Background: Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor.
Objective: To determine whether ambrisentan, an ETA receptor–selective antagonist, reduces the rate of IPF progression.
Design: Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300)
Setting: Academic and private hospitals.
Participants: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans.
Intervention: Ambrisentan, 10 mg/d, or placebo.
Measurements: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.
Results: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.
Limitation: The study was terminated early.
Conclusion: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations.
Primary Funding Source: Gilead Sciences.