L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

Pulmonary Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03542812
• Other study ID #: 97293
• Status: Terminated
• Phase: Early Phase 1
• Start date: July 30, 2019
• Est. completion date: August 31, 2022

Study information

• Verified date: April 2024
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: August 31, 2022
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Days to 3 Months

Eligibility

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

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia
• Hypertension
• Hypertension, Pulmonary
• Infant,Premature
• Pulmonary Hypertension

Intervention

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.

Locations

Country	Name	City	State
United States	University of Utah Health	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
University of Utah

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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).
Primary	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
Primary	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	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)