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Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A multicenter ascending-dose trial (range 1\u201320\u00a0mg, Part A) was followed by a 1\u00a0day, double-blind, randomized, placebo-controlled study (median dose 15\u00a0mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10\u00a0mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine\/seated\/standing blood pressure, and safety.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Thirty-four patients (age 66\u2009\u00b1\u20098\u00a0years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of\u2009\u2265\u200910\u00a0mmHg) was greater with the 5 and 10\u00a0mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7\u00a0mmHg 4\u00a0h after ampreloxetine and decreased 14.2\u00a0mmHg after placebo [least squares mean difference (95% CI) 29.9\u00a0mmHg (7.6\u201352.3); <jats:italic>P<\/jats:italic>\u2009=\u20090.0112]. Part C: Symptoms of dizziness\/lightheadedness improved 3.1\u2009\u00b1\u20093.0 points from baseline and standing systolic blood pressure increased 11\u2009\u00b1\u200912\u00a0mmHg. After 4\u00a0weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Ampreloxetine was well tolerated and improved orthostatic symptoms and seated\/standing blood pressure with little change in supine blood pressure.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>NCT02705755 (first posted March 10, 2016).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10286-021-00827-0","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T10:33:26Z","timestamp":1634466806000},"page":"699-711","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial"],"prefix":"10.1007","volume":"31","clinical-trial-number":[{"clinical-trial-number":"nct02705755","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1851-9981","authenticated-orcid":false,"given":"Horacio","family":"Kaufmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Vickery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whedy","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitendra","family":"Kanodia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyndya A.","family":"Shibao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Norcliffe-Kaufmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Haumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Italo","family":"Biaggioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,17]]},"reference":[{"key":"827_CR1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s10286-011-0119-5","volume":"21","author":"R Freeman","year":"2011","unstructured":"Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, van Dijk JG (2011) Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. 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RV is an employee of Theravance Biopharma Ireland Limited and stockholder of Theravance Biopharma, Inc. WW is a former employee of Theravance Biopharma US, Inc. JK is an employee of Theravance Biopharma US, Inc. and a stockholder of Theravance Biopharma, Inc. CS has received research support from Theravance Biopharma and is a member of the Advisory Board of Lundbeck US. LNK is an employee of Theravance Biopharma US, Inc. BH is a former employee of Theravance Biopharma UK Limited and a stockholder of Theravance Biopharma, Inc. IB is a consultant for and has received research support from Theravance Biopharma and is a patent holder of an automated abdominal binder for the treatment of orthostatic hypotension.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Local IRB approvals were obtained.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have approved the final draft and agree to have these data published.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}