Clinical trial NCT05253209: A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
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 Patients Undergoing Surgery for Congenital Heart Defects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Ventricular Septal Defect
Atrioventricular Septal Defect
Primum Atrial Septal Defect
Lead sponsor: Asklepion Pharmaceuticals, LLC
Sponsor class: INDUSTRY
First posted: 2022-02-23
Enrollment: 64
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a randomized, double-blind, placebo controlled, multicenter study to compare the efficacy and safety of L-citrulline versus placebo in patients undergoing surgery for congenital heart defects. Eligible patients 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.

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 patients undergoing surgery for congenital heart defects. Eligible patients 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.

Each enrolled patient will be randomized to receive either L citrulline or placebo throughout all administrations in the study. Patients will receive:

1. an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass
2. the addition L-citrulline or placebo to maintain a steady state target concentration of approximately 100 μmol/L of L-Citrulline or placebo during cardiopulmonary bypass
3. an L-citrulline bolus of 10 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 µmol/L.

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

Eligibility criteria: Inclusion Criteria:

* Patients, parents, or legal guardian willing and able to sign informed consent
* Male and female subjects aged ≤18 years of age (females of child-bearing potential willing to practice an acceptable form of birth control)
* Patients undergoing cardiopulmonary bypass for repair of a large unrestrictive ventricular septal defect, an ostium primum/secundum atrial septal defect, or a partial or complete atrioventricular septal defect
* Pre-operative echocardiogram confirming cardiovascular anatomy and defect to be repaired

Exclusion Criteria:

* Evidence of pulmonary artery or vein abnormalities that will not be addressed surgically. Specific abnormalities excluded include:

  * 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 IV 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; Sexually active females of child-bearing potential must be willing to practice an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device)
* 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.
* Any condition which, in the opinion of the investigator, might interfere with the study objectives

Primary outcomes:
measure: Post-operative need for mechanical ventilation
timeFrame: Time in hours from separation from CPB until discontinuation of all mechanical ventilation including non-invasive support or Day 28, whichever occurs first
Secondary outcomes:
measure: Intubation
timeFrame: From separation from bypass until discontinuation of intubation or Day 28, whichever occurs first
measure: Early extubation
timeFrame: From end of surgery until 12 hours post-surgery
measure: Positive pressure ventilation
timeFrame: Time in hours from separation from CPB until discontinuation of all non-invasive mechanical ventilation or Day 28, whichever occurs first
measure: Duration of hospitalization
timeFrame: From surgery until discharge from hospital or Day 28, whichever occurs first
measure: Use of inotropes
timeFrame: Measured from first use until discharge or Day 28, whichever occurs first
measure: Use of vasodilators
timeFrame: Measured from first use until discharge or Day 28, whichever occurs first
measure: Duration of chest tube placement
timeFrame: From the end of the surgery to the time the chest tube is removed or Day 28, whichever occurs first
measure: Volume of chest tube drainage
timeFrame: Duration of chest tube placement or Day 28, whichever occurs first
measure: Hemodynamic improvement (heart rate)
timeFrame: 1, 2, 4, 12, 24, and 48 hours post-dose
measure: Hemodynamic improvement (systemic arterial blood pressure)
timeFrame: 1, 2, 4, 12, 24, and 48 hours post-dose
measure: Hemodynamic improvement (oxygen saturation)
timeFrame: 1, 2, 4, 12, 24, and 48 hours post-dose
measure: Hemodynamic improvement (central venous pressure)
timeFrame: 1, 2, 4, 12, 24, and 48 hours post-dose
measure: Hemodynamic improvement (pulmonary arterial pressure)
timeFrame: 1, 2, 4, 12, 24, and 48 hours post-dose
measure: Arterial blood gasses (PaO2)
timeFrame: Intra-operatively to Day 28
measure: Arterial blood gasses (PaCO2)
timeFrame: Intra-operatively to Day 28
measure: Arterial blood gasses (HCO3)
timeFrame: Intra-operatively to Day 28
measure: Arterial blood gasses (pH)
timeFrame: Intra-operatively to Day 28
measure: Plasma levels of L-citrulline to assess PK-PD (exposure-response) relationship
timeFrame: Pre-surgery, 6, 12, 24 and 48 hours after first dose
measure: Health Economics: mechanical ventilation
timeFrame: Total over duration of hospitalization or to Day 28 whichever occurs first
measure: Health Economics: duration of hospitalisation
timeFrame: Total over duration of hospitalization or to Day 28 whichever occurs first
measure: Adverse events
timeFrame: Pre-operatively until Day 28
measure: Incidence of refractory hypotension
timeFrame: From the end of surgery until 48 hours after first dose
measure: Clinical laboratory values (Blood Hemoglobin and Total Bilirubin)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Haematocrit)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Red Blood Cell Count)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (White Blood Cell Count)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Platelet Count)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Sodium, Potassium, Calcium, Magnesium, Chloride)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Urea Nitrogen and Creatinine)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Lactate Dehydrogenase)
timeFrame: Intra-operatively, Days 1, 2 and 28
measure: Clinical laboratory values (Blood Activated Clotting Time)
timeFrame: Intra-operatively, Days 1, 2 and 28
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Aurora
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Chicago
country: United States
facility: Heart Center, Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center Surgical Office of Clinical Research (SOCR)
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital- The Heart Center
state: Ohio
city: Seattle
country: United States
facility: Seattle Children's Research Institute
state: Washington
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: Riley Hospital for Children at Indiana University Health
name: Christopher Mastropietro, MD, FCCM
role: PRINCIPAL_INVESTIGATOR
affiliation: Asklepion Pharmaceuticals, LLC
name: Gurdyal Kalsi, MD, MFPM
role: STUDY_DIRECTOR
References: