BPD - Bronchopulmonary Dysplasia, NEC, Pulmonary Hypertension
Conditions
Keywords
BPD±PH, surgical NEC, L-Citrulline, Pharmacokinetic profile, Pharmacodynamic profile, Preterm neonates
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.
Interventions
DIETARY_SUPPLEMENTL-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).
Sponsors
The Hospital for Sick Children
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
This is a prospective dose-escalation study. Arm 1: BPD-PH Total of 18 infants at 300 mg/kg/day divided q6 hours 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.
Eligibility
Sex/Gender
ALL
Age
1 Months to 6 Months
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of oral L-Citrulline administration | 5 years | The number of patients with adverse events (AE) as a measure of safety and tolerability |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 pressure 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. |
Countries
Canada
Contacts
CONTACTRachana Patel, MSc, CCRP
CONTACTJeffrey Antwi
PRINCIPAL_INVESTIGATOREstelle Gauda, MD
Division Head, Division of Neonatology
Outcome results
None listed