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Atrial Septal DefectPhase 1/2NCT01120964

Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol

A Phase 1/2 study testing Intravenous L-Citrulline in people with Atrial Septal Defect and Ventricular Septal Defect, run by Asklepion Pharmaceuticals, LLC at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it). Read more about this study

Who is it for?
Ages Up to 6 years
What is being tested?
Intravenous L-Citrulline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
22 participants
Where
2 sitesUnited States
Study dates
Sep 2010to Apr 2012
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 6 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Informed Consent signed by the subject's legal representative
  • Subjects < 6 years old
  • Subjects undergoing cardiopulmonary bypass for repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect

Who cannot join

  • Pulmonary artery or vein abnormalities being addressed surgically
  • Preoperative requirement for invasive mechanical ventilation or intravenous inotrope support
  • Any condition which, in the opinion of the investigator, might interfere with study objectives

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Washington University Children's Hospital

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: Phase IB Double Blind, Randomized, Placebo Controlled Clinical Trial to Determine the Pharmacokinetics and Safety of a Revised Protocol of Intravenous L-Citrulline (Citrupress®) Versus Placebo in Children Undergoing Cardiopulmonary Bypass

This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it).

Citrulline is a protein building block in the body that can convert into another substance, nitric oxide (NO), which controls blood pressure in the lungs. Increased blood pressure in the lungs can be an important surgical problem; it may also lead to problems following surgery, such as severe high blood pressure in the lungs (pulmonary hypertension), increased time spent on a breathing machine, and a longer stay in the intensive care unit (ICU). The hypothesis of this study is that perioperative supplementation with intravenous citrulline will increase plasma citrulline, arginine and NO metabolites and prevent elevations in the postoperative PVT leading to a decrease in the duration of postoperative invasive mechanical ventilation.

The objective of this study is to determine in a randomized placebo controlled phase IB multicenter clinical trial if a revised protocol of intravenous L-citrulline delivery given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect,ventricular septal defect or an atrioventricular septal defect.

Read the detailed description

Increased pulmonary vascular tone (PVT) can complicate the postoperative course of the following five surgical procedures for congenital heart defects: 1) unrestrictive ventricular septal defect (VSD) repair; 2) atrioventricular septal (AVSD) repair; 3) arterial switch procedure for transposition of the great arteries (TGA); 4) bidirectional Glenn shunt procedure; and 5) Fontan procedure for single ventricle lesions. PVT is partially controlled by NO. Arginine, the precursor to NO, is a product of the urea cycle. Preliminary data have been presented regarding 169 infants and children who have undergone one of six previous surgical procedures. It was found that urea cycle function and plasma arginine levels were significantly decreased in all participants. Furthermore, participants with increased PVT had significantly lower arginine levels compared to participants with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme (carbamyl phosphate synthetase I [CPSl T1405N]) appeared to affect postoperative plasma arginine levels and PVT. It is hypothesized that perioperative enhancement of urea cycle function with the key urea cycle intermediate (citrulline) will increase plasma arginine and NO metabolites and prevent elevations in PVT.

Being tested
Intravenous L-Citrulline, Placebo of Intravenous L-Citrulline
Medical subject headings
Heart Septal Defects, Atrial, Heart Septal Defects, Ventricular, Atrioventricular Septal Defect

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Intravenous L-CitrullineDrug

  • Placebo of Intravenous L-CitrullineDrug

    Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

Study groups in NCT01120964
Study groupRoleWhat they receive
Intravenous L-CitrullineExperimentalIV bolus of 150 mg/kg L-citrulline at the initiation of bypass, followed by L-citrulline (200 μmol/L) addition to the filtration or hemoconcentration replacement fluid used during bypass. Plus L-citrulline (20 mg/kg) bolus 30 minutes after decannulation from bypass, immediately followed by 9 mg/kg/h continuous L-citrulline infusion for 48 hours.
Receives: Drug: Intravenous L-Citrulline
Placebo of Intravenous L-CitrullinePlacebo comparatorPlacebo administered according to the same schedule as L-citrulline
Receives: Drug: Placebo of Intravenous L-Citrulline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. L-citrulline Plasma Levels

    Citrulline Blood Levels: 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to administration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infusion is discontinued if prior to 48 hours.

    Measured: Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.

Secondary outcomes (15)
  1. Postoperative Invasive Mechanical Ventilation (Mean and SD)

    Duration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.

    Measured: Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first

  2. Postoperative Invasive Mechanical Ventilation (Median and Range)

    Duration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.

    Measured: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first

  3. Total Duration of Respiratory Support

    Analysis included any invasive and non-invasive respiratory support required during the study period

    Measured: Baseline to discharge or Day 30, whichever occurs first

  4. Postoperative Intravenous Inotrope Duration

    The length of time on IV inotropes was documented from the time of first use after surgery until completion of the study medication at Hour 48 (i.e., duration of inotrope use was maximally 48 hours). Patients still receiving inotropes at Hour 48 were censored.

    Measured: Measured at 48 hours

  5. Total Inotrope Score

    The inotrope dose was calculated each hour postoperatively from the time of PICU admission until the completion of study drug using the following scoring system:

    Dopamine (μg/kg/min) x 1 plus Dobutamine (μg/kg/min) x 1 plus Milrinone (μg/kg/min) x10 plus Epinephrine (Adrenaline) (μg/kg/min) x 100 plus Phenylephrine (μg/kg/min) x 100 plus Norepinephrine (Noradrenaline) (μg/kg/min) x 100

    = Total inotrope score

    An ANOVA was performed. Additionally a repeated measures analysis of variance was used to compare total inotrope score between placebo and citrulline.

    Measured: PICU admission until Hour 48

  6. Time on Vasoactive Medications

    The total number of hours on vasoactive medications, including nitroglycerin, nitroprusside and vasopressin, was calculated from the end of surgery until the discontinuation of vasoactive medications or end of study medication (Hour 48), whichever occurred first

    Measured: Hour 0 to Hour 48

  7. Total Vasoactive Score

    Vasoactive 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 vasoactive 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 score in the citrulline group when compared to the placebo group.

    In this study, the score was calculated post-operatively from the time of separation from bypass until the completion of study drug. Vasoactive score was calculated using the following formula:

    Total Vasoactive Score = nitroglycerin dose + nitroprusside dose + vasopressin dose

    The minimum value is zero (i.e., no vasoactive drugs administered), but it is not possible to define a maximum as this is wholly dependent upon the dose of each vasoactive drug administered.

    Measured: Hour 0 to Hour 48

  8. Length of ICU Stay

    Duration of ICU stay was analyzed once as the total number of postoperative hours spent in the ICU and once as the total number of postoperative hours that a patient required postoperative mechanical ventilator or continuous intravenous inotrope or vasodilator support. The latter combination of parameters represents another surrogate endpoint for ICU stay

    Measured: Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first

  9. Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy

    The composite endpoint comprised the longer of the duration of positive pressure ventilatory support or of inotrope therapy. Since inotrope use was only documented until Hour 48 after surgery (end of study medication treatment), patients with inotrope use continuing until Hour 48 and with mechanical ventilation duration of ≤48 h were censored at this time point. If mechanical ventilation was continued beyond the 48-hour time point, the duration of mechanical ventilation was used in the analysis.

    Measured: Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first

  10. Length of Hospitalization

    Measured: Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first

  11. Incidence of Increased PVT (Defined as a Sustained Mean Pulmonary Artery Pressure Greater Than 20 mm Hg for at Least 2 Hours, Measured During the First 48 Hours

    There were insufficient data to analyze ECHO measurements in summary statistics. Additionally, most images were of very low quality and the data from ECHO evaluations were insufficient to determine whether the affected patients had pulmonary hypertension.

    Measured: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first

  12. Duration of Chest Tube Drainage

    Measured: Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred first

  13. Volume of Chest Tube Drainage

    Measured: Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred first

  14. Survival

    28-day postoperative survival and survival to discharge

    Measured: Measured at 28 days post surgical repair

  15. Number of Patients With Clinically Significant Hypotension.

    Age specific mean arterial blood pressure (MAP) limits compared between the citrulline and placebo groups will be used to determine significant hypotension.

    Defined as MAP below a specific age-based value (infants and age 1 year, 40; ; age 2 years, 44; age 3 years, 47; age 4 years, 50; age 5 years, 52; age 6 years, 53), that lasted greater than 30 minutes and was unresponsive to therapeutic interventions such as fluid administration (volume bolus) and increasing inotropic support.

    Measured: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 May 2010 (estimated)
  2. Study startSep 2010
  3. Primary completionApr 2012
  4. Study completionApr 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Investigator
Enrolment
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01120964
Sponsor's protocol ID
CIT-002-01
Status last verified
Jul 2022
First submitted
6 May 2010
Last updated
27 Jul 2022
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Intravenous L-Citrulline in people with Atrial Septal Defect and Ventricular Septal Defect, run by Asklepion Pharmaceuticals, LLC at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Jun 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

L-citrulline Plasma Levels (time frame: Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jul 2022.

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