Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial
Authors: R. James White, Carlos Jerjes-Sanchez, Gisela Martina Bohns Meyer, Tomas Pulido, Pablo Sepulveda, Kuo Yang Wang, Ekkehard Grünig, Shirish Hiremath, Zaixin Yu, Zhang Gangcheng, 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 Diez, Christian Edgardo Botta, John Fitzgerald, Eelke Feenstra, Fiona Dawn Kermeen, Anne Margaret Keogh, Trevor John Williams, Peter Paul Yousseff, Benjamin Joh-Han Ng, David McNaughton Smallwood, Nathan Brent Dwyer, Martin Russell Brown, Irene M Lang, Regina Steringer-Mascherbauer, Jaquelina Sonoe Ota Arakaki, Frederico Thadeu Assis Figueiredo Campos, Ricardo de Amorim Correa, Rogerio de Souza, Gisela M. Bohns Meyer, Maria Auxiliadora Carmo Moreira, Hugo Hyung Bok Yoo, Monica Silveira Lapa, John Swiston, Naushad Hirani, Sanjay Mehta, Evangelos Michelakis, Pablo Andres Sepulveda, Monica Maria Zagolin Blancaire, Jimming Liu, Zhang Shuyang, Lei Pan, Bao Chunde, Yi Qun, Cheng Xiaoshu, Yu Zaixin, Xinli Li, Yao Hua, Zhang Gangcheng, Xianyang Zhu, Yundai Chen, Cheng Zhaozhong, Yuanhua Yang, Zhou Daxin, Shen Jieyan, Jens Erik Nielsen-Kudsk, Jorn Carlsen, Arnaud Bourdin, Eric Hachulla, Claire Dromer, Ari Chaouat, Martine Reynaud-Gauber, Marie-France Seronde, Hans Klose, Michael Halank, Gert Hoffken, Ralf Ewert, Stephan Rosenkranz, Ekkehard Grunig, Ulrich Kruger, Juliane Kronsbein, Barbara Monika Hauptmeier, Andrea Koch, Matthias Held, Tobias Johannes Lange, Claus Neurohr, Heinrike Wilkens, Hubert Rolf Wilhelm Wirtz, Stavros Konstantinides, Paraskevi Argyropoulou-Pataka, Stylianos Orfanos, Shirish Hiremath, Prafulla Gopinath Kerkar, Pujar Venkateshacharya Suresh, Hemang Ashwinkumar Baxi, Abraham Oomman, Rajpal Kanaklal Abhaichand, Padma Kumar Edla Arjun, Vijay Chopra, Rahul Mehrotra, Rajeev Kumar Rajput, Jitendra Pal Singh Sawhney, Subir Bimalendu, Kamal Harishchandra Sharma, Bhagavathula Kutumba Srinivasa Sastry, Mordechai Reuben Kramer, Michael Jonathan Segel, Issahar Ben-Dov, Neville Berkman, Mordechai Yigla, Yochai Adir, Michael D’Alto, Carmine Dario Vizza, Laura Scelsi, Patrizio Vitulo, Tomas Rene Pulido, Carlos Jerjes-Sanchez, Anko Boonstra, Madelon Clementina Vonk, Bozena Sobkowicz, Tatiana Mularek-Kubzdela, Adam Torbicki, Piotr Podolec, Lim Soo Teik, Wei Luen James Yip, Hyuk-Jae Chang, Hyung-Kwan Kim, Jun-Bean Park, Sung-A Chang, Duk-Kyung Kim, Sung-A Chang, Wook-Jin Chung, Jong-Min Song, Magnus Nissell, Clara Hjalmarsson, Bengt Rundqvist, Wei-Chun Huang, Chin-Chang Cheng, Chih-Hsin Hsu, Hsao-Hsun Hsu, Kuo-Yang Wang, John Gerard Coghlan, David Gerard Kiely, Joanna Wanda Pepke-Zaba, James Lawrence Lordan, Paul Anthony Corris, Linda Cadaret, Sif Hansdottir, Ronald Jack Oudiz, David B. Badesch, Michael Mathier, Robert Schilz, Nicholas Hill, Aaron Waxman, Catherine J. Markin, Diane Lynn Zwicke, Micah Fisher, Veronica Franco, Namita Sood, Myung H. Park, Roblee Allen, Jeremy P. Feldman, Vijay Balasubramanian, Vandana Kavita Seeram, Abubakr Bajwa, Austin B. Thompson, Christina Migliore, Jean Elwing, John W. McConnell, Jinesh P. Mehta, Franck Farzad Rahaghi, J. Eduardo Rame, Akram Khan, Bela Patel, Ron M. Oren, James R. Klinger, Hassan Alnuaimat, Samuel Allen, William Harvey, Michael S. Eggert, Antoine Hage, Chad E. Miller, Rana Lee Adawi Awdish, Hector Cajigas, Daniel Grinnan, Benjamin Howard Trichon, Clark McDonough, R. James White, Franz Rischard
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

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.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).