Welcome to United Therapeutics Global Medical Affairs.

This website is a resource intended for U.S. healthcare professionals only. This site is intended to provide balanced, scientific, and evidence-based information to foster scientific exchange. United Therapeutics does not provide medical advice. It is the healthcare professional’s responsibility to use independent clinical judgment when making clinical decisions for individual patients.

This website may include information that has not been approved by the U.S. Food and Drug Administration. United Therapeutics does not recommend or suggest use of its products in a manner inconsistent with FDA-approved labeling. For full prescribing information, including indications, contraindications, warnings, precautions, and adverse events, please refer to the FDA-approved product labeling.

Are you a U.S. Healthcare Professional?

 Skip to main content

FREEDOM EV Trial | Oral Treprostinil

Oral treprostinil for the treatment of PAH

Study Objective

To assess the ability of oral treprostinil to delay clinical worsening for people living with pulmonary arterial hypertension (PAH)

Phase III, international, randomized, placebo-controlled, double-blind, event-driven study

Conclusion

In participants with PAH, the addition of oral treprostinil to background monotherapy can lower the risk of clinical worsening while improving key indicators of disease status

Study Overview

Participants with PAH on background monotherapy receiving oral treprostinil or placebo (1:1)

Oral treprostinil 346

Placebo 344

690 Participants

152 Centers

23 Countries

Oral treprostinil dosing

Line graph of median oral treprostinil TID dose achieved up to week 48. At week 12 median oral treprostinil TID dose was 2.5 mg, at week 24 TID dose was 3.6 mg and at week 48 TID dose was 4.8 mg.

Baseline Characteristics

Time since diagnosis 6.4mo (2.3, 13.3) median (IQR)
Background therapy 5.4mo (2.4, 10.7) median (IQR)
Average age 45.2yrs ± 15.5 years
WHO FC II 63%
6MWD median 405m (342, 461) IQR

Results

Primary Endpoint

Risk of clinical worsening is reduced with oral treprostinil compared to placebo

Time to first adjudicated clinical worsening event

The Kaplan-Meier curve comparing oral treprostinil to placebo over 192 weeks showed a 26% reduction in risk of PAH disease progression/clinical worsening in the treprostinil group. The hazard ratio for this endpoint was 0.74 (95% CI, 0.56-0.97, p = 0.028).

Compared to placebo

26% reduction

in risk of clinical worsening with oral treprostinil

HR 0.74 95% CI, 0.56-0.97 p = 0.028

61% reduction

in incidence of disease progression with oral treprostinil

HR 0.39 95% CI, 0.23-0.66 p < 0.001

Risk-adjusted clinical worsening*

After adjusting for differences in the baseline risk profile, risk of clinical worsening for oral treprostinil vs. placebo

* Data are from a post hoc analysis and should be interpreted with appropriate caution

39% reduction

HR 0.61 95% CI, 0.46–0.81 p < 0.001

Clinical worsening events

Death
Hospitalization due to worsening PAH
Progression of disease
Prostacyclin added, infused or inhaled
Unsatisfactory long-term response

Secondary Endpoints

Risk Assessment

Noninvasive French low risk assessment criteria

WHO FC I-II
NT-proBNP <300pg/mL
6MWD >440m

Improvement in risk category more likely for participants in the oral treprostinil group

Categorical change in noninvasive French risk assessment
A stacked bar chart depicting the change in French PAH risk assessment from baseline to week 60 showed that oral treprostinil led to more improvement in risk scores, while placebo led to more deterioration in risk scores (p = 0.002). Significant differences were also observed at weeks 12, 24, and 36 (p = 0.001).

NT-proBNP

NT-proBNP levels significantly decreased in the oral treprostinil group

NT-proBNP results by study visit
A bar graph comparing median NT-proBNP levels at baseline, 12, 24, and 36 weeks showed a decreasing trend in the oral treprostinil group through week 36, while levels remained relatively unchanged in the placebo group through week 24 and increased at week 36.
Percent change* relative to placebo
A bar graph comparing the percent change in NT-proBNP levels between oral treprostinil and placebo at weeks 12, 24, and 36 showed a significant increasing trend in the percent reduction of NT-proBNP levels with oral treprostinil relative to placebo (p < 0.001).

* Difference (treatment vs. placebo) in geometric mean ratio to baseline

WHO FC

Oral treprostinil significantly improved WHO FC

Oral treprostinil
Line graph of risk categorical change in WHO functional class from baseline to week 48 with oral treprostinil. By week 48, 21% of those taking oral treprostinil had a deterioration in WHO functional class.
Placebo
Line graph of risk categorical change in WHO functional class from baseline to week 48 with placebo. By week 48, 33% of those taking placebo had a deterioration in WHO functional class.
  • w12 p < 0.001
  • w24 p = 0.017
  • w36 p = 0.002
  • w48 p = 0.003

Data collected at discrete time points indicated on the x-axis

6MWD

6MWD significantly improved with oral treprostinil at weeks 36 and 48

(Change in 6MWD was not statistically significant at week 24)

Improved distance over time
A clustered bar chart comparing the change in 6MWD in PAH patients from baseline for oral treprostinil vs. placebo at weeks 12, 24, 36, and 48 showed a significant improvement in 6MWD with oral treprostinil at weeks 36 and 48 compared to placebo.

Borg Dyspnea In Week 12 to Week 48, Borg dyspnea scores after the 6MWT improved in 36-38% of oral treprostinil participants

The safety profile in FREEDOM-EV was consistent with previous studies of oral treprostinil and known prostacyclin-related adverse events