PURPOSE: Hypoxia during exercise testing is associated with increased mortality in IPF. The main objective of this prospective randomized placebo-controlled double-blind study (BUILD 1) was to evaluate the effect of the dual endothelin receptor antagonist bosentan on exercise-induced hypoxia during a 6-minute walk-test (6MWT) in IPF patients.
METHODS: Main inclusion criteria: IPF patients, FVC > 50% predicted, Dlco > 30%, 6MWT distance ≥ 150 m and < 500 m, SpO2 at rest (room air) > 80%. SpO2 recorded before and continuously throughout modified 6MWT. Baseline desaturation defined as ≥ 4% fall in SpO2 during 6MWT. Walk was stopped and distance measured, if SpO2 ≤ 79%. Primary endpoint: change in 6MWD from baseline to end of Period 1 (EP1; month 12 or earlier if study treatment was discontinued). An exploratory endpoint was mean change from baseline to EP1 in SpO2 during the 6MWT; change defined as ≥ 4% difference between baseline and EP1.
RESULTS: Study period: median 54.4 weeks. Baseline 6MWD mean (± SD) was 375±92m (placebo) and 372±74m (bosentan). EP1: 6MWD had fallen 34 ± 127m (mean ± SD) in placebo and 52 ± 121 m in bosentan group (treatment difference [median] = -17m; 95% CI = -47, 10). In patients without baseline desaturation, SpO2 worsened (≥ 4% fall in SpO2) in 10/13 (76.9%) treated with bosentan and 13/23 (56.5%) treated with placebo (p = 0.292). SpO2 improved (≥ 4% improvement in SpO2) in patients with baseline desaturation in 7/56 (12.5%) bosentan patients and 1/57 (1.8%) placebo patients (p = 0.031). The 7 bosentan-treated patients with improved SpO2 trended towards improved FVC at EP1.
CONCLUSION: Over 54.4 weeks a fall in walk distance and worsening exercise gas exchange as measured by 6MWT is seen in patients with IPF. In patients with baseline SpO2 desaturation, gas exchange with exercise improved in some patients treated with bosentan.
CLINICAL IMPLICATIONS: Bosentan, may improve oxygenation during 6MWT in a subgroup of patients with IPF. The effects of bosentan in IPF warrant further study.
DISCLOSURE: Kevin Brown, Consultant fee, speaker bureau, advisory committee, etc. KK Brown, J Behr, RM du Bois, G Raghu and TE King have been remunerated consultants for Actelion Pharmaceuticals Ltd, the manufacturers of bosentan; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, Bosentan is not approved for use in IPF patients.