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

Primary Purpose

BPD - Bronchopulmonary Dysplasia, Pulmonary Hypertension, NEC

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
L-Citrulline
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for BPD - Bronchopulmonary Dysplasia focused on measuring BPD±PH, surgical NEC, L-Citrulline, Pharmacokinetic profile, Pharmacodynamic profile, Preterm neonates

Eligibility Criteria

1 Month - 6 Months (Child)All SexesDoes not accept 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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    BPD±PH

    Surgical NEC

    Arm Description

    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

    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

    Outcomes

    Primary Outcome Measures

    Safety of oral L-Citrulline administration
    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)
    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)
    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)
    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
    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
    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
    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)
    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)
    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)
    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
    Correlation between changes in CIT and arginine levels with nitrite/nitrate levels
    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.
    Oxidative stress
    Oxidative stress (measured in tracheal aspirates and blood)
    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.
    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.
    Changes in Blood Pressure
    Changes in diastolic and systolic blood pressure prior to and during CIT treatment.
    Stoma, nasogastric or stool output
    Volume of stoma, nasogastric or stool output prior to and during CIT treatment
    Ventilation
    Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen
    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 prssure support (high flow, CPAP, NIPPV, or ETT)
    BPD
    number of days of survival free of BPD
    Pre-discharge mortality
    Number of study participants who died during NICU admission.
    Postnatal steroid Use
    Number of days study participants received postnatal steroids during their NICU stay.
    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.

    Full Information

    First Posted
    October 26, 2022
    Last Updated
    April 10, 2023
    Sponsor
    The Hospital for Sick Children
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05636397
    Brief Title
    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

    2. Study Status

    Record Verification Date
    April 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    June 2023 (Anticipated)
    Primary Completion Date
    December 2027 (Anticipated)
    Study Completion Date
    March 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    The Hospital for Sick Children

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. 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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    BPD - Bronchopulmonary Dysplasia, Pulmonary Hypertension, NEC
    Keywords
    BPD±PH, surgical NEC, L-Citrulline, Pharmacokinetic profile, Pharmacodynamic profile, Preterm neonates

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    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)
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    60 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    BPD±PH
    Arm Type
    Experimental
    Arm Description
    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
    Arm Title
    Surgical NEC
    Arm Type
    Experimental
    Arm Description
    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
    Intervention Type
    Dietary Supplement
    Intervention Name(s)
    L-Citrulline
    Intervention Description
    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 Outcome Measure Information:
    Title
    Safety of oral L-Citrulline administration
    Description
    The number of patients with adverse events (AE) as a measure of safety and tolerability
    Time Frame
    5 years
    Secondary Outcome Measure Information:
    Title
    Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax)
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
    Description
    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.
    Time Frame
    5 years
    Title
    Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stool output with the area under the concentration time curve (AUC) for L-CIT
    Description
    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.
    Time Frame
    5 years
    Title
    Association of blood pressure with minimum L-CIT concentration (Cmin)
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin)
    Description
    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.
    Time Frame
    5 years
    Title
    Association of stool output with minimum L-CIT concentration (Cmin)
    Description
    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.
    Time Frame
    5 years
    Title
    Correlation between CIT and arginine levels
    Description
    Correlation between changes in CIT and arginine levels with nitrite/nitrate levels
    Time Frame
    5 years
    Title
    Biomarkers of inflammation
    Description
    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.
    Time Frame
    5 years
    Title
    Oxidative stress
    Description
    Oxidative stress (measured in tracheal aspirates and blood)
    Time Frame
    5 years
    Title
    Respiratory Score (RSS)
    Description
    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.
    Time Frame
    5 years
    Title
    Desaturation index
    Description
    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.
    Time Frame
    5 years
    Title
    Changes in Blood Pressure
    Description
    Changes in diastolic and systolic blood pressure prior to and during CIT treatment.
    Time Frame
    5 years
    Title
    Stoma, nasogastric or stool output
    Description
    Volume of stoma, nasogastric or stool output prior to and during CIT treatment
    Time Frame
    5 years
    Title
    Ventilation
    Description
    Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen
    Time Frame
    5 years
    Title
    BPD severity
    Description
    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)
    Time Frame
    5 years
    Title
    BPD
    Description
    number of days of survival free of BPD
    Time Frame
    5 years
    Title
    Pre-discharge mortality
    Description
    Number of study participants who died during NICU admission.
    Time Frame
    5 years
    Title
    Postnatal steroid Use
    Description
    Number of days study participants received postnatal steroids during their NICU stay.
    Time Frame
    5 years
    Title
    Bayley's scale for infant development
    Description
    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.
    Time Frame
    5 years

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    1 Month
    Maximum Age & Unit of Time
    6 Months
    Accepts Healthy Volunteers
    No
    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
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Rachana Patel, MSc, CCRP
    Phone
    +1(416)-813-7654
    Ext
    202821
    Email
    rachana.patel@sickkids.ca
    First Name & Middle Initial & Last Name or Official Title & Degree
    Rosanna Yankanah, MSc, CCRP
    Phone
    +1(416-)813-7654
    Ext
    202919
    Email
    rosanna.yankanah@sickkids.ca
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Estelle Gauda, MD
    Organizational Affiliation
    Division Head, Division of Neonatology
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    Individual Participant Data will not be shared.

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

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