Combination therapy with oral treprostinil for pulmonary arterial hypertension: A double-blind placebo-controlled clinical trial

R. James White, Carlos Jerjes-Sanchez, Gisela Martina Bohns Meyer, Tomas Pulido, Pablo Sepulveda, Kuo Yang Wang, Ekkehard Grünig, Shirish Hiremath, Zaixin Yu, Gangcheng Zhang, Wei Luen James Yip, Shuyang Zhang, Akram Khan, C. Q. Deng, Rob Grover, Victor F. Tapson, Graciela Noemi Svetliza, Adrian Jose Lescano, Guillermo Roberto Bortman, Fabian Antonio DiezChristian Edgardo Botta, John Fitzgerald, Eelke Feenstra, Fiona Dawn Kermeen, Anne Margaret Keogh, Trevor John Williams, Peter Paul Yousseff, Benjamin Joh Han Ng, David Mc Naughton Smallwood, Nathan Brent Dwyer, Martin Russell Brown, Irene M. Lang, Regina Steringer-Mascherbauer, Jaquelina Ota Arakaki, Frederico Campos, Ricardo De Amorim Correa, Rogerio De Souza, Gisela Martina Bohns Meyer, Maria Carmo Moreira, Hugo Yoo, Monica Silveira Lapa, John Swiston, Naushad Hirani, Sanjay Mehta, Evangelos Michelakis, Pablo Sepulveda, Monica Zagolin, Carmine Dario Vizza, Laura Scelsi, Patrizio Vitulo

Research output: Contribution to journalArticlepeer-review


Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.

Original languageEnglish
Pages (from-to)707-717
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number6
Publication statusPublished - Mar 15 2020


  • Clinical study
  • Combination therapy
  • Oral treprostinil
  • Pulmonary arterial hypertension
  • Sequential therapy

ASJC Scopus subject areas

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


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