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Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double\u2010blind, randomized, placebo\u2010controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6\u2010Minute Walk Distance, WHO functional class, quality of life score, N\u2010terminal pro\u2010brain natriuretic peptide (NT\u2010proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.<\/jats:p>","DOI":"10.4103\/2045-8932.109923","type":"journal-article","created":{"date-parts":[[2014,1,29]],"date-time":"2014-01-29T09:43:43Z","timestamp":1390988623000},"page":"100-107","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":31,"title":["Supplementation of Iron in Pulmonary Hypertension: Rationale and Design of a Phase II Clinical Trial in Idiopathic Pulmonary Arterial Hypertension"],"prefix":"10.1002","volume":"3","author":[{"given":"Luke S.G.E.","family":"Howard","sequence":"first","affiliation":[{"name":"Department of Cardiology National Pulmonary Hypertension Service Hammersmith Hospital UK"},{"name":"National Heart and Lung Institute Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey M.J.","family":"Watson","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine Department of Medicine Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Wharton","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine Department of Medicine Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine Department of Medicine Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kakit","family":"Chan","sequence":"additional","affiliation":[{"name":"Imperial Clinical Trials Unit School of Public Health St Mary's Campus, Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajeshree","family":"Khengar","sequence":"additional","affiliation":[{"name":"NIHR\/Wellcome Trust\u2010Imperial Clinical Research Facility Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A.","family":"Robbins","sequence":"additional","affiliation":[{"name":"Department of Physiology Anatomy and Genetics University of Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David G.","family":"Kiely","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine National Pulmonary Hypertension Service Royal Hallamshire Hospital Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Condliffe","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine National Pulmonary Hypertension Service Royal Hallamshire Hospital Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlie A.","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine National Pulmonary Hypertension Service Royal Hallamshire Hospital Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Pepke\u2010Zaba","sequence":"additional","affiliation":[{"name":"National Pulmonary Hypertension Service Papworth Hospital Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Sheares","sequence":"additional","affiliation":[{"name":"National Pulmonary Hypertension Service Papworth Hospital Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"National Pulmonary Hypertension Service Papworth Hospital Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Cardiology National Pulmonary Hypertension Service Hammersmith Hospital UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Ashby","sequence":"additional","affiliation":[{"name":"Imperial Clinical Trials Unit School of Public Health St Mary's Campus, Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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