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

Abstract

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).

Metadata

Item Type:	Article
Authors/Creators:	White, RJ Jerjes-Sanchez, C Bohns Meyer, GM Pulido, T Sepulveda, P Wang, KY Grünig, E Hiremath, S Yu, Z Gangcheng, Z Yip, WLJ Zhang, S Khan, A Deng, CQ Grover, R Tapson, VF Svetliza, GN Lescano, AJ Bortman, GR Diez, FA Botta, CE Fitzgerald, J Feenstra, E Kermeen, FD Keogh, AM Williams, TJ Yousseff, PP Ng, BJ-H Smallwood, DM Dwyer, NB Brown, MR Lang, IM Steringer-Mascherbauer, R Arakaki, JSO Campos, FTAF de Amorim Correa, R de Souza, R Bohns Meyer, GM Moreira, MAC Yoo, HHB Lapa, MS Swiston, J Hirani, N Mehta, S Michelakis, E Sepulveda, PA Blancaire, MMZ Liu, J Shuyang, Z Pan, L Chunde, B Qun, Y Xiaoshu, C Zaixin, Y Li, X Hua, Y Gangcheng, Z Zhu, X Chen, Y Zhaozhong, C Yang, Y Daxin, Z Jieyan, S Nielsen-Kudsk, JE Carlsen, J Bourdin, A Hachulla, E Dromer, C Chaouat, A Reynaud-Gauber, M Seronde, M-F Klose, H Halank, M Hoffken, G Ewert, R Rosenkranz, S Grunig, E Kruger, U Kronsbein, J Hauptmeier, BM Koch, A Held, M Lange, TJ Neurohr, C Wilkens, H Wilhelm Wirtz, HR Konstantinides, S Argyropoulou-Pataka, P Orfanos, S Hiremath, S Kerkar, PG Suresh, PV Baxi, HA Oomman, A Abhaichand, RK Arjun, PKE Chopra, V Mehrotra, R Rajput, RK Sawhney, JPS Bimalendu, S Sharma, KH Sastry, BKS Kramer, MR Segel, MJ Ben-Dov, I Berkman, N Yigla, M Adir, Y D’Alto, M Vizza, CD Scelsi, L Vitulo, P Pulido, TR Jerjes-Sanchez, C Boonstra, A Vonk, MC Sobkowicz, B Mularek-Kubzdela, T Torbicki, A Podolec, P Teik, LS Yip, WLJ Chang, H-J Kim, H-K Park, J-B Chang, S-A Kim, D-K Chang, S-A Chung, W-J Song, J-M Nissell, M Hjalmarsson, C Rundqvist, B Huang, W-C Cheng, C-C Hsu, C-H Hsu, H-H Wang, K-Y Coghlan, JG Kiely, DG https://orcid.org/0000-0003-0184-6502 Pepke-Zaba, JW Lordan, JL Corris, PA Cadaret, L Hansdottir, S Oudiz, RJ Badesch, DB Mathier, M Schilz, R Hill, N Waxman, A Markin, CJ Zwicke, DL Fisher, M Franco, V Sood, N Park, MH Allen, R Feldman, JP Balasubramanian, V Seeram, VK Bajwa, A Thompson, AB Migliore, C Elwing, J McConnell, JW Mehta, JP Rahaghi, FF Rame, JE Khan, A Patel, B Oren, RM Klinger, JR Alnuaimat, H Allen, S Harvey, W Eggert, MS Hage, A Miller, CE Awdish, RLA Cajigas, H Grinnan, D Trichon, BH McDonough, C White, RJ Rischard, F
Copyright, Publisher and Additional Information:	© 2020 by the American Thoracic Society. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:	pulmonary arterial hypertension; oral treprostinil; clinical study; combination therapy; sequential therapy
Dates:	Accepted: 22 November 2019 Published (online): 25 November 2019 Published: 15 March 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	14 May 2020 11:32
Last Modified:	14 May 2020 11:37
Status:	Published
Publisher:	American Thoracic Society
Refereed:	Yes
Identification Number:	10.1164/rccm.201908-1640oc
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:160525

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

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