TY - JOUR
T1 - A Randomized, Double-Blind, Placebo-Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis
AU - Nathan, Steven D.
AU - Flaherty, Kevin R.
AU - Glassberg, Marilyn K.
AU - Raghu, Ganesh
AU - Swigris, Jeffrey
AU - Alvarez, Roger
AU - Ettinger, Neil
AU - Loyd, Jim
AU - Fernandes, Peter
AU - Gillies, Hunter
AU - Kim, Bo
AU - Shah, Parag
AU - Lancaster, Lisa
N1 - Funding Information:
FUNDING/SUPPORT: This study was sponsored by Bellerophon Therapeutics, Warren, NJ.
Funding Information:
Author contributions: S. N. is the guarantor of the paper. S. N. H. G. P. S. and B. K. wrote the manuscript. All authors reviewed and revised the manuscript. S. N. K. F. M. G. J. S. P. S. and L. L. were responsible for the concept and design. P. S. B. K. and H. G. were responsible for the data acquisition. S. N. K. F. M. G. G. R. P. S. P. F. H. G. B. K. and L. L. analyzed and interpreted the data. P. S. was responsible for the statistical expertise. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. D. N. has served as a consultant for Bellerophon Therapeutics, Third Pole Therapeutics, and United Therapeutics Corporation. K. R. F. has served as a consultant for Boehringer Ingelheim GmbH, Roche/Genentech, Bellerophon Therapeutics, Respivant Sciences, Inc, and Blade Therapeutics, Inc, in the field of interstitial lung diseases. G. R. has served as a consultant for IPF studies over the last 3 years for Avalyn Pharma, Boehringer Ingelheim GmbH, Biogen, Blade Therapeutics, Inc, Bridge Biotherapeutics, Bristol Myers Squibb, Bellerophon Therapeutics, FibroGen, Gilead Sciences, IQVIA, Promedior, Nitto BioPharma, Inc, Respivant Sciences, Inc, Roche/Genentech, Sanofi-Aventis, Veracyte, and Zambon. J. S. serves as a consultant and receives grant monies and honoraria for non-branded talks from Genentech and Boehringer Ingelheim GmbH. R. A. has received grant funding from Bellerophon Therapeutics, United Therapeutics Corporation, and Complexa, as well as benefits (travel accommodations to a scientific meeting) from Arena Pharmaceuticals, Inc. P. S. and P. F. are shareholders of Bellerophon Therapeutics as well as employees and officers of the company. B. K. is an employee and shareholder of Bellerophon Therapeutics. L. L. has received research grants from Bellerophon Therapeutics, Novartis, Celgene, Biogen, Boehringer Ingelheim GmbH, Genentech, Respivant Sciences, Inc, Galapagos NV, and Galactic. She has done disease state education with Genentech and Boehringer Ingelheim and completed consulting with Galapagos NV, Genentech, and Boehringer Ingelheim GmbH. None declared (M. K. G. N. E. J. L.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Additional information: The e-Table can be found in the Supplemental Materials section of the online article. FUNDING/SUPPORT: This study was sponsored by Bellerophon Therapeutics, Warren, NJ.
Publisher Copyright:
© 2020 American College of Chest Physicians
PY - 2020/8
Y1 - 2020/8
N2 - Background: The interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD). Of the fILDs, Idiopathic pulmonary fibrosis is the most common. Pulmonary hypertension (PH) frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy. There is no proven treatment for patients with fILD-PH. We report results from the first cohort of a phase 2b/3 trial with pulsed inhaled nitric oxide (iNO) in patients with fILD-PH. Methods: Subjects in cohort 1 were randomized to iNO 30 μg/kg ideal body weight/h (iNO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on iNO30 followed by dose escalation to iNO45 then iNO75. Activity monitoring was used to assess changes in daily activity. Safety and efficacy were evaluated. Results: Twenty-three patients were randomized to iNO30 and 18 to placebo. During blinded treatment, iNO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity. Placebo subjects showed an average drop of 26% in MVPA and a 12% drop in overall activity. The iNO group had an improvement in oxygen saturation. During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters. Inhaled nitric oxide at all doses (30, 45, and 75) was safe and well tolerated. Conclusions: Treatment with iNO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity. In the OLE, higher doses of iNO were also safe and well tolerated while showing maintenance in activity parameters.
AB - Background: The interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD). Of the fILDs, Idiopathic pulmonary fibrosis is the most common. Pulmonary hypertension (PH) frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy. There is no proven treatment for patients with fILD-PH. We report results from the first cohort of a phase 2b/3 trial with pulsed inhaled nitric oxide (iNO) in patients with fILD-PH. Methods: Subjects in cohort 1 were randomized to iNO 30 μg/kg ideal body weight/h (iNO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on iNO30 followed by dose escalation to iNO45 then iNO75. Activity monitoring was used to assess changes in daily activity. Safety and efficacy were evaluated. Results: Twenty-three patients were randomized to iNO30 and 18 to placebo. During blinded treatment, iNO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity. Placebo subjects showed an average drop of 26% in MVPA and a 12% drop in overall activity. The iNO group had an improvement in oxygen saturation. During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters. Inhaled nitric oxide at all doses (30, 45, and 75) was safe and well tolerated. Conclusions: Treatment with iNO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity. In the OLE, higher doses of iNO were also safe and well tolerated while showing maintenance in activity parameters.
KW - activity monitoring
KW - idiopathic interstitial pneumonia
KW - idiopathic pulmonary fibrosis
KW - interstitial lung disease
KW - nitric oxide
KW - pulmonary fibrosis
UR - http://www.scopus.com/inward/record.url?scp=85086025896&partnerID=8YFLogxK
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U2 - 10.1016/j.chest.2020.02.016
DO - 10.1016/j.chest.2020.02.016
M3 - Article
C2 - 32092321
AN - SCOPUS:85086025896
VL - 158
SP - 637
EP - 645
JO - Diseases of the chest
JF - Diseases of the chest
SN - 0012-3692
IS - 2
ER -