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STATE-OF-THE-ART PAPER

End Points and Clinical Trial Design in Pulmonary Arterial Hypertension

Vallerie V. McLaughlin, MD^_*,_*, David B. Badesch, MD, Marion Delcroix, MD, PhD, Thomas R. Fleming, PhD, Sean P. Gaine, MD, PhD^||, Nazzareno Galiè, MD^¶, J. Simon R. Gibbs, MD^#, Nick H. Kim, MD^_**, Ronald J. Oudiz, MD, Andrew Peacock, MD, Steeve Provencher, MD, MSc, Olivier Sitbon, MD^||||, Victor F. Tapson, MD^¶¶ and Werner Seeger, MD^##

^_* Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado Health Sciences Center, Denver, Colorado
Center for Pulmonary Vascular Disease, Department of Pneumology, Gasthuisberg University Hospital, Leuven, Belgium
Department of Biostatistics, University of Washington, Seattle, Washington
^|| National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
^¶ Pulmonary Hypertension Center, Institute of Cardiology, University of Bologna, Bologna, Italy
^# Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College London, London, United Kingdom
^_** Pulmonary and Critical Care Medicine, University of California San Diego School of Medicine, La Jolla, California
Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California
Department of Respiratory Medicine, Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, Scotland, United Kingdom
Institute of Cardiology and Pulmonology, Laval University, Sainte-Foy, Québec, Canada
^|||| Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère, Clamart, France
^¶¶ Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina
^## Department of Internal Medicine, University of Giessen Lung Center, Giessen, Germany

Manuscript received February 6, 2009; accepted April 15, 2009.

^_* Reprint requests and correspondence: Dr. Vallerie V. McLaughlin, University of Michigan Health System, Cardiovascular Center, 1500 East Medical Center Drive SPC5853, Ann Arbor, Michigan 48109-0273 (Email: vmclaugh{at}med.umich.edu).

New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Key Words: clinical trial design • PAH • end points

Abbreviations and Acronyms   BNP = brain natriuretic peptide   CMRI = cardiac magnetic resonance imaging   CPET = cardiopulmonary exercise test   CTEPH = chronic thromboembolic pulmonary hypertension   FDA = Food and Drug Administration   LV = left ventricular   NT-proBNP = N-terminal pro-brain natriuretic peptide   NYHA = New York Heart Association   PAH = pulmonary arterial hypertension   PH = pulmonary hypertension   RCT = randomized controlled trial   RV = right ventricular   6MW = 6-min walk   TtCW = time to clinical worsening   WHO = World Health Organization

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