- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03649932
Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Texas
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Galveston, Texas, United States, 77550
- University of Texas Medical Branch
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: L-citrulline 100 mg/kg/day
50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.
|
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. |
Experimental: L-citrulline 200 mg/kg/day
100 mg/kg given two times a day (200 mg/kg/day) for total 7 days
|
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. |
Experimental: L-citrulline 300 mg/kg/day
150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.
|
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. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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During the week of intervention (day 0 - day 7)
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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)
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Measured by at least one adverse event that are determined to be related to the study drug.
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During the week of intervention (day 0 - day 7)
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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)
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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.
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During the week of intervention (day 0 - day 7)
|
Collaborators and Investigators
Investigators
- Principal Investigator: Amna Investigator, MD, University of Texas
Publications and helpful links
General Publications
- Schwedhelm 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.
- Abman 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. Erratum In: Circulation. 2016 Jan 26;133(4):e368.
- 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.
- Montgomery 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.
- Fike 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.
- Vadivel 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.
- Waugh 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.
- Smith 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.
- Barr 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Respiratory Tract Diseases
- Infant, Newborn, Diseases
- Pregnancy Complications
- Obstetric Labor Complications
- Obstetric Labor, Premature
- Lung Injury
- Infant, Premature, Diseases
- Ventilator-Induced Lung Injury
- Hypertension
- Lung Diseases
- Hyperplasia
- Premature Birth
- Hypertension, Pulmonary
- Bronchopulmonary Dysplasia
Other Study ID Numbers
- 17-0194
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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