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

Sponsor

The Hospital for Sick Children (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05636397

Collaborator

(none)

Enrollment

Arms

60.9

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
BPD - Bronchopulmonary Dysplasia Pulmonary Hypertension NEC	Dietary Supplement: L-Citrulline	N/A

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

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

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)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)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I, Safety and Pharmacokinetics/Pharmacodynamics Study of Oral L-CIT Supplementation in Preterm Infants With BPD±PH and NEC

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2027

Anticipated Study Completion Date :

Mar 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BPD±PH 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	Dietary Supplement: L-Citrulline Citrulline is a nonessential amino acid made in the small intestine, occurs naturally in the body, and is believed to help reduce inflammation.L-CIT is a part of the urea cycle, produced as a by-product along with nitric oxide (NO).
Experimental: Surgical NEC 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	Dietary Supplement: L-Citrulline Citrulline is a nonessential amino acid made in the small intestine, occurs naturally in the body, and is believed to help reduce inflammation.L-CIT is a part of the urea cycle, produced as a by-product along with nitric oxide (NO).

Arm

Intervention/Treatment

Experimental: BPD±PH

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

Dietary Supplement: L-Citrulline

Citrulline is a nonessential amino acid made in the small intestine, occurs naturally in the body, and is believed to help reduce inflammation.L-CIT is a part of the urea cycle, produced as a by-product along with nitric oxide (NO).

Experimental: Surgical NEC

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

Dietary Supplement: L-Citrulline

Outcome Measures

Primary Outcome Measures

Safety of oral L-Citrulline administration [5 years]
The number of patients with adverse events (AE) as a measure of safety and tolerability

Secondary Outcome Measures

Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax) [5 years]
Blood pressure of the study participants will be associated with PK measures of L-CIT exposure i.e. Cmax using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax) [5 years]
Stoma or nasogastric output of the study participants will be associated with PK measures of L-CIT exposure i.e. Cmax using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax) [5 years]
Stool output from the study participants will be associated with PK measures of L-CIT exposure i.e. Cmax using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT [5 years]
Blood pressure of the study participants will be associated with PK measures of L-CIT exposure i.e. Area under Concentration time curve (AUC) using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen.
Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT [5 years]
Stoma or nasogastric output of the study participants will be associated with PK measures of L-CIT exposure i.e. Area under Concentration time curve (AUC) using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen.
Association of stool output with the area under the concentration time curve (AUC) for L-CIT [5 years]
Stool output from the study participants will be associated with PK measures of L-CIT exposure i.e. Area under Concentration time curve (AUC) using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen.
Association of blood pressure with minimum L-CIT concentration (Cmin) [5 years]
Blood pressure of study participants will be associated with PK measures of L-CIT exposure i.e. Cmin using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin) [5 years]
Stoma or nasogastric output from study participants will be associated with PK measures of L-CIT exposure i.e. Cmin using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Association of stool output with minimum L-CIT concentration (Cmin) [5 years]
Stool output from study participants will be associated with PK measures of L-CIT exposure i.e. Cmin using univariate correlation approaches. The investigator will then attempt to construct a PK/PD model to link PK and PD measures found to be of significance during the univariate screen. Future larger studies will then be used to examine these relationships with adequately powered studies.
Correlation between CIT and arginine levels [5 years]
Correlation between changes in CIT and arginine levels with nitrite/nitrate levels
Biomarkers of inflammation [5 years]
The levels of IL-1β, IL-6, IL-8, IL-10, TNFα will be measured in tracheal aspirates and blood plasma. The aggregated levels fo these cytokines will reflect the inflammatory status of the study participant.
Oxidative stress [5 years]
Oxidative stress (measured in tracheal aspirates and blood)
Respiratory Score (RSS) [5 years]
The respiratory severity score (RSS) is a simplified severity score consisting of the mean airway pressure (MAP) multiplied by the fraction of inspired oxygen (FiO2). This score ranges from 0 to 12, with a higher score indicating more severe lung disease.
Desaturation index [5 years]
The oxygen desaturation index (ODI) is commonly used to evaluate the severity of nocturnal hypoxemia. The ODI is defined as the number of episodes of oxygen desaturation per hour of sleep with desaturation events of >=10sec/ sampled hour.
Changes in Blood Pressure [5 years]
Changes in diastolic and systolic blood pressure prior to and during CIT treatment.
Stoma, nasogastric or stool output [5 years]
Volume of stoma, nasogastric or stool output prior to and during CIT treatment
Ventilation [5 years]
Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen
BPD severity [5 years]
Moderate to severe BPD based on the different mode of ventilatory support needed at 36 wks PMA. No BPD = off all oxygen and positive pressure support Moderate BPD = low flow oxygen only Severe BPD= positive prssure support (high flow, CPAP, NIPPV, or ETT)
BPD [5 years]
number of days of survival free of BPD
Pre-discharge mortality [5 years]
Number of study participants who died during NICU admission.
Postnatal steroid Use [5 years]
Number of days study participants received postnatal steroids during their NICU stay.
Bayley's scale for infant development [5 years]
Bayley Scales of Infant and Toddler Development is an extensive formal developmental assessment tool for diagnosing developmental delays in early childhood. BSID is the commonly used abbreviation for Bayley Scales of Infant and Toddler Development. Bayley-III includes a motor score, and fine and gross motor subtest scores. The standardized mean motor score is 100 (SD 15), with scores lower than 85 indicating mild impairment, and lower than 70 indicating moderate or severe impairment.In this particular trial, the investigator would be looking at the correlation between the inflammatory markers (IL-1β, IL-6, IL-8, IL-10, TNFα) and Neurodevelopmental outcomes from Bayley's scale during 18-24M follow up visit in babies received L-Citrulline during their NICU stay.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 6 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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