Clinical Trials Update
The Clinical Trials Update highlights new and ongoing research trials that are evaluating therapies for PAH. In this issue, Fernando Torres, MD, provides an update on trials of IPF patients with PH.
Citation: Advances in Pulmonary Hypertension 9, 4; 10.21693/1933-088X-9.4.234
Citation: Advances in Pulmonary Hypertension 9, 4; 10.21693/1933-088X-9.4.234
Many patients who develop pulmonary hypertension (PH) also have another concomitant lung disease, such as pulmonary fibrosis. The form of pulmonary fibrosis with unknown cause is termed idiopathic pulmonary fibrosis (IPF). Some patients with IPF will develop pulmonary hypertension. Some studies are now evaluating whether the drugs used to treat pulmonary hypertension alone may be beneficial to those patients who also have IPF.
Since 2005, bosentan has been studied to determine if it may benefit patients with IPF and pulmonary hypertension. In the first trial, called BUILD-1, these patients did not have a significant improvement in the 6-minute walk test (6MWT), which was the primary end point of this pilot trial. There was a trend toward improvement of the secondary end points of disease progression and mortality.
In March 2010, the BUILD-3 trial attempted to treat patients with IPF who did not have pulmonary hypertension with bosentan. BUILD-3 (Bosentan Use in Interstitial Lung Disease) was a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven morbidity/mortality study evaluating the safety and efficacy of bosentan 125mg bid in IPF patients. BUILD-3 enrollment was completed in November 2008 with 616 patients. The study was randomized with 2 bosentan-treated patients to 1 placebo patient. A total of 252 events were recorded in the study. Although the primary end point of events was not met (p=0.21), there was a trend toward improvement in those patients on bosentan. Bosentan has not been studied since then for the treatment of IPF.
Given that bosentan showed some trend toward improvement for the treatment of IPF, ambrisentan was felt to be another potential candidate for the treatment of this disease. In December 2010, the ARTEMIS-ILD trial was initiated and evaluated ambrisentan in IPF, but was stopped due to lack of efficacy. The ARTEMIS-ILD trial enrolled patients with IPF without PH and patients were placed either on ambrisentan or placebo. This was an event-driven study. The study enrolled 660 patients. The data monitoring committee (DMC) in reviewing the unblinded data, felt that the trial would not be positive at an interim analysis and stopped the trial. Shortly afterward, ARTEMIS-PH was stopped by the DMC for lack of efficacy in treating patients with IPF and PH as well.
The ARTEMIS-PH was the first multicenter trial evaluating patients with IPF and pulmonary hypertension. It was disappointing for both the IPF and the PH community that this trial was not successful.
A controlled trial with sildenafil in IPF patients also failed to show a benefit in the primary end point of improvement of >20% 6MWD. A total of 180 patients were enrolled and randomized to placebo or sildenafil. Secondary end points were achieved at 12 weeks, including oxygenation, DLCO degree of dyspnea, and quality of life. Although the trial did not enroll patients with pulmonary hypertension, we look forward to such a study.
Fernando Torres, MD
Deborah Jo Levine, MD
Contributor Notes