Clinical trial NCT05636397: Safety and PK-PD Study of Oral L-CIT in Preterm Infants with BPD±PH and NEC
Official title: A Phase I, Safety and Pharmacokinetics/pharmacodynamics Study of Oral L-CIT Supplementation in Preterm Infants with BPD±PH and NEC
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: BPD - Bronchopulmonary Dysplasia
Pulmonary Hypertension
NEC
Keywords: BPD±PH
surgical NEC
L-Citrulline
Pharmacokinetic profile
Pharmacodynamic profile
Preterm neonates
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2022-12-05
Enrollment: 60
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective dose-escalation study.

Arm 1: BPD-PH Total of 12-24 infants; 6-12 at each dose level. (300 or 500 mg/kg/day divided q6 hours)

Arm 2: sNEC A total of 18-36 infants with Stage III NEC; 6-12 at each dose level. (75, 150 or 225 mg/kg/day divided q6 hours)
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Safety of oral L-Citrulline administration
timeFrame: 5 years
Secondary outcomes:
measure: Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax)
timeFrame: 5 years
measure: Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
timeFrame: 5 years
measure: Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
timeFrame: 5 years
measure: Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT
timeFrame: 5 years
measure: Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT
timeFrame: 5 years
measure: Association of stool output with the area under the concentration time curve (AUC) for L-CIT
timeFrame: 5 years
measure: Association of blood pressure with minimum L-CIT concentration (Cmin)
timeFrame: 5 years
measure: Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin)
timeFrame: 5 years
measure: Association of stool output with minimum L-CIT concentration (Cmin)
timeFrame: 5 years
measure: Correlation between CIT and arginine levels
timeFrame: 5 years
measure: Biomarkers of inflammation
timeFrame: 5 years
measure: Oxidative stress
timeFrame: 5 years
measure: Respiratory Score (RSS)
timeFrame: 5 years
measure: Desaturation index
timeFrame: 5 years
measure: Changes in Blood Pressure
timeFrame: 5 years
measure: Stoma, nasogastric or stool output
timeFrame: 5 years
measure: Ventilation
timeFrame: 5 years
measure: BPD severity
timeFrame: 5 years
measure: BPD
timeFrame: 5 years
measure: Pre-discharge mortality
timeFrame: 5 years
measure: Postnatal steroid Use
timeFrame: 5 years
measure: Bayley's scale for infant development
timeFrame: 5 years
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Hospital For Sick Children
state: Ontario
Study officials:
affiliation: Division Head, Division of Neonatology
name: Estelle Gauda, MD
role: PRINCIPAL_INVESTIGATOR
References: