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

doi:10.1378/chest.11-2212

Chest

Volume 142, Issue 6, December 2012, Pages 1383-1390

https://doi.org/10.1378/chest.11-2212 Get rights and content

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 = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .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

Section snippets

Patient Selection

Eligible patients were 12 to 70 years of age with symptomatic idiopathic PAH (including PAH associated with anorexigen/toxin use); familial PAH; or PAH associated with congenital heart disease (repaired congenital systemic-to-pulmonary shunts for ≥ 5 years), connective tissue disease, or HIV infection. The diagnosis of PAH required a mean pulmonary arterial pressure > 25 mm Hg, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mm Hg, pulmonary vascular

Baseline Patient Characteristics

A total of 354 patients were enrolled at 71 centers between October 20, 2006, and September 17, 2008. Three hundred fifty patients with a mean age of 50 years (range, 15–75 years) received at least one dose of the study drug and were included in the analysis (four subjects were not dosed after randomization so were not included). Of the 350 patients, 174 were randomized to oral treprostinil, and 176 were randomized to placebo. The majority of patients were in WHO functional class III (76%) with

Discussion

Oral treprostinil was compared with placebo in patients with PAH with a baseline 6MWD of 100 to 450 m on stable background PAH therapy. The primary end point of 6MWD at 16 weeks was not met. Patients on oral treprostinil did experience a significant improvement in combined 6MWD and Borg dyspnea score and dyspnea fatigue index score at week 16. There was a statistically significant improvement in 6MWD at week 12; however, this was not a prespecified end point. The most frequent side effects were

Conclusions

The primary end point of change in 6MWD after 16 weeks of oral treprostinil did not meet statistical significance. However, the suggestion that the response could be dose-related, the potential for improved tolerance with lower-dose tablet, and the availability of lower-dose tablets to all patients has prompted further study. This will better characterize the clinical profile of oral treprostinil.

Acknowledgments

Author contributions: Dr Tapson is the guarantor of the manuscript and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Tapson: contributed to study design; collection, analysis, and interpretation of data; and drafting and critical review of the manuscript and has seen and approved the final version.

Dr Torres: contributed to the collection, analysis, and interpretation of data and to the critical review of the manuscript, including review of the final

References (32)

VV McLaughlin et al.
ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc; and the Pulmonary Hypertension Association
J Am Coll Cardiol
(2009)
VF Tapson et al.
Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial
Chest
(2006)
VV McLaughlin et al.
Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial
J Am Coll Cardiol
(2010)
N Galiè et al.
Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial
J Am Coll Cardiol
(2002)
RJ Oudiz et al.
Micrococcus-associated central venous catheter infection in patients with pulmonary arterial hypertension
Chest
(2004)
M Rubenfire et al.
Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial
Chest
(2007)
J Hiremath et al.
Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial
J Heart Lung Transplant
(2010)
AR Feinstein et al.
Changes in dyspnea-fatigue ratings as indicators of quality of life in the treatment of congestive heart failure
Am J Cardiol
(1989)
DB Badesch et al.
Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry
Chest
(2010)
M Humbert et al.
Treatment of pulmonary arterial hypertension
N Engl J Med
(2004)

RJ Barst et al.

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

(1996)

G Simonneau et al.

Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial

Am J Respir Crit Care Med

(2002)

H Olschewski et al.

Inhaled iloprost for severe pulmonary hypertension

N Engl J Med

(2002)

N Galiè et al.

Tadalafil therapy for pulmonary arterial hypertension [published correction appears in Circulation. 2011;124(10):e279. Dosage error in article text.]

Circulation

(2009)

N Galiè et al.

Sildenafil citrate therapy for pulmonary arterial hypertension

N Engl J Med

(2005)

N Galiè et al.

Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2

Circulation

(2008)

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Compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280–15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536–38.9063, p = 0.0109) were associated with a significant increase in 6-min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35–0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46–0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36–1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil.
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Although our knowledge of the epidemiology, pathology and pathophysiology of the disease, as well as the development of innovative therapies, has progressed in recent decades, PAH remains a serious clinical condition. Current treatments for the disease target the three specific pathways of endothelial dysfunction that characterise PAH: the endothelin, nitric oxide and prostacyclin pathways.
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Pediatric pulmonary hypertension (PH) is a condition characterized by elevated pulmonary arterial pressure, which has the potential to be life-limiting. The etiology of pediatric PH varies. When compared with adult cohorts, the etiology is often multifactorial, with contributions from prenatal, genetic, and developmental factors. This review aims to provide an up-to-date overview of the causes and classification of pediatric PH, describe current therapeutics in pediatric PH, and discuss upcoming and necessary research in pediatric PH.
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For editorial comment see page 1363

Funding/Support: This study was funded by United Therapeutics Corporation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original ResearchPulmonary Vascular DiseaseFeaturedOral 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

Background

Methods

Results

Conclusions

Trial registry

Section snippets

Patient Selection

Baseline Patient Characteristics

Discussion

Conclusions

Acknowledgments

J Am Coll Cardiol

Chest

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Chest

J Heart Lung Transplant

Am J Cardiol

Chest

Treatment of pulmonary arterial hypertension

N Engl J Med

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial

Am J Respir Crit Care Med

Inhaled iloprost for severe pulmonary hypertension

N Engl J Med

Tadalafil therapy for pulmonary arterial hypertension [published correction appears in Circulation. 2011;124(10):e279. Dosage error in article text.]

Circulation

Sildenafil citrate therapy for pulmonary arterial hypertension

N Engl J Med

Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2

Circulation

Original Research
Pulmonary Vascular Disease
Featured
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