Safety and PK-PD Study of Oral L-CIT in Preterm Infants with BPD±PH and NEC

The Hospital for Sick Children

Status: Enrolling

Conditions: NEC; BPD - Bronchopulmonary Dysplasia; Pulmonary Hypertension

Treatments: Dietary Supplement: L-Citrulline

Study type: Interventional

Funder types: Other

Identifiers

NCT05636397

1000077413

Details and patient eligibility

About

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.

Full 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.

Enrollment: 60 estimated patients

Sex: All

Ages: 1 to 6 months old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Arm 1: BPD±PH:

Inclusion Criteria:

• Born ≤ 30 weeks at birth
• Post-menstrual age (PMA) ≥ 34 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
• 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 30 ml/kg/day of enteral feeds
• On invasive or non-invasive ventilation (NIPPV/nCPAP) with RSS >2.0 for > 12hours/day for at least 48 hours, 10-14 days post surgery
• 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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60 participants in 2 patient groups

BPD±PH

Experimental group

Description:

Arm 1: BPD±PH Total of 12-24 infants; 6-12 at each dose level of oral dosage form of L-Citrulline. (300 or 500 mg/kg/day divided q6 hours). Dose Level 1 = 300 mg/kg/day Dose Level 2 = 500 mg/kg/day

Treatment:

Dietary Supplement: L-Citrulline

Surgical NEC

Experimental group

Description:

Arm 2: sNEC A total of 18-36 infants with Stage III NEC; 6-12 at each dose level of oral dosage form of L-Citrulline. (75, 150 or 225 mg/kg/day divided q6 hours) Dose Level 1 = 75 mg/kg/day Dose Level 2 = 150 mg/kg/day Dose Level 3 = 225 mg/kg/day

Treatment:

Dietary Supplement: L-Citrulline