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      Clinical trial design and new therapies for pulmonary arterial hypertension


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          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.


          State of the art and research perspectives in clinical trial design and new therapies for pulmonary arterial hypertension http://ow.ly/VHQ030mfRxc

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          Most cited references67

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          The ASA's Statement onp-Values: Context, Process, and Purpose

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            A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.

            Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
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              Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.

              This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.

                Author and article information

                Eur Respir J
                Eur. Respir. J
                The European Respiratory Journal
                European Respiratory Society
                January 2019
                24 January 2019
                : 53
                : 1
                [1 ]Université Paris-Sud, Hôpital Bicêtre, INSERM UMR_S999, Le Kremlin-Bicêtre, France
                [2 ]George Washington University, Dept of Medicine, Washington, DC, USA
                [3 ]University Health Network-General Division, University of Toronto, Toronto, ON, Canada
                [4 ]Pulmonary/Critical Care Division and Smidt Heart Institute, Cedars Sinai Medical Center, UCLA, Los Angeles, CA, USA
                [5 ]Division of Pulmonary and Critical Care, Dept of Medicine, Johns Hopkins University, Baltimore, MD, USA
                [6 ]AbaNovus srl, Sanremo, Italy
                [7 ]Food and Drug Administration, Silver Spring, MD, USA
                [8 ]Dept of Medicine, Faculty of Medicine, Imperial College London, London, UK
                [9 ]Dept of Medicine, Stanford University Medical Center, Stanford, CA, USA
                [10 ]San Diego School of Medicine, University of California, La Jolla, CA, USA
                Author notes
                Olivier Sitbon, Service de Pneumologie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. E-mail: olivier.sitbon@ 123456aphp.fr
                The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2019

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                World Symposium on Pulmonary Hypertension

                Respiratory medicine
                Respiratory medicine


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