Clinical trial NCT03542812: L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
Official title: Pharmacokinetics of L-citrulline in Infants at High Risk of Developing Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Infant,Premature
Bronchopulmonary Dysplasia
Pulmonary Hypertension
Keywords: L-citrulline
Nitric oxide
Lead sponsor: University of Utah
Sponsor class: OTHER
First posted: 2018-05-31
Enrollment: 16
Sex: ALL
Minimum age (years): 14
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Single dose pharmacokinetic studies using population PKs Steady-state pharmacokinetic studies using population PKs
Primary purpose: OTHER

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1
timeFrame: 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
measure: Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2
timeFrame: 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).
measure: Number of Participants With Feedings Being Stopped Following L-citrulline Administration
timeFrame: 48 hours after last study drug dose
measure: Number of Participants With Hypotension Developing Following L-citrulline Administration
timeFrame: 12 hours after last study drug dose
Secondary outcomes:
measure: Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study.
timeFrame: 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)
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
Study officials:
affiliation: University of Utah
name: Candice Fike, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.