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

AbstractBACKGROUND:
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.
AuthorsGanesh Raghu, Juergen Behr, Kevin K Brown, Jim J Egan, Steven M Kawut, Kevin R Flaherty, Fernando J Martinez, Steven D Nathan, Athol U Wells, Harold R Collard, Ulrich Costabel, Luca Richeldi, Joao de Andrade, Nasreen Khalil, Lake D Morrison, David J Lederer, Lixin Shao, Xiaoming Li, Patty S Pedersen, A Bruce Montgomery, Jason W Chien, Thomas G O'Riordan, ARTEMIS-IPF Investigators*
JournalAnnals of internal medicine (Ann Intern Med) Vol. 158 Issue 9 Pg. 641-9 (May 07 2013) ISSN: 1539-3704 [Electronic] United States
PMID23648946 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Endothelin A Receptor Antagonists
  • Phenylpropionates
  • Pyridazines
  • ambrisentan
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Disease Progression
  • Double-Blind Method
  • Endothelin A Receptor Antagonists
  • Female
  • Humans
  • Idiopathic Pulmonary Fibrosis (drug therapy, physiopathology)
  • Lung (physiopathology)
  • Male
  • Middle Aged
  • Phenylpropionates (adverse effects, therapeutic use)
  • Prospective Studies
  • Pyridazines (adverse effects, therapeutic use)
  • Treatment Outcome

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