Inhaled nitric oxide at higher dose shows benefit in pulmonary hypertension, fibrotic ILD

Pulsed, inhaled nitric oxide at a higher dose was safe and well tolerated, and resulted in improvements in physical activity and other outcomes in patients at risk for pulmonary hypertension-associated fibrotic interstitial lung disease.

A new study evaluated safety and efficacy of pulsed, inhaled nitric oxide (Bellerophon Therapeutics) at a dose of 45 µg/kg of ideal body weight per hour.

“Inhaled nitric oxide is a proven vasodilator and has recently been shown to benefit physical activity in a placebo-controlled trial of patients with fibrotic ILD when used at a dose of 30 µg/kg ideal body weight per hour for 2 months. The objective of this current trial was to explore the safety and efficacy of a higher dose — 45 µg/kg ideal body weight per hour — for a longer period of 4 months,” Steven D. Nathan, MD, director of the Advanced Lung Disease Program and Lung Transplant Program at Inova Fairfax Hospital in Virginia, said during a prerecorded presentation at the American Thoracic Society Virtual meeting.

The randomized, double-blind, placebo-controlled study enrolled patients at risk for pulmonary hypertension associated with pulmonary fibrosis on background oxygen therapy. Patients were randomly assigned to inhaled nitric oxide 45 µg/kg of ideal body weight per hour (n = 30) or placebo (n = 14) for 4 months. The researchers monitored changes in activity levels via a wrist-worn medical grade activity monitor.

The primary endpoint was placebo-corrected change from baseline to 4 months in moderate to vigorous physical activity, which represents activities of daily living, such as walking, climbing stairs and yardwork, Nathan said. Additional outcomes included patient-reported outcomes of the St. George’s Respiratory Questionnaire and the University of California San Diego Shortness of Breath Questionnaire.

Researchers reported a statistically significant placebo-corrected benefit of 14 minutes per day in moderate to vigorous physical activity among the patients assigned inhaled nitric (P = .02). Results also showed a 7% benefit in overall activity with inhaled nitric oxide compared with placebo. Moreover, for both activity parameters, Nathan noted that while the inhaled nitric oxide treatment group remained stable, the placebo group deteriorated.

Nathan also reported clinically significant changes in the University of San Diego Shortness of Breath Questionnaire (4.8 points) and the St. George’s Respiratory Questionnaire Total (3.3), Activity (4.8) and Impact (5.7) domain scores. Again, over the study period, patients assigned inhaled nitric oxide remained stable, while the placebo group deteriorated.

The researchers also conducted an anchoring analysis between moderate to vigorous physical activity and the Activity domain in the St. George’s Respiratory Questionnaire, which established an estimated minimally important difference of approximately 5 minutes per day for moderate to vigorous physical activity, Nathan said.

Pulsed, inhaled nitric oxide at the higher dose was well tolerated, with fewer severe adverse events observed compared with the placebo group (10% vs. 21.4%). The overall incidence of adverse events was low and balanced between the two groups. No deaths were reported during the treatment period, according to the results.

The new data confirm the previously reported results with inhaled nitric oxide at a lower concentration, according to the researchers.

“The inhaled nitric oxide 45 µg/kg ideal body weight per hour dose was safe and well tolerated and is currently being studied in a large registrational, phase 3, placebo-controlled clinical trial in patients with fibrosing ILD,” Nathan said.

Reference:

Nathan SD, et al. Am J Respir Crit Care Med. 2020;201;A2757.