U24HL151457

2/2 Kids Mod PAH Trial: Mono- vs. Duo-Therapy for Pediatric Pulmonary Arterial Hypertension-DCC - Abstract

Pulmonary arterial hypertension (PAH) contributes to high morbidity and mortality in children with diverse cardiopulmonary and systemic diseases. Efforts to define optimal treatment strategies for pediatric PAH have been limited by the absence of multicenter randomized controlled trials (MRCTs) and the lack of well-defined and proven endpoints for studies in children. Pediatric PAH remains understudied, and relatively little is known about long-term outcomes, age-appropriate clinical endpoints, and optimal therapeutic strategies for children.

Drug treatment remains suboptimal as MRCTs are rare in children with PAH, and current decision-making is dependent on data from adult studies or small case series in children. Based on the recent success of MRCTs in establishing a new standard of care for adult PAH patients, we propose to study the potential role for initial up-front combination treatment of PAH in children consisting of two PAH-specific oral therapies that have been shown to be well-tolerated in children as monotherapies: sildenafil (a type V phosphodiesterase inhibitor) and bosentan (an endothelin receptor antagonist).

Recent studies in adult PAH suggest that initiation of combined therapy with a phosphodiesterase 5 inhibitor and an endothelin receptor antagonist at the time of diagnosis, rather than sequential combination therapy, improves pulmonary hemodynamics, exercise tolerance, and quality of life when compared with monotherapy. Children with PAH often require additional therapies over time in the setting of disease progression or incomplete responsiveness to monotherapy. However, there are no data regarding the potential benefits of greater and more sustained clinical improvement over time with the more aggressive combination therapy approach from the time of initial diagnosis.

Studies of pediatric PAH have been further limited by the lack of well-coordinated and experienced care programs and the relative rare nature of these diseases. With the collaboration of the Pediatric Pulmonary Hypertension Network (PPHNET), a highly interactive and multidisciplinary group of academic PH programs, we propose to test the hypothesis that initiation of up-front combination therapy with sildenafil and bosentan at the time of PAH diagnosis will result in improved WHO functional class (FC) at 12 months in comparison with the current standard approach, which is sildenafil therapy alone.

Overall, this study addresses critical gaps in pediatric PAH by testing a clinical strategy with strong potential for broad impact and by defining useful study endpoints or novel surrogates that will facilitate evidence-based decision-making and enhance the care of children with PAH.

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]

Durham, North Carolina 277012125 United States

Single Zip Code

Data Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative U24 Clinical Trial Required) (PAR-19-330)

Amendment Since initial award the End Date has been extended from 07/31/26 to 11/30/26 and the total obligations have increased 246% from $935,417 to $3,234,679.