Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing

NCT03649932 | Completed Phase 1 Results DMC

• 1 other identifier: 17-0194
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Bronchopulmonary Dysplasia; Bronchopulmonary Dysplasia Associated Pulmonary Hypertension; Pulmonary Hypertension; Premature Birth; Chronic Lung Disease of Prematurity

Keywords

Bronchopulmonary dysplasia; Pulmonary hypertension; Citrulline

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  During the week of intervention (day 0 - day 7)

Study Arms (3)

L-citrulline 100 mg/kg/day

EXPERIMENTAL

50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.

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

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.

Dietary Supplement: Enteral L-citrulline

Interventions

Enteral L-citrulline DIETARY_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.

L-citrulline 100 mg/kg/day; L-citrulline 200 mg/kg/day; L-citrulline 300 mg/kg/day

Eligibility Criteria

• Age: Up to 30 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Texas Medical Branch, Galveston: lead

Study Sites (1)

University of Texas Medical Branch

Galveston, Texas, 77550, United States

Location

Related Publications (10)

• 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.

  PMID: 24862864 BACKGROUND

• 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.

  PMID: 26780635 BACKGROUND

• 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.

  PMID: 25536367 BACKGROUND

• 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.

  PMID: 20805789 BACKGROUND

• 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.

  PMID: 11688916 BACKGROUND

• 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.

  PMID: 16798303 BACKGROUND

• 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.

  PMID: 26534956 BACKGROUND

• 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.

  PMID: 17662768 BACKGROUND

• 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.

  PMID: 17662090 BACKGROUND

• Qasim 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.

  PMID: 37640809 DERIVED

MeSH Terms

Conditions

Bronchopulmonary Dysplasia; Hypertension, Pulmonary; Premature Birth

Condition Hierarchy (Ancestors)

Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hypertension; Vascular Diseases; Cardiovascular Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Results Point of Contact

• Title: Dr. Sunil Jain
• Organization: University of Texas Medical Branch

amnahqasim@gmail.com

4097722815

Study Officials

• Amna Investigator, MD

  University of Texas

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: August 24, 2018
• First Posted: August 28, 2018
• Study Start: September 25, 2018
• Primary Completion: June 21, 2021
• Study Completion: June 21, 2021
• Last Updated: October 25, 2021
• Results First Posted: October 25, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)