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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BPD±PH | Experimental | Arm 1: BPD±PH Total of 18 infants at 300 mg/kg/day divided q6 hours |
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| Surgical NEC | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Safety of oral L-Citrulline administration | The number of patients with adverse events (AE) as a measure of safety and tolerability | 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax) | 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. |
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Arm 1: BPD±PH:
Inclusion Criteria:
Exclusion Criteria
Arm 2: surgical NEC
Inclusion Criteria:
Exclusion Criteria
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rachana Patel, MSc, CCRP | Contact | +1(416)-813-7654 | 202821 | rachana.patel@sickkids.ca |
| Jeffrey Antwi | Contact | +1(416-)813-7654 | 202919 | jeffrey.antwi@sickkids.ca |
| Name | Affiliation | Role |
|---|---|---|
| Estelle Gauda, MD | Division Head, Division of Neonatology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Hospital For Sick Children | Recruiting | Toronto | Ontario | M5G 1X8 | Canada |
Individual Participant Data will not be shared.
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| ID | Term |
|---|---|
| D001997 | Bronchopulmonary Dysplasia |
| D006976 | Hypertension, Pulmonary |
| ID | Term |
|---|---|
| D055397 | Ventilator-Induced Lung Injury |
| D055370 | Lung Injury |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D002956 | Citrulline |
| ID | Term |
|---|---|
| D000599 | Amino Acids, Diamino |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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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.
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| 5 years |
| Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax) | 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. | 5 years |
| Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax) | 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. | 5 years |
| Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT | 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 years |
| Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT | 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. | 5 years |
| Association of stool output with the area under the concentration time curve (AUC) for L-CIT | 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. | 5 years |
| Association of blood pressure with minimum L-CIT concentration (Cmin) | 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. | 5 years |
| Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin) | 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. | 5 years |
| Association of stool output with minimum L-CIT concentration (Cmin) | 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. | 5 years |
| Correlation between CIT and arginine levels | Correlation between changes in CIT and arginine levels with nitrite/nitrate levels | 5 years |
| Biomarkers of inflammation | 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. | 5 years |
| Oxidative stress | Oxidative stress (measured in tracheal aspirates and blood) | 5 years |
| Respiratory Score (RSS) | 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. | 5 years |
| Desaturation index | 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. | 5 years |
| Changes in Blood Pressure | Changes in diastolic and systolic blood pressure prior to and during CIT treatment. | 5 years |
| Stoma, nasogastric or stool output | Volume of stoma, nasogastric or stool output prior to and during CIT treatment | 5 years |
| Ventilation | Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen | 5 years |
| BPD severity | 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) | 5 years |
| BPD | number of days of survival free of BPD | 5 years |
| Pre-discharge mortality | Number of study participants who died during NICU admission. | 5 years |
| Postnatal steroid Use | Number of days study participants received postnatal steroids during their NICU stay. | 5 years |
| Bayley's scale for infant development | 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. | 5 years |
| D007235 |
| Infant, Premature, Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |