hours after separation from CBP | 3.6 µg/kg/min | Standard Deviation 2.7 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 26 hours after separation from CBP | 1.7 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 14 hours after separation from CBP | 3.1 µg/kg/min | Standard Deviation 2.5 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 27 hours after separation from CBP | 1.5 µg/kg/min | Standard Deviation 2.7 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after separation from CBP | 3.6 µg/kg/min | Standard Deviation 2.6 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 28 hours after separation from CBP | 1.4 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 15 hours after separation from CBP | 3.1 µg/kg/min | Standard Deviation 2.6 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 29 hours after separation from CBP | 1.3 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 8 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 2.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 30 hours after separation from CBP | 1.4 µg/kg/min | Standard Deviation 2.5 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 31 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 16 hours after separation from CBP | 3.0 µg/kg/min | Standard Deviation 2.6 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 32 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 9 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 2.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 33 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 17 hours after separation from CBP | 3.1 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 34 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 5 hours after separation from CBP | 3.7 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 35 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 18 hours after separation from CBP | 3.0 µg/kg/min | Standard Deviation 2.7 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 36 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 10 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 2.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 37 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 19 hours after separation from CBP | 2.8 µg/kg/min | Standard Deviation 2.7 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 38 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.1 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 3 hours after separation from CBP | 4.5 µg/kg/min | Standard Deviation 4.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 39 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.1 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 20 hours after separation from CBP | 2.9 µg/kg/min | Standard Deviation 3.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 40 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.1 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 11 hours after separation from CBP | 3.3 µg/kg/min | Standard Deviation 2.5 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 41 hours after separation from CBP | 0.9 µg/kg/min | Standard Deviation 2.1 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 21 hours after separation from CBP | 2.6 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 42 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.3 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 6 hours after separation from CBP | 3.7 µg/kg/min | Standard Deviation 2.8 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 43 hours after separation from CBP | 0.8 µg/kg/min | Standard Deviation 1.9 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 22 hours after separation from CBP | 2.3 µg/kg/min | Standard Deviation 2.7 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 44 hours after separation from CBP | 0.9 µg/kg/min | Standard Deviation 2.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 3.5 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 45 hours after separation from CBP | 0.7 µg/kg/min | Standard Deviation 2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 23 hours after separation from CBP | 2.2 µg/kg/min | Standard Deviation 3.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 46 hours after separation from CBP | 0.6 µg/kg/min | Standard Deviation 1.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after separation from CBP | 17.2 µg/kg/min | Standard Deviation 98 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 47 hours after separation from CBP | 0.6 µg/kg/min | Standard Deviation 1.4 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after separation from CBP | 2.1 µg/kg/min | Standard Deviation 3.1 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after separation from CBP | 0.4 µg/kg/min | Standard Deviation 1.2 |
| L-citrulline | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after separation from CBP | 14.7 µg/kg/min | Standard Deviation 43 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 48 hours after separation from CBP | 0.7 µg/kg/min | Standard Deviation 1.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 30 hours after separation from CBP | 1.4 µg/kg/min | Standard Deviation 2.4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 1 hour after separation from CBP | 17.4 µg/kg/min | Standard Deviation 44.8 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 2 hours after separation from CBP | 13.5 µg/kg/min | Standard Deviation 58.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 3 hours after separation from CBP | 4.5 µg/kg/min | Standard Deviation 3.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 4 hours after separation from CBP | 4.4 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 5 hours after separation from CBP | 4.4 µg/kg/min | Standard Deviation 2.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 6 hours after separation from CBP | 4.4 µg/kg/min | Standard Deviation 2.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 7 hours after separation from CBP | 4.5 µg/kg/min | Standard Deviation 3.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 8 hours after separation from CBP | 4.5 µg/kg/min | Standard Deviation 3.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 9 hours after separation from CBP | 4.4 µg/kg/min | Standard Deviation 3.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 10 hours after separation from CBP | 4.3 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 11 hours after separation from CBP | 4.1 µg/kg/min | Standard Deviation 2.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 12 hours after separation from CBP | 4.0 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 13 hours after separation from CBP | 3.8 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 14 hours after separation from CBP | 3.7 µg/kg/min | Standard Deviation 3.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 15 hours after separation from CBP | 3.7 µg/kg/min | Standard Deviation 3.4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 16 hours after separation from CBP | 3.5 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 17 hours after separation from CBP | 3.8 µg/kg/min | Standard Deviation 4.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 18 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 19 hours after separation from CBP | 3.4 µg/kg/min | Standard Deviation 3.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 20 hours after separation from CBP | 3.1 µg/kg/min | Standard Deviation 3.4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 21 hours after separation from CBP | 3.1 µg/kg/min | Standard Deviation 3.8 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 22 hours after separation from CBP | 2.7 µg/kg/min | Standard Deviation 3.2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 23 hours after separation from CBP | 2.9 µg/kg/min | Standard Deviation 4.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 24 hours after separation from CBP | 2.3 µg/kg/min | Standard Deviation 3.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 25 hours after separation from CBP | 2.4 µg/kg/min | Standard Deviation 4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 26 hours after separation from CBP | 1.9 µg/kg/min | Standard Deviation 3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 27 hours after separation from CBP | 1.8 µg/kg/min | Standard Deviation 2.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 28 hours after separation from CBP | 2.0 µg/kg/min | Standard Deviation 3.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 29 hours after separation from CBP | 1.5 µg/kg/min | Standard Deviation 2.8 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 31 hours after separation from CBP | 1.4 µg/kg/min | Standard Deviation 2.4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 32 hours after separation from CBP | 1.5 µg/kg/min | Standard Deviation 3.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 33 hours after separation from CBP | 1.4 µg/kg/min | Standard Deviation 2.7 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 34 hours after separation from CBP | 1.3 µg/kg/min | Standard Deviation 2.5 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 35 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.4 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 36 hours after separation from CBP | 1.3 µg/kg/min | Standard Deviation 2.7 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 37 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 38 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 39 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 40 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 41 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 42 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 43 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.1 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 44 hours after separation from CBP | 1.2 µg/kg/min | Standard Deviation 2.9 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 45 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 46 hours after separation from CBP | 1.1 µg/kg/min | Standard Deviation 2.3 |
| Placebo | Inotrope Score | Patients on mechanical ventilation for ≤48 hours (US patients) - 47 hours after separation from CBP | 1.0 µg/kg/min | Standard Deviation 2.3 |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Hospitalization | 4.9 Days | Standard Deviation 2.6 |
| Placebo | Length of Hospitalization | 4.8 Days | Standard Deviation 2.5 |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Pediatric Intensive Care Unit (PICU) Stay | 5.6 Days | Standard Deviation 9.2 |
| Placebo | Length of Pediatric Intensive Care Unit (PICU) Stay | 7.1 Days | Standard Deviation 10.7 |
Post Hoc
Length of Time of Inotrope Use
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time of Inotrope Use | 1428.6 Minutes | Standard Deviation 1344.6 |
| Placebo | Length of Time of Inotrope Use | 1653.1 Minutes | Standard Deviation 1485.7 |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time of Intubation | 329.9 Minutes | Standard Deviation 432.6 |
| Placebo | Length of Time of Intubation | 386.5 Minutes | Standard Deviation 556.6 |
Post Hoc
Length of Time on Mechanical Ventilation
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Mechanical Ventilation | 420.2 Minutes | Standard Deviation 585.1 |
| Placebo | Length of Time on Mechanical Ventilation | 649.7 Minutes | Standard Deviation 786.4 |
Post Hoc
Length of Time on Positive Pressure Ventilation
The same definitions and analyses as described for the primary endpoint will be applied.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Positive Pressure Ventilation | 200.9 Minutes | Standard Deviation 560.5 |
| Placebo | Length of Time on Positive Pressure Ventilation | 358.0 Minutes | Standard Deviation 758.5 |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Length of Time on Vasodilators | 617.9 Minutes | Standard Deviation 910 |
| Placebo | Length of Time on Vasodilators | 624.8 Minutes | Standard Deviation 1077.1 |
Post Hoc
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.
Time frame: 2 Days
Population: Data not available for this endpoint. Full analysis to include all secondary endpoints was not feasible and not done. Several post-hoc analysis were instead conducted on the primary endpoint and presented to the FDA.
Post Hoc
Occurrence of Adverse and Serious Adverse Events
Pre-treatment adverse events and treatment adverse events will be analyzed separately. The number affected subjects will be reported.
Time frame: 28 Days
Population: The analysis of AEs included all patients who were randomized, underwent surgery and received study medication divided into the following subgroups:~* All patients off mechanical ventilation in ≤48 hours (N=147)~* US patients off mechanical ventilation in ≤48 hours (N=112)~* All patients off mechanical ventilation in \>48 hours (N=42)~* US patients off mechanical ventilation in \>48 hours (N=25)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 48 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 48 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 1 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 12 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 4 Participants |
| L-citrulline | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 4 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 30 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 6 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 30 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 2 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 1 Participants |
| Placebo | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 2 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 1 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 7 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 7 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 7 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 20 Participants |
| L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 20 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 3 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 10 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 4 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 4 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 1 Participants |
| L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 10 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 2 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 47 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 9 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 46 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 2 Participants |
| Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 0 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 2 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 30 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 1 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 29 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 6 Participants |
| Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 2 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 4 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 4 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 15 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 3 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 0 Participants |
| Placebo - All Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 15 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any adverse event | 8 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Any serious adverse event | 3 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment-emergent serious adverse events | 3 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment adverse events | 1 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Treatment emergent adverse events | 8 Participants |
| Placebo - US Patients Off Mechanical Ventilation in >48 Hours | Occurrence of Adverse and Serious Adverse Events | Pre-treatment serious adverse events | 0 Participants |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 12 hours | 125.6 umol/L | Standard Deviation 32.9 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 0 hours (post bolus) | 760.1 umol/L | Standard Deviation 369.5 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 1 - 24 hours | 108.4 umol/L | Standard Deviation 43 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - Intra-Op | 2264.6 umol/L | Standard Deviation 890.1 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 2 - 48 hours | 73.3 umol/L | Standard Deviation 49.6 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 6 hours | 133.7 umol/L | Standard Deviation 39.2 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 28/ Discharge | 28.5 umol/L | Standard Deviation 44.3 |
| L-citrulline | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 0 hours (prior to bolus) | 2625.4 umol/L | Standard Deviation 16391.9 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 28/ Discharge | 16.2 umol/L | Standard Deviation 6.4 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - Intra-Op | 26.7 umol/L | Standard Deviation 9.5 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 0 hours (post bolus) | 25.7 umol/L | Standard Deviation 9 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 6 hours | 18.8 umol/L | Standard Deviation 8.6 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 12 hours | 17.6 umol/L | Standard Deviation 7.4 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 1 - 24 hours | 14.6 umol/L | Standard Deviation 6.6 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 2 - 48 hours | 12.4 umol/L | Standard Deviation 6.8 |
| Placebo | Patients With Plasma Concentrations of Citrulline | Patients on mechanical ventilation for ≤48 hours (US patients) - Day 0 - 0 hours (prior to bolus) | 25.4 umol/L | Standard Deviation 8.8 |
Post Hoc
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.
Time frame: 28 Days
Population: Only US patients on mechanical ventilation for ≤48 hours are analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-citrulline | Thoracotomy Output | 209.42 Milliliters | Standard Deviation 141.35 |
| Placebo | Thoracotomy Output | 194.35 Milliliters | Standard Deviation 124.41 |