The Freedom-C trial was a randomized, double-blind, placebo-controlled trial of patients with severe pulmonary arterial hypertension (PAH). The study population consisted of 354 patients who were optimized on an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, or both.
The primary efficacy endpoint of the trial was the median change in six minute walk (6MW) distance at 16 weeks relative to baseline. With regard to the primary efficacy results, the placebo-corrected median change in 6MW distance at week 16 was 11m (p=0.072). A statistically significant treatment effect was observed at week 12, with a placebo-corrected median change of 13m (p=0.015).
Exploratory analyses suggest that the inability to dose titrate was a limiting issue that muted the overall treatment effect. Of the 174 patients who received active drug, 135 completed the study, 25 patients discontinued due to an adverse event and 33 patients were unable to titrate their dose above 1mg twice daily. Accordingly, 58 (33%) patients in the active treatment group did not maintain a dose of oral treprostinil above 1mg twice daily, and in this study a dose of 1mg twice daily or less appeared to be a suboptimal dose.
These patients had a markedly lower exercise benefit at week 16 compared to the other patients who received active drug, with an observed median improvement of only 4 meters. Patients achieving a dose of 1.25mg to 3.25mg twice daily had a median improvement of 18 meters, and patients achieving a dose of 3.25mg to 16mg twice daily had a median improvement of 34 meters.
Adverse events that led to discontinuation or inability to dose-escalate included headache, nausea and vomiting. Dropouts due to adverse events were most common in patients who only had access to 1mg tablets during the study, which was the lowest strength tablet available at the start of the study. There were no dropouts due to adverse events by patients who had access to the 0.25mg strength tablet, which was added later in the study.
Preliminary analysis of other secondary efficacy measures, including change in combined 6MW distance and Borg Dyspnea Score rating and Dyspnea-Fatigue index, demonstrated statistically significant improvements (p<0.05) compared to placebo. Other secondary efficacy measures including change in World Health Organization functional class, time to clinical worsening, and PAH signs and symptoms did not differ significantly between oral treprostinil and placebo (p>0.05).