A Phase I, Safety and Pharmacokinetics/Pharmacodynamics Study of Oral L-CIT Supplementation in Preterm Infants With BPD±PH and NEC
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 36
- Locations
- 2
- Primary Endpoint
- Safety of oral L-Citrulline administration
Study Overview
Brief Summary
The purpose of this study is to evaluate the safety and explore the PK/PD of L-CIT supplementation in preterm infants to prevent the development of inflammatory pathways initiated by low levels of plasma CIT, specifically in preterm infants with post-surgical NEC and BPD±PH.
Detailed Description
Preterm infants are born with underdeveloped organs and immune systems, placing them at great risk for morbidity. They are more susceptible to inflammatory injury, particularly from conditions of prematurity mediated by inflammatory pathways such as bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC).
L-CIT, an amino acid, is the first intermediate in the urea cycle as well as a precursor to arginine and nitric oxide (NO), which promotes blood flow. It is made in the intestine and has been shown to exert vasoprotective and anti-inflammatory effects. BPD-PH and NEC are two specific inflammatory diseases of prematurity involving CIT, arginine or NO deficiencies.
Evaluation of the safety and PK/PD of L-CIT supplementation for diseases involving CIT, arginine or NO deficiencies in preterm infants is important. Therefore, in this trial the investigator would like to evaluate the safety and pharmacokinetics/pharmacodynamics (PD) of L-CIT supplementation in preterm infants post surgical NEC and BPD-PH.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 1 Month to 6 Months (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Arm 1: BPD±PH:
- •Inclusion Criteria:
- •Born ≤ 30 weeks at birth
- •Post-menstrual age (PMA) ≥ 32 weeks
- •Echocardiographic evidence of PH for infants with BPD+PH.
- •On invasive or non-invasive ventilation with RSS >2.0 for >12hours/day for at least 48 hours as an early predictor of evolving BPD
- •Informed written consent (parents/substitute decision maker)
Exclusion Criteria
- •Congenital Heart Disease [Exceptions: small atrial septal defect (ASD), small ventricular septal defect (VSD), small patent ductus arteriosus (PDA)]
- •Infants with pulmonary vein stenosis
- •Concurrent sepsis with hemodynamic instability
- •Infants considered likely to die within next 7 days
- •Any other condition that, in the opinion of the investigator, may adversely affect the infant's ability to complete the study or its measures or pose significant risk to the infant
- •Arm 2: surgical NEC
- •Inclusion Criteria:
- •Born ≤ 30 weeks at birth
- •Recovering from Stage IIIb NEC as per modified Bell's staging (pneumoperitoneum requiring surgery)
- •Tolerating 50 ml/kg/day of enteral feeds
- •Informed written consent (parents/substitute decision maker)
- •Considered medically stable by clinical team
- •Exclusion Criteria
- •Congenital heart disease (except small ASD, small VSD and non hsPDA)
- •Pulmonary vein stenosis
- •Concurrent sepsis with hemodynamic instability
- •Likely to die within next 7 days
- •Other condition significantly affecting pulmonary function independent of prematurity or NEC
Arms & Interventions
BPD±PH
Arm 1: BPD±PH
Total of 18 infants at 300 mg/kg/day divided q6 hours
Intervention: L-Citrulline (Dietary Supplement)
Surgical NEC
Arm 2: sNEC
A total of 18 infants with Stage III NEC:
Dose Level 1 = 150 mg/kg/day divided q6 hours for one week. If study participant tolerates 150mg/kg/day well, then escalate the same study participant to Dose 2 after 1 week of starting Citrulline.
Dose Level 2 = 200 mg/kg/day divided q6 hours At 34 weeks of gestation, if baby is still on respiratory support of >250ml/min of Low flow oxygen, then we will escalate to the dose of 300mg/kg/day and continue until 38 weeks PMA or until discharge, whichever is earlier.
Intervention: L-Citrulline (Dietary Supplement)
Outcomes
Primary Outcomes
Safety of oral L-Citrulline administration
Time Frame: 5 years
The number of patients with adverse events (AE) as a measure of safety and tolerability
Secondary Outcomes
- Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax)(5 years)
- Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax)(5 years)
- Bayley's scale for infant development(5 years)
- Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax)(5 years)
- Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT(5 years)
- Association of stool output with the area under the concentration time curve (AUC) for L-CIT(5 years)
- Association of blood pressure with minimum L-CIT concentration (Cmin)(5 years)
- Oxidative stress(5 years)
- Desaturation index(5 years)
- Changes in Blood Pressure(5 years)
- Ventilation(5 years)
- BPD(5 years)
- Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin)(5 years)
- Respiratory Score (RSS)(5 years)
- Stoma, nasogastric or stool output(5 years)
- Postnatal steroid Use(5 years)
- Association of stool output with minimum L-CIT concentration (Cmin)(5 years)
- Correlation between CIT and arginine levels(5 years)
- Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT(5 years)
- Biomarkers of inflammation(5 years)
- BPD severity(5 years)
- Pre-discharge mortality(5 years)
Investigators
Estelle Gauda
Head, Division of Neonatology
The Hospital for Sick Children