United Therapeutics Corp, Silver Spring, Md, has completed its FREEDOM-M phase 3 trial of treprostinil diethanolamine (oral treprostinil), an investigational sustained-release oral formulation of treprostinil, a stable synthetic form of prostacyclin, in patients with pulmonary arterial hypertension (PAH). FREEDOM-M was a randomized, double-blind, placebo-controlled trial of patients with PAH.

The study enrolled 349 patients who were not receiving any approved PAH medication, with the population for the primary analysis consisting of the 228 patients who had access to the 0.25 mg tablet at randomization. These patients were administered oral treprostinil or placebo twice daily, with the doses titrated to effect over the course of the 12-week trial. The majority of patients were in the World Health Organization (WHO) Functional Class II (~33%) and Class III (~66%) of varied etiologies, including idiopathic or familial PAH (~75%), collagen vascular disease associated with PAH (~19%), and PAH associated with HIV or other associated conditions (~6%). The patients’ mean baseline 6-minute walk distance (6MWD) was approximately 330 meters.

The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the 228 patients. Preliminary analysis of the trial results demonstrated that those patients receiving oral treprostinil improved their median 6MWD by approximately 23 meters (p=0.0125, Hodges-Lehmann estimate and non-parametric analysis of covariance in accordance with the trial’s pre-specified statistical analysis plan) as compared to patients receiving placebo. The median change from baseline was 25 meters for oral treprostinil and -5 meters for placebo at week 12.

The trial results also showed that the combined 6MWD and Borg Dyspnea Score rating (shortness of breath test) was significantly improved (p=0.0497). Preliminary analysis of other secondary efficacy measures, including the Borg Dyspnea Score rating, through walk at week 11, change in Dyspnea Fatigue Index, change in WHO functional class, time to clinical worsening, and PAH signs and symptoms did not differ significantly between oral treprostinil and placebo (p>0.05). Time to clinical worsening was defined by death, transplant, atrial septostomy, hospitalization due to PAH, or at least a 20% decrease in 6-minute walk and initiation of another approved PAH therapy.

An analysis of all 349 FREEDOM-M patients demonstrates that those patients receiving oral treprostinil improved their median 6MWD by approximately 25.5 meters (p=0.0001, Hodges-Lehmann estimate and non-parametric analysis of covariance) as compared to patients receiving placebo.

Adverse events seen in the trial included headache, nausea, diarrhea, and flushing, which are common in patients receiving prostanoid therapy. Detailed analysis of adverse events is ongoing. All patients in the trial had the option to continue receiving oral treprostinil in an open-label continuation study after completion of the 12-week period. Of the 287 patients who were eligible to enroll, approximately 279 patients entered the open-label continuation study. Of these, approximately 183 patients are currently being treated with oral treprostinil, with the longest duration of treatment exceeding three years.

Source: United Therapeutics Corp