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Eur Respir J. 2018 Dec 13. pii: 1801908. doi: 10.1183/13993003.01908-2018. [Epub ahead of print]

Clinical trial design and new therapies for pulmonary arterial hypertension.

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Université Paris-Sud, Hôpital Bicêtre, INSERM UMR_S999, Le Kremlin-Bicêtre, France.
Inova Heart and Vascular Institute, Virginia Commonwealth University, Falls Church, VA, USA.
University Health Network-General Division, University of Toronto, Toronto, ON, Canada.
Pulmonary/Critical Care Division and Smidt Heart Institute, Cedars Sinai Medical Center, UCLA, Los Angeles, CA, USA.
Division of Pulmonary and Critical Care, Dept of Medicine, Johns Hopkins University, Baltimore, MD, USA.
AbaNovus srl, Sanremo, Italy.
Food and Drug Administration, Silver Spring, MD, USA.
Dept of Medicine, Faculty of Medicine, Imperial College London, London, UK.
Dept of Medicine, Stanford University Medical Center, Stanford, CA, USA.
San Diego School of Medicine, University of California, La Jolla, CA, USA.


Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.

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Conflict of interest statement

Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from MSD, Actelion Pharmaceuticals and GSK, personal fees from GossamerBio, Arena Pharmaceuticals and Acceleron Pharmaceuticals, and grants and personal fees from Bayer HealthCare, outside the submitted work. Conflict of interest: M. Gomberg-Maitland is a consultant/data and safety monitoring board member/scientific advisory board member for Actelion, Acceleron, Complexa, Merck, Reata and United Therapeutics. Inova receives research support for her to do research from Actelion, AADi and United Therapeutics. Conflict of interest: J. Granton has received support from Actelion, Bayer and Pfizer to support investigator-initiated research. He is a member of a steering committee for Bellerophon clinical trial in PAH and an adjudication committee member for a clinical trial sponsored by United Therapeutics. Conflict of interest: M.I. Lewis reports that the ALPHA study cited is funded by a grant from the California Institute for Regenerative Medicine (grant CLIN2-09444). Conflict of interest: S.C. Mathai reports personal fees for consultancy and data and safety monitoring board membership from Actelion, personal fees for consultancy from United Therapeutics, and grants from Scleroderma Foundation, outside the submitted work; and is a member of the Scientific Leadership Council, Pulmonary Hypertension Association and of the Rare Disease Advisory Panel of the Patient Centered Outcomes Research Institute. Conflict of interest: M. Rainisio has nothing to disclose. Conflict of interest: N.L. Stockbridge has nothing to disclose. Conflict of interest: M.R. Wilkins reports personal fees from Actelion Pharmaceuticals, Bayer HealthCare, GossamerBio and Morphogen-IX, outside the submitted work. Conflict of interest: R.T. Zamanian is a consultant for Actelion Pharmaceuticals, Merck, Vivus and GossamerBio, and has received grants from Actelion Pharmaceuticals; and has a patent FK506, for the treatment of PAH, issued. Conflict of interest: L.J. Rubin reports personal fees from Actelion, Arena, Bellerophon, SoniVie and Roivant, during the conduct of the study.

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