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

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ClinicalTrials.gov Identifier: NCT02891837
Recruitment Status : Recruiting
First Posted : September 8, 2016
Last Update Posted : December 5, 2018
Sponsor:
Information provided by (Responsible Party):
Asklepion Pharmaceuticals, LLC

Brief Summary:
The purpose of this study is to determine whether L-citrulline is effective and safe in the prevention of clinical sequelae of Acute Lung Injury in pediatric subjects undergoing surgery for congenital heart defects.

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

Detailed Description:

This is a randomized, double-blind, placebo controlled, multicenter study that will compare the efficacy and safety of L-citrulline versus placebo in subjects undergoing surgery for congenital heart defects.

Eligible subjects undergoing repair of a large unrestrictive ventricular septal defect (VSD), a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial septal defect (primum ASD) will be eligible for enrollment in this study.

Each enrolled subject will be randomized to receive either L-citrulline or placebo throughout all administrations in the study. Subjects will receive an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass, the addition of L-citrulline at a concentration of 200 μmol/L or placebo given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L. L-citrulline bolus of 20 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hr continuous L-citrulline infusion or placebo for up to 48 hours.

The study drug or placebo infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever comes first. Subjects will be followed until Day 28 or discharge from the hospital, whichever comes first. For subjects discharged prior to Day 28, a final assessment via telephone will be conducted at Day 28.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 190 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Phase III Double-Blind, Randomized, Placebo Controlled, Multi-Center Clinical Study to Evaluate the Efficacy and Safety of Intravenous L-citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Subjects Undergoing Surgery for Congenital Heart Defects
Study Start Date : August 2016
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : October 2019


Arm Intervention/treatment
Experimental: L-citrulline
  • Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base;
  • Addition of study medication at a concentration of 200 μmol/L given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L;
  • Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass;
  • 9 mg/kg/hr continuous infusion for up to 48 hours.
Drug: L-citrulline
  • Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base;
  • Addition of study medication at a concentration of 200 μmol/L given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L;
  • Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass;
  • 9 mg/kg/hr continuous infusion for up to 48 hours.

Placebo Comparator: Placebo
  • Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass;
  • Addition of placebo matched for volume given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations during bypass;
  • Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass;
  • 9 mg/kg/hr continuous infusion for up to 48 hours.
Other: Placebo
  • Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass;
  • Addition of placebo matched for volume given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations during bypass;
  • Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass;
  • 9 mg/kg/hr continuous infusion for up to 48 hours.




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


Secondary Outcome Measures :
  1. Length of time on mechanical ventilation [ Time Frame: 28 Days ]
    The same definitions and analyses as described for the primary endpoint will be applied.

  2. Length of time on positive pressure ventilation [ Time Frame: 28 Days ]
    The same definitions and analyses as described for the primary endpoint will be applied.

  3. Length of time of inotrope use [ Time Frame: 28 days ]
    The same definitions and analyses as described for the primary endpoint will be applied.

  4. Inotrope score [ Time Frame: 28 Days ]
    Inotrope score will be calculated each hour post-operatively from the time of separation from bypass until the completion of study drug. Additionally, the total inotrope score over time until Day 28 or hospital discharge will be derived.

  5. Hemodynamic Improvement [ Time Frame: 2 Days ]
    Hemodynamic evaluations include heart rate, systemic arterial blood pressure, oxygen saturation, and central venous pressure. The absolute changes from baseline at hours 1, 2, 4, 12, 24, and 48 will be compared between groups.

  6. Hemodynamic Improvement: Heart Rate [ Time Frame: 2 Days ]
    Heart rate will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.

  7. Hemodynamic Improvement: Systemic arterial blood pressure [ Time Frame: 2 Days ]
    Systemic arterial blood pressure will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.

  8. Hemodynamic Improvement: Oxygen saturation [ Time Frame: 2 Days ]
    Oxygen saturation will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.

  9. Hemodynamic Improvement: Central venous pressure [ Time Frame: 2 Days ]
    Central venous pressure will be calculated using the absolute changes from baseline at hours 1, 2, 4, 12, 24 and 48 and will be compared between groups using an ANOVA with a fixed effect for treatment group and baseline level. Summary tables describing descriptive measurements will be generated for absolute values and absolute change from baseline values for all observed time points.

  10. Thoracotomy output [ Time Frame: 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.

  11. Length of time of intubation [ Time Frame: 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.

  12. Length of PICU stay [ Time Frame: 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.

  13. Length of time on vasodilators [ Time Frame: 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.

  14. Length of hospitalization [ Time Frame: 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.

  15. Plasma concentrations of citrulline [ Time Frame: 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.

  16. Occurrence of adverse and serious adverse events [ Time Frame: 28 Days ]
    Pre-treatment adverse events and treatment adverse events will be analyzed separately. AEs will be summarized by system organ class (SOC) and preferred term (PT) according to Medical Dictionary for Regulatory Activities (MedDRA). The number of events, as well as the number and rate of affected subjects will be reported. AEs (SOC and PT) will also be summarized by seriousness, as well as by severity and relationship to study medication.

  17. Incidence of refractory hypotension [ Time Frame: 2 Days ]
    Refractory hypotension is defined as a 20% drop of MAP below specific age-related criteria for more than 30 minutes. The number of subjects with any refractory hypotension from end of surgery until 48 hours will be compared between groups.

  18. Change from baseline in laboratory values [ Time Frame: 2 Days ]
    The laboratory analyses will be performed at the local hospital/institution laboratories. Reference ranges will be supplied by all appropriate laboratory facilities and used by the investigator to assess the laboratory data for clinical significance and pathological changes. Change from baseline in laboratory values (serum electrolytes, blood urea nitrogen [BUN], creatinine, complete blood count, LFTs, and ACT will be tabulated using summary tables listing descriptive measurements for all observed time points.



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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects, parents, or legal guardian of the subject who are willing and able to sign informed consent
  • Male and female subjects aged ≤18 years of age
  • Infants, children and adolescents undergoing 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02891837


Contacts
Contact: Cindy Zychowicz, BA 410-545-0494 ext 104 Cindy.zychowicz@asklepionpharm.com

  Show 23 Study Locations
Sponsors and Collaborators
Asklepion Pharmaceuticals, LLC
Investigators
Study Director: Gurdyal Kalsi, MD Asklepion Pharmaceuticals, LLC

Responsible Party: Asklepion Pharmaceuticals, LLC
ClinicalTrials.gov Identifier: NCT02891837     History of Changes
Other Study ID Numbers: CIT-003-01
2016-002427-28 ( EudraCT Number )
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: December 5, 2018
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Asklepion Pharmaceuticals, LLC:
L-citrulline
pediatric
Lung Injury
Bypass
Heart Defects
Clinical Sequelae

Additional relevant MeSH terms:
Wounds and Injuries
Lung Injury
Acute Lung Injury
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Respiration Disorders