Clinical Research
Clinical Trial
Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled Clinical Trial

https://doi.org/10.1016/j.jacc.2010.01.027Get rights and content
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Objectives

This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil.

Background

There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies.

Methods

Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 μg) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed.

Results

Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated.

Conclusions

This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199)

Key Words

aerosol
inhalation therapy
prostacyclin
pulmonary arterial hypertension
pulmonary heart disease
pulmonary vascular disease
treprostinil sodium

Abbreviations and Acronyms

6MWD
6-min walk distance
CI
confidence interval
eCMH
extended Cochran-Mantel-Haenszel
H-L
Hodges-Lehmann
MLWHF
Minnesota Living with Heart Failure
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PAH
pulmonary arterial hypertension
WRS
Wilcoxon rank sum

Cited by (0)

This research was funded by United Therapeutics Corporation. Dr. McLaughlin has served as consultant/speaker for Actelion Pharmaceuticals, Gilead Sciences, and Pfizer; and has received research grants from Actelion Pharmaceuticals, Encysive, Pfizer, and United Therapeutics Corp.Dr. Benza has received research grants from United Therapeutics Corp., Gilead Sciences, Actelion Pharmaceuticals, Lung Rx, Inc., and Pfizer. Dr. Rubin has served as consultant/investigator for and has stock ownership in United Therapeutics Corp. Dr. Channick has served as consultant/speaker for and received research grants from Actelion Pharmaceuticals, Gilead Sciences, Pfizer, and United Therapeutics Corp.Dr. Tapson has served as consultant/speaker for Actelion Pharmaceuticals, Gilead Sciences, Lung Rx, Inc., United Therapeutics Corp., and Lilly; and has received research grants from Actelion Pharmaceuticals, Gilead Sciences, Lung Rx, Inc.; and United Therapeutics Corp.Dr. Robbins has served as consultant/speaker for Actelion Pharmaceuticals, Gilead Sciences, United Therapeutics Corp., and Lung Rx, Inc.; and has received research grants from Gilead Sciences, Actelion Pharmaceuticals, Pfizer, United Therapeutics Corp., and Lung Rx, Inc.Dr. Olschewski has served as consultant for Bayer Schering AG, GlaxoSmithKline, Myogen, and Novartis; as a speaker for Schering, Actelion Pharmaceuticals, Encysive, Myogen, Pfizer, and Unither; and has received research grants from Deutsche Forschungsgemeinschaft, Osterreichische Nationalbank, and European Union Framework 5 and 6and pharmaceutical grants from Schering AG, Unither, Actelion Pharmaceuticals and Encysive. Dr. Rubenfire has received research grants from Actelion Pharmaceuticals, United Therapeutics Corp., and Pfizer. Dr. Seeger has served as consultant/speaker for Lung Rx, Inc., and has patents with United Therapeutics Corp. (US020080200449A1, WO002007134292A3).