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Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension
Journal article   Open access   Peer reviewed

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

Ekkehard Grünig, Franck Rahaghi, Jean Elwing, Carmine Dario Vizza, Joanna Pepke-Zaba, Jieyan Shen, Hua Yao, Antoine Hage, Stephan Rosenkranz, Madelon Vonk, …
Advances in therapy, Vol.41(2), pp.618-637
02/2024
DOI: 10.1007/s12325-023-02711-x
PMCID: PMC10838815
PMID: 38055186
url
https://doi.org/10.1007/s12325-023-02711-xView
Published (Version of record) Open Access

Abstract

INTRODUCTION In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. METHODS Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. RESULTS Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV.CONCLUSIONInitial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier NCT01560637.

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