R33HL147833

Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia - Pulmonary Hypertension is a deadly complication of Bronchopulmonary Dysplasia (BPD), the most common pulmonary morbidity of prematurity. Up to 40% of premature infants with pulmonary hypertension and BPD will die, and survivors suffer long-term morbidities.

Despite these catastrophic consequences, no drugs are labeled or evidence based for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the FDA for the treatment of pulmonary hypertension in adults. Preclinical BPD models suggest a beneficial effect on lung and vascular development, which may prevent pulmonary hypertension.

Real world evidence shows that neonatologists are increasingly using Sildenafil in premature infants despite lack of data on dosing, safety, and the exposure-response relationship. Led by Drs. Laughon, a neonatologist and trialist, and Dr. Hornik, a pediatric cardiologist and clinical pharmacologist, our multi-institutional and multidisciplinary team is dedicated to developing drugs for the prevention and treatment of cardiopulmonary morbidities in infants, an area of urgent and unmet public health need.

To meet this need, we propose an adaptive, randomized, placebo controlled, double-blind, dose-escalation, prevention trial of 4 weeks of study drug (Sildenafil: placebo 3:1 randomization) in 120 premature infants <29 weeks gestation with severe BPD at risk for pulmonary hypertension at 30 clinical sites under IND (IND#112,374, holder Laughon).

Consistent with the goals of PAR-18-683, the proposed trial will provide the necessary dosing, safety, and preliminary efficacy data needed to design a pivotal phase II/III trial, and move the drug forward toward labeling for this indication. Leveraging partnerships with the NICHD funded Pediatric Trials Network, and the NCATS funded Trial Innovation Network, we will translate several study design and operational innovations not routinely utilized in infant trials including adaptive continual reassessment methods, risk-adjusted endpoints, parent-engagement studios, and site based clinical optimization into the framework of an early phase study conducted under regulatory oversight. These innovations will be implemented during the R61 award phase.

Our team has the expertise, access to participants, and environment necessary to conduct the proposed research. In particular, we have completed a preliminary open-label pharmacokinetic study to identify safe starting doses for this study, and conducted a cohort study to validate an echocardiogram based score as a surrogate endpoint for pulmonary hypertension in premature infants, thereby avoiding the risks associated with invasive cardiac catheterization in this vulnerable population.

This preliminary work, combined with the unparalleled experience of our team to complete early phase infant clinical trials on time and on budget, will ensure the success of the proposed study, and directly improve the public health of premature infants by providing evidence for the only therapeutic to prevent pulmonary hypertension in premature infants.

Duke University

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

North Carolina United States

State-Wide

NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics (R61/R33 Clinical Trial Required) (PAR-18-683)

Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/25 and the total obligations have increased 198% from $2,325,338 to $6,936,735.