Bronchopulmonary DysplasiaPhase 1NCT03649932
Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
A Phase 1 study testing Enteral L-citrulline in people with Bronchopulmonary Dysplasia and Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, run by The University of Texas Medical Branch, Galveston at 1 site in United States.
Trial summary
Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants. Since oral L-citrulline supplementation has never been studied in preterm infants before, the side effect profile and appropriate dosing are still unknown. Read more about this study
- Who is it for?
- Ages Up to 30 weeks
- Conditions the study is for
- Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, Pulmonary Hypertension
- What is being tested?
- Enteral L-citrulline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Sep 2018to 21 Jun 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 Up to 30 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Infants less than or equal to 30 weeks' gestational age born at UTMB, Galveston.
- Parents have provided informed consent/assent in a manner that is approved by the IRB
Who cannot join
- Known congenital or chromosomal anomalies.
- Congenital heart disease affecting cardio-respiratory system (other than PDA, PFO or ASD)
- Necrotizing enterocolitis, sepsis, or any condition requiring surgery prior to recruitment
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Texas Medical Branch
Galveston, Texas, 77550
About this study
Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants. Since oral L-citrulline supplementation has never been studied in preterm infants before, the side effect profile and appropriate dosing are still unknown. In this pilot study, the investigators will determine the safety profile, efficacy and appropriate dosing of oral L-citrulline in preterm infants. In the future, information from this study will be utilized to conduct a randomized placebo-controlled trial to evaluate the role of L-citrulline supplementation in treating BPD_PH.
Read the detailed description
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants (PI). Preterm birth causes disruption in pulmonary vascular growth that leads to decreased vascular surface area that increases pulmonary vascular resistance (PVR). Increased PVR leads to altered vasoreactivity and structural remodeling with intimal hyperplasia and increased muscularization of the small pulmonary arteries. There is no definite treatment for BPD_PH.
Nitric Oxide: Nitric Oxide (NO) is a potent pulmonary vasodilator. Endothelial Nitric oxide synthase (eNOS) mediates production of NO from L-Arginine. L-citrulline is a precursor for L-arginine. L-Arginine is a precursor of nitric oxide (NO). In infants with BPD_PH, there are decreased levels of L-arginine \& L-citrulline with decreased production of NO (measured by urinary nitrates \& nitrites) leading to increased PVR. Several studies have shown the benefit of oral L-citrulline supplementation in increasing serum citrulline levels, increasing NO production and reducing pulmonary hypertension. Oral L-arginine was not effective in increasing NO production in previous studies and it was due to increased break down of oral L-arginine by intestinal arginases.
Source of L-arginine in preterm infants: Routinely, extremely premature infants receive nutrition as total parental nutrition (TPN i.e. infants get infusion of protein, fat and carbohydrate via central venous line) that contains L-arginine (approximately 1mg/1mL) to metabolize ammonia via urea cycle. PIs receive adequate amount of intra venous arginine from TPN. Routinely, PIs are started with small volumes of enteral feeds which are increased slowly overtime. TPN is slowly decreased as enteral feeds are increasing. As the TPN is going down, intra venous L-arginine intake also drops down and ultimately when the PI are off TPN, they don't get any IV supplemental L-arginine.
Why oral citrulline: Enteral feeds (formula as well as breast milk) is poor source of arginine. Once PIs are on full enteral feed, an enteral feed is the only source of arginine. Interestingly, 40% of enteral arginine gets metabolized by arginase enzyme present in intestine. We speculate that plasma levels of arginine drop once TPN is discontinued and infants are on full feeds. Oral L-arginine has poor bio-availability that is why oral L-arginine supplementation does not increase blood levels of arginine. Since oral citrulline has high bioavailability, the best way to increase serum arginine levels is by oral citrulline supplementation. Oral supplementation of L-citrulline in preterm infants once they are off TPN will likely to increase arginine levels and NO production.
Safety of oral citrulline: L-citrulline has been safely used for decades in patients with urea cycle defects. It has been used in pediatric patients with sickle cell disease and in infants undergoing cardiac surgery. No side effects were reported in these studies. In a study in newborn rats exposed to hyperoxia, L-citrulline caused a marked increase in arginase-2 expression in the lungs and this could have an impact on lung development and remodeling. However, this is only a theoretical risk.
- Conditions
- Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, Pulmonary Hypertension, Premature Birth, Chronic Lung Disease of Prematurity
- Being tested
- Enteral L-citrulline
- Keywords
- Bronchopulmonary dysplasia, Pulmonary hypertension, Citrulline
- Medical subject headings
- Bronchopulmonary Dysplasia, Hypertension, Pulmonary, Premature Birth
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Enteral L-citrullineDietary supplement
L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.
Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.
Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.
| Study group | Role | What they receive |
|---|---|---|
| L-citrulline 100 mg/kg/day | Experimental | 50 mg/kg given two times a day (100 mg/kg/day) for total 7 days. Receives: Dietary Supplement: Enteral L-citrulline |
| L-citrulline 200 mg/kg/day | Experimental | 100 mg/kg given two times a day (200 mg/kg/day) for total 7 days Receives: Dietary Supplement: Enteral L-citrulline |
| L-citrulline 300 mg/kg/day | Experimental | 150 mg/kg given two times a day (300 mg/kg/day) for total 7 days. Receives: Dietary Supplement: Enteral L-citrulline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach
L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant.
Measured: During the week of intervention (day 0 - day 7)
Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event
Measured by at least one adverse event that are determined to be related to the study drug.
Measured: During the week of intervention (day 0 - day 7)
Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L
Previous studies have shown that a plasma level of > 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline > 37 micromol/L.
Measured: During the week of intervention (day 0 - day 7)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2018
- Study start25 Sep 2018
- Primary completion21 Jun 2021
- Study completion21 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Bronchopulmonary DysplasiaStudies of the same condition, open and under way.
- More trials run by The University of Texas Medical Branch, GalvestonThe 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Previous studies in patients undergoing cardiac surgery have shown that post-operative pulmonary hypertension did not develop in patients with citrulline level \> 37 micromol/L. A cross-sectional study reported that citrulline levels \< 29 micromol/L was associated with BPD\_PH (100% sensitivity and 75% specificity) hence this may be used as a screening tool for BPD\_PH2. The investigators will use the higher levels of citrulline of the reported levels as our goal (\>37µmol/L). The investigators will supplement infants with 3 different dosages and check serum levels to see what dose is required to achieve the optimal plasma level of citrulline (\>37µmol/L).
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Amna Investigator, MD, Principal investigator, University of Texas
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03649932
- Sponsor's protocol ID
- 17-0194
- Status last verified
- Sep 2021
- First submitted
- 24 Aug 2018
- Last updated
- 25 Oct 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014 Oct;103(10):1019-26. doi: 10.1111/apa.12707. Epub 2014 Jun 20.
PubMed 24862864Montgomery AM, Bazzy-Asaad A, Asnes JD, Bizzarro MJ, Ehrenkranz RA, Weismann CG. Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Neonatology. 2016;109(3):190-4. doi: 10.1159/000442043. Epub 2016 Jan 19.
PubMed 26780635Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs. Am J Respir Cell Mol Biol. 2015 Aug;53(2):255-64. doi: 10.1165/rcmb.2014-0351OC.
PubMed 25536367Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, Eaton F, Thebaud B. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010 Dec;68(6):519-25. doi: 10.1203/PDR.0b013e3181f90278.
PubMed 20805789Waugh WH, Daeschner CW 3rd, Files BA, McConnell ME, Strandjord SE. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc. 2001 Oct;93(10):363-71.
PubMed 11688916Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, Rice GD, Barr FE, Summar ML. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg. 2006 Jul;132(1):58-65. doi: 10.1016/j.jtcvs.2006.02.012.
PubMed 16798303Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99. doi: 10.1161/CIR.0000000000000329. Epub 2015 Nov 3.
PubMed 26534956Barr FE, Tirona RG, Taylor MB, Rice G, Arnold J, Cunningham G, Smith HA, Campbell A, Canter JA, Christian KG, Drinkwater DC, Scholl F, Kavanaugh-McHugh A, Summar ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg. 2007 Aug;134(2):319-26. doi: 10.1016/j.jtcvs.2007.02.043.
PubMed 17662768Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Boger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51-9. doi: 10.1111/j.1365-2125.2007.02990.x. Epub 2007 Jul 27.
PubMed 17662090Qasim A, Mehdi MQ, Bhatia S, Franco-Fuenmayor ME, Jain SK. Enteral L-citrulline supplementation in preterm infants is safe and effective in increasing plasma arginine and citrulline levels-a pilot randomized trial. J Perinatol. 2024 May;44(5):702-708. doi: 10.1038/s41372-023-01761-x. Epub 2023 Aug 28.
PubMed 37640809
Study at a glance
From the registry record, last updated by the sponsor on 25 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
- ClinicalTrials.gov ID
- NCT03649932
- Acronym / sponsor ID
- 17-0194
- Conditions
- Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, Pulmonary Hypertension, Premature Birth, Chronic Lung Disease of Prematurity
- Keywords
- Bronchopulmonary dysplasia, Pulmonary hypertension, Citrulline
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- The University of Texas Medical Branch, GalvestonUniversity, hospital or other
- Study start
- 25 Sep 2018 (actual)
- Primary completion
- 21 Jun 2021 (actual)
- Study completion
- 21 Jun 2021 (actual)
- First posted
- 28 Aug 2018 (actual)
- Results
- Posted 25 Oct 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants. Since oral L-citrulline supplementation has never been studied in preterm infants before, the side effect profile and appropriate dosing are still unknown. In this pilot study, the investigators will determine the safety profile, efficacy and appropriate dosing of oral L-citrulline in preterm infants. In the future, information from this study will be utilized to conduct a randomized placebo-controlled trial to evaluate the role of L-citrulline supplementation in treating BPD_PH.
Detailed description
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants (PI). Preterm birth causes disruption in pulmonary vascular growth that leads to decreased vascular surface area that increases pulmonary vascular resistance (PVR). Increased PVR leads to altered vasoreactivity and structural remodeling with intimal hyperplasia and increased muscularization of the small pulmonary arteries. There is no definite treatment for BPD_PH.
Nitric Oxide: Nitric Oxide (NO) is a potent pulmonary vasodilator. Endothelial Nitric oxide synthase (eNOS) mediates production of NO from L-Arginine. L-citrulline is a precursor for L-arginine. L-Arginine is a precursor of nitric oxide (NO). In infants with BPD_PH, there are decreased levels of L-arginine \& L-citrulline with decreased production of NO (measured by urinary nitrates \& nitrites) leading to increased PVR. Several studies have shown the benefit of oral L-citrulline supplementation in increasing serum citrulline levels, increasing NO production and reducing pulmonary hypertension. Oral L-arginine was not effective in increasing NO production in previous studies and it was due to increased break down of oral L-arginine by intestinal arginases.
Source of L-arginine in preterm infants: Routinely, extremely premature infants receive nutrition as total parental nutrition (TPN i.e. infants get infusion of protein, fat and carbohydrate via central venous line) that contains L-arginine (approximately 1mg/1mL) to metabolize ammonia via urea cycle. PIs receive adequate amount of intra venous arginine from TPN. Routinely, PIs are started with small volumes of enteral feeds which are increased slowly overtime. TPN is slowly decreased as enteral feeds are increasing. As the TPN is going down, intra venous L-arginine intake also drops down and ultimately when the PI are off TPN, they don't get any IV supplemental L-arginine.
Why oral citrulline: Enteral feeds (formula as well as breast milk) is poor source of arginine. Once PIs are on full enteral feed, an enteral feed is the only source of arginine. Interestingly, 40% of enteral arginine gets metabolized by arginase enzyme present in intestine. We speculate that plasma levels of arginine drop once TPN is discontinued and infants are on full feeds. Oral L-arginine has poor bio-availability that is why oral L-arginine supplementation does not increase blood levels of arginine. Since oral citrulline has high bioavailability, the best way to increase serum arginine levels is by oral citrulline supplementation. Oral supplementation of L-citrulline in preterm infants once they are off TPN will likely to increase arginine levels and NO production.
Safety of oral citrulline: L-citrulline has been safely used for decades in patients with urea cycle defects. It has been used in pediatric patients with sickle cell disease and in infants undergoing cardiac surgery. No side effects were reported in these studies. In a study in newborn rats exposed to hyperoxia, L-citrulline caused a marked increase in arginase-2 expression in the lungs and this could have an impact on lung development and remodeling. However, this is only a theoretical risk.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Previous studies in patients undergoing cardiac surgery have shown that post-operative pulmonary hypertension did not develop in patients with citrulline level > 37 micromol/L. A cross-sectional study reported that citrulline levels < 29 micromol/L was associated with BPD_PH (100% sensitivity and 75% specificity) hence this may be used as a screening tool for BPD_PH2. The investigators will use the higher levels of citrulline of the reported levels as our goal (>37µmol/L). The investigators will supplement infants with 3 different dosages and check serum levels to see what dose is required to achieve the optimal plasma level of citrulline (>37µmol/L).
| Arm | Type | Receives |
|---|---|---|
| L-citrulline 100 mg/kg/day | Experimental | Dietary Supplement: Enteral L-citrulline50 mg/kg given two times a day (100 mg/kg/day) for total 7 days. |
| L-citrulline 200 mg/kg/day | Experimental | Dietary Supplement: Enteral L-citrulline100 mg/kg given two times a day (200 mg/kg/day) for total 7 days |
| L-citrulline 300 mg/kg/day | Experimental | Dietary Supplement: Enteral L-citrulline150 mg/kg given two times a day (300 mg/kg/day) for total 7 days. |
Who may qualify
- Ages
- Up to 30 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- Infants less than or equal to 30 weeks' gestational age born at UTMB, Galveston.
- Parents have provided informed consent/assent in a manner that is approved by the IRB
Key exclusion criteria (3 listed)
- Known congenital or chromosomal anomalies.
- Congenital heart disease affecting cardio-respiratory system (other than PDA, PFO or ASD)
- Necrotizing enterocolitis, sepsis, or any condition requiring surgery prior to recruitment
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 |
|---|---|---|
| Enteral L-citrullineL-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient. Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion. Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere. | Dietary supplement | L-citrulline 100 mg/kg/day, L-citrulline 200 mg/kg/day, L-citrulline 300 mg/kg/day |
Primary outcome
Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach
Time frame: During the week of intervention (day 0 - day 7)
L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant.
Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event
Time frame: During the week of intervention (day 0 - day 7)
Measured by at least one adverse event that are determined to be related to the study drug.
Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L
Time frame: During the week of intervention (day 0 - day 7)
Previous studies have shown that a plasma level of > 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline > 37 micromol/L.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Oct 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 24862864Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014 Oct;103(10):1019-26. doi: 10.1111/apa.12707. Epub 2014 Jun 20.
- Background: PubMed 26780635Montgomery AM, Bazzy-Asaad A, Asnes JD, Bizzarro MJ, Ehrenkranz RA, Weismann CG. Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Neonatology. 2016;109(3):190-4. doi: 10.1159/000442043. Epub 2016 Jan 19.
- Background: PubMed 25536367Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs. Am J Respir Cell Mol Biol. 2015 Aug;53(2):255-64. doi: 10.1165/rcmb.2014-0351OC.
- Background: PubMed 20805789Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, Eaton F, Thebaud B. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010 Dec;68(6):519-25. doi: 10.1203/PDR.0b013e3181f90278.
- Background: PubMed 11688916Waugh WH, Daeschner CW 3rd, Files BA, McConnell ME, Strandjord SE. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc. 2001 Oct;93(10):363-71.
- Background: PubMed 16798303Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, Rice GD, Barr FE, Summar ML. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg. 2006 Jul;132(1):58-65. doi: 10.1016/j.jtcvs.2006.02.012.
- Background: PubMed 26534956Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99. doi: 10.1161/CIR.0000000000000329. Epub 2015 Nov 3.
- Background: PubMed 17662768Barr FE, Tirona RG, Taylor MB, Rice G, Arnold J, Cunningham G, Smith HA, Campbell A, Canter JA, Christian KG, Drinkwater DC, Scholl F, Kavanaugh-McHugh A, Summar ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg. 2007 Aug;134(2):319-26. doi: 10.1016/j.jtcvs.2007.02.043.
- Background: PubMed 17662090Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Boger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51-9. doi: 10.1111/j.1365-2125.2007.02990.x. Epub 2007 Jul 27.
- Derived from this study: PubMed 37640809Qasim A, Mehdi MQ, Bhatia S, Franco-Fuenmayor ME, Jain SK. Enteral L-citrulline supplementation in preterm infants is safe and effective in increasing plasma arginine and citrulline levels-a pilot randomized trial. J Perinatol. 2024 May;44(5):702-708. doi: 10.1038/s41372-023-01761-x. Epub 2023 Aug 28.
- Individual participant dataSharing planned: No
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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. This study is not recruiting at the moment.
Amna Investigator, MD principal investigator
University of Texas
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Enteral L-citrulline in people with Bronchopulmonary Dysplasia and Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, run by The University of Texas Medical Branch, Galveston at 1 site in United States.
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 2 inclusion and 3 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: finished, as of the sponsor's last update on 25 Oct 2021. 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 United States. 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach (time frame: During the week of intervention (day 0 - day 7)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03649932, which also lists 10 linked publications.
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 25 Oct 2021.