Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Abstract

Objective. Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD).Method. Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of >500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed.Results. Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsenClinicalTrials.gov identifier: NCT00070590.

Interstitial Lung Disease in Systemic Sclerosis: Diagnosis and Management

“…In the 163 patient study, the drug failed to demonstrate a difference in the primary endpoint of a change in six-minute walk distance. Secondary end points of time to death and worsening of PFTs were also no different [55]. This negative study mirrors negative results seen in trials of endothelin receptor antagonists in IPF [56].…”

Systemic sclerosis–related pulmonary hypertension associated with interstitial lung disease: Impact of pulmonary arterial hypertension therapies

“…Whereas significant improvements in functional class and hemodynamics were observed in the overall cohort of 49 patients, no clear benefits were observed among the 13 subjects with combined PH-ILD (11). Moreover, bosentan was not beneficial in SSc-ILD without PH (38).…”

Inhibitory Effects of the Dual Endothelin Receptor Blocker Bosentan on Thrombin-Activated Lung Fibroblasts Isolated from Scleroderma Patients

“…A smaller, more recent study of nine SSc-ILD patients also failed to demonstrate improvement in lung function or imaging after two years of bosentan treatment [27]. Patient selection might explain some of the negative results reported with bosentan, particularly in the latter trial where all the patients had severely impaired lung function, long disease duration and had demonstrated relapse after cyclophosphamide therapy [27]. In addition to patient selection, other factors such as primary endpoint selection might also have influenced the results.…”

“…Unfortunately, neither trial demonstrated efficacy of bosentan, although there did appear to be a trend in favor of bosentan delaying the time to death or disease progression in patients with biopsy-proven usual interstitial pneumonia [26]. A smaller, more recent study of nine SSc-ILD patients also failed to demonstrate improvement in lung function or imaging after two years of bosentan treatment [27]. Patient selection might explain some of the negative results reported with bosentan, particularly in the latter trial where all the patients had severely impaired lung function, long disease duration and had demonstrated relapse after cyclophosphamide therapy [27].…”

“…Bosentan was employed in two randomized clinical trials, one in IPF (BUILD-1) and another in SSc-ILD (BUILD-2) [26,27]. Unfortunately, neither trial demonstrated efficacy of bosentan, although there did appear to be a trend in favor of bosentan delaying the time to death or disease progression in patients with biopsy-proven usual interstitial pneumonia [26].…”