BPD - Bronchopulmonary DysplasiaNCT05636397
Safety and PK-PD Study of Oral L-CIT in Preterm Infants With BPD±PH and NEC
A study testing L-Citrulline in people with BPD - Bronchopulmonary Dysplasia and Pulmonary Hypertension, run by The Hospital for Sick Children at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 6 months
- Conditions the study is for
- BPD - Bronchopulmonary Dysplasia, Pulmonary Hypertension, NEC
- What is being tested?
- L-Citrulline
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 1 siteCanada
- Study dates
- 1 Nov 2023to Mar 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 6 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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)
- Born ≤ 30 weeks at birth
Show all 10Show fewer
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
The Hospital For Sick Children
Toronto, Ontario, M5G 1X8
Principal investigator, estelle.gauda@sickkids.ca
About this study
Official title: A Phase I, Safety and Pharmacokinetics/Pharmacodynamics Study of Oral L-CIT Supplementation 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.
Read the 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.
- Being tested
- L-Citrulline
- Keywords
- BPD±PH, surgical NEC, L-Citrulline, Pharmacokinetic profile, Pharmacodynamic profile, Preterm neonates
- Medical subject headings
- Bronchopulmonary Dysplasia, Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-CitrullineDietary 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).
| Study group | Role | What they receive |
|---|---|---|
| BPD±PH | Experimental | Arm 1: BPD±PH
Total of 18 infants at 300 mg/kg/day divided q6 hours Receives: Dietary Supplement: L-Citrulline |
| 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. Receives: Dietary Supplement: L-Citrulline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of oral L-Citrulline administration
The number of patients with adverse events (AE) as a measure of safety and tolerability
Measured: 5 years
Secondary outcomes (22)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 5 years
Correlation between CIT and arginine levels
Correlation between changes in CIT and arginine levels with nitrite/nitrate levels
Measured: 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.
Measured: 5 years
Oxidative stress
Oxidative stress (measured in tracheal aspirates and blood)
Measured: 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.
Measured: 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.
Measured: 5 years
Changes in Blood Pressure
Changes in diastolic and systolic blood pressure prior to and during CIT treatment.
Measured: 5 years
Stoma, nasogastric or stool output
Volume of stoma, nasogastric or stool output prior to and during CIT treatment
Measured: 5 years
Ventilation
Days on mechanical ventilation, non-invasive ventilation, and supplementary oxygen
Measured: 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)
Measured: 5 years
BPD
number of days of survival free of BPD
Measured: 5 years
Pre-discharge mortality
Number of study participants who died during NICU admission.
Measured: 5 years
Postnatal steroid Use
Number of days study participants received postnatal steroids during their NICU stay.
Measured: 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.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2022
- Study start1 Nov 2023
- Primary completionDec 2027 (estimated)
- Study completionMar 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for BPD - Bronchopulmonary DysplasiaStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 36 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Estelle Gauda, The Hospital for Sick Children
- Investigators
- Estelle Gauda, MD, Principal investigator, Division Head, Division of Neonatology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05636397
- Sponsor's protocol ID
- 1000077413
- Status last verified
- Apr 2026
- First submitted
- 26 Oct 2022
- Last updated
- 4 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Individual Participant Data will not be shared.
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Safety and Pharmacokinetics/Pharmacodynamics Study of Oral L-CIT Supplementation in Preterm Infants With BPD±PH and NEC
- ClinicalTrials.gov ID
- NCT05636397
- Acronym / sponsor ID
- 1000077413
- Keywords
- BPD±PH, surgical NEC, L-Citrulline, Pharmacokinetic profile, Pharmacodynamic profile, Preterm neonates
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 36 participants (estimated)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Study start
- 1 Nov 2023 (actual)
- Primary completion
- Dec 2027 (estimated)
- Study completion
- Mar 2028 (estimated)
- First posted
- 5 Dec 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| BPD±PH | Experimental | Dietary Supplement: L-CitrullineArm 1: BPD±PH Total of 18 infants at 300 mg/kg/day divided q6 hours |
| Surgical NEC | Experimental | Dietary Supplement: L-CitrullineArm 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. |
Who may qualify
- Ages
- 1 month to 6 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (10 listed)
- 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)
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-CitrullineCitrulline 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). | Dietary supplement | BPD±PH, Surgical NEC |
Primary outcome
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
22 secondary outcomes
Association of blood pressure as one of the PD outcomes with maximum L-CIT concentration (Cmax)
Time frame: 5 years
Association of stoma or nasogastric output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
Time frame: 5 years
Association of stool output as one of the PD outcomes with maximum L-CIT concentration (Cmax)
Time frame: 5 years
Association of blood pressure with the area under the concentration time curve (AUC) for L-CIT
Time frame: 5 years
Association of stoma or nasogastric output with the area under the concentration time curve (AUC) for L-CIT
Time frame: 5 years
Association of stool output with the area under the concentration time curve (AUC) for L-CIT
Time frame: 5 years
Association of blood pressure with minimum L-CIT concentration (Cmin)
Time frame: 5 years
Association of stoma or nasogastric output with minimum L-CIT concentration (Cmin)
Time frame: 5 years
Association of stool output with minimum L-CIT concentration (Cmin)
Time frame: 5 years
Correlation between CIT and arginine levels
Time frame: 5 years
Biomarkers of inflammation
Time frame: 5 years
Oxidative stress
Time frame: 5 years
Respiratory Score (RSS)
Time frame: 5 years
Desaturation index
Time frame: 5 years
Changes in Blood Pressure
Time frame: 5 years
Stoma, nasogastric or stool output
Time frame: 5 years
Ventilation
Time frame: 5 years
BPD severity
Time frame: 5 years
BPD
Time frame: 5 years
Pre-discharge mortality
Time frame: 5 years
Postnatal steroid Use
Time frame: 5 years
Bayley's scale for infant development
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2026.
- Individual participant dataSharing planned: No. Individual Participant Data will not be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Estelle Gauda, MD principal investigator
Division Head, Division of Neonatology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-Citrulline in people with BPD - Bronchopulmonary Dysplasia and Pulmonary Hypertension, run by The Hospital for Sick Children at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 4 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Rachana Patel, MSc, CCRP (+1(416)-813-7654 ext. 202821, rachana.patel@sickkids.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of oral L-Citrulline administration (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2026; AzTrials last refreshed its copy on 7 Nov 2026.