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Safety and Pharmacodynamics of L-Citrulline for the Treatment of Pulmonary Hypertension (PH) in Preterm Neonates with Severe Bronchopulmonary Dysplasia (BPD-PH) [CToP BPD-PH]

Award Number: R61HL185680
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Safety and Pharmacodynamics of L-Citrulline for the Treatment of Pulmonary Hypertension (PH) in Preterm Neonates with Severe Bronchopulmonary Dysplasia (BPD-PH) [CToP BPD-PH] - ABSTRACT Premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) carry alarmingly high mortality rates, experience an unacceptably high burden of morbidities, and have few therapeutic options. To date, no therapeutic agents have been rigorously evaluated for prevention or treatment of BPD-PH in this population. The L-arginine precursor, L-citrulline, serves as a substrate that promotes endogenous nitric oxide (NO) production. L-citrulline has demonstrated bioavailability when administered enterally to human infants and possesses a well-established, favorable safety profile during long-term use in children with inborn errors of metabolism. Our team recently completed a first-in-human phase 0 pharmacokinetic (PK) study of enteral L-citrulline in premature neonates at high risk of developing BPD-PH. The goal of this R61/R33 proposal is to conduct a metric-driven, multi-site, multi-dose, blinded and placebo- controlled safety and pharmacodynamic (PD) study of enteral L-citrulline in premature infants at high risk for developing BPD-PH. The resulting data will inform the selection of an enteral L-citrulline dosing strategy to be evaluated in a future phase 3 randomized controlled efficacy trial. To establish safety and generate pharmacodynamic data we will evaluate the impact of three different L-citrulline dosing strategies on relevant safety endpoints, and measure plasma L-citrulline concentrations to develop a population pharmacokinetic (PK) model. Additionally, we will explore the effects of L-citrulline on clinical parameters that may reflect efficacy. The following specific aims are designed to achieve this goal: Specific Aim 1 (Primary): Establish the safety profile of enteral L-citrulline in premature infants at high risk of developing BPD-PH. Infants will be treated for 4 weeks, from 32 weeks through 36 weeks postmenstrual age (PMA), with one of three different enteral L-citrulline dosing strategies. Specific Aim 2 (Primary): Develop a PK/PD model that links L-citrulline exposure to the proportion of infants who achieve trough plasma citrulline concentrations in the target range of 50-80 µmol/L. Specific Aim 3 (Exploratory): Provide preliminary evidence of clinical efficacy by evaluating whether steady-state trough plasma L-citrulline concentrations are associated with improvements in important clinical endpoints that serve as surrogates for BPD-PH. This study has the potential to improve human health by advancing L-citrulline as a therapy to prevent and mitigate a devastating disease in an understudied, high-risk patient population. Establishing a safe and effective treatment for premature infants with BPD-PH will reduce the unacceptably high rates of mortality and both short- and long-term morbidity, while also alleviating the extensive healthcare burden experienced by families and the medical system.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $470,687 )
2026	2026	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Lung Diseases Research	000	1	9/4/2026	NEW	$470,687
														Subtotal = $470,687

Grand Total All Awards = $470,687

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Safety and Pharmacodynamics of L-Citrulline for the Treatment of Pulmonary Hypertension (PH) in Preterm Neonates with Severe Bronchopulmonary Dysplasia (BPD-PH) [CToP BPD-PH]

Award Number: R61HL185680

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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