L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

Pharmacokinetics of L-citrulline in Infants at High Risk of Developing Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects up to 35% of very low birth weight infants (VLBW < 1500 g). Based on the current numbers of VLBW infants born annually in the U.S., between 5,000-10,000 neonates will develop BPD each year. It is estimated that 8-42% of infants with BPD will develop pulmonary hypertension (PH). Moreover, it has been known since the 1980's that echocardiographic evidence of PH in infants with BPD is associated with up to 40% mortality.

Treatment options to ameliorate PH in infants with BPD (BPD-PH) are limited. There have been no randomized clinical trials of any therapy in infants with BPD-PH. The standard care for the management of BPD-PH is to attempt to resolve the underlying lung disorder and the judicious use of oxygen as a potent pulmonary vasodilator. Using this management approach, which has not changed since the 1980's, the survival rates for infants with BPD-PH in the 2000's has been reported to be 64% at 6 months and 53% at 2 years after diagnosis of PH. The lack of improvement in outcomes for the past 3 decades has led to the widespread agreement that novel and effective therapies are desperately needed for infants with BPD-PH.

The goal is to develop oral L-citrulline clinically for the treatment of pediatric pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH); before pursuing a large scale treatment trial, pharmacokinetic (PK) dose-finding, tolerability studies in patients at high risk of developing BPD-PH are warranted.

The hypothesis is that oral L-citrulline will be well tolerated, without significant adverse effects in infants at high risk of developing pulmonary hypertension (PH) associated with BPD. The investigators propose to first characterize the PK profile of oral L-citrulline in order to define an appropriate dose range and treatment interval for infants at high risk of developing BPD-PH. Then using the doses and intervals generated by the PK profile, with a maximum dose of 3 g/kg/d, the investigators propose to evaluate the tolerability and ability to achieve the target study drug level (100-150 micromolar) in babies treated for 72 hours with oral L-citrulline. These studies will provide the data needed to design a full-scale randomized multi-center trial to evaluate the efficacy of oral L-citrulline therapy to ameliorate BPD-PH in human infants, a patient population that has a desperate need of new therapies.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Hypertension; Bronchopulmonary Dysplasia; Infant,Premature
• Intervention / Treatment: Drug: L-Citrulline

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 3 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Infants born prematurely at < or = 28 weeks gestation requiring invasive (mechanical ventilation) or non-invasive positive pressure support (nasal continuous positive airway pressure, high flow nasal cannula >1 lpm) and FiO2 of at least 0.30 at 32 +/- 1 weeks postmenstrual age

2.Tolerating at least one-half of full volume oral/gavage tube feedings (using 120 ml/kg/d as full volume oral/gavage tube feedings)

3.The continuous need for some form of respiratory support (supplemental oxygen, flow) for the prior 14 days

4.Hemoglobin > 10 mg/dL

Exclusion Criteria:

1. Known major fetal anomaly or chromosomal aneuploidy
2. Clinical evidence of congenital heart disease (except patent ductus arteriosus (PDA), atrial septal defect (ASD), or ventricular septal defect (VSD)
3. Urine output < 1 ml/kg/hr
4. History of or known to have liver failure
5. History of or known to have necrotizing enterocolitis
6. History of or known to have significant feeding intolerance beyond the first week of life
7. Presence of any acute illness defined by fever >100.4 F, vomiting, or diarrhea
8. Hemoglobin < 10 mg/dL
9. Neonatal Intensive Care Unit (NICU) cases determined to be futile (anticipated death prior to hospital discharge)
10. Multiple births

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single-dose; Participants will be enrolled into the two groups, Group 1 (which will consist of 10 participants) and Group 2 (which will consist of 8 participants) in an alternating basis. Both Group 1 and Group 2 participants will receive a single, 150 mg/kg dose of oral L-citrulline. Population PKs will be done for both groups, at up to 3 time points. Multiple interim time points and following completion of enrollment into Groups 1 and 2, data analysis will be done and results reviewed by the data safety monitoring board (DSMB). After the DSMB review is complete, enrollment into Group 3 will begin.	Drug: L-Citrulline; The L-citrulline will be procured in powder form and will be solubilized in sterile water to achieve a concentration of 50 mg/ml. Therefore, 3 ml/kg of the solubilized L-citrulline (50 mg/ml) will be administered per dose for the single-dose groups and the dose administered to the steady-state group will be determined from results from the single-dose studies.
Experimental: Steady-state; To evaluate the tolerability and ability to achieve target trough L-citrulline levels of 100-150 µM, an additional group of 18 infants (group 3) will be given oral L-citrulline doses at intervals over a total of 72 hours. If the participant is not nipple feeding, the dose will be delivered via the participant's indwelling gavage feeding tube. The dose and interval of L-citrulline will be based on results from the studies that assess pharmacokinetic parameters using a maximum daily dose of 3 g/kg/d. Blood draws for PKs will be done at baseline and prior to last dose of L-citrulline. Urine will be collected to measure nitric oxide metabolites.	Drug: L-Citrulline; The L-citrulline will be procured in powder form and will be solubilized in sterile water to achieve a concentration of 50 mg/ml. Therefore, 3 ml/kg of the solubilized L-citrulline (50 mg/ml) will be administered per dose for the single-dose groups and the dose administered to the steady-state group will be determined from results from the single-dose studies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1	Plasma L-citrulline levels will be measured using population pharmacokinetics (PK) before and at intervals following administration of a single dose of oral L-citrulline and used to generate a population pharmacokinetic model in patients at high risk of developing BPD-PH. This arm will be split into two groups of 5 subjects each. Group 1 will have PKs done at baseline (24-48 hours prior to first dose), 1 hour (+/- 10 minutes) after dose given and 2.5 hours (+/- 10 minutes) after dose given. Group 2 will have PKs done at baseline (24-48 hours prior to first dose), 15 minutes (+/- 10 minutes) after dose given and 3 hours (+/- 10 minutes) after dose given.	Group 1- Baseline, 1 hr post-study drug dose, and 2.5 hours post-study drug dose, Group 2- Baseline, 15 minutes post-study drug dose and 3 hours post-study drug dose
Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2	Evaluate the ability to achieve the target trough L-citrulline plasma level of approx.50-80 µM in patients at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline by measuring baseline L-citrulline levels and L-citrulline plasma levels drawn prior to last dose of L-citrulline study drug. Study drug is given orally every 6 hours over 72 hours for a total of 12 doses. A PK will be done on all subjects at baseline (10 minutes to 6 hours prior to first dose) and again 10-30 minutes prior to last dose. If all 12 doses of study drug are given, this will be at approximately 65.5 hours after the first study drug dose is given.	10 min to 1 hour prior to first study drug dose and 10-30 minutes prior to last dose (approx 65.5 hours after the first dose given).
Number of Participants With Feedings Being Stopped Following L-citrulline Administration	The safety outcome of the tolerability of L-citrulline will be measured by whether a subject has feedings held within 48 hours of receiving oral L-citrulline administration for reasons not attributable to underlying condition. For the stead state arm, feeding tolerance was monitored during the 72 hour period in which study was given and then for another 48 hours after the last study drug was given.	48 hours after last study drug dose
Number of Participants With Hypotension Developing Following L-citrulline Administration	The safety outcome of tolerability of L-citrulline will be measured by whether a subject develops a decrease in blood pressure more than 25% below baseline within 12 hours of receiving a dose of oral L-citrulline for reasons not attributable to underlying condition	12 hours after last study drug dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study.	Urine samples will be obtained to assess baseline levels of nitric oxide metabolites (nitrite/nitrate) in the urine within 24 hours prior to first dose and again 4-8 hours after the last dose of study drug given. The purpose is to assess whether there is an increase in levels of nitric oxide metabolites in the urine in response to 72 hours of L-citrulline dosing. Urine samples are only being obtained in infants enrolled in the steady state (second arm) of the study.	Baseline (within 24 hours prior to first study drug dose) and 4-8 hours after last study drug dose given (approximately 70 to 78 hours after first study drug dose)

Collaborators and Investigators

• Sponsor: University of Utah
• Investigators: Principal Investigator: Candice Fike, MD, University of Utah

Publications and helpful links

General Publications

• Fike CD, Avachat C, Birnbaum AK, Aschner JL, Sherwin CM. Pharmacokinetics of L-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension. Paediatr Drugs. 2023 Jan;25(1):87-96. doi: 10.1007/s40272-022-00542-x. Epub 2022 Oct 31.
• Fike CD, Aschner JL, Avachat C, Birnbaum AK, Sherwin CMT. Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia. J Perinatol. 2024 Feb;44(2):280-287. doi: 10.1038/s41372-023-01809-y. Epub 2023 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2019
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: May 2, 2018
• First Submitted That Met QC Criteria: May 18, 2018
• First Posted (Actual): May 31, 2018

Study Record Updates

• Last Update Posted (Actual): June 10, 2024
• Last Update Submitted That Met QC Criteria: May 28, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Nitric oxide; L-citrulline
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Hypertension; Hypertension, Pulmonary; Bronchopulmonary Dysplasia
• Other Study ID Numbers: 97293

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No