Inhaled Nitric Oxide in Fibrotic Lung Disease: A Randomized, Double-Blind, Placebo-Controlled Trial.

ABSTRACT

RATIONALE Inhaled nitric oxide (iNO) has been shown to result in benefits in moderate to vigorous physical activity (MVPA) in patients with fibrotic interstitial lung disease (if-ILD) on supplemental oxygen in two independent trials. OBJECTIVE: This phase 3 randomized double-blind placebo-controlled study sought to validate the benefit of ambulatory iNO in patients with f-ILD requiring supplemental oxygen. METHODS: Patients with f-ILD on supplemental long-term oxygen were randomized in a 11 fashion to inhaled nitric oxide at 45 µg/kg ideal body weight/hour or placebo for 16 weeks. The primary outcome was the change from baseline to week 16 in MVPA assessed by accelerometry. Secondary outcomes included overall activity, six-minute walk distance and patient reported outcomes. MEASUREMENT AND MAIN RESULTS: 145 patients were enrolled; 75 were assigned to receive iNO and 70 to placebo. The change from baseline in MVPA at 16 weeks was -9.2 minute/day (SE 3.51) in the iNO45 group versus -3.7 (3.76) minute/day in the placebo group (difference, 5.5; P=0.265). No statistically significant differences between the two treatment arms were found for any of the secondary outcomes. A subgroup analysis of patients with intermediate or high probability of pulmonary hypertension on echocardiography did not demonstrate any benefit. The most common adverse events reported were respiratory tract infections, but the therapy was generally very well tolerated. CONCLUSIONS: There was no demonstrable benefit to iNO in patients with f-ILD on supplemental oxygen in daily physical activity assessed by actigraphy, a potential novel clinical trial endpoint. Clinical trial registration available at www. CLINICALTRIALS gov, ID NCT03267108.