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      Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

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          Abstract

          Purpose

          In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. 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.

          Methods

          A multicenter ascending-dose trial (range 1–20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, 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.

          Results

          Thirty-four patients (age 66 ± 8 years, 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 ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6–52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration.

          Conclusion

          Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure.

          Trial registration

          NCT02705755 (first posted March 10, 2016).

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          Most cited references32

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          Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

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            Second consensus statement on the diagnosis of multiple system atrophy.

            A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.
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              Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.

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                Author and article information

                Contributors
                Horacio.Kaufmann@nyulangone.org
                Journal
                Clin Auton Res
                Clin Auton Res
                Clinical Autonomic Research
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0959-9851
                1619-1560
                17 October 2021
                17 October 2021
                2021
                : 31
                : 6
                : 699-711
                Affiliations
                [1 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, Department of Neurology, Dysautonomia Center, , NYU Langone Health, New York University School of Medicine, ; 530 First Avenue, Suite 9Q, New York, NY 10016 USA
                [2 ]Theravance Biopharma Ireland Limited, Dublin, Ireland
                [3 ]Formerly of Theravance Biopharma US, Inc., South San Francisco, CA USA
                [4 ]GRID grid.476733.2, ISNI 0000 0004 0465 1214, Theravance Biopharma US, Inc., ; South San Francisco, CA USA
                [5 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Department of Medicine, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [6 ]Formerly of Theravance Biopharma UK Limited, London, UK
                Article
                827
                10.1007/s10286-021-00827-0
                8629777
                34657222
                c1b1fb47-1b0d-4d47-b3f5-fc9d4fda16a1
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Theravance Biopharma R&D, Inc.
                Categories
                Research Article
                Custom metadata
                © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2021

                Medicine
                ampreloxetine,norepinephrine reuptake inhibitor (nri),neurogenic orthostatic hypotension (noh),synucleinopathies

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