L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

Study Overview
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Brief Summary
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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.

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

Conditions
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Infant,Premature, Bronchopulmonary Dysplasia, Pulmonary Hypertension

Intervention / Treatment
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* Drug: L-Citrulline


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

Ages Eligible for Study
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Minimum Age: 14 Days
Maximum Age: 3 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Single dose pharmacokinetic studies using population PKs Steady-state pharmacokinetic studies using population PKs
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-dose<br>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<br>* 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.<br>|
| Experimental: Steady-state<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma L-citrulline levels following administration of a single dose of L-citrulline | Plasma L-citrulline levels will be measured 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 | 48 hours | 
| Evaluate ability to achieve target trough L-citrulline plasma level | Evaluate the ability to achieve the target trough L-citrulline plasma level of approx.100-150 µM in patients at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline | 72 hours | 
| Evaluate incidence of 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 72 hours of receiving oral L-citrulline administration for reasons not attributable to underlying condition | 72 hours | 
| Evaluate incidence of 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary nitrite and nitrate levels will be measured in subjects enrolled into Group 3. | Urine samples will be obtained to assess baseline levels of nitric oxide metabolites (nitrite/nitrate) in the urine and assess whether there is an increase in levels of nitric oxide metabolites in the urine in response to 72 hours of L-citrulline dosing. | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L-citrulline, Nitric oxide