Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial

Raghu, Ganesh; Behr, Juergen; Brown, Kevin K.; Egan, Jim J.; Kawut, Steven M.; Flaherty, Kevin R.; Martinez, Fernando J.; Nathan, Steven D.; Wells, Athol U.; Collard, Harold R.; Costabel, Ulrich; Richeldi, Luca; de Andrade, Joao; Khalil, Nasreen; Morrison, Lake D.; Lederer, David J.; Shao, Lixin; Li, Xiaoming; Pedersen, Patty S.; Montgomery, A. Bruce; ... (2013). Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Annals of internal medicine, 158(9), pp. 641-649. American College of Physicians 10.7326/0003-4819-158-9-201305070-00003

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology

UniBE Contributor:

Geiser, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0003-4819

Publisher:

American College of Physicians

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

30 Apr 2014 08:41

Last Modified:

14 Jul 2014 18:27

Publisher DOI:

10.7326/0003-4819-158-9-201305070-00003

PubMed ID:

23648946

URI:

https://boris.unibe.ch/id/eprint/45666

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