Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study)

A randomized controlled trial

Victor F. Tapson, Fernando Torres, Fiona Kermeen, Anne M. Keogh, Roblee P Allen, Robert P. Frantz, David B. Badesch, Adaani E. Frost, Shelley M. Shapiro, Kevin Laliberte, Jeffrey Sigman, Carl Arneson, Nazzareno Galiè

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P 5.07). Improvements in dyspnea fatigue index score (P 5.01) and combined 6MWD and Borg dyspnea score (P 5.01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. Trial registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Original languageEnglish (US)
Pages (from-to)1383-1390
Number of pages8
JournalChest
Volume142
Issue number6
DOIs
StatePublished - Dec 2012

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Phosphodiesterase 5 Inhibitors
Pulmonary Hypertension
Randomized Controlled Trials
Placebos
Dyspnea
Therapeutics
Fatigue
treprostinil
Endothelin Receptor Antagonists
Registries
Safety

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study) : A randomized controlled trial. / Tapson, Victor F.; Torres, Fernando; Kermeen, Fiona; Keogh, Anne M.; Allen, Roblee P; Frantz, Robert P.; Badesch, David B.; Frost, Adaani E.; Shapiro, Shelley M.; Laliberte, Kevin; Sigman, Jeffrey; Arneson, Carl; Galiè, Nazzareno.

In: Chest, Vol. 142, No. 6, 12.2012, p. 1383-1390.

Research output: Contribution to journalArticle

Tapson, Victor F. ; Torres, Fernando ; Kermeen, Fiona ; Keogh, Anne M. ; Allen, Roblee P ; Frantz, Robert P. ; Badesch, David B. ; Frost, Adaani E. ; Shapiro, Shelley M. ; Laliberte, Kevin ; Sigman, Jeffrey ; Arneson, Carl ; Galiè, Nazzareno. / Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study) : A randomized controlled trial. In: Chest. 2012 ; Vol. 142, No. 6. pp. 1383-1390.
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abstract = "Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. Results: Thirty-nine patients (22{\%}) receiving oral treprostinil and 24 patients (14{\%}) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P 5.07). Improvements in dyspnea fatigue index score (P 5.01) and combined 6MWD and Borg dyspnea score (P 5.01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. Trial registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.",
author = "Tapson, {Victor F.} and Fernando Torres and Fiona Kermeen and Keogh, {Anne M.} and Allen, {Roblee P} and Frantz, {Robert P.} and Badesch, {David B.} and Frost, {Adaani E.} and Shapiro, {Shelley M.} and Kevin Laliberte and Jeffrey Sigman and Carl Arneson and Nazzareno Gali{\`e}",
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T2 - A randomized controlled trial

AU - Tapson, Victor F.

AU - Torres, Fernando

AU - Kermeen, Fiona

AU - Keogh, Anne M.

AU - Allen, Roblee P

AU - Frantz, Robert P.

AU - Badesch, David B.

AU - Frost, Adaani E.

AU - Shapiro, Shelley M.

AU - Laliberte, Kevin

AU - Sigman, Jeffrey

AU - Arneson, Carl

AU - Galiè, Nazzareno

PY - 2012/12

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N2 - Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P 5.07). Improvements in dyspnea fatigue index score (P 5.01) and combined 6MWD and Borg dyspnea score (P 5.01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. Trial registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

AB - Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P 5.07). Improvements in dyspnea fatigue index score (P 5.01) and combined 6MWD and Borg dyspnea score (P 5.01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. Trial registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

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