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Randomized Controlled Trial
. 2023 Jun 29;61(6):2202414.
doi: 10.1183/13993003.02414-2022. Print 2023 Jun.

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study

Aaron Waxman  1 , Ricardo Restrepo-Jaramillo  2 , Thenappan Thenappan  3 , Peter Engel  4 , Abubakr Bajwa  5 , Ashwin Ravichandran  6 , Jeremy Feldman  7 , Amy Hajari Case  8 , Rahul G Argula  9 , Victor Tapson  10 , Peter Smith  11 , Chunqin Deng  11 , Eric Shen  11 , Steven D Nathan  12
Affiliations
Randomized Controlled Trial

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study

Aaron Waxman et al. Eur Respir J. .

Abstract

Introduction: The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.

Methods: Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded.

Results: At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL-1 at RCT baseline to 359 pg·mL-1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49-0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients.

Conclusions: These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

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Conflict of interest statement

Conflict of interest: A. Waxman reports that the present manuscript was funded by United Therapeutics; and reports grants or contracts with payments to his institution from United Therapeutics, Gossamer, Acceleron/Merck, ARIA CV and NIH/NHLBI, patents with Johnson & Johnson, and participation on a data safety monitoring board or advisory board for INSMED. R. Restrepo-Jaramillo reports research grants from Merck, United Therapeutics, Bayer and J&J Actelion, payment of honoraria for speakers bureaus from United Therapeutics, Bayer and J&J Actelion, and participation on advisory boards for Merck, United Therapeutics and Bayer. T. Thenappan reports grants for clinical research studies from United Therapeutics, Tenax Therapeutics, Aria CV and Merck, and consulting fees from United Therapeutics and Acceleron Pharma. P. Engel reports no disclosures. A. Bajwa reports a grant from United Therapeutics for study procedures, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Johnson & Johnson, Boehringer Ingelheim, and Intuitive. A. Ravichandran reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Abbott, Medtronic and Janssen. J. Feldman reports consulting fees from United Therapeutics, Aerovate, Altavant and Liquidia, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen and United Therapeutics, and participation on a data safety monitoring board or advisory board for Liquidia, Altavant and Aerovate. A. Hajari Case reports that the present manuscript is funded by United Therapeutics; and reports clinical research contracts to institution from United Therapeutics, and serving as Senior Medical Advisor for the Pulmonary Fibrosis Foundation. R.G. Argula reports consulting fees from Liquidia Corporation, United Therapeutics, Merck Pharma Inc., Janssen Inc. and CVS Health, and payment or honoraria for lectures and educational events from United Therapeutics. V. Tapson reports research grants paid to institution from Boston Scientific Corporation, Bristol Myers Squibb and Genentech, speaker and consulting fees from Janssen, fees from Boston Scientific Corporation for participating in an executive committee for a clinical trial, that he serves as President for PE Response Team Consortium (unpaid), owns stock in Thrombolex and Inari Medical, and that he is employed as VP of Medical Affairs at Inari Medical. P. Smith reports that he is an employee of the study sponsor, United Therapeutics. C. Deng and E. Shen report that they are employees of and hold stock in United Therapeutics, the study sponsor. S.D. Nathan reports that the present manuscript is funded by United Therapeutics; and reports consulting fees from United Therapeutics, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics.

Figures

FIGURE 1
FIGURE 1
Study schema: INCREASE randomised controlled trial (RCT) and open-label extension (OLE). #: two additional patients entered the OLE who were excluded from the RCT due to a labelling issue; : patients receiving >3 breaths per session four times daily at week 16 of the RCT had their dose reduced to 3 breaths per session four times daily at the start of the OLE.
FIGURE 2
FIGURE 2
Patient disposition diagram: INCREASE randomised controlled trial (RCT) and open-label extension (OLE). #: completed 16 weeks of assessment in the RCT; : includes two patients who were excluded from the RCT due to a labelling issue; +: one patient was inadvertently enrolled in the OLE after not meeting eligibility criteria but withdrew from the OLE before receiving study drug.
FIGURE 3
FIGURE 3
Results for 6-min walk distance (6MWD). a) Mean 6MWD by study visit starting from baseline of the 16-week INCREASE randomised controlled trial (RCT). Data are mean observed values. b) Mean change from baseline in 6MWD by study visit starting at baseline of the 16-week RCT. Note: time 0 for the open-label extension (OLE) is also week 16 for the RCT; all available data at each time-point are included in the figure. Errors bars indicate the sem.
FIGURE 4
FIGURE 4
Median serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels during the INCREASE randomised controlled trial (RCT) and open-label extension (OLE) in patients who received inhaled treprostinil or placebo during the RCT. The interquartile range is given in parentheses.
FIGURE 5
FIGURE 5
Mean change from baseline in forced vital capacity (FVC) in a) millilitres and as b) % predicted in the INCREASE randomised controlled trial (RCT) and open-label extension (OLE). Note: time 0 for the OLE is also week 16 for the RCT; all available data at each time-point are included in the figure. Errors bars indicate the sem.
FIGURE 6
FIGURE 6
Kaplan–Meier estimates of time to exacerbation of lung disease from a) INCREASE open-label extension (OLE) baseline (week 16) in all patients and b) INCREASE randomised controlled trial (RCT) baseline (week 0) in all patients. In a) the Kaplan–Meier plot includes only exacerbations taking place in the OLE; therefore, all patients in both the prior inhaled treprostinil arm and the prior placebo arm are represented without an event at week 16. Hazard ratios, 95% confidence intervals and p-values were calculated from a Cox proportional hazards model with the parent study treatment group as an explanatory variable.
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