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NCT Number: NCT05636397

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

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.

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Key information

Conditions

BPD - Bronchopulmonary Dysplasia Bronchopulmonary Dysplasia Cardiovascular Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Hypertension Hypertension, Pulmonary Infant, Newborn, Diseases Infant, Premature, Diseases Lung Diseases Lung Injury NEC Pulmonary Hypertension Respiratory Tract Diseases Vascular Diseases Ventilator-Induced Lung Injury

Age range

1 month–6 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

The Hospital For Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location status: Recruiting

Location contact

Principal investigator

CONTACT

[email protected]

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

L-citrulline

Dietary Supplement

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).

Primary outcomes

  1. 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

  1. Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax)

    Time frame: 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.

  2. Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax)

    Time frame: 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.

  3. Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax)

    Time frame: 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.

  4. Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT

    Time frame: 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.

  5. Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT

    Time frame: 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.

  6. Association of stool output with the area under the concentration time curve (AUC) for L-CIT

    Time frame: 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.

  7. Association of blood pressure with minimum L-CIT concentration (Cmin)

    Time frame: 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.

  8. Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin)

    Time frame: 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.

  9. Association of stool output with minimum L-CIT concentration (Cmin)

    Time frame: 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.

  10. Correlation between CIT and arginine levels

    Time frame: 5 years

    Correlation between changes in CIT and arginine levels with nitrite/nitrate levels

  11. Biomarkers of inflammation

    Time frame: 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.

  12. Oxidative stress

    Time frame: 5 years

    Oxidative stress (measured in tracheal aspirates and blood)

  13. Respiratory Score (RSS)

    Time frame: 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.

  14. Desaturation index

    Time frame: 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.

  15. Changes in Blood Pressure

    Time frame: 5 years

    Changes in diastolic and systolic blood pressure prior to and during CIT treatment.

  16. Stoma, nasogastric or stool output

    Time frame: 5 years

    Volume of stoma, nasogastric or stool output prior to and during CIT treatment

  17. Ventilation

    Time frame: 5 years

    Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen

  18. BPD severity

    Time frame: 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 pressure support (high flow, CPAP, NIPPV, or ETT)

  19. BPD

    Time frame: 5 years

    number of days of survival free of BPD

  20. Pre-discharge mortality

    Time frame: 5 years

    Number of study participants who died during NICU admission.

  21. Postnatal steroid Use

    Time frame: 5 years

    Number of days study participants received postnatal steroids during their NICU stay.

  22. Bayley's scale for infant development

    Time frame: 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Jeffrey Antwi

CONTACT

[email protected]

+1(416-)813-7654 ext. 202919

Rachana Patel, MSc, CCRP

CONTACT

[email protected]

+1(416)-813-7654 ext. 202821

Sponsors and collaborators

Lead sponsor

The Hospital for Sick Children

Other

Registry information

Official study title

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

Important dates

Study start
2023
Primary completion
2027
Study completion
2028
First posted
Dec 5, 2022
Registry last updated
May 4, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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